The Modular Synthesis and Functionalization of Cyclic Compounds Using Modern Methods Citation Lacker, Caitlin Rebecca (2022) The Modular Synthesis and Functionalization of Cyclic Compounds Using Modern Methods. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/61ky-5w83. https://resolver.caltech.edu/CaltechTHESIS:09072021-162545226 Abstract Accessing libraries of similar compounds quickly is important in the pharmaceutical industry, as it allows for the expedient investigation of a wide variety of parameters. An efficient strategy to access compounds of interest is to start from a single intermediate containing an interesting or pharmaceutically active structure and decorating it with varying functionality to generate a library of related compounds. Cross-coupling is a powerful tool for this type of divergent, modular approach. Herein, we discuss several strategies geared towards the synthesis of small libraries of compounds of interest. First, a modular approach towards a library of enantioenriched trans cyclobutanes is discussed. This strategy allows for the synthesis of diverse substrates from a single enantioenriched intermediate, and this approach was applied to the synthesis of the small molecule (+)-rumphellaone A. Finally, the development of an enantioselective nickel-catalyzed photoredox cross-coupling to form N -(hetero)benzylic azoles in collaboration with researchers at Merck is discussed. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Rumphellaone A, Synthesis, methodology, Wolff Rearrangement, photoredox, cross-coupling, enantioselective Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Reisman, Sarah E. Thesis Committee: Fu, Gregory C. (chair) Reisman, Sarah E. Hsieh-Wilson, Linda C. Stoltz, Brian M. Defense Date: 16 August 2021 Funders: Funding Agency Grant Number National Science Foundation Graduate Research Fellowship DGE-1144469 NIH R35GM118191-01 Cottrell Fred Award 26688 NSF CAREER-1057143 Record Number: CaltechTHESIS:09072021-162545226 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:09072021-162545226 DOI: 10.7907/61ky-5w83 Related URLs: URL URL Type Description https://doi.org/10.1021/acs.joc.8b00728 DOI Article adapted for Chapter 1. https://doi.org/10.1039/C8SC05444D DOI Article adapted for Chapters 1 and 2. ORCID: Author ORCID Lacker, Caitlin Rebecca 0000-0003-2531-2636 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 14355 Collection: CaltechTHESIS Deposited By: Caitlin Lacker Deposited On: 28 Sep 2021 15:57 Last Modified: 08 Nov 2023 00:42 Thesis Files PDF - Final Version See Usage Policy. 13MB Repository Staff Only: item control page

THE MODULAR SYNTHESIS AND FUNCTIONALIZATION OF CYCLIC COMPOUNDS USING MODERN METHODS Thesis by Caitlin Rebecca Lacker In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2022 (Defended August 16, 2021) ii © 2021 Caitlin Rebecca Lacker ORCID: 0000-0003-2531-2636 All Rights Reserved iii To my family and friends, thank you for everything iv ACKNOWLEDGEMENTS I am very grateful for my time at the California Institute of Technology. The Caltech chemistry department is uniquely collaborative and welcoming. I feel very fortunate to have developed as a scientist here and to have had the opportunity to work with so many talented, incredibly intelligent and generous people. In that vein, I have a lot of people to thank. First and foremost, I would like to thank my research advisor, Professor Sarah Reisman, for giving me this opportunity. Sarah is incredibly smart and a talented chemist. Her eye for synthesis is unique, and she is persistent and extremely hard-working. I want to thank her for her support and encouragement over the years. When I’ve needed help or a pep talk, or even to vent about something, she’s always made time for me. I know it’s not easy to do what she does, and I really appreciate how hard she works for her students. I would like to thank the members of my committee, Professors Greg Fu, Brian Stotlz, and Linda Hsieh-Wilson. Greg has been a supportive committee chair from the beginning, always offering insightful advice and checking in to see how my postdoc search was going. Sharing the third floor of Schlinger with Brian and the rest of the Stoltz lab is one of the best parts about working there. Having Brian’s perspective and supportive presence at joint group meetings has been incredibly helpful over the years, and he is always fun to run into in the hallway to chat with. I am also very grateful to Linda for her chemical biology perspective at my yearly meetings, especially in the context of proposal writing. I incredibly grateful to all of the wonderful the people working at Caltech, without whom all the work we do would not be possible. Dr. Scott Virgil does a fantastic job v running the catalysis center. He is always willing to drop what he is doing to help a student with an instrument or work through a problem. Scott’s advice and insight has been key to several research problems I was struggling with during my time here. I would also like to thank Dr. David VanderVelde for all he does in the NMR lab, and Dr. Mona Shahgholi and Naseem Torian for their mass spectrometry assistance. I would like to thank Alison Ross for her hard work as the graduate program manager for CCE. She has always answered my questions and is so helpful. I am also very grateful to Lynne Martinez, Veronica Triay, and Beth Marshall for all they have done for us with everything from writing grants to scheduling meetings and ordering textbooks. During my time in the Reisman lab, I have been fortunate to work with many wonderful labmates. I’m incredibly grateful to have been part of a lab culture that encourages you to ask questions and never shames you for not knowing something. Over the years, whenever I have asked people for help, they have always said yes. I hope that I have been able to help younger students the way I was helped my first few years. First of all, I would like to thank my mentors and my very first project partners, Dr. Jorden Beck and Dr. Lauren Chapmen. I couldn’t have had more wonderful people to work with. Not only are they both incredibly smart and competent chemists, but they were patient and encouraging teachers as well. Lauren was a 5th year when I first started, and she was so kind and generous with her time towards a 1st year. Working next to her in lab made my first year really special. She is who I seek to emulate when mentoring younger students. Jordan was so fun to work with. His energy and intelligence and ability to problem solve helped me stay motivated and encouraged when we ran into problems with chemistry. Jordan taught me so much about how to be a chemist, from setting up a reaction to vi processing 2D NMR data. I’m a proud graduate of the Jordan Casey Beck School of Chromatography. Without him, I wouldn’t be the researcher that I am today. I’m grateful to all of my wonderful project partners I’ve worked with over the years. Everyone that I’ve gotten to work with on Team Nickel has been such an inspiration to me. Their thoughtfulness, intelligence, and creativity have taught me so much. I have thoroughly enjoyed all of our conversations over the years. We all knew each other’s projects almost as well as we knew our own, and it was always fun to bounce ideas off each other and think about how our work fit together in the larger picture of nickel catalysis. I was also privileged to mentor two undergraduate students, Dana Gephart and Robin McDonald. Travis DeLano in particular has been my project partner on and off for the past four years or so. I always know Travis has my back, and that I can trust him with our work. We have a similar approach towards chemistry that makes working together easy. He is so smart and talented; I learned so much from him and I know he will be successful wherever he goes. I’d also like to thank Sara Dibrell. While we were only project partners for a few months, Sara is incredible to work with. She is competent and generous, and someone you are lucky to have on your side. I got to work with Mike Maser for about 6 months or so on our HTE/machine learning collaboration, and it was an extremely rewarding experience. As we were trying to figure out how we were going to carry out this project, it always made my day when I would make a suggestion and Mike would get excited about it. Mike is smart and talented, but also humble and encouraging of other people and their ideas. vii Finally, I would like to thank my newest project partner, Emily Chen. I wish that I got to spend more time with her in the lab, but COVID restrictions and grant-writing cut that time short. Emily is hilarious, kind, and very smart. It has been such a joy working with her, even if it was only for a short time. I know that she is ready for whatever comes her way. The problem with working with so many great people over the years is it makes it for a long list of acknowledgements. As I won’t have time to do them all in person at my defense, I hope that they can look at this document and get a glimpse of how much they meant to me. Thank you to Jordan for being a great mentor and so much fun to work with. Thank you to Dr. Julie Hofstra for her friendship, love, support, and frequent outings to get crepes. Julie was such a wonderful friend to me during my time at Caltech. Thank you to Alice Wong for Gardettos, the Moana soundtrack, and making the office fun. Thank you to Dr. Kelsey Poremba for her kindness and patience. Thank you to Karli Holman for her friendship. Our long talks about life in the bay, playing Pokemon, and watching Avatar the Last Airbender are memories I’ll treasure. Also, I couldn’t have asked for a better co-party planner. Thank you to Travis for being a great project partner over the years and for his enthusiasm and energy. And, perhaps most of all, thanks for the most nicknames I have ever had in my life. And of course, Wednesday Lunch Bunch with the two of them was always a treat. Thank you to Mike for being great to talk to and work with. The quiet days when it was just the two of us in the bay working where we ended up having some really good conversations were some of my favorites. viii Thank you to Alex Shimozono for all of the great discussions about chemistry and for always persevering. And thanks to all four for being great bay mates. Thank you to Ray Turro for just generally being everyone’s favorite person in lab. Ray is incredibly kind, patient, and generous, as well as ridiculously smart. He always has time for me to pester him about chemistry or talk about whatever is going on in life. Thanks to Jeff Kerkovius for being a great person to talk to and be around. Jeff is fun and smart, and makes some really great puns. He is also a ridiculously talented chemist, and I can’t wait to see what he comes up with next. Also, special thanks to his wife Miranda for all of the great talks we have had over the years at various holiday parties, socials, and camping trips about everything from books and videogames to what it means to be a woman in our current culture. Thanks to my fellow Texan Sara Dibrell for somehow being smart, hardworking, organized, and also incredibly kind and friendly. The lab would not function without her. If you need to get something done, Sara can do it. And thank you to Yujia Tao for being so hilarious and sweet. She keeps the lab interesting and fun. Her energy, enthusiasm, and brutal yet hilarious honesty make her a joy to be around. Thanks to Andrea Stegner for her kindness and friendship. Running into her on walks during quarantine always brightened my day. Thanks to Lexie Beard for her kindness. I only recently got the opportunity to know her better, and I wish we’d gotten to spend more time together. Thanks to Ally Stanko for her generosity and positivity. It was fun being bay mates with her for the last few months at Caltech, and I loved to opportunity to get to know her more. Thank you to all of the first years Jordan Thompson, Cedric Lozano, Daniel Cheng, and Emily Chen. I’m excited for what you will do next! Thank you especially to Emily for ix being such a wonderful mentee. I wish you all of the best! Thanks also to my friends outside of the lab Dylan Freas, Wendy Zhang, and the whole of the Stoltz lab. I’d also like to thank all of the wonderful postdocs I’ve had the privilege to work with over the years. Their kindness and support have made all of the difference. In particular, I’d like to thank Dr. Suzie Stevenson, Dr. Elliot Farney, Dr. Justin Su, Dr. Mike Rombola, Dr. Marco Brandstaetter, and Dr. Connor Farley for all of their friendship and mentorship over the years. Most importantly, I have to thank my two classmates, Nick Fastuca and Skyler Mendoza. It’s hard for me to express just how much these two wonderful friends mean to me. They have always been supportive, kind, and generous. They made the Yosemite camping trip one of the most fun experiences of my life. Nick is an incredibly generous friend. One time when I was having a bad week, he baked an entire chocolate cake for me. He is also silly, hilarious, and incredibly cool, and he’s one of those people who can pick up almost any hobby. He can always put a smile on my face. Skyler is one of those people who will drop everything to help you or spend time with you. He is an attentive listener and thoughtful friend. My favorite part of any day was when Skyler would wander over from the other side of the lab to talk to me. He has always been there for me, and I hope I have been able to be even half the friend to him that he’s been to me. These two people made such an impact on my life, and my experience at Caltech would have been drastically different and a lot less fun without them. In addition to my labmates and coworkers, I have a lot of people outside of my lab to thank. I would like to thank my church family at Grace Pasadena for the love, support, and community over the years. I’d especially like to thank Nathan for his friendship these x past five years. His blatant, unrepentant honesty is only matched by his thoughtfulness and generosity. Thanks to him, Sofia, and Kendall for the Thursday night zoom calls during quarantine that helped to keep me sane. Thank you to my friends from various city groups over the years Erisa, Chris, Caroline, Carolyn, Donna, and Marcia for all of the love, support and encouragement in all stages of life. I’d like to thank Julia, Rachel, and Kimi for their enduring friendship since high school. I’m so appreciative for their continued friendship despite the distance that keeps us apart at times. I’d also like to thank Emily Covert, one of my closest friends, for always being there for me and accepting me just as I am. Finally, I’d like to thank Stephanie Breunig, who was my roommate for the past four years. Stephanie is and incredibly kind and thoughtful person. Her selflessness and generosity are inspiring. We have shared so many adventures and life events. I could not have found anyone better to go through graduate school with, with research setbacks, sorrows, quarantines, and holidays away from family. She has been there for me during both the hard times and joyful times, and I’m so incredibly thankful for her. Most of all, I’d like to thank my family for all of their support over the years, especially my parents, Ann and Steve Lacker. They have always shown me unconditional love and support. I can’t fully express all that they have meant to me my whole life. They have encouraged my interests, allowed me to explore the world around me, taught me, loved me, and done their best to answer my many, many questions. They have always been there for me with both love and wisdom. I am so blessed to have them as parents. xi ABSTRACT Accessing libraries of similar compounds quickly is important in the pharmaceutical industry, as it allows for the expedient investigation of a wide variety of parameters. An efficient strategy to access compounds of interest is to start from a single intermediate containing an interesting or pharmaceutically active structure and decorating it with varying functionality to generate a library of related compounds. Cross-coupling is a powerful tool for this type of divergent, modular approach. Herein, we discuss several strategies geared towards the synthesis of small libraries of compounds of interest. First, a modular approach towards a library of enantioenriched trans cyclobutanes is discussed. This strategy allows for the synthesis of diverse substrates from a single enantioenriched intermediate, and this approach was applied to the synthesis of the small molecule (+)-rumphellaone A. Finally, the development of an enantioselective nickel-catalyzed photoredox cross-coupling to form N-(hetero)benzylic azoles in collaboration with researchers at Merck is discussed. xii PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following communications: 1. Chapman, L. M.; Beck, J. C.; Lacker, C. R.; Reisman, S. E. J. Org. Chem. 2018, 83, 6066–6085. DOI: 10.1021/acs.joc.8b00728. Copyright © 2018 American Chemical Society C.R.L. contributed to the reaction development, conducted experiments, and participated in preparation of the supporting data and writing of the manuscript. 2. Beck, J. C.‡; Lacker, C. R. ‡; Chapman, L. M.; Reisman, S. E. Chem. Sci, 2019, 10, 2315–2319. DOI: 10.1039/C8SC05444D. Copyright © 2019 The Royal Society of Chemistry C.R.L. contributed to the reaction development, conducted experiments, and participated in preparation of the supporting data and writing of the manuscript. xiii TABLE OF CONTENTS CHAPTER 1 1 Enantioselective Ketene Trapping and diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1.1 INTRODUCTION ............................................................................................. 1 1.1.1 Asymmetric Ketene Trapping............................................................... 2 1.1.2 C–H Alkenylation ............................................................................... 9 1.2 WOLFF REARRANGEMENT AND ASYMMETRIC KETENE TRAPPING ........... 13 1.3 C–H ARYLATION OF CYCLOBUTAMIDE 6 ................................................... 18 1.4 CONCLUSION ............................................................................................... 20 1.5 EXPERIMENTAL SECTION .............................................................................. 21 1.5.1. Materials and Methods ..................................................................... 21 1.5.2 Synthesis of Hydrogenated and epi-Cinchona Alkaloids .................... 22 1.5.3 Synthesis of Diazoketones 8, 69–72 .................................................. 34 1.5.4 Small-ScaleScreening Protocol for Enantioenriched Amides 6,73–76 27 1.5.5 Large-Scale Protocol for Enantioenriched Amide 6 ............................ 28 1.5.6 Optimized Scale-Up Protocol for Enantioenriched Amides 73–76..... 29 1.5.7 Csp3–H Arylation .............................................................................. 35 1.5.8 Characterization of Arylation Products .............................................. 36 1.5.9 Chiral SFC Traces of Racemic and Enantioenriched Products ............ 51 1.5.10 C–H Proof of Enantiopuritiy 1.6 REFERENCES .................................................................................................. 57 Appendix 1 Spectra Relevant to Chapter 1 60 xiv CHAPTER 2 116 Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Total Synthesis of (+)-Rumphellaone A 2.1 INTRODUCTION ......................................................................................... 116 2.2 STRATEGIES TOWARDS ENANTIOENRICHED CYCLOBUTANES ............... 117 2.2.1 Enantioselective [2+2] Cycloaddition .............................................. 117 2.2.2 Divergent C–H Activation Strategies Towards Cyclobutanes ........... 121 2.3 DECARBOXYLATIVE CROSS-COUPLINGS .................................................. 123 2.4 DIVERSIFICATION OF ENANTIOENRICHED CYCLOBUTANES.................. 128 2.5 TOTAL SYNTHESIS OF (+)-RUMPHELLAONE A .......................................... 134 2.5.1 Background and Biosynthesis .......................................................... 134 2.5.2 Previous Syntheses .......................................................................... 135 2.5.3 Our Strategy: Application of a Modular Approach .......................... 137 2.5.4 C–H Activation Optimization ......................................................... 137 2.5.5 Directing Group Removal and Functionalization ............................ 139 2.5.6 Furan Oxidation and Diastereoselective Methylation ...................... 140 2.5.6.1 Cyclopropanation Strategy ................................................ 141 2.5.6.2 Titanium-Mediated Diastereoselective Methylation ........... 142 2.5.6.3 Discussion of Diastereoselectivity ..................................... 147 2.5.7 Ketone Installation .......................................................................... 148 2.6 SUMMARY ................................................................................................... 150 2.7 CONCLUSION ............................................................................................. 151 2.8 EXPERIMENTAL SECTION ............................................................................ 153 2.8.1 Materials and Methods .................................................................... 153 2.8.2 Carboxylic Acid Derivatization ....................................................... 154 2.8.3 Synthesis of (+)-Rumphellaone A..................................................... 176 2.8.4 Comparison of 1H NMR Spectroscopic Data for Natural and Synthetic (+)-Rumphellaone A ................................................................................. 194 xv 2.8.5 Comparison of 13C NMR Spectroscopic Data for Natural and Synthetic (+)-Rumphellaone A ................................................................................. 195 2.9 REFERENCES ................................................................................................ 196 APPENDIX 2 203 Spectra Relevant to Chapter 2 CHAPTER 3 281 Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole-Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides 3.1 INTRODUCTION ......................................................................................... 281 3.2 OPTIMIZATION ........................................................................................... 286 3.2.1 Initial Conditions from Merck ......................................................... 286 3.2.2 Reaction Stall and Product Inhibition .............................................. 288 3.2.3 Solvent and [Ir] Loading .................................................................. 290 3.2.4 Additives ......................................................................................... 294 3.2.5 Final Ligand Optimization ............................................................. 295 3.3 SUBSTRATE SCOPE ...................................................................................... 297 3.3.1 Scope of Aryl Bromides ................................................................... 297 3.3.3 Scope of Nucleophiles .................................................................... 300 3.4 CONCLUSION ............................................................................................. 304 3.5 EXPERIMENTAL SECTION ............................................................................ 305 3.5.1 Materials and Methods .................................................................... 305 3.5.2 Ligand Preparation .......................................................................... 307 3.5.3 Optimization of Reaction Parameters .............................................. 309 3.5.4 Enantioselective Cross-Couplings .................................................... 309 3.6 REFERENCES ................................................................................................ 327 xvi APPENDIX 3 329 Spectra Relevant to Chapter 3 ABOUT THE AUTHOR ....................................................................................... 376 xvii LIST OF ABBREVIATIONS [a]D angle of optical rotation of plane-polarized light Å angstrom(s) Ac acetyl acac acetylacetonate alk alkyl Am tert-amyl APCI atmospheric pressure chemical ionization app apparent aq aqueous Ar aryl atm atmosphere(s) bathophen bathophenanthroline BBN borabicyclo[3.3.1]nonane BHT 2,6-di-tert-butyl-4-methylphenol (“butylated hydroxytoluene”) BiOX bi(oxazoline) BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1'-bi(2-naphthol) Bn benzyl Boc tert-butoxycarbonyl BOX bis(oxazoline) bp boiling point br broad t xviii Bu butyl Bu iso-butyl Bu butyl or norm-butyl Bu sec-butyl Bu tert-butyl Bz benzoyl c concentration of sample for measurement of optical rotation i n s t 13 C carbon-13 isotope /C supported on activated carbon charcoal °C degrees Celsius calc’d calculated CAM cerium ammonium molybdate cat. catalyst Cbz benzyloxycarbonyl cf. consult or compare to (Latin: confer) cis on the same side cm–1 wavenumber(s) cod 1,5-cyclooctadiene conc. concentrated conv. conversion Cp cyclopentadienyl Cy cyclohexyl Cyp cyclopentyl xix 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 DCE 1,2-dichloroethane DIPEA N,N-diisopropylethylamine DIBAL diisobutylaluminum hydride DFT density functional theory DKR dynamic kinetic resolution DMA N,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DMBA 2,6-dimethylbenzoic acid DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMI 1,3-dimethyl-2-imidazolidinone DMPU N,N'-dimethylpropylene urea DMSO dimethylsulfoxide dppb 1,4-bis(diphenylphosphino)butane dppbz 1,2-bis(diphenylphosphino)benzene dppf 1,1'-bis(diphenylphosphino)ferrocene xx dppe 1,2-bis(diphenylphosphino)ethane dr diastereomeric ratio dtbpy 4,4'-di-tert-butyl-2,2'-bipyridine DYKAT dynamic kinetic asymmetric transformation E methyl carboxylate (CO2CH3) E+ electrophile E trans (entgegen) olefin geometry EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ee enantiomeric excess e.g. for example (Latin: exempli gratia) EI electron impact epi epimeric equiv equivalent(s) ESI electrospray ionization Et ethyl et al. and others (Latin: et alii) FAB fast atom bombardment g gram(s) GC gas chromatography h hour(s) H proton [H] reduction HC homocoupling 1 xxi hex hexyl HMDS hexamethyldisilazane HMPA hexamethylphosphoramide hn light HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz IC50 half maximal inhibitory concentration (50%) i.e. that is (Latin: id est) in situ in the reaction mixture IPA isopropanol IR infrared spectroscopy J coupling constant k rate constant kcal kilocalorie(s) kg kilogram(s) L liter or neutral ligand l levorotatory LA Lewis acid LC/MS liquid chromatography–mass spectrometry LDA lithium diisopropylamide LED light-emitting diode m multiplet or meter(s) xxii M molar or molecular ion m meta µ micro m-CPBA meta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz min minute(s) mL milliliter(s) MM mixed method mol mole(s) MOM methoxymethyl mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves or mass spectrometry m/z mass-to-charge ratio naph naphthyl nbd norbornadiene NBS N-bromosuccinimide ND not determined NHC N-heterocyclic carbene NHP N-hydroxyphthalimide nm nanometer(s) xxiii NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance o ortho [O] oxidation p para Pc phthalocyanine Ph phenyl pH hydrogen ion concentration in aqueous solution phen 1,10-phenanthroline PHOX phosphinooxazoline pin pinacol Piv pivaloyl pKa acid dissociation constant Pr propyl Pr isopropyl Pr propyl or norm-propyl py pyridine PyBOX pyridine-bis(oxazoline) PyOx pyridine-oxazoline pyphos (2-diphenylphosphino)ethylpyridine q quartet quant. quantitative QuinOx quinoline-oxazoline i n xxiv R alkyl group RL large group R rectus RCM ring-closing metathesis recry. recrystallization ref reference Rf retention factor rt room temperature s singlet or seconds S sinister sat. saturated SET single-electron transfer SFC supercritical fluid chromatography SM starting material t triplet TBAB tetra-n-butylammonium bromide TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammonium iodide TBAT tetra-n-butylammonium difluorotriphenylsilicate TBS tert-butyldimethylsilyl TDAE tetrakis(dimethylamino)ethylene Tf trifluoromethanesulfonyl TFA trifluoroacetic acid xxv temp temperature terpy 2,2′:6′,2′′-terpyridine THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl TOF time-of-flight tol toluene trans on the opposite side Ts para-toluenesulfonyl (tosyl) UV ultraviolet vide infra see below v/v volume per volume w/v weight per volume X anionic ligand or halide xs excess Y anionic ligand or halide Z cis (zusammen) olefin geometry 1 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B Chapter 1 Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)Psiguadial B1 1.1 INTRODUCTION Figure 1.1 Cyclobutane-containing natural products, and a strategy towards (+)psiguadial B Me Me H AcO Me Me CHO H Me O H HH Me Me H OMe HO OMe O Me Me Me O O Me Me (+)-pestalotiopsin A (2) (+)-rumphellaone A (4) (±)-artochamin H (3) H Me CHO H Me OH H HO (+)-psiguadial B (1) Me HO OH OH H Me O OH CHO Ph Me Me O Me Me CHO 1 N H Me OH O Ph O O N Me I N2 Me 6 + O OH O 5 7 8 Cyclobutanes are found in a wide variety of natural products. Despite their prominence, cyclobutanes can be challenging to form synthetically, particularly transcyclobutanes, such as those found in 1, 2, and 4 (Figure 1.1).1–6 One common method for 1 Portions of this chapter were adapted from the following communications: Chapman, L. M.; Beck, J. C.; Lacker, C. R.; Wu, L.; Reisman, S. E. J. Org. Chem. 2018, 83, 6066.; DOI: 10.1021/acs.joc.8b00728, copyright 2018 American Chemical Society; Beck, J. C.; Lacker, C. R.; Chapman, L. M.; Reisman, S. E. Chem. Sci. 2019, 10, 2315., DOI: 10.1039/C8SC05444D, copyright 2019 Royal Society of Chemistry. The research discussed in this chapter was completed in collaboration with Dr. Jordan C. Beck as well as Dr. Lauren M. Chapman, former graduate students in the Reisman Lab. 2 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B the synthesis of cyclobutanes is the [2+2] cycloaddition. However, regio- and stereoselectivity can be challenging to control using this methodology. In addition, trans cyclobutanes in particular are difficult to synthesize.7 In light of these challenges, a novel method for the synthesis of cyclobutanes was developed by our lab for the 2016 total synthesis of (+)-psiguadial B (1), a meroterpenoid isolated from the Psidium guajava in 2010, which contains a fused trans-cyclobutane.1,8,9 The cyclobutane was introduced enantioselectively using a photoinduced Wolff rearrangement with asymmetric trapping of the in situ generated ketene. This tandem Wolff rearrangement/asymmetric ketene addition method utilizes a ring contraction approach, obviating some of the selectivity challenges inherent to a [2+2] approach. Intermediate 6 was then elaborated by a directed C–H activation followed by a selective epimerization to afford the desired trans cyclobutane (5). 1.1.1 Asymmetric Ketene Trapping Scheme 1.1 Synthesis of 6 racemically and via a chiral resolution O Me hν, NaHCO3 N2 Me THF, H2O (84% yield) 8 O Me Me 9 N O Me Me • OH NH2 11 Me Me EDCI, CH2Cl2 pyridine, rt (80% yield) (±)10 O N H N (±)6 H Me Me Me O H 2N OH 12 Ph Me Me O PhMe, rt (±)10 H Me O 13 H 3N Ph 14 initial salt: 52 – 57% ee 1. recry. 3x, PhMe 2. Et2O, HCl (aq) (27% yield, 98% ee) Me Me O OH (–)10 Cyclobutamide 6 was chosen as the target compound. It was thought that the quinolinamide could be used as a directing group for C–H activation to build up the framework of (+)-psiguadial B. This compound was first synthesized racemically in two steps (Scheme 1.1). First, a photoinduced Wolff rearrangement was used to generate carboxylic acid ±10 from diazoketone 8.10,11 (±)10 was then coupled with 8- 3 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B aminoquinoline (11) to generate racemic cyclobutamide (±)6. Prior to coupling, carboxylic acid (±)10 could be resolved through recrystallization with chiral amine 12. However, this method required multiple recrystallizations and afforded the enantioenriched acid in low yield. To circumvent this issue, it was proposed that ketene 9 could be trapped in situ with 8-aminoquinoline in an enantioselective fashion using a chiral catalyst. Scheme 1.2 Previous asymmetric and stereospecific nucleophilic ketene trapping a. Fu, 2002 - planar-chiral ferrocenyl DMAP catalysis N O • Et H N + CN 16 CN Et N N PhMe, rt (93% yield, 90% ee) Ph 15 O 18 (2%) Fe Me Me Ph 17 Me Me Me 18 b. Ye, 2008 - chiral NHC catalysis O O Cl OMe O • + Et N (98% yield, 99% ee, >20:1 dr) O 19 20 N H Cl THF, rt H O O Et 22 (10-12%) N Ph Ph OTBS OMe 21 Ph 22 c. Lekta, 2004 - cinchona catalysis O O + Ph Cl N2 Cl Cl 23 Ph Cl Cl Cl Cl 26 (10%) O Cl hν, THF, rt (45% yield, 85% ee) Cl Cl O Ph O O H MeO Cl N Cl 24 N 25 26 d. Wang and Hou, 1998 - addition of a nitrogen nucleophile to an in situ generated ketene H NHTs O PhCO2Ag, NEt3 R N2 27 THF, rt (81–93% yield) • O O R NH NTs R Ts 28 29 There are relatively few examples of enantioselective engagement of ketenes in the literature. The Fu lab has been able to access enantioenriched amides (as well as other enantioenriched products) from isolable ketenes through the use of planar-chiral ferrocenyl DMAP catalysts such as 18 (Scheme 1.2a).12–16 Chiral NHC catalysts (22) have been used by Ye and coworkers for a variety of enantioselective reactions with isolable ketenes, Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 4 including the preparation of chiral b lactones (21) (Scheme 1.2b).17 Though powerful and effective transformations, these reactions have only been reported with isolable ketene substrates, and to the best of our knowledge, have not been effective with ketene substrates generated in situ. At the outset of this project, we were aware of only one literature example of in situ ketene generation with subsequent asymmetric intermolecular nucleophilic addition to afford enantioenriched products. In 2004, the Leckta group disclosed a method to trap an in situ generated ketene from the corresponding diazoketone 23 to access enantioenriched ester 25 using cinchona alkaloid catalysis (Scheme 1.2c).18 Though they were able to access the desired products, the yields and enantioselectivities were still inferior to the systems reported by Fu and Ye, indicating the inherent difficulty of asymmetric trapping of in situ generated ketenes. In 1998, Wang and Hou disclosed an example of an intramolecular addition of a nitrogen nucleophile to an in situ generated ketene to afford cyclic lactams 29 in good yield.19 This example was promising, indicating that an in situ generated ketene could indeed be trapped by a nitrogen nucleophile. With these reactions in mind, these three catalyst types were evaluated for their ability to effect enantioselective trapping of ketene 9.8,9,20 It was anticipated that this transformation would be difficult owing to the large amount of background reactivity observed in the absence of catalyst (Figure 1.2). Gratifyingly, promising reactivity was observed with planar-chiral DMAP-type catalysts such as catalyst ent-18, which afforded the desired enantioenriched cyclobutamide (–)-6 in 46% ee, but with poor yields. Similarly, NHC catalyst 32 afforded (–)-6 with good enantioselectivity, but with poor yields and reproducibility issues. This could be attributed to potential decomposition of the NHC catalysts under the photolytic conditions required to generate the ketene. Despite the low 5 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B Figure 1.2 Summary of catalyst reactivity NH2 O Me N2 Me hυ (254 nm) catalyst N + O O Me Me Me Me • N H THF, rt 8 9 11 (1.0 equiv) N (–)6 Cl N N N Me Me Me Me Me Fe Me Mes O Me MeO O H N Me O H N N Ph O N OMe H MeO N N N N BF4 O N N PPY-Me* (ent-18) (50 mol%) 39% yield, 46% ee (DHQD)2PYR (30) (50 mol%) 65% yield, –15% ee HO H N N (–)-cinchonidine (33) (50 mol%) 58% yield, –59% ee Benzoyl-DHQ (31) (10 mol%) 53% yield, 0% ee HO H Indanyl-NHC (32) (50 mol%) 32% yield, –66% ee N N no catalyst 55% yield (+)-cinchonine (34) (50 mol%) 72% yield, 77% ee (10 mol%, 3 equiv 11, 30 mmol) 62% yield, 79% ee yields, these reactions provided proof of principle for the enantioselective trapping of ketene 9. After further investigation, cinchonine (34), a naturally occurring cinchona alkaloid, was determined to be the optimal catalyst for this reaction, affording the desired product in 72% yield and 77% ee. The pseudo-enantiomer of cinchonine, cinchonidine (33) afforded the opposite enantiomer of product, albeit in lower yield and only –57% ee, which was intractable for synthesis. Investigation of various solvents revealed that THF provided the highest levels of enantioselectivity. More concentrated reaction mixtures led to lower yields, presumably due to poor light penetration as a result of the sparing solubility of 34 in THF. When scaling the reaction to quantities relevant for total synthesis (30 mmol), the catalyst loading of 34 could be reduced to 10 mol %, which provided (–)-6 in 62% yield and 79% ee. Multiple grams of enantiopure material could be obtained through a single 6 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B recrystallization. Development of these scalable, robust conditions allowed for the completion of the total synthesis of (+)-psiguadial B (1). Interestingly, dimeric cinchona catalyst 30 and modified quinine-based catalyst 31, which both lack a free hydroxyl group, gave the desired product with little to no enantioselectivity. Interested in potential applications of this reaction to the preparation of other enantioenriched amides, the possible mechanisms for this reaction were considered. Figure 1.3 Potential reaction mechanisms for enantioselective ketene trapping Catalyst as a Nucleophile (diastereoselective protonation) a. O Me Me Me Me N H N Cat* (–)6 Catalyst as a Brønsted Acid (enantioselective protonation) b. NH2 O O • Me Me N N H 9 N Cat* (–)6 11 37 NH H Cat* N O Me Me O Me Me Cat* 35 Cat* 36 NH N H NH2 N N 11 38 O Me Me 11 39 H N Cat* 37 Me Me O • 9 Two potential mechanisms for enantioselective trapping of ketenes were considered: 1) diastereoselective protonation and 2) enantioselective protonation (Figure 1.3). The diastereoselective protonation mechanism postulates that enantioselectivity is imparted through a diastereoselective protonation of chiral, zwitterionic enolate intermediate 35.21–26 This intermediate would be formed by nucleophilic trapping of ketene 9 by the chiral catalyst (Figure 1.3a). Due to the high nucleophilicity of the quinuclidine core of cinchona-type catalysts, this is thought to be the mechanism of most cinchona alkaloid-mediated asymmetric reactions with ketenes. It has also been shown Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 7 computationally that stabilizing hydrogen bonds can form between the enolate and the quinuclidine core of cinchona catalysts, the rigidity of which could help afford enantioselectivity.25,26 Another potential mechanism was proposed by the Fu group based on their work with planar-chiral ferrocenyl DMAP catalysts.13 Instead of acting as a nucleophile (Lewis base), the catalyst could act as a Brønsted base and deprotonate the amine nucleophile (here, 8-aminoquinoline 11). This nucleophile could engage the ketene to form enolate 39, which could then undergo enantioselective protonation by the protonated chiral catalyst (37) (Figure 5b). A particularly compelling piece of evidence for this mechanism disclosed by the authors for their system is the observation that the resting state of the catalyst is not the neutral catalyst, but the ion pair formed by deprotonation of the amine by the catalyst (such as 37 and 38). Scheme 1.3 Preliminary mechanistic studies a. ion pair formation NH2 HO N + H HO THF-d8 N NH N N N 37 38 (no evidence by NMR) 34 11 N H H b. nucleophilic addition of the catalyst into the ketene O Me N2 Me hν (254 nm) THF-d8 4 h, rt N H O O Me Me 34 • 9 8 O Me Me H N 40 observed by NMR, not isolated c. formation of 6 from complex 40 N O Me N2 Me 8 hν (254 nm) then 34 Me THF-d8 Me 4 h, rt O H O O H 11 (1 equiv) Me Me N H N N 40 (–)6 (9% yield, 26% ee) A number of experiments were performed in hopes of gaining a better understanding of the mechanism responsible for providing the observed product.20 When Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 8 8-aminoquinoline (11) and cinchonine (34) were combined in THF-d8, no formation of the ion pair 37 and 38 was observed by NMR, as would be expected for the enantioselective protonation mechanism (Scheme 1.3a). However, this does not preclude formation of a small amount of this species in the reaction mixture. In addition, when a solution of 8 and 38 was irradiated in THF-d8 for four hours, NMR shifts indicative of the formation of complex 40 were observed, which would support the diastereoselective protonation mechanism (Scheme 1.3b). However, when this complex was then treated with 11, formation of the desired product was observed in only 9% yield and 26 % ee, indicating that complex 40 might not be a viable intermediate in the active mechanism (Scheme 1.3c). Therefore, at this time, the predominant reaction mechanism for the formation of cyclobutamide 6 remains unclear. Figure 1.4 Model for diastereoselective protonation H N H H H O O Me Me O H O O N N N H Me Me Me N (S) H N Me (–)6 40 diastereoselective protonation One interesting aspect of this system is the loss of enantioselectivity when the hydroxyl group of the cinchona catalyst is masked. This contrasts examples from Lekta and Calter, where cinchona catalysts containing a masked hydroxyl group afford the desired product in good enantioselectivity.18,24–26 Based on these results and simple molecular models, formation of a hydrogen bond between this free hydroxyl and the enolate oxygen in complex 40 could be a significant interaction that imparts rigidity to the system and helps to enforce the observed enantioselectivity in this system (Figure 1.4). With the hydrogen bond in place, the conformation of the quinoline over the re face in 40 9 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B could promote protonation from the si face to afford the observed enantiomer (–)6. However, the low enantioselectivity observed upon treatment of 40 with 8-aminoquinoline to form (–)6 renders this hypothesis somewhat tenuous. 1.1.2 C–H Alkenylation Scheme 1.4 C–H functionalizations of cyclobutanes a. proposed reaction O O Me Me + N H N N H Me O 42 41 b. Babu, 2013 ArI (4.0 equiv) Pd(OAc)2 (5%) O N O Ar N H AgOAc (2.2 equiv) PhMe, 110 ºC (57–99% yield) 44 I c. Chen, 2013 CO2Et XX (2.0 equiv) Pd(OAc)2 (10%) O N 43 N Ar 43 N H CO2Et O N H Ag2CO3 (2.0 equiv) (BnO)2PO2H (20%) t-amylOH, 110 ºC, Ar atm (84% yield) N CO2Et 45 d. Yu, 2014 F F CN F O F R N I (–)6 N H O Me [Pd] N H F 46 R = alkyl F 48 (11%) Pd(OAc)2 (10%) ArBPin (2.0 equiv) Ag2CO3 (2.5 equiv) Na2CO3 (2.0 equiv) t-amylOH, H2O 70 ºC (49–75% yield 81–95% ee) CN F O F R N H O F NHOMe NHBoc Ar 47 F 48 e. Yu, 2018 F CF3 F O F N H 49 F 51 (15%) Pd(MeCN)2Cl2 (10%) (Het)ArI (3.0 equiv) Ag2CO3 (2.0 equiv) CHCl3, 80 ºC (50–85% yield 82–94% ee) F CF3 F Me O N H F Me O F AcHN Me N Me (Het)Ar 51 50 With enantioenriched cyclobutamide (–)6 in hand, the next step was to install functionality at the β position to help build up the structure of (+)-psiguadial B. 8- 10 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B aminoquinoline is a well-known directing group for C–H activation of alkyl C–H bonds (Scheme 1.4a,b).27,28 Both Babu and Chen demonstrated that 8-aminoquinoline was a good directing group for palladium-catalyzed diastereoselective arylation and alkylation of cyclobutamide 43 respectively (Scheme 1.4b,c).29,30 Both observed bis-functionalization of the cyclobutane. Yu and coworkers have demonstrated elegant enantioselective C–H Scheme 1.5 C–H functionalization in total synthesis OMe a. Baran, 2011 OMe MeO 53 (2.0 equiv) Pd(OAc)2 (15%) N H MeS OMe (±) 52 MeO O O MeS OMe 54 O MeO OMe O OMe N H N O OMe N H 55 OMe N OMe O OMe O O OMe MeO MeS MeO OMe N O Ag2CO3 (1.5 equiv) PivOH (1.0 equiv) HFIP, 90 ºC 52% yield, 10% sm O OMe OMe I O N MeO O O MeO O MeO piperaborenine B (56) piperaborenine D (57) (proposed) I O b. Baran, 2012 O 1. 59 (2.0 equiv) Pd(OAc)2 (15%) Ag2CO3 t-BuOH, 85 ºC O N H N I O O O N H N N O OMe O O N O OMe O 58 O O O O 2. 60 (2.0 equiv) Pd(OAc)2 (15%) AgOAc PhMe, 85ºC 54% yield 59% yield O 61 O O pipercyclobutanamide A (62) (proposed) OMe c. Maimone, 2014 OMe Me Me Me Me I O O 53 (2.0 equiv) Pd(OAc)2 (15%) O O O HN 63 MeS OMe K2CO3 (1.5 equiv) (BnO)2PO2H (40%) t-amylOH, 110 ºC 58% yield O O OH O TFA O O HN MeO 64 OMe OMe SMe H 2O 76% yield, 1.3:1 dr 1.3:1 O H O O H MeO O OMe OMe podophyllotoxin (65) 11 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B arylation methods of tertiary and secondary cyclobutamides 46 and 49 using chiral ligands to afford the mono-arylated products in good yield and ee.31,32 In addition to C–H activation methodologies for the functionalization of cyclobutanes, diastereoselective C–H activation of more complex substrates in total synthesis has also been shown.33–36 In 2011, Baran and coworkers utilized multiple diastereoselective C–H arylations of cyclobutane intermediates in their racemic syntheses of piperaborenine B (56) and the proposed structure of piperaborenine D (57) (Scheme 1.5a).33 Similarly, in 2012, they utilized a C–H activation strategy in their synthetic efforts towards the proposed structure of pipercyclobutanamide A (62) (Scheme 1.5b).34 Together, these strategies demonstrated that C–H functionalization of cyclobutamides is an effective tool for total synthesis. In 2014, Maimone showed that diastereoselective C– H arylation was also effective in total synthesis for the functionalization of six-membered substrate 53 for their total synthesis of podophyllotoxin (65) (Scheme 1.5c).36 Figure 1.5 Synthesis of both enantiomers of 5 from a single intermediate O Pd(OAc)2 (15%) I Me Me N H Me N β Ag2CO3 TBME, 90 ºC (75% yield) 41 (3.0 equiv) O DBU N H Me 42 (64% yield) N β CH2Cl2, 60 ºC O 1. ethylene glycol Me CH(OMe)3, p-TsOH Me PhMe, 80 ºC O 2. Cp2Zr(H)Cl, THF; then Ph3P CH2; then 5M HCl O 66 (58%, 2 steps) Me Me O N H α β O O (–)-5 undesired N (–)6 O Pd(OAc)2 (15%) I 7 (2.0 equiv) Ag2CO3 TBME, 90 ºC (72% yield) Me Me O α Me N H N O 67 1. Cp2Zr(H)Cl, THF α 2. KOH, MeOH (70%, 2 steps) O Me O 68 Me Me H Ph3P CH2 O then 5 M HCl O (88% yield) O (+)-5 desired We were pleased to find that treatment of (–)6 with Pd(OAc)2 (15 mol %), Ag2CO3, and alkenyl iodide 41 in TBME at 90 °C without the use of a ligand smoothly effected the Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 12 desired C(sp3)−H alkenylation reaction to give cis cyclobutane 42 in 75% yield (Figure 1.5).8 Following epimerization of the β-position, trans cyclobutane 66 could be elaborated to (–)-5. However, it was soon found that this was the undesired enantiomeric series for the synthesis of (+)-psiguadial B. As (+)-5 could not be synthesized in synthetically tenable yield or ee due to the poor catalytic behavior of cinchonidine (33) compared to cinchonine (34) for the asymmetric Wolff rearrangement, another approach was required. Fortunately, simply switching to alkenyl iodide 7 allowed for epimerization at the α position to afford trans cyclobutane 38, which could then be elaborated to (+)-5 in the same number of steps and a higher overall yield. It is notable that this strategy allowed for the efficient synthesis of both enantiomers of 5 from an intermediate synthesized using one enantiomer of organocatalyst. Figure 1.6 Reactions developed for the synthesis of (+)-psiguadial B NH2 O Me N2 Me hυ (254 nm) (+)-cinchonine N + O O Me Me Me Me • THF, rt 8 11 Me Me Pd(OAc)2 (15%) N H N (–)6 Ag2CO3 TBME, 90 ºC (72% yield) N (–)6 (62% yield, 79% ee) recrystallized to >99% ee 9 O N H Me O N H Me N O 67 O Development of these two reactions was key for the completion of the total synthesis of (+)-psiguadial B.8 Both of these reactions were highly scalable and robust, allowing for synthesis of cis cyclobutane products on multigram scale (Figure 1.6). Due to the scalability and utility of these reactions, we sought to investigate them individually to broaden their scope and applicability. 13 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1.2 WOLFF REARRANGEMENT AND ASYMMETRIC KETENE TRAPPING Figure 1.7 General approach for the synthesis of enantioenriched products 6, 73–76 NH2 O N2 + n 8, 69–72 (n = 1–3) O hν (254 nm) catalyst (50 mol %) N N H THF, rt, 18 h N n 6, 73–76 11 (3.0 equiv) First, the tandem Wolff rearrangement/asymmetric ketene addition sequence was investigated. It was hoped that this reaction could be used to access enantioenriched products of various ring sizes (Figure 1.7). To this end, a variety of cyclic α-diazoketones were synthesized using known methods.10,11 In addition, a variety of cinchona alkaloidtype catalysts were investigated. Figure 1.8 Cinchona-type catalysts and dimers HO H Et HO N H MeO Et N N MeO N N cinchonine (34) quinidine (77) O H O N H N N N OMe N (DHQD)2PYR (30) Et HO H HO N N cinchonidine (33) H MeO N quinine (78) Et N N MeO O O H H O O N N OMe N (DHQD)2AQN (79) The four naturally occurring cinchona catalysts are cinchonine (34), cinchonidine (33), quinidine (77), and quinine (79) (Figure 1.8). The differences among these four catalysts can be grouped into two categories: 1) structural differences at the quinuclidine Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 14 and hydroxy core, and 2) the electronic differences on the quinoline ring. For example, cinchonine (34) and cinchonidine (33) have different quinuclidine methine and hydroxyl stereochemistry, yet both have unsubstituted quinoline rings. They are therefore thought of as pseudo-enantiomers, as are quinidine and quinine. Preservation of the quinuclidine stereochemistry at the bridgehead carbon as well as the pendent alkene across all four alkaloids means there are no true enantiomeric pairs. On the other hand, cinchonine (34) and quinidine (77) have identical hydroxyl and quinuclidine methine stereochemistry (highlighted in purple), but only quinidine contains a methoxy group on the quinoline, resulting in different electronic properties on the quinoline. Cinchonidine (33) and quinine (79) have the same relationship. As these are naturally occurring compounds, the opposite enantiomers are not easily accessible. In addition to the natural occurring catalysts, hydrogenated and C9-epimerized versions of each of the parent catalysts were synthesized using known methods (Table 1.1, section 1.5.2).37,38 Two commercially available dimers of dihydroquinidine (DHQD) (81), (DHQD)2PYR (30) and (DHQD)2AQN (79), were also screened to examine whether cinchona catalysts containing masked hydroxyl groups would continue to afford lower enantioselectivities than cinchona catalysts with free hydroxyl groups, as observed previously. Each reaction was run with 50% catalyst on a 0.05 mmol scale in a quartz test tube using conditions previously developed for the synthesis of cyclobutamide 6. The results are shown in Table 1.1. Unfortunately, no one catalyst performed the best overall. While cinchonine was again shown to be the optimal catalyst for cyclopentanone 8, it only afforded the other products with a maximum of 64% ee (entry 1). Interestingly, epiquinidine (85) and quinidine (77) proved to be the optimal catalysts for cyclohexanone and 15 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B Table 1.1 Wolff rearrangement catalyst and substrate screens NH2 O N2 + O O 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Me Me N2 Me N n 6, 73–76 11 (3.0 equiv) Me catalyst N H THF, rt, 18 h n 8, 69–72 (n = 1–3) entry O hν (254 nm) catalyst (50 mol %) N Me Me N2 O O O N2 N2 N2 8 69 70 71 72 % yielda % eeb % yielda % eeb % yielda % eeb % yielda % eeb % yielda % eeb 61c cinchonine (34) DHCN (80) epi-CN (84) cinchonidine (33) DHCD (82) epi-CD (86) quinidine (77) DHQD (81) epi-QD (85) quinine (78) DHQN (83) epi-QN (87) (DHQD)2PYR (30) (DHQD)2AQN (79) 56 50 64 58 51 67 36 58 66 19 58 90 50 79 65 24 –57 –47 4 64 56 48 –54 –18 –9 –16 53 64 58 68 48 52 64 62 –22 61 –3 66 25 69 50 70 40 77c 71 66 0 62 31 67 18 60 –59 49 –23 49 51 60 56 52 55 59c 47 55 54 47 57 65 50 64 61 7 –51 –35 –12 71 64 7 –34 –14 –12 –7 37 48 9 43 7 48 –3 48 25 40 7 48 –26 47 –5 31c 34 54 47 65 38 57 57 42 43 61 42 52 51 42c 35 35 34 42 –20 –10 18 23 25 41 –23 –10 11 –75 –1 a Reactions performed on 0.05 mmol scale and irradiated for 18 hours. Yield determined by 1H NMR analysis versus an added internal standard. b Determined by SFC using a chiral stationary phase. c 0.200 mmol scale, irradiated for 48 hours, isolated yield. Me HO H R Me HO N N R = H, dihydrocinchonine (DHCN, 80) R = OMe, dihydroquinidine (DHQD, 81) H R HO 9 N N R = H, dihydrocinchonidine (DHCD, 82) R = OMe, dihydroquinine (DHQN, 83) H R HO 9 N H R N N N R = H, epi-C9 cinchonine (epi-CN, 84) R = OMe, epi-C9 quinidine (epi-QD, 85) R = H, epi-C9 cinchonidine (epi-CD, 86) R = OMe, epi-C9 quinine (epi-QN, 87) cycloheptanone substrates 69 and 70, respectively, affording the desired products in 71% ee (entries 7, 9). It is notable that cinchonine (34) and quinidine (77) both have the same quinuclidine stereochemistry. Surprisingly, dimeric catalysts 30 and 79 performed the best for substrates 72 and 71, respectively, though 5-membered substrate 71 performed poorly overall and was only isolated at a maximum of 34% ee (entries 13, 14). However, (DHQD)2AQN (79) performed poorly overall, affording the desired products in poor ee and low yield. This low reactivity and selectivity could be attributed to the fact that dissolution of 79 in THF results in a dark brown mixture, leading to poor light penetration 16 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B in the reaction. The moderate yield and good enantioselectivity afforded by (DHQD)2PYR (30) for substrate 72 contrasts the low ee’s observed when using catalysts with masked hydroxyl groups for α-diazoketone 8 (entry 13, Figure 1.2), indicating that another mechanism could be active for these substrates. Overall, hydrogenated catalysts 80–83 afforded the products in lower ee than their parent catalysts (entries 2, 5, 8, 11), and the epi-catalysts (84–87) only improved the ee for 6-membered substrates 69 and 72 over the parent catalyst (entries 3, 6, 9, 12). To test scalability, each substrate was submitted to the reaction conditions on 0.200 mmol scale with its optimal catalyst. After 48 h, each product was isolated with comparable yield and ee to the small-scale reaction (entries 1, 7, 9, 13, 14). Table 1.2 Catalyst loading and reaction scale screening NH2 NH2 N a. O Me Me 69 N b. 11 (3.0 equiv) N2 epi-QD 85 (xx%) hν (254 nm) THF (0.1 M), rt, 48h Me Me Me Me O N H 73 entry cat loading (mol %) % yield %ee 1 50 73 71 2 30 81 O N2 N 70 11 (3.0 equiv) quinidine 77 (xx%) hν (254 nm) THF (0.1 M), rt, 48h Me Me O N H entry cat loading (mol %) % yield %ee 69 1 50 66 73 30 71 66 3 20 76 67 2 4 10 81 63 3 20 61 62 5a 20 80 67 4 10 61 55 6b 20 81 68 5a 20 67 65 a1.00 mmol scale, irradiated for 48h, b5.00 mmol scale, irradiated for 5 days N 74 a1.00 mmol scale, irradiated for 48h Next, catalyst loading was investigated. Substrates 69 and 70 were submitted to reaction conditions with lower catalyst loading (Table 1.2). While 7-membered substrate 70 showed about a 10% decrease in ee upon lowering the catalyst loading to 20% (Table 1.2b, entry 3), 6-membered substrate 69 showed only a minimal decrease in ee (Table 1.2a, 17 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B entry 3), though both suffered at 10% catalyst loading. Both reactions were scaled up to 1.00 mmol at 20% catalyst loading with comparable yields and ee’s (Table 1.2a, entry 5, Table 1.2b, entry 5). 69 was scaled up to 5.00 mmol and afforded the product in 81% yield, 68% ee after 5 days (Table 1.2a, entry 6). Figure 1.9 Wolff rearrangement summary NH2 O N N2 + n 8, 69–72 (n = 1–3) 11 (3.0 equiv) hν (254 nm) catalyst (50 mol %) THF, rt, 18 h (up to 79% ee) HO 9 O N H n 6, 73–76 N H R N N R = H: cinchonine (34) R = OMe: quinidine (77) R = OMe, epi C-9: epi-quinidine (85) Though we were unable to identify a unified catalyst system for all substrates, decent yields as well as enantioselectivities greater than 70% were obtained for all but one substrate (71) after some catalyst optimization (Figure 1.9). In addition, several interesting trends were observed. In particular, the best-performing catalysts were related to quinidine. Cinchonine (34) is nearly structurally identical to quinidine, as is epi-QD (85). (DHQD)2PYR (30) and (DHQD)2AQN (79) are both dimers of dihydroquinidine (DHQD, 81). However, the extreme variation in yields and enantioselectivities between substrates for a single catalyst is indicative of a more complex process. Indeed, the stark differences in results between gem-dimethyl substrates 8, 69, and 70 and fused substrates 71–72 indicate that substrate structure has a profound effect on the ability of the catalyst to impart enantioselectivity. The success of (DHQD)2PYR and the epimerized catalysts on cyclohexanone substrates alone (69 and 72) also suggests the potential influence of ring size on enantioselectivity. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 18 1.3 C–H ARYLATION OF CYCLOBUTAMIDE 6 Table 1.3 C–H arylation substrate scope O O Me Me N H I + N 6 (1.0 equiv) R Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) Me Me N H N TBME, 90 ºC 88a–88p (2.0 equiv) 89a–89p R OMe Me OMe MeO 89a 80% yield 89b 81% yield 89c 69% yield 89d 80% yield CN CN 89e 86% yield 89f 73% yield CF3 Me F O 89g 82% yield N N 89i 81% yield 89h 77% yield Cl 89j 69% yield N Boc N CF3 89l 88% yield N N N N N NBoc O 89m 54% yield N OMe 89k 49% yield 89n 64% yield 89o 79% yield 89p 75% yield Having developed optimized conditions for the C(Csp3)–H alkenylation of cyclobutamide 6, we sought to investigate the breadth of coupling partners that could be utilized in this reaction. In particular, we were interested in the heteroarylation of C(Csp3)– H bonds using these conditions. We were pleased to find that the conditions developed for the synthesis of (+)-psiguadial B (1) (namely, Pd(OAc)2 (15%), AgCO3 (1.0 equiv), and ArI (2.0 equiv) in TBME at 90 ºC) could afford a variety of cross-coupled products in good yields as a single diastereomer (Table 1.3). Substitution is tolerated at the ortho, meta, and para positions (89a–89c), and both electron donating and electron withdrawing groups were tolerated. A variety of nitrogen-containing heterocycles were found to be successful substrates as well. Pyridines with varying functionalities and substitution patterns are well tolerated (89i–89l, 89o). Bicycle 89m and indole 89n both performed moderately well Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 19 under the reaction conditions. In particular, we were pleased to find that highly polar heterocycles 89o and 89p were well-tolerated, yielding products containing five nitrogen atoms each. Table 1.4 Low-yielding C–H arylation substrates O O Me Me TfO/I N H N 6 (1.0 equiv) + R Me Me Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) N H N TBME, 90 ºC 88q–88v (2.0 equiv) 89d, 89q–89u aFrom aryl triflate R N N N CO2Me 89q 37% yield Ph 89r 15% yield N N 89s 13% yield N OMe 89t 34% yield OMe Me OMe 89ua 0% yield 89da 0% yield There were several limitations to this reaction (Table 1.4). Attempting to lower the catalyst loading to 7.5% or lowering the equivalents of aryl iodide to one equivalent both resulted in significant decreases in yield across the board. Some substrates could tolerate lower temperatures, though 90 ºC was required by most. In addition, certain pyridine substrates performed poorly. Pyridines with esters or aryl groups at 2-position all crosscoupled in low yields (89q, 89r), as did 2-pyrrole substrate 89s. Methoxy pyrimidine 89t also performed very poorly, about 15% lower yield than the corresponding pyridine substrate (89k). Aryl triflates were not successful under these reaction conditions, though no further optimization was attempted; it is possible that modifications could be made that would accommodate these substrates. 20 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1.4 CONCLUSION Figure 1.10 Summary of reaction development NH2 O N N2 + n 8, 69–72 (n = 1–3) 11 (3.0 equiv) hν (254 nm) catalyst (50 mol %) THF, rt, 18 h (up to 79% ee) N H H R N n 6, 73–76 N N R = H: cinchonine (34) R = OMe: quinidine (77) R = OMe, epi C-9: epi-quinidine (85) O O Me Me HO 9 O N H I N 6 (1.0 equiv) + R 88a–88v (2.0 equiv) Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) Me Me N H N TBME, 90 ºC (49–88% yield) 89a–89u R In conclusion, two reactions developed for the total synthesis of (+)-psiguadial B were developed into broader methods. The tandem Wolff rearrangement/asymmetric ketene addition suffered from lack of generality with regard to catalyst, but optimal catalysts were found for most substrates to afford products in synthetically useful yields and ee’s. Cyclobutamide 6 was subjected to palladium-catalyzed C–H activation conditions with a variety of aryl and heteroaryl iodides to afford cis arylated products in good yields. These results were disclosed in separate publications in 2018 and early 2019, respectively.9,39 Having developed a robust and scalable method to synthesize enantioenriched cyclobutamide 6 as well as a method to readily diversify 6 to a variety of arylated products, we then hoped to apply these methods to a broader, modular approach towards enantioenriched cyclobutanes as well as towards the synthesis of other transcyclobutane containing natural products (see Chapter 2). Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 21 1.5 EXPERIMENTAL SECTION 1.5.1 Materials and Methods Unless otherwise stated, reactions were performed under a nitrogen atmosphere using freshly dried solvents. Methylene chloride (CH2Cl2), diethyl ether (Et2O), tetrahydrofuran (THF), 1,4-dioxane, tert-butyl methyl ether (TBME), and toluene (PhMe) were dried by passing through activated alumina columns. Methanol (MeOH) was distilled over calcium hydride. Acetonitrile (MeCN), tert-butanol (t-BuOH), anhydrous N,N-dimethylformamide (DMF), anhydrous N,N-dimethylacetamide (DMA), chloroform (CHCl3), and absolute ethanol (EtOH) were used as received from Fisher Scientific. Aryl iodides were purchased from Sigma-Aldrich or Combi-Blocks or prepared according to literature procedures. Pd(OAc)2 was purchased from Strem and stored in a dessicator. All other commercially obtained reagents were purchased from Sigma-Aldrich and used as received unless specifically indicated. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm). Silica gel and basic alumina column chromatography was performed as described by Still et al. (W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.) using silica gel (particle size 0.032–0.063) purchased from Silicycle and aluminum oxide (activated, basic, Brockmann I, 58 Å pore size, powder) purchased from Sigma-Aldrich. 1H and 13C NMR were recorded on a Varian Inova 500 (at 500 MHz and 125 MHz, respectively) or a Bruker Avance III HD with Prodigy cyroprobe (at 400 MHz and 101 MHz, respectively). 19F NMR spectra were recorded on a Varian Inova 400 (at 376 MHz). NMR data is reported relative to internal chloroform (1H, δ = 7.26, 13C, δ = 77.2) or to internal methanol (1H, δ = 3.31, 13C, δ = 49.0) and PhCF3 (19F, δ = –63.7). Data for 1H NMR spectra are reported as follows: chemical Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 22 shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using either an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM) ionization mode. Specific optical rotations were recorded on a Jasco P-2000 polarimeter using a 100 mm cell. Abbreviations used: Et2O – diethyl ether; CH2Cl2 – methylene chloride; PhMe – toluene; EtOAc – ethyl acetate; THF – tetrahydrofuran; t-BuOH – tert-butanol; CHCl3 – chloroform; MeCN – acetonitrile; DMF – N,N-dimethylformamide; DMA – N,Ndimethylacetamide; dtbbpy – 4,4’-ditertbutylbipyridine; dme – 1,2-dimethoxyethane; TBME – tert-butyl methyl ether. 1.5.2 Synthesis of Hydrogenated and epi-Cinchona Alkaloids HO H R N Me 10% Pd/C (1/5 w/w) H2 (g) HO H R MeOH N N R = H, cinchonine (34) R = OMe, quinidine (77) HO H R N N R = H, dihydrocinchonine (DHCN, 80) R = OMe, dihydroquinidine (DHQD, 81) MeOH N R = H, cinchonidine (33) R = OMe, quinine (78) Me 10% Pd/C (1/5 w/w) H2 (g) HO H R N N R = H, dihydrocinchonidine (DHCD, 82) R = OMe, dihydroquinine (DHQN, 83) General Procedure 1: Synthesis of hydrogenated catalysts 80–8337 To a flame-dried round bottom flask was added cinchona alkaloid (33, 34, 77, 78) (1.0 equiv) and 10% Pd/C (1/5 w/w). Flask was evacuated and backfilled with nitrogen x 3. Dry Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 23 methanol (distilled over CaH2) (0.13M) was then added. The reaction mixture was sparged with H2 for 5 minutes, then allowed to stir under a H2 atmosphere at room temperature overnight. The next day the reaction was sparged with nitrogen. The reaction mixture was diluted with formic acid to dissolve the resultant precipitate, and Pd/C was removed by filtration over celite, washing with methanol. The reaction mixture was concentrated in vacuo, then diluted with ~ 5 mL H2O. The solution was stirred and aq conc NH3 was added until a precipitate formed. The precipitate was collected by filtration, washed with water, and dried at 45 ºC under high vac for ~ 6 hours. 80–83 were isolated cleanly without any further purification in 72–85% yield. NMR spectra matched lit report. HO H R N 1. NaH (2.0 equiv), THF 50–60 ºC, 2h; then TsCl (1.5 equiv), 0 ºC; then reflux HO 9 N N N R = H, cinchonine (34) R = OMe, quinidine (77) HO H R H R 2. (+)-tartaric acid H2O, reflux N R = H, epi-C9 cinchonine (epi-CN, 84) R = OMe, epi-C9 quinidine (epi-QD, 85) 1. NaH (2.0 equiv), THF 50–60 ºC, 2h; then TsCl (1.5 equiv), 0 ºC; then reflux 2. (+)-tartaric acid H2O, reflux N R = H, cinchonidine (33) R = OMe, quinine (78) HO 9 H R N N R = H, epi-C9 cinchonidine (epi-CD, 86) R = OMe, epi-C9 quinine (epi-QN, 87) General Procedure 2: Synthesis of epi-C9-cinchona catalysts (84–87)38 To a 3-neck flame-dried flask was added cinchona alkaloid (33, 34, 77, 78) (1.0 equiv). The flask was evacuated and backfilled with nitrogen x 3. THF (0.93 M) was added followed by NaH (2.0 equiv, 60% dispersion in oil). The reaction was heated to 50–60 ºC and stirred for 2 h. Turned banana yellow. After 2 hours, removed from heat and cooled in an ice bath to 0 ºC. Tosyl chloride (TsCl) (1.5 equiv) was dissolved in THF (0.56 M wrt TsCl) and cooled to 0 ºC. The chilled solution was added to the reaction mixture (reaction turned more white). Once the addition was complete, the reaction mixture was heated to Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 24 reflux and stirred overnight. Once the reaction was complete, it was allowed to cool. 1 M HCl (~ 20 equiv HCl) was added and the reaction mixture turned orange. Washed with Et2O x 2, discarded organic layers. Na2CO3 (26 equiv, until pH 11) was added to the aqueous layer. Extracted with Et2O x 4. Combined organic layers, washed with sat. aq. NaCl, and dried over MgSO4, filter, and concentrated in vacuo. Crude material purified by silica gel chromatography (40:1 CHCl3/MeOH). To a flask containing O-tosyl cinchona alkaloid was added (+)-tartaric acid (1.04 equiv) and H2O (0.09 M). The reaction mixture was heated to reflux. As it was heated, the solids began to dissolve. After 1 hour, the reaction mixture was allowed to cool. Na2CO3 was added slowly until the reaction mixture stopped bubbling and turned opaque (~pH 10–11). Extracted with Et2O x 6, washed combined organic layers with sat aq. NaHCO3, dried the organic layer over MgSO4, filtered, and concentrated in vacuo. Purified by silica gel chromatography, 20:20:1:1 hexanes/CHCl3/MeOH/NEt3. NMR spectra of isolated products 84–87 matched lit report. 1.5.3 Synthesis of Diazoketones 8, 69–72 O EtO O Me Me S1 H (2.3 equiv) NaH (1.2 equiv) cat MeOH Et2O, 0 ºC O Me O Me S2 (not isolated) p-ABSA (1.0 equiv) NEt3 (5.0 equiv) Me DCM, –10 ºC Me H O N2 8 Preparation of diazoketone 8:10,11 To each of two flame-dried 1 L round-bottom flasks was added NaH (60% dispersion in mineral oil, 3.17 g, 79.2 mmol, 1.20 equiv) and the atmosphere was exchanged for N2 one time. Dry Et2O (30.0 mL) was then added via syringe, and the suspension was cooled to 0 °C. Ethyl formate (12.4 mL, 152 mmol, 2.30 equiv) was then added, followed by 2,2-dimethylcyclopentanone (7.40 g, 66.0 mmol) either Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 25 neat, or as a 3.0 M solution in Et2O. A catalytic amount of wet methanol (~100 μL) was then added and the reaction left to stir at 0 °C. Upon completion, the reaction solidified to a chunky, white solid that dissolved readily upon the addition of DI H2O. At this point, both reaction mixtures were combined for workup: after dilution with Et2O, the layers were separated, and the aqueous layer was washed with Et2O x 3 to remove organic impurities and a small amount of unreacted starting material. The aqueous layer was then cooled to 0 °C and acidified to pH = 3 using 5 M HCl. Et2O was then added, and the acidified aqueous layer was extracted x 6. The combined organics were then dried over Mg2SO4, filtered, and concentrated in vacuo into a 500 mL round-bottom flask. The crude a-formyl ketone (S2) was taken up in CH2Cl2 (132 mL) and the solution cooled to –10 °C. Triethylamine (55.2 mL, 396 mmol, 5.00 equiv) was added, followed by solid p-ABSA (31.8 g, 132 mmol, 1.00 equiv) in three portions. The reaction was stirred for 3 hours and allowed to gradually reach 10 °C, at which point an aqueous solution of KOH (55.0 mL, 4 M) was added. Additional CH2Cl2 and H2O were added, the layers were separated and the aqueous layer extracted with CH2Cl2 until no product remained by TLC. The combined organics were dried over Mg2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (20–30% Et2O/pentane) to afford 8 (17.4 g, 95% yield) as a bright yellow oil. 1 H NMR (400 MHz, CDCl3) δ 2.88 (t, J = 7.0 Hz, 2H), 1.77 (t, J = 7.2 Hz, 2H), 1.04 (d, J = 1.0 Hz, 6H). 1 H NMR (400 MHz, d8-THF) δ 2.94 (t, J = 7.0 Hz, 2H), 1.79 (t, J = 7.2 Hz, 2H), 1.04 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 204.8, 56.6, 46.3, 35.7, 24.1, 21.2. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 13 26 C NMR (101 MHz, d8-THF) δ 203.6, 56.1, 46.9, 36.6, 24.5, 21.9. FTIR (NaCl, thin film) 3754, 3414, 3332, 2962, 2934, 2892, 2869, 2672, 2642, 2578, 2510, 2080, 1981, 1673, 1581, 1471, 1460, 1382, 1362, 1339, 1309, 1267, 1245, 1204, 1133, 1110, 1058, 1030, 994, 977, 948, 919, 893, 780, 726, 697 cm.-1 Diazoketones 69–72 were prepared according to the procedure developed for 8. Spectroscopic data for 71 and 72 are consistent with that reported in the literature.40–44 (69): Yellow Oil, (1.76 g, 36% yield over 2 steps). O Me Me N2 H NMR (400 MHz, CDCl3) δ 2.71 (t, J = 6.5 Hz, 2H), 1.82 – 1.73 (m, 2H), 1.68 –1.61 (m, 2H), 1.15 (s, 6H). 69 13 1 C NMR (101 MHz, CDCl3) δ 200.1, 62.6, 42.0, 37.5, 26.7, 22.9, 18.5. FTIR (NaCl, thin film) 2943, 2864, 2082, 1626, 1472, 1449, 1381, 1342, 1317, 1275, 1261, 1220, 1201, 1162, 1122, 1044, 1011, 910, 853, 738, 658 cm.-1 HRMS (EI) calc’d for C8H12N2O [M]+ 152.0950, found 152.0956. Me Me (70): Yellow Oil, (400.0 mg, 26% yield over 2 steps) O N2 1 70 13 H NMR (400 MHz, CDCl3) δ 2.55 (ddt, J = 7.0, 4.8, 2.3 Hz, 2H), 1.75 (dt, J = 4.4, 2.8 Hz, 4H), 1.57 (ddt, J = 6.3, 3.4, 1.7 Hz, 2H), 1.17 (s, 6H). C NMR (101 MHz, CDCl3) δ 202.2, 68.3, 47.0, 37.9, 29.5, 25.8, 25.7, 25.6. FTIR (NaCl, thin film) 2981, 2966, 2927, 2858, 2083, 1704, 1617, 1474. 1448, 1387. 1364, 1350, 1324, 1272, 1251, 1231, 1203, 1147, 1113, 1057, 1020, 980, 953, 871, 845, 736, 656 cm.-1 HRMS (EI) calc’d for C9H14N2O [M]+ 166.1106, found 166.1095. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B O Me NaH (1.1 equiv) MeI (1.1 equiv) HMDS (0.15 equiv) THF, Δ O Me Me S3 O 27 S4 MeI (6.7 equiv) t-BuOK (3.5 equiv) Me Me O t-BuOH S5 S6 Gem-dimethyl ketones S4 and S6 were synthesized according to known methods.41,45 1.5.4 Small-scale screening protocol for enantioenriched amides 6, 73–76: Oven-dried quartz tubes were each charged with aminoquinoline (21.6 mg, 0.150 mmol, 3.00 equiv) and catalyst (50 mol %). Inside a N2-filled glovebox, diazoketones 8, 69–72 (0.05 mmol) were then added to each as a solution in 0.500 mL THF (excluding diazoketone 72, which was added as a solid outside of the glovebox). The reactions were then sealed with a 19/38 rubber septum around the outside of each tube and sealed with electrical tape. The reactions were then brought out of the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp. The reactions were irradiated with stirring at room temperature for 18 hours. The reactions were then concentrated in vacuo, and the crude reaction mixtures were analyzed by 1H NMR with an added internal standard to determine % yield. The crude residues were purified by silica gel preparative TLC (2% Et2O/CH2Cl2) to provide 18, 42–45 in varying yields and enantiopurities. 28 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1.5.5 Large-scale protocol for enantioenriched amide 6 NH2 O Me N2 Me N + hυ (254 nm) (+)-cinchonine O Me Me • THF, rt 8 11 9 O Me Me N H N (–)6 (62% yield, 79% ee) recrystallized to >99% ee To a flame-dried, 1 L quartz flask was added 8-aminoquinoline (11) (12.9 g, 89.5 mmol, 3.00 equiv) and (+)-cinchonine (34) (879 mg, 2.99 mmol, 0.100 equiv). The flask was evacuated and backfilled with N2 three times, and dry THF (600 mL) was then added via cannula. Diazoketone 8 (4.12 g, 29.8 mmol, 1.00 equiv) was added last via syringe and the reaction was irradiated with stirring using a Honeywell 254 nm lamp at room temperature. Reaction progress was monitored by TLC (72-168 hours are typically required for complete conversion on this scale, and rotation of the flask every day provided faster conversion). Upon completion, the reaction mixture was concentrated in vacuo, the solids were taken up in CH2Cl2, and the suspension filtered. The filter cake was washed with CH2Cl2 three times and the filtrate was concentrated in vacuo to give a crude residue that was purified by silica gel flash chromatography (isocratic: 6% EtOAc/hexane) to provide 6 (4.69 g, 62%) as a pale-yellow solid. The enantiomeric excess was determined to be 79% by chiral SFC analysis (AD-H, 2.5 mL/min, 20% IPA in CO2, λ = 254 nm): tR (major) = 4.23 min, tR (minor) = 5.64 min. [𝛼]%&.( = –66.0° (c = 0.560, CHCl3). Enantioenriched $ cyclobutane 6 was dissolved in a minimal amount of CH2Cl2 in a 100 mL round-bottom flask. An equal amount of hexanes was carefully layered on top of the CH2Cl2 to form a biphasic mixture. The layers were allowed to diffuse overnight to provide 6 as white, crystalline needles (mp: 66–68 °C). The supernatant was concentrated under reduced Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 29 pressure and this process was repeated again to provide additional 6 (3.50 g total, 83% recovery of theoretical total of the desired enantiomer, 46% overall from 8). [𝛼]%&.( = –109° (c = 0.720, CHCl3). $ 1 H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.79 (dd, J = 13.6, 1.6 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.52 (q, J = 8.2, 7.5 Hz, 1H), 7.48 (dd, J = 8.3, 1.6 Hz, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 3.07 (ddd, J = 9.1, 8.2, 0.9 Hz, 1H), 2.48 (dq, J = 11.4, 9.4 Hz, 1H), 2.06 (dtd, J = 11.6, 8.6, 3.3 Hz, 1H), 1.85 (dt, J = 10.8, 9.1 Hz, 1H), 1.74 (dddd, J = 10.7, 9.5, 3.3, 0.9 Hz, 1H), 1.39 (s, 3H), 1.14 (s, 3H). 13 C NMR δ 171.8, 148.3, 138.6, 136.4, 134.7, 128.1, 127.6, 121.7, 121.3, 116.4, 51.0, 40.4, 32.3, 30.9, 23.4, 17.4. FTIR (NaCl, thin film) 3353, 3047, 2952, 2861, 1685, 1595, 1577, 1526, 1485, 1460, 1424, 1385, 1324, 1261, 1239, 1187, 1169, 1153, 825, 791,756 cm.-1 HRMS (MM) calc’d for C16H19N2O [M+H]+ 255.1492, found 255.1501. 1.5.6 Optimized Scale-Up Protocol for Enantioenriched Amides 73–76 NH2 O Me Me N2 N hυ (254 nm) epi-QD (85) THF, rt 69 11 3 equiv Me Me O N H N 73 (73) 0.2 mmol scale: An oven-dried quartz tube was charged with aminoquinoline (11) (86.5 mg, 0.600 mmol, 3.00 equiv) and epi-QD (85) (32.5 mg, 0.100 mmol, 0.500 equiv) and brought into a N2 filled glovebox. Diazoketone (69) (33.2 mg, 0.200 mmol, 1.00 equiv) was added as a solution in 2.00 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 30 placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (6% EtOAc/hexanes) to afford 73 (37.5 mg, 77% yield) as a brown oil. The enantiomeric excess was determined to be 71% by chiral SFC analysis (AD-H, 2.5 mL/min, 20% IPA in CO2, λ = 254 nm): tR (major) = 4.28 min, tR (minor) = 5.41 min. (73) 1 mmol scale (CRL-1-218): An oven-dried quartz tube was charged with aminoquinoline (11) (433 mg, 3.00 mmol, 3.00 equiv) and epi-QD (85) (64.9 mg, 0.200 mmol, 0.200 equiv) and brought into a N2-filled glovebox. Diazoketone (69) (166 mg, 1.00 mmol, 1.00 equiv) was added as a solution in 10.0 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (6% EtOAc/hexanes) to afford 73 (215 mg, 80% yield) as a brown oil. The enantiomeric excess was determined to be 67% by chiral SFC analysis (AD-H, 2.5 mL/min, 20% IPA in CO2, λ = 254 nm): tR (major) = 4.28 min, tR (minor) = 5.41 min. The same procedure was used for 5.0 mmol scale in a 250 mL quartz flask. Irradiated for 5 days instead of 2. 81% yield, 68% ee (CRL-1-241) [𝛼]%&.( = –32.5° (c = 2.075, CHCl3). $ 1 H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.80 (dd, J = 3.0, 1.7 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 31 2.61 (t, J = 8.4 Hz, 1H), 2.38 – 2.22 (m, 1H), 2.02 (dtd, J = 13.2, 8.5, 4.4 Hz, 1H), 1.95 – 1.82 (m, 1H), 1.79 – 1.65 (m, 2H), 1.63 – 1.57 (m, 1H), 1.31 (s, 3H), 1.01 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.1, 148.3, 138.6, 136.5, 134.8, 128.1, 127.6, 121.7, 121.3, 116.4, 58.1, 43.2, 42.1, 29.7, 27.9, 24.0, 22.5. FTIR (NaCl, thin film) 3362, 2957, 2924, 2854, 1729, 1690, 1525, 1486, 1464, 1424, 1381, 1325, 1262, 1164, 1145, 1132, 1072, 825, 791, 720 cm.-1 HRMS (MM) calc’d for C17H21N2O [M+H]+ 269.1648, found 269.1645. Me Me O NH2 N2 N + 70 hυ (254 nm) quinidine (77) THF, rt 11 3 equiv Me Me O N H N 74 (74) 0.2 mmol scale: An oven-dried quartz tube was charged with 8-aminoquinoline (11) (86.5 mg, 0.600 mmol, 3.00 equiv) and quinidine (77) (32.5 mg, 0.100 mmol, 0.500 equiv) and brought into a N2-filled glovebox. Diazoketone (70) (31.0 mg, 0.200 mmol, 1.00 equiv) was added as a solution in 2.00 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (6% EtOAc/hexanes) to afford 74 (33.3 mg, 59% yield) as a brown oil. The enantiomeric excess was determined to be 71% by chiral SFC analysis (AD-H, 2.5 mL/min, 12% IPA in CO2, λ = 254 nm): tR (major) = 9.67 min, tR (minor) = 10.34 min. (74) 1 mmol scale (CRL-1-228): An oven-dried quartz tube was charged with 8aminoquinoline (11) (433 mg, 3.00 mmol, 3.00 equiv) and quinidine (77) (64.9 mg, 0.200 mmol, 0.200 equiv) and brought into a N2-filled glovebox. Diazoketone (70) (152 mg, 1.00 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 32 mmol, 1.00 equiv) was added as a solution in 10.0 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (6% EtOAc/hexanes) to afford 74 (189 mg, 67% yield) as a brown oil. The enantiomeric excess was determined to be 67% by chiral SFC analysis (AD-H, 2.5 mL/min, 12% IPA in CO2, λ = 254 nm): tR (major) = 9.67 min, tR (minor) = 10.34 min. [𝛼]%&.( = –17.3° (c = 1.68, CHCl3). $ 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.80 (dd, J = 2.7, 1.7 Hz, 1H), 8.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H), 2.30 (dd, J = 11.8, 3.5 Hz, 1H), 1.99 – 1.78 (m, 3H), 1.55 – 1.47 (m, 2H), 1.39 – 1.27 (m, 3H), 1.13 (s, 3H), 1.10 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 173.6, 148.3, 138.6, 136.5, 134.7, 128.1, 127.6, 121.7, 121.3, 116.5, 56.5, 41.6, 33.4, 31.5, 25.7, 25.7, 22.1, 21.2. FTIR (NaCl, thin film) 3364, 2956, 2923, 2852, 1729, 1691, 1523, 1486, 1462, 1424, 1378, 1326, 1273, 1129, 1072, 825, 790 cm.-1 HRMS (MM) calc’d for C18H23N2O [M+H]+ 283.1805, found 283.1796. NH2 O N N2 71 + hυ (254 nm) (DHQD)2AQN (79) THF, rt 11 3 equiv O N H N 75 (75) 0.2 mmol: An oven-dried quartz tube was charged with aminoquinoline (11) (86.5 mg, 0.600 mmol, 3.00 equiv) and (DHQD)2AQN (79) (85.7 mg, 0.100 mmol, 0.500 equiv) and brought into a N2-filled glovebox. Diazoketone (71) (31.6 mg, 0.200 mmol, 1.00 equiv) Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 33 was added as a solution in 2.00 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (5–50 % EtOAc/hexanes followed by 0–1% Et2O/CH2Cl2) to afford 75 (16.8 mg, 31% yield). The enantiomeric excess was determined to be 34% by chiral SFC analysis (AD-H, 2.5 mL/min, 30% IPA in CO2, λ = 254 nm): tR (major) = 5.06 min, tR (minor) = 6.89 min. [𝛼]%&.( = –4.1° (c = 0.565, CHCl3). $ 1 H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.79 (dd, J = 11.5, 1.7 Hz, 1H), δ 8.78 (d, J = 1.7 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.54 (dd, J = 8.3, 7.2 Hz, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.38 – 7.29 (m, 2H), 7.22 – 7.16 (m, 1H), 4.56 (ddt, J = 5.8, 2.9, 0.8 Hz, 1H), 3.69 (ddd, J = 14.2, 5.7, 0.7 Hz, 1H), 3.60 (ddd, J = 14.2, 2.9, 0.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 170.6, 148.4, 144.7, 142.9, 138.7, 136.4, 134.5, 128.6, 128.0, 127.8, 127.5, 123.5, 122.7, 121.7, 121.7, 116.5, 49.3, 35.2. FTIR (NaCl, thin film) 3347, 3066, 2928, 2851, 1680, 1596, 1578, 1526, 1485, 1458, 1424, 1386, 1328, 1262, 1240, 1202, 1162, 1132, 869, 826, 791, 759, 734, 707, 679 cm.-1 HRMS (MM) calc’d for C18H15N2O [M+H]+ 275.1179, found 275.1178. NH2 O N N2 + 72 hυ (254 nm) (DHQD)2PYR (30) THF, rt 11 3 equiv O N H N 76 (76) 0.2 mmol: An oven-dried quartz tube was charged with diazoketone (72) (34.4 mg, 0.200 mmol, 1.00 equiv), aminoquinoline (11) (86.5 mg, 0.600 mmol, 3.00 equiv), and Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 34 (DHQD)2PYR (30) (88.1 mg, 0.100 mmol, 0.500 equiv), and brought into a N2-filled glovebox. The mixture was suspended in 2.00 mL THF and the tube was sealed with a 19/38 rubber septum and secured with electrical tape. The reaction was removed from the glovebox and placed in a bottomless test tube rack in front of a Honeywell 254 nm lamp for 48 hours. The reaction mixture was then concentrated in vacuo. The crude residue was purified via silica gel flash chromatography (5–10% EtOAc/hexanes) to afford 76 (24.1 mg, 42% yield) as a brown oil. The enantiomeric excess was determined to be 75% by chiral SFC analysis (AD-H, 2.5 mL/min, 30% IPA in CO2, λ = 254 nm): tR (major) = 5.73 min, tR (minor) = 4.86 min. [𝛼]%&.( = 65.0° (c = 0.91, CHCl3). $ 1 H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.79 (dd, J = 7.1, 1.9 Hz, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 – 7.46 (m, 3H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.31 – 7.18 (m, 2H), 4.27 (dd, J = 8.4, 6.1 Hz, 1H), 3.23 (dt, J = 15.2, 7.4 Hz, 1H), 3.09 – 2.95 (m, 1H), 2.69 – 2.48 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 172.7, 148.4, 144.8, 141.5, 138.7, 136.4, 134.7, 128.0, 127.9, 127.53, 126.9, 125.1, 125.0, 121.7, 121.7, 116.6, 54.0, 32.1, 30.4. FTIR (NaCl, thin film) 3347, 2957, 2923, 2852, 1728, 1689, 1524, 1484, 1461, 1424, 1380, 1325, 1272, 1163, 1132, 1072, 826, 791, 743 cm.-1 HRMS (MM) calc’d for C19H17N2O [M+H]+ 289.1335, found 289.1334. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 35 1.5.7 Csp3–H arylation O O Me Me N H I N 6 (1.0 equiv) + R 88 (2.0 equiv) Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) Me Me N H N TBME, 90 ºC 89 R General Procedure 3 On the bench-top, a 2-dram vial equipped with a stir bar was charged with Pd(OAc)2 (15 mol %, 0.03 mmol), Ag2CO3 (1 equiv, 0.2 mmol), cyclobutamide (6) (1 equiv, 0.2 mmol), and aryl iodide (2 equiv, 0.4 mmol). TBME (0.2 M, 1 mL) was added to the vial, then the vial was sealed with a Teflon cap and electrical tape and submerged in an oil bath at 90 °C. After approximately 5 minutes for aryl iodide substrates and 30 minutes for heteroaryl iodide substrates, the olive-green mixture became black. The reaction mixture was stirred at 90 °C additional 16 hours, at which point the vial is allowed to cool to room temperature over 15 minutes. The black reaction mixture was diluted with CH2Cl2 and filtered over a pad of 20 grams of tightly packed celite. The celite plug was eluted with an additional 100 mL of CH2Cl2. Following this, the resultant orange solution was concentrated in vacuo and subsequently purified by silica gel column chromatography to give the arylated cyclobutane products. (Note: some substrates required purification with basic alumina as the stationary phase). Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 36 1.5.8 Characterization of Arylation Products 89a Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me N H and 2-iodoanisole (2 equiv, 93.6 mg, 0.4 mmol). The crude N residue was purified by column chromatography (10 → 15 → MeO 20% EtOAc/Hexanes) to give a colorless foam. Run 1: (54.4 mg, 75%), Run 2: (61.2 mg, 84%) Rf = 0.48 (silica gel, 30% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +84.8° (c = 3.3, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.60 (dd, J = 4.9, 4.2 Hz, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.44 – 7.36 (m, 3H), 7.24 (dt, J = 7.4, 1.5 Hz, 1H), 7.09 (dddd, J = 8.2, 7.4, 1.8, 0.8 Hz, 1H), 6.96 (tdd, J = 7.5, 1.1, 0.4 Hz, 1H), 6.61 (dd, J = 8.1, 1.1 Hz, 1H), 4.09 – 3.95 (m, 1H), 3.62 (s, 3H), 3.46 (ddd, J = 8.6, 2.9, 0.8 Hz, 1H), 2.74 (t, J = 10.8 Hz, 1H), 2.13 (ddd, J = 10.4, 8.4, 2.9 Hz, 1H), 1.53 (s, 3H), 1.22 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 171.13, 157.19, 147.90, 138.41, 136.31, 134.88, 130.18, 127.92, 127.66, 127.54, 127.00, 121.45, 120.75, 120.43, 116.27, 109.43, 58.05, 55.05, 37.10, 35.89, 32.81, 30.33, 25.14. FTIR (NaCl, thin film, cm-1): 3366, 2952, 5927, 2863, 2361, 1685, 1523, 1485, 1464, 1424, 1324, 1241, 1161, 1132, 1161, 1029, 826, 792, 751. HRMS (ESI-TOF, m/z): calc’d for C23H25N2O2 [M+H]+: 361.1911; found: 361.1925. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 37 89b Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 3-iodoanisole (2 equiv, 93.6 mg, 0.4 mmol). The crude N residue was purified by column chromatography (10 → 15 → 20% EtOAc/Hexanes) to give a white solid. MeO Run 1: (59.0 mg, 82%), Run 2: (58.3 mg, 81%) Rf = 0.36 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +61.6° (c = 0.4, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.62 (s, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.64 (p, J = 4.3 Hz, 1H), 8.11 (dd, J = 8.3, 1.7 Hz, 1H), 7.45 – 7.38 (m, 3H), 7.13 (t, J = 7.9 Hz, 1H), 6.82 (ddt, J = 7.6, 1.8, 1.0 Hz, 1H), 6.77 (dt, J = 2.7, 1.3 Hz, 1H), 6.63 (ddt, J = 8.2, 2.6, 0.9 Hz, 1H), 4.03 (dtd, J = 11.0, 8.6, 1.1 Hz, 1H), 3.67 (s, 3H), 3.39 (ddd, J = 8.7, 2.9, 0.8 Hz, 1H), 2.76 (t, J = 10.7 Hz, 1H), 2.16 (ddd, J = 10.4, 8.5, 3.0 Hz, 1H), 1.51 (s, 3H), 1.22 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.5, 159.5, 148.0, 143.7, 138.4, 136.4, 134.6, 129.1, 127.9, 127.5, 121.5, 121.2, 119.1, 116.5, 112.3, 111.3, 57.7, 55.1, 37.8, 36.0, 35.8, 30.2, 25.1. FTIR (NaCl, thin film, cm-1): 3357, 2952, 2925, 1684, 1600, 1582, 1521, 1485, 1424, 1386, 1323, 1259, 1160, 1049, 878, 826, 790, 756, 694. HRMS (ESI-TOF, m/z): calc’d for C23H25N2O2 [M+H]+: 361.1911; found: 361.1915. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 38 89c Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me N H and 4-iodoanisole (2 equiv, 93.6 mg, 0.4 mmol). The crude N residue was purified by column chromatography (10 → 15% EtOAc/Hexanes) to give a white, amorphous solid. OMe Run 1: (47.7 mg, 66%), Run 2: (51.2 mg, 71%) Rf = 0.23 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +59.8° (c = 1.3, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (p, J = 4.4 Hz, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.45 – 7.38 (m, 3H), 7.20 – 7.13 (m, 2H), 6.80 – 6.73 (m, 2H), 4.00 (q, J = 11.1, 8.6 Hz, 1H), 3.70 (s, 3H), 3.34 (ddd, J = 8.7, 3.0, 0.8 Hz, 1H), 2.75 (t, J = 10.8 Hz, 1H), 2.13 (ddd, J = 10.4, 8.6, 3.0 Hz, 1H), 1.51 (s, 3H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.6, 157.7, 148.0, 138.4, 136.4, 134.6, 133.7, 127.9, 127.5, 121.5, 121.1, 116.5, 113.6, 57.7, 55.3, 37.9, 35.7, 35.5, 30.2, 25.2. FTIR (NaCl, thin film, cm-1): 2926, 2361, 1685, 1523, 1485, 1288, 1324, 1247, 1160, 1038, 826, 772. HRMS (ESI-TOF, m/z): calc’d for C23H25N2O2 [M+H]+: 361.1911; found: 361.1921. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 39 89d Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me and 4-iodotoluene (2 equiv, 87.2 mg, 0.4 mmol). The crude N H Me N residue was purified by column chromatography (10 → 15 → 20% EtOAc/Hexanes) to give a white, amorphous solid. Me Run 1: (54.1 mg, 79%), Run 2: (55.9 mg, 81%) Rf = 0.29 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +54.2° (c = 2.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.60 (s, 1H), 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.65 (h, J = 4.2 Hz, 1H), 8.11 (dd, J = 8.2, 1.7 Hz, 1H), 7.50 – 7.36 (m, 3H), 7.14 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 7.4 Hz, 2H), 4.01 (td, J = 10.8, 8.1 Hz, 1H), 3.37 (ddd, J = 8.7, 2.9, 0.8 Hz, 1H), 2.76 (t, J = 10.8 Hz, 1H), 2.24 (s, 3H), 2.14 (ddd, J = 10.4, 8.6, 2.9 Hz, 1H), 1.51 (s, 3H), 1.22 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.6, 148.0, 138.7, 138.4, 136.4, 135.0, 134.7, 128.9, 127.9, 127.5, 126.7, 121.5, 121.1, 116.5, 57.7, 37.8, 35.8, 35.7, 30.2, 25.2, 21.2. FTIR (NaCl, thin film, cm-1): 3360, 2924, 2359, 1686, 1522 1485, 1424, 1386, 1324, 1160, 826, 792. HRMS (ESI-TOF, m/z): calc’d for C23H25N2O [M+H]+: 345.1961; found: 345.1971. 89e Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me N H and 2-iodobenzonitrile (2 equiv, 91.8 mg, 0.4 mmol). The N crude residue was purified by column chromatography (10 → NC 15% EtOAc/Hexanes) to give a pale, yellow foam. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 40 Run 1: (57.6 mg, 81%), Run 2: (64.7 mg, 91%) Rf = 0.55 (silica gel, 30% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = –24.4° (c = 5.4, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.76 (s, 1H), 8.81 (dd, J = 4.2, 1.7 Hz, 1H), 8.53 (dd, J = 7.4, 1.7 Hz, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (td, J = 8.0, 7.6, 1.2 Hz, 1H), 7.51 – 7.35 (m, 5H), 7.21 (tdd, J = 7.6, 1.3, 0.7 Hz, 1H), 4.21 (dt, J = 11.1, 8.3, 7.8 Hz, 1H), 3.74 (ddd, J = 8.3, 3.0, 0.8 Hz, 1H), 2.87 (t, J = 10.7 Hz, 1H), 2.16 (ddd, J = 10.4, 8.3, 3.1 Hz, 1H), 1.57 (s, 3H), 1.20 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.0, 148.3, 146.9, 138.5, 136.3, 134.5, 132.6, 128.1, 127.9, 127.2, 126.3, 121.7, 121.4, 118.8, 116.3, 110.6, 57.7, 36.6, 36.1, 35.2, 29.8, 25.1. FTIR (NaCl, thin film, cm-1): 3353, 2954, 2361, 2222, 1683, 1523, 1485, 1424, 1388, 1323, 1260, 1161, 826, 791, 755, 668. HRMS (ESI-TOF, m/z): calc’d for C23H21N3O [M+H]+: 356.1757; found: 356.1773. 89f Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me N H and 4-iodobenzonitrile (2 equiv, 91.8 mg, 0.4 mmol). The N crude residue was purified by column chromatography (10 → 15 → 20 →25 % EtOAc/Hexanes) to give a pale, yellow foam. CN Run 1: (50.5 mg, 71%), Run 2: (53.3 mg, 75%) Rf = 0.32 (silica gel, 30% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +102.7° (c = 5.1, CHCl3). Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1 41 H NMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.56 (dd, J = 7.2, 1.8 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.50 (dt, J = 8.3, 1.8 Hz, 2H), 7.49 – 7.37 (m, 3H), 7.33 – 7.24 (m, 2H), 4.02 (dt, J = 10.8, 8.3 Hz, 1H), 3.43 (ddd, J = 8.5, 3.0, 0.8 Hz, 1H), 2.77 (t, J = 10.7 Hz, 1H), 2.18 (ddd, J = 10.4, 8.5, 3.0 Hz, 1H), 1.53 (s, 3H), 1.20 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 169.9, 148.4, 148.2, 138.3, 136.5, 134.2, 131.9, 128.0, 127.5, 127.3, 121.7, 121.6, 119.5, 116.5, 109.3, 57.7, 37.5, 36.1, 36.0, 29.9, 25.0. FTIR (NaCl, thin film, cm-1): 3353, 2954, 2930, 2361, 2226, 1684, 1608, 1524, 1486, 1424, 1288, 1323, 1161, 826, 792, 755, 668. HRMS (ESI-TOF, m/z): calc’d for C23H22N3O [M+H]+: 356.1757; found: 356.1752. 89g Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 3-iodotrifluorotoluene (2 equiv, 109.1 mg, 0.4 mmol). The N crude residue was purified by column chromatography (10% EtOAc/Hexanes) to give a colorless oil. F3C Run 1: (67.7 mg, 85%), Run 2: (62.9 mg, 79%) Rf = 0.23 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +47.3° (c = 3.3, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.63 (s, 1H), 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.57 (dd, J = 6.6, 2.4 Hz, 1H), 8.12 (dd, J = 8.3, 1.7 Hz, 1H), 7.50 – 7.36 (m, 5H), 7.39 – 7.26 (m, 2H), 4.05 (dt, J = 11.0, 8.7 Hz, 1H), 3.42 (ddd, J = 8.6, 3.0, 0.8 Hz, 1H), 2.80 (t, J = 10.8 Hz, 1H), 2.20 (ddd, J = 10.4, 8.5, 3.0 Hz, 1H), 1.53 (s, 3H), 1.23 (s, 3H). Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 13 42 C NMR (101 MHz, CDCl3): δ 170.2, 148.2, 143.2, 138.5, 136.6, 134.5, 130.4 (q, JC–F = 32 Hz), 130.3, 128.5, 128.1, 127.6, 125.9, 123.7 (q, JC–F = 3.7 Hz), 123.2, 122.8 (q, JC–F = 3.8 Hz), 121.7, 121.5, 116.6, 57.8, 37.8, 36.1, 36.0, 30.2, 30.0, 25.2. 19 F NMR (376 MHz, CDCl3) δ -63.50. FTIR (NaCl, thin film, cm-1): 3355, 2931, 2360, 1684, 1523, 1486, 1425, 1388, 1324, 1162, 1122, 1072, 901, 826, 793, 756, 701, 659. HRMS (ESI-TOF, m/z): calc’d for C23H22F3N2O [M+H]+: 399.1679; found: 399.1679. 89h Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me and 4-iodoacetophenone (2 equiv, 98.7 mg, 0.4 mmol). The N H N crude residue was purified by column chromatography (20% Me O EtOAc/Hexanes) to give a white, amorphous solid. Run 1: (57.3 mg, 77%), Run 2: (56.6 mg, 76%) Rf = 0.41 (silica gel, 40% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +95.0° (c = 3.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.73 (s, 1H), 8.85 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (dd, J = 7.1, 1.8 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.94 – 7.87 (m, 2H), 7.51 (dd, J = 8.5, 4.1 Hz, 2H), 7.48 (q, J = 9.2, 8.2, 8.2 Hz, 1H), 7.39 – 7.33 (m, 2H), 4.12 (td, J = 11.3, 9.7, 8.4 Hz, 1H), 3.51 (ddd, J = 8.6, 2.9, 0.8 Hz, 1H), 2.88 (t, J = 10.7 Hz, 1H), 2.58 (s, 3H), 2.26 (ddd, J = 10.3, 8.5, 3.0 Hz, 1H), 1.61 (s, 3H), 1.29 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 198.1, 170.1, 148.5, 148.1, 138.4, 136.5, 134.8, 134.4, 128.4, 128.0, 127.5, 126.7, 121.6, 121.4, 116.5, 57.8, 37.7, 36.1, 36.0, 30.0, 26.7, 25.1. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 43 FTIR (NaCl, thin film, cm-1): 3354, 2954, 2928, 2866, 1678, 1606, 1523, 1485, 1424, 1387, 1323, 1267, 1161, 956, 826, 792, 754, 657. HRMS (ESI-TOF, m/z): calc’d for C24H25N2O2 [M+H]+: 373.1911; found: 373.1900. 89i Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 2-fluoro-3-iodopyridine (2 equiv, 89.2 mg, 0.4 mmol). The N crude residue was purified by column chromatography using F N silica gel basified with 4 mL of aqueous ammonium hydroxide (10% EtOAc/2% Et3N/88% hexanes → 15% EtOAc/2% Et3N/83% hexanes → 20% EtOAc/2% Et3N/78% hexanes → 35% EtOAc/2% Et3N/63% hexanes) to give a white foam. Run 1: (56.1 mg, 80%), Run 2: (56.4 mg, 81%) Rf = 0.22 (silica gel, 20% EtOAc/Hex, UV, p-Anisaldehyde). [α]D25 = +60.8° (c = 0.415, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 8.77 (dd, J = 4.3, 1.7 Hz, 1H), 8.54 (dd, J = 7.0, 2.1 Hz, 1H), 8.09 (dd, J = 8.3, 1.7 Hz, 1H), 7.96 (ddt, J = 4.9, 2.0, 1.0 Hz, 1H), 7.72 (ddq, J = 9.9, 7.5, 1.2, 0.7 Hz, 1H), 7.45 – 7.34 (m, 3H), 7.15 (ddd, J = 7.1, 4.9, 1.9 Hz, 1H), 3.99 (dtd, J = 11.0, 8.6, 1.1 Hz, 1H), 3.44 (ddt, J = 8.4, 2.5, 1.3 Hz, 1H), 2.76 (t, J = 10.7 Hz, 1H), 2.11 (ddd, J = 10.4, 8.4, 3.0 Hz, 1H), 1.53 (s, 3H), 1.19 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.2, 161.5 (d, JC–F = 237 Hz), 148.2, 144.6 (d, JC–F = 14.7 Hz), 139.3 (d, JC–F = 6.1 Hz), 138.4, 136.3, 134.4, 127.9, 127.3, 124.2 (d, JC–F = 31.2 Hz), 121.6, 121.4, 121.3 (d, JC–F = 4.0 Hz), 116.4, 57.0, 36.4 (d, JC–F = 14.8 Hz), 30.8, 30.7, 29.8, 25.0. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 19 44 F NMR (376 MHz, CDCl3): δ -71.52 (d, J = 10.1 Hz). FTIR (NaCl, thin film, cm-1): 3355, 3058, 2954, 2930, 2866, 1682, 1605, 1577, 1524, 1486, 1431, 1388, 1372, 1324, 1261, 1240, 1162, 1132, 1112, 826, 793, 758. HRMS (ESI-TOF, m/z): calc’d for C21H21FN3O [M+H]+: 350.1663; found: 350.1659. 89j Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me and 5-iodo-2-chloropyridine (2 equiv, 95.8 mg, 0.4 mmol). The N H Me N crude residue was purified by column chromatography using N basic alumina as the stationary phase (0 → 1% MeOH/CH2Cl2) Cl to give a colorless foam. Run 1: (50.6 mg, 69%), Run 2: (49.7 mg, 68%) Rf = 0.24 (silica gel, 40% EtOAc/Hex, UV). [α]D25 = +81.1° (c = 4.3, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 9.64 (s, 1H), 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (dd, J = 6.8, 2.2 Hz, 1H), 8.22 (dt, J = 2.6, 0.8 Hz, 1H), 8.11 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.17 (d, J = 8.2 Hz, 1H), 3.96 (q, J = 11.0, 8.5 Hz, 1H), 3.38 (ddd, J = 8.5, 3.0, 0.8 Hz, 1H), 2.76 (t, J = 10.7 Hz, 1H), 2.15 (ddd, J = 10.4, 8.5, 3.0 Hz, 1H), 1.52 (s, 3H), 1.22 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 169.8, 148.8, 148.5, 148.1, 138.3, 137.7, 136.5, 136.3, 134.2, 127.9, 127.4, 123.5, 121.7, 121.6, 116.5, 57.4, 37.4, 36.3, 33.3, 29.8, 29.8, 25.0. FTIR (NaCl, thin film, cm-1): 3350, 2954, 1682, 1524, 1485, 1460, 1424, 1386, 1324, 1260, 1162, 1133, 1104, 826, 792, 755, 666. HRMS (ESI-TOF, m/z): calc’d for C21H21ClN3O [M+H]+: 366.1368; found: 366.1370. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 45 89k Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 5-iodo-2-trifluoromethylpyridine (2 equiv, 95.8 mg, 0.4 N mmol). The crude residue was purified by column N chromatography using silica gel basified with 5 mL of aqueous CF3 ammonium hydroxide (5% EtOAc/2% Et3N/93% hexanes → 10% EtOAc/2% Et3N/88% hexanes → 15% EtOAc/2% Et3N/83% hexanes → 20% EtOAc/2% Et3N/78% hexanes) to give a pale, yellow foam. Run 1: (71.6 mg, 90%), Run 2: (68.2 mg, 85%) Rf = 0.19 (silica gel, 20% EtOAc/Hex, UV). [α]D25 = +67.7° (c = 4.2, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.61 (s, 1H), 8.69 (dd, J = 4.2, 1.7 Hz, 1H), 8.52 – 8.41 (m, 2H), 8.04 (dd, J = 8.3, 1.7 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.46 (dd, J = 8.1, 0.7 Hz, 1H), 7.41 – 7.28 (m, 3H), 3.95 (q, J = 11.0, 8.5 Hz, 1H), 3.37 (ddd, J = 8.4, 2.9, 0.9 Hz, 1H), 2.73 (t, J = 10.7 Hz, 1H), 2.12 (ddd, J = 10.4, 8.5, 3.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 169.7, 148.8, 148.2, 145.5 (q, JC–F = 35 Hz), 141.2, 138.3, 136.5, 135.7, 134.1, 128.0, 127.4, 123.2, 121.7, 120.5, 119.9, 119.9, 119.8, 119.8, 116.5, 57.4, 37.3, 36.5, 33.7, 29.8, 25.0. 19 F NMR (282 MHz, CDCl3): δ -68.6. FTIR (NaCl, thin film, cm-1): 3351, 2957, 1682, 1524, 1486, 1425, 1387, 1340, 1261, 1164, 1134, 1088, 1030, 826, 792, 756, 667. HRMS (ESI-TOF, m/z): calc’d for C22H21F3N3O [M+H]+: 400.1631; found: 400.1621. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 46 89l Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 5-iodo-2-methoxypyridine (2 equiv, 94.0 mg, 0.4 mmol). N The crude residue was purified by column chromatography N using silica gel basified with 4 mL of aqueous ammonium OMe hydroxide (10% EtOAc/2% Et3N/88% hexanes → 15% EtOAc/2% Et3N/83% hexanes → 20% EtOAc/2% Et3N/78% hexanes → 30% EtOAc/2% Et3N/68% hexanes) to give a white solid. Run 1: (34.9 mg, 48%), Run 2: (36.1 mg, 50%) Rf = 0.14 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +61.1° (c = 0.415, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.60 (s, 1H), 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (dd, J = 5.3, 3.7 Hz, 1H), 8.12 (dd, J = 8.3, 1.7 Hz, 1H), 8.01 (dt, J = 2.5, 0.9 Hz, 1H), 7.54 (ddd, J = 8.6, 2.5, 0.7 Hz, 1H), 7.46 – 7.39 (m, 3H), 6.61 (dd, J = 8.6, 0.7 Hz, 1H), 3.96 (qd, J = 11.0, 8.6, 1.1 Hz, 1H), 3.84 (s, 3H), 3.33 (ddd, J = 8.7, 2.9, 0.8 Hz, 1H), 2.76 (t, J = 10.8 Hz, 1H), 2.14 (ddd, J = 10.4, 8.6, 3.0 Hz, 1H), 1.51 (s, 3H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.3, 162.7, 148.1, 145.3, 138.4, 138.0, 136.4, 134.5, 129.6, 128.0, 127.5, 121.6, 121.4, 116.5, 110.1, 57.6, 53.4, 37.7, 36.1, 33.4, 30.1, 25.1. FTIR (NaCl, thin film, cm-1): 3352, 2922, 2850, 2351, 1682, 1606, 1574, 1523, 1494, 1486, 1424, 1385, 1324, 1285, 1259, 1160, 1132, 1032, 826, 792, 756. HRMS (ESI-TOF, m/z): calc’d for C22H24N3O2 [M+H]+: 362.1863; found: 362.1856 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 47 89m Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me N H Me and 4-iodo-1-indanone (2 equiv, 103.5 mg, 0.4 mmol). The N crude residue was purified by column chromatography (30% EtOAc/Hexanes) to give a pale, yellow foam. O Run 1: (43.4 mg, 56%), Run 2: (39.7 mg, 52%) Rf = 0.32 (silica gel, 40% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +2.0° (c = 5.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.74 (dd, J = 4.3, 1.7 Hz, 1H), 8.54 (dd, J = 7.1, 2.0 Hz, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (ddt, J = 17.3, 7.6, 1.1 Hz, 2H), 7.46 – 7.33 (m, 4H), 4.07 (dt, J = 11.2, 8.4 Hz, 1H), 3.47 (ddd, J = 8.4, 3.0, 0.9 Hz, 1H), 3.10 (ddd, J = 17.1, 7.8, 3.8 Hz, 1H), 2.98 (ddd, J = 17.1, 7.6, 3.9 Hz, 1H), 2.92 (t, J = 10.8 Hz, 1H), 2.57 (dddd, J = 32.0, 19.4, 7.8, 3.7 Hz, 2H), 2.18 (ddd, J = 10.5, 8.4, 3.1 Hz, 1H), 1.58 (s, 3H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.3, 170.1, 153.3, 148.1, 139.5, 138.3, 136.8, 136.5, 134.2, 132.9, 127.9, 127.5, 127.4, 121.6, 121.5, 121.4, 116.6, 57.2, 37.0, 36.5, 36.2, 34.1, 30.1, 25.2, 25.1. FTIR (NaCl, thin film, cm-1): 3353, 3012, 2954, 2927, 2866, 2359, 1709, 1587, 1523, 1485, 1425, 1386, 1324, 1265, 1162, 1055, 827, 790, 754, 666. HRMS (ESI-TOF, m/z): calc’d for C25H25N2O2 [M+H]+: 385.1911; found: 385.1921. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 48 89n Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me Me N H and 6-iodo-N-Boc-indole (2 equiv, 137 mg, 0.4 mmol). The N crude residue was purified by column chromatography (10% NBoc → 15% EtOAc/hexanes) to give a colorless foam. Run 1: (56.1 mg, 60%), Run 2: (62.8 mg, 67%) Rf = 0.36 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +114.7° (c = 5.7, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.64 (s, 1H), 8.65 (dd, J = 4.2, 1.7 Hz, 1H), 8.60 (dd, J = 6.3, 2.8 Hz, 1H), 8.08 (dd, J = 8.3, 1.7 Hz, 1H), 8.03 (s, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.43 – 7.32 (m, 4H), 7.09 (dt, J = 8.1, 1.1 Hz, 1H), 6.44 (dd, J = 3.7, 0.8 Hz, 1H), 4.19 (dt, J = 10.9, 8.6 Hz, 1H), 3.44 (dd, J = 8.7, 2.9 Hz, 1H), 2.85 (t, J = 10.7 Hz, 1H), 2.25 (ddd, J = 10.3, 8.6, 3.0 Hz, 1H), 1.61 (s, 9H), 1.54 (s, 3H), 1.23 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.6, 150.0, 147.9, 138.6, 138.4, 136.3, 135.5, 134.7, 128.7, 127.9, 127.5, 125.3, 121.6, 121.5, 121.1, 120.5, 116.5, 113.4, 107.4, 83.4, 57.9, 38.2, 36.4, 35.9, 30.2, 28.3, 25.3. FTIR (NaCl, thin film, cm-1): 3358, 3008, 2954, 2929, 2866, 1730, 1686, 1618, 1578, 1523, 1485, 1424, 1386, 1370, 1338, 1253, 1214, 1151, 117, 1077, 1022, 826, 816, 756. HRMS (ESI-TOF, m/z): calc’d for C29H32N3O3 [M+H]+: 470.2438; found: 470.2449. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 49 89o Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me and 4-(5-iodopyrin-2-yl)piperazine-1-carboxylic acid tert- N H Me N butyl ester (2 equiv, 156 mg, 0.4 mmol). The crude residue N was purified by column chromatography using silica gel N NBoc basified with 5 mL of aqueous ammonium hydroxide (20% EtOAc/2% Et3N/78% hexanes → 30% EtOAc/2% Et3N/68% hexanes → 40% EtOAc/2% Et3N/58% hexanes) to give a pale, yellow foam. Run 1: (79.9 mg, 77%), Run 2: (84.6 mg, 82%) Rf = 0.27 (silica gel, 40% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = +69.2° (c = 5.1, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 9.58 (s, 1H), 8.74 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (p, J = 4.4 Hz, 1H), 8.10 (dd, J = 8.2, 1.7 Hz, 1H), 8.06 (dt, J = 2.5, 0.8 Hz, 1H), 7.50 (ddd, J = 8.7, 2.5, 0.7 Hz, 1H), 7.46 – 7.37 (m, 3H), 6.53 (dd, J = 8.8, 0.8 Hz, 1H), 3.93 (dt, J = 11.0, 8.6 Hz, 1H), 3.45 (dd, J = 6.6, 3.5 Hz, 4H), 3.39 (dd, J = 6.3, 3.6 Hz, 4H), 3.30 (dd, J = 8.4, 2.9 Hz, 1H), 2.74 (t, J = 10.8 Hz, 1H), 2.10 (ddd, J = 10.4, 8.5, 2.9 Hz, 1H), 1.51 (s, 4H), 1.47 (s, 9H), 1.24 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.4, 158.0, 154.9, 148.0, 146.8, 138.4, 137.0, 136.4, 134.5, 127.9, 127.4, 126.4, 121.6, 121.2, 116.4, 106.9, 79.9, 57.7, 45.5, 37.6, 35.9, 33.5, 30.1, 28.5, 25.1. FTIR (NaCl, thin film, cm-1): 3357, 3007, 2973, 2928, 2864, 2360, 1686, 1605, 1560, 1524, 1486, 1424, 1391, 1324, 1241, 1166, 1129, 1084, 1000, 934, 864, 826, 792, 756, 686, 666. Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 50 HRMS (ESI-TOF, m/z): calc’d for C30H38N5O3 [M+H]+: 516.2969; found: 516.2955. 89p Prepared from cyclobutamide 6 (1 equiv, 50.8 mg, 0.2 mmol) O Me and 5-iodo-2-(1-piperidinyl)pyrimidine (2 equiv, 116 mg, 0.4 N H Me N mmol). The crude residue was purified by column N N chromatography using silica gel basified with 5 mL of aqueous N ammonium hydroxide (10% EtOAc/2% Et3N/88% hexanes → 20% EtOAc/2% Et3N/78% hexanes → 30% EtOAc/2% Et3N/68% hexanes) to give a pale yellow foam. Run 1: (63.0 mg, 76%), Run 2: (60.6 mg, 73%) Rf = 0.44 (silica gel, 40% EtOAc/Hex, UV). [α]D25 = +83.3° (c = 3.1, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.59 (s, 1H), 8.74 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (dd, J = 6.6, 2.4 Hz, 1H), 8.25 (s, 2H), 8.10 (dd, J = 8.2, 1.7 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.40 (dd, J = 8.2, 4.2 Hz, 2H), 3.81 (dt, J = 11.0, 8.6 Hz, 1H), 3.67 (dd, J = 6.2, 4.9 Hz, 4H), 3.27 (dd, J = 8.6, 2.9 Hz, 1H), 2.74 (t, J = 10.8 Hz, 1H), 2.07 (ddd, J = 10.6, 8.5, 2.9 Hz, 1H), 1.60 (p, J = 5.5 Hz, 2H), 1.52 (qd, J = 5.6, 5.1, 2.3 Hz, 4H), 1.49 (s, 3H), 1.24 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 170.2, 160.8, 157.1, 148.1, 138.4, 136.4, 134.5, 127.9, 127.5, 121.6, 121.3, 120.8, 116.5, 57.4, 45.0, 37.3, 36.1, 31.8, 30.0, 25.8, 25.1, 25.0. FTIR (NaCl, thin film, cm-1): 3355, 2031, 2853, 1682, 1603, 1524, 1485, 1462, 1447, 1366, 1324, 1274, 1256, 1160, 1025, 946, 826, 792, 754. HRMS (ESI-TOF, m/z): calc’d for C25H30N5O [M+H]+: 416.2445; found: 416.2440. 51 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 1.5.9 Chiral SFC Traces of Racemic and Enantioenriched Products NH2 O Me N2 Me N + hυ (254 nm) (+)-cinchonine THF, rt 8 11 SFC data for racemic 6 Enantioenriched 6 before recrystallization Enantiopure 6 after a single recrystallization O Me Me N H 6 N 52 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B NH2 O Me Me N N2 + 69 hυ (254 nm) epi-QD (85) THF, rt 11 3 equiv SFC data for racemic 73 Enantioenriched 73 Enantioenriched 73 with 20 mol % catalyst loading Me Me O N H N 73 53 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B Me Me O NH2 N2 N + 70 hυ (254 nm) quinidine (77) Me Me O THF, rt 11 3 equiv SFC data for racemic 74 (12 min run, the rest for 74 are 15 min) Enantioenriched 74 Enantioenriched 74 with 20 mol % catalyst loading N H N 74 54 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B NH2 O N N2 + 71 SFC data for racemic 75 Enantioenriched 75 hυ (254 nm) (DHQD)2AQN (79) THF, rt 11 3 equiv O N H 75 N 55 Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B NH2 O N N2 + 72 SFC data for racemic 76 Enantioenriched 76 hυ (254 nm) (DHQD)2PYR (30) THF, rt 11 3 equiv O N H 76 N Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 56 1.5.10 C–H Proof of Enantiopurity 89m, racemic sample. Chiral SFC: (OD-H, 2.5 mL/min, 20% IPA in CO2, λ = 254 nm): tR(minor) = 9.7 min, tR(major) = 11.1 min. O Me N H Me N 89m, racemic O 9m, enantioenriched sample. Chiral SFC: (OD-H, 2.5 mL/min, 20% IPA in CO2, λ = 254 nm): tR(minor) = 9.7 min, tR(major) = 11.1 min. O Me N H Me N 89m, enantioenriched O Chapter 1 – Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)-Psiguadial B 57 1.6 REFERENCES (1) Shao, M.; Wang, Y.; Liu, Z.; Zhang, D.-M.; Cao, H.-H.; Jiang, R.-W.; Fan, C.-L.; Zhang, X.-Q.; Chen, H.-R.; Yao, X.-S.; Ye, W.-C. Org. Lett. 2010, 12 (21), 5040– 5043. (2) Dembitsky, V. M. J. Nat. Med. 2008, 62 (1), 1–33. (3) Chung, H.-M.; Chen, Y.-H.; Lin, M.-R.; Su, J.-H.; Wang, W.-H.; Sung, P.-J. Tetrahedron Lett. 2010, 51 (46), 6025–6027. (4) Wang, Y.-H.; Hou, A.-J.; Chen, D.-F.; Weiller, M.; Wendel, A.; Staples, R. J. Eur. J. Org. Chem. 2006, 2006 (15), 3457–3463. 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US Patent US20080188452A1, October 2, 2006. Appendix 1 – Spectra Relevant to Chapter 1 60 Appendix 1 Spectra Relevant to Chapter 1: Enantioselective Ketene Trapping and Diastereoselective C–H Activation: Methods Developed from the Total Synthesis of (+)Psiguadial B 61 S32 8 Appendix 1 – Spectra Relevant to Chapter 1 62 S33 8 Appendix 1 – Spectra Relevant to Chapter 1 63 S34 8 Appendix 1 – Spectra Relevant to Chapter 1 64 S35 8 Appendix 1 – Spectra Relevant to Chapter 1 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_113_1_Nov/ 1/ fid Title CRL_01_113_1_Nov.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zg30 Number of Scans 16 Receiver Gain 79 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-11-20T17:48:00 Spectrometer Frequency 400.13 69 Spectral Width 8012.8 Lowest Frequency -1522.5 Nucleus 1H Acquired Size 32768 Spectral Size 65536 CRL_01_113_1_Nov.1.fid S36 5.5 5.0 f1 (ppm) 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 1 – Spectra Relevant to Chapter 1 65 6.09 2.03 2.12 2.00 CRL_01_113_1_Nov.3.fid 200.11 210 200 190 180 170 160 150 140 130 120 S37 110 100 f1 (ppm) Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_113_1_Nov/ 3/ fid Title CRL_01_113_1_Nov.3.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zgpg30 Number of Scans 512 Receiver Gain 72 Relaxation Delay 1.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-11-20T18:09:47 69 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1935.1 Nucleus 13C Acquired Size 32768 Spectral Size 65536 90 80 70 60 50 40 30 18.53 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 66 22.86 26.66 37.45 42.02 62.61 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_203_1_Nov/ 1/ fid Title CRL_01_203_1_Nov.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 294.9 Pulse Sequence zg30 Number of Scans 16 Receiver Gain 88 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-11-20T18:14:57 Spectrometer Frequency 400.13 Spectral Width 8012.8 Lowest Frequency -1520.9 Nucleus 1H Acquired Size 32768 Spectral Size 65536 CRL_01_203_1_Nov.1.fid S38 5.5 5.0 f1 (ppm) 70 4.5 4.0 3.5 3.0 1.00 2.5 2.0 1.03 1.5 1.0 0.5 0.0 -0.5 Appendix 1 – Spectra Relevant to Chapter 1 67 3.09 2.04 CRL_01_203_1_Nov.3.fid 202.17 210 200 190 180 170 160 150 140 130 120 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_203_1_Nov/ 3/ fid Title CRL_01_203_1_Nov.3.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zgpg30 Number of Scans 512 Receiver Gain 88 Relaxation Delay 1.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-11-20T18:36:43 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1933.7 Nucleus 13C 70 Acquired Size 32768 Spectral Size 65536 S39 110 100 f1 (ppm) 90 80 68.26 70 60 50 37.93 40 29.52 25.77 25.74 25.55 30 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 68 46.98 69 S40 6 Appendix 1 – Spectra Relevant to Chapter 1 70 6 S41 Appendix 1 – Spectra Relevant to Chapter 1 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 2.10 1.01 1.01 0.97 1.00 0.98 7.0 6.5 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_2/ 2/ fid Title CRL_01_074_2.2.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 294.9 Pulse Sequence zg30 Number of Scans 1 Receiver Gain 197 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-04-19T21:04:33 Spectrometer Frequency 400.13 Spectral Width 8012.8 Lowest Frequency -1555.6 Nucleus 1H Acquired Size 32768 Spectral Size 65536 CRL_01_074_2.2.fid 6.0 S42 5.5 5.0 f1 (ppm) 73 4.5 4.0 3.5 3.0 1.04 2.5 1.13 1.14 2.15 1.11 2.0 1.5 3.16 1.0 0.5 0.0 -0.5 Appendix 1 – Spectra Relevant to Chapter 1 71 3.30 1.09 116.44 121.67 121.29 128.09 127.61 138.61 136.45 134.80 148.29 173.08 210 200 190 180 170 160 150 140 130 120 S43 110 100 f1 (ppm) Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_2_1scan/ 2/ fid Title CRL_01_074_2_1scan.2.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 294.9 Pulse Sequence zgpg30 Number of Scans 1024 Receiver Gain 79 Relaxation Delay 2.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-04-19T22:06:04 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1931.5 Nucleus 13C 73 Acquired Size 32768 Spectral Size 65536 CRL_01_074_2_1scan.2.fid 90 80 70 58.10 60 50 43.16 42.07 40 29.66 27.88 23.96 22.48 30 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 72 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 2.14 1.03 1.03 1.00 1.00 1.02 7.0 6.5 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_4/ 1/ fid Title CRL_01_074_4.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zg30 Number of Scans 16 Receiver Gain 197 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-04-19T12:22:42 Spectrometer Frequency 400.13 Spectral Width 8012.8 Lowest Frequency -1555.6 Nucleus 1H Acquired Size 32768 Spectral Size 65536 CRL_01_074_4.1.fid 6.0 S44 5.5 5.0 f1 (ppm) 74 4.5 4.0 3.5 3.0 2.5 3.31 2.0 2.16 1.5 3.31 3.21 1.0 0.5 0.0 -0.5 Appendix 1 – Spectra Relevant to Chapter 1 73 3.18 1.11 116.46 121.66 121.30 128.08 127.61 138.63 136.47 134.72 148.27 173.61 210 200 190 180 170 160 150 140 130 120 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_4_C/ 1/ fid Title CRL_01_074_4_C.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zgpg30 Number of Scans 1024 Receiver Gain 79 Relaxation Delay 2.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-04-20T00:15:34 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1931.5 74 Nucleus 13C Acquired Size 32768 Spectral Size 65536 CRL_01_074_4_C.1.fid S45 110 100 f1 (ppm) 90 80 70 60 50 41.62 40 33.39 31.52 30 25.72 25.68 22.07 21.16 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 74 56.51 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 1.05 1.00 2.02 2.06 0.98 1.01 2.03 0.96 7.0 6.5 6.0 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_120A_1/ 1/ fid Title CRL_01_120A_1.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zg30 Number of Scans 1 Receiver Gain 197 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-06-12T17:08:01 Spectrometer Frequency 400.13 Spectral Width 8012.8 Lowest Frequency -1555.6 Nucleus 1H Acquired Size 32768 Spectral Size 65536 S46 5.5 5.0 f1 (ppm) 75 4.5 1.00 CRL_01_120A_1.1.fid 4.0 1.02 1.05 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 1 – Spectra Relevant to Chapter 1 75 170 210 138.67 136.41 134.49 128.57 128.02 127.76 127.51 123.45 122.70 121.73 121.71 116.54 148.41 144.73 142.92 200 190 180 160 150 140 130 120 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_120A_1/ 2/ fid Title CRL_01_120A_1.2.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zgpg30 Number of Scans 1024 Receiver Gain 72 Relaxation Delay 2.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-06-12T18:07:42 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1933.9 Nucleus 13C Acquired Size 32768 Spectral Size 65536 170.55 CRL_01_120A_1.2.fid S47 110 100 f1 (ppm) 75 90 80 70 60 49.29 50 40 30 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 76 35.20 11.0 10.5 0.91 10.0 9.5 9.0 8.5 8.0 7.5 3.10 1.03 1.04 2.00 1.00 1.01 0.99 7.0 6.5 6.0 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_3_H/ 1/ fid Title CRL_01_074_3_H.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 295.0 Pulse Sequence zg30 Number of Scans 1 Receiver Gain 197 Relaxation Delay 1.0000 Pulse Width 11.7000 Acquisition Time 4.0894 Acquisition Date 2017-04-19T22:10:20 Spectrometer Frequency 400.13 Spectral Width 8012.8 Lowest Frequency -1555.6 Nucleus 1H Acquired Size 32768 Spectral Size 65536 CRL_01_074_3_H.1.fid S48 5.5 5.0 f1 (ppm) 4.5 76 4.0 3.5 1.15 3.0 2.13 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 1 – Spectra Relevant to Chapter 1 77 1.05 1.07 128.03 127.87 127.53 126.86 125.14 124.97 121.71 121.66 116.60 148.36 144.82 141.46 138.69 136.42 134.65 172.67 210 200 190 180 170 160 150 140 130 120 Parameter Value Data File Name / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_074_3_1scan/ 1/ fid Title CRL_01_074_3_1scan.1.fid Origin Bruker BioSpin GmbH Solvent CDCl3 Temperature 294.9 Pulse Sequence zgpg30 Number of Scans 1024 Receiver Gain 79 Relaxation Delay 2.0000 Pulse Width 10.0000 Acquisition Time 1.3631 Acquisition Date 2017-04-19T23:09:28 Spectrometer Frequency 100.62 Spectral Width 24038.5 Lowest Frequency -1932.1 Nucleus 13C Acquired Size 32768 Spectral Size 65536 CRL_01_074_3_1scan.1.fid S49 110 100 f1 (ppm) 76 90 80 70 60 50 40 32.08 30.36 30 20 10 0 -10 Appendix 1 – Spectra Relevant to Chapter 1 78 54.00 JCB_03_202.1.fid 2017-05-16T00:54:20 Acquisition Date 1H 89a 2.86 1.03 0.96 0.93 0.97 0.96 0.94 0.98 9.57 1.02 8.78 8.77 8.77 8.76 8.11 8.11 8.09 8.09 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 0.99 Nucleus Spectrometer Frequency 400.13 11.7000 14.9998 15.0000 Relaxation Delay Acquisition Time 55.5 Receiver Gain Pulse Width Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 Number of Scans 1D Experiment Probe 294.9 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_202/ 1/ fid 0.98 Parameter 1.09 7.43 7.42 7.41 7.41 7.40 7.39 7.38 7.38 7.37 7.25 7.25 7.24 7.23 7.23 7.23 7.11 7.11 7.10 7.10 7.09 7.09 7.09 7.08 7.08 7.07 7.07 7.07 7.06 6.98 6.98 6.98 6.98 6.96 6.96 6.96 6.96 6.94 6.94 6.94 6.94 6.62 6.62 6.60 6.60 4.06 4.04 4.04 4.03 4.03 4.02 4.02 4.01 4.01 4.00 3.99 3.62 3.61 3.48 3.47 3.47 3.47 3.45 3.45 3.45 3.44 2.81 1.01 1.53 1.5 3.00 1.22 2.77 2.74 2.72 2.16 2.15 2.14 2.13 2.13 2.13 2.11 2.10 1.0 2.91 Data File Name 0.5 0.0 -0.5 S40 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 Appendix 1 – Spectra Relevant to Chapter 1 79 210 JCB_03_202.2.fid 2017-05-16T01:02:52 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time 2.0000 170 171.1 Pulse Width Relaxation Delay 1D Experiment 87.8 zgpg30 Pulse Sequence Receiver Gain 294.9 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 128 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_202/ 2/ fid Parameter Data File Name 157.2 160 147.9 150 140 130 120 110 89a 100 90 f1 (ppm) 138.4 136.3 134.9 130.2 127.9 127.7 127.5 127.0 121.4 120.8 120.4 116.3 109.4 80 70 58.1 55.1 60 50 30 37.1 35.9 32.8 30.3 25.1 40 20 10 0 S41 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 Appendix 1 – Spectra Relevant to Chapter 1 80 CRL_02_050_1.1.fid 2018-04-06T13:13:53 Acquisition Date 11.5 1H 10.5 9.62 0.98 9.5 0.94 0.88 8.5 0.95 Nucleus Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time Relaxation Delay Pulse Width 78.7 1.0000 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 Number of Scans 1D Experiment Probe 295.2 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin 89b 7.5 6.5 5.5 f1 (ppm) 4.5 3.5 1.15 2.87 1.04 Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_050_1/ 1/ fid 1.00 Parameter 2.5 1.02 8.76 8.76 8.75 8.75 8.12 8.11 8.10 8.09 7.44 7.44 7.43 7.43 7.42 7.42 7.41 7.41 7.41 7.40 7.40 7.39 7.15 7.13 7.11 6.83 6.83 6.83 6.83 6.82 6.81 6.81 6.81 6.81 6.81 6.78 6.78 6.77 6.77 6.77 6.65 6.65 6.65 6.64 6.64 6.64 6.63 6.63 6.62 6.62 6.62 6.62 3.06 0.96 0.98 1.03 1.02 1.51 1.5 2.86 1.22 4.04 4.04 4.04 4.02 4.02 4.01 4.01 3.40 3.40 3.40 3.40 3.38 3.38 3.38 3.37 2.79 2.76 2.74 2.19 2.18 2.17 2.16 2.16 2.16 2.14 2.13 2.90 Data File Name 0.5 -0.5 S42 0 5000 10000 15000 20000 25000 30000 35000 40000 Appendix 1 – Spectra Relevant to Chapter 1 81 CRL_02_050_1.2.fid 2018-04-06T13:36:22 Acquisition Date 13C 159.5 89b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time 170.5 Pulse Width 78.7 512 Number of Scans 1.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Relaxation Delay 1D Experiment Receiver Gain 295.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner 148.0 143.7 138.4 136.4 134.6 129.1 127.9 127.5 121.5 121.2 119.1 116.5 112.3 111.3 Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_050_1/ 2/ fid Parameter Data File Name 80 70 57.7 55.1 60 50 30 37.8 36.0 35.8 30.2 25.1 40 20 10 0 S43 0 500 1000 1500 2000 2500 Appendix 1 – Spectra Relevant to Chapter 1 82 14.9998 2017-04-28T04:00:54 Acquisition Date 9.58 1.05 89c 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 0.94 1.00 1H 0.97 8.75 8.75 8.74 8.63 8.12 8.11 8.11 8.10 8.09 2.96 Nucleus Spectrometer Frequency 400.13 11.7000 Acquisition Time Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Pulse Width 1D Experiment 10.0000 zg30 Pulse Sequence Relaxation Delay 294.9 Temperature 1 CDCl3 Solvent 98.9 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 1.99 7.44 7.44 7.43 7.43 7.42 7.42 7.42 7.41 7.41 7.41 7.40 7.40 7.39 7.19 7.18 7.18 7.18 7.17 7.17 7.16 7.16 7.16 7.15 7.15 7.15 6.79 6.78 6.77 6.76 6.76 6.75 1.99 Comment JCB_03_186_4-OMe.1.fid 1.05 3.10 1.04 Title 0.98 Value 1.06 / Volumes/ nmrdata/ kporemba/ nmr/ JCB_03_186_4-OMe/ 1/ fid 1.5 2.90 1.0 2.78 2.75 2.73 2.16 2.15 2.14 2.13 2.13 2.12 2.11 2.10 3.28 Parameter 4.04 4.02 4.01 4.00 3.99 3.97 3.75 3.75 3.74 3.73 3.72 3.72 3.72 3.72 3.71 3.71 3.70 3.70 3.69 3.69 3.68 3.68 3.67 3.67 3.67 3.65 3.36 3.36 3.35 3.35 3.35 3.33 3.33 3.33 3.32 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 0.5 0.0 -0.5 S44 1.53 1.51 1.48 1.30 1.28 1.27 1.26 1.26 1.24 1.24 1.23 1.19 1.18 Data File Name Appendix 1 – Spectra Relevant to Chapter 1 83 210 1.3631 2017-04-28T04:08:51 Acquisition Time Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 2.0000 10.0000 64.2 Receiver Gain Pulse Width 128 Number of Scans 170 170.6 Relaxation Delay Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 294.9 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment JCB_03_186_4-OMe.2.fid Title Value / Volumes/ nmrdata/ kporemba/ nmr/ JCB_03_186_4-OMe/ 2/ fid Parameter 157.7 160 148.0 150 130 120 110 138.4 136.4 134.6 133.7 127.9 127.5 121.5 121.1 116.5 113.6 140 100 90 f1 (ppm) 80 70 89c 60 57.8 55.3 Data File Name 50 30 37.9 35.7 35.5 30.2 25.2 40 20 10 0 -10 S45 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Appendix 1 – Spectra Relevant to Chapter 1 84 JCB_05_048_P1.1.fid 11.7000 4.0894 2018-03-31T06:55:59 Pulse Width Acquisition Time Acquisition Date 89d 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 1H 9.60 0.92 Nucleus 0.98 0.97 Spectrometer Frequency 400.13 98.9 16 Number of Scans 1.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Relaxation Delay 1D Experiment Receiver Gain 295.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value 3.02 1.02 / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_048_P1/ 1/ fid 1.5 3.01 Parameter 0.99 8.76 8.76 8.75 8.75 7.45 7.44 7.44 7.43 7.42 7.41 7.41 7.40 7.39 7.39 7.19 7.16 7.14 7.14 7.13 7.13 7.12 7.12 7.11 7.11 7.06 7.04 7.04 7.03 7.02 7.02 7.00 6.98 3.04 2.03 2.02 3.38 3.37 3.37 2.79 2.76 2.74 1.00 8.14 8.13 8.13 8.12 8.12 8.11 8.11 8.10 8.10 8.09 8.09 2.28 2.25 2.23 2.23 2.17 2.17 2.16 2.15 2.14 2.14 2.14 2.12 2.11 0.99 4.05 4.03 4.03 4.02 4.02 4.01 4.00 4.00 3.98 1.00 1.0 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 0.5 0.0 -0.5 S46 1.51 1.49 1.24 1.24 1.23 1.22 1.20 1.20 3.14 Data File Name Appendix 1 – Spectra Relevant to Chapter 1 85 JCB_05_048_P1.3.fid spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 128 64.2 2.0000 10.0000 1.3631 2018-03-31T07:09:46 Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 200 190 Nucleus 180 13C 170 160 nmrsu 150 140 130 120 110 100 90 f1 (ppm) 89d 138.7 138.4 136.4 135.0 134.7 128.9 127.9 127.5 126.7 121.5 121.1 116.5 148.0 Spectrometer Frequency 100.62 Bruker BioSpin GmbH Owner 170.6 Origin Comment / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_048_P1/ 3/ fid Title Value Data File Name Parameter 80 70 57.7 60 50 30 20 37.8 35.8 35.7 30.2 25.2 21.2 40 10 0 -10 S47 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 Appendix 1 – Spectra Relevant to Chapter 1 86 JCB_03_196.1.fid 2017-05-12T02:50:05 Acquisition Time Acquisition Date 1H 89e 0.99 1.5 3.10 1.03 0.97 5.08 1.00 0.94 0.98 1.01 9.76 1.06 8.83 8.83 8.82 8.81 8.81 8.80 8.79 8.57 8.54 8.53 8.52 8.51 8.11 8.11 8.10 8.09 8.09 4.24 4.22 4.22 4.21 4.21 4.20 4.20 4.19 4.19 4.17 1.11 3.76 3.75 3.75 2.90 2.87 2.84 1.04 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 1.0 3.20 2.18 2.18 2.17 2.16 2.16 2.16 2.15 2.14 2.13 -50 0 50 100 150 200 250 300 350 400 450 500 550 0.5 0.0 -0.5 S48 1.62 1.60 1.57 1.53 1.23 1.22 1.20 1.19 1.18 1.18 1.18 1.16 7.61 7.61 7.58 7.58 7.58 7.58 7.57 7.56 7.56 7.56 7.56 7.55 7.54 7.54 7.54 7.54 7.53 7.52 7.49 7.49 7.49 7.48 7.47 7.47 7.47 7.47 7.46 7.46 7.45 7.45 7.45 7.44 7.43 7.43 7.42 7.41 7.40 7.40 7.39 7.39 7.38 7.38 7.37 7.36 7.24 7.23 7.23 7.23 7.23 7.22 7.21 7.21 7.21 7.21 7.19 7.19 7.19 7.19 Nucleus Spectrometer Frequency 400.13 11.7000 14.9998 Pulse Width 87.8 1 Number of Scans 15.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Relaxation Delay 1D Experiment Receiver Gain 294.9 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_196/ 1/ fid Title Value Data File Name Parameter Appendix 1 – Spectra Relevant to Chapter 1 87 210 JCB_03_196_2-CN.3.fid CDCl3 295.0 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Solvent Temperature Pulse Sequence Experiment Probe 2017-05-11T07:36:21 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time Relaxation Delay 170 170.0 Pulse Width 64.2 2.0000 Receiver Gain 160 spect Instrument 128 nmrsu 150 148.3 146.9 Number of Scans Bruker BioSpin GmbH Owner 140 130 120 110 100 90 f1 (ppm) 138.5 136.3 134.5 132.6 128.1 127.9 127.2 126.3 121.7 121.4 118.8 116.3 110.6 Origin Comment / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_196_2-CN/ 3/ fid Title Value Data File Name Parameter 80 70 57.7 60 50 30 36.6 36.1 35.2 29.8 25.1 40 89e 20 10 0 S49 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Appendix 1 – Spectra Relevant to Chapter 1 88 JCB_03_200.1.fid 2017-05-12T03:02:58 Acquisition Time Acquisition Date 9.66 1.07 89f 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 1.05 1.02 1H 1.00 8.80 8.79 8.78 8.78 8.15 8.14 8.13 8.12 Nucleus Spectrometer Frequency 400.13 11.7000 14.9998 Pulse Width 78.7 1 Number of Scans 15.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Relaxation Delay 1D Experiment Receiver Gain 294.9 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value 1.09 / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_200/ 1/ fid 1.04 Parameter 1.07 7.52 7.52 7.51 7.51 7.50 7.49 7.49 7.47 7.47 7.46 7.45 7.45 7.44 7.44 7.44 7.43 7.42 7.42 7.40 7.31 7.30 7.30 7.29 7.29 7.28 7.28 7.27 7.27 7.27 2.13 3.16 1.88 1.53 1.5 3.07 4.05 4.03 4.03 4.03 4.02 4.01 4.01 4.00 3.98 1.15 1.20 3.44 3.44 3.44 2.80 2.77 2.74 2.21 2.20 2.18 2.18 2.18 2.17 2.16 2.15 1.0 3.17 Data File Name 0.5 0.0 -0.5 S50 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 Appendix 1 – Spectra Relevant to Chapter 1 89 210 JCB_03_200.2.fid 10.0000 1.3631 2017-05-12T03:10:55 Pulse Width Acquisition Time Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 64.2 2.0000 Relaxation Delay 170 169.9 Receiver Gain 160 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 128 Number of Scans 1D Experiment Probe 295.0 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_200/ 2/ fid 148.2 150 148.4 140 136.5 130 134.2 131.9 127.5 127.3 120 109.3 110 121.7 121.6 116.5 Parameter 100 90 f1 (ppm) 80 70 60 50 89f 57.7 Data File Name 30 37.5 36.1 36.0 29.9 25.0 40 20 10 0 -10 S51 0 100 200 300 400 500 600 700 800 900 Appendix 1 – Spectra Relevant to Chapter 1 90 15.0000 11.7000 14.9998 2017-04-23T21:05:01 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 1H 10.5 9.63 0.92 9.5 8.5 1.00 1.00 Nucleus Spectrometer Frequency 400.13 1 87.8 Number of Scans Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.0 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin 1.00 8.78 8.77 8.77 8.76 8.13 8.13 8.12 8.11 8.10 89g 7.5 6.5 5.5 f1 (ppm) 7.48 7.47 7.47 7.46 7.46 7.46 7.46 7.45 7.44 7.43 7.43 7.43 7.42 7.42 7.41 7.41 7.40 7.39 7.39 7.39 7.36 7.36 7.36 7.35 7.35 7.35 7.35 7.34 7.34 7.33 7.33 7.32 7.31 7.31 7.29 7.29 7.29 5.10 2.15 Comment JCB_03_181_3CF3.1.fid Title Value 4.5 3.5 0.99 / Volumes/ nmrdata/ jbeck/ nmr/ JCB_03_181_3CF3/ 1/ fid 0.98 Parameter 2.5 0.99 4.09 4.06 4.06 4.06 4.04 4.04 4.01 0.99 1.53 1.23 1.5 3.02 3.43 3.43 3.43 2.83 2.80 2.77 2.22 2.22 2.20 2.20 2.19 2.19 2.18 2.17 3.33 Data File Name 0.5 -0.5 S52 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 Appendix 1 – Spectra Relevant to Chapter 1 91 JCB_03_181_3CF3.4.fid 294.9 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Temperature Pulse Sequence Experiment Probe 1.3631 2017-04-23T22:11:28 Pulse Width Acquisition Time Acquisition Date 13C 89g 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus 170.2 148.2 143.2 138.5 136.6 134.5 130.9 130.5 130.3 130.2 129.9 128.5 128.1 127.6 125.9 123.7 123.7 123.7 123.6 123.2 122.8 122.8 122.7 122.7 121.7 121.5 116.6 Spectrometer Frequency 100.62 2.0000 10.0000 Relaxation Delay 768 CDCl3 Solvent 78.7 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ jbeck/ nmr/ JCB_03_181_3CF3/ 4/ fid Parameter Data File Name 80 70 57.8 60 50 30 20 37.8 36.1 36.0 30.2 30.0 25.2 40 10 0 -10 S53 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 Appendix 1 – Spectra Relevant to Chapter 1 92 2017-04-21T19:45:17 Acquisition Date 65536 Acquired Size -62.5 19F Nucleus -62.0 89285.7 Spectral Width Spectrometer Frequency 376.15 3.2333 0.7340 Acquisition Time Relaxation Delay Pulse Width 58 1.0000 Receiver Gain OneNMR 1D Experiment 20 s2pul Pulse Sequence Number of Scans 50.0 Temperature Probe cdcl3 Solvent Author Instrument -63.0 Varian Origin vnmrs STANDARD FLUORINE PARAMETERS Comment Owner JCB_03_181_19F Title Value / Volumes/ nmrdata-2/ jbeck/ vnmrsys/ data/ JCB_03_181_19F.fid/ fid Parameter Data File Name -63.50 -63.5 -64.0 f1 (ppm) 89g -64.5 -65.0 -65.5 S54 0 5000 10000 15000 20000 25000 30000 35000 40000 Appendix 1 – Spectra Relevant to Chapter 1 93 -63.72 JCB_03_184_4-COMe.1.fid 295.0 zg30 1D Temperature Pulse Sequence Experiment 2017-04-24T21:21:44 Acquisition Date 11.5 Nucleus 10.5 1H Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time 9.5 0.98 9.73 Pulse Width 127.1 1.0000 Relaxation Delay 8.5 7.5 0.95 1.96 1.94 1.04 2.02 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin 89h 6.5 5.5 f1 (ppm) 4.5 1.12 Comment Title 3.5 1.02 4.17 4.15 4.13 4.13 4.13 4.11 4.11 4.11 4.10 4.10 4.08 3.53 3.52 3.52 3.52 3.50 3.50 3.50 3.49 2.5 1.03 2.93 1.01 Value / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_184_4-COMe/ 1/ fid 1.5 3.17 Parameter 2.88 8.21 8.21 8.19 8.19 7.91 7.91 7.90 7.89 7.89 7.88 7.54 7.53 7.52 7.52 7.51 7.50 7.50 7.49 7.48 7.48 7.47 7.47 7.46 7.45 7.44 7.38 7.37 7.37 7.37 7.36 7.35 7.35 7.35 7.34 7.34 8.86 8.85 8.85 8.84 0.94 0.96 2.91 2.88 2.85 2.59 2.59 2.58 2.57 2.29 2.28 2.27 2.26 2.26 2.26 2.24 2.24 1.62 1.61 1.33 1.33 1.33 1.31 1.31 1.29 Data File Name 0.5 -0.5 S55 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 Appendix 1 – Spectra Relevant to Chapter 1 94 Parameter 2017-04-24T23:03:06 Acquisition Date Nucleus 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 13C Spectrometer Frequency 100.62 10.0000 1.3631 2.0000 Relaxation Delay 170.1 Acquisition Time 72.0 Receiver Gain 198.1 138.4 136.5 134.8 134.4 128.4 128.0 127.5 126.7 121.6 121.4 116.5 148.5 148.1 Pulse Width Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 128 Experiment Number of Scans 1D Pulse Sequence Probe 294.9 zgpg30 Temperature CDCl3 spect Solvent nmrsu Instrument Bruker BioSpin GmbH JCB_03_184_4-COMe.6.fid Owner Origin Comment Title Value / Volumes/ nmrdata-1/ jbeck/ nmr/ JCB_03_184_4-COMe/ 6/ fid 80 70 57.8 60 50 89h 40 30 20 37.7 36.1 36.0 30.0 26.7 25.1 Data File Name 10 0 -10 S56 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Appendix 1 – Spectra Relevant to Chapter 1 95 2018-04-27T22:29:05 Acquisition Date Nucleus 1H Spectrometer Frequency 400.13 11.7000 4.0894 1.0000 Relaxation Delay Acquisition Time 30.3 Receiver Gain Pulse Width Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 Number of Scans 1D Experiment Probe 295.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment CRL_02_075_1.1.fid Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_075_1/ 1/ fid 89i 12.0 11.0 9.0 8.0 7.0 6.0 5.0 f1 (ppm) 4.0 1.00 0.93 0.96 9.66 1.01 10.0 3.0 1.00 Parameter 2.0 1.02 8.78 8.77 8.77 8.76 8.55 8.54 8.53 8.53 0.95 0.96 1.01 3.03 0.98 1.53 2.87 4.03 4.02 4.01 4.00 4.00 4.00 3.99 3.98 3.98 3.98 3.96 3.95 8.10 8.10 8.08 8.07 7.97 7.96 7.96 7.96 7.96 7.95 7.95 7.95 7.95 7.94 7.75 7.75 7.74 7.74 7.73 7.73 7.72 7.72 7.72 7.71 7.70 7.70 7.70 7.42 7.42 7.42 7.41 7.40 7.40 7.40 7.39 7.38 7.38 7.36 7.16 7.16 7.15 7.15 7.14 7.13 7.13 1.15 1.19 3.45 3.45 3.43 2.78 2.76 2.73 2.14 2.13 2.12 2.11 2.11 2.11 2.09 2.09 1.0 2.90 Data File Name 0.0 S57 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 Appendix 1 – Spectra Relevant to Chapter 1 96 CRL_02_075_1.2.fid 10.0000 1.3631 2018-04-27T22:51:20 Pulse Width Acquisition Time Acquisition Date 13C 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 78.7 1.0000 170.1 Relaxation Delay 148.2 144.7 144.6 139.4 139.3 138.4 136.3 134.4 127.9 127.3 124.3 124.0 121.6 121.4 121.3 121.3 116.4 162.7 160.3 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 Number of Scans 1D Experiment Probe 295.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_075_1/ 2/ fid Parameter Data File Name 80 70 57.0 57.0 60 50 89i 30 20 36.5 36.3 30.7 30.7 29.8 25.0 40 10 0 -500 -10 S58 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 1 – Spectra Relevant to Chapter 1 97 CRL_02_075_1.1.fid Title 1D Z163739_0009 (PI HR-400-S1-BBF/ H/ D-5.0-Z SP) 16 Experiment Probe Number of Scans 2018-07-16T13:51:45 Acquisition Time Acquisition Date -62.0 Nucleus -63.0 -64.0 19F Spectrometer Frequency 376.48 18.0000 0.7209 Pulse Width -66.0 zg Pulse Sequence -65.0 298.1 Temperature 101.0 CDCl3 Solvent 1.0000 Avance Instrument Relaxation Delay nmrsu Owner Receiver Gain Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-3/ clacker/ nmr/ CRL_02_075_1/ 1/ fid Data File Name Value -67.0 -68.0 f1 (ppm) -69.0 -70.0 -71.0 -72.0 89i A (d) -71.52 -71.5 -71.5 1.00 Parameter -73.0 -74.0 S59 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 13000000 14000000 15000000 Appendix 1 – Spectra Relevant to Chapter 1 98 0.7209 2018-07-16T13:56:54 Pulse Width Acquisition Time Acquisition Date -62.0 -63.0 19F -64.0 -63.7 Nucleus Spectrometer Frequency 376.48 1.0000 18.0000 Relaxation Delay 16 101.0 Receiver Gain -65.0 -66.0 Z163739_0009 (PI HR-400-S1-BBF/ H/ D-5.0-Z SP) Number of Scans Probe 298.2 Temperature zg CDCl3 Solvent 1D Avance Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment -67.0 CRL_02_075_1_STANDARD.1.fid Title Value / Volumes/ nmrdata-3/ clacker/ nmr/ CRL_02_075_1_STANDARD/ 1/ fid Parameter -68.0 f1 (ppm) -69.0 -70.0 -71.0 89i -72.0 A (d) -71.52 -71.5 -71.5 1.00 Data File Name -73.0 -74.0 S60 0.0E+00 5.0E+06 1.0E+07 1.5E+07 2.0E+07 2.5E+07 Appendix 1 – Spectra Relevant to Chapter 1 99 Varian Origin autox7991 1 26 1.0000 5.8000 10.0000 2018-03-28T16:08:03 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 80000 Nucleus Acquired Size 89j 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 8000.0 Spectral Width Spectrometer Frequency 499.64 s2pul 1D Experiment 25.0 Temperature Pulse Sequence cdcl3 Solvent Author 1.05 1.03 1.02 1.01 Instrument 1.05 3.04 1.01 inova JCB_05_039_P2 Comment 7.57 7.57 7.56 7.56 7.55 7.55 7.55 7.54 7.47 7.47 7.46 7.45 7.45 7.43 7.43 7.42 7.42 7.41 7.40 7.40 7.18 7.16 8.76 8.76 8.76 8.75 8.59 8.58 8.57 8.57 8.22 8.22 8.22 8.22 8.21 8.12 8.11 8.10 8.10 Owner PROTON01 Title 9.64 0.97 3.99 3.97 3.96 3.95 3.95 3.93 1.05 Value 1.01 / Volumes/ nmrdata/ jbeck/ vnmrsys/ data/ JCB_05_039_P2/ PROTON01.fid/ fid 1.5 2.91 Parameter 1.00 3.38 3.38 2.78 2.76 2.74 1.01 1.64 1.56 1.52 1.47 1.47 1.22 2.18 2.17 2.16 2.16 2.15 2.15 2.14 2.13 1.0 2.99 Data File Name 0.5 0.0 -0.5 S61 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Appendix 1 – Spectra Relevant to Chapter 1 100 JCB_05_039_P2.7.fid 1.3631 2018-03-29T06:23:43 Acquisition Time Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 2.0000 10.0000 170 160 35.5 Receiver Gain Pulse Width 128 Number of Scans 169.8 Relaxation Delay Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.2 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-3/ jbeck/ nmr/ JCB_05_039_P2/ 7/ fid Parameter 140 130 120 110 100 90 f1 (ppm) 148.8 148.5 148.1 138.3 137.7 136.5 136.3 134.2 127.9 127.4 123.5 121.7 121.6 116.5 150 80 70 89j 60 57.4 Data File Name 50 30 20 37.4 36.3 33.3 29.8 29.8 25.0 40 10 0 S62 -50 0 50 100 150 200 250 300 350 400 450 500 550 Appendix 1 – Spectra Relevant to Chapter 1 101 1 197.4 Number of Scans Receiver Gain 11.5 Nucleus 10.5 1H Spectrometer Frequency 400.13 2018-04-20T19:31:06 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 4.0894 1D Experiment Acquisition Date zg30 Pulse Sequence Acquisition Time 295.2 Temperature 1.0000 CDCl3 Solvent 11.7000 spect Instrument 9.60 9.5 1.17 8.77 8.76 8.75 8.75 8.5 1.05 1.06 Pulse Width nmrsu Owner 1.08 1.05 Relaxation Delay Bruker BioSpin GmbH Origin Comment CRL_02_066_1.2.fid Title Value 7.5 6.5 5.5 f1 (ppm) 89k 4.5 1.11 3.14 8.13 8.11 8.11 8.02 8.01 1.10 3.40 4.02 4.00 3.97 3.95 3.93 3.89 3.84 3.5 1.20 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_066_1/ 2/ fid 1.14 Parameter 2.5 1.08 6.62 6.62 6.60 6.60 1.51 1.5 3.36 7.55 7.55 7.55 7.55 7.53 7.53 7.53 7.53 7.52 7.45 7.44 7.43 7.43 7.42 7.41 7.40 1.00 1.23 3.32 3.35 3.35 3.35 3.34 3.34 3.33 3.33 3.32 3.32 2.78 2.76 2.73 2.17 2.16 2.16 2.14 2.14 2.13 2.13 2.12 2.11 Data File Name 0.5 -0.5 S67 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 Appendix 1 – Spectra Relevant to Chapter 1 102 CRL_02_066_1.3.fid 1.0000 10.0000 1.3631 2018-04-20T19:52:20 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 89k 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 512 72.0 170.3 Receiver Gain 162.7 Number of Scans Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.1 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument 148.1 145.3 Experiment nmrsu Owner 138.4 138.0 136.4 134.5 129.6 128.0 127.5 121.6 121.4 116.5 110.1 Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_066_1/ 3/ fid Parameter Data File Name 80 70 50 57.6 53.4 60 30 37.7 36.1 33.4 30.1 25.1 40 20 10 0 -10 S68 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 Appendix 1 – Spectra Relevant to Chapter 1 103 JCB_05_084_P1.2.fid 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 30.3 1.0000 Experiment Probe Number of Scans Receiver Gain Relaxation Delay 1H 1.01 1.00 1.01 1.01 3.06 1.00 1.99 9.61 0.94 89l 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 1.08 3.98 3.98 3.96 3.96 3.95 3.94 3.94 3.93 3.93 3.91 3.91 8.71 8.71 8.70 8.69 8.69 8.68 8.68 8.67 8.67 8.51 8.49 8.48 8.48 8.47 8.46 8.46 8.45 8.44 8.07 8.05 8.04 8.03 8.02 8.01 7.67 7.67 7.67 7.66 7.66 7.65 7.65 7.64 7.64 7.48 7.47 7.46 7.45 7.39 7.38 7.37 7.36 7.36 7.35 7.35 7.34 7.33 7.32 7.31 7.30 Nucleus Spectrometer Frequency 400.13 2018-04-25T16:33:44 zg30 Pulse Sequence Acquisition Date 295.1 Temperature 11.7000 CDCl3 Solvent 4.0894 spect Instrument Acquisition Time nmrsu Owner Pulse Width Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_084_P1/ 2/ fid Parameter 1.02 3.38 3.38 3.38 2.76 2.73 2.70 1.01 1.14 1.46 1.5 1.0 2.15 2.14 2.13 2.13 2.12 2.12 2.10 2.10 Data File Name 0.5 0.0 S63 -2000 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 21000 22000 23000 Appendix 1 – Spectra Relevant to Chapter 1 104 1.3631 2018-04-25T16:41:35 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 Acquisition Time Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Pulse Width 1D Experiment 2.0000 zgpg30 Pulse Sequence Relaxation Delay 295.2 Temperature 128 CDCl3 Solvent 72.0 spect Instrument Receiver Gain nmrsu Owner 170 169.7 160 150 140 130 120 110 100 90 f1 (ppm) 148.8 148.2 146.0 145.6 145.3 144.9 141.2 138.3 136.5 135.7 134.1 128.0 127.4 123.2 121.7 120.5 119.9 119.9 119.8 119.8 116.5 Number of Scans Bruker BioSpin GmbH Origin Comment JCB_05_084_P1.3.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ JCB_05_084_P1/ 3/ fid Parameter Data File Name 80 70 57.4 60 50 30 37.3 36.5 33.7 29.8 25.0 40 89l 20 10 0 S64 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 Appendix 1 – Spectra Relevant to Chapter 1 105 Varian Origin 2018-05-04T23:50:18 Acquisition Date 19F 64000 Nucleus Acquired Size -68.6 89l -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 -50 -51 -52 -53 -54 -55 -56 -57 -58 -59 -60 -61 -62 -63 -64 -65 -66 -67 -68 -69 -70 -71 -72 -73 -74 -75 -76 -77 -78 -79 -80 S65 f1 (ppm) 64935.1 Spectral Width Spectrometer Frequency 282.34 6.3333 0.9856 Acquisition Time Relaxation Delay Pulse Width 30 1.0000 Receiver Gain ASW7284 16 Number of Scans 1D Experiment Probe 25.0 s2pul Pulse Sequence cdcl3 Temperature Solvent Author Instrument mercury JCB_05_107_P1 Comment Owner FLUORINE01 Title Value / Volumes/ nmrdata-1/ jbeck/ vnmrsys/ data/ JCB_05_107_P1/ FLUORINE01.fid/ fid Parameter Data File Name Appendix 1 – Spectra Relevant to Chapter 1 106 JCB_05_107_19F Varian Origin 2018-05-04T23:53:47 Acquisition Date 19F 64000 Nucleus Acquired Size -68.6 -63.7 89l -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 -50 -51 -52 -53 -54 -55 -56 -57 -58 -59 -60 -61 -62 -63 -64 -65 -66 -67 -68 -69 -70 -71 -72 -73 -74 -75 -76 -77 -78 -79 -80 S66 f1 (ppm) 64935.1 Spectral Width Spectrometer Frequency 282.34 6.3333 0.9856 1.0000 Relaxation Delay Acquisition Time 30 Receiver Gain Pulse Width ASW7284 16 Experiment Number of Scans 1D Pulse Sequence Probe 25.0 s2pul Temperature cdcl3 Solvent Author Instrument mercury FLUORINE01 Comment Owner / Volumes/ nmrdata-1/ jbeck/ vnmrsys/ data/ JCB_05_107_19F/ FLUORINE01.fid/ fid Title Value Data File Name Parameter Appendix 1 – Spectra Relevant to Chapter 1 107 JCB_05_038_P1.3.fid 2018-03-29T02:56:12 Acquisition Date 9.57 89m 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 0.97 1H 0.96 0.98 Nucleus Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time Relaxation Delay Pulse Width 55.5 1.0000 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 Number of Scans 1D Experiment Probe 295.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin 0.96 8.74 8.74 8.73 8.73 8.11 8.11 8.10 8.09 8.09 7.60 7.60 7.59 7.59 7.58 7.58 7.57 7.57 7.55 7.55 7.55 7.54 7.53 7.53 7.43 7.43 7.42 7.41 7.41 7.40 7.40 7.39 7.38 7.38 7.37 7.36 7.35 7.34 2.09 4.21 Comment Title Value 0.98 1.00 0.95 1.25 1.93 0.97 / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_038_P1/ 3/ fid 1.5 2.90 Parameter 2.85 4.11 4.09 4.08 4.07 4.06 4.04 1.00 1.64 1.59 1.58 1.55 1.54 1.53 1.23 1.0 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 0.5 0.0 -0.5 S69 3.49 3.49 3.48 3.48 3.47 3.46 3.46 3.46 2.95 2.92 2.90 2.60 2.59 2.58 2.57 2.57 2.56 2.55 2.54 2.18 2.18 Data File Name Appendix 1 – Spectra Relevant to Chapter 1 108 JCB_05_038_P1.7.fid Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 35.5 2.0000 10.0000 1.3631 2018-03-29T04:45:31 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 207.3 200 190 Nucleus 180 13C 170 160 1D Experiment Spectrometer Frequency 100.62 295.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner 170.1 Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_038_P1/ 7/ fid Parameter 148.1 153.3 150 130 120 110 100 90 f1 (ppm) 139.5 138.3 136.8 136.5 134.2 132.9 127.9 127.5 127.4 121.6 121.5 121.4 116.6 140 80 70 60 50 89m 57.2 Data File Name 30 20 37.0 36.5 36.2 34.1 30.1 25.2 25.1 40 10 0 S70 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 Appendix 1 – Spectra Relevant to Chapter 1 109 JCB_05_114_flashed.7.fid 2018-05-10T08:22:22 Acquisition Date 1H 89n 0 500 1000 1500 2000 2500 3000 3500 4000 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 S71 f1 (ppm) Nucleus Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time 15.0000 0.94 9.64 Pulse Width Relaxation Delay 1D Experiment 127.1 zg30 Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 1 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-2/ jbeck/ nmr/ JCB_05_114_flashed/ 7/ fid 0.99 0.97 8.66 8.66 8.65 8.65 1.07 0.86 8.09 8.09 8.07 8.06 8.03 1.01 4.13 0.99 6.44 6.44 6.43 6.43 7.52 7.48 7.47 7.41 7.40 7.40 7.39 7.38 7.38 7.37 7.37 7.36 7.35 7.35 7.11 7.10 7.10 7.09 7.08 7.08 1.00 4.23 4.21 4.20 4.18 4.18 4.16 1.00 Parameter 0.98 2.85 2.82 2.28 2.27 2.25 2.25 2.25 2.24 2.23 2.22 1.04 3.46 3.45 3.44 1.01 1.65 1.64 1.62 1.61 1.56 1.54 1.26 1.23 1.21 1.19 9.63 3.14 3.24 Data File Name Appendix 1 – Spectra Relevant to Chapter 1 110 JCB_05_114_flashed.6.fid zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 128 Pulse Sequence Experiment Probe Number of Scans 2018-05-10T08:20:35 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time 170 170.6 Pulse Width 160 295.2 Temperature 72.0 CDCl3 Solvent 2.0000 spect Relaxation Delay nmrsu Instrument Receiver Gain Bruker BioSpin GmbH Owner 150.0 147.9 150 89n 140 130 120 110 100 90 f1 (ppm) 138.6 138.4 136.3 135.5 134.7 128.7 127.9 127.5 125.3 121.6 121.5 121.1 120.5 116.5 113.4 107.4 Origin Comment / Volumes/ nmrdata-2/ jbeck/ nmr/ JCB_05_114_flashed/ 6/ fid Title Value Data File Name Parameter 83.4 80 70 57.9 60 50 30 20 38.2 36.4 35.9 30.2 28.3 25.3 40 10 0 S72 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Appendix 1 – Spectra Relevant to Chapter 1 111 Varian Origin 2018-04-19T11:44:46 1H 80000 Acquired Size 89o 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 8000.0 Spectral Width Nucleus Spectrometer Frequency 499.64 10.0000 42 Receiver Gain Acquisition Date 1 Number of Scans Acquisition Time autox7991 Probe 1.0000 1D Experiment 5.8000 s2pul Pulse Sequence 9.58 0.97 Pulse Width 25.0 Temperature 8.74 8.74 8.73 8.62 1.06 1.01 Relaxation Delay cdcl3 Solvent Author Instrument 8.07 8.06 1.35 1.26 7.42 7.42 7.42 7.41 1.08 3.18 inova JCB_05_078_P2 Comment 1.00 6.54 6.54 6.52 6.52 6.48 Owner PROTON01 Title Value / Volumes/ nmrdata/ jbeck/ vnmrsys/ data/ JCB_05_078_P2/ PROTON01.fid/ fid 0.99 Parameter 0.97 3.96 3.94 3.93 3.92 3.92 3.90 0.99 3.40 3.39 3.39 3.90 4.32 0.97 1.51 1.47 1.47 1.24 1.5 1.0 3.50 8.95 2.97 2.76 2.74 2.72 2.12 2.12 2.10 2.10 2.10 2.10 2.08 2.08 2.07 Data File Name 0.5 0.0 -0.5 S73 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Appendix 1 – Spectra Relevant to Chapter 1 112 JCB_05_078_P2.6.fid 2018-04-21T02:08:15 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time 170 170.4 Pulse Width 78.7 128 Number of Scans 2.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Relaxation Delay 1D Experiment Receiver Gain 295.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner 158.0 154.9 160 148.0 146.8 150 89o 140 130 120 100 90 f1 (ppm) 106.9 110 137.0 136.4 134.5 127.9 127.4 126.4 121.6 121.2 116.4 Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_078_P2/ 6/ fid Title Value Data File Name Parameter 79.9 80 70 57.7 60 50 30 20 37.6 35.9 33.5 30.1 28.5 25.1 40 10 0 -10 S74 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 Appendix 1 – Spectra Relevant to Chapter 1 113 45.5 Varian Origin cdcl3 2018-04-20T21:56:22 Acquisition Date 1H 16384 Acquired Size 89p 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) 9611.9 Spectral Width Nucleus Spectrometer Frequency 599.60 2.6500 1.7046 Acquisition Time Relaxation Delay Pulse Width 24 1.0000 Receiver Gain penta 1 Experiment Number of Scans 1D Pulse Sequence Probe 25.0 s2pul Temperature Solvent Author Instrument inova JCB_05_081_P1 Comment 0.93 0.92 Owner JCB_05_081_P1 Title Value 1.05 3.99 / Volumes/ nmrdata-2/ jbeck/ vnmrsys/ data/ JCB_05_081_P1.fid/ fid 1.00 Parameter 9.59 0.98 2.76 2.75 2.74 2.72 1.03 7.45 7.44 7.43 7.43 7.43 7.42 7.41 7.41 7.40 7.39 1.84 0.97 3.83 3.82 3.81 3.80 3.80 3.79 3.71 3.70 3.68 3.67 3.67 3.66 3.65 3.64 3.30 3.28 3.27 3.26 3.26 1.04 8.78 8.77 8.75 8.75 8.74 8.74 8.74 8.73 8.69 8.68 8.68 8.67 8.67 8.65 8.63 8.30 8.26 8.26 8.26 8.25 8.24 8.24 8.11 8.11 8.10 8.09 1.94 2.02 1.5 1.0 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 0.5 0.0 -0.5 S75 2.09 2.09 2.08 2.07 2.07 2.07 2.06 2.05 1.69 1.66 1.64 1.62 1.61 1.61 1.60 1.60 1.59 1.58 1.55 1.55 1.54 1.53 1.53 1.52 1.52 1.51 1.51 1.51 1.50 1.49 1.24 2.18 3.75 3.08 3.09 Data File Name Appendix 1 – Spectra Relevant to Chapter 1 114 JCB_05_081_P1.6.fid 2018-04-21T13:22:26 Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 10.0000 1.3631 2.0000 Relaxation Delay Acquisition Time 55.5 Receiver Gain 170 170.2 Pulse Width Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 128 Number of Scans 1D Experiment Probe 295.2 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_081_P1/ 6/ fid Title Value Data File Name Parameter 160.8 157.1 160 148.1 150 140 130 120 110 138.4 136.4 134.5 127.9 127.5 121.6 121.3 120.8 116.5 100 90 f1 (ppm) 89p 80 70 57.4 60 50 30 20 37.3 36.1 31.8 30.0 25.8 25.1 25.0 40 10 0 -10 S76 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 Appendix 1 – Spectra Relevant to Chapter 1 115 45.0 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 116 Chapter 2 Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Total Synthesis of (+)-Rumphellaone A1 2.1 INTRODUCTION Figure 2.1 A modular approach to enantioenriched trans cyclobutanes Me Me Me Me H H OH H Me O H OH HO CHO Ph O α β 6 N H + 99% ee 3 steps from commercially available material H H O Me Me O Me (±)-artochamin H (3) C–H arylation N Me OMe HO OH (+)-psiguadial B (1) Me Me O Me Me CHO O Me Me DG N H (+)-rumphellaone A (4) decarboxylative Me coupling Me I Ar 88 Ar 89 (54–88% yield) 96 R Ar The cyclobutane structural motif is present in a variety of natural products and pharmaceuticals (Figure 2.1).1–7 It is also a versatile synthetic intermediate, as the ring strain inherent to these structures engenders them with unique reactivity that can be leveraged in a variety of transformations to build complex frameworks.8–11 Having developed a short, scalable method for the synthesis of enantioenriched cyclobutamide 6, we sought to demonstrate the utility of this valuable building block.12,13 Previously, our 1 Portions of this chapter were adapted from the following communication: Beck, J. C.; Lacker, C. R.; Chapman, L. M.; Reisman, S. E. Chem. Sci. 2019, 10, 2315., DOI: 10.1039/C8SC05444D, copyright 2019, Royal Society of Chemistry. The research discussed in this chapter was completed in collaboration with Dr. Jordan C. Beck as well as Dr. Lauren M. Chapman, former graduate students in the Reisman Lab. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 117 group had demonstrated that 6 could undergo subsequent C–H arylation with a variety of aryl iodides (88) (see Chapter 1), and we thought that we could derivatize these compounds further. We envisioned that by starting from 6, we could subsequently decorate the enantioenriched cyclobutane core by performing a diastereoselective C–H activation at the β position followed by a diastereoselective decarboxylative cross-coupling at the α position after hydrolysis of the directing group to afford trans cyclobutanes 96 (Figure 2.1). In this way, we hoped to demonstrate a strategy that would allow the expedient synthesis of a library of chiral, polyfunctionalized trans cyclobutanes from a single enantioenriched intermediate. 2.2 STRATEGIES TOWARDS ENANTIOENRICHED CYCLOBUTANES 2.2.1 Enantioselective [2+2] Cycloaddition [2 + 2] cycloaddition reactions represent the most extensively developed approach to construct cyclobutanes and cyclobutenes; recent advances have given rise to elegant enantioselective reactions. In particular, the development of [2+2] cycloaddition reactions between alkenes to directly afford cyclobutanes is a growing area of research. One of the most effective methods for facilitating this transformation in an enantioselective fashion is photoactivation in the presence of a chiral Lewis acid (Scheme 2.1).14–23 Bach and coworkers first demonstrated this in an intramolecular sense using chiral borane catalysis (99) to afford highly substituted, fused cyclobutanes 98 (Scheme 2.1a).14–16 Yoon and coworkers have demonstrated a variety of enantioselective, intermolecular [2+2] cycloadditions of α,β unsaturated esters and activated alkenes to afford enantioenriched cyclobutanes 102 and 104 using photocatalysis (Scheme 2.1b,c). In 2014, Yoon Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 118 Scheme 2.1 Photochemical enantioselective [2+2] cycloadditions a. Bach, 2013 Me O O 99 (50%) hν (λ = 366 nm) CH2Cl2 –70 ºC (84% yield 88% ee) N O 97 N Me Me H N+ H H Br3Al O CF3 98 99 b. Yoon, 2014 O Ru(bpy)3Cl2 (5%) Eu(OTf)3 (10%) 103 (20%) O + R1 R3 R2 100 101 O i-Pr2NEt (2.0 equiv) MeCN (0.2 M) hν, –20 ºC, 15 h Ru(bpy)3Cl2 (5%) Eu(OTf)3 (10%) 105 (30%) O + R1 Me B R3 R2 100 101 R1 = aryl/heteroaryl R2, R3 = alkyl i-Pr2NEt (2.0 equiv) MeCN (0.2 M) hν, rt, 15 h O O R1 Me R3 Me N N R2 102 (34–72% yield, 86–93% ee, 3:1–9:1 dr) O Me Me R3 N N H R2 104 (49–80% yield, 84–97% ee, 2:1–4.5:1 dr) O OH H O + R 1O Ar R2 R 1O Ar B F F Ar = 3,5-Me2Ph 109 O O R3 R3 113 (10%) hν (419 nm) R2 Y PhCF3 –25 ºC + R1 H F Ar d. Bach, 2016 HN N+ NTf2 R2 107 108 4.0 equiv (67–97% yield, R1 = alkyl [Ir] = [Ir(ppy) (dtbbpy)](PF ) 2 6 90–99% ee, R2 = aryl, hetaryl 4:1–20:1 dr) 106 Ar O CH2Cl2 hν, –25 ºC NHBu O 105 c. Yoon, 2019 109 (25%) [Ir] (1%) NHBu O 103 O R1 O OH 111 50 equiv 110 R1 = H or Ph R2, R3 = H or Me Y = ester or ketone H R3 R3 HN Me R2 R1 Y 112 (48–94% yield, 80–95% ee) O N O NH Me Me S O 113 demonstrated this strategy using ruthenium and europium photocatalysis and a peptide-like Lewis acid (103, 105). Interestingly, it was found that the diastereoselectivity depended on whether an imine (103) or amine (105) form of the catalyst was used.17 In 2019, Yoon reported a similar reaction using iridium photocatalysis with a chiral borane catalyst (109) between α,β-unsaturated esters (106) and styrenes (107).18 In 2016, Bach demonstrated the Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 119 use of enantioenriched photocatalyst (113) instead of an enantioenriched Lewis acid to afford enantioenriched cyclobutanes 112 in good yield and good ee (Scheme 2.1d).19 Scheme 2.2 Transition metal-catalyzed enantioselective [2+2] cycloadditions a. Rajanbabu, 2018 R 117•CoCl2 (5–7.5%) + O R PAr2 N AlMe3 or Et2AlCl CH2Cl2, 0ºC to rt Ph Me 114 115 116 (47–85% yield, 82–96% ee) R = alkyl (1º, 2º, or 3º) b. Toste, 2007 Ar = Ph or 3,5-(Me)2-Ph 117 R O R 120 (3%) AgBF4 (6%) R • X CH2Cl2 4 ºC Ar H R X 118 X = NTs, C(CO2R)2 O PAr2AuCl O PAr2AuCl Ar H O 119 Ar = 3,5-t-Bu2-4-OMe-Ph 120 Ph c. González, 2012 124 Au (5%) AgNTf2 (4.5%) NTsAr + • Me O Ar 121 P N * NTsAr Me O Ar Ph CH2Cl2 –70 ºC 122 O 123 * O = (R) or (S) VANOL, (S)SIPHOS-SE, or BINOL 124 d. Echavarren, 2017 Ar + R Ar 128 (2.5%) NaBAr4F (2.5%) CH2Cl2 –20 ºC 125 AuCl Ar Ar R 127 (32–92% yield, 66–96% ee) 126 2.0 equiv R = alkyl R P R Me H + • n 129 130 R = Bn, CH2CF3 H 132 (20%) CH2Cl2 22 ºC, 16h n CO2R H Ar R = t-Bu Ar = 1-Napht 128 e. Brown, 2015 CO2R AuCl P Ar Fe N+ NTf2 H Ph Ph B CF3 131 (48–87% yield, 80–96% ee) Cl 132 Cycloadditions between allenes or alkynes and alkenes to afford enantioenriched cyclobutanes and cyclobutenes has also been explored thoroughly in the literature by a variety of groups (Scheme 2.2).24–35 RajanBabu and coworkers have shown that cobalt with 120 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A an aryl PHOX ligand (117) can be used to catalyze the enantioselective [2+2] cycloaddition of allylic alkynes (114) with ethylene in the presence of alkyl aluminum reagents to afford enantioenriched cyclobutanes containing an all-carbon quaternary center (116) (Scheme 2.2a).24 Later, Rajanbabu also demonstrated that a similar cobalt and PHOX catalyst system in the absence of alkylaluminum reagents could also be used to afford enantioenriched cyclobutenes.25 Toste, González, and Echavarren, as well as others, have showed the ability of gold catalysts to catalyze enantioselective [2+2] cycloadditions to afford enantioenriched cyclobutene products.26,27,30,33 Toste demonstrated this in an intramolecular sense in 2007, utilizing an axially chiral gold catalyst (120) to facilitate this transformation (Scheme 2.2b).26 González similarly showed that a chiral phosphoramidite gold complex (124) could facilitate this transformation in an intermolecular sense (Scheme 2.2c).30 Recently, Echavarren and coworkers demonstrated that gold catalysis (128) could also be applied to alkynes and styrenes to afford enantioenriched cyclobutenes (127) (Scheme 2.2d).32 In addition to transition metal catalysis, Brown and coworkers have demonstrated a variety of transition metal-free enantioselective [2+2] cycloadditions between alkenes and allenes in the presence of a chiral borane catalyst (132) (Scheme 2.2e).35 Though these reactions are powerful tools, they are not necessarily suited to developing a library of compounds. They are limited to specific types of activated substrates (such as allenes or α,β-unsaturated ketones), and enantioselectivity and diastereoselectivity can vary greatly from substrate to substrate. We hoped that by decorating a single easily accessed, scalable, enantioenriched building block, we could 121 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A divergently access a broader library of compounds, albeit potentially in a greater number of steps. 2.2.2 Divergent C–H Activation Strategies towards Cyclobutanes Figure 2.2 Baran’s strategy towards cyclobutane natural products MeO MeO OMe O O HO 1. DG installation MeS 2. C–H arylation OMe OMe N H OMe N N O 134 O 133 common int. OMe O MeO OMe O O epim, C–H aryl., amidation O MeO piperaborenine B (135) 1. DG installation 2. C–H arylation 3. C–H alkenylation O O O O O N N H N OMe O N O O O O O 137 O pipercyclobutanamide A (138) (proposed) MeO O C–H aryl., epim, amidation OMe O OMe N N MeO O O MeO piperaborenine D (136) (proposed) A divergent strategy to access various cyclobutanes has been demonstrated previously. Notably, the Baran lab utilized a similar strategy for their divergent syntheses of piperaborenine B (135) and the proposed structures of piperaborenine D (136) and pipercyclobutanamide A (138) (Figure 2.2).36–38 These syntheses were derived from a common intermediate, cyclobutane 133. By applying C–H activation methods to decorate the rest of the core, Baran was able to afford the desired products. However, this strategy was limited due to the achiral nature of the common intermediate and the choice of racemic C–H activation conditions. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 122 Scheme 2.3 C–H Activations of cyclobutanes a. Yu, 2014 F CN F O F R N H F 139 R = alkyl Ag2CO3 (2.5 equiv) Na2CO3 (2.0 equiv) t-amylOH, H2O 70 ºC (49–75% yield 81–95% ee) F F 141 (11%) Pd(OAc)2 (10%) ArBPin (2.0 equiv) CN F O F R N H O F NHOMe NHBoc Ar 140 F 141 b. Yu, 2018 F CF3 F O F N H 142 F 144(15%) Pd(MeCN)2Cl2 (10%) (Het)ArI (3.0 equiv) Ag2CO3 (2.0 equiv) CHCl3, 80 ºC (50–85% yield 82–94% ee) F CF3 Me F O N H F Me O F AcHN Me N Me (Het)Ar 144 143 The Yu lab has effectively demonstrated the utility of enantioselective C–H activation methodologies to synthesize a variety of functionalized products from achiral starting materials.39–44 In particular, they have been able to apply this strategy to both 3º (139) and 2º (142) cyclobutamide starting materials to afford arylated products in good yield and good enantioselectivity using specialized ligands (141 and 144) and directing groups (Scheme 2.3a,b).39,41 Interestingly, the less substituted 3º aryl products 143 were observed in lower yield and ee than the 4º aryl products (140). In 2018, Baran and coworkers published a strategy that allowed access to a variety of bis-functionalized carbocycles (148) in good yield and good ee starting from racemic anhydrides (145) (Scheme 2.4a).45 After anhydride desymmetrization, sequential, diastereoselective decarboxylative cross-couplings afforded the bis-functionalized products (148). However, these reaction sequences were long and required multiple carboxylic acid activations and deprotections. Similarly, during the course of our investigations, Baran and Yu published a similar strategy towards a variety of functionalized, saturated heterocycles (150) by a doubly diastereoselective C–H Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 123 Scheme 2.4 Baran and Yu’s divergent strategies towards substituted chiral carbocycles and heterocycles a. Baran, 2018 O CO2H desymm. O via cinchona alkaloid n O 145 n = 1–3 n CO2R R1 1. activation 2. cross coupling 3. deprotection n CO2H 2. cross coupling (>40% yield >85% ee) 147 146 R1 1. activation n R2 148 R1, R2 = aryl, alkyl, alkenyl, alkynyl b. Baran and Yu, 2019 ArI (3.0 equiv) Pd(OAc)2 (10%) O N H n AgOAc (2.0 equiv) solvent, 110 ºC N X 149 n = 1–3 from commerical, enantioenriched acid then DG removal O Ar 1. activation OH Ar R 2. cross coupling n X (>90% ee) 150 X n 151 R = aryl, alkyl, alkenyl, alkynyl activation/decarboxylative cross coupling sequence of enantioenriched starting materials (149) (Scheme 2.4b).46 Directing group installation of chiral acids followed by diastereoselective C–H activation and directing group removal afforded chiral acids 150. Activation of the carboxylic acid to form the N-hydroxyphthalimide (NHP) or tetrachloroN-hydroxyphthalimide (TCNHP) ester allowed for diastereoselective decarboxylative cross coupling to afford enantioenriched trans products 151. This sequence is similar to what we proposed, but it is dependent on commercially available chiral acids and focuses on saturated heterocycles. 2.3 DECARBOXYLATIVE CROSS-COUPLINGS Figure 2.3 Modular approach towards enantioenriched cyclobutanes O Me Me α β 6 N H + 99% ee 3 steps from commercially available material C–H arylation N O Me Me DG N H decarboxylative Me coupling Me I Ar 88 Ar 89 (54–88% yield) 96 R Ar Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 124 Having already developed a stereoselective C–H arylation of 6 to afford a variety of aryl- and heteroarylated products (89) in good yields, we sought to diastereoselectively functionalize the α-position of the resulting cyclobutanes after removal of the quinolinamide directing group using a variety of modern decarboxylative coupling techniques to synthesize a library of chiral trans cyclobutanes (96) (Figure 2.3). A number of powerful methods have been developed that leverage the decarboxylative formation of carbon-centered radicals for C–C and C–X bond formation. There were four main categories of decarboxylative cross-coupling reactions that we hoped to investigate: photochemical decarboxylative cross-couplings of free carboxylic acids, photochemical decarboxylative cross-couplings of redox-active esters, transition metal-mediated crosscouplings of activated redox-active esters, and reductive cross-couplings of redox-active esters. Direct decarboxylative cross coupling of free carboxylic acids (152) through metallophotoredox catalysis has become a powerful tool in organic synthesis in recent years (Scheme 2.5).47–62 Starting with MacMillan and Doyle’s disclosure of the decarboxylative cross-coupling of amino acids and aryl bromides (153) in 2014, this field has grown dramatically (Scheme 2.5a).60 MacMillan and coworkers have published decarboxylative alkenylation and alkylation methods with alkenyl (155) and alkyl halides (157), respectively (Scheme 2.5b,c).58,61 Similarly, they disclosed a decarboxylative Giesetype reaction using a variety of electron-poor alkenes (159) (Scheme 2.5d).63 Additional studies in this field have allowed for decarboxylative functionalization with a wide variety of cross-coupling partners. These methods often require stabilized radical intermediates and can be challenging to optimize for individual substrates. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 125 Scheme 2.5 Direct photochemical decarboxylative cross-couplings a. arylation - MacMillan and Doyle, 2014 [Ir] (1%) NiCl2•dme (10%) dtbbpy (15%) O Br OH + R2 Cs2CO3 DMF, 23 ºC 26 W CFL or blue LEDs (60–93% yield) X 152 R2 153 [Ir] = Ir[dF(CF3)ppy]2(dtbbpy)PF6 X 154 b. alkenylation - Macmillan, 2015 O [Ir] (1%) NiCl2•dtbbpy (2%) R3 OH Br/I + X R1 R2 R1 DBU DMSO, 25 ºC 34 W blue LED (60–96% yield) R2 152 155 [Ir] = Ir[dF(Me)ppy]2(dtbbpy)PF6 R3 X 156 c. alkylation - MacMillan, 2016 [Ir] (2%) NiCl2•dme (10%) 4,4’-dOMe-bpy (10%) O + OH R Br R K2CO3, H2O MeCN blue LEDS (40–96% yield) X 157 152 [Ir] = Ir[dF(CF3)ppy]2(dtbbpy)PF6 X 158 d. Giese - Macmillan, 2014 O [Ir] (1%) K2HPO4 R2 OH + EWG X R1 152 159 R1 EWG DMF 26 W CFL or blue LEDs (57–97% yield) R2 X 160 [Ir] = Ir[dF(CF3)ppy]2(dtbbpy)PF6 Scheme 2.6 Photochemical decarboxylative cross-couplings of redox-active esters a. alkylation - Overman, 2015 O Me + N O Ru(bpy)3(PF6)2 (1%) 164 (1.5 equiv) R2 O Me R3 R1 EtO2C R3 i-Pr2NEt (2.2 equiv) R2 CH2Cl2 blue LEDs 162 163 (59–85% yield) these conditions also work with allyl and alkenyl halides Me R1 O 161 + O R3 R3 O R1 N O X [Ir] (2%) X TFA (2 equiv) DMA blue LEDs (50–90% yield) N R2 N H 164 b. Minisci - Shang and Fu, 2017 O CO2Et H 165 166 [Ir] = Ir[dF(CF3)ppy]2(dtbbpy)PF6 R1 N R2 167 c. borylation - Aggarwal, 2017 O R1 R2 O Me 169 (1.25 equiv) DMA, blue LEDs O N O R3 168 then pinacol, NEt3 (29–92% yield) O R1 R2 B R3 Me Me O 170 Me O O B B O O B2cat2 (169) Me Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 126 In addition to oxidative decarboxylation of carboxylic acids through photoredox chemistry, activated carboxylic acids such as NHP esters can undergo fragmentation through single electron reduction from a photocatalyst to afford a phthalimide anion and free alkyl radicals, which can then engage in further reactivity (Scheme 2.6).64–69 Overman has demonstrated that this method is effective for forming all-carbon quaternary centers through Giese-type coupling of tertiary NHP esters 161 with alkenes, as well as allyl and alkenyl halides, in the presence of a Hantzch ester (164) reductant using a ruthenium photocatalyst (Scheme 2.6a).66 Fu and Shang disclosed a photochemical Minisci-type reaction with NHP esters and a variety of nitrogen-containing heterocycles (166) using an iridium photocatalyst to afford heteroarylated products 167 (Scheme 2.6b).68 In 2017, Aggarwal and coworkers published a photocatalyst-free, decarboxylative borylation of NHP esters that utilized B2cat2 (169) as a photosensitizer as well as a borylating agent, obviating the need for a traditional photocatalyst (Scheme 2.6c).69 This type of reactivity can be challenging, however, as there is no catalyst to mediate the reaction upon radical formation. Redox active esters can also be directly cleaved without the use of photochemistry through nickel catalysis, allowing for controlled entry of these radical intermediates into the catalytic cycle (Scheme 2.7).45,70–80 In 2016, Baran and coworkers found that NHP esters (171) can be cross coupled with aryl zinc reagents (172) in a Negishi-type cross coupling to afford arylated products 173 (Scheme 2.7a).79 Later in 2016 and 2017, it was found that this reactivity translates to both alkenyl (175) and alkyl (178) zinc species when using more activated tetra-chloro-N-hydroxyphthalimide(TCNHP) esters (175, 177) to afford alkenylated (176) and alkylated (179) products, respectively (Scheme 2.7b,c).70,74 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 127 Scheme 2.7 Ni-mediated decarboxylative cross-couplings of redox-active esters a. arylation - Baran, 2016 Ar–ZnCl•LiCl O 172 (3.0 equiv) NiCl2•dme (20%) O R1 O N bpy or dtbbpy (40%) DMA/THF 25 ºC (40–89% yield) O R2 171 b. alkenylation - Baran, 2017 Cl Cl O R1 R2 O N R4 R5 bpy (10%), DMA/THF Cl (30–90% yield) O R3 R6 175 (2.0 equiv) NiCl2(acac)2•xH2O (10%) Cl O ClZn R3 R1 R2 173 R4 R5 R1 R2 R3 174 c. alkylation - Baran, 2016 Cl 176 O O R2 R3 Cl Cl O R1 N Cl O 177 R6 Zn R3 178 (2.0 equiv) NiCl2•dme (20%) bpy or dtbbpy (40%) DMA/THF 25 ºC (40–89% yield) R1 R3 R2 179 In addition to Negishi-type cross couplings, the Baran group has applied this strategy to a variety of organometallic cross coupling partners and other transition metal catalysts.78,81,82 In addition to traditional cross coupling, NHP esters can also be reductively cross coupled with a variety of halide cross-coupling partners in the presence of a nickel catalyst and a stoichiometric amount of a terminal reductant (Scheme 2.8). Weix and coworkers have shown that this strategy can be used for the arylation and alkynlation of NHP esters using zinc or manganese dust as the terminal reductant (Scheme 2.8a,b).83–85 Our lab also has a particular interest in enantioselective Ni-mediated reductive cross coupling, and in 2017, we showed that benzylic NHP esters (186) can be enantioselectively cross-coupled with alkenyl halides (187) to afford enantioenriched products (189) in good yield and good ee using tetrakis(N,N,-dimethylamino)ethylene (TDAE) (190) as the homogenous, terminal reductant (Scheme 2.8c).86 To the best of our knowledge, this work demonstrated the first example of NHP esters in enantioselective cross-coupling reactions. 128 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A Scheme 2.8 Reductive decarboxylative cross-couplings of redox-active esters a. arylation - Weix, 2016 R1 O I O R1 O NiBr2•dtbbpy (7%) + N R3 180 R3 Zn0 (2.0 equiv) DMA, rt (41–97 % yield) O R2 R2 181 182 b. alkynlation - Weix, 2017 Br O NiBr2•dtbbpy (10%) O R1 O + N O R3 183 1.5 equiv 184 R2 R3 R1 Mn0 (3.0 equiv) LiBr (1.0 equiv) NMP, rt (41–95 % yield) R2 185 c. enantioselective alkenylation - Reisman, 2017 O O N O O R1 O N + O R2 Ni Br 186 188 (10%) 190 (1.5 equiv) Br R3 N Br R1 R3 NaI (0.5 equiv) TMSBr (1.0 equiv) DMA, –7 ºC (43–91% yield, 82–98% ee) 187 R2 189 Me2N NMe2 Me2N NMe2 TDAE (190) 2.4 DIVERSIFICATION OF ENANTIOENRICHED CYCLOBUTANES Scheme 2.9 Carboxylic acid synthesis I O Me Me Me N H 6 (2.4 mmol) N 88d (2.0 equiv) Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) TBME, 90 ºC (85% yield) O Me Me O N H N NaOH, EtOH 130 °C (>99% yield) 89d Me Me Me OH 191 Me We next prepared to investigate a variety of decarboxylative cross-coupling reactions. Tolyl substrate 88d was chosen due to its high yield and scalability for the C–H activation. Gratifyingly, simple base-mediated cleavage of the 8-aminoquinolinamide directing group afforded trans carboxylic acid 191 in excellent yields (Scheme 2.9).87 With copious amounts of acid 191 in hand, we set out to derivatize this compound using known decarboxylative methods to synthesize a library of enantioenriched trans cyclobutanes. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 129 Figure 2.4 Direct decarboxylative cross-coupling challenges a. O Me Me Me OH entry scale O O 192 (1 equiv) [Ir] (1 mol%) Me Me Me base, DMF blue LEDs 191 193 Me Me O Me Me % yield 15 mg K2HPO4 13 2 10 mg Cs2CO3 63 3 22 mg Cs2CO3 20 4 44 mg Cs2CO3 10 5 22 mg Cs2CO3 32* *freeze-pump-thaw, 2.5 equiv MVK [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 O b. base 1 O Me 192 (1 equiv) [Ir] (1 mol %) OH Me Me K2HPO4, DMF blue LEDs (52% yield) O 194 1.76 mmol scale Me O 195 c. Br Me Me OH 191 Ph 196 (1 equiv) [Ir] (2 mol %) NiCl2•dme (10 mol %) dtbbpy (10 mol %) Cs2CO3, H2O, DMF blue LEDs O Me O Me Me Ph Me 197 not observed Me Me Ph O Me 198 quantitative Initially, several direct decarboxylation methods of free carboxylic acid 191 were attempted. Unfortunately, there were a multitude of reproducibility and scalability issues. For example, a photochemical, decarboxylative Giese reaction with methyl vinyl ketone (MVK) (192) was attempted on tolyl carboxylic acid 191, and, despite promising yields on 10 mg scale using Cs2CO3 (Figure 2.4a, entry 2), increasing the scale to 20 and 40 mg drastically decreased the yield of the desired product (entries 3, 4).63 Even rigorous deoxygenation conditions afforded only a 12% recovery in yield (entry 5). Interestingly, this reaction afforded product 195 in good yields on up to 1.7 mmol scale using furan substrate 194 with K2HPO4 instead of tolyl-substituted acid 191 (Figure 2.4b). Attempts at a decarboxylative alkylation reaction only afforded esterified product 198 (Figure 2.4c).61 Due to these irreproducibility issues and challenges with a variety of direct, 130 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A photochemical decarboxylation methods,51,52,58,60 we chose to explore decarboxylative methods utilizing activated carboxylic acids. Scheme 2.10 Negishi-type decarboxylative cross-couplings of redox-active esters Cl Cl a. Cl O O O Me Me 191 N Me Me NHPI EDC•HCl DMAP CH2Cl2 (82% yield) OH O Me 199 O O Me Me O Me O TCNHPI EDC•HCl DMAP CH2Cl2 (34% yield) OH Me Me Me 191 200 Cl N O O Me O b. Me Me NHP MeO ZnCl•LiCl NiCl2•dme (20 mol %) dtbbpy (40 mol %) Me Me OMe + DMF/THF (2:3) (75% yield) 199 Me 202 201 (3.0 equiv) c. Me Cl Cl Cl O O Me Me Zn Cl N O O Ph 2 (2.0 equiv) NiCl2•dme (20 mol %) dtbbpy (40 mol %) Me Me Ph inseparable from alkyl homocoupling DMF/THF (34% yield) 200 Me 197 Me Simple EDC-mediated coupling of 191 with N-hydroxyphthalimide afforded NHP ester 199 in good yield (Scheme 2.10a). Similar conditions afforded TCNHP ester 200, albeit in lower yield due to ester hydrolysis on silica gel during purification. We first attempted cross-coupling with organometallic reagents. Pleasingly, decarboxylative Negishi arylation conditions afforded bis-arylated compound 202 in 75% yield on up to 0.20 mmol scale (Scheme 2.10b).79 However, attempts at decarboxylative alkylation with alkyl organozinc afforded only 34% alkylated cyclobutane 197, which was found to be inseparable in our hands from primary alkyl homocoupling byproducts (Scheme 2.10c).70 Next were attempted several Ni-catalyzed reductive cross-coupling reactions using Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 131 Scheme 2.11 Reductive cross-coupling of redox-active esters a. 1-Br-1-octyne (1.5 equiv) NiBr2•dme (10%) dtbbpy (10%) O Me Me NHP Me 199 5 Me Me Me LiBr (1.0 equiv) Mn0 (3.0 equiv) NMP (no product) Me 203 b. OMe O Me Me NHP OMe NiBr2•dme (10%) dtbbpy (10%) Me Me + Zn0, DMA (56% yield) Br Me 191 205 204 (1.5 equiv) Me conditions developed by our lab and the Weix lab. Attempts at reductive alkynylation using 1-bromo-1-octyne with Mn0 as the terminal reductant resulted in no formation of desired product 203 (Scheme 2.11a).83 However, simple reductive alkenylation conditions using stoichiometric Zn0 powder as the terminal reductant afforded the desired alkenylated product 205 in 56% yield on 0.20 mmol scale (Scheme 2.11b).84,86 Scheme 2.12 Photochemical decarboxylative cross-coupling of redox-active esters Me a. O Me Me [Ir] (2 mol %) lepidine (1.5 equiv) NHP Me Me N TFA (2 equiv), DMA blue LEDs (54% yield) 199 Me Me 206 [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 b. O Me Me NHP B2cat2 (169), DMA, blue LEDs; then NEt3, pinacol (58% yield) Me Me Bpin Me Me 199 In addition to Ni-catalyzed 207 decarboxylative methods, photochemical decarboxylative cross-couplings of NHP ester 199 were explored as well. Bis-arylated Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 132 product 206 was formed in 54% yield using Ir-catalyzed, photochemical Minisci-type conditions (Scheme 2.12a).68 Interestingly, catalyst-free borylation conditions utilizing B2cat2 as both the photosensitizer and the coupling partner followed by treatment with pinacol and base afforded borylated product 207 in 58% yield (Scheme 2.12b).69 These reactions were applied to furan NHP ester S1 to afford arylated and borylated products in 36% and 47% yields, respectively, demonstrating that this strategy could potentially be applied to provide products with other substitution patterns (Section 2.8.2). Scheme 2.13 Carboxylic acid derivatization a. O Me Me O Me Me OH OH Cu(MeCN)4OTf 4,4’-MeObpy NaBH4, I2 THF, 70 °C (>95% yield) 191 Me Me Me Me ABNO, NMI MeCN, O2 (87% yield) 208 b. 1. (COCl)2, DMF, CH2Cl2 0 to 23 ºC O Me Me OH H 209 Me O Me Me 2. PhB(OH)2 (2 equiv) Pd(PPh3)4 (5 mol %) Cs2CO3 (5 equiv) PhMe, 100 ºC 191 c. Me 1. (COCl)2, DMF, CH2Cl2 0 to 23 ºC O Me Me OH 191 (41%, 2 steps) Me 2. iodocyclohexane (1.5 equiv) NiCl2•dme (5%) dtbbpy (5.5%) Mn0, DMA, 0 ºC (74%, 2 steps) 210 Me O Me Me 211 Me Modifications to the carboxylic acid itself were attempted as well. Simple borane reduction conditions afforded alcohol 208 in >95% crude yield (Scheme 2.13a). Stahl oxidation conditions were successfully applied, yielding aldehyde 209 in 87% yield, though a pure oxygen atmosphere and multiple additions of catalyst solution were required to facilitate full conversion of the starting alcohol.88 Conversion to the acid chloride with oxalyl chloride followed by palladium-catalyzed cross-coupling afforded aryl ketone 210 133 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A in 45% yield over 2 steps (Scheme 2.13b).89 Returning to reductive cross-coupling, it was found that upon conversion to the acid chloride, treatment with NiCl2•dme, di-tertbutylbipyridine (dtbbpy), stoichiometric Mn0, and iodocyclohexane afforded cyclohexyl ketone 211 in 74% yield over two steps (Scheme 2.13c).90 Figure 2.5 Summary of cyclobutane functionalizations Me Me OH ABNO, NMI MeCN, O2 (87% yield) 208 Me NaBH4, I2 THF (>95%) Me Me Cu(MeCN)4OTf 4,4’-MeObpy 209 Me O O Me Me NHP, EDC DMAP CH2Cl2 (82%) OH 191 Br NHP 205 Me [Ir] (2%) lepidine TFA (2 equiv) DMA, blue LEDs (54% yield) Me Cy Me Me NiBr2•dme (10%) dtbbpy (10%) MeO O OMe Zn0, DMA (56% yield) 199 Me Me Me OMe 204 Me Me 1. (COCl)2, DMF, CH2Cl2 0 to 23 ºC 2. iodocyclohexane (1.5 equiv) NiCl2•dme (5%) dtbbpy (5.5%) Mn0, DMA, 0 ºC (74%, 2 steps) H Me Me 201 Me Me NiCl2•glyme (20 mol %) dtbbpy (40 mol %) DMF/THF (2:3) (75% yield) B2cat2, DMA blue LEDs then NEt3, pinacol (58% yield) N Me ZnCl•LiCl OMe 202 Me Me Me Bpin 207 206 211 Me Me Me A summary of all successful cyclobutane functionalizations discussed is detailed in Figure 2.5. Notably, all decarboxylative cross-coupling reactions described here afforded the desired products with perfect trans selectivity. These data, in conjugation with our scope for the C–H arylation of cyclobutamide 6, demonstrate the feasibility of a modular approach to trans cyclobutanes starting from a common, enantioenriched intermediate. We next hoped to demonstrate the utility of this strategy by applying it to the total synthesis of a natural product. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 134 2.5 TOTAL SYNTHESIS OF (+)-RUMPHELLAONE A 2.5.1 Background and Biosynthesis Figure 2.6 A modular approach towards (+)-rumphellaone A Me Me O O O N H C–H arylation N + 6 I Me Me X Me Me decarboxylative coupling Me H O O O Me 212 O 4 (+)-rumphellaone A 213 As this modular approach towards enantioenriched, trans-substituted cyclobutanes was being developed, we sought to apply this strategy towards the total synthesis of a natural product. (+)-Rumphellaone A (4), a 4,5-seco-caryophyllane sesquiterpenoid isolated in 2010 from the gorgonian coral Rumphella antipathies, was chosen as the target due to its trans-cyclobutane core and gem-dimethyl motif (Figure 2.6).7 (+)-Rumphellaone A possesses anti-proliferative activity against human T-cell acute lymphoblastic leukemia tumor cells and contains a γ-lactone functionality. Scheme 2.14 Proposed biosynthesis of (+)-rumphellaone A Me Me H Me epoxidation Me Me H Me [H] O H Me Me O Me Me 215 O H Me OH 217 216 O Me Me H [O] OH H Me OH H β-Caryophyllene (214) Me H Baeyer-Villiger oxidation Me Me H hydrolysis O O H Me OH 218 lactonization oxidation H+ Me Me Me H O Me O 4 (+)-rumphellaone A It is thought that (+)-rumphellaone A and its related compounds arise biosynthetically from β-caryophyllene (214).7 It was hypothesized that after bisepoxidation Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 135 of 214, a series of reductions would deliver diol 216, which could then be oxidized to provide ketone 217. Baeyer-Villiger-type oxidation of the ketone would lead to formation of the macrocyclic ester (218), and hydrolysis and secondary alcohol oxidation would afford the natural product (4). 2.5.2 Previous Syntheses Scheme 2.15 Kuwahara’s enantioselective synthesis of (+)-rumphellaone A Me Me OH Me 4 steps Me CN Me CO2Et 219 2 steps CN H 8 222 2 steps Me Me O O MeO P MeO Me Me OH OTMS OTBS OTBS OH 221 O 2. NaHMDS, PhMe, reflux (86% yield, >20:1 dr 2 steps) O Me Me Me 224 223 1. TBSCl, imidazole (64% yield 92% ee, 2 steps) CHO CN Me 2. L-(+)-DIPT, Ti(i-PrO)4 TBHP, CH2Cl2 220 Me Me Me Me 1. DIBAL, CH2Cl2 Me 3 steps Me NaH, DME OTMS (84% yield) 225 OTBS O Me Me O Me Me OH 226 CO2Et 1. H2, Pd/C 2. CSA (64% yield, 2 steps) Me Me Me H 8 Me 4 18 steps O O There have been several total syntheses of (+)-rumphellaone A since its isolation in 2010. In 2012, the Kuwahara lab published the first enantioselective total synthesis of (+)-rumphellaone A.91,92 a,b-unsaturated ester 220 was synthesized in four steps from alcohol 219 (two steps from commercially available starting materials). Reduction followed by Sharpless asymmetric epoxidation afforded enantioenriched epoxide 221, setting the stereochemistry at the particularly challenging C8 carbon. Silylation followed by epoxy nitrile cyclization of 221 afforded the trans-cyclobutane core (222) of rumphellaone A in good yield and diastereoselectivity. Alcohol protection and nitrile reduction afforded aldehyde 223, which was elaborated to a,b-unsaturated ketone 225 via Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 136 a Horner-Wadsworth Emmons olefination. Further oxidations and olefinations yielded ester 226, which, upon hydrogenation and treatment with acid, cyclized to form (+)rumphellaone A, completing the 18-step total synthesis. Scheme 2.16 Echavarren’s enantioselective synthesis of (+)-rumphellaone A Me Me Me Me Ph O + 228 O Me Me 227 230 (5 mol %) NaBAr4F (5 mol %) 1,2-C6H4Cl2 –20 ºC, 72 h Me Me (70% yield, 82% ee) Me O Me Me O Ar2 Me Me 2. RuO4 O Me Me Me CO2H O 231 232 H Me HO 233 Me Ti(i-PrO)4(30 mol %) (S)-BINOL (30 mol %) O O O Me Me Me P Ar 1 Ar1 i-PrOH, tetraallyltin CH2Cl2, 23 ºC, 18 h (80% yield, 9:1 dr) Me (69% yield) (67% yield, 2 steps) Fe 230 O 4 steps AuCl Ar1 = 3,5-Me2C6H3 Ar2 = 1-Napht 229 Ph O 1. H2, Pd/C ClAu Ar2 P Me2S•BH3 then H2CrO4 Me Me Me Et2O, 13 h –78 to 100 ºC (53% yield) H O Me O 4 10 steps Echavarren and coworkers have published two total syntheses of (+)-rumphellaone A, both utilizing a [2+2] cycloaddition strategy to afford the core of the natural product.93,32 Their most recent synthesis in 2017 utilized an enantioselective [2+2] cycloaddition to afford cyclobutene 229 in 70% yield and 82% ee (Scheme 2.16). From there, it took 6 steps to elaborate to trans-cyclobutane 232. In order to set the C8 stereocenter, it was found that utilization of a chiral BINOL ligand with Ti(i-PrO)4 allowed for the diastereoselective allylation of ketone 232 to afford tertiary alcohol 233 in 9:1 dr. Hydroboration-oxidation and cyclization afforded the natural product in 10 steps overall. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 137 2.5.3 Our Strategy: Application of a Modular Approach Scheme 2.17 Retrosynthetic analysis of (+)-rumphellaone A O Me Me Me decarboxylative coupling O O Me Me Me Me X X H H Me O O 235 (+)-rumphellaone A (4) O Me Me O O O Me N H C–H arylation N 213 O Me Me N H O 234 + 6 N I O 212 Having developed a modular strategy towards the synthesis of enantioenriched trans cyclobutanes utilizing two robust methods developed for the total synthesis of (+)psiguadial B, we hoped to apply this approach towards the synthesis of (+)-rumphellaone A (Scheme 2.17). It was thought that the methyl ketone functionality could be installed at a late stage through a decarboxylative cross-coupling. We envisioned that the γ-lactone could be derived from oxidation and methylation of a furan (213), which could be installed through a diastereoselective C–H arylation with known enantioenriched cyclobutamide 6 and furanyl iodide 212.* 2.5.4 C–H Activation Optimization C–H activation with furanyl iodide 212 was first attempted. Iodides 212 and 236 were synthesized according to known literature conditions (Table 2.1, Table 2.2).94,95 Unsubstituted iodofuran 212 performed well on small scale using 30% Pd(OAc)2 and 3 equivalents of 212 (Table 2.1, entry 1). Attempts to lower the equivalents of 212 resulted * An alternative approach using an alkenyl iodide was attempted with Dr. Lauren Chapman and is further detailed in Appendix 4 of her thesis. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 138 Table 2.1 C–H arylation with furan 212 Me O + N H Me O Pd(OAc)2 (30%) Ag2CO3 (1 equiv) O I Me Me N H TBME, 90 ºC 18 h N 6 N O 212 3 equiv 234 entry scale (mg) equiv iodide % yield 1 20 3 70 2 20 2 54 3 200 3 59 4 300 3 55 aReactions run in a pressure flask or a sealed vial with a Teflon cap under air. Yields determined by 1H NMR analysis against an internal standard. in lower yields (entry 2). Similarly, scaling up the reaction to 200 or 300 mg resulted in yields between 50–60% (entries 3 and 4). Notably, substrate 212 required double the catalytic loading of Pd(OAc)2 compared to the standard reaction conditions. Table 2.2 C–H arylation optimization with TMS furan 236 TMS O Me N H Me 6 + Pd(OAc)2 (x%) Ag2CO3 (1 equiv) N O O Me Me N H TBME 18 h O TMS + N O N H Me O I O TMS x equiv 236 TMS 237 238 equiv iodide % yield 237a % yield 238a 237:238 15 2 57 37 1.5:1 15 1.5 84 5 16:1 90 7.5 2 - - 4:1 70 15 2 86 3 29:1 20 70 7.5 2 83 2 42:1 20 70 15 1.5 88 2 44:1 7 100 70 7.5 2 86b trace - 8 100 70 15 1.5 87b 2 44:1 9 300 70 7.5 2 91b trace - 10 400 70 7.5 2 90b - - 2 88b - - entry scale (mg) temp (ºC) cat loading (mol %) 1 20 90 2 20 90 3 20 4 20 5 6 11 600 70 7.5 N aReactions run in a pressure flask or a sealed vial with a Teflon cap under air. Yields determined by 1H NMR analysis against an internal standard. b Isolated yield. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 139 Similarly, TMS iodofuran 236 was submitted to the reaction conditions. However, in addition to 57% yield of the desired product 237, an interesting bisarylation byproduct 238 arising from a second arylation at the β-face methyl was observed in 37% yield on 20 mg scale (Table 2.2, entry 1). This was particularly surprising as no such bisarylation product had been observed for any other substrates subjected to these arylation conditions (Chapter 1, section 1.3). A time course study revealed facile mono arylation (70% NMR yield after 1 hour) with further conversion to the bisarylated product as the reaction progressed (See 2.8.3, Table S1). Additionally, after 1 hour, 7% 238 was present in the reaction mixture. We therefore sought to optimize the reaction conditions to minimize formation of the undesired byproduct. It was found that reducing the temperature to 70 ºC and lowering the catalyst loading to 7.5% afforded the desired product in 88% yield with minimal formation of 238 (entry 6). Alternatively, if instead of reducing the catalyst loading, the amount of TMS furan 236 was reduced to 1.5 equivalents, similar results were observed (entry 5). We chose to move forward with lower catalyst loading. The reaction also scaled well, affording comparable yields of the product with minimal bisarylation on up to 600 mg scale (entries 7, 9–11). Due to the superior reactivity and scalability, TMS furan 236 was chosen for future study. 2.5.5 Directing Group Removal and Functionalization Scheme 2.18 Schwartz reduction and base-mediated epimerization O O Me Me N H N Cp2Zr(H)Cl THF, rt (34–45% yield) O Me Me O H O TMS TMS 237 KOH 239 MeOH (>90% yield) Me Me H O TMS 240 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 140 In order to afford the trans-cyclobutane core of (+)-rumphellaone A, the 8aminoquinoline directing group had to be cleaved and the stereochemistry at the C1 carbon inverted. Early attempts focused on replicating conditions from the synthesis of (+)psiguadial B, namely reductive cleavage of the amide to form aldehyde 239 using Schwartz’s reagent followed by base-mediated epimerization (Scheme 2.18).12,13 Though this process did yield the desired product (240), the amide reduction was low-yielding, the epimerization conditions were irreproducible, and the aldehyde (240) was unstable. Scheme 2.19 Single step directing group removal and epimerization O O Me Me N H N O NaOH Me Me OH EtOH, 130 ºC O (83–97% yield) TMS 237 194 Due to these challenges, alternative methods to remove the quinolinamide directing group were investigated. Pleasingly, simple base-mediated conditions used previously (Scheme 2.9) not only cleaved the directing group, but also facilitated complete epimerization to afford the trans-cyclobutane carboxylic acid (194) in high yields (Scheme 2.19).87 Surprisingly, these conditions resulted in cleavage of the furan TMS group, but it was decided to move forward with 194 due to the high yields and scalability. These reaction conditions increased the overall yield and afforded a substrate primed for direct decarboxylative coupling. Acid-mediated conditions were also attempted, but without success.96 2.5.6 Furan Oxidation and Diastereoselective Methylation Next, we focused on the functionalization of the furan to afford the desired γlactone (241) found in the natural product. This required oxidation and diastereoselective Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 141 Scheme 2.20 Summary of C8 methylation strategies Kuwahara, 2012 Me Me CN 1. DIBAL, CH2Cl2 Me CO2Et 220 Echavarren, 2017 O O Me Me Me Me O Me CN Me 2. L-(+)-DIPT, Ti(Oi-Pr)4 TBHP, CH2Cl2 (64% yield, 92% ee, 2 steps) Ti(i-PrO)4(30 mol %) (S)-BINOL (30 mol %) Me 8 O OH 221 O O Me Me Me H i-PrOH, tetraallyltin CH2Cl2, 23 ºC, 18 h (80% yield, 9:1 dr) 8 Me HO 232 233 Our proposal: Me O Me OH Me 9 8 O oxidation diastereoselective methylation 194 O O Me Me OH Me Me H H O Me 8 241 O Me 8 O O (+)-rumphellaone A (4) methylation of the furan. The diastereoselective methylation was thought to be challenging due to the free rotation around the C8–C9 bond and the unknown orientation of the furan in solution. Indeed, both previous syntheses of (+)-rumphellaone A relied on chiral catalysis to set the C8 stereocenter (Scheme 2.20).32,91–93 We hoped that perhaps the presence of the carboxylic acid could afford some diastereoselectivity through either coordination of a methylating reagent or coordination to a Lewis acid resulting in facial blocking. 2.5.6.1 Cyclopropanation Strategy It was thought that the C8 methyl group could be installed via a cyclopropanation followed by a ring opening. It was predicted that the cyclopropanation would be selective for the more substituted, electron rich alkene, and that the carboxylic acid could afford diastereoselectivity through coordination to a zinc carbenoid generated from diethyl zinc and diiodomethane (CH2I2).97 Unfortunately, only bis-cyclopropanation product 241 was observed (Scheme 2.21). Iodomethyl ester product 242 was observed when excess CH2I2 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 142 Scheme 2.21 Attempts at directed furan cyclopropanation O O Me OH Me O Me OH Me Me Me I O OH Me + CH2Cl2 –10 ºC to rt O O Me Et2Zn CH2I2 O 194 O 241 O 243 not observed 242 was used. Lowering to one equivalent of cyclopropanating reagents led to the formation of biscyclopropanated products and recovered starting material. These results suggested that after the first cyclopropanation, the loss of aromaticity and electron donation from the adjacent oxygen make the second cyclopropanation very facile, resulting in no observable formation of the mono-cyclopropanated product. Milder cyclopropanation conditions afforded no desired reactivity.98 There are select examples of monocyclopropanation of furans in the literature using diazo carbene precursors, but we chose to turn our efforts elsewhere.99–102 2.5.6.2 Titanium-Mediated Diastereoselective Methylation Scheme 2.22 Titanium-mediated diastereoselective methylation of hydroxybutenolides a. Miles, 2007 TBSO HO O O R 254 Ti(i-PrO)3CH3 (3.3 equiv) TBSO DCM, 22 °C (50–87% yield, >20:1 dr) R Me TBSO O O + Me O O R 255 256 b. Besada and Fall, 2012 Ti(i-PrO)3Cl (6 equiv) MeLi (6 equiv) O O OH 257 Me OTBDPS THF, –78 °C to rt (63% yield, 1.7:1 dr) O O Me Me OTBDPS 258 Inherent to our proposed strategy was the need for a diastereoselective addition of the methyl group to the furan or a furan derivative. In 2007, Miles and coworkers published a diastereoselective methylation of γ-hydroxybutenolides (254) using stoichiometric Ti(i- Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 143 PrO)3CH3 (Scheme 2.22a).103 In 2012, Besada and Fall showed that they could generate Ti(i-PrO)3CH3 in situ by prestirring Ti(i-PrO)3Cl and methyllithium (MeLi) to perform a similar methylation of a γ-hydroxybutenolide (257), though with lower diastereoselectivity (Scheme 2.22b).104 It was proposed that these conditions could be applied to our system. Scheme 2.23 Furan oxidation and undesired diastereoselectivity a. furan oxidation O O Me Me OH Me O OH Me NaH2PO4, NaClO2 H t-BuOH/H2O (5:1) (65% yield, 93% pure) O HO 194 O 259 b. titanium methylation O O O OH Ti(i-PrO)3Cl (6 equiv) MeLi (6 equiv) O THF, –78 ºC to rt, 22h (76% yield, >20:1 dr) Me Me H HO O 259 Me Me Me Me OH Me H H O Me 260 O O Me O epi-C8 rumphellaone A (261) compared to published NMR data for (+)-rumphellaone A Gratifyingly, it was found that Pinnick-type oxidation conditions afforded γhydroxybutenolide 259 in 65% yield and 93% purity after column chromatography (Scheme 2.23a).105 Lower purity material could be acquired in about 5% higher yield without chromatography, though we elected to move forward with cleaner material. Carboxylic acid butenolide 259 was investigated as opposed to 250, which contained the ketone functionality, as it was envisioned that the carboxylic acid could act as a directing group. 259 was added to a preformed solution of Ti(i-PrO)3CH3 to afford γ-methylated product 260 in 76% yield and >20:1 dr (Scheme 2.23b). However, upon elaboration to 261, it was found that this methylation favored the undesired diastereomer, as determined by comparing 1H and 13C NMR data with published isolation and synthetic NMR data for (+)-rumphellaone A.7,32,91–93 Despite this disappointing result, we were pleased to find that Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 144 diastereoselective methylation was possible in good yields, despite being the undesired diastereomer. Investigations into reversing the diastereoselectivity were undertaken. Scheme 2.24 Additional methylation attempts a) O O Me OH Me MeLi (3 equiv) H O HO O 259 b) Me Me OH H THF –78 ºC to rt, 21 h (minor product, 2:1 dr) Me Ti(i-PrO)3Cl (6 equiv) MeLi (6 equiv) Me Me O O 260 O O Me OH Me H O HO O OH H THF, –78 ºC to rt, 22h (recovered XX trace conversion) O Me 262 263 O O c) O Me OH Me MeLi (3 equiv) H O HO O 262 THF –78 ºC, 2.5 h (48% yield, 2.6:1 dr) Me Me OH H O Me O 263 Attempts to perform the transformation with only MeLi resulted in poor reactivity for the desired methylation (Scheme 2.24a). Presumably, this is due to competitive 1,4 addition into butenolide 259. Hydrogenated butenolide 262 was therefore submitted to both titanium-mediated and titanium-free reaction conditions (Scheme 2.24b,c). The titanium conditions led to poor conversion, while the MeLi conditions resulted in poor diastereoselectivity. At this point, efforts turned towards screening other Lewis acids that could facilitate this transformation to afford the desired diastereomer. A wide variety of Lewis acids and organometallic reagents were screened in order to find conditions that afforded the desired product with the correct stereochemistry at the C8 carbon (264) (Table 2.3). Previous reaction conditions still afforded the methylated product in the best yield and was the most selective for a single diastereomer, albeit the Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 145 Table 2.3 Lewis acid screen for methylation diastereoselectivity O O Me LA (6 equiv) MeLi (6 equiv) OH Me H O HO O O Me Me Me Me OH CH2Cl2 –78 ºC to rt OH + H H O O Me 259 Me O 264 O 260 dr (264:260)b time (h) entry scale (mg) conditions prestir % yielda 1 50 TiCl(i-PrO)3 LA and MeLi 76 >1:20 21 2 20 CeCl3, MeLi LA and MeLi 33 1:2 21 3 10 CeCl3, MeLic LA and MeLi 13 – 22 4 20 BF3•Et2O, MeLi LA and MeLi 24 1:2 21 5 10 La(i-PrO)3, MeLi LA and MeLi 6 1:1 4.25 6 10 LaCl3, MeLi LA and MeLi 31 1:2 4.25 7 10 Sc(OTf)3, MeLi LA and MeLi 4 1:5 21 8 10 In(OTf)3, MeLi LA and MeLi – – 21 9 10 Ti(i-PrO)4, MeLi LA and MeLi – – 22 10 10 TiCl4, MeLid LA and MeLi 13 4:1 22 11 10 CeCl3, MeLi LA and sm 12 1:2 8.7 12 10 BF3•Et2O, MeLi LA and sm 12 1:2 6 13 10 Ti(i-PrO)4, MeLi LA and sm 10 1:3 22 14 10 MeMgBr – 38 1:3 20 15 10 AlMe3, then MeLi – – – 41 16 10 ZnMe2, then MeLi – – – 41 a,bdetermined by 1H NMR, c3 equiv. reagents, dCH Cl instead of THF 2 2 undesired diastereomer (260) (entry 1). Most Lewis acids resulted in poor yields and diastereoselectivities (entries 2–9, 11–13). Simple methyl Grignard afforded the methylated product in 38% yield, but 1:3 dr (entry 14). Surprisingly, AlMe3 and ZnMe2 were ineffective methylating reagents, even after extensive stirring times (entries 15,16). Prestirring the Lewis acid with the starting material had little effect (entries 11–13). Interestingly, a combination of TiCl4 and MeLi afforded the methylated product in 4:1 dr favoring the desired diastereomer (264), albeit in poor yield (entry 10). Due to the high reactivity of TiCl4 with ethers, this reaction was run in CH2Cl2 instead of THF. These conditions were chosen for further investigation. These conditions proved to be challenging to optimize (Table 2.4). Adjusting the reaction temperature, equivalents of reagents, and reaction setup afforded no improvements Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 146 Table 2.4 TiCl4 and MeLi methylation optimization O O Me TiCl4 (6 equiv) MeLi (24 equiv) OH Me H Me Me OH OH + H DCM, –78 ºC O HO O Me Me H O Me O 259 O O 264 Me entrya scale (mg) equiv TiCl4 equiv MeLi time (h) % yieldb dr (xx:xx)b notes 1 10 6 6 22c 13 1:4 – 6 23c – 1:1.2 – 2 25 6 O 260 3 10 4 4 23c – – – 4 10 6 6 22 trace – kept at –78ºC 5 10 6 6 22c 14 1:2 –40 ºC to rt 6 10 6 6 3 – – 0 ºC 7 10 6 6 27c – – reverse addition 8 10 6 12 6 11 1:2 – 9 10 6 24 5 54 1:1 – 10 30 6 24 2 35 1:3 – 11 35 6 24 4 61 9:1 sm cooled to –78 ºC, dropwise 12 100 6 24 4 46 1:2 sm cooled to –78 ºC, dropwise 13 50 6 24 4 60 9:1 sm cooled to –78 ºC, slow dropwise aReaction set up: TiCl and MeLi prestirred at –78 ºC ~1h. Add xx as a room temperature solution in DCM via 4 cannula, b determined by 1H NMR, creaction allowed to warm to room temerature in yield or dr to the initial hit (entries 1–7). Indeed, upon scaling up the reaction, the dr decreased (entry 2). Finally, it was found that increasing the amount of MeLi to 24 equivalents (a 4:1 ratio of MeLi to TiCl4) significantly increased reactivity, providing the product in 54% yield, albeit with 1:1 dr 264:260 (entry 9). Based on both the stoichiometry of the reagents and the abrupt change in color from brown to blue/green upon addition of the final equivalent of MeLi, this combination presumably forms Ti(CH3)4 in situ. Upon scaling up this reaction from 10 mg to 30 mg again however, the yield decreased and the diastereoselectivity reversed to favor the undesired diastereomer (entry 10). We hypothesized that this could be due to the increased volume of starting material being added to the reaction mixture, which could be warming up the reaction mixture too quickly. Indeed, upon cooling the solution of starting material to –78 ºC in a dry ice/acetone bath as it was added to the Ti(CH3)4 solution via cannula, the reaction not only increased in 147 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A yield, but the dr increased to 9:1 favoring the desired diastereomer (264) (entry 11). This reaction was scaled up to 100 mg, and, unfortunately, the diastereoselectivity again reversed to 1:2 and the yield dropped to 46%. It appeared that the internal temperature was more unstable than suspected. By monitoring the internal temperature of the reaction mixture as the cooled solution of starting material was added, it was found that even with cannula addition of the cooled starting material, the internal temperature could quickly increase if the starting material was added too quickly. To combat this, the reaction was set up on 50 mg scale, and the solution of starting material was added with a narrow cannula over the course of 20 minutes. This minimized internal temperature fluctuations and afforded the desired product in 60% yield and 9:1 dr after purification (entry 13). This method was found to be reproducible and allowed for independent synthesis of both butenolide diastereomers 264 and 260. 2.5.6.3 Discussion of Diastereoselectivity Figure 2.8 Methylation diastereoselectivity H O O Me H O OM Me O Ti O L L CH3 Ti(i-PrO)3CH3 H Me Me OH Ti(CH3)4 H O ligand exchange, directed methylation HO 265 O H OM Me OH O O O Me H O O Me H O O Li O 266 CH3 O Me Me OH O M H Me O (H3C)3Ti 259 O Me Me lithium coord., intermolecular methylation OLi Me H O Me O common intermediate 260 264 The current hypothesis for the diastereoselectivity observed for these reaction conditions hinges on the differences in reactivity between Ti(i-PrO)3CH3 and Ti(CH3)4. It Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 148 is proposed that under both sets of conditions, hydroxybutenolide 259 undergoes ringopening to form the α,β-unsaturated ketone, which can undergo chelation to a metal species as shown in Figure 2.8. Due to the lability of isopropoxide, Ti(i-PrO)3CH3 could undergo ligand exchange with the carboxylate to afford intermediate 265. The titanium species could then deliver the methyl group intramolecularly from the α face of the ketone, affording the undesired diastereomer (260) as observed under these conditions. On the other hand, Ti(CH3)4 would be unlikely to undergo ligand exchange. Instead, the carboxylate could coordinate to Li+ to afford intermediate X266. Ti(CH3)4 could then deliver the methyl group intermolecularly to the β face of the ketone, which would result in the observed, desired diastereomer (264). 2.5.7 Ketone Installation Scheme 2.25 Ketone installation from aldehyde 239 a. O O Me Me H 1. KOH, MeOH TMS 239 b. MeO Me O O P Me OMe 224 TMS 267 NaH, THF (41%, 2 steps) O O Me Me H 1. KOH, MeOH 2. O TMS Ph3P Me Me Me O O 268 Me TMS CH2Cl2, 0–23 ºC (66%, 2 steps) 239 c. O 2. O Me Me 267 O O Me Me H NaOH (cat) O TMS 239 acetone, H2O 70 ºC (6-18%) Me Me Me O TMS 267 With a strategy to access the desired γ-methyl lactone in place, investigations were made into the installation of the methyl ketone. Early investigations into Horner- Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 149 Wadsworth-Emmons olefination of aldehyde 239 resulted in moderate yields of the desired product (267) with irreproducibility issues (Scheme 2.25a).12,13 Upon switching to a commercially available Wittig reagent (268), the desired product could be obtained in higher yields with greater reproducibility (Scheme 2.25b). Attempts were made to combine the aldehyde epimerization and olefination through a base catalyzed aldol reaction, however this resulted in low yields (Scheme 2.25c). Though Wittig conditions afforded 267 in good yield, this procedure required a rigorous one-day, three-step sequence to cleave the directing group, epimerize the aldehyde, and install the ketone. In addition, the α,β unsaturated ketone in 267 would have to undergo hydrogenation to afford the desired product. Due to these restrictions, and in light of the successes with carboxylic acid 194, investigations were turned toward ways to afford the saturated ketone directly through decarboxylative cross coupling. Table 2.5 Photochemical decarboxylative Giese to install the methyl ketone O O Me Me Me OH O 192 (1 equiv) [Ir] (1%) O Me Me Me K2HPO4, DMF blue LEDS 194 O 195 entry scale (mg) % yield notes 1 16 31 – 2 80 29 – 3 100 40 dried K2HPO4 4 342 52 dried K2HPO4, dist MVK [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 As mentioned previously, several inherent reactivity challenges with direct decarboxylation methods in other aryl cyclobutane systems had been observed, manifesting in low yields and challenges with scalability. However, we were pleased to see promising activity on small scale for a photochemical, decarboxylative Giese reaction of carboxylic acid 194 with methyl vinyl ketone (MVK) (192) using conditions from MacMillan and coworkers (Table 2.5).63 After some optimization, it was found that not Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 150 only could the desired product (195) be obtained in good yield, but that this reaction was scalable (entry 5). In light of this promising and robust reactivity, we sought to apply this reaction to the late-stage intermediates containing the γ-methyl lactone. Scheme 2.26 Final steps towards (+)-rumphellaone A and epi-C8-rumphellaone A O a. OH H2, Pd/C O MeOH (88% yield) H Me Me Me 192 (1 equiv) [Ir] (1%) OH H O Me O 264 O Me O O Me Me O Me Me H K2HPO4, DMF blue LEDS (78% yield) 241 Me O Me O (+)-rumphellaone A (4) O b. O O O Me Me OH H2, Pd/C H O Me 260 O MeOH (quant yield) Me Me Me OH 192 (1 equiv) [Ir] (1%) O K2HPO4, DMF blue LEDS (52% yield) H Me O 263 Me Me Me H O Me O epi-C8-(+)-rumphellaone A (261) Hydrogenation of 264 and 260 under standard hydrogenation conditions was facile, affording γ-methyl lactones 241 and 263 (Scheme 2.26). Gratifyingly, both compounds successfully underwent a photochemical, decarboxylative Giese reaction with MVK to afford (+)-rumphellaone A (4) and epi-C8-(+)-rumphellaone A (261), respectively. This completed our total synthesis of (+)-rumphellaone A. We were pleased to be able to afford both the natural product and its C-8 epimer directly from the corresponding carboxylic acids under photochemical conditions in good yields. 2.6 SUMMARY A robust, enantioselective total synthesis of the natural product (+)-rumphellaone A (4) was completed in 9 steps from commercially available starting materials, making it the shortest synthesis to date (Scheme 2.27).106 Key to our strategy was the application of a modular approach to trans cyclobutanes, which allowed us to quickly access the 151 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A Scheme 2.27 Enantioselective total synthesis of (+)-rumphellaone A O Me N H Me Pd(OAc)2 (7.5 mol %) Me Ag2CO3 (1 equiv) Me TBME, 70 °C (90% yield) N O I 6 TMS 3 steps from commercially 236 available material (2 equiv) N H NaOH, EtOH N O 130 ºC, 18h (96% yield) TMS 237 O Me Me O O OH O NaH2PO4, NaClO2 t-BuOH/H2O (5:1) (65% yield, 93% pure) 194 O Me Me TiCl4 (6 equiv) MeLi (24 equiv) OH H O HO O DCM, –78 ºC (60% yield, 9:1 dr) Me Me OH H O Me 259 O 264 O O Me Me OH H O Me 264 1. H2, Pd/C, MeOH Me Me Me 6 steps from 2. XX (1.5 equiv) H cyclobutamide, [Ir] (1 mol %), K2HPO4 9 steps total O DMF, blue LEDS Me O O (68% yield, 2 steps) [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (+)–rumphellaone A (4) enantioenriched core of (+)-rumphellaone A. Concomitant directing group removal and epimerization allowed us access to key carboxylic acid 194, which enabled diastereoselective installation of the C8 methyl group without the use of a chiral catalyst. Finally, the methyl ketone functionality was installed directly through a photochemical, decarboxylative Giese coupling with methyl vinyl ketone in good yield. This strategy allowed for independent access of both C8 methyl diastereomers of (+)-rumphellaone A. This efficient synthesis demonstrates the efficacy of our modular approach to trans cyclobutanes. 2.7 CONCLUSION In conclusion, a modular strategy towards the synthesis of a library of enantioenriched cyclobutanes was developed, and this strategy was applied toward the enantioselective total synthesis of (+)-rumphellaone A (4). Application of two robust methods developed for the synthesis of (+)-psiguadial B (1) allowed for the development Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 152 Figure 2.10 Summary of work to date Me Me H O CHO H Me O H O OH Me Me CHO Ph 6 + 99% ee 3 steps from commercially available material H N O Me 6 O (+)-rumphellaone A (4) O N H Me OH O α β N H α β (+)-psiguadial B (1) Me Me Me Me C–H arylation N Me Me DG N H decarboxylative coupling Me Me I Ar 88 89 Ar 96 R Ar (54–88% yield) of this strategy.12,13 Enantioenriched cyclobutamide 6 served as a common intermediate, allowing for the synthesis of a broad scope of arylated cis cyclobutanes (Chapter 1). These compounds could then be further functionalized upon directing group removal through a variety of decarboxylative cross-couplings, affording a variety of enantioenriched trans cyclobutanes. The strengths of this strategy include starting from a common, enantioenriched intermediate, as well as two divergence points, allowing for the synthesis of a library of trans cyclobutanes with different substitution at the α and β positions. This strategy was applied towards the total synthesis of (+)-rumphellaone A. The use of a furanyl iodide allowed for the later installation of the distinct γ-lactone moiety, and a photochemical decarboxylative Giese was used to directly form the methyl ketone from the free carboxylic acid. The challenging C8 methyl group was installed diastereoselectively using Ti(CH3)4, marking the first time that this methyl group has been installed synthetically without the use of a chiral catalyst. Our strategy led to the shortest synthesis of (+)-rumphellaone A to date, affording the product in 9 steps from commercially available starting materials; 6 steps from known cyclobutamide 6. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 153 2.8 EXPERIMENTAL SECTION 2.8.1 Materials and methods Unless otherwise stated, reactions were performed under a nitrogen atmosphere using freshly dried solvents. Methylene chloride (CH2Cl2), diethyl ether (Et2O), tetrahydrofuran (THF), 1,4-dioxane, tert-butyl methyl ether (TBME), and toluene (PhMe) were dried by passing through activated alumina columns. Methanol (MeOH) was distilled over calcium hydride. Acetonitrile (MeCN), tert-butanol (t-BuOH), anhydrous N,N-dimethylformamide (DMF), anhydrous N,N-dimethylacetamide (DMA), chloroform (CHCl3), and absolute ethanol (EtOH) were used as received from Fisher Scientific. Methyl vinyl ketone was dried over K2CO3 and CaCl2 and then distilled immediately prior to use. K2HPO4 was flame-dried under vacuum and dried at 0.200 Torr overnight and stored in a dessicator. Aryl iodides were purchased from Sigma-Aldrich or Combi-Blocks or prepared according to literature procedures. NiBr2•dme and NiCl2•dme were purchased from Strem and stored in a N2-filled glovebox. Zinc dust and Pd(OAc)2 were purchased from Strem and stored in a dessicator. Ir[dF(CF3)ppy]2(dtbbpy)PF6 was purchased from Oakwood chemicals and used as received. Pd(PPh3)4 and Cs2CO3 were purchased from Sigma-Aldrich and stored in a N2-filled glovebox. All other commercially obtained reagents were purchased from Sigma-Aldrich and used as received unless specifically indicated. Photochemical reactions were conducted using either Kessil A160WE blue LED lamps positioned 3–6 cm from the reactions using a computer fan to keep the reactions at ambient temperature, or 12W blue LED strips lining a beaker wrapped in aluminum foil. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm). Silica gel and basic alumina column chromatography was performed as described by Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 154 Still et al. (W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.) using silica gel (particle size 0.032–0.063) purchased from Silicycle and aluminum oxide (activated, basic, Brockmann I, 58 Å pore size, powder) purchased from Sigma-Aldrich. 1H and 13C NMR were recorded on a Varian Inova 500 (at 500 MHz and 125 MHz, respectively) or a Bruker Avance III HD with Prodigy cyroprobe (at 400 MHz and 101 MHz, respectively). 19F NMR spectra were recorded on a Varian Inova 400 (at 376 MHz). NMR data is reported relative to internal chloroform (1H, δ = 7.26, 13C, δ = 77.2) or to internal methanol (1H, δ = 3.31, 13 C, δ = 49.0) and PhCF3 (19F, δ = –63.7). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using either an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM) ionization mode. Specific optical rotations were recorded on a Jasco P-2000 polarimeter using a 100 mm cell. Abbreviations used: Et2O – diethyl ether; CH2Cl2 – methylene chloride; PhMe – toluene; EtOAc – ethyl acetate; THF – tetrahydrofuran; t-BuOH – tert-butanol; CHCl3 – chloroform; MeCN – acetonitrile; DMF – N,N-dimethylformamide; DMA – N,Ndimethylacetamide; dtbbpy – 4,4’-ditertbutylbipyridine; dme – 1,2-dimethoxyethane; TBME – tert-butyl methyl ether; ABNO – 9-azabicyclo[3.3.1]nonane N-oxyl. 155 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 2.8.2 Carboxylic Acid Derivatization Large-Scale Synthesis of 89d O I Me N H Me + N Me 6 4-iodotoluene (88d) (2 equiv) O Pd(OAc)2 (15 mol %) Ag2CO3 (1 equiv) TBME, 90 °C, 18h Me N H Me (85% yield) N 89d Me A 48 mL pressure flask was charged with cyclobutamide 6 (608 mg, 2.39 mmol, 1.00 equiv), Ag2CO3 (659 mg, 2.39 mmol, 1.00 equiv), and Pd(OAc)2 (80.5 mg, 0.358 mmol, 15 mol%) followed by 4-iodotoluene (88d) (1.04 g, 4.78 mmol, 2.00 equiv). The solids were suspended in TBME (12 mL, 0.2 M). The vessel was sealed, placed in a preheated oil bath (90 ºC), and allowed to stir for 18 h. The reaction mixture was cooled to room temperature, diluted with CH2Cl2, and filtered through a 40 g celite plug with approx. 150 mL CH2Cl2. The solvent was removed in vacuo, and the crude oil was purified by silica gel flash chromatography (10 → 15% EtOAc/hexanes) to afford 89d as a white solid (700. mg, 85% yield). (See ch 1 for full characterization) Hydrolysis: Preparation of 19187 O O Me Me Me N H N NaOH (15 equiv) OH Me EtOH, 130 °C (>99%) 89d 191 Me Me A 48 mL pressure flask was charged with cis-cyclobutamide 89d (693 mg, 2.01 mmol, 1.00 equiv), sodium hydroxide (1.21 g, 30.2 mmol, 15 equiv), and absolute ethanol Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 156 (8.5 mL, 0.24 M). The flask was sealed and placed in a pre-heated oil bath (130 ºC) and stirred for 18 h. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude residue was diluted with 1 M aq HCl (38 mL) and EtOAc (38 mL). The organic and aqueous layers were separated, and the organic layer was washed with 1 M HCl (2 x 38 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude reddish solid was purified by silica gel flash chromatography (15 → 20% EtOAc/hexanes) to afford 191 as an off-white solid (443 mg, >99% yield). Rf = 0.31 (silica gel, 20% EtOAc/Hexanes, p-anisaldehyde) [α]D25 = +123.6° (c = 0.28, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.13 (d, J = 1.1 Hz, 4H), 3.74 (q, J = 9.8 Hz, 1H), 2.91 (dd, J = 10.0, 0.8 Hz, 1H), 2.32 (s, 3H), 2.11 (ddd, J = 10.9, 8.9, 0.9 Hz, 1H), 1.95 (t, J = 10.5 Hz, 1H), 1.29 (s, 3H), 1.25 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 178.8, 140.7, 135.9, 129.2, 126.6, 55.2, 39.4, 36.6, 35.1, 30.6, 23.6, 21.2. FTIR (NaCl, thin film, cm-1): 3021, 2957, 2927, 2867, 2731, 2647,1699, 1516, 1464, 1421 1370, 1281, 1238, 1162 1118, 937, 806, 716. HRMS (ESI-TOF, m/z): calc’d for C14H22NO2 [M+NH4]+: 236.1645; found: 236.1645. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 157 Preparation of 195: Photochemical Giese with MVK63 O O O Me Me OH Me 192 (1 equiv) Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1%) O 194 Me Me Me K2HPO4, DMF blue LEDs (52% yield) O 195 A 100 mL flame-dried round bottom flask was charged with carboxylic acid 194 (342 mg, 1.76 mmol, 1.00 equiv), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (19.7 mg, 0.0176 mmol, 0.01 equiv), and K2HPO4 (368 mg, 1.76 mmol, 1.00 equiv). The flask was evacuated and backfilled with N2 three times. DMF (17.6 mL, 0.1 M) and freshly distilled methyl vinyl ketone (144 µL, 1.76 mmol, 1. equiv) were then added, and the reaction mixture was sparged with Ar for 5 minutes. The reaction flask was placed about 5 cm from a 34W blue LED lamp and was allowed to stir at room temperature under N2. After 42 h, the reaction was quenched with sat aq NaHCO3 and extracted with EtOAc (75 mL x 3). The combined organics were then dried with MgSO4, filtered, and concentrated in vacuo to afford the product as a crude oil, which was then purified by silica gel flash chromatography (3 → 10% EtOAc/hexanes) to afford 195 as a white solid (201 mg, 52% yield). Rf = 0.79 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +57.8° (c = 1.07, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.30 (dd, J = 1.8, 0.9 Hz, 1H), 6.27 (dd, J = 3.1, 1.9 Hz, 1H), 5.97 (dt, J = 3.2, 0.7 Hz, 1H), 2.97 (td, J = 9.6, 8.5 Hz, 1H), 2.41 – 2.21 (m, 2H), 2.09 – 1.97 (m, 4H), 1.93 (ddd, J = 10.7, 8.5, 0.7 Hz, 1H), 1.88 – 1.79 (m, 1H), 1.74 – 1.59 (m, 2H), 1.11 (s, 3H), 1.08 (s, 3H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 13 158 C NMR (101 MHz, CDCl3): δ 209.1, 158.9, 140.9, 110.3, 104.0, 50.4, 41.5, 39.0, 34.6, 34.3, 30.6, 30.1, 24.2, 22.3. FTIR (NaCl, thin film, cm-1): 3114, 2953, 2933, 2863, 1717, 1593, 1506, 1451, 1411, 1368, 1360, 1235, 1159, 1150, 1009, 799, 729. HRMS (ESI-TOF, m/z): calc’d for C14H20O2Na [M+Na]+: 243.1356; found: 243.1359. O O O Me Me Me OH 192 (1 equiv) [Ir] (1 mol%) Me Me Me base, DMF blue LEDs 191 193 Me base % yield 1 15 mg K2HPO4 13 2 10 mg Cs2CO3 63 3 22 mg Cs2CO3 20 4 44 mg Cs2CO3 10 5 22 mg Cs2CO3 32* *freeze-pump-thaw, 2.5 equiv MVK [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 An analogous procedure was used for the investigation of the O Me Me Me entry scale Me photochemical Giese of 191 with MVK to form 193. This reaction was challenging to scale. Me 1 H NMR (400 MHz, Chloroform-d) δ 7.17 – 7.05 (m, 4H), 2.92 (td, J = 9.8, 8.5 Hz, 1H), 2.32 (s, 3H), 2.28 – 2.20 (m, 2H), 2.04 – 1.90 (m, 5H), 1.79 – 1.63 (m, 3H), 1.13 (s, 3H), 1.12 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 209.16, 142.16, 135.54, 129.13, 126.93, 51.96, 41.81, 41.44, 41.33, 34.00, 30.95, 30.02, 24.68, 22.43, 21.14. 159 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A Undesired Formation of 19861 (CRL-2-152) Br Me Me OH 191 Ph 196 (1 equiv) [Ir] (2 mol %) NiCl2•dme (10 mol %) dtbbpy (10 mol %) Cs2CO3, H2O, DMF blue LEDs O Me O Me Me Ph Me 197 not observed Me Me Ph O Me 198 quantitative A flame-dried 25 mL round bottom flask was charged with carboxylic acid 191 (66 mg, 0.3 mmol, 1 equiv), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (6.7 mg, 0.006 mmol, 0.02 equiv), NiCl2•dme (6.6 mg, 0.030 mmol, 0.10 equiv), dtbbpy (8.1 mg, 0.030 mmol, 0.10 equiv), and Cs2CO3 (293 mg, 0.900 mmol, 3.00 equiv). Sealed with a septa cap and tape. The flask was evacuated and backfilled with N2 x 3. DMF (6.0 mL, 0.05 M), H2O (81 μL, 4.50 mmol, 15 equiv), and 1-bromo-3-phenyl propane (60 mg, 0.300 mmol, 1.0 equiv) were then added. Sparged with argon for about 20 minutes at 0 ºC and placed between 2 blue LEDs (~5 cm each). Let stir at room temperature overnight. Once the reaction was complete, the reaction mixture was diluted with sat aq NH4Cl and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc x 3. The combined organic layers were washed with aq. 1.0 M LiCl, dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography, 2.5–5% EtOAc/hexanes to afford ester 198 as a white solid. (88.0 mg, 87% yield) 1 H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.27 (m, 2H), 7.23 – 7.16 (m, 3H), 7.16 – 7.09 (m, 4H), 4.20 – 4.04 (m, 2H), 3.78 (q, J = 9.7 Hz, 1H), 2.86 (dd, J = 9.9, 0.8 Hz, 1H), 2.74 – 2.61 (m, 2H), 2.32 (s, 3H), 2.10 (ddd, J = 10.7, 8.9, 0.9 Hz, 1H), 2.01 – 1.90 (m, 3H), 1.29 (s, 3H), 1.19 (s, 3H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 13 160 C NMR (101 MHz, CDCl3) δ 172.86, 141.36, 141.07, 135.79, 129.13, 128.58, 128.54, 126.62, 126.14, 63.57, 55.49, 39.35, 36.38, 35.25, 32.43, 30.70, 30.64, 23.74, 21.16. Preparation of NHP Ester 199 (CRL-2-157) O Me O O OH Me Me N-hydroxyphthalimide N O Me O DMAP, EDC•HCl 191 Me (78% yield) 199 Me A 20 mL vial was charged with carboxylic acid 191 (208.9 mg, 0.957 mmol, 1.00 equiv), N-hydroxyphthalimide (156.1 mg, 0.957 mmol, 1.00 equiv), and 4dimethylaminopyridine (11.7 mg, 0.096 mmol, 0.10 equiv). The vial was sealed with a rubber septum and evacuated and backfilled with N2 three times. The solids were dissolved in CH2Cl2 (4 mL), and then EDC•HCl (201.8 mg, 1.05 mmol, 1.10 equiv) was added as a slurry in CH2Cl2 (1.3 mL). The reaction mixture was allowed to stir for 23 hours at room temperature. The reaction mixture was then transferred to a flask containing EtOAc (50 mL), and the resulting solids were removed by filtration. The filtrate was concentrated in vacuo and the crude oil was purified by silica gel flash chromatography (15 → 40% EtOAc/hexanes) to afford 199 as a white solid (272.8 mg, 78% yield). Rf = 0.46 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +100.5° (c = 0.42, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.94 – 7.83 (m, 2H), 7.83 – 7.73 (m, 2H), 7.14 (s, 4H), 3.87 (q, J = 9.8 Hz, 1H), 3.21 (dd, J = 9.9, 0.9 Hz, 1H), 2.33 (s, 3H), 2.20 (ddd, J = 10.8, 8.9, 0.9 Hz, 1H), 2.08 (t, J = 10.5 Hz, 1H), 1.42 (s, 3H), 1.39 (s, 3H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 13 161 C NMR (101 MHz, CDCl3): δ 168.9, 162.2, 139.7, 136.3, 134.8, 129.3, 129.1, 126.5, 124.0, 52.5, 39.6, 37.5, 35.3, 30.5, 23.7, 21.2. FTIR (NaCl, thin film, cm-1): 3520, 3022, 2959, 2927, 2868, 1808, 1794, 1745, 1615, 1516, 1467, 1368, 1274, 1186, 1132, 1081, 1016, 972, 878, 811, 786, 696. HRMS (ESI-TOF, m/z): calc’d for C22H21NO4 [M+NH4]+: 381.1809; found: 381.1814. O O Me Me O OH O NHPI EDC•HCl DMAP CH2Cl2 (68% yield) 194 N Me Me O O O S1 An analogous procedure was used for the preparation of furan NHP ester S1. Concentrated the crude material onto celite and purified by silica gel chromatography, 5–20% EtOAc/hexanes to afford S1 (26.4 mg, 68% yield) Rf = 0.32 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) 1 H NMR (300 MHz, Chloroform-d) δ 7.87 (dt, J = 5.4, 2.7 Hz, 2H), 7.78 (dt, J = 5.6, 2.7 Hz, 2H), 7.35 (q, J = 1.5, 1.0 Hz, 1H), 6.29 (q, J = 2.3, 1.8 Hz, 1H), 6.10 (t, J = 2.6 Hz, 1H), 3.84 (qd, J = 9.6, 2.0 Hz, 1H), 3.41 (dd, J = 9.6, 2.0 Hz, 1H), 2.15 (ddt, J = 18.1, 11.1, 8.8 Hz, 2H), 1.42 (d, J = 2.0 Hz, 3H), 1.38 (d, J = 2.1 Hz, 3H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 162 Cl Cl Cl O O Me Me TCNHPI EDC•HCl DMAP CH2Cl2 (34% yield) OH O Me Me Me 191 Cl N O 200 O Me An analogous procedure 0.4 mmol scale was used for the preparation of tetrachloro NHP ester 200. Dissolved in DCM, triterated with EtOAc to crash out EDC salts. Filter to remove the salts and concentrate the filtrate. Purify the resulting oil by fast silica plug, 10– 30% EtOAc/hex. Isolated 200 (69 mg, 34% yield) plus 53 mg ~1:1 200/191. Rf = 0.74 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) 1 H NMR (300 MHz, Chloroform-d) δ 7.19 – 7.03 (m, 4H), 3.87 (q, J = 9.8 Hz, 1H), 3.21 (d, J = 9.9 Hz, 1H), 2.34 (d, J = 1.3 Hz, 3H), 2.22 (dd, J = 10.7, 9.1 Hz, 1H), 2.09 (t, J = 10.5 Hz, 1H), 1.41 (dd, J = 7.0, 1.4 Hz, 6H). Negishi Coupling to Form Diaryl Cyclobutane 20279 O O Me Me MeO 201 N O ZnCl•LiCl O 3 equiv NiCl2•dme (20%) dtbbpy (40%) OMe Me Me DMF/THF (2:3), rt Me 199 Me (75% yield) 202 A 25 mL round bottom flask was charged with 199 (109 mg, 0.300 mmol, 1.00 equiv), NiCl2•dme (13.2 mg, 0.060 mmol, 0.20 equiv), and dtbbpy (32.2 mg, 0.120 mmol, 0.40 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 163 equiv). The flask was sealed with a septum and then evacuated and backfilled with argon three times. DMF was then added (3.2 mL), forming a green solution. Freshly prepared aryl zinc reagent 201 (4.8 mL, 0.90 mmol, 3.0 equiv, 0.19 M in THF) was then added and the solution turned red. The reaction was allowed to stir for 18 h, at which point the reaction was quenched with 1 M HCl (10 mL) and diluted with EtOAc (10 mL). The organic and aqueous layers were separated, and the organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to afford a red oil. The crude material was then purified by silica gel flash chromatography (2.5 → 25% PhMe/hexanes) to afford 202 as a clear oil (63 mg, 75% yield). Rf = 0.77 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +195° (c = 0.42, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.26 – 7.17 (m, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.81 (ddt, J = 7.6, 1.7, 0.9 Hz, 1H), 6.80 – 6.71 (m, 2H), 3.79 (s, 3H), 3.32 (d, J = 10.4 Hz, 1H), 2.30 (s, 3H), 2.16 (ddd, J = 10.3, 8.5, 0.7 Hz, 1H), 1.90 (t, J = 10.1 Hz, 1H), 1.28 (s, 3H), 0.88 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 159.6, 142.8, 142.1, 135.5, 129.1, 129.0, 126.6, 120.0, 113.6, 111.0, 56.7, 55.2, 40.2, 37.4, 37.2, 30.9, 23.3, 21.1. FTIR (NaCl, thin film, cm-1): 3014, 2947, 2859, 1596, 1514, 1490, 1458, 1428, 1371, 1318, 1292, 1252, 1166, 1040, 832, 808, 797, 694. HRMS (ESI-TOF, m/z): calc’d for C15H25O3 [M+H]+: 281.1900; found: 281.1899. 164 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A Attempted Preparation of 197 from 20070 Cl Cl Cl O O Me Me Zn Cl N O O Ph 2 (2.0 equiv) NiCl2•dme (20 mol %) dtbbpy (40 mol %) Me Me Ph DMF/THF (34% yield) 200 Me 197 Me Alkyl zinc species prepared from 1-bromo-3-phenyl propane using known methods. To a 1-dram vial was added 200 (50.1 mg, 0.1 mmol, 1.0 equiv). The vial was evacuated and backfilled with argon x 3. NiCl2•dme (4.4 mg, 0.02 mmol, 20 mol%) and dtbbpy (10.7 mg, 0.040 mmol, 40 mol%) were added as a stock solution in DMF (1.0 mL, 0.1 M). After stirrin for about 5 min, the alkyl zinc reagent (1.54 mL, 0.13 M in THF, 0.200 mmol, 2.00 equiv) was then added and the reaction mixture was allowed to stir overnight. Once complete, the reaction was quenched with 1M HCl. The aqueous layer was extract with EtOAc, and the organic layer was washed with water and saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography, 1–50% EtOAc/hexanes. Fractions containing the product were isolated and repurified by prep TLC (10% EtOAc/hexanes, let run up the place twice). Isolated 19.4 mg 1:2.4 197:primary alkyl homocoupling. Rf = 0.72 (silica gel, 10% EtOAc/Hexanes x 2, UV, p-anisaldehyde, prep plate) 1H NMR (400 MHz, Chloroform-d) δ 7.24 – 7.13 (m, 7H), 7.13 – 7.06 (m, 9H), 7.04 (d, J = 6.1 Hz, 3H), 7.02 – 6.96 (m, 3H), 2.82 (td, J = 9.8, 8.4 Hz, 1H), 2.56 – 2.48 (m, 5H), 2.43 (q, J = 6.9 Hz, 2H), 2.24 (s, 3H), 1.89 (ddd, J = 10.6, 8.5, 0.8 Hz, 1H), 1.64 (t, J = 10.4 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 165 Hz, 1H), 1.58 – 1.48 (m, 5H), 1.47 – 1.34 (m, 3H), 1.31 – 1.25 (m, 5H), 1.05 (s, 3H), 1.01 (s, 3H). Reductive Coupling of NHP Ester 199 and Vinyl Bromide 204: Preparation of 20584,86 Br O O Me MeO N O Me O OMe 204 2 equiv NiBr2•dme (10%) dtbbpy (10%) Me Me Zn0, DMA (56% yield) 199 Me 205 Me A 1-dram vial containing a 2-dram stir bar was charged with NHP ester 199 (75.7 mg, 0.208 mmol, 1.00 equiv) and vinyl bromide 204 (63.9 mg, 0.300 mmol, 1.50 equiv). A separate ½-dram vial containing a stir bar was charged with dtbbpy (5.4 mg, 0.020 mmol, 0.10 equiv). Both vials were brought into a N2-filled glovebox. The vial containing dtbbpy was charged with NiBr2•dme (6.2 mg, 0.020 mmol, 0.10 equiv) and DMA (0.200 mL, 1.0 M) and allowed to stir for 10 minutes. The vial containing 199 and 204 was charged with Zn powder (25.4 mg, 0.400 mmol, 2.00 equiv). Once the catalyst solution prestir was complete, the catalyst solution was added to the reaction vial via pipette. The vial was then sealed with a Teflon-lined cap, removed from the glovebox, placed in a pre-heated oil bath (28 °C), and allowed to stir for 15 h. Once the reaction was complete, the reaction mixture was diluted with Et2O and passed through a short silica plug, eluting with Et2O. The material was concentrated onto celite in vacuo, and the resulting powder was purified by silica gel flash chromatography (0 → 30% PhMe/hexanes) to afford 205 as a white solid (34.1 mg, 56% yield). Rf = 0.71 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 166 [α]D25 = +238° (c = 1.66, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.35 – 7.28 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.89 – 6.83 (m, 2H), 6.34 (d, J = 15.8 Hz, 1H), 6.22 (dd, J = 15.8, 7.8 Hz, 1H), 3.81 (s, 3H), 3.41 (q, J = 9.5 Hz, 1H), 2.73 (ddt, J = 9.5, 7.7, 0.9 Hz, 1H), 2.33 (s, 3H), 2.11 (ddd, J = 10.7, 8.5, 0.8 Hz, 1H), 1.87 (t, J = 10.3 Hz, 1H), 1.18 (s, 3H), 1.16 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 158.9, 142.3, 135.3, 130.7, 130.0, 129.0, 128.1, 127.3, 126.6, 114.0, 55.9, 55.4, 40.0, 39.6, 36.9, 30.4, 23.6, 21.2. FTIR (NaCl, thin film, cm-1): 2999, 2951, 2921, 2860, 1607, 1511, 1462, 1370, 1249, 1174, 1106, 1036, 966, 806. HRMS (ESI-TOF, m/z): calc’d for C22H27O [M+H]+: 307.2056; found: 307.2062. Photochemical Minisci Arylation: Preparation of 206 and S268 Me Me O O Me Me N N O [Ir] (2%), TFA (2 equiv) O DMA, blue LEDs Me Me N (54% yield) 199 Me 206 Me A flame-dried 2-dram vial was charged with NHP ester 199 (72.7, mg, 0.200 mmol, 1.00 equiv) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (4.5 mg, 0.004 mmol, 0.02 equiv). The vial was evacuated and backfilled with Ar three times. DMA (2.0 mL, 0.1 M) and lepidine (43.0 mg, 0.300 mmol, 1.50 equiv) were then added, and the reaction mixture was cooled to 0 °C and sparged with Ar 10 minutes. The reaction vial was removed from the ice bath, Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 167 trifluoroacetic acid (30.6 µL, 0.400 mmol, 2.00 equiv) was added, and the reaction mixture was allowed to stir in front of a 34W blue LED lamp (~3 cm from the lamp). The reaction was monitored by TLC (20% EtOAc/hexanes). Once the reaction was complete (~4 h), the reaction was quenched with 1 mL NEt3 and 2 mL H2O. The aqueous layer was extracted with EtOAc (3 mL x 4), and the combined organics were washed with 1 M LiCl. The organic layer was then dried with Na2SO4, filtered, and concentrated onto celite in vacuo, and the resulting powder was purified by silica gel flash chromatography (0 → 5% EtOAc/hexanes) to afford 206 as a yellow solid (34.1 mg, 54% yield). Rf = 0.76 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +305° (c = 1.47, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 8.3, 1.4 Hz, 1H), 7.67 (ddd, J = 8.3, 6.7, 1.4 Hz, 1H), 7.50 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.1 Hz, 3H), 4.39 (q, J = 9.7 Hz, 1H), 3.52 (d, J = 10.1 Hz, 1H), 2.67 (s, 3H), 2.30 (s, 3H), 2.20 (dd, J = 10.4, 8.8 Hz, 1H), 2.04 (t, J = 10.3 Hz, 1H), 1.39 (s, 3H), 0.89 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 13C NMR (101 MHz, CDCl3) δ 160.6, 148.0, 143.4, 142.6, 135.2, 130.2, 129.0, 128.9, 128.8, 128.7, 127.1, 126.9, 126.8, 125.4, 123.7, 121.7, 59.1, 39.7, 37.9, 35.4, 31.2, 23.7, 21.1, 18.9. FTIR (NaCl, thin film, cm-1): 3428, 3950, 2925, 2360, 1603, 1558, 1514, 1446, 1379, 1260, 1176, 1162, 1034, 809, 756. HRMS (ESI-TOF, m/z): calc’d for C23H26N [M+H]+: 316.2060; found: 316.2063. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 168 Me O Me Me [Ir] (2 mol %) lepidine (1.5 equiv) NHP Me Me TFA (2 equiv), DMA blue LEDs (36% yield) O S1 N O S2 [Ir] = Ir[dF(CF3)ppy)]2(dtbbpy)PF6 An analogous procedure was used for the preparation of S2. Crude material purified by silica gel chromatography. 5–20% EtOAc/hexanes. Isolated S2 (10 mg, 36% yield). Rf = 0.82 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (ddd, J = 8.5, 1.3, 0.6 Hz, 1H), 7.86 (ddd, J = 8.3, 1.5, 0.6 Hz, 1H), 7.58 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.41 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.23 (dd, J = 1.8, 0.9 Hz, 1H), 6.98 (d, J = 1.1 Hz, 1H), 6.19 (dd, J = 3.2, 1.8 Hz, 1H), 6.03 (dt, J = 3.2, 0.8 Hz, 1H), 4.38 – 4.15 (m, 1H), 3.58 (d, J = 9.9 Hz, 1H), 2.59 (d, J = 1.0 Hz, 3H), 2.10 – 1.98 (m, 2H), 1.34 (s, 3H), 0.78 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.66, 158.38, 147.76, 143.28, 140.81, 129.97, 128.62, 126.91, 125.24, 123.43, 121.40, 110.04, 104.21, 56.83, 38.47, 37.72, 30.85, 29.61, 23.19, 18.70. Photochemical Borylation: Preparation of 207 and S369 Me Me Me O O O Me Me N O O B2cat2, DMA blue LEDs Me Me Me B O then NEt3, pinacol (58% yield) 199 Me 207 Me Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 169 A flame-dried 2-dram vial was charged with NHP ester 199 (72.7, mg, 0.200 mmol, 1.00 equiv) and B2cat2 (59.5 mg, 0.250 mmol, 1.25 equiv). The vial was evacuated and backfilled with Ar three times. DMA (2.0 mL, 0.1 M) was then added, and the reaction mixture was cooled to 0 °C and sparged with Ar for 10 minutes. The reaction vial was removed from the ice bath and suspended inside a large beaker lined with 12W blue LED strips and covered with foil. After 21 h, pinacol (94.5 mg, 0.800 mmol, 4.00 equiv) was added as a solution in NEt3 (700 µL, 5.04 mmol, 25.2 equiv). After 2 h, the reaction was quenched with H2O, saturated aqueous NH4Cl, and EtOAc. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (2 mL x 3). The combined organics were then dried with Na2SO4, filtered, and concentrated onto celite in vacuo, and the resulting powder was purified by silica gel flash chromatography (0 → 5% EtOAc/hexanes) to afford 207 as a white solid (35.1 mg, 58% yield). Rf = 0.81 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +77.5° (c = 1.47, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.09 (s, 4H), 3.53 (td, J = 10.2, 8.2 Hz, 1H), 2.31 (s, 3H), 2.13 (ddd, J = 10.6, 8.2, 0.8 Hz, 1H), 2.02 (t, J = 10.3 Hz, 1H), 1.68 (d, J = 10.5 Hz, 1H), 1.26 (s, 6H), 1.24 (d, J = 1.1 Hz, 9H), 1.16 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 144.1, 134.9, 128.9, 126.3, 83.2, 42.9, 34.3, 34.0, 32.4, 26.6, 25.3, 24.9, 21.1. (Note: the resonance from the carbon attached to the boron was not visible). FTIR (NaCl, thin film, cm-1): 3444, 2980, 2922, 2946, 2862, 2728, 1898, 1652, 1514, 1462, 1414, 1380, 1363, 1345, 1329, 1275, 1237, 1143, 1112, 1080, 1020, 967, 854, 809, 730. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 170 HRMS (ESI-TOF, m/z): calc’d for C19H29BO2Na [M+Na]+: 323.2158; found: 323.2174. Me Me Me Me Me O O B2cat2, DMA, blue LEDs; then NEt3, pinacol (47% yield) NHP O Me Me Me B O O S1 S3 An analogous procedure was used for the preparation of S3. Crude material purified by silica gel chromatography, 5–20% EtOAc/hexanes. Isolated S3 as a pale yellow oil (13.1 mg, 47% yield). Rf = 0.74 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) 1 H NMR (400 MHz, Chloroform-d) δ 7.22 (dd, J = 1.8, 0.9 Hz, 1H), 6.19 (dd, J = 3.1, 1.9 Hz, 1H), 5.89 (dt, J = 3.1, 0.9 Hz, 1H), 3.49 – 3.29 (m, 1H), 2.06 – 2.00 (m, 1H), 2.00 – 1.94 (m, 1H), 1.76 (d, J = 10.1 Hz, 1H), 1.52 (s, 1H), 1.17 (d, J = 5.3 Hz, 13H), 1.13 (s, 3H), 1.11 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.95, 140.58, 109.86, 103.26, 83.04, 41.48, 34.38, 31.98, 27.74, 26.33, 25.01, 24.76. Reduction to Form Alcohol 208 O Me Me OH Me NaBH4, I2 OH Me THF, 0 °C to 70 °C (81% yield) 191 Me 208 Me A 2-dram vial containing a stir bar was charged with 191 (87 mg, 0.400 mmol, 1.00 equiv) and NaBH4 (37.8 mg, 1.00 mmol, 2.5 equiv). The vial was then evacuated and backfilled Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 171 with N2 three times. THF (3.0 mL) was added and the reaction mixture was cooled to 0 °C. I2 (121.8 mg, 0.480 mmol, 1.2 equiv) was then added as a solution in THF (1 mL) dropwise. The vial was then sealed with a Teflon-lined cap, placed in a pre-heated oil bath (70 ºC), and allowed to stir overnight. Once the reaction was complete, the reaction was cooled to room temperature and quenched with MeOH until bubbling stopped and the reaction mixture turned clear. The reaction mixture was then concentrated, then treated with 20% KOH (4 mL) and allowed to stir for 5 h at room temperature. The aqueous layer was then extracted with EtOAc (6 x 5 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 208 (82.2 mg, quant yield) as a white solid which was carried forward without further purification. Rf = 0.38 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +57.0° (c = 0.42, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.18 – 7.08 (m, 4H), 3.75 (qd, J = 11.0, 7.2 Hz, 2H), 3.06 (q, J = 9.5 Hz, 1H), 2.34 (s, 3H), 2.28 (dddd, J = 9.4, 8.3, 6.1, 0.7 Hz, 1H), 2.05 (ddd, J = 10.8, 8.7, 0.8 Hz, 1H), 1.82 (t, J = 10.3 Hz, 1H), 1.21 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 141.9, 135.6, 129.1, 126.7, 63.6, 53.9, 40.6, 37.6, 33.7, 31.4, 22.5, 21.1. FTIR (NaCl, thin film, cm-1): 3248, 2954, 2926, 2896, 2864, 1896, 1514, 1453, 1413, 1379, 1368, 1326, 1260, 1218, 1190, 1110, 1092, 1033, 1013, 812, 772. HRMS (ESI-TOF, m/z): calc’d for C14H24NO [M+NH4]+: 222.1852; found: 222.1846. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 172 Stahl Oxidation to Form Aldehyde 20988 Me Me 208 O OH Cu(MeCN)4OTf 4,4’-MeObpy Me ABNO, NMI MeCN, O2, 3h (88% yield) Me Me 209 H Me 208 (0.400 mmol, 1.00 equiv) was dissolved in 1.2 mL MeCN in a 20 mL scintillation vial. In a separate vial Cu(MeCN)4OTf (7.5 mg, 0.02 mmol, 0.05 equiv) and 4,4’-MeObpy (4.3 mg, 0.02 mmol, 0.05 equiv)) were dissolved in 0.4 mL MeCN and allowed to stir until the solution turned an opaque blue. To this vial was added a solution of ABNO (0.6 mg, 0.004 mmol, 0.01 equiv) and N-methylimidazole (3.3 mg, 0.04 mmol, 0.10 equiv) in 0.4 mL MeCN. Once the catalyst solution turned green, it was added to the reaction mixuture and allowed to stir open to air. After 3 h and 6 h, additional portions of catalyst (Cu(MeCN)4OTf (7.5 mg, 0.02 mmol, 0.05 equiv), 4,4’-MeObpy (4.3 mg, 0.02 mmol, 0.05 equiv) ABNO (0.6 mg, 0.004 mmol, 0.01 equiv), and N-methylimidazole (3.3 mg, 0.04 mmol, 0.10 equiv) dissolved in 0.8 mL MeCN) were added. After the addition at 6 h, the reaction vessel was sealed with a rubber septum and the reaction mixture was sparged with O2(g) and allowed to stir under an O2 atmosphere for an additional 15.5 h. When the reaction was judged to be done by TLC, the reaction mixture was filtered over a short silica plug, eluting with 20% EtOAc/hexanes, and the resulting solution was concentrated in vacuo to give 209 as a brown oil (71.1 mg, 87% yield). Rf = 0.69 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +62.9° (c = 1.66, CHCl3). 173 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 1 H NMR (400 MHz, CDCl3): δ 9.86 (d, J = 1.6 Hz, 1H), 7.21 – 7.01 (m, 5H), 3.88 (q, J = 9.6 Hz, 1H), 2.97 (ddd, J = 9.7, 1.7, 0.9 Hz, 1H), 2.34 (s, 3H), 2.12 (ddt, J = 10.5, 8.9, 0.8 Hz, 1H), 2.02 (t, J = 10.5 Hz, 1H), 1.36 (s, 3H), 1.26 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 203.0, 140.8, 135.8, 129.1, 129.1, 126.5, 126.5, 62.5, 39.9, 37.5, 33.0, 31.3, 24.0, 23.6, 21.1, 21.1. FTIR (NaCl, thin film, cm-1): 3248, 2954, 2926, 2896, 2864, 1896, 1514, 1453, 1413, 1379, 1368, 1326, 1260, 1218, 1190, 1110, 1092, 1033, 1013, 812, 772. HRMS (ESI-TOF, m/z): calc’d for C14H22NO [M+NH4]+: 220.1696; found: 220.1691. Acid Chloride Formation and Suzuki Cross-Coupling to Form Aryl Ketone 21089 O Me O Me OH Me oxalyl chloride DMF (cat) PhB(OH)2 (2 equiv) Pd(PPh3)4 (5 mol %) Cl Me CH2Cl2 0 °C to 23 °C 191 Me S4 Me O Me Me Cs2CO3 (5 equiv) PhMe, 100 ºC (41%, 2 steps) 210 Me To a flame-dried 2-dram vial was added carboxylic acid 191 (87.3 mg, 0.400 mmol, 1 equiv). The vial was sealed with a septum vial cap and tape and was evacuated and backfilled with N2 three times. CH2Cl2 (0.8 mL, 0.5 M) and 1-2 drops DMF were added, and the reaction mixture was cooled to 0 °C. Oxalyl chloride (0.040 mL, 0.480 mmol, 1.2 equiv) was then added dropwise. Once the addition was complete, the reaction was allowed to stir at room temperature for 1 h, at which point the solvent was removed in vacuo to afford acid chloride S4 as a crude oil, 91 mg 96% yield. S4 was taken forward without further purification. (characterization for S4 is in the next section for the synthesis of alkyl ketone 211) Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 174 A flame-dried 2-dram vial was charged with phenyl boronic acid (135 mg, 1.1 mmol, 3.0 equiv). The vial was brought into an N2-filled glovebox and charged with Cs2CO3 (589 mg, 1.8 mmol, 5.0 equiv) and Pd(PPh3)4 (21.3 mg, 0.018 mmol, 5 mol%). S4 (87.1 mg, 0.37 mmol, 1.0 equiv) was then added as a stock solution in PhMe (3.7 mg, 0.1 M). The reaction vessel was sealed with a septa cap and tape, brought out of the glovebox, and placed in a 100 ºC oil bath. The reaction was allowed to stir for 24 hours. Once the reaction was complete and allowed to cool, the reaction mixture was diluted with EtOAc, washed with H2O, sat aq NaHCO3 (goes from green to brown), and sat brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography, 1–5% EtOAc/hexanes to afford 210 as a yellow solid (44 mg, 41% yield over 2 steps). HRMS (ESI-TOF, m/z): calc’d for C20H26NO [M+NH4]+: 296.2009; found: 296.2010. 1 H NMR (400 MHz, Chloroform-d) δ 8.00 – 7.90 (m, 2H), 7.60 – 7.51 (m, 1H), 7.46 (ddt, J = 8.1, 6.6, 1.1 Hz, 2H), 7.12 (t, J = 7.8 Hz, 3H), 4.16 (q, J = 9.5 Hz, 1H), 3.80 (d, J = 9.4 Hz, 1H), 2.30 (s, 3H), 2.17 – 2.07 (m, 2H), 1.36 (s, 3H), 0.98 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 199.25, 141.60, 137.74, 135.61, 133.07, 129.10, 128.67, 128.47, 126.67, 59.12, 38.89, 37.67, 33.18, 30.74, 23.43, 21.13. Reductive Coupling of Acid Chloride SX to Form Alkyl Ketone 21190 I O Me O Me OH Me oxalyl chloride DMF (cat) O (1.50 equiv) NiCl2•dme (5 mol %) dtbbpy (5.5 mol %) Cl Me CH2Cl2 0 °C to 23 °C 191 Me S4 Me Mnº (3.00 equiv) DMA,0 °C, 16 h (74% yield over 2 steps) Me Me 211 Me Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 175 A 1-dram vial containing a stir bar was charged with carboxylic acid 191 (87.3 mg, 0.400 mmol, 1 equiv). The vial was sealed with a septum vial cap and tape and was evacuated and backfilled with N2 three times. CH2Cl2 (0.8 mL, 0.5 M) and 1-2 drops DMF were added, and the reaction mixture was cooled to 0 °C. Oxalyl chloride (0.050 mL, 0.560 mmol, 1.4 equiv) was then added dropwise. Once the addition was complete, the reaction was allowed to stir at room temperature for 1 h, at which point the solvent was removed in vacuo to afford acid chloride S4 as a crude oil. S4 was taken forward without further purification. 1 H NMR (400 MHz, CDCl3): δ 7.16 – 7.06 (m, 4H), 3.79 (q, J = 9.7 Hz, 1H), 3.29 (dd, J = 9.8, 0.9 Hz, 1H), 2.33 (s, 3H), 2.11 (ddd, J = 10.9, 9.1, 1.0 Hz, 1H), 2.01 – 1.88 (m, 1H), 1.41 (s, 3H), 1.31 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 173.3, 139.2, 136.5, 129.4, 126.5, 66.1, 39.0, 37.0, 30.0, 23.2, 21.2. A flame-dried 1-dram vial containing a 2-dram stir bar (tested before to ensure it would stir) was charged with NiCl2•dme (4.4 mg, 0.020 mmol, 0.05 equiv), dtbbpy (5.9 mg, 0.022 mmol, 0.055 equiv), and Mn° powder (65.9 mg, 1.20 mmol, 3.00 equiv). The vial was sealed with a septa and tape and evacuated and backfilled with N2 three times. 0.6 mL DMA was then added, and the reaction mixture was stirred vigorously (~1300 rpm) for about 30 min. The mixture should be a dark black color. The reaction mixture was then cooled to 0 °C in an ice bath. Iodocyclohexane (0.078 mL, 0.600 mmol, 1.50 equiv) was then added, followed by freshly prepared acid chloride S4 (94.7 mg, 0.400 mmol, 1.0 equiv) dissolved in 0.8 mL DMA. The sealed vial was then placed in a cryocool set to 0 °C and allowed to stir for 16 h. The reaction mixture was then quenched with 1.0 mL H2O and 176 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A extracted with CH2Cl2 (4 x 2.0 mL). The combined organic layers were filtered through a Na2SO4 plug and concentrated in vacuo. The resulting crude oil was purified by silica gel flash chromatography (0 → 5% EtOAc/hexanes) to afford 211 as a pale yellow, clear oil (84.6 mg, 74% yield over 2 steps). Rf = 0.76 (silica gel, 20% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +17.1° (c = 2.247, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.11 – 7.05 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 3.85 (q, J = 9.6 Hz, 1H), 3.13 (dd, J = 9.6, 0.8 Hz, 1H), 2.31 (s, 3H), 2.21 (tt, J = 11.3, 3.3 Hz, 1H), 2.02 (ddd, J = 10.6, 8.8, 0.8 Hz, 1H), 1.92 (t, J = 10.5 Hz, 1H), 1.88 – 1.62 (m, 3H), 1.44 (tdd, J = 13.0, 11.4, 3.6 Hz, 1H), 1.34 (s, 3H), 1.31 – 1.11 (m, 4H), 1.06 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 212.7, 141.7, 135.5, 129.1, 126.5, 60.9, 50.8, 39.1, 37.4, 33.2, 31.3, 29.6, 26.9, 26.3, 26.0, 25.5, 24.0, 21.1. FTIR (NaCl, thin film, cm-1): 3380, 3048, 3020, 2929, 2855, 1894, 1698, 1515, 1449, 1370, 1331, 1288, 1244, 1183, 1145, 1066, 1021m 994, 952, 892, 829, 805, 759. HRMS (ESI-TOF, m/z): calc’d for C20H32NO [M+NH4]+: 302.2478; found: 302.2470. 2.8.3 Synthesis of (+)-Rumphellaone A C–H Activation Procedure for the Preparation of 234 Me O N H Me 6 + I O Pd(OAc)2 (30%) Ag2CO3 (1 equiv) O Me Me TBME, 90 ºC 18 h N 212 3 equiv N H O 234 N 177 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A To a 15 mL flame-dried pressure flask was added cyclobutamide 6 (300 mg, 1.18 mmol, 1.0 equiv), Pd(OAc)2 (79 mg, 0.35 mmol, 0.30 equiv), Ag2CO3 (325 mg, 1.18 mmol, 1 equiv), and 2-iodofuran (212) (686 mg, 3.54 mmol, 3.00 equiv), followed by TBME (6.0 mL, 0.2 M). Add a blanket of argon, seal, and place in 90 ºC oil bath. Let stir overnight. Purify by silica gel chromatography, 5–20% EtOAc/hexanes. 234 isolated (206 mg, 55% yield). Rf = 0.52 (silica gel, 30% EtOAc/Hexanes, UV, p-anisaldehyde) 1 H NMR (500 MHz, Chloroform-d) δ 9.63 (s, 1H), 8.79 – 8.67 (m, 2H), 8.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.47 – 7.35 (m, 3H), 7.23 (dd, J = 1.8, 0.8 Hz, 1H), 6.30 – 6.21 (m, 2H), 3.96 (q, J = 9.2 Hz, 1H), 3.32 (ddd, J = 8.9, 2.2, 0.8 Hz, 1H), 2.61 (dd, J = 10.9, 9.6 Hz, 1H), 2.18 (ddd, J = 11.1, 9.0, 2.3 Hz, 1H), 1.46 (s, 3H), 1.32 (s, 4H). Table S1: Time Course Study for the Formation of 238 TMS Me O N H Me 6 + Pd(OAc)2 (15%) Ag2CO3 (1 equiv) TBME, 90 ºC N TMS O O O Me Me N H + N O N H Me O I O TMS 2 equiv 236 N TMS 237 238 entry time (h) % yield pdta % yield bis aryla pdt:bis aryl 1 2 70 7 10:1 2 3 49 7 6.7:1 3 4 69 10 6.7:1 4 5 62 11 5.5:1 5 6 60 11 5.5:1 aReactions run in a pressure flask or a sealed vial with a Teflon cap under air. Yields determined by analysis against an internal standard. 1H NMR 178 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A Large-Scale C–H Activation Procedure for the Preparation of 237 O Me N H Me 6 TMS O I N 236 (2 equiv) Pd(OAc)2 (7.5 mol %) Ag2CO3 (1 equiv) TBME, 70 °C, 18h (90% yield) O Me Me N H N O 237 TMS A 48 mL pressure flask was charged with cyclobutamide 6 (400 mg, 1.57 mmol, 1.00 equiv), Ag2CO3 (434 mg, 1.57 mmol, 1.00 equiv), and Pd(OAc)2 (26.5 mg, 0.118 mmol, 7.5 mol %) followed by TMS-iodofuran 236 (834 mg, 3.15 mmol, 2.00 equiv). The mixture was then suspended in TBME (8.0 mL, 0.2 M). The vessel was sealed under ambient conditions and placed in a pre-heated oil bath (70 ºC). After about 10 minutes, the olivegreen mixture becomes black, and the reaction mixture is stirred for an additional 18 h. The reaction mixture was then concentrated, diluted with toluene (3 mL), and loaded directly onto a silica gel column (0 → 20% EtOAc/hexanes) to afford 237 as a clear yellow oil (556 mg, 90% yield). Rf = 0.56 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). [α]D25 = –57.2° (c = 1.22, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 9.61 (s, 1H), 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (dd, J = 6.7, 2.3 Hz, 1H), 8.11 (dd, J = 8.2, 1.7 Hz, 1H), 7.48 – 7.39 (m, 3H), 6.48 (d, J = 3.1 Hz, 1H), 6.23 (dd, J = 3.2, 1.1 Hz, 1H), 4.07 – 3.94 (m, 1H), 3.34 (ddd, J = 9.0, 2.2, 0.8 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.19 (ddd, J = 11.0, 8.9, 2.3 Hz, 1H), 1.45 (s, 3H), 1.32 (s, 3H), -0.08 (s, 9H). 179 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 13 C NMR (101 MHz, CDCl3): δ 170.1, 160.1, 158.7, 148.0, 138.5, 136.3, 134.8, 127.9, 127.6, 127.5, 121.5, 121.2, 121.1, 120.5, 120.5, 116.5, 106.8, 55.8, 38.1, 36.6, 32.3, 30.9, 30.7, 30.7, 24.9, –1.8. FTIR (NaCl, thin film, cm-1): 3360, 3109, 3049, 2954, 2866, 2613, 1944, 1878, 1687, 1595, 1578, 1522, 1485, 1424, 1385, 1324, 1249, 1161, 1131, 1009, 924, 842, 791, 757. HRMS (ESI-TOF, m/z): calc’d for C23H29N2O2Si [M+H]+: 392.1993; found: 393.1990. Schwartz Reduction and Base-Mediated Epimerization12 O O Me Me N H N Cp2Zr(H)Cl THF, rt (34–45% yield) O Me Me O H O TMS TMS 237 KOH MeOH (>90% yield) 239 Me Me H O TMS 240 In an N2-filled glovebox (lights off), Schwartz reagent (2.00 equiv) was added to a flamedried flask. Added starting material 237 as a solution in THF (0.1 M). Removed from glovebox and let stir for 2h. Once the reaction was complete, quenched with sat aq NaHCO3. Extracted aqueous layer with Et2O, dried combined organic layers over Na2SO4, filter, and concentrated in vacuo. Purified crude by silica gel chromatography, 5–10% EtOAc/hexanes, isolated aldehyde 239. Rf = 0.69 (silica gel, 20% EtOAc/Hex, UV, p-anisaldehyde). 1 H NMR (300 MHz, Chloroform-d) δ 9.71 (d, J = 5.0 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 6.09 (dd, J = 3.2, 0.9 Hz, 1H), 3.88 (q, J = 9.0 Hz, 1H), 2.95 – 2.81 (m, 1H), 2.46 (dd, J = 11.6, 8.7 Hz, 1H), 2.30 (ddd, J = 11.6, 9.3, 2.2 Hz, 1H), 1.32 (s, 3H), 1.22 (s, 3H), 0.23 (d, J = 4.0 Hz, H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 180 To flask containing 239 was added KOH (20 equiv) followed by MeOH (0.1 M). Let the reaction stir, monitored by TLC, 10% EtOAc/hexanes. Once the reaction was complete, added pH 7 buffer, quenched with sat aq NH4Cl, and diluted with water and EtOAc. Separated layers and extracted the aqueous layer with EtOAc. Dried the organic layer over MgSO4, filtered, and concentrated in vacuo. Isolated epimerized aldehyde 240, still some trace 239. 1 H NMR (500 MHz, Chloroform-d) δ 9.79 (d, J = 1.6 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 6.02 (dd, J = 3.1, 0.6 Hz, 1H), 3.89 (q, J = 9.3 Hz, 1H), 3.15 – 3.10 (m, 1H), 1.38 (s, 3H), 1.20 (s, 3H), 0.28 – 0.19 (m, 20H). Hydrolysis: Preparation of 19487 O O Me Me N H NaOH (15 equiv) N Me Me OH EtOH, 130 °C O O 237 TMS (96% yield) 194 A 15 mL pressure flask was charged with cis-cyclobutamide 237 (532 mg, 1.36 mmol, 1.00 equiv), sodium hydroxide (813 mg, 20.33 mmol, 15 equiv), and absolute ethanol (5.7 mL, 0.24 M). The flask was sealed and placed in a pre-heated oil bath (130 ºC) and stirred for 18 h. The solvent was then concentrated in vacuo, and the crude residue was diluted with 1 M HCl (20 mL) and EtOAc (20 mL). The organic layer was separated and washed with 1 M HCl (2 x 20 mL). At this point, the aqueous layers should be yellow, and the organic layer should be faint brown. The combined aqueous layers were extracted with EtOAc (25 mL), and the second organic layer was washed with 1 M HCl (25 mL) until it was free of 8-aminoquinoline as indicated by TLC (usually 1-2 times). The organic layers were Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 181 combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude reddish solid was purified by silica gel flash chromatography (20 → 40 % EtOAc/hexanes) to afford 194 as an off-white solid (250 mg, 96 % yield). Rf = 0.5 (silica gel, 30% EtOAc/Hex, p-anisaldehyde). [α]D25 = +133.0° (c = 0.85, CHCl3). 1 H NMR (400 MHz, CHCl3): δ 7.32 (dd, J = 1.9, 0.9 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz, 1H), 6.05 (dt, J = 3.2, 0.8 Hz, 1H), 3.72 (q, J = 9.5 Hz, 1H), 3.11 – 3.02 (m, 1H), 2.12 – 1.95 (m, 2H), 1.30 (s, 3H), 1.19 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 178.3, 156.6, 141.5, 110.3, 105.0, 53.2, 38.3, 36.8, 30.4, 29.2, 23.4. FTIR (NaCl, thin film, cm-1): 3119, 2993, 2956, 2869, 1722, 1682, 1604, 1506, 1461, 1411, 1390, 1371, 1276, 1224, 1208, 1175, 1161, 1104, 1067, 1008, 946, 918, 884, 850, 804, 743, 730, 695. HRMS (ESI-TOF, m/z): calc’d for C11H15O3 [M+H]+: 195.1016; found: 195.1019. Attempts at Cyclopropanation97,98 Me O OH Me Me Et2Zn (5 equiv) CH2I2 (5 equiv) Me O O Me OH O O Me Me O OH + CH2Cl2 –10 ºC to rt O 194 Me I O 241 O 243 not observed 242 242 (confirmed by 1H NMR, 13 C NMR HSQC, LCMS, and Scott and Dave) entry CRL-01-204 CRL-01-205 CRL-01-207 CRL-01-208 CRL-01-209 CRL-01-210 CRL-01-213 CRL-01-214 CRL-01-216 CRL-01-217 scale 7 mg 23 mg 11 mg 5 mg 5 mg 5 mg 20 mg 20 mg 20 mg 20 mg yield notes 5 equiv Zn and CH2I2; some xs CH2I2 2.4 mg 242, 19 % yield; 0.9 mg 241 still sm, resubjected 7.7 mg 241, 30 % yield (tentative) 194 and 241 premixed reagent and added to sm mostly 194 added sm to premixed reagent 4.6 mg ~1:1 194:241 2.5 equiv Zn and CH2I2 (xs CH2I2) on accident 2.7 mg 242, 29 % yield; 0.9 mg 241 2 equiv Zn, 3 equiv CH2I2 trace 242; 10 mg 241, 44 % yield 2.5 equiv each Zn and CH2I2 mostly sm, some 241 1 equiv each Zn and CH2I2 No A, only sm and 241 No A, only sm, 241, and 242 (~1:1:0.3) 1.5 equiv each Zn and CH2I2 O O OH Me Me Zn (s), CH2I2 O Cu(I)Cl, AcCl Me Me O Et2O, 50 ºC 194 CRL-01-211 OH 243 no reaction Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 182 General procedure: To a 1-dram vial was added 194. Evacuated and backfilled with N2 x 3. Added DCM (0.1 M) and cooled to –10 ºC. Then added Et2Zn (5.00 equiv) and CH2I2 (5.00 equiv) (small volumes, easy to add too much). Allowed and warm to room temperature, monitoring by TLC (20% EtOAc/hexanes). Once conversion was complete, quenched with sat aq NH4Cl and diluted with EtOAc. Separated layers, washed organic with sat aq Na2S2O3 and sat brine. Dried over Na2SO4, filtered, and concentrated in vacuo. Purify by prep TLC, 20% EtOAc/hexanes. Unable to isolate 241 242: 1 H NMR (400 MHz, Chloroform-d) δ 5.98 (d, J = 4.5 Hz, 1H), 5.82 (d, J = 4.6 Hz, 1H), 3.54 (td, J = 5.4, 2.1 Hz, 1H), 2.74 (dd, J = 9.8, 0.8 Hz, 1H), 2.46 (td, J = 9.8, 8.8 Hz, 1H), 1.77 – 1.66 (m, 1H), 1.65 – 1.58 (m, 2H), 1.60 – 1.52 (m, 2H), 1.43 (dd, J = 8.5, 4.5 Hz, 1H), 1.21 (s, 4H), 1.09 (s, 4H), 0.81 (ddd, J = 8.1, 5.7, 4.5 Hz, 1H), 0.59 (dd, J = 8.5, 5.7 Hz, 1H), 0.51 (ddd, J = 6.4, 4.4, 2.0 Hz, 1H), 0.48 – 0.33 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 171.24, 67.93, 57.86, 49.84, 37.25, 34.41, 34.38, 30.72, 30.34, 26.40, 23.89, 22.30, 18.70, 14.65. Pinnick Oxidation: Preparation of 259 O Me O OH Me O Me NaH2PO4, NaClO2 H tBuOH/H O (5:1) 2 (65% yield) 194 OH Me O HO O 259 A 50 mL round bottom flask was charged with carboxylic acid 194 (200 mg, 1.03 mmol, 1.00 equiv) and was evacuated and backfilled with N2 three times. 5:1 tBuOH/H2O (5.2 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 183 mL, 0.2 M) was added. Once the starting material was fully dissolved, NaH2PO4•H2O (213 mg, 1.54 mmol, 1.50 equiv) was added in one portion, followed by NaClO2 (349 mg, 3.09 mmol, 3.00 equiv, 80%). The suspension turned bright yellow within the first 10-15 minutes. The reaction mixture was allowed to stir 2-3 hours, at which point the yellow color dissipated and no more starting material was observed by TLC. The reaction mixture was concentrated in vacuo, and the resulting solids were solubilized with a mixture of EtOAc and minimal H2O. This crude mixture was concentrated onto 4 g SiO2. The powder was applied to a silica gel column and purified by flash silica gel chromatography (0 → 5% MeOH/CH2Cl2, followed by flushing with 50% MeOH/CH2Cl2) to afford 259 as a white solid (151 mg, 65% yield, 93% pure by QNMR). Rf = 0.20 (silica gel, 10% MeOH/CH2Cl2, UV, p-anisaldehyde) [α]D25 +62.6° (c = 0.22, MeOH). 1 H NMR (400 MHz, MeOD-d4): δ 7.27 (d, J = 5.9 Hz, 1H), 6.12 (d, J = 5.8 Hz, 1H), 2.92 (q, J = 9.4 Hz, 1H), 2.72 (d, J = 9.6 Hz, 1H), 1.80 (t, J = 10.3 Hz, 1H), 1.70 (dd, J = 11.0, 9.0 Hz, 1H), 1.20 (s, 3H), 1.10 (s, 3H). 13 C NMR (101 MHz, MeOD-d4): δ 175.7, 172.9, 155.7, 123.6, 51.5, 49.5, 37.8, 37.1, 36.9, 36.2, 33.7, 30.4, 30.3, 24.1, 23.7. FTIR (NaCl, thin film, cm-1): 3098, 2960, 2871, 1726, 1416, 1373, 1280, 1255, 1187, 1160, 1114, 1032, 1007, 935, 852, 829, 713. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 184 (i-PrO)3TiCH3 Conditions for Methylation: Preparation of 260103,104 O O Me (iPrO)3TiCl (6 equiv) MeLi (6 equiv) OH Me Me OH Me H H O HO O THF (0.02 M) –78ºC to rt, 21 h (76% yield, 22:1 dr) 259 O Me O 260 A flame-dried 50 mL round bottom flask was backfilled with N2 and charged with THF (5 mL). The flask was cooled to –78 °C and (i-PrO)3TiCl (1 M solution in hexanes; 1.33 mL, 1.33 mmol, 6.00 equiv) was added. MeLi (1.6 M solution in ether; 0.83 mL, 1.33 mmol, 6.00 equiv) was then added dropwise. This mixture was allowed to stir at –78 °C for 1 h. 259 (50 mg, 0.221 mmol, 1.00 equiv) was then added as a solution in THF (5.5 mL). The reaction mixture was slowly warmed to 23 °C over 21h. The reaction was then carefully quenched with 1 M HCl (11 mL) and stirred vigorously for 30 min. The organic and aqueous layers were then separated, and the aqueous layer was extracted with EtOAc (12 mL x 4). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel flash chromatography (0 → 4% MeOH/CH2Cl2) to afford 260 (37.5 mg, 76% yield, 22:1 dr) Rf = 0.43 (silica gel, 10% MeOH/CH2Cl2, UV, p-anisaldehyde) [α]D25 = +120.4° (c = 1.20, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 7.29 (d, J = 5.6 Hz, 1H), 5.97 (d, J = 5.6 Hz, 1H), 2.79 (td, J = 9.9, 8.9 Hz, 1H), 2.39 (dd, J = 9.8, 0.8 Hz, 1H), 1.93 (t, J = 10.4 Hz, 1H), 1.78 (ddd, J = 10.8, 8.9, 1.0 Hz, 1H), 1.39 (s, 3H), 1.21 (s, 3H), 1.11 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 177.4, 172.9, 159.5, 120.5, 88.4, 46.9, 36.8, 35.5, 33.5, 29.9, 23.6, 21.6. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 185 FTIR (NaCl, thin film, cm-1): 3091, 2936, 2958, 1869, 1741, 1702, 1464, 1454, 1417, 1371, 1282, 1247, 1208, 1166, 1119, 1090, 1051, 956, 912, 820, 727, 661. HRMS (ESI-TOF, m/z): calc’d for C12H20NO4 [M+NH4]+: 242.1387; found: 242.1390. Hydrogenation of butenolide 259 O O Me Me OH Me H2, Pd/C H H MeOH O HO OH Me O O HO (66% yield) 259 O S5 To a flame-dried 2-dram vial were added 259 (40 mg, 0.18 mmol, 1.00 equiv) and Pd/C (64 mg, 10 wt%, 0.34 equiv). The vial was evacuated and backfilled with N2 x 3. Added MeOH (2.0 mL, 0.09M) and sparged with H2 ballon for about 15 minutes. Allowed to stir under an H2 atmosphere at room temperature. Monitored by TLC (10% MeOH/DCM). Once the reaction was complete, sparged with argon. Filtered through a celite plug, washing with methanol and ethyl acetate. Concentrated the crude in vacuo.Purified by silica gel chromatography, 1–10% MeOH/DCM. S5 isolated (27 mg, 66% yield). Rf = 0.16 (silica gel, 10% MeOH/CH2Cl2, p-anisaldehyde) 1 H NMR (300 MHz, Chloroform-d) δ 3.47 (s, 2H), 3.14 (d, J = 9.5 Hz, 0H), 3.07 (d, J = 9.4 Hz, 1H), 2.78 – 2.54 (m, 3H), 2.08 – 1.70 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H). Ti(CH3)4 Conditions for Methylation: Preparation of 264 O O Me TiCl4 (6 equiv) MeLi (24 equiv) OH Me Me OH Me H H O HO 259 O CH2Cl2 (0.0075 M) –78 ºC, 4 h (60 % yield, 9:1 dr) O Me 264 O Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 186 A 50 mL round bottom flask was flame-dried under vacuum and then backfilled with N2. The flask was charged with CH2Cl2 (5 mL) and cooled to –78 ºC, at which point, TiCl4 (142 µL, 1.33 mmol, 6.00 equiv) was added. The flask was then charged with MeLi (1.5 M in Et2O; 4.00 mL, 5.30 mmol, ~24 equiv) dropwise via syringe, until the color of the solution changed from dark brown, to bright orange, and finally to dark green. The resulting solution was stirred for 1h at –78 ºC. A flame-dried 50 mL pear-shaped (pointed) flask was charged with 26 (49.0 mg, 0.217 mmol, 1.00 equiv) and then evacuated and backfilled with N2 three times. The substrate was dissolved in CH2Cl2 (23 mL) and sonicated to dissolve any particulates. The solution was cooled to –78 ºC, then added to the reaction flask via a slow cannula transfer. If the addition proceeds too quickly or the solution of starting material is not sufficiently cooled, the reaction will favor the undesired diastereomer. The flask containing 26 was rinsed with 2 mL CH2Cl2 to complete the transfer. The resulting mixture was allowed to stir at –78 ºC. After 4 h the reaction was quenched with 1 M HCl (20 mL), allowed to warm to 23 °C, and stirred for 30 minutes during which time the aqueous layer became blue/green. The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (20 mL x 4), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (0 → 10% MeOH/CH2Cl2) to afford 28 white solid (29 mg, 9:1 dr, 60% yield) Rf = 0.43 (silica gel, 10% MeOH/CH2Cl2, UV, p-anisaldehyde) [α]D25 = +43.0° (c = 0.46, CHCl3). 1 H NMR (400 MHz, CDCl3): 7.23 (d, J = 5.6 Hz, 1H), 6.01 (d, J = 5.6 Hz, 1H), 3.48 (s, 1H), 2.99 (dd, J = 9.4, 0.8 Hz, 1H), 2.92 – 2.78 (m, 1H), 1.46 – 1.41 (m, 1H), 1.39 (s, 3H), 1.35 (dd, J = 11.1, 9.9 Hz, 1H), 1.20 (s, 3H), 1.10 (s, 3H). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 13 187 C NMR (101 MHz, CDCl3): δ 178.3, 172.9, 172.8, 158.8, 121.1, 88.5, 49.1, 47.1, 36.4, 35.6, 35.5, 32.1, 29.9, 23.8, 21.7. FTIR (NaCl, thin film, cm-1): 3087, 2958, 2869, 1737, 1600, 1463, 1453, 1403, 1380, 1372, 1305, 1280, 1266, 1218, 1183, 1163, 1136, 1093, 1037, 961, 924, 880, 852, 824, 728, 711, 658. HRMS (ESI-TOF, m/z): calc’d for C12H20NO4 [M+NH4]+: 242.1387; found: 242.1394. HWE Preparation of 267 O O Me Me MeO H O TMS 240 O P Me OMe 224 NaH, THF (41%, 2 steps from cis ald 239) O Me Me Me O TMS 267 Preparation of ylide (0.181 M) from 224: A flame-dried 10 mL round-bottom flask was pumped into an N2-filled glovebox while still hot. Once inside the glovebox and cool, the flask was charged with NaH (25 mg, 95 wt%, 1.15 equiv) and THF (0.181 M, 5.0 mL). Sealed flask with rubber septa and tape and removed from the glovebox. Phosphonate 224 (0.125 mL, 1.0 equiv) was added to the reaction flask, and the slurry was allowed to stir for 3 hours. Preparation of 267: To a 25 mL round-bottom flask containing 240 (17.0 mg, 0.067 mmol, 1.00 equiv) under N2 was added the ylide slurry (2.6 mL, 0.181M, 0.47 mmol, 7.00 equiv). Excess THF was used to rinse the sides of the flask. Let stir at room temperature under N2 overnight. The next day, the reaction mixture had dried out. Dissolved in EtOAc and quenched with aq sat NH4Cl. TLC (10% EtOAc/hex) showed still some aldehyde (SX) Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 188 remaining. Diluted further with water and EtOAc, separated layers, and extracted aqueous layer with EtOAc and DCM. Dry over MgSO4, filter, and concentrate in vacuo. Added 4.9 mg pyrazine internal standard and calculated an NMR yield. 45% 267, 13% 240 remaining. Combined with other reactions for purification. Purified by silica gel chromatography to afford clean 267, 2–5% EtOAc/hexanes. See Wittig prep for characterization of 267. Wittig Preparation of 267107 O Me Me O O 268 H Ph3P O CH2Cl2, 0–23 ºC (66%, 2 steps from cis ald 239) TMS 240 Me Me Me Me O TMS 267 To a 2-dram vial under N2 containing trans aldehyde 240 (20. mg, 0.08 mmol, 1.00 equiv) was added CH2Cl2 (0.18 mL, 0.44 M). Let the aldehyde dissolve. Cool to 0 ºC in an ice bath and add 268 (51 mg, 0.16 mmol, 2.0 equiv). Let stir overnight at room temperature. The next day, the reaction had dried out. Added CH2Cl2 (0.5 mL). TLC (20% EtOAc/hexanes) showed still some SX remaining. After ~ 6 hours, still 240 remaining, so added another equivalent 268 (27.3 mg). Purged with nitrogen, then sealed with a teflon cap instead of a rubber septa and let stir overnight. Almost complete conversion. The reaction was flushed through silica plug (20% EtOAc/hexanes). NMR yield was calculated by 1H NMR vs an internal standard. 72% 267, 11% 240remaining. Combined with other reactions for purification. Purified by silica gel chromatography to afford clean 267, 2–5% EtOAc/hexanes. Rf = 0.63 (silica gel, 20% EtOAc/hexanes, UV, p-anisaldehyde) Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 1 189 H NMR (300 MHz, Chloroform-d) δ 6.83 (dd, J = 16.0, 6.9 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 6.11 (dd, J = 15.9, 1.4 Hz, 1H), 6.00 (d, J = 3.1 Hz, 1H), 3.44 (q, J = 9.4 Hz, 1H), 2.90 (dd, J = 9.4, 7.3 Hz, 1H), 2.25 (s, 3H), 2.08 – 1.96 (m, 2H), 1.19 (s, 3H), 1.11 (s, 3H), 0.24 (s, 9H). Hydrogenation of Methylated Products: Preparation of 241 and 263 O O Me Me OH Me H2, Pd/C H H MeOH O Me OH Me O (87% yield) 264 O Me O 241 A 2-dram vial was charged with lactone 264 (29 mg, 0.129 mmol, 1.00 equiv) and Pd/C (10% by weight, 47 mg, 0.044 mmol, 0.34 equiv). The vial was then evacuated and backfilled with N2 three times. The solids were suspended in MeOH (1.4 mL, 0.095 M), and the reaction mixture was sparged with a balloon of H2 for 20 minutes at 0°C, at which point the balloon was replaced with a fresh balloon, and the reaction was allowed to warm to room temperature. The reaction mixture was then stirred for 7 h under an atmosphere of H2. Once the reaction was complete, the reaction mixture was sparged with argon for 20 minutes, diluted with EtOAc (15 mL), and filtered through celite, and concentrated in vacuo. The crude residue was then purified by silica gel flash chromatography (5% MeOH/CH2Cl2) to afford 241 (25 mg, 88% yield) as a white solid. Rf = 0.44 (silica gel, 10% MeOH/CH2Cl2, p-anisaldehyde) [α]D25 = +76.3° (c = 0.72, CHCl3). Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 1 190 H NMR (400 MHz, CDCl3): δ 2.91 (d, J = 9.7 Hz, 1H), 2.72 (t, J = 9.5 Hz, 1H), 2.70 – 2.59 (m, 1H), 2.53 (ddd, J = 18.2, 9.6, 5.0 Hz, 1H), 2.04 – 1.86 (m, 2H), 1.67 (s, 1H), 1.65 (s, 1H), 1.30 (s, 3H), 1.22 (s, 3H), 1.11 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 178.4, 177.1, 86.3, 86.3, 48.7, 39.1, 35.3, 32.6, 30.9, 29.9, 29.3, 24.0, 23.7. FTIR (NaCl, thin film, cm-1): 2958, 2934, 2869, 1773, 1736, 1702, 1459, 1420, 1382, 1369, 1283, 1248, 1166, 1142, 1077, 940, 914, 802, 646. HRMS (ESI-TOF, m/z): calc’d for C12H22NO4 [M+NH4]+: 244.1543; found: 244.1541. O O Me Me OH Me H2, Pd/C H H MeOH O Me OH Me O (quant yield) 260 O Me O 263 260 (31.0 mg, 0.138 mmol, 1.00 equiv) was subjected to analogous conditions to afford 263 (32.2 mg, quant yield), which was taken forward without further purification Rf = 0.44 (silica gel, 10% MeOH/CH2Cl2, p-Anisaldehyde) [α]D25 = +51.2° (c = 0.53, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 2.78 – 2.56 (m, 3H), 2.50 (ddd, J = 18.1, 9.9, 4.9 Hz, 1H), 2.17 – 2.06 (m, 1H), 1.91 (ddd, J = 13.1, 10.0, 4.9 Hz, 1H), 1.81 (td, J = 9.8, 1.2 Hz, 1H), 1.71 (dd, J = 10.8, 8.0 Hz, 1H), 1.29 (s, 3H), 1.21 (s, 3H), 1.11 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 178.4, 177.2, 86.5, 48.1, 39.2, 35.5, 33.6, 30.9, 29.9, 29.3, 23.9, 23.7. FTIR (NaCl, thin film, cm-1): 2958, 2869, 1770, 1738, 1732, 1704, 1699, 1463, 1422, 1383, 1369, 1283, 1245, 1222, 1165, 1138, 1075, 1002, 965, 941, 914, 802, 757, 711, 648. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 191 HRMS (ESI-TOF, m/z): calc’d for C12H22NO4 [M+NH4]+: 244.1543; found: 244.1537. Radical decarboxylative coupling to afford (+)-rumphellaone A (8) and epi-C8rumphellaone A (29)63 O Me O Me 192 (1.25 equiv) Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol %) OH Me H O Me 241 O K2HPO4, DMF blue LEDs (78% yield) O Me Me Me H O Me O (+)-rumphellaone A (4) To a 2-dram vial charged with saturated lactone 241 (16 mg, 0.0707 mmol, 1.00 equiv) was added Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.8 mg, 0.0007 mmol, 0.01 equiv) and K2HPO4 (14.8 mg, 0.0849 mmol, 1.20 equiv). The reaction vessel was evacuated and backfilled with N2 three times. DMF (0.71 mL, 0.1 M) was then added, and the reaction mixture was cooled to 0 °C and sparged with argon for 15 minutes. Freshly distilled methyl vinyl ketone (7.2 µL, 0.0884 mmol, 1.25 equiv) was then added, and the reaction vessel was placed between two 34W blue LEDs (~5-6 cm away from each lamp) and stirred for 24 h with a small fan to keep the reactions at 23 ºC. Once complete, the reaction was diluted with sat. aq. NaHCO3 (0.8 mL) and EtOAc (0.8 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (4 x 1 mL). The combined organic layers were washed with 1 M LiCl (5 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (20 → 40% EtOAc/hexanes) to afford pure (+)-rumphellaone A (4) (15 mg, 78% yield) as a yellow solid. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 192 Rf = 0.27 (silica gel, 40% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +43.4° (c = 0.35, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 2.63 (ddd, J =18.1, 10.0, 8.9 Hz, 1H), 2.53 (ddd, J = 18.1, 10.0, 5.0 Hz, 1H), 2.36 (t, J = 7.9 Hz, 2H), 2.12 (s, 3H), 2.09 – 2.02 (m, 2H), 2.03 – 1.97 (m, 1H), 1.90 (ddd, J = 10.2, 9.6, 5.3 Hz, 2H), 1.88 – 1.81 (m, 1H), 1.69 – 1.61 (m, 2H), 1.57 (ddd, J = 10.8, 8.6, 0.8 Hz, 1H), 1.42 (t, J = 10.3 Hz, 1H), 1.31 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 208.8, 177.1, 87.4, 44.6, 44.4, 42.1, 33.7, 33.1, 31.1, 30.8, 30.1, 29.3, 25.2, 25.0, 22.6. FTIR (NaCl, thin film, cm-1): 2953, 2929, 2865, 1770, 1715, 1455, 1366, 1250, 1162, 1124, 1077, 938, 803, 645. HRMS (ESI-TOF, m/z): calc’d for C15H25O3 [M+H]+: 253.1798; found: 253.1799. O Me O Me 192 (1.25 equiv) Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (1 mol %) OH Me H O Me O 263 O Me Me Me H K2HPO4, DMF blue LEDs (52% yield) O Me O epi-C8 rumphellaone A (261) 263 (15.0 mg, 0.066 mmol, 1.00 equiv) was subjected to an analogous procedure to afford epi-C8-rumphellaone A (260) (8.1 mg, 52% yield) as a white solid. Rf = 0.33 (silica gel, 40% EtOAc/Hexanes, UV, p-anisaldehyde) [α]D25 = +38.5° (c = 0.41, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 2.63 – 2.56 (m, 2H), 2.39 (dd, J = 8.6, 6.6 Hz, 2H), 2.13 (s, 3H), 2.10 – 1.96 (m, 2H), 1.90 (ddd, J = 13.0, 8.8, 7.2 Hz, 1H), 1.78 (tdd, J = 9.2, 6.6, Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 193 0.8 Hz, 1H), 1.71 – 1.57 (m, 3H), 1.51 (t, J = 10.4 Hz, 1H), 1.29 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 208.7, 177.1, 87.3, 44.6, 44.1, 41.9, 34.5, 33.4, 31.6, 31.1, 30.2, 29.3, 25.0, 24.0, 22.6. FTIR (NaCl, thin film, cm-1): 2952, 2932, 2865, 1769, 1715, 1455, 1422, 1365, 1234, 1169, 1155, 1075, 963, 939, 801, 647. HRMS (ESI-TOF, m/z): calc’d for C15H25O3 [M+H]+: 253.1798; found: 253.1799. Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 194 2.8.4 Comparison of 1H NMR Spectroscopic Data for Natural and Synthetic (+)Rumphellaone A (4) (carbon numbering as reported by Sung et al.)7 O 15 Me 11 14 4 3 1 Me 10 H 9 Me 13 Me 12 2 O 8 7 5 6 O (+)-rumphellaone A (4) Carbon Number 1 2 3 6a 6b 7⍺ 7β 9 10⍺ 10β 12 13 14 15 Natural (+)-rumphellaone A 1 H 400 MHz, CDCl3 1.91 (ddd, J = 10.0, 9.2, 5.6 Hz, 2H) 1.67 (m, 2H) 2.37 (t, J = 8.0 Hz, 2H) 2.63 (ddd, J = 18.0, 9.6, 8.8 Hz, 1H) 2.54 (ddd, J = 18.0, 10.0, 4.8 Hz, 1H) 1.84 (m, 1H) 2.01 (m, 1H) 2.06 (ddd, 10.4, 10.0, 10.0 Hz, 2H) 1.57 (dd, J = 10.0, 10.0 Hz, 1H) 1.42 (dd, J = 10.4, 10.0 Hz, 1H)) 2.13 (s, 3H) 1.31 (s, 3H) 1.03 (s, 3H) 1.07 (s, 3H) Synthetic (+)-rumphellaone A 1 H 400 MHz, CDCl3 1.90 (ddd, J = 10.2, 9.6, 5.3 Hz, 2H) 1.65 (m, 2H) 2.36 (t, J = 7.9 Hz, 2H) 2.63 (ddd, J =18.1, 10.0, 8.9 Hz, 1H) 2.53 (ddd, J = 18.1, 10.0, 5.0 Hz, 1H) 1.84 (m, 1H) 2.01 (m, 1H) 2.06 (m, 2H) 1.57 (ddd, J = 10.8, 8.6, 0.8 Hz, 1H) 1.42 (t, J = 10.3 Hz, 1H) 2.12 (s, 3H) 1.31 (s, 3H) 1.03 (s, 3H) 1.06 (s, 3H) 195 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 2.8.5 Comparison of 13C NMR Spectroscopic Data for Natural and Synthetic (+)Rumphellaone A (4)7 O 15 Me 11 14 4 3 1 Me 10 H 9 Me 13 Me 12 2 8 7 O 5 6 O (+)-rumphellaone A (4) Carbon Number Natural (+)-rumphellaone A 13C 100 MHz, CDCl3 Synthetic (+)-rumphellaone A 13C 101 MHz, CDCl3 Δ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 44.5 25.1 42.0 208.6 177.0 29.2 30.6 87.2 44.3 33.6 33.0 29.9 24.9 22.5 30.9 44.6 25.2 42.1 208.8 177.1 29.3 30.8 87.4 44.4 33.7 33.1 30.1 25.0 22.6 31.1 0.1 0.1 0.1 0.2 0.1 0.1 0.2 0.2 0.1 0.1 0.1 0.2 0.1 0.1 0.2 Chapter 2 – Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Synthesis of (+)-Rumphellaone A 196 2.9 REFERENCES (1) Dembitsky, V. 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Soc. 2013, 135 (17), 6677– 6693. Appendix 2 – Spectra Relevant to Chapter 2 203 Appendix 2 Spectra Relevant to Chapter 2: Modular Synthesis of Enantioenriched Cyclobutanes: Applications Towards the Total Synthesis of (+)-Rumphellaone A JCB_05_048_P1.1.fid nmrsu spect CDCl3 295.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 98.9 1.0000 11.7000 4.0894 2018-03-31T06:55:59 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 89d 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 f1 (ppm) Nucleus 9.60 0.92 8.76 8.76 8.75 8.75 0.98 0.97 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment Title Value 3.02 1.02 / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_048_P1/ 1/ fid 1.5 3.01 Parameter 1.0 3.14 Data File Name 0.99 8.14 8.13 8.13 8.12 8.12 8.11 8.11 8.10 8.10 8.09 8.09 7.45 7.44 7.44 7.43 7.42 7.41 7.41 7.40 7.39 7.39 7.19 7.16 7.14 7.14 7.13 7.13 7.12 7.12 7.11 7.11 7.06 7.04 7.04 7.03 7.02 7.02 7.00 6.98 3.04 2.03 2.02 3.38 3.37 3.37 2.79 2.76 2.74 1.00 4.05 4.03 4.03 4.02 4.02 4.01 4.00 4.00 3.98 1.00 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 0.5 0.0 -0.5 1.51 1.49 1.24 1.24 1.23 1.22 1.20 1.20 2.28 2.25 2.23 2.23 2.17 2.17 2.16 2.15 2.14 2.14 2.14 2.12 2.11 0.99 S46 Appendix 2 – Spectra Relevant to Chapter 2 204 / Volumes/ nmrdata/ jbeck/ nmr/ JCB_05_048_P1/ 3/ fid JCB_05_048_P1.3.fid 1.3631 2018-03-31T07:09:46 Acquisition Time Acquisition Date 200 190 Nucleus 180 13C Spectrometer Frequency 100.62 2.0000 10.0000 Pulse Width 170 170.6 Relaxation Delay 128 64.2 Receiver Gain 160 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Number of Scans Probe 295.1 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner 150 148.0 140 130 120 110 138.7 138.4 136.4 135.0 134.7 128.9 127.9 127.5 126.7 121.5 121.1 116.5 Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value Data File Name Parameter 100 90 f1 (ppm) 89d 80 70 57.7 60 50 30 20 37.8 35.8 35.7 30.2 25.2 21.2 40 10 0 -10 S47 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 Appendix 2 – Spectra Relevant to Chapter 2 205 CRL_02_151_1.2.fid CDCl3 295.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 112.8 1.0000 11.7000 4.0894 2018-07-02T12:33:22 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 8.5 spect Instrument 9.5 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 7.5 6.5 7.15 7.15 7.14 7.14 7.13 7.13 7.11 7.10 3.92 Comment Title 5.5 f1 (ppm) 191 4.5 3.78 3.75 3.73 3.71 Value 3.5 2.5 2.92 2.92 2.89 2.89 1.00 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_151_1/ 2/ fid 2.74 0.99 1.02 Parameter 1.5 2.32 2.14 2.14 2.12 2.11 2.11 2.11 2.09 2.09 1.97 1.95 1.92 1.00 1.29 1.25 2.95 2.83 Data File Name 0.5 -0.5 S77 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 Appendix 2 – Spectra Relevant to Chapter 2 206 CRL_02_151_1.3.fid nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 72.0 1.0000 10.0000 1.3631 2018-07-02T12:54:36 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 140.7 135.9 129.2 126.6 191 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 178.8 Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_151_1/ 3/ fid Parameter Data File Name 80 70 60 50 30 39.4 36.6 35.1 30.6 40 23.6 21.2 20 10 0 -500 -10 S78 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 2 – Spectra Relevant to Chapter 2 207 55.2 16 295.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 112.8 1.0000 11.7000 4.0894 2018-05-03T08:13:35 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.4 Lowest Frequency 15 8012.8 Spectral Width 10 CDCl3 Solvent 11 spect Instrument 12 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 6/ fid CRL_02_079_1.6.fid Data File Name Title Value 9 8 7 6 f1 (ppm) 7.14 7.11 7.11 7.09 4.04 Parameter 5 4 3 2 1 0 -1 -2 -3 2.93 2.90 2.32 2.26 2.25 2.24 2.23 2.23 2.22 2.21 2.01 2.01 1.99 1.99 1.99 1.98 1.97 1.95 1.95 1.95 1.74 1.73 1.71 1.71 1.71 1.69 1.69 1.69 1.67 1.67 1.67 1.13 1.12 1.00 3.17 1.92 5.03 3.01 2.86 2.92 CRL_02_079_1.6.fid -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 20000 Appendix 2 – Spectra Relevant to Chapter 2 208 CRL_02_079_1.5.fid 209.16 nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 78.7 1.0000 10.0000 1.3631 2018-05-03T08:11:43 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1945.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment CRL_02_079_1.5.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 5/ fid Parameter 142.16 135.54 129.13 126.93 Data File Name 80 70 60 40 30 20 41.81 41.44 41.33 34.00 30.95 30.02 24.68 22.43 21.14 51.96 50 10 0 -10 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 Appendix 2 – Spectra Relevant to Chapter 2 209 CRL_02_079_1.7.ser 11.7000 0.1970 2018-05-03T08:14:31 Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) Acquired Size Spectral Size 10 (1H, 1H) Nucleus 11 (-207.9, -207.9) Lowest Frequency 12 (5197.5, 5197.5) Spectral Width Spectrometer Frequency (400.13, 400.13) 64.2 2.0000 Receiver Gain 9 8 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 2 Probe COSY Experiment Number of Scans 295.2 CDCl3 Solvent cosygpppqf spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 7/ ser Data File Name Parameter CRL_02_079_1.7.ser 7 6 f2 (ppm) 5 4 3 2 1 0 12 11 10 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 210 f1 (ppm) CDCl3 295.2 hsqcedetgpsisp2.4 HSQC-EDITED Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 2 197.4 1.5000 11.7000 0.2135 2018-05-03T08:25:15 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1H, 13C) (1024, 180) (1024, 1024) Nucleus Acquired Size Spectral Size 9.0 (-527.0, -1265.2) Lowest Frequency 10.0 (4795.4, 16611.3) Spectral Width 7.0 spect Instrument 8.0 nmrsu Owner Spectrometer Frequency (400.13, 100.62) Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 8/ ser CRL_02_079_1.8.ser Data File Name Value Title Parameter CRL_02_079_1.8.ser 6.0 5.0 4.0 f2 (ppm) 3.0 2.0 1.0 0.0 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 2 – Spectra Relevant to Chapter 2 211 f1 (ppm) 0.4260 2018-05-03T08:36:48 Acquisition Time Acquisition Date (1H, 13C) (2048, 256) (2048, 1024) Nucleus Acquired Size Spectral Size 10.0 (-173.0, -1118.9) Lowest Frequency 11.0 (4807.7, 22321.4) Spectral Width 8.0 11.7000 Pulse Width 9.0 2.0000 Relaxation Delay Spectrometer Frequency (400.13, 100.62) 197.4 7.0 6.0 5.0 f2 (ppm) 4.0 3.0 2.0 1.0 0.0 HMBC Experiment Receiver Gain hmbcetgpl3nd Pulse Sequence Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 295.1 Temperature 4 CDCl3 Solvent Probe spect Instrument Number of Scans nmrsu Owner 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 Bruker BioSpin GmbH Origin 10 20 CRL_02_079_1.9.ser Title 0 -10 Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 9/ ser Value Data File Name Parameter CRL_02_079_1.9.ser Appendix 2 – Spectra Relevant to Chapter 2 212 f1 (ppm) 9.5 CRL_02_079_1.10.ser (1024, 1024) Spectral Size 7.5 (1024, 256) Acquired Size 8.0 (1H, 1H) Nucleus 8.5 (-168.0, -168.0) Lowest Frequency 9.0 (4000.0, 4000.0) Spectral Width 6.0 2018-05-03T09:21:16 Acquisition Date 6.5 0.2560 Acquisition Time 7.0 11.7000 Pulse Width Spectrometer Frequency (400.13, 400.13) 1.8000 Relaxation Delay NOESY Experiment 64.2 noesygpphzs Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 4 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_079_1/ 10/ ser Data File Name Parameter CRL_02_079_1.10.ser 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 213 f1 (ppm) nmrsu spect CDCl3 294.9 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 156.2 1.0000 11.7000 4.0894 2017-10-03T11:18:26 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 195 11.5 10.5 9.5 8.5 0.95 5.5 f1 (ppm) 1.00 6.28 6.28 6.27 6.27 5.98 5.98 5.97 5.97 5.97 5.97 6.5 4.5 3.5 1.02 3.00 2.98 2.98 2.96 2.95 2.93 2.5 1.5 2.17 4.43 1.01 1.17 2.19 7.30 7.30 7.29 7.29 0.95 7.5 3.10 2.82 2.34 2.34 2.33 2.32 2.32 2.32 2.31 2.30 2.07 2.07 2.06 2.06 2.05 2.05 2.04 2.03 2.03 2.03 2.03 2.01 2.01 1.99 1.95 1.95 1.93 1.93 1.93 1.93 1.91 1.90 1.87 1.87 1.84 1.84 1.84 1.82 1.81 1.72 1.71 1.70 1.69 1.69 1.68 1.67 1.67 1.66 1.66 1.65 1.65 1.64 1.64 1.62 1.62 1.61 1.11 1.10 1.08 Nucleus Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment CRL_01_235_1.1.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_01_235_1/ 1/ fid Parameter Data File Name 0.5 -0.5 S99 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 110000 120000 130000 140000 Appendix 2 – Spectra Relevant to Chapter 2 214 nmrsu spect CDCl3 295.0 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 64.2 1.0000 10.0000 1.3631 2017-10-03T11:45:31 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 104.0 110.3 140.9 158.9 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 209.1 Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment CRL_01_235_1.3.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_01_235_1/ 3/ fid Parameter 80 70 60 195 50 50.4 Data File Name 30 20 41.5 39.0 34.6 34.3 30.6 30.1 24.2 22.3 40 10 0 -10 S100 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 Appendix 2 – Spectra Relevant to Chapter 2 215 CRL_02_152_1.1.fid 16 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.4 Lowest Frequency 15 8012.8 Spectral Width 12 2018-07-03T19:08:08 Acquisition Date Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time 11 10 1.0000 Pulse Width 112.8 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 295.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment CRL_02_152_1.1.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_152_1/ 1/ fid Parameter Data File Name 9 8 6 f1 (ppm) 2.01 3.04 4.05 7 5 4 2.03 1.00 3 2 1 0 -1 -2 -3 7.31 7.31 7.30 7.29 7.29 7.28 7.27 7.27 7.22 7.21 7.20 7.19 7.19 7.18 7.17 7.17 7.17 7.15 7.15 7.13 7.13 7.10 4.17 4.16 4.16 4.15 4.13 4.12 4.10 4.09 4.09 4.08 3.79 3.77 3.74 2.87 2.85 2.72 2.71 2.70 2.69 2.68 2.32 2.13 2.10 2.08 2.00 1.98 1.98 1.98 1.97 1.97 1.96 1.96 1.95 1.95 1.95 1.94 1.94 1.93 1.93 1.91 1.29 1.19 1.01 2.03 3.11 1.06 3.07 3.33 3.12 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 Appendix 2 – Spectra Relevant to Chapter 2 216 10.0000 1.3631 2018-07-03T19:29:56 Pulse Width Acquisition Time Acquisition Date -1946.2 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 Relaxation Delay 1D Experiment 72.0 zgpg30 Pulse Sequence Receiver Gain 295.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment CRL_02_152_1.3.fid Value Title 172.86 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_152_1/ 3/ fid 141.36 141.07 135.79 129.13 128.58 128.54 126.62 126.14 Data File Name Parameter CRL_02_152_1.3.fid 80 70 55.49 63.57 60 50 30 20 39.35 36.38 35.25 32.43 30.70 30.64 23.74 21.16 40 10 0 -10 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 2 – Spectra Relevant to Chapter 2 217 12.0 nmrsu spect CDCl3 295.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 197.4 1.0000 11.7000 4.0894 2018-07-06T18:28:12 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date Nucleus 11.0 1H 10.0 Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment CRL_02_157_1.2.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_157_1/ 2/ fid 9.0 8.0 7.15 7.14 7.0 6.0 5.0 f1 (ppm) 199 4.0 3.0 2.0 2.85 0.94 0.93 Parameter 1.84 1.86 3.90 3.88 3.85 3.83 3.23 3.22 3.20 3.20 0.92 7.89 7.89 7.88 7.88 7.87 7.81 7.80 7.79 7.79 7.78 7.77 3.77 2.33 2.23 2.23 2.21 2.21 2.20 2.20 2.18 2.18 2.11 2.08 2.05 0.91 1.42 1.39 2.76 2.71 Data File Name 1.0 0.0 S79 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 Appendix 2 – Spectra Relevant to Chapter 2 218 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_157_1/ 3/ fid CRL_02_157_1.3.fid spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 78.7 1.0000 10.0000 1.3631 2018-07-06T19:11:13 Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 199 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 nmrsu 168.9 Bruker BioSpin GmbH 162.2 Owner 139.7 136.3 134.8 129.3 129.1 126.5 124.0 Origin Comment Title Value Data File Name Parameter 80 70 60 52.5 50 30 39.6 37.5 35.3 30.5 40 23.7 21.2 20 10 0 S80 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 Appendix 2 – Spectra Relevant to Chapter 2 219 CRL_02_196_cr1.1.fid 2018-08-21T14:49:57 Acquisition Date 32768 65536 Acquired Size Spectral Size 14 1H Nucleus 15 -1636.5 Lowest Frequency 16 8196.7 Spectral Width 10 3.9977 Acquisition Time 11 10.0000 Pulse Width 12 1.0000 Relaxation Delay 13 32.0 Receiver Gain Spectrometer Frequency 400.15 Z163739_0009 (PI HR-400-S1-BBF/ H/ D-5.0-Z SP) 16 Number of Scans 1D Experiment Probe 298.1 CDCl3 Solvent zg30 Avance Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_196_cr1/ 1/ fid Title 9 2.03 2.13 0.95 8 7 0.97 0.97 6 5 f1 (ppm) 4 1.00 7.87 7.86 7.85 7.85 7.77 7.77 7.76 7.75 7.35 7.35 7.34 7.34 6.29 6.29 6.28 6.28 6.09 6.09 Data File Name 0.99 Value 3 2 2.15 Parameter 1 0 -1 3.87 3.85 3.83 3.80 3.41 3.39 2.21 2.19 2.16 2.13 2.13 2.11 2.11 2.10 2.08 2.08 2.03 1.41 1.38 3.09 2.96 CRL_02_196_cr1.1.fid -2 -3 -4 -1000000 0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000 10000000 11000000 12000000 13000000 14000000 15000000 16000000 17000000 18000000 Appendix 2 – Spectra Relevant to Chapter 2 220 Varian Origin 5.1000 2.4999 2018-08-04T14:27:26 Pulse Width Acquisition Time Acquisition Date 1H 11990 65536 Nucleus Acquired Size Spectral Size 12 -596.6 Lowest Frequency 13 4796.2 Spectral Width 11 1.0000 Relaxation Delay Spectrometer Frequency 300.09 18 Receiver Gain 1D Experiment ASW7284 s2pul Pulse Sequence 8 25.0 Temperature Number of Scans cdcl3 Solvent Probe mercury Instrument Owner PROTON01 CRL_02_178_1 Title 10 9 8 4.47 7 6 f1 (ppm) 5 1.00 4 0.91 Value 3 2 3.23 1.13 1.21 7.13 7.13 7.12 / Volumes/ nmrdata-1/ clacker/ vnmrsys/ data/ CRL_02_178_1/ PROTON01.fid/ fid Comment Data File Name 1 0 3.91 3.88 3.85 3.82 3.81 3.23 3.19 2.34 2.33 2.25 2.22 2.22 2.19 2.13 2.13 2.09 2.06 1.42 1.41 1.40 1.39 5.94 PROTON01 Parameter CRL_02_178_1 -1 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 Appendix 2 – Spectra Relevant to Chapter 2 221 12.0 CRL_02_158_1.2.fid nmrsu spect CDCl3 295.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 30.3 1.0000 11.7000 4.0894 2018-07-07T18:31:00 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date Nucleus 11.0 1H Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 10.0 9.0 8.0 7.0 1.06 1.92 1.86 1.03 1.88 Comment Title Value 202 6.0 5.0 f1 (ppm) 4.0 3.0 2.0 2.83 0.96 0.94 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_158_1/ 2/ fid 3.39 1.3 3.22 Parameter 3.8 3.8 3.8 3.8 3.8 3.7 3.3 3.3 7.2 7.2 7.2 7.2 7.2 7.2 7.2 7.2 7.1 7.1 7.1 7.1 7.1 7.1 7.1 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.8 6.7 6.7 6.7 6.7 2.3 2.2 2.2 2.2 2.2 2.2 2.2 2.1 2.1 1.9 1.9 1.9 0.95 0.9 1.0 3.04 Data File Name 0.0 S89 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 Appendix 2 – Spectra Relevant to Chapter 2 222 nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 38.0 1.0000 10.0000 1.3631 2018-07-07T18:52:16 Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 159.6 202 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Owner 142.8 142.1 135.5 129.1 129.0 126.6 120.0 113.6 111.0 Origin Comment CRL_02_158_1.3.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_158_1/ 3/ fid Parameter Data File Name 80 70 56.7 55.2 60 50 30 40.2 37.4 37.2 30.9 40 23.3 21.1 20 10 0 -10 S90 0 500 1000 1500 2000 2500 3000 3500 4000 Appendix 2 – Spectra Relevant to Chapter 2 223 25.0 s2pul 1D autox7991 8 28 1.0000 5.8000 3.0000 2018-08-10T13:03:49 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 24000 65536 Nucleus Acquired Size Spectral Size 12 -1030.2 Lowest Frequency 13 8000.0 Spectral Width 11 cdcl3 Solvent Spectrometer Frequency 499.64 inova Instrument 9 8 Varian Origin 10 CRL_02_182_1 Comment Owner PROTON01 Title Value / Volumes/ nmrdata/ clacker/ vnmrsys/ data/ CRL_02_182_1/ PROTON01.fid/ fid Data File Name PROTON01 Parameter CRL_02_182_1 9.24 15.07 2.00 7 6 f1 (ppm) 5 4 2 1 1.01 6.97 2.13 2.99 0.98 1.00 1.14 6.96 3.69 6.79 3.01 3.02 3 0 -1 -2 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 Appendix 2 – Spectra Relevant to Chapter 2 224 CRL_02_164_1.2.fid 4.0894 2018-07-14T17:31:43 Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H Spectrometer Frequency 400.13 1.0000 11.7000 Pulse Width Receiver Gain Relaxation Delay 1 55.5 Number of Scans Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.2 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment 9.5 8.5 7.5 205 6.5 5.5 f1 (ppm) 4.5 2.93 Title 3.5 0.97 Value 2.5 0.96 / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_164_1/ 2/ fid 2.93 1.00 0.96 Parameter 6.36 6.32 6.25 6.23 6.21 6.19 7.33 7.32 7.31 7.31 7.16 7.15 7.14 7.14 7.12 7.11 7.10 7.10 6.87 6.87 6.86 6.85 6.84 6.84 1.94 1.97 2.07 1.90 3.81 3.45 3.43 3.40 3.38 3.37 1.5 2.76 2.75 2.75 2.74 2.73 2.73 2.73 2.73 2.71 2.71 2.71 2.33 2.13 2.13 2.11 2.11 2.11 2.10 2.08 2.08 2.07 2.06 2.06 1.90 1.87 1.84 0.95 0.95 1.18 1.16 2.71 2.71 Data File Name 0.5 -0.5 S91 0 500 1000 1500 2000 2500 3000 3500 4000 Appendix 2 – Spectra Relevant to Chapter 2 225 CRL_02_164_1.3.fid 1.3631 2018-07-14T17:52:57 Pulse Width Acquisition Time Acquisition Date 13C 114.0 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 1.0000 10.0000 Relaxation Delay 512 64.2 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Number of Scans Probe 295.1 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument 158.9 Experiment nmrsu Owner 142.3 135.3 130.7 130.0 129.0 128.1 127.3 126.6 Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_164_1/ 3/ fid Parameter Data File Name 80 205 70 55.9 55.4 60 50 30 20 40.0 39.6 36.9 30.4 23.6 21.2 40 10 0 -10 S92 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 Appendix 2 – Spectra Relevant to Chapter 2 226 CRL_02_219_1_dilute.2.fid nmrsu spect CDCl3 295.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 197.4 30.0000 11.7000 4.0894 2018-10-01T18:14:48 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment Title 9.5 8.5 7.5 6.5 5.5 f1 (ppm) 206 4.5 3.5 4.42 4.40 4.38 4.35 1.02 Value 2.5 2.84 2.90 1.04 1.05 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_219_1_dilute/ 2/ fid 1.39 1.5 2.92 Parameter 3.54 3.51 2.67 2.30 2.22 2.20 2.20 2.18 2.07 2.04 2.02 1.00 8.10 8.08 7.96 7.96 7.94 7.94 7.69 7.68 7.67 7.67 7.66 7.65 7.65 7.52 7.51 7.50 7.50 7.49 7.48 7.48 7.22 7.21 7.09 7.07 0.97 0.96 1.05 1.06 2.05 3.19 0.89 3.07 Data File Name 0.5 -0.5 S93 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 Appendix 2 – Spectra Relevant to Chapter 2 227 CRL_02_219_1_redo.3.fid nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 55.5 1.0000 10.0000 1.3631 2018-10-01T15:53:12 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus 148.0 143.4 142.6 135.2 130.2 129.0 128.9 128.8 128.7 127.1 126.9 126.8 125.4 123.7 121.7 160.6 Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_219_1_redo/ 3/ fid Parameter Data File Name 80 206 70 59.1 60 50 30 39.7 37.9 35.4 31.2 40 23.7 21.1 18.9 20 10 0 -10 S94 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 Appendix 2 – Spectra Relevant to Chapter 2 228 16 CRL_02_199_1.1.fid CRL_02_199_1.1.fid 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.1 Lowest Frequency 15 8012.8 Spectral Width 10 2018-09-05T21:08:38 Acquisition Date 11 4.0894 Acquisition Time 12 11.7000 Pulse Width Spectrometer Frequency 400.13 1.0000 Relaxation Delay 1D Experiment 142.8 zg30 Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_199_1/ 1/ fid Parameter Data File Name 9 7 0.99 0.97 6 f1 (ppm) 1.00 1.02 1.04 1.04 0.99 1.01 8 5 4 3 2.14 2 3.02 3.17 0.99 1.00 1 0 -1 8.10 8.08 8.08 7.95 7.95 7.93 7.93 7.93 7.68 7.68 7.66 7.66 7.66 7.64 7.64 7.51 7.51 7.50 7.49 7.49 7.48 7.47 7.47 7.31 7.31 7.31 7.31 7.06 7.06 6.28 6.27 6.27 6.26 6.11 6.10 4.40 4.39 4.37 4.37 4.37 4.35 4.35 4.32 4.32 3.67 3.65 2.67 2.14 2.13 2.13 2.12 2.11 2.11 1.41 0.85 3.33 -2 -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 Appendix 2 – Spectra Relevant to Chapter 2 229 2018-09-05T21:56:26 Acquisition Date -1945.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 104.44 110.27 130.20 128.85 127.14 125.47 123.65 121.63 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 10.0000 1.3631 Acquisition Time 1.0000 Pulse Width Relaxation Delay 1D Experiment 72.0 zgpg30 Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 1024 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_199_1/ 3/ fid CRL_02_199_1.3.fid 159.89 158.61 Data File Name Value 147.99 143.51 141.04 Title Parameter CRL_02_199_1.3.fid 80 70 57.05 60 50 30 20 38.70 37.94 31.08 29.84 23.42 18.93 40 10 0 -10 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 2 – Spectra Relevant to Chapter 2 230 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 4 197.4 1.5000 11.7000 0.2135 2018-09-05T23:27:27 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) Acquired Size Spectral Size 8.0 (1H, 13C) Nucleus 9.0 (-557.5, -1272.9) Lowest Frequency 10.0 (4795.4, 16611.3) Spectral Width 7.0 HSQC-EDITED Experiment Spectrometer Frequency (400.13, 100.62) 295.1 CDCl3 Solvent hsqcedetgpsisp2.4 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment 6.0 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_199_1/ 5/ ser CRL_02_199_1.5.ser Data File Name Value Title Parameter CRL_02_199_1.5.ser 5.0 4.0 f2 (ppm) 3.0 2.0 1.0 0.0 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 2 – Spectra Relevant to Chapter 2 231 f1 (ppm) CRL_02_199_1.2.ser 11.7000 0.1970 2018-09-05T21:09:34 Pulse Width Acquisition Time Acquisition Date (1024, 128) (1024, 1024) Acquired Size Spectral Size 10 (1H, 1H) Nucleus 11 (-238.4, -238.4) Lowest Frequency 12 (5197.5, 5197.5) Spectral Width 8 2.0000 Relaxation Delay 9 64.2 Receiver Gain Spectrometer Frequency (400.13, 400.13) Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 Probe COSY Experiment Number of Scans 295.2 CDCl3 Solvent cosygpppqf spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_199_1/ 2/ ser Data File Name Parameter CRL_02_199_1.2.ser 7 6 f2 (ppm) 5 4 3 2 1 0 12 11 10 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 232 f1 (ppm) CRL_02_199_1.4.ser 2018-09-05T21:58:37 Acquisition Date (-198.6, -198.6) (1H, 1H) (1024, 256) (1024, 1024) Lowest Frequency Nucleus Acquired Size Spectral Size 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f2 (ppm) (4000.0, 4000.0) Spectral Width Spectrometer Frequency (400.13, 400.13) 11.7000 0.2560 Acquisition Time 1.8000 Pulse Width Relaxation Delay NOESY Experiment 112.8 noesygpphzs Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 8 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_199_1/ 4/ ser Data File Name Parameter CRL_02_199_1.4.ser 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 233 f1 (ppm) CDCl3 295.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 197.4 1.0000 11.7000 4.0894 2018-09-21T12:03:49 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 8.5 spect Instrument 9.5 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 7.5 CRL_02_206_1.1.fid Comment Title Value 7.09 3.66 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_206_1/ 1/ fid 6.5 5.5 f1 (ppm) 207 4.5 3.5 2.5 1.5 2.91 1.00 1.02 1.00 Parameter 3.57 3.54 3.54 3.52 3.51 3.49 1.12 1.26 1.24 1.24 1.16 0.5 2.31 2.16 2.15 2.14 2.13 2.13 2.13 2.11 2.11 2.04 2.02 1.99 1.69 1.67 6.62 9.72 2.89 Data File Name -0.5 S95 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 Appendix 2 – Spectra Relevant to Chapter 2 234 CRL_02_206_1.2.fid nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 55.5 1.0000 10.0000 1.3631 2018-09-21T12:45:44 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 134.9 128.9 126.3 144.1 207 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_206_1/ 2/ fid Parameter Data File Name 83.2 80 70 60 50 30 20 34.3 34.0 32.4 26.6 25.3 24.9 21.1 42.9 40 10 0 S96 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 Appendix 2 – Spectra Relevant to Chapter 2 235 16 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1573.3 Lowest Frequency 15 8012.8 Spectral Width 12 2018-09-06T21:20:09 Acquisition Date Spectrometer Frequency 400.13 11.7000 4.0894 Acquisition Time 11 10 1.0000 Pulse Width 78.7 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 295.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 1/ fid CRL_02_200_1.1.fid Data File Name Value Title Parameter 9 8 0.97 7 0.99 0.98 6 5 f1 (ppm) 4 3 2 1 0 -1 -2 7.22 7.22 7.22 7.21 6.19 6.19 6.18 6.18 5.89 5.89 5.89 5.88 5.88 3.46 3.46 3.44 3.43 3.41 3.41 3.41 3.39 3.39 2.02 2.01 2.01 2.00 1.99 1.99 1.78 1.75 1.18 1.16 1.13 1.11 2.08 1.00 6.75 6.22 3.20 3.09 1.00 CRL_02_200_1.1.fid -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 Appendix 2 – Spectra Relevant to Chapter 2 236 CRL_02_200_1.3.fid 10.0000 1.3631 2018-09-06T21:52:05 Pulse Width Acquisition Time Acquisition Date 32768 65536 Spectral Size 103.26 109.86 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 13C Nucleus -1967.9 Lowest Frequency Acquired Size 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 Relaxation Delay 1D Experiment 64.2 zgpg30 Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value 159.95 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 3/ fid 140.58 Data File Name Parameter CRL_02_200_1.3.fid 83.04 80 70 60 50 30 20 41.48 34.38 31.98 27.74 26.33 25.01 24.76 40 10 0 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 Appendix 2 – Spectra Relevant to Chapter 2 237 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 4 197.4 1.5000 11.7000 0.2135 2018-09-06T21:53:26 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1024, 180) (1024, 1024) Acquired Size Spectral Size 8.0 (1H, 13C) Nucleus 9.0 (-554.9, -1272.3) Lowest Frequency 10.0 (4795.4, 16611.3) Spectral Width 7.0 HSQC-EDITED Experiment Spectrometer Frequency (400.13, 100.62) 295.1 CDCl3 Solvent hsqcedetgpsisp2.4 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment 6.0 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 4/ ser CRL_02_200_1.4.ser Data File Name Value Title Parameter CRL_02_200_1.4.ser 5.0 4.0 f2 (ppm) 3.0 2.0 1.0 0.0 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 2 – Spectra Relevant to Chapter 2 238 f1 (ppm) CRL_02_200_1.2.ser 0.1970 2018-09-06T21:21:12 Acquisition Time Acquisition Date (1024, 128) (1024, 1024) Acquired Size Spectral Size 10 (1H, 1H) Nucleus 11 (-235.8, -235.8) Lowest Frequency 12 (5197.5, 5197.5) Spectral Width 8 11.7000 9 2.0000 Pulse Width Spectrometer Frequency (400.13, 400.13) 43.7 COSY Experiment Relaxation Delay cosygpppqf Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 2 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 2/ ser Data File Name Parameter CRL_02_200_1.2.ser 7 6 f2 (ppm) 5 4 3 2 1 0 12 11 10 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 239 f1 (ppm) CRL_02_200_1.5.ser Title 2.0000 11.7000 0.4260 2018-09-06T22:15:25 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 6.0 5.0 f2 (ppm) 4.0 3.0 2.0 1.0 0.0 (2048, 1024) Spectral Size 9.0 (2048, 256) Acquired Size 10.0 (1H, 13C) Nucleus 11.0 140 (-201.0, -1125.9) Lowest Frequency 210 200 190 180 170 160 150 130 (4807.7, 22321.4) Spectral Width 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Spectrometer Frequency (400.13, 100.62) 7.0 197.4 Receiver Gain 8.0 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 4 Probe HMBC Experiment Number of Scans 295.1 CDCl3 Solvent hmbcetgpl3nd spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 5/ ser Value Data File Name Parameter CRL_02_200_1.5.ser Appendix 2 – Spectra Relevant to Chapter 2 240 f1 (ppm) 9.5 CRL_02_200_1.6.ser 0.2560 2018-09-06T22:59:58 Acquisition Time Acquisition Date (1024, 1024) Spectral Size 7.5 (1024, 256) Acquired Size 8.0 (1H, 1H) Nucleus 8.5 (-196.0, -196.0) Lowest Frequency 9.0 (4000.0, 4000.0) Spectral Width 6.0 11.7000 Pulse Width 6.5 1.8000 Relaxation Delay 7.0 64.2 Receiver Gain Spectrometer Frequency (400.13, 400.13) Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 6 Probe NOESY Experiment Number of Scans 295.1 CDCl3 Solvent noesygpphzs spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_200_1/ 6/ ser Data File Name Parameter CRL_02_200_1.6.ser 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 241 f1 (ppm) / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_163_cr/ 1/ fid CRL_02_163_cr.1.fid zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Pulse Sequence Experiment Probe 2018-07-16T11:06:11 Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 9.5 4.0894 Pulse Width Spectrometer Frequency 400.13 1.0000 11.7000 Relaxation Delay 8.5 295.1 Temperature 16 CDCl3 Solvent 30.3 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title 7.5 6.5 5.5 f1 (ppm) 208 4.5 3.5 2.5 2.85 1.02 0.99 0.99 Data File Name 1.5 5.62 Value 2.10 3.80 3.78 3.77 3.75 3.74 3.73 3.71 3.70 3.09 3.07 3.05 3.02 1.00 7.17 7.16 7.16 7.15 7.14 7.11 3.94 1.21 0.5 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 -0.5 S81 2.34 2.31 2.31 2.29 2.29 2.29 2.29 2.28 2.27 2.27 2.27 2.26 2.26 2.25 2.25 2.08 2.08 2.07 2.06 2.05 2.05 2.05 2.04 2.03 2.03 1.84 1.82 1.79 Parameter Appendix 2 – Spectra Relevant to Chapter 2 242 CRL_02_163_cr.3.fid 1.3631 2018-07-16T11:27:54 Pulse Width Acquisition Time Acquisition Date 13C 208 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 1.0000 10.0000 Relaxation Delay 512 64.2 Receiver Gain Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Number of Scans Probe 295.1 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner 141.9 135.6 129.1 126.7 Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_163_cr/ 3/ fid Parameter Data File Name 80 70 63.6 60 50 30 40.6 37.6 33.7 31.4 40 22.5 21.1 20 10 0 S82 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 Appendix 2 – Spectra Relevant to Chapter 2 243 53.9 12.0 4.0894 2018-07-17T14:01:02 Acquisition Time Acquisition Date Nucleus 11.0 1H 10.0 Spectrometer Frequency 400.13 1.0000 11.7000 Pulse Width Receiver Gain Relaxation Delay 1 30.3 Number of Scans 9.0 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.1 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment CRL_02_165_cr.2.fid Title 9.87 9.86 0.85 209 8.0 7.0 6.0 5.0 f1 (ppm) 7.14 7.14 7.14 7.13 7.12 7.11 7.10 7.09 7.09 7.09 4.51 Value / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_165_cr/ 2/ fid 4.0 3.0 2.0 1.0 2.94 2.69 Parameter 0.95 2.98 2.98 2.98 2.98 2.96 2.96 2.96 2.95 3.03 0.95 0.95 3.92 3.89 3.87 3.85 1.00 1.36 1.26 2.34 2.33 2.15 2.15 2.14 2.13 2.12 2.12 2.12 2.12 2.10 2.10 2.10 2.04 2.02 1.99 Data File Name 0.0 S83 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 Appendix 2 – Spectra Relevant to Chapter 2 244 Parameter Value 295.2 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Temperature Pulse Sequence Experiment Probe 1.3631 2018-07-17T14:22:16 Pulse Width Acquisition Time Acquisition Date 13C 209 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 203.0 Nucleus Spectrometer Frequency 100.62 1.0000 10.0000 Relaxation Delay 512 CDCl3 Solvent 72.0 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH CRL_02_165_cr.3.fid / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_165_cr/ 3/ fid 140.8 135.8 129.1 129.1 126.5 126.5 Origin Comment Title Data File Name 80 70 62.5 60 50 20 24.0 23.6 21.1 21.1 30 39.9 37.5 33.0 31.3 40 10 0 S84 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 Appendix 2 – Spectra Relevant to Chapter 2 245 CRL_02_153_cr.2.fid 2018-07-02T16:58:04 Acquisition Date 11.5 Nucleus 10.5 1H 9.5 4.0894 Acquisition Time Spectrometer Frequency 400.13 1.0000 11.7000 Pulse Width Receiver Gain Relaxation Delay 1 197.4 Number of Scans 8.5 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.1 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment Title 7.5 6.5 S4 5.5 f1 (ppm) 7.14 7.14 7.14 7.13 7.12 7.10 7.10 7.09 7.09 7.08 7.08 4.14 Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_153_cr/ 2/ fid 4.5 3.5 2.5 2.87 1.00 1.02 Parameter 1.00 3.83 3.80 3.78 3.75 3.31 3.31 3.28 3.28 1.13 1.41 1.31 2.33 2.13 2.13 2.11 2.11 2.11 2.10 2.08 2.08 1.99 1.99 1.97 1.94 1.5 3.07 3.03 Data File Name 0.5 -0.5 S85 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 Appendix 2 – Spectra Relevant to Chapter 2 246 CRL_02_153_cr.3.fid 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Temperature Pulse Sequence Experiment Probe 1.3631 2018-07-02T17:19:53 Acquisition Time Acquisition Date 13C 129.4 126.5 S4 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 1.0000 10.0000 Pulse Width 173.3 Relaxation Delay 512 CDCl3 Solvent 72.0 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH 139.2 136.5 Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_153_cr/ 3/ fid Parameter Data File Name 80 66.1 70 60 50 39.0 37.0 40 20 30.0 23.2 21.2 30 10 0 S86 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 Appendix 2 – Spectra Relevant to Chapter 2 247 16 CRL_02_155_1.2.fid 2018-07-04T15:40:39 Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.3 Lowest Frequency 15 8012.8 Spectral Width 10 4.0894 Acquisition Time 11 11.7000 12 1.0000 Pulse Width Spectrometer Frequency 400.13 197.4 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 295.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 1 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_155_1/ 2/ fid Parameter Data File Name 9 7 1.99 1.00 1.97 4.04 8 6 f1 (ppm) 5 1.00 1.00 4 3 2 3.06 2.03 7.94 7.94 7.93 7.92 7.91 7.55 7.54 7.48 7.47 7.47 7.46 7.45 7.45 7.44 7.43 7.14 7.14 7.13 7.12 7.12 7.10 7.09 7.08 7.08 7.08 4.20 4.18 4.15 4.13 3.81 3.79 2.30 2.11 2.09 2.09 2.09 1.36 0.98 1 3.08 2.98 CRL_02_155_1.2.fid 0 -1 -2 -3 0 50 100 150 200 250 300 350 400 450 500 Appendix 2 – Spectra Relevant to Chapter 2 248 CRL_02_155_1_redo.1.fid 199.25 1.0000 10.0000 1.3631 2018-07-09T12:28:16 Pulse Width Acquisition Time Acquisition Date -1949.1 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 72.0 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 295.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_155_1_redo/ 1/ fid CRL_02_155_1_redo.1.fid Data File Name Value 141.60 137.74 135.61 133.07 129.10 128.67 128.47 126.67 Title Parameter 80 70 59.12 60 50 30 20 38.89 37.67 33.18 30.74 23.43 21.13 40 10 0 -10 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 Appendix 2 – Spectra Relevant to Chapter 2 249 12.0 4.0894 2018-11-28T19:34:17 Pulse Width Acquisition Time Acquisition Date Nucleus 11.0 10.0 1H Spectrometer Frequency 400.13 1.0000 11.7000 Relaxation Delay 16 72.0 Receiver Gain 9.0 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Number of Scans Probe 295.1 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment CRL_02_277B_1.1.fid Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_277B_1/ 1/ fid Parameter 8.0 7.0 6.0 5.0 f1 (ppm) 211 7.09 7.09 7.09 7.08 7.07 7.03 7.03 7.01 2.03 1.86 3.89 3.86 3.84 3.82 4.0 1.00 Data File Name 3.0 0.93 3.15 3.14 3.12 3.12 2.0 1.0 0.0 2.32 2.31 2.21 2.21 2.20 2.18 2.05 2.05 2.03 2.02 2.02 2.02 2.00 2.00 1.95 1.92 1.90 1.87 1.86 1.83 1.83 1.80 1.79 1.79 1.78 1.78 1.77 1.77 1.76 1.76 1.75 1.75 1.75 1.74 1.73 1.73 1.71 1.70 1.70 1.69 1.69 1.68 1.67 1.67 1.45 1.45 1.34 1.28 1.27 1.26 1.26 1.25 1.24 1.23 1.23 1.22 1.21 1.20 1.20 1.19 1.19 1.17 1.16 1.06 2.80 0.92 0.95 1.01 2.81 0.86 2.83 3.59 2.72 S87 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 Appendix 2 – Spectra Relevant to Chapter 2 250 CRL_02_277B_1.2.fid nmrsu spect CDCl3 295.2 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 50.3 1.0000 10.0000 1.3631 2018-11-28T20:16:15 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 212.7 13C 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_277B_1/ 2/ fid Parameter 141.7 135.5 129.1 126.5 Data File Name 80 70 60.9 60 50 40 30 20 10 50.8 39.1 37.4 33.2 31.3 29.6 27.0 26.3 26.0 25.5 24.0 21.1 211 0 S88 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 Appendix 2 – Spectra Relevant to Chapter 2 251 Varian Origin 1H 24000 65536 Nucleus Acquired Size Spectral Size 12 -1017.7 Lowest Frequency 13 8000.0 Spectral Width Spectrometer Frequency 499.64 11 2017-08-30T18:39:58 1.0000 Relaxation Delay Acquisition Date 18 Number of Scans Receiver Gain 5.8000 8 Probe 3.0000 autox7991 Experiment Acquisition Time 1D Pulse Sequence Pulse Width 25.0 s2pul Temperature inova cdcl3 Instrument Solvent 10 CRL_01_196_1 Comment Owner / Volumes/ nmrdata-2/ clacker/ vnmrsys/ data/ CRL_01_196_1/ PROTON01.fid/ fid PROTON01 Data File Name Value 1.02 0.99 9 1.07 8 7 1.92 6 f1 (ppm) 5 1.00 4 3 0.98 0.97 1.00 9.63 8.76 8.75 8.75 8.74 8.73 8.73 8.72 8.71 Title Parameter 2 1 0 -1 -2 8.07 8.07 8.06 8.05 7.45 7.44 7.42 7.41 7.41 7.39 7.39 7.39 7.38 7.37 7.36 6.28 6.28 6.28 6.27 6.26 6.26 6.26 6.26 6.26 3.97 3.96 3.33 3.33 3.33 3.32 3.31 3.31 3.31 3.31 2.63 2.61 2.59 2.19 2.18 1.46 1.32 2.83 2.97 PROTON01 CRL_01_196_1 0 500 1000 1500 2000 2500 Appendix 2 – Spectra Relevant to Chapter 2 252 3.22 0.96 CRL_01_267_1.2.fid 1 72.0 Number of Scans Receiver Gain 11.5 Nucleus 10.5 1H Spectrometer Frequency 400.13 2017-11-04T11:30:50 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 4.0894 1D Experiment Acquisition Date zg30 Pulse Sequence Acquisition Time 294.9 Temperature 1.0000 CDCl3 Solvent 11.7000 spect Instrument Pulse Width nmrsu Owner 9.5 1.02 9.61 Relaxation Delay Bruker BioSpin GmbH Origin 8.5 1.01 1.03 8.78 8.77 8.76 8.76 8.13 8.11 8.10 1.04 7.45 7.43 7.43 7.43 7.5 3.34 Comment Title 6.5 0.97 Value 237 5.5 f1 (ppm) 4.5 3.5 1.06 / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_267_1/ 2/ fid 2.5 1.03 Parameter 1.03 6.48 6.47 6.46 6.24 6.23 6.23 6.23 6.22 6.22 0.99 1.45 1.32 1.5 3.07 3.07 4.04 4.02 4.02 4.00 4.00 3.97 3.97 1.00 -0.08 0.5 3.36 3.35 3.35 2.58 2.55 2.55 2.55 2.54 2.52 2.51 2.51 2.21 2.21 2.19 2.19 2.18 2.17 2.16 2.16 9.13 Data File Name -0.5 S97 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 7500 8000 Appendix 2 – Spectra Relevant to Chapter 2 253 / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_267_1/ 3/ fid CRL_01_267_1.3.fid 1.3631 2017-11-04T11:52:49 Acquisition Time Acquisition Date 13C 138.5 136.3 134.8 127.9 127.5 121.5 121.1 120.5 116.5 106.8 148.0 160.1 158.7 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 1.0000 10.0000 78.7 Receiver Gain Pulse Width 512 Number of Scans 170.1 Relaxation Delay Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 294.9 Temperature zgpg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment Title Value Data File Name Parameter 80 70 55.8 60 50 237 30 20 38.1 36.6 32.3 30.9 30.7 30.7 24.9 40 10 -1.8 0 S98 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 Appendix 2 – Spectra Relevant to Chapter 2 254 Varian Origin 5.8000 3.0000 2017-08-21T16:02:23 Pulse Width Acquisition Time Acquisition Date 1H 24000 65536 Nucleus Acquired Size Spectral Size 12 -1017.6 Lowest Frequency 13 8000.0 Spectral Width 11 1.0000 Relaxation Delay Spectrometer Frequency 499.65 28 Receiver Gain 1D Experiment autox7991 s2pul Pulse Sequence 8 25.0 Temperature Number of Scans cdcl3 Solvent Probe inova Instrument Owner PROTON01 CRL_01_183_1 Title 10 9 8 / Volumes/ nmrdata-2/ clacker/ vnmrsys/ data/ CRL_01_183_1/ PROTON01.fid/ fid Comment Data File Name Value 0.06 0.91 Parameter 7 0.95 1.06 6 f1 (ppm) 5 1.05 4 0.93 0.99 1.00 3 2 1 3.12 2.97 0 -1 9.72 9.70 7.26 6.10 6.10 6.09 6.09 3.92 3.92 3.91 3.90 3.90 3.88 3.88 3.86 3.86 3.86 2.91 2.91 2.90 2.90 2.90 2.90 2.89 2.89 2.89 2.89 2.89 2.88 2.88 2.88 2.88 2.87 2.49 2.49 2.48 2.47 2.47 2.46 2.46 2.46 2.45 2.45 2.44 2.33 2.33 2.31 2.31 2.30 2.29 2.28 1.33 1.23 0.24 8.35 PROTON01 CRL_01_183_1 -2 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 Appendix 2 – Spectra Relevant to Chapter 2 255 24 1.0000 Relaxation Delay 1H 24000 65536 Nucleus Acquired Size Spectral Size 12 -1017.6 Lowest Frequency 13 8000.0 Spectral Width Spectrometer Frequency 499.65 11 2017-08-16T19:10:15 8 Number of Scans Receiver Gain Acquisition Date autox7991 Probe 5.8000 1D Experiment 3.0000 s2pul Pulse Sequence Acquisition Time 25.0 Temperature Pulse Width inova cdcl3 Instrument Solvent 0.92 0.02 10 8 Varian Origin 9 CRL_01_178_cr Comment Owner / Volumes/ nmrdata-2/ clacker/ vnmrsys/ data/ CRL_01_178_cr/ PROTON01.fid/ fid PROTON01 Data File Name 6.51 6.51 6.03 6.03 6.02 6.02 7 1.03 0.98 6 f1 (ppm) 5 1.00 4 1.37 3 2 1 1.79 1.03 3.08 3.42 9.80 9.79 Value 7.26 Title Parameter 0 -1 -2 3.92 3.90 3.88 3.87 3.13 3.13 3.13 3.13 3.12 3.11 3.11 3.11 2.03 2.02 2.02 1.96 1.94 1.94 1.92 1.92 1.90 1.77 1.75 1.38 1.20 0.26 8.29 PROTON01 CRL_01_178_cr 0 100 200 300 400 500 600 700 800 900 1000 Appendix 2 – Spectra Relevant to Chapter 2 256 / Volumes/ nmrdata/ clacker/ nmr/ CRL_01_269_1/ 2/ fid CRL_01_269_1.2.fid CDCl3 295.0 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 112.8 1.0000 11.7000 4.0894 2017-11-08T11:01:10 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 8.5 spect Instrument 9.5 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 7.32 7.32 7.32 7.32 7.5 0.98 Comment Title 6.5 194 5.5 f1 (ppm) 1.01 1.02 6.29 6.28 6.28 6.27 6.06 6.05 6.05 6.05 6.05 Data File Name 4.5 3.5 1.07 Value 2.5 2.25 3.76 3.76 3.75 3.73 3.71 3.69 3.68 1.00 1.19 1.5 3.31 3.19 0.5 3.07 3.07 3.05 3.05 2.08 2.05 2.04 2.04 2.02 2.02 2.02 2.01 1.99 1.99 Parameter -0.5 S101 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 Appendix 2 – Spectra Relevant to Chapter 2 257 CRL_01_269_1.3.fid nmrsu spect CDCl3 294.9 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 78.7 1.0000 10.0000 1.3631 2017-11-08T11:23:00 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 105.0 110.3 141.5 156.6 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 178.3 Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_01_269_1/ 3/ fid Parameter Data File Name 80 70 60 53.2 50 194 30 38.3 36.8 30.4 29.2 23.4 40 20 10 0 S102 0 500 1000 1500 2000 2500 Appendix 2 – Spectra Relevant to Chapter 2 258 16 CRL_01_204_1.3.fid 295.0 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 197.4 1.0000 11.7000 4.0894 2017-09-09T03:12:25 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.6 Lowest Frequency 15 8012.8 Spectral Width 10 CDCl3 Solvent 11 spect Instrument 12 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_204_1/ 3/ fid 9 8 7 1.06 1.00 6 f1 (ppm) 5 4 3 2 1 0 -1 1.07 1.03 1.38 1.84 4.13 1.07 4.01 3.69 1.27 1.08 1.33 1.27 1.18 -2 -3 5.99 5.98 5.83 5.82 3.55 3.55 3.54 3.53 3.52 3.52 2.75 2.75 2.73 2.72 2.49 2.47 2.47 2.45 2.44 2.42 1.74 1.71 1.69 1.45 1.44 1.43 1.42 1.21 1.09 0.81 0.80 0.80 0.79 0.61 0.59 0.59 0.57 0.53 0.53 0.52 0.52 0.51 0.50 0.50 0.48 0.47 0.47 0.46 0.45 0.45 0.45 0.44 0.43 0.43 Data File Name Parameter CRL_01_204_1.3.fid 0 500 1000 1500 2000 2500 3000 3500 4000 Appendix 2 – Spectra Relevant to Chapter 2 259 CRL_01_204_1.2.fid 1.0000 10.0000 1.3631 2017-09-09T03:10:33 Pulse Width Acquisition Time Acquisition Date -1931.5 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 64.2 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 294.9 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_204_1/ 2/ fid Value Title 171.24 Data File Name Parameter CRL_01_204_1.2.fid 80 67.93 70 57.86 60 49.84 50 30 20 10 37.25 34.41 34.38 30.72 30.34 26.40 23.89 22.30 18.70 14.65 40 0 -10 -20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 Appendix 2 – Spectra Relevant to Chapter 2 260 14 24 1.0000 5.3000 0.1500 2017-09-11T16:21:11 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date (1442, 128) (2048, 1024) Acquired Size Spectral Size 11 (1H, 13C) Nucleus 12 (-1208.3, -1911.9) Lowest Frequency 13 (9611.9, 30154.5) Spectral Width Spectrometer Frequency (599.61, 150.78) penta 8 Experiment Number of Scans HSQC-EDITED Pulse Sequence Probe 25.0 HSQCAD Temperature 6 5 f2 (ppm) 4 3 2 1 0 -1 -2 180 170 160 150 140 130 120 110 100 90 80 70 60 inova cdcl3 Instrument Solvent 50 40 30 20 10 0 -10 Owner 7 Varian Origin 8 STANDARD PROTON PARAMETERS Comment 9 CRL-01-204-1-coupled-hsqc-165 Title 10 / Volumes/ nmrdata-2/ davidv/ vnmrsys/ data/ CRL-01-204-1-coupled-hsqc-165.fid/ fid Value Data File Name Parameter CRL-01-204-1-coupled-hsqc-165 STANDARD PROTON PARAMETERS Appendix 2 – Spectra Relevant to Chapter 2 261 f1 (ppm) cosygpmfphpp COSY Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 4 Pulse Sequence Experiment Probe Number of Scans Acquisition Date (1024, 256) (1024, 1024) Acquired Size Spectral Size 5.5 (1H, 1H) Nucleus 6.0 (-157.4, -157.4) Lowest Frequency 6.5 (2873.6, 2873.6) Spectral Width 5.0 2017-09-09T03:13:28 Acquisition Time Spectrometer Frequency (400.13, 400.13) 11.7000 0.3564 Pulse Width 4.5 294.9 Temperature 197.4 CDCl3 Solvent 1.8407 spect Instrument Relaxation Delay nmrsu Owner Receiver Gain Bruker BioSpin GmbH Origin 4.0 CRL_01_204_1.4.ser Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_204_1/ 4/ ser Data File Name Parameter CRL_01_204_1.4.ser 3.5 3.0 f2 (ppm) 2.5 2.0 1.5 1.0 0.5 0.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 2 – Spectra Relevant to Chapter 2 262 f1 (ppm) CRL_01_204_1.5.ser 2017-09-09T03:53:46 Acquisition Date (-168.3, -168.3) (1H, 1H) (1024, 256) (1024, 1024) Lowest Frequency Nucleus Acquired Size Spectral Size 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f2 (ppm) (4000.0, 4000.0) Spectral Width Spectrometer Frequency (400.13, 400.13) 11.7000 0.2560 Acquisition Time 1.8000 Pulse Width Relaxation Delay NOESY Experiment 197.4 noesygpphzs Pulse Sequence Receiver Gain 295.0 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 4 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_204_1/ 5/ ser Data File Name Parameter CRL_01_204_1.5.ser 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 263 f1 (ppm) CRL_01_204_1.6.ser Title 11.7000 0.4260 2017-09-09T04:38:39 Pulse Width Acquisition Time Acquisition Date (2048, 256) (2048, 1024) Acquired Size Spectral Size 9.0 (1H, 13C) Nucleus 10.0 (-173.3, -1119.0) Lowest Frequency 11.0 (4807.7, 22321.4) Spectral Width 8.0 2.0000 Spectrometer Frequency (400.13, 100.62) 197.4 6.0 5.0 f2 (ppm) 4.0 3.0 2.0 1.0 0.0 HMBC Experiment Relaxation Delay hmbcetgpl3nd Pulse Sequence Receiver Gain 295.0 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 4 spect Instrument Probe nmrsu Owner Number of Scans 30 Bruker BioSpin GmbH Origin 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 20 10 0 -10 Comment 7.0 / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_01_204_1/ 6/ ser Value Data File Name Parameter CRL_01_204_1.6.ser Appendix 2 – Spectra Relevant to Chapter 2 264 f1 (ppm) / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_069_1_redo2/ 1/ fid CRL_02_069_1_redo2.1.fid Title MeOD 297.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 30.3 1.0000 11.7000 4.0894 2018-05-23T18:55:35 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 8.5 spect Instrument 9.5 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment Data File Name 7.5 6.5 6.13 6.12 5.5 f1 (ppm) 1.00 Value 259 4.5 3.5 2.5 1.5 1.00 1.02 7.28 7.26 1.01 2.96 2.93 2.91 2.88 2.73 2.71 1.04 1.06 1.20 1.10 1.83 1.80 1.78 1.75 1.72 1.70 1.70 1.67 3.15 3.15 Parameter 0.5 -0.5 S103 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 Appendix 2 – Spectra Relevant to Chapter 2 265 nmrsu spect MeOD 297.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 64.2 1.0000 10.0000 1.3631 2018-05-23T19:17:31 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 123.6 155.7 259 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus 175.7 172.9 Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment CRL_02_069_1_redo2.2.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_069_1_redo2/ 2/ fid Parameter Data File Name 80 70 60 51.5 49.5 50 30 20 37.8 37.1 36.9 36.2 33.7 30.4 30.3 24.1 23.7 40 10 0 -10 S104 -500 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 Appendix 2 – Spectra Relevant to Chapter 2 266 3.0000 2018-05-03T21:20:53 Acquisition Time Acquisition Date Acquired Size 10.5 24000 Nucleus 11.5 8000.0 1H Spectral Width 9.5 5.8000 Pulse Width Spectrometer Frequency 499.64 1.0000 Relaxation Delay autox7991 Probe 8 1D Experiment 44 s2pul Pulse Sequence Receiver Gain 25.0 Temperature Number of Scans cdcl3 Solvent Author Instrument 8.5 Varian Origin inova CRL_02_083_1 Owner PROTON01 7.5 6.5 5.5 f1 (ppm) 7.29 7.29 7.28 7.23 7.22 1.00 0.04 / Volumes/ nmrdata-1/ clacker/ vnmrsys/ data/ CRL_02_083_1/ PROTON01.fid/ fid 0.04 0.93 Comment 6.02 6.01 5.98 5.97 5.96 5.95 Title 260 4.5 3.5 0.96 Data File Name 2.5 0.96 2.82 2.82 2.80 2.80 2.78 2.78 2.76 2.40 2.40 2.38 2.38 Value 1.5 0.5 1.95 1.93 1.91 1.81 1.80 1.79 1.79 1.78 1.78 1.77 1.76 1.39 1.21 1.11 0.98 0.91 3.03 2.95 3.02 Parameter -0.5 S107 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 Appendix 2 – Spectra Relevant to Chapter 2 267 CRL_02_083_1.3.fid nmrsu spect CDCl3 295.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 72.0 1.0000 10.0000 1.3631 2018-05-07T11:50:32 Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 88.4 120.5 159.5 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 177.4 Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Owner 172.9 Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_083_1/ 3/ fid Parameter 80 70 60 46.9 50 260 40 30 20 36.8 35.5 33.5 29.9 23.6 21.6 Data File Name 10 0 S108 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 2 – Spectra Relevant to Chapter 2 268 1H 11990 65536 Nucleus Acquired Size Spectral Size 12 -596.9 Lowest Frequency 13 4796.2 Spectral Width 11 2017-11-04T14:54:20 Acquisition Date Spectrometer Frequency 300.09 5.1000 2.4999 Acquisition Time 1.0000 Relaxation Delay Pulse Width 14 Receiver Gain 1D Experiment ASW7284 s2pul Pulse Sequence 16 25.0 Temperature Number of Scans cdcl3 Solvent Probe mercury Instrument 9 8 Varian Origin 10 CRL_01_268_1 Comment Owner / Volumes/ nmrdata/ clacker/ vnmrsys/ data/ CRL_01_268_1/ PROTON01.fid/ fid PROTON01 Data File Name Value Title Parameter PROTON01 CRL_01_268_1 3.98 7 6 f1 (ppm) 5 4 3.11 1.00 4.01 3 2.78 2 3.45 4.16 1 0 -1 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 Appendix 2 – Spectra Relevant to Chapter 2 269 2018-05-18T16:25:51 4.0894 11.7000 1.0000 87.8 16 11.5 7.35 Nucleus 10.5 9.5 7.30 7.25 7.20 f1 (ppm) 1H 8.5 7.15 0 10000 20000 30000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1D zg30 297.2 CDCl3 spect nmrsu Bruker BioSpin GmbH Spectrometer Frequency 400.13 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Probe Experiment Pulse Sequence Temperature Solvent Instrument Owner Origin CRL_02_102_1.1.fid 6.10 6.05 6.00 5.95 5.90 f1 (ppm) 7.5 6.5 5.5 f1 (ppm) 7.30 7.29 7.23 7.22 0.10 1.00 Comment 6.02 6.01 5.98 5.96 Title Value 6.02 6.01 0.97 / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_102_1/ 1/ fid 7.23 7.22 1.00 0.11 Parameter 7.30 7.29 0.10 0 10000 20000 30000 3.48 4.5 3.5 1.05 264 2.5 3.01 3.01 2.98 2.98 2.87 2.85 2.85 2.83 2.83 2.82 2.81 2.81 2.80 2.79 2.78 0.99 1.07 5.98 5.96 0.97 0.11 1.5 0.5 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 -0.5 S105 1.46 1.46 1.44 1.43 1.43 1.43 1.42 1.41 1.39 1.39 1.38 1.36 1.35 1.35 1.32 1.20 1.10 1.00 3.14 1.16 3.30 3.35 Data File Name Appendix 2 – Spectra Relevant to Chapter 2 270 CRL_02_102_1.3.fid nmrsu spect CDCl3 297.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 78.7 1.0000 10.0000 1.3631 2018-05-22T18:47:55 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 88.5 88.5 121.1 120.5 159.5 158.8 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_102_1/ 3/ fid Parameter 178.3 172.9 172.8 80 70 60 50 40 30 264 20 10 36.8 36.4 35.6 35.5 35.5 33.5 32.1 29.9 29.9 29.8 29.5 23.8 23.6 22.8 21.7 21.6 49.1 47.1 Data File Name 0 -10 S106 0 500 1000 1500 2000 2500 Appendix 2 – Spectra Relevant to Chapter 2 271 1.0000 5.1000 2.4999 2017-08-19T14:25:52 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 1H 11990 65536 Nucleus Acquired Size Spectral Size 12 -596.9 Lowest Frequency 13 4796.2 Spectral Width 11 16 Receiver Gain Spectrometer Frequency 300.09 ASW7284 8 Number of Scans 1D Experiment Probe 25.0 s2pul Pulse Sequence cdcl3 Solvent Temperature mercury Instrument 9 8 Varian Origin 10 CRL_01_180_1 Comment Owner / Volumes/ nmrdata-1/ clacker/ vnmrsys/ data/ CRL_01_180_1/ PROTON01.fid/ fid PROTON01 Data File Name Value Title Parameter PROTON01 CRL_01_180_1 6 f1 (ppm) 0.99 1.03 0.95 1.10 7 5 4 0.96 3 3.03 2.26 2 3.87 4.10 1 0 -1 0 10 20 30 40 50 60 70 80 90 100 110 Appendix 2 – Spectra Relevant to Chapter 2 272 9.41 1.00 CDCl3 295.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 64.2 1.0000 11.7000 4.0894 2018-06-26T15:01:00 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 9.5 spect Instrument 8.5 241 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 7.5 CRL_02_140_1.2.fid Comment Title Value 6.5 5.5 f1 (ppm) 4.5 3.5 2.5 1.00 1.02 1.21 1.05 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_140_1/ 2/ fid 1.5 2.13 0.99 0.93 2.98 3.28 3.42 Parameter 2.02 1.99 1.98 1.97 1.96 1.94 1.94 1.93 1.92 1.91 1.91 1.90 1.89 1.87 1.67 1.65 1.30 1.22 1.11 0.5 2.92 2.90 2.75 2.74 2.73 2.71 2.71 2.70 2.69 2.68 2.67 2.67 2.65 2.65 2.64 2.63 2.63 2.62 2.62 2.61 2.61 2.60 2.57 2.55 2.54 2.53 2.52 2.51 2.50 2.48 Data File Name -0.5 S109 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 2300 2400 Appendix 2 – Spectra Relevant to Chapter 2 273 nmrsu spect CDCl3 295.2 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 55.5 1.0000 10.0000 1.3631 2018-06-26T15:22:15 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 86.3 86.3 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 178.4 177.1 Nucleus Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin 241 CRL_02_140_1.3.fid Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_140_1/ 3/ fid Parameter Data File Name 80 70 60 48.7 50 30 20 39.1 35.3 32.6 30.9 29.9 29.3 24.0 23.7 40 10 0 -10 S110 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 Appendix 2 – Spectra Relevant to Chapter 2 274 / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_086_cr/ 2/ fid CRL_02_086_cr.2.fid Title 2018-05-07T23:31:24 Acquisition Date 11.5 Nucleus 10.5 1H 9.5 4.0894 Acquisition Time Spectrometer Frequency 400.13 1.0000 11.7000 87.8 Receiver Gain Pulse Width 1 Number of Scans Relaxation Delay Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.2 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin 263 8.5 7.5 6.5 5.5 f1 (ppm) 4.5 3.5 2.5 1.5 3.36 1.00 1.14 1.09 1.10 1.01 Comment Data File Name Value 1.29 1.29 1.21 1.11 0.5 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 -0.5 S111 2.76 2.73 2.71 2.71 2.69 2.67 2.67 2.65 2.65 2.63 2.60 2.60 2.58 2.57 2.54 2.53 2.53 2.51 2.50 2.49 2.49 2.48 2.47 2.46 2.15 2.13 2.13 2.12 2.11 2.11 2.10 2.10 2.07 1.94 1.93 1.92 1.91 1.91 1.90 1.88 1.87 1.84 1.82 1.81 1.79 1.79 1.74 1.71 1.71 1.69 3.27 3.41 3.52 Parameter Appendix 2 – Spectra Relevant to Chapter 2 275 CRL_02_086_cr.3.fid 512 64.2 Number of Scans Receiver Gain 13C 263 86.5 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 178.4 177.2 Nucleus Spectrometer Frequency 100.62 2018-05-07T23:52:39 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Acquisition Date 1D Experiment 1.3631 zgpg30 Pulse Sequence 1.0000 295.2 Temperature 10.0000 CDCl3 Solvent Acquisition Time spect Instrument Pulse Width nmrsu Owner Relaxation Delay Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_02_086_cr/ 3/ fid Parameter Data File Name 80 70 60 48.1 50 30 20 39.2 35.5 33.6 30.9 29.9 29.3 23.9 23.7 40 10 0 S112 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 Appendix 2 – Spectra Relevant to Chapter 2 276 CDCl3 295.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1 98.9 1.0000 11.7000 4.0894 2018-07-09T19:18:42 Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 8.5 spect Instrument 9.5 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin 7.5 CRL_02_148_1_redo2.2.fid Comment Title Value / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_148_1_redo2/ 2/ fid Data File Name Parameter 6.5 5.5 f1 (ppm) 4.5 (+)-rumphellaone A (4) 3.5 2.5 1.5 0.5 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 -0.5 S113 2.65 2.65 2.63 2.62 2.60 2.60 2.60 2.58 2.57 2.56 2.55 2.54 2.53 2.50 2.38 2.36 2.34 2.12 2.08 2.06 2.06 2.04 2.03 2.03 2.01 2.01 2.00 1.98 1.92 1.90 1.88 1.87 1.86 1.85 1.84 1.84 1.82 1.81 1.68 1.68 1.67 1.66 1.66 1.65 1.64 1.64 1.63 1.63 1.62 1.62 1.59 1.59 1.57 1.56 1.56 1.56 1.54 1.54 1.44 1.42 1.39 1.31 1.06 1.03 1.09 0.99 2.11 2.78 1.36 0.92 0.92 0.81 2.62 1.00 0.99 2.95 3.12 3.17 1800 Appendix 2 – Spectra Relevant to Chapter 2 277 Parameter Value 1.0000 10.0000 1.3631 2018-07-09T19:40:44 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 13C 87.4 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 208.8 Nucleus (+)-rumphellaone A (4) 78.7 Receiver Gain Spectrometer Frequency 100.62 512 1D Experiment Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) zgpg30 Pulse Sequence Number of Scans 295.1 177.1 Probe CDCl3 Temperature spect Solvent nmrsu Instrument Bruker BioSpin GmbH CRL_02_148_1_redo2.3.fid / Volumes/ nmrdata-2/ clacker/ nmr/ CRL_02_148_1_redo2/ 3/ fid Owner Origin Comment Title Data File Name 80 70 60 40 30 20 10 44.6 44.4 42.1 33.7 33.1 31.1 30.8 30.1 29.3 25.2 25.0 22.6 50 0 -10 S114 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 2200 Appendix 2 – Spectra Relevant to Chapter 2 278 11.7000 4.0894 2018-04-12T19:32:40 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 11.5 Nucleus 10.5 1H 9.5 1.0000 Receiver Gain Spectrometer Frequency 400.13 16 98.9 Number of Scans 8.5 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 295.2 Temperature zg30 CDCl3 Solvent 1D spect Instrument Experiment nmrsu Owner Pulse Sequence Bruker BioSpin GmbH Origin Comment 7.5 CRL_02_059_2.1.fid Title Value / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_059_2/ 1/ fid Data File Name Parameter 6.5 5.5 f1 (ppm) 4.5 epi-C8-rumphellaone A (261) 3.5 2.5 1.5 0.5 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 -0.5 S115 2.62 2.62 2.60 2.59 2.58 2.58 2.41 2.39 2.39 2.37 2.13 2.12 2.10 2.07 2.06 2.06 2.04 2.04 2.04 2.02 2.02 2.01 1.99 1.93 1.91 1.91 1.90 1.89 1.88 1.88 1.86 1.79 1.79 1.79 1.77 1.77 1.75 1.67 1.67 1.66 1.66 1.65 1.65 1.65 1.64 1.64 1.64 1.63 1.63 1.63 1.62 1.61 1.61 1.61 1.61 1.59 1.58 1.54 1.51 1.49 1.29 1.06 1.06 1.03 1.82 2.00 2.78 2.07 0.96 0.92 3.01 0.94 2.75 3.15 2.93 28000 Appendix 2 – Spectra Relevant to Chapter 2 279 10.0000 1.3631 2018-04-12T20:14:35 Acquisition Date 208.7 13C 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Nucleus Spectrometer Frequency 100.62 1.0000 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Acquisition Time 1D Experiment Pulse Width zgpg30 Pulse Sequence Relaxation Delay 295.2 Temperature 1024 CDCl3 Solvent 64.2 spect Instrument Receiver Gain nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 87.3 epi-C8-rumphellaone A (261) CRL_02_059_2.2.fid Comment / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_02_059_2/ 2/ fid Value Title 177.1 Data File Name Parameter 80 70 60 40 30 20 10 44.6 44.1 41.9 34.5 33.4 31.6 31.1 30.2 29.3 25.0 24.0 22.6 50 0 S116 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 Appendix 2 – Spectra Relevant to Chapter 2 280 Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 281 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Chapter 3 Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides1 3.1 INTRODUCTION Scheme 3.1 Common disconnections for N-(hetero)benzylic azole synthesis C–N bond formation X R N H X 401 + R N C–C bond formation X R N Me het 402 Me het 403 Me 404 X Y X + het 405 N-benzylic azoles (403) are an important class of compounds in the pharmaceutical industry. Azoles such as pyrroles, pyrazoles, and indoles are found in a wide variety of pharmaceuticals.1 N-benzylic azoles can be synthesized several different ways. N-benzylic pyrroles specifically can be synthesized using modified Clauson-Kaas and Paal-Knorr protocols, though care must be taken to prevent racemization of the chiral amine starting materials.2–10 To access a wider variety of N-(hetero)benzylic azoles, two common disconnections are typically used: C–N bond formation, and C–C bond formation (Scheme 3.1). A variety of methods have been developed using both disconnections, though few enantioselective strategies have been disclosed. 1 This chapter was written concurrently with the communication manuscript to be submitted. The research discussed in this chapter was completed in collaboration with Travis J. DeLano, a graduate student in the Reisman lab, and Dr. Tiffany Piou and Kevin Belyk, researchers employed by Merck. Initial screening, HTE screens, and BF3K substrates synthesis were performed by Kevin Belyk and Dr. Tiffany Piou, and 20 g of each enantiomer of 4-heptyl BiOX and certain aryl bromides were donated by Merck. Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 282 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Scheme 3.2 C–N coupling approaches towards N-(hetero)benzylic azoles a. Mitsunobu - Cuny, 2011 Y X N H Y X PPh3 (1.3 equiv) Dt-BAD (1.35 equiv) OH R + R N Me O THF, –40 ºC or rt Ar O Me 406 R = OEt, CCl3 407 1.1 equiv Ar 408 b. Oxidative C–H Activation - Ruan, 2021 Ar2 N N N H Ar2 N 409 n-Bu4NHSO4 (1 equiv) + -or- Ar1 N N N H N R graphite/Pt, MeCN 80 ºC, 8 mA 411 3 equiv R = alkyl, carbonyl, H 410 0.5 mmol N N N N Ar1 -or- N N Ar1 R 412 R 413 c. Carbonyl Condensation - Seidel, 2011 HO O PhCO2H (20%) + CO2H N H H EWG 414 1.2 equiv N PhMe μW, 240 ºC EWG 415 416 d. Cross-Coupling - Breit, 2015, 2016 R1 Me 417 -orR1 • 418 1.5–2.0 equiv + R2 N H R3 R4 [{Rh(cod)Cl}2] (2%) JoSPOphos (5%) N PPTS (20%) PhMe, 80 ºC PPTS = p-toluenesulfonate R3 419 R2 R4 N N R1 420 up to 97% ee from alkyne up to 98% ee from allene A variety of methods developed for the synthesis of N-(hetero)benzylic azoles utilize a C–N bond forming approach (Scheme 3.2). Simple Mitsunobu substitution of enantioenriched alcohols (407) allows for the synthesis of chiral pyrroles, pyrazoles, and indoles (Scheme 3.2a).11,12 However, this approach is dependent on the use of chiral alcohol starting materials to access enantioenriched products. A variety of oxidative C–H activation approaches such as oxidative electrochemistry (Scheme 3.2b),13 oxidative photoredox chemistry,14 and other thermal strategies15–18 have all proven effective at synthesizing N-(hetero)benzylic azoles containing two or more nitrogen atoms. As these methodologies are oxidative, they require a stoichiometric oxidant, which can limit the Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 283 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides substrate scope. Acid-catalyzed thermal condensation of pyrrolidine derivatives (414) and aldehydes (415) allows access to both primary19,20 and secondary pyrroles (Scheme 3.2c).21 Finally, Breit and coworkers have demonstrated that pyrazoles (419) can be cross-coupled with alkynes and allenes to form enantioenriched allylic azoles (420) (Scheme 3.2d).22,23 Scheme 3.3 C–C coupling approaches towards N-(hetero)benzylic azoles a. Decarboxylative photoredox - Hopkins, 2020 Br N + N 1% [Ir] [Ni(dtbbpy)(H2O)4]Cl2 (10%) N N DBU (1.5 equiv) DMA, hν (blue LED) NC CO2H 421 1.5 equiv [Ir] = Ir[dF(CF3)ppy]2(dtbbpy)]PF6 422 CN 423 57% yield (one of two examples) b. Suzuki - Molander and Seapy, 2013 N Cl X + R BF3K 424 1.1 equiv 425 Ar or (het)Ar RuPhos (10%) -orsSPhos (10%) N Pd(OAc)2 (5%) Cs2CO3 (3 equiv) CPME/H2O, 100 ºC 426 X R There have been comparatively few approaches towards the synthesis of N(hetero)benzylic azoles that utilize a C–C bond formation approach (Scheme 3.3). In addition, the majority of C–C bond approaches towards N-(hetero)benzylic azoles are limited to primary azole nucleophiles. Hopkins and Rueping disclosed select examples of the nickel-catalyzed decarboxylative photoredox cross-couplings of α-azole carboxylic acids (421) with aryl bromides (422) and triflates, respectively (Scheme 3.3a).24,25 Molander and Seapy developed palladium-catalyzed Suzuki conditions for the crosscoupling of potassium trifluoro(N-heteroaryl)borates (424) with aryl chlorides (425) (Scheme 3.3b).26 In addition to pyrroles, pyrazoles, and indoles, similar conditions could be applied to phthalimide and isoindolen-1-one substrates.27,28 To the best of our knowledge, there is a single report of enantioselective C–C bond formation to form N-(hetero)benzylic azoles. In 2018, Bonifanzi and Davidson disclosed Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 284 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Scheme 3.4 Enantioselective cross-coupling of α-azole carboxylic acids and aryl bromides Me O N R2 + N R1 best enantioselectivites tBu L70 (21%) NiBr2•dme (20%) Br R3 4CzIPN (4%) Cs2CO3 (1.5 equiv) acetone hν (blue LEDs) CO2H 427 1.5 equiv N 428 R2 Me Me N N N O O Me Me R1 Me R3 CN 429 w/o directing group: ≤ 58% ee w/ directing group: ≤ 88%ee O 430 50% yield, 84% ee 431 34% yield, 88% ee the decarboxylative enantioselective nickel-catalyzed photoredox cross-coupling of azole carboxylic acids (427) with aryl bromides (428) using pyridine oxazoline (PyOX) ligand L70 and 4CzIPN as the photocatalyst, albeit in low to modest enantioselectivities (Scheme 3.4).29 This is one of relatively few enantioselective photochemical cross-couplings published in the literature. Notably, in order to achieve greater than 58% ee, they required the incorporation of a directing group at the 2 position of the pyrrole. Methyl ketones (430, 431) appeared to be the best directing group under their reaction conditions. In addition to poor enantioselectivities, they only disclose a single example of a heteroaryl bromide. Scheme 3.5 Initial conditions from Merck BocHN BocHN Br N N N + N Me BF3K 432a 1.5 equiv L71 (15%) NiCl2•dme (10%) 433a 0.1 mmol SMe [Ir] (1%) K2HPO4 (3.0 equiv) TBME (0.05 M) hν (450 nm) N N nPr Me N 434a N nPr SMe O O N N nPr nPr L71 70% conv, 81% ee [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 Scientists at Merck have been interested in the enantioselective cross-coupling of azole-containing nucleophiles with heteroaryl bromides to form N-heterobenzylic azoles using nickel photoredox catalysis. They developed conditions for cross-coupling pyrazole potassium trifluoroborate 432a with aryl bromides to form N-heterobenzylic azoles such as 434a using a ligand developed previously in our lab, L71 (Scheme 3.5).30 Excitingly, their initial results were already achieving yields and enantioselectivities surpassing Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 285 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Bonifanzi and Davidson’s approach for similar substrates. However, they struggled with reproducibility issues and achieving enantioselectivities greater than ~80%. Therefore, they invited us to join their efforts to further optimize the yield and ee of this reaction and address any reproducibility issues. Scheme 3.6 Proposed mechanism R R N Me Br X + [Ni]L*, [Ir] het base, solvent hν (450 nm) BF3K 432 N X nPr Me het N 444 Ar 446 Me Ar N N nPr nPr L71 R Me N NiI * N O nPr 434–443 433 O hν X [IrIII] * N Ni0 N 445 [IrIII]* Br R 433 N Me X BF3K 432 [IrII] R Me Ar Ar N NiIII * N Br * N NiI Br N N 448 Me 447 X 444 R N Me X 434–443 Ar Based on previous investigations of photoredox cross-couplings of potassium trifluoroborate salts and aryl halides, a catalytic cycle can be proposed (Scheme 3.6).31 First, following excitation of the photocatalyst, single-electron oxidation of the BF3K salt (432) leads to oxidative cleavage and formation of stabilized radical 444. This radical can then be trapped by the nickel catalyst to form alkyl[NiI] 445. Oxidative addition of 433 forms [NiIII] 447. Reductive elimination affords the desired product (434–443) and [NiI]Br 448. Reduction by the photocatalyst regenerates both the [Ni] catalyst and the Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 286 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides photocatalyst. Alternatively, oxidative addition of 433 to [Ni0] could occur first, followed by radical capture of 435 by the resultant [NiII] intermediate. 3.2 OPTIMIZATION 3.2.1 Initial Conditions from Merck Scheme 3.7 HTE studies and ligand optimization BocHN BocHN Br N N N + N Me Ligand (21%) NiCl2•dme (20%) SMe BF3K 432a 1.5 equiv 433a 0.01 mmol [Ir] (3%) K2HPO4 (4.0 equiv) solvent (0.05 M) hν (450 nm) N Me N 434a N SMe [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 PyOX (best example) BiOX (best result) N CNBOX (best example) BiIM (best example) tBu tBu O O CN O O nPr nPr N N nPr nPr L71 O Me N N N Me L72 Ph L73 Ph Me N Me 70% conv, 86% ee (TBME) 98% conv, 58% ee (2-MeTHF) 76% conv, 61% ee (TBME) N N HN 38% conv, 78% ee (THP) 43% conv, 73% ee (THF) Me N L74 Me 100% conv, 67% ee (2-MeTHF) Merck approached us with initial conditions for the enantioselective cross-coupling of α-pyrazole potassium trifluoroborate salt 432a with thiomethyl ether pyrimidine 433a that they had developed after initial high throughput experimentation (HTE) screening (Scheme 3.7). At the time, they found that 4-heptyl bioxazoline (BiOX) (L71) afforded the desired product in the best yield and conversion on HTE scale using 20 mol % NiCl2•dme as the precatalyst, 3% Ir[dF(CF3)ppy]2(bpy)PF6 ([Ir]) as the photocatalyst, 21 mol % L71, and t-butyl methyl ether (TMBE) as the solvent. In general, PyOX ligands such as L72 gave good conversions, but relatively low enantioselectivities. Cyano-bis(oxazoline) (CNBOX ligand) L73 afforded the desired product in promising enantioselectivities, but in relatively low conversions. Biimidazole (BiIM) ligands such as L74 generally gave good Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 287 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides conversions, but moderate enantioselectivities despite their structural similarities to BiOX ligands. Therefore, 4-heptyl BiOX was chosen for further investigation. Scheme 3.8 0.1 mmol scale initial conditions nPr BocHN O N N Br N N 433a 0.1 mmol N [Ir] (1%) K2HPO4 (3.0 equiv) TBME (0.05 M) hν (450 nm) SMe BF3K 432a 1.5 equiv BocHN L71 (15%) NiCl2•dme (10%) N + nPr nPr nPr N Me O Me O O N N N Me Br nPr L71 (15%) nPr NiCl2•dme (10%) N + BF3K N 432b 1.5 equiv 433a 0.1 mmol SMe SMe 434a 66% yield 82% ee nPr CO2Me N N [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 nPr N [Ir] (1%) K2HPO4 (3.0 equiv) TBME (0.05 M) hν (450 nm) [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 N CO2Me Me N N SMe 435a 52% yield, 91% ee Gratifyingly, these results could be replicated on 0.1 mmol scale in a Penn PhD photoreactor on the benchtop using 10 mol % [Ni], 15 mol % L2, TMBE as the solvent, and 1 mol % [Ir], affording cross-coupled product 434a in 66% yield, 82% ee (Scheme 3.8). Some initial issues with reproducibility on scale were addressed by changing the reaction setup to avoid adding reagents as slurries and using repurified L71 stored in the glovebox (see Section 3.2.5). Pyrrole BF3K (435a) was also successfully cross-coupled under these conditions, affording the desired product in 52% yield and 91% ee. It is thought that the ester at the 2 position can act as a better directing group than the pyrazole nitrogen, resulting in higher enantioselectivities.29 Our goals at the outset of this project were to increase the yield and enantioselectivity of this reaction and explore the substrate scope of both cross-coupling partners. Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 288 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides 3.2.2 Reaction Stall and Product Inhibition Table 3.1 Time-course studies nPr BocHN O O N N Br N N N Me 433a 0.1 mmol N [Ir] (1%) K2HPO4 (3.0 equiv) TBME (0.05 M) hν (450 nm) SMe BF3K 432a 1.5 equiv BocHN L71 (15%) NiCl2•dme (10%) N + nPr nPr nPr time % ArBra % pdt % ee 1h 1 42 37 80 4h 2 32 51 82 8h 3 23 58 77 12 h 4 19 62 81 24 h 5 17 62 80 48 h 6 21 61 76 48 hb 7 2 59 80 Note: entries 6–7 run on different days than 1–5, a%ArBr remaining, bsecond charge of [Ni], L71, [Ir] in 1.0 mL solvent entry N Me N N 434a SMe [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 Despite the promising conversions on small scale, the reaction seemed to stall out at around 60% yield with 15-20% ArBr remaining. In order to investigate this, we performed a time course study. Five 0.1 mmol reactions were set up (the maximum capacity for the photoreactor) and were stopped and worked up at different intervals (Table 3.1, entries 1–5). Interestingly, the reaction appeared to be nearly complete after 8 hours (entry 3), with only a slight increase in yield at 12 hours (entry 4), and no change after 24 hours (entry 5). Even after allowing the reaction to run for 48 hours, there was no increase in yield (entry 6). Adding in fresh NiCl2•L71 complex and [Ir] only resulted in increased consumption of ArBr with no increase in product (entry 7). Therefore, it was hypothesized that as the reaction proceeded, formation of the product or other byproducts such as protodeborylation could be resulting in reaction inhibition. Scheme 3.9 Product inhibition studies BocHN Br N N N + + L71 (15%) NiCl2•dme (10%) N Me Me N BF3K N 432a 1.5 equiv 433b 0.1 mmol BocHN BocHN BocHN 434a, (75% ee) 1 equiv SMe N [Ir] (1%) K2HPO4 (3.0 equiv) TBME (0.05 M) hν (450 nm) N N + Me 434b 11% yield (56% w/o 434a) N Me N N SMe 434a 83% recovered, 75% ee Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 289 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides First, inhibition of the reaction by product was investigated directly. 1 equiv compound 434a was added to the cross coupling of pyrazole 432a with phenyl bromide (433b) (Scheme 3.9). Without any added product, the reaction proceeds to afford 434b in 56% yield. However, upon addition of 434a, the reaction only proceeds in 11% yield. This suggests that the product could be inhibiting the reaction. While product and protodeborylation formation could be tracked by NMR, it was difficult to monitor BF3K consumption due to its insolubility in most deuterated solvents. In addition, 434a was recovered with no erosion in ee, indicating that in situ racemization of the product was not occurring. Figure 3.1 Fluorescence quenching [Ir] (40 μM) hν (450 nm) fluorescence [Ir] fluorescence observed energy transfer [Ir] fluorescence diminished [Ir]* to quencher 40 μM [Ir] [Ir] + 110 mM 434a BocHN BocHN N N N N Me 434a N Me Br N N SMe N 449 SMe 40 μM [Ir] [Ir] + 110 mM 433a 433a 40 μM [Ir] [Ir] + 110 mM 449 40 μM [Ir] [Ir] + 30 mM NiCl2•dme/L71 Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 290 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides In order to probe this inhibition more directly, fluorescence studies were undertaken to determine if any of the reaction components could be quenching the photocatalyst. The fluorescence spectrum of the photocatalyst was observed and then compared to the fluorescence spectra of the photocatalyst in the presence of the cross-coupled product (434a), protodeborylation (449), ArBr (433a), or the [Ni]•L71 complex (Figure 3.1). These studies were performed in 2-methyl tetrahydrofuran (2-MeTHF) to fully dissolve [Ir]. These initial results showed that the cross-coupled product 434a and deborylated byproduct 440 were both capable of quenching the photocatalyst, while 433a had little to no impact on the fluorescence of the photocatalyst. Interestingly, [Ni]•L71 complex resulted in a new signal, suggesting it could be photoactive as well, though control studies without [Ir] indicate that the Ni catalyst complex is not a competent photocatalyst. The [Ni]•L71 complex also appears to result in complete quenching of the photocatalyst. This could be indicative of some redox reactivity between these two complexes. These preliminary results suggest that as the reaction proceeds, the products and byproducts of the reaction could be resulting in photocatalyst quenching, causing the reaction to stall out. Therefore, we sought to attenuate these effects through investigation of [Ni]•L71 complex loading, [Ir] loading, and additives. 3.2.3 Solvent and [Ir] Loading One significant challenge inherent to the initial reaction conditions was the minimal solubility of most of the reagents. In particular, the solubility of the [Ni]•L71 complex and the photocatalyst were particularly limiting. The [Ni]•L71 complex is not readily soluble in TBME and requires long stir times at ~60 ºC to undergo complexation. Initial studies had shown that higher catalyst loadings resulted in higher yields. Therefore, finding a Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 291 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides solvent to fully solubilize the catalyst could result in higher yields. Similarly, Ir[dF(CF3)ppy]2(bpy)PF6 is minimally soluble in TBME. This made it difficult to add as a stock solution and resulted in some irreproducibility. Initial studies had indicated that lowering the photocatalyst loading could be beneficial, but very low loadings were difficult to study due to the inability to make accurate stock solutions. Therefore, investigations into alternate solvent systems that solubilize the [Ni]•L71 complex and photocatalyst were undertaken. Table 3.2 Solvent, [Ir], and ligand loading optimization O nPr BocHN N BF3K 432a 1.5 equiv BocHN L71 (x%) nPr NiCl2•dme (10%) N + N Me N nPr nPr Br N N entry O 433a 0.1 mmol SMe [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 N N Me N 434a N SMe 1 2 3 4 5 6 7 8a solvent TBME 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF TBME % [Ir] 1.0 0.125 0.25 1.0 0.125 0.125 0 0.125 % L2 15 30 30 30 20 15 30 30 % pdt 66 70 72 73 72 65 6 51 % ee 82 85 84 74 83 81 85 85 a0.2 mmol scale 2-MeTHF was a potential alternative solvent due to promising observed reactivity on HTE scale and increased polarity compared to TBME. After initial HTE studies, 2MeTHF was initially disregarded in favor of TBME as it resulted in lower enantioselectivities of the desired product. However, the [Ni]•L71 catalyst complex is fully soluble at room temperature in 2-MeTHF after complexation at 60 ºC, and Ir[dF(CF3)ppy]2(bpy)PF6 is fully soluble as well. Therefore, investigations into different ligand and photocatalyst loadings were undertaken in 2-MeTHF (Table 3.2). It was found that by decreasing the photocatalyst loading to 0.125% and increasing the ligand loading to 30% in 2-MeTHF, both the yield and the ee of the reaction increased (entry 2). As the [Ir] loading increased, the enantioselectivity decreased by about 10% (entries 3–4). Decreasing the ligand loading to 20% and 15% (entries 5 and 6, respectively) resulted in a Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 292 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides slight loss in enantioselectivity and a significant decrease in yield. Removing the photocatalyst from the reaction reduced the yield to 6%, though still with high ee (entry 7). When 30% L71 and 0.125% [Ir] were used in TBME, the yield dropped significantly, likely due to the insolubility of the photocatalyst (entry 8). Lowering the light intensity from 100% only resulted in lower yields and comparable enantioselectivities. (See Section 3.5.3). Table 3.3 Reactivity of p-bromoanisole nPr BocHN N + BF3K 432a 1.5 equiv Conditions A (entry 1a) entry % [Ir] solvent 1a 2a 3a 4a TBME TBME TBME TBME 1.0 1.0 0.125 0.125 N N nPr BocHN L71 (x%) nPr NiCl2•dme (10%) OMe Me O nPr Br N O 433c 0.1 mmol % L2 15 30 15 30 % pdt 44 52 16 10 [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) N N Me 434c OMe [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 % ee 81 78 85 85 Conditions B (entry 1b) entry % [Ir] solvent 1b 2b 3b 4b 2-MeTHF 2-MeTHF 2-MeTHF 2-MeTHF 0.125 0.125 1.0 1.0 % L2 30 15 30 15 % pdt 11 20 8 3 % ee 80 83 50 25 Although the yields and ee’s of our model system benefited from these changes, some aryl bromides did not perform as well under these new conditions. Notably, more electron-rich substrates such as 4-bromoanisole (433c) appeared to be more sensitive to changes in reaction conditions. Upon switching from conditions A (Table 3.3a, entry 1a), to conditions B (Table 3.3b, entry 1b), the yield of 434c dropped precipitously from 44% to 11%. Increasing the loading of L71 in TBME resulted in a slight loss in ee and an increase in yield (entry 2a), while decreasing the loading of L71 in 2-MeTHF resulted in a slight increase in yield and ee (entry 2b). Lowering the photocatalyst loading in TBME (entry 3a) results in a significant drop in yield and a slight increase in ee. However, in 2MeTHF increasing the photocatalyst loading to 1.0% results in a significant drop in ee Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 293 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides (entry 3b). This is likely due to the high solubility of [Ir] in 2-MeTHF, resulting in relatively high [Ir] loading, which has been shown to result in lower enantioselectivities in the model system. These data suggest that this reaction is highly substrate-dependent, and that different reaction conditions are optimal for different substrates. Scheme 3.10 Change in nucleophile reactivity nPr CO2Me N Me Br N BF3K 432b 1.5 equiv O N N L71 (x%) nPr NiCl2•dme (10%) SMe 433a 0.1 mmol N Me [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 BocHN BocHN N N N CF3 435d Conditions B: 31% yield, 94% ee 435a N NBoc N N N Me N 434f Conditions A: 42% yield, -% ee CO2Me N N Me 434e Conditions A: 45% yield, -% ee Me Me SMe N N CO2Me N N CF3 N Conditions B: L71 (30%) [Ir] (0.125%) 2-MeTHF (0.05 M) 54% yield, 97% ee N N Me 434d Conditions B: 66% yield, 86% ee CO2Me BocHN N Me Conditions A: L71 (15%) [Ir] (1%) TBME (0.05 M) 52% yield, 91%ee nPr nPr N + O CO2Me Me N NBoc 435e Conditions B: 19% yield, 88% ee N Me 435f Conditions B: 12% yield, 76% ee The identity of the nucleophile also appears to be a significant factor. Excitingly, when these modified conditions (Conditions B) were applied to ester pyrrole BF3K 432b, the ee increased from 91% to 97% with comparable yields (Scheme 3.10). However, the ester pyrrole product 435a was observed in lower yields under both sets of conditions compared to pyrazole product 434a (Table 3.2, entries 1–2). While the reduction in yield when using pyrrole ester 432b compared to pyrazole 432a is relatively minor for most pyrimidines and other very electron-poor aryl bromides, certain substrates resulted in Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 294 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides significantly lower yields. For example, trifluoromethyl product 434d was observed in 66% yield, 86% ee, while the pyrrole adduct (435d) was observed in 31% yield, 94% ee. Other substrates also saw a significant reduction in yield upon switching conditions and nucleophiles. Despite these limitations on scope, we were encouraged by the overall increase in ee to >95% using these conditions with the pyrrole ester and electron-poor aryl bromides, and further screening efforts were undertaken with pyrrole BF3K 432b using 30% L71, 0.125% [Ir], and 2-MeTHF as the solvent. 3.2.4 Additives Table 3.4 Additive studies nPr BocHN nPr Br N N N Me SMe BF3K 432a 1.5 equiv 433a 0.1 mmol entry 1 2 3 4 5 6 7 8 9 10 11 12 13 O N N nPr N [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 conditions A A A A A A A A A B B B B additive (equiv) % ArBra none TEMPO (0.5) NaBF4 (0.5) NaI (0.5) LiBr (0.5) LiCl (0.5) TMSCl (0.5) ZnCl2 (0.5) MnCl2 (0.5) none MnCl2 (0.5)c Fe(OTf)2 (0.2) Fe(OTf)2 (0.2)c Conditions A: L71 (15%) [Ir] (1%) TBME (0.05 M) BocHN nPr L71 (x%) NiCl2•dme (10%) N + O 15 60 24 19 9 17 17 80 32 18 52 64 41 N Me N 434a N % pdt %ee 66 82 12b 18 59 80 65 77 62 79 64 81 52 73 <2 60 53 81 70 85 38 84 23 85 47 81 SMe Conditions B: L71 (30%) [Ir] (0.125%) 2-MeTHF (0.05 M) BocHN N Me Me Me N O N Me Me TEMPO adduct 450 a%ArBr remaining at the end of the reaction bTEMPO adduct XX observed by LCMS and NMR, ~18% yield c0.25% [Ir] instead of 0.125% A variety of additives were screened in an attempt to increase the yield of the reaction further with both sets of conditions. However, despite exploring numerous additives that have been beneficial for Ni catalysis in the past, there was no significant improvement to the yield or ee (Table 3.4). Excitingly, addition of 0.5 equiv of TEMPO Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 295 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides resulted in formation of TEMPO adduct 450, which supports the existence of a radical intermediate generated from the BF3K starting material (entry 2). TEMPO also resulted in significant inhibition of product formation. Most additives, such as NaBF4, NaI, LiBr, and LiCl (entries 3–6) had little to no effect on the yield or ee. TMSCl (entry 7) reduced both the yield and ee slightly. Interestingly, ZnCl2 (entry 8) and MnCl2 (entry 9) afforded very different results, with ZnCl2 completely shutting down reactivity and MnCl2 only resulting in a slight attenuation in yield. Several additives were explored under the modified reaction conditions, but they only resulted in a decrease in yield (entries 11–13). 3.2.5 Final Ligand Optimization Scheme 3.11 Summary of HTE BiOX ligand screening CO2Me N Me nPr nPr N N + Cl 433g 0.005 mmol 432b 1.5 equiv O Ligand (22%) NiCl2•dme (20%) N N BF3K O Br nPr CO2Me [Ir] (1%) Me N K2HPO4 (4.0 equiv) 2-MeTHF (0.05 M) N Cl hν (450 nm) 435g [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 O O O O N N N N nPr L71 4-heptyl BiOX 64% yield, 91% ee N F F L75 Ph BiOX 51% yield, 93% ee L76 4-F-Ph BiOX 64% yield, 95% ee After this prior optimization was complete and the aryl bromide substrate scope was in progress, further HTE screens of 48 BiOX ligands were performed in 2-MeTHF with 20% NiCl2•dme, 22% ligand, and 1% [Ir] to provide more reactivity information. Surprisingly, these studies indicated that both PhBiOX (L75) and 4-F-PhBiOX (L76) gave higher ee’s and comparable yields on small scale to L71 (Scheme 3.11). These two ligands had been investigated previously in TBME, however, due to the complete insolubility of the aryl BiOX [Ni] complexes in TBME, trace reactivity and little to no enantioselectivity Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 296 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides was observed with either ligand. In light of these results in 2-MeTHF, the reaction was investigated on scale using L76. Table 3.5 Ligand reactivity comparison for aryl bromides N Me CO2Me + Br R 433a, g–k 0.1 mmol N Cl 435g L71: 71%, 97% ee L76: 70%, 97% ee N Me O O N N SMe 435a L71: 54%, 97% ee L76: 71%, 97% ee N L71: R = nPr R R R L76: R = F 435a, g–k CN CN N N N CO2Me N [Ir] (0.125%) K2HPO4 (3.0 equiv) 2-Me THF (0.05 M) hν (450 nm) BF3K 432b 1.5 equiv nPr L71 or L76 (30%) NiCl2•dme (10%) CF3 435h L71: 54%, 96% ee L76: 47%, 98% ee N CN 435i L71: 56%, 90% ee L76: 65%, 91% ee N Cl 435j L71: 55%, 97% ee L76: 65%, 97% ee F 435k L71: 38%, 96% ee L76: 68%, 97% ee As previously mentioned, the aryl bromide substrate scope using heptyl BiOX was already underway. This allowed for quick comparison of a variety of aryl bromide coupling partners on 0.1 mmol scale using the photoreactor reaction setup (Table 3.5). Interestingly, unlike on small scale, both heptyl BiOX L71 and 4-F-Ph BiOX L76 gave nearly identical ee’s for a variety of substrates. However, using 4-F-Ph BiOX resulted in increased yields for most aryl bromides. Model system 435g was mostly unaffected on this scale, but pyrimidine 435a and pyridines 435i and 435j saw increases in yield of up to 17%. Trifluoromethyl pyrimidine 435h saw a slight decrease in yield, however. Most promising was compound 435k, which saw an increase in yield from 38% to 68% upon exchanging ligands. These increases in yield led us to decide to redo the aryl bromide substrate scope using 4-F-Ph BiOX L76. In addition, about 6 months into the project, it was found that both enantiomers of L71 received from Merck contained ~5-6% of an undesired contaminant, hypothesized to be hydrolysis of one of the oxazolines based on the NMR and LCMS data (Scheme 3.12). Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 297 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Scheme 3.12 Decomposition of L71 nPr nPr N N nPr HO O O L71 H 2O slow nPr nPr nPr O O N H N L71-H2O nPr nPr -slow under air -byproduct of HPLC purification -easily removed by silica gel chromatography -no hydrolysis when stored in the glovebox This hydrolysis product was observed by NMR in other BiOX ligands previously synthesized by our lab stored in the freezer as well. This is thought to be a relatively slow process for L71. However, the method of separating enantiomers of L71 by outside contractors upon synthesis likely contributed to this hydrolysis, resulting in unusually large amounts of contaminant initially. Fortunately, this contaminant is easily separated by silica gel chromatography (see Section 3.5.2). Following this discovery, we (Caltech) would regularly purify multigram batches of this ligand and bring it into the glovebox for storage, where it was found to be stable. Minor irreproducibility issues previously observed were significantly reduced upon regular use of clean ligand. L76 was not isolated using the same purification process and was immediately stored in the glovebox upon synthesis to prevent decomposition in normal atmosphere. 3.3 SUBSTRATE SCOPE 3.3.1 Scope of Aryl Bromides With optimized conditions in hand, the aryl bromide substrate scope was investigated on 0.2 mmol scale using both L71 and L76 (Table 3.6). Interestingly, upon increasing the scale from 0.1 to 0.2 mmol, the yields significantly increased for almost all aryl bromides when using L76 as the ligand. However, when using heptyl BiOX, most yields were comparable or slightly reduced upon increasing the scale. As previously mentioned, electron-poor aryl and heteroaryl bromides perform the best under these Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 298 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Table 3.6 Aryl bromide scope CO2Me N Me + Br R BF3K 432b 1.5 equiv 433a, g–p 0.2 mmol N Cl Me O O N N N SMe L71: R = nPr R R R L76: R = F 435a, g–p CN CN N 435a L71: 53%, 95% ee L76: 84%, 96% ee 435g L71: 67%, 97% ee L76: 84%, 97% ee CO2Me N [Ir] (0.125%) K2HPO4 (3.0 equiv) 2-Me THF (0.05 M) hν (450 nm) N N N nPr L71 or L76 (30%) NiCl2•dme (10%) CF3 N 435h L71: 54%, 96% ee L76: 50%, 98% ee CN 435i L71: 57%, 90% ee L76: 77%, 91% ee N Cl F 435j L71: 58%, 96% ee L76: 77%, 97% ee F 435k L71: 38%,b 96% ee L76: 79%, 97% ee F F N N N CN 435l L71: 62%, 92% ee L76: 77%, 95% ee N OMe 435m L71: 44%, 90% ee L76: 63%,a 96% ee F 435n L71: 42%,b 95% ee L76: 58%, 97% ee N N CF3 O O 435o L71: 41%, 88 ee L76: 69%, 94% ee 435p L71: 55% yield, 0% ee L76: 27% yield,c 0% ee none: 55% yield Isolated yields are reported unless otherwise indicated; ee determined by SFC using a chiral stationary phase, [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6 aReaction run in THF. bRun on 0.1 mmol scale cDetermined by 1H NMR versus an internal standard reaction conditions, with enantiomeric excesses up to 98%. Pyrimidine and pyridine substrates generally performed well (435a, g–j, l, m), though CF3 pyrimidine 435h and methoxy pyridine 435m were both isolated in lower yields. Methoxy pyrimidine 435h was run in THF due to insolubility of the aryl bromide in 2-MeTHF. Electron-poor aryl groups were tolerated as well, albeit in lower yields (435n, o). In general, more electron-poor substrates were isolated in higher ee (for example 435h), and more electron-rich substrates were isolated with slightly lower enantioselectivity (435o). Overall, these conditions were generally applicable to a variety of electron-poor aryl bromides, affording the desired products in moderate to good yields and excellent enantioselectivities. Interestingly, when (5-bromopyridin-2-yl)(pyrrolidin-1-yl)methanone (433p) was cross-coupled in the presence of either L71 or L76, only racemic 435p was isolated. When ligand was eliminated from the reaction mixture all together, comparable yields of the cross-coupled product were obtained (Table 3.6). This suggests that the pyridine amide Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 299 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides Scheme 3.13 Pyridine amides as ligands OMe Br N Me + O BF3K 435p or 451 (30%) NiCl2•dme (10%) N N 432b 1.5 equiv [Ir] (0.125%) K2HPO4 (3.0 equiv) 2-MeTHF (0.05 M) Cl 433g 0.1 mmol CO2Me N Me N N 435g Cl X [Ni] CO2Me N X= N N H Me O 435p 52% yield via 451 28% yield moiety itself can act as a competent ligand for this cross-coupling. Indeed, when pyridine amide product 435p was used as the ligand for the cross-coupling of model BF3K 432b and pyrimidine 433g, the desired product was observed in 52% yield (Scheme 3.13). Parent pyridine 451 resulted in only 28% yield, however, indicating that substitution at the 5 position of the pyridine is key to ligand efficacy. Table 3.7 Other aryl bromides screened CO2Me N Me + Br R BF3K 432b 1.5 equiv nPr L71 or L76 (30%) NiCl2•dme (10%) 433c–f, p–y 0.1 mmol [Ir] (0.125%) K2HPO4 (3.0 equiv) 2-Me THF (0.05 M) hν (450 nm) CO2Me N Me CF3 N OMe 435c L71: 8%, 77% eea L76: - R N N N Me 435r L71: 41%, 96% eeb L76: - NBoc N N Me 435e 435f L71: 19% yield, 88% ee L71: 12% yield, 76% ee L76: L76: - N R L76: R = F O F 435v L71: 0%, -% ee L76: - Cl N N OMe 435t L71: 19%, -% ee L76: - N 435u L71: 21%, -% ee L76: - O OMe N CF3 435s L71: 24%, -% ee L76: 16%, -% ee OH N N N O N N L71: R = 435c–f, p–y Cl 435q L71: 33%, 94% ee L76: - O nPr R N 435d L71: 31%, 94% ee L76: 19%, -% ee O N N N Cl 435w L71: 37%, -% ee L76: - 435x L71: 26%, -% ee L76: 14%, -% ee N Cl 435y L71: 12%, -% eec L76: - Determined by 1H NMR, a62% recovered ArBr, b32% yield, 95% ee on 0.2 mmol scale with L1, cother byproducts observed, tentatively assigned as radical addition into the heterocycle A variety of other aryl bromides were investigated as well (Table 3.7). Most substrates were screened with L71 as we had over 20 g at our disposal and the increase in Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 300 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides yield with L76 was discovered relatively late in the project. Interestingly substrates 433d, 433s, and 435x actually underwent cross-coupling in lower yields with L76 compared to L71. As previously discussed, aryl bromides without sufficiently electron-withdrawing groups were cross-coupled in relatively low yields (435c–d). Pyridine 435q was observed in poor yield and good ee. Pyrimidine 435r was observed in 41% yield, 96% ee on 0.1 mmol scale, but the yield dropped significantly when run on 0.2 mmol scale (see footnote). Other nitrogen-containing heterocycles cross-coupled in low yields (435s,t), and pyridine 435u that does not have a blocking group at the 2 position was observed in 21% yield. Free carboxylic acids were not tolerated under the reaction conditions (433v), but methyl esters were (433w). Polycyclic heterocylces such as 433y resulted in complex mixtures of products that are believed to result from direct radical addition into the heterocycle to form stabilized radical intermediates. 3.3.3 Scope of Nucleophiles Scheme 3.14 Different nucleophile reactivity R N Me Br X + N BF3K 432a–c 1.5 equiv 433g R L71 (30%) NiCl2•dme (10%) N Cl N [Ir] (0.125%) Me N K2HPO4 (3.0 equiv) 2-MeTHF (0.05 M) Cl 434g, 435g, N hν (450 nm) 436 N N N 435g 67% yield, 97% ee O N N nPr nPr nPr L71 N N Me Cl O tBuO CO2Me Me nPr O BocHN N X N N N Me Cl 434g 70% yield, 80% ee N N Cl 436 13% yield, -% ee While the reaction conditions for the cross coupling of ester pyrrole 432b with a variety of aryl bromides were fairly consistent, conditions had to be re-optimized for Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 301 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides certain BF3K salts. When investigating the nucleophile substrate scope, we were surprised to find that while both pyrrole 432b and pyrazole 432z underwent successful crosscoupling to afford the desired products, ester pyrazole 436 was only observed in 13% yield (Scheme 3.14). This was especially unexpected due to the structural similarity between boc amine pyrazole 432a and ester pyrazole 432c. However, we noticed that while both pyrrole 432b and pyrazole 432b were relatively insoluble in 2-MeTHF, ester pyrazole 432c was highly soluble. Therefore, it was hypothesized that in order for successful crosscoupling to occur, the BF3K salt had to be relatively insoluble. Table 3.8 Re-optimization of reaction conditions for nucleophile 432c O nPr tBuO N Me N N O nPr tBuO L71 (30%) nPr NiCl2•dme (10%) N + N BF3K 432c 1.5 equiv O nPr Br N O Cl 433g N N [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) Me N 436 N entry solvent %[Ir] [Ir] soluble? %ArBra %pdt %ee 1 2 3 4 5 6 7 8 TBME TBME CPME CPME chlorobenzene chlorobenzene dioxane dioxane 0.125 1.0 0.125 1.0 0.125 1.0 0.125 1.0 no no no no yes yes no no 51 55 57 30 43 23 65 53 15 22 13 47 5 37 11 5 82 86 83 - Cl a%ArBr remaining To test this hypothesis, we performed a solvent screen for the cross-coupling of ester pyrazole 432c with 433g. Four solvents in which 432c is insoluble in were screened with two different [Ir] loadings (Table 3.8). It was found that cyclopentyl methyl ether (CPME) with 1.0% [Ir] proved to be the optimal set of conditions for the desired crosscoupling, affording the desired product in 47% yield, 86% ee (entry 4). It is thought that 1.0% [Ir] is needed due to its insolubility in CPME. Despite previous success with other substrates using TBME, it was not the optimal solvent for this substrate, though it did result Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 302 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides in an improvement in yield over 2-MeTHF (entry 2). Due to the insolubility of the [Ni]•L76 complex in CPME, it could not be investigated for this cross-coupling on scale. After this discovery, our collaborators utilized HTE to identify several solvents (2-Me-THF, isopropyl acetate (iPrOAc), CPME, and 1,2-dimethoxy ethane (DME)) that generally performed well across a variety of nucleophiles, simplifying the screening process. In general, it appears that in order for the reaction to afford product in synthetically useful yields, the BF3K salt must be relatively insoluble in the reaction solvent. In addition, the solubility of the [Ir] photocatalyst must be taken into account. When [Ir] is fully soluble, only 0.125 % is required. When [Ir] is relatively insoluble, such as in CPME, the [Ir] loading must be increased. Table 3.9 Ligand reactivity comparison for nucleophiles R Br X N N + Me N BF3K 432a, 1.5 equiv R L71 or L76 (30%) NiCl2•dme (10%) R 433a or 433g 0.2 mmol N [Ir] (x%) K2HPO4(3.0 equiv) solvent (0.05 M) hν (450 nm) nPr X O O N N L71: R = nPr Me N 434a, N 436–439 R R R L76: R = F O BocHN Cl t-BuO N N N N Me N N N Me SMe 434a 2-Me THF, 0.125% [Ir] L71: 56%, 84% ee L76: 56%, 53% ee CO2Me Me N N CO2Me Cl 436 CPME, 1.0% [Ir] L2: 46% yield, 83% ee L7: 5% yield, -% ee N N O N Cl 437 CPME, 1.0% [Ir] L2: 30% yield, 95% ee L7: 10% yield, -% ee N O Me N Me N Cl 438 2-Me THF, 0.125% [Ir] L2: 78%, 66% ee L7: 48%, 56% ee N N Cl 439 DME, 0.125% [Ir] L2: 25%, 53% ee L7: 25%, 77% ee Interestingly, across a variety of nucleophiles, L71 and L76 perform very differently (Table 3.9). While L76 proved to be optimal for the cross-coupling of pyrrole 432a with a wide variety of aryl bromides, it yielded inferior enantioselectivities for other nucleophiles. In particular, L71 afforded 434a and 438 in 84% ee and 66% ee, respectively, while L76 gave 53% ee and 56% ee. As previously stated, the [Ni]•L76 complex is Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 303 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides insoluble in CPME, resulting in inferior yields for 436 and 437. Interestingly, L76 affords higher enantioselectivities than L71 for phthalimide 439. Table 3.10 Nucleophile scope R N Me Br X + N BF3K 432a–j 1.5 equiv R L71 or L76 (30%) NiCl2•dme (10%) N N [Ir] (x%) K2HPO4 (3.0 equiv) solvent (0.05 M) hν (450 nm) Cl 433g 0.2 mmol nPr X O O N N nPr Me N 434g, N 436–443 R N CO2Me CO2Me N CO2Me F 437a 37%, 95%ee L76, 0.125% [Ir] iPrOAc N N CO2Me Me Me Me 440 62%, 97%ee L76, 0.125% [Ir] 2-Me THF L76: R = CO2Me N Me R Cl Cl F L71: R = Me 438 78% yield, 66% ee L71, 0.125% [Ir] 2-MeTHF 441 67% yield, 97% ee L76, 0.125% [Ir] 2-MeTHF 442 64% yield, 95% ee L76, 0.125% [Ir] 2-MeTHF O MeO2C BocHN N N Me 443 59% yield,b 95% ee L71, 1.0% [Ir] CPME t-BuO N N Me 434g 70% yield, 80% ee L71, 0.125% [Ir] 2-MeTHF N N Me 436 46% yield, 83% ee L71, 1% [Ir] CPME O N O Me 439 25% yield,b 77% ee L76, 0.125% [Ir] DME [Ir] = Ir[dF(CF3)ppy]2(bpy)PF6. a0.1 mmol scale, bdetermined by 1H NMR versus an internal standard With these observations in hand, the nucleophile substrate scope was explored (Table 3.10). Halogen substitution at the 4 position of the pyrrole is tolerated, though chlorinated substrate 437 is observed in comparatively low yield. Fluro pyrrole 440 and cyclopropyl pyrrole 441 were isolated in good yield and ee. The hypothesis that the ester at the 2 position acts as a directing group is supported by the decrease in enantioselectivity from 97% ee to 66% ee when the ester is shifted to the 3 position (438). Ethyl pyrrole 442 performs comparably to model pyrrole 435. Excitingly, azaindole 443 acts as a competent directing group for this cross-coupling, with the product observed in 56% yield and 95% ee. Pyrazoles 434g and 436 are also competent coupling partners, albeit with lower enantioselectivity. The nitrogen at the 2 position appears to be a less effective directing Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 304 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides group than the ester or azaindole, though still better than no directing group. Phthalimide substrate 439 was isolated in relatively low yields. It is thought that this could be due to in situ decomposition through single-electron reduction of the photoexcited phthalimide product.32 3.4 CONCLUSION In conclusion, we have developed an enantioselective nickel-catalyzed photoredox cross-coupling of α-N-heterocyclic potassium trifluoroborate salts with a variety of electron-poor aryl and heteroaryl bromides to form chiral N-(hetero)benzylic azoles. Crosscoupled products are afforded in up to 98% ee in good yields. This strategy is a significant improvement in yield and ee over previous approaches towards these types of products and is one of relatively few examples of enantioselective cross-coupling using photochemistry. While some nucleophiles require further reaction optimization, we have developed a simple workflow for optimizing new reaction conditions quickly. Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 305 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides 3.5 EXPERIMENTAL SECTION 3.5.1 Materials and methods Unless otherwise stated, reactions were performed under a nitrogen atmosphere using dried solvents. Anhydrous 2-Methyltetrahydrofuran (2-MeTHF), anhydrous tert-butyl methyl ether (TBME), anhydrous cyclopentyl methyl ether (CPME), anhydrous tetrahydrofuran (THF), anhydrous potassium phosphate monobasic (K2HPO4) were purchased from Millipore Sigma and stored in the glovebox. Nickel(II) chloride dimethoxyethane adduct (NiCl2•dme) was purchased from Strem. BF3K salts 432a–j were synthesized by Merck and used as received, as were aryl bromides 433h, j, k, and n–o. 4-heptyl BiOX (L71) was purchased by Merck from outside contractors. Both enantiomers were sent to us and were purified and stored in the glovebox. Unless otherwise stated, chemicals were used as received. All reactions were monitored by thin-layer chromatography (TLC) using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were visualized by ultraviolet (UV) light or with p-anisaldehyde or potassium permanganate staining. Flash column chromatography was performed as described by Still et al. using silica gel (230400 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 Avance III HD with Prodigy cyroprobe (at 400 MHz and 101 MHz, respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), or a Varian Inova 500 (at 500 MHz and 126 MHz, respectively). 1H and 19F NMR spectra were also recorded on a Varian Inova 300 (at 300 MHz and 282 MHz, respectively). NMR data is reported relative to internal CHCl3 (1H, δ = 7.26), CDCl3 (13C, δ = 77.1), C6F6 (19F, δ = 164.9), CH3C6D5 (1H, δ = 2.09), and CD3C6D5 (13C, δ = 20.4). Data for 1H NMR spectra Chapter 3 – Enantioselective Photoredox Catalysis for the Cross-Coupling of Azole- 306 Containing Alkyl BF3K Salts and Electron-Poor Aryl Bromides are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, 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 chromatography system with Chiralcel AD-H, OD-H, AS-H, OB-H, and OJ-H columns (4.6 mm x 25 cm). LRMS were obtained using an Aglient 1290 Infinity/6140 Quadrupole system (LC-MS) or an Agilent 7890A GC/5975C VL MSD system (GC-MS). HRMS were acquired from the Caltech Mass Spectral Facility using fast-atom bombardment (FAB), electrospray ionization (ESITOF), or electron impact (EI). Commonly Used Abbreviations: ee – enantiomeric excess; Et2O – diethyl ether; EtOAc – ethyl acetate; DCM – dichloromethane; FTIR – Fourier transform infrared; HRMS – high-resolution mass spectrometry; IPA – isopropanol; LRMS – low-resolution mass spectrometry; m.p. – melting point; NHP – N-hydroxyphthalimide; NMR – nuclear magnetic resonance; Rf – retention factor; SFC – supercritical fluid chromatography 307 Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 3.5.2 Ligand Preparation Purification of L71 nPr O O N N nPr L71 HO + nPr nPr nPr nPr O O N H N silica gel chromatography nPr nPr 20–50% EtOAc/hex nPr L71-H2O nPr O O N N L71 nPr nPr To remove undesired hydrolyzed contaminant L71•H2O intermixed with L71, the mixture was purified by silica gel chromatography (20–50% EtOAc/hexanes, load on celite) to afford L71. Azeotroped with pentanes to remove excess EtOAc and scratched the side of the vial with a spatula to induce solidification of the oil. L71 was isolated as an off-white solid and stored in a N2-filled glovebox to prevent hydrolysis. L71 is stable in the glovebox 1 H NMR (500 MHz, Chloroform-d) δ 4.47 – 4.32 (m, 4H), 4.15 (t, J = 7.9 Hz, 2H), 1.65 (h, J = 6.4, 6.0 Hz, 2H), 1.43 – 1.26 (m, 14H), 1.23 – 1.11 (m, 2H), 0.90 (q, J = 6.9 Hz, 12H). F O F OMe MeO O OH NH 2 S1 2.00 equiv PhMe 80 °C O H N HO N H O OH DAST (2.8 equiv) K2CO3 (4.0 equiv) DCM -78 – 18 °C O O N N F F S2 L76 F Synthesis of L76.30,33 Known amino alcohol S1 was synthesized by a borane reduction of the corresponding amino acid. To a 500 mL round bottom flask containing S1 (4.2 g, 27.0 mmol, 2.00 equiv) was added dimethyl oxalate (1.59 g, 13.5 mmol, 1.00 equiv) and PhMe (300 mL, 0.45 M). The flask was affixed with a reflux condenser, and the reaction mixture was heated to 80 ºC under nitrogen for 20 hours. The reaction mixture was then allowed to cool and was concentrated and dried in vacuo to afford S2, which was carried forward without further purification. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 308 To an oven-dried 250 mL rbf was added S2 (1.82 g, 5.00 mmol, 1.00 equiv). The flask was evacuated and backfilled with N2 x 3, and DCM (80 mL, 0.63 M) was then added. The reaction mixture was cooled to –78 ºC, and diethylaminosulfur trifluoride (DAST) (1.2 mL, 14.0 mmol, 2.8 equiv) was added dropwise over 2 minutes. The reaction was allowed to stir at –78 ºC for 1 hour, then K2CO3 (2.8 g, 20 mmol, 4.0 equiv) was added. The reaction was removed from the cold bath and allowed to stir for 1.5 hours. The reaction was then diluted with 40 mL DCM and 60 mL water. The layers were separated, and the organic layer was washed with sat aq. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (75% EtOAc/hexanes) to afford L76 (329 mg, 20% yield). 1 H NMR (400 MHz, Chloroform-d) δ 7.32 – 7.24 (m, 4H), 7.11 – 7.01 (m, 4H), 5.52 – 5.36 (m, 2H), 4.86 (dd, J = 10.4, 8.8 Hz, 2H), 4.33 (t, J = 8.9 Hz, 2H). 309 Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 3.5.3 Optimization of Reaction Parameters Optimization table data gathered by Kevin Belyk at Merck Br N Me CO2Me N + N BF3K Cl 433g 0.1 mmol 432b 1.5 equiv nPr L1 or L2 (30%) NiCl2•dme (10%) [Ir] (0.125%) K2HPO4 (3.0 equiv) 1-MeTHF(0.05 M) hν (450 nm) CO2Me N O O N N L71: R = nPr Me N 435g N R R Cl L76: R = F deviation from Standard conditionsa L71: yieldb (%) / eec (%) L76: yieldb (%) / eec (%) entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 none 10% [Ni], 10% L 10% [Ni], 15% L 10% [Ni], 20% L 5% [Ni], 15% L 1.0% [Ir] 0.5% [Ir] 0.25% [Ir] 1.0% 4 CzIPN no base no light no [Ir] no [Ni] and L no L 81 / 97 53 / 94 81 / 96 81 / 97 73 / 97 74 / 93 71 / 95 81 / 97 69 / 94 32 / 97 N.D. / N.D. / N.D. / 19 / 0 80 / 97 48 / 97 62 / 97 78 / 97 74 / 96 73 / 96 73 / 96 72 / 96 76 / 97 33 / 97 <1 / N.D. / N.D. / 19 / 0 aReaction conditions: XX (0.1 mmol), XX (0.15 mmol), NiCl •dme (10 µmol, 10 mol%), L1 or L2 (30 µmol, 30 mol%), [Ir] 2 = Ir[dF(CF3)ppy]2(bpy)PF6 (0.125 μmol, 0.125 mol%), K2HPO4 (0.3 mmol, 3 equiv.), 2-MeTHF (2 mL, 0.05 molar in XX), Pennoc M1 photoreactor, hν (450 nm), 7 cm sample holder, 500 RPM stir rate, 5200 RPM fan speed (18 h). bDetermined by 1H NMR analysis vs ethylene carbonate as an internal standard. cEnantiomeric excess determined + by chiral RP-HPLC. 3.5.4 Enantioselective Cross-Coupling a. General Procedure a: Reaction on 0.2 mmol scale R R N Me Br X + [Ni]L*, [Ir] het BF3K 432 433 base, solvent hν (450 nm) N X Me het 434–443 On the benchtop, to a 2-dram vial containing a 2-dram Teflon-coated stirbar was added aryl bromide 433 (if solid) (1.0 equiv, 0.2 mmol) and BF3K salt 432 (1.5 equiv, 0.3 mmol). The reaction vial was then brought into a N2-filled glovebox, and K2HPO4 (3 equiv, 0.6 mmol, 105 mg) was then added. Ir[dF(CF3)ppy]2(bpy)PF6 (0.125 mol%, 0.25 μmol, 0.25 mg) was added as a stock solution in 2.0 mL solvent followed by aryl bromide (if liquid) (1.0 equiv, 0.2 mmol). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 310 Meanwhile, NiCl2•dme (0.1 equiv, 0.02 mmol, 4.4 mg), ligand (0.30 equiv, 0.06 mmol) and the remaining solvent (2.0 mL) (4.0 mL total, 0.05 M) were added to a 1-dram vial with a stirbar, sealed with a cap, heated to 55–60 ºC in a heating block, and stirred until complexation was complete, everything was dissolved, and a color change occurred (heptyl BiOX: clear peachy orange solution; 4-F-Ph BiOX: clear yellow solution). Once complexation was complete, the complexed catalyst solution was added to the reaction vial. The vial was sealed with a Teflon cap and tape and removed from the glovebox. The reaction vial was then placed in a vial holder in a 7 cm tall cone in a Penn PhD m2 photoreactor with a 450 nm light module. Stirring was set to 500 rpm, the fan speed was set to 5200 rpm, the LED intensity was set to 100%, and the reaction time was set to 18 hours. After 18 hours, the reaction was diluted with EtOAc and washed with sat. aq. NH4Cl. The aqueous layer was extracted 3 times with EtOAc, and the combined organic layers were pushed through a ~8 mm by 6 cm plug of MgSO4 with a layer of celite on top. The solution was concentrated in vacuo, and the crude material was purified by silica gel column chromatography to afford the desired product. c. General Procedure b: Reaction on 0.1 mmol scale Identical to General Procedure A, but using a 1-dram vial instead of a 2-dram vial. Racemic standards were synthesized on 0.1 mmol scale using the same procedure in a 1-dram vial with rac-L71. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 311 c. Characterization of Reaction Products – Aryl Bromide Scope Note: At the time this section was compiled, we were in the middle of characterization of these products. Therefore, not all products that will appear in the final publication will have all of their characterization data in this document. 435a (TJD-6-002): Prepared from 5-bromo-2-(methylthio)pyrimidine N CO2Me Me (433a, 41 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according N N SMe to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to yield 435a (46.5 mg, 84% yield) in 96% ee as a colorless oil. Rf = 0.39 (silica gel, 20% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = 127° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.27 (s, 2H), 7.06 (dd, J = 2.8, 1.7 Hz, 1H), 7.01 (dd, J = 3.9, 1.7 Hz, 1H), 6.55 (q, J = 7.2 Hz, 1H), 6.23 (dd, J = 3.9, 2.7 Hz, 1H), 3.76 (s, 3H), 2.53 (s, 3H), 1.83 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 171.87, 161.63, 155.41, 131.33, 124.70, 122.15, 119.25, 109.46, 51.46, 51.31, 21.65, 14.25 FTIR (NaCl, thin film, cm-1): 2948, 1699, 1584, 1537, 1438, 1400, 1338, 1227, 1111, 942, 738 HRMS (FAB, m/z): calc'd for C13H16N3O2S [M+H]+ : 278.0963 ; found: 278.0970. Chiral SFC: (IC, 2.5 mL/min, 25% IPA in CO2, λ = 254 nm): Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 312 435g (TJD-5-299): Prepared from 5-bromo-2-chloropyrimidine (433g, N CO2Me Me 38.7 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according to N N Cl General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 8.5–9% EtOAc/hexane) to yield 435g (44.5 mg, 84% yield) in 97% ee as a colorless oil. Rf = 0.36 (silica gel, 20% EtOAc/hexanes, UV). [𝒂]𝟐𝟏 𝑫 = 79° (c = 1.1, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 0.6 Hz, 2H), 7.10 (dd, J = 2.8, 1.7 Hz, 1H), 7.03 (dd, J = 4.0, 1.7 Hz, 1H), 6.59 (q, J = 7.3 Hz, 1H), 6.28 (dd, J = 4.0, 2.8 Hz, 1H), 3.75 (s, 3H), 1.86 (d, J = 7.3 Hz, 3H) 13 C NMR (101 MHz, CDCl3): δ 161.6, 160.5, 157.7, 135.5, 124.6, 122.2, 119.5, 109.8, 51.4, 51.3, 21.7. FTIR (NaCl, thin film, cm-1): 3126, 2984, 2949, 1698, 1549, 1439, 1398, 1338, 1226, 1113, 1059, 940, 829, 740 HRMS (FAB, m/z): calc'd for C12H13ClN3O2 [M+H]+ : 266.0696 ; found: 266.0702. Chiral SFC: (IC, 2.5 mL/min, 30% IPA in CO2, λ = 254 nm): 435h N CO2Me Me (CRL-6-199; TJD-5-241): Prepared from 5-bromo-2- (trifluoromethyl)pyrimidine (433h, 45.4 mg, 0.3 mmol) and BF3K (432b, N N CF3 81.8 mg, 0.2 mmol) according to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 2.5% EtOAc/PhMe) to yield 3b (30 mg, 50% yield) in 98% ee as a colorless oil. Rf = 0.54 (silica gel, 30% EtOAc/hexanes, UV). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 313 [𝒂]𝟐𝟏 𝑫 = 46° (c = 1.5, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.55 (s, 2H), 7.15 (dd, J = 2.8, 1.7 Hz, 1H), 7.05 (dd, J = 4.0, 1.7 Hz, 1H), 6.67 (q, J = 7.3 Hz, 1H), 6.31 (dd, J = 4.0, 2.7 Hz, 1H), 3.74 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.56, 155.78, 139.11, 124.56, 122.28, 120.99, 119.66, 118.26, 109.95, 51.79, 51.42, 21.68. 19 F NMR (282 MHz, CDCl3) δ -73.42. FTIR (NaCl, thin film, cm-1): 3124, 2991, 1956, 1704, 1698, 1714, 1568, 1441, 1353, 1118, 941 HRMS (FAB, m/z): calc'd for C13H13F3O2N3 [M+H]+ : 300.0960 ; found: 300.0973. Chiral SFC: (IC, 2.5 mL/min, 5% IPA in CO2, λ = 254 nm): tR (minor) = 3.0 min, tR (major) = 3.7 min. 435i (CRL-6-072,197): Prepared from 5-bromo-2-pyridinecarbonitrile N CO2Me (433i, 36.6 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according Me N CN to General Procedure a in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 10-30% EtOAc/hex) to yield 435i (39 mg, 77% yield) in 91% ee as a colorless oil. Rf = 0.39 (silica gel, 30% EtOAc/hex, UV). [𝒂]𝟐𝟓 𝑫 = 71° (c = 0.7784, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 8.1, 0.8 Hz, 1H), 7.39 (ddd, J = 8.1, 2.3, 0.7 Hz, 1H), 7.12 (dd, J = 2.8, 1.7 Hz, 1H), 7.04 (dd, J = 4.0, 1.8 Hz, 1H), Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 314 6.63 (q, J = 7.2 Hz, 1H), 6.29 (dd, J = 4.0, 2.7 Hz, 1H), 3.73 (d, J = 0.5 Hz, 3H), 1.86 (d, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.51, 149.29, 143.21, 134.26, 132.70, 128.49, 124.82, 122.29, 119.46, 117.24, 109.59, 53.63, 51.35, 21.92. FTIR (NaCl, thin film, cm-1): 2987, 2950, 2236, 1702, 1438, 1414, 1339, 1240, 1213, 1112, 1054, 1022, 946, 848, 760, 741 HRMS (FAB, m/z): calc'd for C14H14N3O2 [M+H]+ : 256.1086 ; found: 256.1074. Chiral SFC: (AD-H, 2.5 mL/min, 15% IPA in CO2, λ = 254 nm): tR (minor) = 3.3 min, tR (major) = 3.1 min. 435j (TJD-6-003): Prepared from 5-bromo-2-chloronicotinonitrile (4337, N CO2Me CN Me 43.5 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according to General General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The N Cl crude residue was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to yield 435j (44.6 mg, 77% yield) in 97% ee as a colorless oil. Rf = 0.39 (silica gel, 20% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = 87° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.35 (dd, J = 2.5, 0.6 Hz, 1H), 7.55 (dd, J = 2.5, 0.7 Hz, 1H), 7.12 (dd, J = 2.8, 1.7 Hz, 1H), 7.04 (dd, J = 4.0, 1.7 Hz, 1H), 6.58 (q, J = 7.2 Hz, 1H), 6.30 (dd, J = 4.0, 2.8 Hz, 1H), 3.75 (s, 3H), 1.85 (d, J = 7.3 Hz, 3H) 13 C NMR (101 MHz, CDCl3): δ 161.5, 151.5, 150.9, 140.0, 138.9, 124.5, 122.2, 119.7, 114.7, 110.8, 109.9, 52.7, 51.4, 21.9 Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 315 FTIR (NaCl, thin film, cm-1): 2949, 1698, 1558, 1532, 1414, 1341, 1238, 1115, 913, 739 HMRS (ESI-TOF, m/z): C14H13N3O2Cl; cal'd for [M+H]+: 290.0696, found: 290.0682 Chiral SFC: (IC, 2.5 mL/min, 15% MeOH in CO2, λ = 254 nm): 435k (TJD-5-300): Prepared from 3-bromo-5-fluorobenzonitrile (433k, N CO2Me CN Me 40.0 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude F residue was purified by column chromatography (silica gel, 8.5% EtOAc/hexanes) to yield 435k (43 mg, 79% yield) in 97% ee as a colorless oil. Rf = 0.55 (silica gel, 20% EtOAc/hexanes, UV). [𝒂]𝟐𝟏 𝑫 = 56° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.24 – 7.17 (m, 1H), 7.15 – 6.94 (m, 4H), 6.58 (q, J = 7.2 Hz, 1H), 6.33 – 6.22 (m, 1H), 3.75 (d, J = 1.6 Hz, 3H), 1.87 – 1.76 (m, 3H) 13 C NMR (101 MHz, CDCl3): δ 162.5 (d, J = 250.9 Hz), 161.6, 148.4 (d, J = 7.3 Hz), 125.6 (d, J = 3.3 Hz), 124.9, 122.2, 119.3, 118.3 (d, J = 20.2 Hz), 118.2 (d, J = 22.9 Hz), 114.1 (d, J =9.6 Hz), 109.5, 54.7, 51.3, 2.0 19 F NMR (282 MHz, CDCl3) δ -112.41 (dd, J = 9.3, 7.9 Hz). FTIR (NaCl, thin film, cm-1): 2950, 2233, 1699, 1596, 1531, 1437, 1343, 1236, 1115, 964, 874, 743 HRMS (ESI-TOF, m/z): C15H14N2O2F; cal'd for [M+H]+: 273.1039, found: 273.1036 Chiral SFC: (OD-H, 2.5 mL/min, 10% MeOH in CO2, (λ = 254 nm): Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 316 435l (CRL-6-196): Prepared from 5-bromopyrimidine-2-carbonitrile N CO2Me Me (433l, 36.8 mg, 0.3 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according N N CN to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 10 to 40% EtOAc/hexanes) to yield 435l (39 mg, 77% yield) in 95% ee as a colorless oil. Rf = 0.43 (silica gel, 30% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = 60° (c = 1.1, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 0.6 Hz, 2H), 7.15 (dd, J = 2.8, 1.7 Hz, 1H), 7.06 (dd, J = 4.0, 1.7 Hz, 1H), 6.61 (q, J = 7.3 Hz, 1H), 6.32 (dd, J = 4.0, 2.8 Hz, 1H), 3.74 (s, 3H), 1.90 (d, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.53, 155.84, 144.01, 139.70, 124.57, 122.25, 119.79, 115.68, 110.07, 51.97, 51.46, 21.60. FTIR (NaCl, thin film, cm-1): 2950, 1699, 1555, 1438, 1416, 1339, 1242, 1214, 1114, 942, 793, 761, 743 HRMS (FAB, m/z): calc'd for C13H13N4O2 [M+H]+ : 257.1039 ; found: 257.1023. Chiral SFC: (AD-H, 2.5 mL/min, 10% IPA in CO2, λ = 280 nm): tR (minor) = 4.5 min, tR (major) = 4.2 min. 435m (CRL-6-198): Prepared from 5-bromo-2-methoxypyrimidine N CO2Me Me (433m, 37.8 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) N N OMe according to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 30 to 40% EtOAc/hexanes) to yield 435m (33 mg, 63% yield) in 96% ee as a colorless oil. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 317 Rf = 0.30 (silica gel, 30% EtOAc/hexanes, UV). [𝒂]𝟐𝟏 𝑫 = 99° (c = 1.51, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 0.6 Hz, 2H), 7.04 (dd, J = 2.8, 1.7 Hz, 1H), 6.99 (dd, J = 4.0, 1.8 Hz, 1H), 6.57 (q, J = 7.2 Hz, 1H), 6.22 (dd, J = 4.0, 2.8 Hz, 1H), 3.97 (s, 3H), 3.76 (s, 3H), 1.82 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 165.15, 161.63, 157.55, 129.74, 124.67, 122.06, 119.13, 109.38, 55.07, 51.28, 51.17, 21.74. FTIR (NaCl, thin film, cm-1): 2952, 1702, 1598, 1560, 1474, 1411, 1338, 1228, 1112, 1039, 943, 805, 738 HRMS (FAB, m/z): calc'd for C13H16N3O3 [M+H]+ : 262.1192 ; found: 262.1183. Chiral SFC: (IC, 2.5 mL/min, 25% IPA in CO2, λ = 254 nm): tR (minor) = 4.1 min, tR (major) = 4.4 min. 435n N CO2Me F Me CF3 F (CRL-6-200): Prepared from 5-bromo-1,3-difluoro-2- (trifluoromethyl)benzene (433n, 52.2 mg, 0.2 mmol) and BF3K (432b, 81.8 mg, 0.3 mmol) according to General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 2–20% EtOAc/hexanes) to yield 435n (38.7 mg, 58% yield) in 97% ee as a colorless oil. Rf = 0.68 (silica gel, 30% EtOAc/hexanes, UV). [𝒂]𝟐𝟓 𝑫 = 38° (c = 0.97, CHCl3). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 1 318 H NMR (400 MHz, CDCl3): δ 7.09 (dd, J = 2.8, 1.8 Hz, 1H), 7.05 (dd, J = 3.9, 1.7 Hz, 1H), 6.70 – 6.61 (m, 2H), 6.55 (q, J = 7.2 Hz, 1H), 6.28 (dd, J = 4.0, 2.7 Hz, 1H), 3.76 (s, 3H), 1.81 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.55 (d, J = 4.6 Hz), 159.20 – 158.66 (m), 151.63 (t, J = 9.3 Hz), 124.88, 123.04, 122.32, 120.33, 119.31, 110.14 (dd, J = 23.4, 3.3 Hz), 109.47, 54.86 (d, J = 2.0 Hz), 51.34, 21.83. 19 F NMR (282 MHz, CDCl3) δ -59.59 (t, J = 21.6 Hz), -111.09 – -114.78 (m). Chiral SFC: (OJ-H, 2.5 mL/min, 7% IPA in CO2, λ = 254 nm): tR (minor) = 2.9 min, tR (major) = 2.3 min. N CO2Me F F 435o (TJD-6-004): Prepared from 6-bromo-4,4-difluoro-3,4- dihydronaphthalen-1(2H)-one (433o, 52.2 mg, 0.2 mmol) and BF3K Me (432b, 81.8 mg, 0.3 mmol) according to General Procedure A in 2O MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to yield 435o (45.9 mg, 69% yield) in 94% ee as a colorless oil. Rf = 0.43 (silica gel, 20% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = 73° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 7.97 (dt, J = 8.2, 1.3 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.29 – 7.23 (m, 1H), 7.08 (dd, J = 2.8, 1.8 Hz, 1H), 7.03 (dd, J = 3.9, 1.7 Hz, 1H), 6.66 (q, J = 7.2 Hz, 1H), 6.26 (dd, J = 3.9, 2.7 Hz, 1H), 3.75 (s, 3H), 2.94 – 2.82 (m, 2H), 2.70 – 2.55 (m, 2H), 1.85 (d, J = 7.2 Hz, 3H). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 13 319 C NMR (101 MHz, CDCl3): δ 194.4 (t, J = 1.4 Hz), 161.6, 150.6 (t, J = 1.1 Hz), 137.3 (t, J = 25. 9 Hz), 130.5 (t, J = 5.5 Hz), 128.9 (t, J = 1.4 Hz), 127.8, 125.2, 122.3, 122.0 (t, J = 4.1 Hz), 120.6, 119.1, 118.2, 115.7, 109.2, 55.4, 51.2, 34.6 (t, J = 5.3 Hz), 32.4 (t, J = 25.7 Hz), 22.0. 19 F NMR (282 MHz, CDCl3) δ -95.60 (t, J = 13.0 Hz) FTIR (NaCl, thin film, cm-1): 3378, 2950, 1694, 1611, 1530, 1448, 1238, 975, 849, 746 HRMS (ESI-TOF, m/z): C18H18NO3F2; cal'd for [M+H]+: 334.1255, found: 334.1259 Chiral SFC: (OD-H, 2.5 mL/min, 30% IPA in CO2, (λ = 254 nm) 435p N CO2Me (CRL-6-096): Prepared from (5-bromopyridin-2- yl)(pyrrolidin-1-yl)methanone (433p, 51 mg, 0.2 mmol) and BF3K Me N N O (432b, 81.8 mg, 0.3 mmol) according to General Procedure A in 2MeTHF with heptyl BiOX (L71). The crude residue was purified by column chromatography (silica gel, 60–100% EtOAc/hexanes) to yield 435p (35.8 mg, 55% yield) in 0% ee as a colorless oil. Rf = 0.3 (silica gel, 80% EtOAc/DCM, UV). [𝒂]𝟐𝟓 𝑫 = –1.5° (c = 1.89, CHCl3). 1 H NMR (400 MHz, CDCl3): δ δ 8.36 (dt, J = 2.5, 0.7 Hz, 1H), 7.77 (dd, J = 8.1, 0.9 Hz, 1H), 7.43 (ddd, J = 8.2, 2.3, 0.7 Hz, 1H), 7.07 (dd, J = 2.7, 1.8 Hz, 1H), 7.02 (dd, J = 3.9, 1.8 Hz, 1H), 6.65 (q, J = 7.2 Hz, 1H), 6.24 (dd, J = 4.0, 2.7 Hz, 1H), 3.75 (s, 3H), 3.75 – 3.71 (m, 2H), 3.69 – 3.62 (m, 2H), 1.86 (s, 4H), 1.84 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 166.20, 161.60, 153.53, 146.10, 140.00, 134.40, 125.06, 123.99, 122.23, 119.07, 109.19, 53.47, 51.25, 49.28, 47.04, 26.76, 24.14, 22.02, 14.20. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 320 FTIR (NaCl, thin film, cm-1): 2967, 2876, 1702, 1625, 1436, 1339, 1237, 1212, 1111, 1022, 736. HRMS (FAB, m/z): calc'd for C18H22N3O3 [M+H]+ : 328.1661 ; found: 328.1657. c. Characterization of Reaction Products – Nucleophile Scope 434g (TJD-6-010): Prepared from 5-bromo-2-chloropyrimidine (433g, BocHN N 38.7 mg, 0.2 mmol) and BF3K (432a, 95.1 mg, 0.3 mmol) according to N General Procedure A in 2-MeTHF with 4-heptyl BiOX (L71). The N Me N Cl crude residue was purified by column chromatography (silica gel, 30/20/50 EtOAc/DCM/hexanes) to yield 434g (45.6 mg, 70% yield) in 80% ee as a white solid. Rf = 0.4.6 (silica gel, 50% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = –7° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.46 (s, 2H), 7.82 (s, 1H), 7.35 (s, 1H), 6.29 (s, 1H), 5.44 (q, J = 7.1 Hz, 1H), 1.92 (d, J = 7.1 Hz, 3H), 1.49 (s, 9H) 13 C NMR (101 MHz, CDCl3): δ 161.0, 157.9, 153.0, 134.0, 130.8, 122.5, 118.7, 80.9, 56.7, 28.4, 20.8. FTIR (NaCl, thin film, cm-1): 2954, 1700, 1598, 1550, 1399, 1249, 1164, 772, 676 HRMS (ESI-TOF, m/z): C14H19N5O2Cl; cal'd for [M+H]+: 324.1227, found: 324.1240 Chiral SFC: (AD-H, 2.5 mL/min, 35% IPA in CO2, λ = 254 nm): Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 321 436 (CRL-6-204): Prepared from 5-bromo-2-chloropyrimidine O t-BuO (433g, 38.7 mg, 0.2 mmol) and BF3K (432c, 90.6 mg, 0.3 mmol) N N according to General Procedure A in CPME with 4-heptyl BiOX Me N N Cl (L71). The crude residue was purified by column chromatography (silica gel, 5–25% EtOAc/DCM) to yield 436 (28.3 mg, 46% yield) in 83% ee as a yellow oil. Rf = 0.43 (silica gel, 20% EtOAc/DCM, UV). [𝒂]𝟐𝟏 𝑫 = –2° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.52 (s, 2H), 7.93 (d, J = 0.6 Hz, 1H), 7.91 – 7.86 (m, 1H), 5.52 (q, J = 7.1 Hz, 1H), 1.96 (d, J = 7.1 Hz, 3H), 1.54 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 162.11, 161.35, 157.99, 141.98, 133.15, 131.19, 117.65, 81.15, 56.99, 29.85, 28.42, 21.04. Chiral SFC: (IC, 2.5 mL/min, 30% IPA in CO2, λ = 210 nm): tR (minor) = 3.0 min, tR (major) = 4.0 min. 437 (CRL-6-208): Prepared from 5-bromo-2-chloropyrimidine (433g, Cl N CO2Me 38.7 mg, 0.1 mmol) and BF3K (432d, 44 mg, 0.15 mmol) according to N General Procedure B in i-PrOAc with 4-F-Ph BiOX (L76). The crude Me N Cl residue was purified by column chromatography (silica gel, 5–30% EtOAc/hexanes) to yield 437 (11.1 mg, 36% yield) in 95% ee as a colorless oil. Rf = 0.52 (silica gel, 30% EtOAc/hexanes, UV). 1 H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 0.6 Hz, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 6.57 (q, J = 7.2 Hz, 1H), 3.76 (s, 3H), 1.84 (d, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 160.82, 160.79, 157.67, 134.64, 121.86, 121.75, 118.41, 113.69, 51.73, 51.67, 21.56. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 322 Chiral SFC: (AD-H, 2.5 mL/min, 7% IPA in CO2, (λ = 254 nm): tR (minor) = 7.5 min, tR (major) = 9.1 min. 438 (TJD-6-009): Prepared from 5-bromo-2-chloropyrimidine (433g, 38.7 CO2Me mg, 0.2 mmol) and BF3K (432e, 77.7 mg, 0.3 mmol) according to General N Procedure A in 2-MeTHF with 4-heptylBiOX (L71). The crude residue N Me N Cl was purified by column chromatography (silica gel, 30% EtOAc/hexanes) to yield 438 (41.2 mg, 78% yield) in 66% ee as a colorless oil. Rf = 0.50 (silica gel, 50% EtOAc/hexanes, UV). [𝒂]𝟐𝟐 𝑫 = –13° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 0.6 Hz, 2H), 7.39 (t, J = 1.9 Hz, 1H), 6.70 – 6.63 (m, 2H), 5.33 (q, J = 7.1 Hz, 1H), 3.81 (s, 3H), 1.91 (d, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 164.9, 161.3, 157.5, 134.2, 124.2, 120.4, 117.3, 111.5, 54.3, 51.4, 21.4. FTIR (NaCl, thin film, cm-1): 2950, 1698, 1538, 1398, 1158, 994, 826, 762, 67 HRMS (ESI-TOF, m/z): C12H13N3O2Cl; cal'd for [M+H]+: 266.0696, found: 266.0703 Chiral SFC: (AD-H, 2.5 mL/min, 25% IPA in CO2, (λ = 280 nm) 439 (CRL-6-205): Prepared from 5-bromo-2-chloropyrimidine (433g, 38.7 mg, 0.2 mmol) and BF3K (432f, 84.3 mg, 0.3 mmol) according to O N O General Procedure A in DME with 4-F-Ph BiOX (L76). 2.0 mg ethylene Me N N Cl carbonate added, and the 1H NMR was calculated (25% yield 439). The crude residue was purified by column chromatography (silica gel, 20–40% EtOAc/hexanes). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 323 The material was then repurified by prep TLC (5% EtOAc/DCM) to afford 429 as white solids (77% ee). Rf = 0.4 (silica gel, 30% EtOAc/hexanes, UV). 1 H NMR (400 MHz, CDCl3): δ 8.78 (d, J = 0.5 Hz, 2H), 7.91 – 7.79 (m, 2H), 7.79 – 7.69 (m, 2H), 5.67 – 5.49 (m, 1H), 1.94 (d, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 167.71, 160.96, 159.27, 134.60, 132.16, 131.67, 123.74, 44.90, 17.13. Chiral SFC: IC, 2.5 mL/min, 35% MeCN in CO2, λ = 254 nm): tR (minor) = 3.3 min, tR (major) = 4.0 min. 440 (CRL-6-216): Prepared from 5-bromo-2-chloropyrimidine (433g, 38.7 F N CO2Me mg, 0.2 mmol) and BF3K (432g, 83.1 mg, 0.3 mmol) according to General N Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was Me N Cl purified by column chromatography (silica gel, 5–30% EtOAc/hexanes) to yield 440 (35.4 mg, 62% yield) in 97% ee as a colorless oil. Rf = 0.47 (silica gel, 30% EtOAc/hexanes, UV). 1 H NMR (400 MHz, CDCl3): δ 8.36 (d, J = 0.6 Hz, 2H), 6.87 (dd, J = 3.3, 2.1 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.64 – 6.52 (m, 1H), 3.75 (s, 3H), 1.82 (d, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.06 (d, J = 2.9 Hz), 160.71, 157.60, 152.22, 149.80, 134.86, 118.74 (d, J = 5.7 Hz), 109.16 (d, J = 28.0 Hz), 105.73 (d, J = 15.3 Hz), 51.48 (d, J = 36.0 Hz), 21.44. Chiral SFC: (IC, 2.5 mL/min, 15% IPA in CO2, λ = 254 nm): tR (minor) = 7.8 min, tR (major) = 8.9 min. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 324 441 (TJD-6-046): Prepared from 5-bromo-2-chloropyrimidine (433g, 38.7 mg, 0.2 mmol) and BF3K (432h, 89.7 mg, 0.3 mmol) according to N CO2Me Me General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude N N Cl residue was purified by column chromatography (silica gel, 10% EtOAc/PhMe) to yield 441 (41.2 mg, 67% yield) in 97% ee as a colorless oil. [𝒂]𝟐𝟐 𝑫 = 24° (c = 1.0, CHCl3). 1 H NMR (400 MHz, CDCl3): δ 8.32 (s, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.53 (q, J = 7.2 Hz, 1H), 3.73 (s, 3H), 1.83 (d, J = 7.3 Hz, 3H), 1.76 – 1.62 (m, 1H), 0.91 – 0.76 (m, 2H), 0.56 – 0.44 (m, 2H). 13 C NMR (101 MHz, CDCl3): 161.5, 160.4, 157.7, 135.5, 128.2, 121.7, 121.7, 116.7, 51.3, 51.0, 21.5, 8.2, 8.1, 7.8. FTIR (NaCl, thin film, cm-1): 2950, 1699, 1549, 1439, 1401, 1340, 1238, 1105, 980, 830, 677 HRMS (ESI-TOF, m/z): C15H17N3O2Cl; cal'd for [M+H]+: 306.1009, found: 306.0992 Chiral SFC: (IC, 2.5 mL/min, 30% IPA in CO2, λ = 254 nm): 442 (TJD-6-045): Prepared from 5-bromo-2-chloropyrimidine (433g, N CO2Me Me 38.7 mg, 0.2 mmol) and BF3K (432i, 83.9 mg, 0.3 mmol) according to N N Cl General Procedure A in 2-MeTHF with 4-F-Ph BiOX (L76). The crude residue was purified by column chromatography (silica gel, 9% EtOAc/hexanes) to yield 442 (35.6 mg, 64% yield) in 95% ee as a colorless oil. [𝒂]𝟐𝟐 𝑫 = 71° (c = 1.0, CHCl3). Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 1 325 H NMR (400 MHz, CDCl3): δ 8.41 (s, 2H), 7.10 (dd, J = 2.8, 1.7 Hz, 1H), 7.00 (dd, J = 4.0, 1.7 Hz, 1H), 6.36 (dd, J = 9.0, 6.9 Hz, 1H), 6.27 (dd, J = 4.0, 2.8 Hz, 1H), 3.76 (s, 3H), 2.37 – 2.08 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 161.7, 160.6, 158.2, 134.2, 124.4, 122.5, 119.2, 110.0, 57.1, 51.4, 28.5, 11.0. FTIR (NaCl, thin film, cm-1): 2972, 1698, 1579, 1549, 1439, 1400, 1338, 1227, 1155, 1109, 1070, 851, 744 HRMS (ESI-TOF, m/z): C13H15N3O2Cl; cal'd for [M+H]+: 280.0853, found: 280.0842 Chiral SFC: (IC, 2.5 mL/min, 20% IPA in CO2 443 (TJD-6-044): Prepared from 5-bromo-2-chloropyrimidine MeO2C (433g, 38.7 mg, 0.2 mmol) and BF3K (432j, 93.0 mg, 0.3 mmol) N N Me according to General Procedure A in CPME with 4-heptyl BiOX N N Cl (L71). Added 21.0 mg 1,1,2,2,-tetrachloroethane, and the yield was calculated by 1H NMR (59% yield 443. The crude material was purified by prep TLC (1.5% MeOH/DCM). The middle of the band was taken, and purified again by prep TLC (40% Et2O/PhMe) to afford 443 (95% ee). [𝒂]𝟐𝟏 𝑫 = 190° (c = 0.3, CHCl3). 1 H NMR (500 MHz, CDCl3): δ 8.96 (s, 1H), 8.60 (s, 1H), 8.53 (s, 2H), 7.35 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 6.38 – 6.26 (m, 1H), 3.97 (s, 3H), 2.09 – 1.96 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 167.0, 160.9, 158.1, 149.0, 145.5, 134.0, 131.6, 125.6, 120.1, 119.6, 103.1, 52.3, 48.6, 20.0. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 326 FTIR (NaCl, thin film, cm-1): 2922, 1716, 1602, 1576, 1549, 1404, 1315, 1210 ,1162, 937, 730 HRMS (ESI-TOF, m/z): C15H14N4O2Cl; cal'd for [M+H]+: 317.0805, found: 317.0805 Chiral SFC: (OJ-H, 2.5 mL/min, 30% IPA in CO2 Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 327 3.6 REFERENCES (1) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7 (1), 442–495. (2) Josey, A. D.; Jenner, E. L. J. Org. Chem. 1962, 27 (7), 2466–2470. (3) Jefford, C. W.; de Villedon de Naide, F.; Sienkiewicz, K. Tetrahedron Asymmetry 1996, 7 (4), 1069–1076. (4) Polshettiwar, V.; Baruwati, B.; Varma, R. S. Chem. Commun. 2009, No. 14, 1837– 1839. (5) Baig, R. B. N.; Varma, R. S. Green Chem. 2013, 15 (2), 398–417. (6) Aydogan, F.; Yolacan, C. J. Chem. 2013, 2013, e976724. (7) D’Silva, C.; Walker, D. A. J. Org. Chem. 1998, 63 (19), 6715–6718. (8) Aydogan, F.; Basarir, M.; Yolacan, C.; Demir, A. S. Tetrahedron 2007, 63 (39), 9746– 9750. (9) Singh, K.; Kabadwal, L. M.; Bera, S.; Alanthadka, A.; Banerjee, D. J. Org. Chem. 2018, 83 (24), 15406–15414. (10) Borghs, J. C.; Lebedev, Y.; Rueping, M.; El-Sepelgy, O. Org. Lett. 2019, 21 (1), 70–74. (11) Laha, J. K.; Cuny, G. D. J. Org. Chem. 2011, 76 (20), 8477–8482. (12) Laha, J. K.; Bhimpuria, R. A.; Hunjan, M. K. Chem. – Eur. J. 2017, 23 (9), 2044–2050. (13) Ruan, Z.; Huang, Z.; Xu, Z.; Zeng, S.; Feng, P.; Sun, P.-H. Sci. China Chem. 2021, 64 (5), 800–807. (14) Pandey, G.; Laha, R.; Singh, D. J. Org. Chem. 2016, 81 (16), 7161–7171. (15) Song, C.; Dong, X.; Yi, H.; Chiang, C.-W.; Lei, A. ACS Catal. 2018, 8 (3), 2195–2199. (16) Xue, Q.; Xie, J.; Li, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2013, 49 (35), 3700–3702. (17) Liu, W.; Liu, C.; Zhang, Y.; Sun, Y.; Abdukadera, A.; Wang, B.; Li, H.; Ma, X.; Zhang, Z. Org. Biomol. Chem. 2015, 13 (26), 7154–7158. (18) Liu, X.; Yu, G.; Li, J.; Wang, D.; Chen, Y.; Shi, K.; Chen, B. Synlett 2013, 24 (12), 1588–1594. (19) Deb, I.; Coiro, D. J.; Seidel, D. Chem. Commun. 2011, 47 (22), 6473–6475. (20) Wang, J.; Shen, Q.; Zhang, J.; Song, G. Tetrahedron Lett. 2015, 56 (22), 2913–2916. (21) Pahadi, N. K.; Paley, M.; Jana, R.; Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2009, 131 (46), 16626–16627. Chapter 5 – Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 328 (22) Haydl, A. M.; Hilpert, L. J.; Breit, B. Chem. – Eur. J. 2016, 22 (19), 6547–6551. (23) Haydl, A. M.; Xu, K.; Breit, B. Angew. Chem. Int. Ed. 2015, 54 (24), 7149–7153. (24) Shea, M. D.; Mansoor, U. F.; Hopkins, B. A. Org. Lett. 2020, 22 (3), 1052–1055. (25) Fan, L.; Jia, J.; Hou, H.; Lefebvre, Q.; Rueping, M. Chem. – Eur. J. 2016, 22 (46), 16437–16440. (26) Molander, G. A.; Ryu, D.; Hosseini-Sarvari, M.; Devulapally, R.; Seapy, D. G. J. Org. Chem. 2013, 78 (13), 6648–6656. (27) Devulapally, R.; Fleury-Brégeot, N.; Molander, G. A.; Seapy, D. G. Tetrahedron Lett. 2012, 53 (9), 1051–1055. (28) Nadaf, R. N.; Seapy, D. G. Synth. Commun. 2014, 44 (14), 2012–2020. (29) Pezzetta, C.; Bonifazi, D.; Davidson, R. W. M. Org. Lett. 2019, 21 (22), 8957–8961. (30) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc. 2017, 139 (16), 5684–5687. (31) Lipp, A.; Badir, S. O.; Molander, G. A. Angew. Chem. Int. Ed. 2021, 60 (4), 1714– 1726. (32) Cho, D. W.; Mariano, P. S.; Yoon, U. C. Beilstein J. Org. Chem. 2014, 10 (1), 514–527. (33) Bera, S.; Mao, R.; Hu, X. Nat. Chem. 2021, 13 (3), 270–277. Appendix 3 – Spectra Relevant to Chapter 3 329 Appendix 3 Spectra Relevant to Chapter 3: Enantioselective Photoredox Catalysis for the Cross-Coupling of AzoleContaining Alkyl BF3K Salts and Electron-Poor Aryl Bromides 16 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Experiment Probe 2021-02-16T11:37:55 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.0 Lowest Frequency 15 8012.8 Spectral Width 12 4.0894 Pulse Width Spectrometer Frequency 400.13 1.0000 12.5000 Relaxation Delay 10 zg30 Pulse Sequence 11 297.1 Temperature 16 CDCl3 Solvent 197.4 spect Instrument Number of Scans nmrsu Owner Receiver Gain Bruker BioSpin GmbH Origin Comment CRL-heptylBiOX-Feb.1.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL-heptylBiOX-Feb/ 1/ fid Data File Name Parameter CRL-heptylBiOX-Feb.1.fid 9 8 7 6 f1 (ppm) 5 4.07 2.00 4 3 1 2.03 14.52 2.18 12.43 2 0 -1 -2 -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 Appendix 3 – Spectra Relevant to Chapter 3 330 16 TJD-5-287-column.1.fid 2021-04-22T13:52:04 Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 10 4.0894 Acquisition Time 11 12.5000 Pulse Width 12 1.0000 Spectrometer Frequency 400.13 197.4 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-1/ tdelano/ nmr/ TJD-5-287-column/ 1/ fid 9 8 7 4.70 3.98 Parameter Data File Name 6 f1 (ppm) 5 4 7.30 7.28 7.27 7.26 7.26 7.08 7.06 7.04 5.47 5.44 5.42 4.88 4.86 4.85 4.83 4.35 4.33 4.31 1.94 2.00 1.98 TJD-5-287-column.1.fid 3 2 1 0 -1 -2 -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 Appendix 3 – Spectra Relevant to Chapter 3 331 16 TJD-6-002-redo.1.fid Title 1D Experiment 2021-06-18T11:14:58 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 12 4.0894 Pulse Width Spectrometer Frequency 400.13 1.0000 12.5000 Relaxation Delay 11 10 435a 176.8 zg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-6-002-redo/ 1/ fid Data File Name 9 8 7 6 5 f1 (ppm) 3.7 4 3.05 Value 3 2.5 2.97 Parameter 8.2 1.92 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 6.6 6.5 6.5 6.5 6.2 6.2 6.2 6.2 1.00 0.97 1.00 0.99 1.8 1.8 2 3.07 TJD-6-002-redo.1.fid 1 0 -1 -2 -3 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 Appendix 3 – Spectra Relevant to Chapter 3 332 297.2 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Temperature Pulse Sequence Experiment Probe 1.3631 2021-06-18T11:37:18 Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 435a 109.5 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 10.0000 Pulse Width 171.9 Relaxation Delay 512 CDCl3 Solvent 78.7 spect Instrument Number of Scans nmrsu Receiver Gain Bruker BioSpin GmbH 161.6 Owner 155.4 Origin Comment TJD-6-002-redo.2.fid Title Value / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-6-002-redo/ 2/ fid Parameter Data File Name 131.3 124.7 122.1 119.2 TJD-6-002-redo.2.fid 77.2 CDCl3 80 70 60 51.5 51.3 50 40 30 21.6 20 10 0 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 Appendix 3 – Spectra Relevant to Chapter 3 333 14.2 16 1H 32768 65536 Nucleus Acquired Size Spectral Size 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 11 10 2021-05-08T12:53:28 Acquisition Date 12 4.0894 Acquisition Time 13 12.5000 Pulse Width Spectrometer Frequency 400.13 1.0000 Relaxation Delay 1D Experiment 197.4 zg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 32 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 435g TJD-5-299-column.1.fid Comment Title Value / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-5-299-column/ 1/ fid Parameter 9 8 7 6 f1 (ppm) 5 3.8 4 2.98 Data File Name 8.3 1.93 7.3 CDCl3 7.1 7.1 7.1 7.1 7.0 7.0 7.0 7.0 6.6 6.6 6.6 6.6 6.3 6.3 6.3 6.3 1.01 0.98 1.00 0.99 3 1.9 1.9 2 3.08 TJD-5-299-column.1.fid 1 0 -1 -2 -3 -10000 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000 110000 120000 130000 140000 150000 160000 170000 Appendix 3 – Spectra Relevant to Chapter 3 334 10.0000 1.3631 2021-05-08T13:14:39 Pulse Width Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 109.8 124.5 122.2 119.5 161.6 160.5 157.7 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 Relaxation Delay 1D Experiment 43.7 zgpg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 435g TJD-5-299-column.2.fid 135.5 Comment Title Value / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-5-299-column/ 2/ fid Data File Name Parameter TJD-5-299-column.2.fid 77.2 CDCl3 80 70 60 51.4 51.3 50 40 30 21.7 20 10 0 -10 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 Appendix 3 – Spectra Relevant to Chapter 3 335 16 297.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 156.2 1.0000 12.5000 4.0894 2021-05-19T17:08:22 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.3 Lowest Frequency 15 8012.8 Spectral Width 11 CDCl3 Solvent 12 spect Instrument 10 435h nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_199-1-1/ 1/ fid CRL_06_199-1-1.1.fid Data File Name Title 9 8 7 6 f1 (ppm) 1.02 0.98 1.00 0.99 8.55 1.93 Value 5 4 3 7.16 7.16 7.15 7.15 7.06 7.05 7.05 7.04 6.70 6.68 6.66 6.64 6.32 6.31 6.31 6.30 3.74 3.06 Parameter 1.92 1.90 2 3.11 CRL_06_199-1-1.1.fid 1 0 -1 -2 -3 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 75000 Appendix 3 – Spectra Relevant to Chapter 3 336 nmrsu spect CDCl3 297.1 zgpg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 72.0 1.0000 10.0000 1.3631 2021-05-19T17:29:35 Owner Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1944.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 435h 124.56 122.28 120.99 119.66 118.26 109.95 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 Bruker BioSpin GmbH Origin Comment CRL_06_199-1-1.2.fid 161.56 Title Value 155.78 / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_199-1-1/ 2/ fid 139.11 Data File Name Parameter CRL_06_199-1-1.2.fid 80 70 60 51.79 51.42 50 40 30 21.68 20 10 0 -10 -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 2100 Appendix 3 – Spectra Relevant to Chapter 3 337 0.9856 2021-06-11T11:14:21 Acquisition Time Acquisition Date 19F 64000 131072 Nucleus Acquired Size Spectral Size 0 -57362.9 Lowest Frequency 20 64935.1 Spectral Width -20 6.3333 Pulse Width Spectrometer Frequency 282.34 1.0000 ASW7284 Probe Relaxation Delay 1D Experiment 16 s2pul Pulse Sequence 30 25.0 Temperature Number of Scans cdcl3 Solvent Receiver Gain mercury Instrument -40 -60 Varian Origin 435h CRL_06_199-F Comment Owner / Volumes/ nmrdata-1/ clacker/ vnmrsys/ data/ CRL_06_199-F/ FLUORINE01.fid/ fid FLUORINE01 Data File Name Value Title Parameter FLUORINE01 CRL_06_199-F -80 -100 f1 (ppm) -120 -140 -160 -180 -200 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 Appendix 3 – Spectra Relevant to Chapter 3 338 -73.42 16 4.0894 2021-05-14T19:56:48 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.0 Lowest Frequency 15 8012.8 Spectral Width 10 12.5000 Pulse Width 11 1.0000 Relaxation Delay 12 197.4 Receiver Gain Spectrometer Frequency 400.13 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 32 Probe 1D Experiment Number of Scans 297.2 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment 9 435i CRL_06_197-1-redo.1.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_197-1-redo/ 1/ fid Data File Name Parameter CRL_06_197-1-redo.1.fid 7 6 f1 (ppm) 0.99 1.00 0.99 0.96 1.00 0.98 8 5 3.04 4 3 3.09 2 1 0 -1 -2 -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 13000 14000 15000 16000 17000 18000 19000 Appendix 3 – Spectra Relevant to Chapter 3 339 0.96 43.7 1.0000 10.0000 1.3631 2021-05-12T19:34:27 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1944.9 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 134.26 132.70 128.49 124.82 122.29 119.46 117.24 435i 109.59 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 Number of Scans 1D Experiment Probe 297.2 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment CRL_06_197-1.6.fid 161.51 Title Value 149.29 / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_197-1/ 6/ fid 143.21 Data File Name Parameter CRL_06_197-1.6.fid 80 70 60 53.63 51.35 50 40 30 21.92 20 10 0 -10 0 100 200 300 400 500 600 700 800 900 Appendix 3 – Spectra Relevant to Chapter 3 340 16 1D Experiment 2021-05-13T11:36:17 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.1 Lowest Frequency 15 8012.8 Spectral Width 12 4.0894 Pulse Width Spectrometer Frequency 400.13 1.0000 12.5000 Relaxation Delay 11 10 197.4 zg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin 435j TJD-6-003-columnB.7.fid Comment Title Value / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-003-columnB/ 7/ fid 9 8 7 6 f1 (ppm) 0.98 1.01 0.97 1.00 0.99 Parameter 3.7 5 4 3.04 Data File Name 8.4 8.4 8.3 8.3 0.97 1.9 1.8 3 7.6 7.6 7.5 7.5 7.3 CDCl3 7.1 7.1 7.1 7.1 7.1 7.0 7.0 7.0 6.6 6.6 6.6 6.6 6.3 6.3 6.3 6.3 2 3.09 TJD-6-003-columnB.7.fid 1 0 -1 -2 -3 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 Appendix 3 – Spectra Relevant to Chapter 3 341 1.0000 10.0000 1.3631 2021-05-13T11:57:28 Pulse Width Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 124.5 122.2 119.7 114.7 110.8 109.9 151.5 150.9 161.5 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 43.7 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 435j TJD-6-003-columnB.8.fid 140.0 138.9 Comment / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-003-columnB/ 8/ fid Title Value Data File Name Parameter TJD-6-003-columnB.8.fid 77.2 CDCl3 80 70 60 52.7 51.4 50 40 30 21.9 20 10 0 -10 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 Appendix 3 – Spectra Relevant to Chapter 3 342 TJD-5-300-column2.1.fid 2021-05-12T08:45:41 Acquisition Date 32768 65536 Acquired Size Spectral Size 14 1H Nucleus 15 -1637.8 Lowest Frequency 16 8196.7 Spectral Width 13 3.9977 Acquisition Time Spectrometer Frequency 400.15 1.0000 9.8500 Pulse Width 12 11 10 101.0 Receiver Gain Relaxation Delay Z163739_0009 (PI HR-400-S1-BBF/ H/ D-5.0-Z SP) 16 Number of Scans 1D Experiment Probe 296.1 CDCl3 Solvent zg30 Avance Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-5-300-column2/ 1/ fid 435k 9 8 7 6 5 f1 (ppm) 0.97 0.96 1.00 0.95 1.03 1.00 0.98 Parameter 7.3 CDCl3 7.2 7.2 7.2 7.1 7.1 7.0 7.0 7.0 7.0 6.6 6.6 6.6 6.5 6.3 Data File Name 3.01 4 3 1.8 2 1.69 TJD-5-300-column2.1.fid 1 0 -1 -2 -3 -4 -200000 0 200000 400000 600000 800000 1000000 1200000 1400000 1600000 1800000 2000000 2200000 2400000 2600000 Appendix 3 – Spectra Relevant to Chapter 3 343 TJD-5-300-column2.2.fid Avance CDCl3 296.2 zgpg30 1D Z163739_0009 (PI HR-400-S1-BBF/ H/ D-5.0-Z SP) 1024 48.0 2.0000 10.0000 1.3763 2021-05-12T09:46:50 Instrument Solvent Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1830.3 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 435k C (d) 125.60 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 23809.5 Spectral Width Spectrometer Frequency 100.63 nmrsu Owner 163.8 161.6 161.3 1.00 Bruker BioSpin GmbH 148.4 148.3 0.64 Origin Comment / Volumes/ nmrdata-38/ tdelano/ nmr/ TJD-5-300-column2/ 2/ fid Title A (m) 162.21 Value Data File Name Parameter 125.6 125.6 124.9 122.2 119.3 118.4 118.2 118.1 117.9 117.7 117.6 114.2 114.1 109.5 1.27 1.88 1.95 0.46 TJD-5-300-column2.2.fid 77.2 CDCl3 80 70 60 54.7 51.3 50 40 30 22.1 20 10 0 -10 -100000 0 100000 200000 300000 400000 500000 600000 700000 800000 900000 1000000 1100000 1200000 1300000 1400000 1500000 1600000 1700000 1800000 1900000 2000000 Appendix 3 – Spectra Relevant to Chapter 3 344 1.0000 6.3333 0.9856 2021-06-18T10:17:57 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 19F 64000 131072 Nucleus Acquired Size Spectral Size 0 -57365.1 Lowest Frequency 20 64935.1 Spectral Width -20 30 Receiver Gain Spectrometer Frequency 282.34 ASW7284 16 Number of Scans 1D Experiment Probe 25.0 s2pul Pulse Sequence cdcl3 Solvent Temperature mercury Instrument -40 Varian Origin -60 435k TJD-5-300-F-redo Comment Owner / Volumes/ nmrdata-62/ tdelano/ vnmrsys/ data/ TJD-5-300-F-redo/ FLUORINE01.fid/ fid FLUORINE01 Data File Name Value Title Parameter -80 -100 f1 (ppm) -120 A (dd) -112.41 1.00 FLUORINE01 TJD-5-300-F-redo -140 -160 -180 -200 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Appendix 3 – Spectra Relevant to Chapter 3 345 16 CRL_06_196-1-redo.1.fid 4.0894 2021-05-14T19:50:49 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.4 Lowest Frequency 15 8012.8 Spectral Width 11 12.5000 Pulse Width 12 1.0000 Relaxation Delay Spectrometer Frequency 400.13 197.4 Receiver Gain 10 435l Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 32 Number of Scans 1D Experiment Probe 297.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title 9 8 7 6 f1 (ppm) 1.00 0.98 1.00 0.98 8.49 1.92 Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_196-1-redo/ 1/ fid 5 4 3 7.16 7.15 7.15 7.14 7.06 7.06 7.05 7.05 6.64 6.62 6.60 6.58 6.33 6.32 6.32 6.31 3.74 3.04 Parameter Data File Name 1.91 1.89 2 3.10 CRL_06_196-1-redo.1.fid 1 0 -1 -2 -3 -1000 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000 11000 12000 Appendix 3 – Spectra Relevant to Chapter 3 346 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 43.7 1.0000 10.0000 1.3631 2021-05-12T19:07:08 Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1944.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 297.1 zgpg30 Pulse Sequence 60 50 40 30 20 10 0 -10 CDCl3 Solvent Temperature spect Instrument -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 nmrsu Owner 1700 1800 1900 1600 124.57 122.25 119.79 115.68 110.07 Bruker BioSpin GmbH 70 51.97 51.46 Origin 80 21.60 Comment 435l CRL_06_196-1.2.fid 161.53 Title Value 155.84 / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_196-1/ 2/ fid 144.01 139.70 Data File Name Parameter CRL_06_196-1.2.fid Appendix 3 – Spectra Relevant to Chapter 3 347 16 CRL_06_198-1.1.fid 12.5000 4.0894 2021-05-14T20:01:29 Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.0 Lowest Frequency 15 8012.8 Spectral Width 12 1.0000 Relaxation Delay Spectrometer Frequency 400.13 16 78.7 11 10 435m Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Number of Scans 1D Experiment Receiver Gain 297.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_198-1/ 1/ fid Parameter Data File Name 9 1.95 8 7 6 f1 (ppm) 5 8.29 7.05 7.04 7.04 7.04 7.00 7.00 6.99 6.99 6.60 6.58 6.56 6.54 6.23 6.22 6.21 6.21 1.12 1.03 1.00 0.99 CRL_06_198-1.1.fid 3 3.97 3.76 3.10 2 1.83 1.81 3.10 4 1 0 -1 -2 -3 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 Appendix 3 – Spectra Relevant to Chapter 3 348 1.0000 10.0000 1.3631 2021-05-14T20:24:20 Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1946.9 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 109.38 129.74 124.67 122.06 119.13 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 512 64.2 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Number of Scans 1D Experiment Receiver Gain 297.2 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin 435m CRL_06_198-1.2.fid Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_198-1/ 2/ fid 165.15 161.63 157.55 Data File Name Parameter CRL_06_198-1.2.fid 80 70 50 55.07 51.28 51.17 60 40 30 21.74 20 10 0 -10 0 500 1000 1500 2000 2500 3000 3500 4000 Appendix 3 – Spectra Relevant to Chapter 3 349 16 CRL_06_200-1.7.fid 2021-05-14T20:54:12 Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 11 10 4.0894 Acquisition Time 12 12.5000 435n 1.0000 Pulse Width Spectrometer Frequency 400.13 98.9 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment Title 9 8 7 6 f1 (ppm) 1.03 0.96 1.99 1.00 0.99 Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_200-1/ 7/ fid 5 7.09 7.09 7.08 7.08 7.05 7.05 7.04 7.04 6.67 6.64 6.58 6.56 6.55 6.53 6.29 6.28 6.28 6.27 3.76 4 2.98 Parameter Data File Name 3 1.81 1.80 2 3.10 CRL_06_200-1.7.fid 1 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 Appendix 3 – Spectra Relevant to Chapter 3 350 1.0000 10.0000 1.3631 2021-05-14T21:15:26 Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1944.4 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size N (d) 161.55 F (dd) 110.14 435n L (t) 151.63 M (m) 158.96 0.38 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 512 64.2 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Number of Scans 1D Experiment 124.88 123.04 122.32 120.33 119.31 110.28 110.24 110.04 110.01 109.47 1.91 0.54 0.30 Receiver Gain 297.2 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment CRL_06_200-1.8.fid Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_200-1/ 8/ fid 161.57 161.53 161.50 159.00 158.98 158.94 158.92 151.72 151.63 151.54 Data File Name Parameter CRL_06_200-1.8.fid 80 70 60 54.86 51.34 50 40 30 21.83 20 10 0 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 Appendix 3 – Spectra Relevant to Chapter 3 351 Varian Origin 1D ASW7284 Experiment Probe 2021-06-11T11:20:56 Acquisition Time Acquisition Date 19F 64000 131072 Nucleus Acquired Size Spectral Size 0 -57360.4 Lowest Frequency 20 64935.1 Spectral Width -20 0.9856 Pulse Width Spectrometer Frequency 282.34 1.0000 6.3333 Relaxation Delay 16 s2pul Pulse Sequence 30 25.0 Temperature Number of Scans cdcl3 Solvent Receiver Gain mercury Instrument -40 435n CRL_06_200-F Comment Owner FLUORINE01 Title Value / Volumes/ nmrdata-1/ clacker/ vnmrsys/ data/ CRL_06_200-F/ FLUORINE01.fid/ fid -59.51 -59.59 -59.67 Data File Name 3.11 -60 -80 -100 f1 (ppm) -120 -140 -113.02 -113.03 -113.07 -113.07 -113.10 -113.11 -113.11 -113.13 -113.15 -113.15 -113.16 -113.18 -113.18 -113.19 -113.22 -113.23 -113.23 -113.26 -113.27 -113.30 -113.31 -113.31 2.00 FLUORINE01 Parameter CRL_06_200-F -160 -180 -200 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 Appendix 3 – Spectra Relevant to Chapter 3 352 16 1.0000 12.5000 4.0894 2021-05-14T13:22:52 Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 12 197.4 Receiver Gain Spectrometer Frequency 400.13 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 Probe 1D Experiment Number of Scans 297.2 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment TJD-6-004-column.1.fid Title Value / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-004-column/ 1/ fid 435o 11 10 9 8 7 3.7 6 f1 (ppm) 5 4 3.03 Parameter 3 2.04 2.05 Data File Name 8.0 8.0 7.5 7.3 7.3 CDCl3 7.2 7.1 7.1 7.1 7.1 7.0 7.0 7.0 7.0 6.7 6.7 6.7 6.6 6.3 6.3 6.3 6.2 0.98 1.01 1.60 1.01 0.98 1.00 0.97 1.9 1.8 2 3.07 1 0 2.9 2.9 2.9 2.9 2.9 2.9 2.7 2.7 2.7 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 TJD-6-004-column.1.fid -1 -2 -3 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 Appendix 3 – Spectra Relevant to Chapter 3 353 2021-05-14T13:44:42 1.3631 10.0000 1.0000 78.7 512 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1D zgpg30 297.1 CDCl3 spect nmrsu Bruker BioSpin GmbH TJD-6-004-column.2.fid 65536 32768 13C -1945.3 24038.5 435o 109.2 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) Spectral Size Acquired Size Nucleus Lowest Frequency Spectral Width Spectrometer Frequency 100.62 Acquisition Date Acquisition Time Pulse Width Relaxation Delay Receiver Gain Number of Scans Probe Experiment Pulse Sequence Temperature Solvent Instrument Owner Origin Comment 161.6 Title 194.4 Value / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-004-column/ 2/ fid 150.6 Data File Name 137.3 130.5 128.9 127.8 125.2 122.3 122.0 120.6 119.1 118.2 Parameter TJD-6-004-column.2.fid 80 70 50 55.4 51.2 60 30 34.6 32.5 40 22.1 20 10 0 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 Appendix 3 – Spectra Relevant to Chapter 3 354 25.0 s2pul 1D ASW7284 16 30 1.0000 6.3333 0.9856 2021-06-18T10:22:07 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 19F 64000 131072 Nucleus Acquired Size Spectral Size 0 -57365.0 Lowest Frequency 20 64935.1 Spectral Width -20 cdcl3 Solvent Spectrometer Frequency 282.34 mercury Instrument -40 Varian Origin -60 435o TJD-6-004-redo Comment Owner FLUORINE01 Title Value / Volumes/ nmrdata-62/ tdelano/ vnmrsys/ data/ TJD-6-004-redo/ FLUORINE01.fid/ fid Data File Name -95.6 -95.6 -95.7 -80 -100 f1 (ppm) 1.00 FLUORINE01 Parameter TJD-6-004-redo -120 -140 -160 -180 -200 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Appendix 3 – Spectra Relevant to Chapter 3 355 16 CRL_06_096-1.5.fid CRL_06_096-1.5.fid Title 1H 32768 65536 Nucleus Acquired Size Spectral Size 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 11 10 2021-02-27T13:34:03 Acquisition Date 12 4.0894 Acquisition Time 13 12.5000 Pulse Width Spectrometer Frequency 400.13 1.0000 Relaxation Delay 1D Experiment 127.1 zg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_06_096-1/ 5/ fid Data File Name Value 9 435p 8 7 6 f1 (ppm) 1.01 1.02 1.00 1.00 0.98 1.00 0.98 Parameter 5 4 7.21 3 2 1 8.36 8.35 7.78 7.76 7.44 7.44 7.44 7.44 7.42 7.42 7.42 7.42 7.08 7.07 7.07 7.06 7.02 7.02 7.01 7.01 6.67 6.66 6.64 6.62 6.24 6.24 6.23 6.23 3.75 3.75 3.74 3.73 3.73 3.72 3.68 3.66 3.66 3.64 3.64 1.91 1.90 1.90 1.89 1.85 1.83 4.09 3.11 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 36000 38000 Appendix 3 – Spectra Relevant to Chapter 3 356 125.06 123.99 122.23 119.07 1.3631 2021-02-27T13:55:16 Acquisition Time Acquisition Date -10 10.0000 Pulse Width 0 1.0000 Relaxation Delay 10 72.0 Receiver Gain 20 512 Number of Scans 30 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 40 1D Experiment 50 zgpg30 Pulse Sequence 60 297.1 Temperature 70 CDCl3 Solvent -1945.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 spect Instrument -200 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800 1900 2000 nmrsu 2200 2300 2400 Bruker BioSpin GmbH 109.19 Owner 80 53.47 51.25 49.28 47.04 Origin 435p 26.76 24.14 22.02 2100 CRL_06_096-1.6.fid 14.20 Comment Title 166.20 161.60 / Volumes/ nmrdata-1/ clacker/ nmr/ CRL_06_096-1/ 6/ fid Value 153.53 146.10 140.00 134.40 Data File Name Parameter CRL_06_096-1.6.fid Appendix 3 – Spectra Relevant to Chapter 3 357 16 TJD-6-010-column.1.fid 2021-05-24T09:49:15 Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 12 4.0894 Acquisition Time Spectrometer Frequency 400.13 12.5000 11 10 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 1.0000 1D Experiment Pulse Width zg30 Pulse Sequence Relaxation Delay 297.2 Temperature 16 CDCl3 Solvent 197.4 spect Instrument Number of Scans nmrsu Owner Receiver Gain Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-010-column/ 1/ fid Title 9 434g 8.5 Data File Name 8 7 7.8 7.4 7.3 CDCl3 1.94 0.87 1.05 Value 6 f1 (ppm) 5 4 3 2 3.00 Parameter 6.3 0.92 5.5 5.5 5.4 5.4 1.00 1.9 1.9 1.5 9.08 TJD-6-010-column.1.fid 1 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 36000 38000 40000 Appendix 3 – Spectra Relevant to Chapter 3 358 TJD-6-010-column.2.fid 43.7 1.0000 10.0000 1.3631 2021-05-24T10:10:26 Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1944.4 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 161.0 157.9 153.0 434g 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 Probe 1D Experiment Number of Scans 297.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-010-column/ 2/ fid Parameter 134.0 130.8 Data File Name 122.5 118.7 TJD-6-010-column.2.fid 80.9 80 70 56.7 60 50 40 28.5 30 20.8 20 10 0 -10 0 50 100 150 200 250 300 350 400 Appendix 3 – Spectra Relevant to Chapter 3 359 16 CRL_06_204-1-redo.1.fid 4.0894 2021-05-21T09:34:54 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.0 Lowest Frequency 15 8012.8 Spectral Width 11 12.5000 Pulse Width 12 1.0000 Relaxation Delay 10 436 127.1 Receiver Gain Spectrometer Frequency 400.13 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 32 Probe 1D Experiment Number of Scans 297.1 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_204-1-redo/ 1/ fid 9 7 5 8.52 7.93 7.89 1.91 1.00 0.97 6 f1 (ppm) 5.55 5.53 5.51 5.49 1.00 8 4 3 2 3.03 Parameter Data File Name 1.96 1.95 1.54 9.72 CRL_06_204-1-redo.1.fid 1 0 -1 -2 -3 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 Appendix 3 – Spectra Relevant to Chapter 3 360 1.0000 10.0000 1.3631 2021-05-20T15:51:36 Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 117.65 133.15 131.19 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width 436 43.7 Receiver Gain Spectrometer Frequency 100.62 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 Number of Scans 1D Experiment Probe 297.1 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_204-1/ 6/ fid CRL_06_204-1.6.fid 162.11 161.35 157.99 Data File Name Value 141.98 Title Parameter CRL_06_204-1.6.fid 81.15 80 70 56.99 60 50 40 20 29.85 28.42 21.04 30 10 0 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 Appendix 3 – Spectra Relevant to Chapter 3 361 16 297.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 32 197.4 1.0000 12.5000 4.0894 2021-06-03T18:31:20 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.1 Lowest Frequency 15 8012.8 Spectral Width 10 CDCl3 Solvent 11 spect Instrument 12 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment 437 / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_208-1/ 1/ fid CRL_06_208-1.1.fid Data File Name Value Title Parameter CRL_06_208-1.1.fid 9 8.38 1.92 6 f1 (ppm) 1.02 0.96 1.00 7 7.03 7.03 6.92 6.92 6.59 6.57 6.56 6.54 8 5 3.76 4 3 1.85 1.83 2 1 0 -1 -2 -3 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 65000 70000 Appendix 3 – Spectra Relevant to Chapter 3 362 1.0000 10.0000 1.3631 2021-06-03T19:13:16 Pulse Width Acquisition Time Acquisition Date -1944.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 121.86 121.75 118.41 113.69 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 78.7 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 1024 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 134.64 437 CRL_06_208-1.2.fid Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_208-1/ 2/ fid 160.82 160.79 157.67 Data File Name Parameter CRL_06_208-1.2.fid 80 70 60 51.73 51.67 50 40 30 21.56 20 10 0 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 Appendix 3 – Spectra Relevant to Chapter 3 363 16 2021-05-21T12:45:09 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 12 4.0894 Acquisition Date Spectrometer Frequency 400.13 12.5000 Acquisition Time 11 10 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Pulse Width 1D Experiment 1.0000 zg30 Pulse Sequence Relaxation Delay 297.1 Temperature 16 CDCl3 Solvent 197.4 spect Instrument Number of Scans nmrsu Owner Receiver Gain Bruker BioSpin GmbH Origin 438 TJD-6-009-column.1.fid Title Comment / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-009-column/ 1/ fid Data File Name 9 1.93 Value 8 0.99 7 6 f1 (ppm) 5 3.8 4 3.09 Parameter 1.96 7.4 7.4 8.3 7.4 7.4 7.3 CDCl3 6.7 6.7 6.7 6.7 6.7 6.7 6.7 5.4 5.3 5.3 5.3 1.00 3 1.9 1.9 2 3.03 TJD-6-009-column.1.fid 1 0 -1 -2 -3 -5000 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 55000 60000 Appendix 3 – Spectra Relevant to Chapter 3 364 1.0000 10.0000 1.3631 2021-05-21T13:06:20 Pulse Width Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 124.2 120.4 117.3 111.5 164.9 161.3 157.4 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 43.7 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 438 TJD-6-009-column.2.fid 134.2 Comment / Volumes/ nmrdata-60/ tdelano/ nmr/ TJD-6-009-column/ 2/ fid Title Value Data File Name Parameter TJD-6-009-column.2.fid 80 70 60 54.3 51.4 50 40 30 21.4 20 10 0 -10 -50 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 Appendix 3 – Spectra Relevant to Chapter 3 365 16 CRL_06_205-1-1.1.fid 297.1 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 32 197.4 1.0000 12.5000 4.0894 2021-06-21T18:32:37 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.4 Lowest Frequency 15 8012.8 Spectral Width 11 10 CDCl3 Solvent 12 spect Instrument 439 nmrsu Owner Spectrometer Frequency 400.13 Bruker BioSpin GmbH Origin Comment Title 9 1.92 Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_205-1-1/ 1/ fid 8 1.97 2.01 Parameter 7 6 f1 (ppm) 1.00 5 8.78 7.85 7.84 7.84 7.83 7.75 7.74 7.74 7.73 5.60 5.59 5.58 5.58 5.57 5.57 5.56 5.55 Data File Name 4 3 1.95 1.93 2 3.07 CRL_06_205-1-1.1.fid 1 0 -1 -2 -3 -2000 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 20000 22000 24000 26000 28000 30000 32000 34000 36000 Appendix 3 – Spectra Relevant to Chapter 3 366 CRL_06_205-1-1.2.fid Title 10.0000 1.3631 2021-06-21T19:14:31 Pulse Width Acquisition Time Acquisition Date -1944.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 134.60 132.16 131.67 439 123.74 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 Relaxation Delay 1D Experiment 72.0 zgpg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 1024 spect Instrument Number of Scans nmrsu Owner Probe Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_205-1-1/ 2/ fid Value 167.71 160.96 159.27 Data File Name Parameter CRL_06_205-1-1.2.fid 80 70 60 50 40 30 17.13 20 10 0 -10 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Appendix 3 – Spectra Relevant to Chapter 3 367 44.90 16 CRL_06_216-1.1.fid 4.0894 2021-06-17T16:05:28 Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.2 Lowest Frequency 15 8012.8 Spectral Width 11 12.5000 Pulse Width 12 1.0000 Relaxation Delay 10 440 127.1 Receiver Gain Spectrometer Frequency 400.13 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 Number of Scans 1D Experiment Probe 297.2 CDCl3 Solvent zg30 spect Instrument Pulse Sequence nmrsu Owner Temperature Bruker BioSpin GmbH Origin Comment Title Value / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_216-1/ 1/ fid Parameter Data File Name 9 5 4 3 2 0.97 0.95 1.00 6 f1 (ppm) 8.36 6.87 6.87 6.87 6.86 6.69 6.69 6.62 6.60 6.58 6.57 7 3.75 3.00 8 1.83 1.81 3.07 1.90 CRL_06_216-1.1.fid 1 0 -1 -2 -3 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 Appendix 3 – Spectra Relevant to Chapter 3 368 10.0000 1.3631 2021-06-17T16:27:16 Acquisition Time Acquisition Date -1945.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 440 134.86 G (d) 105.73 E (d) 118.74 F (d) 109.16 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 1.0000 Pulse Width A (d) 161.06 78.7 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 512 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment / Volumes/ nmrdata/ clacker/ nmr/ CRL_06_216-1/ 2/ fid CRL_06_216-1.2.fid Data File Name Value Title Parameter 1.14 161.08 161.05 160.71 157.60 152.22 149.80 1.00 118.76 118.71 109.30 109.02 105.81 105.65 3.83 4.06 80 70 60 K (d) 51.48 51.66 51.30 50 7.35 CRL_06_216-1.2.fid 40 30 21.44 20 10 0 -10 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 Appendix 3 – Spectra Relevant to Chapter 3 369 16 1H 32768 65536 Nucleus Acquired Size Spectral Size 14 -1545.1 Lowest Frequency 15 8012.8 Spectral Width 10 2021-07-15T15:26:18 Acquisition Date 11 4.0894 Acquisition Time 12 12.5000 Pulse Width 13 1.0000 Spectrometer Frequency 400.13 112.8 1D Experiment Relaxation Delay zg30 Pulse Sequence Receiver Gain 297.2 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 16 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin 9 441 TJD-6-046-column.1.fid Comment Title Value / Volumes/ nmrdata-1/ tdelano/ nmr/ TJD-6-046-column/ 1/ fid Parameter 8.3 1.91 Data File Name 8 7 6 f1 (ppm) 5 4 3.10 7.3 CDCl3 6.9 6.9 6.7 6.7 6.6 6.5 6.5 6.5 0.98 0.97 1.00 1.8 1.8 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 3 2 1 3.05 1.12 2.21 2.04 0 -1 -2 0.9 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 TJD-6-046-column.1.fid -3 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 Appendix 3 – Spectra Relevant to Chapter 3 370 1.0000 10.0000 1.3631 2021-07-15T15:47:32 Relaxation Delay Pulse Width Acquisition Time Acquisition Date -1946.7 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 512 87.8 Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe Number of Scans 1D Experiment Receiver Gain 297.2 CDCl3 Solvent zgpg30 spect Instrument Pulse Sequence nmrsu Owner 161.4 160.4 157.7 Temperature Bruker BioSpin GmbH Origin 441 TJD-6-046-column.2.fid Comment / Volumes/ nmrdata-1/ tdelano/ nmr/ TJD-6-046-column/ 2/ fid Title Value Data File Name Parameter 135.5 128.2 121.7 121.7 116.7 TJD-6-046-column.2.fid 77.2 CDCl3 80 70 60 51.3 51.0 50 40 30 21.5 20 8.2 8.1 7.8 10 0 -10 -200 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 Appendix 3 – Spectra Relevant to Chapter 3 371 16 297.2 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 112.8 1.0000 12.5000 4.0894 2021-07-15T14:59:46 Temperature Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width Acquisition Time Acquisition Date 32768 65536 Acquired Size Spectral Size 13 1H Nucleus 14 -1545.1 Lowest Frequency 15 8012.8 Spectral Width 10 CDCl3 Solvent 11 spect Instrument 12 nmrsu Spectrometer Frequency 400.13 Bruker BioSpin GmbH Owner 442 9 1.94 Origin 8 7 6 f1 (ppm) 1.01 0.97 1.00 0.98 Comment TJD-6-045-column.1.fid Title 3.8 5 4 3.02 Value / Volumes/ nmrdata-1/ tdelano/ nmr/ TJD-6-045-column/ 1/ fid 3 2 2.09 Parameter 8.4 Data File Name 1.0 1.0 1.0 1 0 -1 7.3 CDCl3 7.1 7.1 7.1 7.1 7.0 7.0 7.0 7.0 6.4 6.4 6.4 6.3 6.3 6.3 6.3 6.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.2 2.2 2.2 2.2 2.2 2.2 2.1 2.1 3.06 TJD-6-045-column.1.fid -2 -3 0 10000 20000 30000 40000 50000 60000 70000 80000 90000 Appendix 3 – Spectra Relevant to Chapter 3 372 TJD-6-045-column.2.fid 1.3631 2021-07-15T15:21:46 Acquisition Date -1946.9 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 442 110.0 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 10.0000 Acquisition Time Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) Probe 1.0000 1D Experiment Pulse Width zgpg30 Pulse Sequence Relaxation Delay 297.1 Temperature 512 CDCl3 Solvent 43.7 spect Instrument Number of Scans nmrsu Receiver Gain Bruker BioSpin GmbH Owner 161.7 160.5 158.2 Origin Comment Title Value / Volumes/ nmrdata-1/ tdelano/ nmr/ TJD-6-045-column/ 2/ fid Parameter 134.2 Data File Name 124.4 122.5 119.2 TJD-6-045-column.2.fid 77.2 CDCl3 80 70 57.1 60 51.4 50 40 28.5 30 20 11.0 10 0 -10 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 Appendix 3 – Spectra Relevant to Chapter 3 373 14 Varian Origin 2021-07-15T16:48:48 Acquisition Date 1H 24000 65536 Nucleus Acquired Size Spectral Size 12 -998.5 Lowest Frequency 13 8000.0 Spectral Width 11 3.0000 Acquisition Time Spectrometer Frequency 499.59 1.0000 5.6500 Pulse Width 60 Receiver Gain Relaxation Delay autox7991 8 Experiment Number of Scans 1D Pulse Sequence Probe 3.0 s2pul Temperature inova cdcl3 Instrument Solvent Owner PROTON01 TJD-6-044-ptlc2 Title Comment 10 443 9 0.99 1.05 1.99 Data File Name 9.0 8.6 8.6 8.5 8 7 A (s) D (d) / Volumes/ nmrdata-1/ tdelano/ vnmrsys/ data/ TJD-6-044-ptlc2/ PROTON01.fid/ fid 8.96 7.35 Value 7.4 7.4 0.98 F (m) 6.32 6 f1 (ppm) 5 G (s) 3.97 4.0 4.0 4 3.25 Parameter 1.01 6.7 6.7 6.3 0.88 3 H (m) 2.02 2.1 2.0 2.0 2.0 2 3.16 PROTON01 TJD-6-044-ptlc2 1 0 -1 -100 0 100 200 300 400 500 600 700 800 900 1000 1100 Appendix 3 – Spectra Relevant to Chapter 3 374 1.0000 10.0000 1.3631 2021-07-17T00:06:13 Pulse Width Acquisition Time Acquisition Date -1945.6 13C 32768 65536 Lowest Frequency Nucleus Acquired Size Spectral Size 443 103.1 149.0 145.5 167.0 160.9 158.1 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 24038.5 Spectral Width Spectrometer Frequency 100.62 72.0 1D Experiment Relaxation Delay zgpg30 Pulse Sequence Receiver Gain 297.1 Temperature Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) CDCl3 Solvent 4092 spect Instrument Probe nmrsu Owner Number of Scans Bruker BioSpin GmbH Origin Comment TJD-6-044-ptlc2B.3.fid Title Value / Volumes/ nmrdata/ tdelano/ nmr/ TJD-6-044-ptlc2B/ 3/ fid Parameter Data File Name 133.9 131.6 125.6 120.1 119.6 TJD-6-044-ptlc2B.3.fid 80 70 60 52.3 48.6 50 40 29.8 30 20.0 20 10 0 -10 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 Appendix 3 – Spectra Relevant to Chapter 3 375 376 ABOUT THE AUTHOR Caitlin Rebecca Lacker was born on September 1, 1993 to Stephen G. Lacker and Ann C. Lacker in Austin, Texas. She grew up in Austin and the surrounding country, frequently visiting interesting and underrated locales all over Texas with her parents. Her family encouraged her curiosity and love of learning through nature walks, library books, and fossil hunts at the local creek. In 2012, Caitlin began her undergraduate education at Southwestern University, not knowing if she wanted to pursue chemistry or engineering. However, she very quickly became fascinated with organic chemistry upon studying it for the first time during her sophomore year. She immediately became interested in summer research and had the privilege of working in the laboratory of Professor Michael Gesinski, who was also her organic chemistry professor. It was with his support and encouragement that she applied for graduate school to pursue her doctorate. Following her graduation from Southwestern, Caitlin moved halfway across the country to pursue her graduate studies under the direction of Professor Sarah E. Reisman at the California Institute of Technology. Her graduate work had allowed her to study a variety of topics, with a focus on modular, stereoselective approaches towards diverse libraries of compounds, most notably cyclobutanes. Following the completion of her Ph.D, Caitlin will move to Madison, Wisconsin to conduct postdoctoral studies under the direction of Professor Tehshik P. Yoon at the University of Wisconsin, Madison.