Development of Oxidation and Transition Metal-Mediated Reactions and Application to Natural Product Synthesis Citation Dibrell, Sara Elise (2023) Development of Oxidation and Transition Metal-Mediated Reactions and Application to Natural Product Synthesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/ve4j-tw63. https://resolver.caltech.edu/CaltechTHESIS:04282023-211208336 Abstract Expedient access to complex molecules via chemical synthesis is important for assessing their biological activity and medicinal properties. In one approach, convergent joining of fragments of similar size and complexity is followed by minimal scaffold tailoring steps to rapidly access natural products. This strategy hinges on the ability to (1) tailor peripheral oxidation, ideally via creative redox transformations, and (2) forge strategic bonds within a complex scaffold through C–C bond formation. We disclose efforts to address these aims by developing broadly useful chemical tools and applying them to the preparation of bioactive natural products. Toward the first aim, we investigated unusual oxidative reactivity mediated by selenium dioxide. To address the second aim, we developed nickel-catalyzed reductive cross-coupling reactions to study: catalyst-controlled enantioselectivity in the preparation of medicinally relevant small molecules, substrate-controlled stereoselectivity, and selectivity for ring formation. The latter studies enabled the exploration of transition metal-mediated cyclization as a convergent annulation strategy toward the rearranged isoryanodane diterpene (+)-cassiabudanol A, as well as the formal synthesis of the macrocyclic cytotoxin (–)-cylindrocyclophane F. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Organic synthesis; natural products; transition metal catalysis Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Restricted to Caltech community only Research Advisor(s): Reisman, Sarah E. Thesis Committee: Robb, Maxwell J. (chair) Stoltz, Brian M. Peters, Jonas C. Reisman, Sarah E. Defense Date: 1 March 2023 Funders: Funding Agency Grant Number NSF Graduate Research Fellowship DGE-1144469 NIH R35GM118191 NSF CHE1800536 Bristol Myers Squibb UNSPECIFIED Record Number: CaltechTHESIS:04282023-211208336 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:04282023-211208336 DOI: 10.7907/ve4j-tw63 Related URLs: URL URL Type Description http://doi.org/10.1021/acs.accounts.0c00858 DOI Review adapted for chapter 1 http://doi.org/10.1021/acscatal.0c01842 DOI Perspective adapted for chapter 2 http://doi.org/10.1021/jacs.9b13818 DOI Communication adapted for chapter 3 ORCID: Author ORCID Dibrell, Sara Elise 0000-0003-0332-1101 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 15148 Collection: CaltechTHESIS Deposited By: Sara Dibrell Deposited On: 16 May 2023 16:16 Last Modified: 20 Aug 2025 19:36 Thesis Files PDF (Full Thesis) - Final Version Restricted to Caltech community only until 16 November 2023. See Usage Policy. 144MB PDF (Front Matter) - Final Version See Usage Policy. 190kB PDF (Chapter 1) - Final Version See Usage Policy. 1MB PDF (Chapter 2) - Final Version See Usage Policy. 663kB PDF (Chapter 3) - Final Version See Usage Policy. 4MB PDF (Chapter 4) - Final Version Restricted to Caltech community only until 16 November 2023. See Usage Policy. 5MB PDF (Chapter 5) - Final Version See Usage Policy. 8MB PDF (Appendix 1) - Final Version See Usage Policy. 6MB PDF (Appendix 2) - Final Version Restricted to Caltech community only until 16 November 2023. See Usage Policy. 18MB PDF (Appendix 3) - Final Version See Usage Policy. 7MB PDF (About the Author) - Final Version See Usage Policy. 25kB Repository Staff Only: item control page

DEVELOPMENT OF OXIDATION AND TRANSITION METAL-MEDIATED REACTIONS AND APPLICATION TO NATURAL PRODUCT SYNTHESIS Thesis by Sara E. Dibrell In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2023 (Defended March 1, 2023) ii © 2023 Sara Elise Dibrell ORCID: 0000-0003-0332-1101 All Rights Reserved iii To Him who made all things iv ACKNOWLEDGEMENTS First and foremost, I thank my parents for their unwavering support and encouragement; they have never doubted me, and this means the world to me. They instilled in me a faith in God and an appreciation for His creation, and they taught me to rely on His strength, rather than my own. These truths have driven my intellectual pursuits and allowed me to arrive at this point. To the many teachers and mentors who were integral to my educational foundation, thank you; your support stretches the 1384 miles from Seguin, TX, to Caltech. From an early age, Pam Krippner instilled in me the joys of thinking outside the box and solving problems. My high school chemistry teacher, Kimberley Shupe Copeland, helped focus that excitement on science. Although I didn’t realize it at the time, she planted the seed that has since blossomed into a real passion for chemistry. I will always be inspired by her sincere commitment to education and dedicate this work to her memory. And to Modi and Janelle, my lifelong friends who have been there for everything, who would I be today without you? We may be scattered across the country, but you’re both close to my heart. I am indebted to my UTSA Top Scholar family. I was fortunate to have found my way into a talented group of people whose successes in school and life have motivated me since the first day of college. Thank you especially to brilliant and grounded Cory Nguyen for your steady friendship and our many adventures. For the shenanigans that broke the tedium of studying, I am grateful to our entire cohort and the one-and-only Oscar Cantua. Special thanks to Kristi Meyer, who encouraged me and challenged me v and opened so many doors for me. She was the force that propelled me into academic research. I cannot express enough my gratitude for Prof. Doug Frantz, a chemist, mentor, and person I strive to emulate. Since he welcomed me, a naïve undergrad, into his lab, his generous support and advice has been unfailing. In the Frantz lab, I first learned how challenging but incredibly rewarding organic chemistry research can be; I was hooked. I owe that to the inspiring women of the group who I still look up to: Marie (could there ever be a kinder or more patient mentor?), Charissa, Ana Cristina, Bobbi, and Melissa. I would also like to thank Dr. Hector Aguilar, an excellent teacher whose organic chemistry lessons were not only digestible but memorable. I’m not likely to forget modeling molecular orbitals with balloons. Thank you to Prof. Jefferson Chan for the opportunity to spend a summer in your lab. What a smart and fun group! Thomas, Nick, Chris, Hailey, and Effie: thank you for the great times in and out of lab. For another decisive summer research experience, I extend my gratitude to Merck. The joy I found in working with the Discovery Chemistry team at West Point, with Dr. Valerie Shurtleff in particular, has been strong motivation throughout my time in graduate school. I am so humbled and excited to call you colleagues in a few months. I am thankful for the intense love for science I encountered within the Caltech community. Thank you to my entire committee, for your commitment to my growth as a scientist: Profs. Sarah Reisman, Brian Stoltz, Max Robb, and Jonas Peters. I am beyond grateful for the opportunity to pursue my PhD in Sarah’s lab. I value the flexibility to investigate a wide variety of interesting chemistry that Sarah provides her students and vi that she always has a good idea, no matter the problem. I am amazed by Sarah’s ability to clearly articulate science and appreciate being able to learn from her. Since the beginning, our 2018 cohort has bonded over challenging problem sets, board game nights, and the daily struggles of lab. I would be lost without Jeff Kerkovius, Ray Turro, and Yujia Tao. It has been a pleasure to spend the last several years working and learning alongside you. Yujia, thank you for the brief but formative experience of sharing a fume hood. I am continually in awe of your creativity and experimental skill. I also thank Kelsey Poremba for lending her hood to me in the early days, because it provided the opportunity to work next to Skyler Mendoza. How can one person know exactly what to do to keep the lab from falling apart, be game for a middle-of-the-night hike into Eaton Canyon, and genuinely care about everyone? My friendships with Yujia and Skyler have been critical to survival both in and out of lab, and I treasure you both. Thank you to Karli Holman, who was also generous with her lab space — and whose upmost organization, aptitude, and kindness are an inspiration to me. A special note of gratitude goes to the best bay mates I could have asked for. I had such a fun time in lab conversing with Drs. Michael Rombola and David Hill, who both possess a captivating combination of genius and gab. I also had the great pleasure of working next to the equally helpful and fun Dr. Dave Charboneau, and I can only hope to one day match the wit of Dr. Sven Richter. Thank you also to my long-time bay mate, office mate, and Big Sib, Alex Shimozono; what a treat to have such a candid and hard-working friend. vii One of the best parts of graduate school has been working with extraordinarily talented project partners. From day one, Mike Maser gave so much of his time and effort as my mentor, and I am deeply appreciative of all he taught me. Thank you to the whole #cylindrocyclofam: Kelsey, Chris, Cedric, and Stephanie. This project forced me to grow in so many ways, and I am very grateful for each of you in the various roles you played in this journey. Travis DeLano and Caitlin Lacker: I am so glad that I teamed up with you both. Travis, thank you for being a clear-headed and enthusiastic leader. Caitlin, thank you for being a consistent force for good. I truly value your rare ability to be both the hardest worker and the nicest person. Tackling the problem of N–N bonds has been another highlight of my time at Caltech. I appreciate the support of Drs. Martin Walsh and Tejas Shah and Corteva. For their patience and perseverance, I sincerely thank Jay Barbor, Dr. Trevor Lohrey, Dr. Vaishnavi Nair, and Kim Sharp; I have learned so much from each of your approaches to problem solving. I would also like to express my appreciation for the newer and vivacious members of the Reisman group. Emily Chen, Jordan Thompson, and Kate Gallagher have infused my time in the group with fresh energy, for which I am grateful. I have thoroughly enjoyed watching Kate hit the ground running in lab and am excited for her bright future. Outside of 315 Schligner, there are many people to whom I owe a great deal. Brooke Versaw and the Robb group have generously taught me about polymers and provided GPC help (and been great friends!). Dr. Scott Virgil has gone above and beyond in helping me, whether handling tough separations with ease, putting in countless hours of instrument upkeep/improvement, or being always at the ready to answer a question. He and Silva have opened their home and hearts to all of us with unparalleled generosity. I viii am grateful for Dr. David VanderVelde and Dr. Mona Shahgholi for their invaluable assistance with NMR and mass spectrometry, respectively. Thank you also to Beth Marshall, who is such a delight to interact with; to Alison Ross, for all that she does to keep things running smoothly; to Nate Siladke, for keeping everyone safe and sound; to Nate Hart, for fixing my Schlenk line too many times; and to Joe Drew, without whom the whole of Schlinger Laboratory would rapidly fall into disarray. For providing neardaily sustenance — and, more importantly, the friendliest smiles — thank you to the entire team at Broad Café. I also acknowledge the generous support from BMS and Merck (and the ACS Women Chemists Committee) during my graduate studies. These awards provided the opportunity to connect with two amazing mentors: Dr. Alyssa Antropow and Dr. Phieng Siliphaivanh. They have been a consistent source of advice and encouragement, instrumental in this last phase of graduate school. Finally, I thank those whose love and prayers have sustained me throughout my time at Caltech. I thank God for sending the late Pastor Chuck Ryor into my life and for my church community. I have been blessed with so many godly role models; Glenn and Rita Biasi, Pat and Macall Horan, Jon and Bella Thomasson, and Isaiah and Aubree Lin, to name a few, have faithfully reminded me to turn my eyes above. To our Thursday night crew: I will dearly miss the constancy of studying, laughing, praying, and eating together. No amount of words is sufficient to express the depth of my love for Michael Zott, “my dime piece straight hottie mega boyfriend baller super chemist” and soon-to-be husband. From orientation onwards, you have not ceased to care for me, to push me, to ix love me, and to inspire me. How exciting that the life we’ve been building together here is just the beginning! I am and forever will be grateful for you. x ABSTRACT Expedient access to complex molecules via chemical synthesis is important for assessing their biological activity and medicinal properties. In one approach, convergent joining of fragments of similar size and complexity is followed by minimal scaffold tailoring steps to rapidly access natural products. This strategy hinges on the ability to (1) tailor peripheral oxidation, ideally via creative redox transformations, and (2) forge strategic bonds within a complex scaffold through C–C bond formation. We disclose efforts to address these aims by developing broadly useful chemical tools and applying them to the preparation of bioactive natural products. Toward the first aim, we investigated unusual oxidative reactivity mediated by selenium dioxide. To address the second aim, we developed nickel-catalyzed reductive cross-coupling reactions to study: catalyst-controlled enantioselectivity in the preparation of medicinally relevant small molecules, substrate-controlled stereoselectivity, and selectivity for ring formation. The latter studies enabled the exploration of transition metal-mediated cyclization as a convergent annulation strategy toward the rearranged isoryanodane diterpene (+)-cassiabudanol A, as well as the formal synthesis of the macrocyclic cytotoxin (–)-cylindrocyclophane F. xi PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following communications: 1. Dibrell, S. E.; Tao, Y.; Reisman, S. E. Acc. Chem. Res. 2021, 54 (6), 1360–1373. DOI: 10.1021/acs.accounts.0c00858. Copyright © 2021 American Chemical Society. S.E.D. contributed to writing of the manuscript. 2. Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. ACS Catal. 2020, 10 (15), 8237–8246. DOI: 10.1021/acscatal.0c01842. Copyright © 2020 American Chemical Society. S.E.D. contributed to writing of the manuscript. 3. Dibrell, S. E.;‡ Maser, M. R.;‡ Reisman, S. E. J. Am. Chem. Soc. 2020, 142 (14), 6483–6487. DOI: 10.1021/jacs.9b13818. Copyright © 2020 American Chemical Society. S.E.D. contributed to the reaction development, conducted experiments, and participated in preparation of the supporting data and writing of the manuscript. xii TABLE OF CONTENTS CHAPTER 1 1 Synthetic Design Guided by Oxidation Pattern Analysis 1.1 INTRODUCTION ............................................................................................ 1 1.1.1 Overview of Oxidized Diterpene Syntheses .............................................. 3 1.2 ADDRESSING DISSONANT CHARGE AFFINITY PATTERNS............................ 4 1.2.1 ent-Kauranoid Diterpenes ......................................................................... 4 1.2.2 Pleuromutilin ............................................................................................ 8 1.3 COMPLEX OXIDATION TOPOLOGY ............................................................ 12 1.3.1 Ryanodane Diterpenes ............................................................................ 12 1.3.1 Isoryanodane Diterpenes......................................................................... 18 1.4 CONCLUDING REMARKS ............................................................................. 24 1.5 REFERENCES.................................................................................................. 25 CHAPTER 2 36 Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 2.1 INTRODUCTION .......................................................................................... 36 2.2 HISTORICAL CONTEXT FOR RCC REACTIONS ............................................ 38 2.3 MECHANISTIC CONSIDERATIONS ............................................................... 40 2.4 ENANTIOCONVERGENT RCCs OF CSP2 AND CP3 ELECTROPHILES ............ 42 2.5 ENANTIOSELECTIVE RCCs OF OLEFINS ....................................................... 48 xiii 2.6 CONCLUDING REMARKS ............................................................................. 52 2.7 REFERENCES.................................................................................................. 54 CHAPTER 3 69 Oxidative Transposition Mediated by Selenium Dioxide 3.1 INTRODUCTION .......................................................................................... 69 3.2 DEVELOPMENT OF DIOXIDATION REACTION............................................ 71 3.2.1 Optimization of Reaction Conditions ...................................................... 71 3.2.2 Reaction Scope ....................................................................................... 73 3.3 MECHANISTIC INVESTIGATION OF DIOXIDATION .................................... 75 3.3.1 Proposed Reaction Pathways................................................................... 75 3.3.2 Investigation of Cycloaddition Pathway................................................... 77 3.3.3 Investigation of Stepwise Pathway ........................................................... 79 3.3.4 Expansion of Dioxidation Scope.............................................................. 82 3.4 DEVELOPMENT OF TRIOXIDATION REACTION .......................................... 83 3.4.1 Optimization of Reaction Conditions ...................................................... 83 3.4.2 Reaction Scope ....................................................................................... 84 3.5 STEREOCHEMICAL ANALYSIS OF DI- AND TRIOXIDATIONS ...................... 85 3.5.1 Investigation of Di- to Trioxidation Conversion ....................................... 85 3.5.2 Investigation of Alternative Trioxidation Pathway .................................... 90 3.5.3 Mechanistic Conclusion: Water-Dependent Product Distribution ............ 93 3.6 SYNTHETIC APPLICATIONS .......................................................................... 94 3.7 CONCLUDING REMARKS ............................................................................. 96 3.8 EXPERIMENTAL SECTION ............................................................................. 96 3.8.1 Materials and Methods ............................................................................ 96 xiv 3.8.2 Substrate Preparation .............................................................................. 98 3.8.3 Reaction Optimization .......................................................................... 133 3.8.4 Dioxidation........................................................................................... 135 3.8.5 Kinetic Analysis .................................................................................... 147 3.8.6 Trioxidation .......................................................................................... 150 3.8.7 Stereochemical Analysis........................................................................ 157 3.8.8 Product Functionalization ..................................................................... 175 3.9 REFERENCES................................................................................................ 181 CHAPTER 4 188 Progress Toward the Synthesis of (+)-Cassiabudanol A 4.1 INTRODUCTION ........................................................................................ 188 4.1.1 Structural Variety and Proposed Biosynthesis ........................................ 190 4.1.2 Medicinal Properties and Biological Activity ......................................... 193 4.1.3 Synthetic Studies ................................................................................... 194 4.1.3.1 Application of Ryanodol Synthesis by Inoue................................... 194 4.1.3.2 Ensley Approach to Cinncassiol D1 ................................................ 195 4.1.3.3 Reisman Synthesis of Perseanol ...................................................... 196 4.2 CONCEPTUAL SYNTHETIC DESIGN ........................................................... 197 4.3 FIRST GENERATION STRATEGY.................................................................. 198 4.3.1 Retrosynthetic Analysis ......................................................................... 198 4.3.2 Tartrate Acetonide: Precedent and Anticipated Challenges .................... 200 4.3.3 Forward Synthetic Efforts ....................................................................... 202 4.3.4 B-Ring Cyclization via Decarboxylative Conjugate Addition ................. 205 4.4 SECOND GENERATION STRATEGY ............................................................ 208 4.4.1 Revised Conceptual Synthetic Design and Retrosynthesis ...................... 208 xv 4.4.2 Preparation and Coupling of the Revised Diol Fragment........................ 210 4.4.3 Exploration of Transition Metal-Mediated B-Ring Formation.................. 213 4.4.3.1 Redox Relay Heck Cyclization ....................................................... 213 4.4.3.2 Interrupted Heck cyclization: Anion Capture.................................. 216 4.4.3.3 Steric Hypothesis: Targeting (E)-Substrate ....................................... 219 4.4.4 Development of Stereodivergent Reductive Coupling ............................ 220 4.4.5 Optimization of Redox Relay Heck Cyclization..................................... 228 4.4.5.1 Investigation of Catalytic Systems: Addressing Byproducts.............. 230 4.4.5.2 Investigation of Catalytic Systems: Catalyst Optimization ............... 234 4.4.5.3 Stoichiometric Studies.................................................................... 237 4.4.6 Toward cis-Fused Ring System .............................................................. 242 4.4.7 Decarboxylative Enol Addition Toward A Ring...................................... 246 4.5 THIRD GENERATION STRATEGY................................................................ 249 4.5.1 Alternative Conceptual Synthetic Design and Retrosynthesis ................. 249 4.5.2 Proton Series: (Z)-Substrate.................................................................... 251 4.5.3 Proton Series: (E)-Substrate .................................................................... 253 4.5.3.1 Silyl Enol Ether Generation via Cyclization..................................... 254 4.5.3.2 Ketone Generation via Cyclization ................................................. 256 4.5.4 Analysis and Comparison to Ester Series ................................................ 262 4.5.5 Route Optimization .............................................................................. 265 4.5.6 Oxidative Enolate Coupling Toward A Ring .......................................... 268 4.6 CONCLUDING REMARKS ........................................................................... 271 4.7 EXPERIMENTAL SECTION ........................................................................... 272 4.7.1 Materials and Methods .......................................................................... 272 4.7.2 First Generation Strategy ....................................................................... 274 4.7.3 Second Generation Strategy .................................................................. 295 4.7.4 Third Generation Strategy ..................................................................... 350 4.8 REFERENCES................................................................................................ 390 xvi CHAPTER 5 408 Formal Synthesis of (–)-Cylindrocyclophane F 5.1 INTRODUCTION ........................................................................................ 408 5.1.1 Natural Paracyclophanes ...................................................................... 410 5.1.2 Synthetic Efforts .................................................................................... 413 5.1.2.1 Cylindrocyclophanes: Macrocyclization ........................................ 414 5.1.2.2 Cylindrocyclophanes: Stereocenter Installation .............................. 418 5.2 CONCEPTUAL SYNTHETIC DESIGN AND RETROSYNTHESIS .................... 421 5.3 SINGLE REDUCTIVE CROSS-COUPING: MODEL REACTION ..................... 423 5.3.1 Investigation Using BiOX Ligands ......................................................... 425 5.3.2 Investigation Using BOX Ligands .......................................................... 440 5.4 SYNTHESIS OF DIMERIZATION SUBSTRATES ............................................ 441 5.4.1 Toward Cylindrocyclophane F .............................................................. 442 5.4.2 Toward Unsubstituted Paracyclophanes ................................................ 454 5.4.3 Toward Cylindrocyclophane A.............................................................. 455 5.5 DOUBLE REDUCTIVE CROSS-COUPLING .................................................. 457 5.5.1 Guiding Mechanistic Design ................................................................. 457 5.5.2 Cyclodimerization versus Polymerization.............................................. 462 5.5.3 Macrocyclization via Depolymerization................................................ 470 5.6 REVISED APPROACH AND FORMAL SYNTHESIS ....................................... 476 5.7 CONCLUDING REMARKS ........................................................................... 484 5.8 EXPERIMENTAL SECTION ........................................................................... 486 5.8.1 Materials and Methods .......................................................................... 486 5.8.2 Single Reductive Cross-Coupling........................................................... 488 5.8.3 Synthesis of Dimerization Substrates ..................................................... 504 5.8.4 Double Reductive Cross-Coupling ........................................................ 540 xvii 5.8.5 Revised Approach and Formal Synthesis ............................................... 555 5.9 REFERENCES................................................................................................ 578 APPENDIX 1 600 Spectra Relevant to Chapter 3 APPENDIX 2 737 Spectra Relevant to Chapter 4 APPENDIX 3 961 Spectra Relevant to Chapter 5 ABOUT THE AUTHOR 1100 xviii LIST OF ABBREVIATIONS [a]D angle of optical rotation of plane-polarized light Å angstrom(s) Ac acetyl acac acetylacetonate aq. aqueous atm atmosphere(s) bpy 2,2'-bipyridine Bn benzyl BOM benzyloxymethyl bp boiling point br broad Bu butyl i Bu iso-butyl n Bu norm-butyl t Bu tert-butyl c concentration of sample for measurement of optical rotation 13 C carbon-13 isotope °C degrees Celcius calcd calculated CAN ceric ammonium nitrate Cbz benzyloxycarbonyl xix cf. consult or compare to (Latin: confer) cis on the same side cm–1 wavenumber(s) CM cross-metathesis CO carbon monoxide COD 1,5-cyclooctadiene conv. conversion COSY homonuclear correlation spectroscopy CSA camphor sulfonic acid D heat or difference d chemical shift in ppm d doublet d deutero or dextrorotatory D deuterium 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 de novo starting from the beginning; anew DIBAL diisobutylaluminum hydride diglyme bis(2-methoxyethyl) ether xx 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 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) EI electron impact ent enantiomer of epi epimeric equiv equivalent(s) ESI electrospray ionization Et ethyl et al. and others (Latin: et alii) FAB fast atom bombardment FD field desorption FI field ionization xxi 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 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 xxii LCMS liquid chromatography–mass spectrometry LDA lithium diisopropylamide m multiplet or meter(s) M molar or molecular ion m meta µ micro Me methyl MeOH methanol MeCN acetonitrile mg milligram(s) MHz megahertz 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 xxiii 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 pKa acid dissociation constant pm picometer(s) PMB para-methoxybenzyl ppm parts per million PPTS pyridinium para-toluenesulfonate Pr propyl i Pr isopropyl n Pr propyl or norm-propyl psi pounds per square inch pyr pyridine q quartet quant. quantitative xxiv R generic group R rectus RCM ring-closing metathesis ref reference Rf retention factor rgt. reagent rr regioisomeric ratio rt room temperature sat. saturated s singlet or seconds S sinister SAR structure-activity relationship sat. saturated SFC supercritical fluid chromatography 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 xxv TMS trimethylsilyl TOF time-of-flight Tol tolyl trans on the opposite side Ts para-toluenesulfonyl (tosyl) UV ultraviolet vide infra see below vide supra see above w/v weight per volume X anionic ligand or halide xs excess Z cis (zusammen) olefin geometry  1100 ABOUT THE AUTHOR Sara Elise Dibrell was born and raised near San Antonio, TX. Her family encouraged her love of learning through endless library books, garage building projects, and a backyard wilderness ripe for exploration. Following graduation as valedictorian of Seguin High School in 2014, Sara pursued undergraduate studies at The University of Texas at San Antonio. She had the privilege of working in the lab of Prof. Doug Frantz, where she focused on catalytic reaction development and synthesis of compounds as potential therapeutic treatments for chronic pain. She obtained a B.S. in biochemistry and a minor in business administration with highest honors from UTSA in 2018. Sara then joined the lab of Prof. Sarah Reisman at the California Institute of Technology to pursue a graduate degree in organic chemistry. Her doctoral studies have allowed Sara to study a variety of topics, from oxidation methodology to stereoselective cross-coupling reactions and their strategic application to the synthesis of natural products. Following the completion of her Ph.D., Sara will join the Discovery Chemistry group at Merck near Philadelphia, PA, and enjoy free time as an amateur foodie and backpacker.  1 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis Chapter 1 Synthetic Design Guided by Oxidation Pattern Analysis† 1.1 INTRODUCTION With complex molecular structures, intriguing oxidation patterns, and wideranging biological activities, natural products have greatly impacted research in organic chemistry and drug discovery. Diterpenes, in particular, have long drawn the attention of synthetic chemists due to their diverse and fascinating molecular architectures. These are coupled to a wide range of biological activities, and promising anticancer, antibacterial, and antimalarial activities have inspired multimillion-dollar campaigns to develop complex diterpenes, such as paclitaxel, pleuromutilin, and artemisinin, as therapeutics.1 Over the past decade, many efforts have been directed toward the synthesis of complex and highly oxygenated diterpenes using functional group-guided topological strategies.2 These efforts highlight how the preparation of diterpenes by chemical- or † Portions of this chapter were adapted from the following communication: Dibrell, S. E.; Tao, Y.; Reisman, S. E. Acc. Chem. Res. 2021, 54 (6), 1360–1373. 2 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis semi-synthesis can transform our ability to use such molecules and their synthetic derivatives as biological probes or as lead compounds for the development of new medicines. Nonetheless, the elaborate polycyclic systems and intricate oxidation patterns that characterize many diterpenes can still hinder traditional medicinal chemistry studies of their biological activity.3 New advances in the science of chemical synthesis, driven both by the invention of new reactions and strategies, are required to provide flexible and modular access to this important class of natural products. Figure 1.1 Synthetic strategies guided by oxidation pattern analysis topology guides C–H oxidation Me Me HO OH H OH O HH Me Me O Me OH O Me Me Me O HO Me HO HO OH charge affinity patterns guide C–C bond formation In this introductory chapter, we present completed total syntheses of several highly oxidized diterpenes and show how analysis of oxidation patterns and inherent functional group relationships can inform key C–C bond disconnections that greatly simplify the complexity of polycyclic structures and streamline their syntheses (Figure 1.1). The approaches to synthetic strategy are based on the formalism that heteroatoms impose an alternating acceptor and donor reactivity pattern upon a carbon skeleton, a particularly useful idea when considering oxidized natural products as synthetic targets. Two major themes emerge. First, reductive cyclizations are strategic umpolung tactics for building polycyclic systems with dissonant oxidation patterns. Second, unexpected, emergent reactivity can be leveraged to effectively balance early-stage oxidation with topology-guided oxidative manipulations at a late stage. We hope that collective 3 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis discussion of the selected diterpene natural products conveys how oxidation pattern analysis can guide effective synthetic design. 1.1.1 Overview of Oxidized Diterpene Syntheses The syntheses discussed can be roughly grouped into two types of strategies, both of which were guided by consideration of the oxidation pattern of the target (Figure 1.2). Figure 1.2 Oxidized diterpene natural products H Me H HO Me Me H OAc O O O O Me O OH OH O HO HH O Me O Me HO Me HO Me O O OH OH H O (+)-pleuromutilin (4) OH Me Me Me (+)-ryanodine (5) O OH OAc (–)-longikaurin E (3) (–)-trichorabdal A (2) Me HO Me Me HO O OH Me O (–)-maoecrystal Z (1) H O NH Me H O Me Me Me OH OH Me OH HO OH (+)-perseanol (6) The first group includes the Isodon diterpenoids maoecrystal Z (1), trichorabdal A (2), and longikaurin E (3), and the antibiotic pleuromutilin (4); each possesses a key ghydroxyketone motif embedded within its polycyclic framework. The g-hydroxyketone is an example of what Evans classified a ‘dissonant’ charge affinity pattern: the polarization imparted along the carbon chain between the oxygen functional groups is mismatched (Figure 1.3).5b,5c Carbon–carbon bond formation within this dissonant path requires a polarity inversion, or as Seebach defined, ‘reactivity umpolung’.5c The position of this dissonant charge affinity pattern in each structure inspired synthetic strategies involving ring closure by Sm-mediated addition of an aldehyde-derived ketyl radical to an a,bunsaturated cabonyl.4,5 These syntheses highlight how this tactic is especially effective when used to simultaneously form rings and introduce 1,4-dioxygenation patterns. 4 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis Figure 1.3 Oxidation guides C–C bond formation Me HO O OH O + + + – R R R OH – + + HH Me R O Me OH consonant charge affinity pattern dissonant charge affinity pattern O R O γ-hydroxy ketone: dissonant charge affinity pattern keys reductive cyclization O + R R – R OH O Me bond formation via reactivity umpolung OH Me H HO Me OAc O O The second group includes the targets ryanodine (5) and perseanol (6), which required a different strategy to address their high degree of oxidation (Figure 1.4). In these systems, the oxidation was introduced in two stages: (1) in the first few steps of the synthesis, prior to construction of the primary carbon framework; and (2) at a late stage, through strategic deployment of C–H oxidation reactions. In both syntheses, nearly all oxidation is introduced in the required oxidation state, with the correct stereochemistry, avoiding lateral functional group manipulations. Figure 1.4 Topology guides oxidation OH O HO Me Me Me OH OH HO Me HO OH OH Me Me oxidation at early stage oxidation at late stage H H O Me Me Me OH HO Me HO OH HO 1.2 ADDRESSING DISSONANT CHARGE AFFINITY PATTERNS 1.2.1 ent-Kauranoid Diterpenes Plants of the Isodon genus are often used in Chinese traditional medicine and are the source of over 600 ent-kauranoid diterpenes.6,7 The parent compound, ent-kaurene, is the first cyclic diterpene produced as part of the gibberellin biosynthetic pathway in 5 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis plants and fungi. 8 One large subfamily of ent-kauranoids bears oxidation at C20. Examples of these natural products include (–)-longikaurin E (3), the 6,7-seco-entkauranoid (–)-trichorabdal A (2), and the rearranged 6,7-seco-ent-kauranoid (–)maoecrystal Z (1).11a,9 Recognizing that these ent-kauranoids share oxidation at C7, C11, and C20, a unified strategy was envisioned which might provide access to all three targets. In the biosynthetic pathway, ent-kaurene is oxidized and rearranges to 1, 2, and 3; an abiotic approach could incorporate key oxidized functional groups in spiro-lactone 8, then form the C6–C7 and C9–C11 bonds through reductive cyclizations. Figure 1.5 Retrosynthetic analysis of ent-kauranoid diterpenes 1,4-dioxidation: keying element for umpole cyclization strategy H Me Me Me Me 20 biosynthetic precursor 1 H Me H OAc O OH O 20 Me O O H OR O O 7 HO 2 (–)-trichorabdal A 6,7-seco-ent-kaurane Me RO Me H O Me 20 3 (–)-longikaurin E C20-oxidized ent-kaurane ent-kaurene Me O OH Me X6 20 Me H 9 7 O 1 HO Me 20 O H C 8 2 O O 21 1 (–)-maoecrystal Z rearranged 6,7-seco-ent-kaurane 3 unified, abiotic strategy H 11 O 11 OAc H Me TBSO H O OH Me Me OH O O 9 Me 10 O OH OAc C 8 common spiro-lactone 8a: X = CHO 8b: X = CH2OTBS 3 2 The general strategy was guided by identification of the g-hydroxyketone motif spanning C7 to C11 (Figure 1.5).10 This dissonant charge affinity pattern keyed the use of a SmI2-mediated reductive cyclization to generate an umpole at the C11 position. In the context of preparing maoecrystal Z, use of a dialdehyde (8a) was envisioned to enable a cascade process;8,9 initial formation of the C9–C11 bond followed by single electron reduction would give the corresponding enolate, which could undergo an intramolecular aldol reaction to close the central five-membered ring.11 Alternatively, SmI2-mediated monocyclization of 8b, followed by subsequent oxidative cyclization to form the 6 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis requisite bicyclo[3.2.1]octane, could enable elaboration to trichorabdal A (3) and longikaurin E (4). Figure 1.6 12-Step total synthesis of (–)-maoecrystal Z 1. TBSCl, imidazole DCM Me Me OH 2. m-CPBA NaHCO3, DCM Me (91% yield, 2 steps) 12 (3:1 anti:syn) 11 (–)-γ-cyclogeraniol CO2CH2CF3 Cp2TiCl2, Zn 2,4,6-collidine·HCl O Me H THF TBSO (74% yield) OTBS O OCH2CF3 H Me TBSO Me O 13 reductive coupling OTBS 15 10 OTiIV Me I Me LHMDS 4:1 THF/HMPA 0 to 23 °C O 14 (74% yield) H 1. H2SiF6, MeCN 2. DMP, DCM Me O O Me H O H O 2 x [O] reductive cyclization 1. SmI2, LiBr, tBuOH THF, –78 °C 2. Ac2O, TMSOTf DCM (40% yield, 2 steps) KHMDS, PhSeBr –78 °C Me TBSO Me (86% yield, 2 steps) O OTBS O O 16 (81% yield) OTBS H H 1. O3, DCM Et3N Me Ac O Me OAc O 12 Me then H2O2 O 17 8a Me TBSO O 7 2 rings, 4 stereogenic centers 2. Et3N, DCM Me N I Me Me Ac H O Me OAc O O 18 O 1:1 MeOH/H2O 1 M NaOH (38% yield) Me H HO Me OAc O O O 1 (–)-maoecrystal Z (80% yield, 2 steps) With (–)-1 as a first target,12 the TiIII-mediated reductive coupling of 12 with a variety of acrylates initially investigated, with the goal of incorporating the requisite side chain to minimize steps after lactone formation (Figure 1.6). Whereas the use of simple acrylates, such as methyl acrylate, gave 14 as the product in varying yield, acrylates with α-substituents failed to undergo the desired coupling. Fortunately, use of 2,2,2trifluoroethyl acrylate as an electrophilic partner under modified Gansäuer conditions13 led to the isolation of lactone 14 as a single diastereomer in good yield. The reaction presumably proceeds through radical intermediate 13, in which approach of the acrylate from opposite the large siloxymethylene group affords the desired C10 stereochemistry. Alkylation of the lactone followed by desaturation, desilylation, and oxidation gave dialdehyde 8a. In the key SmI2-mediated reductive cyclization, lithium salts were found to be critical for desired reactivity. Treatment of dialdehyde 8a with SmI2 in the presence of 7 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis LiBr and tBuOH as a proton source thus provided the tetracyclic diol, which was isolated as a single diastereomer. This transformation builds two rings and introduces two secondary carbinols in a single step. In fact, the cascade reaction was critical to forming the central five-membered ring; attempts to form the two rings sequentially, in a noncascade process, failed to identify conditions that engage the C6 aldehyde derived from tricycle 9 (see Fig. 1.7) in the intramolecular aldol. Diacetylation, ozonolysis, and methenylation gave enal 18, which upon mono-deacetylation delivered (–)-maoecrystal Z (1) in 12 linear steps from (–)-γ-cyclogeraniol (11).1 Figure 1.7 Total synthesis of (–)-longikaurin E and (–)-trichorabdal A Me TBSO Me 17 11 (–)-γ-cyclogeraniol O O Pd(OAc)2 AcOH O Me 21 O (56% yield) H 6M aq HCl 1,4-dioxane 45 °C Me HO 6 11 O Me 22 O OH (89% yield) then PPh3 (69% yield) KHMDS, TBSCl, DMPU 1. TEMPO PhI(OAc)2 H Me TBSO Me O 24 O DMF, 95 °C OMOM 6 Me (57% yield) (82% yield) SmI2 23 O 1 x [O] OAc THF 23 °C 10 O OH O OAc H O 25 O OMOM (91% yield) H 9 Me 2. TEMPO, PhI(OAc)2, DCM (73% yield, 2 steps) O OH OAc 3 (–)-longikaurin E H Me H O OH Me (44% yield, 2 steps) 1. 6M aq HCl 1,4-dioxane, 45 °C O Me DMF, 45 °C 19 2. Me2NCH2NMe2 Ac2O, DMF, 95 °C (55% yield, 75% yield brsm) Me TBSO OMOM 1. O3, DCM, –94 °C then PPh3 OH Me O MOMCl O H Me OH O nBu NI, iPr NEt 2 4 Me reductive cyclization O Me H Me2NCH2NMe2 Ac2O O Me 8b (85% yield) H 2. Ac2O DMAP O THF, –78 °C Me TBSO THF, –78 °C O O OMOM TBS (58% yield, 2 steps) 21 O3, DCM, –94 °C 20 O Me TBSO H H Me O 1 x [O] Me TBSO DMSO, 45 °C air OMOM H O Me (77% yield, 2 steps) OTBS oxidative cyclization H Me TBSO Me TBSO H SmI2, LiBr tBuOH H 2. DMP, DCM Me OH reductive cyclization 1. nBu4NHSO4 p-TsOH MeOH, 0 °C 5 steps Me O O Me O O HO 2 (–)-trichorabdal A 1 x [O] In order to access trichorabdal A and longikaurin E,14 the key spiro-lactone was utilized, and selective deprotection/oxidation of 17 was executed to prepare 8b (Figure 1.7). Fortunately, subjection of monoaldehyde 8b to the previously developed reductive cyclization conditions gave tricycle 9 as a single diastereomer, which was protected as Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 8 the methoxymethyl ether. Taking inspiration from Pd-catalyzed oxidative cyclizations of silyl enol ethers,15 a similar aerobic transformation of a silyl ketene acetal was envisioned that could establish the final carbocyclic ring and leverage the pendant alkene without need for further functionalization. Indeed, following extensive reaction development, subjection of 20 to stoichiometric Pd(OAc)2 in DMSO provided tetracycle 21. At this stage, intermediate 21 was diverted to targets (–)-3 and (–)-2 through slightly different reaction sequences. Global deprotection of 21 followed by selective oxidation at C6 and acetylation at C11 provided aldehyde 23. A SmI2-mediated intramolecular aldehyde–lactone pinacol coupling afforded lactol 10 as a single diastereomer, another example of the strategic use of SmI2 to introduce dissonant oxidation patterns via C–C bond formation. Finally, ozonolysis and methenylation gave (–)-3 in 17 steps (longest linear sequence) from 11. Alternatively, 21 could be advanced to 25 through ozonolyis and methenylation. Acidic deprotection and oxidation then revealed the aldehyde of (–)-2.17 The unified strategy enabled the first total syntheses of three architecturally distinct ent-kauranoids from a common intermediate and illustrates the utility of singleelectron reduction chemistry for the preparation of congested polycyclic systems bearing dissonant oxidation patterns. 1.2.2 Pleuromutilin The fungal diterpene (+)-pleuromutilin (4), first isolated in 1951, inhibits bacterial protein synthesis,16 and semi-synthetic analogues have been advanced into the clinic as antibiotics.17 Importantly, amine-containing 12-epi-4 derivatives have been reported as 9 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis efficacious against gram-negative pathogens. 18 With the goal of providing enabling chemistry for the synthesis of new mutilin-based antibacterial agents, a concise and flexible syntheses of both 4 and its C12 epimer was sought.19 Three prior syntheses20 of 4 all built the eight-membered ring relatively early in the synthesis, requiring lengthy sequences to then introduce the C10-C11-C12 stereotriad. In this synthetic planning, building the eight-membered ring by annulation with a functionalized C10–C14 fragment was envisioned in order to minimize functional group manipulations after tricyclic core formation (Figure 1.8). Figure 1.8 Retrosynthetic analysis of (+)-pleuromutilin R1 HO Me 10 R1 MOMO R2 R2 OH HH 14 O Me H OH O R1 MOMO R2 OSmIII Me Me O R1 MOMO reductive cyclization 14 Me Me 3 4 (+)-pleuromutilin R1 = Me, R2 = vinyl O 27 O 12-epi- 4 R1 = vinyl, R2 = Me 11 Me Me O O 32 30 Me (HO)2B 30 4 or E Me 15 e4 modular strategy R2 crotylation + OTrt R4 Me R3 Z -31 R3 = Me, R4 = CH2CH2OTrt E 32 28 R1 HO 12 H Z O Me 5 Me O O 26 R2 Me O 29 -31 R3 = CH2CH2OTrt, R4 = Me Similar to the approach to the Isodon ent-kauranoids, the dissonant ghydroxyketone pattern from C3 to C14 was identified as a keying element for a SmI2mediated reductive cyclization to form the C5–C14 bond. Although Procter had previously employed a SmI2-mediated cascade cyclization for the synthesis of 4,22c,d the design of that cascade required an ester at C15 to induce a ketyl radical conjugate addition. As a result, the Procter approach required several additional steps to adjust the oxidation states at C3 and C15. In contrast, a SmI2-mediated cyclization of 28 was expected to provide 26 with C3, C14, and C15 in the correct oxidation states. 10 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis Having identified this reductive cyclization tactic for forming the eight-membered ring, a synthetic plan was devised that would allow modular construction of aldehyde 28, so that both (+)-4 and 12-epi-4 could be prepared. It was anticipated that 28 could arise from the bifunctional hydrindanone fragment 30 by crotylation with either Z- or Eboronic acid 31. 21 Hydrindanone enal 30 was mapped back to cyclohexenone 32, available in one step from (+)-trans-dihydrocarvone.22 Figure 1.9 18-Step total synthesis of (+)-pleuromutilin O 1. Me MgBr Me 32 THF, –45 °C, then 32 2. Pd(OAc)2 (10 mol %) DMSO, O2, rt O O O Me O O (71% yield, 4.8:1 dr) 33 (91% yield, 2 steps) (77% yield) 9 –78 to –50 °C Me O 37 HO Me 11 Me reductive cyclization Me MOMO [Cu(MeCN)4]OTf 4-OMebpy, ABNO NMI, MeCN then TMSCl (5 equiv) Me (92% yield) Me O Me HO TFAO OH HH Me 28 1 x [O] O Me O Me O 4 (+)-pleuromutilin CO2H EDCI, DMAP DCM, rt, 1 h (93% yield, 23:1 dr) rigorously deoxygenated then MeOH, Et3N then HCl/THF 50 °C (80% yield) Me Me OTIPS 14 42 H OH Me Me 3 O 38 Me MOMO HH OH Me Li/NH3 EtOH LiHMDS TIPSOTf [1,5]-HAT O Me 41 single diastereomer Me Me (76% yield) OTIPS 39 26 [Mn] Mn(dpm)3 (13 mol %) PhSiH3, TBHP iPrOH, rt H (55% yield) ‡ H Me O Me OTIPS H OH THF –78 to 0 °C Me MOMO H Me Et2O, –78 °C (61% yield, 14:1 dr) 36 Me Me MOMO 20 Me Me MOMO Me O 19 10 Me SmIIIO (69% yield) 30 17 H OSmIII O DMSO, 95 ºC 1 x [O] Me MOMO Me MOMO SmI2 (3 equiv) H2O (6 equiv) THF, 0 °C, 5 min Me (80% yield, 99% brsm, 1.2:1 29a:29b) 29b 11,12-bis-epi O KH2PO4, NaI Me PhMe, 0 °C O Me 29a desired Cl H tBuOH, 3 Å MS Me Me O O (R)-3,3′-Br2-BINOL (20 mol %) OTrt Me (70% yield, 2 steps) OTrt Z -31 + OTrt 2. HCO2H, Et2O Me 1. CeCl3·2LiCl MeMgCl, 0 °C 2. PCC, DCM 35 34 12 1. MOMCl, iPr2NEt O Me O (52% yield, 4.4:1 dr) (HO)2B Me HO Me 2. HCl (aq), THF, 70 °C (78% yield, 2 steps) Me MOMO OH Cl 1. TCCA, EtOAc, 0 °C CuI, THF CuCN·2LiCl, TMSCl O Me MgBr O Me Me transannular redox relay OTIPS 40 In the forward direction, ketone 34, bearing a C9 quaternary center, was prepared via sequential conjugate additions (Figure 1.9). Allylic chlorination of the iso-propenyl group of 34 was performed prior to intramolecular aldol condensation in order to avoid a Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 11 competing, undesired Prins-type cyclization. Ketone 35 could be elaborated to enal 30 in three additional steps. To complete the first of two key bond-forming steps, selective syn-crotylation with boronic acid Z-31 gave desired diastereomer 29a after chromatographic separation. Unfortunately, despite the use of a chiral BINOL catalyst,23 high diastereoface selectivity for addition to the aldehyde was not able to be obtained. Nonetheless, the required diastereomer (29a) could be elaborated in three steps to aldehyde 28. To form the eightmembered ring, a freshly prepared SmI2 solution was added dropwise to 28; quenching of presumed Sm-enolate 38 with trimethylsilyl chloride then delivered tricycle 26 as a separable 23:1 mixture of diastereomers. Substantial optimization determined that rigorously anaerobic conditions were critical for minimizing byproduct formation and that addition of water was important for high diastereoselectivity. At this stage, completion of the synthesis hinged upon selective hydrogenation of the C10 exo-methylene in the presence of the C19 vinyl group. It was hypothesized that metal-catalyzed hydrogen atom transfer (MHAT) reduction might provide a solution, wherein the thermodynamic preference for formation of a tertiary carbon-centered radical could be leveraged. Indeed, chemoselective reduction of the exocyclic C10–C17 olefin was achieved; however, this reduction was accompanied by unanticipated C14 oxidation. Deuterium labeling experiments revealed that this reaction proceeds by a transannular [1,5]-HAT redox relay, thermodynamically driven by formation of the C14 ketone. By protecting the C3 ketone of 26 as a silyl enol ether prior to the MHAT redox relay, the C14 ketone of 41 could be reduced using dissolving metal conditions while preserving the ketone oxidation state at C3. Finally, acylation followed by global deprotection under 12 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis acidic conditions afforded (+)-pleuromutilin (4) in 18 steps in the longest linear sequence.2 Figure 1.10 18-Step total synthesis of (+)-12-epi-pleuromutilin Me O (HO)2B H O 30 HO E -31 11 12 (R)-3,3’-Br2-BINOL (20 mol %) Me Me OTrt OTrt Me tBuOH, 3 Å MS PhMe, 0 °C (85% yield, 2:1 dr at C11) MOMO Me Me O 29c 12-epi 3. [Cu(MeCN)4]OTf 4-OMebpy, ABNO NMI, MeCN (62% yield, 3 steps) reductive cyclization Me 1. MOMCl, iPr2NEt 2. HCO2H, Et2O O Me Me O MOMO SmI2 (3 equiv) H2O (6 equiv) THF, 0 °C, 5 min H 4 steps OH Me then TMSCl (5 equiv) (77% yield, 17:1 dr) 12-epi-28 1 x [O] Me 12-epi- 4 Me O 12-epi-26 An advantage of this modular approach was the ability to readily prepare the 12epi-4 framework by varying the relative configuration of cyclization substrates at C12 (Figure 1.10). To this end, enal 30 was crotylated with E-31 to deliver 29c, which was elaborated to 12-epi-28 without difficulty. Exposure of 12-epi-28 to the optimal SmI2 cyclization conditions furnished 12-epi-26, then advanced via the previously developed 4-step sequence to complete the synthesis of 12-epi-4. The brevity and modularity of these syntheses, enabled by the unique ability of radical cyclizations to overcome the challenges that dissonant charge affinity patterns pose to standard bond constructions, are anticipated to facilitate preparation of new pleuromutilin antibiotics. 1.3 COMPCOMPLEX OXIDATION TOPOLOGY 1.3.1 Ryanodane Diterpenes A classic example of how natural products can impact understanding of biology is the story of (+)-ryanodine. (+)-Ryanodine (5) is a highly oxidized diterpene isolated from the tropical shrub Ryania speciose Vahl. 23 Investigation of ryanodine’s insecticidal properties ultimately led to the purification and characterization of intracellular Ca2+ ion 13 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis channels now known as the ryanodine receptors (RyRs),24,25 which are involved in a number of signal transduction processes. Whereas both 5 and its hydrolysis product (+)ryanodol (43) bind insect RyRs,26 43 exhibits significantly lower affinity for mammalian receptors.27 In addition, structurally related diterpenes that vary in peripheral oxidation, including (+)-20-deoxyspiganthine (44), have also been identified as RyR modulators.28 Due to their biological importance, ryanodanes have been the focus of total synthesis29,30 and medicinal chemistry30,31 efforts for several decades. However, at the outset of these studies, there were no completed total syntheses of ryanodine, due in part to the challenges associated with introduction of the pyrrole-2-carboxylate at the C3 alcohol of ryanodol (43). With the long-term goal of developing new probes of RyR function, a synthetic platform was devised for the preparation of (+)-5 and related congeners (i.e., (+)-44). Figure 1.11 Retrosynthetic analysis of ryanodane diterpenes OH 15 O HO D E Me 10 C 1 OH Me Me 2 12 A B 4 3 6 Me OH OH O HO OH Me Me Me O O OH Me HO Me HO H HO Me OH O HO HO OH H Me Me Me NH O OH HO Me HO H 47 Me O H C 49 C 51 5 44 (+)-ryanodol (+)-ryanodine (+)-20-deoxyspiganthine 43 48 NH 43 44 or 5 late-stage divergence reductive cyclization O Me O HO Me Me OR2 Me HO Me HO OH H (+)-anhydroryanodol (45) R2 = H (+)-anhydroryanodine (46) R2 = pyrrole-2-carboxylate oxidation at late stage cross coupling O Me O BOMO C–H OTf oxidation O BOMO O Me Me BOMO Me HO O oxidation at early stage O Me O O BOMO PKR Me R1 BOMO Me 47 R1 = H 49 H [O] Me BOMOMe 51 (S)-(–)pulegone 50 48 R1 = OH Initial efforts focused on the preparation of (+)-43, with the idea that the synthetic strategy could be applied to (+)-5 and other ryanodanes (Figure 1.11).32,33,34 Inspiration was drawn from early relay studies by Deslongchamps and coworkers, which established that the C1–C15 bond of the bridging E ring could be formed via epoxidation of 45 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 14 followed by reductive cyclization. 32 With (+)-anhydroryanodol (45) as a slightly simpler target, the strategy was directed by the dense oxidation of the tetracyclic core. It was hypothesized that an A-ring cyclopentenone, such as that in 49, could undergo sequential oxidation in the final steps of the synthesis to install the C3 alcohol and the syn-C4–C12diol with the appropriate stereochemistry. In contrast, the C-ring oxidation could be incorporated early in the synthesis while assembling the carbon framework. With this goal in mind, an intramolecular Pauson–Khand reaction (PKR)35 was identified as a key tactic to prepare cyclopentenone 49. The requisite enyne (50) was mapped back to (S)-(– )-pulegone (51), with the expectation that sequential oxidation α to the ketone could be used to install the C6 and C10 alcohols. Studies began with the oxidation of (S)-(–)-pulegone (51, Figure 1.12). Although a multistep sequence to 53 via known pulegone oxide was initially envisioned, it was ultimately found that treatment of 51 with excess KHMDS followed by oxaziridine 52 resulted in dihydroxylation to form 53 as the major diastereomer. Further mechanistic investigations are required, but preliminary studies suggest that the reaction proceeds first by generation of the thermodynamic potassium dienolate, which upon reaction with 52 gives rise to the C6 tertiary alkoxide as a mixture of diastereomers. 36 A second enolization and oxidative trapping gives rise to α,α′-diol 53 in 40–50% yield following silica gel chromatography. In this single transformation, a key building block is accessed with the complete C-ring functionality found in ryanodol and ryanodine. Following protection of the alcohols, the D ring was constructed by a four-step sequence involving 1,2-addition of prop-1-yn-1-yl magnesium bromide followed by ozonolytic olefin cleavage to afford ketone 55. A second 1,2-addition and subsequent Ag- 15 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis catalyzed cyclization/elimination cascade37 then gave α,β-unsaturated lactone 56. The critical all-carbon quaternary center was formed as a single diastereomer by 1,4-addition of a vinyl cuprate reagent, giving 50. Pauson–Khand cyclization with catalytic [RhCl(CO)2]2 under an atmosphere of carbon monoxide (CO) provided cyclopentenone 49 as a single diastereomer.38 Figure 1.12 15-Step total synthesis of (+)-ryanodol Me O KHMDS, then Me 51 HO 52 BOMO Me Me 53 Cl 1. Me MgBr THF, 0 °C O (5:1 dr, 81% yield) Me iPr NEt, TBAI 2 DCM, 50 °C 54 (65% yield) 2 x [O] Me 2. O3/O2, DCM/MeOH –78 °C, then PPh3 Me BOMO OH BOMO O Me BOMO 3 4 O H O BOMO [RhCl(CO)2]2 (1 mol %) O Me CO (1 atm) m-xylene, 110 °C 49 O BOMO MgBr Me Me CuI, THF –78 to –30 °C BOMOMe 50 (85% yield) 1. EtO MgBr THF, 23 °C Me 2. AgOTf (2 mol %) PhMe, 0 °C Me BOMO 56 (84% yield) (68% yield, 2 steps) 3 C–C bonds, 2 new rings 1. SeO2, 4Å MS 1,4-dioxane, 110 °C 2. Comins’ Rgt iPr NEt, DCM 2 –78 to 0 °C (56% yield of 47, 2 steps) OR Me (28% yield of 48, 2 steps) 1. SeO2, H2O 1,4-dioxane, 110 °C O Me O BOMO 2. Comins’ Rgt iPr NEt, DCM 2 –78 to 0 °C 49 Me 55 (91% yield) O 2 12 Me BnO BOMO (50% yield) O Me O BOMO 6 HO THF, –78 °C (S)-(–)-pulegone 10 Me N SO2Ph O Ph Me O HO 3 x [O] 57 R = H 48 R = Tf OH SnBu3 BOMO Me OH O HO OR Me O HO 2 x [O] 58 R = H 47 R = Tf H OH OH HO Me HO OH O 1. LiBH4, THF then KHF2/MeOH 2. H2, Pd(OH)2/C EtOH, 22 °C (61% yield, 2 steps) reductive cyclization Me Me Me BOMO Me HO 59 (64% yield) O Me O BOMO Me Me PdCl2(PPh3)2 LiCl, 2-MeTHF O BOMO Me Me O Me O BOMO OH H 43 (+)-ryanodol Me 1. CF3CO3H, Na2HPO4 1,2-DCE, 20 °C (86% yield) 2. Li0, NH3/THF –78 °C (38% yield) O Me O HO Me Me OH HO Me HO OH Me H (+)-anhydroryanodol (45) Having identified a concise route to tetracycle 49, the remaining task was the challenging introduction of the alcohols at C3, C4, and C12, with the C4 alcohol expected to be the most challenging of the three. Initially, conditions were investigated for allylic oxidation at C4; however, this proved unfruitful and led to the pursuit of SeO2mediated α-oxidation of the C2 ketone.39 Surprisingly, treatment of 49 with SeO2 and K3PO4 in refluxing dioxane resulted in the isolation of hydroxyenone 58, wherein the presumed intermediate enediketone underwent hydration at C12. Careful analysis of the Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 16 reaction mixtures indicated the presence of a minor side-product assigned the structure of 57, a compound which had undergone further oxidation at C4. Although the yield was very low (<5%), it was recognized that this remarkable transformation installs the oxygen atoms at C3, C4, and C12, as well as a functional group handle for incorporation of the C2-iso-propyl group, all in a single step. As result, improvement to the yield was sought, and ultimately heating 49 with excess SeO2 in rigorously anhydrous 1,4-dioxane gave increased amounts of 57, which could be isolated as enol triflate 48 in 28% yield over the two steps. Alternatively, oxidation of 49 with SeO2 and 10 equiv water in 1,4-dioxane, followed by triflation, gave 47 in 56% yield. To complete the synthesis of (+)-43, enol triflate 48 was submitted to Pdcatalyzed Stille cross-coupling, ketone reduction, and hydrogenation to deliver (+)anyhdyroryanodol (45). In slight modification of the reported protocol,32 treatment of 45 with freshly prepared trifluoroperacetic acid cleanly afforded the epi-anhydroryanodol epoxide, which could be subjected to Li in NH3 to effect reductive cyclization to (+)ryanodol (43).3 With only 15 steps, this synthesis represents a ca. 50% reduction in length compared to previous syntheses.32,33 Given the known challenge associated with preparing ryanodine by site-selective C2 acylation of 43, the synthetic strategy to 5 called for departure from the ryanodol end game, such that the pyrrole 2-carboxalate could be introduced selectively without extensive additional protecting group manipulations.33a,c;34,40 Moreover, it was anticipated that dioxidation product 47 could be used to prepare the related natural product 20deoxyspiganthine. Although there was some uncertainty as to whether the pyrrole 2carboxalate could survive the final reductive cyclization, anhydroryanodol derivatives 61 17 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis (Figure 1.13) and 68 (Figure 1.14) were nonetheless identified as potential candidates for acylation. Figure 1.13 18-Step total synthesis of (+)-ryanodine Me O O Me O BOMO 11 steps Me Me Me 51 Me BOMO Me HO O Me O BOMO PtO2 H2 (1 atm) Me O (90% yield) BOMO Me HO OH H KHF2 (aq) MeOH, 40 ºC Me O N H BOMO Me O Me Me Me O HO H BOMO Me OH Me VO(acac)2 TBHP Me O O Me O BOMO (60% yield) 65 H O O O HO H BOMO Me OH 66 NaH, DMF (57% yield) 63 Me O N H N H Me N H 62 O OH reductive cyclization Me OH O BOMO Me O H B Me 61 Me LiDBB Me N H O O B 2 Me (71% yield) O O Me O BOMO Cl3C Me (90% yield) LiBH4, THF –10 to 0 °C O Me O BOMO 64 O BOMO Me 3 O O BOMO Me O B Me 60 (84% yield) O OH Me 59 (S)-(–)-pulegone O Me O BOMO MeB(OH)2 PhH, 23 °C O HO Me Me O OH THF, –78 ºC (65% yield) Me Me HO Me HO OH H O N H 5 (+)-ryanodine The synthesis of (+)-5 commenced with diol 59, which was strategically protected as a dioxaborinane (Figure 1.13). Reduction of the C3-ketone furnished 61, bearing a single unprotected alcohol. A survey of standard acylating reagents derived from pyrrole2-carboxylic acid failed to deliver pyrrole ester 63; however, deprotonation of alcohol 61 before addition of trichloroketone 62 successfully provided 63. This reaction is noteworthy: efforts to perform the acylation on a compound bearing an iso-propyl, instead of iso-propenyl, substituent at C2 were unsuccessful. Subsequent deprotection, hydrogenation, and hydroxyl-directed epoxidation revealed 66. Whereas the use of Li/NH3, the conditions employed for the synthesis of ryanodol, resulted in reductive cyclization with concomitant deacylation, the use of lithium di-tert-butylbiphenylide (LiDBB) in THF effected C–C bond formation and alcohol debenzylation to provide (+)ryanodine (5) in 65% yield.35 18 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis A similar sequence was used to elaborate alcohol 67 to 20-deoxyspiganthine (44, Figure 1.14). In this case, the C12 alcohol was protected as a TMS ether prior to reduction of the C3 ketone. Despite the similarity of 68 to 61, this acylation required further optimization of the reaction conditions in order to minimize non-productive translactonization. Ultimately, 68 was treated with excess KHMDS to enolize the lactone and prevent translactonization; while this enabled acylation of the C3 alcohol with pyrrole 69, a-chlorination of the lactone was also observed. Radical dechlorination of 70 afforded lactone 71, which was uneventfully advanced to (+)-20-deoxyspiganthine (44) by hydrogenation, epoxidation, and reductive cyclization.35 This represents the first total synthesis of a spiganthine-type natural product. Figure 1.14 19-Step total synthesis of (+)-20-deoxyspiganthine Me 47 O BOMO SnBu3 Me PdCl2(PPh3)2 LiCl, 2-MeTHF 12 3 BOMO Me (89% yield) HO H O Me 1. TMSOTf pyridine 2. LiBH4 OH Me Me Me O OH (60% yield, 2 steps) OH O BOMO Me H TMS HO H H O Me (58% yield) O Me O BOMO O 44 (+)-20-deoxyspiganthine HO H O H O Me O O BOMO Me H TMS N H 72 H (TMS)3SiH Et3B, air Me N (90% yield) TBS O 70 1. TAS-F 2. PtO2 H2 (1 atm) Me O Cl O BOMO Me (61% yield, 5.8:1 dr) Me Me BOMO Me 69 N TBS KHMDS H 68 LiDBB N H O Me reductive cyclization Me Cl3C O Me O BOMO 67 O HO HO Me O Me 3. VO(acac)2 TBHP (64% yield, 3 steps) O BOMO O Me Me O O BOMO Me H TMS H Me N O TBS 71 Taken together, these ryanodane studies highlight how managing formation of C– C and C–O bonds to introduce functionality at the correct oxidation level can minimize protecting group adjustments and lead to concise syntheses. 1.3.2 Isoryanodane Diterpenes Having established a synthetic strategy to prepare several ryanodane natural products, attention was turned to a related family of targets: the isoryanodanes. The 19 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis isoryanodanes possess a 5-6-5 ABC ring system instead of the 5-5-6 system found in the ryanodanes but bear a similar, dense oxidation pattern. Although it has not been conclusively established, it seems likely that these compounds are biosynthetically related. One interesting divergence is that none of the isoryanodanes isolated to date possess a pyrrole-2-carboxylate ester like that found in ryanodine, although many retain potent insecticidal properties. For example, (+)-perseanol (6) 41 displays potent antifeedant activity with low toxicity to mammalian cells,42 as do related isoryanodane diterpenes.43 This has raised the question as to whether the target of these compounds is indeed the insect RyR or whether they act through a distinct mode-of-action. Perseanol is decorated by six free hydroxyl groups around a highly caged pentacyclic core that includes a bridging 7-membered lactol. Prior to these studies, there was a single report describing an approach to the complex framework but no completed syntheses.44 Inspired by the potential to further investigate isoryanodane mode-of-action, a convergent synthesis of (+)-6 was developed.45 Figure 1.15 Retrosynthetic analysis of (+)-perseanol OH Me H C OD B E Me Me Me reductive cyclization Me H O Me 15 O Me Me [O] 1 A H O OPMB Me H O Me OH HO Me HO HO OH Me H Me OPMB HO Me Pd-catalyzed carbonylative cyclization H H RO RO Me H Me Br OPMB Me H 52 RO RO Me 92 + I Me Br 91 52 [O] 88 91 convergent strategy Me OH [Pd] OPMB 5 RO Me RO H Me Me 89 90 fragment coupling O H 88 (+)-anhydroperseanol (87) 6 (+)-perseanol Me RO Me RO oxidation at late stage HO Me HO HO OH 92 O Me Me oxidation at Me 51 early stage (R)-(+)-pulegone 6 20 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis Guided by the approach to ryanodine, a late-stage reductive cyclization was envisioned that could be used to form the C1–C15 bond, leading to retrosynthetic simplification of 6 to anhydroperseanol (87, Figure 1.15). Although a Pauson–Khand approach was initially pursued to prepare the carbon framework of anhydroperseanol, this led to challenges in forming the 7-membered lactone-containing enyne. These challenges led us to a revised synthetic strategy. Analysis of the oxidation patterns in 87 suggested that the A–B ring fusion diol could be accessed from tetracyclic alkene 88, whereas the B–C ring fusion diol might be introduced early in the synthesis. Tetracyclic lactone 88 was dissected into two fragments that could be joined in two C–C bond-forming steps. First, 1,2-addition of a metallated fragment derived from 91 into aldehyde 92 was envisioned. Second, the resulting alkenyl bromide (90) could undergo an intramolecular Pd-catalyzed carbopalladation/carbonylation cascade to forge the central 7-membered lactone. To access the enantioenriched fragments required for a convergent fragment coupling, enal 92 was expected to be prepared from (R)-(+)-pulegone (51) and vicinal dihalide 91 from commercially available 3-ethoxycyclopent-2-en-1-one (99). Figure 1.16 Preparation of the C-ring fragment Me O Br2, NaHCO3 Et2O, –10 ºC Me Me Me 51 (78% yield, 1.3:1 dr) (R)-(+)-pulegone O H O Me O H Me 92 1 x [O] Cu(MeObpy)OTf (5 mol %) ABNO (1 mol %) NMI (10 mol %) MeCN, air, 23 ºC Me 94 1 x [O] O (92% yield) 95 Ph Me O H 98 (87% yield) O Ph O H Et2Al(TMP) PhMe, 0 ºC (68% yield) Me Me O H then DIBAL, 0 ºC O CO2Me Me NaHCO3 DCM, 0 ºC Me OH H m-CPBA Me (67% yield, 9:1 dr) 93 Me HO CO2Me 10 P(OMe)3, THF –78 ºC Me Me H Ph Me then NaOMe 55 ºC Me HO KHMDS then O2 (1 atm) CO2Me 97 OMe PhCH(OMe)2 Me CSA, 1,2-DCE 23 ºC H O OMe HO HO Me 96 (98% yield) In the forward sense, the C-ring fragment (92) was prepared by known Favorskii rearrangement 46 of 51 followed by diastereoconvergent α-hydroxylation to yield 94 21 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis (Figure 1.16). Hydroxyl-directed epoxidation and isomerization then provided syn-diol 96. Through this four-step sequence, the B–C ring fusion diol was efficiently introduced at the beginning of the synthesis with the correct relative stereochemistry. Diol 96 could be elaborated in two additional steps to alkenyl aldehyde 92. Figure 1.17 Preparation of the A-ring fragment Me O O I O Me I2, CAN Me EtO LDA, Et2Zn HMPA, THF –78 to 23 ºC 99 Me EtO NaOH (aq) Me MeCN 0 to 23 ºC 100 EtO (73% yield) O Me I 101 Me I Me 1,4-dioxane MeOH, 23 ºC O 102 (70% yield) OPMB Me I Me Br OH I Me Me (–)- 52 91 Br PMBO N (81% yield) O Me (–)-106 (44% yield, 91% ee) matched + Me O I Me O N H B Me Br (–)-105 (56% yield, 68% ee) (43% yield, 93% ee) B 104 1x recycle 0 to 23 ºC (68% yield, 5:1 rr, 2 steps) kinetic resolution Me CSA (20 mol %) DCM, 23 ºC (COBr)2 DMF, DCM I Me H H (R)-(+)-2-Me-CBS -catalyst (40 mol %) BH3•NEt2Ph CH2Cl2, 23 ºC O Me I Me Br (±)-103 Br Synthesis of the A-ring fragment (91) began with alkylation of the zinc enolate of vinylogous ester 99 (Figure 1.17). An iodination/hydrolysis sequence provided diketone 102, which was immediately brominated to yield bromoiodocyclopentenone 103. Finally, an enantioselective Corey–Bakshi–Shibata (CBS) reduction47 of (±)-103 resulted in a kinetic resolution that provided alcohol (–)-106 in 91% enantiomeric excess, which was protected to furnish dihalide fragment 91. With both fragments in hand, a two-step annulation strategy was investigated to forge the tetracyclic ring system. Selective lithiation of iodide 91 and addition to aldehyde 92 provided secondary alcohol 90 in good yield but modest diastereoselectivity (Figure 1.18). To close the central B ring, a carbopalladation/carbonylation cascade was investigated, with the goal of forging two C–C bonds and setting the all-carbon quaternary center in a single step. This reaction required extensive optimization to identify conditions that favored formation of the seven-membered lactone in preference 22 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis to the five-membered lactone accessible via competitive direct carbonylation of the alkenyl bromide. In particular, it was important to maintain a low concentration of CO in solution to avoid inhibition of alkenyl bromide oxidative addition and to favor alkene insertion prior to carbonylation. Ultimately, use of N-formylsaccharin with KF as an activator48 and 50 mol% Pd(PPh3)4 proved optimal; under these conditions, the bridging lactone 88 could be formed in 57% yield as a single diastereomer. Figure 1.18 16-Step total synthesis of (+)-perseanol Me O H H + O Ph (75% yield, 3.2:1 dr) (–)- 52 91 Br 6 steps Ph Me H O OH O Me H O O Me Me Me Me O H O Me Me O O 110 Me Ph Ph O Me pH 7 buffer DCM, 0 ºC H 88 H (80% yield) Ph O O H O Na2SO4 acetone, 23 ºC O Me Me17 VO(OnPr)3 Me TBHP, PhMe 60 ºC O (68% yield) 112 Ph O H Me 107 O Me Me O H O O O Me OH O 113 Ph Ph H Me selective 3º [O] OH Me Me H Me O Ph Me Me OH O 15 H 2 O (78% yield) 111 DMDO O OH O H 108 2 x [O] H 1,4-dioxane 100 ºC O Me H Me Me Me Me O Me HO SeO2 4 O Ph DDQ Me O O O H (55% yield, 3:1 rr, 2 steps) H HO H (57% yield) CeCl3·2LiCl THF, 0 ºC Me HO Me BzO Me 90 MeMgCl 109 O O Me TFA, DCM, 0 ºC Me KF, Et3N 1,4-dioxane, 100 ºC O OPMB Me H O 1 all-carbon quaternary center 2 C–C bonds, 2 new rings Me (90% yield) Pd(PPh3)4 (50 mol %) N-formylsaccharin Me Br H 6 steps oxygen transposition H O Me Me H Me 92 Me OPMB HO H nBuLi I Me O H Me OPMB Me O Me Me OH HO Me HO HO OH 6 (+)-perseanol 15 Me Me Pd(OH)2/C H2 (1 atm) MeOH, 23 ºC (90% yield) O H O O OH Me 1 Me MeO O H Ph 115 OH Me Me O H OH Me Me Me O O O Me Ph O 114 OH Li LiPNap PhH/THF (1:1), 10 ºC (25% yield, 43% brsm) reductive cyclization To complete the synthesis, the tetrasubstituted allylic alcohol needed to be transformed into the A–B ring fusion diol. To this end, PMB deprotection of 88 followed by treatment with dimethyl dioxirane (DMDO) was found to deliver the C15 ketone, in addition to unexpected benzylidene acetal oxidation. This transformation had not been a part of the initial plan; we nonetheless continued with efforts to elaborate towards 6. Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 23 Following 1,2-addition of methyl Grignard to hydroxybenzoate 108, it was discovered that diol 109 could be converted to orthobenzoate 111 by treating with trifluoroacetic acid, presumably proceeding through dioxolenium ion 110. This three-step sequence, although outside of the original synthetic design, allowed us to repurpose the benzylidene acetal from a diol protecting group to an anchimeric directing group. Having enabled installation of the C4 tertiary alcohol, it resumed the role as an alcohol protecting group, now in the form of an orthobenzoate. This series of transformations illustrates how some of the most strategic reaction sequences arise from leveraging the emergent reactivity of the molecule, rather than strictly adhering to a preconceived synthetic design. Tetracyclic alkene 111 was found to undergo selective allylic oxidation of the tertiary C–H bond at C2 to give allylic alcohol 112. Again, an opportunity to revise the synthetic plan arose. Although epoxidizing anhydroperseanol (87) in order to execute a reductive cyclization analogous to those employed in the syntheses of ryanodine and ryanodol had been initially envisioned, it was recognized that the synthesis could be streamlined by instead preparing the isomeric epoxide 113. This type of reductive cyclization was unprecedented; however, given that 112 could be stereoselectively converted to 113 in good yield, it seemed worthwhile to pursue. Extensive investigation of a variety of reductants revealed that lithium 2phenylnaphthalenide in THF/benzene effected the reductive cyclization of 113 to construct the C1–C15 bond and deliver 115 in 25% yield. Interestingly, C2-des-isopropyl-113 undergoes reductive cyclization in >50% yield (not shown), indicating that the steric bulk of the iso-propyl substituent likely slows down the rate of C–C bond formation. Final hydrogenolysis of the orthobenzoate afforded (+)-perseanol (6).4 The Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 24 successful first total synthesis of (+)-6 in 16 linear steps testifies to the power of convergent fragment couplings; additionally, the opportunistic formation of the A–B ring fusion diol illustrates that strategic redox planning can enable fortuitous discoveries to drive synthetic efficiency. 1.4 CONCLUDING REMARKS The preceding sections detail several total syntheses of diterpene natural products. In these examples, synthetic planning was guided by target structures, with bond-forming tactics chosen to leverage inherent functional group relationships and their charge affinity patterns in order to minimize redundant changes to carbon oxidation states. In addition, careful choreography of C–C and C–O bond construction allowed strategic introduction of oxidation, thereby reducing synthetic manipulations ancillary to the direct assembly of the natural product. At the broader level, these intellectual advancements provide a conceptual framework that has motivated our efforts to develop new strategies and methodologies for the synthesis of additional natural products. In Chapter 3, we explore in greater detail unusual oxidative reactivity (see Fig. 1.12) as methods for the simultaneous installation of multiple C–O bonds in natural product-like scaffolds. In the following chapters, we turn to tactics for strategic C–C bond formation complementary to the methods presented above. Specifically, we discuss reductive cross-coupling reactions (introduced in Chapter 2), which we anticipated to be particularly effective for carbocycle construction and enable efforts to synthesize the rearranged isoryanodane diterpene (+)-cassiabudanol A (Chapter 4), as well as the macrocyclic cylindrocyclophane natural products (Chapter 5). Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 25 1.5 REFERENCES (1) Breitmaier, E. Terpenes: Flavors, Fragrances, Pharmaca, Pheromones; John Wiley & Sons, 2006. (2) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley, 1989. (b) Evans, D. A.; Andrews, G. C. Allylic Suloxides: Useful intermediates in orgnic Synthesis. Acc. Chem. Res. 1971, 7, 147–155. (c) Evans, D. A. An Organizational Format for the Classification of Functional Groups. Applications to the Construction of Difunctional Relationships. (c) Seebach, D. Methods of Reactivity Umpolung. Angew. Chem. Int. Ed. 1979, 18 (4), 239–258. (d) Hendrickson, J. B. Systematic Characterization of Structures and Reactions for Use in Organic Synthesis. J. Chem. Soc. 1971, 93 (25), 6847–6854. (3) Koehn, F. E.; Carter, G. T. The Evolving Role of Natural Products in Drug Discovery. Nat. Rev. Drug Discov. 2005, 4 (3), 206–220. (4) (a) Molander, G. A.; Harris, C. R. Sequencing Reactions with Samarium(II) Iodide. Chem. Rev. 1996, 96 (1), 307–338. (b) Edmonds, D. J.; Johnston, D.; Procter, D. J. Samarium(II)-Iodide-Mediated Cyclizations in Natural Product Synthesis. Chem. Rev. 2004, 104 (7), 3371–3404. (5) (a) Fukuzawa, S.-I.; Nakanishi, A.; Fujinami, T.; Sakai, S. Reductive Coupling of Ketones or Aldehydes with Electron-deficient Alkenes Promoted by Samarium diiodide. J. Chem. Commun. 1986, 624–625. (b) Enholm, E. J.; Trivellas, T. Lanthanide Induced Intramolecular Coupling of Aldehydes and Ketones with Electron-Deficient Olefins. Tetrahedron Lett. 1989, 30, 1063–1066. 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Soc. 1948, 70 (9), 3086−3088. (b) Wiesner, K.; Valenta, Z.; Findlay, J. A. The structure of ryanodine. Tetrahedron Lett. 1967, 8 (3), 221–223. 30 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis (24) (a) Pessah, I. N.; Waterhouse, A. L.; Casida, J. E. The calcium-ryanodine receptor complex of skeletal and cardiac muscle. Biochem. Biophys. Res. Commun. 1985, 128 (1), 449−456. (b) Inui, M.; Saito, A.; Fleischer, S. solation of the ryanodine receptor from cardiac sarcoplasmic reticulum and identity with the feet structures. J. Biol. Chem. 1987, 262 (32), 15637−15642. (25) (a) Ryanodine Receptors: Structure, Function and Dysfunction in Clinical Disease; Wehrens, X. H. T., Marks, A. R., Eds.; Developments in Cardiovascular Medicine; Springer US, 2005. (b) Lanner, J. T. Ryanodine Receptor Physiology and Its Role in Disease. In Calcium Signaling; Islam, M. S., Ed.; Advances in Experimental Medicine and Biology; Springer: Dordrecht, The Netherlands, 2012. (26) (a) Meissner, G. Ryanodine activation and inhibition of the Ca2+ release channel of sarcoplasmic reticulum. J. Biol. Chem. 1986, 261 (14), 6300−6306. (b) Meissner, G.; El-Hashem, A. Ryanodine as a functional probe of the skeletal muscle sarcoplasmic reticulum Ca 2+ release channel. Mol. Cell. Biochem. 1992, 114 (1), 119−123. (27) Sutko, J. L.; Airey, J. A.; Welch, W.; Ruest, L. The pharmacology of ryanodine and related compounds. Pharmacol. Rev. 1997, 49 (1), 53−98. (28) (a) Achenbach, H.; Hübner, H.; Vierling, W.; Brandt, W.; Reiter, M. Spiganthine, the cardioactive principle of Spigelia anthelmia. J. Nat. Prod. 1995, 58 (7), 1092−1096. (b) Hübner, H.; Vierling, W.; Brandt, W.; Reiter, M.; Achenbach, H. Minor constituents of Spigelia anthelmia Phytochemistry 2001, 57 (2), 285−296. and their cardiac activities. Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 31 (29) (a) Beĺanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C. C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Saint-Laurent, L.; Saintonge, R.; Soucy, P.; Ruest, L.; Deslongchamps, P. Total Synthesis of Ryanodol. Can. J. Chem. 1979, 57 (24), 3348−3354. (b) Deslongchamps, P.; Beĺanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C. C.; Maclachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. 1. General Strategy and Search for a Convenient Diene for the Construction of a Key Tricyclic Intermediate. Can. J. Chem. 1990, 68 (1), 115−126. (c) Deslongchamps, P.; Beĺanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C. C.; Maclachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. 2. Model Studies for Ring B and Ring C of (+)-Anhydroryanodol. Preparation of a Key Pentacyclic Intermediate. Can. J. Chem. 1990, 68 (1), 127−152. (d) Deslongchamps, P.; Beĺanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C. C.; Maclachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. 3. Preparation of (+)-Anhydroryanodol from a Key Pentacyclic Intermediate. Can. J. Chem. 1990, 68 32 Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis (1), 153−185. (e) Deslongchamps, P.; Beĺanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C. C.; Maclachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. 4. Preparation of (+)-Ryanodol from (+)- Anhydroryanodol. Can. J. Chem. 1990, 68 (1), 186−192. (30) (a) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. Total Synthesis of Ryanodol. J. Am. Chem. Soc. 2014, 136 (16), 5916−5919. (b) Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and α-Alkoxy Bridgehead Radical Reaction. Chem. Eur. J. 2016, 22 (1), 222−229. (c) Masuda, K.; Koshimizu, M.; Nagatomo, M.; Inoue, M. Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. Chem. Eur. J. 2016, 22 (1), 230−236. (d) Koshimizu, M.; Nagatomo, M.; Inoue, M. Unified Total Synthesis of 3-epi-Ryanodol, Cinnzeylanol, Cinncassiols A and B, and Structural Revision of Natural Ryanodol and Cinnacasol. Angew. Chem. Int. Ed. 2016, 55 (7), 2493–2497. (e) Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin Oxidation and α-Alkoxy Bridgehead Radical Reaction. Chem. Eur. J. 2016, 22 (1), 222–229. (f) Masuda, K.; Koshimizu, M.; Nagatomo, M.; Inoue, M. Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 33 Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. Chem. Eur. J. 2016, 22 (1),230–236. (31) (a) Waterhouse, A. L.; Pessah, I. N.; Francini, A. O.; Casida, J. E.; Structural aspects of ryanodine action and selectivity. J. Med. Chem. 1987, 30 (4), 710–716. (b) Welch, W.; Ahmad, S.; Airey, J.A.; Gerzon, K.; Humerickhouse, R. A.; Besch, H. R. J.; Ruest, L.; Deslongchamps, P.; Sutko, J. L. Structural determinants of highaffinity binding of ryanoids to the vertebrate skeletal muscle ryanodine receptor: a comparative molecular field analysis. Biochemistry 1994, 33 (20), 6074–6085. (32) Chuang, K. V.; Xu, C.; Reisman, S. E. A 15-Step Synthesis of (+)-Ryanodol. Science 2016, 353 (6302), 912–915. (33) Xu, C.; Han, A.; Virgil, S. C.; Reisman, S. E. Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine. ACS Cent. Sci. 2017, 3 (4), 278–282. (34) Xu, C.; Han, A.; Reisman, S. E. An Oxidative Dearomatization Approach To Prepare the Pentacyclic Core of Ryanodol. Org. Lett. 2018, 20 (13), 3793–3796. (35) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. Organocobalt complexes. Part II. Reaction of acetylenehexacarbonyldicobalt complexes, (R1C2R2)Co2(CO)6, with norbornene and its derivatives. J. Chem. Soc. Perkin Trans. 1 1973, 977−981. (36) Chuang, K. V. A Total Synthesis of (+)-Ryanodol. PhD Thesis, California Institute of Technology: Pasadena, CA, 2016. DOI: 10.7907/Z95X26ZV (37) Egi, M., Ota, Y.; Nishimura, Y.; Shimizu, K.; Azechi, K.; Akai, S. Efficient intramolecular cyclizations of phenoxyethynyl diols into multisubstituted α, β- Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 34 unsaturated lactones. Org. Lett. 2013, 15 (16), 4150–4153. (38) Koga, Y.; Kobayashi, T.; Narasaka, K. Rhodium-catalyzed intramolecular PausonKhand reaction. Chem. Lett. 1998, 27 (3), 249–250. (39) Riley, H. L.; Morley, J. F.; Friend, N. A. C.; 255. Selenium dioxide, a new oxidising agent. Part I. Its reaction with aldehydes and ketones. J. Chem. Soc. Res. 1932, 1875–1883. (40) Masuda, K.; Nagatomo, M.; Inoue, M. Chemical Conversion of Ryanodol to Ryanodine. Chem. Pharm. Bull. 2016, 64, 874−879. (41) González-Coloma, A.; Terrero, D.; Perales, A.; Escoubas, P.; Fraga, B. M. Insect Antifeedant Ryanodane Diterpenes from Persea Indica. J. Agric. Food Chem. 1996, 44 (1), 296–300. (42) Ling, S.-Q.; Xu, Y.-N.; Gu, Y.-P.; Liu, S.-Y.; Tang, W.-W. Toxicity and Biochemical Effects of Itol A on the Brown Planthopper, Nilaparvata Lugens (Stål) (Hemiptera: Delphacidae). Pestic. Biochem. Physiol. 2018, 152, 90–97. (43) (a) Nohara, T.; Kashiwada, Y.; Tomimatsu, T.; Kido, M.; Tokubuchi, N.; Nishioka, I. Cinncassiol D1 and Its Glucoside, Novel Pentacyclic Diterpenes from Cinnamomi Cortex. Tetrahedron Lett. 1980, 21 (27), 2647–2648. (b) Chai, X.-Y.; Bai, C.-C.; Shi, H.-M.; Xu, Z.-R.; Ren, H.-Y.; Li, F.-F.; Lu, Y.-N.; Song, Y.-L.; Tu, P.-F. Six Insecticidal Isoryanodane Diterpenoids from the Bark and Twigs of Itoa Orientalis. Tetrahedron 2008, 64 (24), 5743–5747. (c) Zeng, J.; Xue, Y.; Shu, P.; Qian, H.; Sa, R.; Xiang, M.; Li, X.-N.; Luo, Z.; Yao, G.; Zhang, Y. Diterpenoids with Immunosuppressive Activities from Cinnamomum Cassia. J. Nat. Prod. 2014, Chapter 1 – Synthetic Design Guided by Oxidation Pattern Analysis 35 77 (8), 1948–1954. (44) Koshimizu, M.; Nagatomo, M.; Inoue, M. Construction of a Pentacyclic Ring System of Isoryanodane Diterpenoids by SmI2-Mediated Transannular Cyclization. Tetrahedron 2018, 74 (26), 3384–3390. (45) Han, A.; Tao, Y.; Reisman, S. E. A 16-Step Synthesis of the Isoryanodane Diterpene (+)-Perseanol. Nature 2019, 573 (7775), 563–567. (46) Shen, Y.; Li, L.; Pan, Z.; Wang, Y.; Li, J.; Wang, K.; Wang, X.; Zhang, Y.; Hu, T.; Zhang, Y. Protecting-group-free total synthesis of (−)-jiadifenolide: development of a [4 + 1] annulation toward multisubstituted tetrahydrofurans. Org. Lett. 2015, 17 (21), 5480–5483. (47) (a) Denmark, S. E.; Beutner, G. L. Lewis Base Catalysis in Organic Synthesis. Angew. Chem. Int. Ed. 2008, 47 (9), 1560–1638. (b) Corey, E. J.; Link, J. O. A new chiral catalyst for the enantioselective synthesis of secondary alcohols and deuterated primary alcohols by carbonyl reduction. Tetrahedron Lett. 1989, 30 (46), 6275–6278. (48) Ueda, T.; Konishi, H.; Manabe, K. Palladium-catalyzed fluorocarbonylation using N-formylsaccharin as CO source: general access to carboxylic acid derivatives. Org. Lett. 2013, 15 (20), 5370–5373.  Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 36 Chapter 2 Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions† 2.1 INTRODUCTION Transition metal catalysis has unlocked new modes of reactivity that have redefined the synthetic strategies used for the preparation of enantioenriched molecules. Cross-couplings constitute one subset of transition metal-catalyzed reactions and canonically refer to the coupling of an organic electrophile (typically an organic halide or pseudohalide) with an organometallic reagent. The use of Csp3 coupling partners has traditionally been limited by slow oxidative addition or transmetalation, as well as decomposition via rapid β-hydride elimination in the presence of palladium or other precious metals.1 Employing base metal catalysts, such as nickel, for sec-alkyl crosscouplings can circumvent these challenges.2 † This chapter was adapted from the following communication: Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. ACS Catal. 2020, 10 (15), 8237–8246. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 37 Recently, Ni-catalyzed reductive cross-coupling (RCC) reactions, which join two electrophiles in the presence of a terminal reductant, have emerged as promising methods for the enantioselective coupling of Csp3 electrophiles (Figure 2.1). 3 RCC reactions typically proceed under less basic conditions at ambient temperatures (between 0 and 40 °C), which allows broad functional group tolerance and avoids racemization of newly formed stereocenters. Given that halide electrophiles are often used as precursors to the organometallic coupling partners for canonical cross-coupling reactions, and the wide commercial availability of the halogenated building blocks, the direct use of these electrophiles in RCCs is appealing.4 RCC reactions can be particularly advantageous for intramolecular C–C bond formation, because they obviate the need to install both an electrophile and an organometallic functional group in the same starting material.5 Figure 2.1 Ni-catalyzed RCC reactions X R1 R1 + X R2 Ni catalyst chiral ligand terminal reductant X + R2 X R2 mild conditions enantioselective R1 R2 cross-selective C–C bonds R1 Several challenges exist that hinder development of reductive cross-coupling reactions. Most methods require a stoichiometric amount of heterogeneous metal dust as a terminal reductant, which renders them sensitive to stir rates, in addition to metal purity and mesh size.6,7a The generation of metal salt byproducts, as well as the common use of amide solvents, reduces the sustainability of RCCs and can introduce reproducibility issues. 8,9 Although RCCs are widely used by medicinal chemists, advances in reductant and solvent choices will be required for application of this technology in process chemistry.8,10,11 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 38 In this chapter, we discuss the development of enantioselective RCCs catalyzed by nickel that employ a terminal reducing agent. We refer the interested reader to reviews of related reactions that are stereospecific,3e that utilize photoredox co-catalysis, 12,13 or that involve 1,2-addition to polar π-systems (e.g. the Nozaki–Hiyama–Kishi coupling),14 which have been reported elsewhere. The work presented in the following sections represents the state of the art at the time we commenced our own studies aiming to apply enantioselective Ni-catalyzed RCCs to natural product synthesis (Chapter 5); we note that additional studies (particularly with respect to mechanistic considerations) are available, and we discuss these in later chapters. 2.2 HISTORICAL CONTEXT FOR RCC REACTIONS Figure 2.2 Seminal reports of Ni-mediated reductive homocoupling Semmelhack, 1971 Br Ni(cod)2 (0.5 equiv) DMF, 50 ºC 82% yield 1 2 Kende, 1975 Br Ni(PPh3)2Cl2 (1 equiv) PPh3 (2 equiv) Zn0 (1 equiv) DMF, 50 ºC 1 73% yield 2 Kumada, 1977 Br Ni(PPh3)2Cl2 (5 mol %) PPh3 (40 mol %) Zn0 (1 equiv) DMF, 50 ºC 1 89% yield 2 Seminal reports by Semmelhack, 15 Kende, 16 and Kumada 17 demonstrated the ability of nickel to mediate the reductive homocoupling of Csp2 halide electrophiles to Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 39 form biaryl products (Figure 2.2). 18 However, extension of this reactivity from homocoupling to the cross-coupling of distinct partners remained elusive for several decades, due to the challenges associated with achieving cross-selectivity. 19 When employing two electrophilic coupling partners, a large excess of the less-reactive electrophile can be one way to outcompete the homocoupling process. A more efficient strategy is to sequence the reactions of the two electrophiles, such as by leveraging the different rates of oxidative addition of a Csp2 or Csp3 electrophile to different Ni species in the catalytic cycle.20,21 If the two electrophiles react selectively with distinct oxidation states of the Ni catalyst, then sequential oxidative addition events can afford the desired cross-coupled product and minimize homocoupled dimers. 22 Thus, optimization campaigns for these reactions often focus on how reaction parameters affect the distribution of the desired cross-coupled product to homodimers and reduction products. Figure 2.3 First reports coupling Csp2 and Csp3 electrophiles with metal reductants (a) Durandetti, 2007 O MeO I Me O NiBr2·bpy (7 mol %) Cl + 4 3 Mn0 (2 equiv) TFA (3 mol %) DMF, rt MeO Me 5 87% yield (b) Weix, 2010 + Me 6 NiI2·xH2O (11 mol %) dtbbpy (5 mol %) dppbe (5 mol %) Br C5H11 I 4 pyridine (10 mol %) Mn0 (2 equiv) DMPU, 60 °C C5H11 Me 7 88% yield Much effort has focused on the Ni-catalyzed cross-selective couplings of sec-alkyl electrophiles. In 2007, Durandetti and coworkers reported the Ni-catalyzed reductive Csp2–Csp3 cross-coupling of α-chloroesters and aryl iodides using Mn0 as a terminal Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 40 reductant (Figure 2.3a).23 Weix and coworkers followed in 2010 with the RCC of a secalkyl bromide and an aryl iodide, also utilizing a Ni(II) catalyst and bipyridine-based ligand (Figure 2.3b).24 Over the last decade, ongoing research has greatly expanded the scope of RCC reactions that use Mn0 or Zn0 as the terminal reductant to include many different sec-alkyl electrophiles, including those generated in situ from olefins.25,26 2.3 MECHANISTIC CONSIDERATIONS Before the last decade, all examples of Ni-catalyzed asymmetric cross-couplings fell into the category of redox-neutral transformations. Extensive methods development and mechanistic investigations by Fu and coworkers on the enantioconvergent crosscoupling of sec-alkyl electrophiles demonstrated the feasibility of generating an alkyl radical through halide abstraction by a NiI complex and engaging this species in enantioselective catalysis. 27 , 28 That mechanistic similarities with enantioconvergent redox-neutral couplings could be leveraged toward the development of enantioselective RCC reactions thus represented a plausible hypothesis. Investigations of Ni-catalyzed reductive cross-couplings have been conducted by several groups and can be organized into two limiting possibilities that are referred to as (1) the sequential reduction mechanism (or sequential oxidative addition) and (2) the radical chain mechanism (Figure 2.4).29,30 In a sequential reduction mechanism, it is proposed that the Csp2 electrophile (shown as aryl halide 8 for clarity) undergoes oxidative addition to a Ni0 species (9) to afford NiII–aryl complex 10,31 which is then reduced by a metal reductant to 11.32,33 The NiI–aryl complex (11) can then effect halide abstraction from a racemic sec-alkyl electrophile (12)34 to generate a prochiral radical 41 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions that undergoes recombination with the metal center to give a NiIII intermediate (13).35 Subsequent reductive elimination affords the enantioenriched product (14) and NiI–halide complex 15, which can be reduced to regenerate the Ni0 catalyst (9) and close the catalytic cycle. Figure 2.4 Proposed mechanistic hypotheses sequential reduction mechanism radical chain mechanism Ar–X 8 N Ni0 9 * redm+1 redm+2 oxidative addition N N * reduction redm Ar NiII N X N NiI X * R1 Ar 14 * R2 enantioenriched product R1 N X NiIII Ar N 13 NiI Ar 11 N oxidative addition R2 R1 X 12 NiII N X N oxidative addition 9 N X R2 * R1 R1 redm+1 N reductive elimination 17 * redm N N Ni0 reduction 10 reduction 15 * Ar–X 8 N * redm X 12 racemic Csp3 electrophile N * 15 NiI X N racemic Csp3 electrophile 10 X 16 R1 N X R2 13 NiIII * Ar N reductive elimination R2 N radical addition R2 halide abstraction Ar NiII R1 Ar 14 R2 enantioenriched product possible enantiodetermining steps highlighted in teal The second proposed mechanism involves a radical chain process.36 The Csp2 electrophile (8) undergoes oxidative addition to Ni0 complex 9. The resulting NiII intermediate (10) then combines with a cage-escaped sec-alkyl radical (16) to give Ni(III) complex 13,37 which upon reductive elimination gives the enantioenriched product (14) and NiI–halide 15.27 The resulting NiI–halide species (15) can abstract a halide from the Csp3 electrophile (12) to generate long-lived sec-alkyl radical 16.38 Finally, the NiII– dihalide species (17) can be reduced, regenerating the Ni0 catalyst (9) to close the catalytic cycle. A major difference between the sequential reduction and radical chain mechanisms is the lifetime of the alkyl radical generated by halide abstraction, which 42 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions either reacts via a radical rebound process in the solvent cage (sequential reduction mechanism) or is long-lived and escapes the cage (radical chain reaction mechanism). Experimental and computational data support each mechanism in different systems, suggesting that the mechanism of Ni-catalyzed reductive cross-couplings varies with different substrates, ligands, and reaction conditions.21 It is also possible that similar mechanisms are operative where the Csp2 electrophile oxidatively adds to a NiI complex, and the cycle does not proceed through reduction of the catalyst to Ni0.7,26d,39 In any of these scenarios, the enantiodetermining step could be radical addition to a NiII complex to form a single diastereomer of a NiIII complex, followed by facile reductive elimination.28b Alternatively, if radical addition to NiII is reversible, then reductive elimination from the NiIII species could be the enantiodetermining step.13a,35 2.4 ENANTIOCONVERGENT RCCs OF CSP2/CSP3 ELECTROPHILES Figure 2.5 First report of enantioconvergent RCC Reisman, 2013 Me NiCl2·dme (10 mol %) L1 (22 mol %) Cl + Ph Cl 18 O 19 Ar Mn0 (3 equiv) DMBA (0.75 equiv) 30% DMA/THF, 3Å MS, rt Ar = 4-MeOPh Me Me Me Ph O O O Ar N 20 Ph N L1 Ph 85% yield, 92% ee In 2013, the Reisman group reported the first highly enantioselective Ni-catalyzed reductive cross-coupling (Figure 2.5).40 In this reaction, racemic benzylic chlorides were cross-coupled with acyl chlorides using a NiII pre-catalyst, a chiral bis(oxazoline) (BOX) ligand (L1), and Mn0 as the terminal reductant. High enantioselectivity but low reactivity was observed in THF, whereas DMA provided higher reactivity, but also more 43 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions homocoupling side-product formation. A mixed solvent system of DMA and THF provided the optimal balance of reactivity and selectivity. Importantly, it was found that the addition of dimethylbenzoic acid (DMBA) suppressed homocoupling of the Csp3 electrophile. A variety of functional groups were tolerated on both coupling partners, providing the products in high yield and enantiomeric excess (ee). Figure 2.6 Enantioconvergent RCCs of alkenyl bromides (a) Reisman, 2014 NiCl2·dme (10 mol %) L2 (11 mol %) Me Ph Cl + Br 18 Ar 21 Mn0 (3 equiv) NaI (0.5 equiv) DMA, 0 ºC Me Ph Ar 22 Ar = 4-MeOPh 91% yield, 93% ee (a) Reisman, 2018 L2·NiCl2 (10 mol %) CoPc (5 mol %) SiMe3 Ph Cl + Br Ar 21 23 Mn0 (3 equiv) NMP, 5 ºC SiMe3 O Ph O Ar N 24 N Ar = 4-MeOPh L2 71% yield, 95% ee (a) Reisman, 2019 NiCl2·dme (10 mol %) L2 (20 mol %) Me Ph Cl 18 + Br Ar 21 NaI (1 equiv) DMA, 0 ºC Zn/RVC, 10 mA, 3.25 h Me Ph Ar 22 Ar = 4-MeOPh 84% yield, 94% ee In 2014, Reisman and coworkers reported a related reaction, in which alkenyl bromides undergo Ni-catalyzed enantioselective RCC with benzylic chlorides (Figure 2.6a).41 Chiral BOX L2 was identified as the optimal ligand for this reaction, giving the products bearing allylic stereocenters in excellent ee when the reaction was conducted in DMA. NaI was determined to be an important additive in the reaction, improving the yield of 22 and decreasing the formation of the dibenzyl homodimer. NaI has been Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 44 suggested to enhance reactivity in reductive cross-couplings through acceleration of electron transfer between Mn0 and Ni or by in situ formation of iodide electrophiles.42 In 2018, this mode of reactivity was extended to chloro(arylmethyl)silanes, allowing access to enantioenriched allylic silanes (Figure 2.6b).43 Co-catalysis with cobalt phthalocyanine (CoPc) was required for efficient coupling of these bulky silyl electrophiles, presumably to facilitate radical generation.44 Figure 2.7 Enantioconvergent reductive decarboxylative cross-coupling Reisman, 2017 Me O O Ph N + L2·NiBr2 (10 mol %) TDAE (1.5 equiv) Br Ar O O 25 21 NaI (0.5 equiv) TMSBr (1 equiv) DMA, –7 °C Ar = 4-MeOPh Me Ph Ar 26 80% yield, 96% ee While attempts to render reductive couplings more sustainable and scalable have been reported for racemic coupling reactions, comparable asymmetric efforts are few in number.8,10,11 The Reisman group demonstrated that Ni-catalyzed enantioselective reductive alkenylation reactions, such as that between 18 and 21 to give 22, can be driven electrochemically (Figure 2.6c).45 In addition, for the Ni-catalyzed asymmetric reductive alkenylation of N-hydroxyphthalimide (NHP) esters,46,47 the best results were obtained with the organic reductant tetrakis(dimethylamino)ethylene (TDAE);8,48 Mn0 and Zn0 as the terminal reductants provided significantly lower yield (Figure 2.7).49 The coupling of NHP esters was advantageous for improving the scope of electron-rich benzylic systems, where the corresponding benzylic chlorides were unstable. In the NHP ester couplings, a significant amount of (E)-1-(2-chlorovinyl)-4-methoxybenzene was observed when using a chloride-containing precatalyst or TMSCl as an additive, presumably due to a Ni- 45 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions catalyzed halide exchange process.50 This alkenyl chloride was inert in the cross-coupling reaction; thus, it was necessary to eliminate all sources of chloride in the catalyst and additives to improve the yield. Figure 2.8 Enantioconvergent RCC of α-chloronitriles Reisman, 2015 CN N NiCl2·dme (10 mol %) L3 (20 mol %) 28 Mn0 (3 equiv) TMSCl (0.4 equiv) 1,4-dioxane, rt I CN + Ph 2 27 Cl N Ph N 2 SPh 76% yield, 91% ee N 29 O SPh Ar2P N Bn L3 Ar = 3,5-diMe-4-OMe-Ph Despite early success with activated Csp3 coupling partners, variation of the Csp2 electrophile necessitated chiral ligands outside of the BOX family. In 2015, Reisman and coworkers published a Ni-catalyzed asymmetric RCC of α-chloronitriles and (hetero)aryl iodides (Figure 2.8).51 This reaction required a phosphinooxazoline (PHOX) ligand (L3) and provided high yields and enantioselectivities of the secondary nitrile products when TMSCl was used as an additive.38, 52 In the case of diarylalkane formation, the development of a new bioxazoline (BiOX) ligand bearing secondary alkyl substituents with long alkyl chains (L4) was required to obtain good yield and enantioselectivity (Figure 2.9a).53 Interestingly, the coupling of either α-chloronitriles or benzylic chlorides with (hetero)aryl iodides worked optimally under similar reaction conditions, but required a different ligand. This highlights the importance of tuning the ligand properties when investigating new electrophile combinations in enantioselective RCC reactions. Contemporaneously to development of the diarylakane formation in Figure 2.9a, the Doyle and Sigman groups published an enantioselective reductive cross-coupling of racemic styrenyl-derived aziridines and aryl iodides, invoking a similar stereoconvergent 46 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions mechanism (Figure 2.9b).54 Using L4, 2-arylphenethylamine products were formed with high levels of enantioselectivity. Multivariate analysis of the effect of chiral BiOX ligands on the reaction revealed that ligand polarizability influences the enantioselectivity, suggesting the presence of noncovalent interactions, such as dispersion forces or CH–π interactions, in the selectivity-determining transition state. Figure 2.9 Enantioconvergent RCCs with a novel BiOX ligand (a) Reisman, 2017 Et Cl NiBr2·diglyme (10 mol %) L4 (20 mol %) + I 30 N Mn0 (3 equiv) TMSCl (0.75 equiv) OMe 1,4-dioxane, rt 31 84% yield, 91% ee Et N OMe 32 (b) Doyle and Sigman, 2017 NiCl2·diglyme (15 mol %) L4 (18 mol %) NTs + I Cl 33 34 TsHN Cl Mn0 (3 equiv) NaI (2 equiv) TMSCl (0.2 equiv) THF, –10 ºC 35 67% yield, 90% ee nPr (c) Walsh and Mao, 2020 Ni(cod)2 (10 mol %) L4 (11 mol %) 4CzIPN (10 mol %) O Cl RO + nPr O N N L4 nPr nPr RO I Me Me O O 36a Me 37 HEH (3 equiv) Cy2NMe (3 equiv) DMA, rt blue light Me 38a R = 2,3,3,-trimethylbut-2-yl 75% yield, 90% ee (d) Reisman, 2021 O Cl RO Me I 36b Me 37 Mn0 (3 equiv) NaBF4 (1 equiv) THF, rt Me O NiBr2·diglyme (10 mol %) L4 (20 mol %) + RO Me 38b R = Ph 86% yield, 85% ee BiOX ligand L4 has recently enabled the enantioconvergent RCC of αchloroesters and aryl iodides (Figure 2.9c). 55 a Photoredox catalyst 1,2,3,5- 47 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) was proposed to turn over the Ni catalyst when Hantzsch ester (HEH) was employed as a soluble terminal reductant. Thus, strategic use of photoredox co-catalysts may preclude the generation of stoichiometric metal waste by Ni-catalyzed reductive cross-couplings. In 2021, we reported that the coupling of similar substrates using L4 with Mn0 as terminal reductant performed with a similar level of reactivity and enantioselectivity (Figure 2.9d).55b Notably, use of αchloroesters with β-branching substituents (not shown) could be cross-coupled with improved enantioselectivity (up to 98% ee) also using L4 as the ligand. In this case, a multi-linear regression model was developed that demonstrated the cooperative influence of the substrate and ligand steric profiles on enantioselectivity. Figure 2.10 Enantioconvergent RCC with Ni/Ti co-catalysis Weix, 2015 BnN O NiCl2·dme (10 mol %) bpy (10 mol %) [Ti·L5] (10 mol %) + I 39 Ac 40 BnN TiCl2 Mn0 (2 equiv) Et3N·HCl (1 equiv) DMPU, rt 99% yield, 86% ee Me OH 2 Ac 41 Me Me [Ti·L5] Expanding the scope of alkyl electrophiles for Ni-catalyzed asymmetric RCC reactions, the Weix group published the enantioselective cross-coupling of mesoepoxides and aryl halides (Figure 2.10). 56 , 57 A chiral titanocene catalyst ([Ti·L5]) proposed to generate a β-titanoxy carbon radical from a meso-epoxide, which can be intercepted by a NiII–Ar complex arising from an aryl halide. Reductive elimination from the resulting NiIII species then gives enantioenriched trans-β-arylcycloalkanols in excellent yields. In this transformation, the enantioselectivity is determined in the epoxide-opening step by the chiral titanocene catalyst.56 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 48 2.5 ENANTIOSELECTIVE RCCs OF OLEFINS Recently, olefins have been employed in enantioselective Ni-catalyzed reductive cross-couplings to forge two C–C bonds and a stereogenic center in one reaction. These dicarbofunctionalizations are advantageous in cases where alkyl (pseudo)halide electrophiles are unstable or require multiple steps to prepare, since the Csp3 electrophilic fragment is generated directly from an alkene and a Csp2 halide. Most of the methods to date involve an initial intramolecular addition of a Csp2 electrophile to an alkene. This represents a potential enantiodetermining step that distinguishes these reactions from non-conjunctive RCCs; in-depth mechanistic investigations will be instructive for future reaction development. In 2018, Kong and coworkers disclosed the enantioselective 1,2- dicarbofunctionalization of activated alkenes to access heterocycles bearing an all-carbon quaternary center (Figure 2.11a).58 This 1,2-diarylation required both Zn and B2pin2 as terminal reductants, as well as an iodide source (KI) to improve the yield. A phosphinoferrocenyloxazoline ligand (L6) induced high levels of enantioselectivity of the products, which featured various arene substitution and tolerance of a few sterically bulky groups at the benzylic position. Similar olefin substrates were found to undergo asymmetric 1,2-arylalkenylation with alkenyl bromide coupling partners (Figure 2.11b).59 In this case, chiral BiOX L7 could be used in the absence of additives to provide oxindoles in good ee. In 2019, Shu and coworkers published a related reductive transformation able to couple unactivated olefins with alkenyl triflates (Figure 2.11c). 60 Making use of a pyridyloxazoline ligand (PyOx, L8), Mn0 as the stoichiometric reductant, and each 49 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions electrophile in an equimolar amount, this reaction gives heterocyclic products in moderate to good yield and excellent ee. While this transformation successfully coupled a range of aryl substituents on the alkene partner, only 1,1-disubstitution of the alkene was tolerated. Figure 2.11 Enantioselective RCCs of olefins and Csp2 electrophiles (a) Kong, 2018 Me Me + N 1 42 iPr O O N N Zn0 (2 equiv) B2pin2 / K3PO4 (2 equiv) KI (0.5 equiv) NMP, 40 ºC O Me Br Ph Ni(cod)2 (10 mol %) L6 (20 mol %) Br Me PPh2 Fe 43 L6 68% yield, 97% ee (b) Kong, 2019 Me Me Br + N Br Ar O 21 Me O N Zn0 (3 equiv) DMA, rt Bn Me Ar = 4-MeOPh 42 Ar Ni(cod)2 (10 mol %) (S)-L7 (20 mol %) O O N N Bn (S)-L7 44 74% yield, 82% ee (c) Shu, 2019 Me + O I Me NiI2 (10 mol %) L8 (14 mol %) TfO 46 45 O Mn0 (4 equiv) 50% DMF/THF rt F3C O N 47 N tBu L8 79% yield, 98% ee Key to these processes is the ability of the catalyst to sequentially engage the olefin and cross-coupling partner. In a redox-neutral system, Fu and coworkers demonstrated that intermediate organonickel species can rapidly undergo olefin insertion to form a fivemembered ring that is able to capture an electrophile in an enantioselective fashion.61 The reductive two-component couplings are thought to proceed via analogous mechanisms.58,60 Oxidative addition of the aryl halide (42 or 45) followed by reduction is proposed to access a NiI–aryl species. This intermediate can undergo migratory insertion 50 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions of the pendant alkene, which may be the enantiodetermining step. The NiI–alkyl species resulting from this 5-exo-trig cyclization is then poised to undergo oxidative addition of the Csp2 coupling partner (1 or 46) to furnish final product 43 or 47, respectively, with high levels of enantioselectivity. Figure 2.12 Enantioselective RCCs of olefins and Csp3 electrophiles (a) Wang, 2019 Me NiBr2·dme (15 mol %) (R)-L7 (15 mol %) + Br Br OAc 4 48 4 Zn0 (4 equiv) Bn DMA, 40 ºC O O N N Bn (R)-L7 50 69% yield, 94% ee 49 OAc Me (b) Wang, 2020 Me NiBr2·dme (10 mol %) L9 (15 mol %) + O Zn0 (2 equiv) DMA, 40 ºC Cl I Me OAc 94% yield 51 98% ee 52 N N OAc 53 tBu L9 (c) Wang, 2020 Me N Cl 54 Me O + NiBr2·dme (20 mol %) L10 (20 mol %) Me I 4 55 Mn0 (2 equiv) 20% NMM/DMA 10 ºC 61% yield, 85% ee Me Me O 4 O N O N Me 56 N N tBu L10 Csp3 electrophiles have also shown competence in olefin RCCs. Wang and coworkers reported the reductive 1,2-arylalkylation and 1,2-arylbenzylation of unactivated olefins to form enantioenriched benzene-fused cyclic products (Figure 2.12a,b). 62 While chiral BiOX ligand L7 was required for primary bromides,62a the coupling of benzylic chlorides was optimal with PyOx L9.62b These reactions are notable for their ability to form indane products; however, the corresponding tetralins are inaccessible, and tetrahydroisoquinolines were formed with significantly reduced ee, 51 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions indicating the difficulty of 6-exo-trig cyclization. These limitations highlight an opportunity for development to access products featuring other ring sizes. Soon after, the Wang group demonstrated the ability to couple styrene-tethered acyl chlorides and Csp3 electrophiles (Figure 2.12c).63 The reaction, which proceeds with Mn0 as terminal reductant, was found to tolerate groups of varying steric bulk at the benzylic position of 54. Competent coupling partners included primary and secondary alkyl iodides and benzyl chloride. Although the heterocyclic products were available in moderate to good yields with PyOx L9, morpholino-substituted PyOx L10 was necessary to obtain good levels of enantioselectivity. Figure 2.13 Enantioselective reductive intermolecular cross-coupling of olefins (a) Diao, 2019 AcO + NiBr2(dme) (10 mol %) L11 (20 mol %) 1 ABNO (8 mol %) Zn0 (2 equiv) 50% DMPU/THF 10 ºC Br 57 Ph Ph O AcO iBu 58 O N N iBu L11 90% yield, 91% ee (b) Chu, 2020 O + Ar O 59 Br 60 + N CF3 I—CF4CF9 61 O NiCl2(dme) (10 mol %) L4 (12 mol %) N Mn0 (2.5 equiv) TMSCl (0.1 equiv) DME, rt Ar = 1-methylindole-3- 76% yield, 90% ee Ar CF4CF9 O R 62 N N R O O N N L4 R = iPr L12 R = nBu R R CF3 In 2019, the Diao group disclosed the first intermolecular enantioselective 1,2dicarbofunctionalization of activated alkenes, using BiOX L11 (Figure 2.13a). 64 Interestingly, catalytic amounts of an N-oxyl radical additive (ABNO) enabled the crosscoupling of styrenes and aryl halides to proceed with consistent and high enantioselectivities. Formation of the dibenzyl homodimer of 57 suggests the presence of an intermediate benzylic radical. In addition, stereochemical results and radical clock Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 52 experiments support a mechanism involving reversible homolysis of the Ni–alkyl bond resulting from olefin migratory insertion, which may precede enantiodetermining reductive elimination. In the following year, Chu and coworkers reported the intermolecular reductive coupling of olefins with (hetero)aryl bromides and perfluorinated alkyl iodides (Figure 2.13b). 65 Use of a pendant directing group facilitated the regiospecific reaction of unactivated alkenes. Chiral BiOX ligands were found to be uniquely effective in this three-component reaction; while previously developed L4 promoted formation of the 1,2fluoroalkylarylated products in high yields, extending the alkyl chains of the ligand (L12) did not result in enhanced enantioselectivity. This transformation is an important advance from intramolecular olefin RCCs; the difunctionalization of olefins with distinct electrophiles will continue to be an interesting and significant extension of this intermolecular methodology. 2.6 CONCLUDING REMARKS Efficient C–C bond construction through Ni-catalyzed enantioselective RCC reactions affords valuable enantioenriched small molecules from simple electrophile precursors. We anticipate that addressing several remaining challenges will be required for further advances in the field. The development of new ligand scaffolds will likely be crucial to enhancing the yield and ee of new reactions. Importantly, techniques such as ligand parameterization with multivariate linear regression analysis may draw connections between seemingly scattered data to reveal important trends in reactivity and stereoselectivity. In addition, transitioning away from heterogenous metal reductants may 53 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions increase industrial use of reductive cross-couplings, as well as facilitate high-throughput screening for development and use of these transformations. Activated alkyl coupling partners currently dominate the enantioselective RCCs of Csp2 and Csp3 electrophiles, and several limitations within this category remain. Orthosubstituted and ortho,ortho-disubstituted benzylic electrophiles exhibit low reactivity, as do those featuring sterically bulky α-substituents, with few exceptions (see Fig. 2.9d).40 The poor stability of electron-rich benzylic halides and α-heteroatom-substituted halides diminishes their utility.4 Unactivated and tertiary halides remain a significant challenge in enantioselective transformations. Thus, diversifying the pool of competent alkyl (pseudo)halide electrophiles is an important future focus. To access a broader scope of Csp3 coupling partners that can serve as alkyl radical precursors, radical generation mechanisms other than halogen abstraction should be explored. For example, using synergistic photoredox/Ni catalysis for C–H functionalization is an exciting new direction; however, it has been challenging to render these reactions enantioselective.66,67 Ultimately, the development of new methods of Csp3 radical generation will improve the accessibility and synthetic utility of enantioselective RCCs. Reductive olefin dicarbofunctionalization reactions offer strategic complementarity to the RCC of (pseudo)halide electrophiles. In principle, unactivated olefins can be leveraged to forge stereocenters remote from α-stabilizing groups, which would diverge from the reactivity of activated halides. An advantage of using olefin coupling partners is the ability to access all-carbon quaternary centers, which has yet to be realized in enantioconvergent RCCs. Although current methods are restricted to Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 54 cyclization of five-membered rings as a strategy to effectively discriminate electrophiles, the recent development of intermolecular olefin RCCs suggests that this is not an intrinsic limitation. Further development of formally three-component couplings will rely on deeper mechanistic understanding to address challenges of electrophile differentiation. Overall, transition metal-catalyzed cross-coupling reactions remain an invaluable tool for the synthesis of small molecules and natural products. In particular, Ni-catalyzed reductive cross-couplings have enabled the development of mild reaction conditions that give the desired products in good yields with high levels of enantioselectivity. We are confident that this field will continue to grow and revolutionize the way that carbon– carbon bonds are constructed in an enantioselective manner. 2.7 REFERENCES (1) (a) Rudolph, A.; Lautens, M. Secondary Alkyl Halides in Transition-Metal-Catalyzed Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2009, 48 (15), 2656–2670. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition Metal (Pd,Ni,Fe)Catalyzed Cross-Coupling Reactions Using Alkyl-Organometallics as Reaction Partners. Chem. Rev. 2011, 111 (3), 1417–1492. (2) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in Homogeneous Nickel Catalysis. Nature 2014, 509 (7500), 299–309. (3) For selected reviews of reductive cross-couplings, see: (a) Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von Wangelin, A. Reductive CrossCoupling Reactions between Two Electrophiles. Chem. Eur. 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In Nickel Catalysis in Organic Synthesis; Ogoshi, S., Ed.; Wiley, 2020; pp 183–222. (4) Dombrowski, A. W.; Gesmundo, N. J.; Aguirre, A. L.; Sarris, K. A.; Young, J. M.; Bogdan, A. R.; Martin, M. C.; Gedeon, S.; Wang, Y. Expanding the Medicinal Chemist Toolbox: Comparing Seven C(Sp2)-C(Sp3) Cross-Coupling Methods by Library Synthesis. ACS Med. Chem. Lett. 2020, 11 (4), 597–604. (5) For selected examples of Ni-catalyzed intramolecular RCCs, see: (a) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Nickel-Mediated Inter- and Intramolecular Reductive Cross-Coupling of Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature. Chem. Eur. J. 2012, 18 (19), 6039–6048. (b) Xue, W.; Xu, H.; Liang, Z.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Cyclization of Alkyl Dihalides. Org. Lett. 2014, 16 (19), 4984–4987. (c) Konev, M. O.; Hanna, L. E.; Jarvo, E. 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Mechanism of Ni-Catalyzed Reductive 1,2- Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141 (44), 17937– 17948. (b) Diccianni, J.; Lin, Q.; Diao, T. Mechanisms of Nickel-Catalyzed Coupling Reactions and Applications in Alkene Functionalization. Acc. Chem. Res. 2020, 53 (4), 906–919. (8) Anka-Lufford, L. L.; Huihui, K. M. M.; Gower, N. J.; Ackerman, L. K. G.; Weix, D. J. Nickel-Catalyzed Cross-Electrophile Coupling with Organic Reductants in NonAmide Solvents. Chem. Eur. J. 2016, 22 (33), 11564–11567. (9) Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H. M.; Clark, J. H.; Farmer, T. J.; Hunt, A. J.; Robert McElroy, C.; Sherwood, J. Tools and Techniques for Solvent Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 57 Selection: Green Solvent Selection Guides. Sustain. Chem. Process. 2016, 4 (1), 7. (10) For a recent method showcasing the utility of electrochemistry on scale, see: Perkins, R. J.; Hughes, A. J.; Weix, D. J.; Hansen, E. C. Metal-Reductant-Free Electrochemical Nickel-Catalyzed Couplings of Aryl and Alkyl Bromides in Acetonitrile. Org. Process Res. Dev. 2019, 23 (8), 1746–1751. (11) For a recent large-scale example of heterogenous RCC, see: Nimmagadda, S. K.; Korapati, S.; Dasgupta, D.; Malik, N. A.; Vinodini, A.; Gangu, A. S.; Kalidindi, S.; Maity, P.; Bondigela, S. S.; Venu, A.; Gallagher, W. P.; Aytar, S.; González-Bobes, F.; Vaidyanathan, R. Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate. Org. Process Res. Dev. 2020. ASAP. (12) (a) Milligan, J. A.; Phelan, J. P.; Badir, S. O.; Molander, G. A. Alkyl Carbon–Carbon Bond Formation by Nickel/Photoredox Cross-Coupling. Angew. Chem. Int. Ed. 2019, 58 (19), 6152–6163. (b) Zhang, H.-H.; Chen, H.; Zhu, C.; Yu, S. A Review of Enantioselective Dual Transition Metal/Photoredox Catalysis. Sci. China Chem. 2020, 63, 637–647. (13) For selected examples of enantioselective photoredox/Ni-catalyzed cross-couplings, see: (a) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings. J. Am. Chem. Soc. 2015, 137 (15), 4896–4899. (b) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillan, D. W. C. Enantioselective Decarboxylative Arylation of α- 58 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions Amino Acids via the Merger of Photoredox and Nickel Catalysis. J. Am. Chem. Soc. 2016, 138 (6), 1832–1835. (c) Stache, E. E.; Rovis, T.; Doyle, A. G. Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic Meso- Anhydrides. Angew. Chem. Int. Ed. 2017, 56 (13), 3679–3683. (d) Gandolfo, E.; Tang, X.; Roy, S. R.; Melchiorre, P. Photochemical Asymmetric Nickel-Catalyzed Acyl Cross-Coupling. 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S.; Liebeskind, L. S.; Braitsch, D. M. In Situ Generation of a Solvated Zerovalent Nickel Reagent. Biaryl Formation. Tetrahedron Lett. 1975, 16 (39), 3375– 3378. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 59 (17) Zembayashi, M.; Tamao, K.; Yoshida, J.; Kumada, M. Nickel-Phosphine ComplexCatalyzed Homo Coupling of Aryl Halides in the Presence of Zinc Powder. Tetrahedron Lett. 1977, 47, 4089–4092. (18) For the first reports of metal-mediated reductive homocoupling, see: (a) Wurtz, A. Sur une nouvelle classe de radicaux organiques. Ann. Chim. Phys. 1855, 44, 275–312. (b) Wurtz, A. Ueber eine neue Klasse organischer Radicale. Ann. Chem. Pharm. 1855, 96 (3), 364–375. (19) For a seminal Ni-catalyzed Csp2–Csp2 cross-selective coupling with a metal reductant, see: Fürstner, A.; Shi, N. A Multicomponent Redox System Accounts for the First Nozaki−Hiyama−Kishi Reactions Catalytic in Chromium. J. Am. Chem. Soc. 1996, 118 (10), 2533–2534. (20) For the first reports of Csp2–Csp3 cross-couplings with a metal reductant, see: (a) Tollens, B.; Fittig, R. Ueber die Synthese der Kohlenwasserstoffe der Benzolreihe. Liebigs Ann.1864, 131 (3), 303–323. (b) Fittig, R.; König, J. Ueber das Aethyl- und Diäthylbenzol. Liebigs. Ann. 1867, 144 (3), 277–294. (21) Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79 (11), 4793–4798. (22) Amatore, C.; Jutand, A.; Périchon, J.; Rollin, Y. Mechanism of the Nickel-Catalyzed Electrosynthesis of Ketones by Heterocoupling of Acyl and Benzyl Halides. Monatsh. Chem. 2000, 131 (12), 1293–1304. (23) Durandetti, M.; Gosmini, C.; Périchon, J. Ni-Catalyzed Activation of α-Chloroesters: A Simple Method for the Synthesis of α-Arylesters and β-Hydroxyesters. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 60 Tetrahedron 2007, 63 (5), 1146–1153. (24) Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive CrossCoupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010, 132 (3), 920– 921. (25) For selected examples of Ni-catalyzed RCCs of Csp2 and sec-alkyl electrophiles, see: (a) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Ketone Formation via Mild NickelCatalyzed Reductive Coupling of Alkyl Halides with Aryl Acid Chlorides. Org. Lett. 2012, 14, 3044–3047. (b) Wang, S.; Qian, Q.; Gong, H. Nickel-Catalyzed Reductive Coupling of Aryl Halides with Secondary Alkyl Bromides and Allylic Acetate. Org. Lett. 2012, 14 (13), 3352–3355. (c) Wotal, A. C.; Weix, D. J. Synthesis of Functionalized Dialkyl Ketones from Carboxylic Acid Derivatives and Alkyl Halides. Org. Lett. 2012, 14 (6), 1476–1479. (d) Zhao, Y.; Weix, D. J. NickelCatalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity. J. Am. Chem. Soc. 2014, 136 (1), 48–51. (e) Molander, G. A.; Traister, K. M.; O’Neill, B. T. 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J.; Nevado, C. NiCatalyzed Reductive Dicarbofunctionalization of Nonactivated Alkenes: Scope and Mechanistic Insights. J. Am. Chem. Soc. 2019, 141 (35), 13812–13821. (e) Jin, Y.; Wang, C. Ni-catalyzed reductive arylalkylation of unactivated alkenes. Chem. Sci. 2019, 10, 1780−1785. (27) Fu, G. C. Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A 62 Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions Radical Alternative to SN1 and SN2 Processes. ACS Cent. Sci. 2017, 3 (7), 692–700. (28) (a) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc. 2014, 136 (47), 16588– 16593. (b) Yin, H.; Fu, G. C. Mechanistic Investigation of Enantioconvergent Kumada Reactions of Racemic α-Bromoketones Catalyzed by a Nickel/Bis(Oxazoline) Complex. J. Am. Chem. Soc. 2019, 141 (38), 15433–15440. (29) Everson, D. A.; Jones, B. A.; Weix, D. J. 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(36) For a related proposal of a radical chain mechanism involving π-allyl–Ni complexes, see: Hegedus, L. S.; Miller, L. L. Reaction of Pi-Allylnickel Bromide Complexes with Organic Halides. Stereochemistry and Mechanism. J. Am. Chem. Soc. 1975, 97 (2), 459–460. (37) Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.; Moll, B. J.; Ly, T. D.; Wang, X.; Gong, H. Ni-Catalyzed Reductive Coupling of Electron-Rich Aryl Iodides with Tertiary Alkyl Halides. J. Am. Chem. Soc. 2018, 140 (43), 14490–14497. (38) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-Catalyzed CrossElectrophile Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2013, 135 (43), 16192–16197. (39) Tsou, T. T.; Kochi, J. K. Mechanism of Biaryl Synthesis with Nickel Complexes. J. Am. Chem. Soc. 1979, 101 (25), 7547–7560. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 64 (40) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis of Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem. Soc. 2013, 135, 7442–7445. (41) Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive CrossCoupling Between Vinyl and Benzyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365–14368. (42) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Nickel-Catalyzed, Sodium IodidePromoted Reductive Dimerization of Alkyl Halides, Alkyl Pseudohalides, and Allylic Acetates. Chem. Commun. 2010, 46 (31), 5743–5745. (43) Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140 (1), 139–142. (44) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J. Cobalt CoCatalysis for Cross-Electrophile Coupling: Diarylmethanes from Benzyl Mesylates and Aryl Halides. Chem. Sci. 2015, 6, 1115–1119. (45) DeLano, T. J.; Reisman, S. E. Enantioselective Electroreductive Coupling of Alkenyl and Benzyl Halides via Nickel Catalysis. ACS Cat. 2019, 9 (8), 6751–6754. (46) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J. Decarboxylative Cross-Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am. Chem. Soc. 2016, 138, 5016–5019. (47) Ni, S.; Padial, N. M.; Kingston, C.; Vantourout, J. C.; Schmitt, D. C.; Edwards, J. T.; Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 65 Kruszyk, M. M.; Merchant, R. R.; Mykhailiuk, P. K.; Sanchez, B. B.; Yang, S.; Perry, M. A.; Gallego, G. M.; Mousseau, J. J.; Collins, M. R.; Cherney, R. J.; Lebed, P. S.; Chen, J. S.; Qin, T.; Baran, P. S. A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines. J. Am. Chem. Soc. 2019, 141 (16), 6726–6739. (48) Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Goto, K.; Mochizuki, M.; Tanaka, H. Tetrakis(dimethylamino)- ethylene (TDAE) as a Potent Organic Electron Source: Alkenylation of Aldehydes Using a Ni/Cr/TDAE Redox System. Tetrahedron Lett. 2000, 41 (1), 81−84. (49) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Nickel-Catalyzed Enantioselective Cross-Coupling of N-Hydroxyphthalimide Esters with Vinyl Bromides. Org. Lett. 2017, 19 (8), 2150–2153. (50) (a) Takagi, K.; Hayama, N.; Inokawa, S. Synthesis of Vinyl Iodides from Vinyl Bromides and Potassium Iodide by Means of Nickel Catalyst. Chem. Lett. 1978, 7 (12), 1435–1436. (b) Tsou, T. T.; Kochi, J. K. Nickel Catalysis in Halogen Exchange with Aryl and Vinylic Halides. J. Org. Chem. 1980, 45 (10), 1930–1937. (c) Hofstra, J. L.; Poremba, K. E.; Shimozono, A. M.; Reisman, S. E. Nickel-Catalyzed Conversion of Enol Triflates into Alkenyl Halides. Angew. Chem. Int. Ed. 2019, 58 (42), 14901–14905. (51) Kadunce, N. T.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive CrossCoupling between Heteroaryl Iodides and α-Chloronitriles. J. Am. Chem. Soc. 2015, 137, 10480–10483. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 66 (52) (a) Takai, K.; Ueda, T.; Hayashi, T.; Moriwake, T. Activation of Manganese Metal by a Catalytic Amount of PbCl2 and Me3SiCl. Tetrahedron Lett. 1996, 37 (39), 7049– 7052. (b) Johnson, K. A.; Biswas, S.; Weix, D. J. Cross-Electrophile Coupling of Vinyl Halides with Alkyl Halides. Chem. Eur. J. 2016, 22 (22), 7399–7402. (53) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E. NickelCatalyzed Asymmetric Reductive Cross-Coupling to Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139 (16), 5684–5687. (54) Woods, B. P.; Orlandi, M.; Huang, C.-Y.; Sigman, M. S.; Doyle, A. G. NickelCatalyzed Enantioselective Reductive Cross-Coupling of Styrenyl Aziridines. J. Am. Chem. Soc. 2017, 139 (16), 5688–5691. (55) (a) Guan, H.; Zhang, Q.; Walsh, P. J.; Mao, J. Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-Coupling of Racemic α-Chloro Esters with Aryl Iodides. Angew. Chem. Int. Ed. 2020, 59 (13), 5172–5177. (b) DeLano, T. J.; Dibrell, S. E.; Lacker, C. R.; Pancoast, A. R.; Poremba, K. E.; Cleary, L.; Sigman, M. S.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of αChloroesters with (Hetero)Aryl Iodides. Chem. Sci. 2021, 12 (22), 7758–7762. (56) Zhao, Y.; Weix, D. J. Enantioselective Cross-Coupling of Meso-Epoxides with Aryl Halides. J. Am. Chem. Soc. 2015, 137 (9), 3237–3240. (57) A related reductive cross-coupling of chiral 3,4-epoxyalcohols with aryl iodides affords 1,1-diaryldiol products with enriched ee; see: Banerjee, A.; Yamamoto, H. Nickel Catalyzed Regio-, Diastereo-, and Enantioselective Cross-Coupling of 3,4Epoxyalcohol with Aryl Iodides. Org. Lett. 2017, 19 (16), 4363–4366. Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 67 (58) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W. Ni-Catalyzed Enantioselective Reductive Diarylation of Activated Alkenes by Domino Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2018, 140 (39), 12364–12368. (59) Li, Y.; Ding, Z.; Lei, A.; Kong, W. Ni-Catalyzed enantioselective reductive arylalkenylation of alkenes: application to the synthesis of (+)-physovenine and (+)physostigmine. Org. Chem. Front. 2019, 6 (18), 3305−3309. (60) Tian, Z.-X.; Qiao, J.-B.; Xu, G.-L.; Pang, X.; Qi, L.; Ma, W.-Y.; Zhao, Z.-Z.; Duan, J.; Du, Y.-F.; Su, P.; Liu, X.-Y.; Shu, X.-Z. Highly Enantioselective CrossElectrophile Aryl-Alkenylation of Unactivated Alkenes. J. Am. Chem. Soc. 2019, 141 (18), 7637–7643. (61) Cong, H.; Fu, G. C. Catalytic Enantioselective Cyclization/Cross-Coupling with Alkyl Electrophiles. J. Am. Chem. Soc. 2014, 136 (10), 3788–3791. (62) (a) Jin, Y.; Wang, C. Ni-Catalyzed Asymmetric Reductive Arylalkylation of Unactivated Alkenes. Angew. Chem. Int. Ed. 2019, 58, 6722–6726. (b) Jin, Y.; Yang, H.; Wang, C. Nickel-Catalyzed Asymmetric Reductive Arylbenzylation of Unactivated Alkenes. Org. Lett. 2020, 22 (7), 2724–2729. (63) Lan, Y.; Wang, C. Nickel-Catalyzed Enantioselective Reductive Carbo-Acylation of Alkenes. Comm. Chem. 2020, 3 (1), 1–9. (64) Anthony, D.; Lin, Q.; Baudet, J.; Diao, T. Nickel-Catalyzed Asymmetric Reductive Diarylation of Vinylarenes. Angew. Chem. Int. Ed. 2019, 58 (10), 3198–3202. (65) Tu, H. Y.; Wang, F.; Hou, L.; Li, Y.; Zhu, S.; Zhao, X.; Li, H.; Qing, F. L.; Chu, L. Enantioselective Three-Component Fluoroalkylarylation of Unactivated Olefins Chapter 2 – Ni-Catalyzed Enantioselective Reductive Cross-Coupling Reactions 68 Through Nickel-Catalyzed Cross-Electrophile Coupling. J. Am. Chem. Soc. 2020, 142 (21), 9604–9611. (66) For isolated examples of enantioselective photoredox/Ni-catalyzed C–H functionalization, see: (a) Ahneman, D.T.; Doyle, A.G. C–H functionalization of amines with aryl halides by nickel-photoredox catalysis. Chem. Sci. 2016, 7 (12), 7002–7006. (b) Shen, Y.; Gu, Y.; Martin, R. Sp3 C–H Arylation and Alkylation Enabled by the Synergy of Triplet Excited Ketones and Nickel Catalysts. J. Am. Chem. Soc. 2018, 140 (38), 12200–12209. (c) Rand, A. W.; Yin, H.; Xu, L.; Giacoboni, J.; Martin-Montero, R.; Romano, C.; Montgomery, J.; Martin, R. Dual Catalytic Platform for Enabling Sp3 α C–H Arylation and Alkylation of Benzamides. ACS Catal. 2020, 10 (8), 4671–4676. (67) For seminal examples of enantioselective photoredox/Ni-catalyzed C–H functionalization, see: (a) Cheng, X.; Lu, H.; Lu, Z. Enantioselective Benzylic C–H Arylation via Photoredox and Nickel Dual Catalysis. Nature Commun. 2019, 10 (1), 1–7. (b) Fan, P.; Lan, Y.; Zhang, C.; Wang, C. Nickel/Photo-Cocatalyzed Asymmetric Acyl-Carbamoylation of Alkenes. J. Am. Chem. Soc. 2020, 142 (5), 2180–2186.  69 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Chapter 3 Oxidative Transpositions Mediated by Selenium Dioxide† 3.1 INTRODUCTION The Pauson–Khand reaction (PKR) is a powerful method to prepare bicyclic cyclopentenones,1,2 structural features found in many natural products. The intramolecular PKR is well-developed and affords 3,4-fused bicyclic systems from the corresponding tethered enynes (Figure 3.1).3 The 3,4-fused bicyclic enone motif is commonly used as a precursor to highly oxidized five-membered carbocycles within complex structures, such as those of ryanodol and merrilactone A. The isomeric enones that are 4,5-fused can also serve as intermediates en route to these and other functionalized cyclopentanes. In addition, the 4,5-fused bicyclopentenones themselves constitute the cores of several natural products, including connatusin A and ferupennin L. † Portions of this chapter were adapted from the following communication: Dibrell, S. E.;‡ Maser, M. R.;‡ Reisman, S. E. J. Am. Chem. Soc. 2020, 142 (14), 6483–6487. The research presented in this chapter was completed in collaboration with Dr. Michael R. Maser, a former graduate student in the Reisman group. 70 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Despite the utility and prevalence of 4,5-fused bicyclic enones within the context of natural product synthesis, there are few expedient methods to build these structures. Although intermolecular PKR could provide access to this oxidation pattern, limitations in scope hinder access to 4,5-fused bicycles that are highly functionalized (in contrast to the intramolecular variant).4 Thus, a method to rapidly access 4,5-fused bicyclic enones with functional handles for further manipulation, which are inaccessible directly by PKR, would provide valuable synthetic building blocks. Figure 3.1 Access to common bicyclopentenone motifs via PKR 3,4-fused bicyclopentenones OH O R1 2 5 3 4 R2 PKR + CO 5 4 2 R 3 X O HO 1 R1 2 Me Me Me OH OH HO H HO Me OH X O Me Me HO O O merrilactone A 4,5-fused bicyclopentenones O OH 2 4 5 + CO + 3 R2 R4 X limited R2 3 2 1 5 R34 X Me Me R1 R3 O HO Me H O OH R4 Me Me O Me ryanodol R1 O Me Me HO O H connatusin A O H OR Me ferupennin L As part of the recent synthesis of the complex diterpene ryanodol, an unusual oxidative transformation mediated by selenium dioxide (SeO2) was discovered (Figure 3.2).5,6 Treatment of 1, the product of intramolecular PKR, with SeO2 under aqueous conditions led to α-oxidation relative to the starting enone in addition to installation of an additional oxygen atom at the β-position, furnishing dioxidation product 2. Surprisingly, when water was omitted from the reaction, a third oxygen atom was incorporated at the γposition of enone 1 to give trioxidation product 3. Discovery of this transformation proved to be crucial to streamlining the synthesis, as it established the complete oxidation 71 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide pattern of the eastern 5-membered ring of the natural product in a single step. Figure 3.2 Discovery of SeO2-mediated oxidative transpositions SeO2 (10 equiv) H2O (10 equiv) 1,4-dioxane, 110 °C O O BOMO Me then triflation O O BOMO OTf Me 1 BOMO Me Me HO 5 H OH O O HO 2, 56% yield O 3 Me 4 Me 1 BOMO Me 1 4 H Me Me SeO2 (10 equiv) molecular sieves 1,4-dioxane, 110 °C then triflation O O BOMO HO Me Me OTf 4 Me Me OH OH HO OH H ryanodol 1 BOMO Me HO 5 O OH 3, 28% yield These di- and trioxidations were modest in yield, with no apparent explanation for the observed divergence in product distribution based on water content. However, the ability to construct oxidation patterns elusive via canonical PKRs sparked our interest in their wider application in synthesis. Specifically, we recognized the ability of these reactions to transpose the enone motif from the 3,4- to the 4,5-position of the fused ring system and questioned whether these transpositions could be general to other carbon scaffolds. We were thus inspired to investigate the scope and mechanism of SeO2mediated oxidative transpositions of 3,4-fused PKR products to prepare highly substituted bicyclopentenones of use in the synthesis of complex molecules.7 3.2 DEVELOPMENT OF DIOXIDATION REACTION 3.2.1 Optimization of Reaction Conditions Our studies began with 3,4-fused bicyclopentenone 4a, which is readily accessible via intramolecular PKR. The C4-γ-quaternary substitution of substrate 4a (R = Me) prevents trioxidation, allowing analysis of the dioxidation process without competitive trioxidation. Under the previously reported conditions,5 4a successfully underwent 72 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide dioxidation to generate 4,5-fused product 5a (Table 3.1, entry 2); however, the yield was significantly lower than that observed in the ryanodane system. The primary mass balance was unreacted starting material (4a) and minor amounts of over-oxidation to tertiary alcohol 6. Table 3.1 Optimization of dioxidation O OH Me 4 R SeO2, H2O Me O HO Me HO R HO O O Me 1,4-dioxane (0.05 M) 100 °C iPrO C 2 CO2iPr iPrO C 2 4a, R = Me 7a, R = H CO2iPr 5a, R = Me 8a, R = H iPrO C 2 CO2iPr over-oxidation (6) Entry R SeO2 (equiv) H2O (equiv) Time (h) Dioxidation (% yield) 1 Me 10 0 3 11 2 Me 10 10 24 13 3 Me 10 100 38 71 4 Me 3 30 24 32 5 Me 3 100 48 62 6 Me 1.5 15 24 29 7 Me 1.5 100 120 42 8 H 10 100 4 64 Increasing the amount of water in the reaction led to a significant boost in conversion, providing dioxidized 5a in 71% yield (Table 3.1, entry 3). In addition to enhancing the yield, the increased concentration of water also significantly improved the reaction profile. We hypothesize that excess water serves to inhibit formation of organic byproducts, such as 6, by hydrolyzing organoselenium intermediates on undesired pathways or by destroying reactive selenium(II) electrophiles known to trap olefins.8 Moreover, water-promoted reduction of selenium afforded the black allotrope, which Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 73 proved easier to remove from organic products than selenium red, a more soluble colloid.8,9 When the equivalents of SeO2 were reduced, the effects of water on the reaction became more pronounced. Using 1.5 or 3 equiv SeO2 while maintaining a 10:1 ratio of water to SeO2, the yield of 5a was approximately halved (Table 3.1, entries 4 and 6 versus 3). However, increasing the equivalents of water compared to SeO2 led to an increase in yield, affording 5a in 62% yield and 42% yield, respectively (entries 5 and 7). The recovery in yield was accompanied by significant retardation of the reaction rate; without excess SeO2, reaction times extended upwards of several days. With reduced equivalents of SeO2, acid and/or base additives failed to improve selective reactivity or reaction time. Instead, closely monitoring the reaction was most important for maximizing the yield, a known limitation of SeO2-mediated oxidations.8,10 If enone 4a was allowed to be fully consumed, the yield of 5a was lower than if the reaction was stopped with approximately 25% of 4a remaining. Capping the reaction at three-fourths conversion of 5a balanced maximum recovery of the enone with minimum over-oxidation and degradation of 5a. 3.2.2 Reaction Scope Having optimized conditions for model substrate 4a, we turned our attention to the effect of substitution around the starting bicyclopentenone on the yield of the dioxidation product. When substrate 7a (R = H), which lacks the C4-γ-quaternary center, was subjected to 10 equiv SeO2 in the presence of excess water, dioxidation product 8a was formed in comparable yield to that of 5a (Table 3.1, entry 8). Bicyclopentenones 74 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide featuring various substituents at the α-position (R1) were also tolerated under the conditions (Table 3.2), including alkyl chains (8g), arenes (5e and 8e,f) and heterocycles (5b and 5d). However, more electron-withdrawing aryl substitution hindered reactivity (e.g., 5f). For substrates bearing saturated oxacycles (X = O), the reaction was tolerant of geminal disubstitution (5b–e, 8d–f). Surprisingly, formation of the C6-γ-epimer of 8g was not observed under the conditions employed. Lastly, substrates containing protected amines afforded dioxidation products in good yields (5c and 8c). Table 3.2 Scope of dioxidation O OH SeO2 (10 equiv) H2O (100 equiv) R1 R2 X OH OH Me O HO Me N iPrO C 2 HO O Me HO Me O O X OH O NBoc Ph 5f, 0% yield O Me O HO H HO H HO H N Boc 8c, 57% yield O 8d, 74% yield O 5e (R = H), 76% yield 9 (R = Tf) syn ring fusion OH OH Me 8b (R = Et), 82% yield Me OH O 8a (R = iPr), 78% yield O 5d, 35% yield Me RO2C CO2R O Me HO Me Me HO Ph OH OR F3CO O N Me HO Ph Ph R2 5c, 53% yield OH OH HO N Me 5b, 64% yield F3C O OH O O CO2iPr 5a, 71% yield F3C 1,4-dioxane (0.05 M) 100 °C R1 O H HO R R nHex HO Me O 8e (R = H), 73% yield 8f (R = Me), 32% yield O H BnO 8g, 24% yield In addition to the moderate to good yields of the 4,5-fused bicyclic products, each was formed as a single diastereomer. Triflation of 5e afforded the enol triflate (9) as a crystalline solid, and single crystal X-ray diffraction confirmed syn ring fusion (Table 3.2). By analogy, all oxidation products are assigned as cis-fused diastereomers. 75 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.3 MECHANISTIC INVESTIGATION OF DIOXIDATION 3.3.1 Proposed Reaction Pathways The developed dioxidation reaction could proceed through a two-step pathway analogous to that suggested by studies of other complex cyclopentenone systems (Figure 3.2).11,12 In synthetic efforts toward batrachotoxinin A, Kishi and coworkers targeted 4,5fused cyclopentenone 12, which features the same oxygenation pattern as dioxidation products (5). Starting from 3,4-fused 10, intramolecular oxy-Michael addition required activation of the enone; a two-step oxidation sequence (α-hydroxylation and Swern oxidation) allowed access to ene-diketone 11 and enabled the desired 1,4-addition, with the adduct trapped as enol triflate 12.13 Formation of the ene-diketone (11) served three major purposes: activation of the enone for nucleophilic attack, stabilization of the resulting enolate, and installation of a functional handle to facilitate downstream chemistry. Figure 3.2 Proposed dioxidation pathway: Riley oxidation then 1,4-addition established: intramolecular 1,4-addition to activated cyclopentenone Ac N TBSO MOMO Me H 1. KHMDS Davis’ oxaziridine O O 2. TFAA DMSO, Et3N OTBS 82% yield (over 2 steps) 10 Ac N TBSO MOMO Ac N O Me O 1. TASF Me 2. PhNTf2 Et3N O H O MOMO 11 OTf O H 95% yield (over 2 steps) OTBS O OTBS 12 proposed: oxidative enone activation then intermolecular 1,4-addition Step 1: Riley Oxidation OH O O R R SeO2 R OH R Se Me Me Step 2: 1,4-Adition Me X X X 4 enol (13) 14 O O Se O O R O Me X 15 OH Me H 2O R O HO Me X X ene-diketone (16) 5 The dioxidation reaction could proceed through a related stepwise pathway 76 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide (Figure 3.2). As a ketone, substrate 4 could undergo Riley oxidation in the presence of SeO2 to form a carbon–oxygen double bond at the α-carbon, resulting in ene-diketone 16.14 Generally, Riley oxidation is thought to proceed via tautomerization followed by electrophilic attack of SeO2, which results in a seleninic acid intermediate (14) primed for seleno-Pummerer rearrangement and dehydration to afford an unstable selenine (15). Rapid selenine hydrolysis can then release reduced selenium and the ene-diketone (16). Now an activated Michael acceptor, enone 16 could proceed to dioxidation product 5 upon intermolecular conjugate addition of water. Figure 3.3 Proposed dioxidation pathway: [4+2] cycloaddition [4+2] cycloaddition with diene TBSO TBSO SeO2 Me Me CDCl3 tBu O Se TBSO Me Me tBu 18 O OH OH R SeO2 Me X X 4 diene (13) O Me X 19 Se O O Me X 21 OH SiO2 OH Me Me tBu OH R TBSO O O 20 tBu OH OH Se O R Me O Se xs. SeO2 O Me Me 17 R H R Se HO Me O H 2O R O HO Me X X 22 5 We also imagined an alternative pathway to dioxidation products, inspired by a report by Lee and coworkers (Figure 3.3).15 In that case, selenino lactone 18 was spectroscopically observed to be the product of allylic ether 17 and anhydrous SeO2. This surprising adduct (18) was proposed to arise from [4+2] cycloaddition of diene 17 and dienophile SeO2. In the current system, cyclopentadiene 13, the enol tautomer of 4, could engage SeO2 in a comparable manner to form cycloadduct 21. Proton transfer could then open selenino lactone 21 to arrive at a selenine (22), from which hydrolysis would directly generate dioxidation product 5. Whereas in the two-step pathway (see Figure 3.2) 77 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide SeO2 engages the substrate as an enol (13),16 the proposed cycloaddition requires 13 to behave as a diene. 3.3.2 Investigation of Cycloaddition Pathway To distinguish between the proposed dioxidation pathways, we investigated the reactivity of common intermediate 13. The ability of diene 13 to undergo cycloaddition was probed using singlet oxygen (1O2), which is known to perform [4+2] cycloadditions in the presence of cyclic dienes (Figure 3.4, teal).17 To this end, cyclopentadiene 13eTBS was designed as a stable and isolable surrogate of enol tautomer 13e. Isolation of products bearing the oxidation pattern of dioxidized 5 (i.e., 5e or 5e-TBS) provide evidence for the generation of cycloadduct 23, which can undergo Kornblum–DeLaMare rearrangement upon addition of base. Indeed, rearranged product 5e-TBS was observed. Figure 3.4 Proposed and experimental [4+2] cycloaddition reactivity OR2 1O 2 OR2 R1 [4+2] R1 Me base OR2 O O Me X R1 O 23 HO Me OR2 X SeO2 diene (13) X R1 5 H 2O Se O O Me X [4+2] 21 OTBS F3CO HO Me Me O 5e-TBS, observed O 1. methylene blue O2, CDCl3, 0 °C Me 2. Et3N, DCM OTBS F3CO Me Me Me 13e-TBS O SeO2 (10 equiv) H2O (0 or 100 equiv) CDCl3, DMSO-d6, or 1,4-dioxane-d8 23–100 ºC OTBS F3CO Me Me O O Se O Me 21e-TBS, not observed The successful cycloaddition of protected 13e-TBS with 1O2 suggests that this diene could likewise engage SeO2 as dienophile, generating a seleno-cycloadduct 78 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide analogous to 23 (21, Figure 3.4, blue). In this case, the intermediacy of seleninic ester 21 could be spectroscopically observable.15 However, under standard dioxidation conditions (i.e., aqueous SeO2), no species en route to protected dioxidation product 5e-TBS from 13e-TBS could be observed by 1H, 13C, or 77Se NMR. Excluding water also failed to yield evidence of intervening organoselenium species. Instead, diene 13e-TBS converted to a distinct species, which we spectroscopically characterized as ene-diketone 16e (Table 3.3).14,18 Monitoring the reaction over time by 1H NMR revealed fast reversion of diene surrogate 13e-TBS to the enone precursor (4e), likely promoted by adventitious water or H2SeO3 generated in situ (entry 1). Subjection of ketone 4e to anhydrous SeO2 also provided ene-diketone 16e, (entry 2), and after extended reaction time, dioxidized 5e was also observed (entry 3). It is possible that SeO2 is unable to engage the sterically hindered silyl protected enol (13e-TBS) but still undergoes cycloaddition with unprotected enol 13e; however, the lability of the TBS ether under the conditions precludes conclusive attribution of enediketone formation to reaction of 13 as a diene. Nevertheless, this study implicates enediketone 16e as a putative intermediate in dioxidation. Table 3.3 Discovery of ene-diketone O F3CO OTBS F3CO or Me Me Me Me Me O Me ketone (4e) O F3CO SeO2 (10 equiv) 1,4-dioxane-d8 + Me O Me Me diene (13e-TBS) OH F3CO O O ene-diketone (16e) Entry Substrate Time Result 1 diene (13e-TBS) 5h 4e + ene-diketone (16e) 2 ketone (4e) 4h 4e + ene-diketone (16e) 3 ketone (4e) 26 h 16e + dioxidation (5e) O HO Me Me Me O 5e 79 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.3.3 Investigation of Stepwise Pathway Given that an ene-diketone is a likely a product of Riley oxidation, generation of this species is indicative of the proposed two-step pathway to dioxidation products (see Figure 3.2). We investigated this pathway by quantitatively tracking the generation and conversion of such species by 1H and 13C NMR. At room temperature, addition of deuterated water to 16e, generated in situ from ketone 4e, rapidly established an equilibrium with deuterated hydrate 16e-OH-d2, which fully converted to deuterated dioxidation product 5e-d2 upon heating (Figure 3.5). Using ketone 4a instead, an analogous ene-diketone species (16a) was spectroscopically observed to form; addition of D2O at 100 ºC then delivered deuterated dioxidation product 5a-d2 in 78% yield. Under anhydrous conditions, adding deuterated methanol to 16a provided 24-d4 in excellent yield.12,13 This result offers support for the hypothesis that oxidative activation of the enone (i.e., ene-diketone generation) and 1,4-addition are distinct and sequential steps. Figure 3.5 Support for ene-diketone as dioxidation intermediate O F3CO O F3CO O D2O (100 equiv) OD Me Me Me O Me Me 1,4-dioxane-d8 23 °C, 5 min Me 16e O Me SeO2 (10 equiv) Me CO2iPr ketone (4a) OD Me O Me 1,4-dioxane-d8 100 °C, 3 h iPrO C 2 O 5e-d2, complete conversion O Me Me DO Me 100 °C 45 min 16e-OH-d2 O iPrO C 2 O OD F3CO OD CO2iPr 16a D2O or CD3OD (100 equiv) 100 °C, 30 min Me O RO Me iPrO C 2 CO2iPr 5a-d2 (R = D), 78% yield 24-d4 (R = CD3), 99% yield To further study the conjugate addition step, we subjected a set of substrates featuring ring systems alternative to 5/5-bicyclic enones to the standard dioxidation 80 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide conditions and monitored the product distribution by 1H NMR (Figure 3.6). In the case of dihydrojasmone (25), a monocyclic cyclopentenone, initial Riley oxidation generated ene-diketone 26; however, 1,4-addition of water was not spontaneous under these conditions. Instead, over-oxidation to aldehyde 27 preferentially occurred. Reaction of monocyclic cyclohexenone 28 similarly stopped after oxidation to α-carbonyl 29, although the dioxidized 6-membered ring 30 was observed in trace amounts. In this case, product 30 could arise from oxy-Michael addition or via an alternative mechanism analogous to that producing byproduct 6 (see discussion of Fig. 3.9). Lastly, 5/6-bicyclic enone 31 afforded ene-diketone 32 in high yield but did not react further. Based on these results, we propose that the release of ring strain from the intermediate 5/5-bicyclic enediketones upon rehybridization serves as a driving force for oxy-Michael addition. Figure 3.6 Dioxidation of alternative ring systems monocyclic cyclopentenone O O npent npent Me 25 O npent O O nhept nhept Me Me Me + Me 26 O O 41% yield (5:1 mixture) O O Me Me O Me 27 Me OH nhept O Me Me Me 5/6-bicyclic enone O + O 68% yield Me (10:1 mixture) HO Me Me O O O 28 29 30 iPrO C 2 CO2iPr 31 iPrO C 2 CO2iPr 32 78% yield We also studied the kinetics of the individual Riley oxidation and conjugate addition steps (Figure 3.7). Quantitative 1H NMR was used to measure the rate of enediketone formation (16) from reaction of ketone 4 with anhydrous SeO2 (k1, teal), as well as the rate of consumption of hydrated ene-diketone 16 upon the addition of D2O (k2, blue). In general, Riley oxidation was slower than oxy-Michael addition by an order of magnitude. This observation suggests that extension of the overall reaction time in the 81 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide presence of excess water (observed during reaction development) is likely a result of depressed rates of the initial oxidation step (i.e., inefficient ene-diketone formation). Figure 3.7 Kinetic analysis of steps toward dioxidation O X O X SeO2 (10 equiv) Me Me Me Me 1,4-dioxane-d8, 100 °C Me k1 Me O 4e,h–k OD X D 2O (100 equiv) O O O 100 °C DO Me k2 Me 16e,h–k Me O 5e,h–k OCF3 0.4 k2, ρ = 0.84 R2 = 0.91 CF3 log(kX/kH) 0.2 Br OMe 0 -0.2 OMe 0.2 H Br -0.2 0.4 OCF3 CF3 k1, ρ = –0.15 R2 = 0.98 σp Preparation of substrate derivatives (4e,h–k) featuring various para-substituents on a pendant α-arene allowed investigation of electronic effects on dioxidation (Figure 3.7). Correlation of the reaction rates with Hammett parameters19 revealed the rate of the conjugate addition (k2) to be more dependent on substrate electronics than the rate of the Riley oxidation (k1); the opposite signs of ρ for k1 and k2 indicate disparate charge buildup in both steps. Whereas 1,4-addition was much faster for electron-deficient systems, initial Riley oxidation was slightly faster for electron-rich substrates, consistent with proposed enol electrophilic attack (see Fig. 3.2). Together, these results account for 82 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide poor-performing substrates which are electron-poor (e.g., 5f, Table 3.2): slow conversion to an ene-diketone intermediate due to deactivating electronics—and exaggerated by the presence of water—likely allows the starting enone to engage SeO2 in undesired byproduct-forming pathways. 3.3.4 Expansion of Dioxidation Scope Table 3.4 Scope of improved dioxidation protocol O R Me X Me O R O HO Me X F3C OH OH F3CO OH SeO2 (1.5 equiv) 1,4-dioxane (0.05 M) 100 °C, 18 h then H2O (100 equiv) 0.5–3 h HO Me HO Me iPrO C 2 O Me CO2iPr 5a, 59% yield (original: 71%) Me O 5e, 63% yield (original: 76%) F3C Me HO Ph Ph O 5f, 79% yield (original: 0%) OH F OH O O N Me HO Ph Ph O 5g, 54% yield (original: 0%) Based on our mechanistic studies, we hypothesized that a protocol separating the requisite steps for dioxidation (i.e., latent addition of water) would promote (1) faster access to dioxidation products with reduced equiv SeO2, (2) cleaner reaction profiles, and (3) successful reaction of heretofore low-yielding substrates. To prevent excessive depression of Riley oxidation rates, the bicyclopentenone and 1.5 equiv SeO2 were first reacted in the absence of water; then, addition of H2O resulted in rapid product generation. For model substrates 4a and 4e, the corresponding dioxidation products were furnished via this protocol in yields comparable to those resulting from the standard aqueous conditions (Table 3.4). Notably, previously inaccessible electron-poor dioxidized 5f and 5g were afforded in 79% and 54% yield, respectively. This improved, 83 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide stepwise protocol has the potential to substantially broaden the scope of 3,4-fused bicyclopentenones in the dioxidation reaction. 3.4 DEVELOPMENT OF TRIOXIDATION REACTION 3.4.1 Optimization of Reaction Conditions Table 3.5 Optimization of trioxidation O OH Me 4 SeO2, H2O H OH Me O HO H or Me O HO OH 1,4-dioxane (0.05 M) 100 °C iPrO C 2 CO2iPr iPrO C 2 7a CO2iPr iPrO C 2 8a CO2iPr 33a Entry SeO2 (equiv) H2O (equiv) Time (h) Dioxidation (% yield) Trioxidation (% yield) 1 10 100 4 64 0 2 10 100 46 0 14 3 10 10 1 0 15 4 10 0 2 0 21 5 3 0 3 0 10 6 3 100 14 7 15 For bicyclopentenones lacking C4-γ-substitution (i.e., 7), both dioxidation and trioxidation processes can occur in the presence of SeO2. Under the optimized conditions for dioxidation of 7a, use of excess water furnished dioxidized 8a (Table 3.5, entry 1). Interestingly, subjection of 7a to these same conditions for extended reaction times led to isolation of trioxidation product 33a (entry 2), which had previously been observed only under rigorously anhydrous conditions.5 Motivated by this observation, we investigated the selective formation of 33a. Reducing the equivalents of water in the SeO2-mediated 84 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide reaction provided trioxidized 33a in faster rates with cleaner reaction profiles (entry 3). The complete exclusion of water provided 33a in 21% yield with no trace of undesired 8a (entry 4), and these conditions were selected as optimal for trioxidation. Reducing the equivalents of SeO2 served to decrease the yield of 33a (Table 3.5, entry 5). Although addition of water to 3 equiv SeO2 effected a minor increase in yield, this improvement came at the expense of selectivity between dioxidation and trioxidation products (8a and 33a, respectively; entry 6). In all cases, the mass balance was an intractable mixture of byproducts arising from over-oxidation and/or decomposition. 3.4.2 Reaction Scope Table 3.6 Scope of trioxidation O OH R H SeO2 (10 equiv) R O 1,4-dioxane (0.05 M) 100 °C HO OH X OH X OH OH O Me O Me O HO OH HO OH HO OH iPrO C 2 O CO2iPr EtO2C CO2Et 33a, 21% yield 33b, 31% yield OH OH Me 33d, 23% yield O HO R R OH O 33f (R = Me), 17% yield 33e (R = H), 0% yield nHex HO Me OH O OH nHex HO Me O OH BnO BnO 33g, 24% yield 33h, 21% yield We next explored the scope of the trioxidation reaction (Table 3.6). While competitive decomposition of the trioxidation products (33a–h) generally resulted in diminished yields relative to those of dioxidations, the desired products could be isolated in approximately 20–30% yield. This range is similar to that observed in the trioxidation of 1, which underscores the importance of installing three oxygens atoms in a single step regardless of moderate yield. Furthermore, each reaction was stereoselective, affording a Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 85 single diastereomer of product; trioxidized 33g and 33h were formed as single diastereomers from the corresponding diastereomeric bicyclopentenones. It should be noted that substrates containing unsubstituted saturated heterocyclic rings, such as 33e, mark a limitation of this method. In such cases, the observation of byproducts tentatively assigned as dienes suggests that the desired products may form but then rapidly eliminate water under the reaction conditions. 3.5 STEREOCHEMICAL ANALYSIS OF DI- AND TRIOXIDATIONS Having developed a mechanistic understanding of dioxidation reaction as well as conditions for selective trioxidation, we set out to explore the origins of selectivity between the dioxidation and trioxidation products. We anticipated that analyzing the stereochemical outcomes of standard di- and trioxidation reactions would facilitate interrogation of possible intermediates and pathways. To this end, we attempted to prepare the requisite enantioenriched bicyclopentenone (7) by asymmetric PKR, but these reactions proved to be inconsistent and not amenable to scale;20 instead, separation of 7a via chiral HPLC afforded this enone substrate as a single enantiomer (7a*). Under standard aqueous and anhydrous reaction conditions, enantioenriched substrate 7a* and products 8a* and 33a* were confirmed by control experiments to be configurationally stable. 3.5.1 Investigation of Di- to Trioxidation Conversion As an initial study, we subjected enantiopure 7a* to aqueous SeO2, which delivered dioxidation product 8a* with retention of enantiopurity, i.e., no loss of 86 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide enantiomeric excess compared to 7a* (Table 3.7, entry 1). This result is consistent with both proposed dioxidation pathways (see section 3.3.1), given that either cycloaddition or 1,4-addition would be expected to be stereospecific and generate the cis-fused bicyclopentenone product that is likely significantly more stable than the trans isomer. Table 3.7 Stereochemical analysis of trioxidation via dioxidation OH SeO2, H2O 59% yield, enantioretention (slow) or Me O HO H SeO2 4% yield, enantioretention (slow) SeO2, H2O 12% yield, enantiorerosion (very slow) or SeO2 24% yield, enantioretention (slow) iPrO C 2 O CO2iPr OH 8a* Me H iPrO C 2 SeO2, H2O 3% yield, enantioerosion (very slow) or SeO2, 15% yield, enantioretention (fast) CO2iPr Me O HO OH iPrO C 2 7a* CO2iPr 33a* Entry Reaction Time (h) ee (%) Yield (%) 1 7a* → 8a* 24 >99 → >99 59 2 7a* → 33a* 24 >99 → 60 3 3 8a* → 33a* 12 >99 → 46 12 4 7a* → 8a* 1 >99 → >99 4 5 8a* → 33a* 1 >99 → >99 15 6 7a* → 33a* 2 >99 → >99 24 Under the same conditions, trace trioxidation product 33a* was formed after extended reaction times (Table 3.7, entry 2); however, formation of 33a* under these conditions proceeded with significant erosion of ee. Treatment of isolated dioxidation product 8a* with H2O/SeO2 also resulted in the slow formation of 33a* with substantial loss of ee (entry 3). The consistencies in reaction time and enantioerosion of the aqueous reaction of enone 7a* and dioxidized 8a* indicate that the dioxidation product could be 87 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide an intermediate toward trioxidation and provide mechanistic insight into this conversion. One mechanistic possibility is that the dioxidation product (8) can dehydrate to reversibly generate an ene-diketone (34; Figure 3.8, blue); as an alkene, 34 could engage SeO2 in standard allylic C–H oxidation,16,21,22 likely proceeding through seleninic acid 36 followed by [2,3] sigmatropic rearrangement and loss of reduced selenium to access 37. The resulting alcohol (37) would be sufficiently activated for oxy-Michael addition to afford trioxidized 33. This process would likely be disfavored in the presence of water, given that the 8/34 equilibrium would lie to the left, which could account for the long reaction times required (e.g., several days) to access trioxidation products under aqueous conditions, i.e., selectivity for dioxidation when excess water is used. Figure 3.8 Trioxidation via allylic oxidation or cycloaddition enantioretentive conversion of dioxidation to trioxidation products Allylic Oxidation OH OH O R O HO H — H 2O R O R O O HO R Se SeO2 H O R O OH O H 2O OH O R O HO OH X X X X X X 8 alkene (34) 35 36 37 33 enantioablative pathway OH OH OH O R O O R R O Se O Me Me O byproduct (38) OH O O Se O O O R O OH X X X X 35 39 40 37 The stereospecific nature of SeO2-mediated allylic oxidation suggests that this pathway would not result in erosion of starting enantiopurity (i.e., of 8*), which is not fully consistent with the data. However, the putative ene-diketone intermediate (34) can tautomerize to enol 35, which is achiral.23,24 Isolation of 38 from reaction of enone 7e provides evidence for such an intermediate (Figure 3.8, purple). Due to the anti-aromatic 88 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide nature of cyclopentadienones, they rapidly oligomerize via Diels–Alder reactions if not stabilized by steric bulk or conjugated substituents.25 aryl Thus, 2- hydroxycyclopentadienone 35, highly reactive toward [4+2] cycloaddition, could be approached by dienophile SeO2 to yield cycloadduct 39. Conversion to 33 could occur via formal C–Se oxidation of seleninic ester 39 (see Fig. 3.3);15 although atom-transfer from selenium is posited to be challenging,26 C–Se oxidation of 39 would ultimately result in 37 following hydrolysis.27,28 This hypothetical pathway should result in complete racemization of chiral substrate 8*, thus it is likely that multiple mechanisms are operative in the observed enantioerosive (but not enantioablative) conversion of dioxidized 8a* to the trioxidation product (33a*) in the presence of water. Figure 3.9 Trioxidation via α-hydroxylation α-Hydroxylation OH R HO Me HO O O Me R Se HO OH O SeO2 CO2iPr byproduct (6) 8 R O HO OSeOH X X 41 42 OH X iPrO C 2 OH O H HO OH O OH H 2O R O HO OH OH X R O HO Se X 43 O OH R O HO O Se OH O X 33 44 In an additional plausible mechanistic scenario, dioxidation product 8 can undergo direct α-hydroxylation to afford trioxidized 33 (Figure 3.9). Isolation of byproduct 6 from reactions of the model substrate (4a) offers support for an αhydroxylation pathway. Although C4-γ-substitution of 4a blocks installation of oxygen adjacent to the newly formed carbonyl group, which would mimic conversion of 8 to 33, an analogous process likely accounts for hydroxylation at C2 of enone 4a. Such a process Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 89 could proceed via electrophilic attack of 8 by selenous acid at oxygen, as proposed by Corey and Schaefer; from enol selenite 41, subsequent [2,3] sigmatropic rearrangement could afford 42.29 Whereas secondary selenium(II) esters can oxidatively decompose, as would be the case for Riley oxidation, they are generally observed to rapidly hydrolyze.18 Excess water would favor hydrolysis, and tertiary Se(II) ester 42 could thus convert to 33. An alternative process could involve electrophilic attack of 8 at carbon to result in selenite 43, which is primed for [1,2] shift or C–Se oxidation (vide supra) to afford the trioxidation product (33) via selenate monoester 44.15,18 In either α-hydroxylation process, the requisite steps are stereospecific and would not be expected to result in erosion of substrate enantiopurity. Also, the dependence on hydrolysis of each process suggests that α-hydroxylation would likely be slow under anhydrous conditions. Considering these two points, α-hydroxylation could account for generation of the trioxidation product (33) from dioxidized 8 in the absence of water. Indeed, treatment of enone 7a* with anhydrous SeO2 slowly provided dioxidation product 8a* with preservation of ee (Table 3.7, entry 4); subjection of isolated 8a* to identical conditions resulted in slow conversion to trioxidized 33a* with complete retention of ee (entry 5). The rate of these transformations, however, starkly contrasts with the standard anhydrous reaction of substrate 7a*, which rapidly provided trioxidation product 33a* in a few hours, also without erosion of ee (entry 6). Thus, although dioxidized 8a* may represent an intermediate en route to trioxidation in the absence of water, there is likely a more kinetically competent pathway. 90 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.5.2 Investigation of Alternative Trioxidation Pathway We envisioned that the trioxidation product (33) could form without the intermediacy of the dioxidation product (8). Reisman and coworkers previously reported a sequence of steps that serve to transform alcohol 45 to 4,5-fused cyclopentenone 47, which features the trioxidation pattern of 33 (Figure 3.10).12 Interestingly, the SeO2mediated oxidation of 45 did not occur with concomitant addition of water; we hypothesize that enhanced stability of ene-diketone 46 due to arene conjugation outweighs ring strain-release that would otherwise drive oxy-Michael addition. Figure 3.10 Trioxidation via γ-hydroxylation stepwise oxidation and 1,4-addition of γ-hydroxy enone OBn Me O Me SeO2, H2O, AcOH 1,4-dioxane 130 °C (microwave) OBn Me O 45 R Me Me BnO OTf R Me then TMSCHN2 OH Me 1. nBuB(OH)2, iPr2NH 4 Å MS, DCM, 45 °C 66% yield 46 R OH Me 2. Tf2O, Et3N, 0 °C O O Me O O B 55% yield (over 2 steps) nBu 47 γ-Hydroxylation O O O SeO2 R H X alkene (7) HO R Se SeO2 R O OH O OH O R OH H 2O R O HO OH X X X X 48 49 37 33 Inspired by this report, we considered that a γ-hydroxy enone analogous to 45 could serve as an intermediate in the current system. If substrate 7 reacts with SeO2 not as a ketone but as an alkene, then allylic oxidation would result in such a compound: alcohol 49 (Figure 3.10). Formation of the trioxidation product (33) through mono-oxidized 49 could occur via steps similar to those postulated for formation of 33 via the dioxidation product. In this case, selectivity for Riley oxidation of intermediate 49 (leading to trioxidized 33) instead of substrate 7, which provides dioxidized 8, could arise from 91 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide increased α-proton acidity of 49. Given that Corey and Schaefer have demonstrated the rate-limiting step of Riley oxidation to be tautomerization,29 this step should be faster for γ-hydroxy enone 49, the α-proton of which is predicted to be six pKa units more acidic than that of 7.30 As in dioxidation, allylic oxidation (i.e., γ-hydroxylation) is stereospecific and should retain substrate enantiopurity. Table 3.8 Stereochemical analysis of alternative trioxidation pathway O OH Me H iPrO C 2 SeO2, H2O 3% yield, enantioerosion (very slow) or SeO2, 15% yield, enantioretention (fast) CO2iPr Me O HO OH iPrO C 2 O 7a* CO2iPr 33a* Me SeO2, H2O 2% yield, enantioerosion (fast) or SeO2 10% yield, enantioretention (fast) OH iPrO C 2 CO2iPr SeO2, H2O 5% yield, enantioretention (very slow) or SeO2 1% yield, enantioretention (fast) 49a* Entry Reaction Time (h) ee (%) Yield (%) 1 7a* → 49a* 1 >99 → 92 10 2 49a* → 33a* 3 92 → 92 1 3 7a* → 33a* 1 >99 → >99 15 4 7a* → 49a* 24 >99 → 36 2 5 49a* → 33a* 1 92 → 92 5 6 7a* → 33a* 24 >99 → 60 3 In support of hypothetical intermediate 49, closely monitoring reactions of enantiopure enone 7a* revealed the presence of several minor species in addition to diand trioxidation products, each with a mass consistent with mono-oxidation. One such species was isolated and characterized as tertiary alcohol 49a*, which was formed with retention of ee in the absence of water (Table 3.8, entry 1). Subjection of 49a* to 92 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide standard anhydrous conditions resulted in conversion to trioxidation product 33a* with retention of enantiopurity (entry 2). Both transformations occurred in a timeframe similar to the overall reaction of substrate 7a* to trioxidized 33a* (entry 3). Taken together, these results demonstrate that γ-hydroxy enone 49a* is a viable intermediate in the anhydrous formation of trioxidation product 33a*. In contrast, mono-oxidation of 7a* in the presence of water furnished putative intermediate 49a* with significant erosion of ee (Table 3.8, entry 4). It is possible that enantioerosion occurs via dissociation of organoselenium intermediates during allylic oxidation which can generate planar species;31 alternatively, reversible elimination of water from 49a* would result in achiral alkene byproducts capable of unselective hydration to regenerate 49a*. Indeed, control experiments showed that 49a* underwent slow loss of enantiopurity in the presence of both SeO2 and H2O. Subsequent treatment of isolated 49a* with SeO2/H2O resulted in enantioretentive formation of trioxidized 33a* (entry 5); altogether, kinetic and ee data are consistent with the intermediacy of 49a* in the aqueous conversion of enone 7a* to trioxidized 33a* (entry 6). Furthermore, the several-day reaction time of this conversion may account for the apparent selectivity for dioxidation in the presence of water. Figure 3.11 Trioxidation of alternative ring system 5/6-bicyclic enone O O Me Me Me H iPrO C 2 O CO2iPr 50 OH iPrO C 2 CO2iPr 51 34% yield O + H iPrO C 2 CO2iPr 52 not observed Given that the γ-hydroxylated intermediate (49a*) was formed in low yields and Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 93 demonstrated poor conversion to 33a*, we searched for a mono-oxidized intermediate homologous to 49a* arising from a more stable substrate. Although we were able to observe the mass of mono-oxidation products during reactions of several C4-γunsubstituted PKR products, isolation of these species remained evasive. Fortuitously, preliminary investigation of the trioxidation of additional ring systems uncovered alcohol 51 (Figure 3.11). Reaction of 5/6-fused bicyclopentenone 50 with anhydrous SeO2 afforded γ-hydroxy enone 51 in 34% yield, a marked increase compared to 49a*. Our ability to cleanly isolate 51 without trace of the ene-diketone (52)—and the reluctance of 51 to advance to the corresponding trioxidation product—demonstrate that the 5/5-fused bicyclic system is unique in that disparate reactivities with SeO2 are competitive processes. 3.5.3 Mechanistic Conclusion: Water-Dependent Product Distribution In conclusion, the distribution of dioxidized versus trioxidized products from the SeO2-mediated reaction of a bicyclopentenone is based on partitioning between two dominant reactivities of SeO2 (Figure 3.12). In the first, the enone substrate (7) behaves as a ketone and undergoes initial Riley oxidation by SeO2 to generate a key intermediate ene-diketone (53), from which the dioxidation product (8) is selectively formed. In the second, SeO2 preferentially performs allylic oxidation on the substrate alkene (7) to furnish a γ-hydroxy intermediate (49) that is then advanced to the trioxidation product (33). The product distribution is dependent on water because water influences how SeO2 engages the substrate and thus which type of reactivity is more favorable. When water is present, the equilibrium between SeO2 and H2SeO3 lies toward 94 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide selenous acid;32 however, kinetic isotope experiments have shown that SeO2, as opposed to H2SeO3, is the energetically favored oxidizing species in the context of allylic oxidations.33 Therefore, under aqueous conditions in which H2SeO3 is more abundant, allylic oxidation is less favored than Riley oxidation, and dioxidation is dominant. Conversely, the absence of water allows allylic oxidation by SeO2 to be favored such that trioxidation occurs selectively. Figure 3.12 Effect of water on product distribution OH O R SeO2 Dioxidation: Riley oxidation of ketone O O R X Trioxidation: Allylic C–H oxidation O H X X dioxidation (8) OH O SeO2 7 R HO ene-diketone (53) H R OH R O HO OH X X γ-hydroxy (49) trioxidation (33) H2SeO3 favored in water SeO2 favored in allylic oxidation Me ΔG = –3.1 kcal/mol H2O + SeO2 H 2O H O HO Se Me OH SeO2 E‡ = 6 kcal/mol Me HO Me Me vs H2SeO3 E‡ = 30 kcal/mol 3.6 SYNTHETIC APPLICATIONS A general advantage of using the developed SeO2-mediated oxidative transpositions to access 4,5-fused bicyclopentenones is that the α-hydroxyenone functionality can be readily elaborated as a way to introduce additional complexity. As a representative example, Pd-catalyzed cross-coupling was used to demonstrate the synthetic utility of the dioxidation products. To this end, the enol triflate of 5a was prepared in excellent yield (54, Figure 3.13). Although oxidative addition of α-hydroxy 95 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide cyclopentenone triflates has previously been challenging for palladium catalysts,34 subjection of 5a to Sonogashira and Suzuki reactions with various coupling partners produced highly functionalized products 55a–d in good to excellent yields.34,35,36 Reaction with alkynyl, aryl, alkenyl, and alkyl partners demonstrates the ability to access fully substituted, diversely carbofunctionalized 4,5-fused bicyclopentenones. Figure 3.13 Functionalization of dioxidation product via cross-coupling R–H Pd(PPh3)2Cl2 CuI, Et3N, 50 °C OH Me O HO Me iPrO C 2 R–B(OH)2 Pd(OAc)2, PCy3 KF, THF OTf triflation CO2iPr Me O HO Me iPrO C 2 5a 55a, 51% yield alkynyl 55b, 92% yield aryl OMe R–B(OH)2 Pd(OAc)2, PCy3 KF, THF 55c, 78% yield alkenyl R–BF3K Pd(dppf)Cl2, CsCO3 THF/H2O, 80 °C 55d, 86% yield alkyl CO2iPr 54, 90% yield Insight from the development of di- and trioxidation reactions on a general scaffold (e.g., 5/5-bicyclic 4a) was found to be applicable to the ryanodane diterpene carbon skeleton (Figure 3.14). Whereas the previously reported conditions5 provided moderate yields of dioxidized triflate ent-2 from complex enone ent-1, use of the optimized aqueous reaction led to significant improvement in the yield of ent-2 (83%). We thus expect our findings to facilitate preparation of ryanoid diterpenes analogs, as well as additional complex molecules featuring a 4,5-fused bicyclopentenone motif. Figure 3.14 Improved access to natural product analogs Me SeO2 (10 equiv) H2O (X equiv) 1,4-dioxane, 100 °C O O OBOM O Me then Me Me OBOM ent-1 O OBOM TfO triflation H O previous: X = 10, 26% yield this study: X = 100, 83% yield Me Me O H OH Me ent-2 OBOM Me Me HO O OH Me RO RO H R OR Me OH ryanoid analogs (56) Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 96 3.7 CONCLUDING REMARKS In summary, we have developed SeO2-mediated oxidative transpositions of the bicyclopentenone products of intramolecular PKRs. The highly oxidized 4,5-fused bicyclic enones accessed with this method would be otherwise challenging to prepare via canonical intermolecular PKRs. The 5/5-fused bicyclopentenone motif studied here also proved to be valuable as a unique platform for comparison of the various chemistries available to SeO2. Kinetic and stereochemical analysis of the reactions, as well as investigation of potential intermediates, provided new insight into the disparate reactivity observed under aqueous or anhydrous conditions. Ultimately, mechanistic understanding enabled the development of an improved protocol that addressed limitations in the substrate scope. Notably, the di- and trioxidations enable the construction of transposed and highly functionalized PKR products that can be readily elaborated to complex intermediates pertinent to the synthesis of natural products. 3.8 EXPERIMENTAL SECTION 3.8.1 Materials and Methods Unless otherwise stated, reactions were performed under a N2 atmosphere with freshly dried solvents. Glassware was oven-dried at 120 °C for a minimum of four hours or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (DCM), acetonitrile (MeCN), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Methanol (MeOH), HPLC grade, was purchased from Fisher Scientific. 1,4-dioxane, anhydrous ≥99.9%, was purchased from Millipore Sigma. Dichloroethane (DCE), triethylamine (Et3N), Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 97 diisopropylamine (iPr2NH), diisopropylethylamine (DIPEA), 2,6-lutidine, and tertbutanol (tBuOH) were distilled from calcium hydride prior to use and stored under N2. Unless otherwise stated, chemicals and reagents were used as received. Reactions were monitored by liquid chromatography mass spectroscopy (LCMS) or by thin layer chromatography (TLC) using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm), visualized by UV (254 nm) and KMnO4, p-anisaldehyde, iodine, or CAM staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1H and 13C NMR spectra were recorded on a Bruker Advance III HD with Prodigy Cryoprobe (at 400 MHz and 101 MHz, respectively) or Varian Inova 500 (at 500 MHz and 126 MHz, respectively) and are reported relative to internal CDCl3 (1H, δ = 7.26), CD3OD (1H, δ = 3.31), 1,4-dioxane-d8 (1H, δ = 3.53), (CD3)2SO (1H, δ = 2.50), or pyridine-d4 (1H, δ = 8.74) and CDCl3 (13C, δ = 77.16), CD3OD (13C, δ = 49.0), 1,4dioxane-d8 (13C, δ = 66.66), (CD3)2SO (13C, δ = 39.51), or pyridine-d4 (13C, δ = 150.35). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). Analytical chiral SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system (CO2 = 1450 psi, column temperature = 40 °C) with a Chiralcel OD–H column (4.6 mm x 25 cm). Preparative and analytical chiral HPLC was performed with an Agilent 1100 Series HPLC with a Chiralpak IH column (4.6 mm x 25 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 98 cm, Daicel Chemical Industries, Ltd.). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI) mode or obtained from the Caltech Mass Spectral Facility in fast-atom bombardment mode (FAB). Molecular formulas of the observed ion fragment of compounds are given (e.g., [M + H]+). Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 3.8.2 Substrate Preparation General Procedure A: To a round bottom flask with a stir bar was added NaH in a N2-filled glovebox. The flask was sealed with a rubber septum, removed from the glovebox, and placed under an atmosphere of N2. THF or DMF was then added and the mixture stirred at 0 °C. The substrate was then added dropwise, with a vent needle in place to ensure efficient release of hydrogen gas. The reaction was stirred at room temperature for 30 minutes then cooled to 0 °C where the alkyl bromide was added dropwise. The mixture was warmed to room temperature while stirring. Upon complete consumption of the substrate, the reaction was quenched by dropwise addition of sat. aq. NH4Cl. The reaction was then diluted with water and Et2O. The layers were separated and the aqueous layer extracted with Et2O twice. Combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography to afford the desired product. General Procedure B: To a round bottom flask with a stir bar was added Pd(PPh3)2Cl2 and CuI in a N2-filled glovebox. The flask was sealed with a rubber septum, removed from the glovebox, and placed under an atmosphere of N2. The alkyne and aryl Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 99 halide were then added. The solids were taken up in amine and solvent and then stirred at the appropriate temperature. Upon complete consumption of the aryl halide, the reaction was warmed to room temperature and then diluted with EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc twice. Combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography to afford the desired product. General Procedure C:37 To a round bottom flask with a stir bar was added the enyne and placed under an atmosphere of N2. Anhydrous solvent was added and the solution stirred at room temperature. Co2(CO)8 was added in one portion, and the reaction mixture was stirred for 1 h with a vent needle to allow efficient release of CO. CAUTION: all manipulations with CO should be performed in a well-ventilated fume hood. Upon complete consumption of the enyne as judged by TLC, anhydrous DMSO was added dropwise via syringe. The reaction mixture was then placed in a preheated oil bath and monitored by TLC. Upon complete consumption of the intermediate Co-alkyne complex, the reaction was allowed to reach room temperature and then diluted with EtOAc. Celite was added and the reaction mixture stirred overnight open to the air to sequester any Co species. The slurry was filtered over a pad of silica gel, washing with additional EtOAc. The filtrate was concentrated, and the crude residue was purified by column chromatography to afford the desired product. Note: initial elution with nonpolar solvent system is particularly important, as it washes away any remaining Co impurities that otherwise hamper purification. General Procedure D:38 To a round bottom flask with a stir bar was added [Rh(CO)2Cl]2 in a N2-filled glovebox. The flask was sealed with a rubber septum, Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 100 removed from the glovebox, and placed under an atmosphere of N2. The solid was taken up in m-xylene or PhMe and stirred, and the enyne was added via syringe. The solution was stirred at room temperature, sparged with dry N2 and then dry CO successively for five minutes each, and was then kept under an atmosphere of CO via balloon. CAUTION: all manipulations with CO should be performed in a well-ventilated fume hood. At this time, the reaction was placed in a preheated oil bath at 120 °C and was stirred and monitored by TLC. Upon complete consumption of the enyne, the reaction was warmed to room temperature, and the CO was cautiously released into the fume hood. The reaction was concentrated, and the crude residue was purified by column chromatography to afford the desired product. General Procedure E:39 To a round bottom flask with a stir bar was added Mo(CO)3(DMF)3 in a glovebox. The flask was sealed with a rubber septum, removed from the glovebox, and placed under an atmosphere of N2. The enyne was added as a solution in DCM, and the reaction was stirred at room temperature with a vent needle to allow efficient release of CO. Note: in the event of solvent evaporation, fresh DCM was added periodically. CAUTION: all manipulations with CO should be performed in a well-ventilated fume hood. Upon completion as judged by TLC, the reaction mixture was filtered over a pad of silica gel and celite, eluting with DCM. The filtrate was concentrated, and the crude residue was purified by column chromatography to afford the desired product. 101 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide diisopropyl 2-(but-2-yn-1-yl)malonate (57) O Br O O iPrO Me OiPr O iPrO OiPr NaH, THF Me Prepared from diisopropyl malonate (11.4 mL, 60.0 mmol, 3.0 equiv), 1-bromobut-2-yne (1.75 mL, 20.0 mmol, 1.0 equiv), NaH (95%, 720 mg, 30.0 mmol, 1.5 equiv), and THF (60 mL, 0.33 M) following General Procedure A. The crude residue was purified by column chromatography (silica, 8 to 15% Et2O/hexanes) to afford 57 (2.99 g, 63% yield) as a colorless oil. 1 H NMR (500 MHz, CD3Cl): δ 5.08 (hept, J = 6.2 Hz, 2H), 3.44 (t, J = 7.8 Hz, 1H), 2.69 (dq, J = 7.7, 2.5 Hz, 2H), 1.75 (t, J = 2.5 Hz, 3H), 1.26 (dd, J = 6.3, 4.3 Hz, 12H). 13 C NMR (126 MHz, CDCl3): δ 167.98, 77.77, 74.96, 69.20, 52.15, 21.79, 21.69, 18.80, 3.60. FTIR (NaCl, thin film, cm-1): 3055, 2978, 2850, 1706, 1655, 1301, 1120, 1026, 907, 766, 696. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C13H21O4: 241.1434; found: 241.1439. diisopropyl 2-(but-2-yn-1-yl)-2-(2-methylallyl)malonate (58) O Me O O Br iPrO OiPr NaH, THF Me iPrO Me O OiPr Me Prepared from 57 (721 mg, 3.0 mmol, 1.0 equiv), methallyl bromide (0.34 mL, 3.3 mmol, 1.1 equiv), NaH (95%, 84.0 mg, 3.3 mmol, 1.1 equiv), and THF (6 mL, 0.50 M) 102 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide following General Procedure A. The crude, clear colorless oil of 58 was used without further purification (821 mg, 93% yield). 1 H NMR (500 MHz, CDCl3): δ 5.05 (hept, J = 6.3 Hz, 2H), 4.88 (dt, J = 2.0, 1.5 Hz, 1H), 4.84 (dq, J = 1.8, 0.9 Hz, 1H), 2.79 (d, J = 0.9 Hz, 2H), 2.74 (q, J = 2.5 Hz, 2H), 1.78 – 1.72 (m, 3H), 1.69 (dd, J = 1.5, 0.8 Hz, 3H), 1.24 (dd, J = 6.3, 1.4 Hz, 12H). 13 C NMR (126 MHz, CDCl3): δ 170.17, 140.58, 115.99, 78.87, 74.05, 69.06, 56.67, 39.39, 23.57, 23.03, 21.68, 3.59. FTIR (NaCl, thin film, cm-1): 3465, 3080, 2980, 2938, 1732, 1645, 1456, 1374, 1277. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H27O4: 295.1904; found: 295.1904. diisopropyl 3a,6-dimethyl-5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)-dicarboxylate (4a) O O O Me iPrO OiPr Co2(CO)8 Me THF, DMSO Me Me iPrO C 2 CO2iPr Prepared from 58 (2.95 g, 10.0 mmol, 1.0 equiv), Co2(CO)8 (3.77 g, 11.0 mmol, 1.1 equiv), DMSO (7.1 mL, 100.0 mmol, 10.0 equiv), and THF (100 mL, 0.10 M) following General Procedure C. The crude residue was purified by column chromatography (silica, 40 to 50% Et2O/hexanes) to afford 4a (3.06 g, 95% yield) as a white, glassy solid. 1 H NMR (500 MHz, CDCl3): δ 5.10 (hept, J = 6.3 Hz, 1H), 5.00 (hept, J = 6.3 Hz, 1H), 3.34 (dq, J = 17.4, 1.9 Hz, 1H), 3.12 (d, J = 17.4 Hz, 1H), 2.55 (d, J = 13.6 Hz, 1H), 2.40 (d, J = 17.5 Hz, 1H), 2.34 (d, J = 17.5 Hz, 1H), 2.11 (d, J = 13.5 Hz, 1H), 1.70 (d, J = 1.7 Hz, 3H), 1.30 – 1.19 (m, 12H), 1.12 (s, 3H). 103 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 13 C NMR (126 MHz, CDCl3): δ 209.55, 181.23, 171.41, 171.17, 131.63, 69.72, 69.68, 60.51, 51.23, 47.67, 44.74, 33.14, 26.76, 21.66, 21.64, 21.60, 21.57, 8.63. FTIR (NaCl, thin film, cm-1): 2981, 2934, 2874, 1727, 1714, 1677, 1375, 1262, 1183, 1104, 1064, 912. HRMS (TOF-ESI, m/z): [M + H]+ calcd C18H27O5: 323.1853; found: 323.1858. 3-((1-((2-methylallyl)oxy)cyclohexyl)ethynyl)pyridine (59) I N HO HO Pd(PPh3)2Cl2 CuI, iPr2NH N Prepared from 1-ethynylcyclohexan-1-ol (1.49 g, 12.0 mmol, 1.2 equiv), 3-iodopyridine (2.05 g, 10.0 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (211 mg, 0.3 mmol, 0.03 equiv), CuI (58 mg, 0.30 mmol, 0.03 equiv), and iPr2NH (20 mL, 0.50 M) at 80 °C following General Procedure B. The crude residue was purified by column chromatography (silica, 55 to 65% EtOAc/hexanes) to afford 59 (2.00 g, >99% yield) as a tan, amorphous solid. Spectral data matched those reported in the literature.40 3-((1-((2-methylallyl)oxy)cyclohexyl)ethynyl)pyridine (60) Me Br HO O NaH, DMF N Me N Prepared from 59 (1.01 g, 5.0 mmol, 1.0 equiv), methallyl bromide (0.56 mL, 5.5 mmol, 104 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1.1 equiv), NaH (95%, 140 mg, 5.5 mmol, 1.1 equiv), and DMF (20 mL, 0.25 M) following General Procedure A. The crude, clear amber oil of 60 was used without further purification (1.23 g, 97% yield). 1 H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 55.6 Hz, 2H), 7.71 (dt, J = 7.9, 1.8 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 5.04 (dp, J = 1.9, 1.0 Hz, 1H), 4.88 (dp, J = 2.4, 1.1 Hz, 1H), 4.07 (d, J = 1.1 Hz, 2H), 2.00 (ddd, J = 12.0, 7.2, 4.5 Hz, 2H), 1.79 (t, J = 1.2 Hz, 3H), 1.72 (qt, J = 9.5, 2.5 Hz, 3H), 1.57 (dddt, J = 17.8, 11.5, 8.6, 3.5 Hz, 3H), 1.45 – 1.30 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 152.51, 148.66, 143.07, 138.68, 123.11, 111.66, 94.60, 82.66, 74.23, 67.62, 37.28, 25.57, 22.96, 20.02. FTIR (NaCl, thin film, cm-1): 3077, 3029, 2935, 2857, 1656, 1560, 1475, 1448, 1406. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H22NO: 256.1696; found: 256.1697. 3a'-methyl-6'-(pyridin-3-yl)-3a',4'-dihydrospiro[cyclohexane-1,1'cyclopenta[c]furan]-5'(3'H)-one (4b) O Mo(CO)3(DMF)3 O N Me DCM Me O N Prepared from 60 (1.22 g, 4.8 mmol, 1.0 equiv) and Mo(CO)3(DMF)3 (2.10 g, 5.3 mmol, 1.1 equiv) following General Procedure E. The crude residue was purified by column chromatography (silica, 30 to 50% EtOAc/hexanes) to afford 4b (241 mg, 18% yield) as a tan, amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 8.53 (dd, J = 4.9, 1.7 Hz, 1H), 8.45 (dd, J = 2.3, 0.9 Hz, 105 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1H), 7.56 (dt, J = 7.8, 2.0 Hz, 1H), 7.28 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 3.96 (d, J = 8.5 Hz, 1H), 3.48 (dd, J = 8.5, 0.9 Hz, 1H), 2.46 (d, J = 1.4 Hz, 2H), 2.17 (dp, J = 14.2, 2.7 Hz, 1H), 1.79 (td, J = 12.9, 4.8 Hz, 1H), 1.71 – 1.45 (m, 4H), 1.41 (s, 3H), 1.40 – 1.25 (m, 2H), 1.07 – 0.90 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 207.28, 191.05, 149.86, 149.59, 136.91, 131.83, 127.70, 123.46, 81.04, 74.72, 50.50, 48.92, 38.56, 32.03, 26.20, 24.90, 22.02, 21.79. FTIR (NaCl, thin film, cm-1): 2934, 2855, 1710, 1652, 1447, 1411, 1117, 1015, 919, 734, 713. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C18H22NO2: 284.1645; found: 284.1642. tert-butyl 4-(but-2-yn-1-yloxy)-4-(prop-1-en-2-yl)piperidine-1-carboxylate (61) Boc N Boc N Me Me MgBr HO THF O Boc N Br Me NaH, DMF O Me Me Step 1: To a round bottom flask with a stir bar was added isopropenylmagnesium bromide (0.5 M in THF, 40.0 mL, 20.0 mmol, 2.0 equiv) and stirred at room temperature under an atmosphere of N2. N-boc-piperidone (2.00 g, 10.0 mmol, 1.0 equiv) was then added as a solution in THF (27 mL, 0.15 M final), and the solution was stirred at room temperature and monitored by TLC. Upon complete consumption of the ketone, the reaction was quenched by slow dropwise addition of sat. aq. NH4Cl, being careful not to cause vigorous propene gas evolution or exotherm. When propene evolution ceased, the reaction was diluted with water and EtOAc. The layers were separated and the aqueous Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 106 extracted twice with EtOAc. Combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated. Step 2: The crude oil (10.0 mmol, 1.0 equiv) was used directly in the next step, following General Procedure A with 1-bromobut-2-yne (1.1 mL, 12.5 mmol, 1.25 equiv), NaH (95%, 316 mg, 12.5 mmol, 1.25 equiv), and DMF (40 mL, 0.25 M). The crude oil was purified by column chromatography (silica, 15 to 25% Et2O/hexanes) to afford 61 (1.64 g, 56% yield over 2 steps) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 5.04 (p, J = 1.4 Hz, 1H), 4.91 (t, J = 1.0 Hz, 1H), 3.99 – 3.72 (m, 4H), 3.18 (s, 2H), 1.93 – 1.84 (m, 2H), 1.84 (t, J = 2.4 Hz, 3H), 1.74 (dd, J = 1.4, 0.7 Hz, 3H), 1.63 – 1.53 (m, 2H), 1.45 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 154.99, 146.69, 114.02, 81.64, 79.44, 77.03, 76.03, 50.94, 28.59, 18.23, 3.89. FTIR (NaCl, thin film, cm-1): 3495, 3364, 3091, 2927, 2318, 2241, 1958, 1822, 1689. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H28NO3: 294.2064; found: 294.2078. tert-butyl 4,6a-dimethyl-5-oxo-3,5,6,6a-tetrahydrospiro[cyclopenta[c]furan-1,4'piperidine]-1'-carboxylate (4c) Boc N O Co2(CO)8 O Me Me PhMe Me O NBoc Me Prepared from 61 (733 mg, 2.5 mmol, 1.0 equiv), Co2(CO)8 (941 mg, 2.75 mmol, 1.1 equiv), and PhMe (25 mL, 0.10 M) following modified General Procedure C without Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 107 addition of DMSO. Upon complete conversion of the enyne to the Co-alkyne complex, the reaction was placed in a preheated oil bath at 110 °C. Upon complete consumption of the Co-alkyne complex, the reaction was allowed to reach room temperature, filtered over a pad of SiO2 and Celite, and the filtrate concentrated. The crude residue was purified by column chromatography (silica, 5 to 40% EtOAc/hexanes) to afford 4c (494 mg, 62% yield) as an off-white, amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 4.64 (dq, J = 16.0, 1.7 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H), 4.14 – 3.82 (m, 2H), 3.01 (s, 2H), 2.34 (d, J = 17.7 Hz, 1H), 2.18 (d, J = 17.7 Hz, 1H), 1.85 – 1.74 (m, 1H), 1.70 (dd, J = 1.6, 1.0 Hz, 3H), 1.54 (td, J = 13.2, 5.3 Hz, 1H), 1.44 (s, 9H), 1.36 (dd, J = 12.7, 4.5 Hz, 1H), 1.29 – 1.19 (m, 1H), 1.18 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 209.39, 180.68, 154.83, 130.62, 81.26, 79.66, 62.56, 52.62, 45.28, 31.68, 29.78, 28.56, 22.72, 8.74. FTIR (NaCl, thin film, cm-1): 3415, 2974, 2935, 1769, 1715, 1693, 1427, 1366, 1247, 1163, 1052, 737. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C18H28NO4: 322.2013; found: 322.2000. (1-((2-methylallyl)oxy)prop-2-yne-1,1-diyl)dibenzene (62) Me Ph HO Ph Ph Br NaH, DMF Ph O Me Prepared from 1,1-diphenylprop-2-yn-1-ol (4.17 g, 20.0 mmol, 1.0 equiv), methallyl bromide (2.22 mL, 22.0 mmol, 1.1 equiv), NaH (95%, 556 mg, 22.0 mmol, 1.1 equiv), and DMF (80 mL, 0.25 M) following General Procedure A. The crude oil was purified by 108 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide column chromatography (silica, 1 to 3% Et2O/hexanes) to afford 62 (4.69 g, 90% yield) as a yellow oil. Spectral data matched those reported in the literature.41 5-(3-((2-methylallyl)oxy)-3,3-diphenylprop-1-yn-1-yl)pyrimidine (63) Ph Ph Br N N O Me Pd(PPh3)2Cl2 CuI, Et3N Ph Ph O Me N N Prepared from 62 (374 mg, 1.42 mmol, 1.0 equiv), 5-bromopyrimidine (240 mg, 1.5 mmol, 1.05 equiv), Pd(PPh3)2Cl2 (43 mg, 0.06 mmol, 0.04 equiv), CuI (11.5 mg, 0.06 mmol, 0.04 equiv), and Et3N (6 mL, 0.25 M) at 50 °C following General Procedure B. The crude residue was purified by column chromatography (silica, 25 to 30% Et2O/hexanes) to afford 63 (365 mg, 75% yield) as a yellow, amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.85 (s, 2H), 7.64 – 7.56 (m, 4H), 7.40 – 7.32 (m, 4H), 7.34 – 7.25 (m, 2H), 5.12 (tp, J = 1.9, 0.9 Hz, 1H), 4.93 (dh, J = 2.6, 1.3 Hz, 1H), 3.97 (d, J = 1.5 Hz, 2H), 1.81 (dd, J = 1.5, 0.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 159.05, 157.30, 143.00, 142.24, 128.52, 128.13, 126.72, 119.29, 111.65, 96.49, 82.48, 80.69, 68.99, 20.13. FTIR (NaCl, thin film, cm-1): 3356, 3312, 2953, 2922, 2851, 2352, 2333, 1633, 1540, 1447, 1415, 1267. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C23H21N2O: 341.1648; found: 341.1653. 109 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3a-methyl-1,1-diphenyl-6-(pyrimidin-5-yl)-3a,4-dihydro-1H-cyclopenta[c]furan5(3H)-one (4d) N Ph Ph O N Mo(CO)3(DMF)3 O Me N DCM Me Ph Ph O N Prepared from 63 (340 mg, 1.0 mmol, 1.0 equiv) and Mo(CO)3(DMF)3 (401 mg, 1.0 mmol, 1.0 equiv) following General Procedure E. The crude residue was purified by column chromatography (silica, 30 to 60% EtOAc/hexanes) to afford 4d (101 mg, 28% yield) as a light yellow, amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 8.92 (s, 1H), 8.22 (s, 2H), 7.50 – 7.37 (m, 5H), 7.07 – 6.93 (m, 3H), 6.84 – 6.76 (m, 2H), 4.39 (d, J = 8.2 Hz, 1H), 4.20 (dd, J = 8.1, 0.8 Hz, 1H), 2.81 (d, J = 17.7 Hz, 1H), 2.71 (d, J = 17.7 Hz, 1H), 1.31 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 206.12, 187.62, 157.69, 156.30, 142.88, 141.70, 133.17, 128.77, 128.70, 128.27, 127.92, 127.76, 127.56, 124.55, 87.88, 78.83, 50.50, 49.64, 27.33. FTIR (NaCl, thin film, cm-1): 3055, 2969, 2926, 2858, 2362, 1715, 1548, 1447, 1413. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C24H21N2O2: 369.1598; found: 369.1612. 110 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1-(3-methyl-3-((2-methylallyl)oxy)but-1-yn-1-yl)-4-(trifluoromethoxy)benzene (64) Me Me OH 1. methallyl bromide NaH, THF 2. Me Me I O Me F3CO Pd(PPh3)2Cl2 CuI, Et3N F3CO Step 1: Intermediate prepared from 2-methyl-3-butyn-2-ol (1.94 mL, 20.0 mmol, 1.0 equiv), methallyl bromide (2.22 mL, 22.0 mmol, 1.1 equiv), NaH (95%, 555 mg, 22.0 mmol, 1.1 equiv), and THF (80 mL, 0.25 M) following General Procedure A. The crude residue was purified by column chromatography (silica, 2 to 4% Et2O/hexanes) to afford the desired intermediate as a clear colorless oil, which was left as a solution in hexanes to avoid product evaporation upon concentration. Step 2: The intermediate (~690 mg in hexanes, ~5.0 mmol, 1.0 equiv) was then used directly in the next step, following General Procedure B with p-trifluoromethoxyiodobenzene (0.79 mL, 5.0 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (141 mg, 0.2 mmol, 0.04 equiv), CuI (38.1 mg, 0.2 mmol, 0.04 equiv), and Et3N (20 mL, 0.25 M). The crude oil was purified by column chromatography (silica, 2 to 3% Et2O/hexanes) to afford 64 (799 mg, 54% yield over 2 steps) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.48 – 7.40 (m, 2H), 7.15 (ddt, J = 7.7, 2.0, 1.0 Hz, 2H), 5.03 (dh, J = 2.2, 1.1 Hz, 1H), 4.88 (dqd, J = 2.4, 1.5, 0.8 Hz, 1H), 4.08 – 4.03 (m, 2H), 1.81 – 1.74 (m, 3H), 1.57 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 148.98, 148.96, 143.00, 133.31, 120.50 (q, 1JCF = 160 Hz), 121.87, 120.96, 111.74, 92.63, 82.78, 70.90, 68.60, 28.96, 19.92. FTIR (NaCl, thin film, cm-1): 3437, 2984, 2935, 1726, 1608, 1507, 1264, 1219, 1162. 111 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide HRMS (TOF-ESI, m/z): [M – C4H7O + H]+ calcd for C8H5F3O: 227.0678; found: 227.0688. 1,1,3a-trimethyl-6-(4-(trifluoromethoxy)phenyl)-3a,4-dihydro-1Hcyclopenta[c]furan-5(3H)-one (4e) Me Me O Me O F3CO Mo(CO)3(DMF)3 DCM Me Me F3CO Me O Prepared from 64 (745 mg, 2.5 mmol, 1.0 equiv) and Mo(CO)3(DMF)3 (1.00 g, 2.5 mmol, 1.0 equiv) following General Procedure E. The crude residue was purified by column chromatography (silica, 30 to 35% EtOAc/hexanes). To remove residual [Mo] byproducts, the sample was taken up in 5 mL DCM, then 450 mg (0.2 mmol) TAAcONa capped silica gel (SiliCycle®) was added and the mixture stirred overnight. The mixture was then filtered and concentrated to afford 4e (330 mg, 41% yield) as an off-white amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 7.31 – 7.23 (m, 2H), 7.23 – 7.15 (m, 2H), 3.95 (d, J = 8.4 Hz, 1H), 3.51 (dd, J = 8.5, 0.9 Hz, 1H), 2.48 (d, J = 1.0 Hz, 2H), 1.67 (s, 3H), 1.44 (s, 3H), 1.02 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.17, 189.24, 149.40, 149.38, 149.36, 133.97, 130.81, 129.80, 120.54 (q, 1JCF = 258 Hz), 120.99, 79.23, 75.06, 50.63, 49.04, 29.60, 26.04, 25.13. FTIR (NaCl, thin film, cm-1): 2977, 2933, 2848, 1712, 1652, 1507, 1263, 1224, 1162. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H18F3O3: 327.1203; found: 327.1203. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 112 6-(3,5-bis(trifluoromethyl)phenyl)-3a-methyl-1,1-diphenyl-3a,4-dihydro-1Hcyclopenta[c]furan-5(3H)-one (4f) F3C O F3C Me Ph Ph 1 O H NMR (400 MHz, CDCl3): δ 7.61 (tt, J = 1.6, 0.8 Hz, 1H), 7.50 – 7.37 (m, 5H), 7.30 (d, J = 1.8 Hz, 2H), 7.00 – 6.93 (m, 1H), 6.93 – 6.84 (m, 2H), 6.75 – 6.67 (m, 2H), 4.39 (d, J = 8.2 Hz, 1H), 4.23 – 4.16 (m, 1H), 2.81 (d, J = 17.6 Hz, 1H), 2.71 (d, J = 17.7 Hz, 1H), 1.32 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 206.16, 186.80, 142.83, 141.75, 136.76, 132.24, 131.50, 131.17, 130.84, 129.29, 128.66, 128.08, 127.68, 127.60, 127.52, 124.44, 121.90, 121.72, 87.88, 78.76, 50.27, 49.67, 27.29. 6-(6-fluoropyridin-3-yl)-3a-methyl-1,1-diphenyl-3a,4-dihydro-1Hcyclopenta[c]furan-5(3H)-one (4g) O F N Me Ph Ph 1 O H NMR (400 MHz, CDCl3): δ 7.81 (dt, J = 2.5, 0.8 Hz, 1H), 7.46 – 7.35 (m, 5H), 7.17 (ddd, J = 8.5, 7.6, 2.5 Hz, 1H), 7.06 – 6.93 (m, 3H), 6.84 – 6.76 (m, 2H), 6.59 (ddd, J = 8.4, 3.0, 0.7 Hz, 1H), 4.37 (d, J = 8.1 Hz, 1H), 4.17 (dd, J = 8.2, 0.8 Hz, 1H), 2.77 (d, J = 17.7 Hz, 1H), 2.68 (d, J = 17.6 Hz, 1H), 1.31 (s, 3H). 113 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 13 C NMR (101 MHz, CDCl3): δ 206.84, 186.03, 164.27, 161.87, 147.82, 147.67, 143.10, 142.03, 141.57, 141.49, 135.07, 128.66, 128.57, 127.93, 127.80, 127.71, 127.68, 124.09, 124.04, 108.79, 108.42, 87.95, 78.79, 50.28, 49.55, 27.34. (3-methyl-3-((2-methylallyl)oxy)but-1-yn-1-yl)benzene (65) Me Me Me Me Me HO Br O Me NaH, THF Prepared from 2-methyl-4-phenylbut-3yn-2-ol (270 mg, 1.7 mmol, 1.0 equiv), methallyl bromide (0.3 mL, 3.4 mmol, 2.0 equiv), NaH (95%, 53.2 mg, 2.1 mmol, 1.25 equiv), and THF (3.4 mL, 0.50 M) following General Procedure A. The crude residue was purified by column chromatography (silica, 0 to 10% EtOAc/hexanes) to afford 65 (127 mg, 35% yield) as a white powder. Spectral data matched those reported in the literature.42 1,1,3a-trimethyl-6-phenyl-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)-one (4h) O Me Me O Me [Rh(CO)2Cl]2 CO PhMe Me Me Me O Prepared from 65 (60 mg, 0.28 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (10.9 mg, 0.03 mmol, 0.1 equiv), and PhMe (1.4 mL, 0.20 M) following General Procedure D. The crude residue was purified by column chromatography (silica, 7% EtOAc/hexanes) to afford 4h (21.7 mg, 32% yield) as a white powder. 1 H NMR (400 MHz, 1,4-dioxane-d8): δ 7.23 – 7.00 (m, 5H), 3.66 (d, J = 8.3 Hz, 1H), 114 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.25 (d, J = 8.3 Hz, 1H), 2.23 (q, J = 16.9 Hz, 2H), 1.46 (s, 3H), 1.21 (s, 3H), 0.77 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 206.54, 188.15, 135.69, 132.59, 130.11, 129.02, 128.94, 79.53, 75.42, 50.96, 49.25, 29.93, 26.00, 25.20. FTIR (NaCl, thin film, cm-1): 2974, 2928, 2852, 1713, 1652, 1235, 1137, 1018, 699. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C16H19O2: 243.1380; found: 243.1385. 2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-3-yn-2-ol (66) I Me Me O Me Me Me Me B Me Me OH Pd(PPh3)2Cl2 CuI, Et3N, THF Prepared from OH O 2-methylbut-3-yn-2-ol O Me Me O Me (0.12 B Me mL, 1.2 mmol, 1.0 equiv), 4- iodophenylboronic acid pinacol ester (450 mg, 1.4 mmol, 1.1 equiv), Pd(PPh3)2Cl2 (8.7 mg, 0.012 mmol, 0.01 equiv), CuI (4.7 mg, 0.025 mmol, 0.02 equiv), and Et3N (0.52 mL, 3.7 mmol, 3.0 equiv), and THF (1.2 mL, 1.00 M) following General Procedure B. The crude residue was purified by column chromatography (silica, 0 to 20% Et2O/hexanes) to afford 66 (355 mg, 73% yield) as a pale yellow powder. 1 H NMR (400 MHz, CDCl3): δ 7.77 – 7.70 (m, 2H), 7.44 – 7.37 (m, 2H), 1.62 (s, 6H), 1.34 (s, 12H). 13 C NMR (101 MHz, CDCl3): δ 134.64, 130.96, 125.54, 114.80, 95.13, 84.11, 82.45, 65.81, 31.60, 25.03. 115 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide FTIR (NaCl, thin film, cm-1): 3390, 2981, 2933, 1608, 1393, 1364, 1146, 1088, 963, 858, 658. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C17H22BO2: 268.1744; found: 268.1743. 4,4,5,5-tetramethyl-2-(4-(3-methyl-3-((2-methylallyl)oxy)but-1-yn-1-yl)phenyl)-1,3,2dioxaborolane (67) Me Me OH Me Me Me O Br Me O Me Me B O Me NaH, DMF Me Me O Me Me B O Me Prepared 66 (242 mg, 0.7 mmol, 1.0 equiv), methallyl bromide (0.7 mL, 1.7 mmol, 2.5 equiv), NaH (95%, 32 mg, 1.3 mmol, 1.9 equiv), and DMF (3.4 mL, 0.20 M) following General Procedure A. The crude residue was purified by column chromatography (silica, 0 to 20% EtOAc/hexanes) to afford 67 (75 mg, 33% yield) as a yellow powder. 1 H NMR (400 MHz, CDCl3): δ 7.77 – 7.70 (m, 2H), 7.44 – 7.37 (m, 2H), 5.05 – 5.00 (m, 1H), 4.90 – 4.84 (m, 1H), 4.07 (s, 2H), 1.81 – 1.76 (m, 3H), 1.57 (s, 6H), 1.34 (s, 12H). 13 C NMR (101 MHz, CDCl3): δ 143.14, 134.65, 130.96, 125.77, 111.72, 93.02, 84.34, 84.10, 70.98, 68.61, 29.02, 25.02, 19.94. FTIR (NaCl, thin film, cm-1): 2981, 2931, 2856, 1608, 1398, 1360, 1323, 1144, 1089. HRMS (TOF-ESI, m/z): [M – C4H7O + H]+ calcd for C17H23BO2: 268.1744; found: 268.1741. 116 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1,1,3a-trimethyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3a,4dihydro-1H-cyclopenta[c]furan-5(3H)-one (68) Me Me O Me Me O Me Me B O Me Me Me [Rh(CO)2Cl]2 CO O Me Me O O B PhMe Me Me Me O Prepared from 67 (75.4 mg, 0.22 mmol), [Rh(CO)2Cl]2 (8.6 mg, 0.022 mmol, 0.1 equiv), and PhMe (1.1 mL, 0.20 M), following General Procedure D. The crude residue was purified by column chromatography (silica, 7% EtOAc/hexanes) to yield 68 (25.1 mg, 31% yield) as an off-white powder. 1 H NMR (400 MHz, CDCl3): δ 7.83 – 7.77 (m, 2H), 7.28 – 7.22 (m, 2H), 3.97 (d, J = 8.4 Hz, 1H), 3.53 (d, J = 8.4 Hz, 1H), 2.50 (s, 2H), 1.69 (s, 3H), 1.46 (s, 3H), 1.32 (s, 12H), 1.01 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.10, 188.65, 135.30, 134.74, 133.86, 128.44, 83.93, 79.26, 75.01, 50.40, 49.09, 29.47, 25.90, 24.99, 24.93, 24.88, 24.84, 14.22 (CAr–B not observed). FTIR (NaCl, thin film, cm-1): 2978, 2927, 2850, 1711, 1610, 1399, 1360, 1144, 1088. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H30BO4: 368.2268; found: 368.2278. 117 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1,1,3a-trimethyl-6-(4-(trifluoromethyl)phenyl)-3a,4-dihydro-1H-cyclopenta[c]furan5(3H)-one (4i) Me Me O Me Me O O B O F3C (phen)CuCF3 KF Me Me Me DMF Me O Me Me O Prepared from 68 (60.0 mg, 0.16 mmol, 1.0 equiv), (phen)CuCF3 (61.1 mg, 0.2 mmol, 1.25 equiv), KF (9.46 mg, 0.16 mmol, 1.0 equiv), and DMF (1.63 mL, 0.10 M) at 100 °C following a literature procedure.43 The crude residue was purified by column chromatography (silica, 0 to 20% EtOAc/hex) to yield 4i (24.5 mg, 48% yield) as an offwhite powder. 1 H NMR (400 MHz, 1,4-dioxane-d8): δ 7.50 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 3.69 (d, J = 8.3 Hz, 1H), 3.28 (d, J = 8.4 Hz, 1H), 2.26 (q, J = 17.0 Hz, 2H), 1.47 (s, 3H), 1.22 (s, 3H), 0.78 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 206.01, 190.02, 136.45, 134.54, 130.69 (q, 2JCF = 32 Hz), 130.58, 126.05 (q, 3JCF = 4 Hz), 125.24 (q, 1JCF = 272 Hz), 79.53, 75.32, 51.30, 49.20, 29.75, 25.92, 25.36. FTIR (NaCl, thin film, cm-1): 2977, 2933, 2851, 1712, 1325, 1163, 1127, 1067, 1018. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H19F3O2: 311.1253; found: 311.1258. 118 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 6-(4-methoxyphenyl)-1,1,3a-trimethyl-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)one (4j) Me Me O Me Me O O B O MeO Cu(OAc)2 Me Me Me MeOH O Me Me Me O Prepared from 68 (60 mg, 0.16 mmol, 1.0 equiv), Cu(OAc)2 (3.0 mg, 0.016 mmol, 0.1 equiv), MeOH (0.8 mL, 0.20 M), and a balloon of O2 following a literature procedure.44 The crude residue was purified by column chromatography (silica, 0 to 20% EtOAc/hexanes) to yield 4j (17 mg, 39% yield) as an off-white powder. 1 H NMR (400 MHz, 1,4-dioxane-d8): δ 7.05 – 6.97 (m, 2H), 6.75 – 6.66 (m, 2H), 3.65 (d, J = 8.2 Hz, 1H), 3.23 (d, J = 8.1 Hz, 1H), 2.24 – 2.11 (m, 2H), 1.46 (s, 3H), 1.19 (s, 3H), 0.80 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 207.02, 186.72, 160.67, 135.20, 131.32, 124.68, 114.38, 79.53, 75.48, 55.34, 50.79, 49.16, 29.97, 26.03, 25.04. FTIR (NaCl, thin film, cm-1): 2974, 2934, 2852, 2342, 1706, 1512, 1249, 1018, 1031. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H21O3: 273.1485; found: 273.1498. 119 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 6-(4-bromophenyl)-1,1,3a-trimethyl-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)-one (4k) Me Me O Me Me O O B O Br Me CuBr2 Me MeOH/H2O Me Me Me O Me O Prepared from 68 (54 mg, 0.15 mmol, 1.0 equiv), CuBr2 (32.7 mg, 0.15 mmol, 1.0 equiv), MeOH (1.8 mL, 0.04 M), and H2O (1.8 mL, 0.04 M) at 100 °C following a literature procedure.45 The crude residue was purified by column chromatography (silica, 0 to 20% EtOAc/hexanes) to yield 4k (26.8 mg, 57% yield) as an off-white powder. 1 H NMR (400 MHz, 1,4-dioxane-d8): δ 7.40 – 7.30 (m, 2H), 7.05 – 6.95 (m, 2H), 3.67 (d, J = 8.3 Hz, 1H), 3.25 (d, J = 8.3 Hz, 1H), 2.30 – 2.14 (m, 2H), 1.45 (s, 3H), 1.20 (s, 3H), 0.79 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 206.21, 188.84, 134.61, 132.28, 131.83, 131.52, 123.11, 79.52, 75.35, 51.12, 49.15, 29.82, 25.93, 25.22. FTIR (NaCl, thin film, cm-1): 2974, 2928, 2849, 1708, 1487, 1234, 1013. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C16H18BrO2: 321.0485; found: 321.0475. diisopropyl 2-allyl-2-(but-2-yn-1-yl)malonate (69) O O O Br iPrO OiPr iPrO O OiPr NaH, THF Me Me Prepared from 57 (1.44 g, 6.0 mmol, 1.0 equiv), allyl bromide (0.55 mL, 6.3 mmol, 1.05 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 120 equiv), NaH (95%, 173 mg, 7.2 mmol, 1.2 equiv), and THF (15 mL, 0.40 M) following General Procedure A. The crude oil was purified by column chromatography (silica, 7 to 10% Et2O/hexanes) to afford 69 (1.63 g, 97% yield) as a colorless oil. Spectral data matched those reported in the literature.46 diisopropyl 6-methyl-5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)-dicarboxylate (7a) O O iPrO O OiPr Me Co2(CO)8 THF, DMSO Me iPrO C 2 CO2iPr Prepared from 69 (1.40 g, 5.0 mmol, 1.0 equiv), Co2(CO)8 (2.06 g, 6.0 mmol, 1.2 equiv), and THF (50 mL, 0.10 M) following General Procedure C. The crude residue was purified by column chromatography (silica, 10 to 60% Et2O/hexanes) to afford 7a (1.30 g, 85% yield) as a white powder. 1 H NMR (400 MHz, CD3OD): δ 5.04 (dhept, J = 20.8, 6.3 Hz, 2H), 3.19 (dt, J = 2.5, 1.5 Hz, 2H), 3.05 – 2.95 (m, 1H), 2.72 (dd, J = 12.7, 7.6 Hz, 1H), 2.61 (dd, J = 18.0, 6.2 Hz, 1H), 2.16 – 2.06 (m, 1H), 1.69 (dt, J = 2.5, 1.3 Hz, 3H), 1.64 (t, J = 12.5 Hz, 1H), 1.27 (d, J = 6.3 Hz, 6H), 1.24 (dd, J = 6.3, 3.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 209.80, 178.32, 171.41, 170.79, 133.14, 69.77, 69.68, 61.28, 42.90, 41.66, 39.32, 34.19, 21.77, 8.81. FTIR (NaCl, thin film, cm-1): 2981, 2924, 1728, 1714, 1678, 1455, 1375, 1271, 911. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H25O5: 309.1697; found: 309.1684. 121 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide diethyl 2-allylmalonate (70) O O O EtO O TMS EtO OEt OEt CAN, MeOH Prepared from diethylmalonate (2.29 mL, 15.0 mmol, 1.0 equiv) following a published procedure.47 The crude oil was purified by column chromatography (silica, 15% Et2O/hexanes) to afford 70 (1.70 g, 57% yield) as a colorless oil. Spectral data matched those reported in the literature.47 diethyl 2-allyl-2-(but-2-yn-1-yl)malonate (71) O EtO O O Br OEt Me EtO O OEt NaH, THF Me Prepared from 70 (1.00 g, 5.0 mmol, 1.0 equiv), 1-bromobut-2-yne (0.44 mL, 5.0 mmol, 1.0 equiv), NaH (60% in mineral oil, 240 mg, 6.0 mmol, 1.2 equiv), and THF (10 mL, 0.50 M) following General Procedure A. The crude residue was purified by column chromatography (12% Et2O/hexanes) to afford 71 (1.12 g, 89% yield) as a colorless oil. Spectral data matched those reported in the literature.48 122 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide diethyl 6-methyl-5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)-dicarboxylate (7b) O O EtO O OEt [Rh(CO)2Cl]2 CO Me m-xylene EtO2C CO2Et Me Prepared from 71 (504 mg, 2.0 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (78.0 mg, 0.2 mmol, 0.1 equiv), and m-xylene (20 mL, 0.10 M) following General Procedure D. The crude residue was purified by column chromatography (silica, 30% EtOAc/hexanes) to afford 7b (438 mg, 79% yield) as an off-white powder. Spectral data matched those reported in the literature.49 tert-butyl allyl(but-2-yn-1-yl)carbamate (72) Br NHBoc Me BocN Me NaH, DMF Prepared from tert-butyl allylcarbamate (786 mg, 5.0 mmol, 1.0 equiv), 1-bromobut-2yne (0.44 mL, 5.0 mmol, 1.0 equiv), NaH (95%, 168 mg, 7.0 mmol, 1.4 equiv), and DMF (20 mL, 0.25 M) following General Procedure A. The crude residue of 72 was used in the next step without further purification (881 mg, 85% yield). Spectral data matched those reported in the literature.50 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 123 tert-butyl 6-methyl-5-oxo-3,3a,4,5-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (7c) O CoBr2 Zn dust BocN Me CO, TMTU PhMe Me N Boc To a vial with a stir bar was added CoBr2 (22 mg, 0.1 mmol, 0.1 equiv) in a glovebox. The flask was sealed with a rubber septum, removed from the glovebox, and placed under an atmosphere of dry CO via balloon. CAUTION: all manipulations with CO should be performed in a well-ventilated fume hood. Zinc dust (131 mg, 2.0 mmol, 2.0 equiv) and tetramethyltiourea (80 mg, 0.6 mmol, 0.6 equiv) were then added and the solids taken up in PhMe (20 mL, 0.50 M) and stirred. The solution was degassed with CO for 5 min and the reaction kept under an atmosphere of CO following addition of 72 (295 mg, 1.0 mmol, 1.0 equiv). The reaction was brought to 70 °C in a preheated oil bath and monitored by TLC. Upon complete consumption of the enyne (typically indicated by a color change from deep green to light turquoise green or colorless), the reaction mixture was filtered over a pad of silica gel and celite, eluting with EtOAc. The filtrate was concentrated, and the crude residue was purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to afford 7c (165 mg, 70% yield) as an off-white, amorphous solid. Spectral data matched those reported in the literature.50 124 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1-(allyloxy)-1-(prop-1-yn-1-yl)cyclohexane (73) Br HO O Me Me NaH, THF Prepared from 1-(prop-1-yn-1-yl)cyclohexan-1-ol (1.39 g, 10.0 mmol, 1.0 equiv), allyl bromide (1.73 mL, 20.0 mmol, 2.0 equiv), NaH (95%, 360 mg, 15.0 mmol, 1.5 equiv), and THF (20 mL, 0.50 M) following General Procedure A. The crude oil was purified by column chromatography (silica, 2 to 5% Et2O/hexanes) to afford 73 (914 mg, 52% yield) as a colorless oil. Spectral data matched those reported in the literature.51 6'-methyl-3a',4'-dihydrospiro[cyclohexane-1,1'-cyclopenta[c]furan]-5'(3'H)-one (7d) O [Rh(CO)2Cl]2 CO O Me Me m-xylene O Prepared from 73 (446 mg, 2.5 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (73 mg, 0.19 mmol, 0.75 equiv), and m-xylene (12.5 mL, 0.20 M) following General Procedure D. The crude oil was purified by column chromatography (silica, 20 to 30% EtOAc/hexanes) to afford 7d (27 mg, 68% yield) as a clear yellow oil. 1 H NMR (500 MHz, CDCl3): δ 4.29 – 4.17 (m, 1H), 3.28 – 3.17 (m, 3H), 2.58 (dd, J = 17.6, 5.9 Hz, 1H), 2.09 (dd, J = 17.5, 3.5 Hz, 1H), 1.79 (d, J = 2.2 Hz, 4H), 1.76 (ddt, J = 11.5, 6.5, 2.5 Hz, 2H), 1.72 – 1.59 (m, 6H), 1.33 – 1.19 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 210.00, 182.70, 130.57, 79.72, 69.77, 44.10, 38.61, 35.28, 32.22, 25.40, 22.19, 21.58, 8.36. 125 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide FTIR (NaCl, thin film, cm-1): 3412, 2924, 2856, 1698, 1682, 1446, 1269, 1058, 1024, 917, 840, 738, 665. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C13H19O2: 207.1380; found: 207.1376. (3-(allyloxy)prop-1-yn-1-yl)benzene (74) HO Br O NaH, THF Prepared from 3-phenylprop-2-yn-1-ol (1.25 mL, 10.0 mmol, 1.0 equiv), allyl bromide (1.73 mL, 20.0 mmol, 2.0 equiv), NaH (95%, 300 mg, 12.5 mmol, 1.25 equiv), and THF (20 mL, 0.50 M) following General Procedure A. The resulting crude, colorless oil of 74 (1.68 g, 98% yield) was used without further purification. Spectral data matched those reported in the literature.52 6-phenyl-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)-one (7e) O O [Rh(CO)2Cl]2 CO m-xylene O Prepared from 74 (345 mg, 2.0 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (59 mg, 0.15 mmol, 0.75 equiv), and m-xylene (20 mL, 0.10 M) following General Procedure D. The crude residue was purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to afford 7e (336 mg, 84% yield) as a white powder. Spectral data matched those reported in the literature.50 126 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide (3-(allyloxy)-3-methylbut-1-yn-1-yl)benzene (75) Me Me Me Br HO Me O NaH, THF Prepared from 2-methyl-4-phenylbut-3-yn-2-ol (801 mg, 5.0 mmol, 1.0 equiv), allyl bromide (0.87 mL, 10.0 mmol, 2.0 equiv), NaH (95%, 158 mg, 6.25 mmol, 1.25 equiv), and THF (10 mL, 0.50 M) following General Procedure A. The resulting yellow oil of 745(283 mg, 48% yield) was used without further purification. Spectral data matched those reported in the literature.53 1,1-dimethyl-6-phenyl-3a,4-dihydro-1H-cyclopenta[c]furan-5(3H)-one (7f) Me O Me O [Rh(CO)2Cl]2 CO PhMe Me Me O Prepared from 75 (20.0 mg, 0.1 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (2.9 mg, 0.0075 mmol, 0.075 equiv), and PhMe (1 mL, 0.10 M) following General Procedure D. The crude residue was purified by column chromatography (silica, 15 to 25% EtOAc/hexanes) to yield 7f (15.5 mg, 68% yield) as a white powder. Spectral data matched those reported in the literature.53 127 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 5-methyltridec-1-en-6-yn-5-ol (76) O nhex Me OH Me Me EtMgBr Et2O To a round bottom flask with a stir bar was added oct-1-yne (8.9 mL, 60.0 mmol, 3.0 equiv) and Et2O (100 mL, 0.1 M). 3 M EtMgBr in Et2O (20.0 mL, 60.0 mmol, 3.0 equiv) was then added dropwise. The solution was then heated to 30 °C for 1 h then allowed to reach room temperature. To a separate round bottom flask with a stir bar was added hex5-en-2-one (2.3 mL, 20.0 mmol, 1.0 equiv) and Et2O (80 mL). This solution was added to the first solution slowly via canula. The reaction was allowed to stir at room temperature and monitored by TLC. Upon completion, the reaction was quenched by dropwise addition of sat. aq. NH4Cl. The resulting mixture was diluted with Et2O and water and the layers separated. The aqueous layer was extracted twice with Et2O. Combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 15 to 20% Et2O/hexanes) to afford 76 (2.89 g, 70% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 5.88 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.07 (dq, J = 17.1, 1.7 Hz, 1H), 4.98 (ddt, J = 10.2, 1.8, 1.3 Hz, 1H), 2.37 – 2.22 (m, 2H), 2.19 (t, J = 7.1 Hz, 2H), 1.96 – 1.91 (m, 1H), 1.80 – 1.66 (m, 2H), 1.55 – 1.48 (m, 2H), 1.47 (s, 3H), 1.43 – 1.35 (m, 2H), 1.35 – 1.24 (m, 3H), 0.90 (t, J = 7.0 Hz, 3H). 13 C NMR (126 MHz, CDCl3): δ 138.74, 114.81, 84.41, 83.80, 68.39, 43.03, 31.44, 30.46, 29.53, 28.81, 28.64, 22.69, 18.73, 14.18. FTIR (NaCl, thin film, cm-1): 3364, 3078, 2930, 2859, 2239, 1642, 1455, 1371, 1127. 128 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C14H23: 191.1800; found: 191.1794. (((5-methyltridec-1-en-6-yn-5-yl)oxy)methyl)benzene (77) Me OH Br Me OBn Me Me NaH, DMF Prepared from 76 (1.04 g, 5.0 mmol, 1.0 equiv), benzyl bromide (0.66 mL, 5.5 mmol, 1.1 equiv), NaH (95%, 139 mg, 5.5 mmol, 1.1 equiv), and DMF (20 mL, 0.25 M) following General Procedure A. The resulting crude residue of 77 was used in the next step without further purification (1.46 g, 98% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.33 (m, 3H), 7.35 – 7.21 (m, 2H), 5.87 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.04 (dq, J = 17.2, 1.7 Hz, 1H), 4.95 (ddt, J = 10.2, 2.3, 1.3 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.57 (d, J = 11.2 Hz, 1H), 2.42 – 2.25 (m, 1H), 2.23 (t, J = 7.0 Hz, 2H), 1.92 – 1.71 (m, 2H), 1.60 – 1.48 (m, 2H), 1.48 (s, 3H), 1.45 – 1.35 (m, 2H), 1.29 (ddtt, J = 10.0, 7.1, 5.1, 2.5 Hz, 3H), 0.96 – 0.82 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 139.64, 138.90, 128.37, 127.73, 127.32, 114.37, 86.46, 81.41, 73.80, 66.17, 41.38, 31.45, 29.08, 28.91, 28.64, 26.97, 22.71, 18.79, 14.19. FTIR (NaCl, thin film, cm-1): 2931, 2860, 2237, 1455, 1088, 1062, 911, 731, 697. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C21H30O: 299.2369; found: 299.2378. 129 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide (4R,6aS)-4-(benzyloxy)-3-hexyl-4-methyl-4,5,6,6a-tetrahydropentalen-2(1H)-one (7g) and (4S,6aS)-4-(benzyloxy)-3-hexyl-4-methyl-4,5,6,6a-tetrahydropentalen2(1H)-one (7h) Me O OBn Me [Rh(CO)2Cl]2 CO m-xylene O nhex nhex H Me BnO + H BnO g Me h Prepared from 77 (1.19 g, 4.0 mmol, 1.0 equiv), [Rh(CO)2Cl]2 (77.7 mg, 0.2 mmol, 0.05 equiv), and m-xylene (40 mL, 0.10 M) following General Procedure D. The crude residue was purified by column chromatography (silica, 15 to 30% EtOAc/hexanes) to afford 7g (693 mg, 53% yield) and 7h (312 mg, 24% yield) as off-white oils. (7g): 1 H NMR (500 MHz, CDCl3): δ 7.37 – 7.25 (m, 5H), 4.45 (d, J = 10.8 Hz, 1H), 4.36 (d, J = 10.7 Hz, 1H), 3.11 (d, J = 8.8 Hz, 1H), 2.68 (dd, J = 17.9, 6.4 Hz, 1H), 2.42 – 2.26 (m, 3H), 2.22 (dtd, J = 12.3, 8.1, 2.8 Hz, 1H), 2.08 (dd, J = 17.9, 3.3 Hz, 1H), 1.99 (ddd, J = 13.6, 8.9, 2.8 Hz, 1H), 1.66 (s, 3H), 1.56 (d, J = 1.1 Hz, 1H), 1.58 – 1.15 (m, 9H), 0.92 – 0.85 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 211.84, 179.39, 139.80, 139.20, 129.01, 128.16, 128.07, 81.63, 66.98, 43.78, 43.18, 42.03, 32.21, 30.37, 29.45, 28.99, 24.37, 23.20, 23.13, 14.68. FTIR (NaCl, thin film, cm-1): 2930, 1713, 1652, 1462, 1086, 736, 697. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H31O2: 327.2319; found: 327.2326. (7h): 1 H NMR (400 MHz, CDCl3): δ 7.36 – 7.30 (m, 4H), 7.32 – 7.19 (m, 1H), 4.45 (d, J = 10.9 Hz, 1H), 4.26 (d, J = 11.2 Hz, 1H), 2.93 – 2.81 (m, 1H), 2.65 (dd, J = 17.9, 6.4 Hz, 130 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1H), 2.47 – 2.39 (m, 1H), 2.39 – 2.25 (m, 2H), 2.19 – 2.09 (m, 3H), 1.95 (ddd, J = 14.5, 12.0, 7.4 Hz, 1H), 1.62 (s, 3H), 1.49 – 1.13 (m, 12H), 0.89 – 0.80 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 210.71, 181.73, 138.82, 138.11, 128.50, 127.55, 127.34, 81.23, 65.78, 42.91, 42.04, 38.46, 31.80, 31.20, 29.82, 28.79, 27.48, 23.53, 23.37, 22.74, 14.23. FTIR (NaCl, thin film, cm-1): 2928, 2858, 1698, 1660, 1455, 1062, 733, 696. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H31O2: 327.2319; found: 327.2314. 2-heptyl-3,5,5-trimethylcyclohex-2-ene-1,4-dione (28) O O octanoic acid AgNO3, (NH4)2S2O8 Me Me Me O MeCN/H2O, 65 °C nhept Me Me Me O To a dry round-bottomed flask with a Teflon-coated stir bar was added ketoisophorone (0.74 mL, 5.0 mmol, 1.0 equiv), MeCN (15 mL), and H2O (3 mL). Octanoic acid (1.98 mL, 12.5 mmol, 2.5 equiv) was added, and the mixture was stirred placed in a preheated oil bath at 65 °C. Silver nitrate (170 mg, 1.00 mmol, 0.20 equiv) was added in a single portion, and the flask was sealed with a rubber septum and flushed with N2. Ammonium persulfate (1.49 g, 6.50 mmol, 1.3 equiv) was added as a solution in MeCN (15 mL) and H2O (12 mL) (0.1 M final concentration) over 1.5 h via syringe pump. Upon complete consumption of the ketoisophorone as judged by TLC, the reaction was allowed to reach room temperature and concentrated to approximately ½ volume. The resulting liquid was extracted three times with EtOAc. Combined organics were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was 131 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide purified by column chromatography (silica, 5 to 10% Et2O/hexanes) to afford 28 (380 mg, 31% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3): δ 2.70 (s, 2H), 2.41 (dd, J = 8.3, 6.4 Hz, 2H), 1.99 (s, 3H), 1.39 – 1.24 (m, 10H), 1.21 (s, 6H), 0.90 – 0.84 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 203.74, 197.83, 149.20, 143.45, 77.48, 77.16, 76.84, 52.01, 45.23, 31.87, 30.01, 29.22, 28.46, 27.05, 26.38, 22.76, 14.22, 13.19. FTIR (NaCl, thin film, cm-1): 3340, 2957, 2923, 2856, 1682, 1614, 1469, 1378, 1276. HRMS (GC-FAB+, m/z): [M + H]+ calcd for C16H28O2: 251.2011; found: 251.2001. diisopropyl 3,7a-dimethyl-2-oxo-1,2,4,6,7,7a-hexahydro-5H-indene-5,5dicarboxylate (31) O iPrO Me O O Br OiPr NaH, DMF O O iPrO OiPr Me Me PhMe Me Me Co2(CO)8 Me iPrO C 2 CO2iPr Step 1: Intermediate prepared from 57 (800 mg, 3.3 mmol, 1.0 equiv), 4-bromo2-methylbut-1-ene (0.44 mL, 3.6 mmol, 1.1 equiv), NaH (95%, 151 mg, 6.0 mmol, 1.8 equiv), and DMF (4.15 mL, 0.80 M) following General Procedure A. The crude residue was purified by column chromatography (silica, 2% EtOAc/hexanes) to afford the crude intermediate (433 mg, 42% yield) as a colorless oil. Step 2: The intermediate (308 mg, 1.0 mmol, 1.0 equiv) was then used directly in the next step with Co2(CO)8 (410 mg, 1.2 mmol, 1.2 equiv) and PhMe (10 mL, 0.10 M), following modified General Procedure C without addition of DMSO. Upon complete 132 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide conversion of the enyne to the Co-alkyne complex, the reaction was placed in a preheated oil bath at 110 °C. Upon complete consumption of the Co-alkyne complex, the reaction was allowed to reach room temperature, filtered over a pad of SiO2 and Celite, and the filtrate concentrated. The crude residue was purified by column chromatography (silica, 10 to 20 to 35% EtOAc/hexanes) to afford 31 (134 mg, 40% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3): δ 5.03 (dp, J = 26.7, 6.3 Hz, 2H), 3.35 (dd, J = 14.0, 2.3 Hz, 1H), 2.67 (dd, J = 14.0, 1.7 Hz, 1H), 2.39 – 2.31 (m, 1H), 2.31 – 2.12 (m, 2H), 2.06 (td, J = 14.1, 4.0 Hz, 1H), 1.87 (ddd, J = 13.6, 3.9, 2.8 Hz, 1H), 1.72 (d, J = 1.4 Hz, 3H), 1.51 (td, J = 13.8, 4.0 Hz, 1H), 1.29 – 1.17 (m, 16H). 13 C NMR (101 MHz, CDCl3): δ 207.88, 173.62, 170.97, 169.30, 135.44, 77.48, 77.16, 76.84, 69.63, 69.21, 56.86, 51.02, 40.64, 36.46, 29.74, 27.66, 24.56, 21.71, 21.68, 8.16. FTIR (NaCl, thin film, cm-1): 3456, 3394, 2980, 2924, 2870, 2049, 2021, 1731, 1704, 1659, 1456. HRMS (GC-EI+, m/z): [M]+ calcd for C19H28O5: 336.1937; found: 336.1919. diisopropyl 3-methyl-2-oxo-1,2,4,6,7,7a-hexahydro-5H-indene-5,5-dicarboxylate (50) O iPrO O O Br OiPr iPrO O O OiPr Me H THF, DMSO NaH, DMF Me Co2(CO)8 Me iPrO C 2 CO2iPr Step 1: Intermediate prepared from 57 (361 mg, 1.5 mmol, 1.0 equiv), homoallyl bromide (0.23 mL, 2.25 mmol, 1.5 equiv), NaH (95%, 57.0 mg, 2.25 mmol, 1.5 equiv), and DMF (3 mL, 0.50 M) following General Procedure A. The crude, clear colorless oil Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 133 of the intermediate was used without further purification (417 mg, 93% yield). Step 2: The intermediate (368 mg, 1.25 mmol, 1.0 equiv) was then used directly in the next step with Co2(CO)8 (513 mg, 1.5 mmol, 1.2 equiv), DMSO (0.89 mL, 12.5 mmol, 10.0 equiv), and THF (12.5 mL, 0.10 M) following General Procedure C. The crude residue was purified by column chromatography (silica, 55 to 65% Et2O/hexanes) to afford 50 (165 mg, 41% yield) as a white, amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 5.04 (dhept, J = 22.4, 6.3 Hz, 2H), 3.49 (dd, J = 14.0, 2.3 Hz, 1H), 2.64 – 2.42 (m, 4H), 2.12 (ddt, J = 13.5, 5.4, 3.4 Hz, 1H), 1.99 – 1.87 (m, 2H), 1.75 (t, J = 1.6 Hz, 3H), 1.29 – 1.17 (m, 13H). 13 C NMR (101 MHz, CDCl3): δ 208.62, 170.97, 170.32, 169.41, 136.06, 77.48, 77.16, 76.84, 69.63, 69.18, 56.46, 41.00, 39.31, 33.25, 31.00, 30.70, 21.71, 21.70, 21.69, 21.67, 8.00. FTIR (NaCl, thin film, cm-1): 3446, 2980, 2932, 2873, 1723, 1714, 1696, 1453, 1373, 1254, 1107. HRMS (GC-EI+, m/z): [M]+ calcd for C18H26O5: 322.1780; found: 322.1782. 3.8.3 Reaction Optimization General Procedure F: To a flame-dried vial with a Teflon-coated stir bar was added 6a or 9a (1.0 equiv), SeO2, and 4 Å molecular sieves (activated by flame-drying under high vacuum for 10 minutes), if applicable. To this mixture was added 1,4-dioxane (0.05 M) and then H2O, if applicable. The reaction was capped and sealed with Teflon tape, stirred, and brought to 100 °C in a preheated aluminum reaction block. The reaction was monitored by LCMS. When the reaction was judged to be complete, it was allowed Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 134 to reach room temperature and then concentrated. To the crude residue was added pyrazine as an internal standard, then the mixture was taken up in CD3OD and filtered over a cotton plug into an NMR tube. Yield determined by 1H NMR versus the internal standard. Note: The reactions were judged to be complete when the greatest amount of starting material had been consumed and the least amount of the desired product was degraded by further oxidation, as judged by LCMS. This is particularly important for the trioxidation; usually, after two-thirds of the starting material converted, rapid degradation of the desired product was observed. diisopropyl 3a,4-dihydroxy-4,6a-dimethyl-5,6-dioxohexahydropentalene-2,2(1H)dicarboxylate (6) O HO Me HO iPrO C 2 O Me CO2iPr Observed to be a major byproduct during optimization of 4a following General Procedure F, generally formed in 10–30% yield (by 1H NMR versus an internal standard). 1 H NMR (400 MHz, CD3OD): δ 5.08 (dp, J = 12.5, 6.2 Hz, 1H), 4.87 (p, J = 6.3 Hz, 1H), 3.01 (dd, J = 15.6, 1.2 Hz, 1H), 2.78 – 2.69 (m, 1H), 2.67 – 2.55 (m, 2H), 1.97 (s, 3H), 1.29 – 1.20 (m, 9H), 1.15 (dd, J = 7.2, 6.3 Hz, 5H). 13 C NMR (101 MHz, CDCl3): δ 202.54, 190.10, 173.51, 168.62, 102.83, 86.53, 77.36, 71.47, 69.94, 57.86, 55.94, 45.12, 42.98, 21.69, 21.53, 21.40, 18.75, 14.34. 135 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.8.4 Dioxidation O OH SeO2 (10 equiv) H2O (100 equiv) R1 R2 X 1,4-dioxane (0.05 M) 100 °C R1 O HO R2 X General Procedure G (Dioxidation): To a round bottom flask with a bar was added the enone (4 or 7) (1 equiv), SeO2 (10 equiv), 1,4-dioxane (0.05 M), and water (100 equiv). The reaction was sealed with a rubber septum, stirred, and brought to 100 °C in a preheated oil bath. After the reaction was judged to be complete, typically 24–48 h (see note in General Procedure F), the reaction was cooled to room temperature and filtered over a pad of celite, washing with EtOAc. The filtrate was washed with sat. aq. NaHCO3 twice then with water. Combined aqueous washings were extracted with EtOAc. Combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by trituration or column chromatography to afford the desired product. diisopropyl 5,6a-dihydroxy-3a,6-dimethyl-4-oxo-3,3a,4,6a-tetrahydropentalene2,2(1H)-dicarboxylate (5a) OH Me O HO Me iPrO C 2 CO2iPr Prepared from 4a (323 mg, 1.0 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 30 to 35% EtOAc/hexanes) to yield 5a Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 136 (251 mg, 71% yield) as an off-white powder. 1 H NMR (400 MHz, CD3OD): δ 5.08 (hept, J = 6.3 Hz, 1H), 4.97 (hept, J = 6.3 Hz, 1H), 3.36 (dq, J = 17.6, 1.9 Hz, 1H), 3.17 (d, J = 17.5 Hz, 1H), 2.55 (d, J = 13.6 Hz, 1H), 2.37 (s, 2H), 2.13 (d, J = 13.7 Hz, 1H), 1.67 (d, J = 1.7 Hz, 3H), 1.28 (dd, J = 6.2, 1.9 Hz, 6H), 1.21 (dd, J = 6.2, 2.9 Hz, 6H), 1.12 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 203.71, 171.01, 169.52, 148.40, 141.75, 85.25, 69.93, 69.61, 58.23, 53.88, 42.74, 42.42, 21.61, 21.60, 21.57, 21.47, 19.31, 9.09. FTIR (NaCl, thin film, cm-1): 3444, 2981, 2937, 1731, 1455, 1372, 1266, 1106, 912, 823. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C18H25O6: 337.1646; found: 337.1658. 5',6a'-dihydroxy-3a'-methyl-6'-(pyridin-3-yl)-3a',6a'-dihydrospiro[cyclohexane-1,1'cyclopenta[c]furan]-4'(3'H)-one (5b) OH O N HO Me O Prepared from 4b (14.4 mg, 0.05 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 5% MeOH/DCM) to yield 5b (10 mg, 64% yield) as an off-white powder. 1 H NMR (400 MHz, pyridine-d5): δ 10.25 (dd, J = 2.3, 0.9 Hz, 1H), 9.11 (dt, J = 8.1, 1.9 Hz, 1H), 8.70 (dd, J = 4.7, 1.7 Hz, 1H), 7.47 (s, 1H), 7.37 (ddd, J = 8.2, 4.7, 0.9 Hz, 1H), 3.76 (d, J = 9.4 Hz, 1H), 2.44 – 2.34 (m, 1H), 1.95 (td, J = 13.8, 4.1 Hz, 1H), 1.79 – 1.52 (m, 5H), 1.48 (s, 3H), 1.08 (qt, J = 13.1, 4.1 Hz, 1H). Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 13 137 C NMR (101 MHz, pyridine-d5): δ 206.56, 153.09, 151.95, 150.63, 149.38, 137.32, 136.22, 135.72, 135.47, 133.14, 124.21, 123.72, 89.73, 86.24, 72.20, 58.90, 36.94, 29.16, 26.38, 23.93, 22.64, 17.80. FTIR (NaCl, thin film, cm-1): 3335, 2911, 2851, 2639, 2544, 2355, 2336, 2004, 1664, 1539. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C18H22NO4: 316.1543; found: 316.1552. tert-butyl 3a,5-dihydroxy-4,6a-dimethyl-6-oxo-3,3a,6,6atetrahydrospiro[cyclopenta[c]furan-1,4'-piperidine]-1'-carboxylate (5c) OH Me O HO Me O NBoc Prepared from 4c (161 mg, 0.5 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 5 to 7% MeOH/DCM) to yield 5c (94 mg, 53% yield) as off-white powder. 1 H NMR (400 MHz, CDCl3): δ 3.95 (d, J = 10.0 Hz, 1H), 3.64 (d, J = 10.1 Hz, 1H), 2.94 (s, 2H), 1.99 (s, 3H), 1.92 – 1.74 (m, 2H), 1.74 – 1.58 (m, 2H), 1.45 (s, 10H), 1.38 – 1.27 (m, 1H), 1.02 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 200.79, 153.90, 147.50, 139.31, 85.58, 85.35, 81.65, 78.73, 69.57, 58.29, 32.10, 28.84, 27.58, 27.15, 13.06, 8.20. FTIR (NaCl, thin film, cm-1): 3367, 2975, 2933, 2874, 1682, 1428, 1367, 1289, 1251. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C18H28NO6: 354.1911; found: 354.1926. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 138 5,6a-dihydroxy-3a-methyl-1,1-diphenyl-6-(pyrimidin-5-yl)-1,3,3a,6a-tetrahydro-4Hcyclopenta[c]furan-4-one (5d) N OH O N HO Ph Ph Me O Prepared from 4d (18.4 mg, 0.05 mmol) following General Procedure G. The crude residue was purified by trituration from DCM and pentanes to yield 5d (7 mg, 35% yield) as an off-white powder. 1 H NMR (400 MHz, pyridine-d4): δ 9.12 (s, 1H), 8.54 (s, 2H), 7.78 (dd, J = 6.7, 3.0 Hz, 2H), 7.57 – 7.50 (m, 2H), 7.39 – 7.30 (m, 3H), 7.30 – 7.23 (m, 3H), 4.48 (d, J = 8.8 Hz, 1H), 3.87 (d, J = 8.8 Hz, 1H), 2.25 (s, 3H). 13 C NMR (101 MHz, pyridine-d4): δ 202.69, 195.78, 186.85, 183.09, 182.92, 176.74, 176.47, 176.20, 169.54, 169.07, 162.36, 162.12, 161.87, 159.35, 157.26, 156.51, 155.15, 154.99, 154.86, 154.46, 154.26, 149.86, 121.19, 103.12, 83.26, 49.23, 26.56. FTIR (NaCl, thin film, cm-1): 3062, 2924, 2870, 2537, 2249, 1714, 1562, 1446, 1413, 1230, 1060. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C24H20N2O4: 401.1496; found: 401.1503. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 139 5,6a-dihydroxy-1,1,3a-trimethyl-6-(4-(trifluoromethoxy)phenyl)-1,3,3a,6atetrahydro-4H-cyclopenta[c]furan-4-one (5e) OH F3CO O Me HO Me Me O Prepared from 4e (164 mg, 0.5 mmol) following General Procedure G. The crude residue was purified by trituration from DCM and pentanes to yield 5e (135 mg, 76% yield) as an off-white powder. 1 H NMR (500 MHz, CDCl3): δ 7.27 (d, J = 9.2 Hz, 10H), 6.25 (dt, J = 8.1, 1.0 Hz, 2H), 5.53 (s, 1H), 3.06 (d, J = 9.7 Hz, 1H), 2.71 – 2.62 (m, 1H), 1.39 (s, 1H), 0.39 (s, 3H), 0.23 (s, 3H), 0.02 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 204.08, 155.58, 149.35, 148.19, 135.62, 131.93, 131.67, 120.43, 89.18, 84.53, 71.45, 58.21, 26.87, 21.58, 16.51. FTIR (NaCl, thin film, cm-1): 3310, 2979, 2371, 2348, 1719, 1701, 1388, 1260, 1198. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C17H17F3O5: 359.1101; found: 359.1114. 6-(3,5-bis(trifluoromethyl)phenyl)-5,6a-dihydroxy-3a-methyl-1,1-diphenyl-1,3,3a,6atetrahydro-4H-cyclopenta[c]furan-4-one (5f) F3C OH O F3C Ph 1 Me HO Ph O H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.27 (d, J = 4.5 Hz, 4H), 7.25 – 7.18 (m, Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 140 1H), 7.17 – 7.11 (m, 3H), 6.65 – 6.51 (m, 2H), 6.47 – 6.39 (m, 2H), 4.13 (d, J = 9.1 Hz, 1H), 3.77 (d, J = 9.1 Hz, 1H), 1.07 (s, 3H). 6-(6-fluoropyridin-3-yl)-5,6a-dihydroxy-3a-methyl-1,1-diphenyl-1,3,3a,6atetrahydro-4H-cyclopenta[c]furan-4-one (5g) OH F O N Me HO Ph O Ph 1 H NMR (400 MHz, CDCl3): δ 7.97 – 7.92 (m, 1H), 7.58 – 7.50 (m, 4H), 7.52 – 7.45 (m, 1H), 7.40 – 7.32 (m, 1H), 7.03 – 6.87 (m, 3H), 6.81 – 6.74 (m, 2H), 6.61 (dd, J = 8.5, 3.0 Hz, 1H), 4.41 (d, J = 9.1 Hz, 1H), 4.05 (d, J = 9.1 Hz, 1H), 1.35 (s, 3H). Diisopropyl 5,6a-dihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene-2,2(1H)dicarboxylate (8a) OH Me O HO iPrO C 2 CO2iPr Prepared from 7a (154.1 mg, 0.5 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 60% EtOAc/hexanes) to yield 8a (132 mg, 78% yield) as an off-white powder. 1 H NMR (400 MHz, CD3OD): δ 4.98 (p, J = 6.3 Hz, 1H), 4.83 (dt, J = 12.6, 6.3 Hz, 1H), 2.72 (dd, J = 13.6, 1.6 Hz, 1H), 2.56 – 2.39 (m, 3H), 2.31 (d, J = 13.5 Hz, 1H), 1.88 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 141 (d, J = 0.6 Hz, 3H), 1.27 – 1.11 (m, 12H). 13 C NMR (101 MHz, CDCl3): δ 200.52, 171.93, 169.63, 147.90, 141.77, 85.26, 70.26, 69.70, 61.98, 55.66, 43.27, 34.53, 21.74, 21.73, 21.69, 21.63, 9.29. FTIR (NaCl, thin film, cm-1): 3431, 2988, 2936, 2742, 1732, 1455, 1377, 1168, 1022, 985, 901, 832, 758. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C17H23O6: 323.1489; found: 323.1480. diethyl 5,6a-dihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene-2,2(1H)dicarboxylate (8b) OH Me O HO EtO2C CO2Et Prepared from 7b (14.1 mg, 0.05 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 60% EtOAc/hexanes) to yield 8b (12.7 mg, 82% yield) as an off-white powder. 1 H NMR (500 MHz, CD3OD): δ 5.73 (s, 1H), 4.25 (qd, J = 7.1, 2.6 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.98 (s, 1H), 2.79 (dd, J = 10.5, 5.3 Hz, 1H), 2.64 (ddd, J = 13.7, 10.4, 0.9 Hz, 1H), 2.61 – 2.50 (m, 2H), 2.43 (ddd, J = 13.8, 5.3, 0.8 Hz, 1H), 2.01 (d, J = 0.6 Hz, 3H), 1.30 (t, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CD3OD): δ 202.81, 171.92, 171.73, 151.49, 144.09, 84.55, 63.03, 62.97, 61.63, 55.97, 43.22, 35.59, 14.27, 14.22, 8.93. FTIR (NaCl, thin film, cm-1): 3381, 2984, 2940, 1727, 1714, 1672, 1437, 1405, 1370, 1262. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 142 HRMS (TOF-ESI, m/z): [M – H]– calcd for C15H19O7: 311.1136; found: 311.1122. tert-butyl 5,6a-dihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole2(1H)-carboxylate (8c) OH Me O HO N Boc Prepared from 7c (24 mg, 0.1 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 75% EtOAc/hexanes) to yield 8c (15 mg, 57% yield) as an off-white powder. 1 H NMR (400 MHz, CD3OD): δ 3.81 (d, J = 11.9 Hz, 1H), 3.73 (dd, J = 11.7, 1.9 Hz, 1H), 3.49 (t, J = 10.2 Hz, 1H), 3.16 (d, J = 11.9 Hz, 1H), 2.55 (dd, J = 8.5, 1.9 Hz, 1H), 1.98 – 1.93 (m, 3H), 1.41 (s, 9H). 13 C NMR (101 MHz, CD3OD, asterisk denotes minor rotamer): δ 201.58, 156.39, 151.57, 144.65*, 144.40*, 83.96*, 83.31*, 81.61, 56.88*, 56.22*, 55.31*, 54.75*, 47.87*, 47.42*, 28.65, 9.22*. FTIR (NaCl, thin film, cm-1): 3446, 2862, 2352, 1698, 1668, 1660, 1634, 1436, 1224. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C13H20O5: 270.1336; found: 270.1341. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 143 5',6a'-dihydroxy-6'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,1'cyclopenta[c]furan]-4'(3'H)-one (8d) OH Me O HO O Prepared from 7d (104 mg, 0.5 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 50% EtOAc/hexanes) to yield 8d (87 mg, 74% yield) as an off-white powder. 1 H NMR (400 MHz, CDCl3): δ 4.00 (dd, J = 9.8, 8.6 Hz, 1H), 3.79 (dd, J = 9.8, 3.9 Hz, 1H), 2.89 – 2.81 (m, 1H), 2.07 – 1.94 (m, 4H), 1.73 – 1.60 (m, 2H), 1.60 – 1.38 (m, 4H), 1.34 – 1.09 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 199.38, 148.53, 140.21, 87.16, 82.89, 62.25, 58.42, 31.52, 28.00, 24.58, 21.43, 20.97, 9.74. FTIR (NaCl, thin film, cm-1): 3342, 2928, 2858, 1713, 1698, 1668, 1402, 1361, 1133. 1060, 1022. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C13H19O4: 239.1278; found: 239.1282. 5,6a-dihydroxy-6-phenyl-1,3,3a,6a-tetrahydro-4H-cyclopenta[c]furan-4-one (8e) OH O HO O Prepared from 7e (500 mg, 2.5 mmol) following General Procedure G. The crude residue was purified by trituration from DCM and pentanes to yield 8e (397.2 mg, 73% yield) as Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 144 an off-white powder. 1 H NMR (400 MHz, CD3OD): δ 8.18 – 8.11 (m, 2H), 7.46 – 7.38 (m, 2H), 7.38 – 7.30 (m, 1H), 4.12 (d, J = 9.2 Hz, 1H), 4.00 – 3.90 (m, 2H), 3.75 (d, J = 9.2 Hz, 1H), 2.74 (dd, J = 5.6, 3.5 Hz, 1H). 13 C NMR (101 MHz, CD3OD): δ 202.00, 151.69, 139.33, 133.66, 130.60, 129.82, 129.29, 85.13, 76.95, 69.52, 58.97. FTIR (NaCl, thin film, cm-1): 3339, 2880, 2753, 1680, 1501, 1369, 1268, 1016, 698. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C13H13O4: 233.0808; found: 233.0802. 5,6a-dihydroxy-1,1-dimethyl-6-phenyl-1,3,3a,6a-tetrahydro-4H-cyclopenta[c]furan4-one (8f) OH O HO Me Me O Prepared from 7f (22.8 mg, 0.11 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 20% EtOAc/hexanes) to yield 8f(8.0 mg, 32% yield) as an off-white powder. 1 H NMR (400 MHz, CD3OD): δ 8.27 – 8.19 (m, 2H), 7.45 – 7.35 (m, 2H), 4.17 – 4.08 (m, 1H), 3.82 (dd, J = 9.4, 3.6 Hz, 1H), 2.94 (dd, J = 8.2, 3.6 Hz, 1H), 1.40 (d, J = 4.0 Hz, 3H), 0.92 (s, 5H). 13 C NMR (101 MHz, CD3OD): δ 202.61, 150.95, 139.36, 135.53, 130.86, 129.53, 128.92, 88.78, 85.74, 64.87, 61.51, 26.00, 22.64. FTIR (NaCl, thin film, cm-1): 3388, 2925, 2855, 1694, 1385, 1204, 1062. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 145 HRMS (TOF-ESI, m/z): [M + H]+ calcd for C15H17O4: 261.1121; found: 261.1122. 5-hydroxy-1,1-dimethyl-6-phenyl-1,3-dihydro-4H-cyclopenta[c]furan-4-one (38) OH O Me O Me Prepared from 7f (30.6 mg, 0.1 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 30% EtOAc/hexanes) and then preparative thin layer chromatography (silica, 10% MeOH/DCM) to yield 38 (7.5 mg, 30% yield) as an off-white powder. 1 H NMR (400 MHz, CDCl3): δ 8.03 – 7.86 (m, 2H), 7.60 (ddt, J = 7.9, 6.9, 1.3 Hz, 1H), 7.57 – 7.42 (m, 2H), 4.89 (s, 2H), 1.40 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 193.41, 165.32, 157.15, 135.83, 134.29, 129.33, 128.91, 128.47, 91.27, 71.82, 29.86, 26.75. (3aR,4R,6aR)-4-(benzyloxy)-3-hexyl-2,3a-dihydroxy-4-methyl-4,5,6,6atetrahydropentalen-1(3aH)-one (8g) OH nhex HO Me O H BnO Prepared from 7g (6.5 mg, 0.02 mmol) following General Procedure G. The crude residue was purified by preparative thin layer chromatography (silica, 40% EtOAc/hexanes) to yield 8g (1.7 mg, 24% yield) as a white amorphous solid. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 1 146 H NMR (400 MHz, CDCl3): δ 7.44 – 7.28 (m, 5H), 5.63 (s, 1H), 4.56 (d, J = 10.9 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.23 (d, J = 0.8 Hz, 1H), 2.76 – 2.68 (m, 1H), 2.52 – 2.38 (m, 1H), 2.38 – 2.23 (m, 1H), 2.23 – 2.11 (m, 1H), 2.11 – 1.98 (m, 1H), 1.77 – 1.59 (m, 5H), 1.42 – 1.25 (m, 5H), 1.24 (s, 3H), 0.93 – 0.81 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ 202.81, 149.56, 145.27, 138.17, 128.69, 127.98, 127.70, 87.38, 84.14, 65.43, 56.15, 35.06, 31.73, 30.07, 27.66, 26.78, 22.75, 22.69, 19.59, 14.25. FTIR (NaCl, thin film, cm-1): 3388, 2925, 2855, 1694, 1385, 104, 1062. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H31O4: 359.2217; found: 359.2205. 4-methyl-3-pentylcyclopent-3-ene-1,2-dione (26) and 3,4-dioxo-2-pentylcyclopent-1ene-1-carbaldehyde (27) O npent Me 26 O O + npent O O 27 Prepared from dihydrojasmone 25 (41.6 mg, 0.25 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 50% EtOAc/hexanes) to yield a 5:1 mixture of 26 and 27 (17.9 mg, 41% combined) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) of 26: δ 2.94 (h, J = 1.2 Hz, 2H), 2.37 (t, J = 7.7 Hz, 2H), 2.23 (d, J = 1.2 Hz, 3H), 1.47 – 1.43 (m, 2H), 1.36 – 1.28 (m, 6H), 0.90 – 0.86 (m, 3H). 13 C NMR (101 MHz, CDCl3) of 26: δ 198.55, 188.85, 166.73, 146.73, 77.48, 77.16, 76.84, 40.04, 31.84, 27.83, 23.45, 22.56, 17.82, 14.12. FTIR (NaCl, thin film, cm-1) of mixture: 3387, 2952, 2924, 2855, 1714, 1455, 1385, 1261, 1094. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 147 HRMS (GC-EI+, m/z) of 26: [M]+ calcd for C11H16O2: 180.1150; found: 180.1141. 6-heptyl-3,3,5-trimethylcyclohex-5-ene-1,2,4-trione (29) and 5-heptyl-4,6-dihydroxy2,2,6-trimethylcyclohex-4-ene-1,3-dione (30) O nhept OH nhept O Me Me Me + O Me Me HO Me O O 29 30 Prepared from 28 (47.3 mg, 0.20 mmol) following General Procedure G. The crude residue was purified by column chromatography (silica, 20% EtOAc/hexanes) to yield a 10:1 mixture of 29 and 30 (35.6 mg, 68% yield combined) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) of 29: δ 2.62 – 2.55 (m, 2H), 2.15 (s, 3H), 1.42 (s, 6H), 1.30 (m, 10H), 0.90 – 0.85 (m, 3H). 13 C NMR (101 MHz, CDCl3) of 29: δ 197.37, 194.47, 184.30, 150.74, 148.59, 77.48, 77.16, 76.84, 61.84, 31.79, 29.96, 29.11, 28.20, 26.91, 22.73, 21.88, 14.45, 14.20. FTIR (NaCl, thin film, cm-1) of mixture: 3442, 2953, 2924, 2854, 1728, 1667, 1463, 1380, 1312, 1156, 1034. HRMS (GC-EI+, m/z) of 29: [M]+ calcd for C16H24O3: 264.1726; found: 264.1749. 3.8.5 Kinetic Analysis General Procedure K: All synthetic manipulations were performed in a glovebox. To a flame-dried vial with a stir bar was added the enone (4e,h–k) (0.1 mmol, 1.0 equiv), SeO2 (111 mg, 1.0 mmol, 10.0 equiv), internal standard 1,2,4,5-tetrachloro-3nitrobenzene (26 mg, 0.1 mmol, 1.0 equiv), and 1,4-dioxane-d8 (0.8 mL, 0.125 M). The Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 148 reaction was capped and sealed with Teflon tape, stirred, and brought to 100 °C in a preheated aluminum reaction block. A t specified time points, the reaction was allowed to reach room temperature and an aliquot (0.1–0.2 mL) was removed and filtered over a cotton plug directly into a dry NMR tube, washing with additional 1,4-dioxane-d8 (0.3– 0.4 mL). The tube was sealed and analyzed by NMR. If applicable, D2O (180 µL, 10.0 mmol, 100.0 equiv) or CD3OD (406 µL, 10.0 mmol, 100.0 equiv) was added to the appropriate aliquot, which was then brought to 100 °C in a preheated oil bath (outside of the glovebox); at specified time points, the aliquots were allowed to reach room temperature, analyzed by NMR, then returned to the heat. Yield determined by 1H NMR versus the internal standard. Note: Structural assignments of 16h–k and 5h–k-d2 made by analogy to 1H and 13 C NMR spectra of 16e and 5e-d2, respectively. diisopropyl 3a,6-dimethyl-4,5-dioxo-3,3a,4,5-tetrahydropentalene-2,2(1H)dicarboxylate (16a) O Me O Me iPrO C 2 1 CO2iPr H NMR (400 MHz, 1,4-dioxane-d8): δ 5.11 – 4.99 (m, 1H), 5.01 – 4.85 (m, 1H), 3.41 – 3.25 (m, 2H), 2.40 (d, J = 13.9 Hz, 1H), 2.26 (d, J = 16.2 Hz, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.28 – 1.21 (m, 12H), 1.18 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 199.87, 191.01, 177.25, 171.39, 170.72, 137.64, 70.37, 59.50, 51.49, 39.00, 34.09, 22.76, 21.70, 21.62, 21.59, 8.93. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 149 diisopropyl 5-hydroxy-6a-methoxy-3a,6-dimethyl-4-oxo-3,3a,4,6atetrahydropentalene-2,2(1H)-dicarboxylate (16e) O F3CO O Me Me Me 1 O H NMR (400 MHz, 1,4-dioxane-d8): δ 7.51 – 7.36 (m, 4H), 3.90 (d, J = 8.5 Hz, 1H), 3.66 (d, J = 8.5 Hz, 1H), 1.74 (s, 3H), 1.58 (s, 3H), 1.07 (s, 3H). 13 C NMR (101 MHz, 1,4-dioxane-d8): δ 198.41, 189.55, 184.81, 150.43, 139.68, 133.93, 131.77, 131.50, 130.59, 122.69, 121.75, 121.61, 121.48, 80.73, 69.54, 55.28, 30.41, 30.11, 25.96, 23.02. diisopropyl 5-hydroxy-6a-methoxy-3a,6-dimethyl-4-oxo-3,3a,4,6atetrahydropentalene-2,2(1H)-dicarboxylate (24) OH Me O MeO Me iPrO C 2 1 CO2iPr H NMR (400 MHz, CDCl3): δ 4.98 (hept, J = 6.2 Hz, 1H), 4.85 (hept, J = 6.3 Hz, 1H), 3.15 (s, 3H), 2.78 (ddd, J = 13.8, 5.8, 2.2 Hz, 2H), 2.43 (d, J = 13.7 Hz, 1H), 1.97 (d, J = 13.9 Hz, 1H), 1.92 (s, 3H), 1.24 – 1.12 (m, 16H). 13 C NMR (101 MHz, CDCl3): δ 203.53, 170.29, 169.71, 150.71, 138.57, 90.56, 77.36, 69.72, 69.64, 57.48, 53.05, 52.79, 44.42, 40.52, 29.86, 21.66, 21.64, 21.62, 21.53, 18.34, 10.29. 150 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide FTIR (NaCl, thin film, cm-1): 3453, 2919, 2851, 1731, 1282, 1076. HRMS (TOF-ESI, m/z): [M – CH3OH + H]+ calcd for C18H25O6: 337.1646; found: 337.1653. 3.8.6 Trioxidation O OH R H SeO2 (10 equiv) R O 1,4-dioxane (0.05 M) 100 °C HO OH X X General Procedure H (Trioxidation): To a flame-dried vial with a stir bar was added the enone (7) (1 equiv), SeO2 (10 equiv), and 1,4-dioxane (0.05 M). The reaction was capped and sealed with Teflon tape, stirred, and brought to 100 °C in a preheated aluminum reaction block. After the reaction was judged to be complete, typically 1–4 h (see note in General Procedure F), the reaction was cooled to room temperature then concentrated. The crude residue was purified by chromatography to afford the desired product. diisopropyl 3a,5,6a-trihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene2,2(1H)-dicarboxylate (33a) OH Me O HO OH iPrO C 2 CO2iPr Prepared from 7a (7.0 mg, 0.02 mmol) following General Procedure H. The crude residue was purified by preparative thin layer chromatography (silica, 70% Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 151 EtOAc/hexanes) to yield 33a (1.7 mg, 21% yield) as a white amorphous solid. 1 H NMR (400 MHz, CD3OD): δ 4.97 (hept, J = 6.3 Hz, 1H), 4.87 – 4.78 (m, 1H), 2.86 (dd, J = 13.8, 1.9 Hz, 1H), 2.80 (dd, J = 13.3, 1.9 Hz, 1H), 2.33 (d, J = 13.4 Hz, 1H), 2.14 (d, J = 13.7 Hz, 1H), 1.86 (s, 3H), 1.30 – 1.11 (m, 12H). 13 C NMR (101 MHz, CDCl3): δ 198.08, 172.12, 169.27, 147.56, 142.77, 83.23, 79.99, 70.64, 69.95, 59.43, 42.99, 42.03, 21.74, 21.68, 9.58. FTIR (NaCl, thin film, cm-1): 3438, 2984, 2931, 1727, 1714, 1660, 1263, 1100, 902. HRMS (TOF-ESI, m/z): [M + NH4]+ calcd for C17H28O8N: 374.1809; found: 374.1813. diethyl 3a,5,6a-trihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene-2,2(1H)dicarboxylate (33b) OH Me O HO OH EtO2C CO2Et Prepared from 7b (14.1 mg, 0.05 mmol) following General Procedure H. The crude residue was purified by column chromatography (silica, 5% MeOH/DCM) to yield 33b (5.1 mg, 31% yield) as a white amorphous solid. 1 H NMR (400 MHz, CD3OD): δ 4.15 (qd, J = 7.1, 1.3 Hz, 2H), 4.03 (qd, J = 7.2, 2.2 Hz, 2H), 2.86 (ddd, J = 20.9, 13.5, 2.0 Hz, 2H), 2.35 (d, J = 13.3 Hz, 1H), 2.17 (d, J = 13.7 Hz, 1H), 1.87 (s, 3H), 1.21 (dt, J = 8.2, 7.1 Hz, 6H). 13 C NMR (101 MHz, CD3OD): δ 201.23, 171.88, 171.37, 152.07, 143.21, 82.47, 79.98, 63.17, 63.08, 57.10, 43.88, 41.87, 14.25, 14.22, 9.06. FTIR (NaCl, thin film, cm-1): 3402, 2984, 2940, 2852, 1728, 1667, 1404, 1366, 1252. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 152 HRMS (TOF-ESI, m/z): [M – NH4]– calcd for C15H19O8: 327.1085; found: 327.1077. 3a',5',6a'-trihydroxy-6'-methyl-3a',6a'-dihydrospiro[cyclohexane-1,1'cyclopenta[c]furan]-4'(3'H)-one (33d) OH Me O HO OH O Prepared from 7d (20.6 mg, 0.1 mmol) following General Procedure H. The crude residue was purified by column chromatography (silica, 40 to 50% EtOAc/hexanes) to yield 33d (6.2 mg, 23% yield) as a white amorphous solid. 1 H NMR (400 MHz, CD3OD): δ 5.49 (s, 1H), 3.89 (d, J = 10.0 Hz, 1H), 3.55 (d, J = 10.1 Hz, 1H), 1.97 (s, 3H), 1.77 – 1.35 (m, 8H), 1.35 – 1.12 (m, 2H). 13 C NMR (101 MHz, CD3OD): δ 201.20, 152.33, 145.38, 85.90, 85.24, 81.39, 70.51, 54.81, 35.25, 30.76, 28.45, 26.69, 23.64, 22.39, 12.11. FTIR (NaCl, thin film, cm-1): 3394, 2925, 2855, 1714, 1650, 1460, 1361, 1109, 1072. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C13H17O4: 237.1121; found: 237.1111. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 153 3a,5,6a-trihydroxy-1,1-dimethyl-6-phenyl-1,3,3a,6a-tetrahydro-4Hcyclopenta[c]furan-4-one (33f) OH O HO Me Me OH O Prepared from 7f (15.0 mg, 0.07 mmol) following General Procedure H. The crude residue was purified by preparative thin layer chromatography (silica, 40 to 55% EtOAc/hexanes then 10% MeOH/DCM) to yield 33f (3.0 mg, 17% yield) as a white amorphous solid. 1 H NMR (400 MHz, CD3OD): δ 8.24 – 8.17 (m, 2H), 7.43 – 7.28 (m, 3H), 3.98 (d, J = 10.1 Hz, 1H), 3.71 (d, J = 10.1 Hz, 1H), 1.35 (s, 3H), 0.90 (s, 3H). 13 C NMR (101 MHz, (CD3)2SO): δ 201.01, 150.42, 138.58, 135.22, 129.95, 128.81, 128.28, 84.91, 84.44, 80.63, 69.83, 27.14, 22.36. FTIR (NaCl, thin film, cm-1): 3341, 2920, 1694, 1463, 1393, 1049, 730. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C15H15O4: 259.0965; found: 259.0963. (3aS,4R,6aS)-4-(benzyloxy)-3-hexyl-2,3a,6a-trihydroxy-4-methyl-4,5,6,6atetrahydropentalen-1(3aH)-one (33g) OH nhex O HO Me OH BnO Prepared from 7g (32.6 mg, 0.1 mmol) following General Procedure H. The crude Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 154 residue was purified by column chromatography (silica, 20% EtOAc/hexanes then 2% MeOH/DCM) to yield 33g (9 mg, 24% yield) as a pale orange amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 7.43 – 7.30 (m, 5H), 4.55 – 4.43 (m, 2H), 4.41 (s, 1H), 3.32 (s, 1H), 2.51 (ddd, J = 13.9, 9.3, 6.7 Hz, 1H), 2.32 (ddd, J = 13.9, 9.1, 7.2 Hz, 1H), 2.13 – 2.02 (m, 2H), 1.94 – 1.80 (m, 1H), 1.77 – 1.60 (m, 1H), 1.39 (s, 3H), 1.37 – 1.18 (m, 6H), 0.92 – 0.83 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 200.48, 150.53, 144.83, 137.59, 128.78, 128.14, 127.78, 85.29, 83.68, 79.42, 64.78, 31.69, 30.50, 30.26, 29.93, 27.83, 27.48, 22.73, 19.88, 14.23. FTIR (NaCl, thin film, cm-1): 3444, 2926, 2856, 1714, 1660, 1393, 1104, 1040, 738. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H31O5: 375.2166; found: 375.2174. (3aS,4S,6aS)-4-(benzyloxy)-3-hexyl-2,3a,6a-trihydroxy-4-methyl-4,5,6,6atetrahydropentalen-1(3aH)-one (33h) OH nhex O HO BnO OH Me Prepared from 7h (32.6 mg, 0.1 mmol) following General Procedure H. The crude residue was purified by column chromatography (silica, 20% EtOAc/hexanes) to yield 33h (7.7 mg, 21% yield) as a pale orange amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.17 (m, 5H), 5.44 (s, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.33 (d, J = 11.4 Hz, 1H), 3.21 (s, 1H), 2.98 (s, 1H), 2.54 (ddd, J = 14.3, 10.4, 5.8 Hz, 1H), 2.41 (ddd, J = 14.3, 10.4, 6.0 Hz, 2H), 2.08 – 1.90 (m, 2H), 1.83 (q, J = 6.4, 5.8 Hz, 1H), 1.77 – 1.67 (m, 1H), 1.68 – 1.51 (m, 1H), 1.49 (s, 3H), 1.37 – 1.11 (m, 6H), 0.84 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 155 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ δ 199.61, 149.37, 148.48, 138.98, 128.37, 127.31, 126.98, 86.24, 85.37, 80.20, 64.78, 33.08, 31.74, 31.59, 30.04, 27.67, 27.42, 22.75, 18.07, 14.24. FTIR (NaCl, thin film, cm-1): 3388, 2927, 2855, 1698, 1651, 1454, 1394, 1106, 1052, 734. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C22H31O5: 375.2166; found: 375.2164. diisopropyl 3,7a-dimethyl-1,2-dioxo-1,2,4,6,7,7a-hexahydro-5H-indene-5,5dicarboxylate (32) O Me O Me iPrO C 2 CO2iPr Prepared from 31 (16.8 mg, 0.05 mmol) following General Procedure H with SeO2 (27.7 mg, 0.25 mmol, 5.0 equiv). The crude residue was purified by column chromatography (silica, 25% EtOAc/hexanes) to yield 32 (12.6 mg, 72% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3): δ 5.08 (hept, J = 6.3 Hz, 1H), 4.98 (hept, J = 6.3 Hz, 1H), 3.49 (dd, J = 14.1, 2.1 Hz, 1H), 2.74 (dq, J = 14.1, 1.4 Hz, 1H), 2.42 (ddt, J = 14.4, 4.1, 2.6 Hz, 1H), 2.15 (td, J = 14.2, 4.0 Hz, 1H), 1.95 (d, J = 1.3 Hz, 3H), 1.89 (ddd, J = 13.9, 4.0, 2.8 Hz, 1H), 1.51 (td, J = 13.9, 4.1 Hz, 1H), 1.31 (s, 3H), 1.26 (dd, J = 6.3, 3.5 Hz, 7H), 1.19 (dd, J = 6.3, 1.5 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 202.05, 188.28, 172.37, 170.29, 168.81, 140.59, 77.48, Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 156 77.16, 76.84, 70.09, 69.70, 56.53, 43.83, 29.93, 29.27, 26.38, 21.68, 21.66, 19.94, 8.55. FTIR (NaCl, thin film, cm-1): 3505, 3408, 2980, 2939, 2872, 1732, 1633, 1456, 1386. HRMS (TOF-ES+, m/z): [M + H]+ calcd for C19H28O6: 351.1808; found: 351.1784. diisopropyl 7a-hydroxy-3-methyl-2-oxo-1,2,4,6,7,7a-hexahydro-5H-indene-5,5dicarboxylate (51) O Me OH iPrO C 2 CO2iPr Prepared from 50 (16.1 mg, 0.05 mmol) following General Procedure H with SeO2 (8.3 mg, 0.075 mmol, 1.5 equiv). The crude residue was purified by column chromatography (silica, 45% EtOAc/hexanes) to yield 51 (5.7 mg, 34% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3): δ 5.03 (dp, J = 29.1, 6.3 Hz, 2H), 3.31 (dd, J = 13.9, 1.5 Hz, 1H), 2.89 (dq, J = 13.8, 1.6 Hz, 1H), 2.55 – 2.40 (m, 2H), 2.35 – 2.28 (m, 2H), 2.19 (dt, J = 14.3, 3.3 Hz, 1H), 1.75 (d, J = 1.5 Hz, 3H), 1.73 – 1.71 (m, 1H), 1.69 – 1.61 (m, 1H), 1.25 (dd, J = 6.3, 1.7 Hz, 7H), 1.20 (dd, J = 6.3, 4.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ 205.34, 170.48, 169.23, 167.35, 137.18, 77.35, 77.03, 76.71, 73.98, 69.55, 69.16, 56.23, 49.77, 35.64, 29.27, 26.74, 21.58, 21.55, 7.90. FTIR (NaCl, thin film, cm-1): 3443, 2981, 2856, 1810, 1714, 1667, 1454, 1376, 1303, 1251, 1104. HRMS (GC-FAB+, m/z): [M + H]+ calcd for C18H28O6: 339.1808; found: 339.1797. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 157 3.8.7 Stereochemical Analysis General Procedure I (Aqueous): To a flame-dried vial with a stir bar was added the substrate (1 equiv), SeO2 (10 equiv), 1,4-dioxane (0.05 M), and water (100 equiv). The reaction was capped and sealed with Teflon tape, stirred, and brought to 100 °C in a preheated aluminum reaction block. At specified time points, the reaction was cooled to room temperature and an aliquot was removed and concentrated. To the residue was added an internal standard (pyrazine, ~1 equiv), then the mixture was taken up in CD3OD and filtered over a cotton plug into an NMR tube. Yield determined by 1H NMR versus the internal standard. Alternatively, isolated yields were determined by concentration of the entire reaction and purification of the crude residue by chromatography to afford the desired product. Enantiomeric excess determined by analytical chiral SFC or HPLC. General Procedure J (Anhydrous): General Procedure I was followed except that the addition of water to the reaction was omitted. 158 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide diisopropyl 6-methyl-5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)-dicarboxylate (7a) Chiral HPLC: (IH, 1.0 mL/min, 10% IPA/hexanes, λ = 254 nm): tR = 4.4 min, tR = 5.2 min. 7a: racemic O Me H iPrO C 2 CO2iPr Prepared by purification of 7a by chiral HPLC (IH, 1.0 mL/min, 10% IPA/hexanes, λ = 254 nm) to yield (+)-7a* as a single enantiomer. +126 (c = 0.2, CHCl3). (+)-7a*: enantioenriched, >99% ee O Me H iPrO C 2 CO2iPr 159 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared by purification of 7a by chiral HPLC (IH, 1.0 mL/min, 10% IPA/hexanes, λ = 254 nm) to yield (–)-7a* as a single enantiomer. –95 (c = 0.3, CHCl3). (–)-7a*: enantioenriched, >99% ee O Me H iPrO C 2 CO2iPr diisopropyl 5,6a-dihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene-2,2(1H)dicarboxylate (8a) Chiral HPLC: (IH, 1.0 mL/min, 65% IPA/hexanes, λ = 254 nm): tR = 3.9 min, tR = 4.6 min. 8a: racemic OH Me O HO H iPrO C 2 CO2iPr 160 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (–)-7a* (176 mg, 0.57 mmol, >99% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 0 to 40% EtOAc/hexanes) to yield (–)-8a* (114 mg, 59% yield) in >99% ee. –67 (c = 0.5, CHCl3). (–)-8a*: enantioenriched, >99% ee OH Me O HO H iPrO C 2 CO2iPr Prepared from (–)-7a* (22 mg, 0.07 mmol, >99% ee) following General Procedure J. The crude residue was purified by preparative thin layer chromatography (silica, 7% MeOH/DCM) to yield (–)-8a* (1.0 mg, 4% yield) in >99% ee. –15 (c = 0.1, CHCl3). (–)-8a*: enantioenriched, >99% ee OH Me O HO H iPrO C 2 CO2iPr Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 161 diisopropyl 3a-hydroxy-6-methyl-5-oxo-3,3a,4,5-tetrahydropentalene-2,2(1H)dicarboxylate (49a) O Me OH iPrO C 2 1 CO2iPr H NMR (500 MHz, CDCl3): δ 5.09 (dp, J = 37.2, 6.2 Hz, 2H), 3.33 (dd, J = 18.5, 2.0 Hz, 1H), 3.26 (d, J = 18.5 Hz, 1H), 3.00 (s, 1H), 2.89 (d, J = 14.3 Hz, 1H), 2.63 (d, J = 17.9 Hz, 1H), 2.51 (d, J = 18.0 Hz, 1H), 2.11 (d, J = 14.4 Hz, 1H), 1.74 (dd, J = 1.9, 1.0 Hz, 3H), 1.37 – 1.14 (m, 12H). 13 C NMR (101 MHz, CDCl3): δ 207.52, 174.39, 173.24, 170.51, 134.39, 82.47, 70.68, 70.01, 61.00, 48.11, 45.22, 32.91, 21.74, 21.70, 8.78. FTIR (NaCl, thin film, cm-1): 3472, 2927, 2855, 1716, 1682, 1456, 1375, 1267, 1188, 1109, 1027, 913. HRMS (TOF-ESI, m/z): calc'd for C17H24O6: 307.1540 [M–H2O+H]+; found: 307.1549. Chiral HPLC: (IH, 1.0 mL/min, 60% IPA/hexanes, λ = 228 nm): tR = 3.9 min, tR = 4.2 min. 162 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 49a: racemic O Me OH iPrO C 2 CO2iPr Prepared from (+)-7a* (200 mg, 0.65 mmol, >99% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 0 to 30% EtOAc/hexanes) followed by preparative thin layer chromatography (silica, 30 to 50% EtOAc/hexanes) to yield (+)-49a* (3.5 mg, 2% yield) in 36% ee. +6 (c = 0.2, CHCl3). (+)-49a*: enantioenriched, 36% ee O Me OH iPrO C 2 CO2iPr 163 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (+)-7a* (150 mg, 0.49 mmol) following General Procedure J. The crude residue was purified by column chromatography (silica, 0 to 30% EtOAc/hexanes). This procedure was repeated seven times, and the combined material yielded yield (+)-49a* (41 mg, 26% yield) in 92% ee. +12 (c = 1.0, CHCl3). (+)-49a*: enantioenriched, 92% ee O Me OH iPrO C 2 CO2iPr 164 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide diisopropyl 3a,5,6a-trihydroxy-6-methyl-4-oxo-3,3a,4,6a-tetrahydropentalene2,2(1H)-dicarboxylate (33a) Chiral SFC: (OD-H, 1.0 mL/min, 15% IPA in CO2, λ = 254 nm): tR = 5.3 min, tR = 6.0 min. 33a: racemic OH Me O HO OH iPrO C 2 CO2iPr 165 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (–)-7a* (176 mg, 0.57 mmol, >99% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 0 to 40% EtOAc/hexanes) followed by preparative thin layer chromatography (7% MeOH/DCM) to yield (–)-33a* (6.9 mg, 3% yield) in 60% ee. –49 (c = 0.5, CHCl3). (–)-33a*: enantioenriched, 60% ee OH Me O HO OH iPrO C 2 CO2iPr 166 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (–)-7a* (31 mg, 0.1 mmol, >99% ee) following General Procedure J. The crude residue was purified by preparative thin layer chromatography (silica, 70% EtOAc/hexanes then 7% MeOH/DCM) to yield (–)-33a* (5.2 mg, 15% yield) in >99% ee. –59 (c = 0.3, CHCl3). (–)-33a*: enantioenriched, >99% ee OH Me O HO OH iPrO C 2 CO2iPr 167 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (–)-8a* (60 mg, 0.18 mmol, >99% ee) following General Procedure I. The crude residue was purified by preparative thin layer chromatography (silica, 10% MeOH/DCM) to yield (–)-33a* (7.5 mg, 12% yield) in 46% ee. –29 (c = 0.3, CHCl3). (–)-33a*: enantioenriched, 46% ee OH Me O HO OH iPrO C 2 CO2iPr Prepared from (–)-8a* (40 mg, 0.12 mmol, >99% ee) following General Procedure J. The crude residue was purified by preparative thin layer chromatography (silica, 10% MeOH/DCM) to yield (–)-33a* (10.1 mg, 24% yield) in >99% ee. –90 (c = 0.7, CHCl3). (–)-33a*: enantioenriched, >99% ee OH Me O HO OH iPrO C 2 CO2iPr 168 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (+)-49a* (20 mg, 0.06 mmol, 92% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 7% MeOH/DCM) to yield (+)-33a* (1.1 mg, 5% yield) in 92% ee. +14 (c = 0.1, CHCl3). OH (+)-33a*: enantioenriched, 92% ee Me O HO OH iPrO C 2 CO2iPr 169 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Prepared from (+)-49a* (20 mg, 0.06 mmol, 92% ee) following General Procedure J. The crude residue was purified by column chromatography (silica, 7% MeOH/DCM) to yield (+)-33a* (0.2 mg, 1% yield) in 92% ee. +1 (c = 0.1, CHCl3). (+)-33a*: enantioenriched, 92% ee OH Me O HO OH iPrO C 2 CO2iPr 170 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Me SeO2 Me OH H iPrO C 2 OH O O CO2iPr iPrO C 2 + Me O HO OH iPrO C 2 CO2iPr O CO2iPr Me + H iPrO C 2 CO2iPr recovered >99% ee >99% ee Recovered from (–)-7a* (22 mg, 0.07 mmol, >99% ee) following General Procedure J. The crude residue was purified by preparative thin layer chromatography (silica, 7% MeOH/DCM) to yield (–)-7a* (1 mg, 4% recovery) in >99% ee. –94 (c = 0.7, CHCl3). (–)-7a*: enantioenriched, >99% ee O Me H iPrO C 2 CO2iPr 171 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide OH O O Me SeO2, H2O Me OH H iPrO C 2 CO2iPr iPrO C 2 + Me O HO H iPrO C 2 CO2iPr O Me + CO2iPr H iPrO C 2 CO2iPr recovered >99% ee >99% ee Recovered from (+)-7a* (200 mg, 0.65 mmol, >99% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 0 to 30% EtOAc/hexanes) to yield (+)-7a* (150 mg, 75% recovery) in >99% ee. +126 (c = 0.2, CHCl3). (+)-7a*: enantioenriched, >99% ee O Me H iPrO C 2 CO2iPr 172 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide OH Me O HO H iPrO C 2 OH OH SeO2, H2O CO2iPr Me O HO OH iPrO C 2 CO2iPr + Me O HO H iPrO C 2 CO2iPr recovered >99% ee >99% ee Recovered from (–)-8a* (60 mg, 0.18 mmol, >99% ee) following General Procedure I. The crude residue was purified by preparative thin layer chromatography (silica, 10% MeOH/DCM) to yield (–)-8a* (2.2 mg, 4% recovery) in >99% ee. –36 (c = 0.1, CHCl3). (–)-8a*: enantioenriched, >99% ee OH Me O HO H iPrO C 2 CO2iPr 173 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide O Me SeO2, H2O Me O HO OH OH iPrO C 2 O OH CO2iPr iPrO C 2 CO2iPr Me + OH iPrO C 2 CO2iPr recovered 84% ee 92% ee Recovered from (+)-49a* (20 mg, 0.65 mmol, 92% ee) following General Procedure I. The crude residue was purified by column chromatography (silica, 0 to 30% EtOAc/hexanes) followed by preparative thin layer chromatography (silica, 7% MeOH/DCM) to yield (+)-49a* (2.2 mg, 11% recovery) in 84% ee. +30 (c = 0.1, CHCl3). (+)-49a*: enantioenriched, 84% ee O Me OH iPrO C 2 CO2iPr 174 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide OH OH Me O HO OH iPrO C 2 H 2O Me O HO OH CO2iPr >99% ee iPrO C 2 CO2iPr recovered >99% ee Recovered from (–)-33a* (10 mg, 0.03 mmol, >99% ee) following General Procedure I except that the addition of SeO2 to the reaction mixture was omitted. The crude residue afforded (–)-33a* (10 mg, 99% recovery) in >99% ee. –90 (c = 0.7, CHCl3). (–)-33a*: enantioenriched, >99% ee OH Me O HO OH iPrO C 2 CO2iPr 175 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 3.8.8 Product Functionalization 6a-hydroxy-1,1,3a-trimethyl-4-oxo-6-(4-(trifluoromethoxy)phenyl)-3,3a,4,6atetrahydro-1H-cyclopenta[c]furan-5-yl trifluoromethanesulfonate (9) OH F3CO O Me Tf2O DIPEA Me HO Me O OTf F3CO DCM 0 ºC to rt O Me HO Me Me O To a 1-dram vial with a stir bar was added 5e (65 mg, 0.2 mmol, 1.0 equiv). The vial was sealed with a rubber septum and placed under an atmosphere of N2. The solid was taken up in DCM (1 mL, 0.20 M) and stirred, iPr2NEt (53 µL, 0.3 mmol, 1.5 equiv) added, and the solution cooled to 0 °C in an ice water bath. Trifluoromethanesulfonic anhydride (34 µL, 0.2 mmol, 1.0 equiv) was then added dropwise via syringe, with a vent needle to release any triflic acid generated. The resulting mixture was allowed to reach room temperature and monitored by TLC. Upon completion, the reaction was quenched by dropwise addition of water then diluted with water and DCM. The layers were separated, and the aqueous layer was extracted twice with DCM. Combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by trituration from DCM and pentanes (1:4) to yield 9 (88 mg, 0.20 mmol, 99% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.00 – 7.92 (m, 2H), 7.32 (ddt, J = 8.0, 2.2, 1.1 Hz, 2H), 4.13 (d, J = 9.9 Hz, 1H), 3.68 (d, J = 9.9 Hz, 1H), 1.31 (d, J = 3.0 Hz, 6H), 0.96 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 197.78, 154.23, 150.22, 142.15, 130.58, 127.74, 120.74, 119.77, 118.92, 118.16, 115.73, 87.96, 83.57, 70.39, 57.68, 28.85, 24.99, 20.77, 15.62. 176 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide FTIR (NaCl, thin film, cm-1): 3446, 2994, 29256, 2854, 2355, 1738, 1732, 1715, 1632, 1506, 1434, 1212. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C18H17F6O7S: 491.0594; found: 491.0603. diisopropyl 6a-hydroxy-3a,6-dimethyl-4-oxo-5-(((trifluoromethyl)sulfonyl)oxy)3,3a,4,6a-tetrahydropentalene-2,2(1H)-dicarboxylate (54) OH OTf Me O HO Me Comins’ Reagent DIPEA Me O HO Me DCM —78 °C to 0 °C iPrO C 2 CO2iPr iPrO C 2 CO2iPr To a round bottom flask with a stir bar was added 5a (648 mg, 1.8 mmol, 1 equiv). The solid was taken up in DCM (37 mL, 0.05 M) and stirred, DIPEA (1.6 mL, 1.25 mmol, 5 equiv) added, and the solution cooled to –78 °C. Comins’ Reagent (719 mg, 0.25 mmol, 1 equiv) was then added and the mixture cooled to 0 °C. Upon complete consumption of the substrate, the reaction was directly purified by column chromatography (silica, 20% EtOAc/hexanes) to afford 54 (797 mg, 90% yield) as an orange oil. 1 H NMR (400 MHz, CDCl3): δ 5.06 (heptd, J = 6.3, 0.9 Hz, 1H), 4.93 (pd, J = 6.3, 0.8 Hz, 1H), 2.72 (d, J = 14.5 Hz, 1H), 2.52 (s, 2H), 2.24 (d, J = 14.5 Hz, 1H), 2.18 (s, 3H), 1.24 (dd, J = 6.3, 3.0 Hz, 6H), 1.21 – 1.09 (m, 9H). 13 C NMR (101 MHz, CDCl3): δ 198.44, 171.95, 169.21, 162.78, 142.51, 120.15, 116.96, 85.09, 70.56, 70.02, 59.41, 55.72, 44.20, 41.99, 21.57, 21.55, 21.35, 19.30, 10.82. FTIR (NaCl, thin film, cm-1): 3477, 2982, 2939, 1738, 1732, 1715, 1428, 1219, 1099, 987, 896. 177 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide HRMS (TOF-ESI, m/z): [M + NH4]+ calcd for C19H29F3O9SN: 504.1510; found: 504.1521. diisopropyl 5-(cyclopropylethynyl)-6a-hydroxy-3a,6-dimethyl-4-oxo-3,3a,4,6atetrahydropentalene-2,2(1H)-dicarboxylate (55a) OTf Me O HO Me iPrO C 2 CO2iPr Pd(PPh3)2Cl2 CuI, Et3N 50 °C Me O HO Me iPrO C 2 CO2iPr Prepared from 54 (24.4 mg, 0.05 mmol, 1.0 equiv), cyclopropyl acetylene (22 L, 0.25 mmol, 5.0 equiv), Pd(PPh3)2Cl2 (3.5 mg, 0.005 mmol, 0.1 equiv), CuI (1.91 mg, 0.01 mmol, 0.2 equiv), Et3N (0.20 mL, 0.25 M) at 50 °C following General Procedure B. The resulting crude residue was purified by column chromatography (silica, 30% EtOAc/hexanes) to afford 55a (10.1 mg, 51% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3): δ 5.02 (hept, J = 6.3 Hz, 1H), 4.89 (hept, J = 6.3 Hz, 1H), 2.73 (dd, J = 14.2, 1.3 Hz, 1H), 2.58 (dd, J = 13.9, 1.2 Hz, 1H), 2.56 (s, 1H), 2.44 (dd, J = 13.9, 0.8 Hz, 1H), 2.16 (s, 3H), 2.12 (dd, J = 14.1, 0.8 Hz, 1H), 1.44 (tt, J = 8.2, 5.0 Hz, 1H), 1.22 (dd, J = 6.3, 2.2 Hz, 6H), 1.18 (t, J = 6.0 Hz, 6H), 1.12 (s, 3H), 0.93 – 0.80 (m, 2H), 0.81 – 0.75 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 206.20, 175.31, 171.87, 169.34, 125.41, 103.47, 87.80, 70.10, 69.76, 65.93, 59.21, 56.14, 44.03, 42.93, 30.10, 29.84, 22.84, 21.58, 21.57, 21.45, 19.47, 13.57, 9.21, 1.16. 178 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide FTIR (NaCl, thin film, cm-1): 3480, 2927, 2870, 2231, 1716, 1627, 1456, 1386, 1259. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C23H31O6: 403.2155; found: 403.2135. diisopropyl 6a-hydroxy-5-(4-methoxyphenyl)-3a,6-dimethyl-4-oxo-3,3a,4,6atetrahydropentalene-2,2(1H)-dicarboxylate (55b) OMe OTf Me OMe O Me HO (HO)2B Me O HO Me Pd(OAc)2, PCy3 KF, THF iPrO C 2 CO2iPr iPrO C 2 CO2iPr Prepared from 54 (43 mg, 0.09 mmol, 1.0 equiv), (p-methoxyphenyl boronic acid (41 mg, 0.27 mmol, 3.0 equiv), potassium fluoride (30.8 mg, 0.53 mmol, 6.0 equiv), THF (5 mL), and catalyst stock solution (0.9 mL, 0.10 M, 0.04 equiv [Pd], 0.05 equiv PCy3), prepared from Pd(OAc)2 (4.5 mg, 0.02 mmol) and tricyclohexyl phosphine (7.1 mg, 0.025 mmol), at 60 ºC following a literature procedure.35 The crude residue was purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to afford 55b (36.4 mg, 92% yield) as a white amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 7.32 – 7.22 (m, 2H), 6.96 – 6.88 (m, 2H), 5.04 (hept, J = 6.3 Hz, 1H), 4.79 (hept, J = 6.3 Hz, 1H), 3.82 (s, 3H), 2.78 (ddd, J = 17.5, 13.9, 1.5 Hz, 2H), 2.48 (d, J = 12.4 Hz, 1H), 2.19 (d, J = 14.0 Hz, 1H), 2.18 (s, 3H), 1.22 (dd, J = 6.3, 1.2 Hz, 6H), 1.09 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.85, 171.68, 169.63, 168.08, 159.46, 138.41, 130.55, 123.30, 113.76, 87.60, 69.99, 69.52, 58.88, 55.67, 55.39, 43.87, 43.14, 21.62, 21.53, 179 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 21.23, 19.59, 12.84. FTIR (NaCl, thin film, cm-1): 3471, 3047, 2843, 2549, 2248, 2056, 1713, 1454, 1249. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C25H33O7: 445.2221; found: 445.2242. diisopropyl (E)-6a-hydroxy-3a,6-dimethyl-4-oxo-5-(3-phenylprop-1-en-1-yl)3,3a,4,6a-tetrahydropentalene-2,2(1H)-dicarboxylate (55c) Ph OTf Me O HO Me iPrO C 2 CO2iPr Br Pd(OAc)2 PCy3, KF 1,4-dioxane Ph Me O HO Me iPrO C 2 CO2iPr Prepared from 54 (49 mg, 0.1 mmol, 1.0 equiv), (E)-(3-bromoallyl)benzene (49 mg, 0.3 mmol, 3.0 equiv), potassium fluoride (35 mg, 0.6 mmol, 6.0 equiv), 1,4-dioxane (1 mL), and catalyst stock solution (0.5 mL, 0.10 M, 0.04 equiv [Pd], 0.05 equiv PCy3), prepared from Pd(OAc)2 (1.8 mg, 0.008 mmol) and tricyclohexyl phosphine (2.8 mg, 0.01 mmol), at 60 ºC following a literature procedure.35 The crude residue was purified by column chromatography (silica, 30% (Et2O/EtOAc, 1:1)/hexanes) to afford 55c (35.3 mg, 78% yield) as a white amorphous solid. 1 H NMR (400 MHz, CDCl3): δ 7.33 – 7.23 (m, 2H), 7.19 (tt, J = 6.4, 1.2 Hz, 3H), 6.94 (dt, J = 15.8, 7.1 Hz, 1H), 6.03 (dt, J = 15.8, 1.6 Hz, 1H), 5.01 (hept, J = 6.2 Hz, 1H), 4.74 (pd, J = 6.3, 1.0 Hz, 1H), 3.51 – 3.44 (m, 2H), 2.74 (dd, J = 13.9, 1.4 Hz, 1H), 2.65 (dt, J = 13.7, 1.2 Hz, 1H), 2.40 (d, J = 13.7 Hz, 1H), 2.12 (d, J = 14.2 Hz, 1H), 2.10 (s, 3H), 1.21 (dd, J = 6.3, 1.5 Hz, 6H), 1.11 (t, J = 3.1 Hz, 6H), 1.05 (d, J = 6.3 Hz, 3H). 180 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 13 C NMR (101 MHz, CDCl3): δ 13C NMR (101 MHz, CDCl3) δ 208.26, 171.72, 169.43, 167.36, 139.74, 136.99, 133.88, 128.78, 128.59, 126.29, 119.62, 87.37, 69.95, 69.56, 58.88, 55.87, 43.83, 43.07, 40.51, 21.59, 21.48, 21.37, 19.59, 12.03. FTIR (NaCl, thin film, cm-1): 3470, 2981, 2929, 1728, 1715, 1454, 1375, 1258, 1258. HRMS (TOF-ESI, m/z): [M –H2O + H]+ calcd for C27H33O5: 437.2323; found: 437.2320. diisopropyl 5-benzyl-6a-hydroxy-3a,6-dimethyl-4-oxo-3,3a,4,6atetrahydropentalene-2,2(1H)-dicarboxylate (55d) Ph OTf Me O HO Me iPrO C 2 CO2iPr KF3B PdCl2(dppf)CH2Cl2 Cs2CO3 PhMe/H2O Me O HO Me iPrO C 2 CO2iPr Prepared from 54 (36.8 mg, 0.08 mmol, 1.0 equiv), BnBF3K (41.9 mg, 0.23 mmol, 3.01 equiv), Cs2CO3 (70.7 mg, 0.22 mmol, 2.9 equiv), PdCl2(dppf)CH2Cl2 (5.9 mg, 0.007 mmol, 0.1 equiv), and PhMe (0.43 mL) and water (0.14 mL, 0.125 M total (PhMe/H2O, 3:1)) at 80 ºC following a literature procedure.36 The crude residue was purified by column chromatography (silica, 10 to 20% EtOAc/hexanes) to afford 55d (27.9 mg, 86% yield) as a yellow gel. 1 H NMR (400 MHz, CDCl3): δ 7.38 – 7.29 (m, 2H), 7.29 – 7.21 (m, 3H), 5.13 (hept, J = 6.2 Hz, 1H), 4.81 (heptd, J = 6.3, 1.3 Hz, 1H), 3.63 (d, J = 14.5 Hz, 1H), 3.47 (d, J = 14.5 Hz, 1H), 2.80 (dd, J = 14.2, 1.1 Hz, 1H), 2.68 (s, 1H), 2.65 (dd, J = 14.0, 1.1 Hz, 1H), 2.53 (d, J = 14.0 Hz, 1H), 2.26 (d, J = 14.1 Hz, 1H), 2.16 (s, 3H), 1.32 (dd, J = 6.3, 2.8 Hz, 6H), 1.23 (dd, J = 6.2, 1.5 Hz, 6H), 1.20 (s, 3H). Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 13 181 C NMR (101 MHz, CDCl3): δ 208.88, 172.03, 169.47, 169.14, 138.67, 138.36, 128.67, 128.61, 126.25, 88.15, 70.00, 69.35, 59.31, 59.29, 55.95, 43.92, 42.41, 29.14, 21.58, 21.55, 21.45, 19.58, 12.18. FTIR (NaCl, thin film, cm-1): 3460, 2981, 2933, 1728, 1645, 1376, 1259, 1098. 3.9 REFERENCES (1) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. Organocobalt Complexes. Part II. Reaction of Acetylenehexacarbonyldicobalt Complexes, (R1C2R2)Co2(CO)6, with Norbornene and its Derivatives. J. Chem. Soc., Perkin Trans. 1 1973, No. 0, 977–981. (2) Ornum, S. G. V.; Hoerner, S.; Cook, J. M. Recent Adventures with the PausonKhand Reaction in Total Synthesis. In The Pauson-Khand Reaction; John Wiley & Sons, Ltd, 2012; pp 211–238. (3) Shibata, T. Recent Advances in the Catalytic Pauson–Khand-Type Reaction. Adv. Synth. Cat. 2006, 348 (16–17), 2328–2336. (4) Gibson, S. E.; Mainolfi, N. The Intermolecular Pauson-Khand Reaction. Angew. Chem. Int. Ed. 2005, 44 (20), 3022–3037. (5) Chuang, K. V.; Xu, C.; Reisman, S. E. A 15-Step Synthesis of (+)-Ryanodol. Science 2016, 353 (6302), 912–915. (6) Xu, C.; Han, A.; Virgil, S. C.; Reisman, S. E. Chemical Synthesis of (+)Ryanodine and (+)-20-Deoxyspiganthine. ACS Cent. Sci. 2017, 3 (4), 278–282. (7) Dibrell, S. E.; Maser, M. R.; Reisman, S. E. SeO2-Mediated Oxidative Transposition of Pauson–Khand Products. J. Am. Chem. Soc. 2020, 142 (14), Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 182 6483–6487. (8) Umbreit, M. A.; Sharpless, K. B. Allylic oxidation of oleins by catalytic and stoichiometric selenium dioxide with tert-butyl hydroperoxide. J. Am. Chem. Soc. 1977, 99 (16), 5526–5528. (9) Greenwood, N. N.; Earnshaw, A. Chemistry of the Elements, 2nd Edition.; Elsevier, 1997. (10) Ippoliti, F. M.; Barber, J. S.; Tang, Y.; Garg, N. K. Synthesis of 8-hydroxy geraniol. J. Org. Chem. 2018, 83 (18), 11323–11326. (11) Trost, B. M.; Dong, G.; Vance, J. A. Cyclic 1,2-diketones as core building blocks: a strategy for the total synthesis of (–)-terpestacin. Chem. Eur. J. 2010, 16 (21), 6265–6277. (12) Xu, C.; Han, A.; Reisman, S. E. An oxidative dearomative approach to prepare the pentacyclic core of ryanodol. Org. Lett. 2018, 20 (13), 3793–3796. (13) Kurosu, M.; Marcin, L. R.; Grinsteiner, T. J.; Kishi, Y. Total Synthesis of Batrachotoxinin A. J. Am. Chem. Soc. 1998, 120 (26), 6627–6628. (14) Riley, H. L.; Morley, J. F.; Friend, N. A. C. 255. Selenium dioxide, a new oxidizing agent. Part I. Its reaction with aldehydes and ketones. J. Chem. Soc. 1932, 1875. (15) Nguyen, T. M.; Lee, D. A Novel Reactivity of SeO2 with 1,3-Dienes: Formation of syn 1,2- and 1,4-Diols via a Facile C−Se Bond Oxidation. Org. Lett. 2001, 3 (20), 3161–3163. (16) Młochowski, J.; Wójtowicz-Młochowska, H. Developments in synthetic application of selenium (IV) oxide and organoselenium compounds as oxygen Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 183 donors and oxygen-transfer agents. Molecules 2015, 20 (6), 10205–10243. (17) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Using Singlet Oxygen to Synthesize Polyoxygenated Natural Products from Furans. Acc. Chem. Res. 2008, 41 (8), 1001–1011. (18) Sharpless, K. B.; Gordon, K. M. Selenium dioxide oxidation of ketones and aldehydes. Evidence for the intermediace of β-ketoseleninic acids. J. Am. Chem. Soc. 1976, 98 (1), 300–301. (19) Hansch, Corwin.; Leo, A.; Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 1991, 91 (2), 165–195. (20) Furusawa, T.; Morimoto, T.; Ikeda, K.; Tanimoto, H.; Nishiyama, Y.; Kakiuchi, K.; Jeong, N. Asymmetric Pauson–Khand-type reactions of 1, 6-enynes using formaldehyde as a carbonyl source by cooperative dual rhodium catalysis. Tetrahedron 2015, 71 (5), 875–881. (21) Sharpless, K. B.; Lauer, R. F. Selenium Dioxide Oxidation of Olefins. J. Am. Chem. Soc. 1972, 94 (20), 7154–7155. (22) Arigoni, D.; Vasella, A.; Sharpless, K. B.; Jensen, H. P. Selenium dioxide oxidations of olefins. Trapping of the allylic seleninic acid intermediate as a sleninolactone. J. Am. Chem. Soc. 1973, 95 (23), 7917–7919. (23) Singh, G. Condensation of 1-Vinyl-6-methoxy-3, 4-dihydronaphthalene and 3Methyl-3-cyclopentene-1, 2-dione. Structure of Dane's Adduct. J. Am. Chem. Soc. 1956, 78 (23), 6109–6115. (24) Sheley, C. F. Enolization Route to Substituted Cyclopentadienones, The Ohio State University, 1966. Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide 184 (25) Pal, R.; Mukherjee, S.; Chandrasekhar, S.; Guru Row, T. N. Exploring cyclopentadienone antiaromaticity: charge density studies of various tetracyclones. J. Phys. Chem. A 2014, 118 (19), 3479–3489. (26) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. BromineCatalyzed Aziridination of Olefins. A Rare Example of Atom-Transfer Redox Catalysis by a Main Group Element. J. Am. Chem. Soc. 1998, 120 (27), 6844– 6845. (27) Sharpless, K. B.; Hori, T.; Truesdale, L. K.; Dietrich, C. O. Allylic Amination of Olefins and Acetylenes by Imido Selenium Compounds. J. Am. Chem. Soc. 1976, 98 (1), 269–271. (28) Jain, V. K. Chapter 1. An Overview of Organoselenium Chemistry: From Fundamentals to Synthesis. In Organoselenium Compounds in Biology and Medicine; Jain, V. K., Priyadarsini, K. I., Eds.; Royal Society of Chemistry: Cambridge, 2017; pp 1–33. (29) Corey, E. J.; Schaefer, J. P. Studies on the mechanism of oxidation of ketones by selenium dioxide (part I). J. Am. Chem. Soc. 1960, 82 (4), 917–929. (30) Roszak, R.; Beker, W.; Molga, K.; Grzybowski, B. A. Rapid and accurate prediction of pKa values of C–H acids using graph convolutional neural networks. J. Am. Chem. Soc. 2019, 141 (43), 17142–17149. (31) Warpehoski, M. A.; Chabaud, B.; Sharpless, K. B. Selenium dioxide oxidation of endocyclic olefins. Evidence for a dissociation-recombination pathway. J. Org. Chem. 1982, 47 (15), 2897–2900. (32) Falk, M.; Giguère, P. A. Infrared spectra and structure of selenious acid. Can. J. 185 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide Chem. 1958, 36 (12), 1680–1685. (33) Singleton, D. A.; Hang, C. Isotope effects and the mechanism of allylic hydroxylation of alkenes with selenium dioxide. J. Org. Chem. 2000, 65 (22), 7554–7560. (34) Jolit, A.; Dickinson, C. F.; Kitamura, K.; Walleser, P. M.; Yap, G. P. A.; Tius, M. A. Catalytic Enantioselective Nazarov Cyclization. Eur. J. Org. Chem. 2017, 2017 (40), 6067–6076. (35) Littke, A. F.; Dai, C.; Fu, G. C. Versatile catalysts for the Suzuki cross-coupling of arylboronic acids with aryl and vinyl halides and triflates under mild conditions. J. Am. Chem. Soc. 2000, 122 (17), 4020–4028. (36) Molander, G. A.; Ito, T. Cross-coupling reactions of potassium alkyltrifluoroborates with aryl and 1-alkenyl trifluoromethanesulfonatesOrg. Lett. 2001, 3 (3), 393–396. (37) Chung, Y. K.; Lee, B. Y.; Jeong, N.; Hudecek, M.; Pauson, P. L. Promoters for the (alkyne) hexacarbonyldicobalt-based cyclopentenone synthesis. Organometallics 1993, 12 (1), 220–223. (38) Koga, Y.; Kobayashi, T.; Narasaka, K. Rhodium-catalyzed intramolecular PausonKhand reaction. Chem. Lett. 1998, 27 (3), 249–250. (39) Adrio, J.; Rivero, M. R.; Carretero, J. C. Mild and efficient molybdenum-mediated Pauson–Khand-type reaction. Org. Lett. 2005, 7 (3), 431–434. (40) Csékei, M.; Novák, Z.; Kotschy, A. Ethynyl-cyclohexanol: an efficient acetylene surrogate in Sonogashira coupling. Tetrahedron 2008, 64 (6), 975–982. (41) Clavier, H.; Nolan, S. P. N-heterocyclic carbene and phosphine ruthenium 186 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide indenylidene precatalysts: a comparative study in olefin metathesis. Chem. Eur. J. 2007, 13 (28), 8029–8036. (42) Tanaka, K.; Okazaki, E.; Shibata, Y. Cationic Rhodium (I)−dppf ComplexCatalyzed Olefin Isomerization/Propargyl Claisen Rearrangement/Carbonyl Migration Cascade. J. Am. Chem. Soc. 2009, 131 (31), 10822–10823. (43) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. A general strategy for the perfluoroalkylation of arenes and arylbromides by using arylboronate esters and [(phen)CuRF]. Angew. Chem. Int. Ed. 2012, 51 (2), 536–539. (44) King, A. E.; Brunold, T. C.; Stahl, S. S. Mechanistic study of copper-catalyzed aerobic oxidative coupling of arylboronic esters and methanol: insights into an organometallic oxidase reaction. J. Am. Chem. Soc. 2009, 131 (14), 5044–5045. (45) Murphy, J. M.; Liao, X.; Hartwig, J. F. Meta halogenation of 1,3-disubstituted arenes via iridium-catalyzed arene borylation. J. Am. Chem. Soc. 2007, 129 (50), 15434–15435. (46) Ohmura, T.; Sasaki, I.; Suginome, M. Catalytic generation of rhodium silylenoid for alkene–alkyne–silylene [2+2+1] cycloaddition. Org. Lett. 2019, 21 (6), 1649– 1653. (47) Hwu, J. R.; Chen, C. N.; Shiao, S.-S. Silicon-controlled allylation of 1,3-dioxo compounds by use of allyltrimethylsilane and ceric ammonium nitrate. J. Org. Chem. 1995, 60 (4), 856–862. (48) Kwong, F. Y.; Li, Y. M.; Lam, W. H.; Qiu, L.; Lee, H. W.; Yeung, C. H.; Chan, K. S.; Chan, A. S. C. Rodium-catalyzed asymmetric aqueous Pauson–Khand-type reaction. Chem. Eur. J. 2005, 11 (13), 3872–3880. 187 Chapter 3 – Oxidative Transpositions Mediated by Selenium Dioxide (49) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. CO-Transfer carbonylation reactions. A catalytic Pauson−Khand-Type reaction of enynes with aldehydes as a source of carbon monoxide. J. Am. Chem. Soc. 2002, 124 (15), 3806–3807. (50) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. Development of a titanocenecatalyzed enyne cyclization/isocyanide insertion reaction. J. Am. Chem. Soc. 1994, 116 (19), 8593–8601. (51) Kinder, R. E.; Widenhoefer, R. A. Rhodium-catalyzed asymmetric cyclization/hydroboration of 1,6-enynes. Org. Lett. 2006, 8 (10), 1967–1969. (52) Bartlett, A. J.; Laird, T.; Ollis, W. D. Base-catalysed intramolecular cycloadditions of allyl 3-phenylprop-2-ynyl ethers and 4-methylpent-4-en-2-ynyl prop-2-ynyl ethers. J. Chem. Soc., Perkin Trans. 1 1975, 0 (14), 1315–1320. (53) Zhao, Z.; Ding, Y.; Zhao, G. Bicyclization of Enynes Using the Cp2TiCl2−Mg−BTC System: A Practical Method to Bicyclic Cyclopentenones. J. Org. Chem. 1998, 63 (25), 9285–9291.  Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 408 Chapter 5 Formal Synthesis of (–)-Cylindrocyclophane F† 5.1 INTRODUCTION Ni-catalyzed reductive cross-coupling (RCC) reactions are powerful and mild methods of joining two electrophiles using a stoichiometric reductant.1 These crosscouplings forge C–C bonds between partners of varying functionality (e.g., halides, redox-active esters, etc.) and carbon hybridization (i.e., Csp3, Csp2, and Csp) and—when performed with a chiral catalyst—can form enantioenriched products from prochiral substrates.2,3 Owing to these advantages, Ni-catalyzed RCCs, in particular those reactions constructing Csp2–Csp3 bonds,4 are useful in the enantioselective preparation of pharmaceutically relevant small molecules.5 Indeed, the success of many RCCs is measured by their practicality in an industrial pharmaceutical setting,6 such as compatibility with aryl bromides7 featuring drug-like functionalization8 or performance † The research presented in this chapter was completed in collaboration with Dr. Christopher Lavoie and Stephanie Cortez, former Reisman group members, as well as Cedric Lozano, a current graduate student in the Reisman group. 409 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F on large scale.9 In contrast to the pharmaceutical landscape, natural product synthesis remains a largely unexplored terrain in which to explore the power of reductive crosscoupling for strategic bond construction. Figure 5.1 Ni-catalyzed reductive ring formation intramolecular conjunctive coupling intramolecular di-electrophile coupling Gong, 2014 Peng, 2016 Kong, 2018 H CbzN CbzN CbzN OEt O Me H Ph O MeO OMe Peng, 2012 Jarvo, 2015 MeO2C N OMe N Me CO2Et HO alkyne–aldehyde reductive macrocyclization this chapter Jamison, 2014 HO OH Me Ph R Me Me O O Me O Me O OH H Ph O nBu O Me Me Me O OH R Me One defining feature of complex molecules, such as natural products and their derivatives, is a carbocyclic skeleton. If drawing from the rapidly expanding pool10 of Nicatalyzed RCCs in developing a synthetic route, the available transformations would be suitable for installation of carbon-based appendages around the skeletal periphery. Given the state-of-the-art, it is significantly more challenging to construct the carbon ring system itself using these methods. Several studies have established the feasibility of Nicatalyzed RCCs in ring formation (Figure 5.1). In the cases where aryl halide substrates feature pendant alkenes, n-exo-trig cyclization can accompany cross-coupling to generate five- or six-membered rings, whether by cyclization of radical intermediates11 or as a pathway toward three-component couplings.12 Difunctional electrophiles can undergo Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 410 intramolecular coupling to access cyclopropanes13 or five-, six-, or seven-membered14 carbocyclic rings. In the generation of rings with greater than seven members, successful intramolecular coupling partners are limited to aldehydes with epoxides, alkenes, or alkynes, which restricts the oxidation pattern around the thus-generated C–C bond.15 Against this backdrop, we view [7.7]paracyclophane16 as an exciting system in which to explore Ni-catalyzed reductive cross-coupling in the formation of stereochemically enriched macrocyclic carbocycles.17 Synthesis of these macrocycles via cyclodimerization is a known proving ground for new methods.18 The success of any transformation in this context requires high levels of efficiency and selectivity as well as the ability to impart stereochemical control across a large, flexible ring. Emblematic of the [7,7]paracyclophanes is the cylindrocyclophane family19 of tumor cytotoxins. The following introductory sections outline our motivation for pursuing the synthesis of the cylindrocyclophane natural products via application of Ni-catalyzed RCC to macrocyclization. 5.1.1 Natural Paracyclophanes Nature produces a large number of cyclophanes which serve as inspiration for biological study and chemical synthesis. The paracyclophane natural product family is found in photosynthetic cyanobacteria and has been continually expanding since 1990— when cylindrocyclophanes were isolated from C. licheniforme in blue-green algae20,21— to 2023, in which year the newest addition to the family was reported.22 Common to members of this family is a carbon-based, 22-membered [7,7]paracyclophane core in which a seven-carbon aliphatic chain bridges two para-substituted arenes. Based on the 411 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F characteristic substitution pattern of the aryl moieties, these natural products are generally termed dialkylresorcinols.19 Figure 5.2 [7.7]Paracyclophane natural products cylindrocyclophanes, ribocyclophanes, carbamidocyclophanes Me R1 1 2 HO HO R3 A A4 B C D E F F4 R3 7 OH OH 20 14 15 R2 Me merocyclophanes R3 OH OH OH OH OAc OAc H H OH OH OAc H OAc H H H Me CHCl2 Me Me Me Me Me CHCl2 R 1O R HO HO R2 nostocyclophanes Me OH R 2O OH R R1 Me Me Me Cl HO OH Cl OR2 OR1 The family is divided into several structural subclasses, including the cylindrocyclophanes,20,21,23 carbamidocyclophanes,24,25,26,27 merocyclophanes,28,29 and nostocyclophanes30 (Figure 5.2). Cylindrocyclophanes A–F feature various C1/C14 oxidation (R1 and R2); they each share a stereodefined methyl group along the alkyl bridge but differ at the terminus of the appended n-butyl chain (R3). Similarly, members of the other subclasses feature a single shared structural feature, such as the benzylic methyl group of the merocyclophanes or the aliphatic chloride substituent of the nostocyclophanes, and diverge with respect to additional peripheral decoration. Based on the solid-state structure of nostocyclophane D,31 the benzylic substituents lie in equatorial positions with the faces of the arenes aligned in parallel—a conformation welldisposed for inclusion of small molecules (e.g., EtOH) within the macrocyclic pocket (Ar–Ar distance ca. 7.85 Å).32 412 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F These macrocyclic natural products are biosynthetically related, and substantial progress toward the identification and validation of key enzymes has been made by the Balskus group33,34,35 and others.31,36 Despite their related biogenesis, the natural paracyclophanes demonstrate wide-ranging therapeutic potential, demonstrating antibacterical26 activity, cytotoxicity toward several cancer cell lines,21,29,37 and proteasome inhibition,23 just among the cylindrocyclophanes. Still other paracyclophanes are antifungal25 and anticancer agents (against additional tumor cells)38 and serve as possible treatments for tuberculosis.25 The breadth of bioactivity reflects the staggering array of metabolites from related cyanobacterial genera that are making significant headway as pharmaceutical candidates across a variety of therapeutic areas.39 In the course of preliminary structure–activity relationship (SAR) studies, a few structural features of paracyclophanes have been implicated as important for bioactivity. Unlike most natural products, both enantiomers of cylindrocyclophane A (1) display a similar level of cytotoxicity.40 The resorcinol warhead is critical for reactivity and is rendered more potent by arrangement in a [7.7]paracyclophane framework40 (as opposed to a half-sized alkyl resorcinol fragment).41 The n-butyl chain is also important for low micromolar activity.42 In addition, several studies have noted a considerable improvement in potency (up to 40x)27 due to n-butyl chain halogenation, particularly with Br-27 but also Cl-substituents.23 To facilitate these studies—and supplement recent advances in the isolation of these complex molecules from natural sources39—efficient methods for their chemical synthesis are required. Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 413 5.1.2 Synthetic Efforts Whether captivated by the cyclophane structure or driven by the promise of their success a pharmaceuticals, chemists and biologists alike have worked to expand the pool of these cyclic compounds for several decades—since the introduction of paracyclophane43 to the chemical community. As examples, many groups have prepared cyclophanes to probe their use as chiral ligands,44 for host-guest chemistry,45 and as building blocks for complex supramolecular structures.46,47 To inform these synthetic studies, the structure and related properties (e.g., conformation, 16,32 strain,48,49,50 dynamics,51 electronic structure,52 etc.) of hypothetical and physically accessible compounds have been computationally investigated. There has also been substantial synthetic work devoted to cyclophanes that are biologically relevant. Nevertheless, many interesting targets in this category feature complex functionalization and stereochemical patterns that are inaccessible via known methods of peripheral modification53 and pose substantial challenges to direct preparation of a fully elaborated macrocycle.54,55 Of utmost concern to the synthesis of a paracyclophane is the ring-forming event. An early approach has been to sequentially form a thiacyclophane and then pyrolyze the sulfone linkage; in this way, a paracyclophane (of type [n,n], where n = even number) is initially generated which can then lead to odd- or mixed-length bridges, [m,m]56 or [n,m],57 respectively. This method represents a commonly used general strategy for macrocycle formation, including up to ring sizes m = 11: use of distinct difunctional substrates that each contain the same reactive group (i.e., di-electrophile and dinucleophile).58 One main challenge to this approach is the difficulty of controlling headto-head versus head-to-tail dimerization. An alternative strategy is to forge the 414 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F macrocycle from a single difunctional substrate (e.g., an ambiphilic monomer), the feasibility of which was established by early implementation of a high-dilution Friedel– Crafts reaction.59 Another traditional approach to paracyclophane synthesis is sequential coupling and ring closure. In this case, a linear precursor is prepared first, followed by macrocycle construction in a separate step.60,32 One advantage of this strategy is that a higher level of control over macrocyclization is generally possible in the ring-closing step. An illustrative example is presented in Figure 5.3;61 notably, two stereocenters are established at the same time as macrocycle closure, albeit with low levels of substratecontrolled diastereoselectivity. Figure 5.3 Concomitant paracyclophane ring closure and stereocenter formation Me Ph Me Ph Ph TfOH + PhH 37% yield 2.7:1 cis:tras 5.1.2.1 Cylindrocyclophanes: Macrocyclization These foundational studies of cyclophane assembly have undoubtedly guided partial and complete syntheses18 of the cylindrocyclphane natural products. The Albizati group designed a two-step approach that would access cylindrocyclophane A (1) via sequential radical–enone addition reactions, but they were unable to observe macrocyclization (Figure 5.4).62 A related report from the Davies and Stoltz groups utilized a C–H functionalization reaction to prepare a linear intermediate, which underwent ring formation via subsequent C–H functionalization (vide infra); this strategy 415 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F which provided access to an undersubstituted model macrocycle63 with the goal of elaborating via C–H acetoxylation to oxidized 1.64 Another successful approach to stepwise ring formation by Smith and coworkers hinged on reductive alkylation followed by ring-closing metathesis (RCM). RCM of 3 was selective against oligomerization, generating the desired macrocycle in 88% yield, advanced to cylindrocyclophane F (2) in two steps.65 Figure 5.4 Prior art: stepwise macrocyclization Martin, 1992 Me Me O I MeO O MeO OMe + MeO Me O OMe MeO OMe 3 steps OMe MeO I OMe MeO OMe O OH I Me O Me Me Smith, 1999 Me Me NTBS I MeO nBu nBu OMe + MeO Me nBu N MeO OMe 4 steps OMe OMe MeO nBu Me MeO OMe RCM MeO MOMO nBu OMe nBu 3 Me 4 Me Because of their C2 symmetry, these natural products have inspired one-step, head-to-tail cyclodimerization as the gold standard. This can be an extremely efficient strategy, as only one half of the target molecule needs to be prepared prior to macrocycle formation. However, development of an appropriately selective and high-yielding method for dimerization is not an insignificant challenge. Indeed, synthetic approaches based on Alder–ene reaction66 or double Suzuki cross-coupling,67 developed by the Trost and MacMillan groups, respectively, were unable to afford the [7.7]paracyclophane skeleton (Figure 5.5). The former dimerization attempt ended in unselective polymerization and 416 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F exemplifies one of the more significant challenges of reacting difunctional monomers. The latter approach illustrates another: the tactic for dimerization must be compatible with synthesis of the requisite substrate, a challenge if the molecule contains both a reactive nucleophile and electrophile (i.e., 5). Figure 5.5 Challenges of single-step cyclodimerization Schnaderbeck, 1998 HO HO nBu HO Alder–ene OMe MeO or MeO OMe MeO nBu OMe MeO nBu HO OMe nBu OH Goodwin, 2007 Me NMe2 NMe3 nBu OTf double Suzuki MeO OMe MeO nBu MeO OMe nBu Me 9-BBN 5 OMe MeO OMe nBu Me Me Successful methods for cyclodimerization include a Horner–Wadsworth–Emmons olefination reported by Hoye and coworkers68 en route to natural product 1, as well as Nicolaou’s double SN2-type displacement of mesolate-containing thioester 6, which was followed by Ramberg–Bäcklund rearrangement and led to the total synthesis of 2 and the formal synthesis of 1 (Figure 5.6).69 The ability of SN2 displacement to forge the macrocycle via reaction at C1/C15 of one fragment, despite the failure of a similar reaction70 at C4/C18 (of 7), encapsulates another key consideration for dimerization design. The choice of which bond of the aliphatic bridge to construct during macrocyclization can profoundly impact the success of ring formation. 417 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.6 Prior art: cyclodimerization Hoye, 2000 Me CO2Me 4 TBSO nBu O I SN2 TIPSO OTIPS nBu MeO P OMe OMe CO2Me nBu 18 SAc MeO O OMe 7 OMe MeO HWE OMe nBu CO2Me Nicolaou, 2010 O 1 nBu S SAc O MeO [O] OMe OMs nBu 6 15 MeO nBu OMe 1 step MeO SN2 OMe nBu MeO MeO O S OMe OMe nBu O It is notable that metathesis has demonstrated surprising71 flexibility with respect to the placement of the resultant double bond within the macrocyclic bridge. Initial application by Smith and coworkers72,70 of cross-metathesis/ring-closing metathesis (CM/RCM) to dimerization attached the resorcinol motifs through the center of the connecting carbon chain. This approach was so successful it has since been applied to additional formal67 and total syntheses40 of cylindrocyclophane A (Figure 5.7). CM/RCM has also been utilized in the formation of a homobenzylic double bond, critical to the total synthesis of cylindrocyclophane F (2) by the Breit group73 and to preparation of nonnatural derivatives of 1.40 418 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.7 Cyclodimerization via CM/RCM Smith, 1999 Me R Me OMe MeO MeO nBu nBu OMe OMe MeO CM/RCM MeO nBu R = H or OTES Me nBu R CM/RCM MeO Breit, 2018 Me R OMe nBu MeO OMe OMe nBu Me Me 5.1.2.2 Cylindrocyclophanes: Stereocenter Installation Synthetic access to the [7.7]paracyclophane skeleton is only part of the problem of cylindrocyclophane preparation, which also requires stereoselective installation of benzylic and homobenzylic substituents. On the one hand, this can be accomplished prior to macrocyclization. Two main challenges arise that have generally led to lengthy linear sequences. First, stereochemical information is not efficiently transmitted across the resorcinol motif, so C20 and C1/C2 must be independently established. Second, the natural products lack functionality at these sites that inherently enable stereocenter formation; instead, lateral steps are required both to install and to remove functional groups used for stereoselective transformations. For instance, Hoye and coworkers68 employed enzymatic resolution followed by an Ireland–Claisen rearrangement to set C20, and the Nicolaou group69 pursued enantioselective ketone reduction then directed hydrogenation (Figure 5.8). Iwabuchi and coworkers derived the C20 stereocenter from commercial chiral material, advanced through a Johnson–Claisen rearrangement to furnish enantioenriched intermediate 8 in 12 steps; an additional eight-step sequence, involving aldol reaction using Evans’ chiral auxiliary, followed to set the remaining stereogenic centers.40 419 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.8 Addressing the benzylic stereocenter Hoye, 2000 HO TBSO Ireland–Claisen rearrangement MeO OMe MeO 6 steps Br O OMe 20 11 steps OTBS nBu MeO O OMe P(OMe)2 nBu CO2Me Nicolaou, 2010 HO AcS directed hydrogenation MeO OMe MeO 7 steps Br AcS OMe 4 steps 20 MeO nBu OMe OMs nBu OTBS HO Iwabuchi, 2009 Me O Johnson–Claisen rearrangement MeO OMe OH HO O MeO 12 steps OMe 8 steps 20 2 1 Evans aldol MeO OMe nBu nBu 8 On the other hand, stereoselective substitution can occur post-cyclodimerization. Exemplified by the Hoye68 and Nicolaou69 syntheses, enantioselective transformations were required to give rise to the trans-C1/C2 hydroxymethyl motif. Hydroboration/oxidation and a sequence of dihydroxylation (and deoxygenation toward 2) followed by methylation served this purpose (Figure 5.9). Figure 5.9 Stereoselective installation of hydroxymethyl motif Hoye, 2000 Nicolaou, 2010 Me CO2Me nBu nBu R 1 MeO OMe MeO nBu 2 MeO OMe OMe or MeO OMe MeO nBu OMe MeO nBu nBu OMe 15 Me CO2Me enantioselective hydroboration, oxidation enantioselective dihydroxylation, deoxygenation, methylation R = OH, 4 steps R = H, 4 steps R = OH, 7 steps 14 R 420 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F A conceptually distinct approach was pioneered by the Davies/Stoltz report (Figure 5.10).63 A chiral dirhodium catalyst was first used to install the C1/C2 stereodiad with good enantioselectivity and excellent dr. In subsequent ring closure, the remaining C14/C15 stereocenters were forged with near-perfect ee but reduced diastereomeric ratio. Thus, existing chiral information (of macrocyclic precursor 9) does not upset the ability of bond formation to proceed with catalyst-controlled enantioselectivity but instead amplifies enantiomeric excess as a consequence of the Horeau principle.74 There is, however, an observable effect of ring formation on diastereoselectivity. If applied to appropriately functionalized substrates, this efficient sequence of stereoselective paracyclophane generation would need to be followed by removal or oxidative cleavage of the guiding C/C14 carboxylates to advance toward natural products 2 or 1, respectively. Figure 5.10 Diastereoselective ring closure Davies/Stoltz, 2018 Me O RO Me O N2 RO 1 Rh2(R-2-Cl-5-BrTPCP)4 (1 mol %) 2 + 4 Å mol. sieves DCM, 40 °C I Me O I R = CH2CF3 Me 83% yield 91% ee, 26:1 dr Me O RO Me RO Rh2(R-2-Cl-5-BrTPCP)4 (1 mol %) 4 Å mol. sieves DCM, 40 °C OR N2 Me O 9 R = CH2CF3 68% yield >99% ee, 5.6:1 dr 15 Me 14 O OR Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 421 5.2 CONCEPTUAL SYNTHETIC DESIGN AND RETROSYNTHESIS Given that cyclodimerization has been proven an efficient approach to C2 symmetric macrocycles, we sought to apply double reductive cross-coupling as a key transformation for accessing, in a single step, the [7,7]paracyclophane skeleton common to all cylindrocyclophanes. We anticipated double RCC to be an advantageous dimerization tactic with respect to difunctional monomer synthesis (e.g., 11), as reductive coupling obviates the need to install incompatible electrophiles and reactive organometallic functionalities on the same molecule. We also postulated that enantioselective RCC would be necessary to establish the stereocenters distally located on the macrocycle, via double asymmetric reaction. Specifically, we envisioned that double reductive alkenylation of Nhydroxyphthalimide (NHP) esters would dimerize difunctional substrate 11 to generate macrocyclic dialkene 10, a known intermediate from which cylindrocyclophane F (2) is accessible via hydrogenation and deprotection (Figure 5.11).73 We drew inspiration from the single decarboxylative RCC reaction75 of alkenyl bromides with NHP esters, which has been shown to proceed in high yield and excellent enantioselectivity following subjection of these coupling partners to a chiral nickel catalyst and an organic reductant, tetrakis(dimethylamino)ethylene (TDAE). These conditions seemed well-suited for application to the substrate of dimerization (alkenyl bromide/NHP ester 11), given that (1) high yield of a single C–C bond formation event would be critical for efficient double coupling to forge the C6–C7 and C19–C20 bonds, and (2) the ability of the catalyst to effectively control enantioselectivity in this step (i.e., generation of the benzylic stereocenters at C7 and C20) would be unlikely to be affected by the distant C2 and C15 422 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F stereochemical elements. Figure 5.11 Retrosynthetic analysis of cylindrocyclophane F Me Ni-catalyzed enantioselective reductive cross-coupling nBu 2 7 HO O OH O R2 NHP HO R1 OH 20 Br 15 nBu O N R1 N R2 Ni + Br Br TDAE, TMSBr, NaI, DMA, –7 °C Me up to 88% yield, up to 99% ee (–)-cylindrocyclophane F (2) Me 6 Me double reductive cross-coupling 13 Br nBu Br O 7 MeO OMe OMe 20 OMe 20 11 19 Me 10 MeO OMe NHP nBu nBu + + nBu NHP MeO MeO Me MeO O Br Me Csp2–Csp3 coupling OMe NHP nBu O 12 To develop double reductive cross-coupling as a cyclodimerization reaction of 11, this key event would need to overcome known limitations of single RCCs. Electrophiles with o-substitution have proven to be challenging substrates in these methods,75,5 and Nicatalyzed cross-coupling reactions of redox-active esters have been generally documented to be capricious and substrate dependent.76 Also, attempts concurrent to our own to apply decarboxylative RCC to the construction of C–C bonds in the context of total synthesis77 have met with failure.78 Nonetheless, we recognized the strategic value of this macrocycle disconnection. As an ester, redox-active 11 could not only facilitate macrocyclization but could allow ready installation of the n-butyl group at the α-position (C20). In light of preliminary SAR data (vide supra), retrosynthetic cleavage through the C7–nBu bond via simple αalkylation would be a boon to the preparation of cylindrocyclophane derivatives. From a 423 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F synthetic efficiency standpoint, removal of the ester functional group concomitant to establishing both the C20 stereocenter and the C19–C20 bond would be advantageous. Retrosynthetically, the aryl–alkyl linkage of intermediate 11 keyed the convergent joining of aryl and alkyl fragments, a strategic disconnection inspired by a proposed biosynthetic route proceeding through this Csp2–Csp3 bond formation.79 The ideal retrons would contain the requisite NHP ester and alkenyl bromide moieties for later dimerization (12 and 13, respectively); however, we anticipated that convergent fragment coupling might require these functional groups to be transiently ‘masked.’ Lastly, we planned to rely on well-established methods of stereoselective methylation to access enantioenriched fragment 13. This strategy would lead to the formal synthesis of cylindrocyclophane 2 and establish the peripheral stereocenters concurrently to the macrocycle. We expected that our synthetic design could readily lend itself to the preparation of additional cylindrocyclophane variants (e.g., 1). As such, we pursued this conceptual synthesis via a multi-pronged approach: investigating the key RCC reaction on a model system alongside development of a synthetic route to a variety of cyclodimerization precursors. 5.3 SINGLE REDUCTIVE CROSS-COUPLING: MODEL REACTION Figure 5.12 Motivation for single reductive cross-coupling Reisman, 2017 O O nBu NHP Me Br 4 14 O N Ni Br + 15 N Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –7 °C 72% yield, 94% ee Me Me 4 16 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 424 In order to apply reductive cyclodimerization to the synthesis of the cylindrocyclophanes, an NHP ester with disubstitution (i.e., intermediate 11, see Fig. 5.11) is required. To demonstrate effective single reductive cross-coupling of an o,odisubstituted benzylic electrophile, we studied the reaction of a 2,6-dimethoxysubstituted NHP ester with a simple alkenyl bromide as a model system. In a previous report,75 treatment of analogous but unsubstituted NHP ester 15 and alkenyl bromide 14 to an IndaBOX-ligated Ni catalyst (NiBr2·L1) in the presence of TDAE as a stoichiometric reductant led to cross-coupled 16 in 72% yield and 94% ee (Figure 5.12). We therefore selected these conditions as a starting point for our model RCC. Early work suggested that this ligand and reductant combination—albeit at higher temperature, higher ligand loading, and lower concentration—failed to effect the coupling of 2,6-dimethoxy 18 (Table 5.1, entry 1).80 These early studies pointed to the potential success of using Mn0 instead of TDAE, as this reductant delivered 15% yield of cross-coupled 19 when bis(oxazoline) (BOX) ligand L1 was used (entry 2).80 Hypothesizing that increased ligand N–N distance might facilitate access to nickel for more sterically demanding coupling partners (i.e., o,o-disubstituted 18), the bi-oxazoline (BiOX) ligand framework was investigated under otherwise identical conditions. Use of BiOX ligand L2 with 2 equiv NHP ester 18 was reported to deliver desired product 19 in 52% yield and 73% ee (entry 3).80 It was noted that TDAE was unsuccessful (0% yield 19) even with BiOX L2 (entry 4).80 425 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Table 5.1 Guiding preliminary results O nBu NHP BnO Br + MeO OMe 18 Entry Ligand O O N MeO reductant (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), rt 17 1 nBu BnO ligand (20 mol %) NiBr2·diglyme (10 mol %) OMe 19 Reductant % Yield 19 % ee TDAE 0 — Mn0 15 62 Mn0 52 73 TDAE 0 — N 2 L1 3 O tBu 4 O N N L2 tBu 5.3.1 Investigation Using BiOX Ligands We were unable to reproduce the results in Table 5.1. Instead, use of Zn0 as an alternative reductant gave similar yield and enantioselectivity to that reported for Mn0 (using BOX L1: 11% yield, 67% ee), and we selected this metal powder for our studies. We ultimately found that modification of the BiOX ligand could substantially affect the enantiomeric excess of the product but led to consistently low yields of 19 (Figure 5.13). Enantioselectivity improved with increasing ring size of carbocycle-substituted ligands (L3–L5). Addition of a methylene linker between the oxazoline and carbocyclic ring, as in L6, moderately decreased ee. However, a similar methylene linker was critical for reactivity with an acyclic tert-butyl substituent (L2 versus L7), and L2 displayed a significant improvement in ee versus cyclic variants. For ligands with alkyl chains branched adjacent to the oxazoline (L7–L10), increased chain length corresponded to an increase in ee. Although 4-heptylBiOX (L10) exhibited the highest level of 426 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F enantioselectivity in this screen, the highest-yielding ligand (CyBiOX, L4) was selected for further optimization due to its availability in large quantities. Figure 5.13 BiOX ligand screen O nBu NHP BnO MeO + Br 17 O N 18 O O N N MeO Zn0 (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA, 27 °C O O N N O O N N L5 6% yield 40% ee 23% yield 57% ee 8% yield 62% ee O N N L2 (8% yield) (74% ee) tBu tBu O N N L7 O tBu sBu 0% yield O N N L8 8% yield 54% ee O sBu Et Et N 14% yield 48% ee O O N O L6 L4 O OMe 19 L3 O tBu OMe nBu BnO ligand (22 mol %) NiBr2·diglyme (20 mol %) Et N L9 7% yield 72% ee Et nPr O N nPr nPr N L10 nPr (18% yield) (88% ee) (yield/ee): NiBr2·diglyme (10 mol %), ligand (20 mol %) Using CyBiOX (L4) as ligand, in combination with a metal reductant, we did not observe significant improvement to yield across a variety of deviations to the reaction conditions (Table 5.2). As examples, changing the concentration (entries 1 and 2), relative equivalents of substrates (entries 3 and 4), and additive quantities (entries 5–7) each resulted in a yield of product 19 within a 9% range. In contrast, use of soluble reductant TDAE instead of Mn0 led to a mild improvement in 19 yield (26%, entry 8); in addition, enantioselectivity in this case (85% ee) was comparable to that when using L10 (88% ee, see Figure 5.13). However, in light of our long-term goal of double RCC, we recognized the need for much higher levels of desired reactivity when performing a single cross-coupling event. 427 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Table 5.2 Reaction optimization using CyBiOX O nBu NHP BnO Br 17 + MeO O O N N OMe MeO Mn0 (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.6 M), 23 °C 18 nBu BnO L4 (20 mol %) NiBr2·diglyme (20 mol %) OMe 19 Entry Deviation from Conditions % Yield 19 % ee 1 — 13 71 2 0.3 M 19 70 3 NHP ester 18 (2 equiv) 18 65 4 alkenyl Br 17 (2 equiv) 20 — 5 NaI (0 equiv) 17 56 6 NaI (1 equiv) 13 56 7 NaI (2 equiv) 11 56 8 TDAE (3 equiv) 26 85 Seeking access to product 19 in yields higher than ca. 30%, we sought to better understand the pathways available to each substrate other than productive cross-coupling, as a way to guide our optimization efforts. Tracking NHP ester 18 under the reaction conditions revealed an assortment of byproducts without any reaction parameter-based trend in yield distribution (Figure 5.14). In general, styrene 20, bibenzyl 21, and reduced 22 were present in the most quantities (10–30% yield each), whereas carboxylic acid 23 was occasionally observed. Presumably, reductive fragmentation of the NHP ester generates an intermediate benzylic radical, which can proceed down several undesired pathways, including: benzylic olefination (20), possibly via a Ni-mediated β-hydride elimination process; dimerization (21), with no diastereoselectivity; hydrogen-atom abstraction to furnish alkane 22; or hydrolysis to return substrate precursor 23. Formation 428 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F of each of these byproducts would not only siphon the starting material away from desired product-forming pathways but could also lead to catalyst inhibition, as conjugated π-systems and carboxylates (i.e., 20 and 23, respectively) readily ligate Ni. Figure 5.14 Byproduct distribution of NHP ester O nBu NHP MeO O O N N Me MeO nBu L4 (20 mol %) NiBr2·diglyme (10 mol %) OMe MeO OMe MeO 20 O nBu H OMe + TDAE (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), 27 °C 18 OMe nBu MeO HO OMe + nBu MeO OMe + 21 22 23 We next performed a series of control experiments to elucidate the pathways involving alkenyl bromide 17 (Table 5.3). Under standard reaction conditions in the presence of coupling partner 18, the product of 17 homocoupling (i.e., diene 24) was consistently observed as the major product. Accordingly, subjection of only substrate 17 to these conditions, without the TMSBr or NaI additives, led to its complete consumption; the majority of 17 was homocoupled, indicating this process is independent of the NHP ester (entry 1). Small quantities of reduced alkene 25 were also identified, but in most cases, protodebromination appeared to be insignificant (i.e., trace 25). Table 5.3 Control experiments: alkenyl bromide BnO Br O O N N L4 (20 mol %) NiBr2·diglyme (10 mol %) 17 OBn BnO TDAE (3 equiv) DMA (0.3 M), 27 °C + BnO 24 H 25 Entry Deviation from Conditions Result 1 — 62% homocoupled 24 trace protodebromination (25) 2 no TDAE 82% recovered 17 3 no Ni/L4 79% recovered 17 429 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F In the presence of the NiII precatalyst and ligand but without the reductant, substrate 17 was recovered in high yield, indicating that NiII alone was not able to engage the substrate (entry 2). Likely, reduction of Ni is required to precede oxidative addition of 17. Alternatively, it could be possible for the alkenyl bromide to be directly reduced, initiating a homocoupling process not mediated by the metal. However, the Csp2 substrate was effectively untouched by the reductant in the absence of nickel (entry 3). Figure 5.15 Working mechanistic hypothesis: single RCC homocoupling N * Nin N 26 R1 oxidative addition * R1 R1 N + Br R1 N X radical capture N X NiIII * N R3 R2 reductive elimination R2 31 + N 30 O R3 NHP R2 R3 NiII 28 27 33 R1 29 reduction * R1 R3 NiI X N 32 R2 R3 R 34 + decomposition R3 R2 + R3 H R2 R2 R2 35 36 37 With the knowledge of the mass balance of each coupling partner, we considered a hypothetical mechanistic scenario, based on recent mechanistic investigation of a BiOX·Ni-catalyzed RCC,81 that could explain the origin of the observed byproducts. Specifically, we hypothesized that the fate of a NiII–alkene species (28) would be a key determinant of reaction outcome (Figure 5.15). Organonickel complex 28 would arise following oxidative addition of an alkenyl bromide (27); we imagine that this intermediate would be partitioned between competing pathways. The desired pathway (en route to product 31) would occur via capture of radical 34, generated from the NHP ester (33). Thus-formed NiIII complex 30 would be expected to proceed to cross-coupled 31 via 430 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F reductive elimination; concomitantly, NiI 32 would be released, available for either reduction or direct substrate interaction to turn over a catalytic cycle. If, however, radical capture is inefficient—potentially due to steric hindrance— hen the NHP-derived intermediate (34) may unselectively decompose, as observed. In this case, the alkenyl Ni complex (28), without a distinct coupling partner, could engage another equivalent of alkenyl bromide 27 or a second organonickel species to form homocoupled 29 (vide infra), also consistent with experimental evidence. The same substrate decomposition products could be formed regardless of whether productive radical capture was hindered by radical 34 instability (i.e., fast decomposition) or rapid alkene–alkene homocoupling. Figure 5.16 Reaction time course: cross-coupling versus byproducts O nBu NHP BnO Br MeO + 17 OMe O O N N nBu BnO L4 (20 mol %) NiBr2·diglyme (10 mol %) MeO TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.05 M), 0 °C 18 OMe 19 80 OBn BnO % yield 60 24 + 40 H 20 nBu MeO 0 30 60 90 120 minutes 150 180 OMe 22 0 To uncover the relative rates of cross-coupling versus homocoupling, we monitored the reaction over time using CyBiOX (L4), at lower temperature and higher dilution than standard conditions. Following analysis of reaction aliquots by quantitative 431 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1 H NMR, we discovered that the rate of alkenyl bromide homocoupling (24, grey; Figure 5.16) far exceeded the rate of desired product (19, blue) generation. Formation of one NHP decomposition product, alkane 22 (teal), was similarly slow, outpaced by the Csp2– Csp2 byproduct. Based on this reaction time course, we hypothesized that disfavoring the most rapid pathway (i.e., homocoupling) might render productive pathways more competitive, leading to an increase in cross-coupling. We considered several scenarios in which homocoupling could occur (Figure 5.17). First, it is often proposed that a Csp2–Ni complex (e.g., 28) can undergo reduction followed by oxidative addition;82 the resulting bisalkenyl NiIII species (39) would be primed for reductive elimination to generated homocoupled 29. If this were operative under the reaction conditions, then the X-type ligand of 28 could be used to electronically tune 28 to render reduction of this species more challenging. Preliminary efforts toward this end involved replacing the NaI additive with sodium salts featuring anions that could serve as stronger σ-donating ligands. However, when X = OTMS or OMe, the yield of the cross-coupled product remained low (<10%) and the homocoupling byproduct was not diminished. Figure 5.17 Mechanistic hypothesis: homocoupling possible homocoupling pathways redm redm+1 R1 N * R1 N * NiII N X 28 oxidative addition NiI N 38 bimetallic alkene transfer R1 N X NiIII * N 39 N reductive elimination * NiI X N 32 + R1 R1 R1 29 A second scenario, inspired by foundational mechanistic investigations of Nicatalyzed biaryl formation,83 implicates an organonickel species, in addition to 28, in an 432 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F alkene transfer step. In effect, this bimetallic oxidative addition would generate homocoupled 29 by way of a NiIII intermediate (i.e., 39). Given the bimolecular nature of this putative pathway, we hypothesized that decreasing the loading of the Ni catalyst could serve to reduce formation of byproduct 29 in favor of the desired cross coupling. Figure 5.18 Catalyst loading O nBu NHP BnO Br + 17 MeO O O N N L4 (20 mol %) NiBr2·diglyme (x mol %) OMe nBu BnO 18 OMe + MeO TDAE (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), 23 °C OBn BnO 24 19 100 90 80 % yield 70 60 50 40 30 20 10 0 2.5 5 7.5 10 mol % Ni 12.5 15 20 Indeed, sequential lowering of the amount of nickel from initial 20 mol % resulted in a corresponding improvement in the yield of 19 (blue), reaching a maximum at 7.5 mol % (ca. 40% yield, Figure 5.18). At sufficiently low amounts of catalyst, the beneficial effect on cross-coupling was countered by inefficient alkenyl bromide (17, teal) activation, indicated by significant levels of remaining starting material. We were encouraged by the empirical success of this screen and questioned whether the yield enhancement could be augmented by additional modifications to the reaction. 433 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Pursuing an alternative strategy, we returned to our working mechanistic hypothesis (see Fig. 5.15) and postulated that instead of disfavoring undesired paths of intermediate 28, we might achieve the same effect (i.e., improvement to cross-coupling) by promoting the desired pathway: facilitating radical capture. As it seemed likely that this step could be challenging for a sterically encumbered radical, we prepared the singly o-substituted NHP ester 40. Compared to the control (dimethoxy 18: 16% yield), this less bulky substrate offered marginal improvement (Figure 5.19). This suggests the existence of a threshold steric effect. It is possible that any ortho aryl substitution effects a drop-off in reactivity, which is often the case for RCCs of o-substituted aryl halide electrophiles;84,5 thus, steric modulation of the substrate would not be compatible with our synthesis objectives. Figure 5.19 Steric modification of NHP ester O nBu NHP BnO Br 17 OMe + 40 O O N N L4 (20 mol %) NiBr2·diglyme (20 mol %) Zn0 (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), 23 °C nBu BnO OMe 41 19% yield Up to this point, we had primarily targeted reaction steps occurring after the formation of key intermediates (i.e., oxidative addition toward organonickel 28 or reductive fragmentation to generate radical 34; see Fig. 5.15), so we turned our attention upstream. Analysis of the reaction time course, with a focus on the rates of substrate conversion, proved instructive (Figure 5.20). The alkenyl bromide (17) was consumed at a faster rate than its counterpart, NHP ester 18, under these conditions. An exaggerated mismatch in the rates of coupling partner activation could inhibit the desired 434 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F organonickel radical capture pathway by skewing the effective concentration of the requisite components (i.e., 28 and 34).85 Figure 5.20 Reaction time course: substrate conversion rates O nBu NHP BnO Br + MeO O N N L4 (20 mol %) NiBr2·diglyme (10 mol %) OMe 17 O TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.05 M), 0 °C 18 nBu BnO MeO OMe 19 80 % yield 60 40 20 0 30 60 90 120 minutes 150 180 0 As a first approach to rectifying this possible scenario, we attempted to disfavor oxidative addition of 17 (i.e., reducing [NiII–alkene]). As such, we prepared the chloride analog of Csp2 substrate 17, alkenyl chloride 40, given the challenging reaction of chloride-based electrophiles in Ni-catalyzed RCCs.86 Treatment of this electrophile with the NHP ester and Ni/L4 combination in the presence of TDAE failed to afford crosscoupled product (Table 5.4, entry 1). Instead, the near-quantitative recovery of 42, even at high temperatures, was observed. It was thus unsurprising that use of NaCl in the reaction led to lower yields of product 19 (entry 2); based on related studies,87 we presume that in situ halide exchange is plausible and, in this case, leads to less-reactive electrophiles. Sodium iodide—which presumably generates the more-reactive alkenyl–I 435 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F species in situ—led to the highest product levels observed in this study (26% yield 19, entry 4). Table 5.4 Alkenyl halide alternatives O nBu NHP BnO X + MeO 1 Cl 42 2 3 BnO N N nBu BnO MeO TDAE (3 equiv) TMSBr (1 equiv), additive (0.5 equiv) DMA (0.6 M), 23 °C X BnO O L4 (20 mol %) NiBr2·diglyme (20 mol %) OMe 18 Entry O Br 4 17 OMe 19 Additive % Yield 19 NaI 0 NaCl 9 NaBr 16 NaI 26 Subsequent efforts focused on promotion of NHP ester reduction to match the facile reaction of alkenyl–Br 17. We posited that the reduction potential of the redoxactive ester would correlate with the rate of radical generation via reductive fragmentation. We expected that introduction of electron-withdrawing substituents on the phthalimide moiety would serve both to anodically shift E1/2red of the corresponding NHP ester and to increase the rate of substrate consumption—importantly, leading to an improvement in the yield of product 19. In the event, only two of the synthesized NHP derivatives (43 and 44) yielded any amount of cross-coupled 19 (Table 5.5, entries 1–3). The disappointing performance of those redox-active esters with >100 mV shift in reduction potential (i.e., 45 and 46) made it challenging to discern any trends from this survey of substrates (entries 4 and 5). A recent report has demonstrated the expected correlation of redox potential and RCC yield, albeit using NHP ester derivatives less challenging to reduce than 18/43–46.88 436 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Table 5.5 Redox-active ester derivatives Br O N N O N BnO O O X O + nBu O MeO OMe MeO TDAE (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.1 M), 0 °C 17 nBu BnO L4 (20 mol %) NiBr2·diglyme (10 mol %) Entry X E1/2red vs SCE, MeCN % Yield XX 1 OMe (43) –1.36 1 2 H (18) –1.34 11 3 Cl (44) –1.28 13 4 Me (45) –1.18 0 5 Br (46) –1.16 0 OMe 19 As reductive radical generation requires participation of both an NHP ester (i.e., 18) and a reductant, we questioned whether the latter might prove more amenable to modification. The reductant mediates a fragmentation process of general NHP ester 33, leading to intermediate 47 that is presumably initiated by single electron transfer (SET) and subsequently ejects phthalimide anion and a molecule of CO2, in addition to radical 34 (Figure 5.21). Traditionally, in reactions of redox-active esters catalyzed by nickel, on- or off-cycle Ni species have been implicated in this SET event.89,90,91,92 Given the multi-faceted role of organonickel intermediates in the reaction, any effort to tune the reducing power of these compounds is unlikely to be straightforward (vide supra). However, in a radical chain mechanism, it is possible that a species independent of the catalyst could provide the electron necessary for NHP ester fragmentation, such as the stoichiometric reductant nominally added to turn over Ni. In the case of related alkyl halide electrophiles, this mechanistic picture has recently been proposed for reactions 437 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F involving Mn0/BiOX·Ni.81 In the absence of Ni or other transition metal catalysts, Zn0 has been demonstrated to effectively reduce select NHP esters,93,94,88 and Zn2+ Lewis acids—the byproducts of reduction—can have an accelerating effect on this event.94 Should this type of terminal reductant-mediated pathway also be operative under the present Ni-containing conditions, TDAE could directly reduce NHP ester 33 without catalyst involvement. Given the tunable nature of this class of soluble, organic reductants,95 appropriate matching of TDAE derivative with a phthalimide-substituted NHP ester could be imagined to offer a fine level of control over the rate of radical generation.96 Figure 5.21 Mechanistic hypothesis: radical generation possible NHP ester reductants O N O O O R3 NHP ≡ R2 N N SET R2 Baran, 2016 Weix, 2016 N R2 CO2 34 Xiao, 2020 Larionov, 2019 unreported Zn Zn + ZnX2 TDAE ? X NiII N Ni0 R3 R2 47 N N O R3 O O 33 Weix, 2017 redm = O R3 O O 33 O redm+1 redm NiI N N To tease out the nature of the reduction step involved in benzylic radical generation, we subjected the NHP ester (18) to various reductant contenders in DMA and analyzed conversion (Figure 5.22). The CyBiOX/NiII catalyst (L4·Ni) without exogenous reductant effected little NHP ester conversion. Metal powder Zn0 was slightly more effective, and NHP ester 18 was recovered in ca. 60% yield. We considered that the additives critical for cross-coupling (i.e., TMSBr and NaI) might one or both function to 438 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F allow the nominally thermodynamically inaccessible reduction by Zn0; perhaps the silyl halide could serve to activate the NHP ester, as proposed for Zn2+ Lewis acids.94 However, inclusion of these additives did not significantly change consumption of 18 in the presence of Zn0. Figure 5.22 NHP ester reduction Me MeO O nBu NHP MeO OMe nBu nBu reductant (3 equiv) OMe MeO OMe MeO OMe + DMA (0.3 M), 23 °C 18 nBu H MeO OMe + 20 21 22 100 % NHP conversion 80 60 40 20 0 2.5 NiBr2·diglyme, CyBiOX 5 7.5 10 12.5 Zn Zn TDAE TDAE + TMSBr, NaI + TMSBr, NaI reductant In contrast, stirring TDAE with NHP ester 18 in the absence of Ni catalyst led to over 60% conversion. Furthermore, addition of TMSBr and NaI, as well as TDAE, led to complete decomposition of 18 in a time frame consistent with standard cross-coupling reactivity at this temperature and concentration. The identification of byproducts 20–22 from this experiment indicates that non-Ni-mediated processes are involved in their formation. Taken together, these results suggest that intermediate radical generation could occur independent to a Ni-based catalytic cycle and that the slightly improved 439 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F performance of the RCC when TDAE is used, as opposed to metal powders, may be a result of more facile NHP ester reduction. Such a discovery was pivotal, because it indicated that throughout our optimization campaign we had significantly underestimated the sensitivity of NHP ester 18 to TDAE. This prompted re-examination of the experimental design. We postulated that our reaction setup, in which TDAE was added after the NHP ester but prior to Ni/L and alkenyl bromide, might allow rapid reductive decomposition of the NHP ester to occur without the possibility of productive capture of any resulting benzylic radical species (Figure 5.23). To determine whether this order of addition was a plausible reason that we had consistently observed low yields of desired product, we reversed the order, adding all components (i.e., NHP ester, alkenyl bromide, Ni/L, NaI, and solvent) to the reaction vessel before addition of TDAE and TMSBr. When L = CyBiOX (L4), the impact of experimental setup was minimal with respect to cross-coupled product yield. At this stage, it appeared that this catalyst system (with a BiOX ligand scaffold) was not suitable for RCC of substrates 17 and 18 and that continued efforts to improve the overall poor performance of reaction in this manifold would lead to diminishing returns. Figure 5.23 Order of addition original order of addition O O R3 NHP 33 + TDAE N N then L4 NaI, TMSBr R2 O + NiBr2·diglyme R1 Br 17% yield 27 optimized order of addition R1 O O N N O Br 27 + NaI + L4 + NiBr2·diglyme then R3 NHP 33 R2 TDAE TMSBr 19% yield 440 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.3.2 Investigation Using BOX Ligands Given that cross-coupling had been reported to be at least minimally viable for BOX ligands (see Table. 5.1),80 we turned our attention to this catalyst system. Although originally dissuaded from use of TDAE as reductant with L1·NiBr2 based on initial investigations, it now seemed plausible that the reported 0% yield of 19 arose from suboptimal reaction setup, as these details were unknown.80 Indeed, revisiting the original conditions for successful RCC of NHP esters75 and adding TDAE/TMSBr last, we observed a remarkable turn-on of desired reactivity between 17 and 18 with L1·NiBr2: 40% yield of cross-coupled 19 (Figure 5.24). Figure 5.24 Catalyst loading: optimized order of addition O O NHP BnO Br + 17 MeO N Br nBu BnO Ni OMe 18 O N nBu Br MeO L1·NiBr2 (x mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –7 °C OMe + OBn BnO 24 24 90 80 70 % yield 60 50 40 30 86% ee 20 10 0 10 20 mol % Ni The stark change to product 19 yield elicited by the BOX versus BiOX ligand scaffold (19% yield with L4; 40% yield with L1)—following the optimized order of addition—was matched by a dramatic decrease in homocoupled 24 formation (from 47% Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 441 to 3% yield). This observation suggested that one important feature of the IndaBOX ligand (L1) might be to inhibit alkenyl bromide homocoupling; this effect could potentially arise via stabilization of key organonickel intermediate 28 or oxidative addition rendered challenging (see Fig. 5.15). In support of the latter, we recovered 40% of the alkenyl bromide (17) from the reaction. Thus, increasing the catalyst loading allowed full consumption of that substrate with a corresponding improvement in crosscoupled yield (49%). Using chiral L1 as ligand allowed isolation of product 19 in 86% ee. The absolute configuration of 19 was assigned by analogy to previous studies of these reaction conditions.75 With viable reaction conditions for single RCC of an o,o-disubstituted NHP ester in hand, we were poised to launch investigation of double RCC toward paracyclophanes (see section 5.5). 5.4 SYNTHESIS OF DIMERIZATION SUBSTRATES Together with model cross-coupling studies, we pursued the synthesis of fully elaborated systems. Our initial target was a substrate for dimerization en route to cylindrocyclophane F, and we envisioned that a route developed with this objective could be readily adjusted to enable access to additional cylindrocyclophane natural products, such as 1. Central to our strategy (see Fig. 5.11) was use of an arene linchpin which could undergo convergent coupling with a number of alkyl units to eventually arrive at either natural product or their derivatives. 442 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.4.1 Toward Cylindrocyclophane F We anticipated that arene 52 would be accessible via enolate arylation followed by C–H borylation/halogenation and commenced our studies with commercial resorcinol derivative 48. Conditions from Hartwig and coworkers97 provided an excellent starting point for effecting the desired α-arylation reaction (Figure 5.25). Likely due to the sterically bulky substitution of aryl bromide 48, tert-butyl acetate (49) was found to be the only competent coupling partner. Irreproducibility upon scale-up required optimization of enolate generation and catalyst identity; ultimately, use of 3.3 equiv LHMDS proved to be critical for intermediate enolate stability and, when combined with the reported catalyst (i.e., Pd(dba)2/PtBu3), provided a successful balance of high yield (79%) and ease of purification on 10-gram scale. The n-butyl chain was then readily installed in a subsequent step to afford arene 50 in 71% yield. Although attempts to perform one-pot arylation/alkylation to generate disubstituted ester 50 directly from starting 48 were unsuccessful, the sequential reactions could be telescoped to provide 50 (66% yield over two steps) after a single chromatographic purification step. Figure 5.25 Synthesis of aryl fragment MeO 48 Br 1. Pd2dba3 (3 mol %) PtBu3 (6 mol %) OMe LHMDS (3.3 equiv) PhMe, 18 °C + Me 49 O OtBu Bpin [Ir(cod)OMe]2 (1 mol %) tmphen (2 mol %) B2pin2 OMe MeO MeO 2. nBuBr, LHMDS THF, –78 °C 66% yield (over 2 steps) OtBu nBu THF, 80 °C OMe CuBr2 OtBu aq. MeOH 100 °C nBu O 50 Br MeO OMe OtBu nBu O 91% yield 51 O 79% yield 52 At this point, we were able to exploit the aryl substitution pattern of 50 to sterically direct C–H functionalization,98 catalyzed by the optimized99 combination of an Ir precatalyst and tmphen, which afforded para-substituted boronic ester 51 in excellent Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 443 yield (91%) and perfect regioselectivity on multi-gram scale. Subsequent treatment with cupric bromide yielded aryl bromide 52 in 79% yield. Subjection of Ar–Bpin 51 to bromination conditions on large scale (ca. 10 g) often led to mixtures of Bpin/ester 51 with its hydrolysis product; attempts to separate these compounds led to hydrolysis of the boronic ester. Instead, we found that allowing complete conversion of substrate 51 to the brominated acid (3 equiv CuBr2, 83% yield) could be followed by ready esterification to afford desired ester 52. Having developed a scalable route to the aryl fragment, we turned to investigate coupling with an alkyl partner. We found that lithiation of the aryl bromide (52) followed by addition of a simple alkyl iodide (54) effected an SN2-type reaction in 71% yield, forging the crucial Csp2–Csp3 bond (Figure 5.26). This alkyl chain served as a model for a substituted variant more closely reflecting the natural product in order to validate the use of a protected alkyne as a masking group for the alkenyl bromide, which would be unlikely to survive treatment with nBuLi required for lithiation at the aryl bromide position.100 A short sequence involving deprotection of the alkyne followed by regioselective hydrozirconation and electrophilic attack of bromine was then used to reveal the requisite moiety (i.e., alkenyl bromide 56) in 81% yield over two steps. Similarly, the NHP ester was unmasked via transformation of the tert-butyl ester to a carboxylic acid substrate of Steglich esterification, affording difunctional 57 in 63% yield over two steps. 444 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.26 Fragment coupling and electrophile unmasking Li TMS I + MeO OMe TMS OtBu nBu MeO THF, –78 °C OMe OtBu nBu 71% yield O O 53 54 55 Br Br 1. TBAF THF, 18 °C 1. TFA DCM, 0 °C 2. Cp2ZrHCl PhH, 18 °C then NBS MeO OtBu 2. NHP, DMAP EDC·HCl DCM, 18 °C 56 63% yield (over 2 steps) OMe nBu O 81% yield (over 2 steps) MeO OMe NHP nBu O 57 As we planned to investigate the effect of stereodefined groups on the alkyl chain (as are present in cylindrocyclophane F) in the macrocyclization reaction, we prepared βmethyl iodoalkane (+)-60 in 92% ee over five steps (Figure 5.27).101 Condensation of Myers’ pseudoephedrine chiral auxiliary with known TMS-protected 5-hexynoic acid (58) produced the chiral amide in 66% yield.102 Subsequent diastereoselective alkylation101 proceeded in 64% yield, then redution103 furnished the intermediate alcohol in 67% yield. Lastly, transformation to iodide 60 occurred in 59% yield to afford the enantioenriched alkyl fragment poised for coupling to aryl linchpin 52. Figure 5.27 Synthesis of enantioenriched alkyl fragment 1. (COCl)2, DMF DCM, 18 °C; then (+)-pseudoephedrine HO O TMS 58 Et3N, THF, 0 °C 2. LDA, LiCl, MeI THF, –78 to 0 °C 42% yield (over 2 steps) OH Me 1. LDA, LiCl BH3·NH3, THF –78 to 0 °C Me N Ph Me O TMS 59 2. I2, PPh3 imidazole DCM, 18 °C Me I TMS (+)-60 42% yield (over 2 steps) We found the developed lithiation/alkylation sequence to perform poorly with this more sterically hindered alkyl iodide (conditions in Fig. 5.26). In lieu of the desired coupled product, we observed protonated arene 50 as the major byproduct, along with 445 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F unreacted iodoalkane 60. We considered that the introduction of the C2/15 methyl group served to slow the displacement reaction with the aryl lithium intermediate enough to render deprotonation of the acidic α-ester proton kinetically competitive, thus stymying productive reactivity. Figure 5.28 Deuterium quenching study: alkyl lithium base Br H D nBuLi THF, –78 °C MeO OMe OtBu nBu MeO then CD3OD OMe + MeO nBu OMe D OtBu OtBu nBu O O O 52 61 62 To test this hypothesis, we treated aryl bromide 52 with nBuLi then quenched with deuterated methanol. We observed the formation of deuterated byproducts 61 and 62 (Figure 5.28). Aryl deuteration (61) suggests that nBuLi is able to exchange with the aryl bromide and remain stable in solution, required for the desired alkylation. However, production of α-deuterated 62 provides support for the self-quenching hypothesis; an initially generated Ar–Li species can deprotonate the α-proton, leading to aryl protonation and delivering 62 upon deuterium quench of the resulting lithium enolate. In addition, prediction—or control—of whether deprotonation of an acidic proton or lithium–halogen exchange occurs first when using alkyl lithium bases has long been the subject of debate.104,105 Figure 5.29 Deuterium quenching study: aryl lithium base Me Li Br H Br Me nBuLi Me THF, –78 °C MeO OMe OtBu nBu then CD3OD MeO OMe OtBu nBu MeO OMe D OtBu nBu O 52 + O O 52 62 446 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F We reasoned that deprotonation with a base unable to exchange with Ar–Br could precede addition of nBuLi to address this challenge. Studies of related substrates suggested that mesityl lithium held promise to play the role of the initial base, as it has been demonstrated to be selective against aryl bromide lithiation106 as well as unreactive toward tert-butyl esters.107 In contrast to this precedent, we found reaction of aryl bromide 52 with MesLi to not be selective, evinced by the presence of α-deuterated 62 (Figure 5.29). Unfortunately, extension of this strategy to additional bases was also unsuccessful, generally due either to incomplete deprotonation (and thus self-quenching) or to decomposition of the ester enolate. Table 5.6 Fragment coupling attempts: Suzuki cross-coupling Bpin TMS conditions + MeO I OMe TMS OtBu nBu THF, –78 °C MeO OMe OtBu nBu O O 51 54 55 Entry Conditions % Yield 55 1 CuI, LiOtBu DMF, 60 °C 10 2 NiBr2·dme, diamine KOtBu, 2-butanol 1,4-dioxane, 80 °C 6 As an alternative solution, we hypothesized that attenuating the basicity108 of intervening metalated species might prove compatible with the acidic proton of aryl bromide 52. We recognized that the aryl boronic ester precursor (51) was in fact a less basic organometallic reagent. Preliminary efforts to couple Ar–Bpin 51 with simple alkyl partner 54 were met with limited success; conditions for Cu-109 or Ni-catalyzed110 Suzuki 447 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F reactions led to cross-coupled 55 but in low yield (<10%; Table 5.6).79 As a further extension of this logic, we considered application of a transition metal-catalyzed reaction but without organometallic reagents of any basicity and thus pursued the crosselectrophile coupling (i.e., RCC) of aryl bromide 52. Specifically, we anticipated that conditions for Ni-catalyzed RCC developed by Weix and coworkers111 might be effective in our system. Although recent precedent112 highlighted the detriment to desired reactivity posed by the stereoelectronic effects of resorcinol motifs, the reported 10% yield of a related substrate under these conditions appeared to us to be a promising foundation for optimization (Figure 5.30). However, subjection of coupling partners 52 and 54 to a Ni catalyst and metal powder reductant generated only trace quantities of product 55. Instead, we observed low levels of conversion of each substrate. We interpreted these data as suggesting catalyst inhibition and attributed this to coordination of the terminal alkyne (i.e., the alkenyl bromide masking group). It stood to reason that an alternative functional group less likely to bind a low-valent metal would lead to successful RCC. Figure 5.30 Fragment coupling attempts: Ni-catalyzed reductive cross-coupling Gellman, 2019 O Br + Br 4 MeO NiI2 (10 mol %), pyridine (10 mol %) 4,4′-OMe-bpy (10 mol %) O OEt OMe NaI (0.25 equiv), Zn0 (2 equiv) DMPU, 75 °C 4 MeO 10% yield OH OEt OMe OH Br + MeO NiI2 (10 mol %), pyridine (10 mol %) 4,4′-OMe-bpy (10 mol %) I OMe TMS OtBu nBu trace product poor conversion O 52 NaI (0.25 equiv), Zn0 (2 equiv) DMPU, 75 °C 54 TMS MeO OMe OtBu nBu O 55 448 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Since we did not expect α-deprotonation to be a significant issue under the mild conditions of RCC, we used commercial 63 as a model for the more-complex aryl bromide (52). In this case, silyl protection of the alkyne was not sufficient to effect full conversion of the starting material, and what amount did convert led predominantly to a protodebrominated arene byproduct (Table 5.7, entry 1). Using an alkenyl boronic ester in lieu of the requisite alkenyl bromide, the presumed alkyl radical intermediate (likely generated from alkyl iodide 64) proceeded down side pathways, such as 5-exo-trig cyclization to form a stable α-boryl radical, instead of productive cross-coupling (entry 2). Finally, protected ether 65 yielded cross-coupled 67 in 22% yield (entry 3), which could be improved to 39% yield upon use of an alternative leaving group (mesylate 66, entry 4). A similar level of cross-coupling was observed for a different model aryl bromide bearing a pendant ester, validating our initial assumption regarding the tolerance of acidic protons under these conditions. Table 5.7 RCC with various alkenyl bromide masking groups NiI2 (10 mol %), pyridine (10 mol %) 4,4′-OMe-bpy (10 mol %) Br + MeO X NaI (0.25 equiv), Zn0 (2 equiv) DMPU, 75 °C OMe MeO 63 OMe 67 Entry X 1 I Masking Group Result 54 protodebromination 64 64 decomposition TMS 2 I 3 I OBn 65 22% yield 67 4 OMs OBn 66 39% yield 67 Bpin 449 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Despite the apparent success of this study, the cross-coupling yield proved to be inversely correlated to the number of subsequent steps required to reveal the alkenyl bromide. A number of such sequences could be imagined, one of which is presented in Figure 5.31. A protected alcohol used to mask a bromoalkene would need to undergo deprotection then oxidation, followed by a homologation sequence. Installation of the requisite bromide substituent on any alkene furnished by this pathway must be stereoselective, in preparation for downstream dimerization. Although a lengthy sequence, it would provide a viable point of entry for investigating the key transformation of the synthesis. As such, we continued exploration of RCC, with the goal of coupling the more complex, stereodefined alkyl electrophile. Figure 5.31 Alkenyl bromide unmasking from protected alcohol O OBn deprotection then MeO OMe OtBu nBu O oxidation Br homologation then MeO OMe OtBu nBu stereoselective bromination MeO OMe OtBu nBu O O Treatment of the model aryl bromide (63) and chiral alkyl iodide 68 to NiII/Zn0 indeed led to cross-coupled 70 formation in 38% yield (Table 5.8, entry 1). Although exciting, this result was overshadowed by (1) an intractable yield with respect to material throughput and (2) the stepwise unmasking sequence required of the protected alcohol. To address the first point (i.e., improve the yield of 70), we transitioned to use of mesylate 69 as the alkyl electrophile, given the previous success of this tactic (see Table 5.7); however, electrophile 69 led to 0% yield of cross-coupled 70 (entry 2). 450 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Table 5.7 RCC with functionalized alkyl fragment Me OTBS Br Me + MeO X OTBS NiI2 (10 mol %), pyridine (10 mol %) 4,4′-OMe-bpy (10 mol %) NaI (0.25 equiv), Zn0 (2 equiv) DMPU, 75 °C OMe 63 Entry X % Yield 70 1 I (68) 38 2 OMs (69) 0 MeO OMe 70 As with the prior lithiation chemistry, it seemed likely that this failure was due to slow displacement of the mesylate leaving group—adjacent to the branched methyl group—by iodide to generate in situ an alkyl iodide required for productive coupling. We thus considered that the effective concentration of reactive iodide in solution (i.e., the rate of alkyl electrophile activation) should be matched to that of the aryl bromide (52) and postulated that an epoxide fit this criterion, given that ring-opening by iodide would be expected to outpace mesylate displacement. Indeed, regioselective epoxide opening/coupling113 occurred upon subjection of epoxide 71 to reductive conditions, delivering alkyl–aryl-joined 72 in much-improved 51% yield (Figure 5.32). As epoxide 71 was prepared with near-perfect enantiopurity (99% ee) via Jacobsen hydrolytic kinetic resolution,114 the RCC effectively installed a stereocenter at the location of the requisite methyl group (C2/15). From homobenzylic alcohol 72, stereospecific conversion was envisioned to proceed via nucleophilic displacement of the corresponding tosylate (73) with Gilman’s reagent to forge the necessary C–C bond with the correct stereochemistry.115,116 While we did observe this expected result (i.e., methylated 74), concomitant elimination of the 451 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F tosylate led to an inseparable mixture with alkene 75. Nevertheless, this epoxide-opening route was able to successfully improve the fragment coupling yield (aim 1, vide supra). However, the equally important goal (aim 2) of reducing the post-coupling step count to unmask the alkenyl bromide remained unaddressed by this workaround. Figure 5.32 Fragment coupling via reductive epoxide opening OH Br O OBn + MeO NaI (0.25 equiv), Zn0 (2 equiv) DMPU, 23 °C OMe OtBu nBu O 51% yield 71 99% ee OMe OtBu O 72 Me OTs Me OBn TsCl DMAP OBn Me2CuLi MeO OMe THF, –78 °C OMe OtBu nBu 76% yield O OBn + MeO OtBu nBu 73% yield MeO nBu 52 pyridine 23 °C OBn NiI2 (10 mol %), pyridine (25 mol %) 4,4′-OMe-bpy (10 mol %) Et3N·HCl (1 equiv) 73 O MeO OMe OtBu nBu O 74 75 With this objective in mind, we elected to refocus our investigation on an alkynecontaining fragment and revisit our hypothesis that the incompatibility of this functional group with cross-coupling owed to catalyst inhibition. It seemed likely that a transition metal rendered electron-poor by back-bonding to an alkyne would be unable to undergo oxidative addition—particularly of a challenging, electron-rich aryl electrophile117—so we targeted a metal for which that catalytic step would be more favorable, either due to a change in oxidative addition mechanism118,119 or to less favorable back-bonding. On the basis of weaker d-electron donation,120 we selected palladium, rather than nickel, as catalyst. Given the relative dearth of Pd-mediated cross-electrophile couplings, this necessitated return to a redox-neutral manifold. 452 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.33 Motivation for Pd-catalyzed Negishi cross-coupling Fürstner, 1997 Me OTf Pd(dppf)Cl2 (7 mol %) + Me 9BBN 10 MeO 10 OMe NaOMe THF, 50 °C MeO OMe 88% yield Breit, 2018 Me OTf Me + MeO nBu ClZn Pd(dppf)Cl2 (5 mol %) THF, 50 °C OMe MeO 96% yield OMe nBu We were motivated by select examples121,73 of high-yielding, Pd-catalyzed reactions of resorcinol-derived electrophiles with alkyl nucleophiles (Figure 5.33). Although these reports lent credence to our redesigned cross-coupling reaction, there were a few outstanding questions of importance to the current system. Namely, tolerance toward alkynes was unknown, and, notwithstanding that complication, it was unclear that aryl bromide 52, as opposed to a triflate, would be able to be activated, as the failure of this event had been previously noted.122 Critically, the alkyl nucleophile would need to be nucleophilic enough123 but less basic enough108 to allow cross-coupling to outcompete αdeprotonation; although this competition had not been explored for either organoboron or organozinc reagents, the success of a β-Me-alkyl–ZnCl partner inspired selection of the latter for our studies. We designed a series of model reactions to interrogate these questions. First, treatment of aryl bromide 63 and organozinc 76 (from alkyl iodide 68, see Table 5.8) with Pd(dppf)Cl2 forged the Csp2–Csp3 bond of product 70 (Figure 5.34). This result provided evidence for the feasibility of oxidative addition of electron-rich aryl bromides 453 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F under these conditions. Second, expected challenges of the pendant alkyne and the αproton were investigated in the reaction of alkynyl organometallic partner 78 with estercontaining 77 (available in one or two steps from commercial material). Cross-coupled 79 was formed in 73% yield, suggesting that neither of these functionalities were a significant detriment to this Negishi reaction. Figure 5.34 Fragment coupling via Negishi cross-coupling: model substrates Me OTBS Br Me + MeO OTBS ZnCl OMe Pd(dppf)Cl2 (5 mol %) THF, 50 °C 63 76 MeO OMe 70 56% yield Br + Pd(dppf)Cl2 (5 mol %) ZnCl TMS OtBu nBu TMS THF, 50 °C 73% yield OtBu nBu O O 77 78 79 Br + MeO Pd(dppf)Cl2 (5 mol %) ZnCl OMe TMS OtBu nBu THF, 50 °C 54% yield TMS MeO OMe OtBu nBu O O 52 78 55 Br + MeO Pd(dppf)Cl2 (5 mol %) ZnCl OMe TMS NHP nBu THF, 50 °C 26% yield MeO OMe NHP nBu O O 80 TMS 78 81 This conclusion was further supported by the successful cross-coupling of 2,6dimethoxy 52 with alkyl iodide 54 (via alkyl–Zn 78), which delivered intermediate 55 in 54% yield. In addition, we discovered that the NHP ester moiety of 80 was compatible with the redox-neutral cross-coupling conditions; if optimized for yield, this reaction 454 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F would expedite access to a difunctional substrate for cyclodimerization in only two steps from coupled 81. In neither case did the presence of an alkynyl motif substantially diminish desired reactivity of simple alkyl–Zn 78. Figure 5.35 Failed Negishi cross-coupling toward cylindrocyclophane F Me Br Pd(dppf)Cl2 (5 mol %) Me + MeO OMe TMS OtBu nBu THF, 50 °C MeO OMe OtBu nBu O O 52 TMS ZnCl 82 83 Therefore, we were surprised to find that when the alkyl coupling partner was generated from iodide 60 (i.e., alkyl–Zn 82), no aryl halide conversion was observed (Figure 5.35). At this time, it is not clear why this specific combination of substrate functional groups prevents Negishi cross-coupling. 5.4.2 Toward Unsubstituted Paracyclophanes Although we were unable to access via Negishi cross-coupling an intermedaite on path to cylindrocyclophane F (i.e., methylated 83), this transformation was useful in furnishing unsubstituted derivatives. The convergent coupling of simplified partners 77 and 78 could be performed on >7 g scale in 49% yield (see Fig. 5.34)—provided sufficient cooling was applied to prevent radical 5-exo-dig cyclization of reduced 78 and coupling of the resultant α-silyl vinyl radical. Aryl/alkyl intermediate 79 was then advanced smoothly through a short sequence used to unmask the difunctional species (85, Figure 5.36). We expected that ready access to gram-quantities of 85 would prove useful 455 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F in optimizing the double RCC and preparing the paracyclophane skeleton, albeit simplified as compared to the natural products. Figure 5.36 Electrophile unmasking: model substrate Br 1. TBAF THF, 18 °C 79 Br 1. TFA DCM, 0 °C 2. Cp2ZrHCl PhH, 18 °C then NBS OtBu 2. NHP, DMAP EDC·HCl DCM, 18 °C 84 83% yield (over 2 steps) nBu O 87% yield (over 2 steps) NHP nBu O 85 In a parallel manner, we also prepared intermediates designed to interrogate the effect of bridge length on [n,n] and [m,m]paracyclophane formation via double reductive coupling (Figure 5.37). The cyclophane structures arising from such unsubstituted monomers would be novel and could find use outside the scope of natural product synthesis (i.e., for host–guest chemistry, as subjects of computational physical organic studies, etc.). Ultimately, however, we planned to return to the system necessary to access natural product 2 (i.e., methoxy/methyl 83) following macrocyclization proof-of-concept. Figure 5.37 Toward paracyclophanes with modified bridge lengths TMS Br n TMS + Pd(dppf)Cl2 (5 mol %) ZnCl n THF, 50 °C OMe nBu O n = 1, 85% yield n = 3, 83% yield n = 4, 84% yield OMe nBu O 5.4.3 Toward Cylindrocyclophane A We also applied the developed general synthetic strategy to an intermediate that could give rise to cylindrocyclophane A (1). Preparation of the requisite alkenyl iodide precursor (88) of fragment coupling proceeded via stereoselective methyliodination and 456 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F basic deprotection of TMS-alkyne 86 (Figure 5.38). The 38% yield of iodoalkene 87, although moderate, was consistent on large scale. Subsequently, the alcohol was transformed to enyne 88 via a sequence of oxidation, Ohira–Bestmann124 homologation, then protection. Available in 42% yield (over three steps), alkenyl iodide 88 was zincated and cross-coupled with aryl bromide 52 to provide intermediate 90 in excellent yield (94%). For maximal convergency in the planned cyclodimerization step, we hoped to install the hydroxymethyl stereodiad prior to macrocyclization using enantioselective hydroboration/oxidation conditions.125 Although this was only briefly surveyed, it appeared likely that this step would need to occur after successful generation of the [7.7]paracyclophane. Nonetheless, we were interested in exploring how the ‘turn’ introduced by the rigid alkene to the structure of these intermediates (e.g., conjugated 90) would affect cyclodimerization of the corresponding alkenyl bromide/NHP ester. Figure 5.38 Successful Negishi cross-coupling toward cylindrocyclophane A TMS OH i. Cp2ZrCl2, AlMe3 DCM, 7 d then I2, THF, –78 °C Me OH ii. NaOMe, MeOH reflux 86 1. DMP, NaHCO3, DCM 2. xxxxxxxxxxxxxxx O O P(OMe)2 Me N2 K2CO3, MeOH 3. NaHMDS, TMSCl THF, –78 °C I 87 38% yield Me I TMS 88 42% yield (over 3 steps) Me Me ZnCl Br 89 Me HO TMS TMS Pd(dppf)Cl2 (5 mol %) OMe MeO OtBu nBu O 52 THF, 50 °C 94% yield MeO OMe OtBu nBu O (–)-IpcBH2·TMEDA BF3·OEt2, THF, 18 °C then 90, THF, –20 °C then NaOH, H2O2 MeO OMe OtBu nBu O 90 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 457 5.5 DOUBLE REDUCTIVE CROSS-COUPLING 5.5.1 Guiding Mechanistic Design We initiated investigation of double RCC as a method for cyclodimerization using unsubstituted difunctional substrate 85. Based on our initial mechanistic design, presented in Figure 5.39, Ni catalysis was deemed well-suited for cyclodimerization. Specifically, we considered the benefit to cyclization provided by formal oxidative addition of NHP esters being mediated primarily by a Ni catalyst, which at the outset of our studies, was a reigning hypothesis in the literature (vide supra). In the context of double RCC, following the first intermolecular C–C bond formation event, continued coordination of the catalyst to the π-system might allow ring closure to proceed via an intramolecular (and unimolecular) pathway with respect to intermediate 91 and catalyst. Electron transfer, followed by radical generation and its subsequent internal capture could occur via associated nickel; from an intermediate [8.7]paracyclophane-type nickelacycle, ring strain-releasing16 reductive elimination would forge the second requisite C–C bond and complete the macrocyclic ring. Critically, we assumed that an operative unimolecular ring-closing process would provide a kinetic basis for cyclization to be favored over competing intermolecular pathways. This hypothetical mechanism was grounded in catalyst-transfer polymerization (CTP), specifically polycondensation of dihaloarenes initiated by Ni0 complexes— including Ni–diamines. In these reactions, successful polymerization is due to a strong association between the catalyst and substrate,126 which affects several propagation steps: (1) interaction of low-valent Ni d-orbitals and substrate π-orbitals allows the catalyst to remain bound following reductive elimination;120 (2) π-complexation127 occurs prior to 458 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F oxidative addition126 of a terminal Csp2 halide; and (3) transfer of Ni across a π-system (i.e., ring-walking) enables subsequent intramolecular oxidative addition.128 Figure 5.39 Working mechanistic hypothesis: double RCC intermolecular coupling intramolecular ring closure Br * N N NiII X O Br NHP O nBu NHP nBu 2 NHP nBu O nBu nBu N 85 * Nin N * NiII N X nBu reduction 91 92 N nBu intramolecular radical capture nBu nBu 93 94 We postulated that the Ni catalyst in the present reaction could be similarly transferred across a singly-coupled intermediate (i.e., 91) to effect the second oxidative addition step in an intramolecular fashion. Although ring-walking has largely been demonstrated in fully conjugated π-systems, over which the metal ‘travels’ by migrating via η2 alkene coordination, specific mechanisms can be substrate dependent;129 it is plausible that analogous transfer of Ni across neighboring aromatic rings or alkenes could take place even if they are not conjugated but rather appropriately arranged in space. Indeed, CTP has been demonstrated for monomers in which arenes are connected by a saturated carbon; this seminal report130 lends credence to our hypothesis regarding adduct 92 generation. Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 459 As a consequence of putative through-space ring-walking-type metal transfer, the molecule (92) could be spatially arranged in a way that would facilitate electron transfer from Ni to the phthalimide moiety, thereby intramolecularly initiating reductive fragmentation and radical generation. In this case, intervening reduction would be required, potentially prior to NHP loss (e.g., NiII→NiI mediated by the terminal reductant, present in excess).90,89 We expected that this type of process would outcompete reaction with distinct organic/organonickel species of either the Ni- or the NHP-terminus of an intermediate like 92, and in so doing, promote cyclodimerization over polymerization. As our understanding of NHP ester reduction was expanded throughout the course of single RCC optimization (vide supra), this conformational arrangement of the incipient macrocycle (ostensibly to promote intramolecular Ni transfer) also seemed crucial in a regime where NHP ester reduction occurred external to Ni involvement. The readiness of intramolecular oxidative addition could build up appreciable [92]; this would increase the probability that an NHP ester undergoing reduction would be Ni-adduct 92, which is poised for immediate intramolecular radical capture (leading to ring formation). In contrast, without an attached alkenyl–Ni moiety, an NHP ester could preferentially decompose or undergo intermolecular reaction (e.g., polymerize) instead. It is also possible that preorganization resembling the macrocycle could stabilize a radical generated by initial NHP reduction in the internal pocket131 (via hydrogen bonds, electrostatic interactions, etc.) until a Ni center suitable for radical capture could be produced. 460 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F The conformational control elements132 installed by nature into the cylindrocyclophanes could serve to effectively promote the requisite preorganization of macrocycle precursors. Although an intuitive assumption, no systematic study of substituent effects on [7.7]paracyclophane construction has been reported; syntheses of structurally related cyclophanes offer indirect experimental support. For instance, the stereocenters along the seven-membered bridge of natural products 1 and 2 could facilitate proper arrangement of open-chain species for ring closure, viz. positioning the aliphatic ‘arms’ in close proximity to each other. Indeed, installation of a single methyl substituent along an aliphatic chain of one cyclophane produced a turn-on effect in its generation via RCM.133 A benzylic hydroxyl group134 and an alkene at the benzylic position135 of other cyclophanes have achieved similar results. Too, the conformational effects of aryl substitution (i.e., the resorcinol motif) could be additive, as o,odisubstitution has been noted to gear alkyl ‘arms’ appended at the para-positions out of the aryl plane (and presumably toward each other).136,137 For difunctional monomers bearing minimal substitution along the periphery of the carbon skeleton (e.g., 35, see Fig. 5.39), intrinsic conformational bias would be comparatively minimal. This model system would thus provide a platform for investigating the extrinsic factors (i.e., RCC reaction conditions) that could favor an appropriately folded conformation of open-chain species en route to cyclodimer 94. Templating is a highly successful tactic in promoting macrocyclization over competitive polymerization, and halide anions (e.g., iodide and bromide) have been demonstrated to serve as templates to preorganize intermediates in the preparation of cyclophanes.138 The exogenous iodide additive in the RCC reaction, as well as in situ-generated bromide, Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 461 could play a similar role. It is also possible for the other ions in solution, such as the Ni catalyst, to engage in cation–π interactions;139 this would be required for through-space metal transfer (vide supra), and metal-binding to one or both arenes of paracyclophanes is well precedented.140 In the same vein, we envisioned that π–π stacking with the aryl groups141 of paracyclophane 94 could play a similar role in facilitating ring closure. This effect has been demonstrated with an electronically biased perfluoroarene covalently bound to a cyclophane precursor.142 In that example, the arrangement of the two arenes rigidified the structure, in which the aliphatic ‘arms’ were hypothesized to be oriented opposite to the additional aromatic ring and thus near each other. The more synthetically efficient approach involves a distinct aryl-containing species in the macrocyclization reaction that could engage noncovalently with the intermediate undergoing cyclization; following this reasoning, cationic N-heterocycles have proven useful in the generation of [12]paracyclophanes.143 In the current system, a phthalimide byproduct might be implicated in this type of interaction. Unlikely to fit inside the cavity32 of the incipient paracyclophane, such arenes could π–π stack on the external face to properly dispose the alkyl chains. Lastly, we reasoned that nonclassical hydrophobic effects could play a role in generating a tight apolar complexation of cyclization intermediates conducive to ring closure. This is established behavior of cyclophanes, and would likely be a factor in the DMA reaction solvent given the extremely nonpolar nature of hydrocarbon 94 (vide infra) and that binding strength increases with solvent polarity.144 Having thus 462 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F rationalized the potential success of cyclodimerization via double RCC, we turned to experimental exploration. 5.5.2 Cyclodimerization versus Polymerization Following the developed synthetic route to access a model difunctional substrate for study of cyclodimerization, we subjected the NHP ester/alkenyl bromide (85) to the optimized conditions for single reductive cross-coupling (Figure 5.40). We were pleased to find that in the crude reaction mixture, the desired macrocycle (94) appeared to be the major product. We identified the mass of dimer 94 by GCMS, and the 1H and 13C NMR spectra were consistent with a C2 symmetric molecule containing diagnostic signals matching those predicted for 94. By both spectroscopic methods, the reaction profile was clean, with no obvious remaining starting material or decomposition byproducts. However, isolated macrocycle 94 was elusive, despite extensive attempts at chromatographic purification. Ultimately, preparative HPLC was successful in delivering isolable quantities of the expected product, but the amount of thus-obtained 94 was significantly less than anticipated. This work-up and purification sequence did not yield additional species, thus the mass balance of the reaction remained in question. Figure 5.40 Analysis of initial double RCC: challenges O Br O N nBu N Ni Br NHP nBu O 85 Br L1·NiBr2 (20 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –4 °C ??? macrocycle evident (NMR/GCMS) challenging isolation clean reaction profile mass balance unclear high concentration reported cyclodimerizations <0.02 M nBu 94 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 463 We also noted that the double RCC was run at a high concentration (1 M). Intramolecular reaction at this concentration would need to be an extremely efficient process, since intermolecular reactivity would generally be expected to dominate in this regime. In comparison, cyclodimerizations reported in syntheses of cylindrocyclophanes are orders of magnitude more dilute (ca. 0.02 M and less concentrated).18 To understand the outcome of treating difunctional electrophile 85 with L1·NiBr2/TDAE in a way that accounted for these observations, we expanded the mechanistic hypothesis presented in Fig. 5.39 to include possible—albeit undesired— reaction pathways (Figure 5.41). If initial C–C bond formation (such as to generate homobenzylic alkene 85) is not followed by the planned ring closure event, which would lead to macrocycle 94, then remaining reactive functionalities (e.g., alkenyl bromide and NHP ester of 85) could decompose. However, byproducts of the nature observed in the single RCC system were not identified in the crude reaction mixture. Alternatively, subsequent intermolecular coupling events could generate larger cyclooligomers (96) or even much larger polymers (97). In these cases, the repeat unit would be spectroscopically similar to the desired cyclodimer (94). In addition, the higher molecular weight of species such as 96 or 97 would render them invisible to the mass spectrometers available for use. Polarity and behavior on silica distinct from cyclic 94 and unamenable to chromatography would account for the challenges of product isolation. We recognized that the large difference in molecular weight between desired dimer 94 and oligomers or polymers containing multiple equivalents of substrate might provide a useful handle for identification of the latter species. 464 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.41 Alternative reaction pathways of double RCC cyclodimerization decomposition Br Me O nBu nBu NHP ring closure nBu nBu nBu 85 94 cyclooligomerization nBu 95 linear polymerization nBu nBu nBu nBu nBu nBu n 96 97 We turned first to diffusion-ordered spectroscopy (DOSY), which is an NMR technique that allows separation of compounds in a mixture based on their translational diffusion coefficients. The DOSY workflow is presented in Figure 5.42; attenuation of 1H NMR signals is observed during a pulsed field gradient experiment and is a function of magnetic gradient pulse amplitude occurring at a rate proportional to the diffusion coefficient.145 In short, the derived diffusion coefficient for each species in solution is related to its molecular weight (and shape). We found DOSY to provide excellent qualitative information regarding the distribution of differently sized species in a hard-toseparate crude reaction mixture. Specifically, analysis of the double RCC via DOSY revealed a bimodal distribution: species with near-identical 1H NMR signals featured diffusion coefficients separated by an order of magnitude. This evidences oligomerization and/or polymerization under the reaction conditions. 465 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.42 DOSY workflow 1H NMR   
 
 
 
                                    

         
 To understand in finer detail the nature of the high-molecular weight products of double RCC, we analyzed the crude reaction via gel permeation chromatography (GPC). A peak in the GPC trace with a short retention time was observed, which would correspond to a macromolecule; indeed, we estimated the molecular weight to be ca. 4–8 kDa (Figure 5.43). Due to the challenges of obtaining a completely purified sample of this polymer, the size and polydispersity (Ð ≈ 1.7) were limited to rough estimates. A peak in the small molecule regime of the GPC trace matched that of a purified sample of macrocycle 94. Figure 5.43 Polymer characterization by GPC Br Mn = 4.5 kDa Mw = 7.5 kDa Ð = 1.7 nBu nBu nBu NHP nBu n O 85 94 98 13 15 17 19 21 Retention Time (min) 23 25 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 466 Characterization by MALDI-TOF of samples from the reaction containing highmolecular weight species, assigned by GPC, determined the the molecular weight of each repeat unit, consistent with polymer structure 98. Connectivity was based on 1H/13C NMR spectra (vide supra) and established 98 as a head-to-tail polymer. Based on these characterization methods, polymerization can be terminated in different ways. The exact nature of the end groups is unclear; however, tentative evidence suggests that alkenyl bromide terminus is reduced in the reaction, generating a terminal alkene. Efforts to determine the tacticity have been unsuccessful to date. In the single cross-coupling, we presume that catalyst L1·NiBr2 mediates bond formation, as opposed to a radical chain mechanism involving direct addition of the benzylic radical to the alkene, based on the (1) high enantioselectivity, (2) lack of alkene isomerization, and (3) lack of byproducts arising from intervening radical species. As such, the stereocenters of polymer 98 (and 94) are represented based on the major enantiomer expected when using L1·NiBr2 as catalyst in the reaction of model substrates 17 and 18 (see Fig. 5.24). Taken together, these results led us to conclude that the double RCC reaction of difunctional monomer 85 provided a mixture of cyclodimer (94) in addition to polymer 98 (Figure 5.44). DOSY was beneficial in identifying the 1H NMR signals assigned to paracyclophane 94 in the crude reaction spectrum, allowing us to quantify the yield of desired product (3%). Unfortunately, determination of the stereochemistry of macrocycle 94 was significantly more challenging. 467 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Figure 5.44 Double RCC: cyclodimerization and polymerization O Br O N nBu nBu N Ni Br NHP nBu O 85 Br L1·NiBr2 (20 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –4 °C + nBu n 94 3% yield 98 major product It is plausible that initial cross-coupling occurs with a similar level of enantioselectivity as that observed in the model RCC (86% ee), and our guiding hypothesis is that formation of one stereocenter will minimally affect subsequent bond construction. If these assumptions hold true, then we expect the initial ee to be amplified based on the Horeau principle such that the diastereomeric ratio of generated macrocycles would offer a greater range with which to judge the stereoselectivity of the cyclodimerization. We were unable to separate enantiomers or diastereomers of cyclophane 94 via chiral SFC or HPLC. However, we have identified a diastereomeric macrocycle by 1H NMR, based on apparent splitting of the signals attributed to aryl and alkene protons. This diastereomer was only observed when a racemic mixture of L1·NiBr2 was used to catalyze the reaction and was therefore assigned as the meso isomer of 94. Although, lack of baseline separation of the diagnostic 1H NMR signals of the diastereomeric macrocycles precluded definitive determination of dr. With a clearer picture of the outcome of double RCC, we attempted to optimize the reaction with the goal of improving cyclodimer formation as opposed to polymerization. The reaction parameter of highest priority for study was concentration. Systematic dilution of the reductive dimerization of difunctional 85 did not result in significantly higher yields of macrocycle 94 (Table 5.9). Instead, under the least 468 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F concentrated conditions, cross-coupling completely failed; neither cyclodimer 94 nor polymer was observed at 0.01 M (entry 4). We postulate that this is due to the intermediate benzylic radical engaging the solvent preferentially to the catalyst or coupling partner (itself), evinced by species tentatively assigned as DMA adducts by mass and diagnostic 1H NMR signals. That the most successful cyclodimerization occurred at an intermediate concentration (i.e., 0.5 M, entry 2) underscores the challenge of balancing the sensitivity to concentration of an intermolecular radical-based reaction with the equal but opposite concentration dependence of intermolecular coupling. Table 5.9 Optimization of cyclodimerization via double RCC O Br O N nBu N Ni Br NHP nBu O Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (x M), –10 °C nBu 85 94 Entry Concentration % Yield 94 1 1M 1 2 0.5 M 7 3 0.1 M 3 4 0.01 M 0 Where concentration had a more pronounced effect was polymer size (Table 5.10). Sequentially increasing concentration resulted in increasingly larger macromolecules. However, polydispersity also followed this trend, and, in general, the size of 98 was on the border between classification as a polymer or a few-repeat unit oligomer. Thus, RCC was equally unfit as a cyclodimerization tactic as it was a practical 469 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F method for polymerization. Regardless, reductive oligomerization/polymerization appeared to be unavoidable under these conditions, and it was not evident how we might be able to overcome this propensity in order to access the desired macrocycle and continue toward our synthetic goals. Table 5.10 Optimization of reductive polymerization O Br O N nBu N Ni Br NHP nBu O Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (x M), –10 °C n 85 98 Entry Concentration Polymer 98 (Mn, Mw; Ð) 1 1M 4.5, 8.6 kDa; 1.9 2 0.5 M 2.3, 3.9 kDa; 1.7 3 0.1 M 1.3, 1.5 kDa; 1.2 4 0.01 M — increasing concentration 14 15 16 17 18 19 Retention Time (min) It is worth commenting that the irreversible coupling steps of cyclodimerization via Ni catalysis are under kinetic control; thus, model alkenyl bromide/NHP ester 85 is expected to be a less favorable substrate for macrocyclization than that required for advancement to cylindrocyclophane F (i.e., functionalized 11, see Fig. 5.11). The conformational control elements inextricably part of the stereochemically enriched substituents on the substrate designed based on the natural product are absent from simplified 85. It could be that the target difunctional monomer (11) demonstrates 470 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F improved cyclization under identical reductive conditions. However, the synthetic inaccessibility of 11 (vide supra) prevented empirical substantiation of this claim. Nonetheless, we were able to treat semi-functionalized monomer 57 to the reductive coupling reaction (Figure 5.45). The outcome of this transformation was analyzed following the protocol established for analogous substrate 85. The 1H NMR signals of the crude mixture established the connectivity expected of head-to-tail crosscoupling, but subjecting this sample to our DOSY workflow revealed only species with mid-range diffusion constants. Consistent with the lack of molecules of the approximate size of desired product 99 (determined via DOSY), the mass of macrocycle 99 was not evident by GCMS. Based on these results, we concluded that the 2,6-dimethoxy substitution of electrophile 57 was not beneficial to cyclization—instead, likely detrimental—suggesting that any intrinsic conformational control of further- functionalized 11 would be based on aliphatic chain substitution. Figure 5.45 Double RCC using 2,6-dimethoxy substrate: oligomerization O Br O N Ni Br MeO OMe NHP nBu O 57 MeO Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.5 M), –10 °C nBu nBu N MeO OMe OMe + MeO OMe nBu n 99 not observed low molecular weight oligomers 5.5.3 Macrocyclization via Depolymerization Determined to progress toward the synthesis of the cylindrocyclophanes, we questioned whether the polymer formed via reductive cross-coupling was not a dead end but could serve as an intermediate en route to the paracyclophane skeleton. In reframing 471 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F the central challenge to macrocyclization in this way, we realized that while the crosscoupling reaction forges a benzylic C–C single bond, the polymer could instead be viewed as a string of alkenes. Therefore, reaction with a metathesis catalyst could, in principle, break down the polymer at each double bond and then reassemble the fragments into the desired macrocycle (Figure 5.46). Figure 5.46 New approach to the challenge of macrocyclization cross-coupling forges benzylic C–C bond nBu nBu nBu nBu n nBu nBu + nBu X + X nBu X alkene used in depolymerization X nBu nBu 94 This approach is not dissimilar to that of Smith and coworkers, who were the first to implement CM/RCM in the synthesis of a cylindrocyclophane (Figure 5.47).72 The Smith reports hinged on the reversible nature of metathesis to effect cyclodimerization of monomer 100; as well, products of a single metathesis reaction (i.e., 101 and 102) poised for formation of alternative, undesired macrocyclic products were successfully funneled to a single paracyclophane (103) in high yield.70 Molecular mechanics calculations were performed to determine relative energies of the low-energy conformers of all possible 472 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F CM/RCM products, attributing metathesis selectivity (i.e., high yield of 103) to a thermodynamic preference for 103, the lowest energy macrocycle.72,70 Figure 5.47 Motivation for depolymerization via reversible metathesis Smith, 2000/2001 Me correct monomer nBu 100 MeO MeO Me OMe nBu nBu MeO OMe MeO CM/RCM or OMe Me MeO MeO Me Me nBu cis-alkene Me 101 OMe OMe nBu OMe 40–55 °C 0.02 M head-to-head dimer 102 MeO OMe nBu Me 103 nBu We attempted to use DFT calculations to similarly assess the thermodynamic driving force for depolymerization/RCM to afford head-to-tail dimer 94. These efforts were stymied by the many conformers available to unsubstituted macrocycle 94 and related metathesis products. We developed a computational workflow to include entropy correction via conformer ensemble generation (GFN-FF, CREST) with DFT sorting (B3LYP/6-31G**, CENSO);146 however, the supercomputing time required was prohibitive. Nevertheless, we anticipated that cyclized 94 would be accessible in this thermodynamically controlled process given that macrocyclic ring strain of 94 should be minimal.147 As a corollary, we did not expect significant enthalpy gain of cyclization, owing to the flexible nature of both the linear precursor and the cyclic product (94). Thus, depolymerization would be an entropically driven process, whereby reducing 473 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F concentration and increasing temperature could be used to push the ring–chain equilibrium toward the macrocycle. Indeed, a two-step sequence consisting of cross-coupling then ring formation delivered the paracyclophane (94) in 34% yield relative to the intermediate polymeric mixture (Figure 5.48). Specifically, subjection of monomer 85 to L1·NiBr2 under reductive conditions furnished a mixture of minimal macrocycle and polymer as the major product, which could be purified away from RCC byproducts, such as phthalimide, by a series of triturations. This was followed by treatment of the mixture with 35 mol % Grubbs second generation catalyst at high dilution (PhH, 0.02 M) and 50 °C. We did not observe the diastereomeric meso macrocycle to form in the two-step procedure, indicating that—notwithstanding the limitations to dr measurement (vide supra)— polymerization occurred with high stereoselectivity, since the stereochemistry would be unaffected by metathesis. Figure 5.48 Two-step macrocyclization: depolymerization/RCM O Br O N nBu nBu N Ni Br NHP nBu O 85 Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.5 M), –10 °C macrocycle: 7% yield linear polymer: 3.9 kDa, Ð = 1.7 + nBu n 94 98 Grubbs II (35 mol %) PhH (0.02 M), 50 °C, 2 h 34% yield single diastereomer Tracking over time the relative amounts of polymer and macrocycle in aliquots of the metathesis reaction by GPC and NMR provided evidence that depolymerization was responsible for the increase in macrocycle 94 yield following initial cyclodimerization via double RCC. It was clear that high-molecular weight macromolecules were 474 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F disassembled upon addition of metathesis catalyst. These analytical methods also provided evidence for the presence of intermediate-weight oligomers, although quantitation of these molecules was elusive. We presume that ca. 34% yield of cyclized 94 represents the thermodynamic ring–chain equilibrium under these conditions. A brief survey of metathesis reaction parameters (e.g., reaction time, catalyst, temperature, solvent, concentration, etc.) did not qualitatively perturb the equilibrium to effect a significant increase in macrocycle 94 yield relative to the putative oligomeric species. Figure 5.49 One-step macrocyclization: depolymerization/RCM O O N N Ni Br Br NHP nBu O 85 Br nBu L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C then Grubbs II (35 mol %) PhH (0.02 M), 50 °C 18% yield nBu 94 The sequence could be accomplished in one pot (Figure 5.49). Following reductive coupling, a solution of metathesis catalyst in benzene was added directly to the mixture in DMA then heated. In this reaction, macrocycle 94 was formed in 18% yield from difunctional monomer 85. While this one-pot approach advantageously avoided intervening purification steps—in which a nonzero amount of macrocycle and/or polymer was lost—we observed that the polymer was reticent to convert to macrocycle in the DMA/PhH solution. This effect could arise from inhibition or degradation of the Ru catalyst by the Lewis basic co-solvent.148 Given the preference of the decarboxylative reductive coupling for amide-based solvents,75 we did not attempt to reoptimize this 475 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F component of the overall transformation to perform under conditions more compatible with metathesis. Theoretically, the yield of cyclodimer 94 arising via this sequence was capped by the molecular weight and polydispersity of the polymer. It is only possible for the internal olefinic units of polymer 98 to be regenerated into diene 94; the exception is if protodebromination leads to one polymeric end group being an alkene, which renders this unit a potential macrocycle precursor. Therefore, a smaller ratio of repeat units to terminal units (i.e., reduced molecular weight of 98) limits cyclophane 94 formation. Figure 5.50 Effect of polymer molecular weight on macrocyclization: GPC analysis step 1: reductive polymerization step 2: depolymerization/RCM 1M 0.5 M 0.1 M macrocycle 14 15 23% macrocycle 17% macrocycle 7% macrocycle macrocycle 16 17 18 Retention Time (min) 19 14 15 16 17 18 19 Retention Time (min) This concept was observed across a range of polymer sizes (Figure 5.50). Running the first (reductive coupling) step at concentrations of 0.1, 0.5, and 1 M, a series of smaller, medium, and larger macromolecules were obtained, respectively. Subsequent subjection of these mixtures to depolymerization conditions afforded desired product 94 in increasing yields: 7%, 17%, and 23%. However, further concentration of the first reaction in the sequence presented practical challenges to reaction setup, so extrapolation of the observed concentration dependence to >1 M was not pursued as a means to achieving higher yields of cyclic 94. 476 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F In sum, this investigation established a novel synthetic approach to paracyclophanes. By viewing the polymer as a viable intermediate toward the desired macrocycle, we were able to harness the high level of selectivity for head-to-tail crosscoupling, as well as the stereoselectivity, of Ni-catalyzed decarboxylative reductive coupling in a manner that significantly outperformed direct cyclodimerization via double RCC. Yet, at the current level of development, both methods for accessing a macrocycle from a difunctional monomer were not maximally efficient. To advance further toward the synthesis of the cylindrocyclophanes, we regarded the metathesis depolymerization as a conceptual springboard. 5.6 REVISED APPROACH AND FORMAL SYNTHESIS Having discovered the power of metathesis for assembly of a paracyclophane structure from a polymer, we questioned the value of proceeding through this intermediate. Of the key advantages, being (1) head-to-tail connectivity and (2) stereoselective aliphatic bridge substitution, only the latter could not also be addressed via metathesis (see Fig. 5.7). As such, we aimed to simplify the system—and reduce the step count—by limiting our demands of the RCC reaction to generation of a single stereocenter (Figure 5.51). Accordingly, the single alkene established by Ni catalysis would be poised for cyclodimerization via CM/RCM. Figure 5.51 Revised conceptual synthetic design nBu Ni R1 + NHP nBu O Br Ru R1 R1 R2 nBu R2 nBu R1 477 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F In our initial investigation of this modified synthetic design plan, we continued to make use of the readily accessible, unsubstituted substrate class. Intercepting the deprotected product of fragment coupling (104), alkyne hydrogenation delivered terminal alkene 105 in 82% yield (Figure 5.52). As our immediate goal was to test the planned macrocyclization, this step allowed rapid preparation of the requisite substrate (i.e., 106), but a more convergent pathway was envisioned in which the alkyl fragment precursor to 106 would contain the alkene functionality prior to coupling. The NHP ester of 106 was then revealed following deprotection and esterification (86% yield over two steps). Figure 5.52 Preparation of NHP ester for single RCC 1. TFA, DCM, 0 °C 2. NHP, DMAP Cp2ZrHCl OtBu nBu O 104 PhH, 18 °C then H2O OtBu nBu 82% yield O 105 EDC·HCl DCM, 18 °C 86% yield (over 2 steps) NHP nBu O 106 In the context of our redesigned approach, the most atom-economical coupling partner would feature R2 = H (see Fig. 5.51). For practical reasons, we selected commercial 1-bromopropene (107) as a surrogate for gaseous vinyl bromide. Reductive cross-coupling of NHP ester 106 with alkenyl bromide partner 107 furnished diene 108 in 79% yield (97:3 E:Z), with the major (E)-alkene isomer generated in 92% ee (Figure 5.53). We assigned the absolute configuration of product 108 by analogy to previous studies.75 To test the feasibility of subsequent cross-metathesis, we subjected monomer 108 to Grubbs second generation catalyst in C6D6 (0.02 M) at 50 °C and monitored the course of the reaction by quantitative 1H NMR. After 30 minutes, target cyclophane 94 was observed to form in 44% yield without evidence of the diastereomeric meso compound. 478 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Given this result, two-step cyclodimerization via single RCC and CM/RCM occurred in 35% overall yield from the monomeric substrate to deliver a single observable diastereomer of paracyclophane. Figure 5.53 Two-step macrocyclization: sequential single RCC and CM/RCM O O N nBu N Grubbs II (35 mol %) Ni Br + Br Me NHP nBu Br L1·NiBr2(10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C C6D6 (0.02 M) 50 °C, 30 min nBu Me nBu O 106 107 79% yield, 92% ee 108 44% yield single diastereomer 94 Continuing to track the metathesis reaction over longer periods of time, we found the macrocycle yield to diminish, approaching the equilibrium concentration of 94. After 2 hours, macrocycle 94 was present in 34% yield, which is consistent with the yield of depolymerization/RCM—run under identical, albeit non-deuterated, conditions for the same length of time (see Fig. 5.48). Likewise, the mass balance of monomer 108 was qualitatively found in oliogomeric/polymeric species. As previously noted, the predominance of macromolecules rendered purification of the macrocycle challenging; cyclized 94 was isolated in 18% yield following silica gel chromatography. With this exciting precedent for sequential single RCC and CM/RCM to deliver the paracyclophane skeleton, we endeavored to apply this approach to a substrate that could be advanced to cylindrocyclophane F (2) upon successful execution of this twostep cyclodimerization. To this end, we prepared an alkene-containing alkyl fragment from the corresponding protected alkyne (60, see Fig. 5.27; 78% yield over two steps) then subjected this compound to Negishi cross-coupling with 2,6-dimethoxy aryl bromide 52 (Figure 5.54). In stark contrast to the alkyne congener, branched organozinc reagent 479 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 109 was coupled in 80% yield. From alkene 110, the NHP ester (111) was accessed in short order (85% yield over two steps). Figure 5.54 Fragment coupling toward cylindrocyclophane F via single RCC Me Me Br Pd(dppf)Cl2 (5 mol %) Me + MeO ZnCl OMe THF, 50 °C OtBu nBu 1. TFA, DCM, 0 °C 2. NHP, DMAP MeO OMe OtBu nBu O 52 80% yield 109 O 110 EDC·HCl DCM, 18 °C MeO OMe NHP nBu 86% yield (over 2 steps) O 111 Treatment of fully substituted electrophile 111 and simple alkenyl bromide 107 with L1·NiBr2 and TDAE afforded cross-coupled product 112 in 47% yield (Figure 5.55). This moderate yield is fully consistent with the performance of the truncated NHP ester bearing identical aryl o,o-disubstitution in the single RCC model reaction; accordingly, we expect the high ee of related product 19 to translate to excellent dr of homobenzylic alkene 112 (see Fig. 5.24). In the case of elaborated 112, no separation of diastereomers (epimeric at the benzylic position) was attained via chiral SFC or HPLC. The diastereomeric cross-coupled product was also unidentifiable by NMR when substrate 111 was subjected to a racemic mixture of Ni catalyst. Although the dr of crosscoupled 112 remained unknown, we expected that determination of the diastereomeric ratio of the downstream macrocycle could be used as a readout for RCC stereoselectivity. Figure 5.55 Successful single RCC toward cylindrocyclophane F Me O O N OMe Me + nBu N Br Grubbs II (35 mol %) Br L1·NiB2(10 mol %) MeO TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) nBu DMA (1 M), –10 °C NHP nBu Me Ni Br MeO Me OMe Me C 6D 6 (0.02 M) 50 °C MeO MeO OMe OMe nBu O Me 111 107 47% yield 112 113 480 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F With diene 112 in hand, we were poised to achieve the formal synthesis of cylindrocyclophane F following CM/RCM. Unfortunately, attempts to cyclodimerize 112 were not met with success. To parse the obstacles to productive reactivity, we monitored the course of this reaction by quantitative 1H NMR. Using the solvent of choice for formation of the model paracyclophane (i.e., C6D6), we observed gradual loss of signals assigned to substrate 112 but without corresponding increase in other signals; we attributed this to oligomerization and/or polymerization. We recognized that use of CDCl3 instead could allow ready identification of macrocyclic signals, as characterization data for 113 have been reported in this solvent.73 However, we were unable to detect paracyclophane 113 upon reaction of monomer 112 with the metathesis catalyst in chlorinated solvent (Figure 5.56). Analysis of the reaction mixture by mass spectrometry allowed us to tentatively assign one of the several resulting species as 114. Compound 114 exemplifies as a possible challenge in this system the inertness of intervening metathesis products toward eventual assembly of desired macrocycle 113. We were surprised by this result, given the resemblance of diene 112 to a successful cyclophane precursor, a des-methyl homolog of 112 (see Fig. 5.7). Figure 5.56 Failure of CM/RCM to afford cyclodimer Me Me Me nBu Me MeO OMe nBu CDCl3 (0.02 M), 50 °C 112 MeO OMe nBu Me tentative OMe MeO Grubbs II (35 mol %) Me 114 MeO OMe nBu 113 Me Three observations led us to hypothesize that the aryl substitution pattern of 112, in combination with the position of internal alkenes (along the bridge of the intended 481 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F paracyclophane), preclude efficient reversibility of the various metathesis reactions required to funnel to head-to-tail dimer 113. (1) Exchanging the simple arene of difunctional monomer 85 with a resorcinol motif (i.e., 2,6-dimethyoxy 57) prevented macrocyclization in the reductive coupling protocol (see Fig. 5.45). (2) For a polymer without aryl substitution that featured internal alkenes at the same positions as monomer 112 (and unreactive 113), RCM—following depolymerization—was successful in generating a paracyclophane (see Fig. 5.48). (3) Smith and coworkers70 demonstrated that resorcinol derivatives (i.e., 101 and 102) could be disassembled at an internal alkene to deliver a single macrocyclic product (see Fig. 5.47). Although presumed that any of the possible metathesis reactions would be reversible, and thus lead to the head-to-tail cyclodimer, only an internal alkene positioned furthest away from the dimethoxy substituents was empirically tested. Figure 5.57 Related failure of CM/RCM toward cylindrocyclophane A Goodwin, 2007 Me Me Me O O Me O OMe DCM, 40 °C MeO OMe MeO nBu nBu Me 115 OMe MeO Grubbs II MeO nBu O OMe nBu MeO OMe nBu O Me Me 116 Me 117 A related synthetic approach to the cylindrocyclophanes via CM/RCM lends credence to this hypothesis (Figure 5.57). MacMillan and coworkers67 applied Grubbs second generation catalyst to terminal alkene/internal alkene 115—bearing a methoxysubstituted arene—in dichloroethane. In lieu of macrocyclization, they obtained only 482 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F head-to-head dimer 116, in which the terminal alkene of monomer 115 dimerized but the internal alkene (positioned adjacent to the OMe groups) was inert. In line with this hypothesis, a feasible solution could be to remove the alkenyl methyl substituent and attempt cyclodimerization of the di-(terminal)alkene. We first attempted this workaround using the unsubstituted model system. The requisite terminal alkene could be indirectly appended via Ni-catalyzed RCC by use of alkenyl silane 118, a readily handled liquid alternative to vinyl bromide hypothesis (Figure 5.58). Reductive cross-coupling of silyl 118 with the simplified NHP ester (106) proceeded in good yield (83%) and ee. Desilylation was then smoothly effected by treatment of the cross-coupled product with TsOH (91% yield), and the enantiomeric excess of the resulting diene (119) was determined to be 96%. Following the NMR-scale protocol previously established for CM/RCM of the methylated variant (108, see Fig. 5.53), paracyclophane 94 was generated in 49% yield after 30 minutes of reaction time. The improvement to macrocyclization afforded by the lack of alkene substitution—albeit slight—bodes well for the more complex system. Figure 5.58 Two-step macrocyclization of dienyl monomer O O N N nBu Ni Br 1. + Br TMS NHP nBu O 106 118 Br Grubbs II (35 mol %) L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C 2. TsOH·H2O, MeCN, 18 °C 80% yield, 96% ee (over 2 steps) C6D6 (0.02 M) 50 °C, 30 min nBu nBu 119 49% yield single diastereomer 94 In an analogous RCC/desilylation sequence, 2,6-dimethoxy-containing diene 120 was prepared in 59% yield over two steps (Figure 5.59). With alkenyl silane 118, the cross-coupling yield (66%) from NHP ester 111 was noticeably improved relative to prior 483 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F RCC using this substrate (cf. 47%; see Fig. 5.55). It stood to reason that the enantioselectivity could also be higher for reaction of this coupling partner combination. Consistent with our inability to measure dr for methylated 112, any minor diastereomers of cross-coupled product 111 formed in the RCC did not yield to separation via chiral SFC or HPLC. As well, the benzyl epimer was not observed by NMR when racemic L1·NiBr2 was the catalyst employed. Figure 5.59 Completion of the formal synthesis of (–)-cylindrocyclophane F formal synthesis of (–)-cylindrocyclophane F O Me Breit, 2018 O N Me N Me nBu Ni Br Br TMS 1. + MeO NHP O 111 118 HO OH L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C 2. TsOH·H2O, MeCN, 18 °C OMe nBu Br 59% yield (over 2 steps) MeO OMe nBu Me HO OH nBu Me (+)-120 (–)-2 To confirm the presumed configuration of the benzylic stereocenter of 120, we compared our synthesized compound to that reported by the Breit group.73 Note that the absolute configuration of the methyl group appended to the aliphatic chain of 120 had been confirmed by Mosher ester analysis149 of an intermediate prior to aryl–alkyl fragment coupling, and this position was expected to be stable against epimerization throughout the remaining steps of the route; thus, only the relative configuration at the benzylic position was in question. Spectroscopic data for 120 were consistent with those reported, as well as the enantiomeric series (i.e., (+)-120), measured by optical rotation. When we prepared an identical diene using the opposite enantiomer of L1·NiBr2 as that presented in Figure 5.59, this compound was found to be in the opposite enantiomeric series compared to both synthesized 120 and reported 120. 484 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Taken together, these data constitute compelling evidence for the structural and stereochemical assignment of 120. As such, macrocyclic precursor 120 represents the completion of a formal synthesis of (–)-cylindrocyclophane F (2). 5.7 CONCLUDING REMARKS This chapter details efforts aimed at addressing the synthetic challenges posed by dialkylresorcinol natural products, which led to several key discoveries. In the context of Ni-catalyzed reductive alkenylation of NHP esters, use of TDAE as the terminal reductant (with silyl halide additives) led to non-Ni-mediated reductive fragmentation of resorcinol-derived NHP esters. This study coincides with an ongoing mechanistic investigation in our lab that suggests this phenomenon is general to other benzylic NHP ester substrates of Ni-catalyzed RCCs. We expect these findings to be of use in the application of reductive cross-coupling reactions which use soluble organic reductants to the synthesis of additional complex molecules or natural products. Of note, we demonstrated the orthogonal reactivity of redox-active esters in redox-neutral crosscoupling (i.e., Pd-catalyzed Negishi reaction), important for synthetic efficiency. Streamlined access to the [7.7]paracyclophane skeleton was accomplished by development of a convergent synthetic route. Modular assembly of the n-butyl substituent, aliphatic bridge, and substituted arene components of the cylindrocyclophanes allowed rapid preparation of a natural product-like macrocycle from simple building blocks and would be advantageous for future SAR studies. The ability of L1·Ni-catalyzed RCC to forge an o,o-disubstituted benzylic stereocenter in high yield and enantioselectivity was critical to this success of this route. 485 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Reductive cyclodimerization via Ni catalysis was demonstrated in three distinct approaches of varying synthetic utility. Direct application of asymmetric reductive crosscoupling conditions to an NHP ester/alkenyl bromide afforded the corresponding head-totail cyclodimer as a single observable diastereomer, albeit in less than 10% yield. The proclivity for di-electrophile polymerization under these conditions inspired development of an unprecedented sequence of reductive polymerization and depolymerization/RCM to deliver the same macrocycle in increased yield with a high level of stereoselectivity. This discovery contributes [7.7]paracyclophanes as new macrocyclic monomers of reversible polymerization and is an exciting entry into the burgeoning field of chemical polymer recycling to monomers.150 Ultimately, use of Ni-catalyzed reductive Csp3–Csp2 cross-coupling to generate an enantioenriched diene monomer followed by CM/RCM furnished a paracyclophane in good yield. This approach led to the formal synthesis of (–)-cylindrocyclophane F (Figure 5.60). Key CM/RCM precursor 120 was synthesized in ten steps in the longest linear sequence from commercial or known materials and could be advanced to the natural product in two steps. Figure 5.60 Formal synthesis of (–)-cylindrocyclophane F via stereoselective RCC Me 6 steps HO 58 O Me I Me Me (+)-141 known TMS Br TMS 118 3 steps Br MeO MeO OMe Br 48 4 steps MeO OMe OtBu nBu 52 O OMe NHP nBu O 111 Ni MeO OMe nBu 120 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 486 5.8 EXPERIMENTAL SECTION 5.8.1 Materials and Methods Unless otherwise stated, reactions were performed under a N2 atmosphere with freshly dried solvents. Glassware was oven-dried at 120 °C for a minimum of four hours or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (DCM), acetonitrile (MeCN), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Diisopropylamine (iPr2NH), was distilled from calcium hydride prior to use and stored under N2. Unless otherwise stated, chemicals and reagents were used as received. Anhydrous tetrabutylammonium iodide, TBAPF6, sodium iodide (NaI), TDAE, trimethylsilyl bromide (TMSBr), trimethylsilyl chloride (TMSCl), lithium chloride (LiCl), tetrabutylammonium fluoride, N,N-dimethylacetamide (DMA), and triethylamine (Et3N) were purchased from SigmaAldrich. Manganese and zinc were purchased from Strem. All metal complexes, including Cp2ZrHCl, Pd(dppf)Cl2, NiBr2·diglyme, Ni(cod)2, Pd2dba3, [Ir(cod)(OMe)]2, and CuBr2, were purchased from Strem or Sigma-Aldrich and stored under N2. Reactions were monitored by liquid chromatography mass spectroscopy (LCMS) or by thin layer chromatography (TLC) using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm), visualized by UV (254 nm) and KMnO4, p-anisaldehyde, iodine, or CAM staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40–63 microns [230 to 400 mesh] (‘silica’) or 20–45 microns (‘extra-fine silica’)) purchased from Silicycle. 1H and 13C NMR spectra were recorded on a Bruker Advance III HD with Prodigy Cryoprobe (at 400 MHz and 101 MHz, respectively) or Varian Inova 500 (at 500 MHz and 126 MHz, respectively) and are reported relative to internal Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 487 CDCl3 (1H, δ = 7.26; 13C, δ = 77.16) or C6D6 (1H, δ = 7.16; 13C, δ = 128.06). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1); alternatively, a Thermo Scientific Nicolet iS5 FTIR Spectrometer FTIR-ATR was used to obtain FTIR-ATR spectra. Analytical chiral SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system (CO2 = 1450 psi, column temperature = 40 °C) with a Chiralcel OB–H column (4.6 mm x 25 cm). Analytical chiral GC was performed with a RESTEK Rt-bDEXse column (30 m, 0.32 mm/D, 0.25 um). HRMS data were acquired using an Agilent 6230 Series time-of-flight (TOF) mass spectrometer with an Agilent G1978A Multimode source in electrospray ionization (ESI) mode, by LC-MS using a Waters LCT Premier XE Electrospray TOF mass spectrometer interfaced with Waters UPLC chromatography, by GC-MS interfaced with a JEOL JMST2000 GC AccuTOF GC-Alpha with Field Ionization, or with Bruker Autoflex MALDI(TOF/TOF)-MS. Molecular formulas of the observed ion fragment of compounds are given (e.g., [M + H]+). Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. Gel permeation chromatography (GPC) was performed using an Agilent 1260 series pump equipped with two Agilent PLgel MIXEDB columns (7.5 x 300 mm), an Agilent 1200 series diode array detector, a Wyatt 18-angle DAWN HELEOS light scattering detector, and an Optilab rEX differential refractive index detector. The mobile phase was THF at a flow rate of 1 mL/min. Molecular weight and dispersity data are reported relative to polystyrene standards. 488 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.8.2 Single Reductive Cross-Coupling (E)-(((4-bromobut-3-en-1-yl)oxy)methyl)benzene (17) HO NaH TBAI, BnBr Br THF, 18 °C BnO Br To a flame-dried round bottom flask with a stir bar was added sodium hydride (361 mg, 14.3 mmol, 1.5 equiv), tetrabutylammonium iodide (35 mg, 0.1 mmol, 0.01 equiv), and THF (19.0 mL, 0.5 M). The mixture was stirred for 5 min, then (E)-4-bromobut-3-en-1ol151 (1.44 g, 9.5 mmol, 1 equiv) was added dropwise. After 5 min of stirring, benzyl bromide (1.3 mL, 10.9 mmol, 1.15 equiv) was added dropwise. After 16 h, the reaction was quenched with sat. aq. NH4Cl and was diluted with water and Et2O. The organic layer was separated, and the aqueous layer was extracted with Et2O thrice. Combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 5% EtOAc/hexanes) to afford 17 (1.95 g, 85% yield) as a yellow oil. 1 H NMR (CDCl3, 500 MHz): δ 7.44 – 7.28 (m, 5H), 6.23 (dt, J = 14.0, 7.1 Hz, 1H), 6.13 (dt, J = 13.6, 1.5 Hz, 1H), 4.52 (s, 2H), 3.52 (t, J = 6.5 Hz, 2H), 2.36 (qd, J = 6.7, 1.3 Hz, 2H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 138.3, 134.8, 128.6, 127.8, 106.2, 73.2, 68.8, 33.5. FTIR (NaCl, thin film, cm-1): 2908, 2857, 1621, 1453, 1362, 1103, 937, 736, 698. HRMS (FI, m/z): [M]+ calcd for C11H13OBr: 240.0150; found: 240.0157. 489 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 2-(2,6-dimethoxyphenyl)hexanoic acid (23) TFA MeO OMe DCM, 0 °C MeO OtBu nBu OMe OH nBu O O To a round bottom flask with a stir bar was added ester 50 (3.2 g, 10 mmol, 1 equiv) and DCM (86 mL, 0.12 M). The solution was cooled to 0 °C in an ice/water bath then TFA (86 mL, 0.12 M) was added dropwise. The red solution was warmed to ambient temperature over 18 h and then concentrated. The crude residue was azeotroped with PhMe to afford 23 (2.52 g, 96% yield) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 7.19 (t, J = 8.3 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.19 (dd, J = 8.9, 5.5 Hz, 1H), 3.79 (s, 6H), 2.09 (ddt, J = 13.3, 10.5, 5.2 Hz, 1H), 1.79 – 1.65 (m, 1H), 1.26 (ddddd, J = 12.6, 10.4, 5.5, 3.4, 1.8 Hz, 2H), 1.20 – 1.01 (m, 1H), 0.91 – 0.77 (m, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.1, 128.3, 117.0, 104.3, 55.9, 39.8, 29.7, 29.6, 22.8, 14.1. FTIR (NaCl, thin film, cm-1): 2955, 2935, 1702, 1594, 1474, 1250, 1115, 1100, 725. HRMS (FI-MS, m/z): [M]+ calcd for C14H20O4: 252.1356; found: 252.1249. 1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxyphenyl)hexanoate (18) MeO OMe OH nBu O NHP EDC·HCl, DMAP DCM, 0 to 18 °C MeO OMe O nBu O N O O To a round bottom flask with a stir bar was added acid 23 (1.0 g, 4 mmol, 1 equiv), Nhydroxyphthalimide (646 mg, 4 mmol, 1 equiv), DMAP (73 mg, 0.6 mmol, 0.15 equiv), Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 490 then DCM (40 mL, 0.1 M). The solution was cooled to 0 °C in an ice/water bath then EDC·HCl (836 mg, 4.4 mmol, 1.1 equiv) was added in portions. The reaction was stirred at 0 °C for 30 min and then concentrated. The crude residue was purified by column chromatography (silica, 20% EtOAc/hexanes) to afford 18 (1.25 g, 79% yield) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 7.84 (s,2), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 7.24 (t, J = 8.3 Hz, 1H), 6.59 (d, J = 8.4 Hz, 2H), 3.87 (s, 6H), 2.28 – 2.13 (m, 1H), 1.92 – 1.78 (m, 1H), 1.42 – 1.11 (m, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.3, 158.0, 134.6, 128.9, 123.8, 114.7, 103.8, 55.9, 37.9, 29.7, 29.2, 22.7, 14.1. FTIR (NaCl, thin film, cm-1): 3422, 2956, 2934, 1814, 1788, 1746, 1596, 1476, 1253, 1110, 966, 698. HRMS (FD, m/z): [M]+ calcd for C22H23NO6: 397.1525; found: 397.1522. 491 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F O NHP BnO Br + MeO nBu OMe O O N N L4 (20 mol %) NiBr2·diglyme (20 mol %) nBu BnO MeO OMe Mn0 (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), 23 °C General Procedure A (original order of addition): On the bench, a flame-dried ½dram vial with a stir bar and Teflon cap was sequentially charged with metal powder reductant (if applicable) (Zn0: 9.8 mg, 0.15 mmol, 3 equiv or Mn0: 8.2 mg, 0.15 mmol, 3 equiv), NaI (3.8 mg, 0.025 mmol, 0.5 equiv), ligand (CyBiOX (L4): 3.0 mg, 0.01 mmol, 0.2 equiv), and NHP ester 18 (19.9 mg, 0.05 mmol, 1 equiv). In a N2-filled glovebox, this vial was sequentially charged with DMA (84 µL), TDAE (if applicable) (35 µL, 0.15 mmol, 3 equiv), and TMSBr (7 µL, 0.05 mmol, 1 equiv) (fumed slightly), each via syringe. A solution of NiBr2·diglyme (3.5 mg, 0.01 mmol, 0.2 equiv) in DMA (84 µL, total 0.3 M) was added, followed by vinyl bromide 17 (12.1 mg, 0.05 mmol, 1 equiv), each by via syringe. The vial was sealed and then stirred at 1000 rpm outside the glovebox at ambient temperature. After 16 h, the reaction mixture was diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes. The filtrate was concentrated and assayed by quantitative 1H NMR. This sample was concentrated and purified by preparative thin layer chromatography (silica, 15% Et2O/hexanes) to afford 19, which was assayed by chiral SFC. 492 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F O NHP BnO Br + MeO nBu OMe O O N N L4 (20 mol %) NiBr2·diglyme (20 mol %) nBu BnO MeO OMe TDAE (3 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.3 M), 23 °C General Procedure B (optimized order of addition): In a N2-filled glovebox, a flamedried ½-dram vial with a stir bar and Teflon cap was sequentially charged with NaI (3.8 mg, 0.025 mmol, 0.5 equiv) and vinyl bromide 17 (12.1 mg, 0.05 mmol, 1 equiv). A solution of NiBr2·diglyme (3.5 mg, 0.01 mmol, 0.2 equiv) and ligand (CyBiOX (L4): 3.0 mg, 0.01 mmol, 0.2 equiv) in DMA (167 µL, 0.3 M) was added via syringe and the reaction stirred for 5 min. Then, NHP ester 18 (19.9 mg, 0.05 mmol, 1 equiv) was added, followed by sequential addition of TDAE (35 µL, 0.15 mmol, 3 equiv) and TMSBr (7 µL, 0.05 mmol, 1 equiv) (fumed slightly), each via syringe. The vial was sealed and then stirred at 1000 rpm outside the glovebox at ambient temperature. After 16 h, the reaction mixture was diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes. The filtrate was concentrated and assayed by quantitative 1H NMR. This sample was concentrated and purified by preparative thin layer chromatography (silica, 15% Et2O/hexanes) to afford 19, which was assayed by chiral SFC. 493 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F O O NHP BnO Br + MeO O N nBu N Ni OMe Br Br nBu BnO MeO OMe L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –7 °C General Procedure C: On the bench, a flame-dried ½-dram vial with a stir bar and Teflon cap was sequentially charged with NaI (3.8 mg, 0.025 mmol, 0.5 equiv) and NHP ester 18 (19.9 mg, 0.05 mmol, 1 equiv). In a N2-filled glovebox, the vial was charged sequentially with L1·NiBr275 (2.9 mg, 0.005 mmol, 0.1 equiv) then DMA (50 µL, 1 M) and vinyl bromide 17 (12.1 mg, 0.05 mmol, 1 equiv), each via syringe. The vial was placed in a temperature-controlled well plate in the glovebox and then cooled to –7 °C. The mixture was stirred at 250 rpm until all reagents fully dissolved. (Note: the recirculating Julabo LH45 chiller was set to –7 °C but an external thermometer in the glovebox read the temperature as –1 °C.) Then, TDAE (17 µL, 0.075 mmol, 1.5 equiv) was added and the solution stirred for 10 min before TMSBr (7 µL, 0.05 mmol, 1 equiv) (fumed slightly) was added, each via syringe. The reaction was stirred at the chilled temperature in the glovebox. After 16 h, the reaction mixture was diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes. The filtrate was concentrated and assayed by quantitative 1H NMR. This sample was concentrated and purified by preparative thin layer chromatography (silica, 15% Et2O/hexanes) to afford 19, which was assayed by chiral SFC. Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 494 (S,E)-2-(1-(benzyloxy)non-3-en-5-yl)-1,3-dimethoxybenzene (19) nBu BnO MeO 1 OMe H NMR (CDCl3, 400 MHz): δ 7.39 – 7.21 (m, 5H), 7.10 (t, J = 8.3 Hz, 1H), 6.53 (d, J = 8.3 Hz, 2H), 5.97 (ddt, J = 15.3, 8.4, 1.4 Hz, 1H), 5.43 (dtd, J = 15.1, 6.9, 1.0 Hz, 1H), 4.49 (s, 2H), 3.94 (q, J = 7.9 Hz, 1H), 3.78 (s, 6H), 3.47 (t, J = 7.1 Hz, 2H), 2.31 (qt, J = 7.1, 1.3 Hz, 2H), 1.74 (q, J = 7.6 Hz, 2H), 1.38 – 1.14 (m, 3H), 1.14 – 1.01 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.5, 138.8, 135.5, 128.5, 127.8, 127.6, 126.9, 125.5, 121.8, 104.8, 72.9, 70.6, 56.0, 39.0, 33.3, 33.3, 30.5, 22.8, 14.3. FTIR (NaCl, thin film, cm-1): 2953, 2927, 2855, 1591, 1471, 1248, 1097, 972, 727, 696. HRMS (TOF-MS, m/z): [M + H]+ calcd for C24H33O3: 369.2424; found: 369.2431. –1 (c = 1.5, CHCl3). Chiral SFC: (OB–H, 2.5 mL/min, 3% IPA/CO2, λ = 210 nm); tR (major) = 9.8 min, tR (minor) = 14.0 min. Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 19: racemic nBu BnO MeO OMe (–)-19: enantioenriched (84% ee) nBu BnO MeO OMe 495 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 496 (E)-1,3-dimethoxy-2-(pent-1-en-1-yl)benzene (20) Me MeO 1 OMe H NMR (CDCl3, 500 MHz): δ 7.10 (t, J = 8.3 Hz, 1H), 6.64 – 6.56 (m, 2H), 6.55 (d, J = 8.3 Hz, 2H), 3.84 (d, J = 0.7 Hz, 6H), 2.28 – 2.19 (m, 2H), 1.51 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.3, 135.8, 127.2, 121.3, 120.1, 104.2, 55.9, 37.0, 23.0, 14.0. 2,2'-(decane-5,6-diyl)bis(1,3-dimethoxybenzene) (21) MeO nBu MeO OMe nBu OMe Diastereomer 21a 1 H NMR (CDCl3, 400 MHz): δ 6.85 (t, J = 8.2 Hz, 1H), 6.26 – 6.18 (m, 2H), 3.85 – 3.78 (m, 1H), 3.63 (s, 3H), 3.53 (s, 3H), 1.94 (dtd, J = 13.1, 10.8, 5.2 Hz, 1H), 1.81 – 1.69 (m, 1H), 1.40 – 1.14 (m, 3H), 1.14 – 0.91 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 159.5, 158.9, 125.7, 121.8, 103.1, 102.8, 55.6, 54.8, 51.5, 38.8, 31.9, 30.9, 23.3, 14.4. Diastereomer 21b 1 H NMR (CDCl3, 400 MHz): δ 7.12 (t, J = 8.2 Hz, 1H), 6.56 (ddd, J = 9.5, 8.2, 1.0 Hz, Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 497 2H), 4.07 (dt, J = 8.2, 2.7 Hz, 1H), 3.83 (d, J = 2.5 Hz, 6H), 1.85 – 1.67 (m, 1H), 1.19 – 0.90 (m, 3H), 0.91 – 0.75 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 160.1, 160.0, 126.4, 122.8, 104.9, 104.9, 56.7, 55.6, 37.4, 30.9, 30.6, 22.7, 14.2. 1,3-dimethoxy-2-pentylbenzene (22) nBu MeO 1 OMe H NMR (CDCl3, 500 MHz): δ 7.10 (t, J = 8.3 Hz, 1H), 6.53 (d, J = 8.3 Hz, 2H), 3.80 (s, 6H), 2.66 – 2.58 (m, 2H), 1.51 – 1.41 (m, 2H), 1.32 (q, J = 3.6 Hz, 4H), 0.88 (t, J = 7.1 Hz, 3H). (3E,5E)-1,8-bis(benzyloxy)octa-3,5-diene (24) OBn BnO 1 H NMR (CDCl3, 400 MHz): δ 7.39 – 7.23 (m, 5H), 6.14 – 6.02 (m, 1H), 5.66 – 5.55 (m, 1H), 4.51 (s, 2H), 3.50 (t, J = 6.8 Hz, 2H), 2.39 (q, J = 6.8 Hz, 2H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 132.1, 129.0, 127.8, 127.7, 73.1, 70.0, 33.2. ((but-3-en-1-yloxy)methyl)benzene (25) BnO 1 H NMR (CDCl3, 500 MHz): δ 7.40 – 7.23 (m, 5H), 5.85 (td, J = 17.1, 7.0 Hz, 1H), 5.11 (d, J = 17.1 Hz, 1H), 5.05 (d, J = 10.3 Hz, 1H), 4.53 (s, 2H), 3.57 – 3.50 (m, 2H), 2.39 (q, J = 6.8 Hz, 2H). 498 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (E)-(((4-chlorobut-3-en-1-yl)oxy)methyl)benzene (42) Ni(cod)2 (10 mol %) LiCl (3 equiv) BnO BnO Br Cl THF/DMA (3:1, 0.25 M) 23 °C, 24 h Prepared following a modified procedure:87 In a N2-filled glovebox, a 2-dram vial with a stir bar and Teflon cap was sequentially charged with Ni(cod)2 (14.2 mg, 0.051 mmol, 0.1 equiv), LiCl (64.4 mg, 1.52 mmol, 5 equiv.), THF (1.5 mL), and DMA (0.5 mL). The mixture was stirred for a short stir period (ca. 1 min), then alkenyl bromide 17 (72.3 mg, 0.3 mmol, 1 equiv) was added dropwise via syringe. Outside of the glovebox, the reaction was stirred at 800 rpm at 23 °C. A baby blue reaction color appeared after ca. 30 min. After 23 h, the crude mixture was directly filtered over a plug of silica, eluting with 20% EtOAc/hexanes. The crude residue was purified by column chromatography (silica, 5% EtOAc/hexanes) to afford 42 as a pale yellow oil with 10% of unreacted 17, which was inseparable. 1 H NMR (CDCl3, 500 MHz): δ 7.40 (m, 4H), 7.35 (td, J = 6.4, 2.0 Hz, 1H), 6.10 (dt, J = 13.3, 1.4 Hz, 1H), 4.58 (s, 2H), 3.57 (t, J = 6.5 Hz, 2H), 2.43 (qd, J = 6.6, 1.3 Hz, 2H). General Procedure D: O HO N O MeO OMe OH nBu O R EDC·HCl, DMAP DCM, 18 °C MeO OMe O nBu O N O O R To a round bottom flask with a stir bar was added acid 23 (93.4 mg, 0.37 mmol, 1 equiv), commercial NHP derivative (0.37 mmol, 1 equiv), DMAP (6.7 mg, 0.055 mmol, 0.15 equiv), then DCM (3.7 mL, 0.1 M). To this solution was added EDC·HCl (78.0 mg, 499 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 0.407 mmol, 1.1 equiv) in portions. The reaction was stirred at ambient temperature. After 24 h, the reaction was concentrated. The crude residue was purified by column chromatography (silica, 20% EtOAc/hexanes) to afford 43– 46 as amorphous solids. 5-methyl-1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxyphenyl)hexanoate (45) MeO OMe O nBu O N O Me O Prepared following General Procedure D in 91% yield. 1 H NMR (CDCl3, 500 MHz): δ 7.77 (br. s, 1H), 7.69 (d, J = 11.3 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 8.3 Hz, 2H), 4.58 (dd, J = 8.9, 5.3 Hz), 3.92 (s, 6H), 2.56 (s, 3H), 2.25 (ddt, J =13.4, 10.6, 5.3 Hz, 1H), 1.91 (dtd, J = 14.1, 9.3, 5.2 Hz, 1H), 1.36 (m, 2H), 1.23 (tdd, J = 12.5, 5.9, 3.5 Hz, 1H), 0.92 (t, J = 6.9 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.3, 157.9, 145.9, 134.9, 128.8, 124.2, 123.6, 114.6, 103.6, 55.7, 37.8, 29.6, 29.1, 22.6, 22.1, 14.0. 5-methoxy-1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxyphenyl)hexanoate (43) MeO OMe O nBu O O O N OMe Prepared following General Procedure D in 94% yield. 1 H NMR (CDCl3, 500 MHz): δ 7.80 (br. s, 1H), 7.37 (d, J = 8.1Hz, 1H), 7.30 (m, 1H), 7.23 (dd, J = 8.3, 2.3 Hz, 1H), 6.64 (d, J = 8.3 Hz, 2H), 4.57 (dd, J = 8.9, 5.3 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 6H), 2.25 (ddt, J = 13.4, 10.6, 5.2 Hz, 1H), 1.91 (dtd, J = 13.9, 9.2, 500 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.0 Hz, 1H), 1.37 (m, 2H), 1.23 (m, 1H), 0.92 (t, J = 6.9 Hz). 13 C{1H} NMR (CDCl3, 126 MHz): δ 171.3, 164.9, 157.9, 128.7, 120.0, 114.6, 108.6, 103.6, 56.1, 37.7, 29.6, 29.1, 22.6, 14.0. 5-chloro-1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxyphenyl)hexanoate (44) MeO OMe O nBu O N O Cl O Prepared following General Procedure D in 97% yield. 1 H NMR (CDCl3, 500 MHz): δ 7.85 (q, J = 9.9, 8.1 Hz, 2H), 7.77 (dd, J = 7.94, 1.84 Hz, 1H), 7.31 (m, 1H), 6.65 (d, J = 8.3 Hz, 2H), 4.58 (dd, J = 8.9, 5.3 Hz, 1H), 3.92 (s, 6H), 2.24 (ddt, J = 13.4, 10.5, 5.2 Hz, 1H), 1.91 (dtd, J = 14.0, 9.1, 5.1 Hz, 1H), 1.37 (m, 2H), 1.23 (dddd, J = 14.5, 12.0, 5.9, 3.5 Hz, 1H), 0.92 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.1, 157.9, 141.2, 134.5, 128.8, 125.0, 124.2, 114.4, 103.6, 55.7, 37.7, 29.6, 29.1, 22.6, 13.9. 5-bromo-1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxyphenyl)hexanoate (46) MeO OMe O nBu O O O N Br Prepared following General Procedure D in 89% yield. 1 H NMR (CDCl3, 500 MHz): δ 8.03 (d, J = 10.0 Hz, 1H), 7.94 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 8.3 Hz, 2H), 4.57 (dd, J = 8.9, 5.3 Hz), 3.92 (s, 6H), 2.24 (ddt, J = 13.4, 10.6, 5.3 Hz, 1H), 1.91 (dtd, J = 14.0, 9.2, 5.1 Hz, 1H), Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 501 1.36 (m, 2H), 1.23 (dddd, J = 11.7, 9.6, 8.4, 6.4 Hz, 1H), 0.92 (td, J = 7.1, 2.3 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.1, 157.9, 137.5, 128.8, 127.0, 125.1, 114.4, 103.6, 55.7, 37.7, 29.6, 29.1, 22.6, 14.0. Determination of NHP ester derivative reduction potential MeO OMe O nBu O N O O R Cyclic voltammograms (CV) were obtained at an analyte concentration of 10 mM and a supporting electrolyte concentration of 0.1 M TBAPF6 in electrochemical grade DMA (Sigma-Aldrich). A glassy carbon working electrode, graphite counter electrode, and silver wire pseudo-reference electrode were employed, and data was collected using a Biologic SP-300 potentiostat. All cyclic voltammograms were normalized by adding 1 equivalent of sublimed ferrocene (relative to analyte) and collecting new CV. The ½wave potential of the Fc/Fc+ peak was identified and set to 0.0 V. 502 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F R = H (18), 100 mV scan rate 0.05 Current (mA) 0 -0.05 -0.1 -0.15 -2.5 -0.2 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Potential vs Fc/Fc+ (V) R = Me (45), 100 mV scan rate 0.01 0.005 Current (mA) 0 -0.005 -0.01 -0.015 -0.02 -3 -0.025 -2.5 -2 -1.5 -1 -0.5 Potential vs Fc/Fc+ (V) 0 0.5 1 1.5 503 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F R = OMe (43), 150 mV scan rate 0.02 0.01 Current (mA) 0 -0.01 -0.02 -0.03 -0.04 -0.05 -3 -0.06 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1 1.5 Potential vs Fc/Fc+ (V) R = Br (46), 100 mV scan rate 0.02 0.01 Current (mA) 0 -0.01 -0.02 -0.03 -3 -0.04 -2.5 -2 -1.5 -1 -0.5 Potential vs Fc/Fc+ (V) 0 0.5 504 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F R = Cl (44), 150 mV scan rate 0.02 0.01 0 Current (mA) -0.01 -0.02 -0.03 -0.04 -0.05 -0.06 -0.07 -3 -0.08 -2.5 -2 -1.5 -1 -0.5 0 0.5 1 1.5 Potential vs Fc/Fc+ (V) 5.8.3 Synthesis of Dimerization Substrates tert-butyl 2-(2,6-dimethoxyphenyl)acetate (121) tBuOAc (2 equiv) Pd2dba3 (3 mol %) PtBu3 (6 mol %) MeO OMe Br LHMDS (3.3 equiv) PhMe, 18 °C MeO OMe OtBu O Prepared following a modified procedure:97 In a N2-filled glovebox, Pd2dba3 (1.37 g, 1.5 mmol, 0.03 equiv), tri-tert-butylphosphine (606 mg, 3 mmol, 0.06 equiv), and 2-bromo1,3-dimethoxybenzene (10.8 g, 50 mmol, 1 equiv) were added to a flame-dried round bottom flask with a stir bar. Also in the glovebox, LiHMDS (27.6 g, 165 mmol, 3.3 equiv) was added to a separate flame-dried round bottom flask with a stir bar. Both flasks were sealed and removed from the glovebox. To the first flask was added PhMe (125 mL, 505 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 0.2 M total); the solution was stirred at ambient temperature for 20 min. To the second flask was added PhMe (125 mL, 0.2 M total); the solution was cooled to 0 °C in an ice/water bath, then tert-butyl acetate (13.4 mL, 100 mmol, 2 equiv) was added dropwise. This solution was stirred for 20 min at 0 °C and then transferred to the first flask via cannula. The reaction was stirred at ambient temperature for 24 h. Upon complete consumption of the aryl bromide, the reaction was quenched with sat. aq. NH4Cl (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 7% EtOAc/hexanes) to afford 121 (9.96 g, 79% yield) as an amorphous white solid. 1 H NMR (CDCl3, 400 MHz): δ 7.18 (t, J = 8.3 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 3.80 (s, 6H), 3.60 (s, 2H), 1.44 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.8, 158.5, 128.1, 112.4, 103.8, 80.1, 55.9, 30.2, 28.2. FTIR (NaCl, thin film, cm-1): 2979, 2968, 2839, 1736, 1599, 1475, 1339, 1142, 1104, 784. HRMS (FI-MS, m/z): [M]+ calcd for C14H20O4: 252.13561; found: 252.1345. tert-butyl 2-(2,6-dimethoxyphenyl)hexanoate (50) Procedure 1: nBuBr LHMDS MeO OMe OtBu O THF, –78 °C MeO OMe OtBu nBu O To a flame-dried round bottom flask with a stir bar was added ester 121 (2.46 g, 9.8 506 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F mmol, 1 equiv) and THF (101 mL, 0.1 M). The solution was cooled to –78 °C in a dry ice/acetone bath, and LiHMDS (1 M in THF, 17.8 mL, 17.8 mmol, 1.8 equiv) was added dropwise. The reaction was stirred for 1.5 h and then warmed to 0 °C followed by dropwise addition of 1-bromobutane (1.92 mL, 17.8 mmol, 1.8 equiv). The reaction was stirred while warming to ambient temperature and monitored by TLC. Upon complete consumption of the ester, the reaction was quenched with slow addition of water then the layers separated. The aqueous layer was extracted with EtOAc thrice. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 7% EtOAc/hexanes) to afford 50 (2.31 g, 77% yield) as a yellow oil. Procedure 2: 1. tBuOAc (2 equiv) Pd2dba3 (3 mol %) PtBu3 (6 mol %) LHMDS (3.3 equiv) PhMe, 18 °C MeO OMe Br 2. nBuBr, LHMDS THF, –78 °C MeO OMe OtBu nBu O Step 1: Prepared following a modified procedure:97 In a N2-filled glovebox, Pd2dba3 (1.37 g, 1.5 mmol, 0.03 equiv), tri-tert-butylphosphine (606 mg, 3 mmol, 0.06 equiv), and 2-bromo-1,3-dimethoxybenzene (10.8 g, 50 mmol, 1 equiv) were added to a flame-dried round bottom flask with a stir bar. Also in the glovebox, LiHMDS (27.6 g, 165 mmol, 3.3 equiv) was added to a separate flame-dried round bottom flask with a stir bar. Both flasks were sealed and removed from the glovebox. To the first flask was added PhMe (125 mL, 0.2 M total); the solution was stirred at ambient temperature for 20 min. To the second flask was added PhMe (125 mL, 0.2 M total); the solution was cooled to 0 °C in an ice/water bath, then tert-butyl acetate (13.4 mL, 100 mmol, 2 equiv) was added Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 507 dropwise. This solution was stirred for 20 min at 0 °C and then transferred to the first flask via cannula. The reaction was stirred at ambient temperature for 24 h. Upon complete consumption of the aryl bromide, the reaction was quenched with sat. aq. NH4Cl (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc twice. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was used directly in the next step without purification. Step 2: To a flame-dried round bottom flask with a stir bar was added the crude residue (1 equiv) as a solution in THF (250 mL, 0.2 M). The solution was cooled to –78 °C in a dry ice/acetone bath, and LiHMDS (1 M in THF, 75.0 mL, 75 mmol, 1.5 equiv) was added slowly. The reaction was stirred for 1 h and then warmed to 0 °C followed by dropwise addition of 1-bromobutane (8.0 mL, 75 mmol, 1.5 equiv). The reaction was allowed to warm to ambient temperature. After 17 h, the reaction was quenched with slow addition of sat. aq. NH4Cl, diluted with Et2O, then the layers separated. The aqueous layer was extracted with Et2O. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 1 to 20% EtOAc/hexanes) to afford 50 (10.2 g, 66% yield over 2 steps) as a yellow oil. 1 H NMR (CDCl3, 500 MHz): δ 7.15 (t, J = 8.3 Hz, 1H), 6.52 (d, J = 8.3 Hz, 2H), 4.02 (dd, J = 9.1, 5.3 Hz, 1H), 3.78 (s, 6H), 2.07 (ddt, J = 13.5, 10.6, 5.4 Hz, 1H), 1.66 (dddd, J = 13.2, 9.7, 9.0, 5.2 Hz, 1H), 1.37 (s, 9H), 1.36 – 1.16 (m, 2H), 1.12 – 1.00 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.4, 158.1, 127.5, 118.5, 103.9, 79.5, 55.7, 41.0, 508 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 29.9, 29.8, 28.14, 22.9, 14.2. FTIR (NaCl, thin film, cm-1): 2953, 2870, 2837, 1731, 1594, 1455, 1249, 1163, 1119, 853, 724. HRMS (FI-MS, m/z): [M]+ calcd for C18H28O4: 308.1982; found: 308.1978. tert-butyl 2-(2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)hexanoate (51) Me Me O Me Me B O [Ir(cod)OMe]2 tmphen B2pin2 MeO OMe OtBu nBu O THF, 80 °C MeO OMe OtBu nBu O Prepared following a modified procedure:98 In a N2-filled glovebox, [Ir(cod)(OMe)]2 (50 mg, 0.08 mmol, 0.01 equiv) and 3,4,7,8-tetramethyl-1,10-phenanthroline (35 mg, 0.15 mmol, 0.02 equiv) were added to a flame-dried round bottom flask with a stir bar. THF (10.0 mL, 0.67 M total) was then added and the dark green mixture was stirred for 1 h. To this mixture was added a solution of ester 50 (2.31 g, 7.5 mmol, 1 equiv) in THF (1.0 mL, 0.67 M total) followed by B2pin2 (3.8 g, 15 mmol, 2 equiv). The flask was sealed, removed from the glovebox, and stirred while heating to 80 °C in an oil bath. Upon complete consumption of the ester, as judged by TLC, the reaction was allowed to reach ambient temperature and then concentrated. The crude residue was purified by column chromatography (silica, 5 to 7% EtOAc/hexanes) to afford 51 (2.94 g, 91% yield) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 6.95 (s, 2H), 4.03 (dd, J = 9.2, 5.2 Hz, 1H), 3.82 (s, 6H), 509 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 2.06 (ddt, J = 14.7, 10.4, 5.2 Hz, 1H), 1.65 (dh, J = 14.4, 5.2 Hz, 1H), 1.36 (d, J = 2.0 Hz, 14H), 1.35 (s, 8H), 1.33 – 1.14 (m, 2H), 1.04 (td, J = 12.1, 10.8, 5.1 Hz, 1H), 0.82 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.2, 157.6, 121.9, 109.8, 84.0, 79.5, 55.8, 41.1, 29.78, 29.7, 28.1, 25.1, 25.0, 22.9, 14.2. 11 B NMR (CDCl3, 128 MHz): δ 30.6. FTIR (NaCl, thin film, cm-1): 2976, 2936, 1731, 1406, 1366, 1146, 1128, 968. HRMS (FI-MS, m/z): [M]+ calcd for C24H39BO6: 434.2834; found: 434.2825. Me Me O Me Me B Me Me O O Me Me B O Br CuBr2 MeO OMe OtBu nBu O aq. MeOH 100 °C MeO OMe OH nBu O + MeO OMe OtBu nBu O Prepared from boronic ester 51 (950 mg, 2.2 mmol, 1 equiv), CuBr2 (488 mg, 2.2 mmol, 1 equiv), and MeOH/water (1:1, 0.04 M) following a published procedure.98 The crude mixture in a minimum amount of EtOAc was triturated with cold hexanes to afford acid 122 as a white solid. The supernatant was concentrated and purified by column chromatography (silica, 2% EtOAc/hexanes) to afford ester 52 (673 mg, 79% yield) as a pale yellow amorphous solid. 2-(2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)hexanoic acid (122) 1 H NMR (DMSO-d6, 400 MHz): δ 11.74 (s, 1H), 6.87 (s, 2H), 6.86 – 6.81 (m, 0H), 3.92 510 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (dd, J = 9.2, 5.3 Hz, 1H), 3.74 (s, 6H), 1.97 (ddt, J = 13.2, 10.3, 5.4 Hz, 1H), 1.58 (dtd, J = 14.2, 9.3, 5.2 Hz, 1H), 1.30 (s, 13H), 1.27 – 1.20 (m, 0H), 1.20 – 1.05 (m, 3H), 0.95 (tdd, J = 12.1, 9.5, 4.7 Hz, 1H), 0.78 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (DMSO-d6, 101 MHz): δ 174.8, 157.3, 121.0, 109.6, 83.8, 55.8, 29.2, 24.7, 24.6, 22.1, 13.9. FTIR (ATR, cm-1): 2932, 2360, 1704, 1405, 11364, 1127. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C20H31BO6: 378.2323; found: 378.2337. tert-butyl 2-(4-bromo-2,6-dimethoxyphenyl)hexanoate (52) 1 H NMR (CDCl3, 400 MHz): δ 6.67 (s, 2H), 3.95 (dd, J = 9.3, 5.2 Hz, 1H), 3.76 (s, 6H), 2.03 (ddt, J = 13.3, 10.3, 5.3 Hz, 1H), 1.69 – 1.55 (m, 1H), 1.36 (s, 9H), 1.33 – 1.10 (m, 2H), 1.02 (dddd, J = 16.5, 12.8, 8.9, 5.3 Hz, 1H), 0.82 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.8, 158.5, 120.6, 117.5, 107.8, 79.7, 55.9, 40.8, 29.8, 29.5, 28.1, 22.8, 14.2. FTIR (NaCl, thin film, cm-1): 2959, 2936, 1731, 1584, 1405, 1166, 1157, 1127, 816. HRMS (FI-MS, m/z): [M]+ calcd for C18H27BrO4: 386.1087; found: 386.1074. 2-(4-bromo-2,6-dimethoxyphenyl)hexanoic acid (123) Me Me O Me Me B O Br CuBr2 MeO OMe OtBu nBu O aq. MeOH 100 °C MeO OMe OH nBu O Prepared following a modified procedure:98 To a three-neck flask with reflux condenser 511 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F and stir bar was added CuBr2 (9.02 g, 40.4 mmol, 3 equiv) and water (135 mL, 0.05 M). To this mixture was added boronic ester 51 (5.85 g, 13.5 mmol, 1 equiv) as a solution in MeOH (135 mL, 0.05 M), then the reaction was stirred while heating to 100 °C in an oil bath and monitored by LCMS. Upon complete conversion to acid 123, the reaction was allowed to reach ambient temperature and diluted with excess sat. aq. NH4Cl (until all solids dissolved). Following extraction thrice with Et2O, the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 50% EtOAc/hexanes) to afford 123 (3.68 g, 83% yield) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 6.73 (s, 2H), 4.13 (dd, J = 9.1, 5.3 Hz, 1H), 3.81 (s, 6H), 2.09 (ddt, J = 13.3, 10.3, 5.3 Hz, 1H), 1.78 – 1.64 (m, 1H), 1.44 – 1.16 (m, 3H), 1.16 – 0.98 (m, 1H), 0.85 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 178.8, 158.6, 121.5, 116.2, 108.2, 56.2, 39.6, 29.7, 29.5, 22.8, 14.2. FTIR (ATR, cm-1): 3215, 2646, 1700, 1582, 1453, 1404, 1220, 1124, 1099, 843, 811. 5012-c2 HRMS (FD-MS, m/z): [M]+ calcd for C14H19BrO4: 330.0461; found: 330.0471. (6-iodohex-1-yn-1-yl)trimethylsilane (54) Cl 1. nBuLi, TMSCl THF, –78 to 18 °C 2. NaI acetone, reflux I TMS Step 1: Prepared from 6-chlorohex-1-yne (22.0 mL, 182 mmol, 1 equiv), TMSCl (25.3 mL, 200 mmol, 1.1 equiv), nBuLi (2.0 M in hexanes, 100 mL, 200 mmol, 1.1 equiv), and THF (363 mL, 0.5 M) following a published procedure152 to afford the alkyne 512 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F intermediate. Spectra matched those reported in the literature.153,154 Step 2: Prepared from the protected alkyne intermediate (14.1 g, 74.6 mmol, 1 equiv), sodium iodide (67.1 g, 448 mmol, 6 equiv), and acetone (186 mL, 0.4 M) following a published procedure155 to afford 54 (19.6 g, 93% yield over 2 steps) as a colorless oil. Spectra matched those reported in the literature.155 1 H NMR (CDCl3, 400 MHz): δ 3.22 (t, J = 6.9 Hz, 2H), 2.26 (t, J = 7.0 Hz, 2H), 1.94 (p, J = 7.0 Hz, 2H), 1.63 (p, J = 7.1 Hz, 2H), 0.15 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 106.6, 85.4, 32.5, 29.3, 19.0, 6.4, 0.3. tert-butyl 2-(2,6-dimethoxy-4-(6-(trimethylsilyl)hex-5-yn-1-yl)phenyl)hexanoate (55) Br TMS nBuLi THF, –78 °C MeO then OMe OtBu nBu O MeO I OMe OtBu nBu to 18 °C TMS O To a flame-dried round bottom flask with a stir bar was added aryl bromide 52 (60 mg, 0.16 mmol, 1 equiv) and THF (0.78 mL, 0.2 M). The solution was cooled to –78 °C in a dry ice/acetone bath, then nBuLi (2.5 M in hexanes, 0.075 mL, 0.19 mmol, 1.2 equiv) was added dropwise. The reaction was stirred at –78 °C for 30 min, then alkyl iodide 54 (87 mg, 0.31 mmol, 2 equiv) was added via syringe, and the reaction was allowed to warm to ambient temperature and then stir for 5 h before being quenched with sat. aq. NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc thrice. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 2% Et2O/hexanes) to afford 55 (51 mg, 71% yield) as a colorless oil. 513 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1 H NMR (CDCl3, 400 MHz): δ 6.34 (s, 2H), 3.96 (dd, J = 8.9, 5.4 Hz, 1H), 3.75 (s, 6H), 2.63 – 2.55 (m, 2H), 2.26 (t, J = 7.1 Hz, 2H), 2.11 – 1.98 (m, 1H), 1.74 (tt, J = 9.0, 6.7 Hz, 2H), 1.69 – 1.49 (m, 6H), 1.33 – 1.14 (m, 3H), 1.06 (qd, J = 11.9, 10.8, 7.2 Hz, 1H), 0.83 (t, J = 7.0 Hz, 3H), 0.15 (s, 8H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.5, 157. 9, 142.1, 115.8, 104.1, 79.4, 55.7, 40.9, 36.1, 30.5, 30.0, 28.4, 28.2, 22.9, 19.9, 14.2, 0.3. FTIR (ATR, cm-1): 3000, 2171, 1726, 1455, 1248, 1157, 1122, 841. HRMS (FI-MS, m/z): [M]+ calcd for C27H44O4Si: 460.3003; found: 460.2989. tert-butyl 2-(4-(hex-5-yn-1-yl)-2,6-dimethoxyphenyl)hexanoate (124) TMS TBAF MeO OMe OtBu nBu THF, 18 °C MeO OMe OtBu nBu O O To a flame-dried round bottom flask with a stir bar was added protected alkyne 55 (60 mg, 0.09 mmol, 1 equiv) followed by THF (4.3 mL, 0.02 M) then tetrabutylammonium fluoride (0.048 mL, 0.17 mmol, 2 equiv). The reaction was stirred at ambient temperature for 5 min and then quenched with sat. aq. Na2HCO3. The layers were separated, and combined organics were washed with water thrice, dried over Na2SO4, filtered, and concentrated to afford 124 (33 mg, 99% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.34 (s, 2H), 3.95 (dt, J = 8.6, 4.3 Hz, 1H), 3.75 (s, 6H), 2.64 – 2.55 (m, 2H), 2.23 (td, J = 7.1, 2.7 Hz, 2H), 2.04 (ddt, J = 13.4, 10.5, 5.4 Hz, 1H), 1.95 (t, J = 2.6 Hz, 1H), 1.82 – 1.69 (m, 2H), 1.69 – 1.56 (m, 6H), 1.36 (s, 9H), 1.34 – 1.15 (m, 3H), 1.11 – 1.00 (m, 1H), 0.83 (t, J = 7.0 Hz, 3H). 514 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.5, 157.9, 141.9, 115.9, 104.1, 84.6, 79.4, 68.5, 66.0, 55.7, 40.9, 36.1, 30.4, 29.9, 29.9, 28.3, 28.2, 22.9, 18.5, 15.4, 14.2. FTIR (ATR, cm-1): 2962, 2875, 2359, 2323, 1574, 1462, 1401, 1250, 1156, 1123, 1010, 735. HRMS (FD, m/z): [M]+ calcd for C24H36O4: 388.2614; found: 388.2618 tert-butyl (E)-2-(4-(6-bromohex-5-en-1-yl)-2,6-dimethoxyphenyl)hexanoate (56) Br Cp2ZrHCl PhH, 18 °C MeO OMe OtBu nBu O then NBS MeO OMe OtBu nBu O Prepared from alkyne 124 (34 mg, 0.09 mmol, 1 equiv), Cp2ZrHCl (28 mg, 0.1 mmol, 1.25 equiv), N-bromosuccinimide (19 mg, 0.1 mmol, 1.25 equiv), and PhH (0.87 mL, 0.1 M) following a published procedure156 to afford 56 (41 mg, 82% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 2H), 6.17 (dt, J = 14.2, 7.2 Hz, 1H), 6.05 – 5.98 (m, 1H), 3.96 (dd, J = 9.0, 5.3 Hz, 1H), 3.76 (d, J = 0.6 Hz, 6H), 2.61 – 2.54 (m, 2H), 2.13 – 2.00 (m, 2H), 1.64 (p, J = 7.7 Hz, 3H), 1.51 – 1.42 (m, 2H), 1.37 (d, J = 0.7 Hz, 9H), 1.34 – 1.17 (m, 1H), 1.12 – 1.02 (m, 1H), 0.84 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.5, 157.9, 142.0, 138.1, 115.9, 104.4, 104.1, 79.4, 55.7, 40.9, 36.4, 32.9, 30.7, 30.0, 29.9, 28.4, 28.2, 28.0, 22.9, 14.2. 515 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1,3-dioxoisoindolin-2-yl (E)-2-(4-(6-bromohex-5-en-1-yl)-2,6dimethoxyphenyl)hexanoate (57) Br Br 1. TFA, DCM, 0 to 18 °C MeO OMe OtBu nBu O 2. NHP EDC·HCl, DMAP DCM, 18 °C MeO OMe O nBu O N O O Step 1: To a round bottom flask with a stir bar was added ester 56 (33 mg, 0.07 mmol, 1 equiv) and DCM (0.7 mL, 0.1 M). The solution was cooled to 0 °C in an ice/water bath, then trifluoroacetic acid (0.054 mL, 10 equiv) was added dropwise. The solution was warmed to 18 °C over 1 hour and then concentrated. The crude residue was azeotroped with PhMe to afford the acid intermediate (29 mg). Step 2: To a round bottom flask with a stir bar was added the acid intermediate (29 mg, 0.07 mmol, 1 equiv), N-hydroxyphthalimide (12 mg, 0.07 mmol, 1 equiv), DMAP (1.7 mg, 0.01 mmol, 0.2 equiv), then DCM (0.35 mL, 0.2 M). Then EDC·HCl (15 mg, 0.08 mmol, 1.1 equiv) was added in one portion. The reaction was stirred at 18 °C overnight and then concentrated. The crude residue was purified by preparative thin layer chromatography (silica, 40% Et2O/hexanes) to afford 57 (25 mg, 63% yield over 2 steps) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 7.84 (t, J = 4.3 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 6.18 (dt, J = 14.1, 7.2 Hz, 1H), 6.07 – 5.98 (m, 1H), 4.47 (dd, J = 8.8, 5.4 Hz, 1H), 3.85 (s, 6H), 2.60 (t, J = 7.8 Hz, 2H), 2.17 (ddt, J = 13.4, 10.5, 5.3 Hz, 1H), 2.09 (qd, J = 7.3, 1.3 Hz, 2H), 1.83 (ddp, J = 13.7, 9.0, 4.9, 4.4 Hz, 1H), 1.72 – 1.61 (m, 2H), 1.47 (dq, J = 13.1, 6.7, 5.8 Hz, 2H), 1.41 – 1.21 (m, 3H), 0.86 (t, J = 6.9 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.5, 157.8, 143.6, 138.1, 134.6, 129.2, 123.8, 516 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 112.1, 104.5, 103.9, 55.8, 37.8, 36.6, 33.0, 30.7, 29.9, 29.3, 28.5, 22.7, 14.1. FTIR (ATR, cm-1): 2933, 2857, 1788, 1745, 1587, 1462, 1119, 697. HRMS (FD, m/z): [M]+ calcd for C28H32NO6Br: 557.1413; found: 557.1392. 6-(trimethylsilyl)hex-5-ynoic acid (58) nBuLi TMSCl HO THF –78 to 18 °C O HO O TMS Prepared from 5-hexynoic acid (1.1 mL, 10 mmol, 1 equiv), nBuLi (2.5 M in hexanes, 8.4 mL, 21 mmol, 2.1 equiv), TMSCl (2.9 mL, 22.8 mmol, 2.28 equiv), and THF (100 mL, 0.1 M) following a published procedure102 to afford 58 (1.42 g, 77% yield) as a yellow oil. Spectra matched those reported in the literature.102 1 H NMR (CDCl3, 300 MHz): δ 2.50 (td, J = 7.5, 0.9 Hz, 2H), 2.37 – 2.26 (m, 2H), 1.92 – 1.76 (m, 2H), 0.23 – 0.05 (m, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 178.4, 105.6, 85.6, 32.4, 32.4, 23.3, 19.1, 0.0. N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-6-(trimethylsilyl)hex-5ynamide (125) (COCl)2, DMF DCM, 18 °C HO O TMS then (+)-pseudoephedrine Et3N, THF, 0 °C OH Me N Ph Me O TMS To a flame-dried round bottom flask with a stir bar and vent needle was added acid 58 (500 mg, 2.7 mmol, 1 equiv) and DCM (27 mL, 0.1 M). Oxalyl chloride (0.25 mL, 3.0 mmol, 1.1 equiv) was added dropwise, followed by a single drop of DMF; gas evolution immediately occurred. The reaction was allowed to stir at ambient temperature overnight Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 517 before being concentrated to afford a yellow oil. To a separate flame-dried round bottom flask with a stir bar was added (1S,2S)-(+)-pseudoephedrine (448 mg, 2.7 mmol, 1 equiv) and THF (7 mL). This solution was treated with triethylamine (0.49 mL, 3.5 mmol, 1.3 equiv) then cooled to 0 °C in an ice/water bath. To this flask was added a solution of the recently prepared acid chloride in THF (7 mL, total 0.2 M). The reaction mixture was allowed to stir at 0 °C for 1 h before being quenched with brine and extracted with EtOAc thrice. Combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 30 to 60% EtOAc/hexanes) to afford 125 (593 mg, 66% yield) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz; 3:1 rotamer ratio, asterisk denotes minor rotamer): δ 7.42 – 7.23 (m, 5H), 4.61 (d, J = 6.8 Hz, 1H), 4.58* (d, J = 9.7 Hz, 1H), 4.46 (s, 1H), 4.05* (p, J = 6.9 Hz, 1H), 2.93* (s, 1H), 2.85 (s, 3H), 2.64* (dt, J = 15.2, 7.4 Hz, 1H), 2.52* (t, J = 7.7 Hz, 1H), 2.49 – 2.36 (m, 2H), 2.36 – 2.22 (m, 3H), 1.89* (p, J = 7.0 Hz, 1H), 1.88 – 1.76 (m, 2H), 1.13 (d, J = 7.0 Hz, 3H), 1.00* (d, J = 6.8 Hz, 1H), 0.15 (s, 9H), 0.14* (s, 3H). 13 C{1H} NMR (CDCl3, 101 MHz; 3:1 rotamer ratio, asterisk denotes minor rotamer): δ 175.0, 173.7*, 142.6, 141.2*, 128.9, 128.7*, 128.6*, 127.9, 127.1*, 126.5, 106.7, 85.5, 75.7, 58.4, 32.9*, 32.3, 24.2*, 24.0, 19.6*, 19.4, 15.4*, 14.6, 0.3. FTIR (NaCl, thin film, cm-1): 3388, 2961, 2899, 2173, 1633, 1453, 1250, 1121, 1041, 840, 758. HRMS (TOF-ESI, m/z): [M – H2O + H]+ calcd for C19H28NOSi: 314.1935; found: 314.1926. +73 (c = 1.0, CHCl3). 518 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (S)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N,2-dimethyl-6-(trimethylsilyl)hex5-ynamide (59) OH Me Ph Me OH LDA, LiCl MeI N O TMS THF –78 to 0 °C Me Me N Ph Me O TMS Prepared from lithium chloride (283 mg, 6.7 mmol, 6 equiv), iPr2NH (0.36 mL, 2.6 mmol, 2.3 equiv), nBuLi (2.5 M in hexanes, 0.94 mL, 2.3 mmol, 2.1 equiv), amide 125 (369 mg, 1.1 mmol, 1 equiv), methyl iodide (0.10 mL, 1.7 mmol, 1.5 equiv), and THF (6.0 mL, 0.2 M) following a published procedure.101 The crude residue was purified by column chromatography (silica, 40 to 50% EtOAc/hexanes) to afford 59 (248 mg, 64% yield) as an orange oil. 1 H NMR (CDCl3, 400 MHz; 3:1 rotamer ratio, asterisk denotes minor rotamer): δ 7.42 – 7.20 (m, 6H), 4.64 (t, J = 6.4 Hz, 1H), 4.60* (d, J = 8.6 Hz, 1H), 4.34 (s, 1H), 4.23* (p, J = 6.9 Hz, 1H), 3.13 – 3.01* (m, 1H), 2.94* (s, 3H), 2.93 – 2.87 (m, 1H), 2.86 (s, 3H), 2.33 – 2.02 (m, 2H), 1.95 – 1.81 (m, 1H), 1.59 – 1.45 (m, 1H), 1.18 (dd, J = 8.8, 6.9 Hz, 3H), 1.04 (t, J = 6.6 Hz, 3H), 0.13 (s, 9H), 0.05* (s, 3H). 13 C{1H} NMR (CDCl3, 101 MHz; 3:1 rotamer ratio, asterisk denotes minor rotamer): δ 177.4, 176.5*, 141.6, 140.2*, 127.9*, 127.6*, 127.5, 126.7, 126.0*, 125.4, 106.0, 84.4, 75.6, 74.7, 57.3, 34.1, 33.3*, 32.5*, 31.6, 17.0*, 17.0*, 16.8, 16.3, 14.9*, 13.6, –0.7. FTIR (NaCl, thin film, cm-1): 3378, 2963, 2933, 2172, 1618, 1249, 841, 756. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C20H32NO2Si: 346.2197; found: 346.2206. +149 (c = 0.4, CHCl3). 519 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (S)-2-methyl-6-(trimethylsilyl)hex-5-yn-1-ol (126) OH Me LDA, LiCl BH3·NH3 Me N Ph Me O TMS Me HO THF –78 to 0 °C TMS Prepared from iPr2NH (0.15 mL, 1.1 mmol, 4 equiv), nBuLi (2.5 M in hexanes, 0.43 mL, 1.1 mmol, 4 equiv), borane·ammonia complex (33 mg, 1.1 mmol, 4 equiv), amide 59 (94 mg, 0.27 mmol, 1 equiv), and THF (3.5 mL, 0.1 M) following a published procedure.103 The crude residue was purified by column chromatography (silica, 30% EtOAc/hexanes) to afford 126 (36 mg, 72% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 3.57 – 3.44 (m, 2H), 2.38 – 2.17 (m, 2H), 1.83 – 1.60 (m, 1H), 1.46 – 1.32 (m, 2H), 0.94 (d, J = 6.7 Hz, 3H), 0.14 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 106.6, 83.7, 66.8, 34.7, 31.1, 16.7, 15.4, –0.7. FTIR (NaCl, thin film, cm-1): 3340, 2957, 2929, 2174, 1249, 1039, 843, 759. HRMS (TOF-ESI, m/z): [M + H]+ calcd for C10H21OSi: 185.1356; found: 185.1361. –4 (c = 0.2, CHCl3). To determine the absolute configuration and enantiomeric excess of alcohol 126, both Mosher acids were prepared and analyzed: configuration as drawn and 92% ee. MeO CF3 Cl Ph Me (S) O HO DMAP, DCM, 18 °C TMS Me MeO CF3 O Ph O 127 (R)-ester TMS Prepared from (S)-(–)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (31 µL, 0.16 mmol, 3 equiv), DMAP (26.5 mg, 0.22 mmol, 4 equiv), alcohol 126 (10.0 mg, 0.054 520 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F mmol, 1 equiv), and DCM (1 mL, 0.054 M) following a published procedure.149 Crude 127 was analyzed by 1H NMR. F3C OMe OH Ph Me (S) O HO DCC, DMAP, DCM, 18 °C F3C OMe O Ph O TMS Me 128 (S)-ester TMS Prepared from (S)-(–)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (39.4 mg, 0.168 mmol, 3.1 equiv), DMAP (20.5 mg, 0.168 mmol, 3.1 equiv), DCC (39 µL, 0.168 mmol, 3.1 equiv), alcohol 126 (10.0 mg, 0.054 mmol, 1 equiv), and DCM (1 mL, 0.054 M) following a published procedure.149 Crude 128 was analyzed by 1H NMR. (S)-(6-iodo-5-methylhex-1-yn-1-yl)trimethylsilane (60) Me I2, PPh3 imidazole HO TMS DCM, 18 °C Me I TMS Prepared from alcohol 126 (36 mg, 0.2 mmol, 1 equiv), iodine (50 mg, 0.2 mmol, 1 equiv), imidazole (40 mg, 0.6 mmol, 3 equiv), triphenylphosphine (52 mg, 0.2 mmol, 1 equiv), and DCM (2 mL, 0.1 M) following a published procedure.103 The crude residue was purified by column chromatography (silica, 0 to 20% EtOAc/hexanes) to afford 60 (34 mg, 59% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 3.26 (dd, J = 9.8, 4.3 Hz, 1H), 3.20 (dd, J = 9.8, 5.3 Hz, 1H), 2.34 – 2.17 (m, 2H), 1.68 – 1.55 (m, 1H), 1.53 – 1.38 (m, 1H), 1.33 – 1.23 (m, 1H), 1.02 – 0.97 (m, 3H), 0.15 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 105.58, 84.27, 34.05, 32.65, 19.45, 16.64, 16.25, - 521 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 0.73. FTIR (NaCl, thin film, cm-1): 2959, 2934, 2174, 1248, 837, 758. HRMS (FI-MS, m/z): [M]+ calcd for C10H19SiI: 294.0295; found: 294.0268. +9 (c = 0.2, CHCl3). tert-butyl 2-(4-bromophenyl)hexanoate (77) Br Br 1. nBuI, NaHMDS THF, –78 °C OH O 2. (COCl)2, DMF DCM, 18 °C then tBuOH OtBu nBu O Step 1: To a flame-dried round bottom flask with a stir bar was added 4bromophenylacetic acid (10.4 g, 48.3 mmol, 1 equiv) and THF (97 mL, 0.5 M). Then, NaHMDS (1 M in THF, 100 mL, 100 mmol, 2.07 equiv) was added via cannula. The mixture was stirred vigorously, slowly turning into a red homogenous solution, at which point 1-iodobutane (5.77 mL, 50.7 mmol, 1.05 equiv) was added. The reaction was stirred at ambient temperature for 20 h, then water was added. The mixture was washed with Et2O twice. The aqueous layer was acidified with 1 M HCl to pH = 1 and then extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude oil was used in the next step without further purification. Step 2: To a flame-dried round bottom flask with a stir bar was added the intermediate acid and DCM (39 mL, 1.2 M). Then, (COCl)2 (4.7 mL, 55.6 mmol, 1.15 equiv) and DMF (0.78 mL, 10 mmol, 0.2 equiv) were added sequentially, and the reaction was stirred at ambient temperature for 2 h. The reaction was concentrated, then 522 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F the residue was diluted in DCM (23 mL, 2.1 M) and tBuOH (23.4 mL, 244 mmol, 5.1 equiv) was added. The reaction was stirred overnight and then diluted with DCM and washed with sat. aq. NaHCO3. The aqueous layer was extracted once with DCM. Combined organics were washed with sat. aq. Na2S2O3 to remove any remaining color, dried over Na2SO4, filtered, and concentrated to afford 77 (10.2 g, 64% yield over 2 steps) as a red oil. 1 H NMR (CDCl3, 400 MHz): δ 7.45 – 7.40 (m, 2H), 7.19 – 7.14 (m, 2H), 3.37 (t, J = 7.7 Hz, 1H), 1.99 (dddd, J = 13.2, 9.8, 8.0, 5.5 Hz, 1H), 1.67 (dddd, J = 13.3, 9.5, 7.4, 5.7 Hz, 1H), 1.39 (s, 9H), 1.36 – 1.25 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.1, 139.1, 131.6, 129.8, 120.9, 80.9, 52.3, 33.3, 29.8, 28.1, 22.6, 14.0. FTIR (ATR, cm-1): 1725, 1614, 1487, 1367, 1254, 1144, 1073, 1011. HRMS (FD-MS, m/z): [M]+ calcd for C16H23O2Br: 326.0876; found: 326.0876. tert-butyl 2-(4-(6-(trimethylsilyl)hex-5-yn-1-yl)phenyl)hexanoate (79) Br + OtBu nBu O 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C I TMS 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C TMS OtBu nBu O Small Scale: Prepared from aryl bromide 77 (34 mg, 0.1 mmol, 1 equiv), alkyl iodide 54 (61 mg, 0.21 mmol, 2 equiv), tBuLi (1.7 M in pentane, 0.32 mL, 0.54 mmol, 5.17 equiv), ZnCl2 (0.5 M in THF, 0.42 mL, 0.21 mmol, 2 equiv), and Pd(dppf)Cl2 (3.9 mg, 0.005 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by preparative Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 523 thin layer chromatography (silica, 5% EtOAc/hexanes) to afford 79 (31 mg, 73% yield) as a colorless oil. Large Scale: To a flame-dried round bottom flask with a stir bar containing Et2O (82 mL) and cooled to –78 °C in a dry ice/acetone bath was slowly added tBuLi (1.7 M in pentane, 41 mL, 69.0 mmol, 3.15 equiv). Alkyl iodide 54 (9.21 g, 32.8 mmol, 1.5 equiv) was added dropwise via syringe at a rate such that the internal reaction temperature remained below –70 °C; this solution was stirred at –78 °C for 30 minutes. (Note: allowing the reaction to warm above –70 °C often resulted in alkyl iodide degradation.) Then, ZnCl2 (0.5 M in THF, 4.4 mL, 32.8 mmol, 1.5 equiv) was added slowly such that the internal reaction temperature remained below –70 °C; this solution was stirred at –78 °C for 1 h. To a separate flame-dried 3-neck flask with a stir bar and a reflux condenser was added Pd(dppf)Cl2 (801 mg, 1.09 mmol, 0.05 equiv) and THF (22 mL, 1 M), followed by aryl bromide 77 (7.17 g, 21.9 mmol, 1 equiv); this suspension was cooled to 0 °C in an ice/water bath. The original solution was warmed to 0 °C then immediately transferred via cannula to the 3-neck flask. The resulting mixture was heated in an oil bath set to 50 °C overnight. (Note: over the course of the reaction, the color generally changed from yellow to green to red.) Upon complete consumption of the aryl bromide, as judged by TLC, the reaction was allowed to reach room temperature then quenched with water. The organic layer was separated, and the aqueous layer was extracted with Et2O twice. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 2% Et2O/hexanes) to afford 79 (4.3 g, 49% yield) as a pale yellow oil. 524 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1 H NMR (CDCl3, 400 MHz): δ 7.23 – 7.17 (m, 2H), 7.14 – 7.08 (m, 2H), 3.38 (dd, J = 8.4, 7.0 Hz, 1H), 2.60 (t, J = 7.7 Hz, 2H), 2.24 (t, J = 7.1 Hz, 2H), 2.00 (dddd, J = 13.3, 9.5, 8.3, 5.3 Hz, 1H), 1.79 – 1.61 (m, 3H), 1.61 – 1.50 (m, 3H), 1.40 (s, 9H), 1.37 – 1.28 (m, 2H), 1.28 – 1.16 (m, 1H), 0.87 (t, J = 7.1 Hz, 3H), 0.14 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.8, 140.9, 137.4, 128.5, 127.8, 107.5, 84.7, 80.5, 52.5, 35.1, 33.6, 30.5, 30.0, 28.3, 28.1, 22.7, 19.9, 14.1, 0.3. FTIR (ATR, cm-1): 2174, 1727, 1367, 1248, 1145, 1020, 840, 758. HRMS (FD-MS, m/z): [M]+ calcd for C25H40O2Si: 400.2792; found: 400.2792. Br I + MeO 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C OMe TMS OtBu nBu 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C TMS MeO OMe OtBu nBu O O Prepared from aryl bromide 52 (250 m, 0.65 mmol, 1 equiv), alkyl iodide 54 (362 mg, 1.3 mmol, 2 equiv), tBuLi (1.7 M in pentane, 1.6 mL, 2.7 mmol, 4.2 equiv), ZnCl2 (0.5 M in THF, 2.6 mL, 1.3 mmol, 2 equiv), and Pd(dppf)Cl2 (24 mg, 0.32 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by column chromatography (silica, 80% PhMe/hexanes) to afford 55 (160 mg, 54% yield) as a colorless oil. 1,3-dioxoisoindolin-2-yl 2-(4-bromophenyl)hexanoate (80) Br Br MeO OMe OH nBu O NHP EDC·HCl, DMAP DCM, 18 °C MeO OMe O nBu O O N O 525 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F To a round bottom flask with a stir bar was added acid 23 (100 mg, 0.30 mmol, 1 equiv), N-hydroxyphthalimide (54.2 mg, 0.33 mmol, 1.1 equiv), DMAP (3.7 mg, 0.03 mmol, 0.1 equiv), then DCM (1.5 mL, 0.2 M). To this solution was added DIC (51 µL, 0.33 mmol, 1.1 equiv) dropwise. The reaction was stirred at ambient temperature and monitored by LCMS. Upon complete consumption of the acid, the reaction was concentrated. The crude residue was purified by column chromatography (silica, 5 to 20% EtOAc/hexanes) to afford 80 (134 mg, 93% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.84 (s, 2H), 7.76 (dd, J = 5.5, 3.1 Hz, 2H), 6.74 (s, 2H), 4.45 (dd, J = 9.1, 5.3 Hz, 1H), 3.86 (s, 6H), 2.16 (ddt, J = 13.3, 10.4, 5.2 Hz, 1H), 1.82 (dtd, J = 14.3, 9.3, 5.2 Hz, 1H), 1.44 – 1.20 (m, 3H), 1.20 – 1.01 (m, 1H), 0.85 (t, J = 7.0 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 170.9, 158.5, 134.8, 129.3, 124.0, 122.3, 113.9, 107.8, 56.3, 37.9, 29.6, 29.3, 22.8, 14.2. FTIR (ATR, cm-1): 1787, 1740, 1582, 1456, 1406, 1224, 1117, 964, 877, 695. HRMS (FD-MS, m/z): [M]+ calcd for C22H22NO6Br: 475.0639; found: 475.0625. 1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxy-4-(6-(trimethylsilyl)hex-5-yn-1yl)phenyl)hexanoate (81) Br + MeO OMe O nBu O N O 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C I TMS 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C TMS MeO OMe O nBu O N O O O Prepared from aryl bromide 80 (40 mg, 0.084 mmol, 1 equiv), alkyl iodide 54 (24.6 mg, 0.088 mmol, 1.05 equiv), tBuLi (1.7 M in pentane, 0.13 mL, 0.23 mmol, 2.7 equiv), 526 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F ZnCl2 (0.5 M in THF, 0.18 mL, 0.088 mmol, 1.05 equiv), and Pd(dppf)Cl2 (3.1 mg, 0.0042 mmol, 0.05 equiv) following a modified procedure.73 The crude residue was purified by preparative thin layer chromatography (silica, 25% EtOAc/hexanes) to afford 81 (12 mg, 26% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.73 (d, J = 4.7 Hz, 2H), 7.64 (dd, J = 5.5, 3.1 Hz, 2H), 6.31 (s, 2H), 4.37 (dd, J = 8.8, 5.4 Hz, 1H), 3.75 (s, 6H), 2.57 – 2.48 (m, 2H), 2.18 (t, J = 7.1 Hz, 2H), 2.07 (ddt, J = 13.3, 10.5, 5.3 Hz, 1H), 1.79 – 1.71 (m, 1H), 1.66 (tdd, J = 7.6, 6.0, 4.8 Hz, 2H), 1.56 – 1.43 (m, 2H), 1.34 – 1.12 (m, 3H), 1.14 – 1.01 (m, 1H), 0.82 – 0.70 (m, 3H), 0.05 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 170.6, 156.9, 142.7, 133.7, 128.3, 122.9, 111.2, 106.6, 103.0, 83.9, 54.9, 36.9, 35.3, 29.5, 29.0, 28.4, 27.5, 21.8, 19.0, 13.2, -0.6. FTIR (ATR, cm-1): 2170, 1787, 1743, 1587, 1458, 1364, 1118, 1079, 841, 696. HRMS (FD-MS, m/z): [M]+ calcd for C31H39NO6Si: 549.2541; found: 549.2538. tert-butyl 2-(4-(hex-5-yn-1-yl)phenyl)hexanoate (104) TMS TBAF OtBu nBu O THF, 18 °C OtBu nBu O To a flame-dried round bottom flask with a stir bar was added protected alkyne 79 (2.2 g, 5.0 mmol, 1 equiv) followed by THF (25 mL, 0.2 M) then tetrabutylammonium fluoride (10 mL, 10.0 mmol, 2 equiv). The reaction was stirred at room temperature for 5 min and then quenched with sat. aq. NaHCO3. The layers were separated, and combined organics were washed with water thrice, dried over Na2SO4, filtered, and concentrated to afford 527 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 104 (1.65 mg, quantitative yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.22 – 7.17 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.38 (dd, J = 8.3, 7.1 Hz, 1H), 2.60 (t, J = 7.7 Hz, 2H), 2.21 (td, J = 7.0, 2.6 Hz, 2H), 2.00 (dddd, J = 13.4, 9.7, 8.4, 5.4 Hz, 1H), 1.78 – 1.62 (m, 2H), 1.62 – 1.49 (m, 4H), 1.39 (d, J = 1.0 Hz, 9H), 1.36 – 1.13 (m, 3H), 0.87 (dd, J = 7.6, 6.6 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.8, 140.8, 137.5, 128.5, 127.9, 84.6, 80.5, 68.4, 52.5, 35.1, 33.6, 30.5, 30.0, 28.2, 28.1, 22.7, 18.4, 14.1. FTIR (ATR, cm-1): 2931, 2860, 1725, 1367, 1265, 1147, 844, 739. HRMS (FD, m/z): [M]+ calcd for C22H32O2: 328.2402; found: 328.2421. tert-butyl (E)-2-(4-(6-bromohex-5-en-1-yl)phenyl)hexanoate (84) Br Cp2ZrHCl PhH, 18 °C OtBu nBu O then NBS OtBu nBu O Prepared from alkyne 104 (1.64 g, 5.0 mmol, 1 equiv), Cp2ZrHCl (1.64 g, 6.4 mmol, 1.3 equiv), N-bromosuccinimide (1.13 g, 6.4 mmol, 1.3 equiv equiv), and PhH (50 mL, 0.1 M) following a published procedure156 to afford 84 (1.77 g, 87% yield) as a colorless oil. 1 H NMR (CDCl3, 500 MHz): δ 7.23 – 7.17 (m, 2H), 7.13 – 7.06 (m, 2H), 6.16 (dt, J = 13.4, 7.3 Hz, 1H), 6.00 (dt, J = 13.4, 1.4 Hz, 1H), 3.39 (dd, J = 8.4, 7.0 Hz, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.07 (qd, J = 7.3, 1.3 Hz, 2H), 2.03 – 1.94 (m, 1H), 1.75 – 1.64 (m, 1H), 1.61 (td, J = 9.3, 8.5, 6.6 Hz, 2H), 1.43 (s, 1H), 1.40 (s, 9H), 1.38 – 1.15 (m, 4H), 0.88 (t, J = 7.1 Hz, 4H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.8, 140.9, 138.1, 137.5, 128.5, 127.9, 104.4, 528 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 80.5, 52.5, 35.4, 33.6, 32.9, 30.8, 30.0, 28.4, 28.1, 22.7, 14.1. FTIR (ATR, cm-1): 3089, 1725, 1621, 1557, 1455, 1144, 1057. HRMS (FD, m/z): [M]+ calcd for C22H33BrO2: 408.1664; found: 408.1665. 2. NHP EDC·HCl, DMAP 1. TFA OtBu nBu Br Br Br DCM, 18 °C OH nBu O O DCM, 18 °C O O nBu N O O Step 1: To a round bottom flask with a stir bar was added ester 84 (1.77 g, 4.3 mmol, 1 equiv) then trifluoroacetic acid/DCM (1:1, 0.2 M). The solution was stirred at 18 °C for 30 min then concentrated. The crude residue was azeotroped with PhMe to afford acid intermediate 129 as a red oil. Step 2: To a round bottom flask with a stir bar was added acid intermediate 129 (1.53 g, 4.3 mmol, 1 equiv), N-hydroxyphthalimide (777 mg, 4.8 mmol, 1.1 equiv), DMAP (106 mg, 0.9 mmol, 0.2 equiv), then DCM (22 mL, 0.2 M). Then EDC·HCl (913 mg, 4.8 mmol, 1.1 equiv) was added in one portion. The reaction was stirred at 18 °C overnight and then concentrated. The crude residue was filtered through a plug of silica, eluting with EtOAc. The filtrate was concentrated then purified by column chromatography (silica, 5 to 7% EtOAc/hexanes) to afford 85 (1.79 g, 83% yield over 2 steps) as a colorless oil. (E)-2-(4-(6-bromohex-5-en-1-yl)phenyl)hexanoic acid (129) 1 H NMR (CDCl3, 400 MHz): δ 7.26 – 7.17 (m, 2H), 7.17 – 7.06 (m, 2H), 6.15 (dt, J = 13.5, 7.2 Hz, 1H), 6.00 (dt, J = 13.5, 1.4 Hz, 1H), 3.51 (t, J = 7.7 Hz, 1H), 2.58 (t, J = 7.7 529 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Hz, 2H), 2.14 – 1.99 (m, 2H), 1.82 – 1.68 (m, 1H), 1.61 (tdd, J = 9.2, 7.4, 6.1 Hz, 2H), 1.53 – 1.35 (m, 2H), 1.39 – 1.13 (m, 5H), 0.88 – 0.84 (m, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 179.4, 141.6, 138.1, 136.1, 128.8, 128.1, 104.4, 51.1, 35.4, 33.0, 32.9, 30.8, 29.8, 28.4, 22.6, 14.0. FTIR (ATR, cm-1): 2930, 1704, 1512, 1290, 939, 739. HRMS (TOF-ESI, m/z): [M – H]– calcd for C18H24BrO2: 351.0965; found: 351.0955. 1,3-dioxoisoindolin-2-yl (E)-2-(4-(6-bromohex-5-en-1-yl)phenyl)hexanoate (85) 1 H NMR (CDCl3, 500 MHz): δ 7.86 (dd, J = 5.6, 3.1 Hz, 2H), 7.77 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 – 7.28 (m, 2H), 7.21 – 7.14 (m, 2H), 6.17 (dt, J = 13.7, 7.2 Hz, 1H), 6.01 (dt, J = 13.5, 1.4 Hz, 1H), 3.90 (t, J = 7.6 Hz, 1H), 2.61 (t, J = 7.7 Hz, 2H), 2.29 – 2.12 (m, 1H), 2.07 (qd, J = 7.3, 1.4 Hz, 2H), 1.97 – 1.82 (m, 1H), 1.63 (p, J = 7.5 Hz, 2H), 1.52 – 1.25 (m, 6H), 0.95 – 0.87 (m, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 170.7, 162.1, 142.0, 138.1, 134.9, 134.6, 129.1, 129.0, 128.1, 124.1, 104.4, 48.5, 35.4, 33.8, 33.0, 30.7, 29.5, 28.4, 22.5, 14.0. FTIR (ATR, cm-1): 1810, 1784, 1742, 1618, 1466, 1359, 1185, 1126, 1058, 966, 877, 695. HRMS (FD-MS, m/z): [M]+ calcd for C26H28NBrO4: 497.1196; found: 497.1189. methyl 2-(4-bromophenyl)hexanoate (130) Br Br 1. nBuI, NaHMDS THF, –78 °C OH O 2. cat. H2SO4 MeOH, reflux OMe nBu O Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 530 Step 1: To a flame-dried round bottom flask with a stir bar was added 4bromophenylacetic acid (9.68 g, 45 mmol, 1 equiv) and THF (90 mL, 0.5 M). The solution was cooled to –78 °C in a dry ice/acetone bath, then NaHMDS (1 M in THF, 93.1 mL, 93.1 mmol, 2.07 equiv) was added dropwise. The mixture was allowed to reach ambient temperature with vigorous stirring; the mixture slowly turned into a red homogenous solution, at which point 1-iodobutane (5.38 mL, 47.3 mmol, 1.05 equiv) was added. The reaction was stirred at room temperature for 20 h, until the solution turned a golden color, at which point water was added. The mixture was washed with Et2O twice. The aqueous layer was acidified with 1 M HCl to pH = 1 and then extracted with Et2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude oil was used in the next step without further purification. Step 2: To a flame-dried 3-neck round bottom flask with a stir bar and reflux condenser was added the intermediate acid and MeOH (25 mL, 1.8 M). Then, H2SO4 (240 µL, 4.5 mmol, 0.1 equiv) was added and the reaction was stirred while heating to 65 °C in an oil bath. After 4 h of stirring at that temperature, the reaction was allowed to reach ambient temperature then diluted in 20% EtOAc/hexanes and washed with 1 M Na2CO3. The aqueous layer was extracted once with 20% EtOAc/hexanes. Combined organics were washed with twice with sat. aq. Na2S2O3 to remove any remaining color, dried over Na2SO4, filtered, and concentrated to afford 130 (11.2 g, 87% yield over 2 steps) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz): δ 7.44 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 3.65 (s, 4H), 3.49 (t, J = 7.7 Hz, 1H), 2.11 – 1.97 (m, 1H), 1.73 (dddd, J = 13.4, 9.3, 7.6, 5.8 Hz, 1H), 1.40 – 1.11 (m, 6H), 0.86 (t, J = 7.2 Hz, 5H). 531 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.3, 138.4, 131.8, 129.8, 121.3, 52.2, 51.2, 33.3, 29.8, 22.5, 14.0. FTIR (ATR, cm-1): 2955, 2359, 2323, 1733, 1616, 1574, 1487, 1434, 1159, 1010, 820. HRMS (FI-MS, m/z): [M]+ calcd for C13H17O2Br: 284.0406; found: 284.0397. (5-iodopent-1-yn-1-yl)trimethylsilane (131) TMS HO I2, PPh3 imidazole TMS I DCM, 18 °C Prepared from 5-(trimethylsilyl)pent-4-yn-1-ol (5.0 mL, 27.5 mmol, 1.05 equiv), iodine (10.5 g, 41.3 mmol, 1.58 equiv), imidazole (2.81 g, 41.3 mmol, 1.58 equiv), triphenylphosphine (6.86 g, 26.2 mmol, 1 equiv), and DCM (110 mL, 0.24 M) following a modified procedure157 to afford 131 (5.17 g, 74% yield) as a colorless oil. Spectra matched those reported in the literature.157 1 H NMR (CDCl3, 500 MHz): δ 3.33 (t, J = 6.8 Hz, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.04 (p, J = 6.8 Hz, 2H), 0.19 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 104.8, 85.8, 32.0, 20.8, 5.1, 0. 0. (7-iodohept-1-yn-1-yl)trimethylsilane (132) 1. nBuLi, TMSCl THF, –78 to 18 °C HO 2. I2, PPh3 imidazole DCM, 18 °C TMS I Prepared following a published procedure.158 Step 1: Prepared from 6-heptyn-1-ol (5.66 mL, 45 mmol, 1 equiv), nBuLi (2.5 M in hexanes, 39.6 mL, 80.6 mmol, 2.2 equiv), TMSCl (17.1 mL, 135 mmol, 3 equiv), and 532 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F THF (12 mL, 3 M) to afford the alkyne intermediate. Step 2: Prepared from the intermediate alkyne (1.05 equiv), iodine (17.1 g, 67.5 mmol, 1.58 equiv), imidazole (4.6 g, 67.5 mmol, 1.58 equiv), triphenylphosphine (11.2 g, 42.8 mmol, 1 equiv), and DCM (180 mL, 0.24 M) to afford 132 (8.08 g, 56% yield over 2 steps) as a colorless oil. Spectra matched those reported in the literature and references therein.158 1 H NMR (CDCl3, 400 MHz): δ 3.20 (t, J = 7.0 Hz, 2H), 2.24 (t, J = 6.6 Hz, 2H), 1.89 – 1.80 (m, 2H), 1.62 – 1.45 (m, 4H), 0.15 (d, J = 0.7 Hz, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 107.1, 85.0, 33.1, 29.8, 27.6, 19.8, 6.9, 0.3. (8-iodooct-1-yn-1-yl)trimethylsilane (133) HO 1. nBuLi, TMSCl THF, –78 to 18 °C I 2. I2, PPh3 imidazole DCM, 18 °C TMS Prepared following a published procedure.158 Step 1: Prepared from 7-octyn-1-ol (5.2 g, 36.6 mmol, 1 equiv), nBuLi (2.5 M in hexanes, 32.2 mL, 80.6 mmol, 3 equiv), TMSCl (13.9 mL, 110 mmol, 3 equiv), and THF (12 mL, 3 M) to afford alkyne intermediate. Step 2: Prepared from the intermediate alkyne (1.05 equiv), iodine (13.9 g, 54.9 mmol, 1.58 equiv), imidazole (3.74 g, 54.9 mmol, 1.58 equiv), triphenylphosphine (9.12 g, 34.8 mmol, 1 equiv), and DCM (146 mL, 0.24 M) to afford 133 (7.84 g, 73% yield over 2 steps) as a colorless oil. Spectra matched those reported in the literature.158 1 H NMR (CDCl3, 400 MHz): δ 3.19 (t, J = 7.0 Hz, 2H), 2.22 (t, J = 7.0 Hz, 2H), 1.89 – 1.77 (m, 2H), 1.59 – 1.46 (m, 2H), 1.46 – 1.34 (m, 4H), 0.14 (s, 9H). 533 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 13 C{1H} NMR (CDCl3, 101 MHz): δ 107.5, 84.7, 33.5, 30.1, 28.5, 27.8, 19.9, 7.2, 0.3. methyl 2-(4-(5-(trimethylsilyl)pent-4-yn-1-yl)phenyl)hexanoate (134) TMS Br TMS + 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C I OMe nBu 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C O OMe nBu O Prepared from aryl bromide 130 (500 mg, 1.75 mmol, 1 equiv), alkyl iodide 131 (933 mg, 3.51 mmol, 2 equiv), tBuLi (1.7 M in pentane, 5.33 mL, 9.06 mmol, 5.17 equiv), ZnCl2 (0.5 M in THF, 7.0 mL, 3.51 mmol, 2 equiv), and Pd(dppf)Cl2 (64 mg, 0.088 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by column chromatography (silica, 1 to 2% EtOAc/hexanes) to afford 134 (511 mg, 85% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.24 – 7.18 (m, 2H), 7.16 – 7.09 (m, 2H), 3.65 (s, 3H), 3.50 (t, J = 7.7 Hz, 1H), 2.78 – 2.66 (m, 2H), 2.23 (t, J = 7.1 Hz, 2H), 2.05 (dddd, J = 13.4, 9.6, 8.0, 5.7 Hz, 1H), 1.83 (dt, J = 8.5, 7.1 Hz, 2H), 1.79 – 1.69 (m, 1H), 1.38 – 1.15 (m, 3H), 0.87 (t, J = 7.2 Hz, 3H), 0.16 (s, 8H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.9, 140.6, 137.0, 128.9, 128.0, 107.2, 85.2, 52.0, 51.4, 34.4, 33.5, 30.2, 29.9, 22.6, 19.4, 14.0, 0.3. FTIR (ATR, cm-1): 2956, 1175, 1736, 1606, 1582, 1456, 1248, 1160, 911, 839, 759, 732. HRMS (FI-MS, m/z): [M]+ calcd for C21H32O2Si: 344.2166; found: 344.2159. 534 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F methyl 2-(4-(7-(trimethylsilyl)hept-6-yn-1-yl)phenyl)hexanoate (135) TMS Br + OMe nBu O TMS I 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C OMe nBu O Prepared from aryl bromide 130 (1.46 g, 5.13 mmol, 1 equiv), alkyl iodide 132 (3.02 g, 10.3 mmol, 2 equiv), tBuLi (1.7 M in pentane, 15.6 mL, 26.5 mmol, 5.17 equiv), ZnCl2 (0.5 M in THF, 20.5 mL, 10.3 mmol, 2 equiv), and Pd(dppf)Cl2 (188 mg, 0.26 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by column chromatography (silica, 3% EtOAc/hexanes) to afford 135 (1.58 g, 83% yield) as a colorless oil. 1 H NMR (CDCl3, 500 MHz): δ 7.24 – 7.17 (m, 2H), 7.15 – 7.09 (m, 2H), 3.65 (s, 3H), 3.50 (t, J = 7.7 Hz, 1H), 2.62 – 2.56 (m, 2H), 2.22 (t, J = 7.1 Hz, 2H), 2.06 (dddd, J = 13.4, 10.0, 8.1, 5.5 Hz, 1H), 1.75 (dddd, J = 13.2, 9.5, 7.3, 5.7 Hz, 1H), 1.66 – 1.58 (m, 2H), 1.55 (q, J = 7.3 Hz, 2H), 1.48 – 1.37 (m, 2H), 1.37 – 1.14 (m, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.15 (s, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.0, 140.6, 135.7, 127.7, 126.9, 106.7, 83.5, 51.0, 50.4, 34.5, 32.5, 30.0, 28.9, 27.7, 27.6, 21.6, 19.0, 13.3, 13.1, –0.7. FTIR (ATR, cm-1): 2956, 2858, 2173, 1736, 1457, 1248, 1159, 992, 839, 758. HRMS (FI-MS, m/z): [M]+ calcd for C23H36O2Si: 372.2479; found: 372.2479. 535 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F methyl 2-(4-(8-(trimethylsilyl)oct-7-yn-1-yl)phenyl)hexanoate (136) Br + OMe nBu O 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C I TMS 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C TMS OMe nBu O Prepared from aryl bromide 130 (1.75 g, 6.14 mmol, 1 equiv), alkyl iodide 133 (3.78 g, 12.3 mmol, 2 equiv), tBuLi (1.7 M in pentane, 18.7 mL, 31.7 mmol, 5.17 equiv), ZnCl2 (0.5 M in THF, 24.5 mL, 12.3 mmol, 2 equiv), and Pd(dppf)Cl2 (225 mg, 0.31 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by column chromatography (silica, 3% EtOAc/hexanes) to afford 136 (2.37 g, 84% yield) as a colorless oil. 1 H NMR (CDCl3, 500 MHz): δ 7.23 (d, J = 8.1 Hz, 2H), 7.18 – 7.06 (m, 2H), 3.68 (s, 3H), 3.54 (t, J = 7.7 Hz, 1H), 2.65 – 2.58 (m, 2H), 2.25 (t, J = 7.1 Hz, 2H), 1.85 – 1.72 (m, 1H), 1.64 (p, J = 7.6 Hz, 2H), 1.55 (q, J = 7.2 Hz, 1H), 1.45 (dq, J = 9.5, 6.5 Hz, 2H), 1.36 (dtd, J = 16.0, 9.1, 8.4, 5.5 Hz, 2H), 1.31 – 1.18 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.19 (s, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.0, 140.8, 135.7, 130.9, 127.7, 126.9, 106.8, 83.5, 51.0, 50.4, 34.6, 32.5, 30.4, 28.9, 27.9, 27.8, 27.7, 21.6, 19.0, 13.1, –0.7. FTIR (ATR, cm-1): 2856, 2175, 1736, 1615, 1570, 1434, 1248, 1159, 1051, 839, 732. HRMS (FI-MS, m/z): [M]+ calcd for C24H38O2Si: 386.2636; found: 386.2641. 536 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (Z)-5-iodo-4-methylpent-4-en-1-ol (87) i. Cp2ZrCl2, AlMe3 DCM, 18 °C then I2, –78 °C OH TMS Me OH ii. NaOMe, MeOH reflux I Prepared from 5-(trimethylsilyl)pent-4-yn-1-ol (4.48 g, 27.5 mmol, 1 equiv), Cp2ZrCl2 (8.88 g, 27.5 mmol, 1 equiv), trimethylaluminum (2 M in toluene, 41.3 mL, 84.6 mmol, 3 equiv), iodine (8.24 g, 32.5 mmol, 1.18 equiv), and sodium methoxide (25% in methanol, 25.8 mL, 113 mmol, 4.1 equiv) following a published procedure159 to afford 87 (2.37 g, 38% yield) as a pale yellow oil. Spectra matched those reported in the literature.159 1 H NMR (CDCl3, 400 MHz): δ 5.87 (d, J = 1.5 Hz, 1H), 3.67 (t, J = 6.4 Hz, 2H), 2.52 – 2.22 (m, 2H), 1.90 (d, J = 1.5 Hz, 3H), 1.78 – 1.63 (m, 2H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 147.2, 74.8, 62.4, 35.2, 30.0, 23.4. HRMS (FI-MS, m/z): [M]+ calcd for C6H11OI: 225.9849; found: 225.9847. 2. Me OH 1. DMP NaHCO3 Me O DCM, 18 °C I I O Me O P(OMe)2 Me N2 K2CO3 MeOH, 18 °C I Step 1: To a round bottom flask with a stir bar was added alcohol 87 (2.32 g, 10.3 mmol, 1 equiv) and NaHCO3 (2.59 g, 30.8 mmol, 3 equiv), and wet DCM (34 mL, 0.3 M), followed by Dess–Martin periodinane (5.22 g, 12.3 mmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature and monitored by TLC. Upon complete consumption of the alcohol, the reaction was quenched with sat. aq. NaHCO3, sat. aq. Na2S2O3, and H2O (1:1:1, 36 mL total); the resulting mixture was stirred for 2 h. The organic layer was separated, and the aqueous layer was extracted with DCM thrice. Combined organics were washed with brine, dried over Na2SO4, filtered, and Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 537 concentrated. The crude pale yellow oil (enal 137) was immediately used. Step 2: To a round bottom flask with a stir bar was added K2CO3 (276 mg, 2.0 mmol, 2 equiv) and MeOH (6.7 mL, 0.15 M), followed by intermediate aldehyde 137 (224 mg, 1.0 mmol, 1 equiv) and Ohira–Bestmann reagent124 (30 wt% in PhMe, 768 mg, 1.2 mmol, 1.2 equiv). The mixture was allowed to stir at ambient temperature for 4 h, at which point the mixture was extracted with hexanes thrice. Combined organics were washed with water, dried over Na2SO4, and concentrated. The crude residue was purified by column chromatography (silica, 5% EtOAc/hexanes) to afford alkyne 138 (110 mg, 50% yield over 2 steps) as a colorless oil. (Z)-5-iodo-4-methylpent-4-enal (137) 1 H NMR (CDCl3, 400 MHz): δ 9.82 (s, 1H), 5.94 (q, J = 1.5 Hz, 1H), 2.60 – 2.49 (m, 5H), 1.90 (d, J = 1.5 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 201.3, 145.7, 75.8, 41.2, 31.5, 23.5. FTIR (ATR, cm-1): 3052, 2909, 2819, 2723, 2358, 1820, 1722, 1437, 1269, 1185, 1131, 1002, 765. HRMS (FI-MS, m/z): [M]+ calcd for C6H9IO: 223.9693; found: 223.9691. (Z)-1-iodo-2-methylhex-1-en-5-yne (138) 1 H NMR (CDCl3, 400 MHz): δ 5.95 (q, J = 1.5 Hz, 1H), 2.46 (ddd, J = 7.7, 7.1, 1.1 Hz, 2H), 2.37 – 2.30 (m, 2H), 1.98 (t, J = 2.6 Hz, 1H), 1.94 (d, J = 1.5 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 145.9, 83.4, 75.8, 69.0, 37.6, 23.7, 16.4. HRMS (FI-MS, m/z): [M]+ calcd for C7H9I: 219.9743; found: 219.9739. 538 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (Z)-(6-iodo-5-methylhex-5-en-1-yn-1-yl)trimethylsilane (88) Me THF, –78 °C I Me NaHMDS TMSCl I TMS To a flame-dried round bottom flask with a stir bar was added alkyne 138 (365 mg, 1.66 mmol, 1 equiv) and THF (5.5 mL, 0.3 M). The reaction was cooled to –78 °C in a dry ice/acetone bath, then NaHMDS (1 M in THF, 2.16 mL, 2.16 mmol, 1.3 equiv) was added slowly. The mixture was stirred at –78 °C for 1 h, then TMSCl (0.32 mL, 2.49 mmol, 1.5 equiv) was added. The reaction was allowed to slowly warm to ambient temperature and stir for 20 h. Water was added, and the resulting mixture was extracted with Et2O. Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (silica, 1% Et2O/hexanes) to afford 88 (408 mg, 84% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 5.93 (q, J = 1.5 Hz, 1H), 2.48 – 2.40 (m, 2H), 2.40 – 2.31 (m, 2H), 1.94 (d, J = 1.4 Hz, 3H), 0.15 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 146.1, 106.2, 85.4, 75.7, 37.7, 23.8, 17.9, 0.2. FTIR (ATR, cm-1): 2960, 2909, 2175, 1439, 1249, 1054, 908, 841, 733. HRMS (FI-MS, m/z): [M]+ calcd for C10H7SiI: 292.0139; found: 292.0122. 539 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F tert-butyl (Z)-2-(2,6-dimethoxy-4-(2-methyl-6-(trimethylsilyl)hex-1-en-5-yn-1yl)phenyl)hexanoate (90) Me Br 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C Me MeO OMe OtBu nBu TMS + I TMS 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C O MeO OMe OtBu nBu O Prepared from aryl bromide 52 (186 mg, 0.48 mmol, 1 equiv), alkenyl iodide 88 (280 mg, 0.56 mmol, 2 equiv), tBuLi (1.7 M in pentane, 1.18 mL, 2.0 mmol, 4.2 equiv), ZnCl2 (0.5 M in THF, 1.9 mL, 0.96 mmol, 2 equiv), and Pd(dppf)Cl2 (17.5 mg, 0.024 mmol, 0.05 equiv) following a published procedure.73 The crude residue was purified by column chromatography (silica, 0 to 5% EtOAc/hexanes) to afford 90 (214 mg, 94% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.41 (s, 2H), 6.30 (d, J = 1.7 Hz, 1H), 3.98 (dd, J = 9.0, 5.4 Hz, 1H), 3.77 (s, 6H), 2.59 – 2.49 (m, 2H), 2.48 – 2.38 (m, 2H), 2.13 – 1.99 (m, 1H), 1.89 (d, J = 1.5 Hz, 3H), 1.71 – 1.47 (m, 2H), 1.37 (s, 9H), 1.35 – 1.15 (m, 2H), 1.15 – 0.99 (m, 1H), 0.83 (t, J = 7.1 Hz, 3H), 0.11 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.5, 157.8, 137.6, 137.5, 127.4, 116.7, 106.8, 104.6, 85.4, 79.6, 55.8, 41.0, 32.2, 30.0, 30.0, 28.2, 24.1, 23.0, 19.1, 14.3, 0.3. FTIR (ATR, cm-1): 2168, 1725, 1605, 1575, 1453, 1248, 1159, 1123, 841, 736. HRMS (FD-MS, m/z): [M]+ calcd for C28H44O4Si: 472.3003; found: 472.3004. 540 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.8.4 Double Reductive Cross-Coupling General Procedure E: O Br O N N nBu nBu + + nBu Ni Br NHP nBu O 85 Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C nBu nBu 94 139 98 n First, a stock solution of the catalyst was prepared. To a ½-dram vial with a stir bar and Teflon cap was added L1·NiBr275 (3.5 mg, 0.006 mmol, 0.1 equiv). In a N2-filled glovebox, the vial was charged with DMA (60 µL) the stirred while heating to 80 °C. The mixture was stirred at that temperature until all solids were completely dissolved and a maroon solution was obtained (ca. 5–10 min). Then the vial was allowed to completely cool to ambient temperature. Second, a separate ½-dram vial with a stir bar and Teflon cap was sequentially charged with NaI (4.5 mg, 0.03 mmol, 0.5 equiv) and electrophile 85 (30.0 mg, 0.06 mmol, 1 equiv). In a N2-filled glovebox, this vial was charged with DMA (60 µL). Then, both vials were transferred into a N2-filled glovebox fitted with a temperature-controlled well plate. The catalyst stock solution was transferred to the second vial via syringe, then the reaction was stirred at ambient temperature at 250 rpm to ensure complete dissolution of 85 and appropriate mixing of all reagents (the catalyst may not be fully dissolved at this temperature). Then, the vial was placed in a well plate pre-cooled to –10 °C (cooled for 30 min). (Note: the recirculating Julabo LH45 chiller was set to –10 °C but an external thermometer in the glovebox read the temperature as –1 to –4 °C.) At this temperature, TDAE (21 µL, 0.09 mmol, 1.5 equiv) was added and the Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 541 solution stirred for 10 min before TMSBr (8 µL, 0.06 mmol, 1 equiv) (fumed slightly) was added, each via syringe. The reaction was stirred at 800 rpm at the chilled temperature in the glovebox. After 16 h, the reaction mixture was diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes; the filtrate was concentrated. The crude residue was assayed by quantitative 1H NMR and DOSY. The sample was concentrated and diluted in THF (2 mg/mL), filtered through a syringe filter, then assayed by GPC and GCMS (50 to 300 °C). The sample was concentrated, diluted in 250 µL PhMe, filtered through a syringe filter, then purified by preparative HPLC (C8, 8 mL/min, 95 to 100% ACN/H2O, 230 nm) to afford 94 (tR = 10.6 min). (Note: for runs employing a racemic mixture of L1·NiBr2, an equimolar amount of each enantiomer was weighed into the vial prior to solvent addition when preparing the catalyst stock solution. Yellow precipitate formed upon cooling this mixture to ambient temperature following heat-induced dissolution; this heterogeneous mixture was added to the second vial using a needle with a sufficiently large gauge.) (2S,3E,10S,11E)-2,10-dibutyl-1,9(1,4)-dibenzenacyclohexadecaphane-3,11-diene (94) 1 H NMR (CDCl3, 400 MHz): δ 7.09 – 7.00 (m, 2H), 6.98 – 6.91 (m, 2H), 5.50 – 5.40 (m, 1H), 5.37 – 5.25 (m, 1H), 3.12 (q, J = 7.4 Hz, 1H), 2.54 (dt, J = 14.8, 7.4 Hz, 1H), 2.42 (dt, J = 14.1, 7.6 Hz, 1H), 2.13 – 1.94 (m, 2H), 1.66 (q, J = 7.3 Hz, 2H), 1.50 – 1.40 (m, 2H), 1.34 – 1.22 (m, 5H), 1.22 – 1.09 (m, 1H), 0.86 (td, J = 7.1, 1.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 142.7, 140.4, 135.8, 128.8, 128.3, 127.5, 48.3, Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 542 35.3, 34.9, 32.1, 30.6, 30.1, 28.4, 22.9, 14.2. FTIR (NaCl, thin film, cm-1): 2926, 2855, 1743, 1510, 1456, 1377, 1259, 1103, 1020, 972, 808, 621. HRMS (FD, m/z): [M]+ calcd for C34H48: 456.3756; found: 456.3744. +1 (c = 0.1, CHCl3). 543 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Analysis of Crude 1H NMR Connectivity of repeat unit: pyrazine internal standard CDCl3 = Me 500 MHz, CDCl3  
 
 
 
 
 
 
 
 



 
 



End group analysis: pyrazine internal standard nBu = possibly CDCl3 = nBu n 500 MHz, CDCl3  
 
 
 
 
 
 
544 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Analysis of Crude via DOSY Bimodal distribution of species size: 
 
 
   
         small molecules polymers 400 MHz, CDCl3 
 
 
 
 
 
 
 
 



Close-up of olefinic region:    macrocycle polymer 400 MHz, CDCl3       
   




 545 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Analysis of Crude 1H NMR for Quantitation of 94 Yield nBu = pyrazine internal standard nBu n CDCl3 nBu = nBu 500 MHz, CDCl3  
 
 
 
 
 
 
 
 



Diastereomeric Ratio Determination via 1H NMR of Macrocycles 94 and 139 400 MHz, CDCl3        

        

    racemic ligand  
 
 
 
 



 
 
 
  
 
 
 

 
   
 
 
 
 



 
 
 
 
 
 
 

 


 400 MHz, CDCl3   
 
 
 
 
   


  


 enantioenriched ligand 


 
 
 
 
  546 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Structural Assignment of Purified Macrocycle 94 1 H NMR:   
                                    
 
  
       Me M L C G I  
  H D J I BC  
 K K’ 
  E 
 
F G 
 J 

H
  F  ML   A 



               14  Me 15      C NMR: 13 3 7 12 9 11    
  5 11 4        8    10 3             9     



 
  12  1
  

15  2
   
 
  10 
8   6   4  5 2   1 Me
  13
   400 MHz CDCl3 D
 K E B 
 A Me 6 7 13 14 101 MHz, CDCl3






















 547 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Identification of Polymer 98 by GPC 1 H NMR of samples following chromatographic separation (silica, 2.5% Et2O/hexanes): spot 1, Rf = 0.25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



spot 2, Rf = 0.1  
 



crude 400 MHz, CDCl3  
 



GPC trace of samples: approx. 5.6 kDa column shedding light scattering refractive index spot 1 spot 2 approx. 8.6 kDa polymers small molecules 548 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Identification of Polymer 98 by MALDI-TOF MS GPC trace of polymer samples from reaction at 0.1 M concentration: reaction run in triplicate macrocycle 10 12 14 16 18 20 22 24 Retention Time (min) MALDI-TOF MS data for samples (different end groups, same repeat unit): 549 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F General Procedure F: O Br O N nBu nBu N Ni Br NHP nBu Grubbs II (35 mol %) Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C O PhH, 50 °C nBu n Step 1: General Procedure E was followed, with substrate 85 (35.0 mg, 0.07 mmol, 1 equiv), TDAE (25 µL, 0.11 mmol, 1.5 equiv), TMSBr (9 µL, 0.07 mmol, 1 equiv), NaI (5.3 mg, 0.035 mmol, 0.5 equiv), L1·NiBr2 (4.0 mg, 0.007 mmol, 0.1 equiv), and DMA (140 µL, 0.5 M) at –3 °C for 16 h. After the silica filtration, the crude residue was diluted in minimal PhMe then sonicated; the white solids (NHP-containing byproducts) were filtered from the pale yellow supernatant over celite, rinsing with PhMe. The filtrate was concentrated and then diluted in minimal MeCN; the precipitate was collected by filtration, rinsing with MeCN, and concentrated to afford a translucent gel (crude polymer) that was used in the next step. Step 2: In a N2-filled glovebox, a 1-dram vial with a stir bar and Teflon cap was charged with the crude polymer (2.2 mg, 0.0096 mmol, 1 equiv). (Note: mmol of polymeric starting material for Step 2 was calculated based on the molecular weight of the repeat unit (228 g/mol).) Then, PhH (0.5 mL, 0.02 M) and Grubbs second generation catalyst (2.9 mg, 0.0034 mmol, 0.35 equiv) were sequentially added. Outside of the glovebox, the mixture was stirred until all solids were dissolved then heated to 50 °C in metal reaction block. After 2 h at that temperature, the reaction was concentrated and assayed by quantitative 1H NMR and DOSY. The sample was concentrated and diluted in THF (2 mg/mL), filtered through a syringe filter, then assayed by GPC and by GCMSFID (50 to 300 °C) with dodecane as standard, which determined the yield of macrocycle Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 550 94 to be 34% with respect to Step 2. (Note: the yield determined by 1H NMR was in good agreement.) 551 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Depolymerization Time Course 1 H NMR: purified macrocycle tetrachloroethane internal standard       
            
            
         
         
   

  
         
   

 16 h, 55 °C   
         
   

 115 h, 18 °C 24 h, 55 °C   macrocycle       
            
            
       
        mixture  
starting            2 h, 55 °C     
   
   

     
   

     
   

     
   
 polymer Reaction: G2 (35 mol %), C6H6 (0.02 M), temp, time; Sample: CDCl3 (0.025 M), 400 MHz       
         
     DOSY (0.0275 M each):   
 
 400 MHz, CDCl3 400 MHz, CDCl3 
 
 
 
 
 
 
 
 

 


 
 
 
 
 
 
GPC: starting mixture reaction: 2 h, 55 °C macrocycle 12 13 14 15 16  

   
   
 reaction: 2 h, 55 °C starting mixture 17 Retention Time (min) 18 19 20  
 



552 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F O O N N Ni Br Br nBu Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) NHP nBu TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C then Grubbs II (35 mol %) PhH, 50 °C nBu O First, General Procedure E was followed with substrate 85 (24.9 mg, 0.05 mmol, 1 equiv), TDAE (17 µL, 0.075 mmol, 1.5 equiv), TMSBr (7 µL, 0.05 mmol, 1 equiv), NaI (3.8 mg, 0.025 mmol, 0.5 equiv), L1·NiBr2 (2.9 mg, 0.005 mmol, 0.1 equiv), and DMA (50 µL, 1 M) at –10 °C for 16 h. Second, in lieu of silica filtration, the reaction was diluted with PhH (1.0 mL) in the glovebox then transferred via pipette to a 2-dram vial with a stir bar and Teflon cap, rinsing with PhH (1.5 mL). To this mixture was added Grubbs second generation catalyst (14.9 mg, 0.0175 mmol, 0.35 equiv). Outside of the glovebox, the mixture was stirred until all solids were dissolved then heated to 50 °C in metal reaction block. After 2 h at that temperature, the reaction mixture was cooled to ambient temperature and then diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes; the filtrate was concentrated and assayed by quantitative 1H NMR to determine formation of 94 occurred in 18% yield. 553 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F O Br O N Ni Br MeO OMe NHP nBu O MeO Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (0.5 M), –10 °C nBu nBu N MeO OMe OMe + MeO OMe nBu n General Procedure E was followed with substrate 57 (35.0 mg, 0.063 mmol, 1 equiv), TDAE (22 µL, 0.094 mmol, 1.5 equiv), TMSBr (8 µL, 0.063 mmol, 1 equiv), NaI (4.7 mg, 0.031 mmol, 0.5 equiv), L1·NiBr2 (3.6 mg, 0.0063 mmol, 0.1 equiv), and DMA (126 µL, 1 M) at –10 °C for 16 h. The crude residue was analyzed by quantitative 1H NMR, DOSY, and GCMS. 554 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Analysis of Crude 1H NMR Connectivity of repeat unit: pyrazine internal standard CDCl3 = OMe MeO Me 500 MHz, CDCl3 
 
 
 
 
 
 
 
 



 
  
     
 Analysis via DOSY: 400 MHz, CDCl3  
 
 
 
 
 
 
 



555 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 5.8.5 Revised Approach and Formal Synthesis tert-butyl 2-(4-(hex-5-en-1-yl)phenyl)hexanoate (105) Cp2ZrHCl PhH, 18 °C OtBu nBu O then H2O OtBu nBu O In a N2-filled glovebox, a flame-dried round-bottom flask was wrapped in foil then charged with Cp2ZrHCl (1.64 g, 6.4 mmol, 1.3 equiv) and PhH (50 mL, 0.1 M). Outside of the glovebox, alkyne 104 (1.64 g, 5.0 mmol, 1 equiv) was added and the reaction stirred at 18 °C in a darkened fume hood. Upon complete consumption of alkyne, as judged by TLC, water was slowly added. The mixture was extracted with Et2O. Combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was filtered through a plug of silica, eluting with 5% Et2O/hexanes. The filtrate was concentrated to afford 105 (1.36 g, 82% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.22 – 7.16 (m, 2H), 7.14 – 7.07 (m, 2H), 5.80 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 4.99 (ddt, J = 17.1, 2.1, 1.6 Hz, 1H), 4.93 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 3.42 – 3.34 (m, 1H), 2.62 – 2.54 (m, 2H), 2.11 – 2.04 (m, 2H), 2.04 – 1.93 (m, 1H), 1.74 – 1.57 (m, 3H), 1.48 – 1.41 (m, 2H), 1.39 (s, 9H), 1.36 – 1.13 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 173.8, 141.3, 139.1, 137.3, 128.5, 127.8, 114.5, 80.5, 52.5, 35.6, 33.8, 33.6, 31.0, 30.0, 28.7, 28.1, 22.7, 14.1. FTIR (ATR, cm-1): 1727, 1619, 1568, 1455, 1366, 1253, 1144, 1056. HRMS (FD, m/z): [M]+ calcd for C22H34O2: 330.2559; found: 330.2560. 556 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 2-(4-(hex-5-en-1-yl)phenyl)hexanoic acid (140) TFA OtBu nBu DCM, 18 °C O OH nBu O To a round-bottom flask with a stir bar was added ester 105 (1.36 g, 4.1 mmol, 1 equiv) then trifluoroacetic acid/DCM (1:1, 0.2 M). The solution was stirred at 18 °C for 30 minutes and then concentrated. The crude residue was azeotroped with PhMe to afford 140 (1.17 g, quantitative yield) as a yellow oil. 1 H NMR (CDCl3, 400 MHz): δ 7.24 – 7.19 (m, 2H), 7.15 – 7.09 (m, 2H), 5.80 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 4.99 (dq, J = 17.1, 1.7 Hz, 1H), 4.94 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 3.50 (t, J = 7.7 Hz, 1H), 2.65 – 2.54 (m, 2H), 2.13 – 1.96 (m, 3H), 1.76 (dddd, J = 13.3, 9.4, 7.4, 5.6 Hz, 1H), 1.68 – 1.54 (m, 2H), 1.50 – 1.39 (m, 2H), 1.39 – 1.15 (m, 4H), 0.86 (t, J = 7.1 Hz, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 180.0, 142.0, 139.0, 136.0, 128.8, 128.0, 114.6, 51.2, 35.6, 33.8, 33.0, 31.0, 29.8, 28.7, 22.6, 14.0. FTIR (ATR, cm-1): 3080, 2929, 2360, 1703, 1456, 1412, 1264, 1188, 909, 737. HRMS (TOF-ESI, m/z): [M – H]– calcd for C18H25O2: 274.1933; found: 273.1860. 557 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1,3-dioxoisoindolin-2-yl 2-(4-(hex-5-en-1-yl)phenyl)hexanoate (106) NHP EDC·HCl, DMAP OH nBu O DCM, 18 °C O O nBu N O O To a round-bottom flask with a stir bar was added acid 140 (1.13 g, 4.1 mmol, 1 equiv), N-hydroxyphthalimide (738 mg, 4.5 mmol, 1.1 equiv), DMAP (100 mg, 0.8 mmol, 0.2 equiv), then DCM (21 mL, 0.2 M). Then EDC·HCl (15 mg, 0.08 mmol, 1.1 equiv) was added in one portion. The reaction was stirred at 18 °C for 12 h and then concentrated. The crude residue was filtered through a plug of silica, eluting with EtOAc. The filtrate was concentrated and then purified by column chromatography (silica, 7 to 10% EtOAc/hexanes) to afford 106 (1.48 g, 86% yield) as a white amorphous solid. 1 H NMR (CDCl3, 400 MHz): δ 7.85 (dt, J = 7.6, 3.8 Hz, 2H), 7.77 (dd, J = 5.5, 3.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.23 – 7.15 (m, 2H), 5.81 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.00 (dq, J = 17.1, 1.7 Hz, 1H), 4.94 (ddt, J = 10.1, 2.2, 1.2 Hz, 1H), 3.89 (t, J = 7.6 Hz, 1H), 2.70 – 2.57 (m, 2H), 2.25 – 2.13 (m, 1H), 2.12 – 2.04 (m, 2H), 1.90 (ddt, J = 13.3, 9.9, 6.3 Hz, 1H), 1.64 (dtd, J = 9.4, 7.7, 6.0 Hz, 2H), 1.45 (pd, J = 7.4, 6.9, 3.7 Hz, 2H), 1.40 – 1.30 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 170.7, 142.4, 139.0, 134.8, 134.4, 129.1, 129.0, 128.0, 124.0, 114.6, 48.5, 35.6, 33.8, 33.8, 30.9, 29.5, 28.7, 22.5, 14.0. FTIR (ATR, cm-1): 3248, 3087, 2934, 2359, 1724, 1633, 1549, 1353, 1057, 877, 695. HRMS (TOF-ESI, m/z): [M + NH4]+ calcd for C26H34N2O4: 437.2435; found: 437.2432. 558 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F General Procedure G: O O N Ni R1 O O nBu O N N + Br Br R2 R1 Br L1·NiBr2 (20 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C nBu R2 O First, a stock solution of the catalyst was prepared. To a ½-dram vial with a stir bar and Teflon cap was added L1·NiBr275 (5.8 mg, 0.01 mmol, 0.1 equiv). In a N2-filled glovebox, the vial was charged with DMA (50 µL) the stirred while heating to 80 °C. The mixture was stirred at that temperature until all solids were completely dissolved and a maroon solution was obtained (ca. 5–10 min). Then the vial was allowed to completely cool to ambient temperature. Second, a separate ½-dram vial with a stir bar and Teflon cap was sequentially charged with NaI (7.5 mg, 0.05 mmol, 0.5 equiv) and NHP ester (0.1 mmol, 1 equiv). In a N2-filled glovebox, this vial was charged with DMA (50 µL). Then, both vials were transferred into a N2-filled glovebox fitted with a temperature-controlled well plate. The catalyst stock solution was transferred to the second vial via syringe, followed by alkenyl bromide (0.1 mmol, 1 equiv), then the reaction was stirred at ambient temperature at 250 rpm to ensure complete dissolution of the NHP ester and appropriate mixing of all reagents (the catalyst may not be fully dissolved at this temperature). Then, the vial was placed in a well plate pre-cooled to –10 °C. (Note: the recirculating Julabo LH45 chiller was set to –10 °C but an external thermometer in the glovebox read the temperature as –1 to –4 °C.) At this temperature, TDAE (35 µL, 0.15 mmol, 1.5 equiv) was added and the solution stirred for 10 min before TMSBr (13 µL, 0.1 mmol, 1 equiv) (fumed slightly) was added, each via syringe. The reaction was stirred at 800 rpm at the chilled temperature in the glovebox. After 16 h, 559 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F the reaction mixture was diluted with 20% EtOAc/hexanes and filtered over a plug of silica, eluting with 20% EtOAc/hexanes. The filtrate was concentrated, assayed by quantitative 1H NMR, then purified to afford the cross-coupled product, which was assayed by chiral SFC. (S,E)-1-(hex-5-en-1-yl)-4-(oct-2-en-4-yl)benzene (108) O O N N Ni O O nBu O N + Br Br Me Br (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –10 °C nBu Me O Prepared from NHP ester 106 (44 mg, 0.1 mmol, 1 equiv), 1-bromoprop-1-ene (9:1 E/Z, 9 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at –10 °C for 16 h following General Procedure G. The crude residue was purified by preparative thin layer chromatography (silica, hexanes) to afford 108 (21 mg, 79% yield, 97:3 E/Z) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.13 – 7.04 (m, 4H), 5.81 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.54 (ddq, J = 15.1, 7.7, 1.4 Hz, 1H), 5.42 (dqd, J = 15.2, 6.2, 0.8 Hz, 1H), 5.00 (dq, J = 17.1, 1.7 Hz, 1H), 4.93 (ddt, J = 10.1, 2.2, 1.2 Hz, 1H), 3.13 (q, J = 7.6 Hz, 1H), 2.64 – 2.49 (m, 2H), 2.15 – 2.03 (m, 2H), 1.70 – 1.56 (m, 8H), 1.49 – 1.38 (m, 2H), 1.36 – 1.21 (m, 3H), 1.21 – 1.08 (m, 1H), 0.86 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 143.1, 140.3, 139.1, 135.7, 128.5, 127.4, 124.3, 114.5, 48.7, 36.0, 35.5, 33.8, 31.1, 30.0, 28.8, 22.8, 18.1, 14.2. FTIR (ATR, cm-1): 2928, 2856, 2361, 2342, 1640, 1510, 1456, 1377, 965, 910. 560 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F HRMS (FI, m/z): [M]+ calcd for C20H30: 270.2348; found: 270.2365. +10 (c = 0.5, CHCl3). Chiral SFC: (OJ-H, 2.5 mL/min, 100% CO2, λ = 210 nm); tR ((E)-major) = 4.1 min, tR ((E)-minor) = 4.4 min; tR ((Z)-major) = 4.8 min, tR ((Z)-minor) = 4.6 min. 108: racemic Me nBu (Z) (E) nBu Me (+)-(E)-108: enantioenriched (92% ee) nBu Me 561 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (Z)-108: enantioenriched (44% ee) Me nBu General Procedure H: nBu Grubbs II (35 mol %) C6D6, 50 °C NMR tube nBu Me nBu In a N2-filled glovebox, a 1-dram vial with a stir bar was sequentially charged with an NMR tube was sequentially charged with 108 (4.3 mg, 0.016 mmol, 1 equiv), C6D6 (0.7 mL, 0.023 M), Grubbs second generation catalyst (4.7 mg, 0.0056 mmol, 0.35 equiv), and 2,3,4,5-tetrachloronitrobenzene (6.4 mg, 0.025 mmol, 1.54 equiv) as internal standard. The reaction was stirred at ambient temperature until all reagents dissolved (ca. 1 min) and then transferred via syringe into an NMR tube, which was capped and sealed with electrical tape. Outside the glovebox, the NMR tube was heated to 50 °C in an oil bath. At varying time points, the reaction was allowed to cool to ambient temperature, assayed by quantitative 1H NMR to determine the yield of 94, then returned to the heated oil bath. 562 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F nBu HBr Grubbs II (35 mol %) PhH, 50 °C nBu nBu Me Prepared following a modified procedure:73 In a N2-filled glovebox, a 1-dram vial with a stir bar and Teflon cap was sequentially charged with 108 (4.7 mg, 0.017 mmol, 1 equiv), PhH (0.87 mL, 0.02 M), and Grubbs second generation catalyst (5.2 mg, 0.006 mmol, 0.35 equiv). Outside of the glovebox, the mixture was stirred until all solids were dissolved and then heated to 50 °C in an oil bath. After 2 h at that temperature, the reaction was concentrated, assayed by quantitative 1H NMR, then purified by sequential preparative thin layer chromatography (silica, hexanes; then, silica, hexanes) to afford 94 (1.4 mg, 18% yield) as a colorless oil. +66 (c = 0.01, CHCl3). (S)-6-iodo-5-methylhex-1-ene (141) 1. DIBAL Et2O, 0 to 30 °C then MeOH, –60 °C Me I TMS 2. TsOH·H2O MeCN, 18 °C Me I Step 1: Prepared from alkyne 60 (1.18 g, 4 mmol, 1 equiv), diisobutylaluminum hydride (1.0 M in hexanes, 4.1 mL, 4.1 mmol, 1.02 equiv), and Et2O (4.2 mL, 0.95 M) following a published procedure160 to afford the alkene intermediate as a clear oil. Step 2: Prepared from the intermediate alkene (1 equiv), p-toluenesulfonic acid monohydrate (1.5 g, 8 mmol, 2 equiv), and MeCN (3.3 mL, 1.2 M) following a published procedure.160 The crude residue was purified by column chromatography (silica, 0 to 1% Et2O/hexanes) to afford 141 (764 mg, 78% yield over 2 steps) as a colorless oil. Spectra 563 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F matched those reported in the literature.73 1 H NMR (CDCl3, 500 MHz): δ 5.79 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.03 (dq, J = 17.1, 1.7 Hz, 1H), 4.97 (ddd, J = 10.2, 2.1, 1.1 Hz, 1H), 3.24 (dd, J = 9.6, 4.4 Hz, 1H), 3.18 (dd, J = 9.6, 5.7 Hz, 1H), 2.07 (dddq, J = 9.8, 6.4, 4.8, 1.6 Hz, 2H), 1.54 – 1.45 (m, 2H), 1.40 – 1.26 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H). +2 (c = 0.3, CHCl3). tert-butyl 2-(2,6-dimethoxy-4-((S)-2-methylhex-5-en-1-yl)phenyl)hexanoate (110) Me Br Me + MeO I OMe OtBu nBu O 1. tBuLi then ZnCl2 Et2O, –78 to 0 °C 2. Pd(dppf)Cl2 (5 mol %) THF, 50 °C MeO OMe OtBu nBu O Prepared from aryl bromide 52 (200 mg, 0.52 mmol, 1 equiv), alkyl iodide 141 (297 mg, 1.03 mmol, 2 equiv), tBuLi (1.7 M in pentane, 1.3 mL, 2.17 mmol, 4.2 equiv), ZnCl2 (0.5 M in THF, 2.1 mL, 1.03 mmol, 2 equiv), and Pd(dppf)Cl2 (18.9 mg, 0.026 mmol, 0.05 equiv) following a modified procedure.73 The crude residue was purified by preparative thin layer chromatography (silica, 2.5% EtOAc/7.5% DCM/hexanes) to afford 110 (167 mg, 80% yield) as a colorless oil. 1 H NMR (CDCl3, 500 MHz): δ 6.30 (s, 2H), 5.80 (ddt, J = 17.3, 10.1, 6.6 Hz, 1H), 5.00 (dd, J = 17.1, 1.9 Hz, 1H), 4.97 – 4.87 (m, 1H), 3.96 (dd, J = 9.0, 5.4 Hz, 1H), 3.75 (s, 6H), 2.65 – 2.55 (m, 1H), 2.38 – 2.26 (m, 1H), 2.15 (td, J = 14.4, 6.3 Hz, 1H), 2.05 (ddt, J = 15.5, 10.3, 5.3 Hz, 2H), 1.77 (q, J = 6.8 Hz, 1H), 1.65 (dtd, J = 14.2, 9.4, 5.1 Hz, 1H), 1.52 – 1.42 (m, 1H), 1.36 (t, J = 1.3 Hz, 8H), 1.34 – 1.13 (m, 4H), 1.08 (q, J = 4.2, 3.4 564 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F Hz, 1H), 0.88 (dd, J = 6.6, 1.4 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 174.6, 157.8, 141.2, 139.3, 115.8, 114.3, 104.9, 79.3, 55.7, 44.4, 40.9, 36.0, 34.5, 31.5, 29.9, 29.6, 28.1, 22.9, 19.6, 14.2. FTIR (ATR, cm-1): 2955, 2929, 1729, 1585, 1455, 1247, 1159, 1125. HRMS (FD, m/z): [M]+ calcd for C25H40O4: 404.2927; found: 404.2943. –6 (c = 0.3, CHCl3). 2-(2,6-dimethoxy-4-((S)-2-methylhex-5-en-1-yl)phenyl)hexanoic acid (142) Me Me TFA OMe MeO OtBu nBu DCM, 18 °C O OMe MeO OH nBu O To a round-bottom flask with a stir bar was added ester 110 (154 mg, 0.38 mmol, 1 equiv) then trifluoroacetic acid/DCM (1:1, 0.2 M). The solution was stirred at 18 °C for 30 minutes and then concentrated. The crude residue was azeotroped with PhMe to afford 142 (136 mg, 97% yield) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz): δ 6.33 (s, 2H), 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01 (dt, J = 17.1, 1.8 Hz, 1H), 4.94 (ddt, J = 10.3, 2.4, 1.2 Hz, 1H), 4.13 (dd, J = 8.9, 5.6 Hz, 1H), 3.77 (s, 6H), 2.71 – 2.50 (m, 1H), 2.32 (ddd, J = 13.4, 8.2, 1.1 Hz, 1H), 2.25 – 1.98 (m, 3H), 1.84 – 1.62 (m, 2H), 1.48 (ddt, J = 13.3, 9.7, 5.8 Hz, 1H), 1.42 – 1.15 (m, 4H), 1.16 – 1.01 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 180.0, 157.8, 142.1, 139.2, 114.4, 114.3, 105.3, 55.8, 44.4, 39.8, 36.0, 34.5, 31.5, 29.7, 29.7, 22.8, 19.6, 14.2. 565 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F FTIR (ATR, cm-1): 2955, 2930, 1703, 1585, 1455, 1125. HRMS (TOF-ESI, m/z): [M – H]– calcd for C21H32O4: 347.2228; found: 347.2225. –8 (c = 0.4, CHCl3). 1,3-dioxoisoindolin-2-yl 2-(2,6-dimethoxy-4-((S)-2-methylhex-5-en-1yl)phenyl)hexanoate (111) Me Me NHP EDC·HCl, DMAP OMe MeO OH nBu O MeO OMe DCM, 18 °C O nBu O N O O To a round-bottom flask with a stir bar was added acid 142 (240 mg, 0.69 mmol, 1 equiv), N-hydroxyphthalimide (112 mg, 0.69 mmol, 1 equiv), DMAP (17 mg, 0.14 mmol, 0.2 equiv), then DCM (3.4 mL, 0.2 M). Then EDC·HCl (132 mg, 0.69 mmol, 1 equiv) was added in one portion. The reaction was stirred at 18 °C overnight and then concentrated. The crude residue was purified by preparative thin layer chromatography (silica, 70% DCM/hexanes) to afford 111 (300 mg, 88% yield) as a thick, colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 5.2 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 6.36 (s, 2H), 5.89 – 5.74 (m, 1H), 5.01 (dt, J = 17.1, 1.8 Hz, 1H), 4.94 (dd, J = 10.4, 1.9 Hz, 1H), 4.47 (dd, J = 8.8, 5.4 Hz, 1H), 3.85 (s, 6H), 2.65 (ddd, J = 13.4, 6.0, 1.8 Hz, 1H), 2.35 (ddd, J = 13.0, 8.3, 3.7 Hz, 1H), 2.17 (dtd, J = 12.7, 6.6, 5.0, 3.2 Hz, 2H), 2.11 – 2.00 (m, 0H), 1.82 (dtd, J = 21.4, 12.2, 10.7, 6.9 Hz, 2H), 1.62 – 1.41 (m, 1H), 1.41 – 1.22 (m, 4H), 1.18 (ddp, J = 10.0, 7.8, 2.7 Hz, 1H), 0.90 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 6.9 Hz, 3H). 566 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 13 C{1H} NMR (CDCl3, 101 MHz): δ 171.5, 157.7, 142.7, 142.7, 139.3, 134.6, 129.3, 123.8, 114.4, 112.1, 104.7, 104.7, 55.8, 44.5, 37.8, 36.1, 34.5, 34.4, 31.5, 29.9, 29.6, 29.3, 22.7, 19.6, 14.1. FTIR (ATR, cm-1): 1742, 1456, 1117, 965, 695. HRMS (FD, m/z): [M]+ calcd for C29H35NO6: 493.2464; found: 493.2453. –6 (c = 1.3, CHCl3). 1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)-2-((S,E)-oct-2-en-4-yl)benzene (112) Me Me O O N N Ni MeO OMe O nBu O N O + Br Br Me Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –1 °C MeO nBu OMe Me O Prepared from NHP ester 111 (49 mg, 0.1 mmol, 1 equiv), 1-bromoprop-1-ene (9:1 E/Z, 9 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at –10 °C for 16 h following General Procedure G. The crude residue was purified by column chromatography (silica, 20% PhMe/hexanes) to afford 112 (16 mg, 47% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 3H), 5.90 (ddq, J = 15.2, 8.6, 1.6 Hz, 1H), 5.81 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.43 (dqd, J = 15.2, 6.4, 1.0 Hz, 2H), 5.01 (dq, J = 17.2, 1.7 Hz, 1H), 4.94 (ddt, J = 10.2, 2.3, 1.2 Hz, 1H), 3.86 (q, J = 8.0 Hz, 1H), 3.78 (s, 8H), 2.58 (dd, J = 13.4, 6.1 Hz, 1H), 2.31 (dd, J = 13.3, 8.2 Hz, 1H), 2.23 – 2.10 (m, 1H), 2.10 – 1.99 (m, 1H), 1.84 – 1.64 (m, 3H), 1.63 (dd, J = 6.1, 1.6 Hz, 4H), 1.48 (dddd, J = 13.3, 567 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 9.7, 6.2, 5.2 Hz, 1H), 1.40 – 1.14 (m, 4H), 1.14 – 1.01 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.2 Hz, 4H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.1, 140.4, 139.3, 134.7, 124.0, 119.3, 114.3, 105.9, 56.0, 44.2, 39.0, 36.0, 34.5, 33.6, 31.6, 30.6, 22.9, 19.6, 18.1, 14.3. FTIR (ATR, cm-1): 2954, 2927, 1579, 1233, 1138, 1118, 970. HRMS (FD, m/z): [M]+ calcd for C23H36O2: 344.2715; found: 344.2739. +8 (c = 0.5, CHCl3). 1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)-2-((E)-oct-2-en-4-yl)benzene (143) Me Me O O N N Ni MeO OMe O nBu O O N O + Br Br Me Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –1 °C MeO nBu OMe Me Prepared from NHP ester 111 (49 mg, 0.1 mmol, 1 equiv), 1-bromoprop-1-ene (9:1 E/Z, 9 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), racemic L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at –10 °C for 16 h following General Procedure G. The crude residue was purified by column chromatography (silica, 20% PhMe/hexanes) to afford 143 (13 mg, 38% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 2H), 5.96 – 5.85 (m, 1H), 5.85 – 5.74 (m, 1H), 5.43 (dqd, J = 15.2, 6.4, 1.0 Hz, 1H), 5.01 (dq, J = 17.1, 1.7 Hz, 1H), 4.94 (ddt, J = 10.2, 2.3, 1.3 Hz, 1H), 3.86 (q, J = 8.0 Hz, 1H), 3.78 (s, 6H), 2.59 (dd, J = 13.4, 6.1 Hz, 1H), 2.31 (dd, J = 13.4, 8.2 Hz, 1H), 2.23 – 2.11 (m, 1H), 2.11 – 1.99 (m, 1H), 1.82 – 1.66 (m, 568 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 3H), 1.63 (dd, J = 6.4, 1.6 Hz, 3H), 1.53 – 1.42 (m, 1H), 1.38 – 1.16 (m, 4H), 1.16 – 1.01 (m, 1H), 0.88 (d, J = 6.6 Hz, 2H), 0.85 (t, J = 7.2 Hz, 2H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.1, 158.1, 140.4, 139.3, 134.7, 124.0, 119.3, 114.3, 105.9, 56.0, 44.2, 39.0, 36.0, 34.5, 33.6, 31.6, 30.6, 22.9, 19.6, 18.1, 14.3. FTIR (ATR, cm-1): 2927, 1579, 1454, 1419, 1233, 1138, 1118, 969. –7 (c = 0.7, CHCl3). (2S,3E,10S,11E)-2,10-dibutyl-12,16,93,95-tetramethoxy-1,9(1,4)dibenzenacyclohexadecaphane-3,11-diene (113) Me Me nBu MeO Grubbs II (35 mol %) MeO C6D6, 50 °C NMR tube OMe nBu MeO OMe OMe nBu Me Me General Procedure H was followed with 112 (1.8 mg, 0.0052 mmol, 1 equiv), C6D6 (261 µL, 0.02 M), Grubbs second generation catalyst (1.6 mg, 0.0019 mmol, 0.36 equiv), and 2,3,4,5-tetrachloronitrobenzene (2.1 mg, 0.008 mmol, 1.54 equiv). (S,E)-1-(hex-5-en-1-yl)-4-(oct-2-en-4-yl)benzene (144) O O N N Ni O O nBu + Br Br TMS N O Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), –6 °C nBu TMS O Prepared from NHP ester 106 (44 mg, 0.1 mmol, 1 equiv), (E)-(2- bromovinyl)trimethylsilane (16 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 569 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at –6 °C for 12 h following General Procedure G. The crude residue was purified by preparative thin layer chromatography (silica, hexanes) to afford 144 (27 mg, 83% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.14 – 7.04 (m, 4H), 6.10 (dd, J = 18.6, 7.1 Hz, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.63 (dt, J = 18.5, 0.9 Hz, 1H), 5.06 – 4.96 (m, 1H), 4.94 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 3.33 – 3.14 (m, 1H), 2.63 – 2.54 (m, 2H), 2.14 – 2.04 (m, 2H), 1.75 – 1.56 (m, 4H), 1.50 – 1.39 (m, 2H), 1.36 – 1.24 (m, 3H), 1.24 – 1.09 (m, 1H), 0.86 (t, J = 7.1 Hz, 3H), 0.04 (d, J = 0.7 Hz, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 150.4, 142.1, 140.4, 139.1, 128.8, 128.5, 127.7, 114.5, 52.2, 35.6, 35.4, 33.8, 31.1, 29.9, 28.8, 22.8, 14.2, -1.0. FTIR (ATR, cm-1): 1979, 1608, 1456, 1258, 988, 866, 835, 739. HRMS (TOF-ESI, m/z): [M + Na]+ calcd for C22H36SiNa: 351.2478; found: 351.1781. HRMS (FD, m/z): [M]+ calcd for C22H36Si: 328.2586; found: 328.2572. +29 (c = 0.3, CHCl3). Chiral SFC: (OJ-H, 2.5 mL/min, 100% CO2, l = 210 nm); tR (major) = 2.5 min, tR (minor) = 2.4 min. 570 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 144: racemic nBu TMS nBu TMS (+)-144: enantioenriched (98% ee) (S,E)-(3-(4-(hex-5-en-1-yl)phenyl)hept-1-en-1-yl)trimethylsilane (119) TsOH·H2O MeCN, 18 °C nBu TMS nBu Prepared from alkenyl silane 144 (26 mg, 0.08 mmol, 1 equiv), p-toluenesulfonic acid monohydrate (30 mg, 0.16 mmol, 2 equiv), and MeCN (65 µL, 1.2 M) following a published procedure160 to afford 119 (19 mg, 91% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 7.10 (d, J = 1.1 Hz, 4H), 5.93 (ddd, J = 17.1, 10.3, 7.7 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 571 Hz, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.09 – 4.99 (m, 2H), 4.98 (dd, J = 3.3, 2.1 Hz, 1H), 4.94 (ddt, J = 10.2, 2.4, 1.3 Hz, 1H), 3.19 (q, J = 7.5 Hz, 1H), 2.64 – 2.51 (m, 2H), 2.15 – 1.99 (m, 2H), 1.74 – 1.57 (m, 4H), 1.44 (p, J = 7.5 Hz, 2H), 1.37 – 1.23 (m, 3H), 1.23 – 1.08 (m, 1H), 0.87 (t, J = 7.1 Hz, 3H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 142.9, 142.1, 140.5, 139.1, 128.5, 127.5, 114.5, 113.8, 49.7, 35.5, 35.3, 33.8, 31.1, 29.9, 28.8, 22.8, 14.2. FTIR (ATR, cm-1): 2956, 2927 1638, 1511, 1413, 991, 909. HRMS (FD, m/z): [M]+ calcd for C19H28: 256.2191; found: 256.2196. +31 (c = 1, CHCl3). Chiral SFC: (OJ-H, 2.5 mL/min, 100% CO2, l = 210 nm); tR (major) = 6.1 min, tR (minor) = 5.8 min. 119: racemic nBu 572 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F (+)-119: enantioenriched (96% ee) nBu nBu Grubbs II (15 mol %) CDCl3, 50 °C NMR tube nBu nBu General Procedure H was followed with 119 (3.7 mg, 0.014 mmol, 1 equiv), C6D6 (0.83 mL, 0.017 M), Grubbs second generation catalyst (1.7 mg, 0.002 mmol, 0.14 equiv), and 2,3,4,5-tetrachloronitrobenzene (9.4 mg, 0.036 mmol, 2.5 equiv). 1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)-2-((E)-oct-2-en-4-yl)benzene (145) Me Me O O N N Ni MeO OMe O nBu O + Br Br TMS N O Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), 0 °C MeO OMe nBu TMS 1 equiv), O Prepared from NHP ester 111 (44 mg, 0.09 mmol, (E)-(2- bromovinyl)trimethylsilane (16 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), 573 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at 0 °C for 12 h following General Procedure G. The crude residue was purified by column chromatography (silica, 0 to 1% Et2O/hexanes) to afford 145 (24 mg, 66% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.40 (dd, J = 18.7, 6.8 Hz, 1H), 6.32 (d, J = 3.7 Hz, 2H), 5.81 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.60 – 5.45 (m, 1H), 5.00 (dq, J = 17.1, 1.7 Hz, 1H), 4.97 – 4.91 (m, 1H), 3.91 (q, J = 7.2 Hz, 1H), 3.75 (s, 6H), 2.60 (dd, J = 13.4, 6.0 Hz, 1H), 2.31 (dd, J = 13.4, 8.0 Hz, 1H), 2.21 – 1.98 (m, 1H), 1.87 – 1.68 (m, 3H), 1.47 (tt, J = 11.5, 4.9 Hz, 1H), 1.25 (tq, J = 17.9, 8.5, 7.6 Hz, 5H), 1.13 – 1.01 (m, 1H), 0.93 – 0.86 (m, 3H), 0.83 (t, J = 7.1 Hz, 3H), 0.01 (s, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.3, 150.6, 140.6, 139.3, 127.4, 119.0, 114.3, 106.0, 56.0, 44.2, 42.1, 36.1, 34.5, 33.0, 31.5, 30.4, 22.9, 19.6, 14.3, -0.8. FTIR (ATR, cm-1): 2953, 2856, 1608, 1580, 1454, 1418, 1245, 121, 867, 836. HRMS (FD, m/z): [M]+ calcd for C25H42O2Si: 402.2954; found: 402.2949. –1 (c = 1.0, CHCl3). 2-((S)-hept-1-en-3-yl)-1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)benzene (120) Me Me TsOH·H2O MeO nBu OMe TMS MeCN, 18 °C MeO OMe nBu Prepared from alkenyl silane 145 (22 mg, 0.05 mmol, 1 equiv), p-toluenesulfonic acid monohydrate (21 mg, 0.1 mmol, 2 equiv), and MeCN (45 µL, 1.2 M) following a published procedure160 to afford 120 (16 mg, 89% yield) as a colorless oil. 574 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 2H), 6.30 – 6.20 (m, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.04 – 4.84 (m, 4H), 3.91 (q, J = 7.8 Hz, 1H), 3.77 (s, 6H), 2.58 (dd, J = 13.4, 6.1 Hz, 1H), 2.35 – 2.22 (m, 1H), 2.21 – 2.10 (m, 1H), 2.10 – 1.98 (m, 1H), 1.75 (dtdt, J = 9.8, 5.9, 3.7, 2.0 Hz, 3H), 1.47 (dddd, J = 13.4, 9.7, 6.2, 5.2 Hz, 1H), 1.36 – 1.16 (m, 4H), 1.15 – 1.03 (m, 1H), 0.85 (dd, J = 14.7, 7.0 Hz, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.2, 142.4, 140.7, 139.3, 118.6, 114.3, 113.2, 105.8, 56.0, 44.2, 40.0, 36.0, 34.5, 33.0, 31.5, 30.5, 22.9, 19.6, 14.3. FTIR (ATR, cm-1): 2954, 2926, 2360, 1580, 1454, 1418, 1232, 1143, 1117, 909, 739. HRMS (FI, m/z): [M]+ calcd for C22H34O2: 330.2559; found: 330.2569. +16 (c = 0.4, CHCl3). ((R,E)-3-(2,6-dimethoxy-4-((S)-2-methylhex-5-en-1-yl)phenyl)hept-1-en-1yl)trimethylsilane (146) Me Me O O N N Ni MeO OMe O nBu O + Br Br TMS N O Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), 0 °C MeO OMe nBu TMS 1 equiv), O Prepared from NHP ester 111 (42 mg, 0.09 mmol, (E)-(2- bromovinyl)trimethylsilane (16 µL, 0.1 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at 0 °C for 12 h following General Procedure G. The crude residue was purified by column chromatography (silica, 0 to 1% Et2O/hexanes) to afford 146 (20 mg, 57% yield) as a 575 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.41 (ddd, J = 18.7, 6.8, 0.9 Hz, 1H), 6.33 (s, 2H), 5.81 (ddtd, J = 16.9, 10.1, 6.7, 0.9 Hz, 1H), 5.55 (dt, J = 18.6, 1.2 Hz, 1H), 5.06 – 4.97 (m, 1H), 4.94 (ddq, J = 10.1, 2.2, 1.1 Hz, 1H), 3.92 (q, J = 7.4 Hz, 1H), 3.76 (d, J = 0.9 Hz, 6H), 2.60 (dd, J = 13.4, 6.1 Hz, 1H), 2.32 (dd, J = 13.3, 8.2 Hz, 1H), 2.23 – 1.99 (m, 2H), 1.83 – 1.69 (m, 3H), 1.56 – 1.41 (m, 1H), 1.39 – 1.13 (m, 4H), 1.08 (dddd, J = 15.4, 13.2, 9.2, 6.4 Hz, 1H), 0.92 – 0.87 (m, 3H), 0.87 – 0.77 (m, 3H), 0.02 (d, J = 0.9 Hz, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.3, 150.6, 140.6, 139.3, 127.4, 119.0, 114.3, 106.0, 56.0, 44.2, 42.1, 36.1, 34.5, 33.0, 31.6, 30.4, 22.9, 19.6, 14.3, -0.8. FTIR (ATR, cm-1): 2953, 1360, 1608, 1580, 1454, 1245, 1122, 867, 836. –10 (c = 0.8, CHCl3). 2-((R)-hept-1-en-3-yl)-1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)benzene (147) Me Me TsOH·H2O MeO nBu OMe TMS MeCN, 18 °C MeO OMe nBu Prepared from alkenyl silane 146 (16 mg, 0.04 mmol, 1 equiv), p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol, 2 equiv), and MeCN (33 µL, 1.2 M) following a published procedure160 to afford 147 (8 mg, 58% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 2H), 6.30 – 6.20 (m, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 – 4.86 (m, 4H), 3.97 – 3.87 (m, 1H), 3.78 (s, 6H), 2.59 (dd, J = 13.3, 6.1 Hz, 1H), 2.31 (dd, J = 13.4, 8.2 Hz, 1H), 2.23 – 1.99 (m, 2H), 1.81 – 1.71 (m, 3H), 1.48 (dddd, J = 13.5, 9.8, 6.2, 5.2 Hz, 1H), 1.39 – 1.15 (m, 4H), 1.17 – 1.03 (m, 1H), 576 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 0.86 (dd, J = 14.5, 7.1 Hz, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.2, 142.4, 140.7, 139.3, 118.6, 114.3, 113.2, 105.8, 56.0, 44.2, 40.0, 36.0, 34.5, 33.0, 31.6, 30.5, 22.9, 19.6, 14.3. FTIR (ATR, cm-1): 2926, 1606, 1580, 1454, 1416, 1232, 1142, 1117, 907. –33 (c = 0.5, CHCl3). ((E)-3-(2,6-dimethoxy-4-((S)-2-methylhex-5-en-1-yl)phenyl)hept-1-en-1yl)trimethylsilane (148) Me Me O O N N Ni MeO OMe O nBu O N O + Br Br TMS Br L1·NiBr2 (10 mol %) TDAE (1.5 equiv) TMSBr (1 equiv), NaI (0.5 equiv) DMA (1 M), 0 °C MeO nBu OMe TMS O Prepared from NHP ester 111 (42 mg, 0.09 mmol, 1 equiv), TDAE (35 µL, 0.15 mmol, 1.5 equiv), TMSBr (13 µL, 0.1 mmol, 1 equiv), (E)-(2-bromovinyl)trimethylsilane (16 µL, 0.1 mmol, 1 equiv), NaI (7.5 mg, 0.05 mmol, 0.5 equiv), racemic L1·NiBr2 (5.8 mg, 0.01 mmol, 0.1 equiv), and DMA (0.1 mL, 1 M) at 0 °C for 12 h following General Procedure G. The crude residue was purified by column chromatography (silica, 0 to 1% Et2O/hexanes) to afford 148 (21 mg, 61% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.41 (ddd, J = 18.6, 6.9, 1.9 Hz, 1H), 6.33 (d, J = 1.9 Hz, 2H), 5.89 – 5.73 (m, 1H), 5.55 (dt, J = 18.6, 1.8 Hz, 1H), 5.01 (dt, J = 17.1, 1.9 Hz, 1H), 4.95 (dtt, J = 10.2, 2.3, 1.2 Hz, 1H), 3.97 – 3.87 (m, 1H), 3.76 (d, J = 2.0 Hz, 6H), 2.61 (ddd, J = 13.3, 6.1, 1.9 Hz, 1H), 2.32 (dd, J = 13.4, 8.1 Hz, 1H), 2.26 – 2.00 (m, 2H), 1.81 – 1.70 (m, 3H), 1.48 (dtd, J = 11.9, 6.9, 6.4, 3.0 Hz, 1H), 1.27 (qt, J = 7.9, 4.1 Hz, 577 Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 4H), 1.09 (dddd, J = 13.0, 10.3, 4.8, 2.9 Hz, 1H), 0.89 (dd, J = 6.6, 1.9 Hz, 3H), 0.84 (t, J = 8.1 Hz, 3H), 0.03 (d, J = 2.1 Hz, 9H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 158.3, 150.6, 140.6, 139.3, 127.3, 119.0, 114.3, 106.0, 56.0, 44.2, 42.1, 36.1, 34.5, 33.0, 31.5, 30.4, 22.9, 19.6, 14.3, -0.8. FTIR (ATR, cm-1): 2928, 1608, 1580, 1454, 1245, 1121, 868, 836. –3 (c = 0.8, CHCl3). 2-(hept-1-en-3-yl)-1,3-dimethoxy-5-((S)-2-methylhex-5-en-1-yl)benzene (149) Me Me TsOH·H2O MeO nBu OMe TMS MeCN, 18 °C MeO OMe nBu Prepared from alkenyl silane 148 (13 mg, 0.03 mmol, 1 equiv), p-toluenesulfonic acid monohydrate (12 mg, 0.6 mmol, 2 equiv), and MeCN (26 µL, 1.2 M) following a published procedure160 to afford 149 (7 mg, 64% yield) as a colorless oil. 1 H NMR (CDCl3, 400 MHz): δ 6.32 (s, 2H), 6.31 – 6.20 (m, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 4.95 (dddd, J = 30.4, 17.3, 10.3, 2.2 Hz, 4H), 3.92 (q, J = 8.0 Hz, 1H), 3.77 (s, 6H), 2.59 (dd, J = 13.3, 6.1 Hz, 1H), 2.31 (dd, J = 13.4, 8.1 Hz, 1H), 2.23 – 1.96 (m, 2H), 1.76 (td, J = 13.8, 9.9, 4.1 Hz, 3H), 1.50 – 1.41 (m, 1H), 1.26 (tt, J = 17.8, 5.5 Hz, 4H), 1.10 (tt, J = 11.6, 6.6 Hz, 1H), 0.94 – 0.73 (m, 6H). 13 C{1H} NMR (CDCl3, 101 MHz): δ 770.4, 754.6, 752.9, 751.5, 730.8, 726.5, 725.4, 718.0, 668.1, 656.4, 652.1, 648.1, 646.6, 645.1, 643.7, 642.6, 635.0, 631.7, 626.4. 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E.; Dewson, G.; Watson, K. G.; Huang, D. C. S.; Lessene, G.; Kile, B. T. A Small Molecule Interacts with VDAC2 to Block Mouse BAK-Driven Apoptosis. Nat. Chem. Biol. 2019, 15 (11), 1057–1066. (154) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Intramolecular MetalloEne-Allene Reactions. A New Carbocycles Synthesis. J. Org. Chem. 1995, 60 (4), 863–871. (155) Jiang, X.-R.; Wang, P.; Smith, C. L.; Zhu, B. T. Synthesis of Novel Estrogen Receptor Antagonists Using Metal-Catalyzed Coupling Reactions and Characterization of Their Biological Activity. J. Med. Chem. 2013, 56 (7), 2779– 2790. (156) Hofstra, J. L.; Cherney, A. H.; Ordner, C. M.; Reisman, S. E. Synthesis of Enantioenriched Allylic Silanes via Nickel-Catalyzed Reductive Cross-Coupling. J. Am. Chem. Soc. 2018, 140 (1), 139–142. (157) Bräse, S.; Wertal (nee Nüske), H.; Frank, D.; Vidović, D.; de Meijere, A. Intramolecular Heck Couplings and Cycloisomerizations of Bromodienes and Enynes with 1′,1′-Disubstituted Methylenecyclopropane Terminators: Efficient Syntheses of [3]Dendralenes. Eur. J. Org. Chem. 2005, 2005 (19), 4167–4178. (158) Rodier, F.; Rajzmann, M.; Parrain, J.-L.; Chouraqui, G.; Commeiras, L. Diastereoselective Access to Polyoxygenated Polycyclic Spirolactones through a Chapter 5 – Formal Synthesis of (–)-Cylindrocyclophane F 599 Rhodium-Catalyzed [3+2] Cycloaddition Reaction: Experimental and Theoretical Studies. Chem. Eur. J. 2013, 19 (7), 2467–2477. (159) Schäckermann, J.-N.; Lindel, T. Synthesis and Photooxidation of the Trisubstituted Oxazole Fragment of the Marine Natural Product Salarin C. Org. Lett. 2017, 19 (9), 2306–2309. (160) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. Intramolecular Carbometallation of Organozinc Reagents. Tetrahedron 1994, 50 (40), 11665– 11692.  Appendix 1 – Spectra Relevant to Chapter 3 600 Appendix 1 Spectra Relevant to Chapter 3: Oxidative Transpositions Mediated by Selenium Dioxide   # '('  ,,(#  #-         ! " )*    $  % &     + * "    % &                    
                                57   

 Appendix 1 – Spectra Relevant to Chapter 3 601      %,    %    ' (  % % "  # $ %    !     + * $     %      )*       &  ' ( 
                               57  
 Appendix 1 – Spectra Relevant to Chapter 3 602             $.    (    & ' ,,-  )*    ( %  & '     + * # $  !  " #                                                         
  58  

 Appendix 1 – Spectra Relevant to Chapter 3 603    $ ($ $(              !  " # %  & ' )*        $,    $((    & ' + * # $         
                               58  
 Appendix 1 – Spectra Relevant to Chapter 3 604         $ (          !  " # %  & ' )*      $.    (    & ' + * # ,,-                                                     !"          
   4a  

 Appendix 1 – Spectra Relevant to Chapter 3 605       & '   $(    $, $(( + * # $       )*   ($ $ %  & '   !  " #                   
                                          4a   
 Appendix 1 – Spectra Relevant to Chapter 3 606           *+,   !  /(0/ ""((( "((((   "%# "#   "  0("0     1 .  ' /((" - .!   )! *+, $ &   ' !  $                                                  
  59   

 Appendix 1 – Spectra Relevant to Chapter 3 607  !    .'/. ""''' "'''' "" "#    !   )*+  "  /'"/     0 -  & .''" , -!   (! )*+ $ %   &     $                                           
                       69   

 Appendix 1 – Spectra Relevant to Chapter 3 608 (%%%%% (#( )! *+, - .!         ( 0%1"   !  *+,     / .  ' (%%# (%%%% $ &   ' % "#       $     !        
                              69  
 Appendix 1 – Spectra Relevant to Chapter 3 609           %(0% "-((( "((((   "% "#     !   *+,  "  0("0     1 /  ' %((" . /!   )! *+, $ &   '   $ !                                                                 
 !     4b  

 Appendix 1 – Spectra Relevant to Chapter 3 610 #/# #((((( #(((( % "#      *+,   !     # 1(%"          0 .  ' #((/ - .!   )! *+, $ &   '    !   $        
                                 4b             
 Appendix 1 – Spectra Relevant to Chapter 3 611         +,,-+  !  " # ()    %  & '     * ) #    & '   $                  $.       
                                                61   

 Appendix 1 – Spectra Relevant to Chapter 3 612     ! "  # $      -  (()   , + $ )    & '     (     ()      *+       %  & ' 
                  61              
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       "                     4c  

 Appendix 1 – Spectra Relevant to Chapter 3 614 &&&& &&&&& # )" *+, -!."      ! "  ! *+,    0&1 !    / . !( &&# %& $ '   ( #   $ !        !"                            
           4c     
 Appendix 1 – Spectra Relevant to Chapter 3 615       ")))) ""))) %)&% *! +,- . /!      !   +,-  "  &)"&     0 /  ( %))" "%&    $ '   ( "# $  !                                               
        62   

 Appendix 1 – Spectra Relevant to Chapter 3 616          !      +,-   !   0)&0 ""%))) ")))) "%#& "#   "  &)"&     1 /  ( 0))" . /!   *! +,- $ '   ( $                                                    
  63    

 Appendix 1 – Spectra Relevant to Chapter 3 617 (((( ((((( / )" *+, -!."          1(% ! " ! *+, !    0 . !' ((/ $%$ # &   '    # !        !"               
            63                     
 Appendix 1 – Spectra Relevant to Chapter 3 618    $  %(0% "-((( "(((( "%  "#     !    "  0("0   *+,     1 /  ' %((" . /!   )! *+, $ &   '      !                                                       
  4d   

 Appendix 1 – Spectra Relevant to Chapter 3 619      !   )*+   !  #.# #''''' #'''' """ "#      #   0'1"     / -  & #''. , -!   (! )*+ $ %   & $                                     
                   4d     
 Appendix 1 – Spectra Relevant to Chapter 3 620    (((( ((( /(%/ )" *+, -!."    ! "  ! *+,    %(% !    0 . !' /(( % $ &   ' # $ !     !"                                                 
  64   

 Appendix 1 – Spectra Relevant to Chapter 3 621 '''' ''''' . (" )*+ ,!-"          0'#1 ! " ! )*+ !    / - !& ''. # $ %   & #   $ !        !"        
                      64                        
 Appendix 1 – Spectra Relevant to Chapter 3 622      (((( ((( /(%/ )" *+, -!."    ! "  ! *+,    %(% !    0 . !' /(( %% $ &   ' # $ !     !"                                                  
     4e  

 Appendix 1 – Spectra Relevant to Chapter 3 623 !" . %%%%% %%%% % #     ! "  ! )*+      0%#1 !    / - !' %%. ,!-"   (" )*+ $ &   ' $ !                              
                                 4e   
 Appendix 1 – Spectra Relevant to Chapter 3 624   ((( %(/% )" *+, -!."    ! "  ! *+,    /(/ !    0 . !' %(( (((( $ &   '             % #   !"  $ !                                                                   
   4f   

 Appendix 1 – Spectra Relevant to Chapter 3 625   !"   ! +,- ! "      % ))))) )))) %& #      &)#1       !    0 / !( ))% .!/"   *" +,- $ '   ( $ !                                    
       4f                 
 Appendix 1 – Spectra Relevant to Chapter 3 626      (((( ((( /(0/ $ &   ' )" *+, -!."    ! "  ! *+,    0(0 !    1 . !' /(( %#   #   !"   $ !                                                                                  
  4g   

 Appendix 1 – Spectra Relevant to Chapter 3 627   !"   ! )*+ ! "     . ''''' '''' # #      0'#1 !    / - !& ''. ,!-"   (" )*+ $ %   & $ !                  
                               6k                      
 Appendix 1 – Spectra Relevant to Chapter 3 628      # ''  +,,#  #-         ! " ()    $  % &     * ) "    % &                    
                                     75   

 Appendix 1 – Spectra Relevant to Chapter 3 629  "(((( -((( %(-% )! *+, . /!      !   *+,  "  -("-     0 /  ' %((" "%    $ &   ' "# $     !                                    
    66   

 Appendix 1 – Spectra Relevant to Chapter 3 630 '""""" '.' (! )*+ , -!         ' $"01   !  )*+     / -  & '"". '"""" # %   & $ """       #     !        
               66          
 Appendix 1 – Spectra Relevant to Chapter 3 631          (((( -((( %(-% )" *+, .!/"    ! "  ! *+,    -(- !    0 / !' %(( % $ &   ' # $ !     !"                                                  
    67   

 Appendix 1 – Spectra Relevant to Chapter 3 632 #### ##### / )" *+, -!."          $#%1 ! " ! *+, !    0 . !( ##/ $ & '   ( #$%   & !        !"        
                 67                
 Appendix 1 – Spectra Relevant to Chapter 3 633       %%%% ,%%% /%,/ $ &   ' (" )*+ -!."    ! "  ! )*+    ,%, !    0 . !' /%% % $ !    #                                      !"                   
  68  

 Appendix 1 – Spectra Relevant to Chapter 3 634 !" / ##### #### &&& #$  ! "   ! *+,      $#1& !    0 . !( ##/ -!."   )" *+, % '   ( % !                                                    
       68  
 Appendix 1 – Spectra Relevant to Chapter 3 635       !" $%$ !%%%% !+%%% .%/.     #     #    & ()* ' ,-         ()*  !  /%!/     0 - & .%%!$                                                 
    4i  

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                              4i   
 Appendix 1 – Spectra Relevant to Chapter 3 637    !" $%$ !%%%% !+%%% .%/.     #     #    & ()* ' ,-         ()*  !  /%!/     0 - & .%%!$                                                     
  4j  

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                         4j   
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    4k  

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                                          69  

 Appendix 1 – Spectra Relevant to Chapter 3 642   # '  +,,-+ ' #.         ! " ()    $  % &     * ) "    % &                    
                                      70   

 Appendix 1 – Spectra Relevant to Chapter 3 643  &&&& +&&& .&/. '! ()* , -!      !   ()*    /&/     0 -  % .&&1     # $   % " #  !                       
                                       
   7a   
 Appendix 1 – Spectra Relevant to Chapter 3 644 %%%% %%%%% . (" )*+ ,!-"             0%1#  ! "  ! )*+ !    / - !' %%. #% $ &   ' #   $ !        !"      
       7a                                
 Appendix 1 – Spectra Relevant to Chapter 3 645     # '  +,,-+ ' #.         ! " ()    $  % &     * ) "    % &                    
                                               71   

 Appendix 1 – Spectra Relevant to Chapter 3 646  # '  +,,-+ ' #.         ! " ()    $  % &     * ) "    % &                    
                                              7b   
 Appendix 1 – Spectra Relevant to Chapter 3 647  '''' ,''' /'$/ # %   & (" )*+ -!."    ! "  ! )*+    $'$ !    0 . !& /'' $  # !       !"                                               
  72   

 Appendix 1 – Spectra Relevant to Chapter 3 648  )))) %))) 0)&0 *" +,- .!/"    ! "  ! +,-    &)& !    1 / !( 0)) %&% $ '   ( # $ !                   !"                                      
   7c   

 Appendix 1 – Spectra Relevant to Chapter 3 649     $.    (    & ' ,,-  )*    ( %  & '     + * # $  !  " #                                                       
    73   

 Appendix 1 – Spectra Relevant to Chapter 3 650     $.    (    & ' ,,-  )*    ( %  & '     + * # $  !  " #                                                      
    7d   

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                                   7d   
 Appendix 1 – Spectra Relevant to Chapter 3 652    $ $ *+++ + *-+. $/       !  " # ()    %  & '     , ) #    & '                    
                                74        
 Appendix 1 – Spectra Relevant to Chapter 3 653  ""-((( 0(%0 )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" "(((( % $ &   '    "# $  !                                                         
     7e     

 Appendix 1 – Spectra Relevant to Chapter 3 654 (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( $% # &   '  # !       !"                                              
  75   

 Appendix 1 – Spectra Relevant to Chapter 3 655 (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' # $ !     !"                                                        
  7f  
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      76  

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                                 76      
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 %     77  

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                          77     
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     7g  

 Appendix 1 – Spectra Relevant to Chapter 3 661 "((((( "/" - .!     !    *+,   " 1(#     0 .  ' "((/ "(((( )! *+, #%# $ &   '    "# $     !                                
                          7g  
 Appendix 1 – Spectra Relevant to Chapter 3 662     /'$/ - .!      !   )*+  "  $'"$     0 .  & /''" "",''' (! )*+ $ ''''    # %   & # " !                                                                         
  7h  

 Appendix 1 – Spectra Relevant to Chapter 3 663 (((( ((((( / )" *+, -!."   ! "   ! *+,    1(# !    0 . !' ((/ %#% $ &   ' # $ !       !"                                
                                 7h  
 Appendix 1 – Spectra Relevant to Chapter 3 664     
         
         




 
 
 
  7h Appendix 1 – Spectra Relevant to Chapter 3 665  (((( -((( 0(%0 )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( % $ &   ' #   $ !     !"                                                
  28  

 Appendix 1 – Spectra Relevant to Chapter 3 666 .  ! " ! )*+       0%1# !    / - !' %%. %%%%% ,!-"   %%%% (" )*+ % #  $ &   ' !"       $ !                                            
     28  
 Appendix 1 – Spectra Relevant to Chapter 3 667   "-((( 0(%0 )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" "(((( % $ &   '    "# $  !                                                                                                
   31  

 Appendix 1 – Spectra Relevant to Chapter 3 668 %%%% %%%%% . (" )*+ ,!-"   ! "        0%1#         ! )*+ !    / - !' %%. % $ &   ' #   $ !        !"      
                                   31   
 Appendix 1 – Spectra Relevant to Chapter 3 669     "(((( "-((( %(0% )! *+, . /!      !   *+,  "  0("0     1 /  ' %((" "%    $ &   ' $ "# !                                                                       
   50  
 Appendix 1 – Spectra Relevant to Chapter 3 670 (((( ((((( / )" *+, -!."   ! "        1(%#         ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                              
           50   
 Appendix 1 – Spectra Relevant to Chapter 3 671    ""-((( $(%$ )! *+, . /!   "     %("% 3  ++ 45   !  *+,     0 /  ' $((" ((((( # &   ' "$% " !        #                                        "1$2+ &                
             6  

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       6  
 Appendix 1 – Spectra Relevant to Chapter 3 673         '''' #''' $'.$ (! )*+ , -!      !   )*+    .'.     / -  & $''0 #$    " %   &  "                !               
                         
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 Appendix 1 – Spectra Relevant to Chapter 3 674      $( ($ $           $, $(( + * # $    & '     )*   %  & '  !  " #               
                                            5a   
 Appendix 1 – Spectra Relevant to Chapter 3 675            #(%# ,((( (((( "% "#     !    )*+    %(%     / .   #((0 - .!   ! )*+ $ &  '  $ !                                                       
  5b  

 Appendix 1 – Spectra Relevant to Chapter 3 676  """"" -%- + ,!      !   ()*     -1 #"-/0     . ,   ""% """" ! ()* %# $ &  '     "# $     !                     
                            5b      
 Appendix 1 – Spectra Relevant to Chapter 3 677      %)))) %&))) #)0# $ '   ( *! +,- . /!      !   +,-  %  0)%0     1 /  ( #))% %&" "#    $  !                                                          
      5c  

 Appendix 1 – Spectra Relevant to Chapter 3 678 "((((( "$" - .!      !    *+,     "   0(1#     / .  ' "(($ "(((( ### )! *+,    % &   ' % "#$  !                                            
       5c    

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  5d     

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 -1 #"-/0     ()*     . ,   ""% """" $ &  '  %# "#       $     !      
  


 

  5d
 
 


 


 









          
 Appendix 1 – Spectra Relevant to Chapter 3 681    


  (((( -((( %(0% )" *+, .!/"    ! "     0(0   ! *+, !    1 / !' %((  %  $ &   ' # $ !     !"                                                     
    5e  

 Appendix 1 – Spectra Relevant to Chapter 3 682 #''''' #.# (! )*+ , -!      !   )*+     # 0'1"     / -  & #''. #'''' $ %   & """ "#       $     !                          
    5e                
 Appendix 1 – Spectra Relevant to Chapter 3 683     ''''' $''' .'$. (" )*+ ,!-"        $'$ 2  ** 34 ! " ! )*+ !    / - !& .'' $ # %   &    # !     !"                                                  
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 Appendix 1 – Spectra Relevant to Chapter 3 684   %((( $(%$ )! *+, - .!   " %("%    2  ++ 34   !  *+,     / .  ' $(("   ((((( "$% # &   '    "    #  !                                                            
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 Appendix 1 – Spectra Relevant to Chapter 3 685   ! !#$ !'''' !!,''' #'$#     "     " %   & )*+ ( -.         )*+  !  $'!$     / . & #''!0 
                                                
      8a  

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                                    8a   
 Appendix 1 – Spectra Relevant to Chapter 3 687       !" $$ $'''' $,''' "'/"        #     # %   & )*+ ( -.         )*+  $  /'$/     0 . & "''$1 
                                           
  8b  

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                  8b        
 Appendix 1 – Spectra Relevant to Chapter 3 689         $''' .'/. (! )*+ , -!      !   )*+    /'/     0 -  & .''1 '''' $$$ # %   &    " #  !                                     
               
  8c   

 Appendix 1 – Spectra Relevant to Chapter 3 690     ! /0/    !    *+,     /2 #"/$&     1 .  ( ""0 """"" - .!   """" &&& "#$  
     )! *+, % '   ( %        
                  8c                    
 Appendix 1 – Spectra Relevant to Chapter 3 691   )))) &))) $)0$ % '   ( *" +,- .!/"    ! "  ! +,-    0)0 !    1 / !( $)) &# #$ % !     !"                                                
      8d  
 Appendix 1 – Spectra Relevant to Chapter 3 692    ! "$"    !  +,-      "   1)&#     0 /  ( "))$ "))))) . /!   ")))) & "#$      *! +,- % '   ( %        
   8d                                 

 Appendix 1 – Spectra Relevant to Chapter 3 693     !" !$  !'''' !,''' $'/$        #     # %   & )*+ ( -.         !  /'!/   )*+     0 . & $''!1  
                                 
        8e     

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    8e                   
 Appendix 1 – Spectra Relevant to Chapter 3 695     #''' $'.$ (! )*+ , -!      !     .'.   )*+     / -  & $''0 ''''  #$  " %   &     "     ! 
                                             
   8f  

 Appendix 1 – Spectra Relevant to Chapter 3 696  "'''' ",''' /'0/ $ %   & (! )*+ - .!      !   )*+  "  0'"0     1 .  & /''" "" "#    $                                     !                                 !      
  8g  

 Appendix 1 – Spectra Relevant to Chapter 3 697 !" #### ##### / % '   ( )" *+, -!."    ! "    ! *+,      $#1& !    0 . !( ##/ &&& % !    #$                               
                        8g  
 Appendix 1 – Spectra Relevant to Chapter 3 698        #   %))) &)& *" +,- .!/"    ! "    )   ! +,- !    0 / !( &)) ))))   $ '   (  %& $ !                        !"                       
   38   

 Appendix 1 – Spectra Relevant to Chapter 3 699 !"   ! *+, ! "   / ##### #### &# #$        $#1            !    0 . !( ##/ -!."   )" *+, % '   ( % !               
         38                
 Appendix 1 – Spectra Relevant to Chapter 3 700       (((( -((( $(%$ # &   ' )" *+, .!/"    ! "  ! *+,    %(% !    0 / !' $(( $% # !       !"                                                  
        26 + 27  

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                                26 + 27  
 Appendix 1 – Spectra Relevant to Chapter 3 702     $$$$ +$$$ .$/. # %   & '" ()* ,!-"    ! "  ! ()*    /$/ !    0 - !& .$$ $  # !       !"                                     
       29 + 30  
 Appendix 1 – Spectra Relevant to Chapter 3 703    )*+    !    #.# #%%%%% #%%%% % "#       # 0%1"     / -  ' #%%. , -!   (! )*+ $ &   '    !   $                                               
     29 + 30  
 Appendix 1 – Spectra Relevant to Chapter 3 704  #(((( #-((( %(0% )! *+, . /!      !   *+,  #  0(#0     1 /  ' %((# #$%    " &   '  "  !                                                         
   24  

 Appendix 1 – Spectra Relevant to Chapter 3 705 )##### )) *! +,- . /!      !    +,-     ) "#&1     0 /  ( )## )#### $ '   ( %&% "#       $     !                              
                         24   
 Appendix 1 – Spectra Relevant to Chapter 3 706   '''' #''' .'$. (! )*+ , -!      !   )*+    $'$     / -  & .''0 #$    " %   &  "  !                                 
                      
   33a  

 Appendix 1 – Spectra Relevant to Chapter 3 707      ! ##    !      # 1)&"        +,-     0 /  ( #)) #))))) . /!   #)))) %&% "#   *! +,- $ '   ( $                             
               33a   
 Appendix 1 – Spectra Relevant to Chapter 3 708   '''' ,''' #'/# $ %   & (! )*+ - .!      !   )*+    /'/     0 .  & #''1 # "#    $  !                             
                 
       33b  
 Appendix 1 – Spectra Relevant to Chapter 3 709 !"# %%% !"""" !""""" !./.!     $     $ &   ' )*+ ,-        )*+      !.2 #".1%     0 - ' !""/      ( 
     
                            33b     
 Appendix 1 – Spectra Relevant to Chapter 3 710        !" !$ !'''' !,''' $'/$        #     # %   & )*+ ( -.         )*+  !  /'!/     0 . & $''!1 
                                     
      33d  

 Appendix 1 – Spectra Relevant to Chapter 3 711 """"" &/& - .!      !    *+,     &2 #"&1%     0 .  ( ""/ """" %"& )! *+,    $ '   ( $ "#  !       
       
                             33d    
 Appendix 1 – Spectra Relevant to Chapter 3 712     ! !#$   !'''' !!#''' $'.$     "     " %   & )*+ ( ,-         !  .'!.   )*+     / - & $''!0 
                                         
  33f  

 Appendix 1 – Spectra Relevant to Chapter 3 713 # !"""" !""""" !--! $ %   & ()* +,        ()*      !-1 #"-/0     . , & !"" !"# $      '      
                          
          33f           
 Appendix 1 – Spectra Relevant to Chapter 3 714      (((( -((( %(0% $ &   ' )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ !                          #     !"                                         
  33g  

 Appendix 1 – Spectra Relevant to Chapter 3 715      ! #.#    !    )*+     # 0%1"     / -  ' #%%. #%%%%% , -!   #%%%% % "#   (! )*+ $ &   ' $                          
                         33g     
 Appendix 1 – Spectra Relevant to Chapter 3 716        "(((( "-((( %(0% )! *+, . /!      !   *+,  "  0("0     1 /  ' %((" "%    $ &   ' $                    "#             !                                          !  
 "    33h  

 Appendix 1 – Spectra Relevant to Chapter 3 717   .  ! " ! )*+       0%1# !    / - !' %%. %%%%% ,!-"   %%%% (" )*+ #% #  $ &   ' !"  $ !                                         
              33h     
 Appendix 1 – Spectra Relevant to Chapter 3 718      #(((( #-((( $(%$ )! *+, . /!      !   *+,  #  %(#%     0 /  ' $((# #$%    " &   '  "  !      !"    #"                                                                              
      32  

 Appendix 1 – Spectra Relevant to Chapter 3 719    ! #.# #%%%%% #%%%% "% "#         !    )*+     # 0%1"     / -  ' #%%. , -!   (! )*+ $ &   ' $                 
                                   32   
 Appendix 1 – Spectra Relevant to Chapter 3 720      %(((( %-((( #(0# )! *+, . /!      !   *+,  %  0(%0     1 /  ' #((% %%    $ &   ' "# $  !                                                                                       
   51  

 Appendix 1 – Spectra Relevant to Chapter 3 721 %%%% %%%%% . (" )*+ ,!-"     ! "  ! )*+      0%1# !    / - !' %%. % $ &   ' #   $ !        !"      
         51                               
 Appendix 1 – Spectra Relevant to Chapter 3 722       # '  +,,  #-         ! " ()    $  % &     * ) "    % &                    
                                                49a   

 Appendix 1 – Spectra Relevant to Chapter 3 723 #))))) #%# *! +,- . /!     !       # &)"          +,-     0 /  ( #))% #)))) $ '   ( %& "#       $     !      
                             49a   
 Appendix 1 – Spectra Relevant to Chapter 3 724      %(((( %-((( #(0# )! *+, . /!      !   *+,  % 0(%0     1 /  ' #((% %# $ &   '  "#    $  !                                                 
  9  

 Appendix 1 – Spectra Relevant to Chapter 3 725    ! "$"    !     *+,     "   0&1#     / .  ( "&&$ "&&&&& - .!   "&&&& #& "#$          )! *+, % '   ( %                    
                             19   

 Appendix 1 – Spectra Relevant to Chapter 3 726   (((( -((( 0(%0 )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( #% $ &   ' # $ !       !"                                               
         54  

 Appendix 1 – Spectra Relevant to Chapter 3 727    ! #/#    !      # %(1"         *+,     0 .  ' #((/ #((((( - .!   #(((( % "#      )! *+, $ &   ' $            
                                54    
 Appendix 1 – Spectra Relevant to Chapter 3 728     #'''' #,''' /'$/ " %   & (! )*+ - .!      !   )*+  #  $'#$     0 .  & /''# ##$  !    "                             $                                     !      "  #       
   55a  

 Appendix 1 – Spectra Relevant to Chapter 3 729 "##### "/" )! *+, - .!      !      " $#&1          *+,     0 .  ( "##/ "#### % '   ( && "#$       %     !      
                                      55a    
 Appendix 1 – Spectra Relevant to Chapter 3 730        ! (-%%% #%0# )! *+, . /!      !   *+,  (  0%(0     1 /  ' #%%( (%%%% % $ &   '    "# $                                                        
  "     !  #        55b   

 Appendix 1 – Spectra Relevant to Chapter 3 731 "((((( "$" )! *+, - .!         !   *+,     " %(0     / .  ' "(($ "(((( # &   ' $% "       #     !             
                                        55b  
 Appendix 1 – Spectra Relevant to Chapter 3 732       (((( %((( /($/ # &   ' )" *+, -!."    ! "  ! *+,    $($ !    0 . !' /(( $%$ # !                       !"                                              #     %  $  !"   
     55c  
 Appendix 1 – Spectra Relevant to Chapter 3 733 )))) )))))  *" +,- .!/"      ! "  ! +,-      1)%# !    0 / !( )) %&% $ '   ( #   $ !        !"                          
                                   55c   
 Appendix 1 – Spectra Relevant to Chapter 3 734    (((( -((( 0(%0 $ &   ' )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( % $ !    # !"                                                $  "  #   %                 !    
             55d  

 Appendix 1 – Spectra Relevant to Chapter 3 735 '''' ''''' . (" )*+ ,!-"      ! "  ! )*+      0'1# !    / - !& ''. ### $ %   & #   $ !        !"                             
                                55d  
 Appendix 1 – Spectra Relevant to Chapter 3 736   Appendix 3 – Spectra Relevant to Chapter 5 961 Appendix 3 Spectra Relevant to Chapter 5: Formal Synthesis of (–)-Cylindrocyclophane F     $ (          !  " # %  & ' )*      $.        & ' + * # ,--(                    BnO       Br                     
          17    

 Appendix 3 – Spectra Relevant to Chapter 5 962 #%%%% #%%%%% #.# (! )*+ , -!         # 0%1"   !  )*+     / -  ' #%%. "% $ &   ' "#       $     !        
              17   BnO   Br            
 Appendix 3 – Spectra Relevant to Chapter 5 963      (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' # $ !            !"             nBu MeO   O  OH OMe                                                
  23 

 Appendix 3 – Spectra Relevant to Chapter 5 964 %%%% %%%%% . $ &   ' (" )*+ ,!-"          0%1# ! " ! )*+ !    / - !' %%. #% #   $ !        !"                      nBu MeO 
  O  OH OMe              23   
 Appendix 3 – Spectra Relevant to Chapter 5 965     #$ ,- ,, (" )*+ .!/"    ! "  ! )*+  #  #$, !    0 / !' 1#- #   % &   '  ## % !          !"                      nBu MeO  O N  O O OMe O                          
         18  
 Appendix 3 – Spectra Relevant to Chapter 5 966   "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$           %     !             nBu MeO          O  
  O O N OMe  O              18   
 Appendix 3 – Spectra Relevant to Chapter 5 967        )))) .))) %)&% *" +,/!0"    ! "  ! +,-    &)& !    1 0 !( %)) %& $ '   (              $   $ !      BnO   MeO           #   nBu       !" OMe                                               #      !  "       
  19  

 Appendix 3 – Spectra Relevant to Chapter 5 968 #'''' #''''' #.# (! )*+ , -!         # 0'1"   !  )*+     / -  & #''. "" $ %   & "#       $     !                         BnO        
  MeO  19   nBu  OMe                
 Appendix 3 – Spectra Relevant to Chapter 5 969          # '             ! " $  % & ()      #-        % & * ) " +,,#                          MeO    OMe Me                              
        20  

 Appendix 3 – Spectra Relevant to Chapter 5 970 #### ##### / )" *+, -!."          $#%1 ! " ! *+, !    0 . !( ##/ $ & '   ( #$%   & !        !"        
      20         MeO   OMe Me         
 Appendix 3 – Spectra Relevant to Chapter 5 971           "%%%% ,-%% ,, (! )*+ . /!      !   )*+  "  "#,     0 /  ' 1%%"- "%"% $ &   ' "#    $  !                      MeO nBu MeO            OMe OMe nBu                                        
  21a  
 Appendix 3 – Spectra Relevant to Chapter 5 972 #### ##### / )" *+, -!."          $#%1 ! " ! *+, !    0 . !( ##/ $ & '   ( #$%   & !        !"                
        MeO nBu MeO    21a  OMe OMe nBu               
 Appendix 3 – Spectra Relevant to Chapter 5 973         %%%% ,-%% ,, (" )*+ .!/"    ! "  ! )*+    #, !    0 / !' 1%%- %% $ &   ' # $ !     !"                        MeO nBu MeO              OMe OMe nBu                                  
  21b 

 Appendix 3 – Spectra Relevant to Chapter 5 974 &"""" &""""" &/& )! *+, - .!         & #"$1   !  *+,     0 .  ( &""/ &# % '   ( "#$       %     !                      MeO nBu MeO   
   OMe OMe nBu         21b   
 Appendix 3 – Spectra Relevant to Chapter 5 975          (((( -((( %(-% $ &   ' )" *+, .!/"    ! "  ! *+,    -(- !    0 / !' %(( % # $ !     !"                        MeO   nBu  OMe                          
      22  

 Appendix 3 – Spectra Relevant to Chapter 5 976 "(((( %((( /(%/ )! *+, - .!      !   *+,  "  %("%     0 .  ' /((" "#% $ &   ' "#    $  !                    BnO                  OBn       
          24     
 Appendix 3 – Spectra Relevant to Chapter 5 977 "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$       %     !        
      BnO             24     OBn          
 Appendix 3 – Spectra Relevant to Chapter 5 978       $            !  " # %  & ' ()     $-        & ' * ) # +,,,                 BnO                             
       25   
 Appendix 3 – Spectra Relevant to Chapter 5 979 O N 45 nBu MeO O O OMe O Me Appendix 3 – Spectra Relevant to Chapter 5 980 45 O N nBu MeO O O OMe O Me Appendix 3 – Spectra Relevant to Chapter 5 981 43 O N nBu MeO O O OMe O OMe Appendix 3 – Spectra Relevant to Chapter 5 982 43 O N nBu MeO O O OMe O OMe Appendix 3 – Spectra Relevant to Chapter 5 983 44 O N nBu MeO O O OMe O Cl Appendix 3 – Spectra Relevant to Chapter 5 984 O N 44 nBu MeO O O OMe O Cl Appendix 3 – Spectra Relevant to Chapter 5 985 46 O N nBu MeO O O OMe O Br Appendix 3 – Spectra Relevant to Chapter 5 986 46 O N nBu MeO O O OMe O Br Appendix 3 – Spectra Relevant to Chapter 5 987  )))) %))) &)0& $ '   ( *" +,.!/"    ! "  ! +,-    0)0 !    1 / !( &)) %& # $ !       !"                            MeO   O OtBu OMe             
        121   

 Appendix 3 – Spectra Relevant to Chapter 5 988 "%%%% "%%%%% "." (! )*+ , -!         " 0%1   !  )*+     / -  ' "%%. $% # &   ' "            #     !                  MeO  
  O  OtBu OMe           121   
 Appendix 3 – Spectra Relevant to Chapter 5 989        $        !  " # %  & ' ()      $-        & ' * ) # +,,                                   nBu MeO   O OtBu OMe                                                      
  50  

 Appendix 3 – Spectra Relevant to Chapter 5 990 "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$         %     !                       nBu MeO  
  O OMe  OtBu               50   
 Appendix 3 – Spectra Relevant to Chapter 5 991        # ''             ! " $  % & ()      #-        % & * ) " +,,#                      nBu MeO O Me Me B   O O OtBu OMe Me Me                                                     
   51 

 Appendix 3 – Spectra Relevant to Chapter 5 992 #(((( #((((( #/# )! *+, - .!         # 1(%"   !  *+,     0 .  ' #((/ % $ &   ' "#         $     !                 nBu O Me Me MeO       B  O O OtBu OMe Me Me     
                  51  
 Appendix 3 – Spectra Relevant to Chapter 5 993                           '(  -    ,(*    # $ ) & ! (*(+ %&        "  # $ ! 
 51        nBu MeO O Me Me B O O  OtBu OMe Me Me 




 Appendix 3 – Spectra Relevant to Chapter 5 994   $'/$       )*+   ! /'!/     0 . & $''!1 !,''' )*+ !'''' -.     ( &  # %   !$ !" #                  nBu MeO O Me Me                B O O  OH  OMe Me Me       !      
                                     
       122  

 Appendix 3 – Spectra Relevant to Chapter 5 995 """" """"" %.% (! )*+ , -!         %2   #"%01   !  )*+     / -  ' "". #% $ &   ' "#         $     ! 
               nBu MeO O Me Me   
 B  O O OH  OMe Me Me             122  
 Appendix 3 – Spectra Relevant to Chapter 5 996      (((( %((( /(%/ $ &   ' )" *+, -!."    ! "  ! *+,    %(% !    0 . !' /(( %% # $ !     !"                 nBu MeO   Br O OtBu OMe                                                   
     52 

 Appendix 3 – Spectra Relevant to Chapter 5 997  # #/& )" *+, -!."    ! "      #   1    ! *+, !    0 . !( #& &# % '   ( #$   % !        !"                   nBu MeO   
  Br O OMe  OtBu                 52   
 Appendix 3 – Spectra Relevant to Chapter 5 998       (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' # $ !     !"             nBu MeO O   Br OMe  OH                                             
  123  

 Appendix 3 – Spectra Relevant to Chapter 5 999 %%%% %%%%% . (" )*+ ,!-"    ! "  ! )*+    0%1# !    / - !' %%. % $ &   ' #   $ !        !"                   nBu MeO      
     Br O OMe  OH             123   
 Appendix 3 – Spectra Relevant to Chapter 5 1000      )))) &))) %)&% *" +,.!/"    ! "  ! +,-    &)& !    0 / !( %)) %& $ '   ( # $ !       !"           I     TMS                                        
       54

 Appendix 3 – Spectra Relevant to Chapter 5 1001 "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$       %     !        
        I    TMS  54              
 Appendix 3 – Spectra Relevant to Chapter 5 1002     "(((( %((( /(%/ )! *+, - .!      !   *+,  "  %("%     0 .  ' /((" "#%    $ &   '         nBu MeO  O   OtBu OMe   TMS          $   "#          !                                !                      
  "   55

 Appendix 3 – Spectra Relevant to Chapter 5 1003 #### ##### . (" )*+ ,!-"          $#01 ! "   ! )*+ !    / - !' ##. $ % &   ' #$   % !        !"                   nBu MeO  O  OtBu OMe 
  TMS                 55      
 Appendix 3 – Spectra Relevant to Chapter 5 1004        ")))) &))) %)&% $ '   ( *! +,. /!      !   +,-  "  &)"&     0 /  ( %))" "%&    "# $        !    nBu MeO   O OtBu OMe                         !                  "                                  
  124  

 Appendix 3 – Spectra Relevant to Chapter 5 1005 #### ##### / )" *+, -!."          $#%1 ! "   ! *+, !    0 . !( ##/ $ & '   ( #$%   & !        !"                      nBu MeO    O  OtBu OMe                  
      124  
 Appendix 3 – Spectra Relevant to Chapter 5 1006            # '('                 ! " $  % & )*      #-        % & + * " ,,(#            !"       nBu MeO O   OtBu OMe     Br                                                          
  56  

 Appendix 3 – Spectra Relevant to Chapter 5 1007 #### ##### / )" *+, -!."    ! "     $#%1     ! *+, !    0 . !( ##/ $ & '   ( #$%   & !        !"                     nBu MeO  O  OtBu OMe  
    Br                    56   
 Appendix 3 – Spectra Relevant to Chapter 5 1008       /(%/ -!."     ! *+, ! "    %(%  %((( )" *+, !    0 . !' /(( ((((    $ &   '    %% $ !       #      nBu MeO              !"  O O O  N OMe O   Br                        $      "             !  #                                  
  57  

 Appendix 3 – Spectra Relevant to Chapter 5 1009 "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$        %  !         nBu MeO O          O O  N OMe     O Br                       
        57   
 Appendix 3 – Spectra Relevant to Chapter 5 1010           $ $ *+++              !  " # %  & ' ()      $/    *-+.    & ' , ) # +         
      HO  O     TMS                         58

 Appendix 3 – Spectra Relevant to Chapter 5 1011 %%%% %%%%% . (" )*+ ,!-"    ! "     0%1#     ! )*+ !    / - !' %%. % $ &   ' #   $ !        !"        
        HO  O    TMS  58           
 
 Appendix 3 – Spectra Relevant to Chapter 5 1012    (((( -((( %(0% $ &   ' )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ !    #         Ph  N Me  Me OH O              !"         TMS                                       
         125

 Appendix 3 – Spectra Relevant to Chapter 5 1013 #### ##### / )" *+, -!."          $#1& ! " ! *+, !    0 . !( ##/ &# % '   ( #$ % !     !"     Ph  Me OH  N Me O                    TMS                       
                125   
 Appendix 3 – Spectra Relevant to Chapter 5 1014     "(((( "%((( /(0/ $ &   ' )! *+, - .!      !   *+,  "  0("0     1 .  ' /((" "%#    $ "# !     %       Ph  Me OH  N Me O Me    !      "  #                TMS                 $                                       
          59

 Appendix 3 – Spectra Relevant to Chapter 5 1015 %%%% %%%%% . $ &   ' (" )*+ ,!-"    ! "  ! )*+        0%1# !    / - !' %%. #% # $ !     !"    Ph Me OH  N Me O               Me   TMS                       
                  59
  
 Appendix 3 – Spectra Relevant to Chapter 5 1016    ")))) ".))) %)&% *! +,/ 0!      !   +,-  "  &)"&     1 0  ( %))" "%& $ '   ( "#    $  !         HO  Me     TMS                                    
      126

 Appendix 3 – Spectra Relevant to Chapter 5 1017 #)))) #))))) #%# *! +,. /!      !   +,-     #   &)1"     0 /  ( #))% %& $ '   ( "#       $     !              HO  Me 
    TMS   126        
  

 Appendix 3 – Spectra Relevant to Chapter 5 1018       (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' # $ !       !"           I  Me    TMS                            
      60

 Appendix 3 – Spectra Relevant to Chapter 5 1019 '''' ''''' . (" )*+ ,!-"          0'1# ! " ! )*+ !    / - !& ''. ### $ %   & #   $ !        !"                I  Me 
   TMS  60               
 Appendix 3 – Spectra Relevant to Chapter 5 1020    "(((( "-((( 0(%0 )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" ""%    $ &   ' "# $  !                     nBu O   Br  OtBu                                                  
  77  

 Appendix 3 – Spectra Relevant to Chapter 5 1021 (((( ((((( / )" *+, -!."          1(%# ! "   ! *+, !    0 . !' ((/ %% $ &   ' #   $ !        !"        
                nBu O  Br  OtBu               77   
 Appendix 3 – Spectra Relevant to Chapter 5 1022     "(((( "-((( 0(%0 $ &   ' )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" %% "# !    $                nBu  O   OtBu   TMS  "          !                                                     
       79

 Appendix 3 – Spectra Relevant to Chapter 5 1023 (((( ((((( / )" *+, -!."          1(%# ! "   ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                    nBu  O  OtBu       TMS     
               79       
 Appendix 3 – Spectra Relevant to Chapter 5 1024     # -((( %(0% )" *+, .!/"    ! "     0(0   ! *+, !    1 / !' %(( ((((   $ &   '  % $ !         !"          nBu MeO  Br O  O O N OMe O                                                     
  80  

 Appendix 3 – Spectra Relevant to Chapter 5 1025 #(((( #((((( #/# )! *+, - .!         # 1(%"   !  *+,     0 .  ' #((/ %% $ &   ' "#       $     !                       nBu MeO O  Br   
   N  O O OMe  O              80   
 Appendix 3 – Spectra Relevant to Chapter 5 1026            *+,   !  "  %("%  0(%0 . /!       1 /  ' 0((" "-((( )! *+, % $ &   '       "((((   $      "#         nBu MeO  O O O N OMe    O       !    TMS              !                   "  #  $                               
  81

 Appendix 3 – Spectra Relevant to Chapter 5 1027 #'''' #''''' #.# (! )*+ , -!         # 0'1"   !  )*+     / -  & #''. """ $ %   & "#           $     !                  nBu MeO 
   O O O N OMe   81  O  TMS                 
 

 Appendix 3 – Spectra Relevant to Chapter 5 1028           (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' # $ !     !"                    nBu O   OtBu                                                                      
  104 

 Appendix 3 – Spectra Relevant to Chapter 5 1029 "#### "##### "/" )! *+, - .!         " $#1&   !  *+,     0 .  ( "##/ &&& % '   ( "#$         %     !        
                 nBu  O OtBu                    104     
 Appendix 3 – Spectra Relevant to Chapter 5 1030       $            !  " # %  & ' ()      $-        & ' * ) # +,,                           nBu  O   OtBu   Br                            !"  #"                              
 $      84  

 Appendix 3 – Spectra Relevant to Chapter 5 1031 %%%% %%%%% . (" )*+ ,!-"          0%1# ! "   ! )*+ !    / - !' %%. #% $ &   ' #   $ !        !"                        nBu  O     OtBu  Br  
                  84   
 Appendix 3 – Spectra Relevant to Chapter 5 1032     "(((( "-((( %(0% $ &   ' )! *+, . /!      !   *+,  "  0("0     1 /  ' %((" "%    "# $  !                                   nBu  O   OH  Br                                                
     129  

 Appendix 3 – Spectra Relevant to Chapter 5 1033 %%%% %%%%% . (" )*+ ,!-"    ! "     0%1#     ! )*+ !    / - !' %%. % $ &   ' #   $ !        !"                      
  nBu  O   OH  Br                 129   
 Appendix 3 – Spectra Relevant to Chapter 5 1034       " 0("0      *+,   !  %(0% . /!       1 /  ' %((" "-((( )! *+,  "%  "((((      $ &   ' $ "#     !                               nBu  O N   O O  O Br                            "  !                     
 #     85  

 Appendix 3 – Spectra Relevant to Chapter 5 1035 #### ##### ' *" +,.!/"          $#%1 ! " ! +,- !    0 / !) ##' '$ & (   ) #$%   & !        !"                   nBu  O N  O O 
              O  Br                   85   
 Appendix 3 – Spectra Relevant to Chapter 5 1036    "(((( "-((( 0(%0 $ &   ' )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" %    "# $  !                        nBu O   Br  OMe                                              
   130  

 Appendix 3 – Spectra Relevant to Chapter 5 1037 #(((( #((((( #/# )! *+, - .!         # 1(%"   !  *+,     0 .  ' #((/ %% $ &   ' "#         $     !        
                 nBu O  Br  OMe       130        
 Appendix 3 – Spectra Relevant to Chapter 5 1038       $ (              !  " # %  & ' )*      $.        & ' + * # ,--         
      I     TMS                               131

 Appendix 3 – Spectra Relevant to Chapter 5 1039 (((( ((((( / )" *+, -!."          %(1# ! " ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"        
        I    TMS  131           
 
 Appendix 3 – Spectra Relevant to Chapter 5 1040    "'''' ",''' /'0/ (! )*+ - .!      !   )*+  "  0'"0     1 .  & /''" "" $ %   & "#    $     !           I      TMS                                    
   132

 Appendix 3 – Spectra Relevant to Chapter 5 1041 #'''' #''''' #.# (! )*+ , -!         # 0'1"   !  )*+     / -  & #''. """ $ %   & "#       $     !        
        I       TMS   132                 
 Appendix 3 – Spectra Relevant to Chapter 5 1042  (((( -((( 0(%0 $ &   ' )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( % # $ !       !"          I       TMS                               
       133

 Appendix 3 – Spectra Relevant to Chapter 5 1043 )))) ))))) % *" +,.!/"          &)1# ! " ! +,- !    0 / !( ))% %& $ '   ( #   $ !        !"        
 133       I        TMS                   
 Appendix 3 – Spectra Relevant to Chapter 5 1044     ! #$#  $+ .$#. "     " %   & ()* ' ,-         ()*    $0$     / - & .               nBu  O   OMe  TMS            !                                                         
      134

 Appendix 3 – Spectra Relevant to Chapter 5 1045 (((( ((((( / )" *+, -!."          %(1# ! "    ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                       nBu O   OMe  TMS 
         134              
 Appendix 3 – Spectra Relevant to Chapter 5 1046     # ''          ! " $  % & ()      #-        % & * ) " +,,'                    nBu  O   OMe  TMS                     !                "                                         
  #    135

 Appendix 3 – Spectra Relevant to Chapter 5 1047 #(((( #((((( #/# )! *+, - .!         #   1(%"   !  *+,     0 .  ' #((/ % $ &   ' "#         $     !              nBu  O  OMe       TMS                    
         135
 
 Appendix 3 – Spectra Relevant to Chapter 5 1048       # ''                 ! " $  % & ()      #-        % & * ) " +,,'               nBu  O OMe    TMS                 #"         !"                                                    
  136

 Appendix 3 – Spectra Relevant to Chapter 5 1049 #(((( #((((( #/# )! *+, - .!         #   1(%"   !  *+,     0 .  ' #((/ % $ &   ' "#         $     !           nBu         
   OMe  O   TMS  136                           
 
 Appendix 3 – Spectra Relevant to Chapter 5 1050   '''' ,''' /'0/ (" )*+ -!."    ! "  ! )*+    0'0 !    1 . !& /''  $ %   & # $ !       !"                I  Me    OH                          
  87   

 Appendix 3 – Spectra Relevant to Chapter 5 1051 #)))) #))))) #%# *! +,. /!         # &)1"   !  +,-     0 /  ( #))% %& $ '   ( "#       $     !        
 87          I  Me   OH          
 Appendix 3 – Spectra Relevant to Chapter 5 1052     H 87 I Me  OH         

         
 Appendix 3 – Spectra Relevant to Chapter 5 1053  0(%0     !   *+,  "  %("%     1 /  ' 0((" "-((( "(((( . /!     ' )! *+,  $ & "#% "#       $     !                      I Me    O       
        137    

 Appendix 3 – Spectra Relevant to Chapter 5 1054 #)))) #))))) #%# $ '   ( *! +,. /!      !  +,-      # &)1"     0 /  ( #))% %&     $ "#  !              
 137         I Me   O           
 Appendix 3 – Spectra Relevant to Chapter 5 1055      (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ &   ' #   $ !        !"                     I Me                          
    138    

 Appendix 3 – Spectra Relevant to Chapter 5 1056 %%%% %%%%% . (" )*+ ,!-"          0%1# ! " ! )*+ !    / - !' %%. % $ &   ' #   $ !        !"        
 138         I Me               
 Appendix 3 – Spectra Relevant to Chapter 5 1057          "(((( %((( /(%/ $ &   ' )! *+, - .!      !   *+,  "  %("%     0 .  ' /((" % "#       $     !                  I  Me    TMS                 
        88

 Appendix 3 – Spectra Relevant to Chapter 5 1058 "#### "##### "." (! )*+ , -!         " $#01   !  )*+     / -  ' "##. "$ % &   ' "#$       %     !        
        I  Me   TMS  88               
 Appendix 3 – Spectra Relevant to Chapter 5 1059      (((( -((( 0(%0 $ &   ' )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( % # !" $ !               nBu MeO  O OtBu OMe   Me    TMS                                                !  "  #              
      90

 Appendix 3 – Spectra Relevant to Chapter 5 1060 (((( ((((( / )" *+, -!."          %(1# ! "   ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                   nBu MeO         O OtBu OMe  Me     TMS  
                  90   
 Appendix 3 – Spectra Relevant to Chapter 5 1061     H nBu MeO 90 O Me  OtBu OMe 
TMS  
 
 
 
 
 
 



 
 
 
 
 
 
 
 



Appendix 3 – Spectra Relevant to Chapter 5 1062  #'''' #,''' $'/$ " %   & (! )*+ - .!      !   )*+  #  /'#/     0 .  & $''# #$  !             "     nBu                nBu                                       "    !                
  94 

 Appendix 3 – Spectra Relevant to Chapter 5 1063 $$$$ $$$$$ % *" +,.!/"          #$'1 ! " ! +,- !    0 / !) $$% '' & (   ) #$%   & !        !"        
                94  nBu     nBu                  
 Appendix 3 – Spectra Relevant to Chapter 5 1064    "(((( "-((( %(0% $ &   ' )! *+, . /!      !   *+,  "  0("0     1 /  ' %((" "% "# !    $                     nBu    O OtBu                                        !       "              
 #      105  

 Appendix 3 – Spectra Relevant to Chapter 5 1065 '''' ''''' . (" )*+ ,!-"          0'1# ! "    ! )*+ !    / - !& ''. ### $ %   & #   $ !        !"                           nBu 
  O OtBu                    105   
 Appendix 3 – Spectra Relevant to Chapter 5 1066     )))) .))) %)&% $ '   ( *" +,/!0"    ! "  ! +,-    &)& !    1 0 !( %)) %& # $ !     !"               nBu    O OH                           "             !                                   
  140  

 Appendix 3 – Spectra Relevant to Chapter 5 1067 (((( ((((( / )" *+, -!."    ! "     1(%#     ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                     nBu 
      O OH                    140   
 Appendix 3 – Spectra Relevant to Chapter 5 1068       " 0("0     *+,   !  %(0% . /!       1 /  ' %((" "-((( )! *+, "% $ &   '      "((((  $ "#         !                   nBu    O N   O O %                      O                  #      $     "                  !                
  106  

 Appendix 3 – Spectra Relevant to Chapter 5 1069 #### ##### / )" *+, -!."          $#&1 ! " ! *+, !    0 . !( ##/ & % '   ( #$   % !        !"                              
  nBu  106  O N  O O  O                      
 Appendix 3 – Spectra Relevant to Chapter 5 1070    (((( -((( %(0% $ &   ' )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % $ !    #   #        nBu "                       !"                !     Me                                           
  108  

 Appendix 3 – Spectra Relevant to Chapter 5 1071 #)))) #))))) #%# *! +,. /!         # &)1"   !  +,-     0 /  ( #))% %& $ '   ( "#       $     !                         
   nBu  108  Me                       
 Appendix 3 – Spectra Relevant to Chapter 5 1072       ! % )           "  # $ &  ' ( *+      %/        ' ( , + $ !--.                     I       Me                                                    
       141  

 Appendix 3 – Spectra Relevant to Chapter 5 1073   ! % !           "  # $ &  ' ( )*      %/        ' ( + * $ ,--.                   nBu MeO O Me    OtBu OMe                        '  $                     &#    %  "#            !                             
            110 

 Appendix 3 – Spectra Relevant to Chapter 5 1074 #### ##### / )" *+, -!."          $#%1 ! "   ! *+, !    0 . !( ##/ % & '   ( #$%   & !        !"                       nBu MeO  
  O Me  OtBu OMe                    110     
 Appendix 3 – Spectra Relevant to Chapter 5 1075         '''' ,''' /'0/ $ %   & (" )*+ -!."    ! "  ! )*+    0'0 !    1 . !& /''               O Me             OH OMe        nBu MeO   $ !             #                #     !  $      "              !"                           
   142  

 Appendix 3 – Spectra Relevant to Chapter 5 1076 #(((( #((((( #/# )! *+, - .!      !   *+,   # 1(%"     0 .  ' #((/ % $ &   ' "#       $     !                          nBu MeO  
  O OMe OH  Me  142                       
 Appendix 3 – Spectra Relevant to Chapter 5 1077        %((( /(0/ )" *+, -!."    ! "     0(0   ! *+, !    1 . !' /(( ((((    %#  $ &   ' $ !    # !"        nBu MeO              O Me O O N OMe  O                                       %      '      $                            !  "  #        &                     
    111  

 Appendix 3 – Spectra Relevant to Chapter 5 1078 (((( ((((( / )" *+, -!."          1(%# ! "     ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                nBu MeO       O Me N  O O OMe   
      O                   111     
 Appendix 3 – Spectra Relevant to Chapter 5 1079         (((( -((( %(0% )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( #% $ &   ' # $ !             nBu MeO  Me    Me OMe                        !"                                 (     )  &  '     %    #   $        !         "                      
     112  
 Appendix 3 – Spectra Relevant to Chapter 5 1080 "#### "##### "/" )! *+, - .!         " $#&1   !  *+,     0 .  ( "##/ && % '   ( "#$       %     !                      nBu MeO 
    Me  Me OMe                     112  
 Appendix 3 – Spectra Relevant to Chapter 5 1081       "&&&& "%&&& /&0/ $ '   ( )! *+, - .!      !   *+,  "  0&"0     1 .  ( /&&" %& "# !             Me   Me OMe        nBu MeO          $                           $   %   )      (     &  '  #       !  "                                    
   143  

 Appendix 3 – Spectra Relevant to Chapter 5 1082 "#### "##### "&" )! *+, - .!         " $#01   !  *+,     / .  ( "##& &$ % '   ( "#$       %     !                   nBu MeO     
     Me  Me OMe                     143  
 Appendix 3 – Spectra Relevant to Chapter 5 1083         (((( -((( 0(%0 $ &   ' )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( % #   "            !       !"  $ !          nBu                     TMS             #                                
        144
 Appendix 3 – Spectra Relevant to Chapter 5 1084 #### ##### / )" *+, -!."          $#&1 ! " ! *+, !    0 . !( ##/ & % '   ( #$   % !        !"                           
   nBu  144   TMS                    
 
 Appendix 3 – Spectra Relevant to Chapter 5 1085     "'''' ",''' /'0/ (! )*+ - .!      !   )*+  "  0'"0     1 .  & /''" ""    $ %   & $ "#                  nBu !                  "         !                             #                             
  119  

 Appendix 3 – Spectra Relevant to Chapter 5 1086 #)))) #))))) #%# *! +,. /!         # &)1"   !  +,-     0 /  ( #))% %& $ '   ( "#       $     !        
                   nBu    119                        
 Appendix 3 – Spectra Relevant to Chapter 5 1087    (((( -((( %(0% $ &   ' )" *+, .!/"    ! "  ! *+,    0(0 !    1 / !' %(( % #            nBu MeO                   !"  $ !              Me TMS OMe                      '  (                        &    $       "  !     #  %                 
      145

 Appendix 3 – Spectra Relevant to Chapter 5 1088 "#### "##### "/" )! *+, - .!         " $#&1   !  *+,     0 .  ( "##/ & % '   ( "#$       %     !                         nBu MeO 
   145  Me  TMS OMe                 
  
 Appendix 3 – Spectra Relevant to Chapter 5 1089      "(((( "-((( 0(%0 $ &   ' )! *+, . /!      !   *+,  "  %("%     1 /  ' 0((" "#% "# !             $   nBu MeO            OMe   Me                           #                  !  "  $                       
   120   

 Appendix 3 – Spectra Relevant to Chapter 5 1090 '''' ''''' . (" )*+ ,!-"          0'1# ! " ! )*+ !    / - !& ''. ### $ %   & #   $ !        !"                      nBu MeO  
    120  Me  OMe                  
 Appendix 3 – Spectra Relevant to Chapter 5 1091          %%%% ,%%% /%0/ $ &   ' (" )*+ -!."    ! "  ! )*+    0%0 !    1 . !' /%% %        nBu MeO                       $ !        #   Me      TMS OMe               !"     &   '     (                         $  #    !      "     %             
       146

 Appendix 3 – Spectra Relevant to Chapter 5 1092 #&&&& #&&&&& #/# )! *+, - .!         # 1&%"   !  *+,     0 .  ( #&&/ %& $ '   ( "#       $     !                         nBu MeO 
   146  Me  TMS OMe                 
  
 Appendix 3 – Spectra Relevant to Chapter 5 1093       "(((( "-((( %(0% $ &   ' )! *+, . /!      !   *+,  "  0("0     1 /  ' %((" #% "# !               nBu MeO         $  OMe   Me                     !                         "      #                       
  147 

 Appendix 3 – Spectra Relevant to Chapter 5 1094 (((( ((((( / )" *+, -!."          1(%# ! " ! *+, !    0 . !' ((/ % $ &   ' #   $ !        !"                      nBu MeO  
    147  Me OMe                   
 Appendix 3 – Spectra Relevant to Chapter 5 1095          "%%%% ",%%% /%0/ (! )*+ - .!      !   )*+  "  0%"0     1 .  ' /%%" %    $ &   '           nBu  Me            TMS OMe     MeO              $                 "#        !      "     $%    &        #     '                   !                         
       148
 Appendix 3 – Spectra Relevant to Chapter 5 1096 #)))) #))))) #%# *! +,. /!         # &)1"   !  +,-     0 /  ( #))% %& $ '   ( "#       $     !                       nBu MeO     
  Me  TMS OMe              148    
  
 Appendix 3 – Spectra Relevant to Chapter 5 1097      (((( -((( 0(%0 )" *+, .!/"    ! "  ! *+,    %(% !    1 / !' 0(( %% $ &   '    $  #    $ !      nBu MeO  Me   OMe !       "          #             !"                                                                 
  149  

 Appendix 3 – Spectra Relevant to Chapter 5 1098  '''' ''''' . (" )*+ ,!-"    ! "  ! )*+     0'1# !    / - !& ''. ## $ %   & #   $ !        !"            
    
        nBu MeO 
  
   149  OMe  Me







 
 



 






 



 Appendix 3 – Spectra Relevant to Chapter 5 1099