Strategies and Tactics in Alkaloid Synthesis: Total Synthesis of Strempeliopidine via a Non-Directed Petasis Reaction and Progress Toward the Synthesis of Mitomycin B Citation Gonzalez, Kevin Jaime (2026) Strategies and Tactics in Alkaloid Synthesis: Total Synthesis of Strempeliopidine via a Non-Directed Petasis Reaction and Progress Toward the Synthesis of Mitomycin B. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/hakn-7h25. https://resolver.caltech.edu/CaltechTHESIS:12112025-115800167 Abstract This thesis describes research toward total synthesis of bioactive alkaloids with complex architectures that have demanded for the invention of methodology. Chapter 1 comprehensively reviews the semi-, partial, and total synthesis of heterodimeric monoterpenoid bisindole alkaloid natural products. Chapter 2 describes the enantioselective total synthesis of the bisindole alkaloid strempeliopidine. A convergent strategy featuring a diastereoselective Petasis reaction enabled the synthesis of the natural product and several stereoisomeric analogs. Chapter 3 details the development of a non-directed Petasis reaction inspired by the key step in the synthesis of strempeliopidine. This methodology couples hydroxyindoles with trifluoroborate salts under mild conditions, thereby enabling the synthesis of non-natural heterodimeric bisindole alkaloids. Chapter 4 explores ongoing efforts toward the asymmetric total synthesis of mitomycin B. Chapter 5 covers the development of an enantioselective 1,3-dipolar cycloaddition for the construction of nitrogen-rich spirocycles. A chiral magnesium Lewis acid catalyst facilitated the asymmetric [3+2] cycloaddition between alpha-methylene lactams and diazoacetates or nitrile oxides. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: organic synthesis, total synthesis, natural products, indole alkaloid, asymmetric catalysis Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Reisman, Sarah E. (chair) Stoltz, Brian M. Fu, Gregory C. Shapiro, Mikhail G. Defense Date: 21 October 2025 Funders: Funding Agency Grant Number NIH NIGMS R35GM145239 NIH NIGMS R01GM080269 NSF Graduate Research Fellowship N/A NIH NIGMS F31 Fellowship 5F31GM154462 Record Number: CaltechTHESIS:12112025-115800167 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:12112025-115800167 DOI: 10.7907/hakn-7h25 Related URLs: URL URL Type Description https://doi.org/10.1021/jacs.2c13146 DOI Article adapted for Chapter 2 https://doi.org/10.1002/chem.202401936 DOI Article adapted for Chapter 3 https://doi.org/10.1002/anie.202218921 DOI Article adapted for Chapter 3 https://doi.org/10.1021/acs.orglett.3c01978 DOI Article adapted for Chapter 5 ORCID: Author ORCID Gonzalez, Kevin Jaime 0000-0002-4904-590X Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17796 Collection: CaltechTHESIS Deposited By: Kevin Gonzalez Deposited On: 19 Dec 2025 00:45 Last Modified: 07 Jan 2026 16:53 Thesis Files PDF (Redacted Thesis. Ch 4, Appendices 8–11 Omitted) - Final Version See Usage Policy. 25MB Repository Staff Only: item control page

Strategies and Tactics in Alkaloid Synthesis: Total Synthesis of Strempeliopidine via a Non-Directed Petasis Reaction and Progress Toward the Synthesis of Mitomycin B Thesis by Kevin Jaime Gonzalez In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2026 (Defended October 21, 2025) ii ã 2025 Kevin Jaime Gonzalez ORCID: 0000-0002-4904-590X iii To my loving family iv ACKNOWLEDGEMENTS There are so many people I want to thank for their support, guidance, and friendship during my time at Caltech. These past years have been an incredible journey of learning and growth, both in the lab and in life, and I’m deeply grateful to everyone who has been part of it. First, I’d like to thank Professor Brian Stoltz for being the best advisor I could have asked for. Brian is a synthesis genius and a caring mentor with a contagious excitement for organic chemistry. I have always appreciated how deeply he invests in the success and growth of his students. Brian gives us the freedom to pursue ambitious, meaningful problems, make mistakes, and develop into independent scientists who think creatively and critically. Thank you, Brian, for your steady support and guidance through every challenge, scientific or otherwise. This has truly been the intellectual journey of a lifetime, and I will miss my time in the Stoltz lab greatly. I am also grateful to the other members of my thesis committee, Professors Sarah Reisman, Greg Fu, and Mikhail Shapiro. My committee chair, Sarah, has offered invaluable advice on everything from synthesis strategy to postdoc decisions and grant writing. I was fortunate to TA Chem 41c for her, and was consistently inspired by her dynamic lectures, impeccable organization, and passion for teaching. Thank you to Greg for your thoughtful life and career advice; our conversations have been pivotal in shaping my aspirations. And thank you to Mikhail for your guidance and insightful feedback on my proposals. v We are incredibly fortunate at Caltech to have dedicated staff who keep the department running and enable us to perform top-notch research. Firstly, a special thank you to Dr. Scott Virgil, the head of Caltech’s Catalysis Center. Scott has played a critical role in so many of my projects at Caltech from helping with a seemingly impossible separation, giving advice on a tough transformation, or maintaining all of our instruments. Scott, I’ve greatly enjoyed all of our conversations, whether about obscure NMR techniques or Napa winery recommendations. And thank you to Scott and Silva for hosting the annual holiday parties; I’ll certainly miss the charcuterie and caroling! Thanks to Dr. David VanderVelde for his NMR expertise and unforgettable emails, Dr. Michael Takase for the crystal structures, and Joe Drew for keeping Schlinger and all of the chemistry department running smoothly. Thank you Yuhsien Wang, for helping me navigate grants and always answering my constant questions on fellowships. Additionally, thank you to Beth Marshall and Tomomi Kano for all of the help scheduling meetings and handling receipts over the years. The Stoltz group has been a welcoming and festive group of researchers that has made conducting organic synthesis research much more fun than I could have imagined. I am especially grateful to the senior graduate students who helped me feel at home when I joined the lab. Tyler Fulton and Nick Hafemen were fantastic chemists, and formidable pingpong opponents, that taught me a lot about total synthesis. Nick was also a great hiking buddy and helped me find a passion for bagging peaks around SoCal. Zack Sercel, Alexia Kim, Tyler “TC” Casselman, and Professor (!!) Alex “Cus” Cusumano fostered such a warm and welcoming environment from day one. Zack, I always enjoyed our conversations about chemistry, life, and the future. Wishing you all the best in your postdoc and beyond! Cus, thank you for answering my endless questions. It’s been inspiring to see you succeed and I vi am so excited to see what your group will accomplish in Chicago! I am also grateful to Melinda Chan and Ally Stanko. Melinda, I had such a great time serving on the board of BOND with you. You are such a driven and hard-working leader with an infectious passion for helping others. Starting out in lab during COVID while never having run a column before certainly wasn’t easy, but all of you managed to make it an incredibly fun and special time for me. I’d like to acknowledge my cohort in the Stoltz lab: Adrian Samkian, Kali Flesch, Elliot Hicks, Samir “Carlos” Rezgui, Farbod Moghadam, and Jay Barbor. When all seven of us joined at once and nearly doubled the lab size, I knew we would be in for a wild ride. It’s been amazing to go through graduate school with all of you and see everyone succeed and flourish. Elliot, I’ll certainly miss our late-night chats on synthesis, graduate school, the state of the field, and more. Samir, thanks for being such a great friend from day one. And thanks for getting me into lifting, I really cherish our times in the gym pushing each other to our best. I promise I’ll think about getting an Xbox. Adrian, it was a pleasure to work beside you all of these years. Thank you for all the gourmet meals, the endless chemistry tips and tricks, and for your sense of humor. Farbod, organizing outreach with you was a highlight of my time here. Kali, thanks for the friendship and all our beach adventures. Jay (Dr. Barbor), thank you for always being such a kind and approachable lab mate. You taught me so much early on, and I will miss hearing about Tuna and Maeby. I’d also like to thank the younger members of the Stoltz lab: Ruby Chen, Ben Gross, Kim Sharp, Christian Strong, Camila Suarez, Hao Yu, Adrian de Almenara, Chloe Cerione, Jonathan Farhi, Bryce Gaskins, Sara Siddiqui, Eli Gonzalez, and Madie Patch. Ben, thanks for all of the conversations about chemistry and academia and for always having a fun fact vii about a professor to share. Hao, your encyclopedic organic chemistry knowledge is unmatched. Thanks for always being willing to teach (and for all of the denksport); I can’t wait to see what you accomplish in the MacMillan lab and beyond. Christian, you have been an incredible project partner and friend. You keep our bay and the office laughing with your great sense of humor and always have an “interesting” paper for me to check out. Best of luck at MIT! Adrian (“student”), thanks for being a great hood mate and friend. Chloe, it’s been a ton of fun working together on the Petasis chemistry, bisindole dimers, and outreach. I’d like to acknowledge the postdocs that I had the pleasure of overlapping with while in the Stoltz lab. Thank you to Dr. Alex Rand, my mentor when I first joined the group, for teaching me the foundations of experimental synthetic organic chemistry. Dr. Yuji Nishiura, my first hood mate, was a pleasure to work alongside. Yuji, I loved hearing about your adventures all around America in your Jeep and hope life in Japan is treating you well. Special thanks to Drs. Veronica Hubble and Stephen Sardini, for helping create such a friendly and lively environment when I first joined. Thanks to Dr. Chris Cooze for being a great gym bud and project partner. Finally, thanks to Prof. Melissa Ramirez for all the advice and encouragement on pursuing academia. Wishing you the best at Minnesota. I’d also like to acknowledge the many visiting scholars that I overlapped with. Liam Hunt, your motivation and creativity always impressed me; thanks for the insightful suggestions, zeolite adventures, and late night chats. Kengo Inoue, you were a fantastic hood mate. I loved learning about Japanese culture from you and playing Smash Bros. Prof. Nasri Nesnas, it was great getting to know you and collaborating toward mitomycin. Michael Hamm, I really enjoyed being project partners and bay mates. Special thanks to Yutaro viii Hatano for all of the chats about chemistry and for sharing takoyaki with all of us. Thanks to Eric Lee for friendship. I’ve had the pleasure of working with several members of the Stoltz lab on a variety of different projects. I’d like to specially thank all of team mitomycin: Christian Strong, Bryce Gaskins, Nasri Nesnas, Michael Hamm, and Lulu Kwan. Christian, thanks for bravely joining right at the start and for your constant optimism and encouragement. Bryce, you are a fantastic chemist and I’m excited to see what you accomplish at Caltech and beyond. Lulu, I had a great time working with you and watching you grow as a chemist in our group. I can’t wait to hear how your PhD unfolds, I know you will do great things! Thank you to all my friends at Caltech outside of the Stoltz lab, especially Sasha, Rob, Jordan, and Emily. Sasha, I’ve treasured our countless late night conversations at the watering hole (the LC-MS) on academia, cursed purifications, or role-playing games. When I came to Caltech for graduate school, I never expected to serve as an RA for an undergraduate dorm, but it became one of the most fulfilling experiences of my time here. I was the RA for Venerable House, where I had the privilege of meeting some of the brightest college students in the world and learning about their passions and aspirations. To all the Vens, it has been wonderful getting to know so many of you and watch you all succeed and grow. Thank you to my co-RAs, Marva and Taylor, it was great to work with both of you. Thank you to RLC Luciano Lemus for being such a kind and supportive mentor. Thank you as well to the rest of the SFE team. I would like to acknowledge the many people at Rice University who supported me and helped me find my path to chemistry and graduate school. Thank you Dr. Mattheau Comerford, my graduate student mentor when I was an Ecology and Evolutionary Biology ix major. Thank you to Professor László Kürti, whose contagious love for organic chemistry shone through in his energizing lectures and helped me find my passion for the field. Professor Jeffrey Hartgerink, my advisor at Rice, guided my transition to chemistry, offered me a place in his lab, and showed me the joys of chemistry research. I’d also like to acknowledge former members of the Hartgerink group, Drs. Sarah Hahn Hulgan and Nicole Carrejo. Both Sarah and Nicole gave invaluable advice in the lab, on life, and during my graduate school and fellowship applications. Finally, thank you to Professor Julian West for your thoughtful guidance on selecting a graduate school, and to Professor Julianne Yost for helping me discover my passion for teaching. There are several friends from before Caltech that I’d like to thank as well. Firstly, the boys back home: Andres, Kyle, David, Ale, and Daniel as well as Gus, Michael, Beasley, and Silva. Moving across the country to California and spending most of my time in lab has certainly made it hard to keep in touch at times, but all of you have helped me to disconnect from the grad school bubble and relax. Andres, thank you for your constant support with my trips back to Miami and for always being willing to lend an ear. David, it’s been amazing living nearby these past two years, our hikes and game nights has been a great way to relax. Second, I’d like to thank my friends from Rice: Johann, Ryley, Olivia, Katharyn, and Michelle. I deeply value my friendship with every one of you. I would have accomplished nothing without my loving and supportive family. Thank you, mom and dad, for giving everything and more to help me accomplish my dreams and for offering endless love and support along the way. Thanks to my sister, Tiffany, for always being there. Chu and Felipe, you two have really served as a second pair of parents to me and I deeply appreciate all of the love and guidance you both provide. Thank you to x Albert, Ana, and Manny as well. Mama, thank you for making the grand move to the US and giving our family so many opportunities, I’m sure you’re smiling down at us all from heaven. Thank you to the Gonzalez family, especially Leilani and Stephanie, and the Ho family. And of course, thank you to Cosmo, my long-distance cat. I love all of you. Finally, I want to express my deepest gratitude to my wonderful partner, Sara. As an older graduate student once said, if being a grad student is hard, being with a grad student is even harder. Going through graduate school while in a long-distance relationship has certainly had its challenges, but Sara has always offered unwavering love and support. Our zoom calls were often the highlight of my day, and our trips together are among my happiest memories from grad school. Sara, you are my anchor; thank you for being such a loving, understanding, empathetic, and supportive partner. Words cannot capture how excited I am for the next chapter of our lives together. xi ABSTRACT Research in the Stoltz group focuses on the synergy between natural product total and reaction development. This thesis describes research toward total synthesis of bioactive alkaloids with complex architectures that have demanded for the invention of methodology. Chapter 1 reviews the synthesis of heterodimeric monoterpenoid bisindole alkaloid natural products. It provides a comprehensive overview of their construction using semi-, partial-, and total synthesis, along with a discussion of the evolution of the field. Chapter 2 describes the enantioselective total synthesis of the bisindole alkaloid strempeliopidine. A convergent strategy featuring a diastereoselective Petasis reaction enabled the synthesis of the natural product and several stereoisomeric analogs, providing evidence in support of the reassignment of the absolute configuration of strempeliopidine. Chapter 3 details the development of a non-directed Petasis reaction inspired by the key step in the synthesis of strempeliopidine. This methodology couples hydroxyindoles with trifluoroborate salts under mild conditions, thereby enabling the synthesis of non-natural heterodimeric bisindole alkaloids. Chapter 4 explores ongoing efforts toward the asymmetric total synthesis of mitomycin B. The synthetic strategies described target the isomitomycin framework and aim to employ a mitomycin rearrangement to complete the synthesis, thereby providing a concise entry into this highly bioactive class of natural products. Chapter 5 covers the development of an enantioselective 1,3-dipolar cycloaddition for the construction of nitrogen-rich spirocycles. A chiral magnesium Lewis acid catalyst facilitated the asymmetric [3+2] cycloaddition between a-methylene lactams and diazoacetates or nitrile oxides. xii PUBLISHED CONTENT AND CONTRIBUTIONS 1. Rand, A. W.; Gonzalez, K. J.; Reimann, C.; Virgil, S.; Stoltz, B. M. Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction. J. Am. Chem. Soc. 2023, 145, 7278–7287. DOI: 10.1021/jacs.2c13146. K.J.G. participated in experimental work, data acquisition and analysis, and manuscript preparation. 2. Gonzalez, K. J.‡; Cerione, C.‡; Stoltz, B. M. Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions. Chem. Eur. J. 2024, 30, e202401936. DOI: 10.1002/chem.202401936. K.J.G. participated in project design, collecting references, and manuscript preparation. 3. Gonzalez, K. J.; Rand, A. W.; Stoltz, B. M. Development of a Non-Directed Petasis– Type Reaction by an Aromaticity-Disrupting Strategy. Angew. Chem. Int. Ed. 2023, 62, e202218921. DOI: 10.1002/anie.202218921. K.J.G. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 4. Nishiura, Y.‡; Gonzalez, K. J.‡; Cusumano, A. Q.; Stoltz, B. M. Enantioselective 1,3Dipolar Cycloadditions of ⍺-Methylene Lactams to Construct Spirocycles. Org. Lett. 2023, 25, 6469–6473. DOI: 10.1021/acs.orglett.3c01978. K.J.G. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. xiii TABLE OF CONTENTS Dedication.......................................................................................... iii Acknowledgements ............................................................................ iv Abstract ............................................................................................. xi Published Content and Contributions ................................................ xii Table of Contents ............................................................................. xiii List of Figures.....................................................................................xxi List of Schemes .................................................................................xliv List of Tables........................................................................................ li List of Abbreviations ......................................................................... lvii CHAPTER 1 The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1 1.1 Introduction .................................................................................................... 1 1.2 Semi- and Partial Syntheses of Bisindole Alkaloids ......................................... 6 1.2.1 Buchi’s Partial Synthesis of Voacamine and Related Alkaloids ........... 6 1.2.2 Hesse’s Partial Synthesis of Pleiomutine ............................................. 7 1.2.3 Le Quesne’s Semi-Synthesis of Alstonisidine ...................................... 8 1.2.4 Le Quesne’s Semi-Synthesis of Villalstonine ..................................... 10 1.2.5 Le Quesne and Cook’s Semi-Synthesis of Macralstonine .................. 11 1.2.6 Potier and Langlois’s Partial Synthesis of Vinblastine ........................ 12 1.2.7 Kutney’s Partial Synthesis of Vinblastine ........................................... 14 1.2.8 Kuehne’s Partial Synthesis of Vinblastine.......................................... 15 1.2.9 Magnus’s Partial Synthesis of Vinblastine ......................................... 17 1.2.10 Cook’s Partial Synthesis of Villalstonine ........................................... 18 xiv 1.2.11 Cook’s Partial Synthesis of Macrocarpamine .................................... 20 1.2.12 Andrade’s Semi-Synthesis of Sungucine, Isosungucine, and Strychnogucine B .............................................................................. 22 1.2.13 Poupon, Evanno, and Vincent’s Partial Synthesis of Bipleiophylline 24 1.2.14 Andrade’s Semi-Synthesis of Melodinine K........................................ 25 1.3 Total Syntheses of Bisindole Alkaloids .......................................................... 27 1.3.1 Magnus’s Total Synthesis of Norpleiomutine ..................................... 27 1.3.2 Cook’s Total Synthesis of Macralstonidine......................................... 30 1.3.3 Fukuyama’s First Generation Total Synthesis of Vinblastine .............. 31 1.3.4 Fukuyama’s Second Generation Total Synthesis of Vinblastine ......... 35 1.3.5 Boger’s Total Synthesis of Vinblastine ............................................... 37 1.3.6 Cook’s Total Synthesis of Accedinisine.............................................. 40 1.3.7 Fukuyama and Tokuyama’s Total Synthesis of Haplophytine ............ 42 1.3.8 Nicolaou and Chen’s Total Synthesis of Haplophytine ...................... 45 1.3.9 Fukuyama and Tokuyama’s Total Synthesis of Conophylline ............ 48 1.3.10 Tokuyama’s Second Generation Total Synthesis of Haplophytine ..... 51 1.3.11 Stoltz’s Total Synthesis of 16′-epi-Leucophyllidine ............................ 52 1.3.12 Zhang’s Total Synthesis of Geissolosimine ........................................ 55 1.3.13 Xie’s Total Synthesis of Geissolosimine ............................................. 57 1.3.14 Movassaghi’s Total Synthesis of Hazuntiphyllidine ........................... 58 1.4 Conclusions .................................................................................................. 60 1.5 References and Notes ................................................................................... 62 CHAPTER 2 82 Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction 2.1 Introduction .................................................................................................. 82 2.2 Retrosynthetic Analysis ................................................................................. 85 xv 2.3 Results and Discussion ................................................................................. 88 2.3.1 Synthesis of the Eburnea and Aspidosperma Coupling Partners......... 88 2.3.2 Total Synthesis of Novotny’s Proposed Strempeliopidine .................. 90 2.3.3 Total Synthesis of Kam’s Proposed Strempeliopidine ......................... 94 2.3.4 Synthesis of Non-Natural Stereoisomers and Structural Revision of Strempeliopidine ............................................................................... 98 2.4 Conclusions ................................................................................................ 101 2.5 Experimental Section ................................................................................. 102 2.5.1 Materials and Methods .................................................................... 102 2.5.2 Experimental Procedures and Spectroscopic Data ........................... 104 2.6 References and Notes ................................................................................. 196 APPENDIX 1 Synthetic Summary for Chapter 2 207 APPENDIX 2 Spectra Relevant to Chapter 2 211 APPENDIX 3 X-Ray Crystallography Reports Relevant to Chapter 2 304 APPENDIX 4 345 Additional Investigations into the Total Synthesis of Strempeliopidine A4.1 Introduction ................................................................................................ 346 A4.2 Results and Discussion ............................................................................... 346 A4.2.1 Alternative Substrates Explored in the Petasis Borono–Mannich Reaction ....................................................................................... 346 A4.2.2 Investigations into pH Dependence of NMR of Strempeliopidine ... 348 A4.2.3 Initial Evaluation of the Biological Activity of Strempeliopidine and Analogs .......................................................................................... 349 xvi A4.3 References and Notes ................................................................................. 351 CHAPTER 3 352 Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy 3.1 Introduction ................................................................................................ 352 3.1.1 Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions ......................................................................................... 352 3.1.1.1 Asymmetric Petasis Reactions ............................................ 354 3.1.1.2 Non-Directed Reactivity ..................................................... 361 3.1.1.3 Summary and Outlook ....................................................... 368 3.1.2 A Directing Group-Free Petasis Reaction of Hydroxyindoles........... 369 3.2 Results and Discussion ............................................................................... 372 3.2.1 Reaction Design and Optimization ................................................. 372 3.2.2 Scope of the Indole Component ...................................................... 373 3.2.3 Scope of the Trifluoroborate Salts .................................................... 375 3.2.4 Synthetic Utility of Petasis-Type Reaction Products ......................... 377 3.2.5 Application to the Synthesis of Non-Natural Bisindole Dimer Analogs ................................................................................ 378 3.2.6 Preliminary Investigations into the Mechanism of the Non-Directed Petasis-Type Reaction ...................................................................... 381 3.3 Conclusions ................................................................................................ 382 3.4 Experimental Section .................................................................................. 383 3.4.1 Materials and Methods .................................................................... 383 3.4.2 Experimental Procedures and Spectroscopic Data ........................... 385 3.4.2.1 Preparation of a-Hydroxy Indole Compounds.................... 385 3.4.2.2 Preparation of Trifluoroborate Salts .................................... 420 3.4.2.3 Petasis-Type Reactions: General Procedure........................ 431 xvii 3.4.2.4 Derivatization of Petasis-Type Reaction Products ............... 469 3.4.2.5..Procedures and Characterization for Mechanistic Experiments ....................................................................... 475 3.5 References and Notes ................................................................................. 479 APPENDIX 5 Spectra Relevant to Chapter 3 490 APPENDIX 6 X-Ray Crystallography Reports Relevant to Chapter 3 628 APPENDIX 7 662 Additional Investigations into the Development of a Non-Directed Petasis-Type Reaction A7.1 Introduction ................................................................................................ 663 A7.2 Results and Discussion ............................................................................... 664 A7.2.1a.Reaction Optimization Using Electron-Rich Aryl- Trifluoroborate Salts...................................................................... 664 A7.2.2 Mechanistic Investigations into the Petasis-Type Coupling with Alkenyl Trifluoroborate Salts ....................................................................... 665 A7.2.3 Evaluation of Other Classes of Trifluoroborate Salts ........................ 667 A7.3 References and Notes ................................................................................. 668 CHAPTER 4 Progress Toward the Asymmetric Total Synthesis of Mitomycin B 669 4.1 Introduction ................................................................................................ 669 4.2 Retrosynthetic Analysis ............................................................................... 676 4.3 Results and Discussion ............................................................................... 677 4.3.1 Synthesis of the Arene and Epoxide Fragments ................................ 677 4.3.2 Selective Aniline Alkylation and Aziridine Formation ..................... 680 xviii 4.3.3 Intramolecular Nitrile Oxide Cycloaddition .................................... 681 4.3.4 Investigations into Isoxazoline N–O Bond Cleavage ....................... 683 4.4 Conclusions and Future Directions ............................................................. 689 4.5 Experimental Section ................................................................................. 691 4.5.1 Materials and Methods .................................................................... 691 4.5.2 Experimental Procedures and Spectroscopic Data ........................... 693 4.6 References and Notes ................................................................................. 735 APPENDIX 8 Synthetic Summary for Chapter 4 742 APPENDIX 9 Spectra Relevant to Chapter 4 744 APPENDIX 10 X-Ray Crystallography Reports Relevant to Chapter 4 790 APPENDIX 11 Additional Strategies and Tactics 823 Toward the Total Synthesis of Mitomycin B A11.1 Introduction ................................................................................................ 824 A11.2 Early Strategies Toward Aziridination ......................................................... 824 A11.3 Preliminary Evaluation of Alternative Nitrile Oxide Cycloaddition Precursors ................................................................................................... 827 A11.4 Reaction Profile for the Cycloaddition of O-Silyl Hydroxamic Acid 539 .... 829 A11.5 Attempted Net Enecarbamate Hydrolysis ................................................... 831 A11.6 References and Notes ................................................................................. 837 xix CHAPTER 5 840 Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams to Construct Spirocycles 5.1 Introduction ................................................................................................ 840 5.2 Results and Discussion ............................................................................... 843 5.2.1 Reaction Design and Optimization ................................................. 843 5.2.2 Scope of the N-Substituent and Diazoacetates ................................ 845 5.2.3 Investigation of Lactam Substrate Scope .......................................... 846 5.2.4 Synthetic Utility of the Cycloadducts ............................................... 849 5.3 Conclusions ................................................................................................ 849 5.4 Experimental Section .................................................................................. 850 5.4.1 Materials and Methods .................................................................... 850 5.4.2 Experimental Procedures and Spectroscopic Data ........................... 852 5.4.2.1..1,3-Dipolar Cycloaddition of Diazoacetates: General Procedure A....................................................................... 852 5.4.2.2..1,3-Dipolar Cycloaddition of Nitrile Oxides: General Procedure B ....................................................................... 874 5.4.2.3 Product Diversification ....................................................... 880 5.4.2.4 Preparation of a-Methylene Lactam Substrates ................... 885 5.4.3 Determination of Absolute Configuration Via Vibrational Circular Dichroism Spectroscopy.................................................................. 906 5.5 References and Notes ................................................................................. 908 APPENDIX 12 Spectra Relevant to Chapter 5 915 xx APPENDIX 13 Notebook Cross-Reference for New Compounds 982 ABOUT THE AUTHOR 990 xxi LIST OF FIGURES CHAPTER 1 The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids Figure 1.1 Representative heterodimeric monoterpenoid bisindole alkaloids. ...... 2 Figure 1.2 Vinblastine, vincristine, and their subunits. ....................................... 12 CHAPTER 2 Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction Figure 2.1.1 (A) Representative members of the monoterpenoid bisindole alkaloid family, (B) Structural revision of strempeliopidine, and (C) Previously proposed structures of strempeliopidine. ........................................... 84 Figure 2.3.4.1 Stereoisomers of strempeliopidine synthesized. .............................. 101 APPENDIX 2 Spectra Relevant to Chapter 2 Figure A2.1. 1H NMR (500 MHz, CDCl3) of compound 236. ................................ 212 Figure A2.2. Infrared spectrum (Thin Film, NaCl) of compound 236. .................... 213 Figure A2.3. 13C NMR (100 MHz, CDCl3) of compound 236. ............................... 213 Figure A2.4. 1H NMR (500 MHz, CDCl3) of compound 237. ................................ 214 Figure A2.5. Infrared spectrum (Thin Film, NaCl) of compound 237. .................... 215 Figure A2.6. 13C NMR (100 MHz, CDCl3) of compound 237. ............................... 215 Figure A2.7. 1H NMR (500 MHz, CDCl3) of compound 322. ................................ 216 Figure A2.8. Infrared spectrum (Thin Film, NaCl) of compound 322. .................... 217 xxii Figure A2.9. 13C NMR (100 MHz, CDCl3) of compound 322. ............................... 217 Figure A2.10. 1H NMR (400 MHz, CDCl3) of compound 238. .............................. 218 Figure A2.11. Infrared spectrum (Thin Film, NaCl) of compound 238. .................. 219 Figure A2.12. 13C NMR (100 MHz, CDCl3) of compound 238. ............................. 219 Figure A2.13. 1H NMR (500 MHz, CDCl3) of compound 239. .............................. 220 Figure A2.14. Infrared spectrum (Thin Film, NaCl) of compound 239. .................. 221 Figure A2.15. 13C NMR (100 MHz, CDCl3) of compound 239. ............................. 221 Figure A2.16. 1H NMR (400 MHz, CDCl3) of compound 240. .............................. 222 Figure A2.17. Infrared spectrum (Thin Film, NaCl) of compound 240. .................. 223 Figure A2.18. 13C NMR (100 MHz, CDCl3) of compound 240. ............................. 223 Figure A2.19. 1H NMR (500 MHz, CDCl3) of compound 105. .............................. 224 Figure A2.20. Infrared spectrum (Thin Film, NaCl) of compound 105. .................. 225 Figure A2.21. 13C NMR (100 MHz, CDCl3) of compound 105. ............................. 225 Figure A2.22. 1H NMR (300 MHz, CDCl3) of compound 295. .............................. 226 Figure A2.23. Infrared spectrum (Thin Film, NaCl) of compound 295. .................. 227 Figure A2.24. 13C NMR (100 MHz, CDCl3) of compound 295. ............................. 227 Figure A2.25. 1H NMR (400 MHz, CDCl3) of a 2.5:1 mixture of compounds 26a and 26b. ....................................................................................................................... 228 Figure A2.26. Infrared spectrum (Thin Film, NaCl) of a 2.5:1 mixture of 26a:26b. 229 Figure A2.27. 13C NMR (100 MHz, CDCl3) of a 2.5:1 mixture of 26a:26b. ............ 229 Figure A2.28. 1H NMR (400 MHz, CDCl3) of compound 287. .............................. 230 Figure A2.29. Infrared spectrum (Thin Film, NaCl) of compound 287. .................. 231 Figure A2.30. 13C NMR (100 MHz, CDCl3) of compound 287. ............................. 231 Figure A2.31. 1H NMR (500 MHz, CDCl3) of compound 325. .............................. 232 Figure A2.32. Infrared spectrum (Thin Film, NaCl) of compound 325. .................. 233 Figure A2.33. 13C NMR (100 MHz, CDCl3) of compound 325. ............................. 233 Figure A2.34. 1H NMR (500 MHz, CDCl3) of compound 326. .............................. 234 xxiii Figure A2.35. Infrared spectrum (Thin Film, NaCl) of compound 326. .................. 235 Figure A2.36. 13C NMR (100 MHz, CDCl3) of compound 326. ............................. 235 Figure A2.37. 1H NMR (400 MHz, CDCl3) of compound 327. .............................. 236 Figure A2.38. Infrared spectrum (Thin Film, NaCl) of compound 327. .................. 237 Figure A2.39. 13C NMR (100 MHz, CDCl3) of compound 327. ............................. 237 Figure A2.40. 1H NMR (500 MHz, CDCl3) of compound 328. .............................. 238 Figure A2.41. Infrared spectrum (Thin Film, NaCl) of compound 328. .................. 239 Figure A2.42. 13C NMR (100 MHz, CDCl3) of compound 328. ............................. 239 Figure A2.43. 1H NMR (500 MHz, CDCl3) of compound 329. .............................. 240 Figure A2.44. Infrared spectrum (Thin Film, NaCl) of compound 329. .................. 241 Figure A2.45. 13C NMR (100 MHz, CDCl3) of compound 329. ............................. 241 Figure A2.46. 1H NMR (500 MHz, CDCl3) of compound 290. .............................. 242 Figure A2.47. Infrared spectrum (Thin Film, NaCl) of compound 290. .................. 243 Figure A2.48. 13C NMR (100 MHz, CDCl3) of compound 290. ............................. 243 Figure A2.49. 1H NMR (400 MHz, CDCl3) of compound 306. .............................. 244 Figure A2.50. Infrared spectrum (Thin Film, NaCl) of compound 306. .................. 245 Figure A2.51. 13C NMR (100 MHz, CDCl3) of compound 306. ............................. 245 Figure A2.52. 1H NMR (400 MHz, CDCl3) of compound 307. .............................. 246 Figure A2.53. Infrared spectrum (Thin Film, NaCl) of compound 307. .................. 247 Figure A2.54. 13C NMR (100 MHz, CDCl3) of compound 307. ............................. 247 Figure A2.55. 1H NMR (400 MHz, CDCl3) of compound 289. .............................. 248 Figure A2.56. Infrared spectrum (Thin Film, NaCl) of compound 289. .................. 249 Figure A2.57. 13C NMR (100 MHz, CDCl3) of compound 289. ............................. 249 Figure A2.58. 1H NMR (400 MHz, CDCl3) of compound 330 at –40°C................. 250 Figure A2.59. Infrared spectrum (Thin Film, NaCl) of compound 330. .................. 251 Figure A2.60. 13C NMR (100 MHz, CDCl3) of compound 330 at –40 °C. .............. 251 Figure A2.61. 1H NMR (400 MHz, acetone-d6) of compound 308. ....................... 252 xxiv Figure A2.62. Infrared spectrum (Thin Film, NaCl) of compound 308. .................. 253 Figure A2.63. 13C NMR (100 MHz, acetone-d6) of compound 308........................ 253 Figure A2.64. 1H NMR (400 MHz, CDCl3) of compound 302. .............................. 254 Figure A2.65. Infrared spectrum (Thin Film, NaCl) of compound 302. .................. 255 Figure A2.66. 13C NMR (100 MHz, CDCl3) of compound 302. ............................. 255 Figure A2.67. 1H NMR (400 MHz, CD2Cl2) of compound 331 at –60 °C. ............. 256 Figure A2.68. Infrared spectrum (Thin Film, NaCl) of compound 331. .................. 257 Figure A2.69. 13C NMR (100 MHz, CD2Cl2) of compound 331 at –60 °C.............. 257 Figure A2.70. 1H NMR (400 MHz, acetone-d6) of compound 303. ....................... 258 Figure A2.71. Infrared spectrum (Thin Film, NaCl) of compound 303. .................. 259 Figure A2.72. 13C NMR (100 MHz, acetone-d6) of compound 303........................ 259 Figure A2.73. 1H NMR (400 MHz, C6D6) of compound 321. ................................ 260 Figure A2.74. Infrared spectrum (Thin Film, NaCl) of compound 321. ................. 261 Figure A2.75. 13C NMR (100 MHz, C6D6) of compound 321. ................................ 261 Figure A2.76. 1H NMR (400 MHz, acetone-d6) of compound 285 at –30 °C. ........ 262 Figure A2.77. 1H NMR (400 MHz, CDCl3) of compound 285. ............................. 263 Figure A2.78. Infrared spectrum (Thin Film, NaCl) of compound 285. ................. 264 Figure A2.79. 13C NMR (100 MHz, acetone-d6) of compound 285 at –30 °C. ...... 264 Figure A2.80. 1H NMR (400 MHz, CDCl3) of compound 299. ............................. 265 Figure A2.81. Infrared spectrum (Thin Film, NaCl) of compound 299. ................. 266 Figure A2.82. 13C NMR (100 MHz, CDCl3) of compound 299. ............................ 266 Figure A2.83. 1H NMR (400 MHz, CDCl3) of compound 300. ............................. 267 Figure A2.84. Infrared spectrum (Thin Film, NaCl) of compound 300. ................. 268 Figure A2.85. 13C NMR (100 MHz, CDCl3) of compound 300. ............................ 268 Figure A2.86. 1H NMR (400 MHz, CDCl3) of compound 301. ............................. 269 Figure A2.87. Infrared spectrum (Thin Film, NaCl) of compound 301. ................. 270 Figure A2.88. 13C NMR (100 MHz, CDCl3) of compound 301. ............................ 270 xxv Figure A2.89. 1H NMR (400 MHz, CDCl3) of compound 313. ............................. 271 Figure A2.90. Infrared spectrum (Thin Film, NaCl) of compound 313. ................. 272 Figure A2.91. 13C NMR (100 MHz, CDCl3) of compound 313. ............................ 272 Figure A2.92. 1H NMR (400 MHz, CDCl3) of compound 332. ............................. 273 Figure A2.93. Infrared spectrum (Thin Film, NaCl) of compound 332. ................. 274 Figure A2.94. 13C NMR (100 MHz, CDCl3) of compound 332. ............................ 274 Figure A2.95. 1H NMR (600 MHz, CDCl3) of compound 333. ............................. 275 Figure A2.96. Infrared spectrum (Thin Film, NaCl) of compound 333. ................. 276 Figure A2.97. 13C NMR (100 MHz, CDCl3) of compound 333. ............................ 276 Figure A2.98. 1H NMR (600 MHz, CDCl3) of compound 334. ............................. 277 Figure A2.99. Infrared spectrum (Thin Film, NaCl) of compound 334. ................. 278 Figure A2.100. 13C NMR (100 MHz, CDCl3) of compound 334. .......................... 278 Figure A2.101. 1H NMR (600 MHz, CDCl3) of compound 286. ........................... 279 Figure A2.102. Infrared spectrum (Thin Film, NaCl) of compound 286. ............... 280 Figure A2.103. 13C NMR (100 MHz, CDCl3) of compound 286. .......................... 280 Figure A2.104. 1H NMR (400 MHz, CDCl3) of compound 284. ........................... 281 Figure A2.105. 1H NMR (600 MHz, CDCl3) of compound 318. ........................... 282 Figure A2.106. Infrared spectrum (Thin Film, NaCl) of compound 318. ............... 283 Figure A2.107. 13C NMR (100 MHz, CDCl3) of compound 318. .......................... 283 Figure A2.108. 1H NMR (600 MHz, CDCl3) of compound 319. ........................... 284 Figure A2.109. Infrared spectrum (Thin Film, NaCl) of compound 319. ............... 285 Figure A2.110. 13C NMR (100 MHz, CDCl3) of compound 319. .......................... 285 Figure A2.111. 1H NMR (600 MHz, CDCl3) of compound 320. ........................... 286 Figure A2.112. Infrared spectrum (Thin Film, NaCl) of compound 320. ............... 287 Figure A2.113. 13C NMR (100 MHz, CDCl3) of compound 320. .......................... 287 Figure A2.114. 1H NMR (400 MHz, CD2Cl2) of compound 317. .......................... 288 Figure A2.115. Infrared spectrum (Thin Film, NaCl) of compound 317. ............... 289 xxvi Figure A2.116. 13C NMR (100 MHz, CD2Cl2) of compound 317. ......................... 289 Figure A2.117. 1H NMR (400 MHz, CDCl3) of compound 311. ........................... 290 Figure A2.118. Infrared spectrum (Thin Film, NaCl) of compound 311. ............... 291 Figure A2.119. 13C NMR (100 MHz, CDCl3) of compound 311. .......................... 291 Figure A2.120. 1H NMR (400 MHz, CDCl3) of compound 335. ........................... 292 Figure A2.121. Infrared spectrum (Thin Film, NaCl) of compound 335. ............... 293 Figure A2.122. 13C NMR (100 MHz, CDCl3) of compound 335. .......................... 293 Figure A2.123. 1H NMR (600 MHz, CDCl3) of compound 336. ........................... 294 Figure A2.124. Infrared spectrum (Thin Film, NaCl) of compound 336. ............... 295 Figure A2.125. 13C NMR (100 MHz, CDCl3) of compound 336. .......................... 295 Figure A2.126. 1H NMR (400 MHz, CDCl3) of compound 338. ........................... 296 Figure A2.127. Infrared spectrum (Thin Film, NaCl) of compound 338. ............... 297 Figure A2.128. 13C NMR (100 MHz, CDCl3) of compound 338. .......................... 297 Figure A2.129. 1H NMR (600 MHz, CDCl3) of compound 339. ........................... 298 Figure A2.130. Infrared spectrum (Thin Film, NaCl) of compound 339. ............... 299 Figure A2.131. 13C NMR (100 MHz, CDCl3) of compound 339. .......................... 299 Figure A2.132. 1H NMR (600 MHz, CDCl3) of compound 340. ........................... 300 Figure A2.133. Infrared spectrum (Thin Film, NaCl) of compound 340. ............... 301 Figure A2.134. 13C NMR (100 MHz, CDCl3) of compound 340. .......................... 301 Figure A2.135. 1H NMR (400 MHz, C2D2Cl4) of compound 341 at 90 °C. ........... 302 Figure A2.136. Infrared spectrum (Thin Film, NaCl) of compound 341. ............... 303 Figure A2.137. 13C NMR (100 MHz, CDCl3) of compound 341. .......................... 303 APPENDIX 3 X-Ray Crystallography Reports Relevant to Chapter 2 Figure A3.2.1. X-Ray Coordinate of Compound 308 (V22106) ............................. 306 Figure A3.3.1. X-Ray Coordinate of Compound 317 (V21262).............................. 325 xxvii APPENDIX 4 Additional Investigations into the Total Synthesis of Strempeliopidine Figure A4.2.2.1. 1 H NMR spectra (600 MHz) of strempeliopidine upon treatment with 0, 0.1, and 0.5 equiv of d-TFA. ......................................... 348 CHAPTER 3 Development of a Non-Directed Petasis-Type Reaction by an AromaticityDisrupting Strategy Figure 3.1.1.1. The Petasis reaction and its applications and limitations. ............. 353 Figure 3.1.2.1. The Petasis reaction, its limitations, and the development of nondirected variants. ......................................................................... 370 APPENDIX 5 Spectra Relevant to Chapter 3 Figure A5.1. 1H NMR (400 MHz, CDCl3) of compound 453g. .............................. 491 Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 453g. .................. 492 Figure A5.3. 13C NMR (100 MHz, CDCl3) of compound 453g............................... 492 Figure A5.4. 1H NMR (400 MHz, CDCl3) of compound 453j. ............................... 493 Figure A5.5. Infrared spectrum (Thin Film, NaCl) of compound 453j. ................... 494 Figure A5.6. 13C NMR (100 MHz, CDCl3) of compound 453j. .............................. 494 Figure A5.7. 1H NMR (400 MHz, CDCl3) of compound 453k. .............................. 495 Figure A5.8. Infrared spectrum (Thin Film, NaCl) of compound 453k. .................. 496 Figure A5.9. 13C NMR (100 MHz, CDCl3) of compound 453k............................... 496 Figure A5.10. 1H NMR (400 MHz, CDCl3) of compound 453l. ............................. 497 xxviii Figure A5.11. Infrared spectrum (Thin Film, NaCl) of compound 453l. ................. 498 Figure A5.12. 13C NMR (100 MHz, CDCl3) of compound 453l. ............................ 498 Figure A5.13. 1H NMR (400 MHz, CDCl3) of compound 426a. ............................ 499 Figure A5.14. Infrared spectrum (Thin Film, NaCl) of compound 426a. ................ 500 Figure A5.15. 13C NMR (100 MHz, CDCl3) of compound 426a............................. 500 Figure A5.16. 1H NMR (400 MHz, CDCl3) of compound 426b. ............................ 501 Figure A5.17. Infrared spectrum (Thin Film, NaCl) of compound 426b. ................ 502 Figure A5.18. 13C NMR (100 MHz, CDCl3) of compound 426b. ........................... 502 Figure A5.19. 1H NMR (400 MHz, CDCl3) of compound 426c. ............................ 503 Figure A5.20. Infrared spectrum (Thin Film, NaCl) of compound 426c. ................ 504 Figure A5.21. 13C NMR (100 MHz, CDCl3) of compound 426c............................. 504 Figure A5.22. 19F NMR (282 MHz, CDCl3) of compound 426c. ............................ 505 Figure A5.23. 1H NMR (400 MHz, CDCl3) of compound 426d. ............................ 506 Figure A5.24. Infrared spectrum (Thin Film, NaCl) of compound 426d. ................ 507 Figure A5.25. 13C NMR (100 MHz, CDCl3) of compound 426d. ........................... 507 Figure A5.26. 1H NMR (400 MHz, CDCl3) of compound 426e. ............................ 508 Figure A5.27. Infrared spectrum (Thin Film, NaCl) of compound 426e. ................ 509 Figure A5.28. 13C NMR (100 MHz, CDCl3) of compound 426e............................. 509 Figure A5.29. 1H NMR (400 MHz, CDCl3) of compound 426f. ............................. 510 Figure A5.30. Infrared spectrum (Thin Film, NaCl) of compound 426f. ................. 511 Figure A5.31. 13C NMR (100 MHz, CDCl3) of compound 426f. ............................ 511 Figure A5.32. 1H NMR (400 MHz, CDCl3) of compound 426g. ............................ 512 Figure A5.33. Infrared spectrum (Thin Film, NaCl) of compound 426g. ................ 513 Figure A5.34. 13C NMR (100 MHz, CDCl3) of compound 426g............................. 513 Figure A5.35. 1H NMR (400 MHz, CDCl3) of compound 426h. ............................ 514 Figure A5.36. Infrared spectrum (Thin Film, NaCl) of compound 426h. ................ 515 Figure A5.37. 13C NMR (100 MHz, CDCl3) of compound 426h. ........................... 515 xxix Figure A5.38. 1H NMR (400 MHz, CDCl3) of compound 426i. ............................. 516 Figure A5.39. Infrared spectrum (Thin Film, NaCl) of compound 426i. ................. 517 Figure A5.40. 13C NMR (100 MHz, CDCl3) of compound 426i. ............................ 517 Figure A5.41. 1H NMR (400 MHz, CDCl3) of compound 426j. ............................. 518 Figure A5.42. Infrared spectrum (Thin Film, NaCl) of compound 426j. ................. 519 Figure A5.43. 13C NMR (100 MHz, CDCl3) of compound 426j. ............................ 519 Figure A5.44. 1H NMR (400 MHz, CDCl3) of compound 426k. ............................ 520 Figure A5.45. Infrared spectrum (Thin Film, NaCl) of compound 426k. ................ 521 Figure A5.46. 13C NMR (100 MHz, CDCl3) of compound 426k............................. 521 Figure A5.47. 1H NMR (400 MHz, CDCl3) of compound 426l. ............................. 522 Figure A5.48. Infrared spectrum (Thin Film, NaCl) of compound 426l. ................. 523 Figure A5.49. 13C NMR (100 MHz, CDCl3) of compound 426l. ............................ 523 Figure A5.50. 1H NMR (400 MHz, CDCl3) of compound 426m. ........................... 524 Figure A5.51. Infrared spectrum (Thin Film, NaCl) of compound 426m. ............... 525 Figure A5.52. 13C NMR (100 MHz, CDCl3) of compound 426m. .......................... 525 Figure A5.53. 1H NMR (400 MHz, CDCl3) of compound 426n. ............................ 526 Figure A5.54. Infrared spectrum (Thin Film, NaCl) of compound 426n. ................ 527 Figure A5.55. 13C NMR (100 MHz, CDCl3) of compound 426n. ........................... 527 Figure A5.56. 1H NMR (400 MHz, CDCl3) of compound 439. .............................. 528 Figure A5.57. Infrared spectrum (Thin Film, NaCl) of compound 439. .................. 529 Figure A5.58. 13C NMR (100 MHz, CDCl3) of compound 439. ............................. 529 Figure A5.59. 1H NMR (400 MHz, acetone) of compound 429k. .......................... 530 Figure A5.60. Infrared spectrum (Thin Film, NaCl) of compound 429k. ................ 531 Figure A5.61. 13C NMR (100 MHz, acetone) of compound 429k. ......................... 531 Figure A5.62. 19F NMR (282 MHz, acetone) of compound 429k. .......................... 532 Figure A5.63. 11B NMR (128 MHz, acetone) of compound 429k. ......................... 532 Figure A5.64. 1H NMR (400 MHz, CDCl3) of compound 462. .............................. 533 xxx Figure A5.65. Infrared spectrum (Thin Film, NaCl) of compound 462. .................. 534 Figure A5.66. 13C NMR (100 MHz, CDCl3) of compound 462. ............................. 534 Figure A5.67. 1H NMR (400 MHz, DMSO) of compound 443. ............................. 535 Figure A5.68. Infrared spectrum (Thin Film, NaCl) of compound 443. .................. 536 Figure A5.69. 13C NMR (100 MHz, DMSO) of compound 443. ............................ 536 Figure A5.70. 19F NMR (282 MHz, DMSO) of compound 443. ............................. 537 Figure A5.71. 11B NMR (128 MHz, DMSO) of compound 443.............................. 537 Figure A5.72. 1H NMR (400 MHz, CDCl3) of compound 428a. ............................ 538 Figure A5.73. Infrared spectrum (Thin Film, NaCl) of compound 428a. ................ 539 Figure A5.74. 13C NMR (100 MHz, CDCl3) of compound 428a............................. 539 Figure A5.75. 1H NMR (400 MHz, CDCl3) of compound 428b. ............................ 540 Figure A5.76. Infrared spectrum (Thin Film, NaCl) of compound 428b. ................ 541 Figure A5.77. 13C NMR (100 MHz, CDCl3) of compound 428b. ........................... 541 Figure A5.78. 1H NMR (400 MHz, CDCl3) of compound 428c. ............................ 542 Figure A5.79. Infrared spectrum (Thin Film, NaCl) of compound 428c. ................ 543 Figure A5.80. 13C NMR (100 MHz, CDCl3) of compound 428c............................. 543 Figure A5.81. 19F NMR (282 MHz, CDCl3) of compound 428c. ............................ 544 Figure A5.82. 1H NMR (400 MHz, CDCl3) of compound 428d. ............................ 545 Figure A5.83. Infrared spectrum (Thin Film, NaCl) of compound 428d. ................ 546 Figure A5.84. 13C NMR (100 MHz, CDCl3) of compound 428d. ........................... 546 Figure A5.85. 1H NMR (400 MHz, CDCl3) of compound 428e. ............................ 547 Figure A5.86. Infrared spectrum (Thin Film, NaCl) of compound 428e. ................ 548 Figure A5.87. 13C NMR (100 MHz, CDCl3) of compound 428e............................. 548 Figure A5.88. 1H NMR (400 MHz, CDCl3) of compound 428f. ............................. 549 Figure A5.89. Infrared spectrum (Thin Film, NaCl) of compound 428f. ................. 550 Figure A5.90. 13C NMR (100 MHz, CDCl3) of compound 428f. ............................ 550 Figure A5.91. 1H NMR (400 MHz, CDCl3) of compound 428g. ............................ 551 xxxi Figure A5.92. Infrared spectrum (Thin Film, NaCl) of compound 428g. ................ 552 Figure A5.93. 13C NMR (100 MHz, CDCl3) of compound 428g............................. 552 Figure A5.94. 1H NMR (400 MHz, CDCl3) of compound 428h. ............................ 553 Figure A5.95. Infrared spectrum (Thin Film, NaCl) of compound 428h. ................ 554 Figure A5.96. 13C NMR (100 MHz, CDCl3) of compound 428h. ........................... 554 Figure A5.97. 1H NMR (400 MHz, CDCl3) of compound 428j. ............................. 555 Figure A5.98. Infrared spectrum (Thin Film, NaCl) of compound 428j. ................. 556 Figure A5.99. 13C NMR (100 MHz, CDCl3) of compound 428j. ............................ 556 Figure A5.100. 1H NMR (400 MHz, CDCl3) of compound 428k. .......................... 557 Figure A5.101. Infrared spectrum (Thin Film, NaCl) of compound 428k. .............. 558 Figure A5.102. 13C NMR (100 MHz, CDCl3) of compound 428k........................... 558 Figure A5.103. 1H NMR (400 MHz, CDCl3) of compound 428l. ........................... 559 Figure A5.104. Infrared spectrum (Thin Film, NaCl) of compound 428l. ............... 560 Figure A5.105. 13C NMR (100 MHz, CDCl3) of compound 428l. .......................... 560 Figure A5.106. 1H NMR (400 MHz, CDCl3) of compound 428m. ......................... 561 Figure A5.107. Infrared spectrum (Thin Film, NaCl) of compound 428m. ............. 562 Figure A5.108. 13C NMR (100 MHz, CDCl3) of compound 428m. ........................ 562 Figure A5.109. 1H NMR (400 MHz, CDCl3) of compound 428n. .......................... 563 Figure A5.110. Infrared spectrum (Thin Film, NaCl) of compound 428n. .............. 564 Figure A5.111. 13C NMR (100 MHz, CDCl3) of compound 428n. ......................... 564 Figure A5.112. 1H NMR (400 MHz, CDCl3) of compound 430a. .......................... 565 Figure A5.113. Infrared spectrum (Thin Film, NaCl) of compound 430a. .............. 566 Figure A5.114. 13C NMR (100 MHz, CDCl3) of compound 430a........................... 566 Figure A5.115. 19F NMR (282 MHz, CDCl3) of compound 430a. .......................... 567 Figure A5.116. 1H NMR (400 MHz, CDCl3) of compound 430b. .......................... 568 Figure A5.117. Infrared spectrum (Thin Film, NaCl) of compound 430b. .............. 569 Figure A5.118. 13C NMR (100 MHz, CDCl3) of compound 430b. ......................... 569 xxxii Figure A5.119. 1H NMR (400 MHz, CDCl3) of compound 430c. .......................... 570 Figure A5.120. Infrared spectrum (Thin Film, NaCl) of compound 430c. .............. 571 Figure A5.121. 13C NMR (100 MHz, CDCl3) of compound 430c........................... 571 Figure A5.122. 1H NMR (400 MHz, CDCl3) of compound 430d. .......................... 572 Figure A5.123. Infrared spectrum (Thin Film, NaCl) of compound 430d. .............. 573 Figure A5.124. 13C NMR (100 MHz, CDCl3) of compound 430d. ......................... 573 Figure A5.125. 1H NMR (400 MHz, CDCl3) of compound 430e. .......................... 574 Figure A5.126. Infrared spectrum (Thin Film, NaCl) of compound 430e. .............. 575 Figure A5.127. 13C NMR (100 MHz, CDCl3) of compound 430e........................... 575 Figure A5.128. 19F NMR (282 MHz, CDCl3) of compound 430e. .......................... 576 Figure A5.129. 1H NMR (400 MHz, CDCl3) of compound 430f. ........................... 577 Figure A5.130. Infrared spectrum (Thin Film, NaCl) of compound 430f. ............... 578 Figure A5.131. 13C NMR (100 MHz, CDCl3) of compound 430f. .......................... 578 Figure A5.132. 1H NMR (400 MHz, CDCl3) of compound 430g. .......................... 579 Figure A5.133. Infrared spectrum (Thin Film, NaCl) of compound 430g. .............. 580 Figure A5.134. 13C NMR (100 MHz, CDCl3) of compound 430g........................... 580 Figure A5.135. 1H NMR (400 MHz, CDCl3) of compound 430h. .......................... 581 Figure A5.136. Infrared spectrum (Thin Film, NaCl) of compound 430h. .............. 582 Figure A5.137. 13C NMR (100 MHz, CDCl3) of compound 430h. ......................... 582 Figure A5.138. 1H NMR (400 MHz, CDCl3) of compound 430i. ........................... 583 Figure A5.139. Infrared spectrum (Thin Film, NaCl) of compound 430i. ............... 584 Figure A5.140. 13C NMR (100 MHz, CDCl3) of compound 430i. .......................... 584 Figure A5.141. 1H NMR (400 MHz, CDCl3) of compound 430j. ........................... 585 Figure A5.142. Infrared spectrum (Thin Film, NaCl) of compound 430j. ............... 586 Figure A5.143. 13C NMR (100 MHz, CDCl3) of compound 430j. .......................... 586 Figure A5.144. 1H NMR (400 MHz, CDCl3) of compound 430k. .......................... 587 Figure A5.145. Infrared spectrum (Thin Film, NaCl) of compound 430k. .............. 588 xxxiii Figure A5.146. 13C NMR (100 MHz, CDCl3) of compound 430k........................... 588 Figure A5.147. 1H NMR (400 MHz, CDCl3) of compound 430l. ........................... 589 Figure A5.148. Infrared spectrum (Thin Film, NaCl) of compound 430l. ............... 590 Figure A5.149. 13C NMR (100 MHz, CDCl3) of compound 430l. .......................... 590 Figure A5.150. 1H NMR (400 MHz, CDCl3) of compound 430m. ......................... 591 Figure A5.151. Infrared spectrum (Thin Film, NaCl) of compound 430m. ............. 592 Figure A5.152. 13C NMR (100 MHz, CDCl3) of compound 430m. ........................ 592 Figure A5.153. 1H NMR (400 MHz, CDCl3) of compound 430p. .......................... 593 Figure A5.154. Infrared spectrum (Thin Film, NaCl) of compound 430p. .............. 594 Figure A5.155. 13C NMR (100 MHz, CDCl3) of compound 430p. ......................... 594 Figure A5.156. 1H NMR (400 MHz, CDCl3) of compound 430q. .......................... 595 Figure A5.157. Infrared spectrum (Thin Film, NaCl) of compound 430q. .............. 596 Figure A5.158. 13C NMR (100 MHz, CDCl3) of compound 430q. ......................... 596 Figure A5.159. 1H NMR (400 MHz, CDCl3) of compound 430r. ........................... 597 Figure A5.160. Infrared spectrum (Thin Film, NaCl) of compound 430r. .............. 598 Figure A5.161. 13C NMR (100 MHz, CDCl3) of compound 430r. .......................... 598 Figure A5.162. 1H NMR (400 MHz, CDCl3) of compound 436a. .......................... 599 Figure A5.163. Infrared spectrum (Thin Film, NaCl) of compound 436a. .............. 600 Figure A5.164. 13C NMR (100 MHz, CDCl3) of compound 436a........................... 600 Figure A5.165. 1H NMR (400 MHz, CDCl3) of compound 436b. .......................... 601 Figure A5.166. Infrared spectrum (Thin Film, NaCl) of compound 436b. .............. 602 Figure A5.167. 13C NMR (100 MHz, CDCl3) of compound 436b. ......................... 602 Figure A5.168. 1H NMR (400 MHz, CDCl3) of compound 440. ............................ 603 Figure A5.169. Infrared spectrum (Thin Film, NaCl) of compound 440. ................ 604 Figure A5.170. 13C NMR (100 MHz, CDCl3) of compound 440. ........................... 604 Figure A5.171. 1H NMR (400 MHz, CD2Cl2) of compound 442. ........................... 605 Figure A5.172. Infrared spectrum (Thin Film, NaCl) of compound 442. ................ 606 xxxiv Figure A5.173. 13C NMR (100 MHz, CD2Cl2) of compound 442. .......................... 606 Figure A5.174. 1H NMR (400 MHz, CDCl3) of compound 444. ............................ 607 Figure A5.175. Infrared spectrum (Thin Film, NaCl) of compound 444. ................ 608 Figure A5.176. 13C NMR (100 MHz, CDCl3) of compound 444. ........................... 608 Figure A5.177. 1H NMR (400 MHz, CDCl3) of compound 445a. .......................... 609 Figure A5.178. Infrared spectrum (Thin Film, NaCl) of compound 445a. .............. 610 Figure A5.179. 13C NMR (100 MHz, CDCl3) of compound 445a........................... 610 Figure A5.180. 1H NMR (400 MHz, CDCl3) of compound 445b. .......................... 611 Figure A5.181. Infrared spectrum (Thin Film, NaCl) of compound 445b. .............. 612 Figure A5.182. 13C NMR (100 MHz, CDCl3) of compound 445b. ......................... 612 Figure A5.183. 1H NMR (400 MHz, CDCl3) of compound 431. ............................ 613 Figure A5.184. Infrared spectrum (Thin Film, NaCl) of compound 431. ................ 614 Figure A5.185. 13C NMR (100 MHz, CDCl3) of compound 431. ........................... 614 Figure A5.186. 1H NMR (400 MHz, CDCl3) of compound 432. ............................ 615 Figure A5.187. Infrared spectrum (Thin Film, NaCl) of compound 432. ................ 616 Figure A5.188. 13C NMR (100 MHz, CDCl3) of compound 432. ........................... 616 Figure A5.189. 1H NMR (400 MHz, CDCl3) of compound 434. ............................ 617 Figure A5.190. Infrared spectrum (Thin Film, NaCl) of compound 434. ................ 618 Figure A5.191. 13C NMR (100 MHz, CDCl3) of compound 434. ........................... 618 Figure A5.192. 1H NMR (400 MHz, CDCl3) of compound 438. ............................ 619 Figure A5.193. Infrared spectrum (Thin Film, NaCl) of compound 438. ................ 620 Figure A5.194. 13C NMR (100 MHz, CDCl3) of compound 438. ........................... 620 Figure A5.195. 1H NMR (400 MHz, CDCl3) of compound 446. ............................ 621 Figure A5.196. Infrared spectrum (Thin Film, NaCl) of compound 446. ................ 622 Figure A5.197. 13C NMR (100 MHz, CDCl3) of compound 446. ........................... 622 Figure A5.198. 1H NMR (400 MHz, CDCl3) of compound 447. ............................ 623 Figure A5.199. Infrared spectrum (Thin Film, NaCl) of compound 447. ................ 624 xxxv Figure A5.200. 13C NMR (100 MHz, CDCl3) of compound 447. ........................... 624 Figure A5.201. 19F NMR (282 MHz, CDCl3) of compound 447. ............................ 625 Figure A5.202. 1H NMR (400 MHz, CDCl3) of compound 449. ............................ 626 Figure A5.203. Infrared spectrum (Thin Film, NaCl) of compound 449. ................ 627 Figure A5.204. 13C NMR (100 MHz, CDCl3) of compound 449. ........................... 627 APPENDIX 6 X-Ray Crystallography Reports Relevant to Chapter 3 Figure A6.2.1 X-Ray Coordinate of Compound 436a•TFA (V22396). ................... 630 Figure A6.3.1 X-Ray Coordinate of Brucine Adduct 442 • HCl (V22221). ............ 646 APPENDIX 7 Additional Investigations into the Development of a Non-Directed PetasisType Reaction Figure A7.1.1 The Petasis-type reaction developed in the synthesis of strempeliopidine and the proposed generalization............................................................................ 663 CHAPTER 4 Progress Toward the Asymmetric Total Synthesis of Mitomycin B Figure 4.1.1. Members of the mitomycin family of natural products. ................... 670 Figure 4.1.2. Introduction to mitomycin B (487). ................................................. 672 Figure 4.1.3. The mitomycin rearrangement. ....................................................... 675 xxxvi APPENDIX 9 Spectra Relevant to Chapter 4 Figure A9.1. 1H NMR (400 MHz, CDCl3) of compound 525. ................................ 745 Figure A9.2. Infrared spectrum (Thin Film, NaCl) of compound 525. .................... 746 Figure A9.3. 13C NMR (100 MHz, CDCl3) of compound 525. ............................... 746 Figure A9.4. 1H NMR (400 MHz, CDCl3) of compound 527. ................................ 747 Figure A9.5. Infrared spectrum (Thin Film, NaCl) of compound 527. .................... 748 Figure A9.6. 13C NMR (100 MHz, CDCl3) of compound 527. ............................... 748 Figure A9.7. 1H NMR (400 MHz, CDCl3) of compound 528. ................................ 749 Figure A9.8. Infrared spectrum (Thin Film, NaCl) of compound 528. .................... 750 Figure A9.9. 13C NMR (100 MHz, CDCl3) of compound 528. ............................... 750 Figure A9.10. 1H NMR (400 MHz, CDCl3) of compound 529. .............................. 751 Figure A9.11. Infrared spectrum (Thin Film, NaCl) of compound 529. .................. 752 Figure A9.12. 13C NMR (100 MHz, CDCl3) of compound 529. ............................. 752 Figure A9.13. 1H NMR (400 MHz, CDCl3) of compound 530. .............................. 753 Figure A9.14. Infrared spectrum (Thin Film, NaCl) of compound 530. .................. 754 Figure A9.15. 13C NMR (100 MHz, CDCl3) of compound 530. ............................. 754 Figure A9.16. 1H NMR (400 MHz, CDCl3) of compound 531. .............................. 755 Figure A9.17. Infrared spectrum (Thin Film, NaCl) of compound 531. .................. 756 Figure A9.18. 13C NMR (100 MHz, CDCl3) of compound 531. ............................. 756 Figure A9.19. 1H NMR (400 MHz, CDCl3) of compound 523. .............................. 757 Figure A9.20. Infrared spectrum (Thin Film, NaCl) of compound 523. .................. 758 Figure A9.21. 13C NMR (100 MHz, CDCl3) of compound 523. ............................. 758 Figure A9.22. 1H NMR (400 MHz, CDCl3) of compound 533. .............................. 759 Figure A9.23. Infrared spectrum (Thin Film, NaCl) of compound 533. .................. 760 Figure A9.24. 13C NMR (100 MHz, CDCl3) of compound 533. ............................. 760 Figure A9.25. 1H NMR (400 MHz, CDCl3) of compound 534. .............................. 761 Figure A9.26. Infrared spectrum (Thin Film, NaCl) of compound 534. .................. 762 xxxvii Figure A9.27. 13C NMR (100 MHz, CDCl3) of compound 534. ............................. 762 Figure A9.28. 1H NMR (400 MHz, CDCl3) of compound 535. .............................. 763 Figure A9.29. Infrared spectrum (Thin Film, NaCl) of compound 535. .................. 764 Figure A9.30. 13C NMR (100 MHz, CDCl3) of compound 535. ............................. 764 Figure A9.31. 1H NMR (400 MHz, CDCl3) of compound 536. .............................. 765 Figure A9.32. Infrared spectrum (Thin Film, NaCl) of compound 536. .................. 766 Figure A9.33. 13C NMR (100 MHz, CDCl3) of compound 536. ............................. 766 Figure A9.34. 1H NMR (400 MHz, CDCl3) of compound 537. .............................. 767 Figure A9.35. Infrared spectrum (Thin Film, NaCl) of compound 537. .................. 768 Figure A9.36. 13C NMR (100 MHz, CDCl3) of compound 537. ............................. 768 Figure A9.37. 1H NMR (400 MHz, CDCl3) of compound 522. .............................. 769 Figure A9.38. Infrared spectrum (Thin Film, NaCl) of compound 522. .................. 770 Figure A9.39. 13C NMR (100 MHz, CDCl3) of compound 522. ............................. 770 Figure A9.40. 1H NMR (400 MHz, CDCl3) of compound 538. .............................. 771 Figure A9.41. Infrared spectrum (Thin Film, NaCl) of compound 538. .................. 772 Figure A9.42. 13C NMR (100 MHz, CDCl3) of compound 538. ............................. 772 Figure A9.43. 1H NMR (600 MHz, CDCl3) of compound 539. .............................. 773 Figure A9.44. Infrared spectrum (Thin Film, NaCl) of compound 539. .................. 774 Figure A9.45. 13C NMR (100 MHz, CDCl3) of compound 539. ............................. 774 Figure A9.46. 1H NMR (400 MHz, CDCl3) of compound 540. .............................. 775 Figure A9.47. Infrared spectrum (Thin Film, NaCl) of compound 540. .................. 776 Figure A9.48. 13C NMR (100 MHz, CDCl3) of compound 540. ............................. 776 Figure A9.49. 1H NMR (400 MHz, CDCl3) of compound 551. .............................. 777 Figure A9.50. Infrared spectrum (Thin Film, NaCl) of compound 551. .................. 778 Figure A9.51. 13C NMR (100 MHz, CDCl3) of compound 551. ............................. 778 Figure A9.52. 1H NMR (400 MHz, CDCl3) of compound 551a. ............................ 779 Figure A9.53. Infrared spectrum (Thin Film, NaCl) of compound 551a. ................ 780 xxxviii Figure A9.54. 13C NMR (100 MHz, CDCl3) of compound 551a............................. 780 Figure A9.55. 1H NMR (600 MHz, CDCl3) of crude compound 546. .................... 781 Figure A9.56. 1H NMR (400 MHz, CDCl3) of compound 554. .............................. 782 Figure A9.57. Infrared spectrum (Thin Film, NaCl) of compound 554. .................. 783 Figure A9.58. 13C NMR (100 MHz, CDCl3) of compound 554. ............................. 783 Figure A9.59. 1H NMR (600 MHz, CDCl3) of compound 556. .............................. 784 Figure A9.60. Infrared spectrum (Thin Film, NaCl) of compound 556. .................. 785 Figure A9.61. 13C NMR (100 MHz, CDCl3) of compound 556. ............................. 785 Figure A9.62. 1H NMR (400 MHz, CDCl3) of compound 557. .............................. 786 Figure A9.63. Infrared spectrum (Thin Film, NaCl) of compound 557. .................. 787 Figure A9.64. 13C NMR (100 MHz, CDCl3) of compound 557. ............................. 787 Figure A9.65. 1H NMR (400 MHz, CDCl3) of compound 561. .............................. 788 Figure A9.66. Infrared spectrum (Thin Film, NaCl) of compound 561. .................. 789 Figure A9.67. 13C NMR (100 MHz, CDCl3) of compound 561. ............................. 789 APPENDIX 10 X-Ray Crystallography Reports Relevant to Chapter 4 Figure A10.2.1 X-Ray Coordinate of Compound 522 (V23354).................... 792 Figure A10.3.1 X-Ray Coordinate of Compound 540 (V24001).................... 810 xxxix CHAPTER 5 Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams to Construct Spirocycles Figure 5.1.1. …Examples of Spirocyclic, Pyrazoline, or Isoxazoline Compounds and Asymmetric 1,3-Dipolar Cycloaddition of Diazoacetates or Nitrile Oxides. ......................................................................................... 842 Figure 5.4.3.1. Comparison of experimental VCD and IR spectra for product 608a to computed spectra for A and (ent)-A. Experimental IR spectrum in good agreement with computed spectrum. Experimental VCD spectrum for 608a is in agreement with computed spectrum for (ent)-A. .......... 907 Figure 5.4.3.2. Overlay of experimental VCD spectrum of 608a with computed spectra for (ent)-A. .................................................................................... 908 APPENDIX 12 Spectra Relevant to Chapter 5 Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 608a. ............................ 916 Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 608a. ................ 917 Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound 608a............................. 917 Figure A12.4. 1H NMR (500 MHz, CDCl3) of compound 608b. ............................ 918 Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 608b. ................ 919 Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound 608b. ........................... 919 Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 608c. ............................ 920 Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 608c. ................ 921 Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound 608c............................. 921 Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound 608d. .......................... 922 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 608d. .............. 923 Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound 608d. ......................... 923 xl Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 608e. .......................... 924 Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 608e. .............. 925 Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound 608e........................... 925 Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 608f. ........................... 926 Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 608f. ............... 927 Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound 608f. .......................... 927 Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 608g. .......................... 928 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 608g. .............. 929 Figure A12.21. 13C NMR (125 MHz, CDCl3) of compound 608g........................... 929 Figure A12.22. 1H NMR (500 MHz, CDCl3) of compound 608h. .......................... 930 Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 608h. .............. 931 Figure A12.24. 13C NMR (125 MHz, CDCl3) of compound 608h. ......................... 931 Figure A12.25. 1H NMR (500 MHz, CDCl3) of compound 608j. ........................... 932 Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 608j. ............... 933 Figure A12.27. 13C NMR (125 MHz, CDCl3) of compound 608j. .......................... 933 Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 608k. .......................... 934 Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 608k. .............. 935 Figure A12.30. 13C NMR (125 MHz, CDCl3) of compound 608k........................... 935 Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 608l. ........................... 936 Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 608l. ............... 937 Figure A12.33. 13C NMR (125 MHz, CDCl3) of compound 608l. .......................... 937 Figure A12.34. 1H NMR (400 MHz, CDCl3) of compound 610a. .......................... 938 Figure A12.35. Infrared spectrum (Thin Film, NaCl) of compound 610a. .............. 939 Figure A12.36. 13C NMR (100 MHz, CDCl3) of compound 610a........................... 939 Figure A12.37. 1H NMR (400 MHz, CDCl3) of compound 610j. ........................... 940 Figure A12.38. Infrared spectrum (Thin Film, NaCl) of compound 610j. ............... 941 Figure A12.39. 13C NMR (100 MHz, CDCl3) of compound 610j. .......................... 941 xli Figure A12.40. 1H NMR (400 MHz, CDCl3) of compound 610l. ........................... 942 Figure A12.41. Infrared spectrum (Thin Film, NaCl) of compound 610l. ............... 943 Figure A12.42. 13C NMR (100 MHz, CDCl3) of compound 610l. .......................... 943 Figure A12.43. 1H NMR (400 MHz, CDCl3) of compound 611. ............................ 944 Figure A12.44. Infrared spectrum (Thin Film, NaCl) of compound 611. ................ 945 Figure A12.45. 13C NMR (100 MHz, CDCl3) of compound 611. ........................... 945 Figure A12.46. 1H NMR (600 MHz, d5-pyridine) of compound 612. ..................... 946 Figure A12.47. Infrared spectrum (Thin Film, NaCl) of compound 612. ................ 947 Figure A12.48. 13C NMR (100 MHz, CD3CN) of compound 612........................... 947 Figure A12.49. 1H NMR (400 MHz, CDCl3) of compound 613. ............................ 948 Figure A12.50. Infrared spectrum (Thin Film, NaCl) of compound 613. ................ 949 Figure A12.51. 13C NMR (100 MHz, CDCl3) of compound 613. ........................... 949 Figure A12.52. 1H NMR (400 MHz, CDCl3) of compound 614 (major diastereomer). .................................................................................................... 950 Figure A12.53. Infrared spectrum (Thin Film, NaCl) of compound 614 (major diastereomer). ........................................................................... 951 Figure A12.54. 13C NMR (100 MHz, CDCl3) of compound 614 (major diastereomer). .................................................................................................. 951 Figure A12.55. 1H NMR (400 MHz, CDCl3) of compound 614 (minor diastereomer). .................................................................................................. 952 Figure A12.56. Infrared spectrum (Thin Film, NaCl) of compound 614 (minor diastereomer). ........................................................................... 953 Figure A12.57. 13C NMR (100 MHz, CDCl3) of compound 614 (minor diastereomer). .................................................................................................. 953 Figure A12.58. 1H NMR (500 MHz, CDCl3) of compound 606a. .......................... 954 Figure A12.59. Infrared spectrum (Thin Film, NaCl) of compound 606a. .............. 955 Figure A12.60. 13C NMR (125 MHz, CDCl3) of compound 606a........................... 955 xlii Figure A12.61. 1H NMR (500 MHz, CDCl3) of compound 606c. .......................... 956 Figure A12.62. Infrared spectrum (Thin Film, NaCl) of compound 606c. .............. 957 Figure A12.63. 13C NMR (125 MHz, CDCl3) of compound 606c........................... 957 Figure A12.64. 1H NMR (500 MHz, CDCl3) of compound 606d. .......................... 958 Figure A12.65. Infrared spectrum (Thin Film, NaCl) of compound 606d. .............. 959 Figure A12.66. 13C NMR (125 MHz, CDCl3) of compound 606d. ......................... 959 Figure A12.67. 1H NMR (500 MHz, CDCl3) of compound 606e. .......................... 960 Figure A12.68. Infrared spectrum (Thin Film, NaCl) of compound 606e. .............. 961 Figure A12.69. 13C NMR (125 MHz, CDCl3) of compound 606e........................... 961 Figure A12.70. 1H NMR (500 MHz, CDCl3) of compound 606f. ........................... 962 Figure A12.71. Infrared spectrum (Thin Film, NaCl) of compound 606f. ............... 963 Figure A12.72. 13C NMR (125 MHz, CDCl3) of compound 606f. .......................... 963 Figure A12.73. 1H NMR (500 MHz, CDCl3) of compound 606g. .......................... 964 Figure A12.74. Infrared spectrum (Thin Film, NaCl) of compound 606g. .............. 965 Figure A12.75. 13C NMR (125 MHz, CDCl3) of compound 606g........................... 965 Figure A12.76. 1H NMR (500 MHz, CDCl3) of compound 606h. .......................... 966 Figure A12.77. Infrared spectrum (Thin Film, NaCl) of compound 606h. .............. 967 Figure A12.78. 13C NMR (125 MHz, CDCl3) of compound 606h. ......................... 967 Figure A12.79. 1H NMR (500 MHz, CDCl3) of compound 606i. ........................... 968 Figure A12.80. Infrared spectrum (Thin Film, NaCl) of compound 606i. ............... 969 Figure A12.81. 13C NMR (125 MHz, CDCl3) of compound 606i. .......................... 969 Figure A12.82. 1H NMR (500 MHz, CDCl3) of compound 606j. ........................... 970 Figure A12.83. Infrared spectrum (Thin Film, NaCl) of compound 606j. ............... 971 Figure A12.84. 13C NMR (125 MHz, CDCl3) of compound 606j. .......................... 971 Figure A12.85. 1H NMR (500 MHz, CDCl3) of compound 606k. .......................... 972 Figure A12.86. Infrared spectrum (Thin Film, NaCl) of compound 606k. .............. 973 Figure A12.87. 13C NMR (125 MHz, CDCl3) of compound 606k........................... 973 xliii Figure A12.88. 1H NMR (500 MHz, CDCl3) of compound 606l. ........................... 974 Figure A12.89. Infrared spectrum (Thin Film, NaCl) of compound 606l. ............... 975 Figure A12.90. 13C NMR (125 MHz, CDCl3) of compound 606l. .......................... 975 Figure A12.91. 1H NMR (400 MHz, CDCl3) of compound 626. ............................ 976 Figure A12.92. Infrared spectrum (Thin Film, NaCl) of compound 626. ................ 977 Figure A12.93. 13C NMR (100 MHz, CDCl3) of compound 626. ........................... 977 Figure A12.94. 1H NMR (400 MHz, CDCl3) of compound 606m. ......................... 978 Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound 606m. ............. 979 Figure A12.96. 13C NMR (100 MHz, CDCl3) of compound 606m. ........................ 979 Figure A12.97. 1H NMR (400 MHz, CDCl3) of compound 627. ............................ 980 Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound 627. ................ 981 Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound 627. ........................... 981 xliv LIST OF SCHEMES CHAPTER 1 The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids Scheme 1.1. Büchi’s semi-synthesis of voacamine, voacamidine, and voacorine (1963). ............................................................................................... 7 Scheme 1.2. Hesse’s partial synthesis of pleiomutine (1966). .................................... 8 Scheme 1.3. Le Quesne’s semi-synthesis of alstonisidine (1972). .............................. 9 Scheme 1.4. Le Quesne’s semi-synthesis of villalstonine (1972). ............................. 10 Scheme 1.5. Le Quesne and Cook’s semi-synthesis of macralstonine (1972)........... 11 Scheme 1.6. Potier and Langlois’s semi-synthesis of vinblastine (1979). .................. 13 Scheme 1.7. Kutney’s semi-synthesis of vinblastine (1988). ..................................... 15 Scheme 1.8. Kuehne’s partial synthesis of vinblastine (1991). ................................. 16 Scheme 1.9. Magnus’s partial synthesis of vinblastine (1992). ................................. 18 Scheme 1.10. Cook’s partial synthesis of villalstonine (1994). ................................. 19 Scheme 1.11. Cook’s partial synthesis of macrocarpamine (1996). ......................... 21 Scheme 1.12. Andrade’s semi-synthesis of sungucine, isosungucine, and strychnogucine B (2016). ................................................................. 23 Scheme 1.13. Poupon, Evanno, and Vincent’s semi-synthesis of bipleiophylline (2017). ............................................................................................ 24 Scheme 1.14. Andrade’s semi-synthesis of melodinine K (2020). ............................ 26 Scheme 1.15. Magnus’s total synthesis of norpleiomutine (1984). ........................... 29 Scheme 1.16. Cook’s total synthesis of macralstonidine (2002). .............................. 30 Scheme 1.17. Fukuyama’s total synthesis of vinblastine monomers (2002). ............ 32 Scheme 1.18. Fukuyama’s total synthesis of vinblastine (2002) and vincristine (2003). ........................................................................................................ 34 Scheme 1.19. Fukuyama’s second generation total synthesis of vinblastine (2007). 36 xlv Scheme 1.20. Boger’s total synthesis of vinblastine (2008). ..................................... 38 Scheme 1.21. Boger’s revised mechanistic proposal and radical cation coupling.... 39 Scheme 1.22. Cook’s total synthesis of accedinisine (2008). ................................... 41 Scheme 1.23. Haplophytine and proposed biosynthetic precursors......................... 42 Scheme 1.24. Fukuyama and Tokuyama’s total synthesis of haplophytine monomers (2009). ............................................................................................. 44 Scheme 1.25. Fukuyama and Tokuyama’s total synthesis of haplophytine (2009). .. 45 Scheme 1.26. Nicolaou and Chen’s total synthesis of haplophytine (2009). ............ 47 Scheme 1.27. Fukuyama and Tokuyama’s total synthesis of conophylline monomers (2011). ............................................................................................. 49 Scheme 1.28. Fukuyama and Tokuyama’s total synthesis of conophylline (2011). .. 50 Scheme 1.29. Tokuyama’s total synthesis of haplophytine (2016). .......................... 51 Scheme 1.30. Stoltz’s total synthesis of 16’-epi-leucophyllidine (2021). .................. 53 Scheme 1.31. Zhang’s total synthesis of geissolosimine (2023). .............................. 56 Scheme 1.32. Xie’s total synthesis of geissolosimine (2023). ................................... 58 Scheme 1.33. Movassaghi’s total synthesis of hazuntiphyllidine (2025). ................. 59 CHAPTER 2 Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction Scheme 2.2.1. (A) Retrosynthetic analysis of the proposed structure by Novotný and coworkers, and (B) Retrosynthetic analysis of the structure proposed by Kam. .......................................................................................... 86 Scheme 2.3.1.1. Preparation of (–)-eburnamine and (+)-epi-eburnamine................. 89 Scheme 2.3.1.2. Preparation of functionalized (+)-aspidospermidine derivative...... 90 xlvi Scheme 2.3.2.1. Cross-coupling of epi-eburnamonine derivative with aspidospermidine derivative. ....................................................... 91 Scheme 2.3.2.2. Completion of the synthesis of the originally proposed structure of strempeliopidine (285). ................................................................ 93 Scheme 2.3.3.1. Attempted Petasis borono–Mannich with aspidospermidine boronic acid derivative. ............................................................................ 97 Scheme 2.3.3.2. Petasis borono–Mannich with aspidospermidine trifluoroborate derivative and determination of the relative configuration of strempeliopidine......................................................................... 98 Scheme 2.3.4.1. Synthesis of heterodimeric stereoisomers and the determination of the absolute configuration of strempeliopidine. ................................. 99 APPENDIX 1 Synthetic Summary for Chapter 2 Scheme A1.1 Synthetic summary of the total synthesis of strempeliopidine. ......... 208 Scheme A1.2 Synthetic summary of the total synthesis of Novotny’s proposed strempeliopidine. ........................................................................... 209 Scheme A1.3 Stereoisomers of strempeliopidine synthesized in Chapter 2. .......... 210 xlvii CHAPTER 3 Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy Scheme 3.1.1.1.1. Examples of thiourea-based catalysts in asymmetric Petasis reactions............................................................................... 355 Scheme 3.1.1.1.2. Examples of biphenol-based catalysts in asymmetric Petasis reactions............................................................................... 358 Scheme 3.1.1.1.3. Examples of Rh-catalyzed asymmetric Petasis-type reactions. . 360 Scheme 3.1.1.1.4. Example of Pd-catalyzed asymmetric Petasis-type reactions. .. 361 Scheme 3.1.1.2.1. Examples of non-directed Petasis reactions. ............................. 362 Scheme 3.1.1.2.2. Examples of non-directed Petasis-type reactions. ..................... 364 Scheme 3.1.1.2.3. Application in the total synthesis of strempeliopidine. ............. 365 Scheme 3.1.1.2.4. Examples of metal-catalyzed non-directed Petasis-type reactions. ................................................................................................ 367 Scheme 3.2.2.1. Exploration of the substrate scope for the Petasis-type reaction using different α-hydroxyindoles. Reactions conducted at 0.1 mmol scale. Yields are of isolated products after column chromatography. ... 374 Scheme 3.2.3.1. Investigations into the substrate scope of trifluoroborate salts in the Petasis-type reaction. Reactions conducted at 0.1 mmol scale. Yields are of isolated products after column chromatography. ............. 376 Scheme 3.2.4.1. Synthetic derivatizations of Petasis-type products. ...................... 378 Scheme 3.2.5.1. Application of the Petasis-type reaction to prepare complex dimers from bioactive natural products and pharmaceuticals................ 380 Scheme 3.2.6.1. Investigations into the mechanism of the non-directed Petasis-type reaction...................................................................................... 382 xlviii APPENDIX 7 Additional Investigations into the Development of a Non-Directed PetasisType Reaction Scheme A7.2.1.1 Optimized reaction conditions for electron-rich aryl boronic acids and potential mechanistic ambiguity. ........................... 665 Scheme A7.2.2.1 Investigations into the mechanism of the Petasis-type reaction ............................................................................................. 666 CHAPTER 4 Progress Toward the Asymmetric Total Synthesis of Mitomycin B Scheme 4.1.1. Proposed mechanism of DNA cross-linking by mitomycin C. ........ 671 Scheme 4.1.2. Summary of Kishi’s landmark total synthesis of the mitomycins. .... 673 Scheme 4.1.3. Summary of Fukuyama’s total synthesis of mitomycin C (483) via isomitomycin A (496). ................................................................. 676 Scheme 4.2.1. Retrosynthetic analysis of mitomycin B. ......................................... 677 Scheme 4.3.1.1. A) Synthesis of aniline 523 and enantioenriched epoxide 524 and B) Alternative, scalable synthesis of aldehyde 529 via an ortho-aldol reaction. ...................................................................................... 679 Scheme 4.3.2.1. Selective aminolysis of epoxide 524 with aniline 523 and subsequent aziridination. ............................................................................... 681 Scheme 4.3.3.1. A) Synthesis of O-silyl hydroxamic acid 539 and B) Intramolecular nitrile oxide cycloaddition using the Carreira protocol. ............. 682 Scheme 4.3.4.1. Challenges remaining in the synthesis and two proposed strategies. .................................................................................................. 684 Scheme 4.3.4.2. Initial investigations into the N–O bond cleavage of mesylate 540. .................................................................................................. 684 Scheme 4.3.4.3. Potential advantages and synthesis of amine 546. ....................... 685 xlix Scheme 4.3.4.4. Attempted reductive N–O bond cleavage of amine 546 and undesired retro-aldol decomposition. .......................................................... 686 Scheme 4.3.4.5. Reduction with nickel boride avoids retro-aldol fragmentation and oxidation with N-tert-butylphenylsulfinimidoyl chloride. .......... 687 Scheme 4.3.4.6. Challenging hydrolysis of enecarbamate 557 and alternative mesyl substrate 561 for future research. ............................................... 689 Scheme 4.4.1. Proposed route for the completion of the synthesis of mitomycin B. ..................................................................................................... 690 APPENDIX 8 Synthetic Summary for Chapter 4 Scheme A8.1 Synthetic summary for the progress toward the asymmetric total synthesis of mitomycin B. ....................................................... 743 APPENDIX 11 Additional Strategies and Tactics Toward the Total Synthesis of Mitomycin B Scheme A11.2.1. Initial investigations toward aziridination. A) Aminolysis of epoxide 562, B) Net [2+2] cycloaddition during tosylation of lactone 564, C) Attempted aziridination from tosylate 563, and D) Appel reaction of alcohol 535.......................................................... 825 Scheme A11.3.1. 1A) Cycloaddition prior to aziridination provides the incorrect isomer and B) Instability of oxime 580. ................................. 828 l Scheme A11.4.1. Reaction profile for the nitrile oxide cycloaddition using the Carreira protocol and proposed mechanistic pathways. ......................... 830 Scheme A11.5.1. Bromo-hydration of enecarbamate 557 and attempted debromination. ......................................................................... 834 Scheme A11.5.2. Net dihydroxylation of enecarbamate 557 and global deprotection. ................................................................................................. 837 CHAPTER 5 Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams to Construct Spirocycles Scheme 5.2.2.1 Investigation of N-Substituent and Diazoacetate Scope: Cycloaddition of Diazoacetates (607a–b) to Lactams (606a, c–i).a ............................................................................................. 846 Scheme 5.2.3.1 Investigation of Lactam Substrate Scope: Cycloaddition of Diazoacetate (607a) or Nitrile Oxide (609) to ⍺-Methylene Lactams.a .............................................................................. 848 Scheme 5.2.4.1 Product Diversification. ........................................................ 849 li LIST OF TABLES CHAPTER 2 Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction Table 2.3.2.1. Attempted small scale hydrogenation and deprotection of benzyl heterodimer (+)-302. ............................................................... 92 Table 2.3.3.1. Development of a Petasis borono–Mannich coupling between boronic acids and hydroxy-indoles. ......................................... 96 Table 2.5.2.1. Experimental for Attempted Small Scale Reduction of Benzyl Heterodimer 302. .................................................................. 195 APPENDIX 3 X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.2.1. Crystal data and structure refinement for V22106. ............... 306 Table A3.2.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22106. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 308 Table A3.2.3. Bond lengths [Å] and angles [°] for V22106.. ....................... 310 Table A3.2.4. Anisotropic displacement parameters (Å2x 103) for V22106. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 315 Table A3.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22106. ...................................... 317 Table A3.2.6. Torsion angles [°] for V22106. ............................................. 319 lii Table A3.3.1. Crystal data and structure refinement for V21262. ............... 325 Table A3.3.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V21262. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 327 Table A3.3.3. Bond lengths [Å] and angles [°] for V21262. ........................ 329 Table A3.3.4. Anisotropic displacement parameters (Å2x 103) for V21262. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 335 Table A3.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V21262. ...................................... 337 Table A3.3.6. Torsion angles [°] for V21262. ............................................. 339 APPENDIX 4 Additional Investigations into the Total Synthesis of Strempeliopidine Table A4.2.2.1. Additional strategies explored to develop a Petasis boronoMannich reaction for accessing heterodimeric bisindole alkaloids. ............................................................................... 347 Table A4.2.3.1. Initial assessment of the cytotoxicity of strempeliopidine, analogs, and the corresponding monomers. ........................................ 350 liii CHAPTER 3 Development of a Non-Directed Petasis-Type Reaction by an AromaticityDisrupting Strategy Table 3.2.1.1. Reaction optimization of the Petasis-type coupling. ............. 373 APPENDIX 6 X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.2.1. Crystal data and structure refinement for V22396. ............... 630 Table A6.2.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22396. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 632 Table A6.2.3. Bond lengths [Å] and angles [°] for V22396. ........................ 634 Table A6.2.4. Anisotropic displacement parameters (Å2x 103) for V22396. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 638 Table A6.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22396. ...................................... 640 Table A6.2.6. Torsion angles [°] for V22396. ............................................. 641 Table A6.2.7. Hydrogen bonds for V22396 [Å and °]................................. 644 Table A6.3.1. Crystal data and structure refinement for V22221. ............... 646 Table A6.3.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22221. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 648 liv Table A6.3.3. Bond lengths [Å] and angles [°] for V22221. ........................ 650 Table A6.3.4. Anisotropic displacement parameters (Å2x 103) for V22221. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 654 Table A6.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22221. ...................................... 656 Table A6.3.6. Torsion angles [°] for V22221. ............................................. 657 Table A6.3.7. Hydrogen bonds for V22221 [Å and °]................................. 661 APPENDIX 7 Additional Investigations into the Development of a Non-Directed PetasisType Reaction Table A7.2.3.1. Investigations into other classes of trifluoroborate salts......... 667 APPENDIX 10 X-Ray Crystallography Reports Relevant to Chapter 4 Table A10.2.1. Crystal data and structure refinement for V23354. ............... 792 Table A10.2.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V23354. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 794 Table A10.2.3. Bond lengths [Å] and angles [°] for V23354. ........................ 796 lv Table A10.2.4. Anisotropic displacement parameters (Å2x 103) for V23354. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 801 Table A10.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V23354. ...................................... 803 Table A10.2.6. Torsion angles [°] for V23354. ............................................. 805 Table A10.3.1. Crystal data and structure refinement for V24001. ............... 810 Table A10.3.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for V24001. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ................................................................................. 812 Table A10.3.3. Bond lengths [Å] and angles [°] for V24001. ........................ 814 Table A10.3.4. Anisotropic displacement parameters (Å2x 103) for V24001. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]. ................................... 817 Table A10.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V24001. ...................................... 819 Table A10.3.6. Torsion angles [°] for V24001. ............................................. 820 APPENDIX 11 Additional Strategies and Tactics Mitomycin B Table A11.5.1. Attempted hydrolysis, Toward the Total Synthesis of hydration, or deprotection of enecarbamate 557................................................................ 832 lvi Table A11.5.2. Bromo-etherification of enecarbamate 557 and attempted reduction. ............................................................................. 836 CHAPTER 5 Enantioselective 1,3-Dipolar Cycloadditions of -Methylene Lactams to Construct Spirocycles Table 5.2.1.1. Optimization of Reaction Conditions.a ................................. 844 APPENDIX 13 Notebook Cross-Reference for New Compounds Table A13.1. Notebook cross-reference for Chapter 2. .............................. 983 Table A13.2. Notebook cross-reference for Chapter 3. .............................. 985 Table A13.3. Notebook cross-reference for Appendix 7. ........................... 986 Table A13.4. Notebook cross-reference for Chapter 4. .............................. 987 Table A13.5. Notebook cross-reference for Appendix 11. ......................... 988 Table A13.6. Notebook cross-reference for Chapter 5. .............................. 989 lvii LIST OF ABBREVIATIONS [a]D specific rotation at wavelength of sodium D line ºC degrees Celsius Å Angstrom Ac acetyl AcOH acetic acid aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl Box bis(oxazoline) bp boiling point br broad Bz benzoyl c concentration for specific rotation measurements calc’d calculated cat catalytic Cbz benzyloxycarbonyl cm–1 wavenumber(s) d doublet D deuterium lviii dba dibenzylideneacetone DCE 1,2-dichloroethane DIBAL diisobutylaluminum hydride DMAP (4-dimethylamino)pyridine DMF N,N-dimethylformamide DMP Dess–Martin periodinane dr diastereomeric ratio ee enantiomeric excess equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate EtOH ethanol g gram(s) GC gas chromatography h hours HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry Hz hertz IPA 2-propanol IR infrared (spectroscopy) J coupling constant (NMR) lix K Kelvin (absolute temperature) kcal kilocalorie KHMDS potassium hexamethyldisilazide L liter; ligand LDA lithium diisopropylamide LHMDS lithium bis(trimethylsilyl)amide m/z mass to charge ratio mCPBA meta-chloroperoxybenzoic acid Me methyl Mes mesityl mg milligram(s) MHz megahertz min minutes mol mole(s) Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether n-Bu n-butyl NBS N-bromosuccinimide NMR nuclear magnetic resonance Pd/C palladium on carbon PG protecting group Ph phenyl lx PHOX phosphinooxazoline (ligand) ppm parts per million Py pyridine R generic for any atom or functional groups Ra/Ni Raney nickel SFC supercritical fluid chromatography t-Bu tert-butyl TBAF tetrabutylammonium fluoride TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography TMS trimethylsilyl Ts para-toluenesulfonyl (tosyl) CHAPTER 1 The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids† 1.1 INTRODUCTION The monoterpenoid bisindole alkaloids1 comprise a diverse class of plant-derived natural products with over 200 isolated members to date.2 Unlike many natural product families which exhibit a high degree of analogy with respect to their molecular architectures due to conserved biosynthetic pathways, “monoterpenoid bisindole alkaloid” is a general descriptor which applies to any natural product composed of two monoterpenederived indole alkaloids joined by at least one C–C bond.3–5 As a result of this broad definition, the molecules in this class exhibit exceptional variation in structure, reactivity, and function with no one member constituting an “archetypal” bisindole alkaloid (Figure 1.1). Consequently, the chemodiversity within this class has attracted the attention of chemists and biologists from various sub-disciplines for over sixty years. To the synthetic chemist, dimeric indole alkaloids present a number of challenging aspects, which have limited the number of successful synthetic efforts compared to their monomeric counterparts. Because of the broad definition, the members of this family often † This review was conducted in collaboration with Dr. Chris Reimann. 2 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids MeOOC N N H Me N H N COOMe N HH NH Me O H Me H NH Me N Me 15’ 14’ Me H MeO X OH COOMe N H H N Me Me N COOMe H Me O O N N H O N N H HO OH H MeOOC X Me 3 Alstonisidine Voacamine, X = H (1) Voacorine, X = OH (2) MeO H Me OMe 4 Villalstonine N H Me COOMe Conophylline, X = -O- (5) Conophyllidine, X = Δ-14’,15’ (6) H H Me N Me O H N OH Me H Me N Me H H Me N MeO O N Me 7 Macralstonine N H H Me N O N H H N O Me COOMe 8 Macrocarpamine OH Et Me N H O N N H MeOOC N O N HO Me H MeO N R O OAc HO COOMe MeO N OMe Me Vinblastine, R = Me (9) Vincristine, R = CHO (10) H O 11 Haplophytine H COOMe Me N H H H H N N N HO H Me N H Me N Me 12 (–)-Accedinisine MeOOC N Me N R Norpleiomutine, R = H (13) Pleiomutine, R = Me (14) Figure 1.1 Representative heterodimeric monoterpenoid bisindole alkaloids. Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 3 display multiple iconic alkaloid architectures—including aspidosperma, corynanthe, eburnea, macroline, vobasine and others within a single chemical entity; in effect, one must complete two separate total syntheses en route to one of these higher order dimers, a challenge that is exacerbated by the need to construct or conjoin these two fragments in a single, sterically congested molecule. Furthermore, while classic retrosynthetic logic indicates that “dimerizing” C–C bonds are strategic disconnections,6 the execution in the forward sense is rarely facile. Convergent coupling reactions must construct sterically encumbered bonds with complete chemo-, regio-, and stereoselectivity between densely functionalized natural product frameworks.7 For this reason, many synthetic strategies have centered on biomimetic coupling reactions, typically a combination of electrophilic aromatic substitution, condensation, or Michael addition.8 However, the ability to replicate this reactivity ex vivo is far from guaranteed, while the requirement for distinction between “electron-rich” and “electron-poor” coupling partners can limit the extension to non-natural products and natural-product analogs. Beyond these intrinsic chemical obstacles, the monoterpenoid bisindole alkaloids have also received attention because of their rich biological activity. A number of newly isolated natural products in this class have demonstrated bioactivities including, but not limited to, antileukemic, antimicrobial, antioxidant, antiulcer, cytotoxic, norepinephrine reuptake-inhibiting, platelet inhibiting, and radical scavenging.3–5 In general, the dimeric alkaloids exhibit more potent activities than their individual component monomers,9–12 which is hypothesized to occur through higher target affinity or greater stabilization of the Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 4 protein-ligand complex.13,14 For most molecules in this class however, the nature of these biological interactions are poorly understood. The most well-studied members of this class vinblastine (9) and vincristine (10) are FDA-approved to treat a variety of rapidly-dividing cancers like Hodgkin’s lymphoma, melanoma, and non-small-cell lung cancer. Mechanistically,15 vinblastine (9) and vincristine (10) inhibit mitotic spindle through disruption of microtubule binding, leading to cell cycle arrest, aberrant division, and necrosis of tumor cells. Small molecule antagonists of protein-protein interactions (PPIs) have been branded “the holy grail of drug discovery,”16 and natural products that disrupt PPIs have immense value as starting points for the evaluation of new leads.17,18 The independent bioactivity of component monomers and structural similarity to established PPI inhibitors have led us to hypothesize that other members of this family could modulate similar interactions. In support of this, Kam recently identified two bisindole alkaloids from Alstonia penangiana that promote tubulinpolymerization with higher efficacy than paclitaxel.19 The goal of this account is to provide a comprehensive review of successful synthetic efforts to date as a resource for chemists who may wish to study monoterpenoid bisindole alkaloids through semi-, partial- or total synthesis. Although a number of excellent book chapters have been dedicated to the subject,2–5 most are broadly focused, and they do not provide a comprehensive summary of synthetic efforts in a single resource. Furthermore, a number of other reviews on the topic of synthesis are either out-of-date20,21 or focused on specific subclass of bisindole alkaloids.22,23 We hope that this resource will Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 5 help to facilitate future synthetic efforts by highlighting key developments in strategies and tactics. Our discussion will be limited to heterodimeric bisindole alkaloids, which we define as alkaloids composed of two structurally unique monomeric subunits that are each monoterpene-derived in origin; thus, the coupling strategies require an element of substrate or reagent control to engender cross-selectivity. This serves to distinguish from homodimeric alkaloids, which are composed of identical subunits resulting from spontaneous dimerization under reaction conditions. Dimeric alkaloids in which one component is not monoterpene-derived (e.g., from a condensed tryptamine or isoquinolinederived unit) fall out of the scope of this review. Polypyrroloindoline alkaloids also will not be included in this discussion, despite the structural analogy to many of the structures discussed herein, though interested parties may be directed to the following excellent reviews.24,25 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2 SEMI- AND PARTIAL SYNTHESES OF BISINDOLE ALKALOIDS 1.2.1 Buchi’s Partial Synthesis of Voacamine and Related Alkaloids 6 The earliest synthesis of a heterodimeric monoterpenoid bisindole alkaloid was that of voacamine (1) and voacorine (2), reported by Büchi in the early 1960’s.26,27 After performing a number of degradation studies to elucidate the structure of the component monomers, Büchi performed a semi-synthesis to confirm the identity of the dimeric structure. Treatment of a mixture of naturally isolated alkaloids voacangine (15) and vobasinol (16) with 1.5% HCl in methanol produced voacamine (1) in 14% yield, along with an undisclosed quantity of its constitutional isomer voacamidine (18) (Scheme 1.1A). This is hypothesized to proceed through the intermediacy of iminium 17 via a Friedel– Crafts alkylation at either the indole C(6) of voacangine (blue) to form voacamine (1) or at C(8) (red) to form voacamidine (18). It was subsequently shown that the latter isomer can be equilibrated back to voacamine (1) under more strongly acidic conditions.28 Under identical reaction conditions, Büchi showed that voacorine (2) could be accessed through the condensation of voacangarine (19) and vobasinol (16) (Scheme 1.1B). Analogous acid-mediated condensations would later be utilized to access vobasine-based alkaloids tabernamine29 (22), bisindole alkaloids from E. orientalis30,31 (20, 21) and T. accedens32 (23, 24), ervahaimines A and B,33 gabunine,34 and several unnatural dimers35 (Scheme 1.1C). 7 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Semi-synthesis of voacamine and voacamidine MeOOC MeO MeOOC N N H H 1.5% HCl Me COOMe MeOH, reflux 15 Voacangine + N H MeO H Me N MeO H N Me 14% yield Me via: MeOOC MeOOC NH Me N N H HO N Me HN COOMe N N Me N MeOOC N H Me 16 Vobasinol Me Me 17 B. Semi-synthesis of voacorine N H MeOOC Me OH + N H HO Me COOMe 19 Voacangarine 1.5% HCl N 16 Vobasinol H H N N H 16% yield NH MeOOC Me H N H Me N COOMe N HO N OMe 20, R = α-Et 21, R = β-Et 22, R = (Z)-CHCH3 tabernamine MeO Me N Me R N N H Me N COOMe H MeOH, reflux C. Other dimeric alkaloids synthesized via acid-mediated condensation MeOOC Me 18 Voacamidine MeOOC MeO N Me 1 Voacamine Me Me N R H 23, R = H 24, R = OH Me 2 Voacorine Scheme 1.1. Büchi’s semi-synthesis of voacamine, voacamidine, and voacorine (1963). 1.2.2 Hesse’s Partial Synthesis of Pleiomutine In 1966, Hesse accomplished the partial synthesis of pleiomutine (14) through an acid-promoted coupling reaction.36 A mixture of pleiocarpinine (25) and eburnamine (26) was allowed to stand in 1N H2SO4 at 20 °C for 48 hours, affording pleiomutine (14) in 8 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids approximately 30% yield (Scheme 1.2). This transformation was proposed to occur via a Friedel–Crafts-type reaction involving iminium ion 27, generated upon acid-mediated activation of eburnamine (26), which subsequently underwent electrophilic aromatic substitution with pleiocarpinine (25). This experiment provided further support for the proposed structure of pleiomutine (14), exemplifying a commonly employed strategy for structural elucidation of newly isolated dimeric alkaloids. The semisynthesis of several related eburnea-containing bisindole alkaloids has been accomplished using similar conditions including strempeliopidine,37 tenuicausine,38 and kopsoffine.39 H N H N + MeOOC N Me N N 1 N H2SO4 20 °C, 48 h HO H MeOOC 26 Eburnamine N Me N Me 30% yield Me 25 Pleiocarpinine N 14 Pleiomutine via H H N N N H Me MeOOC N Me 27 Scheme 1.2. Hesse’s partial synthesis of pleiomutine (1966). 1.2.3 Le Quesne’s Semi-Synthesis of Alstonisidine In 1972, Le Quesne reported the semi-synthesis of alstonisidine40,41 from naturally isolated quebrachidine (28) and macroline (29), obtained via the degradation of the related natural product villamine42 (Scheme 1.3A). In the presence of 0.2 M HCl, quebrachidine (28) and macroline (29) react to generate hemiketal 30. Mechanistically, this is proposed 9 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids to occur via conjugate addition of the indoline nitrogen into the enone and protonation to yield ketone 31 (Scheme 1.3B). Intramolecular ketalization then occurs to produce hemiketal 30. Upon subsequent treatment with BF3•OEt2 at 0 °C, oxocarbenium 32 is generated and intercepted via electrophilic aromatic substitution to afford alstonisidine (3). Although this target has yet to be prepared by total synthesis, both quebrachidine precursors43 and macroline (29)44–48 were later independently accessed through synthetic efforts.49 A. Two-step coupling toward the synthesis of alstonisidine OH COOMe OH COOMe O Me OH COOMe HO H H N H + N N 0.2 M HCl (aq.) Me HH 23 °C, 18 h Me O H H H N Me N OH N HH O Me B. Proposed coupling mechanism. OH COOMe OH COOMe O Me HO H HH O H Me H H O H 29 N proton transfer N Me OH COOMe BF3 N HH N ketal formation H Me O OH H N HH H H 31 30 OH COOMe Me O H OH COOMe N HH –H Friedel– Crafts Me H O H 32 N N HH H H H Me 3 Alstonisidine H 28 N N 70% yield 30 H N HH Me 29 Macroline N N H H N 44% yield N H BF3•OEt2 N 28 Quebrachidine Me 3 Alstonisidine Scheme 1.3. Le Quesne’s semi-synthesis of alstonisidine (1972). 10 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.4 Le Quesne’s Semi-Synthesis of Villalstonine Le Quesne and coworkers also applied this reactivity to the synthesis of the related alkaloid villalstonine (4)41,50 from pleiocarpamine (33) and macroline (29) (Scheme 1.4A). In contrast to quebrachidine (28) the N-alkylated indole pleiocarpamine (33) reacts with the conjugate acceptor of macroline (29) at indole C(3), generating ketone 35; addition of the macroline primary alcohol into the carbonyl then promotes intramolecular hemiaminal formation via addition of the oxygen into the C(2) iminium to form villalstonine (4) in 38% yield (Scheme 1.4B). A. Semi-synthesis of villalstonine Me Me N Me N N + H H H OH O 38% yield Me N H N H O 33 Pleiocarpamine N Me O 23 °C, 18 h H Me H H 0.2 M HCl (aq.) Me N MeOOC N MeOOC H 4 Villalstonine 29 Macroline Me B. Proposed coupling mechanism H H O Me H N N H MeOOC O Me OH transfer H MeOOC Me 34 –H N N H H 33 H H O proton H Me 35 Scheme 1.4. Le Quesne’s semi-synthesis of villalstonine (1972). 4 11 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.5 Le Quesne and Cook’s Semi-Synthesis of Macralstonine Shortly thereafter, these conditions were applied a third time to the semi-synthesis of macralstonine (7)51 from alstophylline (36) and macroline (29) (Scheme 1.5A). Though this initially was proposed to occur via electrophilic aromatic substitution akin to that of villalstonine, an alternative mechanism was later proposed52 where macroline (29) first equilibrates to oxocarbenium species 37 upon loss of water (Scheme 1.5B). This species is then intercepted by the electron rich indole ring of alstophylline (36) to afford conjugate adduct 38; hydration of the dihydropyran via oxocarbenium 39 then produces the natural product (7) in 40% yield. A total synthesis of alstophylline was later accomplished by Cook.53,54 H Me Me Me H Me 29 Macroline H O N N OH H 36 Alstophylline Me H Me O 7 Macralstonine O H +H O Me –H O –H O 2 H 29 Me N MeO Me 37 H 36 H O H O N Me OH H N MeO 40% yield Me H H Me O N N MeO OH Me 23 °C, 120 h H Me O H Me 0.2 M HCl (aq.) + H N N H Me +H N MeO 38 Me H O Me H O H –H 7 N MeO 39 Me Scheme 1.5. Le Quesne and Cook’s semi-synthesis of macralstonine (1972). 12 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.6 Potier and Langlois’s Partial Synthesis of Vinblastine Vinblastine (9) and vincristine (10) are the most well-studied members of this natural product class from a synthetic perspective (Figure 1.2). Isolated from the Madagascar periwinkle Catharanthus roseus G. don in 1958,55–57 these natural products are composed of a northern fragment derived from cleavamine (40), which is synthesized in vivo via C–C bond cleavage of the related natural product catharanthine (41), and a southern fragment derived from vindoline (42). Early attempts to couple cleavamine derivative (40) and vindoline (42) directly through SEAr forged the undesired epimer of vinblastine at C(16’) as the exclusive product.58 21 21’ OH N Et N Et 20 20’ N 15 15’ N 16’ N H MeOOC MeO 7 6 H N R 3 Et OAc HO COOMe Vinblastine, R = Me (9) Vincristine, R = CHO (10) N H N H 16 16 21 20 COOMe 15 Et 41 Catharanthine COOMe 40 Cleavamine derivative N Et MeO N OAc Me H MeOOC OH 42 Vindoline Figure 1.2 Vinblastine, vincristine, and their subunits. Due to their high potency and treatment in low doses, clinical supplies continue to be derived from natural sources. Nevertheless, the chemical complexity of these molecules, in conjunction with questions about their structure-activity relationship and potential derivatives, have attracted significant attention from the synthetic community over the years, from semi-synthetic efforts through the late 20th century to total-synthetic efforts through the early 21st century. 13 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids N H 16 p-(NO2)C6H4CO3H 21 CH2Cl2, 0 °C COOMe 41 Catharanthine Et N N H >99% yield 21’ H MeO N Me 42 Vindoline 15’ H N Me 44 O N 16’ Et OAc 62% yield 4:1 d.r. C(16’) HO COOMe N H MeOOC H MeO N Me OAc Et N 1. H2, Pd/C Et HO COOMe 45 Anhydrovinblastine Et N 20’ NaBH4 N 16’ N H MeOOC Et OAc HO COOMe Et N TFA MeO >99% yield Et Et TFAA 2. m-CPBA COOMe + 43 N CH2Cl2 –78 °C N O N TFAA N N H MeOOC H MeO N Me 46 N –2 TFA Et MeO OAc 47 N TFA N H MeOOC H N Me 48 N Me Et OAc HO COOMe 30% yield Me OAc HO COOMe OH Et NaBH4 N MeO H HO COOMe OAc Et Tl(OAc)3 N N H MeOOC N N H MeOOC H MeO N Me 9 Vinblastine Et OAc HO COOMe Scheme 1.6. Potier and Langlois’s semi-synthesis of vinblastine (1979). In 1979, Potier and Langlois published the first partial synthesis of vinblastine (9) from natural catharanthine (41) and vindoline (42) (Scheme 1.6).59 Following a three-step procedure developed concurrently by the Potier-Langlois60,61 and Kutney62,63 groups, catharanthine (41) is transformed to N-oxide 43 before subjection to trifluoroacetic anhydride initiates a Polonovski–Potier rearrangement to cleave the C(16)–C(21) bond (red) of the iboga framework. The resultant di-cation is intercepted by vindoline (42) at C(16) Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 14 through electrophilic aromatic substitution to generate dimeric iminium 44 which is reduced by sodium borohydride at C(21’) to provide anhydrovinblastine 45 in 62% yield. Low temperatures were essential, as warming from –78 to 0 °C eroded the diastereoselectivity from 4:1 to 1:1 d.r. at C(16’).61 Anhydrovinblastine (45) is then hydrogenated selectively at the D-15’,20’ olefin and N-oxidized with m-CPBA to N-oxide 46. TFAA then initiates a second PolonovskiPotier rearrangement to generate enamine 47 upon subsequent elimination. Oxidation with thallium acetate gives vinblastine-20’-acetate 48 before reductive deprotection with NaBH4 delivers vinblastine (9) in 30% yield. While other oxidants (e.g., OsO4) oxidized from the less-hindered a-face, the thallium reagent offered the desired b-face oxidation due to direction by the enamine nitrogen lone pair.64 1.2.7 Kutney’s Partial Synthesis of Vinblastine Kutney would follow up with an improved route to vinblastine using a similar strategy (Scheme 1.7).65 Following the Polonovski–Potier rearrangement of N-oxide 43 and electrophilic aromatic substitution with vindoline (42), iminium 44 is subsequently treated with nicotinamide derivative 49. 49 promotes selective 1,4-reduction of a,bunsaturated iminium ion 44 at C(15’) (blue) over C(21’) (red) and generates enamine 47 directly. Circumventing the use of toxic thallium reagents, Kutney discovered that aerobic oxidation with iron (III) chloride could advance enamine 47 to vinblastine (9) following subsequent exposure to sodium borohydride in 40% yield over the sequence. A 16% yield of the alcohol epimer leurosine (50) is also obtained. 15 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids Et N N O TFA N N H TFAA H COOMe Et MeO N Me Et OAc HO COOMe 42 Vindoline 43 N N H MeOOC CH2Cl2 –60 °C H MeO 44 Et N N Me Et OAc HO COOMe H then 49 MeOH, –40 °C H MeO N N Me 47 OH Et 1. FeCl3 (2 equiv) H2O, 0 °C, dark N N H MeOOC N 2. NaBH4 Et OAc HO COOMe OH Et CONH2 N N N H MeOOC MeO H N Me Et OAc HO COOMe 9 Vinblastine 40% yield overall N N H MeOOC MeO H N Me Me Et OAc HO COOMe COONa Me 49 50 Leurosine 16% yield overall Scheme 1.7. Kutney’s semi-synthesis of vinblastine (1988). 1.2.8 Kuehne’s Partial Synthesis of Vinblastine Kuehne’s partial synthesis in 199166 targeted a deconstructed cleavamine unit for use in the key coupling reaction (Scheme 1.8). Aldehyde 52, obtained in four steps from 2-ethyl-prop-2-enol (51) via Sharpless epoxidation, was condensed with azepine 53 and alkylated with benzyl bromide to generate quaternary ammonium 54. Heating promotes C– C bond cleavage (red), which following treatment with base initiates a formal [4+2] cycloaddition (54 → 55); subsequent diol deprotection affords tetracycle 56 in modest 16 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids yield, largely due to poor diastereoselectivity in the cycloaddition. Selective tosylation and silylation then delivers dimerization precursor 57. HO O 4 steps OHC Et 51 Me Me O Me Et N H 52 53 O then BnBr COOMe Me O NBn Et Et MeOH, reflux N H COOMe 55 NBn NBn OH N H 46% yield, 2 steps 1. Ts2O Et 2. TMSCl COOMe N H 69% yield HCl MeOH, reflux COOMe 54 OH Me O N H Et 97% yield O Et3N NBn Δ NH + Me OTs OTMS 1. t-BuOCl COOMe 57 56 OTs 2. AgBF4 HBF4•OEt2 Vindoline NBn 42 Et N Cl COOMe 58 OTs OTMS 3. KBH 4 80% yield OTMS Et NBn 1. Δ 2. H2, Pd/C N N H MeOOC Vinblastine (9) 3. TBAF H MeO 59 N Me Et OAc 78% yield HO COOMe Scheme 1.8. Kuehne’s partial synthesis of vinblastine (1991). Exposure to t-butyl hypochlorite affords chloride 58, which is followed by halide abstraction and heterodimerization with vindoline; C–C bond cleavage (red) with potassium borohydride produces dimer 59 in 80% yield. While attempts to use cleavaminederived chloroindenes in coupling reactions had previously58 led to poor diastereocontrol at C(16’), this research demonstrated that deconstruction of the piperidine ring was enough to overturn this inherent selectivity. To complete the natural product, dimer 59 is then Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 17 advanced to vinblastine (9) over a three-step sequence consisting of: 1) intramolecular alkylation to generate a quaternary ammonium salt, 2) cleavage of the benzyl protecting group and 3) deprotection of the tertiary alcohol. A second generation approach to the cleavamine unit was published the next year.67 1.2.9 Magnus’s Partial Synthesis of Vinblastine In 1992, Magnus68 disclosed an approach to vinblastine relying on “non-oxidative” formation of the electrophilic iminium (Scheme 1.9). Tryptamine 60 was first advanced to thioamide 61 over a five-step sequence involving Pictet–Spengler cyclization and Barton decarboxylation, while 2-ethyl-prop-2-enol (51) was advanced to aldehyde 62 over a fourstep sequence involving Sharpless epoxidation. A tin (II)-mediated aldol first affords alcohol 63 in 75% yield, before tosylation and elimination generates a mixture of alkenes (not shown). Raney nickel-mediated desulfuration reduces the thioamide to the tertiary amine before hydrogenation accesses dimerization precursor 64. Treatment with nosyl chloroformate and base promotes acylation of the tertiary amine and C–C bond cleavage to indolene 65, which is intercepted by vindoline (42) to generate dimer 66 with ~2:1 d.r. This intermediate is then advanced to vinblastine (9) over three-step sequence consisting of: 1) acetonide cleavage, 2) Swern oxidation and 3) carbamate cleavage/reductive amination to close the piperidine ring and complete the natural product. 18 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids COOBn NH2 5 steps N H MeOOC N H 60 N S 61 O HO 4 steps O O Et Sn(OTf)2 N-ethyl piperidine THF, 23 °C Me N N H MeOOC O HO Et O 75% yield Me Et 51 S 63 62 O 1. Ts2O, Et3N 2. DBU 3. Raney-Ni 4. H2, Pd/C N N H MeOOC 2,6-(t-Bu)-4-MePy ClCO2CH2C6H4NO2-p O Et O 64 Et N H 42 vindoline O 16’ COOMe 65 O N O C6H4NO2-p 1. HCl aq. 2. Et3N, DMSO Py•SO3 O Et O 3. H2, Pd/C 16’ 59% yield + 31% 16’-epi O MeNO2, –20 °C 35% yield C6H4NO2-p O N N H MeOOC N 58% yield H MeO N Me 66 N OH Et N N H MeOOC Et OAc HO COOMe H MeO N Me 9 Vinblastine Et OAc HO COOMe Scheme 1.9. Magnus’s partial synthesis of vinblastine (1992). 1.2.10 Cook’s Partial Synthesis of Villalstonine In 1994, Cook reported a synthesis44,69 of macroline (29) en route to the first formal synthesis of villalstonine (4) (Scheme 1.10A). Tryptophan (67) was first elaborated to bridging lactam 68 over 7 steps via Pictet–Spengler and Dieckman cyclizations.70 Methylation of the benzyl protected amine is followed by hydrogenolysis and a two-step homologation sequence to access enal 69. Reduction and oxa-Michael addition provides vinyl ether 70, which is heated to promote a Claisen rearrangement, doubly reduced, and protected as acetonide 71. Hydroboration/oxidation of the exo-methylene occurs with 19 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids complete selectivity for the b-face, before silylation and acetonide cleavage affords diol 72. Acetylation of the primary alcohol, oxidation of the secondary alcohol, and elimination of the acetoxy group produces enone 73. TBAF deprotection then furnishes the natural product macroline (29). Using a modified version of conditions described by Le Quesne,41 Friedel–Crafts alkylation forges a C–C bond (blue) before fluoride-triggered C–O bond formation (red) completes the synthesis of villalstonine (4) (Scheme 1.10B). Though a high yielder was observed via qNMR (60%), the isolated yield was comparable to that of the previously disclosed report. A. Synthesis of “electrophilic” macroline monomer COOH Bn NH2 N H 1. MeOTf; then H2, Pd/C 7 steps N Me 67 Me N Me 2. 3-butyn-2-one Et3N Me 83% yield O 69 Me N Me 3. (MeO)2Me2C pTsOH • H2O N Me Me N Me 2. TBSCl, DMAP 3. p-TsOH, MeOH 76% yield H OTBS N Me Me Ac2O, py.; OH H 72 Me Me O 71 H 1. 9-BBN; then H2O2/NaOH O H 53% yield 70 N N Me 64% yield 1. cumene, Δ 2. NaBH4 O N Me 2. LDA, PhSOCH2Cl 2. then KOH 3. LiClO4, PO(Bu)3 N 68 1. LiAlH4 O O N Me then PDC OR N H Me OH 52% yield O TBAF 73 R = TBS 83% yield 29 R=H Macroline B. Biomimetic synthesis of villalstonine Me Me N Me N N + H H Me 0.2 M HCl (aq.), TBAF N 23 °C Me O Me N MeOOC H H OTBS Me 60% NMR yield 40% isolated yield O N 73 O-TBS macroline Scheme 1.10. Cook’s partial synthesis of villalstonine (1994). N H O 33 Pleiocarpamine N MeOOC 4 H Villalstonine Me Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.11 20 Cook’s Partial Synthesis of Macrocarpamine Shortly thereafter, Cook also completed a partial synthesis of macrocarpamine (8).71–73 Previously synthesized ether (–)-70 was subjected to Claisen rearrangement, followed by reduction and hydroboration/oxidation to triol 74 (Scheme 1.11A). Monotosylation is then followed by Swern oxidation and condensation to dihydropyran 75. Reduction of the remaining ketone and elimination then affords anhydromacrosalhinemethine (76). Combining this with natural pleiocarpamine (33) in anhydrous HCl in methanol then gives macrocarpamine (8) in 83% yield (Scheme 1.11B). Mechanistically, this proceeds through protonation of indole C(3), followed by addition of the vinylogous enol ether of (77) to the in-situ generated iminium ion, forming oxocarbenium 78. Deprotonation then furnishes the natural product (Scheme 1.11C). 21 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of “nucleophilic” anhydromacrosalhine-methine monomer H Me N Me 1. cumene, Δ 2. NaBH4 O N Me Me N Me 3. 9-BBN; then NaOH, H2O2 O 1. TsCl, Et3N OH H Me 48% yield (–)-70 OH N 2. (COCl)2, DMSO, Et3N OH 31% yield 74 H Me N Me H O N 1. NaBH4 Me O H 76 Anhydromacrosalhinemethine 83% yield H B. Coupling of macrocarpamine Me N Me Me N + H MeOOC H N Me H 76 Anhydromacrosalhinemethine N Me H H N N H Me N 75% yield MeOOC H Me N Me H N O N H H N H H H H H COOMe O N Me 8 Macrocarpamine H Me H N H THF, 23 °C H C. Proposed coupling mechanism MeOOC dry 0.2N HCl Me 33 Pleiocarpamine N O N O N H N O N N Me 2. p-TsOH•H2O H 75 Me N Me Me H H COOMe 33 Pleiocarpamine 77 78 –H 8 Macrocarpamine Scheme 1.11. Cook’s partial synthesis of macrocarpamine (1996). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.12 Andrade’s Semi-Synthesis of Sungucine, Isosungucine, 22 and Strychnogucine B In 2016, Andrade reported the syntheses of the bis-strychnos alkaloids sungucine (84), isosungucine (85), and strychnogucine B (83).74,75 The requisite monomers were concisely prepared starting from commercially available (–)-strychnine (79) (Scheme 1.12A). Heating 79 with DBU at 200 °C effected an E1cB elimination, and silylation of the resulting alcohol with TBSCl afforded northern fragment 80. For the southern fragment, strychnine (79) was oxidized to the corresponding N–oxide with H2O2 followed by exposure to TFAA and then KOH to initiate a Polonovski–Potier reaction. The resulting carbinolamine was treated with methanol in dichloromethane to effect N,O-aminal ether equilibration to give southern fragment 81 in 52% yield. A biomimetic Mannich reaction was employed to unite the two fragments. Amide 80 was deprotonated with LDA to generate a lithium enolate and then added to the iminium ion derived from the treatment of fragment 81 with BF3•Et2O to smoothly provide dimer 82 as a mixture of diastereomers at C23 (Scheme 1.12B). Silyl group removal with HF•pyridine and olefin isomerization with Cs2CO3 in t-BuOH76 completed the total synthesis of strychnogucine B (83). To access sungucine (84) and isosungucine (85), the oxepine ring of strychnogucine B (83) was opened via E1cB elimination and then acetylated with acetic anhydride to provide an allylic acetate (not shown) as a mixture of olefin isomers. At this stage, classical deoxygenation protocols proved ineffective. Consequently, the acetate was transformed to 23 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids the corresponding bromide using HBr in acetic acid, which was subsequently reduced with NaBH3CN to give sungucine (84) and isosungucine (85) as a 1:2 mixture. A) MeO N N H N H H 1) H2O2 2) TFAA then 2) aq. KOH O 3) MeOH, CH2Cl2 N H N 1) DBU, NMP, 200 °C O 2) TBSCl, imid. N 50% yield O H H OTBS H H 52% yield O O 79 strychnine 81 southern fragment 80 northern fragment N B) N H N 80 H H 1) LDA, 0 °C O 2) 81, BF3•Et2O 23 H H OTBS H N 2) Cs2CO3, t-BuOH, 80 °C H N N O H OH H 1) HF•pyridine N 67% yield H H H H H 62% yield N O H O 83 strychnogucine B 82 N N H H N 3) 33% HBr in AcOH 4) NaBH3CN O H H H Me N H N + O 1.12. strychnogucine B (2016). N H Me N O Andrade’s Me H H semi-synthesis H Me O 84 sungucine Scheme H H H N 35% yield 84:85 = 1:2 O H O 1) DBU, NMP, reflux 2) Ac2O, DMAP H H 85 isosungucine of sungucine, isosungucine, and 24 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.13 Poupon, Evanno, and Vincent’s Partial Synthesis of Bipleiophylline In 2017, Poupon, Evanno, and Vincent published a semi-synthesis77 of bipleiophylline (88) from pleiocarpamine (33) and voacalgine A (87) (Scheme 1.13). Though the natural product contains two pleiocarpamine units, classifying it as homodimeric, we were obliged to include it in this account due to the challenge of installing an aromatic spacer unit with the correct regioselectivity. Coupling of 2,3-dihydroxybenzoic acid 86 and the formate salt of pleiocarpamine (33) affords voacalgine A (87), a structure that was misassigned in the initial report.78 Repeating this procedure in dichloromethane then provides bipleiophylline (88) in 3% yield over two steps. H MeOOC OH O HO OH N H N O OH 86 Ag2O + HCOO O MeCN, 23 °C N N MeOOC N H MeOOC H H 33 Pleiocarpamine • formate salt Me OH 33 O Ag2O HCOOH OH CH2Cl2, 23 °C N H O 3% overall yield H 87 Voacalgine A Me O N Me MeOOC N H H Me 88 Bipleiophylline Scheme 1.13. Poupon, Evanno, and Vincent’s semi-synthesis of bipleiophylline (2017). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.2.14 25 Andrade’s Semi-Synthesis of Melodinine K In 2020, Andrade reported the semi-synthesis of melodinine K (93), a highly cytotoxic bisindole alkaloid derived from 16-hydroxytabersonine and pachysiphine fragments (Scheme 1.14).79,80 The Andrade lab had previously completed the asymmetric total synthesis of tabersonine in 10 steps81 but elected to pursue a semi-synthetic approach toward melodinine K to improve material throughput and synthetic efficiency. Extraction of Voacanga africana seeds using a 5-day isolation procedure delivered multigram quantities of tabersonine (89). The northern fragment was prepared via biocatalytic C–H hydroxylation of tabersonine at C16 using genetically modified yeast expressing tabersonine 16-hydroxylase (T16H), analogous to the biosynthetic installation of this phenol in planta.82 The resulting phenol was protected via treatment with allyl bromide and K2CO3 to afford monomer 90. Fragment coupling was achieved using a strategy analogous to that reported by Fukuyama in the synthesis of the related bisindole conophylline (vide infra). Tabersonine (90) was Troc-protected, selectively N-oxidized, then epoxidized over three steps to give N–oxide 91. Treatment with trifluoroacetic anhydride initiates a Polonovski–Potier reaction that generates an iminium ion, which can be intercepted by fragment 90 via a Friedel–Crafts alkylation. Allyl deprotection of dimer 92 using Pd(PPh3)4 triggers cyclization onto the epoxide and is followed by reductive cleavage of the Troc group to deliver melodinine K (93), completing the six step semi-synthesis. 26 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids N Voacanga africana seeds N grind, extract, purify 1. T16H yeast Et 1.6 g from 100 g seeds N H 1) NaH, TrocCl 2) TFA then mCPBA 3) mCPBA 2. allyl bromide, K2CO3 Et N H AllylO 44% yield gram-scale biocatalyzed C–H oxidation COOMe 89 tabersonine COOMe 90 13% yield Me O COOMe N N O Me NH TFAA then 90 Et N Troc COOMe COOMe N 1. Pd(PPh3)4 pyrrolidine NH 2. Zn, KH2PO4 78% yield H O Allyl N 91 40% yield H O N O H OH N Troc Me COOMe 92 Scheme 1.14. Andrade’s semi-synthesis of melodinine K (2020). N H Me COOMe 93 melodinine K Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3 TOTAL SYNTHESES OF BISINDOLE ALKALOIDS 1.3.1 Magnus’s Total Synthesis of Norpleiomutine 27 In 1984, Magnus published a route83 to the eburnea–kopsia dimer norpleiomutine (13). Amine 94 is first elaborated to tetracyclic indole 95 through a five-step sequence84 involving intramolecular [4+2] cycloaddition (Scheme 1.15A). Esterification with enantioenriched sulfinyl acetic acid and l-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluene sulfonate (CMS) allows for chromatographic separation of diastereomers, affording enantiomerically pure 96. Acylation with TFAA at elevated temperatures generates lactam 97 via an interrupted Pummerer rearrangement, before a-alkylation with allyl bromide and heating delivers caged Diels–Alder adduct 98. Following reduction of olefin 98 with diimide, oxidation of the thioether and heating to 240 °C triggers a formal 1,3-migration to sulfoxide 99. Pummer rearrangement to the ketone followed by methoxide-mediated C–C bond cleavage generates hexacyclic intermediate 100. Deprotection of the indole nitrogen is followed by esterification; conversion of the lactam to the thioamide with Lawesson’s reagent and desulfurization gives kopsinine 101. To access the eburnea fragment, Diels–Alder adduct 102 is subjected to oxidative cleavage and acetal hydrolysis to lactone 103 (Scheme 1.15B). Condensation with tryptamine under acidic conditions promotes a Pictet–Spengler cyclization, affording cisfused pentacycle 104. A reduction/oxidation sequence then produces (±)-eburnamonine (105), before a classical resolution and lithium aluminum hydride reduction furnishes a mixture of (–)-eburnamine (26a) and isoeburnamine (26b). Subjecting a mixture of the two isomers with kopsinine (101) under acidic conditions then yields norpleiomutine (13) in 20 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 28 steps LLS from amine 94 (Scheme 1.15C).85 This marks the first synthesis of a heterodimeric monoterpenoid bisindole alkaloid in which both monomeric precursors are synthetically derived and enantioenriched. 29 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of “nucleophilic” kopsinine monomer O HN H 2N p-Tol 5 steps O S O OH p-Tol O S N CMS H N R Cl H Cl 47% yield N R (±)-95 R = PMPSO2- 94 1. KHMDS, allyl bromide 2. PhCl, 130 °C 1. HN=NH 2. m-CPBA 3. 240 °C N R 59% yield 97 61% yield 98 O O H N S 2. Δ N R 69% yield O O p-Tol N S 1. TFAA 96 single diastereomer O p-Tol Cl S Ph N N N 1. Li, NH3 2. MeOH, HCl 1. TFAA 2. KOH, MeOH N R N R 99 3. Lawesson’s Reagent 4. Raney Ni COOMe 100 67% yield N H 67% yield COOMe 101 Kopsinine B. Synthesis of “electrophilic” eburnamine monomer HO 1. KMnO4 Et MeO O N 2. PPA 58% yield 27% yield 103 H N 104 H 1. Resolution N N 2. CrO3, pyr. N O O O 1. LiAlH4 Me H N N N 2. LiAlH4 O yield not given H 1. Tryptamine AcOH COOH 2. 2M HCl OMe 102 Et HO yield not given Me (±)-105 Eburnamonine HO Me (–)-26a Eburnamine Me (–)-26b Isoeburnamine C. Biomimetic synthesis of norpleiomutine H N H N + N 2% HCl (aq) N N N reflux, 7 h N H COOMe HO 101 Kopsinine 26 Eburnamine Me Me 17% yield N H COOMe Scheme 1.15. Magnus’s total synthesis of norpleiomutine (1984). 13 Norpleiomutine 30 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.2 Cook’s Total Synthesis of Macralstonidine In 2002, Cook and coworkers reported the first total synthesis of macralstonidine (110) from macroline (29) and (+)-Na-methylsarpagine (109).86,87 6-methoxytryptamine 106 was accessed from 4-methoxyaniline through a Japp–Klingemann synthesis88 and advanced to lactam 107 (Scheme 1.16A).87 N-alkylation generates a vinyl iodide, which then undergoes an intramolecular Pd-catalyzed enolate alkenylation to afford bridging ketone 108. Wittig homologation with acidic workup produces an aldehyde before demethylation and borohydride reduction provides Na-methylsarpagine (109). Acidmediated condensation with synthetic macroline (29) under Garnick’s conditions89 then gives the dimer (+)-macralstonidine (110, Scheme 1.16B). A. Synthesis of “nucleophilic” methylsarpagine monomer MeO COOEt NH2 N Me 1. Br MeO 5 steps O NH N Me 106 MeO N Me O 1. CH3COCH2PPh3Cl t-BuOK; then HCl N 73% yield H HO OH N Me 2. BBr3 3. NaBH4 H 63% yield Me 108 I 2. Pd(OAc)2, PPh3 TBAB, K2CO3 107 H Me K2CO3 N H Me 109 (+)-Na-methylsarpagine B. Biomimetic synthesis of macralstonidine H Me N Me OH N NMe Me H Me H O 29 (+)-Macroline HO + MeOH no yield provided H H O Me H OH N Me N 0.2 N HCl H O OH N N Me H Me 109 (+)-Na-methylsarpagine N H Me 110 (+)-Macralstonidine Scheme 1.16. Cook’s total synthesis of macralstonidine (2002). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.3 31 Fukuyama’s First Generation Total Synthesis of Vinblastine The first total synthesis of vinblastine (9) was completed by the Fukuyama group in 2002.90 Starting from aldehyde 111, cyanohydrin formation and acetylation generated a racemic mixture of acetates, which underwent enzymatic resolution to give alcohol 112 in 42% yield and 97% ee (Scheme 1.17A). Following ozonolysis of the styrenyl olefin, the alcohol is activated with mesyl chloride before a tandem lithium aluminum hydride reduction and protection sequence advances to dihydrofuran 113. In parallel, quinoline 114 is cleaved with thiophosgene, which following THPprotection affords isocyanate 115 (Scheme 1.17B). Addition of benzyl methyl malonate precedes a Fukuyama indole synthesis91 and Boc protection to produce indole 116. Hydrogenolysis of the benzyl ether is followed by a decarboxylative Mannich reaction with elimination and THP deprotection to form enoate 117, which is coupled with dihydrofuran 113 through a convergent Mitsunobu reaction to access ether 118. TFA promotes hydration of the enol ether and Boc deprotection, while addition of pyrrolidine at high temperatures opens the hydrated furan ring and promotes an intramolecular [4+2] cycloaddition to construct pentacycle 119. This is advanced through a previously published 7-step sequence92 to vindoline (42). To construct the cleavamine-derived northern fragment, oxazolidinone 120 is advanced to nitrile 121 through a diastereoselective Michael addition to acrylonitrile, reductive auxiliary cleavage, and TBDPS-protection (Scheme 1.17C). The nitrile is reduced to the aldehyde and condensed with hydroxylamine to an oxime, which undergoes a nitrile oxide-olefin 1,3-dipolar cycloaddition to bicycle 122; reduction with zinc then 32 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of dihydrofuran 113 Et Et 1. NaCN, AcOH 2. Ac2O, pyr. NC OHC 3. Lipase PS THF/H2O, 50 °C Ph 42% yield, 97% ee 111 O 3. LiAlH4; then NaOH (aq.), DNsCl Ph OH Et 1. O3; then Me2S 2. MsCl, Et3N DNsHN 48% yield 112 113 B. Total synthesis of vindoline THPO THPO 1. CSCl2, Na2CO3; then NaBH4 2. DHP, CSA N MsO 1. benzyl methyl malonate, NaH NCS MsO 65% yield 114 OH COOBn N Boc MsO 60% yield 115 1. H2, Pd/C 2. Me2NH•HCl HCHO, AcONa 2. AIBN, n-Bu3SnH 3. Boc2O, DMAP Et3N COOMe 116 DNs PPh3 N Boc MsO 3. CSA, MeOH 71% yield O N 113, DEAD Et PhH COOMe N Boc MsO 118 COOMe 79% yield 117 OH N N 7 steps 1. TFA, Me2S Et 2. pyrrolidine N H MsO 73% yield 119 OH N Me H MeO COOMe Et OAc COOMe 42 Vindoline C. Total synthesis of cleavamine derivative Bn O Et N 1. (i-PrO)TiCl3 i-Pr2NEt acrylonitrile NC Et 2. NaBH4 3. TBDPSCl, im. O O 69% yield 120 NaOAc 3. NaClO (aq.) 66% yield O HO 3. TESCl, im; then TMSCl Et OH Et 125 127 124 OTBDPS OTBDPS 67% yield O Ns N Et OTBDPS 1. TFA 2. TsCl, DMEDA 3. TFAA, pyr. 67% yield N Et O 122 1. LDA, 129 2. AIBN, n-Bu3SnH 3. Boc2O, Et3N DMAP 4. AcOH/H2O Et K2CO3 DMF, 90 °C N Boc MeOOC 126 OTBDPS 35% yield 1. TsCl, Bu2SnO 2. NaHCO3 3. NsNH2, DEAD PPh3 OH N H MeOOC MeOOC Et NsHN OH N Boc MeOOC OTMS TESO 74% yield 123 HO 59% yield 121 OTBDPS 1. m-CPBA 2. K2CO3, MeOH Zn, AcOH 1. DIBAL–H 2. H2NOH•HCl OTBDPS OTBDPS Ns N 82% yield THPO OTFA N H MeOOC 128 Et NCS OTs 129 Scheme 1.17. Fukuyama’s total synthesis of vinblastine monomers (2002). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 33 unmasks b-hydroxy ketone 123. Baeyer-Villiger oxidation promotes C–C bond cleavage to a lactone (not shown), which is hydrolyzed with basic methanol and orthogonally protected to afford acyclic fragment 124. Base-mediated addition of ester 124 into isothiocyanate 129 is followed by an additional three-step sequence to generate indole 125 as a mixture of diastereomers a to the ester. Bis-tosylation of the primary alcohols is followed by base-mediated epoxidation and intermolecular SN2 to afford amine 126. Treatment with K2CO3 at elevated temperatures then gives 11-membered cyclic amine 127, which is advanced through an additional three steps to dimerization precursor 128. To link the two monomeric subunits, indole 128 is treated with t-BuOCl, which upon addition of vindoline (42) in the presence of acid generates dimerized product 131 in 97% yield as a single diastereomer (Scheme 1.18A). Deprotections of the trifluoroacetate and nosyl groups are then followed by base-mediated closure of the 6-membered ring, affording vinblastine (9) in 28 steps longest linear sequence from 114. Fukuyama later showed that an analogous sequence could be used to advance desmethyl-vindoline 132 to vincristine (10) (Scheme 1.18B).93 34 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Total synthesis of vinblastine N Ns N Cl OTFA t-BuOCl 128 CH2Cl2, 0 °C TFAO N Ns + N Me H MeO OTs 130 N Me MeO N Me CH2Cl2 0 to 23 °C 97% yield, 2 steps OH Et N N H MeOOC 3. NaHCO3 H OAc COOMe N 1. Et3N, MeOH 2. HSCH2CH2OH DBU OTs TFA 42 vindoline Et N H MeOOC Et OH Et N H MeOOC 50% yield MeO OAc N Me HO COOMe 9 vinblastine 131 Me H OAc HO COOMe B. Total synthesis of vincristine N Ns N Cl OTFA t-BuOCl 128 Et N H MeOOC CH2Cl2, 0 °C TFAO N Ns H N H 133 CH2Cl2 0 to 23 °C 75% yield, 2 steps OH Et N N H MeOOC 3. NaHCO3 Me OAc COOMe N 1. Et3N, MeOH 2. HSCH2CH2OH DBU N N H MeOOC TFA 132 desmethylvindoline Et OTs MeO N H H MeO OTs 130 Et OH + 35% yield MeO OAc HO COOMe H N R Me OAc HO COOMe HCOOH Ac2O 134 R = H, desmethylvinblastine 87% yield 10 R = CHO, vincristine Scheme 1.18. Fukuyama’s total synthesis of vinblastine (2002) and vincristine (2003). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.4 35 Fukuyama’s Second Generation Total Synthesis of Vinblastine Fukuyama then published a second generation approach to vinblastine in 2007 (Scheme 1.19).94 Instrumental to this route was a functional handle at C(20’) to allow for derivatization at this position. Starting from enantioenriched cyclopentene 135, Krapcho decarboxylation and saponification affords acid 136, which is then lactonized and BOMprotected to provide bicycle 137. A three-step sequence then advances the intermediate to dihydropyran 138 before hydroboration/oxidation generates ketone 139. Grignard addition of TMS-acetylene installs the two-carbon handle before acid-mediated BOM-deprotection produces pyran 140. Oxidation of the secondary alcohol and Baeyer–Villiger oxidation delivers hemiacetal 141. Ethanolysis of the lactone, lactol reduction, acid-catalyzed lactonization, and silylation then affords key bis-silyl ether 142. Addition to isothiocyanate 143 and Fukuyama indole synthesis then provides indole 144 as a mixture of diastereomers. An additional eight steps are required to advance to azide 145, which is reduced and nosyl protected to amine 146. Protecting group manipulations are then used to access cyclization precursor 147, which undergoes a Mitsunobu reaction to generate cyclic amine 148. MOM-deprotection and tosylation of the primary alcohol is followed by re-protection of the tertiary alcohol to dimerization precursor 149. An analogous dimerization sequence produces 150, before an additional four steps afford vinblastine (9). Several derivatives of alkyne 150 were prepared as well, but all analogs were less biologically active than vinblastine (9). 36 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids H COOMe H 1. NaCl, 160 °C COOMe H BOMO 77% yield 2. TPAP, NMO O H H BOMO 80% yield H O H R OH 3. CSA 4. TESCl, im. 141 85% yield PMPO R 2. mCPBA O O O PMPO 1. KHMDS OTES 2. n-Bu3SnH Et3B NCS 142 PMPO 143 68% yield OH 1. SnCl2, PhSH Et3N N3 H OTES N Boc MeOOC O 2. p-NsCl, Et3N R OMOM 89% yield 145 HO NHNs H N Boc MeOOC R OTMS 3. TMSCl, Et3N 4. K2CO3, MeOH OTMS OMOM OMOM 147 Ns N 1. BF3•OEt2, EtSH 2. Me2N(CH2)3NMe2, 2. TsCl 2. 42, TFA CH2Cl2, 0 °C OTs 149 81% yield 84% yield OTMS N 20’ N H MeO N Me 150 OH Et 20’ 1. HSCH2COOH, DBU 2. NaHCO3 OTs N H MeOOC 1. t-BuOCl CH2Cl2, 0 °C OTMS N H MeOOC 3. TMSOTf, 2,6-lutidine 148 PhMe, 35 °C N Boc MeOOC 63% yield Ns N TMAD, n-Bu3P H OMOM 146 N Boc MeOOC NHNs 1. CAN 2. TBAF OH N Ns 78% yield + 144 PMPO OH 140, R = TIPS OTES N H O H 8 steps H R 1. TPAP, NMO 87% yield R OTES H HO H 83% yield 137 2. HCl, reflux 1. K2CO3, EtOH 2. NaBH4 O H BOMO O 1. TIPSCCH n-BuLi, LiBr 139 3. CSA, collidine O 66% yield O 1. DIBAL 2. MeOCHPPh3 O 2. BOMCl, TBAI i-Pr2NEt 136 1. BH3•DMS; H2O2, NaOH 138 O COOH 2. KOH (aq) 135 H 1. H2WO4, H2O2 H Me OAc HO COOMe 3. TBAF 4. H2, Pd/C 68% yield N N H MeOOC MeO 9 Vinblastine H N Me Me OAc HO COOMe Scheme 1.19. Fukuyama’s second generation total synthesis of vinblastine (2007). Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.5 37 Boger’s Total Synthesis of Vinblastine A third total synthesis of vinblastine was reported by Boger in 2008.95,96 Their previously reported synthesis of vindoline (42)97 begins with 6-methoxytryptamine (151), which is treated with CDI and 157 to afford urea 152 (Scheme 1.20A). Tosyl chloride induces cyclization to the 1,3,4-oxadiazole before coupling with acid 158 to afford amide 153. Heating in 1,3,5-tri-iso-propylbenzene (1,3,5-TIPB) at 230 °C promotes a tandem [4+2]/[3+2] cycloaddition to forge the alkaloid core as a mixture of enantiomers which are separated by chiral HPLC to afford enantiomerically pure 154. a-Oxidation of the lactam is isolated as silyl ether 155 before amide reduction and acetylation generates piperidine 156. Finally, hydrogenolysis of the cyclic ether, TIPS deprotection, and elimination affords vindoline (42) in 11 steps from 151. A second generation approach was later published starting from the chiral pool.98 Using catharanthine (41) obtained from Raucher’s route,99,100 Boger developed a one-pot oxidative coupling/alkene hydration to synthesize vinblastine (9) directly from the component monomers (Scheme 1.20B). Originally, Fe(III) was proposed to oxidize catharanthine (41) to radical cation 159, which undergoes C–C bond cleavage to stabilized radical 160 (Scheme 1.20C); this is oxidized to dication 161 before undergoing SEAr with vindoline (42) to dimer 44. The addition of iron (III) oxalate and sodium borohydride then initiate H• addition to the trisubstituted olefin (via the intermediate Fe–H species), generating a tertiary radical (162) that traps a molecule of triplet oxygen to the peroxide radical 163. A second hydrogen atom addition then generates peroxide 164, which is reduced to vinblastine (9) in 43% yield, with 23% of leurosine (50) also isolated. The 38 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids intermediates on this route were then elaborated to a number of analogues to study structure activity relationship.101 A. Total synthesis of vindoline NH 1. TsCl, Et3N 1. CDI NH2 N Me MeO N Me MeO 2. 157, AcOH 71% yield 151 HN O HN O 152 N N N Me N Me H O OTIPS Et OBn 1. Lawesson’s Reagent N H 2N COOMe 2. H2, Raney Ni 3. Ac2O, NaOAc O N Me H MeO 62% yield COOMe OTIPS 2. TBAF 3. Ph3P, DEAD Et OAc 42 Vindoline 65% yield COOMe 156 O O OMe OBn HO O N Et 157 OH Et * 158 + N N H MeOOC B. Total synthesis of vinblastine 41 Catharanthine 64% yield 1. H2, PtO2 155 H N TIPSOTf OBn 154 N MeO N Me H MeO 26% yield O Et O 230 °C then chiral HPLC N BnO MeOOC LDA, (TMSO)2 1,3,5-TIPB Et N O 153 78% yield COOMe O O MeO 2. 158, EDCI DMAP FeCl3, 0.1M HCl TFE, 23 °C, 2h; 42 Vindoline MeO then Fe2(ox)3, NaBH4 air, 0 °C, lutidine Me H N Me 9 Vinblastine OAc HO COOMe 66% yield 1.9:1 d.r. C. First generation mechanistic proposal 41 N –e N H COOMe N N H Et 159 N COOMe N H Et 160 Et + H• N –e + O2 N Et 161 O Et N COOMe 42 O O Et + H• N OH Et [H] OH Et N N H MeOOC R 44 162 –H+ 163 Scheme 1.20. Boger’s total synthesis of vinblastine (2008). 164 9 39 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids However, this mechanistic proposal failed to explain two key observations: 1) the coupling reaction proceeded with perfect diastereoselectivity at C(16’), while Kutney and Potier’s procedure, which implicated identical intermediates, favored the undesired epimer, and 2) no fragmented cleavamine-type derivatives were observed, as the remaining mass balance returned as unreacted catharanthine (41). A follow-up study102 proposed a new hypothesis where catharanthine (41) is reversibly oxidized to charge-separated radical cation 165 which lies in equilibrium with iminium radical 160; attack by vindoline (42) forms stabilized radical 165 which is sequentially oxidized and deprotonated to anhydrovinblastine (45) and hydrated to vinblastine through the mechanism described above (Scheme 1.21A). Boger further supported this hypothesis by publishing a new radical-cation based coupling method in 2019 (Scheme 1.21B).103 A. Second generation mechanistic proposal N N H N –e N H Et COOMe COOMe N H MeO N Me 166 –H N Me 44 N Br 1. 42 Vindoline H MeO OAc HO COOMe B. Radical cation mediated coupling + N N H MeOOC –e Me Et COOMe Et N H 42 160 Et N 41 Catharanthine Et 165 41 Catharanthine N H MeOOC N N H SbCl6 9 Vinblastine Me OAc HO COOMe N Et 3 “BAHA” 0.05 M HCl/TFE, 25 °C N N H MeOOC H 2. NaBH4, H2O, 0 °C MeO 85% yield N Me Me OAc HO COOMe 45 Anhydrovinblastine Scheme 1.21. Boger’s revised mechanistic proposal and radical cation coupling. Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.6 40 Cook’s Total Synthesis of Accedinisine In 2008, Cook published the first total synthesis of accedinisine (12).22,104,105 Tryptophan (67) was advanced to pentacycle 167 over six steps (Scheme 1.22A); in a previous report, Liu and coworkers showed that this intermediate could be converted to the nucleophilic affinisine (168) monomer via Wittig homologation and reduction in the opposite enantiomeric series,106 though the correct enantiomer was later correctly accessed en route to macroline (29).46 To access the electrophilic coupling partner (Scheme 1.22B), pentacycle 169 was converted to alcohol 170 via hydroboration/oxidation of an intermediate Wittig methylenation product. Conversion to methyl ester 171 over three steps is followed by Cbz-protection and methanol-induced C–C bond cleavage (red) to methyl ether 172. Deprotection and alkylation then delivers coupling partner 173. Mixing of methyl ether 173 and affinisine 168 in acidic methanol then produces (–)-accedinisine (12) as a single diastereomer (Scheme 1.22C). Cbz-protected amine 172 was also utilized in the coupling reaction to furnish N-desmethyl accedinisine. 41 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of “nucleophilic” affinisine monomer H COOH 6 steps NH2 N H 67 1. CH3COCH2PPh3Cl t-BuOK; then HCl N N Me H Me B. Synthesis of “electrophilic” monomer 68% yield H N H 2. 9-BBN; then NaBO3 Me 169 168 Affinisine Cbz N H 75% yield N H H COOMe H 1. DMP 2. NH2OH•HCl HCOOH, Δ Me Me 1. H2, Pd/C N H 2. MeI, Cs2CO3 MeO 73% yield Me 172 H 171 Pericyclivine 73% yield H COOMe H N N N H 3. HCl, MeOH 170 83% yield CbzCl MeOH, reflux N MeO Me 173 N H N N Me MeO N OH 6–10% HCl(g) OH Me 168 Affinisine N H H H H COOMe H N MeOH, reflux H Me 173 Me H H H COOMe H Me H COOMe H C. Biomimetic coupling of accedinisine Me Me OH 1. PPh3CH3Br t-BuOK N OH H H O H N H N N Me 2. NaBH4 167 H H H O Me N H 35% yield Me Scheme 1.22. Cook’s total synthesis of accedinisine (2008). N Me 12 (–)-Accedinisine 42 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.7 Fukuyama and Tokuyama’s Total Synthesis of Haplophytine Aside from vinblastine (9) and its congeners, haplophytine (11) is perhaps the most well-studied monoterpenoid bisindole alkaloid. Isolated from the leaves of the plant Haplophyton cimicidum and noted for its insecticidal properties,107–110 it is the dimeric combination of the component alkaloids canthiphytine (174) and aspidophytine (175) (Scheme 1.23A). Degradation studies by Cava and Yates show the western portion of the molecule readily undergoes a reversible rearrangement in the presence of acid or base (Scheme 1.23B).111,112 Despite several elegant syntheses of the aspidophytine moiety,113– 117 all were unsuccessful at advancing directly to haplophytine (11). The three published routes to date all utilize simpler precursors in the coupling/rearrangement. A. Haplophytine and its component monomers Me N O N O N HO N OMe Me O N N O HO O MeO Me N MeO OMe H N Me O O 11 Haplophytine 175 Aspidophytine 174 Canthiphytine B. Acid-base mediated semi-pinacol rearrangement Me N O N Me N O OH N HO HBr O MeO N OMe Me 11 Haplophytine Br Br NaHCO3 O N N HO N MeO H OMe Me O H O OH 176 Scheme 1.23. Haplophytine and proposed biosynthetic precursors. The Fukuyama and Tokuyama route118 to haplophytine (11) began with auxiliarycontrolled diastereoselective conjugate addition of cyclopentanone 177, generating Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 43 thioester 178 in 74% yield and 98% ee (Scheme 1.24A). Reduction and mesylation are followed by a Fukuyama ketone synthesis119 to produce phthalimido-ketone 179, before ketalization and elimination of the mesylate forges cyclopentene 180. Following a protecting group exchange (180 → 181), ozonolysis with reductive workup delivers diol 182. Leveraging the difference in steric environments between the two primary alcohols, orthogonal mesylation and oxidation precede alkylation of the nosyl amine to give cyclic amine 183. Finally, ketal and nosyl cleavage promotes an intramolecular Mannich reaction, which following esterification provides key tricyclic ketone 184. In a separate sequence, Vilsmeier–Haack formylation and Henry addition to indole 185 affords nitroolefin 186 (Scheme 1.24B). Exhaustive reduction with LiAlH4, followed by acylation and esterification generates amide 187 which undergoes protecting group exchange at the phenol oxygen to mesylate 188. A Bischler–Napieralski cyclization then provides a cyclic iminium ion, which upon Noyori-type asymmetric transfer hydrogenation120 and Cbz-protection furnishes tricycle 189 in 97% ee. At this juncture, a coupling occurs to install the aryl ring of the southern fragment; iodination of the indole at C(3) is followed by treatment with silver (I) to produce carbocation 190 which reacts with aniline derivative 191 to generate quaternary adduct 192 in 61% yield with 2.0–2.4:1 d.r. 192 is advanced to tetracycle 193 through a lactamization/protecting group exchange sequence. Treatment of the enamine with m-CPBA gives epoxide 194, which undergoes a spontaneous semi-pinacol rearrangement to forge the rearranged northern fragment (195). Fmoc deprotection and nitration then delivers hydrazine 196. 44 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of tricyclic ketone O 1. (S)-phenylethylamine O COOEt O 2. ethyl thioacrylate 177 O 178 3 O O 1. MeNHNH2 2. LiCl, Li2CO3 4Å M.S. COOEt 75% yield NPhth 3 NPhth 1. TMSO(CH2)2OTMS TMSOTf OMs 3. Pd(PPh3)2Cl2 (Phth)N(CH2)3ZnI COOEt 74% yield, 98% ee O O 1. NaBH4, CeCl3 SEt 2. MsCl, Et3N 179 67% yield OH O3 3 then NaBH4 2. NsCl, Et3N COOEt O COOEt quantitative 180 OH NsHN NHNs O 87% yield 181 COOEt 182 Ns 1. 1M HCl 2. PhSH, Cs2CO3; N OHC 1. MsCl, py. 2. PCC, Celite 3. Cs2CO3, 3A M.S. then SiO2; then TMSCH2N2 O COOEt O 69% yield NO2 1. POCl3; then 1M KOH OBn 2. MeNO2 N H 88% yield 185 3. SOCl2, MeOH O MeOOC MsO 188 67% yield, 97% ee N(allyl)2 N(allyl)2 OMe OMe OMe OMe N O N MsO NCbz 194 MsO COOMe 190 OMe OMe m-CPBA NaHCO3 CH2Cl2, 23 °C N MsO NCbz O 193 O 1. piperidine 2. iAmONO 6M HCl; then SnCl2 MsO 84% yield O N NCbz NHFmoc Cbz N Ar 86% yield N 2. AgOTf 189 192 O COOMe COOMe 54% yield MsO 2. MsCl, Et3N 1. NIS N,N’-dimethyl barbituric acid 4. FmocCl NCbz 1. H2, Pd/C NH O 187 NCbz N H N H MeOOC 1. LiOH 2. SOCl2; then i-Pr2NEt 3. Pd(PPh3)4 191 61% yield 2.0–2.4:1 d.r. OBn 71% yield 186 3. CbzCl, i-Pr2NEt COOMe 184 1. LiAlH4 2. succinic anhydride 1. POCl3 2. HCOOH/NEt3 (R,R)-TsDPEN-Ru NH N H OMs OBn O 83% yield 183 B. Coupling and rearrangement N H N 196, R = NHNH2 R MeO OMe 195, R = NHFmoc 74% yield Scheme 1.24. Fukuyama and Tokuyama’s total synthesis of haplophytine monomers (2009). 45 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids To complete the synthesis, a two-step Fischer indole synthesis couples fragments 196 and 184 to dimer 197 bearing the full skeleton of haplophytine (Scheme 1.25). Desaturation of the imine with benzeneselenic anhydride and Cbz-deprotection then occur before the final two methyl groups of 198 are installed by reductive amination. Finally, mesyl deprotection/saponification and oxidative lactonization complete haplophytine (11) in 27 steps LLS from indole 185. Cbz N O 1. H2SO4 (aq) 196 + 184 N O N 2. p-TsOH•H2O N MeO COOMe OMe 47% yield N 3. HCHO, AcOH NaBH3CN 22% yield 197 Me N O 1. (PhSeO)2O 2. BBr3, C6HMe5 MsO Me N O O N 1. 1M NaOH MsO N O N HO 2. K3[Fe(CN)6] NaHCO3 MeO OMe 198 N Me H COOMe O MeO 70% yield OMe N Me H O 11 Haplophytine Scheme 1.25. Fukuyama and Tokuyama’s total synthesis of haplophytine (2009). 1.3.8 Nicolaou and Chen’s Total Synthesis of Haplophytine The Nicolaou and Chen approach121 begins with a nearly identical sequence to the Fukuyama route, accessing tricycle 199 (Scheme 1.26). A PIFA-mediated oxidative coupling then occurs with indoline 200. Mechanistically, this proceeds through ligand exchange between the hypervalent iodine and ortho-bisphenol to generate electrophilic species 201, which reacts with the C(3) indole of tricycle 199 to afford arylated Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 46 intermediate 202. Deprotonation then promotes addition of the oxygen into the newly formed iminium at indole C(2) to furnish coupled product 203 in 23% yield (albeit with only 25% conversion). Following a seven-step sequence to advance to lactam 204, a similar m-CPBA initiated rearrangement occurs to forge the western bridging tetracyclic fragment. Subsequent treatment with DDQ then oxidizes the intermediate to indole 205. Borylation of 205 at C(2) of the newly formed indole is followed by Suzuki coupling with reported vinyl iodide 206117 and methylation of the indole to deliver heptacycle 207. Amide activation with triflic anhydride promotes intramolecular cyclization with the indole C(3), followed by reduction of the resulting iminium. Deprotection of the primary alcohol and activation as the xanthate allows for a 5-exo trig radical cyclization into the indole122 to access 208, bearing the full carbocyclic skeleton of haplophytine. Deprotection of the carboxylic acid and oxidative lactonization then occurs, followed by debenzylation of the phenol oxygen and silylation to intermediate 209. Reductive amination installs the final methyl group but is unfortunately accompanied by reductive lactone opening. This bond is reformed with K3[Fe(CN)6] before desilylation furnishes haplophytine (11) in 33 steps from indole 185. 47 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 9 steps OBn N H AcO COOMe OH MeCN, –30 °C COOMe 200 1.0 equiv 2.0 equiv NCOOMe 23% yield NCOOMe O NCOOMe O I Ph OH H I O AcO N HO 199 185 Ph O NCbz N H PIFA + NCbz N H COOMe NCbz N H AcO COOMe 201 AcO OMe 1. LiTMP MeOBPin 2. Pd(dppf)Cl2, 206 Ph3As, TlOEt 3. NaH, MeI Cbz N N BnO O N O BnO 2. DDQ NCbz COOMe 203 NCOOMe 1. mCPBA NCbz N H 202 OMe 7 steps O 58% yield OTBS 49% yield N MeO O OMe COOMe 204 N 205 O Cbz OTBS 1. Tf2O, DTBMP 2. NaBH4 3. HF•py N O N O N BnO MeO OMe O N O N BnO 4. NaH, CS2; then MeI 5. n-Bu3SnH, AIBN N Me CO2TMSE 2. BCl3, C6HMe5 3. TESOTf OMe CO2TMSE 208 Me N N O O N TESO 1. CH2O, AcOH NaBH3CN O MeO N OMe Me 28% yield N Me H MeO 17% yield H N O CO2TMSE N O 207 1. TBAF; then K3[Fe(CN)6] 206 I Cbz 209 2. K3[Fe(CN)6] 3. TBAF H O N O N HO O N MeO OMe Me 42% yield 11 Haplophytine Scheme 1.26. Nicolaou and Chen’s total synthesis of haplophytine (2009). H O Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.9 48 Fukuyama and Tokuyama’s Total Synthesis of Conophylline In 2011, Fukuyama and Tokuyama published a route toward the dimeric aspidosperma alkaloids conophylline (5) and conophyllidine (6).123 Commercial phenol 210 was first advanced to ester 211 over an eight-step sequence (Scheme 1.27A). Nitro reduction, followed by acylation and dehydration affords isocyanate 212 which undergoes a Fukuyama indole synthesis followed by iodine quench to provide 2-iodoindole 213. After DIBAL reduction and orthogonal protections, indole 214 undergoes Stille coupling with vinylstannane 219 and THP deprotection to give enoate 215. Mitsunobu coupling with dihydrofuran 113, previously implemented in their first-generation vinblastine synthesis,90 followed by hydration/Boc-deprotection and condensation/[4+2] cycloaddition delivers tetracycle 216. After elimination of the secondary alcohol, indoline protection and epoxidation furnishes the electrophilic coupling partner 218, a protected version of the natural product taberhanine. The nucleophilic coupling partner is synthesized from pentacycle 119, another advanced intermediate that was accessed through the vinblastine route (Scheme 1.27B).90 Through an analogous three-step sequence, 119 is advanced to epoxide 220. Trocdeprotection, mesyl group hydrolysis, and allylation produces electrophilic coupling partner 221. 49 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids A. Synthesis of electrophilic coupling partner. HO COOMe MsO COOEt 8 steps MeO MeO OH NO2 1. Zn, AcOH 2. HCOOH, Ac2O MsO 3. POCl3, py MeO OMe 210 NC OMe 64% yield 211 MsO COOEt nBu3SnH, AIBN MeO MeCN, reflux; then I2 OMe 81% yield N H I 212 MeO 3. Boc2O 94% yield N Boc I OTHP 2. CSA, MeOH 62% yield OH PPh3, CCl4 2-methyl2-butene MsO Et MeO OMe N Boc 3. pyrrolidine OMe 215 N Et OMe N H COOMe 35% yield O Et 216 MsO MeO MeCN, 60 °C N H MeO 49% yield COOMe 1. 219 BnPd(PPh3)2Cl P(2-furyl)3, CuI 214 N 1. 113, DEAD, PPh3 2. TFA, Me2S OH MsO 1. DIBAL-H 2. DHP, CSA OMe 213 MsO N 1. t-BuOK, TrocCl 1. DMAP MsO 2. mCPBA 2. aq. HClO4 MeO COOMe Et 42% yield OMe 217 N 1. PPh3, CCl4 2. NaH, TrocCl, DMAP 3. mCPBA 3. aq. HClO4 70% yield N Troc O Et MsO N Troc 220 COOMe Bu3Sn O COOMe COOMe DNsHN 113 218 B. Synthesis of nucleophilic coupling partner. 119 COOEt 219 N 1. Zn, KH2PO4 2. 1M KOH 3, K2CO3, allyl bromide 82% yield O Et AllylO N H 221 COOMe Scheme 1.27. Fukuyama and Tokuyama’s total synthesis of conophylline monomers (2011). To couple the monomeric subunits, electrophilic coupling partner 218 is transformed to N-oxide 222 with m-CPBA (Scheme 1.28). Subjection to TFAA generates acylated species 223 which undergoes regioselective Polonovski-Potier rearrangement124 to iminium ion 224. 224 is then trapped by nucleophilic fragment 221 to give dimer 225. Allyl deprotection with palladium promotes concomitant epoxide opening to forge the final 50 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids dihydrofuran ring before global deprotection with LDA affords conophylline (5) in 27 steps LLS. A similar procedure is used to access the congener conophyllidine (6). O N N O MsO O MsO mCPBA TFAA Et MeO OMe N Troc Et CH2Cl2, 0 °C MeO COOMe OMe 218 N Troc CH2Cl2, 0 → 23 °C COOMe 222 N F3C O O H O –CF3COOH Et OMe N Troc O MsO O MsO MeO Et N N N H AllylO Et MeO OMe N Troc COOMe 221 –H COOMe COOMe 224 223 50% yield O O Me Me COOMe N NH COOMe N 1. Pd(PPh3)4 pyrrolidine NH 2. LDA H O Allyl N O MsO MeO OMe N Troc 225 Me COOMe H 54% yield O N H HO OH MeO OMe N H Me COOMe 5 Conophylline Scheme 1.28. Fukuyama and Tokuyama’s total synthesis of conophylline (2011). 51 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.10 Tokuyama’s Second Generation Total Synthesis of Haplophytine In 2016, Tokuyama published a bio-inspired second-generation total synthesis of haplophytine (11),125 improving upon previously developed chemistry by performing the coupling and rearrangement at a late-stage (Scheme 1.29). Reported intermediates50 were advanced in five steps each to tricycle 226 and aspidosperma skeleton 227.126 Silvermediated coupling proceeds comparably to the previous route to dimer 228, which is saponified and lactamized before protecting group exchange at the indoline nitrogen affords rearrangement precursor 229. CO2Me CO2Me Ns N Ns N N AgNTf2 (2.9 equiv) + N TsO N H OMe Allyl MeO I 226 CO2Me TsO 57% yield 2.4:1 d.r. 1. Me3SnOH 2. (COCl)2, proton sponge 2. then DBU O O HS N N N MeO S Cs2CO3 O THF, 23 °C then air TsO N 230 N N N O + H• TsO OH N 231 N S O Cl TsO Ar Ar O O N TsO Ar 232 Me N O 1. 240 °C 2. HCHO, TFA, 2. NaBH3CN N TsO MeO 70% yield 233 H N N O–O Ar 229 O O N Cl CO2Me H OMe Boc 48% yield O CO2Me 228 TsO 3. Pd(PPh3)4, PPTS 3. dimethylmalonate 4. Boc2O O N H OMe Allyl MeO 227 Ns N O N N CH2Cl2, –10 °C N H OMe Boc 234 CO2Me 3. 1M NaOH 4. K3[Fe(CN)6] O N O N HO O MeO N OMe Me 83% yield 11 Haplophytine Scheme 1.29. Tokuyama’s total synthesis of haplophytine (2016). H O Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 52 Using a modified aerobic rearrangement, treatment with 2-chlorothiophenol, cesium carbonate, and air generates radical 230. Extrusion of SO2 and trapping with oxygen forms peroxyradical 231. Sequential single electron transfers and protonation afford hydroperoxide 232, which is reduced to alkoxide 233 before semi-pinacol rearrangement produces the full carbocyclic skeleton 234 in 70% yield. Thermal Boc-deprotection and double reductive amination install the final two carbons, before tosyl deprotection and oxidative lactamization furnishes haplophytine (11) in 15 steps from previously published intermediates. 1.3.11 Stoltz’s Total Synthesis of 16′-epi-Leucophyllidine In 2021, the Stoltz lab reported an enantioselective total synthesis of 16′-epi- leucophyllidine (251) as part of a synthetic approach toward the bisindole alkaloid leucophyllidine. Synthesis commenced with the preparation of the eburnea coupling partner. Subjection of racemic ester 235 to an enantioselective decarboxylative allylic alkylation127 forges the quaternary center of lactam 236 in 92% ee (Scheme 1.30A). Benzoyl group cleavage with LiOH•H2O furnished amide 237, which serves as a common intermediate toward both fragments. N-alkylation and oxidative cleavage of the olefin then afforded acid 238. Fischer indole synthesis with phenylhydrazine proceeded with concomitant esterification to give indole 239. Bischler–Napieralski cyclization then generated iminium ion 240. Heterogeneous hydrogenation in DMF followed by addition of DBU proved uniquely effective for accomplishing the diastereoselective hydrogenation and accessing eburnamonine (105). Finally, triflation advanced to coupling partner 241. 53 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids O A) Synthesis of eburnea monomer. O allyl Me O NBz O O N O LiOH•H2O Ph MTBE, 60 ºC 91%, 92% ee 98% yield 236 O Br 1) NaH NH MeOH/H2O Me (±)-235 Me O Pd(OAc)2 (1 mol%) (R)-(CF3)3-t-Bu-PHOX (5 mol%) 2) RuCl3, NaIO4 69% yield 237 3 steps from δ-valerolactam Me O O O H N O PhNHNH2•HCl p-TsOH•H2O N Me POCl3, MeCN, reflux O MeOH, reflux OH N 95% yield 239 N N H then 1M LiClO4 OMe 53% yield 238 ClO4 O MeO2C Me CF3 H Pd/C, H2, DMF N N then DBU then HMPA, PhNTf2 O 78% yield 3.4:1 d.r. H LHDMS, –78 °C N Me 240 O N N P F3C t-Bu TfO Me 71% yield CF3 241 105 eburnamonine (R)-(CF3)3-t-BuPHOX B) Synthesis of the eucophylline-derived monomer. Br OH Me 3 steps NH2 MeO Boc N 236 Me 243 Br then KOt-Bu Me N N 63% yield O Me Br SnMe3 Pd(PPh3)4, Sn2Me6 N 2) DMP, NaHCO3 N 65% yield 245 2) Sn(OTf)2 2) then NEt3 O Me 1) Bz2O2, TFA 1) Blue LED, MeOH MeO 1) MeReO3, H2O2 244 72% yield 242 Boc N MeO O Br N N PhMe, 90 °C OMe N 75% yield 246 OMe 247 C) Synthesis of 16’-epi-leucophyllidine. 241 + 247 H O Me Pd(PPh3)4, CuTC N N NMP, 23 °C N 69% yield N OMe Me O Me N 2) NaH, EtSH 2) DMF, 140 °C N 60% yield N 248 H O [Rh(COD)(dppb)]BF4 O Me N 99% yield > 20:1 d.r. N H N N OH 250 1) aq. HCl, 70 °C 2) TMSCH2MgCl H Me N H 39% yield N 16’ 3) KH Me N N OH Me 251 16’-epi-leucophyllidine Scheme 1.30. Stoltz’s total synthesis of 16’-epi-leucophyllidine (2021). N Me OH 249 16’ H2 (20 bar), LiOt-Bu MeOH, 23 °C H O 1) ethylene glycol 1) BF3•Et2O, 0 °C Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 54 Toward the eucophylline-derived monomer, enantioenriched lactam 236 was elaborated over 3 steps to aldehyde 242 which was subjected to modified Friedländer quinoline synthesis with amino alcohol 243 to give quinoline 244 (Scheme 1.30B). Rhenium-catalyzed oxidation afforded an N–oxide (not shown); addition of triethylamine following Boc group cleavage with Sn(OTf)2 triggered cyclization with the pendant amine to produce tetracycle 245. Photoredox-mediated Minisci conditions effect C4-selective quinoline hydroxymethylation to give a benzylic alcohol which is oxidized with DMP to furnish aldehyde 246. Finally, stannylation with Pd(PPh3)4 and Sn2Me6 delivered coupling partner 247. Stille coupling of fragments 241 and 247 proceeded smoothly with Pd(PPh3)4 and CuTC to produce dimer 248 (Scheme 1.30C). Ketal formation with ethylene glycol and methyl ether cleavage with in situ generated NaSEt then gave phenol 248. Directed hydrogenation with [Rh(COD)(dppb)]BF4 afforded quantitative reduction of the trisubstituted alkene to dimer 250, bearing the incorrect stereochemistry at the linking C16’ position. Acetal cleavage and Peterson olefination then furnished 16′-epi-leucophyllidine (251), the structure of which was unambiguously confirmed using X-ray crystallography. Chiral hydrogenation catalysts were unable to overturn the undesired substrate bias and late-stage epimerization attempts led to no reaction or decomposition. While unsuccessful in accessing leucophyllidine, this research demonstrated a novel approach to bisindole alkaloids using transition-metal catalysis, rather than biomimetic couplings, that could hold further promise for accessing non-natural analogs of bisindole alkaloids to enable structureactivity relationship studies. 55 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.12 Zhang’s Total Synthesis of Geissolosimine In 2023, the Zhang lab reported the first total synthesis of the strychnos-sarpagine type dimer geissolosimine (263).128 The group had previously completed the total synthesis of the sarpagine monomer vellosimine (257) in 2021.129 This synthesis began by advancing L-tryptophan (67) over three steps including Pictet–Spengler cyclization, amine arylation, esterification, and Kulinkovich cyclopropanation to access cyclopropanol 252 (Scheme 1.31A). Treatment with diethyl azodicarboxylate and CuCl2 effected tandem amine oxidation to the iminium ion and cyclopropanol ring-opening cyclization to furnish bicycle 253. Amine dearylation and alkylation then gave alkyne 255. Exposure to AgNTf2 and pyrrolidine promoted ketone a-allenylation to construct the bicyclo[2.2.2.]octane skeleton. Mechanistically, it was proposed that the amine generates a nucleophilic enamine while AgNTf2 activates the alkyne for formal SN2’ substitution. Allene 256 was then elaborated via Corey–Chaykovsky epoxidation, Meinwald methylaluminumbis(4-bromo-2,6-di-tert-butylphenoxide) rearrangement (MABR), and with partial hydrogenation of the allene with Pd/C to furnish the natural product vellosimine (257). Toward geissoschizoline (262), enantioselective a-allenylation of ketone 258 (one step from known material) was accomplished with [Rh(cod)Cl]2 and chiral amine 264 to access bicyclo[3.3.1]nonane 259 in 96% ee (Scheme 1.31B).128 The fused indole ring was then introduced via trifluoroketone installation (CF3CO2CH2CF3, NaH), Japp–Klingemann reaction, and Fischer indole annulation. Boc protection of the indole then provided ketone 260. Removal of the nosyl group with thiophenol and reductive amination with bromoacetaldehyde generated an alkyl bromide that was poised for reductive cyclization 56 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids (not shown). SmI2-mediated dearomative 5-exo-trig cyclization delivered ketone 261. Corey–Chaykovsky epoxidation with Me3SOI and borane complexation with BH3•THF produced an epoxide which was opened reductively with Cp2TiCl2. One-pot allene reduction, Boc cleavage, and borane decomplexation then gave geissoschizoline (262). Finally, a biomimetic condensation of geissoschizoline (262) and vellosimine (257) using TFA in dichloromethane completed the first total synthesis of geissolosimine (263). A) OH COOH DEAD CuCl2 1) CH2O 2) CuI, PMPI, then MeI NH2 3) Ti(Oi-Pr)4, EtMgBr N H N H 42% yield 67 L-trytophan N N H 255 R = COOMe Ns N OCOOMe [Rh(cod)Cl]2 264, BHT Ns 1) Me3SOI, NaH 2) MABR •• 1) CF3CO2CH2CF3, NaH 2) PhN2•BF4 then 2) ZnCl2, Cl3CCOOH c• N PhMe, 90 °C Ns 1) PhSH, K2CO3 2) BrCH2CHO 2) NaBH(OAc)3 N 3) Boc2O, DMAP 67% yield 96% ee O N Boc H c • 26% yield Me O NH2 N Ar H O Br N H N H H O H Me Br 264 Ar = 3,5-(CF3)2-C6H3 N H 263 geissolosimine O Al Me t-Bu t-Bu H 60% yield t-Bu t-Bu H CH2Cl2, 40 °C OH 262 geissoschizoline 261 H 50% yield O 260 TFA vellosimine (257) H N H O N N Boc N H 3) Pd/C, H2 then TFA O 50% yield 3) SmI2 c • N 1) Me3SOI, NaH 1) then BH3•THF 2) Cp2TiCl2, Mn N H O 259 H 257 vellosimine H 258 O N N H 55% yield 256 B) 60% yield 253 3) Pd/C, H2 H 75% yield 2) 254, K2CO3 PMP H O N N H OR 254 1) BBr3 then PIFA N N H 55% yield 252 AgNTf2 pyrrolidine O O PMP H N OCOOMe MsO MABR Scheme 1.31. Zhang’s total synthesis of geissolosimine (2023). Me Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.3.13 57 Xie’s Total Synthesis of Geissolosimine Shortly afterwards, Xie published the second total synthesis of geissolosimine.130 Vellosimine (257) was prepared in 13 steps using a route previously developed by the Xie group.131 The authors achieved rapid assembly of the indole-fused azabicyclo[3.3.1]nonane framework (266) as a single diastereomer through a Mannich reaction between sulfinimine 265 and a vinylogous amide, followed by sulfuric acid–induced aza-Michael and Pictet– Spengler cyclizations (Scheme 1.32A). Ketone 266 was then advanced over six steps to enoate 267. Exposure to SmI2 in HMPA/THF effected reductive cyclization to hydroxyester 268 as a 14:1 mixture of diastereomers. Alcohol elimination, two-step conversion of the ester to an aldehyde, and PMB cleavage furnished vellosimine (257). The strychnos monomer geissoschizoline (262) was accessed starting from oxindole 269.130 Xie employed an asymmetric double Michael addition reaction between oxindole 269 and ynone 270 catalyzed by Sc(OTf)3/chiral N,N′-dioxide 274 to prepare spirocycle 271 in 95% ee (Scheme 1.32B). Ten steps were then required to advance to propargyl silane 272. Exposure to SnCl4 and TFA promoted a cascade sequence of Bocdeprotection, olefin protonation, and Sakurai-type cyclization to afford allene 273. Three step reduction of the allene, enamine, and methyl ester the furnished geissoschizoline (262). A biomimetic condensation between geissoschizoline (262) and vellosimine (257) using CSA in acetonitrile produced geissolosimine (263), completing the total synthesis. 58 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids O A) Me N S N H t-Bu NMePh then H2SO4, 40 °C O 6 steps O NaHMDS, –78 °C S N N H O t-Bu 66% yield 265 266 O H COOEt SmI2, HMPA Et 90% yield 14:1 d.r. N N PMB O H OH 268 Me OTBDPS O O N H 77% yield 95% ee 270 OTBDPS 271 N N N TMS SnCl4, TFA H CH2Cl2, –20 °C N Boc COOMe 81% yield c • COOMe N H 1) H2, Pd/C 2) NaBH3CN H 3) LiAlH4 Me H OH N H 57% yield 273 272 Me 10 steps then TMSOTf O N H H 257 vellosimine 274 + 269 NNs Sc(OTf)3 O N N H 14% yield NHNs O H 3) DIBAL 4) TFA, anisole PMB 267 B) OEt N N 1) Burgess’s reagent 2) i-PrMgCl•LiCl 2) MeONHMe•HCl 262 geissoschizoline N H CSA vellosimine (257) H MeCN, 40 °C 50% yield N H N H N H H O O Ar N H N N O O O H N Ar 274 Ar = 2,4,6-Me3-C6H2 H 263 geissolosimine Me Me Scheme 1.32. Xie’s total synthesis of geissolosimine (2023). 1.3.14 Movassaghi’s Total Synthesis of Hazuntiphyllidine In 2025, Movassaghi disclosed the total synthesis of hazuntiphyllidine (280) and other related homodimeric bisindole alkaloids.132 Though the natural product contains two mehranine units, classifying it as homodimeric, we were obliged to discuss it in this account due to the challenge of accessing its unsymmetrical dimeric framework. The synthesis commenced from desmethylmehranine derivative 275, an intermediate that was 59 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids prepared in ten steps in Movassaghi’s 2014 synthesis of mehranine.133 Hydrolysis of the formamide with KOH and N1-oxidation with N-tert-butylphenylsulfinimidoyl chloride and DBU afforded indolenine 276, the first fragment (Scheme 1.33A). Direct treatment of 276 with Eschenmoser’s salt effected mild C3-aminomethylation without the need for strong base; exposure to TFA induced elimination of dimethyl amine to furnish alkene 277, the second fragment. A) N N OHC H 1) aq. KOH 2) DBU, Nt-Bu S Ph Cl O N O N 2) TFA Me 39% yield 276 277 H N N N O O O Me TFA then H2O 3 N H 22’ 2’ Me N N H N Me O Me H O H Me 22 OH N Me 29% yield H 3 N then CH2O HO HN 3’ 277 Me 70% yield B) + N O 1) [Me2NCH2]I Me 275 276 N N H O N O 278 279 280 hazuntiphyllidine Scheme 1.33. Movassaghi’s total synthesis of hazuntiphyllidine (2025). To access the natural product, a mixture of fragments 276 and 277 were subjected to TFA followed by the addition of water to generate methylene-bridged heterodimer 278 (Scheme 1.33B). Mechanistically, imine 276 tautomerizes to an enamine which nucleophilically attacks olefin 277 to forge the C3’–C22’ bond. Hydration of the imine at C2’ then gives carbinolamine 278. A distinct hydration period was required to smoothly enable the formation of intermediate 278. Introduction of aqueous formaldehyde solution promotes condensation to an iminium ion (not shown) which reacts with an enamine to Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 60 generate the C3–C22 bond and central spirocyclic piperidine ring (278 to 279). Finally, transannular attack of the hydroxy group onto the indolenine furnishes hazuntiphyllidine (280). The authors found that the natural product (280) existed in a solvent-dependent dynamic equilibrium with imine-hemiaminal 279 that favored the natural product in all solvents evaluated. 1.4 CONCLUSIONS In summary, the heterodimeric monoterpenoid bisindole alkaloids have inspired a deep and fascinating body of research over the past sixty years. Despite this substantial history, it is surprising that such a storied natural product class remains so dramatically underexplored. While other alkaloid subclasses are subject of dozens of accounts per year, successful bisindole alkaloid syntheses are scarce—especially relative to the continued focus on the monoterpenoid indole alkaloids which frequently compose these dimeric structures. Modern synthetic chemists have largely moved on from the “tour-de-force” approach to natural product total synthesis that was frequently implemented to construct these synthetically challenging targets. By implementing aspects of modern synthetic planning, we can construct these targets with improved efficiency and facilitate the completion of total synthetic efforts. One such strategy to facilitate studies is the implementation of divergent134 or diversity-oriented synthesis135 in the construction of monomeric subunits. Inefficient monomer synthesis continues to be the bottleneck of progress, both in material throughput and time invested in optimizing new routes (vide infra). Monoterpenoid indole alkaloids, Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 61 despite substantial structural variation, all arise from the same biosynthetic precursor strictosidine;136 these monomers are, thus, particularly well-suited for diversity-oriented synthesis, as evidenced by reports from Zhu,137 MacMillan,138 and Stoltz.139 Fukuyama’s skillful repurposing of vinblastine intermediates toward the synthesis of conophylline90,123 offers concrete proof-of-principle that this design element can improve the efficiency of route development. Another area of development is the incorporation of modern advances in crosscoupling to accomplish the convergent linkage of monomeric subunits. Successful efforts to-date have become over reliant on the biomimetic hypotheses to forge the key dimerizing bond; this has thwarted some efforts when these hypotheses have proven unsubstantiated140 and limited other attempts to expand the scope of coupling partners beyond the natural product. Generalizable cross-couplings can be utilized in oligomeric natural product syntheses, as evidenced by work on polypyrroloindolines by MacMillan141 and Movassaghi.142,143 Given the recent advances in C(sp3)–C(sp2) cross-coupling and the everincreasing breadth of new cross-coupling reactions,144 the viability of catalyst-controlled coupling strategies has never been greater. From origins in structural elucidation via semi-synthesis to modern implementation in analog development for structure-activity relationship studies, interest in this natural product class has evolved with the changing demands of modern synthetic chemistry. Given the designation of several accounts described herein as landmark syntheses,145,146 there remains little doubt that this natural product class will continue to garner interest for years to come. Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 1.5 (1) 62 REFERENCES AND NOTES Also known as “bis(monoterpenoid) indole alkaloids,” “bisindole monoterpenoid alkaloids,” “monoterpene bisindole alkaloids,” “dimeric bisindole alkaloids,” “bisindole alkaloids,” and “bis-alkaloids.” (2) Hesse, M.; Dimeric Alkaloids (Bis-alkaloids). In Alkaloids: Nature’s Curse or Blessing? Wiley-VCH/Weinheim: New York, 2002; pp 91-114. (3) Cordell, G.A.; Saxton, J.E. Bisindole Alkaloids. In The Alkaloids: Chemistry and Physiology; Manske, R.H.F., Rodrigo, R.G.A., Eds.; Academic Press: New York, 1981; pp 1–295. (4) Kam, T-S.; Choo, Y-M. Bisindole Alkaloids. In The Alkaloids: Chemistry and Biology; Cordell, G.A. Ed.; Elsevier/Academic Press: New York, 2006; pp 181– 387. 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Enantioselective Total Synthesis of Aspidophytine. Org. Lett. 2003, 5, 1891–1893. (115) Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Stereocontrolled Total Synthesis of (–)-Aspidophytine. Tetrahedron 2003, 59, 8571–8587. (116) Mejía-Oneto, J. M.; Padwa, A. Application of the Rh(II) Cyclization/Cycloaddition Cascade for the Total Synthesis of (±)-Aspidophytine. Org. Lett. 2006, 8, 3275– 3278. (117) Nicolaou, K. C.; Dalby, S. M.; Majumder, U. A Concise Asymmetric Total Synthesis of Aspidophytine. J. Am. Chem. Soc. 2008, 130, 14942–14943. Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 78 (118) Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Total Synthesis of (+)-Haplophytine. Angew. Chem. Int. Ed. 2009, 48, 7600–7603. (119) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. A Novel Ketone Synthesis by a Palladium-Catalyzed Reaction of Thiol Esters and Organozinc Reagents. Tetrahedron Lett. 1998, 39, 3189–3192. 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Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)-Haplophytine by Direct Coupling and Late-Stage Oxidative Rearrangement. Angew. Chem. Int. Ed. 2016, 55, 15157–15161. (126) Satoh, H.; Ueda, H.; Tokuyama, H. Divergent Total Synthesis of (–)-Aspidophytine and Its Congeners via Fischer Indole Synthesis. Tetrahedron 2013, 69, 89–95. 79 Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids (127) a) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740– 751. b) Marziale, A. N.; Duquette, D. C.; Craig II, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst. Adv. Synth. Catal. 2015, 357, 2238–2245. 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Nucleophilic Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 80 (132) Raclea, R.-C.; Mewald, M.; White, K. L.; Movassaghi, M. Total Synthesis of (+)Hazuntiphylline, (–)-Anhydrohazuntiphyllidine, and (–)-Hazuntiphyllidine. J. Am. Chem. Soc. 2025, 147, 13808–13814. (133) Mewald, M.; Medley, J. W.; Movassaghi, M. Concise and Enantioselective Total Synthesis of (–)-Mehranine, (–)-Methylenebismehranine, and Related Aspidosperma Alkaloids. Angew. Chem. Int. Ed. 2014, 53, 11634–11639. (134) Li, L.; Chen, Z.; Zhang, X.; Jia, Y. Divergent Strategy in Natural Product Total Synthesis. Chem. Rev. 2018, 118, 3752–3832. (135) Burke, M. D.; Schreiber, S. L. A Planning Strategy for Diversity-Oriented Synthesis. Angew. Chem. Int. Ed. 2004, 43, 46–58. (136) O’Connor, S. E.; Maresh, J. J. Chemistry and Biology of Monoterpene Indole Alkaloid Biosynthesis. Nat. Prod. Rep. 2006, 23, 532–547. (137) Xu, Z.; Wang, Q.; Zhu, J. Metamorphosis of Cycloalkenes for the Divergent Total Synthesis of Polycyclic Indole Alkaloids. Chem. Soc. Rev. 2018, 47, 7882–7898. (138) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Collective Synthesis of Natural Products by Means of Organocascade Catalysis. Nature 2011, 475, 183–188. (139) Pritchett, B. P.; Donckele, E. J.; Stoltz, B. M. Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)Limaspermidine and (+)-Kopsihainanine A. Angew. Chem. Int. Ed. 2017, 56, 12624–12627. Chapter 1 – The Synthesis of Heterodimeric Monoterpenoid Bisindole Alkaloids 81 (140) Pandey, G.; Mishra, A.; Khamrai, J. Asymmetric Total Synthesis of Eburnamine and Eucophylline: A Biomimetic Attempt for the Total Synthesis of Leucophyllidine. Org. Lett. 2017, 19, 3267–3270. (141) Jamison, C. R.; Badillo, J. J.; Lipshultz, J. M.; Comito, R. J.; MacMillan, D. W. C. 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In Classics in total synthesis III: further targets, strategies, methods; Wiley-VCH: Weinheim, Germany, 2011; pp. 689–718. CHAPTER 2 Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction† 2.1 INTRODUCTION Natural products possess a wealth of structural diversity and biological properties, which continue to motivate investigations into their therapeutic potential.1 Monoterpenoid bisindole alkaloids, a class of natural products that include the FDA-approved anticancer drugs vinblastine (9) and vincristine (10), are hypothesized to modulate protein-protein interactions (PPIs) during cell mitosis, thus inducing cell death.2–5 PPIs are essential for biological processes including immune response, nitric oxide synthesis, and preprogrammed cell death, among many others.6–7 Despite the importance of PPIs in biological function, small molecules that modulate PPIs are relatively rare and therefore understanding their structure-activity relationship is of great interest to the scientific community.4,8 Notably, dimeric alkaloids tend to show greater bioactivity than their monomeric constituents, and thus have captured the interest of the scientific community over the past 60 years.4 The bisindole alkaloid family is comprised of dimeric compounds, generated from two independently biosynthesized monomeric alkaloids unified through at least one carbon–carbon bond (Figure 2.1.1A).9–11 Stemming from their rich bioactivity and wealth † This research was carried out with Rand, A. W.; Reimann, C. E.; Virgil, S. C. Portions of this chapter have been reproduced with permission from Stoltz, et al. J. Am. Chem. Soc. 2023, 145, 7278–7287. © 2023 American Chemical Society. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 83 of structural diversity, numerous syntheses of the requisite monomeric indole alkaloids have been pursued.12–24 In stark contrast, total synthesis of complex bisindole alkaloids remains underexplored; as the parent heterodimers contain elements from aspidosperma, iboga, kopsia, corynanthe, cleavamine, and eburnea alkaloid families,25–28 their syntheses often require two fundamentally different strategies. The direct assembly of heterodimeric bisindole alkaloids from their monomeric components through a convergent coupling is an appealing strategy, though it requires regio- and diastereoselective control of the unifying carbon–carbon bond forming event.12,29 Biomimetic approaches to access numerous members of the bisindole alkaloid family have been attempted with varying levels of success, and often suffer from low yields, poor regioselectivities, and limited extension to analog syntheses.30–32 We envisioned that developing a convergent, modular coupling strategy would enable access to several members of this class of natural products, as well as non-natural analogs, and facilitate the exploration of their biological properties. Strempeliopidine (284) (Figure 2.1.1B) was first isolated from the leaves of Strempeliopsis strempelioides in 1984 by Novotný and coworkers.33–34 This molecule is comprised of two monoterpenoid indole alkaloids: a western pentacyclic fragment derived from aspidospermidine and an eastern pentacyclic fragment derived from eburnamine. Like other bisindole alkaloids, strempeliopidine is proposed to arise from an enzyme-mediated Friedel–Crafts type reaction between aspidospermidine and an iminium ion derived from eburnamine.35–36 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 84 A. Heterodimeric Monoterpenoid Bisindole Alkaloids OH H N Me H H N N H MeO2C Me H N R OAc HO CO2Me N Vinblastine (R=Me) (9) Vincristine (R=CHO) (10) H N N H MeO2C Me Bisleuconothine A (281) H N Me N H Me N H Me NH H HO MeO N N N N N Me OH (–)-Leucophyllidine (283) (+)-Kopsoffine (282) B. Strempeliopidine H N N H Me N Me N H H Strempeliopidine (revised structure – 2023) 284 No syntheses to date • Aspidospermidine and eburnamine dimer • 7 stereocenters • 3 all-carbon quaternary centers This research • Structural analysis via NMR and X-ray • Correct enantiomer identified by optical rotation • Synthesis of eight diastereomers C. Previous Structural Assigments of Strempeliopidine H N N H Me N H H H N Me Originally proposed structure (1984) 285 N N H Me N H H N Me Kam’s proposed structure (2006) 286 (ent-284) Figure 2.1.1. (A) Representative members of the monoterpenoid bisindole alkaloid family, (B) Structural revision of strempeliopidine, and (C) Previously proposed structures of strempeliopidine. Synthetic studies by the isolation chemists, as well as 1H NMR data, were used to establish the proposed structure (285). However, there is some ambiguity regarding the true stereochemistry of strempeliopidine as highlighted by a proposed structural revision Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 85 (286) from Kam and Choo in 2006 (Figure 2.1.1C).10 While the authors did not reisolate strempeliopidine, they proposed the stereochemical revision based on biological data from the Strempeliopsis plant and coupling constant analysis of the originally published 1H NMR data, though the absolute stereochemistry of strempeliopidine has thus far not been substantiated.10 The reported structures of strempeliopidine consists of ten rings, seven stereogenic carbons (three of which are all-carbon quaternary centers), and a challenging C(sp2)–C(sp3) bond that unites the two monomeric natural products. Furthermore, the complexity of these two fragments, as well as the challenges associated with forging the unifying C(sp2)–C(sp3) bond, has precluded synthetic access to this natural product. Although both eburnamine29– 30,37–44 and aspidospermidine13,22,45–48 have been synthesized, there are no reported syntheses of strempeliopidine to date. Conflicting reports in the literature pertaining to the true structure of strempeliopidine,10 as well as the unique biological properties of bisindole alkaloids, further motivated our synthetic investigations. 2.2 RETROSYNTHETIC ANALYSIS Based on the conflicting reports of strempeliopidine’s structure and the potential to access non-natural dimeric analogs, we devised a modular approach to both reported structures of strempeliopidine from enantioenriched monomeric indole alkaloid constituents (Scheme 2.2.1). Specifically, noting the differences between Novotný’s (i.e., 285) and Kam’s (286) proposed structures, a route that would allow precise control over each stereocenter on the eburnamine fragment was necessary. Both the (20’β, 21’⍺) and (20’β, 21’β) ring junctions of the eastern eburnea fragment would need to be prepared, in 86 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers addition to designing complementary strategies to control the stereocenter where the monomers are linked (C16’). To prepare the original structure proposed by Novotný (285), we envisioned using a Suzuki–Miyaura/reduction approach to prepare the 16’ β stereocenter from epi-eburnamine triflate 287 and aspidospermidine-derived boronic ester 289 (Scheme 2.2.1A). To synthesize the requisite eburnamonine vinyl triflate 287, a key Bischler–Napieralski reaction would be employed followed by trans-selective hydrogenation to afford the trans-20’β, 21’⍺-ring fusion.29 Lactam (–)-236 would be derived from δ-valerolactam (289) using our lab’s previously established scalable route exploiting a palladium-catalyzed asymmetric decarboxylative alkylation.49 To access the western fragment 289, we would apply a hydroamination/Pictet–Spengler sequence to A) Retrosynthetic Analysis of XX H N H N N 21’ 20’ 16’ 3 H Me N Me N H H Suzuki– Miyaura Bischler– Napieralski N Reduction Trans-selective hydrogenation Me Me 288 Br O Bpin Decarboxylative alkylation Pictet–Spengler Br N 3 3 N O Me 289 290 Me O NH (–)-236 N 285 (Originally proposed strempeliopidine) Decarboxylative alkylation 20’ 21’ 20’ TfO 287 Bz N O N H 291 B) Retrosynthetic Analysis of XX H N H N N 16’ 3 Me H N H H N 21’ 20’ Petasis borono– Mannich Bischler– Napieralski N 21’ 20’ Bz N O Decarboxylative alkylation O NH 20’ HO Me Cis-selective hydrogenation Me 288 (–)-236 (–)-26 Eburnamine Me 286 (Kam’s revised strempeliopidine) N BF3K Decarboxylative alkylation Pictet–Spengler 3 Me N H N 3 Ph (+)-292 O Me N H (+)-293 294 Scheme 2.2.1. (A) Retrosynthetic analysis of the proposed structure by Novotný and coworkers, and (B) Retrosynthetic analysis of the structure proposed by Kam. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 87 build up the pentacyclic framework of dehydro-aspidospermidine derivative (289) from acyl indole 290.50–51 Another decarboxylative allylic alkylation would be used to set the C3 all-carbon quaternary stereocenter, starting from 5-bromoindole (291). To prepare the revised structure reported by Kam (i.e., 286) (16’⍺, 20’β, 21’β), we designed a highly modular synthesis in which several stereoisomers of eburnamine ((–)26) could be united with aspidospermidine using a 1,2-addition into the eburnaminederived iminium via a Petasis borono–Mannich reaction to prepare the 16’⍺ stereocenter from eburnamine ((–)-26) and aspidospermidine-derived trifluoroborate salt (+)-292 (Scheme 2.2.1B). We posited the diastereoselectivity of this transformation would rely on inherent substrate preference that has been demonstrated in the syntheses of related bisindole alkaloids containing an eburnea monomer.29,31 Eburnamine (26) would be accessed by a Bischler–Napieralski reaction followed by cis-selective hydrogenation to afford the cis-20’β, 21’ β-ring fusion from lactam (–)-236.38 The western fragment (+)-292 would be prepared from an analogous sequence from indole (294) via lactam (+)-293. Through application of these two coupling strategies, we expected to be able to answer the question about the structural assignment of strempeliopidine. Additionally, this would provide access to additional bisindole alkaloids bearing natural and non-natural stereochemistry to explore the biological properties of this class of molecules. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 88 2.3 RESULTS AND DISCUSSION 2.3.1 SYNTHESIS OF THE EBURNEA AND ASIPIDOSPERMA COUPLING PARTNERS Our synthesis commenced with carboxylactam (±)-235, which could be accessed from δ-valerolactam in three steps (Scheme 2.3.1.1).49 Applying our previously developed asymmetric decarboxylative alkylation technology, we could access decagrams of enantioenriched lactam (–)-236 in 87% yield and 96% ee using 1.5 mol% of Pd(OAc)2 and (R)-(CF3)3-t-BuPHOX.29 Using chemistry previously developed in our laboratory, lactam (–)-236 could be converted to iminium salt (–)-240, which we identified as a suitable precursor for both (–)-epi-eburnamonine ((–)-295) and (+)-eburnamonine ((+)-105). Following a procedure outlined by Wenkert, we were able to form the eastern pentacyclic ring system by treatment of iminium (–)-240 with KOAc.38 This allowed for a diastereoselective hydrogenation of the iminium salt using Pd/C to yield (–)-epieburnamonine ((–)-295) in 74% yield and >20:1 d.r. Reversing the order of ring closure and hydrogenation, iminium (–)-240 was exposed to Pd/C and H2, followed by DBU, to deliver the pentacycle in 99% yield and 6.6:1 d.r. favoring (+)-eburnamonine ((+)-105).52 Treatment of either (–)-295 or (+)-105 with lithium aluminum hydride provided access to (–)-eburnamine ((–)-26) and (+)-epi-eburnamine ((+)-296). Additionally, (+)-eburnamine ((+)-26) and (–)-epi-eburnamine ((–)-296) were synthesized through this synthetic route by using (S)-(CF3)3-t-BuPHOX, providing access all four stereoisomers of eburnamonine in ten steps from commercially available material. 89 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O Pd(OAc)2 (1.5 mol%) (R)-(CF3)3-t-BuPHOX (7.5 mol%) O NBz O Me Me 5 steps NBz MTBE, 40 ºC to 60 ºC CF3 ClO4 O N N H O 87% yield, 96% ee MeO2C (–)-236 (±)-235 t-Bu Me (–)-240 CF3 3 steps from δ-valerolactam ref. 29 H N N (R)-(CF3)3-t-BuPHOX H LiAlH4 N THF, 23 ºC HO Me (+)-epi-eburnamine (+)-296 N P F3C N Pd/C (10 mol%) H2 (balloon) DMF, 23 ºC H N (–)-240 O 93% yield KOAc DMF, 23 ºC then Me (–)-epi-eburnamonine (–)-295 Pd/C (10 mol%) H2 (balloon) then DBU 74% yield >20:1 d.r. 99% yield 6.6:1 d.r. H N LiAlH4 Me 96% yield THF, 23 ºC O (+)-eburnamonine (+)-105 N N HO Me (–)-eburnamine (–)-26 Scheme 2.3.1.1. Preparation of (–)-eburnamine and (+)-epi-eburnamine. The synthesis of (+)-aspidospermidine ((+)-298) began with an enantioselective decarboxylative alkylation of acyl indole (±)-297, which can be accessed in six steps from indole (Scheme 2.3.1.2).50 Utilizing 1 mol% of a palladium(II) precatalyst and (S)-(CF3)3t-BuPHOX provided enantioenriched allyl indole (+)-293 in 97% yield and 94% ee. Using conditions employed in our synthesis of a related alkaloid, limaspermidine, a 4-step sequence of hydrozirconation/amination,53 reductive cyclization, alkylation, and annulation provided sufficient quantities of (+)-aspidospermidine ((+)-298) for further evaluation of our divergent coupling.50 To install a functional handle for the coupling of aspidospermidine ((+)-298) and (–)-epi-eburnamonine ((–)-295), we opted to pursue a bromination/borylation approach. Selective monobromination of aspidospermidine ((+)298) could be achieved through benzyl protection of aspidospermidine under reductive amination conditions (94% yield), followed by treatment with NBS. Miyaura borylation of bromoindole (+)-300 produced pinacol ester (+)-301 in 95% yield, setting the stage for our convergent coupling. 90 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Pd(OAc)2 (1 mol%) (S)-(CF3)3-t-BuPHOX (5 mol%) N Me O N MTBE, 60 ºC O PhCHO NaBH(OAc)3 AcOH N 4 steps Me O Me 97% yield, 94% ee (+)-aspidospermidine (+)-298 O (±)-297 CH3CN, 23 ºC N H H (+)-293 94% yield 6 steps from indole ref. 50 N N N Br NBS Me H N CH3CN, –20 ºC Me 85% yield Ph (+)-299 H N Pd(dppf)Cl2 (10 mol%) B2Pin2, KOAc, 1,4-dioxane, 100 ºC 95% yield Ph (+)-300 Bpin Me H N Ph (+)-301 Scheme 2.3.1.2. Preparation of functionalized (+)-aspidospermidine derivative. 2.3.2 TOTAL SYNTHESIS OF NOVOTNY’S PROPOSED STREMPELIOPIDINE With pinacol ester (+)-301 in hand, preparation of the eburnea fragment for the key coupling reaction was achieved by enolization/triflation of (–)-epi-eburnamonine ((–)-295) to provide triflate 287 in 80% yield (Scheme 2.3.2.1). To our delight, subjecting 287 and (+)-301 to canonical Suzuki–Miyaura conditions formed the desired C–C bond in 93% yield (302). We next turned our attention to the challenging diastereoselective reduction of the sterically hindered trisubstituted olefin of 302 and reductive cleavage of the benzyl group. Unfortunately, mild hydride sources under acidic conditions did not lead to any productive reaction. We next explored several homogeneous catalysts (Pfaltz, Crabtree, and Brown catalysts) that are designed for reducing styrenyl tri- and tetra-substituted olefins;54–56 disappointingly, no reaction was observed even at elevated pressures. Turning to heterogenous catalysis, it was found that subjecting dimer 302 to palladium on carbon under an atmosphere of hydrogen resulted in adsorption of the substrate to the solid support, preventing material recovery. Other heterogenous catalysts typically used for Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 91 hydrogenation either failed to provide the desired product or resulted in over-reduction of the substrate. H N LiHMDS, HMPA PhNTf2 N H N N + THF, –78 ºC O TfO 80% yield Me Me (–)-epi-eburnamonine (–)-295 287 H N Bpin Me H PhMe/H2O/EtOH 90 ºC N Ph 93% yield (+)-301 Scheme 2.3.2.1. N Pd(PPh3)4 (10 mol%) K2CO3 Cross-coupling Me N H N Me N Ph 302 of epi-eburnamonine derivative with aspidospermidine derivative. Hypothesizing that using a heterogeneous catalyst that could be degraded upon completion of the reaction would enable recovery of the substrate, dimer 302 was exposed to Raney nickel under an atmosphere of H2 (Table 2.3.2.1, Entry 1). Excitingly, partial hydrogenation of the trisubstituted olefin was observed after 3.5 hours (304). Using conditions described by Okimoto, exposure of 302 to Raney nickel and H2SO4 allowed for removal of the benzyl group, leaving the olefin intact (303) (Entry 2).57 Unfortunately, combining these two procedures either in a two-step or one pot procedure only led to intractable decomposition (Entry 3). The challenges regarding benzyl group removal, in addition to olefin reduction, led us to pursue an alternative strategy that avoided the use of protecting groups. 92 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N 302 N H N N N H N N N N conditions H MeOH, 23 ºC Me N H H Me Me H Me N H H Me Ph 303 285 H N Me 304 entry conditions 285 303 304 302 1 Raney nickel, H2 (balloon) trace – yes yes 2 Raney nickel, H2SO4 trace yes – yes 3 Raney nickel, H2 (balloon), then H2SO4 trace – – no Table 2.3.2.1. Attempted small scale hydrogenation and deprotection of benzyl heterodimer (+)-302. To this end, bromoindole (±)-305 was subjected to palladium-catalyzed asymmetric decarboxylative alkylation to provide allylindole (–)-290 in 97% yield and 92% ee (Scheme 2.3.2.2). Hydrozirconation and subsequent Pictet–Spengler reaction led to tetracycle (–)-306 in 53% yield. Acylation and annulation were accomplished over three steps in 83% yield to provide imine (–)-307. (–)-307 was then used in a Miyaura borylation to produce a coupling partner ((–)-289) that was devoid of protecting groups. Suzuki crosscoupling of (–)-289 with triflate 287 was next conducted to afford imine dimer 308 in 82% yield, the structure of which was unambiguously confirmed by single-crystal X-ray analysis. Gratifyingly, reduction of the imine and amide was simultaneously achieved using LiAlH4, avoiding the difficult benzyl deprotection from our initial route. Lastly, subjection to Ra/Ni at 4 bar H2 produced 285, the structure of Novotný’s proposed assignment (16’ β, 20’β, 21’⍺) in the original isolation paper. 93 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Br Br Pd2(pmdba)3 (5 mol%) (S)-(CF3)3-t-BuPHOX (12.5 mol%) N Me MTBE, 60 ºC O O 97% yield, 92% ee N NH Br then LiAlH4; AcOH, H2O THF, 0 ºC to 23 ºC O Me Me 1) Chloroacetylchloride Et3N, CH2Cl2, 0 ºC 2) NaI, acetone, reflux 3) AgOTf, THF, 23 ºC N H 83% yield (3 steps) O (±)-305 Cp2Zr(H)Cl H2NOSO3H THF, 23 ºC 53% yield (–)-290 (–)-306 6 steps from 5-bromoindole O O N Br Pd(dppf)Cl2•CH2Cl2 (10 mol%) B2Pin2, KOAc, N H Bpin THF, reflux Me N 66% yield (–)-307 N + H N N Pd(PPh3)4 (10 mol%) K2CO3 N PhMe/H2O/EtOH, 90 ºC TfO 287 (–)-289 O N Me N 82% yield Me H 1) LiAlH4, 23 ºC to reflux N N 16’ 2) Ra/Ni, H2 (4 bar) MeOH, 23 ºC Me Me N 54% yield (2 steps) 308 H Me N H H N 21’ 20’ Me 285 Does not match 1H NMR or optical rotation Scheme 2.3.2.2. Completion of the synthesis of the originally proposed structure of strempeliopidine (285). When comparing the NMR spectra of this compound to the list of peaks given by Novotný and coworkers, we noticed several discrepancies. Firstly, this synthetic compound was isolated as a mixture of atropisomers, which is inconsistent with the isolation chemists’ report. Secondly, dimer 285 exhibited instability in CDCl3, thus precluding characterization by 13C NMR. Furthermore, as 13C NMR data for this compound was not included in the initial report of strempeliopidine, 1H NMR, optical rotation, and HRMS were used to compare our compound to that reported by the isolation. When evaluating 285 by 1H NMR, several key peaks, including that of the stereocenter formed through the Suzuki cross-coupling/hydrogenation (C16’) and of C21’, were significantly shifted and possessed different coupling constants than those reported by Novotný and coworkers.34 As previously reported, the ABX spin system of C16’ in related bisindole alkaloids Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 94 norpleiomutine31, 58 and pleiomutine59 was observed at δ 4.95 ppm (dd, J= 12, 5 Hz) and δ 5.0 ppm (dd, J= 11, 5 Hz), respectively. This is comparable to the reported values for strempeliopidine (1H, δ 4.94 ppm, dd, J= 11.5, 4.6 Hz). However, for synthesized 285, we observed 1H, δ 5.51 ppm, d, J= 7.8 Hz.28, 60–62 Our NMR studies and comparison to other related bisindole alkaloids suggest that the initial structural assignment of strempeliopidine from 1984 requires reassessment, in agreement with the assignment by Kam in 2006.10 Before proceeding, we reexamined the synthetic studies initially reported by Novotný and coworkers. In addition to 1H NMR and mass spectrometry, the isolation chemists used degradation studies and semi-synthesis to assist in identifying the structure of strempeliopidine. It was reported that strempeliopidine could be synthesized by stirring aspidospermidine and eburnamine isolated from Strempeliopsis strempelioides in 2 N HCl at 20 ºC for 48 hours.34 However, in our hands, when exposing either (–)-eburnamine (–)26 or (+)-epi-eburnamine (+)-296 and (+)-aspidospermidine (+)-298 to the reported reaction conditions, the desired product was not observed; instead, each of the monomers could be quantitatively reisolated. Based on coupling constant analysis in Kam’s proposed structural revision which is substantiated by comparing the data for our synthesized dimer 285 with the primary data from Novotný and coworkers, we began targeting Kam’s revised structure of strempeliopidine (286). 2.3.3 TOTAL SYNTHESIS OF KAM’S PROPOSED STREMPELIOPIDINE Following the synthesis of 285, we set out to establish the relative configuration at C16’ and C21’ of strempeliopidine. With a reliable route to all four stereoisomers of eburnamonine (see Scheme 2.3.1.1, (+)-105, (–)-105, (+)-295, and (–)-295), we focused on Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 95 developing a method to forge the linkage between the two indole monoterpenoid alkaloids, aspidospermidine ((+)-298) and eburnamine ((–)-26), with ⍺-selectivity at C16’ (see Scheme 2.2.1B, 286). Given the strong bias in facial selectivity for hydrogenation of this class of molecules, we elected to explore addition of aryl nucleophiles to iminium ions as a means to directly forge the requisite stereocenter at C16’. Inspired by previous reports of Petasis borono–Mannich additions of boronic acids to iminium salts, and hypothesizing that aryl nucleophile addition to an iminium ion derived from eburnamine might have a similar facial preference to that observed for hydrogenation, we opted to pursue this strategy.63–65 Preliminary investigations into the Petasis borono–Mannich reaction were conducted on a model system using aryl boronic acid 310 and tertiary amine-containing hydroxy-indole 309 (Table 2.3.3.1). Using several solvents commonly employed in Petasis borono–Mannich reactions, including MeOH, CH2Cl2, or CH3CN, we did not observe an appreciable amount of desired product 311 (Entry 1). Positing that ionization of the hydroxy-indole was slow, we turned to more acidic solvents and found that trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) promoted the reaction in 16% and 79% yield, respectively (Entries 2 and 3). Additionally, we found that changing the solvent to i-PrOH (Entry 4), modifying the equivalency (Entry 5), increasing the temperature (Entry 6), or changing the identity of the aryl boron species (Entries 7 and 8) had detrimental effects on the yield of this reaction. Lastly, when subjecting boronic acid 310 and (–)-eburnamine ((–)-26) or (+)-epi-eburnamine ((+)-296) to the reaction conditions, we were pleased to 96 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers observe a single diastereomer bearing the same C16’⍺ stereochemistry as Kam’s proposed structure of strempeliopidine (286) (see Experimental Procedures). Table 2.3.3.1. Development of a Petasis borono–Mannich coupling between boronic acids and hydroxy-indoles. B(OH)2 N N + Ph HO H conditions N Ph 23 ºC, 16 h Me2N 310 309 N H Me2N 2 equiv entry conditions yielda 1 MeOH, CH2Cl2, or CH3CN – 2 CF3CH2OH 16%b 3 HFIP 79%, 9:1 d.r. (64% isolated) 4 i-PrOH – 5 1 equiv ArB(OH)2, HFIP 31%b 6 60 °C, HFIP 72%b 7 ArBpin, HFIP <5%b 8 ArBF3K, HFIP 34%b 311 a Yields determined by 1H NMR analysis of crude reaction mixture relative to Et4Si internal standard. b Diastereomeric ratio not determined. With this new method in hand, we began by synthesizing the boronic acid coupling partner from aspidospermidine (Scheme 2.3.3.1). Due to stability issues during purification, boronic acid (+)-312 was generated in situ and used immediately in the Petasis borono– Mannich reaction with (–)-eburnamine ((–)-26). Unfortunately, upon mixing these two coupling partners, only products resulting from proto-deborylation ((+)-299) and dehydration ((–)-314) were observed. Hypothesizing that proto-deborylation was more facile than in the initial model system, we explored other, more stable boron nucleophiles.66–67 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers N Br Me H Ph n-BuLi then B(OMe)3 N B(OH)2 THF, –78 ºC N 97 Me H Ph (+)-300 N (+)-312 H N N N (–)-26 X H HFIP, 23 ºC Me H Ph N (–)-313 not detected N H N Me H Me N N Ph (+)-299 96% yield Me (–)-314 99% yield Scheme 2.3.3.1. Attempted Petasis borono–Mannich with aspidospermidine boronic acid derivative. Having previously established the ability of trifluoroborate salts (R–BF3K) to form the desired C–C bond, albeit in diminished yields in the model system (Table 2.3.3.1), we next synthesized trifluoroborate salt (+)-315 (Scheme 2.3.3.2). Upon exposure of (+)-315 to eburnamine ((–)-26) in HFIP, the desired product ((–)-313) was formed in 98% yield as a single diastereomer. It is possible that the aryl–BF3K salts can be hydrolyzed in solution, serving as a reservoir for the slow release of boronic acid. Alternatively, aryl–BF2 has also been proposed to be the active arylation species in similar reactions.68–69 Regardless of the mechanism, the Petasis borono–Mannich coupling of (+)-315 and (–)-26 produced (–)-313 as a single diastereomer and in excellent yield. Finally, deprotection of the N-Bn indoline under acidic conditions using Raney nickel gave Kam’s strempeliopidine 286, the structure 98 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers of which was unambiguously confirmed by X-ray diffraction after treatment with 4bromobenzenesulfonyl chloride. Comparison of the 1H NMR data for the natural material to this synthetic sample suggests that 286 indeed possesses the correct relative configuration at C16’and C21’, as proposed by Kam; however, while the optical rotation was of similar magnitude to the isolated material ([α]21D = –64.0 º), it was of opposite sign ([α]20D = +100 º lit.). H N H X N Me N H N Ph Me KHF2 (–)-eburnamine (–)-26 N N HFIP, 23 ºC 98% yield (single diastereomer) HO X= Bpin, (+)-301 N H Me N H Ph (–)-313 Me Raney nickel H2SO4 MeOH, 23 ºC 71% yield X= BF3K, (+)-315 H N N H 316 N N pyridine N 16’ H Me N H H CH2Cl2, 23 ºC H Me Me 59% yield 286 [α]21D= –64.0 º Matches 1H NMR Optical rotation incorrect sign O O S Cl Me H O S O Br Br 316 N N 21’ 20’ 317 Scheme 2.3.3.2. Petasis borono–Mannich with aspidospermidine trifluoroborate derivative and determination of the relative configuration of strempeliopidine. 2.3.4 SYNTHESIS OF NON-NATURAL STEREOISOMERS AND STRUCTURAL REVISION OF STREMPELIOPIDINE It is well known that members of the eburnea-family of natural products have been isolated as enantiopure compounds and racemic mixtures70 possessing all potential stereochemical permutations. With a route that allows facile access to each of the four stereoisomers of eburnamonine (vide supra, see Scheme 2.3.1.1), we applied our newly 99 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers developed Petasis borono–Mannich reaction to synthesize non-natural stereoisomers of strempeliopidine (Scheme 2.3.4.1). Gratifyingly, the Petasis borono–Mannich coupling followed by debenzylation provided access to analogs of strempeliopidine possessing all four C20’and C21’ diastereomeric combinations in good yields (318–320). In each case, the Petasis borono–Mannich reaction produced diastereomerically pure material with the newly formed C16’ stereocenter having a proton anti to the ethyl group at C20’. This method, in parallel with cross-coupling/hydrogenation approach, allowed for divergent access to different stereochemical outcomes from the same starting materials in an efficient and facile manner. N H N N N 1) HFIP, 23 ºC H Me Me N H H 318 [α]21D= +10.1 º N Me 2) Ra/Ni, H2SO4 MeOH, 23 ºC H KHF2 N Me N H H 320 [α]24D= –70.1 º 2) Ra/Ni, H2SO4 MeOH, 23 ºC X= BF3K, (+)-315 2) Ra/Ni, H2SO4 MeOH, 23 ºC 49% yield over 2 steps N N H Me Me N H H 319 [α]21D= +8.5 º 71% yield over 2 steps N (–)-296 (–)-epi-eburnamine X 1) HFIP, 23 ºC Me N X= Bpin, (+)-301 or (+)-26 (+)-eburnamine H N 1) HFIP, 23 ºC Me H H (+)-26 (+)-eburnamine 1) HFIP, 23 ºC N Ph 83% yield over 2 steps H N X (+)-296 (+)-epi-eburnamine H 16’ N 2) Ra/Ni, H2SO4 MeOH, 23 ºC Ph KHF2 N X= Bpin, (–)-301 X= BF3K, (–)-315 70% yield over 2 steps H Me N H H N 21’ 20’ Me Strempeliopidine (284) [α]24D= +71.0 º Scheme 2.3.4.1. Synthesis of heterodimeric stereoisomers and the determination of the absolute configuration of strempeliopidine. Unfortunately, none of these diastereomers matched the 1H NMR and optical rotation reported by Novotný and coworkers. Since the coupling of (+)-aspidospermidine ((+)-315) with (–)-eburnamine ((–)-26) gave heterodimer 286 that most closely matched the original report by Novotný and coworkers, we elected to synthesize the enantiomer of this compound. To our delight, upon coupling of (–)-aspidospermidine ((–)-315) and (+)- Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 100 eburnamine ((+)-26) and deprotection of the N-Bn indoline, strempeliopidine stereoisomer 284 (ent-Kam’s assignment, i.e., 286) was isolated, which most closely matched the 1H NMR and optical rotation of the natural product ([α]24D = +71.0 º) (Scheme 2.3.4.1). Taken as a whole, these data suggest a revision of the structure of strempeliopidine to 284, the enantiomer of Kam’s proposed assignment (Figure 2.3.4.1); however, as efforts to secure an authentic sample of the natural product have been to date unfruitful, we cannot say with complete certainty that 284 has the correct absolute configuration or if there was an error or impurity in the original measurement of the natural product.71 Given the circumstances, the final determination may never be known. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N N N H Me H N H Me N H H Me H N Me H N N H Me N H H Me N H N N N H H Me N H H Me H N H Me N H H 284 revised strempeliopidine N Me N H H 286 Kam’s proposed strempeliopidine N Me 319 H Me N N H H 318 N Me 321 N H N N H H 285 Novotny’s proposed strempeliopidine N 101 320 H N N N H Me Me N Me N H H ent-319 Figure 2.3.4.1. Stereoisomers of strempeliopidine synthesized. 2.4 CONCLUSIONS In conclusion, eight stereoisomers of the bisindole alkaloid, strempeliopidine, were synthesized via a modular strategy that features a palladium-catalyzed decarboxylative asymmetric allylic alkylation and a Petasis borono–Mannich reaction. Essential to this approach was the identification of conditions that allowed for the convergent coupling of aspidospermidine and eburnamine monomers. A traditional palladium-catalyzed cross- Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 102 coupling approach, followed by hydrogenation, gave complimentary access to an epimer of the natural product, while arene addition to a masked iminium ion by a Petasis borono– Mannich cross-coupling provided the configuration found in strempeliopidine. Analysis of J-couplings, analog synthesis, and X-ray diffraction allowed determination of the relative configuration of previously misassigned stereocenters, while the optical rotation provided by the isolation chemists was used to determine the absolute configuration of the natural product. The general coupling strategy reported herein to access strempeliopidine, and its stereoisomers, serves as a foundation for future studies into the synthesis of other dimeric compounds in the bisindole monoterpenoid alkaloid family. 2.5 EXPERIMENTAL SECTION 2.5.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under a nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.72 Reaction progress was monitored by thin-layer chromatography (TLC). TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, CAM, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 300 MHz, 500 MHz, and 600 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), C6HD5 (δ 7.16 ppm), acetone-d5 (δ 2.05 ppm), C2HDCl4 (δ 6.00 ppm) or CHDCl2 (δ 5.32 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CDCl3 (δ 77.16 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 103 ppm), C6D6 (δ 128.06 ppm), acetone-d6 (δ 29.84 ppm), CD2Cl2 (δ 53.84 ppm), or C2D2Cl4 (δ 73.78 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell. High resolution mass spectra (HRMS) were obtained using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESIAPCI+). Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak OD-J column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. Reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Carboxylactam (±)-235,29 indole (±)297,50 and triflate 24129 were prepared according to the literature. Several compounds in this chapter also had their enantiomers synthesized. These compounds were prepared in the same manner as their enantiomers. All data for them were found to be in good accordance with their enantiomeric counterparts. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 2.5.2 104 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA O Me O NBz O Pd(OAc)2 (1.5 mol%) (S)-(CF3)3-t-Bu-PHOX (7.5 mol%) Me (±)-235 O O N Ph MTBE, 40 ºC to 60 ºC, 96 h 87%, 96% ee (+)-236 N-Benzoyl Lactam (+)-236: In a nitrogen-filled glovebox, Pd(OAc)2 (98.4 mg, 0.44 mmol, 0.01 equiv) and (S)–(CF3)3-t-Bu-PHOX (1.297 g, 2.19 mmol, 0.05 equiv) were added to an oven-dried 500 mL Schlenk flask with a stir bar. MTBE (175 mL) was added, and the flask was heated to 40 ºC for 30 minutes. In a separate flame-dried 50 mL round-bottom flask under nitrogen atmosphere was added carboxylactam (±)-235 (13.83 g, 43.85 mmol, 1.00 equiv). Carboxylactam (±)-235 was dissolved in 15 mL MTBE, then cannula transferred to the Schlenk flask containing the palladium catalyst. The Schlenk flask was sealed and heated to 60 ºC in an oil bath for 48 hours. To remove the carbon dioxide generated during the reaction, the flask was connected to a nitrogen-containing Schlenk line and vented for about 3 seconds every hour for the first 5 hours to remove CO2. A solution of Pd(OAc)2 (49 mg, 0.22 mmol, 0.005 equiv) and (S)–(CF3)3-t-Bu-PHOX (650 mg, 1.05 mmol, 0.025 equiv) in 5 mL MTBE was added and the flask was sealed and removed from the glovebox before heating to 60 ºC for 48 hours. The reaction was cooled to 23 ºC and concentrated under reduced pressure. Flash chromatography (90:10 à 85:15 à 80:20 à 70:30 hexanes/diethyl ether) afforded the N-benzoyl lactam (+)-236 as a colorless oil (10.35 g, 38.15 mmol, 87% yield, 96% ee). All spectra for (+)-236 were found to be in good accordance with literature values.49 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 105 (–)-236 was prepared in the same manner as (+)-236. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (500 MHz, CDCl3) δ 7.51 (dt, J = 7.8, 1.2 Hz, 2H), 7.48 – 7.42 (m, 1H), 7.41 – 7.34 (m, 2H), 5.86 – 5.55 (m, 1H), 5.29 – 4.91 (m, 3H), 3.78 (q, J = 5.3 Hz, 2H), 2.51 (dd, J = 7.0, 1.2 Hz, 1H), 2.28 (dd, J = 13.9, 7.6 Hz, 1H), 2.07 – 1.96 (m, 2H), 1.93 – 1.76 (m, 3H), 1.70 (dq, J = 14.9, 7.3 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 178.2, 175.8, 136.9, 133.8, 131.4, 128.3, 127.6, 118.8, 47.6, 47.1, 41.5, 30.5, 30.4, 19.7, 8.4. IR (Neat Film, NaCl) 3073, 2943, 2882, 1681, 1601, 1478, 1449, 1384, 1273, 1161, 917, 723 cm–1. [α]D21 –44.5º (c 0.62, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C17H22NO2 [M+H]+: 272.1651, found 272.1659. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Me O Me O N Ph LiOH•H2O 106 O NH MeOH/H2O 23 ºC, 24 h (+)-236 99% yield (+)-237 Lactam (+)-237: To a 2 L round-bottom with a stir bar containing a solution of N-benzoyl lactam (+)-236 (10.33 g, 38.05 mmol, 1.00 equiv) in methanol (500 mL) was added a solution of LiOH•H2O (2.37 g, 56.50 mmol, 1.50 equiv) in water (200 mL). The reaction mixture was stirred at 23 ºC for 16 hours. The reaction was then partially concentrated under reduced pressure to remove methanol and transferred to a separatory funnel. sat. NaHCO3 (aq.) was added followed by extracting with ethyl acetate (5x). The combined organics were washed with brine, dried over Na2SO4, then concentrated to afford lactam (+)-237 as a yellow oil that was pure by 1H NMR (6.36 g, 38.0 mmol, 99% yield). All spectra for (+)-237 were found to be in good accordance with literature values.49 (–)-237 was prepared in the same manner as (+)-237. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (500 MHz, CDCl3) δ 5.94 – 5.70 (m, 1H), 5.07 (d, J = 11.7 Hz, 2H), 3.27 (q, J = 3.4 Hz, 2H), 2.50 (dd, J = 13.5, 6.7 Hz, 1H), 2.19 (dd, J = 13.6, 8.0 Hz, 1H), 1.87 – 1.74 (m, 3H), 1.74 – 1.66 (m, 2H), 1.51 (dq, J = 14.8, 7.4 Hz, 1H), 0.90 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 134.8, 118.0, 45.1, 42.9, 31.2, 28.8, 19.9, 8.8. IR (Neat Film, NaCl) 3286, 3199, 3073, 2941, 2876, 1658, 1489, 1462, 1452, 1355, 1308, 1206, 912 cm–1. [α]D21 –11.0º (c 0.33, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C10H18NO [M+H]+: 168.1388, found 168.1392. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O Br Me O O NH Me O NaH (60%) O N DMF 23 ºC, 36 h (+)-237 107 99% yield O (+)-322 Acetal (+)-322: To an oven-dried 100 mL round-bottom flask with a stir bar was added lactam (+)-237 (6.36 g, 38.0 mmol, 1.00 equiv) and DMF (48 mL). The flask was cooled to 0 ºC in an ice bath and NaH (60% in mineral oil) (2.21 g, 55.37 mmol, 1.47 equiv) was added in small portions over 5 minutes. The reaction was stirred at 0 ºC for 1 hour, then bromodioxolane (10.80 g, 55.37 mmol, 1.47 equiv) was added dropwise. The reaction mixture was allowed to slowly warm to 23 ºC, then stirred for 36 hours. Upon completion, the reaction was cooled to 0 ºC in an ice bath and carefully quenched with water and transferred to a separatory funnel. The mixture was extracted with EtOAc (5x), the combined organics were washed with brine (3x) and then dried over Na2SO4. Flash chromatography (1:1 hexanes/ ethyl acetate) afforded the acetal (+)-322 as a colorless oil (11.10 g, 55.36 mmol, 99% yield). All spectra for (+)-322 were found to be in good accordance with literature values.29 (–)-322 was prepared in the same manner as (+)-322. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (500 MHz, CDCl3) δ 5.83 – 5.66 (m, 1H), 5.13 – 5.01 (m, 2H), 4.94 – 4.85 (m, 1H), 4.03 – 3.93 (m, 2H), 3.89 – 3.79 (m, 2H), 3.51 – 3.31 (m, 1H), 3.25 (td, J = 6.0, 2.8 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 108 Hz, 2H), 2.55 – 2.45 (m, 1H), 2.15 (dd, J = 13.5, 8.1 Hz, 1H), 1.88 – 1.73 (m, 3H), 1.73 – 1.63 (m, 6H), 1.55 – 1.40 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.2, 135.2, 117.7, 104.4, 65.0, 48.5, 47.5, 45.2, 43.5, 31.7, 31.29, 29.0, 21.8, 20.1, 8.9. [α]D22 –17.7º (c 0.36, CHCl3). IR (Neat Film, NaCl) 3073, 2942, 2877, 1631, 1489, 1462, 1432, 1356, 1285, 1198, 1136, 914 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C16H28NO3 [M+H]+: 282.2069, found 282.2072. 109 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Me O O N O (+)-322 RuCl3•xH2O (3 mol%) NaIO4 CH3CN/H2O 0 ºC, 1.5 hours 74% yield Me O O O N O OH (+)-238 Carboxylic Acid (+)-238: To a 500 mL round-bottom flask with a stir bar was added acetal (+)-322 (2.00 g, 6.97 mmol, 1.00 equiv), acetonitrile (105 mL), and water (35 mL). The reaction mixture was cooled to 0 ºC and RuCl3•xH2O (43.4 mg, 0.209 mmol, 0.03 equiv) was added, followed by NaIO4 (7.42 g, 34.8 mmol, 5.00 equiv) in a single portion. The reaction was monitored by LCMS and upon consumption of the starting material (110 min), the reaction mixture was filtered through Celite® with acetonitrile and the organics were partially concentrated under reduced pressure. The mixture was then extracted with dichloromethane (5x), dried over Na2SO4, then concentrated. Flash chromatography (99:1 à 98:2 à 97:3 à 95:5 dichloromethane/ methanol) afforded carboxylic acid (+)-238 as a clear oil (1.55 g, 5.18 mmol, 74% yield). All spectra for (+)-238 were found to be in good accordance with literature values.29 (–)-238 was prepared in the same manner as (+)-238. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (400 MHz, CDCl3) δ 4.92 – 4.83 (m, 1H), 4.01 – 3.90 (m, 2H), 3.92 – 3.81 (m, 2H), 3.58 – 3.42 (m, 2H), 3.40 – 3.24 (m, 3H), 2.69 (d, J = 15.8 Hz, 1H), 2.46 (d, J = 15.8 Hz, 1H), 1.98 – 1.60 (m, 8H), 1.60 – 1.47 (m, 1H), 0.93 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 110 C NMR (100 MHz, CDCl3) δ 177.7, 172.1, 104.0, 65.1, 48.4, 48.6, 44.6, 42.9, 31.0, 30.7, 30.6, 27.9, 24.2, 21.2, 18.7, 7.9. IR (Neat Film, NaCl) 2950, 1728, 1600, 1492, 1445, 1212, 1181, 1141, 1045, 944, 734 cm–1. [α]D22 –17.9º (c 0.36, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C15H26NO5 [M+H]+: 300.1811, found 300.1819. 111 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Me O O O N O OH (+)-238 PhNHNH2•HCl p-TsOH•H2O MeOH, reflux, 16 h 52% yield Me O NH O N OMe (+)-239 Indole (+)-239: To an oven-dried 500 mL round-bottom flask with a stir bar equipped with a reflux condenser was added carboxylic acid (+)-238 (3.00 g, 10.00 mmol, 1.00 equiv) and methanol (200 mL). Phenyl hydrazine hydrochloride (2.89 g, 20.00 mmol, 2.00 equiv), and p-toluenesulfonic acid monohydrate (5.71 g, 30.00 mmol, 3.00 equiv) were added and the mixture was heated to reflux for 16 hours. Upon completion of the reaction, 1M HCl (aq.) was added, and the reaction mixture was extracted with dichloromethane (5x). The combined organics were dried over Na2SO4, then concentrated. Flash chromatography (80:20 à 75:25 à 70:30 à 65:35 à 60:40 à 55:45 à 50:50 hexanes/ ethyl acetate) afforded indole (+)-239 as an orange viscous oil (1.80 g, 5.24 mmol, 52% yield). All spectra for (+)-239 were found to be in good accordance with literature values.29 (–)-239 was prepared in the same manner as (+)-239. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (500 MHz, CDCl3) δ 8.11 (bs, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.23 – 7.14 (m, 1H), 7.11 (td, J = 7.4, 0.9 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H), 3.68 – 3.62 (m, 5H), 3.46 – 3.35 (m, 1H), 3.32 – 3.17 (m, 1H), 3.04 (dd, J = 9.0, 6.4 Hz, 2H), 2.97 (d, J = 16.0 Hz, 1H), 2.36 (d, J = 16.0 Hz, 1H), 1.99 – 1.90 (m, 1H), 1.87 – 1.59 (m, 5H), 0.89 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 112 C NMR (100 MHz, CDCl3) δ 174.0, 172.7, 136.4, 128.5, 127.6, 122.2, 122.0, 119.4, 119.0, 113.6, 111.2, 51.6, 49.1, 49.0, 43.6, 422, 31.6, 29.3, 23.1, 20.0, 8.7. [α]D22 +23.6º (c 0.36, CHCl3). IR (Neat Film, NaCl) 3265, 2946, 2361, 2338, 1733, 1716, 1615, 1489, 1456, 1361, 1197, 910 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C20H27N2O3 [M+H]+: 343.2022, found 343.2027. 113 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Me NH O O N OMe ClO4 POCl3 CH3CN, reflux, 16 h 87% yield (+)-239 N H MeO2C N Me (+)-240 Iminium Salt (+)-240: To an oven-dried 250 mL round-bottom flask with a stir bar equipped with a reflux condenser was added a solution of indole (+)-239 (1.79 g, 5.24 mmol, 1.00 equiv) in acetonitrile (110 mL). POCl3 (14.7 mL, 157.25 mmol, 30.00 equiv) was added and the reaction mixture was heated to reflux for 16 hours. Upon completion, the reaction was cooled to 23 ºC and concentrated under reduced pressure. Additional acetonitrile (20 mL) was added, and the solution was reconcentrated to remove exogenous POCl3 to afford an oil. The oil was dissolved in dichloromethane (30 mL) and 1M LiClO4 (aq.) was added. The mixture was stirred vigorously for 30 minutes, then transferred to a separatory funnel. The mixture was extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (1:1 hexanes/ ethyl acetate, then 90:10 dichloromethane/ methanol) afforded iminium salt (+)-240 as a brown solid (1.94 g, 4.56 mmol, 87% yield). All spectra for (+)-240 were found to be in good accordance with literature values.29 (–)-240 was prepared in the same manner as (+)-240. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (400 MHz, CDCl3) δ 10.51 (bs, 1H), 7.84 (dt, J = 8.6, 1.0 Hz, 1H), 7.45 – 7.30 (m, 2H), 7.11 (ddd, J = 8.1, 6.8, 0.9 Hz, 1H), 4.04 (td, J = 15.5, 6.1 Hz, 2H), 3.94 – 3.72 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 114 (m, 2H), 3.55 (d, J = 18.6 Hz, 1H), 3.35 (s, 3H), 2.97 (td, J = 16.6, 6.5 Hz, 1H), 2.79 (ddd, J = 17.2, 6.5, 4.1 Hz, 1H), 2.70 (d, J = 18.7 Hz, 1H), 2.38 – 2.16 (m, 2H), 2.16 – 1.87 (m, 5H), 1.77 (t, J = 12.5 Hz, 1H), 1.01 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 172.2, 172.0, 141.2, 129.0, 125.3, 124.94, 123.0, 121.7, 121.0, 114.7, 54.6, 53.7, 52.0, 42.3, 42.0, 28.8, 27.7, 19.1, 17.8, 8.2. IR (Neat Film, NaCl) 3852, 3744, 3648, 2360, 2338, 1733, 1699, 1558, 1540, 1506, 1099, 667 cm–1. [α]D22 +58.9º (c 0.65, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C20H25N2O2 [M]+: 325.1911, found 325.1919. 115 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers ClO4 N H MeO2C N Pd/C (10 mol%), H2 DMF, 0.2 M, 23 ºC, 3.5 h Me then DBU 23 ºC, 3 h (+)-240 99% yield, 6.6:1 d.r. H N H N O N N O Me (–)-eburnamonine (–)-105 Me (+)-epi-eburnamonine (+)-295 (–)-Eburnamonine (–)-105 and (+)-epi-Eburnamonine (+)-295: To a 2-dram vial with a stir bar was added iminium salt (+)-240 (129 mg, 0.30 mmol, 1.00 equiv) and DMF (1.5 mL). Pd/C (10%, 67% w/w H2O) (64 mg, 0.01 mmol, 0.20 equiv) was added and the reaction mixture was backfilled with H2 (5x), then equipped with a balloon containing H2. The mixture was stirred at 23 ºC for 3.5 hours, then vented and placed under N2. DBU (184 µL, 1.23 mmol, 4.10 equiv) was added dropwise and the reaction mixture was stirred for 3 hours. Upon completion, the reaction was diluted with ethyl acetate and filtered through Celite®. The mixture was transferred to a separatory funnel, and the organics were washed with brine (2x), dried over Na2SO4, then concentrated. Flash chromatography (90:10 dichloromethane/ ethyl acetate, then 90:10 dichloromethane/ methanol) afforded (–)eburnamonine (–)-105 as a tan solid (76.9 mg, 0.26 mmol, 86% yield) and (+)-epieburnamonine (+)-295 as a tan solid (12.8 mg, 0.04 mmol, 13 % yield). All spectra for (–)105 and (+)-295 were found to be in good accordance with literature values.29 (+)-105 was prepared in the same manner as (–)-105. All data for it was found to be in good accordance with its enantiomeric counterpart. (–)-eburnamonine (–)-105: 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.40 – 7.26 (m, 2H), 4.07 (s, 1H), 3.65 (dd, J = 15.6, 8.4 Hz, 1H), 3.43 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 116 – 3.21 (m, 1H), 2.99 – 2.86 (m, 1H), 2.78 – 2.58 (m, 3H), 2.56 (d, J = 15.1 Hz, 1H), 2.46 (t, J = 11.1 Hz, 1H), 2.07 (d, J = 14.4 Hz, 1H), 1.81 (d, J = 13.8 Hz, 1H), 1.69 (dq, J = 14.6, 7.3 Hz, 1H), 1.52 (d, J = 13.9 Hz, 1H), 1.43 (d, J = 13.2 Hz, 1H), 1.07 (td, J = 13.5, 3.8 Hz, 1H), 0.95 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.8, 134.3, 132.2, 130.2, 128.5, 124.5, 124.0, 118., 116.34, 112.7, 57.8, 50.8, 44.5, 44.4, 38.6, 28.5, 27.1, 20.8, 16.7, 7.8. IR (Neat Film, NaCl) 2933, 2858, 1704, 1627, 1452, 1374, 1332, 1137, 1096, 753 cm–1. [α]D22 –75.3º (c 0.97, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C19H23N2O [M+H]+: 295.1810, found 295.1819. (+)-epi-eburnamonine (+)-295: 1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J = 7.6, 1.7 Hz, 1H), 7.48 – 7.36 (m, 1H), 7.35 – 7.25 (m, 1H), 3.10 (dd, J = 11.2, 5.7 Hz, 2H), 3.04 (s, 1H), 2.96 – 2.83 (m, 1H), 2.80 (d, J = 16.7 Hz, 1H), 2.71 – 2.58 (m, 1H), 2.52 (td, J = 11.2, 4.2 Hz, 1H), 2.42 – 2.19 (m, 2H), 1.96 – 1.81 (m, 3H), 1.70 – 1.56 (m, 1H), 1.22 (d, J = 17.6 Hz, 1H), 0.96 – 0.82 (m, 1H), 0.78 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.8, 135.2, 133.4, 130.0, 128.5, 124.2, 123.9, 118.3, 116.3, 113.1, 66., 55.6, 52.4, 44.4, 39.6, 32.0, 21.7, 21.4, 20.9, 7.5. IR (Neat Film, NaCl) 2939, 2795, 1710, 1427, 1322, 1119, 1042, 958, 749 cm–1. [α]D22 +126.9º (c 0.35, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C19H23N2O [M+H]+: 295.1810, found 295.1814. 117 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N THF, 23 ºC, 1 h O Me (–)-eburnamonine (–)-105 H LiAlH4 96% yield N H N HO N N HO Me Me (+)-eburnamine (+)-26a (–)-isoeburnamine (–)-26b (+)-Eburnamine (–)-26: To an oven-dried 2-dram vial with a stir bar was added (–)eburnamonine (–)-105 (64.3 mg, 0.218 mmol, 1.00 equiv). The vial was sealed with a septa and backfilled with N2 (3x) before adding THF (2.2 mL) and cooling the vial to 0 ºC. LiAlH4 (16.6 mg, 0.437 mmol, 2.00 equiv) was added and the reaction was stirred for 1 hour. The reaction was then quenched with brine, transferred to a separatory funnel, and extracted with ethyl acetate (3x). The combined organics were dried over MgSO4 and concentrated under reduced pressure. Flash chromatography (90:10 dichloromethane/ methanol) afforded a 2.54:1 mixture of (+)-eburnamine (+)-26a and (–)-isoeburnamine (–)26b as a yellow powder (62.1 mg, 0.209 mmol, 96% yield). All spectra for (+)-26a and (–)-26b were found to be in good accordance with literature values.42 (–)-26a and (+)-26b were prepared in the same manner as their enantiomers. All data for them was found to be in good accordance with their enantiomeric counterpart. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers ClO4 N H MeO2C N KOAc 23 ºC, 3 h Me then Pd/C (10 mol%), H2 23 ºC, 3.5 h (+)-240 H N 74% yield, >20:1 d.r. 118 N O Me (+)-epi-eburnamonine (+)-295 (+)-epi-Eburnamonine (+)-295: To a 50 mL round-bottom flask with a stir bar was added iminium salt (+)-240 (127.5 mg, 0.30 mmol, 1.00 equiv) and ethanol (15 mL). Potassium acetate (88 mg, 0.90 mmol, 3.00 equiv) was added and the reaction was stirred at 23 ºC for 3 hours. Pd/C (10%, 67% w/w H2O) (64 mg, 0.01 mmol, 0.20 equiv) was added at the reaction mixture was backfilled with H2 (5x), then equipped with a balloon containing H2. The mixture was stirred at 23 ºC for 3 hours. The reaction was vented with N2 and partially concentrated, then diluted with ethyl acetate, washed with brine, dried over Na2SO4, then concentrated. Flash chromatography (90:10 dichloromethane/ ethyl acetate) afforded (+)epi-eburnamonine (+)-295 as a light-yellow solid (65.5 mg, 0.222 mmol, 74% yield). All spectra for (+)-295 were found to be in good accordance with literature values.29 (–)-295 was prepared in the same manner as (+)-295. All data for it was found to be in good accordance with its enantiomeric counterpart. 119 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N THF, 23 ºC, 1 h O Me (+)-epi-eburnamonine (+)-295 H LiAlH4 93% yield N H N HO N N HO Me (–)-epi-eburnamine (–)-296a Me (+)-epi-isoeburnamine (+)-296b (–)-epi-eburnamine (–)-296: To an oven-dried 2-dram vial with a stir bar was added (+)epi-eburnamonine (+)-295 (58.8 mg, 0.20 mmol, 1.00 equiv). The vial was sealed with a septa and backfilled with N2 (3x) before adding THF (2.0 mL) and cooling the vial to 0 ºC. LiAlH4 (15.0 mg, 0.40 mmol, 2.00 equiv) was added and the reaction was stirred for 1 hour. The reaction was then quenched with brine, transferred to a separatory funnel, and extracted with ethyl acetate (3x). The combined organics were dried over MgSO4 and concentrated under reduced pressure. Flash chromatography (80:20 à 1:1 hexanes/ ethyl acetate) afforded a 2:1 mixture of (–)-epi-eburnamine (–)-296a and (+)-epi-isoeburnamine (+)-296b as a light-yellow powder (54.9 mg, 0.186 mmol, 93% yield). All spectra for (–)296a and (+)-296b were found to be in good accordance with literature values.73 (+)-296a and (–)-296b were prepared in the same manner as their enantiomers. All data for them was found to be in good accordance with their enantiomeric counterpart. (–)-epi-eburnamine (–)-296a and (+)-epi-isoeburnamine (+)-296b: 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.62 (m, 1H), 7.46 (ddt, J = 8.5, 6.9, 2.5 Hz, 5H), 7.22 – 7.07 (m, 6H), 5.98 (dd, J = 7.4, 5.0 Hz, 2H), 5.62 (ddd, J = 10.6, 9.2, 5.7 Hz, 1H), 3.19 – 3.01 (m, 6H), 2.98 (s, 1H), 2.93 (ddt, J = 12.4, 6.4, 3.5 Hz, 4H), 2.86 (s, 2H), 2.77 – 2.64 (m, 3H), 2.58 – 2.40 (m, 6H), 2.40 – 2.29 (m, 3H), 2.29 – 2.17 (m, 3H), 2.04 – 1.70 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 120 (m, 8H), 1.44 (dd, J = 13.8, 9.2 Hz, 2H), 1.29 – 1.12 (m, 2H), 1.06 (td, J = 12.9, 4.3 Hz, 5H), 0.88 (t, J = 7.5 Hz, 6H), 0.77 (t, J = 7.6 Hz, 3H). (–)-epi-eburnamine (–)-296a: 13 C NMR (100 MHz, CDCl3) δ 135.5, 132.4, 128.5, 121.0, 120.1, 118.5, 110.7, 106.0, 75.7, 67.8, 56.2, 53.7, 39.7, 35.5, 32.3, 21.3, 21.1, 20.8, 7.5. (+)-epi-isoeburnamine (+)-296b: 13 C NMR (100 MHz, CDCl3) δ 137.9, 134.3, 128.7, 121.3, 120.3, 118.3, 111.8, 106.7, 75.7, 67.6, 55.9, 52.9, 43.3, 38.1, 31.9, 21.6, 21.5, 19.6, 7.6. 2:1 mixture of (+)-epi-eburnamine (–)-296a and (–)-epi-isoeburnamine (+)-296b: [α]D21 17.5º (c 0.38, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C19H25N2O [M+H]+: 297.1967, found 297.1969. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N LiHMDS HMPA PhNTf2 THF, –78 ºC, 16 h O Me H N N TfO Me 80% yield (–)-epi-eburnamonine (–)-295 121 287 Triflate 287: To an oven-dried 1-dram vial with a stir bar was added (–)-epi-eburnamonine (–)-295 (57.0 mg, 0.19 mmol, 1.00 equiv) and THF (1 mL). The vial was cooled to –78 ºC and a 1 M solution of LiHMDS (45.4 mg, 0.27 mmol, 1.4 equiv) in THF was added 1 drop every 5 seconds. The reaction was stirred for 1 hour, then HMPA (68 µL, 0.387 mmol, 2.00 equiv) was added and the reaction was stirred for 10 minutes. A 1 M solution of PhNTf2 (96.8 mg, 0.27 mmol, 1.4 equiv) in THF was added dropwise and the reaction was stirred for 16 hours and allowed to warm slowly to 23 ºC. The reaction was quenched with water, transferred to a separatory funnel, and extracted with diethyl ether (5x). The combined organics were dried over MgSO4 and concentrated under reduced pressure. Flash chromatography (100% hexanes à 80:20 hexanes/ ethyl acetate) afforded triflate 287 as a white powder (64.9 mg, 0.152 mmol, 80% yield).29 1 H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.2, 0.9 Hz, 1H), 7.55 – 7.43 (m, 1H), 7.25 – 7.06 (m, 2H), 5.12 (s, 1H), 3.17 (t, J = 2.6 Hz, 1H), 3.13 – 2.99 (m, 2H), 2.99 – 2.88 (m, 1H), 2.71 – 2.52 (m, 2H), 2.35 (ddd, J = 12.1, 10.8, 3.4 Hz, 1H), 2.02 – 1.81 (m, 3H), 1.75 – 1.57 (m, 2H), 1.57 – 1.43 (m, 1H), 0.85 (dddd, J = 15.5, 8.1, 6.4, 1.4 Hz, 1H), 0.72 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 138.6, 134.4, 133.2, 129.2, 123.0, 121.6, 118.9, 118.7 (q, J = 321.3 Hz) 112.1, 111.0, 106.9, 64.7, 55.3, 52.6, 40.3, 30.7, 23.4, 21.7, 21.6, 8.2. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 122 IR (Neat Film, NaCl) 3348, 2940, 2796, 2740, 1666, 1635, 1455, 1434, 1220, 1138, 1086, 842, 739 cm–1. [α]D21 –16.9º (c 0.61, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C20H22F3N2O3S [M+H]+: 427.1303, found 427.1312. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers succinic anhydride Et3N DMAP Br N H CH2Cl2, 40 ºC, 16 h Br N OH O O 76% yield 291 123 325 Acid 325: To a 1 L round-bottom flask with a stir bar equipped with a reflux condenser was added 5-bromoindole (29.41 g, 150.0 mmol, 1.00 equiv) and dichloromethane (300 mL). Succinic anhydride (22.52 g, 225.0 mmol, 1.50 equiv) and DMAP (1.83 g, 15.0 mmol, 0.10 equiv) were added followed by triethyl amine (62 mL, 450.0 mmol, 3.00 equiv). The reaction mixture was heated to reflux, at which the reaction turned homogenous, under N2 for 16 hours. The reaction was cooled to 23 ºC and the solvent was removed under reduced pressure. The brown residue was suspended in ethyl acetate and 1 M HCl (aq.) was added until the pH=1. The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3x). The combined organics were washed with sat. NH4Cl (aq.), dried over Na2SO4, then concentrated to give a tan powder. The tan powder was then washed with diethyl ether to give acid 325 as an off-white solid (33.57 g, 114.0 mmol, 76% yield).74 1 H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 3.8 Hz, 1H), 7.45 (dd, J = 8.9, 2.1 Hz, 1H), 6.61 (d, J = 3.8 Hz, 1H), 3.27 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 176.0, 169.7, 134.5, 132.2, 128.3, 125.4, 123.8, 118.1, 117.3, 109.0, 30.5, 28.1. IR (Neat Film, NaCl) 3116, 1701, 1447, 1389, 1313, 1200, 916, 819 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C12H11BrNO3 [M+H]+: 295.9922, found 295.9913. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers (COCl)2, DMF CH2Cl2, 0 ºC —> 23 ºC Br N OH O O 325 then AlCl3 reflux, 16 h 124 Br N O O 93% yield 326 Bromoketone 326: To a 1 L round-bottom flask with a stir bar equipped with a reflux condenser was added acid 325 (24.53 g, 82.80 mmol, 1.00 equiv) and dichloromethane (330 mL). The suspension was cooled to 0 ºC and oxalyl chloride (8.53 mL, 99.40 mmol, 1.2 equiv) was added, followed by DMF (10 drops). The reaction was stirred at 0 ºC for 1 hour, then warmed to 23 ºC and stirred for 16 hours, at which the suspension became homogenous. The reaction was cooled to 0 ºC and aluminum trichloride (27.61 g, 207.10 mmol, 2.5 equiv) was added in portions over 5 minutes. The reaction was then heated to reflux for 16 hours. The reaction was cooled and carefully filtered, and the precipitate was washed with dichloromethane. The mother liquor was washed with 1 M HCl (aq.), then dried with brine and concentrated to give bromoketone 326 as a tan crystalline powder (21.68g, 77.00 mmol, 93% yield).74 1 H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.9, 1.9 Hz, 1H), 7.34 (s, 1H), 3.20 (t, J = 7.1 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 187.5, 167.2, 134.7, 134.6, 132.2, 130.0, 125.9, 118.7, 118.4, 112.2, 36.0, 32.4. IR (Neat Film, NaCl) 3116, 1718, 1685, 1546, 1362, 1314, 1181, 1151, 811, 739 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C12H9BrNO2 [M+H]+: 277.9817, found 277.9810. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Br NaBH4 N O 326 Br O THF, 0 ºC —> 40 ºC, 6h 97% yield 125 OH N O 327 Bromo Alcohol 327: To a 2 L round-bottom flask with a stir bar equipped with a reflux condenser was added bromoketone 326 (27.81 g, 100.0 mmol, 1.00 equiv) and THF (1000 mL). The flask was cooled to 0 ºC and finely ground NaBH4 (4.16 g, 110.0 mmol, 1.10 equiv) was added in portions over 5 minutes. The reaction was then warmed to 40 ºC and stirred for 6 hours. Upon consumption of the starting material, the reaction was cooled to 0 ºC and carefully quenched with sat. NH4Cl (aq.). The reaction was partially concentrated to remove most of the THF, then transferred to a separatory funnel and extracted with ethyl acetate (3x), the combined organics washed with brine, dried over Na2SO4, then concentrated to give bromo alcohol 327 as a tan powder (27.12 g, 97.0 mmol, 97% yield) which was carried on to the next step without further purification.50 1 H NMR (400 MHz, CDCl3) δ 8.31 (dt, J = 8.7, 0.7 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.7, 2.0 Hz, 1H), 6.53 (t, J = 0.9 Hz, 1H), 5.10 (t, J = 4.7 Hz, 1H), 3.45 – 2.95 (m, 1H), 2.73 (dt, J = 17.6, 5.3 Hz, 1H), 2.33 – 2.21 (m, 2H) 2.13 (bs, 1H). 13 C NMR (100 MHz, CDCl3) δ 168.9, 141.1, 133.8, 131.0, 128.3, 123.5, 118.1, 117.6, 105.7, 62.5, 29.8, 29.6. IR (Neat Film, NaCl) 3407, 2954, 2934, 2249, 1708, 1594, 1448, 1371, 1175, 1012, 904, 809, 731 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C12H11BrNO2 [M+H]+: 279.9973, found 279.9968. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Et3SiH TFA Br N OH Br THF, 0 ºC —> 23 ºC, 4 h O 327 60% yield 126 N O 328 Acyl Indole 328: To a 1 L round-bottom flask with a stir bar was added bromo alcohol 327 (15.82 g, 56.48 mmol, 1.00 equiv) and dichloromethane (560 mL). The flask was cooled to 0 ºC before adding triethylsilane (27.1 mL, 169.44 mmol, 3.00 equiv), followed by trifluoroacetic acid (25.9 mL, 338.85 mmol, 6.00 equiv). The reaction was warmed to 23 ºC and stirred for 4 hours. The reaction was then cooled to 0 ºC and quenched with sat. NaHCO3 (aq.). The reaction was transferred to a separatory funnel and extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (80:20 à 70:30 à 60:40 hexanes/ diethyl ether) afforded acyl indole 328 as a white solid (9.023 g, 33.89 mmol, 60% yield).50 1 H NMR (500 MHz, CDCl3) δ 8.30 (dd, J = 8.7, 2.2 Hz, 1H), 7.58 (t, J = 2.2 Hz, 1H), 7.36 (dt, J = 8.7, 1.8 Hz, 1H), 6.37 – 6.17 (m, 1H), 3.32 – 2.91 (m, 2H), 2.80 (td, J = 5.9, 2.0 Hz, 2H), 2.11 (pd, J = 5.9, 1.7 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 169.4, 139.6, 133.7, 131.7, 126.9, 122.6, 117.8, 117.3, 104.2, 34.5, 23.9, 21.5. IR (Neat Film, NaCl) 3108, 2954, 1712, 1595, 1447, 1368, 1357, 1174, 1006, 800 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C12H11BrNO [M+H]+: 264.0024, found 264.0016. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Br N O 1) allylcyano formate LiHMDS THF, –78 ºC —> 0 ºC, 4 h 2) EtI, Cs2CO3 CH2Cl2, 23 ºC, 16 h 68% yield (2 steps) 328 127 Br N Me O O O (±)-329 Bromoindole (±)-329: In a nitrogen-filled glovebox, LiHMDS (3.34 g, 20.00 mmol, 2.00 equiv) and THF (51 mL) were added to an oven-dried 250 mL round-bottom flask with a stir bar. The flask was sealed and removed from the glovebox, then cooled to –78 ºC. A solution of acyl indole 328 (2.64 g, 10.00 mmol, 1.00 equiv) in THF (15 mL) was added dropwise. The reaction was stirred for 30 minutes then allyl cyanoformate (1.33 g, 12.00 mmol, 1.2 equiv) was added dropwise. The reaction was then warmed to 0 ºC over 4 hours. The reaction was then quenched with sat. NH4Cl (aq.) and stirred for 30 minutes. The reaction mixture was partially concentrated, then transferred to a separatory funnel and extracted with ethyl acetate (3x), dried over Na2SO4, then concentrated. The crude was carried on to the next step without further purification. To an oven-dried 250 mL round-bottom flask with a stir bar was added the crude reaction product (3.48 g, 10.00 mmol, 1.00 equiv) and dichloromethane (67 mL). Cs2CO3 (13.03 g, 40.00 mmol, 4.00 equiv) was added and the reaction was stirred for 10 minutes. EtI (4.82 mL, 60.00 mmol, 6.00 equiv) was added slowly and the reaction was stirred for 18 hours. The reaction was quenched with Sat. NH4Cl (aq.) and transferred to a separatory funnel, extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (80:20 hexanes/ ethyl acetate) afforded bromoindole (±)-329 as a clear oil (2.55 g, 6.80 mmol, 68% yield).50 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 1 128 H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 6.25 (d, J = 1.0 Hz, 1H), 5.84 (ddt, J = 17.3, 10.5, 5.5 Hz, 1H), 5.46 – 5.15 (m, 2H), 4.65 (dt, J = 5.5, 1.3 Hz, 2H), 3.12 – 2.84 (m, 2H), 2.48 (dt, J = 13.4, 4.5 Hz, 1H), 2.30 – 2.03 (m, 3H), 1.05 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.1, 167.9, 138.7, 134.0, 132.0, 131.3, 127.1, 122.6, 118.9, 118.1, 117.6, 104.4, 66.3, 56.7, 29.2, 28.2, 20.8, 9.4. IR (Neat Film, NaCl) 2926, 2801, 1614, 1520, 1455, 1348, 1134, 907, 814, 743, 729 cm– 1 . HRMS (MM:ESI-APCI+) m/z calculated for C18H19BrNO3 [M+H]+: 376.0548, found 376.0553. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Br 129 Br Pd2(pmdba)3 (5 mol%) (S)-(CF3)3-tBu-PHOX (12.5 mol%) N Me O O O (±)-329 MTBE, 60 ºC, 24 h N O Me 97% yield, 92% ee (–)-290 Allylindole (–)-290: In a nitrogen-filled glovebox, Pd(pmdba)3 (164 mg, 0.015 mmol, 0.05 equiv) and (S)–(CF3)3-t-Bu-PHOX (444 mg, 0.750 mmol, 0.125 equiv) were added to an oven-dried 50 mL round-bottom flask with a stir bar. MTBE (20 mL) was added, and the flask was heated to 40 ºC for 1 hour. In a separate flame-dried 500 mL Schlenk flask under nitrogen atmosphere was added bromoindole (±)-329 (2.258 g, 6.00 mmol, 1.00 equiv) and MTBE (162 mL). The contents of the flask were then transferred to the Schlenk flask containing bromoindole (±)-329. The Schlenk flask was sealed and removed from the glovebox before heated to 60 ºC in an oil bath. After about 15 minutes the solution changed from deep purple to olive green and remained green over the course of the reaction. After 16 hours the reaction was cooled to 23 ºC and crude was concentrated onto SiO2, loaded on a column, and purified by flash chromatography (100% hexanes à 99:1 à 98:2 à 97:3 à 96:4 hexanes/ diethyl ether to give allylindole (–)-290 as a clear oil (1.933 g, 5.82 mmol, 97% yield, 92% ee). 1 H NMR (500 MHz, CDCl3) δ 8.34 (d, J = 8.7 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.8, 2.1 Hz, 1H), 6.23 (s, 1H), 5.91 – 5.70 (m, 1H), 5.32 – 5.08 (m, 2H), 3.16 – 2.97 (m, 2H), 2.63 (dd, J = 14.0, 6.8 Hz, 1H), 2.41 (dd, J = 13.4, 7.2 Hz, 1H), 2.02 (hept, J = 7.6 Hz, 2H), 1.87 (dq, J = 14.9, 7.4 Hz, 1H), 1.76 (dq, J = 14.6, 7.6 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 130 C NMR (100 MHz, CDCl3) δ 173.7, 139.2, 134.0, 133.5, 132.0, 126.7, 122.5, 119.0, 118.0, 117.2, 103.8, 46.7, 40.0, 28.8, 28.5, 19.8, 8.5. IR (Neat Film, NaCl) 3075, 2924, 1704, 1594, 1443, 1369, 1353, 1307, 1185, 1012, 895, 808 cm–1. [α]D21 –50.9º (c 0.41, CHCl3). SFC conditions: 3% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 280 nm, tR (min): major = 9.949, minor = 9.361. HRMS (MM:ESI-APCI+) m/z calculated for C17H19BrNO [M+H]+: 376.0548 found 376.0553. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Cp2Zr(H)Cl H2NOSO3H THF, 23 º C, 1h Br 131 NH Br N O (–)-290 Me then LiAlH4; AcOH, H2O THF, 0 ºC —> 23 ºC, 16 h 53% yield Me N H (–)-306 Tetracycle (–)-306: In a nitrogen-filled glovebox, allylindole (–)-290 (1.935 g, 5.82 mmol, 1.00 equiv) and THF (30 mL) were added to an oven-dried 250 mL round-bottom flask with a stir bar. Cp2Zr(H)Cl (2.103 g, 8.15 mmol, 1.40 equiv) was added in a single portion. The reaction was stirred at 23 ºC for 1 hour, at which the slurry turned yellow and became homogeneous. H2NOSO3H (988 mg, 8.73 mmol, 1.50 equiv) was added and the reaction was stirred for 10 minutes before sealing with a septa and removing from the glovebox. The reaction was cooled to 0 ºC, then LiAlH4 (1 M in THF) (17.47 mL, 17.46 mmol, 3.00 equiv) was added dropwise and the reaction was stirred for 15 minutes. The reaction was then carefully quenched with water (46 mL) and AcOH (145 mL), allowed to warm to 23 ºC, and stirred for 16 hours. The reaction was transferred to a 1 L round-bottom flask and cooled to 0 ºC. 2 M NaOH (aq.) was added until the reaction pH = >12 and then extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (100% ethyl acetate à 95:5 ethyl acetate/triethylamine) afforded tetracycle (–)-306 as a tan foam (1.026 g, 3.08 mmol, 53% yield).51 1 H NMR (400 MHz, CDCl3) δ 7.94 (bs, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.63 (s, 1H), 3.01 (d, J = 12.3 Hz, 1H), 2.91 – 2.61 (m, 3H), 2.32 (dt, J = 13.6, 9.4 Hz, 1H), 1.80 (dtd, J = 13.2, 3.7, 1.5 Hz, 1H), 1.69 – 1.51 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 132 (m, 3H), 1.45 (ddd, J = 15.3, 10.4, 6.1 Hz, 2H), 1.21 – 1.02 (m, 1H), 0.84 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 135.8, 134.9, 129.4, 123.8, 120.4, 112.7, 112.3, 112., 56.6, 46.3, 34.6, 34.1, 29.6, 24.2, 22.9, 20.3, 7.7. IR (Neat Film, NaCl) 3411, 3150, 2930, 2857, 1578, 1450, 1309, 1048, 865, 792, 737, 678 cm–1. [α]D22 –72.5º (c 1.12, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C17H22BrN2 [M+H]+: 333.0966, found 333.0964. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers NH Br 133 O 1) Chloroacetyl chloride Et3N, CH2Cl2, 0 ºC, 2 h 2) NaI, acetone, reflux, 2 h N Br 3) AgOTf, THF, 23 ºC, 1 h Me N H Me N 83% yield (3 steps) (–)-306 (–)-307 Imine (–)-307: To an oven-dried 25 mL round-bottom flask with a stir bar was added tetracycle (–)-306 (82 mg, 0.246 mmol, 1.00 equiv) and dichloromethane (5 mL). The flask was cooled to 0 ºC and triethylamine (51 µL, 0.369 mmol, 1.50 equiv) was added, followed by chloroacetyl chloride (20 µL, 0.246 mmol, 1.00 equiv) dropwise. The reaction was stirred for 2 hours then quenched with water, transferred to a separatory funnel, extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. The crude was carried onto the next step without further purification. The crude acylated product was added to a 25 mL round-bottom flask with a stir bar equipped with a reflux condenser followed by the addition of acetone (5 mL). NaI (369 mg, 2.46 mmol, 10.00 equiv) was added and the flask was wrapped in aluminum foil to block out light and the reaction was heated to reflux for 2 hours. The reaction was cooled to 23 ºC and quenched with water. The reaction was transferred to a separatory funnel, extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. The crude was carried onto the next step without further purification. The crude iodide product was added to a 25 mL round-bottom flask with a stir bar and dissolved in THF (5 mL). AgOTf (126 mg, 0.492 mmol, 2.00 equiv) was added and the reaction was stirred for 30 minutes. The reaction was diluted with dichloromethane, filtered through a cotton plug with dichloromethane, then transferred to a separatory funnel. The organics were washed with brine, dried over Na2SO4, then concentrated. Flash Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 134 chromatography (80:20 dichloromethane/ acetone) afforded imine (–)-307 as a white foam (76 mg, 0.204 mmol, 83% yield). 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.43 (m, 2H), 7.41 (d, J = 8.9 Hz, 1H), 4.32 (dt, J = 13.0, 2.2 Hz, 1H), 3.60 (d, J = 2.2 Hz, 1H), 3.04 – 2.88 (m, 2H), 2.82 – 2.67 (m, 2H), 2.61 – 2.47 (m, 1H), 2.26 – 2.08 (m, 1H), 1.91 – 1.75 (m, 1H), 1.74 – 1.49 (m, 4H), 1.43 – 1.27 (m, 1H), 1.14 – 0.92 (m, 1H), 0.74 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 187.9, 169.9, 147.4, 131.8, 124.6, 121.8, 120.0, 70.1, 54.4, 41.0, 38.6, 37.1, 34.0, 29.4, 24.6, 22.9, 20.3, 7.2. IR (Neat Film, NaCl) 2940, 2868, 1691, 1580, 1462, 1443, 1296, 1254, 1064, 822, 758, 747 cm–1. [α]D21 +38.5º (c 2.31, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C19H22BrN2O [M+H]+: 373.0916, found 337.0908. 135 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O O N Br Me N (–)-307 Pd(dppf)Cl2 (10 mol%) B2Pin2 KOAc THF, reflux, 16 h 66% yield Me N Me Me O Me B Me O N (–)-289 Boryl Imine (–)-289: To an oven-dried 25 mL round-bottom flask equipped with a reflux condenser was added imine (–)-307 (373 mg, 1.00 mmol, 1.00 equiv) and THF (4 mL). B2Pin2 (381 mg, 1.50 mmol, 1.50 equiv), KOAc (294 mg, 3.00 mmol, 3.00 equiv), and Pd(dppf)Cl2 (73 mg, 0.10 mmol, 0.10 equiv) were then added. The reaction mixture was heated to reflux for 16 hours. The reaction was cooled, filtered through Celite® and concentrated. Flash chromatography (98:2 ethyl acetate/triethylamine) afforded boryl imine (–)-289 as a white foam (279 mg, 0.664 mmol, 66% yield). 1 H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.7, 1.1 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 4.41 – 4.28 (m, 1H), 3.65 (d, J = 2.2 Hz, 1H), 3.03 – 2.90 (m, 1H), 2.81 – 2.71 (m, 2H), 2.61 – 2.47 (m, 1H), 2.17 (dt, J = 14.9, 10.0 Hz, 1H), 2.13 – 1.93 (m,1), 1.86 – 1.75 (m, 1H), 1.70 – 1.46 (m, 4H), 1.35 (s, J = 2.3 Hz, 12H), 1.31 (m, 1H) 0.72 (t, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 188.6, 170.4, 157.3, 145.1, 135.8*, 127.1, 120.0, 84.1, 70.1, 53.9, 40.9, 38.8, 37.0, 34.1, 29.4, 25.1, 25.0, 24.9, 24.8, 22.9, 20.4, 7.2. Overlapping carbon at 135.8 ppm (assigned by 1H–13C HMBC). IR (Neat Film, NaCl) 3367, 2976, 2939, 1692, 1579, 1426, 1354, 1291, 1144, 755 cm–1. [α]D21 +50.4º (c 1.31, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C25H34BN2O3 [M+H]+: 421.2662, found 421.2665. 136 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O Me N O B Me N (–)-289 Me H Me O N Me O N TfO Me 241 Pd(PPh3)4 (10 mol%) K2CO3 PhMe/H2O/EtOH 90 ºC, 16 h 88% yield H N N N Me Me N 330 (R,R)-Dimer 330: In a nitrogen-filled glovebox, boryl imine (–)-289 (11.3 mg, 0.0269 mmol, 1.10 equiv), triflate 241 (10.4 mg, 0.0249 mmol, 1.00 equiv), K2CO3 (10.1 mg, 0.0732 mmol, 3.00 equiv), and Pd(PPh3)4 (2.8 mg, 0.0025 mmol, 0.10 equiv) were added to an oven-dried 1-dram vial with a stir bar. The vial was sealed with a septum cap and removed from the glovebox. Toluene (0.2 mL), water (0.2 mL), and EtOH (50 µL) were added via syringe, and the vial was heated to 90 ºC for 16 hours. The reaction was cooled to 23 ºC, diluted with ethyl acetate, and washed with water, then dried over Na2SO4, and concentrated. Flash chromatography (95:5 ethyl acetate/ triethylamine) afforded (R,R)dimer 330 as an inseparable mixture of atropisomers (~4:1) as a tan foam (12.1 mg, 0.0214 mmol, 88% yield). Note: This compound showed atropisomers in 1H NMR in CDCl3. The mixture of atropisomers could be resolved in 1H NMR at –40 ºC. 1 H NMR (400 MHz, CDCl3, –40ºC) δ 7.68 – 7.54 (m, 2H), 7.54 – 7.38 (m, 6H), 7.10 – 6.96 (m, 2H), 6.86 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 6.79 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 6.22 (d, J = 8.5 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), 5.72 (s, 1H), 5.19 (s, 1H), 5.11 (s, 1H), 4.37 (s, 2H), 4.34 (s, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.71 (d, J = 1.9 Hz, 1H), 3.44 (d, J = 1.9 Hz, 4H), 3.27 (qd, J = 7.3, 5.5 Hz, 3H), 3.14 – 3.01 (m, 3H), 3.01 – 2.88 (m, 4H), 2.82 – Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 137 2.56 (m, 8H), 2.49 (d, J = 17.1 Hz, 2H), 2.26 – 2.10 (m, 3H), 1.97 – 1.84 (m, 8H), 1.79 (d, J = 13.8 Hz, 12H), 1.68 – 1.42 (m, 11H), 1.25 – 1.08 (m, 11H), 1.00 (dt, J = 10.4, 7.4 Hz, 6H), 0.88 – 0.71 (m, 6H). 13 C NMR (100 MHz, CDCl3, –40 ºC) δ 188.5, 188.2, 170.4, 169.9, 154.6, 154.5, 146.0, 144.9, 135.9, 135.5, 133.8 133.5, 133.3, 133.0, 132.2, 132.0, 132.0, 129.2, 128.7, 128.6, 121.8, 120.8, 120.4, 119.7, 119.6, 118.4, 118.3, 112.9, 112.8, 107.7, 70.3, 69.7, 56.3, 54.0, 53.6, 51.3, 51.3, 44.8, 41.0, 40.5, 38.8, 38.3, 37.1, 37.0, 36.8, 36.6, 34.5, 33.9, 33.5, 29.9, 29.6, 27.5, 27.4, 24.7, 24.5, 23.7, 22.4, 22.0, 20.3, 20.1, 19.9, 16.3, 14.9, 14.1, 9.1, 8.9, 7.5, 7.3. IR (Neat Film, NaCl) 3319, 2933, 1693, 1681, 1453, 1416, 1301, 1114, 748 cm–1. [α]D20 +39.9º (c 0.75, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H43N4O [M+H]+: 571.3437, found 571.3435. 138 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O Me N O B Me N (–)-289 Me H Me O N Me O N TfO Me 287 Pd(PPh3)4 (10 mol%) K2CO3 PhMe/H2O/EtOH 90 ºC, 16 h H N N N Me Me 82% yield N 308 (S,R)-Dimer 308: In a nitrogen-filled glovebox, boryl imine (–)-289 (200.0 mg, 0.476 mmol, 1.10 equiv), triflate 287 (184.0 mg, 0.431 mmol, 1.00 equiv), K2CO3 (180 mg, 1.30 mmol, 3.00 equiv), and Pd(PPh3)4 (50.0 mg, 0.0431 mmol, 0.10 equiv) were added to an oven-dried 2-dram vial with a stir bar. The vial was sealed with a septum cap and removed from the glovebox. Toluene (2.5 mL), water (2.5 mL), and EtOH (0.75 mL) were added via syringe, and the vial was heated to 90 ºC for 16 hours. The reaction was cooled to 23 ºC, diluted with ethyl acetate, and washed with water, then dried over Na2SO4, and concentrated. Flash chromatography (95:5 ethyl acetate/ triethylamine) afforded (S,R)dimer 308 as a tan foam (202.0 mg, 0.354 mmol, 82% yield). 1 H NMR (400 MHz, acetone-d6) δ 7.56 (d, J = 6.9 Hz, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.12 – 6.87 (m, 1H), 6.81 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.38 (s, 1H), 4.06 (d, J = 12.8 Hz, 1H), 3.73 (s, 1H), 3.25 – 3.07 (m, 3H), 3.07 – 2.99 (m, 1H), 2.99 – 2.76 (m, 5H), 2.76 – 2.54 (m, 3H), 2.42 – 2.29 (m, 2H), 2.29 – 2.14 (m, 1H), 2.03 – 1.84 (m, 3H), 1.79 (d, J = 13.6 Hz, 1H), 1.68 – 1.35 (m, 6H), 1.08 (dq, J = 14.6, 7.3 Hz, 1H), 0.93 – 0.84 (m, 3H), 0.82 – 0.68 (m, 6H). 13 C NMR (100 MHz, acetone) δ 188.4, 168.9, 155.8, 136.6, 135.1, 134.4, 133.1, 129.1, 128.0, 121.2, 120.7, 119.9, 119.7, 118.2, 112.3, 108.3, 69.1, 65.4, 55.1, 54.1, 52.3, 39.9, 38.1, 37.8, 36.7, 33.6, 30.6, 24.2, 23.2, 21.6, 21.4, 19.9, 7.7, 6.5. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 139 IR (Neat Film, NaCl) 3345, 2931, 2856, 2794, 1692, 1579, 1437, 1374, 1276, 1119, 755 cm–1. [α]D20 +181.6º (c 0.34, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H43N4O [M+H]+: 571.3437, found 571.3442. 140 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N H N Bpin N Me TfO Me 287 H N Ph N Pd(PPh3)4 (10 mol%) K2CO3 PhMe/H2O/EtOH 90 ºC 93% yield Me N H N Me N Ph (+)-301 302 (S,R)-Dimer 302: In a nitrogen-filled glovebox, boronic ester (+)-301 (10.0 mg, 0.0201 mmol, 1.0 equiv), triflate 287 (10.0 mg, 0.0234 mmol, 1.17 equiv), K2CO3 (8.4 mg, 0.0602 mmol, 3.0 equiv), and Pd(PPh3)4 (2.4 mg, 0.0021 mmol, 0.10 equiv) were added to an oven-dried 1-dram vial with a stir bar. The vial was sealed with a septum cap and removed from the glovebox. Toluene (0.2 mL), water (0.2 mL), and EtOH (0.050 mL) were added via syringe, and the vial was heated to 90 ºC for 16 hours. The reaction was cooled to 23 ºC, diluted with ethyl acetate, and washed with water, then dried over Na2SO4, and concentrated. Flash chromatography (80:20 to 50:50 hexanes/ ethyl acetate) afforded (S,R)dimer 302 as a yellow oil (12.1 mg, 0.0186 mmol, 93% yield). Note: This compound displayed atropisomers in 1H NMR in CDCl3 at 23 °C. 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.6 Hz, 1H), 7.43 – 7.32 (m, 5H), 7.29 (d, J = 7.1 Hz, 1H), 7.08 – 6.98 (m, 2H), 6.87 (t, J = 8.1 Hz, 1H), 6.45 (bs, 1H), 6.43 – 6.35 (m, 1H), 5.09 (s, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 3.51 – 3.42 (m, 1H), 3.25 (s, 1H), 3.18 – 2.91 (m, 5H), 2.77 – 2.62 (m, 2H), 2.46 – 2.32 (m, 2H), 2.23 – 2.07 (m, 2H), 2.06 – 1.92 (m, 2H), 1.90 – 1.72 (m, 4H), 1.69 – 1.59 (m, 4H), 1.52 – 1.42 (m, Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 141 5H), 1.19 – 0.99 (m, 2H), 0.96 – 0.91 (m, 1H), 0.79 (t, J = 7.5 Hz, 3H), 0.64 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 150.5, 138.4, 137.3, 135.3, 134.7, 128.9, 128.7, 128.6, 128.0, 127.9, 127.3, 125.0, 122.9, 120.7, 119.6, 118.1, 117.0, 113.2, 107.9, 106.2, 66.0, 55.7, 53.7, 52.9, 52.4, 48.4, 37.8, 35.7, 34.8, 34.4, 31.7, 31.0, 30.2, 29.8, 29.4, 25.4, 23.2, 22.8, 22.0, 21.8, 14.3, 8.6, 6.9. IR (Neat Film, NaCl) 3027, 2931, 2855, 2788, 1704, 1652, 1608, 1487, 1453, 1371, 1333, 1277, 1182, 1151, 908, 735, 698 cm–1. [α]D22 +58.3º (c 1.0, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C45H53N4 [M+H]+: 649.4265, found 649.4286. 142 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O H N N H N N N LiAlH4 N THF, 23 ºC —> reflux, 3 h Me Me N 78% yield 330 Me Me N H H 331 (R,R)-Indoline 331: To an oven-dried 1-dram vial with a stir bar was added (R,R)-dimer 330 (6.8 mg, 0.0119 mmol, 1.00 equiv) and THF (2.5 mL). A 1 M solution of LiAlH4 (47 µL, 0.0477 mmol, 4.00 equiv) was added and the reaction was stirred for 15 minutes. The reaction was then heated to reflux for 2.5 hours. The reaction was cooled to 0 ºC and carefully quenched with 1 M NaOH (aq.), transferred to a separatory funnel, and extracted with ethyl acetate (3x). The combined organics were dried over Na2SO4, and concentrated. Preparative TLC (95:5 ethyl acetate/ triethylamine) afforded (R,R)-indoline 331 as a yellow solid (5.1 mg, 0.0093 mmol, 78% yield). Note: This compound is unstable in CDCl3 and changes colors with prolonged exposure. This compound showed atropisomers in 1H NMR in CDCl3. The mixture of atropisomers could be resolved in 1H NMR at –40 ºC in CD2Cl2. 1 H NMR (400 MHz, CD2Cl2, –40 ºC) δ 8.99 (d, J = 7.6 Hz, 1H), 8.88 – 8.58 (b, 2H), 8.58 – 8.53 (m, 1H), 8.41 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 8.21 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 1.5 Hz, 1H), 5.81 (s, 1H), 5.22 – 5.16 (m, 1H), 5.16 – 5.04 (m, 1H), 5.00 – 4.79 (m, 2H), 4.64 (dddd, J = 17.1, 11.0, 6.2, 2.6 Hz, 2H), 4.28 – 4.19 (m, 2H), 4.17 (s, 1H), 4.14 – 4.00 (m, 1H), 3.99 – 3.36 (m, 10H), 3.36 – 3.23 (m, 3H), 3.23 – 3.10 (m, 5H), 2.98 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 143 (dt, J = 10.1, 3.1 Hz, 2H), 2.73 – 2.61 (m, 2H), 2.55 (t, J = 7.4 Hz, 3H), 2.37 – 2.05 (m, 3H). 13 C NMR (100 MHz, CD2Cl2) δ 149.6, 136.2, 136.1, 135.9, 135.8, 133.6, 128.4, 128.3, 127.2, 126.5, 125.6, 122.8, 122.5, 120.4, 118.8, 117.7, 117.5, 117.1, 113.0, 112.8, 109.2, 108.9, 107.1, 70.9, 70.3, 66.0, 56.4, 56.3, 50.7, 44.5, 39.8, 36.3, 36.2, 35.1, 33.9, 30.1, 29.4, 28.6, 28.4, 27.7, 27.5, 27.1, 21.8, 21.2, 20.1, 16.0, 8.2, 8.1, 6.7, 6.5. IR (Neat Film, NaCl) 3361, 2932, 2857, 2783, 1700, 1636, 1610, 1488, 1453, 1415,1388, 1376, 1259, 1178, 1009, 741, 684 cm–1. [α]D21 +83.3º (c 0.08, CH2Cl2). HRMS (MM:ESI-APCI+) m/z calculated for C38H47N4 [M+H]+: 559.3801, found 559.3795. 144 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers O H N N H N N N LiAlH4 N THF, 23 ºC —> reflux, 3 h Me Me N 96% yield Me Me N H H 308 303 (S,R)-Indoline 303: To an oven-dried 20 mL vial with a stir bar was added (S,R)-dimer 308 (50 mg, 0.0876 mmol, 1.00 equiv) and THF (5 mL). A 1 M solution of LiAlH4 (350 µL, 0.350 mmol, 4.00 equiv) was added and the reaction was stirred for 15 minutes. The reaction was then heated to reflux for 2.5 hours. The reaction was cooled to 0 ºC and carefully quenched with 1 M NaOH (aq.), transferred to a separatory funnel, and extracted with ethyl acetate (3x). The combined organics were dried over Na2SO4, and concentrated. Flash chromatography (95:5 ethyl acetate/ triethylamine) afforded (S,R)-indoline 303 as a yellow solid (47.2 mg, 0.00845 mmol, 96% yield). Note: This compound is very unstable in CDCl3 and changes colors with prolonged exposure. This compound showed atropisomers in 1H NMR in CDCl3. The mixture of atropisomers could be resolved in 1H NMR in acetone-d6 at 23 ºC. 1 H NMR (400 MHz, acetone-d6) δ 7.40 (dt, J = 7.9, 1.0 Hz, 1H), 7.08 (bs, 2H), 6.95 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H), 6.79 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.3 Hz, 1H), 5.12 (s, 1H), 5.03 (s, 1H), 3.51 (s, 1H), 3.15 (s, 1H), 3.13 – 2.98 (m, 3H), 2.98 – 2.87 (m, 2H), 2.76 – 2.55 (m, 4H), 2.44 – 2.24 (m, 2H), 2.23 – 2.14 (m, 2H), 2.02 – 1.77 (m, 4H), 1.80 – 1.53 (m, 5H), 1.52 – 1.33 (m, 4H), 1.04 (d, J = 13.9 Hz, 2H), 0.89 (dt, J = 14.2, 4.5 Hz, 1H), 0.80 – 0.71 (m, 3H), 0.64 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 145 C NMR (100 MHz, acetone-d6) δ 152.2, 138.4, 136.5, 136.2, 135.4, 129.9, 128.5, 126.0, 123.8, 121.3, 120.3, 118.8, 117.4, 113.6, 110.0, 108.7, 71.4, 69.7, 69.6, 66.7, 66.4, 56.0, 55.4, 55.5, 54.2, 54.1, 53.2, 39.78, 38.6, 36.6, 35.2, 32.0, 31.6, 28.7, 24.0, 23.6, 23.3, 22.6, 22.4, 22.3, 8.6, 7.0. IR (Neat Film, NaCl) 2927, 2852, 1715, 1653, 1610, 1488 1455, 1437, 1372, 1170, 1037, 739, 682 cm–1. [α]D21 +15.1º (c 0.22, CH2Cl2). HRMS (MM:ESI-APCI+) m/z calculated for C38H47N4 [M+H]+: 559.3801, found 559.3780. 146 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N N H Raney Nickel H2 (3 bar) N N MeOH, 23 ºC, 6 d Me Me N H H 331 34% yield H Me N Me N H H 321 (R,R,R)-Dimer 321: To a 1-dram with a stir bar was added (R,R)-indoline 331 (5.2 mg, 0.00928 mmol, 1.00 equiv) and MeOH (1 mL). A suspension of Raney Nickel® (50:50 w/ water) (25 mg slurry) was added and the vial was sealed with a septa cap pierced with an 18-gauge needle. The vial was then transferred to a hydrogenation vessel, and the entire vessel was backfilled with H2 (10x) before pressurizing to 3 bar. The reaction was checked every 24 hours for completion. An additional 25 mg Raney Nickel® was added each day until the reaction reached full conversion after (6 days). The H2 was carefully vented, and the contents of the reaction were transferred to a separatory funnel with 1 M NaOH (aq.), extracted with ethyl acetate (3x), dried over Na2SO4, and concentrated. Preparative TLC plate (95:5 ethyl acetate/ triethylamine) afforded (R,R,R)-dimer 321 as a clear oil (1.8 mg, 0.0032 mmol, 34% yield). Note: This compound is very unstable in CDCl3 and changes colors with prolonged exposure. This compound showed atropisomers in 1H NMR in CDCl3 that could not be resolved by heating or cooling. The mixture of atropisomers could be resolved in 1H NMR in C6D6 at 23 °C. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 1 147 H NMR (400 MHz, C6D6) δ 7.76 (d, J = 7.8 Hz, 1H), 7.34 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.19 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 6.43 (d, J = 7.8 Hz, 2H), 5.40 (d, J = 7.4 Hz, 1H), 3.90 (s, 1H), 3.46 (dd, J = 10.6, 6.5 Hz, 1H), 3.41 – 3.26 (m, 3H), 3.09 (dt, J = 15.6, 8.3 Hz, 1H), 2.94 (dd, J = 9.1, 5.2 Hz, 3H), 2.75 (d, J = 11.0 Hz, 3H), 2.56 (dd, J = 15.5, 4.9 Hz, 1H), 2.49 – 2.29 (m, 3H), 2.24 – 1.61 (m, 9H), 1.60 – 1.22 (m, 10H), 1.17 – 0.95 (m, 3H), 0.86 (t, J = 7.6 Hz, 3H), 0.75 (d, J = 6.2 Hz, 1H). 13 C NMR (100 MHz, C6D6) δ 148.6, 136.5, 135.3, 133.6, 132.5, 126.2, 122.0, 120.5, 119.4, 118.7, 112.4, 110.1, 104.8, 70.9, 65.6, 60.0, 55.1, 53.9, 53.1, 52.6, 52.2, 45.6, 41.8, 38.9, 36.0, 35.5, 34.7, 30.4, 30.0, 28., 26.3, 22.8, 22.0, 21.8, 17.6, 7.8, 7.1. IR (Neat Film, NaCl) 2929, 2853, 2779, 1704, 1613, 1488, 1457, 1266, 1169, 1097, 1013, 738, 681 cm–1. [α]D21 –26.0º (c 0.14, CH2Cl2). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3958. 148 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N N H Raney Nickel H2 (4 bar) N N MeOH, 23 ºC, 6 d H Me Me N H H 56% yield 303 Me N Me N H H 285 Novotny’s proposed strempeliopidine (S,R,R)-Dimer 285: To a 1-dram with a stir bar was added (S,R)-dimer 303 (5.0 mg, 0.00895 mmol, 1.00 equiv) and MeOH (1 mL). A suspension of Raney Nickel® (50:50 w/ water) (100 mg slurry) was added and the vial was sealed with a septa cap pierced with an 18-gauge needle. The vial was then transferred to a hydrogenation vessel, and the entire vessel was backfilled with H2 (10x) before pressurizing to 4 bar. The reaction was checked every 24 hours for completion. An additional 100 mg Raney Nickel® was added after 3 days. The reaction reached full conversion after 6 days. The H2 was carefully vented, and the contents of the reaction were transferred to a separatory funnel with 1 M NaOH (aq.), extracted with ethyl acetate (3x), dried over Na2SO4, and concentrated. Preparative TLC plate (92.5:7.5 dichloromethane/ methanol) afforded (S,R,R)-dimer 285 as a clear oil as a mixture of atropisomers (2.8 mg, 0.0028 mmol, 56% yield). Note: This compound is very unstable in CDCl3 and changes colors with prolonged exposure. This compound showed atropisomers in 1H NMR in CDCl3 that could not be resolved by heating or cooling. The mixture of atropisomers could be resolved in 1H NMR at –30 ºC in acetone-d6. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 1 149 H NMR (400 MHz, acetone, –30 ºC) δ 7.44 (d, J = 7.4 Hz, 2H), 7.36 (s, 1H), 7.21 (d, J = 1.7 Hz, 1H), 7.10 – 7.05 (m, 1H), 6.99 – 6.92 (m, 2H), 6.92 – 6.83 (m, 1H), 6.75 – 6.66 (m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.11 (d, J = 8.1 Hz, 1H), 5.95 (d, J = 1.9 Hz, 1H), 5.69 – 5.60 (m, 1H), 5.60 – 5.45 (m, 2H), 4.98 – 4.77 (m, 2H), 3.15 – 2.65 (m, 13H), 2.44 – 2.12 (m, 10H), 1.99 – 1.38 (m, 17H), 1.38 – 1.19 (m, 9H), 1.13 – 0.71 (m, 6H), 0.63 (t, J = 7.5 Hz, 3H), 0.54 (t, J = 7.5 Hz, 3H), 0.08 (t, J = 7.5 Hz, 2H), 0.02 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, acetone, –31 ºC) δ 149.7, 149.5, 136.9, 136.8, 134.1, 134.1, 133.0, 132.1, 129.0, 128.3, 126.8, 125.5, 122.2, 121.2, 120.2, 119.3, 119.0, 118.3, 112.8, 112.5, 110.5, 108.3, 105.0, 104.9, 71.3, 71.1, 68.7, 68.7, 66.1, 56.7, 56.7, 55.3, 55.3, 55.1, 54.6, 54.6, 54.1, 53.9, 53.9, 53.7, 53.2, 52.6, 42.2, 41.8, 39.2, 38.9, 36.6, 36.5, 36.2, 35.9, 35.1, 34.9, 33.1, 30.6, 30.6, 28.2, 23.3, 22.5, 22.1, 21.8, 21.7, 21.4, 21.3, 20.2, 19.8, 7.2, 6.9, 6.8, 6.4. IR (Neat Film, NaCl) 2928, 2785, 1460, 1316, 1170, 759, 734 cm–1. [α]D22 –121.4º (c 0.15, CH2Cl2). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3960. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 150 Pd2(OAc)2 (1 mol%) (S)-(CF3)3-tBu-PHOX (5 mol%) N MTBE, 60 ºC, 5 d N Me O O 97% yield, 94% ee O (±)-297 O Me (+)-293 Allyl Indole (+)-293: In a nitrogen-filled glovebox, Pd(OAc)2 (21.0 mg, 0.0923 mmol, 0.01 equiv) and (S)–(CF3)3-t-Bu-PHOX (273.0 mg, 0.462 mmol, 0.05 equiv) were added to an oven-dried 500 mL Schlenk flask with a stir bar. MTBE (40 mL) was added, and the flask was heated to 40 ºC for 30 minutes. In a separate flame-dried 500 mL round-bottom flask under nitrogen atmosphere was added acylindole (±)-297 (2.746 g, 9.23 mmol, 1.00 equiv). Allyl ester (±)-297 was dissolved in 240 mL MTBE, then cannula transferred to the Schlenk flask containing the palladium catalyst. The Schlenk flask was sealed and heated to 60 ºC in an oil bath. The Schlenk flask was vented under nitrogen for 3 second after 1 hour for the first 5 hours to remove CO2, then stirred for 5 days. The reaction was cool to 23 ºC and concentrated under reduced pressure. Flash chromatography (100% hexanes à 97.5:2.5 à 95:5 à 92.5:7.5 hexanes/ diethyl ether) afforded the allyl indole (+)-293 as a colorless oil (2.287 g, 9.03 mmol, 97% yield, 94% ee). All spectra for (+)-293 were found to be in good accordance with literature values.50 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Cp2Zr(H)Cl H2NOSO3H THF, 23 º C, 1h N O Me (+)-293 then LiAlH4; AcOH, H2O THF, 0 ºC —> 23 ºC, 16h 151 NH Me 92% yield N H (+)-323 Amino Tetracycle (+)-323: In a nitrogen-filled glovebox, allyl indole (+)-293 (2.280 g, 9.00 mmol, 1.00 equiv) and THF (45 mL) were added to an oven-dried 500 mL roundbottom flask with a stir bar. Cp2Zr(H)Cl (3.223 g, 12.60 mmol, 1.40 equiv) was added in a single portion. The reaction was stirred at 23 ºC for 1 hour, at which the slurry turned yellow and became homogeneous. H2NOSO3H (1.527 g, 13.50 mmol, 1.50 equiv) was added and the reaction was stirred for 10 minutes before sealing with a septa and removing from the glovebox. The reaction was cooled to 0 ºC, then LiAlH4 (1 M in THF) (27 mL, 27.00 mmol, 3.00 equiv) was added dropwise and the reaction was stirred for 15 minutes. The reaction was then carefully quenched with water (71 mL) and AcOH (224 mL), allowed to warm to 23 ºC, and stirred for 16 hours. The reaction was transferred to a 2 L round-bottom flask and cooled to 0 ºC. 2 M NaOH (aq.) was added until the reaction pH = >12 and then extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (95:5 ethyl acetate/triethylamine) afforded amino tetracycle (+)-323 as a light green powder (2.097 g, 8.28 mmol, 92% yield). All spectra for (+)-323 were found to be in good accordance with literature values.51,75 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers BrCH2CH2OH K2CO3 NH N 152 OH EtOH, 80 ºC Me N H (+)-323 Me 72% yield N H (+)-324 Amino Alcohol (+)-324: To an oven-dried 50 mL round-bottom flask equipped with a reflux condenser with a stir bar was added amino tetracycle (+)-323 (257 mg, 1.01 mmol, 1.00 equiv) and EtOH (15 mL). K2CO3 (1.106 g, 8.00 mmol, 8.00 equiv) and 2bromoethanol (0.57 mL, 8.00 mmol, 8.00 equiv) were added and the flask was heated to 80 ºC for 5 hours. The reaction was cooled to 23 ºC and partially concentrated under reduced pressure. The crude reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3x), dried over Na2SO4, then concentrated. Flash chromatography (98:2 à 96:4 ethyl acetate/triethylamine) afforded amino alcohol (+)-324 as a brown powder (216 mg, 0.725 mmol, 72% yield). All spectra for (+)-324 were found to be in good accordance with literature values.51,76 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers N Me OH N H (+)-324 MsCl, i-Pr2NEt CH2Cl2, –20 ºC then KO-t-Bu, THF –20 —> 0 ºC 153 N then NaBH4, EtOH Me 74% yield (+)-aspidospermidine (+)-298 N H H (+)-Aspidospermidine (+)-298: To an oven-dried 250 mL round-bottom flask with a stir bar was added amino alcohol (+)-324 (1.00 g, 3.35 mmol, 1.00 equiv) and dichloromethane (67 mL). The reaction was cooled to –15 ºC and diisopropyl ethyl amine (0.76 mL, 4.37 mmol, 1.30 equiv) was added. Mesyl chloride (0.26 mL, 3.42 mmol, 1.02 equiv) was added dropwise and the reaction was stirred for 45 minutes. A solution of KO-t-Bu (940 mg, 8.38 mmol, 2.50 equiv) in THF (16.8 mL) was added dropwise before allowing the reaction to warm slowly to 0 ºC over 2 hours. The reaction was quenched with brine and transferred to a separatory funnel, extracted with ethyl acetate (5x), dried over Na2SO4, then concentrated. The crude was redissolved in EtOH (101 mL) and cooled to 0 ºC. NaBH4 (634 mg, 16.75 mmol, 5.00 equiv) was added in three portions over 10 minutes. The reaction was stirred for 15 minutes then warmed to 23 ºC and stirred for an additional 3 hours. The reaction was quenched with sodium citrate dihydrate (4.92 g, 16.75 mmol, 5.00 equiv) and water. The reaction was transferred to a separatory funnel and extracted with ethyl acetate (3x), dried over Na2SO4, then concentrated. Flash chromatography (97.5:2.5 à 95:5 à 92.5:7.5 à 90:10 dichloromethane/ methanol) afforded (+)-aspidospermidine (+)-298 as a white solid (696 mg, 2.48 mmol, 74% yield). All spectra for (+)-298 were found to be in good accordance with literature values.22 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers PhCHO NaBH(OAc)3 acetic acid N 154 N CH3CN, 23 ºC, 16 h Me N H H 94% yield Me (+)-aspidospermidine (+)-298 H N Ph (+)-299 Benzyl Aspidospermidine (+)-299: To an oven-dried 25 mL round-bottom flask with a stir bar was added (+)-aspidospermidine (+)-298 (180.3 mg, 0.638 mmol, 1.00 equiv) and acetonitrile (6.38 mL). Benzaldehyde (0.13 mL, 1.277 mmol, 2.00 equiv) and glacial acetic acid (0.18 mL, 3.19 mmol, 5.00 equiv) were added and the reaction was stirred for 30 minutes at 23 ºC. NaBH(OAc)3 (406 mg, 1.915 mmol, 3.00 equiv) was added in a single portion and the reaction was stirred for 16 hours. The reaction was quenched with sat. NaHCO3 and transferred to a separatory funnel and extracted with dichloromethane (5x), the combined organics dried over Na2SO4, then concentrated. The crude was suspended in water and concentrated under reduced pressure to azeotrope off benzyl alcohol. Flash chromatography (80:20 hexanes/ ethyl acetate) afforded benzyl aspidospermidine (+)-299 as a white crystalline solid (224 mg, 0.600 mmol, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.35 (m, 2H), 7.35 – 7.29 (m, 2H), 7.28 – 7.22 (m, 1H), 7.12 – 6.97 (m, 2H), 6.65 (td, J = 7.4, 1.0 Hz, 1H), 6.37 (d, J = 8.1 Hz, 1H), 4.44 (d, J = 14.8 Hz, 1H), 4.07 (d, J = 14.8 Hz, 1H), 3.38 (dd, J = 10.9, 5.7 Hz, 1H), 3.08 (td, J = 8.8, 2.8 Hz, 1H), 3.01 (dq, J = 9.1, 1.9 Hz, 1H), 2.34 (dt, J = 12.8, 8.6 Hz, 1H), 2.27 – 2.16 (m, 1H), 1.94 (ddd, J = 12.3, 10.8, 2.9 Hz, 1H), 1.84 – 1.42 (m, 7H), 1.40 – 1.21 (m, 2H), 1.20 – 1.03 (m, 2H), 1.01 – 0.81 (m, 1H), 0.64 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 155 C NMR (100 MHz, CDCl3) δ 150.0, 138.8, 136.9, 128.6, 128.0, 127.3, 127.1, 122.5, 117.5, 106.7, 71.3, 69.2, 54.0, 53.1, 52.7, 48.4, 39.2, 35.6, 34.6, 30.2, 23.1, 22.5, 21.9, 7.0. IR (Neat Film, NaCl) 2929, 2778, 1603, 1481, 1452, 1375, 1332, 1181, 1131, 1025, 902, 7373, 698 cm–1. [α]D21 –6.8º (c 0.58, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C26H33N2 [M+H]+: 373.2649, found 373.2644. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers N N NBS (1.0 equiv) Me 156 H N CH3CN/CH2Cl2, –20 ºC, 5 min Br Me 85% yield Ph (+)-299 H N Ph (+)-300 Bromo Aspidospermidine (+)-300: To an oven-dried 20 mL vial with a stir bar was added benzyl aspidospermidine (+)-299 (232 mg, 0.622 mmol, 1.00 equiv) and dichloromethane (4 mL), then acetonitrile (6.2 mL). The solution was cooled to –20 ºC and NBS (110 mg, 0.622 mmol, 1.00 equiv) was added in 10 mg portions over 10 minutes. Conversion was check by LCMS and quenched with sat. Na2S2O3 (aq.) 5 minutes after adding NBS. The reaction was transferred to a separatory funnel and extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (80:20:2 hexanes/ ethyl acetate/ triethylamine) afforded bromo aspidospermidine (+)-300 as a white crystalline solid (238 mg, 0.532 mmol, 85% yield). 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.24 (m, 6H), 7.12 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 4.37 (d, J = 14.8 Hz, 1H), 4.07 (d, J = 14.8 Hz, 1H), 3.38 (dd, J = 11.0, 5.7 Hz, 1H), 3.07 (td, J = 8.7, 2.7 Hz, 1H), 3.00 (ddt, J = 10.8, 3.9, 1.9 Hz, 1H), 2.31 (dt, J = 12.6, 8.6 Hz, 1H), 2.21 (dt, J = 10.0, 8.4 Hz, 1H), 2.15 (s, 1H), 1.92 (ddd, J = 12.3, 10.8, 2.8 Hz, 1H), 1.83 – 1.42 (m, 7H), 1.37 – 1.20 (m, 2H), 1.16 – 1.03 (m, 2H), 0.99 – 0.83 (m, 1H), 0.67 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.0, 139.4, 138.2, 129.9, 128.7, 127.8, 127.3, 125.5, 108.8, 108.2, 71.3, 69.6, 53.9, 53.0, 52.6, 48.5, 39.4, 35.6, 34.5, 30.2, 22.9, 22.7, 21.8, 6.9. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 157 IR (Neat Film, NaCl) 2930, 2780, 1597, 1478, 1375, 1263, 1180, 799, 735, 697 cm–1. [α]D21 +12.4º (c 1.08, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C26H32BrN2 [M+H]+: 451.1749, found 451.1742. 158 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Me N Br Me H N N Pd(dppf)Cl2 (10 mol%) B2Pin2 KOAc, 1,4-dioxane, 90 ºC, 16 h Me 95% yield Ph (+)-300 H Me O Me B Me O N Ph (+)-301 Pinacol Ester (+)-301: To an oven-dried 10 mL round-bottom flask equipped with a reflux condenser with a stir bar was added bromo aspidospermidine (+)-300 (232 mg, 0.514 mmol, 1.00 equiv), B2Pin2 (196 mg, 0.771 mmol, 1.50 equiv), KOAc (151 mg, 1.542 mmol, 3.00 equiv), and Pd(dppf)Cl2. 1,4-Dioxane (2.1 mL) was added, and the reaction mixture was headed to reflux for 16 hours. The reaction was cooled, then filtered through Celite® with dichloromethane and concentrated. Flash chromatography (80:20 ethyl acetate/ hexanes à 80:20:5 hexanes/ethyl acetate/triethylamine) afforded pinacol ester (+)-301 as a white foam (244 mg, 0.488 mmol, 95% yield). 1 H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.8, 1.4 Hz, 1H), 7.47 (d, J = 1.3 Hz, 1H), 7.40 – 7.21 (m, 6H), 6.38 (d, J = 7.8 Hz, 1H), 4.50 (d, J = 14.7 Hz, 1H), 4.10 (d, J = 15.1 Hz, 1H), 3.38 (dd, J = 10.9, 5.7 Hz, 1H), 3.15 – 2.94 (m, 2H), 2.34 (s, 1H), 2.23 (dt, J = 12.5, 8.2 Hz, 2H), 1.94 (t, J = 11.4 Hz, 1H), 1.84 – 1.43 (m, 8H), 1.33 (s, 11H), 1.17 – 1.01 (m, 2H), 1.00 – 0.82 (m, 1H), 0.64 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 152.6, 138.3, 136.2, 135.6, 128.7, 128.6, 127.9, 127.2, 105.8, 83.2, 71.0, 69.12, 54.0, 53.0, 52.4, 47.9, 39.9, 35.6, 34.6, 30.0, 25.2, 25.1, 24.9, 23.2, 23.0, 21.9, 6.9. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 159 IR (Neat Film, NaCl) 2973, 2931, 2861, 2780, 1604, 1436, 1378, 1350, 1144, 965, 860, 738, 698, 680 cm–1. [α]D21 –20.0º (c 0.79, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C32H44BN2O2 [M+H]+: 499.3496, found 499.3502. 160 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H Me N O B Me H N N Me Me O Me (+)-301 H HO (–)-26 N N Me KHF2 MeOH, H2O, 23 ºC, 1.5 h then… HFIP, 23 ºC, 16 h Ph N 98% yield H Me H N Me N Ph (–)-313 (R,R,S)-Benzyl Dimer (–)-313: To a 1-dram vial with a stir bar was added pinacol ester (+)-301 (19.9 mg, 0.0400 mmol, 2.0 equiv) and MeOH (0.5 mL). KHF2 (15.6 mg, 0.200 mmol, 10.0 equiv) was dissolved in water (0.10 mL) and added to the solution of pinacol ester (+)-301. The reaction was stirred for 2 hours at 23 ºC, then concentrated under a stream of N2. Acetonitrile (0.5 mL) was added to the crude reaction and concentrated under a stream of N2 (3x) to azeotrope away water, then (–)-eburnamine (–)-26 (6.4 mg, 0.022 mmol, 1.00 equiv) was added, followed by HFIP (0.2 mL). The reaction was stirred for 16 hours at 23 ºC. The reaction was concentrated under reduced pressure and purified by preparative flash chromatography (100% ethyl acetate à 98:2 ethyl acetate/triethylamine) to afford (R,R,S)-benzyl dimer (–)-313 as a white foam (13.8 mg, 0.021 mmol, 98% yield). 1 H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.7, 1.0 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.37 – 7.29 (m, 2H), 7.28 (ttt, J = 14.4, 6.4, 1.5 Hz, 2H), 7.05 – 6.96 (m, 2H), 6.90 (d, J = 1.8 Hz, 1H), 6.87 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.69 – 6.61 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.94 (dd, J = 11.7, 4.5 Hz, 1H), 4.48 (d, J = 14.5 Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 4.06 (s, 1H), 3.50 – 3.28 (m, 3H), 3.14 – 2.97 (m, 2H), 2.94 (d, J = 11.0 Hz, 1H), 2.62 (d, J = 16.9 Hz, 2H), 2.48 (td, J = 12.0, 3.0 Hz, 1H), 2.36 (dt, J = 13.0, 8.7 Hz, 1H), 2.28 – 2.14 161 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers (m, 2H), 2.09 (dd, J = 14.3, 4.6 Hz, 1H), 2.03 (s, 1H), 1.92 –1.17 (m, 14H), 1.20 – 1.10 (m, 1H), 1.05 – 0.96 (m, 1H), 0.88 (t, J = 7.5 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 149.7, 138.6, 138.4, 136.9, 132.3, 128.6, 128.6, 128.5, 128.1, 127.2, 125.9, 120.5, 119.1, 117.7, 112.4, 106.4, 104.8, 71.0, 69.2, 59.9, 56.3, 53.8, 53.0, 52.5, 51.2, 48.5, 45.7, 44.8, 39.4, 35.5, 35.2, 34.2, 29.9, 29.0, 24.4, 22.9, 22.4, 21.7, 20.9, 17.3, 7.6, 6.5. IR (Neat Film, NaCl) 3026, 2929, 2857, 2779, 1604, 1482, 1460, 1453, 1375, 1224, 1188, 1100, 1026, 739 cm–1. [α]D22 –79.5º (c 0.83, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C45H55N4 [M+H]+: 651.4427, found 651.4430. H Me N O B Me H N N Me Me O Me (–)-301 H HO (+)-26 N N Me KHF2 MeOH, H2O, 23 ºC, 1.5 h then… HFIP, 23 ºC, 16 h Ph N 98% yield H Me H N Me N Ph (+)-313 (S,S,R)-Benzyl Dimer (+)-313: To a 1-dram vial with a stir bar was added pinacol ester (–)-301 (25.0 mg, 0.0501 mmol, 1.5 equiv) and MeOH (0.5 mL). KHF2 (29.0 mg, 0.376 mmol, 7.5 equiv) was dissolved in water (0.15 mL) and added to the solution of pinacol ester (–)-301. The reaction was stirred for 2 hours at 23 ºC, then concentrated under a stream of N2. Acetonitrile (0.5 mL) was added to the crude reaction and concentrated under a stream of N2 (3x) to azeotrope away water, then (+)-eburnamine (+)-26 (10.0 mg, 0.0334 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 162 mmol, 1.0 equiv) was added, followed by HFIP (0.3 mL). The reaction was stirred for 16 hours at 23 ºC. The reaction was concentrated under reduced pressure and purified by preparative flash chromatography (100% ethyl acetate à 98:2 ethyl acetate/triethylamine) to afford (S,S,R)-benzyl dimer (+)-313 as a white foam (21.3 mg, 0.0327 mmol, 98% yield). 1 H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 7.7, 1.0 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.37 – 7.29 (m, 2H), 7.28 (ttt, J = 14.4, 6.4, 1.5 Hz, 2H), 7.05 – 6.96 (m, 2H), 6.90 (d, J = 1.8 Hz, 1H), 6.87 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.69 – 6.61 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.94 (dd, J = 11.7, 4.5 Hz, 1H), 4.48 (d, J = 14.5 Hz, 1H), 4.09 (d, J = 14.8 Hz, 1H), 4.06 (s, 1H), 3.50 – 3.28 (m, 3H), 3.14 – 2.97 (m, 2H), 2.94 (d, J = 11.0 Hz, 1H), 2.62 (d, J = 16.9 Hz, 2H), 2.48 (td, J = 12.0, 3.0 Hz, 1H), 2.36 (dt, J = 13.0, 8.7 Hz, 1H), 2.28 – 2.14 (m, 2H), 2.09 (dd, J = 14.3, 4.6 Hz, 1H), 2.03 (s, 1H), 1.92 –1.17 (m, 14H), 1.20 – 1.10 (m, 1H), 1.05 – 0.96 (m, 1H), 0.88 (t, J = 7.5 Hz, 6H). [α]D22 +70.8º (c 1.5, CHCl3). All spectra for (+)-313 were found to be in good accordance with the enantiomer, (–)-313. 163 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N Me N O B Me H O Me N H HO Me (+)-296 Me KHF2 MeOH, H2O, 23 ºC, 1.5 h Me N then… HFIP, 23 ºC, 16 h Ph (+)-301 97% yield N N H Me H N Me N Ph (–)-332 (S,R,S)-Benzyl Dimer (–)-332: To a 1-dram vial with a stir bar was added pinacol ester (+)-301 (10.3 mg, 0.0207 mmol, 1.50 equiv) and MeOH (0.25 mL). KHF2 (15.5 mg, 0.155 mmol, 7.5 equiv) was dissolved in water (0.10 mL) and added to the solution of pinacol ester (+)-301. The reaction was stirred for 2 hours at 23 ºC, then concentrated under a stream of N2. Acetonitrile (0.5 mL) was added to the crude reaction and concentrated under a stream of N2 (3x) to azeotrope away water, then (+)-epi-eburnamine (+)-296 (4.4 mg, 0.0147 mmol, 1.00 equiv) was added, followed by HFIP (0.2 mL). The reaction was stirred for 16 hours at 23 ºC. The reaction was concentrated under reduced pressure and purified by preparative TLC plate (1:1 hexanes/ ethyl acetate) to afford (S,R,S)-benzyl dimer (–)332 as a yellow solid (9.3 mg, 0.024 mmol, 97% yield). 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 6.7 Hz, 2H), 7.36 – 7.30 (m, 2H), 7.26 (ttt, J =14.3, 6.2, 1.2 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 7.01 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H), 6.96 (dd, J = 8.0, 1.8 Hz, 1H), 6.87 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 11.5, 5.2 Hz, 1H), 4.44 (d, J = 14.6 Hz, 1H), 4.05 (d, J = 14.6 Hz, 1H), 3.40 (dd, J = 11.0, 5.7 Hz, 1H), 3.20 – 3.04 (m, 3H), 2.98 (dddd, J = 17.5, 11.7, 5.3, 2.6 Hz, 2H), 2.83 – 2.71 (m, 1H), 2.57 (td, J = Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 164 11.3, 4.3 Hz, 1H), 2.44 – 2.28 (m, 2H), 2.27 – 2.16 (m, 3H), 2.04 – 1.31 (m, 15H), 1.17 – 0.97 (m, 5H), 0.89 – 0.83 (m, 3H), 0.77 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.7, 138.6, 138.0, 137.5, 135.4, 132.5, 128.6, 128.6, 128.1, 127.2, 125.6, 121.1, 120.3, 119.2, 117.9, 111.9, 107.3, 105.7, 71.0, 69.2, 68.3, 57.5, 56.2, 53.9, 53.2, 52.9, 52.6, 48.6, 45.1, 38.8, 36.3, 35.8, 34.4, 32.0, 30.4, 29.9, 29.4, 25.0, 23.2, 22.4, 21.9, 21.7, 21.7, 19.3, 7.6, 7.3. IR (Neat Film, NaCl) 3025, 2932, 2854, 2788, 2736, 1612, 1487, 1455, 1300, 1182, 1128, 965, 738, 698 cm–1. [α]D22 +18.7º (c 0.72, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C45H55N4 [M+H]+: 651.4427, found 651.4429. 165 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N Me N O B Me H O Me N H HO Me (+)-26 Me KHF2 MeOH, H2O, 23 ºC, 1.5 h Me N then… HFIP, 23 ºC, 16 h Ph (+)-301 N N H Me H N Me N Ph 97% yield (–)-333 (S,S,R)-Benzyl Dimer (–)-333: To a 1-dram vial with a stir bar was added pinacol ester (+)-301 (15.0 mg, 0.03 mmol, 1.50 equiv) and MeOH (0.33 mL). KHF2 (17.6 mg, 0.230 mmol, 7.5 equiv) was dissolved in water (0.11 mL) and added to the solution of pinacol ester (+)-301. The reaction was stirred for 2 hours at 23 ºC, then concentrated under a stream of N2. Acetonitrile (0.5 mL) was added to the crude reaction and concentrated under a stream of N2 (3x) to azeotrope away water, then (+)-eburnamine (+)-26 (5.9 mg, 0.02 mmol, 1.00 equiv) was added, followed by HFIP (0.2 mL). The reaction was stirred for 16 hours at 23 ºC. The reaction was concentrated under reduced pressure and purified by preparative TLC plate (50:50:5 hexanes/ethyl acetate/triethylamine) to afford (S,S,R)benzyl dimer (–)-333 as a white solid (12.6 mg, 0.0194 mmol, 97% yield). (+)-333 was prepared in the same manner as (–)-333. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.28 (m, 1H), 7.05 (s, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.93 (dd, Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 166 J = 11.7, 4.6 Hz, 1H), 4.45 (d, J = 14.6 Hz, 1H), 4.35 (p, J = 6.2 Hz, 1H), 4.08 (d, 14.6 Hz, 1H), 4.05 (s, 1H), 3.41 (dd, J = 11.2, 5.7 Hz, 1H), 3.33 (d, J = 7.8 Hz, 2H), 3.04 (q, J = 8.3 Hz, 2H), 2.98 (d, J = 11.3 Hz, 1H), 2.72 – 2.58 (m, 2H), 2.51 (t, J = 11.9 Hz, 1H), 2.34 (dt, J = 12.7, 8.6 Hz, 1H), 2.24 (s, 1H), 2.09 (dt, J = 13.2, 6.2 Hz, 2H), 1.91 (t, J = 11.5 Hz, 1H), 1.81 (t, J = 13.2 Hz, 3H), 1.77 – 1.71 (m, 1H), 1.72 – 1.57 (m, 3H), 1.56 – 1.44 (m, 3H), 1.44 – 1.24 (m, 4H), 1.21 – 0.93 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H), 0.76 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.8, 138.5, 136.9, 133.7, 132.0, 128.6, 128.6, 128.1, 127.2, 127.2, 125.8, 121.3, 120.6, 119.3, 117.9, 112.4, 107.2, 104.8, 71.0, 69.1, 59.5, 56.4, 53.9, 52.9, 52.5, 51.1, 48.5, 45.6, 44.6, 38.9, 35.8, 35.2, 34.4, 31.1, 30.4, 28.9, 25.0, 24.7, 23.2, 22.5, 21.8, 20.7, 17.2, 7.6, 7.2. IR (Neat Film, NaCl) 2932, 2858, 2781, 1732, 1612, 1488, 1455, 1332, 1266, 1183, 1097, 738, 700 cm–1. [α]D21 +16.6º (c 0.97, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C45H55N4 [M+H]+: 651.4427, found 651.4421. 167 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H Me N O B Me H N N Me O N Me Me H HO (–)-296 Me KHF2 MeOH, H2O, 23 ºC, 1.5 h then… HFIP, 23 ºC, 16 h Ph (+)-301 N N 77% yield H Me H N Me N Ph (–)-334 (R,S,R)-Benzyl Dimer (–)-334: To a 1-dram vial with a stir bar was added pinacol ester (+)-301 (15.0 mg, 0.03 mmol, 1.50 equiv) and MeOH (0.33 mL). KHF2 (17.6 mg, 0.230 mmol, 7.5 equiv) was dissolved in water (0.11 mL) and added to the solution of pinacol ester (+)-301. The reaction was stirred for 2 hours at 23 ºC, then concentrated under a stream of N2. Acetonitrile (0.5 mL) was added to the crude reaction and concentrated under a stream of N2 (3x) to azeotrope away water, then (–)-epi-eburnamine (–)-296 (5.9 mg, 0.02 mmol, 1.00 equiv) was added, followed by HFIP (0.2 mL). The reaction was stirred for 16 hours at 23 ºC. The reaction was concentrated under reduced pressure and purified by preparative TLC plate (1:1 hexanes/ ethyl acetate) to afford (R,S,R)-benzyl dimer (–)-334 as a yellow solid (10.0 mg, 0.0154 mmol, 77% yield). 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.7 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.33 (t, J = 7.5 Hz, 2H), 6.99 (t, J = 7.7 Hz, 2H), 6.93 (s, 1H), 6.87 (ddd, J = 8.3, 7.2, 1.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 4.93 (dd, J = 11.5, 5.1 Hz, 1H), 4.47 (d, J = 14.6 Hz, 1H), 4.08 (d, J = 14.6 Hz, 1H), 3.38 (dd, J = 11.2, 5.6 Hz, 1H), 3.13 (s, 1H), 3.11 – 3.02 (m, 3H), 3.03 – 2.89 (m, 2H), 2.77 (dd, J = 15.1, 4.1 Hz, 1H), 2.60 (td, J = 11.4, 4.4 Hz, 1H), 2.44 – 2.27 (m, 2H), 2.26 – 2.16 (m, 3H), 2.01 – 1.91 (m, 1H), 1.91 – 1.77 (m, Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 168 4H), 1.71 (ddt, J = 15.4, 11.8, 3.7 Hz, 2H), 1.66 – 1.50 (m, 5H), 1.48 – 1.37 (m, 2H), 1.30 (dd, J = 11.2, 3.5 Hz, 2H), 1.09 (td, J = 13.3, 4.5 Hz, 1H), 1.00 (d, J = 13.4 Hz, 1H), 0.94 – 0.86 (m, 1H), 0.84 (d, J = 3.9 Hz, 3H), 0.39 – 0.33 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.58, 138.57, 138.19, 138.07, 135.40, 132.59, 128.62, 128.58, 128.07, 127.21, 125.56, 120.29, 120.17, 119.14, 117.77, 112.06, 106.59, 105.72, 70.99, 69.26, 68.19, 57.26, 56.27, 53.81, 53.20, 52.99, 52.52, 48.57, 45.15, 39.27, 36.24, 35.53, 34.11, 31.89, 31.09, 29.82, 22.96, 22.41, 21.78, 21.75, 21.71, 19.25, 7.56, 6.55. IR (Neat Film, NaCl) 3005, 2934, 2855, 2791, 2740, 1732, 1614, 1486, 1454, 1374, 1279, 1215, 966, 809, 750, 699 cm–1. [α]D21 –79.4º (c 0.77, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C45H55N4 [M+H]+: 651.4427, found 651.4433. 169 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N H Me H N Ph (–)-313 N H Ra/Ni H2SO4 (conc.) N N MeOH, 23 ºC, 7 h Me 71% yield H Me N Me N H H 286 Kam’s proposed strempeliopidine (R,R,S)-Dimer 286: To a 1/2-dram vial with a stir bar was added (R,R,S)-benzyl dimer (–)313 (2.6 mg, 0.00400 mmol, 1.00 equiv) and MeOH (0.20 mL). A suspension of Raney Nickel® (50:50 w/ water) (10 mg slurry) was added, followed by H2SO4 (conc.) (7.5 µL). The vial was quickly sealed with a Teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 2 hours additional H2SO4 (conc.) (5.0 µL) was added and the vial sealed again. After 5 hours the reaction was quenched with 2 M NaOH (aq.) and transferred to a separatory funnel, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford (R,R,S)dimer 286 as a white solid (1.6 mg, 0.0028 mmol, 71% yield). 1 H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 6.99 (t, J = 7.3 Hz, 2H), 6.95 (s, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.64 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.94 (dd, J = 11.8, 4.7 Hz, 1H), 4.03 (s, 1H), 3.51 (dt, J = 13.5, 6.6 Hz, 2H), 3.40 – 3.31 (m, 2H), 3.16 – 3.07 (m, 1H), 3.07 – 3.01 (m, 1H), 3.01 – 2.94 (m, 1H), 2.67 – 2.56 (m, 2H), 2.52 – 2.42 (m, 1H), 2.33 (dt, J = 13.2, 8.6 Hz, 1H), 2.23 (q, J = 7.7 Hz, 1H), 2.18 (dd, J = 14.2, 7.6 Hz, 1H), 2.08 (dd, J = 14.3, 4.8 Hz, 1H), 2.05 (s, 1H), 1.94 – 1.83 (m, 2H), 1.76 (dd, J = 14.4, 11.9 Hz, 2H), 1.71 – 1.61 (m, 6H), 1.55 – 1.45 (m, 2H), 1.41 (d, J = 15.2 Hz, 4H), 1.21 – 1.10 (m, 1H), 0.99 (d, J = 13.7 Hz, 1H), 0.88 (t, J = 7.6 Hz, 3H), 0.36 (m, 3H). 170 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 C NMR (100 MHz, CDCl3) δ 149.2, 137.2, 136.8, 134.2, 134.01, 128.7, 125.9, 120.9, 120.4, 119.1, 117.7, 112.4, 110.3, 104.9, 71.2, 66.1, 59.8, 56.3, 53.9, 53.5, 53.1, 51.2, 45.8, 44.78, 39.2, 35.7, 35.2, 34.3, 29.9, 29.8, 29.0, 28.3, 24.45, 23.0, 21.8, 20.9, 17.3, 7.7, 6.6. IR (Neat Film, NaCl) 3025, 2931, 2857, 2781, 1612, 1487, 1455, 1332, 1263, 1183, 1097, 1027, 809, 738 cm–1. [α]D21 –64.0º (c 0.24, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3962. H N N H Me H N Ph (+)-313 N H Ra/Ni H2SO4 (conc.) N N MeOH, 23 ºC, 7 h Me 71% yield H Me N Me N H H 284 revised strempeliopidine Strempeliopidine 284: To a 1/2-dram vial with a stir bar was added (S,S,R)-benzyl dimer (+)-313 (8.4 mg, 0.013 mmol, 1.0 equiv) and MeOH (0.30 mL). A suspension of Raney Nickel® (50:50 w/ water) (15 mg slurry) was added, followed by H2SO4 (conc.) (15 µL). The vial was quickly sealed with a Teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 3 hours additional H2SO4 (conc.) (15 µL) was added and the vial sealed again. After 5 hours the reaction was quenched with 2 M NaOH (aq.) and transferred to a separatory funnel, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford strempeliopidine 284 as a white solid (5.2 mg, 0.0093 mmol, 71% yield). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 1 171 H NMR 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.06 – 6.96 (m, 2H), 6.95 (s, 1H), 6.88 – 6.81 (m, 1H), 6.64 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 4.94 (dd, J = 11.9, 4.5 Hz, 1H), 4.03 (s, 1H), 3.59 – 3.47 (m, 2H), 3.39 – 3.31 (m, 2H), 3.16 – 3.07 (m, 1H), 3.07 – 2.96 (m, 2H), 2.63 – 2.56 (m, 2H), 2.52 – 2.41 (m, 1H), 2.39 – 2.29 (m, 1H), 2.27 – 2.20 (m, 1H), 2.18 – 2.14 (m, 1H), 2.11 – 2.07 (m, 1H), 1.94 – 1.58 (m, 10H), 1.52 – 1.36 (m, 6H), 1.21 – 1.09 (m, 1H), 1.00 (d, J = 13.3 Hz, 1H), 0.88 (t, J = 7.9 Hz, 3H), 0.44 – 0.27 (m, 3H). [α]D24 +71.0º (c 0.22, CHCl3). All spectra for 284 were found to be in good accordance with the enantiomer, 284. 172 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N H Me H N N H Ra/Ni H2SO4 (conc.) N N MeOH, 23 ºC, 7 h Me 86% yield H Me N Me N H H Ph (–)-332 318 (S,R,S)-Dimer 318: To a 1/2-dram vial with a stir bar was added (S,R,S)-benzyl dimer (–)332 (5.0 mg, 0.00769 mmol, 1.00 equiv) and MeOH (0.20 mL). A suspension of Raney Nickel® (50:50 w/ water) (12 mg slurry) was added, followed by H2SO4 (conc.) (15 µL). The vial was quickly sealed with a Teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 2 hours additional H2SO4 (conc.) (10.0 µL) was added and the vial sealed again. After 5 hours the reaction was quenched with 2 M NaOH (aq.) and transferred to a separatory funnel, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford (S,R,S)dimer 318 as a white solid (3.7 mg, 0.0066 mmol, 86% yield). 1 H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.7 Hz, 1H), 7.07 (s, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 7.7 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.92 (dd, J = 11.5, 5.2 Hz, 1H), 3.57 (s, 1H), 3.12 (td, J = 13.2, 6.5 Hz, 5H), 3.01 (q, J = 7.4 Hz, 4H), 2.81 – 2.71 (m, 1H), 2.57 (td, J = 11.5, 4.4 Hz, 1H), 2.30 (d, J = 12.1 Hz, 3H), 2.23 (dd, J = 14.2, 5.2 Hz, 2H), 1.97 (d, J = 12.7 Hz, 3H), 1.90 – 1.72 (m, 3H), 1.72 – 1.37 (m, 7H), 1.22 – 0.97 (m, 4H), 0.90 – 0.81 (m, 3H), 0.77 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 173 C NMR (100 MHz, CDCl3) δ 149.2, 137.9, 136.4, 135.34, 134.2, 128.6, 125.78, 121.4, 120.4, 119.3, 118.0, 111.8, 111.1, 105.7, 71.2, 68.2, 66.1, 57.5, 56.2, 54,0, 53.5, 53.2, 53.0, 45.0, 38.7, 36.3, 36.0, 34.4, 32.0, 30.3, 29.9, 28.3, 23.3, 21.9, 21.7, 19.3, 7.6, 7.3. IR (Neat Film, NaCl) 3003, 2927, 2855, 2789, 2738, 1730, 1614, 1488, 1455, 1301, 1279, 1215, 1183, 1127, 1014, 819, 750 cm–1. [α]D21 +10.1º (c 0.28, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3963. 174 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N H Me H N N H Ra/Ni H2SO4 (conc.) N N MeOH, 23 ºC, 7 h Me 73% yield H Me N Me N H H Ph (–)-333 319 (S,S,R)-Dimer 319: To a 1/2-dram vial with a stir bar was added (S,S,R)-benzyl dimer (–)333 (6.2 mg, 0.00952 mmol, 1.00 equiv) and MeOH (0.20 mL). A suspension of Raney Nickel® (50:50 w/ water) (15 mg slurry) was added, followed by H2SO4 (conc.) (15.0 µL). The vial was quickly sealed with a Teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 2 hours additional H2SO4 (conc.) (5.0 µL) was added and the vial sealed again. After 5 hours the reaction was quenched with 2 M NaOH (aq.) and transferred to a separatory funnel, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford (S,S,R)dimer 319 as a white solid (3.9 mg, 0.0070 mmol, 73% yield). (–)-319 was prepared in the same manner as (+)-319. All data for it was found to be in good accordance with its enantiomeric counterpart. 1 H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 7.00 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.83 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 4.93 (dd, J = 11.7, 4.6 Hz, 1H), 4.03 (s, 1H), 3.55 (dd, J = 11.0, 6.2 Hz, 1H), 3.40 – 3.29 (m, 3H), 3.09 (t, J = 8.9 Hz, 1H), 3.03 (d, J = 10.8 Hz, 2H), 2.65 – 2.57 (m, 2H), 2.52 – 2.44 (m, 1H), 2.30 (dt, J = 13.0, 8.6 Hz, 1H), 2.24 (s, Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 175 1H), 2.22 – 2.15 (m, 1H), 2.12 – 2.05 (m, 2H), 2.00 (dd, J = 13.9, 3.8 Hz, 1H), 1.93 (t, J = 11.4 Hz, 1H), 1.85 – 1.59 (m, 8H), 1.54 – 1.34 (m, 3H), 1.20 – 0.96 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 149.3, 136.8, 134.3, 133.9, 128.7, 125.9, 121.7, 120.4, 119.2, 117.8, 112.3, 111.0, 105.0, 71.1, 66.0, 59.5, 56.45, 54.0, 53.5, 53.0, 51.2, 45.6, 44.7, 38.7, 35.9, 35.1, 34.4, 30.3, 29.9, 29.0, 28.4, 24.8, 23.4, 21.9, 21.0, 17.3, 14.3, 7.7, 7.2. IR (Neat Film, NaCl) 2923, 2852, 1737, 1612, 1459, 1376, 1262, 1182, 737 cm–1. [α]D21 +8.5º (c 0.14, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3960. 176 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N H Me H N N H Ra/Ni H2SO4 (conc.) N N MeOH, 23 ºC, 7 h Me 64% yield H Me N Me N H H Ph (–)-334 320 (R,S,R)-Dimer 320: To a 1/2-dram vial with a stir bar was added (R,S,R)-benzyl dimer (–)334 (10.0 mg, 0.0154 mmol, 1.00 equiv) and MeOH (0.30 mL). A suspension of Raney Nickel® (50:50 w/ water) (12 mg slurry) was added, followed by H2SO4 (conc.) (30 µL). The vial was quickly sealed with a Teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 2 hours additional H2SO4 (conc.) (15.0 µL) was added and the vial sealed again. After 5 hours the reaction was quenched with 2 M NaOH (aq.) and transferred to a separatory funnel, extracted with dichloromethane, dried over Na2SO4, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford (R,S,R)dimer 320 as a white solid (5.5 mg, 0.0098 mmol, 64% yield). 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.7 Hz, 1H), 7.05 – 6.93 (m, 3H), 6.85 (t, J = 7.7 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 4.93 (dd, J = 11.5, 5.2 Hz, 1H), 3.53 (s, 1H), 3.17 – 3.06 (m, 4H), 3.04 – 2.92 (m, 3H), 2.77 (dd, J = 15.1, 4.1 Hz, 1H), 2.60 (td, J = 11.5, 4.3 Hz, 1H), 2.31 (td, J = 12.0, 3.3 Hz, 2H), 2.25 (s, 1H), 2.19 (dd, J = 14.2, 5.2 Hz, 1H), 2.13 – 2.06 (m, 1H), 2.01 – 1.86 (m, 3H), 1.86 – 1.77 (m, 2H), 1.65 (m, 2H), 1.62 – 1.53 (m, 3H), 1.50 (t, J = 13.6 Hz, 1H), 1.45 – 1.35 (m, 1H), 1.32 – 1.23 (m, 4H), 1.09 (td, J = 13.3, 4.5 Hz, 1H), 1.00 (d, J = 13.3 Hz, 1H), 0.97 – 0.90 (m, 1H), 0.84 (d, J = 3.2 Hz, 3H), 0.50 – 0.36 (m, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 177 C NMR (100 MHz, CDCl3) δ 149.0, 138.0, 135.4, 134.3, 128.6, 128.5, 125.7, 120.5, 120.3, 119.2, 117.8, 112.0, 110.5, 105.8, 71.2, 68.2, 66.0, 57.3, 56.2, 53.8, 53.4, 53.2, 53.0, 45.1, 39.1, 36.23, 35.7, 34.1, 31.9, 29.9, 29.8, 28.3, 23.0, 21.7, 21.7, 19.2, 7.6, 6.6. IR (Neat Film, NaCl) 2937, 2791, 2740, 1732, 1614, 1487, 1456, 1301, 1280, 1215, 1123, 1042, 967, 816, 756 cm–1. [α]D21 –70.1º (c 0.41, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C38H49N4 [M+H]+: 561.3957, found 561.3960. 178 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N N 4-BrC6H4SO2Cl (5 equiv) Pyridine (5 equiv) H N N N CH2Cl2, 23 ºC, 16 h H Me N H H Me H 59% yield Me 286 H Me N S O O 317 Br (R,R,S)-Brosyl Dimer 317: To a 1/2-dram vial with a stir bar was added (R,R,S)-dimer 286 (4.9 mg, 0.00874 mmol, 1.00 equiv) and dichloromethane (0.20 mL). 4bromobenzenesulfonyl chloride (5.6 mg, 0.0218 mmol, 2.5 equiv) and pyridine (7 µL, 0.0874 mmol, 10.0 equiv) were added and the reaction was stirred for 16 hours at 23 ºC. The crude was directly loaded onto a preparative TLC plate (95:5 ethyl acetate/triethylamine) to afford (R,R,S)-brosyl dimer 317 as a white solid (4.0 mg, 0.0051 mmol, 59% yield). 1 H NMR (400 MHz, CD2Cl2) δ 7.76 – 7.65 (m, 2H), 7.64 – 7.55 (m, 3H), 7.42 (dt, J = 7.8, 1.0 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.03 – 6.93 (m, 1H), 6.81 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 6.43 (d, J = 8.3 Hz, 1H), 5.00 (dd, J = 11.8, 4.6 Hz, 1H), 4.08 – 3.98 (m, 2H), 3.37 – 3.25 (m, 2H), 3.01 (dt, J = 17.2, 9.1 Hz, 1H), 2.85 (dt, J = 14.6, 8.3 Hz, 1H), 2.65 – 2.55 (m, 2H), 2.42 (t, J = 11.5 Hz, 1H), 2.21 (dt, J = 15.6, 7.7 Hz, 1H), 2.13 (dd, J = 14.3, 4.8 Hz, 1H), 2.07 – 1.96 (m, 3H), 1.96 – 1.85 (m, 1H), 1.84 – 1.66 (m, 5H), 1.51 – 1.32 (m, 8H), 1.16 – 0.96 (m, 7H), 0.87 (t, J = 7.6 Hz, 6H). 13 C NMR (100 MHz, CD2Cl2) δ 140.8, 140.3, 139.0, 139.0, 136.9, 132.7, 129.0, 128.6, 128.1, 126.8, 121.6, 120.7, 119.5, 118.1, 116.0, 112.2, 105.3, 71.4, 70.7, 60.0, 56.2, 52.7, Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 179 51.3, 45.3, 44.9, 41.7, 35.7, 35.5, 34.3, 30.2, 30.1, 29.1, 28.1, 24.5, 23.0, 21.8, 21.0, 17.4, 14.3, 7.7, 6.5. IR (Neat Film, NaCl) 2931, 2465, 1640, 1573, 1481, 1358, 1166, 820, 745, 612 cm–1. [α]D21 –17.8º (c 0.31, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C44H52BrN4O2S [M+H]+: 779.2994, found 779.2990. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 180 B(OH)2 N NBn H 310 Me2N N 2 equiv HFIP, 23 ºC, 16h Me HO 64% yield 309 NBn H N Me 311 Pentacycle 311: To a 1-dram vial with a stir bar was added hydroxy-indole 309 (32 mg, 0.10 mmol, 1.00 equiv) and boronic acid 310 (34 mg, 0.20 mmol, 2.00 equiv). HFIP (1.0 mL) was added, and the reaction was stirred for 16 hours at 23 ºC. The reaction solvent was evaporated under reduced pressure and SiEt4 was added for 1H NMR (79% NMR yield). The crude was purified by flash chromatography (90:10 à 80:20 hexanes/ ethyl acetate) to afford pentacycle 311 as a white foam (27.0 mg, 0.064 mmol, 64% yield). 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.40 (m, 3H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.05 – 6.97 (m, 1H), 6.88 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 4.92 (dd, J = 11.4, 4.8 Hz, 1H), 4.28 (d, J = 13.6 Hz, 1H), 3.66 (d, J = 11.3 Hz, 1H), 3.41 (d, J = 13.5 Hz, 1H), 3.23 (dd, J = 11.7, 5.9 Hz, 1H), 2.98 (s, 6H), 2.98 – 2.85 (m, 1H), 2.80 – 2.68 (m, 1H), 2.63 (d, J = 9.9 Hz, 1H), 2.53 – 2.35 (m, 2H), 2.06 – 1.86 (m, 1H), 1.61 (q, J = 12.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 150.2, 139.4, 138.0, 136.7, 131.3, 129.1, 128.5, 128.3, 127.3, 126.8, 120.8, 119.4, 118.0, 112.9, 112.2, 106.6, 59.5, 59.6, 57.6, 50.7, 40.8, 35.0, 29.9, 27.0, 21.7. IR (Neat Film, NaCl) 2926, 2801, 1614, 1520, 1455, 1348, 1134, 907, 814, 729 cm–1. HRMS (MM:ESI-APCI+) m/z calculated for C29H32N3 [M+H]+: 422.2596, found 422.2600. 181 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers B(OH)2 H N H N HO N N (–)-eburnamine (–)-26a H 310 N H N N N HFIP, 23 ºC, 16 h HO Me Me2N H Me (+)-isoeburnamine (+)-26b Me2N Me Me 335 52% 314 28% ~2:1 mixture (R,R,S)-Amino Dimer 335: To a 1-dram vial with a stir bar was added a ~2:1 mixure of (–)-eburnamine (–)-26a and (+)-isoeburnamine (+)-26b (29.6 mg, 0.10 mmol, 1.00 equiv) and 4-dimethylaminophenyl boronic acid 310 (34 mg, 0.20 mmol, 2.00 equiv). HFIP (0.5 mL) was added, and the reaction was stirred for 16 hours at 23 ºC. The reaction solvent was evaporated under reduced pressure and crude was purified by flash chromatography (95:5 à 92.5:7.5 dichloromethane/methanol) to afford (R,R,S)-amino dimer 335 as a white foam (20.7 mg, 0.052 mmol, 52% yield) and eburnamenine 314 (8.8 mg, 0.028 mmol, 28% yield).42 (R,R,S)-amino dimer 335: 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.06 (ddd, J = 7.9, 7.1, 1.0 Hz, 1H), 6.92 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.2 Hz, 1H), 4.99 (dd, J = 11.7, 4.8 Hz, 1H), 4.28 (s, 1H), 3.62 – 3.43 (m, 2H), 3.16 – 3.01 (m, 1H), 2.97 (s, 6H), 2.95 – 2.77 (m, 2H), 2.65 (t, J = 12.5 Hz, 1H), 2.33 (d, J = 13.8 Hz, 1H), 2.21 (dd, J = 14.6, 4.8 Hz, 1H), 2.08 – 1.91 (m, 1H), 1.83 (dd, J = 14.6, 11.7 Hz, 1H), 1.66 – 1.41 (m, 3H), 1.28 – 1.12 (m, 1H), 0.90 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 182 C NMR (100 MHz, CDCl3) δ 150.4, 137.1, 129.8, 128.5, 128.0, 127.4, 121.4, 119.8, 118.1, 112.9, 112.6, 104.4, 60.0, 55.6, 51.2, 44.8, 44.5, 40.7, 35.5, 28.8, 23.6, 19.7, 16.8, 7.5. IR (Neat Film, NaCl) 2925, 2854, 1615, 1521, 1456, 1353, 1266, 1192, 1069, 945, 739 cm–1. [α]D21 –21.1º (c 0.26, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H34BrN3 [M+H]+: 400.2753, found 400.2760. 183 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers B(OH)2 H N H N HO N N H 310 N H N N N HFIP, 23 ºC, 16 h HO Me Me2N H Me (+)-epi-eburnamine (–)-epi-isoeburnamine (+)-296a (–)-296b Me2N Me Me 336 47% 337 6% ~2:1 mixture (S,R,S)-Amino Dimer 336: To a 1-dram vial with a stir bar was added added a ~2:1 mixure of (+)-epi-eburnamine (+)-296a and (–)-epi-isoeburnamine (–)-296b (20.0 mg, 0.067 mmol, 1.00 equiv) and 4-dimethylaminophenyl boronic acid 310 (22 mg, 0.135 mmol, 2.00 equiv). HFIP (0.5 mL) was added, and the reaction was stirred for 16 hours at 23 ºC. The reaction solvent was evaporated under reduced pressure and crude was purified by flash chromatography (100% dichloromethane à 95:5 dichloromethane/methanol) to afford (S,R,S)-amino dimer 336 as a white foam (12.7 mg, 0.0315 mmol, 47% yield) and epieburnamenine 337 (1.1 mg, 0.0040 mmol, 6% yield). (S,R,S)-amino dimer 336: 1 H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.3 Hz, 3H), 7.01 (t, J = 7.4 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.2 Hz, 1H), 4.97 (dd, J = 11.4, 5.4 Hz, 1H), 3.08 (d, J = 16.3 Hz, 3H), 3.00 (m, 1H), 2.96 (s, 6H), 2.78 – 2.72 (m, 1H), 2.57 (t, J = 10.6 Hz, 1H), 2.30 (t, J = 11.9 Hz, 1H), 2.26 – 2.20 (m, 1H), 1.96 (d, J = 13.9 Hz, 1H), 1.83 (d, J = 14.1 Hz, 2H), 1.65 – 1.55 (m, 2H), 1.26 (s, 2H), 1.07 (dt, J = 13.0, 6.3 Hz, 1H), 0.85 (d, J = 3.3 Hz, 3H). 13 C NMR (150 MHz, CDCl3) δ 150.1, 137.8, 128.6, 127.2, 120.4, 119.2, 118.0, 113.0, 111.9, 105.7, 68.2, 56.5, 56.2, 53.2, 44.8, 40.8, 36.2, 31.9, 29.9, 21.7, 19.3, 7.6. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 184 IR (Neat Film, NaCl) 2933, 2852, 2793, 2738, 1615, 1521, 1455, 1317, 1205, 1184, 1124, 815, 739 cm–1. [α]D21 +66.9º (c 0.63, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H34BrN3 [M+H]+: 400.2753, found 400.2754. 185 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers B(OH)2 H N Me N N H N N PhMe/H2O/EtOH TfO Me Me 310 Pd(PPh3)4 (10 mol%) K2CO3 71% yield 241 Me Me N Me 338 (R,R)-Amino Olefin 338: In a nitrogen-filled glovebox, 4-dimethylamino boronic acid 310 (4.6 mg, 0.0281 mmol, 1.20 equiv), triflate 241 (10.0 mg, 0.0234 mmol, 1.00 equiv), K2CO3 (9.7 mg, 0.0703 mmol, 3.00 equiv), and Pd(PPh3)4 (2.7 mg, 0.0023 mmol, 0.10 equiv) were added to an oven-dried 1-dram vial with a stir bar. The vial was sealed with a septum cap and removed from the glovebox. Toluene (0.2 mL), water (0.2 mL), and EtOH (50 µL) were added via syringe, and the vial was heated to 90 ºC for 36 hours. The reaction was cooled to 23 ºC, diluted with ethyl acetate, and washed with water, then dried over Na2SO4, and concentrated. Flash chromatography (95:5 dichloromethane/ methanol) afforded (R,R)-amino olefin 338 as a tan foam (6.6 mg, 0.017 mmol, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 7.72 – 7.63 (m, 2H), 7.60 – 7.51 (m, 1H), 7.46 (dddd, J = 9.8, 5.7, 1.8, 0.9 Hz, 2H), 7.02 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 6.87 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 8.4 Hz, 1H), 5.01 (s, 1H), 4.30 (s, 1H), 3.48 – 3.26 (m, 2H), 3.15 – 3.05 (m, 1H), 3.03 (s, 6H), 2.71 – 2.64 (m, 2H), 2.64 – 2.52 (m, 1H), 1.99 – 1.80 (m, 2H), 1.74 (tdd, J = 13.1, 8.8, 3.2 Hz, 1H), 1.53 (d, J = 13.7 Hz, 2H), 1.41 (dt, J = 13.2, 3.2 Hz, 1H), 1.16 (td, J = 13.7, 3.7 Hz, 1H), 0.99 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 150.8, 136.6, 134.5, 133.2, 132.3, 132.2, 132.1, 132.1, 129.7, 129.0, 128.7, 128.6, 123.8, 121.2, 119.5, 118.1, 116.8, 113.4, 111.9, 107.5, 56.9, 51.7, 45.2, 40.6, 37.0, 29.8, 27.9, 20.8, 16.6, 8.8. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 186 IR (Neat Film, NaCl) 3046, 2932, 2855, 1730, 1634, 1612, 1523, 1453, 1415, 1357, 1195, 1118, 947, 823, 741, 723 cm–1. [α]D21 –29.6º (c 0.48, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H32N3 [M+H]+: 398.2596, found 398.2602. 187 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers B(OH)2 H N Me N N H N N PhMe/H2O/EtOH TfO Me Me 310 Pd(PPh3)4 (10 mol%) K2CO3 287 90% yield Me Me N Me 339 (S,R)-Amino Olefin 339: In a nitrogen-filled glovebox, 4-dimethylamino boronic acid 310 (4.6 mg, 0.0281 mmol, 1.20 equiv), triflate 287 (10.0 mg, 0.0234 mmol, 1.00 equiv), K2CO3 (9.7 mg, 0.0703 mmol, 3.00 equiv), and Pd(PPh3)4 (2.7 mg, 0.0023 mmol, 0.10 equiv) were added to an oven-dried 1-dram vial with a stir bar. The vial was sealed with a septum cap and removed from the glovebox. Toluene (0.2 mL), water (0.2 mL), and EtOH (50 µL) were added via syringe, and the vial was heated to 90 ºC for 16 hours. The reaction was cooled to 23 ºC, diluted with ethyl acetate, and washed with water, then dried over Na2SO4, and concentrated. Flash chromatography (90:10 hexanes/ ethyl acetate) afforded (S,R)-amino olefin 339 as a tan foam (8.4 mg, 0.021 mmol, 90% yield). 1 H NMR (600 MHz, CDCl3) δ 7.45 (dd, J = 7.8, 1.2 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.07 – 7.00 (m, 1H), 6.88 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 6.53 (dd, J = 8.4, 1.0 Hz, 1H), 5.09 (s, 1H), 3.22 (s, 1H), 3.15 – 3.09 (m, 1H), 3.09 – 3.04 (m, 1H), 3.03 (s, 6H), 2.74 – 2.70 (m, 1H), 2.69 – 2.59 (m, 1H), 2.37 (t, J = 11.5 Hz, 1H), 1.96 (d, J = 10.9 Hz, 2H), 1.84 (dq, J = 14.7, 7.5 Hz, 1H), 1.67 – 1.54 (m, 2H), 1.44 (dt, J = 16.2, 8.5 Hz, 1H), 1.31 (p, J = 7.2 Hz, 1H), 0.90 (dt, J = 17.7, 7.2 Hz, 1H), 0.78 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 150.9, 136.8, 135.4, 134.7, 129.3, 129.0, 123.8, 120.8, 119.5, 118.1, 117.7, 113.2, 111.9, 108.0, 66.0, 55.7, 52.9, 40.6, 37.9, 31.0, 23.2, 22.0, 21.8, 8.6. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 188 IR (Neat Film, NaCl) 3044, 2935, 2792, 2731, 1610, 1521, 1455, 1435, 1372, 1193, 1039, 947, 800, 739 cm–1. [α]D21 +68.2º (c 0.65, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H32N3 [M+H]+: 398.2596, found 398.2600. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N Pd/C (10%) H2 (60 bar) H N 189 N CH2Cl2, 23 ºC, 16h Me Me N H 43% yield Me Me Me N Me 338 340 (R,R,R)-Amino Dimer 340: To a 1-dram with a stir bar was added (R,R)-amino olefin 338 (4.0 mg, 0.010 mmol, 1.00 equiv) and CH2Cl2 (1 mL). Pd/C (10%) (67% H2O w/w) (15 mg) was added, and the vial was sealed with a septa cap pierced with an 18-gauge needle. The vial was then transferred to a Parr hydrogenation vessel, and the entire vessel was backfilled with H2 (3x) before pressurizing to 60 bar for 16 hours. The H2 was carefully vented, and the reaction was filtered through Celite, concentrated, and purified by preparative TLC plate (95:5 ethyl acetate/ triethylamine) afforded (R,R,R)-amino dimer 340 as a yellow solid (1.7 mg, 0.0043 mmol, 43% yield). Note: This compound is very unstable in CDCl3 and changes colors with prolonged exposure. 1 H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.54 (t, J = 11.4 Hz, 4H), 5.56 (d, J = 7.4 Hz, 1H), 3.95 (s, 2H), 3.59 (s, 1H), 3.41 – 3.25 (m, 2H), 3.15 – 3.03 (m, 1H), 2.88 (s, 6H), 2.72 – 2.60 (m, 4H), 2.35 (dd, J = 14.3, 7.7 Hz, 1H), 2.25 (d, J = 14.1 Hz, 1H), 2.16 – 2.06 (m, 1H), 1.80 (d, J = 16.2 Hz, 1H), 1.61 (s, 1H), 1.40 (d, J = 12.4 Hz, 1H), 0.85 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 190 C NMR (100 MHz, CDCl3) δ 149.0, 135.9, 132.4, 130.6, 128.0, 127.6, 120.4, 119.1, 117.9, 112.0, 112.0, 104.6, 60.0, 54.1, 51.9, 45.4, 41.3, 40.6, 35.3, 29.8, 29.4, 25.5, 21.4, 17.3, 7.8. IR (Neat Film, NaCl) 2921, 1730, 1614, 1519, 1455, 1351, 1163, 946, 801, 744 cm–1. [α]D21 +87.5º (c 0.13, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H34N3 [M+H]+: 400.2753, found 400.2753. Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers H N N Pd/C (10%) H2 (60 bar) H N 191 N CH2Cl2, 23 ºC, 48h Me Me N Me 37% yield H Me 339 Me N Me 341 (S,R,R)-Amino Dimer 341: To a 1-dram with a stir bar was added (S,R)-amino olefin 339 (6.0 mg, 0.0151 mmol, 1.00 equiv) and CH2Cl2 (1 mL). Pd/C (10%) (67% H2O w/w) (15 mg) was added, and the vial was sealed with a septa cap pierced with an 18-gauge needle. The vial was then transferred to a Parr hydrogenation vessel, and the entire vessel was backfilled with H2 (3x) before pressurizing to 60 bar for 48 hours. The H2 was carefully vented, and the reaction was filtered through Celite, concentrated, and purified by preparative TLC plate (80:20 à 1:1 hexanes/ ethyl acetate) afforded (S,R,R)-amino dimer 341 as a white solid (2.2 mg, 0.0055 mmol, 37% yield). Note: This compound is very unstable in CDCl3 and changes colors with prolonged exposure. This compound showed atropisomers in 1H NMR in CDCl3 that could not be resolved by heating or cooling. The mixture of atropisomers could be resolved in 1H NMR at +90 ºC in C2D2Cl4. 1 H NMR (400 MHz, C2D2Cl4, 90 ºC) δ 7.50 (dt, J = 7.8, 1.0 Hz, 1H), 7.09 – 7.00 (m, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.65 – 6.57 (m, 2H), 5.50 (d, J = 8.2 Hz, 1H), 3.31 – 3.03 (m, 4H), 2.93 (s, 6H), 2.81 (d, J = 14.9 Hz, 1H), 2.54 (s, 1H), 2.31 (t, J = 13.8 Hz, 2H), 2.22 – 2.11 (m, 1H), 2.06 – 1.95 (m, 1H), 1.93 – 1.82 (m, 2H), 1.43 – 1.34 (m, 2H), 1.14 – 1.00 (m, 1H), 0.23 (t, J = 7.5 Hz, 3H). Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 13 192 C NMR (100 MHz, CDCl3) δ 149.2, 137.7, 136.5, 133.6, 130.2, 127.9, 127.6, 120.1, 118.9, 117.9, 112.3, 105.1, 68.6, 56.6, 54.8, 54.5, 41.4, 40.7, 36.2, 33.0, 29.4, 21.4, 21.2, 19.9, 6.7. IR (Neat Film, NaCl) 2931, 2854, 12793, 1738, 1614, 1520, 1453, 1341, 1215, 1124, 948, 816, 745 cm–1. [α]D21 –100.8º (c 0.17, CHCl3). HRMS (MM:ESI-APCI+) m/z calculated for C27H34N3 [M+H]+: 400.2753, found 400.2753. 193 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Conditions for attempted small scale reductions shown in Table 2.3.2.1. H N N H N N N H N N N H N N N N conditions Me H Me N Ph 302 H MeOH, 23 ºC Me N H H Me Me 285 Me N H H 303 H Me H Ph N Me 304 General procedure for Raney Nickel + Hydrogen To a 1-dram with a stir bar was added dimer starting material 302 (1.00 equiv) and MeOH (0.05 M). A suspension of Raney Nickel® (50:50 w/ water) (100% wt) was added and the vial was sealed with a septa cap. The vial was rapidly purged and backfilled with nitrogen (10x). The solution was then sparged with H2 (balloon) for 10 min before being allowed to stir under an atmosphere of hydrogen at 23 °C for 3 h. Upon completion, the reaction was analyzed by LCMS. General procedure for Raney Nickel + Sulfuric Acid To a 1/2-dram vial with a stir bar was added dimer starting material 302 (1.00 equiv) and MeOH (0.05 M). A suspension of Raney Nickel® (50:50 w/ water) (100% wt) was added, followed by H2SO4 (conc.) (250% wt). The vial was quickly sealed with a teflon-lined cap and stirred at 1000 rpm behind a blast shield at 23 ºC. After 4 hours, the reaction was analyzed by LCMS. 194 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers General Procedure for Petasis Borono–Mannich Optimization. H B(OH)2 N N Me2N Ph HO 310 solvent (0.1 M) 309 N N Ph 23 ºC, 16 h H Me2N 311 2 equiv To a 1-dram vial with a stir bar was added hydroxy-indole 309 (32 mg, 0.10 mmol, 1.00 equiv) and 4-dimethylaminophenyl boronic acid 310 (34 mg, 0.20 mmol, 2.00 equiv). Solvent (1.0 mL) was added, and the reaction was stirred for 16 hours at 23 ºC. The reaction solvent was evaporated under reduced pressure and SiEt4 was added as an internal standard for 1H NMR analysis. The crude was purified by flash chromatography (90:10 à 80:20 hexanes/ ethyl acetate) to afford pentacycle 311 as a white foam. 195 Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Table 2.5.2.1. Experimental for Attempted Small Scale Reduction of Benzyl Heterodimer 302. H N H N N Me H Me N H H 285 Me N OR H N conditions Me N N H Ph N 302 N H N N N N OR Me Me N H H H Me H N Ph 303 entry conditions result 1 Raney Nickel (100% wt), H2 (balloon) MeOH (0.05 M), 23 °C, 3 h partial reduction to 304 2 Raney Nickel (100% wt), H2SO4 (250% wt) MeOH (0.05 M) 23 °C, 4 h partial deprotection to 303 3 Raney Nickel (100% wt), H2 (balloon) MeOH (0.05 M), 23 °C, 3 h then, H2SO4 (250% wt), 23 °C, 4 h nonspecific decomposition 4 Pd/C (1000% wt), H2 (balloon) AcOH (0.0014 M), 23 °C, 16 h 5 Pd/C (1000% wt), H2 (60 bar) CH2Cl2 (0.0014 M), 23 °C, 16 h 6 Pd/C (250% wt), H2 (65 bar) CH2Cl2/NEt3 (10:1, 0.002 M), 23 °C, 16 h no reaction 7 [Rh(cod)dppb]BF4 (10 mol%), H2 (20 bar) CH2Cl2 (0.008 M), 23 °C, 16 h no reaction 8 [Rh(cod)dppb]BF4 (10 mol%), H2 (50 bar) CH2Cl2 (0.008 M), 23 °C, 16 h trace product 9 [Ir(cod)py(PCy3)]PF6 (10 mol%), H2 (50 bar) CH2Cl2 (0.008 M), 23 °C, 36 h no reaction 10 [Ir(cod)PHOX]BArF24 (30 mol%), H2 (50 bar) CH2Cl2 (0.002 M), 23 °C, 16 h no reaction 11 NaBH(OAc)3 (4 equiv), AcOH (11 equiv) CH2Cl2 (0.008 M), 23 °C, 4 h no reaction substrate adsorbed onto solid support substrate adsorbed onto solid support 304 Me Chapter 2 – Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers 2.6 (1) 196 REFERENCES AND NOTES Newman, D. 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O allyl Me O NBz O O Pd(OAc)2 (1.5 mol%) (S)-(CF3)3-t-Bu-PHOX (7.5 mol%) Me O N Ph 87%, 96% ee (±)-235 (+)-236 Me O O O Me RuCl3•xH2O (3 mol%) NaIO4 N (+)-322 CH3CN reflux, 16 h MeO2C 87% yield (+)-238 Me then DBU 23 ºC, 3 h Me H N NH O N OMe (+)-239 52% yield H LiAlH4 N Me HO Me 96% yield (–)-eburnamonine (–)-105 N N THF 23 ºC, 1 h O 99% yield, 6.6:1 d.r. (+)-240 99% yield O MeOH reflux, 16 h Pd/C (10 mol%), H2 DMF, 0.2 M, 23 ºC, 3.5 h N H (+)-237 PhNHNH2•HCl p-TsOH•H2O OH N POCl3 DMF 23 ºC, 36 h O N 74% yield ClO4 O O O CH3CN/H2O 0 ºC, 1.5 hours NaH (60%) NH 99% yield 3 steps from δ-valerolactam O Br MeOH/H2O 23 ºC, 24 h MTBE, 40 ºC to 60 ºC, 96 h Me O LiOH•H2O (+)-eburnamine (+)-26 B) Synthesis of aspidosperma monomer. Pd2(OAc)2 (1 mol%) (R)-(CF3)3-tBu-PHOX (5 mol%) N Me allyl O N MTBE, 60 ºC, 5 d O Me (±)-297 (–)-293 MsCl, i-Pr2NEt CH2Cl2, –20 ºC then, KO-t-Bu, THF –20 —> 0 ºC OH Me N then NaBH4, EtOH N H Me 74% yield (–)-324 BrCH2CH2OH K2CO3 EtOH, 80 ºC Me N H 72% yield (–)-323 92% yield 6 steps from indole N NH then LiAlH4; AcOH, H2O, THF 0 ºC —> 23 ºC, 16h O 97% yield, 94% ee O Cp2Zr(H)Cl H2NOSO3H THF, 23 º C, 1h N PhCHO, AcOH NaBH(OAc)3 CH3CN, 23 ºC, 16 h N H H Me N H Bn 94% yield (–)-aspidospermidine (–)-298 (–)-299 CF3 N Br NBS (1.0 equiv) CH3CN/CH2Cl2 –20 ºC, 5 min Me 85% yield H N Pd(dppf)Cl2 (10 mol%) B2Pin2, KOAc Me Bn 95% yield (–)-300 N P F3C t-Bu 1,4-dioxane 90 ºC, 16 h N O Bpin H N Bn CF3 (–)-301 (R)-(CF3)3-t-BuPHOX C) Synthesis of revised strempeliopidine. N Bpin Me H N Bn (–)-301 KHF2 MeOH, H2O 23 ºC, 1.5 h then, (+)-eburnamine (26) HFIP, 23 ºC, 16 h 98% yield > 20:1 dr H N N H Me H N Bn N Me N N MeOH, 23 ºC, 7 h 71% yield (+)-313 H Ra/Ni H2SO4 (conc.) H Me N H H N Me 284 revised strempeliopidine 209 Appendix 1 – Synthetic Summary for Chapter 2 Scheme A1.2. Synthetic summary of the total synthesis of Novotny’s proposed strempeliopidine. A) Synthesis of eburnea monomer. ClO4 N H MeO2C H N KOAc , 23 ºC, 3 h Me then, Pd/C (10 mol%), H2 23 ºC, 3.5 h H N THF, –78 ºC, 16 h O Me N TfO Me 80% yield (–)-epi-eburnamonine (–)-295 74% yield, >20:1 d.r. (–)-240 LiHMDS, HMPA PhNTf2 N N (–)-287 B) Synthesis of aspidosperma monomer. Br N Me allyl N MTBE, 60 ºC, 24 h O O Cp2Zr(H)Cl H2NOSO3H THF, 23 º C, 1h Br Pd2(pmdba)3 (5 mol%) (S)-(CF3)3-tBu-PHOX (12.5 mol%) Me O 97% yield, 92% ee O (±)-329 NH Br then LiAlH4; AcOH, H2O, THF 0 ºC —> 23 ºC, 16h Me (–)-290 N H (–)-306 53% yield 6 steps from 5-bromoindole 1) Chloroacetyl chloride Et3N, CH2Cl2, 0 ºC, 2 h 2) NaI, acetone, reflux, 2 h O O Pd(dppf)Cl2 (10 mol%) B2Pin2, KOAc N N Br Bpin THF, reflux, 16 h 3) AgOTf, THF, 23 ºC, 1 h Me 83% yield (3 steps) N 66% yield Me N (–)-307 (–)-289 C) Synthesis of Novotny’s proposed strempeliopidine. O H N N + Bpin N Me (–)-289 82% yield (–)-287 H N N LiAlH4 H N N PhMe/H2O/EtOH 90 ºC, 16 h TfO Me O Pd(PPh3)4 (10 mol%) K2CO3 N N THF, 23 ºC —> reflux, 3 h Me Me N H Raney Nickel H2 (4 bar) N N MeOH, 23 ºC, 6 d Me N H H 56% yield 303 [XRD] 308 H Me 96% yield N Me N Me N H H 285 Novotny’s proposed strempeliopidine 210 Appendix 1 – Synthetic Summary for Chapter 2 Scheme A1.3. Stereoisomers of strempeliopidine synthesized in Chapter 2. H N N N N H Me H N H Me N H H Me N N Me 321 H N N N H H Me N H H Me N H N N N H H Me N H H Me H N H Me N H H 284 revised strempeliopidine N Me N H H 286 Kam’s proposed strempeliopidine N Me 319 H Me N N H H 318 N Me N H H 285 Novotny’s proposed strempeliopidine H N 320 H N N N H Me Me N H H ent-319 N Me APPENDIX 2 Spectra Relevant to Chapter 2: Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction 10 Me 9 N O (+)-236 O Ph 8 6 5 ppm 4 3 2 Figure A2.1. 1H NMR (500 MHz, CDCl3) of compound 236. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 212 Appendix 2 – Spectra Relevant to Chapter 2 213 80 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 Wavenumber [cm-1] 1800 1600 1400 1200 1000 800 600 Figure A2.2. Infrared spectrum (Thin Film, NaCl) of compound 236. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.3. 13C NMR (100 MHz, CDCl3) of compound 236. 0 400 10 9 Me NH (+)-237 O 8 6 5 ppm 4 3 2 Figure A2.4. 1H NMR (500 MHz, CDCl3) of compound 237. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 214 Appendix 2 – Spectra Relevant to Chapter 2 215 115 110 105 100 95 90 85 % Transmittance 80 75 70 65 60 55 50 45 40 35 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.5. Infrared spectrum (Thin Film, NaCl) of compound 237. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.6. 13C NMR (100 MHz, CDCl3) of compound 237. 0 10 Me N 9 (+)-322 O 8 O O 6 5 ppm 4 3 2 Figure A2.7. 1H NMR (500 MHz, CDCl3) of compound 322. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 216 Appendix 2 – Spectra Relevant to Chapter 2 217 115 110 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 50 45 40 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.8. Infrared spectrum (Thin Film, NaCl) of compound 322. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.9. 13C NMR (100 MHz, CDCl3) of compound 322. 0 10 O OH Me 9 O (+)-238 N 8 O 7 6 5 ppm 4 3 2 Figure A2.10. 1H NMR (400 MHz, CDCl3) of compound 238. O 1 0 Appendix 2 – Spectra Relevant to Chapter 2 218 Appendix 2 – Spectra Relevant to Chapter 2 219 95 90 85 80 75 % Transmittance 70 65 60 55 50 45 40 35 30 3600 3400 3200 3000 2800 2600 2400 2200 2000 Wavenumber [cm-1] 1800 1600 1400 1200 1000 800 600 Figure A2.11. Infrared spectrum (Thin Film, NaCl) of compound 238. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.12. 13C NMR (100 MHz, CDCl3) of compound 238. 0 10 O OMe Me 9 N (+)-239 O 8 NH 6 5 ppm 4 3 2 Figure A2.13. 1H NMR (500 MHz, CDCl3) of compound 239. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 220 Appendix 2 – Spectra Relevant to Chapter 2 221 112 110 108 106 104 % Transmittance 102 100 98 96 94 92 90 88 86 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 Wavenumber [cm-1] 1800 1600 1400 1200 1000 800 600 Figure A2.14. Infrared spectrum (Thin Film, NaCl) of compound 239. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.15. 13C NMR (100 MHz, CDCl3) of compound 239. 0 12 11 (+)-240 MeO2C N H 10 Me N ClO4 8 7 6 ppm 5 4 3 Figure A2.16. 1H NMR (400 MHz, CDCl3) of compound 240. 9 2 1 0 Appendix 2 – Spectra Relevant to Chapter 2 222 Appendix 2 – Spectra Relevant to Chapter 2 223 100 95 90 85 % Transmittance 80 75 70 65 60 55 50 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.17. Infrared spectrum (Thin Film, NaCl) of compound 240. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.18. 13C NMR (100 MHz, CDCl3) of compound 240. 0 10 H Me N 9 (–)-eburnamonine (–)-105 O N 8 6 5 ppm 4 3 2 Figure A2.19. 1H NMR (500 MHz, CDCl3) of compound 105. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 224 Appendix 2 – Spectra Relevant to Chapter 2 225 96 94 92 90 88 86 84 % Transmittance 82 80 78 76 74 72 70 68 66 64 62 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.20. Infrared spectrum (Thin Film, NaCl) of compound 105. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.21. 13C NMR (100 MHz, CDCl3) of compound 105. 0 10 H Me N 9 8 (+)-epi-eburnamonine (+)-295 O N 6 5 ppm 4 3 2 Figure A2.22. 1H NMR (300 MHz, CDCl3) of compound 295. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 226 Appendix 2 – Spectra Relevant to Chapter 2 227 100 99 98 97 96 95 94 93 92 91 % Transmittance 90 89 88 87 86 85 84 83 82 81 80 79 78 77 76 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.23. Infrared spectrum (Thin Film, NaCl) of compound 295. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.24. 13C NMR (100 MHz, CDCl3) of compound 295. 0 9 H Me N H Me N 7 6 (–)-isoeburnamine (–)-26b HO N 5 ppm 4 3 2 1 Figure A2.25. 1H NMR (400 MHz, CDCl3) of a 2.5:1 mixture of compounds 26a and 26b. 8 (+)-eburnamine (+)-26a HO N 0 Appendix 2 – Spectra Relevant to Chapter 2 228 Appendix 2 – Spectra Relevant to Chapter 2 229 100 95 90 85 % Transmittance 80 75 70 65 60 55 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.26. Infrared spectrum (Thin Film, NaCl) of a 2.5:1 mixture of 26a:26b. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.27. 13C NMR (100 MHz, CDCl3) of a 2.5:1 mixture of 26a:26b. 10 9 TfO N 287 H Me N 8 6 5 ppm 4 3 2 Figure A2.28. 1H NMR (400 MHz, CDCl3) of compound 287. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 230 Appendix 2 – Spectra Relevant to Chapter 2 231 60 58 56 54 52 50 % Transmittance 48 46 44 42 40 38 36 34 32 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.29. Infrared spectrum (Thin Film, NaCl) of compound 287. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.30. 13C NMR (100 MHz, CDCl3) of compound 287. 0 10 Br 9 O 325 N 8 O OH 6 5 ppm 4 3 2 Figure A2.31. 1H NMR (500 MHz, CDCl3) of compound 325. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 232 Appendix 2 – Spectra Relevant to Chapter 2 233 119 118 117 116 115 114 113 112 111 110 % Transmittance 109 108 107 106 105 104 103 102 101 100 99 98 97 96 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.32. Infrared spectrum (Thin Film, NaCl) of compound 325. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.33. 13C NMR (100 MHz, CDCl3) of compound 325. 0 600 10 Br 9 O 326 N 8 O 6 5 ppm 4 3 2 Figure A2.34. 1H NMR (500 MHz, CDCl3) of compound 326. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 234 Appendix 2 – Spectra Relevant to Chapter 2 235 112 110 108 106 104 102 100 98 % Transmittance 96 94 92 90 88 86 84 82 80 78 76 74 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.35. Infrared spectrum (Thin Film, NaCl) of compound 326. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.36. 13C NMR (100 MHz, CDCl3) of compound 326. 0 600 10 Br 9 O N 327 8 OH 6 5 ppm 4 3 2 Figure A2.37. 1H NMR (400 MHz, CDCl3) of compound 327. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 236 Appendix 2 – Spectra Relevant to Chapter 2 237 155 150 145 140 135 130 % Transmittance 125 120 115 110 105 100 95 90 85 80 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.38. Infrared spectrum (Thin Film, NaCl) of compound 327. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.39. 13C NMR (100 MHz, CDCl3) of compound 327. 0 600 10 9 Br O 328 N 8 6 5 ppm 4 3 2 Figure A2.40. 1H NMR (500 MHz, CDCl3) of compound 328. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 238 Appendix 2 – Spectra Relevant to Chapter 2 239 135 130 125 % Transmittance 120 115 110 105 100 95 90 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.41. Infrared spectrum (Thin Film, NaCl) of compound 328. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.42. 13C NMR (100 MHz, CDCl3) of compound 328. 0 600 10 Br 9 O O (±)-329 O N Me 8 6 5 ppm 4 3 2 Figure A2.43. 1H NMR (500 MHz, CDCl3) of compound 329. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 240 Appendix 2 – Spectra Relevant to Chapter 2 241 Figure A2.44. Infrared spectrum (Thin Film, NaCl) of compound 329. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.45. 13C NMR (100 MHz, CDCl3) of compound 329. 0 10 Br 9 O Me 8 (–)-290 N 6 5 ppm 4 3 2 Figure A2.46. 1H NMR (500 MHz, CDCl3) of compound 290. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 242 Appendix 2 – Spectra Relevant to Chapter 2 243 105 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.47. Infrared spectrum (Thin Film, NaCl) of compound 290. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.48. 13C NMR (100 MHz, CDCl3) of compound 290. 0 600 10 Me N H 9 (–)-306 NH 8 Br 6 5 ppm 4 3 2 Figure A2.49. 1H NMR (400 MHz, CDCl3) of compound 306. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 244 Appendix 2 – Spectra Relevant to Chapter 2 245 Figure A2.50. Infrared spectrum (Thin Film, NaCl) of compound 306. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.51. 13C NMR (100 MHz, CDCl3) of compound 306. 0 10 Me N 9 N (–)-307 O 8 Br 6 5 ppm 4 3 2 Figure A2.52. 1H NMR (400 MHz, CDCl3) of compound 307. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 246 Appendix 2 – Spectra Relevant to Chapter 2 247 95 90 85 80 75 % Transmittance 70 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.53. Infrared spectrum (Thin Film, NaCl) of compound 307. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.54. 13C NMR (100 MHz, CDCl3) of compound 307. 0 600 10 Me N N 9 (–)-289 O Me Me 8 Me B O Me O 6 5 ppm 4 3 2 Figure A2.55. 1H NMR (400 MHz, CDCl3) of compound 289. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 248 Appendix 2 – Spectra Relevant to Chapter 2 249 120 110 100 90 % Transmittance 80 70 60 50 40 30 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.56. Infrared spectrum (Thin Film, NaCl) of compound 289. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.57. 13C NMR (100 MHz, CDCl3) of compound 289. 0 600 10 Me N O 9 N 330 N 8 Me N 7 6 5 ppm 4 3 2 Figure A2.58. 1H NMR (400 MHz, CDCl3) of compound 330 at –40°C. H 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 250 Appendix 2 – Spectra Relevant to Chapter 2 251 105 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.59. Infrared spectrum (Thin Film, NaCl) of compound 330. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.60. 13C NMR (100 MHz, CDCl3) of compound 330 at –40 °C. 600 10 Me N O N 9 308 N 8 H 7 6 5 ppm 4 3 2 Figure A2.61. 1H NMR (400 MHz, acetone-d6) of compound 308. Me N 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 252 Appendix 2 – Spectra Relevant to Chapter 2 253 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 50 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.62. Infrared spectrum (Thin Film, NaCl) of compound 308. 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.63. 13C NMR (100 MHz, acetone-d6) of compound 308. 0 600 10 Me N Ph H 9 N 302 N 8 H Me N 6 5 ppm 4 3 2 Figure A2.64. 1H NMR (400 MHz, CDCl3) of compound 302. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 254 Appendix 2 – Spectra Relevant to Chapter 2 255 Figure A2.65. Infrared spectrum (Thin Film, NaCl) of compound 302. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.66. 13C NMR (100 MHz, CDCl3) of compound 302. 0 10 Me N N H H 9 331 N H 7 6 5 ppm 4 3 2 Figure A2.67. 1H NMR (400 MHz, CD2Cl2) of compound 331 at –60 °C. 8 Me N 1 0 Appendix 2 – Spectra Relevant to Chapter 2 256 Appendix 2 – Spectra Relevant to Chapter 2 257 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.68. Infrared spectrum (Thin Film, NaCl) of compound 331. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.69. 13C NMR (100 MHz, CD2Cl2) of compound 331 at –60 °C. 600 10 Me N N H H 9 303 N 8 H 7 6 5 ppm 4 3 2 Figure A2.70. 1H NMR (400 MHz, acetone-d6) of compound 303. Me N 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 258 Appendix 2 – Spectra Relevant to Chapter 2 259 102 100 98 96 94 92 90 % Transmittance 88 86 84 82 80 78 76 74 72 70 68 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.71. Infrared spectrum (Thin Film, NaCl) of compound 303. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.72. 13C NMR (100 MHz, acetone-d6) of compound 303. -20 10 Me N N H H 9 321 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.73. 1H NMR (400 MHz, C6D6) of compound 321. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 260 Appendix 2 – Spectra Relevant to Chapter 2 261 115 110 105 100 % Transmittance 95 90 85 80 75 70 65 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.74. Infrared spectrum (Thin Film, NaCl) of compound 321. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.75. 13C NMR (100 MHz, C6D6) of compound 321. 0 600 9 Me N 8 N H H 285 H N Me N 6 5 ppm 4 3 2 1 Figure A2.76. 1H NMR (400 MHz, acetone-d6) of compound 285 at –30 °C. 7 H 0 Appendix 2 – Spectra Relevant to Chapter 2 262 10 Me N N H H 9 285 H N 8 H Me N 6 5 ppm 4 3 2 Figure A2.77. 1H NMR (400 MHz, CDCl3) of compound 285. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 263 Appendix 2 – Spectra Relevant to Chapter 2 264 Figure A2.78. Infrared spectrum (Thin Film, NaCl) of compound 285. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.79. 13C NMR (100 MHz, acetone-d6) of compound 285 at –30 °C. 10 Me 9 N N (+)-299 Ph H 8 6 5 ppm 4 3 2 Figure A2.80. 1H NMR (400 MHz, CDCl3) of compound 299. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 265 Appendix 2 – Spectra Relevant to Chapter 2 266 Figure A2.81. Infrared spectrum (Thin Film, NaCl) of compound 299. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.82. 13C NMR (100 MHz, CDCl3) of compound 299. 0 10 Me N N (+)-300 9 Ph H 8 Br 6 5 ppm 4 3 2 Figure A2.83. 1H NMR (400 MHz, CDCl3) of compound 300. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 267 Appendix 2 – Spectra Relevant to Chapter 2 268 Figure A2.84. Infrared spectrum (Thin Film, NaCl) of compound 300. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.85. 13C NMR (100 MHz, CDCl3) of compound 300. 0 10 Me N 9 Ph H (+)-301 N 8 Bpin 6 5 ppm 4 3 2 Figure A2.86. 1H NMR (400 MHz, CDCl3) of compound 301. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 269 Appendix 2 – Spectra Relevant to Chapter 2 270 Figure A2.87. Infrared spectrum (Thin Film, NaCl) of compound 301. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.88. 13C NMR (100 MHz, CDCl3) of compound 301. 0 Me N H N 9 Ph (–)-313 H N 8 H Me N 6 5 ppm 4 3 2 Figure A2.89. 1H NMR (400 MHz, CDCl3) of compound 313. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 271 Appendix 2 – Spectra Relevant to Chapter 2 272 Figure A2.90. Infrared spectrum (Thin Film, NaCl) of compound 313. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.91. 13C NMR (100 MHz, CDCl3) of compound 313. 0 Me N H 9 N Ph H 8 (–)-332 H N Me N 6 5 ppm 4 3 2 Figure A2.92. 1H NMR (400 MHz, CDCl3) of compound 332. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 273 Appendix 2 – Spectra Relevant to Chapter 2 274 Figure A2.93. Infrared spectrum (Thin Film, NaCl) of compound 332. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.94. 13C NMR (100 MHz, CDCl3) of compound 332. 0 10 Me N H 9 N Ph 8 (–)-333 H N H Me N 6 5 ppm 4 3 2 Figure A2.95. 1H NMR (600 MHz, CDCl3) of compound 333. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 275 Appendix 2 – Spectra Relevant to Chapter 2 276 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 50 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.96. Infrared spectrum (Thin Film, NaCl) of compound 333. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.97. 13C NMR (100 MHz, CDCl3) of compound 333. 0 10 Me N H N 9 Ph (–)-334 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.98. 1H NMR (600 MHz, CDCl3) of compound 334. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 277 Appendix 2 – Spectra Relevant to Chapter 2 278 120 110 100 % Transmittance 90 80 70 60 50 40 30 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.99. Infrared spectrum (Thin Film, NaCl) of compound 334. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.100. 13C NMR (100 MHz, CDCl3) of compound 334. 0 N H H H N H Me N 10 9 8 7 6 5 ppm 4 3 2 Figure A2.101. 1H NMR (600 MHz, CDCl3) of compound 286. 286 Kam’s proposed strempeliopidine Me N 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 279 Appendix 2 – Spectra Relevant to Chapter 2 280 Figure A2.102. Infrared spectrum (Thin Film, NaCl) of compound 286. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.103. 13C NMR (100 MHz, CDCl3) of compound 286. 0 Me N H H Me N 9 8 284 revised strempeliopidine N H H N 6 5 ppm 4 3 2 Figure A2.104. 1H NMR (400 MHz, CDCl3) of compound 284. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 281 10 Me N N H H 9 318 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.105. 1H NMR (600 MHz, CDCl3) of compound 318. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 282 Appendix 2 – Spectra Relevant to Chapter 2 283 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.106. Infrared spectrum (Thin Film, NaCl) of compound 318. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.107. 13C NMR (100 MHz, CDCl3) of compound 318. 0 -20 Me N 319 H H Me N Figure A2.108. 1H NMR (600 MHz, CDCl3) of compound 319. N H H N Appendix 2 – Spectra Relevant to Chapter 2 284 200 180 160 140 120 100 ppm 71.09 66.03 59.52 56.48 53.98 53.47 53.02 51.20 45.61 44.72 38.69 35.92 35.11 34.43 30.28 29.85 29.02 28.35 24.83 23.35 21.88 20.97 17.26 14.28 7.65 7.22 136.80 134.27 133.85 128.71 125.88 121.70 120.41 119.23 117.83 112.31 110.96 104.95 149.30 Appendix 2 – Spectra Relevant to Chapter 2 285 Figure A2.109. Infrared spectrum (Thin Film, NaCl) of compound 319. 80 60 40 20 Figure A2.110. 13C NMR (100 MHz, CDCl3) of compound 319. 0 10 Me N N H H 9 320 H N 8 H Me N 6 5 ppm 4 3 2 Figure A2.111. 1H NMR (600 MHz, CDCl3) of compound 320. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 286 Appendix 2 – Spectra Relevant to Chapter 2 287 80 75 70 % Transmittance 65 60 55 50 45 40 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.112. Infrared spectrum (Thin Film, NaCl) of compound 320. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.113. 13C NMR (100 MHz, CDCl3) of compound 320. 0 10 Br Me N H 9 S O O N 317 H N 8 H Me N 6 5 ppm 4 3 2 Figure A2.114. 1H NMR (400 MHz, CD2Cl2) of compound 317. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 288 Appendix 2 – Spectra Relevant to Chapter 2 289 100 95 90 85 % Transmittance 80 75 70 65 60 55 50 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 Figure A2.115. Infrared spectrum (Thin Film, NaCl) of compound 317. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.116. 13C NMR (100 MHz, CD2Cl2) of compound 317. 0 Me Me N 9 311 H N H 8 NBn 6 5 ppm 4 3 2 Figure A2.117. 1H NMR (400 MHz, CDCl3) of compound 311. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 290 Appendix 2 – Spectra Relevant to Chapter 2 291 100 98 96 94 92 % Transmittance 90 88 86 84 82 80 78 76 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.118. Infrared spectrum (Thin Film, NaCl) of compound 311. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.119. 13C NMR (100 MHz, CDCl3) of compound 311. 0 Me2N 9 335 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.120. 1H NMR (400 MHz, CDCl3) of compound 335. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 292 Appendix 2 – Spectra Relevant to Chapter 2 293 Figure A2.121. Infrared spectrum (Thin Film, NaCl) of compound 335. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.122. 13C NMR (100 MHz, CDCl3) of compound 335. 0 Me2N 9 336 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.123. 1H NMR (600 MHz, CDCl3) of compound 336. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 294 Appendix 2 – Spectra Relevant to Chapter 2 295 Figure A2.124. Infrared spectrum (Thin Film, NaCl) of compound 336. 220 200 180 160 140 120 ppm 100 80 60 40 20 Figure A2.125. 13C NMR (100 MHz, CDCl3) of compound 336. 0 10 Me Me N 9 338 N H 8 Me N 6 5 ppm 4 3 2 Figure A2.126. 1H NMR (400 MHz, CDCl3) of compound 338. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 296 Appendix 2 – Spectra Relevant to Chapter 2 297 110 105 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 30 25 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.127. Infrared spectrum (Thin Film, NaCl) of compound 338. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.128. 13C NMR (100 MHz, CDCl3) of compound 338. 0 10 Me Me N 9 339 N H 8 Me N 6 5 ppm 4 3 2 Figure A2.129. 1H NMR (600 MHz, CDCl3) of compound 339. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 2 298 Appendix 2 – Spectra Relevant to Chapter 2 299 110 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.130. Infrared spectrum (Thin Film, NaCl) of compound 339. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.131. 13C NMR (100 MHz, CDCl3) of compound 339. 0 Me Me N 9 340 H N H 8 Me N 6 5 ppm 4 3 2 Figure A2.132. 1H NMR (600 MHz, CDCl3) of compound 340. 7 1 0 -1 Appendix 2 – Spectra Relevant to Chapter 2 300 Appendix 2 – Spectra Relevant to Chapter 2 301 90 88 86 84 82 80 78 76 % Transmittance 74 72 70 68 66 64 62 60 58 56 54 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.133. Infrared spectrum (Thin Film, NaCl) of compound 340. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.134. 13C NMR (100 MHz, CDCl3) of compound 340. 0 10 Me Me N 9 341 H N H Me N 7 6 5 ppm 4 3 2 1 Figure A2.135. 1H NMR (400 MHz, C2D2Cl4) of compound 341 at 90 °C. 8 0 Appendix 2 – Spectra Relevant to Chapter 2 302 Appendix 2 – Spectra Relevant to Chapter 2 303 102 100 98 96 94 92 90 % Transmittance 88 86 84 82 80 78 76 74 72 70 68 66 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A2.136. Infrared spectrum (Thin Film, NaCl) of compound 341. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.137. 13C NMR (100 MHz, CDCl3) of compound 341. 0 APPENDIX 3 X-Ray Crystallography Reports Relevant to Chapter 2: Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers Through a Convergent Petasis Borono–Mannich Reaction Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.1 305 GENERAL EXPERIMENTAL X-Ray crystallographic analysis was obtained from the Caltech X-Ray Crystallography Facility using a Bruker AXS D8 VENTURE KAPPA diffractometer. A3.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF COMPOUND 308 (V22106) An X-Ray quality crystal of dimer 308 was grown by slow evaporation from acetone-d6 at 23 °C. Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IμS micro-source for the structure of compound V22106. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20172 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). All disordered atoms were refined with the help of similarity restraints on the 1,2and 1,3-distances and displacement parameters as well as enhanced rigid bond restraints for anisotropic displacement parameters. Compound V22106 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Figure A3.2.1. X-Ray Coordinate of Compound 308 (V22106) . Table A3.2.1. Crystal data and structure refinement for V22106. Identification code V22106 Empirical formula C38 H42 N4 O Formula weight 570.75 Temperature 100(2) K Wavelength 1.54178 Å 306 307 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 8.4695(10) Å a= 90°. b = 16.5570(17) Å b= 90°. c = 21.444(3) Å g = 90°. Volume 3007.1(6) Å3 Z 4 Density (calculated) 1.261 Mg/m3 Absorption coefficient 0.591 mm-1 F(000) 1224 Crystal size 0.250 x 0.100 x 0.050 mm3 Theta range for data collection 3.372 to 74.566°. Index ranges -10<=h<=10, -20<=k<=20, -26<=l<=26 Reflections collected 40155 Independent reflections 6155 [R(int) = 0.0523] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.6106 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6155 / 63 / 410 Goodness-of-fit on F2 1.030 Final R indices [I>2sigma(I)] R1 = 0.0362, wR2 = 0.0894 R indices (all data) R1 = 0.0405, wR2 = 0.0916 Absolute structure parameter 0.09(11) Extinction coefficient n/a Largest diff. peak and hole 0.252 and -0.241 e.Å-3 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 308 Table A3.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22106. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _______________________________________________________________________ Atom x y z U(eq) _______________________________________________________________________ O(1) -1371(3) 7037(1) 4428(1) 47(1) C(1) -183(3) 6675(1) 4602(1) 35(1) C(2) -124(3) 6092(2) 5142(1) 39(1) C(3) 1592(3) 5765(1) 5166(1) 29(1) C(4) 2217(2) 5724(1) 5821(1) 23(1) C(5) 2556(2) 6322(1) 6247(1) 23(1) C(6) 3131(2) 6098(1) 6835(1) 22(1) C(7) 3333(2) 5275(1) 6976(1) 23(1) C(8) 2963(3) 4672(1) 6548(1) 25(1) C(9) 2419(3) 4908(1) 5967(1) 24(1) N(1) 2078(3) 4401(1) 5445(1) 34(1) C(10) 1659(4) 4876(1) 5000(1) 38(1) C(11) 1433(6) 4643(2) 4334(1) 64(1) C(12) 2568(4) 5136(2) 3918(1) 44(1) C(13) 3537(3) 5814(2) 4229(1) 36(1) C(18) 5078(12) 5563(5) 4616(4) 33(2) C(19) 6253(6) 5001(4) 4281(3) 55(2) C(18A) 4847(15) 5351(8) 4558(7) 60(3) C(19A) 5773(8) 5896(6) 4996(4) 77(3) C(14) 4124(3) 6418(2) 3728(1) 42(1) C(15) 2800(4) 6883(2) 3402(1) 43(1) C(16) 1720(4) 7298(2) 3869(1) 51(1) N(2) 1268(3) 6729(1) 4357(1) 38(1) C(17) 2509(3) 6293(1) 4688(1) 31(1) C(20) 3445(2) 6731(1) 7306(1) 21(1) C(21) 2441(2) 7343(1) 7420(1) 22(1) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 309 C(22) 2776(2) 7984(1) 7911(1) 22(1) C(37) 3953(2) 8604(1) 7639(1) 23(1) C(38) 3382(3) 9029(1) 7048(1) 29(1) C(23) 1274(3) 8393(1) 8161(1) 30(1) C(24) 1663(3) 8907(1) 8738(1) 38(1) C(25) 2601(4) 8447(2) 9229(1) 42(1) N(3) 4020(3) 8086(1) 8957(1) 32(1) C(26) 5030(4) 7685(1) 9419(1) 42(1) C(27) 6589(3) 7406(1) 9140(1) 41(1) C(28) 6295(3) 6996(1) 8523(1) 30(1) C(29) 7267(3) 6552(1) 8097(1) 31(1) C(30) 8858(3) 6325(1) 8111(2) 48(1) C(31) 9483(3) 5936(2) 7605(2) 56(1) C(32) 8571(3) 5770(1) 7082(2) 47(1) C(33) 6963(3) 5969(1) 7052(1) 32(1) C(34) 6326(2) 6356(1) 7570(1) 25(1) N(4) 4811(2) 6652(1) 7687(1) 21(1) C(35) 4868(3) 7049(1) 8256(1) 23(1) C(36) 3505(3) 7528(1) 8469(1) 24(1) _______________________________________________________________________ 310 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.2.3. Bond lengths [Å] and angles [°] for V22106. ________________________________________________________________________ Bond Length (Å) Bond Length (Å) ________________________________________________________________________ O(1)-C(1) C(1)-N(2) C(1)-C(2) C(2)-C(3) C(2)-H(2A) C(2)-H(2B) C(3)-C(4) C(3)-C(10) C(3)-C(17) C(4)-C(5) C(4)-C(9) 1.229(3) 1.339(4) 1.508(3) 1.552(4) 0.9900 0.9900 1.502(3) 1.516(3) 1.556(3) 1.378(3) 1.397(3) C(13)-C(17) C(13)-C(14) C(13)-C(18) C(18)-C(19) C(18)-H(18A) C(18)-H(18B) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(18A)-C(19A) C(18A)-H(18C) 1.535(3) 1.549(3) 1.602(9) 1.540(11) 0.9900 0.9900 0.9800 0.9800 0.9800 1.520(14) 0.9900 C(5)-C(6) C(5)-H(5) C(6)-C(7) C(6)-C(20) C(7)-C(8) C(7)-H(7) C(8)-C(9) C(8)-H(8) C(9)-N(1) N(1)-C(10) C(10)-C(11) C(11)-C(12) C(11)-H(11A) C(11)-H(11B) C(12)-C(13) C(12)-H(12A) C(12)-H(12B) C(13)-C(18A) 1.401(3) 0.9500 1.406(3) 1.480(3) 1.391(3) 0.9500 1.386(3) 0.9500 1.429(3) 1.286(3) 1.492(3) 1.545(5) 0.9900 0.9900 1.543(4) 0.9900 0.9900 1.523(11) C(18A)-H(18D) C(19A)-H(19D) C(19A)-H(19E) C(19A)-H(19F) C(14)-C(15) C(14)-H(14A) C(14)-H(14B) C(15)-C(16) C(15)-H(15A) C(15)-H(15B) C(16)-N(2) C(16)-H(16A) C(16)-H(16B) N(2)-C(17) C(17)-H(17) C(20)-C(21) C(20)-N(4) C(21)-C(22) 0.9900 0.9800 0.9800 0.9800 1.529(4) 0.9900 0.9900 1.521(4) 0.9900 0.9900 1.459(3) 0.9900 0.9900 1.458(3) 1.0000 1.345(3) 1.423(3) 1.522(3) 311 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(21)-H(21) C(22)-C(23) C(22)-C(36) C(22)-C(37) C(37)-C(38) C(37)-H(37A) C(37)-H(37B) C(38)-H(38A) C(38)-H(38B) C(38)-H(38C) C(23)-C(24) C(23)-H(23A) C(23)-H(23B) C(24)-C(25) C(24)-H(24A) C(24)-H(24B) C(25)-N(3) C(25)-H(25A) C(25)-H(25B) N(3)-C(36) N(3)-C(26) C(26)-C(27) C(26)-H(26A) C(26)-H(26B) C(27)-C(28) C(27)-H(27A) C(27)-H(27B) C(28)-C(35) C(28)-C(29) C(29)-C(30) C(29)-C(34) C(30)-C(31) C(30)-H(30) C(31)-C(32) 0.9500 1.538(3) 1.545(3) 1.545(3) 1.527(3) 0.9900 0.9900 0.9800 0.9800 0.9800 1.538(3) 0.9900 0.9900 1.522(4) 0.9900 0.9900 1.464(3) 0.9900 0.9900 1.463(3) 1.467(3) 1.521(4) 0.9900 0.9900 1.508(3) 0.9900 0.9900 1.341(3) 1.433(3) 1.399(3) 1.420(3) 1.368(5) 0.9500 1.389(5) C(31)-H(31) C(32)-C(33) C(32)-H(32) C(33)-C(34) C(33)-H(33) C(34)-N(4) N(4)-C(35) C(35)-C(36) C(36)-H(36) O(1)-C(1)-N(2) O(1)-C(1)-C(2) N(2)-C(1)-C(2) C(1)-C(2)-C(3) C(1)-C(2)-H(2A) C(3)-C(2)-H(2A) C(1)-C(2)-H(2B) C(3)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(4)-C(3)-C(10) C(4)-C(3)-C(2) C(10)-C(3)-C(2) C(4)-C(3)-C(17) C(10)-C(3)-C(17) C(2)-C(3)-C(17) C(5)-C(4)-C(9) C(5)-C(4)-C(3) C(9)-C(4)-C(3) C(4)-C(5)-C(6) C(4)-C(5)-H(5) C(6)-C(5)-H(5) C(5)-C(6)-C(7) C(5)-C(6)-C(20) C(7)-C(6)-C(20) C(8)-C(7)-C(6) 0.9500 1.403(4) 0.9500 1.391(3) 0.9500 1.396(3) 1.387(2) 1.474(3) 1.0000 127.0(2) 124.8(3) 108.2(2) 106.3(2) 110.5 110.5 110.5 110.5 108.7 99.30(16) 112.19(19) 111.5(2) 117.83(18) 111.85(19) 104.41(17) 121.38(18) 131.33(18) 107.29(17) 118.55(17) 120.7 120.7 119.56(17) 119.20(17) 121.18(17) 121.75(18) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(8)-C(7)-H(7) C(6)-C(7)-H(7) C(9)-C(8)-C(7) C(9)-C(8)-H(8) C(7)-C(8)-H(8) C(8)-C(9)-C(4) C(8)-C(9)-N(1) C(4)-C(9)-N(1) C(10)-N(1)-C(9) N(1)-C(10)-C(11) N(1)-C(10)-C(3) C(11)-C(10)-C(3) C(10)-C(11)-C(12) C(10)-C(11)-H(11A) C(12)-C(11)-H(11A) C(10)-C(11)-H(11B) C(12)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(13)-C(12)-C(11) C(13)-C(12)-H(12A) C(11)-C(12)-H(12A) C(13)-C(12)-H(12B) C(11)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(18A)-C(13)-C(17) C(18A)-C(13)-C(12) C(17)-C(13)-C(12) C(18A)-C(13)-C(14) C(17)-C(13)-C(14) C(12)-C(13)-C(14) C(17)-C(13)-C(18) C(12)-C(13)-C(18) C(14)-C(13)-C(18) C(19)-C(18)-C(13) 119.1 119.1 117.70(18) 121.2 121.2 121.04(18) 127.29(18) 111.60(17) 106.06(17) 126.0(2) 115.51(18) 118.1(2) 109.7(2) 109.7 109.7 109.7 109.7 108.2 117.7(2) 107.9 107.9 107.9 107.9 107.2 112.1(6) 102.8(5) 110.6(2) 114.4(6) 107.04(19) 109.9(2) 105.3(4) 117.9(3) 105.4(4) 116.2(5) C(19)-C(18)-H(18A) 108.2 C(13)-C(18)-H(18A) 108.2 C(19)-C(18)-H(18B) 108.2 C(13)-C(18)-H(18B) 108.2 H(18A)-C(18)-H(18B) 107.4 C(18)-C(19)-H(19A) 109.5 C(18)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(18)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(19A)-C(18A)-C(13) 111.3(9) C(19A)-C(18A)-H(18C) 109.4 C(13)-C(18A)-H(18C) 109.4 C(19A)-C(18A)-H(18D) 109.4 C(13)-C(18A)-H(18D) 109.4 H(18C)-C(18A)-H(18D) 108.0 C(18A)-C(19A)-H(19D) 109.5 C(18A)-C(19A)-H(19E) 109.5 H(19D)-C(19A)-H(19E) 109.5 C(18A)-C(19A)-H(19F) 109.5 H(19D)-C(19A)-H(19F) 109.5 H(19E)-C(19A)-H(19F) 109.5 C(15)-C(14)-C(13) 114.0(2) C(15)-C(14)-H(14A) 108.8 C(13)-C(14)-H(14A) 108.8 C(15)-C(14)-H(14B) 108.8 C(13)-C(14)-H(14B) 108.8 H(14A)-C(14)-H(14B) 107.7 C(16)-C(15)-C(14) 111.5(2) C(16)-C(15)-H(15A) 109.3 C(14)-C(15)-H(15A) 109.3 C(16)-C(15)-H(15B) 109.3 C(14)-C(15)-H(15B) 109.3 312 313 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(15A)-C(15)-H(15B) N(2)-C(16)-C(15) N(2)-C(16)-H(16A) C(15)-C(16)-H(16A) N(2)-C(16)-H(16B) C(15)-C(16)-H(16B) H(16A)-C(16)-H(16B) C(1)-N(2)-C(17) C(1)-N(2)-C(16) C(17)-N(2)-C(16) N(2)-C(17)-C(13) N(2)-C(17)-C(3) C(13)-C(17)-C(3) N(2)-C(17)-H(17) C(13)-C(17)-H(17) C(3)-C(17)-H(17) C(21)-C(20)-N(4) C(21)-C(20)-C(6) N(4)-C(20)-C(6) C(20)-C(21)-C(22) C(20)-C(21)-H(21) C(22)-C(21)-H(21) C(21)-C(22)-C(23) C(21)-C(22)-C(36) C(23)-C(22)-C(36) C(21)-C(22)-C(37) C(23)-C(22)-C(37) C(36)-C(22)-C(37) C(38)-C(37)-C(22) C(38)-C(37)-H(37A) C(22)-C(37)-H(37A) C(38)-C(37)-H(37B) C(22)-C(37)-H(37B) H(37A)-C(37)-H(37B) 108.0 109.8(2) 109.7 109.7 109.7 109.7 108.2 116.03(18) 124.4(2) 118.6(2) 110.67(17) 103.8(2) 114.56(18) 109.2 109.2 109.2 118.60(17) 122.99(18) 118.22(16) 122.25(17) 118.9 118.9 113.22(17) 105.65(15) 106.00(16) 108.82(15) 111.87(16) 111.11(16) 114.54(17) 108.6 108.6 108.6 108.6 107.6 C(37)-C(38)-H(38A) C(37)-C(38)-H(38B) H(38A)-C(38)-H(38B) C(37)-C(38)-H(38C) H(38A)-C(38)-H(38C) H(38B)-C(38)-H(38C) C(24)-C(23)-C(22) C(24)-C(23)-H(23A) C(22)-C(23)-H(23A) C(24)-C(23)-H(23B) C(22)-C(23)-H(23B) H(23A)-C(23)-H(23B) C(25)-C(24)-C(23) C(25)-C(24)-H(24A) C(23)-C(24)-H(24A) C(25)-C(24)-H(24B) C(23)-C(24)-H(24B) H(24A)-C(24)-H(24B) N(3)-C(25)-C(24) N(3)-C(25)-H(25A) C(24)-C(25)-H(25A) N(3)-C(25)-H(25B) C(24)-C(25)-H(25B) H(25A)-C(25)-H(25B) C(36)-N(3)-C(25) C(36)-N(3)-C(26) C(25)-N(3)-C(26) N(3)-C(26)-C(27) N(3)-C(26)-H(26A) C(27)-C(26)-H(26A) N(3)-C(26)-H(26B) C(27)-C(26)-H(26B) H(26A)-C(26)-H(26B) C(28)-C(27)-C(26) 109.5 109.5 109.5 109.5 109.5 109.5 110.29(19) 109.6 109.6 109.6 109.6 108.1 113.07(19) 109.0 109.0 109.0 109.0 107.8 110.96(18) 109.4 109.4 109.4 109.4 108.0 107.3(2) 111.80(17) 113.26(19) 112.21(19) 109.2 109.2 109.2 109.2 107.9 109.8(2) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 314 C(28)-C(27)-H(27A) 109.7 C(33)-C(32)-H(32) 119.0 C(26)-C(27)-H(27A) 109.7 C(34)-C(33)-C(32) 116.6(2) C(28)-C(27)-H(27B) 109.7 C(34)-C(33)-H(33) 121.7 C(26)-C(27)-H(27B) 109.7 C(32)-C(33)-H(33) 121.7 H(27A)-C(27)-H(27B) 108.2 C(33)-C(34)-N(4) 131.4(2) C(35)-C(28)-C(29) 106.16(18) C(33)-C(34)-C(29) 121.5(2) C(35)-C(28)-C(27) 119.7(2) N(4)-C(34)-C(29) 107.03(18) C(29)-C(28)-C(27) 134.1(2) C(35)-N(4)-C(34) 106.99(17) C(30)-C(29)-C(34) 119.7(2) C(35)-N(4)-C(20) 119.32(16) C(30)-C(29)-C(28) 132.6(2) C(34)-N(4)-C(20) 132.61(17) C(34)-C(29)-C(28) 107.62(19) C(28)-C(35)-N(4) 112.12(19) C(31)-C(30)-C(29) 118.8(3) C(28)-C(35)-C(36) 127.47(18) C(31)-C(30)-H(30) 120.6 N(4)-C(35)-C(36) 120.12(17) C(29)-C(30)-H(30) 120.6 N(3)-C(36)-C(35) 109.18(18) C(30)-C(31)-C(32) 121.2(2) N(3)-C(36)-C(22) 111.40(15) C(30)-C(31)-H(31) 119.4 C(35)-C(36)-C(22) 109.57(15) C(32)-C(31)-H(31) 119.4 N(3)-C(36)-H(36) 108.9 C(31)-C(32)-C(33) 122.0(3) C(35)-C(36)-H(36) 108.9 C(31)-C(32)-H(32) 119.0 C(22)-C(36)-H(36) 108.9 ______________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 315 Table A3.2.4. Anisotropic displacement parameters (Å2x 103) for V22106. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ___________________________________________________________________ U11 U22 U33 U23 U13 U12 ___________________________________________________________________ O(1) 71(1) 40(1) 29(1) 5(1) 2(1) 30(1) C(1) 65(2) 23(1) 18(1) -3(1) -3(1) 11(1) C(2) 42(1) 39(1) 36(1) 13(1) -17(1) -7(1) C(3) 45(1) 21(1) 20(1) 0(1) -10(1) -4(1) C(4) 30(1) 20(1) 19(1) 2(1) -3(1) 1(1) C(5) 30(1) 17(1) 22(1) 1(1) -4(1) 2(1) C(6) 27(1) 19(1) 19(1) 0(1) -1(1) 2(1) C(7) 31(1) 21(1) 19(1) 2(1) -5(1) 3(1) C(8) 33(1) 17(1) 25(1) 2(1) -3(1) 3(1) C(9) 31(1) 17(1) 23(1) -2(1) -2(1) 0(1) N(1) 60(1) 21(1) 22(1) -2(1) -5(1) -5(1) C(10) 70(2) 22(1) 22(1) -1(1) -9(1) -10(1) C(11) 130(3) 36(1) 25(1) -2(1) -17(2) -24(2) C(12) 69(2) 35(1) 27(1) -10(1) 0(1) 12(1) C(13) 47(1) 36(1) 26(1) 4(1) -1(1) 12(1) C(18) 51(4) 24(3) 24(2) 3(2) -5(3) -4(3) C(19) 36(3) 84(4) 44(3) 27(3) 7(2) 19(3) C(18A) 36(4) 54(7) 91(8) 39(5) 2(4) 5(5) C(19A) 37(3) 132(8) 63(4) 41(5) -23(3) -26(4) C(14) 49(2) 49(2) 30(1) 8(1) 2(1) 10(1) C(15) 57(2) 48(1) 24(1) 13(1) 4(1) 11(1) C(16) 83(2) 36(1) 34(1) 18(1) 15(1) 24(1) N(2) 65(1) 25(1) 23(1) 6(1) 8(1) 18(1) C(17) 53(1) 21(1) 18(1) 2(1) -5(1) -1(1) C(20) 24(1) 20(1) 17(1) 1(1) -2(1) -1(1) C(21) 23(1) 19(1) 22(1) 1(1) -3(1) -1(1) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(22) 24(1) 19(1) 22(1) -3(1) 0(1) 0(1) C(37) 25(1) 20(1) 24(1) 1(1) -1(1) -1(1) C(38) 32(1) 26(1) 29(1) 4(1) 1(1) 1(1) C(23) 30(1) 23(1) 37(1) -2(1) 8(1) 2(1) C(24) 48(1) 29(1) 36(1) -6(1) 14(1) 7(1) C(25) 73(2) 29(1) 24(1) -6(1) 11(1) 2(1) N(3) 55(1) 22(1) 19(1) -3(1) -4(1) 1(1) C(26) 80(2) 25(1) 22(1) -3(1) -15(1) -1(1) C(27) 63(2) 24(1) 36(1) 2(1) -28(1) -2(1) C(28) 38(1) 18(1) 32(1) 4(1) -14(1) -2(1) C(29) 29(1) 17(1) 47(1) 4(1) -8(1) -2(1) C(30) 26(1) 24(1) 94(2) -5(1) -16(1) -3(1) C(31) 21(1) 27(1) 121(3) -10(2) 1(2) -4(1) C(32) 37(1) 21(1) 83(2) -5(1) 28(1) -4(1) C(33) 34(1) 19(1) 44(1) 2(1) 14(1) -1(1) C(34) 25(1) 15(1) 34(1) 5(1) 3(1) -1(1) N(4) 24(1) 19(1) 19(1) 0(1) -2(1) 0(1) C(35) 35(1) 18(1) 17(1) 2(1) -3(1) -2(1) C(36) 36(1) 18(1) 18(1) -1(1) 2(1) -2(1) _____________________________________________________________________ 316 317 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22106. ___________________________________________________________________ Atom x y z U(eq) ___________________________________________________________________ H(2A) H(2B) H(5) H(7) H(8) H(11A) -881 -394 2402 3732 3080 328 5644 6371 6875 5127 4117 4749 5077 5536 6145 7374 6652 4208 47 47 27 28 30 76 H(11B) H(12A) H(12B) H(18A) H(18B) H(19A) H(19B) H(19C) H(18C) H(18D) 1645 3319 1939 5644 4732 5710 7121 6675 4381 5572 4059 4754 5381 6062 5294 4505 4866 5275 4900 5118 4282 3722 3577 4736 5005 4153 4564 3911 4799 4244 76 52 52 40 40 82 82 82 72 72 H(19D) H(19E) H(19F) H(14A) H(14B) H(15A) H(15B) H(16A) H(16B) H(17) 6191 6649 5075 4847 4736 3267 2173 2272 764 3186 6357 5591 6091 6810 6118 7293 6505 7765 7499 6689 4762 5180 5328 3928 3410 3121 3144 4057 3654 4917 116 116 116 51 51 52 52 61 61 37 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(21) 1490 7376 7186 26 H(37A) 4176 9017 7961 27 H(37B) 4957 8323 7545 27 H(38A) 3181 8627 6722 43 H(38B) 4193 9408 6905 43 H(38C) 2406 9325 7139 43 H(23A) 812 8741 7833 36 H(23B) 485 7976 8273 36 H(24A) 2277 9386 8606 45 H(24B) 666 9101 8927 45 H(25A) 2906 8820 9569 50 H(25B) 1931 8016 9410 50 H(26A) 4464 7213 9593 51 H(26B) 5245 8064 9766 51 H(27A) 7295 7876 9079 49 H(27B) 7113 7025 9430 49 H(30) 9492 6439 8465 58 H(31) 10560 5776 7612 68 H(32) 9052 5513 6734 56 H(33) 6341 5846 6696 39 H(36) 2694 7154 8647 29 ___________________________________________________________________ 318 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.2.6. Torsion angles [°] for V22106. __________________________________________________________ O(1)-C(1)-C(2)-C(3) 177.8(2) N(2)-C(1)-C(2)-C(3) -2.7(2) C(1)-C(2)-C(3)-C(4) 137.26(19) C(1)-C(2)-C(3)-C(10) -112.4(2) C(1)-C(2)-C(3)-C(17) 8.5(2) C(10)-C(3)-C(4)-C(5) 176.1(2) C(2)-C(3)-C(4)-C(5) -66.0(3) C(17)-C(3)-C(4)-C(5) 55.3(3) C(10)-C(3)-C(4)-C(9) -4.7(2) C(2)-C(3)-C(4)-C(9) 113.1(2) C(17)-C(3)-C(4)-C(9) -125.6(2) C(9)-C(4)-C(5)-C(6) 0.7(3) C(3)-C(4)-C(5)-C(6) 179.8(2) C(4)-C(5)-C(6)-C(7) -0.6(3) C(4)-C(5)-C(6)-C(20) -177.79(19) C(5)-C(6)-C(7)-C(8) -0.6(3) C(20)-C(6)-C(7)-C(8) C(6)-C(7)-C(8)-C(9) C(7)-C(8)-C(9)-C(4) C(7)-C(8)-C(9)-N(1) C(5)-C(4)-C(9)-C(8) C(3)-C(4)-C(9)-C(8) C(5)-C(4)-C(9)-N(1) C(3)-C(4)-C(9)-N(1) C(8)-C(9)-N(1)-C(10) C(4)-C(9)-N(1)-C(10) C(9)-N(1)-C(10)-C(11) C(9)-N(1)-C(10)-C(3) C(4)-C(3)-C(10)-N(1) C(2)-C(3)-C(10)-N(1) 176.6(2) 1.5(3) -1.4(3) 175.2(2) 0.3(3) -179.0(2) -176.8(2) 3.9(3) -177.9(2) -1.0(3) 169.7(3) -2.5(3) 4.6(3) -113.8(3) C(17)-C(3)-C(10)-N(1) 129.7(2) 319 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(4)-C(3)-C(10)-C(11) C(2)-C(3)-C(10)-C(11) C(17)-C(3)-C(10)-C(11) N(1)-C(10)-C(11)-C(12) C(3)-C(10)-C(11)-C(12) C(10)-C(11)-C(12)-C(13) C(11)-C(12)-C(13)-C(18A) C(11)-C(12)-C(13)-C(17) C(11)-C(12)-C(13)-C(14) C(11)-C(12)-C(13)-C(18) C(17)-C(13)-C(18)-C(19) C(12)-C(13)-C(18)-C(19) C(14)-C(13)-C(18)-C(19) C(17)-C(13)-C(18A)-C(19A) C(12)-C(13)-C(18A)-C(19A) C(14)-C(13)-C(18A)-C(19A) C(18A)-C(13)-C(14)-C(15) C(17)-C(13)-C(14)-C(15) C(12)-C(13)-C(14)-C(15) C(18)-C(13)-C(14)-C(15) C(13)-C(14)-C(15)-C(16) C(14)-C(15)-C(16)-N(2) O(1)-C(1)-N(2)-C(17) C(2)-C(1)-N(2)-C(17) O(1)-C(1)-N(2)-C(16) C(2)-C(1)-N(2)-C(16) C(15)-C(16)-N(2)-C(1) C(15)-C(16)-N(2)-C(17) C(1)-N(2)-C(17)-C(13) C(16)-N(2)-C(17)-C(13) C(1)-N(2)-C(17)-C(3) C(16)-N(2)-C(17)-C(3) C(18A)-C(13)-C(17)-N(2) C(12)-C(13)-C(17)-N(2) -168.2(3) 73.4(3) -43.1(4) -120.1(3) 51.9(4) -6.9(4) 77.7(7) -42.1(3) -160.1(3) 79.1(5) 174.4(5) 50.5(8) -72.6(6) -50.7(11) -169.5(8) 71.4(11) -179.7(6) -54.9(3) 65.2(3) -166.7(4) 53.3(3) -48.0(4) 174.4(2) -5.1(3) 6.2(4) -173.2(2) -139.3(3) 52.8(3) 133.9(2) -57.3(3) 10.5(2) 179.4(2) -180.0(5) -65.9(2) 320 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(14)-C(13)-C(17)-N(2) C(18)-C(13)-C(17)-N(2) C(18A)-C(13)-C(17)-C(3) C(12)-C(13)-C(17)-C(3) C(14)-C(13)-C(17)-C(3) C(18)-C(13)-C(17)-C(3) C(4)-C(3)-C(17)-N(2) C(10)-C(3)-C(17)-N(2) C(2)-C(3)-C(17)-N(2) C(4)-C(3)-C(17)-C(13) C(10)-C(3)-C(17)-C(13) C(2)-C(3)-C(17)-C(13) C(5)-C(6)-C(20)-C(21) C(7)-C(6)-C(20)-C(21) C(5)-C(6)-C(20)-N(4) C(7)-C(6)-C(20)-N(4) N(4)-C(20)-C(21)-C(22) C(6)-C(20)-C(21)-C(22) C(20)-C(21)-C(22)-C(23) C(20)-C(21)-C(22)-C(36) C(20)-C(21)-C(22)-C(37) C(21)-C(22)-C(37)-C(38) C(23)-C(22)-C(37)-C(38) C(36)-C(22)-C(37)-C(38) C(21)-C(22)-C(23)-C(24) C(36)-C(22)-C(23)-C(24) C(37)-C(22)-C(23)-C(24) C(22)-C(23)-C(24)-C(25) C(23)-C(24)-C(25)-N(3) C(24)-C(25)-N(3)-C(36) C(24)-C(25)-N(3)-C(26) C(36)-N(3)-C(26)-C(27) C(25)-N(3)-C(26)-C(27) N(3)-C(26)-C(27)-C(28) 53.8(3) 165.7(4) -63.0(6) 51.0(3) 170.8(2) -77.4(4) -136.14(19) 109.7(2) -10.9(2) 103.1(2) -11.1(3) -131.7(2) 44.6(3) -132.6(2) -140.46(19) 42.4(3) 4.4(3) 179.36(18) -155.63(18) -40.1(2) 79.3(2) 58.9(2) -66.9(2) 174.80(16) 168.94(17) 53.6(2) -67.7(2) -50.7(3) 53.6(3) -60.4(2) 175.7(2) 65.6(3) -173.0(2) -45.2(3) 321 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(26)-C(27)-C(28)-C(35) C(26)-C(27)-C(28)-C(29) C(35)-C(28)-C(29)-C(30) C(27)-C(28)-C(29)-C(30) C(35)-C(28)-C(29)-C(34) C(27)-C(28)-C(29)-C(34) C(34)-C(29)-C(30)-C(31) C(28)-C(29)-C(30)-C(31) C(29)-C(30)-C(31)-C(32) C(30)-C(31)-C(32)-C(33) C(31)-C(32)-C(33)-C(34) C(32)-C(33)-C(34)-N(4) C(32)-C(33)-C(34)-C(29) C(30)-C(29)-C(34)-C(33) C(28)-C(29)-C(34)-C(33) C(30)-C(29)-C(34)-N(4) C(28)-C(29)-C(34)-N(4) C(33)-C(34)-N(4)-C(35) C(29)-C(34)-N(4)-C(35) C(33)-C(34)-N(4)-C(20) C(29)-C(34)-N(4)-C(20) C(21)-C(20)-N(4)-C(35) C(6)-C(20)-N(4)-C(35) C(21)-C(20)-N(4)-C(34) C(6)-C(20)-N(4)-C(34) C(29)-C(28)-C(35)-N(4) C(27)-C(28)-C(35)-N(4) C(29)-C(28)-C(35)-C(36) C(27)-C(28)-C(35)-C(36) C(34)-N(4)-C(35)-C(28) C(20)-N(4)-C(35)-C(28) C(34)-N(4)-C(35)-C(36) C(20)-N(4)-C(35)-C(36) C(25)-N(3)-C(36)-C(35) 11.4(3) -172.3(2) 178.3(3) 1.6(4) 0.3(2) -176.4(2) 1.7(4) -176.1(2) 0.4(4) -1.9(4) 1.1(3) 178.2(2) 1.1(3) -2.6(3) 175.74(18) 179.7(2) -1.9(2) -174.5(2) 2.8(2) -6.9(4) 170.45(19) 17.5(3) -157.72(17) -148.9(2) 35.9(3) 1.6(2) 178.85(18) -172.07(19) 5.2(3) -2.8(2) -172.40(17) 171.35(17) 1.8(3) -170.50(17) 322 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(26)-N(3)-C(36)-C(35) -45.7(3) C(25)-N(3)-C(36)-C(22) 68.4(2) C(26)-N(3)-C(36)-C(22) -166.9(2) C(28)-C(35)-C(36)-N(3) 11.8(3) N(4)-C(35)-C(36)-N(3) -161.40(16) C(28)-C(35)-C(36)-C(22) 134.1(2) N(4)-C(35)-C(36)-C(22) -39.1(2) C(21)-C(22)-C(36)-N(3) 174.81(17) C(23)-C(22)-C(36)-N(3) -64.8(2) C(37)-C(22)-C(36)-N(3) 57.0(2) C(21)-C(22)-C(36)-C(35) 53.9(2) C(23)-C(22)-C(36)-C(35) 174.31(16) C(37)-C(22)-C(36)-C(35) -64.0(2) _________________________________________________________ Symmetry transformations used to generate equivalent atoms: 323 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.3 324 X-RAY CRYSTAL STRUCTURE ANALYSIS OF COMPOUND 317 (V21262) An X-Ray quality crystal of dimer 317 was grown by dissolving the material in minimal dichloromethane at 23 °C and carefully layering with pentane. Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Mo Ka radiation (l = 0.71073 Å) from an IμS micro-source for the structure of compound V21262. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20172 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound V21262 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Figure A3.3.1. X-Ray Coordinate of Compound 317 (V21262). Table A3.3.1. Crystal data and structure refinement for V21262. Identification code V21262 Empirical formula C44 H51 Br N4 O2 S Formula weight 779.85 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic 325 326 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Space group P212121 Unit cell dimensions a = 11.944(5) Å a= 90°. b = 16.143(3) Å b= 90°. c = 19.243(7) Å g = 90°. Volume 3710(2) Å3 Z 4 Density (calculated) 1.396 Mg/m3 Absorption coefficient 1.209 mm-1 F(000) 1640 Crystal size 0.200 x 0.200 x 0.150 mm3 Theta range for data collection 2.007 to 36.327°. Index ranges -19<=h<=19, -24<=k<=26, -32<=l<=32 Reflections collected 61787 Independent reflections 17909 [R(int) = 0.0355] Completeness to theta = 25.242° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7471 and 0.6891 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 17909 / 0 / 471 Goodness-of-fit on F2 1.030 Final R indices [I>2sigma(I)] R1 = 0.0348, wR2 = 0.0810 R indices (all data) R1 = 0.0453, wR2 = 0.0849 Absolute structure parameter -0.0044(17) Extinction coefficient n/a Largest diff. peak and hole 0.507 and -0.389 e.Å-3 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 327 Table A3.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for V21262. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ___________________________________________________________________ Atom x y z U(eq) ___________________________________________________________________ S(1) 5505(1) 6495(1) 7456(1) 14(1) O(1) 5365(1) 6897(1) 8113(1) 20(1) O(2) 6100(1) 6893(1) 6902(1) 20(1) C(1) 4163(1) 6247(1) 7140(1) 14(1) C(2) 3248(2) 6298(1) 7584(1) 17(1) C(3) 2184(2) 6106(1) 7336(1) 20(1) C(4) 2069(2) 5845(1) 6654(1) 18(1) Br(1) 613(1) 5610(1) 6325(1) 28(1) C(5) 2978(2) 5770(1) 6208(1) 18(1) C(6) 4032(2) 5983(1) 6451(1) 16(1) N(1) 6148(1) 5626(1) 7612(1) 13(1) C(11) 5947(1) 5132(1) 8259(1) 12(1) C(12) 7021(1) 5182(1) 8688(1) 14(1) C(13) 7104(1) 4519(1) 9252(1) 15(1) C(14) 6979(1) 3635(1) 8961(1) 12(1) C(28) 7976(1) 3385(1) 8494(1) 15(1) C(29) 9063(2) 3183(1) 8874(1) 22(1) C(15) 6881(2) 3004(1) 9563(1) 16(1) C(16) 5814(2) 3098(1) 9992(1) 21(1) C(17) 4779(2) 3118(1) 9536(1) 20(1) N(2) 4926(1) 3742(1) 8993(1) 14(1) C(18) 5892(1) 3590(1) 8540(1) 11(1) C(19) 3940(1) 3898(1) 8558(1) 16(1) C(20) 4425(1) 4125(1) 7842(1) 13(1) C(21) 5695(1) 4252(1) 7979(1) 10(1) C(22) 6347(1) 4250(1) 7305(1) 10(1) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(23) 6730(1) 3598(1) 6897(1) 11(1) C(24) 7304(1) 3771(1) 6279(1) 12(1) C(25) 7445(2) 4591(1) 6071(1) 16(1) C(26) 7066(2) 5253(1) 6471(1) 16(1) C(27) 6522(1) 5066(1) 7087(1) 12(1) C(30) 7792(1) 3091(1) 5830(1) 12(1) N(3) 8510(1) 2516(1) 6224(1) 12(1) C(31) 6878(1) 2595(1) 5458(1) 14(1) C(32) 7294(1) 1852(1) 5022(1) 12(1) C(47) 6284(2) 1440(1) 4662(1) 17(1) C(48) 5460(2) 975(1) 5128(1) 19(1) C(33) 8125(2) 2144(1) 4461(1) 18(1) C(34) 8730(2) 1421(1) 4112(1) 21(1) C(35) 9298(2) 890(1) 4660(1) 21(1) N(4) 8485(1) 576(1) 5172(1) 15(1) C(36) 9039(2) 60(1) 5699(1) 21(1) C(37) 9968(2) 504(1) 6123(1) 21(1) C(38) 9612(1) 1373(1) 6281(1) 15(1) C(39) 10130(1) 2017(1) 6687(1) 14(1) C(40) 11127(2) 2062(1) 7070(1) 18(1) C(41) 11429(2) 2817(1) 7363(1) 21(1) C(42) 10745(2) 3515(1) 7288(1) 20(1) C(43) 9740(1) 3486(1) 6926(1) 15(1) C(44) 9438(1) 2728(1) 6627(1) 13(1) C(45) 8662(1) 1705(1) 6004(1) 12(1) C(46) 7880(1) 1257(1) 5524(1) 12(1) __________________________________________________________________ 328 329 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.3.3. Bond lengths [Å] and angles [°] for V21262. ________________________________________________________________________ Bond Length (Å) Bond Length (Å) S(1)-O(1) S(1)-O(2) S(1)-N(1) S(1)-C(1) C(1)-C(2) C(1)-C(6) C(2)-C(3) 1.4307(13) 1.4337(14) 1.6280(14) 1.7616(18) 1.389(2) 1.400(2) 1.391(3) C(28)-H(28A) C(28)-H(28B) C(29)-H(29A) C(29)-H(29B) C(29)-H(29C) C(15)-C(16) C(15)-H(15A) 0.9900 0.9900 0.9800 0.9800 0.9800 1.525(3) 0.9900 C(2)-H(2) C(3)-C(4) C(3)-H(3) C(4)-C(5) C(4)-Br(1) C(5)-C(6) C(5)-H(5) C(6)-H(6) N(1)-C(27) 0.9500 1.385(3) 0.9500 1.389(3) 1.8889(19) 1.386(3) 0.9500 0.9500 1.427(2) C(15)-H(15B) C(16)-C(17) C(16)-H(16A) C(16)-H(16B) C(17)-N(2) C(17)-H(17A) C(17)-H(17B) N(2)-C(19) N(2)-C(18) 0.9900 1.517(3) 0.9900 0.9900 1.461(2) 0.9900 0.9900 1.466(2) 1.467(2) N(1)-C(11) C(11)-C(12) C(11)-C(21) C(11)-H(11) C(12)-C(13) C(12)-H(12A) C(12)-H(12B) C(13)-C(14) C(13)-H(13A) C(13)-H(13B) C(14)-C(18) C(14)-C(28) C(14)-C(15) C(28)-C(29) 1.497(2) 1.528(2) 1.548(2) 1.0000 1.528(2) 0.9900 0.9900 1.540(2) 0.9900 0.9900 1.532(2) 1.545(2) 1.546(2) 1.525(2) C(18)-C(21) C(18)-H(18) C(19)-C(20) C(19)-H(19A) C(19)-H(19B) C(20)-C(21) C(20)-H(20A) C(20)-H(20B) C(21)-C(22) C(22)-C(23) C(22)-C(27) C(23)-C(24) C(23)-H(23) C(24)-C(25) 1.537(2) 1.0000 1.539(2) 0.9900 0.9900 1.554(2) 0.9900 0.9900 1.514(2) 1.389(2) 1.400(2) 1.401(2) 0.9500 1.394(2) 330 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24)-C(30) C(25)-C(26) C(25)-H(25) C(26)-C(27) C(26)-H(26) C(30)-N(3) C(30)-C(31) C(30)-H(30) N(3)-C(45) N(3)-C(44) C(31)-C(32) C(31)-H(31A) C(31)-H(31B) C(32)-C(46) C(32)-C(33) C(32)-C(47) C(47)-C(48) C(47)-H(47A) C(47)-H(47B) C(48)-H(48A) C(48)-H(48B) C(48)-H(48C) C(33)-C(34) C(33)-H(33A) C(33)-H(33B) C(34)-C(35) C(34)-H(34A) C(34)-H(34B) C(35)-N(4) C(35)-H(35A) C(35)-H(35B) N(4)-C(36) N(4)-C(46) C(36)-C(37) 1.514(2) 1.392(2) 0.9500 1.385(2) 0.9500 1.473(2) 1.532(2) 1.0000 1.389(2) 1.396(2) 1.546(2) 0.9900 0.9900 1.532(2) 1.540(2) 1.542(2) 1.527(2) 0.9900 0.9900 0.9800 0.9800 0.9800 1.528(2) 0.9900 0.9900 1.519(3) 0.9900 0.9900 1.473(2) 0.9900 0.9900 1.470(2) 1.480(2) 1.552(3) C(36)-H(36A) C(36)-H(36B) C(37)-C(38) C(37)-H(37A) C(37)-H(37B) C(38)-C(45) C(38)-C(39) C(39)-C(40) C(39)-C(44) C(40)-C(41) C(40)-H(40) C(41)-C(42) C(41)-H(41) C(42)-C(43) C(42)-H(42) C(43)-C(44) C(43)-H(43) C(45)-C(46) C(46)-H(46) O(1)-S(1)-O(2) O(1)-S(1)-N(1) O(2)-S(1)-N(1) O(1)-S(1)-C(1) O(2)-S(1)-C(1) N(1)-S(1)-C(1) C(2)-C(1)-C(6) C(2)-C(1)-S(1) C(6)-C(1)-S(1) C(1)-C(2)-C(3) C(1)-C(2)-H(2) C(3)-C(2)-H(2) C(4)-C(3)-C(2) C(4)-C(3)-H(3) C(2)-C(3)-H(3) 0.9900 0.9900 1.498(2) 0.9900 0.9900 1.363(2) 1.439(2) 1.402(2) 1.420(2) 1.390(3) 0.9500 1.400(3) 0.9500 1.389(2) 0.9500 1.399(2) 0.9500 1.499(2) 1.0000 120.82(8) 106.45(7) 106.85(8) 107.57(8) 107.22(8) 107.26(7) 120.81(16) 119.34(13) 119.84(13) 119.62(15) 120.2 120.2 118.87(17) 120.6 120.6 331 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(3)-C(4)-C(5) C(3)-C(4)-Br(1) C(5)-C(4)-Br(1) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(4)-C(5)-H(5) C(5)-C(6)-C(1) C(5)-C(6)-H(6) C(1)-C(6)-H(6) C(27)-N(1)-C(11) C(27)-N(1)-S(1) C(11)-N(1)-S(1) N(1)-C(11)-C(12) N(1)-C(11)-C(21) C(12)-C(11)-C(21) N(1)-C(11)-H(11) C(12)-C(11)-H(11) C(21)-C(11)-H(11) C(13)-C(12)-C(11) C(13)-C(12)-H(12A) C(11)-C(12)-H(12A) C(13)-C(12)-H(12B) C(11)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(12)-C(13)-C(14) C(12)-C(13)-H(13A) C(14)-C(13)-H(13A) C(12)-C(13)-H(13B) C(14)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(18)-C(14)-C(13) C(18)-C(14)-C(28) C(13)-C(14)-C(28) C(18)-C(14)-C(15) 122.28(17) 118.06(14) 119.65(13) 118.69(15) 120.7 120.7 119.70(16) 120.2 120.2 107.61(12) 124.24(11) 122.44(10) 106.62(13) 103.32(11) 113.52(12) 111.0 111.0 111.0 113.66(13) 108.8 108.8 108.8 108.8 107.7 112.67(12) 109.1 109.1 109.1 109.1 107.8 108.50(12) 109.47(12) 112.24(13) 107.48(12) C(13)-C(14)-C(15) C(28)-C(14)-C(15) C(29)-C(28)-C(14) C(29)-C(28)-H(28A) C(14)-C(28)-H(28A) C(29)-C(28)-H(28B) C(14)-C(28)-H(28B) H(28A)-C(28)-H(28B) C(28)-C(29)-H(29A) C(28)-C(29)-H(29B) H(29A)-C(29)-H(29B) C(28)-C(29)-H(29C) H(29A)-C(29)-H(29C) H(29B)-C(29)-H(29C) C(16)-C(15)-C(14) C(16)-C(15)-H(15A) C(14)-C(15)-H(15A) C(16)-C(15)-H(15B) C(14)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(17)-C(16)-C(15) C(17)-C(16)-H(16A) C(15)-C(16)-H(16A) C(17)-C(16)-H(16B) C(15)-C(16)-H(16B) H(16A)-C(16)-H(16B) N(2)-C(17)-C(16) N(2)-C(17)-H(17A) C(16)-C(17)-H(17A) N(2)-C(17)-H(17B) C(16)-C(17)-H(17B) H(17A)-C(17)-H(17B) C(17)-N(2)-C(19) C(17)-N(2)-C(18) 110.22(12) 108.82(12) 115.64(13) 108.4 108.4 108.4 108.4 107.4 109.5 109.5 109.5 109.5 109.5 109.5 113.80(14) 108.8 108.8 108.8 108.8 107.7 111.74(14) 109.3 109.3 109.3 109.3 107.9 109.27(15) 109.8 109.8 109.8 109.8 108.3 115.40(14) 113.84(13) 332 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(19)-N(2)-C(18) N(2)-C(18)-C(14) N(2)-C(18)-C(21) C(14)-C(18)-C(21) N(2)-C(18)-H(18) C(14)-C(18)-H(18) C(21)-C(18)-H(18) N(2)-C(19)-C(20) N(2)-C(19)-H(19A) C(20)-C(19)-H(19A) N(2)-C(19)-H(19B) C(20)-C(19)-H(19B) H(19A)-C(19)-H(19B) C(19)-C(20)-C(21) C(19)-C(20)-H(20A) C(21)-C(20)-H(20A) C(19)-C(20)-H(20B) C(21)-C(20)-H(20B) H(20A)-C(20)-H(20B) C(22)-C(21)-C(18) C(22)-C(21)-C(11) C(18)-C(21)-C(11) C(22)-C(21)-C(20) C(18)-C(21)-C(20) C(11)-C(21)-C(20) C(23)-C(22)-C(27) C(23)-C(22)-C(21) C(27)-C(22)-C(21) C(22)-C(23)-C(24) C(22)-C(23)-H(23) C(24)-C(23)-H(23) C(25)-C(24)-C(23) C(25)-C(24)-C(30) C(23)-C(24)-C(30) 108.76(12) 110.19(12) 100.39(12) 117.94(12) 109.3 109.3 109.3 104.47(13) 110.9 110.9 110.9 110.9 108.9 104.28(12) 110.9 110.9 110.9 110.9 108.9 121.42(12) 101.62(11) 111.36(12) 110.83(12) 100.18(11) 111.72(12) 119.68(13) 130.98(13) 109.31(12) 119.30(13) 120.3 120.3 119.55(13) 118.55(13) 121.90(13) C(26)-C(25)-C(24) C(26)-C(25)-H(25) C(24)-C(25)-H(25) C(27)-C(26)-C(25) C(27)-C(26)-H(26) C(25)-C(26)-H(26) C(26)-C(27)-C(22) C(26)-C(27)-N(1) C(22)-C(27)-N(1) N(3)-C(30)-C(24) N(3)-C(30)-C(31) C(24)-C(30)-C(31) N(3)-C(30)-H(30) C(24)-C(30)-H(30) C(31)-C(30)-H(30) C(45)-N(3)-C(44) C(45)-N(3)-C(30) C(44)-N(3)-C(30) C(30)-C(31)-C(32) C(30)-C(31)-H(31A) C(32)-C(31)-H(31A) C(30)-C(31)-H(31B) C(32)-C(31)-H(31B) H(31A)-C(31)-H(31B) C(46)-C(32)-C(33) C(46)-C(32)-C(47) C(33)-C(32)-C(47) C(46)-C(32)-C(31) C(33)-C(32)-C(31) C(47)-C(32)-C(31) C(48)-C(47)-C(32) C(48)-C(47)-H(47A) C(32)-C(47)-H(47A) C(48)-C(47)-H(47B) 122.00(15) 119.0 119.0 117.35(14) 121.3 121.3 122.08(14) 128.01(14) 109.72(13) 112.81(12) 109.02(12) 111.83(13) 107.7 107.7 107.7 107.29(13) 120.89(12) 126.43(13) 115.51(13) 108.4 108.4 108.4 108.4 107.5 109.83(14) 111.75(13) 108.78(13) 106.86(12) 110.57(13) 109.04(13) 116.92(13) 108.1 108.1 108.1 333 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(32)-C(47)-H(47B) H(47A)-C(47)-H(47B) C(47)-C(48)-H(48A) C(47)-C(48)-H(48B) H(48A)-C(48)-H(48B) C(47)-C(48)-H(48C) H(48A)-C(48)-H(48C) H(48B)-C(48)-H(48C) C(34)-C(33)-C(32) C(34)-C(33)-H(33A) C(32)-C(33)-H(33A) C(34)-C(33)-H(33B) C(32)-C(33)-H(33B) H(33A)-C(33)-H(33B) C(35)-C(34)-C(33) C(35)-C(34)-H(34A) C(33)-C(34)-H(34A) C(35)-C(34)-H(34B) C(33)-C(34)-H(34B) H(34A)-C(34)-H(34B) N(4)-C(35)-C(34) N(4)-C(35)-H(35A) C(34)-C(35)-H(35A) N(4)-C(35)-H(35B) C(34)-C(35)-H(35B) H(35A)-C(35)-H(35B) C(36)-N(4)-C(35) C(36)-N(4)-C(46) C(35)-N(4)-C(46) N(4)-C(36)-C(37) N(4)-C(36)-H(36A) C(37)-C(36)-H(36A) N(4)-C(36)-H(36B) C(37)-C(36)-H(36B) 108.1 107.3 109.5 109.5 109.5 109.5 109.5 109.5 112.30(14) 109.1 109.1 109.1 109.1 107.9 109.68(14) 109.7 109.7 109.7 109.7 108.2 111.36(15) 109.4 109.4 109.4 109.4 108.0 111.06(14) 108.90(13) 111.88(13) 115.09(15) 108.5 108.5 108.5 108.5 H(36A)-C(36)-H(36B) C(38)-C(37)-C(36) C(38)-C(37)-H(37A) C(36)-C(37)-H(37A) C(38)-C(37)-H(37B) C(36)-C(37)-H(37B) H(37A)-C(37)-H(37B) C(45)-C(38)-C(39) C(45)-C(38)-C(37) C(39)-C(38)-C(37) C(40)-C(39)-C(44) C(40)-C(39)-C(38) C(44)-C(39)-C(38) C(41)-C(40)-C(39) C(41)-C(40)-H(40) C(39)-C(40)-H(40) C(40)-C(41)-C(42) C(40)-C(41)-H(41) C(42)-C(41)-H(41) C(43)-C(42)-C(41) C(43)-C(42)-H(42) C(41)-C(42)-H(42) C(42)-C(43)-C(44) C(42)-C(43)-H(43) C(44)-C(43)-H(43) N(3)-C(44)-C(43) N(3)-C(44)-C(39) C(43)-C(44)-C(39) C(38)-C(45)-N(3) C(38)-C(45)-C(46) N(3)-C(45)-C(46) N(4)-C(46)-C(45) N(4)-C(46)-C(32) C(45)-C(46)-C(32) 107.5 109.62(14) 109.7 109.7 109.7 109.7 108.2 106.69(14) 121.64(14) 131.62(14) 119.62(15) 133.48(16) 106.84(14) 118.69(16) 120.7 120.7 120.84(16) 119.6 119.6 121.89(16) 119.1 119.1 117.33(16) 121.3 121.3 130.39(15) 107.99(13) 121.59(15) 111.07(14) 124.79(14) 124.15(14) 109.68(13) 113.54(12) 111.79(13) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 N(4)-C(46)-H(46) 107.2 C(32)-C(46)-H(46) 107.2 C(45)-C(46)-H(46) 107.2 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 334 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 335 Table A3.3.4. Anisotropic displacement parameters (Å2x 103) for V21262. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] __________________________________________________________________ Atom U11 U22 U33 U23 U13 U12 __________________________________________________________________ S(1) 17(1) 8(1) 17(1) -1(1) -3(1) 2(1) O(1) 25(1) 12(1) 21(1) -7(1) -6(1) 5(1) O(2) 21(1) 11(1) 26(1) 5(1) 0(1) -1(1) C(1) 17(1) 10(1) 16(1) 0(1) -2(1) 3(1) C(2) 20(1) 16(1) 15(1) -2(1) 1(1) 3(1) C(3) 18(1) 19(1) 22(1) -1(1) 2(1) 3(1) C(4) 18(1) 14(1) 22(1) 1(1) -4(1) 1(1) Br(1) 20(1) 25(1) 38(1) -1(1) -10(1) 0(1) C(5) 22(1) 17(1) 16(1) -2(1) -3(1) 2(1) C(6) 20(1) 14(1) 14(1) -1(1) 1(1) 1(1) N(1) 16(1) 9(1) 14(1) 0(1) 0(1) 2(1) C(11) 13(1) 10(1) 12(1) -1(1) -1(1) 0(1) C(12) 16(1) 11(1) 16(1) -1(1) -4(1) -2(1) C(13) 16(1) 15(1) 13(1) -1(1) -2(1) -1(1) C(14) 12(1) 12(1) 11(1) 1(1) 0(1) 0(1) C(28) 14(1) 17(1) 14(1) 3(1) 1(1) 4(1) C(29) 14(1) 30(1) 23(1) 6(1) -2(1) 4(1) C(15) 18(1) 17(1) 13(1) 5(1) 0(1) -1(1) C(16) 20(1) 30(1) 13(1) 5(1) 3(1) -2(1) C(17) 17(1) 26(1) 16(1) 4(1) 5(1) -3(1) N(2) 12(1) 18(1) 12(1) 0(1) 3(1) -1(1) C(18) 11(1) 10(1) 11(1) -1(1) 2(1) 0(1) C(19) 12(1) 19(1) 16(1) -2(1) 1(1) -1(1) C(20) 11(1) 15(1) 13(1) -1(1) -1(1) 0(1) C(21) 10(1) 10(1) 10(1) -1(1) 0(1) 0(1) C(22) 12(1) 10(1) 10(1) 1(1) 1(1) 0(1) Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(23) 13(1) 10(1) 11(1) 0(1) 0(1) 0(1) C(24) 13(1) 12(1) 11(1) 0(1) 2(1) 1(1) C(25) 20(1) 15(1) 12(1) 4(1) 4(1) 2(1) C(26) 21(1) 11(1) 17(1) 4(1) 4(1) 2(1) C(27) 13(1) 9(1) 14(1) 0(1) 0(1) 1(1) C(30) 14(1) 14(1) 10(1) 1(1) 2(1) 2(1) N(3) 11(1) 13(1) 11(1) -2(1) -1(1) 1(1) C(31) 14(1) 16(1) 10(1) 0(1) -1(1) 3(1) C(32) 13(1) 14(1) 10(1) 0(1) 1(1) 0(1) C(47) 18(1) 20(1) 14(1) 2(1) -4(1) -2(1) C(48) 13(1) 23(1) 22(1) 0(1) -2(1) -2(1) C(33) 24(1) 17(1) 12(1) -2(1) 5(1) -5(1) C(34) 25(1) 21(1) 17(1) -7(1) 10(1) -6(1) C(35) 14(1) 23(1) 25(1) -12(1) 7(1) -4(1) N(4) 12(1) 14(1) 20(1) -4(1) 0(1) 1(1) C(36) 16(1) 15(1) 32(1) -5(1) -7(1) 3(1) C(37) 14(1) 17(1) 32(1) -4(1) -7(1) 4(1) C(38) 11(1) 15(1) 18(1) -2(1) -2(1) 2(1) C(39) 11(1) 18(1) 15(1) -1(1) 0(1) 1(1) C(40) 12(1) 23(1) 20(1) -2(1) -3(1) 2(1) C(41) 14(1) 28(1) 20(1) -5(1) -4(1) -2(1) C(42) 16(1) 24(1) 19(1) -6(1) 0(1) -4(1) C(43) 16(1) 16(1) 14(1) -4(1) 1(1) -1(1) C(44) 10(1) 18(1) 11(1) -1(1) 1(1) 1(1) C(45) 10(1) 14(1) 13(1) -1(1) 1(1) 0(1) C(46) 9(1) 14(1) 12(1) -1(1) 0(1) 0(1) __________________________________________________________________ 336 337 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V21262. __________________________________________________________________ Atom x y z U(eq) __________________________________________________________________ H(2) 3348 6463 8053 20 H(3) 1548 6153 7630 23 H(5) 2879 5578 5746 22 H(6) 4663 5949 6152 19 H(11) 5294 5356 8525 14 H(12A) 7671 5128 8372 17 H(12B) 7063 5735 8909 17 H(13A) H(13B) H(28A) H(28B) H(29A) H(29B) H(29C) H(15A) H(15B) H(16A) 6513 7838 7754 8124 9243 9670 8973 6906 7535 5756 4617 4568 2895 3843 3632 3122 2664 2437 3069 2629 9603 9488 8217 8165 9198 8536 9133 9367 9874 10321 18 18 18 18 34 34 34 19 19 25 H(16B) H(17A) H(17B) H(18) H(19A) H(19B) H(20A) H(20B) H(23) H(25) 5856 4658 4114 5823 3488 3464 4078 4300 6603 7811 3616 2568 3255 3028 4359 3397 4639 3672 3041 4703 10265 9322 9821 8327 8748 8527 7662 7504 7036 5642 25 24 24 13 19 19 16 16 13 19 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(26) 7176 5810 6327 19 H(30) 8266 3360 5466 15 H(31A) 6461 2975 5148 16 H(31B) 6345 2386 5811 16 H(47A) 5864 1875 4410 21 H(47B) 6572 1047 4311 21 H(48A) 5819 474 5309 29 H(48B) 4797 821 4857 29 H(48C) 5236 1332 5516 29 H(33A) 7716 2464 4103 21 H(33B) 8686 2516 4676 21 H(34A) 8186 1082 3847 25 H(34B) 9296 1635 3782 25 H(35A) 9675 416 4432 25 H(35B) 9875 1222 4901 25 H(36A) 9373 -427 5466 25 H(36B) 8464 -146 6027 25 H(37A) 10105 200 6562 25 H(37B) 10674 511 5853 25 H(40) 11586 1587 7128 22 H(41) 12108 2858 7617 25 H(42) 10975 4024 7491 23 H(43) 9276 3961 6883 19 H(46) 7286 998 5818 14 __________________________________________________________________ 338 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.3.6. Torsion angles [°] for V21262. ______________________________________________________________ O(1)-S(1)-C(1)-C(2) -12.89(15) O(2)-S(1)-C(1)-C(2) -144.25(13) N(1)-S(1)-C(1)-C(2) 101.29(13) O(1)-S(1)-C(1)-C(6) 168.63(12) O(2)-S(1)-C(1)-C(6) 37.26(15) N(1)-S(1)-C(1)-C(6) -77.20(14) C(6)-C(1)-C(2)-C(3) -1.8(2) S(1)-C(1)-C(2)-C(3) 179.76(13) C(1)-C(2)-C(3)-C(4) 1.8(2) C(2)-C(3)-C(4)-C(5) -0.2(3) C(2)-C(3)-C(4)-Br(1) -178.65(13) C(3)-C(4)-C(5)-C(6) -1.4(3) Br(1)-C(4)-C(5)-C(6) 177.01(12) C(4)-C(5)-C(6)-C(1) 1.4(2) C(2)-C(1)-C(6)-C(5) 0.1(2) S(1)-C(1)-C(6)-C(5) 178.59(12) O(1)-S(1)-N(1)-C(27) O(2)-S(1)-N(1)-C(27) C(1)-S(1)-N(1)-C(27) O(1)-S(1)-N(1)-C(11) O(2)-S(1)-N(1)-C(11) C(1)-S(1)-N(1)-C(11) C(27)-N(1)-C(11)-C(12) S(1)-N(1)-C(11)-C(12) C(27)-N(1)-C(11)-C(21) S(1)-N(1)-C(11)-C(21) N(1)-C(11)-C(12)-C(13) C(21)-C(11)-C(12)-C(13) C(11)-C(12)-C(13)-C(14) C(12)-C(13)-C(14)-C(18) -175.10(13) -44.73(15) 69.98(14) 34.88(14) 165.24(12) -80.05(13) 94.17(14) -111.51(13) -25.75(15) 128.58(12) -162.74(12) -49.65(18) 55.31(18) -53.54(17) C(12)-C(13)-C(14)-C(28) 67.56(17) 339 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(12)-C(13)-C(14)-C(15) C(18)-C(14)-C(28)-C(29) C(13)-C(14)-C(28)-C(29) C(15)-C(14)-C(28)-C(29) C(18)-C(14)-C(15)-C(16) C(13)-C(14)-C(15)-C(16) C(28)-C(14)-C(15)-C(16) C(14)-C(15)-C(16)-C(17) C(15)-C(16)-C(17)-N(2) C(16)-C(17)-N(2)-C(19) C(16)-C(17)-N(2)-C(18) C(17)-N(2)-C(18)-C(14) C(19)-N(2)-C(18)-C(14) C(17)-N(2)-C(18)-C(21) C(19)-N(2)-C(18)-C(21) C(13)-C(14)-C(18)-N(2) C(28)-C(14)-C(18)-N(2) C(15)-C(14)-C(18)-N(2) C(13)-C(14)-C(18)-C(21) C(28)-C(14)-C(18)-C(21) C(15)-C(14)-C(18)-C(21) C(17)-N(2)-C(19)-C(20) C(18)-N(2)-C(19)-C(20) N(2)-C(19)-C(20)-C(21) N(2)-C(18)-C(21)-C(22) C(14)-C(18)-C(21)-C(22) N(2)-C(18)-C(21)-C(11) C(14)-C(18)-C(21)-C(11) N(2)-C(18)-C(21)-C(20) C(14)-C(18)-C(21)-C(20) N(1)-C(11)-C(21)-C(22) C(12)-C(11)-C(21)-C(22) N(1)-C(11)-C(21)-C(18) C(12)-C(11)-C(21)-C(18) -170.97(14) -164.88(14) 74.59(18) -47.68(19) -51.91(17) 66.16(18) -170.37(14) 51.0(2) -51.9(2) -173.48(14) 59.72(18) -63.51(17) 166.30(12) 171.39(13) 41.20(15) -63.01(15) 174.21(12) 56.17(15) 51.35(16) -71.43(16) 170.52(12) -148.06(14) -18.73(16) -11.32(15) -167.83(13) 72.54(18) 72.67(14) -46.95(17) -45.62(13) -165.24(12) 28.15(14) -86.91(15) 158.84(12) 43.77(17) 340 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 N(1)-C(11)-C(21)-C(20) C(12)-C(11)-C(21)-C(20) C(19)-C(20)-C(21)-C(22) C(19)-C(20)-C(21)-C(18) C(19)-C(20)-C(21)-C(11) C(18)-C(21)-C(22)-C(23) C(11)-C(21)-C(22)-C(23) C(20)-C(21)-C(22)-C(23) C(18)-C(21)-C(22)-C(27) C(11)-C(21)-C(22)-C(27) C(20)-C(21)-C(22)-C(27) C(27)-C(22)-C(23)-C(24) C(21)-C(22)-C(23)-C(24) C(22)-C(23)-C(24)-C(25) C(22)-C(23)-C(24)-C(30) C(23)-C(24)-C(25)-C(26) C(30)-C(24)-C(25)-C(26) C(24)-C(25)-C(26)-C(27) C(25)-C(26)-C(27)-C(22) C(25)-C(26)-C(27)-N(1) C(23)-C(22)-C(27)-C(26) C(21)-C(22)-C(27)-C(26) C(23)-C(22)-C(27)-N(1) C(21)-C(22)-C(27)-N(1) C(11)-N(1)-C(27)-C(26) S(1)-N(1)-C(27)-C(26) C(11)-N(1)-C(27)-C(22) S(1)-N(1)-C(27)-C(22) C(25)-C(24)-C(30)-N(3) C(23)-C(24)-C(30)-N(3) C(25)-C(24)-C(30)-C(31) C(23)-C(24)-C(30)-C(31) C(24)-C(30)-N(3)-C(45) C(31)-C(30)-N(3)-C(45) -90.06(14) 154.87(13) 164.52(12) 35.10(14) -82.92(14) 35.8(2) 159.96(16) -81.19(19) -146.28(14) -22.14(16) 96.71(14) 1.1(2) 178.79(15) -2.4(2) 176.93(14) 2.3(3) -176.99(16) -0.9(3) -0.4(3) 174.01(16) 0.3(2) -177.84(15) -175.00(14) 6.82(18) -162.53(17) 43.7(2) 12.45(17) -141.30(13) 127.29(16) -52.0(2) -109.40(16) 71.31(18) 153.77(14) 28.91(18) 341 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24)-C(30)-N(3)-C(44) C(31)-C(30)-N(3)-C(44) N(3)-C(30)-C(31)-C(32) C(24)-C(30)-C(31)-C(32) C(30)-C(31)-C(32)-C(46) C(30)-C(31)-C(32)-C(33) C(30)-C(31)-C(32)-C(47) C(46)-C(32)-C(47)-C(48) C(33)-C(32)-C(47)-C(48) C(31)-C(32)-C(47)-C(48) C(46)-C(32)-C(33)-C(34) C(47)-C(32)-C(33)-C(34) C(31)-C(32)-C(33)-C(34) C(32)-C(33)-C(34)-C(35) C(33)-C(34)-C(35)-N(4) C(34)-C(35)-N(4)-C(36) C(34)-C(35)-N(4)-C(46) C(35)-N(4)-C(36)-C(37) C(46)-N(4)-C(36)-C(37) N(4)-C(36)-C(37)-C(38) C(36)-C(37)-C(38)-C(45) C(36)-C(37)-C(38)-C(39) C(45)-C(38)-C(39)-C(40) C(37)-C(38)-C(39)-C(40) C(45)-C(38)-C(39)-C(44) C(37)-C(38)-C(39)-C(44) C(44)-C(39)-C(40)-C(41) C(38)-C(39)-C(40)-C(41) C(39)-C(40)-C(41)-C(42) C(40)-C(41)-C(42)-C(43) C(41)-C(42)-C(43)-C(44) C(45)-N(3)-C(44)-C(43) C(30)-N(3)-C(44)-C(43) C(45)-N(3)-C(44)-C(39) -55.6(2) 179.59(13) -51.04(16) -176.47(12) 61.08(16) -58.41(17) -177.98(12) 48.22(19) 169.66(15) -69.68(18) 51.15(19) -71.45(18) 168.83(14) -55.0(2) 57.91(18) 179.83(13) -58.26(17) 59.39(19) -64.25(19) 39.3(2) -7.0(2) 175.86(18) -177.37(18) 0.1(3) -0.20(18) 177.27(17) -2.1(3) 174.82(18) 1.0(3) 0.5(3) -0.8(2) 174.48(16) 20.6(3) -3.58(17) 342 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(30)-N(3)-C(44)-C(39) -157.47(14) C(42)-C(43)-C(44)-N(3) -178.09(15) C(42)-C(43)-C(44)-C(39) -0.3(2) C(40)-C(39)-C(44)-N(3) 179.99(14) C(38)-C(39)-C(44)-N(3) 2.35(18) C(40)-C(39)-C(44)-C(43) 1.7(2) C(38)-C(39)-C(44)-C(43) -175.91(14) C(39)-C(38)-C(45)-N(3) -2.07(18) C(37)-C(38)-C(45)-N(3) -179.85(15) C(39)-C(38)-C(45)-C(46) 177.94(14) C(37)-C(38)-C(45)-C(46) 0.2(3) C(44)-N(3)-C(45)-C(38) 3.57(18) C(30)-N(3)-C(45)-C(38) 159.20(14) C(44)-N(3)-C(45)-C(46) -176.44(14) C(30)-N(3)-C(45)-C(46) -20.8(2) C(36)-N(4)-C(46)-C(45) 52.51(17) C(35)-N(4)-C(46)-C(45) -70.63(16) C(36)-N(4)-C(46)-C(32) 178.37(13) C(35)-N(4)-C(46)-C(32) 55.22(18) C(38)-C(45)-C(46)-N(4) -23.3(2) N(3)-C(45)-C(46)-N(4) 156.66(14) C(38)-C(45)-C(46)-C(32) -150.20(15) N(3)-C(45)-C(46)-C(32) 29.8(2) C(33)-C(32)-C(46)-N(4) -50.89(17) C(47)-C(32)-C(46)-N(4) 69.94(17) C(31)-C(32)-C(46)-N(4) -170.86(13) C(33)-C(32)-C(46)-C(45) 73.84(16) C(47)-C(32)-C(46)-C(45) -165.33(13) C(31)-C(32)-C(46)-C(45) -46.13(16) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 343 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.4 (1) 344 REFERENCES AND NOTES Sheldrick, G. M. Phase Annealing in SHELX-90: Direct Methods for Larger Structures. Acta. Crystallogr. A Found. Crystallogr. 1990, 46, 467–473. (2) Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta. Crystallogr. C Struct. Chem. 2015, 71, 3–8. (3) Müller, P. Practical Suggestions for Better Crystal Structures. Crystallogr. Rev. 2009, 15, 57–83. APPENDIX 4 Additional Investigations into the Total Synthesis of Strempeliopidine Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine A4.1 346 INTRODUCTION In our total synthesis of strempeliopidine (Chapter 2),1 we developed a Petasis borono–Mannich reaction that coupled hydroxyindoles with in situ generated trifluoroborate salts. Initially, we explored other strategies to develop this reaction centered around aryl boronic acid coupling partners. These early studies, as well as NMR experiments with strempeliopidine and the initial results from cell viability assays, are reported in this appendix. A4.2 RESULTS AND DISCUSSION A4.2.1 ALTERNATIVE SUBSTRATES EXPLORED IN THE PETASIS BORONOMANNICH REACTION During our synthesis of strempeliopidine, we found that N-benzyl- aspidospermidine boronic acid spontaneously decomposed by protodeborylation, which precluded its use in the Petasis borono–Mannich reaction (see Scheme 2.3.3.1). To address this challenge, we employed a model system to examine how nitrogen protecting groups influence the stability of indoline boronic acids and their performance in the Petasis borono–Mannich reaction. An array of indoline boronic acids with different N-protecting groups (342a–f) were synthesized and their efficiency in the Petasis borono–Mannich reaction with tetracycle 309 evaluated (Table A4.2.1.1). Substrates with electron-donating protecting groups (R = Bn, allyl; 342a, 342b) decomposed via protodeborylation before they could be subjected to the Petasis borono–Mannich reaction (Entries 1–2). Silyl-indole 342c was unstable under the reaction conditions; the TIPS group was cleaved by HFIP and the resulting 347 Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine boronic acid decomposed (Entry 3). Indoline monomers with electron-withdrawing protecting groups (R = Ac, Cbz, Ts; 342d–f) were stable yet only provided trace quantities of product (Entries 4–6). Further optimization, such as employing the potassium trifluoroborate salts of 342d–342f, did not lead to improved product yields. The reaction with unprotected pinacol boronic ester 344 led to undesired aminal product 345, highlighting the necessity for an N-protecting group. H OH B OH + N N Ph HFIP (0.1 M) 23 °C, 16 h N HO R 342a–f N N Ph N Ph H N R 309 343a–f 2.0 equiv entry 342 R= results 1 342a Bn rapid protodeborylation 2 342b allyl rapid protodeborylation 3 342c TIPS TIPS labile 4 342d Ac trace product 5 342e Cbz trace product 6 342f Ts trace product H Bpin + N N Ph N HFIP (0.1 M) 23 °C, 16 h N N H HO H 344 309 2.0 equiv 345 Bpin Table A4.2.1.1. Additional strategies explored to develop a Petasis borono-Mannich reaction for accessing heterodimeric bisindole alkaloids. Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine 348 A4.2.2 OF INVESTIGATIONS INTO pH DEPENDENCE OF NMR STREMPELIOPIDINE The 1H NMR spectra of the synthetic and natural strempeliopidine did not perfectly match; we posited that these inconsistencies could be due to trace HCl present in the isolation chemists’ CDCl3, as acid could protonate the natural product and lead to shifts in the 1H NMR. Therefore, the pH dependence of the NMR of strempeliopidine was investigated (Figure A4.2.2.1). Strempeliopidine - no acid 3 0.1 equiv d-TFA 2 0.5 equiv d-TFA 1 8 7 6 5 4 ppm 3 2 1 0 Figure A4.2.2.1. 1H NMR spectra (600 MHz) of strempeliopidine upon treatment with 0, 0.1, and 0.5 equiv of d-TFA. Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine 349 To a sample of ent-strempeliopidine (286) in CDCl3 was added d-TFA (0.1 – 0.5 equiv) and the effects on the 1H NMR studied. The 1H NMR did display dependence with pH, as several peaks shifted significantly during the study. However, the changes in shift did not correspond to the reported 1H NMR for the natural product; none of the acidified 1 H NMRs more closely resembled that of the isolated material. This does suggest the possibility that the 1H NMR of the synthesized and isolated material did not exactly match due to a difference in NMR solvent pH; however, we cannot claim whether the differences were due to this or another error in the original measurement. A4.2.3 INITIAL EVALUATION OF THE BIOLOGICAL ACTIVITY OF STREMPELIOPIDINE AND ANALOGS Our lab is interested in the development of monoterpenoid bisindole alkaloid analogs that can modulate protein–protein interactions. For example, we aim to synthesize heterodimers which can bind to tubulin, prevent mitosis, and kill cells, the same mode of action employed by the chemotherapeutics vinblastine and vincristine.2 These analogs prove a platform to enhance therapeutic potency, improve drug-like properties, and even reveal entirely new biological activities. During our synthesis of strempeliopidine, we synthesized several non-natural heterodimers and sought to investigate the effects of dimerization and stereochemistry on bioactivity. To this end, we have collaborated with Prof. Tsui-Fen Chou to study the bioactivity of the dimers synthesized in our lab. 350 Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine Table A4.2.3.1. Initial assessment of the cytotoxicity of strempeliopidine, analogs, and the corresponding monomers. Monomers: N H Me N H H H N N HO H N N N HO H N HO N N HO Me Me Me Me (+)-aspidospermidine (+)-298 (–)-eburnamine (–)-26 (+)-eburnamine (+)-26 (+)-epi-eburnamine (+)-296 (–)-epi-eburnamine (–)-296 15.5 µM 50.5 µM >105 µM >105 µM >105 µM IC50 (µM) = Petasis dimers: N H N Me N H H H Me 286 IC50 (µM) = H N Me H N H N Me H N H 318 319 320 9.5 µM 13.8 µM 15.1 µM 11.4 µM H N N H H H N Kam’s proposed strempeliopidine N Me N H N Me H N H N Me N Me 284 (= ent-286) IC50 (µM) = revised strempeliopidine ent-319 7.2 µM 10.8 µM Suzuki dimers: N H N Me N H H N Me IC50 (µM) = H N H N Me H N H 285 N Me 331 321 Novotny’s proposed strempeliopidine 8.1 µM 7.1 µM 9.8 µM Cell viability was measured using the CellTiter-Glo assay. Reported IC₅₀ values represent the mean across the RPMI 6666 and Hs 445 lymphoblast cell lines. The cytotoxicity of strempeliopidine, the dimeric analogs, and corresponding monomers was evaluated using a CellTiter-Glo assay in RPMI 6666 and Hs 445 Appendix 4 – Additional Investigations into the Total Synthesis of Strempeliopidine 351 lymphoblast cell lines (Table A4.2.3.1). While (+)-aspidospermidine ((+)-298) demonstrated modest activity (IC50 = 15.5 µM), the eburnea monomers ((–)-26, (+)-26, (+)-296, (–)-296) showed low levels of cytotoxicity (50.5 to >105 µM). Strempeliopidine and the five stereoisomers prepared via the Petasis borono–Mannich reaction sequence (284, 286, 318–320, ent-319) exhibited IC50 values between 7.2 and 15.1 µM. Heterodimers prepared via the Suzuki–Miyaura reaction (331, 321, 285) possessed similar bioactivity (7.1 – 9.8 µM). Overall, while bisindole heterodimers were more active than the parent eburnea fragments, the cytotoxicity values were similar to the IC50 for aspidospermidine alone (15.5 µM). In all cases, stereochemistry possessed little impact on a compound’s IC50 value, regardless of if the dimer was prepared via the Petasis borono–Mannich or Suzuki–Miyaura route. These results suggest that the compounds may act through a general toxicity pathway rather than by binding a specific protein, although further studies are required to test this hypothesis. Looking forward, work is underway to synthesize other heterodimeric analogs and advance our understanding of the structure activity relationship of this exciting class of molecules. A4.3 REFERENCES AND NOTES (1) Rand, A. W.; Gonzalez, K. J.; Reimann, C. E.; Virgil, S. C.; Stoltz, B. M. Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers through a Convergent Petasis Borono–Mannich Reaction. J. Am. Chem. Soc. 2023, 145, 7278–7287. (2) Brossi, M. Suffness in The Alkaloids: Antitumor Bisindole Alkaloids from Catharanthus Roseus (L.), Vol. 37, Academic Press, San Diego, 1990, pp. 1–246. CHAPTER 3 Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy† 3.1 INTRODUCTION 3.1.1 STRATEGIES FOR THE DEVELOPMENT OF ASYMMETRIC AND NON-DIRECTED PETASIS REACTIONS Amine-containing molecules represent a broad class of compounds that includes countless biologically active natural products and pharmaceuticals.[1] A central method for the synthesis of functionalized amines is the addition of nucleophiles into imines (and their derivatives).[2] In particular, methods that utilize organoboron reagents as nucleophiles have grown in prominence due to these reagents’ availability, low toxicity, wide functional group tolerance, and stability to air and water. The Petasis reaction, first reported in 1993, is the three-component coupling of an aldehyde, amine, and organoboron compound which provides ⍺-functionalized amines (Figure 3.1.1.1a).[3,4] This efficient reaction is operationally simple, not requiring rigorously dry or degassed solvents, and proceeds under mild conditions that can tolerate many unprotected moieties. Therefore, it has seen extensive use for the preparation of diverse amine-containing scaffolds including ⍺-amino acids, heterocycles, and natural products (Figure 3.1.1.1b).[5] † This research was carried out with Rand, A. W.; Cerione, C. Portions of this chapter have been reproduced with permission from Stoltz, et al. Angew. Chem. Int. Ed. 2023, 62, e202218921. © 2023 Wiley–VCH & Stoltz, et al. Chem – Eur. J. 2024, 30, e202401936. © 2024 Wiley–VCH. 353 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction a) The Petasis Reaction O OH B + + N H OH N H OH Three-component coupling OH Structurally diverse products Mild reaction conditions b) Synthetic Applications Ph HN H Ph HO OH Br O non-natural ⍺-amino acids H N N N N H H n-Bu H OH Me heterocycles N H H Me natural products c) Limitations N N Chiral Catalyst H H OH achiral N OH enantioenriched Few catalytic asymmetric reports Limited scope and modest ee’s B O directing heteroatom generally required to enable reactivity HO OH 346 Figure 3.1.1.1. The Petasis reaction and its applications and limitations. Despite its utility, the reaction suffers from several restrictions that have limited its scope (Figure 3.1.1.1c): 1) To date, the vast majority of asymmetric Petasis reactions utilize chiral auxiliary-based approaches.[6–10] There are relatively few catalytic asymmetric methods and most suffer from limited scopes and modest levels of enantioselectivity.[11a] 2) In most Petasis reactions, a directing group is required to recruit the boronic acid, generating the more reactive “ate complex” (346), and enabling an intramolecular attack on the iminium ion to furnish product. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 354 In this Introduction, a brief review of methods that have guided the development of asymmetric and non-directed Petasis reactions (or variants) is provided with a focus on how they could be further utilized to develop solutions to long-standing limitations. There have been many outstanding reviews written on the Petasis reaction that should be referred to if the reader desires a more comprehensive overview of the history of this reaction.[4,11] Petasis-type reactions, a subclass of this chemistry based on utilizing preformed imine substrates (or a suitable iminium ion precursor) in a two-component coupling, are discussed.[12] Metal-catalyzed variants are outlined as well; while they present their own challenges (such as air sensitivity/requiring expensive catalysts), these reactions represent an orthogonal reaction manifold that can circumvent many of the traditional limitations of the Petasis reaction. Finally, one area not covered by this Introduction is the allylation of imines via allyl-organoboron compounds. For a detailed discussion of these processes, we refer the reader to the following references.[13] 3.1.1.1 ASYMMETRIC PETASIS REACTIONS Chiral Thiourea Catalysts: Catalytic processes employing small-organic molecules are attractive due to their cost-effective and environmentally friendly nature.[14] Chiral thiourea catalysts have been successful in enabling asymmetric Petasis reactions. In 2007, Takemoto and coworkers reported the use of a chiral thiourea catalyst in the first catalytic asymmetric Petasis-type transformation.[15] The group employed Cat. A, in combination with water and NaHCO3, in the reaction of quinolines with vinylboronic acids and phenyl chloroformate (Scheme 3.1.1.1.1, 347–349). It was proposed that the thiourea moiety activates the N-acylated quinolinium salt through hydrogen-bonding, while the 1,2- 355 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction amino alcohol functionality of the catalyst activates the boronic acid and directs the stereochemical outcome (Scheme 3.1.1.1.1, 351). Thiourea-catalyzed Petasis Reactions: Takemoto, 2007: Ph + O Ph 348 N CH2Cl2/H2O (10:1) N 347 Me Me Cat. A (10 mol%) NaHCO3 (2 equiv) B(OH)2 + Cl O 70% yield 96% ee 349 Ph CO2Ph 350 Mechanistic Proposal: S S Ar Ar N Me NH NH N N H H N O HO activation of nucleophile HO B OR O N activation of electrophile Ar = 3,5-(CF3)2C6H3 Me Cat. A Ph 351 Me Takemoto, 2011: OMe O O N H then, Cat. B (10 mol%) B(OH)2 Cy OMe 354 Ph + O N H MeO Et MeO 53% yield 80% ee NH2 352 Yuan, 2012: Ph Et Cy 355 353 B(OH)2 O N Cat. C (20 mol%) MeO H N + H MTBE, 5 °C OH OMe N H 356 357 MeO 91% yield 95% ee 358 OH OMe 359 S Ar N H N H N H OH O OH HN HN OH Ar = 3,5-(CF3)2C6H3 Ar = 3,5-(CF3)2C6H3 Cat. B Cat. C S Ar Scheme 3.1.1.1.1. Examples of thiourea-based catalysts in asymmetric Petasis reactions. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 356 Subsequently, Takemoto and coworkers expanded their method to prepare N-aryl amino acid derivatives by employing a thiourea catalyst with a Lewis basic ether moiety (Cat. B).[16] In the two step, one pot reaction sequence, an aniline derivative (352) and Nethyl-2-oxo-acetanilide (353) first form the imino-amide intermediate (not shown), which is then reacted with the thiourea-hydroxy catalyst and a vinyl boronate (Scheme 3.1.1.1.1). The reaction demonstrated a wide scope with respect to the vinyl boronate and aniline reaction components. Notably, the enantioselectivity remained high when an aliphaticsubstituted vinyl boronic acid (354) was employed. In 2012, Yuan and coworkers reported a novel thiourea-BINOL-catalyst (Cat. C) in an asymmetric Petasis reaction between salicylaldehyde derivatives, cyclic secondary amines and aryl-, heteroaryl- or vinylboronic acids (Scheme 3.1.1.1.1).[17] The o-hydroxy substituent on the benzaldehyde was necessary for reactivity; it was speculated that thiourea moiety forms critical hydrogen bonds with the phenoxide anion. In general, the reported thiourea-catalyzed asymmetric Petasis reactions are restricted by the requirement for an anchoring group on the generated iminium ion to enable sufficient interaction with the catalyst (i.e., carbonyl in 351). Chiral Diol Catalysts: Chiral diol catalysts have been extensively explored in asymmetric Petasis reactions due to their ability to coordinate with the organoboron and iminium ion species.[4] In 2008, Schaus and coworkers were the first to employ a chiral biphenol-derived catalyst in an asymmetric Petasis reaction which coupled vinylboronic esters, secondary amines and glyoxylates to construct chiral α-amino acids (Scheme 3.1.1.1.2).[18] The (S)-VAPOL catalyzed reaction was tolerant of a variety of vinylboronic Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 357 esters, including dialkyl-substituted 362, and is compatible with benzylic and allylic secondary amines. Subsequently, Shi and coworkers reported a BINOL-catalyzed asymmetric Petasis reaction of salicylaldehydes, dibutyl vinylboronic esters, and secondary amines, including a secondary acyclic alkyl amine 365, in the presence of 4Å MS.[19] 1H and 11B NMR studies led to a proposed cyclic BINOL-boronate intermediate 373, which is formed with phenol 364 and directs vinyl group migration with stereocontrol. The authors found that benzaldehyde did not react under the reaction conditions, confirming the necessity of salicylaldehyde’s ortho-phenolic group. Traceless Petasis reactions have been reported to construct allenes, which are important synthetic building blocks.[20] Schaus and co-workers developed a BINOLcatalyzed approach for the asymmetric addition of substituted-boronates to sulfonyl hydrazones to access enantioenriched allenes.[21] In the highlighted approach, an alkynylboronic ester (370) is reacted with a sulfonylhydrazone to generate a propargylic hydrazide (371), which then undergoes a fragmentation to lose sulfinic acid, followed by a retro-ene reaction to release dinitrogen and form the corresponding allene (372) with complete chirality transfer (Scheme 3.1.1.1.2). In the highlighted method, the hydroxy group within the hydrazone is required for the transformation to proceed. Chiral diol-based catalysts are among the most extensively explored for catalytic asymmetric Petasis reactions.[22] Despite the highlighted advances, BINOL-catalyzed asymmetric Petasis reactions generally only achieve moderate enantioselectivities and yields. Furthermore, these transformations tend to be limited in both the amine and boronate scope. 358 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Biphenol-catalyzed Petasis Reactions: Schaus, 2008: O (S)-VAPOL (15 mol%) n-Bu + Bn2NH + H CO2Et B(OEt)2 Me 360 361 3Å MS, PhCH3, –15 °C 362 n-Bu NBn2 Me CO2Et 363 71% yield 86% ee Shi, 2013: Me O Me H + Me N H OH 364 OBu + BuO 365 Me N (S)-Me2-BINOL (20 mol%) B 4Å MS, PhCH3, 23°C OH 43% yield 80% ee 366 367 Schaus, 2017: OH 1. 3 Å MS mesitylene 23 °C O Ar O S O HN O 2. B 368 O OH NH NH2 Ar = 2,5-(Br)2C6H3 H H • TBS OH 372 TBS 62% yield 90% ee 370 Ar S OEt TBS + O NH OEt OH –HSO2Ar –N2 (S)-CF3-BINOL (10 mol%) PhCH3, 0 °C 371 R1 R2 369 Ph OH Ph OH OH O * O B O R’ R2 NHR2 OH R1 Mechanistic Proposal: (S)-Me2-BINOL: R1 = H, R2 = Me 373 (S)-(CF3)4-BINOL: R1 = R2 = CF3 (S)-VAPOL Scheme 3.1.1.1.2. Examples of biphenol-based catalysts in asymmetric Petasis reactions. Asymmetric Metal-Catalyzed Petasis-Type Reactions: Reports of threecomponent asymmetric transition metal-catalyzed Petasis processes are scarce in the literature. On the other hand, two-component Rh-catalyzed processes have been extensively investigated.[23] Tomioka and coworkers achieved the first asymmetric 359 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction rhodium-catalyzed arylation of imines in 2004.[24] They employed an L -valine aminomonophosphane ((S,S)-L1) as a chiral ligand for the rhodium-catalyzed arylation of various N-tosylimines (374) with arylboroxines (375) to access diarylamines (376) with good enantioselectivities (Scheme 3.1.1.1.3). Despite the widespread success of Rh-catalyzed additions of arylboron reagents to imines, the corresponding addition of alkenylboron reagents remains less developed. To this end, in 2012, Lam and coworkers employed alkenylboron reagents (i.e., 378) in the first enantioselective Rh-catalyzed addition of potassium alkenyltrifluoroborates to cyclic imines.[25] A variety of substituted benzoxathiazine-2,2-dioxides (i.e., 377) were reacted with alkyl or aryl substituted alkenyltrifluoroborates in good yields and enantioselectivities (Scheme 3.1.1.1.3). Despite being limited to cyclic imines, this method is attractive as aryl sulfamates are effective in a range of nickel-catalyzed cross-coupling reactions.[26] Furthermore, we were intrigued by a 2016 report on the asymmetric Rh-catalyzed dearomative arylation/alkenylation of quinolinium salts by Wang and coworkers (Scheme 3.1.1.1.3).[27] This reaction offers access to enantioenriched dihydroquinolines containing tetrasubstituted centers (i.e., 382). The enantioselective addition of boronic acids to quinolinium salts was achieved despite the lack of an accessible coordination site on the quinolinium ion. It was proposed that the π-electron system of the quinoline ring may enhance its coordination abilities to the rhodium-complex. Notably, the three methods highlighted are also examples of non-directed Petasis-type reactions, demonstrating the ability of transition-metal-catalyzed processes to overcome limitations traditionally faced by the Petasis reaction. 360 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Rh-catalyzed Asymmetric Petasis-type Reactions Tomioka, 2004: Ar O Ts N O B B + Ar B MeO [Rh(acac)(C2H4)2]2/L1 (3 mol%) O Ar TMS n-PrOH, 60 °C 375 87% yield 90% ee OMe 374 Ts N H TMS Ar = 376 Lam, 2012: O O S N O O O S NH O [Rh(L2)Cl]2 (1.5 mol%) MeOH (5 equiv) KF3B + H Me Me F 377 Me 1,4-dioxane, 80 °C F 85% yield 95% ee 378 Me 379 Wang, 2016: B(OH)2 I N Me [Rh(COD)Cl]2 (2.5 mol%) L3 (7 mol%) AgBF4 (10 mol%) K3PO4•H2O (1.5 equiv) + N PhCH3, 45 °C Et Et 380 38% yield 98% ee 381 Ph Me 382 Me Me N PPh2 Ph PPh2 PPh2 O Me Ph Me NHBoc (S,S)-L1 (R,R)-L2 (R)-L3 Scheme 3.1.1.1.3. Examples of Rh-catalyzed asymmetric Petasis-type reactions. To a lesser extent, palladium catalysis has also been employed to achieve asymmetric arylations of imines. Manolikakes and coworkers reported the first general enantioselective palladium-catalyzed Petasis reaction of sulfonimides, aldehydes and arylboronic acids utilizing a bis(oxazoline) ligand ((S,S)-L4).[28] A variety of aromatic, heteroaromatic and aliphatic sulfinamides were tolerated under the reaction conditions, as well as both alkyl and aryl aldehydes (Scheme 3.1.1.1.4). 361 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Pd-catalyzed Asymmetric Petasis-type Reactions Manolikakes, 2015: Pd(TFA)2 (10 mol%) (S,S)-L4 (15 mol%) O TsNH2 383 + + H CH3NO2, 40 °C 384 93% yield 92% ee 381 Me Ph Ts PhB(OH)2 O O N N Me N H 385 Me Me (S,S)-L4 Scheme 3.1.1.1.4. Example of Pd-catalyzed asymmetric Petasis-type reactions. Overall, transition metal catalyzed asymmetric Petasis reactions remain underdeveloped. These reactions often rely on preformed imines, which are difficult to prepare and isolate, restricting their practicality.[29] Future development focusing on transition metal-catalyzed three-component reactions between amines, aldehydes and organoboron reagents would fill a large gap in the asymmetric Petasis literature. 3.1.1.2 NON-DIRECTED REACTIVITY Non-Directed Three-Component Petasis Reactions: Since the development of the reaction in 1993, there have been few examples of three-component Petasis reactions that proceed in a non-directed fashion. While it is known that a directing-group is not necessary when using formaldehyde as the carbonyl component, this is not generalizable to other aldehydes.[3] In 1996, Harwood and coworkers reported a chiral-auxiliary approach toward optically active amino acids utilizing a Petasis reaction.[30,31] Intriguingly, the reaction proceeds in a non-directed fashion with a range of aliphatic aldehydes (Scheme 3.1.1.2.1). Though the authors did not conduct any mechanistic studies, this surprising 362 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction reactivity may result from the nucleophilicity of furanyl boronic acid 388, which is known to be highly reactive in Petasis reactions due to its electron-rich nature. While the scope with respect to the amine and boronic acid components was not explored further, this example constitutes a rare case of a non-directed three-component Petasis reaction that proceeds under the canonical mechanistic framework. Harwood, 1996: O O O (HO)2B O + Ph N H 386 H 387 N O + Bu H 388 THF reflux 69% yield 14:1 dr Bu + Ph Ar NH2 390 391 Ph H H O 389 Molander, 2019: O O NHPh [Ir{dF(CF3)2ppy}2(bpy)]PF6 (2 mol%), NaHSO4 KF3B + Ar = p(CO2Me)-C6H4 NBoc Ar NBoc blue LEDs 1,4-dioxane, 23 °C 392 393 83% yield Scheme 3.1.1.2.1. Examples of non-directed Petasis reactions. More recently, in 2019, Molander developed a non-directed Petasis reaction that couples alkyl-trifluoroborates (392), anilines (391), and benzaldehydes (390) utilizing an alternative reaction manifold centered around photoredox chemistry (Scheme 3.1.1.2.1).[32] Single-electron reduction of trifluoroborate salts (i.e., 392) generates alkyl radicals which nucleophilically attack the in situ generated iminium ions. In addition to being non-directed, the use of an alkyl-organoboron component is notable as these substrates are usually unreactive in traditional, polar Petasis reactions. Overall, this method represents an orthogonal framework for expanding the scope of the Petasis reaction which warrants further investigation.[33] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 363 Non-Directed Petasis-Type Reactions: Several different strategies have been employed to develop non-directed Petasis-type reactions. These approaches center around generating a sufficiently electrophilic iminium ion that can achieve intermolecular coupling without a directing group. One strategy that has been explored is the use of ⍺halogenated aldimines as coupling partners (Scheme 3.1.1.2.2a). In 2002, Billard demonstrated that trifluoroacetaldehyde-derived hemiaminals (394) can be reacted with styrenyl-trifluoroborate salts (395) utilizing BF3•Et2O as a Lewis acid.[34, 35] A second strategy that has been examined to render the Petasis-type reaction nondirected is the in-situ generation of N-acyliminium ions as the electrophilic component (Scheme 3.1.1.2.2b). N-Acyliminium ions are reactive species that have been leveraged for countless carbon–carbon bond forming processes due to their highly electrophilic nature.[36] In 2005, Yoon reported a method that couples activated quinolines, formed via the Nacylation of quinoline 397 with diethyl pyrocarbonate, and boronic acids (i.e., 398) to form the corresponding 1,2-dihydroquinolines (399).[37] This reaction demonstrates that Nacyliminium ions can be attacked by sufficiently electron-rich boronic acids. A more recent report from Carrera in 2017 takes advantage of another method for the generation of Nacyliminium ions, the protonation of enamides (and imines, not shown).[38] Specifically, it was found that the acid-promoted addition of trifluoroborate salts (i.e., 401) into carbamate-protected imines and enamines (i.e., 400) can be accomplished. The author posited this was due to their use of a “pre-activated boron species” (a trifluoroborate salt, which is already in the more nucleophilic “ate” complex) in tandem with highly reactive N-acyliminium ions. 364 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction a) α-halo imines Billard, 2002: Bn N Bn N + KF3B CH2Cl2 23 °C 85% yield Me F3C N BF3•Et2O N OTMS 394 F3C 395 Me 396 b) N-acyl iminium ions Yoon, 2005: O + (EtO2C)O (HO)2B CH2Cl2 23 °C 86% yield N 397 398 O N O OEt 399 Carrera, 2017: Boc HN TFA KF3B + Ph 401 Boc i-Pr MeCN 23 °C 90% yield i-Pr 400 HN Ph 402 c) Miscellaneous iminium ions Takemoto, 2007: Ph Ph N + AuCl(PPh3) (10 mol%) AgNTf2 (10 mol%), H2O (HO)2B Ph PMP NPMP 1,4-dioxane, 23 °C H 75% yield 403 Ph 348 404 Thomson, 2015: KF3B NH2NHNs Me 405 O CH3CN 23 °C Ph BF3•Et2O Me 406 N –10 to 23 °C NHNs 89% yield Me C Ph 407 Scheme 3.1.1.2.2. Examples of non-directed Petasis-type reactions. Finally, there have been several examples of Petasis-type reactions that use unique classes of iminium ions with sufficient electrophilicity to engage in non-directed couplings (Scheme 3.1.1.2.2c). Takemoto and coworkers designed a method for the concise synthesis of 1,2-dihydroisoquinolines via a tandem cyclization/Petasis-type reaction sequence.[39, 40] Upon treatment with a gold catalyst, alkynyl aldimine 403 undergoes a 6-endo-dig 365 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction cyclization to generate a transient iminium ion (not shown) which is attacked by styrenyl boronic acid 348 to furnish product 404 in high yield. In 2015, the Thomson lab reported a non-directed, traceless Petasis-type reaction wherein in situ generated hydrazones (406) react with alkynyl trifluoroborate salts to deliver allene products (407).[41] This reaction demonstrates the privileged reactivity of hydrazones to undergo productive non-directed couplings; furthermore, this method is compatible with methyl ketones as the carbonyl component, a class of compounds that have historically been unreactive in Petasis reactions. Stoltz, 2023: H N H N BF3K Me N N H Bn 315 HO 1) 26, HFIP N N N Me 2) Ra/Ni, H2SO4, MeOH 70% over 2 steps single diastereomer H Me N H H Me strempeliopidine (284) Scheme 3.1.1.2.3. Application in the total synthesis of strempeliopidine. The Stoltz lab recently developed a non-directed Petasis coupling centered around acid-promoted ionization of an ⍺-hydroxyindole to generate an iminium ion that can be intercepted by a trifluoroborate salt. The utility of this reaction was demonstrated with its application as the key step in the Stoltz lab’s total synthesis of the monoterpenoid bisindole alkaloid strempeliopidine (284) (Scheme 3.1.1.2.3).[5c] Two complex monomers (315 and 26) were united in a late-stage convergent coupling, furnishing the natural product (284) in good yield after benzyl deprotection. These examples of non-directed reactivity expand the scope of competent electrophiles for this synthetically valuable transformation, although each method displays a limited scope individually. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 366 Metal-Catalyzed Petasis-Type Reactions: Metal-catalyzed additions of organoboron compounds to imines is a powerful and orthogonal reaction manifold that has been used to circumvent the need for a directing group. Both rhodium and palladium catalysts have been used extensively for this transformation; however, since many of these methodologies have been rendered asymmetric, they are discussed above (see Schemes 3.1.1.1.3–4). The use of first-row transition metals is much less common, despite the fact that these catalysts are cheaper and can afford alternative, distinct reaction pathways. In 2008, Li and coworkers reported a copper-catalyzed, oxidative variant of the Petasis reaction that could unite tetrahydroisoquinolines and arylboronic acids using CuBr and t-BuOOH (Scheme 3.1.1.2.4a).[42] The copper catalyst and peroxide regioselectively oxidizes amine 408 to iminium ion 418; 418 then couples with arylboronic acid 409, likely through a process involving copper, although the exact mechanism was not determined. In addition to utilizing a novel strategy for imine generation, this example also demonstrates how metal catalysis can be used to enable productive reactivity with even electron-deficient arylboronic acids (i.e., 409). The Arndtsen lab developed a three-component, coppercatalyzed Petasis-type reaction of imines, acid chlorides, and organoboranes.[43] Acylation of imine 411 by acid chloride 412 delivers an N-acyliminium ion that can be intercepted by pyridine to provide pyridinium 419; the authors posited that this intermediate couples to an in-situ generated organocopper complex (420) to furnish amide 414 and the pyridine– BEt3 adduct. This method enables the rapid synthesis of ⍺-substituted amides as well as provides a Petasis reaction variant that is compatible with alkyl organoboranes. 367 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction a) Copper-catalyzed reactions Li, 2008: NPMP (HO)2B Me + NPMP CuBr (20 mol%) t-BuOOH (70% in H2O) DME, 95 °C 408 O 409 410 52% yield Me O Arndtsen, 2012: N p-tolyl Bn O + + p-tolyl H NaBEt4 Cl CuCl (10 mol%) pyridine O p-tolyl Bn N CH2Cl2, 23 °C p-tolyl 411 412 74% yield 413 Et 414 b) Nickel-catalyzed reactions Doyle, 2011: Ph N O OEt + B O O B B O Ph OEt 415 Ph Ni(cod)2 (7.5 mol%) PPh3 (7.5 mol%) N 1,4-dioxane/t-AmOH 40 °C O 99% yield 416 N RO–[Cu] PMP N p-tolyl [Ni]II Bn Ln[Cu]–Et N 419 N N 420 O 418 OEt 417 Proposed mechanistic intermediates: O p-tolyl Ph 421 OEt O OEt 422 Scheme 3.1.1.2.4. Examples of metal-catalyzed non-directed Petasis-type reactions. The Doyle lab designed a nickel-catalyzed Petasis-type reaction that cross-couples quinolines and boroxines (Scheme 3.1.1.2.4b).[44] The protected quinolines (i.e., 415) serve as N-acyliminium ion precursors that can be coupled to organoboronates. Mechanistic investigation revealed that the boroxine serves as a Lewis acid to facilitate ionization of the starting material and form quinolinium ion 421. Then, the Ni0 catalyst can oxidatively insert to generate π-allyl complex 422, which reacts with the boroxine to furnish product 416.[44c] These examples demonstrate how metal-mediated transformations can surpass Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 368 many of the traditional limitations of the Petasis reaction, including the need for a directing group and electronic requirements of the organoboron component. 3.1.1.3 SUMMARY AND OUTLOOK This Introduction provides an overview of the strategies used for the development of asymmetric as well as non-directed Petasis reactions. The highlighted catalytic asymmetric methods utilize either thiourea, chiral diol, or transition metal catalysis. The different classes of iminium ions as well as reaction manifolds used to develop non-directed Petasis reaction variants are then discussed. The article highlights the strengths and components of each system, helping to identify common features of successful approaches as well as point out weaknesses of the field. Despite the highlighted breakthroughs, further methodology improvements are necessary. Firstly, the reported organic catalyzed, asymmetric Petasis reactions often display limited scopes or modest enantioselectivities with many requiring an anchoring group on the generated iminium ion to enable sufficient interaction with the catalyst. Second, there are few reports of asymmetric transition metal-catalyzed Petasis reactions. Most utilize precious metals and rely on preformed imines, which can be difficult to prepare. These metal-catalyzed reactions show particular promise as they can circumvent many of the traditional limitations of Petasis chemistry (allowing for use of electron pooror alkyl-organoboron species). Petasis transformations catalyzed by first-row transition metals are generally undeveloped when compared to their precious metal analogs. With respect to non-directed Petasis reactions, further investigation into alternative reaction manifolds (such as photoredox or transition metal catalysis) or novel, reactive iminium ion 369 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction classes would be valuable. A general model for understanding and predicting the factors that allow certain iminium ions to undergo non-directed reactivity would be essential for further expanding the scope of the Petasis reaction. We anticipate that advancements in asymmetric and non-directed Petasis chemistry will enable the preparation of novel aminecontaining compounds and broadly serve chemists in all fields. 3.1.2 A DIRECTING GROUP-FREE PETASIS REACTION OF HYDROXYINDOLES Methods for the modification of complex, nitrogen-containing molecules are of paramount importance. Many of these molecules and derivatives thereof serve as pharmaceuticals or drug discovery starting points.[45] Dimeric indole alkaloids have drawn particular interest from researchers owing to their propensity to have desirable biological activities, such as the ability to modulate protein-protein interactions.[46–48] Furthermore, it has been shown that dimeric bioactive compounds often exhibit greater potency and more unique biological mechanisms of action than the corresponding monomers, possibly due to their higher stability and affinity toward their target receptors.[49,50] As such, techniques to access a wide variety of dimeric indole compounds advantageously enable new structure-activity relationship studies and therefore hold potential to further our fundamental understanding of the mechanisms of action of dimeric therapeutics. The Petasis-type reaction, wherein an iminium ion is coupled to a boronic acid nucleophile, has long served as an effective tactic for the preparation of natural products.[51– 53] The reaction is operationally simple and does not require rigorously dried solvents, exclusion of air, or sensitive catalysts. Despite these advantages, a major limitation of the 370 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Petasis reaction is the required use of a directing heteroatom for intramolecular delivery of the nucleophile (Figure 3.1.2.1a).[54,55] a) Petasis reaction and limitations N H + OH B N O –H2O N H H OH B O OH HO OH OH directing heteroatom required to enable productive reactivity b) Previous research: Use of trifluoroborate nucleophiles to circumvent directing group N Carrera, 2017 Boc BF3K + H Boc HN TFA MeCN c) This research: Non-directed Petasis-type reaction via aromaticity-disrupting iminium ion R N 423 R BF3K + H+ R HO R N 424a N 425 N 424b enhanced carbocation character novel mode of undirected reactivity synthesis of dimers from bioactive compounds broad substrate scope air and water tolerant Figure 3.1.2.1. The Petasis reaction, its limitations, and the development of nondirected variants. Trifluoroborate salts are a class of bench stable organoboron nucleophiles that have been employed in non-directed nucleophilic additions into oxocarbenium ions,[56] aldehydes,[57] enones,[58] and benzhydrylium cations.[59] In 2017, Carrera reported a method to overcome the requirement for directing heteroatoms when coupling trifluoroborate salts with Boc-protected aldimines by using TFA (trifluoroacetic acid) as an additive (Figure Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 371 3.1.2.1b).[60] While this method constitutes a large advancement in non-directed Petasistype reactions, the TFA additive renders it incompatible with acid sensitive coupling partners. To address current limitations for the Petasis reaction, we envisioned an alternate strategy that would circumvent the need for strongly acidic additives or adjacent directing groups. Herein, we report the development of a Petasis-type reaction where the generation of a highly electrophilic, aromaticity-disrupting iminium ion enables directing-group free reactivity (Figure 3.1.2.1c). The mild conditions and broad scope of this transformation are exemplified through the functionalization of complex natural products and its application as a method to access dimeric molecules from natural product and pharmaceutical-derived monomers. Investigations began by designing an iminium ion precursor that would be sufficiently electrophilic to obviate the need for a directing group. Inspired by our group’s recent work toward synthesizing heterodimeric bisindole alkaloids, we became interested in using α-hydroxyindoles as iminium ion precursors (Figure 3.1.2.1c, 423).[46g,46h] We hypothesized that acid-promoted ionization of these compounds would result in an iminium ion that would disrupt aromaticity and serve as a highly reactive electrophile (424). In addition to their enhanced reactivity, alkynyl trifluoroborate salts were explored as nucleophiles since the resulting alkyne can potentially serve as a rigid linker or may be utilized as a handle for further functionalization.[60–61] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.2 RESULTS AND DISCUSSION 3.2.1 REACTION DESIGN AND OPTIMIZATION 372 Using α-hydroxyindole 426a and alkynyl trifluoroborate salt 427, our investigations led to the optimized conditions shown in Table 3.2.1.1, wherein performing the reaction in trifluoroethanol (TFE) with benzoic acid (1 equiv) delivered product 428a in 95% yield (Table 3.2.1.1, entry 1). While this reaction performs well without any additives (entry 2), it was found the addition of benzoic acid led to higher yields, presumably due to more facile ionization of the N,O-hemiaminal. Strong acids such as TFA led to decomposition of the α-hydroxyindole (entry 3). Using other solvents like dichloromethane, nitromethane, and methanol led to lower conversions and deleterious reactivity (entries 4–6).[62] Dilute conditions enable the highest levels of conversion due to the limited solubility of the trifluoroborate salts in TFE (entry 7). Gratifyingly, high yields can still be achieved when the reaction is performed with lower loadings of trifluoroborate salt, at ambient temperature, or in the presence of water (entries 8–10). Finally, the reaction did not proceed when phenylacetylene was used instead of the corresponding trifluoroborate salt 427 (entry 11). 373 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Table 3.2.1.1. Reaction optimization of the Petasis-type coupling. BF3K Me 427 Br N HO Me Br Ph (3 equiv) PhCO2H (1 equiv) 426a entrya N CF3CH2OH (0.025 M) 65 °C, 18 h 428a Ph variation from conditions above yield (%)b 1 none 95 2 no PhCO2H 82 3 TFA, instead of PhCO2H 35 4 CH2Cl2, instead of CF3CH2OH 48 5 MeNO2, instead of CF3CH2OH 79 6 MeOH, instead of CF3CH2OH 0 7 0.1 M, instead of 0.025 M 77 8 1 equiv 427 74 9 23 °C, instead of 65 °C 81 10 5 equiv water added 91 11 3 equiv phenylacetylene instead of 427 0 [a] Reactions conducted at 0.05 mmol scale. [b] Yields determined by 1H NMR analysis of crude reaction mixture relative to 1,3,5-trimethoxybenzene internal standard. 3.2.2 SCOPE OF THE INDOLE COMPONENT With optimized reaction conditions in hand, the scope of the α-hydroxyindole component was explored (Scheme 3.2.2.1). Bromo- (426a), chloro- (426b), and fluoro(426c) indoles all provided products 428a, 428b, and 428c in good to excellent yields. Methyl and phenyl-substituted indoles (426d and 426e) were tolerated, albeit in diminished yields presumably due to the instability of the more electron-rich indoles (428d and 428e). 3-Methylindole 426f delivered alkyne 428f in high yield; reaction efficacy was enhanced when performed on gram scale, demonstrating the scalability of this reaction. Pyrazolecontaining substrate 426g delivered alkyne 428g in high yield, establishing the utility of the reaction in the presence of other ubiquitous, pharmacologically-relevant heterocycles. 374 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction R2 R2 R1 R3 N BF3K + R1 PhCO2H (1 equiv) Ph R3 N CF3CH2OH (0.025 M) 65 °C, 18 h HO 426a–n 427 (3 equiv) 428a–n Ph variation at arene (R1, R2) Me Me X N Ph MeN N entry X yield (%) 428a 428b 428c 428d 428e Br Cl F Me Ph 87 94 94 60 67 Me N Ph 428f 85% yield (90%, 1.0 g scale) limitation Br H Br N 3 N N 428i 0% yield Ph 428g 428h Ph 79% yield Ph 86% yield variation at cyclohexyl (R3) Me Me Me Me Me Me N N Me Me Me N Me Me Ph Me 428j Ph 86% yield 428k Ph 76% yield 428l 81% yield special cases Ph Br Br Br N HO 426m formal propargylation Ph HO N N Me 428m 65% yield 426n Br vinylogous reactivity N Me 428n 47% yield Scheme 3.2.2.1. Exploration of the substrate scope for the Petasis-type reaction using different α-hydroxyindoles. Reactions conducted at 0.1 mmol scale. Yields are of isolated products after column chromatography. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 375 3-Bromo substituted indole 426h yielded alkyne 428h, wherein the bromide serves as a handle for further functionalization. Unfortunately, C3-unsubstituted indole 426i underwent nonspecific oligomerization. Substitution on all positions of the cyclohexyl ring was tolerated (426j–l), with the reaction proceeding smoothly at a challenging neopentylic position (428j). Additionally, the reaction can be performed on exocyclic iminium precursors to achieve a net propargylation (428m), obviating the need for highly reactive alkylating reagents. Finally, the reaction can be used to functionalize isomeric alcohol-bearing indoles, such as 428n in moderate yields. 3.2.3 SCOPE OF THE TRIFLUOROBORATE SALTS Having demonstrated the broad range of functionality tolerated on the α- hydroxyindole, the scope with respect to the trifluoroborate salt was next examined (Scheme 3.2.3.1). A diverse set of trifluoroborate salts were employed, including 3-fluoroand 4-bromo-phenylacetylenes (429a and 429b). The ortho-substituted arene, tolyl trifluoroborate 429c, afforded product in excellent yield. Electron-rich (429d) and electronpoor (429e) trifluoborate salts were competent in the reaction (430d and 430e) as well as thiophene-substituted salt 429f. Excitingly, the reaction could be expanded to include nbutyl and t-butyl substituted alkynes (429g and 429h), which delivered the desired αfunctionalized indoles in high yields. Diyne 429i and silyl ether 429j, were also competent nucleophiles. Cyclohexyl and cyclopropyl alkynes (429k and 429l) delivered indoles 430k and 430l in high yields. Furthermore, enyne-derived substrate 429m underwent the transformation in excellent yield. 376 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me Me Br + N R Br PhCO2H (1 equiv) BF3K CF3CH2OH (0.025 M) 65 °C, 18 h N HO 426a 429a–r (3 equiv) 430a–r R ethynylbenzene nucleophiles Me Me Br Me Br Br N N N Me F 430a 430b 430c 84% yield 78% yield 93% yield Br Me Br Me Me Br Br N N N 430d 430e 76% yield 73% yield 430f S 87% yield F3C MeO alkyl-alkynyl nucleophiles Me Me Br Br Br N N 430g Me 430j 430i Me 79% yield Me 61% yield 71% yield TBSO Me Me Br N N 430h Me 84% yield Me Me Me Br limitation Me Br Br Br N N N N 430n R=H 430m 430k 430l 85% yield 99% yield 430o 96% yield R = TIPS 0% yield R additional nucleophile classes Me Me Br Me Br Br N N N Me 430p 90% yield Me 430q 72% yield Ph 430r 82% yield Scheme 3.2.3.1. Investigations into the substrate scope of trifluoroborate salts in the Petasis-type reaction. Reactions conducted at 0.1 mmol scale. Yields are of isolated products after column chromatography. 377 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Unfortunately, trifluoroborate salts derived from acetylene (429n) or (triisopropylsilyl)acetylene (429o) were unsuccessful with the current conditions. However, several additional classes of trifluoroborate salts were competent in this non-directed reaction. Allyl-trifluoroborate 429p provided alkene 430p in excellent yield. Furthermore, alkene 429q and styrene 429r reacted productively, expanding the utility of this reaction to include sp, sp2, and sp3 trifluoroborate nucleophiles.[63] 3.2.4 SYNTHETIC UTILITY OF PETASIS-TYPE REACTION PRODUCTS Having explored the scope of this transformation, the synthetic utility of this method was demonstrated through the diversification of several products. Alkyne 428f can be fully or partially reduced to afford alkane 431 or cis-olefin 432 (Scheme 3.2.4.1a). Moreover, the ability of this method to install bioconjugation-compatible linkers points toward the possibility of designing bioactive, chimeric dimers. As shown in Scheme 3.2.4.1b, copper-catalyzed azide-alkyne click reaction of the antiretroviral zidovudine 433 with diyne 430i provided chimeric dimer 434 in 87% yield. 378 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me a) Pd/C H2 (1 atm) N EtOAc 23 °C, 18 h Me Ph 431 98% yield N Me Ph Lindlar’s catalyst quinoline H2 (1 atm) 428f Ph N Et2O 23 °C, 18 h 432 b) 90% yield (cis olefin) Me Br O NH O Me N N CuSO4 • 5 H2O (6 mol%) sodium ascorbate (10 mol%) + O 3:1 THF/H2O 23 °C, 22 h N3 430i OH bioconjugationcompatible linker installed Br zidovudine (433) HIV treatment Me O H N O N N N N N Me chimeric dimer synthesis O OH 434 87% yield Scheme 3.2.4.1. Synthetic derivatizations of Petasis-type products. 3.2.5 APPLICATION TO THE SYNTHESIS OF NON-NATURAL BISINDOLE DIMER ANALOGS Bearing in mind the rich biological activities of indole alkaloids and their potential as pharmaceutical lead structures, we next leveraged our Petasis-type reaction to modify complex indole alkaloids and synthesize non-natural bisindole dimers.[45,47,64] To this end, vincamine, an indole alkaloid used to increase cerebral blood flow, was derivatized to α- Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 379 hydroxyindole 435 and subjected to our developed reaction conditions; to our delight, it afforded bromoarene 436 in excellent yield (Scheme 3.2.5.1a).[65–67] Coupling of bromide 436 with tabersonine-derived boronic ester 437 afforded the desired tabersonine-vincamine dimer analog 438. In addition to functionalizing vincamine, the exocyclic hemiaminal derived from the anti-inflammatory drug indomethacin (439) reacted to provide alcohol 440 in moderate yield (Scheme 3.2.5.1b). A derivative of the toxic alkaloid brucine (441) underwent the transformation in excellent yield to afford alkyne 442 as a single diastereomer, the structure of which was confirmed by X-ray crystallography (Scheme 3.2.5.1c, 442•HCl).[68] In this case, the ⍺-amino nitrile (441) was used as the iminium precursor due to the instability of the hemiaminal. This exciting example of a complex indoline substrate represents an expansion of the scope beyond indole-based iminium ions, demonstrates the competence of alternative iminium ion precursors, and holds promise to further increase the generality of this non-directed reactivity. Next, a derivative of quinestrol (443), a therapeutic hormone modulator, was evaluted in our Petasis-type reaction (Scheme 3.2.5.1d). Gratifyingly, exposing α- hydroxyindole 426a to trifluoroborate salt 443 under our standard conditions provided alkyne 444 in moderate yield. Additionally, the combination of steroid 443 with vincamine derivative 435 directly afforded complex dimer 445 in high yield. The synthetic applications shown in Scheme 3.2.5.1 reveal the potential for the rapid design of complex heterodimers from bioactive constituents as well as the power of the developed Petasistype reaction as a tool for natural product modification.[69] 380 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction a) H N 437 H 429b N Pd(PPh3)4 (10 mol%) K2CO3 N N PhCO2H (CF3)2CHOH 65 °C, 18 h HO OH Me 5:5:1 PhMe/H2O/EtOH 90 °C, 3 h N Br from vincamine peripheral vasodilator 436 Bpin 92% yield 4:1 dr 429b Br Me OH BF3K 435 Me N MeO2C Boc 437 b) H N OH 427 MeO Me N OH Me N Me 65% yield tabersonine-vincamine bisindole dimer analog N Boc MeO PhCO2H Me CF3CH2OH 65 °C, 18 h N HO 438 MeO2C OH N 439 Ph from indomethacin 440 49% yield c) N MeO MeO N 427 H N H H PhCO2H O (CF3)2CHOH 65 °C, 18 h MeO H N MeO H H H O H NC 441 Ph from brucine 442•HCl 442 80% yield >20:1 dr Br Me d) BF3K 426a, PhCO2H N CF3CH2OH 65 °C, 18 h Me Me O H 444 H H 48% yield 1:1 dr H H H O H 443 from quinestrol N 435, PhCO2H (CF3)2CHOH 65 °C, 18 h O H H N Me OH Me H 445 82% yield 4:1 dr facile complex dimer synthesis Scheme 3.2.5.1. Application of the Petasis-type reaction to prepare complex dimers from bioactive natural products and pharmaceuticals. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.2.6 381 PRELIMINARY INVESTIGATIONS INTO THE MECHANISM OF THE NON-DIRECTED PETASIS-TYPE REACTION Lastly, to gain insight into our newly developed Petasis-type reaction, several mechanistic experiments were performed. Enamine 446, which represents an intermediate formed by deprotonation of the key iminium ion (424a, Figure 3.1.2.1c), was prepared and found to be competent under the standard reaction conditions (Scheme 3.2.6.1a). It has been proposed that N,O-acetals can serve as inert reservoirs for reactive iminium ions and prevent deleterious side reactions.[70] To test this possibility, mixed acetal 447 was independently prepared and found to be a competent substrate in the reaction (Scheme 3.2.6.1b).[71] The possibility of protodeborylation prior to Friedel–Crafts-type reactivity was explored, though deemed unlikely, as no reaction was observed when using simple olefin coupling partners.[72] Finally, to probe the intermediacy of an iminium ion, allylsilane 448 was subjected to our standard reaction conditions, which provided alkene 449 (Scheme 3.2.6.1c).[73] Taken together, these data support the generation of the iminium ion under the canonical reaction conditions from a variety of precursors and further demonstrate the ability of the iminium ion to react with an appropriate nucleophile.[74] 382 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction a) BF3K Me 427 Br N Me Br Ph (3 equiv) PhCO2H (1 equiv) N CF3CH2OH (0.025 M) 65 °C, 18 h 446 Ph b) BF3K Me 427 Br N Me Br Ph (3 equiv) PhCO2H (1 equiv) N CF3CH2OH (0.025 M) 65 °C, 18 h O F3C 428a 74% yield 447 c) Ph Me Me Me Br Me3Si N HO 428a 87% yield 448 (3 equiv) PhCO2H (1 equiv) CF3CH2OH (0.025 M) 65 °C, 18 h 426a Br N Me 449 96% yield Scheme 3.2.6.1. Investigations into the mechanism of the non-directed Petasis-type reaction. 3.3 CONCLUSIONS In summary, we have developed a non-directed Petasis-type reaction that couples trifluoroborate salts with α-hydroxyindoles. The reaction proceeds under mild conditions that tolerate air and moisture and displays a diverse scope for both coupling partners. Additionally, its application to the synthesis of complex heterodimers of bioactive indole alkaloids and pharmaceuticals highlights the ability of the Petasis-type reaction to serve as a robust method for natural product modification. This reaction represents a novel strategy for undirected couplings that will both expand the utility of the Petasis reaction and act as a template for designing directing-group free reactions. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4 EXPERIMENTAL SECTION 3.4.1 MATERIALS AND METHODS 383 Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.[75] Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) was used for silica gel flash chromatography. Sigma Aldrich aluminum oxide (activated, basic, Brockmann I) was used for basic alumina flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian Mercury 300 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), (CD2H)(CD3)CO (δ 2.05 ppm), (CD2H)(CD3)SO (δ 2.50 ppm), or CDHCl2 (δ 5.32 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CDCl3 (δ 77.16 ppm), (CD3)2CO (δ 29.84 ppm), (CD3)2SO (δ 39.52 ppm) or CD2Cl2 (δ 53.84 ppm). 19F NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (282 MHz). 11B NMR spectra were recorded on a Bruker 400 MHz spectrometer (128 MHz). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR, 19F NMR, and 11B NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained 384 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using either a JEOL JMS-T2000 AccuTOF GC-Alpha time-offlight mass spectrometer using Field Desorption (FD) ionization (ions detected are M+•), an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in mixed ionization mode (MM: ESI-APCI), or an LC-MS using a Waters LCT Premier XE Electrospray (ES) TOF mass spectrometer interfaced with a Waters UPLC chromatography system (negative ion mode, ions detected are M–). The Caltech Chemistry Division Mass Spectrometry laboratory acknowledges DOW Chemical Company (DOW Next Generation Instrumentation Grant) and the NSF CRIF program for providing funds that enabled the purchase of this instrumentation. Reagents were purchased from commercial sources and used as received unless otherwise stated. NBS was recrystallized from water prior to use. 10-bromo-8,9dihydropyrido[1,2-a]indol-6(7H)-one (453h),[76] 2,5,5-trimethylcyclohexane-1,3-dione,[77] 2,4,4-trimethylcyclohexane-1,3-dione,[78] potassium ethynyltrifluoroborate 429n,[79] potassium trifluoro((triisopropylsilyl)ethynyl)borate 429o,[79] tabersonine pinacol boronic ester 437,[80] and ⍺-cyanoindoline 441[81] were prepared according to the literature. 385 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 3.4.2.1 Preparation of a-Hydroxy Indole Compounds General sequence: HN NH2 Me + O O Me Fischer indole synthesis/acyl migration R N General Procedure 1 or 2 R Me R reduction R N General Procedure 3 O R R HO General Procedure 1: Fischer indole synthesis + acyl migration HN NH2 Me Me • HCl + O Br O H2SO4 (conc) N H2O:EtOH reflux, 12 h O Br 451 452 453a To a solution of 2-methylcyclohexane-1,3-dione 452 (5.7 g, 45 mmol, 1.0 equiv) in EtOH (450 mL, 0.1 M) was added 4-bromophenylhydrazine hydrochloride 451 (12 g, 54 mmol, 1.2 equiv) followed by H2O (110 mL). Concentrated H2SO4 (100 mL) was then added slowly, and the resulting solution refluxed for 12 h. Upon completion, the reaction was concentrated to a slurry, diluted with CH2Cl2 and H2O, and then basified with NaOH. The mixture was transferred to a separatory funnel, washed with saturated aqueous NaHCO3 twice, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (15 to 25% EtOAc in hexanes) to afford an orange solid (9.8 g, 78% yield). 386 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction General Procedure 2: Fischer indole synthesis + acyl migration HN NH2 Me Me • HCl + O F O 2N HCl N toluene 100 °C, 24 h O F 454 452 453c A procedure was adapted from the literature as follows.[82] A flask was charged with a magnetic stirring bar, 2-methylcyclohexane-1,3-dione 452 (2 g, 16 mmol, 1.0 equiv), 4-fluorophenylhydrazine hydrochloride 454 (2.6 g, 16 mmol, 1.0 equiv), and toluene (32 mL). Aqueous HCl (2N, 8 mL) was then added at 23 °C. The flask was fitted with a reflux condenser, placed in an oil bath, and the reaction was heated to 100 °C with stirring. After 24 h, the reaction mixture was cooled to 23 °C, diluted with H2O and extracted three times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel flash column chromatography (15 to 20% EtOAc in hexanes) afforded the acyl indole 453c (2.3 g, 67% yield) as an orange solid. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 387 Me Br N 453a O 2-bromo-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453a) Prepared according to general procedure 1 using 4-bromophenylhydrazine hydrochloride (12 g, 54 mmol) and 2-methylcyclohexane-1,3-dione (5.7 g, 45 mmol). Purification by column chromatography (15 to 25% EtOAc in hexanes) provided an orange solid (9.8 g, 78% yield). 1 H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 8.6, 0.5 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.7, 2.0 Hz, 1H), 2.89 (t, J = 5.9 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.13 (t, J = 1.0 Hz, 3H), 2.08 (tt, J = 7.2, 5.8 Hz, 2H); All characterization data match those reported in the literature.[83] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 388 Me Cl N 453b O 2-chloro-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453b) Prepared according to general procedure 2 using 4-chlorophenylhydrazine hydrochloride (3.1 g, 17 mmol) and 2-methylcyclohexane-1,3-dione (2.0 g, 16 mmol). Purification by column chromatography (15 to 25% EtOAc in hexanes) provided an orange solid (1.7 g, 45% yield). 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.6, 2.1 Hz, 1H), 2.88 (t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.13 (s, 3H), 2.08 (p, J = 6.5 Hz, 2H) All characterization data match those reported in the literature.[83] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 389 Me F N 453c O 2-fluoro-10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453c) Prepared according to general procedure 2 using 4-fluorophenylhydrazine hydrochloride (2.6 g, 16 mmol) and 2-methylcyclohexane-1,3-dione (2.0 g, 16 mmol). Purification by column chromatography (15 to 20% EtOAc in hexanes) provided an orange solid (2.3 g, 67% yield). 1 H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 8.9, 4.8 Hz, 1H), 7.04 (dd, J = 8.9, 2.6 Hz, 1H), 6.97 (td, J = 9.1, 2.6 Hz, 1H), 2.88 (t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.13 (s, 3H), 2.08 (p, J = 6.4 Hz, 2H) All characterization data match those reported in the literature.[83] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 390 Me Me N 453d O 2,10-dimethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453d) Prepared according to general procedure 2 using 4-methylphenylhydrazine hydrochloride (2.3 g, 14 mmol) and 2-methylcyclohexane-1,3-dione (1.5 g, 12 mmol). Purification by column chromatography (18% EtOAc in hexanes) provided an orange solid (2.2 g, 84% yield). 1 H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 8.2, 1.4 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 2.87 (t, J = 6.3 Hz, 2H), 2.74 (t, J = 6.2 Hz, 2H), 2.46 (s, 3H), 2.15 (s, 3H), 2.06 (p, J = 6.3 Hz, 2H); All characterization data match those reported in the literature.[83] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me Br N 453a O PhB(OH)2 Pd(PPh3)4 (10 mol%) K2CO3 PhMe:H2O:EtOH reflux, 16 h 391 Me Ph N 453e O 10-methyl-2-phenyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453e) A solution of aryl bromide 453a (278 mg, 1 mmol, 1.0 equiv), phenyl boronic acid (146 mg, 1.2 mmol, 1.2 equiv), and K2CO3 (414 mg, 3 mmol, 3.0 equiv) in toluene/H2O/EtOH (5:5:1; 2.2 mL) was sparged with argon followed by the addition of Pd(PPh3)4 (115.6 mg, 0.1 mmol, 0.1 equiv). The reaction was heated to 90 °C for 15 h then cooled to 23 °C, diluted with CH2Cl2 and H2O, extracted four times with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (17% EtOAc in hexanes) to afford a yellow-white solid (196 mg, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.5 Hz, 1H), 7.70 – 7.66 (m, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.35 (dt, J = 7.2, 1.2 Hz, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.22 (s, 3H), 2.10 (p, J = 6.0 Hz, 2H); All characterization data match those reported in the literature.[83] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 392 Me N 453f O 10-methyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453f) Prepared according to general procedure 1 using phenylhydrazine (2.9 mL, 29 mmol) and 2-methylcyclohexane-1,3-dione (3.0 g, 24 mmol). Purification by column chromatography (10 to 20% EtOAc in hexanes) provided a white solid (3.4 g, 70% yield). 1 H NMR (400 MHz, CDCl3) δ 8.48 – 8.42 (m, 1H), 7.47 – 7.37 (m, 1H), 7.32 – 7.26 (m, 2H), 2.94 – 2.86 (m, 2H), 2.81 – 2.72 (m, 2H), 2.17 (bs, 3H), 2.08 (p, J = 6.3 Hz, 2H); All characterization data match those reported in the literature.[83] 393 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me 1-methyl-1H-pyrazole-4-boronic acid Pd(PPh3)4 (10 mol%), K2CO3 Br N MeN N Me PhMe:H2O:EtOH reflux, 16 h 453a O N 453g O 10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453g) A solution of aryl bromide 453a (1.47 g, 5.3 mmol, 1.0 equiv), 1-methyl-1H-pyrazole-4boronic acid (0.8 g, 6.3 mmol, 1.2 equiv), and K2CO3 (2.2 g, 15.9 mmol, 3.0 equiv) in toluene/H2O/EtOH (5:5:1; 12 mL) was sparged with argon followed by the addition of Pd(PPh3)4 (0.6 g, 0.53 mmol, 0.1 equiv). The reaction was heated to 95 °C for 12 h then cooled to 23 °C, diluted with CH2Cl2 and H2O, extracted four times with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by recrystallization (refluxing THF/hexanes) to afford a green-grey solid (0.85 g, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.39 (dd, J = 8.5, 1.8 Hz, 1H), 3.96 (s, 3H), 2.91 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H), 2.09 (p, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.2, 136.9, 133.9, 133.3, 131.8, 128.4, 127.0, 123.9, 122.1, 116.7, 114.6, 112.3, 39.2, 34.5, 21.9, 21.3, 8.6; IR (Neat Film, NaCl) 2941, 2358, 1694, 1623, 1456, 1399, 1369, 1333, 1176, 1119, 1072, 985, 949, 813, 731 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H18N3O [M+H]+: 280.1444, found 280.1443. 394 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction HN NH2 Me Me • HCl O + O Me Me Me 455 456 Me Me Me 2N HCl N toluene 100 °C, 24 h Me Me + N O Me Me O 453j 453l 58% yield 18% yield 2,7,7,10-tetramethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453j) 2,9,9,10-tetramethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453l) Prepared according to general procedure 2 using 4-methylphenylhydrazine hydrochloride (2.5 g, 16 mmol) and 2,4,4-trimethylcyclohexane-1,3-dione (2.0 g, 13 mmol). Purification by column chromatography (5 to 7.5% EtOAc in hexanes) provided separately red solid 453j (1.8 g, 58% yield) and orange solid 453l (0.56 g 18% yield). Me Me N O Me Me 453j 2,7,7,10-tetramethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453j): 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.10 (dd, J = 8.4, 1.7 Hz, 1H), 2.99 – 2.90 (m, 2H), 2.45 (s, 3H), 2.15 (t, J = 1.1 Hz, 3H), 1.97 (t, J = 6.6 Hz, 2H), 1.37 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 175.0, 133.2, 133.2, 133.1, 131.7, 125.3, 117.9, 116.2, 111.7, 39.9, 35.0, 25.6, 21.6, 18.6, 8.5; IR (Neat Film, NaCl) 2973, 2932, 2862, 2364, 1694, 1621, 1463, 1393, 1358, 1330, 1271, 1196, 1077, 935, 868, 807, 609 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H20NO [M+H]+: 242.1539, found 242.1543. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 395 Me Me Me Me N O 453l 2,9,9,10-tetramethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453l): 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.3 Hz, 1H), 7.24 – 7.21 (m, 1H), 7.16 – 7.09 (m, 1H), 2.79 (t, J = 6.7 Hz, 2H), 2.47 (s, 3H), 2.32 (s, 3H), 1.93 (t, J = 6.5 Hz, 2H), 1.49 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 169.2, 140.1, 133.2, 132.3, 132.0, 125.7, 117.7, 116.3, 112.2, 36.9, 32.3, 30.9, 27.8, 21.6, 9.9; IR (Neat Film, NaCl) 3021, 2960, 2928, 2866, 1697, 1599, 1472, 1385, 1355, 1318, 1294, 1211, 1192, 1160, 1128, 1087, 1038, 951, 906, 809,735, 671, 633, 617 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H20NO [M+H]+: 242.1539, found 242.1539. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 396 Me Me N Me Me O 453k 2,8,8,10-tetramethyl-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (453k) Prepared according to general procedure 2 using 4-methylphenylhydrazine hydrochloride (2.3 g, 14 mmol) and 2,5,5-trimethylcyclohexane-1,3-dione (1.8 g, 12 mmol). Purification by column chromatography (5% EtOAc in hexanes) provided a dark red solid (1.9 g, 57% yield). 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.2 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.10 (dd, J = 1.7, 0.7 Hz, 1H), 2.70 (s, 2H), 2.57 (s, 2H), 2.46 (s, 3H), 2.15 (s, 3H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6, 133.3, 132.6, 132.4, 131.8, 125.4, 118.0, 116.0, 113.2, 47.9, 35.6, 32.7, 28.0, 21.7, 8.6; IR (Neat Film, NaCl) 2956, 2357, 1693, 1622, 1465, 1395, 1361, 1331, 1214, 1151, 1105, 808, 636 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H20NO [M+H]+: 242.1539, found 242.1542. 397 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction General Procedure 3: Reduction by Lithium Aluminum Hydride Me Me Br Br LiAlH4 N 453a O THF 0 °C, 30 min N 426a HO To a suspension of LiAlH4 (800 mg, 21 mmol, 2 equiv) in THF (42 mL) at 0 °C was added dropwise a solution of acyl indole 453a (2.9 g, 10.5 mmol, 1 equiv) in THF (42 mL). The addition funnel was washed with THF (21 mL) and the reaction stirred for 30 min at 0 °C. After 30 min, the reaction was diluted with Et2O, cooled to 0 °C, and quenched by dropwise addition of H2O (0.8 mL). 15% aqueous NaOH (0.8 mL) was then added followed by H2O (2.4 mL). The mixture was warmed to 23 °C and stirred for 15 min. MgSO4 was then added and the slurry stirred for 15 min before filtration and concentration under reduced pressure. The resulting crude residue was then purified by chromatography (silica gel or basic alumina) (SiO2, 50 to 100% CH2Cl2 in hexanes) to afford the hemiaminal as an orange solid (2.1 g, 73 % yield). Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 398 Me Br N 426a HO 2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426a) Prepared according to general procedure 3 using acyl indole 453a (2.9 g, 10.5 mmol) and LiAlH4 (800 mg, 21 mmol). Purification by column chromatography (SiO2, 50 to 100% CH2Cl2 in hexanes) provided an orange solid (2.1 g, 73% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.6, 1.8 Hz, 1H), 5.90 (dt, J = 6.7, 3.4 Hz, 1H), 2.97 (dt, J = 16.4, 4.3 Hz, 1H), 2.78 – 2.65 (m, 1H), 2.42 (d, J = 6.6 Hz, 1H), 2.21 – 1.99 (m, 6H), 1.92 – 1.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.0, 133.4, 131.4, 123.6, 120.8, 113.3, 110.7, 106.1, 75.0, 31.6, 22.3, 16.1, 8.2; IR (Neat Film, NaCl) 3324, 2947, 2358, 1463, 1338, 1272, 1239, 1071, 989, 928, 882, 809, 794, 730 cm–1 HRMS (FD) m/z calc’d for C13H14BrNO [M]+•: 279.0259, found 279.0250. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 399 Me Cl N 426b HO 2-chloro-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426b) Prepared according to general procedure 3 using acyl indole 453b (1 g, 4.3 mmol) and LiAlH4 (330 mg, 8.6 mmol). Purification by column chromatography (basic alumina, 10 to 20% EtOAc in hexanes) provided an orange solid (792 mg, 77% yield). 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 5.90 (dt, J = 6.7, 3.4 Hz, 1H), 2.97 (dt, J = 16.6, 4.3 Hz, 1H), 2.78 – 2.65 (m, 1H), 2.42 (d, J = 6.7 Hz, 1H), 2.21 – 1.98 (m, 6H), 1.96 – 1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 133.7, 133.6, 130.8, 125.7, 121.1, 117.7, 110.3, 106.2, 75.0, 31.6, 22.4, 16.1, 8.2; IR (Neat Film, NaCl) 3322, 2940, 2356, 1575, 1454, 1384, 1348, 1273, 1239, 1169, 1071, 989, 930, 885, 793, 732, 680 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H15ClNO [M+H]+: 236.0837, found 236.0828. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 400 Me F N 426c HO 2-fluoro-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426c) Prepared according to general procedure 3 using acyl indole 453c (1 g, 4.6 mmol) and LiAlH4 (350 mg, 9.2 mmol). Purification by column chromatography (basic alumina, 10 to 20% EtOAc in hexanes) provided an orange solid (948 mg, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 8.7, 4.3 Hz, 1H), 7.12 (dd, J = 9.6, 2.5 Hz, 1H), 6.89 (td, J = 9.1, 2.5 Hz, 1H), 5.89 (dt, J = 6.7, 3.4 Hz, 1H), 2.97 (dt, J = 16.6, 4.3 Hz, 1H), 2.78 – 2.65 (m, 1H), 2.46 (d, J = 6.6 Hz, 1H), 2.18 – 2.09 (m, 5H), 2.09 – 1.97 (m, 1H), 1.95 – 1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.4 (d, J = 234.6 Hz), 133.9, 131.8, 130.1 (d, J = 9.5 Hz), 109.8 (d, J = 9.7 Hz), 108.9 (d, J = 26.0 Hz), 106.5 (d, J = 4.5 Hz), 103.3 (d, J = 23.2 Hz), 75.0, 31.6, 22.4, 16.1, 8.2; 19F NMR (282 MHz, CDCl3) δ – 124.36 (td, J = 9.4, 4.4 Hz); IR (Neat Film, NaCl) 3316, 2940, 2861, 2357, 1650, 1622, 1583, 1476, 1385, 1353, 1277, 1236, 1210, 1171, 1071, 989, 912, 847, 793, 733, 660 cm– 1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C13H15FNO [M+H]+: 220.1132, found 220.1127. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 401 Me Me N 426d HO 2,10-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426d) Prepared according to general procedure 3 using acyl indole 453d (1.5 g, 7 mmol) and LiAlH4 (530 mg, 14 mmol). Purification by column chromatography (basic alumina, 10 to 15% EtOAc in hexanes) provided an orange solid (1442 mg, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.31 – 7.27 (m, 2H), 7.00 (dd, J = 8.3, 1.6 Hz, 1H), 5.92 (dt, J = 6.0, 3.0 Hz, 1H), 3.04 – 2.93 (m, 1H), 2.79 – 2.64 (m, 1H), 2.48 (s, 3H), 2.17 (s, 3H), 2.16 – 1.99 (m, 3H), 1.94 – 1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 133.6, 132.1, 129.9, 129.2, 122.4, 118.0, 108.8, 105.9, 74.8, 31.4, 22.4, 21.6, 16.3, 8.2; IR (Neat Film, NaCl) 3324, 3019, 2938, 2859, 2360, 1649, 1588, 1505, 1479, 1407, 1353, 1292, 1170, 1071, 988, 930, 901, 832, 792, 734, 604 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H18NO [M+H]+: 216.1383, found 216.1378. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 402 Me Ph N 426e HO 10-methyl-2-phenyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426e) Prepared according to general procedure 3 using acyl indole 453e (174 mg, 0.6 mmol) and LiAlH4 (48 mg, 1.3 mmol). Purification by column chromatography (basic alumina, 0 to 25% EtOAc in hexanes) provided a white solid (141 mg, 80% yield). 1 H NMR (400 MHz, CDCl3) δ 7.71 – 7.65 (m, 3H), 7.50 – 7.41 (m, 4H), 7.34 – 7.29 (m, 1H), 6.01 (dt, J = 6.1, 3.0 Hz, 1H), 3.03 (dt, J = 15.7, 4.1 Hz, 1H), 2.82 – 2.69 (m, 1H), 2.44 (d, J = 6.1 Hz, 1H), 2.23 (s, 3H), 2.21 – 2.03 (m, 3H), 1.98 – 1.85 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 142.9, 134.8, 133.7, 132.8, 130.2, 128.7, 127.5, 126.4, 120.8, 116.8, 109.4, 106.8, 75.0, 31.5, 22.4, 16.3, 8.3; IR (Neat Film, NaCl) 3321, 3031, 2930, 1599, 1458, 1352, 1246, 1170, 1071, 987, 928, 909, 884, 808, 762, 732, 697 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H20NO [M+H]+: 278.1539, found 278.1535. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 403 Me N 426f HO 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426f) Prepared according to general procedure 3 using acyl indole 453f (600 mg, 3 mmol) and LiAlH4 (230 mg, 6 mmol). Purification by column chromatography (SiO2, 20% EtOAc in hexanes) provided a white solid (562 mg, 92% yield). 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.22 – 7.10 (m, 2H), 5.98 (dt, J = 6.0, 3.0 Hz, 1H), 3.06 – 2.94 (m, 1H), 2.79 – 2.66 (m, 1H), 2.45 (d, J = 6.0 Hz, 1H), 2.19 (s, 3H), 2.19 – 2.00 (m, 3H), 1.96 – 1.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 135.2, 132.0, 129.7, 121.0, 120.0, 118.2, 109.1, 106.4, 74.8, 31.5, 22.4, 16.2, 8.2; IR (Neat Film, NaCl) 3317, 3047, 2935, 2360, 1649, 1467, 1404, 1353, 1309, 1242, 1171, 1071, 990, 928, 882, 793, 736 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H16NO [M+H]+: 202.1226, found 202.1218. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction MeN N 404 Me N 426g HO 10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426g) Prepared according to general procedure 3 using acyl indole 453g (555 mg, 2 mmol) and LiAlH4 (150 mg, 4 mmol). Purification by recrystallization (refluxing CH2Cl2/hexanes) provided a tan solid (341 mg, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 5.96 (dt, J = 6.1, 2.9 Hz, 1H), 3.89 (s, 3H), 3.07 – 2.93 (m, 2H), 2.80 – 2.65 (m, 1H), 2.24 – 2.01 (m, 6H), 1.94 – 1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 136.8, 134.4, 132.7, 130.1, 126.7, 124.8, 124.6, 119.4, 114.9, 109.6, 106.3, 74.9, 39.0, 31.6, 22.4, 16.3, 8.3; IR (Neat Film, NaCl) 3260, 2940, 2357, 2242, 1588, 1558, 1462, 1415, 1363, 1269, 1170, 1073, 990, 908, 846, 800, 721, 681, 643, 613 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H20N3O [M+H]+: 282.1601, found 282.1605. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 405 Br N HO 426h 10-bromo-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426h) Prepared according to general procedure 3 using acyl indole 453h (137 mg, 0.5 mmol) and LiAlH4 (39 mg, 1 mmol). Purification by column chromatography (basic alumina, 100% CH2Cl2) provided a yellow solid (117 mg, 84% yield). 1 H NMR (400 MHz, CDCl3) δ 7.55 – 7.48 (m, 1H), 7.46 – 7.39 (m, 1H), 7.25 – 7.16 (m, 2H), 5.93 (s, 1H), 3.09 – 2.98 (m, 1H), 2.81 – 2.66 (m, 1H), 2.56 (d, J = 5.7 Hz, 1H), 2.22 – 1.99 (m, 3H), 1.98 – 1.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.8, 133.6, 127.8, 122.2, 121.3, 118.5, 109.7, 89.2, 75.0, 31.4, 23.0, 15.7; IR (Neat Film, NaCl) 3326, 3055, 2952, 2362, 1555, 1455, 1398, 1332, 1313, 1229, 1179, 1071, 998, 955, 922, 832, 740, 677 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H13BrNO [M+H]+: 266.0175, found 266.0164. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 406 Br N HO 426i 2-bromo-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426i) Prepared according to general procedure 3 using acyl indole 453i (266 mg, 1 mmol) and LiAlH4 (76 mg, 2 mmol). Purification by column chromatography (basic alumina, 100% CH2Cl2) provided a powdery white solid (232 mg, 87% yield). 1 H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.23 – 7.18 (m, 2H), 6.09 (s, 1H), 5.75 (bs, 1H), 2.97 (dt, J = 16.1, 4.5 Hz, 1H), 2.86 – 2.75 (m, 2H), 2.08 – 1.90 (m, 3H), 1.84 – 1.74 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 137.8, 134.3, 130.6, 123.6, 122.3, 113.7, 111.1, 98.6, 75.0, 31.6, 24.1, 16.3; IR (Neat Film, NaCl) 3318, 2943, 2249, 1568, 1543, 1456, 1406, 1332, 1312, 1268, 1179, 1165, 1069, 993, 936, 901, 885, 871, 791, 779, 768, 733, 692 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H13BrNO [M+H]+: 266.0175, found 266.0176. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 407 Me Me N HO Me Me 426j 2,7,7,10-tetramethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426j) Prepared according to general procedure 3 using acyl indole 453j (800 mg, 3.3 mmol) and LiAlH4 (250 mg, 6.6 mmol). Purification by column chromatography (basic alumina, 10% EtOAc in hexanes) provided an orange solid (702 mg, 86% yield). 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.03 (dd, J = 8.3, 1.6 Hz, 1H), 5.39 (d, J = 5.5 Hz, 1H), 2.95 (ddd, J = 17.0, 6.5, 2.3 Hz, 1H), 2.89 – 2.75 (m, 1H), 2.52 (s, 3H), 2.29 (d, J = 5.5 Hz, 1H), 2.21 (s, 3H), 2.05 (ddd, J = 13.5, 12.1, 6.5 Hz, 1H), 1.58 – 1.51 (m, 1H), 1.22 (s, 3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 133.9, 130.8, 130.2, 129.1, 122.2, 117.9, 108.5, 105.9, 81.7, 34.7, 28.2, 26.1, 23.3, 21.6, 19.1, 8.3; IR (Neat Film, NaCl) 3360, 3015, 2926, 2861, 2359, 2244, 1589, 1476, 1421, 1383, 1348, 1292, 1241, 1193, 1163, 11037, 1009, 989, 908, 863, 792, 763, 731, 648, 622 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H22NO [M+H]+: 244.1696, found 244.1697. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 408 Me Me N Me Me HO 426k 2,8,8,10-tetramethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426k) Prepared according to general procedure 3 using acyl indole 453k (874 mg, 3.6 mmol) and LiAlH4 (275 mg, 7.2 mmol). Purification by column chromatography (basic alumina, 10 to 15% EtOAc in hexanes) provided an orange solid (672 mg, 76% yield). 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.61 (ddd, J = 9.6, 7.1, 5.4 Hz, 1H), 2.61 – 2.50 (m, 2H), 2.49 (s, 3H), 2.30 (d, J = 9.7 Hz, 1H), 2.17 (s, 3H), 2.06 (ddd, J = 13.6, 5.6, 1.9 Hz, 1H), 1.52 (dd, J = 13.6, 7.2 Hz, 1H), 1.14 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.1, 130.2, 129.2, 122.5, 117.8, 110.9, 106.1, 76.8, 46.2, 36.1, 30.9, 30.0, 26.3, 21.6, 8.3; IR (Neat Film, NaCl) 3501, 3015, 2953, 2920, 2862, 2363, 1715, 1645, 1591, 1481, 1407, 1349, 1291, 1242, 1181, 1166, 1083, 1036, 999, 966, 864, 791, 721, 612 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H22NO [M+H]+: 244.1696, found 244.1689. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 409 Me Me Me Me N HO 426l 2,9,9,10-tetramethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-ol (426l) Prepared according to general procedure 3 using acyl indole 453l (400 mg, 1.7 mmol) and LiAlH4 (126 mg, 3.3 mmol). Purification by column chromatography (basic alumina, 10 to 15% EtOAc in hexanes) provided an orange solid (244 mg, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.24 (d, J = 3.5 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.93 – 5.86 (m, 1H), 2.59 (d, J = 5.1 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H), 2.20 – 2.01 (m, 3H), 1.58 – 1.51 (m, 4H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 132.8, 130.3, 129.2, 122.8, 117.8, 108.6, 105.7, 74.1, 32.7, 32.4, 29.8, 27.6, 27.5, 21.6, 10.2; IR (Neat Film, NaCl) 3229, 3027, 2959, 2863, 2358, 2245, 1855, 1723, 1655, 1483, 1352, 1333, 1231, 1173, 1070, 1024, 997, 905, 905, 797, 735, 616 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C16H22NO [M+H]+: 244.1696, found 244.1686. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction succinic anhydride NEt3, DMAP Br N H 291 CH2Cl2, 40 °C, 16 h 410 Br N 325 O OH O 4-(5-bromo-1H-indol-1-yl)-4-oxobutanoic acid (325) To a 1 L round-bottom flask with a stir bar equipped with a reflux condenser was added 5bromoindole (29.41 g, 150.0 mmol, 1.00 equiv) and dichloromethane (300 mL). Succinic anhydride (22.52 g, 225.0 mmol, 1.50 equiv) and DMAP (1.83 g, 15.0 mmol, 0.10 equiv) were added followed by triethylamine (62 mL, 450.0 mmol, 3.00 equiv). The reaction mixture was heated to reflux, at which the solution turned homogenous. After 16 hours, the reaction was cooled to 23 ºC and the solvent was removed under reduced pressure. The brown residue was suspended in ethyl acetate and 1 M HCl (aq.) was added until the pH=1. The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3x). The combined organics were washed with sat. NH4Cl (aq.), dried over Na2SO4, then concentrated to give a tan powder. The tan powder was then washed with diethyl ether to remove residual 5-bromoindole to give an off-white solid (33.57 g, 114.0 mmol, 76% yield). 1 H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 3.8 Hz, 1H), 7.45 (dd, J = 8.9, 2.1 Hz, 1H), 6.61 (d, J = 3.8 Hz, 1H), 3.27 (t, J = 6.4 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 176.0, 169.7, 134.5, 132.2, 128.3, 125.4, 123.8, 118.1, 117.3, 109.0, 30.5, 28.1; IR (Neat Film, NaCl) 3116, 1701, 1447, 1389, 1313, 1200, 916, 819 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H11BrNO3 [M+H]+: 295.9922, found 295.9913. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction oxalyl chloride DMF Br N 325 O OH O Br O CH2Cl2, 0 to 23 °C, 17 h then, AlCl3, 0 °C to reflux, 16 h 411 N 326 O 2-bromo-7,8-dihydropyrido[1,2-a]indole-6,9-dione (326) To a 1 L round-bottom flask with a stir bar equipped with a reflux condenser was added bromoindole acid 325 (24.53 g, 82.80 mmol, 1.00 equiv) and dichloromethane (330 mL). The suspension was cooled to 0 ºC and oxalyl chloride (8.53 mL, 99.40 mmol, 1.2 equiv) was added, followed by DMF (10 drops). The reaction was stirred at 0 ºC for 1 hour, then warmed to 23 ºC and stirred for 16 hours, at which the suspension became homogenous. The reaction was cooled to 0 ºC and aluminum trichloride (27.61 g, 207.10 mmol, 2.5 equiv) was added in portions over 5 minutes. The reaction was then heated to reflux for 16 hours. The reaction was cooled and carefully filtered, and the precipitate was washed with dichloromethane. The mother liquor was washed with 1 M HCl (aq.), then dried with brine and concentrated to give a tan powder (21.68g, 77.00 mmol, 93% yield). 1 H NMR (500 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.9, 1.9 Hz, 1H), 7.34 (s, 1H), 3.20 (t, J = 7.1 Hz, 2H), 3.03 (t, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.5, 167.2, 134.7, 134.6, 132.2, 130.0, 125.9, 118.7, 118.4, 112.2, 36.0, 32.4; IR (Neat Film, NaCl) 3116, 1718, 1685, 1546, 1362, 1314, 1181, 1151, 811, 739 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H9BrNO2 [M+H]+: 277.9817, found 277.9810. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Br O N 326 NaBH4 THF, 0 to 40 °C, 6 h O Br 412 OH N 327 O 2-bromo-9-hydroxy-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (327) To a 2 L round-bottom flask with a stir bar equipped with a reflux condenser was added bromoketoindole 326 (27.81 g, 100.0 mmol, 1.00 equiv) and THF (1000 mL). The flask was cooled to 0 ºC and finely ground NaBH4 (4.16 g, 110.0 mmol, 1.10 equiv) was added in portions over 5 minutes. The reaction was then warmed to 40 ºC and stirred for 6 hours. Upon consumption of the starting material, the reaction was cooled to 0 ºC and carefully quenched with sat. NH4Cl (aq.). The reaction was partially concentrated to remove most of the THF, then transferred to a separatory funnel and extracted with ethyl acetate (3x). The combined organics were then washed with brine, dried over Na2SO4, and concentrated to give a tan powder (27.12 g, 97.0 mmol, 97% yield) which was carried on to the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 8.31 (dt, J = 8.7, 0.7 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.7, 2.0 Hz, 1H), 6.53 (t, J = 0.9 Hz, 1H), 5.10 (t, J = 4.7 Hz, 1H), 3.45 – 2.95 (m, 1H), 2.73 (dt, J = 17.6, 5.3 Hz, 1H), 2.33 – 2.21 (m, 2H) 2.13 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 168.9, 141.1, 133.8, 131.0, 128.3, 123.5, 118.1, 117.6, 105.7, 62.5, 29.8, 29.6; IR (Neat Film, NaCl) 3407, 2954, 2934, 2249, 1708, 1594, 1448, 1371, 1175, 1012, 904, 809, 731 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H11BrNO2 [M+H]+: 279.9973, found 279.9968. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Br OH N 327 O Et3SiH, TFA 413 Br CH2Cl2, 0 to 23 °C, 4 h N 353i O 2-bromo-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (353i) To a 1 L round-bottom flask with a stir bar was added bromoindole alcohol 327 (15.82 g, 56.48 mmol, 1.00 equiv) and dichloromethane (560 mL). The flask was cooled to 0 ºC before adding triethylsilane (27.1 mL, 169.44 mmol, 3.00 equiv), followed by trifluoroacetic acid (25.9 mL, 338.85 mmol, 6.00 equiv). The reaction was warmed to 23 ºC and stirred for 4 hours. The reaction was then cooled to 0 ºC and quenched with sat. NaHCO3 (aq.). The reaction was transferred to a separatory funnel and extracted with dichloromethane (3x), dried over Na2SO4, then concentrated. Flash chromatography (80:20 à 70:30 à 60:40 hexanes/ diethyl ether) afforded a white solid (9.023 g, 33.89 mmol, 60% yield). 1 H NMR (500 MHz, CDCl3) δ 8.30 (dd, J = 8.7, 2.2 Hz, 1H), 7.58 (t, J = 2.2 Hz, 1H), 7.36 (dt, J = 8.7, 1.8 Hz, 1H), 6.37 – 6.17 (m, 1H), 3.32 – 2.91 (m, 2H), 2.80 (td, J = 5.9, 2.0 Hz, 2H), 2.11 (pd, J = 5.9, 1.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.4, 139.6, 133.7, 131.7, 126.9, 122.6, 117.8, 117.3, 104.2, 34.5, 23.9, 21.5; IR (Neat Film, NaCl) 3108, 2954, 1712, 1595, 1447, 1368, 1357, 1174, 1006, 800 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H11BrNO [M+H]+: 264.0024, found 264.0016. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 414 Br Br N H paraformaldehyde K2CO3 1,4-dioxane 35 °C, 16 h 457 N 426m OH (6-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)methanol (426m) A solution of known indole 457[84] (1 g, 4 mmol, 1 equiv), paraformaldehyde (144 mg, 4.8 mmol, 1.2 equiv), K2CO3 (1.7 g, 12 mmol, 3 equiv) in 1,4-dioxane (40 mL) was stirred at 35 °C. After 16 h, the reaction was concentrated, diluted with ethyl acetate and water, and extracted three times with EtOAc. The combined organics were dried over Na2SO4 and concentrated under reduced pressure to an orange residue. This residue was purified by column chromatography (SiO2, 20 to 25% EtOAc in hexanes) to afford a yellow solid (1089 mg, 97% yield). 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.6, 1.9 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 5.34 (d, J = 5.3 Hz, 2H), 2.66 – 2.59 (m, 2H), 2.58 – 2.51 (m, 2H), 2.43 (t, J = 6.4 Hz, 1H), 1.89 – 1.80 (m, 2H), 1.80 – 1.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 136.4, 134.7, 130.0, 124.0, 120.8, 113.1, 111.2, 110.1, 66.2, 23.0 (2C, overlapping), 21.8, 20.9; IR (Neat Film, NaCl) 3394, 2934, 2850, 1646, 1465, 1361, 1329, 1182, 1044, 989, 842, 793 cm–1; HRMS (FD) m/z calc’d for C13H14BrNO [M]+•: 279.0259, found 279.0254. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction O 415 O Br NBS N Me 458 CH2Cl2 23 °C, 1 h N 453n Me 6-bromo-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (453n) To a solution of 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (1.6 g, 8 mmol, 1 equiv) in CH2Cl2 (24 mL) was added NBS (1.4 g, 8 mmol, 1 equiv). The mixture was stirred at 23 °C for 1 h before being diluted with aqueous Na2S2O3. The solution was extracted with EtOAc three times and the combined organics washed with aqueous NaHCO3, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by recrystallization from hot CH2Cl2/EtOAc to afford a white powder (1.76 g, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 8.3, 1.7 Hz, 1H), 3.67 (s, 3H), 2.92 (t, J = 6.2 Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.26 (p, J = 6.4 Hz, 2H); All characterization data match those reported in the literature.[85] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction O Br 416 HO Br NaBH4 N Me 453n EtOH 55 °C, 3 h N Me 426n 6-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-ol (426n) A suspension of indole 453n (800 mg, 2.9 mmol, 1 equiv) and NaBH4 (522 mg, 13.8 mmol, 4.8 equiv) in EtOH (12 mL) was stirred at 55 °C. After 3 h, the slurry was concentrated under reduced pressure and then diluted with water (100 mL). The suspension was filtered to provide a white powdery crude residue which was further purified by recrystallization from hot benzene to afford a white solid (477 mg, 59% yield). 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.3, 1.6 Hz, 1H), 5.08 (bs, 1H), 3.56 (s, 3H), 2.74 (dt, J = 16.6, 4.6 Hz, 1H), 2.65 – 2.52 (m, 1H), 2.14 – 2.01 (m, 1H), 2.01 – 1.87 (m, 3H), 1.70 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 138.6, 137.9, 125.2, 122.6, 119.6, 114.7, 112.1, 111.9, 63.2, 32.6, 29.3, 22.1, 18.5; IR (Neat Film, NaCl) 3323, 2933, 2854, 2357, 1612, 1556, 1473, 1455, 1379, 1332, 1243, 1151, 1063, 978, 921, 888, 817, 802, 684 cm–1; HRMS (FD) m/z calc’d for C13H14BrNO [M]+•: 279.0259, found 279.0249. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction H N N THF 45 °C, 2.5 h MeO O OH 459 H LiAlH4 Me N 417 N HO OH Me 435 (15S,17S,19S)-15-Ethyl-17-(hydroxymethyl)-1,11-diazapentacyclo[9.6.2.02,7.08,18.015,19] nonadeca-2,4,6,8(18)-tetraen-17-ol (435) To a solution of vincamine (1109.8 mg, 3.13 mmol, 1.0 equiv) in THF (31 mL, 0.1 M) at 0 °C was added LiAlH4 (594 mg, 15.7 mmol, 5.0 equiv). The reaction mixture was then warmed to 45 °C for 2.5 h after which it was cooled to 0 °C and diluted with Et2O. Water (0.6 mL) was slowly added, then 15% aq. NaOH (0.6 mL) was added, and finally water (1.8 mL) was added and the mixture allowed to warm to 23 °C for 15 min. MgSO4 was added and the reaction was stirred for 15 min; it was filtered and concentrated under reduced pressure to afford the crude solid residue. Purification by silica gel chromatography (0 to 7% NEt3 in EtOAc) afforded a white solid (967.7 mg, 95% yield). 1 H NMR (500 MHz, CDCl3) δ 7.70 – 7.65 (m, 1H), 7.52 – 7.47 (m, 1H), 7.20 – 7.11 (m, 2H), 4.20 (d, J = 11.5 Hz, 1H), 4.00 (d, J = 11.5 Hz, 1H), 3.85 (s, 1H), 3.38 – 3.30 (m, 1H), 3.30 – 3.21 (m, 1H), 3.06 – 2.92 (m, 2H), 2.65 – 2.51 (m, 2H), 2.41 (t, J = 11.9 Hz, 1H), 2.25 (d, J = 15.2 Hz, 1H), 2.15 (d, J = 15.2 Hz, 1H), 1.78 (q, J = 13.8 Hz, 1H), 1.54 (d, J = 13.6 Hz, 1H), 1.47 (m, 1H), 1.35 (m, 4H), 0.95 (t, J = 7.6 Hz, 3H); All characterization data match those reported in the literature.[86] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 418 OH MeO Me N H XX 2-(5-methoxy-2-methyl-1H-indol-3-yl)ethan-1-ol (460) Prepared according to a modified general procedure 3 using indomethacin (2.9 g, 8 mmol) and LiAlH4 (912 mg, 24 mmol, 3 equiv). Purification by column chromatography (SiO2, 50 to 65% EtOAc in hexanes) provided a yellow solid (918 mg, 55% yield). 1 H NMR (500 MHz, CDCl3) δ 7.75 (bs, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.7, 2.4 Hz, 1H), 3.88 – 3.80 (m, 5H), 2.95 (t, J = 6.5 Hz, 2H), 2.39 (s, 3H), 1.52 – 1.47 (m, 1H); All characterization data match those reported in the literature.[87] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction OH OH paraformaldehyde K2CO3 MeO Me N H 419 MeO MeCN 23 °C, 6 h Me N OH 460 439 2-(1-(hydroxymethyl)-5-methoxy-2-methyl-1H-indol-3-yl)ethan-1-ol (439) A solution of indole 460 (205 mg, 1 mmol, 1 equiv), paraformaldehyde (30 mg, 1 mmol, 1 equiv), and K2CO3 (414 mg, 3 mmol, 3 equiv) in acetonitrile (10 mL) was stirred at 23 °C. After 6 h, the reaction was diluted with ethyl acetate and water and extracted three times with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure to a yellow residue. This residue was purified by column chromatography (SiO2, 50 to 90% EtOAc in hexanes) to afford a yellow solid (151 mg, 64% yield). 1 H NMR (400 MHz, CDCl3) δ 7.26 – 7.23 (m, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.5 Hz, 1H), 5.55 (d, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.85 – 3.77 (m, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.45 – 2.35 (m, 4H), 1.48 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 154.7, 134.3, 131.1, 129.3, 111.1, 109.4, 109.0, 100.9, 66.7, 62.8, 56.1, 28.0, 10.1; IR (Neat Film, NaCl) 3372, 2917, 2359, 1506, 1483, 1420, 1345, 1229, 1157, 1046 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C13H18NO3 [M+H]+: 236.1281, found 236.1280. 420 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4.2.2 Preparation of Trifluoroborate Salts General Procedure 4 H R 1) nBuLi (1.0 equiv), THF, –78 °C, 1 h 2) B(OMe)3(1.5 equiv), –78 to –20 °C, 2 h 3) KHF2(aq) (6.0 equiv), –20 to 23 °C, 14 h General Procedure 4 BF3K R Trifluoroborate salts were prepared according to the following procedure adapted from the literature.[88] To a flame-dried round bottom flask under nitrogen was added terminal alkyne (1.0 equiv) and THF (0.5 M). The solution was cooled to –78 °C followed by dropwise addition of nBuLi (1.0 equiv, 2.5 M in hexanes). The mixture was then stirred at –78 °C for 1 h. Afterwards, B(OMe)3 (1.5 equiv) was rapidly added and the solution stirred at –78 °C for 1 h followed by warming to –20 °C for 1 h. A saturated aqueous solution of KHF2 (6.0 equiv) was added and the solution stirred at –20 °C for 1 h followed by warming to 23 °C for 14 h. Upon completion, the reaction was concentrated under reduced pressure at 45 °C followed by co-evaporation with toluene in order to remove water. The resulting solid was then extracted with hot acetone and filtered through Celite and the process repeated three more times. The filtrate was then concentrated and recrystallized from hot acetone/ether to afford pure trifluoroborate salts. 421 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction BF3K 427 Potassium(phenylethynyl)trifluoroborate (427) Prepared according to general procedure 4 using phenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (3.2 g, 78%). 1 H NMR (400 MHz, DMSO) δ 7.38 – 7.18 (m, 5H); All characterization data match those reported in the literature.[88] BF3K F 429a Potassium((3-fluorophenyl)ethynyl)trifluoroborate (429a) Prepared according to general procedure 4 using 3-fluorophenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (900 mg, 80%). 1 H NMR (300 MHz, DMSO) δ 7.4 – 7.2 (m, 1H), 7.2 – 7.0 (m, 3H); All characterization data match those reported in the literature.[89] 422 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction BF3K Br 429b Potassium((4-bromophenyl)ethynyl)trifluoroborate (429b) Prepared according to general procedure 4 using 4-bromophenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (472.3 mg, 36%). 1 H NMR (500 MHz, acetone) δ 7.45 – 7.38 (m, 1H), 7.26 – 7.20 (m, 2H); All characterization data match those reported in the literature.[90] Me BF3K 429c Potassium(o-tolylethynyl)trifluoroborate (429c) Prepared according to general procedure 4 using 2-methylphenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (950 mg, 86%). 1 H NMR (300 MHz, Acetone) δ 7.3 – 7.2 (m, 1H), 7.2 – 7.0 (m, 3H), 2.4 (s, 3H); All characterization data match those reported in the literature.[91] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 423 BF3K MeO 429d Potassium((4-methoxyphenyl)ethynyl)trifluoroborate (429d) Prepared according to general procedure 4 using 4-methoxyphenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (905 mg, 76%). 1 H NMR (300 MHz, DMSO) δ 7.3 – 7.2 (m, 2H), 6.9 – 6.8 (m, 2H), 3.7 (s, 3H); All characterization data match those reported in the literature.[92] BF3K F3C 429e Potassium((4-(trifluoromethyl)phenyl)ethynyl)trifluoroborate (429e) Prepared according to general procedure 4 using 4-(trifluoromethyl)phenylacetylene. Recrystallization from hot acetone/ether afforded a white solid (820 mg, 59%). 1 H NMR (300 MHz, Acetone) δ 7.6 – 7.5 (m, 2H), 7.5 – 7.5 (m, 2H); All characterization data match those reported in the literature.[93] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 424 BF3K S 429f Potassium(thiophen-2-ylethynyl)trifluoroborate (429f) Prepared according to general procedure 4 using thiophen-2-ylethyne. Recrystallization from hot acetone/ether afforded a white solid (518.5 mg, 81%). 1 H NMR (400 MHz, Acetone) δ 7.20 (m, 1H), 6.98 (m, 1H), 6.90 (m, 1H); All characterization data match those reported in the literature.[94] BF3K Me 429g Potassium(1-hexyn-1-yl)trifluoroborate (429g) Prepared according to general procedure 4 using 1-hexyne. Recrystallization from hot acetone/ether afforded a white solid (638 mg, 67%). 1 H NMR (400 MHz, Acetone) δ 2.04 – 1.98 (m, 2H), 1.46 – 1.30 (m, 4H), 0.94 – 0.80 (m, 3H); All characterization data match those reported in the literature.[88] Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 425 BF3K Me Me Me 429h Potassium(3,3-dimethyl-1-butyn-1-yl)trifluoroborate (429h) Prepared according to general procedure 4 using 3,3-dimethyl-1-butyne. Recrystallization from hot acetone/ether afforded a white solid (520 mg, 57%). 1 H NMR (300 MHz, Acetone) δ 1.1 (s, 9H); All characterization data match those reported in the literature.[95] BF3K 429i Potassium(1,6-heptadiyn-1-yl)trifluoroborate (429i) Prepared according to general procedure 4 using 1,6-heptadiyne. Recrystallization from hot acetone/ether afforded a white solid (503.9 mg, 51%). 1 H NMR (500 MHz, acetone) δ 2.32 – 2.23 (m, 3H), 2.18 – 2.10 (m, 2H), 1.60 (p, J = 7.0 Hz, 2H); All characterization data match those reported in the literature.[90] 426 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction BF3K TBSO 429j Potassium(4-t-butyldimethylsiloxy-1-butyn-1-yl)trifluoroborate (429j) Prepared according to general procedure 4 using 4-t-butyldimethylsiloxy-1-butyne but was only stirred with KHF2 at 23 °C for 1 h rather than 14 h to avoid TBS deprotection. Recrystallization from hot acetone/ether afforded a white solid (440.0 mg, 51%). 1 H NMR (400 MHz, Acetone) δ 3.65 (t, J = 7.9 Hz, 2H), 2.23 (td, J = 7.9, 1.9 Hz, 2H), 0.88 (s, 9H), 0.06 (s, 6H); All characterization data match those reported in the literature.[88] BF3K 429k Potassium(3-cyclohexyl-1-propyn-1-yl)trifluoroborate (429k) Prepared according to general procedure 4 using 3-cyclohexyl-1-propyne. Recrystallization from hot acetone/ether afforded a white solid (820 mg, 85%). 1 H NMR (400 MHz, Acetone) δ 1.95 – 1.87 (m, 2H), 1.85 – 1.77 (m, 2H), 1.73 – 1.55 (m, 3H), 1.39 – 1.06 (m, 4H), 1.01 – 0.86 (m, 2H); 13C NMR (100 MHz, Acetone) δ 38.8, 33.5, 28.0, 27.1, 26.9 (sp carbons not observed due to Boron quadrupolar relaxation); 11B NMR (128 MHz, Acetone) δ –1.6; 19F NMR (282 MHz, Acetone) δ –133.9 to –134.5 (m); IR (Neat Film, NaCl) 3420, 2921, 2849, 2180, 1634, 1539, 1112, 1067, 966 cm–1; HRMS (MM:ES) m/z calc’d for C9H13BF3 [M]–: 189.1062, found 189.1080. 427 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction BF3K 429l Potassium(cyclopropylethynyl)trifluoroborate (429l) Prepared according to general procedure 4 using ethynylcyclopropane. Recrystallization from hot acetone/ether afforded a white solid (590 mg, 68%). 1 H NMR (300 MHz, Acetone) δ 1.1 – 1.0 (m, 1H), 0.6 – 0.5 (m, 2H), 0.5 – 0.4 (m, 2H); All characterization data match those reported in the literature.[95] BF3K 429m Potassium(cyclohex-1-en-1-ylethynyl)trifluoroborate (429m) Prepared according to general procedure 4 using 1-ethynylcyclohex-1-ene. Recrystallization from hot acetone/ether afforded a white solid (729 mg, 68%). 1 H NMR (300 MHz, Acetone) δ 5.81 – 5.73 (m, 1H), 2.03 – 1.95 (m, 4H), 1.63 – 1.45 (m, 4H); All characterization data match those reported in the literature.[92] 428 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction H Me Me OH POCl3 H H H H pyridine 0 to 23 °C, 48 h O H O 461 “Dehydrated – H + H H H O 462 Quinestrol” Me Cl • 463 (8S,9S,13S,14S)-3-(cyclopentyloxy)-17-ethynyl-13- methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthrene (462) Alkyne 462 was prepared by a procedure adapted from the literature[96] as follows: Quinestrol (956.0 mg, 2.62 mmol, 1.0 equiv) was dissolved in pyridine (53 mL, 0.05 M) and cooled to 0 °C. POCl3 (5.9 mL, 63 mmol, 24 equiv) was then added dropwise over 10 min and the mixture allowed to warm to 23 °C. After 48 h, the solution was poured onto a mixture of ice and 0.25 M HCl and extracted three times with EtOAc; the combined organics were washed with water, saturated NaHCO3 (aq), and brine, and dried over Na2SO4. After concentration under reduced pressure, the crude residue was purified by silica gel chromatography to afford the desired product 462 as a colorless oil (351.8 mg, 39% yield) as an inseparable mixture with chloro-allene 463 (6.5:1 mixture, stereochemistry of allene not determined). This mixture was used directly in the synthesis of trifluoroborate salt 443. NMR data are provided for the desired alkyne product XX: 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.7 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 6.15 (dd, J = 3.3, 1.9 Hz, 1H), 4.72 (tt, J = 6.0, 3.0 Hz, 1H), 3.09 (s, 1H), 2.97 – 2.79 (m, 2H), 2.42 – 2.35 (m, 1H), 2.35 – 2.22 (m, 2H), 2.14 – 2.04 (m, 1H), 2.02 – 1.95 (m, 1H), 1.95 – 1.72 (m, 7H), 1.67 – 1.58 (m, 6H), 1.52 – 1.38 (m, 1H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 137.9, 137.8, 136.6, 132.4, 126.1, 115.8, 113.0, 80.5, 79.7, 79.1, 55.5, Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 429 48.3, 44.5, 37.7, 34.6, 33.0, 32.0, 29.9, 28.0, 26.6, 24.1, 16.3; IR (Neat Film, NaCl) 3307, 2928, 2870, 2353, 2090, 1610, 1573, 1539, 1496, 1454, 1355, 1280, 1251, 1235, 1169, 1133, 1010, 995, 908, 818, 732, 643 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C25H31O [M+H]+: 347.2369, found 347.2359. BF3K Me H H H O 443 Potassium Dehydrated-Quinestrol Trifluoroborate (443) Prepared according to general procedure 4 using the mixture of 462 and 463. Recrystallization from hot acetone/ether afforded a white solid (220 mg, 41%). 1 H NMR (400 MHz, DMSO) δ 7.14 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 8.6, 2.7 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 5.71 (t, J = 2.4 Hz, 1H), 4.78 – 4.69 (m, 1H), 2.88 – 2.71 (m, 2H), 2.41 – 2.27 (m, 1H), 2.24 – 2.11 (m, 2H), 2.04 – 1.93 (m, 1H), 1.92 – 1.77 (m, 4H), 1.75 – 1.62 (m, 4H), 1.60 – 1.50 (m, 2H), 1.49 – 1.30 (m, 5H), 0.76 (s, 3H); 13C NMR (100 MHz, DMSO) δ 155.3, 139.5, 137.3, 132.0, 130.7, 125.9, 115.2, 112.7, 78.2, 55.0, 47.4, 43.8, 37.2, 34.5, 32.3, 30.9, 29.1, 27.3, 26.1, 23.6, 16.0 (sp carbons not observed due to Boron quadrupolar relaxation); 11B NMR (128 MHz, DMSO) δ –1.6; 19F NMR (282 MHz, DMSO) δ –131.0 to –131.5 (m); IR (Neat Film, NaCl) 3401, 2942, 2361, 1635, 1193, 1011 cm–1; HRMS (FD) m/z calc’d for C25H30O (mass found for –BF3K) [M]+•: 346.2297, found 346.2313. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 430 Me Me BF3K 429q Potassium(2-methyl-1-propen-1-yl)trifluoroborate (429q) Trifluoroborate salt 429q was prepared according to the literature.[97] 1 H NMR (500 MHz, acetone) δ 5.06 – 4.98 (m, 1H), 1.68 (s, 3H), 1.61 (s, 3H); All characterization data match those reported in the literature.[97] BF3K 429r Potassium trans-Styryl Trifluoroborate (429r) Trifluoroborate 429r was prepared according to the literature (604.3 mg, 71% yield).[98] 1 H NMR (500 MHz, acetone) δ 7.32 (d, J = 7.5 Hz, 2H), 7.21 (t, J = 7.7 Hz, 2H), 7.07 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 18.2 Hz, 1H), 6.32 (dq, J = 18.2, 3.6 Hz, 1H); All characterization data match those reported in the literature.[89] 431 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4.2.3 Petasis-Type Reactions: General Procedure General Procedure 5 R3 R1 N R3 R2 BF3K + PhCO2H (1 equiv) R1 N CF3CH2OH (0.025 M) 65 °C, 18 h R4 R2 HO (3 equiv) General Procedure 5 R4 An oven-dried 2-dram vial was charged with a stir bar, ⍺-hydroxyindole (0.1 mmol, 1.0 equiv), and trifluoroborate salt (0.3 mmol, 3.0 equiv), respectively. To this was added a solution of benzoic acid in trifluoroethanol (4 mL, 0.025 M, 1.0 equiv benzoic acid) and the vial sealed with a Teflon cap. The vial was then placed in a pre-heated heating mantle at 65 °C and stirred for 18 h unless otherwise noted. Upon completion, the reaction was diluted with ethyl acetate and aqueous sodium bicarbonate, extracted four times with ethyl acetate, dried over sodium sulfate, concentrated, and purified by silica gel chromatography (unless otherwise noted) to provide the desired product. Note: For substrates containing basic amines, the reaction was performed using hexafluoroisopropanol (rather than trifluoroethanol) as the solvent. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 432 Me Br N Ph 428a 2-bromo-10-methyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428a) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (2 to 6% Et2O in hexanes) provided a white solid (31.7 mg, 87% yield). 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 7.33 – 7.30 (m, 1H), 7.28 – 7.20 (m, 4H), 5.32 (dd, J = 5.3, 4.0 Hz, 1H), 3.00 (dt, J = 16.4, 4.7 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.42 – 2.19 (m, 3H), 2.17 (s, 3H), 2.05 – 1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.4, 133.3, 131.9, 130.9, 128.5, 128.3, 123.2, 122.5, 120.5, 112.8, 111.1, 105.6, 87.6, 83.9, 44.8, 30.5, 22.5, 18.4, 8.2; IR (Neat Film, NaCl) 3647, 3053, 2930, 2858, 2359, 2596, 1573, 1488, 1452, 1442, 1414, 1354, 1326, 1274, 1240, 1158, 1069, 1049, 907, 882, 860, 810, 789, 756, 733, 690, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H19BrN [M+H]+: 364.0695, found 364.0689. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 433 Me Cl N Ph 428b 2-chloro-10-methyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428b) Prepared according to general procedure 5 using ⍺-hydroxyindole 426b (23.7 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (0 to 8% Et2O in hexanes) provided a white solid (30.3 mg, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.49 – 7.39 (m, 2H), 7.35 – 7.31 (m, 2H), 7.28 – 7.20 (m, 3H), 7.11 (dd, J = 8.6, 2.0 Hz, 1H), 5.32 (dd, J = 5.3, 4.0 Hz, 1H), 3.00 (dt, J = 16.4, 4.7 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.41 – 2.11 (m, 6H), 1.97 (dddd, J = 13.2, 8.5, 6.1, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 134.1, 133.5, 131.9, 130.3, 128.5, 128.3, 125.2, 122.6, 120.7, 117.4, 110.7, 105.7, 87.7, 83.8, 44.8, 30.5, 22.5, 18.4, 8.3; IR (Neat Film, NaCl) 3056, 2930, 2858, 2362, 1574, 1488, 1463, 1353, 1335, 1327, 1274, 1158, 1070, 885, 856, 818, 791, 756, 691, 636, 611 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H19ClN [M+H]+: 320.1201, found 320.1200. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 434 Me F N Ph 428c 2-fluoro-10-methyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428c) Prepared according to general procedure 5 using ⍺-hydroxyindole 426c (22.3 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (2 to 8% Et2O in hexanes) provided a colorless oil (29.1 mg, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.8, 4.4 Hz, 1H), 7.27 – 7.22 (m, 2H), 7.20 – 7.11 (m, 3H), 7.05 (dd, J = 9.7, 2.5 Hz, 1H), 6.81 (td, J = 9.1, 2.5 Hz, 1H), 5.24 (dd, J = 5.3, 4.0 Hz, 1H), 2.91 (dt, J = 16.5, 4.7 Hz, 1H), 2.76 – 2.63 (m, 1H), 2.33 – 2.03 (m, 6H), 1.95 – 1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 158.2 (d, J = 233.8 Hz), 133.8, 132.3, 131.9, 129.5 (d, J = 9.5 Hz), 128.4, 128.3, 122.6, 110.2 (d, J = 9.6 Hz), 108.5 (d, J = 26.0 Hz), 106.0 (d, J = 4.6 Hz), 103.0 (d, J = 23.2 Hz), 87.9, 83.7, 44.8, 30.6, 22.5, 18.4, 8.3; 19 F NMR (282 MHz, CDCl3) δ –125.2 (td, J = 9.5, 4.3 Hz); IR (Neat Film, NaCl) 3052, 2928, 2859, 2362, 1621, 1583, 1476, 1443, 1418, 1336, 1276, 1236, 1165, 1139, 1069, 1028, 909, 844, 789, 756, 690, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H19FN [M+H]+: 304.1496, found 304.1499. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 435 Me Me N Ph 428d 2,10-dimethyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428d) Prepared according to general procedure 5 using ⍺-hydroxyindole 426d (21.5 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (0 to 25% CH2Cl2 in hexanes) provided a white solid (18.0 mg, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.31 – 7.29 (m, 1H), 7.29 – 7.22 (m, 3H), 7.01 (dd, J = 8.3, 1.7 Hz, 1H), 5.35 (t, J = 4.6 Hz, 1H), 3.01 (dt, J = 16.3, 4.7 Hz, 1H), 2.79 (ddd, J = 16.0, 10.1, 5.5 Hz, 1H), 2.48 (s, 3H), 2.41 – 2.12 (m, 6H), 2.03 – 1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.2, 131.9, 131.9, 129.3, 128.6, 128.3, 128.3, 122.9, 122.0, 117.7, 109.4, 105.3, 88.3, 83.4, 44.7, 30.7, 22.5, 21.7, 18.6, 8.3; IR (Neat Film, NaCl) 3017, 2925, 2856, 2357, 2244, 1697, 1596, 1487, 1477, 1415, 1353, 1335, 1299, 1242, 1158, 1089, 1026, 909, 863, 789, 756, 691, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H22N [M+H]+: 300.1747, found 300.1750. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 436 Me Ph N Ph 428e 10-methyl-2-phenyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428e) Prepared according to general procedure 5 using ⍺-hydroxyindole 426e (27.2 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (5 to 40% CH2Cl2 in hexanes) provided a white solid (23.8 mg, 67% yield). 1 H NMR (400 MHz, CDCl3) δ 7.72 – 7.66 (m, 3H), 7.59 (dd, J = 8.5, 0.6 Hz, 1H), 7.48 – 7.41 (m, 3H), 7.38 – 7.34 (m, 2H), 7.33 – 7.29 (m, 1H), 7.28 – 7.21 (m, 3H), 5.40 (dd, J = 5.2, 4.1 Hz, 1H), 3.04 (dt, J = 16.3, 4.7 Hz, 1H), 2.88 – 2.76 (m, 1H), 2.44 – 2.16 (m, 6H), 1.99 (dddt, J = 13.1, 8.4, 5.9, 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.1, 135.3, 133.0, 132.6, 131.9, 129.6, 128.7, 128.4, 128.3, 127.5, 126.2, 122.8, 120.4, 116.5, 109.9, 106.3, 88.1, 83.7, 44.8, 30.8, 22.6, 18.6, 8.4; IR (Neat Film, NaCl) 3030, 2928, 2340, 1598, 1488, 1357, 1336, 1247, 1070, 912, 880, 760, 693, 613 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C27H24N [M+H]+: 362.1903, found 300.1899. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 437 Me N Ph 428f 10-methyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428f) 0.1 mmol scale: Prepared according to general procedure 5 using ⍺-hydroxyindole 426f (19.9 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (1 to 5% Et2O in hexanes) provided a colorless oil (24.1 mg, 85% yield). 5.0 mmol scale: Prepared according to general procedure 5 using ⍺-hydroxyindole 426f (1.0064 g, 5 mmol) and trifluoroborate salt 427 (3.1204 g, 15 mmol). Purification by column chromatography (8 to 25% CH2Cl2 in hexanes) provided a golden oil that solidified upon standing (1.2786 g, 90% yield). 1 H NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.37 – 7.31 (m, 2H), 7.28 – 7.22 (m, 3H), 7.21 – 7.11 (m, 2H), 5.39 (dd, J = 5.2, 4.0 Hz, 1H), 3.04 (dt, J = 16.4, 4.6 Hz, 1H), 2.87 – 2.74 (m, 1H), 2.43 – 2.14 (m, 6H), 2.05 – 1.93 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 135.7, 131.9, 131.8, 129.1, 128.3, 128.3, 122.8, 120.6, 119.4, 117.9, 109.7, 105.8, 88.2, 83.5, 44.7, 30.7, 22.5, 18.6, 8.3.; IR (Neat Film, NaCl) 3051, 2930, 2858, 2361, 2339, 1597, 1488, 1463, 1415, 1353, 1320, 1241, 1158, 1069, 1012, 915, 756, 740, 691 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H20N [M+H]+: 286.1590, found 286.1595. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction MeN N 438 Me N Ph 428g 10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-6-(phenylethynyl)-6,7,8,9tetrahydropyrido[1,2-a]indole (428g) Prepared according to general procedure 5 using ⍺-hydroxyindole 426g (27.8 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (20 to 65% EtOAc in hexanes) provided an orange solid (28.6 mg, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.61 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 – 7.33 (m, 2H), 7.29 (dd, J = 8.3, 1.7 Hz, 1H), 7.27 – 7.22 (m, 3H), 5.36 (dd, J = 5.2, 4.1 Hz, 1H), 3.95 (s, 3H), 3.02 (dt, J = 16.4, 4.7 Hz, 1H), 2.80 (ddd, J = 16.2, 10.2, 5.6 Hz, 1H), 2.40 – 2.15 (m, 6H), 2.04 – 1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 136.9, 134.8, 132.5, 131.9, 129.6, 128.4, 128.3, 126.6, 125.0, 124.1, 122.8, 119.1, 114.7, 110.0, 105.9, 88.1, 83.6, 44.8, 39.1, 30.7, 22.5, 18.6, 8.4; IR (Neat Film, NaCl) 3646, 2929, 2357, 1488, 1458, 1364, 1335, 1272, 1159, 1070, 986, 907, 879, 850, 795, 757, 730, 683 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C25H24N3 [M+H]+: 366.1965, found 366.1971. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 439 Br N Ph 428h 10-bromo-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428h) Prepared according to general procedure 5 using ⍺-hydroxyindole 426h (26.6 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). The reaction was stopped after 1 h due to instability of the product. Purification by column chromatography (5 to 12% CH2Cl2 in hexanes) provided a partially solid white residue (30.0 mg, 86% yield). 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.38 (m, 2H), 7.26 – 7.22 (m, 2H), 7.20 – 7.07 (m, 5H), 5.29 (dd, J = 5.1, 3.8 Hz, 1H), 2.98 (dt, J = 16.9, 4.5 Hz, 1H), 2.71 (ddd, J = 16.7, 10.4, 5.8 Hz, 1H), 2.35 – 2.26 (m, 1H), 2.25 – 2.06 (m, 2H), 1.99 – 1.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 135.2, 133.4, 131.9, 128.6, 128.3, 127.4, 122.4, 121.8, 120.7, 118.2, 110.1, 88.4, 87.3, 84.2, 45.0, 30.5, 23.1, 18.0; IR (Neat Film, NaCl) 3052, 2950, 2867, 2361, 1597, 1549, 1488, 1455, 1402, 1336, 1316, 1228, 1159, 1142, 1112, 1067, 1012, 956, 913, 756, 740, 690, 612 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H17BrN [M+H]+: 350.0539, found 350.0534. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 440 Me Me N Me Me Ph 428j 2,7,7,10-tetramethyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428j) Prepared according to general procedure 5 using ⍺-hydroxyindole 426j (24.0 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (10 to 25% CH2Cl2 in hexanes) provided a colorless oil (27.6 mg, 86% yield). 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz, 1H), 7.38 – 7.33 (m, 3H), 7.30 – 7.25 (m, 3H), 7.04 (dd, J = 8.4, 1.7 Hz, 1H), 4.92 (d, J = 1.1 Hz, 1H), 3.08 – 2.97 (m, 1H), 2.88 (dddd, J = 17.3, 11.3, 6.6, 1.2 Hz, 1H), 2.52 (s, 3H), 2.24 (s, 3H), 2.23 – 2.15 (m, 1H), 1.67 (dddd, J = 13.4, 6.5, 3.3, 1.2 Hz, 1H), 1.41 (s, 3H), 1.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.3, 131.9, 130.6, 129.6, 128.5, 128.2 (3C, overlapping), 123.0, 121.8, 117.6, 109.2, 105.3, 86.8, 84.9, 54.9, 34.4, 30.9, 27.4, 24.6, 21.7, 19.3, 8.5.; IR (Neat Film, NaCl) 3016, 2960, 2922, 2859, 2363, 1597, 1487, 1471, 1387, 1353, 1319, 1286, 1206, 1173, 1041, 907, 788, 736, 690, 648 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C24H26N [M+H]+: 328.2060, found 328.2065. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 441 Me Me N Me Me Ph 428k 2,8,8,10-tetramethyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428k) Prepared according to general procedure 5 using ⍺-hydroxyindole 426k (24.3 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (10 to 20% CH2Cl2 in hexanes) provided a colorless oil (24.8 mg, 76% yield). 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.31 – 7.20 (m, 4H), 6.96 (dd, J = 8.3, 1.7 Hz, 1H), 5.10 (dd, J = 8.5, 6.7 Hz, 1H), 2.62 (d, J = 3.0 Hz, 2H), 2.44 (s, 3H), 2.18 – 2.11 (m, 5H), 1.20 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 134.5, 132.5, 131.7, 129.9, 128.6, 128.39, 128.37, 123.0, 122.0, 117.7, 110.7, 105.8, 88.8, 84.6, 43.9, 43.7, 36.3, 30.0, 29.9, 25.6, 21.6, 8.3; IR (Neat Film, NaCl) 3015, 2953, 2919, 2860, 2364, 1597, 1488, 1468, 1356, 1319, 1297, 1285, 1240, 1207, 1153, 1045, 909, 864, 790, 755, 733, 690, 614 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C24H26N [M+H]+: 328.2060, found 328.2061. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 442 Me Me Me Me N Ph 428l 2,9,9,10-tetramethyl-6-(phenylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (428l) Prepared according to general procedure 5 using ⍺-hydroxyindole 426l (24.3 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (10 to 15% CH2Cl2 in hexanes) provided a colorless oil (26.4 mg, 81% yield). 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m, 3H), 7.29 (dt, J = 1.6, 0.8 Hz, 1H), 7.26 – 7.20 (m, 3H), 7.01 (dd, J = 8.4, 1.6 Hz, 1H), 5.34 (dd, J = 5.2, 2.6 Hz, 1H), 2.46 (s, 3H), 2.37 (s, 3H), 2.36 – 2.16 (m, 3H), 1.73 – 1.62 (m, 1H), 1.55 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 133.1, 131.9, 129.7, 128.6, 128.28, 128.25, 122.9, 122.4, 117.5, 109.2, 105.1, 88.4, 83.1, 44.5, 35.3, 32.8, 29.8, 28.0, 27.0, 21.7, 10.4; IR (Neat Film, NaCl) 3017, 2924, 2859, 2363, 1597, 1481, 1353, 1297, 1231, 1186, 1035, 962, 910, 863, 788, 756, 691, 620 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C24H26N [M+H]+: 328.2060, found 328.2065. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 443 Br N Ph 428m 6-bromo-9-(3-phenylprop-2-yn-1-yl)-2,3,4,9-tetrahydro-1H-carbazole (428m) Prepared according to general procedure 5 using ⍺-hydroxyindole 426m (28.0 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (8 to 18% CH2Cl2 in hexanes) provided a colorless oil (23.7 mg, 65% yield). 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 1.8 Hz, 1H), 7.37 – 7.32 (m, 2H), 7.28 – 7.21 (m, 5H), 4.92 (s, 2H), 2.79 (tt, J = 6.3, 1.7 Hz, 2H), 2.65 (tt, J = 6.1, 1.7 Hz, 2H), 2.00 – 1.89 (m, 2H), 1.88 – 1.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 136.6, 134.8, 131.9, 129.5, 128.7, 128.4, 123.6, 122.4, 120.7, 112.6, 110.5, 110.2, 84.2, 83.6, 33.2, 23.2, 23.1, 22.2, 21.0; IR (Neat Film, NaCl) 3054, 2933, 2851, 2356, 1575, 1456, 1419, 1360, 1340, 1303, 1277, 1211, 1178, 1044, 995, 908, 840, 788, 755, 690 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C21H19BrN [M+H]+: 364.0695, found 364.0679. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 444 Ph Br N Me 428n 6-bromo-9-methyl-4-(phenylethynyl)-2,3,4,9-tetrahydro-1H-carbazole (428n) Prepared according to general procedure 5 using ⍺-hydroxyindole 426n (28.0 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (10 to 18% CH2Cl2 in hexanes) provided a white solid (17.0 mg, 47% yield). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 1H), 7.43 – 7.33 (m, 3H), 7.31 – 7.22 (m, 3H), 7.20 (dd, J = 8.4, 1.7 Hz, 1H), 4.10 (ddd, J = 6.8, 4.9, 2.3 Hz, 1H), 3.57 (s, 3H), 2.80 – 2.62 (m, 2H), 2.29 – 2.13 (m, 2H), 2.10 – 1.97 (m, 1H), 1.97 – 1.86 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 137.9, 136.4, 131.7, 128.3, 127.7, 125.5, 124.0, 122.3, 120.1, 114.5, 111.8, 108.9, 92.4, 80.9, 30.7, 29.3, 25.8, 22.0, 21.3; IR (Neat Film, NaCl) 3732, 2928, 2853, 2359, 1601, 1472, 1455, 1312, 1236, 1051, 909, 801, 756, 691 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H19BrN [M+H]+: 364.0695, found 364.0682. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 445 Me Br N F 430a 2-bromo-6-((3-fluorophenyl)ethynyl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430a) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (26.1 mg, 0.093 mmol) and trifluoroborate salt 429a (67.8 mg, 0.3 mmol). Purification by column chromatography (10 to 20% CH2Cl2 in hexanes) provided a colorless oil (30.0 mg, 84% yield). 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.28 – 7.15 (m, 2H), 7.11 – 7.07 (m, 1H), 7.04 – 6.93 (m, 2H), 5.31 (dd, J = 5.4, 3.9 Hz, 1H), 3.00 (dt, J = 16.5, 4.7 Hz, 1H), 2.77 (ddd, J = 16.4, 10.5, 5.6 Hz, 1H), 2.41 – 2.10 (m, 6H), 2.04 – 1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.3 (d, J = 246.7 Hz), 134.4, 133.2, 130.9, 129.9 (d, J = 8.6 Hz), 127.8 (d, J = 3.1 Hz), 124.3 (d, J = 9.5 Hz), 123.3, 120.6, 118.7 (d, J = 22.9 Hz), 115.9 (d, J = 21.2 Hz), 112.9, 111.0, 105.8, 88.6, 82.7 (d, J = 3.3 Hz), 44.7, 30.4, 22.4, 18.3, 8.2; 19F NMR (282 MHz, CDCl3) δ –113.0 (td, J = 9.0, 5.8 Hz); IR (Neat Film, NaCl) 3745, 3058, 2932, 2858, 2358, 1697, 1607, 1579, 1539, 1485, 1452, 1441, 1383, 1354, 1326, 1273, 1240, 1170, 1143, 1049, 950, 877, 808, 786, 680, 608 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H18BrFN [M+H]+: 382.0601, found 382.0587. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 446 Me Br N 430b Br 2-bromo-6-((4-bromophenyl)ethynyl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430b) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429b (86.1 mg, 0.3 mmol). Purification by column chromatography (8 to 20% CH2Cl2 in hexanes) provided a colorless oil (34.7 mg, 78% yield). 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 1.9 Hz, 1H), 7.41 – 7.36 (m, 2H), 7.35 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.6, 1.9 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 5.31 (dd, J = 5.4, 3.9 Hz, 1H), 3.01 (dt, J = 16.5, 4.6 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.40 – 2.10 (m, 6H), 2.05 – 1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.3, 133.2, 131.6, 130.9, 123.3, 122.8, 121.5, 120.6, 112.9, 111.0, 105.8, 88.8, 82.8, 44.7, 30.4, 22.4, 18.3, 8.2; IR (Neat Film, NaCl) 2930, 2857, 2360, 1574, 1485, 1462, 1354, 1335, 1326, 1274, 1158, 1067, 101, 907, 882, 823, 789, 733, 634, 608 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H17Br2N [M+H]+: 441.9760, found 441.9768. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 447 Me Br N Me 430c 2-bromo-10-methyl-6-(o-tolylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (430c) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429c (66.6 mg, 0.3 mmol). Purification by column chromatography (8 to 16% CH2Cl2 in hexanes) provided a colorless oil (35.3 mg, 93% yield). 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.28 (dd, J = 7.6, 1.4 Hz, 1H), 7.25 – 7.20 (m, 1H), 7.18 – 7.08 (m, 2H), 7.05 (td, J = 6.8, 1.2 Hz, 1H), 5.35 (dd, J = 5.2, 3.8 Hz, 1H), 2.99 (dt, J = 16.5, 4.5 Hz, 1H), 2.76 (ddt, J = 16.2, 9.6, 5.7 Hz, 1H), 2.40 – 2.32 (m, 1H), 2.32 – 2.12 (m, 8H), 2.04 – 1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 140.3, 134.5, 133.3, 132.1, 131.0, 129.5, 128.5, 125.5, 123.1, 122.3, 120.5, 112.8, 111.2, 105.7, 91.6, 82.8, 44.9, 30.6, 22.4, 20.8, 18.4, 8.2; IR (Neat Film, NaCl) 3020, 2929, 2856, 2225, 1698, 1574, 1484, 1461, 1412, 1354, 1326, 1274, 1158, 1048, 908, 883, 810, 754, 605 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H21BrN [M+H]+: 378.0852, found 378.0838. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 448 Me Br N 430d MeO 2-bromo-6-((4-methoxyphenyl)ethynyl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430d) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.1 mg, 0.1 mmol) and trifluoroborate salt 429d (71.4 mg, 0.3 mmol). Purification by column chromatography (25 to 35% CH2Cl2 in hexanes) provided a colorless oil (30.0 mg, 76% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.29 – 7.18 (m, 3H), 6.80 – 6.71 (m, 2H), 5.29 (dd, J = 5.2, 4.1 Hz, 1H), 3.76 (s, 3H), 2.98 (dt, J = 17.6, 4.7 Hz, 1H), 2.82 – 2.70 (m, 1H), 2.38 – 2.08 (m, 6H), 2.01 – 1.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.7, 134.4, 133.4, 133.3, 130.9, 123.2, 120.5, 114.6, 113.9, 112.8, 111.2, 105.5, 86.2, 83.8, 55.4, 44.8, 30.6, 22.5, 18.4, 8.2; IR (Neat Film, NaCl) 2929, 2857, 2835, 2354, 2228, 1697, 1605, 1573, 1508, 1462, 1441, 1414, 1335, 1289, 1248, 1171, 1106, 1031, 908, 882, 831, 794, 733, 605 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H21BrNO [M+H]+: 394.0801, found 394.0786. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 449 Me Br N 430e F3C 2-bromo-10-methyl-6-((4-(trifluoromethyl)phenyl)ethynyl)-6,7,8,9tetrahydropyrido[1,2-a]indole (430e) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429e (82.8 mg, 0.3 mmol). Purification by column chromatography (8 to 15% CH2Cl2 in hexanes) provided a colorless oil (31.5 mg, 73% yield). 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.6 Hz, 1H), 7.28 – 7.21 (m, 1H), 5.35 (dd, J = 5.4, 3.8 Hz, 1H), 3.02 (dt, J = 16.5, 4.6 Hz, 1H), 2.85 – 2.72 (m, 1H), 2.43 – 2.24 (m, 2H), 2.17 (m, 4H), 2.07 – 1.91 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.4, 133.2, 132.1, 131.0, 130.3 (q, J = 32.7 Hz), 126.3, 125.3 (q, J = 3.8 Hz), 123.4, 124.0 (q, J = 272.2 Hz), 120.7, 113.0, 110.9, 105.9, 90.1, 82.6, 44.7, 30.3, 22.4, 18.4, 8.2; 19F NMR (282 MHz, CDCl3) δ –62.9; IR (Neat Film, NaCl) 2932, 2860, 2360, 1614, 1574, 1462, 1354, 1322, 1274, 1166, 1127, 1105, 1064, 1016, 842, 810, 790, 731, 635 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H18BrF3N [M+H]+: 432.0569, found 432.0549. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 450 Me Br N S 430f 2-bromo-10-methyl-6-(thiophen-2-ylethynyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (430f) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (27.9 mg, 0.1 mmol) and trifluoroborate salt 429f (64.2 mg, 0.3 mmol). Purification by column chromatography (8 to 15% CH2Cl2 in hexanes) provided a white solid (32.1 mg, 87% yield). 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.20 (dd, J = 5.2, 1.2 Hz, 1H), 7.11 (dd, J = 3.7, 1.2 Hz, 1H), 6.92 (dd, J = 5.2, 3.6 Hz, 1H), 5.34 (dd, J = 5.4, 3.9 Hz, 1H), 3.01 (dt, J = 16.5, 4.6 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.43 – 2.32 (m, 1H), 2.32 – 2.23 (m, 1H), 2.23 – 2.10 (m, 4H), 2.03 – 1.92 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.2, 132.4, 130.9, 127.3, 127.0, 123.3, 122.4, 120.5, 112.9, 111.0, 105.7, 91.4, 77.2 (overlap with residual CHCl3), 44.9, 30.3, 22.4, 18.3, 8.2; IR (Neat Film, NaCl) 3101, 2931, 2858, 2362, 2220, 1574, 1462, 1413, 1355, 1325, 1274, 1238, 1201, 1184, 1158, 1148, 1049, 968, 906, 853, 809, 789, 732, 703, 632 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H17BrNS [M+H]+: 370.0260, found 370.0242. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 451 Me Br N Me 430g 2-bromo-6-(hex-1-yn-1-yl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (430g) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429g (56.4 mg, 0.3 mmol). Purification by column chromatography (2 to 30% CH2Cl2 in hexanes) provided a colorless oil (28.9 mg, 84% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 5.08 (tt, J = 4.3, 2.0 Hz, 1H), 2.96 (dt, J = 16.7, 4.7 Hz, 1H), 2.80 – 2.67 (m, 1H), 2.25 – 2.04 (m, 8H), 1.96 – 1.84 (m, 1H), 1.46 – 1.37 (m, 2H), 1.37 – 1.29 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.4, 130.8, 123.0, 120.4, 112.7, 111.3, 105.3, 84.4, 78.6, 44.4, 30.8, 30.8, 22.5, 22.0, 18.4, 18.2, 13.7, 8.2; IR (Neat Film, NaCl) 2954, 2929, 2858, 2365, 1574, 1462, 1355, 1335, 1274, 1159, 1050, 883, 857, 811, 789, 736, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H23BrN [M+H]+: 344.1008, found 344.0994. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 452 Me Br N 430h Me Me Me 2-bromo-6-(3,3-dimethylbut-1-yn-1-yl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430h) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.1 mg, 0.1 mmol) and trifluoroborate salt 429h (56.4 mg, 0.3 mmol). Purification by column chromatography (5 to 12.5% CH2Cl2 in hexanes) provided a white solid (27.1 mg, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.6, 0.5 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 5.03 (t, J = 5.1 Hz, 1H), 2.93 (dt, J = 16.5, 6.3 Hz, 1H), 2.77 (m, 1H), 2.23 – 2.14 (m, 5H), 2.12 – 2.01 (m, 1H), 1.92 – 1.79 (m, 1H), 1.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 134.4, 133.5, 130.8, 122.8, 120.3, 112.6, 111.5, 105.1, 92.8, 77.1, 44.6, 31.2, 31.0, 27.5, 22.6, 18.5, 8.2; IR (Neat Film, NaCl) 2966, 2927, 2862, 2357, 2238, 1715, 1609, 1574, 1462, 1415, 1335, 1321, 1274, 1159, 1049, 949, 908, 802, 789, 734, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H23BrN [M+H]+: 344.1008, found 344.1005. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 453 Me Br N 430i 2-bromo-6-(hepta-1,6-diyn-1-yl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (430i) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (27.8 mg, 0.1 mmol) and trifluoroborate salt 429i (59.4 mg, 0.3 mmol). Purification by column chromatography (0 to 30% CH2Cl2 in hexanes) provided a colorless oil (21.6 mg, 61% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 5.08 (tt, J = 4.3, 2.1 Hz, 1H), 2.96 (dt, J = 16.6, 4.6 Hz, 1H), 2.79 – 2.67 (m, 1H), 2.27 – 2.16 (m, 6H), 2.15 (s, 3H), 2.12 – 2.03 (m, 1H), 1.94 (t, J = 2.7 Hz, 1H), 1.93 – 1.87 (m, 1H), 1.64 (p, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.3, 130.8, 123.1, 120.5, 112.7, 111.1, 105.4, 83.6, 83.1, 79.4, 69.0, 44.3, 30.7, 27.5, 22.4, 18.2, 17.8, 17.6, 8.2; IR (Neat Film, NaCl) 3299, 2920, 2852, 2118, 1715, 1462, 1336, 1274, 1159, 1049, 884, 859, 811, 790, 739, 633 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H21BrN [M+H]+: 354.0852, found 354.0848. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 454 Me Br N TBSO 430j 2-bromo-6-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-10-methyl-6,7,8,9tetrahydropyrido[1,2-a]indole (430j) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429j (87.1 mg, 0.3 mmol). Purification by column chromatography (4 to 20% CH2Cl2 in hexanes) provided a colorless oil (31.8 mg, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.6, 0.6 Hz, 1H), 7.20 (dd, J = 8.6, 1.9 Hz, 1H), 5.08 (tt, J = 4.1, 1.9 Hz, 1H), 3.62 (td, J = 6.9, 1.5 Hz, 2H), 2.95 (dt, J = 16.6, 4.6 Hz, 1H), 2.79 – 2.66 (m, 1H), 2.32 (td, J = 7.0, 2.0 Hz, 2H), 2.26 – 2.03 (m, 6H), 1.97 – 1.84 (m, 1H), 0.86 (s, 9H), 0.01 (d, J = 1.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 134.6, 133.6, 131.1, 123.4, 120.8, 113.0, 111.5, 105.7, 81.6, 79.9, 62.2, 44.6, 31.0, 26.3, 23.5, 22.7, 18.7, 18.5, 8.5, -4.90, -4.92; IR (Neat Film, NaCl) 2951, 2929, 2856, 2360, 1574, 1462, 1443, 1415, 1356, 1336, 12252, 1160, 1105, 1058, 915, 836, 811, 777, 736, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C23H33BrNOSi [M+H]+: 446.1509, found 446.1507. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 455 Me Br N 430k 2-bromo-6-(3-cyclohexylprop-1-yn-1-yl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430k) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trifluoroborate salt 429k (68.4 mg, 0.3 mmol). Purification by column chromatography (4 to 10% CH2Cl2 in hexanes) provided a colorless oil (32.7 mg, 85% yield). 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 5.12 – 5.06 (m, 1H), 2.96 (dt, J = 16.3, 4.7 Hz, 1H), 2.74 (ddd, J = 16.1, 10.3, 5.6 Hz, 1H), 2.24 – 2.06 (m, 6H), 2.00 (dd, J = 6.6, 2.1 Hz, 2H), 1.96 – 1.88 (m, 1H), 1.73 – 1.64 (m, 5H), 1.42 – 1.32 (m, 1H), 1.25 – 1.15 (m, 2H), 1.14 – 1.04 (m, 1H), 0.95 – 0.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 134.4, 133.4, 130.9, 122.9, 120.4, 112.7, 111.3, 105.3, 83.3, 79.5, 44.5, 37.3, 32.7, 32.7, 30.8, 26.5, 26.3, 26.2, 22.5, 18.3, 8.2; IR (Neat Film, NaCl) 2922, 2850, 2356, 1705, 1574, 1505, 1461, 1447, 1415, 1355, 1335, 1274, 1240, 1159, 1049, 954, 858, 811, 789, 632 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H27BrN [M+H]+: 384.1321, found 384.1313. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 456 Me Br N 430l 2-bromo-6-(cyclopropylethynyl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (430l) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (27.8 mg, 0.1 mmol) and trifluoroborate salt 429l (51.6 mg, 0.3 mmol). Purification by column chromatography (10 to 20% CH2Cl2 in hexanes) provided a white solid (32.4 mg, 99% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.6, 1.9 Hz, 1H), 5.04 (td, J = 4.7, 1.7 Hz, 1H), 2.95 (dt, J = 16.6, 4.7 Hz, 1H), 2.73 (m, 1H), 2.24 – 2.02 (m, 6H), 1.96 – 1.83 (m, 1H), 1.22 – 1.10 (m, 1H), 0.74 – 0.65 (m, 2H), 0.64 – 0.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.3, 130.8, 123.0, 120.4, 112.6, 111.2, 105.3, 87.4, 73.7, 44.4, 30.8, 22.4, 18.2, 8.4, 8.3, 8.2, -0.5; IR (Neat Film, NaCl) 3090, 3005, 2928, 2857, 2340, 2242, 1574, 1462, 1355, 1334, 1274, 1050, 1029, 955, 882, 847, 810, 790, 733, 634, 605 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H19BrN [M+H]+: 328.0695, found 328.0686. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 457 Me Br N 430m 2-bromo-6-(cyclohex-1-en-1-ylethynyl)-10-methyl-6,7,8,9-tetrahydropyrido[1,2a]indole (430m) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (27.9 mg, 0.1 mmol) and trifluoroborate salt 429m (63.6 mg, 0.3 mmol). Purification by column chromatography (10 to 20% CH2Cl2 in hexanes) provided a yellow oil (35.2 mg, 96% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.6, 1.9 Hz, 1H), 6.01 (dq, J = 3.7, 1.8 Hz, 1H), 5.20 (t, J = 4.7 Hz, 1H), 2.96 (dt, J = 16.5, 4.8 Hz, 1H), 2.81 – 2.69 (m, 1H), 2.28 – 2.06 (m, 6H), 2.02 (tt, J = 4.2, 3.2 Hz, 4H), 1.96 – 1.86 (m, 1H), 1.63 – 1.47 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 135.5, 134.3, 133.3, 130.8, 123.0, 120.4, 120.1, 112.7, 111.2, 105.4, 85.7, 84.9, 44.8, 30.7, 29.2, 25.7, 22.5, 22.3, 21.5, 18.3, 8.2; IR (Neat Film, NaCl) 3025, 2930, 2857, 2359, 2220, 1702, 1574, 1461, 1414, 1354, 1334, 1274, 1240, 1212, 1158, 1146, 1049, 907, 882, 858, 809, 789, 735, 633, 612 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H23BrN [M+H]+: 368.1008, found 368.0995. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 458 Me Br N 430p 6-allyl-2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (430p) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.1 mg, 0.1 mmol) and potassium allyltrifluoroborate 429p (44.4 mg, 0.3 mmol). Purification by column chromatography (8 to 12% CH2Cl2 in hexanes) provided a colorless oil (27.5 mg, 90% yield). 1 H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.6, 1.9 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 5.81 (dddd, J = 17.6, 9.7, 8.0, 6.2 Hz, 1H), 5.22 – 5.09 (m, 2H), 4.43 (ddt, J = 10.7, 5.6, 3.0 Hz, 1H), 3.05 – 2.92 (m, 1H), 2.71 (m, 2H), 2.39 (m, 1H), 2.16 (m, 4H), 1.94 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 134.6, 133.9, 133.6, 130.8, 122.7, 120.6, 118.2, 112.3, 110.6, 104.6, 51.4, 37.6, 25.9, 22.3, 16.2, 8.2; IR (Neat Film, NaCl) 3647, 2941, 2357, 1456, 1346, 786, 681 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H19BrN [M+H]+: 304.0695, found 304.0688. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 459 Me Br N Me Me 430q 2-bromo-10-methyl-6-(2-methylprop-1-en-1-yl)-6,7,8,9-tetrahydropyrido[1,2a]indole (430q) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.1 mg, 0.1 mmol) and potassium(2-methyl-1-propen-1-yl)trifluoroborate 429q (48.6 mg, 0.3 mmol). Purification by column chromatography (8 to 25% CH2Cl2 in hexanes) provided a colorless oil (22.9 mg, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.6, 1.9 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.22 (dhept, J = 8.8, 1.4 Hz, 1H), 4.98 (dt, J = 8.8, 5.4 Hz, 1H), 2.99 – 2.75 (m, 2H), 2.17 (s, 3H), 2.16 – 2.08 (m, 1H), 2.02 – 1.77 (m, 6H), 1.73 (d, J = 1.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.5, 134.4, 133.0, 130.7, 126.5, 122.6, 120.2, 112.3, 111.5, 104.7, 51.5, 31.0, 25.8, 22.7, 18.5, 18.1, 8.2; IR (Neat Film, NaCl) 2933, 2856, 2358, 1671, 1570, 1505, 1461, 1443, 1415, 1375, 1347, 1321, 1275, 1160, 1048, 888, 856, 809, 786, 741 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H21BrN [M+H]+: 318.0852, found 318.0842. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 460 Me Br N Ph 430r (E)-2-bromo-10-methyl-6-styryl-6,7,8,9-tetrahydropyrido[1,2-a]indole (430r) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (28.1 mg, 0.1 mmol) and potassium trans-styryl trifluoroborate 429r (63.0 mg, 0.3 mmol). Purification by column chromatography (6 to 15% CH2Cl2 in hexanes) provided a colorless oil (30.1 mg, 82% yield). 1 H NMR (400 MHz, CDCl3) δ 7.63 (t, J = 1.3 Hz, 1H), 7.31 – 7.24 (m, 4H), 7.24 – 7.18 (m, 1H), 7.12 (d, J = 1.2 Hz, 2H), 6.27 (dd, J = 15.9, 5.9 Hz, 1H), 6.17 (dd, J = 15.9, 1.0 Hz, 1H), 5.05 (tdd, J = 5.7, 3.9, 1.1 Hz, 1H), 2.99 (dt, J = 16.7, 4.9 Hz, 1H), 2.91 – 2.76 (m, 1H), 2.27 – 2.16 (m, 4H), 2.14 – 2.05 (m, 1H), 2.05 – 1.92 (m, 1H), 1.88 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 136.4, 134.5, 134.0, 131.0, 130.7, 130.0, 128.7, 127.8, 126.5, 122.9, 120.4, 112.5, 111.6, 105.0, 54.7, 30.3, 22.6, 17.3, 8.3; IR (Neat Film, NaCl) 3025, 2942, 2858, 2365, 1699, 1575, 1494, 1462, 1415, 1357, 1320, 1274, 1159, 1048, 966, 908, 862, 789, 750, 733, 692, 635 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H21BrN [M+H]+: 366.0852, found 366.0840. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction H N OH H N N Me Br OH 461 N Me Br 436a (major dias.) 436b (minor dias.) ((41S,12R,13aS)-12-((4-bromophenyl)ethynyl)-13a-ethyl-2,3,41,5,6,12,13,13aoctahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl)methanol (436) Prepared according to general procedure 5 instead using hexafluoroisopropanol as the solvent as well as using ⍺-hydroxyindole 435 (65.1 mg, 0.2 mmol) and trifluoroborate salt 429b (174.2 mg, 0.6 mmol). Purification by column chromatography (basic alumina, 60 to 100% CH2Cl2 in hexanes then 0 to 6% MeOH in CH2Cl2) provided two diastereomers that were yellow solids; major diastereomer 436a (70.4 mg, 72.1% yield), minor diastereomer 436b (19.2 mg, 19.7% yield, 4:1 dr). Note: The diastereomeric ratio was determined by LCMS analysis of the crude reaction residue. Stereochemistry at the newly formed center was determined via X-ray crystallography (vide infra). Major diastereomer 436a: 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.1 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.47 – 7.39 (m, 2H), 7.31 – 7.27 (m, 2H), 7.21 – 7.07 (m, 2H), 4.52 (d, J = 11.1 Hz, 1H), 3.99 (bs, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.40 – 3.20 (m, 2H), 3.07 – 2.96 (m, 1H), 2.90 (d, J = 14.9 Hz, 1H), 2.74 – 2.52 (m, 3H), 2.37 – 2.26 (m, 1H), 2.12 (d, J = 14.9 Hz, 1H), 1.87 – 1.69 (m, 1H), 1.65 – 1.52 (m, 1H), 1.49 – 1.29 (m, 3H), 0.97 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.6, 133.4, 131.8, 131.3, 128.9, 123.2, 121.1, 121.0, 119.7, 118.6, 112.4, Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 462 105.7, 90.9, 84.8, 65.7, 59.9, 57.3, 51.3, 45.0, 40.8, 35.7, 29.6, 26.3, 21.1, 16.8, 7.7; IR (Neat Film, NaCl) 3371, 2965, 2274, 1672, 1485, 1452, 1371, 1313, 1272, 1199, 1162, 1134, 1069, 1052, 1010, 828, 798, 745, 720 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C28H30BrN2O [M+H]+: 489.1536, found 489.1549; [⍺]D25 –129.2 (c 1.0, CHCl3). Minor diastereomer 436b: 1 H NMR (400 MHz, CDCl3) δ 7.75 – 7.64 (m, 1H), 7.56 – 7.47 (m, 1H), 7.45 – 7.37 (m, 2H), 7.24 – 7.19 (m, 2H), 7.19 – 7.12 (m, 2H), 4.54 (d, J = 11.6 Hz, 1H), 3.86 – 3.77 (m, 2H), 3.37 – 3.18 (m, 2H), 3.06 – 2.92 (m, 1H), 2.60 – 2.49 (m, 2H), 2.45 – 2.33 (m, 2H), 2.31 – 2.20 (m, 2H), 1.78 – 1.69 (m, 1H), 1.55 – 1.48 (m, 3H), 1.36 – 1.29 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.3, 133.2, 133.1, 131.7, 129.1, 123.0, 121.3, 121.0, 119.9, 118.6, 112.0, 105.7, 89.7, 85.9, 67.6, 59.4, 55.3, 50.8, 44.4, 42.6, 34.7, 28.9, 25.4, 20.9, 17.1, 7.8; IR (Neat Film, NaCl) 3048, 2931, 2857, 2245, 1725, 1485, 1453, 1364, 1327, 1305, 1185, 1069, 1011, 911, 822, 736, 682 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C28H30BrN2O [M+H]+: 489.1536, found 489.1553; [⍺]D25 –170.4 (c 0.23, CHCl3). Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 463 OH MeO Me N 440 2-(5-methoxy-2-methyl-1-(3-phenylprop-2-yn-1-yl)-1H-indol-3-yl)ethan-1-ol (440) Prepared according to general procedure 5 using ⍺-hydroxyindole 439 (23.3 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (20 to 50% EtOAc in hexanes) provided a white solid (15.4 mg, 49% yield). 1 H NMR (400 MHz, CDCl3) δ 7.39 – 7.35 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.31 – 7.23 (m, 3H), 7.02 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 5.01 (s, 2H), 3.86 (s, 3H), 3.84 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.3, 134.4, 131.9, 131.4, 128.7, 128.6, 128.4, 122.5, 110.9, 109.8, 107.7, 100.8, 84.0, 83.9, 63.0, 56.2, 33.7, 28.2, 10.5; IR (Neat Film, NaCl) 3392, 2931, 1616, 1584, 1483, 1419, 1337, 1262, 1228, 1152, 1043, 962, 759 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H22NO2 [M+H]+: 320.1645, found 320.1647. 464 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction N MeO MeO N Ph H N H BF3K H PhCO2H O (CF3)2CHOH 65 °C, 18 h MeO H N MeO H H H O H NC 441 Ph 442 (4aR,4a1R,5aS,8aR,8a1S,14S,15aS)-10,11-dimethoxy-14-(phenylethynyl)2,4a,4a1,5,5a,7,8,8a1,15,15a-decahydro-14H-4,6-methanoindolo[3,2,1ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline (442) Prepared according to general procedure 5 instead using hexafluoroisopropanol as the solvent as well as using ⍺-cyanoindoline 441 (40.5 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (95:5 to 90:10 CH2Cl2/MeOH) provided a tan solid (38.3 mg, 80% yield). 1 H NMR (400 MHz, CD2Cl2) δ 7.46 – 7.40 (m, 2H), 7.36 – 7.30 (m, 3H), 6.78 (s, 1H), 6.49 (s, 1H), 6.30 – 6.23 (m, 1H), 4.41 (t, J = 5.8 Hz, 1H), 4.38 – 4.35 (m, 1H), 4.31 (dd, J = 14.1, 7.0 Hz, 1H), 4.21 – 4.15 (m, 1H), 4.15 – 4.00 (m, 3H), 3.96 – 3.87 (m, 1H), 3.86 – 3.75 (m, 6H), 3.25 – 3.09 (m, 3H), 2.43 – 2.14 (m, 4H), 1.89 – 1.79 (m, 1H), 1.79 – 1.71 (m, 1H), 1.49 (dt, J = 11.1, 2.4 Hz, 1H); 13C NMR (100 MHz, CD2Cl2) δ 151.3, 145.2, 143.3, 135.1, 133.8, 131.9, 128.8, 128.7, 123.5, 117.6, 108.7, 95.1, 90.4, 82.9, 79.3, 65.4, 61.1, 60.2, 57.5, 56.4, 53.0, 52.7, 51.6, 44.5, 40.2, 36.2, 36.1, 33.1, 25.7; IR (Neat Film, NaCl) 2931, 2545, 2392, 1683, 1506, 1214, 1092, 1017, 679 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C31H33N2O3 [M+H]+: 481.2486, found 481.2497. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Br 465 Me N Me O H 444 H H 2-bromo-6-(((8S,9S,13S,14S)-3-(cyclopentyloxy)-13-methyl-7,8,9,11,12,13,14,15octahydro-6H-cyclopenta[a]phenanthren-17-yl)ethynyl)-10-methyl-6,7,8,9tetrahydropyrido[1,2-a]indole (444) Prepared according to general procedure 5 using ⍺-hydroxyindole 426a (13.9 mg, 0.05 mmol) and trifluoroborate salt 443 (67.9 mg, 0.15 mmol). Purification by column chromatography (12 to 30% CH2Cl2 in hexanes) provided a white solid (14.6 mg, 48% yield). Note: The product was isolated as a 1:1 mixture of diastereomers at the newly formed stereocenter that were unable to be resolved by 1H NMR. Slight resolution is observed in four peaks in the 13C NMR. 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.5, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 5.95 (bs, J = 1.4 Hz, 1H), 5.27 (t, J = 4.7 Hz, 1H), 4.76 – 4.69 (m, 1H), 3.04 – 2.71 (m, 4H), 2.37 – 2.09 (m, 11H), 2.09 – 1.70 (m, 10H), 1.66 – 1.36 (m, 5H), 0.77 (d, J = 8.2 Hz, 3H) (the doublet is the result of the two diastereomers being partially resolved); 13C NMR (100 MHz, CDCl3) δ 156.1, 137.9, 136.7, 136.2 (d, the doublet is the result of the two diastereomers being partially resolved), 134.4, 133.4, 132.4, 130.9, 126.1, 123.1, 120.5, 115.7, 113.0, 112.8, 111.3, 105.6, 91.1, 79.6, 79.1, 55.5 (d, the doublet is the result of the two diastereomers being partially resolved), 48.4, 45.0, 44.4 (d, the doublet is the Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 466 result of the two diastereomers being partially resolved), 37.6, 34.6 (d, the doublet is the result of the two diastereomers being partially resolved), 33.0, 31.9, 30.8, 29.8, 27.9, 26.6, 24.1, 22.5, 18.4, 16.4, 8.3; IR (Neat Film, NaCl) 2927, 2855, 2248, 1609, 1572, 1496, 1461, 1441, 1354, 1325, 1275, 1251, 1239, 1171, 1158, 1010, 995, 907, 813, 806, 789, 732 cm– 1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C38H43BrNO [M+H]+: 608.2523, found 608.2507; [⍺]D25 +36.9 (c 0.79, CHCl3). 467 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction H N O H H H N N O Me OH Me H 445a (major dias.) H H N Me OH Me H 445b (minor dias.) ((41S,12R,13aS)-12-(((8S,9S,13S,14S)-3-(cyclopentyloxy)-13-methyl7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-yl)ethynyl)-13aethyl-2,3,41,5,6,12,13,13a-octahydro-1H-indolo[3,2,1-de]pyrido[3,2,1ij][1,5]naphthyridin-12-yl)methanol (445) Prepared according to general procedure 5 instead using hexafluoroisopropanol as the solvent as well as using ⍺-hydroxyindole 435 (16.2 mg, 0.05 mmol) and trifluoroborate salt 443 (67.9 mg, 0.15 mmol). Purification by column chromatography (basic alumina, 50 to 100% CH2Cl2 in hexanes) provided two diastereomers that were white solids; major diastereomer 445a (23.0 mg, 70.8% yield), minor diastereomer 445b (3.5 mg, 10.8% yield). Note: The diastereomeric ratio was determined by LCMS analysis of the crude reaction residue. Stereochemistry at the newly formed center was assigned via analogy to 436 (vide supra). Major diastereomer 445a: 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.20 – 7.06 (m, 3H), 6.67 (d, J = 8.6 Hz, 1H), 6.60 (s, 1H), 6.08 (s, 1H), 4.76 – 4.67 (m, 1H), 4.42 (d, J = 11.0 Hz, 1H), 3.95 (s, 1H), 3.74 (d, J = 11.1 Hz, 1H), 3.40 – 3.19 (m, 2H), 3.08 – 2.95 (m, 1H), 2.92 – 2.79 (m, 3H), 2.71 – 2.50 (m, 3H), 2.40 – 2.21 (m, 4H), 2.15 – 2.01 (m, 3H), 1.96 – 1.72 (m, 6H), 1.70 – 1.52 (m, 8H), 1.49 – 1.24 (m, 5H), 0.96 (t, J = 2.2 Hz, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 137.9, 137.4, 136.3, 134.6, 132.3, Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 468 131.6, 128.9, 126.1, 120.7, 119.6, 118.4, 115.8, 113.0, 112.7, 105.6, 92.8, 82.1, 79.2, 65.7, 60.0, 57.5, 55.5, 51.4, 48.5, 45.1, 44.4, 41.2, 37.6, 35.7, 34.8, 33.0, 32.1, 29.8, 29.6, 27.9, 26.6, 26.4, 24.1, 21.2, 16.9, 16.6, 7.7; IR (Neat Film, NaCl) 3048, 2928, 2873, 2244, 1612, 1495, 1453, 1361, 1305, 1251, 1170, 1123, 1095, 1050, 908, 814, 735 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C45H55N2O2 [M+H]+: 655.4258, found 655.4278; [⍺]D25 –45.5 (c 0.22, CHCl3). Minor diastereomer 445b: 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.25 – 7.17 (m, 2H, overlaps with residual CHCl3), 7.14 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 8.6, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 6.00 (dd, J = 3.3, 1.9 Hz, 1H), 4.75 – 4.67 (m, 1H), 4.54 (d, J = 11.5 Hz, 1H), 3.80 (d, J = 11.5 Hz, 1H), 3.44 – 3.26 (m, 2H), 3.01 – 2.77 (m, 3H), 2.49 (d, J = 14.5 Hz, 1H), 2.38 – 2.15 (m, 5H), 2.11 – 1.98 (m, 1H), 1.93 – 1.72 (m, 10H), 1.69 – 1.36 (m, 13H, overlaps with residual H2O), 1.33 (m, 1H, overlaps with residual grease), 0.98 (t, J = 7.4 Hz, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 137.9, 136.6 (2C, overlapping), 136.5, 134.3, 132.3, 129.0, 126.0, 120.8, 119.8, 118.4, 115.7, 113.0, 112.4, 105.5, 91.8, 82.8, 79.1, 67.9, 59.5, 55.5, 55.4, 50.8, 48.5, 44.4, 44.4, 42.9, 37.6, 34.8, 34.7, 33.0, 32.0, 29.8, 29.8, 28.9, 27.9, 26.6, 24.1, 20.8, 17.2, 16.5, 7.8; IR (Neat Film, NaCl) 3048, 2927, 2853, 2246, 1678, 1611, 1493, 1453, 1360, 1327, 1305, 1252, 1215, 1169, 1088, 1012, 911, 819, 734 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C45H55N2O2 [M+H]+: 655.4258, found 655.4282; [⍺]D25 –235.1 (c 0.16, CHCl3). Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4.2.4 Derivatization of Petasis-Type Reaction Products Me N Me Pd/C H2 (1 atm) N EtOAc 23 °C, 18 h Ph 469 Ph 428f 431 10-methyl-6-phenethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole (431) To a flame-dried round bottom flask was added a stir bar, alkyne 428f (28.5 mg, 0.1 mmol, 1.0 equiv), and EtOAc (1 mL, 0.1 M). 10 wt.% Pd/C was then added (3 mg, 10 wt.%) and the headspace was rapidly purged and backfilled with nitrogen ten times. The headspace and solution were then sparged with a hydrogen gas balloon for 15 min. The reaction was then stirred for 14 h at 23 °C under 1 atm of hydrogen gas. Upon completion, the hydrogen was vented, and the reaction was passed through a plug of silica gel with EtOAc and concentrated under reduced pressure to afford a colorless oil (28.4 mg, 98%). 1 H NMR (400 MHz, CDCl3) δ 7.49 – 7.41 (m, 1H), 7.31 – 7.24 (m, 2H), 7.22 – 7.15 (m, 3H), 7.09 – 6.95 (m, 3H), 4.38 (ddt, J = 10.7, 5.8, 2.9 Hz, 1H), 2.96 (dt, J = 16.1, 4.0 Hz, 1H), 2.80 – 2.60 (m, 3H), 2.27 – 2.09 (m, 5H), 2.05 – 1.80 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 141.4, 134.9, 132.4, 129.0, 128.6, 128.5, 126.2, 120.0, 118.8, 117.9, 109.1, 104.7, 51.0, 34.4, 32.7, 26.3, 22.4, 16.7, 8.3; IR (Neat Film, NaCl) 3051, 3024, 2939, 2858, 2339, 1602, 1566, 1462, 1354, 1324, 1241, 1160, 1088, 1013, 908, 787, 700, 625 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H24N [M+H]+: 290.1903, found 290.1906. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 470 Me N Et2O 23 °C, 18 h Ph 428f Me Lindlar’s catalyst quinoline H2 (1 atm) Ph N 432 (Z)-10-methyl-6-styryl-6,7,8,9-tetrahydropyrido[1,2-a]indole (432) To a flame-dried round bottom flask was added a stir bar, Lindlar’s catalyst (6 mg, 20 wt.%) and Et2O (1 mL, 0.1 M). The flask was then charged with quinoline (5.5 µl) and alkyne 428f (28.8 mg, 0.1 mmol, 1.0 equiv). The headspace was rapidly purged and backfilled with nitrogen ten times. The headspace and solution were then sparged with a hydrogen gas balloon for 10 min. The reaction was then stirred for 17 h at 23 °C under 1 atm of hydrogen gas. Upon completion, the hydrogen was vented, and the reaction was passed through a plug of silica gel with Et2O and concentrated under reduced pressure to afford a colorless residue. This residue was purified by silica gel chromatography (12 to 30% CH2Cl2 in hexanes) to afford a colorless oil (26.0 mg, 90%). 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.45 (m, 3H), 7.45 – 7.40 (m, 2H), 7.40 – 7.34 (m, 1H), 7.10 – 7.05 (m, 1H), 7.04 – 6.99 (m, 1H), 6.94 (dt, J = 8.0, 1.0 Hz, 1H), 6.60 (d, J = 11.6 Hz, 1H), 5.76 (dd, J = 11.7, 9.5 Hz, 1H), 5.43 – 5.33 (m, 1H), 3.01 (dt, J = 16.3, 5.4 Hz, 1H), 2.93 – 2.79 (m, 1H), 2.40 – 2.30 (m, 1H), 2.28 – 2.16 (m, 4H), 2.13 – 2.00 (m, 1H), 2.00 – 1.89 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 136.8, 135.8, 133.5, 132.4, 129.8, 129.0, 128.9, 128.7, 127.5, 120.1, 119.0, 117.7, 110.1, 105.4, 50.3, 30.7, 22.6, 18.8, 8.3; IR (Neat Film, NaCl) 3732, 3051, 3022, 2939, 2856, 2357, 1613, 1574, 1493, 1461, 1350, 1322, 1241, 1160, 1055, 1013, 912, 885, 804, 728, 697, 677 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C21H22N [M+H]+: 288.1747, found 288.1747. 471 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me Br O Br Me NH O Me N N CuSO4 • 5 H2O (6 mol%) sodium ascorbate (10 mol%) O 3:1 THF/H2O 23 °C, 22 h + N3 O H N O N N N N N Me O 430i 433 OH OH 434 1-((2R,4S,5S)-4-(4-(5-(2-bromo-10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-6yl)pent-4-yn-1-yl)-1H-1,2,3-triazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-5methylpyrimidine-2,4(1H,3H)-dione (434) Prepared by a procedure adapted from Wang and coworkers.[99] To a mixture of alkyne 430i (35.4 mg, 0.1 mmol, 1.0 equiv) and zidovudine 433 (32.1 mg, 0.12 mmol, 1.2 equiv) in 3:1 THF/H2O (1 mL, 0.1 M) (that had been sparged with argon) was added a freshly prepared aqueous 1 M solution of sodium ascorbate (10 µL, 0.01 mmol, 0.1 equiv). This was followed by addition of a freshly prepared aqueous 1 M solution of CuSO4·5H2O (6 µL, 0.006 mmol, 0.06 equiv). The solution was stirred for 22 h at 23 °C after which it was diluted with water and EtOAc, extracted three times with EtOAc, washed twice with saturated NH4Cl, washed twice with brine, dried over MgSO4, and concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (50 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in EtOAc) to afford a white solid (54.3 mg, 87% yield). Note: As alkyne 430i was racemic, the product was isolated as a 1:1 mixture of diastereomers that were unable to be resolved by 1H NMR. Slight resolution is observed in five peaks in the 13C NMR. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 1 472 H NMR (400 MHz, CDCl3) δ 9.75 – 9.67 (m, 1H), 7.57 (dd, J = 6.1, 1.9 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.29 (dd, J = 8.6, 1.9 Hz, 1H), 7.21 – 7.12 (m, 1H), 7.04 (dd, J = 14.1, 2.4 Hz, 1H), 6.25 (t, J = 6.5 Hz, 1H), 5.36 – 5.26 (m, 1H), 5.14 – 5.05 (m, 1H), 4.39 – 4.30 (m, 1H), 4.04 – 3.91 (m, 2H), 3.81 – 3.71 (m, 1H), 3.02 – 2.89 (m, 1H), 2.88 – 2.79 (m, 2H), 2.76 – 2.56 (m, 3H), 2.25 – 2.00 (m, 7H), 1.96 – 1.82 (m, 4H), 1.75 (p, J = 7.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 164.3, 150.7, 147.3, 137.7, 134.3, 133.6 (d, the doublet is the result of the two diastereomers being partially resolved), 130.9, 122.8, 121.2, 120.4, 112.5, 111.3, 111.2, 105.5, 87.9, 85.2, 83.3, 79.7 (d, the doublet is the result of the two diastereomers being partially resolved), 61.6 (d, the doublet is the result of the two diastereomers being partially resolved), 59.1 (d, the doublet is the result of the two diastereomers being partially resolved), 44.3, 37.8, 30.4, 27.8 (d, the doublet is the result of the two diastereomers being partially resolved), 24.1, 22.4, 18.1, 17.9, 12.5, 8.2. IR (Neat Film, NaCl) 3186, 3061, 2934, 2355, 2337, 2247, 1695, 1462, 1355, 1335, 1273, 1241, 1160, 1102, 106, 908, 811, 732, 606 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C30H34BrN6O4 [M+H]+: 621.1819, found 621.1834. 473 Chapter 3 – Development of a Non-Directed Petasis-Type Reaction H N Br Bpin + OH 436a H N N Me Me MeO2C N Boc 437 Pd(PPh3)4 (10 mol%) K2CO3 N toluene:H2O:EtOH 90 °C, 3 h N OH N Me Me MeO2C N Boc 438 Tabersonine-Vincamine Dimer (438) A solution of aryl bromide 436a (24.3 mg, 0.05 mmol, 1.0 equiv), aryl–Bpin 437 (33.8 mg, 0.06 mmol, 1.2 equiv), and K2CO3 (20.7 mg, 0.15 mmol, 3.0 equiv) in toluene/H2O/EtOH (5:5:1; 0.44 mL, 0.11 M) was sparged with argon followed by the addition of Pd(PPh3)4 (5.8 mg, 0.005 mmol, 0.1 equiv). The reaction was heated to 90 °C for 3 h then cooled to 23 °C, diluted with CH2Cl2 and H2O, extracted four times with CH2Cl2, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic alumina gel chromatography (0 to 10% MeOH in CH2Cl2) to afford a white solid (27.4 mg, 65% yield). 1 H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.53 – 7.46 (m, 5H), 7.43 (dd, J = 8.4, 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.21 – 7.09 (m, 2H), 5.81 (ddd, J = 9.9, 4.8, 1.5 Hz, 1H), 5.65 (dt, J = 9.8, 2.0 Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 4.00 (s, 1H), 3.80 (d, J = 11.1 Hz, 1H), 3.76 (s, 3H), 3.50 (ddd, J = 15.9, 4.9, 1.6 Hz, 1H), 3.40 – 3.20 (m, 2H), 3.11 (dt, J = 15.9, 2.0 Hz, 1H), 3.08 – 2.97 (m, 2H), 2.92 (d, J = 14.9 Hz, 1H), 2.73 (d, J = 15.2 Hz, 1H), 2.71 – 2.47 (m, 5H), 2.38 – 2.26 (m, 2H), 2.23 – 2.12 (m, 2H), 1.87 – 1.71 (m, 2H), 1.56 (s, 9H), 1.52 – 1.29 (m, 4H), 1.18 – 1.07 (m, 1H), 1.05 – 0.99 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H), 0.63 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 151.1, 149.9, 141.4, 140.6, 139.5, 135.8, 134.7, 132.8, 132.4, 131.5, 128.9, 127.0, 126.6, 125.3, 120.9, 120.7, 119.7, 119.6, 118.5, 116.4, 112.6, 112.0, 105.7, 90.3, 85.9, 82.6, 68.2, 65.8, 60.0, 57.4, 52.7, 51.8, 51.6, 51.4, 51.2, 45.1, 43.2, 41.6, 40.9, 35.7, Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 474 31.4, 29.7, 28.3, 26.6, 26.4, 21.2, 16.8, 7.8, 7.8; IR (Neat Film, NaCl) 3482, 2963, 2935, 2790, 2249, 1723, 1614, 1473, 1453, 1349, 1330, 1271, 1256, 1170, 1159, 1111, 1051, 908, 823, 732 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C54H61N4O5 [M+H]+: 845.4636, found 845.4677; [⍺]D25 –54.8 (c 0.42, CHCl3). Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.4.2.5 475 Procedures and Characterization for Mechanistic Experiments BF3K Me 427 Br N Me Br Ph (3 equiv) PhCO2H (1 equiv) N CF3CH2OH (0.025 M) 65 °C, 18 h 446 Ph 428a Prepared according to the Petasis-type reaction general procedure (general procedure 5) using enamine 446 (26.1 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (5 to 18% CH2Cl2 in hexanes) provided a white solid (27.0 mg, 74% yield). BF3K Me 427 Br Me Br Ph N O F3C (3 equiv) PhCO2H (1 equiv) N CF3CH2OH (0.025 M) 65 °C, 18 h 447 Ph 428a Prepared according to the Petasis-type reaction general procedure (general procedure 5) using acetal 447 (36.4 mg, 0.1 mmol) and trifluoroborate salt 427 (62.4 mg, 0.3 mmol). Purification by column chromatography (8 to 18% CH2Cl2 in hexanes) provided a white solid (31.8 mg, 87% yield). Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me Me Me Br Me3Si N HO 476 448 (3 equiv) PhCO2H (1 equiv) CF3CH2OH (0.025 M) 65 °C, 18 h 426a Br N Me 449 2-bromo-10-methyl-6-(2-methylallyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole (449) Prepared according to the Petasis-type reaction general procedure (general procedure 5) using ⍺-hydroxyindole 426a (28.0 mg, 0.1 mmol) and trimethyl(2-methylallyl)silane 448 (53 µL, 0.3 mmol). Purification by column chromatography (80:15 hexanes/Et2O) provided a clear oil (30.5 mg, 96% yield). 1 H NMR (400 MHz, CDCl3) δ 7.63 (bs, 1H), 7.23 – 7.18 (m, 1H), 7.12 (d, J = 8.5 Hz, 1H), 4.93 (bs, 1H), 4.81 (bs, 1H), 4.62 – 4.52 (m, 1H), 3.05 – 2.95 (m, 1H), 2.79 – 2.67 (m, 1H), 2.62 (bd, J = 14.5 Hz, 1H), 2.39 – 2.30 (m, 1H), 2.16 (s, 3H), 2.15 – 2.09 (m, 1H), 2.00 – 1.85 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 142.2, 133.8, 133.4, 130.8, 122.6, 120.6, 113.8, 112.2, 110.3, 104.6, 49.7, 40.9, 25.3, 22.6, 22.3, 15.9, 8.2; IR (Neat Film, NaCl) 3069, 2940, 2858, 1571, 1462, 1446, 1348, 1277, 1161, 1080, 1044, 972, 896, 870, 808, 786 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H21BrN [M+H]+: 318.0852, found 318.0853. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction Me 477 Me Br Br MsCl, NEt3 N N CH2Cl2, 0 °C HO 426a 446 2-bromo-10-methyl-8,9-dihydropyrido[1,2-a]indole (446) To a flame-dried round bottom flask was added ⍺-hydroxyindole 426a (176.3 mg, 0.63 mmol, 1.0 equiv). The flask was purged and backfilled three times with nitrogen. CH2Cl2 (12.5 mL, 0.05 M) and NEt3 (0.24 mL, 1.75 mmol, 2.8 equiv) were added and the resulting mixture cooled to 0 °C. MsCl (0.09 mL, 1.13 mmol, 1.8 equiv) was then added and the solution stirred at 0 °C for 2.5 h. The reaction was quenched with water, extracted three times with CH2Cl2, washed with saturated NaHCO3(aq), washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was then purified by silica gel flash column chromatography (0 to 5% Et2O in hexanes) to afford a white solid (97.2 mg, 59% yield). 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.6, 1.9 Hz, 1H), 7.15 (dd, J = 8.6, 0.5 Hz, 1H), 7.00 (dt, J = 7.8, 1.8 Hz, 1H), 5.35 (dt, J = 7.7, 4.4 Hz, 1H), 2.98 – 2.90 (m, 2H), 2.38 (tdd, J = 7.2, 4.5, 1.8 Hz, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 132.5, 132.4, 131.0, 124.1, 122.3, 121.0, 113.0, 109.3, 108.0, 107.1, 20.4, 20.2, 8.3; IR (Neat Film, NaCl) 3065, 2942, 2919, 2832, 2360, 1844, 1709, 1647, 1469, 1437, 1404, 1354, 1272, 1231, 1139, 1040, 979, 883, 857, 790, 747, 706, 635 cm–1; HRMS (FD) m/z calc’d for C13H12BrN [M] +•: 261.0153, found 261.0161. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 478 Me Me Br Br PhCO2H N N CF3CH2OH, 23 °C O HO 426a F3C 447 2-bromo-10-methyl-6-(2,2,2-trifluoroethoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indole (447) To a round bottom flask was added ⍺-hydroxyindole 426a (98.1 mg, 0.35 mmol, 1.0 equiv) and benzoic acid (8.6 mg, 0.07 mmol, 0.2 equiv). Trifluoroethanol (14 mL, 0.025 M) was then added, and the solution stirred at 23 °C for 2 h. The reaction was concentrated under reduced pressure and the resulting white residue purified by basic alumina flash chromatography (0 to 20% CH2Cl2 in hexanes) to afford a white solid (120.9 mg, 95% yield). 1 H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 1.8 Hz, 1H), 7.24 (dd, J = 8.5, 1.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 5.78 (t, J = 3.4 Hz, 1H), 3.91 – 3.75 (m, 2H), 3.01 (dt, J = 16.7, 4.8 Hz, 1H), 2.82 – 2.71 (m, 1H), 2.34 – 2.26 (m, 1H), 2.22 – 2.10 (m, 4H), 2.06 – 1.96 (m, 1H), 1.93 – 1.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 134.7, 133.6, 131.4, 123.9, 123.8 (q, J = 278.7 Hz), 120.9, 113.5, 110.5, 106.9, 81.6, 64.7 (q, J = 34.8 Hz), 28.3, 21.9, 15.8, 8.2; 19 F NMR (282 MHz, CDCl3) δ –73.9 (t, J = 8.5 Hz); IR (Neat Film, NaCl) 2944, 2361, 1581, 1463, 1355, 1276, 1141, 1101, 1063, 975, 885, 813, 792, 663 cm–1; HRMS (FD) m/z calc’d for C15H15BrF3NO [M]+•: 361.0289, found 361.0277. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction 3.5 (1) 479 REFERENCES AND NOTES a) N. 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Ratnayake, J. R. Rocca, K. A. Abboud, C. Li, H. Luesch, J. P. McLaughlin, R. W. Huigens, J. Med. Chem. 2020, 63, 5119–5138. (87) C. Liu, W. Zhang, L.-X. Dai, S.-L. You, Org. Lett. 2012, 14, 4525–4527. (88) G. A. Molander, B. W. Katona, F. Machrouhi, J. Org. Chem. 2002, 67, 8416–8423. (89) K. M. Fisher, Y. Bolshan, J. Org. Chem. 2015, 80, 12676–12685. Chapter 3 – Development of a Non-Directed Petasis-Type Reaction (90) 489 P. Xiong, H. Long, J. Song, Y. Wang, J.-F. Li, H.-C. Xu, J. Am. Chem. Soc. 2018, 140, 16387–16391. (91) G. Wang, Y. Mao, L. Liu, Org. Lett. 2016, 18, 6476–6479. (92) R. William, S. Wang, A. Mallick, X.-W. Liu, Org. Lett. 2016, 18, 4458–4461. (93) J.-F. Wang, X. Meng, C.-H. Zhang, C.-M. Yu, B. Mao, Org. Lett. 2020, 22, 7427– 7432. (94) M. Wan, Z. Meng, H. Lou, L. Liu, Angew. Chem. Int. Ed. 2014, 53, 13845–13849. (95) K. Jouvin, F. Couty, G. Evano, Org. Lett. 2010, 12, 3272–3275. (96) D. Kovács, Z. Kádár, G. Mótyán, G. Schneider, J. Wölfling, I. Zupkó, É. Frank, Steroids 2012, 77, 1075–1085. (97) Z.-Y. Wang, B. Ma, H. Xu, X. Wang, X. Zhang, H.-X. Dai, Org. Lett. 2021, 23, 8291–8295. (98) G. A. Molander, L. A. Felix, J. Org. Chem. 2005, 70, 3950–3956. (99) V. R. Sirivolu, S. K. V. Vernekar, T. Ilina, N. S. Myshakina, M. A. Parniak, Z. Wang, J. Med. Chem. 2013, 56, 8765–8780. APPENDIX 5 Spectra Relevant to Chapter 3: Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy 10 MeN N 9 453g O N Me 8 6 5 ppm 4 3 2 Figure A5.1. 1H NMR (400 MHz, CDCl3) of compound 453g. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 491 Appendix 5 – Spectra Relevant to Chapter 3 492 84 82 80 78 76 % Transmittance 74 72 70 68 66 64 62 60 58 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 453g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.3. 13C NMR (100 MHz, CDCl3) of compound 453g. 0 10 Me 9 453j 8 O Me Me N Me 6 5 ppm 4 3 2 Figure A5.4. 1H NMR (400 MHz, CDCl3) of compound 453j. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 493 Appendix 5 – Spectra Relevant to Chapter 3 494 60 55 50 % Transmittance 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.5. Infrared spectrum (Thin Film, NaCl) of compound 453j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.6. 13C NMR (100 MHz, CDCl3) of compound 453j. 0 10 Me 9 453k O N Me Me 8 Me 6 5 ppm 4 3 2 Figure A5.7. 1H NMR (400 MHz, CDCl3) of compound 453k. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 495 Appendix 5 – Spectra Relevant to Chapter 3 496 52 50 48 46 44 42 40 % Transmittance 38 36 34 32 30 28 26 24 22 20 18 16 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.8. Infrared spectrum (Thin Film, NaCl) of compound 453k. 200 180 160 140 120 ppm 100 80 60 40 20 Figure A5.9. 13C NMR (100 MHz, CDCl3) of compound 453k. 0 10 Me 9 453l O N Me Me Me 8 6 5 ppm 4 3 2 Figure A5.10. 1H NMR (400 MHz, CDCl3) of compound 453l. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 497 Appendix 5 – Spectra Relevant to Chapter 3 498 Figure A5.11. Infrared spectrum (Thin Film, NaCl) of compound 453l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.12. 13C NMR (100 MHz, CDCl3) of compound 453l. 0 Br 9 426a HO N Me 8 6 5 ppm 4 3 2 Figure A5.13. 1H NMR (400 MHz, CDCl3) of compound 426a. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 499 Appendix 5 – Spectra Relevant to Chapter 3 500 40 39 38 37 36 35 34 33 32 % Transmittance 31 30 29 28 27 26 25 24 23 22 21 20 19 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.14. Infrared spectrum (Thin Film, NaCl) of compound 426a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.15. 13C NMR (100 MHz, CDCl3) of compound 426a. 0 10 Cl 9 426b HO N Me 8 6 5 ppm 4 3 2 Figure A5.16. 1H NMR (400 MHz, CDCl3) of compound 426b. 7 1 0 Appendix 5 – Spectra Relevant to Chapter 3 501 Appendix 5 – Spectra Relevant to Chapter 3 502 60 58 56 54 52 50 48 46 % Transmittance 44 42 40 38 36 34 32 30 28 26 24 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.17. Infrared spectrum (Thin Film, NaCl) of compound 426b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.18. 13C NMR (100 MHz, CDCl3) of compound 426b. 0 10 F 9 426c HO N Me 8 6 5 ppm 4 3 2 Figure A5.19. 1H NMR (400 MHz, CDCl3) of compound 426c. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 503 Appendix 5 – Spectra Relevant to Chapter 3 504 85 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 15 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.20. Infrared spectrum (Thin Film, NaCl) of compound 426c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.21. 13C NMR (100 MHz, CDCl3) of compound 426c. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 505 -80 ppm -100 -120 -140 -160 -180 Figure A5.22. 19F NMR (282 MHz, CDCl3) of compound 426c. 10 Me 426d 9 HO N Me 8 6 5 ppm 4 3 2 Figure A5.23. 1H NMR (400 MHz, CDCl3) of compound 426d. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 506 Appendix 5 – Spectra Relevant to Chapter 3 507 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.24. Infrared spectrum (Thin Film, NaCl) of compound 426d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.25. 13C NMR (100 MHz, CDCl3) of compound 426d. 0 10 Ph 9 426e HO N Me 8 6 5 ppm 4 3 2 Figure A5.26. 1H NMR (400 MHz, CDCl3) of compound 426e. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 508 Appendix 5 – Spectra Relevant to Chapter 3 509 Figure A5.27. Infrared spectrum (Thin Film, NaCl) of compound 426e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.28. 13C NMR (100 MHz, CDCl3) of compound 426e. 0 10 426f 9 HO N Me 8 6 5 ppm 4 3 2 Figure A5.29. 1H NMR (400 MHz, CDCl3) of compound 426f. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 510 Appendix 5 – Spectra Relevant to Chapter 3 511 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.30. Infrared spectrum (Thin Film, NaCl) of compound 426f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.31. 13C NMR (100 MHz, CDCl3) of compound 426f. 0 10 MeN N 9 426g HO N Me 8 6 5 ppm 4 3 2 Figure A5.32. 1H NMR (400 MHz, CDCl3) of compound 426g. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 512 Appendix 5 – Spectra Relevant to Chapter 3 513 85 80 75 % Transmittance 70 65 60 55 50 45 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.33. Infrared spectrum (Thin Film, NaCl) of compound 426g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.34. 13C NMR (100 MHz, CDCl3) of compound 426g. 0 10 426h 9 HO N Br 8 6 5 ppm 4 3 2 Figure A5.35. 1H NMR (400 MHz, CDCl3) of compound 426h. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 514 Appendix 5 – Spectra Relevant to Chapter 3 515 75 70 65 % Transmittance 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.36. Infrared spectrum (Thin Film, NaCl) of compound 426h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.37. 13C NMR (100 MHz, CDCl3) of compound 426h. 0 10 Br 9 426i HO N 8 6 5 ppm 4 3 2 Figure A5.38. 1H NMR (400 MHz, CDCl3) of compound 426i. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 516 Appendix 5 – Spectra Relevant to Chapter 3 517 115 110 105 100 % Transmittance 95 90 85 80 75 70 65 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.39. Infrared spectrum (Thin Film, NaCl) of compound 426i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.40. 13C NMR (100 MHz, CDCl3) of compound 426i. 0 10 Me 9 426j HO Me Me N Me 8 6 5 ppm 4 3 2 Figure A5.41. 1H NMR (400 MHz, CDCl3) of compound 426j. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 518 Appendix 5 – Spectra Relevant to Chapter 3 519 80 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.42. Infrared spectrum (Thin Film, NaCl) of compound 426j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.43. 13C NMR (100 MHz, CDCl3) of compound 426j. 0 10 Me 426k 9 HO N Me Me Me 8 6 5 ppm 4 3 2 Figure A5.44. 1H NMR (400 MHz, CDCl3) of compound 426k. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 520 Appendix 5 – Spectra Relevant to Chapter 3 521 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 10 5 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.45. Infrared spectrum (Thin Film, NaCl) of compound 426k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.46. 13C NMR (100 MHz, CDCl3) of compound 426k. 0 10 Me 9 426l HO N Me Me Me 8 6 5 ppm 4 3 2 Figure A5.47. 1H NMR (400 MHz, CDCl3) of compound 426l. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 522 Appendix 5 – Spectra Relevant to Chapter 3 523 80 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 10 5 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.48. Infrared spectrum (Thin Film, NaCl) of compound 426l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.49. 13C NMR (100 MHz, CDCl3) of compound 426l. 0 10 Br 426m 9 N OH 8 6 5 ppm 4 3 2 Figure A5.50. 1H NMR (400 MHz, CDCl3) of compound 426m. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 524 Appendix 5 – Spectra Relevant to Chapter 3 525 39 38 37 36 35 34 33 32 31 30 % Transmittance 29 28 27 26 25 24 23 22 21 20 19 18 17 16 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.51. Infrared spectrum (Thin Film, NaCl) of compound 426m. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.52. 13C NMR (100 MHz, CDCl3) of compound 426m. 0 10 Br 9 426n Me N HO 8 6 5 ppm 4 3 2 Figure A5.53. 1H NMR (400 MHz, CDCl3) of compound 426n. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 526 Appendix 5 – Spectra Relevant to Chapter 3 527 60 58 56 54 52 50 48 46 % Transmittance 44 42 40 38 36 34 32 30 28 26 24 22 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.54. Infrared spectrum (Thin Film, NaCl) of compound 426n. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.55. 13C NMR (100 MHz, CDCl3) of compound 426n. 0 10 MeO 9 439 N OH Me OH 8 6 5 ppm 4 3 2 Figure A5.56. 1H NMR (400 MHz, CDCl3) of compound 439. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 528 Appendix 5 – Spectra Relevant to Chapter 3 529 70 69 68 67 66 65 64 % Transmittance 63 62 61 60 59 58 57 56 55 54 53 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.57. Infrared spectrum (Thin Film, NaCl) of compound 439. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.58. 13C NMR (100 MHz, CDCl3) of compound 439. 0 10 9 429k 8 BF3K 6 5 ppm 4 3 2 Figure A5.59. 1H NMR (400 MHz, acetone) of compound 429k. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 530 Appendix 5 – Spectra Relevant to Chapter 3 531 50 48 46 44 42 40 % Transmittance 38 36 34 32 30 28 26 24 22 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.60. Infrared spectrum (Thin Film, NaCl) of compound 429k. 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.61. 13C NMR (100 MHz, acetone) of compound 429k. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 532 -80 ppm -100 -120 -140 -160 -180 Figure A5.62. 19F NMR (282 MHz, acetone) of compound 429k. 80 70 60 50 40 30 20 10 0 ppm -10 -20 -30 -40 -50 -60 -70 Figure A5.63. 11B NMR (128 MHz, acetone) of compound 429k. -80 10 O 9 462 H H H Me 8 6 5 ppm 4 3 2 Figure A5.64. 1H NMR (400 MHz, CDCl3) of compound 462. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 533 Appendix 5 – Spectra Relevant to Chapter 3 534 75 70 65 % Transmittance 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.65. Infrared spectrum (Thin Film, NaCl) of compound 462. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.66. 13C NMR (100 MHz, CDCl3) of compound 462. 0 10 O 9 H H 443 H Me 8 7 6 5 ppm 4 3 2 Figure A5.67. 1H NMR (400 MHz, DMSO) of compound 443. BF3K 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 535 Appendix 5 – Spectra Relevant to Chapter 3 536 22 21 20 19 18 17 % Transmittance 16 15 14 13 12 11 10 9 8 7 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.68. Infrared spectrum (Thin Film, NaCl) of compound 443. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.69. 13C NMR (100 MHz, DMSO) of compound 443. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 537 -80 ppm -100 -120 -140 -160 -180 Figure A5.70. 19F NMR (282 MHz, DMSO) of compound 443. 80 70 60 50 40 30 20 10 0 ppm -10 -20 -30 -40 -50 -60 -70 -80 Figure A5.71. 11B NMR (128 MHz, DMSO) of compound 443. 10 Br 9 Ph N 8 428a Me 6 5 ppm 4 3 2 Figure A5.72. 1H NMR (400 MHz, CDCl3) of compound 428a. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 538 Appendix 5 – Spectra Relevant to Chapter 3 539 80 75 70 % Transmittance 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.73. Infrared spectrum (Thin Film, NaCl) of compound 428a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.74. 13C NMR (100 MHz, CDCl3) of compound 428a. 0 10 Cl 9 Ph N 428b Me 8 6 5 ppm 4 3 2 Figure A5.75. 1H NMR (400 MHz, CDCl3) of compound 428b. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 540 Appendix 5 – Spectra Relevant to Chapter 3 541 85 80 75 70 % Transmittance 65 60 55 50 45 40 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.76. Infrared spectrum (Thin Film, NaCl) of compound 428b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.77. 13C NMR (100 MHz, CDCl3) of compound 428b. 0 10 F 9 Ph N 428c Me 8 6 5 ppm 4 3 2 Figure A5.78. 1H NMR (400 MHz, CDCl3) of compound 428c. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 542 Appendix 5 – Spectra Relevant to Chapter 3 543 80 75 70 % Transmittance 65 60 55 50 45 40 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.79. Infrared spectrum (Thin Film, NaCl) of compound 428c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.80. 13C NMR (100 MHz, CDCl3) of compound 428c. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 544 -80 ppm -100 -120 -140 -160 -180 Figure A5.81. 19F NMR (282 MHz, CDCl3) of compound 428c. 10 Me 9 Ph N 428d Me 8 6 5 ppm 4 3 2 Figure A5.82. 1H NMR (400 MHz, CDCl3) of compound 428d. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 545 Appendix 5 – Spectra Relevant to Chapter 3 546 85 80 75 % Transmittance 70 65 60 55 50 45 40 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.83. Infrared spectrum (Thin Film, NaCl) of compound 428d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.84. 13C NMR (100 MHz, CDCl3) of compound 428d. 0 10 Ph 9 Ph N 428e Me 8 6 5 ppm 4 3 2 Figure A5.85. 1H NMR (400 MHz, CDCl3) of compound 428e. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 547 Appendix 5 – Spectra Relevant to Chapter 3 548 75 74 73 72 71 70 69 68 67 66 % Transmittance 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.86. Infrared spectrum (Thin Film, NaCl) of compound 428e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.87. 13C NMR (100 MHz, CDCl3) of compound 428e. 0 10 Ph 9 N Me 428f 8 6 5 ppm 4 3 2 Figure A5.88. 1H NMR (400 MHz, CDCl3) of compound 428f. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 549 Appendix 5 – Spectra Relevant to Chapter 3 550 80 75 70 65 % Transmittance 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.89. Infrared spectrum (Thin Film, NaCl) of compound 428f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.90. 13C NMR (100 MHz, CDCl3) of compound 428f. 0 10 MeN N 9 Ph N 428g Me 8 6 5 ppm 4 3 2 Figure A5.91. 1H NMR (400 MHz, CDCl3) of compound 428g. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 551 Appendix 5 – Spectra Relevant to Chapter 3 552 75 74 73 72 71 70 69 % Transmittance 68 67 66 65 64 63 62 61 60 59 58 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.92. Infrared spectrum (Thin Film, NaCl) of compound 428g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.93. 13C NMR (100 MHz, CDCl3) of compound 428g. 0 10 Ph 9 N 428h Br 8 6 5 ppm 4 3 2 Figure A5.94. 1H NMR (400 MHz, CDCl3) of compound 428h. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 553 Appendix 5 – Spectra Relevant to Chapter 3 554 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.95. Infrared spectrum (Thin Film, NaCl) of compound 428h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.96. 13C NMR (100 MHz, CDCl3) of compound 428h. 0 10 Me Ph 9 N Me 428j Me Me 8 6 5 ppm 4 3 2 Figure A5.97. 1H NMR (400 MHz, CDCl3) of compound 428j. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 555 Appendix 5 – Spectra Relevant to Chapter 3 556 90 88 86 84 82 80 78 % Transmittance 76 74 72 70 68 66 64 62 60 58 56 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.98. Infrared spectrum (Thin Film, NaCl) of compound 428j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.99. 13C NMR (100 MHz, CDCl3) of compound 428j. 0 10 Me Ph 9 428k N Me Me Me 8 6 5 ppm 4 3 2 Figure A5.100. 1H NMR (400 MHz, CDCl3) of compound 428k. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 557 Appendix 5 – Spectra Relevant to Chapter 3 558 80 75 70 65 % Transmittance 60 55 50 45 40 35 30 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.101. Infrared spectrum (Thin Film, NaCl) of compound 428k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.102. 13C NMR (100 MHz, CDCl3) of compound 428k. 0 10 Me 9 Ph N 8 Me Me 428l Me 6 5 ppm 4 3 2 Figure A5.103. 1H NMR (400 MHz, CDCl3) of compound 428l. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 559 Appendix 5 – Spectra Relevant to Chapter 3 560 Figure A5.104. Infrared spectrum (Thin Film, NaCl) of compound 428l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.105. 13C NMR (100 MHz, CDCl3) of compound 428l. 0 10 Ph Br 9 N 428m 8 6 5 ppm 4 3 2 Figure A5.106. 1H NMR (400 MHz, CDCl3) of compound 428m. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 561 Appendix 5 – Spectra Relevant to Chapter 3 562 85 80 75 70 % Transmittance 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.107. Infrared spectrum (Thin Film, NaCl) of compound 428m. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.108. 13C NMR (100 MHz, CDCl3) of compound 428m. 0 10 Br 9 428n N Me Ph 8 6 5 ppm 4 3 2 Figure A5.109. 1H NMR (400 MHz, CDCl3) of compound 428n. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 563 Appendix 5 – Spectra Relevant to Chapter 3 564 76 74 72 70 68 % Transmittance 66 64 62 60 58 56 54 52 50 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.110. Infrared spectrum (Thin Film, NaCl) of compound 428n. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.111. C NMR (100 MHz, CDCl3) of compound 428n. 0 10 F Br 9 N 430a Me 8 6 5 ppm 4 3 2 Figure A5.112. 1H NMR (400 MHz, CDCl3) of compound 430a. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 565 Appendix 5 – Spectra Relevant to Chapter 3 566 80 75 70 65 % Transmittance 60 55 50 45 40 35 30 25 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.113. Infrared spectrum (Thin Film, NaCl) of compound 430a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.114. 13C NMR (100 MHz, CDCl3) of compound 430a. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 567 -80 ppm -100 -120 -140 -160 -180 Figure A5.115. 19F NMR (282 MHz, CDCl3) of compound 430a. 10 Br Br 9 N 430b Me 8 6 5 ppm 4 3 2 Figure A5.116. 1H NMR (400 MHz, CDCl3) of compound 430b. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 568 Appendix 5 – Spectra Relevant to Chapter 3 569 85 80 75 70 % Transmittance 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.117. Infrared spectrum (Thin Film, NaCl) of compound 430b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.118. 13C NMR (100 MHz, CDCl3) of compound 430b. 0 10 Br Me 9 N 430c Me 8 6 5 ppm 4 3 2 Figure A5.119. 1H NMR (400 MHz, CDCl3) of compound 430c. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 570 Appendix 5 – Spectra Relevant to Chapter 3 571 85 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.120. Infrared spectrum (Thin Film, NaCl) of compound 430c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.121. 13C NMR (100 MHz, CDCl3) of compound 430c. 0 10 MeO Br 9 N 430d Me 8 6 5 ppm 4 3 2 Figure A5.122. 1H NMR (400 MHz, CDCl3) of compound 430d. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 572 Appendix 5 – Spectra Relevant to Chapter 3 573 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.123. Infrared spectrum (Thin Film, NaCl) of compound 430d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.124. 13C NMR (100 MHz, CDCl3) of compound 430d. 0 10 F3C Br 9 N 430e Me 8 6 5 ppm 4 3 2 Figure A5.125. 1H NMR (400 MHz, CDCl3) of compound 430e. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 574 Appendix 5 – Spectra Relevant to Chapter 3 575 70 65 60 55 50 45 % Transmittance 40 35 30 25 20 15 10 5 0 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.126. Infrared spectrum (Thin Film, NaCl) of compound 430e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.127. 13C NMR (100 MHz, CDCl3) of compound 430e. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 576 -80 ppm -100 -120 -140 -160 -180 Figure A5.128. 19F NMR (282 MHz, CDCl3) of compound 430e. 10 Br S 9 430f N Me 8 6 5 ppm 4 3 2 Figure A5.129. 1H NMR (400 MHz, CDCl3) of compound 430f. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 577 Appendix 5 – Spectra Relevant to Chapter 3 578 80 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.130. Infrared spectrum (Thin Film, NaCl) of compound 430f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.131. 13C NMR (100 MHz, CDCl3) of compound 430f. 0 10 Me Br 9 430g N Me 8 6 5 ppm 4 3 2 Figure A5.132. 1H NMR (400 MHz, CDCl3) of compound 430g. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 579 Appendix 5 – Spectra Relevant to Chapter 3 580 85 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.133. Infrared spectrum (Thin Film, NaCl) of compound 430g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.134. 13C NMR (100 MHz, CDCl3) of compound 430g. 0 10 Br Me Me Me N 9 430h Me 8 6 5 ppm 4 3 2 Figure A5.135. 1H NMR (400 MHz, CDCl3) of compound 430h. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 581 Appendix 5 – Spectra Relevant to Chapter 3 582 85 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.136. Infrared spectrum (Thin Film, NaCl) of compound 430h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.137. 13C NMR (100 MHz, CDCl3) of compound 430h. 0 10 Br 9 N 430i Me 8 6 5 ppm 4 3 2 Figure A5.138. 1H NMR (400 MHz, CDCl3) of compound 430i. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 583 Appendix 5 – Spectra Relevant to Chapter 3 584 36 34 32 30 28 % Transmittance 26 24 22 20 18 16 14 12 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.139. Infrared spectrum (Thin Film, NaCl) of compound 430i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.140. 13C NMR (100 MHz, CDCl3) of compound 430i. 0 10 TBSO Br 9 430j N Me 8 6 5 ppm 4 3 2 Figure A5.141. 1H NMR (400 MHz, CDCl3) of compound 430j. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 585 Appendix 5 – Spectra Relevant to Chapter 3 586 85 80 75 70 % Transmittance 65 60 55 50 45 40 35 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.142. Infrared spectrum (Thin Film, NaCl) of compound 430j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.143. 13C NMR (100 MHz, CDCl3) of compound 430j. 0 10 Br 9 430k N Me 8 6 5 ppm 4 3 2 Figure A5.144. 1H NMR (400 MHz, CDCl3) of compound 430k. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 587 Appendix 5 – Spectra Relevant to Chapter 3 588 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.145. Infrared spectrum (Thin Film, NaCl) of compound 430k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.146. 13C NMR (100 MHz, CDCl3) of compound 430k. 0 10 Br 9 N 430l Me 8 6 5 ppm 4 3 2 Figure A5.147. 1H NMR (400 MHz, CDCl3) of compound 430l. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 589 Appendix 5 – Spectra Relevant to Chapter 3 590 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.148. Infrared spectrum (Thin Film, NaCl) of compound 430l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.149. 13C NMR (100 MHz, CDCl3) of compound 430l. 0 10 Br 9 N 430m Me 8 6 5 ppm 4 3 2 Figure A5.150. 1H NMR (400 MHz, CDCl3) of compound 430m. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 591 Appendix 5 – Spectra Relevant to Chapter 3 592 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.151. Infrared spectrum (Thin Film, NaCl) of compound 430m. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.152. 13C NMR (100 MHz, CDCl3) of compound 430m. 0 10 Br 9 430p N Me 8 6 5 ppm 4 3 2 Figure A5.153. 1H NMR (400 MHz, CDCl3) of compound 430p. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 593 Appendix 5 – Spectra Relevant to Chapter 3 594 64.0 63.5 63.0 62.5 62.0 61.5 61.0 % Transmittance 60.5 60.0 59.5 59.0 58.5 58.0 57.5 57.0 56.5 56.0 55.5 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.154. Infrared spectrum (Thin Film, NaCl) of compound 430p. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.155. 13C NMR (100 MHz, CDCl3) of compound 430p. 0 10 Br Me Me 9 430q N Me 8 6 5 ppm 4 3 2 Figure A5.156. 1H NMR (400 MHz, CDCl3) of compound 430q. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 595 Appendix 5 – Spectra Relevant to Chapter 3 596 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.157. Infrared spectrum (Thin Film, NaCl) of compound 430q. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.158. 13C NMR (100 MHz, CDCl3) of compound 430q. 0 10 Br Ph 9 430r N Me 8 6 5 ppm 4 3 2 Figure A5.159. 1H NMR (400 MHz, CDCl3) of compound 430r. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 597 Appendix 5 – Spectra Relevant to Chapter 3 598 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.160. Infrared spectrum (Thin Film, NaCl) of compound 430r. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.161. 13C NMR (100 MHz, CDCl3) of compound 430r. 0 10 Br OH H 9 436a (major dias.) N 8 Me N 6 5 ppm 4 3 2 Figure A5.162. 1H NMR (400 MHz, CDCl3) of compound 436a. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 599 Appendix 5 – Spectra Relevant to Chapter 3 600 Figure A5.163. Infrared spectrum (Thin Film, NaCl) of compound 436a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.164. 13C NMR (100 MHz, CDCl3) of compound 436a. 0 10 Br OH H Me N 9 8 436b (minor dias.) N 6 5 ppm 4 3 2 Figure A5.165. 1H NMR (400 MHz, CDCl3) of compound 436b. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 601 Appendix 5 – Spectra Relevant to Chapter 3 602 Figure A5.166. Infrared spectrum (Thin Film, NaCl) of compound 436b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.167. 13C NMR (100 MHz, CDCl3) of compound 436b. 0 10 MeO N 9 440 Me OH 8 6 5 ppm 4 3 2 Figure A5.168. 1H NMR (400 MHz, CDCl3) of compound 440. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 603 Appendix 5 – Spectra Relevant to Chapter 3 604 65 60 55 50 % Transmittance 45 40 35 30 25 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.169. Infrared spectrum (Thin Film, NaCl) of compound 440. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.170. 13C NMR (100 MHz, CDCl3) of compound 440. 0 10 MeO MeO Ph N N 9 442 H H H O H 8 6 5 ppm 4 3 2 Figure A5.171. 1H NMR (400 MHz, CD2Cl2) of compound 442. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 605 Appendix 5 – Spectra Relevant to Chapter 3 606 37 36 35 34 33 32 % Transmittance 31 30 29 28 27 26 25 24 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.172. Infrared spectrum (Thin Film, NaCl) of compound 442. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.173. 13C NMR (100 MHz, CD2Cl2) of compound 442. 0 10 O H 9 H H Br Me 8 444 N Me 6 5 ppm 4 3 2 Figure A5.174. 1H NMR (400 MHz, CDCl3) of compound 444. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 607 Appendix 5 – Spectra Relevant to Chapter 3 608 Figure A5.175. Infrared spectrum (Thin Film, NaCl) of compound 444. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.176. 13C NMR (100 MHz, CDCl3) of compound 444. 0 O 10 H Me 9 H OH 8 445a (major dias.) H H N 7 6 5 ppm 4 3 2 Figure A5.177. 1H NMR (400 MHz, CDCl3) of compound 445a. Me N 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 609 Appendix 5 – Spectra Relevant to Chapter 3 610 Figure A5.178. Infrared spectrum (Thin Film, NaCl) of compound 445a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.179. 13C NMR (100 MHz, CDCl3) of compound 445a. 0 O 10 H Me 9 H OH 8 445b (minor dias.) H H N 7 6 5 ppm 4 3 2 Figure A5.180. 1H NMR (400 MHz, CDCl3) of compound 445b. Me N 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 611 Appendix 5 – Spectra Relevant to Chapter 3 612 Figure A5.181. Infrared spectrum (Thin Film, NaCl) of compound 445b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.182. 13C NMR (100 MHz, CDCl3) of compound 445b. 0 10 Ph 9 431 N Me 8 6 5 ppm 4 3 2 Figure A5.183. 1H NMR (400 MHz, CDCl3) of compound 431. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 613 Appendix 5 – Spectra Relevant to Chapter 3 614 65 60 55 50 45 % Transmittance 40 35 30 25 20 15 10 5 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.184. Infrared spectrum (Thin Film, NaCl) of compound 431. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.185. 13C NMR (100 MHz, CDCl3) of compound 431. 0 10 Ph 9 432 N Me 8 6 5 ppm 4 3 2 Figure A5.186. 1H NMR (400 MHz, CDCl3) of compound 432. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 615 Appendix 5 – Spectra Relevant to Chapter 3 616 75 70 65 60 55 % Transmittance 50 45 40 35 30 25 20 15 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.187. Infrared spectrum (Thin Film, NaCl) of compound 432. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A5.188. 13C NMR (100 MHz, CDCl3) of compound 432. 0 10 Me O H N N 9 O O OH N N N 8 7 N Me 6 5 ppm 4 3 2 Figure A5.189. 1H NMR (400 MHz, CDCl3) of compound 434. 434 Br 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 617 Appendix 5 – Spectra Relevant to Chapter 3 618 65 60 55 50 45 % Transmittance 40 35 30 25 20 15 10 5 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.190. Infrared spectrum (Thin Film, NaCl) of compound 434. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.191. C NMR (100 MHz, CDCl3) of compound 434. 0 10 9 MeO2C Me Boc N N 8 OH H 6 Me N 5 ppm 4 3 2 Figure A5.192. 1H NMR (400 MHz, CDCl3) of compound 438. 7 438 N 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 619 Appendix 5 – Spectra Relevant to Chapter 3 620 115 110 105 100 % Transmittance 95 90 85 80 75 70 65 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.193. Infrared spectrum (Thin Film, NaCl) of compound 438. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.194. C NMR (100 MHz, CDCl3) of compound 438. 0 10 Br 9 446 N Me 8 6 5 ppm 4 3 2 Figure A5.195. 1H NMR (400 MHz, CDCl3) of compound 446. 7 1 0 Appendix 5 – Spectra Relevant to Chapter 3 621 Appendix 5 – Spectra Relevant to Chapter 3 622 48 46 44 42 40 38 36 34 % Transmittance 32 30 28 26 24 22 20 18 16 14 12 10 8 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.196. Infrared spectrum (Thin Film, NaCl) of compound 446. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.197. C NMR (100 MHz, CDCl3) of compound 446. 0 10 9 Br F3C O N 8 447 Me 6 5 ppm 4 3 2 Figure A5.198. 1H NMR (400 MHz, CDCl3) of compound 447. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 623 Appendix 5 – Spectra Relevant to Chapter 3 624 85 80 75 70 65 60 % Transmittance 55 50 45 40 35 30 25 20 15 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.199. Infrared spectrum (Thin Film, NaCl) of compound 447. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.200. C NMR (100 MHz, CDCl3) of compound 447. 0 Appendix 5 – Spectra Relevant to Chapter 3 20 0 -20 -40 -60 625 -80 ppm -100 -120 -140 -160 -180 Figure A5.201. 19F NMR (282 MHz, CDCl3) of compound 447. 10 Br 9 Me N 449 Me 8 6 5 ppm 4 3 2 Figure A5.202. 1H NMR (400 MHz, CDCl3) of compound 449. 7 1 0 -1 Appendix 5 – Spectra Relevant to Chapter 3 626 Appendix 5 – Spectra Relevant to Chapter 3 627 120 115 110 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 50 45 40 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A5.203. Infrared spectrum (Thin Film, NaCl) of compound 449. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A5.204. C NMR (100 MHz, CDCl3) of compound 449. 0 APPENDIX 6 X-Ray Crystallography Reports Relevant to Chapter 3: Development of a Non-Directed Petasis-Type Reaction by an Aromaticity-Disrupting Strategy Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 A6.1 629 GENERAL EXPERIMENTAL X-Ray crystallographic analysis was obtained from the Caltech X-Ray Crystallography Facility using a Bruker AXS D8 VENTURE KAPPA diffractometer. A6.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF COMPOUND 436a • TFA (V22396) An X-Ray quality crystal of the TFA salt of vincamine adduct 436a was grown by dissolving the material in minimal acetone at 23 °C and carefully layering with pentane. Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IμS micro-source for the structures of compounds V21281, V22396, and V22221. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL2017 or SHELXL-20192 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound V22396 (CCDC 2218937) crystallizes in the monoclinic space group C2 with one molecule in the asymmetric unit along with one molecule of trifluoroacetate. The coordinates for the hydrogen atoms bound to O1 and N2 were located in the difference Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 630 Fourier synthesis and refined semi-freely with the help of a restraint on the O-H or N-H distance (0.84(4) Å or 0.88(4) Å, respectively). Figure A6.2.1. X-Ray Coordinate of Compound 436a•TFA (V22396) . Table A6.2.1. Crystal data and structure refinement for V22396. Identification code V22396 Empirical formula C30 H30 Br F3 N2 O3 Formula weight 603.47 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic 631 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Space group C2 Unit cell dimensions a = 17.973(5) Å a= 90°. b = 6.9465(14) Å b= 100.550(17)°. c = 22.039(5) Å g = 90°. Volume 2705.2(11) Å3 Z 4 Density (calculated) 1.482 Mg/m3 Absorption coefficient 1.575 mm-1 F(000) 1240 Crystal size 0.400 x 0.100 x 0.100 mm3 Theta range for data collection 2.305 to 36.334°. Index ranges -28<=h<=29, -11<=k<=11, -36<=l<=36 Reflections collected 48745 Independent reflections 13109 [R(int) = 0.0564] Completeness to theta = 25.242° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7471 and 0.5648 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 13109 / 3 / 359 Goodness-of-fit on F2 1.023 Final R indices [I>2sigma(I)] R1 = 0.0431, wR2 = 0.0872 R indices (all data) R1 = 0.0688, wR2 = 0.0963 Absolute structure parameter -0.001(4) Extinction coefficient n/a Largest diff. peak and hole 0.426 and -0.368 e.Å-3 632 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22396. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ Atom x y z U(eq) ________________________________________________________________________ Br(1) 7564(1) 5806(1) 3649(1) 26(1) C(1) 7167(1) 5765(5) 4387(1) 16(1) C(2) 6406(1) 5369(4) 4360(1) 19(1) C(3) 6116(1) 5397(4) 4902(1) 20(1) C(4) 6584(1) 5805(4) 5467(1) 15(1) C(7) 6313(1) 5815(5) 6039(1) 18(1) C(8) 6144(1) 5782(5) 6544(1) 16(1) C(9) 6020(1) 5467(3) 7179(1) 14(1) C(26) 6627(1) 3968(4) 7474(1) 16(1) O(1) 7364(1) 4709(3) 7500(1) 22(1) C(10) 6091(1) 7382(3) 7539(1) 15(1) C(11) 5711(1) 7559(3) 8115(1) 14(1) C(12) 6012(1) 6151(3) 8640(1) 15(1) C(27) 5805(1) 9681(4) 8337(1) 18(1) C(28) 6616(2) 10232(4) 8627(1) 22(1) C(13) 5559(1) 6307(4) 9163(1) 19(1) C(14) 4741(1) 5761(5) 8923(1) 19(1) N(2) 4402(1) 6999(3) 8382(1) 16(1) C(15) 3599(1) 6397(4) 8113(1) 19(1) C(16) 3551(1) 4354(4) 7860(1) 18(1) C(17) 4167(1) 4047(4) 7494(1) 16(1) C(18) 4282(1) 2539(3) 7080(1) 15(1) 633 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(19) 3858(1) 913(5) 6849(1) 19(1) C(20) 4126(2) -236(4) 6426(1) 22(1) C(21) 4810(2) 185(4) 6229(1) 22(1) C(22) 5241(1) 1774(4) 6450(1) 19(1) C(23) 4974(1) 2944(3) 6880(1) 15(1) N(1) 5264(1) 4640(3) 7164(1) 14(1) C(24) 4760(1) 5281(3) 7530(1) 14(1) C(25) 4869(1) 7125(3) 7878(1) 14(1) C(5) 7352(1) 6159(3) 5478(1) 16(1) C(6) 7646(1) 6136(3) 4939(1) 16(1) O(1S) 7876(1) 5308(4) 8708(1) 34(1) O(2S) 9142(1) 5215(3) 8985(1) 31(1) C(1S) 8486(1) 5611(4) 9049(1) 20(1) C(2S) 8422(2) 6759(4) 9641(1) 23(1) F(3S) 7801(1) 6342(3) 9857(1) 38(1) F(4S) 9007(1) 6510(3) 10097(1) 42(1) F(5S) 8383(1) 8656(3) 9512(1) 38(1) ________________________________________________________________________ 634 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.2.3. Bond lengths [Å] and angles [°] for V22396. ________________________________________________________________________ Bond Length (Å) Bond Length (Å) ________________________________________________________________________ Br(1)-C(1) 1.8924(19) C(12)-H(12A) 0.9900 C(1)-C(6) 1.380(3) C(12)-H(12B) 0.9900 C(1)-C(2) 1.386(3) C(27)-C(28) 1.529(3) C(2)-C(3) 1.388(3) C(27)-H(27A) 0.9900 C(2)-H(2) 0.9500 C(27)-H(27B) 0.9900 C(3)-C(4) 1.397(3) C(28)-H(28A) 0.9800 C(3)-H(3) 0.9500 C(28)-H(28B) 0.9800 C(4)-C(5) 1.398(3) C(28)-H(28C) 0.9800 C(4)-C(7) 1.435(3) C(13)-C(14) 1.516(3) C(7)-C(8) 1.204(3) C(13)-H(13A) 0.9900 C(8)-C(9) 1.475(3) C(13)-H(13B) 0.9900 C(9)-N(1) 1.469(3) C(14)-N(2) 1.505(3) C(9)-C(10) 1.541(3) C(14)-H(14A) 0.9900 C(9)-C(26) 1.561(3) C(14)-H(14B) 0.9900 C(26)-O(1) 1.413(3) N(2)-C(25) 1.513(3) C(26)-H(26A) 0.9900 N(2)-C(15) 1.516(3) C(26)-H(26B) 0.9900 N(2)-H(2N) 0.90(2) O(1)-H(1O) 0.81(2) C(15)-C(16) 1.521(4) C(10)-C(11) 1.554(3) C(15)-H(15A) 0.9900 C(10)-H(10A) 0.9900 C(15)-H(15B) 0.9900 C(10)-H(10B) 0.9900 C(16)-C(17) 1.500(3) C(11)-C(12) 1.536(3) C(16)-H(16A) 0.9900 C(11)-C(25) 1.538(3) C(16)-H(16B) 0.9900 C(11)-C(27) 1.552(3) C(17)-C(24) 1.359(3) C(12)-C(13) 1.531(3) C(17)-C(18) 1.429(3) 635 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(18)-C(19) 1.404(4) C(2)-C(3)-H(3) 119.7 C(18)-C(23) 1.422(3) C(4)-C(3)-H(3) 119.7 C(19)-C(20) 1.379(4) C(3)-C(4)-C(5) 118.90(18) C(19)-H(19) 0.9500 C(3)-C(4)-C(7) 122.54(19) C(20)-C(21) 1.407(4) C(5)-C(4)-C(7) 118.52(19) C(20)-H(20) 0.9500 C(8)-C(7)-C(4) 174.6(2) C(21)-C(22) 1.385(4) C(7)-C(8)-C(9) 170.7(3) C(21)-H(21) 0.9500 N(1)-C(9)-C(8) 109.70(18) C(22)-C(23) 1.398(3) N(1)-C(9)-C(10) 109.79(17) C(22)-H(22) 0.9500 C(8)-C(9)-C(10) 110.3(2) C(23)-N(1) 1.391(3) N(1)-C(9)-C(26) 108.74(18) N(1)-C(24) 1.391(3) C(8)-C(9)-C(26) 106.15(18) C(24)-C(25) 1.487(3) C(10)-C(9)-C(26) 112.08(19) C(25)-H(25) 1.0000 O(1)-C(26)-C(9) 110.6(2) C(5)-C(6) 1.386(3) O(1)-C(26)-H(26A) 109.5 C(5)-H(5) 0.9500 C(9)-C(26)-H(26A) 109.5 C(6)-H(6) 0.9500 O(1)-C(26)-H(26B) 109.5 O(1S)-C(1S) 1.229(3) C(9)-C(26)-H(26B) 109.5 O(2S)-C(1S) 1.245(3) H(26A)-C(26)-H(26B) 108.1 C(1S)-C(2S) 1.550(4) C(26)-O(1)-H(1O) 109(3) C(2S)-F(3S) 1.324(3) C(9)-C(10)-C(11) 118.74(19) C(2S)-F(4S) 1.326(3) C(9)-C(10)-H(10A) 107.6 C(2S)-F(5S) 1.347(4) C(11)-C(10)-H(10A) 107.6 C(6)-C(1)-C(2) 121.72(19) C(9)-C(10)-H(10B) 107.6 C(6)-C(1)-Br(1) 118.84(16) C(11)-C(10)-H(10B) 107.6 C(2)-C(1)-Br(1) 119.44(16) H(10A)-C(10)-H(10B) 107.1 C(1)-C(2)-C(3) 118.9(2) C(12)-C(11)-C(25) 108.70(18) C(1)-C(2)-H(2) 120.5 C(12)-C(11)-C(27) 111.40(19) C(3)-C(2)-H(2) 120.5 C(25)-C(11)-C(27) 109.71(18) C(2)-C(3)-C(4) 120.6(2) C(12)-C(11)-C(10) 114.74(18) 636 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(25)-C(11)-C(10) 104.96(18) C(13)-C(14)-H(14B) 109.4 C(27)-C(11)-C(10) 107.08(18) H(14A)-C(14)-H(14B) 108.0 C(13)-C(12)-C(11) 111.01(18) C(14)-N(2)-C(25) 114.63(17) C(13)-C(12)-H(12A) 109.4 C(14)-N(2)-C(15) 111.69(19) C(11)-C(12)-H(12A) 109.4 C(25)-N(2)-C(15) 110.20(18) C(13)-C(12)-H(12B) 109.4 C(14)-N(2)-H(2N) 106(2) C(11)-C(12)-H(12B) 109.4 C(25)-N(2)-H(2N) 108(2) H(12A)-C(12)-H(12B) 108.0 C(15)-N(2)-H(2N) 106(2) C(28)-C(27)-C(11) 114.2(2) N(2)-C(15)-C(16) 112.76(19) C(28)-C(27)-H(27A) 108.7 N(2)-C(15)-H(15A) 109.0 C(11)-C(27)-H(27A) 108.7 C(16)-C(15)-H(15A) 109.0 C(28)-C(27)-H(27B) 108.7 N(2)-C(15)-H(15B) 109.0 C(11)-C(27)-H(27B) 108.7 C(16)-C(15)-H(15B) 109.0 H(27A)-C(27)-H(27B) 107.6 H(15A)-C(15)-H(15B) 107.8 C(27)-C(28)-H(28A) 109.5 C(17)-C(16)-C(15) 109.4(2) C(27)-C(28)-H(28B) 109.5 C(17)-C(16)-H(16A) 109.8 H(28A)-C(28)-H(28B) 109.5 C(15)-C(16)-H(16A) 109.8 C(27)-C(28)-H(28C) 109.5 C(17)-C(16)-H(16B) 109.8 H(28A)-C(28)-H(28C) 109.5 C(15)-C(16)-H(16B) 109.8 H(28B)-C(28)-H(28C) 109.5 H(16A)-C(16)-H(16B) 108.2 C(14)-C(13)-C(12) 109.60(19) C(24)-C(17)-C(18) 107.2(2) C(14)-C(13)-H(13A) 109.8 C(24)-C(17)-C(16) 121.9(2) C(12)-C(13)-H(13A) 109.8 C(18)-C(17)-C(16) 130.9(2) C(14)-C(13)-H(13B) 109.8 C(19)-C(18)-C(23) 119.6(2) C(12)-C(13)-H(13B) 109.8 C(19)-C(18)-C(17) 133.6(2) H(13A)-C(13)-H(13B) 108.2 C(23)-C(18)-C(17) 106.9(2) N(2)-C(14)-C(13) 111.0(2) C(20)-C(19)-C(18) 118.5(2) N(2)-C(14)-H(14A) 109.4 C(20)-C(19)-H(19) 120.7 C(13)-C(14)-H(14A) 109.4 C(18)-C(19)-H(19) 120.7 N(2)-C(14)-H(14B) 109.4 C(19)-C(20)-C(21) 121.4(2) 637 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(19)-C(20)-H(20) 119.3 N(2)-C(25)-C(11) 113.85(18) C(21)-C(20)-H(20) 119.3 C(24)-C(25)-H(25) 108.0 C(22)-C(21)-C(20) 121.4(2) N(2)-C(25)-H(25) 108.0 C(22)-C(21)-H(21) 119.3 C(11)-C(25)-H(25) 108.0 C(20)-C(21)-H(21) 119.3 C(6)-C(5)-C(4) 120.8(2) C(21)-C(22)-C(23) 117.5(2) C(6)-C(5)-H(5) 119.6 C(21)-C(22)-H(22) 121.2 C(4)-C(5)-H(5) 119.6 C(23)-C(22)-H(22) 121.2 C(1)-C(6)-C(5) 119.0(2) N(1)-C(23)-C(22) 130.6(2) C(1)-C(6)-H(6) 120.5 N(1)-C(23)-C(18) 107.8(2) C(5)-C(6)-H(6) 120.5 C(22)-C(23)-C(18) 121.6(2) O(1S)-C(1S)-O(2S) 130.5(2) C(23)-N(1)-C(24) 107.57(18) O(1S)-C(1S)-C(2S) 114.2(2) C(23)-N(1)-C(9) 127.62(19) O(2S)-C(1S)-C(2S) 115.3(2) C(24)-N(1)-C(9) 123.98(19) F(3S)-C(2S)-F(4S) 107.6(2) C(17)-C(24)-N(1) 110.6(2) F(3S)-C(2S)-F(5S) 106.0(2) C(17)-C(24)-C(25) 126.9(2) F(4S)-C(2S)-F(5S) 106.9(2) N(1)-C(24)-C(25) 122.40(19) F(3S)-C(2S)-C(1S) 112.8(2) C(24)-C(25)-N(2) 106.90(18) F(4S)-C(2S)-C(1S) 113.6(2) C(24)-C(25)-C(11) 111.91(18) F(5S)-C(2S)-C(1S) 109.6(2) ________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: 638 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.2.4. Anisotropic displacement parameters (Å2x 103) for V22396. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ________________________________________________________________________ U11 U22 U33 U23 U13 U12 ________________________________________________________________________ Br(1) 29(1) 35(1) 16(1) 0(1) 12(1) -6(1) C(1) 19(1) 16(1) 13(1) 2(1) 6(1) 1(1) C(2) 18(1) 25(1) 13(1) 1(1) 2(1) -2(1) C(3) 14(1) 29(2) 17(1) 1(1) 5(1) -2(1) C(4) 19(1) 15(1) 13(1) 2(1) 6(1) 1(1) C(7) 20(1) 19(1) 16(1) 1(1) 7(1) 2(1) C(8) 16(1) 16(1) 15(1) -1(1) 5(1) 1(1) C(9) 12(1) 17(1) 15(1) 0(1) 5(1) 0(1) C(26) 15(1) 19(1) 15(1) 0(1) 4(1) 3(1) O(1) 12(1) 33(1) 21(1) -3(1) 3(1) 0(1) C(10) 16(1) 15(1) 15(1) 0(1) 6(1) -1(1) C(11) 14(1) 14(1) 14(1) 2(1) 4(1) 1(1) C(12) 14(1) 17(1) 13(1) 2(1) 2(1) 2(1) C(27) 20(1) 16(1) 17(1) -1(1) 4(1) 1(1) C(28) 25(1) 20(1) 21(1) -3(1) 2(1) -3(1) C(13) 19(1) 24(1) 14(1) 3(1) 3(1) 3(1) C(14) 20(1) 25(1) 14(1) 4(1) 7(1) -1(1) N(2) 15(1) 18(1) 15(1) -1(1) 5(1) 2(1) C(15) 12(1) 26(1) 20(1) 0(1) 5(1) 3(1) C(16) 13(1) 26(1) 17(1) 1(1) 4(1) 0(1) C(17) 14(1) 19(1) 14(1) 3(1) 3(1) 1(1) C(18) 13(1) 15(1) 15(1) 3(1) 1(1) 1(1) 639 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(19) 16(1) 20(1) 20(1) 2(1) -1(1) 0(1) C(20) 21(1) 20(1) 22(1) -4(1) -2(1) -1(1) C(21) 23(1) 20(1) 21(1) -5(1) 1(1) 3(1) C(22) 18(1) 22(1) 17(1) -4(1) 3(1) 2(1) C(23) 14(1) 17(1) 14(1) 1(1) 2(1) 1(1) N(1) 13(1) 15(1) 15(1) -1(1) 4(1) 1(1) C(24) 13(1) 16(1) 13(1) 1(1) 4(1) 2(1) C(25) 15(1) 14(1) 12(1) 1(1) 5(1) 2(1) C(5) 17(1) 16(1) 13(1) -1(1) 2(1) -1(1) C(6) 16(1) 16(1) 17(1) 1(1) 5(1) -2(1) O(1S) 21(1) 54(2) 25(1) -13(1) 0(1) 2(1) O(2S) 19(1) 38(1) 36(1) -15(1) 7(1) 0(1) C(1S) 22(1) 21(1) 19(1) -3(1) 5(1) 0(1) C(2S) 22(1) 30(1) 19(1) -3(1) 5(1) -2(1) F(3S) 39(1) 53(1) 28(1) -7(1) 19(1) -8(1) F(4S) 38(1) 64(1) 20(1) -10(1) -5(1) 8(1) F(5S) 48(1) 26(1) 40(1) -8(1) 11(1) -2(1) ________________________________________________________________________ 640 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22396. ________________________________________________________________________ Atom x y z U(eq) ________________________________________________________________________ H(2) 6088 5083 3977 22 H(3) 5595 5136 4890 24 H(26A) 6551 3648 7896 19 H(26B) 6567 2770 7226 19 H(1O) 7540(20) 4980(50) 7854(11) 33 H(10A) 5881 8411 7246 18 H(10B) 6637 7656 7672 18 H(12A) 5978 4819 8478 18 H(12B) 6551 6436 8804 18 H(27A) 5630 10537 7980 21 H(27B) 5474 9907 8643 21 H(28A) 6791 9410 8986 33 H(28B) 6629 11582 8758 33 H(28C) 6946 10058 8324 33 H(13A) 5777 5437 9505 23 H(13B) 5585 7641 9323 23 H(14A) 4714 4392 8795 23 H(14B) 4445 5915 9257 23 H(2N) 4371(18) 8190(40) 8535(15) 24 H(15A) 3387 7296 7777 22 H(15B) 3285 6493 8437 22 H(16A) 3606 3421 8205 22 641 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 H(16B) 3051 4145 7593 22 H(19) 3398 611 6982 23 H(20) 3843 -1335 6264 26 H(21) 4979 -637 5938 26 H(22) 5702 2059 6315 23 H(25) 4657 8184 7590 16 H(5) 7677 6418 5860 19 H(6) 8169 6372 4949 19 ________________________________________________________________________ Table A6.2.6. Torsion angles [°] for V22396. ________________________________________________________________ C(6)-C(1)-C(2)-C(3) 1.7(4) Br(1)-C(1)-C(2)-C(3) -178.2(2) C(1)-C(2)-C(3)-C(4) -0.4(4) C(2)-C(3)-C(4)-C(5) -0.9(4) C(2)-C(3)-C(4)-C(7) -178.8(3) N(1)-C(9)-C(26)-O(1) -179.79(18) C(8)-C(9)-C(26)-O(1) 62.3(2) C(10)-C(9)-C(26)-O(1) -58.2(2) N(1)-C(9)-C(10)-C(11) 37.3(3) C(8)-C(9)-C(10)-C(11) 158.31(19) C(26)-C(9)-C(10)-C(11) -83.6(2) C(9)-C(10)-C(11)-C(12) 61.6(3) C(9)-C(10)-C(11)-C(25) -57.7(3) C(9)-C(10)-C(11)-C(27) -174.3(2) C(25)-C(11)-C(12)-C(13) -57.8(2) C(27)-C(11)-C(12)-C(13) 63.2(2) Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(10)-C(11)-C(12)-C(13) -174.96(19) C(12)-C(11)-C(27)-C(28) 55.4(3) C(25)-C(11)-C(27)-C(28) 175.77(19) C(10)-C(11)-C(27)-C(28) -70.8(2) C(11)-C(12)-C(13)-C(14) 62.3(3) C(12)-C(13)-C(14)-N(2) -56.8(3) C(13)-C(14)-N(2)-C(25) 50.5(3) C(13)-C(14)-N(2)-C(15) 176.7(2) C(14)-N(2)-C(15)-C(16) -62.3(3) C(25)-N(2)-C(15)-C(16) 66.3(2) N(2)-C(15)-C(16)-C(17) -44.2(3) C(15)-C(16)-C(17)-C(24) 14.4(3) C(15)-C(16)-C(17)-C(18) -167.3(2) C(24)-C(17)-C(18)-C(19) -177.8(3) C(16)-C(17)-C(18)-C(19) 3.7(5) C(24)-C(17)-C(18)-C(23) 0.5(3) C(16)-C(17)-C(18)-C(23) -178.0(2) C(23)-C(18)-C(19)-C(20) -0.8(4) C(17)-C(18)-C(19)-C(20) 177.4(3) C(18)-C(19)-C(20)-C(21) 0.4(4) C(19)-C(20)-C(21)-C(22) -0.2(4) C(20)-C(21)-C(22)-C(23) 0.2(4) C(21)-C(22)-C(23)-N(1) -177.6(2) C(21)-C(22)-C(23)-C(18) -0.6(4) C(19)-C(18)-C(23)-N(1) 178.5(2) C(17)-C(18)-C(23)-N(1) -0.1(3) C(19)-C(18)-C(23)-C(22) 0.9(4) C(17)-C(18)-C(23)-C(22) -177.7(2) C(22)-C(23)-N(1)-C(24) 177.0(2) C(18)-C(23)-N(1)-C(24) -0.4(2) 642 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(22)-C(23)-N(1)-C(9) -13.3(4) C(18)-C(23)-N(1)-C(9) 169.4(2) C(8)-C(9)-N(1)-C(23) 57.7(3) C(10)-C(9)-N(1)-C(23) 179.1(2) C(26)-C(9)-N(1)-C(23) -58.0(3) C(8)-C(9)-N(1)-C(24) -134.1(2) C(10)-C(9)-N(1)-C(24) -12.7(3) C(26)-C(9)-N(1)-C(24) 110.3(2) C(18)-C(17)-C(24)-N(1) -0.7(3) C(16)-C(17)-C(24)-N(1) 177.9(2) C(18)-C(17)-C(24)-C(25) 176.4(2) C(16)-C(17)-C(24)-C(25) -4.9(4) C(23)-N(1)-C(24)-C(17) 0.7(3) C(9)-N(1)-C(24)-C(17) -169.5(2) C(23)-N(1)-C(24)-C(25) -176.6(2) C(9)-N(1)-C(24)-C(25) 13.2(3) C(17)-C(24)-C(25)-N(2) 23.2(3) N(1)-C(24)-C(25)-N(2) -160.0(2) C(17)-C(24)-C(25)-C(11) 148.5(2) N(1)-C(24)-C(25)-C(11) -34.7(3) C(14)-N(2)-C(25)-C(24) 76.1(2) C(15)-N(2)-C(25)-C(24) -51.0(2) C(14)-N(2)-C(25)-C(11) -48.0(3) C(15)-N(2)-C(25)-C(11) -175.06(19) C(12)-C(11)-C(25)-C(24) -71.1(2) C(27)-C(11)-C(25)-C(24) 166.91(18) C(10)-C(11)-C(25)-C(24) 52.2(2) C(12)-C(11)-C(25)-N(2) 50.3(2) C(27)-C(11)-C(25)-N(2) -71.7(2) C(10)-C(11)-C(25)-N(2) 173.51(18) 643 644 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(3)-C(4)-C(5)-C(6) 1.0(4) C(7)-C(4)-C(5)-C(6) 179.0(3) C(2)-C(1)-C(6)-C(5) -1.6(4) Br(1)-C(1)-C(6)-C(5) 178.27(18) C(4)-C(5)-C(6)-C(1) 0.3(4) O(1S)-C(1S)-C(2S)-F(3S) 34.7(4) O(2S)-C(1S)-C(2S)-F(3S) -148.0(3) O(1S)-C(1S)-C(2S)-F(4S) 157.5(3) O(2S)-C(1S)-C(2S)-F(4S) -25.2(4) O(1S)-C(1S)-C(2S)-F(5S) -83.0(3) O(2S)-C(1S)-C(2S)-F(5S) 94.3(3) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A6.2.7. Hydrogen bonds for V22396 [Å and °]. ________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ________________________________________________________________________ C(26)-H(26B)...Br(1)#1 0.99 3.02 3.792(2) 135.7 O(1)-H(1O)...O(1S) 0.81(2) 1.88(2) 2.685(3) 172(4) C(14)-H(14B)...F(5S)#2 0.99 2.61 3.307(3) 127.5 N(2)-H(2N)...O(2S)#3 0.90(2) 1.81(2) 2.683(3) 163(3) C(15)-H(15A)...O(1)#3 0.99 2.48 3.309(3) 140.9 C(16)-H(16B)...Br(1)#4 0.99 2.99 3.696(3) 129.1 ________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+3/2,y-1/2,-z+1 #4 -x+1,y,-z+1 #2 x-1/2,y-1/2,z #3 x-1/2,y+1/2,z Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 A6.3 645 X-RAY CRYSTAL STRUCTURE ANALYSIS OF COMPOUND 442 • HCl (V22221) The HCl salt of brucine adduct 442 was crystallized by slow evaporation from acetone-d6 at 23 °C to provide crystals suitable for X-ray analysis. Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IμS micro-source for the structures of compounds V21281, V22396, and V22221. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL2017 or SHELXL-20192 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound V22221 (CCDC 2216879) crystallizes in the orthorhombic space group P21212 with one molecule in the asymmetric unit along with a chloride ion, half an acetone, and half a water. The highest residual density are located in the bonds between atoms. The coordinates for the hydrogen atoms bound to N1 and O1W were located in the difference Fourier synthesis and refined semi-freely with the help of a restraint on the N-H and O-H distances (0.91(4) and 0.84(4) Å, respectively). 646 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Figure A6.3.1. X-Ray Coordinate of Brucine Adduct 442 • HCl (V22221). Table A6.3.1. Crystal data and structure refinement for V22221. Identification code V22221 Empirical formula C32.50 H37 Cl N2 O4 Formula weight 555.09 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P21212 Unit cell dimensions a = 15.8289(11) Å a= 90°. b = 16.5890(13) Å b= 90°. c = 10.4502(10) Å g = 90°. Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Volume 2744.1(4) Å3 Z 4 Density (calculated) 1.344 Mg/m3 Absorption coefficient 1.567 mm-1 F(000) 1180 Crystal size 0.150 x 0.150 x 0.100 mm3 Theta range for data collection 3.860 to 74.522°. Index ranges -19<=h<=19, -20<=k<=20, -13<=l<=11 Reflections collected 44307 Independent reflections 5626 [R(int) = 0.0449] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.6360 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5626 / 2 / 367 Goodness-of-fit on F2 1.051 Final R indices [I>2sigma(I)] R1 = 0.0293, wR2 = 0.0792 R indices (all data) R1 = 0.0309, wR2 = 0.0799 Absolute structure parameter 0.004(3) Extinction coefficient n/a Largest diff. peak and hole 0.279 and -0.150 e.Å-3 647 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 648 Table A6.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for V22221. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. __________________________________________________________________ Atom x y z U(eq) __________________________________________________________________ Cl(1) 3800(1) -672(1) 7944(1) 27(1) N(1) 3361(1) 1098(1) 7792(2) 22(1) C(1) 2674(1) 1155(1) 8796(2) 26(1) C(2) 2031(1) 1780(1) 8436(2) 24(1) C(3) 1834(1) 2384(1) 9216(2) 27(1) C(4) 1193(1) 3030(1) 8898(2) 29(1) O(1) 1434(1) 3532(1) 7844(1) 26(1) C(5) 1244(1) 3188(1) 6624(2) 23(1) C(6) 1393(1) 3826(1) 5603(2) 25(1) C(7) 2332(1) 4025(1) 5361(2) 24(1) C(22) 2676(1) 4627(1) 6257(2) 25(1) C(23) 3008(1) 5137(1) 6897(2) 26(1) C(31) 3486(1) 5717(1) 7624(2) 26(1) C(32) 4006(2) 5461(1) 8620(2) 34(1) C(33) 4522(2) 6002(2) 9259(2) 35(1) C(34) 4540(1) 6803(1) 8902(2) 31(1) C(35) 4007(1) 7071(1) 7941(2) 29(1) C(36) 3475(1) 6540(1) 7313(2) 25(1) N(2) 2885(1) 3312(1) 5353(2) 21(1) C(8) 2721(1) 2692(1) 6334(2) 19(1) C(9) 1786(1) 2448(1) 6304(2) 20(1) C(10) 1649(1) 1688(1) 7111(2) 22(1) C(11) 2085(1) 997(1) 6402(2) 22(1) C(12) 3033(1) 1154(1) 6413(2) 20(1) C(13) 4041(1) 1732(1) 7952(2) 23(1) Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 649 C(14) 4189(1) 2068(1) 6610(2) 22(1) C(15) 3322(1) 1993(1) 5948(2) 18(1) C(16) 3375(1) 2120(1) 4516(2) 18(1) C(17) 3699(1) 1624(1) 3557(2) 20(1) C(18) 3736(1) 1917(1) 2309(2) 21(1) O(2) 4006(1) 1490(1) 1261(1) 26(1) C(24) 4271(2) 683(1) 1482(2) 34(1) C(19) 3470(1) 2710(1) 2039(2) 21(1) O(3) 3543(1) 2935(1) 783(1) 26(1) C(25) 3248(2) 3722(1) 454(2) 31(1) C(20) 3153(1) 3209(1) 2991(2) 21(1) C(21) 3111(1) 2901(1) 4233(2) 19(1) O(1W) 5000 0 5750(2) 38(1) O(1S) 5000 5000 2892(4) 78(1) C(1S) 5000 5000 4038(4) 47(1) C(2S) 4862(2) 4241(2) 4798(3) 51(1) ________________________________________________________________________ 650 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.3.3. Bond lengths [Å] and angles [°] for V22221. ________________________________________________________________________ Bond Length (Å) Bond Length (Å) ________________________________________________________________________ N(1)-C(13) N(1)-C(1) N(1)-C(12) N(1)-H(1N) C(1)-C(2) C(1)-H(1A) C(1)-H(1B) C(2)-C(3) C(2)-C(10) C(3)-C(4) C(3)-H(3) 1.513(2) 1.514(3) 1.535(2) 0.90(2) 1.502(3) 0.9900 0.9900 1.329(3) 1.519(3) 1.512(3) 0.9500 C(32)-H(32) C(33)-C(34) C(33)-H(33) C(34)-C(35) C(34)-H(34) C(35)-C(36) C(35)-H(35) C(36)-H(36) N(2)-C(21) N(2)-C(8) C(8)-C(9) 0.9500 1.381(4) 0.9500 1.385(3) 0.9500 1.385(3) 0.9500 0.9500 1.400(2) 1.474(2) 1.535(2) C(4)-O(1) C(4)-H(4A) C(4)-H(4B) O(1)-C(5) C(5)-C(6) C(5)-C(9) C(5)-H(5) C(6)-C(7) C(6)-H(6A) C(6)-H(6B) C(7)-N(2) C(7)-C(22) C(7)-H(7) C(22)-C(23) C(23)-C(31) C(31)-C(32) C(31)-C(36) C(32)-C(33) 1.433(3) 0.9900 0.9900 1.429(2) 1.522(3) 1.534(3) 1.0000 1.544(3) 0.9900 0.9900 1.472(2) 1.473(3) 1.0000 1.200(3) 1.441(3) 1.394(3) 1.403(3) 1.385(4) C(8)-C(15) C(8)-H(8) C(9)-C(10) C(9)-H(9) C(10)-C(11) C(10)-H(10) C(11)-C(12) C(11)-H(11A) C(11)-H(11B) C(12)-C(15) C(12)-H(12) C(13)-C(14) C(13)-H(13A) C(13)-H(13B) C(14)-C(15) C(14)-H(14A) C(14)-H(14B) C(15)-C(16) 1.554(2) 1.0000 1.532(3) 1.0000 1.529(3) 1.0000 1.522(3) 0.9900 0.9900 1.545(2) 1.0000 1.528(3) 0.9900 0.9900 1.542(2) 0.9900 0.9900 1.513(3) 651 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(16)-C(21) C(16)-C(17) C(17)-C(18) C(17)-H(17) C(18)-O(2) C(18)-C(19) O(2)-C(24) C(24)-H(24A) C(24)-H(24B) C(24)-H(24C) C(19)-O(3) C(19)-C(20) O(3)-C(25) C(25)-H(25A) C(25)-H(25B) C(25)-H(25C) C(20)-C(21) C(20)-H(20) O(1W)-H(1WO) O(1W)-H(1WO)#1 O(1S)-C(1S) C(1S)-C(2S) C(1S)-C(2S)#2 C(2S)-H(2S1) C(2S)-H(2S2) C(2S)-H(2S3) C(13)-N(1)-C(1) C(13)-N(1)-C(12) C(1)-N(1)-C(12) C(13)-N(1)-H(1N) C(1)-N(1)-H(1N) C(12)-N(1)-H(1N) C(2)-C(1)-N(1) C(2)-C(1)-H(1A) 1.392(3) 1.395(3) 1.393(3) 0.9500 1.373(2) 1.410(3) 1.421(3) 0.9800 0.9800 0.9800 1.369(3) 1.387(3) 1.429(3) 0.9800 0.9800 0.9800 1.397(3) 0.9500 0.85(2) 0.85(2) 1.197(6) 1.505(4) 1.505(4) 0.9800 0.9800 0.9800 112.99(15) 107.62(15) 113.76(14) 110.6(17) 104.6(17) 107.1(17) 110.94(16) 109.5 N(1)-C(1)-H(1A) C(2)-C(1)-H(1B) N(1)-C(1)-H(1B) H(1A)-C(1)-H(1B) C(3)-C(2)-C(1) C(3)-C(2)-C(10) C(1)-C(2)-C(10) C(2)-C(3)-C(4) C(2)-C(3)-H(3) C(4)-C(3)-H(3) O(1)-C(4)-C(3) O(1)-C(4)-H(4A) C(3)-C(4)-H(4A) O(1)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(5)-O(1)-C(4) O(1)-C(5)-C(6) O(1)-C(5)-C(9) C(6)-C(5)-C(9) O(1)-C(5)-H(5) C(6)-C(5)-H(5) C(9)-C(5)-H(5) C(5)-C(6)-C(7) C(5)-C(6)-H(6A) C(7)-C(6)-H(6A) C(5)-C(6)-H(6B) C(7)-C(6)-H(6B) H(6A)-C(6)-H(6B) N(2)-C(7)-C(22) N(2)-C(7)-C(6) C(22)-C(7)-C(6) N(2)-C(7)-H(7) C(22)-C(7)-H(7) 109.5 109.5 109.5 108.0 121.77(19) 122.83(19) 115.37(17) 123.85(19) 118.1 118.1 113.69(17) 108.8 108.8 108.8 108.8 107.7 113.45(15) 108.36(16) 113.36(16) 108.45(16) 108.9 108.9 108.9 114.41(16) 108.7 108.7 108.7 108.7 107.6 109.19(17) 113.65(16) 113.40(17) 106.7 106.7 652 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(6)-C(7)-H(7) C(23)-C(22)-C(7) C(22)-C(23)-C(31) C(32)-C(31)-C(36) C(32)-C(31)-C(23) C(36)-C(31)-C(23) C(33)-C(32)-C(31) C(33)-C(32)-H(32) C(31)-C(32)-H(32) C(34)-C(33)-C(32) C(34)-C(33)-H(33) C(32)-C(33)-H(33) C(33)-C(34)-C(35) C(33)-C(34)-H(34) C(35)-C(34)-H(34) C(36)-C(35)-C(34) C(36)-C(35)-H(35) C(34)-C(35)-H(35) C(35)-C(36)-C(31) C(35)-C(36)-H(36) C(31)-C(36)-H(36) C(21)-N(2)-C(7) C(21)-N(2)-C(8) C(7)-N(2)-C(8) N(2)-C(8)-C(9) N(2)-C(8)-C(15) C(9)-C(8)-C(15) N(2)-C(8)-H(8) C(9)-C(8)-H(8) C(15)-C(8)-H(8) C(10)-C(9)-C(5) C(10)-C(9)-C(8) C(5)-C(9)-C(8) C(10)-C(9)-H(9) 106.7 173.8(2) 174.3(2) 118.5(2) 120.0(2) 121.38(19) 120.7(2) 119.6 119.6 120.4(2) 119.8 119.8 119.5(2) 120.2 120.2 120.7(2) 119.7 119.7 120.1(2) 120.0 120.0 123.23(16) 106.67(15) 116.87(15) 109.85(15) 103.41(15) 112.87(15) 110.2 110.2 110.2 117.31(16) 110.03(15) 108.90(16) 106.7 C(5)-C(9)-H(9) C(8)-C(9)-H(9) C(2)-C(10)-C(11) C(2)-C(10)-C(9) C(11)-C(10)-C(9) C(2)-C(10)-H(10) C(11)-C(10)-H(10) C(9)-C(10)-H(10) C(12)-C(11)-C(10) C(12)-C(11)-H(11A) C(10)-C(11)-H(11A) C(12)-C(11)-H(11B) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(11)-C(12)-N(1) C(11)-C(12)-C(15) N(1)-C(12)-C(15) C(11)-C(12)-H(12) N(1)-C(12)-H(12) C(15)-C(12)-H(12) N(1)-C(13)-C(14) N(1)-C(13)-H(13A) C(14)-C(13)-H(13A) N(1)-C(13)-H(13B) C(14)-C(13)-H(13B) H(13A)-C(13)-H(13B) C(13)-C(14)-C(15) C(13)-C(14)-H(14A) C(15)-C(14)-H(14A) C(13)-C(14)-H(14B) C(15)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(16)-C(15)-C(14) C(16)-C(15)-C(12) 106.7 106.7 109.73(16) 111.26(16) 106.66(15) 109.7 109.7 109.7 108.23(15) 110.1 110.1 110.1 110.1 108.4 109.33(15) 116.36(15) 104.43(14) 108.8 108.8 108.8 105.19(15) 110.7 110.7 110.7 110.7 108.8 104.21(15) 110.9 110.9 110.9 110.9 108.9 112.53(15) 116.99(15) Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 653 C(14)-C(15)-C(12) 101.27(14) C(19)-O(3)-C(25) 116.86(15) C(16)-C(15)-C(8) 100.73(15) O(3)-C(25)-H(25A) 109.5 C(14)-C(15)-C(8) 111.64(15) O(3)-C(25)-H(25B) 109.5 C(12)-C(15)-C(8) 114.15(15) H(25A)-C(25)-H(25B) 109.5 C(21)-C(16)-C(17) 120.47(18) O(3)-C(25)-H(25C) 109.5 C(21)-C(16)-C(15) 108.86(16) H(25A)-C(25)-H(25C) 109.5 C(17)-C(16)-C(15) 130.40(17) H(25B)-C(25)-H(25C) 109.5 C(18)-C(17)-C(16) 118.80(17) C(19)-C(20)-C(21) 117.78(17) C(18)-C(17)-H(17) 120.6 C(19)-C(20)-H(20) 121.1 C(16)-C(17)-H(17) 120.6 C(21)-C(20)-H(20) 121.1 O(2)-C(18)-C(17) 125.41(17) C(16)-C(21)-C(20) 121.52(17) O(2)-C(18)-C(19) 114.55(17) C(16)-C(21)-N(2) 110.60(17) C(17)-C(18)-C(19) 120.04(18) C(20)-C(21)-N(2) 127.67(17) C(18)-O(2)-C(24) 116.63(16) H(1WO)-O(1W)-H(1WO)#1107(5) O(2)-C(24)-H(24A) 109.5 O(1S)-C(1S)-C(2S) 121.85(19) O(2)-C(24)-H(24B) 109.5 O(1S)-C(1S)-C(2S)#2 121.84(19) H(24A)-C(24)-H(24B) 109.5 C(2S)-C(1S)-C(2S)#2 116.3(4) O(2)-C(24)-H(24C) 109.5 C(1S)-C(2S)-H(2S1) 109.5 H(24A)-C(24)-H(24C) 109.5 C(1S)-C(2S)-H(2S2) 109.5 H(24B)-C(24)-H(24C) 109.5 H(2S1)-C(2S)-H(2S2) 109.5 O(3)-C(19)-C(20) 123.75(17) C(1S)-C(2S)-H(2S3) 109.5 O(3)-C(19)-C(18) 114.87(17) H(2S1)-C(2S)-H(2S3) 109.5 C(20)-C(19)-C(18) 121.38(19) H(2S2)-C(2S)-H(2S3) 109.5 ________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y,z #2 -x+1,-y+1,z 654 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A6.3.4. Anisotropic displacement parameters (Å2x 103) for V22221. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ___________________________________________________________________ Atom U11 U22 U33 U23 U13 U12 ___________________________________________________________________ Cl(1) 28(1) 19(1) 33(1) 5(1) 3(1) 0(1) N(1) 24(1) 19(1) 22(1) 1(1) -4(1) 2(1) C(1) 28(1) 28(1) 21(1) 4(1) -1(1) 0(1) C(2) 21(1) 27(1) 22(1) 4(1) 1(1) -2(1) C(3) 26(1) 34(1) 21(1) 0(1) 1(1) 0(1) C(4) 28(1) 35(1) 24(1) -4(1) 4(1) 5(1) O(1) 28(1) 26(1) 23(1) -4(1) 2(1) 3(1) C(5) 20(1) 24(1) 24(1) -3(1) -1(1) 4(1) C(6) 28(1) 23(1) 25(1) -1(1) -3(1) 7(1) C(7) 30(1) 16(1) 25(1) 1(1) 0(1) 4(1) C(22) 27(1) 19(1) 29(1) 1(1) 4(1) 2(1) C(23) 28(1) 22(1) 29(1) 2(1) 2(1) 3(1) C(31) 24(1) 25(1) 27(1) 0(1) 2(1) -1(1) C(32) 37(1) 27(1) 38(1) 8(1) -5(1) -1(1) C(33) 30(1) 40(1) 34(1) 4(1) -7(1) 3(1) C(34) 27(1) 35(1) 32(1) -8(1) 3(1) -7(1) C(35) C(36) N(2) C(8) C(9) C(10) C(11) C(12) C(13) 30(1) 28(1) 24(1) 19(1) 20(1) 19(1) 22(1) 22(1) 22(1) 25(1) 26(1) 16(1) 17(1) 20(1) 23(1) 20(1) 18(1) 23(1) 31(1) 23(1) 22(1) 20(1) 19(1) 22(1) 24(1) 19(1) 24(1) -1(1) 1(1) -1(1) -1(1) -2(1) 1(1) 1(1) 0(1) 0(1) 8(1) 2(1) 1(1) -1(1) -2(1) -1(1) -3(1) -2(1) -4(1) -2(1) 3(1) 2(1) 1(1) 1(1) -2(1) -2(1) 1(1) 1(1) Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(14) 18(1) 24(1) 24(1) -1(1) -3(1) 1(1) C(15) 19(1) 17(1) 20(1) -2(1) -3(1) 1(1) C(16) 17(1) 18(1) 21(1) -1(1) -2(1) 0(1) C(17) 16(1) 19(1) 24(1) -1(1) -2(1) 2(1) C(18) 16(1) 23(1) 23(1) -3(1) -1(1) 3(1) O(2) 29(1) 26(1) 23(1) -4(1) 1(1) 10(1) C(24) 44(1) 29(1) 29(1) -6(1) -4(1) 16(1) C(19) 17(1) 24(1) 22(1) 2(1) 2(1) 0(1) O(3) 29(1) 26(1) 22(1) 4(1) 5(1) 5(1) C(25) 41(1) 25(1) 28(1) 8(1) 8(1) 2(1) C(20) 20(1) 17(1) 24(1) 2(1) 0(1) 1(1) C(21) 17(1) 18(1) 22(1) -2(1) 0(1) -2(1) O(1W) 33(1) 46(1) 35(1) 0 0 -17(1) O(1S) 89(3) 93(3) 53(2) 0 0 12(2) C(1S) 25(2) 69(3) 49(2) 0 0 8(2) C(2S) 31(1) 62(2) 61(2) -1(2) 7(1) -2(1) ___________________________________________________________________ 655 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 656 Table A6.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for V22221. __________________________________________________________________ Atom x y z U(eq) __________________________________________________________________ H(1N) 3580(16) 599(13) 7890(30) 26 H(1A) 2394 625 8886 31 H(1B) 2929 1297 9631 31 H(3) 2112 2412 10021 32 H(4A) 646 2769 8696 35 H(4B) 1107 3373 9662 35 H(5) 635 3027 6609 27 H(6A) 1098 4326 5860 30 H(6B) 1138 3639 4790 30 H(7) 2366 4268 4487 28 H(32) 4007 4909 8863 41 H(33) 4866 5821 9947 42 H(34) 4916 7167 9312 37 H(35) 4007 7625 7710 34 H(36) 3101 6733 6671 30 H(8) 2875 2901 7200 22 H(9) 1653 2299 5399 24 H(10) 1031 1574 7185 26 H(11A) 1960 478 6830 26 H(11B) 1877 967 5510 26 H(12) 3319 731 5885 24 H(13A) 4565 1490 8297 28 H(13B) 3850 2163 8540 28 H(14A) 4623 1749 6151 26 H(14B) 4374 2638 6648 26 H(17) 3891 1095 3751 23 H(24A) 4742 681 2091 51 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 H(24B) 4453 440 673 51 H(24C) 3799 372 1836 51 H(25A) 2661 3784 740 47 H(25B) 3276 3793 -476 47 H(25C) 3602 4128 873 47 H(20) 2971 3741 2804 25 H(1WO) 5350(20) 240(20) 6230(30) 57 H(2S1) 4323 4277 5257 77 H(2S2) 5323 4174 5414 77 H(2S3) 4849 3777 4217 77 __________________________________________________________________ Table A6.3.6. Torsion angles [°] for V22221. _______________________________________________________________ C(13)-N(1)-C(1)-C(2) C(12)-N(1)-C(1)-C(2) N(1)-C(1)-C(2)-C(3) N(1)-C(1)-C(2)-C(10) C(1)-C(2)-C(3)-C(4) C(10)-C(2)-C(3)-C(4) C(2)-C(3)-C(4)-O(1) C(3)-C(4)-O(1)-C(5) C(4)-O(1)-C(5)-C(6) C(4)-O(1)-C(5)-C(9) O(1)-C(5)-C(6)-C(7) C(9)-C(5)-C(6)-C(7) C(5)-C(6)-C(7)-N(2) C(5)-C(6)-C(7)-C(22) C(36)-C(31)-C(32)-C(33) C(23)-C(31)-C(32)-C(33) C(31)-C(32)-C(33)-C(34) C(32)-C(33)-C(34)-C(35) C(33)-C(34)-C(35)-C(36) 82.7(2) -40.4(2) -124.8(2) 53.2(2) 179.81(19) 2.0(3) -65.1(3) 82.7(2) 170.86(16) -68.7(2) 71.6(2) -51.8(2) 41.1(2) -84.4(2) -2.2(4) 174.6(2) -1.2(4) 3.2(4) -1.8(3) 657 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(34)-C(35)-C(36)-C(31) C(32)-C(31)-C(36)-C(35) C(23)-C(31)-C(36)-C(35) C(22)-C(7)-N(2)-C(21) C(6)-C(7)-N(2)-C(21) C(22)-C(7)-N(2)-C(8) C(6)-C(7)-N(2)-C(8) C(21)-N(2)-C(8)-C(9) C(7)-N(2)-C(8)-C(9) C(21)-N(2)-C(8)-C(15) C(7)-N(2)-C(8)-C(15) O(1)-C(5)-C(9)-C(10) C(6)-C(5)-C(9)-C(10) O(1)-C(5)-C(9)-C(8) C(6)-C(5)-C(9)-C(8) N(2)-C(8)-C(9)-C(10) C(15)-C(8)-C(9)-C(10) N(2)-C(8)-C(9)-C(5) C(15)-C(8)-C(9)-C(5) C(3)-C(2)-C(10)-C(11) C(1)-C(2)-C(10)-C(11) C(3)-C(2)-C(10)-C(9) C(1)-C(2)-C(10)-C(9) C(5)-C(9)-C(10)-C(2) C(8)-C(9)-C(10)-C(2) C(5)-C(9)-C(10)-C(11) C(8)-C(9)-C(10)-C(11) C(2)-C(10)-C(11)-C(12) C(9)-C(10)-C(11)-C(12) C(10)-C(11)-C(12)-N(1) C(10)-C(11)-C(12)-C(15) C(13)-N(1)-C(12)-C(11) C(1)-N(1)-C(12)-C(11) C(13)-N(1)-C(12)-C(15) -1.6(3) 3.6(3) -173.18(19) -137.87(19) 94.4(2) 86.4(2) -41.3(2) -90.26(17) 52.2(2) 30.45(18) 172.92(15) 67.3(2) -172.28(16) -58.4(2) 62.0(2) 168.09(15) 53.3(2) -62.04(19) -176.86(15) 173.08(19) -4.9(2) 55.3(3) -122.68(18) -74.3(2) 50.9(2) 166.01(15) -68.80(19) -54.3(2) 66.33(19) 66.31(19) -51.6(2) -143.12(15) -17.1(2) -17.93(18) 658 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(1)-N(1)-C(12)-C(15) C(1)-N(1)-C(13)-C(14) C(12)-N(1)-C(13)-C(14) N(1)-C(13)-C(14)-C(15) C(13)-C(14)-C(15)-C(16) C(13)-C(14)-C(15)-C(12) C(13)-C(14)-C(15)-C(8) C(11)-C(12)-C(15)-C(16) N(1)-C(12)-C(15)-C(16) C(11)-C(12)-C(15)-C(14) N(1)-C(12)-C(15)-C(14) C(11)-C(12)-C(15)-C(8) N(1)-C(12)-C(15)-C(8) N(2)-C(8)-C(15)-C(16) C(9)-C(8)-C(15)-C(16) N(2)-C(8)-C(15)-C(14) C(9)-C(8)-C(15)-C(14) N(2)-C(8)-C(15)-C(12) C(9)-C(8)-C(15)-C(12) C(14)-C(15)-C(16)-C(21) C(12)-C(15)-C(16)-C(21) C(8)-C(15)-C(16)-C(21) C(14)-C(15)-C(16)-C(17) C(12)-C(15)-C(16)-C(17) C(8)-C(15)-C(16)-C(17) C(21)-C(16)-C(17)-C(18) C(15)-C(16)-C(17)-C(18) C(16)-C(17)-C(18)-O(2) C(16)-C(17)-C(18)-C(19) C(17)-C(18)-O(2)-C(24) C(19)-C(18)-O(2)-C(24) O(2)-C(18)-C(19)-O(3) C(17)-C(18)-C(19)-O(3) O(2)-C(18)-C(19)-C(20) 108.05(17) -134.41(16) -7.97(19) 30.99(19) -167.23(15) -41.51(18) 80.34(18) -80.6(2) 158.83(15) 156.74(16) 36.14(17) 36.6(2) -83.95(17) -28.78(17) 89.87(18) 90.88(17) -150.47(16) -155.03(15) -36.4(2) -100.80(18) 142.53(16) 18.21(19) 73.0(2) -43.6(3) -167.96(18) -1.3(3) -174.55(18) -177.26(17) 1.6(3) -0.3(3) -179.17(17) -1.6(2) 179.37(17) 177.83(16) 659 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 C(17)-C(18)-C(19)-C(20) -1.1(3) C(20)-C(19)-O(3)-C(25) -2.0(3) C(18)-C(19)-O(3)-C(25) 177.45(17) O(3)-C(19)-C(20)-C(21) 179.81(17) C(18)-C(19)-C(20)-C(21) 0.4(3) C(17)-C(16)-C(21)-C(20) 0.6(3) C(15)-C(16)-C(21)-C(20) 175.14(16) C(17)-C(16)-C(21)-N(2) -174.53(16) C(15)-C(16)-C(21)-N(2) 0.0(2) C(19)-C(20)-C(21)-C(16) -0.1(3) C(19)-C(20)-C(21)-N(2) 174.12(17) C(7)-N(2)-C(21)-C(16) -159.27(17) C(8)-N(2)-C(21)-C(16) -19.8(2) C(7)-N(2)-C(21)-C(20) 26.0(3) C(8)-N(2)-C(21)-C(20) 165.47(18) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y,z #2 -x+1,-y+1,z 660 Appendix 6 – X-Ray Crystallography Reports Relevant to Chapter 3 661 Table A6.3.7. Hydrogen bonds for V22221 [Å and °]. ________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ________________________________________________________________________ ____ N(1)-H(1N)...Cl(1) 0.90(2) 2.14(2) 3.0214(17) 166(2) C(1)-H(1B)...O(2)#3 0.99 2.43 3.375(2) 159.2 C(3)-H(3)...O(3)#3 0.95 2.55 3.292(3) 134.7 C(4)-H(4B)...Cl(1)#4 0.99 2.97 3.941(2) 168.8 C(13)-H(13A)...Cl(1)#1 0.99 2.95 3.843(2) 151.3 C(25)-H(25A)...Cl(1)#5 0.98 2.84 3.784(2) 162.3 O(1W)-H(1WO)...Cl(1)#10.85(2) 2.35(2) 3.1780(19) 166(3) ________________________________________________________________________ ____ Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y,z #2 -x+1,-y+1,z #3 x,y,z+1 #4 -x+1/2,y+1/2,-z+2 #5 -x+1/2,y+1/2,-z+1 A6.4 (1) REFERENCES AND NOTES Sheldrick, G. M. Phase Annealing in SHELX-90: Direct Methods for Larger Structures. Acta. Crystallogr. A Found. Crystallogr. 1990, 46, 467–473. (2) Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta. Crystallogr. C Struct. Chem. 2015, 71, 3–8. (3) Müller, P. Practical Suggestions for Better Crystal Structures. Crystallogr. Rev. 2009, 15, 57–83. APPENDIX 7 Additional Investigations into the Development of a Non-Directed Petasis-Type Reaction 663 Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction A7.1 INTRODUCTION In our total synthesis of strempeliopidine (Chapter 2),1 we developed a non-directed Petasis-type reaction that coupled a-hydroxyindoles with electron-rich aryl-trifluoroborate salts (Figure A7.1.1). Due to the directing group-free nature of the transformation and the medicinal value of the dimeric products, we sought to expand this methodology to be compatible with “simplified” indoles and trifluoroborate salts. Initially, we envisioned developing the coupling of aryl-trifluoroborate salts with a-hydroxyindoles (464 + 465), but the mechanistic ambiguity of this transformation led us to instead explore alternative classes of nucleophiles (Chapter 3).2 These early studies, as well as further mechanistic investigations and the evaluation of alternative organoboron nucleophiles, are reported in this appendix. Figure A7.1.1. The Petasis-type reaction developed in the synthesis of strempeliopidine and the proposed generalization. H Me N O B Me H N Me H HO Me O N 26 Me N N Me KHF2 MeOH, H2O, 23 ºC, 1.5 h N H Me then… HFIP, 23 ºC, 16 h Ph 301 H Me N Ph 98% yield 284 directing group-free mild conditions Generalize high yielding R BF3K R + R N N HFIP HO R 464 465 N 466 Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction A7.2 RESULTS AND DISCUSSION A7.2.1 REACTION OPTIMIZATION USING ELECTRON-RICH 664 ARYL- TRIFLUOROBORATE SALTS Research commenced with exploring the non-directed coupling of hydroxyindoles with aniline boronic acids, in analogy to the reaction developed toward strempeliopidine. Indole 426a and boronic acid 310 could be combined using trifluoroethanol as the solvent and a benzoic acid additive in an excellent 87% yield (Scheme A7.2.1.1a). However, some data collected during our initial substrate scope prompted us to perform the control reaction wherein aniline 468 (rather than boronic acid 310) was used as the nucleophile. Surprisingly, under the same conditions, this reaction delivered a 60% yield of indole 467, suggesting that a Friedel–Crafts-type (rather than Petasis-type) mechanism played a large role in the transformation’s efficacy (Scheme A7.2.1.1b). Furthermore, time course studies showed that boronic acid 310 decomposed in less than an hour under the reaction conditions, at which point the reaction was at less than 10% conversion. Collectively, these data suggest a mechanism wherein boronic acid 310 first protodeborylates to generate aniline 468 and borate 470 (which could serve as a Lewis acid to promote the reaction), which then couples with the in situ generated iminium ion (471) via a Friedel–Crafts-type pathway (Scheme A7.2.1.1c). Intriguingly, when a similar control was performed in the natural product system toward strempeliopidine, no reaction was observed, suggest that a Petasis-type mechanism may be operative in that case. Further research is required to delineate when a Friedel– Crafts versus a Petasis mechanism is at play. Due to this mechanistic ambiguity, we elected 665 Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction to pursue alternative organoboron nucleophiles and eventually identified alkynyltrifluoroborate salts as readily accessible starting materials that couple through a Petasistype mechanism (see Chapter 3). Scheme A7.2.1.1. Optimized reaction conditions for electron-rich aryl boronic acids and potential mechanistic ambiguity. Me a) Optimized reaction conditions using electron-rich aryl boronic acids. Br Me OH Br B + N Me N PhCO2H (1 equiv) OH CF3CH2OH (0.2 M) 23 °C, 18 h N Me HO 87% yield 310 (3 equiv) 426a Me N 467 Me b) Control reaction suggests a Friedel–Crafts-type mechanism. Me Br Me Br N + N PhCO2H (1 equiv) Me CF3CH2OH (0.2 M) 23 °C, 18 h N Me HO 60% yield 468 (3 equiv) 426a Me N Me 467 Me c) Proposed Friedel–Crafts-type pathway. Br N OH B Me A7.2.2 OH Me N Me HO OH B O 310 N Me MECHANISITIC +H+ –H+ Me CF3 469 471 (HO)2B O CF3 470 INVESTIGATIONS INTO 467 N Me 468 THE PETASIS-TYPE COUPLING WITH ALKENYL TRIFLUOROBORATE SALTS Given the above results, wherein electron-rich aromatics can couple through a Friedel–Crafts-type (rather than Petasis-type) mechanism, we sought to investigate if 666 Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction alkenes are reacting through a Prins-type pathway. Recall, styrene 429r coupled to hydroxyindole 426a in 82% isolated yield (Scheme A7.2.2.1a, Entry 1). The analogous boronic acid (348) did not furnish any product (Entry 2). We hypothesize this is due to the lower stability of boronic acids (protodeboronation was observed) and the requirement of a directing group when using boronic acids under traditional Petasis reaction conditions. Styrene (472) was also not competent, demonstrating the activating effect of the trifluoroborate (Entry 3). This is in contrast to the electron-rich aniline substrates, which react productively under a Friedel–Crafts type pathway. These data suggest that a mechanism involving protodeborylation followed by Prins-type attack of the iminium ion is not likely in the developed methodology. Scheme A7.2.2.1. Investigations into the mechanism of the Petasis-type reaction. a) Me Me Br Br N + R Ph PhCO2H (1 equiv) N CF3CH2OH (0.025 M) 65 °C, 18 h HO Ph 426a entry R= yield (%) 1 –BF3K, 429r 82% 2 –B(OH)2, 348 0% 3 –H, 472 0% 430r (3 equiv) b) BF3K N H 473 HN PhCO2H (1 equiv) X CF CH OH (0.025 M) + 3 427 (3 equiv) 2 65 °C, 18 h H 474 not observed Afterward, we attempted the reaction using benzaldehyde-derived imine 473, as it would be unable to form the proposed “aromaticity-disrupting iminium ion” (Scheme A7.2.2.1b). As expected, no reaction was observed, supporting the privileged reactivity of hydroxyindole-derived iminium ions. Taken together, these data suggest that the developed Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction 667 method proceeds through a Petasis-type pathway, wherein the trifluoroborate increases the nucleophilicity of the olefin,3 and couples to sufficiently active electrophiles. A7.2.3 EVALUATION OF OTHER CLASSES OF TRIFLUOROBORATE SALTS Following the development of the Petasis-type coupling using alkynyl trifluoroborate salts, a variety of different trifluoroborate salts were investigated under the optimized conditions (Table A7.2.3.1). Table A7.2.3.1. Investigations into other classes of trifluoroborate salts. Me Me Br Br + N R PhCO2H (1 equiv) BF3K N CF3CH2OH (0.025 M) 65 °C, 18 h HO R (3 equiv) 426a 475 Nucleophiles Evaluated: Me BF3K BF3K 476 477 Me BF3K Me 429q 478 429r BF3K BF3K 480 481 product? 1 476 not detected 2 477 not detected 3 478 not detected 4 429q 72% yield 5 429r 82% yield 6 479 not detected 7 480 not detected 8 481 not detected 9 429p 90% yield 479 BF3K Ph MeO nucleophile BF3K BF3K Ph entry BF3K 429p Alkyl trifluoroborate salts (476 and 477) were not competent nucleophiles (Entries 1–2). These data agree with the literature, which notes that the organoboron must be adjacent to a p-system to facilitate nucleophilic attack.4 While the unsubstituted potassium Appendix 7 – Additional Investigations on the Non-Directed Petasis-Type Reaction 668 vinyltrifluoroborate 478 did not yield any product, more electron-rich olefins (429q and 429r) were compatible (Entries 3–5). Surprisingly, neither phenyl trifluoroborate 479 nor anisole derivative 480 delivered any product, despite several examples of their use in the literature (Entries 6–7).4 Finally, while benzyl trifluoroborate 481 was not compatible, allyl salt 429p provided product in excellent yield (Entries 8–9). Future research is focused on the application of organometallic catalysis to the Petasis reaction to overcome this limitation and enable enantioselective couplings.5 A7.3 REFERENCES AND NOTES (1) Rand, A. W.; Gonzalez, K. J.; Reimann, C. E.; Virgil, S. C.; Stoltz, B. M. Total Synthesis of Strempeliopidine and Non-Natural Stereoisomers through a Convergent Petasis Borono–Mannich Reaction. J. Am. Chem. Soc. 2023, 145, 7278–7287. (2) Gonzalez, K. J.; Rand, A. W.; Stoltz, B. M. Development of a Non-Directed PetasisType Reaction by an Aromaticity-Disrupting Strategy. Angew. Chem. Int. Ed. 2023, 62 , e202218921. (3) Berionni, G.; Maji, B.; Knochel, P.; Mayr, H. Nucleophilicity Parameters for Designing Transition Metal-Free C–C Bond Forming Reactions of Organoboron Compounds. Chem. Sci. 2012, 3, 878–882. (4) Wu, P.; Givskov, M.; Nielsen, T. E. Reactivity and Synthetic Applications of Multicomponent Petasis Reactions. Chem. Rev. 2019, 119, 11245–11290. (5) Gonzalez, K. J.; Cerione, C.; Stoltz, B. M. Strategies for the Development of Asymmetric and Non-Directed Petasis Reactions. Chem. – Eur. J. 2024, 30, e202401936. Chapter 4 and Appendices 8–11 are under embargo. CHAPTER 5 Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams to Construct Spirocycles† 5.1 INTRODUCTION Nitrogen-containing heterocycles are ubiquitous in small molecule drugs where their stereochemical complexity often correlates with their success in moving from discovery, through clinical testing, to drugs.1 Spirocyclic structures are embedded into variety of approved drugs and drug candidates (Figure 5.1.1A), and are expected to have a positive impact on activity and selectivity, physicochemical properties, and pharmacokinetic profile due to their three-dimensional structures.2 However, construction of spirocycles, especially in an enantioselective manner, is often challenging.3 Therefore, there is a need for the development of efficient synthetic methods for the asymmetric preparation of nitrogen-containing spirocycles. We became interested in pyrazoline- and isoxazoline-bearing spirocyclic lactams due to these heterocycles’ ubiquity in drug design as well as approved drugs and drug candidates,4 such as Edaravone,4a Ocedurenone,4b AZD8165,4c and Zenuzolac4f (Figure 5.1.1B). Asymmetric 1,3-dipolar cycloadditions are an efficient means to construct stereochemically complex rings through a two bond disconnection strategy.5 While several methods have been developed to enantioselectively prepare spirocycles by 1,3-dipolar † This research was carried out with Nishiura, Y.; Cusumano, A. Q. Portions of this chapter have been reproduced with permission from Stoltz, et al. Org. Lett. 2023, 25, 6469–6473. © 2023 American Chemical Society. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 841 cycloadditions,6 there is a lack of asymmetric cycloadditions of 1,3-dipoles with ⍺methylene lactams except methyleneindolinones.7 These substrates would furnish spirocyclic lactams that could serve as valuable enantioenriched building blocks. These lactam moieties are frequently used in drug discovery,8 and the related saturated Nheterocycle is readily available by exhaustive reduction. Several groups have reported asymmetric 1,3-dipolar cycloadditions to construct pyrazolines9 and isoxazolines.10 In one such report, Sibi and coworkers developed an asymmetric 1,3-dipolar cycloaddition of diazoacetates and nitrile oxides using a chiral magnesium Lewis acid (Figure 5.1.1C).9d,10g The method required a pyrazolidinone imide templating group as, in their model, magnesium is bound to the bidentate substrate in an scis conformation, and shielding by the ligand blocks the bottom face of the olefin. From this model, we considered it may be possible to replace this pyrazolidinone template with a protected lactam that could still bind the magnesium and instead furnish enantioenriched spirocyclic lactams (Figure 5.1.1D). This approach would allow for the asymmetric 1,3dipolar cycloaddition to proceed in a substrate-controlled manner rather than requiring a templating group. We now report the development of an asymmetric 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with ⍺-methylene lactams to construct nitrogen-rich spirocycles in high yield and enantioselectivity. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 842 Figure 5.1.1. Examples of Spirocyclic, Pyrazoline, or Isoxazoline Compounds and Asymmetric 1,3-Dipolar Cycloaddition of Diazoacetates or Nitrile Oxides. A. Examples of Drugs and Drug Candidates Containing a Spirocylic Ring. CF3 O N H Ph HN N H N N O CF3 Cipargamin N O O O CF3 HN N HO Cl HN Cl NH F Ubrogepant Rolapitant B. Examples of Drugs and Drug Candidates Containing a Pyrazoline or Isoxazoline. O O N N O OH CN N N N N N Cl Zenuzolac Edaravone N N O O HO NH Cl O N N O N N O Ocedurenone AZD8165 C. Chiral Mg-Catalyzed 1,3-Dipolar Cycloaddition of Diazoacetates or Nitrile Oxides with ⍺,𝞫-Unsaturated Pyrazolidinone Imide. Sibi (2004) ref. 9d, (2007) ref. 10g O O ent-605 / Mg(NTf2)2 (10 to 30 mol%) R2 N + N R1 Ph N N CO2Et templating group (= TG) O O O R2 N + N TG MS 4Å, CH2Cl2 –20 to 50 °C R1 15 examples up to 99% yield up to 99% ee O N O R1 TG MS 4Å, CH2Cl2 –20 to 50 °C Ph CO2Et R1 R2 605 / MgI2 (30 mol%) N N HN R2 O 10 examples up to 90% yield up to 99% ee Nitrile Oxide O O N X X N O O N N Mg N Ph O 605 N O BOX type ligand Stereochemical model D. This Research: Chiral Mg-Catalyzed 1,3-Dipolar Cycloaddition of Diazoacetates or Nitrile Oxides to Construct Spirocyclic Lactams. N N CO2R2 O R1 O R1 O HN N CO2R2 N 11 examples up to 91% yield up to 89% ee O n 605 / Mg(NTf2)2 (10 mol%) N n •Templating group free DCE 23 °C, 18 h O O O N R3 R1 O N R3 N n 3 examples up to 89% yield up to 87% ee Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 5.2 RESULTS AND DISCUSSION 5.2.1 REACTION DESIGN AND OPTIMIZATION 843 We began by examining the asymmetric 1,3-dipolar cycloaddition of ethyl diazoacetate 607a and ⍺-methylene δ-valerolactam 606a using chiral ligand 605 and magnesium Lewis acids (Table 5.2.1.1). Investigation of a number of magnesium Lewis acids revealed the remarkable impact of the counterion on the reaction (Entries 1–4). We found using Mg(NTf2)2 afforded desired spirocyclic product 608a in good yield with high levels of enantioselectivity and with almost complete consumption of lactam 606a (Entry 1). On the other hand, when Mg(ClO4)2, MgI2, or Mg(OTf)2 was employed as the Lewis acid, a decrease in the isolated yield was observed and starting lactam 606a was not consumed completely (Entries 2–4). Presumably, these results indicate that the strong Lewis acidity of Mg(NTf2)2 accelerates this reaction compared to other magnesium Lewis acids. Mg(NTf2)2 also afforded the highest levels of enantioselectivity. Interestingly, Mg(OTf)2 provided the enantiomeric product using the same chiral ligand. We next investigated reaction time, temperature, and additives. Shortening the reaction time to 3 h increased the amount of unreacted lactam 606a and led to lower isolated yields (Entry 5). With the aim of improving enantioinduction, the reaction temperature was reduced to 0 ˚C, however, enantioselectivity was not improved (Entry 6). The addition of 4 Å molecular sieves, which has been reported to improve enantioselectivity in other 1,3-dipolar cycloadditions,9d decreased enantioselectivity and yield (Entry 7). In an effort to further improve enantioinduction, we investigated the effect of solvent. To our delight, replacing dichloromethane with 1,2-dichloroethane (DCE) led to an enhancement in Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 844 enantioselectivity (Entry 8). In contrast, using more polar solvents such as tetrahydrofuran or acetonitrile led to decreases in enantioselectivity as well as yield (Entries 9, 10). Furthermore, we examined a series of other bisoxazoline (BOX) type ligands but were not able to identify any that provided higher enantioselectivities than ligand 605. From these optimization results, we decided to examine the substrate scope using Mg(NTf2)2 as the Lewis acid and DCE as solvent at 23 °C for 18 h (Entry 8). Table 5.2.1.1 Optimization of Reaction Conditions.a O O N O CbzN N 605 + N N CO2Et HN N CO2Et CbzN Solvent Temp., Time 607a 606a O Mg source 608a Entry Mg source Solvent Temp. (°C) Time (h) Yield (%) b ee (%) c 1 Mg(NTf2)2 CH2Cl2 23 18 82 81 2 Mg(ClO4)2 CH2Cl2 23 18 67 59 3 MgI2 CH2Cl2 23 18 22 10 4 Mg(OTf)2 CH2Cl2 23 18 74 –33 5 Mg(NTf2)2 CH2Cl2 23 3 50 80 6 Mg(NTf2)2 CH2Cl2 0 3 28 69 7d Mg(NTf2)2 CH2Cl2 23 3 22 49 8 Mg(NTf2)2 DCE 23 18 80 86 9 Mg(NTf2)2 THF 23 18 48 52 10 Mg(NTf2)2 MeCN 23 18 51 70 [a] Conditions: Reactions were performed with lactam 606a (0.10 mmol, 1.0 equiv), ethyl diazoacetate 607a (0.15 mmol, 1.5 equiv), Mg source (10 mol%), ligand 605 (11 mol%) in the given solvent (1.5 ml). [b] Isolated yields. [c] ee was determined by chiral SFC and absolute chemistry by VCD (see Appendix 12). [d] MS 4Å was added. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 5.2.2 845 SCOPE OF THE N-SUBSTITUENT AND DIAZOACETATES Under the optimized reaction conditions, we began investigating the scope of the reaction with a number of lactams with different N-substituents/protecting groups (R1) and different diazoacetates (R2) (Scheme 5.2.2.1). In the case of the reaction with tert-butyl diazoacetate 607b, the product 608b was obtained in good yield (62%) and high enantioselectivity (82% ee). This result demonstrates that bulky substituents on the ester are tolerated. Reactions with Fmoc (606c) or Teoc (606d) substrates also showed high enantioselectivity (81–87% ee). On the other hand, the reaction with Troc substrate 606e, which has inductively electron-withdrawing chlorine atoms, exhibited appreciably decreased enantioselectivity (74% ee). Further reduction in yield (38%) and enantioselectivity (59% ee) was observed with Boc substrate 606f. It is likely that the coordination to Mg is inhibited by the bulky tert-butyl group, resulting in lower turnover and enantioselectivity. Next, we investigated acyl protecting groups such as acetyl (606g) and benzoyl (606h). Products 608g and 608h were obtained in good yields (66–91%) but lower enantioselectivities compared to Cbz-protected product 608a. For all substrates investigated, only a single isomer of product was observed, possibly to avoid steric clash between the ester and lactam ring. Reaction with benzyl substrate 606i, which does not have an additional carbonyl group, did not proceed. This result indicates that the use of protecting groups with a carbonyl is necessary for the cycloaddition to proceed. We hypothesize this is because the imide chelates the magnesium Lewis acid, lowering the energy of the exocyclic olefin’s LUMO and enabling the reaction. From the above results, we chose the Cbz group and ethyl diazoacetate for further investigation of substrate scope. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 846 Scheme 5.2.2.1. Investigation of N-Substituent and Diazoacetate Scope: Cycloaddition of Diazoacetates (607a–b) to Lactams (606a, c–i). a O O N 605 O R1 N + N O N CO2R2 CO2Et N Cbz O CO2t-Bu 608b 62% Yield, 82%ee O O CO2Et Cl C 3 N O O HN N O HN N CO2Et N O 608c 608a 80% Yield, 86%ee TMS CO2R2 608a–i HN N N HN N N DCE 23 °C, 18 h O HN N O R1 Mg(NTf2)2 607a–b 606a, c–i Cbz N O 34% Yield, 87%ee CO2Et N O O HN N Boc HN N CO2Et N 608d 608e 608f 83% Yield, 81%ee 72% Yield, 74%ee 38% Yield, 59%ee O O O HN N CO2Et N O O HN N CO2Et N HN N CO2Et N 608g 608h 608i 66% Yield, 71%ee 91% Yield, 58%ee No Reaction [a] Conditions: Reactions were performed with lactams 606a, c–i (0.10 mmol, 1.0 equiv), diazoacetates 607a–b (0.15 mmol, 1.5 equiv), Mg(NTf2)2 (10 mol%), ligand 605 (11 mol%) in DCE (1.5 ml) at 23 °C for 18 h. Isolated yields. ee was determined by chiral SFC and absolute chemistry by VCD (see Appendix 12). 5.2.3 INVESTIGATION OF LACTAM SUBSTRATE SCOPE We next sought to examine lactam substrates with different ring sizes or substitution patterns (Scheme 5.2.3.1). We found that the reaction was robust with 7membered ring substrate 606j, providing the target product 608j in excellent Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 847 enantioselectivity (89% ee) and good yield (72%). Furthermore, the reaction performed well on 2 mmol scale, affording product with the same high levels of enantioselectivity and yield as on smaller scale. Reactions with 5-membered ring substrate 606k and 3,4dihydroquinolinone substrate 606l furnished the respective lactam products (608k, 608l) in high yields, albeit with moderate enantioselectivity. As for substrate 606k, we posit that the lowered enantioinduction may be due to the different bite angle of the imide moiety. On the other hand, reactions with ⍺-methylene lactams having either an isopropyl group (606m) or phenyl group (606n) at the b position did not furnish any desired product; instead, most of the starting lactam was recovered. When both reactions were conducted at higher temperatures to improve conversion, removal of the Cbz group was observed rather than the desired cycloaddition. These results indicate that substrates with substituents at the b position are less reactive, likely due to steric hinderance. Subsequently, we investigated the 1,3-dipolar cycloaddition of nitrile oxides using our optimized conditions in order to access enantioenriched spirocyclic isoxazolines. In this investigation, mesityl nitrile oxide 609, which is a stable dipole,10g was used to avoid the traditional requirement for an amine base to generate nitrile oxides as they would deactivate the magnesium Lewis acid catalyst.11 To our delight, we found that the reaction with 6- and 7-membered ring lactams (606a, 606j) furnished the desired products (610a, 610j) in high yields (82–89%) and excellent enantioselectivities (87% ee). Reaction with 3,4-dihydroquinolinone substrate 606l afforded desired spirocyclic product 610l in high yield, albeit with lower enantioselectivity. Overall, the yields and enantioselectivities of Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 848 reactions with nitrile oxides are analogous to reactions with diazoacetates and point toward the general nature of our reaction design with other dipoles. Scheme 5.2.3.1. Investigation of Lactam Substrate Scope: Cycloaddition of Diazoacetate (607a) or Nitrile Oxide (609) to ⍺-Methylene Lactams.a N O CO2Et Cbz 607a O Cbz N HN N CO2Et N n R1 N n 605 608j–n Mg(NTf2)2 O DCE 23 °C, 18 h 606a, j–n O Cbz N O N Mes N 609 n 610a, j, l O HN N Cbz O CO2Et N Cbz 608k 72% Yield, 89%ee (83% Yield, 89%ee on 2 mmol scale) Cbz O HN N CO2Et N CO2Et N 608j O HN N Cbz 80% Yield, 67%ee O HN N CO2Et N Cbz HN N CO2Et N Ph 608l 608m 87% Yield, 40%ee No Reaction O Cbz O N Mes N O Cbz 608n No Reaction O O N Cbz Mes N O N Mes N 610a 610j 610l 82% Yield, 87%ee 89% Yield, 87%ee 65% Yield, 38%ee [a] Conditions: Reactions were performed with lactams 606a, j–n (0.10 mmol, 1.0 equiv), diazoacetate 607a or nitrile oxide 609 (0.15 mmol, 1.5 equiv), Mg(NTf2)2 (10 mol%), ligand 605 (11 mol%) in DCE (1.5 ml) at 23 °C for 18 h. Isolated yields. ee was determined by chiral SFC and absolute chemistry by VCD (see Appendix 12). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 5.2.4 849 SYNTHETIC UTILITY OF THE CYCLOADDUCTS Having explored the substrate scope of this transformation, we next diversified product 608j to display its synthetic utility (Scheme 5.2.4.1). Raney nickel-mediated hydrogenolysis of the Cbz group furnished amide 611 in good yield (77%). Saponification of the resulting ethyl ester was then accomplished using lithium hydroxide to provide acid 612. Treatment of imide 608j with sodium ethoxide initiates ring opening of the 7membered ring to yield pyrazoline 613. Finally, oxidation of the pyrazoline can be accomplished using N-bromosuccinimide to deliver the brominated product 614 in near quantitative yield as a 1.5:1 mixture of separable diastereomers. Scheme 5.2.4.1. Product Diversification. O HN N CO2Et HN O Ra/Ni H2 (1 atm) NaOEt 3:1 i-PrOH/H2O 23 °C, 27 h 2:1 EtOH/THF 0 °C, 20 min 77% yield 62% yield HN N CO2Et EtO CbzHN 611 613 LiOH (aq) 1,4-dioxane 23 °C, 1.5 h O Cbz HN N N CO2Et 69% yield 608j O HN CO2H HN •TFA 612 5.3 O N NBS Cbz N N CO2Et Br N CCl4 0 to 23 °C, 3 h 97% yield 1.5:1 dr 614 CONCLUSIONS In summary, we have developed a high-yielding (up to 91% yield) and enantioselective (up to 89% ee) 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with ⍺-methylene lactams to construct spirocyclic heterocycles. Importantly, reactions using Cbz-protected 6- and 7-membered ring ⍺-methylene lactams provided the products Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 850 with high enantioselectivity and yield. Reactions utilizing other carbamate N-protecting groups such as Fmoc and Teoc afforded the desired spirocyclic products with high enantioinduction. Additionally, diazoacetates with bulky substituents such as tert-butyl were tolerated. Excitingly, our method could be applied to the 1,3-dipolar cycloaddition with nitrile oxides to furnish spirocyclic lactams containing isoxazolines. Catalysis proceeds at ambient temperature with a commercially available catalyst and ligand to prepare enantioenriched, nitrogen-rich building blocks. We are currently conducting further research on this method and its application to drug discovery and will report it in due course. 5.4 EXPERIMENTAL SECTION 5.4.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.12 Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 μm) was used for silica gel flash chromatography. Reverse phase chromatography was performed on a Teledyne Isco High Performance RediSep Rf Gold column (15.5g HP C18). 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian Inova 600 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm) or pyridine-d4 (δ 8.74 ppm). 13C Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 851 NMR spectra were recorded on Varian Inova 500 MHz spectrometer (125 MHz) and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CDCl3 (δ 77.16 ppm) or CD3CN (δ 1.32 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad singlet. Data for 13C NMR is reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H, AS-H or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in mixed ionization mode (MM: ESI-APCI). The authors acknowledge the NSF CRIF program for providing funds that enabled the purchase of this instrumentation. Absolute configuration of 608a was determined by vibrational circular dichroism (VCD), and all other products are assigned by analogy. Reagents were purchased from commercial sources and used as received unless otherwise stated. Mesityl nitrile oxide (609) was prepared according to the literature.13 607a and 607b were purchased from Sigma Aldrich, and all ligands were purchased from Combi-Blocks. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 852 CAUTION: Diazo compounds are high energy compounds that should be handled with particular care in a well-ventilated fume hood. While we experienced no difficulties/energetic decomposition during our research, care should be taken, especially when handling large quantities of diazo compounds. Reactions, especially those on large scale, should be conducted behind a blast shield and only after rigorous risk assessment.14 5.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 5.4.2.1 1,3-Dipolar Cycloaddition of Diazoacetates: General Procedure A O O N N 605 O Cbz N O + 606a N N Mg(NTf2)2 CO2Et Cbz HN N CO2Et N DCE 23 °C, 18 h 607a 608a 7-benzyl 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate (608a) A screw-top 2 dram vial was charged with a stir bar, benzyl 3-methylene-2-oxopiperidine1-carboxylate 606a (24.5 mg, bis(trifluoromethanesulfonyl)imide (5.8 0.100 mmol, 1.00 eq.), magnesium mg, 0.010 mmol, 0.10 eq.) and (3aS,3′aS,8aR,8′aR)-2,2′-Cyclopropylidenebis[3a,8a-dihydro-8H-indeno[1,2-d]oxazole] 605 (3.9 mg, 0.011 mmol, 0.11 eq.). The vial was purged and backfilled three times with nitrogen and then the solids were dissolved in dichloroethane (1.0 ml). After being stirred at 23 ˚C for 30 min, ethyl diazoacetate 607a (17.1 mg, 0.150 mmol, 1.50 eq.) in dichloroethane (0.5 mL) was added to reaction mixture at 23 °C. After being stirred at 23˚C for 18 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 853 water. The aqueous layer was extracted with dichloromethane two times. The combined extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to yield 7-benzyl 3ethyl (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608a as a colorless oil (28.7 mg, 0.080 mmol, 80%). 1 H NMR (500 MHz, CDCl3) δ 7.43 – 7.31 (m, 5H), 6.62 (br s, 1H), 5.30 (d, J = 12.3 Hz, 1H), 5.26 (d, J = 12.3 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.83 – 3.73 (m, 2H), 3.50 (d, J = 17.5 Hz, 1H), 2.92 (d, J = 17.5 Hz, 1H), 2.11 – 2.08 (m, 2H), 2.03 – 1.93 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 172.3, 162.1, 154.4, 142.0, 135.1, 128.7, 128.6, 128.3, 71.0, 69.1, 61.5, 46.8, 43.4, 34.4, 20.5, 14.4; IR (Neat Film, NaCl) 3321, 2957, 1768, 1714, 1559, 1387, 1299, 1264, 1170, 1016, 978, 747, 636 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H21N3NaO5 [M+Na]+: 382.1373, found 382.1374; [a]D23 +178.6° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 5.14, minor = 5.56. General Procedure for the Synthesis of Racemic Products Racemic products were synthesized in a manner analogous to general procedure A but without chiral ligand. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 854 Spectroscopic Data for Enantioenriched Pyrazoline Cycloadducts O HN N CO2t-Bu CbzN 608b 7-benzyl 3-(tert-butyl) (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate (608b) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 7-benzyl 3-(tert-butyl) (S)-6-oxo-1,2,7triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608b as white solid (24.1 mg, 0.062 mmol, 62%). 1 H NMR (500 MHz, CDCl3) δ 7.43 – 7.31 (m, 5H), 6.55 (s, 1H), 5.30 (d, J = 12.3 Hz, 1H), 5.26 (d, J = 12.3 Hz, 1H), 3.83 – 3.72 (m, 2H), 3.46 (d, J = 17.6 Hz, 1H), 2.88 (d, J = 17.6 Hz, 1H), 2.09 – 2.06 (m, 2H), 2.00 – 1.92 (m, 2H), 1.53 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 172.5, 161.4, 154.4, 143.5, 135.2, 128.7, 128.6, 128.3, 82.3, 70.8, 69.1, 46.7, 43.7, 34.5, 28.2, 20.4.; IR (Neat Film, NaCl) 3329, 2976, 1773, 1714, 1578, 1379, 1295, 1264, 1170, 1132, 1005, 975, 748, 698 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H25N3NaO5 [M+Na]+: 410.1686, found 410.1691; [a]D23 –168.0° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 3.23, minor = 3.73. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 855 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 856 HN N CO2Et FmocN 608c 7-((9H-fluoren-9-yl)methyl) 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7- dicarboxylate (608c) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 7-((9H-fluoren-9-yl)methyl) 3-ethyl (S)-6oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608c as a colorless oil (15.2 mg, 0.034 mmol, 34%). 1 H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz, 2H), 7.66 (dd, J = 15.0, 7.5 Hz, 2H), 7.40 (t, J = 7.5, 2H), 7.34 – 7.30 (m, 2H), 6.72 (s, 1H), 4.57 – 4.41 (m, 2H), 4.34 – 4.28 (m, 3H), 3.79 –3.71 (m, 2H), 3.55 (d, J = 17.6 Hz, 1H), 2.96 (d, J = 17.6, 1H), 2.15 – 2.12 (m, 2H), 2.03 – 1.93 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4, 162.2, 154.5, 143.5, 142.1, 141.4, 128.0, 127.4, 125.5, 120.1, 71.2, 69.7, 61.6, 46.71, 46.66, 43.5, 34.5, 20.6, 14.4; IR (Neat Film, NaCl) 3334, 2954, 1769, 1714, 1573, 1450, 1378 1297, 1264, 1173, 1123, 1019, 971, 760, 737, 683 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C25H25N3NaO5 [M+Na]+: 470.1686, found 470.1691; [a]D23 +104.2° (c 1.00, CHCl3); SFC Conditions: 40% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR(min): major = 3.91, minor = 6.16. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 857 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O TMS O HN N CO2Et N O 858 608d 3-ethyl 7-(2-(trimethylsilyl)ethyl) (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7- dicarboxylate (608d) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 3-ethyl 7-(2-(trimethylsilyl)ethyl) (S)-6-oxo1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608d as a white solid (30.6 mg, 0.083 mmol, 83%). 1 H NMR (500 MHz, CDCl3) δ 6.64 (br s, 1H), 4.35 – 4.27 (m, 4H), 3.81 – 3.72 (m, 2H), 3.50 (d, J = 17.5 Hz, 1H), 2.92 (d, J = 17.5 Hz, 1H), 2.12 – 2.09 (m, 2H), 2.01 – 1.94 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.12 – 1.09 (m, 2H), 0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 172.4, 162.1, 154.6, 142.1, 71.0, 66.3, 61.5, 46.6, 43.5, 34.5, 20.6, 17.6, 14.4, 1.5; IR (Neat Film, NaCl) 3323, 2953, 1769, 1721, 1575, 1425, 1378 1300, 1260, 1173, 1127, 964, 860, 837, 683 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H27N3NaO5Si [M+Na]+: 392.1612, found 392.1620; [a]D23 +118.9° (c 1.00, CHCl3); SFC Conditions: 10% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 3.02, minor = 3.42. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 859 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 860 HN N CO2Et TrocN 608e 3-ethyl 7-(2,2,2-trichloroethyl) (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7- dicarboxylate (608e) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 3-ethyl 7-(2,2,2-trichloroethyl) (S)-6-oxo1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608e as a white solid (29.0 mg, 0.072 mmol, 72%). 1 H NMR (500 MHz, CDCl3) δ 6.65 (br s, 1H), 4.88 (d, J = 11.9 Hz, 1H), 4.84 (d, J = 11.9 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.90 – 3.87 (m, 2H), 3.52 (d, J = 17.6 Hz, 1H), 2.94 (d, J = 17.6 Hz, 1H), 2.16 – 2.14 (m, 2H), 2.11 – 1.98 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 172.2, 162.1, 152.4, 142.1, 94.4, 76.0, 71.2, 61.6, 47.1, 43.5, 34.4, 20.6, 14.4; IR (Neat Film, NaCl) 3322, 2954, 1764, 1701, 1564, 1422, 1302, 1257, 1172, 1128, 1032, 927, 715, 684 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H16Cl3N3NaO5 [M+Na]+: 422.0048, found 422.0048; [a]D24 +131.1° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 2.94, minor = 3.30. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 861 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 862 HN N CO2Et BocN 608f 7-(tert-butyl) 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate (608f) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 7-(tert-butyl) 3-ethyl (S)-6-oxo-1,2,7triazaspiro[4.5]dec-2-ene-3,7-dicarboxylate 608f as a colorless oil (12.4 mg, 0.038 mmol, 38%). 1 H NMR (500 MHz, CDCl3) δ 6.60 (br s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.77-3.72 (m, 1H), 3.68 – 3.63 (m, 1H), 3.51 (d, J = 17.5 Hz, 1H), 2.90 (d, J = 17.5 Hz, 1H), 2.09 – 2.06 (m, 2H), 2.01 – 1.92 (m, 2H), 1.52 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 172.2, 162.2, 153.0, 142.2, 83.9, 70.9, 61.5, 46.3, 43.4, 34.6, 28.1, 20.4, 14.4; IR (Neat Film, NaCl) 3341, 2979, 1766, 1727, 1566, 1369, 1297, 1257, 1152, 1020, 853, 778 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H23N3NaO5 [M+Na]+: 348.1530, found 348.1534; [a]D24 +51.5° (c 1.00, CHCl3); SFC Conditions: 10% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 3.06, minor = 3.68. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 863 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 864 HN N CO2Et AcN 608g ethyl (S)-7-acetyl-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3-carboxylate (608g) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford ethyl (S)-7-acetyl-6-oxo-1,2,7triazaspiro[4.5]dec-2-ene-3-carboxylate 608g as a colorless oil (17.6 mg, 0.066 mmol, 66%). 1 H NMR (500 MHz, CDCl3) δ 6.62 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.87 – 3.81 (m, 1H), 3.74 – 3.69 (m, 1H), 3.48 (d, J = 17.5 Hz, 1H), 2.96 (d, 1H), 2.47 (s, 3H), 2.11 (br dd, J = 7.3, 5.7 Hz, 2H), 2.02 – 1.89 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.2, 174.0, 162.1, 141.9, 71.1, 61.6, 43.9, 43.6, 34.3, 27.1, 20.1, 14.4; IR (Neat Film, NaCl) 3324, 2934, 1698, 1575, 1368, 1299, 1258, 1184, 1123, 1034, 975, 847, 746, 623 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H17N3NaO4 [M+Na]+: 290.1111, found 290.1111; [a]D23 +97.1° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 3.42, minor = 2.69. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 865 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 866 HN N CO2Et BzN 608h ethyl (S)-7-benzoyl-6-oxo-1,2,7-triazaspiro[4.5]dec-2-ene-3-carboxylate (608h) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford ethyl (S)-7-benzoyl-6-oxo-1,2,7triazaspiro[4.5]dec-2-ene-3-carboxylate 608h as a colorless oil (29.9 mg, 0.091 mmol, 91%). 1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 7.0 Hz, 2H), 7.52 – 7.46 (m, 1H), 7.40 – 7.37 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.92 – 3.88 (m, 1H), 3.82 – 3.76 (m, 1H), 3.70 (d, J = 17.6 Hz, 1H), 2.95 (d, J = 17.6 Hz, 1H), 2.22 – 2.08 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.4, 173.8, 162.1, 142.2, 135.1, 132.2, 128.5, 127.8, 71.1, 61.5, 46.7, 42.2, 34.9, 20.4, 14.4; IR (Neat Film, NaCl) 3327, 2944, 1684, 1571, 1449, 1389, 1275, 1148, 1127, 1024, 923, 724, 682 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H19N3NaO4 [M+Na]+: 352.1268, found 352.1271; [a]D23 +147.2° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 4.21, minor = 4.95. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 867 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 868 O HN N CO2Et CbzN 608j 7-benzyl 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3,7-dicarboxylate (608j) 0.1 mmol scale: Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 7-benzyl 3-ethyl (S)-6-oxo1,2,7-triazaspiro[4.6]undec-2-ene-3,7-dicarboxylate 608j as a colorless oil (26.9 mg, 0.072 mmol, 72%). 2.0 mmol scale: Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 30:70) to afford 7-benzyl 3-ethyl (S)-6-oxo1,2,7-triazaspiro[4.6]undec-2-ene-3,7-dicarboxylate 608j as a colorless oil (617.5 mg, 1.65 mmol, 83%). 1 H NMR (500 MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 5.29 (d, J = 12.2 Hz, 1H), 5.26 (d, J = 12.2 Hz, 1H), 4.36 – 4.27 (m, 3H), 3.40 (dd, J = 15.6, 10.9 Hz, 1H), 3.34 (d, J = 17.5 Hz, 1H), 3.14 (d, J = 17.5 Hz, 1H), 2.05 – 1.87 (m, 4H), 1.77 – 1.69 (m, 1H), 1.58 – 1.49 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 175.5, 162.2, 155.0, 141.2, 135.1, 128.7, 128.5, 128.2, 74.6, 69.3, 61.5, 45.3, 39.1, 35.8, 27.7, 24.4, 14.4; IR (Neat Film, NaCl) 3341, 2937, 1764, 1716, 1558, 1450, 1378, 1256, 1168, 1123, 1003, 971, 777, 696 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H23N3NaO5 [M+Na]+: 396.1530, found 396.1534; [a]D23 +171.8° (c 1.00, CHCl3); SFC Conditions: 15% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 8.11, minor = 7.63. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 869 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 870 HN N CO2Et CbzN 608k 7-benzyl 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.4]non-2-ene-3,7-dicarboxylate (608k) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 7-benzyl 3-ethyl (S)-6-oxo-1,2,7triazaspiro[4.4]non-2-ene-3,7-dicarboxylate 608k as a colorless oil (27.8 mg, 0.080 mmol, 80%). 1 H NMR (500 MHz, CDCl3) δ 7.45 – 7.32 (m, 5H), 5.30 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.88 – 3.83 (m, 1H), 3.72 – 3.67 (m,1H), 3.41 (d, J = 17.5 Hz, 1H), 3.01 (d, J = 17.5 Hz, 1H), 2.23 (t, J = 6.8 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 172.6, 162.0, 151.4, 141.0, 134.9, 128.8, 128.7, 128.4, 71.7, 68.7, 61.5, 42.4, 41.5, 32.4, 14.4; IR (Neat Film, NaCl) 3317, 2982, 1789, 1726, 1567, 1446, 1380, 1297, 1125, 1007, 970, 775, 695 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H19N3NaO5 [M+Na]+: 368.1217, found 368.1217; [a]D23 +91.8° (c 1.00, CHCl3); SFC Conditions: 20% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 7.23, minor = 6.44. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 871 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O 872 HN N CO2Et CbzN 608l 1'-benzyl 5-ethyl (S)-2'-oxo-2,4-dihydro-2'H-spiro[pyrazole-3,3'-quinoline]- 1',5(4'H)-dicarboxylate (608l) Synthesized according to general procedure A and purified by flash chromatography (hexanes/EtOAc = 70:30 to 40:60) to afford 1'-benzyl 5-ethyl (S)-2'-oxo-2,4-dihydro-2'Hspiro[pyrazole-3,3'-quinoline]-1',5(4'H)-dicarboxylate 608l as a colorless oil (35.6 mg, 0.087 mmol, 87%). 1 H NMR (500 MHz, CDCl3) δ 7.46 – 7.44 (m, 2H), 7.42 – 7.37 (m, 3H), 7.24 – 7.11 (m, 3H), 6.91 –6.89 (m, 1H), 6.63 (s, 1H), 5.45 – 5.40 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.33 (d, J = 17.9 Hz, 1H), 3.28 (d, J = 15.5 Hz, 1H), 3.02 (d, J = 15.5 Hz, 1H), 2.81 (d, J = 17.9 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 169.2, 161.9, 153.1, 142.8, 135.9, 134.1, 129.3, 129.1, 128.93, 128.86, 128.4, 125.5, 123.9, 118.8, 70.6, 68.6, 61.6, 40.8, 37.9, 14.3; IR (Neat Film, NaCl) 3342, 2984, 1773, 1701, 1573, 1459, 1284, 1219, 1122, 1073, 1010, 753, 700 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H22N3O5 [M+H]+: 408.1554, found 408.1562; [a]D23 +43.8° (c 1.00, CHCl3); SFC Conditions: 30% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 4.70, minor = 3.54. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 873 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 5.4.2.2 874 1,3-Dipolar Cycloaddition of Nitrile Oxides: General Procedure B O O N N 605 O Cbz O O Mg(NTf2)2 N Cbz + N O N N DCE 23 °C, 18 h 609 606a 610a benzyl (S)-3-mesityl-6-oxo-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate (610a) A screw-top 2 dram vial was charged with a stir bar, benzyl 3-methylene-2-oxopiperidine1-carboxylate 606a (24.5 mg, bis(trifluoromethanesulfonyl)imide (5.8 0.100 mmol, 1.00 eq.), magnesium mg, 0.010 mmol, 0.10 eq.) and (3aS,3′aS,8aR,8′aR)-2,2′-Cyclopropylidenebis[3a,8a-dihydro-8H-indeno[1,2-d]oxazole] 605 (3.9 mg, 0.011 mmol, 0.11 eq.). The vial was purged and backfilled three times with nitrogen and then the solids were dissolved in dichloroethane (1.0 ml). After being stirred at 23 ˚C for 30 min, mesityl nitrile oxide 609 (24.2 mg, 0.150 mmol, 1.50 eq.) in dichloroethane (0.5 mL) was added to reaction mixture at 23 °C. After being stirred at 23˚C for 18 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into water. The aqueous layer was extracted with dichloromethane two times. The combined extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 80:20 to 65:35) to yield benzyl (S)-3mesityl-6-oxo-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-7-carboxylate 610a as a colorless oil (33.3 mg, 0.082 mmol, 82%). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 1 875 H NMR (400 MHz, CDCl3) δ 7.48 – 7.31 (m, 5H), 6.90 (s, 2H), 5.31 (s, 2H), 4.08 (d, J = 17.5 Hz, 1H), 4.03 – 3.93 (m, 1H), 3.85 (ddd, J = 13.0, 8.5, 4.9 Hz, 1H), 2.86 (d, J = 17.5 Hz, 1H), 2.47 – 2.38 (m, 1H), 2.29 (m, 9H), 2.26 – 2.16 (m, 1H), 2.05 – 1.96 (m, 1H), 1.96 – 1.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.6, 157.5, 154.1, 139.1, 136.9, 135.3, 128.7, 128.53, 128.46, 128.2, 125.5, 86.0, 68.9, 47.5, 46.1, 33.4, 21.2, 19.80, 19.77; IR (Neat Film, NaCl) 3032, 2948, 2920, 1774, 1719, 1609, 1455, 1378, 1312, 1266, 1224, 1166, 983, 852, 737, 700 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C24H27N2O4 [M+H]+: 407.1965, found 407.1969; [a]D23 +169.3 (c 1.00, CHCl3); SFC Conditions: 15% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 6.36, minor = 11.15. General Procedure for the Synthesis of Racemic Products Racemic products were synthesized in a manner analogous to the general procedure but without chiral ligand. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 876 Spectroscopic Data for Enantioenriched Pyrazoline Cycloadducts O Cbz O N N 610j benzyl (S)-3-mesityl-6-oxo-1-oxa-2,7-diazaspiro[4.6]undec-2-ene-7-carboxylate (610j) Synthesized according to general procedure B and purified by flash chromatography (hexanes/EtOAc = 90:10 to 80:20) to afford benzyl (S)-3-mesityl-6-oxo-1-oxa-2,7diazaspiro[4.6]undec-2-ene-7-carboxylate 610j as a yellow oil (37.4 mg, 0.089 mmol, 89%). 1 H NMR (400 MHz, CDCl3) δ 7.45 – 7.29 (m, 5H), 6.88 (s, 2H), 5.29 (dd, J = 16.8, 12.7 Hz, 2H), 4.36 (dd, J = 14.6, 4.5 Hz, 1H), 4.31 (d, J = 17.9 Hz, 1H), 4.09 (dd, J = 15.2, 10.5 Hz, 1H), 2.96 (d, J = 17.9 Hz, 1H), 2.29 (s, 3H), 2.18 (s, 6H), 2.15 – 1.91 (m, 4H), 1.88 – 1.78 (m, 1H), 1.58 – 1.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.0, 159.2, 155.1, 139.1, 136.7, 135.5, 128.63, 128.55, 128.4, 128.1, 125.6, 90.9, 68.9, 50.4, 45.0, 35.9, 28.0, 24.3, 21.2, 19.8; IR (Neat Film, NaCl) 3030, 2936, 2863, 1769, 1713, 1610, 1456, 1379, 1330, 1264, 1252, 1185, 1006, 979, 872, 842, 698 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C25H29N2O4 [M+H]+: 421.2122, found 421.2135; [a]D23 +44.0 (c 1.00, CHCl3); SFC Conditions: 5% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 14.71, minor = 15.97. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 877 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O Cbz 878 O N N 610l benzyl (S)-3-mesityl-2'-oxo-2'H,4H-spiro[isoxazole-5,3'-quinoline]-1'(4'H)- carboxylate (610l) Synthesized according to general procedure B and purified by flash chromatography (hexanes/EtOAc = 85:15 to 70:30) to afford benzyl (S)-3-mesityl-2'-oxo-2'H,4Hspiro[isoxazole-5,3'-quinoline]-1'(4'H)-carboxylate 610l as a white solid (29.6 mg, 0.065 mmol, 65%). 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.35 (m, 5H), 7.27 – 7.19 (m, 2H), 7.12 (t, J = 7.9 Hz, 1H), 6.92 – 6.88 (m, 3H), 5.46 (s, 2H), 3.99 (d, J = 17.6 Hz, 1H), 3.40 (d, J = 16.1 Hz, 1H), 3.31 (d, J = 16.1 Hz, 1H), 3.00 (d, J = 17.7 Hz, 1H), 2.29 (d, J = 2.4 Hz, 9H).; 13C NMR (100 MHz, CDCl3) δ 166.0, 157.5, 153.2, 139.2, 136.9, 135.9, 134.3, 129.2, 129.0, 128.83, 128.79, 128.6, 128.1, 125.3, 125.1, 122.9, 118.0, 83.5, 70.5, 45.9, 37.6, 21.2, 19.8; IR (Neat Film, NaCl) 3033, 2953, 2923, 1771, 1698, 1607, 1497, 1460, 1374, 1327, 1286, 1217, 1011, 953, 850, 734, 699 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C28H27N2O4 [M+H]+: 455.1965, found 455.1978; [a]D23 +39.4 (c 1.00, CHCl3); SFC Conditions: 25% EtOH, 2.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 3.99, minor = 5.32. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 879 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 5.4.2.3 880 Product Diversification O Cbz HN N N CO2Et Ra/Ni H2 (1 atm) 3:1 i-PrOH/H2O 23 °C, 27 h 608j O HN N CO2Et HN 611 ethyl (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3-carboxylate (611) To a round bottom flask was added a stir bar, 7-benzyl 3-ethyl (S)-6-oxo-1,2,7triazaspiro[4.6]undec-2-ene-3,7-dicarboxylate (608j) (299 mg, 0.8 mmol, 1.0 equiv), and i-PrOH/H2O (3:1, 10 mL). A suspension of Raney Nickel® (50:50 w/water) (300 mg slurry) was added and the headspace was rapidly purged and backfilled with nitrogen ten times. The headspace and the solution were then sparged with a hydrogen gas balloon for 15 min. The reaction was then stirred for 27 h at 23 °C under 1 atm of hydrogen gas. Upon completion, the hydrogen was vented, and the reaction was passed through a pad of Celite with EtOAc and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (hexanes/EtOAc = 20:80 to 0:100 to EtOAc/MeOH = 99:1) to afford 611 as a white foam (147.1 mg, 77%). 1 H NMR (400 MHz, CDCl3) δ 7.24 (bs, 1H), 6.24 – 6.12 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.32 – 3.16 (m, 3H), 3.07 (dd, J = 17.4, 1.8 Hz, 1H), 2.05 – 1.95 (m, 2H), 1.91 – 1.79 (m, 2H), 1.78 – 1.65 (m, 1H), 1.54 – 1.39 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 162.5, 142.2, 72.6, 61.4, 42.6, 38.5, 34.8, 29.3, 25.4, 14.4; IR (Neat Film, NaCl) 3309, 3101, 2980, 2932, 1699, 1655, 1575, 1456, 1431, 1332, 1257, 1121, 1049, 1015 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C11H18N3O3 [M+H]+: 240.1343, found 240.1338; [a]D23 +86.9 (c 0.33, CHCl3). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O HN O N HN 611 CO2Et LiOH (aq) 1,4-dioxane 23 °C, 1.5 h HN N 881 •TFA CO2H HN 612 (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3-carboxylic acid • trifluoroacetate salt (612) To a solution of ethyl (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3-carboxylate (611) (18.0 mg, 0.075 mmol, 1.0 equiv) in 1,4-dioxane (0.75 mL) was added an aqueous solution of LiOH (2 M, 94 µL, 2.5 equiv). The resulting solution was stirred for 1.5 h at 23 °C after which it was diluted with H2O and EtOAc, acidified to a pH of 2 with 1 M HCl, extracted five times with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase chromatography (C18 column, 0 to 30% MeCN/(H2O + 0.1% TFA)) to afford 612 as a white solid (16.8 mg, 69%). 1 H NMR (600 MHz, pyridine) δ 8.83 (s, 1H), 3.76 (d, J = 17.3 Hz, 1H), 3.28 (d, J = 16.9 Hz, 2H), 3.14 (bs, 1H), 2.02 – 1.73 (m, 3H), 1.65 – 1.53 (m, 2H), 1.39 – 1.23 (m, 1H); 13C NMR (100 MHz, CD3CN) δ 177.1, 163.6, 142.7, 74.2, 42.5, 39.0, 35.5, 29.8, 25.7; IR (Neat Film, NaCl) 3308, 2933, 1687, 1651, 1440, 1303, 1206, 1185, 1135, 800, 722 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C9H12N3O3 [M–H]–: 210.0884, found 210.0881; [a]D23 +73.8 (c 0.29, pyridine). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O Cbz HN O N N CO2Et NaOEt 2:1 EtOH/THF 0 °C, 20 min 608j diethyl HN 882 N EtO CO2Et CbzHN 613 (S)-5-(4-(((benzyloxy)carbonyl)amino)butyl)-4,5-dihydro-1H-pyrazole-3,5- dicarboxylate (613) To a solution of 7-benzyl 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3,7dicarboxylate (608j) (37.3 mg, 0.10 mmol, 1.0 equiv) in EtOH/THF (2:1, 1.7 mL) at 0 °C was added a solution of NaOEt in EtOH (1 M, 0.11 mL, 1.1 equiv). The resulting mixture was stirred at 0 °C for 20 min after which it was quenched with pH 7 aqueous phosphate buffer. The solution was then extracted three times with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (hexanes/EtOAc = 80:20 to 20:80) to afford 613 as a colorless oil (26.0 mg, 62%). 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 5H), 6.76 (s, 1H), 5.07 (s, 2H), 4.82 (t, J = 5.9 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.44 (d, J = 17.7 Hz, 1H), 3.16 (q, J = 6.7 Hz, 2H), 2.83 (d, J = 17.7 Hz, 1H), 1.94 – 1.75 (m, 2H), 1.50 (p, J = 7.3 Hz, 2H), 1.35 – 1.23 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 173.6, 162.2, 156.5, 142.5, 136.6, 128.6, 128.2 (3C, overlapping, 73.1, 66.8, 62.2, 61.4, 40.7, 39.7, 37.4, 29.9, 21.8, 14.3, 14.2; IR (Neat Film, NaCl) 3374, 2980, 2938, 1722, 1528, 1456, 1369, 1261, 1136, 1062, 1019, 912, 737, 698 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H30N3O6 [M+H]+: 420.2129, found 420.2141; [a]D23 +10.3 (c 1.00, CHCl3). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O Cbz HN O N N CO2Et NBS Cbz CCl4 0 to 23 °C, 3 h 608j 7-benzyl 3-ethyl N N 883 CO2Et Br N 1.5:1 dr 614 (5S)-3-bromo-6-oxo-1,2,7-triazaspiro[4.6]undec-1-ene-3,7- dicarboxylate (614) To a solution of 7-benzyl 3-ethyl (S)-6-oxo-1,2,7-triazaspiro[4.6]undec-2-ene-3,7dicarboxylate (608j) (37.3 mg, 0.10 mmol, 1.0 equiv) in CCl4 (1.3 mL) at 0 °C was added NBS (17.8 mg, 0.10 mmol, 1.0 equiv). The resulting mixture was then stirred at 0 °C for 3 h and then warmed to 23 °C for 35 min. Upon completion, the reaction was filtered through Celite and concentrated. The crude residue was purified by column chromatography (hexanes/EtOAc = 90:10 to 70:30) to afford 614 as a separable mixture of two diastereomers that were colorless oils (major: 26.0 mg, 57.5%; minor: 17.7 mg, 39.1%; 97% yield, 1.5:1 dr). Major diastereomer: 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 5H), 5.26 (dd, J = 13.8, 1.7 Hz, 2H), 4.68 (ddd, J = 15.2, 10.0, 1.7 Hz, 1H), 4.38 – 4.22 (m, 2H), 4.18 – 4.08 (m, 1H), 3.36 (d, J = 15.3 Hz, 1H), 2.39 – 2.32 (m, 1H), 2.30 (d, J = 15.2 Hz, 1H), 2.12 – 1.95 (m, 3H), 1.87 – 1.71 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 165.7, 154.7, 135.2, 128.7, 128.5, 128.2, 103.7, 89.8, 69.2, 63.8, 44.9, 42.1, 35.3, 27.9, 24.2, 13.9; IR (Neat Film, NaCl) 2937, 2866, 1770, 1731, 1497, 1455, 1378, 1269, 1249, 1177, 1112, 1010, 744 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H23BrN3O5 [M+H]+: 452.0816, found 452.0816; [a]D23 +94.5 (c 1.00, CHCl3). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 884 Minor diastereomer: 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.29 (m, 5H), 5.27 (s, 2H), 4.61 (ddd, J = 15.2, 10.0, 1.5 Hz, 1H), 4.45 – 4.25 (m, 2H), 4.16 (ddd, J = 15.2, 6.9, 2.3 Hz, 1H), 3.20 (d, J = 15.0 Hz, 1H), 2.57 (d, J = 15.0 Hz, 1H), 2.18 – 1.90 (m, 4H), 1.86 – 1.71 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 166.3, 154.8, 135.3, 128.7, 128.5, 128.1, 103.9, 90.5, 69.2, 64.0, 45.0, 42.5, 37.1, 27.9, 24.5, 14.0; IR (Neat Film, NaCl) 2936, 2868, 1770, 1718, 1497, 1379, 1269, 1250, 1177, 1125, 1081, 1006, 772, 737 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H23BrN3O5 [M+H]+: 452.0816, found 452.0814; [a]D23 +12.7 (c 1.00, CHCl3). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 885 Preparation of a-Methylene Lactam Substrates 5.4.2.4 O HN O O 1) NaBH4, CaCl2 1) MeOH, 23 °C 2) EDC, CuI 2) PhMe, reflux CbzCl, LHMDS CbzN HN 16% 615 O O THF, –78 ˚C 48% 616 606a 3-methylenepiperidin-2-one[15] (616) To a stirred solution of ethyl 2-oxopiperidine-3-carboxylate 615 (6.00 g, 35.1 mmol, 1.00 eq.) in MeOH (72 mL) was added calcium chloride (4.28 g, 38.6 mmol, 1.10 eq.) and sodium borohydride (2.92 g, 77.1 mmol, 2.20 eq.) at 0 ˚C. After being stirred at room temperature for 63 h, the reaction mixture was poured into citric acid solution (1 M aq., 75 ml). The aqueous layer was extracted with ethyl acetate three times and then dichloromethane three times. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue (3.07 g) was used for the next reaction without further purification. To a stirred solution of the residue (3.07 g) in toluene (30 mL) was added copper (I) iodide (453 mg, 2.38 mmol, 0.07 eq.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.84 g, 35.7 mmol, 1.02 eq.) at room temperature. After being stirred at 110 ˚C in an oil bath for 6 h, water (30 ml) was added to reaction mixture at room temperature. After being stirred at the same temperature for 1 h, Et2O (60 ml) was added to reaction mixture and filtered. The filtrate was poured into water (30 ml), the layers were partitioned and extracted with dichloromethane three times. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/MeOH = 97:3 to 96:4) to afford 3-methylenepiperidin- Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 886 2-one 616 as a colorless oil (635 mg, 5.71 mmol, 2 steps 16%). All characterization data matched those reported in the literature.15 benzyl 3-methylene-2-oxopiperidine-1-carboxylate (606a) To a stirred solution of 3-methylenepiperidin-2-one 616 (400 mg, 3.60 mmol, 1.00 eq.) in THF (15 mL) was added LHMDS (1 M in THF, 4.32 mL, 4.32 mmol, 1.20 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 20 min, CbzCl (3 M in toluene, 1.44 ml, 4.32 mmol, 1.20 eq.) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with NH4Cl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/Et2O = 90:10 to 60:40) to afford benzyl 3-methylene-2-oxopiperidine-1-carboxylate 606a as a white solid (425 mg, 1.73 mmol, 48%). 1 H NMR (500 MHz, CDCl3) δ 7.47 – 7.29 (m, 5H), 6.36 (d, J = 1.7 Hz, 1H), 5.44 (d, J = 1.7 Hz, 1H), 5.30 (s, 2H), 3.86 – 3.75 (m, 2H), 2.61 – 2.57 (m, 2H), 1.92 – 1.87 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.7, 154.6, 138.4, 135.5, 128.7, 128.4, 128.2, 125.8, 68.7, 47.2, 29.3, 22.6; IR (Neat Film, NaCl) 2952, 1769, 1713, 1624, 1454, 1377, 1305, 1265, 1172, 1017, 941, 799, 698 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H16NO3 [M+H]+: 246.1125, found 246.1123. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O HN 887 O FmocCl LHMDS FmocN THF, –78 ˚C 97% 616 606c (9H-fluoren-9-yl)methyl 3-methylene-2-oxopiperidine-1-carboxylate (606c) To a stirred solution of 3-methylenepiperidin-2-one 616 (50.0 mg, 0.450 mmol, 1.00 eq.) in THF (1.0 mL) was added LHMDS (1 M in THF, 0.495 mL, 0.495 mmol, 1.10 eq.) at – 78 ˚C under N2. After being stirred at the same temperature for 20 min, FmocCl (128 mg, 0.495 mmol, 1.10 eq.) in THF (1.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with NH4Cl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 95:5 to 85:15) to afford (9H-fluoren-9-yl)methyl 3-methylene-2-oxopiperidine-1carboxylate 606c as a colorless oil (145 mg, 0.435 mmol, 97%). 1 H NMR (500 MHz, CDCl3) δ 7.81 – 7.72 (m, 4H), 7.44 – 7.38 (m, 2H), 7.34 (td, J = 7.5, 1.2 Hz, 2H), 6.43 (d, J = 1.7 Hz, 1H), 5.50 (d, J = 1.7 Hz, 1H), 4.52 (d, J = 7.4 Hz, 2H), 4.35 (t, J = 7.4 Hz, 1H), 3.86 – 3.71 (m, 2H), 2.65 – 2.62 (m, 2H), 1.99 – 1.83 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.7, 154.8, 143.8, 141.4, 138.5, 127.9, 127.3, 125.9, 125.5, 120.1, 69.3, 47.2, 46.8, 29.3, 22.6; IR (Neat Film, NaCl) 3064, 2950, 1769, 1712, 1622, 1477, 1450, 1378, 1305, 1262, 1168, 1017, 942, 799, 740 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H19NNaO3[M+Na]+: 356.1257, found 356.1258. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 888 O O TMS O O O HN 616 N O O LHMDS THF, –78 ˚C 74% TMS O O N 606d 2-(trimethylsilyl)ethyl 3-methylene-2-oxopiperidine-1-carboxylate (606d) To a stirred solution of 3-methylenepiperidin-2-one 616 (100 mg, 0.900 mmol, 1.00 eq.) in THF (2.0 mL) was added LHMDS (1 M in THF, 0.900 mL, 0.900 mmol, 1.00 eq.) at – 78 ˚C under N2. After being stirred at the same temperature for 20 min, 2,5dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate (233 mg, 0.900 mmol, 1.00 eq.) in THF (1.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with sat. NH4Cl and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 100:0 to 85:15) to afford 2(trimethylsilyl)ethyl 3-methylene-2-oxopiperidine-1-carboxylate 606d as a colorless oil (170 mg, 0.666 mmol, 74%). 1 H NMR (500 MHz, CDCl3) δ 6.35 (d, J = 1.7 Hz, 1H), 5.43 (d, J = 1.7 Hz, 1H), 4.37 – 4.34 (m, 2H), 3.79 – 3.77 (m, 2H), 2.61 – 2.58 (m, 2H), 1.92 – 1.87 (m, 2H), 1.16 – 1.12 (m, 2H), 0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 164.7, 154.9, 138.5, 125.6, 65.8, 47.1, 29.4, 22.7, 17.7, -1.5; IR (Neat Film, NaCl) 2953, 1769, 1714, 1625, 1477, 1451, 1378, 1306, 1264, 1169, 1042, 1101, 937, 851, 799, 771, 694 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C12H21NNaO3Si [M+Na]+: 278.1183, found 278.1185. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O TrocCl LHMDS HN 889 THF, –78 ˚C 60% 616 TrocN 606e 2,2,2-trichloroethyl 3-methylene-2-oxopiperidine-1-carboxylate (606e) To a stirred solution of 3-methylenepiperidin-2-one 616 (80.0 mg, 0.720 mmol, 1.00 eq.) in THF (2.0 mL) was added LHMDS (1 M in THF, 0.720 mL, 0.720 mmol, 1.00 eq.) at – 78 ˚C under N2. After being stirred at the same temperature for 20 min, TrocCl (0.099 ml, 0.720 mmol, 1.00 eq.) in THF (1.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with NH4Cl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/Et2O = 90:10 to 60:40) to afford 2,2,2-trichloroethyl 3-methylene-2-oxopiperidine-1-carboxylate 606e as a colorless oil (124 mg, 0.433 mmol, 60%). 1 H NMR (500 MHz, CDCl3) δ 6.41 (d, J = 1.7 Hz, 1H), 5.50 (d, J = 1.7 Hz, 1H), 4.88 (s, 2H), 3.91 – 3.88 (m, 2H), 2.65 – 2.62 (m, 2H), 2.03 – 1.89 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.5, 152.4, 137.9, 126.6, 94.6, 75.8, 47.5, 29.2, 22.5; IR (Neat Film, NaCl) 2954, 1781, 1713, 1625, 1476, 1443, 1372, 1304, 1252, 1172, 1042, 940, 881, 810, 711 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C9H10Cl3NNaO3 [M+Na]+: 307.9618, found 307.9621. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O HN Boc2O LHMDS 890 O BocN THF, –78 ˚C 55% 616 606f tert-butyl 3-methylene-2-oxopiperidine-1-carboxylate (606f) To a stirred solution of 3-methylenepiperidin-2-one 616 (50 mg, 0.438 mmol, 1.00 eq.) in THF (1.0 mL) was added LHMDS (1 M in THF, 0.526 mL, 0.526 mmol, 1.20 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 20 min, Boc2O (115 mg, 0.526 mmol, 1.20 eq.) in THF (1.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with NH4Cl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 100:0 to 85:15) to afford tert-butyl 3-methylene-2-oxopiperidine-1-carboxylate 606f as a colorless oil (51.3 mg, 0.243 mmol, 55%). 1 H NMR (500 MHz, CDCl3) δ 6.32 (d, J = 1.7 Hz, 1H), 5.40 (d, J = 1.7 Hz, 1H), 3.76 – 3.64 (m, 2H), 2.63 – 2.52 (m, 2H), 1.91 – 1.86 (m, 2H), 1.55 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 164.8, 153.2, 138.7, 125.2, 83.1, 46.9, 29.4, 28.1, 22.7; IR (Neat Film, NaCl) 2979, 1767, 1715, 1625, 1476, 1368, 1306, 1150, 1006, 943, 853, 801, 689 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C11H17NNaO3 [M+Na]+: 234.1101, found 234.1101. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 891 O O Ac2O, NEt3 AcN HN THF, 60 ˚C 38% 616 606g 1-acetyl-3-methylenepiperidin-2-one (606g) To a stirred solution of 3-methylenepiperidin-2-one 616 (80.0 mg, 0.720 mmol, 1.00 eq.) in THF (2.0 mL) was added triethylamine (0.150 mL, 1.08 mmol, 1.50 eq.) and acetic anhydride (0.102 mL, 1.08 mmol, 1.50 eq.) at room temperature under N2. After being stirred at 60 ˚C in an oil bath for 16 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 100:0 to 85:15) to afford 1-acetyl-3-methylenepiperidin-2-one 606g as a colorless oil (41.5 mg, 0.271 mmol, 38%). 1 H NMR (500 MHz, CDCl3) δ 6.37 (d, J = 1.7 Hz, 1H), 5.49 (d, J = 1.7 Hz, 1H), 3.79 – 3.76 (m, 2H), 2.63 – 2.60 (m, 2H), 2.59 (s, 3H), 1.91 – 1.86 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 174.5, 166.6, 138.7, 125.9, 44.8, 29.5, 28.2, 22.4; IR (Neat Film, NaCl) 2941, 1692, 1620, 1386, 1309, 1256, 1253, 1176, 1119, 1047, 965, 800, 684 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C8H12NO2 [M+H]+: 154.0863, found 154.0864. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O BzCl, NEt3 HN 616 892 THF, 23 °C 96% BzN 606h 1-benzoyl-3-methylenepiperidin-2-one (606h) To a stirred solution of 3-methylenepiperidin-2-one 616 (50.0 mg, 0.450 mmol, 1.00 eq.) in THF (2.0 mL) was added triethylamine (0.188 mL, 1.35 mmol, 3.00 eq.) and benzoyl chloride (0.105 mL, 0.900 mmol, 2.00 eq.) at room temperature under N2. After being stirred at the same temperature for 7 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 100:0 to 85:15) to afford 1-benzoyl-3-methylenepiperidin-2-one 606h as a white solid (93.2 mg, 0.433 mmol, 96%). 1 H NMR (500 MHz, CDCl3) δ 7.56 – 7.38 (m, 5H), 6.29 (d, J = 1.7 Hz, 1H), 5.48 (d, J = 1.7 Hz, 1H), 3.91 – 3.88 (m, 2H), 2.74 – 2.70 (m, 2H), 2.07 – 2.02 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 174.9, 166.6, 138.1, 136.4, 131.6, 128.2, 127.9, 125.8, 46.0, 29.5, 22.8; IR (Neat Film, NaCl) 2954, 1681, 1624, 1448, 1395, 1307, 1285, 1172, 1149, 1058, 942, 801, 729, 694 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H13NNaO2 [M+Na]+: 238.0838, found 238.0843. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O BnBr, n-BuLi HN 616 893 THF –78 to 50 ˚C 56% BnN 606i 1-benzyl-3-methylenepiperidin-2-one (606i) To a stirred solution of 3-methylenepiperidin-2-one 616 (63.7 mg, 0.573 mmol, 1.00 eq.) in THF (1.0 mL) was added n-BuLi (2.5 M in hexanes, 0.252 mL, 0.630 mmol, 1.10 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 20 min, benzyl bromide (0.075 ml, 0.630 mmol, 1.10 eq.) was added to reaction mixture at –78 °C. After being stirred at 50 ˚C in an oil bath for 1 h, the reaction mixture was quenched with NH4Cl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 90:10 to 70:30) to afford 1-benzyl-3-methylenepiperidin-2-one 606i as a colorless oil (64.6 mg, 0.321 mmol, 56%). 1 H NMR (500 MHz, CDCl3) δ 7.35 – 7.22 (m, 5H), 6.28 (d, J = 1.9 Hz, 1H), 5.33 (d, J = 1.9 Hz, 1H), 4.67 (s, 2H), 3.31 (t, J = 5.9 Hz, 2H), 2.60 – 2.57 (m, 2H), 1.87 – 1.82 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.5, 137.9, 137.3, 128.7, 128.2, 127.5, 122.2, 50.8, 47.9, 30.3, 23.2; IR (Neat Film, NaCl) 2930, 1652, 1612, 1487, 1452, 1340, 1222, 1197, 1078, 975, 935, 800, 739, 703 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H16NO [M+H]+: 202.1226, found 202.1226. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O CbzCl LHMDS HN CbzN THF, –78 ˚C 89% 617 894 O LHMDS Eschenmoser’s salt N CbzN THF, –78 ˚C 618 619 O Br CbzN Na2CO3 EtOH, 23 °C 2 steps 16% 606j benzyl 2-oxoazepane-1-carboxylate[16] (618) To a stirred solution of azepan-2-one 617 (500 mg, 4.42 mmol, 1.00 eq.) in THF (10 mL) was added LHMDS (1 M in THF, 4.86 mL, 4.86 mmol, 1.10 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 20 min, CbzCl (3 M in toluene, 1.62 ml, 4.86 mmol, 1.10 eq.) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 1 h, the reaction mixture was quenched with 1M HCl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 90:10 to 80:20) to afford benzyl 2-oxoazepane-1-carboxylate 618 as a colorless oil (970 mg, 3.92 mmol, 89%). All characterization data matched those reported in the literature.16 benzyl 3-methylene-2-oxoazepane-1-carboxylate (606j) To a stirred solution of benzyl 2-oxoazepane-1-carboxylate 618 (670 mg, 2.71mmol, 1.00 eq.) in THF (14 mL) was added LHMDS (1 M in THF, 3.52 mL, 3.52 mmol, 1.30 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 1 h, the suspension of Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 895 Eschenmoser’s salt (1.10 g, 5.96 mmol, 2.2 eq.) in THF (6.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used for the next reaction without further purification. To a stirred solution of residue in ethanol (20 mL) was added allyl bromide (1.87 ml, 21.7 mmol, 8.00 eq.) and Na2CO3 (1.72 g, 16.3 mmol, 6.00 eq.) at room temperature. After being stirred at the same temperature for 18 h, the reaction mixture was poured into water. The aqueous layer was extracted with ethyl acetate two times. The residue was purified by silica gel chromatography (hexanes/Et2O = 90:10 to 65:35) to afford benzyl 3-methylene2-oxoazepane-1-carboxylate 606j as a colorless oil (110 mg, 0.424 mmol, 2 steps 16%). 1 H NMR (500 MHz, CDCl3) δ 7.45 – 7.43 (m, 2H), 7.38 – 7.30 (m, 3H), 5.82 (d, J = 1.3 Hz, 1H), 5.44 (d, J = 1.3 Hz, 1H), 5.30 (s, 2H), 3.76 – 3.74 (m, 2H), 2.44 –2.42 (m, 2H), 1.80 – 1.73 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 172.4, 154.1, 146.8, 135.7, 128.7, 128.3, 127.9, 124.0, 68.5, 46.5, 32.5, 29.2, 28.1; IR (Neat Film, NaCl) 2934, 1765, 1707, 1451, 1378, 1339, 1272, 1151, 1013, 932, 741, 695 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H17NNaO3 [M+Na]+: 282.1101, found 282.1107. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O HN O 1) NaBH4, CaCl2 1) MeOH, 23 °C 2) EDC, CuI 2) PhMe, reflux O 2 steps, 13% 620 621 [17] 3-methylenepyrrolidin-2-one O CbzCl, LHMDS HN 896 CbzN THF, –78 ˚C 53% 606k (621) To a stirred solution of ethyl 2-oxopyrrolidine-3-carboxylate 620 (3.87 g, 24.6 mmol, 1.00 eq.) in MeOH (50 mL) was added calcium chloride (3.01 g, 27.1 mmol, 1.10 eq.) and sodium borohydride (2.05 g, 54.2 mmol, 2.20 eq.) at 0 ˚C. After being stirred at room temperature for 64 h, the reaction mixture was poured into citric acid (1 M aq., 50 ml). The aqueous layer was extracted with ethyl acetate three times and dichloromethane three times. The combined extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue (1.42 g) was used for the next reaction without further purification. To a stirred solution of residue (1.42 g) in toluene (30 mL) was added copper (I) iodide (235 mg, 1.23 mmol, 0.05 eq.) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.56 g, 18.5 mmol, 0.75 eq.) at room temperature. After being stirred at 110 ˚C in an oil bath for 6 h, water (16 ml) was added to reaction mixture at room temperature. After being stirred at the same temperature for 1 h, Et2O (36 ml) was added to reaction mixture and filtered. The filtrate was poured into water (16 ml), the layers were partitioned and extracted with dichloromethane three times. The combined extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/MeOH = 97:3 to 96:4) to afford 3-methylenepyrrolidin2-one 621 as a white solid (311 mg, 3.20 mmol, 2 steps 13%). All characterization data matched those reported in the literature.17 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 897 benzyl 3-methylene-2-oxopyrrolidine-1-carboxylate (606k) To a stirred solution of 3-methylenepyrrolidin-2-one 621 (34.0 mg, 0.350 mmol, 1.00 eq.) in THF (2.0 mL) was added LHMDS (1 M in THF, 0.420 mL, 0.420 mmol, 1.20 eq.) at – 78 ˚C under N2. After being stirred at the same temperature for 20 min, CbzCl (3 M in toluene, 0.140 ml, 0.420 mmol, 1.20 eq.) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 30 min, the reaction mixture was quenched with 1M HCl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 90:10 to 80:20) to afford benzyl 3-methylene-2-oxopyrrolidine-1-carboxylate 606k as a white solid (42.6 mg, 0.184 mmol, 53%). 1 H NMR (500 MHz, CDCl3) δ 7.48 – 7.41 (m, 2H), 7.41 – 7.29 (m, 3H), 6.23 (t, J = 2.9 Hz, 1H), 5.52 (t, J = 2.6 Hz, 1H), 5.32 (s, 2H), 3.81 (t, J = 7.4 Hz, 2H), 2.81 – 2.77 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 166.3, 152.2, 138.7, 135.4, 128.7, 128.5, 128.2, 120.6, 68.2, 43.1, 23.4; IR (Neat Film, NaCl) 2913, 1781, 1720, 1659, 1382, 1300, 1168, 1013, 937, 770, 735, 697 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C13H13NNaO3 [M+Na]+: 254.0788, found 254.0792. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O O HN CbzCl LHMDS CbzN LHMDS Eschenmoser’s salt N CbzN THF, –78 ˚C THF, –78 ˚C 99% 622 623 624 O Br Na2CO3 898 CbzN EtOH, 23 °C 2 steps 54% 606l benzyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate[18] (623) To a stirred solution of 3,4-dihydroquinolin-2(1H)-one 622 (1.00 g, 6.79 mmol, 1.00 eq.) in THF (40 mL) was added LHMDS (1 M in THF, 7.47 mL, 7.47 mmol, 1.10 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 30 min, CbzCl (3 M in toluene, 2.27 ml, 6.79 mmol, 1.00 eq.) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 3 h, the reaction mixture was quenched with 1M HCl aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc = 100:0 to 80:20) to afford benzyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate 623 as a colorless oil (1.89 g, 6.72 mmol, 99%). All characterization data matched those reported in the literature.18 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 899 benzyl 3-methylene-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (606l) To a stirred solution of benzyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate 623 (800 mg, 2.84 mmol, 1.00 eq.) in THF (20 mL) was added LHMDS (1 M in THF, 3.70 mL, 3.70 mmol, 1.30 eq.) at –78 ˚C under N2. After being stirred at the same temperature for 1 h, the suspension of Eschenmoser’s salt (1.16 g, 6.26 mmol, 2.20 eq.) in THF (8.0 ml) was added to reaction mixture at –78 °C. After being stirred at the same temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 aq. and poured into water. The aqueous layer was extracted with ethyl acetate two times. The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was used for the next reaction without further purification. To a stirred solution of residue in ethanol (40 mL) was added allyl bromide (1.97 ml, 22.8 mmol, 8.00 eq.) and Na2CO3 (1.81 g, 17.1 mmol, 6.00 eq.) at room temperature. After being stirred at the same temperature for 19 h, the reaction mixture was poured into water. The aqueous layer was extracted with ethyl acetate two times. The residue was purified by silica gel chromatography (hexanes/Et2O = 100:0 to 70:30) to afford benzyl 3-methylene2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate 606l as a colorless oil (452 mg, 1.54 mmol, 2 steps 54%). 1 H NMR (500 MHz, CDCl3)δ7.48 – 7.45 (m, 2H), 7.41 – 7.34 (m, 3H), 7.21 – 7.08 (m, 4H), 6.26 (d, J = 1.3 Hz, 1H), 5.60 (d, J = 1.3 Hz, 1H), 5.42 (s, 2H), 3.72 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 164.6, 153.2, 136.1, 135.9, 134.7, 128.81, 128.79, 128.7, 127.5, 127.4, 125.6, 125.3, 125.1, 119.4, 69.9, 34.3; IR (Neat Film, NaCl) 3035, 2955, 1769, 1728, 1681, Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 900 1604, 1497, 1459, 1283, 1220, 1168, 1018, 954, 752, 696 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H16NO3 [M+H]+: 294.1125, found 294.1124. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O 1) TFAA, PhMe, 0 to 23 °C HN 2) KOt-Bu, isobutyraldehyde 2) THF, 0 to 55 °C 625 28% yield O LHMDS, CbzOSu HN THF, –78 to 23 °C 626 901 54% yield CbzN 606m (E)-3-(2-methylpropylidene)piperidin-2-one (626) Olefin 626 was prepared by a procedure adapted from the literature as follows:19 A solution of piperidin-2-one 625 (1190 mg, 12 mmol, 1.0 equiv) in toluene (12 mL) at 0 °C was stirred for 10 min. Trifluoroacetic anhydride (1.84 mL, 13.2 mmol, 1.1 equiv) was added dropwise over 10 minutes and the resulting mixture stirred for 10 min at 0 °C. The reaction was then warmed to 23 °C and stirred for 1 h after which it was concentrated. The crude residue was dried by coevaporation with toluene to yield a clear oil that was used directly in the next reaction without any further purification. A flame-dried round bottom flask was charged with a stir bar and a solution of KOt-Bu (1 M in THF, 16 mL, 1.3 equiv). The mixture was cooled to 0 °C and stirred for 10 min. In a separate flask, the clear residue from the above step and freshly distilled isobutyraldehyde (0.99 mL, 10.8 mmol, 0.9 equiv) were combined neat. The resulting mixture was added dropwise over 15 minutes to the THF solution and then stirred for 10 min at 0 °C. The reaction was then heated to 55 °C in an oil bath for 1 h, after which it was cooled to 23 °C and concentrated. The residue was then suspended in water and extracted with EtOAc three times, dried with Na2SO4, and concentrated. The crude residue was purified by recrystallization (refluxing EtOAc/hexanes, 10 mL, 1:1) to afford 626 as a white solid (455 mg, 28%). Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 1 902 H NMR (400 MHz, CDCl3) δ 6.66 (dt, J = 9.9, 2.1 Hz, 1H), 6.64 – 6.59 (m, 1H), 3.33 (td, J = 5.8, 2.8 Hz, 2H), 2.64 – 2.53 (m, 1H), 2.51 – 2.44 (m, 2H), 1.86 – 1.78 (m, 2H), 1.01 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.2, 145.7, 126.4, 42.1, 27.1, 24.4, 23.0, 22.1; IR (Neat Film, NaCl) 3183, 3049, 2953, 2864, 1670, 1624, 1491, 1416, 1335, 1169, 907, 842, 732 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C9H16NO [M+H]+: 154.1226, found 154.1229. benzyl (E)-3-(2-methylpropylidene)-2-oxopiperidine-1-carboxylate (606m) To a solution of amide 626 (306.5 mg, 2 mmol, 1.0 equiv) in THF (20 mL) at –78 °C was added a solution of LHDMS (1 M in hexanes, 2 mL, 1.0 equiv). The mixture was stirred at –78 °C for 30 min and then N-(benzyloxycarbonyloxy)succinimide (498 mg, 2 mmol, 1.0 equiv) was added. The reaction was warmed to 23 °C and stirred for 16 h. The reaction was diluted with H2O and CH2Cl2, extracted with CH2Cl2 three times, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexanes/EtOAc = 90:10 to 75:25) to afford substrate 606m as a colorless oil (312.9 mg, 54%). 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.40 (m, 2H), 7.40 – 7.28 (m, 3H), 6.81 (dt, J = 10.0, 2.2 Hz, 1H), 5.29 (s, 2H), 3.81 – 3.72 (m, 2H), 2.63 – 2.51 (m, 1H), 2.48 (td, J = 6.1, 2.1 Hz, 2H), 1.86 (p, J = 6.2 Hz, 2H), 1.02 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7, 154.7, 149.9, 135.7, 128.6, 128.3, 128.1, 127.7, 68.5, 46.4, 27.7, 24.2, 22.3, 21.8; IR (Neat Film, NaCl) 3032, 2958, 2868, 1768, 1704, 1629, 1455, 1377, 1306, 1260, 1166, Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 903 1112, 1051, 969, 910, 777, 733, 698 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H22NO3 [M+H]+: 288.1594, found 288.1605. Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams O O O 1) TFAA, PhMe, 0 to 23 °C HN 2) KOt-Bu, benzaldehyde 2) THF, 0 to 55 °C 625 HN 43% yield 904 Ph 627 LHMDS, CbzOSu THF, –78 to 23 °C Ph CbzN 34% yield 606n (E)-3-benzylidenepiperidin-2-one (627) Olefin 627 was prepared by a procedure adapted from the literature as follows:19 A solution of piperidin-2-one 625 (1190 mg, 12 mmol, 1.0 equiv) in toluene (12 mL) at 0 °C was stirred for 10 min. Trifluoroacetic anhydride (1.84 mL, 13.2 mmol, 1.1 equiv) was added dropwise over 10 minutes and the resulting mixture stirred for 10 min at 0 °C. The reaction was then warmed to 23 °C and stirred for 1 h after which it was concentrated. The crude residue was dried by coevaporation with toluene to yield a clear oil that was used directly in the next reaction without any further purification. A flame-dried round bottom flask was charged with a stir bar and a solution of KOt-Bu (1 M in THF, 16 mL, 1.3 equiv). The mixture was cooled to 0 °C and stirred for 10 min. In a separate flask, the clear residue from the above step and benzaldehyde (1.1 mL, 10.8 mmol, 0.9 equiv) were combined neat. The resulting mixture was added dropwise over 15 minutes to the THF solution and then stirred for 10 min at 0 °C. The reaction was then heated to 55 °C in an oil bath for 1 h, after which it was cooled to 23 °C and concentrated. The residue was then suspended in water and extracted with EtOAc three times, dried with Na2SO4, and concentrated. The crude residue was purified by recrystallization (refluxing EtOAc/hexanes 40 mL, 3:1) to afford 627 as a white solid (859.3 mg, 43%). 1 H NMR (400 MHz, CDCl3) δ 7.81 (t, J = 2.1 Hz, 1H), 7.41 – 7.28 (m, 5H), 6.84 (s, 1H), 3.48 – 3.39 (m, 2H), 2.85 – 2.77 (m, 2H), 1.86 (p, J = 6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.0, 135.9, 135.7, 129.9, 129.6, 128.4, 128.2, 42.2, 26.3, 23.1; IR (Neat Film, Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 905 NaCl) 3267, 3182, 3048, 2967, 1663, 1615, 1481, 1444, 1410, 1337, 1306, 1216, 1135, 910, 826, 775 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H14NO [M+H]+: 188.1070, found 188.1075. benzyl (E)-3-benzylidene-2-oxopiperidine-1-carboxylate (606n) To a suspension of amide 627 (131.0 mg, 0.7 mmol, 1.0 equiv) in THF (7 mL) at –78 °C was added a solution of LHDMS (1 M in hexanes, 0.7 mL, 1.0 equiv). The mixture was stirred at –78 °C for 30 min and then N-(Benzyloxycarbonyloxy)succinimide (175 mg, 0.7 mmol, 1.0 equiv) was added. The reaction was warmed to 23 °C and stirred for 16 h. The reaction was diluted with H2O and CH2Cl2, extracted with CH2Cl2 three times, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexanes/EtOAc = 80:20 to 70:30) to afford a solid which was further purified by recrystallization from hot EtOAc (0.5 mL) to yield 606n as a white solid (76.3 mg, 34%). All characterization data matched those reported in the literature.19 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 906 5.4.3 DETERMINATION OF ABSOLUTE CONFIGURATION VIA VIBRATIONAL CIRCULAR DICHROISM SPECTROSCOPY Experimental Protocol. A solution of 608a (50 mg/mL) in CDCl3 was loaded into a frontloading SL-4 cell (International Crystal Laboratories) possessing BaF2 windows and a 100 mm path length. Infrared (IR) and VCD spectra were acquired on a BioTools ChiralIR-2X VCD spectrometer as a set of 24 one-hour blocks (24 blocks, 3120 scans per block) in dual PEM mode. A 15-minute acquisition of neat (+)-α-pinene control yielded a VCD spectrum in agreement with literature spectra. IR and VCD spectra were background corrected using a 30-minute block IR acquisition of the empty instrument chamber under gentle N2 purge, and were solvent corrected using a 4-hour (4 blocks, 3120 scans per block) IR/VCD acquisition of CDCl3 in the same 100 μm BaF2 cell. The reported spectra represent the result of block averaging. Computational Protocol. An arbitrarily chosen enantiomer of compound 608a (A) was subjected to an exhaustive initial molecular mechanics-based conformational search (OPLS_2005 force field, CHCl3 solvent, 10.0 kcal/mol cutoff, “Enhanced” torsional sampling) as implemented in MacroModel program.20 The resulting ensemble was subsequently optimized using the B3PW91 functional, cc-pVTZ(-f) basis using the Jaguar program.21 Harmonic frequencies computed at the B3PW91/cc-pVTZ(-f) level were scaled by 0.98. The resultant structurally unique conformers possessing all positive Hessian eigenvalues were Boltzmann weighted by relative free energy at 298.15 K. The predicted IR and VCD frequencies and intensities of the retained conformers were convolved using Lorentzian line shapes (γ = 4 cm-1) and summed using the respective Boltzmann weights Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 907 to yield the final predicted IR and VCD spectra of A. The predicted VCD of the corresponding enantiomer ((ent)-A) was generated by inversion of sign. The strong features at 1290 and 1270 cm–1 in the computed VCD spectrum of (ent)-A match that of the experimental spectrum of 608a. The weaker signals between 1200–900 cm–1 are also of the correct sign but given their weak intensity they are not used in the final assignment. Figure 5.4.3.1. Comparison of experimental VCD and IR spectra for product 608a to computed spectra for A and (ent)-A. Experimental IR spectrum in good agreement with computed spectrum. Experimental VCD spectrum for 608a is in agreement with computed spectrum for (ent)-A. O O HN N CO2Et CbzN HN N CO2Et CbzN (ent)-A A IR Spectra VCD Spectra 3 Experimental IR Computed IR 1.0 Experimental VCD Noise 2 0.9 0.8 0 0.7 -1 -2 0.6 -3 5 0.5 4 0.4 Computed VCD (ent)-Computed VCD 3 2 0.3 5 Absorbance 5 1 1 0 0.2 -1 -2 0.1 -3 -4 0.0 1500 1400 1300 cm -1 1200 1100 -5 1400 1300 1200 cm -1 1100 1000 Chapter 5 – Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams 908 Figure 5.4.3.2. Overlay of experimental VCD spectrum of 608a with computed spectra for (ent)-A. Experimental VCD Noise Computed (R) VCD 4.0 3.0 5 2.0 1.0 0.0 -1.0 -2.0 -3.0 1350 1250 1150 1050 950 cm -1 5.5 (1) REFERENCES AND NOTES (a) Kerru, K.; Gummidi, L.; Maddila, S.; Gangu, K. K.; Jonnalagadda S. B. Molecules 2020, 25, 1909. (b) Humblet, C.; Bikker, J.; Lovering, F. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. (2) (a) Hiesinger, K.; Dar’in, D.; Proschak, E.; Krasavin, M. 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Front. 2020, 7, 709–714. (20) Schrödinger Release 2021-4: MacroModel, Schrödinger, LLC, New York, NY, 2021. (21) Bochevarov, A. D.; Harder, E.; Hughes, T. F.; Greenwood, J. R.; Braden, D. A.; Philipp, D. M.; Rinaldo, D.; Halls, M. D.; Zhang, J.; Friesner, R. A. Jaguar: A highperformance quantum chemistry software program with strengths in life and materials sciences. Int. J. Quantum Chem., 2013, 113, 2110-2142. APPENDIX 12 Spectra Relevant to Chapter 5: Enantioselective 1,3-Dipolar Cycloadditions of a-Methylene Lactams to Construct Spirocycles Appendix 12 – Spectra Relevant to Chapter 5 9.5 10.5 Cbz N O 10.0 HN N 608a 9.0 CO2Et Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 608a. 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 916 Appendix 12 – Spectra Relevant to Chapter 5 917 Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 608a. Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc.Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. -10 Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound 608a. Figure A12.4. 1H NMR (500 MHz, CDCl3) of compound XXb. Figure A12.4. 1H NMR (500 MHz, CDCl3) of compound XXb.Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa. Appendix 12 – Spectra Relevant to Chapter 5 9.5 10.5 CbzN 10.0 O HN N 608b 9.0 CO2t-Bu Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.4. 1H NMR (500 MHz, CDCl3) of compound 608b. 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 918 Appendix 12 – Spectra Relevant to Chapter 5 919 105 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 30 25 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 608b. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb. 220 210 200 Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb. 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 1 13 Figure A12.7. NMR 13 (500 MHz, CDCl C 3) of compound XXc.Figure A12.6. FigureHA12.6. C NMR (125 MHz, CDCl3) of compound 608b. NMR (125 MHz, CDCl3) of compound XXb. Figure 13A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb. Figure A12.6. C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound XXc.Figure A12.6. 13C FmocN O 608c HN N 10 CO2Et Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. 8 7 6 5 ppm 4 3 Figure A12.7. 1H NMR (500 MHz, CDCl ) of compound XXc. Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound XXc. Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 608c. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 920 Appendix 12 – Spectra Relevant to Chapter 5 921 Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 608c. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc. 230 220 210 Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc. 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 1 13 Figure A12.10. NMR13(500 MHz, CDCl C 3) of compound XXd.Figure A12.9. Figure H A12.9. C NMR (125 MHz, CDCl3) of compound 608c. NMR (125 MHz, CDCl3) of compound XXc.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. 1 13 Infrared spectrum of compound XXc. Figure A12.10. H NMR (500 (Thin MHz,Film, CDClNaCl) C 3) of compound XXd.Figure A12.9. TMS 10.5 O 10.0 O N 9.0 608d HN N 9.5 O Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.10. 1H NMR (500 MHz, CDCl ) of compound XXd. Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound 608d. 8.5 CO2Et 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 922 Appendix 12 – Spectra Relevant to Chapter 5 923 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 608d. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd.Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe.Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd.Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.11. Infrared spectrum NaCl) of compound XXd. Figure A12.12. C NMR (125(Thin MHz,Film, CDCl 3) of compound 608d. 13 Figure A12.12. C NMR13(125 MHz, CDCl 3) of compound XXd.Figure A12.11. Figure A12.12. C NMR (125 MHz, CDCl3) of compound XXd. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe.Figure A12.12. 13C 10.5 TrocN 9.5 608e HN N 10.0 O 9.0 CO2Et Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.13. 1H NMR (500 MHz, CDCl ) of compound XXe. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 608e. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 924 Appendix 12 – Spectra Relevant to Chapter 5 925 Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 608e. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe.Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf.Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe.Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.14. Infrared spectrum NaCl) of compound XXe. Figure A12.15. C NMR (125(Thin MHz,Film, CDCl 3) of compound 608e. 13 Figure A12.15. C NMR13(125 MHz, CDCl 3) of compound XXe.Figure A12.14. Figure A12.15. C NMR (125 MHz, CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf.Figure A12.15. 13C 10.5 BocN 9.5 608f HN N 10.0 O 9.0 CO2Et Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 1 Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 608f. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 926 Appendix 12 – Spectra Relevant to Chapter 5 927 Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 608f. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf.Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.22. 1H NMR (500 MHz, CDCl3) of compound XXh.Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf.Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.17. Infrared spectrum NaCl) of compound XXf. Figure A12.18. C NMR (125(Thin MHz,Film, CDCl 3) of compound 608f. 13 Figure A12.18. C NMR13(125 MHz, CDCl 3) of compound XXf.Figure A12.17. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.22. 1H NMR (500 MHz, CDCl3) of compound XXh.Figure A12.18. 13C 10.5 AcN O 10.0 608g HN N 9.5 CO2Et 9.0 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.19. 1H NMR (500 MHz, CDCl ) of compound XXg. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 608g. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 928 Appendix 12 – Spectra Relevant to Chapter 5 929 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 608g. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.21. 13C NMR (125 MHz, CDCl3) of compound XXg.Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.21. 13C NMR (125 MHz, CDCl3) of compound XXg. Figure A12.25. 1H NMR (500 MHz, CDCl3) of compound XXj.Figure A12.21. 13C NMR (125 MHz, CDCl3) of compound XXg.Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 220 210 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.21. C NMR13C (125 MHz, 3) of compound XXg.Figure A12.20. Figure A12.21. NMR (125CDCl MHz, CDCl3) of compound 608g. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.25. 1H NMR (500 MHz, CDCl3) of compound XXj.Figure A12.21. 13C Figure A12.20.NMR Infrared (Thin Film, NaCl) of compound XXg. (125spectrum MHz, CDCl 3) of compound XXg. BzN O 608h HN N 10 CO2Et 8 7 6 5 ppm 4 3 Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.22. 1H NMR (500 MHz, CDCl3) of compound 608h. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 930 Appendix 12 – Spectra Relevant to Chapter 5 931 Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 608h. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.24. 13C NMR (125 MHz, CDCl3) of compound XXh.Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound XXh. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.24. 13C NMR (125 MHz, CDCl3) of compound XXh. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg.Figure A12.24. 13C NMR (125 MHz, CDCl3) of compound XXh.Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound XXh. Figure A12.24. 13C NMR (125 MHz, CDCl3) of compound 608h. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. 13 0 -10 10.5 CbzN 10.0 9.5 608j O HN N 9.0 CO2Et Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound XXj. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.25. 1H NMR (500 MHz, CDCl ) of compound XXj. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.25. 1H NMR (500 MHz, CDCl3) of compound 608j. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 932 Appendix 12 – Spectra Relevant to Chapter 5 933 Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 608j. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.27. 13C NMR (125 MHz, CDCl3) of compound XXj.Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound XXj. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.27. 13C NMR (125 MHz, CDCl3) of compound XXj. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound XXk.Figure A12.27. 13C NMR (125 MHz, CDCl3) of compound XXj.Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound XXj. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.14. Infrared spectrum NaCl) of compound XXe. Figure A12.27. C NMR (125(Thin MHz,Film, CDCl 3) of compound 608j. 13 Figure A12.27. C NMR13(125 MHz, CDCl 3) of compound XXj.Figure A12.26. Figure A12.15. C NMR (125 MHz, CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XXj. Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound XXk.Figure A12.27. 13C 10.5 CbzN O 10.0 9.5 608k HN N 9.0 CO2Et Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound XXk. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.28. 1H NMR (500 MHz, CDCl ) of compound XXk. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 608k. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 934 Appendix 12 – Spectra Relevant to Chapter 5 935 Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 608k. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.30. 13C NMR (125 MHz, CDCl3) of compound XXk.Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound XXk. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.30. 13C NMR (125 MHz, CDCl3) of compound XXk. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound XXl.Figure A12.30. 13C NMR (125 MHz, CDCl3) of compound XXk.Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound XXk. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.17. Infrared spectrum of compound XXf. Figure A12.30. C NMR (125(Thin MHz,Film, CDClNaCl) 3) of compound 608k. 13 Figure A12.30. C NMR13(125 MHz, CDCl 3) of compound XXk.Figure A12.29. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XXk. Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound XXl.Figure A12.30. 13C Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound XXl. 10.5 CbzN O 10.0 608l HN N 9.5 CO2Et 9.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.31. 1H NMR (500 MHz, CDCl ) of compound XXl. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 608l. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 936 Appendix 12 – Spectra Relevant to Chapter 5 937 Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 608l. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.33. 13C NMR (125 MHz, CDCl3) of compound XXl.Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound XXl. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.33. 13C NMR (125 MHz, CDCl3) of compound XXl. Figure A12.34. 1H NMR (400 MHz, CDCl3) of compound XXa.Figure A12.33. 13C NMR (125 MHz, CDCl3) of compound XXl.Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound XXl. 220 210 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.33. C NMR13C (125 MHz, 3) of compound XXl.Figure A12.32. Figure A12.33. NMR (125CDCl MHz, CDCl3) of compound 608l. Infrared spectrum (Thin Film, NaCl) of compound XXl. Figure A12.34. 1H NMR (400 MHz, CDCl3) of compound XXa.Figure A12.33. 13C Figure A12.20.NMR Infrared spectrum (Thin Film, NaCl) of compound XXg. (125 MHz, CDCl 3) of compound XXl. 10 Cbz N 9 O 610a O N 8 Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.35. Infrared spectrum (Thin Film, NaCl) of compound XXa. 6 5 ppm 4 3 2 Figure A12.34. 1H NMR (400 MHz, CDCl ) of compound XXa. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa. Figure A12.34. 1H NMR (400 MHz, CDCl3) of compound 610a. 7 1 0 Appendix 12 – Spectra Relevant to Chapter 5 938 Appendix 12 – Spectra Relevant to Chapter 5 939 110 100 90 80 % Transmittance 70 60 50 40 30 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.35. Infrared spectrum (Thin Film, NaCl) of compound 610a. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.36. 13C NMR (100 MHz, CDCl3) of compound XXa.Figure A12.35. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.36. 13C NMR (100 MHz, CDCl3) of compound XXa. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa. Figure A12.37. 1H NMR (400 MHz, CDCl3) of compound XXj.Figure A12.36. 13C NMR (100 MHz, CDCl3) of compound XXa.Figure A12.35. Infrared spectrum (Thin Film, NaCl) of compound XXa. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.36. 13C NMR (100 MHz, CDCl3) of compound 610a. Figure A12.3. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.2. 13 Infrared spectrum (Thin Film, NaCl) of 3compound XXa.XXa. Figure A12.3. C NMR (125 MHz, CDCl ) of compound Figure A12.37. A12.36. 113HCNMR NMR(400 (100MHz, MHz,CDCl CDCl33))of ofcompound compoundXXj.Figure XXa.FigureA12.36. A12.35.13C Figure Cbz N O O 610j N 10 Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.38. Infrared spectrum (Thin Film, NaCl) of compound XXj. 8 7 6 5 ppm 4 3 Figure A12.37. 1H NMR (400 MHz, CDCl ) of compound XXj. Figure A12.4. 1H NMR (500 MHz, CDCl3) of compound XXb. Figure A12.37. 1H NMR (400 MHz, CDCl3) of compound 610j. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 940 Appendix 12 – Spectra Relevant to Chapter 5 941 110 100 90 80 % Transmittance 70 60 50 40 30 20 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.38. Infrared spectrum (Thin Film, NaCl) of compound 610j. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.39. 13C NMR (100 MHz, CDCl3) of compound XXj.Figure A12.38. Infrared spectrum (Thin Film, NaCl) of compound XXj. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound XXb. Figure A12.39. 13C NMR (100 MHz, CDCl3) of compound XXj. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb. Figure A12.40. 1H NMR (400 MHz, CDCl3) of compound XXl.Figure A12.39. 13C NMR (100 MHz, CDCl3) of compound XXj.Figure A12.38. Infrared spectrum (Thin Film, NaCl) of compound XXj. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.39. 13C NMR (100 MHz, CDCl3) of compound 610j. Figure A12.6. 13C NMR (125 MHz, CDCl3) of compound XXb.Figure A12.5. 13 Infrared spectrum (Thin Film, NaCl) of 3compound XXb.XXb. Figure A12.6. C NMR (125 MHz, CDCl ) of compound FigureA12.40. A12.39.113 NMR(400 (100MHz, MHz,CDCl CDCl3)3)ofofcompound compoundXXl.Figure XXj.FigureA12.39. A12.38.13C Figure HCNMR Cbz N O 610l O N 10 Figure A12.41. Infrared spectrum (Thin Film, NaCl) of compound XXl. 8 7 6 5 ppm 4 3 Figure A12.40. 1H NMR (400 MHz, CDCl ) of compound XXl. Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound XXc. Figure A12.40. 1H NMR (400 MHz, CDCl3) of compound 610l. 9 2 1 0 Appendix 12 – Spectra Relevant to Chapter 5 942 Appendix 12 – Spectra Relevant to Chapter 5 943 110 100 90 % Transmittance 80 70 60 50 40 30 20 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.41. Infrared spectrum (Thin Film, NaCl) of compound 610l. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.42. 13C NMR (100 MHz, CDCl3) of compound XXl.Figure A12.41. Infrared spectrum (Thin Film, NaCl) of compound XXl. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.42. 13C NMR (100 MHz, CDCl3) of compound XXl. Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc. Figure A12.43. 1H NMR (400 MHz, CDCl3) of compound XX.Figure A12.42. 13C NMR (100 MHz, CDCl3) of compound XXl.Figure A12.41. Infrared spectrum (Thin Film, NaCl) of compound XXl. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.42. 13C NMR (100 MHz, CDCl3) of compound 610l. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. 13 Infrared spectrum (Thin Film, NaCl) of 3compound XXc.XXc. Figure A12.9. C NMR (125 MHz, CDCl ) of compound Figure A12.43. A12.42. 113HCNMR NMR(400 (100MHz, MHz,CDCl CDCl33))of ofcompound compoundXX.Figure XXl.FigureA12.42. A12.41.13C Figure HN O HN 611 N 10 CO2Et Figure A12.44. Infrared spectrum (Thin Film, NaCl) of compound XX. 8 7 6 5 ppm 4 3 Figure A12.43. 1H NMR (400 MHz, CDCl ) of compound XX. Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.43. 1H NMR (400 MHz, CDCl3) of compound 611. 9 2 1 0 Appendix 12 – Spectra Relevant to Chapter 5 944 Appendix 12 – Spectra Relevant to Chapter 5 945 115 110 105 100 95 % Transmittance 90 85 80 75 70 65 60 55 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.44. Infrared spectrum (Thin Film, NaCl) of compound 611. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.45. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.44. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.45. 13C NMR (100 MHz, CDCl3) of compound XX. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.46. 1H NMR (600 MHz, d5-pyridine) of compound XX.Figure A12.45. 13 C NMR (100 MHz, CDCl3) of compound XX.Figure A12.44. Infrared spectrum (Thin Film, NaCl) of compound XX. 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.11. Infrared Film, NaCl) of compound XXd. Figure A12.45. C spectrum NMR (100(Thin MHz, CDCl 3) of compound 611. 13 Figure A12.45. C NMR13C (100 MHz, 3) of compound XX.Figure A12.44. Figure A12.12. NMR (125CDCl MHz, CDCl3) of compound XXd. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.46. 1H NMR (600 MHz, d5-pyridine) of compound XX.Figure A12.45. HN O HN 10 CO2H •TFA 612 N Figure A12.47. Infrared spectrum (Thin Film, NaCl) of compound XX. 8 7 6 5 ppm 4 3 2 Figure A12.46. 1H NMR (600 MHz, d -pyridine) of compound XX. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.46. 1H NMR (600 MHz, d5-pyridine) of compound 612. 9 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 946 Appendix 12 – Spectra Relevant to Chapter 5 947 120 115 110 105 100 % Transmittance 95 90 85 80 75 70 65 60 55 50 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.47. Infrared spectrum (Thin Film, NaCl) of compound 612. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.48. 13C NMR (100 MHz, CD3CN) of compound XX.Figure A12.47. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.48. 13C NMR (100 MHz, CD3CN) of compound XX. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.49. 1H NMR (400 MHz, CDCl3) of compound XX.Figure A12.48. 13C NMR (100 MHz, CD3CN) of compound XX.Figure A12.47. Infrared spectrum (Thin Film, NaCl) of compound XX. 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.14. Infrared spectrum NaCl) compound XXe. Figure A12.48. C NMR (100(Thin MHz,Film, CD3CN) ofof compound 612. 13 Figure A12.48. C NMR13(100 MHz, CDMHz, 3CN) of compound XX.Figure A12.47. Figure A12.15. C NMR (125 CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.49. 1H NMR (400 MHz, CDCl3) of compound XX.Figure A12.48. 13C CbzHN EtO O HN 613 N 10 CO2Et Figure A12.50. Infrared spectrum (Thin Film, NaCl) of compound XX. 8 7 6 5 ppm 4 3 Figure A12.49. 1H NMR (400 MHz, CDCl ) of compound XX. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.49. 1H NMR (400 MHz, CDCl3) of compound 613. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 948 Appendix 12 – Spectra Relevant to Chapter 5 949 110 100 90 80 % Transmittance 70 60 50 40 30 20 10 0 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.50. Infrared spectrum (Thin Film, NaCl) of compound 613. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.51. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.50. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.51. 13C NMR (100 MHz, CDCl3) of compound XX. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.52. 1H NMR (400 MHz, CDCl3) of compound XX (major diastereomer).Figure A12.51. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.50. Infrared spectrum (Thin Film, NaCl) of compound XX. 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.17. Infrared spectrum NaCl) of compound XXf. Figure A12.51. C NMR (100(Thin MHz,Film, CDCl 3) of compound 613. 13 Figure A12.51. C NMR13(100 MHz, CDCl 3) of compound XX.Figure A12.50. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.52. 1H NMR (400 MHz, CDCl3) of compound XX (major Cbz N O Figure A12.53. Infrared spectrum (Thin Film, NaCl) of compound XX Br CO2Et 10 614 N 9 8 7 6 5 ppm 4 3 2 Figure A12.52. 1H NMR (400 MHz, CDCl ) of compound XX (major diastereomer). Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.52. 1H NMR (400 MHz, CDCl3) of compound 614 (major diastereomer). N 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 950 Appendix 12 – Spectra Relevant to Chapter 5 951 120 110 100 90 80 % Transmittance 70 60 50 40 30 20 10 0 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.53. Infrared spectrum (Thin Film, NaCl) of compound 614 (major diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.54. 13C NMR (100 MHz, CDCl3) of compound XX (major diastereomer).Figure A12.53. Infrared spectrum (Thin Film, NaCl) of compound XX (major diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.54. 13C NMR (100 MHz, CDCl3) of compound XX (major diastereomer). Figure A12.58. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.54. 13C NMR (100 MHz, CDCl3) of compound XX (major diastereomer).Figure A12.53. Infrared spectrum (Thin Film, NaCl) of compound XX (major diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.54. C 13 NMR (100 MHz, CDCl 3) of compound XX (major diastereomer).Figure Figure A12.54. C NMR (100 MHz, CDCl 3) of compound 614 (major diastereomer). A12.53. Infrared spectrum (Thin Film, NaCl) of compound XX (major diastereomer). Figure A12.58. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.54. 13C Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. NMR (100 MHz, CDCl 3) of compound XX (major diastereomer). Cbz N O Figure A12.56. Infrared spectrum (Thin Film, NaCl) of compound XX Br CO2Et 10 614 N 9 8 7 6 5 ppm 4 3 2 Figure A12.55. 1H NMR (400 MHz, CDCl ) of compound XX (minor diastereomer). Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.55. 1H NMR (400 MHz, CDCl3) of compound 614 (minor diastereomer). N 1 0 Appendix 12 – Spectra Relevant to Chapter 5 952 Appendix 12 – Spectra Relevant to Chapter 5 953 120 110 100 90 % Transmittance 80 70 60 50 40 30 20 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.56. Infrared spectrum (Thin Film, NaCl) of compound 614 (minor diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.57. 13C NMR (100 MHz, CDCl3) of compound XX (minor diastereomer).Figure A12.56. Infrared spectrum (Thin Film, NaCl) of compound XX (minor diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.57. 13C NMR (100 MHz, CDCl3) of compound XX (minor diastereomer). Figure A12.70. 1H NMR (500 MHz, CDCl3) of compound XXf.Figure A12.57. 13C NMR (100 MHz, CDCl3) of compound XX (minor diastereomer).Figure A12.56. Infrared spectrum (Thin Film, NaCl) of compound XX (minor diastereomer). Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 180 160 140 120 100 ppm 80 60 40 20 0 13 Figure A12.57. C 13 NMR (100 MHz, CDCl 3) of compound XX (minor diastereomer).Figure Figure A12.57. C NMR (100 MHz, CDCl 3) of compound 614 (minor diastereomer). A12.56. Infrared spectrum (Thin Film, NaCl) of compound XX (minor diastereomer). Figure A12.70. 1H NMR (500 MHz, CDCl3) of compound XXf.Figure A12.57. 13C NMR Figure (100 A12.20. Infrared (Thin Film, NaCl)diastereomer). of compound XXg. MHz, CDCl3spectrum ) of compound XX (minor 606a CbzN O 10 8 7 6 5 ppm 4 3 2 Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.58. 1H NMR (500 MHz, CDCl3) of compound 606a. 9 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 954 Appendix 12 – Spectra Relevant to Chapter 5 955 130 120 110 100 90 % Transmittance 80 70 60 50 40 30 20 10 0 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.59. Infrared spectrum (Thin Film, NaCl) of compound 606a. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.60. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.59. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.60. 13C NMR (125 MHz, CDCl3) of compound XXa. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.61. 1H NMR (500 MHz, CDCl3) of compound XXc.Figure A12.60. 13C NMR (125 MHz, CDCl3) of compound XXa.Figure A12.59. Infrared spectrum (Thin Film, NaCl) of compound XXa. Figure A12.60. 13C NMR (125 MHz, CDCl3) of compound 606a. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. 13 0 -10 10.5 10.0 9.5 606c FmocN O 9.0 Figure A12.62. Infrared spectrum (Thin Film, NaCl) of compound XXc. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.61. 1H NMR (500 MHz, CDCl ) of compound XXc. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.61. 1H NMR (500 MHz, CDCl3) of compound 606c. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 956 Appendix 12 – Spectra Relevant to Chapter 5 957 Figure A12.62. Infrared spectrum (Thin Film, NaCl) of compound 606c. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.63. 13C NMR (125 MHz, CDCl3) of compound XXc.Figure A12.62. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.63. 13C NMR (125 MHz, CDCl3) of compound XXc. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.64. 1H NMR (500 MHz, CDCl3) of compound XXd.Figure A12.63. 13C NMR (125 MHz, CDCl3) of compound XXc.Figure A12.62. Infrared spectrum (Thin Film, NaCl) of compound XXc. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.14. Infrared spectrum NaCl) of compound XXe. Figure A12.63. C NMR (125(Thin MHz,Film, CDCl 3) of compound 606c. 13 Figure A12.63. C NMR13(125 MHz, CDCl 3) of compound XXc.Figure A12.62. Figure A12.15. C NMR (125 MHz, CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.64. 1H NMR (500 MHz, CDCl3) of compound XXd.Figure A12.63. 13C 10.5 TMS 10.0 O N O 9.5 606d O 9.0 Figure A12.65. Infrared spectrum (Thin Film, NaCl) of compound XXd. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.64. 1H NMR (500 MHz, CDCl ) of compound XXd. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.64. 1H NMR (500 MHz, CDCl3) of compound 606d. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 958 Appendix 12 – Spectra Relevant to Chapter 5 959 Figure A12.65. Infrared spectrum (Thin Film, NaCl) of compound 606d. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.66. 13C NMR (125 MHz, CDCl3) of compound XXd.Figure A12.65. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.66. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.67. 1H NMR (500 MHz, CDCl3) of compound XXe.Figure A12.66. 13C NMR (125 MHz, CDCl3) of compound XXd.Figure A12.65. Infrared spectrum (Thin Film, NaCl) of compound XXd. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.17. Infrared spectrum of compound XXf. Figure A12.66. C NMR (125(Thin MHz,Film, CDClNaCl) 3) of compound 606d. 13 Figure A12.66. C NMR13(125 MHz, CDCl 3) of compound XXd.Figure A12.65. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.67. 1H NMR (500 MHz, CDCl3) of compound XXe.Figure A12.66. 13C 10.5 10.0 606e TrocN O 9.5 9.0 Figure A12.68. Infrared spectrum (Thin Film, NaCl) of compound XXe. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.67. 1H NMR (500 MHz, CDCl ) of compound XXe. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.67. 1H NMR (500 MHz, CDCl3) of compound 606e. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 960 Appendix 12 – Spectra Relevant to Chapter 5 961 Figure A12.68. Infrared spectrum (Thin Film, NaCl) of compound 606e. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.69. 13C NMR (125 MHz, CDCl3) of compound XXe.Figure A12.68. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.69. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.55. 1H NMR (400 MHz, CDCl3) of compound XX (minor diastereomer).Figure A12.69. 13C NMR (125 MHz, CDCl3) of compound XXe.Figure A12.68. Infrared spectrum (Thin Film, NaCl) of compound XXe. 220 210 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.69. C NMR13C (125 MHz, 3) of compound XXe.Figure A12.68. Figure A12.69. NMR (125CDCl MHz, CDCl3) of compound 606e. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.55. 1H NMR (400 MHz, CDCl3) of compound XX (minor 13 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of 3compound XXg. XXe. diastereomer).Figure A12.69. C NMR (125 MHz, CDCl ) of compound 10.5 10.0 BocN 9.5 606f O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.70. 1H NMR (500 MHz, CDCl3) of compound 606f. 8.0 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 962 Appendix 12 – Spectra Relevant to Chapter 5 963 Figure A12.71. Infrared spectrum (Thin Film, NaCl) of compound 606f. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.72. 13C NMR (125 MHz, CDCl3) of compound XXf.Figure A12.71. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.72. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.73. 1H NMR (500 MHz, CDCl3) of compound XXg.Figure A12.72. 13C NMR (125 MHz, CDCl3) of compound XXf.Figure A12.71. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.72. 13C NMR (125 MHz, CDCl3) of compound 606f. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. 13 0 -10 10.5 10.0 606g AcN O 9.5 9.0 Figure A12.74. Infrared spectrum (Thin Film, NaCl) of compound XXg. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.73. 1H NMR (500 MHz, CDCl ) of compound XXg. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.73. 1H NMR (500 MHz, CDCl3) of compound 606g. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 964 Appendix 12 – Spectra Relevant to Chapter 5 965 Figure A12.74. Infrared spectrum (Thin Film, NaCl) of compound 606g. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.75. 13C NMR (125 MHz, CDCl3) of compound XXg.Figure A12.74. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.75. 13C NMR (125 MHz, CDCl3) of compound XXg. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.76. 1H NMR (500 MHz, CDCl3) of compound XXh.Figure A12.75. 13C NMR (125 MHz, CDCl3) of compound XXg.Figure A12.74. Infrared spectrum (Thin Film, NaCl) of compound XXg. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.14. Infrared spectrum NaCl) of compound XXe. Figure A12.75. C NMR (125(Thin MHz,Film, CDCl 3) of compound 606g. 13 Figure A12.75. C NMR13(125 MHz, CDCl 3) of compound XXg.Figure A12.74. Figure A12.15. C NMR (125 MHz, CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.76. 1H NMR (500 MHz, CDCl3) of compound XXh.Figure A12.75. 13C 10.5 10.0 9.5 606h BzN O 9.0 Figure A12.77. Infrared spectrum (Thin Film, NaCl) of compound XXh. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.76. 1H NMR (500 MHz, CDCl ) of compound XXh. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.76. 1H NMR (500 MHz, CDCl3) of compound 606h. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 966 Appendix 12 – Spectra Relevant to Chapter 5 967 Figure A12.77. Infrared spectrum (Thin Film, NaCl) of compound 606h. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.78. 13C NMR (125 MHz, CDCl3) of compound XXh.Figure A12.77. Infrared spectrum (Thin Film, NaCl) of compound XXh. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.78. 13C NMR (125 MHz, CDCl3) of compound XXh. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.79. 1H NMR (500 MHz, CDCl3) of compound XXi.Figure A12.78. 13C NMR (125 MHz, CDCl3) of compound XXh.Figure A12.77. Infrared spectrum (Thin Film, NaCl) of compound XXh. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.17. Infrared spectrum of compound XXf. Figure A12.78. C NMR (125(Thin MHz,Film, CDClNaCl) 3) of compound 606h. 13 Figure A12.78. C NMR13(125 MHz, CDCl 3) of compound XXh.Figure A12.77. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XXh. Figure A12.79. 1H NMR (500 MHz, CDCl3) of compound XXi.Figure A12.78. 13C Figure A12.80. Infrared spectrum (Thin Film, NaCl) of compound XXi. 13 606i BnN O 12 10 9 8 7 6 f1 (ppm) 5 4 3 2 Figure A12.79. 1H NMR (500 MHz, CDCl ) of compound XXi. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.79. 1H NMR (500 MHz, CDCl3) of compound 606i. 11 1 0 -1 -2 Appendix 12 – Spectra Relevant to Chapter 5 968 Appendix 12 – Spectra Relevant to Chapter 5 969 Figure A12.80. Infrared spectrum (Thin Film, NaCl) of compound 606i. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.81. 13C NMR (125 MHz, CDCl3) of compound XXi.Figure A12.80. Infrared spectrum (Thin Film, NaCl) of compound XXi. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.81. 13C NMR (125 MHz, CDCl3) of compound XXi. Figure A12.82. 1H NMR (500 MHz, CDCl3) of compound XXj.Figure A12.81. 13C NMR (125 MHz, CDCl3) of compound XXi.Figure A12.80. Infrared spectrum (Thin Film, NaCl) of compound XXi. 220 210 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.81. C NMR13C (125 MHz, 3) of compound XXi.Figure A12.80. Figure A12.81. NMR (125CDCl MHz, CDCl3) of compound 606i. Infrared spectrum (Thin Film, NaCl) of compound XXi. Figure A12.82. 1H NMR (500 MHz, CDCl3) of compound XXj.Figure A12.81. 13C Figure A12.20.NMR Infrared spectrum (Thin Film, NaCl) of compound XXg. (125 MHz, CDCl 3) of compound XXi. 10.5 10.0 CbzN 9.5 606j O 9.0 Figure A12.83. Infrared spectrum (Thin Film, NaCl) of compound XXj. 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.82. 1H NMR (500 MHz, CDCl ) of compound XXj. Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound XXe. Figure A12.82. 1H NMR (500 MHz, CDCl3) of compound 606j. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 970 Appendix 12 – Spectra Relevant to Chapter 5 971 Figure A12.83. Infrared spectrum (Thin Film, NaCl) of compound 606j. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.84. 13C NMR (125 MHz, CDCl3) of compound XXj.Figure A12.83. Infrared spectrum (Thin Film, NaCl) of compound XXj. Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound XXe. Figure A12.84. 13C NMR (125 MHz, CDCl3) of compound XXj. Figure A12.15. 13C NMR (125 MHz, CDCl3) of compound XXe. Figure A12.85. 1H NMR (500 MHz, CDCl3) of compound XXk.Figure A12.84. 13C NMR (125 MHz, CDCl3) of compound XXj.Figure A12.83. Infrared spectrum (Thin Film, NaCl) of compound XXj. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.14. Infrared spectrum NaCl) of compound XXe. Figure A12.84. C NMR (125(Thin MHz,Film, CDCl 3) of compound 606j. 13 Figure A12.84. C NMR13(125 MHz, CDCl 3) of compound XXj.Figure A12.83. Figure A12.15. C NMR (125 MHz, CDCl3) of compound XXe. Infrared spectrum (Thin Film, NaCl) of compound XXj. Figure A12.85. 1H NMR (500 MHz, CDCl3) of compound XXk.Figure A12.84. 13C 10.0 CbzN 9.5 606k O 9.0 8.5 Figure A12.86. Infrared spectrum (Thin Film, NaCl) of compound XXk. 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.85. 1H NMR (500 MHz, CDCl ) of compound XXk. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.85. 1H NMR (500 MHz, CDCl3) of compound 606k. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant to Chapter 5 972 Appendix 12 – Spectra Relevant to Chapter 5 973 Figure A12.86. Infrared spectrum (Thin Film, NaCl) of compound 606k. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.87. 13C NMR (125 MHz, CDCl3) of compound XXk.Figure A12.86. Infrared spectrum (Thin Film, NaCl) of compound XXk. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.87. 13C NMR (125 MHz, CDCl3) of compound XXk. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.88. 1H NMR (500 MHz, CDCl3) of compound XXl.Figure A12.87. 13C NMR (125 MHz, CDCl3) of compound XXk.Figure A12.86. Infrared spectrum (Thin Film, NaCl) of compound XXk. 220 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.17. Infrared spectrum of compound XXf. Figure A12.87. C NMR (125(Thin MHz,Film, CDClNaCl) 3) of compound 606k. 13 Figure A12.87. C NMR13(125 MHz, CDCl 3) of compound XXk.Figure A12.86. Figure A12.18. C NMR (125 MHz, CDCl3) of compound XXf. Infrared spectrum (Thin Film, NaCl) of compound XXk. Figure A12.88. 1H NMR (500 MHz, CDCl3) of compound XXl.Figure A12.87. 13C Figure A12.89. Infrared spectrum (Thin Film, NaCl) of compound XXl. 10.5 CbzN 10.0 O 9.5 606l 9.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 2.0 Figure A12.88. 1H NMR (500 MHz, CDCl ) of compound XXl. Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound XXg. Figure A12.88. 1H NMR (500 MHz, CDCl3) of compound 606l. 8.5 1.5 1.0 0.5 0.0 -0.5 -1.0 Appendix 12 – Spectra Relevant to Chapter 5 974 Appendix 12 – Spectra Relevant to Chapter 5 975 Figure A12.89. Infrared spectrum (Thin Film, NaCl) of compound 606l. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.90. 13C NMR (125 MHz, CDCl3) of compound XXl.Figure A12.89. Infrared spectrum (Thin Film, NaCl) of compound XXl. Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. Figure A12.90. 13C NMR (125 MHz, CDCl3) of compound XXl. Figure A12.91. 1H NMR (400 MHz, CDCl3) of compound XX.Figure A12.90. 13C NMR (125 MHz, CDCl3) of compound XXl.Figure A12.89. Infrared spectrum (Thin Film, NaCl) of compound XXl. 220 210 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound XXg. 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 13 Figure A12.90. C NMR13C (125 MHz, 3) of compound XXl.Figure A12.89. Figure A12.90. NMR (125CDCl MHz, CDCl3) of compound 606l. Infrared spectrum (Thin Film, NaCl) of compound XXl. Figure A12.91. 1H NMR (400 MHz, CDCl3) of compound XX.Figure A12.90. 13C Figure A12.20.NMR Infrared spectrum (Thin Film, NaCl) of compound XXg. (125 MHz, CDCl 3) of compound XXl. HN 626 O 10 Figure A12.92. Infrared spectrum (Thin Film, NaCl) of compound XX. 8 7 6 5 ppm 4 3 Figure A12.91. 1H NMR (400 MHz, CDCl ) of compound XX. Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound XXc. Figure A12.91. 1H NMR (400 MHz, CDCl3) of compound 626. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 976 Appendix 12 – Spectra Relevant to Chapter 5 977 105 100 95 90 % Transmittance 85 80 75 70 65 60 55 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.92. Infrared spectrum (Thin Film, NaCl) of compound 626. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.93. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.92. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound XXc. Figure A12.93. 13C NMR (100 MHz, CDCl3) of compound XX. Figure A12.9. 13C NMR (125 MHz, CDCl3) of compound XXc. Figure A12.94. 1H NMR (400 MHz, CDCl3) of compound XXm.Figure A12.93. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.92. Infrared spectrum (Thin Film, NaCl) of compound XX. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.93. 13C NMR (100 MHz, CDCl3) of compound 626. Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound XXa.Figure A12.8. 13 Infrared spectrum (Thin Film, NaCl) of 3compound XXc.XXc. Figure A12.9. C NMR (125 MHz, CDCl ) of compound FigureA12.94. A12.93.1H13C NMR (100 MHz, CDCl 3) of compound XX.Figure A12.92. 13C Figure NMR (400 MHz, CDCl 3) of compound XXm.Figure A12.93. CbzN 606m O 10 Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound XXm. 8 7 6 5 ppm 4 3 2 Figure A12.94. 1H NMR (400 MHz, CDCl ) of compound XXm. Figure A12.10. 1H NMR (500 MHz, CDCl3) of compound XXd. Figure A12.94. 1H NMR (400 MHz, CDCl3) of compound 606m. 9 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 978 Appendix 12 – Spectra Relevant to Chapter 5 979 120 110 100 90 % Transmittance 80 70 60 50 40 30 20 10 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound 606m. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound XXm. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.96. 13C NMR (100 MHz, CDCl3) of compound XXm.Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound XXm. Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.95. Infrared spectrum (Thin Film, NaCl) of compound XXm. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound XXd. Figure A12.96. 13C NMR (100 MHz, CDCl3) of compound 606m. Figure A12.12. 13C NMR (125 MHz, CDCl3) of compound XXd. Figure A12.97. 1H NMR (400 MHz, CDCl3) of compound XX. HN O 627 10 Ph Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound XX. 8 7 6 5 ppm 4 3 Figure A12.97. 1H NMR (400 MHz, CDCl ) of compound XX. Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound XXf. Figure A12.97. 1H NMR (400 MHz, CDCl3) of compound 627. 9 2 1 0 -1 Appendix 12 – Spectra Relevant to Chapter 5 980 Appendix 12 – Spectra Relevant to Chapter 5 981 110 105 100 95 90 85 80 % Transmittance 75 70 65 60 55 50 45 40 35 30 25 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 Wavenumber [cm-1] 2000 1800 1600 1400 1200 1000 800 600 Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound 627. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound XX. Figure A12.18. 13C NMR (125 MHz, CDCl3) of compound XXf. Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound XX. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound 627. Figure A12.99. 13C NMR (100 MHz, CDCl3) of compound XX.Figure A12.98. Infrared spectrum (Thin Film, NaCl) of compound XX. Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound XXf. APPENDIX 13 Notebook Cross-Reference for New Compounds Appendix 13 – Notebook Cross-Reference for New Compounds Table A13.1. Notebook cross-reference for Chapter 2. Compound 235 236 237 322 238 239 240 105 295 26 296 287 325 326 327 328 329 290 306 307 289 330 308 302 331 303 321 285 297 293 323 324 298 299 300 301 313 332 333 334 286 284 Notebook Reference AWR-1-072 AWR-1-232 AWR-1-235 AWR-1-241 AWR-1-243 AWR-1-245 AWR-1-246 AWR-1-254 AWR-1-253 AWR-1-263 AWR-1-262 KJG-5-173 AWR-1-097 AWR-1-103 AWR-1-108 AWR-1-113 AWR-1-123 AWR-1-178 AWR-1-182 AWR-2-190 AWR-2-222 AWR-2-224 AWR-2-226 KJG-5-175 AWR-2-227 AWR-2-219 AWR-2-223 KJG-4-285 AWR-1-114 AWR-2-294 AWR-3-023 AWR-3-042 AWR-3-043 AWR-3-045 AWR-3-048 AWR-3-049 AWR-3-051 AWR-1-228 KJG-4-287 AWR-1-265 AWR-1-223 AWR-3-053 983 Appendix 13 – Notebook Cross-Reference for New Compounds 318 319 320 317 311 335 336 338 339 340 341 241 AWR-1-274 KJG-4-289 AWR-1-273 AWR-2-230 AWR-1-122 AWR-1-094 AWR-1-083 AWR-2-038 AWR-2-051 AWR-2-037 AWR-2-059 AWR-1-276 984 Appendix 13 – Notebook Cross-Reference for New Compounds Table A13.2. Notebook cross-reference for Chapter 3. Compound 453a 453b 453c 453d 453e 453f 453g 453j 453k 453l 426a 426b 426c 426d 426e 426f 426g 426h 426i 426j 426k 426l 426m 426n 435 439 427 429j 429k 462 443 428a 428b 428c 428d 428e 428f 428g 428h 428j 428k 428l Notebook Reference KJG-2-235 KJG-3-037 KJG-3-035 KJG-3-027 KJG-2-205 KJG-2-257 KJG-2-245 KJG-2-255 KJG-2-237 KJG-2-255 KJG-3-223 KJG-3-061 KJG-3-065 KJG-3-029 KJG-3-075 KJG-4-089 KJG-3-081 KJG-3-293 KJG-3-227 KJG-3-051 KJG-2-293 KJG-3-053 KJG-2-265 KJG-3-063 KJG-3-291 KJG-4-143 KJG-3-161 KJG-4-033 AWR-2-286 KJG-4-141 AWR-3-032 KJG-3-177 KJG-3-167 KJG-3-175 KJG-3-171 KJG-3-185 KJG-4-103 KJG-3-183 KJG-4-079 KJG-3-195 KJG-3-237 KJG-3-263 985 Appendix 13 – Notebook Cross-Reference for New Compounds 428m 428n 430a 430b 430c 430d 430e 430f 430g 430h 430i 430j 430k 430l 430m 430p 430q 430r 436a 436b 440 442 444 445a 445b 431 432 434 438 449 446 447 KJG-3-239 KJG-3-243 KJG-3-193 KJG-4-227 KJG-4-043 KJG-3-229 KJG-4-037 KJG-4-081 KJG-3-189 KJG-3-273 KJG-4-209 KJG-4-039 KJG-4-049 KJG-3-209 KJG-3-205 KJG-4-053 KJG-4-195 KJG-3-235 KJG-4-243 major KJG-4-243 minor KJG-4-153 AWR-3-016 KJG-4-205 KJG-4-247 major KJG-4-247 minor KJG-4-119 KJG-4-137 KJG-4-221 KJG-4-269 AWR-2-298 KJG-3-163 KJG-4-239 Table A13.3. Notebook cross-reference for Appendix 7. Compound 467 467 475 Notebook Reference KJG-3-103 (Petasis) KJG-3-135 (control) KJG-3-197 986 Appendix 13 – Notebook Cross-Reference for New Compounds Table A13.4. Notebook cross-reference for Chapter 4. Compound 525 527 528 529 530 531 523 533 534 529 535 536 537 522 538 539 540 551 551a 546 554 555 556 557 561 Notebook Reference CSS-5-063 CSS-3-281 KJG-5-083 KJG-5-085 (Duff route) KJG-5-095 CSS-4-173 CSS-4-231 CSS-4-141 CSS-4-149 CSS-5-265 (ortho-aldol route) KJG-8-225 KJG-7-237 KJG-7-241 KJG-7-243 KJG-10-171 KJG-9-237 CSS-5-127 KJG-9-243 KJG-10-031 KJG-9-253 KJG-9-279 KJG-9-281 KJG-9-283 KJG-10-067 KJG-11-059 987 Appendix 13 – Notebook Cross-Reference for New Compounds Table A13.5. Notebook cross-reference for Appendix 11. Compound 563 564 565 569 572 575 577 579 580 588 589 591 592 594 596 600 603 595 604 Notebook Reference KJG-6-263 KJG-6-263 KJG-6-297 KJG-6-297 KJG-7-129 KJG-8-223 KJG-8-231 KJG-7-167 KJG-7-169 KJG-10-269 KJG-10-265 KJG-10-267 KJG-10-079 KJG-10-117 KJG-10-069 KJG-10-119 KJG-10-137 KJG-10-277 KJG-10-165 988 Appendix 13 – Notebook Cross-Reference for New Compounds Table A13.6. Notebook cross-reference for Chapter 5. Compound 608a 608b 608c 608d 608e 608f 608g 608h 608j 608k 608l 610a 610j 610l 611 612 613 614 606a 606c 606d 606e 606f 606g 606h 606i 606j 606k 606l 626 606m 627 Notebook Reference YN-3-047 YN-2-291 YN-3-037 YN-3-005 YN-2-303 YN-2-301 YN-3-015 YN-3-021 YN-3-087 YN-3-071 YN-3-153 KJG-5-091 KJG-5-151 KJG-5-107 KJG-6-015 KJG-6-127 KJG-6-093 KJG-6-119 YN-2-267 YN-3-031 YN-3-001 YN-2-299 YN-2-293 YN-3-003 YN-3-019 YN-3-035 YN-3-081 YN-3-053 YN-3-147 KJG-5-011 KJG-5-049 KJG-4-303 989 990 ABOUT THE AUTHOR Kevin Jaime Gonzalez was born in Miami, Florida on October 21st, 1997, to Ana and Mitchell Gonzalez. He attended Belen Jesuit Preparatory School, where he developed a keen interest in science. In 2016, Kevin began his undergraduate studies at Rice University as a pre-medical student majoring in Ecology and Evolutionary Biology. During this time, he conducted research in the lab of Professor Scott Egan on the effects of spatial sorting on the red-shouldered soapberry bug, Jadera haematoloma. An introductory organic chemistry course taught by Professors László Kürti and Jeffrey Hartgerink sparked his fascination in chemistry, inspiring him to change his major to Chemistry at the start of his junior year. At Rice, Kevin carried out research in the lab of Professor Hartgerink on the supramolecular structure of collagen and efforts to stabilize a collagen-based hydrogel. Mentorship from Professor Hartgerink, as well as Professor Julian West, further encouraged him to pursue graduate studies in organic synthesis. Kevin graduated from Rice University in 2020 with a B.S. degree in Chemistry. Upon completing his undergraduate studies, Kevin moved to Pasadena, California, to pursue graduate research at the California Institute of Technology under the guidance of Professor Brian Stoltz. His doctoral research focused on developing strategies and tactics for the total synthesis of bioactive alkaloid natural products. Following completion of his graduate studies, Kevin will return to the field of chemical biology as a postdoctoral fellow in the lab of Professor Carolyn Bertozzi at Stanford University.