Development of a Convergent Fragment Coupling Strategy Toward Grayanane Diterpenoids: Enantioselective Synthesis of (+)-Auriculatol A Citation Thompson, Jordan Kenji (2026) Development of a Convergent Fragment Coupling Strategy Toward Grayanane Diterpenoids: Enantioselective Synthesis of (+)-Auriculatol A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/8sth-7196. https://resolver.caltech.edu/CaltechTHESIS:12152025-191624055 Abstract Total synthesis is a cornerstone of organic chemistry, serving not only as a demonstration of synthetic strategy and innovation but also as a gateway to accessing biologically active natural products that are often scarce or inaccessible from natural sources. Among such natural products, the grayanane diterpenoids represent a structurally complex and medicinally intriguing family of compounds. These molecules, first identified as the active agents in “mad honey,” have a rich history of traditional use and a modern resurgence in medicinal interest due to their activity as sodium channel modulators, carbonic anhydrase inhibitors, and potential analgesics. Grayanotoxin III, in particular, exhibits great pain-relieving properties, positioning it and its analogs as compelling targets for chemical synthesis. Despite their early isolation and full structural elucidation by the early 1960s, the grayananes remain difficult to access in the realm of total synthesis, a testament to their dense stereochemical architecture and unusual [5-7-6-5] fused tetracyclic core. This work explores synthetic strategies toward the construction of these challenging natural products, with the aim of enabling broader access to their biological potential and deepening our understanding of chemical tools to use in their synthesis. This work introduces complex bond-forming strategies and methods development, with a particular emphasis on nickel catalysis to advance the total synthesis of grayanane diterpenoids. A convergent approach was designed to maximize efficiency at each stage, beginning with the development of a model system to rapidly evaluate γ-functionalization strategies of butenolides or masked butenolide equivalents using siloxyfuran intermediates as a polarity reversal tactic. Key advances include the synthesis of a 5,5-fused butenolide fragment and the discovery and optimization of a unique vinylogous Mukaiyama aldol reaction. Early studies on the diastereoselective 1,4-reduction of butenolides and the development of a nickel-catalyzed α-enolate arylation reaction are highlighted. Subsequent chapters explore the construction of the 3.2.1 bicycle through a range of innovative transformations, including a Snider radical cascade, palladium-catalyzed decarboxylative Tsuji-Stoltz allylation, and a nickel catalyzed intramolecular carbonyl 1,2-addition. The result of these efforts is a rapid fragment coupling strategy that enables access to the pentacyclic core of auriculatol A through the use of a nickel catalyzed α-enolate alkenylation reaction using a unique olefin-supported nickel catalyst. In addition to discovering that low-valent olefin-supported nickel catalysts are privileged for α-enolate arylation and alkenylation, an unexpected 6-membered ring-containing side product was isolated in these reactions, which could have unique mechanistic implications in the area of dehydrogenative catalysis. To follow, detailed investigations into late-stage olefin functionalization and hydrogenation ultimately culminate in the first synthesis of (+)- auriculatol A along with its epimer (+)-9-epi-auriculatol A. Collectively, these studies offer a blueprint for future synthetic approaches to the broader grayanane diterpenoid family and stand as a hallmark achievement for the synthesis of grayanane natural products containing an embedded e ring in an uncommon pentacyclic scaffold. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Total Synthesis, Grayanane Diterpenoid, Chemical Synthesis, Nickel Catalysis Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Awards: NSF GRFP, ACS-Merck Pride Award, Genentech Graduate Student Symposium Award Thesis Availability: Public (worldwide access) Research Advisor(s): Reisman, Sarah E. Thesis Committee: Stoltz, Brian M. (chair) Peters, Jonas C. Fu, Gregory C. Reisman, Sarah E. (chair) Defense Date: 27 June 2025 Funders: Funding Agency Grant Number National Institute of Health (NIH) R35GM118191 National Science Foundation Graduate Research Fellowship (NSF GRFP) DGE-1745301 Projects: Enantioselective Synthesis of (+)-Auriculatol A Record Number: CaltechTHESIS:12152025-191624055 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:12152025-191624055 DOI: 10.7907/8sth-7196 Related URLs: URL URL Type Description https://pubs.acs.org/doi/10.1021/jacs.5c17269 DOI Enantioselective Synthesis of (+)-Auriculatol A ORCID: Author ORCID Thompson, Jordan Kenji 0009-0007-6395-7087 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17799 Collection: CaltechTHESIS Deposited By: Jordan Thompson Deposited On: 19 Dec 2025 00:45 Last Modified: 07 Jan 2026 16:54 Thesis Files PDF - Final Version See Usage Policy. 37MB Repository Staff Only: item control page

DEVELOPMENT OF A CONVERGENT FRAGMENT COUPLING STRATEGY TOWARD GRAYANANE DITERPENOIDS: ENANTIOSELECTIVE SYNTHESIS OF (+)-AURICULATOL A Thesis by Jordan Kenji Thompson In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2026 (Defended June 27th, 2025) ii © 2026 Jordan Kenji Thompson ORCID: 0009-0007-6395-7087 All Rights Reserved iii To the spirit of science, discovery, and the pursuit of knowledge iv ACKNOWLEDGEMENTS As I reflect on the last five years, I am filled with gratitude for the experience of conducting research at Caltech. This campus has been a vibrant, inspiring home where ideas flourished. The friendships formed within this program have been integral to the experience, and I will always cherish the memories we created while developing exciting new chemical reactions and pushing the boundaries of our field. Every breakthrough, challenge, and late-night discussion has shaped me into the scientist I am today. I leave Caltech with a full heart, immensely thankful for the people, the science, and the unforgettable spirit of discovery that defined these years. I am profoundly grateful to Professor Sarah Reisman for her exceptional mentorship and unwavering dedication to my growth as a researcher. I thank her for welcoming me into her group and for believing in me throughout the years, even when I doubted myself. Her leadership, which has been full of fervor, creativity, and intellectual rigor, has shaped the way I approach science and inspired me to pursue bold, meaningful questions. She has instilled in me a deep curiosity and a focused intensity for developing chemical reactions, lessons I will carry with me throughout my career. Thanks to her guidance, I leave the group ready to tackle complex synthetic challenges, explore new scientific frontiers, and contribute thoughtfully to medicinal chemistry at Bristol Myers Squibb. I am sincerely grateful to my thesis committee, composed of Professor Brian Stoltz (chair), Professor Greg Fu, and Professor Jonas Peters, for their guidance and support throughout my PhD. Their insights during my proposition’s exam challenged me to think more critically and deeply about chemistry. I am especially thankful for their continued v investment in my growth over the years. I’ve been incredibly fortunate to work alongside the outstanding research staff at Caltech, especially Dr. Scott Virgil, whose tireless work running the 3CS facility—and somehow always being in two places at once—has supported students across campus with unmatched dedication. Scott’s presence in our group meetings and his enthusiasm for tackling tough chemistry have made him an invaluable part of our community. I’m also deeply thankful to Dr. David Vander Velde, whose deep expertise and generosity have shaped much of my understanding of NMR spectroscopy. Thank you to Tomomi Kano and Beth Marshall for their help scheduling and keeping Schlinger running and the administrative support of Anya Janowski, Alison Kinard, Rebecca Fox, Joe Drew, Alison Ross, Greg Rolette, and Armando Villasenor. I am deeply grateful to all the past and present members of the Reisman group who have made these years so memorable, collaborative, and enriching. When I first joined, Skyler Mendoza welcomed me with warmth and set an incredible example of how to thrive as productive chemists during a busy time. I am thankful to Yujia Tao, whose brilliance and dedication made her a scientific role model to work next to, and to Conner Farley, who laid the essential foundation for the auriculatol project, welcomed me into the group, and made me feel a part of the team. Dave Charboneau's energy and guidance, especially in connecting our work to inorganic chemistry, brought a valuable perspective to every project. I have cherished the friendship and deep scientific conversations with Alex Shimozono, as well as the kindness and support of senior group members like Ray Turro, Sara Dibrell, Karli Holman, Travis DeLano, and Jeff Kerkovius. Thank you to Sven Richter for the fun times playing badminton (while also discussing chemistry on our way to vi practice together), and to Simon Cooper for the many shared adventures, including yoga classes, exploring Los Angeles, and learning more organic synthesis from you. Thank you to Philip Boehm, who always encouraged me to keep going and brought such a genuine friendship and enthusiasm for scientific discovery. Yasuki Soda showed me what it truly means to be a focused and productive scientist, and I am very glad we worked next to each other. Thank you to Shawn Teh for all your contributions to the project in his 6-month research stay and putting together a wonderful master’s thesis. It was incredible to see how much you were able to achieve in this short time. I feel lucky to have found wonderful friends in Andrea Stegner and Ally Stanko. I would sincerely like to thank Kala Youngblood for her partnership and dedication on the auriculatol project; you’re positivity during the project’s most challenging times carried us through. Thank you to Olivia Morales for the scientific conversations, shared chemical usage, and late night chats. Thank you to Will Chen, Nathan Friede, and Chung Shin for their expertise and guidance in reaction development (and maintenance of the glovebox). I feel especially fortunate to have formed close friendships with Stanna Dorn, who cultivated an enriching environment, and Gino Occhialini, who helped me with DFT and brainstormed creative strategies for endgame strategies in the auriculatol synthesis. To my cohort, Emily Chen and Cedric Lozano, there is no one else I would have rather gone through the past five years with, and your friendship and support have made the experience so much better. I would like to thank Garry Zhang for his inquisitiveness, enthusiasm, and genuine excitement to learn organic synthesis. Mentoring you has been one of the most fulfilling parts of my graduate experience, and it has been a joy to watch you grow and develop as a scientist, from a high school student to a Caltech admit, freshman student, and beyond. vii Prior to joining Caltech, I am deeply indebted to my scientific mentors who propelled my early development during my undergraduate studies at UC Berkeley. First and foremost, thank you to Professor Tom Maimone for welcoming me into his group and for his steady support, even after I left Berkeley. Thank you for supporting our published work, along with your constant encouragement and sharpness. I would like to express my sincerest gratitude to Danny Thach for his pivotal roles in my early development. Danny generously took the time to teach me most of the knowledge I had upon starting at Caltech, always encouraging me to learn and to keep running reactions with curiosity and perseverance. He connected me to other research colleagues, encouraged me to enroll in graduate-level synthesis courses, and stayed patient through my learning, and I am so happy we have stayed in touch post-Berkeley. I am also deeply thankful to my supportive lab colleagues during the pre-COVID Berkeley days — including Andrew Musacchio, Mikiko Okumura, Ken Esguerra, Bingqi Tong, Claire Harmange-Magnani, Karl Haelsig, Rachel Rosen, Vasil Vasilev, Andre Sanchez, Lukas Spessert, Beth Zhang, Danny Huang, among others — whose camaraderie and encouragement were essential to my growth. Thank you to Stephen Harwood for all his advice over the years. I am also grateful to Professor Richmond Sarpong, Professor Dean Toste, Professor John Hartwig, and Professor Anne Baranger for their invaluable support during coursework and their thoughtful guidance through the graduate school application process. Their mentorship laid the foundation for my growth as a scientist. Finally, I want to express my deepest gratitude to my beautiful family. To my parents, Michele and Jim Thompson, thank you for raising me with endless love, patience, and strength. You have always put me and my brothers first, making countless sacrifices viii to support our education, dreams, and happiness. The life lessons that you have taught me, especially during life’s toughest moments, has carried me further than I ever thought possible. To my brothers, Justin and Jack, thank you for your kindness, humor, and steady presence in my life. Growing up with you has been one of life’s greatest joys, and your support has meant everything to me. To my nephew JJ Thompson, uncles and aunts, Ryan and Yen Oshima, Tracy and Will Womack, and to my cousin Miranda Mead, thank you for the warmth, encouragement, and love throughout this journey. Lastly, I would like to thank my grandparents, Bernie and June Oshima and David and Jean Thompson, for their love and support. Your encouragement has been a consistent source of strength. You have taught me so much about how to live a full, meaningful, and enriching life. ix ABSTRACT Total synthesis is a cornerstone of organic chemistry, serving not only as a demonstration of synthetic strategy and innovation but also as a gateway to accessing biologically active natural products that are often scarce or inaccessible from natural sources. Among such natural products, the grayanane diterpenoids represent a structurally complex and medicinally intriguing family of compounds. These molecules, first identified as the active agents in “mad honey,” have a rich history of traditional use and a modern resurgence in medicinal interest due to their activity as sodium channel modulators, carbonic anhydrase inhibitors, and potential analgesics. Grayanotoxin III, in particular, exhibits great pain-relieving properties, positioning it and its analogs as compelling targets for chemical synthesis. Despite their early isolation and full structural elucidation by the early 1960s, the grayananes remain difficult to access in the realm of total synthesis, a testament to their dense stereochemical architecture and unusual [5-7-6-5] fused tetracyclic core. This work explores synthetic strategies toward the construction of these challenging natural products, with the aim of enabling broader access to their biological potential and deepening our understanding of chemical tools to use in their synthesis. This work introduces complex bond-forming strategies and methods development, with a particular emphasis on nickel catalysis to advance the total synthesis of grayanane diterpenoids. A convergent approach was designed to maximize efficiency at each stage, beginning with the development of a model system to rapidly evaluate γ-functionalization strategies of butenolides or masked butenolide equivalents using siloxyfuran intermediates as a polarity reversal tactic. Key advances include the synthesis of a 5,5-fused butenolide fragment and the discovery and optimization of a unique vinylogous Mukaiyama aldol x reaction. Early studies on the diastereoselective 1,4-reduction of butenolides and the development of a nickel-catalyzed α-enolate arylation reaction are highlighted. Subsequent chapters explore the construction of the 3.2.1 bicycle through a range of innovative transformations, including a Snider radical cascade, palladium-catalyzed decarboxylative Tsuji-Stoltz allylation, and a nickel-catalyzed intramolecular carbonyl 1,2-addition. The result of these efforts is a rapid fragment coupling strategy that enables access to the pentacyclic core of auriculatol A through the use of a nickel catalyzed a-enolate alkenylation reaction using a unique olefin-supported nickel catalyst. In addition to discovering that low-valent olefin-supported nickel catalysts are privileged for a-enolate arylation and alkenylation, an unexpected 6-membered ring-containing side product was isolated in these reactions, which could have unique mechanistic implications in the area of dehydrogenative catalysis. To follow, detailed investigations into late-stage olefin functionalization and hydrogenation ultimately culminate in the first synthesis of (+)auriculatol A along with its epimer (+)-9-epi-auriculatol A. Collectively, these studies offer a blueprint for future synthetic approaches to the broader grayanane diterpenoid family and stand as a hallmark achievement for the synthesis of grayanane natural products containing an embedded e ring in an uncommon pentacyclic scaffold. xi PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following publication: Thompson, J. K.; Youngblood, K. C.; Teh, S. Y. H.; Farley, C. M.; Zhang, Z.; Virgil, S. C.; Reisman, S. E. J. Am. Chem. Soc. 2025, 147, 42170–42174. DOI: 10.1021/jacs.5c17269, Copyright © 2025 Journal of the American Chemical Society. This article is available online at: https://pubs.acs.org/doi/10.1021/jacs.5c17269. xii TABLE OF CONTENTS CHAPTER 1 1 Introduction to the grayanane diterpenoids 1.1 INTRODUCTION ........................................................................................................ 1 1.2 BACKGROUND ON THE GRAYANANE DITERPENOIDS ................................... 1 1.2.1 Grayanane diterpenoid discovery and biological activity ...................................... 1 1.2.2 Prior art: synthetic access to the grayanotoxins ..................................................... 4 1.2.3 Prior art: access to the principinol skeleton ........................................................... 5 1.2.4 Prior art: divergent access to the grayanotoxin and principinol frameworks ........ 8 1.2.5 Summary of approaches ....................................................................................... 10 1.2.6 Other grayanane synthesis attempts ..................................................................... 11 1.2.7 Biosynthesis of the grayanane diterpenoids ......................................................... 11 1.2.8 Introduction to auriculatol A ................................................................................ 13 1.3 CONCLUDING REMARKS ...................................................................................... 14 1.4 NOTES AND REFERENCES .................................................................................... 15 xiii CHAPTER 2 20 Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.1 INTRODUCTION ...................................................................................................... 20 2.2 A NOTE ON MODEL SYSTEMS ............................................................................. 21 2.3 MODEL SYSTEM ROUTE DESIGN........................................................................ 21 2.3.1 Retrosynthetic analysis ........................................................................................ 21 2.3.2 Aldehyde synthesis .............................................................................................. 23 2.3.3 Butenolide synthesis ............................................................................................ 24 2.3.4 Final optimization of the butenolide route ........................................................... 27 2.3.5 Investigation of direct g-functionalization methods............................................. 31 2.4 THE VINYLOGOUS MUKAIYAMA ALDOL REACTION ................................... 32 2.4.1 Siloxyfuran formation .......................................................................................... 32 2.4.2 Hit identification and reaction optimization ........................................................ 33 2.4.3 Stereochemical analysis ....................................................................................... 36 2.5 A-ENOLATE ARYLATION SUBSTRATE SYNTHESIS ....................................... 39 2.5.1 Secondary alcohol protection ............................................................................... 39 2.5.2 Chemoselective butenolide reduction .................................................................. 39 2.6 Ni-CATALYZED INTRAMOLECULAR A-ENOLATE ARYLATION ................. 41 2.6.1 Buchwald’s intermolecular a-enolate arylation of lactones ................................ 41 2.6.2 Phosphine ligand modifications ........................................................................... 42 2.6.3 Other ligands ........................................................................................................ 47 2.6.4 Final control studies ............................................................................................. 52 xiv 2.7 CONCLUDING REMARKS ...................................................................................... 52 2.8 EXPERIMENTAL SECTION .................................................................................... 54 2.9 NOTES AND REFERENCES .................................................................................... 98 APPENDIX 2 105 Supporting Information Relevant to Chapter 2 A2.1 SPECTRA RELEVANT TO CHAPTER 2 ........................................................... 106 A2.2 CRYSTALLOGRAPHIC DATA RELEVANT TO CHAPTER 2 ........................ 180 A2.2.1 Enolate arylation product 57 ........................................................................... 180 xv CHAPTER 3 200 Late stage d ring installation on the a-enolate arylation product 3.1 INTRODUCTION .................................................................................................... 200 3.2 EXPLORATION OF LATE-STAGE ARENE REDUCTION................................. 201 3.2.1 Birch Reduction with liquid ammonia ............................................................... 201 3.2.2 Ammonia-free Birch Reduction strategies......................................................... 209 3.3 ATTEMPT AT D-RING INSTALLATION ............................................................. 211 3.3.1 Hydrolysis and b-g isomerization ..................................................................... 211 3.3.2 Photochemical allene [2+2] ............................................................................... 212 3.3.3 Exploration of Dowd-Beckwith ......................................................................... 213 3.5 CONCLUDING REMARKS .................................................................................... 216 3.6 EXPERIMENTAL SECTION .................................................................................. 217 3.7 NOTES AND REFERENCES .................................................................................. 226 APPENDIX 3 Spectra Relevant to Chapter 3 230 xvi CHAPTER 4 257 3.2.1 bicycle synthesis 4.1 INTRODUCTION .................................................................................................... 257 4.2 VERSATILE 3.2.1 BICYCLE SYNTHESIS THROUGH THE SNIDER RADICAL CASCADE ...................................................................................................................... 258 4.2.1 A transform-based approach for 3.2.1 bicyclic aldehyde synthesis: use of the Snider Radical Cascade............................................................................................... 258 4.2.2 Synthesis of the Snider Radical Cascade substrate ............................................ 261 4.2.3 Studies to affect the Snider Radical Cascade ..................................................... 262 4.2.4 Advancement to the key fragment (107A)......................................................... 263 4.2.5 Further derivatization of the key fragment (107A) ............................................ 265 4.2.6 Strategies to shorten the key fragment (107B) synthesis ................................... 266 4.3 ASYMMETRIC 3.2.1 BICYCLE SYNTHESIS THROUGH RADICAL INTERMEDIATES......................................................................................................... 271 4.3.1 Chiral induction through the use of a chiral auxiliary 4.3.2 Chiral atom-transfer reactions............................................................................ 273 4.3.3 Asymmetric radical cascade from chiral enamine ............................................. 279 4.4 ASYMMETRIC STRATEGIES THROUGH CYCLOHEXANONE SUBSTRATES ......................................................................................................................................... 285 4.4.1 Early studies from cyclohexanone substrates .................................................... 285 4.4.2 Tsuji-Stoltz Allylation as a method for quaternary stereocenter formation ...... 289 4.4.3 Strategies for ring closure .................................................................................. 293 4.4.4 Nickel-catalyzed carbonyl 1,2-addition ............................................................. 297 xvii 4.4.5 Advancement to the asymmetric key fragment (107B) ..................................... 306 4.4.6 Other avenues for more expedient 3.2.1 bicycle synthesis: use of a Michael-Aldol cascade ........................................................................................................................ 308 4.5 CONCLUDING REMARKS .................................................................................... 311 4.6 EXPERIMENTAL SECTION .................................................................................. 312 4.7 NOTES AND REFERENCES .................................................................................. 378 APPENDIX 4 Spectra Relevant to Chapter 4 392 xviii CHAPTER 5 500 Development of a vinylogous Mukaiyama Aldol fragment coupling reaction and intramolecular Ni-catalyzed a-enolate alkenylation 5.1 INTRODUCTION .................................................................................................... 500 5.2 CONVERGENT FRAGMENT COUPLING: OPTIMIZATION OF THE VINYLOGOUS MUKAIYAMA ALDOL ADDITION ................................................ 501 5.2.1 Early optimization of enol triflate substrate (107A) VMAR ............................. 501 5.2.2 Investigation of Br substrate (107B) .................................................................. 506 5.3 Ni-CATALYZED A-ENOLATE ALKENYLATION ............................................. 510 5.3.1 Synthesis of OTf and Br substrates.................................................................... 510 5.3.2 Initial experimentation on the key intramolecular cross-coupling: use of phosphine ligands ......................................................................................................................... 511 5.3.3 Discovery of electron-deficient olefin (EDO) ligands for the intramolecular aenolate alkenylation .................................................................................................... 518 5.3.4 Assessing the necessity of reaction components and scalability of the Ni-catalyzed a-enolate alkenylation ................................................................................................ 529 5.4 CONCLUDING REMARKS .................................................................................... 530 5.5 EXPERIMENTAL SECTION .................................................................................. 531 5.6 NOTES AND REFERENCES .................................................................................. 547 APPENDIX 5 Supporting Information Relevant to Chapter 5 557 xix CHAPTER 6 609 End Game 6.1 INTRODUCTION .................................................................................................... 609 6.2 PREFUNCTIONALIZED EXO-OLEFIN STRATEGIES ....................................... 610 6.2.1 Mukaiyama hydration of the exo-olefin ............................................................. 610 6.2.2 Elaboration of hydrated products ....................................................................... 614 6.2.3 Synthesis of new hydrogenation substrates ....................................................... 617 6.3 SELECTIVE FUNCTIONALIZATION STRATEGIES ......................................... 619 6.3.1 Elaboration of substrate 105 .............................................................................. 619 6.3.2 Completion of the synthesis of (+)-auriculatol A .............................................. 623 6.4 CONCLUDING REMARKS .................................................................................... 624 6.5 EXPERIMENTAL SECTION .................................................................................. 625 6.6 NOTES AND REFERENCES .................................................................................. 662 APPENDIX 6 667 Spectra Relevant to Chapter 6 ABOUT THE AUTHOR 783 xx LIST OF ABBREVIATIONS [a]D angle of optical rotation of plane-polarized light Ac acetyl acac acetylacetonate aq. aqueous atm atmosphere(s) bpy 2,2'-bipyridine Bn benzyl bp boiling point br broad Bu butyl iBu iso-butyl nBu norm-butyl tBu tert-butyl c concentration of sample for measurement of optical rotation 13 C carbon-13 isotope °C degrees Celcius calcd calculated cis on the same side cm–1 wavenumber(s) CO carbon monoxide COD 1,5-cyclooctadiene xxi conv. conversion COSY homonuclear correlation spectroscopy D heat or difference d chemical shift in ppm d doublet D deuterium DA Diels–Alder dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N'-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIBAL diisobutylaluminum hydride diglyme bis(2-methoxyethyl) ether DMA N,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene dr diastereomeric ratio xxii dtbbpy 4,4′-di-tert-butyl-2,2′-dipyridyl ee enantiomeric excess E trans (entgegen) olefin geometry EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride e.g. for example (Latin: exempli gratia) ent enantiomer of epi epimeric equiv. equivalent(s) ESI electrospray ionization Et ethyl et al. and others (Latin: et alii) FD field desorption FI field ionization FTIR fourier transform infrared spectroscopy g gram(s) glyme dimethoxyethane h hour(s) 1 H proton [H] reduction HFIP hexafluoroisopropanol HMBC heteronuclear multiple-bond correlation spectroscopy HMDS hexamethyldisilazide HMPA hexamethylphosphoramide xxiii hu irradiation with light HPLC high performance liquid chromatography HRMS high resolution mass spectrometry HSQC heteronuclear single quantum coherence spectroscopy Hz hertz i.e. that is (Latin: id est) in situ in the reaction mixture iso isomeric J coupling constant in Hz k rate constant kcal kilocalorie(s) L liter l levorotatory LCMS liquid chromatography–mass spectrometry LDA lithium diisopropylamide m multiplet or meter(s) M molar or molecular ion µ micro Me methyl MeOH methanol MeCN acetonitrile mg milligram(s) MHz megahertz xxiv min minute(s) mL milliliter(s) mol mole(s) MOM methoxymethyl Ms methanesulfonyl (mesyl) m/z mass-to-charge ratio NBS N-bromosuccinimide nm nanometer(s) nM nanomolar NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance nOe nuclear Overhauser effect NOESY nuclear Overhauser enhancement spectroscopy o ortho [O] oxidation OMe methoxy p para PCC pyridinium chlorochromate Ph phenyl pH hydrogen ion concentration in aqueous solution PhH benzene PhMe toluene pin pinacol xxv pKa acid dissociation constant pm picometer(s) PMB para-methoxybenzyl ppm parts per million PPTS pyridinium para-toluenesulfonate Pr propyl iPr isopropyl nPr propyl or norm-propyl psi pounds per square inch pyr pyridine q quartet quant. quantitative R generic group R rectus RCM ring-closing metathesis ref reference Rf retention factor rr regioisomeric ratio rt room temperature sat. saturated s singlet or seconds SAR structure-activity relationship SFC supercritical fluid chromatography xxvi t triplet TBACl tetra-n-butylammonium chloride TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammonium iodide TBS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TOF time-of-flight Tol tolyl trans on the opposite side Ts para-toluenesulfonyl (tosyl) TS transition state UV ultraviolet vide infra see below vide supra see above w/v weight per volume VMAR vinylogous Mukaiyama aldol reaction X anionic ligand or halide xs excess Z cis (zusammen) olefin geometry 1 Chapter 1 – Introduction to the grayanane diterpenoids Chapter 1 Introduction to the grayanane diterpenoids1 1.1 INTRODUCTION The initial discovery of the grayanane diterpenoids is described, followed by a thorough analysis of past work in grayanane diterpenoid total synthesis. This chapter concludes in an introduction to auriculatol A as an intriguing target for total synthesis. 1.2 BACKGROUND ON THE GRAYANANE DITERPENOIDS 1.2.1 Grayanane diterpenoid discovery and biological activity The grayanane diterpenoids are a class of biologically active natural products that were first discovered as the active ingredients in “mad honey”.1 Upon ingestion of “mad honey”, one may experience a variety of symptoms: dizziness, weakness, nausea, and in some cases, vomiting. Although Mad Honey Disease remains one of the most common food intoxications in Turkey and Japan for both humans and livestock, it is rarely lethal. 2 Chapter 1 – Introduction to the grayanane diterpenoids Rather, in small doses, it has been used as a homeopathic medicine for the treatment of gastric pains, bowel disorders, and hypertension.1 Furthermore, it is believed to be a sexual stimulant.1 While grayanotoxins I, II, III, and IV (1-4) have all been shown to exist in mad honey, grayanotoxin III (2) is the principal constituent in rhododendron and, in some studies, has been shown to possess greater pain-relieving properties than morphine (Scheme 1.1).2 Scheme 1.1. Initial discovery of the grayanane diterpenoids. Ingestion causes dizziness, weakness, nausea, paresthesia One of the most common food poisonings in Turkey Traditionally has been used as an rhododendron mad honey alternative medicine grayanotoxin I Me OHH HO HO a Me Hb Me OHH Me c d OH HO OAc 1 HO a Me Me HO grayanotoxin II grayanotoxin III Hb Me c d H OH HO Me Me HO OH 2 HO Hb grayanotoxin IV Me c d H OH HO Me Me HO OH 3 HO Hb Me HO Me c d OH OAc 4 Principle toxic isomer in rhododenron Potent voltage-gated Na+ channel inhibitor (IC50 < 10μM) Possibly more pain relieving than morphine 1 completed total synthesis Many grayananes are neurotoxins, interfering with the transmission of the action potential by blocking sodium channels in cell membranes. These compounds prevent inactivation of neurons, which keeps them in a state of depolarization, during which entry of calcium into the cells may be facilitated. More recently, honey extracts from the endemic plant in the Black Sea region, Rhododendron ponticum, have shown micromolar inhibitory Chapter 1 – Introduction to the grayanane diterpenoids 3 potency as carbonic anhydrase inhibitors, specifically the human (h) isomers hCA I and hCA II.3 The World Health Organization (WHO) has outlined compounds that target these inhibitors as essential medicines.4 Additionally, compounds of this class have been shown to exhibit promising bioactivity against several other human diseases, including HIV (Scheme 1.2).5 Scheme 1.2. About the grayanane diterpenoids. grayananes > 300 compounds isolated and characterized 20 2 3 19 4 10 1 5 7 1 6 18 14 9 Diverse preliminary biological activity 15 11 13 [5-7-6-5] core 16 12 17 Potent carbonic anhydrase inhibitors Anti-HIV, anti-microbial, and immunomodulatory activity Low isolation efficiency Rare success in total synthesis Since their initial discovery, more than 300 members of this class have been isolated and characterized.7 Common to all grayanane diterpenoids is a tetracyclic fused [5-7-6-5] ring skeleton decorated with hydroxyl groups around their perimeter. Despite their promising biological studies, isolation yields are incredibly low. In one study, the concentration of grayanotoxins in several rhododendron species was found to be approximately 10 mg / 100 g of plant leaves or 0.01% w/w.8 Some species, however, have been shown to contain 0.2% grayanotoxin I, such as Rhododendron catawibiense or Rhododendron ponticum.8 Overall, these targets are rare in total synthesis despite full characterization of grayanane structure dating back to the early 1960’s.9 The structural and stereochemical complexity of grayanane diterpenoids may be the primary reason for their synthetic elusiveness. 4 Chapter 1 – Introduction to the grayanane diterpenoids 1.2.2 Prior art: synthetic access to the grayanotoxins Despite isolation of grayanotoxin I dating back to 1912 (earliest report) by German phytochemist, Otto Tunmann, many early studies were executed by Japanese researchers.10 Shikiro Miyajima and Sankichi Takei isolated grayanotoxins I–III from 1934 to 1936, and the full characterization of their structures was assigned in 1961 and 1962 by groups of researchers at Nagoya University, Kyoto University, and Tokyo University.10 Over a decade later, in 1976, Matsumoto and coworkers achieved a landmark total synthesis of (±)-grayanotoxin II in relay fashion.11 Utilization of dienone rearrangement, reminiscent of studies on the santonin rearrangement,12 afforded intermediate cyclopropyloxyallylcation 6 (Scheme 1.3). Nucleophilic attack from acetate delivered 7, which was elaborated to (±)–grayanotoxin II (2) in a total synthetic sequence of greater than 40 steps. This was undoubtedly a pivotal achievement for the total synthesis community but left room for further improvement considering the steps to elaborate the unfunctionalized c and d rings. Scheme 1.3. Matsumoto’s utilization of the dienone rearrangement to form the a and b rings of grayanotoxin II. OAc H Me H Me OH AcO H OH 254nm hv H Me H H photosantonin rearrangement O Me 5 HO Me 6 OH > 20 steps H HO Me O Me 7 HO Me HO Me OH H OH grayanotoxin II (3) In 1994, Shirahama and coworkers used reductive couplings to access (−)grayanotoxin III (2).13 Nucleophilic opening of epoxide 9 with 8 formed 10. A SmI2mediated reductive cyclization set two stereocenters with excellent stereocontrol to afford 5 Chapter 1 – Introduction to the grayanane diterpenoids 11 in 79% yield (Scheme 1.4). Pinacol coupling formed the b ring in 13, which was elaborated to the natural product (3). The use of a pre-functionalized c and d ring accounted for a longest linear sequence of 28 steps, drastically reducing step count compared to Matsumoto’s efforts. Furthermore, the synthesis was asymmetric, with fragment 8 originating from the chiral pool and 9 through Sharpless asymmetric epoxidation. Scheme 1.4. Shirahama’s use of reductive couplings to assemble the a and b rings. OPMB SPh SPh Me H Me 9 O Li OR OR Me fragment coupling H Me OR OR Me OTBS reductive coupling Me O O 12 OR OR Me SmI2 HMPA 54% yield reductive coupling Me H Me Me OH OR 11 Me OMOM H TBSO H TBSO 10 Me OMOM H H Me O Me 8 TBSO SmI2 HMPA 79% yield > 20 : 1 dr H HO Me OHH Me OR H HO Me Me HO OR Me OR 13 HO Me OH H Me HO OAc grayanotoxin III (2) 1.2.3 Prior art: access to the principinol skeleton Recently, there has been a surge in interest from the total synthesis realm in providing synthetic access to the principinol framework. This has likely been elicited by the recency in isolation and characterization of these novel targets.14 Structurally, some principinols differ only slightly from the grayanotoxins. Principinol D and F, for example, are simply the C1 epimer of grayanotoxin III and II, respectively (Scheme 1.5). On the contrary, principinol C contains a C6 ketone rather than a C5-C6 diol and is the C9-C10 epimer when compared to grayanotoxin III. The dissimilarity of principinol C to other grayanane natural products has large implications when trying to contextualize the biosynthesis of these compounds. It brings into question the biochemical mechanism for formation of these natural products, which will be discussed later in this chapter. 6 Chapter 1 – Introduction to the grayanane diterpenoids Scheme 1.5. Structure of principinols C-F. HO Me H HO a Me H Me Hb Me c d H OH HO a Me O OAc principinol C (14) HO Hb Me c d H OH HO Me Me HO OH principinol D (15) HO Me HO Hb H Me c HO d Me OH principinol E (16) HO Me HO Hb Me c d OH OAc principinol F (17) In 2018, Newhouse and others disclosed an elegant synthesis of (−)-principinol D.15 Functionalized 3.2.1 bicycle 19 was synthesized in 8 steps and coupled with building block 18 via a 1,2 addition/protection sequence (Scheme 1.6). Selective olefin oxidative cleavage was achieved in 3 steps to form 21, setting the stage for Giese addition of the ketyl radical formed from SmI2 reduction of the pendant aldehyde to furnish 22 in 63% yield. Functional group manipulations and installation of the C10 terminal alkene formed (−)-principinol D in 18 steps longest linear sequence, establishing a high standard for other synthetic groups publishing in this area. The use of convergent fragment coupling strategy with two stereochemically rich, functionalized substrates is impressive and enabled rapid formation of molecular complexity. While construction of 18 was originally enantioenriched through Corey–Bakshi–Shibata (CBS) reduction, fragment 19 is racemic, providing low yield in the 1,2-addition step due to formation of 4 diastereomers. For this reason, further development in the domain of asymmetric 3.2.1 bicycle fragment synthesis could improve synthetic efforts toward these natural products. 7 Chapter 1 – Introduction to the grayanane diterpenoids Scheme 1.6. Convergent fragment coupling synthesis by Newhouse. TBSO H Me Me + O MOMO H I MOMO 18 Me (+/-) tBuLi then MOMCl TBSO RO 23% yield RO Me Me 1,2 addition RO Me H RO Me H MOMO 19 O RO H H O RO H Me 20 HO HO H H H SmI2 H 2O O H 63% yield MOMO Giese addition 21 H Me OH H MOMO 22 Me H HO H HO Me OH principinol D (15) In 2022, the Jia group disclosed an expedient synthesis of (−)-principinol C in 21 steps.16 Central to their strategy was a unique Pauson–Khand reaction to construct the 7,5bicyclic ring system. This work contrasts nicely with strategies from Matsumoto and Shirahama. Indeed, use of prefunctionalized building blocks reduced the subsequent functional group manipulations required later in the synthesis. 3.2.1 bicycle 28 was prepared in 97% ee through the use of an asymmetric conjugate addition of 24, catalyzed by copper/Taddol-derived monodentate phosphonite system (25), followed by quenching of the resultant enolate with Mander’s reagent (Scheme 1.7).17 Installation of a propargyl group proceeded smoothly, and the alkyne could be coupled to the alpha position of the ketone through a Mn-mediated reductive cyclization (28). Elaboration to 29 enabled investigation of the key step. In the optimized condition, the Pauson–Khand reaction occurred in 45% yield to form 30, which could be elaborated to the natural product. The use of the Pauson–Khand reaction represents a remarkably powerful disconnection, furnishing three carbon-carbon bonds in a single step. 8 Chapter 1 – Introduction to the grayanane diterpenoids Scheme 1.7. Pauson–Khand forms the core of (−)-principinol C. 23 Ph2P EtO2C O Me O P tBuPh then NCCO2Et Me O O H K2CO3 TMS Ph Ph O TMS Br 24 cat. CuI•DMS O TMS MgBr TMS O 26 60% over 2 steps Mn(OAc)3 • H2O EtO2C O 97% ee TMS 53% yield EtO2C O Mn-mediated reductive cyclization 27 H Me 28 Ph 25 asymmetric conjugate addition Me O TESO OMOM Me H H H OTMS 29 O Pauson–Khand H O Me OMOM Me 45% yield H H OTMS 30 OH OH 6 steps TESO Co2(CO)8 HO H H H Me OH H H Me O principinol C (15) 1.2.4 Prior art: divergent access to the grayanotoxin and principinol frameworks Luo et al. published the shortest synthetic sequence to any grayanane, (−)grayanotoxin III (2), in 18 steps.18 Their strategy utilized convergent fragment coupling of 31 and 32 through sequential diastereoselective Mukaiyama Aldol with a squaramide catalyst (33) followed by Sakurai Allylation to form 34 in the same pot (Scheme 1.8). Following vinylation, diene 35 was cyclized in a Prins-type manner to an acid-generated bridgehead carbocation to access 36. Taken together, three Lewis acid-mediated cyclizations efficiently constructed a minimally-oxidized core of the molecule (36), impressively, in just 8 steps. Notably, however, synthetic efforts to rearrange the c and d rings were necessary, as the correct connectivity of the c and d rings had not been established. Because the synthetic strategy relied on late-stage oxidation, synthetic access to a variety of grayanane skeletons was achieved. Namely, by judicious choice of oxidation sequences, the syntheses of (−)-grayanotoxin III (2), (+)-principinol E (17), and (−)- 9 Chapter 1 – Introduction to the grayanane diterpenoids rhodomollein XX (not pictured) could be achieved. This work represents one of two papers detailing divergent synthetic access to grayanotoxin and principinol cores to date. Scheme 1.8. Luo’s rapid and divergent synthesis of grayanane diterpenoids. MeO Me OMe + Br AcO Me cat. TMSOTf hydrogen donor cat. (33) TMS then EtAlCl2 TMSO 31 32 83% ee 86% ee 90% yield HO Me O MeO 44% yield Me MeO Me H HO c and d ring rearrangement Me Me 35 H Me Me OHH HO Me Me HO OH Me Me HO O BF3K Pd(PPh3)4 then NaOH 34 Me 1. DMP, NaHCO3 2. Tf2O, py then iPrOH then 4-Ph-py Me H Br 58% yield AcO Mukaiyama Aldol Me Sakurai Allylation Me cationic cyclization MeO OTBS 37 HO Me HO Me OH H OAc grayanotoxin III (2) 36 O O CF3 H tBu N Ar O HO N H N H 33 Ar = 1-pyrenyl CF3 Me HO Me HO Me H OH principinol E (17) An elegant divergent synthesis of a plethora of grayanane natural products was disclosed by Ding and coworkers.19 Utilization of a more advanced photosantonin rearrangement than the early report from Matsumoto enabled synthetic access to the grayanotoxin skeleton.20 The substrate for their photosantonin rearrangement was assembled through an oxidative dearomatization induced (ODI) [5+2] cycloaddition, a strategy that is similar to previous disclosures from this group in their synthetic studies towards (−)-rhodomollanol A.21 With synthetic access to 39, functional group manipulations enabled the succinct synthesis of (−)-principinol D (15) in 19 steps (Scheme 1.9). Brilliantly, treatment of intermediate 39 with PPTS enabled a grob fragmentation/carbonyl cascade to epimerize the C1 stereochemistry and enable the 10 Chapter 1 – Introduction to the grayanane diterpenoids synthesis of several grayanotoxin natural products in addition to the principinols. Overall, this paper disclosed the synthesis of nine grayanane natural products, namely grayanotoxin II (3), grayanotoxin III (2), rhodojaponin III (not pictured), grayanotoxin XV (not pictured), principinol D (15), iso-grayanotoxin II (not pictured), 1,5-seco-grayanotoxinD1,10-ene (not pictured), and leucothols B and D (not pictured). Key to their synthetic strategy is the judicious use of the ODI [5+2] and photosantonin rearrangement to rapidly build molecular complexity. Computational studies reveal the mechanism for the unique Grob fragmentation/carbonyl-ene sequence, while judicious choice of oxidation reactions and rearrangements of the established 5,7,6,5 skeleton enable divergent access to a myriad of natural products. Scheme 1.9. Ding’s divergent approach to the grayanane and principinol frameworks. O HO H H Me TBSO 39 O O Me Me Ac Me photosantonin rearrangement H 2 steps Me HO Me Me O 40 Grob fragmentation assembled via [5+2] ODI cascade OH Me O H H HO Me OH H HO principinol D (15) O H O Me HO HO H Me Me HO Me Me 41 O 2 steps O O carbonyl-ene Me HO HO Me HO O H Me H Me OH OH grayanotoxin III (2) 1.2.5 Summary of approaches An excellent chemical review of syntheses prior to 2022 is available online.22 Therein, a table and schematic containing brief advantages and disadvantages are described (Table 1.1) in addition to a nice overview schematic (Scheme 1.10). 11 Chapter 1 – Introduction to the grayanane diterpenoids Table 1.1. Summary of approaches prior to 2022. synthesis advantages drawbacks <0.0005% – many steps, racemic 0.05% enantioselective many steps 0.4% convergent, few steps limited to C1 epimers of the general structure number of steps overall yield Matsumoto (1976) > 40 Shirahama (1994) 38 Newhouse (2019) 19 Ding (2019 22—23 1.2—1.4% Luo (2022) 18—19 0.01—0.05% few steps, flexible lower yields 0.5% few steps, modular not convergent Jia (2022) 22 few steps, highest yielding limited to C1—C5 dehydrogenated grayananes Scheme 1.10. Overview of synthetic strategies. O TESO OMOM Me H H Luo’s strategy O O Me OH Me HO MeO H O TMS Ding’s strategy O O 1,2-shift HO Me 1 7 16 12 O H Me H Me Me 6 H OH OH O 13 dearomatization Diels—Alder O OH radical cyclization lithiation addition TfO 1,2-shift H 10 Me H H Pauson–Khand Me Me Jia’s strategy H EtO2C O H OTMS H HO bridgehead carbocation trapping TMS Mn-mediated reductive cyclization O OMe H O OTIPS O Me Me OH aldol/Sakurai cascade TMSO AcO Me Me OMe + OMe Br H TBSO TMS Me Me Me MOMO + Br nickel-catalyzed enolate coupling I O H Newhouse’s strategy O OTBS MOMO 1.2.6 Other grayanane synthesis attempts There have been many attempts in the literature towards grayanane natural products that have contributed significantly to provide foundational studies towards these targets. An in-depth discussion of these works can be found online.23 1.2.7 Biosynthesis of the grayanane diterpenoids Generally, the biosynthesis of complex diterpenes is thought to occur through two phases: 1) a cyclization phase and 2) an oxidation phase.24 Specifically, the grayananes are Chapter 1 – Introduction to the grayanane diterpenoids 12 thought to arise from polyene cyclization of geranylgeranyl diphosphate (42), catalyzed by copalyl diphosphate synthase and ent-kaurene synthase to access the ent-kaurene (43) (Scheme 1.11). Internal bond migration of the kaurene skeleton, and a series of oxidations furnish the grayanotoxin framework (44). Interestingly, the grayananes are very closely related to the gibberellanes, a classic target for synthetic organic chemists, and only differ in the direction of bond migration from the kaurane skeleton (not pictured). Oxidation of the ent-kaurene affords the ent-kauranoids (45), and there has been a unified synthetic strategy disclosed for these targets from the Reisman group in the past.25 An L-serinemediated oxidation and C7-C10 bond formation allow access to the napelline type diterpenoid alkaloids (DAs) (46). An alternative polyene cyclization can generate the entatisane structure (47), and an analogous oxidation/C7-C10 bond formation furnishes the denutatine-type DAs (48). Wagner-Meerwein and oxidation events bioenzymatically form the aconitine-type DAs, which also have been successful targets from the Reisman group (not pictured).26 13 Chapter 1 – Introduction to the grayanane diterpenoids Scheme 1.11. Biosynthesis of representative diterpenoids. Me HO HO bond migration Me HO Me OH O H Me H 44 OH grayanatoxin III grayanane copalyl diphosphate synthase; H oxidation Me Me 7 ent-kaurene synthase Me O OH Me O OH Me 45 43 longikaurin E ent-kauranoid ent-kaurene Me Me oxidation; L-serine Me Me HO OH Me C7–C10 bond formation PPO OH N Et Me 46 napelline C20 nappeline type DA 42 geranylgeranyl diphosphate OAc 10 copalyl diphosphate synthase; ent-atiserene synthase oxidation; L-serine Me 7 Me Me 10 47 ent-atisane C7–C10 bond formation OH Me N Et HO OH H 48 lepenine C20 denudatine type DA 1.2.8 Introduction to auriculatol A In 2019, a new pentacyclic grayanane diterpenoid, auriculatol A (49), was isolated and structurally characterized from Rhododendron auriculatum (Scheme 1.12).27 14 mg was isolated from > 50 kg of rhododendron leaves. Similar isolation yields were disclosed in this report for the newly discovered auriculatol B (50), auriculatol C (51), and 19Hydroxy-3-epi-auriculatol B (52). The compounds, along with grayanotoxins I (1) and IV (3), were tested for analgesic activities in a writhing test induced by HOAc. It was found that some of these grayanane diterpenoids exhibited significant analgesic activities, with inhibition rates > 50% at doses of 0.2 and 0.04 mg/kg, exhibiting greater analgesic potency than morphine. 14 Chapter 1 – Introduction to the grayanane diterpenoids Structurally, auriculatol A is the first 5,20-epoxygrayanane diterpenoid containing a 7-oxabicyclo[4.2.1]-nonane motif (the e ring in 49) and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring structure (Scheme 1.12). The rarity of this motif points to a way to conduct structure-activity relationship (SAR) studies with respect to the more common grayanotoxin and principinol scaffolds. Moreover, the development of a robust and modular approach to access this novel grayanane framework remains underdeveloped. Scheme 1.12. Structure of auriculatol A and other new grayananes isolated from Rhododendron auriculatum. H MeO HO Me e O a HH Hb Me c d H OH OH MeO Me a O e HO Me c HO auriculatol A (49) 1.3 Me OHH Me OH Me HO H Me Me OH H OH auriculatol C (51) Me OH HO OH HO HO H Me OH OH H auriculatol F (54) Me H OH HO Me OH 19-Hydroxy-3-epi-auriculatol B (52) HO Me OH H Me H Me Me HO HO auriculatol B (50) H d H Me OH H b OH H auriculatol A (49) HO H HO Me Me HO Me Me Me Me H Me OH OH Me OH auriculatol D (53) 2α-hydroxyauriculatol F (55) CONCLUDING REMARKS In conclusion, this chapter has provided an analysis of completed grayanane syntheses up to January 2024. While there have been many syntheses, representing a variety of strategies for assembly of these complex targets, they can be subdivided into three main groups: 1) synthesis of the grayanotoxin framework 2) synthesis of the principinol framework and 3) divergent access to both the grayanotoxins and principinols. The benefits and limitations of these approaches were discussed in detail. Typical step 15 Chapter 1 – Introduction to the grayanane diterpenoids counts of recent syntheses were in the realm of 18-25 steps and 0.4-1.4% overall yield. The biosynthesis of the grayananes and related congeners like the ent-kauranoids and diterpenoid alkaloids were introduced. Finally, auriculatol A was introduced and discussed. 1.4 NOTES AND REFERENCES (1) (a) Koca, A. F.; Koca, I. Poisoning by mad honey: A brief review. Food Chem. Toxicol. 2007, 45, 1315−1318. (b) Gunduz, A.; Turedi, S.; Russell, R. M.; Ayaz, F. A. Clinical review of grayanotoxin/mad honey poisoning past and present. Clin. Toxicol. 2008, 46, 437−442. (c) Jansen, S. A.; Kleerekooper, I.; Hofman, Z. L.; Kappen, I. F. P.; Stary-Weinzinger, A.; van der Heyen, M. A. G. Grayanotoxin poisoning: ‘Mad Honey Disease’ and beyond. Cardiovasc. Toxicol. 2012, 12, 208−215. 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Total Synthesis of (−)- Rhodomoollanol A. J. Am. Chem. Soc. 2020, 142, 10, 4592–4597. (22) Fay, N.; Blieck, R.; Kouklovsky, C.; de la Torre, A. Total synthesis of grayanane natural products. Beilstein J. Org. Chem. 2022, 18, 1707–1719. (23) (a) Kan, T.; Matsuda, F.; Yanagiya, M.; Shirahama, H. Stereocontrolled construction of B-ring of graynotoxins via samarium(II) iodide promoted pinacol coupling Chapter 1 – Introduction to the grayanane diterpenoids 19 cyclization. Synlett. 1991, 391–392. (b) Paquette, L. A.; Borelly, S. Studies directed toward the total synthesis of kalmanol. An approach to construction of the C/D diquinane substructure. J. Org. Chem. 1995, 60, 6912–6921. (c) Borelly, S.; Paquette, L. Studies directed to the synthesis of unusual cardiotoxic agent kalmonol. Enantioselective construction of the advanced tetracyclic 7-oxy-5,6-dideoxy congener. J. Am. Chem. Soc. 1996, 118, 727–740. (d) Chow, S.; Kreß, C.; Albæk, N.; Jessen, C.; Williams, C. M. Determining a synthetic approach to pierisformaside C. Org. Lett. 2011, 13, 5286–5289. (24) Cherney, E. C.; Baran, P. S. Terpenoid-Alkaloids: Their Biosynthetic Twist of Fate and Total Synthesis. Isr. J. of Chem. 2011, 51, 3-4, 391–405. (25) Yeoman, J. T. S., Mak, V. W.; Reisman, S. E. A Unified Strategy to ent-Kauranoid Natural Products: Total Syntheses of (−)-Trichorabdal A and (−)-Longikaurin E. J. Am. Chem. Soc. 2013, 135, 32, 11764–11767. (26) Wong, A. R.; Fastuca, N. J.; Mak, V. W.; Kerkovius, J. K.; Stevenson, S. M.; Reisman, S. E. Total Syntheses of the C19 Diterpenoid Alkaloids (−)-Talatisamine, (−)Liljestrandisine, and (−)-Liljestrandinine by a Fragment Coupling Approach. ACS Cent. Sci. 2021, 7, 8, 1311–1316. (27) Sun, N.; Zheng, G.; He, M.; Feng, Y.; Liu, J.; Wang, M.; Zhang, H.; Zhou, J.; Yao, G. Grayanane diterpenoids from the leaves of Rhododendron auriculatum and their analgesic activities. J Nat Prod. 2019, 82, 1849–1858. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 20 Chapter 2 Vinylogous Mukaiayama Aldol and a-enolate arylation model studies† 2.1 INTRODUCTION This chapter discusses a model system that rapidly tested strategies for g- functionalization of butenolides. This includes the synthesis of a key, 5-5-fused butenolide fragment in addition to the initial discovery and optimization of a unique vinylogous Mukaiyama Aldol reaction. Early application of 1,4-reduction of butenolides to lactones is discussed. Concepts in the development of a Ni-catalyzed a-enolate arylation reaction are also explored in detail. This chapter provides a model system for the synthesis of auriculatol A, and with Chapter 3, could provide a nice entry to the synthesis of auriculatol A itself or other grayanane ditepenoid natural products more generally. † Portions of this chapter were adapted from the following communication: Thompson, J. K.; Youngblood, K. C.; Teh, S. Y. H.; Farley, C. M.; Zhang, Z.; Virgil, S. C.; Reisman, S. E. J. Am. Chem. Soc. 2025, 147, 42170–42174. J.K.T. was supported by the NSF GRFP (DGE-1745301). S.E.R. acknowledges fellowship support by the NIH (R35GM118191). The research presented in this chapter was completed in collaboration with Dr. Conner Farley, a former postdoctoral researcher in the Reisman group. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.2 21 A NOTE ON MODEL SYSTEMS The use of a model system is appealing in many aspects, as it provides quick synthetic access to test preliminary hypotheses. In troubleshooting difficult reactivity on simpler systems, model systems may provide insight into the challenges of certain strategies, decrease long-term synthetic burden, and provide a platform to learn reactivity trends before abandoning the development of novel strategies on challenging substrates. However, the results obtained from model systems are not always generalizable, model systems may require optimizations themselves, and model system substrate synthesis is not always trivial. A good model system, nevertheless, takes these considerations into account, often through an in-depth cost-benefit analysis, and is modular, allowing changes in approach as challenges arise. 2.3 MODEL SYSTEM ROUTE DESIGN 2.3.1 Retrosynthetic analysis We envisioned that the model system route could aid in the development of a vinylogous Mukaiyama aldol addition on an aryl aldehyde followed by a Ni-catalyzed aenolate arylation reaction – which could then be parlayed into the development of a vinylogous Mukaiyama aldol addition on a 3.2.1 bicyclic aldehyde and an a-enolate alkenylation reaction. Retrosynthetically from auriculatol A (49), disconnection of the d ring could provide enone 56, which could be accessed from Birch Reduction of 57. Utilizing the intramolecular a-enolate arylation transform, 58 was targeted as a key precursor. It was thought that 58 could be accessed from conjugate reduction of butenolide 22 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 59, which could be formed using various g-functionalization methods. Perhaps the simplest transformation would be the vinylogous aldol reaction, conjoining two fragments 60 and 61 and allowing access to 59. We hoped to leverage the reactivity of the butenolide as a polarity reversal tactic. While there are reactions known to functionalize butenolides at the g-position, there are few reports to form fully substituted centers in aldehyde couplings (typically couplings are done with Michael acceptors).1 Furthermore, past reports do not contain such a hindered site for reactivity of the nucleophile at the g-center and are often left unsubstituted (Scheme 2.1B). In some cases, a-alkylation has been reported to dominate over the desired vinylogous reactivity.2 In anticipation of these challenges, concise syntheses of building blocks 60 and 61 were targeted. Scheme 2.1. A. Second generation retrosynthetic analysis B. Key challenge: a hindered site for reactivity. A MeO HO Me O O H O d-ring installation H Me d HO Me RO Birch Reduction H O Me Me OH α-enolate arylation O TBSO Me OR O Me OR 56 HO Ni OMe 57 auriculatol A (49) O TBSO O Me 58 Me Me vinylogous aldol H 60 Br Me HO Br O O O TBSO Me OR TBSO O Me conjugate reduction OMe Br O 59 MeO MeO 61 B TBSO O Me Me 60 H O γ TBSO O α Me Base O Br Me O hindered site for reactivity MeO 61 23 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.3.2 Aldehyde synthesis Target aldehyde 61 was envisioned to be accessed from commercially available 2bromo-5-methoxybenzaldehyde (62). Treatment with methylene triphenylphosphorane afforded 63 in 50% yield. Consistent with literature precedent, hydroboration of 63 provided 64 in modest yield due to competing formation of the Markovnikov product.3 From 64, 61 could be formed by DMP oxidation in 79% yield.4 Scheme 2.2. Original synthesis of fragment 61. MeO O (Ph3PMe)Br (1.2 equiv) KOtBu (1.2 equiv) THF, 0 °C to 21 °C, 8 h Br 62 THF, 21 °C, 12 h then NaOH 0 °C, 1 h then H2O2 0 °C, 30 min Br 63 50% yield MeO 9BBN (1.5 equiv) MeO $20/g OH Br 64 36% yield DMP (1 equiv) O MeO CH2Cl2, 22 °C, 1 h Br 61 79% yield Given the low yield in the hydroboration of styrene 63, it was found that 3methoxybenzeneethanol (65) could be purchased for $15/g, undergo selective parabromination5 and the same oxidation with DMP, and provide 61 in 77% yield over two steps (Scheme 2.3). Scheme 2.3. Improved synthesis of 61. MeO OH Br2 (1 equiv) MeO OH DCM, 22 °C, 1 h 65 $15/g 99% yield Br 64 DMP (1 equiv) O MeO DCM, 22 °C, 1 h 79% yield Br 61 24 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.3.3 Butenolide synthesis To access butenolide 60, it was envisioned that direct cyclization of 66 would offer a straightforward, direct approach (Scheme 2.4). Alcohol 66 could be formed via reduction of enone 67, which could be formed from aldol condensation with ethyl glyoxylate (68), tracing back to known ketone 69. Ketone 69 could arise from a known protection reaction of 70, allowing for a known CBS reduction of 63. This would necessitate the use of 2,2dimethyl-1,3-cyclopentadione (71) as the starting material for this fragment. Scheme 2.4. Butenolide synthesis: the original synthetic plan. O Cyclization TBSO O Me Me H TBSO O Me Me 60 TBSO OEt OH Me Me O OEt + HO Me Me O 68 CBS Reduction Protection TBSO 69 O O OEt 67 66 H Aldol Condensation O Reduction Me Me 70 O O Me Me O 71 In practice, the plan in Scheme 2.4 was more difficult to implement than expected. Although the CBS reduction and protection sequence formed the desired product, in our hands, it did not occur in the same yield or ee as reported (Scheme 2.5A).6,7 One significant, unanticipated challenge was achieving high yields in the aldol condensation protocol. Utilizing conditions from Vashchenko,8 the direct condensation of 69 with ethyl glyoxylate (68) did not occur under a variety of thermodynamic aldol reaction conditions (Scheme 2.5B). Attempts using kinetic bases such as LHMDS or LDA and treatment with 68 resulted in unconsumed starting material and poor yields of 72 (Scheme 2.5C). Mukaiyama aldol conditions9 from silyl enol ether 73 provided 72 in 33% yield with high recovery of 69 (Scheme 2.5D). 25 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.5. A. CBS reduction/protection of 71. B. Failed aldol condensation results. C. Difficulties inducing the Aldol reaction. D. Low-yielding Mukaiyama Aldol. H Ph Ph A O N B (0.5 equiv) Me Catecholborane (1.4 equiv) Et2NPh (0.5 equiv) O Me O HO Tol, −60 °C, 2 h Me TBSCl (1.4 equiv) Imidazole (2.8 equiv) DMAP (0.2 equiv) Me 43% yield 83% ee 71 Me DMF, 60 °C, 2 h 70 99% yield O TBSO O Me Me 69 O B H OEt O OH 68 O Base (1 equiv) TBSO Me Me O TBSO DMSO, 100 °C, 13 h O Me Me 69 O TBSO OEt O Me Me OEt 72 67 entry base conversion result 1 NaOMe < 5% sm, trace 72 2 NaOEt < 5% sm, trace 72 3 NaOHa < 9% sm, trace 72 4 KOHa < 5% sm, trace 72 5 KOtBu < 5% sm, trace 67 a0.3 eq of base was used C LHMDS or LDA (1.5 equiv) TBSO OH O TBSO Me Me O 69 then O H OEt O O Me Me OEt 72 68 THF, 0 °C to 22 °C, 13 h < 5% conversion O H D LHMDS (1.5 equiv) then TMSCl (1.5 equiv) TBSO Me Me 69 O THF, 0 °C, 2 h 91% yield OEt O 68 then TiCl4 (1.1 equiv) TBSO Me Me 73 OTMS DCM, −78 °C to 22 °C, 1 h 33% yield 40% recovery of 104 H OH O TBSO Me Me 72 O OEt 26 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies A one-step protocol involving DABCO as a base10 afforded alcohol 72 in 24% yield (Scheme 2.6). Elimination with Burgess reagent proceeded in 59% yield (67). Unfortunately, the direct cyclization of 67 proved troublesome. Upon treatment with NaBH4, for example, no cyclization was observed (not shown). However, hydrogenation with H2 and Pd/C proceeded smoothly, forming 74 in 75% yield as a 20:1 mixture of diastereomers, from which ketone reduction with NaBH4 occurred with concomitant lactonization to form 75 in 91% yield. From there, a two-step protocol involving aselenylation and H2O2-mediated elimination afforded target butenolide 60 in 65% yield over two steps. Scheme 2.6. Second-generation route to butenolide 60. O H OEt O 68 H OH O DABCO (1.2 equiv) TBSO Me Me 69 O TBSO toluene, 21 °C, 16 h Me Me 24% yield O O 60 OEt benzene, 50 °C, 9 h 1. LHMDS (1.05 equiv) then PhSeBr THF, −78 °C, 1 h 2. H2O2, DCM, 6 h, 0 °C 65% yield (2 steps) Pd/C (10 wt%), H2 O TBSO Me Me O OEt MeOH, 22 °C, 1 h 59% yield 72 TBSO Me Me H O Burgess’ reagent (1.8 equiv) 75% yield, dr = 20 : 1 67 H NaBH4 (1 equiv) TBSO O O Me Me H 75 MeOH, 21 °C, 30 min 91% yield O TBSO Me Me O OEt 74 While this route served to test ideas with regards to fragment coupling reactions, it did not provide enough material for extensive front-line investigation. Instead, a higher yielding route was desired. To this end, 69 was oxidized to enone 76 with 3 equivalents of IBX and NMO.6 Luche Reduction converted 76 to 77, which set the stage for a Ueno Stork Cyclization11 to access 78 (Scheme 2.7). The bromoketal 78 could then be converted to the lactone 75 via Jones oxidation,12 albeit in low yield. A two-step desaturation protocol 27 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies consisting of a-selenylation to form 80 and Grieco-type elimination provided 60 in 65% yield over two steps. Starting with 10 g of 71, more than 1 g of butenolide 60 could be synthesized. Scheme 2.7. Third-generation route to butenolide 60. IBX (3.0 equiv), NMO • H2O (3.0 equiv) TBSO Me Me DMSO, 80 °C, 10 h 69 70% yield O H SePh TBSO O Me Me H DCM, 0 °C, 1 h 90% yield Me MeOH, 22 °C, 1 h 76 90% yield dr = 12.5:1 O Me Me H 75 OEt (6 equiv) NBS (4 equiv) TBSO Me OH TBSO Me DCM, −20 °C to 0 °C, 3.5 h 77 75% yield Me O Me EtO 78 Br H TBSO 72% yield TBSO O Me H THF, −78 °C, 1 h 80 H2O2 (aq) TBSO LHMDS (1.1 equiv) then, PhSeBr (1.05 equiv) O NaBH4 (1 equiv) CeCl3 • 7H2O (1.3 equiv) O CrO3 (3 equiv) H2SO4 (3 equiv) TBSO H2O/acetone 0 °C, 1 h OEt Me Me H 30% yield 79 O AIBN (10 mol%) HSnBu3 (2 equiv) Benzene, 4 h, 90 °C 76% yield O Me Me H O 60 9 steps 2.3.4 Final optimization of the butenolide route While allowing gram-scale access to butenolide 60, the third-generation route could be improved. The route used superstoichiometric quantities of tributyltinhydride, chromium(III) trioxide, and totaled 9 steps, with 3% overall yield. Significant improvements reducing step-count and minimizing toxic, reactive reagents could be made. One of the major challenges was the CBS reduction. This reaction required close monitoring of an internal temperature of −60 °C and could only comfortably be scaled-up to 20 g. Furthermore, the use of catecholborane on this scale was prohibitively expensive. Noyori hydrogenation could provide higher yields and ee’s of the target secondary alcohol (70). Indeed, building off work done by Metz,14 Baudoin’s protocol for Noyori Transfer Hydrogenation15 provided 85% yield and > 99% ee, as determined by supercritical fluid 28 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies chromatography (SFC) analysis of the benzoylated alcohol 81 (Scheme 2.8). Scheme 2.8. Noyori Transfer Hydrogenation of 71. (S,S)-Ts-DENEB Me (S,S)-Ts-DENEB (1.25 mol%) O Me O HO Me NEt3/Formic Acid (1:1), 22 °C, 18 h 71 85% yield Me O Ru NTs Cl O HN Me 70 Ph Ph ee determination BzCl (5 equiv) NEt3 (5 equiv) HO Me O Me BzO DCM, 0 °C to 22 °C, overnight O Me 70 Me 81 >99% ee With higher yields of enantiopure material, we turned to shortening the route and minimizing toxic reagents. In our analysis of current and past routes, it became clear that most strategies utilized oxidation/reduction steps to facilitate C-C and C-O forming events. It was recognized that ester 82 was in the same oxidation level as butenolide 60 (Scheme 2.9B). Thus, it was envisioned that a direct cyclization and isomerization of 82 could provide access to 60. Taken together, we believed that strategies testing the direct cyclization of 82 could provide direct formation of butenolide 60. Scheme 2.9. New ideas for rapid butenolide synthesis. A O aldol TBSO TBSO Me Me O difficult Me Me O OEt 67 60 B TBSO O Me Me H 60 O Cyclization O TBSO Me Me 82 O OEt Alkylation TBSO Me Me 69 O Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 29 In order to access 82, silyl enol ether 73 could be cyclopropanated to yield 83 (Scheme 2.10A). Upon acid-mediated fragmentation,17 82 could be formed in good yield. 82 was then investigated for direct cyclization. Acid-mediated cyclizations inspired by Paul Knorr furan synthesis18 primarily resulted in no reaction, likely due to an electronic mismatch for cyclization, while treatment with larger equivalencies or heat led to TBSdeprotection (not shown). Reduction of 82 was also explored. Treatment with sodium borohydride, zinc borohydride, and SmI2 were all ineffective, giving rise to secondary alcohol 84, which could not be cyclized to butenolide 60. As a result, cyclization from the acid was tested (Scheme 2.10B). Following saponification of 82 to form 85, treatment with NaOAc in boiling Ac2O proceeded to form undesired spirocycle 86. A plausible mechanism involves intramolecular acylation of the enol tautomer of ketone in 85. Gratifyingly, treatment of acid 85 with SOCl2 resulted in formation of chlorolactone 87 (Scheme 2.10C). A plausible mechanism consistent with prior work involves ketone acylation of the acid chloride followed by trapping with chloride.20 The direct elimination of chloride was more challenging than other systems in the literature, where weak bases such as pyridine or triethylamine were sufficient. Opting for gold-induced chloride elimination conditions from Chida,51 silyl ether cleavage was observed (not shown). Moving to stronger bases, it was found that the elimination could be accomplished using lithium hexamethyldisilazide (LHMDS) in 71% yield (Scheme 2.11D). The respective sodium and potassium bases led to diminished yields (not shown). 30 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.10. A. Reductive approach to 60. B. Unexpected spirolactonization side reaction. C. Promising chlorolactone formation D. Fruitful elimination conditions. H EtO2C A N2 (1.5 equiv) Cu(acac)2 (1 mol%) TBSO Me OTMS O TBSO benzene, 90 °C, 3 h then 30 °C, 12 h Me 73 PPTS (3 equiv) CO2Et Me MeOH, 10 min, 23 °C OTMS Me TBSO OEt 83 82 NaBH4, SmI2 or Zn(BH4)2 OEt TBSO O Me Me H O O OH Me Me 60 84 B HO2C O LiOH (10 equiv) TBSO Me OEt Me THF/H2O (3:1) 22 °C, 16 h 82 quant. yield O O NaOAc (15 equiv) TBSO Me O TBSO Ac2O (neat) 150 °C, 6 h O Me Me O Me 86 67% yield 85 Ac2O −H2O Me O Me O O O O O Me HO taut. TBSO TBSO Me Me OH Me Me O TBSO SOCl2 (4.5 equiv) OH O TBSO DCM, 22 °C, 11 h Me 85 O Me Me Cl O 87 66% yield O Cl S Cl O TBSO O O Me Me S Cl −SO2 TBSO Me O O O Me Cl D TBSO Me O Me Cl 87 O LHMDS (3 equiv) THF, −78 °C, 4.5 h 71% yield O O TBSO O Me C Me Me 78% yield dr = 5 : 1 64% yield TBSO O Me TBSO O Me Me H 60 O O Me 31 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies The final optimized route to 60 is depicted in Scheme 2.10 below. The cycloproponation of the silyl enol ether in Scheme 2.10A could be avoided using a simple alkylation procedure with ethyl bromoacetate, shortening the synthesis by 3 steps (Scheme 2.11). This 6-step synthesis enabled multi-gram scale synthesis of butenolide fragment 60. Scheme 2.11. Optimized route to butenolide 60. Me O Ru NTs Cl HN OEt Ph Ph (S,S)-Ts-DENEB (1.25 mol%) O Me O Me NEt3/Formic Acid (1:1), 22 °C, 18 h TBSO O O LHMDS (3 equiv) THF, −78 °C, 4.5 h 71% yield 60 HO Me 85% yield >99% ee 71 Me Me H TBSCl (1.4 equiv) Imidazole (2.8 equiv) DMAP (0.2 equiv) TBSO DMF, 60 °C, 2 h O Me 99% yield 70 TBSO Me Me O Me Cl 87 O Br O (3.7 equiv) LHMDS (1.2 equiv) HMPA (2 equiv) O Me THF, −78 °C, 3 h DCM, 22 °C, 11 h 66% yield TBSO Me OH O Me 85 OEt O Me 82 O SOCl2 (4.5 equiv) TBSO Me 93% yield 69 O LiOH (10 equiv) THF/H2O (3:1) 22 °C, 16 h quant. yield 6 steps 2.3.5 Investigation of direct g-functionalization methods Upon optimization of the butenolide synthesis, exploration of g-functionalization methods could commence. Work by Shenvi and coworkers detailed a unique, butenolide heterodimerization enabled by electronic complementarity.21 Adapting Shenvi’s procedure, deprotonation of 60 with strong bases such as LDA and treatment with aldehyde 61 only led to a complex mixture with no detectible heterocoupling products formed by LCMS analysis (Scheme 2.12). We did, however, detect products corresponding to butenolide dimerization. Treatment of the lithium enolate of 60 and use of ZnI2 as an additive also led to no desired product, detection of dimerization masses in crude LCMS samples, and formation of a complex mixture. From these results, it became clear that the Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 32 lithium enolate of butenolide 60 engages too quickly in undesired side-reactions, even at cryogenic temperatures. A new strategy would be necessary for testing the coupling of fragments 60 and 61, given that they were now in hand. Scheme 2.12. Attempt at direct vinylogous aldol addition. LDA (1.1 equiv) then MeO O Br TBSO O Me Me H THF, −78 °C, 2 h 60 OR same conditions with ZnI2 (1.1 equiv) 2.4 O TBSO O O Me 61 Br Me HO 59 MeO instead, mass of butenolide dimerization detected THE VINYLOGOUS MUKAIYAMA ALDOL REACTION 2.4.1 Siloxyfuran formation The literature contains better precedent for g-functionalization of siloxyfurans rather than directly from butenolides. Classified as a type of vinylogous Mukaiyama Aldol reaction, siloxyfuran addition to aldehydes is well-studied and documented on relatively simple substrates.1,22 Siloxyfurans are thought to contain larger HOMO-coefficients at the g-position rather than the a-position and engage in a variety of g-functionalization reactions.1,23 While they are unique in reactivity when compared to lithium enolates of butenolides, some studies have also been able to tune the degree of a- to g-selectivity depending on the Lewis acid invoked.24 Whereas Shirahama’s seminal synthesis formed the C5-C6 bond using an intramolecular pinacol coupling, the respective intermolecular coupling remains underdeveloped. We hoped to leverage the use of the siloxyfuran as a Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 33 polarity reversal tactic. When synthesizing siloxyfuran 88, the methods of Newton and coworkers were helpful.25 Upon a brief base screen, it was revealed that use of NEt3 in Et2O provided 99% yield of 88 (Scheme 2.13). Key to the success of this reaction was the use of vigorous stirring and quality of TBSOTf. During the purification of the siloxyfuran, expeditious purification through phosphate-buffered silica is required. Depending on the level of HOTf present in the TBSOTf or length of the column used for purification, some acid-mediated hydrolysis back to the butenolide starting material (60) may be observed, resulting in yields generally ranging from 80-99%. Scheme 2.13. Silylation of butenolide (60) to the corresponding siloxyfuran (88). O TBSO Me O[Si] O Silylation Reagent (1.65 eq) Base (2.0 eq) H Me Solvent, 0 °C to 21 °C, 12 h O TBSO 60 Me Me 88 silylation reagent base solvent result TMSCl NEt3 CH2Cl2 < 5% conversion TESOTf NEt3 CH2Cl2 < 5% conversion TBSOTf EtN(iPr)2 Et2O 50% conversion TBSOTf LHMDS Et2O 50% yield, full conversion TBSOTf NEt3 Et2O 99% yield 2.4.2 Hit identification and reaction optimization Unfortunately, treatment of a stirring solution of siloxyfuran 88 and aldehyde 61 with canonical Lewis acids for this transformation led to substrate decomposition (Scheme 2.14, entries 1-3). Indeed, the siloxyfuran fragment 88 is more hindered than reported substrates for this reaction. Rarely do substrates contain substitution at the 5-position of Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 34 the furan. The presence of a bulky, all-carbon center in proximity to the desired position for reactivity also deems substrate 88 considerably more challenging. Nevertheless, screening a broad array of Lewis acids revealed a small amount of g-functionalized product 59 isolated from a reaction utilizing ZnBr2. When compared to ZnCl2, ZnI2, and Zn(OTf)2, ZnBr2 was the highest yielding (Scheme 2.14, entries 3-6). Switching to THF as solvent considerably increased the yield, likely due to the increased solubility of ZnBr2 in THF and the coordinating ability of THF when compared to CH2Cl2. At a reaction time of 7 h, the vinylogous Mukaiyama Aldol reaction formed 52% yield of the desired product, and the reaction was completed on 2.5 gram scale to afford greater than 2 grams of desired product (Scheme 2.14, entry 7). The reactivity was unique with ZnX2 salts. To date, no other Lewis acids attempted promoted the desired coupling reaction. Scheme 2.14. Vinylogous Mukaiyama aldol reaction optimization. O Me OMe Lewis acid (1.1 equiv) O TBSO OTBS O Me Me TBSO + Br 61 88 O −78 °C Me HO solvent, time 59 Br MeO entry Lewis acid time solvent yield (%) dr 1 BF3•OEt2 2h CH2Cl2 – – 2 TMSOTf 2h CH2Cl2 – – 3 SnCl4 2h CH2Cl2 – – 4 ZnCl2 2h CH2Cl2 11 5:1 5 ZnBr2 2h CH2Cl2 14 5:1 6 ZnI2 2h CH2Cl2 12 5:1 7 Zn(OTf)2 2h CH2Cl2 – – 8 ZnBr2 2h THF 40 5:1 9 ZnBr2 7h THF 52 8:1 One notable consideration throughout the optimization of this reaction was the diastereoselectivity. Throughout the optimization of this process, it became clear that the diastereoselectivity of the reaction was quite high at the fully substituted center (C5, Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 35 Scheme 2.15). Other diastereomers at the C5 have not been observed in this reaction (alkylation from the si face of the siloxyfuran). On the contrary, the diastereoselectivity of the secondary alcohol (C6) seemed to possess a temperature dependence. At higher temperatures, the diastereoselectivity decreased to the point where it was 1:1 at room temperatures, while at cryogenic temperatures, the diastereoselectivity was as high as 8:1 (Scheme 2.15). Scheme 2.15. Temperature dependence of the vinylogous Mukaiyama aldol reaction. O Me 2 TBSO 3 7 O OTBS 5 Me Me O + OMe 6 Br 61 88 ZnBr2 (1.1 equiv) 2 TBSO 3 5 temperature, Me HO THF, 2 h 59 O 7 6 Br MeO entry temperature diastereoselectivity yield (%) 1 −78 °C 5:1 40 2 0 °C 3:1 34 3 22 °C 1:1 26 4* −78 °C 8:1 52 * reaction was run for 7 h instead of 2 h NOESY analysis of the major diastereomer revealed a strong correlation between the hydrogen at C6 and C3, indicating they were in close proximity in the lowest energy conformation of the compound (Scheme 2.16A). Branching out from the key C6 center, strong NOESY correlations between the OH hydrogen and C2 were observed. This suggested that the reaction formed the wrong stereochemistry required for auriculatol A (49, Scheme 2.15B). These results were confirmed by crystallization of a downstream compound. 36 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.16. A. NOESY analysis of 59. B. Necessary epimerization of C6. A O O Me O 2 5 TBSO 3 Me H H 6 OH 7 MeO Br 180° H 6 2 Me Br TBSO 59 O O O Me HO 6 3 OH 59 Me OTBS 5 strong NOESY correlations strong NOESY MeO correlations B Me O 7 TBSO O C6 requires epimerization Br Me 59 MeO MeO HO Me H Me 6 OR 57 OMe H O H Me HO Me OH 6 H HO auriculatol A (49) 2.4.3 Stereochemical analysis Several mechanisms could be operative for this vinylogous Mukaiyama aldol reaction. A brief discussion of possible mechanisms is provided: it is possible that the siloxyfuran engages in a hetero-Diels–Alder (DA) reaction, followed by fragmentation to the observed product. Indeed, this is a precedented process for Lewis acid catalyzed DA reactions with aldehydes (Scheme 2.17A); although, this process is not documented for siloxyfuran dienes.26 In some hetero-DA papers, the “Mukaiyama aldol pathway” and the “hetero-DA pathway” have been tuned based on the identity of the Lewis acid.27 The next possibility is that the reaction proceeds through a closed transition state in a Cram-chelation model (Scheme 2.17B).29 Through activation of both the siloxyfuran and aldehyde, they may be brought in close proximity by ZnBr2. If a Cram-chelation model is in effect, Zn2+ would likely bind the Lewis basic oxygen that is a part of the 5-membered furan rather than the silyl-protected oxygen. This is due to the fact that silyl ethers are often thought to be too large for chelation models when compared to Bn or alkyl ethers, and Felkin–Ahn 37 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies selectivity has been shown to dominate.30 Though, there are exceptions to these rules,31 and a chelation model cannot be definitively ruled out. As drawn in Scheme 2.17B, there is a gauche interaction between the R group and the gem-dimethyl group in this model, which may deem this model unlikely. The third option, and perhaps most convincing, is an open transition state (TS) (Scheme 2.17C). This is what is suggested in prior reports of these types of reactions.1,22 Binding of the aldehyde to the Lewis acid lowers the LUMO, allowing engagement with the siloxyfuran in the key C-C bond-forming step.26 Scheme 2.17. Mechanisms for the vinylogous Mukaiyama aldol addition. A TBSO OTBS OTBS O Me Me Me Hetero DA 88 TBSO O O Br Me H O Me O fragmentation Br Me HO H Br O TBSO 89 59 MeO MeO 61 OMe B TBSO OTBS OTBS O Me Me H 88 H O R Br TBSO O Zn(II) O Me O TBSO Br Me HO O Me Me 59 MeO 61 OMe C TBSO OTBS OTBS O Me Me R 88 H O H Me TBSO LA Me O Br O O Me O TBSO Br Me HO 59 MeO 61 OMe 38 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Given that the reaction likely proceeds through an open transition state, we can construct a model to justify the observed diastereoselectivity. Approach of the aldehyde from the re face of the siloxyfuran may be due to the bulkiness of the beta OTBS ether. In the favored transition state, the hydrogen is closest to the bulkiest part of the siloxyfuran: the gem-dimethyl group. Due to sterics, it is believed the Lewis acid should chelate the face of the aldehyde opposite to the R group. We believe two transition states are possible for the disfavored transition state. In disfavored transition state 1, we suggest a gauche interaction between the bound Lewis acid and the OTBS group of the siloxyfuran. In a second interpretation, the hydrogen is kept pointed towards the bulky, gem-dimethyl group (disfavored transition state 2). In this case, it is believed that steric clash between the OTBS group and the LA group would be present. Scheme 2.18. Vinylogous Mukaiyama aldol transition state analysis: the favored transition state and two possible disfavored transition states. favored R OTBS O O O H Me TBSO LA Me O R Me TBSO OH H Me 59 disfavored transition state 1 O O R Me TBSO LA Me O Me 59 O R Me TBSO O OTBS O OTBS H disfavored transition state 2 H OH R TBSO LA O O H Me Me R Me TBSO Me 59 H OH Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.5 39 A-ENOLATE ARYLATION SUBSTRATE SYNTHESIS 2.5.1 Secondary alcohol protection Elaboration of product 59 was challenging. Unsurprisingly, treatment of 59 with strong base led to a retro-aldol reaction and isolation of a mixture of butenolide 60 with aldehyde 61 (Scheme 2.19, entries 1-3). Surprisingly, use of a variety of protecting group conditions were unsuccessful, even ones that avoided the use of strong bases (Scheme 2.19, entries 4-6). This is likely attributed to the steric hindrance of the secondary alcohol. In its lowest energy conformation, the alcohol likely sits buried underneath the butenolide. After some screening, it became clear that protection as the MOM ether provided optimal yields of 90 (Scheme 2.19, entry 7). Scheme 2.19. Difficult secondary alcohol protection. O Me O TBSO Br Me HO O Me 59 base reagent solvent, 𝚫 O TBSO Br Me O PG 90 MeO MeO base reagent solvent result 1 NaH BnBr THF retro-aldol 2 NaOtBu BnBr THF retro-aldol 3 LDA BnBr THF retro-aldol 4 Imidazole TBSCl, DMAP DMF NR 5 NEt3 TBSOTf CH2Cl2 NR 6 Pyridine TBSOTf CH2Cl2 NR 7 EtNiPr2 MOMCl DCE 86% yield entry 2.5.2 Chemoselective butenolide reduction Conjugate reduction of 90 was originally developed using a NEt3-NaBH4 mixture,32 but this reaction was difficult to scale-up (Scheme 2.20, entry 1). Moving onto conditions employing stoichiometric NiH (NiCl2 + NaBH4),33 though these conditions led to higher Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 40 yields and could be scaled up, they suffered from irreproducible yields due to competitive protodebromination (Scheme 2.20, entry 2). Eventually, conjugate reduction was improved using Buchwald’s catalytic CuH system,34 which delivered high yields of the product lactone 58 in excellent diastereoselectivity (dr > 20:1). Formation of the more cis-lactone over the trans-lactone is likely more energetically accessible. It is also possible that the TBS ether aids in blocking the re face of the butenolide on approach of CuH. Importantly, Stryker’s reagent35 did not react in this system (not shown). Scheme 2.20. Conjugate reduction of butenolide 90. O Me O TBSO Br Me O MOM O Me conditions TBSO O H Me O MOM Br 58 90 MeO MeO entry conditions 1* NEt3 (6 equiv), NaBH4 (3 equiv) 49% yield THF, 0 °C to 21 °C, 1 h dr > 20 : 1 2 ** 3 result NiCl2 • 6H2O (1.5 equiv), NaBH4 (1.1 equiv) 73% yield THF/MeOH, −50 °C to 0 °C, 1 h dr > 20 : 1 CuCl2 • 2H2O (5 mol%), (R)-tol-BINAP (5 mol%), 85% yield PMHS (6 equiv), NaOtBu (1.2 equiv), tBuOH (12 equiv) dr > 20 : 1 THF/DCM (3:1), 21 °C, 24 h * difficulty scaling ** difficulty yielding reproducable results Crystallization of product 58 could be completed by the slow evaporation of toluene. These data indicated that the NOESY analysis in Scheme 2.16A was correct in assigning the C5 and C6 stereochemistry from the vinylogous Mukaiyama aldol step. With rapid access to butyrolactone 58, future studies could focus on exploring the intramolecular a-enolate arylation. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 41 Scheme 2.21. Crystallization of 58. 2.6 Ni-CATALYZED INTRAMOLECULAR A-ENOLATE ARYLATION 2.6.1 Buchwald’s intermolecular a-enolate arylation of lactones Turning to the literature, we became interested in Buchwald’s disclosure of an intermolecular a-enolate arylation of lactones catalyzed by Ni-BINAP.36 These conditions used low loadings of Ni(COD)2 preligated with BINAP as the active catalyst species. The lactone enolate was generated from sodium hexamethyldisilazide (NaHMDS), while catalytic quantities of ZnBr2 were used to facilitate faster catalytic turnover. The reaction was compatible with both aryl chlorides and aryl bromides, albeit aryl chlorides seemed to be more general and higher yielding. Different ZnX2 salts were shown to boost the rate of reaction in catalytic quantities but hinder conversion in stoichiometric loadings. A variety of electron donating and electron withdrawing aryl halides were explored, with excellent yield and enantioselectivity. 42 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.22. Buchwald’s a-enolate arylation of lactones. prepared in-situ Ph Ph P Ni P Ph Ph (5 mol%) O R O + NaHMDS (2.3 equiv) ZnBr2 (15 mol%) ArCl or ArBr Tol/THF (3:1), 60 °C, 17-20 h O R O * Ar (2 equiv) representative scope: R = aryl, alkyl O O O Me O Me O O Me OMe O O O Me O Me Me O CO2Me O OMe from ArCl 95% yield 94% ee from ArCl 86% yield 96% ee from ArBr 33% yield 98% ee from ArBr 29% yield 99% ee from ArCl 76% yield 94% ee from ArCl 86% yield 97% ee from ArCl 58% yield 94% ee from ArCl 73% yield 90% ee CO2Me 2.6.2 Phosphine ligand modifications In an initial attempt to modify Buchwald’s conditions for an intramolecular reaction instead of an intermolecular reaction, the catalyst loading was changed to 10 mol% and the base loading was reduced to 1.3 equivalents. Under these conditions using (BINAP)Ni(COD), trace quantities of the desired arylation product were isolated with the remaining mass balance accounted for in recovered starting material (Scheme 2.23, entry 1). It was hypothesized that different monodentate phosphines could free up coordination sites on Ni and promote catalyst turnover, as many monodentate phosphines have proven to be competent ligands in the enolate arylation of ketones.37 While conversion was low with the alkyl phosphine tBuDavePhos, the conversion was better for RuPhos and DavePhos. On small scale, the yield for the DavePhos reaction exceeded 75% (Scheme 2.23, entry 4). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 43 Scheme 2.23. Initial exploration of Ni-catalyzed a-enolate arylation chemistry. O Me TBSO Me H Br TBSO Me Toluene/THF (2:1), 60 °C, 16 h O MOM 58 O cat. (10 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) O O H Me O MeO entry OMe MOM 57 cat. starting material (%) desired (%) 1 (COD)Ni(BINAP) 76 3 2 (COD)Ni(tBuDavePhos)2 74 2 3 (COD)Ni(RuPhos)2 31 8 4* (COD)Ni(DavePhos)2 0 79 * not reproducible or scalable PtBu2 PPh2 PPh2 rac-BINAP Me2N tBuDavePhos PCy2 PCy2 iPr O O iPr RuPhos Me2N DavePhos Upon scaling up this process, the selectivity of the reaction flipped to favor a new, unknown product in 51% yield, with only 2% desired product formation. In the 1H NMR of the new product (91), the presence of two methylene peaks corresponding to C10 obviated that a-functionalization had not occurred. 91 contained a C10 singlet that did not engage in splitting with the methine C-H at C1. It was initially thought that the species observed was protodebromination; however when 91 was compared to a previous isolation of protodebromination, the spectra did not match. LCMS analysis confirmed that 91 possessed the same mass as compound 57. This suggested that the unknown structure was the b-arylated product. In further support of this hypothesis, analysis of the HMBC data of 57 showed correlations between C20 and C11 but none present in the HMBC of compound 91 (Scheme 2.24). 44 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.24. Scale-up reveals a change in selectivity for b-arylation. 20 Me O O TBSO Me H Br O MOM 58 O Ni(COD)2 (10 mol%) DavePhos (17 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) 11 toluene, 60 °C, 16 h MeO No HMBC correlation X 20 O TBSO Me O OMe Me OMOM HMBC! 20 TBSO 11 + Me O H Me 11 O 51% yield MOM 2% yield 91 57 OMe Ultimately, the structure of 57 was confirmed via X-ray crystallography (Scheme 2.25). In this structure, the newly formed C9-C11 bond and the structure of the 5-5-7-6 tetracyclic structure could be verified in addition to the presence of the TBS ether, MOM ether, and methoxy-arene. Scheme 2.25. Crystal structure of 57. Surprised by the finding that scaling up of the conditions employing DavePhos as ligand led to b-arylation, we speculated the mechanism of the product’s formation. Starting with the productive pathway, product 57 could arise from oxidative addition into the aryl bromide, transmetallation from the Na or Zn enolate, and reductive elimination (Scheme 2.26A). In the undesired pathway, we thought that deviation in the mechanism could occur from the “key intermediate”. Instead of direct reductive elimination, b-hydride elimination 45 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies could install desaturation. Migratory insertion and reductive elimination could furnish 91 (Scheme 2.26B). Scheme 2.26. A. Productive catalysis mechanism. B. Posited mechanism for sideproduct formation. A O O TBSO Me O Me O TBSO H O Me MOM Me LnNi0 OMe H Br O MOM 58 57 reductive elimination MeO oxidative addition XZnO O Ln NiII O NiIILn TBSO OMe TBSO Me Br O H Me Me O Me OR MOM OMe key intermediate transmetallation O B O TBSO OMe Me Me OMOM O H NiIILn O O Me 91 O TBSO reductive elimination Me H LnNi0 OMe Br O MOM TBSO 58 Me Me OR MeO oxidative addition olefin insertion XZnO O O O Ln NiII H β-hydride elimination TBSO Me Me OR OMe O TBSO Me Ln NiII O H NiIILn TBSO OMe Me OR key intermediate Br Me Me O MOM OMe transmetallation Given the proposed mechanism, it was hypothesized that use of bidentate phosphine ligands could disfavor b-hydride elimination by occupying the requisite 46 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies coordination site required for the b-hydride elimination pathway; tuning the steric and/or electronic properties of the ligand could increase conversion and limit the formation of 91. It was ultimately found that using rigorously anhydrous toluene and THF, as prepared by Williams & Lawton,38 was necessary for high conversions. Under conditions utilizing rigorously anhydrous solvents, many bidentate ligands proved to be competent at forming 57 in great yields (Scheme 2.27). Scheme 2.27. Bidentate phosphines as ligands for nickel-catalyzed intramolecular aenolate arylation. cat. (10 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) O TBSO Me H Br TBSO Me Toluene/THF (2:1), 60 °C, 16 h O MOM 58 O O O Me O O TBSO H Me O Me OMe MOM α-arylation MeO OMe Me OMOM β-arylation 57 91 entry cat. starting material (%) 1 (COD)Ni(Me-DuPhos) 99 0 0 2 (COD)Ni(DCPE) 75 1 0 3 (COD)Ni(DCPB) 41 25 3 4 (COD)Ni(N-XantPhos) 13 53 17 5 (COD)Ni(DPPF) 12 57 8 6 (COD)Ni(tBuXantPhos) 12 63 5 7 (COD)Ni(DPPE) 12 73 8 8 (COD)Ni(XantPhos) 10 77 11 9 (COD)Ni(DPPP) 0 77 10 10 (COD)Ni(DPPP)* 5 77 10 α-arylation (%) β-arylation (%) * 200 mg scale Me PtBu2 PPh2 P Me Me Me Me Me O P Me P(NEt2)2 PPh2 Me O O Me Ph2P PtBu2 PPh2 Fe P(NEt2)2 Me Me-DuPhos Xanphos tBu-Xantphos PPh2 PCy2 PPh2 PPh2 PCy2 PPh2 DPPE DCPE DPPP N-Xantphos PPh2 PPh2 DCPB DPPF Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 47 These data proved that the nickel catalysis and specifically the inhibition of the bhydride elimination pathway was robust and could be conducted reproducibly for a wide variety of ligands – granted the caveat that use of specialty, anhydrous solvents was necessary, and the reaction itself was sensitive to quality of the glovebox atmosphere. The reaction was successfully scaled up to 200 mg scale using DPPP in a pressure flask without a drop in reaction yield, achieving an 11-step synthesis (LLS) of key tetracycle 57. Future investigation into the role of the DavePhos ligand in achieving good yields of b-arylation could be conducted. One explanation could be that the Lewis basic amine on DavePhos offers stabilizing dative interactions that facilitates in phosphine decoordination to a 16 e- Ni complex, capable of b-hydride elimination over reductive elimination from the “key intermediate”. Although this is speculative, it is reminiscent of work from the Newhouse group in the realm of carbonyl dehydrogenation and oxidative cycloalkenylations of ketones39,40 and could be leveraged as a complimentary approach to b-arylated products. More studies are required to test the generalizability of the reaction and the mapping of chemical space when targeting b-arylation over a-arylation – these were to be considered outside of the scope of this work – and could be of interest in future work. 2.6.3 Other ligands A control reaction to test the background reactivity of Ni(COD)2 in the absence of phosphine ligand revealed the desired product was isolated in good yield; this result was both reproducible and scalable (Scheme 2.28). 48 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.28. Phosphine leave-out experiment. O Me O TBSO Me H Br O MOM 58 MeO Ni(COD)2 (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Toluene/THF (2:1), 60 °C, 16 h O O TBSO Me O H Me O TBSO O OMe MOM α-arylation Me OMe Me OMOM β-arylation 57 91 78% yield 6% yield Generally, a combination of factors including cone angle, bite angle, and stereoelectronic properties may enhance a ligand’s efficiency in catalysis. These attributes have been intensely documented in the literature.41,42 What was surprising is that olefin ligands are electron-deficient when compared to phosphine ligands. At the time, it was believed that oxidative addition would not be energetically accessible without strongly sdonating ligands; it was, perhaps naively assumed that the background reactivity of unligated Ni(COD)2 would not effect the outcome of the reaction. This result opened possibility to explore catalysts broader in scope, ligated by olefins, containing different electron counts, and possessing different stereoelectronic properties. Many Ni(0) catalysts and precatalysts have been recently reported in the literature, including Mongomery’s original report of NHC-ligated Ni(0) catalysts for C-C and C-N bond formation43 and Cornella’s Ni(0) stillbene (stb) catalysts44 (Scheme 2.29). Doyle’s air-stable commercially available TMEDA-ligated Ni(II) catalyst capable of insitu reduction to Ni(0) simply by heating45 and Engle’s commercially available nickel precatalysts46,47 were also great options to explore. If the reaction did not require phosphine ligands, then the realm of possible opportunities for innovation could be expanded. Use of different precatalysts with or without phosphine ligands had the potential to catalyze the reaction. A simple leave-out experiment had far-reaching implications. 49 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Scheme 2.29. Some recently reported Ni(0) precatalysts. O N Mes Mes N Ni tBu (IMes)Ni(tBufumarate)2 Montgomery 2018 Ph Ph N N MeO Ar Ph Ni Ar Ar OMe Ph Ph Ar Ni Ph Ph OPh PhO O O (IPr*OMe)Ni(phenylacrylate)2 Montgomery 2018 Me Me O Ni(COD)(DQ) Schrauzer, 1962 Engle 2022 CO2tBu tBuO2C Ph Me Ni CO2tBu tBuO2C Me Ni(tBustb)3 Cornella 2020 Me Me N Ar O Ph S Ni Cl N Me Me (TMEDA)Ni(o-tolyl)Cl Doyle 2015 Ph Ph Ni Ph Ni(COD)(TSO-Ph) Engle 2022 O tBu Ni tBu O Ni(COD)(tBu-DQ) Engle 2022 To fully understand the high yielding result without phosphine ligand, a variety of different ligands and precatalysts were tested to probe the reactivity. Up until this point, all reactions were setup the way Buchwald had described.36 Ni(COD)2 was preligated with phosphine ligand before being added to a solution of ArCl or ArBr, ZnBr2, and the lactone enolate. We wondered if the preligation was necessary, and if the procedure involving addition of all solids to the starting material, followed by solvent at the end, would work. Changing the order of addition and using 1,3-Bis(dicyclohexylphosphino)propane (DCPP) as ligand in slight excess (1.5 equivs. with respect to Ni(COD)2), indeed, no reaction was observed (Scheme 2.30, entry 1). With this new method for reaction setup, most nickel catalysts and precatalysts were inactive (Scheme 2.30, entries 2-6). In the literature, it has been shown that addition of electron-deficient olefins could help with catalyst stability and faster reductive elimination.48,49 Use of phenyl acrylate, 4-CF3 styrene, dimethylfumarate, and benzonitrile all led to no reaction (Scheme 2.30, entries 7-10); although, it is unclear if the electron-deficient olefin was able to ligate to nickel given that the reaction was setup 50 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies by adding all components and then solvent last. The only-phosphine ligated complex that seemed to work with the new order of addition was Ni(PPh3)4 in 24% yield (Scheme 2.30, entry 11). Scheme 2.30. New order of addition with no phosphine preligation to Ni(COD)2. O Me O TBSO H Me Br O O O TBSO Me Tol/THF (2:1, 31 mM), 60 °C, 16 h MOM 58 cat. (5 mol%) DCPP (7.5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) O H Me O TBSO O Me OMe MOM α-arylation MeO OMe Me OMOM β-arylation 57 91 cat. additive (12 mol%) starting material (%) α-arylation (%) β-arylation (%) 1 Ni(COD)DQ - 42 - - 2 (COD)Ni(TSO-Ph) - 81 - - 3 (IMes)Ni(tBufumarate)2 - 69 - - 4 (IPr*OMe)Ni(phenyl acrylate)2 - 55 - - 5 (TMEDA)Ni(o-tolyl)Cl - 62 - 4 6 Ni(tBustb)3 - 23 - - 7 Ni(COD)2 phenyl acrylate 40 - - 8 Ni(COD)2 4-CF3 styrene 60 - - 9 Ni(COD)2 dimethylfumarate 60 - - 10 Ni(COD)2 benzonitrile 62 7 - 11 Ni(PPh3)4 - 40 24 4 entry The data in Scheme 2.30 are in stark contrast to the experimental results obtained without phosphine ligand (Scheme 2.31). The reaction underwent higher conversions with many different catalysts. Although (COD)Ni(TSO-Ph) and (IPr*OMe)Ni(phenylacrylate)2 only led to trace yields, use of Cornella’s tBu stillbene catalyst led to 12% yield, with minimal b-arylation (Scheme 2.31, entries 1-3). Compared to the (TSO-Ph)Ni(COD), use of (COD)Ni(tBu-DQ) led to an increase in yield to 30% (Scheme 2.31, entry 4). Doyle’s Ni(II) precatalyst led to a 44% yield of a-arylation (Scheme 2.31, entry 5). Both Ni(COD)2 and Ni(COD)DQ catalyze the intramolecular a-enolate arylation in high yields (Scheme 2.31, entries 6-7). In the case of Ni(COD)DQ, we believe the use of the more electrondeficient duroquinone ligand with respect to cyclooctadiene promotes faster reductive 51 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies elimination, prohibiting b-hydride elimination and therefore the formation of the b-arylated product. Scheme 2.31. Got ligand? Phosphine-ligand free Ni(0) catalysts for a-enolate arylation. O TBSO Me H Br O 58 cat. (5 mol%) TBSO NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Me Tol/THF (2:1, 31 mM), 60 °C, 16 h MOM O O O Me O H Me O TBSO O OMe MOM α-arylation MeO OMe Me Me OMOM β-arylation 57 91 cat. starting material (%) α-arylation (%) β-arylation (%) 1 (COD)Ni(TSO-Ph) 77 2 0 2 (IPr*OMe)Ni(phenyl acrylate)2 85 4 0 3 Ni(tBustb)3 40 12 1 4 (COD)Ni(tBu-DQ) 52 30 0 5 (TMEDA)Ni(o-tolyl)Cl 32 44 6 6 Ni(COD)2 0 78 6 7 Ni(COD)DQ 0 80 0 entry These data suggest that Ni(COD)2 had been catalyzing the reaction when phosphine ligands were used (Scheme 2.27) given that Ni(COD)2 and the bidentate phosphine were used in a 1:1 ratio. This is evident when thinking about the equilibrium of Ni(COD)2 with phosphines, as studied by Mori.50 Using PPh3, full exchange with COD was only observed after heating for prolonged periods at 80 °C. In our method for phosphine ligation to Ni(COD)2, the equilibrium may lie slightly to the left, leaving phosphine ligand-free Ni(COD)2 to catalyze the reaction while phosphine-ligated catalyst is inert. These conclusions are speculations and have not been confirmed. 52 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.6.4 Final control studies Some control experiments elucidated what elements of the reaction were required (Scheme 2.32). Indeed, ZnBr2 and heat were required for the reaction, which exhibited sluggish reaction profiles and recovery of starting material (Scheme 2.32, entries 2-3). The reactions were scalable and could be setup in the glovebox or using Schlenk technique (Scheme 2.32, entries 4 & 6). Scheme 2.32. Control studies in the phosphine-ligand free Ni-catalyzed a-enolate arylation. O TBSO Me H Br O 58 2.7 cat. (5 mol%) TBSO NaHMDS (1.6 equiv) Me ZnBr2 (15 mol%) Tol/THF (2:1, 31 mM), 60 °C, 16 h MOM O O O Me O O TBSO H Me O OMe MOM α-arylation MeO OMe Me Me OMOM β-arylation 57 91 deviation α-arylation (%) β-arylation (%) 5 mg — 78 6 5 mg No ZnBr2 5 1 Ni(COD)2 5 mg 21 °C 3 1 4 Ni(COD)2 25 mg scale 78 8 5 Ni(COD)DQ 5 mg — 80 0 6 Ni(COD)DQ 25 mg scale 79 0 entry cat. scale 1 Ni(COD)2 2 Ni(COD)2 3 CONCLUDING REMARKS This chapter introduces a model system used towards the synthesis of auriculatol A – first through explanation of the retrosynthetic logic and second through the forward synthesis of key butenolide building block 60 and aldehyde 61. While the aldehyde fragment, 61, was straightforward, synthetic access to 60 was far more challenging. Strategies attempted to form 72 through aldol condensation chemistry from compound 69 and Mukaiyama aldol reactions from 73. While these were unsuccessful strategies, use of a Ueno-Stock bromoacetal 79 was applied in the development of a 9-step butenolide Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 53 fragment 60 synthesis. Later, a 6-step synthesis of 60 was developed, which utilized a Noyori transfer hydrogenation reaction and chlorinative cyclization-elimination sequence. Central to this strategy was thinking about direct cyclization approaches from compound 82 rather than superfluous oxidative or reductive chemistry. Upon access to both model system fragments, the vinylogous Mukaiyama aldol addition reaction was developed. Key to this development was the use of Zn(II) Lewis acids and specifically the use of ZnBr2. At cryogenic temperatures, the reaction could be conducted on gram-scales, providing synthetic access to gram-quantities of aldol product. Stereochemical analysis and transition-state analysis were described in detail. It is likely that the reaction proceeds through an open transition-state. The development of a Nicatalyzed a-enolate arylation reaction was also explored in detail. Originally, adapting conditions from Buchwald’s intermolecular a-enolate arylation of lactones employing bidentate phosphines as ligands, and later, use of olefin ligands. Specifically, the development of an Ni-catalyzed a-enolate arylation reaction to form the central 7membered ring in auriculatol A was discovered using Ni(COD)dppp, Ni(COD)2, and Ni(COD)DQ catalyst systems, ranging in yields from 77–80%. Taken together, this chapter provides a compelling demonstration of a model system for the synthesis of auriculatol A entry point for other grayanane ditepenoid natural products. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.8 54 EXPERIMENTAL SECTION Preparation of 1-bromo-4-methoxy-2-vinylbenzene (63): MeO O Br 62 (Ph3PMe)Br (1.2 equiv) KOtBu (1.2 equiv) MeO THF, 0 °C to 21 °C, 8 h 50% yield 69% brsm Br 63 Styrene 63 was prepared according to the procedure described by Phumjan et. al.52 KOtBu (6.8 g, 60.4 mmol, 1.3 equiv) was added to a stirred solution of CH3PPh3Br (21.6 g, 60.4 mmol, 1.3 equiv) in dry THF (10 mL/mmol) at −78°C under a N2 atmosphere. The reaction was warmed to room temperature slowly, stirred for 30 minutes, cooled to −78 °C again, and charged with the corresponding benzaldehyde 62 (10.0 g, 46.4 mmol, 1.0 equiv) in THF. The reaction was stirred at −78 °C, warmed to room temperature, stirred for 3 hours, and quenched with H2O. The aq. layer was extracted with EtOAc (3 x 100 mL), and the organic phase was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography on silica (3% EtOAc/hexane) to obtain 1-bromo-4-methoxy-2vinylbenzene (63) (4.9 g, 50% yield). Characterization data is consistent with that reported in the literature.52 MeO Br 63 1 H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 7.02 (dd, J = 17.6, 11.3 Hz, 1H), 6.71 (dd, J = 8.7, 3.1 Hz, 1H), 5.69 (d, J = 17.3 Hz, 1H), 5.37 (dd, J = 10.9, 1.2 Hz, 1H), 3.82 (s, 3H). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 55 Preparation of 2-bromo-5-methoxybenzeneethanol (64): MeO OH Br2 (1 equiv) MeO OH DCM, 22 °C, 1 h 65 Br 64 99% yield 2-(3-Methoxyphenyl)ethanol (65) (4.92 g, 32.3 mmol, 1 equiv.) was dissolved in 323 mL of CH2Cl2 and cooled to 0 °C. To the solution was added dropwise bromine (1.66 mL, 32.3 mmol, 1 equiv.). After stirring for 5 h at 0 °C, an NMR aliquot was taken for analysis to ensure complete conversion. Following NMR aliquot, the reaction was quenched with 10% sodium metabisulfite (300 mL), extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were washed with brine (250 mL) and dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude residue. The crude residue was columned using a gradient column 30-40% EtOAc/hexanes to provide 2-bromo-5-methoxybenzeneethanol (64) (7.47 g, 99%). The characterization of this compound is consistent with that reported in the literature.5 MeO OH Br 64 1 H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.1 Hz, 1H), 6.79 (d, J = 6.5 Hz, 2H), 3.87 (t, J = 6.5 Hz, 2H), 3.81 (s, 3H), 2.86 (t, J = 6.5 Hz, 2H). Preparation of aldehyde 61. MeO OH Br 64 DMP (1 equiv) O MeO DCM, 22 °C, 1 h 79% yield Br 61 Dess-Martin periodinane (10.3g, 24.2 mmol, 1 equiv) was added to a three neck round bottom flask containing 225 mL CH2Cl2 under N2 atmosphere. The resulting solution was Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 56 stirred for 3 minutes. The starting material (5.60 g, 24.2 mmol) was added to the resulting solution, and it was stirred for 1 hour. The reaction mixture was subjected to vacuum filtration over silica gel. The filtrate was collected, evaporated, and reduced under negative pressure to afford the product aldehyde as a yellowish-green oil (4.4 g, 79% yield). O MeO Br 61 TLC (20% EtOAc/Hexanes): Rf 0.37 (yellow then grey with p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.74 (t, J = 1.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 6.80 – 6.71 (m, 2H), 3.82 (d, J = 1.8 Hz, 2H), 3.79 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 198.39, 159.31, 133.71, 128.47, 117.48, 115.41, 115.07, 55.65, 50.82. FTIR (Neat, NaCl, thin film): 3428, 2938, 2905, 2936, 1723, 1595, 1475, 1314, 1242, 1162, 1054, 1025, 814 cm-1. HRMS (ESI): calc’d for [M+H]+ 227.9780, found 227.9788. Preparation of 2,2-dimethylcyclopenta-1,3-dione (71). KOH (1.05 equiv) MeI (1.1 equiv) O O Me Dioxane/H2O (3.3 : 1) 50 to 100 °C, 16 h 36% yield O Me O Me 71 A 2 L round bottom flask was charged with 2-methylcyclopentane-1,3-dione (75.0 g, 669 mmol, 1.0 equiv), 731 mL of a 3:1 mixture of 1,4-dioxane/H2O (562 mL 1,4-dioxane, 169 mL H2O, 0.915 M), and a magnetic stir bar. The resulting suspension was stirred at room temperature for 15 min. KOH (39.4 g, 1.05 equiv) was added, stirred for 2 min, then iodomethane (104 g, 45.8 mL, 736 mmol, 1.1 equiv) was added. A small amount of water Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 57 and dioxane (<50 mL) were used to rinse the KOH that stuck to the sides of the neck of the flask down. The flask was fitted with a reflux condenser, and a Keck clamp was fitted to secure the reflux condenser. The mixture was heated from 50 °C to 100 °C and stirred for 15 h. After cooling to room temperature, the crude reaction mixture was poured into 200 mL of H2O and then extracted with Et2O (8 x 300 mL). The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc in hexanes) and then recrystallized from hot hexanes upon cooling to 0 °C to provide 2,2-dimethylcyclopentane1,3-dione as a white crystalline solid (32.7 g, 36% yield). O Me O Me 71 TLC (50% EtOAc/Hexanes): Rf 0.58 (p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 300 MHz): δ 2.80 (s, 4H), 1.15 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 216.49, 52.77, 34.82, 20.38. FTIR (CH2Cl2, NaCl, thin film): 2976, 1722, 1398, 1282, 1082, 792 cm-1. HRMS (ESI): calc’d for [M+H]+ 126.06753, found 126.06750. Melting Point: 42-44 °C Preparation of (+)-3-hydroxy-2,2-dimethylcyclopentan-1-one (70) via Corey-BakshiShibata Reduction (not recommended). (R)-oxazaborolidine (0.5 equiv) Catecholborane (1.4 equiv) Et2NPh (0.5 equiv) O Me O Me 71 Tol, −60 °C, 2 h 45% yield 83% ee (R)-oxazaborolidine H Ph HO Me O Me N O B Me 70 Ph Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 58 A dried 1L flask was charged 2,2-dimethylcyclopentanedione 71 (20 g, 159 mmol, 1.00 equiv) and (R)-oxazaborolidine 22.0 g, 79.3 mmol, 0.50 equiv) and evacuated and backfilled with nitrogen. Toluene (500 mL) was added in, followed by PhNEt2 (12.6 mL, 79.3 mmol, 0.50 equiv). In order to dissolve of the (R)-oxazaborolidine, the reaction mixture was heated to 50 °C for 20 min. Then, the reaction mixture was cooled to –60 °C with a chloroform/dry ice bath. A solution of catecholborane (24.9 g, 208 mmol) as a 4 M solution in toluene was added with syringe pump over 2 h. The solution was prepared by taking 30 g of catecholborane (d = 1.12, so 26.8 mL = 250.2 mmol) and dissolving it in 35.7 mL of toluene. The reaction was stirred for 30 min at the same temperature and then quenched with MeOH (60 mL). The mixture was allowed to warm to room temperature and diluted with Et2O (400 mL). Then, saturated aq. NaHCO3 (200 mL) and 3 M NaOH aqueous solution (200 mL) were added to the flask. The mixture was stirred vigorously for 1 h. Vigorous stirring is very important to ensure decomposition of the leftover oxazaborolidine ligand. The mixture was loaded into a separatory funnel and the layers were separated. The aqueous phase was extracted with Et2O (3 x 250 mL). The combined organic layers were washed with H2O (400 mL), 0.5 M HCl aqueous solution (160 mL), and brine and dried over Na2SO4. Then, the solvent was removed in vacuo. The resulting solution was loaded onto a 2 L column, which was filled 1/3 with silica and subjected to a gradient 20 to 25% EtOAc/Hex and held at 25% until it all is eluted. Rotatory evaporation afforded 70 as a clear oil (9.10 g, 45% yield). Derivatization by benzoylation of the resultant secondary alcohol showed that the compound was formed in 83% enantiomeric excess by supercritical fluid chromatography (S3C1 05MIN10, see below). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 59 HO Me O Me 70 TLC (15% EtOAc/Hexanes): Rf 0.10 (p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 4.07 – 4.02 (m, 1H), 2.51 – 2.41 (m, 1H), 2.31 – 2.19 (m, 2H), 1.96 – 1.86 (m, 1H), 1.03 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 221.23, 78.35, 50.18, 34.27, 27.84, 22.29, 16.93. FTIR (Neat, NaCl, thin film): 3444, 2967, 1467, 1459, 1406, 1382, 1288, 1105, 1079, 1062, 990, 968, 888 cm-1. HRMS (ESI): calc’d for [M+H]+ 128.08318, found 128.08294. [a]D23 : +9.3 (c 1.0 in CHCl3) Preparation of (+)-3-hydroxy-2,2-dimethylcyclopentan-1-one (70) via Noyori Transfer Hydrogenation (recommended). (S,S)-Ts-DENEB (S,S)-Ts-DENEB (1.25 mol%) O Me O Me 71 NEt3/Formic Acid (1:1), 22 °C, 18 h 85% yield 99% ee Me HO Me O Me 70 O Ru NTs Cl HN Ph Ph To a flame-dried 250 mL flask was added freshly distilled triethylamine (29.3 mL). Distilled formic acid (30 mL) acid was slowly added dropwise at 0 °C. In a nitrogen filled glovebox, a second flame-dried 250 mL round bottom flask was charged with 2,2dimethyl-1,3-cyclopentadione 71 (15.0 g, 119 mmol, 1.0 equiv.) and (S,S)-Ts-DENEB (966 mg, 1.49 mmol, 1.25 mol%). A Teflon coated stir bar was then added in, and the flask was sealed with a rubber septum. The flask was removed from the glovebox. The viscous Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 60 solution of formic acid and triethylamine was transferred to the reaction flask via cannulation for a final concentration of 2 M. The reaction was stirred for a total of 18 h then quenched by addition of water (200 mL) and extracted with EtOAc (3 x 250 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL). The organic layers were dried over Na2SO4, filtered and then concentrated under reduced pressure. The crude material was purified via flash column chromatography (SiO2, 40% to 50% EtOAc/Hexanes gradient) to afford 70 as a colorless oil (13.0 g, 85% yield). Spectral data were in agreement with literature values.53 Enantioselectivity was measured in the subsequent step following benzoyl protection as 99% ee. A racemic standard of (±)-70 was prepared using previously reported methods.54 Experimental note: Formic acid (40 mL) was freshly distilled over boric anhydride (20 g) prior to use. HO Me O Me 70 TLC (15% EtOAc/Hexanes): Rf 0.10 (p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 4.07 – 4.02 (m, 1H), 2.51 – 2.41 (m, 1H), 2.31 – 2.19 (m, 2H), 1.96 – 1.86 (m, 1H), 1.03 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 221.23, 78.35, 50.18, 34.27, 27.84, 22.29, 16.93. FTIR (Neat, NaCl, thin film): 3444, 2967, 1467, 1459, 1406, 1382, 1288, 1105, 1079, 1062, 990, 968, 888 cm-1. HRMS (ESI): calc’d C7H11O2 for [M+H]+ 128.08318, found 128.08294. [a]D23 : +9.3 (c 1.0 in CHCl3) 61 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Preparation of (S)-2,2-dimethyl-3-oxocyclopentyl benzoate (81). O HO To BzCl (5 equiv) NEt3 (5 equiv) Me Me DCM, 22 °C, 12 h 70 14% yield (+)-3-hydroxy-2,2-dimethylcyclopentan-1-one O BzO Me Me 81 (70) (5 mg, 39 umol) in dichloromethane (150 uL, 260 mM) was added triethylamine (27 uL, 195 umol, 5 equiv) at 0 °C. Then, benzoyl chloride (23 uL, 195 umol, 5 equiv) was added, and the reaction was warmed to room temperature over 2 hours. After stirring for 10 more hours, sodium bicarbonate (300 uL) was added, and the reaction was extracted with Et2O (3 x 150 uL). The crude mixture was purified by preparatory TLC (20% EtOAc in Hex) to provide 81 (14% yield). The enantiomeric excess was determined to be 99% by chiral SFC (IC3, 2.5 mL/min, 5% IPA in CO2, λ = 245 nm): tR (major) = 2.76 min, tR (minor) = 3.02 min. O BzO Me Me 81 TLC (20% EtOAc/Hexanes): Rf 0.44 (UV, p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 8.01 (dd, J = 8.4, 1.4 Hz, 2H), 7.61 – 7.55 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.41 – 5.34 (m, 1H), 2.56 – 2.36 (m, 3H), 2.16 – 2.05 (m, 1H), 1.14 (d, J = 3.8 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 219.82, 165.95, 133.39, 129.73, 128.64, 80.48, 49.55, 34.30, 25.63, 22.78, 17.90. FTIR (Neat, NaCl, thin film): 2947, 2921, 1744, 1720, 1272, 1110 cm-1. HRMS (ESI): calc’d for C14H19O2 [M+H]+ 233.1172, found 233.1170. SFC Method: S3C1 05MIN10 [a]D23 : +10.1 (c 1.0 in CHCl3) Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 62 SFC data for racemate 81: SFC data for enantioenriched 81: Preparation of (+)-3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylcyclopentan-1-one (69). TBSCl (1.4 equiv) Imidazole (2.8 equiv) DMAP (0.2 equiv) HO Me O Me 70 DMF, 2 h, 60 °C 98% yield TBSO Me O Me 69 A 250 mL round bottom flask was charged with (+)-3-hydroxy-2,2dimethylcyclopentan-1-one 70 (9.1 g, 71.0 mmol, 1.0 equiv), DMF (47.3 mL, 1.5 M), and a magnetic stir bar. To this solution, Imidazole (13.5 g, 199 mmol, 2.8 equiv), DMAP (1.73 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 63 g, 14.2 mmol, 0.2 equiv), and TBSCl (15.0 g, 99.4 mmol, 1.4 equiv) were sequentially added. The flask was fitted with a reflux condenser and stirred at 60 °C for 2 h. After cooling to room temperature, the crude reaction mixture was charged with ammonium chloride (200 mL). The mixture was extracted with a 1:1 solution of Et2O in hexanes (200 mL x 3), then hexanes (100 mL x 2). The organic layers were washed with brine (200 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (SiO2, 0 to 5% EtOAc/Hexanes gradient) to afford 69 (16.9 g, 98% yield). TBSO Me O Me 69 TLC (15% EtOAc/Hexanes): Rf 0.52 (p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 3.95 (t, J = 5.2 Hz, 1H), 2.48 – 2.39 (m, 1H), 2.24 – 2.07 (m, 2H), 1.87 – 1.79 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 221.65, 78.75, 50.52, 34.38, 28.53, 25.86, 22.24, 18.18, 17.65, -4.41, -4.81. FTIR (Neat, NaCl, thin film): 2958, 2930, 2958, 2887, 2857, 1744, 1470, 1383, 1254, 1085, 878, 776 cm-1. HRMS (ESI): calc’d for C13H27O2Si [M+H]+ 242.16966, found 242.16954. [a]D23 : + 28.0 (c 1.0 in CHCl3) Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 64 Preparation of (+)-3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylcyclopenten-1-one (76). IBX (3 equiv) NMO • H2O (3 equiv) TBSO Me O Me DMSO, 80 °C, 12 h 69 74% yield TBSO Me O Me 76 TBS Ketone 69 (16.9 g, 69.7 mmol) was dissolved in DMSO (700 mL, 0.1 M). IBX (see preparation of IBX procedure below, 58.6 g, 209 mmol, 3.0 equiv) was added, followed by NMO • H2O (24.5, 209 mmol, 3.0 equiv). The reaction apparatus was heated to 80 °C. After 12 hours, the reaction was cooled to 0 °C and ½ sat. aq. NaHCO3 (500 mL) was added, at first dropwise (be careful, as a large amount of bubbling was observed). 300 mL of EtOAc was added, then the reaction mixture was loaded into a 2 L separatory funnel, and the organic phase was separated out. The resulting aqueous layer was extracted with EtOAc (300 mL x 4). The combined organic layers were washed with sat. aq. NaHCO3 (500 mL), then washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure by rotary evaporation. Column chromatography with 10% EtOAc in hexanes afforded (+)-3-((tert-butyldimethylsilyl)oxy)-2,2- dimethylcyclopenten-1-one 76 (12.4 g, 74%) as a pale-yellow oil along with 5% starting material, which was carried forward to the next step. TBSO Me O Me 76 TLC (15% EtOAc/Hexanes): Rf 0.53 (p-anisaldehyde, KMnO4, UV). 1 H NMR (CDCl3, 400 MHz): δ 7.30 (dd, J = 5.6, 2.3 Hz, 1H), 6.13 (d, J = 6.6 Hz, 1H), 4.50 (s, 1H), 2.35 (s, 1H), 1.12 (s, 3H), 1.00 (s, 3H), 0.92 (s, 9H), 0.13 (d, J = 4.8 Hz, 6H). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 13 65 C NMR (CDCl3, 101 MHz): δ 212.02, 161.66, 131.92, 80.12, 49.00, 25.90, 22.65, 21.16, 18.31, -4.51, -4.61. FTIR (Neat, NaCl, thin film): 2956, 2858, 1716, 1464, 1255, 1113, 877, 777 cm-1. HRMS (ESI): calc’d for [M+H]+ 241.1619, found 241.1621. Preparation of IBX: O oxone OH (1.46 equiv.) I H2O, 75 °C, 3 h 97% yield O O I OH O oxone (2.0 equiv.) O H2O, 75 °C, 3 h 90% yield I O OH IBX Procedure was adapted from Frigerio and coworkers.45 A two-liter three-necked round bottom flask equipped with a mechanical stirrer was charged with deionized water (975 mL), oxone (271 g, 442 mmol, 1.46 equiv.), and 2iodobenzoic acid (75 g, 302 mmol, 1.0 equiv.). The reaction was heated to 75 °C over 30 min and vigorously stirred for 3 h. The reaction was cooled to 0 °C and stirred for 1 h 30 min under mild agitation. The crude reaction mixture was filtered and the solid was washed with ice-cold water (6 x 150 mL) and acetone (2 x 150 mL) to afford 63.2 g of di-oxidized product (97%) and then put directly into the next step. NMR (DMSO-d6) revealed that the di-oxidized product was formed. The di-oxidized product (63.2 g, 239 mmol, 1 equiv.) was added into a 2L and setup to a mechanical stirrer. To the RBF was added deionized water (772 mL, 310 mM), and oxone (147 g, 479 mmol, 2 equiv.). The reaction was heated to 75 °C over 30 min and vigorously stirred for 3 h. The reaction was cooled to 0 °C and stirred for 1 h 30 min under mild agitation. The crude reaction mixture was filtrated and the solid was washed with ice-cold water (6 x 150 mL) and acetone (2 x 150 mL) to afford 60.0 g (90% yield) of IBX. Full characterization data is consistent with that in the literature.45 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 66 O O I OH dioxidized product 1 H NMR (500 MHz, DMSO) δ 8.03 (s, 1H), 8.00 (dd, J = 7.5, 1.5 Hz, 1H), 7.95 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 7.83 (dd, J = 8.1, 1.0 Hz, 1H), 7.69 (td, J = 7.3, 1.0 Hz, 1H). O O I O OH IBX 1 H NMR (500 MHz, DMSO) δ 8.13 (d, J = 7.9 Hz, 1H), 8.05 – 7.96 (m, 2H), 7.83 (t, J = 7.3 Hz, 1H). Preparation of silyl enol ether 73. LHMDS (1.5 equiv) then TMSCl (1.5 equiv) TBSO Me Me O 69 THF, 0 °C, 2 h 91% yield TBSO Me Me OTMS 73 To a stirred solution of LHMDS (1 M in THF, 12.4 mL, 12.4 mmol) in THF (33 mL) was added dropwise 69 (2 g, 8.25 mmol) in THF (8 mL) at −78 ºC under N2, and the reaction mixture was stirred for 1 h at –78 ºC. To the mixture was added dropwise TMSCl (1.6 mL, 12.6 mmol) at 0 ºC, and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with cooled sat. NaHCO3 aqueous solution and extracted with hexanes (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. Column chromatography in pure hexanes yielded 73 (118 mg, 91% yield) of a clear oil. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 67 TBSO Me Me OTMS 73 TLC: (100% Hexanes): Rf 0.38 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 4.33 (dd, J = 3.0, 1.9 Hz, 1H), 3.88 (t, J = 7.2 Hz, 1H), 2.32 (ddd, J = 14.2, 7.4, 3.0 Hz, 1H), 2.04 (ddd, J = 14.2, 7.1, 1.9 Hz, 1H), 0.94 (s, 3H), 0.89 (d, J = 3.6 Hz, 12H), 0.19 (s, 9H), 0.04 (d, J = 3.2 Hz, 6H). 13 C NMR (CDCl3, 101 MHz: δ 159.52, 95.64, 79.30, 46.13, 35.49, 25.99, 24.24, 18.61, 18.25, 0.22, -4.29, -4.73. FTIR (Neat, NaCl, thin film): 2957, 2857, 1637, 1253, 1104, 893, 841 cm-1. HRMS (ESI): N/A, does not ionize (Silyl enol ether hydrolyzes on HRMS column). Preparation of ketoester 72. O H OEt O 68 H OH O DABCO (1.2 equiv) TBSO Me Me 69 O toluene, 21 °C, 16 h 24% yield TBSO Me Me O OEt 72 Cyclopentanone (69) (10.3 g, 42.5 mmol) was added to a flame dried single neck round bottom flask (100 mL) followed by anhydrous toluene (21.2 mL, 0.2 mM) at room temperature. To this mixture DABCO (572 mg, 5.1 mmol, 1.2 equiv) was added slowly over 10 minutes at room temperature, followed by ethyl glyoxylate (68, 50% solution in toluene, 842 uL, 1 equiv) dropwise. Then, the reaction was stirred for 24 h at room temperature and neutralized with aqueous 2N HCl. The aqueous phase was extracted with EtOAc (3 x 20 mL), and the combined organic layers were dried over anhydrous Na2SO4, Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 68 filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (SiO2, 15% EtOAc/hexane) to afford ethyl 2hydroxy-2-(2-oxocyclopentyl)acetate (72) (2.0 g, 24% , a mixture of two diastereomers) as a colorless liquid. H OH O TBSO Me Me O OEt 72 1 H NMR (300 MHz, CDCl3) δ 4.72 (s, 1H), 4.37 – 4.11 (m, 6H), 4.00 – 3.93 (m, 2H), 3.28 – 3.03 (m, 2H), 2.97 – 2.69 (m, 1H), 2.37 – 2.13 (m, 1H), 2.11 – 1.64 (m, 3H), 1.37 – 1.23 (m, 9H), 1.05 (d, J = 2.9 Hz, 3H), 0.96 – 0.94 (m, 6H), 0.88 (d, J = 1.2 Hz, 9H), 0.07 (d, J = 4.0 Hz, 6H). FTIR (Neat, NaCl, thin film): 3221, 2927, 1615, 1006 cm-1. HRMS (ESI): calc’d for [M+H]+ 345.2092, found 345.2091. Preparation of alkene 67. H OH O TBSO Me Me 72 O OEt Burgess’ reagent (1.8 equiv) benzene, 50 °C, 9 h O TBSO Me Me O OEt 59% yield 67 The diastereomeric mixture of ketoesters 72 (13.2 g, 22.1 mmol, 1.0 equiv.) was dissolved in benzene (220 mL, 0.10 M) in a flask equipped with a reflux condenser. Burgess reagent (9.48 g, 39.8 mmol, 1.8 equiv.) was added to the obtained solution. The mixture was heated to 50 °C. After 9 hours, the solution was allowed to cool to room temperature and NH4Cl (sat. aq. 150 mL) was added. The layers were separated, and the aqueous layer was extracted with benzene (2 × 100 mL). The organic layers were combined, dried over Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 69 MgSO4 and concentrated. The crude product was purified by flash column chromatography (SiO2, 10% EtOAc/hexanes) to afford 59% yield (4.3 g) of 67 as a single diastereomer. O TBSO Me Me O OEt 67 1 H NMR (300 MHz, CDCl3) δ 6.60 (t, J = 2.9 Hz, 1H), 4.24 (s, 2H), 4.04 – 3.94 (m, 1H), 3.29 (ddd, J = 19.3, 6.0, 2.9 Hz, 1H), 2.93 (ddd, J = 19.4, 5.2, 3.0 Hz, 1H), 1.30 (s, 3H), 1.05 (s, 6H), 0.87 (s, 9H), 0.08 (d, J = 4.5 Hz, 6H). FTIR (Neat, NaCl, thin film): 2934, 1667, 1215, 1210, 1157, 953, 931, 815 cm-1. HRMS (ESI): calc’d for [M+H]+ 327.1986, found 327.1999. Preparation of ketoester 74. O TBSO Me Me 67 O OEt Pd/C (10 wt%), H2 (1 atm) O TBSO MeOH, 22 °C, 1 h Me Me 75% yield, dr = 20 : 1 74 O OEt The enone (236 mg, 723 umol) was dissolved in MeOH (29 mL) to make a total concentration of 0.025 M, and Pd/C was added in (7.69 mg, 10 wt%). The flask was purged and backfilled 3x with N2 and then 3x with H2. The resulting was stirred for 1 h, and the reaction was done by TLC analysis. The reaction was worked up by filtration through celite, and the activated Pd/C that was collected on celite was disposed of in segregated waste and kept over water. The product was purified with 10% EtOAc/hexanes to afford 125 mg of product, corresponding to a 53% yield. NOESY determined it to be the cis diastereomer (> 20 : 1). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 70 O TBSO Me Me O OEt 74 1 H NMR (400 MHz, CDCl3) δ 4.15 (q, J = 7.1 Hz, 2H), 4.00 – 3.90 (m, 1H), 2.82 (dd, J = 16.4, 4.2 Hz, 1H), 2.36 (dd, J = 16.4, 9.4 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.05 (s, 3H), 0.94 (s, 3H), 0.89 (s, 9H), 0.07 (d, J = 4.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 172.35, 60.81, 50.21, 42.82, 35.46, 35.13, 25.87, 22.75, 18.16, 17.89, 14.36, -4.30, -4.79. FTIR (Neat, NaCl, thin film): 2930, 2848, 1616, 1314, 1278, 1109, 896, 756 cm-1. HRMS (ESI): calc’d for [M+H]+ 329.2143, found 329.2151. Preparation of allylic alcohol 77. NaBH4 (1 equiv) CeCl3 • 7H2O (1.3 equiv) TBSO Me O Me 76 MeOH, 22 °C, 1 h 90% yield dr = 12.5:1 TBSO Me OH Me 77 (+)-3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylcyclopenten-1-one (76) (12.4 g, 51.6 mmol) was dissolved in 507 mL of methanol (0.1 M) and CeCl3 • H2O (25.2 g, 67.6 mmol, 1.3 equiv) was added in. The reaction was stirred vigorously until all the CeCl3 was dissolved (20 minutes). It was cooled to 0 °C with an ice bath. Then, at 0 °C, sodium borohydride (1.95 g, 51.6 mmol, 1 equiv) was added in very slowly (CAUTION: a lot of bubbling was observed). The solution was warmed to room temperature and stirred for 1 h and then quenched with saturated aqueous NH4Cl (300 mL). Again, be careful when quenching sodium borohydride, as some bubbling was observed. Add aq. NH4Cl slowly. The organic phase was partitioned with the aqueous phase in a separatory funnel, and the Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 71 resultant mixture was extracted with CHCl3 (3 x 300mL). The combined extracts were dried over Na2SO4, filtered, and concentrated. Flash chromatography (20% EtOAc in hexanes) provided (+)-3-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-cyclopenten-1-ol (77) as a white solid (11.3 g, 90% yield) as a 10 : 1 mixture of cis : trans products. The diastereoselectivity is dependent on the addition rate of the NaBH4, where slow addition maintaining an internal temperature of 0 °C delivers the product in >10:1 dr. TBSO Me OH Me 77 TLC (20% EtOAc/Hexanes): Rf 0.5 (p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.95 (ddd, J = 5.9, 2.1, 0.9 Hz, 1H), 5.86 (ddd, J = 5.9, 2.1, 1.1 Hz, 1H), 4.08 (s, 1H), 4.00 (s, 1H), 1.01 (s, 3H), 0.96 (s, 3H), 0.89 (s, 9H), 0.07 (d, J = 3.7 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 136.46, 135.30, 83.09, 82.78, 47.22, 26.33, 25.98, 18.27, 17.04, -4.35, -4.70. FTIR (Neat, NaCl, thin film): 3375, 2930, 2858, 1464, 1361, 1254, 1076, 887, 775 cm-1. HRMS (ESI): calc’d for [M+H]+ 243.1775, found 243.1178. Preparation of Ueno-Stork bromoacetal 78. OEt (6 equiv) NBS (4 equiv) TBSO Me OH Me DCM, −20 °C to 0 °C, 3.5 h 75% yield 77 TBSO Me O Me EtO Br 78 A 50 mL round bottom flask was charged with (±)-3-((tert-butyldimethylsilyl)oxy)-2,2dimethyl-cyclopenten-1-ol 77 (1.0 g, 4.12 mmol, 1.0 equiv.) and CH2Cl2 (33.3 mL). The Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 72 resulting solution was cooled to —20 °C and N-bromosuccinamide (2.94 g, 16.5 mmol, 4.0 equiv.) was added directly followed by dropwise addition of ethyl vinyl ether (2.37 mL, 24.7 mmol, 6.0 equiv.). The reaction was stirred for 30 min at −20 °C and 3 h at 0 °C. The reaction mixture was cooled to −20 °C and N-bromosuccinamide (1.47 g, 8.25 mmol, 2.0 equiv.) was added directly followed by dropwise addition of ethyl vinyl ether (1.16 mL, 12.4 mmol, 3.0 equiv.). The reaction was stirred for 30 min at —20 °C and 3 h at 0 °C. The reaction was quenched by the addition of sat. aq. Na2S2O3 (40 mL) at 0 °C and warmed to 21 °C. The phases were separated and the aq. phase was extracted with CH2Cl2 (3x 70 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The crude product was flushed through a flash chromatography column with phosphate buffered silica (pH = 7) (5-10% EtOAc in hexanes) to afford a yellow oil 78, which was carried forward to the next step without any further purification. TBSO Me O Me EtO Br 78 TLC (10% EtOAc/Hexanes): Rf 0.66 (p-anisaldehyde stains green). 1 H NMR (CDCl3, 400 MHz): δ = 5.95 – 5.47 (m, 1H), 4.85 – 4.55 (m, 1H), 4.10 (dq, J = 3.3, 1.7 Hz, 1H), 4.05 (dq, J = 8.3, 1.7 Hz, 1H), 3.69 – 3.51 (m, 1H), 3.41 – 3.28 (m, 1H), 1.17 (td, J = 7.0, 3.0 Hz, 2H), 1.08 (d, J = 6.2 Hz, 2H), 0.84 (s, 4H), -0.00 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 136.03, 135.92, 132.10, 131.33, 102.55, 101.12, 88.11, 86.70, 82.43, 82.40, 61.93, 61.28, 50.16, 49.68, 32.29, 32.05, 25.76, 18.32, 16.71, 16.68, 15.36, 15.33, -4.39, -4.67. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 73 FTIR (Neat, NaCl, thin film): 2954, 2928, 2855, 1463, 1363, 1250, 1118, 1052, 893, 859, 838, 813, 777 cm-1. Preparation of ethyl acetal 79. TBSO Me AIBN (10 mol%) HSnBu3 (2 equiv) O Me EtO 78 Benzene, 4 h, 90 °C Br 76% yield H TBSO OEt Me Me H O 79 A flame-dried 100 mL three necked round-bottom flask was charged with the yellow oil 78 (1.43 g, 3.63 mmol, 1.0 equiv.) and benzene (32.9 mL). The reaction solution was degassed using N2 for at least 15 min. To the degassed solution was added n-Bu3SnH (2.11 g, 7.24 mmol, 2.0 equiv.) and 2,2’-azobisisobutyronitrile (3.64 mL 0.2 M in toluene, 119 mg, 724 µmol, 0.2 equiv.) and a reflux condenser was attached under a N2 stream. The reaction mixture was heated to 90 °C and stirred for 10 h. After cooling to room temperature, the crude reaction mixture was concentrated in vacuo and directly purified with flash column chromatography (0 à 5% EtOAc in hexanes). The residue was resubjected under the identical condition to give cyclized product 79 as a colorless oil (546 mg, 1.74 mmol, 48% yield over two steps). H TBSO OEt Me Me H O 79 TLC (10% EtOAc/Hexanes): Rf 0.53 and 0.48 (p-anisaldehyde stains green). 1 H NMR (CDCl3, 400 MHz): δ = 5.45 – 4.98 (m, 1H), 4.06 (d, J = 8.0 Hz, 1H), 3.70 (dt, J = 9.7, 7.1 Hz, 1H), 3.66 (q, J = 5.5 Hz, 1H), 2.87 – 2.69 (m, 1H), 2.12 – 2.06 (m, 3H), Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 74 1.85 (ddd, J = 12.6, 7.7, 4.9 Hz, 1H), 1.42 (dt, J = 13.4, 4.6 Hz, 1H), 1.18 (t, J = 7.1 Hz, 4H), 0.95 (s, 4H), 0.90 (s, 4H), 0.88 (s, 10H), 0.02 (d, J = 2.1 Hz, 7H). 13 C NMR (101 MHz, CDCl3) δ 106.53, 92.70, 81.25, 63.59, 44.94, 38.74, 38.31, 37.23, 28.06, 25.96, 17.64, 15.24, -4.28, -4.82. FTIR (Neat, NaCl, thin film): 2991, 2857, 1744, 1721, 1464, 1382, 1360, 1255, 1125, 877, 836, 775 cm-1. HRMS (FD): m/z: calc. for C17H34O3Si [M]·+ 314.22772, found 314.22956. Preparation of lactone 75 (recommended). H TBSO OEt Me Me H 79 O CrO3 (3 equiv) H2SO4 (3 equiv) H2O/acetone 0 °C, 1 h 30% yield H TBSO O Me Me H O 75 CrO3 (5.48 g, 54.8 mmol, 3 equiv) was added into a 250 mL RBF equipped with a magnetic stir bar and water (69 mL) was added. H2SO4 (1.0 mL) was then added dropwise and with caution. In a separate 1L round bottom flask, the starting material (5.75 g, 18.3 mmol) was dissolved in acetone (183 mL) and cooled to 0 °C using an ice bath. To the starting material was then added the Jones reagent via syringe transfer dropwise, and the reaction was stirred under N2 atmosphere for 15 min at 0 °C. After completion, as determined by TLC, the reaction was quenched with iPrOH and neutralized with saturated NaHCO3 by dropwise addition at 0 °C. CAUTION: Add the NaHCO3 slowly, as evolution of gas and bubbling was observed for 5 minutes. The mixture was extracted with Et2O (250 mL x 3), washed with brine, and the organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by flash chromatography with 15 to 20% EtOAc/Hex, Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 75 isolating 75 as a white solid (1.65 g, 6.2 mmol, 30%). Segregate chromium waste, which is contained in the aq. layers, and tag appropriately. H TBSO O Me Me H O 75 TLC (20% EtOAc/Hexanes): Rf 0.27 (blue with p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 4.42 (dd, J = 7.4, 1.0 Hz, 1H), 3.73 (dt, J = 4.3, 1.3 Hz, 1H), 3.03 (ddddd, J = 11.3, 9.4, 7.4, 3.4, 2.0 Hz, 1H), 2.90 – 2.74 (m, 1H), 2.49 – 2.37 (m, 1H), 2.28 (ddd, J = 13.9, 9.5, 4.3 Hz, 1H), 1.59 (dt, J = 14.1, 1.8 Hz, 1H), 1.13 (s, 3H), 0.88 (s, 9H), 0.87 (s, 3H), 0.04 (d, J = 1.5 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 177.67, 92.07, 81.58, 47.58, 41.42, 37.91, 35.74, 25.84, 25.11, 18.91, 18.18, -4.63, -4.99. FTIR (Neat, NaCl, thin film): 2949, 2927, 2856, 1768, 1471, 1359, 1254, 1179, 1086, 1038, 833, 770 cm-1. HRMS (ESI): calc’d for [M+H]+ 285.18805, found 285.18673. Preparation of lactone 75 (not recommended). H TBSO OEt Me Me H 79 O mCPBA (3 equiv) BF3 • OEt2 (2 equiv) CH2Cl2, 0 °C, 10 min 27% yield H TBSO O Me Me H O 75 To a solution of ethyl ketal starting material (5.5 g, 17.6 mmol) and mCPBA (13.0 g, 52.8 mmol, 3 equiv) in CH2Cl2 at 0 °C was added BF3 • Et2O (4.35 mL, 35.2 mmol, 2 equiv). The solution was stirred for 15 min, then quenched with saturated aqueous thiosulfate. The aqueous layer was extracted with Et2O (3 x 250 mL). The combined organic layer was Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 76 washed with sodium bicarbonate five times and brine, dried over MgSO4, and concentrated. The residue was purified with flash column chromatography (10 to 15% EtOAc in hexanes) to afford the lactone product 75 (1.3 g, 5.6 mmol, 27% yield) as a white solid. H TBSO O Me Me H O 75 TLC (20% EtOAc/Hexanes): Rf 0.27 (blue with p-anisaldehyde, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 4.42 (dd, J = 7.4, 1.0 Hz, 1H), 3.73 (dt, J = 4.3, 1.3 Hz, 1H), 3.03 (ddddd, J = 11.3, 9.4, 7.4, 3.4, 2.0 Hz, 1H), 2.90 – 2.74 (m, 1H), 2.49 – 2.37 (m, 1H), 2.28 (ddd, J = 13.9, 9.5, 4.3 Hz, 1H), 1.59 (dt, J = 14.1, 1.8 Hz, 1H), 1.13 (s, 3H), 0.88 (s, 9H), 0.87 (s, 3H), 0.04 (d, J = 1.5 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 177.67, 92.07, 81.58, 47.58, 41.42, 37.91, 35.74, 25.84, 25.11, 18.91, 18.18, -4.63, -4.99. FTIR (Neat, NaCl, thin film): 2949, 2927, 2856, 1768, 1471, 1359, 1254, 1179, 1086, 1038, 833, 770 cm-1. HRMS (ESI): calc’d for [M+H]+ 285.18805, found 285.18673. Preparation of a-selenate 80. H TBSO O Me Me H 75 O LHMDS (1.1 equiv) then, PhSeBr (1.05 equiv) THF, −78 °C, 1 h 72% yield H SePh TBSO O Me Me H O 80 An oven dried 250 mL round-bottom flask was charged with LHMDS in THF (12.1 mL, titrated to be 0.83 M, 10.1 mmol) and cooled to −78 °C using a dry ice-acetone bath. Lactone starting material (2.60 g, 9.14 mmol, 1 equiv) was added dropwise as a 0.5 M Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 77 solution in THF to the solution of base at −78 °C and stirred for 25 min. Then, to a separate oven dried 200 mL flask, PhSeBr (2.26 g, 9.60 mmol, 1.05 equiv) was weighed out, and added as a 0.5 M solution to the stirring solution of enolate. The reaction was stirred at −78 °C for 25 more min. Ammonium chloride (50 mL) was then added, and the solution was warmed to room temperature. The flasks contents were then transferred to a 1L separatory funnel, extracted 3x with ether (3 x 100 mL), and washed with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated down. The crude oil was purified via flash chromatography 0% EtOAc/Hex for one column volume, 2.5% EtOAc/Hex for two column volumes (gets off the orange impurity), then 5% EtOAc/Hex until the product is fully eluted to afford the a-selenylated product as a yellow oil (2.9 g, 6.7 mmol, 72% yield). H SePh TBSO O Me Me H O 80 TLC (20% EtOAc/Hexanes): Rf 0.52 (blue with p-anisaldehyde, KMnO4, UV). 1 H NMR (CDCl3, 400 MHz): δ 7.69 – 7.64 (m, 2H), 7.40 – 7.29 (m, 3H), 3.88 (dd, J = 7.1, 1.0 Hz, 1H), 3.75 (d, J = 2.9 Hz, 1H), 3.67 (dt, J = 4.2, 1.2 Hz, 1H), 3.08 (ddt, J = 9.8, 7.2, 2.4 Hz, 1H), 2.30 (ddd, J = 14.3, 9.9, 4.2 Hz, 1H), 1.66 (dt, J = 14.3, 1.6 Hz, 1H), 1.06 (s, 3H), 0.85 (s, 9H), 0.75 (s, 3H), 0.01 (d, J = 2.6 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 176.49, 136.03, 129.47, 129.17, 127.10, 90.49, 81.21, 47.51, 45.72, 45.45, 41.50, 25.83, 24.76, 18.90, 18.16, -4.67, -5.02. FTIR (Neat, NaCl, thin film): 2954, 2929, 2856, 1765, 1472, 1256, 1169, 1089, 1058, 1003, 835, 775, 740 cm-1. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 78 HRMS (ESI): calc’d for [M+H]+ 440.12804, found 440.12879. Preparation of butenolide 60. H SePh TBSO O Me Me H 80 O H2O2 (aq) DCM, 0 °C, 1 h 90% yield TBSO O Me Me H O 60 The a-selenylated lactone (2.98 g, 6.78 mmol, 1 equiv) was dissolved in DCM (93 mL) and charged with a large magnetic stir bar. H2O2 (6.93 mL, 30% solution in H2O, 10 equiv) via direct injection was then added and the reaction was stirred vigorously (1000 rpm) for 3 h with a large stir bar. The reaction was monitored by TLC, as it may take longer. At the baseline there are some spots that appear by TLC, but they are not in enough quantity to observe in the NMR. I think the bright pink one at the baseline is selenoxide from the Greico-elimination. It was worked up by addition of sodium bicarbonate (100 mL), extraction with DCM (3 x 100 mL), washing with brine, drying with Na2SO4, and concentration in vacuo. Column chromatography of the crude mixture, loading the column by dissolving and rinsing with a minimal amount of toluene, was achieved with a gradient column: 12% EtOAc/Hex to get off the starting material (usually a very small amount <5%) then 15% EtOAc/Hex to isolate the product as a white solid (1.6 g, 90% yield). TBSO O Me Me H O 60 TLC (20% EtOAc/Hexanes): Rf 0.27 (grey with p-anisaldehyde, UV, KMnO4). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 1 79 H NMR (CDCl3, 400 MHz): δ 5.75 (q, J = 2.1 Hz, 1H), 4.67 – 4.65 (m, 1H), 4.14 (dd, J = 9.1, 7.4 Hz, 1H), 2.96 (ddd, J = 18.7, 9.5, 2.2 Hz, 1H), 2.31 (ddt, J = 18.7, 7.3, 1.7 Hz, 1H), 1.23 (s, 3H), 0.90 (s, 9H), 0.61 (s, 3H), 0.07 (d, J = 4.9 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 175.42, 173.32, 113.11, 90.78, 79.05, 45.02, 32.89, 25.88, 24.61, 18.10, 11.65, -4.46, -4.92. FTIR (Neat, NaCl, thin film): 2954, 1774, 1130, 880 cm-1. HRMS (ESI): calc’d for [M+H]+ 283.1723, found 283.1736. [a]D23 : +190.9 (c 1.0 in CHCl3) Melting Point: 72-74 °C Preparation of g-keto ester 82. OEt Br TBSO Me O Me 69 O (3.7 equiv) LHMDS (1.2 equiv) HMPA (2 equiv) THF, −78 °C, 3 h 93% yield O TBSO Me OEt O Me 82 A 100 mL, oven dried flask with a magnetic stir bar was flame dried under vacuum. Then, it was cooled to 22 °C and 80 mL of THF was added. The solution was cooled to −78 °C and LHMDS solution (1M) was added in (1.2 equiv). It was stirred for 1 min before the starting material as a 1M solution was added in dropwise to maintain temp. below −75 °C, followed by HMPA (2 equiv, neat, also added in dropwise to maintain temp. below −75 °C). The mixture was stirred for 45 minutes at −78 °C before it was charged with freshly distilled ethyl bromoacetate (distilled over CaH2) at that temperature dropwise. The solution was stirred for 10 minutes at −78 °C then removed from the bath to warm it up to room temperature. It was stirred 2 h at room temperature. Then, ammonium chloride (100 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 80 mL) was added in, followed by extracting with ethyl acetate three times (3 x 100 mL). Then, Na2SO4 was added in, and the mixture was filtered, concentrated, and NMR'd. The crude mixture was columned 0-10% EtOAc/Hex gradient to afford mixed fractions containing ethyl bromoacetate which could be purified via heating on full high vacuum at 75 °C for 8 hours to afford 6.3 g as a pure pale yellow oil, corresponding to a 93% yield. O TBSO Me OEt O Me 82 TLC: (10% EtOAc/Hexanes): Rf 0.34 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 4.22 – 4.06 (m, 2H), 4.00 (dd, J = 4.4, 2.5 Hz, 1H), 2.95 – 2.83 (m, 1H), 2.74 (dd, J = 16.5, 4.4 Hz, 1H), 2.41 (dd, J = 16.5, 8.4 Hz, 1H), 2.15 (ddd, J = 13.2, 8.9, 2.6 Hz, 1H), 1.93 (ddd, J = 13.2, 10.6, 4.4 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.88 (s, 9H), 0.07 (d, J = 10.1 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 221.61, 172.12, 77.09 60.75, 51.02, 41.85, 35.38, 34.90, 25.88, 23.13, 18.90, 18.21, 14.35, -4.54, -4.84. FTIR (Neat, NaCl, thin film): 2930, 2857, 1753, 1464, 1361, 1178, 1039, 937, 775 cm-1. HRMS (ESI): calc’d for C17H33O4Si [M+H]+ 329.2143, found 329.2154. [a]D23 : +23.2 (c 1.0 in CHCl3) Preparation of g-keto acid 85. O O LiOH (10 equiv) TBSO Me OEt O Me 82 THF/H2O (3:1) 22 °C, 16 h quant. yield dr = 1 : 1 TBSO Me OH O Me 85 A 250 mL round bottom flask was charged with 82 (5.10 g, 15.5 mmol), THF (57 mL), Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 81 water (57 mL), and a magnetic stir bar. To the flask was cooled to 0 °C, then solid LiOH (3.71 g, 10 equiv) was added slowly at 0 °C. The stirring solution was warmed to room temperature and stirred for 7 hours. The reaction was quenched with 1M HCl dropwise until a pH of 3 was reached. The solution was extracted with ethyl acetate (3 x 30 mL), then dried with sodium sulfate, filtered and concentrated under vacuum. The acid was telescoped into the next step without any further purification, and a yield over two steps was reported. Experimental note: It is important to not acidify the crude solition past a pH of 3 to prevent TBS deprotection. HO2C HO2C TBSO Me TBSO O Me Me O Me 85 TLC: (40% EtOAc/Hexanes): Rf 0.10 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 4.00 (dd, J = 4.4, 2.4 Hz, 1H), 3.95 (dd, J = 7.7, 5.7 Hz, 1H), 3.00 – 2.82 (m, 2H), 2.78 (dd, J = 16.9, 4.8 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.50 – 2.39 (m, 2H), 2.17 (ddd, J = 13.2, 8.9, 2.5 Hz, 1H), 1.94 (ddd, J = 13.2, 10.8, 4.4 Hz, 1H), 1.63 (ddd, J = 12.8, 9.7, 7.7 Hz, 2H), 1.05 (d, J = 2.8 Hz, 6H), 0.98 (s, 3H), 0.94 (s, 3H), 0.89 (d, J = 4.8 Hz, 18H), 0.17 – 0.01 (m, 12H). 13 C NMR (101 MHz, CDCl3) δ 221.96, 220.69, 176.70, 176.50, 51.09, 50.31, 42.43, 41.59, 35.38, 35.16, 34.50, 30.11, 25.87, 23.20, 22.74, 18.21, 18.15, 17.91, -4.29, -4.55, 4.80, -4.85. FTIR (Neat, NaCl, thin film): 3200, 2955, 2857, 1740, 1715, 1253, 1113, 1077, 834, 776 cm-1. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 82 HRMS (ESI): calc’d for C15H29O4Si [M+H]+ 301.1830, found 301.1830. [a]D23 : +17.7 (c 1.0 in CHCl3) Preparation of chlorolactone 87. O SOCl2 (4.5 equiv) TBSO Me OH O Me 85 DCM, 22 °C, 11 h 71% yield TBSO Me O Me Cl O 87 An oven dried 500 mL round bottom flask was charged with carboxylic acid 85 (4.66 g, 15.5 mmol), DCM (155 mL,100 mM), and a magnetic stir bar. Thionyl chloride (5.09 mL, 4.5 equiv, 69.8 mmol) was added to the reaction flask and stirred at room temperature for 11 hours. The thionyl chloride and DCM were removed via vacuum distillation, heating from 40 °C to 80 °C. The resulting crude oil was purified via flash column chromatography (SiO2, 1% to 7% EtOAc/Hexanes). The volatiles were concentrated under reduced pressure to afford an inconsequential mixture of diastereomers 87 (1:1) obtained as a pale yellow amorphous and sticky solid (3.5 g, 71% yield over 2 steps). Analytically pure samples of both diastereomers were obtained and representative spectrum of the mixture as used in the next step is also provided. TBSO Me O Me Cl O 87A TLC: (10% EtOAc/Hexanes): Rf 0.42 (p-anisaldehyde, brown). 1 H NMR (CDCl3, 400 MHz): δ 2.60 (dddd, J = 14.2, 10.3, 4.9, 1.0 Hz, 1H), 2.43 (dd, J = 17.6, 1.1 Hz, 1H), 1.50 – 1.42 (m, 1H), 1.19 (s, 3H), 1.06 (s, 3H), 0.86 (s, 9H), 0.03 (d, J = 8.0 Hz, 6H). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 13 83 C NMR (CDCl3, 101 MHz): δ 174.42, 115.66, 80.59, 52.71, 46.69, 40.62, 37.11, 25.73, 25.61, 18.09, 17.15, -4.72, -5.03. FTIR (Neat, NaCl, thin film): 2950, 1806, 1471, 1251, 1158, 1042, 885, 779 cm-1. HRMS (ESI): calc’d for C15H27O3Si [M−Cl]+ 283.1724, found 283.1726. [a]D22 : +43.5 (c 1.0 in CHCl3) TBSO Me O Me Cl O 87B TLC: (10% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde, brown). 1 H NMR (CDCl3, 400 MHz): δ 3.87 (dd, J = 9.0, 8.3 Hz, 1H), 3.17 – 2.97 (m, 2H), 2.39 (d, J = 17.4 Hz, 1H), 2.16 – 1.97 (m, 1H), 1.65 (ddd, J = 13.9, 8.2, 3.1 Hz, 1H), 1.13 (s, 3H), 1.01 (s, 3H), 0.88 (s, 9H), 0.02 (d, J = 10.8 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 174.98, 114.05, 76.22, 50.84, 44.15, 38.21, 35.68, 25.83, 18.98, 18.39, 18.06, -4.38, -4.82. FTIR (Neat, NaCl, thin film): 2856, 1806, 1471, 1206, 1128, 1025, 859 cm-1. HRMS (ESI): calc’d for C15H27O3Si [M−Cl]+ 283.1724, found 283.1726. [a]D23 : +22.2 (c 1.0 in CHCl3). Preparation of butenolide 60. TBSO Me O Me 87 Cl O LHMDS (3 equiv) THF, −78 °C to 22 °C, 16 h 71% yield TBSO O Me Me H O 60 A flame-dried 200 mL RBF equipped with a magnetic stir bar and placed under N2. The flask was charged with LHMDS (22.6 mL, 22.6 mmol, 3 equiv, 1 M in THF), followed Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 84 by THF (7 mL), and cooled to –78 °C. The chloro-lactone 87 was added dropwise as a solution in THF (2.4 g, 7.53 mmol, 1 equiv, 7 mL). The reaction was stirred at –78 °C for 4 hours then warmed to room temperature and stirred for 12 h. The reaction was quenched by addition of sat. aq. sodium bicarbonate (50 mL), the layers separated and the aqueous later extracted with Et2O (3 x 50 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mixture was purified via flash column chromatography (SiO2, 0% to 10% EtOAc/Hexanes) affording the pure butenolide 60 as a white solid (1.5 g, 71% yield). TBSO O Me Me H O 60 TLC (20% EtOAc/Hexanes): Rf 0.27 (grey with p-anisaldehyde, UV, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.75 (q, J = 2.1 Hz, 1H), 4.67 – 4.65 (m, 1H), 4.14 (dd, J = 9.1, 7.4 Hz, 1H), 2.96 (ddd, J = 18.7, 9.5, 2.2 Hz, 1H), 2.31 (ddt, J = 18.7, 7.3, 1.7 Hz, 1H), 1.23 (s, 3H), 0.90 (s, 9H), 0.61 (s, 3H), 0.07 (d, J = 4.9 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 175.42, 173.32, 113.11, 90.78, 79.05, 45.02, 32.89, 25.88, 24.61, 18.10, 11.65, -4.46, -4.92. FTIR (Neat, NaCl, thin film): 2954, 1774, 1130, 880 cm-1. HRMS (ESI): calc’d for C15H27O3Si [M+H]+ 283.1723, found 283.1736. [a]D23 : +195.9 (c 1.0 in CHCl3) Melting Point: 72-74 °C Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 85 Preparation of cyclopropane 83. EtO2C N2 (1.5 equiv) Cu(acac)2 (1 mol%) TBSO Me H OTMS Me 73 benzene, 90 °C, 3 h then 30 °C, 12 h TBSO Me CO2Et Me OTMS 83 64% yield In an N2-filled glovebox was weighed out Cu(acac)2 (0.5 mg, 2.07 umol, 1 mol%), and it was dispensed into a vial containing neat starting material (65.0 mg, 207 umol, 1 equiv) and a magnetic stir bar. Then, a solution of ethyl diazoacetate in 132 uL of benzene was made, and it was added to a stirring solution of starting material and Cu(acac)2 at 90 °C over 3 hours. After the addition, the reaction was stirred at 30 °C overnight. The next morning, the reaction was concentrated and filtered through a pad of silica. NMR reveals a ratio of 1.7 : 1 product to starting material. Column chromatography, eluting with 10% EA/hex provides 53.0 mg of product, corresponding to a 64% yield as a inconsequential mixture of diastereomers that could be converged to a single diastereomer in the next step. TBSO Me CO2Et Me OTMS 83 1 H NMR (500 MHz, CDCl3) δ 4.18 – 4.04 (m, 4H), 3.67 – 3.62 (m, 1H), 3.25 (dd, J = 9.1, 7.0 Hz, 1H), 2.18 – 2.13 (m, 2H), 1.90 – 1.80 (m, 3H), 1.81 – 1.65 (m, 2H), 1.62 (d, J = 3.8 Hz, 1H), 1.32 – 1.26 (m, 6H), 1.06 (d, J = 1.4 Hz, 3H), 1.03 (s, 3H), 0.97 (s, 6H), 0.88 (d, J = 1.7 Hz, 18H), 0.19 – 0.15 (m, 18H). 13 C NMR (101 MHz, CDCl3) δ 170.89, 170.54, 78.64, 76.50, 76.40, 75.70, 73.21, 60.66, 60.49, 46.08, 45.65, 33.26, 32.29, 31.80, 30.40, 28.69, 26.62, 25.98, 25.95, 25.88, 22.25, 21.60, 19.31, 18.22, 18.14, 14.54, 14.39, 1.68, 1.41, -4.32, -4.86. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 86 FTIR (Neat, NaCl, thin film): 2920, 2861, 1697, 1478, 1373, 1152, 1052, 942, 756 cm-1. HRMS (ESI): calc’d for [M+H]+ 401.2538, found 401.2543. Preparation of g-keto ester 82. O TBSO Me CO2Et Me 83 OTMS PPTS (3 equiv) TBSO MeOH, 10 min, 23 °C 78% yield dr = 5 : 1 Me OEt O Me 82 To a solution of starting material (25 mg, 62.4 umol) in EtOH (750 uL) was added solid PPTS (47.0 mg, 187 umol) at room temperature. The reaction was stirred 10 minutes and monitored by TLC. The reaction was worked up by addition of saturated aqueous sodium bicarbonate. Then, the mixture was extracted 3 times with ether (3 x 1 mL). The organic phases were dried with Na2SO4 and filtered, then concentrated. Crude NMR reveals a clean NMR spectrum of product that can be columned. Column conditions include a pipet column eluting with 0, 1, then 2% EtOAc/Hex. O TBSO Me OEt O Me 82 TLC: (10% EtOAc/Hexanes): Rf 0.34 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 4.22 – 4.06 (m, 2H), 4.00 (dd, J = 4.4, 2.5 Hz, 1H), 2.95 – 2.83 (m, 1H), 2.74 (dd, J = 16.5, 4.4 Hz, 1H), 2.41 (dd, J = 16.5, 8.4 Hz, 1H), 2.15 (ddd, J = 13.2, 8.9, 2.6 Hz, 1H), 1.93 (ddd, J = 13.2, 10.6, 4.4 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.88 (s, 9H), 0.07 (d, J = 10.1 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 221.61, 172.12, 77.09 60.75, 51.02, 41.85, 35.38, 34.90, 25.88, 23.13, 18.90, 18.21, 14.35, -4.54, -4.84. 87 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies FTIR (Neat, NaCl, thin film): 2930, 2857, 1753, 1464, 1361, 1178, 1039, 937, 775 cm-1. HRMS (ESI): calc’d for [M+H]+ 329.2143, found 329.2154. Preparation of secondary alcohol 84. O TBSO Me OEt O directed reduction OEt NaBH4 (1 equiv) Me MeOH, 21 °C, 30 min 82 97% yield TBSO Me O OH Me 84 Me H OEt O O TBSO Me BH3 H The starting material 82 (20 mg, 60.9 umol) in a 1-dram vial was diluted with squirt-bottle MeOH (500 uL, 122 mM), and it was cooled to 0 °C. NaBH4 (2.30 mg, 60.9 umol, 1 equiv) was added in slowly, and the reaction was stirred for 10 minutes, upon which TLC indicated full conversion of starting material. The reaction was worked up by addition of saturated aq. NH4Cl (500 uL), and the resulting aqueous phase was extracted with diethyl ether (3 x 500 uL). The product was purified by preparatory thin layer chromatography (prep. TLC) in 50% EA/hex to isolate 19.5 mg of product, corresponding to 97% yield. OEt TBSO Me O OH Me 84 TLC: (20% EtOAc/Hexanes): Rf 0.34 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 4.14 (q, J = 7.2 Hz, 2H), 3.66 (t, J = 7.2 Hz, 1H), 3.34 – 3.25 (m, 1H), 2.62 (d, J = 6.0 Hz, 1H), 2.51 (dd, J = 15.9, 8.1 Hz, 1H), 2.41 (dd, J = 15.9, 6.8 Hz, 1H), 2.34 – 2.25 (m, 1H), 1.89 (ddd, J = 13.6, 11.0, 6.9 Hz, 1H), 1.55 – 1.49 (m, 1H), 1.25 (d, J = 7.1 Hz, 3H), 0.96 (s, 3H), 0.88 (d, J = 4.5 Hz, 12H), 0.02 (d, J = 5.1 Hz, 6H). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 13 88 C NMR (CDCl3, 101 MHz): δ 173.93, 83.98, 78.01, 60.77, 46.09, 40.07, 39.87, 37.26, 25.93, 25.20, 18.15, 14.94, 14.35, -4.36, -4.83. FTIR (Neat, NaCl, thin film): 3474, 2958, 2932, 1736, 1464, 1255, 1076, 856 cm-1. HRMS (ESI): calc’d for [M+Na]+ 353.2118, found 353.2125. Preparation of spirocycle 86. HO2C TBSO Me O NaOAc (15 equiv) O Me 85 Ac2O (neat) 150 °C, 6 h 67% yield O TBSO Me O Me 86 To the starting material (5 mg, 16.6 umol) in an oven-dried 1-dram vial was added in sodium acetate solid (20.5 mg, 250 umol, 15 equiv). Then, acetic anhydride (380 uL, 44 mM) was added in, and the reaction was stirred at 150 °C for 6 hours. The reaction was worked up by cooling to 0 °C and adding 0.5 mL of EtOAc. The mixture was concentrated, then filtered through a pad of cotton. Purification with preparatory TLC (15% EA/hex) allows for isolation of 3.6 mg of product 86 (67% yield). The stereochemistry of the spirocycle is not known but hypothesized to contain beta stereochemistry. O O O TBSO Me Me 86 1 H NMR (400 MHz, CDCl3) δ 4.86 – 4.79 (m, 1H), 4.24 – 4.18 (m, 1H), 4.11 – 4.05 (m, 1H), 2.88 (dd, J = 18.1, 1.5 Hz, 1H), 2.69 – 2.56 (m, 2H), 2.18 – 2.10 (m, 1H), 1.11 (dd, J = 13.6, 1.3 Hz, 6H), 0.93 – 0.84 (m, 9H), 0.10 (dd, J = 5.0, 1.3 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 217.89, 172.04, 159.60, 88.85, 53.66, 51.89, 42.34, 41.57, Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 89 25.88, 22.95, 18.99, 18.17, -4.45, -4.88. FTIR (Neat, NaCl, thin film): 2951, 2852, 1713, 1479, 1360, 1134, 1026, 934, 721 cm-1. HRMS (ESI): calc’d for [M+H]+ 325.1830, found 325.1823. Preparation of TBS siloxyfuran 88. TBSO O Me Me H 60 O NEt3 (2.25 equiv.) TBSOTf (1.75 equiv.) Et2O, 0 °C to 22 °C, 2 h 99% yield TBSO OTBS O Me Me 88 A flame-dried 50 mL RBF was charged with butenolide 60 (250 mg, 885 umol, 1.0 equiv.), a magnetic stir bar, and placed under nitrogen. To the starting material was added dry Et2O (17.7 mL) and freshly distilled NEt3 (278 uL, 1.99 mmol, 2.25 equiv.). It was stirred at room temperature until all butenolide starting material was dissolved. The reaction was cooled to 0 °C and TBSOTf (356 uL, 1.55 umol, 1.75 equiv.) was added dropwise. The reaction was stirred for 0 °C for 30 min then warmed to room temperature and stirred for 90 min. After stirring for 2 hours total, the reaction mixture was loaded directly on a phosphate-buffered silica plug (10 g of buffered silica) prewet with hexanes and the crude material was loaded onto the plug with Et2O. The crude material was filtered through the silica plug with hexanes (3 x 50 mL). The eluent was reduced in vacuo and the residue was redissolved in MeCN (10 mL) and pentane (10 mL). The pentane layer was separated out, and the resulting ACN layer was extracted with pentane (2 x 10 mL). The combined pentane phases were reduced in vacuo. The residue was put on high vac for 12 h to afford 88 as a yellow oil (317 mg, 90% yield). Experimental Note: the purity of TBSOTf is important, impurities such as TfOH will reduce the yield of this reaction. The phosphate buffered silica was prepared according to Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 90 literature procedures.25 TBSO OTBS O Me Me 88 TLC: N/A (unstable to silica) 1 H NMR (CDCl3, 400 MHz): 1H NMR (400 MHz, CDCl3) δ 4.96 (s, 1H), 4.24 (t, J = 6.9 Hz, 1H), 2.72 (dd, J = 14.1, 7.1 Hz, 1H), 2.31 (dd, J = 14.1, 6.7 Hz, 1H), 1.19 (s, 3H), 1.00 (s, 3H), 0.96 (s, 9H), 0.91 (s, 9H), 0.22 (s, 6H), 0.08 (s, 6H). 13 C NMR (CDCl3, 101 MHz): δ 158.14, 151.21, 117.77, 83.58, 82.65, 42.97, 34.05, 25.96, 25.66, 25.22, 20.41, 18.27, 18.24, -4.35, -4.69, -4.71, -4.75. FTIR (Neat, NaCl, thin film): 2956, 2930, 2859, 1585, 1471, 1361, 1255, 1101, 866, 787 cm-1. HRMS (ESI): calc’d for C21H41O3Si2 [M+H]+ 396.25105, found 396.25179. [a]D22 : +38.4 (c 1.0 in CHCl3) Preparation of aldol product 59. O Me ZnBr2 OMe (1.1 equiv) O TBSO OTBS O Me Me 88 + Br 61 −78 °C THF, 7 h 52% yield O TBSO Br Me HO 59 MeO Before attempting this reaction, troubleshoot on small scale. The way 88 is purified is important. Follow the procedure for preparation of 88 above exactly. A stirring solution of siloxyfuran starting material 88 (3.3 g, 8.29 mmol, 1 equiv) and aldehyde 61 (2.1 g, 9.29 mmol, 1.12 equiv) in THF (33 mL, 0.25 M) at −78 °C was Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 91 subjected to ZnBr2 (2.1 g, 9.29 mmol, 3M solution in THF) via rapid injection. The resulting solution was stirred for 6.5 h then quenched at that temperature with NH4Cl (50 mL) and extracted 3x with EtOAc (50 mL). The solution was dried with Na2SO4, filtered, and concentrated. Flash chromatography with 12% EtOAc in hexanes afforded the product 59 (2.2 g, 52% yield) as an 8:1 mixture of diastereomers and recovered butenolide 60 (702 mg, 30% yield. The product is a thick, gooey yellow-green oil that can be high vac'd into a foam and then crushed with a spatula into a nice yellow crystalline solid. O Me O TBSO Br Me HO 59 MeO TLC (15% EtOAc/Hexanes): Rf 0.10 (p-anisaldehyde, stains brown). 1 H NMR (CDCl3, 400 MHz): δ 7.45 (d, J = 8.8 Hz, 1H), 6.75 – 6.73 (m, 1H), 6.69 (dd, J = 8.7, 3.1 Hz, 1H), 5.91 – 5.89 (m, 1H), 4.67 (dd, J = 10.0, 4.8 Hz, 1H), 4.34 (dt, J = 10.8, 3.1 Hz, 1H), 3.78 (s, 3H), 3.18 – 3.08 (m, 2H), 2.58 (dd, J = 13.6, 10.5 Hz, 1H), 2.29 (dd, J = 16.6, 4.8 Hz, 1H), 1.64 (d, J = 3.8 Hz, 1H), 1.26 (s, 3H), 0.89 (s, 9H), 0.78 (s, 3H), 0.04 (s, 6H). 13 C NMR (CDCl3, 101 MHz): δ 176.23, 174.36, 159.26, 137.84, 133.97, 117.61, 115.49, 115.11, 114.65, 97.10, 79.94, 71.23, 55.68, 47.41, 38.47, 35.09, 25.89, 20.59, 18.15, 16.19, 5.46, -4.47, -4.92. FTIR (Neat, NaCl, thin film): 3449, 2954, 2929, 2892, 2856, 1746, 1651, 1595, 1572, 1471, 1444, 1416, 1389, 1290, 1252, 1193, 1164, 1132, 1091, 1049, 1006, 870, 838, 734 cm-1. HRMS (ESI): calc’d for [M+H]+ 510.14316, found 510.14169. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 92 Preparation of MOM-protected compound 90. O Me O TBSO Br Me HO O Me MOMCl (3 equiv.) Et2NiPr (3 equiv.) DCE, 80 °C, 12 h 59 MeO 80% yield O TBSO Br Me O MOM 90 MeO To a three-neck oven-dried 50 mL RBF was added the starting alcohol 59 (2.2 g, 4.3 mmol, 1 equiv) and 1,2-dichloroethane (21.5 mL, 0.2 M). The flask was fitted with a reflux condenser, cooled to 0 °C and charged with DIPEA (2.25 mL, 12.9 mmol, 3 equiv) and MOMCl (0.98 mL, 12.9 mmol, 3 equiv). The mixture was stirred for 12 h at 80 ºC. After cooling the reaction to room temperature, the reaction mixture was quenched with sat. NaHCO3 aqueous solution and extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. After silica gel chromatography with 15% EtOAc in hexanes, the product 90 was isolated as a greenishyellow, thick oil (1.9 g, 80% yield). O Me O TBSO Br Me O MOM 90 MeO TLC (30% EtOAc/Hexanes): Rf 0.56 (p-anisaldehyde, stains brown). 1 H NMR (CDCl3, 400 MHz): δ 7.39 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 3.1 Hz, 1H), 6.67 (dd, J = 8.8, 3.1 Hz, 1H), 5.83 (dd, J = 2.4, 1.2 Hz, 1H), 4.51 (dd, J = 9.9, 5.7 Hz, 1H), 4.17 (dd, J = 10.4, 2.7 Hz, 1H), 4.01 (d, J = 6.8 Hz, 1H), 3.86 (d, J = 6.8 Hz, 1H), 3.77 (s, 3H), 3.23 (dd, J = 13.8, 2.7 Hz, 1H), 3.09 (ddd, J = 9.9, 9.9, 2.4 Hz, 1H), 3.08 (s, 3H), 2.97 (dd, J = 14.0, 10.4 Hz, 1H), 2.31 (ddd, J = 17.9, 5.7, 1.2 Hz, 1H), 1.36 (s, 3H), 0.90 (s, 9H), 0.78 (s, 3H), 0.07 (d, J = 3.9 Hz, 6H). Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 13 93 C NMR (CDCl3, 101 MHz): δ 175.86, 174.66, 158.95, 138.72, 133.31, 118.50, 115.07, 114.73, 114.62, 97.97, 97.67, 79.50, 77.59, 56.57, 55.65, 47.20, 38.80, 33.81, 25.81, 21.88, 18.08, 16.32, -4.45, -4.99. FTIR (Neat, NaCl, thin film): 2954, 2856, 1757, 1472, 1254, 1094, 1021, 869, 778 cm-1. HRMS (ESI): calc’d for [M+H]+ 555.1699, found 555.1772. Preparation of lactone 58. O Me O TBSO Br Me O MOM 90 CuCl2 • 2H2O (5 mol%), (R)-tol-BINAP (5 mol%), PMHS (6 equiv), NaOtBu (1.2 equiv), BuOH (12 equiv) THF/DCM (3:1), 21 °C, 24 h MeO 85% yield O Me TBSO O Br H Me O MOM 58 MeO In the glovebox in a 25 mL oven-dried round bottom flask was added a magnetic stir bar and all solid reagents: CuCl2 • 2H2O (4.60 mg, 27.0 umol, 5 mol%), (R)-Tol-BINAP (18.3 mg, 27.0 umol, 5 mol%), and NaOtBu (62.3 mg, 648 umol, 1.2 equiv). The round bottom flask was capped, taped, and pumped out of the glovebox. Following attachment to an N2 inlet, 9 mL of SPS THF was added, and the reaction was stirred for 5 min. Then, PMHS (effective mass per hydride = 60 g/mol; d = 1.006, 190 uL, 6 equiv) was added dropwise, and the reaction was stirred for 5 more minutes. The starting material 58 (300 mg) as a solution in 3 mL of DCM and tBuOH (207 uL, 2.16 mmol, 4 equiv) was added in last, and the reaction was monitored by TLC. Upon completion as determined by TLC, the reaction was stirred for 2 hours before saturated aqueous NH4Cl (10 mL) was added in dropwise. The ammonium chloride mixture was stirred vigorously to ensure mixing of layers for 15 minutes (bubbling was observed). Then, the solution was loaded into a 60 mL separatory funnel and extracted with EtOAc (3 x 10 mL). The combined organics were dried over Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 94 Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with 7.5% EtOAc in hexanes to give the product 58 as a white crystalline solid as a single diastereomer (256 mg, 85% yield). O Me O TBSO Br Me O MOM 90 CuCl2 • 2H2O (5 mol%), (R)-tol-BINAP (5 mol%), PMHS (6 equiv), NaOtBu (1.2 equiv), BuOH (12 equiv) THF/DCM (3:1), 21 °C, 24 h MeO O Me TBSO O Br H Me O MOM 85% yield 58 MeO TLC (30% EtOAc/Hexanes): Rf 0.52 (p-anisaldehyde, stains brown) 1 H NMR (CDCl3, 400 MHz): δ 7.37 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 3.1 Hz, 1H), 6.67 (dd, J = 8.8, 3.1 Hz, 1H), 4.08 – 3.97 (m, 2H), 3.77 (s, 1H), 3.76 (s, 3H), 3.71 (d, J = 6.9 Hz, 1H), 3.21 – 2.94 (m, 2H), 2.41 – 2.28 (m, 2H), 1.57 (s, 2H), 1.50 (d, J = 14.2 Hz, 1H), 1.26 (s, 3H), 1.25 (s, 1H), 1.15 (s, 3H), 0.91 (s, 8H), 0.91 (d, J = 5.9 Hz, 1H), 0.06 (d, J = 4.7 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 178.18, 159.04, 138.57, 133.09, 118.48, 115.14, 114.96, 100.20, 98.38, 86.10, 80.19, 56.96, 55.72, 48.96, 41.93, 40.40, 40.15, 38.71, 25.88, 23.48, 19.92, 18.25, -4.57, -4.97. FTIR (Neat, NaCl, thin film): 2928, 2855, 1770, 1594, 1472, 1230, 1090, 1044, 835, 774 cm-1. HRMS (ESI): calc’d for [M+H]+ 557.1856, found 557.1940. 95 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies Preparation of a-enolate arylation product 57. minor side product 2% yield O Me O Br TBSO H Me MOM Tol/THF (2:1, 31 mM), 60 °C, 16 h O MeO 58 Ni(COD)2 (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) 75% yield O O O TBSO OMe Me Me H O MOM 57 O TBSO Me H Me OMe OMOM 91 Reagents were purchased from STREM chemicals. Solvents were taken from the SPS and cannula'd into oven-dried schlenk flasks and stored over dried molecular sieves. The solvent was then degassed via freeze-pump thaw three times and pumped into the glovebox for use. NaHMDS and ZnBr2 were stored in the glovebox at room temperature. Ni(COD)2 was stored in the glovebox fridge at −30 °C. In the glovebox, 15.0 mg of starting material (26.9 umol) along with a magnetic stir bar and 440 uL of toluene were added to a 2-dram vial. A stock solution of Ni(COD)2 was prepared by dissolving 3.7 mg of Ni(COD)2 in 1.4 mL of toluene. ZnBr2 stock solution was prepared by taking 9.1 mg and dissolving it in 2.9 mL of THF. NaHMDS (7.9 mg, 43.0 umol, 1.6 equiv) was added directly to the vial of the starting material and toluene, followed by the ZnBr2 stock solution (290 uL, 910 ug, 15 mol%) in THF and lastly the Ni(COD)2 stock solution (140 uL, 370 ug, 5 mol%) in toluene. The reaction was then put on a stir plate for 16 hours at 60 °C. Upon completion, the reaction was removed from the hot plate and allowed to cool to room temperature. TLC in 2% ether/DCM shows basically only product in the reaction mixture. The mixture was quenched with a saturated aqueous NH4Cl (1 mL) solution and extracted with Et2O (3 × 1 mL). Then, 0.1 mL of technazene stock solution in ethyl acetate was added. The technazene stock solution was prepared fresh every time by weighing out 5 mg of technazene into a 1-dram vial, adding 0.5 mL of ethyl Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 96 acetate, and syringing out 0.1 mL. The combined extract was dried over Na2SO4, filtered, and dried under reduced pressure. Column chromatography in 0 to 5% ether/DCM affords a 10 mg mixture of desired product (75% yield) and undesired 6-membered "Heck-type" product (2% yield). O O TBSO OMe Me Me H O MOM 57 TLC (5% Ether/DCM): Rf 0.64 (p-anisaldehyde, stains blue). 1 H NMR (CDCl3, 400 MHz): δ 7.07 (d, J = 8.2 Hz, 1H), 6.74 – 6.68 (m, 2H), 4.71 (d, J = 6.9 Hz, 1H), 4.15 (d, J = 6.9 Hz, 1H), 4.15 (dd, J = 4.6, 2.0 Hz, 1H), 3.77 (s, 3H), 3.72 (dd, J = 5.9, 2.8 Hz, 1H), 3.53 (s, 1H), 3.30i (s, 3H), 3.27 – 3.22 (m, 1H), 3.13 (dd, J = 16.4, 4.6 Hz, 1H), 2.98 (dd, J = 10.6, 5.5 Hz, 1H), 2.52 (ddd, J = 14.3, 10.6, 5.9 Hz, 1H), 1.53 (ddd, J = 14.4, 5.5, 2.8 Hz, 1H), 1.15 (s, 3H), 0.95 (s, 3H), 0.91 (s, 9H), 0.05 (d, J = 1.8 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 175.81, 158.71, 137.00, 130.69, 130.57, 119.38, 111.69, 98.07, 97.44, 82.16, 56.91, 56.30, 55.36, 50.01, 43.87, 39.56, 36.72, 25.88, 23.96, 18.82, 18.14, -4.48, -4.91. FTIR (Neat, NaCl, thin film): 3417, 2928, 2855, 1774, 1470, 1257, 1095, 1045 835 cm1 . HRMS (ESI): calc’d for [M+H]+ 477.2594, found 477.2671. Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 97 O O TBSO Me H Me OMe OMOM 91 TLC (5% Ether/DCM): Rf 0.62 (p-anisaldehyde, stains blue). 1 H NMR (400 MHz, CDCl3): δ 6.98 (d, J = 8.6 Hz, 1H), 6.80 (dd, J = 8.6, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 4.84 (d, J = 6.7 Hz, 1H), 4.74 (d, J = 6.7 Hz, 1H), 4.13 (dd, J = 11.5, 6.2 Hz, 1H), 3.78 (s, 3H), 3.74 (dd, J = 4.6, 1.5 Hz, 1H), 3.42 (s, 3H), 3.18 – 3.08 (m, 2H), 3.02 (dd, J = 16.7, 6.3 Hz, 1H), 2.91 (dd, J = 18.1, 0.9 Hz, 1H), 2.35 (ddd, J = 14.1, 4.6, 1.0 Hz, 1H), 2.15 (dd, J = 14.0, 1.5 Hz, 1H), 1.32 (s, 3H), 1.16 (s, 3H), 0.92 (s, 9H), 0.06 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 175.32, 157.85, 136.66, 131.85, 128.33, 114.45, 112.77, 97.60, 96.70, 83.32, 80.55, 77.23, 55.75, 55.29, 52.54, 52.25, 52.09, 49.19, 34.56, 25.80, 23.49, 21.10, 18.22, -4.77, -5.01. FTIR (Neat, NaCl, thin film): 3423, 2932, 2856, 1774, 1412, 1313, 1011, 1045 845 cm1 . HRMS (ESI): calc’d for [M+H]+ 477.2594, found 477.2695. 98 Chapter 2 – Vinylogous Mukaiyama Aldol and a-enolate arylation model studies 2.9 NOTES AND REFERENCES (1) Casiraghi, G.; Battistini, L.; Claudio, C.; Rassu, G.; Zanardi, F. The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress. Chem. Rev. 2011, 111, 3076–3154. (2) Adamkiewicz, A.; Weglarz, I.; Butkiewicz, A.; Woyciechowska, M.; Mlynarski, J. Lewis Acid-Catalyzed Stereoselective a-Addition of Chiral Aldehydes to Cyclic Dienol Silanes: Aqueous Synthesis of Chiral Butenolides. Adv. Synth. Catal. 2020, 362, 667–678. (3) Wu, T.; Kang, X.; Bai, H.; Xiong, W.; Xu, G.; Tang, W. Enantioselective Construction of Spiro Quaternary Carbon Stereocenters via Pd-Catalyzed Intramolecular a-Arylation. Org. Lett. 2020, 22, 4602–4607. (4) Kapadia, N.; Harding, W. Facile Synthesis of 4,5,6a,7- tetrahydrodibenzo[de,g]chromene Heterocycles and Their Transformation to Phenanthrene Alkaloids. Tetrahedron, 2013, 69, 8914–8920. 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Tetrahedron Letters. 2017, 58, 4285–4288. 105 Appendix 2 – Supporting Information Relevant to Chapter 2 Appendix 2 Supporting Information Relevant to Chapter 2: Vinylogous Mukaiayama Aldol and -enolate arylation model studies 8 .0 Spectral Size Acquired Size Nucleus 7.5 65536 24000 1H 8000.0 7.0 1.02 0.98 Spectral Width 6.5 2021-07-22T12 10 51 3 .0000 5.6500 1.0000 60 8 1D s2pul 3 .0 cdcl3 Varian PROTON01 6.0 63 5.5 f1 (ppm) 5.0 / Volumes/ nmrdata/ jkthomps/ vnmrsys/ data/ JKT-1-163-1/ PROTON01. fid/ fid 7.08 7.02 Spectrometer Frequency 499.59 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title Data File Name 6.71 1.01 7.43 1.00 Value 1.12 Parameter 1.12 4.5 4.0 3.82 3.47 3 .5 3 .0 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 7.6 7.23 6.82 6.78 7.4 7.2 1.05 Spectral Size Acquired Size Nucleus 7.0 Spectral Width 6. 8 0.99 1.98 Value 6.6 6.4 65536 24000 1H 8000.0 6.2 6.0 2021-08-02T10 17 44 3 .0000 5.6500 1.0000 42 8 1D s2pul 3 .0 cdcl3 Varian PROTON01 5. 8 5.6 5.4 5.2 5.0 64 4. 8 f1 (ppm) 4.6 4.4 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 3.87 3.81 1.98 2.99 / Volumes/ nmrdata/ jkthomps/ vnmrsys/ data/ JKT-1-178 _sm/ PROTON01. fid/ fid Spectrometer Frequency 499.59 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title Data File Name Parameter 2.86 2.00 2.6 2.4 2.2 2.0 -400 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 cdcl3 3 .0 s2pul 1D 8 54 1.0000 5.6500 3 .0000 2022-01-31T14 23 09 Solvent Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 8 .5 8 .0 65536 Spectral Size 9.0 24000 Acquired Size 9.5 1H Nucleus 10.0 8000.0 Spectral Width Spectrometer Frequency 499.58 Varian Origin 7.5 7.0 6.5 6.0 5.5 5.0 f1 (ppm) 61 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 / Users/ jordankthompson/ Desktop/ JKT-1-305 _smaldehyde/ PROTON01. fid/ fid PROTON01 21000 22000 Value 7.49 1.05 Title Data File Name Parameter 6.77 2.05 9.74 1.00 3.82 3.79 2.09 3.13 159.31 1.1622 2022-01-31T18 04 56 Acquisition Time Acquisition Date 200 65536 Spectral Size 210 32768 Acquired Size 220 13C Nucleus 230 28195.5 Spectral Width 130 f1 (ppm) 120 10.0000 Pulse Width 140 1.0000 Relaxation Delay 150 72.0 Receiver Gain 160 512 Number of Scans 170 1D Experiment 180 zgpg30 Pulse Sequence 190 297.1 Temperature 61 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 198.39 JKT-1-305 _smaldehyde.2. fid 133.71 Title 128.47 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-305 _smaldehyde/ 2/ fid Value 117.48 115.41 115.07 Data File Name Parameter 110 100 90 80 70 60 50 50.82 55.65 40 30 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 7.5 1D 16 142. 8 1.0000 12.5000 4.0894 2021-12-22T10 22 26 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.0 f1 (ppm) 3 .5 zg30 Pulse Sequence 4.5 297.2 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin 71 JKT-1-characterization-1.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-characterization-1/ 1/ fid Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.15 6.17 2.80 4.00 1.0 0.5 0.0 -30000 -20000 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 110000 120000 130000 140000 150000 160000 170000 180000 190000 200000 210000 220000 230000 240000 210 38 .0 1.0000 10.0000 1. 3631 2021-12-22T10 44 26 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 160 65536 Spectral Size 180 32768 Acquired Size 190 13C Nucleus 200 24038 .5 Spectral Width 110 f1 (ppm) 90 512 Number of Scans 100 1D Experiment 120 zgpg30 Pulse Sequence 130 297.2 Temperature 140 CDCl3 Solvent 150 Bruker BioSpin GmbH Origin 71 JKT-1-characterization-1.2. fid Title Spectrometer Frequency 100.62 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-characterization-1/ 2/ fid Value Data File Name Parameter 80 70 60 50 40 30 20 20.38 34.82 52.77 216.49 10 0 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 1D 8 48 1.0000 5.6500 3 .0000 2024-01-22T11 59 49 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 24000 Acquired Size 6.5 1H Nucleus 7.0 8000.0 Spectral Width 0.97 4.0 3 .5 f1 (ppm) 3 .0 s2pul Pulse Sequence 4.5 25.0 Temperature 5.0 cdcl3 Solvent 5.5 Varian Origin 70 PROTON01 Title Spectrometer Frequency 499.55 / Users/ jordankthompson/ Desktop/ JKT-5-224_sm/ PROTON01. fid/ fid Value 4.05 Data File Name Parameter 1.5 2.25 2.05 2.47 1.00 1.0 1.91 1.01 2.0 1.77 1.03 2.5 1.04 6.00 0.5 0.0 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 10.0000 1.2496 2022-05-13T18 03 43 Pulse Width Acquisition Time Acquisition Date 190 180 65536 Spectral Size 200 32768 Acquired Size 210 13C Nucleus 220 26223 . 8 Spectral Width 110 f1 (ppm) 100 1.0000 Relaxation Delay 120 87. 8 Receiver Gain 130 512 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature 170 CDCl3 Solvent 70 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-1_monoketone.2. fid Value Title Parameter / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-1_monoketone/ 2/ fid 221.23 Data File Name 90 78.35 80 70 60 50.18 50 40 27.84 30 22.29 20 16.93 34.27 10 0 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 7.5 1D 8 54 1.0000 5.6500 3 .0000 2024-03-07T14 09 59 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 24000 Acquired Size 6.5 1H Nucleus 7.0 8000.0 Spectral Width 1.00 4.0 3 .5 f1 (ppm) 3 .0 s2pul Pulse Sequence 4.5 25.0 Temperature 5.0 cdcl3 Solvent 5.5 Varian Origin 69 PROTON01 Title Spectrometer Frequency 499.55 / Users/ jordankthompson/ Desktop/ JKT-6-13 _sm/ PROTON01. fid/ fid Value 3.95 Data File Name Parameter 2.0 1.5 0.5 2.17 2.01 2.44 1.05 0.0 1.84 0.98 1.0 1.00 0.98 0.90 6.14 9.06 2.5 0.08 5.65 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 1.0000 10.0000 1.2059 2024-03-15T16 36 57 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 190 180 65536 Spectral Size 200 32768 Acquired Size 210 13C Nucleus 220 27173 .9 Spectral Width 120 72.0 Receiver Gain 130 300 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.2 Temperature 170 CDCl3 Solvent 110 100 f1 (ppm) 69 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-13 _sm_13C_RR.1. fid Title Value / Users/ jordankthompson/ Desktop/ JKT-6-13 _sm_13C_RR/ 1/ fid 221.65 Data File Name Parameter 90 78.75 80 70 60 50.52 50 40 20 28.53 25.86 22.24 18.18 17.65 30 10 0 -4.41 -4.81 34.38 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 7.5 7.0 Spectral Size Acquired Size Nucleus Spectral Width 6.5 6.0 65536 11990 1H 4796.2 5.5 2021-04-15T13 15 19 2.4999 5.1000 1.0000 34 8 1D s2pul 25.0 cdcl3 Varian PROTON01 Spectrometer Frequency 300.09 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title 3.99 5.0 4.5 4.0 1.00 4.25 1.98 3 .5 f1 (ppm) 67 3 .0 2.5 / Users/ jordankthompson/ Desktop/ CMF_1_136_columnSpotA/ PROTON01. fid/ fid Value 3.27 0.97 Data File Name 6.60 0.84 2.91 1.00 Parameter 2.0 1.5 0.5 1.05 5.97 1.31 3.06 0.0 0.87 9.29 1.0 0.08 5.78 0 50 100 150 200 250 300 350 400 450 500 1D 8 30 1.0000 5.1000 2.4999 2021-04-14T16 34 15 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 65536 Spectral Size 6.5 11990 Acquired Size 7.0 1H Nucleus 7.5 4796.2 Spectral Width 4.5 s2pul Pulse Sequence 5.0 25.0 Temperature 5.5 cdcl3 Solvent Spectrometer Frequency 300.09 Varian Origin 4.72 Downloads 4.0 3 .5 f1 (ppm) 4.28 6.00 Title 3.96 2.00 / Users/ jordankthompson/ Downloads/ fid Value 3.13 1.98 Data File Name Parameter 3 .0 72 2.5 2.0 1.5 0.5 1.30 9.05 1.88 3.01 2.25 1.03 2.81 1.07 0.0 1.04 1.00 0.88 3.29 6.10 9.09 1.0 0.06 5.89 1.00 0 50 100 150 200 250 300 350 400 450 16 78 .7 1.0000 12.5000 4.0894 2024-03-07T20 13 25 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 3 .5 f1 (ppm) 1D Experiment 4.0 zg30 Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6_13 _pure.1. fid Title 4.15 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6_13 _pure/ 1/ fid Value 3.69 Data File Name Parameter 3 .0 73 2.5 0.0 2.14 1.02 0.5 1.85 1.03 1.0 0.75 0.70 0.69 2.97 12.14 1.5 0.00 9.02 2.0 -0.15 5.97 1.01 1.00 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 512 64.2 1.0000 10.0000 1. 3631 2024-03-07T20 34 38 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 130 65536 Spectral Size 140 32768 Acquired Size 150 13C Nucleus 160 24038 .5 Spectral Width 80 f1 (ppm) 1D Experiment 90 zgpg30 Pulse Sequence 100 297.1 Temperature 110 CDCl3 Solvent 120 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6_13 _pure.2. fid 159.52 Title 95.64 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6_13 _pure/ 2/ fid Value 79.30 Data File Name Parameter 70 60 73 50 40 30 18.25 18.61 20 10 0.22 0 -4.29 -4.73 25.99 24.24 35.49 46.13 -10 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 1D 16 156.2 1.0000 12.5000 4.0894 2021-04-15T19 31 47 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 zg30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent f1 (ppm) 1.00 4.0 3 .5 74 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 CMF_1_137 _spotA.1. fid Title 4.14 / Users/ jordankthompson/ Desktop/ CMF_1_137 _spotA/ 1/ fid Value 3.95 Data File Name Parameter 3 .0 2.5 2.0 1.5 0.5 1.25 3.43 1.62 0.99 2.38 1.96 2.62 0.93 2.82 0.98 0.0 1.05 0.94 0.89 2.99 3.00 8.99 1.0 0.08 6.00 1.94 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 10.0000 1. 3631 2021-04-15T19 46 58 Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Size 150 32768 Acquired Size 160 13C Nucleus 170 24038 .5 Spectral Width 80 2.0000 Relaxation Delay f1 (ppm) 43 .7 Receiver Gain 90 256 Number of Scans 100 1D Experiment 110 zgpg30 Pulse Sequence 120 297.2 Temperature 130 CDCl3 Solvent 74 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 CMF_1_137 _spotA.2. fid Title Value / Users/ jordankthompson/ Desktop/ CMF_1_137 _spotA/ 2/ fid 172.35 Data File Name Parameter 70 60.81 60 50.21 50 40 30 18.16 17.89 14.36 20 10 0 -4.30 -4.79 22.75 25.87 35.46 35.13 42.82 -100 0 100 200 300 400 500 600 700 800 900 1000 10.5 197.4 1.5000 12.5000 0.2135 2021-04-15T19 58 44 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 7.5 7.0 (4.68 , 16.22) Digital Resolution 8 .0 (1024, 1024) Spectral Size 8 .5 (1024, 180) Acquired Size 9.0 (1H, 13C) Nucleus 9.5 (-517.1, -1262. 8) Lowest Frequency 10.0 (4795.4, 16611. 3) Spectral Width 3 .5 2 Number of Scans 4.0 HSQC-EDITED Experiment 4.5 f2 (ppm) hsqcedetgpsisp 2.4 Pulse Sequence 5.0 297.2 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 6.5 CMF_1_137 _spotA. 3 .ser Title Spectrometer Frequency (400.13 , 100.62) / Users/ jordankthompson/ Desktop/ CMF_1_137 _spotA/ 3/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 74 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 4 197.4 1. 8000 12.5000 0.2560 2021-04-16T00 15 22 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 7.0 (3 .91, 3 .91) Digital Resolution 7.5 (1024, 1024) Spectral Size 8 .0 (1024, 256) Acquired Size 8 .5 (1H, 1H) Nucleus 9.0 (-158 .1, -158 .1) Lowest Frequency 9.5 (4000.0, 4000.0) Spectral Width 4.0 NOESY Experiment 4.5 f2 (ppm) noesygpphzs Pulse Sequence 5.0 297.2 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 6.5 CMF_1_137 _spotA.4.ser Title Spectrometer Frequency (400.13 , 400.13) / Users/ jordankthompson/ Desktop/ CMF_1_137 _spotA/ 4/ ser Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 74 0.0 9 8 7 6 5 4 3 2 1 0 f1 (ppm) 8 .0 1 64.2 1.9205 12.5000 0.2765 2021-04-16T14 51 22 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .62, 3 .62) Digital Resolution 5.5 (1024, 1024) Spectral Size 6.0 (1024, 128) Acquired Size 6.5 (1H, 1H) Nucleus 7.0 (-460.9, -460.9) Lowest Frequency 7.5 (3703 .7, 3703 .7) Spectral Width 2.5 COSY Experiment 3 .0 cosygpppqf Pulse Sequence 3 .5 f2 (ppm) 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin 5.0 CMF_1_137 _ COSY.2.ser Title Spectrometer Frequency (400.13 , 400.13) / Users/ jordankthompson/ Desktop/ CMF_1_137 _ COSY/ 2/ ser Value Data File Name Parameter 2.0 1.5 1.0 0.5 0.0 -0.5 74 -1.0 8 7 6 5 4 3 2 1 0 -1 f1 (ppm) 7.5 1D 16 197.4 1.0000 12.5000 4.0894 2022-01-25T21 51 45 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 4.0 zg30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 75 Bruker BioSpin GmbH Origin 1.00 Spectrometer Frequency 400.13 JKT-1-297-3 _washed. 3 . fid Title 4.42 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-297-3 _washed/ 3/ fid Value 3.73 Data File Name Parameter 1.01 3 .5 f1 (ppm) 2.0 1.5 0.5 2.42 2.29 1.04 1.05 2.83 1.03 3.03 1.03 0.0 1.59 1.03 1.0 1.13 3.09 2.5 0.88 0.87 8.74 3.59 3 .0 0.04 6.15 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 23000 177.67 10.0000 1. 3631 2022-01-25T08 44 08 Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Size 160 32768 Acquired Size 170 13C Nucleus 180 24038 .5 Spectral Width 110 80 1.0000 Relaxation Delay f1 (ppm) 64.2 Receiver Gain 90 512 Number of Scans 100 1D Experiment 120 zgpg30 Pulse Sequence 130 297.2 Temperature 140 CDCl3 Solvent 75 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-1-297-3 _washed.2. fid Title 92.07 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-297-3 _washed/ 2/ fid Value 81.58 Data File Name Parameter 70 60 50 41.42 37.91 35.74 40 30 18.91 18.18 20 10 0 -4.63 -4.99 25.84 25.11 47.58 -10 -50 0 50 100 150 200 250 300 350 400 450 500 1.0000 12.5000 4.0894 2023-08-26T14 16 05 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 3.5 176. 8 Receiver Gain f1 (ppm) 16 Number of Scans 4.0 1D Experiment 5.0 zg30 Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 60 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-4-Compound5. 3 . fid 5.74 1.00 Title 4.66 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-Compound5/ 3/ fid Value 4.14 Data File Name Parameter 2.5 2.0 1.5 0.5 1.23 3.02 2.31 1.05 2.96 1.09 0.0 0.90 9.03 1.0 0.61 3.03 3.0 0.07 6.05 1.05 1.03 0 5000 10000 15000 20000 25000 30000 35000 40000 180 113.11 1.0000 10.0000 1. 3631 2023-08-26T14 37 55 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Size 150 32768 Acquired Size 160 13C Nucleus 170 24038 .5 Spectral Width 80 72.0 Receiver Gain 90 f1 (ppm) 512 Number of Scans 100 1D Experiment 110 zgpg30 Pulse Sequence 120 297.1 Temperature 130 CDCl3 Solvent 60 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-4-Compound5.4. fid 175.42 173.32 Title 90.78 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-Compound5/ 4/ fid Value 79.05 Data File Name Parameter 70 60 50 40 30 18.10 20 11.65 10 0 -4.46 -4.92 25.88 24.61 32.89 45.02 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 1D 16 72.0 1.0000 12.5000 4.0894 2023-07-08T01 38 51 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 6.0 4.5 zg30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 1.00 1.00 4.0 3.5 f1 (ppm) 77 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-4-203 _pure.1. fid Title 5.96 5.86 1.00 1.04 / Users/ jordankthompson/ Desktop/ JKT-4-203 _pure/ 1/ fid Value 4.09 4.00 Data File Name Parameter 3.0 2.5 2.0 1.5 0.5 0.0 1.01 0.96 0.89 3.10 3.18 9.43 1.0 0.07 5.96 -0.5 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 136.46 135.30 1D 512 64.2 1.0000 10.0000 1. 3631 2023-07-08T02 00 04 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 110 65536 Spectral Size 120 32768 Acquired Size 130 13C Nucleus 140 24038 .5 Spectral Width 70 f1 (ppm) zgpg30 Pulse Sequence 80 297.2 Temperature 90 CDCl3 Solvent 100 Bruker BioSpin GmbH Origin 60 77 JKT-4-203 _pure.2. fid Title Spectrometer Frequency 100.62 / Users/ jordankthompson/ Desktop/ JKT-4-203 _pure/ 2/ fid Value 83.09 82.78 Data File Name Parameter 50 40 30 18.27 17.04 20 10 0 -4.35 -4.70 26.33 25.98 47.22 -10 0 500 1000 1500 2000 2500 3000 3500 4000 zg30 1D 16 197.4 1.0000 12.5000 4.0894 2024-05-17T15 14 13 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 ST-BrAcetal-1-h.1. fid 5.71 2.00 Title 4.71 / Users/ shawnteh/ Desktop/ ST-BrAcetal-1-h/ 1/ fid 4.10 4.04 Data File Name Value 0.97 0.99 4.0 3.59 2.18 3.5 f1 (ppm) 78 3.33 2.05 Parameter 3.0 2.5 2.0 1.5 0.0 1.17 1.09 3.77 3.01 0.5 0.84 10.55 1.0 -0.00 6.62 0.98 -0.5 0 5000 10000 15000 20000 25000 136.03 135.92 132.10 131.33 1024 78 .7 1.0000 10.0000 1. 3631 2024-05-17T23 23 56 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 120 32768 Acquired Size 130 13C Nucleus 140 24038 .5 Spectral Width 70 1D Experiment 80 zgpg30 Pulse Sequence 90 297.2 Temperature 100 CDCl3 Solvent 110 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-BrAcetal-1-c. 3 . fid 102.55 101.12 Title Value 88.11 86.70 / Users/ shawnteh/ Desktop/ ST-BrAcetal-1-c/ 3/ fid Parameter 82.43 82.40 Data File Name f1 (ppm) 61.93 61.28 60 78 50.16 49.68 50 40 32.29 32.05 30 18.32 16.71 16.68 15.36 15.33 20 10 0 -4.39 -4.67 25.76 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 3.41 3.69 3.65 2024-04-12T17 17 30 Acquisition Date 6.0 65536 Spectral Size 6.5 16384 Acquired Size 7.0 1H Nucleus 7.5 9592. 3 Spectral Width 1.04 4.0 0.99 1.03 3.5 f1 (ppm) 2.18 2.0 1.06 1.5 1.0 1.7080 Acquisition Time 2.5 2.6500 Pulse Width 3.0 1.0000 Relaxation Delay 4.5 38 Receiver Gain 5.0 8 Number of Scans 5.5 1D Experiment 79 s2pul Pulse Sequence 1.06 Spectrometer Frequency 599.56 25.0 Temperature 5.19 1.00 cdcl3 4.06 Solvent 2.79 Varian 2.09 Origin 1.85 KCY-2-ST-sp3-PROTON_ 01 1.43 Title 1.18 / Volumes/ nmrdata/ kyoungbl/ vnmrsys/ data/ KCY-2-ST-sp3 _20240412_ 01/ KCY-2-ST-sp3-PROTON_ 01. fid/ fid Value 0.5 0.0 0.95 0.90 0.88 3.16 3.58 9.62 Data File Name Parameter 0.02 5.72 3.21 1.08 1.05 -50 0 50 100 150 200 250 300 350 400 450 500 106.53 81.25 1.0000 10.0000 1. 3631 2024-05-17T23 47 29 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 105 100 95 65536 Spectral Size 110 32768 Acquired Size 115 13C Nucleus 120 24038 .5 Spectral Width 60 55.5 Receiver Gain 65 512 Number of Scans 70 1D Experiment 75 zgpg30 Pulse Sequence 80 297.1 Temperature 85 CDCl3 Solvent 90 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-Acetal-2-c. 3 . fid Title 92.70 / Users/ shawnteh/ Desktop/ ST-Acetal-2-c/ 3/ fid Value 63.59 Data File Name Parameter 55 50 f1 (ppm) 79 44.94 45 35 38.74 38.31 37.23 40 30 28.06 25.96 25 20 15.24 15 10 5 0 -5 -4.28 -4.82 17.64 -10 -15 0 50 100 150 200 250 300 350 400 450 500 7.34 7.67 7.0 6.5 65536 Spectral Size 7.5 32768 Acquired Size 8 .0 1H 8012. 8 Nucleus Spectral Width 6.0 5.5 2022-01-25T21 27 06 Acquisition Date Spectrometer Frequency 400.13 4.0894 Acquisition Time 1.0000 Relaxation Delay 12.5000 78 .7 Receiver Gain Pulse Width 16 Number of Scans zg30 Pulse Sequence 1D 297.2 Experiment CDCl3 Bruker BioSpin GmbH JKT-1-298 _pure. 3 . fid Temperature 1.96 Value 5.0 4.5 80 4.0 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-298 _pure/ 3/ fid Solvent Origin Title Data File Name 3.02 3.88 3.75 3.67 f1 (ppm) 1.00 0.96 1.01 Parameter 3 .5 2.5 2.0 1.5 0.5 1.66 1.05 2.30 1.01 3.08 1.01 0.0 1.06 3.17 1.0 0.85 0.75 9.87 3.03 3 .0 0.01 6.00 -0.5 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 176.49 129.47 129.17 127.10 64.2 1.0000 10.0000 1. 3631 2022-01-25T12 16 51 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 160 150 65536 Spectral Size 170 32768 Acquired Size 180 13C Nucleus 190 24038 .5 Spectral Width 110 90 f1 (ppm) 512 Number of Scans 100 1D Experiment 120 zgpg30 Pulse Sequence 130 297.1 Temperature 140 CDCl3 Solvent 80 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-1-298 _pure.2. fid Title 136.03 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-298 _pure/ 2/ fid Value 90.49 Data File Name Parameter 81.21 80 70 60 40 47.51 45.72 45.45 41.50 50 30 18.90 18.16 20 10 0 -4.67 -5.02 25.83 24.76 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 8.01 Data File Name 8 .5 Spectral Size Acquired Size Nucleus Spectral Width 8 .0 1.98 7.5 Value 7.0 65536 32768 1H 8012. 8 6.5 6.0 2024-01-23T20 04 33 4.0894 12.5000 1.0000 197.4 16 1D zg30 297.1 CDCl3 Bruker BioSpin GmbH JKT-5-224_pure.1. fid 5.5 5.0 4.5 4.0 f1 (ppm) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-5-224_pure/ 1/ fid Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title 7.58 7.45 1.05 2.16 5.38 1.00 Parameter 3 .5 81 3 .0 2.0 1.5 2.12 0.90 2.47 3.07 2.5 1.15 6.08 1.0 0.5 0.0 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 219.82 1.0000 10.0000 1.2059 2024-01-23T20 25 08 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 200 190 65536 Spectral Size 210 32768 Acquired Size 220 13C Nucleus 230 27173 .9 Spectral Width 120 f1 (ppm) 55.5 Receiver Gain 130 512 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.2 Temperature 170 CDCl3 Solvent 180 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-5-224_pure.2. fid Title 165.95 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-5-224_pure/ 2/ fid Value 133.39 129.73 128.64 Data File Name Parameter 110 100 81 90 80.48 80 70 60 49.55 50 40 30 20 17.90 25.63 22.78 34.30 0 100 200 300 400 500 600 700 800 900 1000 1D 16 197.4 1.0000 12.5000 4.0894 2024-03-15T18 22 03 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 1.00 4.0 f1 (ppm) zg30 Pulse Sequence 5.0 297.2 Temperature 5.5 CDCl3 Solvent 82 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-24-1. 3 . fid Title 4.14 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-24-1/ 3/ fid Value 4.01 Data File Name Parameter 3 .5 3 .0 2.5 1.5 0.5 1.94 0.99 2.16 1.00 2.41 1.03 2.74 1.02 2.89 1.00 0.0 1.25 3.14 1.0 1.04 0.98 0.88 3.00 3.00 9.01 2.0 0.08 6.02 2.02 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 10.0000 1. 3631 2024-03-15T18 50 51 Pulse Width Acquisition Time Acquisition Date 200 190 180 65536 Spectral Size 210 32768 Acquired Size 220 13C Nucleus 230 24038 .5 Spectral Width 130 100 f1 (ppm) 1.0000 Relaxation Delay 110 64.2 Receiver Gain 120 700 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature 170 CDCl3 Solvent 82 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-24-1.2. fid Value Title 221.61 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-24-1/ 2/ fid 172.11 Data File Name Parameter 90 80 70 60.74 60 51.01 50 41.84 40 30 25.87 23.13 18.89 18.21 14.35 20 10 0 -4.54 -4.84 35.38 34.90 77.09 -10 -20 -30 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1.0000 5.6500 3 .0000 2024-03-15T11 01 23 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 24000 Acquired Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 5.0 4.0 48 .0 Receiver Gain 4.5 8 Number of Scans 5.5 1D Experiment 83 s2pul Pulse Sequence Spectrometer Frequency 499.55 25.0 Temperature 4.12 cdcl3 3.65 Varian 0.98 3 .5 f1 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 3.25 1.00 Solvent 2.15 2.05 Origin 1.84 1.72 1.62 3.00 1.99 1.00 PROTON01 1.28 6.04 Title 1.03 0.95 0.88 3.14 3.01 6.05 18.05 / Users/ jordankthompson/ Desktop/ JKT-6-14-1_nextweek / PROTON01. fid/ fid Value 0.18 18.08 Data File Name Parameter 0.01 12.02 4.02 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 10.0000 1. 2496 2024-03-15T15 27 50 Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 26223 . 8 Spectral Width 70 1.0000 Relaxation Delay 80 f1 (ppm) 72.0 Receiver Gain 90 750 Number of Scans 100 1D Experiment 110 z gpg30 Pulse Sequence 120 297.1 Temperature 130 CDCl3 Solvent 83 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-6-14-1_13C.1. fid Origin 170.89 170.54 Title Value 78.64 76.50 76.40 75.70 73.21 / Volumes/ nmrdata-1/ data/ florence/ backup_nas/ jkthomps/ nmr/ JKT-6-14-1_13C/ 1/ fid Parameter 60 60.66 60.49 Data File Name 50 30 20 10 33.26 32.29 31.80 30.40 28.69 26.62 25.98 25.95 25.88 22.25 21.60 19.31 18.22 18.14 14.54 14.39 40 1.68 1.41 0 -4.32 -4.86 46.08 45.65 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1D 16 112. 8 1.0000 12.5000 4.0894 2024-04-05T07 51 36 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 4.0 zg30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 84 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-59-1.1. fid Title 4.14 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-59-1/ 1/ fid Value 3.66 Data File Name Parameter 1.00 3 .5 f1 (ppm) 3 .0 2.0 0.5 1.88 1.02 2.61 2.50 2.42 2.29 1.03 1.03 1.04 1.04 3.29 1.01 0.0 1.52 1.02 1.0 1.26 3.15 1.5 0.96 0.88 0.87 3.02 12.17 2.5 0.03 6.02 2.01 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 180 750 64.2 1.0000 10.0000 1.1796 2024-04-05T08 20 07 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Size 150 32768 Acquired Size 160 13C Nucleus 170 27777. 8 Spectral Width 110 83.98 90 f1 (ppm) 1D Experiment 100 zgpg30 Pulse Sequence 120 297.1 Temperature 130 CDCl3 Solvent 84 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-59-1.2. fid Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-59-1/ 2/ fid 173.93 Data File Name Parameter 80 70 60.77 60 50 40.07 39.87 37.26 40 30 18.15 14.94 14.35 20 10 0 -4.36 -4.83 25.93 25.20 46.09 78.01 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 1D 16 176. 8 1.0000 12.5000 4.0894 2024-12-05T10 07 02 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 z g30 Pulse Sequence 5.0 297. 2 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 85 JKT-6-268 _pure2.1. fid Title Spectrometer Frequency 400.13 / Users/ jordankthompson/ Desktop/ JKT-6-268 _pure2/ 1/ fid Data File Name Value 4.01 3.96 4.0 1.00 3 .5 f1 (ppm) 3 .0 2.5 2.89 2.87 2.77 2.62 2.46 2.04 Parameter 1.94 2.0 1.5 0.5 0.0 1.06 0.97 0.89 3.03 2.99 8.99 1.0 0.07 6.05 1.64 0.99 2.03 2.17 -0.5 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 221.93 220.65 1.0000 10.0000 1.1796 2024-12-05T10 16 52 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 200 190 65536 Spectral Siz e 210 32768 Acquired Siz e 220 13C Nucleus 230 27777. 8 Spectral Width 130 78 .7 Receiver Gain 140 250 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297.1 Temperature 180 CDCl3 Solvent 120 85 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-268 _pure2. 2. fid Title Value / Users/ jordankthompson/ Desktop/ JKT-6-268 _pure2/ 2/ fid Parameter 177.01 176.83 Data File Name 110 f1 (ppm) 100 90 80 70 60 51.08 50.31 50 30 20 10 42.40 41.57 35.38 35.18 35.14 34.50 25.91 25.87 23.20 22.74 18.90 18.21 18.15 17.91 40 0 -10 -4.28 -4.55 -4.80 -4.85 0 50 100 150 200 250 300 350 400 1D 16 197.4 1.0000 12.5000 4.0894 2024-03-25T23 59 45 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 4.5 z g30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-30_pure.1. fid Title Value 4.83 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-30_pure/ 1/ fid Parameter 4.21 4.08 Data File Name 0.98 4.0 f1 (ppm) 86 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.10 6.10 0.89 9.30 1.12 5.99 2.14 1.01 2.62 2.02 2.89 0.99 0.99 1.00 0.0 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 1.0000 10.0000 1.1796 2024-03-26T00 38 30 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 190 180 65536 Spectral Siz e 200 32768 Acquired Siz e 210 13C Nucleus 220 27777. 8 Spectral Width 120 72.0 Receiver Gain 130 1024 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 170 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Value JKT-6-30_pure. 2. fid 217.89 Title 172.04 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-30_pure/ 2/ fid 159.61 Data File Name Parameter 110 100 f1 (ppm) 86 88.86 90 80 70 60 53.66 51.89 50 42.34 41.57 40 30 25.88 22.95 19.00 18.17 20 10 0 -4.44 -4.88 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 7.5 COSY 2 176. 8 1.9185 12.5000 0. 2785 2024-03-26T00 49 03 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .59, 3 .59) Spectral Siz e Digital Resolution 5.5 (1024, 128) Acquired Siz e 6.0 (1H, 1H) Nucleus 6.5 (-384.9, -378 .6) Lowest Frequency 7.0 (3676.5, 3676.5) Spectral Width 3 .5 f2 (ppm) cosygpppqf Pulse Sequence 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-6-30_pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-30_pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 86 -0.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 f1 (ppm) 197.4 1.5000 12.5000 0. 2135 2024-03-26T01 11 13 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 4.0 (4.68 , 16. 22) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 180) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.2 (-518 .5, -1262. 8) Lowest Frequency 5.4 (4795.4, 16611. 3) Spectral Width 2.6 2.4 f2 (ppm) 4 Number of Scans 2. 8 HSQC-EDITED Experiment 3 .0 hsqcedetgpsisp 2.4 Pulse Sequence 3 .2 297.1 Temperature 3 .4 CDCl3 Solvent 3 .6 Bruker BioSpin GmbH 3.8 JKT-6-30_pure.4.ser Origin Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-30_pure/ 4/ ser Title Value Data File Name Parameter 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 0.2 0.0 86 -0.2 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) HMBC 4 197.4 2.0000 12.5000 0.4 260 2024-03-26T01 54 58 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2. 35, 21. 80) Digital Resolution 6.0 (2048 , 1024) Spectral Siz e 6.5 (2048 , 256) Acquired Siz e 7.0 (1H, 13C) Nucleus 7.5 (-166.7, -1116.4) Lowest Frequency 8 .0 (4807.7, 22321.4) Spectral Width 4.0 f2 (ppm) hmbcetgpl3nd Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-6-30_pure.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-30_pure/ 5/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 86 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 50. 3 1.0000 12.5000 4.0894 2024-12-06T14 55 30 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 7.5 65536 Spectral Siz e 8 .0 32768 Acquired Siz e 8 .5 1H Nucleus 9.0 8012. 8 Spectral Width 6.0 4.5 16 Number of Scans 5.0 1D Experiment 5.5 z g30 Pulse Sequence 6.5 297. 2 Temperature 7.0 CDCl3 Solvent 87 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-269_pure_RR.1. fid Title Value / Users/ jordankthompson/ Desktop/ JKT-6-269_pure_RR/ 1/ fid Parameter Data File Name 3 .5 0.5 3.11 2.03 3.86 1.00 0.0 2.59 0.55 1.0 2.40 1.02 1.5 2.08 0.57 2.0 1.64 0.54 2.5 1.45 0.55 3 .0 1.16 1.04 0.87 3.04 3.11 9.15 4.0 f1 (ppm) 0.02 6.02 -0.5 -1.0 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 1.0000 10.0000 1.1796 2024-12-06T15 15 08 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 27777. 8 Spectral Width 140 100 78 .7 Receiver Gain 110 512 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent 87 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-269_pure_RR. 2. fid Title 174.94 174.39 / Users/ jordankthompson/ Desktop/ JKT-6-269_pure_RR/ 2/ fid Value 115.65 114.03 Data File Name Parameter f1 (ppm) 90 80.58 80 70 60 40 52.69 50.82 46.68 44.14 40.61 38.19 37.10 35.65 50 20 10 25.81 25.72 25.59 18.97 18.37 18.08 18.04 17.13 30 0 -10 -4.40 -4.73 -4.84 -5.04 76.20 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 1D 16 197.4 1.0000 12.5000 4.0894 2024-03-30T09 31 33 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.5 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 3 .5 f1 (ppm) zg30 Pulse Sequence 4.0 297.2 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 87A JKT-6-42-2.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-42-2/ 1/ fid Value 3.88 Data File Name Parameter 3 .0 2.0 0.5 1.47 0.95 2.42 1.03 2.60 1.05 3.15 2.03 0.0 1.19 3.10 1.0 1.06 3.06 1.5 0.86 9.03 2.5 0.03 6.04 1.00 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 1D 1000 55.5 1.0000 10.0000 1.1796 2024-03-30T10 09 25 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 80.59 180 170 160 150 140 130 100 50 40 30 20 10 0 -10 65536 Spectral Size -200 -100 0 100 200 300 400 500 600 700 800 900 32768 Acquired Size 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 13C 52.71 Nucleus 46.69 1000 60 40.62 27777. 8 37.11 Spectral Width 25.73 25.61 1100 70 18.09 17.15 Spectrometer Frequency 100.62 80 f1 (ppm) zgpg30 Pulse Sequence 90 297.1 Temperature 110 CDCl3 Solvent 120 Bruker BioSpin GmbH Origin 87A JKT-6-42-2.2. fid Title 174.42 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-42-2/ 2/ fid Value 115.66 Data File Name Parameter -4.72 -5.03 16 197.4 1.0000 12.5000 4.0894 2024-03-30T10 17 06 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 3 .5 f1 (ppm) 1D Experiment 4.0 zg30 Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin 87B JKT-6-42-1.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-42-1/ 1/ fid Value 3.87 Data File Name Parameter 2.5 1.5 0.5 2.37 1.00 3.07 2.00 0.0 2.07 0.95 1.0 1.65 1.00 2.0 1.13 1.01 0.88 2.88 2.89 9.19 3 .0 0.02 6.04 1.00 -0.5 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 1.0000 10.0000 1.1796 2024-03-30T10 54 57 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 150 Acquired Size Spectral Size 180 160 13C Nucleus 170 27777. 8 Spectral Width f1 (ppm) 55.5 Receiver Gain 90 1000 Number of Scans 100 1D Experiment 110 zgpg30 Pulse Sequence 120 297.2 Temperature 130 CDCl3 Solvent 140 Bruker BioSpin GmbH Origin 87B JKT-6-42-1.2. fid Spectrometer Frequency 100.62 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-42-1/ 2/ fid 174.98 Title Value 114.05 Data File Name Parameter 80 70 60 50.84 50 38.21 35.68 40 30 18.98 18.39 18.06 20 10 0 -4.38 -4.82 25.83 44.15 76.22 -10 -100 0 100 200 300 400 500 600 700 800 900 112. 8 1.0000 12.5000 4.0894 2022-01-31T14 46 01 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.00 4.0 f1 (ppm) 16 Number of Scans 3 .5 1D Experiment 4.5 zg30 Pulse Sequence 5.0 297.2 Temperature 5.5 CDCl3 Solvent 88 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-1-304_pure.1. fid 7.04 Title 4.74 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-304_pure/ 1/ fid Value 4.03 4.01 3.99 Data File Name Parameter 3 .0 0.0 2.52 2.51 2.49 2.47 1.02 0.5 2.11 2.10 2.08 2.06 1.02 1.0 0.97 3.02 1.5 0.78 0.73 0.69 2.97 9.01 9.02 2.0 0.00 6.01 2.5 -0.15 6.03 0.97 -0.5 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 190 117.77 1.0000 10.0000 1.1622 2022-01-31T15 07 54 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Size 160 32768 Acquired Size 170 13C Nucleus 180 28195.5 Spectral Width 110 80 f1 (ppm) 87. 8 Receiver Gain 90 512 Number of Scans 100 1D Experiment 120 zgpg30 Pulse Sequence 130 297.2 Temperature 140 CDCl3 Solvent 88 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-1-304_pure.2. fid 158.14 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-304_pure/ 2/ fid 151.21 Title Value 83.58 82.65 Data File Name Parameter 70 60 50 40 20 25.96 25.66 25.22 20.41 18.27 18.24 30 10 0 -10 -4.35 -4.69 -4.71 -4.75 34.05 42.97 -20 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 7.45 6.75 6.69 1D 16 197.4 1.0000 12.5000 4.0894 2021-08-05T13 57 57 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8012. 8 0.99 0.98 Spectral Width 6.0 z g30 Pulse Sequence Spectrometer Frequency 400.13 297. 2 Temperature Bruker BioSpin GmbH JKT-1-181-5.1. fid CDCl3 7.5 Value 5.5 5.0 59 4.5 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-181-5/ 1/ fid 5.90 1.00 Solvent Origin Title Data File Name 1.00 4.67 1.01 Parameter 3 .5 3 .0 2.0 1.5 1.0 0.5 1.65 1.04 2.29 1.00 2.58 1.04 3.12 2.05 3.78 3.04 4.34 1.00 0.0 1.26 3.01 2.5 0.89 0.78 9.16 2.99 4.0 f1 (ppm) 0.04 6.01 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 176.23 174.36 1. 3631 2021-12-22T14 01 33 Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 24038 .5 Spectral Width f1 (ppm) 10.0000 Pulse Width 90 1.0000 Relaxation Delay 100 55.5 Receiver Gain 110 512 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 140 297.1 59 CDCl3 Temperature Spectrometer Frequency 100.62 Bruker BioSpin GmbH Solvent 159.26 Origin 137.84 JKT-1-characterization-4.6. fid 133.97 Title Value 117.61 115.49 115.11 114.65 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-characterization-4/ 6/ fid Parameter 97.10 Data File Name 79.94 80 71.23 70 60 50 38.47 35.09 40 30 20.59 18.15 16.19 20 10 0 -4.47 -4.92 5.46 25.89 47.41 55.68 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 1.0000 10.0000 1. 3631 2021-12-22T14 01 33 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 13C Nucleus 7.5 24038 .5 Spectral Width 3 .5 55.5 Receiver Gain f2 (ppm) 512 Number of Scans 4.0 1D Experiment 4.5 z gpg30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-1-characterization-4.6. fid Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-characterization-4/ 6/ fid Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 59 0.0 8 .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) Parameter 8 .0 7.5 Spectral Size Acquired Size Nucleus 7.0 6.5 65536 32768 1H 8012. 8 0.99 Spectral Width 6.0 2024-02-06T15 41 27 4.0894 12.5000 1.0000 30. 3 16 1D zg30 297.2 CDCl3 Bruker BioSpin GmbH 5.5 JKT-5-246_sm_pure.1. fid Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title 6.65 Value 5.0 90 / Users/ jordankthompson/ Desktop/ JKT-5-246_sm_pure/ 1/ fid 4.50 4.5 1.01 7.38 1.00 5.82 0.99 6.80 1.00 4.16 4.00 3.86 3.76 4.0 f1 (ppm) 0.99 1.00 1.01 3.05 Data File Name 3 .5 2.5 2.0 1.5 1.0 0.5 1.35 3.01 2.30 1.05 3.22 3.08 3.07 2.96 1.03 4.00 1.03 0.0 0.89 0.77 8.99 3.03 3 .0 0.07 6.03 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 118.50 115.07 114.62 114.73 10.0000 1. 3631 2024-02-06T16 02 41 Pulse Width Acquisition Time Acquisition Date 65536 150 Spectral Size 180 140 32768 Acquired Size 160 13C Nucleus 170 24038 .5 Spectral Width 100 80 1.0000 Relaxation Delay 90 f1 (ppm) 64.2 Receiver Gain 110 512 Number of Scans 120 1D Experiment 130 zgpg30 Pulse Sequence 90 297.2 Temperature Spectrometer Frequency 100.62 CDCl3 Solvent 175.86 174.66 Bruker BioSpin GmbH 158.95 Origin 138.72 JKT-5-246_sm_pure.2. fid 133.31 Title 97.97 97.67 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-5-246_sm_pure/ 2/ fid Value 79.50 77.59 Data File Name Parameter 70 60 50 38.80 40 30 25.81 21.88 18.08 16.32 20 10 0 -4.45 -4.99 33.81 47.20 56.57 55.65 -10 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 COSY 1 10. 8 1.9308 12.5000 0. 2662 2024-02-06T16 08 25 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .76, 3 .76) Digital Resolution 5.5 (1024, 1024) Spectral Siz e 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-478 .5, -452.6) Lowest Frequency 7.5 (3846. 2, 3846. 2) Spectral Width 3 .5 f2 (ppm) cosygpppqf Pulse Sequence 4.0 297. 2 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-5-246 _sm_pure. 3 .ser Title Value / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-5-246 _sm_pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 90 0.0 -0.5 8 .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 7.37 2022-05-07T15 43 45 Acquisition Date 8 .0 7.5 Spectral Size Acquired Size Nucleus 7.0 6.5 65536 32768 1H 8012. 8 6.0 4.0894 Acquisition Time Spectrometer Frequency 400.13 12.5000 1.0000 Relaxation Delay Pulse Width 156.2 16 Number of Scans Receiver Gain 1D zg30 Pulse Sequence Experiment 297.1 CDCl3 Bruker BioSpin GmbH 5.5 JKT-1-compound11_1H.1. fid 1.00 1.02 Spectral Width Value 5.0 58 4.5 4.0 f1 (ppm) 3 .5 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-compound11_1H/ 1/ fid 6.82 6.68 Temperature Solvent Origin Title Data File Name 0.92 4.04 4.01 3.77 3.76 3.71 0.99 1.00 1.07 3.02 0.99 Parameter 2.5 2.0 0.5 2.34 2.09 3.08 3.07 2.94 4.22 0.0 1.48 1.03 1.0 1.26 1.15 2.91 3.04 1.5 0.91 9.37 3 .0 0.06 6.06 -0.5 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 178.18 118.48 115.14 114.96 1. 3631 2022-05-07T16 05 35 Acquisition Time Acquisition Date 160 65536 Spectral Size 170 32768 Acquired Size 180 13C Nucleus 190 24038 .5 Spectral Width 90 10.0000 Pulse Width 100 f1 (ppm) 1.0000 Relaxation Delay 110 64.2 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 zgpg30 Pulse Sequence 150 297.2 Temperature 58 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 159.04 Origin 138.58 JKT-1-compound11_13C.2. fid 133.09 Title 100.20 98.38 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-compound11_13C/ 2/ fid Value 86.10 Data File Name Parameter 80.19 80 70 60 48.96 50 41.93 40.40 40.15 38.71 40 30 20 25.88 23.48 19.92 18.25 56.96 55.72 10 0 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 2021-12-08T14 14 10 Acquisition Date Spectral Siz e Acquired Siz e Nucleus Spectral Width 7.0 6.5 6.0 65536 24000 1H 8000.0 5.5 3 .0000 Acquisition Time Spectrometer Frequency 499.58 5.6500 1.0000 Relaxation Delay Pulse Width 52 8 Receiver Gain 1D Number of Scans s2pul Experiment 3 .0 Pulse Sequence cdcl3 Varian PROTON01 5.0 57 4.5 4.0 / Users/ jordankthompson/ Desktop/ JKT-1-268-1/ PROTON01. fid/ fid Temperature Solvent Origin Title Data File Name Value 4.71 2.02 7.07 1.00 4.15 0.98 6.71 2.04 3.77 3.72 2.0 0.5 3.53 0.98 0.0 3.30 3.25 3.13 2.98 2.93 0.99 1.01 0.98 1.0 2.52 1.05 1.5 1.60 1.53 1.18 2.5 1.15 2.98 3 .0 0.95 0.91 2.89 8.98 3 .5 f1 (ppm) 3.02 1.03 Parameter 0.05 5.52 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 175.81 43 .7 2.0000 10.0000 1. 3631 2021-11-17T21 56 07 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 24038 .5 Spectral Width 120 100 128 Number of Scans 110 1D Experiment 130 z gpg30 Pulse Sequence 140 297.1 Temperature 57 CDCl3 Spectrometer Frequency 100.62 Bruker BioSpin GmbH 158.71 Solvent 137.00 Origin 130.69 130.57 JKT-1-263-1_13C. 2. fid 119.38 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-1_13C/ 2/ fid 111.69 Title Value 98.07 97.44 Data File Name Parameter 90 80 82.16 f1 (ppm) 70 56.91 56.30 55.36 60 50.01 50 43.87 39.56 36.72 40 30 18.82 18.14 20 10 0 -4.48 -4.91 25.88 23.96 -10 -50 0 50 100 150 200 250 300 350 400 450 2 64. 2 1.9349 12.5000 0. 2621 2021-11-17T22 06 35 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 . 81, 3 . 81) 7.0 Acquired Siz e Spectral Siz e Digital Resolution 8 .5 6.5 (1H, 1H) Nucleus 7.5 (-473 .4, -481.0) Lowest Frequency 8 .0 (3906. 3 , 3906. 3) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin 6.0 JKT-1-263-1_ COSY. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-1_ COSY/ 3/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 57 -0.5 -1.0 8 7 6 5 4 3 2 1 0 -1 f1 (ppm) 197.4 2.0000 12.5000 0.4 260 2021-11-18T12 05 12 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 9.0 8 .5 (2. 35, 21. 80) Digital Resolution 9.5 (2048 , 1024) Spectral Siz e 10.0 (2048 , 256) Acquired Siz e 10.5 (1H, 13C) Nucleus 11.0 (-172. 3 , -1116.4) Lowest Frequency 11.5 (4807.7, 22321.4) Spectral Width 5.5 f2 (ppm) 4 Number of Scans 6.0 HMBC Experiment 6.5 hmbcetgpl3nd Pulse Sequence 7.0 297. 2 Temperature 7.5 CDCl3 Solvent 8 .0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-1-263-1_HMBC.7.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-1_HMBC/ 7/ ser Parameter Data File Name 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 57 0.5 0.0 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 10.5 HSQC-EDITED 2 197.4 1.5000 12.5000 0.2135 2021-11-17T22:18:16 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (4.68, 16.22) Digital Resolution 8 .0 (1024, 1024) Spectral Size 8 .5 (1024, 180) Acquired Size 9.0 (1H, 13C) Nucleus 9.5 (-526.7, -1262.8) Lowest Frequency 10.0 (4795.4, 16611.3) Spectral Width 5.5 hsqcedetgpsisp2.4 Pulse Sequence 6.0 297.2 Temperature 6.5 CDCl3 Solvent 7.0 Bruker BioSpin GmbH 7.5 JKT-1-263-1_HSQC.4.ser Origin Spectrometer Frequency (400.13, 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-1_HSQC/ 4/ ser Title Value Data File Name Parameter 5.0 4.5 f2 (ppm) 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 57 -0.5 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) NOESY 4 64. 2 1. 8000 12.5000 0. 2560 2021-11-17T23 03 50 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) 8 .0 Spectral Siz e Digital Resolution 9.5 7.0 (1024, 256) Acquired Siz e 7.5 (1H, 1H) Nucleus 8 .5 (-165.0, -165.9) Lowest Frequency 9.0 (4000.0, 4000.0) Spectral Width 4.5 f2 (ppm) noesygpphzs Pulse Sequence 5.0 297. 2 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 6.5 JKT-1-263-1_NOESY.9.ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-1_NOESY/ 9/ ser Value Data File Name Parameter 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 57 0.5 0.0 9 8 7 6 5 4 3 2 1 0 f1 (ppm) 6.98 6.80 7.5 7.0 1.00 Spectral Siz e Acquired Siz e Nucleus Spectral Width 1.08 Value 6.5 65536 32768 1H 8012. 8 6.0 2021-11-18T00 44 30 4.0894 12.5000 1.0000 176. 8 16 1D z g30 297.1 CDCl3 Bruker BioSpin GmbH JKT-1-263-2-3 .1. fid 5.5 5.0 91 4.5 4.0 2.5 2.0 1.5 0.5 3.13 3.02 2.91 2.06 1.09 1.04 3.42 3.01 3.78 3.74 3.02 1.03 4.13 1.03 0.0 2.35 1.08 1.0 2.15 1.00 3 .0 1.32 2.98 3 .5 1.16 3.05 f1 (ppm) 0.92 8.99 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3/ 1/ fid Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title Data File Name 6.56 0.98 4.79 0.99 0.99 Parameter 0.06 5.96 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 157.85 10.0000 1. 3631 2021-11-18T12 31 30 Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 100 1.0000 Relaxation Delay 110 43 .7 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 91 297. 2 Temperature Spectrometer Frequency 100.62 CDCl3 Solvent 175.32 Bruker BioSpin GmbH 136.66 JKT-1-263-2-3 _. 2. fid 131.85 Origin 128.33 Title 114.45 112.77 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3 _/ 2/ fid Value 97.60 96.70 Data File Name Parameter 90 83.32 80.55 77.23 80 f1 (ppm) 70 50 55.75 55.29 52.54 52.25 52.09 49.19 60 40 30 25.80 23.49 21.10 18.22 20 10 0 -4.77 -5.01 34.56 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 2 197.4 1.5000 12.5000 0. 2135 2021-11-18T12 43 16 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 8 .0 7.5 (4.68 , 16. 22) Digital Resolution 8 .5 (1024, 1024) Spectral Siz e 9.0 (1024, 180) Acquired Siz e 9.5 (1H, 13C) Nucleus 10.0 (-553 .0, -1262. 8) Lowest Frequency 10.5 (4795.4, 16611. 3) Spectral Width 4.5 f2 (ppm) HSQC-EDITED Experiment 5.0 hsqcedetgpsisp 2.4 Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 6.5 Bruker BioSpin GmbH Origin 7.0 JKT-1-263-2-3 _. 3 .ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3 _/ 3/ ser Title Value Data File Name Parameter 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 91 -0.5 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 197.4 2.0000 12.5000 0.4 260 2021-11-18T21 59 03 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 8 .5 (2. 35, 21. 80) Digital Resolution 9.0 (2048 , 1024) Spectral Siz e 9.5 (2048 , 256) Acquired Siz e 10.0 (1H, 13C) Nucleus 10.5 (-196.9, -1116.4) Lowest Frequency 11.0 (4807.7, 22321.4) Spectral Width 5.5 f2 (ppm) 4 Number of Scans 6.0 HMBC Experiment 6.5 hmbcetgpl3nd Pulse Sequence 7.0 297. 2 Temperature 7.5 CDCl3 Solvent 8 .0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-1-263-2-3 _.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3 _/ 4/ ser Parameter Data File Name 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 91 0.5 0.0 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1 112. 8 1.9062 12.5000 0. 2908 2021-11-18T00 50 11 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .44, 3 .44) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-389.4, -389.4) Lowest Frequency 7.5 (3521.1, 3521.1) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-1-263-2-3 _ COSY. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3 _ COSY/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 91 -0.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 f1 (ppm) 4 197.4 1. 8000 12.5000 0. 2560 2021-11-18T01 35 56 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .91, 3 .91) Digital Resolution 7.0 (1024, 1024) Spectral Siz e 7.5 (1024, 256) Acquired Siz e 8 .0 (1H, 1H) Nucleus 8 .5 (-196. 8 , -189.1) Lowest Frequency 9.0 (4000.0, 4000.0) Spectral Width 4.5 f2 (ppm) NOESY Experiment 5.0 noesygpphzs Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 6.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-1-263-2-3 _NOESY.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-263-2-3 _NOESY/ 4/ ser Parameter Data File Name 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 91 0.0 9 8 7 6 5 4 3 2 1 0 f1 (ppm) 180 Appendix 2 – Supporting Information Relevant to Chapter 2 A2.2 CRYSTALLOGRAPHIC DATA RELEVANT TO CHAPTER 2 A2.2.1 Enolate arylation product 57 O O TBSO OMe Me Me H O MOM 57 Table A2.1. Crystal data and structure refinement for V22068. Identification code V22068 Empirical formula C26 H40 O6 Si Formula weight 476.67 Temperature 200(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P21/c Unit cell dimensions a = 20.0766(16) Å a= 90°. b = 9.3852(11) Å b= 94.599(9)°. c = 14.149(2) Å g = 90°. Volume 2657.3(5) Å3 Z 4 Density (calculated) 1.191 Mg/m3 Absorption coefficient 1.077 mm-1 F(000) 1032 Crystal size 0.300 x 0.300 x 0.150 mm3 Theta range for data collection 4.419 to 74.585°. Index ranges -25<=h<=25, -11<=k<=11, -17<=l<=17 Reflections collected 63428 Independent reflections 5421 [R(int) = 0.0660] 181 Appendix 2 – Supporting Information Relevant to Chapter 2 Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.5818 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5421 / 431 / 376 Goodness-of-fit on F2 1.026 Final R indices [I>2sigma(I)] R1 = 0.0414, wR2 = 0.1024 R indices (all data) R1 = 0.0540, wR2 = 0.1129 Extinction coefficient n/a Largest diff. peak and hole 0.268 and -0.272 e.Å-3 Table A2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22068. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ O(1) 6995(1) 5679(1) 2646(1) 42(1) C(1) 6980(1) 4476(2) 3164(1) 40(1) O(2) 6816(1) 3354(1) 2812(1) 54(1) C(2) 7188(1) 4803(1) 4197(1) 38(1) C(3) 7573(1) 6204(2) 4138(1) 38(1) C(4) 8321(1) 6072(2) 3970(1) 50(1) C(5) 8396(1) 6572(2) 2950(1) 44(1) O(3) 8377(1) 5377(1) 2329(1) 46(1) Si(1) 9029(1) 4802(1) 1828(1) 53(1) C(21) 9707(3) 4331(11) 2740(6) 120(3) C(22) 9324(2) 6204(4) 1032(3) 95(1) 182 Appendix 2 – Supporting Information Relevant to Chapter 2 C(23) 8717(2) 3216(3) 1130(2) 70(1) C(24) 9249(4) 2615(9) 525(6) 151(4) C(25) 8477(2) 2049(3) 1754(3) 92(1(26) 8090(3) 3739(6) 492(4) 96(2) Si(1A) 8928(1) 4111(3) 2163(2) 50(1) C(21A) 8669(5) 2452(8) 2742(7) 88(3) C(22A) 9777(8) 4660(20) 2703(16) 87(5) C(23A) 8921(3) 3848(8) 866(5) 60(2) C(24A) 9430(9) 2612(17) 699(12) 85(5) C(25A) 8260(7) 3394(18) 406(14) 124(6) C(26A) 9168(4) 5184(9) 386(6) 81(2) C(6) 7802(1) 7591(2) 2715(1) 44(1) C(16) 7627(1) 7770(2) 1649(1) 55(1) C(17) 7998(1) 9045(2) 3150(1) 62(1) C(7) 7234(1) 6890(1) 3233(1) 38(1) C(8) 6610(1) 7767(2) 3410(1) 42(1) O(4) 6803(1) 8798(1) 4124(1) 46(1) C(18) 6422(1) 10071(2) 4085(1) 63(1) O(5) 5846(1) 9997(1) 4564(1) 65(1) C(19) 5972(1) 10028(2) 5561(1) 65(1) C(9) 6020(1) 6868(2) 3690(1) 42(1) C(10) 6105(1) 6022(1) 4607(1) 37(1) C(11) 5642(1) 6256(2) 5275(1) 39(1) C(12) 5647(1) 5448(2) 6098(1) 40(1) O(6) 5220(1) 5651(1) 6796(1) 51(1) C(20) 4784(1) 6847(2) 6709(1) 58(1) C(13) 6105(1) 4354(2) 6251(1) 41(1) C(14) 6576(1) 4134(2) 5605(1) 39(1) C(15) 6596(1) 4971(1) 4793(1) 36(1) ________________________________________________________________________ 183 Appendix 2 – Supporting Information Relevant to Chapter 2 Table A2.3. Bond lengths [Å] and angles [°] for V22068. _____________________________________________________ O(1)-C(1) 1.3472(17) O(1)-C(7) 1.4663(16) C(1)-O(2) 1.1989(17) C(1)-C(2) 1.5196(19) C(2)-C(15) 1.5180(19) C(2)-C(3) 1.5312(19) C(2)-H(2) 1.0000 C(3)-C(7) 1.5416(18) C(3)-C(4) 1.544(2) C(3)-H(3) 1.0000 C(4)-C(5) 1.536(2) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(5)-O(3) 1.4234(18) C(5)-C(6) 1.544(2) C(5)-H(5) 1.0000 O(3)-Si(1) 1.6299(13) O(3)-Si(1A) 1.654(2) Si(1)-C(21) 1.853(7) Si(1)-C(22) 1.859(3) Si(1)-C(23) 1.866(3) C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 C(22)-H(22A) 0.9800 C(22)-H(22B) 0.9800 C(22)-H(22C) 0.9800 C(23)-C(25) 1.509(4) 184 Appendix 2 – Supporting Information Relevant to Chapter 2 C(23)-C(24) 1.528(6) C(23)-C(26) 1.568(6) C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 C(25)-H(25A) 0.9800 C(25)-H(25B) 0.9800 C(25)-H(25C) 0.9800 C(26)-H(26A) 0.9800 C(26)-H(26B) 0.9800 C(26)-H(26C) 0.9800 Si(1A)-C(23A) 1.850(7) Si(1A)-C(21A) 1.854(7) Si(1A)-C(22A) 1.882(11) C(21A)-H(21D) 0.9800 C(21A)-H(21E) 0.9800 C(21A)-H(21F) 0.9800 C(22A)-H(22D) 0.9800 C(22A)-H(22E) 0.9800 C(22A)-H(22F) 0.9800 C(23A)-C(25A) 1.492(11) C(23A)-C(26A) 1.528(9) C(23A)-C(24A) 1.577(11) C(24A)-H(24D) 0.9800 C(24A)-H(24E) 0.9800 C(24A)-H(24F) 0.9800 C(25A)-H(25D) 0.9800 C(25A)-H(25E) 0.9800 C(25A)-H(25F) 0.9800 C(26A)-H(26D) 0.9800 185 Appendix 2 – Supporting Information Relevant to Chapter 2 C(26A)-H(26E) 0.9800 C(26A)-H(26F) 0.9800 C(6)-C(16) 1.530(2) C(6)-C(17) 1.536(2) C(6)-C(7) 1.549(2) C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(17)-H(17A) 0.9800 C(17)-H(17B) 0.9800 C(17)-H(17C) 0.9800 C(7)-C(8) 1.536(2) C(8)-O(4) 1.4299(17) C(8)-C(9) 1.533(2) C(8)-H(8) 1.0000 O(4)-C(18) 1.4171(19) C(18)-O(5) 1.388(2) C(18)-H(18A) 0.9900 C(18)-H(18B) 0.9900 O(5)-C(19) 1.413(2) C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(9)-C(10) 1.5195(19) C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 C(10)-C(11) 1.395(2) C(10)-C(15) 1.405(2) C(11)-C(12) 1.389(2) C(11)-H(11) 0.9500 186 Appendix 2 – Supporting Information Relevant to Chapter 2 C(12)-O(6) 1.3715(18) C(12)-C(13) 1.384(2) O(6)-C(20) 1.423(2) C(20)-H(20A) 0.9800 C(20)-H(20B) 0.9800 C(20)-H(20C) 0.9800 C(13)-C(14) 1.382(2) C(13)-H(13) 0.9500 C(14)-C(15) 1.3959(19) C(14)-H(14) 0.9500 C(1)-O(1)-C(7) 111.26(10) O(2)-C(1)-O(1) 121.81(13) O(2)-C(1)-C(2) 128.45(13) O(1)-C(1)-C(2) 109.74(11) C(15)-C(2)-C(1) 112.88(12) C(15)-C(2)-C(3) 111.22(11) C(1)-C(2)-C(3) 102.78(11) C(15)-C(2)-H(2) 109.9 C(1)-C(2)-H(2) 109.9 C(3)-C(2)-H(2) 109.9 C(2)-C(3)-C(7) 102.34(10) C(2)-C(3)-C(4) 116.18(13) C(7)-C(3)-C(4) 105.99(11) C(2)-C(3)-H(3) 110.6 C(7)-C(3)-H(3) 110.6 C(4)-C(3)-H(3) 110.6 C(5)-C(4)-C(3) 106.82(12) C(5)-C(4)-H(4A) 110.4 C(3)-C(4)-H(4A) 110.4 187 Appendix 2 – Supporting Information Relevant to Chapter 2 C(5)-C(4)-H(4B) 110.4 C(3)-C(4)-H(4B) 110.4 H(4A)-C(4)-H(4B) 108.6 O(3)-C(5)-C(4) 109.88(12) O(3)-C(5)-C(6) 111.89(12) C(4)-C(5)-C(6) 105.05(12) O(3)-C(5)-H(5) 110.0 C(4)-C(5)-H(5) 110.0 C(6)-C(5)-H(5) 110.0 C(5)-O(3)-Si(1) 123.16(10) C(5)-O(3)-Si(1A) 131.95(11) O(3)-Si(1)-C(21) 110.3(3) O(3)-Si(1)-C(22) 109.57(14) C(21)-Si(1)-C(22) 109.8(4) O(3)-Si(1)-C(23) 104.32(11) C(21)-Si(1)-C(23) 112.0(3) C(22)-Si(1)-C(23) 110.71(15) Si(1)-C(21)-H(21A) 109.5 Si(1)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 109.5 Si(1)-C(21)-H(21C) 109.5 H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 Si(1)-C(22)-H(22A) 109.5 Si(1)-C(22)-H(22B) 109.5 H(22A)-C(22)-H(22B) 109.5 Si(1)-C(22)-H(22C) 109.5 H(22A)-C(22)-H(22C) 109.5 H(22B)-C(22)-H(22C) 109.5 C(25)-C(23)-C(24) 109.3(4) 188 Appendix 2 – Supporting Information Relevant to Chapter 2 C(25)-C(23)-C(26) 106.5(3) C(24)-C(23)-C(26) 110.9(5) C(25)-C(23)-Si(1) 112.3(2) C(24)-C(23)-Si(1) 111.8(4) C(26)-C(23)-Si(1) 105.9(3) C(23)-C(24)-H(24A) 109.5 C(23)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 C(23)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 C(23)-C(25)-H(25A) 109.5 C(23)-C(25)-H(25B) 109.5 H(25A)-C(25)-H(25B) 109.5 C(23)-C(25)-H(25C) 109.5 H(25A)-C(25)-H(25C) 109.5 H(25B)-C(25)-H(25C) 109.5 C(23)-C(26)-H(26A) 109.5 C(23)-C(26)-H(26B) 109.5 H(26A)-C(26)-H(26B) 109.5 C(23)-C(26)-H(26C) 109.5 H(26A)-C(26)-H(26C) 109.5 H(26B)-C(26)-H(26C) 109.5 O(3)-Si(1A)-C(23A) 106.5(2) O(3)-Si(1A)-C(21A) 109.0(3) C(23A)-Si(1A)-C(21A) 110.2(4) O(3)-Si(1A)-C(22A) 109.9(7) C(23A)-Si(1A)-C(22A) 112.0(8) C(21A)-Si(1A)-C(22A) 109.2(7) Si(1A)-C(21A)-H(21D) 109.5 189 Appendix 2 – Supporting Information Relevant to Chapter 2 Si(1A)-C(21A)-H(21E) 109.5 H(21D)-C(21A)-H(21E) 109.5 Si(1A)-C(21A)-H(21F) 109.5 H(21D)-C(21A)-H(21F) 109.5 H(21E)-C(21A)-H(21F) 109.5 Si(1A)-C(22A)-H(22D) 109.5 Si(1A)-C(22A)-H(22E) 109.5 H(22D)-C(22A)-H(22E) 109.5 Si(1A)-C(22A)-H(22F) 109.5 H(22D)-C(22A)-H(22F) 109.5 H(22E)-C(22A)-H(22F) 109.5 C(25A)-C(23A)-C(26A) 110.4(10) C(25A)-C(23A)-C(24A) 106.8(10) C(26A)-C(23A)-C(24A) 107.4(9) C(25A)-C(23A)-Si(1A) 114.1(9) C(26A)-C(23A)-Si(1A) 110.7(5) C(24A)-C(23A)-Si(1A) 107.0(7) C(23A)-C(24A)-H(24D) 109.5 C(23A)-C(24A)-H(24E) 109.5 H(24D)-C(24A)-H(24E) 109.5 C(23A)-C(24A)-H(24F) 109.5 H(24D)-C(24A)-H(24F) 109.5 H(24E)-C(24A)-H(24F) 109.5 C(23A)-C(25A)-H(25D) 109.5 C(23A)-C(25A)-H(25E) 109.5 H(25D)-C(25A)-H(25E) 109.5 C(23A)-C(25A)-H(25F) 109.5 H(25D)-C(25A)-H(25F) 109.5 H(25E)-C(25A)-H(25F) 109.5 C(23A)-C(26A)-H(26D) 109.5 190 Appendix 2 – Supporting Information Relevant to Chapter 2 C(23A)-C(26A)-H(26E) 109.5 H(26D)-C(26A)-H(26E) 109.5 C(23A)-C(26A)-H(26F) 109.5 H(26D)-C(26A)-H(26F) 109.5 H(26E)-C(26A)-H(26F) 109.5 C(16)-C(6)-C(17) 109.22(13) C(16)-C(6)-C(5) 113.13(13) C(17)-C(6)-C(5) 107.13(14) C(16)-C(6)-C(7) 113.18(13) C(17)-C(6)-C(7) 111.24(13) C(5)-C(6)-C(7) 102.68(11) C(6)-C(16)-H(16A) 109.5 C(6)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(6)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(6)-C(17)-H(17A) 109.5 C(6)-C(17)-H(17B) 109.5 H(17A)-C(17)-H(17B) 109.5 C(6)-C(17)-H(17C) 109.5 H(17A)-C(17)-H(17C) 109.5 H(17B)-C(17)-H(17C) 109.5 O(1)-C(7)-C(8) 105.86(11) O(1)-C(7)-C(3) 104.40(10) C(8)-C(7)-C(3) 113.58(11) O(1)-C(7)-C(6) 106.30(11) C(8)-C(7)-C(6) 119.33(12) C(3)-C(7)-C(6) 106.17(11) O(4)-C(8)-C(9) 111.08(12) 191 Appendix 2 – Supporting Information Relevant to Chapter 2 O(4)-C(8)-C(7) 107.45(11) C(9)-C(8)-C(7) 113.90(12) O(4)-C(8)-H(8) 108.1 C(9)-C(8)-H(8) 108.1 C(7)-C(8)-H(8) 108.1 C(18)-O(4)-C(8) 115.40(13) O(5)-C(18)-O(4) 113.99(14) O(5)-C(18)-H(18A) 108.8 O(4)-C(18)-H(18A) 108.8 O(5)-C(18)-H(18B) 108.8 O(4)-C(18)-H(18B) 108.8 H(18A)-C(18)-H(18B) 107.6 C(18)-O(5)-C(19) 113.34(15) O(5)-C(19)-H(19A) 109.5 O(5)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 O(5)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(10)-C(9)-C(8) 118.20(11) C(10)-C(9)-H(9A) 107.8 C(8)-C(9)-H(9A) 107.8 C(10)-C(9)-H(9B) 107.8 C(8)-C(9)-H(9B) 107.8 H(9A)-C(9)-H(9B) 107.1 C(11)-C(10)-C(15) 118.73(12) C(11)-C(10)-C(9) 117.42(12) C(15)-C(10)-C(9) 123.75(13) C(12)-C(11)-C(10) 121.39(13) C(12)-C(11)-H(11) 119.3 192 Appendix 2 – Supporting Information Relevant to Chapter 2 C(10)-C(11)-H(11) 119.3 O(6)-C(12)-C(13) 115.89(13) O(6)-C(12)-C(11) 124.36(14) C(13)-C(12)-C(11) 119.75(13) C(12)-O(6)-C(20) 117.55(13) O(6)-C(20)-H(20A) 109.5 O(6)-C(20)-H(20B) 109.5 H(20A)-C(20)-H(20B) 109.5 O(6)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5 C(14)-C(13)-C(12) 119.30(13) C(14)-C(13)-H(13) 120.4 C(12)-C(13)-H(13) 120.4 C(13)-C(14)-C(15) 121.81(13) C(13)-C(14)-H(14) 119.1 C(15)-C(14)-H(14) 119.1 C(14)-C(15)-C(10) 118.84(13) C(14)-C(15)-C(2) 118.32(12) C(10)-C(15)-C(2) 122.57(12) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 193 Appendix 2 – Supporting Information Relevant to Chapter 2 Table 4. Anisotropic displacement parameters (Å2x 103) for V22068. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12] ________________________________________________________________________ U11 U22 U33 U23 U13 U12 ________________________________________________________________________ O(1) 54(1) 38(1) 32(1) -1(1) -3(1) -5(1) C(1) 43(1) 35(1) 42(1) -1(1) 5(1) -1(1) O(2) 64(1) 39(1) 58(1) -12(1) 10(1) -8(1) C(2) 44(1) 33(1) 37(1) 6(1) 2(1) 3(1) C(3) 46(1) 38(1) 30(1) 3(1) -1(1) -4(1) C(4) 46(1) 63(1) 39(1) 7(1) -1(1) -6(1) C(5) 50(1) 44(1) 39(1) 2(1) 4(1) -11(1) O(3) 49(1) 42(1) 47(1) -1(1) 3(1) -5(1) Si(1) 51(1) 51(1) 59(1) -2(1) 13(1) -9(1) C(21) 63(3) 167(8) 129(5) -24(5) -2(3) 30(4) C(22) 126(3) 70(2) 97(2) -17(2) 58(2) -47(2) C(23) 94(2) 44(2) 78(2) -7(1) 36(2) -16(1) C(24) 166(6) 113(5) 193(8) -85(5) 123(6) -63(4) C(25) 104(2) 48(2) 128(3) 18(2) 31(2) -11(2) C(26) 157(4) 61(3) 66(2) -4(2) -22(2) -45(3) Si(1A) 58(1) 35(1) 55(1) 7(1) 1(1) -3(1) C(21A) 124(7) 48(4) 95(6) 27(4) 25(6) -1(4) C(22A) 56(7) 86(7) 112(11) 19(6) -42(7) 6(5) C(23A) 58(4) 53(4) 73(4) -3(3) 17(3) -2(3) C(24A) 104(9) 75(8) 77(6) -2(6) 23(6) 29(8) C(25A) 111(7) 90(10) 160(13) -72(8) -56(8) 21(6) C(26A) 82(5) 92(6) 70(5) 24(4) 21(4) 11(4) C(6) 36(1) 36(1) 4(1) 8(1) -7(1) 60(1) 194 Appendix 2 – Supporting Information Relevant to Chapter 2 C(16) 76(1) 53(1) 37(1) 12(1) 10(1) 7(1) C(17) 82(1) 43(1) 62(1) -4(1) 22(1) -18(1) C(7) 51(1) 32(1) 30(1) 1(1) -1(1) -4(1) C(8) 56(1) 36(1) 33(1) 6(1) -2(1) 2(1) O(4) 59(1) 33(1) 47(1) -1(1) 4(1) 2(1) C(18) 94(1) 39(1) 57(1) 9(1) 16(1) 15(1) O(5) 64(1) 65(1) 64(1) -7(1) -1(1) 18(1) C(19) 81(1) 56(1) 60(1) -12(1) 15(1) -4(1) C(9) 46(1) 40(1) 39(1) 4(1) -4(1) 3(1) C(10) 42(1) 32(1) 36(1) 0(1) -2(1) -4(1) C(11) 40(1) 35(1) 42(1) -3(1) -2(1) -3(1) C(12) 42(1) 40(1) 39(1) -5(1) 5(1) -9(1) O(6) 52(1) 56(1) 48(1) -4(1) 14(1) -4(1) C(20) 50(1) 62(1) 64(1) -14(1) 12(1) 0(1) C(13) 51(1) 37(1) 36(1) 3(1) 4(1) -10(1) C(14) 48(1) 30(1) 40(1) 3(1) 2(1) -3(1) C(15) 43(1) 30(1) 36(1) 2(1) 1(1) -3(1) Table A2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22068. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ H(2) 7492 4039 4472 46 H(3) 7512 6813 4704 46 H(4A) 8594 6674 4427 59 H(4B) 8470 5071 4052 59 H(5) 8827 7097 2920 53 195 Appendix 2 – Supporting Information Relevant to Chapter 2 H(21A) 9812 5156 3149 181 H(21B) 10106 4050 2429 181 H(21C) 9562 3536 3124 181 H(22A) 9003 6303 475 142 H(22B) 9761 5935 827 142 H(22C) 9361 7113 1373 142 H(24A) 9663 2450 925 227 H(24B) 9333 3298 24 227 H(24C) 9091 1714 238 227 H(25A) 8337 1224 1362 138 H(25B) 8098 2396 2083 138 H(25C) 8840 1768 2220 138 H(26A) 7931 2971 61 145 H(26B) 8212 4568 121 145 H(26C) 7735 4005 894 145 H(21D) 8761 2538 3431 132 H(21E) 8918 1644 2511 132 H(21F) 8189 2299 2592 132 H(22D) 10108 3944 2557 131 H(22E) 9766 4742 3392 131 H(22F) 9898 5584 2442 131 H(24D) 9608 2736 80 127 H(24E) 9202 1691 717 127 H(24F) 9799 2640 1198 127 H(25D) 8316 3063 -240 186 H(25E) 7950 4202 382 186 H(25F) 8080 2617 773 186 H(26D) 9098 5077 -304 121 H(26E) 9645 5317 568 121 H(26F) 8919 6015 586 121 196 Appendix 2 – Supporting Information Relevant to Chapter 2 H(16A) 7228 8371 1543 83 H(16B) 7538 6833 1359 83 H(16C) 8002 8220 1361 83 H(17A) 8407 9384 2889 92 H(17B) 8077 8948 3840 92 H(17C) 7637 9729 3000 92 H(8) 6466 8289 2812 50 H(18A) 6705 10856 4358 75 H(18B) 6296 10307 3413 75 H(19A) 6231 9183 5770 98 H(19B) 5547 10032 5857 98 H(19C) 6226 10888 5748 98 H(9A) 5633 7514 3731 51 H(9B) 5902 6190 3168 51 H(11) 5316 6984 5164 47 H(20A) 5048 7722 6678 87 H(20B) 4518 6889 7259 87 H(20C) 4486 6756 6128 87 H(13) 6096 3762 6794 50 H(14) 6894 3391 5717 47 Table A2.6. Torsion angles [°] for V22068. ________________________________________________________________ C(7)-O(1)-C(1)-O(2) -177.96(14) C(7)-O(1)-C(1)-C(2) 2.62(16) O(2)-C(1)-C(2)-C(15) -80.38(19) O(1)-C(1)-C(2)-C(15) 98.99(13) O(2)-C(1)-C(2)-C(3) 159.72(15) O(1)-C(1)-C(2)-C(3) -20.91(15) 197 Appendix 2 – Supporting Information Relevant to Chapter 2 C(15)-C(2)-C(3)-C(7) -91.73(13) C(1)-C(2)-C(3)-C(7) 29.31(14) C(15)-C(2)-C(3)-C(4) 153.33(12) C(1)-C(2)-C(3)-C(4) -85.63(13) C(2)-C(3)-C(4)-C(5) 108.60(14) C(7)-C(3)-C(4)-C(5) -4.26(16) C(3)-C(4)-C(5)-O(3) -95.21(15) C(3)-C(4)-C(5)-C(6) 25.31(16) C(4)-C(5)-O(3)-Si(1) -109.59(13) C(6)-C(5)-O(3)-Si(1) 134.12(12) C(4)-C(5)-O(3)-Si(1A) -73.7(2) C(6)-C(5)-O(3)-Si(1A) 170.00(17) C(5)-O(3)-Si(1)-C(21) 58.2(4) C(5)-O(3)-Si(1)-C(22) -62.82(17) C(5)-O(3)-Si(1)-C(23) 178.62(14) O(3)-Si(1)-C(23)-C(25) -62.6(3) C(21)-Si(1)-C(23)-C(25) 56.7(4) C(22)-Si(1)-C(23)-C(25) 179.6(3) O(3)-Si(1)-C(23)-C(24) 174.2(4) C(21)-Si(1)-C(23)-C(24) -66.5(6) C(22)-Si(1)-C(23)-C(24) 56.5(5) O(3)-Si(1)-C(23)-C(26) 53.3(3) C(21)-Si(1)-C(23)-C(26) 172.6(4) C(22)-Si(1)-C(23)-C(26) -64.5(3) C(5)-O(3)-Si(1A)-C(23A) -137.5(3) C(5)-O(3)-Si(1A)-C(21A) 103.6(4) C(5)-O(3)-Si(1A)-C(22A) -15.9(8) O(3)-Si(1A)-C(23A)-C(25A) -60.5(9) C(21A)-Si(1A)-C(23A)-C(25A) 57.6(9) C(22A)-Si(1A)-C(23A)-C(25A) 179.3(11) 198 Appendix 2 – Supporting Information Relevant to Chapter 2 O(3)-Si(1A)-C(23A)-C(26A) 64.8(5) C(21A)-Si(1A)-C(23A)-C(26A) -177.1(6) C(22A)-Si(1A)-C(23A)-C(26A) -55.4(9) O(3)-Si(1A)-C(23A)-C(24A) -178.4(8) C(21A)-Si(1A)-C(23A)-C(24A) -60.3(9) C(22A)-Si(1A)-C(23A)-C(24A) 61.4(11) O(3)-C(5)-C(6)-C(16) -39.17(17) C(4)-C(5)-C(6)-C(16) -158.35(13) O(3)-C(5)-C(6)-C(17) -159.58(12) C(4)-C(5)-C(6)-C(17) 81.24(14) O(3)-C(5)-C(6)-C(7) 83.17(13) C(4)-C(5)-C(6)-C(7) -36.01(14) C(1)-O(1)-C(7)-C(8) -103.38(12) C(1)-O(1)-C(7)-C(3) 16.77(15) C(1)-O(1)-C(7)-C(6) 128.77(12) C(2)-C(3)-C(7)-O(1) -28.44(14) C(4)-C(3)-C(7)-O(1) 93.73(13) C(2)-C(3)-C(7)-C(8) 86.39(13) C(4)-C(3)-C(7)-C(8) -151.44(12) C(2)-C(3)-C(7)-C(6) -140.53(11) C(4)-C(3)-C(7)-C(6) -18.37(15) C(16)-C(6)-C(7)-O(1) 45.12(16) C(17)-C(6)-C(7)-O(1) 168.53(13) C(5)-C(6)-C(7)-O(1) -77.18(12) C(16)-C(6)-C(7)-C(8) -74.27(16) C(17)-C(6)-C(7)-C(8) 49.14(17) C(5)-C(6)-C(7)-C(8) 163.42(12) C(16)-C(6)-C(7)-C(3) 155.89(13) C(17)-C(6)-C(7)-C(3) -80.70(15) C(5)-C(6)-C(7)-C(3) 33.59(14) 199 Appendix 2 – Supporting Information Relevant to Chapter 2 O(1)-C(7)-C(8)-O(4) 169.05(10) C(3)-C(7)-C(8)-O(4) 55.08(14) C(6)-C(7)-C(8)-O(4) -71.34(14) O(1)-C(7)-C(8)-C(9) 45.57(14) C(3)-C(7)-C(8)-C(9) -68.40(15) C(6)-C(7)-C(8)-C(9) 165.18(12) C(9)-C(8)-O(4)-C(18) -82.78(15) C(7)-C(8)-O(4)-C(18) 152.02(13) C(8)-O(4)-C(18)-O(5) 86.43(18) O(4)-C(18)-O(5)-C(19) 73.7(2) O(4)-C(8)-C(9)-C(10) -58.82(17) C(7)-C(8)-C(9)-C(10) 62.67(17) C(8)-C(9)-C(10)-C(11) 124.43(14) C(8)-C(9)-C(10)-C(15) -59.31(19) C(15)-C(10)-C(11)-C(12) -1.9(2) C(9)-C(10)-C(11)-C(12) 174.59(12) C(10)-C(11)-C(12)-O(6) 177.88(13) C(10)-C(11)-C(12)-C(13) -2.1(2) C(13)-C(12)-O(6)-C(20) 174.21(13) C(11)-C(12)-O(6)-C(20) -5.8(2) O(6)-C(12)-C(13)-C(14) -176.47(12) C(11)-C(12)-C(13)-C(14) 3.5(2) C(12)-C(13)-C(14)-C(15) -1.0(2) C(13)-C(14)-C(15)-C(10) -3.0(2) C(13)-C(14)-C(15)-C(2) 171.18(13) C(11)-C(10)-C(15)-C(14) 4.36(19) C(9)-C(10)-C(15)-C(14) -171.86(13) C(11)-C(10)-C(15)-C(2) -169.58(12) C(9)-C(10)-C(15)-C(2) 14.2(2) C(1)-C(2)-C(15)-C(14) 125.46(13) 200 Appendix 2 – Supporting Information Relevant to Chapter 2 C(3)-C(2)-C(15)-C(14) -119.62(13) C(1)-C(2)-C(15)-C(10) -60.57(17) C(3)-C(2)-C(15)-C(10) 54.35(17) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Chapter 3 – Late stage d ring installation on the a-enolate arylation product 200 Chapter 3 Late stage d ring installation on the a-enolate arylation product† 3.1 INTRODUCTION Herein are the efforts that were undertaken to elaborate the a-enolate arylation product. The major challenges include the installation of the d ring and formation of the ering, along with some functional group interconversions necessary for completion of the target. Optimization of a Birch reduction protocol, photochemical allene [2+2], and skeletal rearrangement to form the desired 3.2.1 bicycle are discussed. Taken together, this chapter summarizes failed attempts to install the d-ring. Birch reduction yields were low, and material throughput greatly hampered further exploration. In order for the route to be viable for future studies, further exploration of dearomative strategies and development of the skeletal rearrangement (Dowd-Beckwith ring expansion) † J.K.T. was supported by the NSF GRFP (DGE-1745301). S.E.R. acknowledges fellowship support by the NIH (R35GM118191). 201 Chapter 3 – Late stage d ring installation on the a-enolate arylation product are required. Key, positive results garnered from this chapter include the ease at which b-g isomerization and photochemical allene 2+2 cycloaddition occur, with excellent yield and adequate diastereoselectivity. The synthesis of 57 is relatively short (just 11 steps longestlinear sequence) and may be amenable to further exploration in the future. 3.2 EXPLORATION OF LATE-STAGE ARENE REDUCTION 3.2.1 Birch Reduction with liquid ammonia Synthetic access to 57 enabled exploration of chemistry to elaborate the tetracycle and conduct studies on late-stage d ring installation. Indeed, the original synthetic plan from the enolate arylation product used the Birch reduction as a way of mapping out downstream chemistry and the viability of late-stage d ring installation. Following b-g isomerization and hydrolysis of the methoxy group, enone 56 was envisioned to be accessible (Scheme 3.1). Such a proposal seemed straightforward in planning but very difficult in practice. Scheme 3.1. Future plans in elaborating the tetracycle. O TBSO Me O O H Me difficult TBSO Me O MOM 57 OMe H Me O β-γ isomerization hydrolysis O TBSO Me O MOM 92 OMe H O H Me O O MOM 56 Initial synthetic studies on the Birch reduction investigated the identity of the metal reductant and led to no product formation; lactone reduction was primarily observed (Scheme 3.2). Surveying the literature, it became clear that dissolving metal conditions are often used to reduce lactones to the lactol1,2 or the diol3-5. It seemed from preliminary observation that the electron-rich arene was more difficult to reduce than the lactone. Chapter 3 – Late stage d ring installation on the a-enolate arylation product 202 Scheme 3.2. Initial attempts to induce Birch reduction of 57. O TBSO Me OH O H Me metal reductant (50 equiv) O liq. NH3/THF −78 °C, 2 h OMe TBSO Me MOM OH H Me O OMe MOM 57 93 metal reductant result Li0 32% yield Na0 65% yield K0 47% yield Two main questions were put forth to investigate: 1) could use of more equivalents of metal reductant reduce the lactone and methoxyarene in a single step and 2) could the lactone be converted to a substrate that would not undergo Birch reduction? For the case of 1), it was found that, indeed, while use of higher equivalents of metal reductant formed diol 93, the yield remained low (Scheme 3.3). The main difference in protocol for these experiments included the use of the Rabideau modification. The Rabideau modification uses alcohol additives as a component of the dissolving metal conditions rather than use in quenching the reaction. In order to accommodate alcohol additives under the reaction conditions, higher loadings of metal reductants (typically > 150 equiv) are required. These conditions are believed to help reduce electron-rich substrates due to protonation of the radical anion intermediate in the Birch reduction mechanism, which more easily accepts a second electron.6 This could fundamentally change the mechanism of the process when compared to the conditions as shown in Scheme 3.2, which do not include an alcohol additive. Na0 was used in this optimization rather than Li0 or K0, as an overall messier reaction profile of overreduction products was observed 203 Chapter 3 – Late stage d ring installation on the a-enolate arylation product with other metals. Furthermore, this observation is consistent with the findings of similar electron-rich systems in the literature.7 A dependence of product distribution on alcohol additive was found (Scheme 3.3). More hindered alcohol additives, such as iPrOH and tBuOH led to less arene reduction and higher yields of 93 (Scheme 3.3, entries 1-2). Interestingly, use of less hindered additives such as sBuOH and EtOH led to mixtures of lactol 94 and the desired product 95 (Scheme 3.3, entries 3-4). EtOH, being the least hindered alcohol additive in the series, led to 30% yield of the product (Scheme 3.3, entry 4). Surprisingly, MeOH as an additive led to no observed quantity of product (not shown). Taken together, these data suggest an interplay between the sterics of the alcohol additive and the ease of methoxy arene reduction. Scheme 3.3. Product distribution depends on the identity of the alcohol additive. O TBSO Me O H Me O Na0 (200 equiv), liq. NH3 TBSO then THF, ROH (125 equiv) Me −78 °C to −30 °C, 3 h OMe OH H Me Me O OMe 57 Me H Me O OMe MOM 95 entry TBSO O TBSO MOM MOM OH OH OH OH H Me O OMe MOM 93 94 ROH 95 (%) 94 (%) 93 (%) 57 (%) 1 iPrOH 12 — 30 3 2 tBuOH 15 — 33 6 3 sBuOH 21 27 — 5 4 EtOH 30 15 — 2 In order to investigate if the lactone moiety could be converted to a functional group that would not undergo Birch reduction, several steps were explored. It was noticed that auriculatol A’s e-ring is comprised of a methyl acetal. If the installation of the methyl acetal in auriculatol could be accomplished from substrate 57, the Birch reduction in the presence of the methyl acetal might be tolerated,7 and the yield could be increased in the stepwise process. As a result, 96 was targeted (Scheme 3.4). In theory, lactol 94 should be formed 204 Chapter 3 – Late stage d ring installation on the a-enolate arylation product relatively easily by using diisobutylaluminum hydride (DIBAL), which could form a stable Al-ate complex at cryogenic temperatures. The lactol (94) could be methylated directly or converted to the methyl acetal in acidic methanol to produce 96. Scheme 3.4. New synthetic plan: methyl acetal formation prior to Birch reduction. O TBSO Me OH O H Me DIBAL TBSO Me O MOM 57 OMe MeO methylating agent O H Me O MOM OMe or acidic MeOH TBSO Me 94 H O H Me O OMe MOM 96 In practice, monoreduction of 57 to 94 was more difficult than envisioned. In the presence of less than one equivalent of DIBAL, even at cryogenic temperatures, no evidence of 94 was observed (Scheme 3.5, entry 1). Instead, a 1:1 mixture of 57 and 93 was isolated, indicating that the Al-ate complex formed upon monoreduction of 57 likely had collapsed to the open-chain aldehyde form. More facile reduction of the aldehyde by another equivalent of DIBAL would form diol 93. It’s possible that the ring strain of the fused a-b-e scaffold makes ring-opening more energetically accessible. Reductive ring-opening was observed under several other reaction conditions, including Buchwald’s Ti-hydride8, super hydride, and tritertbutoxylithium aluminum hydride (Scheme 3.5, entry 2, 3, & 5). Inspired by the work of Motoyama, use of Pd/C/Cu(acac)2 system for silyl acetal formation led to no reaction (Scheme 3.5, entry 4).9 In line with this, conditions for iridium-catalyzed silylation of esters led to no reaction, even at elevated temperatures (Scheme 3.5, entries 8-9).10 It is reported that for sugar lactol synthesis, use of triethoxylithium aluminum hydride was uniquely effective.11 Unfortunately, in our hands, no reaction was observed (Scheme 3.5, entry 7). The only conditions that gave appreciable quantities of lactol were dissolving metal reduction; 205 Chapter 3 – Late stage d ring installation on the a-enolate arylation product specifically, using a THF/EtOH solvent combination provided 32% yield of the target lactol 94, along with 35% of the diol 93 (Scheme 3.5, entry 10). Although 94 was isolated as a single diastereomer, further NOESY analysis is required to assign the product’s stereochemistry. Scheme 3.5. Reduction of 57; attempts to generate intermediate lactol 94. O TBSO Me TBSO Me O OMe solvent, temp. O Me H Me MOM OH TBSO reducing agent H Me OH OH O O OMe H Me MOM 57 O OMe MOM 93 94 entry reducing agent solvent 1 DIBAL (0.8 equiv) Et2O −78 57, 93 - 2 Cp2TiF2/PMHS THF 40 57, 93 - 3 super hydride CH2Cl2 0 57, 93 - 4 Pd/C/Cu(acac)2, TMDS THF 0 to 22 57 - 5 LiAlH(OtBu)3 THF 0 57, 93 - 6 LiAlH(OtBu)3 THF 50 93 - 7 LiAlH(OEt)3 THF 0 57 - 8 [Ir(COE)Cl]2, H2SiEt2 CH2Cl2 21 57 - 9 [Ir(COE)Cl]2, H2SiEt2 CH2Cl2 50 57 - 10 Na0, NH3 (l) EtOH/THF −78 94, 57 32 temperature (°C) products observed yield 167 (%) Because of the low yield of the monoreduction of the lactol, only two conditions were attempted to methylate it. Both gave primarily starting material, as shown in Scheme 3.6. If this were to be attempted in the future, use of pTsOH in MeOH would likely lead to the desired methyl acetal; however, careful monitoring of equivalents, temperature, and time should be taken in order to ensure there is no competitive silyl ether cleavage. Chapter 3 – Late stage d ring installation on the a-enolate arylation product 206 Scheme 3.6. Efforts to methylate lactol 94. OMe OH condition Me H Me O TBSO O TBSO O Me OMe H Me O OMe MOM MOM 94 97 condition result NaH, MeI rsm PPTS, MeOH rsm PTsOH • H2O, MeOH decomp. It was also thought that a one-step methylation-reduction protocol could be accomplished, allowing direct access to 97 from 57. To this end, trimethyloxonium tetrafluoroborate and MeOTf were used as reagents thought to be electrophilic enough for lactone methylation in the presence of weak borohydride sources like sodium cyanoborohydride. For the case of trimethyloxonium tetrafluoroborate, strong precedent of the formation of zwitterion 99 was observed by mixing one equivalent of trimethyloxonium tetrafluoroborate with d-butyrolactone 98 in dichloromethane at room temperature overnight (Scheme 3.7).12 Scheme 3.7. Trimethyloxonium tetrafluoroborate as a lactone methylation reagent. Me3O+BF4(1 equiv) O 98 O CH2Cl2, rt, overnight BF4 O 99 OMe NaOMe MeOH −78 °C to rt O OMe OMe 100 Unfortunately, on 57, use of trimethyloxonium led to silyl ether cleavage (101), and in larger equivalents, decomposition of starting material (Scheme 3.8A). Use of MeOTf led to lactone opening and isolation of methyl ester 102 (Scheme 3.8B). Unfortunately, perhaps unsurprisingly, any attempts to elaborate methyl ester 102 led to substrate reclosure and isolation of 57. As a testament to this, 102 would close when left overnight 207 Chapter 3 – Late stage d ring installation on the a-enolate arylation product in an NMR tube containing deuterated chloroform. Conformationally, 102 displays strong NOESY correlations between the a-proton of the ester and the methylene between the arene and the MOM ether, indicating a change in conformation when compared to 57. This is likely a strain-releasing process and perhaps the reason for formation of this unique compound. Scheme 3.8. A. Trimethyloxonium tetrafluoroborate leads to silyl ether cleavage and decomposition B. MeOTf provides methyl ester 102. A O TBSO Me O O H Me Me3O+BF4(1 equiv) O OMe MOM HO Me CH2Cl2, 22 °C, overnight O H Me O OMe MOM 20% yield 57 101 B O TBSO Me MeOTf (10 equiv) 3,6 ditertbutypyridine (3 equiv) O H Me O MeO TBSO HO Me O MOM OMe THF, 30 °C, 24 h H Me O OH MOM TBSO attempts to manipulate OMe Me O H Me O OMe MOM 40% yield 57 102 57 Given the interesting result that the lactone in 57 could be opened using MeOTf, the possibility to induce nucleophilic lactone opening through other means was explored. Quickly, it became clear that the use of MeOTf as an electrophilic lactone methylation source was unique. A variety of nucleophiles explored did not add in to the lactone (Scheme 3.8, entries 1-7). Presumably, this was indication that, while there may be some addition into the lactone, the equilibrium heavily favors ring closure to the starting material. Acidic conditions ultimately led to silyl ether cleavage (Scheme 3.9, entries 8-10). 208 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.9. Investigation of nucleophilic opening of 57. O TBSO Me O Nuc O nucleophile H Me TBSO HO Me O OMe solvent, temp. MOM H Me HO O Me OH MOM 57 OMe H Me O OMe MOM 101 102 entry O nucleophile solvent temperature (°C) result 1 LiOH THF 110 °C no reaction 2 NaOH THF 110 °C no reaction 3 KOH THF 110 °C no reaction 4 LiOMe MeOH 40 °C no reaction 5 NaOMe MeOH 40 °C no reaction 6 NH3 MeOH 40 °C no reaction 7 1,3 dithiane THF 0 °C no reaction 8 MeOH, HCl MeOH/H2O 40 °C 101 9 NaOH, HCl MeOH/H2O 40 °C 101 10 KOH, HCl MeOH/H2O 40 °C 101 Due to the shortcomings of the approaches explored to convert the lactone to a different functionality, it was thought that the diol 93 could be a competent substrate in the Birch reduction. Carboxylic acids, for example, have been shown to be competent functionalities in Birch reductions.13 Furthermore, the use of benzoic acid, for example, as a Birch reduction substrate is common. Unfortunately, using canonical Birch reduction conditions, product yields were even lower than the direct reduction from lactone 57, providing product 95 in a mere 7% yield for the case of Li0 (Scheme 3.10). No improvement was seen when using Na0 instead of Li0. These data necessitated the exploration of other means for methoxy-arene reduction. Indeed, when surveying the literature, a variety of protocols that do not use liquid ammonia are reported that could offer select advantages over traditional liquid ammonia-containing conditions. 209 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.10. 93 as a Birch reduction substrate. OH TBSO Me OH Li0 or Na0 (10 equiv), liq. NH3/THF OH H Me O OMe −78 °C to −30 °C, 3 h MOM 93 OH TBSO Me H Me then tBuOH (quench) < 10% yield O OMe MOM 95 3.2.2 Ammonia-free Birch Reduction strategies In 2021, Koide and coworkers disclosed a scalable Birch reduction protocol without the use of liquid ammonia (Scheme 3.11).14 Instead, their method used ethylenediamine as an economical, safe replacement for liquid ammonia. Indeed, the use of ammonia-free Birch reduction strategies has been an exciting area of development in the past few decades. In 2002, Donohoe demonstrated the ability of di-tert-butylbiphenyl/Li0 at reducing heteroaromatic compounds and some electron-deficient aromatics.15 Then, in 2018, An disclosed the Birch reduction of arenes and heteroarenes using a Na0 disperson/15-crown6 mixture in an iPrOH/THF mixture.16 Electrochemical and photochemical Birch reduction methodologies have also been developed. For the former, Baran developed an electrochemical reduction of electron-rich arenes using tri(pyrrolidine-1-yl)phosphine oxide as an overcharge protectant and 1,3-dimethylurea as a water-soluble proton source using sacrificial magnesium or aluminum electrodes.17 The latter involves two key precedents from König and Miyake that use blue LED’s and an iridium photocatalyst and organophotocatalyst, respectively.18,19 Chapter 3 – Late stage d ring installation on the a-enolate arylation product 210 Scheme 3.11. New, ammonia-free strategies for Birch reduction. Koide Li0 (2.5º - 7 equiv) TMEDA (6 to 14 equiv) R E R tBuOH, THF, 10 to 26 °C, 15 - 60 min then E Donohoe An Na0 dispersion 15-brown-5 (3 to 9 equiv) Li0, DBB (0.5 equiv) X Baran THF, −78 °C, 18 h R X Miyake LiBr (7.5 equiv), TPPA (10 equiv) DMU (3 equiv), THF, 10mA R R Mg(+), Galvanized steel (−), 25 °C or Al(+)/Zn(-), −78 °C R iPrOH, THF, 0 °C, 5 - 30 min organo-PC NMe4OH, tAmylOH R R MeOH, blue LEDs, 21 °C, 5 d Under Koide’s conditions, the reaction profiles were far worse than the dissolving metal conditions. Even after multiple attempts, varying the amount of metal reductant, additive, solvent, and temperature, reaction yields were consistently less than 10% (Scheme 3.12, entry 1). Within the reaction mixture contained a myriad of reduction products, including overreduction to saturated cyclohexane-containing products and even products corresponding to loss of the methoxy group. Donoe, Baran, and Miyake’s conditions led to no reaction, likely due to the fact that electron rich arenes are thought to be less-easily reduced than other electron poor arenes (Scheme 3.12, entries 2, 4, & 5). An’s conditions led to diol (93) formation, and no further reduction was observed (Scheme 3.12, entry 3). Chapter 3 – Late stage d ring installation on the a-enolate arylation product 211 Scheme 3.12. Slim promise for alternative ammonia-free Birch reduction protocols. OH O TBSO Me reaction conditions H Me OH TBSO O O Me OMe H Me 57 entry 3.3 O OMe MOM MOM 95 reaction conditions result 1 Koide < 10% yield 95 in all cases, complex mixture 2 Donohoe no reaction 3 An formation of diol 93 (42% isolated yield) 4 Baran no reaction 5 Miyake no reaction ATTEMPT AT D-RING INSTALLATION 3.3.1 Hydrolysis and b-g isomerization While the prospect of further optimization of the Birch reduction protocol seemed dreary, the result from Scheme 3.3, entry 4 gave ~30% yield of product 95, and this result was repeatable and scalable. Given the fact that material throughput at the time allowed for more than 200 mg of the a-enolate arylation product, the yield was acceptable to further test some downstream chemistry. The first step necessitated the use of acid-mediated hydrolysis and b-g isomerization. Fortunately, simple treatment of product 95 with 1 equivalent of 1M HCl led to the desired enone 103. When conducted at 0 °C, the diastereoselectivity of this process formed from g-protonation favored the desired diastereomer. This was confirmed by NOESY, which indicated strong coupling between the g-proton and the methylene hydrogens a to the primary alcohol. 212 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.13. Hydrolysis b-g isomerization goes as planned. OH TBSO Me OH OH H Me HCl (1 equiv, 1M aqueous) TBSO Me O OMe MOM 95 THF, 0 °C, 2 h 69% yield dr = 3 : 1 H OH H Me O O MOM 103 3.3.2 Photochemical allene [2+2] One strategy envisioned for end-game of this route entailed precedent from Nagaoka and coworkers.18 Following photochemical allene [2+2], the intermediate cyclobutane could be ring-expanded by ketyl radical formation and Dowd-Beckwith fragmentation. Theoretically, the allene [2+2] should proceed with good regioselectivity. The frontier molecular orbitals should align for secondary orbital overlap between the s* C=O and the HOMO of the allene.19,20 It is also possible the process goes through a stepwise mechanism.21 In this case, starting from the triplet allene diradical, Giese addition to the enone forms a stabilized allylic and enolic radical that can recombine. Radical addition from the allene occurs at the terminal position to form the more stable, secondary, allylic radical, and the Giese addition occurs at the b-position of the enone due to a match in polarity. Regardless of the mechanism, in practice this result was confirmed experimentally, not only with good regioselectivity but also with good diastereoselectivity. Using an adaption from Corey’s protocol,22 104 was isolated in 72% yield as a single diastereomer, as determined by strong NOESY correlations between the allylic methylene protons on the cyclobutane, the methine proton a to the cyclobutane, and the methylene a to the primary alcohol (Scheme 3.14). 213 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.14. [2+2] allene cycloaddition. OH TBSO Me H Me OH hv H OH • O MOM 103 O hexanes, −30 °C, 1 h 72% yield TBSO Me OH H Me O O MOM 104 3.3.3 Exploration of Dowd–Beckwith ring expansion Excited by the isolation of product 104, attention was turned to the subsequent ring expansion. Nagaoka’s work involves three different conditions that were optimized to allow adaption to various substrates for the skeletal rearrangement. The first condition (condition A) uses SmI2 (3 equiv), HMPA (12 equiv), and tBuOH (1 equiv) in THF at room temperature, while the second condition (condition B) involves SmI2 (3 equiv), LiCl (6 equiv), and tBuOH (1 equiv) in THF at refluxing temperature. The third condition (condition C) uses SmI2 (4 equiv), TBABr (8 equiv) and HMPA (16 equiv) at refluxing temperature. The substrate scope contained a variety of substrates, delivering unique 3.2.1 bicycle-containing compounds in moderate to good yields (Scheme 3.15). Notably, substrates could bear ester functionalities, protected amines, aromatics, protected alcohols, and in some cases, free alcohols (although these substrates did not require tBuOH as an additive). Mechanistic studies were conducted to validate anion formation at the 1-bridge of the 3.2.1 bicycle by use of deuterated methanol as an additive in the rearrangement (96% deuterium incorporation). 214 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.15. Nagaoka’s SmI2-mediated skeletal rearrangement.18 condensed scope: R1 R1 R2 R2 condition A, B, or C R3 OH R3 O OTMS CO2Me CO2Me BocN O OH OH OH OH condition A: 83% yield condition A: 91% yield condition A: 89% yield condition A: 90% yield Me OH OTBS OTBS Me BocN OH OH OH Me H H OH H HO condition B: 94% yield condition B: 85% yield condition A: 54% yield condition B: 94% yield condition C: 92% yield condition B: 89% yield In our hands, employing Nagaoka’s conditions led to no observed reaction, even with HMPA or LiCl as additives (Scheme 3.16). While this was disappointing, material throughput at the Birch reduction stage remained prohibitively low. This severely hindered further investigation. Scheme 3.16. Attempts at Dowd-Beckwith ring expansion. OH OH TBSO Me OH H Me SmI2 (3 equiv) additive (X equiv) TBSO Me O THF, reflux, 12 h O H OH H Me O MOM MOM OH 104 entry additive X tBuOH (1 equiv) added? result 1 HMPA 12 yes no reaction 2 LiCl 6 yes no reaction 3 HMPA 12 no no reaction 4 LiCl 6 no no reaction Later, it was revealed from a publication from Dai and coworkers that higher Chapter 3 – Late stage d ring installation on the a-enolate arylation product 215 loadings of SmI2 may have been necessary to achieve the desired reactivity (Scheme 3.17).23 In this report, 10 equivalents of SmI2 along with 20 equivalents and 40 equivalents of TBAB and HMPA as additives, respectively, were required for optimal yield of the rearrangement. The density of functional groups in the molecule that could intervene or chelate with SmI2 first before coordination to the ketone SET to the desired ketyl radical are notable reasons why the desired rearrangement may not have occurred. For the case of substrate 104, it is clear that the diol motif may have been problematic. In future attempts, it would be necessary to try higher loadings of SmI2, HMPA, and use of TBAB as an additive. Scheme 3.17. Precedent for SmI2 skeletal rearrangement from Dai and coworkers. Me O H AcO PivO Me Me OH SmI2 (10 equiv) TBAB (20 equiv) HMPA (40 equiv) THF, reflux Me OH H AcO PivO Me Me OH 70% yield Given the difficulty in forming the d-ring using the methoxyarene reduction strategy, an interest in a new route developed. Using what was uncovered in Chapter 1 and 2 surrounding g-functionalization of siloxyfurans and a-enolate arylation chemistry, establishing a route that brought in the eastern 3.2.1 bicycle already intact could offer some advantages. The obvious advantage is that the Birch reduction would be avoided, which would greatly advance material throughput and avoid the need for exhaustive reduction of the lactone to the diol. Secondly is that such a route would be more convergent. Convergency may increase synthetic efficiency in certain contexts.23,24 At a fundamental level, convergent synthesis may allow for maximization of complexity-building steps compared to divergent synthesis, where the complexity-building steps are limited to one 216 Chapter 3 – Late stage d ring installation on the a-enolate arylation product fragment. This is what would be undertaken for the new, ambitious plan. Following some functional group interconversions, an a-enolate alkenylation could form the bond to deliver the key pentacycle (Scheme 3.18). The potential route would use a similar vinylogous Mukaiyama aldol on a more complex aldehyde fragment, bearing the 3.2.1 bicycle already intact. This would not only be in line with some of the research goals of the Reisman group, but potentially offer some benefits in circumventing the Birch reduction. While there are some notable challenges in developing this chemistry, this idea for a new route was pursued in full and discussed in detail in Chapter 4 & 5. Scheme 3.18. Revised, convergent route circumvents the use of the Birch reduction. MeO HO Me O H functional group interconversions H Me HO Me O O TBSO Me OH Me R HO O RO 105 auriculatol A (49) TBSO vinylogous Mukaiyama aldol O α-enolate alkenylation O TBSO X OTBS O Me Me 88 Me Ni Me O R 106 RO OR X 107 3.4 O CONCLUDING REMARKS This chapter summarizes efforts to elaborate a-enolate arylation products to end- game stages of the synthesis. Unfortunately, in many areas, these efforts were cumbersome due to a difficult Birch reduction step that often led to intractable mixtures of products possessing products from overreduction. Furthermore, attempts to convert the lactone functional group to the methyl acetal were not promising. The only condition that was found to form monoreduced lactone (lactol) was dissolving metal conditions, as shown in 217 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Scheme 3.4, entry 10 – the low yield due to competitive formation of the overreduced diol. Despite difficulty in achieving Birch reduction of the methoxyarene, the subsequent hydrolysis/b-g isomerization step and 2+2 allene cycloaddition were incredibly efficient and provided high diastereoselectivity of the desired product in high yield. From a-enolate arylation product 57, 104 could be formed in 3 steps in 15% yield as a single diastereomer, with the major costly step to yield being the Birch reduction. Nevertheless, while this was good for exploration of the 2+2 cycloaddition, material throughput limited the exhaustive exploration of the key skeletal rearrangement (Dowd-Beckwith ring expansion of cyclobutane 104). Preliminary efforts were not fruitful but could be conducted more indepth in the future, such as adaption of Dai’s condition that employ 10 equivalents of SmI2, 20 equivalents of TBAB, and 40 equivalents of HMPA in refluxing THF. A new route was drawn up to avoid the use of a Birch reduction, as shown in Scheme 3.17. The main challenges would be the application of the a-enolate alkenylation and vinylogous Mukaiyama aldol to a more complex reaction than the chemistry developed in Chapter 1 & 2. A more in-depth exploration of the route can be found in subsequent Chapters 4 & 5. 3.5 EXPERIMENTAL SECTION Preparation of diol 93: O TBSO Me OH O H Me DIBAL (2.2 equiv) O MOM 57 OMe Et2O (70 mM), −78 °C to 22 °C, 1 h 76% yield TBSO Me OH H Me O OMe MOM 93 An oven-dried 1-dram vial was charged with starting material 57 (7 mg, 15 umol, 1.0 Chapter 3 – Late stage d ring installation on the a-enolate arylation product 218 equiv), a magnetic stir bar, and the vial was put under N2 atmosphere. Dry Et2O was added (210 uL) to make a total concentration of 70 mM. Then, the vial was cooled to −78 °C and stirred for one minute. DIBAL (1 M solution in toluene, 17 uL, 1.2 equiv.) was added in using a microsyringe, and the reaction was stirred for 50 min at −78 °C, then rapidly warmed to room temperature, where it was stirred for 10 minutes. The reaction was quenched by addition of a saturated aqueous solution of Rochelle’s salt (0.3 mL), stirred for 1 h, then extracted with dichloromethane three times (3 x 0.3 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to afford the product as a yellow oil, which was analytically pure without any further purification (5.3 mg, 76% yield). OH TBSO Me OH H Me O OMe MOM 93 TLC (20% EtOAc/Hexanes): Rf 0.32 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 7.04 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 6.65 (ddd, J = 8.2, 2.7, 0.7 Hz, 1H), 5.66 (dd, J = 8.9, 0.8 Hz, 1H), 5.37 (d, J = 8.8 Hz, 1H), 4.65 (q, J = 6.8 Hz, 2H), 3.97 (dd, J = 4.7, 1.9 Hz, 1H), 3.88 (d, J = 6.7 Hz, 1H), 3.76 (s, 3H), 3.34 (d, J = 17.1 Hz, 2H), 3.26 (d, J = 0.6 Hz, 3H), 2.99 – 2.86 (m, 2H), 2.69 (ddd, J = 15.3, 12.2, 6.8 Hz, 1H), 1.94 (dd, J = 15.4, 3.9 Hz, 1H), 1.19 (s, 3H), 0.94 (s, 9H), 0.90 (s, 4H), 0.13 (d, J = 3.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 158.07, 137.38, 134.31, 130.40, 119.14, 110.94, 106.20, 100.70, 97.27, 85.04, 63.40, 56.82, 55.31, 51.75, 44.77, 39.88, 37.24, 30.47, 26.00, 19.00, 18.48, -4.58, -4.94. FTIR (NaCl, thin film): 3440, 2963, 1467, 1387, 1291, 1079, 1061, 990, 807 cm-1. Chapter 3 – Late stage d ring installation on the a-enolate arylation product 219 HRMS (ESI): calc’d for [M+H]+ 481.2980, found 281.2980. Preparation of Birch-reduced compound 95: O TBSO Me O H Me O MOM Na0 (200 equiv), liq. NH3 TBSO then THF, EtOH (125 equiv) Me −78 °C to −30 °C, 3 h OMe 30% yield 57 OH OH H Me O OMe MOM 95 A 10 mL round-bottom flask was flame dried with a glass stir bar and then the flask was added to a dry ice/acetone bath (–78 °C). An ammonia balloon was stuck through the rubber septa and ammonia (about 5 mL) was condensed in by pulling slight vacuum and removing the vacuum inlet. Solid sodium (183 mg, 200 equiv.) was added to the reaction flask, and the reaction mixture was stirred for 5 min at –78 °C. Then, via syringe pump, a solution of starting material 57 (19 mg, 40 umol, 1.0 equiv.) and ethanol (280 uL, 125 equiv) in 2 mL of THF was added. The reaction was allowed to warm to −10 °C over 3 h. Upon cooling the reaction mixture to –78 °C to lower the internal pressure, solid NH4Cl (20 mg) was added slowly, followed by EtOAc (5 mL). The cold bath was removed from the reaction apparatus, and the mixture was allowed to warm to ambient temperature overnight under a stream of nitrogen. EtOAc (5 mL) was added, and the mixture was poured into H2O (5 mL). The extracts were separated, and the aqueous extract was further extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (2 x 5 mL), dried with MgSO4, filtered through cotton, and concentrated in vacuo. The crude was loaded onto a pipet column, eluting with 5 to 10% EtOAc/Hexanes to provide 95 as a clear oil (5.8 mg, 30% yield). Chapter 3 – Late stage d ring installation on the a-enolate arylation product 220 OH TBSO Me OH H Me O OMe MOM 95 TLC (20% EtOAc/Hexanes): Rf 0.35 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.63 (d, J = 8.9 Hz, 1H), 5.29 (d, J = 7.9 Hz, 1H), 4.65 – 4.60 (m, 2H), 4.57 – 4.55 (m, 1H), 3.85 (d, J = 6.7 Hz, 1H), 3.79 (dd, J = 4.3, 2.1 Hz, 1H), 3.52 (s, 3H), 3.34 (s, 3H), 2.93 (ddd, J = 15.8, 10.1, 4.4 Hz, 3H), 2.70 – 2.64 (m, 3H), 2.54 (s, 1H), 2.11 (dd, J = 16.3, 4.3 Hz, 1H), 1.81 (dd, J = 15.4, 3.9 Hz, 1H), 1.14 (s, 3H), 0.92 (s, 9H), 0.90 (d, J = 0.9 Hz, 3H), 0.11 (d, J = 5.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 152.78, 132.31, 123.74, 106.14, 100.85, 97.22, 90.54, 85.09, 66.02, 61.18, 56.53, 53.92, 51.62, 43.10, 39.82, 37.03, 35.02, 34.58, 30.47, 29.86, 25.99, 25.77, 19.00, 18.45, 15.43, -4.60, -4.97. FTIR (NaCl, thin film): 3445, 2973, 1472, 1387, 1341, 1079, 990, 807 cm-1. HRMS (ESI): calc’d for [M+H]+ 483.3136, found 481.3129. Preparation of lactol 94: O TBSO Me O H Me OH Na0 (20 equiv) EtOH (60 equiv) O MOM NH3 (l)/THF OMe −78 °C to −50 °C, 1 h TBSO Me O H Me O OMe MOM 32% yield 57 94 Ammonia (2.1 mL) was condensed using a cold finger into an oven-dried 10 mL roundbottom flask equipped with a glass magnetic stir bar. Freshly cut sodium wire (19 mg, 839 umol, 20 equiv) was added in, and the resulting blue solution was stirred for 15 minutes at −78 °C. A solution of starting material 57 (20 mg, 42 umol) in 0.5 mL of THF and 140 uL Chapter 3 – Late stage d ring installation on the a-enolate arylation product 221 of EtOH (60 equiv.) was added in using a syringe pump at a rate of 3.9 mL per hour. Following 1 h and after monitoring by TLC carefully, the solutions blue color faded, and the reaction could be quenched by allowing the ammonia to boil off under a stream of nitrogen for 15 minutes, addition of saturated aqueous NH4Cl (1 mL), extracting the aq. layer with EtOAc (3 x 1 mL), washing with brine, drying with sodium sulfate, filtering, and concentrating. Preparatory TLC in 30% EtOAc allows for isolation of a clear oil 94 (6.4 mg, 32% yield) along with 36% yield of the diol 93 (overreduction). OH TBSO Me O H Me O OMe MOM 94 TLC (20% EtOAc/Hexanes): Rf 0.36 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 6.58 (dd, J = 8.2, 2.7 Hz, 1H), 5.19 (s, 1H), 4.66 (qd, J = 6.7, 2.8 Hz, 2H), 4.17 (d, J = 15.3 Hz, 1H), 3.85 – 3.79 (m, 1H), 3.73 (s, 3H), 3.71 – 3.66 (m, 1H), 3.60 (s, 1H), 3.30 (s, 3H), 2.92 (dd, J = 15.6, 4.2 Hz, 1H), 2.70 (dd, J = 11.5, 5.6 Hz, 1H), 2.38 – 2.26 (m, 1H), 2.13 (ddd, J = 14.6, 5.7, 2.8 Hz, 1H), 0.84 (s, 9H), 0.80 (s, 3H), 0.42 (s, 3H), 0.11 (d, J = 2.7 Hz, 6H). FTIR (NaCl, thin film): 3461, 2929, 1469, 1244, 1167, 1088, 1061, 919, 800 cm-1. HRMS: calc’d for [M+H]+ 479.2823, found 479.2834. Preparation of alcohol 101: O TBSO Me O O H Me Me3O+BF4(1 equiv) O MOM OMe CH2Cl2, 22 °C, overnight 20% yield 57 HO Me O H Me O MOM 101 OMe Chapter 3 – Late stage d ring installation on the a-enolate arylation product 222 To the starting material 57 (4.9 mg, 10 umol, 1 equiv) in an oven-dried vial equipped with a magnetic stir bar was added 200 uL of CH2Cl2 to make a total concentration of 50 mM. Then, solid trimethyloxonium tetrafluoroborate (1.5 mg, 10 umol, 1 equiv) was added in, the vessel was capped, and the reaction was stirred overnight. The next day, preparatory TLC in 50% EtOAc/Hexanes delivered the product 101 as a clear oil (1 mg, 20% yield). O HO Me O H Me O OMe MOM 101 TLC (50% EtOAc/Hexanes): Rf 0.21 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 7.13 – 7.07 (m, 1H), 6.75 – 6.69 (m, 2H), 4.74 – 4.66 (m, 2H), 4.20 (dd, J = 4.6, 2.1 Hz, 1H), 3.77 (s, 4H), 3.62 (s, 1H), 3.29 (s, 3H), 3.21 (ddt, J = 16.5, 2.0, 1.0 Hz, 1H), 3.14 (dd, J = 16.5, 4.6 Hz, 1H), 3.03 (dd, J = 11.1, 4.8 Hz, 1H), 2.73 (ddd, J = 15.3, 11.1, 6.7 Hz, 1H), 1.96 (d, J = 8.2 Hz, 1H), 1.63 (ddd, J = 15.4, 4.9, 1.6 Hz, 1H), 1.24 (s, 3H), 0.97 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 176.10, 158.95, 136.82, 130.88, 129.63, 119.21, 111.86, 99.30, 97.31, 82.52, 57.01, 56.68, 55.39, 49.93, 43.86, 39.52, 36.20, 24.21, 17.75. HRMS: calc’d for [M+H]+ 363.1802, found 363.1802. Preparation of ester 102: O TBSO Me MeOTf (10 equiv) 3,6 ditertbutypyridine (3 equiv) O H Me MeO TBSO HO Me O MOM OMe THF, 30 °C, 24 h H Me O OH MOM OMe 40% yield 57 102 To the starting material 57 (10 mg, 21 umol, 1 equiv.) in an oven-dried 1-dram vial 223 Chapter 3 – Late stage d ring installation on the a-enolate arylation product equipped with a magnetic stir bar was added 2,6-di-tert-butylpyridine (14 uL, 3 equiv.) followed by MeOTf (7 uL, 3 equiv). The reaction was put on a hot plate at 30 °C. The reaction was stirred for one day before it was worked up by addition of methanol (50 uL). The solvent was removed in vacuo and preparatory TLC in 20% EtOAc/Hexanes provided the product as a clear oil (4.3 mg, 40% yield). MeO TBSO HO Me H Me O OH MOM OMe 102 TLC (20% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 6.92 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.63 (dd, J = 8.2, 2.7 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 4.58 – 4.53 (m, 2H), 3.92 (d, J = 6.2 Hz, 1H), 3.76 (s, 4H), 3.68 (dd, J = 4.6, 1.5 Hz, 2H), 3.60 (s, 3H), 3.33 (s, 3H), 2.88 (dd, J = 15.1, 6.5 Hz, 1H), 2.82 (td, J = 8.0, 4.0 Hz, 1H), 2.70 – 2.62 (m, 1H), 2.52 (ddd, J = 14.7, 11.5, 6.3 Hz, 1H), 1.05 (s, 3H), 0.95 (s, 3H), 0.94 (s, 9H), 0.13 (d, J = 25.8 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 174.35, 158.42, 140.30, 131.86, 130.70, 119.23, 110.43, 95.95, 85.00, 83.05, 75.37, 57.12, 55.24, 51.92, 51.49, 50.48, 43.78, 36.03, 34.85, 30.46, 29.85, 26.00, 24.89, 18.25, 17.59, -4.50, -5.04. HRMS: calc’d for [M+H]+ 509.2929, found 509.2939. Preparation of enone 103: OH TBSO Me OH OH H Me HCl (1 equiv, 1M aqueous) TBSO Me O MOM 95 OMe THF, 0 °C, 2 h 69% yield dr = 3 : 1 H OH H Me O MOM 103 O Chapter 3 – Late stage d ring installation on the a-enolate arylation product 224 Aqueous hydrochloric acid solution (1 M, 1.00 equiv) was added to a solution of starting material (2.6 mg, 5.4 umol) in THF (975 uL, 5.5 mM) at 0 °C. The reaction was stirred vigorously for 2 h at 0 °C then quenched with saturated sodium bicarbonate (300 uL). The solution was extracted with Et2O (3 x 0.5 mL), dried with sodium sulfate, filtered, and concentrated down. Preparatory TLC in 40% EtOAc/Hex afforded product as a yellow oil (1.7 mg, 69% yield) as a 3:1 mixture of diastereomers favoring the desired (103, as determined by NOESY analysis). OH TBSO Me H OH H Me O O MOM 103 TLC (40% EtOAc/Hexanes): Rf 0.33 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.94 (d, J = 2.5 Hz, 1H), 5.85 (d, J = 9.3 Hz, 1H), 5.34 (d, J = 9.3 Hz, 1H), 4.68 – 4.62 (m, 2H), 3.86 (d, J = 6.4 Hz, 1H), 3.82 (dd, J = 4.7, 2.2 Hz, 1H), 3.40 (s, 3H), 2.71 – 2.53 (m, 5H), 2.52 – 2.45 (m, 1H), 2.43 – 2.34 (m, 1H), 2.31 (s, 1H), 2.11 – 2.01 (m, 1H), 1.95 – 1.87 (m, 1H), 1.76 (dd, J = 15.1, 3.2 Hz, 1H), 1.15 (s, 3H), 0.95 (s, 3H), 0.92 (s, 9H), 0.12 (d, J = 5.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 198.84, 161.70, 132.75, 107.80, 100.02, 97.47, 85.53, 77.23, 61.85, 57.22, 51.17, 42.90, 40.73, 40.30, 37.66, 37.58, 31.00, 26.03, 25.82, 19.31, 18.35, -4.74, -5.13. FTIR (NaCl, thin film): 3380, 2954, 1490, 1222, 1081, 997, 887 cm-1. HRMS: calc’d for [M+H]+ 469.2980, found 469.2993. 225 Chapter 3 – Late stage d ring installation on the a-enolate arylation product Preparation of cyclobutane 104: OH Me H Me OH hv H OH TBSO • O MOM O hexanes, −30 °C, 1 h TBSO Me 72% yield 103 OH H Me O O MOM 104 A solution of starting material 103 (1.7 mg, 3.6 umol, 1 equiv.) in hexanes (1.0 mL, 3.6 mM) was prepared in a quartz tube, and a stir bar was added in. Allene gas was bubbled through the solution at −30 °C, and noticeable change in volume indicated that allene had condensed. As bubbling continued, the solution was irradiated with UVC light in a photobox, put in place in order to shield from UV radiation exposure. After 10 minutes, the allene gas line was closed, and the reaction was further irradiated for 1 h at −30 °C. After 1 h, the solvent and allene were evaporated under a stream of nitrogen, and the product was analytically pure following high-vac, delivering the product 104 (1.3 mg, 72% yield) as a single diastereomer (as determined by NOESY analysis). OH TBSO Me OH H Me O O MOM 104 TLC (20% EtOAc/Hexanes): Rf 0.51 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.98 (s, 1H), 5.20 (s, 1H), 4.91 (s, 1H), 4.86 (s, 1H), 4.66 (s, 2H), 4.14 (s, 1H), 3.80 (s, 1H), 3.75 (s, 1H), 3.43 (s, 3H), 2.77 (s, 1H), 2.60 (s, 2H), 2.42 (s, 5H), 2.13 (s, 1H), 1.97 (s, 1H), 1.93 (s, 1H), 1.84 (s, 1H), 1.76 (s, 1H), 1.10 (s, 3H), 0.91 (s, 12H), 0.10 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 209.60, 141.99, 110.37, 109.23, 100.24, 98.22, 85.76, Chapter 3 – Late stage d ring installation on the a-enolate arylation product 226 78.78, 62.78, 58.65, 57.11, 51.29, 47.80, 43.52, 41.66, 39.86, 39.66, 39.60, 33.82, 27.74, 26.51, 25.81, 19.51, 18.33, -4.75, -5.13. 3.6 NOTES AND REFERENCES (1) Holton, R. A.; Kennedy, R. M. Stereocontrol of the Metal-Ammonia Reduction: Formation of Either Cis- or Trans-Fused Decalones from a Common Intermediate. Tetrahedron Lett. 1987, 28, 3, 303–306. (2) Janini, T. E.; Sampson, P. Cyclopropanation/Reduction of a 3,4-Disubstituted 2(5H)-Furanone: A Model for C-8 Methylation at the Taxane BC Ring Juncture. J. Org. Chem. 1997, 62, 5069–5073. (3) Chakraborti, A. K.; Saha, B.; Ray, C.; Ghatak, U. R. Alkali Metal-Liquid Ammonia Reduction of g-lactones to Diols and Cyclic Hemiacetals: Stereochemical Influence by the Neighbouring Group on the Nature of the Products. Tetrahedron 1987, 43, 19, 4433–4437. (4) Jeong, B. S.; Choi, N. S.; Ahn, S. K.; Bae, H.; Kim, H. S.; Kim, D. Total Synthesis and Antiangiogenic Activity of Cyclopentane Analogues of Fumagillol. Bioorg. Med. Chem. Lett. 2005, 15, 3580–3583. (5) Ho, G. M.; Zulueta, M. M. L.; Hung, S. C. Stereoselective One-Pot Synthesis of Polypropionates. Nat. Commun. 2017, 8, 15293. (6) Murthy, A. R.; Sundar, N. S.; Rao, G. S. R. S. Studies in Metal-Ammonia Reduction–5: Reduction and Reductive Methylation of Some Naphthoic Acids. Tetrahedron. 1982, 38, 2831–2836. (7) Roosen, P. C.; Karns, A. S.; Ellis, B. D.; Vanderwal, C. D. Evolution of a Short and Stereocontrolled Synthesis of (+)-7,20-Diisocyanoadociane. J. Org. Chem. 2022, 87, Chapter 3 – Late stage d ring installation on the a-enolate arylation product 227 1398–1420. (8) Verdaguer, X.; Hansen, M. C.; Berk, S. C.; Buchwald, S. L. Titanocene-Catalyzed Reduction of Lactones to Lactols. J. Org. Chem. 1997, 62, 8522–8528. (9) Hosokawa, S.; Toya, M.; Noda, A.; Morita, M.; Ogawa, T.; Motoyama, Y. Catalytic Silane-Reduction of Carboxylic Esters and Lactones: Selective Synthetic Methods to Aldehydes, Lactols, and Ethers via Silyl Acetal Intermediates. ChemistrySelect, 2018, 3, 2958–2961. (10) Cheng, C.; Brookhart, M. Efficient Reduction of Esters to Aldehydes through Iridium-Catalyzed Hydrosilylation. Angew. Chem. Int. Ed. 2012, 51, 9422–9424. (11) Gonzalez, C.; Kavoosi, S.; Sanchez, A.; Wnuk, S. F. Reduction of Sugar Lactones to Hemiacetals with Lithium Triethylborohydride. Carbohydrate Research, 2016, 432, 17– 22. (12) Deslongchamps, P.; Lessard, J.; Nadeau, Y. The Products of Hydrolysis of Cyclic Orthoesters as a Function of pH and the Theory of Stereoelectronic Control. Can. J. Chem. 1985, 63, 2485–2492. (13) House, H. O.; Strickland, R. C.; Zaiko, E. J. Perhydroindan Derivatives. 17. Application of the Reduction-Methylation Sequence to 7-Methoxyhexahydrofluorene Derivatives. J. Org. Chem. 1976, 41, 2401–2408 (14) Burrows, J.; Kamo, S.; Koide, K. Scalable Birch Reduction with Lithium and Ethylenediamine in Tetrahydrofuran. Science. 2021, 374, 741–746. (15) Donohoe, T. J.; House, D. Ammonia Free Partial Reduction of Aromatic Compounds Using Lithium Di-tert-Butylbiphenyl (LiDBB). J. Org. Chem. 2002, 67, 5015–5018. 228 Chapter 3 – Late stage d ring installation on the a-enolate arylation product (16) Lei, P.; Ding, Y.; Zhang, X.; Adijiang, A.; Li, H.; Ling, Y.; An, J. A Practical and Chemoselective Ammonia-Free Birch Reduction. Org. Lett. 2018, 20, 3439–3442. (17) Peters, B. K.; Rodriguez, K. X.; Reisberg, S. H.; Beil, S. B.; Hickey, D. P.; Kawamata, Y.; Collins, M.; Starr, J.; Chen, L.; Udyavara, S.; Klunder, K.; Gorey, T. J.; Anderson, S. L.; Neurock, M.; Minteer, S. D.; Baran, P. S. Scalable and Safe Synthetic Organic Electroreduction Inspired by Li-ion Battery Chemistry. Science. 2019, 363, 838– 845. (18) Takatori, K.; Ota, S.; Tendo, K.; Matsunaga, K.; Nagasawa, K.; Watanabe, S.; Kishida, A.; Kogen, H.; Nagaoka, H. Synthesis of Methylenebicyclo[3.2.1]octanol by a Sm(II)-Induced 1,2-Rearrangement Reaction with Ring Expansion of Methylenebicyclo[4.2.0]octanone. Org. Lett. 2017, 19, 3763–3766. (19) Hou, S. Y.; Yan, B. C.; Sun, H. D.; Puno, P. T. Recent Advances in the Application of [2+2] Cycloaddition in the Chemical Synthesis of Cyclobutane-Containing Natural Products. Na. Prod. and Bioprospect. 2024, 14, https://doi.org/10.1007/s13659-02400457-9. (20) McVeigh, M. S.; Sorrentino, J. P.; Hands, A. T.; Garg, N. K. Access to Complex Scaffolds Through [2+2] Cycloadditions of Strained Cyclic Allenes. J. Am. Chem. Soc. 2024, 146, 15420–15427. (21) Alcaide, B.; Almendros, P.; Aragoncillo, C. Exploiting [2+2] Cycloaddition Chemistry: Achievements with Allenes. Chem. Soc. Rev. 2010, 39, 783–816. (22) Corey, E. J.; Liu, K. Enantioselective Total Synthesis of the Potent Anti-HIV Agent Neotripterifordin. Reassignment of Stereochemistry at C(16). J. Am. Chem. Soc. 1997, 119, 9929–9930. Chapter 3 – Late stage d ring installation on the a-enolate arylation product (23) 229 Hsu, I. T.; Tomanik, M.; Herzon, S. B. Metric-Based Analysis of Convergence in Complex Molecule Synthesis. Acc. Chem. Res. 2021, 54, 903–916. (24) Kerkovious, J. K.; Wong, A. R.; Mak, V. W.; Reisman, S. E. A Convergent Fragment Coupling Strategy to Access Quaternary Stereogenic Centers. Chem. Sci. 2023, 14, 4397–4400. 230 Appendix 3 – Spectra Relevant to Chapter 3 Appendix 3 Spectra Relevant to Chapter 3: Late stage d ring installation on the a-enolate arylation product 6.70 6.66 7.04 Value 5.37 5.66 1.00 7.0 6.5 6.0 65536 32768 1.04 1.03 Spectral Siz e 1H Acquired Siz e 8012. 8 Nucleus Spectral Width 5.5 2021-12-19T12 29 51 Acquisition Date Spectrometer Frequency 400.13 4.0894 Acquisition Time 1.00 12.5000 1.0000 Relaxation Delay 1.00 Pulse Width 197.4 16 Number of Scans Receiver Gain 1D z g30 Pulse Sequence Experiment 297. 2 CDCl3 Bruker BioSpin GmbH JKT-1-274_proton.1. fid Temperature Solvent Origin Title 5.0 4.5 3.97 3.88 3.76 1.01 1.00 3.10 3 .0 3.34 3.26 2.04 3.15 4.0 3 .5 2.92 2.12 f1 (ppm) 2.70 0.99 4.65 2.11 Data File Name / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-274_proton/ 1/ fid 2025-6-26_Appendix_2 Parameter 2025-6-26_Appendix_2 2.5 93 1.5 0.5 1.19 3.16 1.94 0.97 1.0 0.94 0.90 8.90 3.86 2.0 0.13 6.02 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 78 .7 1.0000 10.0000 1. 3631 2021-12-19T12 51 04 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 130 32768 Acquired Siz e 140 13C Nucleus 150 24038 .5 Spectral Width 90 512 Number of Scans 100 1D Experiment 110 z gpg30 Pulse Sequence 120 297. 2 Temperature Spectrometer Frequency 100.62 CDCl3 Solvent 137.38 134.31 130.40 Bruker BioSpin GmbH 119.14 Origin 106.20 JKT-1-274_13C. 2. fid 100.70 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-274_13C/ 2/ fid 97.27 Title 158.07 160 110.94 Value 85.04 Data File Name Parameter 80 f1 (ppm) 70 60 50 44.77 93 39.88 37.24 40 30.47 30 19.00 18.48 20 10 0 -4.58 -4.94 26.00 56.82 55.31 51.75 63.40 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 2500 hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2021-12-19T13 02 49 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.68 , 16. 22) Spectral Siz e Digital Resolution 5.5 (1024, 180) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-574.0, -1262. 8) Lowest Frequency 7.0 (4795.4, 16611. 3) Spectral Width 3 .5 f2 (ppm) 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH 5.0 JKT-1-274_HSQC. 3 .ser Origin Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-274_HSQC/ 3/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 93 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) NOESY 3 197.4 1. 8000 12.5000 0. 2560 2021-12-19T13 37 30 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-223 .4, -218 .6) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 3 .5 f2 (ppm) noesygpphzs Pulse Sequence 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-1-274_NOESY.4.ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-274_NOESY/ 4/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 93 0.0 -0.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 f1 (ppm) 197.4 1.0000 12.5000 4.0894 2022-02-21T22 28 18 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 2.16 1.04 4.5 4.0 16 Number of Scans 5.0 1D Experiment 5.5 z g30 Spectrometer Frequency 400.13 297.1 Pulse Sequence 5.63 1.00 Temperature 5.29 CDCl3 4.63 4.56 Solvent f1 (ppm) 3 .5 3 .0 2.5 3.85 3.79 1.03 1.12 Bruker BioSpin GmbH 3.52 2.98 Origin 3.34 3.00 JKT-1-325-5-1_3D.1. fid 2.93 3.04 Title 2.68 2.95 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-325-5-1_3D/ 1/ fid Value 2.54 0.96 Data File Name Parameter 95 2.0 1.5 0.5 0.92 0.90 8.95 2.92 1.14 2.99 1.81 1.04 2.11 1.00 1.0 0.11 6.25 1.27 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 152.78 1.0000 10.0000 1. 3631 2022-02-22T00 10 26 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 140 32768 Acquired Siz e 150 13C Nucleus 160 24038 .5 Spectral Width 90 38 .0 Receiver Gain 100 2500 Number of Scans 110 1D Experiment 120 z gpg30 Pulse Sequence 130 297. 2 Temperature Spectrometer Frequency 100.62 CDCl3 132.31 Solvent 123.74 Bruker BioSpin GmbH 106.14 Origin 100.85 JKT-1-325-5-1_3D. 2. fid 97.22 Title Value 90.54 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-325-5-1_3D/ 2/ fid Parameter 85.09 Data File Name 80 f1 (ppm) 70 61.18 60 50 95 43.10 39.82 37.03 35.02 34.58 40 30.47 29.86 25.99 25.77 30 19.00 18.45 15.43 20 10 0 -4.60 -4.97 56.53 53.92 51.62 66.02 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 Spectral Siz e Acquired Siz e Nucleus Spectral Width 7.0 6.5 2.91 0.94 3.30 2.86 3.81 3.73 3.68 3.60 1.03 3.00 1.03 0.98 6.0 65536 24000 1H 8000.0 5.5 2022-05-23T10 48 28 3 .0000 5.6500 1.0000 52 8 1D s2pul 3 .0 cdcl3 Varian PROTON01 5.0 4.5 4.0 3 .5 f1 (ppm) 3 .0 2.71 1.14 / Users/ jordankthompson/ Desktop/ JKT-2-24-1/ PROTON01. fid/ fid Spectrometer Frequency 499.58 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title 5.19 1.03 Data File Name Value 4.66 2.02 Parameter 4.19 0.96 7.08 1.00 2.14 0.91 2.32 1.24 2.5 94 2.0 1.5 1.0 0.84 0.80 9.03 3.03 6.63 6.59 1.02 1.03 0.42 0.5 0.01 0.0 6.01 3.01 1.58 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 Parameter 6.72 7.2 7.0 6. 8 Spectral Siz e Acquired Siz e Nucleus 6.6 6.4 6.2 65536 32768 1H 8012. 8 5. 8 5.6 2022-05-18T02 10 22 Acquisition Date 6.0 4.0894 Acquisition Time Spectrometer Frequency 400.13 12.5000 1.0000 Relaxation Delay Pulse Width 197.4 16 Receiver Gain 1D z g30 297. 2 CDCl3 Bruker BioSpin GmbH JKT-2-20_pure.1. fid Number of Scans Spectral Width Value 5.4 5.2 5.0 4. 8 4.6 4.4 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-20_pure/ 1/ fid Experiment Pulse Sequence Temperature Solvent Origin Title 2.02 4.71 2.01 7.09 1.01 3 .4 3 .0 4.20 1.00 3 .2 3.77 4.08 3 .6 3.62 0.99 3.8 3.29 3.19 3.15 3.03 3.00 1.00 0.98 0.98 4.2 4.0 f1 (ppm) 2. 8 2.6 101 2.73 1.02 Data File Name 2.4 2.2 1. 8 1.4 1.0 1.97 0.99 1.2 1.64 1.06 1.6 1.24 3.00 2.0 0.97 3.01 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 180 130.88 129.63 1500 72.0 1.0000 10.0000 1. 3631 2022-05-18T03 11 32 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 110 1D Experiment 120 z gpg30 Pulse Sequence 130 297. 2 Temperature 140 CDCl3 Spectrometer Frequency 100.62 Bruker BioSpin GmbH Solvent 176.10 JKT-2-20_pure. 2. fid 158.95 Origin 136.82 Title Value 119.21 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-20_pure/ 2/ fid Parameter 111.86 Data File Name f1 (ppm) 99.30 97.31 100 90 80 70 57.01 56.68 55.39 60 101 49.93 50 39.52 40 30 20 17.75 24.21 36.20 43.86 82.52 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 cosygpppqf COSY 3 197.4 1. 8898 12.5000 0. 3072 2022-05-18T03 26 52 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 . 26, 3 . 26) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 1H) Nucleus 6.5 (-44. 3 , -44. 3) Lowest Frequency 7.0 (3333 . 3 , 3333 . 3) Spectral Width f2 (ppm) 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-2-20_pure. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-20_pure/ 3/ ser Title Value Data File Name Parameter 4.0 3 .5 3 .0 2.5 2.0 1.5 101 1.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 4 197.4 1.5000 12.5000 0. 2135 2022-05-18T03 49 02 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 13C) Nucleus 6.5 (-524.5, -1262. 8) Lowest Frequency 7.0 (4795.4, 16611. 3) Spectral Width 4.0 f2 (ppm) 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH 5.5 JKT-2-20_pure.4.ser Origin Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-20_pure/ 4/ ser Title Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 101 1.0 130 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) Parameter 7.0 Spectral Siz e Acquired Siz e Nucleus Spectral Width 6.5 6.0 65536 32768 1H 8012. 8 5.5 2022-05-21T08 15 05 4.0894 12.5000 1.0000 Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay 176. 8 16 Number of Scans Receiver Gain 1D z g30 297. 2 CDCl3 Bruker BioSpin GmbH JKT-2-21-1-2.1. fid Experiment Pulse Sequence Temperature Solvent Origin Title Value 5.0 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-21-1-2/ 1/ fid 4.75 1.02 6.92 6.75 6.64 1.00 1.01 1.02 4.55 4.5 2.04 Data File Name 4.0 3 .0 3.33 3.04 3.91 3.78 3.69 3.60 0.98 4.01 2.09 3.00 2.5 2.88 2.81 2.66 2.53 1.09 0.97 1.03 1.05 3 .5 f1 (ppm) 102 2.0 1.5 0.5 1.05 0.95 0.93 3.01 3.03 9.09 1.0 0.12 6.05 0.0 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 158.42 119.23 50. 3 1.0000 10.0000 1. 3631 2022-05-21T08 57 03 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 90 1024 Number of Scans 100 1D Experiment 110 z gpg30 Pulse Sequence 120 297. 2 Temperature 130 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 174.35 JKT-2-21-1-2_13C.6. fid 140.30 Origin 131.86 130.70 Title Value 110.43 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-21-1-2_13C/ 6/ fid Parameter 95.95 Data File Name 85.00 83.05 80 f1 (ppm) 70 60 57.12 55.24 51.92 50.48 51.49 50 102 40 34.85 36.03 30.46 29.85 26.00 24.89 30 18.25 17.59 20 10 0 -4.50 -5.04 43.78 75.37 -10 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 HSQC-EDITED 2 197.4 1.5000 12.5000 0.1704 2022-05-21T09 08 29 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5. 87, 16. 22) Spectral Siz e Digital Resolution 5.5 (1024, 180) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-1133 .0, -1262. 8) Lowest Frequency 7.0 (6009.6, 16611. 3) Spectral Width 3 .5 f2 (ppm) hsqcedetgpsisp 2.4 Pulse Sequence 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-2-21-1-2_HSQC.7.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-21-1-2_HSQC/ 7/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 102 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) NOESY 4 197.4 1. 8000 12.5000 0. 2560 2022-05-21T09 59 52 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 7.0 (1024, 256) Acquired Siz e 7.5 (1H, 1H) Nucleus 8 .0 (-167.0, -166.5) Lowest Frequency 8 .5 (4000.0, 4000.0) Spectral Width 4.5 f2 (ppm) noesygpphzs Pulse Sequence 5.0 297. 2 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 6.5 JKT-2-21-1-2_NOESY.9.ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-21-1-2_NOESY/ 9/ ser Title Value Data File Name Parameter 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 102 0.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 1 112. 8 1.9185 12.5000 0. 2785 2022-05-21T09 14 08 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 .59, 3 .59) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 1H) Nucleus 6.5 (-388 .0, -394. 3) Lowest Frequency 7.0 (3676.5, 3676.5) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-2-21-1-2_ COSY. 8 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-21-1-2_ COSY/ 8/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 102 0.0 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 16 197.4 1.0000 12.5000 4.0894 2022-03-11T10 10 30 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.0 1D Experiment 4.5 z g30 Pulse Sequence 5.0 297. 2 Temperature 5.5 CDCl3 Solvent 103 Bruker BioSpin GmbH Spectrometer Frequency 400.13 JKT-1-341-6 _3D.1. fid Origin 5.94 5.85 0.94 1.00 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-341-6 _3D/ 1/ fid 5.34 Title Value 4.65 Data File Name Parameter 3 .5 f1 (ppm) 3 .0 1.5 0.5 2.06 1.91 1.76 1.07 1.06 0.94 2.62 2.49 2.39 2.31 5.05 0.99 0.99 0.95 3.39 2.99 3.86 3.82 1.04 1.12 1.0 1.15 3.01 2.0 0.95 0.92 3.26 8.86 2.5 0.12 5.98 2.06 1.04 0.0 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 10.0000 1. 3631 2022-03-10T21 16 30 Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 110 1.0000 Relaxation Delay 120 38 .0 Receiver Gain 130 1000 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297.1 Temperature 103 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 198.84 JKT-1-331-6 _pure. 2. fid 161.70 Title Value 132.75 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-331-6 _pure/ 2/ fid Parameter 107.80 Data File Name 100.02 97.47 100 f1 (ppm) 90 80 70 61.85 60 51.17 50 42.90 40.73 40.30 37.66 37.58 40 31.00 26.03 25.82 30 19.31 18.35 20 10 0 -4.74 -5.13 57.22 77.23 85.53 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 2 176. 8 1.9205 12.5000 0. 2765 2022-03-11T10 20 59 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .62, 3 .62) Digital Resolution 6.0 (1024, 1024) Spectral Siz e 6.5 (1024, 128) Acquired Siz e 7.0 (1H, 1H) Nucleus 7.5 (-399.1, -399.5) Lowest Frequency 8 .0 (3703 .7, 3703 .7) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-1-341-6 _3D. 2.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-341-6 _3D/ 2/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 103 -0.5 8 7 6 5 4 3 2 1 0 f1 (ppm) NOESY 4 197.4 1. 8000 12.5000 0. 2560 2022-03-11T11 06 35 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-166.7, -167.5) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width f2 (ppm) noesygpphzs Pulse Sequence 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-1-341-6 _3D. 3 .ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-341-6 _3D/ 3/ ser Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 103 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 297.1 hsqcedetgpsisp 2.4 HSQC-EDITED 4 197.4 1.5000 12.5000 0. 2135 2022-03-10T21 38 43 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-574.9, -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width 3 .0 f2 (ppm) CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-1-331-6 _pure. 3 .ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-331-6 _pure/ 3/ ser Title Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 103 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 4.91 4.86 16 197.4 1.0000 12.5000 4.0894 2022-03-13T13 39 09 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 6.0 0.96 1.07 5.0 4.0 1D Experiment 4.5 z g30 Pulse Sequence 5.5 297. 2 Temperature 1.00 104 CDCl3 0.97 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Solvent 5.98 JKT-1-34 2_pureflushed.1. fid 5.20 Origin 4.66 Title Value 4.14 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-34 2_pureflushed/ 1/ fid Parameter 3.80 3.75 Data File Name 1.12 1.12 f1 (ppm) 3 .0 1.5 1.0 0.5 2.13 1.97 1.93 1.84 1.76 1.08 1.10 1.11 1.01 1.09 2.42 4.95 2.60 2.12 2.77 0.98 3.43 2.98 2.0 1.10 3.10 2.5 0.91 12.15 3 .5 0.10 6.03 2.07 0.97 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 141.99 78 .7 1.0000 10.0000 1. 3631 2022-03-13T14 10 00 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 120 100.24 98.22 100 f1 (ppm) 750 Number of Scans 110 1D Experiment 130 z gpg30 Pulse Sequence 140 297.1 Temperature 150 CDCl3 Solvent 160 Bruker BioSpin GmbH 104 JKT-1-34 2_pureflushed. 2. fid Origin Spectrometer Frequency 100.62 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-34 2_pureflushed/ 2/ fid 209.60 Title Value 110.37 109.23 Data File Name Parameter 90 78.78 80 70 62.78 58.65 57.11 60 40 51.29 47.80 43.52 41.66 39.86 39.66 39.60 33.82 50 27.74 26.51 25.81 30 19.51 18.33 20 10 0 -4.75 -5.13 85.76 0 50 100 150 200 250 300 350 400 450 197.4 1.5000 12.5000 0. 2135 2022-03-13T14 32 13 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.2 4.0 (4.68 , 16. 22) Digital Resolution 4.4 (1024, 1024) Spectral Siz e 4.6 (1024, 180) Acquired Siz e 4. 8 (1H, 13C) Nucleus 5.0 (-527.1, -1273 . 3) Lowest Frequency 5.2 (4795.4, 16611. 3) Spectral Width 2.4 4 Number of Scans 2. 8 2.6 f2 (ppm) HSQC-EDITED Experiment 3 .0 hsqcedetgpsisp 2.4 Pulse Sequence 3 .2 297. 2 Temperature 3 .4 CDCl3 Solvent 3 .6 Bruker BioSpin GmbH Origin 3.8 JKT-1-34 2_pureflushed. 3 .ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-34 2_pureflushed/ 3/ ser Title Value Data File Name Parameter 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 104 0.2 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 2 197.4 1.9164 12.5000 0. 2806 2022-03-13T14 4 2 40 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .56, 3 .56) Spectral Siz e Digital Resolution 5.0 (1024, 128) Acquired Siz e 5.5 (1H, 1H) Nucleus 6.0 (-413 .9, -413 .9) Lowest Frequency 6.5 (3649.6, 3649.6) Spectral Width 2.5 COSY Experiment 3 .0 f2 (ppm) cosygpppqf Pulse Sequence 3 .5 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-1-34 2_pureflushed.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-34 2_pureflushed/ 4/ ser Parameter Data File Name 2.0 1.5 1.0 0.5 0.0 -0.5 104 8 .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 197.4 1. 8000 12.5000 0. 2560 2022-03-13T15 28 16 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-167. 3 , -166.7) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 3 .5 4 Number of Scans f2 (ppm) NOESY Experiment 4.0 noesygpphzs Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-1-34 2_pureflushed.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-1-34 2_pureflushed/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 104 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 257 Chapter 4 – 3.2.1 bicycle synthesis Chapter 4 3.2.1 bicycle synthesis† 4.1 INTRODUCTION This chapter summarizes efforts to complete 3.2.1 bicycle synthesis in the context of the total synthesis of auriculatol A. Various radical cascade processes, transition metal catalyzed reactions, and annulations are discussed, including a Snider radical cascade, palladium-catalyzed decarboxylative Tsuji-Stoltz allyation, nickel-catalyzed intramolecular carbonyl 1,2-addition, and Michael-Aldol cascade. Several failed routes are discussed in detail. Taken together, these data provide foundational information for † Portions of this chapter were adapted from the following communication: Thompson, J. K.; Youngblood, K. C.; Teh, S. Y. H.; Farley, C. M.; Zhang, Z.; Virgil, S. C.; Reisman, S. E. J. Am. Chem. Soc. 2025, 147, 42170–42174. Scott C. Virgil is acknowledged for his expertise enabling the preparatory HPLC purification of 107A. J.K.T. was supported by the NSF GRFP (DGE-1745301). S.E.R. acknowledges fellowship support by the NIH (R35GM118191). The research presented in this chapter was completed in collaboration with Shawn Teh and Kala Youngblood, a former master’s student and graduate student in the Reisman group, respectively. 258 Chapter 4 – 3.2.1 bicycle synthesis disclosure of a standalone approach for the synthesis of 3.2.1 bicycles through the use of Tsuji-Stoltz allylation and nickel-catalyzed intramolecular carbonyl 1,2-addition. Coupled with work done by other colleagues, Dr. Sven Richter and Dr. Ray Turro, these data may be of particular interest for future publication. 4.2 VERSATILE 3.2.1 BICYCLE SYNTHESIS THROUGH THE SNIDER RADICAL CASCADE 4.2.1 A transform-based approach for 3.2.1 bicyclic aldehyde synthesis: use of the Snider Radical Cascade As described in the concluding paragraph of Chapter 3.3.3, a new route that could circumvent the use of the Birch reduction was devised. The simplest and perhaps most elegant solution invoked the use of a fragment containing the eastern part of the molecule already intact. The key fragment would need to be synthesized and tested in the vinylogous Mukaiyama aldol coupling reaction. Scheme 4.1. Revised, convergent route necessitates the development of 3.2.1 bicyclic aldehyde synthesis. MeO HO Me O H functional group interconversions H Me HO Me O O TBSO Me OH Me R HO O RO 105 auriculatol A (49) TBSO vinylogous Mukaiyama aldol O α-enolate alkenylation O TBSO X OTBS O Me Me 88 Me Ni Me O R 106 RO OR X 107 O key fragment 259 Chapter 4 – 3.2.1 bicycle synthesis Several strategies were outlined as potentially feasible to the key fragment. Searching the literature, it became clear that 3.2.1 bicycle synthesis is often accomplished through the use of a radical cascade from acyclic a-allylated b-keto esters, colloquially referred to as the Snider radical cascade.1 This is often accomplished with stoichiometric loadings of Mn(OAc)3. MnIII, following coordination to ketone, oxidizes b-keto esters to the corresponding a-radical, which can cyclize to form an alkyl radical. It has been shown that MnIII has the ability to oxidize tertiary radicals to cations but is not oxidizing enough to oxidize primary and secondary radicals.2 For this reason, Cu(OAc)2 is often employed as a stoichiometric oxidant under the reaction conditions. Taken together, the Snider radical cascade has been applied to 3.2.1 bicycle synthesis in various contexts. Indeed, compound 110 was identified as a viable substrate that could be applied to the synthesis of the key fragment (Scheme 4.2).3 Due to the fact that MEM groups are acid-labile, the reaction was conducted in EtOH rather than AcOH. In this report, unique solvent effects were observed and discussed as they apply to various substrates, such as the greater propensity for 5-exo and alkene-containing products in EtOH, while alcohols and lactones were generated in AcOH.3 In our transform-based approach, compound 110 could be accessed in 2 steps from a-allyl methyl acetoacetate (108, Scheme 4.2), but it was not known how scalable the reaction to form 109 would be and if the step could support the first step of a total synthesis. Scheme 4.2. Important precedent from Snider and coworkers. OMEM O Me MeO O Weiler Dianion Mn(OAc)3 (2.0 equiv) Cu(OAc)2 (1.0 equiv) MeO O EtOH, 60 °C, 13 h O O MeO2C OMEM 52% yield 108 109 110 In our retrosynthetic analysis of 107A, it was believed the product could be formed 260 Chapter 4 – 3.2.1 bicycle synthesis from acid-mediated hydrolysis of vinyl methoxy ether 111 (Scheme 4.3). 111 could arise from a Wittig homologation of aldehyde 112, which could be formed from a 2-step oxidation/reduction protocol from ester 114. 114 could be formed through ketone triflation of 110, which was shown to be accessible from the Snider radical cascade of 109 (Scheme 4.3). Scheme 4.3. Retrosynthetic analysis of 107A. Wittig Homologation TfO Acid-Mediated Hydrolysis TfO OMEM OMEM O OMEM O MeO 107A Alcohol Oxidation 111 TfO Ester Reduction OMEM TfO H 112 TfO Ketone Triflation MeO2C OMEM O MeO2C OMEM HO 113 114 110 During the early synthetic planning of the fragment synthesis, we were aware that compound 107A could be prepared as the racemate to test the vinylogous Mukaiyama Aldol but anticipated that it could be resolved through the use of chiral preparatory HPLC. This would enable access to (R,S)-107A (Scheme 4.4). Furthermore, upon subjection to our triflex methodology4 to form the alkenyl bromide, fragment 107B could also be prepared and tested. Depending on the competency of the fragment in the vinylogous Mukaiayama Aldol coupling reaction and the functional group required for the Nicatalyzed alkenylation, a variety of substrates could be synthesized and tested. 261 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.4. Elaboration of 107A (if necessary). chiral preparatory high-performance liquid chromatography TfO TfO OMEM O OMEM O 107A (R,S)-107A Ni TfO OMEM O (R,S)-107A Br Triflex OMEM O (R,S)-107B 4.2.2 Synthesis of the Snider Radical Cascade substrate Allylation of methyl acetoacetate could be accomplished using NaH and allyl bromide; however, the yields to form 108 were lower than reported in the literature (see experimental section for preparation details).5 Literature precedent for the a-alkylation of 108 with a-chloroethers exists through the Weiler dianion;6 nevertheless, in our hands, only substrates containing the MEM group produced the coupled product when compared to MOM (116 or 109). As shown in Scheme 4.5, use of vinyl MOM ethers led to coupling and hydrolysis to compound 117. HMPA was a necessary additive, but the reaction could be accomplished using 1.1 equiv. of 115. An essential aspect of the reaction is the use of dry, 90% NaH, which is stored and handled in a nitrogen-filled glovebox. Use of 60% NaH in mineral oil led to diminished yields (< 20%) of the product and messier reaction profiles to several uncharacterized side products. Weiler dianions are reported to be extremely sensitive to moisture. For that reason, and taking the data from Scheme 4.5 into account, a protocol employing 2 equivalents of hexamethylphosphoramide (HMPA) and 90% NaH, used and handled in the glovebox, provided 52% yield of 109. The yield and scalability of 262 Chapter 4 – 3.2.1 bicycle synthesis this reaction up to 20 g scale was tolerated. Scheme 4.5. Exploration of Weiler dianion functionalization. O OR Me O NaO NaH (1.1 equiv) MeO THF, 0 °C, 15 min O Me O nBuLi, 0 °C, 45 min MeO O MeO then additive (2 equiv) O (1.1 equiv) Cl 108 O O OR Me MeO 117 115 R = MOM, 116 R = MEM, 109 −78 °C to 21 °C, 16 h entry R additive equiv. 115 yield product (%) yield 117 (%) 1 MOM - 1.1 - - 2 MOM - 1.1 - - 3 MOM - 2.0 - - 4 MOM HMPA 1.1 - 56 5 MEM - 1.1 - - 6 MEM HMPA 1.1 52 - 4.2.3 Studies to affect the Snider Radical Cascade With 109 in hand, the Snider Radical Cascade could be tested. Excitingly, the precedent from Snider could be repeated in identical yield, given a couple of considerations that were imperative to the yield of the reaction: the use of homemade Mn(OAc)3 was essential to good yields of the product; use of Mn(OAc)3, as supplied by Combi Blocks, led to diminished formation of the product (< 20% yield, result not shown). Additionally, the yield of the Snider Radical Cascade could be increased to 58% by use of degassed EtOH. While the reaction had yields ranging consistently from 40-58%, it could be conducted on 20 g scale without reduction in yield and with good reproducibility. 263 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.6. Formation of 110. NaH (1.1 equiv), 0 °C, 15 min then nBuLi, 0 °C, 45 min then HMPA (2 equiv) O Me Cl OMEM OMEM (1.1 equiv) O MeO MeO O 108 THF, −78 °C to 21 °C, 16 h 52% yield O Mn(OAc)3 (2.0 equiv) Cu(OAc)2 (1.0 equiv) 115 degassed EtOH, 60 °C, 13 h O 109 MeO2C 58% yield OMEM 110 While the route to 110 was amenable to large scale and reliable, the use of expensive, toxic reagents on scale were somewhat prohibitive. The use of superstoichiometric MEMCl to prepare fragment 115 over two steps, followed by stoichiometric nBuLi and HMPA to form 109, followed by super stoichiometric quantities of Mn(OAc)3 (that could not be purchased and had to be made), limited material throughput when trying to exceed 20 g scale. See the experimental section for more details. Nevertheless, for early proof-of-concept studies, the route could suffice. 4.2.4 Advancement to the key fragment (107A) With 110 in hand, triflation could be accomplished under literature-reported conditions to form 114 (Scheme 4.7).4 The enol triflate (114), containing a bridgehead methyl ester, could be subjected to a four-step homologation sequence to aldehyde 107A through: 1) exhaustive DIBAL reduction to alcohol 113, 2) Swern oxidation to aldehyde 112, 3) Wittig olefination to vinyl methyl ether 111, and finally 4) hydrolysis to the terminal aldehyde 107A. 264 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.7. Initial route to 107A. LDA (1.2 equiv) THF, −78 °C then Comin’s (1.15 equiv) O MeO2C OMEM TfO MeO2C 1.5 h TfO DIBAL-H (3 equiv) HO OMEM OMEM DCM, 0 °C, 1 h 77% yield 97% yield 114 110 Oxalyl chloride DMSO then NEt3 113 DCM, −78 °C, 1 h pTsOH • H2O (1 equiv) TfO OMEM O Acetone/H2O, 21 °C, 8 h 107A OMe Cl Ph3P (3 equiv) LHMDS (2.7 equiv) TfO OMEM THF, 0 °C to rt, 1.5 h MeO 50% yield 111 66% yield 75% yield TfO H OMEM O 112 The development of the route depicted in Scheme 4.7 occurred swiftly with only a few challenges. Screening oxidation conditions of 113 to 114 was uneventful; use of Stahl oxidation led to a messy reaction profile and low conversion, likely due to side reactivity with the enol triflate, although this is not confirmed (Scheme 4.8, entry 1). Ley oxidation (TPAP/NMO) led to 56% yield, while Swern oxidation delivered the product in 75% yield (Scheme 4.8, entry 2-3). Scheme 4.8. Oxidation of alcohol 113. TfO conditions TfO O HO OMEM OMEM H 114 113 entry conditions yield 114 (%) 1 Cu(NCCH3)4 • CF3SO3, bpy, ABNO, 1-methylimidazole 27 2 TPAP, NMO • H2O 57 3 DMSO, oxalyl chloride, NEt3 75 One challenge that arose was the Wittig olefination step. Surprisingly, use of KOtBu did not lead to the desired product but instead resulted in formation of an unidentified side product (Scheme 4.9, entry 1). However, LHMDS furnished the product 265 Chapter 4 – 3.2.1 bicycle synthesis in 50% yield as a 2:1 inconsequential mixture of diastereomers (Scheme 4.9, entry 2). The yield of this reaction was low but was adequate for material throughput. One of the other challenges that arose was the vinyl methyl ether hydrolysis. While use of pTsOH • H2O led to 66% yield, BBr3 led to substrate decomposition (Scheme 4.9, entry 3-4), and HCl led to primarily cleavage of the MEM protecting group (not shown). More thorough investigation could be conducted to try to optimize the yield, but for the purpose of exploring downstream chemistry, was adequate. Scheme 4.9. Wittig Homologation of 114 followed by acid-mediated hydrolysis. Cl OMe Ph3P TfO TfO O MeO OMEM TfO reagent (X equiv) base (5 equiv) OMEM OMEM O H 114 111 entry base 1 KOtBu LHMDS 2 107A reagent yield 111 (%) entry - - 3 BBr3 (1 equiv) - 2:1 50 4 pTsOH • H2O (3 equiv) 66 dr yield 107A (%) 4.2.5 Further derivatization of the key fragment (107A) As shown in Scheme 4.4, 107A could be resolved through the use of chiral preparatory HPLC and subjected to adapted conditions from our Triflex methodology to form enantioenriched 107B. 1.5 g of compound could be separated to afford 500 mg of product; this took a total of 10 h at the instrument, however, with only modest yield overall. Scheme 4.10. Access to enantioenriched 107B. TfO OMEM O 25 mg/injection 60 injections 107A TfO IB column 10% IPA/Hexanes OMEM O DMA, 21 °C, 12 h (R,S)-107A Br Ni(COD)2 (10 mol%) LiBr (5 equiv) 70% yield OMEM O (R,S)-107B The halide exchange of 107A to 107B occurred uneventfully. Use of 10 mol% 266 Chapter 4 – 3.2.1 bicycle synthesis Ni(COD) with 1.5 equiv of LiBr for 3 h led to 65% yield and > 90% conversion, while stirring for 12 h led to an increase in conversion and 68% yield (Scheme 4.11). Scheme 4.11. Access to enantioenriched 107B. TfO Ni(COD)2 (10 mol%) Br LiBr (1.5 equiv) OMEM O THF/DMA, 22 °C time (R,S)-107B (R,S)-107A entry OMEM O time (h) conversion (%) yield 107B (%) 1 3 91 65 2 12 95 68 4.2.6 Strategies to shorten the key fragment (107B) synthesis Several strategies to shorten the fragment synthesis at this stage were brainstormed. One of the least step-economical parts of the fragment synthesis involves the conversion of ester 110 to aldehyde 107A. As shown in Scheme 4.7, this is accomplished in 5 steps and 18% overall yield. The most thoroughly investigated strategy was the application of a decarboxylative Giese addition in order to install the pendant aldehyde in the key fragment in a more expedient manner (Scheme 4.12). In theory, aldehyde 107A could arise from alkyl sulfone 118 and be traced back to 119 following ketone triflation. Alkyl sulfone 119 could arise from decarboxylative Giese addition, providing carboxylic acid 120. In the forward sense, decarboxylation of 120 using photoredox catalysis could deliver a radical intermediate, which could engage in Giese addition with the desired Giese acceptor. The ideal Giese addition unit would add two-carbons that could be converted to the terminal aldehyde. A variety of Giese acceptors were envisioned under these conditions. Perhaps the most exciting was Hwu and Murphree’s use of phenyl vinyl sulfone, which is literaturereported to undergo a one-pot oxidation with KHMDS and O2.7 Other acceptors were 267 Chapter 4 – 3.2.1 bicycle synthesis thought to be plausible for investigation of the reactivity, including methyl vinyl ketone, various acrylates, and 2-propenenitrile. These three-carbon units could form the terminal aldehyde following ozonolytic cleavage of the silyl enol ether or some other internal olefin equivalent (although this route would be less direct than the sulfone). While there is certainly a flurry of papers in the realm of decarboxylative Giese additions, we were drawn to the work of Morita, Liang, Aggarwal, MacMillan, and Pospech.8-13 A review from Lee and coworkers in this area nicely summarizes the state of the art for this research aim.14,15 Scheme 4.12. Decarboxylative Giese addition. oxidative desulfonation TfO OMEM 107A PhO2S 118 O Ir decarboxylative Giese addition O triflation PhO2S OMEM O TfO OMEM 119 O saponification O OMEM HOOC PhO2S radical intermediate OMEM 120 MeO2C OMEM 110 While the operation seemed simple in synthetic planning, it was difficult in practice. Saponification of ester 110 to 120 proved challenging (Scheme 4.13). Upon subjection to LiOH, NaOH, and KOH in THF/H2O mixtures, no reaction was observed. There are a variety of reasons this could be, likely sterics, but it is also possible that the ketone is deprotonated to an anionic intermediate. Perhaps charge repulsion prevents a second addition of hydroxide in the saponification mechanism. Other reagents such as BBr3 or trimethyltin hydroxide led to MEM deprotection and no reaction, respectively (not shown). 268 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.13. Failure to induce saponification on substrate 180. O O -OH MeO2C HOOC OMEM OMEM no reaction 120 110 O MeO2C OMEM anionic intermediate formed instead? We then turned to the hypothesis that switching the order of the steps could provide a suitable decarboxylative Giese addition substrate. Namely, ketone triflation of 110 could provide 121, which could act itself as a decarboxylative Giese addition substrate (Scheme 4.14). Alternatively, 114 could be converted to 121 via triflate-bromide exchange, which could also undergo saponification to 123 and thus allow investigation of the decarboxylative Giese addition to provide 122. The same oxidative desulfonation could deliver 107B. Scheme 4.14. Changing the order of the steps could solve saponification issue. oxidative desulfonation Br PhO2S OMEM O decarboxylative Giese addition Br OMEM Br Triflex MeO2C OMEM 121 saponification HOOC 122 107B Br OMEM 123 TfO triflation MeO2C OMEM 114 O MeO2C OMEM 110 When opting to perform the saponification on enol triflate 114, less than 10% yield was isolated (Scheme 4.15). Instead, triflate hydrolysis was observed as the primary product. Indeed, triflates are base-labile upon hydroxide addition to form the tetrahedral sulfoxide intermediate.16 As described in Scheme 4.13, substrate 110 (the product of triflate 269 Chapter 4 – 3.2.1 bicycle synthesis hydrolysis) is incompetent under saponification conditions. Turning our attention to screen triflex conditions on substrate 114, it quickly became clear that protodebromination was an issue. Nevertheless, after some screening, it was revealed that the protodebromination increased with NiII loading. Keeping the Ni(OAc)2 • H2O loading to 5 mol%, 51% of product could be formed (Scheme 4.15, entry 1). Increasing the amounts of nickel, COD, or LiBr led to increased levels of protodebromination (Scheme 4.15, entry 2-5). Scheme 4.15. Vinyl halide (121) formation. HOOC THF, H2O < 10% yield LDA (1.2 equiv) THF, −78 °C then Comin’s (1.15 equiv) O MeO2C OMEM 1.5 h 110 77% yield O TfO NaOH OMEM MeO2C OMEM THF/DMA (3:1), 22 °C, 15 h OMEM 110 formed instead 123 Ni(OAc)2 • 4H2O (X equiv) COD (Y equiv) Zn (Y equiv) LiBr (Z equiv) TfO MeO2C Br H MeO2C OMEM MeO2C 121 114 OMEM 124 entry X Y Z ratio 114 : 121 : 124 yield 121 (%) 1 0.05 0.1 1.5 0.07 : 1 : 0.06 51 2 0.1 0.2 3 0.51 : 1 : 0.2 36 3 0.15 0.3 4.5 0.42 : 1 : 0.42 10 4 0.83 1.7 10 1.09 : 1 : 4.66 10 5 0.15 0.3 6 0.27 : 1 : 0.60 10 Substrate 121 proved competent under saponification reaction conditions, affording 123 in 85% yield after treatment with excess NaOH. These data bolster the hypothesis that enolization of the ketone was the issue in the saponification after all. Finally, with access to a decarboxylative Giese addition substrate, the key photoredox catalysis step could be tested; however, the difficulties of this route did not subside. Additional efforts to engage the carboxylic acid under photoredox catalysis conditions were unfruitful. In almost all cases, no reaction was observed, even at elevated reaction temperatures and times (Scheme 4.16). 270 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.16. Low conversion of 123 and 120 under photoredox conditions. Ir (1 mol%) Phenyl Vinyl Sulfone (1 equiv) K2HPO4 (1.2 equiv) PhO2S OMEM DMF, 36 W Kessil Br Br NaOH (4.8 equiv.) MeO2C OMEM HOOC THF/H2O 21 °C, 16 h 121 HO2C 120 [Acr-Mes]ClO4 (2.5 mol%) O Na2CO3 (20 mol%) E (1 equiv) OMEM E Blue LED’s (Merck Photoreactor) MeOH, 21 °C, 18 h 122 Ir temp, time result 1 Ir[dF(CF3)ppy)]2(bpy)PF6 (1 mol%) 21 °C, 12 h 123 2 Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol%) 21 °C, 12 h 123 3 Ir[dF(CF3)ppy)]2(bpy)PF6 (1 mol%) 40 °C, 12 h 123 4 Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol%) 40 °C, 12 h 123 5 Ir[dF(CF3)ppy)]2(bpy)PF6 (1 mol%) 40 °C, 72 h 123 6 Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol%) 40 °C, 72 h 123 O OMEM HO2C OMEM Ir (1 mol%) Cs2CO3 (1.1 equiv) VinylBPin (1.5 equiv) O 40 W Kessel Lamps DMF or DMA, 23 °C, 18 h E OMEM 120 E result entry 1 vinyl-SO2Ph 120 2 diethyl-ethylidene malonate 120 entry OMEM 123 85% yield entry O Br Ir result 1 [Ir(dtbbpy)(ppy)2]PF6 120 2 [Ir(dF(Me)ppy)2(dtbbpy)]PF6 120 Given that there was difficulty getting reactivity of the carboxylic acid, we opted to abandon the research goal of applying decarboxylative Giese addition chemistry. However, one area that could be interesting is finding a higher yield to the two-step homologation sequence (112 to 107A), which provided 107A in a modest 33% yield over 2 steps. Nonetheless, finding a one-step, higher-yielding reaction could make the route more efficient. To this end, strategies utilizing ylides were literature searched, but never tried due to time constraints. Use of conditions from Scheidt, for example, offer a mild, selective homologation of esters to aldehydes in a single step and could be potentially useful in applying in this system.17 Generally, several types of ylides could be synthesized and tested for the homologation chemistry and optimized for yield. Chapter 4 – 3.2.1 bicycle synthesis 4.3 271 ASYMMETRIC 3.2.1 BICYCLE SYNTHESIS THROUGH RADICAL INTERMEDIATES 4.3.1 Chiral induction through the use of a chiral auxiliary With a suitable route to rac-107B and acknowledging the shortcomings of the preparatory HPLC for material throughput, we wondered if asymmetry could be induced through the use of a chiral auxiliary. Indeed, chiral auxiliary’s have been demonstrated in the Snider radical cascade. The chiral auxiliary is usually installed through the ester functionality of the Snider b-keto ester substrate. Most notably, menthol, phenylmenthol, oxazolidinone, sultam, sulfoxide, and pyrrolo groups have been reported previously.18-23 Substrates could be prepared simply by mixing the starting material with DMAP in refluxing toluene. The substrates provided a wide range of observed diastereoselectivity, from 0 to 92% diastereomeric excess (de) (Scheme 4.17). Additionally, the auxiliaries could be cleaved simply by saponification or exhaustive reduction to the primary alcohol (not shown). 272 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.17. Asymmetric induction in Mn-based oxidative radical cascades. Me Me DMAP (0.3 equiv) ROH (1 equiv) O Mn(OAc)3 (2.0 equiv) Cu(OAc)2 (1.0 equiv) O R MeO toluene, 110 °C, 3-5 days O 125 Me ROC degassed AcOH, 21 °C, 16-34 h O O O Ph R = OMe R = NEt2 86% yield 45% yield R= R= O Me R = naph O Me Me 87% yield de = 23% Me R= Me Me 80% yield de = < 10% Me N Ph Me Me O SO2N(C6H11)2 83% yield de = 60% 89% yield de = 60% 0% yield Me Me R= O O R= R= Ph Ph 92% yield de = 60% N Me 28% yield de = 92% R= O Me 89% yield de = 86% Despite the strong precedent in this area, Snider’s substrates never contained oxygen-containing functionalities at the bridgehead system required in auriculatol A. When attempting the derivative bearing 8-phenyl menthol (127), unfortunately, only a modest de was observed. Furthermore, the yield of both the transesterification and the radical cascade suffered compared to the racemic methyl ester system, providing 128 in 5% yield over 3 steps. Given these results, a new strategy would be necessary to investigate asymmetric 3.2.1 bicycle synthesis; the material throughput of this route was simply too limiting. Trying other chiral auxiliaries did not seem very promising, given the relatively low yields and de’s for other substrates shown in Scheme 4.17. 273 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.18. 8-phenyl menthol derivative provides low yield and moderate de. OMEM Cl O O Me MeO (−)-phenylmenthol (1.1 equiv) DMAP (0.3 equiv) O Me 44% yield 108 Ph NaH (1.1 equiv) nBuLi (1.1 equiv) HMPA (2 equiv) O Me O toluene, 120 °C, 24 h 115 (1.1 equiv) Me THF, −78 °C to 21 °C, 5 h Me 57% yield 2.46 : 1 dr (inconsequential) 126 Me O Me Mn(OAc)3 • 2 H2O (2 equiv) Cu(OAc)2 • H2O (1 equiv) O Me 21% yield 56% de 128 O O EtOH, 60 °C, 15 h O Me Me Ph O OMEM Ph OMEM Me 127 4.3.2 Chiral atom-transfer reactions Due to the difficulties with the chiral auxiliary strategy, a new approach through the use of a chiral atom-transfer reaction was imagined. In theory, a-bromination of 109 could provide 129, from which chelation to a chiral ligand, halogen atom abstraction, 6endo cyclization, 5-exo cyclization, and bromine atom termination could provide 130 (Scheme 4.19). The primary bromide 130 could undergo elimination to deliver the terminal olefin in (R,S)-110. Scheme 4.20. Access to (R,S)-110 through chiral atom-transfer strategy OMEM OMEM O OMEM O XAT MeO MeO O O 6-endo O −Br Br O O *L MeO2C OMEM OMe 129 109 O O 5-exo MeO2C OMEM O +Br MeO2C OMEM DBU MeO2C OMEM Br 130 (R,S)-110 When searching the literature in the realm of chiral atom-transfer reactions, it 274 Chapter 4 – 3.2.1 bicycle synthesis became clear that most systems employ bisoxazoline ligands. Lewis acids such as Mg2+ that chelate to the ligand. In two seminal reports for the enantioselective atom-transfer radical cyclization catalyzed by chiral Lewis acids, Mg(ClO4)2 as the Mg2+ source and BEt3/O2 as the radical generation mode were essential to high yields and ee of the reaction (Scheme 4.20).24,25 Furthermore, specifically the use of (4R,4'R)-2,2'-(propane-2,2diyl)bis(4-(tert-butyl)-4,5-dihydrooxazole (131) as the ligand led to superior enantioselectivity over other ligands. Scheme 4.20. Cheung and Zhu’s precedent for chiral atom transfer reactions. Cheung Me Me N N O O Me Br 131 tBu O Me O tBu Mg(ClO4)2, Et3B, O2, 4 Å MS OEt Me Zhu N Me Br Me Me O N 131 tBu O Me Me O O CO2Et toluene –78 °C, 5 h 67% yield 94% ee Me O tBu O Mg(ClO4)2, Et3B, O2, 4 Å MS OEt SePh CO2Et Me toluene –78 °C, 6 h 82% yield 89% ee Me via: SePh H Me Me Me O O N N tBu Mg tBu O O EtO H Me Et In order to test the reactivity, 125 was envisioned as a model substrate that could be accessed quickly. The model system would also allow sufficient exploration of the key chiral atom transfer reaction, given that compound 109 was unstable and could not be 275 Chapter 4 – 3.2.1 bicycle synthesis stored frozen in benzene, for example, for periods of time greater than one week due to the hydrolytic instability of the methyl ether. As a result, the model system allowed for a more stable substrate to explore the chiral atom transfer reaction. The synthesis of the model substrate 132 goes as follows: allylation of a-allyl methylacetoacetate (108) delivers 125 in 42% yield, which can be subsequently a-brominated to form 132 in quantitative yield. Scheme 4.21. Model system synthesis. LDA (2.2 equiv) HMPA (2.2 equiv) Me O Me Br Me (1.1 equiv) Me O NaH (1.1 equiv) NBS (1.2 equiv) MeO O OMe 108 THF, 0 °C to 21 °C, 2 h 42% yield THF, 0 °C to 21 °C, 2 h O 125 100% yield O MeO O Br 132 Following the model system substrate synthesis, application of Cheung and Zhu’s protocol led to a 14% yield of 130. In the reaction mixture contained a mix of starting material (22%), monocyclization and bromine radical capture (34%, not shown), and protodebromination (10%, not shown). While the yield was low, indicating that the 5-exotrig product was either thermodynamically uphill or kinetically inaccessible under the reaction conditions, the enantioselectivity following elimination with DBU of the reaction was quite good (79% ee). As a result, the model study was concluded and a new route was envisioned that would bear bridgehead oxidation to turn the model system into one that could be relevant for the synthesis. 276 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.22. Model system delivers 79% ee. Me Me O O MeO O 131 tBu O Br 132 N N Me (1.21 equiv) tBu Mg(ClO4)2 (1.1 equiv) Et3B (3 equiv) O2 (3 equiv) Mol. sieves (5 equiv) O O DBU (2.5 equiv) MeO2C Me Benzene, 90 °C, 24 h Br 130 30% yield 79% ee toluene, −78 °C, 10 h MeO2C Me (S,R)-131’ 14% yield Keeping in mind the degradation of 109 when stored over time, even frozen in benzene and stored at −20 °C, phosphonate ester-protected compound 134 was targeted to alleviate these stability concerns. The electrophile for the Weiler coupling reaction could be formed through a Perkow reaction in 91% yield (Scheme 4.23).26 Scheme 4.23. Phosphonate ester electrophile (134) synthesis with Perkow reaction. O O Cl Cl 133 O P(OEt)3 (1 equiv) 60 °C to 100°C, 3 h 91% yield P OEt OEt Cl 134 When mining the literature, the phosphonate ester protecting group was identified as a less-labile protecting group that has also displayed competence in Snider radical cascade chemistry.3 In order to verify these data in our own hands and gain access to a racemic-trace of 214, substrate 213 was synthesized in the same manner to the OMEMsubstrate (179) and tested in the Snider radical cascade. Indeed, the product (rac-214) was isolated in 79% yield, consistent with the literature-reported yield.3 277 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.24. Racemic phosphonate ester-protected 3.2.1 bicycle (136) synthesis. NaH (1.1 equiv), 0 °C, 15 min then nBuLi, 0 °C, 45 min then HMPA (2 equiv) O O Me O Cl MeO O P OEt O OEt 134 O O 108 Mn(OAc)3 (2.0 equiv) Cu(OAc)2 (1.0 equiv) MeO THF, −78 °C to 21 °C, 16 h 38% yield P OEt OEt AcOH, 22 °C, 15 h O 135 79% yield O O MeO2C O P OEt OEt 136 From there, a-bromination of 135 was explored as the final step of the chiral atomtransfer substrate. Unfortunately, however, use of conditions from the model system (NaH & NBS) delivered allyl bromide 137 instead of the desired a-brominated compound 138 (Scheme 4.25). It was thought that the allyl bromide could arise from a-bromination, but the intermediate 137 could undergo elimination to form a diene which could be susceptible to 1,4 nucleophilic addition of bromide. 278 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.25. Difficulties with a-bromination of 135. O O P OEt O OEt O THF, −78 °C to 22 °C, 3 h MeO O NaH (1.1 equiv) NBS (1.2 equiv) O O P OEt OEt O O O Br MeO MeO O 55% yield P OEt OEt Br O 138 (desired) 135 137 not observed O O O P OEt O OEt P OEt O OEt O O N Br O O NaO NaH O OMe OMe OMe H2 Br O O O P OEt OEt O N O O O O MeO O P OEt OEt O O Br Br O P OEt OEt Base O OMe HBase +. Br After exhaustive screening and screening other bromination conditions,27-30 it was revealed that running the reaction at more dilute concentration reduces the amount of allylic bromination and allows for 36% yield of compound 138 (Scheme 4.26). a-selenylation was also accomplished under similar reaction conditions (not shown). With access to 138, a variety of halogen atom-transfer conditions were explored using the magnesium (4R,4'R)2,2'-(propane-2,2-diyl)bis(4-(tert-butyl)-4,5-dihydrooxazole ligand system (131) and various radical generation modes. 279 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.26. A) Preparation of atom-transfer substrates. B) Various radical generation modes do not lead to any observed cyclization products. A O O P OEt OEt O NaH (1.1 equiv) NBS (1.2 equiv) O O THF, −78 °C to 22 °C, 3 h MeO O MeO 36% yield O Br more dilute (50 mM) 135 P OEt OEt O 138 O O P OEt OEt O NaH (1.1 equiv) PhSeBr (1.2 equiv) O O THF, −78 °C to 22 °C, 3 h MeO O MeO 52% yield O SePh 135 139 O O O P OEt OEt NaH (1.1 equiv) NCS (1.2 equiv) O O O MeO 62% yield O Cl 135 140 Me Me O O O Br MeO tBu O N N O B 131 tBu (1.2 equiv) Mg(ClO4)2 (1.1 equiv) Radical generation mode Mol. sieves (5 equiv) Solvent, Temp, Time O P OEt OEt O THF, −78 °C to 22 °C, 3 h MeO P OEt O OEt P OEt OEt O O P OEt OEt O O MeO MeO2C Br 135 138 OPO(OEt)2 O 141 entry radical generation mode solvent temp time 1 Et3B (5 equiv), O2 (1000 equiv) Et2O/DCM −78 °C 4.5 h 0:1 2 (BzO)2 (0.2 equiv) Toluene 90 °C 12 h 1 : 0.1 3 (Bu3Sn)2 Toluene 50 °C 2h 1 : 0.06 4 (Bu3Sn)2, hv (UVA) Toluene 25 °C 12 h 1 : 0.85 5 Purple LED’s EtOAc 25 °C 12 h 1 : 0.05 6 hv (UVA) EtOAc 25 °C 12 h 0:1 138 : 135 : 141 280 Chapter 4 – 3.2.1 bicycle synthesis With difficulty from the bromide, the a-selenylated and a-chloro compound were also explored. Unfortunately, the a-selenylated and a-chloro substrates were also incompetent in the reaction, leading to higher levels of protodeselenation or protodechlorination and no reaction, respectively. Scheme 4.27. Atom-transfer substrate modifications do not promote cyclization. Me Me O O P OEt O OEt O MeO O X O N O N 131 tBu (1.21 equiv) tBu Mg(ClO4)2 (1.1 equiv) Et3B/O2 O P OEt OEt O O MeO2C MeO toluene, 4 Å MS −78 °C, 10 h Br O 138-140 135 X sm : 135 : 141 1 Br 1:1:0 2 SePh 5:1:0 3 Cl no reaction entry OPO(OEt)2 141 4.3.3 Asymmetric radical cascade from chiral enamine A final strategy that was explored regarding asymmetric radical cascade chemistry involved the use of chiral enamine catalysis. In theory, starting from substrate 135, chiral amines could be condensed onto the ketone moiety, providing chiral b-enamino-esters. Recently, a-oxidation of various chiral enamines has been well-documented in the literature, and the redox properties of some chiral enamines has been investigated by Luo, Macmillan, and others.31-33 Following a-oxidation of the chiral enamines, these a-imino radicals have been demonstrated in several reactions, including alkynylation (Scheme 2.48),34 amination,35 hydroxyamination,36 allylation,37 oxyamination,38 and arylation,39,40 among others. 281 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.28. Luo’s photochemical alkynylation of a-imino radicals. H tBu N Me NH2 O Me (20 mol %) [Ru], BI-OH (1.5 equiv) O Me OEt Me O rt, blue LEDs Me Ar O Me OEt 18-57% yield up to 99% ee COO–BI Ar tBu N H N H N H SET Me N O Me Me Me Me tBu H Me OEt tBu - H+ Me O Me N H+ O Me OEt OEt Me Me Me N H Using various a-oxidation techniques and tuning the redox properties of the oxidant or the enamine employed, we set out to study the possibility of inducing a radical cascade from the a-radical generated from a-oxidation of chiral enamines. Given that the a-imino radical has been implicated before in various contexts, such as the alkynylation from Luo shown in Scheme 4.28, we wondered if it could be applied to systems similar to Snider’s studies (Scheme 4.29). Scheme 4.29. Use of enamine catalysis for asymmetric 3.2.1 synthesis. via: R 2N O H N R 2N R O – 1e- RO oxidation OMEM H R 2N R R N R N H N O O RO OMOM OMEM RO OMEM OR Me In practice, the condensation of the chiral enamine with the new b-keto ester substrate was challenging. Simply taking the model substrate 125 and screening various conditions41-44 led to no observed reaction (Scheme 4.30). This was surprising given the precedent in the area for these kinds of reactions, and we hypothesized that the 282 Chapter 4 – 3.2.1 bicycle synthesis incorporation of the allyl group could be deactivating for the amine addition. Scheme 4.30. Low conversion for canonical enamine formation conditions on model substrate. Me Me O R 2N amine, additive MeO MeO benzene O O 125 entry amine 1 2 condition conversion yield (%) pyrrolidine (1.5 equiv) FeCl3 0 - pyrrolidine (1.5 equiv) Zn(OAc)2 0 - 3 pyrrolidine (1.5 equiv) CeCl3 0 - 4 pyrrolidine (1.5 equiv) Yb(OTf)3 24 - 5 pyrrolidine (1.5 equiv) L-Proline 28 - 6 aniline (1.5 equiv) L-Proline (5 mol%) 0 - 7 pyrrolidine (3 equiv) L-Proline (15 mol%) 11 - 8 L-Proline (2 equiv) - 0 - 9 L-Proline methyl ester HCl (2 equiv) - 0 - 10 L-Proline methyl ester HCl (2 equiv) L-Proline (10 mol%) 0 - 11 BnNH2 (2 equiv) L-Proline (10 mol%) 0 - 12 BuNH2 (2 equiv) L-Proline (10 mol%) 0 - 13 iPr2NH (2 equiv) L-Proline (10 mol%) 0 - 14 p-MeOPhNH2 (2 equiv) L-Proline (10 mol%) 0 - 15 p-FPhNH2 (2 equiv) L-Proline (10 mol%) 0 - 16 MeBuNH (2 equiv) L-Proline (10 mol%) 0 - The results were equally bleak for attempted conditions from substrate 135. Acidmediated conditions that had been successful on the model system (not shown) led to trace formation of the desired enamine (Scheme 4.31). Other conditions, such as use of Fe(OTf)3, led to substrate decomposition, and use of HFIP as solvent led to no conversion (not shown). 283 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.31. Low conversion for canonical enamine formation conditions on phosphonate ester-protected substrate. R 2N O Me P OEt O OEt Me O NR2 Me NH2 Me (4 equiv) Me PTsOH • H2O (0.1 equivs) MeO H O Me O P OEt OEt N O Toluene, 120 °C, overnight O OMe 135 entry NR2 result 1 NEt2 < 5% conversion 2 morpholine < 5% conversion 3 pyrrolidine < 5% conversion Difficulties in enamine substrate preparation thwarted attempts to exhaustively explore chiral enamine radical cascade strategies. Although enamine formation was a challenge, in the future exploration of nickel-catalyzed methodologies, specifically through the a-keto substrate bearing an imidazole, could be fruitful. To elaborate, in 2022, Guo and coworkers disclosed the controlled liberation of chiral a-keto radical species from electrogenerated nickel-mediated oxidation toward enantioselective radical capture of alkene partners. The scope of the transformation included a variety of coupling partners in good ee.45 284 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.32. Future opportunity within this research aim. R3 R2 R1 N N O BDD(+) | Pt(−) | = 2.0mA NiCl2 (10 mol%), L (20 mol%) O 2,6-di-tert-butylpyridine (0.5 equiv) nBu4NPF6 (0.06 M) DCM/MeOH (1:1), 10 °C, Ar undivided cell R Ph N Th Ph Ph 73% yield, 93% ee O Ph N N N Ph R1 Ph Ph N Cl O Ph Cl Ph N OMe N Ph OMe Th 72% yield, 94% ee Ph N F Cl 72% yield, 94% ee 71% yield, 87% ee Ph O O N OMe Ph N N 84% yield, 88% ee Cl OMe N OMe Th Br HN Th O Ph OMe Th Ph R NH L Ph N OMe N Ar Cl R4 O O O N R3 N Ar Ph 72% yield, 93% ee Ph OMe Ph N N Ph OMe Th Th Me 69% yield, 94% ee OMe 45% yield, 97% ee The key intermediate for this process involves ligation of the chiral nickel catalyst to the “enolate equivalent” followed by electrochemical activation to the a-keto radical (Scheme 4.33). Alkene radical coupling and oxidation yield a tertiary carbocation that can be trapped by the nucleophilic solvent. While this strategy is intriguing, due to time constraints, it was not attempted. Future work in this realm could provide an elegant asymmetric 3.2.1 bicycle synthesis through a chiral radical cascade. 285 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.33. Posited mechanism invokes a-keto radical formation. R3 R1 N N NH2 Ni chiral catalyst H 2N O R NH2 H 2N Ni Ni R1 N N NH2 H 2N O electrochemical activation radical coupling R1 N N R R2 O N R 4.4 R2 O R1 N R Ni −Ni R3 OMe R2 R3 NH2 H 2N R1 Ni N R O N NH2 H 2N oxidation O R1 N N R R2 + MeOH R3 OMe ASYMMETRIC STRATEGIES THROUGH CYCLOHEXANONE SUBSTRATES 4.4.1 Early studies from cyclohexanone substrates One way to circumvent the issue of product selectivity for mono versus dicyclization would be to do the reactions stepwise. Although this can lead to higher step counts, it is possible that the route can be shortened by other means. Furthermore, utilizing symmetry of cyclohexanone starting materials, an expedient synthesis to fragment 107A may be possible. For this reason, it was envisioned that fragment 107A could be simplified to allyl compound 142. From there, following ketone triflation of 143, the nickel-catalyzed 1,2-addition transform could trace back to diketone 144. The key quaternary center in 144 could be formed from a palladium-catalyzed decarboxylative allylation of 145, from which deprotection of the product of that reaction could provide 144. Racemic 145 could simply be formed from alkylation of 146 with 2,3-dibromo propene or the 2-chloro equivalent. 286 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.34. Asymmetric 3.2.1 bicycle retrosynthesis through cyclohexanone intermediates. TfO Lemeiux-Johnson Oxidation Ketone Triflation TfO OMEM O O OMEM OMEM H 107A 142 Pd Ni 1,2-Addition Deprotection 143 O Tsuji-Stoltz Allylation X O O O O O O O Alkylation O O O O X 144 145 146 In the forward direction, it was prudent to investigate the acylation of 147 to form 146. To that end, treatment of 147 with lithium diisopropylamine followed by allyl chloroformate, in our hands, led to 14% yield of the desired product (Scheme 4.35, entry 1). In order to increase the yield under these reaction conditions, further drying and meticulous preparation of allyl chloroformate could increase the yield.46,47 Use of conditions reported in the literature using NaH and diallylcarbonate were equally ineffective, delivering 10% yield of the product (Scheme 4.35, entry 2); again, however, the literature reports a higher yield for this reaction.48 Synthesis of allyl 1H-imidazole-1carboxylate (148) and use with lithium hexmethyldisilazide (LHMDS) was much more effective, providing 44% yield of the product (Scheme 4.35, entry 3). After some experimentation, it was found that increasing the concentration to 2 M could increase the yield to 73% (Scheme 4.35, entry 4). It is worth noting that compound 146 was found to tautomerize to the enol form. 146 was typically isolated as a 1 : 0.27 ratio of enol : keto tautomers. 287 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.35. Acylation of 147. OH O O O conditions O O O O 147 entry 146 base reagent solvent, temp, time yield (%) 1 LDA allyl chloroformate THF, −78 °C to 21 °C, 4 h 14 2 NaH diallylcarbonate THF, 21 °C, 18 h 10 3 LHMDS allyl 1H-imidazole-1-carboxylate THF, −78 °C to 21 °C, 18 h 44 4* LHMDS allyl 1H-imidazole-1-carboxylate THF, −78 °C to 21 °C, 18 h 73 *reaction run at higher concentration (2M) synthesis of allyl 1H-imidazole-1-carboxylate O O N HO N N N N THF/DCM (1:1) 0 °C, 3 h O N 96% yield 148 From 146, it was found that alkylation with 2,3-dibromopropene was difficult. Using conditions from Newhouse and Berkowitz,49,50 only 14% yield was isolated. Use of 2-chloro-3-bromopropene led to no yield of the product. In some reports, hexamethylphosphoramide (HMPA) was used as a superstoichiometric additive to facilitate conversion of the sodium enolate.51 However, use of HMPA was not desired, especially so early in the synthesis. Instead, use of Cs2CO3 and KI in acetone led to 87% yield of the product (Scheme 4.36). We commend Xu for their disclosure of these conditions in their 2024 publication.52 The analogous reaction also worked for the chloro and iodo variants, providing 145A, B, and C in excellent yields. 288 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.36. Alkylation of 146. OH X O O O Br O O O conditions O O 146 O X 145A X = Br 145B X = Cl 145C X = I entry base additive solvent, temp, time X yield (%) 1 NaH - DMF, 0 °C to 21 °C, 14 h Br 14 2 NaH - DMF, 0 °C to 21 °C, 14 h Cl - 3 Cs2CO3 KI Acetone, 21 °C, 4 h Br 87 4 Cs2CO3 KI Acetone, 21 °C, 4 h Cl 89 5 Cs2CO3 KI Acetone, 21 °C, 4 h I 90 A variety of other Tsuji-Stoltz allylation substrates were prepared. It was found that 147 could be acylated with 2-haloallyl 1H-imidazole-1-carboxylates 149A and 149B (Scheme 4.37). Both the bromide and chloride could be prepared (150A and 150B). Scheme 4.37. Preparation of 150A and 150B. O O O O N O 147 O X X N 149A X = Br 149B X = Cl O LHMDS (1.1 equiv) O THF, −78 °C to 21 °C, 5 h O O 150A X = Br, 57% yield 150B X = Cl, 72% yield From 150A and 150B, a variety of a-substituted b-keto esters (Stoltz precursors) were synthesized. Specifically, the preparation of alkylated and allylated substrates bearing a-alkoxy (or protected variants), a-cyano, and allyl groups were prepared (a total of at least six Tsuji-Stoltz decarboxylative allylation substrates), which could be tested under the palladium-catalyzed reaction conditions (Scheme 4.38). 289 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.38. Preparation of a myriad of a-substituted b-keto esters for investigation of the palladium-catalyzed Tsuji-Stoltz allylation. O O Br O X O conditions X O O O R R O O O see “prod.” for compound number 150A/B entry X R base additive solvent, temp, time prod. yield (%) 1 Br —CH2CN NaH KI DMF, 21 °C, 18 h 151 52 2 Cl —CH2CN NaH KI DMF, 21 °C, 18 h 152 65 3 Br —CH2OH NaHCO3 - THF, 0 °C to 21 °C, 16 h 153 78 4 Cl —CH2OH NaHCO3 - THF, 0 °C to 21 °C, 16 h 154 55 5 Br allyl NaH KI THF, 0 °C to 21 °C, 16 h 155 71 6 Cl allyl NaH KI THF, 0 °C to 21 °C, 16 h 156 90 7 Br —CH2CH2OTES NaH - DMF, 21 °C, 18 h - - 8 Cl —CH2CH2OTES NaH - DMF, 21 °C, 18 h - - 9 Br —CH2CH2OTES NaH KI THF, 50 °C, 18 h - - 4.4.2 Tsuji-Stoltz Allylation as a method for quaternary stereocenter formation In addition to substrate 145A, 145B, and 145C, which contained parent allyl compounds, compounds 151 through 156 enabled access to a plethora of Tsuji-Stoltz allylation precursors. Reading the literature and talking to colleagues in the Stoltz group, it became apparent that most successful screening campaigns identify either solvent screening or use of CF3-tBu-Phox as a ligand compared to tBu-Phox as very impactful to enantioselectivity.53,54 Ether, 1,4-dioxane, THF, and toluene were identified as some of the most common solvents. Additionally, reactions typically require 12.5 mol% ligand with 5 mol% Pd2dba3 and are run between 21-40 °C for extended reaction times.55,56 Finally, the reactions are most often carried out at dilute concentrations of approximately 30 mM, often requiring more than 36 h to achieve full conversion.57 290 Chapter 4 – 3.2.1 bicycle synthesis Moving on to test the Tsuji-Stoltz allylation, 145C and 145A were tested first. Although the vinyl iodide-containing substrate (145C) led to no reaction, use of (S)-tBuPhox with the bromide substrate (145A) led to 70% isolated yield and 40% ee. The iodide substrate did not react likely due to either: 1) coordination to the iodine atom and catalyst deactivation or 2) oxidative addition into the vinyl iodide (~5% palladium oxidative addition complex) which may idle as the resting state. Scheme 4.39. Initial studies for the Tsuji-Stoltz decarboxylative allylation on parentallyl substrates. O O O O Br THF, 21 °C, 18 h 145A 70% yield 40% ee O O Pd2dba3 (5 mol%) (S)-tBu-Phox (12.5 mol%) O P Br O N tBu O 157 (S)-tBu-Phox O O O Pd2dba3 (5 mol%) (S)-tBu-Phox (12.5 mol%) no reaction O O I THF, 21 °C, 48 h 145C Turning to compounds 151 through 156, which contained substitution on the migrating allyl group, moderate success was seen. Specifically, for the substrate 156, which contained chloride substitution on the migrating allyl group and an allyl group as “R”, the product 161 was formed in 70% yield and 93% ee (Scheme 4.40). Substrate 154’, which contained an a-OTES group on the R-group formed 52% yield of 160. While this was exciting, other substrates 151 and 152, which contained a-cyano substitution on the Rgroup, did not react. Furthermore, substrate 155, which contained bromide substitution on 291 Chapter 4 – 3.2.1 bicycle synthesis the migrating allyl group, also led to no observed reaction and no observed formation of product 157. Similar observations on the poor reactivity of the alkenyl bromide substrates have been noted by Stoltz.55-57 Scheme 4.40. Decarboxylative allylation studies on new substrates: promising results on vinyl-Cl containing substrate 156. O O O O X (S)-tBuPhox (12.5 mol%) Pd2(dba)3 (5 mol%) R O THF, 21 °C, 18 h O R X O see “starting material” for compound number O see “prod.” for compound number entry starting material X 1 151 Br 2 prod. yield (%) CN 158 - CN 159 - OTES 160 52% yield R 152 Cl 3 154’ Cl 4 155 Br 157 - 5 156 Cl 161 70% yield, 93% ee A mechanistic hypothesis for the lack in reactivity of substrate 151 and 152 is depicted in Scheme 4.41.The elucidated active catalyst species is believed to be [Pd((S)tBuPhox)(dba))].58 It is possible that chelating groups, such as larger bromine and iodide heteroatoms or nitriles could inhibit the catalyst through s-donation or (in the case of the nitrile) p-backdonation from the metal center into the p*-nitrile orbitals.59 Turning to computational studies from Goddard and coworkers, it is believed the oxidative addition begins with ligand exchange to form an olefin bound active species, from which oxidative addition into the C-O bond of the allyl group can be facilitated. The oxidative addition is believed to lead to anti-displacement in an Sn2-type mechanism to form [Pd((S)tBuPhox)(h3-allyl)+(RCOO)-, from rapid equilibration to the h1-bound allyl as the resting 292 Chapter 4 – 3.2.1 bicycle synthesis state occurs.60 Scheme 4.41. Mechanistic hypothesis for catalyst deactivation. N N P P Pd N N Pd X O O O O O O O O O [Pd((S)-tBuPhOX)(dba)] O P Pd O X O R O O O O O O O P O N Pd X X With the chloride substrate 156 showing success in the decarboxylative allylation, forming 161 in 70% yield and 93% ee, we turned to optimization of the bromide-containing substrate in order to provide both vinyl chloride and vinyl bromide handles for ring closure to the 3.2.1 bicycle. Attempting to increase the ee through ligand modification, the (R)(CF3)3-tBu-Phox ligand was synthesized. Using keto ester 145A, a variety of solvents were evaluated, with yields ranging from 50–73% to form 157 (Scheme 4.42). The higher enantioselectivity of the process compared to the parent phenyl-containing ligand is believed to be due to greater charge separation in the transition state between the electron rich palladium catalyst and the electron deficient Phox ligand.58 Larger charge separation leads to stronger ligand-catalyst interactions, which prevents unligated, racemic palladium background reactivity. On scaling this reaction up, it was found that reducing the palladium-loading to 5 mol% enabled an increase in yield to 70% yield and 85% ee. 293 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.42. Solvent screening with the p-(CF3)3-tBuPhox ligand on substrate 145A: optimized Tsuji-Stoltz conditions for the vinyl-Br containing substrate. CF3 O O O O O O Pd2dba3 (10 mol%) (R)-(CF3)3-tBu-Phox (25 mol%) O solvent, 21 °C, 48 h Br P O tBu O CF3 157 145A N F3C Br (R)-(CF3)3-tBu-Phox entry solvent yield (%)* ee (%) 1 dioxane 49% 86 2 DME 55% 83 3 Et2O 73% 80 4 EtOAc 64% 78 5 MeCN 52% 5 6 MTBE 38% 85 7 2-MeTHF 55% 84 8 THF 62% 83 9 toluene 50% 88 *all yields are QNMR yields O O O O O Pd2dba3 (5 mol%) (R)-(CF3)3-tBu-Phox (12.5 mol%) Br toluene, 21 °C, 48 h 145A 10 g scale 70% yield 85% ee O Br O O 157 4.4.3 Strategies for ring closure With the palladium-catalyzed Tsuji-Stoltz allylation delivering good yields and ee’s of two substrates, 161 (vinyl-Cl) and 157 (vinyl-Br), efforts to close the 3.2.1 bicycle were pursued. Many strategies were envisioned. Common to all routes involved deprotection of the ethylene glycol moiety, both of which proceeded on each substrate in 91% yield (144B) and 99% yield (144A), respectively. 294 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.43. Acetal deprotection to form ring closure substrates 144A and 144B. O O pTsOH • H2O (3 equiv) Cl O O acetone/water (15:1), reflux, 12 h 91% yield Cl O 161 144B O O pTsOH • H2O (3 equiv) Br O O acetone/water (15:1), reflux, 12 h 99% yield 157 Br O 144A The first strategy explored involved treatment with SmI2. Reading the literature, it became clear that Barbier addition of vinyl bromides to ketones to form 3.2.1 bicycles is a well-studied process.61 Furthermore, many reviews for Barbier addition exist in the literature; although, most examples involve alkyl halides, especially alkyl iodides, rather than the corresponding vinyl bromides or chlorides.62 Nevertheless, we opted to first test HMPA and Ni(acac)2 as additives due to their precedence for Barbier addition.63 To our surprise, the primary product involved ketyl radical formation and 5-exo cyclization with the allyl group, followed by HAT to form an exocyclic methyl group (162) in both cases (Scheme 4.44). The reaction proceeded in 70% yield to give 162 as a single diastereomer, while the Ni(acac)2 reaction formed a messier reaction profile with a 1:1 diastereoselectivity. This might indicate that the HMPA-ligated SmI2 • THF complex is likely much more of a controlled cyclization due to steric bulk of what is presumably the SmIII alkoxide. Indeed, SmI2-HMPA-induced 5-exo trig cyclization with an unactivated allyl group is a documented process.64,65 What was reassuring by this result was the fact that ketyl radical formation selectively engaged the less-hindered ketone. This was exciting due to the chance of developing a Pinacol coupling of a substrate bearing the methyl ketone 295 Chapter 4 – 3.2.1 bicycle synthesis rather than the vinyl bromide. With methods to convert the vinyl bromide to methyl ketone formation being known, it was seen as a high-priority experiment to test substrate 164 in a Pinacol coupling. Due to time constraints, however, this was not pursued further. Scheme 4.44. Efforts to induce SmI2-mediated Barbier addition thwarted by engagement with unactivated olefin followed by keyl radical formation. Br O SmI2 (2 equiv) additive Br THF, 22 °C, 16 h O O O ** Me HO 144A HO 163 162 entry additive yield (%) sm 5-exo-trig (%) mass balance (%) 1 HMPA (10.5 equiv) 6 2 Ni(acac)2 (1 mol%) 3 14 70* 90 31 38** 72 *single diastereomer **1:1 mixture of diastereomers O O O Me hydration Br O 144A O O 164 pinacol HO HO Me 165 Alternatively, it was thought that the chemoselectivity problem of having two olefins could be avoided by selectively dihydroxylating and protecting the unactivated allyl group. Given that the unactivated allyl group needs to be cleaved to the aldehyde, this strategy seemed strategic for fixing the problem of engagement of the unactivated olefin. Unfortunately, while dihydroxylation of the unactivated allyl group worked, cyclization of the secondary alcohol to compound 166 occurred (Scheme 4.45), which could not be protected or cleaved in subsequently attempted experiments (not shown). 296 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.45. Efforts to induce selective dihydroxylation of 144A. OH O OsO4 (X equiv) NMO • H2O (1.3 equiv) Br HO solvent (100 mM), 21 °C, 15 h O 144A Barbier O * O Br 166 entry X solvent product (%) dr* 1 0.05 tBuOH/Acetone (1:1) 56 1.2 : 1 2 0.05 tBuOH/Water (1:1) 47 1.3 : 1 3 0.10 tBuOH/Acetone (5:1) 51 1.5 : 1 4 0.10 tBuOH/Water (5:1) 45 1.3 : 1 5 0.10 tBuOH 80 1.7: 1 addition through organocopper-catalyzed reactions,66,67 organolithiates,68,69,70 or use in the Nozaki-Hiyama-Kishi (NHK) reaction are reported.71 Although, organolithiates are not really precedented from the vinyl bromide; the vinyl iodide is typically invoked instead. Additionally, the NHK reaction is typically performed on aldehydes rather than ketones. When lithiation and cupration chemistry was attempted on both the chloride and bromide substrates, no evidence for 1,2-addition was observed for most reactions (Scheme 4.46). Instead, either no reaction (in the case of the vinyl-Cl substrate) or a messy reaction profile with trace amounts of product (< 5% for the vinyl-Br substrate) was observed. The most promising result involved the use of Bu2CuLi at lower temperatures, which formed the 1,2-addition product 163 in 25% yield. The primary product corresponded to protodebromination and other unidentified products. Attempts to further optimize the process was not beneficial. The NHK was not attempted but could be undertaken in future studies. 297 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.46. Explored lithiation and cupration chemistry. O O reagent X solvent, temp, time O HO 144A/B 163 time (h) yield 163 (%) −78 °C to 21 °C 1 < 5% −78 °C to 21 °C 12 - Et2O −78 °C to 21 °C 1 < 5% entry X reagent solvent temp (°C) 1 Br nBuLi (2.5 equiv) Et2O 2 Cl nBuLi (2.5 equiv) Et2O 3 Br tBuLi (2.5 equiv) 4 Cl tBuLi (2.5 equiv) Et2O −78 °C to 21 °C 12 - 5 Br nBu2CuLi (2 equiv) Et2O −50 °C to 10 °C 1 25 6 Cl nBu2CuLi (2 equiv) Et2O −50 °C to 10 °C 12 - 7 Br nBu2CuLi (6 equiv) Et2O −50 °C to 10 °C 1 25 8 Cl nBu2CuLi (6 equiv) Et2O −50 °C to 10 °C 12 - Moving forward, it was clear that a separate strategy for 1,2-addition of the vinyl halide was necessary. Mining the literature and through the expertise in the Reisman group, we believed that the Ni-catalyzed 1,2-addition could be developed. 4.4.4 Nickel-catalyzed carbonyl 1,2-addition In 2000, Cheng and coworkers disclosed the intermolecular nickel-catalyzed 1,2addition of aryl bromides to aromatic aldehydes accomplished by a Ni(II)/Zn(0)-powder system (Scheme 4.47).72 In this report, they disclosed the dramatic ligand effects of the reaction, eventually arriving at dppe as optimal, but the reaction could also tolerate use of bisoxazoline. The reaction, however, could not be developed in an asymmetric manner to the extent that they tried. Shortly thereafter, Cheng disclosed the 1,2 addition of aryl iodides to aromatic aldehydes.73 Interestingly, the reaction used identical conditions to their publication in 2000, except for the fact that it required higher temperatures, and led to the formation of diaryl ketones due to an additional b-hydride elimination step to turn over the catalyst following 1,2-addition. 298 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.47. Cheng’s nickel-catalyzed 1,2-addition of aryl bromides and iodides to aryl aldehydes. aryl bromides O H R1 THF, 75 °C, 48 h R2 OH OH Ni(dppe)Br2 (10 mol%) Zn0 (2.75 equiv) Br R1 R2 OH MeO OH MeO Me OH MeO OMe MeO CN 91% yield 87% yield 57% yield 71% yield OH OH OH OH OMe OMe Cl CO2Me 75% yield 58% yield O aryl iodides H R2 O THF, 110 °C, 24-36 h O CN Me 72% yield O Ni(dppe)Br2 (10 mol%) Zn0 (2.75 equiv) I R1 65% yield R1 R2 O Me MeO O OMe Cl 57% yield 79% yield 87% yield 66% yield O O O O Me Me Me MeO2C Me 69% yield 84% yield 69% yield 53% yield Since these initial discoveries, several nickel-catalyzed carbonyl additions have been developed, both intramolecularly and intermolecularly.74-79 Turning to our desired transformation, we were drawn to the report from Xu for the nickel-catalyzed intramolecular desymmetrization of aryl halides to 1,3-diketones (Scheme 4.48).83 Key to Chapter 4 – 3.2.1 bicycle synthesis 299 Xu’s success was the use of 2,2-bipyridine as a ligand and superstoichiometric quantities of Mn0 and MgCl2 in dimethylacetamide (DMA) at elevated temperature. The reaction displayed good functional group tolerance for modification on the aryl group, although it is not documented if vinyl bromides were prepared or ever tried. In comparison to our desired transformation (144 to 163), the reaction forms a single five-membered ring through an intramolecular process with two possible electrophilic ketones, making it relatively similar to the desired transformation. Perhaps the largest difference between the desired transformation is that the reaction uses aryl bromides rather than vinyl bromides. The Reisman group has a standing interest in nickel-catalyzed reductive cross couplings, specifically utilizing the NiII oxidative addition complex for radical capture to form NiIII complexes,80,81 along with the development of a nickel-catalyzed enantioselective acyl coupling of prochiral benzyl chlorides with acid chlorides.82 Due to our studies, for example, in the mechanism of specifically nickel-catalyzed vinyl bromide reductive cross couplings, we believed that Xu’s protocol could extend to the use of vinyl bromides and chlorides in the desired context. Perhaps one of the largest anticipated challenges would be avoiding engagement with the unsubstituted allyl group in 144. If this were to occur, however, we believed in the potential to tune the ligand on the nickel center to promote carbonyl 1,2-addition. 300 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.48. Xu’s nickel-catalyzed intramolecular desymmetrization addition of aryl halides to 1,3-diketones. O Br HO O Me HO HO MeO 79% yield HO O 48% yield Cl Me O 70% yield 77% yield HO HO Me O O iPr O 76% yield 58% yield 76% yield HO HO HO O O O PMB O 54% yield HO Me O O Me O 81% yield HO HO O HO Me Me O F R2 86% yield HO Me O R1 Me O O Ph 89% yield 96% yield F Mn (2 equiv), MgCl2 (2 equiv) DMA (0.1 M), 50 °C, 8-12 h HO Me O HO Ni(COD)2 (5 mol%) 2,2-bipyridine (10 mol%) R2 R1 93% yield 62% yield O S 57% yield Ph SMe O O ? X O 144 HO 163 Using Xu’s exact conditions, we were excited by the fact that 3% product had been formed starting from both the bromide and chloride substrates 144A and 144B (Scheme 4.49, entry 1-2). Nevertheless, and perhaps disappointingly, engagement with the allyl group to form diene 167 and halide exchange from the bromide (144A) to the chloride (144B) were observed. Switching to di-tBu-bpy as ligand, no reaction was observed (Scheme 4.49, entry 3-4). Interestingly, the yield of the diene side product was increased to 25% and 44% using BPhen (Scheme 4.49, entry 5-6). Use of terpy as ligand from the bromide and chloride led to adequate yield (43% and 33% yield) of the product (Scheme 301 Chapter 4 – 3.2.1 bicycle synthesis 4.49, entry 7-8). Use of tri-tBu-terpy, however, led to a complex mixture (Scheme 4.49, entry 9). 1-bpp led to halide exchange to the chloride in nearly quantitative yield (Scheme 4.49, entry 10). Without ligand, halide exchange to the chloride from the bromide and recovery of chloride was observed (Scheme 4.49, entry 10-11). It is worth noting that it was later found that the products were volatile, and the yields of this table (with exception of recovery of starting materials, which were not volatile), are likely deflated. Scheme 4.49. Ligand screen adopting Xu’s protocol. Ni(COD)2 (5 mol%) ligand (10 mol%) MgCl2 (2 equiv) Mn0 (2 equiv) O X O O Br DMA (0.1 M), 50 °C, 3 h O O O Cl O HO O 144A 163 O 144B entry X ligand 163 (%)* 144A (%) 144B (%) 1 Br bpy < 3% - 19 17 36 2 Cl bpy < 3% - 38 16 54 3 Br di-tBu-bpy - 38 - - 38 4 Cl di-tBu-bpy - - 74 - 74 5 Br Bphen < 3% - - 25 25 6 Cl Bphen < 3% - - 44 44 7 Br terpy 43 - - - 43 8 Cl terpy 33 - - - 33 9 Br tri-tBu-terpy 5 - - - 5 10 Br 1-bpp - - 93 - - 11 Br - - - 72 - 72 12 Cl - - - 86 - 86 167 167 (%) mass balance (%) *all yields are QNMR yields tBu tBu Ph tBu N N bpy N N di-tBu-bpy N N N terpy tBu Ph N tBu N N N N Bphen N N N tri-tBu-terpy N N 1-bpp Diene formation was an interesting result. We reasoned that, following oxidative addition, engagement with the terminal allyl group was favored for certain ligands, such as 302 Chapter 4 – 3.2.1 bicycle synthesis BPhen, for steric or electronic purposes (Scheme 4.50). Scheme 4.50. Mechanistic hypothesis for diene formation (167). O Cl O Ni not formed O O O O O β-hydride O elimination Cl Ni O favored for BPhen OH Ni X 163 formed 167 From the preliminary ligand screen, it became clear that oxidative addition into the vinyl chloride and bromide had been occurring. The halide exchange from the bromide to the chloride, for example, is a good indication of this. In general, good conversions for the different ligands was observed. The halide exchange results made us wonder about what would occur if the MgCl2 was switched to other additives, such as MgBr2 or MgI2, or Mg(OTf)2. We also wondered generally about other Lewis acids used in carbonyl 1,2addition chemistry, such as Ti(OiPr)2/HFIP disclosed by Zhou and coworkers.76 Perhaps, following oxidative addition into the alkenyl bromide, the carbonyl 1,2-addition was slow with MgCl2 as an additive, and reductive elimination to form the alkenyl chloride dominates (Scheme 4.51). Indeed, certain reports for halide exchange posit a NiI mechanism, whereby either irreversible oxidative addition or irreversible halide transmetallation occurs, rather than a thermodynamically-driven process.4,84,85 Although the mechanism is unclear, the results of the ligand screen were exciting and drove a much more expansive investigation into Lewis acid additive exploration, reaction setup, and reaction design. Especially due to the fact that the terpy ligand seemed to be relatively effective, delivering adequate yields of the product, we wanted to know if the yield could be further optimized under these conditions. 303 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.51. Mechanistic hypothesis for halide exchange and diene formation. O L2 NiIII Br Cl O + NiIClL2 Oxidative Addition L2 Ni O Cl Ketone Chelation O Br Migratory Insertion Br slow step? O O O 144A O MgCl NiL2 O Reductive Elimination Cl favored for certain ligands O 144B Investigation of different Lewis acids with 1-bpp as ligand did not provide productive results. The most promising Lewis acid seemed to be ZnBr2, which provided an increased yield of 16% compared to other Lewis acids, such as TESBr, BF3 • OEt2, and Ti(iOPr)4/HFIP (Scheme 4.52). Scheme 4.52. Lewis acid screen with 1-bpp as ligand. Ni(COD)2 (10 mol%) 1-bpp (10 mol%) additive (2 equiv) Mn0 (2 equiv) O Br O O HO O DMA (0.1 M), 50 °C, 5 h O O Br 163 O 144A 167 additive 163 (%)* 144A (%) 167 (%) 1 none - 52 - 52 2 Ti(iOPr)4, HFIP - - - substrate decomposition 3 TESBr - 5 - 49** 4 BF3•OEt2 - 13 10 23 5 ZnBr2 16 74 - 90 entry mass balance (%) *all yields are QNMR yields ** isolated compound contains 2 TES groups, but no cyclization observed Turning back to terpy as ligand, other Mg2+ halide sources were screened. We speculated that the counterion in the magnesium salt could greatly inhibit or enhance the rate and/or product distribution of the reaction. To our delight, it was realized that MgI2 seemed optimal, delivering 55% yield, while other Mg2+ halide salts provided between 304 Chapter 4 – 3.2.1 bicycle synthesis 43% and 46% yield (Scheme 4.53). Scheme 4.53. Lewis acid screen with terpy as ligand. Ni(COD)2 (10 mol%) terpy (10 mol%) Lewis acid (2 equiv) Mn0 (2 equiv) O Br O O HO O DMA (0.1 M), 50 °C, 5 h O O Br 163 144A O 144A 167 Lewis acid 163 (%)* 144A (%) 167 (%) mass balance (%) 1 MgCl2 34 - - 43 2 MgBr2 • OEt2 46 - - 46 3 MgI2 55 - - 55 4 MgOTf2 40 6 2 61** entry *all yields are QNMR yields ** 13% protodebromination (not shown) Although MgCl2 seemed to work in moderate yields (Scheme 4.49, entry 7 and Scheme 4.53, entry 1), the result was not scalable even with multiple attempts at different setups (Scheme 4.54). Scheme 4.54. Attempts to scale up MgCl2 as a Lewis acid. Ni(COD)2 (10 mol%) terpy (10 mol%) MgCl2 (2 equiv) Mn0 (2 equiv) O Br O O O HO O DMA (0.1 M), 50 °C, 5 h O O O O Br 144A 144A 163 168 entry scale time 1 100 mg 15 h round bottom flask, under N2, outside gb in oil bath 10 14 2 50 mg 15 h 1-dram vial, large magnetic stir bar, on gb hot plate 7 12 3 30 mg 5h vial in the glovebox as normal, larger stir bar 10 45 setup method 163 (%) 144A (%) 168 (%) 167 167 (%) mass balance 10 - 34 9 - 28 - - 55 With MgI2 providing optimal yield with terpy as the ligand (Scheme 4.53), we next moved on to investigate the catalyst. It is unclear the exact mechanism of the reaction, but it is possible that the reaction proceeds through a Ni0-NiII or a Ni1-NiIII cycle. In either case, we wondered if we could start from a NiII precatalyst, such as NiBr2 • dme, rather than 305 Chapter 4 – 3.2.1 bicycle synthesis Ni(COD)2. Furthermore, we wanted to investigate the ligand/catalyst loading to see if lower or higher yields of catalyst loading could boost the yield. Indeed, use of NiBr2 • dme with 10 mol% catalyst loading seemed optimal (Scheme 4.55, entry 4), while other entries also provided somewhat promising results. Integral to the increased yields was a new workup procedure. After extensive investigation, it was realized that product 163 is volatile when subjected to in vacuo concentration. In order to prevent loss of product during in vacuo concentration, solvent was blown off under a stream of nitrogen (see experimental section for further information). Scheme 4.55. Catalyst/ligand loading screen. cat. (X mol%) terpy (X mol%) MgI2 (2 equiv) Mn0 (2 equiv) O DMA (0.1 M), 50 °C, 5 h Br O O HO O O O O O Br O 144A 163 144A 163 (%) 144A (%) 168 (%) 168 167 167 (%) mass balance 2 - 58 5 - 66 - 9 - 80 76 - 2 - 78 44 2 8 - 54 entry cat. X 1 Ni(COD)2 5* 56 - 2 Ni(COD)2 15 61 - 3 NiBr2dme 5* 71 4 NiBr2dme 10 5 NiBr2dme 15 * stirred overnight (16 h) The results in Scheme 4.55 were ultimately scalable with one major change: no additive. It was found that MgI2 introduces impurities on scale (perhaps trace moisture) which is detrimental to reaction yield. A simple leave-out experiment verified that the additive was not necessary. Given the newly found volatility of the product, the data in Scheme 4.53 suggests the identity of the Lewis Acid is relatively agnostic to the reaction yield and may not be implicated in the reaction mechanism. Using a pressure flask, the reaction could be scaled up to 480 mg scale without any 306 Chapter 4 – 3.2.1 bicycle synthesis significant reduction in yield (Scheme 4.56). At much larger scales (8 g scale), the yield of the reaction dropped to 55% yield. Scheme 4.56. Successful scale-up of Ni-catalyzed 1,2-addition using additive-free conditions. NiBr2 • dme (5 mol%) terpy (5 mol%) Mn0 (2 equiv) O DMA (0.1 M), 50 °C, 16 h Br 144A O O O O Br O HO O entry O O 144A 163 168 167 scale time purification vessel size (%) 163 (%) 144A (%) 168 (%) 167. (%) mass balance 1 36 mg 5h none, QNMR 1-dram vial 70 - 4 - 74 2 108 mg 5h none, QNMR 15 mL pressure flask 71 - 3 - 74 3 480 mg 5h column 75 mL pressure flask 72 - 3 - 75 4 8g 5h column 500 mL RBF 55 - 4 - 59 4.4.5 Advancement to the asymmetric key fragment From compound 163, the route to compound 107B could be accomplished in a relatively straightforward manner (Scheme 4.57). MEM protection could be accomplished to form 143 in 84% yield,86 followed by triflation with N-Ph bistriflimide to form 142.87 Notably, Comin’s reagent could not be used in this case, leading to partial conversions (see Scheme 4.58 for more information).88 Selective Lemiux-Johnson oxidation occurred uneventfully in 50% yield to form 107A.89,90 Enol triflate to alkenyl bromide exchange occurred in 70%, allowing access to fragment 107B. 307 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.57. Completing the 3.2.1 bicycle synthesis. O O MEMCl (1.4 equiv) Et2NiPr (3 equiv) DCM, 45 °C, 4 h HO OsO4 (0.0045 equiv.) NaIO4 (2 equiv.) 2,6-Lutidine (1 equiv.) OTf KHMDS (1.2 equiv) N-Ph-bistriflimide (1.2 equiv) H2O, Dioxane (3:1, 55 mM) 22 °C, 17 h THF (3:1), −78 °C to 21 °C, 30 min MEMO 84% yield MEMO 50% yield 84% yield 163 143 142 O O Br Ni(COD)2 (10 mol%) LiBr (5 equiv) Br OMEM O = THF/DMA (3:1, 60 mM), 21 °C, 12 h MEMO H OTf 70% yield 107B MEMO 107A Although it is surprising that triflation could not be accomplished successfully with Comin’s reagent, N-Ph bistriflimide could be used in 84% yield using KHMDS as base, without the need for 18-crown-6 or other additives (Scheme 4.58). Scheme 4.58. Identification of optimal triflation conditions. O Base (1.2 equiv) Additive (1.5 equiv) then E (1.2 equiv) MEMO Solvent, Temp 2-4 h OTf MEMO 143 142 142 (%)* recovered 143 (%) mass balance - - 97 97 - 9 88 97 0 °C - 12 84 96 Et2O 0 °C - 32 60 92 Comin’s (Jordan’s, new bottle) Et2O −78 °C - - 98 98 KHMDS Comin’s (Jordan’s, new bottle) Et2O −78 °C - 50 50 100 7 KHMDS Comin’s (Jordan’s, new bottle) Et2O −78 °C - 32 64 96 8 KHMDS Comin’s (Jordan’s, new bottle) Tol/THF −78 °C 18-crown-6 47 42 89 9 KHMDS Comin’s (Jordan’s, new bottle) Tol/THF −78 °C 18-crown-6 45 42 87 10 KHMDS Comin’s (Jordan’s, new bottle) THF −78 °C 18-crown-6 57 39 96 11 KHMDS N-phenyl-bis-triflimide THF −78 °C 18-crown-6 83 - 83 12 KHMDS N-phenyl-bis-triflimide THF −78 °C none 84 - 84** 13 KHMDS N-phenyl-bis-triflimide THF −78 °C 18-crown-6 84 - 84 entry Base E (source) Solvent Temp Additive 1 LDA Comin’s (Jordan’s, old bottle) THF −78 °C 2 LHMDS Comin’s (Jordan’s, old bottle) THF −78 °C 3 NaHMDS Comin’s (Andrea’s) Et2O 4 KHMDS Comin’s (Andrea’s) 5 KHMDS 6 *QNMR yields **reaction conducted for 30 minutes rather than 2-4 hours. 308 Chapter 4 – 3.2.1 bicycle synthesis 4.4.6 Other avenues for more expedient 3.2.1 bicycle synthesis: use of a Michael-Aldol cascade While the development of a viable asymmetric route to 107B was incredibly enabling for the project, allowing access to more than double the quantity of material in a single pass than the Snider/chiral preparatory hplc route, some brainstorming on more direct annulations to access 107B more efficiently were explored. One of the more exciting approaches involved the use of a Michael-Aldol cascade to forge the 3.2.1 bicycle in a single step (Scheme 4.59). When using a fragment such as phenyl acrylate, Baeyer-Villager oxidation could install the tertiary alcohol required in auriculatol A. Scheme 4.59. A Michael-Aldol cascade quickly forges 3.2.1 bicycle. O O OEt O 169 OPh O phenyl acrylate MichaelAldol Cascade O O OEt OPh OH 170 O BaeyerVillager Oxidation O Me O H OEt OH O 171 O O OPh OR O = OH O O OR X EtO OPh 172 O target The route was undertaken by studying the acylation of 1,4-dioxaspiro[4.5]decan-8one (147). This could simply be accomplished using HMPA as a stoichiometric additive in 59% yield (Scheme 4.60).91 Interestingly, use of NaH and diethylcarbonate92 or LDA and Mander’s reagent93 (without HMPA) led to no observed yield of the product. 309 Chapter 4 – 3.2.1 bicycle synthesis Scheme 4.60. Acylation of 147 with Mander’s reagent. O O O conditions O OEt O O O 147 173 temp/time product (%) - 140 °C, 1 h - THF −78 °C, 1 h - 0 °C, 1 h 59 entry base reagent additive solvent 1 NaH diethylcarbonate - 2 LDA Mander’s - 3 LDA Mander’s HMPA (1 equiv) THF With 173 in hand, we were curious about attempting the direct Michael addition before ethylene glycol deprotection rather than the cascade process. Identification of viable Michael addition conditions before moving on to study the more complex cascade process could help with troubleshooting. After a quick base and solvent screen, it was shown that the Michael addition occurred to form 174 in 44% using triethylamine in acetonitrile (Scheme 4.61).94 Shockingly, switching to other bases, such as K2CO3, DBU, or KOtBu, or switching from acetonitrile to ethanol, led to no yield of the product. The reaction was noticeably slow, as monitoring the reaction after 72 h still had leftover starting material. Scheme 4.61. Testing the Michael addition with phenyl acrylate. O O O OEt O O OPh (1.2 equiv) base (2 equiv) 72 h, 21 °C O O OEt O OPh O O 173 174 entry base solvent product (%) 1 K2CO3 EtOH - 2 K2CO3 ACN - 3 DBU EtOH - 4 DBU ACN - 5 TEA EtOH - 6 TEA ACN 44% yield 7 KOtBu EtOH - 8 KOtBu ACN - 310 Chapter 4 – 3.2.1 bicycle synthesis With viable Michael addition conditions identified, moving on to the cascade process seemed fruitful. Deprotection of the ethylene glycol ketal could be accomplished in an ethanol/water mixture with HCl. The cascade process worked in roughly the same yield as the single-step Michael addition (48% yield) to deliver 176. Scheme 4.62. Preparation and testing of a racemic Michael-Aldol cascade substrate. LDA then HMPA, Mander’s O O THF, 0 °C, 1 h O O O OH OEt O HCl (25 equiv) OEt O 85% yield 173 O O OEt EtOH, 22 °C, 24 h EtOH/Water (2:1) 21 °C, 14 h O 59% yield 147 phenyl acrylate (1.3 equiv) DBU (2 equiv) O OH EtO 48% yield 175 O 176 Future studies in this area should center on achieving enantioselectivity. There are several reports in the literature, focused on using chiral copper enolates,95 lanthanumBINOL complexes,96 chiral Michael acceptors (enamines),97 gallium-BINOL complexes,98 aluminum-BINOL complexes,99 and chiral nickel enolates.100 These ideas, for the most part, have not been extensively explored. Taken together, this approach could provide a more expedient route to the key 3.2.1 bicycle used in the vinylogous Mukaiyama Aldol coupling; although, some major challenges, such as achieving enantioselectivity and the exact route to achieving the synthesis of the target aldehyde (107B) remains elusive. Scheme 4.63. Future studies: development of an asymmetric Michael-Aldol cascade. O O OEt O 169 OPh O phenyl acrylate MichaelAldol Cascade O O OEt OPh OH 170 O BaeyerVillager Oxidation O Me O H OEt OH O 171 O OPh O OPh OR O = OH O O EtO OR X 172 target O Chapter 4 – 3.2.1 bicycle synthesis 4.5 311 CONCLUDING REMARKS Taken together, this chapter provides foundational studies for 3.2.1 bicycle synthesis in the context of the total synthesis of auriculatol A. Several challenging transformations were explored. For example, this chapter describes the synthesis of key aldehyde fragment 107B originally through the use of the Snider radical cascade. Despite the unsuccessful endeavors toward applying a decarboxylative Giese addition, fragment 107B was synthesized in 10 steps and resolved through the use of chiral preparatory HPLC. Although the development of the 10-step route had very few challenges, it lacked scalability, and yields were typically quite low (~50% yield) for most steps. Several asymmetric strategies for 3.2.1 bicycle synthesis through chiral radical cascades were attempted, including the development of a chiral radical cascade process through halogenatom transfer reactions, chiral a-imino catalysis, and use of chiral auxiliaries. Unfortunately, with unproductive results to induce enantioselectivity in this research aim, we opted to pivot strategies. A palladium-catalyzed decarboxylative Tsuji-Stoltz allylation for enantioselective quaternary center formation provided compelling results on several substrates, the most exciting of which contained a vinyl halide substituent and unsubstituted allyl unit. Coupled with the discovery of a unique nickel-catalyzed intramolecular carbonyl 1,2 addition of vinyl bromides to 1,3-diketones, a new, more efficient route to 107B was found. Seminal to the success of the route is the optimization of triflation reaction to form compound 142 and development of a chemoselective Lemeuix-Johnson oxidation to furnish 107A. Insights into product selectivity (product vs. diene) in the nickel-catalyzed 1,2addition based on tuning of the ligand are intriguing and could be useful to the community 312 Chapter 4 – 3.2.1 bicycle synthesis in the realm of nickel-catalyzed reaction development. Furthermore, it is possible that the methods for the palladium-catalyzed decarboxylative Tsuji-Stoltz allylation and nickelcatalyzed 1,2-addition could be compared more generally; that is, a paper disclosing our group’s longstanding interest in 3.2.1 bicycle synthesis could be of interest. Preliminary data investigating a Michael-Aldol cascade are disclosed; nonetheless, this strategy needs considerable development in order to become a viable option for the synthesis. 4.6 EXPERIMENTAL SECTION Preparation of methyl 2-acetylpent-4-enoate (108): O Me Me O NaH (1.2 equiv) allyl bromide (1 equiv) MeO O OMe methyl acetoacetate THF, 0 °C, 90 min O 108 In a flame-dried 500 mL flask with a stir bar was added 13.8 g of NaH (1.2 equiv, 60% mineral oil). The flask was capped with a 250 mL addition funnel (also flame dried) and vacuumed and backfilled with N2 three times before 150 mL of THF was added via cannula directly from the SPS. The NaH/THF mixture was allowed to stir for 1 min at room temperature to evenly disperse before it was cooled to 0 °C with an ice bath. Methyl acetoacetate (46.5 mL, 1.5 equiv) was measured and poured into addition funnel via a graduated cylinder. The flask was capped with a rubber septum, vacuumed, and backfilled three times with N2. Then, 150 mL of dry SPS THF was again added, this time into the addition funnel. The methyl acetoacetate solution was added over a 1.5 h period at 0 °C using the addition funnel. CAUTION: This is an exothermic deprotonation that evolves a large quantity of H2 gas. Be sure that the addition funnel does not add too quickly, as over- Chapter 4 – 3.2.1 bicycle synthesis 313 pressurization of the system may occur and cause the addition funnel to pop off and break. Do not have an open flame in the hood during this time to avoid potential explosion hazards from the H2 that is emitted. Following addition of the methyl acetoacetate solution, the sides of the addition funnel were rinsed with 20 mL of THF, and the system was removed from the ice bath and allowed to warm to room temperature, where it was stirred for 1 h. After 1 h of stirring at room temperature, the system was cooled back to 0 °C before 24.8 mL of allyl bromide (1 equiv) was added via direct injection (not dropwise). The reaction was stirred for 90 min before 200 mL of water was added to the reaction. The mixture was partitioned in a 1 L separatory funnel, the organic phase was collected, and the aqueous phase was extracted 3x with ether. The combined organic phases were washed with brine, dried with Na2SO4, and concentrated. Column chromatography using a 4 L column using very minimal silica and 5 to 8% EtOAc/Hex gradient going up by 1% per column volume gave 54% yield (24.0 g). O Me MeO O 108 TLC (30% EtOAc/Hexanes): Rf 0.66 (p-anis (red/pink), KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.74 (ddt, J = 17.1, 10.3, 6.9 Hz, 1H), 5.12 – 5.03 (m, 2H), 3.74 (s, 3H), 3.54 (t, J = 7.4 Hz, 1H), 2.59 (tt, J = 7.0, 1.3 Hz, 2H), 2.23 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 202.55, 169.86, 134.27, 117.70, 59.23, 52.59, 32.35, 29.33. FTIR (Neat, NaCl, thin film): 2955, 1746, 1643, 1435, 1233, 920 cm-1. HRMS (ESI): calc’d for [M+H]+ 156.07864, found 156.07796. 314 Chapter 4 – 3.2.1 bicycle synthesis Preparation of 1,3-dichloro-2-((2-methoxyethoxy)methoxy)propane: OH Cl Cl MEMCl (2.2 equiv) iPr2NEt (3 equiv) DCE, 80 °C, 12 h 1,3-dichloropropan-2-ol OMEM Cl Cl 1,3-dichloro-2-((2-methoxyethoxy) methoxy)propane To an oven-dried, 3-neck, 2L flask was added the starting material (60 g, 465 mmol, 1 equiv), dichloroethane (800 mL, 581 mM), and a large, cylindrical magnetic stir bar. The flask was capped with two rubber septa and a reflux condenser, backfilled with N2 three times, and cooled to 0 °C. Then, one of the rubber septa was removed and freshly distilled diisopropylethylamine (243 mL, 1.4 mol, 3 equiv) was poured into the stirring solution and stirred for 3 min. Methoxyethoxymethyl chloride (117 mL, 1.02 mol, 2.2 equiv) was then added by pouring directly from a clean, glass graduated cylinder. CAUTION: the mixture will smoke up upon addition of MEMCl. While an exotherm has not been observed, it is important to add the reagent at 0 °C and turn on the emergency exhaust to limit exposure. Pour MEMCl in the hood and segregate waste. Following addition of MEMCl, the septa was put back onto the flask and the apparatus was removed from the ice bath and placed into an 80 °C oil bath and stirred for 13 h. After stirring for 13 h, the apparatus was brought out of the oil bath and cooled to room temperature before addition of 800 mL of saturated aqueous ammonium chloride. The solution was added to a 2 L separatory funnel, and the bottom DCE layer was collected. The aqueous layer was then extracted with DCM (3 x 400 mL), and the collected organic fractions were washed with brine, dried with Na2SO4, and concentrated in vacuo. The crude red/brown oil was loaded directly onto a column and flushed with 30% EtOAc/Hex (2 L). Following the short silica plug, the 2L collected were concentrated, affording a pale-yellow oil that was carried forward to the next step (82 g, 81% yield). 315 Chapter 4 – 3.2.1 bicycle synthesis OMEM Cl Cl 1,3-dichloro-2-((2-methoxyethoxy) methoxy)propane TLC (30% EtOAc/Hexanes): Rf 0.5 (KMnO4). 1 H NMR (CDCl3, 400 MHz): 1H NMR (400 MHz, CDCl3) δ 4.84 (s, 2H), 4.03 (p, J = 5.2 Hz, 1H), 3.79 – 3.76 (m, 2H), 3.76 – 3.69 (m, 4H), 3.56 (dd, J = 5.7, 3.5 Hz, 2H), 3.39 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 95.53, 76.81, 71.75, 67.67, 59.22, 43.87. FTIR (Neat, NaCl, thin film): 2928, 1440, 1114, 753 cm-1. HRMS (ESI): calc’d for [M+H] 217.0393, found 217.0390. Preparation of 3-chloro-2-((2-methoxyethoxy)methoxy)prop-1-ene (115): OMEM Cl Cl OMEM KOtBu (1.05 equiv) THF, −10 °C to 22 °C, 15 h 1,3-dichloro-2-((2-methoxyethoxy) methoxy)propane Cl 115 A 1 L flask fitted with a cylindrical stir bar was added the starting material (47.0 g, 217 mmol, 1 equiv) and 361 mL of anhydrous THF (600 mM). The solution was cooled to -10 °C using a salted ice bath. Solid KOtBu (25.5 g, 227 mmol, 1.05 equiv) was added in slowly, a few chunks at a time. Following completion of the addition, the septum was used to cap the top, and the reaction flask was evacuated and backfilled 3x with nitrogen. The reaction was stirred vigorously overnight. The next day, 175 mL of H2O was added, and following separation of the aq. and organic phases, the aq. phase was extracted three times with DCM (3 x 200 mL). The combined organics were washed with brine, dried with Na2SO4, filtered, and concentrated. The crude oil was loaded onto a silica gel column and eluted with 10-15% EtOAc/Hexanes, going up by 1% each column volume, to provide 38.7 316 Chapter 4 – 3.2.1 bicycle synthesis g of product, corresponding to a 99% yield. OMEM Cl 115 TLC (10% EtOAc/Hex): Rf 0.13 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.11 (s, 2H), 4.46 (d, J = 2.5 Hz, 1H), 4.41 (d, J = 2.5 Hz, 1H), 3.98 (s, 2H), 3.80 – 3.76 (m, 2H), 3.57 (dd, J = 5.7, 3.7 Hz, 2H), 3.39 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 155.87, 93.12, 89.83, 71.70, 68.04, 59.18, 45.21. FTIR (Neat, NaCl, thin film): 2922, 1638, 1299, 1188, 1022 cm-1. HRMS (ESI): calc’d for [M+H]+ 180.05532, found 180.05544. Preparation of methyl 2-allyl-6-((2-methoxyethoxy)methoxy)-3-oxohept-6-enoate (109): O Me NaH (1.1 equiv), 0 °C, 15 min then nBuLi, 0 °C, 45 min then HMPA (2 equiv) then OMEM (1.1 equiv) Cl OMEM O MeO MeO O 108 THF, 16 h, −78 °C to 21 °C O 109 An oven-dried 1L round bottom flask and large magnetic stir bar were pumped into the glovebox and charged with NaH (90% purity, 3.76 g, 141 mmol, 1.1 equiv). The flask was capped, brought out of the glovebox, and put under nitrogen with a 250 mL addition funnel hooked in. Then, 400 mL of anhydrous THF was added via cannulation from the SPS, and the flask was cooled to 0 °C. To the stirring solution at 0 °C was added a 1M solution of methyl-2-allylacetoacetate (20.0 g, 128 mmol, 1 equiv) in anhydrous THF dropwise over 35 min using an addition funnel. The deprotonation was evidently exothermic, as bubbling and melting of the ice in the ice bath was observed. The resulting enolate was stirred for Chapter 4 – 3.2.1 bicycle synthesis 317 15 min at 0 °C. Then, to the stirring solution at 0 °C was added nBuLi (1.69 M in hexanes, 83.4 mL, 1.1 equiv) dropwise over 5 min. A change in color from grey/pale yellow to a dark orange was observed. The double enolate was stirred for 45 min at 0 °C, after which time HMPA (44.6 mL, 256 mmol, 2 equiv, distilled over CaH2 and stored in a Schlenk with activated molecular sieves) was added dropwise over 2 min. The ice bath was then replaced by a − 78 °C dry-ice/acetone bath. To the resulting diluted solution at −78 °C was added the electrophile (azeotroped with benzene three times) dropwise over 45 min neat (25.4 g, 141 mmol, 1.1 equiv). The resulting solution was stirred for 16 h and gradually allowed to warm to room temperature from − 78 °C upon which a color change from dark red to bright orange was observed. Following 16 h, 500 mL of water was added. The solution was stirred for 5 min, then transferred over to a separatory funnel and extracted with diethyl ether (3 x 400 mL). The combined organic phases were washed with brine, dried with NaSO4, and filtered. The organic phases were then concentrated on the rotatory evaporator and loaded onto the 8 L column packed 35% full with silica. The crude material was then it was loaded onto a column and purified with 7% EtOAc/Hexanes for one column volume, 9% EtOAc/Hexanes for one column volume, 11% EtOAc/Hexanes for two column volumes, 12% EtOAc/Hexanes for two column volumes, 13% EtOAc/Hexanes for two column volumes, and 15% EtOAc/Hex until all the product had eluted, affording a yellow oil which was determined to be 96% pure (20.3 g, 55% yield) by qNMR with technazene (2.0 mg as compared to 8.6 mg of the crude oil). This compound cannot be stored overnight, as decomposition (MEM group deprotection) will occur, so it was carried forward directly into the next step. 318 Chapter 4 – 3.2.1 bicycle synthesis OMEM O MeO O 109 TLC (20% Hexanes/EtOAc): Rf 0.13 (p-anisaldehyde, stains black/blue). 1 H NMR (CDCl3, 400 MHz): δ 5.78 – 5.68 (m, 1H), 5.11 – 4.99 (m, 4H), 4.14 (d, J = 2.2 Hz, 1H), 4.00 (d, J = 2.1 Hz, 1H), 3.74 – 3.70 (m, 5H), 3.57 – 3.55 (m, 2H), 3.39 (s, 3H), 2.78 – 2.68 (m, 2H), 2.59 (ddd, J = 7.4, 6.5, 1.3 Hz, 2H), 2.39 (td, J = 7.3, 0.8 Hz, 2H). 13 C NMR (CDCl3, 101 MHz): δ 203.62, 169.75, 159.21, 134.36, 117.69, 92.77, 85.17, 71.76, 68.01, 59.20, 58.47, 52.57, 40.07, 32.37, 28.97. FTIR (Neat, NaCl, thin film): 3444, 2922, 1758, 1643, 1434, 1267, 1034 cm-1. HRMS (ESI): calc’d for [M+H]+ 300.15729, found 300.15670. Preparation of Methyl 5-[(2-methoxyethoxy)methoxy]-6-methylene-2- oxobicyclo[3.2.1]octane-1-carboxylate (110): OMEM O MeO Mn(OAc)3 • 2H2O (2.0 equiv) Cu(OAc)2 • H2O (1.0 equiv) EtOH, 60 °C, 15 h O 109 O MeO2C OMEM 110 To a two-neck 2 L round bottom flask charged with a large (2 x 1 inch), cylindrical stir bar and the starting material (21.3 g, 70.9 mmol) was added 740 mL of EtOH (degassed, 93.8 mM), and the reaction was stirred for 1 min to ensure complete homogeneity of the solution. Then, to the stirring solution was added Mn(OAc)3 • 2H2O (38.0 g, 142.0 mmol, 2 equiv) following immediately by Cu(OAc)2 • H2O (14.2 g, 70.9 mmol, 1 equiv). 16 mL of additional EtOH was added to wash any salts that were stuck to the neck of the flask Chapter 4 – 3.2.1 bicycle synthesis 319 down. The flask was fitted with a reflux condenser and connected to a nitrogen inlet. The headspace was evacuated and backfilled three times with N2. The dark brown solution was stirred vigorously at 60 °C using an oil bath for 15 h. After the 2nd hour, it was noted that the dark brown solution had turned a bright turquoise color, likely from change in oxidation state of the added Mn(III)/Cu(II) salts. After the 15th hour, the flask was brought out of the oil and cooled back down to room temperature. The mixture was poured slowly into a 1L separatory funnel that contained 500 mL of water and 50 mL of saturated sodium bisulfite solution (aq). A color change to a dark green was observed, and some bubbling was observed but no exotherm. The aq. phase was extracted with dichloromethane (4 x 300 mL). The collected organic phases were then washed with brine, dried with NaSO4, filtered, and concentrated down in vacuo. The crude material was then loaded onto a 2 L column filled 50% with silica and purified with 10% EtOAc/Hexanes to 20% EtOAc/Hexanes and holding at 20% until all product was eluted (took like 4 column volumes of this), affording a yellow oil (11.0 g, 52% yield). The primary impurity is a less-polar impurity that is quite difficult to separate (hence the very moderate gradient from 10-20% EtOAc/Hex). It corresponds to hydrolyzing the MEM group of the product and is usually formed between 20 and 30% yield. O MeO2C OMEM 110 TLC (30% Hexanes/EtOAc): Rf 0.16 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.25 (t, J = 2.6 Hz, 1H), 5.22 (s, 1H), 4.92 (s, 1H), 4.78 (s, 1H), 3.83 (s, 1H), 3.75 (s, 3H), 3.65 (s, 1H), 3.55 (s, 2H), 3.38 (s, 3H), 2.95 (s, 1H), 2.77 (s, 1H), 2.63 (s, 1H), 2.48 (s, 2H), 2.30 (s, 1H), 2.18 (s, 1H), 1.90 (s, 1H). 320 Chapter 4 – 3.2.1 bicycle synthesis 13 C NMR (CDCl3, 101 MHz): δ 206.17, 171.07, 148.22, 108.61, 91.36, 82.91, 71.87, 67.37, 60.60, 59.16, 52.43, 42.19, 38.19, 37.52, 35.08. FTIR (Neat, NaCl, thin film): 2921, 1742, 1446, 1265, 1073 cm-1. HRMS (ESI): calc’d for [M+H]+ 298.14164, found 298.14211. Preparation of enol triflate bicycle 114: O LDA (1.3 equiv) Comin’s Reagent (1.15 equiv) MeO2C OMEM 110 THF, −78 °C, 1 h TfO MeO2C OMEM 114 The starting material was azeotroped in benzene (3 x 10 mL). In a flame dried, N2 filled 500 mL round bottom flask was added 2.87 mL of diisopropylamine (20.5 mmol, 1.3 equiv) and 50 mL of SPS THF. The vessel was cooled to −78 °C before n-Butylithium was added dropwise via syringe addition (8.19 mL, 2.5 M, 20.5 mmol). The reaction mixture was stirred for 15 minutes at −78 °C, warmed to 0 °C with an ice bath and stirred for 15 minutes, then cooled back down to −78 °C. Methyl 5-[(2-methoxyethoxy)methoxy]-6methylene-2-oxobicyclo[3.2.1]octane-1-carboxylate was then added dropwise by syringe addition dropwise to the stirring solution of lithium diisopropylamine as a 1M solution in THF (4.7 g, 15.8 mL, 15.8 mmol) and stirred for 45 minutes at −78 °C. A small amount of THF was used to transfer residual starting material to the reaction flask to ensure quantitative transfer. Comin’s reagent (1M in THF, 18.1 mmol, 18.1 mL, 1.15 equiv) was then added via cannula as a steady stream (about 3 min to add all 18 mL), and the reaction was stirred for 90 minutes at −78 °C. Upon addition of Comin's reagent, the mixture turned orange and a small amount of white gas evolved from the solution. After 90 minutes, the reaction was quenched by addition of saturated aq. NaHCO3 (100 mL) at -78 °C and Chapter 4 – 3.2.1 bicycle synthesis 321 warmed to room temperature. The crude mixture was diluted with 50 mL of Et2O, and the organic phase was collected (separating from the aqueous phase) using a 250 mL separatory funnel. The aqueous phase was then extracted with Et2O (3 x 100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The product was purified by column chromatography (silica, 20% EtOAc/hexanes to 25% to fully elute) to isolate a yellow oil with some residual white solids (Comin's reagent byproduct). To get rid of the solid, a filtration of the starting material was done through a pad of cotton, eluting with hexanes. The yield of the isolated product was 5.2 g (77% yield) as a yellow oil. Starting material was reisolated in the column (if present). TfO MeO2C OMEM 114 TLC (30% EtOAc/Hexanes): Rf 0.35 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.67 (dd, J = 5.1, 2.7 Hz, 1H), 5.20 (dt, J = 8.7, 2.3 Hz, 2H), 4.92 (d, J = 7.6 Hz, 1H), 4.72 (d, J = 7.6 Hz, 1H), 3.88 – 3.79 (m, 1H), 3.77 (s, 3H), 3.67 – 3.59 (m, 1H), 3.56 – 3.52 (m, 2H), 3.38 (s, 3H), 3.07 – 2.92 (m, 2H), 2.77 (dd, J = 16.9, 2.7 Hz, 1H), 2.58 (dd, J = 11.0, 1.8 Hz, 1H), 2.38 – 2.24 (m, 2H). 13 C NMR (CDCl3, 101 MHz): δ 170.16, 149.51, 149.02, 116.26, 110.12, 91.26, 82.58, 71.86, 67.41, 59.15, 52.76, 51.88, 44.09, 42.68, 40.62. FTIR (Neat, NaCl, thin film): 2891, 1734, 1667, 1415, 1300, 1000, 858 cm-1. HRMS (ESI): calc’d for [M+H] 431.09875, found 431.10053. 322 Chapter 4 – 3.2.1 bicycle synthesis Preparation of primary alcohol 113: TfO TfO DIBAL-H (3 equiv) MeO2C OMEM 114 HO OMEM DCM, 0 °C, 60 min 113 A 500 mL round bottom flask was charged with the starting material (7.14 g, 16.6 mmol) and a magnetic stir bar. 116 mL of dichloromethane were added from a graduated cylinder, and the round bottom was capped with a rubber septum, hooked up to the Schlenk, and vacuumed and backfilled with an N2 atmosphere three times. The flask was put into an ice bath and cooled to 0 °C. DIBAL-H (7.07 g, 49.8 mmol, 1M, 49.8 mL) was added dropwise as a premade Aldrich solution in dichloromethane via syringe. Following the addition, the mixture was stirred for 10 minutes at 0 °C, TLC'd to ensure completion, and worked up by: 1) dropwise addition of ethyl acetate (4 mL) and 2) addition of saturated aqueous Rochelle’s salt (200 mL). The flask was then removed from the ice bath and warmed to room temperature, where it was stirred for 1 h to ensure complete decomposition of Al salts. After an hour of stirring, it was noted that a once cloudy, clumpy mixture (that slightly warmed up upon formation of the Al aggregate) was clear in the dichloromethane layer and a murky white in the aqueous layer. The mixture was poured into a 500 mL separatory funnel, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (3 x 200 mL). The collected organic phases were then washed with brine, dried with Na2SO4, filtered and concentrated. The NMR revealed the relatively high purity of the sample (some residual solvent peaks) and so it was carried forward into the Swern Oxidation without further purification. 6.68 g was isolated, corresponding to quantitative yield. 323 Chapter 4 – 3.2.1 bicycle synthesis TfO HO OMEM 113 TLC (30% EtOAc/Hex): Rf 0.10 (p-anis (blue), KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.64 (dd, J = 4.8, 2.8 Hz, 1H), 5.19 (t, J = 2.4 Hz, 1H), 5.13 (t, J = 2.0 Hz, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.72 (d, J = 7.6 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.88 – 3.80 (m, 1H), 3.66 – 3.56 (m, 2H), 3.54 (dd, J = 5.6, 3.7 Hz, 2H), 3.37 (d, J = 0.8 Hz, 3H), 2.75 (q, J = 2.4 Hz, 1H), 2.71 (d, J = 2.8 Hz, 1H), 2.39 (dt, J = 16.0, 3.0 Hz, 1H), 2.34 – 2.24 (m, 2H), 2.15 (dd, J = 11.0, 2.7 Hz, 1H), 1.95 (s, 1H). 13 C NMR (CDCl3, 101 MHz): δ 152.40, 150.71, 116.65, 109.61, 91.20, 83.06, 71.88, 67.22, 64.27, 59.09, 47.52, 43.37, 42.08, 41.05. FTIR (Neat, NaCl, thin film): 3464, 2889, 1666, 1409, 1217, 1046, 883 cm-1. HRMS (ESI): calc’d for [M+H] 403.10383, found 403.10408. Preparation of aldehyde 112: Oxalyl chloride (5 equiv) DMSO (10 equiv) then NEt3 (15 equiv) TfO HO OMEM 113 DCM, −78 °C, 1 h TfO O OMEM H 112 To a solution of oxalyl chloride (3.07 mL, 36.3 mmol) and in CH2Cl2 (36 mL) at -78 °C under N2 is added dropwise a solution of DMSO (5.15 mL, 72.6 mmol). A noticeable exotherm and bubbling was observed. After 15 min a solution of the alcohol (2.92 g, 7.26 mmol) in CH2Cl2 (30 mL, 0.24 M) is slowly added dropwise (rxn turned cloudy white), and the reaction was warmed to -40 °C over 30 min. After 30 min, the mixture was cooled back down to -78 °C and Et3N (15.2 mL, 109 mmol) is added dropwise. The reaction is 324 Chapter 4 – 3.2.1 bicycle synthesis stirred 30 min at -78 °C then slowly allowed to warm to rt. In order to work the reaction up, the flask was cooled to 0 ° C and ammonium chloride (60 mL) was added. Separate the phases and extract the aqueous phase with CH2Cl2 (60 mL) three times. Wash the combined organic phases with saturated aq. ammonium chloride and brine, dry over Na2SO4, and concentrate. The crude reaction mixture was loaded onto a column and purified with a 30 to 35% EtOAc/Hex gradient as a pale yellow oil (2.18 g, 75% yield). TfO O OMEM H 112 TLC (30% EtOAc/Hexanes): Rf 0.20 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.77 (s, 1H), 5.80 (dd, J = 5.1, 2.8 Hz, 1H), 5.24 (dd, J = 2.6 Hz, 2.2 Hz, 2H), 4.93 (d, J = 7.6 Hz, 1H), 4.73 (d, J = 7.6 Hz, 1H), 3.87 – 3.79 (m, 1H), 3.66 – 3.59 (m, 1H), 3.57 – 3.52 (m, 2H), 3.37 (s, 3H), 2.93 (p, J = 2.4 Hz, 2H), 2.78 (dd, J = 17.1, 2.8 Hz, 1H), 2.46 (dt, J = 10.9, 1.3 Hz, 1H), 2.35 (ddd, J = 17.6, 5.3, 1.8 Hz, 1H), 2.19 (dd, J = 11.2, 2.1 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 196.52, 148.83, 148.49, 117.90, 110.65, 91.26, 82.79, 71.85, 67.48, 59.18, 55.88, 42.39, 40.99, 40.77. FTIR (Neat, NaCl, thin film): 2887, 1731, 1415, 1211, 1047, 851 cm-1. HRMS (ESI/FD+): calc’d for [M]+ 400.08036, found 400.07842. Preparation of methyl ether 111: Cl OMe Ph3P (3 equiv) LHMDS (2.7 equiv) TfO O OMEM H 112 THF, 0 °C, 80 min TfO MeO OMEM 111 Chapter 4 – 3.2.1 bicycle synthesis 325 A 500 mL round bottom flask was flame-dried under vacuum and cooled to room temperature. Methoxymethylphosphonium chloride (5.73 g, 16.7 mmol) was added, and the flask was evacuated and backfilled with N2 3x. THF (100 mL) was added, and the flask was cooled to 0 °C. LHMDS (15 mL, 15.0 mmol, 1 M soln in THF) was added dropwise, which turned the stirring solution turned orange/red. The reaction was then stirred at 0 °C for 45 min. Next, the starting material 193 (2.23 g, 5.57 mmol, 1.0 equiv.) was added as a solution in 1 M THF (5.57 mL). After 30 min the now yellow colored reaction mixture was treated with NH4Cl and extracted 3x with ether. The organic layer was then dried (Na2SO4) and concentrated in vacuo. A 2 L column was loaded slightly less than halfway with silica, and the compound was loaded with toluene. A 20% EtOAc/Hexanes isocratic column condition was used. A yellow oil was isolated (1.19 g, 50% yield) as an inconsequential mixture of E/Z diastereomers. TfO MeO OMEM 111 TLC (30% EtOAc/Hexanes): Rf 0.44 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 6.43 (d, J = 13.0 Hz, 1H), 5.99 (d, J = 6.5 Hz, 1H), 5.57 (dd, J = 5.1, 2.7 Hz, 1H), 5.53 (dd, J = 5.0, 2.7 Hz, 1H), 5.20 – 5.07 (m, 4H), 4.94 – 4.89 (m, 3H), 4.73 (dd, J = 7.6, 1.9 Hz, 2H), 4.31 (d, J = 6.5 Hz, 1H), 3.84 (ddd, J = 8.4, 6.9, 3.7 Hz, 2H), 3.67 – 3.60 (m, 5H), 3.55 (d, J = 5.0 Hz, 7H), 3.39 (d, J = 1.0 Hz, 6H), 3.12 – 3.04 (m, 1H), 2.99 – 2.90 (m, 1H), 2.74 (dd, J = 16.6, 2.7 Hz, 2H), 2.62 (dt, J = 16.3, 3.0 Hz, 1H), 2.52 (dt, J = 15.8, 3.0 Hz, 1H), 2.39 (dt, J = 11.1, 2.2 Hz, 2H), 2.34 – 2.20 (m, 3H), 2.12 (dd, J = 11.0, 2.8 Hz, 1H). 326 Chapter 4 – 3.2.1 bicycle synthesis 13 C NMR (CDCl3, 101 MHz): δ 153.77, 153.71, 151.95, 151.24, 149.62, 149.56, 115.09, 114.27, 109.40, 108.71, 103.01, 101.08, 91.24, 82.87, 82.85, 71.93, 67.28, 67.20, 60.11, 59.17, 59.14, 55.88, 47.06, 46.19, 45.97, 45.83, 44.61, 44.42, 40.96, 40.83. FTIR (Neat, NaCl, thin film): 2937, 1657, 1416, 1211, 1012 cm-1. HRMS (ESI/FD+): calc’d for [M]+ 428.11166, found 428.11188. Preparation of aldehyde 107A: TfO MeO OMEM 111 Acetone, 21 °C, 14 hr TfO TfO TsOH • H2O (1 equiv) H2O (10 equiv) OMEM O 107A OH O 107A’ TsOH monohydrate (1.13 g, 5.95 mmol, 1 equiv) was added as a solid at room temperature (23 °C) to a stirring solution of starting material (2.55 g, 5.95 mmol, 1 equiv) in acetone (95.6 mL, 62.2 M) and water (1.07 mL, 59.5 mmol, 10 equiv). The reaction was monitored with TLC. After 8 hours of monitoring by TLC, TLC indicated that the starting material was just about barely present. 100 mL of aqueous sodium bicarbonate solution was added slowly, and the now quenched solution was transferred to a 500 mL separatory funnel, where it was diluted with 100 mL of ether, the organic phase was separated and collected, and the aqueous phase was extracted with ether three times (3 x 200 mL). The organic phase was then washed with brine. The combined organic phases were dried with Na2SO4, filtered, and concentrated. The crude material was loaded onto a column and flushed with 20-29% EtOAc/Hex, going up by 1% EtOAc with each 500 mL solvent eluted (see photo attached of column setup and number of fractions). MEM deprotection was carefully separated out from the desired product. The product was stored frozen in benzene under N2. If the product is not cleanly separated out from any acidic byproducts, it will 327 Chapter 4 – 3.2.1 bicycle synthesis decompose in the fridge (MEM deprotection), making the column chromatography step very important. TfO OMEM O 107A TLC (30% EtOAc/Hexanes): Rf 0.26 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.76 (s, 1H), 5.65 (s, 1H), 5.20 (p, J = 1.2 Hz, 1H), 5.16 – 5.13 (m, 1H), 4.92 (s, 1H), 4.71 (s, 1H), 3.84 (s, 1H), 3.61 (s, 1H), 3.53 (s, 2H), 3.37 (s, 3H), 2.95 (s, 2H), 2.77 (s, 1H), 2.52 (s, 1H), 2.40 (s, 2H), 2.28 (s, 2H). 13 C NMR (CDCl3, 101 MHz): δ 198.76, 151.49, 149.90, 115.31, 109.70, 91.22, 83.06, 71.86, 67.27, 59.13, 47.66, 46.08, 44.98, 42.26, 41.10. FTIR (Neat, NaCl, thin film): 2922, 1731, 1416, 1238, 1006, 682 cm-1. HRMS (ESI): calc’d for [M+H] 415.10383, found 415.10539. Chiral preparatory HPLC of 107A. TfO TfO IB column 5% IPA/Hexanes OMEM O 25 mg/injection 60 injections O 107A OMEM (R,S)-107A 1.46 g was used with 12 mL hexanes for 120 injections (overestimate) but can add more, vial position set to 81. See experimental notes, below. The procedure began by disconnecting all equipment and refilling the solvents. Solvent A was hexanes, connected to the top tubes, and Solvent B was isopropanol (IPA), connected to the bottom tubes, used at 5%. The method was loaded without overwriting the existing one, and a method such as C18 was selected to start. The flow rate was reduced from 40 to 328 Chapter 4 – 3.2.1 bicycle synthesis 20, and all flow rates were adjusted to 20 as well. Solvent A was flushed by setting its flow to 0, and all systems, including the multi-wavelength detector (MWD), were turned on. The system was flushed with 5% IPA in hexanes, followed by a flush with pure hexanes. Once the pressure dropped, the IB column was connected at both ends, taking care not to overtighten or misalign the fittings. The system was then unhooked from the fraction collector, and a green line was connected instead. Although the method could have been loaded into the sequence table at this point, it was noted that it might be better to recreate it for next time. A first pass using small injections was recommended to check if the retention times were consistent, using 5% IPA in hexanes at a flow rate of 30 mL per minute. Finally, the sample was loaded into an LCMS vial and placed in position 81, with the wavelength detector set to store data at 210 nm and 280 nm. Compounds related to 107A have been enantiomerically resolved by classical resolution. See PhD theses of Jordan Beck and Andrea Stegner for representative examples. Preparation of vinyl bromide 107B. Ni(COD)2 (10 mol%) LiBr (1.5 equiv) TfO OMEM O 107A THF/DMA (3:1, 60 mM), 21 °C, 12 h 70% yield Br OMEM O 107B The starting material was added to an oven-dried 1-dram vial cooled under vacuum and pumped into the glovebox. To a different oven-dried, 2-dram vial was added solid Ni(COD)2 and LiBr. DMA (200 uL) and THF (300 mL, rigorously anhydrous dried over mol. sieves) were added. The vial was capped and stirred for 5 min in the glovebox. Then, the starting material was transferred to the reaction vial in 300 uL of THF. The reaction Chapter 4 – 3.2.1 bicycle synthesis 329 was capped with a rubber septum and taped shut, pumped out of the glovebox and stirred for 16 h at room temperature. The color should be a deep aqua blue. Then it should turn kind of a grey/green. Then a bright green. Monitor by TLC under air-free technique, and an NMR aliquot is valuable information in case the conversion stalls. The TLC is best in 20% acetone/hexanes (due to streakiness in EtOAc/Hex). In order to work this reaction up, it was filtered through a silica plug, eluting with 50% EtOAc/Hex. Then, the resulting organics were subjected to 3 saturated aqueous LiCl washes (3 x 0.3 mL). Column chromatography was performed in 3-10% acetone/hexanes. Br OMEM O 107B TLC (20% Acetone/Hexanes): Rf 0.29 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.81 (dd, J = 1.9, 1.2 Hz, 1H), 5.94 (dd, J = 5.3, 2.5 Hz, 1H), 5.17 (dd, J = 3.2, 1.8 Hz, 1H), 5.10 (t, J = 2.1 Hz, 1H), 4.92 (d, J = 7.6 Hz, 1H), 4.71 (d, J = 7.6 Hz, 1H), 3.83 (ddd, J = 10.6, 4.8, 3.6 Hz, 1H), 3.64 – 3.57 (m, 1H), 3.56 – 3.48 (m, 2H), 3.37 (s, 3H), 3.10 (dd, J = 17.6, 1.2 Hz, 1H), 2.75 – 2.66 (m, 2H), 2.43 – 2.26 (m, 4H), 2.16 (dddd, J = 16.4, 5.3, 2.1, 0.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 200.39, 151.00, 128.93, 128.15, 109.33, 91.14, 83.41, 71.86, 67.19, 59.13, 51.41, 46.65, 45.81, 45.31, 45.09. FTIR (Neat, NaCl, thin film): 2924, 1725, 1453, 1048 cm-1. HRMS (ESI): calc’d for [M+H] 345.0696, found 345.0701. [a]D23 : +103.8 (c 1.0 in CHCl3). 330 Chapter 4 – 3.2.1 bicycle synthesis Preparation of vinyl bromide 121. Ni(OAc)2 • 4H2O (5 mol%) COD (10 mol%) Zn (10 mol%) LiBr (1.5 equiv) TfO MeO2C OMEM THF/DMA (3:1), 22 °C, 15 h Br MeO2C OMEM 121 114 An oven-dried 1-dram vial equipped with a stir bar was brought into an N2-filled glovebox. The vial was charged with Ni(OAc)2 • 4H2O (0.05 equiv), Zn (0.1 equiv), LiBr (1.5 equiv), and COD (0.1 equiv). Anhydrous DMA and THF were added in a 1:3 ratio (0.25 M overall), resulting in a blue color. Enol triflate (50 mg, 116 umol, 1 equiv) was added neat, and the vial was sealed with a Teflon cap, and brought out of the glovebox to stir on the bench (600 rpm) for 24 hours at room temperature. For the workup, 1/2 saturated ammonium chloride (1 mL) was added, and the aqueous residue was extracted three times with ether (2 mL), washed with water (1 mL) four times, washed with brine, dried Na2SO4, filtered, and concentrated in vacuo. For purification, the crude residue was purified by test tube column (15x150) with a 10-20% EtOAc/Hex gradient, going up by 5% each 25 mL to afford 21.4 mg of product, corresponding to 51% yield. Reaction also contained approximately 3% protodebromination. Preparation of carboxylic acid 123. Br Br NaOH (4.8 equiv.) MeO2C OMEM 121 THF/H2O 21 °C, 16 h 85% yield HOOC OMEM 123 A 2M NaOH stock solution was created. Then, the substrate (20 mg, 55.4 umol, 1 equiv) was dissolved in THF to a total concentration of 200 mM. NaOH (4.8 equiv, 133 uL, 2 M) was added in dropwise. After 16 h, the reaction was diluted with Et2O (0.5 mL) and acidified with 2M HCl. The organic layer was collected. Then, the aqueous layer was 331 Chapter 4 – 3.2.1 bicycle synthesis extracted with Et2O (3 x 0.5 mL), dried (Na2SO4), and concentrated to provide 199 in 85% yield. Preparation of carboxylic acid 120: O TfO NaOH (4.8 equiv.) MeO2C OMEM 114 THF/H2O 21 °C, 16 h 5% yield HOOC OMEM 120 A 2M NaOH stock solution was created. Then, the substrate (20 mg, 55.4 umol, 1 equiv) was dissolved in THF to a total concentration of 200 mM. NaOH (4.8 equiv, 133 uL, 2 M) was added in dropwise. After 16 h, the reaction was diluted with Et2O (0.5 mL) and acidified with 2M HCl. The organic layer was collected. Then, the aqueous layer was extracted with Et2O (3 x 0.5 mL), dried (Na2SO4), and concentrated to provide 199’ in 5% yield. O HO2C OMEM 120 TLC (99% EtOAc/1% AcOH): Rf 0.20 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.28 (dd, J = 3.2, 2.1 Hz, 1H), 5.22 (dd, J = 3.2, 2.1 Hz, 1H), 4.94 (d, J = 7.5 Hz, 1H), 4.80 (d, J = 7.5 Hz, 1H), 3.85 – 3.79 (m, 1H), 3.69 – 3.63 (m, 1H), 3.54 (m, 2H), 3.38 (s, 3H), 3.12 (dt, J = 17.9, 3.0 Hz, 1H), 2.81 – 2.70 (m, 2H), 2.60 – 2.53 (m, 2H), 2.31 – 2.17 (m, 2H), 2.02 – 1.89 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 209.75, 173.52, 147.71, 108.82, 91.36, 82.88, 71.85, 67.44, 59.18, 58.30, 43.20, 38.54, 38.17, 35.44. FTIR (MeOH, NaCl, thin film): 2932, 1731, 1415, 1240, 1039 cm-1. HRMS (ESI): calc’d for [M+H]+ 285.13381, found 285.13265. 332 Chapter 4 – 3.2.1 bicycle synthesis Preparation of 8-phenthylmenthol derivative 127. OMEM Cl Me O O Me Ph 115 (1.1 equiv) 126 O Me THF, −78 °C to 21 °C, 5 h Me Me NaH (1.1 equiv) nBuLi (1.1 equiv) HMPA (2 equiv) O 57% yield 2.46 : 1 dr (inconsequential) O O Me Ph OMEM Me 127 To a stirred solution of NaH (1.15mg, 1.1 equiv) from the glovebox in THF (340 uL) at 0 °C was added phenylmenthyl-2-allylacetoacetate (in 44 uL of a 50uL stock solution of 15.8mg). The mixture was stirred at 0 °C for 15 min at which time nbuli (1.1 equiv) was added dropwise. The resulting yellow solution was stirred for 30 min at 0 °C. HMPA (13.7 uL) was then added, followed by addition of 200uL of THF and the reaction was cooled to -78 °C. At -78 °C, 3-iodo-2-((2-methoxyethoxy)methoxy)propene (43 uL, 1M solution) was added. The mixture was warmed to 21 °C and stirred overnight for 9 h. The reaction was quenched by the addition of water (1 mL). The mixture was acidified with saturated NaH2PO4 and extracted with three parts of ether. The combined organic phases were washed with saturated brine solution and dried Na2SO4. Removal of the solvent in vacuo gave 333 mg of crude material. Columned 5-7% acetone/hexanes. Me O O O Me Ph OMEM Me 127 1 H NMR (CDCl3, 400 MHz): 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.25 (m, 5H), 7.16 – 7.11 (m, 1H), 5.59 (dddt, J = 27.0, 17.1, 10.3, 6.9 Hz, 1H), 5.09 – 4.89 (m, 5H), 4.80 (tt, J = 10.8, 4.1 Hz, 1H), 4.14 (dd, J = 5.7, 2.2 Hz, 1H), 3.96 – 3.93 (m, 1H), 3.75 – 3.70 (m, 2H), 3.59 – 3.54 (m, 2H), 3.39 (d, J = 5.8 Hz, 3H), 2.66 – 2.54 (m, 1H), 2.52 – 2.32 (m, 333 Chapter 4 – 3.2.1 bicycle synthesis 4H), 2.28 – 2.20 (m, 2H), 2.03 (dddd, J = 16.2, 9.6, 6.0, 3.5 Hz, 1H), 1.89 – 1.61 (m, 3H), 1.44 (dt, J = 11.7, 3.2 Hz, 1H), 1.29 (d, J = 5.4 Hz, 3H), 1.27 – 1.14 (m, 5H), 0.92 – 0.81 (m, 5H). Preparation of 3.2.1 bicycle 128. Me O O Mn(OAc)3 • 2 H2O (2 equiv) Cu(OAc)2 • H2O (1 equiv) O Me O Me Ph O OMEM O Me Me Ph 21% yield 56% de 127 OMEM O Me EtOH, 60 °C, 15 h OMEM Me O O Me Me Ph 128 The substrate (100 mg) was dissolved in EtOH. Mn(OAc)3 and Cu(OAc)2 were added, followed by a reflux condenser. The dark brown solution was stirred vigorously at 60 °C using an oil bath for 15 h. The mixture was poured slowly into a 60 mL separatory funnel that contained 1 mL of water and 0.1 mL of saturated sodium bisulfite solution (aq). A color change to a dark green was observed, and some bubbling was observed but no exotherm. The aq. phase was extracted with dichloromethane (4 x 1 mL). The collected organic phases were then washed with brine, dried with NaSO4, filtered, and concentrated down in vacuo. The crude material was then loaded onto a column and purified with 20% EtOAc/Hexanes to 20% EtOAc/Hexanes and holding at 25% until all product was eluted (took like 4 column volumes of this), affording the product in 21% yield as a 3.6:1 mixture of diastereomers (~60% de). O Me O O Me OMEM O Me O O Me Me Ph Me Ph 128 OMEM 334 Chapter 4 – 3.2.1 bicycle synthesis 1 H NMR (CDCl3, 400 MHz): δ 7.32 – 7.22 (m, 7H), 7.14 (ddd, J = 8.8, 4.3, 1.7 Hz, 1H), 5.16 (t, J = 2.6 Hz, 1H), 5.05 (t, J = 2.2 Hz, 1H), 4.97 – 4.80 (m, 3H), 4.75 (dd, J = 7.5, 2.6 Hz, 1H), 3.89 – 3.75 (m, 1H), 3.72 – 3.48 (m, 5H), 3.43 (s, 3H), 3.37 (s, 1H), 2.38 (tdd, J = 14.3, 6.6, 3.6 Hz, 3H), 2.32 – 2.23 (m, 2H), 2.22 – 1.98 (m, 6H), 1.84 – 1.59 (m, 6H), 1.33 (d, J = 4.8 Hz, 5H), 1.26 (s, 3H), 1.16 (s, 4H), 0.89 (dd, J = 6.5, 2.9 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 206.11, 206.02, 169.85, 169.77, 152.46, 151.76, 148.64, 148.56, 135.89, 128.06, 127.98, 125.84, 125.76, 125.66, 125.14, 108.13, 108.04, 91.37, 91.19, 82.84, 82.78, 76.62, 76.25, 71.89, 71.84, 67.34, 67.23, 60.62, 60.41, 59.23, 59.17, 50.25, 49.83, 42.02, 41.68, 41.63, 40.87, 40.02, 39.69, 38.12, 37.96, 36.82, 36.53, 35.27, 34.99, 34.79, 34.76, 34.36, 31.45, 31.44, 30.45, 29.84, 29.58, 27.06, 26.76, 26.63, 23.95, 22.83, 21.92, 14.27. FTIR (Neat, NaCl, thin film): 3131, 3001, 1656, 1555, 1067, 967 cm-1. HRMS (ESI): calc’d for [M+H+]: 499.3054, found: 499.3054. Preparation of b-keto ester 125: LDA (2.2 equiv) HMPA (2.2 equiv) Me O Me Br Me (1.1 equiv) O MeO O OMe 108 THF, 0 °C to 21 °C, 2 h 42% yield O 125 207 was prepared according to the procedure by Xu et. al.101 LDA was prepared conventionally: To a solution of THF (70 mL) in a flame-dried schlenk tube was added a newly distilled iPr2NH (5.6 mL, 40.3 mmol), and the formed solution was cooled to -78 °C. To this solution was slowly added a solution of nBuLi (2.5M, 16.2 mL, 40.3 mmol, Chapter 4 – 3.2.1 bicycle synthesis 335 THF), and the mixture was then warmed up to 0 °C, followed by stirring for additional 20 min. To the solution of the above freshly prepared LDA was added the compounds 108 (3 g, 19.2 mmol) at -78 °C in a drop-wise manner, and the formed mixture was then warmed up to 0 °C, and stirred for 30 min. To this solution was sequentially added hexamethylphosphoramide (7.0 mL, 40.3 mmol) and 6 (2.1 mL, 21.1 mmol), and the formed mixture was warmed up to room temperature, and stirred for additional 2 h. The reaction was quenched by addition of a saturated solution of NH4Cl (50 mL), and the mixture was extracted with Et2O (3 x 40 mL). The combined extracts were dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash chromatography on silica gel (EtOAc/hexane =1/20) to give compound 125 as colorless oil. Me O MeO O 125 TLC (20% EtOAc/Hexanes): Rf = 0.59 (p-anisaldehyde). 1 H NMR (500 MHz, CDCl3) δ 5.73 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.14 – 5.01 (m, 2H), 4.73 (s, 1H), 4.65 (s, 1H), 3.72 (s, 3H), 3.57 (t, J = 7.4 Hz, 1H), 2.70 (t, J = 7.6 Hz, 1H), 2.64 (t, J = 7.5 Hz, 1H), 2.60 (t, J = 7.1 Hz, 2H), 2.28 (t, J = 7.5 Hz, 2H), 1.72 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 203.85, 169.78, 144.23, 134.43, 117.58, 110.46, 77.41, 77.16, 76.91, 58.58, 52.44, 40.60, 32.38, 31.15, 22.68. HRMS (ESI): calc’d for [M+H+]: 211.1334, found: 211.1333. 336 Chapter 4 – 3.2.1 bicycle synthesis Preparation of a-brominated b-keto ester 132: Me Me O NaH (1.1 equiv) NBS (1.2 equiv) MeO THF, 0 °C to 21 °C, 2 h O 125 O MeO O 100% yield Br 132 To a suspension of NaH (60% oil dispersion, 1.23 g, 30.8 mmol) in THF (90 mL) was added slowly compound 6a (5.45 g,25.6 mmol) in THF (10 mL) at 0 °C. After 1.0 h, Nbromosuccinimide (5.03 g, 28.2 mmol) was added in one portion at –78 °C. The mixture was stirred for 3 h. After removal of THF, the residue was extracted with ether. The combined extracts were washed with water, dried over MgSO4 and then concentrated. The crude product was purified by filtering through a silica plug, eluting with 10% EA/hexanes to isolate a white solid. O O OMe Br Me 132 TLC (20% EtOAc/Hexanes): Rf 0.71 (UV, p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.83 – 5.71 (m, 1H), 5.19 (s, 1H), 5.15 (d, J = 6.4 Hz, 1H), 4.75 (s, 1H), 4.69 (s, 1H), 3.80 (s, 3H), 2.99 (t, J = 6.7 Hz, 2H), 2.92 (t, J = 7.3 Hz, 1H), 2.82 – 2.72 (m, 1H), 2.32 (t, J = 7.6 Hz, 2H), 1.73 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 199.55, 167.89, 144.06, 131.75, 120.42, 110.71, 67.68, 53.86, 41.94, 37.34, 32.16, 22.70. FTIR (Neat, NaCl, thin film): 3080, 2954, 1737, 1714, 1434, 1233, 926 cm-1. HRMS (ESI): calc’d for [M+H]+ 289.0433, found 289.0432. 337 Chapter 4 – 3.2.1 bicycle synthesis Preparation of bromine atom-transfer product 130: Me Me O O tBu MeO O Br 132 N N Me O 206 (1.21 equiv) tBu Mg(ClO4)2 (1.1 equiv) Et3B (3 equiv) O2 (3 equiv) Mol. sieves (5 equiv) O MeO2C Me Br 130 toluene, −78 °C, 10 h 14% yield Chiral ligand 2,2'-isopropylidenebis[(4s)-4-tert-butyl-2-oxazoline] (4, 49 mg, 0.23 mmol) and Mg(ClO4)2 (49 mg, 0.22 mmol) were mixed in dry toluene (10 mL) for 0.5 h at room temperature. Then substrate 132 (60 mg, 0.21 mmol) was added. The mixture was stirred at room temperature for 15 min and cooled to –78 °C. After 30 min, Et3B (1.0 M in hexane, 0.6 mL, 0.6 mmol) and O2 gas (4 mL) were added via syringe. When the reaction was completed, the mixture was filtered through a thin pad of silica gel and then concentrated. The crude product was purified by prep plate in 20% EA/hex to afford 14% yield product, along with 22% starting material, 10% protodebromination, 34% monocyclization and bromine radical capture. O MeO2C Me Br 130 TLC (20% EtOAc/Hexanes): Rf 0.62 (p-anisaldehyde, yellow). 1 H NMR (CDCl3, 400 MHz): δ 3.75 (s, 3H), 3.63 (ddd, J = 21.4, 9.7, 4.3 Hz, 1H), 3.39 – 3.22 (m, 1H), 2.73 – 2.34 (m, 4H), 2.23 – 2.06 (m, 2H), 1.99 – 1.90 (m, 1H), 1.88 – 1.76 (m, 1H), 1.75 – 1.63 (m, 1H), 1.15 (s, 3H). 338 Chapter 4 – 3.2.1 bicycle synthesis 13 C NMR (101 MHz, CDCl3): δ 207.72, 207.31, 171.99, 171.82, 63.59, 52.36, 49.93, 48.81, 46.29, 45.09, 43.21, 42.84, 40.83, 39.60, 38.30, 38.07, 34.78, 34.62, 33.25, 32.96, 24.81, 21.43. FTIR (Neat, NaCl, thin film): 3083, 2950, 1637, 1514, 1434, 1223, 947 cm-1. HRMS (ESI): calc’d for [M+H]+ 289.0433, found 289.0430. Preparation of 3.2.1 bicycle 131’: O O DBU (2.5 equiv) MeO2C Me Br 209 Benzene, 90 °C, 24 h 30% yield 79% ee MeO2C Me 131’ The starting material (5 mg, 1 equiv) was dissolved in benzene and DBU (2.5 equiv) was added. The reaction was heated in a sealed vial at 90 °C overnight for 24 h. Then, to work the reaction up, 0.3 mL of NH4Cl was added, and the aq. phase was extracted three times with diethyl ether. Drying with sodium sulfate and concentrating, followed by prep TLC with 20% EA/hex provided 2 mg (30% yield) of product 3.2.1 bicycle. O MeO2C Me 131’ TLC (20% EtOAc/Hexanes): Rf 0.40 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.06 (t, J = 2.2 Hz, 1H), 5.00 (t, J = 2.6 Hz, 1H), 3.75 (s, 3H), 2.98 – 2.90 (m, 1H), 2.83 (d, J = 18.0 Hz, 1H), 2.55 – 2.44 (m, 1H), 2.36 (dd, J = 15.6, 5.8 Hz, 1H), 2.09 (s, 2H), 1.79 (td, J = 12.4, 6.6 Hz, 1H), 1.72 – 1.64 (m, 1H), 1.24 (s, 3H). 339 Chapter 4 – 3.2.1 bicycle synthesis 13 C NMR (101 MHz, CDCl3): δ 207.76, 171.95, 153.72, 106.54, 62.37, 52.30, 47.19, 44.17, 40.48, 40.11, 35.75, 22.92. FTIR (Neat, NaCl, thin film): 2954, 2871, 2744, 1714, 1434, 1329, 1240, 1080, 897 cm1 . HRMS (ESI): calc’d for [M+H]+ 231.0991, found 231.0993. Preparation of 3-chloro-2-[(diethoxyphosphoryl)oxy]-1-propene (134): O O Cl Cl 133 O P(OEt)3 (1 equiv) 60 °C to 100°C, 3 h 91% yield P OEt OEt Cl 134 A 25-mL, single-necked, round-bottomed flask equipped with a thermocouple, a reflux condenser, a nitrogen inlet, and a magnetic stirring bar was charged with 1,3dichloroacetone (5.93 g, 44.4 mmol). The solid was warmed to 40 °C and the solid melted. Then, it was moved to a water bath and triethyl phosphite (8.01 mL, 46.7 mmol) was syringed into the flask, under vigorous stirring, at such a rate that the temperature was maintained between 40 and 50 °C. To increase the rate at which triethylphosphite could be added, the flask was removed from the oil bath and put into a room temperature water bath. Following addition of triethylphosphite, the reaction mixture was then stirred for 1 h at 60 °C, 1 h at 80 °C,and then 1 h at 100 °C. Bulb-to-bulb distillation (kugelrohr) of the crude product with full high vac (14 mTorr) and 115 °C on the kugelrohr oven with three bulbs (two in the oven, one over ice) gave 9.73 g from the second bulb (91% yield). O O Cl 134 P OEt OEt 340 Chapter 4 – 3.2.1 bicycle synthesis TLC (45% EtOAc/Hexanes): Rf 0.28 (p-anisaldehydealdehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.10 – 5.08 (m, 1H), 4.91 (t, J = 2.3 Hz, 1H), 4.24 – 4.16 (m, 4H), 4.06 (s, 2H), 1.36 (td, J = 7.1, 1.2 Hz, 6H). 31 P NMR (162 MHz, CDCl3): δ -6.94. 13 C NMR (101 MHz, CDCl3): δ 150.40, 101.40, 64.88, 44.19, 16.21. FTIR (Neat, NaCl, thin film): 2984, 1653, 1280, 1163, 1030, 926 cm-1. HRMS (ESI): calc’d for [M+H]+ 229.0390, found 229.0392. Preparation of vinyl phosphonate ester 135: NaH (1.1 equiv), 0 °C, 15 min then nBuLi, 0 °C, 45 min then HMPA (2 equiv) O O O Me Cl MeO O 108 O P OEt O OEt 134 THF, −78 °C to 21 °C, 16 h 38% yield P OEt OEt O MeO O 135 An oven-dried 250 mL round bottom flask and large magnetic stir bar were pumped into the glovebox and charged with NaH (90% purity). Then, anhydrous THF was added, and the flask was capped with a rubber septum, brought out of the glovebox, put under nitrogen, and cooled to 0 °C. To the stirring solution at 0 °C was added a 1M solution of starting material in anhydrous THF dropwise over 2 min. The deprotonation was evidently exothermic, as bubbling and melting of the ice in the ice bath was observed. The resulting enolate was stirred for 15 min at 0 °C. Then, to the stirring solution at 0 °C was added nBuLi dropwise over 5 min. A change in color from grey/pale yellow to a orange was observed. The double enolate was stirred for 45 min at 0 °C, after which time HMPA (2 equiv, distilled over CaH2 and stored in a Schlenk with activated molecular sieves) was Chapter 4 – 3.2.1 bicycle synthesis 341 added dropwise over 1 min. The ice bath was then replaced by a −78 °C dry-ice/acetone bath, and to the resulting diluted solution at −78 °C was added the electrophile dropwise over 45 min neat. The resulting orange solution was stirred for 3.5 h and gradually allowed to warm to 0 °C upon which a color change from dark orange to bright yellow was observed. Following 3.5 h, 50 mL of water was added. The solution was stirred for 5 min, then transferred over to a separatory funnel and extracted with diethyl ether (3 x 20 mL). The combined organic phases were washed with brine, dried with NaSO4, and filtered. The organic phases were then concentrated on the rotatory evaporator and loaded onto the 100 mL column packed 70% full with silica. The crude material was loaded onto a column and purified with a 30%, 35%, 40%, 42.5%, 45%, 47.5%, 50% then flushed with 100% EtOAc to afford 38% yield of pure product as a clear or pale-yellow oil. O O P OEt OEt O MeO O 135 TLC (45% EtOAc/Hexanes): Rf 0.20 (p-anisaldehydealdehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.72 (ddt, J = 17.1, 10.1, 6.8 Hz, 1H), 5.13 – 5.01 (m, 2H), 4.84 (t, J = 2.1 Hz, 1H), 4.53 (s, 1H), 4.21 – 4.11 (m, 4H), 3.72 (s, 3H), 3.57 (t, J = 7.4 Hz, 1H), 2.87 – 2.66 (m, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.35 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 202.97, 169.65, 154.09, 134.22, 117.80, 97.90, 64.49, 58.42, 52.62, 39.24, 32.34, 28.50, 16.26. FTIR (Neat, NaCl, thin film): 3477, 2983, 1735, 1654, 1438, 1273, 1050, 860 cm-1. HRMS (ESI): calc’d for [M+H]+ 349.1411, found 349.1444. 342 Chapter 4 – 3.2.1 bicycle synthesis Preparation of 3.2.1 bicycle 136: O O P OEt OEt O Mn(OAc)3 (2.0 equiv) Cu(OAc)2 (1.0 equiv) MeO AcOH, 22 °C, 15 h O 135 O O MeO2C 79% yield O P OEt OEt 136 To a stirred solution of Mn(OAc)3 2H2O (154 mg, 574 umol) and Cu(OAc)2 H2O (57.3 mg, 574 umol) in 2.5 mL of glacial acetic acid was added the starting material (100 mg, 287 umol) in 0.85 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 h at which time 2 mL of water was added. A solution of 10% NaHSO3 (1 mL) was added dropwise to the mixture to decompose any residual Mn(OAc)3. The resulting solution was extracted with three 3-mL portions of methylene chloride. The combined organic extracts were poured into a 125 mL separatory funnel and saturated NaHCO3 solution was added dropwise slowly (CAUTION: lots of bubbling neutralizing AcOH) and dried over anhydrous Na2SO4. Removal of the solvent invacuo gave 70 mg of crude product which was purified by silica gel chromatography (40% EA/hexanes). O O MeO2C O P OEt OEt 136 TLC (45% EtOAc/Hexanes): Rf 0.17 (p-anisaldehydealdehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.43 – 5.40 (m, 1H), 5.22 (t, J = 2.6 Hz, 1H), 4.16 – 4.07 (m, 4H), 3.74 (s, 3H), 3.02 (dt, J = 18.1, 2.9 Hz, 1H), 2.79 – 2.70 (m, 2H), 2.66 (dd, J = 12.0, 2.1 Hz, 1H), 2.56 – 2.44 (m, 3H), 2.14 – 2.05 (m, 1H), 1.34 (tdd, J = 7.1, 2.6, 1.1 Hz, 6H). 343 Chapter 4 – 3.2.1 bicycle synthesis 13 C NMR (101 MHz, CDCl3): δ 204.91, 170.48, 147.73, 109.40, 84.95, 64.08, 60.84, 52.52, 42.78, 37.70, 36.57, 34.91, 16.21. FTIR (Neat, NaCl, thin film): 2983, 2953, 1744, 1717, 1269, 1246, 1026, 971 cm-1. HRMS (ESI): calc’d for [M+H]+ 347.1254, found 347.1261. Preparation of a-brominated b-keto ester 138: O O O P OEt OEt O NaH (1.1 equiv) NBS (1.2 equiv) THF, −78 °C to 22 °C, 3 h MeO O 36% yield 135 O P OEt OEt O MeO O Br 138 To a suspension of NaH (5.74 mg, 144 umol, 60% in mineral oil) in 0.4 mL of THF was added the starting material dropwise in a solution of THF (0.1 mL) at 0 °C. After 1 hour stirring at 0 °C, NBS stock solution (1M) was added in. The vial was shielded form light with aluminum foil. The mixture was stirred at −78 °C for 2 h. Following completion by TLC, the mixture was treated with ammonium chloride at −78 °C, allowed to warm to 21 °C, and extracted with ether three times, and concentrated down. The crude resideue was columned 0 to 2.5% to 5% ether in DCM and kept at 5% until all product was eluted to isolate 138 as an orange oil (3 mg, 36% yield). O O P OEt OEt O MeO O Br 138 TLC (5% ether/DCM): Rf 0.40 (p-anisaldehydealdehyde). 344 Chapter 4 – 3.2.1 bicycle synthesis 1 H NMR (CDCl3, 400 MHz): δ 5.78 (ddt, J = 15.9, 11.0, 7.1 Hz, 1H), 5.23 – 5.15 (m, 2H), 4.89 (t, J = 2.2 Hz, 1H), 4.58 (td, J = 2.1, 1.0 Hz, 1H), 4.19 (tt, J = 7.6, 6.6 Hz, 4H), 3.83 (s, 3H), 3.12 – 2.87 (m, 4H), 2.58 – 2.48 (m, 2H), 1.38 (td, J = 7.1, 1.1 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 198.70, 167.75, 153.83, 153.75, 131.60, 120.55, 98.15, 98.11, 67.28, 64.57, 64.51, 53.94, 41.90, 36.14, 30.45, 29.59, 29.53, 16.27, 16.20. FTIR (Neat, NaCl, thin film): 2982, 2911, 1727, 1275, 1031 cm-1. HRMS (ESI): calc’d for [M+H]+ 427.0515, found 427.0531. Preparation of a-selenylated b-keto ester 139: O O O P OEt OEt O NaH (1.1 equiv) PhSeBr (1.2 equiv) THF, −78 °C to 22 °C, 3 h MeO O 52% yield 135 O P OEt OEt O MeO O SePh 139 To a suspension of NaH (5.74 mg, 144 umol, 60% in mineral oil) in 0.4 mL of THF was added the starting material dropwise in a solution of THF (0.1 mL) at 0 °C. After 1 hour stirring at 0 °C, PhSeBr stock solution (1M) was added in. The vial was shielded form light with aluminum foil. The mixture was stirred at -78 °C for 2 h. Following completion by TLC, the mixture was treated with ammonium chloride, allowed to warm to rt, and extracted with ether three times, and concentrated down. The crude resideue was columned 0 to 2.5% to 5% ether in DCM and kept at 5% until all product was eluted to isolate 139 as an clear oil (5 mg, 52% yield). 345 Chapter 4 – 3.2.1 bicycle synthesis O O P OEt OEt O MeO O SePh 139 1 H NMR (300 MHz, CDCl3): δ 7.51 – 7.27 (m, 5H), 5.89 (ddt, J = 17.2, 10.3, 6.9 Hz, 1H), 5.19 – 5.05 (m, 2H), 4.87 (t, J = 2.2 Hz, 1H), 4.61 – 4.53 (m, 1H), 4.26 – 4.08 (m, 4H), 3.77 (s, 3H), 3.16 (ddd, J = 17.0, 9.3, 6.2 Hz, 1H), 2.77 – 2.60 (m, 2H), 2.59 – 2.44 (m, 3H), 1.36 (tt, J = 7.1, 1.0 Hz, 6H). Preparation of a-chloro b-keto ester 140: O O O P OEt OEt O NaH (1.1 equiv) NCS (1.2 equiv) THF, −78 °C to 22 °C, 3 h MeO O 62% yield O P OEt OEt O MeO O 135 Cl 140 To a suspension of NaH (5.74 mg, 144 umol, 60% in mineral oil) in 0.4 mL of THF was added the starting material dropwise in a solution of THF (0.1 mL) at 0 °C. After 1 hour stirring at 0 °C, NCS stock solution (1M) was added in. The vial was shielded form light with aluminum foil. The mixture was stirred at −78 °C for 2 h. Following completion by TLC, the mixture was treated with ammonium chloride, allowed to warm to room temperature, and extracted with ether three times, and concentrated down. The crude resideue was columned 0 to 2.5% to 5% ether in DCM and kept at 5% until all product was eluted to isolate 140 as an orange oil (3.5 mg, 62% yield). 346 Chapter 4 – 3.2.1 bicycle synthesis O O P OEt OEt O MeO O Cl 140 1 H NMR (300 MHz, CDCl3): δ 5.90 – 5.60 (m, 1H), 5.22 – 5.09 (m, 2H), 4.87 (t, J = 2.2 Hz, 1H), 4.56 (tt, J = 2.0, 0.9 Hz, 1H), 4.17 (dq, J = 8.2, 7.1 Hz, 4H), 3.88 – 3.75 (m, 3H), 3.09 – 2.78 (m, 4H), 2.56 – 2.44 (m, 2H), 1.36 (td, J = 7.1, 1.1 Hz, 6H). Preparation of acyl imidazole 148: O N HO N O N N N THF/DCM (3:1) 76% yield O N 148 A 1L flask with a magnetic stir bar and an addition funnel was flame dried under vacuum. Following cooling, 83.8 g of CDI (1.5 equiv, 517 mmol) was added. The apparatus was evacuated and backfilled and 517 mL of THF was added in. Then, into the addition funnel was added 172 mL of DCM and 23.4 mL of allyl alcohol (344 mmol, 1 equiv). The reaction was cooled to 0 °C. The allyl alcohol mixture was added in dropwise over 30 min. Then, the reaction was stirred for 2 more hours at 0 °C. After completion of 2 hrs. of stirring at 0 °C, the septum was removed, the stir bar was removed, and the solvent was evacuated. The crude oil was loaded onto a column and columned with a 30-50% EA/hex gradient, moving up by 10% each column volume until reaching 50% EA/hex. O N O N 148 TLC (50% EtOAc/Hexanes): Rf 0.25 (p-anisaldehyde). FTIR (Neat, NaCl, thin film): 3129, 1760, 1474, 1394, 1166, 998, 945, 769 cm-1. 347 Chapter 4 – 3.2.1 bicycle synthesis HRMS (ESI): calc’d for [M+H]+ 153.0659, found 153.0662. Preparation of b-keto ester 146: LDA (1.2 equiv) then 1 : 0.27 O O N N O O OH O (1.1 equiv) THF, −78 °C to 22 °C, 12 h O O O O O O O O O 73% yield 147 146 To a flame dried 1L flask with a stir bar under N2 was added diisopropylamine (50.2 mL, 358 mmol) and THF (100 mL), and it was cooled to −78 °C. nBuLi (143 mL, 2.5 M, 358 mmol) was added in dropwise by use of an addition funnel over 10 minutes. After the addition, the LDA was stirred for 15 min at −78 ºC, warmed to 0 °C for 15 min, then cooled back to −78 °C. The starting material in 150 mL of THF (299 mmol, 2 M) was added dropwise over 10 min. The resulting solution was stirred for 30 min before the electrophile (50.0 g, 329 mmol) was added dropwise at −78 ºC neat over 60 min using a syringe pump. Reaction turned orange then brown as carbamate was added. Reaction was kept at −78 °C for a few hours and slowly allowed to warm to room temperature. After 3 hours at −78 °C, TLC shows some conversion, but not a lot. I think extended reaction time and slowly increasing the temperature to room temperature is important. Reaction was quenched with 300 mL NaHCO3. The organic layer was separated out from the aqueous layer. The remaining aqueous layer was extracted three times with DCM (3 x 300 mL). The organics were washed with brine, dried over MgSO4, filtered through celite, then concentrated. The crude was subjected to column chromatography (5 to 12% EtOAc/Hex) 348 Chapter 4 – 3.2.1 bicycle synthesis to afford the product as a pale oil (52.3 g, 218 mmol, 73% yield) as a 1:0.27 mixture of enol to keto forms. 1 OH : 0.27 O O O O O O O O O 146 TLC (25% EtOAc/Hexanes): Rf 0.48 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 12.14 (s, 1H), 6.01 – 5.82 (m, 1H), 5.32 (dd, J = 17.2, 1.5 Hz, 1H), 5.24 (dd, J = 10.5, 1.3 Hz, 1H), 4.64 (dt, J = 5.6, 1.4 Hz, 3H), 4.07 – 3.94 (m, 5H), 2.55 – 2.47 (m, 4H), 1.84 (t, J = 7.0 Hz, 2H). 13 C NMR (CDCl3, 101 MHz) δ 204.73, 171.84, 171.61, 169.14, 132.18, 131.91, 118.71, 118.26, 107.34, 106.75, 95.33, 65.99, 65.06, 64.97, 64.92, 64.72, 54.11, 38.30, 36.67, 34.54, 32.81, 30.41, 28.08. FTIR (Neat, NaCl, thin film): 2944, 2884, 1744, 1719, 1650, 1421, 1241, 1059, 998, 844 cm-1. HRMS (ESI): calc’d for [M+H]+ 241.1071, found 241.1078. Preparation of vinyl bromide 145A: OH O O O 2,3-dibromopropene (1.5 equiv) Cs2CO3 (2 equiv) KI (2 equiv) Acetone, 22 °C, 4 h O O O O O O Br 87% yield 146 145A A 3-neck, round bottom flask with a mechanical stirrer were set up and a N2 inlet was charged to the flask to allow for a continuous stream of N2. To the starting material (20.0 Chapter 4 – 3.2.1 bicycle synthesis 349 g, 83.2 mmol, 1 equiv.) was added 400 mL of acetone. Then, KI (27.6 g, 166 mmol, 2 equiv.) and Cs2CO3 (54.2 g, 166 mmol, 2 equiv.) were added in sequentially. 155 mL of acetone were used to rinse all of the salts into the flask to allow for a total reaction concentration of 150 mM. Then, 2,3-dibromopropene (12.7 mL, 104 mmol, 80% technical grade Sigma Aldrich, 1.25 equiv.) was added in dropwise. The reaction was stirred overnight with the mechanical stirrer for 12 h. The reaction was quenched by the addition of H2O (200 mL) and saturated NaHCO3 aqueous solution (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 300 mL), the organic layers were combined, washed with saturated brine (300 mL), dried with anhydrous Na2SO4, filtered, and subjected to column chromatography (10 to 20% EA/hex) to afford 26.0 g of pale-yellow product, corresponding to 87% yield. O O O O O Br 145A TLC (25% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.91 (dd, J = 16.9, 10.7 Hz, 1H), 5.66 (s, 1H), 5.57 (d, J = 1.4 Hz, 1H), 5.38 – 5.22 (m, 2H), 4.67 – 4.57 (m, 2H), 4.06 – 4.00 (m, 1H), 3.97 (dd, J = 5.5, 1.8 Hz, 3H), 3.09 (d, J = 15.0 Hz, 1H), 3.03 – 2.92 (m, 2H), 2.74 (dd, J = 14.1, 3.1 Hz, 1H), 2.57 – 2.50 (m, 1H), 2.05 – 1.96 (m, 3H). 13 C NMR (CDCl3, 101 MHz): δ 204.88, 170.94, 131.58, 127.22, 122.47, 119.09, 106.76, 66.52, 65.00, 64.49, 58.69, 44.85, 40.69, 37.68, 34.93. FTIR (Neat, NaCl, thin film): 3508, 2957, 2891, 1731, 1429, 1367, 1098, 936 cm-1. HRMS (ESI): calc’d for [M+H]+ 359.0489, found 359.0490. 350 Chapter 4 – 3.2.1 bicycle synthesis Preparation of ligand (R)-(CF3)3-tBuPhox:53 CF3 CF3 O O Mg0 H P OEt EtO Et2O Br highly exothermic CF3 CF3 66% yield OH OH H 2N Cl DCM, 23 °C, 12 h O Et2O MgBr F3C CF3 oxalyl chloride (2.0 equiv) DMF (8 mol%) Br H P CF3 Na2CO3 (3.0 equiv) tBu Br O 100% yield 85% yield OH H N DCM/H2O Br O tBu O H P CF3 (1.3 equiv) CuI (1.0 equiv) N,N’-dimethylethylenediamine (3.0 equiv) CsCO3 (3.7 equiv) F3C CF3 MsCl (1.2 equiv) NEt3 (2.4 equiv) DCM, 40 °C, 20 h O Br N (R) tBu 100% yield toluene, 110 °C, 15 h CF3 CF3 Ph2SiH2 (7 equiv) O O PAr2 N tBu 70% yield O 140 °C, X h PAr2 N (R) 50-80% yield (R) tBu Preparation of diketone 144A: O O O O O toluene, 21 °C, 48 h Br 145A O Pd2dba3 (5 mol%) (R)-(CF3)-tBu-Phox (12.5 mol%) O pTsOH • H2O (3 equiv) Br O O 86% ee acetone/water (15:1), reflux, 12 h 69% yield over 2 steps 157 Br O 144A In the glovebox, (R)-(CF3)3-tBuPhox (0.125 equiv) and Pd2dba3 (0.05 equiv) were weighed out in an oven-dried 1000 mL flask equipped with a magnetic stir bar. Toluene was added in (800 mL). The reaction was stirred at room temperature for 30 min before the starting material (10.0 g, 50 mL) was added in. The flask was stirred at room temperature for 3 days. After 1 day, the reaction was completely converted. The crude reaction mixture was hooked up to a rotavap to get off all the toluene. The crude was NMR'd and purified by Chapter 4 – 3.2.1 bicycle synthesis 351 silica gel chromatography 10-20% EtOAc/Hex to afford 8.2 g of mixed product with ligand. The mixture was carried forward to the next step. SFC analysis on a pure fraction taken from column shows 86% ee. SFC method: PAPCl_S3C6_10_05min. O Br O O 157 TLC (20% EtOAc/Hexanes): Rf 0.48 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.73 – 5.51 (m, 3H), 5.10 (d, J = 8.0 Hz, 2H), 4.01 (d, J = 2.1 Hz, 4H), 2.93 (d, J = 9.1 Hz, 2H), 2.51 (d, J = 7.4 Hz, 2H), 2.03 (d, J = 12.8 Hz, 4H). 13 C NMR (CDCl3, 101 MHz): δ 204.88, 170.94, 131.58, 127.22, 122.47, 119.09, 106.76, 66.52, 65.00, 64.49, 58.69, 44.85, 40.69, 37.68, 34.93. FTIR (Neat, NaCl, thin film): 3059, 2912, 1660, 1431, 1263, 843, 742 cm-1. HRMS (ESI): calc’d for [M+H]+ 315.0590, found 315.0594. [a]D23 : +16.0 (c 1.0 in CHCl3). SFC data for racemic 157: Chapter 4 – 3.2.1 bicycle synthesis 352 SFC data for enantioenriched 157: The deprotection of 157 was telescoped forward with analytically impure material from the Tsuji-Stoltz decarboxylative allylation due to difficulty in separating the substrate from the ligand in the prior purification. Assuming 70% yield from the Tsuji-Stoltz reaction, the starting material (6.10 g, 19.4 mmol, 1 equiv.) was dissolved in acetone. To do this, adding in 10 mL of acetone and sonicating at 40 °C could be performed. The dissolved starting material was added into a 1 L flask equipped with a magnetic stir bar and charged with acetone/H2O (15 : 1, 914 mL / 61 mL, 20 mM total concentration). pTsOH monohydrate (11.0 g, 58.1 mmol, 3.0 equiv.) was added in, and the reaction was fitted with a reflux condenser and heated to reflux for 12 h. After 12 h the reaction was cooled to room temperature and quenched with sat. aq. NaHCO3 (250 mL, pH paper shows neutral pH = 7). The crude mixture was diluted with 400 mL of Et2O and a white solid (probably pTsOH) was filtered off. The phases were separated; the aq. phase was extracted with Et2O (3 x 100 mL). The combined organic phases were washed with brine twice (2 x 300 mL). The organic phase was dried over anhydrous Na2SO4 and reduced in vacuo. The 353 Chapter 4 – 3.2.1 bicycle synthesis residue was purified by flash column chromatography (10-30% EtOAc in hexanes) to diketone 220A (5.20 g, 19.2 mmol, 69% yield over 2 steps) as a colorless (or slightly pale yellow) oil. O Br O 144A TLC (25% EtOAc/Hexanes): Rf 0.39 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.73 – 5.56 (m, 3H), 5.20 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 16.9 Hz, 1H), 3.12 (d, J = 14.5 Hz, 1H), 3.05 – 2.89 (m, 2H), 2.86 – 2.49 (m, 5H), 2.39 (dd, J = 13.9, 7.0 Hz, 1H), 2.17 (dd, J = 13.9, 7.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 210.76, 208.48, 131.27, 127.80, 122.79, 121.24, 50.39, 47.66, 46.59, 42.64, 37.97, 35.94. FTIR (Neat, NaCl, thin film): 2975, 2912, 1712, 1623, 1429, 1296, 1250, 1164, 989 cm1 . HRMS (ESI): calc’d for [M+H]+ 271.0328, found 271.0331. [a]D23 : +21.1 (c 1.0 in CHCl3). Preparation of 3.2.1 bicycle 162: Br O SmI2 (2 equiv) HMPA (10.5 equiv) Br O 144A O THF, 22 °C, 16 h HO 70% yield single diastereomer (unassigned stereochemistry) Me 162 A mixture of starting material in THF (1.2 mL) was added to a solution of SmI2 in THF (0.10 M) containing HMPA (10.5 equiv). The reaction was stirred at 23°C for 12 h 354 Chapter 4 – 3.2.1 bicycle synthesis and then quenched with sat. NH4Cl and extracted with ether. The organic extracts were washed with water, 3% Na2S2O3, and brine and dried over MgSO4. Filtration and concentration gave a crude oil which was purified via prep plate in 50% EA/hexanes to provide 56% isolated yield of the 5-exo trig product 162. Br O HO Me 162 TLC (36% EtOAc/Hexanes): Rf 0.30 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.51 (d, J = 6.9 Hz, 2H), 2.80 (d, J = 15.5 Hz, 1H), 2.64 (d, J = 15.9 Hz, 1H), 2.59 – 2.47 (m, 1H), 2.43 – 2.22 (m, 4H), 2.13 – 2.03 (m, 1H), 1.85 – 1.74 (m, 2H), 1.30 – 1.23 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 211.43, 129.55, 121.27, 78.56, 52.94, 48.14, 43.43, 41.95, 38.43, 34.27, 32.26, 14.01. FTIR (Neat, NaCl, thin film): 3420, 2940, 1614, 1513, 1332, 1112, 919 cm-1.\ HRMS (ESI): calc’d for [M+H]+ 273.0485, found 273.0489. Preparation of 3.2.1 bicycle 163: O NiBr2•dme (5 mol%) terpy (5 mol%) Mn0 (2 equiv) Br O 144A DMA (0.1 M), 50 °C, 5 h 68% yield O HO 163 In a nitrogen-filled glovebox, Mn0 (1.50 g, 27.2 mmol, 2 equiv.) and 2,2':6',2''-terpyridine (159 mg, 680 umol, 0.05 equiv.) and NiBr2•dme (210 mg, 680 umol, 0.05 equiv.) were weighed out into an oven-dried 500 mL round-bottom flask equipped with a large stir bar. Chapter 4 – 3.2.1 bicycle synthesis 355 DMA (108 mL) was added. A color change from a turquoise lighter green to a much darker green upon stirring for 30 minutes at room temperature in order to allow ligation of the 2,2':6',2''-terpyridine to the Ni catalyst. Then, the starting material as a stock solution in DMA was added in (3.69 g, 15 mL). The flask was capped, taped, and pumped out of the glovebox. It was heated in an oil bath at 50 °C for 17 h. After 17 h, the reaction was cooled to 0 °C. Then, it was quenched with sat. aq. NH4Cl (100 mL). Add the NH4Cl slowly, as reaction with leftover Mn0 was observed (evolution of H2 gas), and following the addition, stir vigorously open to air for 5 min. The reaction was filtered to remove Mn salts and washed with water (~100 mL) and 60 mL of Et2O. The organic phase was collected, and the remaining aqueous layer was three times more (3 x 100 mL). The combined organic extract was washed with 10% LiCl three times (50 mL x 3), brine twice (50 mL x 2), and dried over anhydrous Na2SO4, filtered, and the solvent was blown off using a strong stream of N2 for 120 minutes. This compound is volatile and cannot be concentrated using a rotavap. The crude reaction was loaded onto a column and subject to a very generous gradient of 50 to 75% ether/hexanes to elute the product rather quickly. The product-containing fractions were concentrated again by blowing off the solvent using a strong stream of N2 to isolate the product 163 as a white solid (1.77 g, 68% yield). Product is volatile but can be left uncapped overnight to fully dry rather than high-vac'd. Only use volatile solvents like hexanes or ether so that they come off easier. O HO 163 TLC (36% EtOAc/Hexanes): Rf 0.36 (p-anisaldehyde). Chapter 4 – 3.2.1 bicycle synthesis 1 356 H NMR (CDCl3, 400 MHz): δ 5.87 – 5.71 (m, 1H), 5.29 (t, J = 2.7 Hz, 1H), 5.10 – 5.02 (m, 3H), 2.57 (dt, J = 17.9, 2.6 Hz, 1H), 2.47 – 2.36 (m, 3H), 2.29 (dd, J = 12.3, 6.9 Hz, 2H), 2.08 (td, J = 11.7, 7.6 Hz, 1H), 1.97 – 1.86 (m, 3H), 1.75 (s, 1H). 13 C NMR (CDCl3, 101 MHz): δ 211.52, 153.74, 134.55, 118.15, 106.74, 78.95, 51.95, 48.18, 39.24, 38.70, 37.75, 35.65. FTIR (DCM, NaCl, thin film): 3418, 2933, 1711, 1432, 1332, 1132, 917 cm-1. HRMS (ESI): calc’d for [M+H]+ 193.1223, found 193.1230. [a]D23 : +15.7 (c 1.0 in CHCl3). Melting Point: 57-59 °C Other products in the reaction: O O 167 TLC (36% EtOAc/Hexanes): Rf 45 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 6.18 (d, J = 9.8 Hz, 1H), 5.69 (t, J = 5.0 Hz, 1H), 4.97 (s, 1H), 4.87 (s, 1H), 2.91 – 2.77 (m, 2H), 2.72 – 2.63 (m, 3H), 2.63 – 2.54 (m, 3H), 2.21 (d, J = 17.1 Hz, 1H), 1.97 – 1.91 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 211.35, 207.82, 138.57, 128.83, 125.44, 114.98, 47.56, 46.98, 38.34, 37.10, 36.36, 33.24. FTIR (Neat, NaCl, thin film): 2940, 1717, 1450, 1215, 1146, 990, 918 cm-1. HRMS (ESI): calc’d for [M+H]+ 191.1067, found 191.1067. Chapter 4 – 3.2.1 bicycle synthesis 357 O O 168 TLC (36% EtOAc/Hexanes): Rf 0.59 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3) δ 5.72 – 5.57 (m, 2H), 5.16 – 5.06 (m, 4H), 2.72 – 2.65 (m, 6H), 2.48 – 2.41 (m, 2H), 2.14 – 2.08 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 211.57, 209.02, 132.13, 120.42, 50.98, 47.25, 41.93, 37.90, 36.10. FTIR (Neat, NaCl, thin film): 2932, 1715, 1433, 1253, 1131, 998, 917 cm-1. HRMS (FD): calc’d for [M+H]+ 193.1223, found 193.1227. if MgCl2 is used: O Cl O 144B TLC (30% EtOAc in hexanes): Rf 0.31 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.65 (dddd, J = 17.1, 10.1, 8.1, 7.1 Hz, 1H), 5.31 (d, J = 0.9 Hz, 1H), 5.21 – 5.08 (m, 3H), 3.02 – 2.87 (m, 3H), 2.78 – 2.57 (m, 4H), 2.40 (dd, J = 14.0, 7.0 Hz, 2H), 2.16 (dd, J = 13.8, 7.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 210.80, 208.49, 137.67, 131.33, 121.22, 118.03, 50.05, 46.63, 45.98, 42.66, 37.74, 35.94. FTIR (Neat, NaCl, thin film): 3417, 3078, 2915, 2253, 1711 1422, 1300, 1255, 1169, 986, 906 cm-1. HRMS (ESI): calc’d for [M+H]+ 227.0833, found 227.0838. 358 Chapter 4 – 3.2.1 bicycle synthesis Preparation of MEM-protected compound 143. O O MEMCl (1.4 equiv) Et2NiPr (3 equiv) CH2Cl2, 21 °C, 13 h HO MEMO 84% yield 163 143 The starting material (1.70 g, 8.84 mmol, 1 equiv.) as a solution in CH2Cl2 (20 mL) was dispensed into an flame-dried 250 mL, 3-neck round-bottom flask equipped with a magnetic stir bar and a reflux condenser. CH2Cl2 (24 mL) was added in to make a total concentration of 200 mM, and the vessel was cooled to 0 °C. MEMCl (1.41 mL, 12.4 mmol, 1.4 equiv.) was added slowly, dropwise. Then, even slower, Hunig’s base (4.62 mL, 26.5 mmol, 3 equiv.) was added in. The reaction was removed from the ice bath and allowed to warm to room temperature, then it was heated to reflux (55 °C) for 12 h. Make sure there is good refluxing throughout the reaction vessel and up into the reflux condenser. After 12 h, to make sure there is full conversion, an NMR aliquot was taken, evacuated, high vac'd, and NMR'd. To workup the reaction, sat. aq. NH4Cl (50 mL) was added, and the organic phase was collected. The remaining aq. phase was extracted with dichloromethane three times (3 x 50 mL). The organic phase was washed with water and brine, dried with sodium sulfate, filtered, and concentrated. The residue was loaded onto a column and eluted with 10 to 15% EtOAc/Hexanes to afford 2.08 g of pure product (84% yield) as a pale yellow oil after high vac overnight. O MEMO 143 TLC (24% EtOAc/Hexanes): Rf 0.23 (p-anisaldehyde). 359 Chapter 4 – 3.2.1 bicycle synthesis 1 H NMR (CDCl3, 400 MHz): δ 5.76 (s, 1H), 5.19 (s, 1H), 5.11 (s, 1H), 5.05 (d, J = 6.3 Hz, 1H), 5.02 (s, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.77 (d, J = 7.5 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.69 – 3.61 (m, 1H), 3.54 (t, J = 4.7 Hz, 2H), 3.38 (s, 3H), 2.52 – 2.25 (m, 7H), 2.12 (d, J = 7.4 Hz, 1H), 1.85 (d, J = 12.1 Hz, 2H). 13 C NMR (CDCl3, 101 MHz): δ 211.68, 150.31, 134.73, 117.93, 107.51, 91.29, 83.63, 71.91, 67.18, 59.16, 52.22, 44.52, 39.78, 38.49, 38.18, 35.79. FTIR (Neat, NaCl, thin film): 2930, 1715, 1445, 1145, 1045, 913 cm-1. HRMS (ESI): calc’d for [M+H]+ 281.1747, found 281.1750. [a]D23 : +37.3 (c 1.0 in CHCl3). Preparation of hemiacetal 166. OH O OsO4 (0.1 equiv) NMO • H2O (1.3 equiv) Br O 144A tBuOH (100 mM), 21 °C, 15 h 80% yield dr = 1.7 : 1 HO O * O Br 166 The starting material and stir bar were added to a 10 mL round-bottom flask, and solid NMO monohydrate (1.3 equiv) was added in. Then, a 0.01 M stock solution of OsO4 was added in (0.1 equiv). The reaction was stirred overnight for 12 h. Following completion of the reaction, 4 mL of acetone was added to the reaction. The reaction was transferred to a separatory funnel containing 25 mL of 10% NaHSO3 and 25 mL of ethyl acetate. The separatory funnel was shaken very vigorously to ensure complete reduction of osmium, then the organic layer was separated. The remaining aq. layer was extracted three times with a 1:2 mixture of acetone/ethyl acetate, and the combined organic layer was washed with brine. All aq. waste was tagged as osmium-containing waste in a separate, labeled 360 Chapter 4 – 3.2.1 bicycle synthesis waste container and disposed of properly. The organic layer was dried with sodium sulfate, filtered, and concentrated. The crude oil was filtered through a silica plug, eluting with ethyl acetate, and isolation of a yellow oil (80% yield). Crude NMR reveals pure product, in a 1.7 : 1 mixture of inconsequential diastereomers. OH HO O * O Br 166 Preparation of enol triflate 142. O MEMO KHMDS (1.2 equiv) −78 °C, 30 min then N-Ph bistriflimide (1.2 equiv) THF, −78 °C to 21 °C, 30 min 89% yield 143 OTf MEMO 142 To an oven-dried round-bottom flask (200 mL) was added KHMDS solution (8.13 mL, 1 M in THF, 8.13 mmol, 1.2 equiv.), and it was cooled to -78 °C. The dissolved starting material (1.90 g, 6.78 mmol, 1 equiv.) in 44 mL of THF was added to the KHMDS. The deprotonation was stirred for 30 min at -78 °C. Color change from yellow to orange was observed. The reaction was stirred for 30 more minutes, then a stock solution of N-Ph bistriflimide (12.7 mL, 0.64 M in THF, 8.13 mmol, 1.2 equiv) was added in dropwise. The anionic reaction was quenched with NH4Cl (50 mL). The phases were separated, and the aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The crude oil obtained was loaded onto a silica gel column and 361 Chapter 4 – 3.2.1 bicycle synthesis eluted with 5 to 15% EA/hexanes to afford 2.50 g of product as an orange oil, corresponding to 89% yield. OTf MEMO 142 TLC (24% EtOAc/Hexanes): Rf 0.38 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.76 (s, 1H), 5.19 (s, 1H), 5.11 (s, 1H), 5.05 (d, J = 6.3 Hz, 1H), 5.02 (s, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.77 (d, J = 7.5 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.69 – 3.61 (m, 1H), 3.54 (t, J = 4.7 Hz, 2H), 3.38 (s, 3H), 2.52 – 2.25 (m, 7H), 2.12 (d, J = 7.4 Hz, 1H), 1.85 (d, J = 12.1 Hz, 2H). 13 C NMR (CDCl3, 101 MHz): δ 211.63, 150.31, 134.72, 117.91, 107.49, 91.28, 83.61, 71.90, 67.17, 59.15, 52.21, 44.52, 39.77, 38.48, 38.17, 35.78. FTIR (Neat, NaCl, thin film): 2924, 2891, 1414, 1206, 1168, 1048. 914, 872 cm-1. HRMS (ESI): calc’d for [M+H]+ 413.1240, found 413.1246. [a]D23 : +103.8 (c 1.0 in CHCl3). Preparation of aldehyde 107A. O OTf OsO4 (0.0045 equiv.) NaIO4 (2 equiv.) 2,6-Lutidine (1 equiv.) OTf H2O, Dioxane (3:1, 55 mM) 22 °C, 17 h MEMO 142 MEMO 50% yield 107A To the starting material (2.50 g, 6.06 mmol, 1 equiv.) in 1,4-dioxane/H2O (83 mL dioxane, 28 mL H2O, 3:1, 55 mM) was added 2,6-lutidine (706 uL, 6.06 mmol, 1 equiv.) and NaIO4 (2.59 g, 12.1 mmol, 2 equiv). OsO4 as a solution (6.06 mL, 0.01 M in H2O, 0.01 Chapter 4 – 3.2.1 bicycle synthesis 362 equiv.). The reaction was capped and stirred for 17 h. TLC analysis is tough to interpret, so an NMR aliquot was taken. NMR aliquot reveals full conversion with ~10-20% diol (dihydroxylation without oxidative cleavage, see attached crude NMR stacked with pure isolated diol). The solution was treated with H2O (100 mL) and extracted with CH2Cl2 (75 mL x 4). The combined organic extracts were washed with H2O (150 mL), and brine (150 mL). The segregated aqueous waste was tagged as osmium-containing waste. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (10-15% then flushing 20% Acetone/Hex) to afford pure product (1.43 g, 57% yield) as a clear or pale brown oil. O OTf MEMO 107A TLC (30% EtOAc/Hexanes): Rf 0.26 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.76 (s, 1H), 5.65 (s, 1H), 5.20 (p, J = 1.2 Hz, 1H), 5.16 – 5.13 (m, 1H), 4.92 (s, 1H), 4.71 (s, 1H), 3.84 (s, 1H), 3.61 (s, 1H), 3.53 (s, 2H), 3.37 (s, 3H), 2.95 (s, 2H), 2.77 (s, 1H), 2.52 (s, 1H), 2.40 (s, 2H), 2.28 (s, 2H). 13 C NMR (CDCl3, 101 MHz): δ 198.76, 151.49, 149.90, 115.31, 109.70, 91.22, 83.06, 71.86, 67.27, 59.13, 47.66, 46.08, 44.98, 42.26, 41.10. FTIR (Neat, NaCl, thin film): 2922, 1731, 1416, 1238, 1006, 682 cm-1. HRMS (ESI): calc’d for [M+H]+ 415.10383, found 415.10539. [a]D23 : +184.4 (c 1.0 in CHCl3). 363 Chapter 4 – 3.2.1 bicycle synthesis Preparation of vinyl bromide 150A: LHMDS (1.2 equiv) then O N O N O O O 149A O Br O (1.1 equiv) THF, −78 °C to 22 °C, 12 h O Br O O 52% yield 147 150A To a cooled solution of 1,4-cyclohexanedione mono-ethylene ketal (223, 1.0 equiv.) in THF (661 mM) was added LiHMDS solution in THF (1.06 M, 1.1 equiv.) at −78 °C. The reaction mixture was stirred for 15 min, then a solution of acylimidazole (1.2 equiv.) in THF (685 mM) was dropwise added. The reaction mixture was allowed to warm to 21 °C. After 4 h the reaction was quenched with sat. aq. NH4Cl and the phases were separated. The aq. phase was extracted with EtOAc (3 x), the combined organic phases were washed with brine and dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography. The title compound was synthesized according to the general procedure for alkylation with acylimidazole using mono-ethylene ketal (500 mg, 3.2 mmol, 1.0 equiv.) and 2-bromoallyl 1H-imidazole-1-carboxylate (717 mg, 3.8 mmol, 1.2 equiv.). Purification by flash column chromatography (15% EtOAc in hexanes) gave title compound 150A (52% yield) as a white waxy solid. O O O Br O O 150A TLC (30% EtOAc in hexanes): Rf 0.71 (p-anisaldehyde, UV). 364 Chapter 4 – 3.2.1 bicycle synthesis 1 H NMR (400 MHz, CDCl3): δ 11.96 (s, 1H), 5.91 (q, J = 1.6 Hz, 1H), 5.67 – 5.64 (m, 1H), 4.77 (t, J = 1.2 Hz, 2H), 4.05 – 3.95 (m, 5H), 2.55 – 2.50 (m, 4H), 2.04 (s, 1H), 1.86 (t, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 172.52, 170.99, 126.22, 119.03, 107.25, 95.06, 67.34, 64.75, 32.71, 30.36, 28.17. Preparation of vinyl chloride 150B: LHMDS (1.2 equiv) then O N O N O O O 149B O Cl O (1.1 equiv) THF, −78 °C to 22 °C, 12 h O Cl O O 74% yield 147 150B To a cooled solution of 1,4-cyclohexanedione mono-ethylene ketal (223, 1.0 equiv.) in THF (661 mM) was added LiHMDS solution in THF (1.06 M, 1.1 equiv.) at −78 °C. The reaction mixture was stirred for 15 min, then a solution of acylimidazole (1.2 equiv.) in THF (685 mM) was dropwise added. The reaction mixture was allowed to warm to 21 °C. After 4 h the reaction was quenched with sat. aq. NH4Cl and the phases were separated. The aq. phase was extracted with EtOAc (3 x), the combined organic phases were washed with brine and dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography. The title compound was synthesized according to the general procedure for alkylation with acylimidazole using mono-ethylene ketal (500 mg, 3.2 mmol, 1.0 equiv.) and 2-chloroallyl 1H-imidazole-1-carboxylate (717 mg, 3.8 mmol, 1.2 equiv.). Purification by flash column chromatography (15% EtOAc in hexanes) gave title compound 150B (637 mg, 2.3 mmol, 72% yield) as a white waxy solid. 365 Chapter 4 – 3.2.1 bicycle synthesis O O O Cl O O 150B TLC (30% EtOAc in hexanes): Rf 0.73 (p-anisaldehyde, UV). 1 H NMR (CDCl3, 400 MHz): δ 11.97 (s, 1H), 5.52 – 5.45 (m, 1H), 5.44 – 5.37 (m, 1H), 4.71 (dd, J = 1.2, 0.7 Hz, 2H), 4.09 – 3.94 (m, 5H), 2.55 – 2.50 (m, 4H), 2.04 (s, 1H), 1.85 (tt, J = 6.9, 0.9 Hz, 2H), 1.30 – 1.21 (m, 2H). (mixture of tautomeric form) 13 C NMR (101 MHz, CDCl3): δ 172.49, 171.10, 135.84, 114.91, 107.24, 95.05, 69.54, 65.80, 64.75, 60.55, 32.73, 30.36, 28.16, 21.21, 14.35. FTIR (Neat, NaCl, thin film): 2946, 1751, 1663, 1355, 1285, 1229, 1193, 1060, 1015 cm1 . HRMS (FD): m/z: calc. for C12H15O5Cl [M]·+ 274.06080, found 274.06135. Preparation of allylated 155: O Br O O (3 equiv) NaH (1.05 equiv) KI (1 equiv) O O O Br O O DMF, 0 °C to 21 °C, 18 h Br O O 71% yield 149A 155 A flame-dried flask was charged with NaH (1.0 equiv.) and a magnetic stir bar. The NaH was suspended in DMF (1 M) at 0 °C. To the cooled suspension was dropwise added a solution of starting material (1.0 equiv.) in DMF (3.2 M) and stirred for 1 h. The the crude reaction mixture was added electrophile in one portion, stirred for 10 min before KI (1.0 equiv.) was added. The reaction was stirred for 18 h, before quenched with sat. aq. NH4Cl. The crude reaction mixture was extracted with EtOAc (4 x), the combined organic layers 366 Chapter 4 – 3.2.1 bicycle synthesis were washed with aq. sat. LiCl twice, dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography. (5% → 15% EtOAc in hexanes) gave title compound 155 (71% yield) as a colorless oil. O O O Br O O 155 TLC (20% EtOAc in hexanes): Rf 0.53 (p-anisaldehyde). 1 H NMR (600 MHz, CDCl3): δ 5.95 – 5.92 (m, 1H), 5.79 (ddt, J = 16.5, 10.7, 7.3 Hz, 1H), 5.66 (d, J = 1.9 Hz, 1H), 5.09 – 5.04 (m, 2H), 4.76 (dt, J = 13.7, 1.1 Hz, 1H), 4.68 (dt, J = 13.9, 1.0 Hz, 1H), 4.03 – 3.96 (m, 4H), 3.05 (ddd, J = 14.7, 11.6, 8.6 Hz, 1H), 2.60 – 2.55 (m, 1H), 2.54 – 2.46 (m, 4H), 2.02 – 1.98 (m, 2H). Preparation of allylated 156: O Br O O (3 equiv) NaH (1.05 equiv) KI (1 equiv) O O O Cl O O DMF, 0 °C to 21 °C, 18 h Cl O O 90% yield 150B 156 A flame-dried flask was charged with NaH (1.0 equiv.) and a magnetic stir bar. The NaH was suspended in DMF (1 M) at 0 °C. To the cooled suspension was dropwise added a solution of starting material (1.0 equiv.) in DMF (3.2 M) and stirred for 1 h. The the crude reaction mixture was added electrophile in one portion, stirred for 10 min before KI (1.0 equiv.) was added. The reaction was stirred for 18 h, before quenched with sat. aq. NH4Cl. The crude reaction mixture was extracted with EtOAc (4 x), the combined organic layers were washed with aq. sat. LiCl twice, dried over anhydrous Na2SO4 and reduced in vacuo. 367 Chapter 4 – 3.2.1 bicycle synthesis The residue was purified by flash column chromatography. (5% → 15% EtOAc in hexanes) gave title compound 156 (85 mg, 215 µmol, 90% yield) as a colorless oil. O O O Cl O O 156 TLC (20% EtOAc in hexanes): Rf 0.51 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.88 – 5.65 (m, 1H), 5.49 (d, J = 1.6 Hz, 1H), 5.41 (d, J = 1.7 Hz, 1H), 5.09 – 5.00 (m, 2H), 4.69 (d, J = 13.6 Hz, 1H), 4.61 (d, J = 13.5 Hz, 1H), 4.06 – 3.99 (m, 1H), 3.96 (td, J = 5.0, 3.0 Hz, 3H), 3.12 – 2.94 (m, 1H), 2.56 (dt, J = 14.1, 1.9 Hz, 1H), 2.54 – 2.48 (m, 1H), 2.46 (d, J = 7.3 Hz, 2H), 2.04 – 1.96 (m, 2H), 1.85 (d, J = 14.1 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 206.10, 171.29, 135.43, 133.20, 119.32, 115.83, 106.83, 66.98, 65.08, 64.45, 58.64, 41.41, 39.70, 37.93, 35.22. FTIR (Neat, NaCl, thin film): 2932, 1719, 1437, 1106, 1043, 924 cm-1. HRMS (FD): m/z: calc. for C15H19O5Cl [M]·+ 314.09210, found 314.09469. Preparation of decarboxylative allylic alkylation product 161: O O Cl O O 156 O Pd2dba3 (5 mol%) (S)-tBu-Phox (12.5 mol%) O THF, 21 °C, 18 h 73% yield 93% ee Cl O O 161 An oven-dried 250 mL round bottom flask was charged with Pd2(dba)3 (124 mg, 136 µmol, 5 mol%), (S)-tBuPhOX (131 mg, 339 µmol, 12.5 mol%) and a magnetic stir bar in the glovebox and capped with a rubber septum and sealed with electrical tape. To the solids 368 Chapter 4 – 3.2.1 bicycle synthesis was added argon sparged THF (78.2 mL) and the mixture was allowed to stir for 30 min. To the reaction mixture was added diallyl chloro 232 as a solution in argon sparged THF (4 mL) in one portion. After 18 h the reaction was filtered through a celite plug and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (15% → 20% EtOAc in hexanes) to give chloro diallyl 161 (524 mg, 2.0 mmol, 73% yield, 93% ee) as a colorless oil. O Cl O O 161 TLC (30% EtOAc in hexanes): Rf 0.68 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.73 – 5.55 (m, 1H), 5.27 (s, 1H), 5.17 – 5.02 (m, 3H), 4.00 (d, J = 2.0 Hz, 4H), 2.86 (d, J = 14.8 Hz, 1H), 2.75 (d, J = 14.8 Hz, 1H), 2.72 – 2.55 (m, 2H), 2.51 (d, J = 7.7 Hz, 2H), 2.10 – 1.91 (m, 4H). 13 C NMR (CDCl3, 101 MHz): δ 211.90, 138.75, 133.37, 119.28, 117.02, 107.73, 64.67, 64.55, 50.68, 44.35, 42.17, 40.26, 36.37, 34.35. FTIR (Neat, NaCl, thin film): 3077, 2955, 2887, 1712, 1629, 1430, 1365, 1306, 1284, 1114,1042, 994, 947, 913, 740, 644 cm-1. HRMS (FD): m/z: calc. for C14H19O3Cl [M]·+ 270.10227, found 270.10028. Preparation of deprotected compound 144B: O O pTsOH • H2O (3 equiv) Cl O O acetone/water (15:1), reflux, 12 h 91% yield 161 Cl O 144B Chapter 4 – 3.2.1 bicycle synthesis 369 A 50 mL round bottom flask was charged with chloro diallyl 161 (150 mg, 554 µmol, 1.0 equiv.), p-TsOH (316 mg, 1.66 mmol, 3.0 equiv.), acetone (26.2 mL), H2O (1.75 mL) and magnetic stir bar. To the reaction flask was attached a reflux condenser and the mixture was heated to reflux. After 12 h the reaction was cooled to room temperature and quenched with sat. aq. NaHCO3 (25 mL). The phases were separated, the aq. phase was extracted with Et2O (3 x 45 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography (30% EtOAc in hexanes) to diketone 144B (106 mg, 416 µmol, 91% yield) as a colorless oil. O Cl O 144B TLC (30% EtOAc in hexanes): Rf 0.31 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ 5.65 (dddd, J = 17.1, 10.1, 8.1, 7.1 Hz, 1H), 5.31 (d, J = 0.9 Hz, 1H), 5.21 – 5.08 (m, 3H), 3.02 – 2.87 (m, 3H), 2.78 – 2.57 (m, 4H), 2.40 (dd, J = 14.0, 7.0 Hz, 2H), 2.16 (dd, J = 13.8, 7.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 210.80, 208.49, 137.67, 131.33, 121.22, 118.03, 50.05, 46.63, 45.98, 42.66, 37.74, 35.94. FTIR (Neat, NaCl, thin film): 3417, 3078, 2915, 2253, 1711 1422, 1300, 1255, 1169, 986, 906 cm-1. HRMS (FD): m/z: calc. for C12H15O2Cl [M]·+ 226.07606, found 226.07519. Chapter 4 – 3.2.1 bicycle synthesis 370 General Procedure for the Second Alkylation A flame-dried flask was charged with NaH (1.0 equiv.) and a magnetic stir bar. The NaH was suspended in DMF (1 M) at 0 °C. To the cooled suspension was dropwise added a solution of starting material (1.0 equiv.) in DMF (3.2 M) and stirred for 1 h. The the crude reaction mixture was added electrophile in one portion, stirred for 10 min before KI (1.0 equiv.) was added. The reaction was stirred for 18 h, before quenched with sat. aq. NH4Cl. The crude reaction mixture was extracted with EtOAc (4 x), the combined organic layers were washed with aq. sat. LiCl twice, dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography. 2-bromoallyl 7-(cyanomethyl)-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (158) The title compound was synthesized according to the general procedure for the second alkylation using bromo allyl carboxylate 151 (150 mg, 470 µmol, 1.0 equiv.) and bromoacetonitrile (98.2 µL, 169 mg, 940 µmol, 3.0 equiv.). Purification by flash column chromatography (50% EtOAc in hexanes) gave title compound 158 (87.5 mg, 244 µmol, 52% yield) as a colorless oil. O O O O O CN Br 158 TLC (50% EtOAc in hexanes): Rf 0.53 (KMnO4). 1 H NMR (CDCl3, 600 MHz): δ = 5.97 (dq, J = 2.2, 0.9 Hz, 1H), 4.04 – 3.92 (m, 3H), 3.18 – 3.07 (m, 1H), 2.93 – 2.85 (m, 1H), 2.76 (dt, J = 14.0, 1.5 Hz, 1H), 2.70 (d, J = 16.4 Hz, 1H), 2.62 (dt, J = 15.2, 4.4 Hz, 1H), 2.11 – 2.05 (m, 3H). Chapter 4 – 3.2.1 bicycle synthesis 13 371 C NMR (101 MHz, CDCl3): δ 203.22, 169.33, 124.90, 121.10, 116.23, 106.13, 69.52, 65.32, 64.71, 60.54, 56.43, 41.38, 37.19, 34.92, 23.70, 21.20, 14.34. FTIR (Neat, NaCl, thin film): 2964, 2250, 1743, 1721, 1633, 1433, 1368, 1215, 1116, 1050, 912, 729 cm-1. HRMS (FD): m/z: calc. for C14H16NO5Br [M]·+ 357.02119, found 357.01888. 2-chloroallyl 7-(cyanomethyl)-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (159) The title compound was synthesized according to the general procedure for the second alkylation using chloro allyl carboxylate 152 (129 mg, 470 µmol, 1.0 equiv.) and bromoacetonitrile (98.2 µL, 169 mg, 940 µmol, 3.0 equiv.). Purification by flash column chromatography (50% EtOAc in hexanes) gave title compound 159 (95.8 mg, 306 µmol, 71% yield) as a colorless oil. O O O O O CN Cl 159 TLC (50% EtOAc in hexanes): Rf 0.53 (KMnO4). 1 H NMR (CDCl3, 600 MHz): δ = 5.53 (dt, J = 2.0, 1.0 Hz, 1H), 5.46 (d, J = 1.8 Hz, 1H), 4.79 (dd, J = 13.2, 1.1 Hz, 1H), 4.68 (dd, J = 13.2, 1.1 Hz, 1H), 4.03 – 3.93 (m, 4H), 3.10 (dt, J = 15.2, 10.0 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 2.75 (dt, J = 14.0, 1.8 Hz, 1H), 2.68 (d, J = 16.5 Hz, 1H), 2.61 (dt, J = 15.1, 4.4 Hz, 1H), 2.08 – 2.04 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 203.24, 134.80, 116.93, 116.21, 106.13, 68.00, 65.32, 64.71, 56.42, 41.39, 37.15, 34.94, 23.67. FTIR (Neat, NaCl, thin film): 2957, 1720, 1171, 1100, 1051, 947, 684 cm-1. Chapter 4 – 3.2.1 bicycle synthesis 372 HRMS (FD): m/z: calc. for C14H16NO5Cl [M]·+ 313.07170, found 313.06922. General Procedure for the Formaldehyde Condensation The starting material was dissolved in THF (0.55 M) and cooled to 0°C. To the cooled solution was added aq. formaldehyde solution (12 M, 7.0 equiv.) and NaHCO3 (3.0 equiv.). The reaction was allowed to warm up to 21 °C over 16 h, the reaction was quenched with water. The crude reaction mixture was extracted with CH2Cl2 (3 x) the combined organic phases were washed with brine and dried over anhydrous Na2SO4 and reduced in vacuo. The residue was purified by flash column chromatography. Preparation of 2-bromoallyl 7-(hydroxymethyl)-8-oxo-1,4-dioxaspiro[4.5]decane-7carboxylate (153) The title compound was synthesized according to the general procedure for the second alkylation using bromo allyl carboxylate 150A (150 mg, 470 µmol, 1.0 equiv.). Purification by flash column chromatography (10% → 50% EtOAc in hexanes) gave title compound 153 (128 mg, 367 µmol, 78% yield) as a colorless oil. O O O O O OH Br 153 TLC (50% EtOAc in hexanes): Rf 0.50 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ = 5.97 (d, J = 1.9 Hz, 1H), 5.67 (d, J = 2.2 Hz, 1H), 4.83 (d, J = 13.9 Hz, 2H), 4.74 (d, J = 13.9 Hz, 1H), 4.06 – 3.94 (m, 5H), 3.85 (dd, J = 11.4, 4.8 Chapter 4 – 3.2.1 bicycle synthesis 373 Hz, 1H), 3.68 (t, J = 10.7 Hz, 1H), 3.15 (ddd, J = 15.0, 11.4, 9.1 Hz, 1H), 2.93 (dd, J = 10.1, 4.8 Hz, 1H), 2.59 – 2.45 (m, 2H), 2.07 – 1.90 (m, 3H), 1.82 (d, J = 13.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 209.61, 170.36, 125.38, 120.03, 106.50, 68.78, 66.78, 65.23, 64.63, 60.26, 38.71, 38.24, 34.88, 31.09. FTIR (Neat, NaCl, thin film): 3516, 2888, 1713, 1213, 1123, 1036, 947 cm-1. HRMS (FD): m/z: calc. for C13H17O6Br [M]·+ 348.02085, found 348.02140. Preparation of 2-chloroallyl 7-(hydroxymethyl)-8-oxo-1,4-dioxaspiro[4.5]decane-7carboxylate (154) The title compound was synthesized according to the general procedure for the second alkylation using chloro allyl carboxylate 150B (129 mg, 470 µmol, 1.0 equiv.). Purification by flash column chromatography (10% → 50% EtOAc in hexanes) gave title compound 154 (79.1 mg, 259 µmol, 55% yield) as a colorless oil. O O O O O OH Cl 154 TLC (50% EtOAc in hexanes): Rf 0.50 (p-anisaldehyde). 1 H NMR (CDCl3, 400 MHz): δ = 5.61 – 5.43 (m, 1H), 5.36 (d, J = 1.8 Hz, 1H), 4.79 – 4.59 (m, 3H), 3.99 – 3.87 (m, 5H), 3.80 – 3.75 (m, 1H), 3.61 (dd, J = 11.3, 10.1 Hz, 1H), 3.07 (ddd, J = 15.0, 11.4, 9.3 Hz, 1H), 2.86 (dd, J = 10.2, 4.8 Hz, 1H), 2.52 – 2.38 (m, 3H), 1.97 (d, J = 3.6 Hz, 2H), 1.76 (d, J = 13.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ = 209.50, 170.34, 135.05, 115.78, 106.36, 67.10, 66.63, 65.11, 64.50, 60.12, 38.57, 38.07, 34.77. 374 Chapter 4 – 3.2.1 bicycle synthesis FTIR (Neat, NaCl, thin film): 2959, 1713, 1109, 1033 cm-1. HRMS (FD): m/z: calc. for C13H17O6Cl [M]·+ 304.07137, found 304.07097. Preparation of acylated compound 173: Mander’s reagent (1.2 equiv) HMPA (1 equiv) O O O THF, 0 °C, 1 h O O OEt O O 59% yield 147 173 LDA was prepared. To do this, oven dried flask was cooled under vacuum. 1.2 equiv of diisopropylamine was dissolved in 64 mL of THF. It was cooled to -78 °C. Then, nBuLi was added via cannula addition (1.2 equiv). The reaction was stirred for 15 min at -78 °C, 15 min at 0 °C, and then 15 min at -78 °C again before the substrate was added dropwise as a 2M solution in THF. Then, It was stirred for 30 min at -78 °C before freshly distilled HMPA was added in. It was stirred for 30 min at -78°C before being warmed to 0 °C and freshly distilled ethyl chloroformate (1.25 equiv) was added in dropwise. It was stirred for 1 h at 0 °C. TLC shows full conversion of starting material and the presence of a less polar, purple spot (staining with p-anisaldehyde, see attached photo) that is copolar with a grey spot. These are both product! Just enol and keto forms. LCMS analysis using PES10AX shows mass hit with retention time of about 4 min. Looks like there are some more nonpolar impurity spots and a massive more polar spot. Looks like a tough separation by LCMS. Product was purified via column with a 5-10% EA/hex gradient. O O OEt O O 173 375 Chapter 4 – 3.2.1 bicycle synthesis TLC (24% EtOAc/Hexanes): Rf 0.54 (UV, p-anisaldehyde). 1 H NMR (500 MHz, CDCl3): δ 4.26 (q, J = 7.1 Hz, 2H), 3.96 (s, 4H), 2.45 – 2.25 (m, 4H), 1.83 (t, J = 6.4 Hz, 4H), 1.34 (t, J = 7.1 Hz, 3H). FTIR (Neat, NaCl, thin film): 2959, 2887, 1743, 1718, 1407, 1357, 1124, 849, 832 cm-1. HRMS (ESI): calc’d for [M+H]+ 229.1071, found 229.1077. Preparation of Michael adduct 174: O O O OEt O O O OPh (1.2 equiv) NEt3 (2 equiv) ACN, 72 h, 21 °C O OEt O O 44% yield 173 OPh O 174 The starting material was dissolved in acetonitrile (200 mM). Then, TEA (2 equiv) was added in, and the reaction was stirred for 3 days at room temperature. After 3 days, ammonium chloride (sat. aq., 3 mL) was added in, and the crude was purified via 5 to 20% EA/hex gradient to afford 44% yield of the desired Michael adduct product (174). O O OEt O OPh O O 174 TLC (24% EtOAc/Hexanes): Rf 0.31 (UV, p-anisaldehyde). 1 H NMR (500 MHz, CDCl3): δ 7.40 – 7.32 (m, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 4.29 (dq, J = 10.7, 7.1 Hz, 1H), 4.19 (dq, J = 10.7, 7.1 Hz, 1H), 4.09 – 4.04 (m, 1H), 4.02 – 3.94 (m, 3H), 3.09 (ddd, J = 14.5, 12.1, 8.4 Hz, 1H), 2.90 – 2.79 (m, 1H), 2.66 (dd, J = 13.9, 3.9 Hz, 1H), 2.51 (dt, J = 14.5, 4.3 Hz, 1H), 2.42 (ddd, J = 16.6, 10.9, 376 Chapter 4 – 3.2.1 bicycle synthesis 5.4 Hz, 1H), 2.23 (ddd, J = 13.9, 10.9, 5.2 Hz, 1H), 2.08 – 1.94 (m, 3H), 1.82 (d, J = 13.9 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.06, 172.04, 171.61, 150.83, 129.53, 125.90, 121.70, 106.73, 65.12, 64.45, 61.76, 57.44, 42.50, 37.99, 35.46, 30.36, 29.99, 14.17. FTIR (Neat, NaCl, thin film): 2965, 2901, 1755, 1710, 1195, 1139, 1033 cm-1. HRMS (ESI): calc’d for [M+H]+ 377.1595, found 377.1602. Preparation of deprotected compound 175: O O OH OEt O O OEt EtOH/Water (2:1) 21 °C, 14 h 85% yield 173 O HCl (25 equiv) O 175 The starting material was dissolved in ethanol in a round bottom flask. No precaution to exclude moisture or air was taken. Then, 25 equiv of HCl were added in, neat. Then, finally, water was added. The reaction was stirred overnight. LCMS shows full conversion. The reaction was worked up by addition SLOW sodium bicarbonate until pH = 9. Watch out for bubbling. At pH = 9, a color change was observed from clear to yellow. Then, the mixture was diluted with 50 mL of EtOAc and the phases were separated, and the aqueous phase was extracted three times with 50 mL of EtOAc. The combined organic extracts were concentrated to afford a crude oil that was NMR'd and loaded onto a column. A 5% to 20% slow gradient was run to afford 85% yield of a clear oil. Stains grey with p-anisaldehyde. Looks like starting material by TLC but LCMS shows the mass of the product. 377 Chapter 4 – 3.2.1 bicycle synthesis OH O OEt O 175 TLC (24% EtOAc/Hexanes): Rf 0.50 (UV, p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 12.28 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.10 (s, 2H), 2.69 (t, J = 7.0 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). FTIR (Neat, NaCl, thin film): 3437, 2984, 1728, 1662, 1367, 1245, 1067, 1025 cm-1. HRMS (ESI): calc’d for [M+H]+ 185.0808, found 185.0817. Preparation of Michael-Aldol cascade product 251: O OH O OEt OPh (1.2 equiv) TEA (2 equiv) ACN 36 h, 21 °C O 46% yield 175 O O OEt OH PhO O 176 To the two starting materials in EtOH (200 mM) was added TEA (2 equiv). The reaction was stirred for 24 h at room temperature before NH4Cl was added in. The aq. phase was extracted 3 times with diethyl ether (3 x 0.5 mL) before concentration afforded a crude oil. Purification by preparatory TLC in 50% EA/hexanes afforded 46% yield of the desired Michael-Aldol cascade product as a clear oil. O O OEt OH PhO O 176 TLC (36% EtOAc/Hexanes): Rf 0.27 (UV, p-anisaldehyde). Chapter 4 – 3.2.1 bicycle synthesis 1 378 H NMR (400 MHz, CDCl3): δ 4.23 – 4.18 (m, 4H), 3.14 (s, 1H), 3.04 (dd, J = 10.1, 6.3 Hz, 1H), 2.63 – 2.50 (m, 4H), 2.42 – 2.27 (m, 1H), 2.22 (t, J = 11.1 Hz, 1H), 2.13 – 2.03 (m, 2H), 1.30 (d, J = 7.3 Hz, 8H). FTIR (Neat, NaCl, thin film): 3420, 2933, 1715, 1332, 1297, 1135, 918 cm-1. HRMS (ESI): calc’d for [M+H]+ 333.1333, found 333.1338. 4.7 NOTES AND REFERENCES (1) Snider, B. B. Manganese(III)-Based Oxidative Free-Radical Cyclizations. Chem. Rev. 1996, 96, 339–363. (b) Dombroski, M. A.; Kates, S. A.; Snider, B. B. Manganese(III)Based Oxidative Free-Radical Tandem and Triple Cyclizations. J. Am. Chem. Soc. 1990, 112, 2759–2767. (2) (a) de Klein, W. J. In Organic Syntheses by Oxidation with Metal Compounds; Mijs, W. J.; de Jonge, C. R. H. 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Lett. 2011, 13, 2630–2633. 392 Appendix 4 – Spectra Relevant to Chapter 4 Appendix 4 Spectra Relevant to Chapter 4: 3.2.1 bicycle synthesis 5.74 1.0000 12.5000 4.0894 2022-12-23T11 11 38 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 5.0 4. 8 4.6 f1 (ppm) 176. 8 Receiver Gain 5.2 16 Number of Scans 5.4 1D Experiment 5.6 z g30 Pulse Sequence 5. 8 297. 2 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH Origin 108 JKT-2-allylation_pure.1. fid 2.04 Spectrometer Frequency 400.13 / Users/ jordankthompson/ Desktop/ JKT-2-allylation_pure/ 1/ fid Title Value 5.10 5.05 Data File Name Parameter 4.4 4.2 4.0 3 .4 3 .2 3 .0 2. 8 2.4 2.2 3.74 3.00 2.6 3.54 0.97 3 .6 2.59 2.02 3.8 2.23 3.01 1.00 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 72.0 1.0000 10.0000 1. 2496 2022-12-23T11 32 27 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 26223 . 8 Spectral Width 117.70 110 108 120 f1 (ppm) 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-2-allylation_pure. 2. fid 202.55 / Users/ jordankthompson/ Desktop/ JKT-2-allylation_pure/ 2/ fid 169.86 Title Value 134.27 Data File Name Parameter 100 90 80 70 59.23 60 50 40 30 32.35 29.33 52.59 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 CDCl3 298 . 2 z g30 1D 16 101.0 1.0000 9. 8500 3 .9977 2022-08-13T15 39 08 Solvent Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 7.0 6. 8 65536 Spectral Siz e 7.2 32768 Acquired Siz e 7.4 1H Nucleus 7.6 8196.7 Spectral Width 6.6 6.4 6.2 6.0 5. 8 5.6 5.4 Bruker BioSpin GmbH Origin 1,3-dichloro-2-((2methoxyethoxy)methoxy)propane JKT-2-MEMprotection.1. fid Spectrometer Frequency 400.15 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-MEMprotection/ 1/ fid Title Value Data File Name Parameter 5.2 f1 (ppm) 5.0 4.6 4.4 4.2 4.84 2.00 3.8 4.03 0.98 4.0 3.77 3.73 2.03 4.01 4. 8 3.56 3 .6 3.39 3 .4 2.99 3 .2 3 .0 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 13000000 14000000 15000000 95.53 z gpg30 1D 500 45. 2 2.0000 10.0000 1. 3763 2022-08-13T16 10 23 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 130 32768 Acquired Siz e 140 13C Nucleus 120 110 100 90 1,3-dichloro-2-((2methoxyethoxy)methoxy)propane 23809.5 Spectral Width f1 (ppm) 298 . 2 Temperature 70 CDCl3 Solvent 80 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-MEMprotection. 2. fid 76.81 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-MEMprotection/ 2/ fid 71.75 Title Value 67.67 Data File Name Parameter 59.22 60 50 43.87 40 30 20 10 0 -10 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 1100000 1200000 1300000 1400000 1500000 1600000 16 101.0 1.0000 9. 8500 3 .9977 2022-08-01T17 13 14 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8196.7 Spectral Width 5.0 4.5 1D Experiment 5.5 z g30 Pulse Sequence 6.0 298 . 2 Temperature 115 CDCl3 Solvent Spectrometer Frequency 400.15 Bruker BioSpin GmbH 5.11 Origin f1 (ppm) 4.0 3 .5 4.46 4.41 1.00 1.01 CHM-1-12_pure_.1. fid 3.98 2.00 / Volumes/ nmrdata/ jkthomps/ nmr/ CHM-1-12_pure_/ 1/ fid 3.79 1.99 Title Value 3.58 2.07 Data File Name Parameter 3.39 3.06 2.04 3 .0 2.5 2.0 1.5 1.0 -2000000 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 13000000 14000000 15000000 16000000 17000000 18000000 19000000 20000000 21000000 22000000 23000000 24000000 1D 500 45. 2 2.0000 10.0000 1. 3763 2022-08-01T17 44 09 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 32768 65536 150 Nucleus Acquired Siz e Spectral Siz e 170 160 23809.5 Spectral Width 110 100 z gpg30 Pulse Sequence 120 298 . 2 Temperature 130 CDCl3 Solvent 140 Bruker BioSpin GmbH Origin 115 CHM-1-12_pure_. 2. fid Spectrometer Frequency 100.63 / Volumes/ nmrdata/ jkthomps/ nmr/ CHM-1-12_pure_/ 2/ fid Value Title 155.87 Data File Name Parameter 89.83 93.12 90 f1 (ppm) 80 71.70 70 59.18 60 50 45.21 68.04 40 30 20 10 -50000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000 600000 650000 700000 750000 800000 1.0000 12.5000 4.0894 2024-03-13T14 31 56 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6. 8 6.6 65536 Spectral Siz e 7.0 32768 Acquired Siz e 7.2 1H Nucleus 7.4 8012. 8 Spectral Width 5.2 112. 8 Receiver Gain 5.4 16 Number of Scans 5.6 1D Experiment 5. 8 z g30 Pulse Sequence 6.0 297.1 Temperature 6.2 CDCl3 Solvent 6.4 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 snider _sm_RR.1. fid Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ snider _sm_RR/ 1/ fid Parameter 5.73 Data File Name 5.05 4.07 5.0 4. 8 f1 (ppm) 4.6 4.4 109 3.8 3 .2 3 .0 2. 8 4.00 1.00 4.14 0.98 2.4 3.72 5.21 2.6 3.56 2.08 3 .4 3.39 3.18 3 .6 2.73 2.02 4.0 2.59 2.18 4.2 2.38 2.00 1.05 2.2 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 72.0 1.0000 10.0000 1. 3631 2024-03-13T14 53 10 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 130 512 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297.1 170 CDCl3 Temperature Spectrometer Frequency 100.62 Bruker BioSpin GmbH Solvent Value Origin 203.62 snider _sm_RR. 2. fid 169.75 Title 159.21 / Volumes/ nmrdata-1/ jkthomps/ nmr/ snider _sm_RR/ 2/ fid Parameter 134.36 Data File Name f1 (ppm) 117.69 120 110 109 100 90 80 71.76 70 59.20 58.47 60 50 40.07 40 30 28.97 32.37 52.57 68.01 85.17 92.77 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 7.4 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8196.7 Spectral Width 5.4 1.00 1.00 5.2 4. 8 2022-08-17T13 25 54 Acquisition Date 5.0 3 .9977 Acquisition Time 5.6 9. 8500 Pulse Width 5. 8 1.0000 Relaxation Delay 6.0 101.0 Receiver Gain 6.2 16 110 1D Number of Scans Spectrometer Frequency 400.15 z g30 Experiment 5.22 Pulse Sequence 4.92 298 . 2 4.6 f1 (ppm) 4.4 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 4.78 1.01 Temperature 3.83 3.75 3.65 3.55 1.02 3.03 1.00 2.02 CDCl3 3.38 3.03 Bruker BioSpin GmbH 2.95 1.05 Solvent 2.77 1.05 Origin 2.63 1.07 JKT-2-95-4_pure.1. fid 2.48 1.98 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-95-4_pure/ 1/ fid 2.30 0.95 Title Value 2.18 1.06 Data File Name Parameter 1.90 1.01 1.00 1. 8 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 2.0000 10.0000 1. 3763 2022-08-17T13 55 18 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 23809.5 Spectral Width 130 45. 2 Receiver Gain 140 500 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 298 . 2 Temperature 110 CDCl3 Solvent Spectrometer Frequency 100.63 Bruker BioSpin GmbH Origin Value JKT-2-95-4_pure. 2. fid 206.17 Title 171.07 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-95-4_pure/ 2/ fid Parameter 148.22 Data File Name 120 f1 (ppm) 108.61 110 100 91.36 90 80 71.87 70 60.60 59.16 60 50 40 42.19 38.19 37.52 35.08 52.43 67.37 82.91 30 -50000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000 600000 650000 700000 750000 800000 850000 5.67 16 101.0 1.0000 9. 8500 3 .9977 2022-07-28T14 18 34 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8196.7 Spectral Width 5.6 1.03 0.95 5.2 5.0 1D Experiment 5.4 z g30 Pulse Sequence 5. 8 298 .1 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH Origin 114 JKT-2-76 _pure.1. fid 1.00 Spectrometer Frequency 400.15 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-76 _pure/ 1/ fid Title Value 5.20 Data File Name Parameter 4.6 4.4 4.2 4.0 3 .2 4.92 1.01 2.4 4.72 1.01 2.6 3.83 1.01 2.98 2. 8 3.62 3.53 1.04 2.00 3 .0 3.38 3.09 3 .4 3.00 2.05 3 .6 2.77 1.02 3.8 2.58 1.01 4. 8 f1 (ppm) 2.34 2.30 2.06 2.2 -500000 0 500000 1000000 1500000 2000000 2500000 3000000 3500000 4000000 4500000 5000000 5500000 6000000 6500000 7000000 7500000 8000000 8500000 9000000 170.16 45. 2 2.0000 10.0000 1. 3763 2022-07-28T14 50 44 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 160 155 150 65536 Spectral Siz e 165 32768 Acquired Siz e 170 13C Nucleus 175 23809.5 Spectral Width 125 520 Number of Scans 130 1D Experiment 135 z gpg30 Pulse Sequence 140 298 . 2 Temperature 145 CDCl3 Solvent 120 115 114 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-76 _pure. 2. fid Value Title 149.51 149.02 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-76 _pure/ 2/ fid Parameter 116.26 Data File Name 110.12 110 105 f1 (ppm) 100 95 91.26 90 85 80 75 70 65 59.15 60 55 52.76 51.88 50 45 40 44.09 42.68 40.62 67.41 71.86 82.58 -100000 -50000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000 600000 650000 700000 750000 5.64 1.0000 9. 8500 3 .9977 2022-07-28T18 18 45 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6. 8 6.6 65536 Spectral Siz e 7.0 32768 Acquired Siz e 7.2 1H Nucleus 7.4 8196.7 Spectral Width 1.00 5.6 5.4 1.06 1.05 5.2 4. 8 101.0 Receiver Gain 5.0 16 Number of Scans 5. 8 1D Experiment 6.0 z g30 Pulse Sequence 6.2 298 .1 Temperature 6.4 CDCl3 Solvent 113 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.15 JKT-2-77 _crude.1. fid Title Value 5.19 5.13 / Users/ jordankthompson/ Desktop/ JKT-2-77 _crude/ 1/ fid Parameter 4.93 Data File Name 4.6 f1 (ppm) 4.4 4.2 4.0 3 .2 3 .0 2.6 2.0 4.72 1.07 2.2 3.92 3.83 1.03 1.12 2.4 3.60 3.54 2.26 2.13 2. 8 3.37 3.26 3 .4 2.73 0.96 1.14 3 .6 2.39 2.30 2.16 1.07 2.16 1.05 3.8 1.96 1.00 1.11 1. 8 1.6 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 13000000 14000000 15000000 16000000 17000000 18000000 19000000 20000000 21000000 152.40 150.71 2.0000 10.0000 1. 3763 2022-07-28T18 49 52 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 145 140 65536 Spectral Siz e 155 32768 Acquired Siz e 160 13C Nucleus 165 23809.5 Spectral Width 110 45. 2 Receiver Gain 115 500 Number of Scans 120 1D Experiment 125 z gpg30 Pulse Sequence 130 298 . 2 Temperature 135 CDCl3 Solvent 105 113 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-77 _crude. 2. fid Title Value 116.65 / Users/ jordankthompson/ Desktop/ JKT-2-77 _crude/ 2/ fid Parameter 109.61 Data File Name 100 95 f1 (ppm) 91.20 90 85 80 75 70 64.27 65 59.09 60 55 50 45 40 43.37 42.08 41.05 47.52 67.22 71.88 83.06 35 30 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 1100000 1200000 1300000 1400000 1500000 1600000 1700000 1800000 1900000 2000000 2100000 2200000 9.77 Parameter z g30 1D 16 101.0 1.0000 9. 8500 3 .9977 2022-08-31T15 01 43 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 9.0 32768 Acquired Siz e 9.5 1H Nucleus 10.0 8196.7 Spectral Width 8 .0 298 . 2 8 .5 CDCl3 Temperature Spectrometer Frequency 400.15 Bruker BioSpin GmbH JKT-2-108-2_pure.1. fid Solvent 0.96 Value 7.5 7.0 112 6.5 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-108-2_pure/ 1/ fid Origin Title Data File Name 6.0 f1 (ppm) 5.5 4.5 4.0 4.73 1.07 4.93 1.08 5.24 1.00 1.05 5.80 1.00 2.5 3.83 1.11 3 .0 3.63 3.53 3.37 1.07 1.99 3.05 3 .5 2.93 2.79 2.02 1.02 5.0 2.46 2.35 2.19 1.08 1.02 1.05 2.0 -500000 0 500000 1000000 1500000 2000000 2500000 3000000 3500000 4000000 4500000 196.52 1D 500 45. 2 2.0000 10.0000 1. 3107 2022-08-31T15 32 08 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 25000.0 Spectral Width 140 z gpg30 Pulse Sequence 150 298 . 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin 130 112 JKT-2-108-2_pure. 2. fid Spectrometer Frequency 100.63 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-108-2_pure/ 2/ fid Title Value 148.83 148.49 Data File Name Parameter 117.90 120 f1 (ppm) 110.65 110 100 91.26 90 80 70 59.18 60 50 40 42.39 40.99 40.77 55.88 67.48 71.85 82.79 -50000 0 50000 100000 150000 200000 250000 300000 350000 400000 450000 500000 550000 600000 650000 7.6 3 .9977 2022-08-05T18 31 36 Acquisition Time Acquisition Date 6. 8 6.6 65536 Spectral Siz e 7.0 32768 Acquired Siz e 7.2 1H Nucleus 7.4 8196.7 Spectral Width 6.4 0.97 6.0 5.6 5.4 4.11 5.2 5.0 9. 8500 Pulse Width 5. 8 1.0000 Relaxation Delay 6.2 101.0 Receiver Gain 111 16 Number of Scans 0.99 0.93 Spectrometer Frequency 400.15 1D 6.43 1.00 z g30 5.99 Experiment 5.55 Pulse Sequence 5.17 5.11 298 . 2 4. 8 4.6 f1 (ppm) 4.4 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 4.92 4.88 1.94 1.10 CDCl3 4.73 2.05 Temperature 4.31 1.02 Bruker BioSpin GmbH 3.84 2.01 Solvent 3.64 3.60 3.56 2.14 2.93 7.02 Origin 3.39 6.21 JKT-2-86 _pure.1. fid 3.08 1.03 Title Value 2.94 1.06 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-86 _pure/ 1/ fid Parameter 2.74 2.62 2.52 2.39 2.27 2.06 1.09 1.01 2.00 3.18 Data File Name 2.12 1.17 2.0 1. 8 -1000000 -500000 0 500000 1000000 1500000 2000000 2500000 3000000 3500000 4000000 4500000 5000000 5500000 6000000 153.77 153.71 151.95 151.24 149.62 149.56 500 45. 2 2.0000 10.0000 1. 3763 2022-08-05T19 02 21 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 140 32768 Acquired Siz e 150 13C Nucleus 160 23809.5 Spectral Width 100 1D Experiment 110 z gpg30 Pulse Sequence 120 298 . 2 Temperature 130 CDCl3 Solvent 111 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-86 _pure. 2. fid 115.09 114.27 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-86 _pure/ 2/ fid 109.40 108.71 Title Value 103.01 101.08 Data File Name Parameter 91.24 90 f1 (ppm) 80 70 60.11 59.17 59.14 55.88 60 50 40 47.06 46.19 45.97 45.83 44.61 44.42 40.96 40.83 67.28 67.20 71.93 82.87 82.85 30 20 -20000 0 20000 40000 60000 80000 100000 120000 140000 160000 180000 200000 220000 240000 260000 280000 300000 320000 340000 360000 10.0 9.76 298 . 2 z g30 1D 16 101.0 1.0000 9. 8500 3 .9977 2022-08-07T14 21 40 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 9.0 1H Nucleus 9.5 8196.7 Spectral Width 8 .0 CDCl3 Solvent 8 .5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.15 JKT-2-87 _pure.1. fid 0.96 Value 7.5 7.0 6.5 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-87 _pure/ 1/ fid Title Data File Name Parameter 6.0 f1 (ppm) 107A 5.5 4.5 4.0 3.84 1.00 4.71 0.99 4.92 1.04 5.17 1.00 1.00 5.65 0.99 2.5 3.61 3.53 3.37 1.02 2.04 3.05 3 .0 2.95 2.06 3 .5 2.77 1.02 5.0 2.52 2.40 2.28 1.03 2.10 2.18 -2000000 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 500 45. 2 2.0000 10.0000 1. 3763 2022-08-07T14 51 01 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 23809.5 Spectral Width 130 1D Experiment 140 z gpg30 Pulse Sequence 150 298 . 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-87 _pure. 2. fid Value Title 198.76 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-87 _pure/ 2/ fid Parameter 151.49 149.90 Data File Name 120 f1 (ppm) 107A 109.70 110 100 91.22 90 80 70 59.13 60 50 40 47.66 46.08 44.98 42.26 41.10 67.27 71.86 83.06 115.31 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 16 9.82 z g30 1D 16 87. 8 1.0000 12.5000 4.0894 2022-11-02T15 22 46 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 13 32768 Acquired Siz e 14 1H Nucleus 15 8012. 8 Spectral Width 0.94 10 8 297.1 Temperature 9 CDCl3 Solvent 11 Bruker BioSpin GmbH Origin 12 JKT-2-165-1.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-2-165-1/ 1/ fid Data File Name Value 7 6 f1 (ppm) 5 4 3 5.17 5.10 4.92 4.71 0.98 1.00 1.02 1.00 107B 5.94 0.95 Parameter 3.83 3.61 3.52 3.37 3.10 2.70 2.36 2.15 1.00 1.00 2.00 3.02 0.97 1.97 4.00 1.05 2 1 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 1D 512 72.0 1.0000 10.0000 1. 3631 2022-11-02T15 43 59 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 32768 65536 180 Nucleus Acquired Siz e Spectral Siz e 200 190 24038 .5 Spectral Width 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-2-165-1. 2. fid Origin Value Title 200.39 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-2-165-1/ 2/ fid Parameter 151.00 Data File Name 128.93 128.15 130 f1 (ppm) 120 107B 109.33 110 100 91.14 90 80 70 59.13 60 50 51.41 46.65 45.81 45.31 45.09 67.19 71.86 83.41 40 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 16 197.4 1.0000 12.5000 4.0894 2023-01-25T05 51 18 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 6.2 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 0.99 1.00 5.2 1.00 5.0 1.01 4. 8 4.4 f1 (ppm) 123 4.6 1D Experiment 5.4 z g30 Pulse Sequence 5.6 297. 2 Temperature 5. 8 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-2-18 _pure_char.1. fid 5.28 5.22 Title Value 4.94 / Users/ jordankthompson/ Desktop/ JKT-2-18 _pure_char/ 1/ fid Parameter 4.80 Data File Name 4.2 4.0 3 .2 3 .0 2.4 3.66 1.03 3.83 1.03 2.0 3.55 2.00 2.2 3.38 3.02 2.6 3.12 1.05 2. 8 2.76 2.05 3 .4 2.56 1.99 3 .6 2.27 2.21 1.01 0.99 3.8 1.95 1.00 1. 8 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 72.0 1.0000 10.0000 1. 2496 2023-01-25T06 18 46 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 26223 . 8 Spectral Width 140 700 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297.1 Temperature 130 120 f1 (ppm) 123 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Value JKT-2-18 _pure_char. 2. fid 209.75 Title 173.52 / Users/ jordankthompson/ Desktop/ JKT-2-18 _pure_char/ 2/ fid Parameter 147.71 Data File Name 108.82 110 100 91.36 90 80 71.85 70 59.18 58.30 60 50 40 38.54 38.17 35.44 43.20 67.44 82.88 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 7.5 Spectral Siz e Acquired Siz e Nucleus Spectral Width 7.0 6.5 65536 24000 1H 8000.0 6.0 2022-10-12T15 47 50 Acquisition Date 127 3 .0000 Acquisition Time Spectrometer Frequency 499.57 5.6500 1.0000 Relaxation Delay Pulse Width 50 8 Receiver Gain 1D Number of Scans s2pul Pulse Sequence Experiment 25.0 cdcl3 Varian PROTON01 Temperature Solvent Origin Title Value 5.5 5.0 4.5 3.39 3.13 3.55 2.24 3.71 2.20 4.13 4.00 3.95 1.10 0.33 0.75 4.0 2.0 2.94 0.29 f1 (ppm) 2.5 2.71 2.62 1.06 3 .0 2.42 4.14 3 .5 2.22 1.61 5.58 1.08 / Users/ jordankthompson/ Desktop/ JKT-2-147-2_pure/ PROTON01. fid/ fid 5.00 4.57 Parameter 2.01 1.11 0.33 7.28 4.51 1.79 2.90 7.13 1.10 4.78 1.18 Data File Name 1.5 1.0 0.84 5.26 1.43 1.29 1.18 1.09 3.42 4.57 1.62 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 2022-10-13T14 02 18 Acquisition Date 7.5 Spectral Siz e Acquired Siz e Nucleus 7.0 Spectral Width 6.5 65536 32768 1H 8012. 8 6.0 4.0894 Acquisition Time Spectrometer Frequency 400.13 12.5000 1.0000 Pulse Width 78 .7 Relaxation Delay 16 Receiver Gain 1D Number of Scans z g30 Pulse Sequence Experiment 297. 2 CDCl3 Bruker BioSpin GmbH JKT-2-148-2.1. fid 5.5 128 5.0 4.5 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-148-2/ 1/ fid Temperature Solvent Origin Title Data File Name Value 4.0 f1 (ppm) 3.80 3.64 3.55 3.50 3.38 4.58 3 .5 3 .0 2.5 2.01 2.0 6.08 3.08 0.85 1.48 7.25 6.98 1.74 5.99 7.10 1.23 5.16 5.13 5.02 4.98 4.86 4.72 0.27 0.97 0.36 1.00 3.09 1.28 Parameter 1.5 1.0 0.86 6.49 1.29 1.23 1.19 1.16 4.53 3.15 4.03 2.37 2.25 2.95 2.34 2.62 0.45 0.5 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 64. 2 1.0000 10.0000 1. 3631 2022-10-13T14 24 17 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 150 130 512 Number of Scans 140 1D Experiment 160 z gpg30 Pulse Sequence 170 297.1 Temperature 128 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 206.11 206.02 JKT-2-148-2. 2. fid 169.85 169.77 Title Value 152.46 151.76 148.64 148.56 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-148-2/ 2/ fid Parameter 120 135.89 128.06 127.98 125.84 125.76 125.66 125.14 Data File Name 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 108.13 108.04 91.37 91.19 82.84 82.78 76.62 76.25 71.89 71.84 67.34 67.23 60.62 60.41 59.23 59.17 50.25 49.83 42.02 41.68 41.63 40.87 40.02 39.69 38.12 37.96 36.82 36.53 35.27 34.99 34.79 34.76 34.36 31.45 31.44 30.45 29.84 29.58 27.06 26.76 26.63 23.95 22.83 21.92 14.27 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 2500 1D 16 64.2 1.0000 12.5000 4.0894 2023-08-21T13 21 18 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 5.0 zg30 Pulse Sequence 5.5 297.2 Temperature 6.0 CDCl3 Solvent 4.5 f1 (ppm) 132 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-4-273 _sm.1. fid Title 5.78 5.77 1.00 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-273 _sm/ 1/ fid 4.0 3.5 2.0 2.99 2.92 2.79 2.75 1.05 3.80 3.01 3.0 2.5 2.32 2.01 2.07 0.98 5.19 5.16 5.15 Value 4.75 4.69 Data File Name Parameter 1.73 3.02 0.99 0.99 1.03 0.98 1.5 1.0 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 199.55 10.0000 1. 3631 2023-08-21T13 42 31 Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 110 1.0000 Relaxation Delay 120 64.2 Receiver Gain 130 512 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature 100 f1 (ppm) 132 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 167.89 Origin 144.06 JKT-4-273 _sm.2. fid 131.75 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-273 _sm/ 2/ fid 120.42 Title Value 110.71 Data File Name Parameter 90 80 67.68 70 60 50 41.94 37.34 32.16 40 30 22.70 53.86 20 10 0 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 1D 16 197.4 1.0000 12.5000 4.0894 2023-08-17T18 51 03 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.8 4.6 65536 Spectral Siz e 5.0 32768 Acquired Siz e 5.2 1H Nucleus 5.4 8012. 8 Spectral Width 3.01 3.8 1.00 3.6 3.4 z g30 Pulse Sequence 4.0 297. 2 Temperature 4.2 CDCl3 Solvent 4.4 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-4-269-3 _pure.1. fid 3.75 Title Value 3.63 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-269-3 _pure/ 1/ fid Parameter 3.28 Data File Name 3.2 3.0 f1 (ppm) 130 2.8 2.6 2.4 1.6 1.4 2.14 1.98 2.52 4.09 1.2 1.95 0.98 1.8 1.81 1.00 2.0 1.71 1.06 2.2 1.15 3.03 0.98 1.0 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 50. 3 1.0000 10.0000 1. 3631 2023-08-17T19 22 44 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 120 750 Number of Scans 130 1D Experiment 140 zgpg30 Pulse Sequence 150 297.2 Temperature 160 CDCl3 Solvent 110 f1 (ppm) 130 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-4-269-3 _pure.2. fid Value Title 207.72 207.31 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-269-3 _pure/ 2/ fid 171.99 171.82 Data File Name Parameter 100 90 80 70 50 40 30 52.36 49.93 48.81 46.29 45.09 43.21 42.84 40.83 39.60 38.30 38.07 34.78 34.62 33.25 32.96 24.81 60 20 21.43 63.59 10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 5.06 5.00 zg30 1D 16 197.4 1.0000 12.5000 4.0894 2023-08-25T14 17 16 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.00 1.01 5.0 4.5 297.1 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 4.0 f1 (ppm) 131' JKT-4-279_pdt_std_char.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-279_pdt_std_char/ 1/ fid Value 3.75 Data File Name Parameter 3.5 2.0 1.5 1.79 1.07 2.09 2.03 2.36 1.04 2.50 1.05 2.83 1.02 2.94 1.01 2.5 1.68 1.06 3.0 1.24 3.12 3.00 1.0 -10000 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 1. 3631 2023-08-25T14 39 16 Acquisition Time Acquisition Date 180 170 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 100 f1 (ppm) 90 10.0000 Pulse Width 110 1.0000 Relaxation Delay 120 72.0 Receiver Gain 130 512 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature 131' CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 207.76 JKT-4-279_pdt_std_char.2. fid 171.95 Title 153.72 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-279_pdt_std_char/ 2/ fid Value 106.54 Data File Name Parameter 80 70 60 40 52.30 47.19 44.17 40.48 40.11 35.75 50 30 22.92 62.37 20 10 0 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 4.91 5.09 1D 16 87. 8 1.0000 12.5000 4.0894 2023-08-26T18 50 00 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.5 32768 Acquired Size 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 1.02 1.00 5.0 4.5 zg30 Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 2.04 4.0 f1 (ppm) 134 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-4-276_distilled.1. fid Title 4.20 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-276_distilled/ 1/ fid Value 4.06 Data File Name Parameter 3.5 3.0 2.5 2.0 1.5 1.36 6.10 4.04 1.0 0.5 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 110000 120000 130000 110 100 90 80 70 60 65536 Spectral Size 120 32768 Acquired Size 130 31P Nucleus 140 64102.6 Spectral Width -50 -60 f1 (ppm) -70 2023-08-26T18 52 01 Acquisition Date -40 0.5112 Acquisition Time -30 12.0000 Pulse Width -20 2.0000 Relaxation Delay -10 197.4 Receiver Gain 0 16 Number of Scans 10 1D Experiment 20 zgpg30 Pulse Sequence 30 297.2 Temperature 40 CDCl3 Solvent 50 Bruker BioSpin GmbH Origin 134 JKT-4-276_distilled.2. fid Title Spectrometer Frequency 161.97 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-276_distilled/ 2/ fid Value Data File Name Parameter -6.94 -80 -90 -100 -110 -120 -130 -140 -150 -160 -170 -180 -190 -200 -210 -220 -230 -240 0 5000 10000 15000 20000 25000 30000 35000 40000 1.0000 10.0000 1. 3631 2023-08-26T19 14 10 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 110 64.2 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 zgpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 100 f1 (ppm) 134 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-4-276_distilled. 3 . fid Value Title 150.40 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-276_distilled/ 3/ fid Parameter 101.40 Data File Name 90 80 70 60 50 40 30 20 16.21 44.19 64.88 10 0 0 500 1000 1500 2000 2500 3000 3500 4000 4500 112. 8 1.0000 12.5000 4.0894 2023-08-28T13 48 47 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.8 6.6 6.4 6.2 65536 Spectral Size 7.0 32768 Acquired Size 7.2 1H Nucleus 7.4 8012. 8 Spectral Width 5.8 5.2 5.0 1.02 4.8 1.04 4.6 4.0 3.4 3.2 3.0 2.4 2.2 2.0 1.8 1.6 4.16 4.11 1.4 3.72 2.99 2.6 3.57 0.98 2.8 2.76 2.02 3.6 2.59 2.02 3.8 2.48 2.00 4.4 4.2 f1 (ppm) 16 Number of Scans 5.4 1D Experiment 5.6 zg30 Pulse Sequence 6.0 297.1 Temperature 135 CDCl3 Solvent 2.04 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 5.72 1.00 JKT-4-281_pure.1. fid 5.06 Title 4.84 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-281_pure/ 1/ fid Value 4.53 Data File Name Parameter 1.35 6.12 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 210 1.0000 10.0000 1. 3631 2023-08-28T14 10 47 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Size 180 32768 Acquired Size 190 13C Nucleus 200 24038 .5 Spectral Width 120 78 .7 Receiver Gain 130 512 Number of Scans 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.2 Temperature 110 f1 (ppm) 135 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 202.97 Origin 169.65 JKT-4-281_pure.2. fid 154.09 Title 134.22 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-281_pure/ 2/ fid Value 117.80 Data File Name Parameter 97.90 100 90 80 70 58.42 60 50 39.24 40 28.50 30 20 16.26 32.34 52.62 64.49 10 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 2500 5.22 4.0894 2023-08-30T09 10 22 Acquisition Time Acquisition Date 6.8 6.6 6.4 6.2 65536 Spectral Size 7.0 32768 Acquired Size 7.2 1H Nucleus 7.4 8012. 8 Spectral Width 1.00 5.4 1.00 5.2 5.0 4.4 4.2 f1 (ppm) 12.5000 Pulse Width 4.6 1.0000 Relaxation Delay 4.8 78 .7 Receiver Gain 5.6 16 Number of Scans 5.8 1D Experiment 6.0 zg30 Pulse Sequence 136 297.2 Temperature Spectrometer Frequency 400.13 CDCl3 Solvent 5.41 Bruker BioSpin GmbH 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 4.11 4.05 Origin 3.74 3.02 JKT-4-284_pure.1. fid 3.03 1.02 Title 2.74 2.66 2.06 1.01 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-284_pure/ 1/ fid Value 2.50 2.99 Data File Name Parameter 2.4 2.2 2.0 1.8 1.6 1.34 1.4 6.02 0.99 1.2 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 210 zgpg30 1D 512 78 .7 1.0000 10.0000 1. 3631 2023-08-30T09 32 09 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 190 180 170 160 150 120 110 f1 (ppm) 80 70 60 50 40 30 20 65536 Spectral Size 200 32768 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 Acquired Size 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 2500 13C 84.95 Nucleus 64.08 1100 90 60.84 24038 .5 52.52 Spectral Width 42.78 1200 100 37.70 36.57 34.91 Spectrometer Frequency 100.62 130 297.1 Temperature 140 CDCl3 Solvent 136 Bruker BioSpin GmbH Origin 204.91 JKT-4-284_pure.2. fid 170.48 Title 147.73 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-284_pure/ 2/ fid Value 109.40 Data File Name Parameter 16.21 98 .9 1.0000 12.5000 4.0894 2023-09-05T00 27 13 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 5.0 16 Number of Scans 5.5 1D Experiment 6.0 z g30 Pulse Sequence 138 297.1 Spectrometer Frequency 400.13 CDCl3 5.78 Temperature 5.19 Bruker BioSpin GmbH 4.89 Solvent 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 1.5 4.59 1.01 Origin 4.19 4.05 JKT-4-299_pure.1. fid 3.83 3.02 Title Value 2.99 4.04 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-299_pure/ 1/ fid Parameter 2.54 1.98 Data File Name 1.38 6.12 1.00 2.04 0.99 1.0 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 72.0 1.0000 10.0000 1. 3631 2023-09-05T00 25 21 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 130 512 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 120 138 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 198.70 Origin 167.75 JKT-4-299_pure. 2. fid 153.83 153.75 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-4-299_pure/ 2/ fid 131.60 Title Value 120.55 Data File Name Parameter 110 f1 (ppm) 98.15 98.11 100 90 80 67.28 64.57 64.51 70 60 50 41.90 40 29.59 29.53 30 20 16.27 16.20 36.14 53.94 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 s2pul 1D 8 30 1.0000 5.1000 1.7089 2023-09-02T13 41 14 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 8192 Acquired Siz e 7.0 1H Nucleus 7.5 4793 .9 Spectral Width 6.0 25.0 Temperature Spectrometer Frequency 300.09 cdcl3 Varian Solvent Origin PROTON01 5.5 2.17 1.00 5.0 139 4.5 f1 (ppm) 4.0 / Users/ jordankthompson/ Desktop/ JKT_ 4_293 _prepped01/ PROTON01. fid/ fid 1.10 Title 1.07 Data File Name 5.12 Value 4.20 Parameter 3.5 3.0 3.20 2.5 2.0 1.5 6.33 2.16 1.04 3.16 0 50 100 150 200 250 300 350 400 450 500 7.4 34 1.0000 5.1000 1.7089 2023-09-02T13 43 46 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6.8 8192 Acquired Siz e 7.0 1H Nucleus 7.2 4793 .9 Spectral Width 5.8 2.15 5.2 1.10 4.8 4.6 4.21 4.4 4.2 f1 (ppm) 4.0 8 Number of Scans 5.0 1D Experiment 5.4 s2pul Pulse Sequence 5.6 25.0 Temperature 6.0 cdcl3 Solvent 6.2 Varian Origin 140 PROTON01 1.12 Spectrometer Frequency 300.09 / Users/ jordankthompson/ Desktop/ JKT_ 4_294_prepped01/ PROTON01. fid/ fid Value Title 1.00 Data File Name Parameter 3.26 3.8 3.6 3.4 3.2 4.39 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 6.28 2.20 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 1D 16 87. 8 1.0000 12.5000 4.0894 2024-11-06T17 58 13 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 12.0 10.5 32768 Acquired Siz e 11.0 1H 11.5 8012. 8 Nucleus 1.00 Spectral Width 10.0 8 .0 z g30 Pulse Sequence 8 .5 297.1 Temperature 9.0 CDCl3 Solvent 9.5 Bruker BioSpin GmbH Origin 146 Compound_ 86.1. fid Spectrometer Frequency 400.13 / Users/ jordankthompson/ Desktop/ Compound_ 86/ 1/ fid Value Title 12.14 Data File Name Parameter 7.5 7.0 f1 (ppm) 6.5 5.5 5.0 4.5 3 .5 3 .0 4.66 2.57 5.35 5.25 1.27 1.27 5.94 1.24 2.0 4.00 5.20 2.5 3.71 0.21 4.0 2.69 2.57 2.52 2.46 0.23 0.18 4.40 0.23 6.0 2.15 2.06 1.86 0.21 0.45 2.20 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 1.0000 10.0000 1. 2059 2024-11-06T18 18 04 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 27173 .9 Spectral Width 130 72.0 Receiver Gain 140 512 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297. 2 Temperature 146 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Value Compound_ 86. 2. fid 204.73 Title 171.84 171.61 169.14 / Users/ jordankthompson/ Desktop/ Compound_ 86/ 2/ fid Parameter 132.18 131.91 Data File Name 118.71 118.26 120 f1 (ppm) 107.34 106.75 110 100 90 80 60 65.99 65.06 64.97 64.92 64.72 70 50 40 30 38.30 36.67 34.54 32.81 30.41 28.08 54.11 95.33 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 5.67 1D 16 101.0 1.0000 9. 8500 3 .9977 2024-09-11T18 31 29 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8196.7 Spectral Width 5.0 z g30 Pulse Sequence 5.5 298 .1 Temperature 6.0 CDCl3 4.05 4.61 2.00 2.0 3.96 1.01 3.01 2.5 3.11 1.02 3 .0 2.97 2.03 4.5 f1 (ppm) 3 .5 2.73 1.00 4.0 2.55 1.02 145A Bruker BioSpin GmbH & Co. KG Solvent Spectrometer Frequency 400.15 JKT-6-165 _pure.1. fid Origin 5.92 1.00 Title Value 5.57 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-165 _pure/ 1/ fid Parameter 5.29 Data File Name 2.01 3.00 2.05 1.01 1.03 -20000 0 20000 40000 60000 80000 100000 120000 140000 160000 180000 200000 220000 240000 260000 280000 300000 45. 2 1.0000 10.0000 1. 2190 2024-09-11T18 51 21 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 26881.7 Spectral Width 130 512 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 298 .1 Temperature 170 CDCl3 122.47 119.09 120 f1 (ppm) 145A Bruker BioSpin GmbH & Co. KG Solvent Spectrometer Frequency 100.63 JKT-6-165 _pure. 2. fid 204.88 Origin 170.94 Title Value 131.58 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-165 _pure/ 2/ fid Parameter 127.22 Data File Name 110 100 90 80 70 58.69 60 50 40 40.69 37.68 34.93 44.85 66.52 65.00 64.49 106.76 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 7.4 197.4 1.0000 12.5000 4.0894 2024-09-13T06 02 43 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 2.94 5.6 5.2 16 Number of Scans 5.4 1D Experiment 5. 8 z g30 Pulse Sequence 6.0 297. 2 Temperature 6.2 CDCl3 Solvent 5.0 157 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-167-2.1. fid Title Value 5.65 5.56 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-167-2/ 1/ fid Parameter 5.09 Data File Name 4. 8 4.6 f1 (ppm) 4.4 4.2 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.4 2.2 2.92 1.98 4.01 3.99 2.0 2.66 2.01 2.6 2.52 2.01 4.0 2.03 3.99 2.00 1. 8 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 2000 72.0 1.0000 10.0000 1.1796 2024-12-22T22 21 22 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27777. 8 Spectral Width 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297.1 Temperature 170 CDCl3 Solvent 130 157 Bruker BioSpin GmbH Spectrometer Frequency 100.62 Compound88 . 2. fid Origin 211.88 Title 133.33 / Users/ jordankthompson/ Desktop/ Compound88/ 2/ fid Value 129.10 Data File Name Parameter 107.74 121.70 119.32 120 110 f1 (ppm) 100 90 80 70 60 51.08 50 40 46.10 42.04 40.33 36.55 34.29 64.69 64.55 30 20 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 297.1 z g30 1D 16 127.1 1.0000 12.5000 4.0894 2024-09-18T14 02 43 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH 6.0 JKT-6-174_pure.1. fid Origin Spectrometer Frequency 400.13 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-174_pure/ 1/ fid 5.63 Title Value 5.17 5.10 Data File Name Parameter f1 (ppm) 144A 4.5 4.0 3 .5 2.5 2.36 1.08 2.65 5.25 2.94 2.01 3.10 1.00 3 .0 2.15 1.02 1.00 1.02 2.99 2.0 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 1D 512 55.5 1.0000 10.0000 1. 2059 2024-09-18T14 22 35 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27173 .9 Spectral Width 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-174_pure. 2. fid Title 210.76 208.48 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-174_pure/ 2/ fid Value 122.79 121.24 120 f1 (ppm) 144A 127.80 130 131.27 Data File Name Parameter 110 100 90 80 70 60 50.39 47.66 46.59 50 40 37.97 35.94 42.64 30 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 CDCl3 297. 2 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2024-10-20T10 52 57 Solvent Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.5 4.5 Bruker BioSpin GmbH Origin 5.0 JKT-6-203A-1.1. fid Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-203A-1/ 1/ fid Value Title 5.50 1.91 Data File Name Parameter f1 (ppm) 162 4.0 3 .5 3 .0 2.0 1.5 1.25 0.94 1.82 2.08 2.07 1.18 2.31 4.07 2.51 1.10 2.63 0.95 2.79 1.00 2.5 1.12 2.95 1.0 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 512 64. 2 1.0000 10.0000 1. 2059 2024-10-20T11 12 48 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27173 .9 Spectral Width 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-203A-1. 2. fid Value Title 211.43 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-203A-1/ 2/ fid Parameter 129.55 Data File Name 121.27 120 110 f1 (ppm) 162 100 90 78.56 80 70 60 48.14 50 43.43 41.95 38.43 34.27 32.26 40 30 20 14.01 52.94 10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 297.1 cosygpppqf COSY 1 197.4 1.7956 12.5000 0.4014 2024-10-20T11 18 32 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (2.49, 2.49) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 1H) Nucleus 5.0 (19.5, 25.1) Lowest Frequency 5.5 (2551.0, 2551.0) Spectral Width f2 (ppm) CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-6-203A-1. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-203A-1/ 3/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 162 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) 1.5000 12.5000 0. 2135 2024-10-20T11 30 13 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 4. 8 (4.68 , 16. 22) Digital Resolution 5.2 (1024, 1024) Spectral Siz e 5.4 (1024, 180) Acquired Siz e 5.6 (1H, 13C) Nucleus 5. 8 (-556. 3 , -1262. 8) Lowest Frequency 6.0 (4795.4, 16611. 3) Spectral Width 3 .4 3 .2 f2 (ppm) 197.4 Receiver Gain 3 .6 2 Number of Scans 3.8 HSQC-EDITED Experiment 4.0 hsqcedetgpsisp 2.4 Pulse Sequence 4.2 297.1 Temperature 4.4 CDCl3 Solvent 4.6 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-6-203A-1.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-203A-1/ 4/ ser Parameter Data File Name 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 162 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) 197.4 2.0000 12.5000 0.4 260 2024-10-20T21 45 56 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 4. 8 (2. 35, 21. 80) Digital Resolution 5.2 (2048 , 1024) Spectral Siz e 5.4 (2048 , 256) Acquired Siz e 5.6 (1H, 13C) Nucleus 5. 8 (-199.5, -1116.4) Lowest Frequency 6.0 (4807.7, 22321.4) Spectral Width 3 .4 f2 (ppm) 4 Number of Scans 3 .6 HMBC Experiment 3.8 hmbcetgpl3nd Pulse Sequence 4.0 297.1 Temperature 4.2 CDCl3 Solvent 4.4 Bruker BioSpin GmbH 4.6 JKT-6-203A-1.5.ser Origin Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-203A-1/ 5/ ser Title Value Data File Name Parameter 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 162 0. 8 140 130 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) 7.2 5.30 1.0000 12.5000 4.0894 2024-10-10T15 03 25 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.4 6.2 6.0 65536 Spectral Size 6.6 32768 Acquired Size 6. 8 1H Nucleus 7.0 8012. 8 Spectral Width 5. 8 3.02 5.0 4.4 f1 (ppm) 197.4 Receiver Gain 4.6 16 Number of Scans 4. 8 1D Experiment 5.2 zg30 Pulse Sequence 5.4 297.1 Temperature 5.6 CDCl3 Solvent 4.2 163 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-191C-2.1. fid Title 5.78 0.99 / Users/ jordankthompson/ Desktop/ JKT-6-191C-2/ 1/ fid Value 5.06 Data File Name Parameter 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.2 2.0 2.31 1.99 2.41 3.01 2.59 1.04 1. 8 2.09 1.05 2.4 1.93 3.04 2.6 1.75 0.96 1.02 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 153.74 64.2 1.0000 10.0000 1. 3631 2024-10-10T15 32 15 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 120 f1 (ppm) 700 Number of Scans 130 1D Experiment 140 zgpg30 Pulse Sequence 150 297.2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-191C-2.2. fid 211.52 Title 134.55 / Users/ jordankthompson/ Desktop/ JKT-6-191C-2/ 2/ fid Value 118.15 Data File Name Parameter 106.74 110 163 100 90 78.95 80 70 60 48.18 51.95 50 40 39.24 38.70 37.75 35.65 30 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 197.4 1.7956 12.5000 0.4014 2024-10-10T15 37 58 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 4. 8 4.6 (2.49, 2.49) Digital Resolution 5.2 (1024, 1024) Spectral Size 5.4 (1024, 128) Acquired Size 5.6 (1H, 1H) Nucleus 5. 8 (51.5, 50.6) Lowest Frequency 6.0 (2551.0, 2551.0) Spectral Width 3 .2 1 Number of Scans 3 .4 f2 (ppm) COSY Experiment 3 .6 cosygpppqf Pulse Sequence 3.8 297.2 Temperature 4.0 CDCl3 Solvent 4.2 Bruker BioSpin GmbH Origin 4.4 JKT-6-191C-2. 3 .ser Title Spectrometer Frequency (400.13 , 400.13) / Users/ jordankthompson/ Desktop/ JKT-6-191C-2/ 3/ ser Value Data File Name Parameter 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 163 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2024-10-10T15 49 38 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 13C) Nucleus 5.5 (-517.1, -1262. 8) Lowest Frequency 6.0 (4795.4, 16611. 3) Spectral Width 3 .5 f2 (ppm) 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-6-191C-2.5.ser Title Value / Users/ jordankthompson/ Desktop/ JKT-6-191C-2/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 163 130 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) 7.2 60 1.0000 5.6500 3 .0000 2024-09-05T12 46 31 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.4 6.2 65536 Spectral Siz e 6.6 24000 Acquired Siz e 6. 8 1H Nucleus 7.0 8000.0 Spectral Width 1.00 5.6 3.15 5.2 4. 8 8 Number of Scans 5.0 1D Experiment 5.4 s2pul Pulse Sequence 5. 8 25.0 Temperature 6.0 cdcl3 Solvent 4.6 f1 (ppm) 4.4 144B Varian Spectrometer Frequency 499.54 PROTON01 Origin 5.64 Title Value 5.31 / Users/ jordankthompson/ Desktop/ JKT-6-156-2/ PROTON01. fid/ fid Parameter 5.20 5.14 Data File Name 4.2 4.0 3.8 3 .6 3 .4 3 .2 2. 8 2.6 2.94 3.14 2.2 2.69 4.23 2.4 2.40 2.11 3 .0 2.16 1.05 1.05 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 8000 8500 9000 1D 512 78 .7 1.0000 10.0000 1. 3631 2024-05-01T12 05 48 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Spectrometer Frequency 100.62 ST-1-151-prod-c. 3 . fid Origin 210.80 208.49 Title Value 137.67 / Users/ jordankthompson/ Desktop/ ST-1-151-prod-c/ 3/ fid Parameter 130 131.33 Data File Name 118.03 121.22 120 f1 (ppm) 144B 110 100 90 80 70 60 50.05 46.63 45.98 42.66 50 40 37.74 35.94 0 500 1000 1500 2000 2500 7.4 1.0000 12.5000 4.0894 2024-10-10T16 19 19 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 1.00 6.2 1.04 1.04 5.0 4. 8 197.4 Receiver Gain 5.2 16 Number of Scans 5.4 1D Experiment 5.6 z g30 Pulse Sequence 5. 8 297.1 Temperature 6.0 CDCl3 Solvent Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 6.18 JKT-6-191D-2.1. fid 5.69 / Users/ jordankthompson/ Desktop/ JKT-6-191D-2/ 1/ fid 4.97 Title Value 4.88 Data File Name Parameter 4.6 4.4 f1 (ppm) 167 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2.4 2.83 2.10 2.0 2.69 2.2 2.58 3.11 3.10 2.6 2.21 1.07 2. 8 1.95 1.07 1.01 1. 8 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 1D 512 35.5 1.0000 10.0000 1. 3631 2024-10-10T16 40 30 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-6-191D-2. 2. fid Origin 211.35 / Users/ jordankthompson/ Desktop/ JKT-6-191D-2/ 2/ fid 207.82 Title Value 138.57 Data File Name Parameter 128.83 130 114.98 125.44 120 f1 (ppm) 167 110 100 90 80 70 60 47.56 46.98 50 40 38.34 37.10 36.36 33.24 30 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 297. 2 cosygpppqf COSY 1 197.4 1. 8202 12.5000 0. 3768 2024-10-10T16 46 14 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (2.65, 2.65) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 1H) Nucleus 5.5 (46.4, 40.4) Lowest Frequency 6.0 (2717.4, 2717.4) Spectral Width 3 .5 f2 (ppm) CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-6-191D-2. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Users/ jordankthompson/ Desktop/ JKT-6-191D-2/ 3/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 167 0.5 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 197.4 1.5000 12.5000 0. 2135 2024-10-10T16 57 54 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.2 (4.68 , 16. 22) Digital Resolution 5.4 (1024, 1024) Spectral Siz e 5.6 (1024, 180) Acquired Siz e 5. 8 (1H, 13C) Nucleus 6.0 (-526.7, -1258 .0) Lowest Frequency 6.2 (4795.4, 16611. 3) Spectral Width 4.0 f2 (ppm) 2 Number of Scans 4.2 HSQC-EDITED Experiment 4.4 hsqcedetgpsisp 2.4 Pulse Sequence 4.6 297.1 Temperature 4. 8 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-6-191D-2.4.ser Title Value / Users/ jordankthompson/ Desktop/ JKT-6-191D-2/ 4/ ser Parameter Data File Name 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 167 1. 8 140 130 120 110 100 90 80 70 60 50 40 30 f1 (ppm) 7.4 7.2 16 197.4 1.0000 12.5000 4.0894 2024-10-13T11 59 32 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.4 6.2 65536 Spectral Siz e 6.6 32768 Acquired Siz e 6. 8 1H Nucleus 7.0 8012. 8 Spectral Width 2.00 5.6 4. 8 1D Experiment 5.0 z g30 Pulse Sequence 5.2 297.1 Temperature 5.4 CDCl3 Solvent 5. 8 Bruker BioSpin GmbH Origin 6.0 JKT-6-179-1.6. fid Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-179-1/ 6/ fid 5.64 Title Value 5.12 Data File Name Parameter 4.6 f1 (ppm) 4.4 168 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.2 2.45 2.03 2.68 6.46 2.4 2.12 2.02 4.01 2.0 1. 8 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 220 211.57 209.02 1D 750 50. 3 1.0000 10.0000 1. 2059 2024-10-13T12 28 25 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27173 .9 Spectral Width 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin 180 JKT-6-179-1.7. fid Title Spectrometer Frequency 100.62 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-179-1/ 7/ fid Value Data File Name Parameter 132.13 130 f1 (ppm) 120.42 120 168 110 100 90 80 70 60 50.98 50 40 41.93 37.90 36.10 47.25 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 297.1 cosygpppqf COSY 3 197.4 1.9001 12.5000 0. 2970 2024-10-13T12 43 46 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 . 37, 3 . 37) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 1H) Nucleus 6.5 (-216. 2, -216. 2) Lowest Frequency 7.0 (3448 . 3 , 3448 . 3) Spectral Width 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-6-179-1. 8 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-179-1/ 8/ ser Title Value Data File Name Parameter 4.0 f2 (ppm) 3 .5 3 .0 2.5 2.0 1.5 1.0 168 0.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 4 197.4 1.5000 12.5000 0. 2135 2024-10-13T13 05 56 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 (4.68 , 16. 22) Digital Resolution 5.2 (1024, 1024) Spectral Siz e 5.4 (1024, 180) Acquired Siz e 5.6 (1H, 13C) Nucleus 5. 8 (-517.1, -1262. 8) Lowest Frequency 6.0 (4795.4, 16611. 3) Spectral Width 4.0 f2 (ppm) HSQC-EDITED Experiment 4.2 hsqcedetgpsisp 2.4 Pulse Sequence 4.4 297.1 Temperature 4.6 CDCl3 Solvent 4. 8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-6-179-1.9.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-179-1/ 9/ ser Parameter Data File Name 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 168 2.0 130 120 110 100 90 80 70 60 50 40 f1 (ppm) 16 156. 2 1.0000 12.5000 4.0894 2024-10-18T03 47 35 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 1.00 5. 8 5.2 5.0 4.6 4.4 f1 (ppm) 4.2 4.0 3 .2 3 .0 2. 8 2.6 2.2 2.0 3.65 1.05 3.82 1.04 4.78 1.05 2.4 3.55 2.11 3 .4 3.37 3.10 3 .6 2.37 7.10 3.8 2.11 1.06 4. 8 1D Experiment 5.4 z g30 Pulse Sequence 5.6 297.1 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH Origin 143 JKT-6-201_pure.1. fid 1.03 1.04 1.01 0.98 1.06 Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-201_pure/ 1/ fid 5.81 Title Value 5.19 5.11 5.02 4.93 Data File Name Parameter 1.87 2.05 1. 8 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 211.68 512 78 .7 1.0000 10.0000 1. 2059 2024-10-18T04 07 27 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 190 65536 Spectral Siz e 200 32768 Acquired Siz e 210 13C Nucleus 220 27173 .9 Spectral Width 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297. 2 Temperature 180 CDCl3 Solvent 140 143 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-201_pure. 2. fid Title Value 150.31 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-201_pure/ 2/ fid Parameter 134.73 Data File Name 117.93 130 120 f1 (ppm) 110 100 91.29 90 80 71.91 70 59.16 60 50 40 39.78 38.49 38.18 35.79 44.52 52.22 67.18 83.63 107.51 30 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 cosygpppqf COSY 1 64. 2 1.7977 12.5000 0. 3994 2024-12-17T07 4 2 44 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (2.50, 2.50) Spectral Siz e Digital Resolution 5.0 (1024, 128) Acquired Siz e 5.5 (1H, 1H) Nucleus 6.0 (56.0, 56.0) Lowest Frequency 6.5 (2564.1, 2564.1) Spectral Width 3 .0 297.1 Temperature 3 .5 f2 (ppm) CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-6-280-1_high_vac. 3 .ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-280-1_high_vac/ 3/ ser Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 143 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) cat. Parameter 297.1 hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2024-10-18T04 19 12 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 (4.68 , 16. 22) Digital Resolution 5.2 (1024, 1024) Spectral Siz e 5.4 (1024, 180) Acquired Siz e 5.6 (1H, 13C) Nucleus 5. 8 (-517.1, -1262. 8) Lowest Frequency 6.0 (4795.4, 16611. 3) Spectral Width 4. 8 CDCl3 Spectrometer Frequency (400.13 , 100.62) Bruker BioSpin GmbH JKT-6-201_pure. 3 .ser Solvent cat. Value 4.6 4.4 4.2 4.0 3.8 f2 (ppm) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-201_pure/ 3/ ser Origin Title Data File Name 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 143 1.6 130 120 110 100 90 80 70 60 50 40 30 f1 (ppm) 7.4 16 197.4 1.0000 12.5000 4.0894 2024-11-14T13 27 52 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 1.00 5. 8 1.00 5.6 4.04 5.2 4. 8 1D Experiment 5.0 z g30 Pulse Sequence 5.4 297.1 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH Spectrometer Frequency 400.13 JKT-6-246 _pure.1. fid 5.77 Origin 5.15 Title 4.92 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-246 _pure/ 1/ fid 1.02 4.6 f1 (ppm) 4.4 142 4.2 4.0 3 .2 3 .0 3.63 3.54 1.01 1.99 3.84 1.01 2.6 3.39 3.03 2. 8 2.81 1.00 3 .4 2.69 1.00 3 .6 2.54 0.99 3.8 1.03 2.4 2.2 2.37 2.26 2.14 2.05 5.61 Value 4.71 Data File Name Parameter 1.99 2.0 1.00 0.99 1.02 1. 8 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 153.19 151.44 512 64. 2 1.0000 10.0000 1. 2059 2024-11-14T13 47 43 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 140 32768 Acquired Siz e 150 13C Nucleus 160 27173 .9 Spectral Width 100 1D Experiment 110 z gpg30 Pulse Sequence 120 297.1 Temperature 130 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 133.35 JKT-6-246 _pure. 2. fid 118.89 Title 115.76 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-246 _pure/ 2/ fid Value 109.35 Data File Name Parameter f1 (ppm) 91.19 90 142 80 70 59.17 60 50 41.04 40 37.77 45.43 45.28 44.71 67.20 71.91 83.03 30 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 10.0 9.76 298 . 2 z g30 1D 16 101.0 1.0000 9. 8500 3 .9977 2022-08-07T14 21 40 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 9.0 1H Nucleus 9.5 8196.7 Spectral Width 8 .0 CDCl3 Solvent 8 .5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.15 JKT-2-87 _pure.1. fid 0.96 Value 7.5 7.0 6.5 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-87 _pure/ 1/ fid Title Data File Name Parameter 6.0 f1 (ppm) 107A 5.5 4.5 4.0 3.84 1.00 4.71 0.99 4.92 1.04 5.17 1.00 1.00 5.65 0.99 2.5 3.61 3.53 3.37 1.02 2.04 3.05 3 .0 2.95 2.06 3 .5 2.77 1.02 5.0 2.52 2.40 2.28 1.03 2.10 2.18 -2000000 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 500 45. 2 2.0000 10.0000 1. 3763 2022-08-07T14 51 01 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 23809.5 Spectral Width 130 1D Experiment 140 z gpg30 Pulse Sequence 150 298 . 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.63 JKT-2-87 _pure. 2. fid Value Title 198.76 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-87 _pure/ 2/ fid Parameter 151.49 149.90 Data File Name 120 f1 (ppm) 107A 109.70 110 100 91.22 90 80 70 59.13 60 50 40 47.66 46.08 44.98 42.26 41.10 67.27 71.86 83.06 115.31 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 16 9.82 z g30 1D 16 87. 8 1.0000 12.5000 4.0894 2022-11-02T15 22 46 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 13 32768 Acquired Siz e 14 1H Nucleus 15 8012. 8 Spectral Width 0.94 10 8 297.1 Temperature 9 CDCl3 Solvent 11 Bruker BioSpin GmbH Origin 12 JKT-2-165-1.1. fid Title Spectrometer Frequency 400.13 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-2-165-1/ 1/ fid Data File Name Value 7 6 f1 (ppm) 5 4 3 5.17 5.10 4.92 4.71 0.98 1.00 1.02 1.00 107B 5.94 0.95 Parameter 3.83 3.61 3.52 3.37 3.10 2.70 2.36 2.15 1.00 1.00 2.00 3.02 0.97 1.97 4.00 1.05 2 1 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 1D 512 72.0 1.0000 10.0000 1. 3631 2022-11-02T15 43 59 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 32768 65536 180 Nucleus Acquired Siz e Spectral Siz e 200 190 24038 .5 Spectral Width 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-2-165-1. 2. fid Origin Value Title 200.39 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-2-165-1/ 2/ fid Parameter 151.00 Data File Name 128.93 128.15 130 f1 (ppm) 120 107B 109.33 110 100 91.14 90 80 70 59.13 60 50 51.41 46.65 45.81 45.31 45.09 67.19 71.86 83.41 40 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 12.5 11.96 Parameter Value 1D 16 101.0 1.0000 9. 8500 3 .9977 2024-04-12T15 50 01 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 12.0 10.5 32768 Acquired Siz e 11.0 1H 11.5 8196.7 Nucleus 0.89 Spectral Width 9.5 z g30 Pulse Sequence 10.0 298 . 2 Temperature 9.0 150A CDCl3 Spectrometer Frequency 400.15 Bruker BioSpin GmbH & Co. KG Solvent ST-1-111-prod.1. fid 8.5 8.0 7.5 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-111-prod/ 1/ fid Origin Title Data File Name 7.0 6.5 f1 (ppm) 5.5 5.0 4.5 3.5 3.0 1.5 4.00 4.81 4.76 2.10 5.65 1.11 5.90 1.00 2.0 2.53 4.10 2.5 2.04 0.77 4.0 1.86 2.11 6.0 1.26 0.70 1.0 -200000 0 200000 400000 600000 800000 1000000 1200000 1400000 1600000 1800000 2000000 2200000 2400000 2600000 2800000 3000000 172.52 170.99 126.22 1D 512 72.0 1.0000 10.0000 1. 3631 2024-05-17T00 20 05 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 130 110 z gpg30 Pulse Sequence 120 297.1 Temperature 140 CDCl3 Solvent 150A Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-1-111-c.1. fid Title Value 119.03 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-111-c/ 1/ fid Parameter 107.25 Data File Name 95.06 100 f1 (ppm) 90 80 70 60 50 40 30 32.71 30.36 28.17 67.34 64.75 20 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 Value 7.5 150B 6.5 f1 (ppm) 6.0 5.0 4.5 3.5 3.0 297.1 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2024-05-16T18 20 12 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 10.5 32768 Acquired Siz e 11.0 1H Nucleus 11.5 8012. 8 Spectral Width 9.5 CDCl3 Solvent 10.0 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 ST-chloro-h.1. fid Title 9.0 8.5 8.0 2.0 1.5 0.85 2.5 5.47 5.41 0.92 1.00 4.0 4.71 2.25 7.0 4.02 4.08 / Users/ shawnteh/ Desktop/ ST-chloro-h/ 1/ fid 2.52 2.65 5.5 Parameter 2.04 1.00 Data File Name 1.85 1.87 12.0 11.97 1.28 1.53 1.0 0 5000 10000 15000 20000 25000 30000 35000 40000 180 172.49 171.10 z gpg30 1D 512 78 .7 1.0000 10.0000 1. 3631 2024-05-16T22 44 27 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 120 297.1 Temperature 130 CDCl3 Solvent 140 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-chloro-c. 3 . fid Title Value 135.84 / Users/ shawnteh/ Desktop/ ST-chloro-c/ 3/ fid Parameter 114.91 Data File Name 110 100 150B 95.05 f1 (ppm) 90 80 69.54 65.80 64.75 70 60.55 60 50 40 32.73 30.36 28.16 30 21.21 20 14.35 107.24 10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 5.05 42 1.0000 2.6500 1.7080 2024-04-12T20 03 45 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 16384 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 9592. 3 Spectral Width 6.0 1.39 1.02 f1 (ppm) 4.27 4.0 3.5 16 Number of Scans 4.5 1D Experiment 5.0 s2pul Pulse Sequence 5.5 25.0 0.95 155 cdcl3 Temperature 0.99 Spectrometer Frequency 599.56 Varian Solvent 5.94 1.04 Origin 5.80 ST-1-109-prod-PROTON_ 01 5.66 Title Value 4.75 4.69 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-109-prod_20240412_ 01/ ST-1-109-prod-PROTON_ 01. fid/ fid Parameter 4.00 Data File Name 2.0 3.06 1.06 2.5 2.57 2.49 1.11 4.07 3.0 2.00 2.08 2.13 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 5.79 16 72.0 1.0000 12.5000 4.0894 2024-08-21T17 27 28 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 7.0 6. 8 6.6 65536 Spectral Siz e 7.2 32768 Acquired Siz e 7.4 1H Nucleus 7.6 8012. 8 Spectral Width 1.00 5. 8 0.99 0.99 5.4 5.2 1D Experiment 5.6 z g30 Pulse Sequence 6.0 297.1 Temperature 6.2 CDCl3 Solvent 6.4 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-137 _pure.1. fid Title Value 5.49 5.41 / Users/ jordankthompson/ Desktop/ JKT-6-137 _pure/ 1/ fid Parameter 5.07 5.04 Data File Name 1.99 5.0 4. 8 4.2 3.8 3 .6 3 .4 3 .2 2. 8 2.6 2.4 2.2 1. 8 4.69 4.61 1.00 1.02 2.0 4.03 3.96 0.99 3.01 3 .0 3.03 0.99 4.0 2.51 3.99 4.6 f1 (ppm) 4.4 2.00 2.03 156 1.85 0.98 -10000 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 87. 8 1.0000 10.0000 1. 3631 2024-08-21T17 48 4 2 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 130 512 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297.1 Temperature 170 CDCl3 119.32 120 f1 (ppm) 156 Bruker BioSpin GmbH Solvent Spectrometer Frequency 100.62 JKT-6-137 _pure. 2. fid Origin 206.10 Title 171.29 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-137 _pure/ 2/ fid Value 135.43 133.20 Data File Name Parameter 110 100 90 80 70 58.64 60 50 40 41.41 39.70 37.93 35.22 66.98 65.08 64.45 106.83 115.83 30 0 500 1000 1500 2000 2500 3000 3500 4000 4500 7.4 5.66 127.1 1.0000 12.5000 4.0894 2024-08-27T06 02 56 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6. 8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8012. 8 Spectral Width 1.00 5.6 5.0 16 Number of Scans 5.2 1D Experiment 5.4 z g30 Pulse Sequence 5. 8 297.1 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-140_pure.1. fid Title Value 5.28 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-140_pure/ 1/ fid Parameter 5.09 Data File Name 4. 8 4.6 f1 (ppm) 161 4.4 4.2 3.8 3 .6 3 .4 3 .2 3 .0 2.4 2.2 2.86 4.00 4.05 2.0 2.76 1.00 1.01 2.6 2.63 2.09 2. 8 2.50 1.99 4.0 2.00 4.08 3.04 0.99 1. 8 0 5000 10000 15000 20000 25000 512 35.5 1.0000 10.0000 1. 3631 2024-08-27T06 24 07 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-6-140_pure. 2. fid 211.90 Title Value 138.75 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-140_pure/ 2/ fid Parameter 133.37 Data File Name 119.28 117.02 120 f1 (ppm) 161 110 100 90 80 70 60 50.68 50 40 44.35 42.17 40.26 36.37 34.35 64.67 64.55 107.73 30 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 7.2 60 1.0000 5.6500 3 .0000 2024-09-05T12 46 31 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.4 6.2 65536 Spectral Siz e 6.6 24000 Acquired Siz e 6. 8 1H Nucleus 7.0 8000.0 Spectral Width 1.00 5.6 3.15 5.2 4. 8 8 Number of Scans 5.0 1D Experiment 5.4 s2pul Pulse Sequence 5. 8 25.0 Temperature 6.0 cdcl3 Solvent 4.6 f1 (ppm) 4.4 144B Varian Spectrometer Frequency 499.54 PROTON01 Origin 5.64 Title Value 5.31 / Users/ jordankthompson/ Desktop/ JKT-6-156-2/ PROTON01. fid/ fid Parameter 5.20 5.14 Data File Name 4.2 4.0 3.8 3 .6 3 .4 3 .2 2. 8 2.6 2.94 3.14 2.2 2.69 4.23 2.4 2.40 2.11 3 .0 2.16 1.05 1.05 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 8000 8500 9000 1D 512 78 .7 1.0000 10.0000 1. 3631 2024-05-01T12 05 48 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Spectrometer Frequency 100.62 ST-1-151-prod-c. 3 . fid Origin 210.80 208.49 Title Value 137.67 / Users/ jordankthompson/ Desktop/ ST-1-151-prod-c/ 3/ fid Parameter 130 131.33 Data File Name 118.03 121.22 120 f1 (ppm) 144B 110 100 90 80 70 60 50.05 46.63 45.98 42.66 50 40 37.74 35.94 0 500 1000 1500 2000 2500 4.74 1.0000 2.6500 1.7080 2024-04-19T15 55 02 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 16384 Acquired Siz e 7.0 1H Nucleus 7.5 9592. 3 Spectral Width 6.0 f1 (ppm) 4.19 4.0 3.0 38 Receiver Gain 3.5 8 Number of Scans 4.5 1D Experiment 5.0 s2pul Pulse Sequence 5.5 25.0 158 cdcl3 Temperature Spectrometer Frequency 599.56 Varian 5.98 1.00 Solvent 5.71 Origin 4.86 ST-1-126-prod-PROTON_ 01 4.00 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-126-prod_20240419_ 01/ ST-1-126-prod-PROTON_ 01. fid/ fid 3.12 Title Value 2.5 2.0 2.89 2.75 2.70 2.62 1.11 1.14 1.11 1.17 Data File Name Parameter 2.08 2.84 1.09 1.12 1.04 0.97 1.5 1.0 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 72.0 1.0000 10.0000 1. 3631 2024-05-17T01 07 48 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 120 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 203.22 ST-1-126-c.1. fid 169.33 Title Value 124.90 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-126-c/ 1/ fid Parameter 121.10 Data File Name 106.13 110 f1 (ppm) 158 100 90 80 70 69.52 65.32 64.71 60.54 56.43 60 50 41.38 37.19 34.92 40 30 23.70 21.20 20 14.34 116.23 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 6.6 7.4 6.4 65536 Spectral Siz e 6.8 16384 Acquired Siz e 7.0 1H Nucleus 7.2 9592. 3 Spectral Width 5.4 1.00 0.98 5.6 5.2 0.91 4.8 1.05 4.6 f1 (ppm) 3.94 4.0 3.4 2024-04-19T17 47 44 Acquisition Date 3.6 1.7080 Acquisition Time 3.8 2.6500 Pulse Width 4.2 1.0000 Relaxation Delay 4.4 42 Receiver Gain 5.0 8 Number of Scans 5.8 1D Experiment 6.0 s2pul Pulse Sequence 6.2 25.0 Temperature 159 cdcl3 Solvent Spectrometer Frequency 599.56 Varian Origin 5.53 5.46 St-1-127-prod-PROTON_ 01 4.80 / Users/ shawnteh/ Desktop/ Tobesorted/ St-1-127-prod_20240419_ 01/ St-1-127-prod-PROTON_ 01. fid/ fid 4.67 Title Value 3.99 Data File Name Parameter 3.2 3.0 2.4 2.2 2.0 3.09 1.10 2.6 2.88 2.75 2.67 2.62 1.08 1.12 1.11 1.13 2.8 2.06 3.86 1.8 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 512 72.0 1.0000 10.0000 1. 3631 2024-05-17T01 30 53 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 170 CDCl3 Solvent 130 159 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-1-127-c.1. fid Value Title 203.24 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-127-c/ 1/ fid Parameter 134.80 Data File Name 110 f1 (ppm) 116.93 116.21 120 100 90 80 68.00 65.32 64.71 70 60 50 41.39 37.15 34.94 40 30 23.67 56.42 106.13 20 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 5.67 16 101.0 1.0000 9. 8500 3 .9977 2024-04-18T11 44 50 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 7.4 6.4 65536 Spectral Siz e 6.8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8196.7 Spectral Width 6.0 1.12 5.6 5.0 1D Experiment 5.2 z g30 Pulse Sequence 5.4 298 . 2 Temperature 5.8 CDCl3 Solvent 6.2 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency 400.15 ST-1-119-prod.1. fid 5.97 1.00 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-119-prod/ 1/ fid 4.84 Title Value 4.74 Data File Name Parameter 1.37 1.24 4.8 4.6 4.4 f1 (ppm) 153 4.2 3.6 3.4 2.8 2.4 2.2 3.98 3.94 1.8 3.84 1.26 2.0 3.68 1.09 2.6 3.14 0.97 3.0 2.94 0.86 3.2 2.52 1.88 3.8 2.02 2.35 4.0 1.82 1.10 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 1100000 1200000 1300000 1400000 1500000 1600000 1700000 1800000 1900000 2000000 2100000 2200000 512 72.0 1.0000 10.0000 1. 3631 2024-05-16T23 56 03 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent 170 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 ST-1-119-c.1. fid Value Title 209.61 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-119-c/ 1/ fid Parameter 170.36 Data File Name 120.03 120 f1 (ppm) 153 110 100 90 80 68.78 66.78 65.23 64.63 70 60.26 60 50 40 30 38.71 38.24 34.88 31.09 106.50 125.38 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 5.47 1.0000 9. 8500 3 .9977 2024-04-18T11 49 39 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.6 6.4 65536 Spectral Siz e 6.8 32768 Acquired Siz e 7.0 1H Nucleus 7.2 8196.7 Spectral Width 0.99 5.4 4.8 101.0 Receiver Gain 5.0 16 Number of Scans 5.2 1D Experiment 5.6 z g30 Pulse Sequence 5.8 298 . 2 Temperature 6.0 CDCl3 Solvent 6.2 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency 400.15 ST-1-120-prod.1. fid Title Value 5.37 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-120-prod/ 1/ fid Parameter 4.64 Data File Name 2.40 4.6 4.4 f1 (ppm) 4.2 154 3.4 3.2 2.6 2.2 1.8 3.91 4.22 2.0 3.78 1.18 2.4 3.61 1.19 2.8 3.07 1.12 3.0 2.85 1.02 3.6 2.45 2.20 3.8 1.95 1.83 4.0 1.76 1.11 1.00 -200000 0 200000 400000 600000 800000 1000000 1200000 1400000 1600000 1800000 2000000 2200000 2400000 72.0 1.0000 10.0000 1. 3631 2024-05-17T00 44 13 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 130 512 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 170 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Value ST-1-120-c.1. fid 209.63 Title 170.47 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-120-c/ 1/ fid Parameter 135.18 Data File Name 115.91 120 f1 (ppm) 154 110 100 90 80 60 67.23 66.76 65.23 64.62 60.25 70 50 40 38.70 38.20 34.90 106.49 30 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 4.72 4.61 36 1.0000 2.6500 1.7080 2024-04-24T15 36 25 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 16384 Acquired Siz e 7.0 1H Nucleus 7.5 9592. 3 Spectral Width 1.00 0.96 5.5 0.89 4.61 4.0 f1 (ppm) 3.5 8 Number of Scans 4.5 1D Experiment 5.0 s2pul Pulse Sequence 6.0 25.0 Temperature 154' cdcl3 Solvent 1.10 Spectrometer Frequency 599.56 Varian Origin 5.50 5.40 ST-1-135-2-PROTON_ 01 4.05 3.98 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-135-2_202404 24_ 01/ ST-1-135-2-PROTON_ 01. fid/ fid 3.75 Title Value 2.97 Data File Name Parameter 1.08 3.0 1.5 2.54 1.96 0.5 2.14 1.08 1.0 2.01 2.13 2.0 0.93 8.99 2.5 0.58 5.97 1.24 1.04 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 78 .7 1.0000 10.0000 1. 3631 2024-05-17T01 55 15 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 24038 .5 Spectral Width 120 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 160 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 204.76 ST-1-135-c.1. fid 170.21 Title Value 135.30 / Users/ shawnteh/ Desktop/ Tobesorted/ ST-1-135-c/ 1/ fid Parameter 115.34 Data File Name 107.09 110 100 f1 (ppm) 154' 90 80 60 66.83 65.06 64.53 64.50 60.95 70 50 38.29 38.14 34.77 40 30 20 10 6.83 4.39 0 0 500 1000 1500 2000 2500 7.5 1D 8 48 1.0000 5.6500 3 .0000 2024-08-21T21 41 52 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 24000 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 4.5 s2pul Pulse Sequence 5.0 25.0 Temperature 5.5 cdcl3 Solvent 6.0 Varian Origin 173 PROTON01 Spectrometer Frequency 499.54 / Users/ jordankthompson/ Desktop/ JKT-6-139-2/ PROTON01. fid/ fid Title Value 4.27 Data File Name Parameter 2.00 f1 (ppm) 3 .5 3 .0 2.5 2.0 1.5 1.83 3.95 2.34 3.90 3.96 4.04 4.0 1.34 3.03 1.0 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 7.07 7.37 Parameter 7.21 2024-08-26T11 24 30 Acquisition Date 7.5 2.03 Spectral Siz e Acquired Siz e Nucleus Spectral Width 7.0 6.5 65536 24000 1H 8000.0 6.0 3 .0000 Acquisition Time Spectrometer Frequency 499.54 5.6500 1.0000 Relaxation Delay Pulse Width 42 8 Receiver Gain 1D Number of Scans s2pul Experiment Pulse Sequence cdcl3 Varian PROTON01 25.0 1.98 Value 4.29 4.23 5.5 5.0 4.5 174 / Users/ jordankthompson/ Desktop/ JKT-6-141-C2-3/ PROTON01. fid/ fid Temperature Solvent Origin Title 0.97 4.06 3.98 f1 (ppm) 4.0 1.00 0.99 0.94 3.05 Data File Name 3 .5 3 .0 1.5 2.02 3.08 2.23 1.03 2.51 2.46 1.02 1.02 1.00 2.0 1.83 1.01 2.5 1.33 2.99 2.65 2.84 1.03 3.08 1.04 1.0 -500 0 500 1000 1500 2000 2500 3000 3500 4000 210 64. 2 1.0000 10.0000 1. 3631 2024-08-26T12 46 39 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 120 700 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 207.06 JKT-6-141-C2-3 . 2. fid 172.04 171.61 Title Value 150.83 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-141-C2-3/ 2/ fid Parameter 129.53 125.90 121.70 Data File Name 106.73 110 f1 (ppm) 100 174 90 80 70 65.12 64.45 61.76 60 50 37.99 35.46 40 30.36 29.99 30 20 14.17 42.50 57.44 10 -500 0 500 1000 1500 2000 2500 3000 3500 1D 16 112. 8 1.0000 12.5000 4.0894 2024-08-30T14 57 29 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 7.0 32768 Acquired Siz e 7.5 1H Nucleus 8 .0 8012. 8 Spectral Width 5.0 z g30 Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 6.5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-6-153-1.1. fid Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-153-1/ 1/ fid Parameter Data File Name 4.5 4.0 3 .5 3 .0 2.0 1.5 3.10 2.00 4.23 2.12 2.5 2.69 2.57 2.03 1.98 f1 (ppm) 175 1.30 3.13 1.0 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 1D 16 32.0 1.0000 10.0000 0.0000 2024-09-03T14 46 14 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 0 Acquired Siz e 7.0 1H Nucleus 7.5 8196.7 Spectral Width 6.0 z g30 Pulse Sequence Spectrometer Frequency 400.15 298 .0 Temperature 5.5 5.0 4.5 4.0 f1 (ppm) Bruker BioSpin GmbH & Co. KG Origin Solvent JKT-6-155-B3-L.1.1.1r Title Value 4.24 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-6-155-B3-L/ 1/ pdata/ 1/ 1r Parameter 3 .5 176 3.14 3.04 3 .0 1.00 1.00 Data File Name 2.0 1.5 2.33 2.22 2.08 1.12 1.11 2.13 2.54 4.47 2.5 1.28 7.63 4.04 1.0 0.5 8 0.0 5.0×10 1.0×10 9 9 1.5×10 9 2.0×10 9 2.5×10 9 3 .0×10 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 500 Chapter 5 Development of a vinylogous Mukaiyama Aldol fragment coupling reaction and intramolecular Ni-catalyzed a-enolate alkenylation† 5.1 INTRODUCTION This chapter describes the development of the two most important steps of the synthesis: the vinylogous Mukaiyama aldol reaction and the Ni-catalyzed a-enolate alkenylation. Early hit identification in the vinylogous Mukaiyama aldol reaction along with the subsequent reaction optimization are explored. Synthesis of the a-enolate alkenylation substrate followed by development of Ni-catalyzed a-enolate alkenylation conditions using electron-deficient olefin ligands is presented. Taken together, this chapter † Portions of this chapter were adapted from the following communication: Thompson, J. K.; Youngblood, K. C.; Teh, S. Y. H.; Farley, C. M.; Zhang, Z.; Virgil, S. C.; Reisman, S. E. J. Am. Chem. Soc. 2025, 147, 42170–42174. Dr. Michael Takase is acknowledged for acquiring the X-ray diffraction data, and Preston Mott is thanked for assistance in solving the X-ray structure of 106A. J.K.T. was supported by the NSF GRFP (DGE-1745301). S.E.R. acknowledges fellowship support by the NIH (R35GM118191). 501 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation reports a rapid fragment coupling assembly to establish the pentacyclic core of auriculatol A. 5.2 CONVERGENT FRAGMENT COUPLING: OPTIMIZATION OF THE VINYLOGOUS MUKAIYAMA ALDOL ADDITION 5.2.1 Early optimization of enol triflate substrate (107A) VMAR Initially, using conditions optimized on the model aryl aldehyde from Chapter 2 for the vinylogous Mukaiyama aldol reaction (VMAR) on the more complex 3.2.1 bicyclic aldehyde (107A) led to 8% yield of 106A (Scheme 5.1). Clearly, exploration of the reaction conditions and a thorough optimization campaign were required to increase the yield to adequate quantities. Scheme 5.1. Initial experimentation in the more advanced VMAR coupling. OTBS O TBSO + O Me TfO ZnBr2 (1.1 equiv) OMEM O Me Me (1 equiv) 80% ee (1 equiv) >95% ee 88 107A THF, −78 °C, 8 h 8% yield O OTf TBSO Me HO MEMO 106A Recrystallization by slow evaporation of toluene overnight enabled isolation of crystals suitable for X-ray diffraction (XRD) analysis. In line with previous results described in Chapter 2, the major diastereomer exhibited a-stereochemistry at the alcohol stereogenic center (Scheme 5.2). While this was undesired for the synthesis of auriculatol A, it was envisioned that epimerization later in the synthesis would be possible. The crystal structure verified g-functionalization of the silyloxyfuran starting material, establishing the fully-substituted g-position of the product butenolide in the desired fashion; that is, functionalization of the silyloxyfuran starting material occurred from the less-hindered Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 502 face, opposite to that of the TBS group, in line with results from Chapter 2. Scheme 5.2. XRD verifies major product (106A) structure and stereochemistry. In comparison to the aryl aldehyde 61, which provided the desired coupled product in 52% yield, the conversion with 107A was much lower (< 20%, Scheme 5.3). It was hypothesized that the steric bulk of the 3.2.1-bicycle in 107A, despite being distal to the aldehyde-functionality, disfavors the desired coupling reaction – or any coupling reaction for the matter. It is possible, as well, that the electronic effect of the homobenzylic aldehyde is important in the aryl-aldehyde (61) system. The distribution of recovered butenolide 60 in the model system VMAR was also of interest. Higher levels of butenolide 60 in the reaction with 61 vs. 107A were observed. Although this product could result from hydrolysis under the work up conditions, it is also possible that the butenolide 60 forms under the reaction conditions from deprotonation of the a-aldehyde protons (Scheme 5.3, protons highlighted in purple). The increased acidity of the benzylic a-aldehyde protons in 61 could explain the higher conversion and formation of 60. 503 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.3. Model system VMAR vs. more advanced VMAR conversions and yields. H OTBS H Br O O ZnBr2 (1 equiv) O TBSO Me Me ZnBr2 (1 equiv) OMEM 88 Me H H Me 60 O O O OTf O H TBSO THF, −78 °C, 7 h < 20% conversion 61 Me 30% yield MeO Me O Me 59 TfO O TBSO 52% yield 61 OTBS TBSO full conversion MeO 88 O H Br Me HO THF, −78 °C, 7 h TBSO O O Me Me HO 8% yield TBSO MEMO 106A Me Me 12% yield 60 As with the model system, choice of solvent had a dramatic influence on conversion. Preliminary results indicated that the reaction could be conducted at 22 °C and give higher conversion (not shown). For this reason, early studies focused on screening parameters of the reaction at room temperature broadly. No yield was observed across several solvents, including non-polar (toluene), alcohol-containing (TFE), amidecontaining (DMA), and nitrile-containing (ACN) solvents (Scheme 5.4). Carbonylcontaining solvents (EtOAc, acetone, and isopropyl acetate) were determined to be better, providing yields ranging from 13-16%. Et2O was identified as the best solvent, leading to slightly increased yields (25%) when compared to THF (16%). Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 504 Scheme 5.4. Solvent screen in the more advanced key VMAR coupling. OTBS TfO O TBSO + Me Me O Me ZnBr2 (1 equiv) (1 equiv) 80% ee (1 equiv) >95% ee 88 107A OTf O TBSO OMEM O Solvent, 22 °C, 16 h Me HO MEMO 106A Solvent Result Solvent Result ACN TFE no product THF 16% yield no product THP 7% yield DMA no product EtOAc 13% yield DMSO no product Acetone 13% yield Dioxane no product Isopropyl Acetate 13% yield 2-methyl THF trace product Dimethyl Carbonate 16% yield Toluene no product Et2O 25% yield Next, studies investigating different Zn(II) salts were conducted. Preliminary investigations identified that Zn-halide salts were important over pseudo-halide or noncoordinating counterions such as OTf and BF4 (Scheme 5.6). These data are consistent with a mechanism that relies on a nucleophilic counterion, possibly one that can displace TBS from the silyloxyfuran, generating TBS-X, where X is the halide counterion. Scheme 5.5. Zn-salt screen in the more advanced key VMAR coupling. OTBS TfO ZnII (1 equiv) + TBSO Me Me O Me O OMEM O (1 equiv) 80% ee (1 equiv) >95% ee 88 107A O OTf TBSO Et2O, 22 °C, 16 h Me HO MEMO 106A ZnII Result ZnBr2 25% yield ZnCl2 17% yield ZnI2 27% yield, messier reaction profile Zn(OTf)2 no product Zn(BF4)2 no product In a brief equivalency screen, 1 equivalent was identified as optimal (Scheme 5.6). Catalytic loading led to reduced yield, while super stoichiometric loading led to lower 505 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation yields. One possibility for the lower yield involves competitive MEM-deprotection of 107A or 106A under the reaction conditions. Scheme 5.6. Zn-salt equivalence screen in the more advanced key VMAR coupling. OTBS TfO + TBSO Me Me O Me O ZnII (equiv) OMEM O (1 equiv) 80% ee (1 equiv) >95% ee 88 107A OTf O TBSO Et2O, 22 °C, 16 h Me HO MEMO 106A equiv Result 0.2 12% yield 1 25% yield 2 17% yield 5 7% yield 10 7% yield Scaling up of the reaction confirmed the occurrence of Zn-mediated MEMdeprotection (Scheme 5.7). Turning to the literature, it became clear that deprotection does not occur as readily in non-polar, aromatic solvents like benzene or toluene.1 While the VMAR did not convert in toluene (Scheme 5.4) a 1:1 cosolvent mixture led to reduction in MEM deprotection and 40% yield of the desired product (Scheme 5.7). Scheme 5.7. Et2O/benzene cosolvent: importance for reduced MEM-deprotection. OTBS O TBSO TfO O Me ZnBr2 (1 equiv) + OMEM O Me Me (1 equiv) 80% ee (1 equiv) >95% ee 88 107A TBSO Et2O 0 to 22 °C, 16 h Me HO MEMO HO 25% yield 17% yield 106A 177 OTBS O TBSO Me Me O Me ZnBr2 (1 equiv) + OMEM O (1 equiv) 80% ee (1 equiv) >95% ee 88 107A O TBSO Et2O/benzene (1:1) 0 to 22 °C, 16 h OTf O TBSO Me HO TfO O Me OTf O O Me OTf OTf O TBSO Me HO Me HO MEMO HO 40% yield 3% yield 106A 177 506 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 5.2.2 Investigation of Br substrate (107B) In addition to investigating the VMAR of triflate-containing aldehyde 107A, the reaction of alkenyl bromide substrate 107B was pursued. After 2D NMR analysis, it became clear that the product (106B) was formed as a mixture of diastereomers at the alcohol (178) and fully substituted center (179). Additionally, high levels of silyl enol ether product 180 were observed, along with recovered silyloxyfuran (88), butenolide (60), and aldehyde (107B, Scheme 5.8). For these data, yields were back-calculated from the crude reaction mixture, taking into account the isolated yield of analytically pure product 106B. Therefore, the yields provided in Scheme 5.8 are estimates. Scheme 5.8. Characterization of all products on Br-containing substrate. O Me O TBSO Me HO OTBS TBSO Me Me ZnBr2 (1 equiv) OMEM O (1 equiv) 99% ee (1 equiv) 86% ee 88 107B Me HO MEMO MEMO 38% yield 13% yield 106B 178 Br HO Br + Br OMEM Me Et2O/Benzene 0 to 22 °C, 16 h O TBSO 6% yield 15% yield 179 107B OTBS O O Me Me OMEM O O Me TBSO Br O TBSO O O Me Br Br O TBSO TBSO OMEM Me Me 25% yield 14% yield 32% yield 88 60 180 The formation of 180 was surprising and required a closer look at the posited mechanism. Presumably ZnBr2 acts as a Lewis acid, chelating to the aldehyde functionality in 107B (Scheme 5.9). Following ZnBr2 chelation, 88 could add in to form a silylium intermediate, from which addition of Br- could generate TBSBr.2,3 The resulting Zn- 507 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation alkoxide intermediate could be subjected to another nucleophilic attack of Br-, ) regenerating ZnBr2 and liberating the alkoxide-containing butenolide. Alternatively, the Zn-alkoxide intermediate is protonated upon workup with NH4Cl to deliver the product 106B. Scheme 5.9. Posited mechanism for silyl enol ether formation involves TBSBr. Br 106B OMEM O ZnBr2 107B NH4Cl workup O Me O Br Br Br TBSO Me O TBSBr O BrZn MEMO OMEM ZnBr Br −H+ TBSO OMEM 180 OTBS Br TBSBr O TBS Me O TBSO Me BrZn Br O Br TBSO Me Me 88 O MEMO A simple hypothesis was formed from this mechanistic picture: what would happen if the bromide counterion was replaced with chloride? One possibility is that the TBSCl would be less reactive under the reaction conditions, preventing formation of 180. Indeed, this seemed to be the case. Indeed, replacing ZnBr2 with ZnCl2 led to diminished formation of 180 (Scheme 5.10). 508 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.10. Use of ZnCl2 prevents silyl-transfer. OTBS Br Br ZnBr2 (1 equiv) O TBSO Me OMEM O Me 88 180 Br Br ZnCl2 (1 equiv) O OMEM O Me 32% yield 107B OTBS TBSO OMEM TBSO Et2O/toluene, 0 °C Me 88 OMEM TBSO Et2O/toluene, 0 °C < 3% yield 107B 180 From the observation in Scheme 5.10, a screen of ZnI2/ZnBr2/ZnCl2 was conducted. While ZnI2 and ZnBr2 led to low yields (20-24%, Scheme 5.11, entry 1-2), use of ZnCl2 led to 48% yield (Scheme 5.11, entry 3). The increase in yield is attributed to the less reactive in situ generated TBSCl the more reactive TBSBr and TBSI in the side reaction to form 180. Scheme 5.11. Optimization of VMAR on Br-containing substrate. OTBS O TBSO O Me Br Zn(II) (1.0 equiv) + OMEM O Me Me Br Br O TBSO Me HO Et2O/benzene 0 °C, 20 h OMEM TBSO MEMO (1.6 equiv) 107B 88 entry Zn(II) 106B silyl enol ether 180 aldehyde 107B (%) product 106B (%) silyl enol ether 180 (%) 1 ZnI2 14 20 2 ZnBr2 21 24 32 3 ZnCl2 21 48 <3 37 Upon scaling up the VMAR, it became clear that the diastereoselectivity of the process dropped significantly, mostly at the formed fully-substituted center at the gposition of the butenolide. This was surprising, as previously the g-position was set in good dr. It became apparent the diastereoselectivity was not consistent; setting up two of the same reaction in parallel led to 3:1 and 5:1 observed diastereoselectivity (Scheme 5.12, 509 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation entry 1-2). In repeating a third time, increasing the equivalents of the furan to 1.4 to try to push the conversion led to observation of a 3:1 dr (5.12, entry 3). An important observation was made at this time: crashing out of ZnCl2. It was reasoned that, while addition of benzene in cosolvent mixtures helped reduce MEM-deprotection, it also made the ZnCl2 less-soluble in the reaction media. Switching to a 3:1 mixture of Et2O:benzene led to complete MEM-deprotection. However, turning the stir rate to 800 rpm and using a large stir bar that exhibited good surface coverage and milling was essential to repeatability of the dr on-scale. The reaction was successfully scaled up to 700 mg scale (Scheme 5.12, entry 6). The drop in dr with less stirring is of interest and might be due to non-Zn-mediated background reactivity. Scheme 5.12. Scale-up optimization of the VMAR. OTBS O 88 TBSO Me Me (1.1 equiv.) ZnCl2 (1 equiv.) Br OMEM O Et2O/Benzene (1:1, 100 mM) 0 to 22 °C, 20 h 107B O Me O Br TBSO Me HO 106B MEMO entry scale vessel size deviation dr (%) product (%) furan rsm (%) rsm butenolide aldehyde rsm 1 30 mg 2-dram - 3 : 2.3 : 1 51 - 42 48 2 30 mg 2-dram - 5 : 1.9 : 1 65 - 41 32 3 30 mg 2-dram 1.4 equiv. furan 3 : 1.2 : 1 61 - 54 35 4* 30 mg 2-dram - 7 : 2.4 : 1 72 - 36 25 5* 180 mg 40 mL vial - 7 : 2.3 : 1 70 - 34 24 6* 694 mg 40 mL vial - 7.7 : 1.7 : 1 56 - 31 29 *stirring 800 rpm The final reaction conditions are displayed below in Scheme 5.13. The separation of the three diastereomers was tricky. Isolation of the pure, major diastereomer resulted in ~40% yield due to several mixed fractions. Isolation of all product-containing fractions Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 510 resulted in 56% yield as a 7.7.1.7:1 mixture of diastereomers. Scheme 5.13. Final optimized conditions. OTBS O TBSO 5.3 O Me Br ZnCl2 (1 equiv) + OMEM O Me Me (1.1 equiv) 99% ee (1 equiv) 86% ee 88 107B O Br TBSO Et2O/Benzene, 0 °C to 22 °C, 20 h 56% yield dr = 7.7 : 1.7 : 1 Me HO MEMO 106B Ni-CATALYZED A-ENOLATE ALKENYLATION 5.3.1 Synthesis of OTf and Br substrates From the product of the VMAR (106A/B), the Ni-catalyzed a-enolate alkenylation substrate synthesis proceeded smoothly (Scheme 5.14). Protection with TMS-imidazole occurred in 74% yield (181A/B). Importantly, the use of electrophilic reagents for protecting group installation and avoidance of strong base were important to avoid retroaldol. Use of TBSOTf and other silyl protecting group agents led to no reaction (not shown). Next, Cu-H reduction occurred in good yield (182A/B).21-23 Notably, the diastereoselectivity of the reduction is > 20:1 due to the preference for formation of the cis lactone. It is believed that the trans lactone is kinetically and/or thermodynamically inaccessible under the reaction conditions. From these substrates, investigation to ring closure to key compound 105 could be investigated. 511 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.14. a-enolate alkenylation substrate synthesis. OTBS O TBSO 88 Me Me (1.1 equiv) ZnCl2 (1 equiv) X OMEM O X = OTf, 107A X = Br, 107B O Me O X TMS-imidazole (6 equiv) TBSO Me HO Et2O/Benzene 0 °C, 20 h X = OTf, 52% yield X = Br, 56% yield, dr = 7.7:1.7:1 O X = OTf, 77% yield X = Br, 74% yield X = OTf, 106A X = Br, 106B X TBSO DCM, 40 °C, 12 h MEMO O Me Me O TMS MEMO X = OTf, 181A X = Br, 181B O O O TBSO Me α-enolate alkenylation TBSO Me Me H 105 O OMEM Ni TMS O X H Me O TMS MEMO X = OTf, 182A X = Br, 182B CuCl2 H2O (5 mol%) R-(tol)-BINAP (5 mol%) PMHS (6 equiv) NaOtBu (1.2 equiv) tBuOH (4 equiv) THF/DCM (3:1) 22°C, 16 h X = OTf, 85% yield X = Br, 95% yield 11 steps LLS 5.3.2 Initial experimentation on the key intramolecular cross-coupling: use of phosphine ligands Drawing inspiration from the model study involving the a-enolate arylation reaction (Chapter 2), we were eager to try the identical reaction conditions utilizing a variety of bidentate phosphine ligands. Unfortunately, use of Ni(COD)dppp on substrates 182A resulted in decomposition and recovery of starting material, respectively (Scheme 5.15, entry 1). Alternative conditions, including DavePhos, inverse order of addition, and use of Ni(COD)DQ provided recovered starting material or substrate decomposition for substrate 182A (Scheme 5.15, entries 2-4). In the cases where substrate decomposition was observed, the presence of trace quantities of product 183 accompanied, formed from hydrolysis of the enol triflate moiety. Upon initial experimentation, substrate 182B, bearing the vinyl bromide, was unreactive to Ni(COD)dppp (Scheme 5.15, entry 5). 512 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.15. Discouraging initial studies on substrates 182A/B using dppp as the ligand. O Me O TBSO O O Ni(COD)dppp (10 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) X H Me TBSO Tol/THF (3:1), 60 °C, 5 h Me O TMS MEMO Me O TBSO H Me O Me OMEM TMS MEMO 183 105 X 1 2 O decomposition product α-alkenylation entry O H TMS X = OTf, 182A X = Br, 182B O deviation result OTf none decomposition, 183 OTf DavePhos (20 mol%) decomposition, 183 3 OTf inverse order of addition decomposition, 183 4 OTf Ni(COD)DQ recovered 182A 5 Br none recovered 182B Over time, it became clear that the substrate decomposition was likely basemediated and could be prevented by decreasing the base stoichiometry (Scheme 5.16). Upon a simple base equivalency screen, the decomposition could be reduced (albeit the conversion of the reaction was < 10%). After exhaustive screening on this substrate, it was ultimately concluded that further exploration on the vinyl bromide substrate was required. Scheme 5.16. Base and temperature screen on enol triflate substrate 182A with dppp. O Me TBSO O OTf NaHMDS (X equiv) ZnBr2 (15 mol%) Ni(COD)DQ (10 mol%) dppp (10 mol%) H Me O TBSO Me Tol/THF (3:1), temp, 5 h Me O TMS MEMO O O TBSO Me H O OMEM O Me TMS TMS O MEMO α-alkenylation 182A O H 183 105 entry X inverse addition? temp. (°C) starting material (%) α-alkenylation (%) 183 (%) mass balance (%) 1 1.3 - 60 10 - 9 19 2 0.7 - 60 38 - 8 46 3 1.3 yes 60 6 - 16 22 4 0.7 - 21 73 - 7 80 5 1.3 - 21 27 - 7 34 6 2.6 - 60 0 - 7 7 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 513 Investigation of the vinyl bromide substrate 182B proved to be more fruitful. Preliminary investigations on this substrate focused on screening various phosphine ligands. A brief screen identified tBuXantPhos and dCypp as potentially fruitful ligands, delivering the product in 30% and 64% yield, respectively (Scheme 5.17). However, in follow up screens, the yields dropped below 10%. The reactions seemed to exhibit on/off reactivity. Additionally, different selectivities between a and b-alkenylation were observed in seemingly “identical” runs. Desperately to repeat the results, several parameters were investigated, including the purity of the starting material/reagents, reaction concentration, catalyst loading, base loading, and setting the reactions up in duplicate. Nevertheless, in about 50 entries experiments, the reaction only worked successfully approximately four times. Clearly, an alternative strategy would need to be explored or the reason for reaction success elucidated. As a result of the base sensitivity of the enol triflate, the Br substrate 182B was pursued moving forward. Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 514 Scheme 5.17. Use of phosphines: disfavored selectivity and irreproducible results. O Me TBSO O O cat. (5 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) Br H Me O TMS MEMO O O TBSO O TBSO Me Me Tol/THF (2:1), 60 °C, 16 h Me H O H Me OMEM α-alkenylation 182B 183 105 entry O OMEM TMS β-alkenylation TMS cat. starting material (%) 1 (COD)Ni(DPPP) 10 12 37 2 (COD)Ni(DTBPF) - 13 15 3* (COD)Ni(XantPhos) - 34 44 4* (COD)Ni(tBuXantPhos) - 30 47 5* (COD)Ni(DCPP) - 64 6 6 (COD)Ni(tBuXantPhos) 15 6 22 7 (COD)Ni(DCPP) 17 3 27 α-alkenylation (%) β-alkenylation (%) *high yielding results with phosphine ligands were not reproducible PR2 PtBu2 PPh2 Fe PPh2 DPPP tBu2P Me Me PCy2 O PR2 PCy2 DCPP DTBPF R = Ph, XantPhos R = tBu, tBuXantPhos For the case of (COD)Ni(DCPP), efforts to prepare and isolate this catalyst independently were undertaken. It was thought that perhaps some of the reproducibility issues stemmed from irreproducible formation of the active catalyst in situ. Following the procedure from Mézailles,24 the DCPP-ligated Ni complex was prepared. Additionally, the Ni(II) variant that did not contain COD could be prepared in 85% yield for use of in situ reduction protocols (use of Mn as a reductant, for example). In the literature, there exist multiple reports attempting a-enolate functionalization starting from NiII precatalysts; however, these reports claim that there is difficulty in achieving high conversion and high yields under such conditions.25-28 Testing of complex 185 could possibly provide insight as to whether COD was inhibitory for the a-enolate alkenylation chemistry. In the presence of COD, for example, Mézailles reports oxidative addition with an aryl chloride taking 90 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 515 days at 60 °C. In the absence of COD, using phenyl-bound 184, oxidative addition occurred on the timescale of minutes to hours (Scheme 5.18).24 Scheme 5.18. Precedent for isolation of Ni(COD)DCPP. Mézzailes 2020 Cy2P Ni COD Cy2P 2 novel catalysts studies in ligand exchange studies in Kumada cross coupling Ni PCy2 COD 185 PCy2 184 Cy2P ArCl Ni Ar PCy2 Cl 186 dmeNiBr2 + dcpp THF (0.1 M), 5 min, 22 °C 85% yield PCy2 Ni Br Br PCy2 187 Unfortunately, use of these catalysts in the a-enolate alkenylation chemistry were unfruitful (Scheme 5.19). In both cases, complex mixtures likely resulting from of substrate decomposition were observed. At this point in time, it remained unclear why the reaction had worked so well off-hand but was not reproducible. Nevertheless, these data served as motivation that the reaction could work well; promising results using nickel catalysis had been achieved, but the problem needed to be approached from a different angle. Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 516 Scheme 5.19. Use of pure, crystalized Ni catalysts. O Me O TBSO cat. (10 mol%) NaHMDS (1.3 equiv) ZnBr2 (15 mol%) additive Br H O Me Tol/THF (2:1), 60 °C, 16 h Me O TMS MEMO O TBSO H Me O OMEM TMS α-alkenylation 182B 105 entry cat. 1 2 catalyst source reductant (COD)Ni(DCPP) prepared in situ - 6% yield 105 (COD)Ni(DCPP) isolated by crystalization - complex mixture 3 Br2Ni(DCPP) isolated by crystalization Mn0 complex mixture 4 Br2Ni(DCPP) isolated by crystalization Zn0 complex mixture result In addition to the Ni-catalyzed conditions, palladium-catalyzed reactions were also investigated next. Indeed, there exist some reports for palladium-catalyzed a-enolate alkenylation but very few to form medium sized rings.29-34 Although the data shown does not describe an exhaustive screen, preliminary investigations did not show significantly more promise compared to the explored Ni-catalyzed methodology (Scheme 5.20). Attempts to further optimize the conditions from entry 3 were not fruitful, providing messy reaction profiles and uncharacterized side products (not shown). Scheme 5.20. Palladium-catalyzed methods deliver low yields. O O Me TBSO O Br conditions H Me O TMS MEMO Me Me H O OMEM TMS 182B entry O TBSO 105 conditions result 1 [PdBrPtBu3]2 (1.25 mol%), LHMDS (2.5 equiv), Tol, 80 °C, 15 h decomposition 2 LiTMP (1.3 equiv), Pd2(dba)3 (5 mol%), dtbpf (5 mol%), ZnBr2 (1.4 equiv), THF, 45 °C, 16 h 22% yield, 36% brsm 3 LiTMP (1.3 equiv), Pd2(dba)3 (5 mol%), dtbpf (5 mol%), ZnBr2 (1.4 equiv), THF, 60 °C, 16 h 14% yield Attempts to approach the problem directly from butenolide 106A were also undertaken (Scheme 5.21). The idea involved Cu-H 1,4-addition to be intercepted by the Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 517 Pd catalytic cycle. Transmetalation between a Cu-enolate with Pd, for example, could lead to intermediates en-route to the desired coupled product 105 in a single step.35-40 One challenge that arose, however, was identification of Cu-catalyzed conditions that could reduce the butenolide. In Buchwald’s precedent, less-hindered, acyclic alkenes were used as substrates, not butenolides. Indeed, application of Buchwald’s conditions led to low conversion in the reduction step of the butenolide. It was thought then that the Cu-H conditions used in the stepwise approach could be adapted for Cu/Pd synergistic catalysis (not shown). In the conditions from Scheme 5.14, for example, use of superstoichiometric tBuOH and NaOtBu are required and encourage rapid proton transfer with the Cu-enolate to turnover the catalyst.24-27 Employing conditions in the absence of tBuOH or NaOtBu and in the presence of Pd0 precatalysts led to low conversions (not shown). Furthermore, attempts to affect CuH reduction from CuI salts were not fruitful on the model system, as CuI is often used for these kinds of reactions shown by Buchwald and others.35-40 Scheme 5.21. A. Attempts at Cu-Pd Synergistic catalysis B. Attempts from Cu(I). A. O Me O OTf O Cu Pd TBSO Me TMS O THF [25 mM], 60 °C, 18 h TBSO Me Me MEMO H O OMEM TMS 182A entry O 105 Cu/Ligand(5 mol%)/Silane (2 equiv) Base (2 equiv) Pd (4 mol%) result 1 CuCl2•2H2O/(R)-ptol-BINAP/Me2PhSiH NaOTMS Pd(cinnamyl)(Cl)(dppbz) no product 2 CuCl2•2H2O/(R)-ptol-BINAP/Me2PhSiH NaOTMS Pd BrettPhos G4 no product 3 CuCl2•2H2O/(R)-ptol-BINAP/Me2PhSiH NaOTMS Pd(OAc)2/dppp no product Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation B. O Me O TBSO Br Me O MOM O CuCl (5 mol%) ptol-BINAP (5 mol%) Me2PhSiH (2 equiv) NaOTMS (2.4 equiv) THF, 21 °C, 2 h Me TBSO no reaction 90 518 MeO O Br H Me O MOM 58 MeO 5.3.3 Discovery of electron-deficient olefin (EDO) ligands for the intramolecular a-enolate alkenylation Other nickel-catalyzed methods for a-enolate alkenylation exist, although they are few and far between. In 2015, Helquist reported the Ni-catalyzed cross coupling of ketone enolates with alkenyl halides (Scheme 5.22A).41 The intermolecular coupling utilizes lithium enolates of ketones and a unique N-heterocyclic carbene (NHC) ligand, IPrHCl. LiI was found as a successful additive to increase the reaction rate. In their substrate scope, a variety of electron-neutral and electron-rich substrates underwent coupling in high yields, while electron-deficient aryl ketones were somewhat lower yielding. Furthermore, reactions generating a-quaternary centers proceeded in high yield. An attractive feature of the reaction is its mild reaction conditions: just 5 mol% catalyst, 1.05 equiv. of base, short reaction times, and low temperatures were effective at delivering products in proficient yields. Nevertheless, while the Helquist example was attractive, subjection to 182B led to no observed product (Scheme 5.22B). 519 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.22. A. Helquist’s41 Ni-catalyzed a-enolate alkenylation B. Failure to apply conditions to substrate 182B. Me A. O Ni(COD)2 (5 mol%) IPrHCl (5 mol%) LiHMDS (105 mol%) LiI (10 mol%) R4 R3 R1 R5 Br R2 O Me N N R4 Me Me Me R5 R1 THF, 6 °C, 0.5 - 2 h R6 Me R2 R3 R6 Me Cl Me IPrHCl O O Me Me Me Me Me Me2N 89% yield O Me Me F3C O 39% yield O O Me Me 74% yield Me Me O Me Me 74% yield O 72% yield O Br O O Me Me2N Me 71% yield B. Me 85% yield Me Me 27% yield Me Me 57% yield Me Me Me Me 79% yield Me O O OMe 79% yield O Me TBSO O H Me O TMS MEMO 182B Br Ni(COD)2 (5 mol%) IPrHCl (5 mol%) LiHMDS (105 mol%) LiI (10 mol%) O O TBSO Me THF, 6 °C, 2 h no product observed Me H O OMEM TMS 105 Since Helquist’s report in 2015, very few nickel catalyzed a-enolate alkenylations have been disclosed. While Ni-catalyzed a-enolate arylation has been explored to much greater depths (see Chapter 2 for more information on Ni-catalyzed a-enolate arylation),4245 the corresponding a-enolate alkenylations literature seemed are rare. Dating back to 1977, Rathke disclosed the stoichiometric Ni-coupling of lithium ester enolates with alkenyl bromides utilizing NiBr2-nBuLi.46-48 Pregenerating the enolate with lithium diisopropylamine (LDA) and adding to a stirring solution of NiBr2-nBuLi led to excellent 520 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation yields up to 99% (Scheme 5.23A). It is possible that nBuLi leads to NiII reduction via sequential Br- displacement and b-hydride elimination, which would lead to an olefinbound active catalyst. Although the reaction employed stoichiometric loadings of Ni, it did not require addition of exogenous ligands. In 2002, the conditions were applied in the synthesis of terrecyclic acid A in 81% yield (Scheme 5.23B).49 While this was exciting, unfortunately, these conditions did not yield any desired product in the desired reaction for auriculatol A (Scheme 5.23C). It was thought that either oxidative addition into the more hindered alkenyl bromide or transmetalation with the lithium enolate of the lactone might be challenging in the desired system, leading to recovery of starting material (182B). Scheme 5.23. A. Rathke’s46-48 Ni-mediated a-enolate alkenylation. B. Application by Wender.49 C. Failure in the desired reaction providing recovered starting material. A. Rathke 1977 Li O R RO Br + NiBr2 (1 equiv) nBuLi (0.33 equiv) R R R pregenerated with LDA THF, −78 °C to 22 °C, 0.5 h O R RO R R R 40-99% yield R = alkyl, Ar, H Me solv Br + nBuLi solv Ni Br solv β-hydride elimination Ni Br − LiBr −H2 H Me Ni Ni solv Br solv solv solv olefin-bound active catalyst? B. Wender 2002: Rathke’s conditions applied toward the synthesis of Terrecyclic Acid A OTBDMS Me OTBDMS Me Me + NiBr2 (1 equiv) nBuLi (0.33 equiv) tBuO CH(OMe)2 OLi Br (1.5 equiv) THF, −78 °C to 25 °C 81% yield Me tBuO CH(OMe)2 O Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation C. 521 O Me TBSO O O Br NiBr2 (1 equiv) nBuLi (0.33 equiv) H Me O TMS MEMO THF, −78 °C to 25 °C, 12 h 182B no product observed recovered starting material O TBSO Me Me H O OMEM TMS 105 Despite the difficulties adapting the a-enolate arylation conditions from Chapter 2 to the more ambitious a-enolate alkenylation described herein, scrutinizing of literature outside the realm of the alkenylation literature for Ni(0)-catalyzed reactions provided key insights. Among the explored reports, papers disclosing Ni(0)-catalyzed amination,50-52 carboxylation,53 desaturation,54,55 Michael addition,56,57 and Kumada cross-coupling58,61 were particularly notable. Two common themes emerged from reading these papers – first, was the absence of exogeneous ligands. Traditionally, Ni-catalysis often requires phosphine or nitrogen ligands. Presumably, the strongly nucleophilic phosphine or nitrogen ligand can displace COD under the reaction conditions, and it is the ligand-bound catalyst that is active in the reaction. Several reports, however, use Ni(0) precatalysts without the addition of phosphine or nitrogen ligands, meaning that the precatalyst ligands (often olefin-containing ligands) are suitable for catalyst activity. Particularly, we were intrigued by the report from Li and coworkers, in which the precatalyst Ni(COD)(DQ) in the presence of base was able to catalyze the C–N cross-coupling for the synthesis of N,N-diarylsulfonamides (Scheme 5.24A).50 Engle and coworkers have found Ni(COD)DQ to be privileged for the 1,2difunctionalization of olefins (Scheme 5.24B).61, Murphy and coworkers disclosed the synthesis of biaryls from aryl halides and PhH utilizing Ni(COD)DQ and KOtBu.62 522 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.24. Recent reports of Ni-catalyzed reactions using Ni(0) precatalysts in the absence of exogenous ligands. A Li and coworkers N H O Br O Ni(COD)DQ (20 mol%) NaOtBu (1.1 equiv) O S N O S PhMe, 150 °C, 1 h Me R Me R O O O S N N 94% yield O Me 85% yield O O S N Me 93% yield O O O S N N 90% yield O S Me Me Me N OMe 76% yield Cl O O S Me O S N Me Me N O O S N Me CN O O S O 49% yield 46% yield 21% yield BPin Engle and coworkers B Ts O O Me S Me N (nep)B R1 N H R2 S Ni(COD)DQ (1-10 mol%) LiOtBu (2.0 equiv.) Ts THF (0.05 M), 50 °C, 16 h N H R1 R2 > 20 examples Ts Ni(COD)(BQiPr) (15 mol%) Me2Zn (2 equiv.) TsN3 (2 equiv.) N H THF, 80 °C, 12 h Ts N H Me NHTs 95% yield C Murphy and coworkers I Me Ni(COD)(DQ) (10 mol%) KOtBu (2 equiv.) PhH, 130 °C, 16 h Ph Me 95% yield The second observation from the Ni(0)-catalyzed literature is the use of electrondeficient olefins as ligands. We were particularly inspired by the report of benzonitrile as a privileged ligand for the BINAP-ligated Ni-catalyzed amination of aryl and heteroaryl 523 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation chlorides (Scheme 5.25A).52 The (BINAP)Ni(h2-NC-Ph) catalyst was found to limit the formation of Ni(I) and (BINAP)2Ni species that were found to be detrimental to the reaction. It was hypothesized that the benzonitrile may act as a stabilizing ligand for the Ni-center through p-backdonation with benzonitrile. Indeed, Rousseux has incorporated a benzonitrile functionality within a single pyrazole ligand scaffold for Ni-catalyzed cross coupling of tertiary nucleophiles,63 while Doyle has utilized the electron-withdrawing FroDO ligand for aziridine cross coupling64 (Scheme 5.25 B&C). Scheme 5.25. Hartwig’s amination of aryl and heteroaryl chlorides. A. amination of aryl chlorides MeO Cl R RNH2 (BINAP)Ni(η2-NC-Ph) (2 mol%) NaOtBu (1.5 equiv.) NHR MeO R toluene, 50 °C 76-96% yield PhPh P Ni P Ph Ph >10 examples amination of heteroaryl chlorides Cl R RNH2 (BINAP)Ni(η2-NC-Ph) (2 mol%) NaOtBu (1.5 equiv.) NHR R N N Ph (BINAP)Ni(η2-NC-Ph) toluene, 50 °C N 57-96% yield > 20 examples CN B. NC CN Ar MeO PhMgBr•LiBr THF reflux, 40 min R NC MgBr Ar R N ligand (20 mol%) N NiCl2(dme) (10 mol%) ArI (1 equiv) PhMe/THF, 30 °C, 6 h PhCN NC Ar Ar R > 20 examples 40-89% yield O O S Me C. Me Ni(acac)2 (5 mol%) Fro-DO Ligand (10 mol%) NTs NHTs nBuZnBr F DMA, 23 °C, 18 h 90% yield nBu F N N S O O O Fro-DO We were also inspired by Cornella’s mechanistic study on the Ni-catalyzed Kumada cross-coupling. In this study, investigation into the mechanism of the low Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 524 temperature C(sp2)–C(sp3) Kumada cross-coupling helped uncover olefin-bound 16electron nickel complexes as privileged catalysts in the reaction.65 Specifically, a series of NMR experiments revealed that Grignard coordination of hexyl magnesium bromide to the Ni(nor)3 catalyst is required before oxidative addition of 2-bromovinyl benzene (Scheme 5.26). No evidence of oxidative addition in the absence of hexyl magnesium bromide occurred when monitored in an NMR tube. Conversely, in a separate experiment, precomplexation of hexyl magnesium bromide to the Ni-catalyst followed by addition of 2-bromovinyl benzene led to catalyst turnover. In line with their studies, the Cornella group successfully crystallized an analogous olefin-bound Ni-complex coordinated to (Me)2Mg(TMEDA) and showed it was competent in the reaction (not shown). These studies are consistent with a grignard coordination first mechanism as shown in Scheme 5.26. While olefin-bound 16 e- Ni-complexes are extremely reactive and unstable to air,66,67 they were essential to success of the reaction, as other 18 e- Ni complexes were ineffective. Furthermore, strongly s-donating ligands such as phosphines, NHC’s, and diamines were incompetent, likely because these ligands destabilize or are too electron rich for Grignard coordination. We wondered if parallels between this study and the a-enolate alkenylation reaction we were working to develop existed and what implications this study has on Ni-catalyzed cross coupling more generally.68-70 525 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Scheme 5.26. Cornella’s mechanistic study of the Ni-catalyzed Kumada cross coupling. hex MgBr Ni0 Ni(nor)3 (5 mol%) THF, −40 °C, 36 h Br hex Ni(nor)3 74% yield MgR2 Ni0 Ph R reductive elimination grignard addition Ph solv Mg R 0 solv NiII Ni R R oxidative addition Br Ph These hypotheses were consistent with model studies in the a-enolate arylation reaction from Chapter 2, which showed it did not require phosphine ligands (Scheme 5.27). Taking just Ni(COD)2, the a-enolate arylation reaction could be achieved in 75% yield, reproducibly, and on larger scales (> 20 mg). Use of Ni(COD)DQ precatalyst led to 80% yield and no observed b-arylation (not shown). Scheme 5.27. Use of 16 e- EDO-ligated Ni(COD)DMFU provides promising results. O Me O TBSO Me H Br O MOM 58 MeO Ni(COD)2 (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Toluene/THF (2:1), 60 °C, 16 h O O TBSO Me O H Me O TBSO O MOM α-arylation OMe Me OMe Me OMOM β-arylation 57 91 78% yield 6% yield 526 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation Because of the promising results of olefin ligands from the model study, a series of experiments were designed to test Ni complexes with varying electronic properties (Scheme 5.28). Mongomery reported NHC-ligated Ni(0) catalysts for C–C and C–N bond formation,71 while Cornella developed Ni(0) stillbene (stb) catalysts, containing 4-F, 4-Me, 3,5-Me, and 4-tBu substitution.65 Engle has a library of bench-stable, commercially available nickel precatalysts, containing a unique plethora of olefin ligands,72 and Doyle’s air-stable TMEDA-ligated nickel precatalyst was also appealing.73 In 2016, Jamison reported an air-stable nickel precatalyst for internally selective benzylation of terminal alkenes.74 Finally, there was a recently disclosed Ni(COD)DMFU catalyst from the Engle group, which was privileged for 1,2-diarylation of alkenes.75,76 Scheme 5.28. Some recently reported Ni(0) precatalysts. O N Mes Mes N Ar Me Me N Ni Ni CO2tBu tBuO2C Ph Ph Ph N N MeO Ni Ph OPh O O (IPr*OMe)Ni(phenylacrylate)2 Montgomery 2018 Me Me Ni Cl N O Ni(COD)(DQ) Schrauzer, 1962 Engle 2022 O Me Me Ni(tBustb)3 Cornella 2020 OMe PhO Ar Ar Ph Ph Ph Ph Ar Ar (IMes)Ni(tBufumarate)2 Montgomery 2018 Me Ni tBu CO2tBu tBuO2C Me CO2Me Ni MeO2C Ni(COD)DMFU Engle 2021 (TMEDA)Ni(o-tolyl)Cl Doyle 2015 Ph S Ni Ph Ph Ph Ni(COD)(TSO-Ph) Engle 2022 Cl Ni PCy2Ph O PhCy2P Me (PCy2Ph)Ni(o-tolyl)Cl Jamison 2013 tBu Ni tBu O Ni(COD)(tBu-DQ) Engle 2022 With these precatalysts in mind and adapting conditions tested in the model study (Scheme 5.27), both Ni(COD)2 and Ni(COD)DQ were tested in the absence of exogenous ligands. Unfortunately, trace product with a low mass balance was observed (Scheme 5.29, Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 527 entry 1 & 2). Furthermore, in the case of Ni(COD)2, formation of nickel black was observed. Screening other nickel precatalysts revealed that Ni(COD)DMFU and (TMEDA)Ni(o-tolyl)Cl delivered moderate yield of the desired product with relatively low selectivity for a-alkenylation over b-alkenylation (Scheme 5.29, entry 3 & 4). Lowering the catalyst loading in the case of Ni(COD)DMFU to 5 mol% led to a rapid change of product selectivity, minimalizing the formation of b-alkenylation to 4% (Scheme 5.29, entry 5). In this case, however, only moderate conversion of the starting material was observed. While it was thought that adding LiCl could increase conversion,69 the hypothesis turned out to be incorrect (Scheme 5.29, entry 6). The optimal reaction was conducted for 12 h using 5 mol% of Ni(COD)DMFU, allowing for a 59% isolated yield of the product as an inseparable mixture with 6% b-alkenylation (Scheme 5.29). Scheme 5.29. Use of 16 e- EDO-ligated Ni(COD)DMFU provides promising results. O Me TBSO O O cat. (10 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Br H O TBSO Me Tol/THF (2:1, 31 mM), 60° C, 4 h Me O TMS MEMO O O TBSO Me Me H O OMEM H Me TMS TMS α-alkenylation 182B O OMEM β-alkenylation 188 105 entry cat. 1 Ni(COD)2* 32 4 2 Ni(COD)(DQ) 34 7 0 3 Ni(COD)DMFU 7 37 31 4 (TMEDA)Ni(o-tolyl)Cl 18 31 27 5 Ni(COD)DMFU (5 mol%) 30 37 4 6 Ni(COD)DMFU, LiCl (2 equiv) 12 3 17 7 Ni(COD)DMFU (5 mol%), 12 h 0 59 6 starting material (%) α-alkenylation (%) β-alkenylation (%) 16 *formation of nickel black O Me Ni Me Me N Ni CO2Me Ni Ni Me Ni(COD)2 Me O Ni(COD)(DQ) Me N Cl Me Me (TMEDA)Ni(o-tolyl)Cl MeO2C Ni(COD)DMFU Ni(COD)DMFU works well compared to other metal-ligand systems due to its 528 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation unique coordination sphere and electron properties. Ni(COD)DMFU contains an interesting 16 e- heteroleptic structure and can be stored at low temperature under inert atmosphere. The Engle group has shown that X-ray crystallography and density functional theory calculations are consistent with a zerovalent metal center engaging in high levels of p-backbonding interactions with DMFU.75,76 The electron deficient olefin ligand is believed to possess valence electrons that more formally reside on the ligand, leading to a more electron-deficient, stable Ni-center (Scheme 5.30). Scheme 5.30. Ni(COD)DMFU: a unique Ni0 catalyst system (figure adapted from Engle and coworkers)61. R reactivity stability R R = Electron-withdrawing R = Electron-donating CO2Me Ni MeO2C 16 e- complex containing an empty coordination site R R R R R = Electron-withdrawing R = Electron-donating poor M-L overlap no backbonding weak M-L bond poor M-L overlap no backbonding weak M-L bond When considering Cornella’s mechanistic study on Ni-catalyzed Kumada cross coupling, a possible mechanistic paradigm should be considered: does the a-enolate alkenylation operate via a “transmetalation first” mechanism? The requirement for an olefin-bound, 16 e- metal center provides support for this hypothesis in which enolate coordination to the Ni center is required before oxidative addition. This would perhaps explain why using electron-deficient olefin ligands could aid in the reaction; that is, a more electron deficient metal center would engage the Lewis basic enolate in faster, more rapid 529 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation transmetalation, The electron deficient metal center could also undergo faster reductive elimination.77 Although further mechanistic investigation would be required to definitively prove this hypothesis, the observations from this study combined with Cornella’s work provide interesting implications for the design and development of enolate functionalization methods using nickel catalysis more broadly. Scheme 5.31. A possible mechanistic paradigm for nickel-catalyzed a-enolate alkenylation. OZnBr O O TBSO Me O Ni0 Me Me H TBSO O OMEM Br H Me O TMS MEMO TMS reductive elimination O O TBSO Me transmetalation O Ln NiII O H Me OR TBSO Me OMEM oxidative addition Ln Ni0 Br Me OR OMEM 5.3.4 Assessing the necessity of reaction components and scalability of the Ni-catalyzed a-enolate alkenylation For the purpose of synthetic studies toward auriculatol A, a focused set of controls were conducted in order to determine the necessary aspects of the reaction. First, the standard condition was repeated, verifying the yield and selectivity upon attempting separate runs (Scheme 5.32, entry 1). In some cases, small amounts of recovered starting material are observed, likely attributed to the sensitivity of the reaction to trace moisture or O2, leading to slightly diminished yields (Scheme 5.32, entry 2). Performing the reaction Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 530 without ZnBr2 (Scheme 5.32, entry 3) and heat (Scheme 5.32, entry 4), suggests that both were necessary for the reaction. Finally, the reaction was scaled up to 290 mg scale without a reduction in yield or selectivity (Scheme 5.32, entry 7). Scheme 5.32. a-alkenylation controls and scale-up. O Me TBSO O O Br H Ni(COD)DMFU (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) TBSO Me Tol/THF (2:1, 31 mM), 60° C, 12 h scale Me O TMS MEMO O O TBSO Me Me H O OMEM TMS product (%) selectivity (α : β) - - 70 9:1 - 6 58 9:1 4 mg no ZnBr2 28 19 9:1 4 mg no heat 21 40 > 20 : 1 5 4 mg DavePhos* 9 42 3:1 6 150 mg - - 74 9:1 7 290 mg - - 79 9:1 deviation 1 4 mg 2 4 mg 3 4 OMEM 188 rsm (%) scale O β-alkenylation 105 entry H Me TMS α-alkenylation 182B O *10 mol% 5.4 CONCLUDING REMARKS In conclusion, a vinylogous Mukaiyama aldol (VMAR) addition of silyloxyfuran intermediate with 3.2.1 bicyclic aldehyde has been developed on substrates bearing an enol triflate and alkenyl bromide functionality. Central to the development of the reaction was close monitoring of temperature and judicious solvent selection. Additionally, it was important to pay close attention to the purification method used for the silyloxyfuran fragment and the quality of TBSOTf used. Following the intermolecular coupling reaction, strategies to elaborate to an a-enolate alkenylation substrate were undertaken, consisting of TMS protection and CuH reduction. For the CuH reduction, Buchwald’s reduction worked uniquely well, delivering the product in high yields and as a single diastereomer. Synthetic methods for ring closure were explored in detail. Originally, conditions from the Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 531 model system were attempted to be adapted for the intramolecular cross coupling, both on the enol triflate and the alkenyl bromide. While the reaction worked a few times, it was not reproducible and mainly returned decomposition. It was not until the reaction was tested with olefin-containing ligands, in the absence of phosphines, that the reaction began to work well. Ultimately, it was found that Ni(COD)DMFU was a privileged catalyst in the reaction, delivering the product in 65% yield in good selectivity. The study of the reaction may have implications in electrondeficient olefins as ligands in nickel catalysis more broadly, perhaps leading to the future development of related nickel catalyzed methods within the group. Taken together, this chapter details the rapid construction of molecular complexity through two powerful C-C bond forming reactions en-route to auriculatol A and other grayanane natural products. With the two most difficult key steps of the synthesis developed, efforts focused on the end-game stages of the synthesis were undertaken. 5.5 EXPERIMENTAL SECTION Preparation of silyloxyfuran (88): TBSO O Me Me H 60 O NEt3 (2.25 equiv.) TBSOTf (1.75 equiv.) Et2O, 0 °C to 22 °C, 2 h 90% yield TBSO OTBS O Me Me 88 A 100 mL round-bottom flask was flame-dried under vacuum. Upon cooling to room temperature, the cap was removed and the flask was charged with butenolide 60 (625 mg, 2.21 mmol, 1.0 equiv), a magnetic stir bar, and placed under N2 atmosphere. To the starting material was added dry Et2O (44 mL) and freshly distilled NEt3 (700 uL, 5.0 mmol, 2.25 equiv). The reaction was stirred at room temperature until all butenolide starting Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 532 material was dissolved, then cooled to 0 °C. At 0 °C, TBSOTf (900 uL, 3.9 umol, 1.75 equiv) was added dropwise. The reaction was vigorously stirred at 0 °C to make sure there is complete mixing of TBSOTf, which in some cases may crash out of solution. After 30 min stirring at. 0 °C, the reaction was warmed to room temperature and stirred for 90 min. After 2 h total, the reaction mixture was poured directly onto a phosphate-buffered silica plug (25 g of buffered silica) pre-packed with hexanes, and the flask was rinsed with Et2O (~15 mL) to guarantee minimal loss of product. The eluent was collected in a 500 mL receiving flask as it was passed through the buffered silica, and the silica was further rinsed with hexanes (3 x 50 mL) to ensure complete elution of product. The eluent was concentrated under reduced pressure, and the crude residue was redissolved in MeCN (50 mL). The MeCN solution was subjected to sequential pentane extractions (4 x 50 mL). The combined pentane extracts were concentrated under reduced pressure and subjected to high vacuum for 12 h to afford 88 as a yellow oil (790 mg, 90% yield). Experimental Note: the purity of TBSOTf is important for this step, as it may affect the aldol step depending on the concentration of trace silyl impurities. It is considered best practice to store the TBSOTf cold under a blanket of Ar to ensure the reagent quality is maintained over time. The phosphate buffered silica was prepared according to literaturereported procedures from Newton and coworkers. TBSO OTBS O Me Me 88 TLC: N/A (unstable to silica) Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 1 533 H NMR (CDCl3, 400 MHz): 1H NMR (400 MHz, CDCl3) δ 4.96 (s, 1H), 4.24 (t, J = 6.9 Hz, 1H), 2.72 (dd, J = 14.1, 7.1 Hz, 1H), 2.31 (dd, J = 14.1, 6.7 Hz, 1H), 1.19 (s, 3H), 1.00 (s, 3H), 0.96 (s, 9H), 0.91 (s, 9H), 0.22 (s, 6H), 0.08 (s, 6H). 13 C NMR (CDCl3, 101 MHz): δ 158.1, 151.2, 117.8, 83.6, 82.7, 43.0, 34.1, 26.0, 25.7, 25.2, 20.41, 18.3, 18.2, -4.4, -4.7, -4.1, -4.8. FTIR (Neat, NaCl, thin film): 2956, 2930, 2859, 1585, 1471, 1361, 1255, 1101, 866, 787 cm-1. HRMS (ESI-TOF): calc’d for C21H41O3Si2 [M+H]+ 397.2589, found 396.2597. [a]D22: +38.4 (c 1.0 in CHCl3). Preparation of vinyl bromide 107B. Ni(COD)2 (10 mol%) LiBr (1.5 equiv) TfO OMEM O 107A THF/DMA (3:1, 60 mM), 21 °C, 12 h 68% yield Br OMEM O 107B In an N2-filled glovebox, an oven-dried 100 mL round-bottom flask containing a magnetic stir bar was charged with Ni(COD)2 (80 mg, 290 umol, 10 mol%) and LiBr (380 mg, 4.3 mmol, 1.5 equiv). DMA (2.90 mL) and THF (7.0 mL) were added in, and the solution was stirred for 5 min or until all the Ni(COD)2 dissolved. Then, aldehyde 107A (1.20 g, 2.90 mmol, 1 equiv) was added as a solution in THF (1.7 mL). The reaction vessel was capped with a rubber septum, removed from the glovebox, connected to an N2 inlet, and stirred for 12 h at room temperature. An initial color of deep aqua blue was observed, which turned to a pale-green, then finally a bright green. After 12 h, an NMR aliquot was taken, which confirmed full conversion. The reaction was filtered through a short silica plug, eluting with 50% EtOAc/hexanes (200 mL). The eluent was then washed with sat. Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 534 aq. LiCl (3 x 50 mL), and the organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography (SiO2, 3% to 10% acetone/hexanes slow gradient) to afford the vinyl bromide 107B (683 mg, 68% yield) as a colorless oil. Experimental note: This reaction is sensitive to air. Br OMEM O 107B TLC (20% Acetone/Hexanes): Rf 0.29 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.82 (s, 1H), 5.94 (dd, J = 5.3, 2.5 Hz, 1H), 5.17 (dd, J = 3.2, 1.8 Hz, 1H), 5.10 (s, 1H), 4.92 (d, J = 7.6 Hz, 1H), 4.71 (d, J = 7.6 Hz, 1H), 3.83 (ddd, J = 10.6, 4.8, 3.6 Hz, 1H), 3.64 – 3.57 (m, 1H), 3.56 – 3.48 (m, 2H), 3.37 (s, 3H), 3.10 (dd, J = 17.6, 1.2 Hz, 1H), 2.75 – 2.66 (m, 2H), 2.43 – 2.26 (m, 4H), 2.15 (dddd, J = 16.4, 5.3, 2.1, 0.9 Hz, 1H). 13 C NMR (CDCl3, 101 MHz): δ 200.4, 151.0, 128.3, 128.2, 109.3, 91.1, 83.4, 71.9, 67.2, 59.1, 51.4, 46.7, 45.8, 45.3, 45.1. FTIR (Neat, NaCl, thin film): 2924, 1725, 1453, 1048, 887 cm-1. HRMS (ESI-TOF): calc’d for C15H22BrO4 [M+H] 345.0696, found 345.0701. [a]D23: +103.8 (c 1.0 in CHCl3). Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 535 Preparation of aldol product 106A. OTBS ZnCl2 (1 equiv) O OMEM O TBSO Me Me (1.1 equiv) O Me TfO 107A Et2O/Benzene 0 °C, 20 h O OTf TBSO Me HO MEMO 52% yield 88 106A An oven-dried 2 dram vial was charged with aldehyde (44.2 mg, 107 µmol, 1.0 equiv.), silyloxyfuran 88 in benzene and Et2O and a magnetic stir bar in a glovebox to make a solution of concentration equal to 100 mM. The reaction mixture was cooled to 0 °C and ZnCl2 (1M in Et2O, 111 uL, 1.04 equiv.) was added dropwise. After the reaction time the reaction was quenched with sat. aq. NH4Cl at 0 °C, warmed to room temperature, extracted with Et2O (3 x 1 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4 and reduced in vacuo. The title compound was purified by flash column chromatography (0% to 10% Et2O in CH2Cl2) to give product 106A (33.7 mg, 56.3 µmol, 52% yield) as a white solid. XRD analysis for 106A is provided in Appendix 5. O Me O TBSO OTf Me HO 106A MEMO TLC (30% EtOAc/Hexanes): Rf 0.20 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.87 – 5.84 (m, 1H), 5.57 (dd, J = 5.2, 2.5 Hz, 1H), 5.18 (dd, J = 3.2, 1.7 Hz, 1H), 5.13 (t, J = 2.1 Hz, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.75 (d, J = 7.6 Hz, 1H), 4.61 (dd, J = 9.9, 4.8 Hz, 1H), 4.20 (t, J = 6.9 Hz, 1H), 3.88 – 3.80 (m, 1H), 3.63 (ddd, J = 10.7, 5.4, 3.6 Hz, 1H), 3.60 – 3.54 (m, 2H), 3.39 (s, 3H), 3.06 (ddd, J = 17.9, 10.0, 2.5 Hz, 1H), 2.82 (ddt, J = 16.0, 3.1, 1.6 Hz, 1H), 2.74 (dd, J = 16.5, 2.6 Hz, 1H), 2.39 (dt, J = 16.1, 2.9 Hz, 1H), 2.34 (dd, J = 11.0, 1.9 Hz, 1H), 2.31 – 2.22 (m, 2H), 2.11 (dd, J = Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 536 11.0, 2.8 Hz, 1H), 2.01 (d, J = 6.9 Hz, 1H), 1.83 (dd, J = 15.0, 10.1 Hz, 1H), 1.59 (dd, J = 15.1, 2.6 Hz, 1H), 1.23 (s, 3H), 0.89 (s, 9H), 0.74 (s, 3H), 0.05 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 175.53, 173.50, 152.89, 150.58, 120.08, 116.89, 114.94, 109.71, 91.22, 82.98, 79.77, 71.80, 67.37, 59.17, 47.44, 44.02, 43.52, 40.95, 35.04, 30.46, 29.85, 25.83, 21.06, 18.09, 17.24, 1.48, 0.92, -4.51, -5.04. FTIR (Neat, NaCl, thin film): 3435, 2930, 1731, 1416, 1211, 1049 cm-1. HRMS (ESI): calc’d for [M+H]+ 697.2684, found 697.2681. Preparation of TMS-protected 181A. O Me O TBSO Me HO OTf TMS-imidazole (6 equiv) DCM, 40 °C, 12 h MEMO 106A 77% yield O Me O OTf TBSO Me O TMS MEMO 181A 106A (33.7 mg, 48.4 umol, 1 equiv) in an oven-dried round-bottom flask equipped with a magnetic stir bar was dissolved in CH2Cl2 (242 uL, 200 mM). TMS-imidazole (43 uL, 6 equiv) was added dropwise at room temperature, and the reaction was heated to reflux for 12 h. After 12 h, TLC showed complete conversion. The reaction was quenched by addition of water (1 mL). The aqueous phase was separated from the organic phase, and it was extracted with CH2Cl2 (3 x 1 mL). The combined organic phases were washed with NH4Cl to remove imidazole (3 x 1 mL), brine, and dried with MgSO4. Following concentration, column chromatography (15% EA/hex) delivered the pure product 181A (28.6 mg, 77% yield) as a yellow oil. Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 537 O Me O TBSO OTf Me O TMS MEMO 181A TLC (30% EtOAc/Hexanes): Rf 0.39 (KMnO4). 1 H NMR (CDCl3, 400 MHz: δ 5.88 – 5.83 (m, 1H), 5.50 (dd, J = 5.3, 2.4 Hz, 1H), 5.17 (dd, J = 3.1, 1.7 Hz, 1H), 5.14 (t, J = 2.1 Hz, 1H), 4.94 (d, J = 7.7 Hz, 1H), 4.72 (d, J = 7.7 Hz, 1H), 4.46 (dd, J = 9.8, 5.6 Hz, 1H), 3.85 (dt, J = 10.8, 4.2 Hz, 1H), 3.66 – 3.58 (m, 1H), 3.52 (dd, J = 5.3, 4.0 Hz, 2H), 3.36 (s, 3H), 3.02 – 2.93 (m, 1H), 2.85 (d, J = 16.1 Hz, 1H), 2.70 (dd, J = 16.6, 2.6 Hz, 1H), 2.44 – 2.20 (m, 4H), 1.96 (dd, J = 10.7, 2.7 Hz, 1H), 1.25 (s, 3H), 0.89 (s, 9H), 0.72 (s, 3H), 0.19 (s, 9H), 0.07 (d, J = 5.4 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 175.53, 173.50, 152.89, 150.58, 120.08, 116.89, 114.94, 109.71, 91.22, 82.98, 79.77, 71.80, 67.37, 59.17, 47.44, 44.02, 43.52, 40.95, 35.04, 30.46, 29.85, 25.83, 21.06, 18.09, 17.24, 0.92, -4.51, -5.04. FTIR (Neat, NaCl, thin film): 3437, 2928, 1729, 1412, 1282, 1070 cm-1. HRMS (ESI): calc’d for [M+NH4]+ 786.3344, found 786.3345. Preparation of lactone 182A. O Me O TBSO Me O TMS MEMO 181A OTf CuCl2 H2O (5 mol%) R-(tol)-BINAP (5 mol%) PMHS (6 equiv) tBuOH (4 equiv) NaOtBu (1.2 equiv) THF/DCM (3:1), 22°C, 16 h 85% yield O Me TBSO O OTf H Me O TMS MEMO 182A An oven-dried vial equipped with a Teflon-coated magnetic stir bar was charged with copper (II) chloride dihydrate (0.3 mg, 1.86 umol, 0.05 equiv), (R)-Tol-BINAP (1.3 mg, 1.86 umol, 0.05 equiv.), and sodium tert-butoxide (4.3 mg, 44.6 umol, 1.2 equiv) in the Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 538 glovebox. The vial was capped with a rubber septum, taped, and pumped out of the glovebox. SPS THF (0.6 mL) was then added to the vial and the mixture was allowed to stir at room temperature for 5 minutes. PMHS (50 uL, 223 umol, 6 equiv.) was then added dropwise and allowed to stir for 5 minutes. There is a color change to orange and then potentially a darker orange/black following addition of PMHS and 5 min of stirring. After 5 minutes of stirring, the starting material was added as a solution in remaining THF / CH2Cl2 / t-BuOH (330 uL / 310 uL / 14 uL) and allowed to stir at room temperature 12 h, at which point TLC indicated complete conversion of the starting material. At this point, ammonium chloride (1 mL) was carefully added to the reaction and allowed to stir for 15 minutes. The aq and organic phase were then separated, and the aq phase was extracted with EtOAc (3 x 1 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness with the aid of a rotary evaporator. The resulting residue was then purified by flash chromatography (30% EtOAc/hexanes) to provide the product 182A (24.4 mg, 85% yield) as a white solid. O Me TBSO O OTf H Me O TMS MEMO 182A TLC (30% EtOAc/Hexanes): Rf 0.43 (p-anisaldehyde, blue, KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 5.53 (dd, J = 5.2, 2.5 Hz, 1H), 5.19 (dd, J = 3.2, 1.7 Hz, 1H), 5.14 (d, J = 2.1 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.74 (d, J = 7.6 Hz, 1H), 4.01 – 3.87 (m, 1H), 3.87 – 3.80 (m, 1H), 3.75 (dd, J = 5.9, 3.2 Hz, 1H), 3.69 – 3.61 (m, 1H), 3.53 (dd, J = 5.4, 4.0 Hz, 2H), 3.36 (s, 3H), 2.89 – 2.79 (m, 2H), 2.72 (dd, J = 16.6, 2.6 Hz, 1H), Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 539 2.43 – 2.15 (m, 7H), 2.00 (dd, J = 10.8, 2.7 Hz, 1H), 1.63 (dd, J = 15.1, 2.7 Hz, 1H), 1.48 (dt, J = 13.7, 3.7 Hz, 1H), 1.03 (d, J = 5.9 Hz, 6H), 0.88 (s, 9H), 0.18 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 176.67, 152.72, 150.88, 120.05, 116.87, 115.18, 109.68, 99.35, 91.22, 82.95, 67.40, 60.54, 59.14, 49.60, 46.81, 44.10, 43.78, 40.83, 39.82, 39.08, 38.56, 35.82, 25.87, 23.38, 21.20, 20.62, 18.21, 1.31, -4.52, -4.93. FTIR (Neat, NaCl, thin film): 2929, 1779, 1412, 1213, 1050 cm-1. HRMS (ESI): calc’d for [M+NH4]+ 788.3501, found 788.3503. Preparation of aldol product 106B. OTBS O TBSO O Me Br ZnCl2 (1 equiv) + OMEM O Me Me (1.1 equiv) 99% ee (1 equiv) 86% ee 88 107B Et2O/Benzene, 0 °C to 22 °C, 20 h 56% yield dr = 7.7 : 1.7 : 1 TBSO O * Br Me HO * MEMO 106B An oven-dried 40 mL vial with a magnetic stir bar was cooled under vacuum. The vial was then charged with aldehyde 107B (683 mg, 1.98 mmol, 1 equiv) and silyloxyfuran 88 (785 mg, 1.98 mmol, 1 equiv), capped with a rubber septum, and evacuated and backfilled with N2 three times. To the vial was added dry benzene (9.9 mL) and dry Et2O (7.9 mL). The reaction vessel was cooled to 0 °C and vigorous stirring (800 rpm) was initiated. A solution of ZnCl2 (1 M in Et2O, 270 mg, 1.98 mmol, 1.98 mL) was added dropwise to the vial at 0 °C. The reaction was stirred for 9 h maintaining a constant temperature of 0 °C. After 9 h, the reaction was allowed to slowly warm to room temperature and stirred for 11 more h. After stirring for a total of 20 h, the reaction was quenched with sat. aq. NH4Cl (20 mL). The phases were separated, and the aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were washed with brine Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 540 (50 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude oil was purified via flash column chromatography (SiO2, slow gradient, 5-10% acetone/hexanes). The volatiles were concentrated under reduced pressure to afford 106B as a mixture of diastereomers (7.7 : 1.7 : 1.0) obtained as a thick yellow oil (694 mg, 56% yield) Analytically pure samples of the diastereomers were obtained, but on larger scales the mixture was carried forward and the single diastereomer of compound 181B was separated during the subsequent step. O Me O TBSO Br Me HO MEMO 106B TLC (24% Acetone/Hexanes): Rf 0.32 (p-anisaldehyde, brown, UV). 1 H NMR (CDCl3, 400 MHz): δ 5.92 (dd, J = 5.5, 2.3 Hz, 1H), 5.87 (s, 1H), 5.15 (s, 1H), 5.07 (s, 1H), 4.91 (d, J = 7.4 Hz, 1H), 4.74 (d, J = 7.4 Hz, 1H), 4.67 (dd, J = 10.0, 4.7 Hz, 1H), 4.26 – 4.17 (m, 1H), 3.86 – 2.80 (m, 1H), 3.67 – 3.61 (m, 1H), 3.56 (t, J = 4.6 Hz, 2H), 3.39 (s, 3H), 3.10 – 2.97 (m, 1H), 2.70 (dd, J = 16.4, 2.4 Hz, 1H), 2.66 – 2.57 (m, 1H), 2.36 – 2.24 (m, 3H), 2.24 – 2.18 (m, 1H), 2.17 – 2.04 (m, 3H), 1.58 (dd, J = 15.2, 3.2 Hz, 1H), 1.24 (s, 3H), 0.89 (s, 9H), 0.73 (s, 3H), 0.04 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 175.9, 174.1, 151.7, 131.7, 128.6, 115.5, 109.4, 97.3, 91.2, 83.1, 79.9, 72.0, 70.0, 67.2, 59.2, 48.1, 47.4, 47.3, 44.8, 44.2, 38.3, 35.2, 25.9, 20.5, 18.1, 16.3, -4.5, -4.9. FTIR (Neat, NaCl, thin film): 3461, 2930, 2888, 1785, 1738, 1253, 1195, 1089, 1045, 836 cm-1. HRMS (ESI-TOF): calc’d for C30H47BrO7SiNa [M+Na]+ 649.2166, found 649.2170. Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 541 [a]D22: +171.8 (c 1.0 in CHCl3). Preparation of TMS-protected 181B. O Me O Br TMS-imidazole (6 equiv.) TBSO Me HO O Br TBSO DCM, 40 °C, 12 h MEMO O Me 72% yield 106B Me O TMS MEMO 181B TMS•imidazole was purchased from Millipore Sigma and used as is. An oven-dried two neck 25 mL round-bottom flask was equipped with a magnetic stir bar, and reflux condenser then charged with the alcohol 106B (694 mg, 1.10 mmol, 1 equiv). The flask was evacuated and backfilled with N2 three times. DCM (5.5 mL, 200 mM) was added to the vial followed by dropwise addition of TMS-imidazole (970 uL, 6.60 mmol, 6 equiv) at room temperature. The reaction was then lowered into an oil bath and refluxed at 45 °C for 12 h. Upon TLC indicating complete conversion, the reaction was cooled to 0 °C and quenched by slow addition of H2O (10 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were washed with sat. aq. NH4Cl (3 x 10 mL), brine (10 mL), dried with MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (SiO2, 5% to 30% EtOAc/hexanes gradient) to afford a single diastereomer 181B (557 mg, 72% yield) as a white solid. O Me O TBSO Br Me O TMS MEMO 181B TLC: (20% EtOAc/hexanes): Rf 0.22 (p-anisaldehyde, brown, UV). Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 1 542 H NMR (CDCl3, 400 MHz): δ 5.89 (s, 1H), 5.85 (dd, J = 5.4, 2.3 Hz, 1H), 5.15 (t, J = 2.3 Hz, 1H), 5.10 (s, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.73 (d, J = 7.6 Hz, 1H), 4.50 (dd, J = 9.8, 5.4 Hz, 1H), 3.94 (bs, 1H), 3.85 (dt, J = 11.0, 4.3 Hz, 1H), 3.64 (dt, J = 10.7, 5.1 Hz, 1H), 3.53 (t, J = 4.8 Hz, 2H), 3.37 (s, 3H), 3.01 (ddd, J = 18.1, 9.9, 2.4 Hz, 1H), 2.69 – 2.54 (m, 2H), 2.45 – 2.22 (m, 3H), 2.20 – 1.60 (m, 4H), 1.27 (s, 3H), 0.90 (s, 9H), 0.72 (s, 3H), 0.21 (s, 9H), 0.07 (d, J = 6.1 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 176.0, 173.7, 133.0, 127.1, 125.7, 116.8, 109.2, 91.2, 83.2, 79.90, 71.9, 67.4, 66.0, 59.1, 51.4, 47.4, 46.7, 45.0, 39.9, 35.2, 30.5, 25.8, 21.2, 18.1, 17.1, 15.4, 1.1, -4.4, -4.8. FTIR (Neat, NaCl, thin film): 2930, 1758, 1461, 1249, 1096, 1051, 836 cm-1. HRMS (ESI-TOF): calc’d for C33H55BrO7Si2Na [M+Na]+ 721.2563 found 721.2563. [a]D23: +95.2 (c 1.0 in CHCl3). Melting Point: 135-137 °C. Preparation of lactone 182B. O Me O TBSO Me O TMS MEMO 181B Br CuCl2 H2O (5 mol%) R-(tol)-BINAP (5 mol%) PMHS (6 equiv) tBuOH (4 equiv) NaOtBu (1.2 equiv) THF/DCM (3:1), 22°C, 16 h 85% yield > 20:1 dr O Me TBSO O Br H Me O TMS MEMO 182B In an N2-filled glovebox, an oven-dried round-bottom flask was equipped with a magnetic stir bar and charged with CuCl2•2H2O (7.5 mg, 44 umol, 0.075 equiv), (rac)-tolBINAP (30 mg, 44 umol, 0.075 equiv), and NaOtBu (67 mg, 700 umol, 1.20 equiv) The vial was sealed with a rubber septum and removed from the glovebox. Anhydrous THF (13 Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 543 mL) was added to the vial, and the solution was stirred at room temperature (22 °C) for 5 min. After 5 min, poly(methylhydrosiloxane) (390 uL, 940 umol, 3 equiv) was added dropwise, and the reaction was stirred for 5 more min. A color change to bright orange and then brown was observed. Finally, 181B (408 mg, 583 umol, 1 equiv) was added as a solution in THF/DCM/tBuOH (2 mL/4.9 mL/0.22 mL) and the reaction was allowed to stir at room temperature for 14 h. Upon completion of the reaction as determined by TLC analysis, the reaction was quenched by slow addition of sat. aq. NH4Cl (20 mL), and the solution was stirred for 15 min or until bubbling ceased. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography (5-10% acetone/hexanes) to afford lactone 182B (348 mg, 85% yield) as a viscous, colorless oil. The reduction occurred in >20:1 dr. Experimental notes: The purification can be difficult to separate the product 182B from yellow copper or PMHS-derived compounds. It is advised to carefully load the column in a small amount of 5% acetone/hexanes to increase ease of separation. The starting material 181B and product 182B have a similar Rf but can be differentiated based on UV activity. O Me TBSO O Br H Me O TMS MEMO 182B TLC (30% EtOAc/hexanes): Rf 0.57 (p-anisaldehyde, blue). Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 1 544 H NMR (600 MHz, CDCl3): δ 5.83 (dd, J = 5.5, 2.3 Hz, 1H), 5.16 (s, 1H), 5.08 (s, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.75 (d, J = 7.5 Hz, 1H), 3.96 (s, 1H), 3.84 (dt, J = 10.8, 4.4 Hz, 1H), 3.80 – 3.70 (m, 1H), 3.65 (dt, J = 10.7, 5.1 Hz, 1H), 3.53 (t, J = 4.8 Hz, 2H), 3.37 (s, 3H), 2.91 – 2.83 (m, 1H), 2.77 (s, 1H), 2.41 – 2.20 (m, 2H), 2.41 – 2.27 (m, 4H), 2.24 (m, 1H), 2.14 (dd, J = 16.3, 5.5 Hz, 1H), 2.02 (dd, J = 10.7, 2.7 Hz, 1H), 1.80 (dd, J = 15.4, 3.0 Hz, 1H), 1.49 (dt, J = 13.7, 3.4 Hz, 1H), 1.07 (s, 3H), 1.03 (bs, 3H), 0.89 (s, 9H), 0.20 (s, 9H), 0.04 (d, J = 6.1 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 177.1, 152.3, 132.9, 127.2, 109.1, 99.8, 91.2, 83.3, 71.9, 67.3, 66.0, 59.1, 49.5, 46.8, 44.9, 44.3, 40.5, 39.9, 39.3, 38.8, 30.5, 29.8, 25.9, 23.5, 18.2, 15.4, 1.5, -4.5, -4.9. FTIR (Neat, NaCl, thin film): 2950, 2853, 1776, 1251, 1047, 840 cm-1. HRMS (ESI-TOF): calc’d for C33H61BrNO7Si2 [M+NH4]+ 718.3164, found 718.3163. [a]D23: +70.8 (c 1.0 in CHCl3). Preparation of pentacycle 105: O O O Me TBSO O H Me O TMS MEMO 182B Br Ni(COD)DMFU (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Tol/THF (2:1, 30 mM), 60° C, 12 h 79% yield selectivity α:β = 9:1 TBSO O TBSO O Me Me Me H O OMEM TMS α-alkenylation 105 H Me O OMEM TMS β-alkenylation 188 In an N2-filled glovebox, an oven-dried 50 mL Schlenk flask equipped with a magnetic stir bar was charged with 182B (290 mg, 413 umol, 1 equiv) in toluene (2 mL). A 5.0 M solution of NaHMDS was prepared by dissolving 150.0 mg in 1.5 mL of toluene along with a 0.02 M solution of Ni(COD)DMFU by dissolving 12.8 mg in 2 mL. Both stock solutions were stirred for 5 minutes to ensure complete dissolution of the solids. The Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 545 NaHMDS solution (1.3 mL, 121 mg, 661 umol, 1.6 equiv) was drawn up and dispensed dropwise into the Schlenk flask containing the starting material. ZnBr2 (14.0 mg, 62.0 umol, 0.15 equiv) as a solution in THF (4.6 mL) was added next in one portion. Finally, the Ni(COD)DMFU solution (1.0 mL, 6.4 mg, 20.7 umol, 0.05 equiv) was added slowly dropwise to create a final reaction concentration of 30 mM and a 2:1 ratio of toluene:THF. The Schlenk flask was closed with a tightly-fitted Kontes valve, pumped out of the glovebox, connected to an N2-inlet, and lowered into an oil bath. The reaction was stirred for 16 h at 60 °C. After 16 h, TLC indicated complete conversion, and the solution was filtered through a silica plug eluting with 50% Et2O/hexanes (100 mL). The collected volatiles were concentrated under reduced pressure. The crude residue was purified via flash column chromatography (10% to 30% Et2O/hexanes gradient) to afford the product 105 (203 mg, 79% yield) as a 9:1 mixture of isomers (a:b). O O TBSO Me Me H O OMEM TMS 105 TLC (50% Et2O/hexanes): Rf 0.71 (p-anisaldehyde, light blue). 1 H NMR (CDCl3, 400 MHz): δ 5.36 (dd, J = 4.3, 2.8 Hz, 1H), 5.02 (s, 1H), 4.92 (d, J = 7.5 Hz, 2H), 4.71 (d, J = 7.5 Hz, 1H), 4.30 – 4.27 (m, 1H), 3.83 (dt, J = 10.9, 4.0 Hz, 1H), 3.68 – 3.62 (m, 2H), 3.53 (t, J = 5.0 Hz, 2H), 3.37 (s, 3H), 3.10 (s, 1H), 2.98 (dd, J = 11.1, 4.7 Hz, 1H), 2.68 (d, J = 13.8 Hz, 1H), 2.60 – 2.46 (m, 2H), 2.29 (dd, J = 16.0, 2.1 Hz, 1H), 2.23 – 2.13 (m, 3H), 1.98 (d, J = 12.2 Hz, 1H), 1.70 (dd, J = 16.0, 5.5 Hz, 1H), 1.39 (ddd, J = 14.7, 4.7, 2.0 Hz, 1H), 1.07 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.19 (s, 9H), 0.00 (d, J = 5.0 Hz, 6H). Chapter 5 – Convergent fragment coupling and Ni-catalyzed a-enolate alkenylation 13 546 C NMR (CDCl3, 101 MHz): δ 177.1, 152.3, 143.2, 123.9, 107.0, 98.9, 91.2, 85.0, 83.0, 71.9, 71.0, 67.2, 59.1, 57.8, 51.2, 50.8, 49.9, 44.9, 43.5, 42.4, 42.3, 39.7, 25.8, 24.4, 18.5, 18.1, 1.3, -4.6, -5.00. FTIR (Neat, NaCl, thin film): 2951, 2929, 1768, 1265, 1046, 840, 736 cm-1. HRMS (ESI-TOF): calc’d for C33H57O7Si2 [M+H]+ 621. 3638, found 621.3670. [a]D24: +74.8 (c 0.2 in CHCl3). Melting Point: 104-106 °C O TBSO O Me H Me O TMS OMEM 188 TLC (50% Et2O/hexanes): Rf 0.68 (p-anisaldehyde, pink). 1 H NMR (CDCl3, 400 MHz): δ 5.36 (dd, J = 4.6, 2.6 Hz, 1H), 5.10 (s, 1H), 5.02 (s, 1H), 4.95 (d, J = 7.5 Hz, 1H), 4.73 (d, J = 7.5 Hz, 1H), 4.08 (dd, J = 11.8, 4.1 Hz, 1H), 3.87 – 3.82 (m, 1H), 3.62 (m, 2H), 3.54 (m, 2H), 3.38 (s, 3H), 2.76 (dd, J = 16.3, 9.6 Hz, 3H), 2.63 (dd, J = 16.6, 2.6 Hz, 1H), 2.47 (dd, J = 14.0, 4.6 Hz, 1H), 2.30 (d, J = 15.5 Hz, 1H), 2.26 – 1.93 (m, 4H), 1.81 (bs, 1H), 1.64 – 1.57 (m, 1H), 1.23 (s, 3H), 1.08 (s, 3H), 0.88 (s, 9H), 0.15 (s, 9H), 0.03 (d, J = 4.9 Hz, 6H). 13 C NMR (CDCl3, 101 MHz): δ 175.4, 152.6, 142.7, 124.2, 108.2, 108.1, 98.3, 91.1, 83.5, 83.3, 72.0, 67.1, 59.2, 52.4, 50.6, 48.5, 48.1, 43.9, 42.2, 30.5, 29.9, 25.9, 25.8, 24.4, 21.3, 18.4, 0.4, -4.7, -4.9. FTIR (Neat, NaCl, thin film): 2951, 2929, 1768, 1265, 1046, 840, 736 cm-1. HRMS (ESI-TOF): calc’d for C33H56O7Si2Na [M+Na]+ 643.3457, found 643.3461. 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R.; Eastgate, M. D.; Engle, K. M. Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides. J. Am. Chem. Soc. 2018, 140, 17878–17883. (77) Hartwig, J. F. (2010). Organotransition Metal Chemistry: From Bonding to Catalysis. University Science Books. 557 Appendix 5 – Supporting Information Relevant to Chapter 5 Appendix 5 Supporting Information Relevant to Chapter 5: Development of a vinylogous Mukaiyama Aldol fragment coupling reaction and Intramolecular Ni-catalyzed -enolate alkenylation 558 Appendix 5 – Supporting Information Relevant to Chapter 5 X-Ray Crystallography Data O TfO O TBSO Me Me OH OMEM 106A Table A5.1. Crystal data and structure refinement for 106A (V22432). Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.679° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) V22432 C31 H47 F3 O10 S Si 696.83 100(2) K 1.54178 Å Orthorhombic P212121 a = 7.5072(7) Å b = 17.6749(18) Å c = 26.655(3) Å 3536.8(6) Å3 a= 90°. b= 90°. g = 90°. 4 1.309 Mg/m3 1.729 mm-1 1480 0.400 x 0.200 x 0.100 mm3 3.000 to 74.561°. -9<=h<=9, -22<=k<=22, -33<=l<=33 48096 7212 [R(int) = 0.0467] 100.0 % Semi-empirical from equivalents 0.7538 and 0.4186 Full-matrix least-squares on F2 7212 / 1 / 426 1.023 R1 = 0.0303, wR2 = 0.0837 R1 = 0.0305, wR2 = 0.0839 559 Appendix 5 – Supporting Information Relevant to Chapter 5 Absolute structure parameter Extinction coefficient Largest diff. peak and hole 0.007(6) n/a 0.578 and -0.302 e.Å-3 Table A5.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22432. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ ______ x y z U(eq) ________________________________________________________________________ ______ C(1) 9557(4) 8019(1) 4588(1) 34(1) F(1) 10162(2) 8594(1) 4856(1) 39(1) F(2) 10882(3) 7716(2) 4340(1) 79(1) F(3) 8882(4) 7516(1) 4885(1) 75(1) S(1) 7885(1) 8378(1) 4151(1) 25(1) O(1) 6534(3) 8689(2) 4449(1) 66(1) O(2) 8748(4) 8822(1) 3792(1) 62(1) O(3) 7343(2) 7588(1) 3942(1) 18(1) C(2) 6448(3) 7535(1) 3465(1) 15(1) C(3) 4918(3) 7891(1) 3394(1) 18(1) C(4) 4008(3) 7867(1) 2888(1) 18(1) C(5) 5258(3) 7531(1) 2490(1) 14(1) O(4) 4460(2) 7448(1) 2006(1) 17(1) C(11) 2606(3) 7346(1) 1972(1) 18(1) O(5) 1980(2) 6677(1) 2194(1) 17(1) C(12) 2414(3) 6013(1) 1913(1) 20(1) C(13) 1485(3) 5344(1) 2141(1) 20(1) O(6) -390(2) 5435(1) 2092(1) 23(1) C(14) -1316(3) 4779(1) 2248(1) 25(1) C(6) 6050(3) 6791(1) 2699(1) 12(1) C(7) 7455(2) 7095(1) 3070(1) 12(1) C(15) 8760(3) 6503(1) 3274(1) 13(1) 560 Appendix 5 – Supporting Information Relevant to Chapter 5 C(16) O(7) C(17) O(8) C(18) 7863(2) 6529(2) 9224(2) 10667(2) 12169(3) 5813(1) 6034(1) 5305(1) 5179(1) 5508(1) 3514(1) 3864(1) 3792(1) 3441(1) 3625(1) 12(1) 15(1) 11(1) 12(1) 14(1) O(9) 13540(2) 5503(1) 3386(1) 20(1) C(19) 11813(3) 5800(1) 4132(1) 16(1) C(20) 10106(3) 5664(1) 4236(1) 13(1) C(21) 8992(3) 5571(1) 4692(1) 17(1) C(22) 7806(3) 4873(1) 4558(1) 14(1) O(10) 7950(2) 4291(1) 4920(1) 18(1) Si(1) 6887(1) 4231(1) 5463(1) 16(1) C(24) 4432(3) 4301(2) 5353(1) 30(1) C(25) 7591(4) 5000(1) 5898(1) 30(1) C(26) 7594(3) 3275(1) 5702(1) 19(1) C(27) 7163(3) 2669(1) 5308(1) 23(1) C(28) 6594(4) 3083(1) 6191(1) 30(1) C(29) 9610(3) 3277(1) 5801(1) 28(1) C(23) 8453(3) 4571(1) 4036(1) 12(1) C(30) 6931(3) 4196(1) 3746(1) 17(1) C(31) 9960(3) 3993(1) 4107(1) 17(1) C(8) 8418(3) 7686(1) 2733(1) 15(1) C(9) 6918(3) 8029(1) 2430(1) 14(1) C(10) 6987(3) 8645(1) 2146(1) 20(1) ________________________________________________________________________ ______ 561 Appendix 5 – Supporting Information Relevant to Chapter 5 Table A5.3. Bond lengths [Å] and angles [°] for V22432. _____________________________________________________ C(1)-F(3) 1.295(3) C(1)-F(2) 1.309(4) C(1)-F(1) 1.323(3) C(1)-S(1) S(1)-O(2) S(1)-O(1) S(1)-O(3) O(3)-C(2) C(2)-C(3) C(2)-C(7) C(3)-C(4) C(3)-H(3) C(4)-C(5) C(4)-H(4A) C(4)-H(4B) C(5)-O(4) C(5)-C(9) C(5)-C(6) O(4)-C(11) C(11)-O(5) C(11)-H(11A) C(11)-H(11B) O(5)-C(12) C(12)-C(13) C(12)-H(12A) C(12)-H(12B) C(13)-O(6) C(13)-H(13A) C(13)-H(13B) O(6)-C(14) C(14)-H(14A) 1.825(3) 1.398(2) 1.400(2) 1.5576(15) 1.442(2) 1.323(3) 1.511(3) 1.513(3) 0.9500 1.536(3) 0.9900 0.9900 1.431(2) 1.535(3) 1.540(3) 1.407(2) 1.403(2) 0.9900 0.9900 1.431(3) 1.501(3) 0.9900 0.9900 1.423(3) 0.9900 0.9900 1.415(3) 0.9800 C(14)-H(14B) 0.9800 562 Appendix 5 – Supporting Information Relevant to Chapter 5 C(14)-H(14C) C(6)-C(7) C(6)-H(6A) C(6)-H(6B) C(7)-C(15) 0.9800 1.544(3) 0.9900 0.9900 1.532(3) C(7)-C(8) C(15)-C(16) C(15)-H(15A) C(15)-H(15B) C(16)-O(7) C(16)-C(17) C(16)-H(16) O(7)-H(7O) C(17)-O(8) C(17)-C(20) C(17)-C(23) O(8)-C(18) C(18)-O(9) C(18)-C(19) C(19)-C(20) C(19)-H(19) C(20)-C(21) C(21)-C(22) C(21)-H(21A) C(21)-H(21B) C(22)-O(10) C(22)-C(23) C(22)-H(22) O(10)-Si(1) Si(1)-C(25) Si(1)-C(24) Si(1)-C(26) C(24)-H(24A) 1.556(3) 1.533(3) 0.9900 0.9900 1.423(2) 1.549(2) 1.0000 0.82(2) 1.449(2) 1.498(3) 1.563(2) 1.361(2) 1.210(3) 1.472(3) 1.333(3) 0.9500 1.483(3) 1.563(3) 0.9900 0.9900 1.415(2) 1.569(3) 1.0000 1.6542(14) 1.864(2) 1.870(2) 1.883(2) 0.9800 C(24)-H(24B) 0.9800 563 Appendix 5 – Supporting Information Relevant to Chapter 5 C(24)-H(24C) C(25)-H(25A) C(25)-H(25B) C(25)-H(25C) C(26)-C(27) 0.9800 0.9800 0.9800 0.9800 1.533(3) C(26)-C(29) C(26)-C(28) C(27)-H(27A) C(27)-H(27B) C(27)-H(27C) C(28)-H(28A) C(28)-H(28B) C(28)-H(28C) C(29)-H(29A) C(29)-H(29B) C(29)-H(29C) C(23)-C(30) C(23)-C(31) C(30)-H(30A) C(30)-H(30B) C(30)-H(30C) C(31)-H(31A) C(31)-H(31B) C(31)-H(31C) C(8)-C(9) C(8)-H(8A) C(8)-H(8B) C(9)-C(10) C(10)-H(10A) C(10)-H(10B) 1.536(3) 1.542(3) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.530(3) 1.536(3) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.513(3) 0.9900 0.9900 1.326(3) 0.9500 0.9500 F(3)-C(1)-F(2) F(3)-C(1)-F(1) 109.0(3) 109.4(2) F(2)-C(1)-F(1) 109.0(2) 564 Appendix 5 – Supporting Information Relevant to Chapter 5 F(3)-C(1)-S(1) F(2)-C(1)-S(1) F(1)-C(1)-S(1) O(2)-S(1)-O(1) O(2)-S(1)-O(3) 111.1(2) 110.1(2) 108.25(18) 120.23(19) 112.30(11) O(1)-S(1)-O(3) O(2)-S(1)-C(1) O(1)-S(1)-C(1) O(3)-S(1)-C(1) C(2)-O(3)-S(1) C(3)-C(2)-O(3) C(3)-C(2)-C(7) O(3)-C(2)-C(7) C(2)-C(3)-C(4) C(2)-C(3)-H(3) C(4)-C(3)-H(3) C(3)-C(4)-C(5) C(3)-C(4)-H(4A) C(5)-C(4)-H(4A) C(3)-C(4)-H(4B) C(5)-C(4)-H(4B) H(4A)-C(4)-H(4B) O(4)-C(5)-C(9) O(4)-C(5)-C(4) C(9)-C(5)-C(4) O(4)-C(5)-C(6) C(9)-C(5)-C(6) C(4)-C(5)-C(6) C(11)-O(4)-C(5) O(5)-C(11)-O(4) O(5)-C(11)-H(11A) O(4)-C(11)-H(11A) O(5)-C(11)-H(11B) 111.47(13) 108.23(16) 105.87(15) 95.51(10) 119.66(13) 119.98(18) 125.46(18) 114.46(16) 120.38(18) 119.8 119.8 110.55(16) 109.5 109.5 109.5 109.5 108.1 107.68(15) 114.05(16) 110.25(16) 113.63(16) 102.20(15) 108.37(16) 118.96(15) 114.38(17) 108.7 108.7 108.7 O(4)-C(11)-H(11B) 108.7 565 Appendix 5 – Supporting Information Relevant to Chapter 5 H(11A)-C(11)-H(11B) C(11)-O(5)-C(12) O(5)-C(12)-C(13) O(5)-C(12)-H(12A) C(13)-C(12)-H(12A) 107.6 113.18(15) 109.14(16) 109.9 109.9 O(5)-C(12)-H(12B) C(13)-C(12)-H(12B) H(12A)-C(12)-H(12B) O(6)-C(13)-C(12) O(6)-C(13)-H(13A) C(12)-C(13)-H(13A) O(6)-C(13)-H(13B) C(12)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(14)-O(6)-C(13) O(6)-C(14)-H(14A) O(6)-C(14)-H(14B) H(14A)-C(14)-H(14B) O(6)-C(14)-H(14C) H(14A)-C(14)-H(14C) H(14B)-C(14)-H(14C) C(5)-C(6)-C(7) C(5)-C(6)-H(6A) C(7)-C(6)-H(6A) C(5)-C(6)-H(6B) C(7)-C(6)-H(6B) H(6A)-C(6)-H(6B) C(2)-C(7)-C(15) C(2)-C(7)-C(6) C(15)-C(7)-C(6) C(2)-C(7)-C(8) C(15)-C(7)-C(8) C(6)-C(7)-C(8) 109.9 109.9 108.3 109.43(17) 109.8 109.8 109.8 109.8 108.2 111.42(18) 109.5 109.5 109.5 109.5 109.5 109.5 101.54(15) 111.5 111.5 111.5 111.5 109.3 115.13(16) 106.48(15) 115.20(16) 106.83(16) 111.46(15) 100.43(14) C(7)-C(15)-C(16) 114.21(16) 566 Appendix 5 – Supporting Information Relevant to Chapter 5 C(7)-C(15)-H(15A) C(16)-C(15)-H(15A) C(7)-C(15)-H(15B) C(16)-C(15)-H(15B) H(15A)-C(15)-H(15B) 108.7 108.7 108.7 108.7 107.6 O(7)-C(16)-C(15) O(7)-C(16)-C(17) C(15)-C(16)-C(17) O(7)-C(16)-H(16) C(15)-C(16)-H(16) C(17)-C(16)-H(16) C(16)-O(7)-H(7O) O(8)-C(17)-C(20) O(8)-C(17)-C(16) C(20)-C(17)-C(16) O(8)-C(17)-C(23) C(20)-C(17)-C(23) C(16)-C(17)-C(23) C(18)-O(8)-C(17) O(9)-C(18)-O(8) O(9)-C(18)-C(19) O(8)-C(18)-C(19) C(20)-C(19)-C(18) C(20)-C(19)-H(19) C(18)-C(19)-H(19) C(19)-C(20)-C(21) C(19)-C(20)-C(17) C(21)-C(20)-C(17) C(20)-C(21)-C(22) C(20)-C(21)-H(21A) C(22)-C(21)-H(21A) C(20)-C(21)-H(21B) C(22)-C(21)-H(21B) 111.35(15) 108.01(14) 111.78(15) 108.5 108.5 108.5 109(2) 104.19(14) 105.86(14) 115.12(15) 114.69(14) 100.74(15) 115.88(15) 108.73(14) 120.77(18) 129.84(19) 109.32(16) 107.61(17) 126.2 126.2 137.07(19) 109.68(17) 110.57(16) 102.81(15) 111.2 111.2 111.2 111.2 H(21A)-C(21)-H(21B) 109.1 567 Appendix 5 – Supporting Information Relevant to Chapter 5 O(10)-C(22)-C(21) O(10)-C(22)-C(23) C(21)-C(22)-C(23) O(10)-C(22)-H(22) C(21)-C(22)-H(22) 112.03(16) 109.50(15) 107.17(15) 109.4 109.4 C(23)-C(22)-H(22) C(22)-O(10)-Si(1) O(10)-Si(1)-C(25) O(10)-Si(1)-C(24) C(25)-Si(1)-C(24) O(10)-Si(1)-C(26) C(25)-Si(1)-C(26) C(24)-Si(1)-C(26) Si(1)-C(24)-H(24A) Si(1)-C(24)-H(24B) H(24A)-C(24)-H(24B) Si(1)-C(24)-H(24C) H(24A)-C(24)-H(24C) H(24B)-C(24)-H(24C) Si(1)-C(25)-H(25A) Si(1)-C(25)-H(25B) H(25A)-C(25)-H(25B) Si(1)-C(25)-H(25C) H(25A)-C(25)-H(25C) H(25B)-C(25)-H(25C) C(27)-C(26)-C(29) C(27)-C(26)-C(28) C(29)-C(26)-C(28) C(27)-C(26)-Si(1) C(29)-C(26)-Si(1) C(28)-C(26)-Si(1) C(26)-C(27)-H(27A) C(26)-C(27)-H(27B) 109.4 127.29(13) 111.11(10) 109.56(10) 109.20(13) 102.55(9) 111.34(11) 112.95(11) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.07(19) 108.78(19) 109.53(19) 109.67(15) 109.51(16) 110.26(15) 109.5 109.5 H(27A)-C(27)-H(27B) 109.5 568 Appendix 5 – Supporting Information Relevant to Chapter 5 C(26)-C(27)-H(27C) H(27A)-C(27)-H(27C) H(27B)-C(27)-H(27C) C(26)-C(28)-H(28A) C(26)-C(28)-H(28B) 109.5 109.5 109.5 109.5 109.5 H(28A)-C(28)-H(28B) C(26)-C(28)-H(28C) H(28A)-C(28)-H(28C) H(28B)-C(28)-H(28C) C(26)-C(29)-H(29A) C(26)-C(29)-H(29B) H(29A)-C(29)-H(29B) C(26)-C(29)-H(29C) H(29A)-C(29)-H(29C) H(29B)-C(29)-H(29C) C(30)-C(23)-C(31) C(30)-C(23)-C(17) C(31)-C(23)-C(17) C(30)-C(23)-C(22) C(31)-C(23)-C(22) C(17)-C(23)-C(22) C(23)-C(30)-H(30A) C(23)-C(30)-H(30B) H(30A)-C(30)-H(30B) C(23)-C(30)-H(30C) H(30A)-C(30)-H(30C) H(30B)-C(30)-H(30C) C(23)-C(31)-H(31A) C(23)-C(31)-H(31B) H(31A)-C(31)-H(31B) C(23)-C(31)-H(31C) H(31A)-C(31)-H(31C) H(31B)-C(31)-H(31C) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 108.91(16) 115.24(15) 109.34(15) 111.37(16) 110.21(15) 101.57(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 C(9)-C(8)-C(7) 103.39(15) 569 Appendix 5 – Supporting Information Relevant to Chapter 5 C(9)-C(8)-H(8A) C(7)-C(8)-H(8A) C(9)-C(8)-H(8B) C(7)-C(8)-H(8B) H(8A)-C(8)-H(8B) 111.1 111.1 111.1 111.1 109.0 C(10)-C(9)-C(8) 127.2(2) C(10)-C(9)-C(5) 124.21(19) C(8)-C(9)-C(5) 108.60(16) C(9)-C(10)-H(10A) 120.0 C(9)-C(10)-H(10B) 120.0 H(10A)-C(10)-H(10B) 120.0 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 570 Appendix 5 – Supporting Information Relevant to Chapter 5 Table A5.4. Anisotropic displacement parameters (Å2x 103) for V22432. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ________________________________________________________________________ ______ U11 U22 U33 U23 U13 U12 ________________________________________________________________________ ______ C(1) 39(1) 26(1) 36(1) -5(1) -18(1) -3(1) F(1) 49(1) 34(1) 35(1) -7(1) -18(1) -14(1) F(2) 39(1) 90(2) 110(2) -59(2) -37(1) 31(1) F(3) 128(2) 46(1) 50(1) 25(1) -54(1) -44(1) S(1) 32(1) 18(1) 25(1) -5(1) -8(1) 2(1) O(1) 45(1) 71(2) 82(2) -55(2) -11(1) 21(1) O(2) 113(2) 38(1) 33(1) 12(1) -24(1) -43(1) O(3) 22(1) 18(1) 16(1) -2(1) -4(1) 0(1) C(2) 14(1) 16(1) 14(1) 1(1) -1(1) -1(1) C(3) 16(1) 20(1) 18(1) -1(1) 3(1) 4(1) C(4) 11(1) 22(1) 20(1) 1(1) -1(1) 4(1) C(5) 10(1) 15(1) 15(1) 1(1) -2(1) 1(1) O(4) 11(1) 23(1) 16(1) 4(1) -2(1) -2(1) C(11) 13(1) 19(1) 22(1) 6(1) -3(1) -2(1) O(5) 15(1) 17(1) 20(1) 1(1) 2(1) -3(1) C(12) 19(1) 22(1) 18(1) -2(1) 3(1) -2(1) C(13) 21(1) 20(1) 19(1) 0(1) -2(1) 0(1) O(6) 20(1) 20(1) 28(1) 4(1) -3(1) -6(1) C(14) 26(1) 23(1) 25(1) 0(1) 1(1) -9(1) C(6) 10(1) 13(1) 14(1) 1(1) 0(1) 0(1) C(7) 7(1) 13(1) 16(1) 1(1) 1(1) -1(1) C(15) 8(1) 15(1) 17(1) 4(1) 0(1) 0(1) C(16) 8(1) 14(1) 13(1) 1(1) 0(1) 0(1) O(7) 7(1) 18(1) 20(1) 1(1) 3(1) 2(1) C(17) 7(1) 12(1) 13(1) 0(1) 1(1) 0(1) 571 Appendix 5 – Supporting Information Relevant to Chapter 5 O(8) C(18) O(9) C(19) C(20) 7(1) 10(1) 10(1) 14(1) 14(1) 15(1) 15(1) 27(1) 18(1) 12(1) 14(1) 18(1) 24(1) 17(1) 14(1) 0(1) 4(1) 4(1) 1(1) 1(1) 1(1) -2(1) 2(1) -5(1) -2(1) 1(1) 1(1) 0(1) -3(1) 1(1) C(21) 19(1) 19(1) 14(1) -2(1) 1(1) -5(1) C(22) 13(1) 15(1) 12(1) 2(1) 2(1) 0(1) O(10) 20(1) 20(1) 14(1) 5(1) 3(1) 0(1) Si(1) 16(1) 18(1) 14(1) 2(1) 3(1) -1(1) C(24) 17(1) 37(1) 37(1) 9(1) 3(1) 2(1) C(25) 43(1) 25(1) 21(1) -3(1) 6(1) -3(1) C(26) 21(1) 20(1) 16(1) 3(1) 2(1) -2(1) C(27) 22(1) 20(1) 28(1) -1(1) 4(1) -4(1) C(28) 41(2) 27(1) 23(1) 9(1) 13(1) 2(1) C(29) 26(1) 31(1) 26(1) 3(1) -7(1) 1(1) C(23) 11(1) 12(1) 13(1) 1(1) 0(1) -2(1) C(30) 16(1) 15(1) 19(1) 0(1) -1(1) -4(1) C(31) 17(1) 16(1) 19(1) 4(1) 2(1) 3(1) C(8) 10(1) 15(1) 19(1) 3(1) 0(1) -2(1) C(9) 13(1) 15(1) 15(1) -1(1) -1(1) 0(1) C(10) 20(1) 19(1) 22(1) 5(1) -3(1) -3(1) ________________________________________________________________________ ______ 572 Appendix 5 – Supporting Information Relevant to Chapter 5 Table A5.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22432. ________________________________________________________________________ ______ x y z U(eq) ________________________________________________________________________ ______ H(3) H(4A) H(4B) H(11A) H(11B) H(12A) H(12B) H(13A) H(13B) H(14A) H(14B) H(14C) H(6A) H(6B) H(15A) H(15B) H(16) H(7O) H(19) H(21A) H(21B) H(22) H(24A) H(24B) 4388 3659 2914 2010 2261 3718 2031 1866 1806 -1004 -2601 -982 6606 5135 9537 9529 7287 5550(30) 12648 8256 9736 6534 4166 3809 8162 8386 7557 7781 7346 5931 6076 4874 5301 4355 4871 4656 6485 6484 6747 6328 5508 5908(16) 6042 6027 5470 5037 4771 4300 3663 2788 2911 2134 1614 1917 1560 1970 2500 2028 2231 2594 2430 2872 3527 2995 3243 3756(10) 4347 4754 4991 4532 5173 5676 21 21 21 22 22 24 24 24 24 37 37 37 15 15 16 16 14 23 20 21 21 16 45 45 H(24C) 4036 3868 5152 45 573 Appendix 5 – Supporting Information Relevant to Chapter 5 H(25A) H(25B) H(25C) H(27A) H(27B) 8889 7022 7234 7542 7795 4987 4926 5491 2172 2784 5938 6225 5760 5432 4996 44 44 44 35 35 H(27C) 5877 2662 5245 35 H(28A) 5313 3053 6123 46 H(28B) 6819 3479 6440 46 H(28C) 7015 2595 6320 46 H(29A) 9985 2772 5911 41 H(29B) 9888 3648 6062 41 H(29C) 10242 3410 5491 41 H(30A) 7357 4041 3414 25 H(30B) 5948 4556 3709 25 H(30C) 6515 3750 3931 25 H(31A) 9493 3542 4276 26 H(31B) 10908 4218 4311 26 H(31C) 10441 3849 3779 26 H(8A) 9024 8076 2939 18 H(8B) 9306 7439 2513 18 H(10A) 8067 8921 2118 25 H(10B) 5955 8809 1971 25 ________________________________________________________________________ ______ 5.17 5.14 1D 16 98 .9 1.0000 12.5000 4.0894 2022-12-05T03 39 47 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 0.98 5.5 1.04 5.0 4.5 4.0 z g30 Pulse Sequence 6.0 297. 2 Temperature 106A CDCl3 0.99 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Solvent 5.86 0.97 Origin 5.50 JKT-2-215 _pure.1. fid 4.94 Title Value 4.72 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 1/ fid Parameter 4.46 Data File Name 2.5 1.5 1.0 0.5 1.96 1.00 2.32 3.01 2.97 2.85 2.70 0.81 0.85 0.98 3.63 3.52 3.36 0.97 2.04 2.97 3.85 1.08 0.0 1.25 3.05 2.0 0.89 9.01 3 .0 0.72 3.00 3 .5 f1 (ppm) 0.19 0.07 9.05 6.04 1.05 1.02 1.03 -0.5 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 175.53 173.50 512 64. 2 1.0000 10.0000 1. 3631 2022-12-05T04 01 00 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 24038 .5 Spectral Width 110 100 1D Experiment 120 z gpg30 Pulse Sequence 130 297. 2 Temperature 140 CDCl3 Solvent 106A Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-2-215 _pure. 2. fid 152.89 150.58 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 2/ fid 120.08 116.89 114.94 Title Value 109.71 Data File Name Parameter 91.22 90 f1 (ppm) 82.98 79.77 80 71.80 70 59.17 60 50 47.44 44.02 43.52 40.95 40 30.46 29.85 25.83 30 21.06 18.09 17.24 20 10 0 1.48 0.92 -4.51 35.04 67.37 0 100 200 300 400 500 600 700 800 900 1000 1100 1 64. 2 1.9492 12.5000 0. 2478 2022-12-05T04 06 39 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.04, 4.04) Spectral Siz e Digital Resolution 6.5 (1024, 128) Acquired Siz e 7.0 (1H, 1H) Nucleus 7.5 (-789.7, -799.4) Lowest Frequency 8 .0 (4132. 2, 4132. 2) Spectral Width 4.0 f2 (ppm) COSY Experiment 4.5 cosygpppqf Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-2-215 _pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 3/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 106A 7 6 5 4 3 2 1 0 -1 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2022-12-05T04 18 21 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.68 , 16. 22) Spectral Siz e Digital Resolution 5.0 (1024, 180) Acquired Siz e 5.5 (1H, 13C) Nucleus 6.0 (-527. 8 , -1359.6) Lowest Frequency 6.5 (4795.4, 16611. 3) Spectral Width 3 .0 f2 (ppm) 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-2-215 _pure.4.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 4/ ser Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 106A 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 5.15 5.07 4.91 z g30 1D 16 72.0 1.0000 12.5000 4.0894 2025-02-11T13 00 19 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.01 1.00 1.04 5.0 4.5 4.0 297. 2 Temperature 5.5 CDCl3 Solvent 106B Bruker BioSpin GmbH 1.02 Spectrometer Frequency 400.13 JKT-7-57 _pure.1. fid Origin 5.92 5.87 1.04 1.00 Title 4.74 4.67 / Users/ jordankthompson/ Desktop/ JKT-7-57 _pure/ 1/ fid Value 4.22 Data File Name Parameter 2.5 2.0 1.0 0.5 1.58 1.02 2.30 2.21 2.11 3.04 1.05 3.06 2.70 2.62 1.04 1.00 3.05 1.02 3.39 2.99 3.64 3.56 1.00 2.02 3.84 1.07 0.0 1.24 3.03 1.5 0.89 9.32 3 .0 0.73 2.97 3 .5 f1 (ppm) 0.04 6.05 1.04 1.02 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 36000 180 1.0000 10.0000 1.1796 2025-02-11T13 19 58 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 27777. 8 Spectral Width 110 100 72.0 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 106B 297. 2 Spectrometer Frequency 100.62 CDCl3 Temperature 175.85 174.14 Bruker BioSpin GmbH 151.67 Solvent 131.73 Origin 128.56 JKT-7-57 _pure. 2. fid 115.54 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-7-57 _pure/ 2/ fid 109.39 Title Value 97.31 Data File Name Parameter 91.16 90 83.13 f1 (ppm) 79.91 80 71.98 70.04 67.19 70 59.17 60 48.13 47.35 47.30 44.83 44.20 50 38.31 40 30 20.50 18.11 16.27 20 10 0 -4.47 -4.90 25.86 35.24 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 f2 (ppm) 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 106B -1.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2025-02-11T13 37 25 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.68 , 16. 22) Spectral Siz e Digital Resolution 5.5 (1024, 180) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-517.1, -1262. 8) Lowest Frequency 7.0 (4795.4, 16611. 3) Spectral Width 3 .5 f2 (ppm) 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin 5.0 JKT-7-57 _pure.4.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-7-57 _pure/ 4/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 106B 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-02-11T14 21 10 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2. 35, 21. 80) Digital Resolution 6.0 (2048 , 1024) Spectral Siz e 6.5 (2048 , 256) Acquired Siz e 7.0 (1H, 13C) Nucleus 7.5 (-163 .1, -1116.4) Lowest Frequency 8 .0 (4807.7, 22321.4) Spectral Width 4.0 f2 (ppm) hmbcetgpl3nd Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-57 _pure.5.ser Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-7-57 _pure/ 5/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 106B 0.0 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 2024-01-02T17 49 14 3 .0000 5.6500 1.0000 48 8 1D s2pul 25.0 cdcl3 Varian PROTON01 7.0 Spectral Size Acquired Size Nucleus 6.5 Spectral Width 6.0 65536 24000 1H 8000.0 Spectrometer Frequency 499.55 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin 2.73 3.64 3.54 3.38 5.5 4.92 1.10 5.0 4.5 180 4.0 3.84 1.08 3.5 f1 (ppm) 1.08 2.14 3.08 1.02 4.74 1.10 3.0 2.5 / Users/ jordankthompson/ Desktop/ JKT-5-186_mystery_pdt/ PROTON01. fid/ fid 5.52 1.01 Title 4.38 Value 3.11 1.02 Data File Name 5.16 5.11 1.10 1.11 6.29 1.00 2.61 1.06 1.01 Parameter 2.0 1.5 0.5 0.92 9.83 2.38 2.25 2.18 2.02 1.11 3.09 1.0 0.14 5.70 0.0 -1000 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 2024-01-02T19 26 22 Acquisition Date 180 170 65536 Spectral Size 190 32768 Acquired Size 200 13C Nucleus 210 24038 .5 Spectral Width 100 f1 (ppm) 90 1. 3631 Acquisition Time 110 10.0000 Pulse Width 120 1.0000 Relaxation Delay 130 64.2 Receiver Gain 140 512 Number of Scans 150 1D Experiment 160 zgpg30 Pulse Sequence 180 297.1 Temperature Spectrometer Frequency 100.62 CDCl3 Solvent 206.98 Bruker BioSpin GmbH 153.69 151.69 Origin 142.09 JKT-5-186_mystery.2. fid 120.06 116.88 114.13 Title 108.60 105.92 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-5-186_mystery/ 2/ fid Value 91.06 Data File Name Parameter 80 71.76 70 59.01 60 50 46.80 45.65 44.13 40.83 40 30.95 30.33 30 17.98 20 10 0 -5.52 -5.56 25.44 67.07 82.76 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 4.94 5.17 5.14 297. 2 z g30 1D 16 98 .9 1.0000 12.5000 4.0894 2022-12-05T03 39 47 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.5 1.04 5.0 4.5 4.0 CDCl3 Solvent 181A Bruker BioSpin GmbH 0.99 Spectrometer Frequency 400.13 JKT-2-215 _pure.1. fid 5.86 0.97 Origin 5.50 0.98 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 1/ fid 4.72 Title Value 4.46 Data File Name Parameter 2.5 1.5 1.0 0.5 1.96 1.00 2.32 3.01 2.97 2.85 2.70 0.81 0.85 0.98 3.63 3.52 3.36 0.97 2.04 2.97 3.85 1.08 0.0 1.25 3.05 2.0 0.89 9.01 3 .0 0.72 3.00 3 .5 f1 (ppm) 0.19 0.07 9.05 6.04 1.05 1.02 1.03 -3000 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 120.08 116.89 114.94 64. 2 1.0000 10.0000 1. 3631 2022-12-05T04 01 00 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 110 512 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 140 297. 2 Temperature 100 181A CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 175.53 173.50 JKT-2-215 _pure. 2. fid 152.89 150.58 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-2-215 _pure/ 2/ fid 109.71 Title Value 90 91.22 Data File Name Parameter 82.98 79.77 80 f1 (ppm) 71.80 70 59.17 60 50 47.44 44.02 43.52 40.95 40 30.46 29.85 25.83 30 21.06 18.09 17.24 20 10 0.92 0 -4.51 -5.04 35.04 67.37 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 zg30 1D 16 197.4 1.0000 12.5000 4.0894 2024-04-20T22 33 13 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.5 297.1 Temperature Spectrometer Frequency 400.13 CDCl3 Solvent 5.15 5.10 1.04 1.04 Bruker BioSpin GmbH 4.93 Origin 4.50 compound81.1. fid 3.94 3.85 Title 3.64 / Volumes/ nmrdata-1/ jkthomps/ nmr/ compound81/ 1/ fid 1.05 5.0 1.00 4.5 1.84 4.0 3 .5 1.06 2.13 f1 (ppm) 3.00 1.00 3.37 3.21 3 .0 2.5 181B 2.0 1.96 3.98 2.33 3.25 4.73 Value 3.53 Data File Name 5.89 5.85 1.00 1.01 2.63 2.12 Parameter 1.5 1.0 0.5 0.21 9.40 0.72 3.15 0.90 8.97 1.27 2.91 0.0 0.07 6.47 2.14 1.05 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 1.0000 10.0000 1.1796 2024-04-21T00 57 33 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 170 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27777. 8 Spectral Width 110 50. 3 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 175.95 173.73 Origin 133.00 compound81_RR. 2. fid 127.06 125.66 / Volumes/ nmrdata/ jkthomps/ nmr/ compound81_RR/ 2/ fid 116.80 Title Value 109.20 Data File Name Parameter 100 f1 (ppm) 91.17 90 83.21 79.90 80 71.88 67.35 66.00 70 51.43 47.37 46.70 44.95 59.13 60 50 181B 40 20 39.86 35.24 30.45 25.84 21.20 18.11 17.12 15.42 30 10 1.12 0 -4.37 -4.80 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 5.19 5.14 1.0000 12.5000 4.0894 2022-12-15T20 18 20 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.5 32768 Acquired Siz e 7.0 1H Nucleus 7.5 8012. 8 Spectral Width 5.5 1.02 5.0 4.5 4.0 72.0 Receiver Gain 6.0 16 Number of Scans 182A 1D Spectrometer Frequency 400.13 z g30 5.53 1.00 Experiment 4.93 297.1 4.74 Pulse Sequence 3 .5 f1 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 3.94 3.85 3.75 3.65 3.53 3.36 1.02 1.04 1.02 1.05 2.01 3.03 Temperature 2.84 2.72 2.00 1.02 CDCl3 2.30 6.04 Bruker BioSpin GmbH 2.00 1.02 Solvent 1.63 1.29 JKT-2-227 _pure.1. fid 1.48 1.12 Origin 1.04 5.95 Title Value 0.88 9.16 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-227 _pure/ 1/ fid Parameter 0.18 9.01 Data File Name 0.03 6.03 1.00 1.03 1.05 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 176.67 512 98 .9 1.0000 10.0000 1. 3631 2022-12-15T20 39 34 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 24038 .5 Spectral Width 110 1D Experiment 120 z gpg30 Pulse Sequence 130 297. 2 Temperature 140 CDCl3 Solvent 100 182A Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-2-227 _pure. 2. fid 152.72 150.88 Origin 120.05 116.87 115.18 Title 109.68 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-227 _pure/ 2/ fid Value 99.35 Data File Name Parameter 82.95 91.22 90 f1 (ppm) 80 70 60.54 59.14 60 40 49.60 46.81 44.10 43.78 40.83 39.82 39.08 38.56 35.82 50 30 25.87 23.38 21.20 20.62 18.21 20 10 1.31 0 -4.52 -4.93 67.40 -10 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1 38 .0 1.9410 12.5000 0. 2560 2022-12-15T20 45 21 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-618 . 2, -627.1) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297. 2 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-2-227 _pure. 3 .ser Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-227 _pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 182A -0.5 7 6 5 4 3 2 1 0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2022-12-15T20 57 02 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.68 , 16. 22) Spectral Siz e Digital Resolution 5.5 (1024, 180) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-528 .9, -1385.6) Lowest Frequency 7.0 (4795.4, 16611. 3) Spectral Width 3 .5 f2 (ppm) 297.1 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin 5.0 JKT-2-227 _pure.4.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-2-227 _pure/ 4/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 182A 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 2.6500 1.7046 2022-12-22T12 06 14 Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 16384 Acquired Siz e 6.5 1H Nucleus 7.0 9611.9 Spectral Width 1.04 1.05 1.05 5.0 0.96 1.00 1.01 1.06 2.06 3.04 3 .5 f1 (ppm) 2.5 1.0000 Relaxation Delay 3 .0 26 Receiver Gain 4.0 8 Number of Scans 4.5 1D Experiment 5.5 s2pul Pulse Sequence 182B 25.0 Temperature Spectrometer Frequency 599.56 cdcl3 Solvent 5.84 1.00 Varian 5.16 5.08 4.93 JKT-2-333 _pure-PROTON_ 01 4.75 Origin 3.96 3.84 3.76 3.65 3.53 3.37 Title 2.87 2.78 2.64 / Users/ jordankthompson/ Desktop/ JKT-2-333 _pure_20221222_ 01/ JKT-2-333 _pure-PROTON_ 01. fid/ fid Value 2.33 2.24 2.14 2.02 Data File Name Parameter 4.01 1.04 1.02 0.98 2.0 0.5 1.49 1.00 1.80 0.87 0.0 1.07 1.03 0.89 3.09 2.61 9.32 1.0 0.20 8.94 1.5 0.04 5.87 1.05 1.05 2.03 1.04 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 180 2023-06-15T13 47 33 Acquisition Date 140 65536 Spectral Size 150 32768 Acquired Size 160 13C Nucleus 170 24038 .5 Spectral Width 100 80 1. 3631 Acquisition Time f1 (ppm) 10.0000 Pulse Width 90 1.0000 Relaxation Delay 110 64.2 Receiver Gain 120 750 Number of Scans 130 1D Experiment 182B zgpg30 Pulse Sequence Spectrometer Frequency 100.62 297.2 Temperature 177.05 CDCl3 152.29 Solvent 132.91 Bruker BioSpin GmbH 127.17 Origin 109.12 JKT-4-185 _pure.2. fid 99.81 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-4-185 _pure/ 2/ fid 91.15 Title Value 83.31 Data File Name Parameter 70 59.14 60 40 49.51 44.87 46.80 44.33 40.46 39.88 38.78 39.31 50 30.46 29.84 30 18.22 15.42 20 10 0 -4.48 -4.88 1.47 25.89 23.52 67.32 66.00 71.88 -400 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 1 112. 8 1.9226 12.5000 0. 2744 2022-12-23T13 07 52 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .64, 3 .64) Digital Resolution 6.0 (1024, 1024) Spectral Siz e 6.5 (1024, 128) Acquired Siz e 7.0 (1H, 1H) Nucleus 7.5 (-495.4, -494. 3) Lowest Frequency 8 .0 (3731. 3 , 3731. 3) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 297. 2 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-2-235 _rsm. 3 .ser Title Value / Users/ jordankthompson/ Desktop/ JKT-2-235 _rsm/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 182B -1.0 8 7 6 5 4 3 2 1 0 -1 f1 (ppm) NOESY 4 197.4 1. 8000 12.5000 0. 2560 2022-12-23T13 53 31 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-251.7, -247.0) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 4.0 f2 (ppm) noesygpphzs Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-2-235 _rsm.4.ser Title Value / Users/ jordankthompson/ Desktop/ JKT-2-235 _rsm/ 4/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 182B 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 1D 16 176. 8 1.0000 12.5000 4.0894 2023-07-25T18 49 53 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Size 6.0 32768 Acquired Size 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.0 4.0 zg30 Pulse Sequence 4.5 297.2 Temperature 5.5 CDCl3 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Solvent 5.36 1.01 Origin 5.02 4.93 4.92 1.00 2.05 JKT-4-enolate_vinylation.1. fid 4.71 Title 3.83 3.66 3.62 3.53 3.37 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 1/ fid 3.10 2.98 Data File Name 2.08 2.07 3.12 3 .5 f1 (ppm) 0.95 1.01 3 .0 2.68 2.56 2.50 2.5 1.95 1.02 4.28 Value 1.98 1.01 2.0 0.0 1.70 1.05 0.5 1.39 1.08 1.0 1.07 0.92 0.87 3.02 3.16 9.29 1.5 0.19 9.09 105 2.29 2.18 1.03 3.09 Parameter -0.00 6.02 1.06 1.00 1.03 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 107.02 150 65536 Spectral Size 160 32768 Acquired Size 170 13C Nucleus 180 24038 .5 Spectral Width 70 2023-07-25T19 11 50 Acquisition Date 80 1. 3631 Acquisition Time 90 f1 (ppm) 10.0000 Pulse Width 100 1.0000 Relaxation Delay 110 50. 3 Receiver Gain 120 512 Number of Scans 130 1D Experiment 140 zgpg30 Pulse Sequence Spectrometer Frequency 100.62 297.2 Temperature 177.12 CDCl3 152.25 Solvent 143.18 Bruker BioSpin GmbH 123.93 Origin 98.94 JKT-4-enolate_vinylation.2. fid 91.16 Title 85.03 82.98 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 2/ fid Value 71.86 71.03 67.19 Data File Name Parameter 59.11 57.75 60 50 40 51.23 50.78 49.93 44.92 43.46 42.40 42.32 39.67 105 30 18.48 18.06 20 10 1.34 0 -4.57 -4.97 25.78 24.40 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 cosygpppqf COSY 1 98 .9 1.9205 12.5000 0. 2765 2023-07-25T19 17 33 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 .62, 3 .62) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 1H) Nucleus 5.5 (-4 23 .0, -414. 8) Lowest Frequency 6.0 (3703 .7, 3703 .7) Spectral Width 3 .0 f2 (ppm) 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-4-enolate_vinylation. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 3/ ser Title Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 105 0.0 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 2 197.4 1.5000 12.5000 0. 2135 2023-07-25T19 29 15 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-535. 3 , -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width 2.5 HSQC-EDITED Experiment f2 (ppm) hsqcedetgpsisp 2.4 Pulse Sequence 3 .0 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-4-enolate_vinylation.4.ser Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 4/ ser Parameter Data File Name 2.0 1.5 1.0 0.5 105 0.0 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) HMBC 4 197.4 2.0000 12.5000 0.4 260 2023-07-25T20 13 00 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 1024) (2. 35, 21. 80) Spectral Siz e Digital Resolution 5.5 (2048 , 256) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-163 .1, -1116.4) Lowest Frequency 7.0 (4807.7, 22321.4) Spectral Width 3 .5 f2 (ppm) hmbcetgpl3nd Pulse Sequence 4.0 297. 2 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-4-enolate_vinylation.5.ser Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 105 0.0 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 112. 8 1. 8000 12.5000 0. 2560 2023-07-25T20 58 48 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .91, 3 .91) Digital Resolution 7.0 (1024, 1024) Spectral Siz e 7.5 (1024, 256) Acquired Siz e 8 .0 (1H, 1H) Nucleus 8 .5 (-158 .1, -158 .1) Lowest Frequency 9.0 (4000.0, 4000.0) Spectral Width 4.0 4 Number of Scans 4.5 f2 (ppm) NOESY Experiment 5.0 noesygpphzs Pulse Sequence 5.5 297. 2 Temperature 6.0 CDCl3 Solvent 6.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-4-enolate_vinylation.6.ser Title Value / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-4-enolate_vinylation/ 6/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 105 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 1D 16 197.4 1.0000 12.5000 4.0894 2025-07-15T08 30 46 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.02 1.02 1.03 5.0 4.0 z g30 Pulse Sequence 4.5 297. 2 Temperature 5.5 CDCl3 Solvent 188 Bruker BioSpin GmbH Spectrometer Frequency 400.13 JKT-7-284-2.1. fid Origin 5.36 1.00 Title 4.73 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 1/ fid 1.03 3.62 3.54 3.38 3.03 3.84 1.04 2.00 2.02 3 .5 f1 (ppm) 3 .0 2.76 2.63 2.47 0.97 2.5 2.10 4.01 2.0 1.68 1.00 1.81 1.00 2.30 0.92 2.99 1.02 5.10 5.02 4.95 Value 4.08 Data File Name Parameter 1.5 0.5 1.08 3.01 1.23 3.02 0.0 0.88 9.00 1.0 0.15 0.03 9.01 6.02 1.03 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 1.0000 10.0000 1.1796 2025-07-15T22 49 38 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 200 190 65536 Spectral Siz e 210 32768 Acquired Siz e 220 13C Nucleus 230 27777. 8 Spectral Width 130 64. 2 Receiver Gain 140 2750 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297.1 Temperature 180 CDCl3 Solvent 120 188 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-284-2. 2. fid 175.42 Title 152.63 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 2/ fid Value 124.15 Data File Name Parameter 108.19 110 98.34 100 f1 (ppm) 91.10 90 80 71.95 70 59.15 60 50 40 30.46 25.92 24.40 30 18.35 20 10 0 0.39 -4.68 -4.90 43.86 67.09 83.31 -10 -20 -30 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 HSQC-EDITED 10 197.4 1.5000 12.5000 0. 2135 2025-07-16T01 18 23 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-525.5, -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width f2 (ppm) hsqcedetgpsisp 2.4 Pulse Sequence 3 .0 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-284-2.7.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 7/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 188 0.0 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) cosygpppqf COSY 1 176. 8 1.9164 12.5000 0. 2806 2025-07-15T22 55 21 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .56, 3 .56) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-446. 2, -446. 2) Lowest Frequency 7.5 (3649.6, 3649.6) Spectral Width 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-7-284-2. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 3/ ser Title Value Data File Name Parameter 3 .5 f2 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 188 -1.0 7 6 5 4 3 2 1 0 -1 f1 (ppm) HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-07-15T23 39 07 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2. 35, 21. 80) Digital Resolution 6.0 (2048 , 1024) Spectral Siz e 6.5 (2048 , 256) Acquired Siz e 7.0 (1H, 13C) Nucleus 7.5 (-163 .1, -1116.4) Lowest Frequency 8 .0 (4807.7, 22321.4) Spectral Width 4.0 f2 (ppm) hmbcetgpl3nd Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-284-2.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 5/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 188 0.0 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) noesygpphzs NOESY 4 197.4 1. 8000 12.5000 0. 2560 2025-07-16T00 24 44 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-165.6, -158 .1) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-7-284-2.6.ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-284-2/ 6/ ser Title Value Data File Name Parameter f2 (ppm) 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 188 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) Chapter 6 – End Game 609 Chapter 6 End Game† 6.1 INTRODUCTION This chapter describes the completion of the first enantioselective synthesis of (+)- auriculatol A from the key pentacyclic intermediate (105) accessed in Chapter 5. Various olefin functionalization strategies, lactone reduction, and hydrogenation strategies were investigated. Although many routes were explored, the successful route overcame challenges in the diastereoselective C9-C11 double bond reduction, culminating in the first synthesis of (+)-auriculatol A (49) and (+)-9-epi-auriculatol A (219) in 19 steps from 1,4dioxaspiro[4.5]decan-8-one. The studies captured in this chapter could provide a synthetic † Portions of this chapter were adapted from the following communication: Thompson, J. K.; Youngblood, K. C.; Teh, S. Y. H.; Farley, C. M.; Zhang, Z.; Virgil, S. C.; Reisman, S. E. J. Am. Chem. Soc. 2025, 147, 42170–42174. Scott C. Virgil is acknowledged for his analytical chemistry expertise, especially in completing the separation of the natural product from its C9-epimer. J.K.T. was supported by the NSF GRFP (DGE-1745301). S.E.R. acknowledges fellowship support by the NIH (R35GM118191). 610 Chapter 6 – End Game blueprint for the future end-game of related grayanane natural products. 6.2 PREFUNCTIONALIZED EXO-OLEFIN STRATEGIES 6.2.1 Mukaiyama hydration of the exo-olefin With a fragment coupling and intramolecular cyclization strategy established, efforts were centered around the end-game stages of the synthesis. One of the strategies that emerged as potentially fruitful became Mukaiyama hydration of the exo-olefin. Preliminary studies on the 3.2.1 bicycle drew inspiration from the reaction development of Shenvi and coworkers, among others.1-6 We were particularly inspired by Carreira and coworker’s use of Shenvi’s conditions toward (±)-indoxamycin B, which formed 49% yield of product in the presence of other olefins (Scheme 6.1).7 Scheme 6.1. Precedent for Mukaiyama hydration of exo-olefins.7 Me CO2Me H Me Me Mn(dpm)3 (10 mol%) PhSiH3 (2.5 equiv) Me HO O2 (1 atm) Me Me O OTBS Me CO2Me H EtOH (0.02 M), rt, 5 h 49% yield 1:1 dr Me O OTBS Me It was thought that Mukaiayma hydration early in the 3.2.1 bicycle synthesis could provide a fragment that could be leveraged in the vinylogous Mukaiyama aldol addition. Indeed, both substrates 107B and 141 were competent using Shenvi’s protocol, but the reaction proceeded in low diastereoselectivity (Scheme 6.2 and Scheme 6.3). Performing a temperature screen on substrate 107B, the highest dr and yield at −20 °C (Scheme 6.2). Warming to room temperature led to lower observed diastereoselectivity (~1.1:1, not shown). 611 Chapter 6 – End Game Scheme 6.2. Preliminary results in the Mukaiyama hydration of exo-olefins: Temperature screen on substrate 107B. Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (2.2 equiv) Br O OMEM Br O OMEM Me EtOH, temp, time O2 balloon OH 107B 189 temp entry time conversion dr yield (%) 1 0 °C 1h >99 2.1 : 1 48 2 −20 °C 3.5 h >99 3.5 : 1 50 3 −40 °C 12 h 58 2.3 : 1 21 4 −78 °C to 21 °C 12 h 90 2.3 : 1 < 10 Later studies on substrate 141 revealed the effect of catalyst loading on the diastereoselectivity, with higher catalyst loadings giving higher dr (Scheme 6.3). It was hypothesized that the higher catalyst loading would increase the presence of inner-sphere manganese intermediates that could undergo inner-sphere oxygen-atom transfer and result in higher dr. Nevertheless, the improvement in dr was moderate at best, and scaling up of the reaction led to lower dr (not shown). Scheme 6.3. Preliminary results in the Mukaiyama hydration of exo-olefins: Catalyst loading screen on substrate 141. Mn(dpm)3 (X equiv) PPh3 (1.5 equiv) PhSiH3 (2.2 equiv) TfO MeO2C EtOH, 0 °C, 3.5 h O2 balloon OMEM TfO MeO2C OMEM Me OH 190 141 entry X 1 conversion dr yield (%) 0.15 90 2.4 : 1 52 2 0.3 >99 2.6 : 1 49 3 1 >99 3.3 : 1 47 While not extensively tested, the vinylogous Mukaiyama aldol addition containing the hydrated exo-olefin did not proceed very effectively. Preliminary data showed low 612 Chapter 6 – End Game yields (19%) and lower conversions than the optimized substrates containing the exo-olefin (Scheme 6.3). Scheme 6.3. Preliminary results on the tertiary alcohol substrate 189 in the VMAR. OTBS O TBSO + Br O Me Me 22 °C, 16 h, OMEM ether/benzene (0.1 M) Me OH (2 equiv) (1 equiv) 88 189 < 20% yield O Me ZnCl2 (1 equiv) O Br TBSO Me HO Me MEMO 191 OH As a result of the shortcomings of the pre-hydrated olefin tactic, it was envisioned that Mukaiyama hydration of the exo-alkene could be accomplished prior to Ni-catalyzed a-enolate alkenylation but after the VMAR. To this end, a brief screen of conditions identified Mn(dpm)3 as the best catalyst when compared to Co(dpm)3, Co(acac)3, and Mn(acac)3 (not shown). After a brief optimization effort, the two diastereomers (192) could be isolated in 64% yield and 2.7:1 dr (Scheme 6.4A). While the yield of the reaction was considered adequate, the dr of the reaction was still only moderate. Our attention turned to Studer’s Fe-mediated oxygenation conditions, which employ an organic oxidant and are reported to provide higher dr;8 however, the presence of the alkenyl bromide in substrate 282B likely thwarted the attempt. A complex reaction mixture with no detectible product was formed (Scheme 6.4B). 613 Chapter 6 – End Game Scheme 6.4. Mukaiyama hydration prior to Ni-alkenylation O O A Me TBSO O Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (3.5 equiv) Br H Me TMS EtOH, 0 °C, 1 h O2 balloon O Me TBSO O Me Br H Me TMS TBSO O OH 282B TMS Me MEMO Br H Me O 64% yield MEMO O O OH MEMO Me 192 2.7 : 1 dr O B Me TBSO O H Me TMS O MEMO 282B Br Fe(acac)3 (2.5 mol%) SO2ArNO2 (1.3 equiv) NaHCO3 (2 equiv) PhSiH3 (3 equiv) MeOH, 0 °C to 21 °C monitored for 7 h then left overnight complex mixture, no product O Me TBSO O Br H Me O TMS MEMO 192 Me OH Protection of the tertiary alcohol prior to the Ni-catalyzed alkenylation reaction was necessary. The alkenylation reaction was very sensitive to polar functionalities, including alcohols or other chelating groups. Additionally, traces of CDCl3, MeOH, O2, H2O, and other alcohol-containing impurities were found to be detrimental to the reaction. As a result, a protection sequence was pursued. In general, the yield of the Mukaiyama hydration and the protection were reported in the two-step protocol, yielding 193 and 194 from a common starting material (192). Separation of both the MOM ether product (193) and the TMS ether (194) were effectively completed by preparatory TLC or pipet column, although the yield of the process was relatively low due to the difficulty of achieving separation of the diastereomers. 614 Chapter 6 – End Game 6.2.2 Elaboration of hydrated products Scheme 6.5. Protection of tertiary alcohol in 192. O O A Me TBSO O Me Br H Me TMS TBSO O Br H O Me MEMO TMS Me OH O MOMCl (30 equiv) EtNiPr2 (35 equiv) DCE, 40 °C, overnight O OH MEMO Me 192 Me TBSO O Me TBSO O 46% yield (2 steps) H Me TMS O Me Me TBSO O Me MEMO TMS Me OH Br TMS • Imidazole (6 equiv) H O DCM, 40 °C, 12 h O OH MEMO 192 Me OMOM single diastereomer 193 O Br Br H Me O TMS MEMO 2.7 : 1 dr B O Me 42% yield (2 steps) 2.7 : 1 dr TBSO O Br H Me TMS O Me MEMO OTMS 194 single diastereomer When both substrates were attempted in the Ni-catalyzed a-enolate alkenylation reaction, to our surprise, only substrate 194 provided high yields of the respective product (196, Scheme 6.6B). It was hypothesized that the chelating nature of the MOM and MEM group – and the additive effect that the Ni-center experienced due to their proximity – could have inhibited the reaction with substrate 193 (Scheme 6.6A). 615 Chapter 6 – End Game Scheme 6.6. Ni-catalyzed a-enolate alkenylation on substrates 193 and 194. O A Me TBSO O Ni(COD)DMFU (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Br H Me Tol/THF (2:1, 30 mM), 60° C, 16 h O TMS O O TBSO Me Me Me H Me MEMO OMOM 193 O OMEM OMOM TMS 26% yield 36% rsm 195 O B Me TBSO O Ni(COD)DMFU (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Br H Me TMS Tol/THF (2:1, 30 mM), 60° C, 16 h O MEMO 194 Me OTMS 81% yield selectivity 13:1 (α:β) O O TBSO Me Me Me H O OMEM OTMS TMS 196 With access to pentacyclic product 196, subsequent steps focused on the reduction of the trisubstituted olefin. Very quickly, it became clear that the trisubstituted olefin was quite hindered and resistant to hydrogenation. Both Pd/C and Crabtree’s catalyst were incompetent at 1 atm in MeOH and DCM, respectively (Scheme 6.7A); however, the literature precedent for similar types of bicyclic systems indicated that much higher pressures of hydrogen would be needed.9-12 In contrast, under metal hydrogen atom transfer (MHAT) conditions, a single diastereomer of 198 was isolated in 71% yield (Scheme 6.7B). NOESY analysis determined that the product possessed the undesired stereochemistry at C9. A correlation between C1 and C9 in the NOESY was observed. The MHAT literature confirmed that hydrogen atom transfer (HAT) likely involves a complex mechanism, involving both inner-sphere and cage escaped intermediates.2 Nevertheless, the product formed may be referred to as the thermodynamic product, owing to the trans nature of the substituents when the reaction forms a ring fusion stereocenter and the mechanism by which the product forms from the radical intermediate.13 On the other hand, homogeneous or heterogeneous olefin hydrogenation may exhibit complimentary 616 Chapter 6 – End Game selectivity to MHAT olefin hydrogenation, due to the different mechanism these reactions operate.13 For the simple case of Pd/C, the hydrogenation is most often depicted to hydrogenate the face of the molecule that is the most accessible and least hindered by the large heterogeneous palladium catalyst and may provide different selectivity than the MHAT method. Due to the interplay of these mechanistic heuristics, high-pressure hydrogenation was pursued as a strategy to overturn the C9-C11 hydrogenation diastereoselectivity. Scheme 6.7. MHAT reduction of 196. A O Pd/C or Crabtrees H2 (1 atm) O TBSO Me Me Me H O OMEM OTMS TMS O Me Me Me H O TMS 196 Me Me H OMEM OTMS hexanes (30 mM), 22 ° C, 4 h 71% yield single diastereomer OMEM OTMS O TMS 198 O Mn(dpm)3 (0.15 equiv) PhSi(iOPr)H2 (2.5 equiv) TBSO TBHP (1.5 equiv) O TBSO H Me no reaction 196 B MeOH or DCM, 22 ° C, 16 h O O TBSO H O Me Me Me H O OMEM OTMS TMS 198 A survey of homogeneous and heterogeneous catalysts were tested to induce the hydrogenation of 196. Unfortunately, the alkene proved unreactive to the attempts, and only protecting group cleavage was observed. It is likely that the olefin is hindered and would require higher pressures (80-100 bar). 617 Chapter 6 – End Game Scheme 6.8. Hydrogenation screen on substrate 196. O O TBSO Me O Me H OTMS H OMEM Me TMSO cat. (10 mol%) H2 (pressure) TBSO solvent, 22 °C or 50 °C, 23 h O Me H O Me OH H TBSO OMEM Me Me TMSO 196 O 199 Me Me OH H OMEM Me HO 200 O TBSO H H Me H OH O H OMEM Me HO 201 (desired) entry scale cat. pressure (bar) solvent 199 200 201 1 1.8 mg Pd/C 67 MeOH 19 56 - 2 1.8 mg PtO2 65 MeOH 5 70 - 3 1.8 mg Crabtrees 65 DCM 84 - - 4 1.8 mg Pd/C 65 EtOAc 31 43 - 5 1.8 mg PtO2 65 EtOAc 29 43 - 6 1.8 mg Crabtrees 67 IPA - 65 - 7 1.8 mg Crabtrees 67 THF 55 - - 6.2.3 Synthesis of new hydrogenation substrates In order to more easily test the hydrogenation, substrate 202 was pursued for several reasons: 1) it was hypothesized that the Me group in 196 may be sterically blocking the desired face of the alkene 2) substrate 202 does not contain the labile tertiary OTMS group that was cleaved under hydrogenation and 3) substrate 202 circumvents the Mukaiyama hydration and the low dr of the step, allowing for better material throughput. Substrate 202 was formed from 105 using canonical Lemieux-Johnson oxidation conditions.18-20 The optimization of the reaction went smoothly. Use of 2,6-lutidine as an additive was detrimental to the conversion of the reaction (Scheme 6.10, entry 1).21 Increasing the catalyst loading led to better conversions rather than stirring the reaction for longer periods of time (Scheme 6.10, entries 1-2). Close monitoring of the reaction by TLC was required. 618 Chapter 6 – End Game Scheme 6.10. Synthesis of hydrogenation substrate 202. O TBSO Me O O OsO4 (X equiv.) NaIO4 (Y equiv) Additive H H OMEM Me TMSO TBSO Dioxane/H2O (3:1) 22 °C, time O Me H TBSO H O OMEM Me Me TMSO 105 HO O O H H OH OMEM Me TMSO 202 203 entry X Y Additive 1 0.01 2 2,6-lutidine 4h 2 0.05 6 - 48 h 3 0.10 6 More NaIO4 (6 equiv) 16 h then 5 h 4 0.10 6 More NaIO4 (6 equiv) 16 h then 8 h time diol starting material - - 91 27 20 - 57 3 10 40 13 - ketone Hydrogenation of substrate 202 proceeded in full conversion in the presence of both Pd/C and PtO2 but not Crabtree’s catalyst to form 204 (Scheme 6.11). NOESY analysis of 204 again revealed a correlation between C1 and C9, indicating the a-orientation of both hydrogens, which was confirmed upon deprotection of 204 in a separate step (not shown). Scheme 6.11. A. Hydrogenation of substrate 202. O TBSO Me O H O O H OMEM Me TMSO cat. (50 wt%) H2 (63 bar) TBSO solvent (5 mM), 23 °C, 15 h Me 202 O H H O H OMEM Me TMSO 204 entry cat. solvent dr yield (%) 1 Pd/C EtOAc > 20 : 1 89 2 PtO2 EtOAc 5:1 83 3 Crabtree’s DCM - no reaction As a result of the difficulty of both MHAT reduction and high-pressure hydrogenation, goals to induce selective Mukaiyama hydration were prioritized in order to allow for better material throughput to intermediates closer to the end. 619 Chapter 6 – End Game 6.3 SELECTIVE FUNCTIONALIZATION STRATEGIES 6.3.1 Elaboration of substrate 105 Due to the difficulty of achieving diastereoselective hydrogenation of the C9-C11 double bond, strategies to induce epimerization of the C6 secondary alcohol were pursued directly following the Ni-catalyzed a-enolate alkenylation reaction. The TMS silyl ether could be cleaved utilizing PPTS in MeOH, affording 205 in 89% yield (Scheme 6.12). Then, the secondary alcohol could be oxidized using IBX in DMSO, providing 206 in 74% yield. Notably for this reaction, use of DMP or Swern oxidation led to incomplete conversions and diminished yields. Scheme 6.12. Deprotection/oxidation sequence on pentacycle 105. O TBSO Me O Me TMSO O H PPTS (3 equiv) H OMEM TBSO MeOH, 22 °C, 10 h 105 89% yield O Me Me HO O H H IBX (3 equiv) H TBSO OMEM 205 DMSO, 40 °C, 12 h Me O Me 74% yield H O OMEM 206 Both the substrates 205 and 206 were tested in the Mukaiyama hydration conditions from Scheme 6.4A. Unfortunately, in both cases, <10% yield of the product was isolated. Scheme 6.13. Failed Mukaiyama hydration of substrates 205 and 206. O TBSO Me O H Me HO Me O Me OMEM <10% yield H Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (3.5 equiv) H O EtOH, 0 °C, 1 h O2 balloon 205 O TBSO Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (3.5 equiv) H TBSO Me <10% yield H H Me HO Me H Me OH O Me OMEM 200 O TBSO Me OH O H OMEM EtOH, 0 °C, 1 h O2 balloon 206 O O 207 OMEM 620 Chapter 6 – End Game Acid mediated hydration was also attempted using 3M HCl. Unfortunately, under these conditions, a Semi-Pinacol rearrangement to form 306 in 87% yield was observed (Scheme 6.14A).28 While the result was interesting, it was not useful for the auriculatol A synthesis. Nevertheless, searching the literature, it became apparent that a different natural product, micranthanone A, could be mapped on to this scaffold. While studies toward micranthanone were not thoroughly explored, the rearrangement of [3.2.1]-bicyclic compounds containing the bridgehead hydroxyl to the bicyclic scaffold of micranthanone could present future avenues for exploration. Scheme 6.14. A. Acid-mediated rearrangement of 105. B. Micranthanone A: a future avenue for exploration. O A TBSO O Me Me O H 3M HCl H HO OMEM Acetone/H2O (3:1), 60 °C, 12 h O Me Me 87% yield 206 H O H Me O O 208 B H H HO Me HO H Me HO microanthanone A Me X TBSO OMEM O Me Me 69 O O key building block possibly accessible from intermediates from Chapter 4 Pivoting away from the Mukaiyama hydration, a double reduction protocol to target 210 was pursued. Upon treatment with excess DIBAL, 40% yield of 210 was obtained utilizing CH2Cl2 as solvent (Scheme 6.15, entry 1). Unfortunately, in ethereal solvents, 209 was almost exclusively formed (Scheme 6.14, entry 2-3). Switching back to CH2Cl2, it was found that the yield could be slightly increased when the reaction was warmed to 0 °C. Importantly, warming of the reaction higher than 0 °C leads to unselective deprotection of the TBS or MEM either, or both, creating mixtures that are difficult to characterize. The 621 Chapter 6 – End Game final yield of 210 may vary slightly but typically ranges from 45-52% yield (Scheme 6.14, entry 4-5). Reproducibility of this reaction may be a concern, likely due to the temperature dependence of the reaction, which could be affected by the rate of warming of the reaction, the rate of addition of DIBAL, and the quality of the reagent. Unfortunately, attempts to manipulate 210 for selective olefin functionalization to progress this compound failed. Scheme 6.15. DIBAL reduction of ketone 206. O O TBSO Me DIBAL (5 equiv) O Me H O OMEM TBSO solvent, t1 (°C) to t2 (°C), 4 h 206 Me HO H H TBSO O H Me HO O OMEM Me 209 TBSO Me HO HO H H H H OMEM Me HO 210 OMEM Me HO 211 entry scale t1 (°C) t2 (°C) solvent starting material (%) 209 (%) 1 1.5 mg −78 °C −78 °C DCM 16 17 40 22 2 3.0 mg −78 °C 0 °C THF - 73 < 10 < 10 3 1.5 mg −78 °C 0 °C Et2O - 69 < 10 < 10 4 1.5 mg −78 °C 0 °C DCM - 12 45 23 5 1.5 mg −78 °C 0 °C DCM - 11 52 23 210 (%) 211 (%) * caution: allowing the reaction to warm higher than 0 °C will lead to silyl ether cleavage or MEM reduction to the methyl ether. Other functionalization strategies were envisioned on substrate 105 to provide more viable synthetic routes to intermediates that could help overturn the selectivity of the C9C11 hydrogenation. One potential strategy includes hydroboration of the exo-olefin.16-17 Upon treatment with 9-BBN, no reaction was observed (Scheme 6.16A). A series of dihydroxylation conditions were tested to no avail (Scheme 6.16B).22 622 Chapter 6 – End Game Scheme 6.16. A. Attempted hydroboration of 105. B. Attempted dihydroxylation of 105. A O TBSO Me O O H H 9BBN (1 equiv) TBSO O OMEM THF, 0 °C, 1 h then 22 °C, 1 h then NaOH (3 equiv) H2O2 (8 equiv) Me TMSO 105 Me OH H H OMEM H Me TMSO 212 no reaction O B TBSO Me O Me TMSO O H H 105 OsO4 (0.1 equiv) NMO • H2O (4 equiv) OMEM Dioxane/H2O (2:1) 22 °C, 24 h no reaction TBSO Me O H OH OH H OMEM Me TMSO 213 Turning to reductive lactone opening, diol 215 was targeted as a substrate that could direct the hydrogenation of the C9-C11 double bond. To our surprise, the lactone proved resistant to opening, even upon treatment with 3 equiv. of LAH (Scheme 6.17A). The reaction could be optimized to form 214 in 80% yield upon treatment with DIBAL (Scheme 6.17B). Excitingly, installation of the methyl acetal (216) occurred smoothly and forming the correct diastereomer with regard to auriculatol A (Scheme 6.17C). The NOESY assignment of this compound is largely based on correlations between the methyl acetal hydrogen and other methylene hydrogens on nearby rings. Modeling of this compound, either in Avogadro or through use of a plastic model, suggests that in most conformations of this structure, the hydrogens highlighted in blue should be in close proximity. DFT computations in order to sample the lowest energy conformations of this and related structures were performed. 623 Chapter 6 – End Game Scheme 6.17. A. Reductive lactone opening attempt with LAH B. Yield of DIBAL reduction to access 214. C. Methyl acetal installation on substrate 216. A O TBSO O Me H H OMEM Me TMSO TBSO DCM, −78 °C to 0°C, 45 min then 0 °C, 45 min 105 H TBSO O Me HO H HO LAH (3 equiv) H HO Me Me TMSO 214 65% yield H OMEM Me TMSO OMEM 215 not observed some minor protecting group cleavage observed O B TBSO Me O H HO DIBAL (5 equiv) H OMEM Me TMSO HO TBSO O Me DCM, −78 °C to 0 °C, 30 min 80% yield 105 C H MeO H PPTS (3 equiv) H Me TMSO 214 OMEM TBSO MeOH, 21 °C, 18 h 67% yield HO Me O Me H O Me TMSO H H OMEM 214 NOESY H H H Me HO MeO OMEM HO O H H HH H OMEM Me 216 Me HO acetal stereochemical verification 6.3.2 Completion of the synthesis of (+)-auriculatol A Substrate 105 was more exhaustively investigated with respect to Mukaiyama hydration of the exo-olefin. While Mn(dpm)3 and Fe(acac)3 were ineffective in the transformation, use of Co(acac)2 uniquely delivered the product in 80% yield as a single diastereomer (199, Scheme 6.18B).23-25 For more information on Co-mediated MHAT catalysis, see the following recent references.26,27 624 Chapter 6 – End Game Scheme 6.18. Successful Mukaiyama hydration of 105. O TBSO Me O O H conditions H TBSO H OH O H OMEM then Na2S2O3 Me TMSO Me 105 199 conditions dr yield (%) 1 Mn(dpm)3 (0.15 equiv), PhSiH3 (2.2 equiv), O2 - < 10 > 20 : 1 19 Co(acac)2 (0.2 equiv.), PhSiH3 (2 equiv), O2 > 20 : 1 80 3 OMEM Me TMSO entry 2 Me Fe(acac)3 (2.5 mol%), SO2ArNO2 (1.3 equiv) NaHCO3 (2 equiv), PhSiH3 (3 equiv) Substrate 199 can be advanced in a 2-step protocol to 200 through TMSdeprotection and to 206 through IBX-oxidation (Scheme 6.19). With access to 206, DIBAL reduction occurred in 61% yield to form 217 along with 24% 6-epi-217 (see experimental procedures for more information). Treatment with acidic methanol converted 218 to C9C11-dehydro-auriculatol A by way of acetal exchange and global deprotection. Using MHAT conditions developed by Shenvi and coworkers30, the reduction to (+)-auriculatol A occurred in 43% yield along with 41% yield (+)-9-epi-auriculatol A (219). The NMR data for 49 is consistent with that reported by Yao and coworkers (see the Experimental Section for more information).31 625 Chapter 6 – End Game Scheme 6.19. The successful end-game strategy: elaboration to the natural product. O O TBSO Me Me H PPTS (1 equiv) OH O H OMEM TBSO MeOH, 21 °C, 18 h Me TMSO Me Mn(dpm)3 (0.20 equiv) PhSiH3 (6 equiv) TBHP (6.5 equiv) IPA (10 mM), 22 ° C, 14 h H MeO HO Me H HO Me H Me H H OH OH O H H Me HO (+)-auriculatol A (49) 43% yield 6.4 MeO HO O OH Me H H HCl (65 equiv) MeOH, 22 °C, 16 h Me HO Me H OMEM DMSO, 60 °C, 1 h 73% yield TBSO Me Me HO TBSO Me O H H H Me H OMEM O 206 Me OH Me HO H OH O 88% yield 200 C9-C11-dehydro-auriculatol A (218) MeO IBX (2 equiv) Me HO OH O O Me OH O 92% yield 199 H OMEM DIBAL (6 equiv) toluene, −78 °C, 30 min 61% yield 217 Me OH H H OH Me HO 9-epi-auriculatol A (219) 41% yield CONCLUDING REMARKS This chapter describes early efforts in selective Mukaiyama hydration of the exo- olefin on several substrates, both before and after the VMAR. While Mukaiyama hydration prior to the VMAR was challenging, conducting the reaction after the VMAR but before the Ni-catalyzed a-enolate alkenylation was possible. Although the dr of the Mukaiyama hydration was low, a protection sequence allowed for separation of diastereomers. The MOM-protected tertiary alcohol was not a competent substrate in the a-enolate alkenylation, but the TMS-protected tertiary alcohol was. With access to a cyclized product bearing the hydrated alkene, hydrogenation of the C9-C11 bond was pursued. While resistant to hydrogenation, the compound could be subjected to radical based MHAT hydrogenation conditions to produce the astereochemistry at the newly formed ring fusion stereocenter. This was unfortunate, as the 626 Chapter 6 – End Game b-stereochemistry is what is required in the natural product. Various hydrogenation substrates and strategies were investigated to overturn the selectivity. A Lemeiux-Johnson was developed to selectively cleave the exo-olefin of the Ni-catalyzed a-enolate alkenylation product; however, these substrates were also not competent at delivering the correct C9-stereochemistry. Ultimately, a synthesis of C9-C11dehydro-auriculatol A was devised after optimization of the DIBAL reduction to deliver direduced compound. Testing the hydrogenation on this new substrate provided a ~1.1:1.0 mixture of the natural product and 9-epi-auriculatol A, which could be separated using preparatory HPLC. 6.5 EXPERIMENTAL SECTION Preparation of hydrated product 189. Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (2.2 equiv) Br O OMEM 107B EtOH, −20 °C, 3.5 h O2 balloon 50% yield 3.5 : 1 dr Br O OMEM Me OH 189 Mn(dpm)3 (0.15 equiv) and PPh3 (1.50 equiv) were weighed out outside the glovebox and added to a vial containing the starting material (1 equiv). EtOH (1.2 mL, 77.0 mM) was added in at once and it was stirred until all PPh3 dissolved (5 min). The vial was cooled to −20 °C. An O2 balloon with a thick, purple needle was added on. After the dropwise addition of PhSiH3 (3.5 equiv), the reaction mixture was then stirred under an oxygen atmosphere at −20 °C for 3.5 hrs. To quench the reaction, sat. aq. Na2S2O3 was added. The reaction was stirred for 1 h before the aq. phase was extracted with EtOAc (4x). Then, it was concentrated in vacuo and eluted through a short pipette plug of silica gel with 627 Chapter 6 – End Game pure ether (5 column volumes) to remove the Mn in solution. Upon crude NMR, a 3.5 : 1 dr and full conversion with no peroxide adduct was observed. The crude mixture was purified via column, eluting with 50% EtOAc/Hex to isolate the product 189 (50% yield). Br O OMEM Me OH 189 TLC (75% EtOAc/Hexanes): Rf 0.5 (KMnO4). 1 H NMR (CDCl3, 400 MHz): δ 9.79 (dd, J = 1.9, 1.1 Hz, 1H), 5.92 (dd, J = 5.0, 2.8 Hz, 1H), 4.94 – 4.84 (m, 2H), 3.78 (dt, J = 11.0, 4.7 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.54 (t, J = 4.6 Hz, 2H), 3.38 (s, 3H), 3.25 (s, 1H), 3.06 (dd, J = 17.7, 1.2 Hz, 1H), 2.72 (dd, J = 17.7, 2.8 Hz, 1H), 2.46 – 2.22 (m, 4H), 2.08 (dd, J = 13.5, 2.3 Hz, 1H), 1.85 (d, J = 13.5 Hz, 1H), 1.27 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 200.50, 130.76, 126.78, 91.78, 84.28, 78.36, 71.84, 67.89, 59.22, 54.39, 52.12, 45.33, 42.84, 36.98, 25.16. FTIR (Neat, NaCl, thin film): 2930, 1667, 1145, 1011, 996, 756 cm-1. HRMS (ESI): calc’d for [M+H]+ 363.0802, found 363.0802. Preparation of tertiary alcohol 192. O O Me TBSO O H Me TMS O MEMO 282B Br Mn(dpm)3 (0.15 equiv) PPh3 (1.5 equiv) PhSiH3 (3.5 equiv) EtOH, 0 °C, 1 h O2 balloon 64% yield 2.7 : 1 dr Me TBSO O O Me Br H TBSO Me O TMS MEMO Me OH 192 O Br H Me O TMS MEMO OH Me Mn(dpm)3 (8.3 mg, 13.7 umol, 0.15 equiv) and PPh3 (33.5 mg, 128 umol, 1.40 equiv) were weighed out outside the glovebox and added to a vial containing the starting material (64.0 628 Chapter 6 – End Game mg, 91.2 umol, 1 equiv). EtOH (1.2 mL, 77.0 mM) was added in at once and it was stirred until all PPh3 dissolved (5 min). The vial was cooled to 0 °C. An O2 balloon with a thick, purple needle was added on. After the dropwise addition of PhSiH3 (40 µL, 319 umol, 3.5 equiv), the reaction mixture was then stirred under an oxygen atmosphere at 0 °C for 1.5 hrs. To quench the reaction, 1.20 mL sat. aq. Na2S2O3 was added. The reaction was stirred for 1 h before the aq. phase was extracted with EtOAc (4 x 2 mL). Then, it was concentrated in vacuo and eluted through a short pipette plug of silica gel with pure ether (5 column volumes) to remove the Mn in solution. Upon crude NMR, a 2.7 : 1 dr and full conversion with no peroxide adduct was observed. The peroxide could be observed by TLC throughout the course of the reaction as a less-polar, pink spot staining with p-anisaldehyde. The crude mixture was purified via column, eluting with 30% EA to isolate the products as a thick, clear oil that can puff up into a white solid under high vac (50.0 mg, 76% yield). Notably, the diastereomers were inseparable at this stage and were isolated together. O Me TBSO O O Me TBSO H Me TMS O Br Me O TMS Me MEMO Br H O OH MEMO Me OH 192 TLC (50% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde, grey/blue). 1 H NMR (400 MHz, CDCl3): δ 5.81 (dd, J = 5.4, 2.6 Hz, 1H), 4.94 (d, J = 7.4 Hz, 1H), 4.86 (d, J = 7.4 Hz, 1H), 3.92 – 3.62 (m, 4H), 3.54 (q, J = 3.9 Hz, 2H), 3.38 (d, J = 3.8 Hz, 3H), 2.84 (ddd, J = 18.3, 11.3, 7.3 Hz, 1H), 2.76 – 2.47 (m, 2H), 2.38 – 2.11 (m, 5H), 2.12 – 1.88 (m, 3H), 1.87 – 1.59 (m, 3H), 1.48 (dt, J = 13.7, 2.9 Hz, 1H), 1.25 (d, J = 2.6 Hz, 3H), 1.09 (d, J = 4.2 Hz, 3H), 0.88 (s, 9H), 0.19 (s, 9H). 629 Chapter 6 – End Game 13 C NMR (101 MHz, CDCl3): δ 175.43, 175.42, 134.38, 133.19, 131.82, 126.87, 125.39, 124.14, 124.10, 98.77, 98.57, 90.21, 89.85, 83.93, 82.79, 79.38, 77.37, 70.32, 66.35, 65.53, 64.48, 57.67, 57.63, 48.08, 44.57, 43.81, 42.95, 40.40, 39.49, 39.27, 38.28, 38.24, 37.73, 35.41, 34.02, 32.85, 28.94, 28.32, 27.04, 24.38, 23.76, 22.20, 19.33, 19.31, 16.71, 13.90, 12.82, 12.75, 0.00, -0.01, -6.01, -6.03, -6.43. FTIR (DCM, NaCl, thin film): 3477, 2951, 2929, 1771, 1469, 1302, 1098, 1040, 889, 839 cm-1. HRMS (ESI): calc’d for [M+NH4]+ 741.2824, found 741.2854. [a]D23 : +22.3 (c 1.0 in CHCl3). Preparation of MOM-protected 193. O Me TBSO O O MOMCl (30 equiv) EtNiPr2 (35 equiv) Br DCE, 40 °C, overnight H Me O TMS MEMO 192 2.7 : 1 dr * Me OH 72% yield Me TBSO O Br H Me O TMS MEMO * Me 193 OMOM single diastereomer To a 2-dram vial was added the starting material (29.0 mg, 40.3 umol, 1 equiv.) and a magnetic stir bar. Dichloroethane (1.61 mL, 25.0 mM) was added, and the vial was agitated to ensure that the starting material is dissolved. Hunig's base (246 uL, 1.41 mmol, 35 equiv.) and MOMCl (92 uL, 1.21 mmol, 30 equiv.) were added sequentially, and the vial was capped and taped shut. The reaction was stirred at 40 °C. After 12 h, the reaction was worked up by filtration through silica (eluting with pure ether) then concentration down. Column chromatography with a gradient 10-20% EA/hex affords the product 193 as a single diastereomer as a pale yellow oil (22.2 mg, 72% yield). Chapter 6 – End Game 630 O Me TBSO O Br H Me O TMS MEMO 193 Me OMOM TLC (50% EtOAc/Hexanes): Rf 0.64 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.78 (dd, J = 5.2, 2.6 Hz, 1H), 5.08 (d, J = 7.5 Hz, 1H), 4.93 – 4.86 (m, 2H), 4.82 (d, J = 7.5 Hz, 1H), 4.63 (d, J = 7.3 Hz, 1H), 3.94 (s, 1H), 3.82 – 3.76 (m, 1H), 3.74 (dd, J = 4.3, 1.3 Hz, 1H), 3.67 (dt, J = 10.7, 4.9 Hz, 1H), 3.53 (t, J = 4.7 Hz, 2H), 3.37 (s, 3H), 3.34 (s, 3H), 2.87 (dd, J = 18.1, 11.3 Hz, 2H), 2.53 (dd, J = 17.9, 2.7 Hz, 1H), 2.44 (d, J = 10.7 Hz, 1H), 2.40 – 2.18 (m, 5H), 2.07 (d, J = 10.6 Hz, 1H), 2.01 – 1.89 (m, 2H), 1.72 (d, J = 15.0 Hz, 1H), 1.51 – 1.48 (m, 1H), 1.10 (s, 3H), 1.03 (s, 3H), 0.88 (s, 11H), 0.20 (s, 9H), 0.04 (d, J = 4.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 177.04, 134.33, 125.85, 100.15, 92.10, 91.76, 85.18, 84.15, 71.92, 71.85, 67.19, 59.17, 55.37, 49.61, 45.39, 41.92, 41.21, 39.86, 39.21, 38.87, 30.46, 29.84, 25.89, 23.69, 22.83, 21.84, 18.23, 14.27, 1.44, -4.51, -4.56, -4.91. FTIR (Neat, NaCl, thin film): 2928, 2860, 1780, 1715, 1562, 1212, 1093, 1048, 1030, 840 cm-1. HRMS (ESI): calc’d for [M+NH4]+ 780.3532, found 780.3563. 631 Chapter 6 – End Game Preparation of TMS-protected 194. O O Me Me TBSO O Br TMS • Imidazole (6 equiv) H DCM, 40 °C, 12 h Me O TMS MEMO Me OH 192 2.7 : 1 dr TBSO O Br H Me TMS O Me MEMO 42% yield (2 steps) OTMS 194 single diastereomer The starting material (50.0 mg, 69.5 umol, 1 equiv.) as a 2.7:1 mixture of diastereomers was added to a 2-dram vial with a magnetic stir bar, and DCM (347 uL, 200 mM) was added in. The solution was treated with TMS-imidazole (102 uL, 695 umol, 10 equiv.) and the reaction was capped and heated to 40 °C overnight. Following completion of the reaction, as indicated by TLC analysis in 50% EtOAc/Hex, the reaction was quenched by addition of H2O (1 mL). The resulting solution was extracted with DCM (3 x 1 mL), washed with saturated aq. NH4Cl (3 x 1 mL), brine, and dried with sodium sulfate. Upon filtration and concentration, the mixture of diastereomers were carefully subjected to column chromatography, eluting with 10% EtOAc/Hex in order to isolate the major product 194 as a single diastereomer (36.3 mg, 66% yield) as a pale yellow oil. Notably, the desired diastereomer is the less-polar spot on the TLC plate. O Me TBSO O Br H Me TMS O MEMO 194 Me OTMS TLC (25% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde, dark blue). 1 H NMR (400 MHz, CDCl3): δ 5.77 (dd, J = 5.2, 2.6 Hz, 1H), 5.20 (d, J = 7.5 Hz, 1H), 4.76 (d, J = 7.5 Hz, 1H), 3.94 (broad s, 1H), 3.82 – 3.74 (m, 2H), 3.66 – 3.61 (m, 1H), 3.53 632 Chapter 6 – End Game (dd, J = 5.3, 4.2 Hz, 2H), 3.37 (s, 3H), 2.85 (dd, J = 18.1, 11.2 Hz, 1H), 2.78 (broad s, 1H), 2.49 – 2.42 (m, 2H), 2.32 – 2.20 (m, 3H), 2.04 – 1.97 (m, 2H), 1.81 (d, J = 13.7 Hz, 1H), 1.72 (dd, J = 15.2, 2.8 Hz, 1H), 1.48 (dd, J = 13.5, 3.3 Hz, 1H), 1.32 (s, 3H), 1.08 (s, 3H), 0.88 (s, 9H), 0.20 (s, 9H), 0.12 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 176.98, 134.40, 125.92, 99.88, 91.83, 83.37, 82.91, 71.95, 66.97, 59.13, 49.53, 45.25, 41.67, 41.31, 39.89, 39.46, 39.25, 38.80, 30.45, 29.83, 25.88, 25.62, 23.54, 20.62, 18.21, 2.77, 1.46, -4.50, -4.90. FTIR (Neat, NaCl, thin film): 2953, 2929, 1779, 1251, 1163, 1101, 1046, 889, 838, 773, 753 cm-1. HRMS (ESI): calc’d for [M+H]+ 791.3400, found 791.3402. [a]D23 : +14.5 (c 1.0 in CHCl3). Preparation of pentacycle 196. O Me TBSO O Ni(COD)DMFU (5 mol%) NaHMDS (1.6 equiv) ZnBr2 (15 mol%) Br H Me TMS Tol/THF (2:1, 30 mM), 60° C, 16 h O MEMO 194 Me OTMS 81% yield selectivity 13:1 (α:β) O O TBSO Me Me Me H O OMEM OTMS TMS 196 0.5 M solution of NaHMDS was prepared by dissolving 55 mg (0.3 mmol) in 0.6 mL. A 10x stock solution of Ni(COD)DMFU (2.4 mg, 7.58 umol) was prepared in toluene (1 mL). To a 2-dram vial of the starting material (12.0 mg, 15.2 umol, 1 equiv.) was added a 2dram stir bar and 180 uL of toluene. 5.1 mg of ZnBr2 was dissolved in 1.30 mL of THF, and 130 uL of ZnBr2 as a stock solution in THF was added followed by NaHMDS (100 uL, 24.2 umol, 0.5 M, 1.6 equiv.) and Ni(COD)DMFU (100 uL, 0.76 umol). The final Chapter 6 – End Game 633 concentration of the reaction mixture was 30 mM, with a 2:1 ratio of toluene:THF. The vial was stirred at 60 °C for 16 h using an oil bath in the hood, After 16 h, the reaction was TLC'd, and worked up by filtration through a silica plug. The product was purified via pipet column in 10-30% diethyl ether/hexanes to provide a product 196 (8.7 mg, 81% yield) as a mixture of diastereomers (13:1 a:b). O O TBSO Me Me Me H O OMEM OTMS TMS 196 TLC (25% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde, light blue). 1 H NMR (400 MHz, CDCl3): δ 5.18 (t, J = 3.6 Hz, 1H), 5.06 (d, J = 7.3 Hz, 1H), 4.65 (d, J = 7.3 Hz, 1H), 4.17 – 4.12 (m, 1H), 3.71 – 3.66 (m, 1H), 3.57 – 3.52 (m, 2H), 3.44 (d, J = 4.4 Hz, 2H), 3.28 (s, 3H), 2.97 (s, 1H), 2.86 (dd, J = 11.1, 4.4 Hz, 1H), 2.41 (ddd, J = 14.5, 10.9, 5.8 Hz, 1H), 2.32 – 2.19 (m, 2H), 2.15 – 2.07 (m, 2H), 2.03 – 1.94 (m, 2H), 1.68 – 1.53 (m, 2H), 1.31 – 1.25 (m, 1H), 1.15 (s, 3H), 0.97 (s, 3H), 0.82 (s, 3H), 0.77 (s, 9H), 0.09 (s, 9H), -0.02 (s, 9H), -0.10 (d, J = 5.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 177.34, 145.97, 123.07, 99.05, 91.80, 84.94, 83.08, 82.21, 72.02, 71.09, 66.77, 61.38, 59.14, 57.82, 49.98, 47.85, 44.42, 43.38, 41.44, 39.77, 37.53, 29.86, 25.78, 24.56, 24.35, 18.47, 18.06, 2.72, 1.31, -4.57, -4.97. FTIR (Neat, NaCl, thin film): 2930, 1775, 1252, 1096, 1022, 883, 838 cm-1. HRMS (ESI): calc’d for [M+H]+ 711.4138, found 711.4144. [a]D23 : −14.1 (c 1.0 in CHCl3). 634 Chapter 6 – End Game Preparation of C9-C11-hydrogenated 201. O TBSO Me H Me OH O H Me HO 205 OMEM Mn(dpm)3 (0.15 equiv) PhSi(iOPr)H2 (3 equiv) TBHP (1.5 equiv) hexanes/IPA 1:1 (10 mM), 22 ° C, 4 h O TBSO Me 65% yield single diastereomer O H Me OH H H OMEM Me HO 201 A stirring solution of starting material (7.0 mg, 12.4 umol, 1 equiv.) and Mn(dpm)3 (1.1 mg, 1.85 umol, 0.15 equiv.) in IPA (400 uL, 36 mM) was degassed by bubbling with Ar for 5 min. Although 400 uL of IPA was added, after degassing, only ~300 uL remained. A stock solution of Ph(i-PrO)SiH2 (20x in hexanes) and TBHP (20x in hexanes) were created. Sequentially at room temperature were added Ph(i-PrO)SiH2 (133 uL, 3 equiv., 20x stock solution in hexanes) and TBHP (67 uL, 20x stock solution in hexanes, 1.5 equiv.) to the reaction vial containing the starting material and Mn(dpm)3. The reaction mixture was stirred for 12 h before TLC indicated complete conversion. The solution was evaporated with aid from rotatory evaporator and loaded directly onto silica gel pipet column for purification 36-100% EtOAc/Hexanes to afford the product 201 as a clear oil (4.6 mg, 65% yield). O TBSO Me O H Me OH H H OMEM Me HO 201 TLC (100% EtOAc): Rf 0.30 (p-anisaldehyde, purple) 1 H NMR (400 MHz, CDCl3): δ 4.90 – 4.73 (m, 2H), 4.11 (dd, J = 10.5, 5.0 Hz, 1H), 3.77 – 3.62 (m, 3H), 3.54 (t, J = 4.6 Hz, 2H), 3.38 (s, 3H), 2.75 (dd, J = 10.9, 2.7 Hz, 1H), 2.55 (ddd, J = 14.7, 10.9, 5.5 Hz, 1H), 2.32 – 2.21 (m, 2H), 2.05 – 1.79 (m, 4H), 1.76 – 1.60 (m, 635 Chapter 6 – End Game 3H), 1.46 (d, J = 10.6 Hz, 1H), 1.30 (dd, J = 14.7, 2.6 Hz, 2H), 1.23 (s, 4H), 1.16 (s, 3H), 1.10 (s, 3H), 0.88 (s, 9H), 0.01 (d, J = 14.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 176.29, 100.70, 91.62, 85.01, 84.63, 79.36, 71.97, 71.87, 67.40, 59.18, 55.07, 51.67, 51.23, 50.37, 49.48, 43.45, 42.36, 42.22, 40.65, 31.16, 29.86, 25.89, 24.81, 20.94, 18.49, 18.22, -4.69, -4.90. FTIR (Neat, NaCl, thin film): 3458, 2928, 1763, 1412, 1169, 1010, 840 cm-1. HRMS (ESI): calc’d for [M+Na]+ 591.3323, found 591.3329. [a]D23 : +112.4 (c 0.2 in CHCl3). Preparation of ketone 197. O TBSO Me O Me HO O Me H OH H OMEM H 201 IBX (2 equiv) DMSO, 60 °C, 1 h 83% yield TBSO Me Me H Me OH O H H OMEM O 197 The starting secondary alcohol (5.0 mg, 8.79 umol, 1 equiv) was dissolved in solvent (440 uL, 20 mM). Then, a 1-dram stir bar was added in, followed by IBX (4.9 mg, 17.6 umol, 2.0 equiv.). The reaction was capped, taped, and heated at 60 °C for 1 h. The reaction was worked up by addition of ½ sat. NaHCO3 by slow, dropwise addition at room temperature. The remaining solution was extracted with EtOAc (4 x 0.5 mL). The combined organic extract was washed with H2O (5 x 1 mL, or as many washes as it takes to get rid of DMSO), brine (1 x 2 mL), dried with sodium sulfate, filtered, and concentrated to afford analytically pure product 197 as a clear oil (3.8 mg, 83% yield). 636 Chapter 6 – End Game O TBSO Me Me OH O Me H H H OMEM O 197 TLC (100% EtOAc): Rf 0.42 (p-anisaldehyde, brown) 1 H NMR (400 MHz, CDCl3): δ 4.83 (q, J = 7.6 Hz, 2H), 3.76 – 3.65 (m, 3H), 3.53 (t, J = 4.6 Hz, 2H), 3.38 (s, 3H), 3.07 (d, J = 14.3 Hz, 1H), 2.99 – 2.92 (m, 1H), 2.65 – 2.58 (m, 1H), 2.54 (d, J = 2.6 Hz, 1H), 2.43 (d, J = 14.4 Hz, 1H), 2.26 (dd, J = 10.7, 2.9 Hz, 1H), 2.03 – 1.88 (m, 3H), 1.85 – 1.78 (m, 2H), 1.68 (d, J = 11.5 Hz, 2H), 1.49 (dd, J = 10.7, 1.9 Hz, 1H), 1.44 – 1.39 (m, 1H), 1.33 (s, 3H), 1.15 (s, 3H), 0.87 (s, 9H), 0.84 (s, 3H), 0.00 (d, J = 12.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 202.33, 176.22, 96.97, 91.59, 84.50, 82.78, 79.42, 71.83, 67.44, 59.18, 56.70, 54.47, 50.96, 50.12, 49.70, 46.50, 43.27, 42.44, 40.23, 30.82, 25.78, 25.77, 22.32, 20.84, 18.51, 18.06, -4.65, -4.98. FTIR (Neat, NaCl, thin film): 3473, 2930, 1775, 1703, 1267, 848, 776 cm-1. HRMS (ESI): calc’d for [M+Na]+ 589.3167, found 589.3161. [a]D23 : +87.8 (c 0.2 in CHCl3). Preparation of reduction product 198. O Me Me Me H O TMS 196 O Mn(dpm)3 (0.15 equiv) PhSi(iOPr)H2 (2.5 equiv) TBSO TBHP (1.5 equiv) O TBSO hexanes (30 mM), OMEM OTMS 22 ° C, 4 h 71% yield single diastereomer H O Me Me Me H O OMEM OTMS TMS 198 A stirring solution of Mn(dpm)3 (0.15 equiv) in hexanes (180 uL, 36 mM) was degassed by bubbling with Ar for 5 min. Some extra hexanes may be necessary to add to prevent Chapter 6 – End Game 637 complete evaporation of solvent. Regardless, the final amount of hexanes should amount to 180 uL (36 mM). Sequentially at room temperature were added Ph(i-PrO)SiH2 (3.6 uL, 3 equiv) and TBHP (1.80 uL, 5.5-6.5 M in pentane, 1.5 equiv). The reaction mixture was stirred for 4 h before TLC indicated complete conversion. The solution was evaporated with aid from rotatory evaporator and loaded directly onto silica gel pipet column for purification 5-15% EtOAc/Hexanes to afford the product 198 as a yellow oil (3 mg, 71% yield). O H O TBSO Me Me Me H O OMEM OTMS TMS 198 TLC (25% EtOAc/Hexanes): Rf 0.38 (p-anisaldehyde, purple). 1 H NMR (400 MHz, CDCl3): δ 5.19 (d, J = 7.5 Hz, 1H), 4.64 (d, J = 7.5 Hz, 1H), 4.08 (dd, J = 10.7, 4.7 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.63 – 3.52 (m, 4H), 3.39 (s, 3H), 2.79 (dd, J = 11.0, 2.6 Hz, 1H), 2.53 (ddd, J = 14.6, 10.9, 5.4 Hz, 1H), 2.41 (dd, J = 10.9, 2.6 Hz, 1H), 2.24 (d, J = 2.7 Hz, 1H), 2.10 – 2.00 (m, 1H), 1.93 – 1.76 (m, 2H), 1.76 – 1.56 (m, 6H), 1.43 (d, J = 10.7 Hz, 1H), 1.28 (d, J = 2.6 Hz, 1H), 1.19 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.87 (s, 10H), 0.16 (s, 10H), 0.08 (s, 9H), -0.00 (d, J = 13.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 176.55, 101.52, 91.71, 85.16, 83.82, 83.57, 73.08, 72.06, 66.47, 59.13, 55.19, 51.62, 51.15, 51.05, 49.51, 45.10, 43.77, 41.33, 40.72, 33.51, 29.85, 25.90, 25.82, 24.65, 20.50, 18.21, 2.74, 0.79, -4.70, -4.90. FTIR (Neat, NaCl, thin film): 2930, 1787, 1262, 1074, 1042, 875, 776 cm-1. HRMS (ESI): calc’d for [M+H]+ 713.4295, found 713.4297. [a]D23 : +12.1 (c 1.0 in CHCl3). 638 Chapter 6 – End Game Preparation of ketone 202. O TBSO Me O OsO4 (0.10 equiv.) NaIO4 (6 equiv) H H Me TMSO 105 OMEM Dioxane/H2O (3:1) 22 °C, 16 h 57% yield O TBSO Me O H H O OMEM Me TMSO 202 The starting material (8 mg, 12.9 umol, 1 equiv.) was dissolved in 1,4 dioxane and H2O (3 : 1, 690 uL : 230 uL, 14 mM). OsO4 (129 uL, 0.01 M in H2O, 0.10 equiv.) was added in, and the reaction was stirred at room temperature for 5 min. Then, NaIO4 (16.5 mg, 77.3 umol, 6 equiv) was added in, and the reaction was stirred at room temperature for 15 h. Monitor this reaction closely. Stirring too long will result in over-oxidation products that show up near the baseline of the TLC! Just look for enough conversion to get full conversion. May need to add more NaIO4. After 15 h, H2O (500 uL) was added. The resulting solution was extracted with EtOAc (4 x 1 mL), washed with brine (1 mL), dried with sodium sulfate, filtered, and concentrated. Preparatory TLC (50% EtOAc/Hex) affords the product 202 (4.6 mg, 57% yield) as a white solid. O TBSO Me O H H O OMEM Me TMSO 202 TLC (50% EtOAc/hexanes): Rf 0.60 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.44 (t, J = 3.5 Hz, 1H), 4.94 (d, J = 7.6 Hz, 1H), 4.77 (d, J = 7.7 Hz, 1H), 4.35 (d, J = 3.5 Hz, 1H), 3.78 – 3.67 (m, 3H), 3.49 (dt, J = 5.9, 3.7 Hz, 2H), 3.36 (s, 3H), 3.18 (s, 1H), 3.05 (dd, J = 11.0, 4.5 Hz, 1H), 2.64 – 2.41 (m, 5H), 2.28 (d, J = 12.6 Hz, 2H), 2.06 (d, J = 11.3 Hz, 1H), 1.80 (dd, J = 16.0, 5.2 Hz, 1H), 1.47 – 1.37 (m, 1H), 1.09 (s, 3H), 0.93 (s, 3H), 0.88 (s, 9H), 0.22 (s, 9H), 0.08 (s, 6H). 639 Chapter 6 – End Game 13 C NMR (101 MHz, CDCl3): δ 214.95, 176.54, 143.90, 123.44, 98.88, 91.49, 83.72, 82.85, 71.75, 70.92, 67.60, 59.10, 57.47, 55.29, 50.01, 48.70, 44.85, 42.32, 39.72, 39.68, 37.03, 25.76, 24.38, 18.45, 18.04, 1.38, -4.56, -4.98. FTIR (Neat, NaCl, thin film): 2934, 1776, 1754, 1064, 1042, 834 cm-1. HRMS (ESI): calc’d for [M+H]+ 623.3430, found 623.3441. [a]D23 : −195.9 (c 0.2 in CHCl3). Melting Point: 146-148 °C Preparation of hydrogenation product 204. O TBSO Me O H H Me TMSO 202 O OMEM O Pd/C (50 wt%) H2 (63 bar) EtOAc (5 mM), 23 °C, 15 h 89% yield single diastereomer TBSO Me O Me TMSO H H O H OMEM 204 The starting material (3.8 mg, 6.10 umol, 1 equiv.) was dissolved in EtOAc (1 mL, 5 mM) in a 1-dram vial equipped with a. magnetic stir bar. 10% Pd/C was added in (1.9 mg, 50 wt%) was added in, and a rubber septum was added on top. A pink 20 gage needle was pierced through the septum, and the vial was loaded in a bomb hydrogenator apparatus. After equilibrating the bomb hydrogenator vessel with H2 (3 times), the pressure was increased to 63 bar. The reaction was left to stir at that pressure of H2 overnight. After stirring for 15 h, the reaction was filtered through a pad of Celite to remove the Pd/C and rinsed with EtOAc. The resultant plug was disposed by separately rinsing with H2O (3 x 0.3 mL) and tagged as activated Pd/C waste. The resultant EtOAc solution was concentrated to afford the product 204 (3.4 mg, 89% yield) as a white solid. 640 Chapter 6 – End Game O TBSO Me O H H O H OMEM Me TMSO 204 TLC (50% EtOAc/hexanes): Rf 0.51 (p-anisaldehyde, purple). 1 H NMR (400 MHz, CDCl3): δ 4.89 (d, J = 7.7 Hz, 1H), 4.73 (d, J = 7.7 Hz, 1H), 4.10 (dd, J = 10.3, 4.9 Hz, 1H), 3.77 – 3.66 (m, 2H), 3.63 (d, J = 5.2 Hz, 1H), 3.53 – 3.46 (m, 2H), 3.37 (d, J = 0.7 Hz, 3H), 2.83 (dd, J = 10.9, 2.7 Hz, 1H), 2.64 – 2.49 (m, 2H), 2.34 (d, J = 1.9 Hz, 1H), 2.14 – 2.04 (m, 2H), 1.98 – 1.65 (m, 8H), 1.33 – 1.29 (m, 1H), 1.16 (s, 3H), 1.04 (s, 3H), 0.87 (s, 9H), 0.16 (d, J = 0.7 Hz, 9H). 13 C NMR (101 MHz, CDCl3): δ 214.56, 175.59, 101.03, 91.28, 84.90, 83.57, 72.45, 71.81, 67.34, 59.11, 55.03, 51.83, 51.01, 50.76, 48.40, 43.52, 43.03, 40.54, 39.25, 33.61, 25.85, 25.64, 24.72, 18.28, 18.21, 0.85, -4.67, -4.93. FTIR (Neat, NaCl, thin film): 2930, 1776, 1752, 1112, 1057, 834 cm-1. HRMS (ESI): calc’d for [M+H]+ 625.3586, found 625.3596. [a]D23 : −42.9 (c 0.2 in CHCl3). Preparation of secondary alcohol 205. O O O TBSO PPTS (3 equiv) Me Me H O TMS 105 OMEM MeOH, 22 °C, 10 h 93% yield O TBSO Me Me H OH OMEM 205 A solution of trimethylsilylated alcohol (23.0 mg, 37 umol, 1 equiv.) in methanol (740 uL, 50 mM) was treated with pyridinium p-toluenesulfonate (27.9 mg, 111 umol, 3 equiv) at room temperature and stirred for 19 hours. No care to exclude air or moisture was taken, Chapter 6 – End Game 641 and the PPTS was just added in as the solid, capped, and taped. TLC in 50% ether/hexanes reveals full conversion after 19 h. The reaction was worked up by addition of NH4Cl (750 uL) and the resulting solution was extracted with diethyl ether (3 x 1 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. A pipet column with 10-30% EA/hexanes afforded the product as a foamy, clear oil (18.9 mg, 93% yield). O O TBSO Me Me H OH OMEM 205 TLC: (50% EtOAc/Hexanes): Rf 0.52 (p-anisaldehyde, blue). 1 H NMR (CDCl3, 400 MHz): δ 5.41 – 5.34 (m, 1H), 5.03 (s, 1H), 4.97 – 4.90 (m, 2H), 4.72 (d, J = 7.5 Hz, 1H), 4.31 (d, J = 3.8 Hz, 1H), 3.87 – 3.80 (m, 1H), 3.73 (dd, J = 6.2, 3.2 Hz, 1H), 3.65 – 3.59 (m, 1H), 3.57 – 3.52 (m, 2H), 3.38 (s, 3H), 3.14 (s, 1H), 2.95 (dd, J = 10.5, 6.4 Hz, 1H), 2.69 (d, J = 13.7 Hz, 1H), 2.59 – 2.45 (m, 2H), 2.38 (d, J = 16.3 Hz, 1H), 2.32 – 2.14 (m, 3H), 2.04 (d, J = 10.8 Hz, 1H), 1.74 (dd, J = 16.3, 5.6 Hz, 1H), 1.41 (ddd, J = 14.4, 6.5, 3.3 Hz, 1H), 1.05 (s, 3H), 1.00 (s, 3H), 0.87 (s, 9H), 0.00 (d, J = 4.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 177.07, 152.12, 143.03, 124.39, 106.91, 98.22, 91.09, 85.03, 82.19, 71.98, 69.95, 66.99, 59.11, 56.68, 50.67, 50.45, 49.27, 45.12, 43.65, 42.22, 41.71, 39.16, 29.85, 25.82, 24.08, 18.59, 18.07, -4.50, -4.93. FTIR (Neat, NaCl, thin film): 3459, 2928, 1751, 1464, 1249, 1098, 1042, 1019, 883, 837, 773 cm-1. HRMS (ESI): calc’d for [M+H]+ 549.3242 found 549.3271. [a]D23 : +30.3 (c 0.2 in CHCl3). 642 Chapter 6 – End Game Preparation of ketone 206. O TBSO O O IBX (3 equiv) TBSO DMSO, 40 °C, 12 h Me H Me Me OH OMEM 74% yield 205 O Me O OMEM 206 The starting secondary alcohol (18.0 mg, 32.8 umol, 1 equiv) was dissolved in DMSO (164 uL, 200 mM). Then, a 1/2-dram stir bar was added in, followed by IBX (11.9 mg, 42.6 umol, 1.3 equiv.). The reaction was capped, taped, and heated at 50 °C for 1 h. Despite the identical polarity of the two products, TLC analysis was effective at monitoring conversion due to the difference in p-anisaldehyde staining (blue for the starting material and brown for the product). The reaction was worked up by addition of 1/2 saturated NaHCO3 (1 mL), and the aqueous phase was extracted with EtOAc (3 x 1 mL). A pipet column 10-30% EtOAc/Hex provides the product as a pale yellow oil (13.3 mg, 74% yield). O O TBSO Me Me O OMEM 206 TLC: (50% EtOAc/Hexanes): Rf 0.52 (p-anisaldehyde, brown). 1 H NMR (CDCl3, 400 MHz): δ 5.65 (dd, J = 5.0, 2.4 Hz, 1H), 5.07 (s, 1H), 5.00 (s, 1H), 4.90 (d, J = 7.6 Hz, 1H), 4.71 (d, J = 7.6 Hz, 1H), 3.86 – 3.78 (m, 1H), 3.74 (d, J = 5.8 Hz, 1H), 3.66 – 3.58 (m, 1H), 3.53 (t, J = 4.8 Hz, 2H), 3.38 (s, 3H), 3.29 (s, 1H), 3.21 (d, J = 14.1 Hz, 1H), 3.12 (dd, J = 11.0, 4.4 Hz, 1H), 2.74 – 2.51 (m, 3H), 2.44 (d, J = 14.2 Hz, 1H), 2.34 (dt, J = 16.0, 3.0 Hz, 1H), 2.24 – 2.16 (m, 1H), 2.11 (dd, J = 10.8, 2.0 Hz, 1H), 1.94 (dd, J = 10.8, 2.8 Hz, 1H), 1.43 (s, 1H), 1.34 (s, 3H), 0.90 (s, 5H), 0.88 (d, J = 3.2 Hz, 14H), 0.86 (s, 4H), 0.01 (d, J = 10.1 Hz, 6H). 643 Chapter 6 – End Game 13 C NMR (CDCl3, 101 MHz): δ 203.21, 175.89, 151.81, 139.28, 127.78, 109.24, 97.45, 91.15, 82.95, 82.61, 71.93, 67.19, 66.01, 59.15, 53.42, 49.71, 47.49, 44.67, 44.58, 43.04, 39.84, 34.27, 25.76, 22.49, 18.52, 18.06, 15.43, 14.21, 1.17, -4.63, -4.96. FTIR (Neat, NaCl, thin film): 2926, 2856, 1779, 1714, 1461, 1259, 1093, 1048, 1032, 837 cm-1. HRMS (ESI): calc’d for [M+H]+ 547.3086 found 547.3090. [a]D23 : +37.6 (c 0.2 in CHCl3). Preparation of rearranged product 208. O TBSO Me O Me O H H 3M HCl Acetone/H2O (3:1), 60 °C, 12 h O 206 HO OMEM Me H O Me 87% yield H O Me O 208 To the starting material (5 mg, 9.1 umol, 1 equiv.) was added acetone (300 uL). Then, 3 M aqueous HCl (670 uL, 219 equiv.) was added in, and the reaction was stirred overnight for 12 h at 60 °C. To workup the reaction, the reaction was neutralized with sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc (3 x 0.5 mL), and the combined organic extracts were dried with NaSO4, filtered, and concentrated. Prep plate in 50% EtOAc/Hex affords the product 208 (2.7 mg, 87% yield) as a white solid. O HO Me O Me H H Me O O 208 TLC (50% EtOAc/Hexanes): Rf 0.22 (p-anisaldehyde, brown). 644 Chapter 6 – End Game 1 H NMR (500 MHz, CDCl3): δ 5.67 (t, J = 3.4 Hz, 1H), 3.78 – 3.71 (m, 1H), 3.52 – 3.46 (m, 2H), 3.38 (s, 1H), 2.86 – 2.74 (m, 2H), 2.41 (dd, J = 17.5, 3.5 Hz, 1H), 2.32 (d, J = 17.5 Hz, 1H), 2.22 – 2.09 (m, 4H), 1.71 (dd, J = 11.4, 1.1 Hz, 1H), 1.62 – 1.58 (m, 1H), 1.28 – 1.23 (m, 6H), 1.14 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 218.65, 205.21, 177.18, 139.20, 128.15, 100.11, 82.82, 58.13, 54.56, 50.55, 50.28, 48.94, 48.09, 44.69, 40.96, 40.29, 38.88, 23.20, 20.35, 16.97. FTIR (Neat, NaCl, thin film): 3463, 2925, 1775, 1740, 1457, 1086 cm-1. HRMS (ESI): calc’d for [M+H]+ 345.1696, found 345.1693. [a]D23 : +127.1 (c 0.2 in MeOH). Preparation of DIBAL products 209, 210, and 211. O DIBAL-H (14 equiv.) TBSO Me Me O 206 OMEM CH2Cl2, −78 °C to 0 °C, 2 h then 0 °C, 2 h OH OH O O TBSO TBSO O TBSO HO O Me Me Me HO Me H OMEM HO Me H OMEM HO Me H 209 210 211 11% yield 42% yield 23% yield OMEM The starting material (3 mg, 5.3 umol, 1 equiv.) was dissolved in DCM (230 uL, 20 uM). Then, it was cooled to −78 °C and DIBAL solution (32 uL, 1M in hexanes, 6 equiv.) was added slowly dropwise. The mixture was immediately warmed to 0 °C by replacing the dry ice/acetone bath with an ice bath and the reaction was stirred for 30 min at that temperature. Following complete conversion by TLC (30 min at 0 °C), the reaction was quenched by addition of sat. aq. Rochelle’s salt (250 uL). The reaction was slowly warmed to room temperature and vigorously stirred for 1 h until complete decomposition of aluminum aggregates. The remaining solution was extracted with EtOAc (3 x 0.5 mL), and the combined organics were washed with brine (1 mL), dried with sodium sulfate, filtered, and Chapter 6 – End Game 645 concentrated. The lactol was isolated by careful preparatory TLC in 75% EtOAc/Hex to afford 210 as a clear oil (1.4 mg, 42% yield). O O TBSO Me HO Me OMEM H 209 TLC: (50% EtOAc/Hexanes): Rf 0.55 (p-anisaldehyde, light blue). 1 H NMR (CDCl3, 400 MHz): δ 5.31 (q, J = 3.0 Hz, 1H), 5.04 (s, 1H), 4.96 – 4.90 (m, 2H), 4.73 (d, J = 7.5 Hz, 1H), 4.14 (d, J = 5.1 Hz, 1H), 3.90 – 3.80 (m, 2H), 3.67 – 3.59 (m, 1H), 3.54 (dd, J = 5.7, 3.7 Hz, 2H), 3.38 (d, J = 2.5 Hz, 3H), 3.04 (s, 1H), 2.79 (dd, J = 12.2, 4.0 Hz, 1H), 2.70 – 2.61 (m, 1H), 2.61 – 2.51 (m, 2H), 2.44 (d, J = 15.6 Hz, 1H), 2.33 – 2.24 (m, 2H), 2.18 (dd, J = 16.2, 4.1 Hz, 1H), 2.01 (d, J = 10.4 Hz, 1H), 1.87 (dd, J = 15.3, 4.0 Hz, 1H), 1.11 (s, 3H), 0.95 (s, 3H), 0.92 (d, J = 1.6 Hz, 9H), 0.20 – 0.00 (m, 6H). 13 C NMR (151 MHz, CDCl3): δ 177.95, 152.62, 146.15, 121.89, 106.12, 102.66, 99.66, 90.89, 85.11, 84.82, 71.81, 70.31, 66.78, 64.66, 58.93, 51.56, 50.79, 46.01, 43.53, 42.48, 39.28, 25.84, 25.19, 18.51, -4.79, -5.08. FTIR (Neat, NaCl, thin film): 3457, 2928, 1754, 1267, 1157, 1098, 1042, 869, cm-1. HRMS (ESI): calc’d for [M+H]+ 549.3242 found 549.3277. [a]D23 : +43.3 (c 0.2 in CHCl3). OH TBSO O Me HO Me H OMEM 210 TLC: (50% EtOAc/Hexanes): Rf 0.52 (p-anisaldehyde, dark blue). 1 H NMR (CDCl3, 400 MHz): δ 6.20 (d, J = 9.3 Hz, 1H), 5.39 (dd, J = 4.6, 2.5 Hz, 1H), 5.26 (d, J = 9.2 Hz, 1H), 5.04 (s, 1H), 4.96 (s, 1H), 4.89 (d, J = 7.4 Hz, 1H), 4.72 (d, J = Chapter 6 – End Game 646 7.4 Hz, 1H), 4.08 (s, 1H), 3.91 (d, J = 6.6 Hz, 1H), 3.84 – 3.79 (m, 1H), 3.65 – 3.60 (m, 1H), 3.57 – 3.53 (m, 2H), 3.38 (s, 3H), 3.05 (s, 1H), 2.70 – 2.50 (m, 5H), 2.15 – 2.04 (m, 1H), 2.03 – 1.95 (m, 2H), 1.86 – 1.76 (m, 3H), 1.24 (s, 3H), 0.98 (s, 3H), 0.92 (s, 9H), 0.11 (d, J = 7.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 154.13, 144.18, 123.65, 107.51, 106.62, 100.42, 91.00, 85.42, 82.82, 71.84, 69.61, 66.95, 66.19, 59.00, 51.60, 50.72, 47.89, 46.27, 44.27, 43.60, 43.29, 39.45, 29.71, 26.61, 25.80, 19.25, 18.29, -4.76, -5.09. FTIR (Neat, NaCl, thin film): 3461, 2928, 1750, 1222, 1042, 948, 898, cm-1. HRMS (ESI): calc’d for [M−OH]+ 532.3215, found 532.3215. [a]D23 : +57.0 (c 0.2 in CHCl3). OH TBSO HO Me HO Me H OMEM 211 TLC: (50% EtOAc/Hexanes): Rf 0.50 (p-anisaldehyde, dark blue). 1 H NMR (CDCl3, 400 MHz): δ 5.33 (s, 1H), 5.08 (s, 1H), 5.01 – 4.93 (m, 2H), 4.77 (d, J = 7.4 Hz, 1H), 4.11 – 4.01 (m, 1H), 3.84 (d, J = 10.6 Hz, 2H), 3.72 – 3.52 (m, 6H), 3.40 (d, J = 8.7 Hz, 3H), 2.94 – 2.82 (m, 1H), 2.60 (d, J = 16.5 Hz, 2H), 2.44 – 2.30 (m, 3H), 2.22 – 2.02 (m, 4H), 1.40 (d, J = 14.4 Hz, 1H), 1.14 (s, 3H), 0.98 (s, 3H), 0.91 (s, 12H), 0.08 (d, J = 3.6 Hz, 6H). 647 Chapter 6 – End Game Preparation of lactol 214. O TBSO Me O H HO DIBAL (5 equiv) H Me TMSO 105 OMEM DCM, −78 °C to 0 °C, 30 min 80% yield TBSO Me O Me TMSO H H H OMEM 214 The starting material (5 mg, 8.05 umol, 1 equiv.) in an oven-dried, 1-dram vial equipped with a magnetic stir bar was evacuated and backfilled with N2 three times. CH2Cl2 (810 uL, 10 mM) was added, and the vial was stirred for 2 minutes to ensure complete dissolution of the starting material. Then, the vial was cooled to −78 °C using a dry ice/acetone bath, and DIBAL (40 uL, 40.3 umol, 1 M in hexanes, 5 equiv.) was added in slowly dropwise. The reaction was immediately warmed to 0 °C by replacing the dry ice/acetone bath with an ice bath. At 0 °C, the reaction was TLC’d, indicating complete conversion to a slightly less polar, darker blue spot, and the reaction was quenched by careful addition of sat. aq. Rochelle’s salt (500 uL). The ice bath was replaced and the reaction was warmed to room temperature, where it was stirred for 20 minutes to ensure complete decomposition of the aluminum aggregates. The organic phase of the resulting solution was collected, and the remaining aqueous phase was extracted with CH2Cl2 (3 x 0.5 mL). The combined organics were washed with brine (1 mL), dried with sodium sulfate, filtered, and concentrated. Preparatory TLC in 50% Ether/Hexanes affords the product 214 (4 mg, 80% yield) as a clear oil. HO TBSO Me O Me TMSO H H H OMEM 214 TLC (50% Ether/Hexanes): Rf 0.75 (p-anisaldehyde, dark-blue). 648 Chapter 6 – End Game 1 H NMR (CDCl3, 400 MHz): δ 5.32 (d, J = 8.7 Hz, 1H), 5.28 – 5.22 (m, 2H), 5.03 (t, J = 2.6 Hz, 1H), 4.92 (d, J = 7.5 Hz, 2H), 4.72 (d, J = 7.5 Hz, 1H), 4.11 (dd, J = 5.1, 1.8 Hz, 1H), 3.86 – 3.77 (m, 2H), 3.66 – 3.59 (m, 1H), 3.55 – 3.50 (m, 2H), 3.37 (s, 3H), 2.99 (s, 1H), 2.78 (dd, J = 12.2, 3.6 Hz, 1H), 2.64 (ddd, J = 15.3, 12.2, 6.7 Hz, 1H), 2.55 (dt, J = 16.3, 2.4 Hz, 2H), 2.37 (dd, J = 15.5, 1.9 Hz, 1H), 2.27 (dt, J = 16.3, 2.9 Hz, 1H), 2.21 – 2.10 (m, 2H), 1.93 (dd, J = 10.6, 1.4 Hz, 1H), 1.81 (dd, J = 15.3, 3.7 Hz, 1H), 1.54 – 1.49 (m, 1H), 1.08 (s, 3H), 0.91 (s, 9H), 0.88 (s, 3H), 0.15 (s, 9H), 0.09 (d, J = 3.9 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 152.99, 146.43, 121.39, 106.27, 103.00, 100.23, 91.14, 85.58, 85.37, 71.86, 71.35, 67.19, 65.36, 59.11, 52.13, 51.33, 51.25, 46.26, 43.51, 42.57, 41.91, 39.69, 26.31, 26.00, 18.77, 18.44, 1.43, -4.60, -4.94. FTIR (Neat, NaCl, thin film): 3412, 2887, 1701, 1414, 1210, 898, 840 cm-1. HRMS (ESI): calc’d for [M+Na]+ 645.3613 found 645.3615. Preparation of methyl acetal 216. HO TBSO Me O H MeO H PPTS (3 equiv) H Me TMSO 214 OMEM MeOH, 21 °C, 18 h 67% yield HO Me O Me HO NOESY H H H MeO OMEM HO O H H HH H OMEM Me 216 Me HO acetal stereochemical verification The starting material (4 mg, 6.44 umol, 1 equiv.) was dissolved in MeOH (130 uL, 50 mM). PPTS (4.9 mg, 19.3 umol, 3 equiv.) was added. The vial was capped and stirred overnight for 18 h. Monitoring by TLC for the first 3 hours indicates complete conversion to two polar spots that should be TLC’d in 75% EtOAc/hexanes. The bottom spot was larger, indicating that it was likely formed in short reaction periods in higher quantites. After stirring overnight for 18 h, the top spot became the major spot, corresponding to Chapter 6 – End Game 649 structure 216. The reaction was worked up by addition of sat. aq. NaHCO3 (300 uL). The solution was extracted with EtOAc (4 x 0.5 mL), washed with brine, dried with sodium sulfate, filtered, and concentrated. Preparatory TLC in 75% EtOAc/hexanes affords the product (2.4 mg, 67% yield) as a clear oil. MeO HO Me O Me HO H H H OMEM 216 TLC (100% EtOAc/Hexanes): Rf 0.40 (p-anisaldehyde, light-blue). 1 H NMR (CDCl3, 400 MHz): δ 5.36 (t, J = 3.6 Hz, 1H), 5.07 (t, J = 2.6 Hz, 1H), 4.97 (s, 1H), 4.95 (s, 1H), 4.93 (d, J = 7.5 Hz, 1H), 4.73 (d, J = 7.5 Hz, 1H), 4.17 (dd, J = 5.5, 1.5 Hz, 1H), 3.87 – 3.79 (m, 1H), 3.66 – 3.58 (m, 2H), 3.56 – 3.51 (m, 2H), 3.41 (s, 3H), 3.38 (s, 3H), 3.01 (s, 1H), 2.73 (dd, J = 12.0, 3.8 Hz, 1H), 2.69 – 2.61 (m, 1H), 2.58 (ddd, J = 16.4, 5.5, 2.3 Hz, 2H), 2.39 – 2.27 (m, 3H), 2.21 – 2.12 (m, 1H), 2.04 – 2.00 (m, 1H), 1.78 (dd, J = 14.9, 3.8 Hz, 1H), 1.67 (dd, J = 15.8, 5.5 Hz, 1H), 1.16 (s, 3H), 0.94 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 152.68, 145.43, 122.55, 109.45, 106.55, 101.46, 91.07, 85.15, 83.81, 71.97, 70.07, 66.98, 61.96, 59.13, 56.52, 51.82, 50.75, 50.39, 46.42, 43.72, 42.31, 41.85, 38.78, 25.29, 18.00. FTIR (Neat, NaCl, thin film): 3430, 2919, 1763, 1420, 1364, 1067, 955 cm-1. HRMS (ESI): calc’d for [M+Na]+ 473.2510 found 473.2521. 650 Chapter 6 – End Game Preparation of hydrated product 199. O TBSO Me O O H H Me TMSO 105 Co(acac)2 (0.2 equiv.) PhSiH3 (2 equiv.) OMEM EtOH (25 mM), 0 °C, 1.5 h then Na2S2O3 80% yield TBSO Me O H Me OH H OMEM Me TMSO 199 A 10x stock solution of Co(acac)2 was made by dissolving 3.0 mg of the solid in 1 mL of EtOH in a 1-dram vial. Then, the vial was capped with a rubber septum and a vent needle was attached. An O2 balloon with a long needle was inserted into the Co(acac)2/EtOH solution to sparge the solution with O2, while, at the same time, the vial was sonicated for 30 seconds or until all Co(acac)2 was dissolved. Once the stock solution was prepared, the vent needle was removed, and it was left under O2 and used within 10 minutes. The starting material (18 mg, 29.0 umol, 1 equiv.) in a 1-dram vial was dissolved in EtOH (560 uL) and a magnetic stir bar was added in. Then, Co(acac)2 was added in (500 uL, 5.80 umol, 0.2 equiv.), and the stirring solution was cooled to 0 °C and an O2 balloon with a purple (thick) needle was added on. PhSiH3 as a 10x stock solution was added in slowly, dropwise (100 uL, 58.0 umol, 2 equiv.) at 0 °C, and the reaction was stirred at 0 °C for 3 h. After 15 min, a color change from pink to yellow/green was observed. After 45 min to 1 h, the color was a deeper green. Following completion (3 h), as determined by TLC, the reaction was quenched by addition of sat. aq. Na2S2O3 (250 uL) at 0 °C, warmed to room temperature, and stirred at room temperature for 20 minutes to ensure complete degradation of the peroxide intermediate. The resulting solution was extracted with EtOAc (4 x 0.5 mL), washed with brine, dried with Na2SO4, filtered, and concentrated. The crude oil was purified by pipet column (12-24% EtOAc/hexanes) to afford the product 199 as a clear oil (14.8 mg, 80% yield). Chapter 6 – End Game O TBSO Me O H 651 Me OH H OMEM Me TMSO 199 TLC (36% EtOAc/hexanes): Rf 0.35 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.31 (t, J = 3.6 Hz, 1H), 4.91 – 4.83 (m, 2H), 4.25 (td, J = 4.5, 2.0 Hz, 1H), 3.83 – 3.75 (m, 1H), 3.73 – 3.64 (m, 2H), 3.54 (q, J = 4.7 Hz, 2H), 3.38 (s, 3H), 3.09 (s, 1H), 2.95 (dd, J = 11.0, 4.5 Hz, 1H), 2.59 – 2.44 (m, 2H), 2.28 (dt, J = 11.2, 4.6 Hz, 2H), 2.18 (dd, J = 10.2, 2.0 Hz, 1H), 2.10 – 2.04 (m, 2H), 1.75 – 1.69 (m, 2H), 1.42 – 1.37 (m, 1H), 1.19 (s, 3H), 1.06 (s, 3H), 0.91 (s, 3H), 0.87 (s, 9H), 0.17 (s, 9H), -0.01 (d, J = 5.2 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 177.12, 145.98, 122.85, 98.92, 91.69, 85.82, 82.99, 78.03, 71.86, 71.04, 67.63, 66.01, 59.18, 58.82, 57.70, 49.94, 44.57, 42.22, 39.71, 35.25, 25.77, 24.41, 18.49, 18.05, 15.42, 1.35, -4.58, -4.98. FTIR (Neat, NaCl, thin film): 3411, 2932, 1772, 1462, 1252, 1129, 1098, 1025, 840 cm1 . HRMS (ESI): calc’d for [M+Na]+ 661.3562, found 661.3570. [a]D23 : +25.6 (c 0.8 in CHCl3). 652 Chapter 6 – End Game Preparation of alcohol 200. O TBSO Me O H O Me OH H OMEM Me TMSO 199 PPTS (1 equiv) MeOH, 22 °C, 18 h TBSO Me O H Me OH H OMEM Me HO 90% yield 200 A solution of trimethylsilylated alcohol (10.0 mg, 14.1 umol, 1 equiv.) in methanol (560 uL, 25 mM) was treated with pyridinium p-toluenesulfonate (7.1 mg, 28.1 umol, 1 equiv) at room temperature and stirred for 18 hour. No care to exclude air or moisture was taken, and the PPTS was just added in as the solid, capped, and taped. TLC in 75% EtOAc/hexanes reveals full conversion to a more polar spot after 18 h. The reaction was worked up by addition of NH4Cl (500 uL) and the resulting solution was extracted with EtOAc (3 x 0.5 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. A pipet column with 50-75% EA/hexanes afforded the product 200 as a white solid (7.2 mg, 90% yield). O TBSO Me O H Me OH H OMEM Me HO 200 TLC (75% EtOAc/hexanes): Rf 0.38 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.33 (t, J = 3.6 Hz, 1H), 4.91 – 4.81 (m, 2H), 4.28 (dd, J = 5.5, 1.6 Hz, 1H), 3.79 – 3.67 (m, 3H), 3.54 (t, J = 4.6 Hz, 2H), 3.38 (s, 3H), 3.12 (s, 1H), 2.92 (dd, J = 10.5, 6.2 Hz, 1H), 2.60 – 2.37 (m, 2H), 2.39 – 2.27 (m, 3H), 2.17 – 2.02 (m, 2H), 1.78 – 1.70 (m, 2H), 1.44 – 1.37 (m, 1H), 1.21 (s, 3H), 1.05 (s, 3H), 0.99 (s, 3H), 0.87 (s, 9H). 653 Chapter 6 – End Game 13 C NMR (101 MHz, CDCl3): δ 177.07, 146.01, 123.32, 98.20, 91.61, 85.86, 82.21, 78.02, 71.89, 69.89, 67.60, 59.17, 58.50, 56.65, 49.30, 47.70, 44.66, 42.24, 42.07, 39.18, 35.45, 25.79, 24.34, 24.03, 18.61, 18.05, -4.52, -4.94. FTIR (Neat, NaCl, thin film): 3458, 2930, 2857, 1768, 1469, 1255, 1098, 1020, 839, 775 cm-1. HRMS (ESI): calc’d for [M+Na]+ 589.3167, found 589.3170. [a]D23 : −35.1 (c 0.8 in CHCl3). Melting Point: 142-144 °C Preparation of ketone 206 O TBSO Me O Me HO H O Me OH H 205 OMEM IBX (2 equiv) DMSO, 60 °C, 1 h 88% yield TBSO Me Me OH O Me H H OMEM O 206 The starting secondary alcohol (8.0 mg, 14.1 umol, 1 equiv) was dissolved in solvent (700 uL, 20 mM). Then, a 1-dram stir bar was added in, followed by IBX (7.9 mg, 28.2 umol, 2.0 equiv.). The reaction was capped, taped, and heated at 60 °C for 1 h. The reaction was worked up by addition of ½ sat. NaHCO3 by slow, dropwise addition at room temperature. The remaining solution was extracted with EtOAc (4 x 0.5 mL). The combined organic extract was washed with H2O (5 x 1 mL, or as many washes as it takes to get rid of DMSO), brine (1 x 2 mL), dried with sodium sulfate, filtered, and concentrated. A pipet column 5075% EtOAc/hexanes afforded analytically pure product 206 as a pale yellow oil (7.0 mg, 88% yield). 654 Chapter 6 – End Game O TBSO Me Me OH O Me H H OMEM O 206 TLC (75% EtOAc/Hexanes): Rf 0.42 (p-anisaldehyde, brown). 1 H NMR (400 MHz, CDCl3): δ 5.63 (dd, J = 4.7, 2.6 Hz, 1H), 4.94 – 4.82 (m, 2H), 3.82 – 3.75 (m, 1H), 3.74 – 3.67 (m, 2H), 3.54 (t, J = 4.4 Hz, 2H), 3.38 (d, J = 1.0 Hz, 3H), 3.30 (s, 1H), 3.20 – 2.96 (m, 3H), 2.72 – 2.58 (m, 2H), 2.47 (d, J = 14.1 Hz, 1H), 2.31 (ddd, J = 18.1, 4.9, 1.7 Hz, 1H), 2.16 (dd, J = 10.2, 1.8 Hz, 1H), 2.01 – 1.85 (m, 3H), 1.45 – 1.40 (m, 1H), 1.33 (s, 3H), 1.18 (s, 3H), 0.89 (s, 3H), 0.87 (d, J = 1.0 Hz, 9H). 13 C NMR (101 MHz, CDCl3): δ 176.01, 141.19, 126.49, 97.66, 91.56, 83.65, 82.63, 79.78, 71.83, 67.70, 59.19, 58.88, 54.72, 53.78, 49.82, 47.42, 44.61, 44.09, 39.84, 35.14, 29.85, 25.75, 25.21, 22.45, 18.52, 18.04, -4.63, -4.98. FTIR (Neat, NaCl, thin film): 3503, 2928, 2856, 1778, 1713, 1458, 1255, 1168, 1094, 1031, 832, 776 cm-1. HRMS (ESI): calc’d for [M+Na]+ 587.3010, found 587.3013. [a]D23 : +12.6 (c 0.3 in CHCl3). Preparation of lactol 217. O TBSO Me Me H O 206 H HO OH O Me H OMEM DIBAL (6 equiv) toluene (10 mM), −78 °C, 30 min TBSO Me H Me OH O H HO 217 61% yield H Me OH O H OMEM Me Me HO H HO OMEM Me HO 6-epi-217 27% yield The starting material (13 mg, 23.0 umol, 1 equiv.) was dissolved in toluene (2.1 mL, 10 mM). The solution was stirred for 3 min to ensure complete dissolution into toluene. Then, 655 Chapter 6 – End Game it was cooled to −78 °C and DIBAL solution (130 uL, 1 M in hexanes, 5.65 equiv.) was added slowly dropwise. The mixture was stirred for 30 minutes at −78 °C. Following complete conversion by TLC (30 min at −78 °C), the reaction was quenched by slow addition of EtOAc (xs, 100 uL). Then, the vial was removed from the dry ice/acetone bath and allowed to warm to 0 °C. Once at 0 °C, sat. aq. Rochelle’s salt (2 mL) was added. The reaction was slowly warmed to room temperature and vigorously stirred for 1 h until complete decomposition of aluminum aggregates. The remaining solution was extracted with EtOAc (3 x 0.5 mL), and the combined organics were washed with brine (2 x 1 mL), dried with sodium sulfate, filtered, and concentrated. The lactol was isolated by careful preparatory TLC in 100% EtOAc to afford 217 as a clear oil (8.0 mg, 61% yield) and 6epi-217 as a clear oil (3.4 mg, 27% yield). HO TBSO Me O H H Me OH H OMEM Me HO 217 TLC (75% EtOAc/Hexanes): Rf 0.28 (p-anisaldehyde, dark blue) TLC (10% MeOH/DCM): Rf 0.48 (p-anisaldehyde, blue). 1 H NMR (400 MHz, CDCl3): δ 5.92 (d, J = 9.2 Hz, 1H), 5.28 – 5.19 (m, 2H), 4.81 – 4.71 (m, 2H), 3.88 (s, 1H), 3.78 (d, J = 6.7 Hz, 1H), 3.70 – 3.59 (m, 2H), 3.45 (t, J = 4.6 Hz, 2H), 3.28 (s, 3H), 2.93 (s, 1H), 2.59 – 2.51 (m, 1H), 2.44 (dd, J = 17.8, 3.0 Hz, 1H), 2.31 (dd, J = 12.2, 3.7 Hz, 1H), 2.17 – 2.10 (m, 1H), 2.00 – 1.87 (m, 3H), 1.80 – 1.67 (m, 4H), 1.14 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H), 0.82 (s, 9H). 656 Chapter 6 – End Game 13 C NMR (101 MHz, CDCl3) δ 146.92, 122.36, 106.18, 100.51, 91.55, 85.67, 84.11, 79.48, 71.87, 70.94, 67.58, 65.90, 59.18, 55.99, 51.92, 47.95, 47.44, 45.30, 42.74, 39.82, 35.39, 26.04, 25.93, 25.25, 19.56, 18.41, -4.63, -4.96. FTIR (Neat, NaCl, thin film): 3430, 2930, 1461, 1244, 1029, 861 cm-1. HRMS (ESI): calc’d for [M+Na]+ 591.3323, found 591.3330. [a]D23 : +61.0 (c 0.2 in MeOH). H HO TBSO Me H Me OH O H OMEM Me HO 6-epi-217 TLC (75% EtOAc/Hexanes): Rf 0.34 (p-anisaldehyde, light blue). 1 H NMR (400 MHz, CDCl3): δ 5.30 (t, J = 4.0 Hz, 1H), 5.25 (t, J = 3.6 Hz, 1H), 5.07 (d, J = 8.5 Hz, 1H), 4.91 – 4.83 (m, 2H), 4.10 (dd, J = 5.3, 1.6 Hz, 1H), 3.85 (d, J = 6.5 Hz, 1H), 3.79 – 3.70 (m, 2H), 3.55 (d, J = 4.6 Hz, 2H), 3.38 (d, J = 2.0 Hz, 3H), 3.00 (s, 1H), 2.76 (dd, J = 12.2, 3.7 Hz, 1H), 2.64 (ddd, J = 15.2, 12.2, 6.7 Hz, 1H), 2.51 (dd, J = 17.8, 3.3 Hz, 1H), 2.38 (dd, J = 15.7, 1.6 Hz, 1H), 2.32 – 2.24 (m, 2H), 2.11 – 2.06 (m, 1H), 1.96 (dd, J = 13.5, 2.0 Hz, 1H), 1.82 (td, J = 14.4, 4.6 Hz, 2H), 1.61 (d, J = 10.4 Hz, 1H), 1.20 (s, 3H), 1.10 (s, 3H), 0.92 (d, J = 7.6 Hz, 12H), 0.09 (d, J = 3.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 149.19, 121.09, 102.86, 99.90, 91.56, 86.07, 85.04, 78.04, 71.90, 70.41, 67.58, 64.72, 59.80, 59.18, 51.07, 48.09, 45.68, 43.16, 41.61, 39.49, 35.42, 25.98, 25.37, 24.46, 18.70, 18.41, -4.62, -4.94. FTIR (Neat, NaCl, thin film): 3410, 2935, 1401, 1207, 1111, 1013 cm-1. HRMS (ESI): calc’d for [M+Na]+ 591.3323, found 591.3320. [a]D23 : +2.2 (c 0.2 in MeOH). 657 Chapter 6 – End Game Preparation of C9-C11 dehydro auriculatol A (218). HO TBSO Me O H H Me MeO OH H Me HO 217 OMEM HCl (65 equiv) MeOH, 22 °C, 16 h 73% yield HO Me O H H Me OH H OH Me HO C9-C11-dehydro-auriculatol A (218) The starting material (3.5 mg, 6.15 umol, 1 equiv.) was dissolved in MeOH (200 uL). Then, a 1.25 M solution of HCl in MeOH (300 uL, 65 equiv.) was added dropwise at room temperature. The reaction was stirred overnight for 16 h. Upon completion, as determined by TLC, which showed complete conversion to a slightly more polar spot, the reaction was treated with NaHCO3 (300 uL). The solution was extracted with EtOAc (0.3 mL x 5), washed with brine (1 x 1 mL), dried with MgSO4, filtered, and concentrated. Careful preparatory TLC, loading the TLC plate with 10% MeOH/DCM and running the plate in 60% acetone/hexanes enabled isolation of the product 218 (1.7 mg, 73% yield) as a clear oil. TLC (60% acetone/hexanes): Rf 0.50 (p-anisaldehyde, dark blue) 1 H NMR (400 MHz, CD3OD): δ 5.28 (t, J = 3.6 Hz, 1H), 5.07 (s, 1H), 3.78 (dd, J = 10.9, 3.1 Hz, 1H), 3.49 (d, J = 6.7 Hz, 1H), 3.43 (s, 3H), 2.92 (s, 1H), 2.71 (ddd, J = 15.5, 11.8, 7.0 Hz, 1H), 2.37 – 2.17 (m, 3H), 2.11 – 1.97 (m, 3H), 1.85 – 1.78 (m, 2H), 1.70 (dd, J = 15.5, 4.2 Hz, 1H), 1.58 (dd, J = 14.7, 3.2 Hz, 1H), 1.30 (s, 3H), 1.18 (s, 3H), 1.02 (s, 3H). 13 C NMR (101 MHz, CD3OD): δ 150.03, 122.52, 112.02, 103.30, 85.87, 80.77, 78.90, 74.36, 63.18, 60.81, 56.57, 52.75, 52.73, 50.02, 46.82, 41.04, 40.47, 38.54, 24.14, 23.79, 20.08. FTIR (Neat, NaCl, thin film): 3413, 2928, 2854, 1444, 1382, 1172, 1078 cm-1. HRMS (ESI): calc’d for [M+Na]+ 403.2091, found 403.2091. 658 Chapter 6 – End Game [a]D23 : +113.9 (c 0.2 in MeOH). Preparation of auriculatol A (49) and 9-epi-auriculatol A (219). MeO HO Me MeO HO Me O H H Me OH H OH Me HO C9-C11-dehydro-auriculatol A (218) Mn(dpm)3 (0.20 equiv) PhSiH3 (6 equiv) TBHP (6.5 equiv) O H H Me OH H H OH Me HO auriculatol A (49) 43% yield IPA (10 mM), 22 ° C, 14 h MeO HO Me O H H Me OH H H OH Me HO 9-epi-auriculatol A (219) 41% yield The pentacycle 218 (10.5 mg, 27.6 umol, 1 equiv) was dissolved in isopropanol (1 mL) in a 2-dram vial, and the solution was charged with a magnetic stir bar. Phenylsilane (20 uL, 6 equiv) and TBHP (33 uL, 5.5 M solution in decane, 6.5 equiv) were added to the vial. A separate 2-dram vial was equipped with a magnetic stir bar and charged with Mn(dpm)3 (6.7 mg, 11.0 umol) isopropanol (1 mL), then stirred at room temperature for 5 minutes until the solids dissolved. Both vials were capped with a rubber septum, evacuated and backfilled with N2 three times, and freeze-pump-thawed three times to remove any trace O2. After freeze-pump-thaw, both vials were warmed to room temperature and stirred for 5 minutes to ensure complete dissolution of all components. Then, Mn(dpm)3 stock solution (0.5 mL, 5.5 umol) was dispensed into the vial containing the starting material, phenylsilane, and TBHP. The reaction was left to stir at room temperature overnight for 14 h, upon which TLC in 60% acetone/hexanes indicated complete conversion to a slightly more polar spot. The reaction was worked up by removal of the stir bar, rinsing with Chapter 6 – End Game 659 isopropanol, and rotatory evaporation. The crude residue was initially purified by preparatory TLC in 60% acetone/hexanes, isolating the major band (9 mg, 90% yield) that contained a 1.1:1 mixture of auriculatol A and 9-epi-auriculatol A. The separation of auriculatol A and 9-epi-auriculatol A was carried out via HPLC-TOF reverse phase chromatography (Eclipse XDB-C18 – 9.4 mm x 250 mm column, 30% ACN/70% H2O, flow rate: 0.6 mL/min, tR (auriculatol A = 6.4 min) tR (9-epi-auriculatol A) = 7.1 min, to yield auriculatol A as a colorless oil (4.5 mg, 43% yield) and 9-epi-auriculatol A as a colorless oil (4.3 mg, 41% yield). NMR data of the mixture and analytically pure samples have been provided. MeO HO Me O H H Me OH H H OH Me HO auriculatol A (49) TLC (60% acetone/hexanes): Rf 0.42 (p-anisaldehyde, blue). 1 H NMR (600 MHz, MeOD): δ 4.98 (s, 1H), 3.71 (dd, J = 11.0, 3.7 Hz, 1H), 3.48 (d, J = 6.7 Hz, 1H), 3.41 (s, 3H), 2.75 – 2.70 (m, 1H), 2.62 (dd, J = 12.0, 3.6 Hz, 1H), 2.08 (s, 1H), 1.97 (dd, J = 14.0, 11.0 Hz, 1H), 1.90 (d, J = 11.3, 1H), 1.88 – 1.75 (m, 3H), 1.75 – 1.59 (m, 5H), 1.58 – 1.48 (m, 2H), 1.30 (s, 3H), 1.22 (s, 3H), 1.03 (s, 3H). 13 C NMR (101 MHz, MeOD): δ 117.80, 103.91, 85.93, 80.99, 78.73, 74.01, 61.49, 61.48, 56.37, 52.82, 49.21, 48.13, 42.96, 41.30, 41.27, 39.91, 32.57, 29.22, 24.72, 21.50, 20.45. FTIR (DCM, NaCl, thin film): 3413, 2935, 1446, 1192, 1087, 946, 735 cm-1. HRMS (ESI): calc’d for C21H34O6Na [M+Na]+ 405.2247, found 405.2248. [a]D23 : +158.0 (c 0.4 in MeOH). 660 Chapter 6 – End Game Comparison of synthetic and natural product auriculatol A (49) 21 H MeO 2 HO 3 4 Me 18 20 1 O 10 17 H H 11 Me 12 9 8 5 Me 19 HO 6 OH OH 16 15 H 13 14 7 (+)-auriculatol A (49) Table 6.1: Comparison of synthetic and natural auriculatol A (1) by 1H NMR in MeOD No. This Report Sun et al.31 Auriculatol A Auriculatol A (MeOD, 600 MHz) (MeOD, 400 MHz) ! 1 2.62, dd (12.0, 3.6) 2.61, dd (12.0, 3.5) 2! 2.71, ddd (14.8, 12.0, 6.9) 2.71, ddd (14.8, 12.0, 6.7) 2β 1.56, dd (14.7, 3.4) 1.55, dd (14.8, 3.5) 3! 3.48, d (6.5) 3.48, d (6.7) 6! 3.71, dd (11.0, 3.8) 3.70, dd (11.0, 3.6) 7! 1.51, dd (14.0, 3.6) 1.52, dd (14.0, 3.6) 7β 1.97, dd, (13.9, 11.0) 1.97, dd (14.0, 11.0) 9β 1.69, m 1.69, m 10 2.08, s 2.08, s 11! 1.61, m 1.60, m 11β 1.69, m 1.69, m 12! 1.66, m 1.67, m 12β 1.86, m 1.85, m 14! 1.77, d (11.5) 1.77, d (11.6) 14β 1.90, d, (11.0) 1.90, d (11.6) 15! 1.68, d (14.4) 1.68, d (14.5) 15β 1.80, d (14.7) 1.80, d (14.5) 17 1.22, s 1.22, s 18 1.30, s 1.30, s 19 1.03, s 1.03, s 20 4.98, s 4.98, s 21 3.41, s 3.41, s 661 Chapter 6 – End Game 21 H MeO 2 HO 3 4 Me 18 20 1 O 10 17 H H 11 Me 12 9 8 5 6 Me 19 HO OH OH 16 15 H 13 14 7 (+)-auriculatol A (49) Table 6.2: Comparison of synthetic and natural auriculatol A (1) by 13C NMR in MeOD No. This Report Sun et al.31 Difference Auriculatol A Auriculatol A (ppm) (MeOD, 101 MHz) (MeOD, 100 MHz) 1 42.8 43.0 0.2 2 41.2 41.3 0.1 3 85.8 85.9 0.1 4 52.7 52.8 0.1 5 103.8 103.9 0.1 6 73.9 74.0 0.1 7 48.0 48.1 0.1 8 39.8 39.9 0.1 9 49.1 (overlap with 49.2 0.1 MeOD) 10 61.4 (overlap) 61.5 0.1 11 29.1 29.2 0.1 12 32.5 32.6 0.1 13 78.6 78.8 0.2 14 41.1 41.3 0.2 15 61.4 (overlap) 61.5 0.1 16 80.9 81.0 0.1 17 21.4 21.5 0.1 18 20.3 20.5 0.2 19 24.6 24.8 0.2 20 117.7 117.8 0.1 21 56.2 56.4 0.2 Chapter 6 – End Game H MeO HO Me OH O Me H 662 H H OH Me HO C9-epi-auriculatol A (219) TLC (60% acetone/hexanes): Rf 0.43 (p-anisaldehyde, blue). 1 H NMR (400 MHz, MeOD): δ 5.23 (s, 1H), 4.11 (dd, J = 4.5, 2.7 Hz, 1H), 3.56 (dd, J = 6.6, 2.9 Hz, 1H), 3.42 (s, 3H), 2.56 – 2.45 (m, 2H), 2.32 (d, J = 2.3 Hz, 1H), 2.12 – 2.00 (m, 3H), 1.86 (dd, J = 15.4, 2.2 Hz, 1H), 1.73 – 1.66 (m, 4H), 1.63 – 1.55 (m, 3H), 1.25 (m), 1.21 (s, 3H), 1.17 (s, 3H), 0.99 (s, 3H). 13 C NMR (101 MHz, MeOD): δ 108.87, 101.12, 84.79, 79.63, 79.20, 71.07, 59.73, 56.68, 56.12, 51.42, 48.86, 48.67, 48.04, 46.07, 42.95, 39.21, 34.55, 28.12, 26.83, 20.73, 19.58. FTIR (Neat, NaCl, thin film): 3436, 2925, 1456, 1083, 998, 735 cm-1. HRMS (ESI): calc’d for C21H34O6Na [M+Na]+ 405.2247, found 405.2249. [a]D23 : +27.5 (c 0.4 in MeOH). 6.6 (1) NOTES AND REFERENCES Crossley, S. W. M.; Martinez, R. M.; Obradors, C.; Shenvi, R. A. Mn, Fe, and CoCatalyzed Radical Hydrofunctionalizations of Olefins. Chem. Rev. 2016, 116, 8912-9000. (2) Shevick, S. L.; Wilson, C. V.; Kotesova, S.; Kim, D.; Holland, P. L.; Shenvi, R. A. Catalytic hydrogen atom transfer to alkenes: a roadmap for metal hydrides and radicals. Chem. Sci. 2020, 11, 12401–12422. (3) Wu, J.; Ma, Z. Metal-Hydride Hydrogen Atom Transfer (MHAT) Reactions in Natural Product Synthesis. Org. Chem. Front. 2021, 8, 7050–7076. Chapter 6 – End Game (4) 663 Matos, J. L. M.; Green, S. A.; Shenvi, R. A. Chapter 7. Markovnikov Functionalization by Hydrogen Atom Transfer, Organic Reactions, 2019, 100, 383–470. (5) Green, S.A.; Crossley, S.W.M.; Matos, J.L.M.; Vásquez-Céspedes, S.; Shevick, S. L.; Shenvi, R. A. The High Chemofidelity of Metal-Catalyzed Hydrogen Atom Transfer Acc. Chem. Res., 2018, 51, 2628–2640. (6) Obradors, C. L.; Martinez, R.; Shenvi, R. A. Ph(i-PrO)SiH2: An Exceptional Reductant for Metal-Catalyzed Hydrogen Atom Transfers. J. Am. Chem. Soc. 2016, 138, 4962-4971. (7) Jeker, O. F.; Carreira, E. M. Total Synthesis and Stereochemical Reassignment of (±)Indoxamycin B. Angew. Chem., Int. Ed. 2012, 51, 3474−3477. (8) Bhunia, A.; Bergander, K.; Daniliuc, C. G.; Studer, A. Fe-Catalyzed Anaerobic Mukaiyama-Type Hydration of Alkenes using Nitroarenes. Angew. Chem. Int. Ed. 2021, 60, 8313–8320. (9) Ali, G.; Cuny, G. D. Syntheses of Gymnothespirolignans B and C and Non-Isomer 9-Epigymnothespirolignan B. J. Org. Chem. 2021, 86, 10517–10525. (10) Huang, S.-H.; Liang, K.-H.; Lu, J.-S.; Chang, W.-S.; Su, M.-D.; Yang, T.-F. Total Synthesis of (+)-Antrocin and Its Diastereomer and Clarification of the Absolute Stereochemistry of (−)-Antrocin. J. Org. Chem. 2017, 82, 9576–9584. (11) Zhao, Y.; Hu, J.; Chen, R.; Xiong, F.; Xie. H.; Ding, H. Divergent Total Syntheses of (−)Crinipellins Facilitated by a HAT-Initiated Dowd–Beckwith Rearrangement. J. Am. Chem. Soc. 2022, 144, 2495–2500. (12) Nishiyama, Y.; Yokoshima, S.; Fukuyama, T. Total Synthesis of (−)-Cardiopetaline. Org. Lett. 2016, 18, 2359–2362. Chapter 6 – End Game (13) 664 Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. Simple, Chemoselective Hydrogenation with Thermodynamic Stereocontrol. J. Am. Chem. Soc. 2014, 136, 1300–1303. (14) Garrett, C. E.; Fu, G. C. Hydroboration of Olefins with Catecholborane at Room Temperature in the Presence of N,N-Dimethylacetamide. J. Org. Chem. 1996, 61, 3224– 3225. (15) Pozzi, D.; Scanlan, E. M.; Renaud, P. A Mild Radical Procedure for the Reduction of BAlkylcatecholborane to Alkanes. J. Am. Chem. Soc. 2005, 127, 14204–14205. (16) Dhillon, R. S. Hydroboration and Organic Synthesis. Springer, © 2007, ISBN 978-3-54049075-3 Springer-Verlag Berlin Hedelberg. (17) Wang, J.; Ma, D. 6-Methylenebicyclo[3.2.1]oct-1-en-3-one: A Twisted Olefin as DielsAlder Dienophile for Expedited Syntheses of Four Kaurane Diterpenoids. Angew. Chem. Int. Ed. 2019, 58, 15731–15735. (18) Takahashi, K.; Watanabe, M.; Honda, T. Highly Efficient Stereocontrolled Total Synthesis of (+)-Upial. Angew. Chem. Int. Ed. 2007, 47, 131–133. (19) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. Osmium Tetroxide-Catalyzed Periodate Oxidation of Olefinic Bonds. J. Am. Chem. Soc. 1956, 21, 478–479. (20) Morrison, E.; Chandler, P. M.; Thomson, R. J.; Mander, L. N. Synthesis and Bioactivity of the Gibberellin, 18-hydroxy-GA1 (GA132). Org. Biomol. Chem. 2008, 6, 1416–1424. (21) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Improved Procedure for the Oxidative Cleavage of Olefin by OsO4-NaIO4. Org. Lett. 2004, 6, 3217–3219. (22) Schröder, M. Osmium Tetoxide Cis Hydroxylation of Unsaturated Substrates. Chem. Rev. 1980, 80, 187–213. Chapter 6 – End Game (23) 665 Shen, Y.; Li, L.; Xiao, X.; Yang, S.; Hua, Y.; Wang, Y.; Zhang, Y.-W.; Zhang, Y. SiteSpecific Photochemical Desaturation Enables Divergent Syntheses of Illicium Sesquiterpenes. J. Am. Chem. Soc. 2021, 143, 3256–3263. (24) Yu, K.; Yang, Z.-N.; Liu, C.-H.; Wu, S.-Q.; Hong, X.; Zhao, X.-L.; Ding, H. Total Syntheses of Rhodomolleins XX and XXII: A Reductive Epoxide-Opening/BeckwithDowd Approach. Angew. Chem. Int. Ed. 2019, 58, 8556–8560. (25) Hu, X.; Musacchio, A. J.; Shen X.; Yao, Y.; Maimone, T. J. Allylative Approaches to the Synthesis of Complex Guaianolide Sesquiterpenes from Apiaceae and Asteraceae. J. Am. Chem. Soc. 2019, 141, 14904–14915. (26) Xiao, S.; Ai, L.; Liu, Q.; Yang, B.; Huang, J.; Xue, W.; Chen, Y. Total Synthesis of Natural Terpenoids Enabled by Cobalt Catalysis. Frontiers in Chemistry. 2022, 10, 1–7. (27) Li, Y.; Fu, Y. Recent Advances in the Cobalt-Catalyzed Regio- or Stereoselective Hydrofunctionalization of Alkenes and Alkynes. CCS. Chem. 2024, 6, 1130–1156. (28) Eggert, A.; Schuppe, K. T.; Fuchs, H. L. S.; Brönstrup, M.; Kalesse, M. Total Synthesis of Acanthodoral Using a Rearrangement Strategy. Org. Lett. 2024, 26, 2893–2896. (29) Zhang, M.; Zhu, Y.; Zhan, G.; Shu, P.; Sa, R.; Lei, L.; Xiang, M.; Xue, Y.; Luo, Z.; Wan, Q.; Yao, G.; Zhang, Y. Micranthanone A, a New Diterpene with an Unprecedented Carbon Skeleton from Rhododendrum micranthum. Org. Lett. 2013, 15, 3094–3097. (30) (a) Iwasaki, K.; Wan, K.; Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. Simple, Chemoselective Hydrogenation with Thermodynamic Stereocontrol. J. Am. Chem. Soc. 2014, 136, 1300−1303. (b) Pan, L.; Schneider, F.; Ottenbruch, M.; Wiechert, R.; List, T.; Schoch, P.; Mertes, B.; Gaich, T. A General Strategy for the Synthesis of Taxane Diterpenes. Nature 2024, 632, 543−549. Chapter 6 – End Game (31) 666 Sun, N.; Zheng, G.; He, M.; Feng, Y.; Liu, J.; Wang, M.; Zhang, H.; Zhou, J.; Yao, G. Grayanane diterpenoids from the leaves of Rhododendron auriculatum and their analgesic activities. J. Nat. Prod. 2019, 82, 1849−1860. 667 Appendix 6 – Spectra Relevant to Chapter 6 Appendix 6 Spectra Relevant to Chapter 6: End Game 9.79 Parameter CDCl3 297.1 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2024-02-06T02 28 23 Solvent Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 8 .5 32768 Acquired Siz e 9.0 1H Nucleus 9.5 8012. 8 Spectral Width 8 .0 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-5-244_pure.1. fid 10.0 Value 7.5 7.0 6.5 6.0 189 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-5-244_pure/ 1/ fid Title 1.00 5.92 1.00 Data File Name 5.5 f1 (ppm) 5.0 4.5 4.0 3 .0 2.5 1.5 2.08 1.03 2.35 4.24 2.73 1.00 3.78 3.73 3.54 3.38 3.25 3.06 1.10 1.16 2.28 3.37 0.94 0.98 4.89 2.08 2.0 1.85 1.00 3 .5 1.27 3.00 1.0 -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 78 .7 1.0000 10.0000 1. 3631 2024-02-06T03 10 46 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 24038 .5 Spectral Width 120 1024 Number of Scans 130 1D Experiment 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 Solvent 189 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-5-244_pure. 2. fid 200.50 Title Value 130.76 / Volumes/ nmrdata-2/ jkthomps/ nmr/ JKT-5-244_pure/ 2/ fid Parameter 126.78 Data File Name 110 f1 (ppm) 100 91.78 90 78.36 80 71.84 70 59.22 60 45.33 52.12 50 40 30 25.16 36.98 42.84 54.39 67.89 84.28 20 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 4.96 4.86 4.81 58 1.0000 5.6500 3 .0000 2024-01-31T16 44 53 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 24000 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 6.0 5.0 4.0 32 Number of Scans 4.5 1D Experiment 5.5 s2pul Pulse Sequence 0.42 192 25.0 Temperature 1.08 1.73 0.61 Spectrometer Frequency 499.55 cdcl3 5.95 Solvent 5.82 1.00 Varian 3.90 3.80 3.75 3.71 Origin 3.55 PROTON01 0.98 1.44 4.20 3.36 3 .5 f1 (ppm) 3 .0 3.38 5.16 / Users/ jordankthompson/ Desktop/ JKT-5-238 _pure/ PROTON01. fid/ fid 2.86 1.76 Title Value 2.71 1.90 Data File Name Parameter 0.37 2.5 2.49 2.37 2.25 2.11 1.96 1.85 1.77 3.52 3.72 1.18 3.00 0.84 1.26 1.5 1.51 1.67 2.0 1.0 0.5 0.21 14.16 0.90 16.86 0.0 0.04 9.78 4.95 8.36 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 180 134.38 133.19 131.82 126.87 125.39 124.14 124.10 64. 2 1.0000 10.0000 1. 3631 2024-05-22T18 39 43 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 100 512 Number of Scans 110 1D Experiment 120 z gpg30 Pulse Sequence 130 297.1 Temperature 140 CDCl3 Solvent 192 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-6-130_pure. 2. fid Origin 175.43 175.42 Title 98.77 98.57 / Volumes/ nmrdata-3/ jkthomps/ nmr/ JKT-6-130_pure/ 2/ fid Value 90 80 83.93 82.79 79.38 77.37 f1 (ppm) 90.21 89.85 Data File Name Parameter 70.32 66.35 65.53 64.48 70 50 40 30 20 10 57.67 57.63 48.08 44.57 43.81 42.95 40.40 39.49 39.27 38.28 38.24 37.73 35.41 34.02 32.85 28.94 28.32 27.04 24.38 23.76 22.20 19.33 19.31 16.71 13.90 12.82 12.75 60 0.00 -0.01 0 -6.01 -6.03 -6.43 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 7.5 1D 64 197.4 1.0000 12.5000 4.0894 2024-02-01T12 01 08 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.04 5.0 4.5 4.0 z g30 Pulse Sequence 5.5 297.1 Temperature 6.0 CDCl3 Solvent 193 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-5-240_pure.1. fid 5.78 1.00 / Users/ jordankthompson/ Desktop/ JKT-5-240_pure/ 1/ fid 4.90 4.81 Title 1.02 3.94 3.79 3.75 3.67 3.53 3.37 3.34 3 .5 0.88 0.95 0.95 1.07 2.06 f1 (ppm) 3 .0 2.71 2.01 3.19 3.14 5.08 Value 4.63 Data File Name Parameter 0.5 1.70 1.01 2.05 1.96 1.11 2.20 2.29 0.98 1.06 5.27 0.0 1.47 0.98 1.0 1.10 1.5 0.88 3.36 3.15 11.26 2.0 0.20 9.05 2.51 2.45 2.5 0.03 5.96 2.88 1.77 1.04 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 87. 8 1.0000 10.0000 1. 3631 2024-08-20T13 27 29 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 24038 .5 Spectral Width 110 100 512 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 140 297. 2 Temperature 193 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 134.33 JKT-6-138 _sm. 2. fid 125.85 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-6-138 _sm/ 2/ fid 100.15 Title Value 90 92.10 91.76 Data File Name Parameter 85.18 84.15 f1 (ppm) 80 71.92 71.85 70 59.17 60 40 49.61 45.39 41.92 41.21 39.86 39.21 38.87 50 30.46 29.84 30 25.89 23.69 22.83 21.84 18.23 20 10 0 1.44 -4.51 -4.56 -4.91 14.27 55.37 67.19 177.04 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 1D 16 90.5 1.0000 9. 8500 3 .9977 2025-05-07T23 28 12 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8196.7 Spectral Width 4.5 z g30 Pulse Sequence 5.0 298 .1 Temperature 5.5 CDCl3 Solvent 194 Bruker BioSpin GmbH & Co. KG Spectrometer Frequency 400.15 JKT-7-188 _pure3 .1. fid 5.76 1.00 Origin 5.18 Title 4.74 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 1/ fid Value 3.93 3.79 3.63 3.52 3.36 Data File Name Parameter 1.01 4.0 3.02 2.05 1.04 2.04 3 .5 f1 (ppm) 3 .0 0.5 1.79 1.69 1.01 1.03 1.98 2.02 2.27 4.01 2.46 2.02 0.0 1.47 1.11 1.0 1.31 3.03 1.5 1.08 3.05 2.0 0.88 9.00 2.5 0.20 0.12 0.02 9.02 9.05 6.02 2.81 2.01 1.04 1.02 -0.5 -20000 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 110000 120000 130000 140000 150000 160000 170000 180000 190000 200000 210000 220000 230000 240000 180 101.0 1.0000 10.0000 1.1796 2025-05-07T23 54 38 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 27777. 8 Spectral Width 110 700 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 140 298 . 2 Temperature 100 194 CDCl3 Solvent Spectrometer Frequency 100.63 Bruker BioSpin GmbH & Co. KG 176.98 JKT-7-188 _pure3 . 2. fid 134.40 Origin 125.92 Title Value 99.88 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 2/ fid Parameter 90 91.83 Data File Name 83.37 82.91 f1 (ppm) 80 70 59.13 60 40 49.53 45.25 41.67 41.31 39.89 39.46 39.25 38.80 50 20 30.45 29.83 25.88 25.62 23.54 20.62 18.21 30 10 2.77 1.46 0 -4.50 -4.90 66.97 71.95 -10 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 cosygpppqf COSY 1 101.0 2.0000 9. 8500 0.1946 2025-05-08T00 00 12 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.14, 5.14) Spectral Siz e Digital Resolution 5.0 (1024, 128) Acquired Siz e 5.5 (1H, 1H) Nucleus 6.0 (-230.7, -230.7) Lowest Frequency 6.5 (5263 . 2, 5263 . 2) Spectral Width 3 .0 f2 (ppm) 298 .1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH & Co. KG Origin 4.5 JKT-7-188 _pure3 . 3 .ser Title Spectrometer Frequency (400.15, 400.15) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 3/ ser Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 0.0 194 -0.5 8 7 6 5 4 3 2 1 0 f1 (ppm) 298 . 2 hmbcgplpndqf HMBC 4 101.0 1.5000 9. 8500 0.5980 2025-05-08T00 19 26 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 512) (1.67, 43 . 24) Spectral Siz e Digital Resolution 4.5 (2048 , 128) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.5 (-245.1, -1007. 3) Lowest Frequency 6.0 (34 24.7, 22138 .1) Spectral Width 3 .0 f2 (ppm) CDCl3 Solvent 3 .5 Bruker BioSpin GmbH & Co. KG Origin 4.0 JKT-7-188 _pure3 .4.ser Title Spectrometer Frequency (400.15, 100.63) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 4/ ser Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 194 0.0 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) HSQC-EDITED 2 32.0 1.5000 9. 8500 0.1946 2025-05-08T00 30 47 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.14, 16. 21) Spectral Siz e Digital Resolution 5.0 (1024, 180) Acquired Siz e 5.5 (1H, 13C) Nucleus 6.0 (-750.9, -755. 3) Lowest Frequency 6.5 (5263 . 2, 16603 . 2) Spectral Width f2 (ppm) hsqcedetgpsisp 2. 3 Pulse Sequence 3 .5 298 . 2 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency (400.15, 100.63) JKT-7-188 _pure3 .5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 194 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) noesygpphzs NOESY 4 64.0 1.5000 9. 8500 0. 2580 2025-05-08T01 10 58 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 . 88 , 3 . 88) Spectral Siz e Digital Resolution 4.5 (1024, 256) Acquired Siz e 5.0 (1H, 1H) Nucleus 5.5 (-103 .4, -103 .4) Lowest Frequency 6.0 (3968 . 3 , 3968 . 3) Spectral Width 3 .0 f2 (ppm) 298 .1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency (400.15, 400.15) JKT-7-188 _pure3 .6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-188 _pure3/ 6/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 194 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 1D 16 127.1 1.0000 8 .7000 4.0894 2025-03-28T09 00 57 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 4.0 z g30 Pulse Sequence 5.0 298 .1 Temperature 5.5 CDCl3 Solvent 197 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-3-7 _crude.1. fid Title 4.83 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-7 _crude/ 1/ fid Value 4.12 Data File Name Parameter 3.38 2.98 3.54 1.92 3.71 3.05 0.0 2.74 1.03 0.5 2.54 1.02 1.0 2.26 2.09 1.5 1.92 3.60 2.0 1.68 3.24 2.5 1.44 1.29 1.16 1.10 1.04 1.97 4.17 3.00 3.12 3 .0 0.89 11.24 3 .5 f1 (ppm) -0.00 6.43 1.00 1.86 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 3500 197.4 1.0000 10.0000 1.1796 2025-03-29T00 03 06 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 27777. 8 Spectral Width 110 100 1D Experiment 120 z gpg30 Pulse Sequence 130 298 .1 Temperature 140 CDCl3 Solvent 197 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-3-7 _crude.6. fid Value Title 176.29 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-7 _crude/ 6/ fid Parameter 100.70 Data File Name 85.01 84.63 91.62 90 f1 (ppm) 79.36 80 71.97 71.87 70 50 59.18 55.07 51.67 51.23 50.37 49.48 60 43.45 42.36 42.22 40.65 40 20 31.16 29.86 25.89 24.81 20.94 18.49 18.22 30 10 0 -4.69 -4.90 67.40 -10 0 500 1000 1500 2000 2500 3000 3 64. 2 1.9205 8 .7000 0. 2765 2025-03-28T09 40 4 2 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .62, 3 .62) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-4 26.9, -4 28 .0) Lowest Frequency 7.5 (3703 .7, 3703 .7) Spectral Width f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 298 .1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-3-7 _crude. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-7 _crude/ 3/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 197 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 4 197.4 1.5000 8 .7000 0. 2135 2025-03-28T10 03 17 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.0 (1H, 13C) Nucleus 4.5 (-517.1, -1262. 8) Lowest Frequency 5.0 (4795.4, 16611. 3) Spectral Width 2.5 f2 (ppm) 298 . 2 Temperature 3 .0 CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-3-7 _crude.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-7 _crude/ 4/ ser Parameter Data File Name 2.0 1.5 1.0 0.5 197 0.0 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 98 .9 1. 8000 8 .7000 0. 2560 2025-03-28T14 51 18 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 (3 .91, 3 .91) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 256) Acquired Siz e 5.0 (1H, 1H) Nucleus 5.2 (-158 .1, -158 .1) Lowest Frequency 5.4 (4000.0, 4000.0) Spectral Width 2. 8 2.6 f2 (ppm) 4 Number of Scans 3 .0 NOESY Experiment 3 .2 noesygpphzs Pulse Sequence 3 .4 298 .1 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin 4.0 JKT-3-7 _crude.5.ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-7 _crude/ 5/ ser Value Data File Name Parameter 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 197 0.2 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 8 .7000 4.0894 2025-03-21T21 05 11 Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 1.0000 Relaxation Delay 5.0 112. 8 Receiver Gain 5.5 16 Number of Scans 198 1D Spectrometer Frequency 400.13 z g30 5.19 Experiment 4.65 Pulse Sequence 4.07 298 .1 1.06 4.0 3 .5 f1 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 3.81 1.00 Temperature 3.58 4.15 CDCl3 3.39 3.22 Solvent 2.80 1.03 Bruker BioSpin GmbH 2.53 2.40 2.24 1.01 0.99 1.00 Origin 2.06 1.01 JKT-7-107 _pure.1. fid 1.85 1.96 Title Value 1.65 6.06 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 1/ fid Parameter 1.43 1.28 1.19 1.17 1.03 0.87 0.95 1.17 3.04 3.00 3.04 9.69 Data File Name 0.16 0.08 0.01 -0.02 9.79 9.03 6.33 1.00 1.00 -0.5 -1000 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 8000 176.55 3000 197.4 1.0000 10.0000 1.1796 2025-03-21T22 58 33 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 27777. 8 Spectral Width 110 100 1D Experiment 120 z gpg30 Pulse Sequence 130 298 . 2 Temperature 140 CDCl3 Solvent 198 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-107 _pure. 2. fid Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 2/ fid Parameter 101.52 Data File Name 85.16 83.82 83.57 91.71 90 f1 (ppm) 80 73.08 72.06 70 50 59.13 55.19 51.62 51.15 51.05 49.51 60 45.10 43.77 41.33 40.72 40 33.51 29.85 25.90 25.82 24.65 30 20.50 18.21 20 10 2.74 0.79 0 -4.70 -4.90 66.47 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 COSY 1 64. 2 1.9226 8 .7000 0. 2744 2025-03-21T23 04 12 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 .64, 3 .64) Acquired Siz e Spectral Siz e Digital Resolution 4.0 (1H, 1H) Nucleus 4.5 (-523 .1, -523 .1) Lowest Frequency 5.0 (3731. 3 , 3731. 3) Spectral Width f2 (ppm) cosygpppqf Pulse Sequence 2.5 298 .1 Temperature 3 .0 CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-107 _pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 3/ ser Parameter Data File Name 2.0 1.5 1.0 0.5 0.0 198 -0.5 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 f1 (ppm) 1.5000 8 .7000 0. 2135 2025-03-21T23 26 22 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 4.0 (4.68 , 16. 22) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 180) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.2 (-590. 2, -1243 .7) Lowest Frequency 5.4 (4795.4, 16611. 3) Spectral Width 2.6 2.4 f2 (ppm) 197.4 Receiver Gain 2. 8 4 Number of Scans 3 .0 HSQC-EDITED Experiment 3 .2 hsqcedetgpsisp 2.4 Pulse Sequence 3 .4 298 . 2 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-107 _pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 4/ ser Parameter Data File Name 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 198 0.2 0.0 -0.2 90 80 70 60 50 40 30 20 10 0 f1 (ppm) HMBC 5 197.4 2.0000 8 .7000 0.4 260 2025-03-22T00 20 49 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 256) (2048 , 1024) (2. 35, 21. 80) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-237. 8 , -1110.0) Lowest Frequency 5.5 (4807.7, 22321.4) Spectral Width f2 (ppm) hmbcetgpl3nd Pulse Sequence 3 .0 298 .1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-107 _pure.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 5/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 198 0.0 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 64. 2 1. 8000 8 .7000 0. 2560 2025-03-22T01 28 22 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 4.0 (3 .91, 3 .91) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 256) Acquired Siz e 5.0 (1H, 1H) Nucleus 5.2 (-166.6, -163 . 8) Lowest Frequency 5.4 (4000.0, 4000.0) Spectral Width 2. 8 2.6 f2 (ppm) 6 Number of Scans 3 .0 NOESY Experiment 3 .2 noesygpphzs Pulse Sequence 3 .4 298 . 2 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-107 _pure.6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _pure/ 6/ ser Parameter Data File Name 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 198 0.4 0.2 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) hmbcetgpl3nd HMBC 12 197.4 2.0000 8 .7000 0.4 260 2025-03-22T12 52 28 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 256) (2048 , 1024) (2. 35, 21. 80) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-234.7, -1116.4) Lowest Frequency 5.5 (4807.7, 22321.4) Spectral Width f2 (ppm) 298 .1 Temperature 3 .0 CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-7-107 _HMBC. 2.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-107 _HMBC/ 2/ ser Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 198 0.0 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1D 16 112. 8 1.0000 12.5000 4.0894 2025-07-09T04 33 02 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 4.0 z g30 Pulse Sequence 5.0 297. 2 Temperature 5.5 CDCl3 Solvent 199 Bruker BioSpin GmbH Spectrometer Frequency 400.13 JKT-7-269_pure.1. fid Origin 5.32 1.00 Title Value 4.87 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-269_pure/ 1/ fid Parameter 4.25 Data File Name 2.0 1.5 0.5 2.30 2.19 2.08 2.01 1.11 2.01 2.53 2.01 2.94 0.94 3.09 1.00 3.38 3.02 3.78 3.68 3.54 1.02 2.01 2.05 0.0 1.72 2.02 1.0 1.39 1.05 2.5 1.19 1.06 0.91 0.87 3.14 3.23 3.14 9.63 3 .0 0.17 9.20 3 .5 f1 (ppm) 0.00 6.12 1.03 2.03 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 180 122.84 750 64. 2 1.0000 10.0000 1.1796 2025-07-09T05 01 33 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 27777. 8 Spectral Width 110 100 1D Experiment 120 z gpg30 Pulse Sequence 130 297.1 Temperature 140 CDCl3 Solvent 199 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-269_pure. 2. fid 177.12 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-269_pure/ 2/ fid 145.95 Title Value 98.92 Data File Name Parameter 85.81 82.97 91.67 90 f1 (ppm) 78.03 80 71.85 71.02 67.62 70 59.17 58.80 57.69 60 40 49.93 48.08 44.56 42.67 42.21 39.70 50 30 18.48 18.04 20 10 1.35 0 -4.59 -4.98 25.76 24.48 24.40 35.23 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 COSY 3 64. 2 1.9554 12.5000 0. 2417 2025-07-09T05 16 49 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (4.14, 4.14) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 1H) Nucleus 5.0 (-654.9, -658 .7) Lowest Frequency 5.5 (4 237. 3 , 4 237. 3) Spectral Width f2 (ppm) cosygpppqf Pulse Sequence 3 .0 297. 2 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-269_pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-269_pure/ 3/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 199 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 f1 (ppm) 1.5000 12.5000 0. 2135 2025-07-09T05 49 29 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.2 4.0 (4.68 , 16. 22) Digital Resolution 4.4 (1024, 1024) Spectral Siz e 4.6 (1024, 180) Acquired Siz e 4. 8 (1H, 13C) Nucleus 5.0 (-594.5, -1262. 8) Lowest Frequency 5.2 (4795.4, 16611. 3) Spectral Width 2.6 2.4 f2 (ppm) 197.4 Receiver Gain 2. 8 6 Number of Scans 3 .0 HSQC-EDITED Experiment 3 .2 hsqcedetgpsisp 2.4 Pulse Sequence 3 .4 297.1 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-269_pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-269_pure/ 4/ ser Parameter Data File Name 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 0.2 199 0.0 -0.2 -0.4 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1D 16 101.0 1.0000 9. 8500 3 .9977 2025-06-04T16 05 12 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8196.7 Spectral Width 4.5 4.0 z g30 Pulse Sequence 5.0 298 . 2 Temperature 5.5 CDCl3 Solvent 200 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency 400.15 JKT-7-243 _pure.1. fid 5.33 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 1/ fid 4.88 Title Value 4.29 Data File Name Parameter 2.0 1.5 0.5 2.33 3.01 2.51 2.00 2.93 0.98 3.12 1.00 3.38 3.08 3.54 2.02 3.74 3.05 0.0 2.09 2.00 1.0 1.76 2.07 2.5 1.41 1.11 3 .0 1.21 1.05 0.99 0.87 3.18 3.02 3.05 9.10 3 .5 f1 (ppm) 0.01 6.01 1.00 2.01 0.99 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 177.07 123.32 750 101.0 2.0000 10.0000 1.1796 2025-06-04T16 47 36 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 27777. 8 Spectral Width 110 100 1D Experiment 120 z gpg30 Pulse Sequence 130 298 .1 Temperature 140 CDCl3 Solvent 200 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency 100.63 JKT-7-243 _pure. 2. fid Title 146.01 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 2/ fid Value 98.20 Data File Name Parameter 80 85.86 82.21 78.02 91.61 90 f1 (ppm) 71.89 69.89 67.60 70 59.17 58.50 56.65 60 40 49.30 47.70 44.66 42.24 42.07 39.18 35.45 50 30 18.61 18.05 20 10 0 -4.52 -4.94 25.79 24.34 24.03 -10 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 COSY 1 101.0 2.0000 9. 8500 0.1946 2025-06-04T20 24 21 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.14, 5.14) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-230.7, -230.7) Lowest Frequency 7.5 (5263 . 2, 5263 . 2) Spectral Width f2 (ppm) cosygpppqf Pulse Sequence 4.0 298 . 2 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH & Co. KG Origin 5.5 JKT-7-243 _pure. 3 .ser Title Spectrometer Frequency (400.15, 400.15) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 3/ ser Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 200 0.0 8 7 6 5 4 3 2 1 0 f1 (ppm) HMBC 4 101.0 1.5000 9. 8500 0.5980 2025-06-04T20 44 10 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 512) (1.67, 43 . 24) Spectral Siz e Digital Resolution 6.0 (2048 , 128) Acquired Siz e 6.5 (1H, 13C) Nucleus 7.0 (-263 .4, -1007. 3) Lowest Frequency 7.5 (34 24.7, 22138 .1) Spectral Width 3 .5 f2 (ppm) hmbcgplpndqf Pulse Sequence 4.0 298 . 2 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH & Co. KG Origin 5.5 JKT-7-243 _pure.4.ser Title Spectrometer Frequency (400.15, 100.63) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 4/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 200 0.0 -0.5 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 7.5 298 . 2 hsqcedetgpsisp 2. 3 HSQC-EDITED 4 101.0 1.5000 9. 8500 0.1946 2025-06-04T21 14 39 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 256) (1024, 1024) (5.14, 16. 21) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 13C) Nucleus 6.5 (-750.9, -755. 3) Lowest Frequency 7.0 (5263 . 2, 16603 . 2) Spectral Width 4.5 f2 (ppm) CDCl3 Solvent 5.0 Bruker BioSpin GmbH & Co. KG Origin 5.5 JKT-7-243 _pure.5.ser Title Spectrometer Frequency (400.15, 100.63) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 5/ ser Value Data File Name Parameter 4.0 3 .5 3 .0 2.5 200 2.0 150 140 130 120 110 100 90 80 70 60 50 40 30 f1 (ppm) 4 101.0 1. 8239 9. 8500 0.4301 2025-06-04T22 00 56 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4. 8 4.6 (2. 33 , 2. 33) Digital Resolution 5.0 (1024, 1024) Spectral Siz e 5.2 (1024, 256) Acquired Siz e 5.4 (1H, 1H) Nucleus 5.6 (23 .5, 23 .5) Lowest Frequency 5. 8 (2381.0, 2381.0) Spectral Width 3 .4 3 .2 f2 (ppm) NOESY Experiment 3 .6 noesygpphpp Pulse Sequence 3.8 298 .1 Temperature 4.0 CDCl3 Solvent 4.2 Bruker BioSpin GmbH & Co. KG 4.4 JKT-7-243 _pure.6.ser Origin Spectrometer Frequency (400.15, 400.15) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-243 _pure/ 6/ ser Title Value Data File Name Parameter 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 200 1.0 0. 8 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 1D 16 197.4 1.0000 12.5000 4.0894 2025-07-16T06 29 08 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 32768 65536 6.0 Nucleus Acquired Siz e Spectral Siz e 7.0 6.5 8012. 8 Spectral Width 4.5 4.0 z g30 Pulse Sequence 5.0 297.1 Temperature 5.5 CDCl3 Solvent 201 Bruker BioSpin GmbH Spectrometer Frequency 400.13 JKT-7-287 _pure.1. fid 3 .5 f1 (ppm) 2.95 3 .0 3.72 3.03 Origin 3.53 2.06 Title 2.62 2.54 2.42 2.27 1.03 1.04 1.02 2.5 1.05 4.82 Value 3.38 3.01 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-287 _pure/ 1/ fid Parameter 3.07 1.00 1.02 Data File Name 2.0 1.0 0.5 1.15 3.01 1.50 1.40 1.33 1.03 1.05 3.01 1.93 1.82 1.67 3.00 2.01 2.00 0.0 0.88 0.84 9.02 3.02 1.5 0.01 6.00 2.02 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 210 64. 2 0. 3000 10.0000 1.1796 2025-07-16T22 45 33 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 27777. 8 Spectral Width 130 110 4000 Number of Scans 120 1D Experiment 140 z gpg30 Pulse Sequence 150 297. 2 Temperature 160 CDCl3 201 Bruker BioSpin GmbH Solvent Spectrometer Frequency 100.62 JKT-7-287 _pure. 2. fid Origin Value Title 202.33 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-287 _pure/ 2/ fid Parameter 176.22 Data File Name 91.59 96.97 100 90 f1 (ppm) 84.50 82.78 79.42 80 71.83 70 50 40 59.18 56.70 54.47 50.96 50.12 49.70 46.50 43.27 42.44 40.23 60 20 30.82 25.78 25.77 22.32 20.84 18.51 18.06 30 10 0 -4.65 -4.98 67.44 -10 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 HSQC-EDITED 8 197.4 1.5000 12.5000 0. 2135 2025-07-16T07 12 20 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-527. 2, -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width f2 (ppm) hsqcedetgpsisp 2.4 Pulse Sequence 3 .0 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-287 _pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-287 _pure/ 3/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 0.0 201 -0.5 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) COSY 2 156. 2 2.0000 12.5000 0.1970 2025-07-17T00 25 24 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.08 , 5.08) Spectral Siz e Digital Resolution 6.5 (1024, 128) Acquired Siz e 7.0 (1H, 1H) Nucleus 7.5 (-211. 2, -216.7) Lowest Frequency 8 .0 (5197.5, 5197.5) Spectral Width 6.0 4.0 f2 (ppm) cosygpppqf Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-287 _pure.6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-287 _pure/ 6/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 201 0.0 8 7 6 5 4 3 2 1 0 f1 (ppm) 297. 2 hmbcetgpl3nd HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-07-16T23 29 23 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.5 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 (2. 35, 21. 80) Digital Resolution 6.0 (2048 , 1024) Spectral Siz e 6.5 (2048 , 256) Acquired Siz e 7.0 (1H, 13C) Nucleus 7.5 (-173 .7, -1116.4) Lowest Frequency 201 90 (4807.7, 22321.4) Spectral Width 200 190 180 170 160 150 140 130 120 110 100 80 70 60 50 40 30 20 10 0 Spectrometer Frequency (400.13 , 100.62) f2 (ppm) CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-7-287 _pure.4.ser 5.0 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-287 _pure/ 4/ ser Title Value Data File Name Parameter f1 (ppm) 5.0 4. 8 4.6 4.4 4.2 4.0 3.8 3 .6 3 .4 3 .2 3 .0 2. 8 2.6 2.4 f2 (ppm) 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 201 0.2 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) s2pul 1D 8 60 1.0000 3 . 3500 3 .0000 2025-05-15T11 21 14 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 24000 Acquired Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 5.5 0.99 5.0 4.0 25.0 Temperature 4.5 cdcl3 Solvent 202 Varian Origin Spectrometer Frequency 499.54 PROTON01 5.44 1.00 Title 2.53 4.97 3.05 0.96 3.18 0.98 3.36 3.03 3.49 2.15 1.5 2.29 2.03 2.0 2.05 1.00 2.5 1.78 1.02 3 .0 1.44 1.02 2.98 3 .5 f1 (ppm) 2.85 4.95 / Users/ jordankthompson/ Desktop/ JKT-7-199-1/ PROTON01. fid/ fid 4.36 1.01 1.09 0.93 0.88 1.0 3.38 9.88 4.77 Value 3.73 Data File Name Parameter 0.5 0.22 9.05 0.0 0.01 6.03 1.01 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 8000 220 72.0 1.0000 10.0000 1.1796 2025-05-16T21 25 14 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27777. 8 Spectral Width 130 750 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297.1 Temperature 170 CDCl3 Solvent 120 202 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-7-206 _pure. 2. fid 214.95 Origin 176.54 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-206 _pure/ 2/ fid 143.90 Title Value 123.44 Data File Name Parameter 110 98.88 100 f1 (ppm) 91.49 90 83.72 82.85 80 71.75 70.92 67.60 70 50 40 59.10 57.47 55.29 50.01 48.70 44.85 42.32 39.72 39.68 37.03 60 30 18.45 18.04 20 10 1.38 0 -4.56 -4.98 25.76 24.38 -10 0 50 100 150 200 250 300 350 400 450 500 550 6.0 hsqcedetgpsisp 2.4 HSQC-EDITED 4 197.4 1.5000 12.5000 0. 2135 2025-05-17T06 26 55 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-531.0, -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width 3 .0 f2 (ppm) 297. 2 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-206 _pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-206 _pure/ 3/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 202 0.5 0.0 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1.0000 12.5000 4.0894 2025-05-18T16 55 00 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.0 197.4 Receiver Gain 5.5 16 Number of Scans 4.5 204 1D Spectrometer Frequency 400.13 z g30 4.90 Experiment 4.74 Pulse Sequence 4.0 3 .5 f1 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 4.10 1.02 297.1 3.72 3.62 3.50 3.37 2.01 1.01 2.04 3.01 Temperature 2.84 0.99 CDCl3 2.57 2.01 Bruker BioSpin GmbH 2.34 1.01 Solvent 2.11 2.02 Origin 1.82 8.01 JKT-7-209-2.1. fid 1.29 1.16 1.04 1.03 3.01 3.02 Title 0.87 9.34 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 1/ fid Value 0.16 9.04 Data File Name Parameter 0.01 6.15 1.00 0.98 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 220 72.0 1.0000 10.0000 1.1796 2025-05-18T17 32 51 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 180 65536 Spectral Siz e 190 32768 Acquired Siz e 200 13C Nucleus 210 27777. 8 Spectral Width 130 120 1000 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 170 CDCl3 Solvent 204 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-209-2. 2. fid Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 2/ fid 214.56 Title 175.59 Data File Name Parameter 110 101.03 100 f1 (ppm) 91.28 90 80 72.45 71.81 67.34 70 50 40 59.11 55.03 51.83 51.01 50.76 48.40 43.52 43.03 40.54 39.25 60 20 25.85 25.64 24.72 18.28 18.21 30 10 0.85 0 -4.67 -4.93 33.61 84.90 83.57 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 1.5000 12.5000 0. 2135 2025-05-18T17 55 04 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.2 4.0 (4.68 , 16. 22) Digital Resolution 4.4 (1024, 1024) Spectral Siz e 4.6 (1024, 180) Acquired Siz e 4. 8 (1H, 13C) Nucleus 5.0 (-527.7, -1250. 8) Lowest Frequency 5.2 (4795.4, 16611. 3) Spectral Width 2.6 2.4 f2 (ppm) 197.4 Receiver Gain 2. 8 4 Number of Scans 3 .0 HSQC-EDITED Experiment 3 .2 hsqcedetgpsisp 2.4 Pulse Sequence 3 .4 297. 2 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-209-2. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 3/ ser Parameter Data File Name 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 204 0.2 0.0 -0.2 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 197.4 1. 8000 12.5000 0. 2560 2025-05-18T21 48 01 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.2 4.0 (3 .91, 3 .91) Digital Resolution 4.4 (1024, 1024) Spectral Siz e 4.6 (1024, 256) Acquired Siz e 4. 8 (1H, 1H) Nucleus 5.0 (-168 .0, -168 . 3) Lowest Frequency 5.2 (4000.0, 4000.0) Spectral Width 2. 8 4 Number of Scans 3 .0 NOESY Experiment 3 .2 noesygpphzs Pulse Sequence 3 .4 297.1 Temperature 3 .6 CDCl3 Solvent 3.8 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-209-2.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 4/ ser Parameter Data File Name 2.6 f2 (ppm) 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 204 0.2 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 297. 2 cosygpppqf COSY 1 197.4 1.9205 12.5000 0. 2765 2025-05-18T21 53 38 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 .62, 3 .62) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 1H) Nucleus 5.0 (-4 28 . 3 , -4 28 .7) Lowest Frequency 5.5 (3703 .7, 3703 .7) Spectral Width 3 .0 CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-7-209-2.5.ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 5/ ser Title Value Data File Name Parameter f2 (ppm) 2.5 2.0 1.5 1.0 0.5 204 0.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 2.0000 12.5000 0.4 260 2025-05-18T22 37 24 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 (2. 35, 21. 80) Digital Resolution 4.6 (2048 , 1024) Spectral Siz e 4. 8 (2048 , 256) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.2 (-175. 3 , -1116.4) Lowest Frequency 5.4 (4807.7, 22321.4) Spectral Width 2. 8 2.6 f2 (ppm) 197.4 Receiver Gain 3 .0 4 Number of Scans 3 .2 HMBC Experiment 3 .4 hmbcetgpl3nd Pulse Sequence 3 .6 297.1 Temperature 3.8 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-209-2.6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-209-2/ 6/ ser Parameter Data File Name 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 204 0.2 0.0 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1.0000 12.5000 4.0894 2025-05-21T14 55 08 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 65536 Spectral Siz e 4.6 32768 Acquired Siz e 4. 8 1H Nucleus 5.0 8012. 8 Spectral Width 4.0 2. 8 197.4 Receiver Gain 3 .0 16 Number of Scans 3 .2 1D Experiment 3 .4 z g30 Pulse Sequence 3 .6 297. 2 Temperature 3.8 Me OD Solvent Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 3.97 1.00 JKT-7-213-1.1. fid 3.71 1.02 Title Value 2.94 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-7-213-1/ 1/ fid 2.64 2.6 0.99 4.87 CD3OD Parameter 204' 2.42 2.4 f1 (ppm) 1.96 Data File Name 2.2 1.6 1.0 0. 8 0.6 0.4 0.2 2.15 2.06 1.99 1.06 1.04 0.97 0.0 1.87 1.82 1.75 1.70 1.09 2.83 1.04 2.12 1.2 1.36 1.02 1.4 1.22 1.15 3.00 2.98 1. 8 0.87 9.64 2.0 0.02 6.14 0.99 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 230 87. 8 1.0000 10.0000 1.1796 2025-05-22T01 11 07 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 190 65536 Spectral Siz e 200 32768 Acquired Siz e 210 13C Nucleus 220 27777. 8 Spectral Width 130 3000 Number of Scans 140 1D Experiment 150 z gpg30 Pulse Sequence 160 297. 2 Temperature 170 Me OD Solvent 180 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-213-1.7. fid Value Title 219.68 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-213-1/ 7/ fid Parameter 178.72 Data File Name 120 103.31 110 f1 (ppm) 100 204' 90 80.00 80 71.90 70 50 40 30 56.60 55.35 52.35 50.42 49.71 49.50 49.00 CD3OD 44.51 43.36 41.55 40.00 36.09 30.78 26.78 26.35 25.05 60 19.03 18.71 20 10 0 -4.61 -4.88 86.49 -10 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 hsqcedetgpsisp 2.4 HSQC-EDITED 8 197.4 1.5000 12.5000 0. 2135 2025-05-22T01 54 23 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1H, 13C) (1024, 180) (1024, 1024) (4.68 , 16. 22) Nucleus Acquired Siz e Spectral Siz e Digital Resolution 4.0 (-529. 2, -1155.4) Lowest Frequency 4.5 (4795.4, 16611. 3) Spectral Width 2.5 297.1 Temperature 3 .0 Me OD Solvent 3 .5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-213-1. 8 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-213-1/ 8/ ser Parameter Data File Name f2 (ppm) 2.0 1.5 1.0 0.5 204' 0.0 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1 156. 2 1.7874 12.5000 0.4096 2025-05-21T22 32 22 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 3 .6 (2.44, 2.44) Digital Resolution 3.8 (1024, 1024) Spectral Siz e 4.0 (1024, 128) Acquired Siz e 4.2 (1H, 1H) Nucleus 4.4 (-276. 8 , -276. 8) Lowest Frequency 4.6 (2500.0, 2500.0) Spectral Width 2.4 COSY Experiment 2.6 cosygpppqf Pulse Sequence 2. 8 297.1 Temperature 3 .0 Me OD Solvent 3 .2 Bruker BioSpin GmbH Origin 3 .4 JKT-7-213-1. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-213-1/ 3/ ser Title Value Data File Name Parameter 2.2 f2 (ppm) 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 0.2 204' 0.0 -0.2 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) NOESY 4 197.4 1. 8000 12.5000 0. 2560 2025-05-21T23 17 58 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 3 .4 (3 .91, 3 .91) Digital Resolution 3 .6 (1024, 1024) Spectral Siz e 3.8 (1024, 256) Acquired Siz e 4.0 (1H, 1H) Nucleus 4.2 (-169. 3 , -171.4) Lowest Frequency 4.4 (4000.0, 4000.0) Spectral Width 2.4 noesygpphzs Pulse Sequence 2.6 297. 2 Temperature 2. 8 Me OD Solvent 3 .0 Bruker BioSpin GmbH Origin 3 .2 JKT-7-213-1.6.ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-213-1/ 6/ ser Value Data File Name Parameter 2.2 2.0 f2 (ppm) 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 0.2 204' 0.0 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 197.4 2.0000 12.5000 0.4 260 2025-05-22T03 20 57 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.2 4.0 (2. 35, 21. 80) Digital Resolution 4.4 (2048 , 1024) Spectral Siz e 4.6 (2048 , 256) Acquired Siz e 4. 8 (1H, 13C) Nucleus 5.0 (-175.7, -1116.4) Lowest Frequency 5.2 (4807.7, 22321.4) Spectral Width 2.6 2.4 f2 (ppm) 8 Number of Scans 2. 8 HMBC Experiment 3 .0 hmbcetgpl3nd Pulse Sequence 3 .2 297. 2 Temperature 3 .4 Me OD Solvent 3 .6 Bruker BioSpin GmbH Origin 3.8 JKT-7-213-1.9.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-213-1/ 9/ ser Value Data File Name Parameter 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 204' 0.2 0.0 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) 1D 16 197.4 1.0000 12.5000 4.0894 2025-03-01T10 04 06 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 1.00 1.99 5.0 4.0 z g30 Pulse Sequence 4.5 297.1 Temperature 5.5 CDCl3 Solvent 205 Bruker BioSpin GmbH Origin 0.99 Spectrometer Frequency 400.13 JKT-7-73 _pure.1. fid 5.38 1.01 / Users/ jordankthompson/ Desktop/ JKT-7-73 _pure/ 1/ fid 4.72 Title 0.5 3.83 3.73 3.62 3.54 3.38 1.01 0.99 1.06 2.01 3.05 0.0 3.14 0.99 1.0 2.94 0.98 1.5 2.70 2.56 2.50 2.39 2.24 1.98 1.00 3.01 2.0 2.04 1.01 2.5 1.75 1.03 3 .0 1.42 0.99 3 .5 f1 (ppm) 1.05 1.00 0.87 3.00 2.96 9.04 1.03 5.04 4.93 Value 4.30 Data File Name Parameter 0.01 6.02 0.99 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 124.39 1.0000 10.0000 1.1796 2025-03-01T10 50 57 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 27777. 8 Spectral Width 100 72.0 Receiver Gain 110 1200 Number of Scans 120 1D Experiment 130 z gpg30 Pulse Sequence 140 297. 2 Temperature 205 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 177.07 JKT-7-73 _pure. 2. fid 152.12 Origin 143.03 Title 106.91 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-73 _pure/ 2/ fid Value 98.22 Data File Name Parameter 85.03 82.19 91.09 90 f1 (ppm) 80 71.98 69.95 66.99 70 59.11 56.68 60 40 50.67 50.45 49.27 45.12 43.65 42.22 41.71 39.16 50 30 18.59 18.07 20 10 0 -4.50 -4.93 25.82 24.08 -10 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 1.0000 5.4000 1.7080 2025-04-04T08 46 47 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 16384 Acquired Siz e 6.5 1H Nucleus 7.0 9592. 3 Spectral Width 1.01 1.00 1.01 5.0 4.5 1.03 1.00 1.05 2.04 2.99 1.01 1.01 1.02 3 .5 f1 (ppm) 2.5 34 Receiver Gain 3 .0 8 Number of Scans 4.0 1D Experiment 5.5 s2pul Pulse Sequence 206 25.0 Temperature Spectrometer Frequency 599.55 cdcl3 5.65 1.00 Solvent 5.07 4.99 4.90 Varian 4.70 Origin 3.81 3.74 3.64 3.53 3.38 3.29 3.22 3.13 JKT-7-134_pure_RR-PROTON_ 01 2.62 / Users/ jordankthompson/ Desktop/ JKT-7-134_pure_RR_20250404_ 01/ JKT-7-134_pure_RR-PROTON_ 01. fid/ fid 2.45 2.33 2.20 2.12 Title Value 1.95 Data File Name Parameter 1.00 2.0 0.5 0.0 1.44 1.34 1.06 3.05 1.0 0.90 0.88 3.00 9.02 1.5 0.02 5.93 1.04 1.04 1.03 1.03 3.14 1.02 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 210 170 65536 Spectral Siz e 180 32768 Acquired Siz e 190 13C Nucleus 200 4 2964.6 Spectral Width 120 110 100 f1 (ppm) 90 80 70 60 2025-04-03T17 09 05 Acquisition Date 130 0.7627 Acquisition Time 140 4.7250 Pulse Width 150 1.0000 Relaxation Delay 160 30 Receiver Gain 206 256 Number of Scans Spectrometer Frequency 150.77 1D Experiment 203.20 s2pul 175.87 25.0 151.83 Pulse Sequence 139.29 Temperature 127.78 cdcl3 109.21 Varian 97.45 Solvent 91.15 Origin 82.95 82.62 JKT-7-134_pure-CARBON_ 01 71.94 Title 67.19 / Users/ jordankthompson/ Desktop/ JKT-7-134_pure_20250403 _ 01/ JKT-7-134_pure-CARBON_ 01. fid/ fid Value 50 40 59.15 59.14 53.42 49.76 49.71 47.49 44.68 44.58 43.05 39.85 Data File Name Parameter 30 25.76 22.53 18.52 18.06 20 10 0 -4.63 -4.96 -10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2025-03-07T03 28 43 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency 400.13 JKT-7-92_pure.1. fid Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 1/ fid Parameter 5.68 1.00 Data File Name 3.76 1.05 4.0 f1 (ppm) 208 1.66 3 .5 3 .0 2.5 2.0 1.5 1.25 1.14 10.03 1.70 1.59 1.43 1.71 2.16 4.17 2.41 2.33 1.03 1.10 2.82 2.01 3.38 1.00 3.12 1.0 0.5 -5000 -4000 -3000 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 218.65 1.0000 10.0000 1.1796 2025-03-07T05 22 53 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 200 65536 Spectral Siz e 210 32768 Acquired Siz e 220 13C Nucleus 230 27777. 8 Spectral Width 128.15 130 72.0 Receiver Gain 140 3000 Number of Scans 150 1D Experiment 160 z gpg30 Pulse Sequence 170 297.1 Temperature 180 CDCl3 Solvent 190 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-7-92_pure. 2. fid 205.21 Title 177.18 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 2/ fid Value 139.20 Data File Name Parameter 120 f1 (ppm) 208 110 100.11 100 90 80 70 50 40 58.13 54.56 50.55 50.28 48.94 48.09 44.69 40.96 40.29 38.88 60 30 20 23.20 20.35 16.97 82.82 10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 1.5000 12.5000 0. 2135 2025-03-07T06 00 25 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 4. 8 (4.68 , 16. 22) Digital Resolution 5.2 (1024, 1024) Spectral Siz e 5.4 (1024, 180) Acquired Siz e 5.6 (1H, 13C) Nucleus 5. 8 (-528 .1, -1262. 8) Lowest Frequency 6.0 (4795.4, 16611. 3) Spectral Width 3 .4 3 .2 f2 (ppm) 197.4 Receiver Gain 3 .6 4 Number of Scans 3.8 HSQC-EDITED Experiment 4.0 hsqcedetgpsisp 2.4 Pulse Sequence 4.2 297.1 Temperature 4.4 CDCl3 Solvent 4.6 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-92_pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 4/ ser Parameter Data File Name 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 208 0. 8 0.6 0.4 130 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) cosygpppqf COSY 3 197.4 1. 8980 12.5000 0. 2990 2025-03-07T05 38 15 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 . 34, 3 . 34) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 1H) Nucleus 5.5 (-112. 8 , -113 .4) Lowest Frequency 6.0 (34 24.7, 34 24.7) Spectral Width 3 .5 f2 (ppm) 297. 2 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-92_pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 208 0.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) hmbcetgpl3nd HMBC 6 197.4 2.0000 12.5000 0.4 260 2025-03-07T07 05 34 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 256) (2048 , 1024) (2. 35, 21. 80) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 13C) Nucleus 5.5 (-174.5, -1116.4) Lowest Frequency 6.0 (4807.7, 22321.4) Spectral Width 3 .5 f2 (ppm) 297. 2 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-92_pure.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 208 1.0 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) NOESY 6 197.4 1. 8000 12.5000 0. 2560 2025-03-07T08 13 09 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 256) (1024, 1024) (3 .91, 3 .91) Acquired Siz e Spectral Siz e Digital Resolution 6.0 (1H, 1H) Nucleus 6.5 (-168 . 3 , -168 .5) Lowest Frequency 7.0 (4000.0, 4000.0) Spectral Width 4.0 f2 (ppm) noesygpphzs Pulse Sequence 4.5 297.1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-92_pure.6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-92_pure/ 6/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 208 1.0 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) 5.04 4.93 8 58 1.0000 3 . 3500 3 .0000 2025-04-04T09 47 41 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 24000 Acquired Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 1.29 1.82 5.0 4.0 1D Experiment 4.5 s2pul Pulse Sequence 5.5 25.0 Temperature 209 cdcl3 1.00 Spectrometer Frequency 499.54 Varian Solvent 5.33 1.05 Origin 4.13 PROTON01 3.84 Title 3.62 3.54 / Users/ jordankthompson/ Desktop/ JKT-3-11-1_pure/ PROTON01. fid/ fid 1.03 2.09 3 .5 f1 (ppm) 3.00 4.72 Value 3.38 Data File Name Parameter 0.79 3 .0 2.00 0.93 2.80 2.65 2.56 2.43 2.29 2.16 0.91 1.17 1.90 0.92 2.30 1.06 2.0 1.88 1.10 2.5 1.5 0.5 0.95 0.92 3.02 9.05 1.11 2.99 1.0 0.10 5.91 1.26 2.02 0.95 0.0 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 177.95 106.12 102.66 99.66 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 43715. 8 Spectral Width 120 70 60 50 40 2025-04-04T11 24 04 Acquisition Date 80 0.7496 Acquisition Time 90 f1 (ppm) 4.7250 Pulse Width 100 1.0000 Relaxation Delay 110 30 Receiver Gain 130 2000 Number of Scans 140 1D Experiment 209 s2pul Spectrometer Frequency 150.77 25.0 Pulse Sequence 152.62 Temperature 146.15 cdcl3 121.89 Varian 90.89 Solvent 85.11 84.82 Origin 71.81 70.31 66.78 64.66 JKT-3-11-1_pure-CARBON_ 01 58.93 Title Value 51.56 50.79 / Volumes/ nmrdata/ jkthomps/ vnmrsys/ data/ JKT-3-11-1_pure_20250404_ 01/ JKT-3-11-1_pure-CARBON_ 01. fid/ fid Parameter 46.01 43.53 42.48 39.28 Data File Name 30 18.51 20 10 0 -4.79 -5.08 25.84 25.19 -10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 7.0 Spectral Siz e Acquired Siz e Nucleus Spectral Width 6.5 6.0 65536 32768 1H 8012. 8 5.5 2025-04-15T02 01 51 4.0894 8 .7000 1.0000 14 2. 8 16 1D z g30 298 . 2 CDCl3 Bruker BioSpin GmbH JKT-3-20-1_lactol.4. fid Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin 4.71 1.06 1.01 1.01 5.0 1.02 4.5 210 4.0 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-20-1_lactol/ 4/ fid 5.39 1.02 Title 5.04 4.96 4.88 Value 4.08 0.95 Data File Name 5.24 1.01 6.21 1.00 3.90 3.81 1.03 1.07 Parameter 2.5 1.5 0.5 2.08 1.97 1.00 2.04 2.62 5.31 3.05 1.02 3.38 3.35 3.62 3.54 1.05 2.16 1.0 1.81 3.01 2.0 1.24 3.20 3 .0 0.98 0.92 3.00 9.33 3 .5 f1 (ppm) 0.12 6.29 0.0 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 144.18 107.51 106.62 5500 197.4 1.0000 10.0000 1. 3631 2025-04-15T05 44 40 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 130 65536 Spectral Siz e 140 32768 Acquired Siz e 150 13C Nucleus 160 24038 .5 Spectral Width 100 90 1D Experiment 110 z gpg30 Pulse Sequence 120 298 . 2 Temperature 210 CDCl3 Spectrometer Frequency 100.62 Bruker BioSpin GmbH Solvent 154.13 JKT-3-20-1_lactol. 3 . fid 123.65 Origin 100.42 Title Value 91.00 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-20-1_lactol/ 3/ fid Parameter 85.42 82.82 Data File Name 80 f1 (ppm) 71.84 69.61 66.95 66.19 70 59.00 60 40 51.60 50.72 47.89 46.27 44.27 43.60 43.29 39.45 50 29.71 26.61 25.80 30 19.25 18.29 20 10 0 -4.76 -5.09 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 1.5000 8 .7000 0. 2135 2025-04-15T06 38 22 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 (4.68 , 16. 22) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 180) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.2 (-521. 8 , -1300. 8) Lowest Frequency 5.4 (4795.4, 16611. 3) Spectral Width 2. 8 f2 (ppm) 197.4 Receiver Gain 3 .0 10 Number of Scans 3 .2 HSQC-EDITED Experiment 3 .4 hsqcedetgpsisp 2.4 Pulse Sequence 3 .6 298 . 2 Temperature 3.8 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-3-20-1_lactol_.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-3-20-1_lactol_/ 5/ ser Parameter Data File Name 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 210 0.4 0.2 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 4.76 1.0000 3 . 3500 3 .0000 2025-04-14T19 16 59 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 24000 Acquired Siz e 6.5 1H Nucleus 7.0 8000.0 Spectral Width 0.95 2.00 5.0 4.5 60 Receiver Gain 5.5 8 Number of Scans 211 1D Experiment Spectrometer Frequency 499.54 s2pul 5.33 1.00 25.0 5.08 Pulse Sequence 4.95 Temperature 4.05 cdcl3 3.83 Solvent 3.65 3.57 Varian 0.97 4.0 5.51 3 .5 f1 (ppm) 3 .0 2.5 3.41 3.40 Origin 2.88 0.96 PROTON01 2.58 2.09 / Users/ jordankthompson/ Desktop/ JKT-3-20-2/ PROTON01. fid/ fid 2.35 2.80 Title Value 2.10 3.93 Data File Name Parameter 2.0 1.5 0.5 0.0 1.14 0.98 0.91 2.76 2.96 11.67 1.0 0.08 6.06 0.83 2.01 0.94 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 5.31 5.24 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2025-05-23T19 58 54 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 0.97 1.93 5.0 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.5 Bruker BioSpin GmbH Origin 214 JKT-7-221_pure.1. fid 1.00 1.87 Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 1/ fid 4.71 Title 2.5 2.99 0.96 3.36 2.95 3.63 3.53 1.03 1.96 3.83 2.00 2.0 0.5 2.77 2.64 2.56 0.98 1.01 1.86 1.0 2.35 2.25 2.16 0.95 1.00 1.96 1.5 1.92 1.81 0.91 3 .0 1.50 0.93 3 .5 1.08 2.93 f1 (ppm) 0.91 0.88 9.00 3.10 0.91 5.02 4.91 Value 4.12 Data File Name Parameter 0.15 0.10 9.00 6.00 0.97 1.00 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 200 1.0000 10.0000 1.1796 2025-05-23T20 37 39 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 160 65536 Spectral Siz e 170 32768 Acquired Siz e 180 13C Nucleus 190 27777. 8 Spectral Width 130 100 72.0 Receiver Gain 110 1000 Number of Scans 120 1D Experiment 140 z gpg30 Pulse Sequence 150 297.1 Temperature 214 CDCl3 Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 152.99 JKT-7-221_pure. 2. fid 146.43 Title Value 121.39 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 2/ fid Parameter 106.27 103.00 100.23 Data File Name 85.58 85.37 91.14 90 f1 (ppm) 80 71.86 71.35 67.19 65.36 70 59.11 60 40 52.13 51.33 51.25 46.26 43.51 42.57 41.91 39.69 50 30 18.77 18.44 20 10 1.43 0 -4.60 -4.94 26.31 26.00 -10 -20 0 500 1000 1500 2000 2500 6.0 297. 2 hsqcedetgpsisp 2.4 HSQC-EDITED 6 197.4 1.5000 12.5000 0. 2135 2025-05-23T21 06 29 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 158) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-525. 8 , -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width 3 .0 f2 (ppm) CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-7-221_pure. 3 .ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 3/ ser Title Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 214 0.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 1.9164 12.5000 0. 2806 2025-05-23T21 16 00 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.4 4.2 (3 .56, 3 .56) Digital Resolution 4.6 (1024, 1024) Spectral Siz e 4. 8 (1024, 128) Acquired Siz e 5.0 (1H, 1H) Nucleus 5.2 (-376.1, -380.0) Lowest Frequency 5.4 (3649.6, 3649.6) Spectral Width 2. 8 2.6 f2 (ppm) 127.1 Receiver Gain 3 .0 1 Number of Scans 3 .2 COSY Experiment 3 .4 cosygpppqf Pulse Sequence 3 .6 297. 2 Temperature 3.8 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-221_pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 4/ ser Parameter Data File Name 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 299 0.2 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 297.1 hmbcetgpl3nd HMBC 7 197.4 2.0000 12.5000 0.4 260 2025-05-23T22 31 53 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 1024) (2. 35, 21. 80) Spectral Siz e Digital Resolution 4.5 (2048 , 256) Acquired Siz e 5.0 (1H, 13C) Nucleus 5.5 (-163 .1, -1116.4) Lowest Frequency 6.0 (4807.7, 22321.4) Spectral Width 3 .0 f2 (ppm) CDCl3 Solvent 3 .5 Bruker BioSpin GmbH Origin 4.0 JKT-7-221_pure.5.ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 5/ ser Title Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 214 0.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) NOESY 4 197.4 1. 8000 12.5000 0. 2560 2025-05-23T23 17 33 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1H, 1H) (1024, 256) (1024, 1024) (3 .91, 3 .91) Nucleus Acquired Siz e Spectral Siz e Digital Resolution 4.5 (-167.4, -168 .1) Lowest Frequency 5.0 (4000.0, 4000.0) Spectral Width f2 (ppm) noesygpphzs Pulse Sequence 3 .0 297. 2 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-221_pure.6.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-221_pure/ 6/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 214 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 5.36 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2025-06-01T16 32 25 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 0.94 0.96 0.92 1.04 5.0 4.5 297.1 Temperature 5.5 CDCl3 Solvent 6.0 Bruker BioSpin GmbH Origin 216 JKT-7-234_pure.1. fid 1.00 Spectrometer Frequency 400.13 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 1/ fid 5.07 4.97 4.95 4.94 Title Value 4.73 Data File Name Parameter 2.5 1.5 2.18 0.95 2.33 2.86 2.72 2.64 2.59 1.03 0.92 2.02 3.01 0.98 3.61 3.54 3.41 3.38 2.05 2.02 3.06 3.17 3.83 1.00 4.18 1.00 1.0 2.01 1.00 2.0 1.79 0.96 3 .0 1.66 1.19 3 .5 1.16 2.99 4.0 f1 (ppm) 0.94 2.98 0.98 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 1500 38 .0 1.0000 10.0000 1.1796 2025-06-02T00 44 04 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 140 65536 Spectral Siz e 150 32768 Acquired Siz e 160 13C Nucleus 170 27777. 8 Spectral Width 110 1D Experiment 120 z gpg30 Pulse Sequence 130 297.1 Temperature 100 216 CDCl3 Spectrometer Frequency 100.62 Bruker BioSpin GmbH 152.68 Solvent 145.43 Origin 122.55 JKT-7-234_pure. 2. fid 109.45 Title Value 106.55 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 2/ fid Parameter 101.46 Data File Name 85.15 83.81 91.07 90 f1 (ppm) 80 71.97 70.07 66.98 70 61.96 59.13 56.52 60 51.82 50.75 50.39 50 46.42 43.72 42.31 41.85 38.78 40 30 20 18.00 25.29 10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 cosygpppqf COSY 3 197.4 1. 8878 12.5000 0. 3092 2025-06-02T00 59 23 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) (3 . 23 , 3 . 23) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 1H) Nucleus 5.0 (-82. 2, -82. 2) Lowest Frequency 5.5 (3311. 3 , 3311. 3) Spectral Width f2 (ppm) 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-7-234_pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 216 1.0 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) hsqcedetgpsisp 2.4 HSQC-EDITED 6 197.4 1.5000 12.5000 0. 2135 2025-06-02T01 32 03 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) (4.68 , 16. 22) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 13C) Nucleus 5.0 (-552.5, -1262. 8) Lowest Frequency 5.5 (4795.4, 16611. 3) Spectral Width 3 .0 f2 (ppm) 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-7-234_pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 4/ ser Parameter Data File Name 2.5 2.0 1.5 216 1.0 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) 197.4 2.0000 12.5000 0.4 260 2025-06-02T02 58 37 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.2 5.0 4. 8 (2. 35, 21. 80) Digital Resolution 5.4 (2048 , 1024) Spectral Siz e 5.6 (2048 , 256) Acquired Siz e 5. 8 (1H, 13C) Nucleus 6.0 (-163 .1, -1116.4) Lowest Frequency 6.2 (4807.7, 22321.4) Spectral Width 3 .4 f2 (ppm) 8 Number of Scans 3 .6 HMBC Experiment 3.8 hmbcetgpl3nd Pulse Sequence 4.0 297. 2 Temperature 4.2 CDCl3 Solvent 4.4 Bruker BioSpin GmbH Origin 4.6 JKT-7-234_pure.5.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 5/ ser Value Data File Name Parameter 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 216 1.0 0. 8 0.6 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) 197.4 1. 8000 12.5000 0. 2560 2025-06-02T04 17 11 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.6 (3 .91, 3 .91) Digital Resolution 4. 8 (1024, 1024) Spectral Siz e 5.0 (1024, 256) Acquired Siz e 5.2 (1H, 1H) Nucleus 5.4 (-194.9, -195.1) Lowest Frequency 5.6 (4000.0, 4000.0) Spectral Width 3 .2 3 .0 f2 (ppm) 7 Number of Scans 3 .4 NOESY Experiment 3 .6 noesygpphzs Pulse Sequence 3.8 297.1 Temperature 4.0 CDCl3 Solvent 4.2 Bruker BioSpin GmbH Origin 4.4 JKT-7-234_pure.6.ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-7-234_pure/ 6/ ser Value Data File Name Parameter 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 216 1.0 0. 8 0.6 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 16 101.0 1.0000 9. 8500 3 .9977 2025-07-27T22 18 19 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8196.7 Spectral Width 4.0 1D Experiment 4.5 z g30 Pulse Sequence 5.0 298 .1 Temperature 5.5 CDCl3 Solvent 217 Bruker BioSpin GmbH & Co. KG Origin 2.00 Spectrometer Frequency 400.15 JKT-8-17 _pure.1. fid 5.91 0.98 Title Value 5.24 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 1/ fid Parameter 4.77 Data File Name 3.28 3.02 3.45 2.02 3.88 3.79 3.65 0.99 1.02 2.05 0.0 2.93 1.00 0.5 2.55 2.45 2.32 1.01 1.01 1.09 1.0 2.15 1.10 1.5 1.93 3.43 2.0 1.72 3.89 2.5 1.14 1.10 3.00 3.00 3 .0 0.88 0.82 3.00 8.99 3 .5 f1 (ppm) -0.00 6.03 2.01 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 106.18 45. 2 2.0000 10.0000 1.1796 2025-07-28T01 29 24 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 130 32768 Acquired Siz e 140 13C Nucleus 150 27777. 8 Spectral Width 90 3500 Number of Scans 100 1D Experiment 110 z gpg30 Pulse Sequence 120 298 .1 Temperature 217 CDCl3 Solvent Spectrometer Frequency 100.63 Bruker BioSpin GmbH & Co. KG 146.92 Origin 122.36 JKT-8-17 _pure. 2. fid 100.51 Title Value 91.55 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 2/ fid Parameter 85.67 84.11 Data File Name 79.48 80 71.87 70.94 67.58 65.90 70 f1 (ppm) 59.18 60 50 47.95 47.44 45.30 42.74 39.82 40 30 19.56 18.41 20 10 0 -4.63 -4.96 26.04 25.93 25.25 35.39 51.92 55.99 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 2 101.0 2.0000 9. 8500 0.1946 2025-07-28T01 39 45 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.14, 5.14) Spectral Siz e Digital Resolution 6.0 (1024, 128) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-283 .6, -230.7) Lowest Frequency 7.5 (5263 . 2, 5263 . 2) Spectral Width 3 .5 f2 (ppm) COSY Experiment 4.0 cosygpppqf Pulse Sequence 4.5 298 .1 Temperature 5.0 CDCl3 Solvent 5.5 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency (400.15, 400.15) JKT-8-17 _pure. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 3/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 217 0.0 8 .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) HMBC 10 101.0 1.5000 9. 8500 0.5980 2025-07-28T02 26 35 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 512) (1.67, 43 . 24) Spectral Siz e Digital Resolution 5.0 (2048 , 128) Acquired Siz e 5.5 (1H, 13C) Nucleus 6.0 (-286.7, -1007. 3) Lowest Frequency 6.5 (34 24.7, 22138 .1) Spectral Width 3 .0 f2 (ppm) hmbcgplpndqf Pulse Sequence 3 .5 298 . 2 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency (400.15, 100.63) JKT-8-17 _pure.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 4/ ser Parameter Data File Name 2.5 2.0 1.5 1.0 0.5 217 0.0 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) HSQC-EDITED 10 32.0 1.5000 9. 8500 0.1946 2025-07-28T03 41 09 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (5.14, 16. 21) Spectral Siz e Digital Resolution 5.0 (1024, 256) Acquired Siz e 5.5 (1H, 13C) Nucleus 6.0 (-798 .0, -755. 3) Lowest Frequency 6.5 (5263 . 2, 16603 . 2) Spectral Width f2 (ppm) hsqcedetgpsisp 2. 3 Pulse Sequence 3 .5 298 . 2 Temperature 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH & Co. KG Origin Spectrometer Frequency (400.15, 100.63) JKT-8-17 _pure.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 5/ ser Parameter Data File Name 3 .0 2.5 2.0 1.5 1.0 0.5 217 0.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) noesygpphpp NOESY 5 101.0 1. 8730 9. 8500 0. 3809 2025-07-28T04 38 29 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 256) (1024, 1024) (2.63 , 2.63) Acquired Siz e Spectral Siz e Digital Resolution 5.0 (1H, 1H) Nucleus 5.5 (-23 .6, -23 .6) Lowest Frequency 6.0 (2688 . 2, 2688 . 2) Spectral Width 3 .0 f2 (ppm) 298 .1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH & Co. KG Origin 4.5 JKT-8-17 _pure.6.ser Spectrometer Frequency (400.15, 400.15) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-17 _pure/ 6/ ser Title Value Data File Name Parameter 2.5 2.0 1.5 1.0 0.5 217 0.0 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 5.06 297.1 z g30 1D 16 197.4 1.0000 12.5000 4.0894 2025-07-27T04 33 21 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 65536 Spectral Siz e 6.0 32768 Acquired Siz e 6.5 1H Nucleus 7.0 8012. 8 Spectral Width 5.5 CDCl3 Solvent 0.98 5.0 4.5 4.0 C6-epi-217 Bruker BioSpin GmbH 1.03 Spectrometer Frequency 400.13 JKT-8-15-1.1. fid Origin 5.30 5.26 1.10 1.00 Title Value 4.86 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1/ 1/ fid Parameter 4.10 Data File Name 1.5 0.5 3.00 1.00 3.38 3.03 3.54 2.00 3.74 1.04 2.10 0.0 2.76 2.65 2.52 2.39 2.27 0.99 1.14 1.03 1.15 2.07 1.0 2.09 1.96 1.81 1.13 1.11 2.40 2.0 1.60 1.29 2.5 1.20 1.10 3.24 3.05 3 .0 0.92 11.90 3 .5 f1 (ppm) 0.09 5.98 3.86 2.05 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 1D 500 98 .9 1.0000 10.0000 1.1796 2025-07-27T05 10 08 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 150 65536 Spectral Siz e 160 32768 Acquired Siz e 170 13C Nucleus 180 27777. 8 Spectral Width 120 z gpg30 Pulse Sequence 130 297.1 Temperature 140 CDCl3 Solvent 110 100 C6-epi-217 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-8-15-1.5. fid 149.19 Title Value 121.09 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1/ 5/ fid Parameter 102.86 99.90 Data File Name 86.07 85.04 91.56 90 f1 (ppm) 78.04 80 71.90 70.41 67.58 64.72 70 59.80 59.18 60 40 51.07 48.09 45.68 43.16 41.61 39.49 50 30 18.70 18.41 20 10 0 -4.62 -4.94 25.98 25.37 24.46 35.42 -10 0 50 100 150 200 250 300 350 400 450 500 550 600 650 297.1 hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2025-07-27T04 50 43 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (4.68 , 16. 22) Digital Resolution 5.5 (1024, 1024) Spectral Siz e 6.0 (1024, 180) Acquired Siz e 6.5 (1H, 13C) Nucleus 7.0 (-524.1, -1262. 8) Lowest Frequency 7.5 (4795.4, 16611. 3) Spectral Width 4.0 CDCl3 Solvent 4.5 Bruker BioSpin GmbH Origin 5.0 JKT-8-15-1.4.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1/ 4/ ser Value Data File Name Parameter 3 .5 f2 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 C6-epi-217 -0.5 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 f1 (ppm) cosygpppqf COSY 1 156. 2 1.9185 12.5000 0. 2785 2025-07-27T04 39 03 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (3 .59, 3 .59) Digital Resolution 6.0 (1024, 1024) Spectral Siz e 6.5 (1024, 128) Acquired Siz e 7.0 (1H, 1H) Nucleus 7.5 (-445. 3 , -445. 3) Lowest Frequency 8 .0 (3676.5, 3676.5) Spectral Width 4.0 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-8-15-1. 3 .ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1/ 3/ ser Title Value Data File Name Parameter 3 .5 f2 (ppm) 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 C6-epi-217 -0.5 -1.0 8 7 6 5 4 3 2 1 0 -1 f1 (ppm) noesygpphzs NOESY 4 197.4 1. 8000 12.5000 0. 2560 2025-07-27T17 17 45 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 256) (1024, 1024) (3 .91, 3 .91) Acquired Siz e Spectral Siz e Digital Resolution 4.5 (1H, 1H) Nucleus 5.0 (-198 .7, -204.1) Lowest Frequency 5.5 (4000.0, 4000.0) Spectral Width 3 .0 297.1 Temperature 3 .5 CDCl3 Solvent 4.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-8-15-1_. 2.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1_/ 2/ ser Parameter Data File Name f2 (ppm) 2.5 2.0 1.5 1.0 0.5 C6-epi-217 0.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 f1 (ppm) 8 .0 hmbcetgpl3nd HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-07-27T18 01 30 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 1024) (2. 35, 21. 80) Spectral Siz e Digital Resolution 6.0 (2048 , 256) Acquired Siz e 6.5 (1H, 13C) Nucleus 7.0 (-163 .1, -1116.4) Lowest Frequency 7.5 (4807.7, 22321.4) Spectral Width 4.0 f2 (ppm) 297.1 Temperature 4.5 CDCl3 Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-8-15-1_. 3 .ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-15-1_/ 3/ ser Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 C6-epi-217 0.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 5.28 4.0894 Acquisition Time Spectral Siz e Acquired Siz e Nucleus Spectral Width 5.0 65536 32768 1H 8012. 8 Spectrometer Frequency 400.13 4.5 2025-07-29T09 27 53 12.5000 1.0000 Relaxation Delay Pulse Width 14 2. 8 Receiver Gain 16 z g30 297. 2 Me OD Bruker BioSpin GmbH 4.0 218 JKT-8-22_pure_dehydro.1. fid 1D Acquisition Date Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 1/ fid Number of Scans 4.87 CD3OD Experiment Pulse Sequence Temperature Solvent Origin Title Data File Name 1.00 3.77 1.00 5.07 1.01 3.49 3.43 3 .5 1.05 3.01 Parameter 2.5 1.5 1.57 1.01 1.68 1.01 1.81 2.01 2.05 3.06 2.26 3.01 2.71 1.00 2.92 1.00 1.0 1.30 3.02 2.0 1.18 3.00 3 .0 f1 (ppm) 1.02 3.00 0.5 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 150.03 112.02 1.0000 10.0000 1.1796 2025-07-29T10 06 27 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Siz e Spectral Siz e 140 13C Nucleus 150 27777. 8 Spectral Width f1 (ppm) 38 .0 Receiver Gain 90 1000 Number of Scans 100 1D Experiment 110 z gpg30 Pulse Sequence 120 297.1 Temperature 130 Me OD Solvent 218 Bruker BioSpin GmbH Origin Spectrometer Frequency 100.62 JKT-8-22_pure_dehydro. 2. fid 122.52 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 2/ fid 103.30 Title Value 85.87 Data File Name Parameter 80.77 78.90 80 70 60.81 60 52.75 52.73 50.02 49.00 CD3OD 46.82 50 41.04 40.47 38.54 40 30 20 20.08 24.14 23.79 56.57 63.18 74.36 0 50 100 150 200 250 300 350 400 450 500 550 600 650 0.4403 2025-07-29T11 47 43 Acquisition Time Acquisition Date 4. 8 4.6 (2. 27, 2. 27) Digital Resolution 5.0 (1024, 1024) Spectral Siz e 5.2 (1024, 128) Acquired Siz e 5.4 (1H, 1H) Nucleus 5.6 (59. 2, 56.9) Lowest Frequency 5. 8 (2325.6, 2325.6) Spectral Width 2. 8 12.5000 Pulse Width 3 .0 f2 (ppm) 1.7567 Relaxation Delay 3 .2 64. 2 Receiver Gain 3 .4 1 Number of Scans 3 .6 COSY Experiment 3.8 cosygpppqf Pulse Sequence 4.0 297.1 Temperature 4.2 Me OD Solvent 4.4 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-8-22_pure_dehydro. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 3/ ser Parameter Data File Name 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 218 0.6 0.4 0.2 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 12.5000 0. 2135 2025-07-29T12 00 30 Pulse Width Acquisition Time Acquisition Date 4. 8 (4.68 , 16. 22) Digital Resolution 5.0 (1024, 1024) Spectral Siz e 5.2 (1024, 180) Acquired Siz e 5.4 (1H, 13C) Nucleus 5.6 (-526.6, -1137.9) Lowest Frequency 5. 8 (4795.4, 16611. 3) Spectral Width 3 .2 1.5000 Relaxation Delay 3 .4 f2 (ppm) 197.4 Receiver Gain 3 .6 2 Number of Scans 3.8 HSQC-EDITED Experiment 4.0 hsqcedetgpsisp 2.4 Pulse Sequence 4.2 297. 2 Temperature 4.4 Me OD Solvent 4.6 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-8-22_pure_dehydro.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 4/ ser Parameter Data File Name 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 218 1.2 1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) 4 197.4 2.0000 12.5000 0.4 260 2025-07-29T12 44 15 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 256) (2048 , 1024) (2. 35, 21. 80) 7.5 Acquired Siz e Spectral Siz e Digital Resolution 9.0 7.0 (1H, 13C) Nucleus 8 .0 (-172.9, -976. 8) Lowest Frequency 8 .5 (4807.7, 22321.4) Spectral Width 4.0 HMBC Experiment 4.5 f2 (ppm) hmbcetgpl3nd Pulse Sequence 5.0 297.1 Temperature 5.5 Me OD Solvent 6.0 Bruker BioSpin GmbH Origin 6.5 JKT-8-22_pure_dehydro.5.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 5/ ser Value Data File Name Parameter 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 218 0.0 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 f1 (ppm) 4 197.4 1. 8000 12.5000 0. 2560 2025-07-29T13 30 00 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (3 .91, 3 .91) Spectral Siz e Digital Resolution 6.0 (1024, 256) Acquired Siz e 6.5 (1H, 1H) Nucleus 7.0 (-161.5, -167. 2) Lowest Frequency 7.5 (4000.0, 4000.0) Spectral Width 3 .5 NOESY Experiment f2 (ppm) noesygpphzs Pulse Sequence 4.0 297. 2 Temperature 4.5 Me OD Solvent 5.0 Bruker BioSpin GmbH Origin 5.5 JKT-8-22_pure_dehydro.6.ser Title Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-22_pure_dehydro/ 6/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 218 0.0 6.0 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 4.98 4.98 CD3OD 5.2 Spectral Siz e Acquired Siz e Nucleus Spectral Width 5.0 4. 8 4.6 65536 16384 1H 9592. 3 4.2 2025-07-31T12 48 4 2 Acquisition Date 4.4 1.7080 Spectrometer Frequency 599.55 2. 8500 Acquisition Time 1.0000 Relaxation Delay Pulse Width 38 8 Receiver Gain 1D Number of Scans s2pul Experiment 25.0 Pulse Sequence cd3od Varian 4.0 JKT-8-30_crude-PROTON_ 01 Temperature Solvent Origin Title 3.49 3.48 3.41 Value 3.72 3.71 3.70 3.70 3.8 3 .6 1.02 3.02 3 .4 3 .2 3 .0 f1 (ppm) 2. 8 1.01 1.00 2.6 2.4 2.2 / Users/ jordankthompson/ Desktop/ JKT-8-30_crude_20250731_ 01/ JKT-8-30_crude-PROTON_ 01. fid/ fid 2.74 2.73 2.72 2.72 2.71 2.71 2.70 2.69 2.63 2.62 2.61 2.60 0.93 Parameter 0.90 2.09 1.22 Data File Name 2.0 1. 8 1.6 1.4 1.2 1.0 1.22 3.02 3.01 1.31 360 0. 8 -40 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 566a43443031303004030201000000000000000000000080000000000300130000004368656d447261772032332e312e322e3708002f 1.03 2.99 117.80 117.80 CD3OD 64. 2 1.0000 10.0000 1.1796 2025-07-30T20 4 2 51 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 110 105 65536 Spectral Siz e 115 32768 Acquired Siz e 120 13C Nucleus 125 27777. 8 Spectral Width 74.01 75 1000 Number of Scans 80 1D Experiment 85 z gpg30 Pulse Sequence 90 297.1 Temperature 95 Me OD Solvent 100 Bruker BioSpin GmbH Spectrometer Frequency 100.62 JKT-8-28-1. 2. fid 103.91 Origin 85.93 Title 80.99 / Volumes/ nmrdata-1/ jkthomps/ nmr/ JKT-8-28-1/ 2/ fid Value 78.73 Data File Name Parameter 71.19 70 65 f1 (ppm) 60 55 50 45 42.97 41.30 39.90 40 35 29.22 30 24.72 25 20 21.50 20.45 32.57 48.14 52.82 56.36 61.49 15 10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 4.87 CD3OD z g30 1D 16 127.1 1.0000 12.5000 4.0894 2025-08-02T07 27 39 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.0 4.6 4.4 65536 Spectral Siz e 4. 8 32768 5.2 1H Acquired Siz e 8012. 8 Nucleus Spectral Width 4.2 4.0 3.8 auriculatol A (49) 297.1 Temperature Spectrometer Frequency 400.13 Me OD Bruker BioSpin GmbH JKT-8-30-F1-RR2.14. fid 3 .6 3 .4 3 .2 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 14/ fid Solvent Origin Title 3.71 1.00 Data File Name Value 3.48 1.02 4.98 1.00 3.41 3.00 Parameter 3 .0 f1 (ppm) 2. 8 2.4 2.2 2.0 1.6 1.4 1.67 5.01 1.97 1.90 1.82 1.05 1.00 3.11 2.08 1.00 2.62 1.00 2.71 1.00 1.0 1.53 2.04 1.2 1.30 3.03 1. 8 1.22 3.02 2.6 1.03 3.04 0. 8 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 117.80 512 38 .0 1.0000 10.0000 1. 3631 2025-08-02T07 49 22 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 105 65536 Spectral Siz e 110 32768 Acquired Siz e 115 13C Nucleus 120 24038 .5 Spectral Width 100 95 90 75 1D Experiment 80 z gpg30 Pulse Sequence 85 297. 2 Temperature auriculatol A (49) Me OD Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH 103.91 JKT-8-30-F1-RR2.9. fid 85.93 Origin 80.99 Title Value 78.73 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 9/ fid Parameter 74.01 Data File Name 70 65 f1 (ppm) 61.49 61.48 60 55 49.21 48.13 50 45 42.96 41.30 41.27 39.91 40 35 29.22 30 24.72 25 20 21.50 20.45 32.57 52.82 56.37 15 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 297.1 hsqcedetgpsisp 2.4 HSQC-EDITED 2 197.4 1.5000 12.5000 0. 2135 2025-08-02T08 06 46 Temperature Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 1024) (4.68 , 16. 22) Spectral Siz e Digital Resolution 5.0 (1024, 180) Acquired Siz e 5.5 (1H, 13C) Nucleus 6.0 (-517.1, -1262. 8) Lowest Frequency 6.5 (4795.4, 16611. 3) Spectral Width 3 .5 f2 (ppm) Me OD Solvent 4.0 Bruker BioSpin GmbH Origin 4.5 JKT-8-30-F1-RR2.11.ser Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 11/ ser Title Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 auriculatol A (49) 0.5 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) 1.7198 12.5000 0.4772 2025-08-02T07 55 06 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.6 4.4 (2.10, 2.10) Digital Resolution 4. 8 (1024, 1024) Spectral Siz e 5.0 (1024, 128) Acquired Siz e 5.2 (1H, 1H) Nucleus 5.4 (108 .7, 108 .7) Lowest Frequency 5.6 (2145.9, 2145.9) Spectral Width 3 .0 2. 8 f2 (ppm) 64. 2 Receiver Gain 3 .2 1 Number of Scans 3 .4 COSY Experiment 3 .6 cosygpppqf Pulse Sequence 3.8 297. 2 Temperature 4.0 Me OD Solvent 4.2 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-8-30-F1-RR2.10.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 10/ ser Parameter Data File Name 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 auriculatol A (49) 0.4 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) hmbcetgpl3nd HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-08-02T08 50 31 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2048 , 1024) (2. 35, 21. 80) Spectral Siz e Digital Resolution 5.5 (2048 , 256) Acquired Siz e 6.0 (1H, 13C) Nucleus 6.5 (-168 .0, -978 .5) Lowest Frequency 7.0 (4807.7, 22321.4) Spectral Width 3 .5 f2 (ppm) 297.1 Temperature 4.0 Me OD Solvent 4.5 Bruker BioSpin GmbH Origin 5.0 JKT-8-30-F1-RR2.12.ser Title Spectrometer Frequency (400.13 , 100.62) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 12/ ser Value Data File Name Parameter 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 auriculatol A (49) 130 120 110 100 90 80 70 60 50 40 30 20 10 f1 (ppm) 1. 8000 12.5000 0. 2560 2025-08-02T09 36 06 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 5.4 5.2 (3 .91, 3 .91) Digital Resolution 5.6 (1024, 1024) Spectral Siz e 5. 8 (1024, 256) Acquired Siz e 6.0 (1H, 1H) Nucleus 6.2 (-160.1, -158 .1) Lowest Frequency 6.4 (4000.0, 4000.0) Spectral Width 3.8 3 .6 f2 (ppm) 64. 2 Receiver Gain 4.0 4 Number of Scans 4.2 NOESY Experiment 4.4 noesygpphzs Pulse Sequence 4.6 297.1 Temperature 4. 8 Me OD Solvent 5.0 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-8-30-F1-RR2.13 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F1-RR2/ 13/ ser Parameter Data File Name 3 .4 3 .2 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 auriculatol A (49) 0. 8 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) 5. 8 5.6 5.4 Spectral Siz e Acquired Siz e Nucleus Spectral Width 5.2 5.0 4. 8 65536 32768 1H 8012. 8 4.6 4.4 4.2 4.0 3.8 9-epi-auriculatol A (219) 2025-08-04T23 33 14 4.0894 12.5000 1.0000 176. 8 16 1D z g30 297. 2 Me OD Bruker BioSpin GmbH JKT-8-30-F2-RR-2.1. fid Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Experiment Pulse Sequence Temperature Solvent Origin Title 4.87 CD3OD / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2-RR-2/ 1/ fid Value 4.11 1.03 Parameter 3.56 3 .6 1.01 5.23 1.00 3.42 3 .4 3.03 Data File Name 3 .2 3 .0 f1 (ppm) 2. 8 2.6 2.4 2.2 2.0 1. 8 1.4 1.70 4.05 1.86 1.01 2.08 3.00 2.32 1.00 2.51 2.00 1.0 1.59 3.03 1.2 1.21 1.17 4.00 3.02 1.6 0.99 3.01 0. 8 0.6 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 101.12 z gpg30 1D 1000 78 .7 1.0000 10.0000 1.1796 2025-08-01T08 25 07 Pulse Sequence Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 95 65536 Spectral Siz e 100 32768 Acquired Siz e 105 13C Nucleus 110 27777. 8 Spectral Width 90 297. 2 Temperature 85 80 75 70 9-epi-auriculatol A (219) Me OD Solvent Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 108.87 JKT-8-30-F2. 2. fid 84.79 Title Value 79.63 79.20 / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2/ 2/ fid Parameter 71.07 Data File Name 65 f1 (ppm) 59.73 60 56.68 56.12 55 45 49.00 CD3OD 48.86 48.67 48.04 46.07 50 39.21 40 34.55 35 30 25 20 20.73 19.58 28.12 26.83 42.95 51.42 15 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 1.74 24 12.5000 0.4547 2025-08-01T08 30 53 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4. 8 4.6 (2. 20, 2. 20) Digital Resolution 5.0 (1024, 1024) Spectral Siz e 5.2 (1024, 128) Acquired Siz e 5.4 (1H, 1H) Nucleus 5.6 (99. 8 , 99. 8) Lowest Frequency 5. 8 (2252. 3 , 2252. 3) Spectral Width 3 .2 3 .0 f2 (ppm) 127.1 Receiver Gain 3 .4 1 Number of Scans 3 .6 COSY Experiment 3.8 cosygpppqf Pulse Sequence 4.0 297.1 Temperature 4.2 Me OD Solvent 4.4 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 400.13) JKT-8-30-F2. 3 .ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2/ 3/ ser Parameter Data File Name 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 0.4 9-epi-auriculatol A (219) 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 f1 (ppm) 197.4 1. 2000 12.5000 0. 2135 2025-08-01T08 36 14 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.6 4.4 (4.68 , 16. 22) Digital Resolution 4. 8 (1024, 1024) Spectral Siz e 5.0 (1024, 90) Acquired Siz e 5.2 (1H, 13C) Nucleus 5.4 (-524.1, -1110.4) Lowest Frequency 5.6 (4795.4, 16611. 3) Spectral Width 3 .2 f2 (ppm) 2 Number of Scans 3 .4 HSQC-EDITED Experiment 3 .6 hsqcedetgpsisp 2.4 Pulse Sequence 3.8 297. 2 Temperature 4.0 Me OD Solvent 4.2 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-8-30-F2.4.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2/ 4/ ser Parameter Data File Name 3 .0 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 9-epi-auriculatol A (219) 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) HMBC 4 197.4 2.0000 12.5000 0.4 260 2025-08-02T10 22 17 Experiment Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (2. 35, 21. 80) Digital Resolution 6.0 (2048 , 1024) Spectral Siz e 6.5 (2048 , 256) Acquired Siz e 7.0 (1H, 13C) Nucleus 7.5 (-166.9, -975.7) Lowest Frequency 8 .0 (4807.7, 22321.4) Spectral Width 4.0 f2 (ppm) hmbcetgpl3nd Pulse Sequence 4.5 297.1 Temperature 5.0 Me OD Solvent 5.5 Bruker BioSpin GmbH Origin Spectrometer Frequency (400.13 , 100.62) JKT-8-30-F2.5.ser Title Value / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2/ 5/ ser Parameter Data File Name 3 .5 3 .0 2.5 2.0 1.5 1.0 0.5 0.0 9-epi-auriculatol A (219) 120 110 100 90 80 70 60 50 40 30 20 f1 (ppm) 4 197.4 1. 8000 12.5000 0. 2560 2025-08-02T11 07 56 Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 4.6 4.4 (3 .91, 3 .91) Digital Resolution 4. 8 (1024, 1024) Spectral Siz e 5.0 (1024, 256) Acquired Siz e 5.2 (1H, 1H) Nucleus 5.4 (-164.7, -158 .1) Lowest Frequency 5.6 (4000.0, 4000.0) Spectral Width 3 .2 3 .0 f2 (ppm) NOESY Experiment 3 .4 noesygpphzs Pulse Sequence 3 .6 297.1 Temperature 3.8 Me OD Solvent 4.0 Bruker BioSpin GmbH Origin 4.2 JKT-8-30-F2.6.ser Spectrometer Frequency (400.13 , 400.13) / Volumes/ nmrdata/ jkthomps/ nmr/ JKT-8-30-F2/ 6/ ser Title Value Data File Name Parameter 2. 8 2.6 2.4 2.2 2.0 1. 8 1.6 1.4 1.2 1.0 0. 8 0.6 9-epi-auriculatol A (219) 5.5 5.0 4.5 4.0 3 .5 3 .0 2.5 2.0 1.5 1.0 f1 (ppm) 783 ABOUT THE AUTHOR Jordan Kenji Thompson was born on November 2nd, 1998 in Tarzana, CA to Michele H. and Jim J. Thompson. In 2003, the family moved to Calgary, AB, where he grew up in the rural outskirts of Springbank, one of the last suburban communities of Calgary. He spent his childhood being ushered around the city to compete in community hockey alongside his two brothers, Justin and Jack. From a young age, he took an interest in math and the sciences, and in high school primarily enjoyed his chemistry courses. In 2016, Jordan moved to Berkeley, CA, matriculating at the College of Chemistry of UC Berkeley as a chemistry major. There, he began research in Professor Tom Maimone’s lab, where he learned the craft of total synthesis and was a part of the team that completed the synthesis of (+)-6-epi-ophiobolin A. After graduating in 2020, he moved to Pasadena, CA and began his graduate studies in Professor Sarah Reisman’s lab, continuing his work in natural product total synthesis. In Sarah’s lab, he has largely undertaken the auriculatol A project but has also been involved in a collaborative project with Professor Diane Newman’s lab and the checking of two OrgSyn procedures. In 2024, he conducted a 10-week internship in the Merck Discovery-Process group in Boston, MA. Following completion of his Ph.D., Jordan will move to Cambridge, MA, where he will join the medicinal chemistry team at Bristol Myers Squibb.