Enantioselective Syntheses of Tetrahydroisoquinolines (THIQs) via Iridium-Catalyzed Asymmetric Hydrogenation and Progress Toward the Total Synthesis of (+)-Cyanocycline A Citation Kim, Alexia Nahyun (2023) Enantioselective Syntheses of Tetrahydroisoquinolines (THIQs) via Iridium-Catalyzed Asymmetric Hydrogenation and Progress Toward the Total Synthesis of (+)-Cyanocycline A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/4xty-8711. https://resolver.caltech.edu/CaltechTHESIS:06022023-190747966 Abstract Described herein are two reviews and three projects related to the asymmetric syntheses of tetrahydroisoquinoline (THIQs) alkaloids, and the progress toward the total synthesis of (+)-cyanocycline A. In Chapter 1, a review of the development of asymmetric methodologies for the preparation of enantioenriched N -heteroarenes is detailed. In Chapter 2, the development of an iridium-catalyzed enantio- and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines to achieve cis -THIQs is reported. Chapter 3 describes the iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines that can afford trans -THIQs in a single transformation. Preliminary mechanistic insights to the iridium-catalyzed asymmetric hydrogenation method using deuterium experiments are detailed. Chapter 4 details a comprehensive review of the advances in the total syntheses of complex THIQ alkaloids from 2000 – 2020, ranging from simple benzyl THIQ natural products to complex THIQ alkaloids such as Ecteinascidin-743. In Chapter 5, efforts toward the total synthesis of (+)-cyanocycline A are described, harnessing a non- biomimetic synthetic route through a convergent cross-coupling of two heterocyclic fragments followed by a global hydrogenation event. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: tetrahydroisoquinolines, total synthesis, asymmetric catalysis, hydrogenation Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Awards: Outstanding Mentee Award, 2021. Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Robb, Maxwell J. (chair) Reisman, Sarah E. Hsieh-Wilson, Linda C. Stoltz, Brian M. Defense Date: 22 May 2023 Record Number: CaltechTHESIS:06022023-190747966 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:06022023-190747966 DOI: 10.7907/4xty-8711 Related URLs: URL URL Type Description https://doi.org/10.1021/acscatal.0c03958 DOI Article adapted for Chapter 1 https://doi.org/10.1021/acscatal.0c00211 DOI Article adapted for Chapter 2 https://doi.org/10.1039/D1SC06729J DOI Article adapted for Chapter 3 https://doi.org/10.1021/jacs.1c08920 DOI Other Publication ORCID: Author ORCID Kim, Alexia Nahyun 0000-0002-4060-8892 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 16058 Collection: CaltechTHESIS Deposited By: Alexia Kim Deposited On: 02 Jun 2023 23:50 Last Modified: 08 Nov 2023 00:39 Thesis Files PDF - Final Version See Usage Policy. 28MB Repository Staff Only: item control page

ENANTIOSELECTIVE SYNTHESES OF TETRAHYDROISOQUINOLINES (THIQS) VIA IRIDIUM-CATALYZED ASYMMETRIC HYDROGENATION AND PROGRESS TOWARD THE TOTAL SYNTHESIS OF (+)-CYANOCYCLINE A Thesis by Alexia Nahyun Kim In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2023 (Defended: May 22, 2023) ii ã 2023 Alexia Kim ORCID: 0000-0002-4060-8892 All Rights Reserved iii To 엄마 and 아빠 iv ACKNOWLEDGEMENTS Words truly can’t express the gratitude and appreciation that I have for everyone that has helped me throughout my graduate career. First, I would like to thank my advisor, Professor Brian Stoltz, for being an incredible mentor throughout the past five years. I still distinctly remember the first mechanism bootcamp class I took with Brian in my first year, quickly realizing how supportive and encouraging he is as a teacher. He kindly took me in as a summer student the month before I started graduate school, and my time interacting with him as well as the rest of the group made me feel incredibly welcomed during a time when I felt major imposter syndrome. His mentorship style of providing us the freedom to explore our own chemistry while giving direction and feedback when we need it is quite amazing–and I believe it has truly made me a stronger, more independent scientist. I am deeply grateful for his unwavering support over the past five years. I would also like to especially thank Professor Sarah Reisman for her expertise and support as another advisor on the 3rd floor of Schlinger, and contributing advice to my talks in our joint group meetings and committee meetings. Sarah is also a leader I look up to, and I am constantly in awe of her creativity and highly intellectual ideas that she brings to every single meeting. I would like to thank the chair of my committee Professor Max Robb, and committee member Professor Linda Hsieh-Wilson for their continuous support and valuable feedback during my committee meetings and exams. Even throughout the pandemic they have handled all my committee meetings with class and a level of professionalism that I can only hope to aspire to. v I would also like to thank my previous teachers before graduate school that truly instilled in me a passion for chemistry. First, I’d like to thank Mr. Hadan Kauffman, an excellent chemistry teacher in my high school who was one of the first people who introduced me to chemistry. If not for him and the summer chemistry bootcamp class I took my freshman year, perhaps I would not have been as fascinated with chemistry in the same way. Dr. Brian Kennedy was also a fantastic teacher who introduced me to organic chemistry in my senior year of high school. Both of their teachings has built in me a foundational passion for chemistry that led me to pursue chemistry as a major at Princeton. In college, I was incredibly fortunate to have worked with Professor Rob Knowles, who like Brian was also a very supportive and encouraging advisor. It was ultimately his mentorship and his group that made me consider applying to graduate school for chemistry. I would also like to thank Professor Tim Warren for having me in his group for a year at Georgetown, learning about organometallic chemistry and getting very comfortable with glovebox chemistry before I started graduate school at Caltech. I’d like to express my deepest gratitude to the Caltech staff that kept our research going in such a high-paced environment. First and foremost, I would like to thank Dr. Scott Virgil for all of his help running the 3rd floor catalysis center and helping me at any time whenever I had trouble using an instrument or the Parr bomb reactor. I truly enjoy the chances I get to converse with him due to his endless knowledge and expertise on instrumentation, spectroscopy, and synthesis. I would like to thank Scott and Silva as well for hosting the annual holiday party each year, and getting to hear Scott play the piano and talk about classical music is always a treat. vi I’d like to thank Dr. David VanderVelde for his expertise in NMR spectroscopy, and his unrelenting support in maintaining the NMR facility. I’m grateful for Dr. Mike Takase and Larry Henling for their expertise in X-ray crystallography and obtaining publishable crystal structures. I would also like to thank Dr. Mona Shahgoli for her expertise in mass spectrometry. It was a pleasure to work for her as a GLA for a year, as I truly learned a lot about high-resolution mass spectrometry techniques. I’d like to thank Nate Siladke and Joe Drew for maintaining Caltech facilities and EH&S, especially during my time as the safety officer of the lab. I definitely appreciated the support especially during the pandemic as we had to create documentation and figure out shift schedules. Finally, I’d like to thank Greg and Armando, Alison Ross, Leslie, and Beth Marshall for keeping everything running smoothly in the CCE department. I have been so lucky to work with so many amazing and talented scientists up on the 3rd floor of Schlinger. I’d like to thank Dr. Eric Alexy who was my very first mentor when I joined in the summer, and taught me all the basic lab skills and techniques to get started in the Stoltz lab. I’d also like to thank Dr. Fa Ngamnithiporn who brought me on to her project, and for being an amazing mentor, project partner, and friend. Not only is she an excellent chemist with an incredible work ethic, but she is also a great friend that I could rely on for anything. I really enjoyed our times grabbing coffee, going to hip-hop dance classes, and playing video games outside of the lab. I distinctly remember her being the first person to invite me out to group lunch, where she randomly threw a french fry coated in ketchup on Eric Alexy’s shirt. That was the moment I knew I wanted to join the Stoltz group. Jokes aside, I’ve been incredibly fortunate to work with her and Dr. Eric Welin on vii THIQ alkaloids, and learned a lot in a short amount of time about working with these molecules and developing a methods project. I’d also like to thank Dr. Chris Reimann, Dr. Carina Jette, and Dr. Sean Feng for being wonderful scientists and friends of the same cohort. Hearing drunk Chris spit out words of wisdom was always a treat, and he was also a friend that I looked up to as a first and second year graduate student. Dr. Sean Feng and Dr. Skyler Mendoza were also close friends especially during my first few years of graduate school, and I truly enjoyed the random outings we had to get soufflé pancakes or go out to LA. Dr. Nick Fastuca was also a good friend who helped me navigate graduate school, and I enjoyed our random trips watching artsy movies at the Laemmle Pasadena. I’d like to thank Dr. Nick Hafeman and Dr. Tyler Fulton for being incredible scientists and great friends as well. I enjoyed the times we went to Ernie’s to grab lunch before the pandemic, when I could barely finish three tacos and they ate a huge Jaws sandwich in its entirety. Their sarcastic humor, Twin Peaks references, and the random print-outs of collaged photos and memes never failed to make me laugh no matter the circumstances. It was tough on everyone during the pandemic, but they have gone above and beyond to ensure our lab was running smoothly and that everyone was on the same page. Thank you for the ping-pong sessions, the random Zoom hangout sessions, the insightful advice and ideas about chemistry, and all the guidance you have given me throughout the years. I’m thankful for my cohort, including Zack Sercel, Tyler Casselman, and Alex Cusumano, for keeping me sane and for all their help going through this PhD journey viii together. I especially would like to thank Alex for being the best hoodmate, and “partner in crime” that I could ask for. He has supported me since day one with his insight and humor, and truly has helped me through the darkest times of graduate school. It’s been a blast navigating through graduate school together, especially in recruiting the younger graduate students to our group, revamping the group website, and stress-relieving by “dancing” in the bay. I’m so proud of how far we’ve come over these 5 years, and am so grateful to have had you there each step of the way. I’d like to thank Melinda Chan, Dr. Stephen Sardini, Joel Monroy, and Dr. Veronica Hubble who have been especially supportive during the pandemic. Without them I definitely would have gone insane from social isolation, and I appreciate all their support as I was struggling through graduate school. I enjoyed all the food adventures, mahjong sessions, and random memes that have helped me relieve stress during such stressful times. I’d also like to thank the younger graduate students that I’ve had the pleasure of getting to know over the last couple of years. The current third and fourth years–Ally, Melinda, Adrian, Farbod, Kevin, Elliot, Jay, Kali, and Samir–are some of the brightest and most humble people I’ve ever met. All of you are incredible chemists, and I can’t wait to see how the group flourishes as you all become fifth years. I’d like to thank Kali for being my gym buddy with Veronica and Vaishnavi over the past year–it has truly helped me grow stronger (literally). I’d also like to thank Jay for taking over almost all of my group jobs and going above and beyond with them–and going to fun concerts with me. To the second and first years–Ruby, Ben, Kim, Christian, Cami, Marva, Hao, Adrian, Sydney, Chloe, and Jonathan–you all are incredibly talented and thank you for ix making the lab such a fun place to be. I wish I had gotten to know each of you more before I turned into a reclusive senior graduate student, but I’m excited to see where you will take the group moving forward. I’d especially like to thank Cami for joining the cyanocycline A project and allowing me to mentor her the past two years. It’s been exciting to watch her grow as a skilled and independent chemist, and I am confident that she’ll continue to flourish and succeed during the rest of her PhD. Outside of my academic career, I would like to thank the Caltech community for being so supportive over the years. First, I’d like to thank Denise Lin and Dr. Maria Oh for being indispensable therapists during my five years at Caltech. They have truly helped me during the hardest times, and due to their guidance I’ve grown a lot as a person that has definitely contributed to my development as a scientist as well. I’d also like to thank the Caltech music community, including the Caltech orchestra, Dr. Glenn Price, and Dr. Hyesung Park for allowing me to continue playing music. Outside of Caltech, I am deeply grateful for my close friends who have kept me grounded throughout all these years. I’m thankful to my friends from high school– Ben, Esther, Hans, Jackie, Ji Soo, Jiyoung, Justin, Kevin, Michelle, and Yujin–who I rarely get to see because they mostly all live in Virginia, but no matter how long time has passed, the conversation always picks up so naturally when we do hang out. It’s been such a joy watching everyone go through major milestones over the past 15 years, and I’m so grateful to have you guys in my life for so many years. I’d also like to thank my college friends–Rachel Klebanov and Monica Magalhaes– for being so supportive despite being on the opposite coast. Both have visited me several x times in the LA area when I was too busy with school to travel and visit them, for which I’m extremely grateful, and at the same time regretful for not being able to do the same. Thank you for keeping it fun and grounded whenever we do get the chance to hang out, and for staying connected despite the distance and our chaotic schedules. I am deeply grateful for my partner Matthew Chen and the Chen and Tan family for their incredible support over the last three years. Being a graduate student is often extremely isolating, but they truly made me feel at home with their hospitality and kindness when I started to join Sunday family dinners and holiday festivities. I’d like to thank Audrey Chen for all her support and generosity especially over the last year. Moreover, I’d like to thank Matthew for being the best support system, partner, and best friend I could ask for. Even when I come home from lab in a sour mood, he never fails to cheer me up and make me laugh with his infectious humor, compassion, and patience. I am so lucky to have his overwhelming love and support, and am looking forward to the next chapter of our lives. Finally, I would like to thank my family for their unconditional support and sacrifice to make this possible. My mom (엄마) and dad (아빠) immigrated to the U.S. in 1992 so that my dad could complete his PhD studies, so in a way it feels like my PhD journey is coming full circle. Despite the challenges of being an immigrant, they decided to stay in the U.S. so that my brothers and I could continue our education, and I am eternally grateful and indebted to them for that. I am deeply thankful for my parents, Branden, Caelan, and my dog Daisy for their continued support and love to make this journey even possible. 감사하고 사랑합니다! xi ABSTRACT Described herein are two reviews and three projects related to the asymmetric syntheses of tetrahydroisoquinoline (THIQs) alkaloids, and the progress toward the total synthesis of (+)-cyanocycline A. In Chapter 1, a review of the development of asymmetric methodologies for the preparation of enantioenriched N-heteroarenes is detailed. In Chapter 2, the development of an iridium-catalyzed enantio- and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines to achieve cis-THIQs is reported. Chapter 3 describes the iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines that can afford trans-THIQs in a single transformation. Preliminary mechanistic insights to the iridium-catalyzed asymmetric hydrogenation method using deuterium experiments are detailed. Chapter 4 details a comprehensive review of the advances in the total syntheses of complex THIQ alkaloids from 2000 – 2020, ranging from simple benzyl THIQ natural products to complex THIQ alkaloids such as Ecteinascidin-743. In Chapter 5, efforts toward the total synthesis of (+)-cyanocycline A are described, harnessing a nonbiomimetic synthetic route through a convergent cross-coupling of two heterocyclic fragments followed by a global hydrogenation event. xii PUBLISHED CONTENT AND CONTRIBUTIONS 1. Kim, A. N.;‡ Ngamnithiporn, A.; ‡ Welin, E. R.; Daiger, M. T.; Grünanger, C. U.; Bartberger, M. D.; Virgil, S. C.; Stoltz, B. M. “Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines.” ACS Catal. 2020, 10, 3241–3248. DOI: 10.1021/acscatal.0c00211 A.N.K. participated in reaction optimization, experimental work, data analysis, and manuscript preparation. 2. Kim, A. N.; Stoltz, B. M. “Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes.” ACS Catal. 2020, 10, 13834–13851. DOI: 10.1021/acscatal.0c03958 A.N.K. participated in collecting references and manuscript preparation. 3. Kim, K. E.; Kim, A. N.; McCormick, C. J.; Stoltz, B. M. “Late-Stage Diversification: A Motivating Force in Organic Synthesis.” J. Am. Chem. Soc. 2021, 143, 16890–16901. DOI: 10.1021/jacs.1c08920 A.N.K. participated in collecting references and manuscript preparation. 4. Kim, A. N.; Ngamnithiporn, A.; Bartberger, M. D.; Stoltz, B. M. “IridiumCatalyzed Asymmetric trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines.” Chem. Sci. 2022, 13, 3227–3232. DOI: 10.1039/D1SC06729J xiii A.N.K. participated in reaction optimization, experimental work, data analysis, and manuscript preparation. 5. Kim, A. N.; Ngamnithiporn, A.; Du, E.; Stoltz, B. M. “Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020).” Chem. Rev. Manuscript Submitted. A.N.K. participated in collecting references and manuscript preparation. xiv TABLE OF CONTENTS Dedication............................................................................................................. iii Acknowledgements .............................................................................................. iv Abstract ............................................................................................................... xi Published Content and Contributions................................................................... xii Table of Contents ............................................................................................... xiv List of Figures ...................................................................................................... xx List of Schemes .................................................................................................... xlv List of Tables......................................................................................................... lvi List of Abbreviations ........................................................................................... lviii CHAPTER 1 Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes (2002–2020) 1 1.1 Introduction ................................................................................................ 1 1.2 General Mechanistic Considerations .......................................................... 2 1.3 Ruthenium-Catalyzed Asymmetric Hydrogenation ..................................... 6 1.4 Iridium-Catalyzed Asymmetric Hydrogenation ......................................... 14 1.5 Rhodium-Catalyzed Asymmetric Hydrogenation ...................................... 23 1.6 Palladium-Catalyzed Asymmetric Hydrogenation .................................... 25 1.7 Iron-Catalyzed Asymmetric Hydrogenation .............................................. 29 1.8 Borane-Catalyzed Asymmetric Hydrogenation ......................................... 31 1.9 Chiral Phosphoric Acid-Catalyzed Asymmetric Hydrogenation ................. 34 xv 1.10 Conclusion .............................................................................................. 38 1.11 References and Notes .............................................................................. 41 CHAPTER 2 Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 51 2.1 Introduction .............................................................................................. 51 2.2 Substrate Syntheses .................................................................................. 55 2.3 Reaction Optimization ............................................................................. 56 2.4 Substrate Scope ........................................................................................ 58 2.5 Synthetic Utility ....................................................................................... 65 2.6 Conclusion ............................................................................................... 67 2.7 Experimental Section ............................................................................... 67 2.7.1 Materials and Methods .................................................................. 67 2.7.2 Experimental Procedures and Spectroscopic Data .......................... 69 2.7.2.1 Syntheses of Hydroxymethyl 1,3-Disubstituted Isoquinolines .... 69 2.7.2.2 Syntheses of Isoquinolines with Different Directing Groups ..... 108 2.7.2.3 Hydrogenation Reactions ......................................................... 112 2.7.2.4 Product Transformations .......................................................... 139 2.7.3 Additional Optimization Results................................................... 144 2.7.4 Determination of Enantiomeric Excess ......................................... 145 2.7.5 Determination of Relative and Absolute Stereochemistry ............. 151 2.8 References and Notes ............................................................................ 156 APPENDIX 1 Spectra Relevant to Chapter 2 161 xvi APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 2 377 CHAPTER 3 Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 385 3.1 Introduction ............................................................................................ 385 3.2 Reaction Optimization ........................................................................... 387 3.3 Substrate Scope ...................................................................................... 390 3.4 Synthetic Utility ..................................................................................... 392 3.5 Preliminary Mechanistic Insights ............................................................. 393 3.6 Conclusions ........................................................................................... 395 3.7 Experimental Section ............................................................................. 396 3.7.1 Materials and Methods ................................................................ 396 3.7.2 Experimental Procedures and Spectroscopic Data ........................ 397 3.7.2.1 Syntheses of Hydroxymethyl 1,3-Disubstituted Isoquinolines .. 397 3.7.2.2 Syntheses of Isoquinolines with Different Directing Groups ..... 415 3.7.2.3 Hydrogenation Reactions ......................................................... 419 3.7.2.4 Product Transformations .......................................................... 435 3.7.3 Additional Optimization Results................................................... 438 3.7.4 Deuterium Incorporation Experiments .......................................... 439 3.7.5 Proposed Catalytic Cycle ............................................................. 440 3.7.6 Determination of Enantiomeric Excess ......................................... 441 3.7.7 Determination of Relative and Absolute Stereochemistry ............. 444 3.8 References and Notes ............................................................................ 446 APPENDIX 3 Spectra Relevant to Chapter 3 451 xvii APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3 501 CHAPTER 4 Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020) 512 4.1 Introduction ............................................................................................ 512 4.2 Tetrahydroisoquinoline Alkaloids ........................................................... 513 4.2.1 4.3 General Structure and Biosynthesis ............................................. 513 Spirocyclic Tetrahydroisoquinoline Alkaloids ........................................ 514 4.3.1 General Structure and Biosynthesis ............................................. 514 4.3.2 Total Synthesis of Erythrina Alkaloids .......................................... 515 4.4 Benzyltetrahydroisoquinoline Alkaloids ................................................. 523 4.4.1 4.4.1.1 General Structure and Biosynthesis .................................. 525 4.4.1.2 Total Synthesis of Aporphine Alkaloids.............................. 526 4.4.2 Bisbenzyltetrahydroisoquinoline Alkaloids .................................. 534 4.4.2.1 General Structure and Biosynthesis .................................. 534 4.4.2.2 Total Synthesis of Bisbenzyl THIQ Alkaloids ..................... 536 4.4.3 Protoberberine Alkaloids ............................................................. 541 4.4.3.1 General Structure and Biosynthesis .................................. 541 4.4.3.2 Total Synthesis of Protoberberine Alkaloids ....................... 542 4.4.4 Morphinan Alkaloids ................................................................... 553 4.4.4.1 General Structure and Biosynthesis .................................. 553 4.4.4.2 Total Synthesis of Morphinan Alkaloids ............................. 555 4.4.5 4.5 Aporphine Alkaloids ................................................................... 525 Pavine and Isopavine Alkaloids ................................................... 570 4.4.5.1 General Structure and Biosynthesis .................................. 570 4.4.5.2 Total Synthesis of Pavine and Isopavine Alkaloids ............. 571 THIQ Alkaloids from the Saframycin Family .......................................... 575 xviii 4.5.1 4.5.1.1 General Structure and Biosynthesis .................................. 576 4.5.1.2 Total Synthesis of Saframycin Alkaloids ............................ 579 4.5.2 Safracin Alkaloids ....................................................................... 581 4.5.2.1 General Structure and Biosynthesis .................................. 582 4.5.2.2 Total Synthesis of Safracin Alkaloids.................................. 582 4.5.3 Renieramycin Alkaloids .............................................................. 583 4.5.3.1 General Structure and Biosynthesis .................................. 583 4.5.3.2 Total Synthesis of Renieramycin Alkaloids......................... 585 4.5.4 4.6 Saframycin Alkaloids ................................................................... 576 Ecteinascidin Alkaloids ............................................................... 602 4.5.4.1 General Structure and Biosynthesis .................................. 602 4.5.4.2 Total Synthesis of Ecteinascidin Alkaloids.......................... 604 THIQ Alkaloids from the Naphthyridinomycin Family ............................ 612 4.6.1 General Structure and Biosynthesis ............................................. 612 4.6.2 Total Synthesis of Naphthyridinomycin Alkaloids......................... 615 4.7 THIQ Alkaloids from the Quinocarcin Family ........................................ 616 4.7.1 General Structure and Biosynthesis ............................................. 617 4.7.2 Total Synthesis of Quinocarcin Alkaloids ..................................... 618 4.7.3 Total Synthesis of Tetrazomine ..................................................... 623 4.7.4 Total Synthesis of Lemonomycin .................................................. 626 4.8 Conclusions ........................................................................................... 629 4.9 References and Notes ............................................................................ 629 CHAPTER 5 Progress Toward the Total Synthesis Of (+)-Cyanocycline A 645 5.1 Introduction ............................................................................................ 645 5.2 Retrosynthetic Analysis .......................................................................... 648 xix 5.3 First Generation Approach ..................................................................... 649 5.4 Second Generation Approach ................................................................ 661 5.5 Third Generation Approach .................................................................... 665 5.6 Conclusion and Future Directions .......................................................... 669 5.7 Experimental Section ............................................................................. 671 5.7.1 Materials and Methods ................................................................ 671 5.7.2 Experimental Procedures and Spectroscopic Data ........................ 672 5.8 References and Notes ............................................................................ 711 APPENDIX 5 Synthetic Summary of Chapter 5 715 APPENDIX 6 Spectra Relevant to Chapter 5 721 Comprehensive Bibliography .............................................................................. 778 About the Author ................................................................................................ 808 xx LIST OF FIGURES CHAPTER 1 Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes (2002–2020) Figure 1.1 Overview of the total number of published reports on the asymmetric hydrogenation of common heteroarenes .......................................... 3 Figure 1.2 Common Ru-based catalyst systems for the asymmetric hydrogenation of heteroarenes ......................................................... 7 Figure 1.3 Proposed catalytic cycle for the asymmetric hydrogenation of quinolines with a Ru/TsDPEN catalyst ............................................ 11 Figure 1.4 Common Ir-based catalyst systems for the asymmetric hydrogenation of heteroarenes .............................................................................. 15 Figure 1.5 Proposed catalytic cycle for the Ir-catalyzed asymmetric hydrogenation of quinolines........................................................... 17 Figure 1.6 Common Rh-based catalyst systems for the asymmetric hydrogenation of heteroarenes ....................................................... 24 Figure 1.7 Proposed catalytic cycle for the Rh-catalyzed asymmetric hydrogenation of indoles ............................................................... 26 Figure 1.8 Common Pd-based catalyst systems for the asymmetric hydrogenation of heteroarenes ....................................................... 27 Figure 1.9 Proposed catalytic cycle for the Pd-catalyzed asymmetric hydrogenation of indoles ............................................................... 28 Figure 1.10 Proposed cooperative catalytic cycle for the Fe-catalyzed asymmetric hydrogenation of benzoxazines ..................................................... 31 Figure 1.11 Common chiral phosphoric acid catalyst systems for the asymmetric hydrogenation of heteroarenes ....................................................... 35 Figure 1.12 Proposed catalytic cycle for the asymmetric transfer hydrogenation of quinolines using a chiral phosphoric acid and Hantzch ester ........ 37 xxi CHAPTER 2 Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines Figure 2.1 Limitations in enantioselective hydrogenation of N-heterocycles and previous examples of Ir-catalyzed asymmetric hydrogenation ........ 53 Figure 2.2 Our research on Ir-catalyzed enantioselective and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines ........................... 54 Figure 2.3 Experimental and computed IR and VCD spectra for the cis isomers of 167e ........................................................................................ 153 Figure 2.4 Experimental and computed IR and VCD spectra for the trans isomers of 167e ....................................................................................... 153 APPENDIX 1 Spectra Relevant to Chapter 2 Figure A1.1 1 H NMR (400 MHz, CDCl3) of compound 159a ........................... 162 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 159a............... 163 Figure A1.3 13 Figure A1.4 1 C NMR (100 MHz, CDCl3) of compound 159a .......................... 163 H NMR (400 MHz, CDCl3) of compound 159b ........................... 164 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound 159b .............. 165 Figure A1.6 13 C NMR (100 MHz, CDCl3) of compound 159b .......................... 165 Figure A1.7 19 F NMR (282 MHz, CDCl3) of compound 159b .......................... 166 Figure A1.8 1 H NMR (400 MHz, CDCl3) of compound 159c ........................... 167 Figure A1.9 Infrared spectrum (Thin Film, NaCl) of compound 159c............... 168 Figure A1.10 13C NMR (100 MHz, CDCl3) of compound 159c .......................... 168 Figure A1.11 1H NMR (400 MHz, CDCl3) of compound 159d ........................... 169 xxii Figure A1.12 Infrared spectrum (Thin Film, NaCl) of compound 159d .............. 170 Figure A1.13 13C NMR (100 MHz, CDCl3) of compound 159d .......................... 170 Figure A1.14 1H NMR (400 MHz, CDCl3) of compound 160a ........................... 171 Figure A1.15 Infrared spectrum (Thin Film, NaCl) of compound 160a............... 172 Figure A1.16 13C NMR (100 MHz, CDCl3) of compound 160a .......................... 172 Figure A1.17 19F NMR (282 MHz, CDCl3) of compound 160a ........................... 173 Figure A1.18 1H NMR (400 MHz, CDCl3) of compound 160b ........................... 174 Figure A1.19 Infrared spectrum (Thin Film, NaCl) of compound 160b .............. 175 Figure A1.20 13C NMR (100 MHz, CDCl3) of compound 160b .......................... 175 Figure A1.21 19F NMR (282 MHz, CDCl3) of compound 160b .......................... 176 Figure A1.22 1H NMR (400 MHz, CDCl3) of compound 160c ........................... 177 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 160c............... 178 Figure A1.24 13C NMR (100 MHz, CDCl3) of compound 160c .......................... 178 Figure A1.25 19F NMR (282 MHz, CDCl3) of compound 160c ........................... 179 Figure A1.26 1H NMR (400 MHz, CDCl3) of compound 160d ........................... 180 Figure A1.27 Infrared spectrum (Thin Film, NaCl) of compound 160d .............. 181 Figure A1.28 13C NMR (100 MHz, CDCl3) of compound 160d .......................... 181 Figure A1.29 19F NMR (282 MHz, CDCl3) of compound 160d .......................... 182 Figure A1.30 1H NMR (400 MHz, CDCl3) of compound 161a ........................... 183 Figure A1.31 Infrared spectrum (Thin Film, NaCl) of compound 161a............... 184 Figure A1.32 13C NMR (100 MHz, CDCl3) of compound 161a .......................... 184 Figure A1.33 1H NMR (400 MHz, CDCl3) of compound 161b ........................... 185 xxiii Figure A1.34 Infrared spectrum (Thin Film, NaCl) of compound 161b .............. 186 Figure A1.35 13C NMR (100 MHz, CDCl3) of compound 161b .......................... 186 Figure A1.36 1H NMR (400 MHz, CDCl3) of compound 161c ........................... 187 Figure A1.37 Infrared spectrum (Thin Film, NaCl) of compound 161c............... 188 Figure A1.38 13C NMR (100 MHz, CDCl3) of compound 161c .......................... 188 Figure A1.39 1H NMR (400 MHz, CDCl3) of compound 161d ........................... 189 Figure A1.40 Infrared spectrum (Thin Film, NaCl) of compound 161d .............. 190 Figure A1.41 13C NMR (100 MHz, CDCl3) of compound 161d .......................... 190 Figure A1.42 1H NMR (400 MHz, CDCl3) of compound 161e ........................... 191 Figure A1.43 Infrared spectrum (Thin Film, NaCl) of compound 161e............... 192 Figure A1.44 13C NMR (100 MHz, CDCl3) of compound 161e .......................... 192 Figure A1.45 19F NMR (282 MHz, CDCl3) of compound 161e ........................... 193 Figure A1.46 1H NMR (400 MHz, CDCl3) of compound 161f ........................... 194 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 161f ............... 195 Figure A1.48 13C NMR (100 MHz, CDCl3) of compound 161f ........................... 195 Figure A1.49 19F NMR (282 MHz, CDCl3) of compound 161f ........................... 196 Figure A1.50 1H NMR (400 MHz, CDCl3) of compound 161g ........................... 197 Figure A1.51 Infrared spectrum (Thin Film, NaCl) of compound 161g............... 198 Figure A1.52 13C NMR (100 MHz, CDCl3) of compound 161g .......................... 198 Figure A1.53 1H NMR (400 MHz, CDCl3) of compound 161h ........................... 199 Figure A1.54 Infrared spectrum (Thin Film, NaCl) of compound 161h .............. 200 Figure A1.55 13C NMR (100 MHz, CDCl3) of compound 161h .......................... 200 xxiv Figure A1.56 1H NMR (400 MHz, CDCl3) of compound 161i ............................ 201 Figure A1.57 Infrared spectrum (Thin Film, NaCl) of compound 161i ............... 202 Figure A1.58 13C NMR (100 MHz, CDCl3) of compound 161i ........................... 202 Figure A1.59 19F NMR (282 MHz, CDCl3) of compound 161i ........................... 203 Figure A1.60 1H NMR (400 MHz, CDCl3) of compound 161j ............................ 204 Figure A1.61 Infrared spectrum (Thin Film, NaCl) of compound 161j ............... 205 Figure A1.62 13C NMR (100 MHz, CDCl3) of compound 161j ........................... 205 Figure A1.63 1H NMR (400 MHz, CDCl3) of compound 161k ........................... 206 Figure A1.64 Infrared spectrum (Thin Film, NaCl) of compound 161k............... 207 Figure A1.65 13C NMR (100 MHz, CDCl3) of compound 161k .......................... 207 Figure A1.66 1H NMR (400 MHz, CDCl3) of compound 161l ............................ 208 Figure A1.67 Infrared spectrum (Thin Film, NaCl) of compound 161l ............... 209 Figure A1.68 13C NMR (100 MHz, CDCl3) of compound 161l ........................... 209 Figure A1.69 1H NMR (400 MHz, CDCl3) of compound 161m .......................... 210 Figure A1.70 Infrared spectrum (Thin Film, NaCl) of compound 161m ............. 211 Figure A1.71 13C NMR (100 MHz, CDCl3) of compound 161m ......................... 211 Figure A1.72 1H NMR (400 MHz, CDCl3) of compound 161n ........................... 212 Figure A1.73 Infrared spectrum (Thin Film, NaCl) of compound 161n .............. 213 Figure A1.74 13C NMR (100 MHz, CDCl3) of compound 161n .......................... 213 Figure A1.75 1H NMR (400 MHz, CDCl3) of compound 161o ........................... 214 Figure A1.76 Infrared spectrum (Thin Film, NaCl) of compound 161o .............. 215 Figure A1.77 13C NMR (100 MHz, CDCl3) of compound 161o .......................... 215 xxv Figure A1.78 1H NMR (400 MHz, CDCl3) of compound 161p ........................... 216 Figure A1.79 Infrared spectrum (Thin Film, NaCl) of compound 161p .............. 217 Figure A1.80 13C NMR (100 MHz, CDCl3) of compound 161p .......................... 217 Figure A1.81 1H NMR (400 MHz, CDCl3) of compound 161q ........................... 218 Figure A1.82 Infrared spectrum (Thin Film, NaCl) of compound 161q .............. 219 Figure A1.83 13C NMR (100 MHz, CDCl3) of compound 161q .......................... 219 Figure A1.84 1H NMR (400 MHz, CDCl3) of compound 161r ........................... 220 Figure A1.85 Infrared spectrum (Thin Film, NaCl) of compound 161r ............... 221 Figure A1.86 13C NMR (100 MHz, CDCl3) of compound 161r .......................... 221 Figure A1.87 1H NMR (400 MHz, CDCl3) of compound 172a ........................... 222 Figure A1.88 Infrared spectrum (Thin Film, NaCl) of compound 172a............... 223 Figure A1.89 13C NMR (100 MHz, CDCl3) of compound 172a .......................... 223 Figure A1.90 19F NMR (282 MHz, CDCl3) of compound 172a ........................... 224 Figure A1.91 1H NMR (400 MHz, CDCl3) of compound 172b ........................... 225 Figure A1.92 Infrared spectrum (Thin Film, NaCl) of compound 172b .............. 226 Figure A1.93 13C NMR (100 MHz, CDCl3) of compound 172b .......................... 226 Figure A1.94 19F NMR (282 MHz, CDCl3) of compound 172b .......................... 227 Figure A1.95 1H NMR (400 MHz, CDCl3) of compound 172c ........................... 228 Figure A1.96 Infrared spectrum (Thin Film, NaCl) of compound 172c............... 229 Figure A1.97 13C NMR (100 MHz, CDCl3) of compound 172c .......................... 229 Figure A1.98 19F NMR (282 MHz, CDCl3) of compound 172c ........................... 230 Figure A1.99 1H NMR (400 MHz, CDCl3) of compound 172d ........................... 231 xxvi Figure A1.100 Infrared spectrum (Thin Film, NaCl) of compound 172d ......... 232 Figure A1.101 13 Figure A1.102 1 Figure A1.103 Infrared spectrum (Thin Film, NaCl) of compound 172e ......... 234 Figure A1.104 13 Figure A1.105 1 Figure A1.106 Infrared spectrum (Thin Film, NaCl) of compound 172f .......... 236 Figure A1.107 13 Figure A1.108 1 Figure A1.109 Infrared spectrum (Thin Film, NaCl) of compound 162a ......... 238 Figure A1.110 13 Figure A1.111 1 Figure A1.112 Infrared spectrum (Thin Film, NaCl) of compound 162b ......... 240 Figure A1.113 13 Figure A1.114 1 Figure A1.115 Infrared spectrum (Thin Film, NaCl) of compound 162c ......... 242 Figure A1.116 13 Figure A1.117 1 Figure A1.118 Infrared spectrum (Thin Film, NaCl) of compound 162d ......... 244 Figure A1.119 13 Figure A1.120 1 Figure A1.121 Infrared spectrum (Thin Film, NaCl) of compound 162e ......... 246 C NMR (100 MHz, CDCl3) of compound 172d .................... 232 H NMR (400 MHz, CDCl3) of compound 172e ..................... 233 C NMR (100 MHz, CDCl3) of compound 172e .................... 234 H NMR (400 MHz, CDCl3) of compound 172f ...................... 235 C NMR (100 MHz, CDCl3) of compound 172f ..................... 236 H NMR (400 MHz, CDCl3) of compound 162a ..................... 237 C NMR (100 MHz, CDCl3) of compound 162a .................... 238 H NMR (400 MHz, CDCl3) of compound 162b ..................... 239 C NMR (100 MHz, CDCl3) of compound 162b .................... 240 H NMR (400 MHz, CDCl3) of compound 162c ..................... 241 C NMR (100 MHz, CDCl3) of compound 162c .................... 242 H NMR (400 MHz, CDCl3) of compound 162d ..................... 243 C NMR (100 MHz, CDCl3) of compound 162d .................... 244 H NMR (400 MHz, CDCl3) of compound 162e ..................... 245 xxvii Figure A1.122 13 C NMR (100 MHz, CDCl3) of compound 162e .................... 246 Figure A1.123 19 F NMR (282 MHz, CDCl3) of compound 162e ..................... 247 Figure A1.124 1 Figure A1.125 Infrared spectrum (Thin Film, NaCl) of compound 162f .......... 249 Figure A1.126 13 C NMR (100 MHz, CDCl3) of compound 162f ..................... 249 Figure A1.127 19 F NMR (282 MHz, CDCl3) of compound 162f ...................... 250 Figure A1.128 1 Figure A1.129 Infrared spectrum (Thin Film, NaCl) of compound 162g ......... 252 Figure A1.130 13 Figure A1.131 1 Figure A1.132 Infrared spectrum (Thin Film, NaCl) of compound 162h ......... 254 Figure A1.133 13 Figure A1.134 1 Figure A1.135 Infrared spectrum (Thin Film, NaCl) of compound 162i .......... 256 Figure A1.136 13 C NMR (100 MHz, CDCl3) of compound 162i ..................... 256 Figure A1.137 19 F NMR (282 MHz, CDCl3) of compound 162i ...................... 257 Figure A1.138 1 Figure A1.139 Infrared spectrum (Thin Film, NaCl) of compound 162j .......... 259 Figure A1.140 13 Figure A1.141 1 Figure A1.142 Infrared spectrum (Thin Film, NaCl) of compound 162k ......... 261 Figure A1.143 13 H NMR (400 MHz, CDCl3) of compound 162f ...................... 248 H NMR (400 MHz, CDCl3) of compound 162g ..................... 251 C NMR (100 MHz, CDCl3) of compound 162g .................... 252 H NMR (400 MHz, CDCl3) of compound 162h ..................... 253 C NMR (100 MHz, CDCl3) of compound 162h .................... 254 H NMR (400 MHz, CDCl3) of compound 162i ...................... 255 H NMR (400 MHz, CDCl3) of compound 162j ...................... 258 C NMR (100 MHz, CDCl3) of compound 162j ..................... 259 H NMR (400 MHz, CDCl3) of compound 162k ..................... 260 C NMR (100 MHz, CDCl3) of compound 162k .................... 261 xxviii Figure A1.144 1 Figure A1.145 Infrared spectrum (Thin Film, NaCl) of compound 162l .......... 263 Figure A1.146 13 Figure A1.147 1 Figure A1.148 Infrared spectrum (Thin Film, NaCl) of compound 162m ........ 265 Figure A1.149 13 Figure A1.150 1 Figure A1.151 Infrared spectrum (Thin Film, NaCl) of compound 162n ......... 267 Figure A1.152 13 Figure A1.153 1 Figure A1.154 Infrared spectrum (Thin Film, NaCl) of compound 162o ......... 269 Figure A1.155 13 Figure A1.156 1 Figure A1.157 Infrared spectrum (Thin Film, NaCl) of compound 162p ......... 271 Figure A1.158 13 Figure A1.159 1 Figure A1.160 Infrared spectrum (Thin Film, NaCl) of compound 162q ......... 273 Figure A1.161 13 Figure A1.162 1 Figure A1.163 Infrared spectrum (Thin Film, NaCl) of compound 162r ......... 275 Figure A1.164 13 Figure A1.165 1 H NMR (400 MHz, CDCl3) of compound 162l ...................... 262 C NMR (100 MHz, CDCl3) of compound 162l ..................... 263 H NMR (400 MHz, CDCl3) of compound 162m .................... 264 C NMR (100 MHz, CDCl3) of compound 162m ................... 265 H NMR (400 MHz, CDCl3) of compound 162n ..................... 266 C NMR (100 MHz, CDCl3) of compound 162n .................... 267 H NMR (400 MHz, CDCl3) of compound 162o ..................... 268 C NMR (100 MHz, CDCl3) of compound 162o .................... 269 H NMR (400 MHz, CDCl3) of compound 162p ..................... 270 C NMR (100 MHz, CDCl3) of compound 162p .................... 271 H NMR (400 MHz, CDCl3) of compound 162q ..................... 272 C NMR (100 MHz, CDCl3) of compound 162q .................... 273 H NMR (400 MHz, CDCl3) of compound 162r ...................... 274 C NMR (100 MHz, CDCl3) of compound 162r ..................... 275 H NMR (400 MHz, CDCl3) of compound 164a ..................... 276 xxix Figure A1.166 Infrared spectrum (Thin Film, NaCl) of compound 164a ......... 277 Figure A1.167 13 C NMR (100 MHz, CDCl3) of compound 164a .................... 277 Figure A1.168 19 F NMR (282 MHz, CDCl3) of compound 164a ..................... 278 Figure A1.169 1 Figure A1.170 Infrared spectrum (Thin Film, NaCl) of compound 164b ......... 280 Figure A1.171 13 C NMR (100 MHz, CDCl3) of compound 164b .................... 280 Figure A1.172 19 F NMR (282 MHz, CDCl3) of compound 164b ..................... 281 Figure A1.173 1 Figure A1.174 Infrared spectrum (Thin Film, NaCl) of compound 164c ......... 283 Figure A1.175 13 C NMR (100 MHz, CDCl3) of compound 164c .................... 283 Figure A1.176 19 F NMR (282 MHz, CDCl3) of compound 164c ..................... 284 Figure A1.177 1 Figure A1.178 Infrared spectrum (Thin Film, NaCl) of compound 164d ......... 286 Figure A1.179 13 Figure A1.180 1 Figure A1.181 Infrared spectrum (Thin Film, NaCl) of compound 164e ......... 288 Figure A1.182 13 Figure A1.183 1 Figure A1.184 Infrared spectrum (Thin Film, NaCl) of compound 164f .......... 290 Figure A1.185 13 Figure A1.186 1 Figure A1.187 Infrared spectrum (Thin Film, NaCl) of compound 166a ......... 292 H NMR (400 MHz, CDCl3) of compound 164b ..................... 279 H NMR (400 MHz, CDCl3) of compound 164c ..................... 282 H NMR (400 MHz, CDCl3) of compound 164d ..................... 285 C NMR (100 MHz, CDCl3) of compound 164d .................... 286 H NMR (400 MHz, CDCl3) of compound 164e ..................... 287 C NMR (100 MHz, CDCl3) of compound 164e .................... 288 H NMR (400 MHz, CDCl3) of compound 164f ...................... 289 C NMR (100 MHz, CDCl3) of compound 164f ..................... 290 H NMR (400 MHz, CDCl3) of compound 166a ..................... 291 xxx Figure A1.188 13 Figure A1.189 1 Figure A1.190 Infrared spectrum (Thin Film, NaCl) of compound 166b ......... 294 Figure A1.191 13 Figure A1.192 1 Figure A1.193 Infrared spectrum (Thin Film, NaCl) of compound 166c ......... 296 Figure A1.194 13 Figure A1.195 1 Figure A1.196 Infrared spectrum (Thin Film, NaCl) of compound 166d ......... 298 Figure A1.197 13 Figure A1.198 1 Figure A1.199 Infrared spectrum (Thin Film, NaCl) of compound 166f .......... 300 Figure A1.200 13 Figure A1.201 1 Figure A1.202 Infrared spectrum (Thin Film, NaCl) of compound 163a ......... 302 Figure A1.203 13 Figure A1.204 1 Figure A1.205 13 Figure A1.206 1 Figure A1.207 Infrared spectrum (Thin Film, NaCl) of compound 163b ......... 306 Figure A1.208 13 Figure A1.209 1 C NMR (100 MHz, CDCl3) of compound 166a .................... 292 H NMR (400 MHz, CDCl3) of compound 166b ..................... 293 C NMR (100 MHz, CDCl3) of compound 166b .................... 294 H NMR (400 MHz, CDCl3) of compound 166c ..................... 295 C NMR (100 MHz, CDCl3) of compound 166c .................... 296 H NMR (400 MHz, CDCl3) of compound 166d ..................... 297 C NMR (100 MHz, CDCl3) of compound 166d .................... 298 H NMR (400 MHz, CDCl3) of compound 166f ...................... 299 C NMR (100 MHz, CDCl3) of compound 166f ..................... 300 H NMR (400 MHz, CDCl3) of compound cis•163a ............... 301 C NMR (100 MHz, CDCl3) of compound cis•163a............... 302 H NMR (400 MHz, CDCl3) of compound trans•163a ............ 303 C NMR (100 MHz, CDCl3) of compound trans•163a ........... 304 H NMR (400 MHz, CDCl3) of compound 163b ..................... 305 C NMR (100 MHz, CDCl3) of compound 163b .................... 306 H NMR (400 MHz, CDCl3) of compound 163c ..................... 307 xxxi Figure A1.210 Infrared spectrum (Thin Film, NaCl) of compound 163c ......... 308 Figure A1.211 13 Figure A1.212 1 Figure A1.213 Infrared spectrum (Thin Film, NaCl) of compound 163d ......... 310 Figure A1.214 13 Figure A1.215 1 Figure A1.216 Infrared spectrum (Thin Film, NaCl) of compound 163e ......... 312 Figure A1.217 13 C NMR (100 MHz, CDCl3) of compound 163e .................... 312 Figure A1.218 19 F NMR (282 MHz, CDCl3) of compound 163e ..................... 313 Figure A1.219 1 Figure A1.220 Infrared spectrum (Thin Film, NaCl) of compound 163f .......... 315 Figure A1.221 13 C NMR (100 MHz, CDCl3) of compound 163f ..................... 315 Figure A1.222 19 F NMR (282 MHz, CDCl3) of compound 163f ...................... 316 Figure A1.223 1 Figure A1.224 Infrared spectrum (Thin Film, NaCl) of compound 163g ......... 318 Figure A1.225 13 Figure A1.226 1 Figure A1.227 Infrared spectrum (Thin Film, NaCl) of compound 163h ......... 320 Figure A1.228 13 Figure A1.229 1 Figure A1.230 Infrared spectrum (Thin Film, NaCl) of compound 163i .......... 322 Figure A1.231 13 C NMR (100 MHz, CDCl3) of compound 163c .................... 308 H NMR (400 MHz, CDCl3) of compound 163d ..................... 309 C NMR (100 MHz, CDCl3) of compound 163d .................... 310 H NMR (400 MHz, CDCl3) of compound 163e ..................... 311 H NMR (400 MHz, CDCl3) of compound 163f ...................... 314 H NMR (400 MHz, CDCl3) of compound 163g ..................... 317 C NMR (100 MHz, CDCl3) of compound 163g .................... 318 H NMR (400 MHz, CDCl3) of compound 163h ..................... 319 C NMR (100 MHz, CDCl3) of compound 163h .................... 320 H NMR (400 MHz, CDCl3) of compound 163i ...................... 321 C NMR (100 MHz, CDCl3) of compound 163i ..................... 322 xxxii Figure A1.232 19 Figure A1.233 1 Figure A1.234 Infrared spectrum (Thin Film, NaCl) of compound 163j .......... 325 Figure A1.235 13 Figure A1.236 1 Figure A1.237 Infrared spectrum (Thin Film, NaCl) of compound 163k ......... 327 Figure A1.238 13 Figure A1.239 1 Figure A1.240 Infrared spectrum (Thin Film, NaCl) of compound 163l .......... 329 Figure A1.241 13 Figure A1.242 1 Figure A1.243 Infrared spectrum (Thin Film, NaCl) of compound 163m ........ 331 Figure A1.244 13 Figure A1.245 1 Figure A1.246 Infrared spectrum (Thin Film, NaCl) of compound 163n ......... 333 Figure A1.247 13 Figure A1.248 1 Figure A1.249 Infrared spectrum (Thin Film, NaCl) of compound 163o ......... 335 Figure A1.250 13 Figure A1.251 1 Figure A1.252 Infrared spectrum (Thin Film, NaCl) of compound 163p ......... 337 Figure A1.253 13 F NMR (282 MHz, CDCl3) of compound 163i ...................... 323 H NMR (400 MHz, CDCl3) of compound 163j ...................... 324 C NMR (100 MHz, CDCl3) of compound 163j ..................... 325 H NMR (400 MHz, CDCl3) of compound 163k ..................... 326 C NMR (100 MHz, CDCl3) of compound 163k .................... 327 H NMR (400 MHz, CDCl3) of compound 163l ...................... 328 C NMR (100 MHz, CDCl3) of compound 163l ..................... 329 H NMR (400 MHz, CDCl3) of compound 163m .................... 330 C NMR (100 MHz, CDCl3) of compound 163m ................... 331 H NMR (400 MHz, CDCl3) of compound 163n ..................... 332 C NMR (100 MHz, CDCl3) of compound 163n .................... 333 H NMR (400 MHz, CDCl3) of compound 163o ..................... 334 C NMR (100 MHz, CDCl3) of compound 163o .................... 335 H NMR (400 MHz, CDCl3) of compound 163p ..................... 336 C NMR (100 MHz, CDCl3) of compound 163p .................... 337 xxxiii Figure A1.254 1 Figure A1.255 Infrared spectrum (Thin Film, NaCl) of compound 163q ......... 339 Figure A1.256 13 Figure A1.257 1 Figure A1.258 Infrared spectrum (Thin Film, NaCl) of compound 163r ......... 341 Figure A1.259 13 Figure A1.260 1 Figure A1.261 Infrared spectrum (Thin Film, NaCl) of compound 165a ......... 343 Figure A1.262 13 C NMR (100 MHz, CDCl3) of compound 165a .................... 343 Figure A1.263 19 F NMR (282 MHz, CDCl3) of compound 165a ..................... 344 Figure A1.264 1 Figure A1.265 Infrared spectrum (Thin Film, NaCl) of compound 165b ......... 346 Figure A1.266 13 C NMR (100 MHz, CDCl3) of compound 165b .................... 346 Figure A1.267 19 F NMR (282 MHz, CDCl3) of compound 165b ..................... 347 Figure A1.268 1 Figure A1.269 Infrared spectrum (Thin Film, NaCl) of compound 165c ......... 349 Figure A1.270 13 C NMR (100 MHz, CDCl3) of compound 165c .................... 349 Figure A1.271 19 F NMR (282 MHz, CDCl3) of compound 165c ..................... 350 Figure A1.272 1 Figure A1.273 Infrared spectrum (Thin Film, NaCl) of compound 165d ......... 352 Figure A1.274 13 Figure A1.275 1 H NMR (400 MHz, CDCl3) of compound 163q ..................... 338 C NMR (100 MHz, CDCl3) of compound 163q .................... 339 H NMR (400 MHz, CDCl3) of compound 163r ...................... 340 C NMR (100 MHz, CDCl3) of compound 163r ..................... 341 H NMR (400 MHz, CDCl3) of compound 165a ..................... 342 H NMR (400 MHz, CDCl3) of compound 165b ..................... 345 H NMR (400 MHz, CDCl3) of compound 165c ..................... 348 H NMR (400 MHz, CDCl3) of compound 165d ..................... 351 C NMR (100 MHz, CDCl3) of compound 165d .................... 352 H NMR (400 MHz, CDCl3) of compound 165e ..................... 353 xxxiv Figure A1.276 Infrared spectrum (Thin Film, NaCl) of compound 165e ......... 354 Figure A1.277 13 Figure A1.278 1 Figure A1.279 Infrared spectrum (Thin Film, NaCl) of compound 165f .......... 356 Figure A1.280 13 Figure A1.281 1 Figure A1.282 Infrared spectrum (Thin Film, NaCl) of compound 167a ......... 358 Figure A1.283 13 Figure A1.284 1 Figure A1.285 Infrared spectrum (Thin Film, NaCl) of compound 167b ......... 360 Figure A1.286 13 Figure A1.287 1 Figure A1.288 Infrared spectrum (Thin Film, NaCl) of compound 167c ......... 362 Figure A1.289 13 Figure A1.290 1 Figure A1.291 Infrared spectrum (Thin Film, NaCl) of compound 167d ......... 364 Figure A1.292 13 Figure A1.293 1 Figure A1.294 Infrared spectrum (Thin Film, NaCl) of compound 167e ......... 366 Figure A1.295 13 Figure A1.296 1 Figure A1.297 Infrared spectrum (Thin Film, NaCl) of compound 168 ........... 368 C NMR (100 MHz, CDCl3) of compound 165e .................... 354 H NMR (400 MHz, CDCl3) of compound 165f ...................... 355 C NMR (100 MHz, CDCl3) of compound 165f ..................... 356 H NMR (400 MHz, CDCl3) of compound 167a ..................... 357 C NMR (100 MHz, CDCl3) of compound 167a .................... 358 H NMR (400 MHz, CDCl3) of compound 167b ..................... 359 C NMR (100 MHz, CDCl3) of compound 167b .................... 360 H NMR (400 MHz, CDCl3) of compound 167c ..................... 361 C NMR (100 MHz, CDCl3) of compound 167c .................... 362 H NMR (400 MHz, CDCl3) of compound 167d ..................... 363 C NMR (100 MHz, CDCl3) of compound 167d .................... 364 H NMR (400 MHz, CDCl3) of compound 167e ..................... 365 C NMR (100 MHz, CDCl3) of compound 167e .................... 366 H NMR (400 MHz, CDCl3) of compound 168 ....................... 367 xxxv Figure A1.298 13 Figure A1.299 1 Figure A1.300 Infrared spectrum (Thin Film, NaCl) of compound 169 ........... 370 Figure A1.301 13 Figure A1.302 1 Figure A1.303 Infrared spectrum (Thin Film, NaCl) of compound 170 ........... 372 Figure A1.304 13 Figure A1.305 1 Figure A1.306 Infrared spectrum (Thin Film, NaCl) of compound 171 ........... 374 Figure A1.307 13 C NMR (100 MHz, CDCl3) of compound 168 ...................... 368 H NMR (400 MHz, CDCl3) of compound 169 ....................... 369 C NMR (100 MHz, CDCl3) of compound 169 ...................... 370 H NMR (400 MHz, CDCl3) of compound 170 ....................... 371 C NMR (100 MHz, CDCl3) of compound 170 ...................... 372 H NMR (400 MHz, CDCl3) of compound 171 ....................... 373 C NMR (100 MHz, CDCl3) of compound 171 ...................... 374 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 2 Figure A2.1 X-Ray crystal structure of THIQ 163p ......................................... 377 CHAPTER 3 Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines Figure 3.1 Challenges in diastereoselectivity of trans-selective arene hydrogenation .............................................................................. 386 Figure 3.2 Proposed catalytic cycle............................................................... 440 Figure 3.3 Experimental and theoretical IR and VCD spectra of 174 ............. 446 APPENDIX 3 Spectra Relevant to Chapter 3 xxxvi Figure A3.1 1 H NMR (400 MHz, CDCl3) of compound 161s ........................... 452 Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound 161s ............... 453 Figure A3.3 13 Figure A3.4 1 C NMR (100 MHz, CDCl3) of compound 161s .......................... 453 H NMR (400 MHz, CDCl3) of compound 173l ............................ 454 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound 173l ............... 455 Figure A3.6 13 Figure A3.7 1 C NMR (100 MHz, CDCl3) of compound 173l ........................... 455 H NMR (400 MHz, CDCl3) of compound 166g ........................... 456 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound 166g............... 457 Figure A3.9 13 C NMR (100 MHz, CDCl3) of compound 166g .......................... 457 Figure A3.10 1H NMR (400 MHz, CDCl3) of compound 167d ........................... 458 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound 167d .............. 459 Figure A3.12 13C NMR (100 MHz, CDCl3) of compound 167d .......................... 459 Figure A3.13 1H NMR (400 MHz, CDCl3) of compound 175a ........................... 460 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound 175a............... 461 Figure A3.15 13C NMR (100 MHz, CDCl3) of compound 175a .......................... 461 Figure A3.16 1H NMR (400 MHz, CDCl3) of compound 175b ........................... 462 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound 175b .............. 463 Figure A3.18 13C NMR (100 MHz, CDCl3) of compound 175b .......................... 463 Figure A3.19 1H NMR (400 MHz, CDCl3) of compound 175c ........................... 464 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound 175c............... 465 Figure A3.21 13C NMR (100 MHz, CDCl3) of compound 175c .......................... 465 Figure A3.22 1H NMR (400 MHz, CDCl3) of compound 175d ........................... 466 xxxvii Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound 175d .............. 467 Figure A3.24 13C NMR (100 MHz, CDCl3) of compound 175d .......................... 467 Figure A3.25 19F NMR (282 MHz, CDCl3) of compound 175d ........................... 468 Figure A3.26 1H NMR (400 MHz, CDCl3) of compound 175e ........................... 469 Figure A3.27 Infrared spectrum (Thin Film, NaCl) of compound 175e............... 470 Figure A3.28 13C NMR (100 MHz, CDCl3) of compound 175e .......................... 470 Figure A3.29 19F NMR (282 MHz, CDCl3) of compound 175e ........................... 471 Figure A3.30 1H NMR (400 MHz, CDCl3) of compound 175f ........................... 472 Figure A3.31 Infrared spectrum (Thin Film, NaCl) of compound 175f ............... 473 Figure A3.32 13C NMR (100 MHz, CDCl3) of compound 175f ........................... 473 Figure A3.33 1H NMR (400 MHz, CDCl3) of compound 175g ........................... 474 Figure A3.34 Infrared spectrum (Thin Film, NaCl) of compound 175g............... 475 Figure A3.35 13C NMR (100 MHz, CDCl3) of compound 175g .......................... 475 Figure A3.36 1H NMR (400 MHz, CDCl3) of compound 175h ........................... 476 Figure A3.37 Infrared spectrum (Thin Film, NaCl) of compound 175h .............. 477 Figure A3.38 13C NMR (100 MHz, CDCl3) of compound 175h .......................... 477 Figure A3.39 1H NMR (400 MHz, CDCl3) of compound 175i ............................ 478 Figure A3.40 Infrared spectrum (Thin Film, NaCl) of compound 175i ............... 479 Figure A3.41 13C NMR (100 MHz, CDCl3) of compound 175i ........................... 479 Figure A3.42 1H NMR (400 MHz, CDCl3) of compound 175j ............................ 480 Figure A3.43 Infrared spectrum (Thin Film, NaCl) of compound 175j ............... 481 Figure A3.44 13C NMR (100 MHz, CDCl3) of compound 175j ........................... 481 xxxviii Figure A3.45 1H NMR (400 MHz, CDCl3) of compound 175k ........................... 482 Figure A3.46 Infrared spectrum (Thin Film, NaCl) of compound 175k............... 483 Figure A3.47 13C NMR (100 MHz, CDCl3) of compound 175k .......................... 483 Figure A3.48 1H NMR (400 MHz, CDCl3) of compound 175l ............................ 484 Figure A3.49 Infrared spectrum (Thin Film, NaCl) of compound 175l ............... 485 Figure A3.50 13C NMR (100 MHz, CDCl3) of compound 175l ........................... 485 Figure A3.51 1H NMR (400 MHz, CDCl3) of compound 175m .......................... 486 Figure A3.52 Infrared spectrum (Thin Film, NaCl) of compound 175m ............. 487 Figure A3.53 13C NMR (100 MHz, CDCl3) of compound 175m ......................... 487 Figure A3.54 19F NMR (282 MHz, CDCl3) of compound 175m .......................... 488 Figure A3.55 1H NMR (400 MHz, CDCl3) of compound 175n ........................... 489 Figure A3.56 Infrared spectrum (Thin Film, NaCl) of compound 175n .............. 490 Figure A3.57 13C NMR (100 MHz, CDCl3) of compound 175n .......................... 490 Figure A3.58 19F NMR (282 MHz, CDCl3) of compound 175n ........................... 491 Figure A3.59 1H NMR (400 MHz, CDCl3) of compound 174 ............................. 492 Figure A3.60 Infrared spectrum (Thin Film, NaCl) of compound 174 ................ 493 Figure A3.61 13C NMR (100 MHz, CDCl3) of compound 174 ............................ 493 Figure A3.62 1H NMR (400 MHz, CDCl3) of compound 176 ............................. 494 Figure A3.63 Infrared spectrum (Thin Film, NaCl) of compound 176 ................ 495 Figure A3.64 13C NMR (100 MHz, CDCl3) of compound 176 ............................ 495 Figure A3.65 1H NMR (400 MHz, CDCl3) of compound d5-174 ........................ 496 Figure A3.66 2H NMR (61 MHz, CDCl3) of compound d5-174 .......................... 497 xxxix Figure A3.67 1H NMR (400 MHz, CDCl3) of compound dn-cis-174 ................... 498 Figure A3.68 1H NMR (400 MHz, CDCl3) of compound dn-174 ........................ 499 Figure A3.69 1H NMR (400 MHz, CDCl3) of compound dn-174 ........................ 500 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3 Figure A4.1 X-Ray crystal structure of THIQ 175a ......................................... 503 CHAPTER 4 Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020) Figure 4.1 Tetrahydroisoquinoline alkaloids (–)-salsolidine 183 and ecteinascidin 743 184 .................................................................. 513 Figure 4.2 General structures of THIQ alkaloid families ................................ 514 Figure 4.3 General structure of simple THIQ alkaloids.................................. 514 Figure 4.4 General structure of the Erythrina alkaloids .................................. 515 Figure 4.5 Proposed biosynthesis of the Erythrina alkaloids........................... 516 Figure 4.6 Synthetic approaches to Erythrina alkaloids.................................. 517 Figure 4.7 Early biosynthetic pathways to yield (S)-reticuline 247 ................. 524 Figure 4.8 Diverging biosynthetic pathways from (S)-reticuline 247 that access a wide variety of structural classes of THIQ alkaloids ..................... 525 Figure 4.9 General structure of the aporphine alkaloids ................................ 526 Figure 4.10 Proposed biosynthesis of aporphine alkaloid (S)-magnoflorine 249.................................................................... 526 Figure 4.11 General structure of bisbenzyl THIQ alkaloids ............................. 535 xl Figure 4.12 Proposed biosynthesis of bisbenzyl THIQ alkaloids 303 and 304 . 536 Figure 4.13 General structure of the protoberberine THIQ alkaloids ............... 542 Figure 4.14 Proposed biosynthesis of protoberberine alkaloids 345 and 351 .. 543 Figure 4.15 General structure of the morphinan THIQ alkaloids ..................... 554 Figure 4.16 Proposed biosynthesis of morphine 423 and related morphinan alkaloids ...................................................................................... 555 Figure 4.17 General structure of the pavine and isopavine THIQ alkaloids ..... 571 Figure 4.18 Core skeleton of THIQ alkaloids in the saframycin family ............ 576 Figure 4.19 General structure and representative examples of saframycin alkaloids ...................................................................................... 577 Figure 4.20 General structure of safracin alkaloids.......................................... 582 Figure 4.21 General structure and representative examples of renieramycin alkaloids ...................................................................................... 584 Figure 4.22 Ecteinascidin natural products...................................................... 603 Figure 4.23 Fukuyama’s synthetic strategy toward Et-743 184 ........................ 605 Figure 4.24 Core skeleton of THIQ alkaloids in the naphthyridinomycin family and examples ............................................................................... 614 Figure 4.25 General skeleton of THIQ alkaloids in the quinocarcin family ..... 617 CHAPTER 5 Progress Toward the Total Synthesis Of (+)-Cyanocycline A Figure 5.1 General skeleton of THIQ alkaloids in the naphthyridinomycin family and examples ............................................................................... 646 Figure 5.2 Structure of (+)-cyanocycline A (771) ........................................... 646 xli Figure 5.3 Initial retrosynthetic analysis of (+)-cyanocycline A (771) ............. 649 Figure 5.4 2nd generation retrosynthetic analysis of (+)-cyanocycline A (771) 662 Figure 5.5 3rd generation retrosynthetic analysis of (+)-cyanocycline A (771) 666 APPENDIX 6 Spectra Relevant to Chapter 5 Figure A6.1 1 H NMR (400 MHz, CDCl3) of compound 896 ............................. 722 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 896 ................ 723 Figure A6.3 13 Figure A6.4 1 C NMR (100 MHz, CDCl3) of compound 896 ............................ 723 H NMR (400 MHz, CDCl3) of compound 897 ............................. 724 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 897 ................ 725 Figure A6.6 13 Figure A6.7 1 C NMR (100 MHz, CDCl3) of compound 897 ............................ 725 H NMR (400 MHz, CDCl3) of compound 898 ............................. 726 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 898 ................ 727 Figure A6.9 13 C NMR (100 MHz, CDCl3) of compound 898 ............................ 727 Figure A6.10 1H NMR (400 MHz, CDCl3) of compound 899 ............................. 728 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 899 ................ 729 Figure A6.12 13C NMR (100 MHz, CDCl3) of compound 899 ............................ 729 Figure A6.13 1H NMR (400 MHz, CDCl3) of compound 900 ............................. 730 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 900 ................ 731 Figure A6.15 13C NMR (100 MHz, CDCl3) of compound 900 ............................ 731 Figure A6.16 1H NMR (400 MHz, CDCl3) of compound 901 ............................. 732 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 901 ................ 733 xlii Figure A6.18 13C NMR (100 MHz, CDCl3) of compound 901 ............................ 733 Figure A6.19 1H NMR (400 MHz, CDCl3) of compound 902 ............................. 734 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 902 ................ 735 Figure A6.21 13C NMR (100 MHz, CDCl3) of compound 902 ............................ 735 Figure A6.22 1H NMR (400 MHz, CDCl3) of compound 903 ............................. 736 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 903 ................ 737 Figure A6.24 13C NMR (100 MHz, CDCl3) of compound 903 ............................ 737 Figure A6.25 1H NMR (400 MHz, CDCl3) of compound 904 ............................. 738 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 904 ................ 739 Figure A6.27 13C NMR (100 MHz, CDCl3) of compound 904 ............................ 739 Figure A6.28 1H NMR (400 MHz, CDCl3) of compound 907 ............................. 740 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 907 ................ 741 Figure A6.30 13C NMR (100 MHz, CDCl3) of compound 907 ............................ 741 Figure A6.31 1H NMR (400 MHz, CDCl3) of compound 908 ............................. 742 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 908 ................ 743 Figure A6.33 13C NMR (100 MHz, CDCl3) of compound 908 ............................ 743 Figure A6.34 1H NMR (400 MHz, CDCl3) of compound 909 ............................. 744 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 909 ................ 745 Figure A6.36 13C NMR (100 MHz, CDCl3) of compound 909 ............................ 745 Figure A6.37 1H NMR (400 MHz, CDCl3) of compound 910 ............................. 746 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 910 ................ 747 Figure A6.39 13C NMR (100 MHz, CDCl3) of compound 910 ............................ 747 xliii Figure A6.40 1H NMR (400 MHz, CDCl3) of compound 911 ............................. 748 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 911 ................ 749 Figure A6.42 1H NMR (400 MHz, CDCl3) of compound 912 ............................. 750 Figure A6.43 Infrared spectrum (Thin Film, NaCl) of compound 912 ................ 751 Figure A6.44 13C NMR (100 MHz, CDCl3) of compound 912 ............................ 751 Figure A6.45 1H NMR (400 MHz, CDCl3) of compound 914 ............................. 752 Figure A6.46 Infrared spectrum (Thin Film, NaCl) of compound 914 ................ 753 Figure A6.47 13C NMR (100 MHz, CDCl3) of compound 914 ............................ 753 Figure A6.48 1H NMR (400 MHz, CDCl3) of compound 915 ............................. 754 Figure A6.49 Infrared spectrum (Thin Film, NaCl) of compound 915 ................ 755 Figure A6.50 13C NMR (100 MHz, CDCl3) of compound 915 ............................ 755 Figure A6.51 1H NMR (400 MHz, CDCl3) of compounds 916 + 917 ................. 756 Figure A6.52 1H NMR (400 MHz, CDCl3) of compound 924 ............................. 757 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound 924 ................ 758 Figure A6.54 13C NMR (100 MHz, CDCl3) of compound 924 ............................ 758 Figure A6.55 1H NMR (400 MHz, CDCl3) of compound 921 ............................. 759 Figure A6.56 Infrared spectrum (Thin Film, NaCl) of compound 921 ................ 760 Figure A6.57 13C NMR (100 MHz, CDCl3) of compound 921 ............................ 760 Figure A6.58 19F NMR (282 MHz, CDCl3) of compound 921 ............................. 761 Figure A6.59 1H NMR (400 MHz, CDCl3) of compound 927 ............................. 762 Figure A6.60 Infrared spectrum (Thin Film, NaCl) of compound 927 ................ 763 Figure A6.61 13C NMR (100 MHz, CDCl3) of compound 927 ............................ 763 xliv Figure A6.62 1H NMR (400 MHz, CDCl3) of compound 928 ............................. 764 Figure A6.63 Infrared spectrum (Thin Film, NaCl) of compound 928 ................ 765 Figure A6.64 13C NMR (100 MHz, CDCl3) of compound 928 ............................ 765 Figure A6.65 1H NMR (400 MHz, CDCl3) of compound 929 ............................. 766 Figure A6.66 Infrared spectrum (Thin Film, NaCl) of compound 929 ................ 767 Figure A6.67 13C NMR (100 MHz, CDCl3) of compound 929 ............................ 767 Figure A6.68 1H NMR (400 MHz, CDCl3) of compound 935 ............................. 768 Figure A6.69 Infrared spectrum (Thin Film, NaCl) of compound 935 ................ 769 Figure A6.70 13C NMR (100 MHz, CDCl3) of compound 935 ............................ 769 Figure A6.71 1H NMR (400 MHz, CDCl3) of compound 936 ............................. 770 Figure A6.72 Infrared spectrum (Thin Film, NaCl) of compound 936 ................ 771 Figure A6.73 13C NMR (100 MHz, CDCl3) of compound 936 ............................ 771 Figure A6.74 1H NMR (400 MHz, CDCl3) of compound 932 ............................. 772 Figure A6.75 Infrared spectrum (Thin Film, NaCl) of compound 932 ................ 773 Figure A6.76 13C NMR (100 MHz, CDCl3) of compound 932 ............................ 773 Figure A6.77 1H NMR (400 MHz, CDCl3) of compound 938 ............................. 774 Figure A6.78 Infrared spectrum (Thin Film, NaCl) of compound 938 ................ 775 Figure A6.79 13C NMR (100 MHz, CDCl3) of compound 938 ............................ 775 Figure A6.80 1H NMR (400 MHz, CDCl3) of compound 939 ............................. 776 Figure A6.81 Infrared spectrum (Thin Film, NaCl) of compound 939 ................ 777 Figure A6.82 13C NMR (100 MHz, CDCl3) of compound 939 ............................ 777 xlv LIST OF SCHEMES CHAPTER 1 Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes (2002–2020) Scheme 1.1 Examples for the asymmetric hydrogenation of heteroarenes............ 4 Scheme 1.2 Possible mechanistic pathways for the hydrogenation of 2methylquinoline 11 .......................................................................... 5 Scheme 1.3 Ru-catalyzed asymmetric hydrogenation of quinolines and applications of hydrogenated products ............................................. 9 Scheme 1.4 Ru-catalyzed asymmetric hydrogenation with PhTRAP ligand L1 ... 12 Scheme 1.5 Ru-catalyzed asymmetric hydrogenation of furans and benzofurans with NHC ligand L2 ....................................................................... 13 Scheme 1.6 First reported Ir-catalyzed asymmetric hydrogenation of quinolines .................................................................................. 14 Scheme 1.7 Ir-catalyzed asymmetric hydrogenation of isoquinolines and pyridines using TCCA as the activator ............................................ 18 Scheme 1.8 Ir-catalyzed asymmetric hydrogenation of quinolines, quinoxalines, and benzoxazines .......................................................................... 19 Scheme 1.9 Key Ir-catalyzed enantioselective hydrogenation step in the total synthesis of jorumycin.................................................................... 19 Scheme 1.10 Ir-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines.................................................................................. 20 Scheme 1.11 Ir-catalyzed asymmetric hydrogenation with P–OP ligand L8 ......... 21 xlvi Scheme 1.12 Ir-catalyzed asymmetric hydrogenation with SpinPHOX ligand L9 ...................................................................... 22 Scheme 1.13 Ir-catalyzed asymmetric hydrogenation of quinolines with Ir/TsDPEN catalyst 78...................................................................................... 23 Scheme 1.14 Rh-catalyzed asymmetric hydrogenation of N-heteroarenes using ZhaoPhos ligand L10 ..................................................................... 25 Scheme 1.15 Pd-catalyzed asymmetric hydrogenation of N-H indoles ................ 28 Scheme 1.16 Fe-catalyzed asymmetric hydrogenation of quinoxalines and benzoxazines with chiral phosphoric acid 105 .............................. 30 Scheme 1.17 In situ formation of chiral borane catalyst 115 from chiral dienes... 32 Scheme 1.18 Metal-free asymmetric hydrogenation of heteroarenes through in situ formation of a chiral borane catalyst from ligand 117 .................... 33 Scheme 1.19 Asymmetric hydrogenation of quinolines using spiro-bicyclic bisborane catalyst 122 ................................................................... 33 Scheme 1.20 First reported chiral phosphoric acid-catalyzed asymmetric hydrogenation of quinolines........................................................... 34 Scheme 1.21 Asymmetric transfer hydrogenation with SPINOL-derived phosphoric acid 135......................................................................................... 36 Scheme 1.22 Biomimetic asymmetric transfer hydrogenation of heteroarenes ..... 39 CHAPTER 2 Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines xlvii Scheme 2.1 Syntheses of 1-(hydroxymethyl)-3-aryl isoquinoline substrates ....... 56 Scheme 2.2 Substrate scope of different aryl substituents................................... 60 Scheme 2.3 Substrate scope of heteroaryl substituents....................................... 61 Scheme 2.4 Substrate scope of IQ backbone substituents .................................. 62 Scheme 2.5 Substrate scope of different directing groups .................................. 64 Scheme 2.6 Derivatization of hydrogenated product 163l ................................. 66 CHAPTER 3 Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines Scheme 3.1 Substrate scope of the trans-selective hydrogenation of 1,3disubstituted isoquinolines ........................................................... 391 Scheme 3.2 Substrate scope of heteroaryl and fluorinated isoquinolines ......... 392 Scheme 3.3 Synthetic derivatizations of product 175a..................................... 393 Scheme 3.4 Control experiments of the asymmetric trans-selective hydrogenation ....................................................... 394 Scheme 3.5 Deuterium experiments of substrate 173a .................................... 395 CHAPTER 4 Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002–2020) Scheme 4.1 Matsumoto’s total synthesis of O-methylerysodienone 199 .......... 517 Scheme 4.2 Matsumoto’s enantioselective synthesis of O-methylerysodienone 199 .............................................................................................. 518 Scheme 4.3 Padwa’s synthetic strategy toward the Erythrinan alkaloids........... 518 Scheme 4.4 Padwa’s total synthesis of erysotramidine 208 .............................. 519 Scheme 4.5 Padwa’s total synthesis of demethoxyerythratidinone 213 ............ 520 xlviii Scheme 4.6 Simpkin’s enantioselective synthesis of (+)-demethoxyerythratidinone 213 .............................................................................................. 520 Scheme 4.7 Reisman’s enantioselective synthesis of (–)-demethoxyerythratidinone 213 .............................................................................................. 521 Scheme 4.8 Ciufolini’s enantioselective synthesis of (+)-demethoxyerythratidinone 213 .............................................................................................. 522 Scheme 4.9 Ciufolini’s enantioselective synthesis of (+)-erysotramidine 208 ... 523 Scheme 4.10 Kaluza’s enantioselective synthesis of (–)-erysotramidine 208 ....... 524 Scheme 4.11 Cuny’s synthesis of aporphine 255 ............................................... 527 Scheme 4.12 Vicario’s synthesis of (+)-glaucine 260 ......................................... 528 Scheme 4.13 Fürstner’s synthesis of O-methyl-dehydroisopiline 264................. 529 Scheme 4.14 Raminelli’s synthesis of (–)-aporphine 255 ................................... 529 Scheme 4.15 Nimgirawath’s synthesis of telisatin A 272 ................................... 530 Scheme 4.16 Cuny’s synthesis of (–)-artabonatine A 276 ................................... 531 Scheme 4.17 A. Honda’s synthesis of stepharine 280 and pronuciferine 281 B. Magnus’ synthesis of stepharine 280 ........................................ 532 Scheme 4.18 Takao’s synthesis of (–)-misramine 290 ........................................ 533 Scheme 4.19 Fagnou’s synthesis of aporphine alkaloids .................................... 534 Scheme 4.20 Opatz’s synthesis of (+)-tetramethylmagnolamine 313 and (+)-O-methylthalibrine 312 .......................................................... 537 Scheme 4.21 Bracher’s synthesis of tetrandine 321 and isotetrandine 322......... 538 Scheme 4.22 Georghiou’s synthesis of (–)-tejedine 334 ..................................... 539 xlix Scheme 4.23 Nishiyama’s electrochemical synthesis of (+)-O-methylthalibrine 312 .......................................................... 540 Scheme 4.24 Lumb’s synthesis of tetramethylmagnolamine 313........................ 541 Scheme 4.25 Davis’ synthesis of (–)-xylopinine 356 .......................................... 544 Scheme 4.26 Ruano’s synthesis of (–)-xylopinine 356........................................ 544 Scheme 4.27 Cho’s synthesis of oxypalmatine 364............................................ 545 Scheme 4.28 Chrzanowska’s synthesis of A. oxoberberine 367 and B. (–)-oxoxylopinine 370 .............................................................. 546 Scheme 4.29 Ender’s synthesis of (–)-tetrahydropalmatine 346 .......................... 546 Scheme 4.30 Yang’s synthesis of (–)-stepholidine 379 ....................................... 547 Scheme 4.31 Harding’s synthesis of isocorypalmine 382................................... 547 Scheme 4.32 Georghiou’s synthesis of (–)-corytenchine 385 ............................. 548 Scheme 4.33 Hiemstra’s synthesis of (+)-javaberine A 392 and (+)-javaberine B 393.............................................................. 549 Scheme 4.34 van Maarseveen’s synthesis of (–)-govaniadine 397 ...................... 549 Scheme 4.35 Opatz’s synthesis of A. xylopinine 356 B. Pseudopalmatine 401 .. 550 Scheme 4.36 Donohoe’s synthesis of palmatine 405 ......................................... 551 Scheme 4.37 Mhaske’s synthesis of oxotetrahydropalmitine 408 ....................... 551 Scheme 4.38 Cheng’s synthesis of corysamine 411 ........................................... 551 Scheme 4.39 Glorius’ general synthesis of protoberberine alkaloids .................. 552 Scheme 4.40 Tong’s synthesis of thalictricavine 419 and dehydrothalictricavine 420.................................................... 553 l Scheme 4.41 Ward’s chemoenzymatic synthesis of tetrahydroprotoberberine alkaloid 422 ................................................................................. 553 Scheme 4.42 Fukuyama’s synthesis of (–)-morphine 423 ................................... 557 Scheme 4.43 Chida’s formal synthesis of (–)-morphine 423 ............................... 558 Scheme 4.44 Smith’s total synthesis of morphine 423 ....................................... 559 Scheme 4.45 Tu’s total synthesis of (–)-morphine 423 ....................................... 560 Scheme 4.46 Fukuyama’s total synthesis of (–)-oxycodone 474 ......................... 561 Scheme 4.47 Chen’s total synthesis of (+)-oxycodone 474 ................................ 562 Scheme 4.48 Chen’s total synthesis of (+)-dihydrocodeinone 489 ..................... 563 Scheme 4.49 Opatz’s total synthesis of (–)-dihydrocodeine 497 ........................ 564 Scheme 4.50 A. Opatz’s electrochemical oxidative coupling. B. Application toward the total synthesis of (–)-thebaine 428............................... 565 Scheme 4.51 Hudlicky’s total synthesis of (+)-oxycodone 474 .......................... 566 Scheme 4.52 Zhang’s total synthesis of codeine 430 ......................................... 568 Scheme 4.53 Ellman’s total synthesis of (–)-naltrexone 424 ............................... 569 Scheme 4.54 Metz’s total synthesis of thebainone A 536................................... 570 Scheme 4.55 Marazano’s enantioselective synthesis of (–)-argemonine 542 ...... 572 Scheme 4.56 Nishigaichi’s synthesis of argemonine 542 and eschscholtzidine 550............................................................. 572 Scheme 4.57 Jiang’s enantioselective synthesis of (–)-amurensinine 556 ........... 573 Scheme 4.58 Stoltz’s enantioselective synthesis of (+)-amurensinine 556 .......... 574 Scheme 4.59 Martin’s synthesis of roelactamine 568......................................... 575 li Scheme 4.60 Nakagawa-Goto’s synthesis of neocaryachine 574 ....................... 575 Scheme 4.61 A. Domain organization of saframycin A NRPS. B. Proposed biosynthetic mechanism for the construction of saframycin A’s pentacyclic skeleton..................................................................... 578 Scheme 4.62 Liu’s total synthesis of (–)-saframycin A 575 ................................. 579 Scheme 4.63 Saito’s total synthesis of saframycin A 575 ................................... 581 Scheme 4.64 A. Domain organization of renieramycins NRPS. B. Proposed biosynthetic mechanism for the construction of renieramycin E’s pentacyclic skeleton..................................................................... 585 Scheme 4.65 Danishefsky’s total synthesis of (–)-cribrostatin 4 602 ................... 587 Scheme 4.66 William’s total synthesis of (–)-cribrostatin 4 602 ......................... 588 Scheme 4.67 Zhu’s strategy to prepare the pentacyclic skeleton of (–)-cribrostatin 4 602 .............................................................................................. 590 Scheme 4.68 William’s total synthesis of (–)-renieramycin G 597 and (–)-jorumycin 613 .............................................................................................. 591 Scheme 4.69 William’s unexpected C3-epimerization toward the synthesis of 3epi-renieramycin G, and 3-epi-jorumycin .................................... 592 Scheme 4.70 Magnus’ total synthesis of renieramycin G 597 ............................ 593 Scheme 4.71 Zhu’s total synthesis of (–)-renieramycins G 597, M 599, (–)jorunnamycin A 608, and (–)-jorumycin 613................................ 595 Scheme 4.72 Saito’s total synthesis of renieramycin G 597 ............................... 596 lii Scheme 4.73 Yang’s strategy to assemble the pentacyclic core of renieramycin alkaloids ...................................................................................... 597 Scheme 4.74 Yokoya’s and Williams’ total synthesis of (–)-renieramycin T 606. 599 Scheme 4.75 Chen’s total synthesis of (–)-renieramycin T 606........................... 600 Scheme 4.76 Stoltz’s total synthesis of (–)-jorunnamycin A 608 and (–)-jorumycin 613 .............................................................................................. 601 Scheme 4.77 A. Domain organization of Et-743 NRPS. B. Proposed biosynthetic mechanism for the construction of Et-743’s pentacyclic skeleton . 604 Scheme 4.78 Fukuyama’s total synthesis of Et-743 184 ..................................... 606 Scheme 4.79 Fukuyama’s revised total synthesis of Et-743 184 ......................... 608 Scheme 4.80 Danishefsky’s formal total synthesis of Et-743 184 ....................... 609 Scheme 4.81 Zhu’s total synthesis of ecteinascidin 770 699 and ecteinascidin 743 184 .............................................................................................. 610 Scheme 4.82 Zhu’s total synthesis of ecteinascidin 597 705 and ecteinascidin 583 704 .............................................................................................. 611 Scheme 4.83 Ma’s total synthesis of ecteinascidin 743 184 and lurbinectedin 769 .................................................................. 613 Scheme 4.84 Garner’s formal synthesis of cyanocycline A 771 and bioxalomycin b2 788 ......................................................................................... 616 Scheme 4.85 Proposed biosynthetic mechanism for the construction of the quinocarcin core .......................................................................... 618 Scheme 4.86 Myers’ total synthesis of (–)-quinocarcin 789................................ 619 liii Scheme 4.87 Zhu’s total synthesis of (–)-quinocarcin 789 ................................. 620 Scheme 4.88 Stoltz’s total synthesis of (–)-quinocarcin 789 ............................... 622 Scheme 4.89 Ohno’s total synthesis of (–)-quinocarcin 789............................... 623 Scheme 4.90 Williams’ total synthesis of (–)-tetrazomine 791 ........................... 624 Scheme 4.91 Williams’ synthesis of tetrazomine analogues............................... 625 Scheme 4.92 Stoltz’s total synthesis of (–)-lemonomycin 792 ............................ 627 Scheme 4.93 Fukuyama and Kan’s total synthesis of (–)-lemonomycin 792 ....... 619 CHAPTER 5 Progress Toward the Total Synthesis Of (+)-Cyanocycline A Scheme 5.1 Synthesis of the western isoquinoline fragment 887 ..................... 650 Scheme 5.2 Synthesis of the eastern pyrrole fragment 898............................... 651 Scheme 5.3 One-pot Pd-catalyzed borylation/Suzuki cross-coupling reaction of heterocycles 887 and 898 ............................................................ 651 Scheme 5.4 2nd generation synthesis of pyrrole fragment 902 .......................... 652 Scheme 5.5 Stille cross-coupling of heterocycles 887 and 902 ........................ 653 Scheme 5.6 Key asymmetric hydrogenation of pyrrole-substituted isoquinoline 904 .............................................................................................. 654 Scheme 5.7 3rd generation synthesis of pyrrole fragment 908........................... 654 Scheme 5.8 Stille cross-coupling and synthesis of hydrogenation precursor 910 ....................................................... 655 Scheme 5.9 Key asymmetric hydrogenation attempts of isoquinoline 910 ....... 656 Scheme 5.10 Heterogeneous hydrogenation investigation of isoquinoline 910.. 658 liv Scheme 5.11 Investigation of solvent in heterogeneous hydrogenation of isoquinoline 910 .......................................................................... 659 Scheme 5.12 Investigation of solvent in heterogeneous hydrogenation of isoquinoline 910 at ambient temperature ..................................... 660 Scheme 5.13 Competitive cyclization of secondary amine on to esters at C3- and C5-positions of the pyrrolidine ring .............................................. 661 Scheme 5.14 Synthesis of dihydropyrrole coupling partner 921 ........................ 662 Scheme 5.15 Conversion of isoquinoline triflate 887 to a nucleophilic coupling partner ......................................................................................... 663 Scheme 5.16 Cross-coupling of heterocycles 921 and 927 and synthesis of hydrogenation precursor .............................................................. 664 Scheme 5.17 Synthesis of oxazoline dihydropyrrole coupling partner 932 ........ 666 Scheme 5.18 Initial Pd-catalyzed CMD cross-coupling reaction of triflate 887 and dihydropyrrole 932 ...................................................................... 667 Scheme 5.19 Optimization of Pd-catalyzed CMD cross-coupling reaction of triflate 887 and dihydropyrrole 938 ........................................................ 668 Scheme 5.20 Proposed completion of (+)-cyanocycline A (771) ........................ 670 APPENDIX 5 Synthetic Summary of Chapter 5 Scheme A5.1 Synthesis of the western isoquinoline fragment 887 ..................... 716 Scheme A5.2 Synthesis of the eastern pyrrole fragment 898............................... 716 Scheme A5.3 2nd generation synthesis of pyrrole fragment 902 .......................... 716 lv Scheme A5.4 Cross-coupling of heterocycles 887 and 902, and synthesis of hydrogenation precursor 904 ....................................................... 717 Scheme A5.5 3rd generation synthesis of pyrrole fragment 908 ........................... 717 Scheme A5.6 Stille cross-coupling and synthesis of hydrogenation precursor 910 ....................................................... 717 Scheme A5.7 Hydrogenation attempts of isoquinoline 910 ................................ 718 Scheme A5.8 Synthesis of dihydropyrrole coupling partner 921 ........................ 718 Scheme A5.9 Stannylation of isoquinoline triflate 887 and synthesis of dihydropyrrole hydrogenation precursor 929 ............................... 719 Scheme A5.10 Synthesis of oxazoline dihydropyrrole coupling partner 932 ...... 719 Scheme A5.11 Reduction of oxazoline 932 and Pd-catalyzed CMD cross-coupling of heterocycles 887 and 938 ...................................................... 720 lvi LIST OF TABLES CHAPTER 2 Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines Table 2.1 Optimization of the enantioselective hydrogenation of isoquinolines to afford cis-THIQs ......................................................................... 57 Table 2.2 Additional ligand screen .............................................................. 144 Table 2.3 Additive effects in Ir-catalyzed enantio- and diastereoselective hydrogenation .............................................................................. 145 Table 2.4 Determination of enantiomeric excess ......................................... 145 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 2 Table A2.1 Crystal data and structure refinement for product 163p ................ 377 Table A2.2 Atomic coordinates (x 105) and equivalent isotropic displacement parameters (Å2 x 104) and population for 163p. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor .................. 378 Table A2.3 Bond lengths [Å] and angles [°] for 163p...................................... 377 Table A2.4 Anisotropic displacement parameters (Å2 x 104) for 163p. The anisotropic displacement factor exponent takes the form: -2p2[h2a*2U11 + … + 2hka*b*U12] ................................................. 382 Table A2.5 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 103) for 163p ....................................................................... 382 Table A2.6 Torsion angles [°] for 163p ........................................................... 383 Table A2.7 Hydrogen bonds for 163p [Å and °] ............................................. 384 lvii CHAPTER 3 Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines Table 3.1 Optimization of the asymmetric trans-selective hydrogenation..... 388 Table 3.2 Investigation of different directing groups to optimize the asymmetric trans-selective hydrogenation ....................................................... 389 Table 3.3 Additional additive, acid, and pressure studies ............................. 438 Table 3.4 Additional ligand screen .............................................................. 438 Table 3.5 Determination of enantiomeric excess ......................................... 441 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1 Crystal data and structure refinement for product 175a ................ 503 Table A4.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2 x 103) and population for 175a. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor .................. 504 Table A4.3 Bond lengths [Å] and angles [°] for 175a ...................................... 505 Table A4.4 Anisotropic displacement parameters (Å2 x 103) for 175a. The anisotropic displacement factor exponent takes the form: -2p2[h2a*2U11 + … + 2hka*b*U12] ................................................. 508 Table A4.5 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 103) for 175a ........................................................................ 509 Table A4.6 Torsion angles [°] for 175a ........................................................... 509 lviii LIST OF ABBREVIATIONS [a]D specific rotation at wavelength of sodium D line °C degrees Celsius Å Ångstrom Ac acetyl AcOH acetic acid APCI atmospheric pressure chemical ionization app apparent aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c concentration for specific rotation measurements (g/100 mL) ca. about (Latin circa) calc’d calculated cat catalytic CDI 1,1'-carbonyldiimidazole cm–1 wavenumber(s) cod 1,5-cyclooctadiene lix CPME cyclopentyl methyl ether DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL diisobutylaluminum hydride DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMP Dess–Martin periodinane DMS dimethyl sulfide DMSO dimethyl sulfoxide dr diastereomeric ratio e.g. for example (Latin exempli gratia) ee enantiomeric excess EI+ electron impact equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate EWG electron withdrawing group lx FAB fast atom bombardment g gram(s) GC gas chromatography gCOSY gradient-selected correlation spectroscopy h hour(s) HFIP hexafluoroisopropanol HMBC heteronuclear multiple bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy HSQC heteronuclear single quantum correlation Hz hertz hn light i-Pr isopropyl i.e. that is (Latin id est) IPA isopropanol, 2-propanol IQ isoquinoline IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie KHMDS potassium hexamethyldisilazide L liter; ligand lxi LAH Lithium aluminium hydride L* chiral ligand LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide LG leaving group lit. literature value m multiplet; milli m meta M metal; molar; molecular ion m-CPBA meta-chloroperoxybenzoic acid m/z mass to charge ratio Me methyl mg milligram(s) MHz megahertz min minute(s) MM mixed method mol mole(s) mp melting point MS molecular sieves n nano N normal n-Bu butyl NBS N-bromosuccinimide lxii NHSI N-hydroxysuccinimide NMR nuclear magnetic resonance Nu nucleophile o ortho p para Pd/C palladium on carbon Ph phenyl pH hydrogen ion concentration in aqueous solution Phth phthalimide PHOX phosphinooxazoline ligand PIDA Phenyliodine(III) diacetate Pin 2,3-dimethylbutane-2,3-diol (pinacol) Piv trimethylacetyl, pivaloyl pKa pK for association of an acid pMBz 4-methoxy-benzoyl ppm parts per million Pr propyl Py pyridine q quartet R generic for any atom or functional group RCM ring-closing metathesis Ref. reference Rf retention factor lxiii rr rotameric ratio s singlet or strong or selectivity factor sat. saturated SFC supercritical fluid chromatography STAB Sodium triacetoxyborohydride t triplet t-Bu tert-butyl TBABr tetrabutylammonium bromide TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBME/MTBE tert-butyl methyl ether TBS tert-butyldimethylsilyl TES triethylsilyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran THIQ tetrahydroisoquinoline TIPS triisopropylsilyl TLC thin-layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl lxiv TOF time-of-flight Tol tolyl tR retention time Ts p-toluenesulfonyl (tosyl) UV ultraviolet v/v volume to volume w weak w/v weight to volume X anionic ligand or halide l wavelength μ micro Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes 1 CHAPTER 1 Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes (2000 – 2020)† 1.1 INTRODUCTION Heterocycles are important structural motifs found frequently in natural products1 and industrial products, such as pharmaceuticals 2 and agrochemicals. 3 Nitrogen heterocycles constitute approximately 59% of recent FDA-approved small-molecule drugs, with an average of two to three nitrogen atoms per drug.2a In the context of pharmaceutical development, a significant positive correlation exists between key structural elements of drug candidates, such as degree of saturation and number of stereogenic centers, with observed clinical success.2c,d Thus, the ability to access stereochemically complex heterocyclic scaffolds has been of great interest in recent years. Considering the ubiquity of both aromatic and saturated heterocycles in pharmaceuticals, the direct access to enantiopure heterocycles via heteroarene hydrogenation continues to be an important research area in both academia and industry.2 ________________________________________________ † Portions of this chapter have been reproduced with permission from Kim, A. N.; Stoltz, B. M. ACS Catal. 2020, 10, 13834–13851. © 2020 American Chemical Society. 2 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes While significant progress has been made in the area of asymmetric heteroarene hydrogenation, these transformations continue to pose a challenge for catalytic processes, ostensibly due to the high energetic cost of breaking aromaticity, and the presence of heteroatoms that may poison and deactivate the catalyst.4 Nevertheless, the asymmetric hydrogenation of heteroarenes, including quinolines, isoquinolines, quinoxalines, pyridines, indoles, furans, and benzoxazines has been extensively explored, and several comprehensive reviews have been published on this subject (Figure 1.1).4 The hydrogenation of many common heteroarenes can be achieved using a variety of catalyst systems, including homogeneous and heterogeneous catalysts, such as metal nanoparticles.4d Among these, homogeneous catalyst systems have found widespread application for the asymmetric hydrogenation of heteroarenes, often providing access to different enantioenriched motifs with a simple adjustment of the chiral ligand.4, 5 This Perspective is focused on highlighting homogeneous catalyst systems that have recently been developed for the asymmetric hydrogenation of heteroarenes, evaluating the general relationships between different catalyst complexes and their reactivity for various heterocycles. The following sections will feature reports that have been published since 2011, as previous reports have already been discussed comprehensively in prior review articles.4 1.2 GENERAL MECHANISTIC CONSIDERATIONS Heteroarenes pose a significant challenge for asymmetric catalysis due to their inherent thermodynamic stability and the tendency of both reactants and products to 3 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes deactivate catalysts. Three general strategies have been employed to overcome these difficulties: catalyst activation, substrate activation, and relay catalysis.4a Figure 1.1 Overview of the total number of published reports on the asymmetric hydrogenation of common heteroarenes (≥90% ee, minimum of three substrates). N N N N R N N R N R N N O O O N O S N N 44 14 X 2 X 5 28 7 5 5 3 3 1 X 1 X X X X B 3 OC 13 Ru 1 1 1 1 2 1 3 4 77 Ir X X 1 2 45 Rh 4 2 X X X 8 1 X X 1 X X X X X X 2 X X X X X X 3 1 2 X 46 Pd 26 Fe 1 5 5 1 R = H, Me, Boc, Ts, Ac OC = organic catalyst Catalyst activation involves either the preformation of the active catalyst or the addition of reagents to form a more active catalyst species in situ. For instance, the addition of halide sources to an iridium precatalyst was reported by Mashima and coworkers to prevent the irreversible formation of catalytically inactive dimeric iridium hydride species 3 (Scheme 1.1A). 6 The substrate activation approach introduces reagents to overcome the inherent aromatic stability of heteroarenes through in situ generation or pre-formation of activated substrates, such as quinolinium or pyridinium salts (e.g., 6, Scheme 1.1B).7 Finally, relay catalysis involves the use of two or more catalysts for the asymmetric hydrogenation of heteroarenes. For example, an achiral transition metal catalyst is often employed to induce initial partial hydrogenation of the substrate 8, followed by an enantioselective hydrogenation of an intermediate such as imine 9 aided by a chiral Brønsted acid catalyst 4 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes (Scheme 1.1C).8 Overall, these distinct strategies enable high stereoselectivity and functional group tolerance in the asymmetric hydrogenation of heteroarenes. Scheme 1.1. Examples for the asymmetric hydrogenation of heteroarenes. A. Catalyst Activation with Halides Cl H P Cl P * Ir Cl H2 S P 1 H P P = chiral bisphosphine ligand * BnBr 5 N R H2 general P Cl Ir H P P Cl * 4 N Bn of R H N chiral catalyst R 9 mechanism Cl 7 N 8 The Ir R Br H N achiral catalyst N Cl * 3 6 C. Relay Catalysis P [H] N Bn R H P catalytically active B. Substrate Activation with Reagents N Cl Ir Cl Cl * P P H catalytically inactive * P Ir H 2 S P * H Ir H2 N H R 10 the asymmetric hydrogenation of heteroarenes can be thought of to involve the following steps (depending on the degree of unsaturation): formation of the active catalyst species, hydride addition from the catalyst to the substrate, and regeneration of the catalyst from a hydrogen source.9 However, several questions regarding the mechanism of asymmetric hydrogenation that could be addressed include the order of hydride addition (1,2- vs. 1,4-addition), substrate coordination to the catalyst (inner- vs. outer-sphere), the rate-determining step, and the enantiodetermining step.4a–d,9c For instance, both inner-sphere and outer-sphere processes have been 5 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes proposed to explain the mechanism for the iridium-catalyzed hydrogenation of 2methylquinoline 11 (Scheme 1.2).9b In an outer-sphere pathway, protonation of the substrate occurs to form iminium intermediate 12, followed by external hydride delivery to the activated substrate from the transition metal center. In contrast, an inner-sphere process involves a substrate that is bound to the metal hydride species (13) that undergoes a hydride transfer step. While other catalyst systems have been proposed to undergo an outersphere mechanism for the hydrogenation of various heterocycles (vide infra), other studies also support an inner-sphere coordination of the substrate to the catalyst.10 Thus, the coordinating ability of different heteroatom-containing substrates to the catalyst complex is not explicitly defined, and therefore difficult to predict how it would behave under different hydrogenation systems. Scheme 1.2. Possible mechanistic pathways for the hydrogenation of 2-methylquinoline 11. “outer-sphere” [H] N H Me 12 N Me N H 11 Me 14 “inner-sphere” N Me [H] H MLn 13 Although the asymmetric hydrogenation of heteroarenes is often difficult to monitor due to the use of high-pressure reactors, several mechanistic studies have been conducted using empirical data and computational modeling to elucidate the mechanisms of transition metal-catalyzed and organic-catalyzed heteroarene hydrogenation reactions. 6 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes The proposed catalytic cycles of these studies will be addressed in the following sections of this Perspective for each transition metal and organic catalyst system. 1.3 RUTHENIUM-CATALYZED ASYMMETRIC HYDROGENATION With regards to homogeneous catalysis, ruthenium was among the first transition metals explored in asymmetric hydrogenation reactions. In 1995, Noyori and coworkers introduced a Ru(II) catalyst with a chiral diamine ligand that promotes the highly stereoselective reduction of aromatic ketones through an asymmetric transfer hydrogenation process.11 Shortly after, this catalyst system was applied to the asymmetric hydrogenation of imines with a formic acid–triethylamine mixture as the hydrogen source. 12 Since then, several established ruthenium catalyst systems with common ligand scaffolds were developed for the asymmetric hydrogenation of heteroarenes (Figure 1.2), as well as the hydrogenation of carbocyclic aromatic compounds.13 The air-stable Ru/TsDPEN catalyst (TsDPEN = N-(p-toluenesulfonyl)-1,2diphenylethylenediamine), initially developed by Fan and Chan for the hydrogenation of quinolines, has found widespread applications in the asymmetric hydrogenation of Nheterocycles (Figure 1.2).14–19 In these reports, hydrogen gas is activated by the catalyst to reduce quinolines at ambient temperatures in ionic liquids and even under solvent-free conditions. Subsequent studies also utilize this system for sequential reductive amination and asymmetric hydrogenation cascade reactions of quinoline derivatives to access structurally diverse scaffolds.15 Since 2011, the Ru/TsDPEN catalyst 7 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes system has evolved with important applications toward the development of novel chiral ligands. Fan and coworkers demonstrated that chiral Ru/TsDPEN catalysts can reduce 2,2’bisquinoline and bisquinoxaline derivatives with high stereoselectivity.16 Figure 1.2. Common Ru-based catalyst systems for the asymmetric hydrogenation of heteroarenes (≥90% ee, minimum three substrates). Only one enantiomer of ligand shown for simplicity. Heteroarenes Enantioenriched Heterocycles Ru Hydrogen Source: H2 Catalyst System Heteroarenes References 14–17 Ru/DPEN N R3 N 1 X Ru N R R2 N H Ph 14c N Ph 15d N R1 = Ts, Ms R2 = H, Me R3 = p-cymene, hexamethylbenzene X = OTf, PF6, BF4, OPOPh2 15c, 18 N H O 19 N 23a N Boc Ru/PhTRAP, base Me Ph2P 23b N Boc N Fe Fe Boc N 23c PPh2 Me (S,S)-(R,R)-PhTRAP (L1) Boc N N O N 23d Ru/NHC, KOt-Bu O 25a N Me N BF4 Me NHC•BF4 (L2) 25b–c O 8 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes More recently, the system was applied to hydrogenate 2-(pyridine-2-yl)quinoline derivatives for the synthesis of novel N,P-ligands (Scheme 1.3).17 Using chiral catalyst complex 16 (Scheme 1.3A), selective hydrogenation of the quinoline ring was observed in a range of substrates 15 with high enantioselectivities. Although ortho-substituents on the pyridine ring are necessary to prevent catalyst deactivation, this requirement further enables the tuning of the steric effect of the chiral ligand generated. The hydrogenated products 17a–d can then be transformed into a novel class of chiral N,P-ligands by treatment with PPh2Cl in NEt3. After recrystallization, these ligands are then treated with [Ir(COD)Cl]2, followed by anion metathesis to yield chiral iridium complexes 19a–d.17 These catalysts are then successfully used for the asymmetric hydrogenation of olefins and seven-membered cyclic imines (Scheme 1.3B). Notably, replacement of the phenyl substituent on the pyridine ring of 19d with an alkyl group (19a–c) improves the enantioselectivity of the hydrogenation of trisubstituted olefin 20 to 21 in 88–92% ee. Catalyst 19b is further utilized in the asymmetric hydrogenation of benzazepines and benzodiazepines, providing products 23 in up to 99% ee and 20:1 dr. The efficient synthesis of a novel class of chiral ligands through the asymmetric hydrogenation of heteroarenes is a promising application of this hydrogenation technology. The Ru/TsDPEN catalyst system is also effective for the asymmetric hydrogenation of unprotected indoles, which traditionally require protection of the indole nitrogen to prevent catalyst deactivation,18 C(3)-substituted benzoxazines,19 and a variety of polycyclic heteroarenes.20 9 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Based on experimental results and theoretical calculations, Fan and coworkers propose a catalytic cycle for the asymmetric hydrogenation of quinolines with Ru/TsDPEN catalysts (Figure 1.3). The Ru(II) catalyst activates molecular H2 to form dihydrogen complex 24. After heterolytic cleavage of H2 to generate complex 27 and the activated substrate 26, subsequent 1,4-hydride addition affords an enamine intermediate 29.4e,15a Scheme 1.3. Ru-catalyzed asymmetric hydrogenation of quinolines and applications of hydrogenated products. 10 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes A. R2 N N (R,R)-16 (2 mol %) 50 atm H2 R1 R2 15 R1 = alkyl, aryl, Br R2 = OMe, CF3, Ph, alkyl TfO R1 17 13 examples >99% conversion 77–98% ee Ru N Ts N Me H Ph N N H i-PrOH (0.1 M), 25 °C, 12 h Ph (R,R)-16 1) Et3N (3 equiv), 0 °C, CH2Cl2 R1 N N H N N 2) PPh2Cl (1 equiv), 0 °C, 12 h R1 PPh2 18a–d 50–65% yield 99% ee 17a–d 1) [Ir(cod)Cl]2 (0.5 equiv) N 2) NaBArF (1.5 equiv), CH2Cl2 Ph2P R1 = Me, 19a R1 = i-Pr, 19b R1 = Cy, 19c R1 = Ph, 19d N Ir R1 19a–d 50–65% yield 99% ee B. Me Me 19a–d (1 mol %) 50 atm H2 R R CH2Cl2 (0.1 M), 25 °C, 12 h 20 21 2 examples >99% conversion 88–92% ee R = CO2Et, Ph X R2 N 22 X = CH, N R1 = aryl, alkyl R2 = H, OMe, Cl R1 19b (1 mol %) 50 atm H2 CH2Cl2 (0.1 M), 25 °C, 12 h R1 R2 X N H R1 R1 23 16 examples >99% conversion 86–99% ee 5:1 to >20:1 dr Tautomerization then occurs to form imine 30, which is protonated by complex 24 to produce iminium 31. Intermediate 31 undergoes an asymmetric 1,2-hydride transfer from complex 27 to deliver product 32 via TS1. The enantioselectivity is proposed to originate from the attractive CH/π interaction between the η6-arene ligand and the 11 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes carbocyclic ring of the dihydroquinoline via a 10- membered transition state with participation of the triflate anion, as shown in TS1.15a,21 Although Ru/TsDPEN systems are efficient catalysts for the hydrogenation of bicyclic aromatic compounds, preformation of the active catalyst is required. Alternatively, other common chiral bisphosphine ligands that are explored in ruthenium-catalyzed asymmetric hydrogenations include PhTRAP (2,2”-bis[1-(diphenylphosphino)-ethyl]1,1”-biferrocene), a C2 symmetric biferrocene framework. 22 Kuwano and coworkers demonstrate that ruthenium catalysts bearing PhTRAP ligand (L1) are productive in the hydrogenation of N-Boc-protected indoles (Scheme 1.4A), as well as substituted N-Bocprotected pyrroles and imidazoles (Scheme 1.4B, C). 23 Considering the high aromatic stability of single-ring aromatic compounds, the exhaustive hydrogenation of trisubstituted pyrroles to yield chiral pyrrolidines under this catalyst manifold is a significant advancement.4a,23c The Ru/PhTRAP catalyst can also be applied to the hydrogenation of other 5-membered heterocycles such as disubstituted imidazoles and oxazoles, however, only partial hydrogenation is observed in these cases.23d Figure 1.3. Proposed catalytic cycle for the asymmetric hydrogenation of quinolines with a Ru/TsDPEN catalyst. 12 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Ru H TsN NH2 Ph H2 N R 25 H Ph N H 24 R 26 First Reduction Ru TsN Ru S TsN Ph NH2 Ph H NH2 Ph 27 Ph 28 1,4-hydride addition ‡ H Ru TsN Ph H N H R 26 N N H N H H R H O O S Ph F3C O R 29 tautomerization TS1 H2 N Ru H TsN NH2 Ph R 30 H N H Ph 24 Ru TsN Ph Second Reduction Ru TsN S H NH2 Ph NH2 R 31 Ph Ph 27 28 1,2-hydride addition 32 N H N H R R 31 S = solvent molecule Finally, ruthenium N-heterocyclic carbene (NHC) complexes have found many applications in the transfer hydrogenation of ketones, nitriles, as well as the regioselective hydrogenation of heterocycles.24 Scheme 1.4. Ru-catalyzed asymmetric hydrogenation with PhTRAP ligand L1. 13 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes A. R2 [RuCl2(p-cymene)]2 (1 mol %) L1 (1.1 mol %) Cs2CO3 (10 mol %) R1 N Boc R2 R1 N Boc H2 (50 atm) i-PrOH or MeOH, 60 °C 33 34 8 examples 91–99% yield 87–95% ee R1 = alkyl, aryl R2 = H, OMe, F B. R2 R1 R3 N Boc [Ru(η3-methallyl)2(cod)] (2.5 mol %) L1 (2.8 mol %) NEt3 (25 mol %) H2 (50 atm) EtOAc, 80 °C, 24 h 35 R1, R2, R3 = alkyl, aryl C. R1 N Ph N Boc R2 R3 H2 (50 atm) EtOAc, 60–80 °C, 24 h R1 = Me, Et, CF3, n-hexyl R1 N Ph O 40 R1 = alkyl, aryl [Ru(η3-methallyl)2(cod)] (2.5 mol %) L1 (2.8 mol %) TMG (25 mol %) H2 (50 atm) t-BuOH, 80 °C, 4 h Ph2P Fe Me Me N Boc R1 R1 + R3 36 3 examples 85–96% yield 74–96% ee [Ru(η3-methallyl)2(cod)] (2.5 mol %) (R,R)-(S,S)-L1 (2.8 mol %) NEt3 (25 mol %) 38 R2 R1 N Boc 37 6 examples 70–99% yield 95–99.7% ee N Ph N Boc 39 7 examples 35–99% yield 86–99% ee R1 N Ph O 41 11 examples 13–99% yield 50–98% ee Fe PPh2 (S,S)-(R,R)-PhTRAP (L1) Glorius and coworkers first demonstrated the regioselective hydrogenation of the aromatic carbocyclic ring of quinoxalines, albeit with moderate enantioselectivity. They observed that the identity of NHC ligand was critical in determining the regioselectivity of hydrogenation, and found that these catalytic systems can also be applied toward the asymmetric hydrogenation of furans and benzofurans. 25 Using chiral NHC ligand SINpEt•HBF4 (L2), the asymmetric hydrogenation of disubstituted furans and 2substituted benzofurans proceeded in high yields and enantioselectivities (Scheme 1.5). A wide range of substituted furans were hydrogenated with this catalyst system, 14 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes demonstrating a significant correlation between strongly electron-withdrawing groups on the substrate and diminished enantioselectivity.25a Overall, the Ru/NHC complex demonstrated its capability to hydrogenate a range of heteroarenes, particularly oxygencontaining heterocycles, allowing direct access to natural metabolites such as (+)-corsifuran A (Scheme 1.5A). Further studies of the Ru/L2 catalyst system by Glorius and coworkers revealed that hydrogenation of the naphthyl substituents of the NHC ligand was a key step in accessing the active catalyst.26 Scheme 1.5. Ru-catalyzed asymmetric hydrogenation of furans and benzofurans with NHC ligand L2. A. R1 O [Ru(2-methylallyl)2(cod)] (5 mol %) L2 (10 mol %) KOt-Bu (15 mol %) H2 (10 atm) n-hexane, 25–70 °C, 12–16 h 42 R1 = alkyl, aryl MeO R1 O 43 17 examples 38–99% yield 58–98% ee MeO OMe OMe O O 44 45 (+)-corsifuran A B. R2 O R1 [Ru(2-methylallyl)2(cod)] (5 mol %) L2 (11 mol %) KOt-Bu (15 mol %) 46 H2 (128 atm) n-hexane, 25 °C, 24 h R1 = OMe, F, Me, NMe2, CF3 R2 = Me, n-Bu N Me R2 O R1 47 13 examples 59–91% yield 38–90% ee 3.9:1 to 14.5:1 dr N BF4 Me NHC SINpEt•HBF4 (L2) 1.4 IRIDIUM-CATALYZED ASYMMETRIC HYDROGENATION 15 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Following the initial disclosure of the enantioselective hydrogenation of quinolines using [Ir(cod)Cl]2 and bisphosphine ligand MeO-BIPHEP (L3) in 2003 (Scheme 1.6),27 much attention has been devoted toward the development of the iridium-catalyzed hydrogenation of heteroarenes. Most studies have focused on the exploration of different types of activating agents to reduce substrate aromaticity, as well as to prevent the irreversible formation of catalytically inactive dimeric iridium hydride species 3.6,27 Common ligand scaffolds utilized in this transformation include atropisomeric biaryl bisphosphine ligands, as well as phosphine-phosphite ligands, N,P-ligands, and chiral diamine ligands that have been explored for the asymmetric hydrogenation of a range of heterocycles (Figure 1.4). Scheme 1.6. First reported Ir-catalyzed asymmetric hydrogenation of quinolines. [Ir(cod)Cl]2 (0.5 mol %) (R)-MeO-BIPHEP L3 (1.1 mol %) R2 N R1 I2 (10 mol %), H2 (48 atm) PhMe, 25 °C 48 R1 = alkyl, aryl R2 = H, F, Me, OMe MeO PPh2 MeO PPh2 R2 N H R1 49 19 examples 83–95% yield 72–96% ee (R)-MeO-BIPHEP (L3) The biaryl bisphosphine ligand scaffold is most common in iridium-catalyzed asymmetric hydrogenation due to its excellent steric and electronic tunability. Structural variations of the ligand include alteration of P-substitution and modifications of the phenyl backbone, including the synthesis of supramolecular chiral ligands appended with crown ethers that induce strong complexation between the ligand and alkali cations.28 16 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Figure 1.4. Common Ir-based catalyst systems for the asymmetric hydrogenation of heteroarenes (≥90% ee, minimum three substrates). Only one enantiomer of ligand shown for simplicity. Heteroarenes Enantioenriched Heterocycles Ir Hydrogen Source: H2 Catalyst System Heteroarenes Ir/P–P* biaryl bisphosphine ligands: R2 References Catalyst System 27–29, 35 Ir/P–OP* P–OP* ligand (L8): N Ph2P PAr2 R1 PAr2 N 38b O O O P O Ph 38c N S 6, 30 O 38c X N R2 Ar = Ph, xylyl X = CH, N R1 = OMe, OCF3, OTf, OC12H25, OPEG, O2(C5H10) (TunePhos) R2 = H, OMe, OPEG Ir/N–P* N–P* ligands: N 29e, 31 N 39a N Boc Select Examples: O Fe N PPh2 39a,b t-Bu O PPh2 30e PPh2 O N = SEGPHOS (L4), DIFLUORPHOS SYNPHOS, BINAP, H8-BINAP 39b PPh2 N N R1 32 OPPh2 X X Ph 39d O (L9) N N OPPh2 O R1 33 X = CH2, O R1 = H, Et 2 TfO Ir N SO2R N PR2 Fe 37 N R1 H Ph 16c, 40 N Ph R1 = H, Me R2 = 4-CH3C6H4, 4-CF3C6H4 Me N Ar = Ph, DMM (4-methoxy-3,5-dimethylphenyl) R = xylyl, t-Bu Ir/N–N* TsDPEN ligands: N Ir/P–P* Josiphos ligands (L6/L7): Ar2P References N H OMe X R1 Heteroarenes 32a N Since 2011, the combination of iridium and biaryl bisphosphine ligands has been extensively studied by Zhou, Agbossou-Niedercorn, and Mashima in the asymmetric hydrogenation of heteroarenes, including quinolines,29 isoquinolines,6,30 quinoxalines,29e,31 pyridines,30e pyrazines, 32 and benzoxazines. 33 Iodine, chloroformates, amines, and Brønsted acids are common activating reagents for enhancing catalytic activity of these heterocyclic substrates. 17 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes The mechanism and the role of iodine as an activator was initially proposed by Zhou and Li (Figure 1.5).27b Starting from [Ir(cod)Cl]2, the addition of I2 oxidizes the Ir(I) precursor to an Ir(III) species 51. Subsequent heterolytic cleavage of H2 with release of HI forms catalytically active Ir(III) complex 53. The heteroarene then coordinates to generate octahedral complex 54, followed by a 1,4-hydride transfer to form intermediate 55. An additional molecule of H2 regenerates the iridium hydride species 53 and protonates the enamine, which can isomerize to imine 30 and undergo a second reduction. The enantiodetermining step is proposed to be a 1,2-hydride addition that establishes the stereogenic center, with the addition of H2 releasing the product and regenerating Ir(III) species 53. It is unclear, however, whether substrate coordination to the metal center occurs, as other studies have proposed an outer-sphere pathway for the homogeneous iridium-catalyzed hydrogenation of quinolines and isoquinolines (vide supra).6,9b Recently, Zhou and coworkers employed trichloroisocyanuric acid (TCCA) as a traceless activating reagent for the iridium-catalyzed hydrogenation of isoquinolines and pyridines (Scheme 1.7). This method circumvents the additional steps of installing and removing the N-acyl group to activate the substrates. Pairing [Ir(cod)Cl]2 and bisphosphine ligand (R)-SEGPHOS (L4), a range of disubstituted isoquinolines and pyridines were hydrogenated in high yield and excellent enantioselectivity.30e The use of TCCA as a halogen-bond activator gave the highest enantioselectivity compared to Nchlorosuccinimide or N-iodosuccinimide. Notably, 2,3,6-trisubstituted pyridines 60 were also converted to chiral piperidines 61 with higher enantioselectivity than previous methods, which often require more activated pyridinium salts as substrates.7 18 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Figure 1.5. Proposed catalytic cycle for the Ir-catalyzed asymmetric hydrogenation of quinolines with I2 as additive. [Ir(cod)Cl]2 50 I P 1. ligand * 2. I2 Ir P H2 Cl I S I P Ir P I Ir Cl P H H 51 * P * I 52 –HI Cl H 53 N R 25 First Reduction P * P R 29 N H I Ir Cl H N R P * tautomerization I Ir Cl 1,4-hydride addition P R 54 N H2 55 N R P * 30 I Ir P R Cl H N 1,2-hydride addition 56 P * I Ir P Second Reduction Cl P * R H I Ir Cl P N 53 57 H2 N H * P R 32 P = chiral bisphosphine ligand S = solvent molecule Extending BINAP-derived ligand scaffolds, biaryl spirocyclic ligands have emerged as powerful tools for asymmetric catalysis due to their higher rigidity. 34 Nagorny and 19 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes coworkers reported that chiral spiroketal-based bisphosphinite ligand (SPIRAPO) (L5) is effective in the asymmetric hydrogenation of quinolines, quinoxalines, and benzoxazinones (Scheme 1.8).35 Using 10 mol % I2 and low catalyst loadings, the synthesis of a range of enantioenriched saturated heterocycles was achieved at 24 atm H2 and room temperature. Scheme 1.7. Ir-catalyzed asymmetric hydrogenation of isoquinolines and pyridines using TCCA as the activator. R3 R3 R2 N R1 R2 [Ir(cod)Cl]2 (2 mol %) (R)-SegPhos (L4) (4.4 mol %) Ar TCCA (1 equiv), H2 (82 atm) THF, 80 °C, 48 h 60 R1 = Me, Et, n-Bu R2 = H, CF3 R1 59 18 examples 80–99% yield 87–99% ee R1 = alkyl, aryl R2 = alkyl, aryl R3 = H, F N NH TCCA (0.36 equiv), H2 (82 atm) THF, 80 °C, 48 h 58 R1 R2 [Ir(cod)Cl]2 (1 mol %) (R)-SegPhos (L4) (2.2 mol %) O O PPh2 O PPh2 R2 R1 N H Ar 61 14 examples 64–98% yield 73–90% ee O (R)-SEGPHOS (L4) While there has been extensive development of biaryl bisphosphine (vide supra) and phosphoramidite36 ligands for iridium-catalyzed hydrogenation, ferrocenyl-based Josiphos ligands are also efficacious ligand scaffolds for N-heterocycles, imparting excellent enantioselectivity and diastereoselectivity.37 Inspired by the iridium catalyst system employed in the ether-directed asymmetric imine reduction en route to the herbicide metolachlor,10 Stoltz and coworkers explored the potential of directing groups as iridium catalyst chelating agents for the directed hydrogenation to a specific face of the substrate. Toward the total synthesis of the complex bis-tetrahydroisoquinoline alkaloid jorumycin, the hydroxymethyl functionality was utilized as a directing group for the iridium-catalyzed 20 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes asymmetric hydrogenation of bis-isoquinoline 64 to generate pentacyclic intermediate 65 in one step as a single diastereomer in 88% ee (1.9).37 Scheme 1.8. Ir-catalyzed asymmetric hydrogenation of quinolines, quinoxalines, and benzoxazinones. X [Ir(cod)Cl]2 (0.5 mol %) (R,S,S)-SPIRAPO (L5) (1 mol %) Y R2 I2 (10 mol %), H2 (24 atm) THF, 25 °C, 10 h R1 N 62 X = N, O, CH Y = CH, C=O R1 = alkyl, aryl R2 = H, Cl, Me Et X Y R2 R1 N H 63 20 examples 67–99% yield 42–96% ee OPPh2 O O OPPh2 Et (R,S,S)-SPIRAPO (L5) Scheme 1.9. Key Ir-catalyzed enantioselective hydrogenation step in the total synthesis of jorumycin. Me Me MeO OMe MeO OMe [Ir(cod)Cl]2 (10 mol %) Josiphos ligand (L6) (21 mol %) Me N MeO OMe Me CO2Me H2 (60 bar), TBAI 60 °C, 18 h N then 80 °C, 24 h N MeO OMe OH CO2Me NH OH 64 Ar2P P(xyl)2 Fe Me Ar = BTFM (3,5-bistrifluoromethyl) Josiphos ligand (L6) OMe Me MeO Me H Me NH OMe OMe H Me N MeO OMe O OH 65 83% yield 88% ee NH MeO OMe N H H CO2Me OH Utilizing directing groups is an underdeveloped activation strategy for the asymmetric hydrogenation of N-heterocycles, as Lewis basic functional groups are not as 21 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes well tolerated with previous hydrogenation methods.30 However, Stoltz and coworkers have extended this application of using a hydroxymethyl directing group toward the asymmetric hydrogenation of a range of 1,3-disubstituted isoquinolines. Using 1.25 mol % of [Ir(cod)Cl]2 and 3 mol % of chiral Josiphos ligand (L7), a range of differentially substituted isoquinolines were hydrogenated in high yields and enantio- and diastereoselectivity (Scheme 1.10, see Chapter 2).37b Heterocyclic substituents, such as furan and thiophene, at the C(3) position were also tolerated in this transformation. Interestingly, altering the directing groups at the C(1) position of the isoquinoline lowered the levels of conversion but maintained similar levels of stereoselectivity. Stoltz and coworkers later reported the first trans-selective asymmetric hydrogenation of 1,3-disubstituted isoquinolines as well with a similar catalyst system, wherein non-coordinating chlorinated solvents and halide additives were necessary to enable trans-selectivity (see Chapter 3).37c Scheme 1.10. Ir-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines. R1 R2 66 R1 N [Ir(cod)Cl]2 (1.25 mol %) Josiphos ligand (L7) (3 mol %) X TBAI (7.5 mol %), H2 (20–60 atm) 9:1 THF:AcOH, 23–60 °C, 18 h NH X 67 29 examples 30–99% yield 49–95% ee 2.4:1 to >20:1 dr X = H, OH, OR, NR2 R1 = aryl, heteroaryl R2 = H, F, dioxolane, naphthyl Ar2P R2 P(xyl)2 Fe Me Ar = DMM (4-methoxy-3,5-dimethylphenyl) Josiphos ligand (L7) Phosphine-phosphite (P–OP) ligands, an emerging class of chiral bisphosphine ligands, have been developed by Vidal-Ferran and coworkers for the iridium-catalyzed asymmetric hydrogenation of heterocycles.38 This catalyst system is particularly reactive in 22 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes the enantioselective synthesis of indolines from unprotected indoles,38b as well as the asymmetric hydrogenation of benzoxazines and benzothiazinones.38c Although stoichiometric amounts of sulfonic acids are needed to promote isomerization to the iminium intermediate, the transformation can be carried out using only 0.5 mol % of [Ir(cod)Cl]2 (Scheme 1.11).38 Scheme 1.11. Ir-catalyzed asymmetric hydrogenation with P–OP ligand L8. R2 [Ir(cod)Cl]2 (0.5 mol %) P–OP ligand (L8) (1.1 mol %) R3 R1 R2 R3 R1 rac-CSA (1 equiv), H2 (79 atm) 2-Me-THF, 25 °C N H N H 69 6 examples 51–78% yield 90–91% ee 68 R1, R2 = alkyl R3 = H, F, Me R3 X R2 N [Ir(cod)Cl]2 (0.5–2 mol %) P–OP ligand (L8) (1.1–4.4 mol %) Y R1 H2 (39–79 atm), THF 25 °C, 20 h 70 X = O, S Y = CH2, C=O R1 = Me, aryl R2, R3 = H, Cl, Me, nBu Ph2P Ph R3 X R2 N H Y R1 71 16 examples 49–99% conversion 89–99% ee OMe O O P O P–OP ligand (L8) Although chiral bisphosphine ligands are most commonly employed for iridiumcatalyzed asymmetric hydrogenation, chiral PHOX ligands with nitrogen and phosphorous chelating groups (N,P) have also been used to reduce a range of heteroarenes. 39 Most recently, Ding and coworkers reported the use of a SpinPHOX (spiro[4,4]-1,6-nonadienebased phosphinooxazoline) ligand (L9) for the enantioselective hydrogenation of indole and benzofuran derivatives (Scheme 1.12). This iridium catalyst system is effective for the asymmetric hydrogenation of a diverse range of indoles with high functional group 23 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes tolerance, using 1 mol % of catalyst loading and mild reaction conditions.39a Although preformation of the Ir/SpinPHOX catalyst complex is necessary, up to 99% isolated yield and 99% enantiomeric excess are observed across differentially substituted indole and benzofuran substrates. Scheme 1.12. Ir-catalyzed asymmetric hydrogenation with SpinPHOX ligand L9. R2 R2 R3 R1 (S,S)-Ir/SpinPHOX (L9) (1 mol %) R3 R1 H2 (50 atm), CH2Cl2, 25 °C, 24 h N R 72 N R R = Boc, Ts R1, R2 = alkyl R3 = H, F, Cl, Br, OMe, Me 73 21 examples 62–99% yield 93–99% ee R2 R2 R1 O (S,S)-Ir/SpinPHOX (L9) (2 mol %) H2 (50 atm), CH2Cl2, 25 °C, 24 h 74 R1, R2 = alkyl PPh2 N Ph R1 O 75 5 examples 89–95% conversion 97–99% ee O SpinPHOX ligand (L9) Unlike the ruthenium catalyst system, only a few reports employ the TsDPEN ligand for iridium-catalyzed asymmetric heteroarene hydrogenation.16c,40 In 2019, Fan and coworkers developed Ir/TsDPEN catalyst complex 78 for the enantioselective synthesis of vicinal chiral diamines. These products are synthesized through a relay sequence of intermolecular reductive amination followed by asymmetric hydrogenation of a range of 2-quinoline aldehydes and aromatic amines (Scheme 1.13).16c For more sterically encumbered substrates, an addition of 10 mol % TfOH is required to generate chiral diamines with high levels of selectivity. 24 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Scheme 1.13. Ir-catalyzed asymmetric hydrogenation of quinolines with Ir/TsDPEN catalyst 78. R1 + Ar NH2 N CHO 76 77 (R,R)-Ir/TsDPEN 78 (5 mol %) H2 (50 atm), i-PrOH 25 °C, 20 h R1 = H, F, Me, OMe Ar = Ph, tolyl, p-OMe, p-F, mesityl, p-i-Pr R1 N H H N Ar 79 15 examples 67–95% yield 46–98% ee TfO Ir N Ts Me N H Ph Ph (R,R)-Ir/TsDPEN 78 1.5 RHODIUM-CATALYZED ASYMMETRIC HYDROGENATION Apart from iridium and ruthenium catalyst systems in the asymmetric hydrogenation of heteroarenes, rhodium catalysts have also been effective for the reduction of quinolines, isoquinolines, and indoles (Figure 1.6). The combination of a rhodium(I) source and either a PhTRAP41 or TsDPEN42 ligand have been explored for the enantioselective hydrogenation of indoles and quinolines, respectively. More recently, Zhang and coworkers have developed a novel ferrocene-based bisphosphine-thiourea ligand, ZhaoPhos (L10), for the cooperative catalysis of a transition metal center for hydrogenation and anion binding of the thiourea derivative. 43 This strategy allows a broader range of Brønsted acids to be tolerated through hydrogen bonding interactions with the thiourea moiety, and simple tunability with the phosphine substituents to improve selectivity. Using ligand L10 with 0.5 mol % rhodium catalyst loading, differentially substituted quinolines, isoquinolines, and unprotected indoles are hydrogenated with excellent yield and enantioselectivity (Scheme 1.14). The addition of HCl as a strong acid is well tolerated under this catalyst system due to the stabilizing interaction with the thiourea derivative. 25 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Figure 1.6. Common Rh-based catalyst systems for the asymmetric hydrogenation of heteroarenes (≥90% ee, minimum three substrates). Only one enantiomer of ligand shown for simplicity. Heteroarenes Enantioenriched Heterocycles Rh Hydrogen Source: H2 Catalyst System Heteroarenes Rh/P–P* bisphosphine–thiourea ligand (L10): References 43b N CF3 S N H F3C N H Ph2P N 43b Fe Ph2P 43c N H Rh/PhTRAP, base Me Ph2P Fe Fe PPh2 Me 41 N R R = Ac, Ts, Ms, Tf (S,S)-(R,R)-PhTRAP (L1) Rh/N–N* TsDPEN ligands: 2 Cl Rh N SO2R N R1 H Ph 42 N Ph R1 = H, CH2C6H4 (tethered) R2 = 4-CH3C6H4, 4-C(CH3)3C6H4 Zhang and coworkers performed DFT calculations to gain insight into the mechanism of the Rh-catalyzed transformation (Figure 1.7).43c Rh(I) catalyst 86 undergoes oxidative addition with H2 to generate the active Rh(III) species 88. Protonation of the indole substrate with HCl allows anion binding with the thiourea moiety to form intermediate 90, allowing hydrogen bonding interactions between the chloride ion and the indole N–H group. Hydride transfer then proceeds through an outer-sphere pathway to release the chiral indoline product 26 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes 91 and complex 92. Addition of another molecule of H2 facilitates heterolytic cleavage of dihydrogen in complex 93 to generate Rh(III) catalyst 94 and HCl, in what was computed to be the rate-determining step. Overall, the thiourea–chloride anion binding proved to be crucial for inducing high enantioselectivity and reactivity in this system.43c Scheme 1.14. Rh-catalyzed asymmetric hydrogenation of N-heteroarenes using ZhaoPhos ligand L10. [Rh(cod)Cl]2 (0.5 mol %) (S,R)-ZhaoPhos (L10) (1 mol %) R2 N R1 •HCl R2 80 81 13 examples 73–99% yield 91–99% ee R1 = alkyl, aryl R2 = H, Me, OMe, Cl, F, Br R3 R2 [Rh(cod)Cl]2 (0.5 mol %) (S,R)-ZhaoPhos (L10) (1 mol %) N•HCl 82 R3 R2 N H NH R1 83 10 examples 73–99% yield 91–99% ee R1 = H, Me R2 = H, Me, F, Cl, CF3 R3 = alkyl, aryl 84 R3 R2 H2 (40 atm), 2:1 CH2Cl2:i-PrOH 25 °C, 48 h; then basic work-up R1 R1 N H H2 (40 atm), 2:1 CH2Cl2:i-PrOH 25 °C, 48 h; then basic work-up R3 [Rh(cod)Cl]2 (0.5 mol %) (S,R)-ZhaoPhos (L10) (1 mol %) R1 H (40 atm), 2:1 CH Cl :i-PrOH 2 2 2 25 °C, 48 h; then basic work-up R1 R2 N H 85 22 examples 48–99% yield 82–99% ee R1 = alkyl, aryl R2 = H, Me, F, Cl, Br, OMe R3 = alkyl, aryl CF3 S F3C N H N H Ph2P Fe Ph2P (S,R)-ZhaoPhos (L10) 1.6 PALLADIUM-CATALYZED ASYMMETRIC HYDROGENATION Compared to ruthenium, iridium, and rhodium catalysts, homogeneous palladium catalysts for the asymmetric hydrogenation of heteroarenes remain relatively unexplored.4 In 27 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes 2010, Zhou and Zhang reported the first Pd-catalyzed asymmetric hydrogenation of N–H indoles using Pd(OCOCF3)2, a chiral H8-BINAP ligand, and (–)-camphorsulfonic acid.44 Figure 1.7. Proposed catalytic cycle for the Rh-catalyzed asymmetric hydrogenation of indoles with ZhaoPhos ligand L10. S Ar [Rh(cod)Cl]2 86 H 1. ligand H 2. H2 Cl N H P Rh * P 87 R N Cl HCl S Ar N H H P Rh P H * 88 R N H H Cl P H Rh Cl P H N H N H 89 * 90 Ar S HCl N H N H H Cl H P N H Rh(III) Catalytic Cycle Cl * Cl 94 P H S 92 Cl N H H2 H P Rh Cl P H H N H Rh Ar N H 91 S Ar P Rh R N H P * * 93 Since their seminal report, the homogeneous palladium catalyst system has been extended to accommodate a range of N-heteroarenes, including quinolines,45 indoles,46 quinoxalinones,47 and the partial hydrogenation of pyrroles (Figure 1.8).48 Common amongst all these catalytic systems is the use of chiral biaryl bisphosphine ligands with different steric environments of the naphthyl ring. Zhou and coworkers have extensively developed palladium catalyst systems for the hydrogenation of N-heteroarenes, as palladium complexes demonstrate a higher tolerance for 28 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes strong Brønsted acids. Using chiral ligand (R)-H8-BINAP (L11), palladium(II) trifluoroacetate, and 1 equivalent of (–)-camphorsulfonic acid or TsOH•H2O, the asymmetric hydrogenation of 2-substituted and 2,3-disubstituted indoles is achieved to synthesize enantioenriched indolines in up to 99% yield and 98% ee (Scheme 1.15).46c Isotope-labeling studies demonstrate that the acid is necessary for formation of the iminium salt, which then undergoes hydrogenation by a Pd–H species. Figure 1.8. Common Pd-based catalyst systems for the asymmetric hydrogenation of heteroarenes (≥90% ee, minimum three substrates). Only one enantiomer of ligand shown for simplicity. Heteroarenes Enantioenriched Heterocycles Pd Hydrogen Source: H2 Catalyst System Heteroarenes References Pd/P–P* biaryl bisphosphine ligands: 45 N PPh2 PPh2 H N = SEGPHOS, H8-BINAP (L11) O PPh2 O PPh2 O 47 N H N 48 O (CH2)10 PPh2 PPh2 46 N H O Using both experimental and theoretical methods, Zhou and coworkers analyzed several possible mechanisms and propose a stepwise outer-sphere pathway (Figure 1.9).46c The indole is initially protonated by TsOH to give iminium 97, which subsequently induced 29 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes hydrogen-bonding interactions with the trifluoroacetate ligand to generate intermediate 99. A hydride transfer from the Pd(II) center to the hydrogen-bound iminium of complex 100 is proposed to be the enantiodetermining step. Scheme 1.15. Pd-catalyzed asymmetric hydrogenation of N–H indoles. R3 Pd(OCOCF3)2 (0.5 mol %) (R)-H8-BINAP (L11) (1 mol %) (–)-CSA/TsOH•H2O (1 equiv) R1 R2 95 N H H2 (20–48 atm) 1:1/2:1 CH2Cl2:CF3CH2OH R1 = alkyl, aryl R2 = H, F, Me R3 = alkyl, aryl R3 R1 R2 N H 96 17 examples 78–99% yield 84–98% ee PPh2 PPh2 (R)-H8-BINAP (L11) Figure 1.9. Proposed catalytic cycle for the Pd-catalyzed asymmetric hydrogenation of indoles. R N H TsOH P * TsOH R N H –OTs 89 97 H Pd P OCOCF3 98 OTs + H2 P * P P Pd OCOCF3 101 R H Pd(II) Catalytic Cycle N H Pd * P O CF3 O 99 * P P R N H 102 RH N ‡ Pd O H O CF3 100 The addition is postulated to occur through an eight-membered transition state, in which differentiation of the enantiotopic face is achieved through steric interactions with the 30 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes chiral bisphosphine ligand. After dissociation of the chiral indoline product 102, palladium hydride species 98 is regenerated with the release of TsOH from activation of H2. Additional mechanistic studies of palladium-catalyzed asymmetric hydrogenation of N-heteroarenes may provide key insights for further chiral catalyst design to improve the substrate scope of this transformation. 1.7 IRON-CATALYZED ASYMMETRIC HYDROGENATION Despite the development of many efficient transition metal catalysts for the asymmetric hydrogenation of heteroarenes, the application of earth-abundant metals such as iron as hydrogenation catalysts are a promising avenue of further development. The first report of the homogeneous asymmetric hydrogenation of imines using first-row transition metals has only recently been published in 2011.49 Beller and coworkers developed a novel cooperative catalytic system combining an achiral iron hydrogenation catalyst with a chiral Brønsted acid that facilitates the enantioselective reduction of quinoxalines and benzoxazines. 50 Using chiral phosphoric acid 105 to activate the substrate and control the enantioselectivity, an iron complex (104) reacts with the activated intermediate to deliver enantioenriched tetrahydroquinoxalines and dihydrobenzoxazines in high yields and selectivity (Scheme 1.16).50a Notably, both electron-donating and electron-withdrawing substituents on the C2-substituted phenyl ring, as well as meta- and para-substituted substrates, had little impact on the reactivity and enantioselectivity of the hydrogenation reaction. The levels of selectivity observed with 31 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes the iron catalyst system rival those of late transition metal-based catalysts for the hydrogenation of the same heteroarenes. Scheme 1.16. Fe-catalyzed asymmetric hydrogenation of quinoxalines and benzoxazines with chiral phosphoric acid 105. X X Fe catalyst 104 (3 mol %) Brønsted acid 105 (1 mol %) R2 N R1 103 R2 N H H2 (5 atm), PhMe, 60 °C, 24 h 106 19 examples 67–97% yield 58–94% ee X = N, O R1 = alkyl, aryl R2 = H, Me R TMS OH TMS OC R1 O Fe H CO O Fe catalyst 104 P O OH R (R)-Brønsted acid 105 Although the mechanism for this transformation has been previously investigated computationally using acyclic imines,51 Hopmann has proposed an alternative mechanism with benzoxazine as the substrate (Figure 1.10). 52 Calculations indicate that hydrogenation may likely occur through a stepwise mechanism, in which initially the resting state 107 involves an adduct between the deprotonated acid and the iron complex. A molecule of H2 generates dihydrogen complex 108, subsequently splitting H2 through proton abstraction by the phosphate to yield iron hydride species 109. Benzoxazine 110 then coordinates to the chiral acid through hydrogen bonding interactions, allowing hydride transfer to occur to form catalyst species 112. Finally, product 113 is released with regeneration of the catalyst complex 107.52 Computationally predicted enantioselectivities are in excellent agreement with experimental values, and the proposed mechanism is consistent with experimental observations by Beller and coworkers on possible reaction intermediates.50 32 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Figure 1.10. Proposed cooperative catalytic cycle for the Fe-catalyzed asymmetric hydrogenation of benzoxazines in the presence of a chiral phosphoric acid. TMS HO TMS O R O P O O H2 Fe CO CO 107 R O N H TMS HO TMS O H Fe O P CO O H * O CO R 113 O O P O * O Fe H N O R CO CO TMS HO TMS O O P OH * O 112 O O P * O O 1.8 108 Fe(II) Catalytic Cycle TMS HO TMS Fe CO CO 109 TMS HO TMS O Fe H H H N CO R O 111 CO N R 110 BORANE-CATALYZED ASYMMETRIC HYDROGENATION Avoiding the use of transition metals for catalysis, the metal-free asymmetric hydrogenation of heteroarenes is an emerging research field for further development. Recently, frustrated Lewis pair (FLP) catalysis has been explored for the hydrogenation of heteroarenes with hydrogen gas or NH3•BH3 as the hydrogen source.53 Du and coworkers reported a novel FLP catalyst system using a chiral borane catalyst (115), generated in situ from the direct hydroboration of chiral dienes 114 with HB(C6F5)2 (Scheme 1.17).54 The binaphthyl substituent presumably serves to control the stereoselectivity of the transformation, often requiring bulky aryl groups to achieve high selectivity. Although the mechanism for the asymmetric hydrogenation of heteroarenes using chiral borane catalysts 33 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes has not been investigated thoroughly, FLP catalysts are well known to activate H2 splitting and undergo hydride transfer.55 Scheme 1.17. In situ formation of chiral borane catalyst 115 from chiral dienes. R R B(C6F5)2 HB(C6F5)2 B(C6F5)2 R R 115 114 Chiral borane catalysts such as 115 are effective for the asymmetric hydrogenation of trisubstituted quinolines and disubstituted quinoxalines.53 Du optimized the catalyst system to generate the borane catalyst in situ with 2 to 5 mol % of the chiral diene ligand 117 and HB(C6F5)2 in the presence of molecular H2 gas (Scheme 1.18). Under mild reaction conditions, a range of chiral tetrahydroquinolines and tetrahydroquinoxalines were synthesized in high yield and enantioselectivity.53a–d Overall, this catalyst system is a promising step toward the in situ generation of a library of chiral borane catalysts, and their application to the asymmetric hydrogenation of other heteroarenes could be explored. In 2019, Wang and coworkers developed a similar catalytic system, employing chiral spiro-bicyclic bisborane catalysts for the asymmetric hydrogenation of C(2)substituted quinolines.53e The novel spiro-bicyclic bisborane catalyst 122 exhibited excellent activity and selectivity for alkyl-substituted quinolines at the C(2)-position, which previously have not been well tolerated (Scheme 1.19). A range of quinolines bearing alkenes, alkynes, and heterocycles were hydrogenated in excellent yield, 34 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes enantioselectivity, and chemoselectivity, demonstrating the catalyst’s broad functional group tolerance. Scheme 1.18. Metal-free asymmetric hydrogenation of heteroarenes through in situ formation of a chiral borane catalyst from ligand 117. R3 R3 N R2 Diene Ligand 117 (2–5 mol %) HB(C6F5)2 (4–10 mol %) R1 H2 (20 atm), PhMe 0–40 °C, 24 h R2 N H 118 20 examples 76–99% yield 82–99% ee 116 R1 = aryl R2 = alkyl R3 = aryl N R2 R3 N R1 Diene Ligand 117 (5 mol %) HB(C6F5)2 (10 mol %) R1 R2 N H R1 R3 H2 (20 atm), n-hexanes 25 °C, 24 h 119 H N R1 = aryl R2 = Me, Et R3 = H, Me, OMe, Cl, Br 120 14 examples 71–99% yield 67–96% ee R R R = 2-i-PrO-5-t-Bu, 2-OMe-5-t-Bu Diene Ligand 117 Scheme 1.19. Asymmetric hydrogenation of quinolines using spiro-bicyclic bisborane catalyst 122. Borane catalyst 122 (2–5 mol %) H2 (20 or 50 atm) R2 R2 N R1 PhCF3, –20 °C, 24 h 121 N H R1 123 26 examples 63–99% yield 86–99% ee R1 = alkyl, aryl, heteroaryl R2 = Br, BPin, OR Ph (p-C6F4H)2B B(p-C6F4H)2 Ph Borane Catalyst 122 35 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes 1.9 CHIRAL PHOSPHORIC ACID-CATALYZED ASYMMETRIC HYDROGENATION Since Rueping’s first report of an organic-catalyzed asymmetric reduction of heteroarenes in 2006, various chiral Brønsted acid catalysts have emerged as powerful agents for asymmetric arene hydrogenation (Scheme 1.20).4,56 Asymmetric transfer hydrogenation (ATH) reactions are promising alternatives to the use of transition metals or high pressure reactors, instead employing hydrogen sources like Hantzsch esters (HEH), dihydrophenanthridine (DHPD), and 4,5-dihydropyrrolo[1,2-a]quinoxalines. 57 In most cases, however, an unrecyclable excess of reductant is required for hydrogenation. Scheme 1.20. First reported chiral phosphoric acid-catalyzed asymmetric hydrogenation of quinolines. Chiral Phosphoric Acid 125 (2 mol %) N R1 Hantzch Ester 126 (2.4 equiv) PhH, 60 °C, 12–60 h N H 124 R1 127 16 examples 54–95% yield 87–99% ee R1 = alkyl, aryl, heteroaryl Ar H H O O P O EtO2C CO2Et OH Me Ar Ar = 9-phenanthryl N H Me Hantzch Ester 126 Chiral Phosphoric Acid 125 Over the past decade, several effective organic catalyst systems have been developed with chiral phosphoric acids (CPA) for the asymmetric reduction of quinolines, 58 indoles,58b, 59 quinoxalines,58c benzoxazines,57,58b,c,f, 60 benzothiazines,60 and the partial hydrogenation of pyridines (Figure 1.11). 61 Rueping, Zhou, Gong, and Bhanage have reported the use of BINOL-based phosphoric acid catalysts for the asymmetric hydrogenation of heteroarenes, with similar catalyst systems as shown in Scheme 1.20.56 36 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes More recently, Shi and coworkers have developed a new class of CPA catalysts with a 1,1’spirobiindane-7,7’-diol (SPINOL) backbone for the enantioselective hydrogenation of a range of quinolines and benzoxazines.58f Using 1 mol % of CPA 135 and 1.25 to 2.5 equivalents of HEH (126), electron-withdrawing and electron-donating substituents at the C(2)-position are all well tolerated and afforded excellent enantioselectivities (Scheme 1.21).58f The metal-free and mild reaction conditions of this transformation is an appealing alternative to transition metal catalyst systems. Figure 1.11. Common chiral phosphoric acid catalyst systems for the asymmetric hydrogenation of heteroarenes (≥90% ee, minimum three substrates). Only one enantiomer of ligand shown for simplicity. Heteroarenes Enantioenriched Heterocycles CPA Hydrogen Source: H2, HEH, DHPD Catalyst System Heteroarenes References Chiral phosphoric acids (CPA): 58 Ar N O O P O OH R1 R1 R2 Ar = 9-phenanthryl 125 = 9-anthracenyl 128 = Ph 129 = Ph [H8] 130 = 2-MeC6H4 131 = SiPh3 132 = SiPh3 [H8] 133 = 2,4,6-(iPr)3C6H2 134 Ar O O P 58b, 59 N Ar N 58c N 61 N O 57, 58b,c,f, 60 O OH Ar N S 60 Ar = 9-anthracenyl 135 N The general mechanism of the asymmetric transfer hydrogenation of quinolines by Hantzsch esters has been explored computationally by Frison and coworkers.62 It is well- 37 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes precedented that two subsequent reduction cycles occur, each with one equivalent of the hydride source and a chiral phosphoric acid. Scheme 1.21. Asymmetric transfer hydrogenation with SPINOL-derived phosphoric acid 135. O O Chiral Phosphoric Acid 135 (1 mol %) R2 Hantzsch Ester 126 (1.25 equiv) CH2Cl2, 25 °C, 24 h R1 N 136 R1 = aryl R2 = H, Me, Cl, F R2 R1 N H 137 20 examples 85–99% yield 91–99% ee Chiral Phosphoric Acid 135 (1 mol %) N 138 R1 Hantzsch Ester 126 (2.5 equiv) PhH, 60 °C, 24 h R1 = aryl, heteroaryl R2 = H, Me, Cl, F Ar O O P N H R1 139 11 examples 76–93% yield 86–99% ee O OH Ar Ar = 9-anthracenyl Chiral Phosphoric Acid 135 Quinoline 25 is first activated through a proton transfer from the phosphoric acid to the substrate, followed by a 1,4-hydride addition using HEH. The resulting dihydroquinoline can then isomerize to the imine, entering a second reduction cycle involving a similar stepwise process (Figure 1.12). Although previous studies have proposed the hydride transfer from 146 to 147 to be the rate- and enantiodetermining step,63 Frison revisited these calculations and proposed that the stereocontrol is determined from the steric constraints by the aryl substituent of the CPA with HEH instead. Thus, the enantiodetermining step would not be the hydride transfer, but rather the coordination of HEH to complex 145 to generate intermediate 146, hindering access of the HEH to the catalytic site and controlling the facial approach of the hydride addition.62 38 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Figure 1.12. Proposed catalytic cycle for the asymmetric transfer hydrogenation of quinolines using a chiral phosphoric acid and Hantzch ester. H H EtO2C * N P O Me O O 25 N H R 141 Me HEH H N O R CO2Et H EtO2C R H CO2Et Me N O O O P O OH * O First Reduction Me H O P O H N R 140 R 142 EtO2C EtO2C CO2Et CO2Et Me Me N N Me 144 O * O + N H 29 P Me H O O R H N 143 R tautomerization N R * 30 O HEH O O P H N O 145 O N O P O Second Reduction OH H O * O P O H N R 140 EtO2C Me 146 EtO2C CO2Et N N 144 * N H 32 CO2Et Me Me + R H CO2Et Me R O H EtO2C R O O O P H O H N 147 R Me R Me 39 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes Using relay catalysis, Zhou and coworkers took inspiration from NAD(P)H models that enable the biomimetic asymmetric hydrogenation of heteroarenes, harnessing the in situ generation of dihydrophenanthridine (DHPD) from catalytic amounts of ruthenium, phenanthridine, and H2 as the terminal reductant.58c, 64 Using 0.5 mol % of [Ru(pcymene)I2]2, 10 mol % of DHPD, and 1 mol % of CPA 130 or 131, the asymmetric hydrogenation of 2-substituted quinolines, quinoxalines, and benzoxazines proceeded in up to 99% yield and 97% ee (Scheme 1.22A). The mechanism of the biomimetic asymmetric hydrogenation reaction is proposed to involve two catalytic cycles, initially with Ru-catalyzed hydrogenation of phenanthridine 149 to generate DHPD 153. DHPD then coordinates to the chiral phosphoric acid to enantioselectively reduce the substrate 154, which is then regenerated to DHPD by the ruthenium hydride species (Scheme 1.22B). Interestingly, using a Hantzsch ester as the hydride source reverses the stereoselectivity due to the different steric demands of the coordination of the substrate and CPA, favoring the Re-face reduction instead.58c Although a transition metal is employed to recycle the hydride source, the biomimetic cascade hydrogenation can be performed under mild conditions with excellent activities and enantioselectivities. 1.10 CONCLUSION Over the past decade, many effective catalyst systems have been developed for the asymmetric hydrogenation or asymmetric transfer hydrogenation of heteroarenes. Although transition metal catalysts are most commonly employed for stereoselective 40 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes hydrogenation with molecular hydrogen gas, a number of organic catalysts and dual catalytic systems have also been successfully applied for the synthesis of enantioenriched saturated heterocycles. Scheme 1.22. Biomimetic asymmetric transfer hydrogenation of heteroarenes. A. X N R1 148 [Ru(p-cymene)I2)2 (0.5 mol %) Chiral Phosphoric Acid 130 (1 mol %) X Phenanthridine 149 (10 mol %) H2 (7–27 atm), PhH, 25 °C, 48 h N H 150 20 examples 64–99% yield 85–95% ee X = CH, N R1 = aryl O N 151 R1 [Ru(p-cymene)I2)2 (0.5 mol %) Chiral Phosphoric Acid 131 (1 mol %) O Phenanthridine 149 (10 mol %) H2 (1–3 atm), CH2Cl2, 25 °C, 48 h N H Ar O P R1 152 11 examples 95–99% yield 86–97% ee R1 = aryl O R1 O OH Ar N Ar = Ph [H8] 130 Ar = 2-MeC6H4 131 Phenanthridine 149 Chiral Phosphoric Acids B. X H2 N H N 149 R1 155 Ru(II) CPA X H N H H DHPD 153 N X = CH, N, O R1 154 Despite the recent advances made in the field of asymmetric hydrogenation, as well as reports that have been discussed in prior reviews,4 significant challenges in this field remain. The discovery of a catalyst system with a broad substrate scope of more than four 41 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes different heteroarenes has still not been achieved. Moreover, many asymmetric hydrogenation systems rely on acid activation of the substrates, which can be a limitation for more basic products. Development of novel ligand scaffolds and homogeneous catalyst systems will continue to be explored to design hydrogenation catalysts with improved selectivity. Creative activation strategies for these transformations should also be considered to extend the substrate scope, whether it be through pendant directing groups or recyclable activating reagents. Exploring these strategies will also provide insight into the challenge of developing a technology for the exhaustive asymmetric hydrogenation of simple 5- or 6-membered heteroarenes and benzene derivatives. Finally, a thorough mechanistic understanding of these asymmetric transformations is necessary to advance this field. Although experimental mechanistic studies are often limited by high pressure reactors and catalyst deactivation pathways, further investigation is needed to guide the development of the next generation of hydrogenation catalyst systems. The asymmetric hydrogenation of heteroarenes using homogeneous catalysts continues to be a valuable technology for the direct synthesis of enantioenriched, saturated heterocycles. These small molecules are critical structural motifs in natural products,1 as well as pharmaceuticals,2 and other molecules of industrial importance.3 Thus, the development of efficient catalyst systems for the enantioselective hydrogenation of a broad range of heteroarenes in good yields, stereoselectivity, and chemoselectivity remains highly desirable. We anticipate further advances in asymmetric hydrogenation technology that will revolutionize this field of research. 42 Chapter 1 – Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes 1.11 (1) REFERENCES AND NOTES a) Heterocycles in Natural Product Synthesis; Majumdar, K. C.; Chattopadhyay, S. K., Eds.; John Wiley & Sons: New York, 1991; pp 1−611. b) Walsh, C. T. Tetrahedron Lett. 2015, 56, 3075−3081. (2) a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257−10274; b) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. 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Sci. 2020, 11, 10220−10224. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 51 CHAPTER 2 Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines† 2.1 INTRODUCTION The stereocontrolled synthesis of nitrogen-containing heterocycles remains a challenge of great importance, as it provides direct access to chiral compounds that are prevalent structural motifs in many biologically active molecules. 1 As a result, the asymmetric hydrogenation of various hetero-aromatic compounds has been extensively explored as a direct, efficient synthesis of enantiopure cyclic amines. 2 Despite recent progress made toward the asymmetric hydrogenation of N-heterocycles such as quinolines, quinoxalines, and pyridines, the synthesis of 1,2,3,4-tetrahydroisoquinolines (THIQs) from isoquinolines remains significantly under-developed (Figure 2.1A).2 This is due in part to the stronger basicity and coordinating ability of the THIQ products compared to those of other ________________________________________________ † This research was performed in collaboration with Dr. Ngamnithiporn, Dr. Eric Welin, Martin T. Daiger, Christian U. Grünanger, Dr. Michael D. Bartberger, and Dr. Scott C. Virgil. Portions of this chapter have been reproduced with permission from Kim, A. N.; Ngamnithiporn, A.; Welin, E. R.; Daiger, M. T.; Grünanger, C. U.; Bartberger, M. D.; Virgil, S. C.; Stoltz, B. M. ACS Catal. 2020, 10, 3241–3248. © 2020 American Chemical Society. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 52 heterocycles (e.g., quinolines), leading to catalyst deactivation, as well as the overall lower reactivity of isoquinoline substrates. 3 Although a few effective strategies toward the asymmetric hydrogenation of substituted isoquinolines have been reported, these typically require preparation of the isoquinolinium salt, substrate activation with halogenides, and harsher hydrogenation reaction conditions (Figure 2.1B).4 Furthermore, previous to our research, there were only 2 catalytic systems describing efficient methods to access chiral 1,3-disubstituted tetrahydroisoquinolines,4c,e,g a more complex and sterically challenging system that generates two stereogenic centers. In addition, the limited substrate scope from these reports demonstrates the low tolerance of additional Lewis basic functionalities, such as alcohols or heteroaryl-substituted isoquinolines, which limit the applicability of these methodologies in synthesis. Since 1,3disubstituted tetrahydroisoquinolines with Lewis basic moieties are ubiquitous motifs present in a wide range of natural products, such as the saframycin, naphthyridinomycin, and quinocarcin families,5 a general method for highly enantioselective and diastereoselective hydrogenation of neutral disubstituted isoquinolines under mild reaction conditions would be a significant advancement toward the preparation of chiral amine-containing cyclic molecules. Recently, our group has successfully completed the total synthesis of jorumycin (156) and jorunnamycin A (157), two bis-tetrahydroisoquinoline natural products that exhibit potent antiproliferative activity, as well as strong Gram-positive and Gram-negative antibiotic character.6 Through an unprecedented, nonbiomimetic synthetic route, we were successful in harnessing catalysis to allow expedient access to these natural products, as well Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 53 as a diverse range of non-natural analogs that are otherwise inaccessible using prior biomimetic synthetic approaches. Figure 2.1 A) Limitations in enantioselective hydrogenation of N-heterocycles. B) Previous examples of iridium-catalyzed enantioselective and diastereoselective hydrogenation of monoand di-substituted isoquinolines. A. Asymmetric Hydrogenation of N-Heterocycles: Substrates: N N >50 reports N N N >20 reports <10 reports >20 reports B. Prior Art in Ir-Catalyzed Asymmetric Hydrogenation of Isoquinolines: a) Substrate Activation via Isoquinolinium Salts • 4 reports with only 1 report describing 1,3-disubstituted isoquinolines • Requires prior formation of the salt for activation • No example of substrate with additional Lewis basic functionalities R2 R2 HCl N preformed chiral Ir dimer H2 R2 * NH NH R1 R1 * X R1 R1, R2 = alkyl, aryl b) in situ and Transient Activation • 3 reports with only 1 report describing 1,3-disubstituted isoquinolines • Requires high temperature & pressure • No example of substrate with additional Lewis basic functionalities R2 N R1 Ir/L* H2 halogenide/ chloroformate R2 * NH * R1 R1, R2 = alkyl, aryl One of the key steps of this synthesis involves a catalytic enantioselective hydrogenation of bis-isoquinoline 64 to afford the THIQ motif, a crucial intermediate that forms the pentacyclic carbon skeleton 65 in one step by further hydrogenation of the second isoquinoline and eventual amide ring closure (Figure 2.2). Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 54 Figure 2.2 Our research on iridium-catalyzed enantioselective and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines. Jorumycin Synthesis: A Key Enantioselective Hydrogenation Step OMe O O Me N H H Me H N MeO MeO O Me O O H Me OMe Me O OH OAc N CN OR O Jorumycin (156) O Me N Jorunnamycin A (157) Me Me MeO OMe MeO OMe [Ir(cod)Cl]2 (5 mol %) BTFM-xyliphos (12 mol %) Me N MeO OMe Me CO2Me H2 (60 bar), TBAI 60 °C, 18 h N then 80 °C, 24 h N MeO OMe OH CO2Me NH OH 64 OMe Me MeO Me H Me NH OMe OMe H Me N MeO OMe NH MeO O OH OMe N H H CO2Me OH 65 This Research: • 30 examples of 1,3-disubstituted isoquinolines • General method for a variety of substitution patterns Ar/Het R N Ir/L* H2 X = H, OH, OR1, NR2 X R * Ar/Het * • No need for prior activation NH • Mild reaction conditions • Additional Lewis basic functionalities tolerated X Considering the ubiquity of the hydroxymethyl group at the C1 position, and the amino alcohol functionality in a large number of natural products, we envision that this synthetic method could access a wide variety of THIQs as well as chiral amino alcohols, both highly valuable pharmacophores. Following the successful development of our asymmetric Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 55 hydrogenation technology for bis-isoquinolines, herein we disclose a mild, general method for the enantioselective and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines. 2.2 SUBSTRATE SYNTHESES Due to a limited number of methods for the syntheses of 1,3-disubstituted isoquinolines, 7 we first established a simple and divergent sequence to access a wide variety of 1-(hydroxymethyl)-3-arylisoquinoline substrates (i.e., 162, Scheme 2.1). Utilizing Pd-catalyzed arylation of ester enolates reported by Donohoe and coworkers,8 monoarylated tert-butyl acetate 158 was isolated in an excellent 92% yield. Cyclization to isoquinoline triflate 160 was then achieved via hydrolysis of the ketal, followed by isoquinoline annulation with aqueous ammonium hydroxide, and alcohol triflation.9 At this stage, different aryl or heteroaryl groups could be coupled with intermediate 160 using Suzuki coupling conditions to deliver a wide range of 1,3-disubstituted isoquinolines (i.e., 161), highlighting the divergent synthesis of our synthetic route. Finally, SeO2 oxidation to the aldehyde and subsequent NaBH4 reduction provided our desired isoquinoline starting materials 162a–r. It is worth noting that this sequence allows for an introduction of various aryl and heteroaryl groups at the C3-position of isoquinolines, as well as different substituents with varied electronics on the isoquinoline carbocycle (e.g., 164a–f, vide infra, Scheme 4). Currently in the literature, the 1,3-disubstituted isoquinoline motif is typically accessed via transition-metal-catalyzed tandem C–H activation/annulation of arenes with alkynes.10 These methods have shown limited success in producing C3-heteroaryl isoquinolines.11 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 56 Scheme 2.1. Syntheses of 1-(hydroxymethyl)-3-aryl isoquinoline substrates. O Br t-Bu acetate, LiHMDS Pd2(dba)3, P(t-Bu)3•HBF4 Me O O Me PhMe, 23 °C O 92% yield 158 Ar/Het N 1) 33% TFA:CH2Cl2, 23 °C 2) aq. NH4OH CH3CN, 70 °C OTf N 3) Tf2O, pyridine CH2Cl2, 0 °C Me 38% yield over 3 steps 160 Ar/Het 1) SeO2, dioxane 110 °C N Me 2) NaBH4 4:1 CH2Cl2:MeOH, 23 °C 161 75–97% yield 2:1 K3PO4:THF, 40 °C 77–95% yield O 159 aryl/heteroaryl boronic acid XPhos Pd G3 2.3 Ot-Bu OH 162 REACTION OPTIMIZATION With a divergent sequence to access 1,3-disubstituted isoquinolines, we began our hydrogenation studies with 1-(hydroxymethyl)-3-phenylisoquinoline (162a) as our model substrate, using slightly modified conditions from our previously reported hydrogenation on the bis-isoquinoline system (Table 1). An initial experiment, employing 1.25 mol % [Ir(cod)Cl]2 and 3 mol % of the BTFM-xyliphos ligand (L6), gave high conversion of the substrate but surprisingly modest enantioselectivity (49% ee, entry 1). Seeking to improve the ee, we surveyed a wide variety of chiral ligand scaffolds (see Supporting Information) and found the xyliphos ligand framework to be optimal. By exploring different electronics of this ligand scaffold, we observed that replacing the 3,5bistrifluoromethylphenyl (BTFM) with more electron-rich aryl groups provided the product with both excellent conversion and higher enantio-selectivity (entries 1–5). Ligand L7, which features 4-methoxy-3,5-dimethylphenyl (DMM) substituted phosphine delivers the product with the highest ee of 89%, albeit with a low 2:1 diastereoselectivity (entry 5). Interestingly, a background reaction was observed in the absence of the chiral ligand, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 57 providing the product in excellent conversion and diastereoselectivity (entry 6). From this finding, we obtained all racemic hydrogenated products by simply performing the hydrogenation in the absence of ligand, affording the cis-product as a single diastereomer. Table 2.1. Optimization of the enantioselective hydrogenation of isoquinolines to afford cisTHIQs.a Ph N [Ir(cod)Cl]2 (1.25 mol %) ligand (3 mol %) H2 (60 bar), TBAI (7.5 mol %) OH solvent (0.02 M) 60 °C, 18 h Ph NH OH 162a 163a entry ligand Solvent % conversionb cis:transb % ee of cisc 1 L6 PhMe:AcOH >95 >20:1 –49d 2 L12 PhMe:AcOH >95 3.2:1 84 3 L13 PhMe:AcOH 66 4.5:1 63 4 L14 PhMe:AcOH 92 4.9:1 3 5 L7 PhMe:AcOH >95 2.0:1 89 6 – PhMe:AcOH >95 >20:1 0 7 L7 CH2Cl2:AcOH >95 1.5:1 84 8 L7 dioxane:AcOH 66 5.5:1 87 9 L7 THF:AcOH >95 9.7:1 90 10 L7 CPME:AcOH 38 >20:1 88 11 L7 2-MeTHF:AcOH >95 9.5:1 90 12e L7 THF:AcOH >95 15.7:1 92 P(Ar)2 P(Xyl)2 Fe L6: Ar = BTFMd L12: Ar = Ph Me L13: Ar = 2-napthyl L14: Ar = furyl L7: Ar = DMM [a] Reaction conditions: 0.04 mmol of 162a, 1.25 mol % [Ir(cod)Cl]2, 3 mol % ligand, 7.5 mol % TBAI, 60 bar H2 in 2.0 mL 9:1 solvent:AcOH. [b] Determined from crude 1H NMR using 1,3,5trimethoxybenzene as standard. [c] Determined by chiral SFC analysis of Cbz-protected product. [d] Opposite enantiomer of ligand used. [e] Reaction performed on a 0.2 mmol scale at 23 °C, 20 bar H2, and 0.1 M concentration of 162a. BTFM = 3,5-bis(trifluoromethyl)phenyl; DMM = 4-methoxy3,5-dimethylphenyl. Investigation of different solvents with L7 as the optimal ligand reveals that while the use of CH2Cl2 provided similar results to toluene (entry 7), the diastereoselectivity could be improved with the use of ethereal solvents (entries 8–11). Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 58 Although bulkier ethereal solvents proved to worsen conversion (entries 8 and 10), we were delighted to find that THF and the more sustainable solvent 2-MeTHF delivered the product in excellent conversion with high levels of diastereoselectivity and enantioselectivity (entries 9 and 11). The absence of AcOH resulted in low conversion,12 while further exploration of different additives (e.g., LiI, NaI, KI, etc.) demonstrated that TBAI is the optimal additive (see Table 2.3, Section 2.7.3). Finally, we were excited to observe that lowering the temperature to 23 °C and H2 pressure to 20 bar maintained excellent levels of conversion, diastereo-selectivity, and enantioselectivity (entry 12). To the best of our knowledge, these are the mildest reaction conditions reported for isoquinoline hydrogenation to afford chiral THIQs to date.4 2.4 SUBSTRATE SCOPE With optimized reaction conditions identified, we explored the general substrate scope for this transformation (Scheme 2.2). Gratifyingly, a wide variety of aryl substituents at the 3-position of the isoquinoline are well tolerated under the mild reaction conditions of 20 bar H2 at ambient temperature. Substitution at the para-position of the 3-aryl ring delivered the hydrogenated products 163a–g in consistently high yields and enantioselectivity. Electron-rich substrates such as the 3-(p-tert-butylphenyl)isoquinoline (162b) and the p-methoxyphenyl (162d) afforded chiral THIQs with excellent yields, diastereoselectivity, and enantioselectivity, similar to 162a. Interestingly, however, a general trend of lower diastereoselectivity was observed with electron-withdrawing substituents both at the para- and meta- positions (163f–i). We envision that the observed lower diastereoselectivity arises from the weaker coordinating ability of the nitrogen to the Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 59 iridium catalyst in electron-poor substrates, discouraging coordination to the catalyst in a bidentate fashion,13 and thus resulting in poorer facial selectivity in the second hydride addition step. However, at this time, we still cannot rule out the possibility that epimerization in situ also influences the trend seen in diastereoselectivity.14 Investigation of steric effects revealed that more sterically encumbered isoquinolines such as the 3napthyl and 3-xylyl substrates furnished the products (163j–k) in excellent isolated yields with similarly high enantioselectivity (95% and 92% ee, respectively) as a single diastereomer. The most sterically demanding substrate 162m, bearing an ortho-tolyl substituent, provided product 163m in a modest 64% yield with lower enantioselectivity (49% ee), albeit still with a high 10.1:1 diastereoselectivity. Additionally, we were pleased to find that the nitrile and nitro functional groups as well as the napthyl substituent were not reduced (163g, 163h, and 163j), highlighting the chemoselectivity of this catalytic process. Pleased to find the reaction tolerable to a range of 3-aryl substituted isoquinolines, we sought to further extend the scope of the transformation by exploring heteroarylsubstituted isoquinolines (Scheme 2.3). Although performing the hydrogenation at 23 °C and 20 bar H2 resulted in lower conversion, partially due to solubility issues, we found that heterocyclic substituents including furan, thiophene, pyrazole, and pyridine were well tolerated at 60 °C and under higher pressure of 60 bar H2, producing THIQs 163n–r. We also observed that the substitution pattern on the heteroaryl groups strongly affects the reaction conversion. For instance, an isoquinoline with a 3-substituted thiophene proceeded with a significantly lower conversion than the 2-thiophene substrate (163o and 163p). Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 60 Scheme 2.2. Substrate scope of different aryl substituents.a Ar N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBAI (7.5 mol %) OH 9:1 THF:AcOH (0.1 M) 23 °C, 18 h Ar NH OH 162a–m 163a–m R NH OH Product R %yield dr %ee 163a 163b 163c 163d 163e 163f 163g b H t-Bu Ph OMe F CF3 CN 95 87 79 75 99 81 83 15.7:1 13.3:1 9.0:1 13.3:1 10.1:1 4.6:1 2.4:1 92 91 92 92 93 92 82 F NO2 F F NH NH NH OH OH OH 163h 163i 163j 78% yield 3.2:1 dr, 86% ee 94% yield 3.5:1 dr, 89% ee 87% yield >20:1 dr, 95% ee Me OMe OMe Me NH NH NH OH OH OH 163k 163l c 163m 95% yield >20:1 dr, 92% ee 98% yield >20:1 dr, 88% ee Me 64% yield 10.1:1 dr, 49% ee [a] Reactions performed on a 0.2 mmol scale. [b] Reaction performed at 60 °C and 60 bar H2. [c] CH2Cl2 cosolvent used to improve substrate solubility. Similarly, no conversion was observed with 3- and 4-pyridyl substrates, whereas 2pyridyl THIQ 163r was isolated in 48% yield under the same reaction conditions. We speculate that this may be due to the competitive binding of the catalyst by the more distal heteroatom of 3- and 4-substituted heterocycles that inhibits directed hydrogenation of the isoquinoline ring. From product 163p we were successful in obtaining an X-ray crystal Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 61 structure to confirm the relative and absolute stereochemistry of our hydrogenation product. Scheme 2.3. Substrate scope of heteroaryl substituents.a Het N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (60 bar), TBAI (7.5 mol %) OH 9:1 THF:AcOH (0.1 M) 60 °C, 18 h 162n–r Het NH OH 163n–r S S O NH NH NH OH OH OH 163n 163o 163p 74% yield 3.0:1 dr, 92% ee 94% yield 3.5:1 dr, 90% ee 49% yield 7.3:1 dr, 89% ee Me N N N NH NH OH OH 163q 163r 98% yield 2.9:1 dr, 87% ee 48% yield 2.5:1 dr, 85% ee X-ray of 163p [a] Reactions performed on a 0.2 mmol scale. Furthermore, we were interested in exploring the substrate scope of isoquinolines with different electronics and substitution patterns on the isoquinoline carbocycle (Scheme 2.4). Electron-poor fluorinated isoquinolines with varied electronics at the 3-position provided THIQs in high yields (77–94%) with high diastereoselectivity and enantioselectivity under our standard conditions (165a–c). It should be noted that these electron-poor THIQs would be difficult to access utilizing electrophilic aromatic substitution strategies, a classical method for the syntheses of THIQs. On the other hand, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 62 the electron-rich dioxolane-appended isoquinolines (164d–e) afforded lowered conversion under the same reaction conditions, due in part to the poor solubility of the substrates in THF. Nevertheless, executing the reaction at 60 °C and 60 bar H2 with CH2Cl2 as cosolvent improved the solubility and conversion to yield products 165d–e with high diastereoselectivity.15 Scheme 2.4. Substrate scope of IQ backbone substituents.a Ar R N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBAI (7.5 mol %) OH 9:1 THF:AcOH (0.1 M) 23 °C, 18 h Ar R NH OH 165a–f 164a–f OMe F NH F OH NH F CF3 NH OH OH 165a 165b 165c 94% yield 11.5:1 dr, 93% ee 87% yield >20:1 dr, 90% ee 77% yield 6.7:1 dr, 94% ee OMe OMe O O O NH OH O NH OH NH OH 165d b,c 165e b,c 165f b 30% yield 4.9:1 dr, 58% ee 41% yield >20:1 dr, 54% ee 43% yield 15.7:1 dr, 82% ee [a] Reactions performed on a 0.2 mmol scale. [b] Reaction performed at 60 °C and 60 bar H2. [c] CH2Cl2 cosolvent used to improve substrate solubility. Interestingly, we observed significantly lower enantioselectivity for the dioxolane THIQs, which is observed in other reports as well.4a,g Finally, the napthyl-fused THIQ 165f was obtained with high diastereoselectivity and enantio-selectivity, despite its extended Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 63 aromatic system and larger steric hindrance. Although we observed modest conversion for these highly decorated isoquinolines, we were pleased to see that we were able to isolate unreacted starting material after column chromatography to obtain 80%, 99%, and 79% yield, respectively, of 165d–f based on recovered starting material. Consistent with our results for THIQs 163j and 163r, we observed that only the ring with the least degree of aromatic stabilization was reduced for 165f. Having demonstrated that this transformation is general for a wide variety of 1,3disubstituted isoquinolines, we then turned our attention to investigate the effects of different “directing” groups at the C1-position (Scheme 2.5). Isoquinolines bearing other polar groups such as an ester (167a), ethers (167b–c), and a Boc-protected amine (167d) delivered the products in lower yields than the hydroxy-directed substrate at 23 °C and 20 bar H2. However, to our delight, by increasing the temperature and H2 pressure, these yields could be improved with no erosion of enantioselectivity and diastereoselectivity. Additionally, we found that aldehyde 166f was reduced to the alcohol in situ, affording the hydroxymethyl THIQ 163a in comparable yield, enantioselectivity, and diastereoselectivity to that of the hydroxy-directing substrate 162a (vide supra). Interestingly, an isoquinoline lacking a potential directing group (167e) also afforded chiral THIQs with no erosion of enantioselectivity (90% ee),16 although elevated temperature and pressure are needed to obtain a synthetically useful yield (64%). While the hydroxy-directing aspect is the enabling feature in the context of our total synthesis of jorumycin, we are pleased to find that we can obviate this requirement in our developed hydrogenation technology. Nevertheless, surveying a variety of different directing groups demonstrates the importance of a functional group for directed hydrogenation, with the hydroxy functionality Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 64 acting as the best directing group for mild and efficient asymmetric hydrogenation. Notably, this is the first asymmetric hydrogenation method of isoquinolines in which additional Lewis basic functionalities are tolerated. It is also the first report investigating the effects of different directing groups in enantioselective hydrogenation of isoquinolines. Scheme 2.5. Substrate scope of different directing groups.a Ph N Ph [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBAI (7.5 mol %) NH 9:1 THF:AcOH (0.1 M) 23 °C, 18 h X 166a–f X 167a–e NH NH NH OMe OAc OBn 167a 167b b 167c b 56% yield >20:1 dr, 86% ee 80% yield >20:1 dr, 89% ee 90% yield >20:1 dr, 88% ee NH NH Me NHBoc 167d b 71% yield 9.0:1 dr, 90% ee N O 166f 167e b,c 64% yield >20:1 dr, 90% ee [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBAI (7.5 mol %) 9:1 THF:AcOH (0.1 M) 23 °C, 18 h NH OH 167a 81% yield 19:1 dr, 92% ee [a] Reactions performed on a 0.2 mmol scale. [b] Reaction performed at 60 °C and 60 bar H2. [c] Relative and absolute stereochemistry determined by experimental and computed VCD and optical rotation, see Section 2.7.4. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 2.5 65 SYNTHETIC UTILITY Overall, the broad application of our hydrogenation technology to afford chiral THIQs provides access to a range of decorated analogs that are difficult to synthesize via biomimetic approaches (e.g., Pictet-Spengler, Bischler-Napieralski). These often require electron-rich substrates to undergo cyclization (eq 1).17 R1 R aldehyde NH2 R = electron-donating substituents R1, R2 = alkyl, aryl R1 (1) R NH R2 With the scope of the transformation established, we sought to demonstrate the synthetic utility of the produced chiral THIQs toward more complex scaffolds that could be applicable to natural products. Additionally, we envisioned taking advantage of the chiral β-amino alcohol that is generated in our product as a building block to forge more complex enantioenriched heterocyclic scaffolds (Scheme 2.6).18 Prior to our investigation into the synthetic utilitiy of THIQ products, we performed the hydrogenation of isoquinoline 162l on a larger scale (1 mmol). We were pleased to find that the hydrogenated product 163l was still obtained in good yield (91% isolated yield) with excellent selectivity (>20:1 dr, 88% ee). With an ample amount of 163l in hand, we subjected THIQ 163l to aqueous fomaldehyde solution and found that the tricyclic 1,2fused oxazolidine THIQ 168 was formed rapidly via the cyclization of the alcohol onto the iminium generated in situ. Furthermore, the reaction of amino alcohol 163l with carbonyldiimidazole (CDI) afforded oxazolidinone-fused THIQ 169 in 84% yield.19 To our delight, we found that these 6,6,5-tricyclic systems are conserved structural motifs in a number of natural products such as quinocarcin, tetrazomine, and bioxalomycin.5 Lastly, a Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 66 different tricyclic scaffold containing fused morpholinone (170) can be isolated in 41% yield by the addition of excess glyoxal to 163l at room temperature.20 Being able to access a variety of complex heterocyclic scaffolds in one step from our hydrogenated THIQs further highlights the advantages of the hydroxymethyl functionality at the C1 position, beyond directing hydrogenation. In addition to the tricyclic scaffold, we were pleased to find that an analog of tetrahydroprotoberberine alkaloids, a family of natural products with a tetracyclic bisTHIQ core,21 can be synthesized via a 2-step sequence. First, reaction of 163l with glyoxal dimethyl acetal delivered the oxazolidine-fused intermediate with a dimethoxy acetal substituent at the carbinol-amine carbon. Subsequently, exploration of both Brønsted and Lewis acid-mediated Pomeranz-Fritsch reaction revealed that the use of Eaton’s reagent22 delivered pentacyclic THIQ 171 in 38% yield as a single diastereomer. This complex scaffold could be of medicinal interest, as previous studies have shown that tetrahydroprotobeberine derivatives possess a wide array of interesting biological activities.17,23 Scheme 2.6. Derivatization of hydrogenated product 163l. Ar Ar N H 37% aq. CH2O CDI DCE, 23 °C THF, 50 °C O N H Ar 93% yield 168 84% yield NH O O 169 OMe OMe OH H 163l Ar Ar = 3,4-(OMe)2C6H3 N 40% aq. glyoxal H O 170 O OMe H OMe O DCE, 23 °C DCE, 23 °C then Eaton’s reagent CH2Cl2, 23 °C 41% yield 38% yield N H O 171 H OH Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 2.6 67 CONCLUSION We have developed a general, efficient enantioselective hydrogenation reaction of 1,3-disubstituted isoquinolines toward the syntheses of chiral THIQs. Key to the success of this reaction is the installation of a directing group at the C1-position that facilitates hydrogenation to reduce a variety of isoquinolines under mild reaction conditions. The developed method affords chiral THIQs in good yields, with high levels of diastereoselectivity and enantioselectivity. The reaction conditions tolerate a wide range of substitution on the 1-, 3-, 6-, 7-, and 8-position of the isoquinoline core. To date, this report represents the broadest scope and highest tolerance of Lewis-basic functionality of any asymmetric isoquinoline reduction technology currently known. Furthermore, this method is amenable to the production of electron-deficient THIQs that are difficult to obtain through the classical Pictet–Spengler approach. To demonstrate the synthetic utility of the hydrogenated products, we utilize the hydroxyl directing group as a functional handle for further synthetic manipulations. As a result, we have completed the syntheses of various tricyclic and pentacyclic skeletons that are of potential medicinal interest. Further exploration of the mechanism, and other applications of this technology are currently underway. 2.7 EXPERIMENTAL SECTION 2.7.1 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 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 68 passage through an activated alumina column under argon. 24 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, oxr 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 500 MHz and Oxford 600 MHz spectrometers and are reported relative to residual CHCl3 (δ = 7.26 ppm) or TMS (δ = 0.00 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ = 77.16 ppm), C6D6 (δ = 128.06 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 path-length cell. High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Reagents were purchased from commercial sources and used as received unless otherwise stated. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 69 2.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 2.7.2.1 Syntheses of hydroxymethyl 1,3-disubstituted isoquinolines General Sequence: O Br Ot-Bu enolate alkylation R R O O Suzuki cross-coupling General Procedure 1 O Ar/Het R N General Procedure 3 Me OTf annulation/ triflation O R N General Procedure 2 Me Ar/Het oxidation/ reduction R N General Procedure 4 OH General Procedure 1: Enolate Alkylation of Aryl Bromide t-butyl acetate, LiHMDS Pd2(dba)3 (5 mol %) P(t-Bu)3•HBF4 (10 mol %) Br R O 158a–d O Ot-Bu O O O Toluene, 23 °C, 18 h O Ot-Bu O O R 159a–d 159a tert-butyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acetate (159a): This procedure has been adapted from a previous report.8 In a Schlenk flask was added P(t-Bu)3•HBF4 (119 mg, 0.41 mmol), Pd2(dba)3 (188 mg, 0.21 mmol), a solution of 2-(2-bromophenyl)-2methyl-1,3-dioxolane (158a) (1.0 g, 4.1 mmol, 0.42 M), and tert-butyl acetate (0.95 g, 8.2 mmol), respectively. The reaction mixture was cooled to –78 °C and sparged with nitrogen for 15 minutes. A degassed solution of LiHMDS (1.72 g, 10.25 mmol, 1 M in toluene) was Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 70 then added via syringe. The reaction mixture was degassed for an additional 15 minutes at –78 °C, and allowed to slowly warm to room temperature. The reaction was stirred at room temperature for 18 hours, and then quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with Et2O twice. The combined organic phases were dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc in hexanes) to afford 159a as a yellow oil (1.05 g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.45 (m, 1H), 7.20 – 7.06 (m, 3H), 3.96 – 3.83 (m, 2H), 3.71 (s, 2H), 3.68 – 3.55 (m, 2H), 1.60 (s, 3H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.6, 141.1, 132.6, 132.3, 128.2, 127.1, 126.4, 109.2, 80.4, 64.3, 40.4, 28.2, 28.2, 27.6; IR (Neat Film, NaCl) 3454, 3062, 2977, 2936, 2893, 1731, 1484, 1455, 1392, 1368, 1218, 1196, 1168, 1037, 952, 869, 763, 706 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H23O4 [M+H]+: 279.1591, found 279.1589. F O Ot-Bu O O 159b tert-butyl 2-(4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acetate (159b): Compound 159b was prepared from aryl bromide (2-(2-bromo-5-fluorophenyl)-2-methyl-1,3dioxolane) (158b) using general procedure 1, and purified by column chromatography (10% EtOAc in hexanes) to afford 159b with impurities. The compound was then subjected to the second column chromatography (15% Et2O in hexanes) to obtain 159b as a colorless solid (74 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 10.3, 2.8 Hz, 1H), 7.15 (dd, J = 8.4, 5.7 Hz, 1H), 6.94 (td, J = 8.2, 2.9 Hz, 1H), 4.06 – 3.90 (m, 2H), 3.74 (s, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 71 2H), 3.72 – 3.69 (m, 2H), 1.65 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.5, 161.9 (d, J = 245.1 Hz), 143.9 (d, J = 6.2 Hz), 134.2 (d, J = 7.8 Hz), 127.9 (d, J = 3.3 Hz), 114.9 (d, J = 21.1 Hz), 113.5 (d, J = 23.0 Hz), 108.6, 80.6, 64.4, 39.6, 28.2, 27.3; 19F NMR (282 MHz, CDCl3) δ –115.6 (ddd, J = 10.3, 8.0, 5.8 Hz); IR (Neat Film, NaCl) 2980, 1732, 1613, 1493, 1412, 1392, 1368, 1340, 1256, 1200, 1179, 1147, 1037, 947, 878 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H22FO4 [M+H]+: 297.1497, found 297.1494. O Ot-Bu O O O O 159c tert-butyl 2-(6-(2-methyl-1,3-dioxolan-2-yl)benzo[d][1,3]dioxol-5-yl)acetate (159c): Compound 159c was prepared from aryl bromide (5-bromo-6-(2-methyl-1,3-dioxolan-2yl)benzo[d][1,3]dioxole) (158c) using general procedure 1, and purified by column chromatography (5% to 15% EtOAc in hexanes) to afford 159c as a pale yellow oil (83.4 mg, 63% yield): 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 3.95 – 3.93 (m, 2H), 3.72 – 3.69 (m, 2H), 3.62 (s, 2H), 1.64 (s, 3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.7, 147.2, 146.7, 135.2, 125.9, 112.3, 109.1, 107.0, 101.3, 80.6, 64.3, 40.0, 28.3, 27.6; IR (Neat Film, NaCl) 2978, 2897, 1732, 1504, 1486, 1369, 1332, 1259, 1197, 1166, 1142, 1041, 929, 869, 935 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H23O6 [M+H]+: 323.1489, found 323.1501. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines O Ot-Bu O O 72 159d tert-butyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)naphthalen-1-yl)acetate (159d): Compound 159d was prepared from aryl bromide (2-(1-bromonaphthalen-2-yl)-2-methyl1,3-dioxolane) (158d) using general procedure 1, and purified by column chromatography (0% to 5% EtOAc in hexanes) to afford 159d as a pale yellow oil (2.15 g, 98% yield): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.76 (s, 2H), 7.48 (ddd, J = 7.9, 6.7, 1.4 Hz, 2H), 4.38 (s, 2H), 4.04 – 4.00 (m, 2H), 3.79 – 3.73 (m, 2H), 1.78 (s, 3H), 1.45 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 171.4, 139.3, 133.6, 128.7, 128.6, 127.8, 126.5, 125.8, 124.3, 124.1, 109.7, 80.7, 64.4, 36.2, 28.2, 27.8. IR (Neat Film, NaCl) 2980, 2890, 1732, 1454, 1368, 1336, 1142, 1100, 1037, 951, 884, 870, 822, 750 cm1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C20H25O4 [M+H]+: 329.1747, found 329.1739. General Procedure 2: Isoquinoline Annulation and Triflation O Ot-Bu 1. 33% TFA in CH2Cl2 23 °C R O O 159a–d 2. NH4OH, MeCN 70 °C, 12 h OH R N Me pyridine, Tf2O OTf R N CH2Cl2, 0 °C Me 160a–d Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 73 OTf N Me 160a 1-methylisoquinolin-3-yl trifluoromethanesulfonate (160a): This procedure has been adapted from a previous report.9 In a RBF were added ester 159a (2.78 g, 10.0 mmol), anhydrous CH2Cl2 (75 mL, 0.13 M), and TFA (25 mL, 33% volume of CH2Cl2), respectively. The reaction was stirred at room temperature for 2 hours, and then concentrated in vacuo. The crude was transferred to a Schlenk tube, dissolved in MeCN (10 mL, 1 M), and aqueous NH4OH (28–30%, 20 mL, 200% volume of MeCN). The tube was sealed with Kontes valve to prevent loss of gaseous ammonia and stirred at 70 °C. Within 1 hour, the yellow solid of the 3-hydroxyisoquinoline began to precipitate from the reaction solution. After stirring for 18 hours at 70 °C, the reaction was cooled to room temperature, then placed in a –20 °C freezer, and the yellow solid was collected via vacuum filtration. This yellow powder was then washed with cold MeCN and dried at high vacuum to provide 3-hydroxyisoquinoline intermediate (0.70 g, 4.39 mmol). If any starting material remains, the filtrate could be transferred to a flask and concentrated in vacuo to undergo a second condensation reaction. To a separate flame-dried RBF containing CH2Cl2 (22 mL, 0.2 M) and distilled pyridine (3.6 mL, 44 mmol), the collected yellow powder (0.70 g, 4.39 mmol) was added, and the resulting mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.5 mL, 8.8 mmol) was then added dropwise at 0 °C, and the reaction was stirred at 0 °C for 1 hour. The reaction was then quenched with saturated aqueous NaHCO3 at 0 °C, and then slowly warmed to room temperature. The reaction was extracted with CH2Cl2, dried over Na2SO4, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 74 and concentrated in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to afford 160a as a pale yellow oil (1.11 g, 38% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 8.5, 1.0 Hz, 1H), 7.88 (dt, J = 8.3, 1.0 Hz, 1H), 7.76 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.67 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.42 (s, 1H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 151.3, 138.6, 131.5, 128.1, 127.8, 127.6, 126.1, 118.9 (q, J = 320.5 Hz), 109.0, 22.1; 19F NMR (282 MHz, CDCl3) δ –73.0; IR (Neat Film, NaCl) 1624, 1600, 1563, 1422, 1327, 1213, 1138, 1116, 987, 958, 891, 832, 742, 616 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C11H9F3NO3S [M+H]+: 292.0250, found 292.0253. OTf N F Me 160b 7-fluoro-1-methylisoquinolin-3-yl trifluoromethanesulfonate (160b): Compound 160b was prepared from ester 159b using general procedure 2 and purified by column chromatography (10% EtOAc in hexanes) to provide a pale brown oil (384 mg, 31% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 9.0, 5.3 Hz, 1H), 7.76 (dd, J = 9.6, 2.5 Hz, 1H), 7.56 (ddd, J = 8.9, 8.0, 2.5 Hz, 1H), 7.43 (s, 1H), 2.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4 (d, J = 251.1 Hz), 159.4 (d, J = 6.1 Hz), 151.1 (d, J = 3.3 Hz), 135.5, 130.3 (d, J = 8.7 Hz), 128.5 (d, J = 8.3 Hz), 122.2 (d, J = 25.6 Hz), 118.9 (q, J = 320.5 Hz), 109.8 (d, J = 21.8 Hz), 108.9, 22.1; 19F NMR (282 MHz, CDCl3) δ –73.0, – 109.0 (ddd, J = 9.5, 8.0, 5.4 Hz); IR (Neat Film, NaCl) 1598, 1573, 1516, 1416, 1209, 1136, 1114, 986, 960, 933, 875, 805, 764 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C11H8F4NO3S [M+H]+: 310.0156, found 310.0149. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 75 OTf O N O Me 160c 5-methyl-[1,3]dioxolo[4,5-g]isoquinolin-7-yl trifluoromethanesulfonate (160c): Compound 160c was prepared from ester 159c using general procedure 2 and purified by column chromatography (10 to 20% EtOAc in hexanes) to provide a white solid (608 mg, 58% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.15 (s, 2H), 2.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 151.9, 150.9, 149.2, 137.3, 124.8, 118.8 (q, J = 321.2 Hz), 108.4, 103.3, 102.2, 101.8, 22.2; 19F NMR (282 MHz, CDCl3) δ –73.0; IR (Neat Film, NaCl) 2918, 1584, 1504, 1464, 1416, 1223, 1134, 1038, 964, 940, 873, 840 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C12H9F3NO5S [M+H]+: 336.0148, found 336.0146. OTf N Me 160d 4-methylbenzo[f]isoquinolin-2-yl trifluoromethanesulfonate (160d): Compound 160d was prepared from ester 159d using general procedure 2 and purified by column chromatography (5 to 10% EtOAc in hexanes) to provide a white solid (497 mg, 65% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 8.63 – 8.57 (m, 1H), 8.15 (s, 1H), 8.01 – 7.95 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.81 – 7.73 (m, 2H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 152.5, 138.6, 133.3, 129.6, 129.1, 128.9, 128.6, 127.8, 125.8, 123.6, 122.2, 118.8 (q, J = 321.2 Hz), 105.1, 22.4; 19F NMR (282 MHz, CDCl3) δ –78.3; IR (Neat Film, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 76 NaCl) 1588, 1416, 1377, 1207, 1180, 1138, 972, 878, 846, 817, 754 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H11F3NO3S [M+H]+: 342.0406, found 342.0399. General Procedure 3: Suzuki Cross-Coupling OTf R N Me 160a–d Ar/Het XPhos Pd G3 + Ar/Het–B(OH)2 R N 2:1 K3PO4(0.5 M aq):THF 40 °C, 2 h Me 161a–q, 172a–f N Me 161a 1-methyl-3-phenylisoquinoline (161a): This procedure has been adapted from a previous report.25 To a flame-dried 20-mL scintillation vial capped with a PTFE-lined septum was added XPhos Pd G3 (11.63 mg, 0.014 mmol) and phenyl boronic acid (126 mg, 1.03 mmol). The reaction vial was then evacuated and backfilled with N2 three times. The isoquinoline triflate 160a (200 mg, 0.687 mmol) in degassed THF (2 mL, 0.3 M) was then added to the vial, followed by degassed 0.5 M K3PO4 solution (4 mL, 0.2 M). The reaction was then stirred at 40 °C for 2 hours. Afterwards, the reaction was diluted with water and the aqueous layer was extracted with Et2O. The combined organic phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (5% EtOAc in hexanes) to afford 161a as a white solid (138 mg, 92% yield): 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.13 (m, 3H), 7.93 (s, 1H), 7.86 (dt, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.57 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.42 – 7.38 (m, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 150.2, 140.0, 136.9, 130.2, 128.9, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 77 128.4, 127.8, 127.1, 126.9, 126.7, 125.8, 115.4, 22.9; IR (Neat Film, NaCl) 3060, 1621, 1589, 1571, 1501, 1440, 1390, 1332, 1030, 902, 880, 786, 765, 692 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C16H14N [M+H]+: 220.1121, found 220.1129. N Me 161b 3-(4-(tert-butyl)phenyl)-1-methylisoquinoline (161b): Compound 161b was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a pale yellow oil (177 mg, 93% yield); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H) 8.06 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.57 – 7.52 (m, 3H), 3.04 (s, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.6, 151.5, 150.3, 137.3, 136.9, 130.1, 127.7, 126.8, 126.7, 126.6, 125.8, 125.8, 115.0, 34.8, 31.5, 22.8; IR (Neat Film, NaCl) 2961, 1622, 1591, 1568, 1515, 1442, 1390, 1362, 1333, 1268, 1112, 1017, 837, 754, 743, 685 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H22N [M+H]+: 276.1747, found 276.1749. Ph N Me 161c 3-([1,1'-biphenyl]-4-yl)-1-methylisoquinoline (161c): Compound 161c was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a colorless solid (191 mg, 94% yield); 1H NMR (400 MHz, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 78 CDCl3) δ 8.24 – 8.22 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.75 – 7.73 (m, 2H), 7.70 – 7.67 (m, 3H), 7.58 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.39 – 7.37 (m, 1H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 149.7, 141.2, 141.0, 138.9, 136.9, 130.2, 128.9, 127.8, 127.6, 127.5, 127.5, 127.2, 126.9, 126.8, 125.8, 115.2, 22.9; IR (Neat Film, NaCl) 3028, 1621, 1568, 1488, 1440, 1389, 1334, 842, 766, 730, 696 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H18N [M+H]+: 296.1434, found 296.1426. OMe N Me 161d 3-(4-methoxyphenyl)-1-methylisoquinoline (161d): Compound 161d was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to afford a white solid (79 mg, 93% yield): 1H NMR (400 MHz, CDCl3) 1 H NMR (400 MHz, CDCl3) δ 8.14 – 8.07 (m, 3H), 7.84 (s, 1H), 7.81 (d, J = 8.5, 1H), 7.64 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.53 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.06 – 7.01 (m, 2H), 3.88 (s, 3H), 3.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 158.4, 149.8, 136.9, 132.6, 130.0, 128.2, 127.5, 126.4, 126.3, 125.7, 114.1, 114.1, 55.4, 22.7; IR (Neat Film, NaCl) 3060, 2955, 2835, 1608, 1568, 1514, 1439, 1390, 1290, 1249, 1174, 1034, 833, 751, 730 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16NO [M+H]+: 250.1226, found 250.1220. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 79 F N Me 161e 3-(4-fluorophenyl)-1-methylisoquinoline (161e): Compound 161e was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (155 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.07 (m, 3H), 7.89 – 7.81 (m, 2H), 7.68 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.20 – 7.16 (m, 2H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.3 (d, J = 247.3 Hz), 162.1, 158.8, 149.1, 136.9, 136.0 (d, J = 3.3 Hz), 130.3, 128.8 (d, J = 8.2 Hz), 127.7, 127.0, 126.6, 125.8, 115.8, 115.6, 115.1, 22.8; 19F NMR (282 MHz, CDCl3) δ –114.2; IR (Neat Film, NaCl) 1605, 1570, 1510, 1440, 1390, 1332, 1231, 1156, 836, 749, 723 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13FN [M+H]+: 238.1027, found 238.1030. CF3 N Me 161f 1-methyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (161f): Compound 161f was prepared from triflate 160a using general procedure 3 and purified by column chromatography (2% to 3% EtOAc in hexanes) to afford a white solid (89 mg, 91% yield): 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.4, 1H), 7.96 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.73 – 7.67 (m, 1H), 7.63 – 7.59 (m, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 148.5, 143.3, 136.7, 130.4, 130.2 (q, J Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 80 = 32.5 Hz), 127.9, 127.5, 127.3, 127.1, 125.8, 125.7 (q, J = 3.8 Hz), 124.4 (q, J = 271.9 Hz), 116.1, 22.8; 19F NMR (282 MHz, CDCl3) δ –62.4; IR (Neat Film, NaCl) 3070, 2357, 1622, 1573, 1418, 1390, 1324, 1162, 1122, 1066, 1015, 842, 754, 742, 682 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H13F3N [M+H]+: 288.0995, found 288.0988. CN N Me 161g 4-(1-methylisoquinolin-3-yl)benzonitrile (161g): Compound 161g was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% to 20% EtOAc in hexanes) to provide a white solid (144 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.22 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J = 8.3, 1H), 7.82 – 7.75 (m, 2H), 7.73 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.64 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 147.6, 144.0, 136.6, 132.7, 130.7, 128.0, 127.9, 127.6, 127.3, 125.9, 119.3, 116.6, 111.8, 22.8; IR (Neat Film, NaCl) 2224, 1618, 1570, 1508, 1441, 1390, 1334, 878, 844, 748, 731 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H13N2 [M+H]+: 245.1073, found 245.1070. NO2 N Me 161h 1-methyl-3-(3-nitrophenyl)isoquinoline (161h): Compound 161h was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 81 EtOAc in hexanes) to provide a white solid (139 mg, 77% yield); 1H NMR (400 MHz, CDCl3) δ 9.01 (t, J = 2.0 Hz, 1H), 8.51 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 8.24 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.16 (dd, J = 8.3, 1.0 Hz, 1H), 8.01 (s, 1H), 7.90 (dd, J = 8.1, 0.7 Hz, 1H), 7.72 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.72 – 7.59 (m, 2H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 149.0, 147.3, 141.7, 136.6, 132.8, 130.6, 129.7, 127.9, 127.8, 127.2, 125.9, 123.0, 121.9, 116.0, 22.8; IR (Neat Film, NaCl) 1619, 1568, 1524, 1442, 1390, 1350, 880, 806, 749, 692 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13N2O2 [M+H]+: 265.0972, found 265.0974. F F F N Me 161i 1-methyl-3-(3,4,5-trifluorophenyl)isoquinoline (161i): Compound 161i was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to afford a white solid (103 mg, 87% yield): 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4, 1H), 7.86 – 7.78 (m, 4H), 7.72 – 7.68 (m, 1H), 7.65 – 7.58 (m, 1H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 151.6 (ddd, J = 248.4, 10.1, 4.1 Hz), 146.5, 140.0 (dt, J = 252.6, 15.7 Hz), 136.6, 136.0 (td, J = 7.5, 4.5 Hz), 130.6, 127.8, 127.7, 127.1, 125.8, 115.4, 110.9 – 110.7 (m), 22.7; 19F NMR (282 MHz, CDCl3) δ –134.4 (dd, J = 20.5, 9.2 Hz), –161.1 – –161.3 (m); IR (Neat Film, NaCl) 1619, 1570, 1526, 1446, 1392, 1352, 1237, 1034, 879, 847, 753 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H11F3N [M+H]+: 274.0838, found 274.0841. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 82 N Me 161j 1-methyl-3-(naphthalen-2-yl)isoquinoline (161j): Compound 161j was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (159 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (dd, J = 8.6, 1.8 Hz, 1H), 8.16 (dq, J = 8.3, 1.0 Hz, 1H), 8.07 (s, 1H), 8.00 – 7.96 (m, 2H), 7.91 – 7.86 (m, 2H), 7.70 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.56 – 7.46 (m, 2H), 3.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 149.9, 137.2, 137.0, 133.9, 133.5, 130.2, 128.9, 128.5, 127.8, 127.8, 127.0, 126.8, 126.3, 126.3, 125.8, 124.9, 115.7, 22.9; IR (Neat Film, NaCl) 3059, 1621, 1585, 1567, 1508, 1439, 1390, 879, 848, 816, 744 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H16N [M+H]+: 270.1277, found 270.1270. Me Me N Me 161k 3-(3,5-dimethylphenyl)-1-methylisoquinoline (161k): Compound 161k was prepared from triflate 160a using general procedure 3 and purified by column chromatography to provide a white solid (156 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.4, 1.1 Hz, 1H), 7.90 (s, 1H), 7.85 (dd, J = 8.2, 0.7 Hz, 1H), 7.75 (s, 2H), 7.66 (ddd, J = Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 83 8.2, 6.8, 1.2 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.05 (s, 1H), 3.05 (s, 3H), 2.43 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 158.6, 150.5, 139.9, 138.3, 136.9, 130.2, 130.1, 127.7, 126.8, 126.7, 125.8, 125.0, 115.4, 22.8, 21.7; IR (Neat Film, NaCl) 2919, 2358, 1622, 1582, 1568, 1443, 1391, 1335, 874, 846, 786, 750, 711 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C18H18N [M+H]+: 248.1434, found 248.1434. OMe OMe N Me 161l 3-(3,4-dimethoxyphenyl)-1-methylisoquinoline (161l): Compound 161l was prepared from triflate 160a using general procedure 3 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (195 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4, 1H), 7.89 – 7.81 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.55 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.95 (s, 3H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 149.8, 149.6, 149.3, 137.0, 132.9, 130.2, 127.6, 126.7, 126.5, 125.8, 119.5, 114.5, 111.4, 110.3, 56.1, 22.8; IR (Neat Film, NaCl) 2936, 2833, 1568, 1516, 1454, 1436, 1317, 1259, 1236, 1170, 1026, 874, 817, 751 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H18NO2 [M+H]+: 280.1332, found 280.1337. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 84 Me N Me 161m 1-methyl-3-(o-tolyl)isoquinoline (161m): Compound 161m was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (153 mg, 96% yield); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4, 1H), 7.84 (d, J = 8.3, 1H), 7.70 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.53 – 7.45 (m, 1H), 7.32 – 7.30 (m, 3H), 3.04 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1, 152.7, 140.9, 136.5, 136.3, 130.9, 130.1, 130.1, 128.1, 127.5, 127.0, 126.2, 126.0, 125.7, 118.9, 22.6, 20.6; IR (Neat Film, NaCl) 3053, 2950, 2920, 2355, 1622, 1584, 1567, 1498, 1446, 1392, 1360, 1330, 1144, 1033, 969, 906, 884, 763, 752, 726 cm1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16N [M+H]+: 234.1277, found 234.1286. O N Me 161n 3-(furan-2-yl)-1-methylisoquinoline (161n): Compound 161n was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (106 mg, 99% yield): 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J = 8.4 Hz, 1H), 7.67 – 7.59 (m, 1H), 7.57 – 7.49 (m, 2H), 7.13 (dd, J = 3.4, 0.8 Hz, 1H), 6.56 (dd, J = 3.4, 1.8 Hz, 1H), 2.99 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 159.0, 154.4, 142.9, 142.3, 136.5, 130.2, 127.6, 126.7, 126.6, 125.8, 113.0, 112.0, 108.1, 22.6; IR (Neat Film, NaCl) 3067, 1622, 1568, 1488, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 85 1447, 1390, 1325, 1288, 1216, 1157, 1007, 970, 883, 814, 736 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C14H12NO [M+H]+: 210.0913, found 210.0910. S N Me 161o 1-methyl-3-(thiophen-2-yl)isoquinoline (161o): Compound 161o was prepared from triflate 160a using general procedure 3 and purified by column chromatography (3% EtOAc in hexanes) to provide a white solid (103 mg, 92% yield): 1H NMR (400 MHz, CDCl3) δ 8.07 (dt, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.79 (dd, J = 8.2 Hz, 1H), 7.69 (dd, J = 3.6, 1.1 Hz, 1H), 7.64 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.38 (dd, J = 5.1, 1.1 Hz, 1H), 7.14 (dd, J = 5.0, 3.6 Hz, 1H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 145.5, 145.4, 136.6, 130.2, 128.1, 127.4, 126.7, 126.6, 125.8, 123.8, 113.1, 22.5; IR (Neat Film, NaCl) 3068, 1620, 1586, 1568, 1446, 1387, 1330, 1238, 1194, 1036, 876, 820, 748, 704 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H12NS [M+H]+: 226.0685, found 226.0680. S N Me 161p 1-methyl-3-(thiophen-3-yl)isoquinoline (161p): Compound 161p was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (148 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.4, 1.0 Hz, 1H), 8.04 (dd, J = 3.1, 1.3 Hz, 1H), 7.81 (dt, J = 8.2, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 86 0.9 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J = 5.0, 1.3 Hz, 1H), 7.65 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.54 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.42 (dd, J = 5.0, 3.1 Hz, 1H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 146.4, 142.7, 136.9, 130.2, 127.6, 126.7, 126.6, 126.3, 126.2, 125.8, 123.2, 114.7, 22.8; IR (Neat Film, NaCl) 3056, 2920, 1622, 1591, 1568, 1496, 1446, 1388, 1317, 874, 842, 795, 749, 696 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H12NS [M+H]+: 226.0685, found 226.0687. Me N N N Me 161q 1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (161q): Compound 161q was prepared from triflate 160a using general procedure 3 and purified by column chromatography (50% to 60% EtOAc in hexanes) to provide a white solid (112 mg, 99% yield): 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 8.04 – 8.00 (m, 2H), 7.77 (dd, J = 8.2, 1.1 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.54 – 7.47 (m, 1H), 3.98 (s, 3H), 2.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.8, 137.4, 136.8, 130.1, 128.9, 127.1, 126.2, 126.1, 125.7, 113.3, 39.1, 22.6; IR (Neat Film, NaCl) 2940, 2351, 1620, 1601, 1568, 1556, 1493, 1416, 1182, 983, 840, 750, 702 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H14N3 [M+H]+: 224.1182, found 224.1176. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines Pd(OAc)2 (5 mol%) P(t-Bu)3•HBF4 (10 mol%) K2CO3 (2 equiv) OTf N + N Me 160a O N N Toluene, 130 °C Me O 87 N PCl3 N CH2Cl2, 0 °C Me 161r 1-methyl-3-(pyridin-2-yl)isoquinoline (161r): Compound 161r was prepared from triflate 160a using a procedure adapted from a previous report.6 To a microwave vial was added flame-dried K2CO3 (142 mg, 1.03 mmol), Pd(OAc)2 (5.8 mg, 0.026 mmol), P(tBu)3•HBF4 (15 mg, 0.052 mmol), and the N-oxide (147 mg, 1.55 mmol). The vial was then evacuated and backfilled with argon three times. A solution of 160a (150 mg, 0.52 mmol) in toluene (2 mL, 0.3 M) was then added, and the reaction was stirred at 130 °C overnight. The reaction was then cooled to room temperature, filtered through celite, and dissolved in CH2Cl2 (10 mL, 0.05 M). The reaction flask was then cooled to 0 °C and PCl3 (0.27 mL, 3.1 mmol) was added dropwise, then the reaction stirred for 30 minutes at 0 °C. The reaction was then quenched with saturated aqueous K2CO3, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid (56 mg, 50% yield over 2 steps); 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J = 4.8, 1.9 Hz, 1H), 8.62 (s, 1H), 8.56 (dd, J = 8.0, 1.1 Hz, 1H), 8.14 (dd, J = 8.3, 1.0 Hz, 1H), 7.95 (dt, J = 8.2, 1.0 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.68 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.60 (ddd, J = 8.2, 6.9, 1.4 Hz, 1H), 7.29 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 3.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.5, 156.9, 149.4, 148.7, 137.1, 136.9, 130.2, 128.6, 127.7, 127.5, 125.8, 123.3, 121.4, 116.5, 22.9; IR (Neat Film, NaCl) 3053, 3004, 2916, 1621, 1580, 1568, 1474, 1443, 1426, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 88 1391, 1335, 1142, 891, 796, 742, 681, 624 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H13N2 [M+H]+: 221.1073, found 221.1076. N F Me 172a 7-fluoro-1-methyl-3-phenylisoquinoline (172a): Compound 172a was prepared from triflate 160b using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (110 mg, 93% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.11 (m, 2H), 7.90 (s, 1H), 7.85 (dd, J = 9.2, 5.7 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.54 – 7.48 (m, 2H), 7.48 – 7.38 (m, 2H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7 (d, J = 248.3 Hz), 158.0 (d, J = 5.8 Hz), 149.8 (d, J = 2.8 Hz), 139.7, 133.9, 130.3 (d, J = 8.5 Hz), 128.9, 128.5, 127.3 (d, J = 7.8 Hz), 127.0, 120.6 (d, J = 25.3 Hz), 114.9 (d, J = 1.7 Hz), 109.4 (d, J = 21.0 Hz), 22.8; 19F NMR (282 MHz, CDCl3) δ –109.7 – –111.8 (m); IR (Neat Film, NaCl) 3031, 2358, 1576, 1506, 1446, 1393, 1372, 1313, 1230, 1183, 1028, 972, 922, 904, 881, 822, 777, 764, 704 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13FN [M+H]+: 238.1027, found 238.1027. OMe N F Me 172b 7-fluoro-3-(4-methoxyphenyl)-1-methylisoquinoline (172b): Compound 172b was prepared from triflate 160b using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (110 mg, 99% yield): 1H Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 89 NMR (400 MHz, CDCl3) δ 8.10 – 8.04 (m, 2H), 7.87 – 7.81 (m, 2H), 7.70 (dd, J = 9.9, 2.6 Hz, 1H), 7.44 (ddd, J = 9.0, 8.3, 2.5 Hz, 1H), 7.06 – 6.99 (m, 2H), 3.88 (s, 3H), 2.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4 (d, J = 248.5 Hz), 160.1, 157.7 (d, J = 5.7 Hz), 149.4 (d, J = 2.8 Hz), 133.9, 132.2, 130.0 (d, J = 8.5 Hz), 128.1, 126.7 (d, J = 7.7 Hz), 120.5 (d, J = 25.3 Hz), 114.2, 113.7 (d, J = 1.8 Hz), 109.3 (d, J = 20.9 Hz), 55.4, 22.7; 19F NMR (282 MHz, CDCl3) δ –111.9 (ddd, J = 9.3, 9.1, 5.7 Hz); IR (Neat Film, NaCl) 1608, 1514, 1443, 1393, 1288, 1252, 1186, 1029, 878, 863, 836, 821 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C17H15FNO [M+H]+: 268.1132, found 268.1133. CF3 N F Me 172c 7-fluoro-1-methyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (172c): Compound 172c was prepared from triflate 160b using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (150 mg, 98% yield): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.0 Hz, 2H), 7.94 (s, 1H), 7.90 – 7.85 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.71 – 7.69 (m, 1H), 7.53 – 7.43 (m, 1H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1 (d, J = 249.4 Hz), 158.4 (d, J = 6.2 Hz), 148.1, 143.0, 133.7, 130.4 (d, J = 8.5 Hz), 130.2 (q, J = 32.4 Hz), 127.8 (d, J = 8.1 Hz), 127.2, 125.8 (q, J = 3.8 Hz), 124.5 (q, J = 272.7 Hz), 120.9 (d, J = 24.9 Hz), 115.6, 109.5 (d, J = 21.4 Hz), 22.8 ; 19F NMR (282 MHz, CDCl3) δ –62.5, –110.2 (ddd, J = 9.9, 8.2, 5.5 Hz); IR (Neat Film, NaCl) 1592, 1418, 1393, 1330, 1157, 1126, 1107, 1067, 880, 868, 847, 816 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H12NF4 [M+H]+: 306.0900, found 306.0895. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 90 O N O Me 172d 5-methyl-7-phenyl-[1,3]dioxolo[4,5-g]isoquinoline (172d): Compound 172d was prepared from triflate 160c using general procedure 3 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (153 mg, 97% yield): 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H), 7.77 (s, 1H), 7.52 – 7.44 (m, 2H), 7.41 – 7.32 (m, 2H), 7.11 (s, 1H), 6.10 (s, 2H), 2.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.4, 150.5, 149.5 148.1, 140.0, 135.1, 128.7, 128.1, 126.8, 123.5, 115.1, 103.4, 101.9, 101.6, 23.0; IR (Neat Film, NaCl) 2914, 1591, 1486, 1462, 1232, 1189, 1039, 945, 878, 846, 695, 684 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H14NO2 [M+H]+: 264.1019, found 264.1021. OMe OMe O N O Me 172e 7-(3,4-dimethoxyphenyl)-5-methyl-[1,3]dioxolo[4,5-g]isoquinoline (172e): Compound 172e was prepared from triflate 160c using general procedure 3 at 65 °C and purified by column chromatography via dry loading (40% EtOAc in hexanes) to provide a white solid (202 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 2.1 Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.09 (s, 2H), 4.02 (s, 3H), 3.94 (s, 3H), 2.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.2, 150.5, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 91 149.3, 149.2, 147.9, 135.2, 134.3, 133.0, 123.2, 119.1, 114.3, 111.2, 110.0, 103.3, 101.8, 101.5, 56.0, 56.0, 23.0; IR (Neat Film, NaCl) 2935, 1591, 1517, 1462, 1267, 1230, 1165, 1143, 1024, 872, 731 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H18NO4 [M+H]+: 324.1230, found 324.1229. N Me 172f 4-methyl-2-phenylbenzo[f]isoquinoline (172f): Compound 172f was prepared from triflate 160d using general procedure 3 and the product was collected via vacuum filtration to provide a white solid (246 mg, 63% yield); 1H NMR (400 MHz, CDCl3) δ 8.55 – 8.40 (m, 2H), 7.96 – 7.88 (m, 2H), 7.73 (t, J = 8.7 Hz, 1H), 7.69 – 7.61 (m, 1H), 7.54 (t, J = 8.3 Hz, 1H), 7.45 – 7.42 (m, 2H), 7.26 (td, J = 7.6, 1.7 Hz, 2H), 7.16 (td, J = 7.3, 1.7 Hz, 1H), 2.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9, 152.0, 140.3, 135.6, 133.4, 129.3, 128.8, 128.7, 128.5, 128.4, 127.7, 127.2, 127.1, 124.4, 123.4, 122.9, 111.0, 23.1; IR (Neat Film, NaCl) 2342, 1574, 1506, 1483, 1444, 1386, 1242, 1028, 876, 824, 760, 725, 692 cm1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C20H16N [M+H]+: 270.1277, found 270.1289. General Procedure 4: Oxidation and Reduction to Hydroxymethyl Isoquinoline Ar/Het R 1. SeO2, dioxane 110 °C N Me 161a–r, 172a–f 2. NaBH4 CH2Cl2/MeOH, 23 °C Ar/Het R N OH 162a–r, 164a–f Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 92 N OH 162a (3-phenylisoquinolin-1-yl)methanol (162a): This procedure has been adapted from a previous report.6 To a 20-mL microwave vial containing a stir bar was added SeO2 (140 mg, 1.26 mmol), isoquinoline 161a (138 mg, 0.63 mmol), and 1,4-dioxane (13 mL, 0.05 M). The reaction vial was then sealed and heated to 110 °C while stirring for 2 hours. The reaction was then cooled to room temperature, filtered through celite, and rinsed with EtOAc. The filtrate was then concentrated in vacuo to afford the aldehyde intermediate, which was used in the next step without further purification. A scintillation vial containing the crude in 4:1 DCM:MeOH (0.1 M) was added sodium borohydride (24 mg, 0.63 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC, and then quenched by the addition of citric acid monohydrate (132 mg, 0.63 mmol). The reaction was stirred for an additional 10 minutes then basified by the addition of saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (20% acetone in hexanes) to afford 162a as a white solid (100 mg, 68% yield over 2 steps): 1H NMR (400 MHz, CDCl3) δ 8.18 – 8.15 (d, J = 7.0 Hz, 2H), 8.03 (s, 1H), 7.94 – 7.92 (m, 2H), 7.73 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.46 – 7.42 (m, 1H), 5.31 (s, 2H), 5.26 (br s, 1H, OH); Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 13 93 C NMR (100 MHz, CDCl3) δ 157.4, 148.7, 138.9, 137.1, 130.9, 129.0, 128.9, 128.0, 127.5, 127.0, 124.2, 123.3, 116.3, 61.6; IR (Neat Film, NaCl) 3378, 3060, 2867, 1624, 1574, 1502, 1461, 1443, 1370, 1331, 1304, 1088, 1072, 1024, 1009, 882, 782, 766, 693 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H14NO [M+H]+: 236.1070, found 236.1078. N OH 162b ((3-(4-(tert-butyl)phenyl)isoquinolin-1-yl)methanol (162b): Compound 162b was prepared from isoquinoline 161b using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (162 mg, 95% yield); 1 H NMR (400 MHz, CDCl3) δ 8.20 – 8.06 (m, 2H), 8.00 (s, 1H), 7.97 – 7.85 (m, 2H), 7.72 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.58 – 7.52 (m, 2H), 5.30 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.2, 152.1, 148.7, 137.1, 136.2, 130.8, 127.9, 127.3, 126.7, 125.9, 124.1, 123.3, 115.9, 61.5, 34.9, 31.5; IR (Neat Film, NaCl) 3385, 2958, 1626, 1574, 1514, 1446, 1416, 1360, 1333, 1265, 1088, 1014, 841, 744, 680 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H22NO [M+H]+: 292.1696, found 292.1696. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 94 Ph N OH 162c (3-([1,1'-biphenyl]-4-yl)isoquinolin-1-yl)methanol (162c): Compound 162c was prepared from isoquinoline 161c using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a colorless solid (181 mg, 92% yield); 1 H NMR (400 MHz, CDCl3) δ 8.30 – 8.20 (m, 2H), 8.07 (s, 1H), 7.98 – 7.88 (m, 2H), 7.81 – 7.66 (m, 5H), 7.62 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.49 (dd, J = 8.2, 6.8 Hz, 2H), 7.43 – 7.34 (m, 1H), 5.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 148.3, 141.7, 140.7, 137.8, 137.1, 130.9, 129.0, 128.0, 127.7, 127.7, 127.6, 127.3, 127.2, 124.2, 123.3, 116.2, 61.6; IR (Neat Film, NaCl) 3382, 3060, 2359, 1623, 1574, 1488, 1445, 1412, 1374, 1334, 1088, 1006, 840, 766, 729, 697 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H18NO [M+H]+: 312.1382, found 312.1383. OMe N OH 162d (3-(4-methoxyphenyl)isoquinolin-1-yl)methanol (162d): Compound 162d was prepared from isoquinoline 161d using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (48 mg, 73% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.07 (m, 2H), 7.93 (s, 1H), 7.91 – 7.85 (m, 2H), 7.69 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.06 – 7.03 (m, 2H), 5.28 (s, 3H), 3.89 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 157.0, 148.3, 137.1, 131.4, 130.7, 128.1, 127.7, 127.0, 123.7, 123.1, 115.0, 114.2, 61.4, 55.4; IR (Neat Film, NaCl) 3376, 2928, 2836, 1608, 1573, 1515, 1442, 1372, 1334, 1287, 1250, 1175, 1087, 1032, 1010, 832, 750, 730 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16NO2 [M+H]+: 266.1176, found 266.1185. F N OH 162e (3-(4-fluorophenyl)isoquinolin-1-yl)methanol (162e): Compound 162e was prepared from isoquinoline 161e using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a colorless solid (149 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.9, 5.4 Hz, 2H), 7.96 (s, 1H), 7.95 – 7.89 (m, 2H), 7.73 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.21 (dd, J = 8.9, 8.5 Hz, 2H), 5.30 (s, 2H), 5.17 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 163.5 (d, J = 248.3 Hz), 157.5, 147.8, 137.0, 135.1 (d, J = 3.2 Hz), 131.0, 128.7 (d, J = 8.2 Hz), 127.9, 127.6, 124.1, 123.3, 116.0, 115.8, 61.6; 19F NMR (282 MHz, CDCl3) δ –113.3 – –113.4 (m); IR (Neat Film, NaCl) 3382, 3059, 2354, 1622, 1604, 1574, 1512, 1446, 1331, 1230, 1157, 1087, 1011, 837, 750, 725 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13FNO [M+H]+: 254.0974, found 254.0976. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 96 CF3 N OH 162f (3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)methanol (162f): Compound 162f was prepared from isoquinoline 161f using general procedure 4 and purified by column chromatography (10% to 20% EtOAc in hexanes) to provide a white solid (23 mg, 25% yield); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 2H), 8.07 (s, 1H), 8.00 – 7.92 (m, 2H), 7.82 – 7.73 (m, 3H), 7.70 – 7.61 (m, 1H), 5.32 (s, 2H), 5.10 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 157.9, 147.1, 142.3, 136.8, 131.2, 130.7 (q, J = 32.5 Hz), 128.2, 128.1, 127.2, 125.9 (q, J = 3.8 Hz), 124.6, 124.4 (q, J = 273.7 Hz), 123.4, 117.2, 61.6; 19F NMR (282 MHz, CDCl3) δ –62.5; IR (Neat Film, NaCl) 3408, 1623, 1574, 1418, 1324, 1166, 1111, 1075, 1014, 842, 753, 682 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H13F3NO [M+H]+: 304.0944, found 304.0934. CN N OH 162g 4-(1-(hydroxymethyl)isoquinolin-3-yl)benzonitrile (162g): Compound 162g was prepared from isoquinoline 161g using general procedure 4 and purified by column chromatography (30% EtOAc in hexanes) to provide a white solid (138 mg, 92% yield); 1 H NMR (400 MHz, CDCl3) δ 8.31 – 8.18 (m, 2H), 8.09 (s, 1H), 7.97 (m, 2H), 7.86 – 7.74 (m, 3H), 7.68 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 5.32 (s, 2H), 4.99 (s, 1H); 13C NMR (100 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 97 MHz, CDCl3) δ 158.2, 146.5, 143.2, 136.7, 132.8, 131.4, 128.5, 128.2, 127.4, 124.7, 123.5, 119.0, 117.7, 112.3, 61.7; IR (Neat Film, NaCl) 3404, 2895, 2358, 2224, 1416, 1332, 1303, 1085, 1006, 840, 764, 682 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H13N2O [M+H]+: 261.1022, found 261.1032. NO2 N OH 162h (3-(3-nitrophenyl)isoquinolin-1-yl)methanol (162h): Compound 162h was prepared from isoquinoline 161h using general procedure 4 and purified by column chromatography (20% EtOAc in CH2Cl2) to provide a white solid (67 mg, 38% yield); 1H NMR (400 MHz, CDCl3) δ 8.95 (t, J = 2.0 Hz, 1H), 8.52 (dt, J = 7.9, 1.3 Hz, 1H), 8.27 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.11 (s, 1H), 8.04 – 7.90 (m, 2H), 7.78 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H), 7.73 – 7.60 (m, 2H), 5.33 (s, 2H), 4.96 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 158.2, 149.0, 146.1, 140.7, 136.8, 132.7, 131.4, 129.9, 128.4, 128.2, 124.7, 123.5, 123.4, 121.6, 117.2, 61.7; IR (Neat Film, NaCl) 3389, 2614, 1538, 1520, 1505, 1353, 1333, 1088, 1007, 892, 751, 690 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13N2O3 [M+H]+: 281.0921, found 281.0930. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 98 F F F N OH 162i (3-(3,4,5-trifluorophenyl)isoquinolin-1-yl)methanol (162i): Compound 162i was prepared from isoquinoline 161i using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (90 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.89 (m, 3H), 7.84 – 7.71 (m, 3H), 7.65 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 5.30 (s, 2H), 4.89 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 158.0, 151.7 (ddd, J = 249.3, 10.2, 4.1 Hz), 145.4 (d, J = 2.5 Hz), 140.2 (dt, J = 253.9, 15.7 Hz), 136.7, 135.1 (td, J = 7.6, 4.5 Hz), 131.4, 128.3, 128.0, 124.5, 123.4, 116.6 (d, J = 1.4 Hz), 110.9 – 110.7 (m), 61.7; 19F NMR (282 MHz, CDCl3) δ –133.8 – –133.9 (m), –160.1 – – 160.3 (m); IR (Neat Film, NaCl) 3351, 2882, 1557, 1531, 1451, 1350, 1326, 1080, 1039, 1008, 864, 848, 778, 747, 706 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H11F3NO [M+H]+: 290.0787, found 290.0795. N OH 162j (3-(naphthalen-2-yl)isoquinolin-1-yl)methanol (162j): Compound 162j was prepared from isoquinoline 161j using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (158 mg, 97% yield); 1H NMR (400 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 99 MHz, CDCl3) δ 8.67 (s, 1H), 8.27 (dd, J = 8.6, 1.8 Hz, 1H), 8.16 (s, 1H), 8.05 – 7.93 (m, 4H), 7.91 – 7.89 (m, 1H), 7.75 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 – 7.47 (m, 2H), 5.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.5, 148.5, 137.1, 136.2, 133.7, 133.7, 130.9, 128.8, 128.6, 128.0, 127.8, 127.6, 126.7, 126.6, 126.3, 124.6, 124.2, 123.3, 116.6, 61.6; IR (Neat Film, NaCl) 3393, 3056, 1622, 1573, 1506, 1445, 1410, 1375, 1344, 1314, 1086, 1008, 856, 817, 744 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H16NO [M+H]+: 286.1231, found 286.1226. Me Me N OH 162k (3-(3,5-dimethylphenyl)isoquinolin-1-yl)methanol (162k): Compound 162k was prepared from isoquinoline 161k using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (155 mg, 95% yield); 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.94 – 7.91 (m, 2H), 7.78 – 7.76 (m, 2H), 7.72 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.60 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.09 (s, 1H), 5.30 (s, 3H), 2.44 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.2, 149.0, 138.9, 138.5, 137.1, 130.8, 130.6, 127.9, 127.4, 124.8, 124.1, 123.3, 116.3, 61.6, 21.7; IR (Neat Film, NaCl) 3382, 2913, 2338, 1622, 1574, 1503, 1444, 1379, 1332, 1084, 1011, 882, 849, 824, 750, 709 cm1 ; HRMS (MM:ESI-APCI+) m/z calc’d for C18H18NO [M+H]+: 264.1382, found 264.1383. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 100 OMe OMe N OH 162l (3-(3,4-dimethoxyphenyl)isoquinolin-1-yl)methanol (162l): Compound 162l was prepared from isoquinoline 161l using general procedure 4 and purified by column chromatography (40% EtOAc in hexanes) to provide a white solid (180 mg, 91% yield); 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.93 – 7.90 (m, 2H), 7.77 – 7.67 (m, 3H), 7.58 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.03 – 7.01 (m, 1H), 5.30 (s, 2H), 5.26 (br s, 1H, OH), 4.03 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.0, 149.8, 149.3, 148.3, 137.0, 131.8, 130.7, 127.7, 127.1, 123.8, 123.2, 119.5, 115.3, 111.3, 110.0, 61.4, 56.1, 56.0; IR (Neat Film, NaCl) 3372, 2936, 2838, 1623, 1604, 1573, 1518, 1456, 1438, 1314, 1260, 1237, 1134, 1027, 1008 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H18NO3 [M+H]+: 296.1284, found 296.1283. N Me OH 162m (3-(o-tolyl)isoquinolin-1-yl)methanol (162m): Compound 162m was prepared from isoquinoline 161m using general procedure 4 and purified by column chromatography (15% EtOAc in hexanes) to provide a white solid (130 mg, 79% yield); 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.4, 1.1 Hz, 1H), 7.91 (dd, J = 8.2, 1.2 Hz, 1H), 7.75 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.71 (s, 1H), 7.64 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.53 (d, J = 6.6 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 101 Hz, 1H), 7.39 – 7.29 (m, 3H), 5.30 (s, 2H), 5.14 (s, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.8, 151.4, 140.1, 136.7, 136.5, 131.0, 130.8, 130.2, 128.4, 127.8, 127.6, 126.1, 123.7, 123.3, 120.0, 61.6, 20.9; IR (Neat Film, NaCl) 3389, 3057, 2932, 1626, 1573, 1502, 1455, 1402, 1377, 1330, 1087, 1069, 1008, 884, 786, 757, 727 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C17H16NO [M+H]+: 250.1226, found 250.1232. O N OH 162n (3-(furan-2-yl)isoquinolin-1-yl)methanol (162n): Compound 162n was prepared from isoquinoline 161n using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (56 mg, 52% yield): 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.92 (m, 1H), 7.90 – 7.82 (m, 2H), 7.70 – 7.66 (m, 1H), 7.60 – 7.50 (m, 2H), 7.16 – 7.14 (m, 1H), 6.58 – 6.56 (m, 1H), 5.23 (s, 2H), 5.05 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 157.5, 153.7, 143.1, 140.9, 136.6, 130.9, 127.8, 127.2, 124.0, 123.3, 113.6, 112.1, 108.6, 61.3; IR (Neat Film, NaCl) 3390, 3118, 2886, 1624, 1574, 1492, 1372, 1323, 1306, 1157, 1092, 1079, 1006, 884, 836, 743 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H12NO2 [M+H]+: 226.0863, found 226.0871. S N OH 162o (3-(thiophen-2-yl)isoquinolin-1-yl)methanol (162o): Compound 162o was prepared from isoquinoline 161o (0.5 mmol) using general procedure 4 and purified by column Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 102 chromatography (10% to 20% EtOAc in hexanes) to provide a white solid (46 mg, 38% yield): 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.88 – 7.83 (m, 2H), 7.75 – 7.65 (m, 2H), 7.55 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.41 (dd, J = 5.0, 1.2 Hz, 1H), 7.16 (dd, J = 5.0, 3.6 Hz, 1H), 5.25 (s, 2H), 5.02 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 157.4, 144.4, 144.1, 136.8, 131.0, 128.2, 127.6, 127.2, 127.0, 124.1, 124.0, 123.3, 114.0, 61.3; IR (Neat Film, NaCl) 3382, 3066, 2868, 1621, 1589, 1573, 1501, 1452, 1402, 1329, 1084, 1006, 878, 822, 748, 701 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H12NOS [M+H]+: 242.0634, found 242.0637. S N OH 162p (3-(thiophen-3-yl)isoquinolin-1-yl)methanol (162p): Compound 162p was prepared from isoquinoline 161p (0.58 mmol) using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (127 mg, 91% yield); 1 H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 3.1, 1.3 Hz, 1H), 7.94 – 7.84 (m, 3H), 7.76 (dd, J = 5.1, 1.3 Hz, 1H), 7.71 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.45 (dd, J = 5.1, 3.0 Hz, 1H), 5.27 (s, 2H), 5.19 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 157.4, 145.0, 141.7, 137.0, 130.9, 127.8, 127.3, 126.6, 126.0, 124.1, 123.4, 123.4, 115.6, 61.5; IR (Neat Film, NaCl) 3372, 3098, 2888, 2363, 1622, 1594, 1573, 1456, 1350, 1318, 1299, 1086, 1008, 880, 842, 793, 748, 697 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H12NOS [M+H]+: 242.0634, found 242.0631. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 103 Me N N N OH 162q (3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)methanol (162q): Compound 162q was prepared from isoquinoline 161q using general procedure 4 and purified by column chromatography (70% to 80% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid (72 mg, 62% yield): 1H NMR (400 MHz, CDCl3) δ 8.08 – 7.95 (m, 2H), 7.85 – 7.79 (m, 2H), 7.71 – 7.59 (m, 2H), 7.53 – 7.49 (m, 1H), 5.21 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 143.2, 137.3, 136.9, 130.8, 128.8, 127.2, 126.7, 123.5, 123.2, 114.1 61.2, 39.2; IR (Neat Film, NaCl) 3370, 3068, 2937, 1626, 1603, 1573, 1503, 1416, 1321, 1278, 1186, 1092, 1011, 845, 753, 702 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H14N3O [M+H]+: 240.1131, found 240.1123. N N OH 162r (3-(pyridin-2-yl)isoquinolin-1-yl)methanol (162r): Compound 162r was prepared from isoquinoline 161r using general procedure 4 and purified by column chromatography (10% to 20% acetone in CH2Cl2 + 1% NEt3) to provide a pale cream solid (52 mg, 86% yield); 1 H NMR (400 MHz, CDCl3) δ 8.74 – 8.72 (m, 2H), 8.52 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.78 – 7.69 (m, 1H), 7.63 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 5.31 (s, 2H), 5.13 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 104 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 157.2, 155.8, 149.5, 147.3, 137.2, 137.0, 130.9, 128.7, 128.1, 125.1, 123.6, 123.3, 121.1, 117.6, 61.6; IR (Neat Film, NaCl) 3390, 3048, 2359, 1622, 1583, 1474, 1428, 1333, 1309, 1166, 1087, 1009, 897, 793, 747, 681 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H13N2O [M+H]+: 237.1022, found 237.1020. F N OH 164a (7-fluoro-3-phenylisoquinolin-1-yl)methanol (164a): Compound 164a was prepared from isoquinoline 172a using general procedure 4 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (94 mg, 81% yield): 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.96 – 7.87 (m, 1H), 7.57 – 7.47 (m, 4H), 7.44 (td, J = 6.9, 6.4, 1.4 Hz, 1H), 5.21 (s, 2H), 5.11 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 161.0 (d, J = 250.3 Hz), 156.8 (d, J = 5.9 Hz), 148.4, 138.6, 134.1, 130.5 (d, J = 8.6 Hz), 129.0, 126.8, 124.7 (d, J = 8.5 Hz), 121.4 (d, J = 25.2 Hz), 115.9 (d, J = 2.0 Hz), 107.2 (d, J = 21.3 Hz), 61.6; 19F NMR (282 MHz, CDCl3) δ –109.5 – –109.6 (m); IR (Neat Film, NaCl) 3393, 3063, 2878, 1594, 1579, 1506, 1417, 1392, 1321, 1232, 1185, 1085, 1015, 930, 777, 694 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H13FNO [M+H]+: 254.0976, found 254.0968. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 105 OMe F N OH 164b (7-fluoro-3-(4-methoxyphenyl)isoquinolin-1-yl)methanol (164b): Compound 164b was prepared from isoquinoline 172b using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (116 mg, 99% yield): 1 H NMR (400 MHz, CDCl3) δ 8.10 – 8.08 (m, 2H), 7.93 (s, 1H), 7.92 – 7.88 (m, 1H), 7.52 – 7.45 (m, 2H), 7.07 – 7.02 (m, 2H), 5.21 (s, 2H), 5.14 (s, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8 (d, J = 249.0 Hz), 160.5, 156.6 (d, J = 5.9 Hz), 148.3 (d, J = 2.9 Hz), 134.3, 131.3, 130.4 (d, J = 8.6 Hz), 128.1, 124.3 (d, J = 8.2 Hz), 121.4 (d, J = 25.3 Hz), 114.8 (d, J = 1.7 Hz), 114.4, 107.2 (d, J = 21.3 Hz), 61.6, 55.6; 19F NMR (282 MHz, CDCl3) δ –110.2 (ddd, J = 8.9, 8.8, 5.5 Hz); IR (Neat Film, NaCl) 3388, 2936, 1608, 1593, 1516, 1389, 1289, 1251, 1180, 1069, 1032, 1015, 929, 835 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H15FNO2 [M+H]+: 284.1081, found 284.1074. CF3 F N OH 164c (7-fluoro-3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)methanol (164c): Compound 164c was prepared from isoquinoline 172c using general procedure 4 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (80 mg, 60% yield): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.1 Hz, 2H), 8.02 (s, 1H), 7.95 (dd, J = Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 106 9.8, 5.4 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.58 – 7.47 (m, 2H), 5.21 (s, 2H), 4.94 (br s, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 161.3 (d, J = 251.5 Hz), 157.3 (d, J = 5.9 Hz), 146.8 (d, J = 2.9 Hz), 141.8 (d, J = 1.5 Hz), 133.8, 130.7 (d, J = 8.7 Hz), 130.7 (q, J = 33.3 Hz), 127.0, 125.9 (q, J = 3.8 Hz), 125.2 (d, J = 8.4 Hz), 124.3 (q, J = 272.7 Hz), 121.7 (d, J = 25.3 Hz), 116.8 (d, J = 1.7 Hz), 107.4 (d, J = 21.5 Hz), 61.7; 19F NMR (282 MHz, CDCl3) δ –62.5, –108.4 (ddd, J = 8.7, 8.7, 5.4 Hz); IR (Neat Film, NaCl) 3410, 2886, 1619, 1597, 1504, 1416, 1391, 1328, 1233, 1165, 1124, 1111, 1074, 1016, 931, 847, 680 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H12F4NO [M+H]+: 322.0850, found 322.0839. O N O OH 164d (7-phenyl-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)methanol (164d): Compound 164d was prepared from isoquinoline 172d using general procedure 4 and purified by column chromatography (30% to 40% EtOAc in hexanes) to provide a white solid (135 mg, 83% yield): 1H NMR (400 MHz, CDCl3) δ 8.13 – 8.05 (m, 2H), 7.82 (s, 1H), 7.50 (m, 2H), 7.44 – 7.37 (m, 1H), 7.15 – 7.06 (m, 2H), 6.10 (s, 2H), 5.28 (br s, 1H, OH), 5.10 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 154.9, 151.1, 148.6, 147.8, 138.9, 135.4, 128.8, 128.5, 126.6, 120.9, 115.9, 103.6, 101.9, 99.3, 61.4; IR (Neat Film, NaCl) 3324, 2914, 2355, 1597, 1497, 1463, 1436, 1422, 1236, 1066, 1036, 995, 940, 877, 775, 692 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C17H14NO3 [M+H]+: 280.0968, found 280.0975. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 107 OMe OMe O N O OH 164e (7-(3,4-dimethoxyphenyl)-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)methanol (164e): Compound 164e was prepared from isoquinoline 172e using general procedure 4 and purified by column chromatography (40% EtOAc in hexanes) via dry-loading to provide a pale pink solid (126 mg, 65% yield): 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.69 – 7.60 (m, 2H), 7.16 – 7.07 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.11 (s, 2H), 5.26 (br s, 1H, OH), 5.11 (s, 2H), 4.01 (s, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.7, 151.1, 149.7, 149.2, 148.4, 147.7, 135.5, 131.9, 120.6, 119.2, 115.1, 111.3, 109.7, 103.5, 101.8, 99.3, 61.4, 56.0, 56.0; IR (Neat Film, NaCl) 3378, 2912, 2353, 1595, 1519, 1496, 1463, 1456, 1435, 1258, 1234, 1034, 862, 730 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H18NO5 [M+H]+: 340.1179, found 340.1172. N OH 164f (2-phenylbenzo[f]isoquinolin-4-yl)methanol (164f): Compound 164f was prepared from isoquinoline 172f using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (51 mg, 62% yield): 1H NMR (400 MHz, CDCl3) δ 8.78 – 8.76 (m, 2H), 8.23 – 8.20 (m, 2H), 7.94 – 7.92 (m, 1H), 7.88 – 7.78 (m, 1H), 7.78 – 7.62 (m, 3H), 7.57 (t, J = 7.5 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 5.46 – 5.19 (m, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 108 3H); 13C NMR (100 MHz, CDCl3) δ 156.3, 150.4, 139.2, 135.9, 133.5, 129.0, 129.0, 129.0, 128.8, 128.6, 127.5, 127.1, 123.5, 122.1, 120.0, 120.0, 111.7, 61.7; IR (Neat Film, NaCl) 3322, 3064, 2890, 1589, 1494, 1428, 1386, 1304, 1242, 1081, 1050, 814, 747 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H16NO [M+H]+: 286.1226, found 286.1235. 2.7.2.2 Syntheses of isoquinolines with different directing groups Ac2O, pyridine DMAP N THF, 23 °C N OH OAc 162a 166a (3-phenylisoquinolin-1-yl)methyl acetate (166a): To a scintillation vial containing a stir bar and isoquinoline 162a (165 mg, 0.70 mmol) in THF (7 mL, 0.1 M) was added DMAP (8.6 mg, 0.07 mmol) and pyridine (0.14 mL, 1.75 mmol). Acetic anhydride (0.1 mL, 1.05 mmol) was then added dropwise. The reaction was stirred overnight at room temperature then diluted with Et2O and washed with saturated aqueous NH4Cl. The organic phase was collected, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to afford 166a as a colorless viscous oil (194 mg, >99% yield): 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.13 (m, 2H), 8.11 (dd, J = 8.4, 1.0 Hz, 1H), 8.07 (s, 1H), 7.92 (dt, J = 8.3, 0.9 Hz, 1H), 7.71 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.61 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.45 – 7.38 (m, 1H), 5.79 (s, 2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 154.4, 150.2, 139.3, 137.5, 130.5, 128.9, 128.7, 128.0, 127.6, 127.1, 126.0, 124.8, 117.2, 66.1, 21.1; IR (Neat Film, NaCl) 2826, 2364, 1704, 1574, 1455, 1333, 1054, 904, 783, 764, 748, 719, 678 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H16NO2 [M+H]+: 278.1176, found 278.1178. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 109 MeI, t-BuOK N THF, 0 to 23 °C N OH OMe 162a 166b 1-(methoxymethyl)-3-phenylisoquinoline (166b): To a scintillation vial containing a stir bar and isoquinoline 162a (165 mg, 0.70 mmol) in THF (7 mL, 0.1 M) was added KOt-Bu (86 mg, 0.77 mmol) at room temperature. The resulting mixture was stirred for 5 minutes, then cooled to 0 °C, and MeI (0.05 mL, 0.77 mmol) was added. The reaction was allowed to slowly warm to room temperature overnight and then was quenched with saturated aqueous NH4Cl. The organic phase was collected and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography (5% EtOAc in hexanes) to afford 166b as a white solid (79 mg, 45% yield): 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 8.4, 1.1 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.04 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.69 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.60 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.51 (td, J = 7.3, 6.5, 1.2 Hz, 2H), 7.45 – 7.37 (m, 1H), 5.14 (s, 2H), 3.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 149.9, 139.7, 137.5, 130.4, 128.9, 128.6, 127.7, 127.3, 127.1, 126.5, 125.9, 117.1, 75.8, 58.7; IR (Neat Film, NaCl) 3058, 2918, 2817, 1622, 1590, 1500, 1455, 1338, 1188, 1104, 885, 770, 752, 695, 668 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16NO [M+H]+: 250.1226, found 250.1236. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 110 NaH, BnBr N THF, 0 to 23 °C N OH OBn 162a 166c 1-((benzyloxy)methyl)-3-phenylisoquinoline (166c): This procedure has been adapted from a previous report.26 To a flame-dried RBF equipped with a stir bar was added NaH (36.4 mg, 60% w/w in oil, 0.91 mmol) and THF (7 mL, 0.1 M). To this suspension, isoquinoline 162a (165 mg, 0.70 mmol) was added. After 5 minutes of stirring at room temperature, the reaction mixture was cooled to 0 °C and BnBr (0.91 mL, 0.91 mmol) was added. The reaction was allowed to slowly warm to room temperature overnight. Silica (1 g) was then added and the solvent was evaporated under vacuum. The crude product was purified by column chromatography (5% EtOAc in hexanes) to afford 166c as a colorless viscous oil (153 mg, 67% yield): 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 8.4, 1.1 Hz, 1H), 8.21 – 8.14 (m, 2H), 8.04 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.69 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.58 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.51 (dd, J = 8.4, 6.9 Hz, 2H), 7.45 – 7.27 (m, 6H), 5.24 (s, 2H), 4.67 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.2, 149.9, 139.7, 138.2, 137.6, 130.4, 128.9, 128.6, 128.5, 128.3, 127.9, 127.7, 127.3, 127.1, 126.6, 126.1, 117.1, 73.6, 72.8; IR (Neat Film, NaCl) 3062, 2858, 1622, 1574, 1496, 1454, 1384, 1337, 1207, 1094, 1030, 885, 796, 768, 737, 696 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C23H20NO [M+H]+: 326.1539, found 326.1544. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 111 Boc-amide TFA, Et3SiH N H MeCN, 23 °C O 166f N NHBoc 166d tert-butyl ((3-phenylisoquinolin-1-yl)methyl)carbamate (166d): This procedure has been adapted from a previous report.27 To a solution of aldehyde 166f (150 mg, 0.64 mmol) and t-butyl carbamate (150 mg, 1.28 mmol) in MeCN (6.5 mL, 0.1 M) were added trifluoroacetic acid (0.15 mL, 1.92 mmol) and triethylsilane (1.0 mL, 6.4 mmol). The reaction was stirred at room temperature overnight and then quenched with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (15% EtOAc in hexanes) to afford 166d as a white solid (160 mg, 75% yield): 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.70 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.48 – 7.40 (m, 1H), 6.43 (br s, 1H), 5.03 (d, J = 4.4 Hz, 2H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.3, 155.0, 149.3, 139.4, 137.1, 130.6, 128.9, 128.8, 127.9, 127.6, 127.0, 125.1, 124.0, 116.3, 79.6, 43.5, 28.7; IR (Neat Film, NaCl) 3418, 2976, 1713, 1622, 1574, 1487, 1367, 1251, 1167, 1056, 882, 765, 695 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H23N2O2 [M+H]+: 335.1754, found 335.1760. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 112 SeO2 N dioxane, 110 °C N Me H 161a O 166f 3-phenylisoquinoline-1-carbaldehyde (166f): To a Schlenk flask containing a stir bar was added SeO2 (140 mg, 1.26 mmol) and isoquinoline 161a (138 mg, 0.63 mmol) in 1,4dioxane (13 mL, 0.05 M). The reaction vial was then sealed and heated to 110 °C while stirring for 2 hours. The reaction was then cooled to room temperature and filtered through celite rinsing with EtOAc. The crude product was then purified by column chromatography (5% EtOAc in hexanes) to afford 166f as a pale yellow solid (1.32 g, 96% yield): 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.32 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 7.3 Hz, 1H), 7.84 – 7.67 (m, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 196.2, 150.8, 149.7, 138.5, 138.1, 131.0, 129.9, 129.3, 129.1, 127.5, 127.1, 125.9, 125.5, 121.3; IR (Neat Film, NaCl) 2826, 2364, 1704, 1574, 1455, 1333, 1054, 904, 783, 764, 748, 719, 678 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C16H12NO [M+H]+: 234.0913, found 234.0914. 2.7.2.3 Hydrogenation reactions General Procedure 5: Hydrogenation Reactions Ar/Het Ar/Het N [Ir(cod)Cl]2 (1.25 mol %) ligand (3 mol %) H2 (20 bar), TBAI (7.5 mol %) NH Fe X 9:1 THF:AcOH (0.1 M) 23 °C, 18 h X ligand: SL-J418-1 P(DMM)2 P(Xyl)2 Me To an oven-dried 20-mL scintillation vial equipped with a stir bar and isoquinoline (0.2 mmol) was capped with a PTFE-lined septum and pierced with two 21 gauge green needles. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 113 The vials were then placed in a Parr bomb and brought into the glovebox, with the exception of the pressure gauge. A layer of plastic wrap and a rubber band were also brought in to seal the top of the bomb. In a nitrogen-filled glovebox, a solution of the ligand (SL-J418-1) (4.53 mg, 0.006 mmol per reaction) and [Ir(cod)Cl]2 (1.68 mg, 0.0025 mmol per reaction) in THF (1.8 mL per reaction) was prepared and allowed to stand for 10 minutes. Meanwhile, a solution of TBAI (5.54 mg, 0.015 mmol per reaction) in AcOH (0.2 mL per reaction) was prepared in a 1-dram vial, and 0.2 mL of the solution was added to each reaction vial via a syringe. Afterwards, 1.8 mL of the homogeneous iridium catalyst solution was added to each reaction vial via a syringe. After re-capping the vials with caps equipped with needles, the reactions were placed in the bomb and the top was covered tightly with plastic wrap secured by a rubber band. The bomb was then removed from the glovebox, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was repeated two more times, before charging the bomb to 20 bar of H2 (or 60 bar H2). The bomb was then left stirring at 200 rpm at room temperature (or placed in an oil bath and heated to 60 °C) for 18 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics layers were then dried over Na2SO4, and concentrated in vacuo. The product was then purified by column chromatography to furnish the product as an inseparable mixture of diastereomers. Please note that the NMR data listed is for the major diastereomer, and that the provided spectra for the following compounds reflect the inseparable mixture of cis- and Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 114 trans-products. The enantiomeric excess was determined by chiral SFC analysis of the Cbz-protected amine (see Table 2.4). The absolute configuration was determined for compound 163p via x-ray crystallographic analysis. Absolute configuration of compound 167e were determined using vibrational circular dichroism (VCD), vide infra. The absolute configuration for all other products has been inferred by analogy. NH OH 163a ((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163a): Compound 163a was prepared from isoquinoline 162a using general procedure 5 and purified by column chromatography (5% MeOH in CH2Cl2) to provide a tan solid as a mixture of diastereomers (47 mg, 98% yield) (dr = 15.7:1); 92% ee for major diastereomer; [α]D25 +110.2 (c 1.02, CHCl3); Cis-diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.43 (m, 2H), 7.41 – 7.34 (m, 2H), 7.34 – 7.28 (m, 1H), 7.25 – 7.17 (m, 3H), 7.15 – 7.10 (m, 1H), 4.43 – 4.41 (m, 1H), 4.10 (dd, J = 11.1, 3.5 Hz, 1H), 4.02 (dd, J = 10.8, 3.3 Hz, 1H), 3.90 (dd, J = 10.9, 5.4 Hz, 1H), 3.02 (ddt, J = 15.9, 11.1, 1.4 Hz, 1H), 2.90 (dd, J = 15.7, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.3, 136.7, 134.9, 129.3, 128.8, 127.7, 126.8, 126.7, 126.5, 125.5, 66.7, 58.7, 57.7, 39.0; IR (Neat Film, NaCl) 3296, 3060, 2910, 2360, 1494, 1455, 1314, 1116, 1036, 909, 742, 700 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H18NO [M+H]+: 240.1383, found 240.1385; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.34, minor = 4.02. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 115 Trans-diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H), 7.42 – 7.38 (m, 2H), 7.36 – 7.27 (m, 1H), 7.26 – 7.10 (m, 4H), 4.23 (dd, J = 10.5, 4.8 Hz, 1H), 4.16 (dd, J = 11.2, 3.9 Hz, 1H), 3.80 (dd, J = 10.8, 4.8 Hz, 1H), 3.71 (t, J = 10.7 Hz, 1H), 3.07 (dd, J = 16.4, 3.9 Hz, 1H), 2.95 (dd, J = 15.9, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.5, 135.5, 134.7, 129.5, 128.8, 127.5, 127.0, 126.7, 126.6, 126.4, 63.8, 57.4, 50.7, 36.8. NH OH 163b ((1S,3R)-3-(4-(tert-butyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163b): Compound 163b was prepared from isoquinoline 162b using general procedure 5 and purified by column chromatography (50% EtOAc in hexanes) to provide a tan solid as a mixture of diastereomers (51 mg, 87% yield) (dr = 13.3:1); 91% ee for major diastereomer; [α]D25 +78.8 (c 1.03, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.38 (m, 4H), 7.26 – 7.21 (m, 2H), 7.21 – 7.17 (m, 1H), 7.12 (d, J = 7.7 Hz, 1H), 4.42 – 4.40 (m, 1H), 4.08 (dd, J = 11.2, 3.4 Hz, 1H), 4.01 (dd, J = 10.8, 3.3 Hz, 1H), 3.89 (dd, J = 10.8, 5.4 Hz, 1H), 3.03 (dd, J = 15.8, 11.2 Hz, 1H), 2.89 (dd, J = 15.7, 3.4 Hz, 1H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 150.7, 141.2, 136.7, 135.0, 129.3, 126.7, 126.5, 126.5, 125.7, 125.5, 66.6, 58.7, 57.3, 38.8, 34.7, 31.5; IR (Neat Film, NaCl) 3318, 2961, 2868, 1494, 1454, 1362, 1312, 1270, 1116, 1038, 820, 743 cm-1; HRMS (MM:ESI-APCI+) Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 116 m/z calc’d for C20H26NO [M+H]+: 296.2009, found 296.2005; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 1.81, minor = 2.73. Ph NH OH 163c ((1S,3R)-3-([1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163c): Compound 163c was prepared from isoquinoline 162c using general procedure 5 and purified by column chromatography (50% EtOAc in hexanes) to provide a tan solid as a mixture of diastereomers (50 mg, 79% yield) (dr = 9.0:1); 92% ee for major diastereomer; [α]D25 +73.2 (c 1.03, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.58 (m, 4H), 7.55 – 7.53 (m, 2H), 7.47 – 7.44 (m, 2H), 7.39 – 7.32 (m, 1H), 7.28 – 7.16 (m, 3H), 7.15 (d, J = 6.2 Hz, 1H), 4.46 – 4.44 (m, 1H), 4.15 (dd, J = 11.2, 3.4 Hz, 1H), 4.04 (dd, J = 10.9, 3.3 Hz, 1H), 3.91 (dd, J = 10.9, 5.5 Hz, 1H), 3.12 – 3.00 (m, 1H), 2.94 (dd, J = 15.6, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.2, 141.0, 140.7, 136.5, 134.9, 129.3, 128.9, 127.5, 127.4, 127.3, 127.2, 126.8, 126.6, 125.5, 66.6, 58.7, 57.4, 38.9; IR (Neat Film, NaCl) 3318, 3029, 2924, 2365, 1487, 1455, 1312, 1218, 1112, 1038, 833, 763, 748, 699 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C22H22NO [M+H]+: 316.1696, found 316.1686; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 4.08, minor = 5.18. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 117 OMe NH OH 163d ((1S,3R)-3-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163d): Compound 163d was prepared from isoquinoline 162d using general procedure 5 and purified by column chromatography (50% to 60% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (40 mg, 75% yield) (dr = 13.3:1); 92% ee for major diastereomer; [α]D25 +69.3 (c 1.01, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.36 (m, 2H), 7.24 – 7.15 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H), 6.94 – 6.90 (m, 2H), 4.41 – 4.39 (m, 1H), 4.07 – 3.97 (m, 2H), 3.86 (dd, J = 10.9, 5.9 Hz, 1H), 3.83 (s, 3H), 3.06 – 2.95 (m, 1H), 2.86 (dd, J = 15.7, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 136.6, 136.3, 134.8, 129.2, 127.8, 126.6, 126.3, 125.3, 114.0, 66.5, 58.6, 57.0, 55.4, 38.8; IR (Neat Film, NaCl) 3342, 2929, 2835, 1612, 1514, 1494, 1453, 1302, 1250, 1176, 1108, 1036, 824, 801, 743 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H20NO2 [M+H]+: 270.1489, found 270.1486; SFC Conditions: 45% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.59, minor = 3.61. F NH OH 163e ((1S,3R)-3-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163e): Compound 163e was prepared from isoquinoline 162e using general procedure 5 and Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 118 purified by column chromatography (40% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (51 mg, 99% yield) (dr = 10.1:1); 93% ee for major diastereomer; [α]D25 +79.2 (c 1.00, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.24 – 7.18 (m, 3H), 7.12 (d, J = 6.9 Hz, 1H), 7.08 – 7.04 (m, 2H), 4.42 – 4.40 (m, 1H), 4.08 (dd, J = 11.0, 3.5 Hz, 1H), 4.02 (dd, J = 10.8, 3.3 Hz, 1H), 3.88 (dd, J = 10.9, 5.5 Hz, 1H), 3.03 – 2.91 (m, 1H), 2.87 (dd, J = 15.7, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.3 (d, J = 245.5 Hz), 140.0 (d, J = 3.0 Hz), 136.4, 134.8, 129.3, 128.4 (d, J = 7.9 Hz), 126.6 (d, J = 19.9 Hz), 125.5, 115.5 (d, J = 21.2 Hz), 66.7, 58.6, 57.1, 39.1; 19F NMR (282 MHz, CDCl3) δ –115.0 – –115.1 (m); IR (Neat Film, NaCl) 3310, 3069, 2924, 2828, 1605, 1511, 1494, 1454, 1225, 1158, 1063, 1040, 844, 826, 744 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H17FNO [M+H]+: 258.1289, found 258.1286; SFC Conditions: 45% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 1.93, minor = 2.87. CF3 NH OH 163f ((1S,3R)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163f): Compound 163f was prepared from isoquinoline 162f using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a yellow solid as a mixture of diastereomers (49 mg, 80% yield) (dr = 4.6:1); 92% ee for major diastereomer; [α]D25 +35.5 (c 1.01, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.55 (m, 2H, integration overlapped with minor diastereomer), 7.51 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 119 (d, J = 8.3 Hz, 2H), 7.18 – 7.10 (m, 3H), 7.10 – 7.03 (m, 1H), 4.36 – 4.34 (m, 1H), 4.08 (dd, J = 10.6, 4.0 Hz, 1H), 3.97 (dd, J = 10.8, 3.3 Hz, 1H), 3.81 (dd, J = 10.9, 5.8 Hz, 1H), 2.95 – 2.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1, 135.9, 134.6, 129.1, 127.1, 127.0, 126.9, 126.7, 126.7, 126.6, 126.5, 125.7 – 125.5 (m), 125.4, 66.6, 58.4, 57.3, 38.8; 19 F NMR (282 MHz, CDCl3) δ –115.1 (qd, J = 8.7, 5.6 Hz); IR (Neat Film, NaCl) 3304, 2917, 1621, 1418, 1325, 1166, 1123, 1068, 1018, 844, 745 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H17F3NO [M+H]+: 308.1257, found 308.1265; SFC Conditions: 25% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.11 minor = 5.54. CN NH OH 163g 4-((1S,3R)-1-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)benzonitrile (163g): Compound 163g was prepared from isoquinoline 162g using general procedure 5 and purified by column chromatography (30% EtOAc in CH2Cl2 + 1% NEt3) to provide a pale tan solid as a mixture of diastereomers (44 mg, 83% yield) (dr = 2.4:1); 82% ee for major diastereomer; [α]D25 +57.4 (c 1.00, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.66 (m, 2H), 7.60 – 7.57 (m, 2H), 7.26 – 7.17 (m, 3H, integration overlapped with minor diastereomer), 7.16 – 7.12 (m, 1H), 4.43 – 4.41 (m, 1H), 4.16 (dd, J = 10.0, 4.6 Hz, 1H), 4.06 (dd, J = 10.9, 3.3 Hz, 1H), 3.89 (dd, J = 10.9, 5.8 Hz, 1H), 2.99 – 2.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 149.6, 135.7, 134.5, 132.6, 129.2, 127.6, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 120 126.9, 126.8, 125.5, 118.9, 111.5, 66.7, 58.5, 57.4, 38.8; IR (Neat Film, NaCl) 3314, 3060, 2925, 2227, 1608, 1494, 1454, 1311, 1115, 1040, 910, 846, 826, 780, 740 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H17N2O [M+H]+: 265.1335, found 265.1336; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.03, minor = 3.33. NO2 NH OH 163h ((1S,3R)-3-(3-nitrophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163h): Compound 163h was prepared from isoquinoline 162h using general procedure 5 and purified by column chromatography (0% to 2% MeOH in CH2Cl2) to provide a pale yellow solid as a mixture of diastereomers (44 mg, 78% yield) (dr = 3.2:1); 86% ee for major diastereomer; [α]D25 +54.4 (c 1.02, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.62 – 7.47 (m, 1H), 7.25 – 7.07 (m, 4H, integration overlapped with minor diastereomer), 4.43 – 4.41 (m, 1H), 4.20 (dd, J = 9.2, 5.4 Hz, 1H), 4.07 (dd, J = 10.9, 3.2 Hz, 1H), 3.91 – 3.83 (m, 1H), 3.15 – 3.02 (m, 1H), 2.98 – 2.91 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.7, 146.5, 135.7, 134.6, 133.2, 129.8, 129.4, 127.0, 126.9, 125.6, 122.9, 122.0, 66.8, 58.7, 57.2, 38.9; IR (Neat Film, NaCl) 3388, 2924, 1635, 1531, 1495, 1454, 1350, 1220, 1117, 1038, 802, 781, 748, 738, 682 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H17N2O3 [M+H]+: Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 121 285.1234, found 285.1234; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.45, minor = 3.23. F F F NH OH 163i ((1S,3R)-3-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163i): Compound 163i was prepared from isoquinoline 162i using general procedure 5 and purified by column chromatography (5% to 10% EtOAc in CH2Cl2 + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (55 mg, 94% yield) (dr = 3.5:1); 89% ee for major diastereomer; [α]D25 +61.6 (c 1.02, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.18 (m, 2H, integration overlapped with minor diastereomer), 7.16 – 7.08 (m, 4H), 4.40 – 4.38 (m, 1H), 4.09 – 4.00 (m, 2H), 3.87 (dd, J = 10.9, 5.9 Hz, 1H), 2.88 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 157.0, 151.4 (ddd, J = 250.1, 9.8, 3.6 Hz), 139.0 (dt, J = 250.9, 15.6 Hz), 135.5, 134.4, 129.2, 127.0, 126.8, 125.5, 110.9 – 110.6 (m), 66.7, 58.5, 56.2, 38.8; 19F NMR (282 MHz, CDCl3) δ – 133.6 – –134.4 (m), –161.8 – –162.0 (m); IR (Neat Film, NaCl) 3307, 2928, 1621, 1532, 1454, 1372, 1340, 1235, 1043, 866, 804, 748, 698 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H15F3NO [M+H]+: 294.1100, found 294.1095; SFC Conditions: 40% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 1.67, minor = 2.20. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 122 NH OH 163j ((1S,3R)-3-(naphthalen-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163j): Compound 163j was prepared from isoquinoline 162j using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a single diastereomer (49 mg, 80% yield); 95% ee; [α]D25 +90.7 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.88 – 7.84 (m, 3H), 7.60 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.28 – 7.20 (m, 3H), 7.15 (d, J = 6.8 Hz, 1H), 4.48 – 4.46 (m, 1H), 4.27 (dd, J = 11.1, 3.5 Hz, 1H), 4.06 (dd, J = 10.9, 3.3 Hz, 1H), 3.94 (dd, J = 10.8, 5.4 Hz, 1H), 3.14 – 3.07 (m, 1H), 2.98 (dd, J = 15.7, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.8, 136.7, 135.1, 133.7, 133.2, 129.4, 128.6, 128.1, 127.9, 126.9, 126.7, 126.4, 126.1, 125.6, 125.3, 66.8, 58.8, 57.9, 39.1; IR (Neat Film, NaCl) 3056, 2917, 2356, 1602, 1494, 1454, 1425, 1366, 1314, 1276, 1112, 1047, 862, 820, 743 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H20NO [M+H]+: 290.1539, found 290.1540; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.61, minor = 5.81. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 123 Me Me NH OH 163k ((1S,3R)-3-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163k): Compound 163k was prepared from isoquinoline 162k using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a single diastereomer (49 mg, 80% yield); 92% ee; [α]D25 +93.5 (c 0.98, CHCl3): 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.16 (m, 3H), 7.12 (d, J = 6.5 Hz, 1H), 7.07 (s, 2H), 6.95 (s, 1H), 4.41 – 4.39 (m, 1H), 4.02 (dd, J = 10.9, 3.3 Hz, 2H), 3.90 (dd, J = 10.8, 5.4 Hz, 1H), 3.04 – 3.00 (m, 1H), 2.88 (dd, J = 15.8, 3.4 Hz, 1H), 2.34 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 144.2, 138.3, 136.8, 135.0, 129.3, 126.7, 126.4, 125.4, 124.6, 66.6, 58.7, 57.6, 38.9, 21.5; IR (Neat Film, NaCl) 3318, 3014, 2916, 1607, 1494, 1454, 1313, 1117, 1038, 854, 782, 746, 725 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H22NO [M+H]+: 268.1696, found 268.1702; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 1.95, minor = 3.02. OMe OMe NH OH 163l ((1S,3R)-3-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163l): Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 124 Compound 163l was prepared from isoquinoline 162l using general procedure 5 and purified by column chromatography (1% MeOH in CH2Cl2 + 1% NEt3) to provide a pale yellow solid as a single diastereomer (49 mg, 80% yield); 88% ee; [α]D25 +62.4 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.16 (m, 3H), 7.12 (d, J = 6.7 Hz, 1H), 7.04 – 6.94 (m, 2H), 6.87 – 6.84 (m, 1H), 4.38 – 4.36 (m, 1H), 4.01 (dt, J = 11.2, 4.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84 (dd, J = 11.0, 6.0 Hz, 1H), 3.08 – 3.00 (m, 1H), 2.87 (dd, J = 15.8, 3.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.2, 148.5, 136.5, 136.4, 134.6, 129.3, 126.7, 126.4, 125.3, 119.0, 111.2, 110.0, 66.3, 58.8, 57.6, 56.1, 38.7; IR (Neat Film, NaCl) 3332, 2934, 2832, 1593, 1518, 1494, 1454, 1264, 1238, 1141, 1028, 745, 720 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H22NO3 [M+H]+: 300.1594, found 300.1600; SFC Conditions: 45% IPA, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.28, minor = 2.93. NH Me OH 163m ((1S,3R)-3-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163m): Compound 163m was prepared from isoquinoline 162m using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid as a mixture of diastereomers (49 mg, 80% yield) (dr = 10.1:1); 49% ee from major diastereomer; [α]D25 +53.7 (c 1.01, CHCl3): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.1 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.26 – 7.17 (m, 5H), 7.14 (d, J = 7.3 Hz, 1H), 4.44 – 4.42 (m, 1H), 4.32 (dd, J = 10.9, 3.5 Hz, 1H), 4.04 (dd, J = 10.8, 3.2 Hz, 1H), 3.92 (dd, J = 10.8, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 125 5.3 Hz, 1H), 3.03 – 2.92 (m, 1H), 2.88 (dd, J = 15.8, 3.5 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.2, 136.9, 135.2, 135.0, 130.6, 129.4, 127.3, 126.7, 126.5, 125.6, 125.5, 66.6, 58.9, 53.4, 37.7, 19.5; IR (Neat Film, NaCl) 3318, 3022, 2925, 2354, 1492, 1454, 1316, 1117, 1037, 864, 751, 743, 727 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H20NO [M+H]+: 254.1539, found 254.1539; SFC Conditions: 30% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.91, minor = 6.39. O NH OH 163n ((1S,3R)-3-(furan-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163n): Compound 163n was prepared from isoquinoline 162n using general procedure 5 and purified by column chromatography (40% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (34 mg, 74% yield) (dr = 3.3:1); 92% ee for major diastereomer; [α]D25 +35.5 (c 1.00, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.39 (m, 1H), 7.24 – 7.14 (m, 4H, integration overlapped with minor diastereomer), 6.37 (dd, J = 3.3, 1.9 Hz, 1H), 6.28 (d, J = 3.2 Hz, 1H), 4.37 – 4.35 (m, 1H), 4.20 (dd, J = 11.0, 3.7 Hz, 1H), 4.03 (dd, J = 11.0, 3.3 Hz, 1H), 3.86 – 3.75 (m, 1H), 3.18 – 3.05 (m, 1H), 3.05 – 2.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 141.8, 135.5, 134.7, 129.4, 126.9, 126.7, 126.5, 125.3, 110.2, 105.3, 66.2, 57.9, 50.7, 34.5; IR (Neat Film, NaCl) 3304, 2920, 1495, 1454, 1316, 1146, 1114, 1062, 1037, 1009, 883, 740 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H16NO2 [M+H]+: 230.1176, found 230.1181; SFC Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 126 Conditions: 35% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): major = 1.52, minor = 1.82. S NH OH 163o ((1S,3R)-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163o): Compound 163o was prepared from isoquinoline 162o using general procedure 5 and purified by column chromatography (40% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid as a mixture of diastereomers (46 mg, 94% yield) (dr = 3.6:1); 90% ee for major diastereomer; [α]D25 +57.4 (c 1.04, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 1H), 7.28 – 7.21 (m, 3H, integration overlapped with minor diastereomer), 7.19 – 7.15 (m, 1H), 7.11 – 7.09 (m, 1H), 7.07 – 7.04 (m, 1H), 4.47 – 4.42 (m, 2H), 4.06 (dd, J = 10.9, 3.4 Hz, 1H), 3.87 (dd, J = 11.0, 5.9 Hz, 1H), 3.19 – 2.98 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1, 135.8, 134.7, 129.1, 126.7, 126.7, 126.6, 125.3, 124.2, 123.5, 66.4, 58.5, 53.1, 39.3; IR (Neat Film, NaCl) 3312, 2923, 2360, 1494, 1454, 1424, 1310, 1280, 1112, 1038, 850, 830, 744, 704 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H16NOS [M+H]+: 246.0947, found 246.0941; SFC Conditions: 35% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): major = 2.86, minor = 6.02. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 127 S NH OH 163p ((1S,3R)-3-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163p): Compound 163p was prepared from isoquinoline 162p using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid as a mixture of diastereomers (25.5 mg, 52% yield) (dr = 7.3:1). The isolated product contained long-chain hydrocarbon impurities, so it was repurified by partitioning between acetonitrile and hexanes. The acetonitrile layer was collected and concentrated to afford 163p as a pale yellow solid (24.0 mg, 49% yield); 89% ee for major diastereomer; [α]D25 +86.8 (c 0.99, CHCl3): 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 4.9, 3.0 Hz, 1H), 7.18 – 7.16 (m, 1H), 7.13 – 7.07 (m, 4H), 7.05 – 7.02 (m, 1H), 4.28 – 4.26 (m, 1H), 4.10 (dd, J = 10.8, 3.8 Hz, 1H), 3.93 (dd, J = 10.9, 3.4 Hz, 1H), 3.73 (dd, J = 11.0, 6.1 Hz, 1H), 2.99 – 2.90 (m, 1H), 2.86 (dd, J = 15.8, 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.3, 136.2, 134.9, 129.3, 126.7, 126.5, 126.5, 126.2, 125.3, 120.9, 66.3, 58.5, 53.3, 38.1; IR (Neat Film, NaCl) 3318, 2924, 2366, 1494, 1454, 1424, 1313, 1279, 1218, 1116, 1038, 854, 782, 748 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H16NOS [M+H]+: 246.0947, found 246.0952; SFC Conditions: 35% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.19, minor = 4.05. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 128 Me N N NH OH 163q ((1S,3R)-3-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163q): Compound 163q was prepared from isoquinoline 162q using general procedure 5 and purified by column chromatography (5% to 10% MeOH in EtOAc + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (48 mg, 98% yield) (dr = 2.9:1); 87% ee for major diastereomer; [α]D25 +37.1 (c 1.021, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.61 (m, 2H), 7.26 – 7.16 (m, 2H, integration overlapped with minor diastereomer), 7.19 – 7.06 (m, 2H), 4.50 – 4.98 (m, 1H), 4.20 (dd, J = 11.8, 3.3 Hz, 1H), 4.02 (dd, J = 11.6, 3.3 Hz, 1H), 3.84 (s, 3H), 3.34 – 3.22 (m, 1H), 3.13 – 2.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 138.2, 134.7, 132.2, 129.3, 129.2, 127.2, 126.9, 125.4, 121.5, 64.6, 58.6, 49.1, 39.0, 36.1; IR (Neat Film, NaCl) 3315, 2931, 2371, 1560, 1494, 1455, 1408, 1295, 1169, 1031, 1008, 986, 748, 724 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C14H18N3O [M+H]+: 244.1444, found 244.1448; SFC Conditions: 25% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): minor = 1.84, major = 2.60. N NH OH 163r ((1S,3R)-3-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (163r): Compound 163r was prepared from isoquinoline 162r using general procedure 5 and Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 129 purified using reverse-phase (C18) preparative-HPLC (MeCN/0.4% acetic acid in water, 5.0 mL/min, monitor wavelength = 255 nm, 5–23% MeCN over 6 min, ramp to 95% MeCN over 0.5 min, and hold at 95% for 3.5 min) to provide a tan solid as a mixture of diastereomers (49 mg, 80% yield) (dr = 2.5:1). This compound appears to be unstable and significant decomposition was observed under prolonged storage; 85% ee for major diastereomer; [α]D25 +49.0 (c 1.01, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.60 – 8.57 (m, 1H), 7.72 – 7.67 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.22 – 7.11 (m, 4H, integration overlapped with minor diastereomer), 4.41 – 4.39 (m, 1H), 4.23 – 4.20 (m, 1H, integration overlapped with minor diastereomer), 4.07 (dd, J = 11.1, 3.4 Hz, 1H), 3.85 (dd, J = 11.0, 6.4 Hz, 1H), 3.08 – 3.00 (m, 2H, integration overlapped with minor diastereomer); 13C NMR (100 MHz, CDCl3) δ 162.2, 149.4, 137.0, 136.0, 135.3, 129.4, 126.7, 126.5, 125.4, 122.6, 121.1, 66.4, 58.6, 58.0, 36.5; IR (Neat Film, NaCl) 3300, 3056, 2934, 1592, 1574, 1473, 1454, 1435, 1316, 1142, 1060, 910, 744 cm-1; HRMS (MM:ESIAPCI+) m/z calc’d for C15H17N2O [M+H]+: 241.1335, found 241.1334; SFC Conditions: 30% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 210 nm, tR (min): minor = 2.52, major = 2.79. F NH OH 165a ((1S,3R)-7-fluoro-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (165a): Compound 165a was prepared from isoquinoline 164a using general procedure 5 and purified by column chromatography (30% EtOAc in hexanes + 1% NEt3) to provide a pale Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 130 yellow solid as a mixture of diastereomers (49 mg, 94% yield) (dr = 11.5:1); 93% ee for major diastereomer; [α]D25 +76.9 (c 1.04, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.42 (m, 2H), 7.40 – 7.36 (m, 2H), 7.33 – 7.30 (m, 1H), 7.08 (dd, J = 8.4, 5.8 Hz, 1H), 6.97 – 6.87 (m, 2H), 4.38 – 4.36 (m, 1H), 4.06 (dd, J = 10.8, 3.7 Hz, 1H), 3.99 (dd, J = 10.9, 3.3 Hz, 1H), 3.86 (dd, J = 10.9, 5.2 Hz, 1H), 3.00 – 2.82 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 161.5 (d, J = 243.8 Hz), 144.0, 136.9 (d, J = 6.8 Hz), 132.2 (d, J = 3.0 Hz), 130.6 (d, J = 7.9 Hz), 128.8, 127.8, 126.8, 113.9 (d, J = 21.3 Hz), 112.1 (d, J = 21.8 Hz), 66.4, 58.6 (d, J = 2.1 Hz), 57.7, 38.2; 19F NMR (282 MHz, CDCl3) δ –116.2 – –116.4 (m); IR (Neat Film, NaCl) 3309, 2918, 1614, 1498, 1455, 1428, 1255, 1221, 1031, 911, 868, 808, 758, 745, 700 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H17FNO [M+H]+: 258.1289, found 258.1281; SFC Conditions: 40% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.56, minor = 3.04. OMe F NH OH 165b ((1S,3R)-7-fluoro-3-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (165b): Compound 165b was prepared from isoquinoline 164b using general procedure 5 and purified by column chromatography (30% to 40% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a single diastereomer (57 mg, 99% yield); 90% ee; [α]D25 +57.8 (c 0.99, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.34 (m, 2H), 7.07 (dd, J = 8.4, 5.8 Hz, 1H), 6.97 – 6.84 (m, 4H), 4.36 – 4.34 (m, 1H), 3.99 (ddd, J = 12.3, 10.9, 3.4 Hz, 2H), 3.86 – 3.84 (m, 1H), 3.82 (s, 3H), 2.99 – 2.87 (m, 1H), 2.83 (dd, J = 15.6, 3.5 Hz, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 131 1H); 13C NMR (100 MHz, CDCl3) δ 161.5 (d, J = 243.7 Hz), 159.2, 136.9 (d, J = 6.7 Hz), 136.2, 132.3, 130.6 (d, J = 7.9 Hz), 127.9, 114.1, 113.8 (d, J = 21.3 Hz), 112.1 (d, J = 21.8 Hz), 66.4, 58.7 (d, J = 2.0 Hz), 57.1, 55.5, 38.3; 19F NMR (282 MHz, CDCl3) δ –116.3 – – 116.4 (m); IR (Neat Film, NaCl) 3305, 2930, 2838, 1614, 1591, 1514, 1498, 1304, 1249, 1178, 1111, 1034, 912, 868, 830, 816, 736 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H19FNO2 [M+H]+: 288.1394, found 288.1404; SFC Conditions: 30% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): major = 1.93, minor = 2.42. CF3 F NH OH 165c ((1S,3R)-7-fluoro-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1yl)methanol (165c): Compound 165c was prepared from isoquinoline 164c using general procedure 5 and purified by column chromatography (20% to 30% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (50 mg, 77% yield) (dr = 6.7:1); 94% ee for major diastereomer; [α]D25 +44.2 (c 1.002, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.09 (dd, J = 8.4, 5.7 Hz, 1H), 7.00 – 6.87 (m, 2H), 4.39 – 4.37 (m, 1H), 4.13 (dd, J = 8.9, 5.7 Hz, 1H), 4.02 (dd, J = 10.9, 3.3 Hz, 1H), 3.88 (dd, J = 10.9, 5.4 Hz, 1H), 2.94 – 2.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.6 (d, J = 244.2 Hz), 148.0, 136.7 (d, J = 6.7 Hz), 131.5 (d, J = 3.1 Hz), 130.6 (d, J = 7.9 Hz), 130.1 (q, J = 32.5 Hz), 127.2, 125.7 (q, J = 3.8 Hz), 124.2 (q, J = 272.1 Hz), 114.0 (d, J = 21.3 Hz), 112.1 (d, J = 21.9 Hz) 66.4, 58.5 (d, J = 2.0 Hz), 57.4, 38.2; 19F NMR (282 MHz, CDCl3) δ –62.5, –115.8 – –115.9 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 132 (m); IR (Neat Film, NaCl) 3304, 2922, 1620, 1593, 1500, 1428, 1326, 1255, 1222, 1165, 1125, 1068, 1018, 868, 836, 816 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16F4NO [M+H]+: 326.1163, found 326.1175; SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.93, minor = 4.46. O NH O OH 165d ((5S,7R)-7-phenyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)methanol (165d): Compound 165d was prepared from isoquinoline 164d using general procedure 5 and purified by column chromatography (75% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid as a mixture of diastereomers (17 mg, 30% yield) (dr = 4.9:1); 58% ee for major diastereomer; [α]D25 +29.2 (c 0.940, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.41 (m, 2H), 7.39 – 7.37 (m, 2H), 7.33 – 7.27 (m, 1H), 6.71 (s, 1H), 6.60 – 6.58 (m, 1H), 5.95 – 5.89 (m, 2H), 4.32 – 4.30 (m, 1H), 4.04 (dd, J = 11.1, 3.4 Hz, 1H), 3.93 (dd, J = 10.9, 3.2 Hz, 1H), 3.82 (dd, J = 10.9, 5.1 Hz, 1H), 2.97 – 2.88 (m, 1H), 2.78 (dd, J = 15.5, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 146.5, 146.4, 144.2, 130.0, 128.8, 127.9, 127.7, 126.8, 109.0, 105.5, 101.0, 66.7, 58.6, 57.7, 39.0; IR (Neat Film, NaCl) 3324, 3028, 2897, 1504, 1486, 1454, 1434, 1384, 1306, 1279, 1231, 1128, 1038, 936, 910, 858, 750, 733, 701 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H18NO3 [M+H]+: 284.1281, found 284.1276; SFC Conditions: 45% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.00, minor = 7.22. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 133 OMe OMe O O NH OH 165e ((5S,7R)-7-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin5-yl)methanol (165e): Compound 165e was prepared from isoquinoline 164e using general procedure 5 and purified by column chromatography (100% EtOAc to 10% MeOH in EtOAc + 1% NEt3) to provide a pale yellow solid as a single diastereomer (28 mg, 41% yield); 54% ee; [α]D25 +25.5 (c 0.197, CH3OH); 1H NMR (400 MHz, CDCl3) δ 6.99 – 6.96 (m, 2H), 6.87 – 6.85 (m, 1H), 6.71 (s, 1H), 6.60 – 6.58 (m, 1H), 5.94 – 5.91 (m, 2H), 4.32 – 4.30 (m, 1H), 3.99 (dd, J = 11.1, 3.4 Hz, 1H), 3.94 (dd, J = 11.1, 3.4 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.83 (dd, J = 11.0, 5.0 Hz, 1H), 2.97 – 2.85 (m, 1H), 2.76 (dd, J = 15.6, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.3, 148.7, 146.7, 146.5, 136.9, 130.1, 127.8, 119.0, 111.4, 110.0, 109.1, 105.6, 101.1, 66.7, 58.8, 57.7, 56.2, 39.1; IR (Neat Film, NaCl) 3374, 2890, 2360, 1505, 1487, 1268, 1260, 1237, 1140, 1076, 1024, 971, 932, 918, 730 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H22NO5 [M+H]+: 344.1492, found 344.1483; SFC Conditions: 45% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.89, minor = 5.16. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 134 NH OH 165f ((2R,4S)-2-phenyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)methanol (165f): Compound 165f was prepared from isoquinoline 164f using general procedure 5 and purified by column chromatography (40% to 60% EtOAc in hexanes + 1% NEt3) to provide a pale yellow solid as a mixture of diastereomers (25 mg, 43% yield) (dr = 15.7:1); 82% ee for major diastereomer; [α]D25 +85.7 (c 1.01, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.91 (m, 1H), 7.85 – 7.82 (m, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.50 – 7.47 (m, 2H), 7.45 – 7.34 (m, 4H), 4.61 – 4.59 (m, 1H), 4.20 (dd, J = 11.0, 3.4 Hz, 1H), 4.09 (dd, J = 10.9, 3.2 Hz, 1H), 4.01 (dd, J = 10.9, 4.8 Hz, 1H), 3.50 – 3.39 (m, 1H), 3.23 – 3.10 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 144.4, 132.2, 132.1, 132.0, 131.9, 128.8, 128.4, 127.7, 126.8, 126.7, 126.3, 125.5, 123.4, 122.9, 66.4, 59.1, 57.6, 35.4; IR (Neat Film, NaCl) 3306, 3056, 2918, 1417, 1308, 1034, 910, 884, 813, 762, 700, 736, 682 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H20NO [M+H]+: 290.1539, found 290.1534; SFC Conditions: 45% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.31, minor = 10.01. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 135 NH OAc 167a ((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl acetate (167a): Compound 167a was prepared from isoquinoline 166a using general procedure 5 and purified by column chromatography (5% EtOAc in CH2Cl2 + 1% NEt3) to provide a yellow oil as a single diastereomer (32 mg, 56% yield); 86% ee; [α]D25 +103.8 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.45 (m, 2H), 7.41 – 7.37 (m, 2H), 7.34 – 7.30 (m, 1H), 7.27 – 7.24 (m, 1H), 7.23 – 7.18 (m, 2H), 7.16 – 7.10 (m, 1H), 4.78 (dd, J = 10.8, 3.5 Hz, 1H), 4.54 – 4.51 (m, 1H), 4.14 (dd, J = 10.8, 8.7 Hz, 1H), 4.05 (dd, J = 11.1, 3.4 Hz, 1H), 3.08 – 3.01 (m, 1H), 2.90 (dd, J = 15.5, 3.6 Hz, 1H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1, 144.4, 136.3, 134.1, 129.5, 128.8, 127.7, 126.9, 126.9, 126.3, 125.3, 69.1, 57.9, 56.4, 39.2, 21.2; IR (Neat Film, NaCl) 3024, 2926, 2802, 1741, 1494, 1454, 1386, 1366, 1314, 1229, 1118, 1034, 754, 701 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H20NO2 [M+H]+: 282.1489, found 282.1492; SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): major = 3.32, major = 3.93. NH OMe 167b (1S,3R)-1-(methoxymethyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167b): Compound 167b was prepared from isoquinoline 166b using general procedure 5 and Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 136 purified by column chromatography (10% EtOAc in CH2Cl2+ 1% NEt3) to provide a viscous yellow oil as a single diastereomer (40 mg, 80% yield); 89% ee; [α]D25 +94.3 (c 0.98, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.46 (m, 2H), 7.39 – 7.35 (m, 2H), 7.32 – 7.27 (m, 1H), 7.25 – 7.20 (m, 1H), 7.20 – 7.15 (m, 2H), 7.16 – 7.10 (m, 1H), 4.45 – 4.42 (m, 1H), 4.07 – 3.94 (m, 2H), 3.59 (t, J = 8.7 Hz, 1H), 3.43 (s, 3H), 3.06 (dd, J = 16.0, 11.1 Hz, 1H), 2.92 (dd, J = 16.0, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.5, 136.3, 135.4, 129.5, 128.7, 127.5, 126.9, 126.6, 126.1, 124.8, 59.3, 58.1, 57.4, 39.0; IR (Neat Film, NaCl) 3028, 2895, 2812, 1604, 1494, 1454, 1313, 1194, 1112, 1072, 1030, 958, 923, 840, 744, 700 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H20NO [M+H]+: 254.1539, found 254.1531; SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 210 nm, tR (min): major = 4.82, major = 5.25. NH OBn 167c (1S,3R)-1-((benzyloxy)methyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167c): Compound 167c was prepared from isoquinoline 166c using general procedure 5 and purified by column chromatography (5% EtOAc in CH2Cl2 + 1% NEt3) to provide a pale yellow oil as a single diastereomer (60 mg, 90% yield); 88% ee; [α]D25 +80.4 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.46 (m, 2H), 7.40 – 7.34 (m, 6H), 7.32 – 7.28 (m, 2H), 7.22 – 7.16 (m, 3H), 7.14 – 7.11 (m, 1H), 4.61 (s, 2H), 4.48 (dd, J = 8.7, 3.4 Hz, 1H), 4.12 (dd, J = 9.0, 3.6 Hz, 1H), 4.04 (dd, J = 11.1, 3.5 Hz, 1H), 3.67 (t, J = 8.7 Hz, 1H), 3.05 (dd, J = 15.9, 11.1 Hz, 1H), 2.91 (dd, J = 15.8, 3.5 Hz, 1H); 13C NMR (100 MHz, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 137 CDCl3) δ 144.6, 138.3, 136.3, 135.3, 129.5, 128.7, 128.6, 127.9, 127.8, 127.5, 126.9, 126.6, 126.1, 124.9, 74.8, 73.6, 58.1, 57.5, 39.2; IR (Neat Film, NaCl) 3060, 3028, 2862, 1494, 1454, 1366, 1312, 1098, 1028, 742, 698 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C23H24NO [M+H]+: 330.1852, found 330.1857; SFC Conditions: 25% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 210 nm, tR (min): major = 5.66, major = 6.38. NH NHBoc 167d tert-butyl (((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)carbamate (167d): Compound 167d was prepared from isoquinoline 166d using general procedure 5 and purified by column chromatography (15% EtOAc in hexanes + 1% NEt3) to provide a white solid as a mixture of diastereomers (44 mg, 71% yield) (dr = 9.0:1); 90% ee for major diastereomer; [α]D25 +50.4 (c 0.99, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.1 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.36 – 7.26 (m, 2H), 7.26 – 7.14 (m, 2H), 7.11 (d, J = 6.7 Hz, 1H), 5.02 (s, 1H), 4.44 (s, 1H), 4.04 (dd, J = 11.0, 3.5 Hz, 1H), 3.77 – 3.72 (m, 1H), 3.49 (dt, J = 13.2, 6.3 Hz, 1H), 3.00 (dd, J = 15.8, 10.9 Hz, 1H), 2.89 (dd, J = 15.8, 3.5 Hz, 1H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.4, 144.4, 136.4, 135.2, 129.2, 128.7, 127.7, 126.8, 126.6, 126.4, 125.7, 79.4, 58.0, 57.1, 46.3, 39.1, 28.5; IR (Neat Film, NaCl) 3352, 2978, 2932, 1704, 1495, 1455, 1392, 1366, 1247, 1171, 752, 701 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H27N2O2 [M+H]+: 339.2067, found 339.2063; SFC Conditions: 40% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 1.41, major = 1.76. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 138 NH Me 167e (1R,3R)-1-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167e): Compound 167e was prepared from 1-methyl-3-phenylisoquinoline 161a using general procedure 5 and purified by column chromatography (10% to 20% EtOAc in hexanes + 1% NEt3) to provide a colorless oil as a single diastereomer (29 mg, 64% yield); 90% ee; [α]D25 +133.3 (c 0.79, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.46 (m, 2H), 7.41 – 7.37 (m, 2H), 7.33 – 7.29 (m, 1H), 7.28 – 7.23 (m, 1H), 7.23 – 7.14 (m, 2H), 7.11 (d, J = 6.9 Hz, 1H), 4.34 (q, J = 6.6 Hz, 1H), 4.08 (dd, J = 11.1, 3.9 Hz, 1H), 3.12 – 3.01 (m, 1H), 2.96 (dd, J = 16.2, 4.1 Hz, 1H), 1.55 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 139.9, 135.2, 129.1, 128.7, 127.5, 126.7, 126.2, 126.2, 125.4, 58.8, 53.6, 38.9, 22.4; IR (Neat Film, NaCl) 3024, 2962, 2926, 2792, 1602, 1494, 1453, 1372, 1352, 1306, 1140, 1118, 1031, 790, 753, 733, 700 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H18N [M+H]+: 224.1434, found 224.1426; SFC Conditions: 20% IPA, 3.5 mL/min, Chiralpak AS-H column, λ = 210 nm, tR (min): major = 2.16, minor = 2.62. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 2.7.2.4 139 Product transformations OMe OMe OMe OMe CH2O (aq) NH OH 163l N DCE, 23 °C 93% yield H O 168 (5R,10bS)-5-(3,4-dimethoxyphenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinoline (168): To a 1-dram vial equipped with a stir bar was added tetrahydroisoquinoline 163l (20.0 mg, 0.067 mmol) in 1,2-dichloroethane (1.3 mL, 0.05 M). Formaldehyde solution (37 wt% in H2O, 9.2 µL, 0.124 mmol) was then added and the reaction was stirred for 15 minutes at room temperature. The reaction was then basified with K2CO3, and extracted with CH2Cl2. The collected organic layers were dried over Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography (50% EtOAc in hexanes + 1% NEt3) to afford 168 as a white solid (19.3 mg, 93% yield): [α]D25 +134.8 (c 1.03, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.14 (m, 3H), 7.04 (d, J = 2.0 Hz, 1H), 7.02 – 6.90 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 4.58 – 4.43 (m, 2H), 3.97 (t, J = 7.6 Hz, 1H), 3.94 – 3.87 (m, 2H), 3.89 (s, 6H), 3.83 (dd, J = 10.6, 4.8 Hz, 1H), 3.23 (dd, J = 16.8, 10.6 Hz, 1H), 3.11 (dd, J = 16.8, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.4, 148.7, 135.1, 134.7, 134.6, 128.6, 127.2, 126.3, 125.0, 119.6, 110.9, 110.2, 84.2, 71.5, 62.9, 61.3, 56.1, 56.0, 37.3; IR (Neat Film, NaCl) 2930, 1592, 1513, 1454, 1263, 1237, 1167, 1060, 1027, 918, 752, 680 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H22NO3 [M+H]+: 312.1594, found 312.1594. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines OMe 140 OMe OMe OMe CDI (4 equiv) NH OH 163l THF, 50 °C 15 h 84% yield N H O O 169 (5R,10bS)-5-(3,4-dimethoxyphenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinolin-3-one (169): To a 1-dram vial equipped with a stir bar was added tetrahydroisoquinoline 163l (10.0 mg, 0.033 mmol), THF (0.7 mL, 0.05 M), and CDI (21.7 mg, 0.134 mmol). The solution was stirred at 50 °C for 15 h. After complete conversion of the starting material monitored by TLC, the reaction concentrated and the crude product was purified by preparative-TLC (100% EtOAc) to afford 169 as a white solid (9.2 mg, 84% yield): [α]D25 +71.4 (c 0.76, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.3, 7.0 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.08 (t, J = 6.6 Hz, 2H), 6.66 (d, J = 8.2 Hz, 1H), 6.52 (dd, J = 8.2, 2.1 Hz, 1H), 6.33 (d, J = 2.1 Hz, 1H), 5.14 – 5.02 (m, 2H), 4.92 (t, J = 7.9 Hz, 1H), 4.49 (dd, J = 10.1, 8.2 Hz, 1H), 3.78 (s, 3H), 3.60 (s, 3H), 3.36 (dd, J = 14.9, 6.4 Hz, 1H), 2.99 (dd, J = 14.9, 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 156.1, 148.7, 148.3, 136.0, 134.2, 133.9, 129.4, 128.5, 127.5, 122.4, 118.5, 110.9, 109.3, 67.5, 55.9, 55.6, 54.6, 53.4, 36.8; IR (Neat Film, NaCl) 2933, 1756, 1515, 1464, 1396, 1260, 1234, 1139, 1025, 779, 762, 748 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H20NO4 [M+H]+: 326.1387, found 326.1386. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines OMe 141 OMe OMe OMe glyoxal (aq) NH OH N DCE, 23 °C 41% yield 163l H O O 170 (6R,11bS)-6-(3,4-dimethoxyphenyl)-1,6,7,11b-tetrahydro-[1,4]oxazino[3,4a]isoquinolin-3(4H)-one (170): To a 1-dram vial equipped with a stir bar was added tetrahydroisoquinoline 163l (20.0 mg, 0.067 mmol) in 1,2-dichloroethane (1.3 mL, 0.05 M). Glyoxal solution (40 wt% in H2O, 0.15 mL, 1.336 mmol) was then added, and the reaction was stirred at room temperature overnight. After complete conversion of the starting material monitored by TLC, the reaction was diluted with H2O, and extracted with CH2Cl2. The collected organic layers were dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative-TLC (50% EtOAc in hexanes) to afford 170 as a white solid (9.2 mg, 41% yield): [α]D25 +187.8 (c 0.61, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.20 (m, 2H), 7.20 – 7.10 (m, 2H), 6.95 – 6.81 (m, 3H), 4.84 (dd, J = 10.5, 3.4 Hz, 1H), 4.33 (t, J = 10.7 Hz, 1H), 4.04 – 3.94 (m, 1H), 3.90 (s, 6H), 3.62 (d, J = 17.7 Hz, 1H), 3.43 (dd, J = 11.2, 3.2 Hz, 1H), 3.32 – 3.19 (m, 1H), 2.98 – 2.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.7, 149.8, 149.1, 135.0, 132.8, 130.6, 129.1, 127.7, 126.7, 124.7, 120.5, 111.4, 110.2, 73.3, 63.8, 59.5, 56.1, 56.1, 54.9, 38.9; IR (Neat Film, NaCl) 2932, 1745, 1511, 1463, 1421, 1263, 1242, 1137, 1028, 809, 746 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H22NO4 [M+H]+: 340.1543, found 340.1545. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines OMe 142 OMe OMe OMe 1. 60% aq. 2,2-dimethoxyacetaldehyde DCE, 23 °C, 18 h H 2. Eaton’s Reagent CH2Cl2, 23 °C, 3 h N NH H 38% yield over 2 steps OH O H OH 171 163l (4bS,6aS,7S,11bR)-9,10-dimethoxy-4b,5,6a,7,11b,12hexahydrodibenzo[a,g]oxazolo[2,3,4-de]quinolizin-7-ol (171): To a 1-dram vial equipped with a stir bar was added tetrahydroisoquinoline 163l (10.0 mg, 0.033 mmol) in 1,2-dichloroethane (0.5 mL, 0.07 M). 2,2- Dimethoxyacetaldehyde solution (60 wt% in H2O, 9.2 µL, 0.061 mmol) was then added and the reaction stirred at room temperature overnight. The reaction was then concentrated under vacuum to afford a yellow oil, which was then used in the next step without further purification. To a 1-dram vial was added the crude product and CH2Cl2 (0.5 mL, 0.07 M). Eaton’s reagent (0.28 mL, 0.134 mmol) was then added dropwise, and the reaction was stirred for 3 hours. The reaction was then quenched by slow addition of saturated aqueous NaHCO3, diluted with H2O and extracted with CH2Cl2. The collected organic phases were dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative-TLC (100% EtOAc) twice to afford 171 as a white solid as a single diastereomer (4.3 mg, 38% yield over 2 steps): [α]D25 +32.0 (c 0.29, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 1H), 7.24 – 7.20 (m, 1H), 7.16 (d, J = 6.0 Hz, 1H), 7.08 (d, J = 6.8 Hz, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 4.89 – 4.82 (m, 1H), 4.79 (t, J = 7.8 Hz, 1H), 4.71 (dd, J = 8.3, 2.1 Hz, 1H), 4.65 (d, J = 2.1 Hz, 1H), 4.47 (dd, J = 9.1, 7.0 Hz, 1H), 3.93 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 143 (s, 3H), 3.91 (s, 3H), 3.86 (dd, J = 7.9, 5.3 Hz, 1H), 2.89 – 2.87 (m, 2H), 2.79 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 149.4, 148.6, 136.5, 133.1, 130.9, 129.3, 127.3, 127.3, 126.8, 126.6, 113.6, 109.2, 86.7, 74.4, 67.9, 57.3, 56.2, 56.1, 54.2, 31.1; IR (Neat Film, NaCl) 3442, 2918, 1610, 1515, 1464, 1380, 1353, 1270, 1242, 1160, 1117, 1074, 1010, 868, 762, 732, 642 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C20H22NO4 [M+H]+: 340.1543, found 340.1548. The stereochemistry of 171 was assigned using diagnostic nOe correlations (highlighted arrows, vide infra). Due to the ambiguous nOe correlations observed in 171, the stereochemistry was determined by derivatizing the hydroxyl group of 171 to the methoxy group. 2.7 2.8 2.9 3.0 3.1 3.2 3.3 Hb–Hc 3.4 Hc–He 3.5 3.6 OMe 3.7 OMe 3.9 Ha He–Hf Ha–Hb 4.0 nOe Hc 4.1 Hf N Hb 3.8 OMe O He 4.2 4.3 nOe 4.4 4.5 Hd 4.6 4.7 4.8 nOe 4.9 171•Me 5.2 5.0 4.8 4.6 4.4 4.2 4.0 ppm 3.8 3.6 3.4 2D NOESY NMR of compound 171•Me. 3.2 3.0 5.0 2.8 f1 (ppm) nOe Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 2.7.3 144 Additional optimization results Table 2.2. Additional ligand screen. Ph N NH H2 (60 bar), TBAI (7.5 mol %) 9:1 PhMe: AcOH (0.02 M), 60 °C OH OH F O F O PPh2 F O PPh2 F O PPh2 (xyl)2P Me Ph Ir(cod)Cl (2.5 mol %) ligand (3.0 mol %) P(Cy)2 P(BTFM)2 Fe SL-J008-2 > 95% conversion 86% yield, 49% ee P(Ph)2 Fe P(Ph)2 Fe Me Me Walphos (SL-002-1) 23% conversion 9% yield, ee ND SL-J004-1 56% conversion 37% yield, –61% ee PPh2 PPh2 59% conversion 59% yield, –61% ee 36% conversion 23% yield, 19% ee OMe O O CF3 N O PPh2 O PPh2 MeO PPh2 O PPh2 O PPh2 O PPh2 MeO PPh2 O PPh2 O N O O N (CF3Ph)2P t-Bu OMe 50% conversion 20% yield, ee ND 15% conversion 16% yield, ee ND 59% conversion 46% yield, –41% ee 50% conversion 20% yield, ee ND 65% conversion 71% yield, 2% ee Et CF3 CF3 P(Ph)2 P O Me2N P(Ph)2 Fe Fe Et Et P (C6F5)2P >95% conversion 80% yield, –40% ee >62% conversion 48% yield, –44% ee 55% conversion 39% yield, –4% ee F3C N (CF3FPh)2P N HN PAr2 Ar2P CF3 t-Bu t-Bu Et O NH O O 74% conversion 46% yield, 5% ee 0% conversion 0% yield, ee ND P(Ph)2 Me Me2N P(Ph)2 Fe (Ph)2P Ph PPh2 Me PPh2 Me Me O PPh2 O PPh2 PPh2 (R, R)-chiralphos 78% conversion 57% yield, –37% ee P(t-Bu)2 Fe Me SL-J013-1 0% conversion 0% yield P(DMM-Ph)2 Fe Norphos 31% conversion 20% yield, ee ND P(Cy)2 O SL-J007-1 16% conversion 6% yield, ee ND P Me PPh2 (R, R)-DIOP 37% conversion 28% yield, 5% ee Me Me P NMe2 SL-M001-2 > 61% conversion 51% yield, 49% ee P(DMM-Ph)2 Me O P N Monophos 42% conversion 29% yield, 5% ee Me Me-BPE 22% conversion 10% yield, ee ND PPh2 PPh2 PhanePhos 67% conversion 74% yield, –19% ee Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 145 Table 2.3. Additive effects in Ir-catalyzed enantio- and diastereoselective hydrogenation.a Ph N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (60 bar), salt (7.5 mol %) OH 9:1 THF:acid (0.02 M) 60 °C Ph P(DMM)2 NH OH 162a salt additive acid % conversionb Me L7: SL-J418-1 163a entry P(Xyl)2 Fe cis:transb % ee of cisc 1 TBAI AcOH >95 10:1 89 2 LiI AcOH >95 10:1 89 90 3 NaI AcOH >95 10:1 4 KI AcOH 92 10:1 87 5 TBACl AcOH >95 1:1.2 31 6 TBABr AcOH >95 1.2:1 63 7 none AcOH 50 1:1 27 8 TBAI none 31 ND 67 9 TBAI TFA >95 10:1 90 10 TBAI (n-BuO)2PO2H >95 7:1 84 [a] Reaction conditions: 0.04 mmol of 162a, 1.25 mol % [Ir(cod)Cl]2, 3 mol % ligand, 7.5 mol % TBAI, 60 bar H2 in 2.0 mL 9:1 solvent:AcOH. [b] Determined by crude 1H NMR using 1,3,5trimethoxybenzene as a standard. [c] Determined by chiral SFC analysis of Cbz-protected product. 2.7.4 Determination of enantiomeric excess Table 2.4. Determination of enantiomeric excess. entry 1 compound NCbz SFC analytic conditions ee (%) Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 2.34, minor 4.02 92 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 1.81, minor 2.73 91 OH 163a-Cbz 2 NCbz OH 163b-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 146 SFC analytic conditions ee (%) Chiracel AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 4.08, minor 5.18 92 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 2.5 mL/min tR (min) major 2.59, minor 3.61 92 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 2.5 mL/min tR (min) major 1.93, minor 2.87 93 Chiralpak AD-H, λ = 210 nm 25% IPA/CO2, 2.5 mL/min tR (min) major 3.11, minor 5.54 92 Ph 3 NCbz OH 163c-Cbz OMe 4 NCbz OH 163d-Cbz F 5 NCbz OH 163e-Cbz CF3 6 NCbz OH 163f-Cbz CN 7 NCbz Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 2.03, minor 3.33 82 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 2.45, minor 3.23 86 OH 163g-Cbz NO2 8 NCbz OH 163h-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 147 SFC analytic conditions ee (%) Chiracel AD-H, λ = 210 nm 40% IPA/CO2, 2.5 mL/min tR (min) major 1.67, minor 2.20 89 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 3.61, minor 5.81 95 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 1.95, minor 3.02 92 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 2.28, minor 2.93 88 Chiralpak AD-H, λ = 210 nm 30% IPA/CO2, 2.5 mL/min tR (min) major 5.91, minor 6.39 49 F F F 9 NCbz OH 163i-Cbz 10 NCbz OH 163j-Cbz Me Me 11 NCbz OH 163k-Cbz OMe OMe 12 NCbz OH 163l-Cbz 13 NCbz Me OH 163m-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 148 SFC analytic conditions ee (%) Chiralpak OJ-H, λ = 210 nm 35% IPA/CO2, 2.5 mL/min tR (min) major 1.52, minor 1.82 92 Chiracel OJ-H, λ = 210 nm 35% IPA/CO2, 2.5 mL/min tR (min) major 2.86, minor 6.02 90 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 3.19, minor 4.05 89 Chiralpak OJ-H, λ = 210 nm 25% IPA/CO2, 2.5 mL/min tR (min) minor 1.84, major 2.60 87 Chiralpak OD-H, λ = 210 nm 30% IPA/CO2, 2.5 mL/min tR (min) major 2.52, minor 2.79 85 Chiralpak AD-H, λ = 210 nm 40% IPA/CO2, 2.5 mL/min tR (min) major 2.56, minor 3.04 93 O NCbz 14 OH 163n-Cbz S NCbz 15 OH 163o-Cbz S NCbz 16 OH 163p-Cbz Me N N 17 NCbz OH 163q-Cbz N NCbz 18 OH 163r-Cbz 19 F NCbz OH 165a-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 149 SFC analytic conditions ee (%) Chiralpak OJ-H, λ = 210 nm 30% IPA/CO2, 2.5 mL/min tR (min) major 1.93, minor 2.42 90 Chiracel AD-H, λ = 210 nm 20% IPA/CO2, 2.5 mL/min tR (min) major 3.93, minor 4.46 94 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 2.5 mL/min tR (min) major 5.00, minor 7.22 58 OMe 20 NCbz F OH 165b-Cbz CF3 21 NCbz F OH 165c-Cbz O 22 O NCbz OH 165d-Cbz OMe OMe O 23 O NCbz Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 2.5 mL/min tR (min) major 3.89, minor 5.16 54 Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 2.5 mL/min tR (min) major 5.31, minor 10.01 82 OH 165e-Cbz 24 NCbz OH 165f-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 25 NCbz 150 SFC analytic conditions ee (%) Chiralpak OJ-H, λ = 210 nm 20% IPA/CO2, 2.5 mL/min tR (min) major 3.32, minor 3.93 86 Chiracel OD-H, λ = 210 nm 20% IPA/CO2, 2.5 mL/min tR (min) major 4.82, minor 5.25 89 Chiralpak OD-H, λ = 210 nm 25% IPA/CO2, 2.5 mL/min tR (min) major 5.66, minor 6.38 88 Chiralpak AD-H, λ = 210 nm 40% IPA/CO2, 2.5 mL/min tR (min) major 1.41, minor 1.76 90 Chiralpak AS-H, λ = 210 nm 20% IPA/CO2, 3.5 mL/min tR (min) major 2.16, minor 2.62 90 OAc 167a-Cbz 26 NCbz OMe 167b-Cbz 27 NCbz OBn 167c-Cbz 28 NCbz NHBoc 167d-Cbz 29 NCbz Me 167e-Cbz Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 2.7.5 151 Determination of relative and absolute configuration Method 1 – Vibrational Circular Dichroism (VCD) Experimental Protocol. A solution of 167e (60 mg/mL) was prepared in CDCl3 and loaded into a front-loading SL-4 cell (International Crystal Laboratories) possessing BaF2 windows and 100 μm path length. Infrared (IR) and VCD spectra were acquired on a BioTools ChiralIR-2X VCD spectrometer as a set of set of 27 one-hour blocks (27 blocks, 3120 scans per block) in dual PEM mode. A 15-minute acquisition of neat (-)-α-pinene control (separate 75 μm BaF2 cell) 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 an 8-hour (8 blocks, 3120 scans per block) IR/VCD acquisition of CDCl3 in the same 100 μm BaF2 cell as used for 167e. The reported spectra represent the result of block averaging. Computational Protocol. The arbitrarily chosen (S,S) stereoisomer of compound 167e ((S) at methyl, (S) at phenyl; thus cis) was subjected to an exhaustive initial molecular mechanics-based conformational search (MMFF94 force field, 0.08 Å geometric RMSD cutoff, and 30 kcal/mol energy window) as implemented in MOE 2019.0102 (Chemical Computing Group, Montreal, CA). All conformers retained the (S) configuration at both centers. Separately, a study involving the trans stereoisomer possessing the (R) configuration at the methyl group and (S) configuration at phenyl was performed in identical fashion, with stereochemical integrity again retained throughout the stochastic conformational search. All MMFF94 conformers within a 10 kcal/mol energy window were then subjected to geometry optimization, harmonic frequency calculation, and VCD Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 152 rotational strength evaluation using density functional theory. All quantum mechanical calculations first utilized the B3LYP functional, small 6-31G* basis, and IEFPCM model (chloroform solvent) as an initial filter, followed by subsequent optimization using B3PW91 functional, cc-pVTZ basis, and implicit IEFPCM chloroform solvation model on all IEFPCM-B3LYP/6-31G* conformers below 5 kcal/mol. All calculations were performed with the Gaussian 16 program system (Rev. C.01; Frisch et al., Gaussian, Inc., Wallingford, CT). Resultant IEFPCM-B3PW91/cc-pVTZ harmonic frequencies were scaled by 0.98. All 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 to yield the final predicted IR and VCD spectra of the species described above. The predicted VCD of the corresponding enantiomers were generated by inversion of sign. From a combination of (a) the best overall agreement of (R,R)-167e with experiment among all of the theoretical spectra in the useful range of the VCD (~ 1000-1450 cm-1, regions A-D; see below) coupled with (b) support of this assignment by the agreement between predicted versus measured optical rotation (see Method 2) the absolute configuration of 167e was established as cis and (R,R). Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 153 Figure 2.3. Experimental (left) and computed (right) IR and VCD spectra for the cis isomers of 167e. The better agreement with the (R,R) stereoisomer, upon alignment of the achiral IR spectra and correlation to VCD signals, is readily evident. Figure 2.4. Experimental (left) and computed (right) IR and VCD spectra for the trans isomers of 167e. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 154 The worse agreement with experiment between either of the predicted trans stereoisomers, compared to the cis- and (R,R) stereoisomer above, can be seen. This assertion is further supported to an extent by the optical rotation data below. Method 2 – Optical Rotation (OR) Computational Protocol. The ensemble of unique IEFPCM-B3PW91/cc-pVTZ conformers of 167e generated in Method 1 above were subjected to optical rotation calculation at 589.0 nm using the B3LYP hybrid density functional, the large and diffuse 6-311++G(2df,2pd) basis set, and the IEFPCM implicit chloroform solvent model. The computed IEFPCM-B3LYP/6-311++G(2df,2pd) optical rotations (weighted by IEFPCMB3PW91/cc-pVTZ free energies at 298.15 K) along with those resulting from alternatively weighting by either the IEFPCM-B3PW91/cc-pVTZ total energies or IEFPCM-B3LYP/6311++G(2df,2pd)//IEFPCM-B3PW91/cc-pVTZ total energies are reported in (a)-(d) below. (S) NH (a) (S) CH3 Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ free energies: -144.5° Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ total energies: -144.6° Predicted OR, weighted by IEFPCM-B3LYP/6-311++G(2df,2pd)//IEFPCM-B3PW91/ccpVTZ total energies: -147.0° (R) NH (b) (R) CH3 Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 155 Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ free energies: +144.5° Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ total energies: +144.6° Predicted OR, weighted by IEFPCM-B3LYP/6-311++G(2df,2pd)//IEFPCM-B3PW91/ccpVTZ total energies: +147.0° (S) NH (c) (R) CH3 Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ free energies: -94.5° Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ total energies: -101.0° Predicted OR, weighted by IEFPCM-B3LYP/6-311++G(2df,2pd)//IEFPCM-B3PW91/ccpVTZ total energies: -100.1° (R) NH (d) (S) CH3 Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ free energies: +94.5° Predicted OR, weighted by IEFPCM-B3PW91/cc-pVTZ total energies: +101.0° Predicted OR, weighted by IEFPCM-B3LYP/6-311++G(2df,2pd)//IEFPCM-B3PW91/ccpVTZ total energies: +100.1° Measured optical rotation: [α]D25 +133.3 (c 0.79, CHCl3). Assuming only that the sign of the optical rotation is correctly predicted by theory, given the experimentally measured value of +133.3°, the absolute configuration of 167e must either be: (i) (R) at both chiral centers (and therefore cis); or (b) (S) at phenyl and (R) at methyl (trans). Scenario (b) is unlikely, given the wrong (opposite) directionality of the VCD signals in Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 156 regions C and D of the experimental spectrum. Scenario (a) also gives rise to the best agreement between the predicted and measured VCD spectra. 2.8 (1) REFERENCES AND NOTES a) Tayor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257– 10274. c) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752– 6756. d) Lovering, F. Med. Chem. Commun. 2013, 4, 515–519. e) Roughley, S. D.; Jordan, A. 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J. 2015, 21, 1915–1927. f) Guo, R.-N.; Cai, Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 157 X.-F.; Shi, L.; Ye, Z.-S.; Chen, M.-W.; Zhou, Y.-G. Chem. Commun. 2013, 49, 8537–8539. g) Chen, M.-W.; Ji, Y.; Wang, J.; Chen, Q.-A.; Shi, L.; Zhou, Y.-G. Org. Lett. 2017, 19, 4988–4991. For Ru-Catalyzed Enatioselective Hydrogenation of Isoquinolines, see h) Wen, J.; Tan, R.; Liu, S.; Zhao, Q.; Zhang, X. Chem. Sci. 2016, 7, 3047–3051. (5) a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–1730. b) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev. 2008, 37, 2676–2690. (6) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.; Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C. D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.; Grünanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.; Stoltz, B. M. Science. 2019, 363, 270–275. (7) For C–H activation/annulation strategy, see a) Zhang, Z.-W.; Lin, A.; Yang, J. J. Org. Chem. 2014, 79, 7041–7050. For ketone enolate-arylation/annulation, see b) Donohoe, T. J.; Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 11605–11608. For benzannulation of isocoumarins, see c) Manivel, P. Probakaran, K.; Khan, F. N.; Jin, J. S. Res. Chem. Intermed. 2012, 38, 347–357. (8) Pilgrim, B. S.; Gatland, A. E.; Esteves, C. H. A.; McTernan, C. T.; Jones, G. R.; Tatton, M. R. Procopiou, P. A.; Donohoe, T. J. Org. Biomol. Chem. 2016, 14, 1065– 1090. (9) Allan, K. M.; Hong, B. D.; Stoltz, B. M. Org. Biomol. Chem. 2009, 7, 4960–4964. (10) For example of transition-metal-catalyzed tandem C–H activation/annulation of arenes and alkynes, see a) Zhu, Z.; Tang, X.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 158 J. Org. Chem. 2016, 81, 1401–1409. b) Zhou, S.; Wang, M.; Wang, L.; Chen, K.; Wang, J.; Song, C.; Zhu, J. Org. Lett. 2016, 18, 5632–5635. c) Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M. Org. Lett. 2012, 14, 3032–3035. d) Zhao, D.; Lied, F.; Glorius, F. Chem. Sci. 2014, 5, 2869–2873. (11) a) Chu, H.; Sun, S.; Yu, J.-T.; Cheng, J. Chem. Commun. 2015, 51, 13327. b) Arambasic, M.; Hooper, J. F.; Willis, M. C. Org. Lett. 2013, 15, 5162–5165. (12) See Table 2.3, Section 2.7.3 for additional results using other acids. Although further studies are required to fully understand the role of acid, we speculate that the acid helps promoting a) the tautomerization of enamine to imine prior to the second reduction and b) the dissociation of THIQ product from Ir-complex through protonation. (13) In a similar Ir-xyliphos system, it is reported that the alpha-alkoxy imine binds to the catalyst complex in a bidentate fashion, see a) Dorta, R.; Broggini, D.; Stoop, R.; Rüegger, H. Spindler, F.; Togni, A. Chem. Eur. J. 2004, 10, 267–278. b) Dorta, R.; Broggini, D.; Kissner, R.; Togni, A. Chem. Eur. J. 2004, 10, 4546– 4555. (14) Hopmann, K. H.; Bayer, A. Organometallics. 2011, 30, 2483–2497. (15) Increasing the catalyst loading to 2.5 mol % of [Ir(cod)Cl]2 and 6 mol % of L7 does not improve the conversion any further. (16) The absolute stereochemistry of product 167e was determined via the combination of measured and computed vibrational circular dichroism (VCD) spectra and optical rotations. The configuration of 167e (R, R) was found to be analogous to Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines that determined for hydroxymethyl product 163a and also 159 observed crystallographically for 163p. (17) a) Chrzanowska, M. Grajewska, A.; Rozwadowska, M. D. Chem. Rev. 2016, 116, 12369–12465. b) Carrillo, L.; Badia, D.; Dominguez, E.; Anakabe, E.; Osante, I.; Tellitu, I.; Vicario, J. L. J. Org. Chem. 1999, 64, 115–1120. (18) Haftchenary, S.; Nelson, S. D.; Furst, L.; Dandapani, S.; Ferrara, S. J.; Bošković, Z. V.; Lazú, S. F.; Guerrero, A. M.; Serrano, J. C.; Crews, D. K.; Brackeen, C.; Mowat, J.; Brumby, T.; Bauser, M.; Schreiber, S. L.; Phillips, A. J. ACS. Comb. Sci. 2016, 18, 569–574. (19) Alternatively, the oxazolidinone-fused product 169 could be synthesized utilizing a 2-step sequence. First is the Boc-protection of the amine. The Boc-protected product was subsequently cyclized to afford oxazolidinone-fused THIQ 169 under the Appel reaction conditions. (20) Zhang, G.-L.; Chen, C.; Xiong, Y.; Zhang, L.-H.; Ye, J.; Ye, X.-S. Carbohydrate Research. 2010, 345, 780–786. (21) Gadhiya, S. V.; Giri, R.; Cordone, P.; Karki, A.; Harding, W. W. Curr. Org. Chem. 2018, 22, 1893–1905. (22) Thimmaiah, S.; Ningegowda, M.; Shivananju, N. S.; Ningegowda, R.; Siddaraj, R.; Priya, B. S. Eur. J. Chem. 2016, 7, 391–396. (23) Guo, D.; Li, J.; Lin, H.; Zhou, Y.; Chen, Y.; Sun, H.; Zhang, D.; Li, H.; Shoichet, B. K.; Shan, L.; Xie, X.; Jiang, H.; Liu, H. J. Med. Chem. 2016, 59, 9489–9502. (24) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. Chapter 2 – Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 160 (25) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916–920. (26) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966–8967. (27) Xu, Z.; Xu, X.; O’Laoi, R.; Ma, H.; Zheng, J.; Chen, S.; Luo, L.; Hu, Z.; He, S.; Li, J.; Zhang, H.; Zhang, X. Bioorg. Med. Chem. 2016, 24, 5861–5872. Appendix 1 – Spectra Relevant to Chapter 2 161 APPENDIX 1 Spectra Relevant to Chapter 2: Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines 8 7 O O 159a Ot-Bu O 5 4 ppm 3 2 Figure A1.1 1H NMR (400 MHz, CDCl3) of compound 159a. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 2 162 Appendix 1 – Spectra Relevant to Chapter 2 163 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 159a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.3 13C NMR (100 MHz, CDCl3) of compound 159a. 0 8 F 159b O O 7 O Ot-Bu 6 4 ppm 3 2 Figure A1.4 1H NMR (400 MHz, CDCl3) of compound 159b. 5 1 0 Appendix 1 – Spectra Relevant to Chapter 2 164 Appendix 1 – Spectra Relevant to Chapter 2 165 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound 159b. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.6 13C NMR (100 MHz, CDCl3) of compound 159b. Appendix 1 – Spectra Relevant to Chapter 2 -114.9 -115.0 -115.1 -115.2 -115.3 -115.4 -115.5 166 -115.6 ppm -115.7 -115.8 -115.9 -116.0 -116.1 Figure A1.7 19F NMR (282 MHz, CDCl3) of compound 159b. -116.2 -116.3 O O 7 159c O O O Ot-Bu 5 4 ppm 3 Figure A1.8 1H NMR (400 MHz, CDCl3) of compound 159c. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 167 Appendix 1 – Spectra Relevant to Chapter 2 168 Figure A1.9 Infrared spectrum (Thin Film, NaCl) of compound 159c. 180 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.10 13C NMR (100 MHz, CDCl3) of compound 159c. 20 10 9 8 O O 159d Ot-Bu O 6 5 ppm 4 3 Figure A1.11 1H NMR (400 MHz, CDCl3) of compound 159d. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 169 Appendix 1 – Spectra Relevant to Chapter 2 170 Figure A1.12 Infrared spectrum (Thin Film, NaCl) of compound 159d. 180 160 140 120 13 100 ppm 80 60 40 20 Figure A1.13 C NMR (100 MHz, CDCl3) of compound 159d. 9 160a Me 8 N OTf 6 5 ppm 4 3 Figure A1.14 1H NMR (400 MHz, CDCl3) of compound 160a. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 171 Appendix 1 – Spectra Relevant to Chapter 2 172 Figure A1.15 Infrared spectrum (Thin Film, NaCl) of compound 160a. 200 180 160 140 13 120 100 ppm 80 60 40 20 Figure A1.16 C NMR (100 MHz, CDCl3) of compound 160a. 0 Appendix 1 – Spectra Relevant to Chapter 2 -30 -40 -50 -60 -70 173 ppm -80 -90 -100 -110 Figure A1.17 19F NMR (282 MHz, CDCl3) of compound 160a. -120 9 F 8 160b Me N OTf 7 5 ppm 4 3 Figure A1.18 1H NMR (400 MHz, CDCl3) of compound 160b. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 174 Appendix 1 – Spectra Relevant to Chapter 2 175 Figure A1.19 Infrared spectrum (Thin Film, NaCl) of compound 160b. 180 160 140 120 100 ppm 80 60 40 Figure A1.20 13C NMR (100 MHz, CDCl3) of compound 160b. 20 0 Appendix 1 – Spectra Relevant to Chapter 2 -65 -70 -75 -80 -85 176 -90 ppm -95 -100 -105 -110 Figure A1.21 19F NMR (282 MHz, CDCl3) of compound 160b. -115 8 O O 7 160c Me N OTf 5 ppm 4 3 Figure A1.122 1H NMR (400 MHz, CDCl3) of compound 160c. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 177 Appendix 1 – Spectra Relevant to Chapter 2 178 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 160c. 160 150 140 130 120 110 100 90 80 ppm 70 60 50 40 30 Figure A1.24 13C NMR (100 MHz, CDCl3) of compound 160c. 20 10 0 Appendix 1 – Spectra Relevant to Chapter 2 -64 -66 -68 -70 -72 -74 ppm 179 -76 -78 -80 -82 Figure A1.25 19F NMR (282 MHz, CDCl3) of compound 160c. -84 9 Me 8 160d N OTf 6 5 ppm 4 3 Figure A1.26 1H NMR (400 MHz, CDCl3) of compound 160d. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 180 Appendix 1 – Spectra Relevant to Chapter 2 181 Figure A1.27 Infrared spectrum (Thin Film, NaCl) of compound 160d. 160 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 Figure A1.28 C NMR (100 MHz, CDCl3) of compound 160d. 20 10 Appendix 1 – Spectra Relevant to Chapter 2 -65 -70 -75 19 182 ppm -80 -85 -90 Figure A1.29 F NMR (282 MHz, CDCl3) of compound 160d. 8 161a Me N 6 5 ppm 4 3 Figure A1.30 1H NMR (400 MHz, CDCl3) of compound 161a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 183 Appendix 1 – Spectra Relevant to Chapter 2 184 Figure A1.31 Infrared spectrum (Thin Film, NaCl) of compound 161a. 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.32 13C NMR (100 MHz, CDCl3) of compound 161a. 10 8 161b Me N 7 5 ppm 4 3 Figure A1.33 1H NMR (400 MHz, CDCl3) of compound 161b. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 185 Appendix 1 – Spectra Relevant to Chapter 2 186 Figure A1.34 Infrared spectrum (Thin Film, NaCl) of compound 161b. 180 160 140 120 13 100 ppm 80 60 40 20 Figure A1.35 C NMR (100 MHz, CDCl3) of compound 161b. 0 9 8 161c Me N Ph 6 5 ppm 4 3 Figure A1.36 1H NMR (400 MHz, CDCl3) of compound 161c. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 187 Appendix 1 – Spectra Relevant to Chapter 2 188 Figure A1.37 Infrared spectrum (Thin Film, NaCl) of compound 161c. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.38 13C NMR (100 MHz, CDCl3) of compound 161c. 0 9 8 161d Me N OMe 6 5 ppm 4 3 Figure A1.39 1H NMR (400 MHz, CDCl3) of compound 161d. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 189 Appendix 1 – Spectra Relevant to Chapter 2 190 Figure A1.40 Infrared spectrum (Thin Film, NaCl) of compound 161d. 180 160 140 120 13 100 ppm 80 60 40 20 Figure A1.41 C NMR (100 MHz, CDCl3) of compound 161d. 0 9 161e Me N 8 F 6 5 ppm 4 3 Figure A1.42 1H NMR (400 MHz, CDCl3) of compound 161e. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 191 Appendix 1 – Spectra Relevant to Chapter 2 192 Figure A1.43 Infrared spectrum (Thin Film, NaCl) of compound 161e. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.44 13C NMR (100 MHz, CDCl3) of compound 161e. 10 Appendix 1 – Spectra Relevant to Chapter 2 -50 -60 -70 -80 -90 -100 -110 ppm 193 -120 -130 -140 -150 -160 -170 Figure A1.45 19F NMR (282 MHz, CDCl3) of compound 161e. -180 9 8 161f Me N 7 6 5 ppm 4 3 Figure A1.46 1H NMR (400 MHz, CDCl3) of compound 161f. CF3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 194 Appendix 1 – Spectra Relevant to Chapter 2 195 180 160 140 120 100 ppm 22.81 136.68 130.70 130.44 130.38 130.06 129.74 128.55 127.91 127.54 127.29 127.10 125.83 125.78 125.74 125.70 123.14 120.44 116.12 143.33 148.46 159.11 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 161f. 80 60 40 20 Figure A1.48 13C NMR (100 MHz, CDCl3) of compound 161f. 0 Appendix 1 – Spectra Relevant to Chapter 2 -50 -55 -60 196 ppm -65 -70 -75 Figure A1.49 19F NMR (282 MHz, CDCl3) of compound 161f. -80 9 8 161g Me N 7 CN 5 ppm 4 3 Figure A1.50 1H NMR (400 MHz, CDCl3) of compound 161g. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 197 Appendix 1 – Spectra Relevant to Chapter 2 198 Figure A1.51 Infrared spectrum (Thin Film, NaCl) of compound 161g. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.52 13C NMR (100 MHz, CDCl3) of compound 161g. 0 10 Me 9 161h N NO2 7 6 ppm 5 4 3 Figure A1.53 1H NMR (400 MHz, CDCl3) of compound 161h. 8 2 1 Appendix 1 – Spectra Relevant to Chapter 2 199 Appendix 1 – Spectra Relevant to Chapter 2 200 Figure A1.54 Infrared spectrum (Thin Film, NaCl) of compound 161h. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.55 13C NMR (100 MHz, CDCl3) of compound 161h. 10 8 161i Me N F 7 F F 5 ppm 4 3 Figure A1.56 1H NMR (400 MHz, CDCl3) of compound 161i. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 201 Appendix 1 – Spectra Relevant to Chapter 2 202 Figure A1.57 Infrared spectrum (Thin Film, NaCl) of compound 161i. c 180 160 140 120 13 100 ppm 80 60 40 20 Figure A1.58 C NMR (100 MHz, CDCl3) of compound 161i. 0 Appendix 1 – Spectra Relevant to Chapter 2 -30 -40 -50 -60 -70 19 -80 -90 203 -100 ppm -110 -120 -130 -140 -150 -160 Figure A1.59 F NMR (282 MHz, CDCl3) of compound 161i. -170 9 161j Me N 8 6 5 ppm 4 3 Figure A1.60 1H NMR (400 MHz, CDCl3) of compound 161j. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 204 Appendix 1 – Spectra Relevant to Chapter 2 205 Figure A1.61 Infrared spectrum (Thin Film, NaCl) of compound 161j. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.62 13C NMR (100 MHz, CDCl3) of compound 161j. 10 0 9 8 161k Me N Me Me 6 5 ppm 4 3 Figure A1.63 1H NMR (400 MHz, CDCl3) of compound 161k. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 206 Appendix 1 – Spectra Relevant to Chapter 2 207 Figure A1.64 Infrared spectrum (Thin Film, NaCl) of compound 161k. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.65 C NMR (100 MHz, CDCl3) of compound 161k. 10 161l 8 Me N OMe OMe 6 5 ppm 4 Figure A1.66 1H NMR (400 MHz, CDCl3) of compound 161l. 7 3 2 Appendix 1 – Spectra Relevant to Chapter 2 208 Appendix 1 – Spectra Relevant to Chapter 2 209 Figure A1.67 Infrared spectrum (Thin Film, NaCl) of compound 161l. c 180 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.68 C NMR (100 MHz, CDCl3) of compound 161l. 10 9 161m Me N 8 Me 6 5 ppm 4 3 Figure A1.69 1H NMR (400 MHz, CDCl3) of compound 161m. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 210 Appendix 1 – Spectra Relevant to Chapter 2 211 Figure A1.70 Infrared spectrum (Thin Film, NaCl) of compound 161m. c 180 160 140 13 120 100 ppm 80 60 40 20 Figure A1.71 C NMR (100 MHz, CDCl3) of compound 161m. 0 10 9 161n Me N O 8 6 5 ppm 4 3 Figure A1.72 1H NMR (400 MHz, CDCl3) of compound 161n. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 212 Appendix 1 – Spectra Relevant to Chapter 2 213 Figure A1.73 Infrared spectrum (Thin Film, NaCl) of compound 161n. c 180 160 140 120 13 100 ppm 80 60 40 20 Figure A1.74 C NMR (100 MHz, CDCl3) of compound 161n. 0 8 161o Me N S 7 5 ppm 4 3 Figure A1.75 1H NMR (400 MHz, CDCl3) of compound 161o. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 214 Appendix 1 – Spectra Relevant to Chapter 2 215 Figure A1.76 Infrared spectrum (Thin Film, NaCl) of compound 161o. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.77 13C NMR (100 MHz, CDCl3) of compound 161o. 20 10 Me 8 161p N S 7 5 ppm 4 3 Figure A1.78 1H NMR (400 MHz, CDCl3) of compound 161p. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 216 Appendix 1 – Spectra Relevant to Chapter 2 217 Figure A1.79 Infrared spectrum (Thin Film, NaCl) of compound 161p. c 180 160 140 120 100 ppm 80 60 40 20 Figure A1.80 13C NMR (100 MHz, CDCl3) of compound 161p. 0 9 8 161q Me N 7 6 5 ppm 4 3 Figure A1.81 1H NMR (400 MHz, CDCl3) of compound 161q. N Me N 2 1 Appendix 1 – Spectra Relevant to Chapter 2 218 Appendix 1 – Spectra Relevant to Chapter 2 219 Figure A1.82 Infrared spectrum (Thin Film, NaCl) of compound 161q. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.83 13C NMR (100 MHz, CDCl3) of compound 161q. 20 10 10 9 161r Me N N 7 6 ppm 5 4 Figure A1.84 1H NMR (400 MHz, CDCl3) of compound 161r. 8 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 220 Appendix 1 – Spectra Relevant to Chapter 2 221 Figure A1.85 Infrared spectrum (Thin Film, NaCl) of compound 161r. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.86 C NMR (100 MHz, CDCl3) of compound 161r. 20 10 9 F 8 172a Me N 6 5 ppm 4 3 Figure A1.87 1H NMR (400 MHz, CDCl3) of compound 172a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 222 Appendix 1 – Spectra Relevant to Chapter 2 223 Figure A1.88 Infrared spectrum (Thin Film, NaCl) of compound 172a. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.89 13C NMR (100 MHz, CDCl3) of compound 172a. 20 10 Appendix 1 – Spectra Relevant to Chapter 2 -108.0 -108.5 -109.0 -109.5 -110.0 -110.5 -111.0 ppm 224 -111.5 -112.0 -112.5 -113.0 -113.5 Figure A1.90 19F NMR (282 MHz, CDCl3) of compound 172a. -114.0 9 F 8 172b Me N 6 5 ppm 4 3 Figure A1.91 1H NMR (400 MHz, CDCl3) of compound 172b. 7 OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 225 Appendix 1 – Spectra Relevant to Chapter 2 226 180 160 140 120 100 ppm 80 60 22.69 55.38 133.91 132.22 129.99 129.91 128.08 126.78 126.71 120.52 120.27 114.16 113.66 113.65 109.30 109.09 149.43 149.40 161.61 160.06 159.15 157.74 157.68 Figure A1.92 Infrared spectrum (Thin Film, NaCl) of compound 172b. c 40 20 Figure A1.93 13C NMR (100 MHz, CDCl3) of compound 172b. 0 Appendix 1 – Spectra Relevant to Chapter 2 -109.5 -110.0 -110.5 -111.0 -111.5 -112.0 ppm 227 -112.5 -113.0 -113.5 -114.0 Figure A1.94 19F NMR (282 MHz, CDCl3) of compound 172b. -114.5 -115.0 9 F 8 172c Me N 6 5 ppm 4 3 Figure A1.95 1H NMR (400 MHz, CDCl3) of compound 172c. 7 CF3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 228 Appendix 1 – Spectra Relevant to Chapter 2 229 Figure A1.96 Infrared spectrum (Thin Film, NaCl) of compound 172c. c 160 140 120 13 100 ppm 80 60 40 20 Figure A1.97 C NMR (100 MHz, CDCl3) of compound 172c. 0 Appendix 1 – Spectra Relevant to Chapter 2 -50 -60 -70 -80 230 ppm -90 -100 -110 Figure A1.98 19F NMR (282 MHz, CDCl3) of compound 172c. -120 8 O O 172d Me N 7 5 ppm 4 3 Figure A1.99 1H NMR (400 MHz, CDCl3) of compound 172d. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 231 Appendix 1 – Spectra Relevant to Chapter 2 232 Figure A1.100 Infrared spectrum (Thin Film, NaCl) of compound 172d. c 170 160 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 20 Figure A1.101 C NMR (100 MHz, CDCl3) of compound 172d. 10 16 14 O O Me 12 172e N OMe 10 8 6 ppm 4 4.02 3.94 3.08 3.09 7.72 7.71 7.69 7.62 7.61 7.59 7.59 7.34 7.09 6.98 6.95 6.09 1.97 2.02 1.00 0.98 0.98 1.03 2 Figure A1.102 1H NMR (400 MHz, CDCl3) of compound 172e. OMe 2.91 3.01 0 -2 233 Appendix 1 – Spectra Relevant to Chapter 2 Appendix 1 – Spectra Relevant to Chapter 2 234 200 180 160 140 120 100 ppm 80 60 22.99 56.00 55.97 123.22 119.12 114.31 111.22 109.99 103.26 101.83 101.53 135.18 132.99 156.19 150.51 149.30 149.18 149.15 147.92 Figure A1.103 Infrared spectrum (Thin Film, NaCl) of compound 172e. c 40 20 Figure A1.104 13C NMR (100 MHz, CDCl3) of compound 172e. 0 9 8 Me 172f N 6 5 ppm 4 3 Figure A1.105 1H NMR (400 MHz, CDCl3) of compound 172f. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 235 Appendix 1 – Spectra Relevant to Chapter 2 236 Figure A1.106 Infrared spectrum (Thin Film, NaCl) of compound 172f. c 160 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 Figure A1.107 C NMR (100 MHz, CDCl3) of compound 172f. 20 10 9 162a OH N 8 6 5 ppm 4 3 Figure A1.108 1H NMR (400 MHz, CDCl3) of compound 162a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 237 Appendix 1 – Spectra Relevant to Chapter 2 238 Figure A1.109 Infrared spectrum (Thin Film, NaCl) of compound 162a. c 180 170 160 150 140 130 13 120 110 100 ppm 90 80 70 60 50 40 30 Figure A1.110 C NMR (100 MHz, CDCl3) of compound 162a. 20 10 9 162b OH N 8 6 5 ppm 4 3 Figure A1.111 1H NMR (400 MHz, CDCl3) of compound 162b. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 239 Appendix 1 – Spectra Relevant to Chapter 2 240 Figure A1.112 Infrared spectrum (Thin Film, NaCl) of compound 162b. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.113 C NMR (100 MHz, CDCl3) of compound 162b. 20 10 9 162c OH N 7 6 ppm 5 4 Figure A1.114 1H NMR (400 MHz, CDCl3) of compound 162c. 8 Ph 3 2 Appendix 1 – Spectra Relevant to Chapter 2 241 Appendix 1 – Spectra Relevant to Chapter 2 242 Figure A1.115 Infrared spectrum (Thin Film, NaCl) of compound 162c. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A1.116 13C NMR (100 MHz, CDCl3) of compound 162c. 20 9 8 162d OH N 7 6 5 ppm 4 3 Figure A1.117 1H NMR (400 MHz, CDCl3) of compound 162d. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 243 Appendix 1 – Spectra Relevant to Chapter 2 244 Figure A1.118 Infrared spectrum (Thin Film, NaCl) of compound 162d. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 Figure A1.119 13C NMR (100 MHz, CDCl3) of compound 162d. 40 30 20 9 162e OH N F 7 6 ppm 5 4 Figure A1.120 1H NMR (400 MHz, CDCl3) of compound 162e. 8 3 2 Appendix 1 – Spectra Relevant to Chapter 2 245 Appendix 1 – Spectra Relevant to Chapter 2 246 Figure A1.121 Infrared spectrum (Thin Film, NaCl) of compound 162e. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A1.122 13C NMR (100 MHz, CDCl3) of compound 162e. 20 10 Appendix 1 – Spectra Relevant to Chapter 2 -112.2 -112.4 -112.6 -112.8 -113.0 -113.2 -113.4 ppm 247 -113.6 -113.8 -114.0 -114.2 -114.4 Figure A1.123 19F NMR (282 MHz, CDCl3) of compound 162e. -114.6 -114.8 9 8 162f OH N 7 6 ppm 5 4 Figure A1.124 1H NMR (400 MHz, CDCl3) of compound 162f. CF3 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 248 Appendix 1 – Spectra Relevant to Chapter 2 249 Figure A1.125 Infrared spectrum (Thin Film, NaCl) of compound 162f. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 30 Figure A1.126 C NMR (100 MHz, CDCl3) of compound 162f. 20 Appendix 1 – Spectra Relevant to Chapter 2 -62.52 250 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A1.127 19F NMR (282 MHz, CDCl3) of compound 162f. 10 9 162g OH N CN 7 6 5 ppm 4 3 Figure A1.128 1H NMR (400 MHz, CDCl3) of compound 162g. 8 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 251 Appendix 1 – Spectra Relevant to Chapter 2 252 Figure A1.129 Infrared spectrum (Thin Film, NaCl) of compound 162g. c 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 Figure A1.130 13C NMR (100 MHz, CDCl3) of compound 162g. 40 10 162h OH N 9 NO2 7 6 ppm 5 4 3 Figure A1.131 1H NMR (400 MHz, CDCl3) of compound 162h. 8 2 1 Appendix 1 – Spectra Relevant to Chapter 2 253 Appendix 1 – Spectra Relevant to Chapter 2 254 Figure A1.132 Infrared spectrum (Thin Film, NaCl) of compound 162h. c 170 160 150 140 130 13 120 110 100 ppm 90 80 70 60 50 Figure A1.133 C NMR (100 MHz, CDCl3) of compound 162h. 40 30 9 8 162i OH N F 6 5 ppm 4 3 Figure A1.134 1H NMR (400 MHz, CDCl3) of compound 162i. 7 F F 2 1 Appendix 1 – Spectra Relevant to Chapter 2 255 Appendix 1 – Spectra Relevant to Chapter 2 256 Figure A1.135 Infrared spectrum (Thin Film, NaCl) of compound 162i. c 180 170 160 150 140 130 13 120 110 100 ppm 90 80 70 60 50 40 Figure A1.136 C NMR (100 MHz, CDCl3) of compound 162i. 30 20 Appendix 1 – Spectra Relevant to Chapter 2 -120 -125 -130 -135 -140 -145 257 -150 ppm -155 -160 -165 -170 Figure A1.137 19F NMR (282 MHz, CDCl3) of compound 162i. -175 -180 9 162j OH N 8 6 ppm 5 4 3 Figure A1.138 1H NMR (400 MHz, CDCl3) of compound 162j. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 258 Appendix 1 – Spectra Relevant to Chapter 2 259 Figure A1.139 Infrared spectrum (Thin Film, NaCl) of compound 162j. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.140 13C NMR (100 MHz, CDCl3) of compound 162j. 30 20 9 162k OH N Me 8 Me 6 ppm 5 4 3 Figure A1.141 1H NMR (400 MHz, CDCl3) of compound 162k. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 260 Appendix 1 – Spectra Relevant to Chapter 2 261 Figure A1.142 Infrared spectrum (Thin Film, NaCl) of compound 162k. c 180 160 140 120 100 ppm 80 60 40 Figure A1.143 13C NMR (100 MHz, CDCl3) of compound 162k. 20 9 162l OH N OMe 8 OMe 6 ppm 5 4 Figure A1.144 1H NMR (400 MHz, CDCl3) of compound 162l. 7 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 262 Appendix 1 – Spectra Relevant to Chapter 2 263 Figure A1.145 Infrared spectrum (Thin Film, NaCl) of compound 162l. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 30 Figure A1.146 C NMR (100 MHz, CDCl3) of compound 162l. 20 9 162m OH N Me 8 6 ppm 5 4 3 Figure A1.147 1H NMR (400 MHz, CDCl3) of compound 162m. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 264 Appendix 1 – Spectra Relevant to Chapter 2 265 Figure A1.148 Infrared spectrum (Thin Film, NaCl) of compound 162m. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.149 13C NMR (100 MHz, CDCl3) of compound 162m. 20 10 9 8 162n OH N O 6 5 ppm 4 3 Figure A1.150 1H NMR (400 MHz, CDCl3) of compound 162n. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 266 Appendix 1 – Spectra Relevant to Chapter 2 267 Figure A1.151 Infrared spectrum (Thin Film, NaCl) of compound 162n. c 180 160 140 120 100 ppm 80 60 40 Figure A1.152 13C NMR (100 MHz, CDCl3) of compound 162n. 20 9 8 162o OH N S 6 5 ppm 4 3 Figure A1.153 1H NMR (400 MHz, CDCl3) of compound 162o. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 268 Appendix 1 – Spectra Relevant to Chapter 2 269 Figure A1.154 Infrared spectrum (Thin Film, NaCl) of compound 162o. c 180 160 140 13 120 100 ppm 80 60 40 Figure A1.155 C NMR (100 MHz, CDCl3) of compound 162o. 20 9 162p OH N S 8 6 5 ppm 4 3 Figure A1.156 1H NMR (400 MHz, CDCl3) of compound 162p. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 270 Appendix 1 – Spectra Relevant to Chapter 2 271 Figure A1.157 Infrared spectrum (Thin Film, NaCl) of compound 162p. c 170 160 150 140 130 13 120 110 100 ppm 90 80 70 60 50 40 Figure A1.158 C NMR (100 MHz, CDCl3) of compound 162p. 30 9 8 162q OH N N Me N 6 5 ppm 4 3 Figure A1.159 1H NMR (400 MHz, CDCl3) of compound 162q. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 272 Appendix 1 – Spectra Relevant to Chapter 2 273 Figure A1.160 Infrared spectrum (Thin Film, NaCl) of compound 162q. c 180 160 140 120 100 ppm 80 60 40 Figure A1.161 13C NMR (100 MHz, CDCl3) of compound 162q. 20 10 9 162r OH N N 7 6 ppm 5 4 3 Figure A1.162 1H NMR (400 MHz, CDCl3) of compound 162r. 8 2 1 Appendix 1 – Spectra Relevant to Chapter 2 274 Appendix 1 – Spectra Relevant to Chapter 2 275 Figure A1.163 Infrared spectrum (Thin Film, NaCl) of compound 162r. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.164 13C NMR (100 MHz, CDCl3) of compound 162r. 30 9 F 8 164a OH N 6 5 ppm 4 3 Figure A1.165 1H NMR (400 MHz, CDCl3) of compound 164a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 276 Appendix 1 – Spectra Relevant to Chapter 2 277 Figure A1.166 Infrared spectrum (Thin Film, NaCl) of compound 164a. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 Figure A1.167 13C NMR (100 MHz, CDCl3) of compound 164a. 40 30 Appendix 1 – Spectra Relevant to Chapter 2 -101 -102 -103 -104 -105 -106 -107 -108 -109 -110 ppm 278 -111 -112 -113 -114 -115 -116 Figure A1.168 19F NMR (282 MHz, CDCl3) of compound 164a. -117 -118 8 F 7 164b OH N 6 5 ppm 4 3 Figure A1.169 1H NMR (400 MHz, CDCl3) of compound 164b. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 279 Appendix 1 – Spectra Relevant to Chapter 2 280 Figure A1.170 Infrared spectrum (Thin Film, NaCl) of compound 164b. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 Figure A1.171 C NMR (100 MHz, CDCl3) of compound 164b. 40 30 Appendix 1 – Spectra Relevant to Chapter 2 -107 -108 -109 -110 ppm 281 -111 -112 -113 Figure A1.172 19F NMR (282 MHz, CDCl3) of compound 164b. -114 9 F 8 164c OH N 6 5 ppm 4 3 Figure A1.173 1H NMR (400 MHz, CDCl3) of compound 164c. 7 CF3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 282 Appendix 1 – Spectra Relevant to Chapter 2 283 Figure A1.174 Infrared spectrum (Thin Film, NaCl) of compound 164c. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 Figure A1.175 C NMR (100 MHz, CDCl3) of compound 164c. 30 20 Appendix 1 – Spectra Relevant to Chapter 2 -40 -50 -60 -70 -80 284 ppm -90 -100 -110 Figure A1.176 19F NMR (282 MHz, CDCl3) of compound 164c. -120 9 O O OH 8 164d N 6 ppm 5 4 Figure A1.177 1H NMR (400 MHz, CDCl3) of compound 164d. 7 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 285 Appendix 1 – Spectra Relevant to Chapter 2 286 Figure A1.178 Infrared spectrum (Thin Film, NaCl) of compound 164d. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.179 13C NMR (100 MHz, CDCl3) of compound 164d. 30 20 10 9 O O 8 164e OH N 7 OMe 6 5 ppm 4 3 Figure A1.180 1H NMR (400 MHz, CDCl3) of compound 164e. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 287 Appendix 1 – Spectra Relevant to Chapter 2 288 Figure A1.181 Infrared spectrum (Thin Film, NaCl) of compound 164e. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 Figure A1.182 C NMR (100 MHz, CDCl3) of compound 164e. 30 20 9 8 164f OH N 6 ppm 5 4 3 Figure A1.183 1H NMR (400 MHz, CDCl3) of compound 164f. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 289 Appendix 1 – Spectra Relevant to Chapter 2 290 Figure A1.184 Infrared spectrum (Thin Film, NaCl) of compound 164f. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.185 13C NMR (100 MHz, CDCl3) of compound 164f. 30 20 9 166a OAc N 8 6 5 ppm 4 3 Figure A1.186 1H NMR (400 MHz, CDCl3) of compound 166a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 291 Appendix 1 – Spectra Relevant to Chapter 2 292 Figure A1.187 Infrared spectrum (Thin Film, NaCl) of compound 166a. c 180 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.188 13C NMR (100 MHz, CDCl3) of compound 166a. 20 10 9 8 166b OMe N 1 6 5 ppm 4 3 Figure A1.189 H NMR (400 MHz, CDCl3) of compound 166b. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 293 Appendix 1 – Spectra Relevant to Chapter 2 294 Figure A1.190 Infrared spectrum (Thin Film, NaCl) of compound 166b. c 180 170 160 150 140 130 13 120 110 100 ppm 90 80 70 60 50 40 Figure A1.191 C NMR (100 MHz, CDCl3) of compound 166b. 30 20 9 8 166c OBn N 6 5 ppm 4 3 Figure A1.192 1H NMR (400 MHz, CDCl3) of compound 166c. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 295 Appendix 1 – Spectra Relevant to Chapter 2 296 Figure A1.193 Infrared spectrum (Thin Film, NaCl) of compound 166c. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.194 13C NMR (100 MHz, CDCl3) of compound 166c. 20 10 9 8 166d NHBoc N 6 5 ppm 4 3 Figure A1.195 1H NMR (400 MHz, CDCl3) of compound 166d. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 297 Appendix 1 – Spectra Relevant to Chapter 2 298 Figure A1.196 Infrared spectrum (Thin Film, NaCl) of compound 166d. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A1.197 13C NMR (100 MHz, CDCl3) of compound 166d. 20 10 11 10 H 166f O N 8 7 6 ppm 5 4 Figure A1.198 1H NMR (400 MHz, CDCl3) of compound 166f. 9 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 299 Appendix 1 – Spectra Relevant to Chapter 2 300 Figure A1.199 Infrared spectrum (Thin Film, NaCl) of compound 166f. c 200 180 160 140 13 120 ppm 100 80 60 40 Figure A1.200 C NMR (100 MHz, CDCl3) of compound 166f. 20 9 cis-163a OH NH 8 6 5 ppm 4 3 Figure A1.201 1H NMR (400 MHz, CDCl3) of compound cis-163a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 301 Appendix 1 – Spectra Relevant to Chapter 2 302 Figure A1.202 Infrared spectrum (Thin Film, NaCl) of compound 163a. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.203 C NMR (100 MHz, CDCl3) of compound 163a. 20 10 9 8 7 6 5 ppm 4 3 Figure A1.204 1H NMR (400 MHz, CDCl3) of compound trans-163a. trans-163a OH NH 2 1 Appendix 1 – Spectra Relevant to Chapter 2 303 Appendix 1 – Spectra Relevant to Chapter 2 180 170 160 150 140 130 120 110 100 ppm 304 90 80 70 60 50 40 30 20 Figure A1.205 13C NMR (100 MHz, CDCl3) of compound trans-163a. 10 8 163b OH NH 7 5 ppm 4 3 Figure A1.206 1H NMR (400 MHz, CDCl3) of compound 163b. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 305 Appendix 1 – Spectra Relevant to Chapter 2 306 Figure A1.207 Infrared spectrum (Thin Film, NaCl) of compound 163b. c 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 Figure A1.208 C NMR (100 MHz, CDCl3) of compound 163b. 30 20 9 163c OH NH 8 Ph 6 5 ppm 4 3 Figure A1.209 1H NMR (400 MHz, CDCl3) of compound 163c. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 307 Appendix 1 – Spectra Relevant to Chapter 2 308 Figure A1.210 Infrared spectrum (Thin Film, NaCl) of compound 163c. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.211 13C NMR (100 MHz, CDCl3) of compound 163c. 20 9 8 163d OH NH 7 6 5 ppm 4 3 Figure A1.212 1H NMR (400 MHz, CDCl3) of compound 163d. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 309 Appendix 1 – Spectra Relevant to Chapter 2 310 Figure A1.213 Infrared spectrum (Thin Film, NaCl) of compound 163d. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.214 13C NMR (100 MHz, CDCl3) of compound 163d. 30 20 9 8 163e OH NH F 6 5 ppm 4 3 Figure A1.215 1H NMR (400 MHz, CDCl3) of compound 163e. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 311 Appendix 1 – Spectra Relevant to Chapter 2 312 Figure A1.216 Infrared spectrum (Thin Film, NaCl) of compound 163e. c 180 160 140 120 100 ppm 80 60 40 20 Figure A1.217 13C NMR (100 MHz, CDCl3) of compound 163e. 0 Appendix 1 – Spectra Relevant to Chapter 2 -113.0 -113.5 -114.0 -114.5 -115.0 ppm 313 -115.5 -116.0 -116.5 Figure A1.218 19F NMR (282 MHz, CDCl3) of compound 163e. -117.0 8 163f OH NH 7 6 5 ppm 4 3 Figure A1.219 1H NMR (400 MHz, CDCl3) of compound 163f. CF3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 314 Appendix 1 – Spectra Relevant to Chapter 2 315 Figure A1.220 Infrared spectrum (Thin Film, NaCl) of compound 163f. c 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.221 13C NMR (100 MHz, CDCl3) of compound 163f. 20 10 Appendix 1 – Spectra Relevant to Chapter 2 -109 -110 -111 -112 -113 -114 -115 ppm 316 -116 -117 -118 -119 -120 Figure A1.222 19F NMR (282 MHz, CDCl3) of compound 163f. -121 -122 8 163g OH NH 7 6 5 ppm 4 3 Figure A1.223 1H NMR (400 MHz, CDCl3) of compound 163g. CN 2 1 Appendix 1 – Spectra Relevant to Chapter 2 317 Appendix 1 – Spectra Relevant to Chapter 2 318 Figure A1.224 Infrared spectrum (Thin Film, NaCl) of compound 163g. c 180 160 140 120 13 100 ppm 80 60 40 Figure A1.225 C NMR (100 MHz, CDCl3) of compound 163g. 20 9 8 163h OH NH 6 5 ppm 4 3 Figure A1.226 1H NMR (400 MHz, CDCl3) of compound 163h. 7 NO2 2 1 Appendix 1 – Spectra Relevant to Chapter 2 319 Appendix 1 – Spectra Relevant to Chapter 2 320 Figure A1.227 Infrared spectrum (Thin Film, NaCl) of compound 163h. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A1.228 13C NMR (100 MHz, CDCl3) of compound 163h. 20 9 8 163i OH NH F 7 6 5 ppm 4 3 Figure A1.229 1H NMR (400 MHz, CDCl3) of compound 163i. F F 2 1 Appendix 1 – Spectra Relevant to Chapter 2 321 Appendix 1 – Spectra Relevant to Chapter 2 322 Figure A1.230 Infrared spectrum (Thin Film, NaCl) of compound 163i. c 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.231 13C NMR (100 MHz, CDCl3) of compound 163i. 30 Appendix 1 – Spectra Relevant to Chapter 2 -120 -125 -130 -135 -140 323 ppm -145 -150 -155 -160 Figure A1.232 19F NMR (282 MHz, CDCl3) of compound 163i. -165 9 163j OH NH 8 6 ppm 5 4 3 Figure A1.233 1H NMR (400 MHz, CDCl3) of compound 163j. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 324 Appendix 1 – Spectra Relevant to Chapter 2 325 Figure A1.234 Infrared spectrum (Thin Film, NaCl) of compound 163j. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.235 13C NMR (100 MHz, CDCl3) of compound 163j. 30 9 8 163k OH NH Me Me 6 5 ppm 4 3 Figure A1.236 1H NMR (400 MHz, CDCl3) of compound 163k. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 326 Appendix 1 – Spectra Relevant to Chapter 2 327 Figure A1.237 Infrared spectrum (Thin Film, NaCl) of compound 163k. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A1.238 13C NMR (100 MHz, CDCl3) of compound 163k. 10 9 163l OH NH 8 OMe 7 6 5 ppm 4 3 Figure A1.239 1H NMR (400 MHz, CDCl3) of compound 163l. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 328 Appendix 1 – Spectra Relevant to Chapter 2 329 Figure A1.240 Infrared spectrum (Thin Film, NaCl) of compound 163l. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.241 13C NMR (100 MHz, CDCl3) of compound 163l. 30 20 9 8 163m OH NH Me 6 5 ppm 4 3 Figure A1.242 1H NMR (400 MHz, CDCl3) of compound 163m. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 330 Appendix 1 – Spectra Relevant to Chapter 2 331 Figure A1.243 Infrared spectrum (Thin Film, NaCl) of compound 163m. c 150 140 130 120 110 100 90 80 ppm 70 60 50 40 30 20 Figure A1.244 13C NMR (100 MHz, CDCl3) of compound 163m. 10 8 163n OH NH O 7 5 ppm 4 3 Figure A1.245 1H NMR (400 MHz, CDCl3) of compound 163n. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 332 Appendix 1 – Spectra Relevant to Chapter 2 333 Figure A1.246 Infrared spectrum (Thin Film, NaCl) of compound 163n. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.247 C NMR (100 MHz, CDCl3) of compound 163n. 20 10 9 8 163o OH NH S 6 5 ppm 4 3 Figure A1.248 1H NMR (400 MHz, CDCl3) of compound 163o. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 334 Appendix 1 – Spectra Relevant to Chapter 2 335 Figure A1.249 Infrared spectrum (Thin Film, NaCl) of compound 163o. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 Figure A1.250 C NMR (100 MHz, CDCl3) of compound 163o. 30 20 9 163p 8 OH NH S 6 5 ppm 4 3 Figure A1.251 1H NMR (400 MHz, CDCl3) of compound 163p. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 336 Appendix 1 – Spectra Relevant to Chapter 2 337 Figure A1.252 Infrared spectrum (Thin Film, NaCl) of compound 163p. c 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.253 13C NMR (100 MHz, CDCl3) of compound 163p. 30 9 8 163q OH NH N Me N 7 5 ppm 4 3 Figure A1.254 1H NMR (400 MHz, CDCl3) of compound 163q. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 338 Appendix 1 – Spectra Relevant to Chapter 2 339 Figure A1.255 Infrared spectrum (Thin Film, NaCl) of compound 163q. c 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.256 13C NMR (100 MHz, CDCl3) of compound 163q. 30 20 10 9 163r OH NH N 7 6 ppm 5 4 3 Figure A1.257 1H NMR (400 MHz, CDCl3) of compound 163r. 8 2 1 Appendix 1 – Spectra Relevant to Chapter 2 340 Appendix 1 – Spectra Relevant to Chapter 2 341 Figure A1.258 Infrared spectrum (Thin Film, NaCl) of compound 163r. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.259 C NMR (100 MHz, CDCl3) of compound 163r. 20 10 9 F 8 165a OH NH 6 5 ppm 4 3 Figure A1.260 1H NMR (400 MHz, CDCl3) of compound 165a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 342 Appendix 1 – Spectra Relevant to Chapter 2 343 Figure A1.261 Infrared spectrum (Thin Film, NaCl) of compound 165a. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 Figure A1.262 13C NMR (100 MHz, CDCl3) of compound 165a. 40 30 Appendix 1 – Spectra Relevant to Chapter 2 -108 -110 -112 -114 -116 ppm 344 -118 -120 -122 -124 Figure A1.263 19F NMR (282 MHz, CDCl3) of compound 165a. -126 8 F 165b OH NH 7 6 5 ppm 4 3 Figure A1.264 1H NMR (400 MHz, CDCl3) of compound 165b. OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 345 Appendix 1 – Spectra Relevant to Chapter 2 346 Figure A1.265 Infrared spectrum (Thin Film, NaCl) of compound 165b. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.266 13C NMR (100 MHz, CDCl3) of compound 165b. 30 20 Appendix 1 – Spectra Relevant to Chapter 2 -112 -113 -114 -115 347 -116 ppm -117 -118 -119 Figure A1.267 19F NMR (282 MHz, CDCl3) of compound 165b. -120 F 8 165c OH NH 7 CF3 5 ppm 4 3 Figure A1.268 1H NMR (400 MHz, CDCl3) of compound 165c. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 348 Appendix 1 – Spectra Relevant to Chapter 2 349 Figure A1.269 Infrared spectrum (Thin Film, NaCl) of compound 165c. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.270 13C NMR (100 MHz, CDCl3) of compound 165c. 30 Appendix 1 – Spectra Relevant to Chapter 2 -40 -50 -60 -70 -80 350 -90 ppm -100 -110 -120 Figure A1.271 19F NMR (282 MHz, CDCl3) of compound 165c. -130 -140 9 O O 8 165d OH NH 6 5 ppm 4 3 Figure A1.272 1H NMR (400 MHz, CDCl3) of compound 165d. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 2 351 Appendix 1 – Spectra Relevant to Chapter 2 352 Figure A1.273 Infrared spectrum (Thin Film, NaCl) of compound 165d. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.274 13C NMR (100 MHz, CDCl3) of compound 165d. 30 O O 8 165e OH NH OMe OMe 7 5 ppm 4 3 Figure A1.275 1H NMR (400 MHz, CDCl3) of compound 165e. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 353 Appendix 1 – Spectra Relevant to Chapter 2 354 Figure A1.276 Infrared spectrum (Thin Film, NaCl) of compound 165e. c 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 Figure A1.277 C NMR (100 MHz, CDCl3) of compound 165e. 30 9 8 165f OH NH 7 5 ppm 4 3 Figure A1.278 1H NMR (400 MHz, CDCl3) of compound 165f. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 355 Appendix 1 – Spectra Relevant to Chapter 2 356 180 160 140 120 13 100 ppm 80 60 35.44 59.07 57.56 66.38 144.41 132.21 132.12 132.02 131.89 128.75 128.42 127.74 126.84 126.71 126.29 125.53 123.37 122.94 Figure A1.279 Infrared spectrum (Thin Film, NaCl) of compound 165f. c 40 Figure A1.280 C NMR (100 MHz, CDCl3) of compound 165f. 20 8 167a OAc NH 7 5 ppm 4 3 Figure A1.281 1H NMR (400 MHz, CDCl3) of compound 167a. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 357 Appendix 1 – Spectra Relevant to Chapter 2 358 Figure A1.282 Infrared spectrum (Thin Film, NaCl) of compound 167a. c 180 160 140 120 13 100 ppm 80 60 40 Figure A1.283 C NMR (100 MHz, CDCl3) of compound 167a. 20 0 8 7 167b OMe NH 5 ppm 4 3 Figure A1.284 1H NMR (400 MHz, CDCl3) of compound 167b. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 359 Appendix 1 – Spectra Relevant to Chapter 2 360 Figure A1.285 Infrared spectrum (Thin Film, NaCl) of compound 167b. c 160 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 Figure A1.286 C NMR (100 MHz, CDCl3) of compound 167b. 20 10 9 8 167c OBn NH 6 5 ppm 4 Figure A1.287 1H NMR (400 MHz, CDCl3) of compound 167c. 7 3 2 1 Appendix 1 – Spectra Relevant to Chapter 2 361 Appendix 1 – Spectra Relevant to Chapter 2 362 Figure A1.288 Infrared spectrum (Thin Film, NaCl) of compound 167c. c 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A1.289 13C NMR (100 MHz, CDCl3) of compound 167c. 30 8 7 167d 6 5 ppm 4 3 Figure A1.290 1H NMR (400 MHz, CDCl3) of compound 167d. NHBoc NH 2 1 Appendix 1 – Spectra Relevant to Chapter 2 363 Appendix 1 – Spectra Relevant to Chapter 2 364 Figure A1.291 Infrared spectrum (Thin Film, NaCl) of compound 167d. c 180 160 140 120 100 ppm 80 60 40 Figure A1.292 13C NMR (100 MHz, CDCl3) of compound 167d. 20 8 167e Me NH 7 5 ppm 4 3 Figure A1.293 1H NMR (400 MHz, CDCl3) of compound 167e. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 365 Appendix 1 – Spectra Relevant to Chapter 2 366 Figure A1.294 Infrared spectrum (Thin Film, NaCl) of compound 167e. c 170 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A1.295 C NMR (100 MHz, CDCl3) of compound 167e. 20 10 8 H 7 168 O N OMe OMe 5 ppm 4 3 Figure A1.296 1H NMR (400 MHz, CDCl3) of compound 168. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 367 Appendix 1 – Spectra Relevant to Chapter 2 368 Figure A1.297 Infrared spectrum (Thin Film, NaCl) of compound 168. c 170 160 150 140 130 120 13 110 100 ppm 90 80 70 60 50 40 Figure A1.298 C NMR (100 MHz, CDCl3) of compound 168. 30 8 H 169 O N O OMe 7 OMe 5 ppm 4 3 Figure A1.299 1H NMR (400 MHz, CDCl3) of compound 169. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 369 Appendix 1 – Spectra Relevant to Chapter 2 370 Figure A1.300 Infrared spectrum (Thin Film, NaCl) of compound 169. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A1.301 13C NMR (100 MHz, CDCl3) of compound 169. 20 8 H 170 O N O 7 OMe OMe 5 ppm 4 3 Figure A1.302 1H NMR (400 MHz, CDCl3) of compound 170. 6 2 1 Appendix 1 – Spectra Relevant to Chapter 2 371 Appendix 1 – Spectra Relevant to Chapter 2 372 Figure A1.303 Infrared spectrum (Thin Film, NaCl) of compound 170. c 180 160 140 120 100 ppm 80 60 40 Figure A1.304 13C NMR (100 MHz, CDCl3) of compound 170. 20 8 7 H O H 6 OH OMe 5 ppm 4 3 Figure A1.305 1H NMR (400 MHz, CDCl3) of compound 171. 171 N H OMe 2 1 Appendix 1 – Spectra Relevant to Chapter 2 373 Appendix 1 – Spectra Relevant to Chapter 2 374 Figure A1.306 Infrared spectrum (Thin Film, NaCl) of compound 171. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A1.307 13C NMR (100 MHz, CDCl3) of compound 171. 30 20 10 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 375 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 2: Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 A2.1 376 GENERAL EXPERIMENTAL A crystal was mounted on a polyimide MiTeGen loop with STP Oil Treatment and placed under a nitrogen stream. Low temperature (100K) X-ray data were collected with a Bruker AXS KAPPA APEX II diffractometer diffractometer running at 50 kV and 30 mA (Mo Ka = 0.71073 Å; PHOTON 100 CMOS detector with TRIUMPH graphite monochromator). All diffractometer manipulations, including data collection, integration, and scaling were carried out using the Bruker APEX3 software. An absorption correction was applied using SADABS in point group 2. The space group was determined and the structure solved by intrinsic phasing using XT. Refinement was full-matrix least squares on F2 using XL. All non-hydrogen atoms were refined using anisotropic displacement parameters. Hydrogen atoms were placed in idealized positions and the coordinates refined (each of the two disordered pairs were constrained to the same position). The isotropic displacement parameters of all hydrogen atoms were fixed at 1.2 times (1.5 times for methyl groups and alcohol) the Ueq value of the bonded atom. A2.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF THIQ 163P The tetrahydroisoquinoline (THIQ) product 163p (87% ee) was crystallized by slow evaporation from chloroform at 23 °C to provide crystals suitable for X-ray analysis. Compound d19110 (163p) crystallizes in the monoclinic space group P21(#4) with one molecule in the asymmetric unit. The S atom and one C atom were disordered 60:40; the anisotropic displacement parameters of each of the C S bonded pairs were constrained to be the same. Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 Figure A2.1 X-ray crystal structure of THIQ 163p. Table A2.1 Crystal data and structure refinement for product 163p. Identification code d19110 Empirical formula C14 H15 N O S Formula weight 245.33 Temperature 100 K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 1 21 1 Unit cell dimensions a = 8.3309(19) Å a= 90° b = 6.6556(18) Å b= 96.337(8)° c = 10.916(3) Å g = 90° Volume 601.6(3) Å3 Z 2 Density (calculated) 1.354 g/cm3 Absorption coefficient 0.251 mm-1 F(000) 260 Crystal size 0.38 x 0.17 x 0.08 mm3 Theta range for data collection 1.877 to 35.613°. Index ranges -13 £ h £ 13, -10 £ k £ 10, -17 £ l £ 17 377 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 Reflections collected 25734 Independent reflections 5228 [R(int) = 0.0337] Completeness to theta = 25.242° 99.5 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.9299 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5228 / 1 / 209 Goodness-of-fit on F2 1.058 Final R indices [I>2sigma(I)] R1 = 0.0383, wR2 = 0.0909 R indices (all data) R1 = 0.0484, wR2 = 0.0960 Absolute structure parameter [Flack] 0.04(2) Absolute structure parameter [Hooft] 0.03(2) Extinction coefficient n/a Largest diff. peak and hole 0.457 and -0.227 e.Å-3 378 5 Table A2.2 Atomic coordinates (x 10 ), and equivalent isotropic displacement 2 4 parameters (Å x 10 ), and population for 163p. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ x y z U(eq) pop ________________________________________________________________________ S(1) -1782(9) 10112(13) 8554(8) 192(2) 0.61(1) S(1A) -12835(17) 26880(20) 15351(16) 200(4) 0.40(1) O(1) 46731(15) 90530(20) 2239(13) 250(3) 1 N(1) 38190(14) 60130(20) 16462(10) 126(2) 1 C(1) 31520(15) 47500(20) 25761(12) 119(2) 1 C(2) 45361(17) 34360(20) 31317(14) 146(2) 1 C(3) 59104(16) 47440(20) 36870(12) 135(2) 1 C(4) 69583(19) 40430(30) 46858(14) 193(3) 1 C(5) 81732(19) 52630(30) 52519(15) 236(3) 1 C(6) 83610(20) 71900(30) 48189(15) 243(4) 1 C(7) 73300(20) 79110(30) 38302(15) 210(3) 1 C(8) 60916(17) 66970(20) 32554(13) 140(2) 1 C(9) 49394(17) 75610(20) 22155(13) 133(2) 1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 C(10) C(11) C(12) C(13) C(13A) C(14) 58373(18) 16954(16) 17083(17) -10370(60) 1840(80) 1166(19) 84320(30) 36170(20) 18760(20) 29940(90) 11730(130) 42160(30) 11976(14) 20222(13) 13110(13) 16190(50) 9760(70) 21889(15) 174(3) 127(2) 147(2) 192(2) 200(4) 177(3) Table A2.3 Bond lengths [Å] and angles [°] for 163p. _____________________________________________________ S(1)-C(12) 1.6959(16) S(1)-C(13) 1.755(6) S(1A)-C(13A) 1.746(9) S(1A)-C(14) 1.6492(19) O(1)-H(1) 0.93(3) O(1)-C(10) 1.419(2) N(1)-H(1A) 0.90(2) N(1)-C(1) 1.4732(18) N(1)-C(9) 1.4799(19) C(1)-H(1B) 1.03(2) C(1)-C(2) 1.5193(19) C(1)-C(11) 1.4985(19) C(2)-H(2A) 0.98(2) C(2)-H(2B) 1.00(2) C(2)-C(3) 1.511(2) C(3)-C(4) 1.400(2) C(3)-C(8) 1.396(2) C(4)-H(4) 0.91(3) C(4)-C(5) 1.389(2) C(5)-H(5) 0.93(3) C(5)-C(6) 1.382(3) C(6)-H(6) 0.85(3) C(6)-C(7) 1.388(3) C(7)-H(7) 0.99(3) C(7)-C(8) 1.403(2) C(8)-C(9) 1.517(2) C(9)-H(9) 0.99(2) C(9)-C(10) 1.521(2) C(10)-H(10A) 0.96(3) C(10)-H(10B) 1.01(3) C(11)-C(12) 1.395(2) 379 1 1 1 0.61(1) 0.40(1) 1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 C(11)-C(14) C(12)-C(13A) C(12)-H(12) C(12)-H(12A) C(13)-H(13) C(13)-C(14) C(13A)-H(13A) C(14)-H(14A) C(14)-H(14) C(12)-S(1)-C(13) C(14)-S(1A)-C(13A) C(10)-O(1)-H(1) C(1)-N(1)-H(1A) C(1)-N(1)-C(9) C(9)-N(1)-H(1A) N(1)-C(1)-H(1B) N(1)-C(1)-C(2) N(1)-C(1)-C(11) C(2)-C(1)-H(1B) C(11)-C(1)-H(1B) C(11)-C(1)-C(2) C(1)-C(2)-H(2A) C(1)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(3)-C(2)-C(1) C(3)-C(2)-H(2A) C(3)-C(2)-H(2B) C(4)-C(3)-C(2) C(8)-C(3)-C(2) C(8)-C(3)-C(4) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(5)-C(6)-C(7) C(7)-C(6)-H(6) 1.405(2) 1.365(6) 0.94(2) 0.94(2) 0.91(5) 1.357(5) 1.04(8) 0.90(3) 0.90(3) 91.08(18) 91.0(2) 112.9(17) 108.6(14) 112.10(10) 106.4(15) 110.5(13) 106.04(11) 111.07(11) 108.3(12) 106.3(12) 114.61(12) 112.8(13) 110.8(13) 106(2) 109.66(12) 108.2(13) 109.0(13) 120.00(14) 120.42(12) 119.48(14) 117.4(15) 120.85(16) 121.3(15) 120.5(18) 119.70(16) 119.6(18) 122.3(19) 120.17(15) 117.3(19) 380 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 C(6)-C(7)-H(7) 122.1(15) C(6)-C(7)-C(8) 120.68(17) C(8)-C(7)-H(7) 117.2(15) C(3)-C(8)-C(7) 119.12(14) C(3)-C(8)-C(9) 121.50(12) C(7)-C(8)-C(9) 119.33(14) N(1)-C(9)-C(8) 111.60(12) N(1)-C(9)-H(9) 108.5(13) N(1)-C(9)-C(10) 107.26(12) C(8)-C(9)-H(9) 111.2(13) C(8)-C(9)-C(10) 111.69(12) C(10)-C(9)-H(9) 106.4(14) O(1)-C(10)-C(9) 107.91(12) O(1)-C(10)-H(10A) 111.9(15) O(1)-C(10)-H(10B) 111.6(13) C(9)-C(10)-H(10A) 109.0(14) C(9)-C(10)-H(10B) 110.1(14) H(10A)-C(10)-H(10B) 106(2) C(12)-C(11)-C(1) 125.94(13) C(12)-C(11)-C(14) 111.87(13) C(14)-C(11)-C(1) 122.19(13) S(1)-C(12)-H(12) 119.9(15) C(11)-C(12)-S(1) 112.40(11) C(11)-C(12)-H(12) 127.7(16) C(11)-C(12)-H(12A) 127.7(16) C(13A)-C(12)-C(11) 111.7(4) C(13A)-C(12)-H(12A) 120.6(16) S(1)-C(13)-H(13) 105(3) C(14)-C(13)-S(1) 111.3(4) C(14)-C(13)-H(13) 143(3) S(1A)-C(13A)-H(13A) 105(3) C(12)-C(13A)-S(1A) 112.0(5) C(12)-C(13A)-H(13A) 143(4) S(1A)-C(14)-H(14A) 120.7(15) C(11)-C(14)-S(1A) 113.35(14) C(11)-C(14)-H(14A) 125.9(15) C(11)-C(14)-H(14) 125.9(15) C(13)-C(14)-C(11) 113.4(3) C(13)-C(14)-H(14) 120.7(15) _____________________________________________________________ 381 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 2 382 4 Table A2.4 Anisotropic displacement parameters (Å x 10 ) for 163p. The anisotropic 2 displacement factor exponent takes the form: -2p [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ________________________________________________________________________ U11 U22 U33 U23 U13 U12 ________________________________________________________________________ S(1) 146(4) 220(4) 204(4) -44(3) -7(3) -76(3) S(1A) 121(7) 246(7) 223(6) -49(5) -15(4) -92(4) O(1) 205(6) 302(7) 251(6) 151(5) 60(4) 14(5) N(1) 133(5) 113(5) 131(5) 14(4) 8(4) -15(4) C(1) 109(5) 126(5) 121(5) 0(4) 13(4) -11(4) C(2) 129(6) 135(6) 168(6) 39(5) -7(4) -20(5) C(3) 101(5) 182(6) 123(5) 1(5) 14(4) 5(5) C(4) 157(6) 274(8) 144(6) 12(6) 2(5) 45(5) C(5) 127(6) 437(10) 143(6) -57(6) 2(5) 35(6) C(6) 148(6) 416(11) 167(6) -123(7) 23(5) -95(6) C(7) 191(7) 255(8) 193(6) -75(6) 54(5) -94(6) C(8) 125(5) 173(6) 126(5) -31(5) 35(4) -21(5) C(9) 150(6) 94(5) 161(6) -5(5) 45(4) -16(4) C(10) 171(6) 166(6) 191(6) 30(5) 53(5) -35(5) C(11) 124(5) 138(6) 114(5) 5(4) -2(4) -20(4) C(12) 150(6) 141(6) 147(6) -16(5) 10(4) -27(5) C(13) 146(4) 220(4) 204(4) -44(3) -7(3) -76(3) C(13A) 121(7) 246(7) 223(6) -49(5) -15(4) -92(4) C(14) 153(6) 197(7) 186(6) -13(5) 45(5) -5(5) ________________________________________________________________________ 4 Table A2.5 Hydrogen coordinates (x 10 ) and isotropic displacement parameters 2 3 (Å x 10 ) for 163p. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ H(1) 5130(30) 9700(50) -410(30) 38 H(1A) 3010(30) 6680(40) 1220(20) 15 H(1B) 2770(20) 5620(40) 3270(20) 14 H(2A) 4220(30) 2540(40) 3780(20) 18 H(2B) 4930(30) 2550(40) 2490(20) 18 H(4) 6740(30) 2820(40) 5010(20) 23 H(5) 8820(30) 4820(50) 5950(20) 28 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 H(6) H(7) H(9) H(10A) H(10B) H(13) H(13A) H(12) H(12A) H(14A) H(14) 9050(30) 7390(30) 4290(30) 6490(30) 6600(30) -2130(60) -450(70) 2610(30) 2610(30) -150(30) -150(30) 8010(40) 9310(40) 8670(40) 9530(40) 7400(40) 2800(70) -40(120) 1210(40) 1210(40) 5310(40) 5310(40) 5180(20) 3530(20) 2510(20) 1520(20) 910(20) 1480(40) 550(60) 1060(20) 1060(20) 2600(20) 2600(20) 383 29 25 16 21 21 23 24 21 21 21 21 Table A2.6 Torsion angles [°] for 163p. ________________________________________________________________ S(1)-C(13)-C(14)-C(11) 0.6(4) N(1)-C(1)-C(2)-C(3) 58.56(14) N(1)-C(1)-C(11)-C(12) 78.77(18) N(1)-C(1)-C(11)-C(14) -102.09(16) N(1)-C(9)-C(10)-O(1) 52.73(16) C(1)-N(1)-C(9)-C(8) 44.46(15) C(1)-N(1)-C(9)-C(10) 167.09(12) C(1)-C(2)-C(3)-C(4) 151.33(13) C(1)-C(2)-C(3)-C(8) -25.09(17) C(1)-C(11)-C(12)-S(1) 179.50(12) C(1)-C(11)-C(12)-C(13A) 178.1(4) C(1)-C(11)-C(14)-S(1A) -177.87(13) C(1)-C(11)-C(14)-C(13) -179.8(3) C(2)-C(1)-C(11)-C(12) -41.36(19) C(2)-C(1)-C(11)-C(14) 137.77(14) C(2)-C(3)-C(4)-C(5) -176.42(14) C(2)-C(3)-C(8)-C(7) 176.81(13) C(2)-C(3)-C(8)-C(9) -0.66(19) C(3)-C(4)-C(5)-C(6) -0.5(2) C(3)-C(8)-C(9)-N(1) -7.99(18) C(3)-C(8)-C(9)-C(10) -128.05(14) C(4)-C(3)-C(8)-C(7) 0.4(2) C(4)-C(3)-C(8)-C(9) -177.09(13) C(4)-C(5)-C(6)-C(7) 0.7(2) C(5)-C(6)-C(7)-C(8) -0.3(2) C(6)-C(7)-C(8)-C(3) -0.3(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 2 384 C(6)-C(7)-C(8)-C(9) 177.26(14) C(7)-C(8)-C(9)-N(1) 174.55(12) C(7)-C(8)-C(9)-C(10) 54.49(17) C(8)-C(3)-C(4)-C(5) 0.0(2) C(8)-C(9)-C(10)-O(1) 175.30(13) C(9)-N(1)-C(1)-C(2) -71.23(14) C(9)-N(1)-C(1)-C(11) 163.67(12) C(11)-C(1)-C(2)-C(3) -178.55(11) C(11)-C(12)-C(13A)-S(1A) 0.4(6) C(12)-S(1)-C(13)-C(14) -0.3(4) C(12)-C(11)-C(14)-S(1A) 1.37(18) C(12)-C(11)-C(14)-C(13) -0.6(3) C(13)-S(1)-C(12)-C(11) 0.0(2) C(13A)-S(1A)-C(14)-C(11) -0.9(3) C(14)-S(1A)-C(13A)-C(12) 0.3(5) C(14)-C(11)-C(12)-S(1) 0.29(16) C(14)-C(11)-C(12)-C(13A) -1.1(4) ________________________________________________________________ Table A2.7 Hydrogen bonds for 163p [Å and °]. ________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ________________________________________________________________________ O(1)-H(1)...N(1)#1 0.93(3) 1.90(3) 2.8310(18) 177(2) ________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y+1/2,-z Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 385 CHAPTER 3 Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines† 3.1 INTRODUCTION The asymmetric hydrogenation of heteroarenes has recently emerged as a powerful strategy to directly access enantioenriched, saturated heterocycles. 1 , 2 While significant progress has been made in this field, controlling selectivity in the formation of multiple stereocenters in a single reaction remains challenging. Transition metal-catalyzed hydrogenation of arenes typically proceeds through initial dearomative reduction of the substrate and subsequent rapid hydrogenation, resulting in high cis-selectivity of product (Figure 3.1A, path A).3,4 In contrast, accessing the trans-isomer requires a p-facial exchange of the arene to allow hydride delivery from the more sterically hindered face, rendering its synthesis significantly more difficult (Figure 3.1A, path B). While several reports describe the trans-selective hydrogenation of arenes, most are limited in scope and not ________________________________________________ † This research was performed in collaboration with Dr. Fa Ngamnithiporn, and Dr. Michael D. Bartberger. Portions of this chapter have been reproduced with permission from Kim, A. N.; Ngamnithiporn, A.; Bartberger, M. D.; Stoltz, B. M. Chem. Sci. 2022, 13, 3227–3232. © 2022 Royal Society of Chemistry. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 386 1,3-Disubstituted Isoquinolines enantioselective. 5 , 6 Considering the synthetic value of trans-substituted saturated heterocycles, a general method for an asymmetric trans-selective hydrogenation of heteroarenes would be a highly desirable and powerful strategy.7,8 Figure 3.1 A) Challenges in diastereoselectivity of trans-selective arene hydrogenation. B) Our research on iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines. A. 1) Diastereoselectivity in Asymmetric Arene Hydrogenation H Path A cis-selective R2 [M] H2 X R2 X H X R1 H X = CH, N R2 H R1 well-established [M] R1 H Path B trans-selective R2 X hydride delivery from more hindered face H R1 underdeveloped 2) Prior Art in trans-selective Hydrogenation Glorius, 2020: OH R 5 wt% Pd/Al2O3 (2–4 mol %) H2 (5–10 bar) OH R n-heptane (0.4 M) or i-PrOH (0.2 M) X X 80 °C, 24 h 62–99% overall yield X = CH, N 56:44–93:7 dr R = alkyl, aryl, NHBoc Beller, 2019: OH R [Co] catalyst (9 mol %) H2 (50 bar) OH R t-BuOH, 135 °C, 24 h R = alkyl 62–95% overall yield 52:48–93:7 dr No general method of a trans- and enantioselective hydrogenation of arenes reported B. Previous Research: This Research: Ar/Het Ar/Het R NH X ref. 9 R N OH Ir/L* H2 Ar/Het R NH OH trans-selective • enantioselective • mild reaction conditions • broad scope Recently, our group has reported the asymmetric hydrogenation of 1,3-disubstituted isoquinolines to access enantioenriched cis-1,2,3,4-tetrahydroisoquinolines (THIQs).9 This Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 387 1,3-Disubstituted Isoquinolines method enables the asymmetric hydrogenation of isoquinolines with Lewis basic functionalities, such as primary alcohols and heteroaryl-substituted isoquinolines, that significantly expanded the scope of the transformation compared to prior reports.10 During the course of this investigation, we also observed formation of the trans-THIQ under certain conditions with excellent enantioselectivity, albeit in small amounts. Herein, we disclose our efforts to develop the first examples of an asymmetric trans-selective hydrogenation of 1,3disubstituted isoquinolines to access enantioenriched trans-THIQs (Figure 3.1B). 3.2 REACTION OPTIMIZATION We began our hydrogenation studies with 1-(hydroxymethyl)-3-phenylisoquinoline (173a) as our model substrate. An initial experiment employing 1.25 mol % [Ir(cod)Cl]2, 3 mol % of chiral Josiphos ligand L7, and 7.5 mol % of TBAI in THF delivered the THIQ product with high cis-selectivity (Table 3.1, entry 1).9 We observed that using CH2Cl2 as solvent gave higher levels of diastereoselectivity for trans-isomer 174, with excellent enantioselectivity as well (97% ee, entry 2).11 Gratified by this result, we explored different additives and observed that smaller halides afforded higher levels of the desired diastereoselectivity, albeit with diminished conversion of 173a. Overall, TBABr provided the best combination of diastereo- and enantioselectivity (entry 3). Other additives such as TBAPF6 previously investigated by Pfaltz and coworkers completely shut down the reaction, demonstrating that halide salts were crucial for this transformation (entry 5).12 Seeking to improve the diastereoselectivity, we surveyed a variety of chiral ligand scaffolds and found the xyliphos ligand framework to be optimal (Table 3.4). We observed that more electron-rich aryl groups on the chiral ligand provided the trans-product with higher selectivity, with the DMM-substituted phosphine L7 affording the highest Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 388 1,3-Disubstituted Isoquinolines diastereoselectivity of 2:1 trans:cis (entry 3 vs. entries 6–9). In contrast, more electronwithdrawing aryl groups such as L6 favored the formation of the cis-product (entry 9). Table 3.1. Optimization of the asymmetric trans-selective hydrogenation.a Ph N [Ir(cod)Cl]2 (1.25 mol %) ligand (3 mol %) H2 (20 bar), additive (7.5 mol %) OH 9:1 solvent:AcOH (0.02 M) 23 °C, 18 h ligand NH OH 173a entry Ph 174 solvent additive % conversionb trans:cisb % ee of transc 1 L7 THF TBAI >95 1:15.7 – 2 L7 CH2Cl2 TBAI >95 1:1.5 97 3 L7 CH2Cl2 TBABr >95 2:1 93 4 L7 CH2Cl2 TBACl 75 2.3:1 80 5 L7 CH2Cl2 TBAPF6 <10 – – 6 L12 CH2Cl2 TBABr >95 1.8:1 94 7 L13 CH2Cl2 TBABr 95 1.4:1 99 8 L14 CH2Cl2 TBABr 45 1:2.3 35 9 L6 CH2Cl2 TBABr 83 1:2.9 81 10 L7 PhMe TBABr >95 1.2:1 91 11 L7 EtOAc TBABr >95 1:1.1 89 12 L7 CHCl3 TBABr 68 2.4:1 93 13 L7 1,2-DCE TBABr >95 2.4:1 92 P(Ar)2 P(Xyl)2 Fe Me L6: Ar = BTFM L7: Ar = DMM L13: Ar = 2-napthyl L14: Ar = furyl L12: Ar = Ph [a] Reaction conditions: 0.04 mmol of 173a, 1.25 mol % [Ir(cod)Cl]2, 3 mol % ligand, 7.5 mol % additive, 20 bar H2 in 2.0 mL 9:1 solvent:AcOH. [b] Determined from crude 1H NMR using 1,3,5trimethoxybenzene as standard. [c] Determined by chiral SFC analysis of Cbz-protected trans-product. BTFM = 3,5-bis(trifluoromethyl)phenyl; DMM = 4-methoxy-3,5-dimethylphenyl Having identified L7 as the optimal ligand, we briefly investigated different solvents. We observed that non-coordinating chlorinated solvents such as chloroform and 1,2dichloroethane (1,2-DCE) delivered product 174 with the highest trans-selectivity (entries 12–13), while non-chlorinated solvents toluene and ethyl acetate gave nearly a 1:1 diastereomeric ratio (entries 10–11).13 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 389 1,3-Disubstituted Isoquinolines We also explored different directing groups at the C1 position to probe their effects on the diastereoselectivity of this reaction. Isoquinolines bearing functionalities such as a methyl ether, benzyl ether, or acetate substituent (166a–c) solely provided the cis-THIQ, suggesting that they are not functioning as directing groups in the reaction (Table 3.2, entries 1–3). Indeed, the hydrogenation of isoquinoline 166e that lacks any potential directing group also afforded only the cis-diastereomer of product (entry 4). Table 3.2. Investigation of different directing groups to optimize the asymmetric transselective hydrogenation. Ph N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) X 9:1 1,2-DCE:AcOH (0.02 M) 23 °C, 18 h 173a, 166a–f Ph NH X 174, 167a–f entry X % conversionb trans:cisb % ee of transc 1 OAc (166a) 57 1:>20 – 2 OMe (166b) >95 1:17 – 3 OBn (166c) >95 1:>20 – 4 H (166e) 92 1:>20 – 5 NHBoc (166d) >95 1.4:1 25 6 NH2 (166g) 0 – – 7 OH (173a) >95 2.4:1 92 [a] Reaction conditions: 0.04 mmol of substrate, 1.25 mol % [Ir(cod)Cl]2, 3 mol % L7, 7.5 mol % TBABr, 20 bar H2 in 2.0 mL 9:1 1,2-DCE:AcOH. [b] Determined from crude 1H NMR using 1,3,5trimethoxybenzene as standard. [c] Determined by chiral SFC analysis of Cbz-protected trans-product. While Boc-protected amine 166d provided the product in 1.4:1 dr favoring the transTHIQ, basic amine functionalities such as primary amine 166g gave trace product, potentially due to catalyst deactivation (entries 5–6). Nevertheless, the investigation of different directing groups demonstrates that the hydroxyl functionality serves as the best directing group to selectively access the trans-diastereomer by enabling a p-facial exchange Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 390 1,3-Disubstituted Isoquinolines of the substrate and facilitating hydride delivery from the more sterically hindered face via a directed hydrogenation (entry 7). 3.3 SUBSTRATE SCOPE With optimized reaction conditions identified, we explored the substrate scope for this transformation (Scheme 3.1). Due to the inseparable nature of the cis- and transdiastereomers of the hydrogenated products, the crude reaction mixture was subsequently treated with 1,1-dicarbonyldiimidazole (CDI) to afford the oxazolidinone-fused THIQs that were then easily separable by column chromatography. From 175a, the relative and absolute stereochemistry of the trans-THIQ product was confirmed by X-ray crystallography.14 Gratifyingly, a wide variety of aryl substituents at the 3-position of the isoquinoline were well tolerated, selectively yielding the trans-product in moderate to excellent ee.15 Substitution at the para-position of the 3-aryl ring delivered hydrogenated products 175b– 175g in high selectivities, ranging from electron-rich substrates 175b–175c to more electronwithdrawing substrates 175d–175f. Sterically encumbered substrates such as 3-naphthyl, 3xylyl isoquinolines also afforded products 175h–175i in good isolated yields, with slightly diminished enantioselectivity. Furthermore, the nitrile functional group in 175f and naphthyl substituent of 175h were not reduced in this process, highlighting the chemoselectivity of this transformation. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 391 Scheme 3.1. Substrate scope of the trans-selective hydrogenation of 1,3-disubstituted isoquinolines.a N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH (0.1 M), 23 °C, 18 h N then CDI (4 equiv) THF, 50 °C, 15 h OH O O 173a–j 175a–j t-Bu OMe N N O N O O O O O 175a 175b 175c 63% yield 2.3:1 trans:cisb, 91% ee 64% yield 2.6:1 trans:cisb, 96% ee 67% yield 2.1:1 trans:cisb, 95% ee F N O N N O N O O O 175e 70% yield 3.3:1 trans:cisb, 95% ee 64% yield 2.7:1 trans:cisb, 91% ee O O O 175d Ph CN CF3 175f 175g 47% yieldc 1.9:1 trans:cisb, 83% ee 56% yield 2.5:1 trans:cisb, 75% ee Me OMe OMe Me N O O N O O N O O 175h 175i 175j 54% yield 2.1:1 trans:cisb, 89% ee 61% yield 1.8:1 trans:cisb, 86% ee 51% yield 1.3:1 trans:cisb, 87% ee [a] Isolated yields of the trans-isomer on a 0.2 mmol scale. SFC analysis was used to determine ee. [b] Determined by 1H NMR analysis of crude reaction. Additionally, we were pleased to observe that heteroaryl-substituted isoquinolines were well tolerated at 60 °C and 60 bar H2 to produce trans-THIQs 175k,l in high enantioselectivities (97% and 94% ee, respectively), and with no erosion of diastereoselectivity (Scheme 3.2). Finally, different electronics of the isoquinoline Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 392 1,3-Disubstituted Isoquinolines carbocycle such as fluorinated isoquinolines (173m–173n) were hydrogenated to afford electron-poor THIQs 175m–175n in high selectivities under our standard conditions. Scheme 3.2. Substrate scope of heteroaryl and fluorinated isoquinolines.a [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH (0.1 M), 23 °C, 18 h N N then CDI (4 equiv) THF, 50 °C, 15 h OH O O 173k–n 175k–n Me OMe N N N N N O O O O 175k 175l 88% yieldc,d 3.0:1 trans:cisb, 97% ee 64% yieldc 2.6:1 trans:cisb, 95% ee CF3 F N O O F N O O 175m 175n 67% yield 2.5:1 trans:cisb, 95% ee 54% yield 1.5:1 trans:cisb, 92% ee [a] Isolated yields of the trans-isomer on a 0.2 mmol scale. SFC analysis was used to determine ee. [b] Determined by 1H NMR analysis of crude reaction. [c] Performed at 60 bar H2 and 60 °C. [d] Total isolated yield of inseparable diastereomers. 3.4 SYNTHETIC UTILITY Having demonstrated that this transformation is general for a wide range of 1,3- disubstituted isoquinolines, we sought to derivatize the oxazolidinone-fused THIQs (Scheme 3.3). We were pleased to find that the oxazolidinone functional group could be efficiently removed with Ba(OH)2 •8H2O to afford THIQ 174 in 81% yield.16,17 Alternatively, reduction Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 393 1,3-Disubstituted Isoquinolines with DIBAL afforded N-methyl THIQ 176 in 73% yield, providing a facile access of our hydrogenated products to N-methyl protected THIQs. Scheme 3.3. Synthetic derivatizations of product 175a. Ba(OH)2 • 8H2O NH 1:1 1,4-dioxane:H2O 120 °C, 3 h OH 174 81% yield N O O 175a DIBAL NMe CH2Cl2 0 °C, 30 min OH 176 73% yield 3.5 PRELIMINARY MECHANISTIC INSIGHTS To elucidate the factors controlling the trans-selectivity in this transformation, several control experiments were conducted to probe the reaction mechanism (Scheme 3.4). Substituting TBABr for TBAI as the additive gave a 1:1.2 dr favoring the cis-product, with high enantioselectivities exhibited for both products. This suggests that the bromide ligand facilitates p-facial exchange of the substrate over iodide to afford higher levels of the transdiastereomer. 18 , 19 Replacing 1,2-DCE solvent for THF also delivered similar results, indicating that ethereal solvents inhibit the formation of trans-174 through stronger coordination with iridium (Scheme 3.4B).20 Overall, the combination of non-coordinating, chlorinated solvents and smaller halides are crucial in governing the observed transselectivity. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 394 Scheme 3.4. Control experiments of the asymmetric trans-selective hydrogenation. A. N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBAI (7.5 mol %) * NH 9:1 1,2-DCE:AcOH (0.02 M), 23 °C, 18 h OH OH 174 173a 1:1.2 trans:cis 97% ee of trans 84% ee of cis B. N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 9:1 THF:AcOH (0.02 M), 23 °C, 18 h OH 173a * NH OH 174 1:1.1 trans:cis 84% ee of trans 63% ee of cis Deuterium experiments were also conducted to determine the degree of deuteration of our hydrogenated products (Scheme 3.5). Interestingly, the combination of both D2 and CD3COOD delivered deuterium at the C1-, C3-, and C4-positions of the THIQ, as well as at the methylene carbon of the hydroxymethyl functional group (Scheme 3.5A). We attribute this exocyclic deuteration to a competitive b-hydride elimination pathway that is operative in situ under our trans-hydrogenation conditions (Scheme 3.5B).21,22 However, this is likely not a critical pathway toward the trans-product, as deuterium incorporation in the corresponding cis-isomer (cis-174) is also observed. Exchanging either D2 or CD3COOD for their protic counterparts demonstrated deuteride delivery primarily from the gas at the C1and C3-positions of 174, yet the acid also enables reduction of the isoquinoline ring. This suggests a proton-hydride exchange occurring between the acid and the iridium hydride species for hydrogenation.19,23 Further investigation of the mechanism and other applications of this technology will be reported in due course.24 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 395 Scheme 3.5. Deuterium experiments of substrate 173a. A. 98–99% D D 4 1 D 54–55% D [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) N 3 D NH 99% D 100% OH 174 + 9:1 1,2-DCE:CD3COOD 23 °C, 18 h 97% D D OH 173a D NH 91% D 32–33% D D 94% OH cis-174 B. Ph Ph β-hydride elimination N N [IrIII] + H H H O [IrIII] H C. N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH 23 °C, 18 h OH O 85–86% D D D NH 89% D 22–35% D 173a D. N OH 173a 3.6 [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:CD3COOD 23 °C, 18 h D 91% OH 174 59–61% D D D NH 14% D 22% D D 16% OH 174 CONCLUSIONS In conclusion, we have developed an asymmetric trans-selective hydrogenation reaction of 1,3-disubstituted isoquinolines for the syntheses of enantioenriched trans-THIQs. Key to this enantio- and diastereoselective reaction is the hydroxymethyl directing group at the C1-position which enables p-facial exchange of the substrate and facilitates hydride Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 396 1,3-Disubstituted Isoquinolines delivery from the sterically more hindered face. This method tolerates a wide range of electronics, Lewis basic functionalities, and substitution at the C1, C3, and C8-positions of the isoquinoline core, representing one of the first examples of an asymmetric hydrogenation technology to selectively access the trans-diastereomer of hydrogenated aromatic compounds. 3.7 EXPERIMENTAL SECTION 3.7.1 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. 25 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, oxr 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 500 MHz and Oxford 600 MHz spectrometers and are reported relative to residual CHCl3 (δ = 7.26 ppm) or TMS (δ = 0.00 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ = 77.16 ppm), C6D6 (δ = 128.06 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 13 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 397 1,3-Disubstituted Isoquinolines 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 path-length cell. High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Reagents were purchased from commercial sources and used as received unless otherwise stated. 3.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 3.7.2.1 Syntheses of hydroxymethyl 1,3-disubstituted isoquinolines General Sequence: O Br Ot-Bu enolate alkylation R R O O General Procedure 1 O O R N General Procedure 2 Me 160a–b 159a–b 158a–b Suzuki cross-coupling OTf annulation/ triflation Ar/Het R N General Procedure 3 Me Ar/Het oxidation/ reduction R N General Procedure 4 OH 161a–s, 166e, 172a,c 173a–n General Procedure 1: Enolate Alkylation of Aryl Bromide Pd2(dba)3 (5 mol %) P(t-Bu)3•HBF4 (10 mol %) tert-butyl acetate (2 equiv) LiHMDS (2.5 equiv) Br R O 158a–b O PhMe, 23 °C, 18 h O Ot-Bu O O R 159a–b Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines O Ot-Bu O O 398 159a tert-butyl 2-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acetate (159a): This procedure has been adapted from a previous report.9 In a Schlenk flask was added P(t-Bu)3•HBF4 (119 mg, 0.41 mmol), Pd2(dba)3 (188 mg, 0.21 mmol), a solution of 2-(2-bromophenyl)-2-methyl-1,3dioxolane (158a) (1.0 g, 4.1 mmol, 0.42 M), and tert-Butyl acetate (0.95 g, 8.2 mmol), respectively. The reaction mixture was cooled to –78 °C and sparged with nitrogen for 15 minutes. A degassed solution of LiHMDS (1.72 g, 10.25 mmol, 1 M in toluene) was then added via syringe. The reaction mixture was degassed for an additional 15 minutes at –78 °C, and allowed to slowly warm to room temperature. The reaction was stirred at room temperature for 18 hours, and then quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with Et2O twice. The combined organic phases were dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc in hexanes) to afford 159a as a yellow oil (1.05 g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.45 (m, 1H), 7.20 – 7.06 (m, 3H), 3.96 – 3.83 (m, 2H), 3.71 (s, 2H), 3.68 – 3.55 (m, 2H), 1.60 (s, 3H), 1.39 (s, 9H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines F O Ot-Bu O O 399 159b tert-butyl 2-(4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acetate (159b): Compound 159b was prepared using general procedure 1 and purified by column chromatography (10% EtOAc in hexanes) to provide a colorless solid (1.9 g, 60% yield); 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 10.3, 2.8 Hz, 1H), 7.15 (dd, J = 8.4, 5.7 Hz, 1H), 6.94 (td, J = 8.2, 2.9 Hz, 1H), 4.06 – 3.90 (m, 2H), 3.74 (s, 2H), 3.72 – 3.69 (m, 2H), 1.65 (s, 3H), 1.45 (s, 9H); All characterization data match those reported.9 General Procedure 2: Isoquinoline Annulation and Triflation O Ot-Bu 1. 33% TFA in CH2Cl2 23 °C R O O 159a–b 2. NH4OH, MeCN 70 °C, 12 h OH R N Me pyridine, Tf2O OTf R N CH2Cl2, 0 °C Me 160a–b OTf N Me 160a 1-methylisoquinolin-3-yl trifluoromethanesulfonate (160a): To a RBF was added ester 159a (2.78 g, 10.0 mmol), anhydrous CH2Cl2 (75 mL, 0.13 M), and TFA (25 mL, 33% volume of CH2Cl2), respectively. The reaction was stirred at room temperature for 2 hours, and then concentrated in vacuo. The crude was transferred to a Schlenk tube, dissolved in MeCN (10 mL, 1 M), and aqueous NH4OH (28–30%, 20 mL, 200% volume of MeCN). The Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 400 1,3-Disubstituted Isoquinolines tube was sealed with Kontes valve to prevent loss of gaseous ammonia and stirred at 70 °C. Within 1 hour, the yellow solid of the 3-hydroxyisoquinoline began to precipitate from the reaction solution. After stirring for 18 hours at 70 °C, the reaction was cooled to room temperature, then placed in a –20 °C freezer, and the yellow solid was collected via vacuum filtration. This yellow powder was then washed with cold MeCN and dried at high vacuum to provide 3-hydroxyisoquinoline intermediate (0.70 g, 4.39 mmol). If any starting material remains, the filtrate could be transferred to a flask and concentrated in vacuo to undergo a second condensation reaction. To a separate flame-dried RBF containing CH2Cl2 (22 mL, 0.2 M) and distilled pyridine (3.6 mL, 44 mmol), the collected yellow powder (0.70 g, 4.39 mmol) was added, and the resulting mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.5 mL, 8.8 mmol) was then added dropwise at 0 °C, and the reaction was stirred at 0 °C for 1 hour. The reaction was then quenched with saturated aqueous NaHCO3 at 0 °C, and then slowly warmed to room temperature. The reaction was extracted with CH2Cl2, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to afford 160a as a pale yellow oil (1.11 g, 38% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 8.5, 1.0 Hz, 1H), 7.88 (dt, J = 8.3, 1.0 Hz, 1H), 7.76 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.67 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.42 (s, 1H), 2.97 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 401 OTf N F Me 160b 7-fluoro-1-methylisoquinolin-3-yl trifluoromethanesulfonate (160b): Compound 160b was prepared from ester 159b using general procedure 2 and purified by column chromatography (10% EtOAc in hexanes) to provide a pale brown oil (384 mg, 31% yield over 3 steps): 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 9.0, 5.3 Hz, 1H), 7.76 (dd, J = 9.6, 2.5 Hz, 1H), 7.56 (ddd, J = 8.9, 8.0, 2.5 Hz, 1H), 7.43 (s, 1H), 2.92 (s, 3H); All characterization data match those reported.9 General Procedure 3: Suzuki Cross-Coupling OTf R N Me 160a–b Ar/Het XPhos Pd G3 + Ar/Het–B(OH)2 R N 2:1 K3PO4(0.5 M aq):THF 40 °C, 2 h Me 161b–s, 166e, 172a,c N Me 166e 1-methyl-3-phenylisoquinoline (166e): To a flame-dried 20-mL scintillation vial capped with a PTFE-lined septum was added XPhos Pd G3 (11.63 mg, 0.014 mmol) and phenyl boronic acid (126 mg, 1.03 mmol). The reaction vial was then evacuated and backfilled with N2 three times. The isoquinoline triflate 160a (200 mg, 0.687 mmol) in degassed THF (2 mL, 0.3 M) was then added to the vial, followed by degassed 0.5 M K3PO4 solution (4 mL, 0.2 M). The reaction was then stirred at 40 °C for 2 hours. Afterwards, the reaction was diluted with water and the aqueous layer was extracted with Et2O. The combined organic Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 402 1,3-Disubstituted Isoquinolines phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (5% EtOAc in hexanes) to afford 166e as a white solid (138 mg, 92% yield): 1 H NMR (400 MHz, CDCl3) δ 8.15 – 8.13 (m, 3H), 7.93 (s, 1H), 7.86 (dt, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.57 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.52 – 7.48 (m, 2H), 7.42 – 7.38 (m, 1H), 3.05 (s, 3H); All characterization data match those reported.9 N Me 161b 3-(4-(tert-butyl)phenyl)-1-methylisoquinoline (161b): Compound 161b was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a pale yellow oil (177 mg, 93% yield); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H) 8.06 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.57 – 7.52 (m, 3H), 3.04 (s, 3H), 1.38 (s, 9H); All characterization data match those reported.9 Ph N Me 161c 3-([1,1'-biphenyl]-4-yl)-1-methylisoquinoline (161c): Compound 161c was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a colorless solid (191 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 8.24 – 8.22 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.75 – Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 403 1,3-Disubstituted Isoquinolines 7.73 (m, 2H), 7.70 – 7.67 (m, 3H), 7.58 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.39 – 7.37 (m, 1H), 3.06 (s, 3H); All characterization data match those reported.9 OMe N Me 161d 3-(4-methoxyphenyl)-1-methylisoquinoline (161d): Compound 161d was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to afford a white solid (79 mg, 93% yield): 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.07 (m, 3H), 7.84 (s, 1H), 7.81 (d, J = 8.5, 1H), 7.64 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.53 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.06 – 7.01 (m, 2H), 3.88 (s, 3H), 3.03 (s, 3H); All characterization data match those reported.9 F N Me 161e 3-(4-fluorophenyl)-1-methylisoquinoline (161e): Compound 161e was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (155 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.07 (m, 3H), 7.89 – 7.81 (m, 2H), 7.68 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.20 – 7.16 (m, 2H), 3.04 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 404 CF3 N Me 161f 1-methyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (161f): Compound 161f was prepared from triflate 160a using general procedure 3 and purified by column chromatography (2% to 3% EtOAc in hexanes) to afford a white solid (89 mg, 91% yield): 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.4, 1H), 7.96 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.73 – 7.67 (m, 1H), 7.63 – 7.59 (m, 1H), 3.05 (s, 3H); All characterization data match those reported.9 CN N Me 161g 4-(1-methylisoquinolin-3-yl)benzonitrile (161g): Compound 161g was prepared from triflate 160a using general procedure 3 and purified by column chromatography (10% to 20% EtOAc in hexanes) to provide a white solid (144 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 8.38 – 8.22 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J = 8.3, 1H), 7.82 – 7.75 (m, 2H), 7.73 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.64 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 3.05 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 405 N Me 161j 1-methyl-3-(naphthalen-2-yl)isoquinoline (161j): Compound 161j was prepared from triflate 160a using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (159 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (dd, J = 8.6, 1.8 Hz, 1H), 8.16 (dq, J = 8.3, 1.0 Hz, 1H), 8.07 (s, 1H), 8.00 – 7.96 (m, 2H), 7.91 – 7.86 (m, 2H), 7.70 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.59 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.56 – 7.46 (m, 2H), 3.09 (s, 3H); All characterization data match those reported.9 Me Me N Me 161k 3-(3,5-dimethylphenyl)-1-methylisoquinoline (161k): Compound 161k was prepared from triflate 160a using general procedure 3 and purified by column chromatography to provide a white solid (156 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.4, 1.1 Hz, 1H), 7.90 (s, 1H), 7.85 (dd, J = 8.2, 0.7 Hz, 1H), 7.75 (s, 2H), 7.66 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.05 (s, 1H), 3.05 (s, 3H), 2.43 (s, 6H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 406 OMe OMe N Me 161l 3-(3,4-dimethoxyphenyl)-1-methylisoquinoline (161l): Compound 161l was prepared from triflate 160a using general procedure 3 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (195 mg, 99% yield); 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4, 1H), 7.89 – 7.81 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.55 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.95 (s, 3H), 3.04 (s, 3H); All characterization data match those reported.9 Me N N N Me 161q 1-methyl-3-(1-methyl-1H-pyrazol-4-yl)isoquinoline (161q): Compound 161q was prepared from triflate 160a using general procedure 3 and purified by column chromatography (50% to 60% EtOAc in hexanes) to provide a white solid (112 mg, 99% yield): 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 8.04 – 8.00 (m, 2H), 7.77 (dd, J = 8.2, 1.1 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.54 – 7.47 (m, 1H), 3.98 (s, 3H), 2.97 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 407 OMe N N Me 161s 3-(6-methoxypyridin-3-yl)-1-methylisoquinoline (161s): Compound 161s was prepared from triflate 160a using general procedure 3 and purified by column chromatography (15% EtOAc in hexanes) to afford a white solid (232 mg, 90% yield): 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 2.5, 0.8 Hz, 1H), 8.36 (dd, J = 8.6, 2.5 Hz, 1H), 8.11 (dd, J = 8.4, 1.0 Hz, 1H), 7.85 – 7.83 (m, 2H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.56 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 6.87 (dd, J = 8.6, 0.8 Hz, 1H), 4.01 (s, 3H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 159.0, 147.7, 145.7, 137.6, 136.8, 130.3, 129.2, 127.6, 126.9, 126.6, 125.8, 114.5, 110.8, 53.8, 22.8; IR (Neat Film, NaCl) 2937, 2363, 1604, 1568, 1498, 1443, 1326, 1278, 1254, 1119, 1021, 831, 745; HRMS (MM:ESI-APCI+) m/z calc’d for C16H15N2O [M+H]+: 251.1184, found 251.1185. N F Me 172a 7-fluoro-1-methyl-3-phenylisoquinoline (172a): Compound 172a was prepared from triflate 160b using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (110 mg, 93% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.11 (m, 2H), 7.90 (s, 1H), 7.85 (dd, J = 9.2, 5.7 Hz, 1H), 7.73 – 7.68 (m, 1H), 7.54 – 7.48 (m, 2H), 7.48 – 7.38 (m, 2H), 2.99 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 408 CF3 N F Me 172c 7-fluoro-1-methyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (172c): Compound 172c was prepared from triflate 160b using general procedure 3 and purified by column chromatography (5% EtOAc in hexanes) to provide a white solid (150 mg, 98% yield): 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.0 Hz, 2H), 7.94 (s, 1H), 7.90 – 7.85 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.71 – 7.69 (m, 1H), 7.53 – 7.43 (m, 1H), 2.99 (s, 3H); All characterization data match those reported.9 General Procedure 4: Oxidation and Reduction to Hydroxymethyl Isoquinoline Ar/Het R 1. SeO2, dioxane 110 °C N Me 161a–s, 166e, 172a,c 2. NaBH4 CH2Cl2/MeOH, 23 °C Ar/Het R N OH 173a–n N OH 173a (3-phenylisoquinolin-1-yl)methanol (173a): To a 20-mL microwave vial containing a stir bar was added SeO2 (140 mg, 1.26 mmol), isoquinoline 166e (138 mg, 0.63 mmol), and 1,4dioxane (13 mL, 0.05 M). The reaction vial was then sealed and heated to 110 °C while stirring for 2 hours. The reaction was then cooled to room temperature, filtered through celite, and rinsed with EtOAc. The filtrate was then concentrated in vacuo to afford the aldehyde intermediate, which was used in the next step without further purification. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 409 1,3-Disubstituted Isoquinolines A scintillation vial containing the crude in 4:1 DCM:MeOH (0.1 M) was added sodium borohydride (24 mg, 0.63 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC, and then quenched by the addition of citric acid monohydrate (132 mg, 0.63 mmol). The reaction was stirred for an additional 10 minutes then basified by the addition of saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (20% acetone in hexanes) to afford 173a as a white solid (100 mg, 68% yield over 2 steps): 1H NMR (400 MHz, CDCl3) δ 8.18 – 8.15 (d, J = 7.0 Hz, 2H), 8.03 (s, 1H), 7.94 – 7.92 (m, 2H), 7.73 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.46 – 7.42 (m, 1H), 5.31 (s, 2H), 5.26 (br s, 1H, OH); All characterization data match those reported.9 OMe N OH 173b (3-(4-methoxyphenyl)isoquinolin-1-yl)methanol (173b): Compound 162d was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (48 mg, 73% yield): 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.07 (m, 2H), 7.93 (s, 1H), 7.91 – 7.85 (m, 2H), 7.69 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.06 – 7.03 (m, 2H), 5.28 (s, 3H), 3.89 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 410 N OH 173c ((3-(4-(tert-butyl)phenyl)isoquinolin-1-yl)methanol (173c): Compound 173c was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (162 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.06 (m, 2H), 8.00 (s, 1H), 7.97 – 7.85 (m, 2H), 7.72 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.62 – 7.58 (m, 1H), 7.58 – 7.52 (m, 2H), 5.30 (s, 3H), 1.40 (s, 9H); All characterization data match those reported.9 F N OH 173d (3-(4-fluorophenyl)isoquinolin-1-yl)methanol (173d): Compound 173d was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a colorless solid (149 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.9, 5.4 Hz, 2H), 7.96 (s, 1H), 7.95 – 7.89 (m, 2H), 7.73 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.21 (dd, J = 8.9, 8.5 Hz, 2H), 5.30 (s, 2H), 5.17 (br s, 1H, OH); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 411 CF3 N OH 173e (3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)methanol (173e): Compound 173e was prepared using general procedure 4 and purified by column chromatography (10% to 20% EtOAc in hexanes) to provide a white solid (23 mg, 25% yield); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 2H), 8.07 (s, 1H), 8.00 – 7.92 (m, 2H), 7.82 – 7.73 (m, 3H), 7.70 – 7.61 (m, 1H), 5.32 (s, 2H), 5.10 (br s, 1H, OH); All characterization data match those reported.9 CN N OH 173f 4-(1-(hydroxymethyl)isoquinolin-3-yl)benzonitrile (173f): Compound 173f was prepared using general procedure 4 and purified by column chromatography (30% EtOAc in hexanes) to provide a white solid (138 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 8.31 – 8.18 (m, 2H), 8.09 (s, 1H), 7.97 (m, 2H), 7.86 – 7.74 (m, 3H), 7.68 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 5.32 (s, 2H), 4.99 (s, 1H); All characterization data match those reported.9 Ph N OH 173g (3-([1,1'-biphenyl]-4-yl)isoquinolin-1-yl)methanol (173g): Compound 173g was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 412 1,3-Disubstituted Isoquinolines to provide a colorless solid (181 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 8.30 – 8.20 (m, 2H), 8.07 (s, 1H), 7.98 – 7.88 (m, 2H), 7.81 – 7.66 (m, 5H), 7.62 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.49 (dd, J = 8.2, 6.8 Hz, 2H), 7.43 – 7.34 (m, 1H), 5.32 (s, 3H); All characterization data match those reported.9 N OH 173h (3-(naphthalen-2-yl)isoquinolin-1-yl)methanol (173h): Compound 173h was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (158 mg, 97% yield); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.27 (dd, J = 8.6, 1.8 Hz, 1H), 8.16 (s, 1H), 8.05 – 7.93 (m, 4H), 7.91 – 7.89 (m, 1H), 7.75 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 – 7.47 (m, 2H), 5.34 (s, 3H); All characterization data match those reported.9 Me Me N OH 173i (3-(3,5-dimethylphenyl)isoquinolin-1-yl)methanol (173i): Compound 173i was prepared using general procedure 4 and purified by column chromatography (20% EtOAc in hexanes) to provide a white solid (155 mg, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.94 – 7.91 (m, 2H), 7.78 – 7.76 (m, 2H), 7.72 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.60 (ddd, J = Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 413 1,3-Disubstituted Isoquinolines 8.2, 6.9, 1.2 Hz, 1H), 7.09 (s, 1H), 5.30 (s, 3H), 2.44 (s, 6H); All characterization data match those reported.9 OMe OMe N OH 173j (3-(3,4-dimethoxyphenyl)isoquinolin-1-yl)methanol (173j): Compound 173j was prepared using general procedure 4 and purified by column chromatography (40% EtOAc in hexanes) to provide a white solid (180 mg, 91% yield); 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.93 – 7.90 (m, 2H), 7.77 – 7.67 (m, 3H), 7.58 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.03 – 7.01 (m, 1H), 5.30 (s, 2H), 5.26 (br s, 1H, OH), 4.03 (s, 3H), 3.97 (s, 3H); All characterization data match those reported.9 Me N N N OH 173k (3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1-yl)methanol (173k): Compound 173k was prepared using general procedure 4 and purified by column chromatography (70% to 80% EtOAc in hexanes + 1% NEt3) to provide a pale beige solid (72 mg, 62% yield): 1H NMR (400 MHz, CDCl3) δ 8.08 – 7.95 (m, 2H), 7.85 – 7.79 (m, 2H), 7.71 – 7.59 (m, 2H), 7.53 – 7.49 (m, 1H), 5.21 (s, 2H), 3.98 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 414 OMe N N OH 173l (3-(pyridin-2-yl)isoquinolin-1-yl)methanol (173l): Compound 173l was prepared from isoquinoline 161s using general procedure 4 and purified by column chromatography (20% to 30% EtOAc in hexanes) to provide a white solid (177 mg, 72% yield); 1H NMR (400 MHz, CDCl3) δ 8.94 (dd, J = 2.6, 0.7 Hz, 1H), 8.34 (dd, J = 8.7, 2.5 Hz, 1H), 7.94 – 7.91 (m, 3H), 7.73 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.89 (dd, J = 8.7, 0.7 Hz, 1H), 5.30 (s, 2H), 5.10 (br s, 1H, OH), 4.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.6, 157.7, 146.4, 145.7, 137.2, 137.0, 131.1, 128.2, 127.8, 127.6, 124.1, 123.3, 115.4, 111.1, 61.6, 53.9; IR (Neat Film, NaCl) 3380, 3058, 2948, 2363, 1624, 1606, 1573, 1504, 1447, 1380, 1326, 1286, 1088, 1024, 832, 747 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H15N2O2 [M+H]+: 267.1128, found 267.1131. F N OH 173m (7-fluoro-3-phenylisoquinolin-1-yl)methanol (173m): Compound 173m was prepared using general procedure 4 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (94 mg, 81% yield): 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.96 – 7.87 (m, 1H), 7.57 – 7.47 (m, 4H), 7.44 (td, J = 6.9, 6.4, 1.4 Hz, 1H), 5.21 (s, 2H), 5.11 (br s, 1H, OH); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 415 OMe N F OH 173n (7-fluoro-3-(4-(trifluoromethyl)phenyl)isoquinolin-1-yl)methanol (173n): Compound 173n was prepared using general procedure 4 and purified by column chromatography (10% EtOAc in hexanes) to provide a white solid (80 mg, 60% yield): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.1 Hz, 2H), 8.02 (s, 1H), 7.95 (dd, J = 9.8, 5.4 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.58 – 7.47 (m, 2H), 5.21 (s, 2H), 4.94 (br s, 1H, OH); All characterization data match those reported.9 3.7.2.2 Syntheses of isoquinolines with different directing groups Ac2O, pyridine DMAP N THF, 23 °C N OH OAc 173a 166a (3-phenylisoquinolin-1-yl)methyl acetate (166a): To a scintillation vial containing a stir bar and isoquinoline 173a (165 mg, 0.70 mmol) in THF (7 mL, 0.1 M) was added DMAP (8.6 mg, 0.07 mmol) and pyridine (0.14 mL, 1.75 mmol). Acetic anhydride (0.1 mL, 1.05 mmol) was then added dropwise. The reaction was stirred overnight at room temperature then diluted with Et2O and washed with saturated aqueous NH4Cl. The organic phase was collected, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (10% EtOAc in hexanes) to afford 166a as a colorless viscous oil (194 mg, >99% yield): 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.13 (m, 2H), 8.11 (dd, J = 8.4, 1.0 Hz, 1H), 8.07 (s, 1H), 7.92 (dt, J = 8.3, 0.9 Hz, 1H), 7.71 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 416 1,3-Disubstituted Isoquinolines 7.61 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.45 – 7.38 (m, 1H), 5.79 (s, 2H), 2.20 (s, 3H); All characterization data match those reported.9 MeI, t-BuOK N THF, 0 to 23 °C N OH OMe 173a 166b 1-(methoxymethyl)-3-phenylisoquinoline (166b): To a scintillation vial containing a stir bar and isoquinoline 173a (165 mg, 0.70 mmol) in THF (7 mL, 0.1 M) was added KOt-Bu (86 mg, 0.77 mmol) at room temperature. The resulting mixture was stirred for 5 minutes, then cooled to 0 °C, and MeI (0.05 mL, 0.77 mmol) was added. The reaction was allowed to slowly warm to room temperature overnight and then was quenched with saturated aqueous NH4Cl. The organic phase was collected and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography (5% EtOAc in hexanes) to afford 166b as a white solid (79 mg, 45% yield): 1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 8.4, 1.1 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.04 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.69 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.60 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.51 (td, J = 7.3, 6.5, 1.2 Hz, 2H), 7.45 – 7.37 (m, 1H), 5.14 (s, 2H), 3.51 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 417 NaH, BnBr N N THF, 0 to 23 °C OH OBn 173a 166c 1-((benzyloxy)methyl)-3-phenylisoquinoline (166c): This procedure has been adapted from a previous report.26 To a flame-dried RBF equipped with a stir bar was added NaH (36.4 mg, 60% w/w in oil, 0.91 mmol) and THF (7 mL, 0.1 M). To this suspension, isoquinoline 173a (165 mg, 0.70 mmol) was added. After 5 minutes of stirring at room temperature, the reaction mixture was cooled to 0 °C and BnBr (0.91 mL, 0.91 mmol) was added. The reaction was allowed to slowly warm to room temperature overnight. Silica (1 g) was then added and the solvent was evaporated under vacuum. The crude product was purified by column chromatography (5% EtOAc in hexanes) to afford 166c as a colorless viscous oil (153 mg, 67% yield): 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 8.4, 1.1 Hz, 1H), 8.21 – 8.14 (m, 2H), 8.04 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.69 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.58 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.51 (dd, J = 8.4, 6.9 Hz, 2H), 7.45 – 7.27 (m, 6H), 5.24 (s, 2H), 4.67 (s, 2H); All characterization data match those reported.9 SeO2 N Me 166e N dioxane, 110 °C H O 166f 3-phenylisoquinoline-1-carbaldehyde (166f): To a Schlenk flask containing a stir bar was added SeO2 (140 mg, 1.26 mmol) and isoquinoline 166e (138 mg, 0.63 mmol) in 1,4-dioxane (13 mL, 0.05 M). The reaction vial was then sealed and heated to 110 °C while stirring for 2 hours. The reaction was then cooled to room temperature and filtered through celite rinsing Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 418 1,3-Disubstituted Isoquinolines with EtOAc. The crude product was then purified by column chromatography (5% EtOAc in hexanes) to afford 166f as a pale yellow solid (1.32 g, 96% yield): 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.32 (d, J = 8.2 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 7.3 Hz, 1H), 7.84 – 7.67 (m, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H); All characterization data match those reported.9 Boc-amide TFA, Et3SiH N H O 166f MeCN, 23 °C N NHBoc 166d tert-butyl ((3-phenylisoquinolin-1-yl)methyl)carbamate (166d): To a solution of aldehyde 166f (150 mg, 0.64 mmol) and t-butyl carbamate (150 mg, 1.28 mmol) in MeCN (6.5 mL, 0.1 M) were added trifluoroacetic acid (0.15 mL, 1.92 mmol) and triethylsilane (1.0 mL, 6.4 mmol). The reaction was stirred at room temperature overnight and then quenched with saturated aqueous Na2CO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (15% EtOAc in hexanes) to afford 166d as a white solid (160 mg, 75% yield): 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.70 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.61 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.48 – 7.40 (m, 1H), 6.43 (br s, 1H), 5.03 (d, J = 4.4 Hz, 2H), 1.54 (s, 9H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 419 TFA N N CH2Cl2, 23 °C NHBoc NH2 166d 166g (3-phenylisoquinolin-1-yl)methanamine (166g): To a solution of carbamate 166d (225 mg, 0.67 mmol) in CH2Cl2 (2.2 mL, 0.3 M) was added trifluoroacetic acid (1.03 mL, 13.48 mmol, 20 equiv). The reaction was stirred at 23 °C for 1 hour and then neutralized to neutral pH with 1M NaOH. The organic phase was washed with water and extracted with CH2Cl2 (2 x 20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (5% MeOH in CH2Cl2 with 1% NEt3) to afford 166g as a yellow solid (113 mg, 72% yield): 1H NMR (400 MHz, CDCl3) δ 8.21 – 8.18 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.68 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.58 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.53 – 7.49 (m, 2H), 7.44 – 7.39 (m, 1H), 4.56 (s, 2H), 2.31 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 159.9, 149.5, 139.6, 137.1, 130.3, 128.9, 128.6, 128.0, 127.2, 127.0, 125.2, 124.1, 115.7, 44.6; IR (Neat Film, NaCl) 3276, 3054, 2968, 2924, 1622, 1574, 1501, 1456, 1439, 1365, 1326, 1201, 882, 784, 766, 694 cm–1; HRMS (MM:ESIAPCI+) m/z calc’d for C16H15N2 [M+H]+: 235.1235, found 235.1231. 3.7.2.3 Hydrogenation reactions General Procedure 5: Hydrogenation Reactions Ar/Het N OH 173a–n [Ir(cod)Cl]2 (1.25 mol %) ligand (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH (0.1 M), 23 °C, 18 h N then CDI (4 equiv), THF, 50 °C, 15 h O Ar/Het P(DMM)2 175a–n O P(Xyl)2 Fe Me ligand: SL-J418-1 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 420 1,3-Disubstituted Isoquinolines An oven-dried 20-mL scintillation vial containing a magnetic stir bar and an isoquinoline substrate (0.2 mmol) was capped with a PTFE-lined septum and pierced with two 21-gauge needles. The vials were then placed in a Parr bomb and brought into a N2-filled glovebox, with the exception of the pressure gauge. In a nitrogen-filled glovebox, a solution of the ligand (SL-J418-1) (4.53 mg, 0.006 mmol per reaction) and [Ir(cod)Cl]2 (1.68 mg, 0.0025 mmol per reaction) in 1,2-DCE (1.8 mL per reaction) was prepared and allowed to stand for 10 minutes. Meanwhile, a solution of TBABr (4.83 mg, 0.015 mmol per reaction) in AcOH (0.2 mL per reaction) was prepared in a 1-dram vial, and 0.2 mL of the solution was added to each reaction vial by syringe. Afterwards, 1.8 mL of the homogeneous iridium catalyst solution was added to each reaction vial by syringe. After re-capping the vials with caps equipped with needles, the reaction vials were placed in the bomb and the top was covered tightly with plastic wrap secured by a rubber band. The bomb was then removed from the glovebox, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was repeated two more times, before charging the bomb to 20 bar of H2 (or 60 bar H2). The bomb was then left stirring at 200 rpm at 23 °C (or placed in an oil bath and heated to 60 °C) for 18 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3 (2 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organics layers were then dried over Na2SO4 and concentrated in vacuo. The diastereoselectivity of the hydrogenation reaction was determined by crude 1H NMR analysis. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 421 1,3-Disubstituted Isoquinolines Then, to a scintillation vial containing the crude reaction mixture in THF (0.05 M) was added 1,1’-carbonyldiimidazole (CDI) (130 mg, 0.8 mmol, 4 equiv) and heated at 50 °C for 15 hours. The reaction mixture was then cooled to 23 °C, concentrated, and purified by column chromatography to separate the diastereomers and isolate the trans-product. Please note that the NMR data listed is for the major diastereomer. The enantiomeric excess was determined by chiral SFC analysis of the trans-product (see Table 3.5). The absolute configuration was determined for compound 175a via X-ray crystallographic analysis, and the absolute configuration for all other products has been inferred by analogy. NH OAc 167a ((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl acetate (167a): Compound 167a was prepared from isoquinoline 166a using general procedure 5 and determined by 1H NMR spectroscopy of the crude reaction mixture to consist of a mixture of diastereomers; (dr = >20:1); 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.45 (m, 2H), 7.41 – 7.37 (m, 2H), 7.34 – 7.30 (m, 1H), 7.27 – 7.24 (m, 1H), 7.23 – 7.18 (m, 2H), 7.16 – 7.10 (m, 1H), 4.78 (dd, J = 10.8, 3.5 Hz, 1H), 4.54 – 4.51 (m, 1H), 4.14 (dd, J = 10.8, 8.7 Hz, 1H), 4.05 (dd, J = 11.1, 3.4 Hz, 1H), 3.08 – 3.01 (m, 1H), 2.90 (dd, J = 15.5, 3.6 Hz, 1H), 2.08 (s, 3H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 422 NH OMe 167b (1S,3R)-1-(methoxymethyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167b): Compound 167b was prepared from isoquinoline 166b using general procedure 5 and determined by 1H NMR spectroscopy of the crude reaction mixture to consist of a mixture of diastereomers; (dr = 17:1); 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.46 (m, 2H), 7.39 – 7.35 (m, 2H), 7.32 – 7.27 (m, 1H), 7.25 – 7.20 (m, 1H), 7.20 – 7.15 (m, 2H), 7.16 – 7.10 (m, 1H), 4.45 – 4.42 (m, 1H), 4.07 – 3.94 (m, 2H), 3.59 (t, J = 8.7 Hz, 1H), 3.43 (s, 3H), 3.06 (dd, J = 16.0, 11.1 Hz, 1H), 2.92 (dd, J = 16.0, 3.6 Hz, 1H); All characterization data match those reported.9 NH OBn 167c (1S,3R)-1-((benzyloxy)methyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167c): Compound 167c was prepared from isoquinoline 166c using general procedure 5 and determined by 1H NMR spectroscopy of the crude reaction mixture to consist of a mixture of diastereomers; (dr = >20:1); 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.46 (m, 2H), 7.40 – 7.34 (m, 6H), 7.32 – 7.28 (m, 2H), 7.22 – 7.16 (m, 3H), 7.14 – 7.11 (m, 1H), 4.61 (s, 2H), 4.48 (dd, J = 8.7, 3.4 Hz, 1H), 4.12 (dd, J = 9.0, 3.6 Hz, 1H), 4.04 (dd, J = 11.1, 3.5 Hz, 1H), 3.67 (t, J = 8.7 Hz, 1H), 3.05 (dd, J = 15.9, 11.1 Hz, 1H), 2.91 (dd, J = 15.8, 3.5 Hz, 1H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 423 NH NHBoc 167d tert-butyl (((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)carbamate (167d): Compound 167d was prepared from isoquinoline 166d using general procedure 5 and determined by 1H NMR spectroscopy of the crude reaction mixture as a mixture of diastereomers; (dr = 1.4:1); 25% ee for major diastereomer; [α]D25 –1.3 (c 0.53, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.45 (m, 2H), 7.40 – 7.36 (m, 2H), 7.32 – 7.28 (m, 1H), 7.20 – 7.18 (m, 3H), 7.14 – 7.12 (m, 1H), 5.12 (br s, 1H), 4.18 (dd, J = 10.7, 4.0 Hz, 1H), 3.59 – 3.54 (m, 1H), 3.39 (ddd, J = 14.2, 10.7, 4.9 Hz, 1H), 3.02 (dd, J = 16.3, 4.2 Hz, 1H), 2.94 (dd, J = 16.3, 10.8 Hz, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.0, 142.8, 134.5, 134.3, 128.2, 127.6, 126.4, 126.0, 125.7, 125.7, 125.1, 55.2, 50.1, 43.6, 36.1, 28.9, 27.4; IR (Neat Film, NaCl) 3733, 3330, 2924, 2368, 2335, 1699, 1492, 1394, 1366, 1268, 1258, 1171, 754 cm-1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H27N2O2 [M+H]+: 339.2073, found 339.2075; SFC Conditions: 30% IPA, 2.5 mL/min, Chiralpak ADH column, λ = 210 nm, tR (min): major = 1.95, minor = 4.28. NH Me 167e (1R,3R)-1-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline (167e): Compound 167e was prepared from isoquinoline 166e using general procedure 5 and determined by 1H NMR spectroscopy of the crude reaction mixture to consist of a mixture of diastereomers; (dr = Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 424 1,3-Disubstituted Isoquinolines >20:1); 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.46 (m, 2H), 7.41 – 7.37 (m, 2H), 7.33 – 7.29 (m, 1H), 7.28 – 7.23 (m, 1H), 7.23 – 7.14 (m, 2H), 7.11 (d, J = 6.9 Hz, 1H), 4.34 (q, J = 6.6 Hz, 1H), 4.08 (dd, J = 11.1, 3.9 Hz, 1H), 3.12 – 3.01 (m, 1H), 2.96 (dd, J = 16.2, 4.1 Hz, 1H), 1.55 (d, J = 6.5 Hz, 3H); All characterization data match those reported.9 NH OH 174 ((1S,3R)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (174): Compound 174 was prepared from isoquinoline 173a from general procedure 5 and purified by column chromatography (5% MeOH in CH2Cl2) to provide a tan solid as a mixture of diastereomers (47 mg, 98% yield) (dr = 2.4:1); 92% ee for major diastereomer; [α]D25 –8.3 (c 0.15, CHCl3); Trans-diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H), 7.42 – 7.38 (m, 2H), 7.36 – 7.27 (m, 1H), 7.26 – 7.10 (m, 4H), 4.23 (dd, J = 10.5, 4.8 Hz, 1H), 4.16 (dd, J = 11.2, 3.9 Hz, 1H), 3.80 (dd, J = 10.8, 4.8 Hz, 1H), 3.71 (t, J = 10.7 Hz, 1H), 3.07 (dd, J = 16.4, 3.9 Hz, 1H), 2.95 (dd, J = 15.9, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.5, 135.5, 134.7, 129.5, 128.8, 127.5, 127.0, 126.7, 126.6, 126.4, 63.8, 57.4, 50.7, 36.8. Cis-diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.43 (m, 2H), 7.41 – 7.34 (m, 2H), 7.34 – 7.28 (m, 1H), 7.25 – 7.17 (m, 3H), 7.15 – 7.10 (m, 1H), 4.43 – 4.41 (m, 1H), 4.10 (dd, J = 11.1, 3.5 Hz, 1H), 4.02 (dd, J = 10.8, 3.3 Hz, 1H), 3.90 (dd, J = 10.9, 5.4 Hz, 1H), 3.02 (ddt, J = 15.9, 11.1, 1.4 Hz, 1H), 2.90 (dd, J = 15.7, 3.5 Hz, 1H); All characterization data match those reported.9 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines N 425 O O 175a (5S,10bS)-5-phenyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-3-one (175a): Compound 175a was prepared from isoquinoline 173a using general procedure 5 and purified by column chromatography (20% to 40% to 60% EtOAc in hexanes) to provide a clear solid (33 mg, 63% yield); 91% ee; [α]D25 +124.3 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.19 (m, 8H), 6.91 (d, J = 7.3 Hz, 1H), 5.31 (dd, J = 6.7, 2.8 Hz, 1H), 4.74 (t, J = 8.0 Hz, 1H), 4.69 – 4.66 (m, 1H), 4.29 (dd, J = 7.8, 5.9 Hz, 1H), 3.41 (dd, J = 16.8, 6.7 Hz, 1H), 3.22 (dd, J = 16.7, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.5, 138.8, 134.4, 133.2, 129.4, 128.8, 128.1, 127.9, 127.2, 127.2, 124.4, 68.7, 51.7, 51.5, 31.4; IR (Neat Film, NaCl) 2910, 1751, 1601, 1494, 1452, 1402, 1221, 1114, 1066, 1030, 758, 701 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H16NO2 [M+H]+: 266.1176, found 266.1177; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 2.61, minor = 2.41. OMe N O O 175b (5S,10bS)-5-(4-methoxyphenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-3one (175b): Compound 175b was prepared from isoquinoline 173b using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a pale yellow oil (38 mg, 64% yield); 96% ee; [α]D25 +150.4 (c 1.01, CHCl3); 1H Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 426 1,3-Disubstituted Isoquinolines NMR (400 MHz, CDCl3) δ 7.29 – 7.24 (m, 3H), 7.22 – 7.20 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.82 – 6.78 (m, 2H), 5.32 (dd, J = 6.7, 2.4 Hz, 1H), 4.77 (t, J = 8.0 Hz, 1H), 4.71 – 4.67 (m, 1H), 4.30 (dd, J = 8.0, 6.2 Hz, 1H), 3.75 (s, 3H), 3.44 (dd, J = 16.6, 6.8 Hz, 1H), 3.23 (dd, J = 16.7, 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 157.4, 134.4, 133.2, 130.7, 129.4, 128.4, 128.1, 127.2, 124.5, 114.1, 68.8, 55.3, 51.6, 50.8, 31.4; IR (Neat Film, NaCl) 2907, 2836, 1750, 1610, 1513, 1402, 1304, 1251, 1178, 1066, 1030, 828, 756 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H18NO3 [M+H]+: 296.1281, found 296.1280; SFC Conditions: 10% MeOH, 3.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): major = 8.66, minor = 7.52. N O O 175c (5S,10bS)-5-(4-(tert-butyl)phenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin3-one (175c): Compound 175c was prepared from isoquinoline 173c using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a clear oil (43 mg, 67% yield); 95% ee; [α]D25 +115.6 (c 1.01, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 4H), 7.24 – 7.22 (m, 1H), 7.21 – 7.19 (m, 2H), 6.93 (d, J = 7.2 Hz, 1H), 5.31 (dd, J = 6.8, 2.5 Hz, 1H), 4.74 (t, J = 8.0 Hz, 1H), 4.72 – 4.68 (m, 1H), 4.29 (dd, J = 7.3, 5.3 Hz, 1H), 3.42 (dd, J = 16.6, 6.9 Hz, 1H), 3.23 (dd, J = 16.7, 2.6 Hz, 1H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.5, 150.8, 135.7, 134.5, 133.4, 129.4, 128.1, 127.1, 126.9, 125.7, 124.5, 68.7, 51.6, 51.1, 34.6, 31.4, 31.3; IR (Neat Film, NaCl) 3010, 2962, 1754, 1455, 1401, 1267, 1215, 1115, 1068, 1026, 828, 757 cm–1; Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 427 1,3-Disubstituted Isoquinolines HRMS (MM:ESI-APCI+) m/z calc’d for C21H24NO2 [M+H]+: 322.1802, found 322.1801; SFC Conditions: 20% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.04, minor = 5.44. F N O O 175d (5S,10bS)-5-(4-fluorophenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-3-one (175d): Compound 175d was prepared from isoquinoline 173d using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a clear oil (40 mg, 70% yield); 95% ee; [α]D25 +150.5 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.21 (m, 5H), 6.96 – 6.91 (m, 3H), 5.29 (dd, J = 6.8, 2.8 Hz, 1H), 4.76 (t, J = 8 Hz, 1H), 4.67 (ddd, J = 8.7, 6.2, 1.1 Hz, 1H), 4.30 (dd, J = 8.1, 6.2 Hz, 1H), 3.42 (ddd, J = 16.7, 6.6, 1.3 Hz, 1H), 3.19 (dd, J = 16.7, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.3 (d, J = 246.8 Hz), 157.5, 134.6 (d, J = 3.3 Hz), 134.3, 132.9, 129.4, 129.0 (d, J = 8.1 Hz), 128.3, 127.4, 124.5, 115.7 (d, J = 21.5 Hz), 68.7, 51.6, 50.9, 31.6; 19F NMR (282 MHz, CDCl3) δ –114.4 – –114.5 (m); IR (Neat Film, NaCl) 2910, 1753, 1605, 1510, 1402, 1223, 1161, 1068, 1043, 1029, 885, 828, 758, 745 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H15FNO2 [M+H]+: 284.1081, found 284.1078; SFC Conditions: 35% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 2.39, major = 2.58. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 428 CF3 N O O 175e (5S,10bS)-5-(4-(trifluoromethyl)phenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinolin-3-one (175e): Compound 175e was prepared from isoquinoline 173e using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a white solid (43 mg, 64% yield); 91% ee; [α]D25 +118.2 (c 1.02, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.32 – 7.26 (m, 3H), 7.00 – 6.97 (m, 1H), 5.35 (dd, J = 6.7, 3.4 Hz, 1H), 4.82 (t, J = 8.0 Hz, 1H), 4.76 – 4.72 (m, 1H), 4.38 (dd, J = 8.1, 5.9 Hz, 1H), 3.47 (ddd, J = 16.6, 6.6, 1.2 Hz, 1H), 3.24 (dd, J = 16.6, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.6, 143.0, 143.0, 134.2, 132.7, 130.2 (q, J = 32.6 Hz), 129.3, 128.4, 127.5, 125.9 (q, J = 3.8 Hz), 124.4, 124.0 (q, J = 271.0 Hz), 68.6, 51.8, 51.5, 31.6; 19F NMR (282 MHz, CDCl3) δ 62.7; IR (Neat Film, NaCl) 2916, 1753, 1620, 1402, 1326, 1225, 1162, 1114, 1068, 1017, 889, 829, 757 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H15F3NO2 [M+H]+: 334.1049, found 334.1048; SFC Conditions: 25% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 2.22, major = 2.37. CN N O O 175f 4-((5S,10bS)-3-oxo-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-5yl)benzonitrile (175f): Compound 175f was prepared from isoquinoline 173f using general Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 429 1,3-Disubstituted Isoquinolines procedure 5 and purified by column chromatography (25% to 35% to 50% EtOAc in hexanes) to provide a white solid (27 mg, 47% yield); 83% ee; [α]D25 +112.3 (c 1.00, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.61 – 7.58 (m, 2H), 7.46 – 7.43 (m, 2H), 7.32 – 7.27 (m, 3H), 7.01 – 6.99 (m, 1H), 5.31 (dd, J = 6.5, 3.8 Hz, 1H), 4.83 (t, J = 8.4 Hz, 1H), 4.76 – 4.72 (m, 1H), 4.40 (dd, J = 8.3, 5.9 Hz, 1H), 3.45 (dd, J = 16.5, 6.4 Hz, 1H), 3.20 (dd, J = 16.6, 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.6, 144.5, 134.1, 132.7, 132.5, 129.3, 128.5, 127.9, 127.7, 124.3, 118.6, 111.9, 68.5, 51.9, 51.8, 31.7; IR (Neat Film, NaCl) 2909, 2228, 1747, 1679, 1608, 1402, 1224, 1160, 1114, 1043, 1031, 829, 764, 733 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H15N2O2 [M+H]+: 291.1134, found 291.1137; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 3.97, major = 4.48. Ph N O O 175g (5S,10bS)-5-([1,1'-biphenyl]-4-yl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin3-one (175g): Compound 175g was prepared from isoquinoline 173g using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a white solid (38 mg, 56% yield); 75% ee; [α]D25 +108.5 (c 1.01, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.55 – 7.51 (m, 4H), 7.44 – 7.37 (m, 4H), 7.36 – 7.31 (m, 3H), 7.30 – 7.25 (m, 1H), 6.98 (d, J = 7.1 Hz, 1H), 5.40 (dd, J = 6.7, 2.8 Hz, 1H), 4.83 – 4.76 (m, 2H), 4.39 – 4.32 (m, 1H), 3.49 (dd, J = 16.7, 6.7 Hz, 1H), 3.31 (dd, J = 16.7, 2.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 157.5, 140.8, 140.6, 137.8, 134.4, 133.2, 129.4, 128.9, 128.2, 127.6, 127.6, 127.5, 127.3, 127.1, 124.5, 68.7, 51.7, 51.3, 31.5; IR (Neat Film, NaCl) 3028, Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 430 1,3-Disubstituted Isoquinolines 2908, 1751, 1487, 1454, 1402, 1220, 1162, 1070, 1042, 886, 830, 760 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C23H20NO2 [M+H]+: 342.1489, found 342.1501; SFC Conditions: 45% MeOH, 3.5 mL/min, Chiralcel OJ-H column, λ = 210 nm, tR (min): minor = 5.72, major = 6.80. N O O 175h (5S,10bS)-5-(naphthalen-2-yl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-3one (175h): Compound 175h was prepared from isoquinoline 173h using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a pale white solid (34 mg, 54% yield); 89% ee; [α]D25 +91.3 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.79 (m, 2H), 7.73 – 7.70 (m, 1H), 7.68 (s, 1H), 7.50 (dd, J = 8.6, 1.9 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.38 – 7.30 (m, 2H), 7.27 – 7.23 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.52 (dd, J = 6.5, 3.2 Hz, 1H), 4.79 (t, J = 8.0 Hz, 1H), 4.74 – 4.70 (m, 1H), 4.35 (dd, J = 8.0, 6.0 Hz, 1H), 3.54 (dd, J = 16.7, 6.6 Hz, 1H), 3.41 (dd, J = 16.8, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.6, 136.1, 134.4, 133.2, 133.1, 132.9, 129.4, 128.8, 128.2, 128.1, 127.7, 127.2, 126.4, 126.3, 125.9, 125.4, 124.5, 68.8, 51.8, 51.6, 31.3; IR (Neat Film, NaCl) 3017, 1750, 1454, 1401, 1327, 1215, 1070, 1030, 818, 756 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C21H18NO2 [M+H]+: 316.1332, found 316.1332; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min):, minor = 4.21, major = 4.61. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 431 Me Me N O O 175i (5S,10bS)-5-(3,5-dimethylphenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin3-one (175i): Compound 175i was prepared from isoquinoline 173i using general procedure 5 and purified by column chromatography (10% to 20% to 30% to 40% EtOAc in hexanes) to provide a pale white solid (36 mg, 61% yield); 86% ee; [α]D25 +125.3 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 3H), 6.97 (d, J = 7.1 Hz, 1H), 6.92 (s, 2H), 6.89 (s, 1H), 5.26 (dd, J = 6.7, 3.2 Hz, 1H), 4.82 – 4.75 (m, 2H), 4.39 – 4.32 (m, 1H), 3.42 (dd, J = 16.6, 6.7 Hz, 1H), 3.24 (dd, J = 16.6, 3.2 Hz, 1H), 2.25 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.5, 138.9, 138.3, 134.5, 133.4, 129.5, 129.3, 128.1, 127.1, 124.8, 124.3, 68.5, 51.8, 51.5, 31.7, 21.5; IR (Neat Film, NaCl) 3010, 2916, 1752, 1606, 1454, 1402, 1265, 1220, 1070, 1043, 1030, 758, 747 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H20NO2 [M+H]+: 294.1489, found 294.1489; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 2.47, major = 2.71. OMe OMe N O O 175j (5S,10bS)-5-(3,4-dimethoxyphenyl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinolin-3-one (175j): Compound 175j was prepared from isoquinoline 173j using general procedure 5 and purified by column chromatography (40% to 50% to 75% EtOAc in Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 432 1,3-Disubstituted Isoquinolines hexanes) to provide a pale yellow oil (33 mg, 51% yield); 87% ee; [α]D25 +120.9 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.28 (m, 2H), 7.27 – 7.23 (m, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.3, 2.0 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 5.32 (d, J = 6.7, 2.3 Hz, 1H), 4.78 (t, J = 8.0 Hz, 1H), 4.70 – 4.66 (m, 1H), 4.30 (dd, J = 8.1, 6.2 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.45 (dd, J = 16.8, 6.5 Hz, 1H), 3.24 (dd, J = 16.8, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.4, 149.2, 148.7, 134.4, 133.3, 131.1, 129.3, 128.1, 127.2, 124.5, 119.1, 111.0, 110.9, 68.9, 56.0, 56.0, 51.6, 51.1, 31.4; IR (Neat Film, NaCl) 2929, 2836, 1748, 1592, 1516, 1403, 1259, 1237, 1142, 1026, 758, 749 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C19H20NO4 [M+H]+: 326.1387, found 326.1385; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 2.13, minor = 2.74. Me N N N O O 175k (5S,10bS)-5-(1-methyl-1H-pyrazol-4-yl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinolin-3-one (175k): Compound 175k was prepared from isoquinoline 173k using general procedure 5 and purified by column chromatography (80% to 90% to 100% EtOAc in hexanes) to provide a pale yellow oil as a mixture of diastereomers (47 mg, 88% overall yield) (dr = 3.0:1); 97% ee for major diastereomer; [α]D25 +113.6 (c 1.00, CHCl3); Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.27 – 7.21 (m, 3H), 7.17 (s, 1H), 6.96 – 6.94 (m, 1H), 5.34 (dd, J = 6.6, 2.0 Hz, 1H), 4.77 – 4.74 (m, 2H), 4.29 – 4.23 (m, 1H), 3.78 (s, 3H), 3.42 (dd, J = 16.5, 6.7 Hz, 1H), 3.03 (dd, J = 16.4, 1.9 Hz, 1H); 13C NMR (100 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 433 1,3-Disubstituted Isoquinolines MHz, CDCl3) δ 157.1, 138.1, 134.1, 132.8, 129.7, 128.8, 128.0, 127.3, 124.7, 119.7, 69.1, 51.5, 44.2, 39.1, 32.3; IR (Neat Film, NaCl) 2930, 1750, 1444, 1401, 1276, 1216, 1070, 1021, 988, 761, 751 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C15H16N3O2 [M+H]+: 270.1237, found 270.1238; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 2.24, major = 2.67. OMe N N O O 175l (5S,10bS)-5-(6-methoxypyridin-3-yl)-1,5,6,10b-tetrahydro-3H-oxazolo[4,3a]isoquinolin-3-one (175l): Compound 175l was prepared from isoquinoline 173l using general procedure 5 and purified by column chromatography (25% to 35% to 50% EtOAc in hexanes) to provide a pale yellow oil (38 mg, 64% yield); 95% ee; [α]D25 +124.9 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 2.6 Hz, 1H), 7.54 (dd, J = 8.7, 2.6 Hz, 1H), 7.29 – 7.27 (m, 2H), 7.25 – 7.23 (m, 1H), 6.95 (dd, J = 6.9 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 5.31 (dd, J = 6.7, 2.5 Hz, 1H), 4.78 (t, J = 8.0 Hz, 1H), 4.69 (dd, J = 8.8, 6.2 Hz, 1H), 4.31 (dd, J = 8.1, 6.0 Hz, 1H), 3.86 (s, 3H), 3.45 (dd, J = 16.7, 6.8 Hz, 1H), 3.21 (dd, J = 16.8, 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.8, 157.4, 145.4, 138.3, 134.1, 132.6, 129.5, 128.3, 127.4, 126.9, 124.6, 111.3, 68.9, 53.5, 51.6, 49.3, 31.1; IR (Neat Film, NaCl) 2945, 1752, 1608, 1494, 1400, 1288, 1262, 1068, 1027, 827, 758, 742 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+: 297.1234, found 297.1236; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 2.80, major = 3.30. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines F N 434 O O 175m (5S,10bS)-9-fluoro-5-phenyl-1,5,6,10b-tetrahydro-3H-oxazolo[4,3-a]isoquinolin-3-one (175m): Compound 175m was prepared from isoquinoline 173m using general procedure 5 and purified by column chromatography (20% to 30% to 40% EtOAc in hexanes) to provide a white solid (38 mg, 67% yield); 95% ee; [α]D25 +163.7 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.21 (m, 6H), 6.98 (td, J = 8.6, 2.5 Hz, 1H), 6.65 (dd, J = 8.9, 2.4 Hz, 1H), 5.33 (dd, J = 6.6, 2.7 Hz, 1H), 4.74 (t, J = 8.5 Hz, 1H), 4.67 – 4.63 (m, 1H), 4.28 (dd, J = 8.2, 5.9 Hz, 1H), 3.38 (dd, J = 16.6, 6.4 Hz, 1H), 3.22 (dd, J = 16.6, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7 (d, J = 246.6 Hz), 157.4, 138.4, 136.1 (d, J = 6.6 Hz), 131.0 (d, J = 7.8 Hz), 128.9, 128.8 (d, J = 3.3 Hz), 128.0, 127.1, 115.4 (d, J = 21.3 Hz), 111.4 (d, J = 22.1 Hz), 68.4, 51.7 (d, J = 2.2 Hz), 51.4, 30.6; 19F NMR (282 MHz, CDCl3) δ –114.3 – – 114.4 (m); IR (Neat Film, NaCl) 3061, 2914, 1752, 1613, 1593, 1499, 1450, 1430, 1402, 1327, 1241, 1216, 1162, 1069, 1034, 868, 814, 756 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H15FNO2 [M+H]+: 284.1081, found 284.1083; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 2.09, major = 2.53. CF3 F N O O 175n (5S,10bS)-9-fluoro-5-(4-(trifluoromethyl)phenyl)-1,5,6,10b-tetrahydro-3Hoxazolo[4,3-a]isoquinolin-3-one (175n): Compound 175n was prepared from isoquinoline 173n using general procedure 5 and purified by column chromatography (20% to 30% to Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 435 1,3-Disubstituted Isoquinolines 40% EtOAc in hexanes) to provide a pale yellow oil (38 mg, 54% yield); 92% ee; [α]D25 +115.7 (c 1.02, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.29 (dd, J = 8.6, 5.4 Hz, 1H), 7.02 (td, J = 8.4, 2.5 Hz, 1H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 5.35 (dd, J = 6.6, 3.4 Hz, 1H), 4.80 (t, J = 8.5, 1H), 4.69 (dd, J = 8.6, 5.9 Hz, 1H), 4.35 (dd, J = 8.4, 5.8 Hz, 1H), 3.42 (dd, J = 16.6, 6.3 Hz, 1H), 3.22 (dd, J = 16.6, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.9 (d, J = 247.2 Hz), 157.5, 142.7, 136.0 (d, J = 6.8 Hz), 131.0 (d, J = 7.9 Hz), 130.3 (q, J = 32.6 Hz), 128.4 (d, J = 3.3 Hz, 1H), 127.5, 125.9 (q, J = 3.7 Hz), 124.0 (q, J = 271.0 Hz), 115.7 (d, J = 21.3 Hz), 111.5 (d, J = 22.4 Hz), 68.3, 51.9 (d, J = 2.2 Hz), 51.5, 30.8; 19F NMR (282 MHz, CDCl3) δ –62.7, –113.7 – –113.8 (m); IR (Neat Film, NaCl) 2921, 1754, 1620, 1594, 1500, 1402, 1326, 1241, 1162, 1115, 1068, 1018, 839, 759 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C18H14F4NO2 [M+H]+: 352.0955, found 352.0954; SFC Conditions: 40% MeOH, 3.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 1.43, major = 1.60. 3.7.2.4 Product transformations Ba(OH)2 • 8H2O N O 175a O 1,4-dioxane:H2O 81% yield NH OH 174 ((1S,3S)-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (174): This procedure has been adapted from a previous report.27 To a 1-dram vial equipped with a stir bar was added a solution of tetrahydroisoquinoline 175a (4.4 mg, 0.02 mmol) in 1:1 1,4dioxane:H2O (0.4 mL total, 0.05 M). Barium hydroxide octahydrate (24 mg, 4.1 equiv, 0.07 mmol) was then added and the vial was capped with a PTFE-lined septum and sealed with Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 436 1,3-Disubstituted Isoquinolines electrical tape. The reaction mixture was heated to 120 °C and stirred for 3 hours until TLC analysis indicated complete consumption of the starting material. The reaction was then diluted with H2O, extracted with EtOAc, and the collected organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (50% EtOAc in hexanes + 1% NEt3) to afford 174 as a white solid (3.2 mg, 81% yield): [α]D25 –8.3 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.44 (m, 2H), 7.42 – 7.38 (m, 2H), 7.33 – 7.29 (m, 1H), 7.22 – 7.18 (m, 2H), 7.17 – 7.13 (m, 2H), 4.23 (dd, J = 10.6, 4.8 Hz, 1H), 4.15 (dd, J = 11.2, 3.9 Hz, 1H), 3.80 (dd, J = 10.8, 4.8 Hz, 1H), 3.71 (t, J = 10.7 Hz, 1H), 3.07 (dd, J = 16.4, 3.9 Hz, 1H), 2.95 (dd, J = 16.3, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.5, 135.5, 134.7, 129.5, 128.8, 127.5, 127.0, 126.7, 126.6, 126.4, 63.8, 57.4, 50.7, 36.8; IR (Neat Film, NaCl) 3411, 2357, 2086, 1733, 1716, 1700, 1652, 1558, 1540, 1457, 678 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C16H18NO [M+H]+: 240.1388, found 240.1387. DIBAL N O 175a O CH2Cl2, 0 °C, 30 min 73% yield NMe OH 176 ((1S,3S)-2-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol (176): This procedure has been adapted from a previous report.28 To a 1-dram vial equipped with a stir bar was added a solution of tetrahydroisoquinoline 5a (5.0 mg, 0.02 mmol) in CH2Cl2 (0.4 mL, 0.05 M). The reaction mixture was cooled to 0 °C, and a solution of DIBAL (1.0 M in THF, 0.38 mL, 0.2 mmol) was added dropwise. After stirring for 1 hour, the reaction mixture showed complete consumption of starting material by TLC, and was quenched with MeOH, H2O, and saturated aqueous Rochelle’s salt and stirred for an additional hour. The Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 437 1,3-Disubstituted Isoquinolines reaction was then diluted with H2O, extracted with CH2Cl2 (2 x 5 mL), and the collected organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (30% EtOAc in hexanes) to afford 6a as a clear oil (3.5 mg, 73% yield): [α]D25 +115.8 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.45 (m, 2H), 7.42 – 7.38 (m, 2H), 7.33 – 7.29 (m, 1H), 7.25 – 7.22 (m, 3H), 7.17 – 7.13 (m, 1H), 4.34 (dd, J = 12.2, 4.0 Hz, 1H), 3.93 (dd, J = 10.5, 5.3 Hz, 1H), 3.81 (dd, J = 10.8, 5.3 Hz, 1H), 3.72 (t, J = 10.6 Hz, 1H), 3.37 (dd, J = 16.5, 12.2 Hz, 1H), 2.92 (dd, J = 16.5, 4.0 Hz, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9, 134.5, 133.7, 129.5, 128.5, 127.9, 127.8, 127.4, 126.9, 126.7, 65.8, 63.4, 53.2, 35.7, 25.1; IR (Neat Film, NaCl) 3423, 3058, 3024, 2918, 2854, 2366, 1496, 1450, 1406, 1222, 1130, 1044, 774, 752, 699 cm–1; HRMS (MM:ESI-APCI+) m/z calc’d for C17H20NO [M+H]+: 254.1545, found 254.1543. 3.7.3 Additional optimization results Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 438 Table 3.3. Additional additive, acid, and pressure studies.a Ph N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (X bar), salt (7.5 mol %) OH 9:1 CH2Cl2:acid (0.02 M) 23 °C, 18 h Ph P(DMM)2 NH OH 173a P(Xyl)2 Fe Me L7: SL-J418-1 174 entry salt additive acid pressure % conversionb cis:transb % ee of transc 1 TBACl AcOH 20 bar 75 1:2.3 90 2 TBAI AcOH 20 bar >95 1.5:1 97 3 TBAPF6 AcOH 20 bar <10 – – 4 TBABF4 AcOH 20 bar <10 – – 5 TBABPh4 AcOH 20 bar <10 – – 6 LiBr AcOH 20 bar >95 1:2.3 91 7 NaBr AcOH 20 bar 90 1:2.3 89 8 9 KBr TBABr AcOH TFA 20 bar 20 bar 35 <10 1:2.4 – 86 – 10 TBABr MsOH 20 bar <10 – – 11 TBABr AcOH >95 1:2.3 91 12 TBABr AcOH 10 bar 60 bar >95 1:2.6 93 [a] Reaction conditions: 0.04 mmol of 173a, 1.25 mol % [Ir(cod)Cl]2, 3 mol % ligand, 7.5 mol % salt additive, 20 bar H2 in 0.5 mL 9:1 CH2Cl2:acid. [b] Determined by crude 1H NMR using 1,3,5trimethoxybenzene as a standard. [c] Determined by chiral SFC analysis of Cbz-protected product. Table 3.4. Additional ligand screen.a Ph N OH Ph [Ir(cod)Cl]2 (1.25 mol %) ligand (3.0 mol %) NH H2 (20 bar), TBABr (7.5 mol %) 9:1 CH2Cl2: AcOH (0.02 M), 18 h 173a OH 174 CF3 P(DMM-Ph)2 P(t-Bu)2 Fe Me SL-J013-1 <10% conversion P(DMM-Ph)2 PPh2 P(Cy)2 Fe SL-J007-1 15% conversion 2:1 cis:trans, ee ND O PPh2 Me (CF3Ph)2P 62% conversion >20:1 cis:trans, ee ND N t-Bu <10% conversion [a] Reaction conditions: 0.04 mmol of 173a, 1.25 mol % [Ir(cod)Cl]2, 3 mol % ligand, 7.5 mol % TBABr, 20 bar H2 in 0.5 mL 9:1 CH2Cl2:AcOH. Determined by crude 1H NMR using 1,3,5-trimethoxybenzene as a standard. 3.7.4 Deuterium incorporation experiments Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 439 1,3-Disubstituted Isoquinolines Deuterium experiments were conducted according to general procedure 5 for the hydrogenation of isoquinoline 173a using deuterium gas instead of hydrogen gas, and/or d4AcOH instead of protio acetic acid. N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2/D2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH/CD3COOD then CbzCl (1.1 equiv) 1:1 aq. NaHCO3:EtOAc 10 wt % Pd/C H2 (1 atm) Dn NCbz OH OH 173a Cbz-174 Dn NH MeOH (0.1 M) OH 174 Due to the inseparable nature of the cis- and trans-diastereomers, the hydrogenated products were subsequently protected with benzyl chloroformate (6.3 µL, 0.044 mmol, 1.1 equiv) in 1:1 saturated aq. NaHCO3 and EtOAc (1 mL total). After the reaction showed full conversion of the hydrogenated product, the crude reaction mixture was washed with ethyl acetate and the collected organic layers were dried over Na2SO4 and concentrated under vacuum. Both the cis- and trans-isomers were isolated by preparative TLC (40% EtOAc in hexanes) of the Cbz-protected THIQ, then subsequently deprotected using 10 wt% Pd/C catalyst (1 mg) under a H2 balloon in MeOH (0.1 M) to afford deuterium-labelled 174. The major transisomer was analyzed by 1H and 2H NMR spectroscopy. N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:CD3COOD 23 °C, 18 h OH 98–99% D D D NH 99% D 54–55% D 174 173a N OH 173a D 100% OH [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 9:1 1,2-DCE:AcOH 23 °C, 18 h 85–86% D D D NH 89% D 22–35% D D 91% OH 174 97% D D D NH 91% + D 32–33% D D 94% OH cis-174 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines N 59–61% D D [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) D NH 14% 9:1 1,2-DCE:CD3COOD 23 °C, 18 h D 22% D OH 173a 3.7.5 440 D 16% OH 174 Proposed catalytic cycle Figure 3.2 Proposed catalytic cycle. [Ir(cod)Cl]2 1) Josiphos ligand, TBABr, H+ H 2) H2 P * Br H IrIII Br IrIII P Br P P Br * 177 IQ 1,2-addition HO N P IrIII * P H Ar Br H+, H2 THIQ H+, H2, IQ 178 HO P IrIII * P N HO H N P IrIII * P Ar Br β-hydride elimination * P IrIII H N Br Br Ar 179 O P 181 H Ar H 182 H+, H2 isomerization/ tautomerization 1,2-addition HO P IrIII H * P N Br 180 Ar hydroxyl-directed addition Based on preliminary mechanistic studies and literature precedent, a proposed catalytic cycle for the trans-selective asymmetric hydrogenation is described. Pre-formation of the chiral catalyst using [Ir(cod)Cl]2, chiral ligand, and TBABr, followed by oxidative addition with H2 delivers the halogen-bridged dinuclear IrIII catalyst complex 177. Without the halide, the iridium bisphosphane catalysts tend to irreversibly form dimeric iridium hydride complexes that are catalytically inactive.10c Addition of the isoquinoline substrate Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 441 1,3-Disubstituted Isoquinolines then undergoes bidentate coordination to the metal to generate the corresponding mononuclear IrIII complex 178, followed by a 1,2-hydride addition to establish the C1stereocenter (179).19 Isomerization and tautomerization of the substrate then enables a directed hydrogenation (180) guided by the hydroxymethyl group to deliver the hydride on the opposite face of the molecule. The addition of H2 in the presence of acid regenerates the catalyst species and liberates the enantioenriched trans-THIQ product. Alternatively, based on our deuterium experiments, β-hydride elimination can also proceed from intermediate 181 to generate aldehyde intermediate 182, which is subsequently reduced to provide the same THIQ product. However, the possibility of β-hydride elimination occurring at other intermediates still cannot be ruled out, and further investigations of the mechanism are currently underway. 3.7.6 Determination of enantiomeric excess Table 3.5. Determination of enantiomeric excess. entry 1 compound NCbz SFC analytic conditions ee (%) Chiralpak AD-H, λ = 210 nm 45% IPA/CO2, 3.5 mL/min tR (min) major 1.69, minor 2.04 92 Chiralpak AD-H, λ = 210 nm 30% IPA/CO2, 2.5 mL/min tR (min) major 1.95, minor 4.28 25 OH 174•Cbz 2 NCbz NHBoc 167d•Cbz Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound SFC analytic conditions ee (%) 3 N Chiralpak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 2.41, major 2.61 91 Chiralcel OJ-H, λ = 210 nm 10% MeOH/CO2, 3.5 mL/min tR (min) minor 7.52, major 8.66 96 O O 175a OMe 4 N O O 175b tBu 5 N O Chiralpak AD-H, λ = 210 nm 20% MeOH/CO2, 3.5 mL/min tR (min) major 5.04, minor 5.44 95 Chirapak IC, λ = 210 nm 35% MeOH/CO2, 3.5 mL/min tR (min) minor 2.39, major 2.58 95 Chiralpak IC, λ = 210 nm 25% MeOH/CO2, 3.5 mL/min tR (min) minor 2.22, major 2.37 91 Chiralpak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 3.97, major 4.48 83 O 175c F 6 N O O 175d CF3 7 N O O 175e CN 8 N O 175f O 442 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound SFC analytic conditions ee (%) Chiralcel OJ-H, λ = 210 nm 45% MeOH/CO2, 3.5 mL/min tR (min) minor 5.72, major 6.80 75 Chiralpak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 4.21, major 4.61 89 Chirapak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 2.47, major 2.71 86 Chiralpak AD-H, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) major 2.13, minor 2.74 87 Chiralpak AD-H, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 2.24, major 2.67 97 Chiralpak AD-H, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 2.80, minor 3.30 95 Ph 9 N O O 175g 10 N O O 175h 11 Me Me N O O 175i OMe OMe 12 N O O 175j Me N N 13 N O O 175k OMe N 14 N O 175l O 443 Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines entry compound 15 N F O SFC analytic conditions ee (%) Chiralpak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 2.09, major 2.53 95 Chiralpak IC, λ = 210 nm 40% MeOH/CO2, 3.5 mL/min tR (min) minor 1.43, major 1.60 92 444 O 175m CF3 16 F N O O 175n 3.7.7 Determination of relative and absolute stereochemistry Experimental Protocol. A solution of the isolated trans isomer of 174 (11 mg) was prepared in CDCl3 (225 μL; 49 mg/mL) and loaded into a front-loading SL-4 cell (International Crystal Laboratories) possessing BaF2 windows and 100 μm path length. Infrared (IR) and VCD spectra were acquired on a BioTools ChiralIR-2X VCD spectrometer as a set of 30 one-hour blocks (30 blocks, 3120 scans per block) at 4 cm–1 resolution in dual PEM mode. A 15-minute acquisition of neat (–)-α-pinene control (separate 75 μm BaF2 cell) yielded a VCD spectrum in agreement with literature spectra and identical to those previously acquired on the same instrument. 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 6-hour (6 blocks, 3120 scans per block) IR/VCD acquisition of CDCl3 in the same 100 μm BaF2 cell as used for 174. The reported spectra represent the result of block averaging. The baseline of the resultant VCD spectrum (top left panel below) was vertically offset by a constant such that that the y-value was zero at a frequency of 1000 cm-1 for ease of viewing and assignment. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 445 1,3-Disubstituted Isoquinolines Computational Protocol. The arbitrarily chosen (R,R) enantiomer of 174 (ultimately corresponding to ent-174) was subjected to an initial exhaustive stochastic molecular mechanics-based conformational search (MMFF94 force field, 0.06 Å geometric RMSD cutoff, and 30 kcal/mol energy window) as implemented in MOE 2019.0102 (Chemical Computing Group, Montreal, CA). All conformers retained the (R,R) configuration and were subjected to geometry optimization, harmonic frequency calculation, and VCD rotational strength evaluation using density functional theory utilizing the B3PW91 functional, ccpVTZ basis, and implicit IEFPCM chloroform solvation model. All calculations were performed with the Gaussian 16 program system (Rev. C.01; Frisch et al., Gaussian, Inc., Wallingford, CT). Resultant IEFPCM-B3PW91/cc-pVTZ harmonic frequencies were scaled by 0.98. All 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 to yield the final predicted IR and VCD spectra. The predicted VCD spectrum of the (S,S) enantiomer (ultimately agreeing with the experimentally measured spectrum of isolated 174) was generated by inversion of sign. From alignment of the experimentally measured and theoretical IR spectra, in particular regions A-E corresponding to unambiguous regions of the experimental VCD spectrum (see below) the absolute configuration of the isolated and measured 174 could be confidently assigned as (S,S). Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 446 Figure 3.3 Experimental (left) and theoretical (right) IR and VCD spectra of 174. 3.8 (1) REFERENCES AND NOTES For recent reviews of asymmetric hydrogenation of heteroarenes, see: a) Wang, D.S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem. Rev. 2012, 112, 2557–2590; b) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–1366; c) Zhao, D.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52, 9616–9618; d) Kim, A. N.; Stoltz, B. M. ACS Catal. 2020, 10, 13834–13851; e) Luo, Y.-E.; He, Y.-M.; Fan, Q.-H. Chem. Rec. 2016, 16, 2697– 2711; f) Fleury-Brégeot, N.; de la Fuente, V.; Castillón, S.; Claver, C. ChemCatChem 2010, 2, 1346–1371. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 447 1,3-Disubstituted Isoquinolines (2) For recent reviews of asymmetric C=N bond hydrogenation, see: a) Cabré, A.; Verdaguer, X.; Riera, A.; Chem. Rev. 2022, 122, 269–339; b) Abed Ali Abdine, R.; Hedouin, G.; Colobert, F.; Wencel-Delord, J. ACS Catal. 2021, 11, 215–247; c) Molina Betancourt, R.; Echeverria, P.-G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Synthesis 2021, 53, 30–50; d) Barrios-Rivera, J.; Xu, Y.; Wills, M.; Vyas, V. K. Org. Chem. Front. 2020, 7, 3312–3342; e) Liu, Y.; Yue, X.; Luo, C.; Zhang, L.; Lei, M. Energy Environ. Mater. 2019, 2, 292–312. (3) Wiesenfeldt, M.P.; Nairoukh, Z.; Dalton, T.; Glorius, F. Angew. Chem. Int. Ed. 2019, 58, 10460–10476. (4) Gelis, C.; Heusler, A.; Nairoukh, Z.; Glorius, F. Chem. Eur. J. 2020, 26, 14090– 14094. (5) For examples of trans-selective arene hydrogenation, see: a) Wollenburg, M.; Heusler, A.; Bergander, K.; Glorius, F. ACS Catal. 2020, 10, 11365–11370; b) Murugesan, K.; Senthamarai, T.; Alshammari, A. S.; Altamimi, R. M.; Kreyenschulte, C.; Pohl, M.-M.; Lund, H.; Jagadeesh, R. V.; Beller, M. ACS Catal. 2019, 9, 8581–8591; c) Li, H.; Wang, Y.; Lai, Z.; Huang, K.-W. ACS Catal. 2017, 7, 4446–4450; d) Tungler, A.; Szabados, E. Org. Process. Res. Dev. 2016, 20, 1246– 1251; e) Maegawa, T.; Akashi, A.; Yaguchi, K.; Iwasaki, Y.; Shigetsura, M.; Monguchi, Y.; Sajiki, H. Chem.-Eur. J. 2009, 15, 6953–6963; f) Jansat, S.; Picurelli, D.; Pelzer, K.; Philippot, K.; Gómez, M.; Muller, G.; Lecante, P.; Chaudret, B. New. J. Chem. 2006, 30, 115–122. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 448 1,3-Disubstituted Isoquinolines (6) For an example of a sequential enantioselective hydrogenation to access the transdiastereomer of product, see: Wiesenfeldt, M. P.; Moock, D.; Paul, D.; Glorius, F. Chem. Sci. 2021, 12, 5611–5615. (7) a) Matsuda, H.; Ninomiya, K.; Shimoda, H.; Nishida, N.; Yoshikawa, M. Heterocycles 2001, 55, 2043–2050; b) Rochfort, S. J.; Towerzey, L.; Carroll, A.; King, G.; Michael, A.; Pierens, G.; Rali, T.; Redburn, J.; Whitmore, J.; Quinn, R. J. J. Nat. Prod. 2005, 68, 1080–1082. (8) For recent total syntheses of trans-THIQ natural products, see: a) Uenishi, S.; Kakigi, R.; Hideshima, K.; Miyawaki, A.; Matsuoka, J.; Ogata, T.; Tomioka, K.; Yamamoto, Y. Tetrahedron 2021, 90, 132165–132176; b) J. Kayhan, M. J. Wanner, S. Ingemann, J. H. van Maarseveen and H. Hiemstra, Eur. J. Org. Chem. 2016, 3705–3708. (9) a) Kim, A. N.; Ngamnithiporn, A.; Welin, E. R.; Daiger, M. T.; Grünanger, C. U.; Bartberger, M. D.; Virgil, S. C.; Stoltz, B. M. ACS Catal. 2020, 10, 3241–3248; b) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.; Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C. D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.; Grünanger, C.; Allan, K. M.; Virgil, S. C.; Slamon, D. J. Stoltz, B. M. Science 2019, 363, 270–275. (10) For recent reports of Ir-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines, see: a) Chen, M.-W.; Ji, Y.; Wang, J.; Chen, Q.-A.; Shi, L.; Zhou, Y.G. Org. Lett. 2017, 19, 4988–4991; b) Wen, J.; Tan, R.; Liu, S.; Zhao, Q.; Zhang, X. Chem. Sci. 2016, 7, 3047–3051; c) Kita, Y.; Yamaji, K.; Higashida, K.; Sathaiah, K.; Iimuro, A.; Mashima, K. Chem. Eur. J. 2015, 21, 1915–1927. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 449 1,3-Disubstituted Isoquinolines (11) The absolute configuration of the trans-diastereomer was assigned as (S,S) by VCD, see Section 3.7.7. (12) Smidt, S. P.; Zimmermann, N.; Studer, M.; Pfaltz, A. Chem. Eur. J. 2004, 10, 4685– 4693. (13) Attempts to further improve the diastereoselectivity were unsuccessful, see Tables 3.3–3.4. (14) The absolute stereochemistry for all other hydrogenated products were assigned by analogy to 175a. (15) Attempts to prepare 3-alkyl substituted isoquinolines were unsuccessful. (16) Liu, C.-Y.; Angamuthu, V.; Chen, W.-C.; Hou, D.-R. Org. Lett. 2020, 22, 2246– 2250. (17) Cbz-protected 174 was obtained in 91% ee, ruling out any racemization occurring in the reaction. (18) Fagnou, K.; Lautens, M. Angew. Chem. Int. Ed. 2002, 41, 26–47. (19) Dorta, R.; Broggini, D.; Stoop, R.; Rüegger, H.; Spindler, F.; Togni, A. Chem. Eur. J. 2004, 10, 267–278. (20) Díaz-Torres, R.; Alvarez, S. Dalton. Trans. 2011, 40, 10742–10750. (21) a) Jiménez, M. V.; Fernández-Tornos, J.; Modrego, F. J.; Pérez-Torrente, J. J.; Oro, L. A. Chem. Eur. J. 2015, 21, 17877–17889; b) Blum, O.; Milstein, D. J. Am. Chem. Soc. 1995, 117, 4582–4594. (22) The same deuterium experiment under the cis-selective hydrogenation conditions demonstrates no deuteration at the methylene carbon of 173a, ruling out an alternative tautomerization mechanism. Chapter 3 – Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 450 1,3-Disubstituted Isoquinolines (23) a) Liu, H.; Wang, W.-H.; Xiong, H.; Nijamudheen, A.; Ertem, M. Z.; Wang, M.; Duan, L. Inorg. Chem. 2021, 60, 3410–3417; b) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman, R. G. J. Am. Chem. Soc. 2002, 124, 2092–2093. (24) A proposed catalytic cycle is described in the Supporting Information, see Figure 3.1. (25) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. (26) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966–8967. (27) Liu, C.-Y.; Angamuthu, V.; Chen, W.-C.; Hou, D.-R. Org. Lett. 2020, 22, 2246– 2250. (28) Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R.; Abboud, K. Tetrahedron Lett. 1996, 37, 8155–8158. Appendix 3 – Spectra Relevant to Chapter 3 451 APPENDIX 3 Spectra Relevant to Chapter 3: Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines 9 8 161s Me N N OMe 6 ppm 5 4 3 Figure A3.1 1H NMR (400 MHz, CDCl3) of compound 161s. 7 2 1 Appendix 3 – Spectra Relevant to Chapter 3 452 Appendix 3 – Spectra Relevant to Chapter 3 453 Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound 161s. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.3 13C NMR (100 MHz, CDCl3) of compound 161s. 20 10 9 173l OH N 8 N OMe 6 ppm 5 4 3 Figure A3.4 1H NMR (400 MHz, CDCl3) of compound 173l. 7 2 1 Appendix 3 – Spectra Relevant to Chapter 3 454 Appendix 3 – Spectra Relevant to Chapter 3 455 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound 173l. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A3.6 13C NMR (100 MHz, CDCl3) of compound 173l. 10 9 8 166g NH2 N 7 5 ppm 4 3 Figure A3.7 1H NMR (400 MHz, CDCl3) of compound 166g. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 456 Appendix 3 – Spectra Relevant to Chapter 3 457 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound 166g. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.9 13C NMR (100 MHz, CDCl3) of compound 166g. 20 10 9 8 167d NHBoc NH 7 5 ppm 4 3 2 Figure A3.10 1H NMR (400 MHz, CDCl3) of compound 167d. 6 1 0 Appendix 3 – Spectra Relevant to Chapter 3 458 Appendix 3 – Spectra Relevant to Chapter 3 459 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound 167d. 160 150 140 130 120 110 100 90 80 ppm 70 60 50 40 30 20 Figure A3.12 13C NMR (100 MHz, CDCl3) of compound 167d. 10 8 7 175a O N O 5 ppm 4 3 Figure A3.13 1H NMR (400 MHz, CDCl3) of compound 175a. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 460 Appendix 3 – Spectra Relevant to Chapter 3 461 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound 175a. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.15 13C NMR (100 MHz, CDCl3) of compound 175a. 20 10 9 8 175b O N O 7 OMe 5 ppm 4 3 Figure A3.16 1H NMR (400 MHz, CDCl3) of compound 175b. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 462 Appendix 3 – Spectra Relevant to Chapter 3 463 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound 175b. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A3.18 13C NMR (100 MHz, CDCl3) of compound 175b. 10 9 8 175c O N O 7 5 ppm 4 3 Figure A3.19 1H NMR (400 MHz, CDCl3) of compound 175c. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 464 Appendix 3 – Spectra Relevant to Chapter 3 465 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound 175c. 160 150 140 130 120 13 110 100 90 ppm 80 70 60 50 40 30 Figure A3.21 C NMR (100 MHz, CDCl3) of compound 175c. 20 10 9 8 7 O 6 5 ppm 4 3 Figure A3.22 1H NMR (400 MHz, CDCl3) of compound 175d. 175d O N F 2 1 Appendix 3 – Spectra Relevant to Chapter 3 466 Appendix 3 – Spectra Relevant to Chapter 3 467 Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound 175d. 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A3.24 13C NMR (100 MHz, CDCl3) of compound 175d. 20 Appendix 3 – Spectra Relevant to Chapter 3 -112.5 -113.0 -113.5 19 -114.0 -114.5 ppm 468 -115.0 -115.5 -116.0 Figure A3.25 F NMR (282 MHz, CDCl3) of compound 175d. -116.5 9 8 175e O N O 6 5 ppm 4 3 Figure A3.26 1H NMR (400 MHz, CDCl3) of compound 175e. 7 CF3 2 1 Appendix 3 – Spectra Relevant to Chapter 3 469 Appendix 3 – Spectra Relevant to Chapter 3 470 Figure A3.27 Infrared spectrum (Thin Film, NaCl) of compound 175e. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.28 13C NMR (100 MHz, CDCl3) of compound 175e. 20 10 Appendix 3 – Spectra Relevant to Chapter 3 -50 -52 -54 -56 -58 19 -60 -62 -64 ppm 471 -66 -68 -70 -72 -74 -76 Figure A3.29 F NMR (282 MHz, CDCl3) of compound 175e. -78 9 8 175f O N O CN 7 5 ppm 4 3 Figure A3.30 1H NMR (400 MHz, CDCl3) of compound 175f. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 472 Appendix 3 – Spectra Relevant to Chapter 3 473 Figure A3.31 Infrared spectrum (Thin Film, NaCl) of compound 175f. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A3.32 13C NMR (100 MHz, CDCl3) of compound 175f. 30 20 9 8 175g O N O Ph 7 5 ppm 4 3 Figure A3.33 1H NMR (400 MHz, CDCl3) of compound 175g. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 474 Appendix 3 – Spectra Relevant to Chapter 3 475 Figure A3.34 Infrared spectrum (Thin Film, NaCl) of compound 175g. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.35 13C NMR (100 MHz, CDCl3) of compound 175g. 20 10 9 8 175h O N O 7 5 ppm 4 3 Figure A3.36 1H NMR (400 MHz, CDCl3) of compound 175h. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 476 Appendix 3 – Spectra Relevant to Chapter 3 477 Figure A3.37 Infrared spectrum (Thin Film, NaCl) of compound 175h. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A3.38 13C NMR (100 MHz, CDCl3) of compound 175h. 30 20 10 8 175i O N O 7 Me 6 5 ppm 4 3 Figure A3.39 1H NMR (400 MHz, CDCl3) of compound 175i. Me 2 1 Appendix 3 – Spectra Relevant to Chapter 3 478 Appendix 3 – Spectra Relevant to Chapter 3 479 Figure A3.40 Infrared spectrum (Thin Film, NaCl) of compound 175i. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A3.41 13C NMR (100 MHz, CDCl3) of compound 175i. 10 9 8 175j O N O OMe 7 OMe 5 ppm 4 3 Figure A3.42 1H NMR (400 MHz, CDCl3) of compound 175j. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 480 Appendix 3 – Spectra Relevant to Chapter 3 481 Figure A3.43 Infrared spectrum (Thin Film, NaCl) of compound 175j. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.44 13C NMR (100 MHz, CDCl3) of compound 175j. 20 10 9 8 175k O N O N Me N 6 5 ppm 4 3 Figure A3.45 1H NMR (400 MHz, CDCl3) of compound 175k. 7 2 1 Appendix 3 – Spectra Relevant to Chapter 3 482 Appendix 3 – Spectra Relevant to Chapter 3 483 Figure A3.46 Infrared spectrum (Thin Film, NaCl) of compound 175k. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 Figure A3.47 13C NMR (100 MHz, CDCl3) of compound 175k. 30 20 9 175l O N 8 O N OMe 6 5 ppm 4 3 Figure A3.48 1H NMR (400 MHz, CDCl3) of compound 175l. 7 2 1 Appendix 3 – Spectra Relevant to Chapter 3 484 Appendix 3 – Spectra Relevant to Chapter 3 485 Figure A3.49 Infrared spectrum (Thin Film, NaCl) of compound 175l. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.50 13C NMR (100 MHz, CDCl3) of compound 175l. 20 10 9 F 8 175m O N O 6 5 ppm 4 3 Figure A3.51 1H NMR (400 MHz, CDCl3) of compound 175m. 7 2 1 Appendix 3 – Spectra Relevant to Chapter 3 486 Appendix 3 – Spectra Relevant to Chapter 3 487 Figure A3.52 Infrared spectrum (Thin Film, NaCl) of compound 175m. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.53 13C NMR (100 MHz, CDCl3) of compound 175m. 20 10 Appendix 3 – Spectra Relevant to Chapter 3 -111 -112 -113 -114 ppm -115 488 -116 -117 -118 Figure A3.54 19F NMR (282 MHz, CDCl3) of compound 175m. 9 F 8 175n O N O 7 CF3 5 ppm 4 3 Figure A3.55 1H NMR (400 MHz, CDCl3) of compound 175n. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 489 Appendix 3 – Spectra Relevant to Chapter 3 490 Figure A3.56 Infrared spectrum (Thin Film, NaCl) of compound 175n. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.57 13C NMR (100 MHz, CDCl3) of compound 175n. 20 10 Appendix 3 – Spectra Relevant to Chapter 3 -50 -60 -70 -80 ppm 491 -90 -100 -110 Figure A3.58 19F NMR (282 MHz, CDCl3) of compound 175n. -120 9 8 174 OH NH 7 5 ppm 4 3 Figure A3.59 1H NMR (400 MHz, CDCl3) of compound 174. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 492 Appendix 3 – Spectra Relevant to Chapter 3 493 Figure A3.60 Infrared spectrum (Thin Film, NaCl) of compound 174. c 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A3.61 13C NMR (100 MHz, CDCl3) of compound 174. 20 9 8 176 OH NMe 7 5 ppm 4 3 Figure A3.62 1H NMR (400 MHz, CDCl3) of compound 176. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 3 494 Appendix 3 – Spectra Relevant to Chapter 3 495 Figure A3.63 Infrared spectrum (Thin Film, NaCl) of compound 176. c 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 Figure A3.64 C NMR (100 MHz, CDCl3) of compound 176. 20 10 9 8 7 6 5 9:1 1,2-DCE:CD3COOD 23 °C, 18 h ppm 4 D 54–55% D OH D 100% D NH 99% 3 174 1 4 98–99% D D 3 Figure A3.65 1H NMR (400 MHz, CDCl3) of compound d5-174. 173a OH N [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 2 1 Appendix 3 – Spectra Relevant to Chapter 3 496 Appendix 3 – Spectra Relevant to Chapter 3 6 5 4 3 ppm 497 2 1 0 Figure A3.66 2H NMR (61 MHz, CDCl3) of compound d5-174. c 8 173a OH N 6 D 94% OH ppm cis-174 D 32–33% D D NH 91% 5 4 Figure A3.67 1H NMR (400 MHz, CDCl3) of compound dn-cis-174. 7 9:1 1,2-DCE:CD3COOD 23 °C, 18 h [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 97% D D 3 Appendix 3 – Spectra Relevant to Chapter 3 498 8.0 7.5 173a OH N 7.0 6.0 D 19–22% D 5.5 174 OH D 91% D NH 89% 85–86% D D 5.0 ppm 4.5 4.0 3.5 Figure A3.68 1H NMR (400 MHz, CDCl3) of compound dn-174. 6.5 9:1 1,2-DCE:AcOH 23 °C, 18 h [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) D2 (20 bar), TBABr (7.5 mol %) 3.0 2.5 2.0 Appendix 3 – Spectra Relevant to Chapter 3 499 173a 8 OH N 6 D 22% D 174 OH D 16% D NH 14% 59–61% D D ppm 5 4 Figure A3.69 1H NMR (400 MHz, CDCl3) of compound dn-174. 7 9:1 1,2-DCE:CD3COOD 23 °C, 18 h [Ir(cod)Cl]2 (1.25 mol %) L7 (3 mol %) H2 (20 bar), TBABr (7.5 mol %) 3 2 Appendix 3 – Spectra Relevant to Chapter 3 500 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 501 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3: Iridium-Catalyzed Asymmetric Trans-Selective Hydrogenation of 1,3-Disubstituted Isoquinolines Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 A4.1 502 GENERAL EXPERIMENTAL A crystal was mounted on a polyimide MiTeGen loop with STP Oil Treatment and placed under a nitrogen stream. Low temperature (100K) X-ray data (f-and w-scans) were collected with 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 microsource for the structure of compound V21097. The structure was solved by direct methods using SHELXS and refined against F2 on all data by full-matrix least squares with SHELXL-2017 using established refinement techniques. All non-hydrogen atoms were refined using anisotropic displacement parameters. Hydrogen atoms were placed in idealized positions and the coordinates refined (each of the two disordered pairs were constrained to the same position). The isotropic displacement parameters of all hydrogen atoms were fixed at 1.2 times (1.5 times for methyl groups and alcohol) the Ueq value of the bonded atom. A4.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF THIQ 175a The tetrahydroisoquinoline (THIQ) product 175a (91% ee) was crystallized by slow evaporation from chloroform at 23 °C to provide crystals suitable for X-ray analysis. Compound V21097 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Figure A4.1 X-ray crystal structure of THIQ 175a. Table A4.1 Crystal data and structure refinement for product 175a. Identification code V21097 Empirical formula C17 H15 N O2 Formula weight 265.30 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 6.5620(8) Å a= 90°. b = 14.2320(17) Å b= 90°. c = 14.4563(19) Å g = 90°. Volume 1350.1(3) Å3 Z 4 Density (calculated) 1.305 Mg/m3 Absorption coefficient 0.687 mm-1 F(000) 560 Crystal size 0.300 x 0.150 x 0.150 mm3 Theta range for data collection 4.359 to 79.624°. Index ranges -8<=h<=8, -17<=k<=18, -18<=l<=18 Reflections collected 23786 503 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Independent reflections 2903 [R(int) = 0.0368] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7543 and 0.6141 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2903 / 0 / 181 Goodness-of-fit on F2 1.106 Final R indices [I>2sigma(I)] R1 = 0.0314, wR2 = 0.0806 R indices (all data) R1 = 0.0317, wR2 = 0.0807 Absolute structure parameter 0.04(5) Extinction coefficient n/a Largest diff. peak and hole 0.157 and -0.228 e.Å-3 504 4 Table A4.2 Atomic coordinates (x 10 ), and equivalent isotropic displacement 2 3 parameters (Å x 10 ), and population for 175a. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ C(1) 5632(2) 5374(1) 8245(1) 20(1) O(1) 7103(2) 4818(1) 8618(1) 26(1) O(2) 3839(2) 5236(1) 8370(1) 30(1) C(2) 9070(3) 5142(1) 8341(2) 39(1) C(3) 8729(2) 6082(1) 7842(1) 20(1) C(4) 9357(2) 6972(1) 8337(1) 18(1) C(5) 10846(3) 7016(1) 9020(1) 24(1) C(6) 11296(3) 7867(2) 9444(1) 32(1) C(7) 10246(3) 8669(2) 9192(1) 35(1) C(8) 8766(3) 8632(1) 8500(1) 28(1) C(9) 8329(2) 7787(1) 8060(1) 19(1) C(10) 6807(2) 7701(1) 7288(1) 19(1) Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 505 C(11) 5305(2) 6893(1) 7469(1) 16(1) C(12) 3921(2) 6716(1) 6645(1) 16(1) C(13) 4020(3) 5903(1) 6111(1) 20(1) C(14) 2681(3) 5771(1) 5375(1) 22(1) C(15) 1261(3) 6451(1) 5150(1) 23(1) C(16) 1180(3) 7277(1) 5665(1) 22(1) C(17) 2487(2) 7401(1) 6413(1) 19(1) N(1) 6496(2) 6060(1) 7731(1) 19(1) ________________________________________________________________________ Table A4.3 Bond lengths [Å] and angles [°] for 175a. _____________________________________________________ C(1)-O(2) 1.206(2) C(1)-N(1) 1.352(2) C(1)-O(1) 1.360(2) O(1)-C(2) 1.428(2) C(2)-C(3) 1.536(2) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(3)-N(1) 1.474(2) C(3)-C(4) 1.512(2) C(3)-H(3) 1.0000 C(4)-C(5) 1.391(2) C(4)-C(9) 1.401(2) C(5)-C(6) 1.389(3) C(5)-H(5) 0.9500 C(6)-C(7) 1.383(3) C(6)-H(6) 0.9500 C(7)-C(8) 1.395(3) C(7)-H(7) 0.9500 C(8)-C(9) 1.390(2) C(8)-H(8) 0.9500 C(9)-C(10) 1.503(2) C(10)-C(11) C(10)-H(10A) 1.537(2) 0.9900 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 C(10)-H(10B) C(11)-N(1) C(11)-C(12) C(11)-H(11) C(12)-C(13) C(12)-C(17) C(13)-C(14) C(13)-H(13) C(14)-C(15) C(14)-H(14) C(15)-C(16) C(15)-H(15) C(16)-C(17) C(16)-H(16) C(17)-H(17) 0.9900 1.4693(19) 1.518(2) 1.0000 1.392(2) 1.395(2) 1.393(2) 0.9500 1.382(3) 0.9500 1.391(2) 0.9500 1.391(2) 0.9500 0.9500 O(2)-C(1)-N(1) O(2)-C(1)-O(1) N(1)-C(1)-O(1) C(1)-O(1)-C(2) O(1)-C(2)-C(3) 127.52(16) 122.54(15) 109.93(14) 110.03(13) 106.31(14) O(1)-C(2)-H(2A) C(3)-C(2)-H(2A) O(1)-C(2)-H(2B) C(3)-C(2)-H(2B) H(2A)-C(2)-H(2B) N(1)-C(3)-C(4) N(1)-C(3)-C(2) C(4)-C(3)-C(2) N(1)-C(3)-H(3) C(4)-C(3)-H(3) C(2)-C(3)-H(3) C(5)-C(4)-C(9) C(5)-C(4)-C(3) C(9)-C(4)-C(3) 110.5 110.5 110.5 110.5 108.7 109.86(13) 100.27(13) 117.83(15) 109.5 109.5 109.5 120.26(15) 124.42(15) 115.32(14) 506 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(4)-C(5)-H(5) C(7)-C(6)-C(5) C(7)-C(6)-H(6) C(5)-C(6)-H(6) C(6)-C(7)-C(8) C(6)-C(7)-H(7) C(8)-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)-C(10) C(4)-C(9)-C(10) C(9)-C(10)-C(11) C(9)-C(10)-H(10A) C(11)-C(10)-H(10A) C(9)-C(10)-H(10B) C(11)-C(10)-H(10B) H(10A)-C(10)-H(10B) 120.11(17) 119.9 119.9 119.90(17) 120.1 120.1 120.27(17) 119.9 119.9 120.30(17) 119.9 119.9 119.13(15) 123.21(15) 117.66(14) 111.16(13) 109.4 109.4 109.4 109.4 108.0 N(1)-C(11)-C(12) N(1)-C(11)-C(10) C(12)-C(11)-C(10) N(1)-C(11)-H(11) C(12)-C(11)-H(11) C(10)-C(11)-H(11) C(13)-C(12)-C(17) C(13)-C(12)-C(11) C(17)-C(12)-C(11) C(12)-C(13)-C(14) C(12)-C(13)-H(13) C(14)-C(13)-H(13) C(15)-C(14)-C(13) C(15)-C(14)-H(14) 112.78(13) 107.82(12) 111.92(12) 108.0 108.0 108.0 118.59(15) 122.95(14) 118.46(14) 120.40(15) 119.8 119.8 120.71(15) 119.6 507 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 508 C(13)-C(14)-H(14) 119.6 C(14)-C(15)-C(16) 119.42(15) C(14)-C(15)-H(15) 120.3 C(16)-C(15)-H(15) 120.3 C(15)-C(16)-C(17) 119.92(15) C(15)-C(16)-H(16) 120.0 C(17)-C(16)-H(16) 120.0 C(16)-C(17)-C(12) 120.94(15) C(16)-C(17)-H(17) 119.5 C(12)-C(17)-H(17) 119.5 C(1)-N(1)-C(11) 120.07(13) C(1)-N(1)-C(3) 111.82(13) C(11)-N(1)-C(3) 122.70(12) _____________________________________________________________ 2 3 Table A4.4 Anisotropic displacement parameters (Å x 10 ) for 175a. The anisotropic 2 displacement factor exponent takes the form: -2p [ h2 a*2U11 + ... + 2 h k a* b* U12] ________________________________________________________________________ U11 U22 U33 U23 U13 U12 ________________________________________________________________________ C(1) O(1) O(2) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) 20(1) 22(1) 20(1) 20(1) 14(1) 14(1) 16(1) 20(1) 27(1) 23(1) 16(1) 19(1) 16(1) 13(1) 19(1) 23(1) 26(1) 28(1) 21(1) 25(1) 36(1) 49(1) 39(1) 28(1) 24(1) 17(1) 17(1) 19(1) 20(1) 34(1) 43(1) 68(1) 25(1) 16(1) 20(1) 26(1) 39(1) 35(1) 18(1) 19(1) 16(1) 15(1) 2(1) 12(1) 11(1) 18(1) 2(1) 1(1) 0(1) -11(1) -21(1) -10(1) -3(1) 2(1) 2(1) 3(1) 2(1) 1(1) 7(1) -9(1) 1(1) 5(1) 2(1) -6(1) -7(1) -6(1) 1(1) -1(1) 1(1) 2(1) 2(1) 5(1) 0(1) -2(1) 1(1) 0(1) 4(1) 6(1) 3(1) 4(1) 0(1) -1(1) 1(1) -2(1) Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 509 C(13) 20(1) 20(1) 18(1) 2(1) 2(1) 1(1) C(14) 25(1) 24(1) 18(1) 0(1) 3(1) -6(1) C(15) 21(1) 32(1) 16(1) 5(1) -2(1) -8(1) C(16) 16(1) 27(1) 22(1) 8(1) 0(1) 1(1) C(17) 17(1) 20(1) 20(1) 2(1) 2(1) 0(1) N(1) 14(1) 20(1) 22(1) 6(1) 0(1) 0(1) ________________________________________________________________________ 4 Table A4.5 Hydrogen coordinates (x 10 ) and isotropic displacement parameters 2 3 (Å x 10 ) for 175a. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ H(2A) 9723 4683 7921 47 H(2B) 9959 5231 8888 47 H(3) 9391 6060 7219 24 H(5) 11557 6463 9197 29 H(6) 12322 7897 9906 38 H(7) 10535 9249 9491 42 H(8) 8054 9187 8328 34 H(10A) 7534 7586 6698 22 H(10B) 6043 8297 7227 22 H(11) 4430 7072 8007 20 H(13) 5007 5436 6250 24 H(14) 2744 5208 5024 27 H(15) 348 6356 4649 28 H(16) 234 7755 5505 26 H(17) 2402 7959 6770 22 ________________________________________________________________________ Table A4.6 Torsion angles [°] for 175a. ________________________________________________________________ O(2)-C(1)-O(1)-C(2) 179.11(18) N(1)-C(1)-O(1)-C(2) -0.1(2) C(1)-O(1)-C(2)-C(3) 8.0(2) Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 O(1)-C(2)-C(3)-N(1) O(1)-C(2)-C(3)-C(4) N(1)-C(3)-C(4)-C(5) C(2)-C(3)-C(4)-C(5) N(1)-C(3)-C(4)-C(9) C(2)-C(3)-C(4)-C(9) C(9)-C(4)-C(5)-C(6) C(3)-C(4)-C(5)-C(6) C(4)-C(5)-C(6)-C(7) C(5)-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)-C(10) C(5)-C(4)-C(9)-C(8) C(3)-C(4)-C(9)-C(8) C(5)-C(4)-C(9)-C(10) C(3)-C(4)-C(9)-C(10) C(8)-C(9)-C(10)-C(11) C(4)-C(9)-C(10)-C(11) C(9)-C(10)-C(11)-N(1) C(9)-C(10)-C(11)-C(12) -11.7(2) 107.34(18) 138.89(15) 25.0(2) -41.39(18) -155.28(15) 1.2(2) -179.11(16) 0.6(3) -1.3(3) 0.2(3) 1.6(3) -177.85(17) -2.3(2) 178.00(15) 177.19(14) -2.5(2) -130.25(17) 50.33(18) -48.40(16) -172.99(12) N(1)-C(11)-C(12)-C(13) C(10)-C(11)-C(12)-C(13) N(1)-C(11)-C(12)-C(17) C(10)-C(11)-C(12)-C(17) C(17)-C(12)-C(13)-C(14) C(11)-C(12)-C(13)-C(14) C(12)-C(13)-C(14)-C(15) C(13)-C(14)-C(15)-C(16) C(14)-C(15)-C(16)-C(17) C(15)-C(16)-C(17)-C(12) C(13)-C(12)-C(17)-C(16) C(11)-C(12)-C(17)-C(16) O(2)-C(1)-N(1)-C(11) O(1)-C(1)-N(1)-C(11) -9.5(2) 112.26(16) 170.44(13) -67.77(18) -1.4(2) 178.59(14) 1.3(2) 0.3(2) -1.7(2) 1.5(2) 0.0(2) -179.99(14) 17.7(3) -163.14(14) 510 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 O(2)-C(1)-N(1)-C(3) 172.42(17) O(1)-C(1)-N(1)-C(3) -8.43(19) C(12)-C(11)-N(1)-C(1) -80.48(17) C(10)-C(11)-N(1)-C(1) 155.43(14) C(12)-C(11)-N(1)-C(3) 127.63(15) C(10)-C(11)-N(1)-C(3) 3.6(2) C(4)-C(3)-N(1)-C(1) -112.36(15) C(2)-C(3)-N(1)-C(1) 12.38(19) C(4)-C(3)-N(1)-C(11) 41.6(2) C(2)-C(3)-N(1)-C(11) 166.32(16) ________________________________________________________________ 511 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 512 CHAPTER 4 Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) † 4.1 INTRODUCTION The tetrahydroisoquinoline (THIQ) alkaloids make up one of the largest groups of natural products with a wide range of structural diversity and biological activity. 1 From simple tetrahydroisoquinolines such as salsolidine 183, to complex tris- tetrahydroisoquinoline systems like Ecteinsacidin 743 184, there is a wide variety in structure and activity between the families of isoquinoline alkaloids that possess the 1,2,3,4tetrahydroisoquinoline ring system (Figure 4.1). Thus, the chemical syntheses of these alkaloids have been extensively investigated toward the development of efficient total syntheses and understanding of their biological activity.2 While several review articles on the total synthesis of isoquinoline alkaloids have been published, including Williams’ seminal review on the THIQ antitumor antibiotics,3 there has been no comprehensive review of the chemical syntheses of tetrahydroisoquinoline alkaloids over the past several decades. Moreover, recent total syntheses have emerged ________________________________________________ † This review was conducted in collaboration with Dr. Fa Ngamnithiporn and Emily Du. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 513 Alkaloids (2002 – 2020) harnessing modern chemical methods and novel technology. As these synthetic strategies diverge from biomimetic approaches, they often provide a highly efficient route toward complex THIQ alkaloids compared to previous syntheses. This review will cover literature from 2002 to 2020, highlighting the chemical syntheses of a range of THIQ alkaloids that especially feature creative, novel synthetic approaches (Figure 4.2). Figure 4.1 Tetrahydroisoquinoline alkaloids (–)-salsolidine 183 and Ecteinascidin 743 184. HO NH MeO O OAcO S MeO Me Me H H N NH MeO OMe HO Me N O Me H O (–)-Salsolidine (183) H OH Ecteinascidin 743 (184) 4.2 TETRAHYDROISOQUINOLINE ALKALOIDS 4.2.1 GENERAL STRUCTURE AND BIOSYNTHESIS Most simple THIQ alkaloids come from the Cactaceae, Chenopodiaceae, and Fabaceae cacti families.1 These cactus species contain βphenylethylamine alkaloids, as well as simple tetrahydroisoquinolines that bear a stereogenic center at the C1 carbon with various oxidation patterns on the arene ring (Figure 4.3). Figure 4.3 General structure of simple THIQ alkaloids. R NR2 * R = OMe, OH R1 = Me, alkyl R2 = H, Me R1 THIQ Alkaloids Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 514 Figure 4.2 General structures of THIQ alkaloid families. R C D R N B A B C A R Erythrina NR1 H R A A B A N R = OMe, OH R1 = H, Me C D R R = OMe, OH R1 = H, Me D R = OMe, OH R1 = H, OH, =O R2 = H, OH C NR3 R3 = H, Me, alkyl B R2 O D R1 Morphinan Alkaloids Protoberberine Alkaloids Aporphine Alkaloids R1 B OMe Head NR O Me O C B A Tail C N MeO O A RN B D N O R = OMe, OH, -OCH2OR1 = H, Me X A B MeO R O N C D N Me R1 NH O NH2 O Saframycin Alkaloids Bisbenzyl THIQ Alkaloids E Me Me R1 NH O R1 C Me HO E Me Safracin Alkaloids R OMe E A B N D N C O Me X A B N Me A R1 R = OH, ester R1 = H, OH, CN X = H, OH, OMe Renieramycin Alkaloids R OAcO S C D N R 1O R N OR1 F N E H B O Me HO C D N R2 X R = NH2, THIQ, =O R1 = OH, OMe, -OCH2OR2 = H, Me X = H, OH, CN A A B R NR1 C D D NR N C R = H, Me Naphthyridinomycin Alkaloids Ecteinascidin Alkaloids R B E A R C B N D R1 R R = OMe, OH, -OCH2OR1 = H, Me R = H, Me Quinocarcin Alkaloids Pavine Alkaloids Isopavine Alkaloids The biosynthesis of these simple THIQs is generally achieved from the condensation of the corresponding β-phenylethylamine with a formaldehyde or acetaldehyde equivalent, accessing the tetrahydroisoquinoline motif as a single enantiomer. 4 These naturally require electron-rich functional groups on the arene ring to undergo electrophilic aromatic substitution chemistry. Throughout this review, this key heterocyclic motif serves as a fundamental scaffold in all THIQ natural products that requires unique and creative synthetic approaches to install. 4.3 SPIROCYCLIC TETRAHYDROISOQUINOLINE ALKALOIDS 4.3.1. GENERAL STRUCTURE AND BIOSYNTHESIS Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 515 Alkaloids (2002 – 2020) From the Fabaceae family, the Erythrina genus consists of about 143 alkaloids that are characterized by the spirocyclic motif embedded in the tetracyclic scaffold (Figure 4.4).1 There are three main classes of Erythrina alkaloids referred to as the dienoid, alkenoid, and lactonic alkaloids.5 The dienoid alkaloids feature a conjugated diene system, whereas the alkenoids have a 1,6-double bond in the A ring, and the lactonic alkaloids possess a lactone ring in ring D. These alkaloids have been discovered to possess an array of biological activity, including antiepileptic, anticonvulsant, and CNS depressing properties. Figure 4.4 General structure of the Erythrina alkaloids. R1 R1 D C N B X R A R = OH, OMe R1 = OH, OMe, =O X = H, O Erythrina R N X N N O MeO R 1O R1 DIenoid Alkenoid MeO Lactonic The biosynthesis of the Erythrina alkaloids is proposed to stem from norreticuline 185 as a key precursor (Figure 4.5).1, 6 Oxidative phenol coupling occurs to generate intermediate 186, followed by rearrangement and ring opening of the tetrahydroisoquinoline ring to form dibenzazonine 188. Zenk and coworkers utilizes 13C-labelling studies to suggest an allylic cation intermediate 189 that undergoes subsequent ring closure to access the natural product skeleton 190. However, the specific enzymes that catalyze these transformations have not yet been fully elucidated. 4.3.2. TOTAL SYNTHESIS OF ERYTHRINA ALKALOIDS Approaches to the synthesis of the core spirocyclic system of the Erythrina alkaloids are diverse, accessing several natural product members of this family both in racemic and Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 516 Alkaloids (2002 – 2020) enantioselective fashion. Three general strategies toward the construction of the THIQ core have been described, either through the disconnection of the C1–C8a,7 C1–N,8 and/or the N– C3 bond (Figure 4.6). While electrophilic aromatic substitution chemistry through iminium ion cyclization is most common to assemble the scaffold, other novel disconnections have also been explored to build the A, B, and C rings. Figure 4.5 Proposed biosynthesis of the Erythrina alkaloids. OH OH MeO MeO MeO NH HO H OMe NH H MeO MeO OH O OH Norreticuline (185) Norisosalutaridine (186) O O O O O O H NH NH – 2e– H+ O OH OH 189 Dibenzazonine (188) 187 O NH MeO MeO MeO NH O N O MeO N O MeO O 190 Erythraline (191) In 2004, Matsumoto sought to construct the Erythrinan scaffold utilizing substitution chemistry for the key spirocyclization of ortho-quinone monoacetal 197 to establish the C ring.8a Toward the synthesis of O-methylerysodienone 199, Matsumoto and coworkers initially access the biphenyl precursor 194 from a Suzuki–Miyaura coupling of arylboronic acid 192 and aryl bromide 193 (Scheme 4.1). Further oxidative manipulations and substitution chemistry results in the installation of the nucleophilic nitrogen functional group in intermediate 196. The C-ring was then established through the key spirocyclization step Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 517 Alkaloids (2002 – 2020) from ortho-quinone acetal 197, using BF3•OEt2 as the optimal Lewis acid compared to other metal triflates. Finally, N-alkylation to furnish the B-ring occurred smoothly under methanol and phosphate buffer. Figure 4.6 Synthetic approaches to Erythrina alkaloids. 5 4 D C 6 3 7 8a 1 8 Iminium Ion Cyclization C D N B N B A A N-alkylation aza-Michael, Oxidative Amidation X C D C H N B D HN B A A Scheme 4.1 Matsumoto’s total synthesis of O-methylerysodienone 199. OMe MeO OMe OMe CHO MeO MeO Br B(OH)2 OSi(i-Pr)3 193 Pd(PPh3)4 Ba(OH)2 CHO MeO 93% yield OBn OH 1) Ph3P=CH2 OSi(i-Pr)3 OSi(i-Pr)3 2) (sia)2BH; H2O2, NaOH aq. MeO MeO 80% yield (2 steps) OBn 192 OBn 195 194 OMe OMe MeO MeO 1) MsCl, pyridine 2) NaN3 NHBoc OSi(i-Pr)3 3) PMe3 4) (Boc)2O, NEt3 1) H2, 5% Pd/C NHBoc BF3•OEt2 2) (AcO)2IPh, MeOH OSi(i-Pr)3 MS 4Å, CH2Cl2, –20 °C MeO MeO 82% yield (4 steps) 99% yield (2 steps) OBn MeO 196 MeO 84% yield O 197 MeO NBoc MeO OSi(i-Pr)3 1) Bu4NF 2) MsCl, pyridine 3) TMSOTf, CH2Cl2 then MeOH, pH 7 phosphate buffer MeO O 198 56% yield (3 steps) N MeO MeO O O-methylerysodienone (199) Matsumoto and coworkers also demonstrated the enantioselective synthesis of Omethylerysodienone 199 by installing an additional ortho substituent on the A-ring, Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 518 Alkaloids (2002 – 2020) transmitting axial chirality of the biphenyl intermediate from its hindered rotation to the spirocyclic center of the natural product (Scheme 4.1). Adding a trimethylsilyl group ortho to the biphenyl bond that was easily cleaved with Bu4NF allowed separation of both enantiomers and enabled the enantioselective synthesis of (+)-O-methylerysodienone. Scheme 4.2 Matsumoto’s enantioselective synthesis of O-methylerysodienone 199. OMe OMe MeO MeO Br OH 1) (Me3Si)2NH 2) nBuLi OSi(i-Pr)3 3) 0.1 M HCl MeO 6 steps OH Me3Si A A HO 82% yield (3 steps) MeO HO O OBn OBn 196a N MeO OSi(i-Pr)3 (+)-199 196b Alternatively, Padwa and coworkers sought to construct the A ring of the Erythrina alkaloids through an intramolecular Diels–Alder reaction that could yield intermediate 201. The oxabicyclic adduct could then undergo regioselective ring-opening reactions with rhodium or tin to access building blocks 202 and 203 (Scheme 4.3).9 Scheme 4.3 Padwa’s synthetic strategy toward the Erythrinan alkaloids. OH [Rh] O O R N Boc 200 R=H R = CO2Me [4+2] O BocN R 202 BocN Me O 201 [Sn] O Me O O CO2Me BocN 203 O A Rh(I)-catalyzed ring-opening cascade as demonstrated in Pathway A delivers intermediate 202 that undergoes N-alkylation with alkyl bromide to yield 204 (Scheme 4.4). The bicyclic lactam then underwent smooth cyclization to generate the spirocyclic Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 519 Alkaloids (2002 – 2020) tetrahydroisoquinoline 205 with NBS in CH3CN. Reduction of the bromide and elimination of the alcohol then produces 206, which undergoes stereoselective allylic oxidation, subsequent reduction, and O-methylation to synthesize erysotramidine 208. Scheme 4.4 Padwa’s total synthesis of erysotramidine 208. OH MeO OTBS O 1) TBSCl, imidazole 2) Mg(ClO4)2 NBS, CH3CN MeO MeO N Br 3) POCl3, DBU 3) NaH; ArCH2CH2Br BocN N MeO O 202 OTBS O 60% yield (3 steps) 89% yield 204 205 MeO MeO O N MeO 50% yield (3 steps) MeO O SeO2, HCO2H 50% yield N MeO O 206 1) n-Bu3SnH, AIBN 2) TBAF, THF O 1) MeCOCl, EtOH 2) MeI, KOH O N MeO MeO 207 55% yield (2 steps) Erysotramidine (208) Pathway B commences with ring-opening by SnCl2 followed by addition of acetone to access acetonide 203 (Scheme 4.5). N-alkylation and treatment of acetonide with trifluoroacetic acid led to tetrahydroindolinone 210. A Pictet–Spengler reaction with PPA then establishes the Erythrinan scaffold 211, which was then subjected to hydrolysis, Barton decarboxylation, and reduction to access demethoxyerythratidinone 213. This novel strategy toward the tetrahydroindolinone core allows access to several natural products of the Erythrina alkaloids, based on an intramolecular Diels–Alder reaction of 2-imido-substituted furans. Enantioselective approaches to the synthesis of demethoxyerythratidinone 213 have been explored over the past two decades. 10 Simpkins and coworkers demonstrated an asymmetric total synthesis of 213 through a key N-acyliminium ion cyclization using (S)malic acid-derived lactams (Scheme 4.6).11 Initially, addition of butenyl magnesium bromide to imide 214 resulted in hydroxylactam 215 with excellent regiocontrol. Protection of the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 520 Alkaloids (2002 – 2020) secondary alcohol followed by exposure to BF3•OEt2 formed an acyliminium intermediate that allowed cyclization to occur with diastereocontrol. Wacker oxidation of 216 and subsequent reduction removed the amide carbonyl, and aldol cyclization of the two oxidized ketones yielded (+)-demethoxyerythratidinone 213 in 50% yield, allowing access to both enantiomers of the natural product in simply eight steps. Scheme 4.5 Padwa’s total synthesis of demethoxyerythratidinone 213. Me Me Me Me O O CO2Me CO2Me MeO CO2Me MeO 65% yield (2 steps) O 93% yield 209 MeO MeO O 1) NaOH, H+ N MeO N MeO CO2Me 90% yield 210 MeO O 1) ethylene glycol, H+ N MeO 2) (COCl)2, CBrCl3; sodium pyrithione 2) AlH3, HCl O O O 212 56% yield (2 steps) 211 PPA N MeO O O 203 TFA N MeO BocN O O O 1) Mg(ClO4)2 2) NaH; ArCH2CH2Br Demethoxyerythratidinone (213) Scheme 4.6 Simpkin’s enantioselective synthesis of (+)-demethoxyerythratidinone 213. MeO MeO N MeO MgBr O HO MeO O N O 82% yield, 3:1 dr (2 steps) HO MeO N 86% yield O TIPSO 217 1) LiAlH4, AlCl3 O 2) (COCl) , DMSO 2 NEt3, CH2Cl2, –78 °C 32% yield (2 steps) O TIPSO MeO MeO MeO N 216 215 214 PdCl2, CuCl O2, DMF•H2O MeO MeO 61% yield AcO 1) TIPSOTf 2) BF3•OEt2, CH2Cl2 N MeO 20% KOH, MeOH N MeO 50% yield O O 218 O (+)-213 Distinct from classic electrophilic aromatic substitution strategies to forge the THIQ core, Reisman and coworkers utilized their developed method of installing enantioenriched 4-aminocyclohexadienones to access 213. 12 Having optimized a method for the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 521 Alkaloids (2002 – 2020) diastereoselective 1,2-addition of organometallic reagents to benzoquinone monoketalderived sulfinimines, they established spirocyclic THIQ 221 through addition of aryllithium 220 to bromosulfinimine 219 to provide a single diastereomer in 74% yield (Scheme 4.7). Stille coupling then furnished the corresponding enol ether, with sulfinamide deprotection and in situ condensation accessing the natural product scaffold 223. Selective hydrogenation of triene 223 then completed the elegant and rapid total synthesis of (–)demethoxyerythratidinone in only six steps and 26% overall yield. Scheme 4.7 Reisman’s enantioselective synthesis of (–)-demethoxyerythratidinone 213. O t-Bu S Cl MeO MeO t-Bu MeO N S Br O N Li MeO Br 220 Et2O, –78 °C then 1 N HCl, –78 to 23 °C MeO O OMe 74% yield, >98:2 dr 219 MeO OEt SnBu3 MeO 222 1) Pd2(dba)3 AsPh3, DMF N MeO 2) 2 N HCl/Et2O THF, 0 °C 75% yield (2 steps) 221 H2, Pd/CaCO3 O 223 65% yield N MeO O (–)-213 Toward the total syntheses of (+)-demethoxyerythratidinone 213 and (+)erysotramidine 208, Ciufolini and coworkers employed an oxidative cyclization of a phenolic oxazoline, establishing the stereogenic center of the spirocycle. 13 Starting from oxazoline 224 prepared in five steps, oxidative amidation occurred smoothly to access 225 in 62% yield (Scheme 4.8). Upon treatment with TsOH, oxa-Michael addition then proceeds to furnish enone 226 as a single diastereomer. After several steps to remove the bridging serine moiety and further oxidative manipulations, late-stage intermediate 227 served as a universal precursor to access both natural products. First, N-acylation of 227 with (EtO)2P(O)CH2COCl and subsequent treatment with aq. KOH established a mixture of Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 522 Alkaloids (2002 – 2020) lactams 229 and 230. Reduction of the mixture of products and acidic hydrolysis then resulted in the total synthesis of (+)-213. Scheme 4.8 Ciufolini’s enantioselective synthesis of (+)-demethoxyerythratidinone 213. MeO OMe MeO O N O N MeO PhI(OCOCF3)2 MeO OH CO2Me HFIP O CH2Cl2 O MeO (EtO)2P(O)CH2COCl NEt3, THF, 18 h NH O MeO O N MeO O O O O 227 + N MeO OH O 229 O O MeO O O N P(OEt)2 228 MeO MeO 226 O then 10% aq. KOH MeO CO2Me O 90% yield 225 62% yield MeO 5 steps N MeO TsOH•H2O CO2Me 224 HO O O 230 1) Me2EtN•AlH3 0 °C to 23 °C, 1 h N MeO 2) 1.5 M aq. HCl acetone, reflux 63% yield (2 steps) O (+)-213 Alternatively, silica gel chromatography of 227 and subsequent protection provided quantitative conversion to 231, which underwent conjugate reduction with Li/NH3 and elimination with t-BuOK to deliver 232 in 64% overall yield (Scheme 4.9). N-acylation and cyclization then established the natural product scaffold, which was advanced to (+)erysotramidine 208 in two subsequent steps. Overall, a unified approach to the Erythrina alkaloids was demonstrated through a key oxidative amidation and cyclization strategy. Kaluza’s synthetic strategy toward the asymmetric synthesis of (–)-erysotramidine 208 utilized a late-stage Heck cyclization to assemble the A ring of the natural product scaffold.14 Starting from imide 233 prepared in two steps from L-tartaric acid, addition of Grignard reagent 234, and Lewis-acid mediated cyclization provided an epimeric mixture of Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 523 Alkaloids (2002 – 2020) diacetate 235 (Scheme 4.10). Silver-catalyzed cyclization then furnished dihydrofuranyl derivative 236, with further reduction accessing key intermediate 237. Preparation of the (Z)vinyl iodide for the late-stage Heck cyclization was achieved through Swern oxidation, then Wittig olefination of the crude aldehyde and protection of the hydroxyl group to provide 239. A Heck cyclization then established the A ring of the natural product scaffold, providing 240 in 62% yield as the sole product. A final methylation step of the alcohol furnished the unnatural enantiomer (–)-erysotramidine 208 in good yield. Scheme 4.9 Ciufolini’s enantioselective synthesis of (+)-erysotramidine 208. MeO MeO 1) silica gel NH chromatography O MeO 2) TBDPSCl, imidazole, DMF O OTBDPS O 59% yield (2 steps) 231 MeO MeO NH O MeO 232 4.4 2) t-BuOK THF, 0 °C O 82% yield (2 steps) 227 1) Li, NH3 (liq), THF t-BuOH, –78 °C NH O MeO O 1) (EtO)2P(O)CH2COCl DCC, DMAP, NEt3 2) 10% aq. KOH 3) SeO2, dioxane AcOH, reflux 4) MeI, KOH, Bu4NBr 27% yield (4 steps) N MeO MeO (+)-Erysotramidine (208) BENZYLTETRAHYDROISOQUINOLINE ALKALOIDS Benzyltetrahydroisoquinoline alkaloids specifically feature a benzyl group at the C1 position of the isoquinoline ring and comprise one of the largest and most diverse groups of alkaloids. Despite the considerable variation in structure of benzyl THIQ alkaloids, the biosynthesis of these natural products is proposed to share early biosynthetic precursors.1 Isoquinoline biosynthesis stems from dopamine 241 and p- hydroxyphenylacetaldehyde 242 to yield the central biosynthetic intermediate (S)-reticuline 247 (Figure 4.7).15 Condensation of 241 and 242 is catalyzed by the enzyme norcoclaurine synthase (NCS) to form (S)-norcoclaurine 243. methylation then occurs by a S-adenosyl Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 524 Alkaloids (2002 – 2020) methionine-(SAM)-dependent O-methyl transferase to access (S)-coclaurine 244. After Nmethylation to yield intermediate 245, hydroxylation by N-methylcoclaurine 3’-hydroxylase (NMTC) followed by O-methylation produces the key precursor (S)-reticuline 247. From this key intermediate, the biosynthetic pathways branch to form a variety of different structural classes of THIQ alkaloids (Figure 4.8). Scheme 4.10 Kaluza’s enantioselective synthesis of (–)-erysotramidine 208. TIPSO MeO MeO MeO O N MeO 1) THF, 234 MgBr TMSO N MeO 2) Ac2O, DMAP 3) BF3•Et2O, CH2Cl2, 0 °C OTMS O O TIPSO AcO OAc 235 76% yield (3 steps) 233 1) NaOMe, MeOH 3) LiI, CH3CN 4) Pd/C, NaHCO3, MeOH 1) TBAF, AcOH, THF N MeO O 2) (COCl) , DMSO 2 NEt3, CH2Cl2, –60 °C O N MeO O MeO Pd(PPh3)4 (25 mol %) Na2CO3, TBABr MeO O MeI, KOH, TBABr N MeO OTES N MeO THF, R.T., 24 h HO 62% yield 239 2) TfOTES, NEt3 O DMF, 80 °C, 24 h I I 1) Ph3PCH2I, NaHMDS 238 MeO O MeO 96% yield 240 (–)-Erysotramidine (208) Figure 4.7 Early biosynthetic pathways to yield (S)-reticuline 247. HO Dopamine (241) MeO HO NH2 HO NCS NH HO NH HO 6-OMT CNMT + O HO (S)-norcoclaurine (243) (S)-coclaurine (244) MeO MeO HO HO HO H p-hydroxyphenylacetaldehyde (242) NMe HO (S)-N-methylcoclaurine (245) OH 37% yield (2 steps) O 237 MeO N 236 O O TIPSO 67% yield (4 steps) O TIPSO 91% yield (2 steps) MeO MeO 1) Pd/C, H2, PhMe 2) Tf2O, 2,6-lutidine N MeO 2) AgNO3 (20 mol %) NEt3, THF, 55 °C NMTC HO MeO NMe HO HO (S)-3’-hydroxyN-methylcoclaurine (246) 4’-OMT HO NMe HO MeO (S)-reticuline (247) Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 4.4.1 APORPHINE ALKALOIDS 4.4.1.1. 525 GENERAL STRUCTURE AND BIOSYNTHESIS The aporphine alkaloids are based on the 4H-dibenzo[de,g]quinoline structure or its N-methyl derivative, with a tetracyclic core as distinguished in Figure 4.9.16 They contain a biphenyl ring system and highly oxidized substitution patterns, with hydroxyl, methoxy, and methylenedioxy moieties situated over all four rings. Figure 4.8 Diverging biosynthetic pathways from (S)-reticuline 247 that access a wide variety of structural classes of THIQ alkaloids. RO R N O H H R1 R1 H NR NMe O RO Morphinan Alkaloids Protoberberine Alkaloids O R1 MeO R RN NR2 NMe HO H Bisbenzylisoquinoline Alkaloids HO R1 MeO Aporphine Alkaloids (S)-reticuline 247 R R2 R NR1 Pavine Alkaloids R2 R NR1 O H NR1 Isopavine Alkaloids R2 Cularine Alkaloids The aporphine alkaloids have been isolated from a variety of plants, including the genera Glaucium flavum, Beilschmiedia elliptica, and Nandina domestica. They are known to be promising agents in the prevention and treatment of metabolic syndrome due to their broad biological activity, including anti-hypertension, anti-diabetes, anti-obesity, antioxidation, and anti-inflammation.17 In particular, many of the aporphines show various levels of preventing insulin resistance and regulating glucose homeostasis. The methoxy and hydroxyl substituents may be important for these biological activities.17 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 526 Figure 4.9 General structure of the aporphine alkaloids. R A B C R NR1 H R = OMe, OH R1 = H, Me Tetracyclic skeleton Biphenyl Ring System Highly Oxidized Functionalities D Aporphine Alkaloids The aporphine alkaloids are presumably derived from reticuline 247, which undergoes an intramolecular bis-phenol coupling to construct the core. 18 The CYP80G subfamily of cytochrome P450 monooxygenases has been correlated with aporphine biosynthesis, in which CYP80G2 (corytuberine synthase) catalyzes conversion of (S)reticuline 247 to (S)-corytuberine 248 via intramolecular C–C coupling (Figure 4.10). Nmethylation of corytuberine 248 by reticuline N-methyl transferase (RNMT) enzyme then delivers one of the aporphine natural products magnoflorine 249. Other related aporphine members of the family are proposed to arise from a similar route, either delivering the N–H, N-methyl aporphine or the quaternary aporphine salt. Figure 4.10 Proposed biosynthesis of aporphine alkaloid (S)-magnoflorine 249. HO NMe CYP80G HO NMe HO HO MeO MeO (S)-reticuline (247) 4.4.1.2. MeO MeO MeO (S)-Corytuberine (248) RNMT HO N Me Me HO MeO (S)-Magnoflorine (249) TOTAL SYNTHESIS OF APORPHINE ALKALOIDS Approaches toward the syntheses of the aporphine alkaloids commonly feature EAS chemistry to establish the THIQ core, followed by an intramolecular phenol arylation to achieve the natural product scaffold. In 2004, Cuny described the synthesis of aporphine 255 utilizing this synthetic strategy starting from N-tosyl tyramine 250 (Scheme 4.11). 19 A Pictet–Spengler cyclization with 2-bromophenylacetaldehyde 251 was affected to afford Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 527 Alkaloids (2002 – 2020) THIQ 252 in 55% yield. A Pd-catalyzed intramolecular phenol ortho-arylation then delivered the key aporphine scaffold 253 in moderate yield. Finally, removal of the hydroxyl group and the sulfonamide followed by reductive amination with 37% aqueous formaldehyde in the presence of NaBH4 afforded aporphine 255. Similar synthetic strategies have also been utilized in subsequent reports to access different aporphine natural products.20 Scheme 4.11 Cuny’s synthesis of aporphine 255. Br Me H N CHO 251 NTs HO Pd(OAc)2 (20 mol %) PCy3 (40 mol %) CsCO3 S O O HO DMA, 110 °C, 24 h 55% yield 56% yield 250 Br 252 NTs HO 1) Tf2O, 2,6-lutidine CH2Cl2, 0 °C NH 37% aq. CH2O MeOH, 30 min. then NaBH4 2) Pd(OAc)2 (10 mol %) dppf (10 mol %), NEt3 HCO2H, DMF, 80 °C 3) Na, NpH, DME, –56 °C 253 69% yield (3 steps) NMe 84% yield 254 Aporphine (255) Circumventing the need for prefunctionalization of the arene before direct arylation, Vicario and coworkers reported the total synthesis of (+)-glaucine using an oxidative biaryl coupling to establish the aporphine scaffold (Scheme 4.12).21 From imine 256, addition of Grignard benzylic reagents followed by hydrogenation to remove the chiral appendage delivered amine 257. N-alkylation with bromoacetaldehyde diethylacetal (BADA) allowed a Pomeranz–Fritsch cyclization to construct THIQ 259. After reduction of the hydroxyl group, the final C–C biaryl oxidative coupling was accomplished using hypervalent iodine(III) reagent (bis(trifluoroacetoxy)iodo)benzene (PIFA) that allowed the synthesis of (+)-glaucine 260 cleanly with no racemization observed. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 528 Scheme 4.12 Vicario’s synthesis of (+)-glaucine 260. Br MeO EtO MeO OH N MeO Ph 1) ArCH2MgCl THF, 40 °C 2) H2, Pd/C HCl, MeOH 74% yield (2 steps) MeO MeO OEt 1) K2CO3, 258 CH3CN, reflux 2) HCHO, NaBH3CN CH3CN 3) 1:1 HCl:acetone 67% yield (3 steps) OMe 256 257 OH MeO MeO NMe MeO NH2 1) NaBH4, TFA CH2Cl2 2) PIFA, BF3•OEt2 CH2Cl2, –20 °C NMe MeO MeO MeO OMe 259 64% yield, 94% ee (2 steps) OMe (+)-Glaucine (260) Alternatively, Fürstner and co-workers constructed the aporphine scaffold through a key In-mediated cycloisomerization reaction from biphenyl derivatives. 22 From enamide 261, a Suzuki coupling with 2-formylbenzeneboronic acid yielded functionalized biphenyl derivative 262, constructing the C–C biphenyl bond early in the synthesis (Scheme 4.13). Conversion of the aldehyde to alkyne 263 then sets the stage for the key carbocyclization, which was effected using InCl3 in toluene. After removal of the phthalimide protecting group, intramolecular amination forged the THIQ ring and completed the total synthesis of Omethyl-dehydroisopiline 264. An unusual approach toward the synthesis of the aporphine scaffold employs benzyne chemistry to construct two of the four rings in a single transformation. Raminelli and coworkers described the synthesis of aporphine 255 from amide 265, which was converted to isoquinoline 266 through a Bischler–Napieralski reaction (Scheme 4.14). 23 Treatment with acetic anhydride then yielded isoquinoline 267, which served as the nonpolar diene for the [4+2] annulation. Thus, adding 267 and benzyne precursor 268 in the presence of CsF delivered aporphine core 269 from a [4+2] reaction followed by hydrogen migration. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 529 Alkaloids (2002 – 2020) Hydrolysis of 269 followed by reductive amination delivered aporphine 255, which was then subjected to chiral resolution using (+)-DBTA to provide the enantiomer of the aporphine alkaloid. Raminelli and coworkers were further able to demonstrate the syntheses of different aporphine alkaloids using benzyne chemistry to couple isoquinoline derivatives and various silylaryl triflates, allowing rapid access to functionalized aporphine scaffolds.24 Scheme 4.13 Fürstner’s synthesis of O-methyl-dehydroisopiline 264. OMe OMe NPhth MeO Pd(OAc)2 Cy2P(o-biphenyl) 2-formylbenzeneboronic acid K3PO4, PhMe MeO NPhth MeO 1) CBr4, PPh3 CH2Cl2, 0 °C MeO 2) DBU, DMSO CHO 94% yield Br 70% yield (2 steps) 261 262 OMe MeO NPhth MeO Br OMe 1) InCl3 PhMe, 80 °C 2) hydrazine MeOH, reflux MeO NH MeO 3) CuI, CsOAc DMSO 62% yield (3 steps) 263 O-methyl-dehydroisopiline (264) Scheme 4.14 Raminelli’s synthesis of (–)-aporphine 255. NHCOMe Ac2O pyridine PPA N 130 °C, 30 min 200 °C, 3 h 265 CsF (3 equiv) >99% yield NCOMe OTf Me 266 1) LiOH EtOH:H2O MW, 180 °C 2) CH2O (37%) MeOH, 30 min then NaBH4 CH3CN, 24 h 77% yield 269 TMS NCOMe + 60 °C, 3 h 46% yield (2 steps) CH2 74% yield N H 267 Me Aporphine (255) 1) (+)-DBTA EtOAc, i-PrOH reflux 2) K2CO3, H2O (pH 10) 41% yield 81% ee 268 N H Me (–)-255 Beyond the syntheses of the classic aporphine natural product scaffold, others have targeted unique members of the aporphine alkaloids which share the characteristic tetracyclic nucleus but with varying oxygenation patterns and bond connectivity. For instance, Nimgirawath and coworkers completed the total synthesis of telisatin A 272 and other members of the telisatin-type alkaloids that are distinguished by an oxalyl moiety fused to Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 530 Alkaloids (2002 – 2020) the THIQ core (Scheme 4.15).25 From dihydroisoquinoline 270 that was established from a Bischler–Napieralski reaction, treatment with oxalyl chloride and NEt3 afforded dione 271. A radical cyclization using SnBu3H in the presence of 1,1’-azobis(cyclohexanecarbonitrile) (ACCN) then delivered telisatin A 272 and other telisatin alkaloids in 30–34% yields. Scheme 4.15 Nimgirawath’s synthesis of telisatin A 272. MeO MeO MeO N MeO (COCl)2 NEt3 CHCl3 N MeO PhMe O 60% yield Br 270 O SnBu3H ACCN MeO N O O 33% yield Br 271 Telisatin A (272) Cuny and coworkers described the syntheses of C7-oxygenated aporphine alkaloids through a diastereoselective reductive cyclization followed by a Pd-catalyzed ortho-arylation to form the biaryl C–C bond (Scheme 4.16).26 From carbamate 273, selective reduction of the methyl ester using DIBAL, followed by an acid-mediated cyclization with BF3•OEt2 delivered oxazolidinone 274 of both anti- and syn-diastereomers. Demethylation and formation of the dioxolane moiety with CH2Br2 provided 275, which underwent an orthophenyl arylation with an XPhos precatalyst to afford (–)-artabonatine A 276. This natural product has been revised after observing that the specific rotation and 1H and 13C NMR spectral data for the natural product possessed the syn-configuration rather than its reported structure of the trans-diastereomer. Lastly, the proaporphine alkaloids are recognized as biosynthetic precursors of aporphine alkaloids that are distinguished by the spiro-cyclohexadienone ring system. Toward the construction of this unique spirocycle, Honda and coworkers first reported the total synthesis of stepharine 280 and pronuciferine 281 utilizing an intramolecular aromatic oxidation of a common phenol intermediate (Scheme 4.17A). 27 From aldehyde 277, Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 531 Alkaloids (2002 – 2020) condensation with nitromethane followed by reduction and acetylation delivered amide 278. After removal of the benzyl group, a Bischler–Napieralski reaction with POCl3 then acylation with trifluoroacetic anhydride yielded enamide 279 for the key aromatic oxidation. Ultimately, the oxidation of 279 with iodobenzene diacetate (PIDA) was successful in allowing cyclization to stepharine 280 in 90% yield. N-methylation of 280 further delivered pronuciferine 281. Alternatively, Magnus and coworkers demonstrated that the spirocyclization could be achieved through an intramolecular displacement of a mesylate derivative 282 using CsF in NMP at 150 °C to deliver stepharine 280 as well (Scheme 4.17B).28 Scheme 4.16 Cuny’s synthesis of (–)-artabonatine A 276. MeO MeO HN O TBSO 7 MeO O O 1) DIBAL, PhMe, –78 °C 2) MeOH, –20 °C H HO 3) BF3•OEt2, –20 °C Cl 4) TBAF, CH2Cl2 O 1) BBr3, CH2Cl2 2) CH2Br2, Cs2CO3 DMF, 60 °C O H 94% yield, 6.7:1 dr (4 steps) 273 N 7 78% yield (2 steps) Cl 274 O O H O N 7 H Cl O O XPhos precatalyst Cs2CO3 H O 7 DMA, 90 °C, 30 min N O O H 86% yield (–)-Artabonatine A (276) 275 Takao and coworkers reported the enantioselective synthesis of a distinct proaporphine alkaloid (–)-misramine 290 utilizing their previously developed enantioselective Friedel–Crafts 1,4-addition of enones.29 From phenethyl enone 283, their key enantioselective intramolecular 1,4-addition was accomplished using epi-cinchonine amine C1 as a catalyst (Scheme 4.18). With enantioenriched spiroindane 284, a Rubottom oxidation followed by treatment with camphorsulfonic acid (CSA) and trimethyl orthoformate induced an intramolecular hemiacetalization of the phenol and carbonyl to Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 532 Alkaloids (2002 – 2020) deliver tetracycle 285. After several protecting group manipulations, a benzylic oxidation with CrO3 furnished ketone 286. Next, to establish the THIQ core, the 2-oxoethyl group was incorporated into the benzene ring via a Claisen rearrangement to afford the C-allylated product 287, then ozonolysis followed by deoxygenation to produce aldehyde 289. Finally, reductive amination and removal of the TBS group afforded (–)-misramine 290 as a single diastereomer. Scheme 4.17 A. Honda’s synthesis of stepharine 280 and pronuciferine 281. B. Magnus’ synthesis of stepharine 280. A. MeO CHO MeO NHAc MeO 1) MeNO2, NH4OAc 2) LiAlH4, THF, reflux MeO OBn 277 278 MeO NH CF3 O 58% yield (3 steps) 71% yield (3 steps) OBn MeO N MeO 3) TFAA, NEt3 CH2Cl2, 0 °C 3) AcCl, NEt3 CH2Cl2, 0 °C PIDA MeO 1) Pd(OH)2, H2 MeOH 2) POCl3, MeCN HCHO NaBH3CN AcOH TFE, 0 °C then NaBH4 MeCN, 0 °C 90% yield 79% yield OH 279 MeO NMe MeO O O Stepharine (280) Pronuciferine (281) B. MeO MeO MeO NCO2Et 1) CsF NMP, 150 °C OMs 2) KOH, ethylene glycol H2O, 100 °C NH MeO 66% yield (2 steps) OTIPS O 282 Stepharine (280) Fagnou and coworkers further utilized the Pd-catalyzed direct arylation of aryl halides for the preparation of aporphine analogues, including C2-substituted aporphines and the syntheses of (R)-nornuciferine 302 and (R)-nuciferine 301 (Scheme 4.19). 30 First, a Bischler–Napieralski cyclization of differentially substituted amides under either POCl3 or polyphosphoric acid yielded the dihydroisoquinoline intermediate which was immediately Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 533 Alkaloids (2002 – 2020) reduced to THIQ 292 using NaBH4 in MeOH. After protection of the secondary amine, the key direct arylation step was explored for each substrate, enabling the direct coupling of aryl bromides, chlorides, and iodides, as well as different N-protecting groups (Scheme 4.19A). Scheme 4.18 Takao’s synthesis of (–)-misramine 290. OH O C1 (30 mol %) H2O (1 equiv) p-bromophenol (1 equiv) HO 1) MOMCl, i-Pr2NEt DMAP, CH2Cl2 2) LDA, TMSCl, NEt3 THF, –78 to 0 °C O 3) DMDO, acetone then 1 M aq. HCl 4) CSA, HC(OMe)3 MeOH HO MeO PhH, 65 °C OH NH2 MeO OH N N 283 MeO O HO MeO 57% yield (4 steps) 284 285 C1 60% yield, 73% ee OH OBz 1) BzCl, K2CO3 acetone, reflux 2) TBSCl, imidazole DMAP, CH2Cl2 3) CrO3 3,5-dimethylpyrazole CH2Cl2, reflux MeO O TBSO 65% yield (3 steps) 1) K2CO3, MeOH 2) allyl bromide K2CO3, acetone O 3) N,N-diethylaniline 230 °C MeO TBSO 81% yield (3 steps) MeO 287 286 O MeO MeO O TBSO 1) Pd/C, HCO2NH4 MeOH, reflux 2) TFA, H2O CH2Cl2 288 O O TBSO 63% yield (2 steps) MeO 95% yield (3 steps) MeO OTf EtO OEt O O O 1) PhNTf2, NaH 2) O3, CH2Cl2, then Me2S 3) PPTS, HC(OEt)3 EtOH, reflux MeO MeO 1) MeNH2, AcOH NaBH3CN, MeOH 2) HF•Py Py:THF 47% yield (2 steps) 289 NMe O H HO MeO (–)-Misramine (290) Fagnou also performed SAR studies to probe the effects of C2-substitutents on their biological activity. In this experiment, aporphine derivative 295 was coupled with different nucleophilic coupling partners, installing a range of functionalities such as a morpholine, pyridine, and pyrazine N-oxides (Scheme 4.19B). This strategy was also employed for the synthesis of (R)-nornuciferine 302 and (R)-nuciferine 301 by utilizing a Ru-catalyzed asymmetric transfer hydrogenation after Bischler–Napieralski cyclization to provide THIQ 298 in 99% yield and with 95% ee (Scheme 4.19C) Then, Pd-catalyzed arylation followed by reduction or deprotection of the Boc group delivered both natural products. Overall, these Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 534 Alkaloids (2002 – 2020) syntheses highlight the utility of direct arylation methodology for both target-oriented and diversity-oriented synthesis. Scheme 4.19 Fagnou’s synthesis of aporphine alkaloids. A. R2 R2 R2 NH O R1 R3 1) POCl3, CH2Cl2 or PPA, 150 °C R1 2) NaBH4, MeOH R3 Boc2O, DMAP NH i-Pr2NEt, CH2Cl2 or TsCl, py., CH2Cl2 or Ac2O, DMAP i-Pr2NEt, CH2Cl2 54–99% yield X 292 R1, R2, R3 = H, OMe, Cl, F X = Br, Cl, I R2 Pd(OAc)2 (5 mol %) ligand (10 mol %) R1 R3 Br PG = Boc, Ac, Ts X 291 NPG R1 293 NPG K2CO3, DMA, 130 °C 58–99% yield R3 294 B. Cl 2 Pd(OAc)2 (10 mol %) O PCy2-2-BiPh (20 mol %) NaOt-Bu, PhMe, 110 °C NBoc or Pd(OAc)2 (5-10 mol %) P(t-Bu)3-HBF4 (15-30 mol %) K2CO3, PhMe, 110 °C X = CH, N 295 X 2 NH NBoc X N O 296 70–83% yield X = morpholine, pyridine N-oxide, pyrazine N-oxide C. MeO N MeO Ru catalyst (5 mol %) HCO2H/NEt3 Br 297 Ph NH MeO DMF, 1 h Ph MeO H N Cl Ru N cymene H C2 Br 2) Pd(OAc)2 ligand 299 KOAc, DMA 49–72% yield 298 99% yield, 95% ee MeO 1) (ROC)2O, DMAP i-Pr2NEt PPh2 MeO Me2N NR MeO LiAlH4, THF, 0 °C MeO NR or TFA, CH2Cl2 299 53–88% yield 300 R = CO2Me, CO2t-Bu R = Me, (R)-Nuciferine (301) R = H, (R)-Nornuciferine (302) 4.4.2. BISBENZYLTETRAHYDROISOQUINOLINE ALKALOIDS 4.4.2.1. GENERAL STRUCTURE AND BIOSYNTHESIS Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 535 Alkaloids (2002 – 2020) The bisbenzyltetrahydroisoquinoline alkaloids consist of two monomeric benzyl THIQ fragments linked through diphenyl ether or biphenyl bonds (Figure 4.11). The substitution on the arene mainly consist of hydroxyl, methoxy, or methylenedioxy groups. Over hundreds of bisbenzyl THIQ alkaloids have been isolated and characterized, with the diaryl ether linkage either involved in “tail-to-tail” coupling of the benzyl unit, or “head-totail” coupling of the THIQ linked to the benzyl C ring. Figure 4.11 General structure of bisbenzyl THIQ alkaloids. R1 A B Head NR O C Dimers of Benzyl THIQ Monomers Tail C Highly Oxidized Functionalities O A RN B R1 “Head-to-Tail” or “Tail-to-Tail” Coupling R = OMe, OH, -OCH2OR1 = H, Me Bisbenzyl THIQ Alkaloids The bisbenzyl THIQ alkaloids have been isolated from an array of plant species, including Chondrodendron tomentosum, and opium poppy Papaver somniferum.31 They are widely known for their dopaminergic, antitumor, and neuroprotectant properties. This class of alkaloids is proposed to be formed from the coupling of two monomer units derived from N-methylcoclaurine (NMC) 245 in either the (R) or (S)-configuration, catalyzed by enzyme CYP80A1 (Figure 4.12). First, epimerization of 245 is performed by dehydroreticuline synthase-dehydroreticuline reductase (DRS-DRR) to yield (R)-245, then either (R)+(R) coupling or (R)+(S) coupling delivers guattegaumerine 303 or berbamunine 304, respectively. However, dimerization of benzyl THIQs can occur either between both benzyl units or between the THIQ moiety to a benzyl unit, and thus the structural diversity of these alkaloids is extensive.31 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 536 Figure 4.12 Proposed biosynthesis of bisbenzyl THIQ alkaloids 303 and 304. MeO MeO NMe HO NMe HO DRS-DRR CYP80A1 [245 + (R)-245] [(R)-245 + (R)-245] HO HO (R)-245 (S)-N-methylcoclaurine (245) OH OH OMe NMe OMe O HO NMe MeN MeO O + HO MeN MeO OH OH Guattegaumerine (R,R product) (303) 4.4.2.2. Berbamunine (R,S product) (304) TOTAL SYNTHESIS OF BISBENZYL THIQ ALKALOIDS In 2011, Opatz and coworkers described the modular syntheses of (+)tetramethylmagnolamine 313 and (+)-O-methylthalibrine 312 from a common intermediate THIQ 305 (Scheme 4.20). 32 Alkylation of deprotonated aminonitrile 305 with benzyl bromide 306 and subsequent reductive methylation gives THIQ monomer 307, while bromination of 308 followed by formamide reduction yielded the other THIQ monomer 309. Finally, an Ullman coupling of 307 forged the biaryl ether linkage with THIQ 310 to afford (+)-O-methylthalibrine dimer 312, or alternatively with THIQ 309 and 311 to synthesize (+)tetramethylmagnolamine 313. Opatz and coworkers utilized a similar synthetic strategy for the C–O coupling of two benzyl THIQ monomers to access the macrocyclic skeleton of the curare alkaloids as well.32b A similar synthetic approach was described by Bracher and coworkers for the total synthesis of tetrandine 321 and isotetrandine 322, featuring a Pictet–Spengler condensation to construct the THIQ moieties followed by an Ullmann coupling for biaryl ether formation (Scheme 4.21).33 First, benzyl-THIQ 316 was constructed from a Pictet–Spengler cyclization of carbamate 314 with enol ether 315, which further underwent a C–O coupling using a Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 537 Alkaloids (2002 – 2020) copper(I) bromide-dimethylsulfide complex with Cs2CO3 in pyridine to yield 318. After deprotection, a second Pictet–Spengler reaction with enol ether 319 delivered secobisbenzylisoquinoline 320 in 42–46% overall yield. A second Ullmann coupling using the same optimized conditions then afforded the macrocycle and accessed both natural products tetrandine 321 and isotetrandine 322 after reduction with LiAlH4. Scheme 4.20 Opatz’s synthesis of (+)-tetramethylmagnolamine 313 and (+)-Omethylthalibrine 312. MeO MeO NH MeO MeO NH MeO 3) BH3•THF MeO CN 305 311 1) HCO2Et 2) Br2, CH2Cl2 CuI, Cs2CO3 NMe DMF, 160 °C MeO MeO MeO Br MeO Br MeO 308 NMe MeO 50% yield 54% yield (3 steps) 2 steps MeO 309 MeO Br O OMe 306 MeO H2CO, NaBH4 38% yield (3 steps) MeO 310 MeO MeO NMe MeO MeO NMe CuI, Cs2CO3 DMF, 160 °C MeO 51% yield NMe R1 NMe (+)-Tetramethyl magnolamine (313) R2 R1 = OH, R2 = OMe, 310 R1 = H, R2 = OH, 311 MeO O Br 307 MeO NMe MeO (+)-O-methylthalibrine (312) Apart from macrocyclic bisbenzyltetrahydroisoquinoline alkaloids, several novel strategies to access seco-bisbenzyltetrahydroisoquinolines have been explored. In 2002, Georghiou and coworkers described the total synthesis of (–)-tejedine 334 from a key Bischler–Napieralski cyclization and diaryl ether coupling (Scheme 4.22). 34 One of the synthons for the key cyclization was synthesized from phenyl acetic acid 323, which upon reaction with (S)-methylbenzylamine 324 delivered amide 325, and further reduction afforded synthon 326. The diaryl ether coupling partner was then achieved from a Cu(OAc)2- Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 538 Alkaloids (2002 – 2020) catalyzed C–O coupling of phenol 327 with phenyl boronic acid 328, which was then hydrolyzed to carboxylic acid 329. Scheme 4.21 Bracher’s synthesis of tetrandine 321 and isotetrandine 322. OMe OMe MeO EtO2C HN MeO CO2Et BnO 315 pyridine, 110 °C 41% yield OMe 316 OMe EtO2C OMe 1) Pd/C, H2 MeOH 2) TFA, 139 CH2Cl2, 0 °C + O MeO EtO C NH 2 MeO OH 317 OMe OMe OBn OBn 47% yield OMe N EtO2C CuBr, SMe2, Cs2CO3 Br CH2Cl2, 0 °C 314 EtO2C OMe TFA + Br N OMe NH 42–46% yield Br 319 318 N O OMe OMe MeO OH N CO2Et Br OMe 320 OMe OMe 1) CuBr, SMe2 Cs2CO3, py. 110 °C 2) LiAlH4 THF, 80 °C O MeN N Me 61–63% yield MeO O Tetrandine (321) (R,R)/(S,S) Isotetrandine (322) (S,R)/(R,S) With the two partners in hand, a diastereoselective Bischler–Napieralski reaction was performed using the chiral auxiliary-bearing synthon 326 condensed with 329 to deliver amide 330, followed by cyclization using POCl3 and reduction to deliver THIQ 331 as a single diastereomer. Finally, the dihydroisoquinolone unit was installed from phenylethylamine 332 which underwent a base-mediated SNAr coupling with 331 to deliver 333. After converting the nitro group to a methoxy substituent, N-methylation and cyclization afforded (–)-tejedine 334. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Scheme 4.22 Georghiou’s synthesis of (–)-tejedine 334. O OMe 1) (COCl)2 PhH, 2 h Me 2) OMe HO2C OBn OMe 1) B2H6•THF BF3•Et2O, THF Me NH2 NH OMe Me 2) 20% HCl OMe Ph NH 98% yield OBn 324 323 539 OMe Ph OBn 326 325 5% NaOH:CH2Cl2 90% yield CO2Me Oi-Pr + OH (HO)2B OTBS 327 328 N Ph Oi-Pr OMe Me OBn 2) LiOH 1:3:1 MeOH:THF:H2O O 330 326 HOBt, EDCI DMF, 0 °C OTBS 73% yield 329 1) TBAF, THF, 0 °C 2) DMP, 1 h 3) NaClO2, Na2HPO4 resorcinol, DMSO 4) TMSCHN2, MeOH OMe BocN 5) POCl3, PhH, reflux 6) NaBH4, MeOH, –78 °C 7) H2, Pd/C, EtOH, EtOAc 8) (Boc)2O, NEt3, –78 °C O OTBS Oi-Pr 57% yield OMe O CO2H 1) Cu(OAc)2, py. CH2Cl2 Oi-Pr MeO2C OMe OH O 331 19% yield (8 steps) OMe F + Me N CO2C2H5 O2N BocN CsF DMSO OMe Oi-Pr O 90% yield MeO2C 332 36% yield (6 steps) N CO2C2H5 O2N 333 1) H2, Pd/C, MeOH 2) HBF4, i-amylONO, CH3CN; aq. KI, –45 °C; i-PrMgCl; B(OMe)3, –60 to –40 °C; H2O2, 1 M NaOH, – 20 °C 3) MeI, DMF, 0 °C; TFA, THF 4) aq. 37% CH2O, NaBH3CN 5) Tf2O, DMAP, CH2Cl2 6) AlCl3, CH2Cl2 O Me OMe MeN OH MeO2C O OMe O O NMe MeO (–)-Tejedine (334) Toward the synthesis of (+)-O-methylthalibrine 312, Nishiyama and coworkers employed an electrochemical method to construct the diaryl ether core along with a stereoselective Bischler–Napieralski reaction to establish the THIQ moieties. 35 First, the electrochemical halogenation of phenol 335 was optimized to deliver dichlorinated phenol 336 using TBACl as the halogen source (Scheme 4.23). Then, oxidative dimerization of 336 was performed to deliver 337 in 60% yield, followed by cathodic reduction to afford the desired diaryl ether product 338. After methylation of the phenol, catalytic hydrogenolysis delivered 339 in 85% overall yield. Alternatively, an electrochemical reductive Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 540 Alkaloids (2002 – 2020) dechlorination reaction was also developed by passing a methanol solution of 338 through a Pd tube (cathode) and a Pt wire (anode) in aqueous H2SO4 solution outside the flow cell. Hydrogen, which was generated by electrolysis, was absorbed into the Pd tube and thus the successive reduction was conducted to give 339 in 76% yield.35a After hydrolysis, the reaction of the resulting diacid with phenylethylamine 340 provided the corresponding bisamide which underwent a Bischler–Napieralski cyclization followed by reduction to deliver bis-THIQ in 75% overall yield. Finally, a one-pot conversion of removing the chiral auxiliaries and N-methylation afforded the natural product 312. Scheme 4.23 Nishiyama’s electrochemical synthesis of (+)-O-methylthalibrine 312. Pt CO2Me HO Pt 1.02 V vs. SCE 4.5 F/mol TBACl, MeOH 335 CO2Me Cl 1) MeI, K2CO3 DMF, 0 °C 2) H2, 5% Pd/C MeOH 99% yield 1) NaOH, MeOH 2) BOP, NEt3, CH3CN MeO MeO Cl O 338 OH 85% yield (2 steps) 340 Me OMe OMe Ph OMe 3) POCl3, PhMe 4) NaBH4, MeOH 5) H2, aq. CH2O, Pd(OH)2 52% yield (4 steps) O NMe MeO HN 337 O CO2Me CO2Me 339 MeO Cl O Cl 60% yield 336 cathodic red. Cl OMe Cl CO2Me Cl HClO4, AcOH MeOH Pt HClO4 (0.1 M), MeOH 50% yield Pt Pt anodic oxidation HO CO2Me Pt CO2Me MeO2C Cl OMe O N Me (+)-O-methylthalibrine (312) Alternatively, Lumb and coworkers adopted a bioinspired strategy for the synthesis of (S,S)-tetramethylmagnolamine 313 utilizing a catalytic aerobic desymmetrization of phenols.36 From THIQ 341, which was established from a Bischler–Napieralski cyclization followed by asymmetric reduction, a Boc protection and subsequent aerobic oxidative coupling using CuPF6 and N,N’-di-tert-butylethylenediamine (DBED) under 1 atm of O2 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 541 Alkaloids (2002 – 2020) formed oxygenated radical intermediate 342 (Scheme 4.24). Upon treatment of another THIQ molecule 343, a radical C–O coupling afforded the desymmetrized bis-THIQ dimer 344 after reductive workup. Subsequent methylation and reduction of the Boc groups furnished tetramethylmagnolamine 313 in 7 steps with 21% overall yield. By taking advantage of the natural product’s pseudosymmetry and biosynthesis, this synthetic approach concisely assembles the target by only preparing a single coupling partner. Scheme 4.24 Lumb’s synthesis of tetramethylmagnolamine 313. OH CuLn O OH O MeO H N Boc N MeO 1) Boc2O, MeOH 2) CuPF6 (4 mol %) DBED (5 mol %) O2 (1 atm), CH2Cl2 MeO OH O NBoc OMe 343 then Na2S2O4 work up Boc N OMe MeO MeO OMe 341 OH Boc N OMe OMe 53% yield (2 steps) 344 342 OMe Me N OMe 1) MeI, Cs2CO3 DMSO 2) LiAlH4, THF O OMe Me N OMe 44% yield (2 steps) MeO OMe Tetramethylmagnolamine (313) 4.4.3. PROTOBERBERINE ALKALOIDS 4.4.3.1. GENERAL STRUCTURE AND BIOSYNTHESIS The protoberberine alkaloids constitute a tetracyclic ring system with varied functionalities on the arene ring. These alkaloids are derived from benzyl THIQs through phenolic oxidation and coupling with the N-methyl group, which serves as the “berberine bridge” carbon (Figure 4.13).37 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Figure 4.13 General structure of the protoberberine THIQ alkaloids. R A B Tetracyclic skeleton N N-Methyl Bridging Carbon C R 542 Highly Oxidized Functionalities R = OMe, OH R1 = H, Me D Protoberberine Alkaloids Protoberberines Tetrahydroprotoberberines MeO O N O MeO OMe OMe Berberine (345) 14-oxoprotoberberines MeO N H MeO OMe N Me O O O OMe Tetrahydropalmatine (346) Cryptopine (347) Primarily isolated from the Papaveraceae (e.g., Corydalis, Papaver), Berberidaceae (e.g., Berberis, Mahonia), and Menispermaceae family, the protoberberine alkaloids consist of several variations of the tetracyclic ring system: the protoberberines such as berberine 345, the tetrahydroprotoberberines like tetrahydropalmatine 346, and C14-oxo derivatives, such as cryptopine 347. These three distinct scaffolds are only several of the myriad number of skeleton types identified. Plants that contain the protoberberine alkaloids are known to be used as analgesics, sedatives, and antiseptics in traditional medicine. Both the quaternary alkaloid salts and their tetrahydroderivatives have important biological and therapeutic activity, and thus their chemical syntheses have been extensively explored. Their biosynthesis stems from oxidation of reticuline 247 catalyzed by a berberine bridge enzyme (BBE) to generate iminium 348, with release of H2O2 as by-product (Figure 4.14).38 Electrophilic aromatic substitution then delivers the protoberberine scaffold (S)-scoulerine 350, which upon methylation by (S)adenosyl methionine (SAM) forms tetrahydroprotoberberine 351. Further oxidation of the amine by a cytochrome P450-dependent enzyme and formation of the dioxolane ring gives berberine 345.39 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Figure 4.14 Proposed biosynthesis of protoberberine alkaloids 345 and 351. MeO MeO NMe HO HO BBE HO O2 –H2O2 HO MeO MeO N N HO HO H H MeO MeO (S)-reticuline (247) HO 349 N H OH OMe (S)-Scoulerine (350) O N H CYP OMe O N OMe O2 NADPH OMe (S)-Tetrahydrocolumbamine (351) 4.4.3.2. O OMe 348 MeO SAM 543 OMe Berberine (345) TOTAL SYNTHESIS OF PROTOBERBERINE ALKALOIDS While there have been vast reports on the syntheses of the protoberberine alkaloids, some feature distinct synthetic strategies to access the natural product. In 2002, Davis and coworkers reported the synthesis of protoberberine alkaloid (–)-xylopinine 356 involving the addition of a lithiated ortho-tolyl nitrile into an enantiopure sulfinimine.40 Using enantiopure sulfinimine 352, which was prepared from condensation of the aldehyde with enantiopure sulfinamide, reaction with lithiated ortho-tolyl nitrile 353 delivered sulfinamide 354 as a mixture of diastereomers (Scheme 4.25). Treatment with DIBAL followed by hydrolysis reduced the nitrile and removed the sulfinyl group to allow cyclization to afford dihydroisoquinoline 355. Reduction of the imine, tosylation, and cyclization of the amine using NaH gave (–)-xylopinine 356 in 73% yield. Similarly, Ruano and coworkers harnessed a similar strategy toward the synthesis of (–)-xylopinine 356, instead using toluenesulfinamide 358 to add into N-sulfinylimine 357 that produced benzyl THIQ 359 in 58% yield (Scheme 4.26).41 Treatment with TFA and tBuLi removed both sulfinyl groups to access (–)-norlaudanosine 360, and a Pictet–Spengler cyclization with formaldehyde ultimately delivered (–)-xylopinine 356. Both Yang,42 and Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 544 Alkaloids (2002 – 2020) Rozwadowska43 have also harnessed this synthetic approach of the addition of nucleophiles to enantiopure sulfinimines to synthesize other members of the protoberberine alkaloid family. Scheme 4.25 Davis’ synthesis of (–)-xylopinine 356. MeO 1) LDA, –78 °C MeO MeO OTBDMS N O S MeO 353 CN 2) then 352 3) NH4Cl p-Tolyl 352 OMe Me MeO MeO OTBDMS 68% yield MeO 1) DIBAL HN S p-Tolyl CN O MeO 2) 3 N HCl 70% yield (2 steps) 354 OMe OMe OMe 1) NaBH4 2) TsCl, pyr. MeO MeO 3) NaH N MeO H 355 N MeO 62% yield (3 steps) OH (–)-Xylopinine (356) Scheme 4.26 Ruano’s synthesis of (–)-xylopinine 356. OMe 1) LDA, –78 °C Cl MeO MeO N MeO OMe Me MeO 358 SO-p-Tolyl SO-p-Tolyl 2) then 357 357 H MeO 1) TFA, MeOH N MeO 88% yield p-Tolyl SO SO-p-Tolyl 359 OMe OMe MeO MeO HN 56% yield (2 steps) OMe OMe H 2) t-BuLi THF, –78 °C CH2O H MeO HCOOH N MeO 66% yield (–)-Norlaudanosine (360) (–)-Xylopinine (356) The convergent synthetic approach of the addition of lithiated nucleophiles to dihydroisoquinolines or benzonitriles have been well explored to quickly build the protoberberine scaffold. Cho and coworkers demonstrated the convergent coupling of benzonitrile 361 and lithiated ortho-toluamide 362 to access isoquinolone 363 in 32% yield (Scheme 4.27). 44 Then, removal of protecting groups and reaction with p-TsCl in the presence of K2CO3 delivered oxypalmatine 364. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Scheme 4.27 Cho’s synthesis of oxypalmatine 364. 545 Me MOMO OMe NC OMe OMe O OMe 362 n-BuLi OMe 361 MOMO NEt2 MeO NH MeO THF OMe O 32% yield 363 OMe OMe 1) 10% HCl, THF 2) TsCl, K2CO3, DMF 59% yield (2 steps) N MeO OMe O Oxypalmatine (364) Utilizing lithiated oxazoline or oxazolidine chiral auxiliaries to add into dihydroisoquinolines, Iwao45 and Chrzanowska46 were able to synthesize both enantiomers of the protoberberine alkaloids. From enantioenriched oxazolidine 365, treatment with nBuLi generated the carbanion followed by addition to dihydroisoquinoline 366 directly afforded oxoberbine 367 in 33% yield with 81% ee (Scheme 4.28A). More recently, Chrzanowska and coworkers also applied the same strategy toward the synthesis of (–)oxoxylopinine 370 from the addition of lithiated oxazolidine 368 to dihydroisoquinoline 369 (Scheme 4.28B). Finally, Enders and coworkers demonstrated the addition of lithiated benzamides to enantioenriched hydrazones to assemble dihydroisoquinolones toward the synthesis of tetrahydropalmatine 346.47 Lithiated benzamide 371 was reacted with hydrazone 372, which was prepared from condensation of enantiopure “SAMP” hydrazines with 3,4dimethoxybenzaldehyde, to deliver isoquinolone 373 as a single diastereomer (Scheme 4.29). Then, treatment of 373 with BH3•THF cleaved the N–N bond of the chiral auxiliary, followed by installation of the diethyl acetal moiety to afford 374. A Pomeranz–Fritsch cyclization was then induced using concentrated HCl to obtain protoberberine scaffold 375 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 546 Alkaloids (2002 – 2020) as a mixture of diastereomers. Removing the hydroxyl group was achieved using BF3•OEt2 and Et3SiH to ultimately synthesize (–)-tetrahydropalmatine 346 in 92% yield with 98% ee. Scheme 4.28 Chrzanowska’s synthesis of A. Oxoberberine 367 and B. (–)-oxoxylopinine 370. A. Me O O O Me N O N Me Me O N O 366 n-BuLi Ph O H THF 33% yield 81% ee 365 (–)-Oxoberbine (367) B. MeO MeO O MeO Me N MeO N 369 t-BuLi O N O H THF Me Me Me MeO MeO OMe 13% yield 84% ee 368 OMe (–)-Oxoxylopinine (370) Scheme 4.29 Ender’s synthesis of (–)-tetrahydropalmatine 346. MeO N N OMe MeO OMe N 372 MeO NEt2 Me OMe OMe O MeO OMe O N MeO AlMe3, Et2O, –40 °C OMe 55% yield 373 OMe 2) bromoacetaldehyde diethyl acetal KI, K2CO3, DMF acetone 83% yield 1.3:1 to 1.7:1 dr OMe 374 52% yield (2 steps) OMe OMe OMe MeO OEt 1) BH3•THF; 1 N HCl TMEDA, s-BuLi 371 conc. HCl OEt N N OH MeO BF3•OEt2, Et3SiH CH2Cl2, –78 °C H OMe 375 OMe 92% yield 98% ee N H OMe OMe (–)-Tetrahydropalmatine (346) More classic approaches to the protoberberine alkaloids involve electrophilic aromatic substitution chemistry to assemble the THIQ core. Both the Yang48 and Harding49 groups demonstrated a Bischler–Napieralski strategy toward building the THIQ core, with a tethered methyl ester allowing cyclization to the protoberberine scaffold. From amide 376, treatment with POCl3 followed by NaBH4 reduction established enantioenriched THIQ 377 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 547 Alkaloids (2002 – 2020) induced from the chiral auxiliary (Scheme 4.30). Then, introduction of the methyl ester through a lithium halogen exchange and quenching with methyl chloroformate, and intramolecular cyclization of the amine delivered protoberberine scaffold 378. Yang was then able to achieve the synthesis of (–)-stepholidine 379 after carbonyl reduction and protecting group removal. Similarly, Harding utilized amide 380 with a pendent methyl ester to undergo Bischler–Napieralski cyclization and reduction to access the protoberberine scaffold 381 directly (Scheme 4.31). Methylation and reduction of the carbonyl then delivered isocorypalmine 382. Scheme 4.30 Yang’s synthesis of (–)-stepholidine 379. MeO MeO N O i-PrO 92% yield (2 steps) Br Ph 1) n-BuLi MeOCOCl 2) Pd(OH)2, EtOH AcOH Me 2) NaBH4 Me i-PrO N i-PrO 1) POCl3 Br i-PrO 90% yield (2 steps) OMe OMe 376 377 MeO MeO N i-PrO H 378 1) LiAlH4 O N HO OMe 2) BCl3 CH2Cl2 Oi-Pr 80% yield (2 steps) H OMe OH (–)-Stepholidine (379) Scheme 4.31 Harding’s synthesis of isocorypalmine 382. MeO MeO MeO O BnO NH 1) POCl3 BnO N 2) NaBH4 EtO 1) CH3I, K2CO3 DMF O OMe 79% yield O CO2Me (2 steps) OMe 380 OH 381 2) LiAlH4, THF 3) conc. HCl MeOH 74% yield (3 steps) HO N OMe OMe Isocorypalmine (382) Other electrophilic aromatic substitution strategies utilize formaldehyde or aldehyde equivalents to close the C-ring and access the natural product scaffold. In 2010, Georghiou and coworkers harnessed a chiral auxiliary-assisted Bischler–Napieralski cyclization and Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 548 Alkaloids (2002 – 2020) reduction of amide 383 to achieve THIQ 384, upon which addition of formaldehyde followed by NaBH3CN reduction delivered (–)-corytenchine 385 (Scheme 4.32).50 Scheme 4.32 Georghiou’s synthesis of (–)-corytenchine 385. MeO MeO O N Me HO MeO MeO MeO 1) POCl3; Ph NaBH4, MeOH 2) H2, Pd/C EtOH MeO OH 2) NaBH3CN, AcOH MeO N H 95% yield 64% yield, 95% ee (2 steps) 383 1) CH2O, CH3CN NH OMe 384 OMe OH (–)-Corytenchine (385) Alternatively, Hiemstra 51 and van Maarseveen 52 and coworkers demonstrated a regioselective ortho- or para-directed Pictet–Spengler reaction to construct the THIQ core. First, a Pictet–Spengler condensation of protected amine 386 with aldehyde 387 afforded THIQ 388 in 85% yield with 90% ee (Scheme 4.33). Then, a second Pictet–Spengler reaction was effected with another equivalent of aldehyde 387 to deliver either the para- or orthoisomer depending on the solvent. Increasing H-bonding character of the solvent such as HFIP and trifluoroethanol increased the amount of para-substituted product 391, while aprotic, apolar solvents such as toluene gave the highest selectivity of ortho-isomer 390. Treatment with BBr3 led to the formation of (+)-javaberine A 392 and (+)-javaberine B 393. Van Maarseveen and coworkers demonstrated an ortho-selective Pictet–Spengler reaction using aldehyde 395 with equimolar amounts of 394 in toluene as solvent to achieve the orthoisomer 396 in good selectivity (Scheme 4.34). Debenzylation and cyclization of the C-ring using formaldehyde under acidic conditions produced (–)-govaniadine 397 in 61% yield, allowing access to several other ortho-oxygenated alkaloids as well. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 549 Scheme 4.33 Hiemstra’s synthesis of (+)-javaberine A 392 and (+)-javaberine B 393. CHO HO OMe HO HN MeO NNps MeO OTBS 1) conc. HCl PhSH 387 S 2) NH4F, MeOH (R)-TRIP (5 mol %) (S)-BINOL (20 mol %) Na2SO4, PhMe NO2 OMe 85% yield 90% ee 386 388 67% yield (2 steps) OTBS OMe HO OTBS NH MeO HO 387 PhMe:CH2Cl2 OMe 389 N MeO H OH 71% yield OH OMe 390 387 TFE, 0 °C 85% yield BBr3 CH2Cl2 OH OMe 87% yield OH OH OTBS OH HO HO BBr3 N MeO H CH2Cl2 H HO N HO 99% yield H OH OH OMe 391 N HO OH OH OH (+)-Javaberine A (392) (+)-Javaberine B (393) Scheme 4.34 van Maarseveen’s synthesis of (–)-govaniadine 397. CHO HO O MeO HN Ph Me 394 O N MeO Ph 1) H2, Pd/C EtOH Me OH 395 PhMe, 105 °C 48% yield N MeO 396 O O OH H 2) CH2O, HCO2H EtOH 60% yield (2 steps) O O (–)-Govaniadine (397) Apart from the classical synthetic approaches to the protoberberine alkaloids, Opatz and coworkers utilize a Stevens rearrangement of ammonium ylides to synthesize the protoberberine alkaloids.53 From common synthetic intermediate THIQ 398,54 reaction with dibromide 399 delivered spirocyclic ammonium salt 400, which upon deprotonation induced a Stevens rearrangement followed by reduction with NaCNBH3 to obtain xylopinine 356 (Scheme 4.35A). This was further optimized to a one-pot cascade synthesis of Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 550 Alkaloids (2002 – 2020) pseudopalmatine 401 from 398 and 399 using DIPEA as base, and aromatization under air to protoberberine alkaloid 401 (Scheme 4.35B).55 Scheme 4.35 Opatz’s synthesis of A. Xylopinine 356. B. Pseudopalmatine 401. A. MeO NH MeO Br 399 MeO N CN 94% yield 398 Br Br DIPEA, THF CN MeO MeO MeO MeO 400 MeO N KHMDS, THF OMe then NaCNBH3 OMe 98% yield OMe OMe Xylopinine (356) B. MeO Br 399 MeO NH MeO CN DIPEA dioxane, air reflux MeO N 54% yield OMe OMe 398 Pseudopalmatine (401) Several transition metal-catalyzed annulations have been developed to apply toward the synthesis of the protoberberine alkaloids. In 2014, Donohoe and coworkers described a Pd-catalyzed enolate arylation of aryl bromides and ketones to generate masked 1,5dicarbonyl intermediates that could readily cyclize with a source of NH3 to an array of isoquinolines. 56 The coupling of ketone 402 and aryl bromide 403 was effected using Pd(amphos)2Cl2 and Cs2CO3 to access ketone 404 in 93% yield (Scheme 4.36). Then, a onepot aromatization and cyclization using NH4Cl in ethanol and water delivered palmatine 405. This protocol was successfully utilized for a variety of substituted aryl bromides and ketones for the rapid synthesis of the protoberberine alkaloids. Alternatively, Mhaske and coworkers employed a Pd-catalyzed intramolecular tandem olefin amidation and C–H activation method for the synthesis of the protoberberine core.57 From amide 406, iodination and Stille coupling with vinyl tributyltin afforded key precursor 407 (Scheme 4.37). Using Pd(OAc)2 as catalyst and Cu(OAc)2•H2O and O2 as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 551 Alkaloids (2002 – 2020) oxidant, 407 first underwent amidation to assemble the THIQ, followed by C–H activation of the arene to allow cyclization to oxotetrahydropalmitine 408 in 55% yield. Scheme 4.36 Donohoe’s synthesis of palmatine 405. OMe O O OPiv MeO O Me MeO O MeO OMe 402 93% yield OMe Cl MeO N O Br 403 Pd(amphos)2Cl2 Cs2CO3, THF; H2O OMe OPiv O NH4Cl OMe 404 OMe EtOH:H2O 90 to 110 °C OMe 88% yield OMe Palmatine (405) Scheme 4.37 Mhaske’s synthesis of oxotetrahydropalmitine 408. MeO MeO MeO MeO HN O 1) I2, AgOTf HN MeO OMe 2) Pd2(dba)3 vinyl tributyltin AsPh3, DMF OMe 407 47% yield (2 steps) 406 Pd(OAc)2 (10 mol %) Cu(OAc)2•H2O, O2 O NaOAc OMe 10:1 DMSO:H2O 100 °C N MeO OMe 55% yield OMe O OMe Oxotetrahydropalmitine (408) In 2016, Cheng and coworkers developed a general Rh-catalyzed C–H activation and annulation method to afford various natural and unnatural protoberberine alkaloids.58 An array of substituted benzaldehydes, such as 409, were coupled with alkyne 410 using [RhCp*(CH3CN)3][SbF6]2 as catalyst with Cu(BF4)2•6 H2O and O2 as oxidant to deliver protoberberine alkaloid corysamine 411 in 92% yield (Scheme 4.38). This one-pot transformation was successfully employed for a variety of benzaldehydes and alkyne amines to provide a library of protoberberine salts in good yield and selectivity. Scheme 4.38 Cheng’s synthesis of corysamine 411. H 2N O O O O CHO Me O N 410 [RhCp*(CH3CN)3][SbF6]2 (2.5 mol %) Cu(BF4)2•6 H2O (60 mol %) O2, MeOH, 60 °C 409 BF4 92% yield O O Me O Corysamine (411) Glorius and coworkers also reported a C–H activation annulation approach of substituted benzamides to install the oxyprotoberberine core. 59 Using Cp*Co(CO)I2 as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 552 Alkaloids (2002 – 2020) catalyst, benzamide 412 underwent alkyne insertion, reductive C–N bond formation and N– O bond cleavage to achieve isoquinolone 413 in a single transformation (Scheme 4.39). A Mitsunobu reaction then constructed the oxyprotoberberine scaffold 414 in 80% yield, which could be further elaborated into the protoberberine or tetrahydroprotoberberine alkaloids. Scheme 4.39 Glorius’ general synthesis of protoberberine alkaloids. O MeO O N H O Cp*Co(CO)I2 (10 mol %) AgSbF6 (20 mol %) CsOPiv, HOPiv TFE, 100 °C MeO MeO OH NH THF, 0 °C MeO MeO N MeO 80% yield 77% yield 412 O DIAD PPh3 413 Oxyprotoberberine (414) Harnessing a Cu-catalyzed three component coupling reaction of an amine, aldehyde, and alkyne, Tong and coworkers optimized a general annulation strategy that enabled the syntheses of over 30 natural protoberberine alkaloids. 60 To this end, THIQ 415, benzaldehyde 416, and trimethylsilylacetylene were employed in a three component condensation reaction to afford THIQ 417 in 81% yield (Scheme 4.40). Then, a Pd-catalyzed reductive carbocyclization reaction successfully provided the desired tetracycle 418 of the protoberberine core. Hydrogenation of the exo-olefin delivered the natural product thalictricavine 419 as a single diastereomer. A Rh-catalyzed isomerization of 418 with concomitant oxidation under air also provided the protoberberine salt dehydrothalictricavine 420 in 65% yield. With this highly efficient synthetic route, a variety of 13-methylprotoberberine alkaloids were synthesized for the first time, including their analogues in excellent overall yields. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 553 Scheme 4.40 Tong’s synthesis of thalictricavine 419 and dehydrothalictricavine 420. OMe OHC OMe O Br O NH O 415 N O 416 TMS acetylene CuI (10 mol %) PhCO2H (0.1 equiv); K2CO3, MeOH OMe Pd(PPh3)4 Br HCO2Na OMe 79% yield 417 81% yield O O O PtO2 H2 N H AcOH OMe 418 N O OMe Me 99% yield OMe Thalictricavine (419) OMe O RhCl3 (10 mol %) O2 N O EtOH OMe Me 65% yield OMe Dehydrothalictricavine (420) Finally, Ward and coworkers employed a novel chemoenzymatic cascade toward the synthesis of the tetrahydroprotoberberine alkaloids.61 From dopamine 241, first a Pictet– Spengler condensation using a transaminase enzyme (TAm) from CV2025 Chromobacterium violaceum and a norcoclaurine synthase enzyme (NCS) delivered THIQ 421 in 87% yield with 99% ee (Scheme 4.41). Then, the addition of formaldehyde induced a second Pictet–Spengler reaction to deliver tetrahydroprotoberberine alkaloid 422 in 64% yield. Scheme 4.41 Ward’s chemoenzymatic synthesis of tetrahydroprotoberberine alkaloid 422. HO HO TAm enzyme NCS enzyme HO NH2 HO HO NH pyruvate HO N OH 1 M sodium phosphate 87% conversion 99% ee 241 CH2O 64% yield 421 OH OH 4.4.4. MORPHINAN ALKALOIDS 4.4.4.1. GENERAL STRUCTURE AND BIOSYNTHESIS 422 OH Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 554 Alkaloids (2002 – 2020) The morphinan alkaloids are distinguished by their phenanthrene core with a bridging piperidine ring and a fused benzodihydrofuran moiety. They are famous THIQ-derived natural products well-known for their analgesic and anesthetic bioactivity. Morphine 423 is commonly used to treat severe pain, while other members such as naltrexone 424 and naloxone 425 are commercially produced for treatment of opiate overdoses and alcohol addiction (Figure 4.15).62 Isolated primarily from opium poppy Papaver somniferum, the global production of opium poppy concentrate is estimated to be around 8700 tons per year, of which morphine and codeine are the principal ingredients.63 Figure 4.15 General structure of the morphinan THIQ alkaloids. R A O R = OMe, OH R1 = H, OH, =O R2 = H, OH C NR3 R3 = H, Me, alkyl B R2 D Phenanthrene Core Bridging Piperidine Ring Dihydrobenzofuran Moiety R1 Morphinan Alkaloids HO O H HO H O NMe H HO OH O N HO O Morphine (423) Naltrexone (424) H OH N O Naloxone (425) The biosynthesis of morphine and its related congeners stems from key intermediate reticuline 247, which is converted to the (R)-enantiomer by 1,2-dehydroreticuline reductase (Figure 4.16).62 Then, an oxidative phenol coupling catalyzed by salutaridine synthase (CYP719B1) establishes the morphinan skeleton in salutaridine 426. Tetracycle 426 is then reduced by salutaridine reductase and acetylated by salutaridinol acetyltransferase to deliver salutaridinol-7-O-acetate 427. An SN2’-type cyclization then occurs to establish the dihydrobenzofuran moiety in thebaine 428. Thebaine-6-O-demethylase (T6ODM) cleaves Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 555 Alkaloids (2002 – 2020) off the methyl group to give neopinone 429, which can undergo isomerization and reduction of the carbonyl by codeinone reductase (COR) to yield codeine 430.64 Finally, demethylation catalyzed by codeine O-demethylase (CODM) produces morphine 423. Figure 4.16 Proposed biosynthesis of morphine 423 and related morphinan alkaloids. MeO HO [O] HO 1,2-dehydroreticuline reductase HO NADPH HO MeO MeO MeO NMe NMe HO CYP719B1 NMe NADPH, O2 MeO (R)-247 MeO SalR T6ODM O H MeO O H NMe NMe O MeO OAc Neopinone (429) Thebaine (428) 427 Salutaridine (426) MeO MeO NMe O OH HO SalAT NMe MeO MeO MeO (S)-reticuline (247) HO HO MeO CODM COR O H 4.4.4.2. O H NMe H H NMe HO HO Codeine (430) Morphine (423) TOTAL SYNTHESIS OF MORPHINAN ALKALOIDS Since Gates’ first synthesis of morphine in 1952, many others have pursued the synthesis of this alkaloid and other related natural products from this family. 65 The continuing interest in the morphinan alkaloids as synthetic targets have resulted in numerous reviews in the total synthesis of these alkaloids, and thus this section will only cover the most recent syntheses from the past decade.66 A myriad number of strategies for the synthesis of morphine have been well explored in the past several decades. In particular, Fukuyama and coworkers have disclosed several syntheses of morphine featuring an intramolecular Mannich cyclization to construct the THIQ core.67 However, their most recent synthesis of (–)-morphine utilizes chiral substrate Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 556 Alkaloids (2002 – 2020) 431 to construct the morphine skeleton via a Friedel–Crafts cyclization and dehydration to deliver 432 (Scheme 36). 68 Hydroxyselenenylation of the resulting olefin followed by oxidation and elimination generates allylic alcohol 433 which undergoes a retro-aldol/aldol sequence to furnish enone 434. Construction of the dihydrofuran ring commenced with Baeyer–Villiger oxidation and methanolysis of the lactone to afford dienone 435. Luche reduction of the enone followed by treatment with HCl then caused formation of a dienyl cation and interception with the phenol to furnish the dihydrofuran ring 436. With the tetracyclic scaffold in place, functional manipulations with the pendent methyl ester moiety to the protected tertiary amine 437 set up for oxidation with singlet oxygen to give endoperoxide 438. Treatment with triethylamine induced cleavage of the O–O bond to afford hydroxyenone 439, with dehydration of the alcohol and removal of the DNs group facilitating 1,6-addition to access natural products neopinone 429 and codeinone 440, with further reduction to deliver codeine 430 and morphine 423. In an alternative fashion, Chida and coworkers sought to access (–)-morphine 423 through an elegant sequential Claisen rearrangement of an allylic vicinal diol, resulting in the stereoselective formation of two C–C bonds and two contiguous stereocenters in a single operation (Scheme 4.43).69 Starting from allylic vicinal diol 441, a Johnson-type Claisen rearrangement with MeC(OEt)3 in the presence of 2-nitrophenol initiated the sequential Claisen/Claisen rearrangement to provide 442. In this transformation, both vicinal quaternary and tertiary stereocenters were installed in a single transformation. Construction of the benzofuran moiety then was accomplished by treatment of 442 with mCPBA, inducing demethylative etherification of the epoxide to deliver 443. Further oxidative manipulations afforded enone 444, and following reduction, protection of the resulting alcohol, global Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 557 Alkaloids (2002 – 2020) reduction, and Swern oxidation, dialdehyde 445 was accessed to construct the tetracyclic scaffold. A Friedel–Crafts cyclization using p-TsOH•H2O allowed the installation of the tetracycle 446 with concomitant removal of the TBS group. Finally, reductive amination and protection of the secondary amine generated late-stage intermediate 447, which was only two steps away from the natural product synthesis.65,70 Scheme 4.42 Fukuyama’s synthesis of (–)-morphine 423. MeO MeO MeO MeO 1:9 TfOH:CH2Cl2 O t-BuO2C 431 O 60% yield OH Me 432 O 1) PhSeCl CH3CN:H2O 2) mCPBA NaHCO3, CH2Cl2 O Me O Cs2CO3, EtOH O OH Me 53% yield (2 steps) OH 60 °C 57% yield O 433 434 MeO MeO 1) mCPBA NaHCO3, CH2Cl2 2) K2CO3, MeOH; CH2Cl2, HCl; TMSCHN2 MeO Me HO CO2Me NaBH , CeCl •7 H O 4 3 2 O EtOH:THF, 0 °C; HCl, 0 °C 54% yield (2 steps) CO2Me 76% yield O MeO MeO Me 86% yield Me N DNs O 2) PhSH, i-Pr2NEt CH2Cl2, 0 °C OH O O 33% yield (2 steps) MeO O + O NMe O Neopinone (429) 439 MeO 62% yield (2 steps) 1) Martin’s sulfurane CH2Cl2, 0 °C N DNs O O 438 1) HCl in 1,4-dioxane CHCl3 2) NaBH4, MeOH 437 436 MeO O N DNs O 2) DNsNHMe, DEAD PPh3, PhMe 80% yield (2 steps) 435 O2, hv (405 nm) TPP CH2Cl2; NEt3 1) LiAlH4, THF H NMe O Codeinone (440) HO BBr3 H NMe HO Codeine (430) O CH2Cl2 51% yield H NMe HO Morphine (423) Toward the synthesis of (±)-morphine, Smith and coworkers utilized a diastereoselective light-mediated cyclization to establish the benzofuran moiety, and a cascade ene-yne-ene ring closing metathesis to forge the tetracyclic scaffold (Scheme 4.44).71 First, a challenging sp3-sp2 Suzuki–Miyaura cross-coupling of vinyl bromide 448 with b-amino borane derivative 449 was accomplished using Pd(dppf)Cl2•CH2Cl2 as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 558 Alkaloids (2002 – 2020) catalyst. Photocyclization of 450 then proceeded smoothly to deliver cis-fused 451 as the sole product. After subsequent functional group manipulations to install the terminal alkyne and vinyl ketone in 452, the cascade ene-yne-ene metathesis was accomplished using Hoveyda–Grubbs II catalyst (C3). It is proposed that the transformation proceeds via reaction of the ruthenium catalyst with the allyl component of 452 first, followed by an intramolecular reaction with the alkyne to generate alkylidene intermediate 453. Ring closing metathesis with the vinyl ketone then afforded tetracycle 454 which was subjected further to deprotection of the amine and 1,6-addition to afford the morphine scaffold 455. Diastereoselective reduction of the ketone delivered codeine 430 as a single diastereomer, as well as morphine 423 after demethylation. Scheme 4.43 Chida’s formal synthesis of (–)-morphine 423. MeO MeO MeO MeO 2-nitrophenol (5 mol %) MeC(OEt)3 HO 140 to 170 °C MeO m-CPBA CO2Et CO2Et 36% yield 1) IBX, DMSO 60 °C 2) PhSeCl, AgOTf CO2Et BF •Et O, EtOAc; 3 2 Davis reagent, CHCl3 CO2Et O CH2Cl2 79% yield HO HO 441 MeO 442 1) CeCl3•7 H2O NaBH4, MeOH 2) TBSOTf 2,6-lutidine CO2Et 3) LiAlH4, THF CO2Et 4) (COCl) 2, DMSO NEt3, CH2Cl2 –78 to 23 °C O O 444 MeO 445 O 79% yield (2 steps) HO 446 HO ref. 65, 70 O H NMe H HO 1) aq. NH2Me MeOH, 0 °C; NaBH4 CHO 2) p-TsCl, DMAP pyridine, 80 °C H CH2Cl2 53% yield (2 steps) TBSO Me N Ts p-TsOH•H2O CHO CHO MeO O MeO O 93% yield (3 steps) 55% yield (2 steps) 443 HO 447 Morphine (423) Most recently, Tu and coworkers disclosed an enantioselective synthesis of (–)morphine harnessing a catalytic enantioselective Robinson annulation to rapidly construct the benzofuran moiety of the natural product.72 From enone 456, which was prepared in four Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 559 Alkaloids (2002 – 2020) steps from commercially available materials, an intramolecular Michael addition followed by Robinson annulation was thoroughly investigated and optimized. Ultimately, spiropyrrolidine catalyst C4 with triisopropylbenzoic acid as an additive proved to be most effective in delivering tricycle 458 in 66% yield with 94% ee (Scheme 4.45). This key transformation performed well on up to a 5-gram scale to rapidly build stereochemical complexity toward the morphine scaffold. Scheme 4.44 Smith’s total synthesis of morphine 423. Me Br Me O O OMe N N Boc BBN 449 hv Pd(dppf)Cl2•CH2Cl2 O O 58% yield O Me N Boc OMe 448 Boc HG II cat. C3 37% yield H 452 O N Boc H TFA [Ru] O H NMe O 454 455 HO Mes O O then Na2CO3 H 453 MeO NaBH4 MeO O O 64% yield (3 steps) Me N Boc O O MeO Me N H 451 MeO OMe OMe 450 Me O O 37% yield O 1) KOH; Na2RuO4 2) Ohira-Bestmann reagent K2CO3 Boc then Me(MeO)NH•HCl NMM, DMTMM O 3) vinylmagnesium bromide BBr3 H O N Mes Cl H Ru NMe NMe N HO HO Codeine (430) Morphine (423) Cl Me O Me C3 With large amounts of 458 in hand, prenylation followed by ozonolysis and treatment with a catalytic amount of polyphosphoric acid induced a Friedel–Crafts cyclization to afford tetracycle 460. After selective epoxidation and Wharton reaction to achieve allylic alcohol 461, cleavage of the benzyl group and an intermolecular Mitsunobu reaction delivers amine 462. Inversion of the allylic alcohol stereocenter and deprotection of the tosyl group promoted the hydroamination reaction to access (–)-codeine 430, and subsequent demethylation to synthesize (–)-morphine 423. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 560 Scheme 4.45 Tu’s total synthesis of (–)-morphine 423. OBn BnO N H O MeO 2,4,6-triisopropyl benzoic acid CH2Cl2, –30 °C O OMe O 456 OBn O 2) N2H4•HCl NEt3 CH3CN H H 54% yield (2 steps) O 460 O PhMe, 90 °C Me 458 29% yield (3 steps) MeO OBn 1) DDQ, PhCl H2O, 45 °C O 2) NHMeTs, PBu3 ADDP, PhMe H H Ts N O H H 26% yield (2 steps) HO HO 462 461 I 2) O3, Sudan Red III; OBn PPh3, CH2Cl2 3) PPA, 1,2-DCE O 66% yield 94% ee MeO 459 1) DMP NaHCO3; NaBH4 Me 2) LiDBB t-BuOH THF, –78 °C 63% yield (2 steps) HO MeO O PTSA, MgSO4 457 1) 35% H2O2 NaOH, H2O CH3CN Me O O OMe O MeO 1) LiHMDS, DMPU THF, –78 °C OTBDPS C4 BBr3 H NMe 81% yield HO (–)-Codeine (430) O CHCl3 H NMe HO (–)-Morphine (423) Toward the synthesis of other related morphine alkaloids, Fukuyama and coworkers disclosed the synthesis of oxycodone 474, which is distinguished from morphine by the ketone and additional hydroxyl functionality.73 Their synthetic approach commenced with alkylation of arene 463 with the enolate derived from imide 464 to furnish 465 as a single diastereomer (Scheme 4.46). Removal of the chiral auxiliary and subsequent methylation of the acid delivered 466 to set up for the direct arylation. Thus, treatment of 466 with Pd(OAc)2 resulted in arylation to establish the tricycle, which upon reduction of the ester, acetylation, and debenzylation gave phenol 468. Next, a key oxidative dearomatization was attempted to install the hydroxyl group. Reaction of 468 with PhI(OAc)2 afforded the desired intermediate 469 in 69% yield, followed by selective hydrogenation and acylation to deliver enone 470. Upon treatment with Cs2CO3, an intramolecular Michael addition proceeded to deliver the desired lactone 471 after two additional manipulations. Selective a-bromination of the ketone allowed the formation of the benzofuran moiety 472 by displacement with the phenol. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 561 Alkaloids (2002 – 2020) Functionalization of the acetate to the amide set up for a Hofmann rearrangement, followed by hydrolysis of the resulting isocyanate to the primary amine, and amidation to form the desired lactam 473. Finally, reduction of the lactam, N-methylation, and oxidation of the secondary alcohol furnished (–)-oxycodone 474. Scheme 4.46 Fukuyama’s total synthesis of (–)-oxycodone 474. O O MeO Bn MOMO MeO N MeO O BnO MOMO Br O Br NaHMDS THF –78 to 0 °C Br 463 464 N Bn O BnO 88% yield 465 MeO Pd(OAc)2 (15 mol %) PPh3 (45 mol %) K2CO3, PivOH 1) H2O2, LiOH THF, H2O O MOMO 94% yield (2 steps) >99% ee 1) LiAlH4, THF 2) Ac2O, pyridine MOMO 466 PhI(OAc)2 MOMO 469 MeO 1) Cs2CO3, CH3CN 2) NaCl, H2O DMSO, 120 °C 3) TFA, CH2Cl2 MOMO OAc O O O OAc O O 472 3) DMTMM, NH3 MeOH 4) PhI(OAc)2 CH3CN, H2O 69% yield (5 steps) 2) NEt3, LiI CH3CN, 60 °C O 69% yield (5 steps) O CO Me 60% yield (2 steps) 2 O 471 MeO 1) K2CO3, MeOH 2) CrO3, H2SO4 acetone, H2O 1) Py•HBr3 CH2Cl2, AcOH HO 470 MeO O OH O 468 MeO OAc OAc 69% yield HO 467 O MOMO OAc HFIP, H2O –20 °C 89% yield (3 steps) BnO 2) methyl malonyl chloride pyridine, CH2Cl2, 0 °C O BnO MeO 3) H2, Pd/C CO2Me MeOH 1) RhCl(PPh3)3 H2 (200 psi), PhH OMe MeO 1,4-dioxane, 100 °C 98% yield Br 2) TMSCHN2 MeOH, CH2Cl2 O 1) BH3•THF; MeOH; AcOH aq. HCHO NaBH(OAc)3 OH NH O O 2) DMP CH2Cl2 OH NMe O O 473 MeO (–)-Oxycodone (474) 46% yield (2 steps) Other approaches toward the synthesis of oxycodone include a desymmetrizationbased strategy reported by Chen and coworkers.74 To this end, an oxidative dearomatization of phenol 475 under hypervalent iodine conditions afforded hydroxy dienone 476 that could rapidly build tricycle 477 using an intramolecular Heck cyclization (Scheme 4.47). Installation of the all-carbon quaternary stereocenters was accomplished through a radical cyclization of iodoacetal 478 to deliver lactol 479, which could then be further oxidized to Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 562 Alkaloids (2002 – 2020) deliver morphinan scaffold 480. Protection of the ketone followed by amidation and reduction led to the formation of amine 481, which furnished oxycodone 474 after desaturation and deprotection steps. This developed sequence demonstrated a shorter stepcount in comparison to the original Fukuyama synthesis. Scheme 4.47 Chen’s total synthesis of (+)-oxycodone 474. MeO MeO MOMO Br Pd(OAc)2, PPh3 K2CO3 MOMO PIDA Br CH3CN:H2O 0 °C OH PhMe, 110 °C OH 2) NIS ethyl vinyl ether CH2Cl2 477 476 475 MOMO O O HO O O OEt 478 I MeO MeO 1) m-CPBA BF3•OEt2 MOMO PhH, 12 h 48% yield (3 steps) 1) Rh(PPh3)3Cl, H2 MOMO 80% yield 66% yield n-Bu3SnH, BEt3 MeO MeO O O O 2) PyH•Br3; LiBr, NEt3 CH3CN, 60 °C 48% yield (2 steps) OEt 3) LiAlH4; TsCl O O 43% yield (3 steps) O 480 479 MeO 1) ethylene glycol TMSCl 2) MeNH2 MeO 1) NBS; NEt3 O O OH O NMeTs 481 O 2) Li, NH3; HCl 29% yield (2 steps) OH NMe O (+)-Oxycodone (474) Chen and coworkers’ alternative synthetic approach to the morphinan family of natural products was developed from their method of oxidative dearomatization of atropisomerically pure biaryl phenols to achieve complex intramolecular Diels–Alder products such as 482.75 To demonstrate the synthetic utility of these intermediates, 482 was elaborated into lactam 484 via Beckmann rearrangement of oxime 483 (Scheme 4.48). Reduction of the amide followed by Hoffmann elimination induced further cleavage of the bridgehead C–N bond to furnish amine 485. Selective reduction, deoxygenation, and demethylation were sequentially performed to deliver key intermediate 487. Then, phenolic demethylation followed by treatment with pyridinium tribromide established the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 563 Alkaloids (2002 – 2020) dihydrobenzofuran ring 488, with subsequent olefin isomerization and detosylation to synthesize dihydrocodeinone 489. 489 serves as a valuable intermediate to access a variety of morphinan alkaloids including codeine, morphine, thebaine, and oxycodone. Scheme 4.48 Chen’s total synthesis of (+)-dihydrocodeinone 489. MeO MeO MeO H O OTBS 1) BH •THF; PCC 3 2) PTSA•H2O 3) NH2OH•HCl 4) TsCl MeO MeO 1) Pd-CaCO3, H2; HCl 2) Ac2O, pyr. 3) SmI2 Cl ZnCl2 H O N MeO CH3CN OTs 100 °C 73% yield MeO 486 NaHCO3; MeOH; TsCl 33% yield (4 steps) H O O MeO MeO NH 484 1) LiAlH4 2) MeI 3) KOH 34% yield (3 steps) O 487 38% yield (3 steps) MeO HO MeO MeO NMe2 485 MeO MeO 1) ethylene glycol; TMSCl 2) L-Selectride; HCl 3) PyH•Br3; LiBr, NEt3, NMeTs CH3CN, 60 °C MeO Me O MeO 483 Cl O 4) MeO 34% yield (4 steps) MeO 482 MeO MeO 1) Pd/C, H2; TMSCl, ethylene glycol O O NMeTs 488 2) NBS, benzoyl peroxide CCl4, 80 °C; NEt3, 80 °C 3) Li, NH3; HCl 25% yield (3 steps) O H NMe O (+)-Dihydrocodeinone (489) In 2014, Opatz and coworkers have also disclosed a general strategy toward the enantioselective synthesis of (–)-dihydrocodeine 497 and other related morphinan alkaloids (Scheme 4.49). 76 Their key intermediate is prepared from aminonitrile 490, which upon deprotonation with KHMDS furnished a stabilized a-aminocarbanion which was alkylated with benzyl bromide 491 to deliver 492 upon spontaneous dehydrocyanation. Enantioselective reduction of 492 using Noyori’s asymmetric hydrogenation catalyst C5 delivered THIQ 493 with 95% ee. With the C1 stereocenter established, the secondary amine was protected, followed by Birch reduction furnishing carbamate 494 which was immediately set up for a Grewe cyclization to establish two new stereogenic centers of the tetracycle 495. a-bromination and treatment with NaOH closed the dihydrobenzofuran ring, with subsequent triflation and Pd-catalyzed detriflation furnishing 496 in 80% yield. Treatment with DIBAL ultimately reduced both the ketone and carbamate, accessing Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 564 Alkaloids (2002 – 2020) dihydrocodeine 497 in 81% yield. Intermediate 497 also constitutes the formal synthesis of thebaine 428, while 496 served as a precursor for the synthesis of codeine and morphine. Scheme 4.49 Opatz’s total synthesis of (–)-dihydrocodeine 497. Br Me BnO OBn MeO OMe MeO N 491 NH CN KHMDS Ph THF –78 °C to RT BnO MeO Ts N Ru N Cl H2 Ph C5 HCO2H:NEt3 DMF, 0 °C MeO 490 492 OBn NH Me Me 68% yield (2 steps) 95% ee BnO 1) ClCO2Me THF, NEt3 2) Li, NH3 t-BuOH MeO OBn 493 OH MeO MeO N CO2Me HO HCl:Et2O reflux HO H 88% yield (3 steps) MeO CO2Me O OH 494 N 495 1) CuBr2 CHCl3:EtOAc 2) 0.5 M NaOH 3) Tf2O, pyr. 4) Pd(PPh3)4 HCO2H, NEt3 DMF, 60 °C 72% yield (4 steps) MeO O H N CO2Me O 496 MeO DIBAL O THF, 0 °C 81% yield H NMe HO (–)-Dihydrocodeine (497) This synthetic strategy toward the morphinan alkaloids as well as their biosynthesis also further inspired the development of an electrochemical oxidative coupling of benzyl THIQs. 77 Toward the synthesis of thebaine 428, Opatz and coworkers optimized an electrochemical oxidative coupling of THIQ 498 using Pt electrodes in an undivided cell, achieving tetracycle 499 regio- and diastereoselectively (Scheme 4.50A). With this developed methodology, they demonstrated the synthesis of both racemic and (–)-thebaine 428 through several functional group manipulations and a biomimetic SN2’, involving activation of the allylic alcohol 501 with N,N-dimethylformamide dineopentyl acetal to close the dihydrobenzofuran ring (Scheme 4.50B). This electrochemical coupling strategy has also been applied toward the total synthesis of (–)-oxycodone 474 from tetracycle 499.77b Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 565 Scheme 4.50 A. Opatz’s electrochemical oxidative coupling. B. Application toward the total synthesis of (–)-thebaine 428. A. OBn MeO MeO NMe MeO AcO Pt Pt anodic oxidation AcO HBF4, CH3CN, 0 °C MeO 58–62% yield OBn NMe MeO O 498 B. 499 OBn OTf MeO MeO 1) Pd/C 1,4-cyclohexadiene EtOH AcO Pd(PPh3)4 NEt3, HCO2H HO DMF, 60 °C 2) Tf2O, pyr. NMe NMe 74% yield (2 steps) MeO MeO O OH 499 MeO 500 MeO HO DMF dineopentyl acetal NMe dioxane, 80 °C O NMe 31% yield (2 steps) MeO OH 501 MeO (–)-Thebaine (428) The synthesis of the morphinan alkaloids, and in particular oxycodone, has been extensively explored by Hudlicky and coworkers for more than 25 years. Several generations of the chemoenzymatic synthesis of ent-oxycodone have been reported, featuring a key Heck cyclization to achieve the dihydrobenzofuran ring and ultimately a keto-nitrone coupling to establish the natural product scaffold.78 The final synthetic route began with the enzymatic dihydroxylation of phenethyl acetate by whole-cell fermentation with E. coli JM109 (pDTG601A) to produce cis-diol 503, which was subsequently reduced and protected as a silyl ether to deliver 504 (Scheme 4.51). A Mitsunobu coupling of the allylic alcohol with phenol 505 then afforded intermediate 506, which upon an intramolecular Heck reaction constructed the dihydrobenzofuran ring 507. Dihydroxylation of the olefin followed by DBU-mediated elimination via formation of an intermediate lactol furnished ketone 508 in Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 566 Alkaloids (2002 – 2020) 63% yield. Oxidative manipulations to transform the acetate to a methyl ester delivered intermediate 509, then deprotection of the acetal afforded an aldehyde intermediate, which was treated with N-methyl hydroxylamine to provide nitrone 510. Treatment with SmI2 then induced cyclization to the lactone with the desired stereochemistry, which upon Raney nickel reduction furnished lactam 511. Finally, further reduction of the amide carbonyl and oxidation of the alcohol delivered ent-oxycodone 474. Overall, the fourth-generation synthesis of oxycodone was accomplished in 11 steps from phenethyl acetate via a key nitrone intermediate to achieve the correct stereochemistry. Scheme 4.51 Hudlicky’s total synthesis of (+)-oxycodone 474. MeO OMe HO OAc OAc 2 steps E. coli JM109 dihydroxylation OH OH 502 MeO MeO Pd(OAc)2, dppp Ag2CO3, DMF OMe I 87% yield OTBS 83% yield 504 MeO 1) OsO4, NMO 2) MsCl, NEt3 OMe O O 3) DBU, PhMe 51% yield (3 steps) TBSO TBSO OAc 506 O OMe O OAc MeO MeO 3) EDC•HCl DMAP, MeOH OMe 508 507 1) 3 M NaOH 2) TPAP, NMO 505 TMAD, PBu3 THF, 0 °C OMe OMe O I OH OTBS 503 OAc OMe OAc OMe OMe 1) TFA, PhMe 2) MeNHOH•HCl O NaOAc, EtOH CO2Me O N O OH CO2Me TBSO 70% yield (3 steps) TBSO 510 509 Me 1) SmI2 THF, –78 °C 2) Raney Ni H2, EtOH 29% yield (4 steps) MeO MeO O 1) BH3 THF, 65 °C NMe 2) TBAF, THF 3) DMP, CH2Cl2 O OH TBSO 511 47% yield (3 steps) O OH NMe O (+)-Oxycodone (474) More recent synthetic approaches to the morphinan alkaloids harness C–H activation strategies to efficiently establish the natural product scaffold. For instance, Zhang and coworkers report the total synthesis of codeine and morphine featuring a cascade cyclization Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 567 Alkaloids (2002 – 2020) to construct the dihydrofuran ring, and an intramolecular Pd-catalyzed C–H olefination of an unactivated alkene to install the morphinan skeleton (Scheme 4.52).79 Starting from phenol 512 which was quickly accessed by a Suzuki coupling, treatment with ethyl vinyl ether followed by Michael addition with vinyl magnesium bromide in the presence of copper(I) bromide delivered ketone 513 in 1.8:1 dr relative to the ketal center. The undesired diastereomer could be converted to 513 upon treatment with 2N HCl. Treatment of 513 with NaH afforded spiro-ketone 514 as a single diastereomer, with subsequent manipulations of the ketone to give epoxide 515. Then, the key cascade cyclization was accomplished using MeOH in the presence of NaOH by opening the lactone ring and attacking the epoxide to deliver 516. Next, an intramolecular Pd-catalyzed C–H alkenylation was performed to deliver 517 in high regioselectivity. With the tetracycle established, 517 was eventually converted to the natural product using oxidative manipulations to achieve enone 518, DIBAL reduction and reductive amination to furnish amine 519, and a radical cyclization to synthesize codeine 430. Ellman and coworkers alternatively devised a Rh-catalyzed C–H alkenylation and electrocyclization cascade strategy to synthesize the THIQ framework toward the total synthesis of (–)-naltrexone 424 (Scheme 4.53).80 From imine 520, which was prepared in 8 steps from commercial starting materials, a Rh(I)-catalyzed C–H activation of the olefin was initiated, followed by alkyne insertion to deliver an azatriene intermediate 521. Triene 521 undergoes rapid electrocyclization in situ to access dihydropyridine 522, which was subsequently reduced to deliver THIQ 523. Treatment of 523 with dilute H3PO4 then afforded morphinan scaffold 525 in 66% yield. They propose that this transformation likely proceeded through removal of the silyl and acetonide protecting groups, followed by allylic alcohol Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 568 Alkaloids (2002 – 2020) ionization and hydride shift to provide ketone 525. A Grewe cyclization then established the desired morphinan skeleton. Treatment of 525 with Br2 then afforded a dibrominated intermediate due to facile bromination of the electron-rich aromatic ring, followed by nucleophilic displacement to establish the dihydrofuran ring. Triflation of the phenol followed by dehydrogenation of the ketone using Pd(TFA)2 installed enone 526. Finally, a late-stage C–H hydroxylation of enone 526 was explored to access the natural product. Using pyridine as solvent and ketoglutaric acid to reduce the peroxide intermediate, treatment of 526 with CuSO4 and O2 successfully installed the hydroxyl group with the correct stereochemistry to yield 527. Removing the bromide and triflate groups, reduction of the enone, and demethylation with BBr3 ultimately afforded (–)-naltrexone 424. Scheme 4.52 Zhang’s total synthesis of codeine 430. MeO 1) vinyl ethyl ether Br2, iPr2NEt 2) vinyl MgCl CuBr•Me2S, TMSCl THF, –78 °C HO O Br 90% yield, 1.8:1 dr 512 O NaH O DMF 100% yield 513 56% yield (3 steps) O THF, reflux H CO2Me O O O O 515 1) DMP, NaHCO3 2) TMSOTf, NEt3 60% yield (3 steps) HO 517 CO2Me O 3) Pd(OAc)2 CH3CN H 69% yield HO MeO MeO MeO PdCl2 (10 mol %) CuCl2 (2 equiv) O2 CO2Me 516 1) DIBAL CH2Cl2 2) MeNH2, MeOH NaBH4 3) p-TsCl, DMAP pyridine 514 O EtO MeO MeOH, NaOH THF O 1) NaBH4, MeOH 2) Burgess reagent PhH 3) TsOH•H2O acetone 4) Jones reagent 5) mCPBA, NaHCO3 CH2Cl2 MeO MeO EtO H H O 518 MeO MeO Li, NH3 (l) t-BuOH O NMeTs O THF, –78 °C H NMe H HO 58% yield (3 steps) HO 519 Codeine (430) In 2020, Metz and coworkers described the total synthesis of thebainone A 536, harnessing an intramolecular nitrone cycloaddition and a Heck cyclization to construct the natural product scaffold (Scheme 4.54).81 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Scheme 4.53 Ellman’s total synthesis of (–)-naltrexone 424. Me Me Me Me O Me O O N Me O O H 569 O [Rh(coe)2Cl]2 (5 mol %) (p-NMe2)PhPEt2 (10 mol %) N NaBH(OAc)3 AcOH N PhMe, 85 °C EtOH TIPSO OTIPS MeO OMe 520 Me OTIPS TIPSO 66% yield (2 steps) MeO OTIPS OTIPS 522 521 Me O MeO 55% H3PO4 125 °C TIPSO H HO HO MeO OTIPS N O 523 OTf 48% yield (3 steps) H N O 525 OTf 526 HO 1) Pd(OH)2, NEt3, H2 EtOAc:MeOH OH N 59% yield H Br MeO pyridine, O2 O 3) Pd(TFA)2 TFA, DMSO OH 524 O 1) Br2, AcOH 2) Tf2O, pyr. H 66% yield CuSO4 ketoglutaric acid Br MeO N N MeO OTf OH O O O OH N 2) BBr3, CH2Cl2 –40 to 0 °C O 67% yield (2 steps) O (–)-Naltrexone (424) 527 From ester 528 which was accessed in 4 steps from isovanillin, a Heck cyclization using Pd2(dba)3 and Ag2CO3 induced formation of spiro-lactone 529 in 83% yield. Deprotection of the ketone and aldehyde followed by treatment with N- methylhydroxylamine induced a diastereoselective nitrone cycloaddition to achieve isoxazolidine 530. Since this ketolactone was rather unstable, subsequent reduction with LiAlH4 delivered 531, and conversion of the primary alcohol to a tosylate was then followed by reductive cleavage of the heterocycle with concomitant nucleophilic substitution to generate 532. To install the enone moiety, the cis diol was reductively eliminated by formamide acetal pyrolysis, with subsequent acetylation and ethyl carbamate formation to give 533. Allylic oxidation followed by DMP oxidation then successfully installed the enone Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 570 Alkaloids (2002 – 2020) 534 in 21% yield over two steps. Finally, protection of the ketone was required to reduce the carbamate and acetate group, and deprotection with 1N HCl ultimately provided thebainone A 536. Scheme 4.54 Metz’s total synthesis of thebainone A 536. OMe OMe I MeO Pd2(dba)3 (5 mol %) Ag2CO3 OMe OMe MeO THF, 81 °C O O 83% yield O O NMe H LiAlH4 MeO O H OH 56% yield (3 steps) OH OH 531 H OAc 21% yield (2 steps) 533 O NMe H 4) [Ts-DMAP]+ Cl-, NEt3 5) H2, Raney Ni, NEt3 EtOH, EtOAc 6) KOH, THF, H2O MeO OH 86% yield (6 steps) 1) Me2NCH(OMe)2 2) Ac2O, 150 °C OH 3) ClCO2Et, K2CO3 72% yield (3 steps) OH 532 CO2Et 1) TMSOTf, TsOH•H2O 2) DMP, CH2Cl2 MeO H O O 1) TBSCl, imidazole 2) Ac2O, DMAP, NEt3 3) TBAF, AcOH N 1) SeO2 dioxane, 70 °C H MeO OAc 534 O O MeO 2) MeNHOH•HCl, NaHCO3 MgSO4, CH3CN –20 to –15 °C 530 CO2Et N NMe H 529 H THF –78 °C to RT O O O 528 O H 1) Pd(CH3CN)2Cl2 (2 mol %) MeCHO, acetone TMSO 535 NMe H OTMS 2) LiAlH4, THF 3) 1 N HCl, THF 60% yield (3 steps) 4.4.5. PAVINE AND ISOPAVINE ALKALOIDS 4.4.5.1. GENERAL STRUCTURE AND BIOSYNTHESIS MeO OH O Thebainone A (536) The pavine and isopavine alkaloids contain a characteristic tetracyclic tetrahydroisoquinoline core structure consisting of a dibenzo-9-azabicyclo[3.3.1]nonane and dibenzo-9-azabicyclo[3.2.2]nonane, respectively (Figure 4.17). 82 They are mainly found in four plant families, the Papaveraceae, Berberidaceae, Lauraceae, and Ranunculaceae families. These alkaloids have been shown to possess interesting bioactivity for the treatment of nerve system disorders such as Alzheimer’s, Parkinson’s disease, and Huntington’s chorea.83 Although the complete biosynthesis of the pavine and isopavine alkaloids has not been entirely elucidated, there are some speculations of their biogenetic precursors. It is Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 571 Alkaloids (2002 – 2020) likely that they are derived from benzyl THIQ reticuline 247 or a similar analog thereof, which undergoes cyclization at either the C3 or C4 position of the THIQ ring to achieve the pavine or isopavine scaffold, respectively.84 For the isopavine alkaloids, a 4-hydroxybenzyl THIQ is postulated as a precursor that could undergo dehydration and cyclization to achieve the azabicyclo[3.2.2]nonane core.85 Alternatively, it has been suggested that pavine alkaloids are derived from a similar intermediate such as 4-hydroxynorlaudanosoline, from which a dehydration reaction and cyclization at the C3 position would yield the pavine skeleton.84 More recently, Ng and coworkers elucidated the structure of an N-methyltransferase enzyme (pavine NMT) that is involved in the N-methylation of the pavine alkaloids.86 Figure 4.17 General structure of the pavine and isopavine THIQ alkaloids. R A B R NR1 C D Pavine Alkaloids R A C B N R1 R R = OMe, OH, -OCH2OR1 = H, Me Isopavine Alkaloids Benzannulated Azabicyclononane Core 4.4.5.2. D Highly Oxidized Functionalities TOTAL SYNTHESIS OF PAVINE AND ISOPAVINE ALKALOIDS In 2004, Marazano reported the synthesis of (–)-argemonine 542, enabled by a key enantioselective transformation of isoquinolinium salt 537 to 1-benzyl isoquinoline derivative 539 (Scheme 4.55).87 Isoquinolinium salt 539 was prepared in two steps from salt 537, and reduction of 539 with LiAlH4 formed tertiary amine 540. Cyclization of 540 in the presence of formic acid and H3PO4 supplied benzylamine 541 with 93:7 dr. Hydrogenolysis with Pd/C (10 mol %) and H2 cleaved the chiral auxiliary, which was dissolved in formic acid and aqueous formaldehyde to furnish the methylated natural product (–)-argemonine 542. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 572 Alkaloids (2002 – 2020) Nishigaichi and coworkers also developed a modular synthesis of argemonine 363 and eschscholtzidine 371 from the coupling of isoquinolines and electron-rich potassium trifluoroborate reagents (Scheme 4.56). 88 After synthesizing potassium trifluoroborate reagent 366 from benzyl chloride 364, treatment of 366 with isoquinolines 367–368 under thermal or photochemical conditions followed by reduction with LiAlH4 resulted in the concise syntheses of argemonine 363 and eschscholtzidine 371. Scheme 4.55 Marazano’s enantioselective synthesis of (–)-argemonine 542. MeO MeO Me Ph N MeO Cl MeO K3Fe(CN)6, KOH MeOH, 0 °C MeO H2O:PhMe, 45 °C H O 62% yield 537 Me CeCl3, (MeO)2PhCH2MgCl Ph PhMe, THF then HBr, H2O H N 538 MeO LiAlH4 THF, –78 °C HCO2H H3PO4 Me Ph N MeO 77% yield 77% yield MeO MeO OMe HCO2H, HCHO H 2O OMe Pd/C, H2 HCl, AcOEt, EtOH MeO OMe 541 NH MeO H 539 MeO OMe 540 MeO Br Ph Me H N H MeO MeO 92% yield Me Ph N MeO MeO OMe MeN MeO OMe 50% yield (2 steps) (–)-Argemonine (542) Scheme 4.56 Nishigaichi’s synthesis of argemonine 542 and eschscholtzidine 550. MeO Me Me Cl O Me Me 543 HC(OMe)3 MeCN 400 nm light Me Me 1) Pd(PPh3)4, K2CO3 dioxane MeO Me Me 2) KHF2, MeOH/H2O MeO B B + MeO O O O CO2Me R1 OMe N R2 OMe 548: R1, R2 = -OCH2O74% yield 549: R1 = R2 = OMe >99% yield LiAlH4 THF K Me R1 + R2 N 546: R1, R2 = -OCH2O547: R1 = R2 = OMe 545 37% yield (2 steps) 544 R1 BF3 OMe N R2 OMe 550: R1, R2 = -OCH2O(–)-Eschscholtzidine 64% yield 542: R1 = R2 = OMe (–)-Argemonine 41% yield Jiang and coworkers reported a general approach to access isopavines, including (–)-amurensinine, (–)-reframidine, (–)-reframine, and other non-natural isopavine Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 573 Alkaloids (2002 – 2020) derivatives within five or six steps with >95% ee.89 Their retrosynthetic strategy began with the formation of bridging C–N and C–C bonds through Pictet–Spengler reaction of an amino dimethyl acetal 554 (Scheme 4.57). From aldehyde 551, a Henry reaction with nitromethane, followed by dehydration with methanesulfonyl chloride and excess trimethylamine delivered β-nitrostyrene 552. A Pd-catalyzed asymmetric addition of 552 with aryl boronic acid 553, followed by reduction and conversion to the carbamate yielded 554. The Pictet–Spengler reaction of carbamate 554, followed by reduction of carbamate 555 formed (–)-amurensinine 556. Scheme 4.57 Jiang’s enantioselective synthesis of (–)-amurensinine 556. MeO OMe MeO O MeO MeO + MeO 2) CH3SO2Cl, NEt3 CH2Cl2, 0 °C MeO NO2 H 551 O O 72% yield (2 steps) 3) i-PrOCOCl, Et3N –5 °C to 23 °C B(OH)2 65% yield (3 steps) 95% ee 553 552 OMe OMe OMe OMe O p-TsOH O CH2Cl2, 40 °C OMe Me HN Me 1) Pd(TFA)2/i-Pr-IsoQuinox MeOH, 40 °C 2) NaBH4, NiCl2● 6H2O OMe 1) CH3NO2, KOH MeOH/H2O, 0 °C O O OMe O O OMe N 94% yield 555 Oi-Pr O LiAlH4 THF, 0 °C O O OMe N Me 76% yield (–)-Amurensinine (556) 554 In 2006, Stoltz and coworkers reported the enantioselective total synthesis of amurensinine 556.90 They envisioned to apply their developed Pd-catalyzed oxidative kinetic resolution methodology to rapidly access the isopavine core in a modular fashion (Scheme 4.58).90b To this end, (3,4-dimethoxyphenyl)acetic acid 557 was treated to form a diazoester compound, then subjected to a Rh2(OAc)4-catalyzed C–H insertion to produce β-ketoester 558 in 91% yield over 6 steps. Coupling of β-ketoester 558 and aryne precursor 559 in the presence of CsF afforded a net C–C insertion to form the central carbocyclic ring of ketoester 560. Diastereoselective reduction of ketoester 560 and protection of the primary alcohol Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 574 Alkaloids (2002 – 2020) provided 561. Oxidative kinetic resolution using Pd(sparteine)Cl2 and (–)-sparteine as the chiral ligand provided enantioenriched (–)-561 with 99% ee. Conversion of the alcohol to the azide with inversion using (PhO)2P(O)N3 (DPPA) produced azido alcohol (–)-562 with no loss of optical purity. After oxidation of the alcohol, reduction of the azide delivered the desired lactam (+)-563. Reductive methylation produced (+)-amurensinine 556 with 99% ee. Scheme 4.58 Stoltz’s enantioselective synthesis of (+)-amurensinine 556. O OEt OMe OMe O 6 steps HO O O OTf O OTMS CsF (2.5 equiv) + OMe OMe CH3CN, 80 °C 57% yield 557 558 559 O OMe 1) LiAlH4, THF, 0 °C O 2) TIPSCl, imidazole O OMe TIPSO OMe EtO2C OMe Cs2CO3, O2 2-methyl-2-butene CHCl3 O 86% yield (2 steps) O HO (±)-560 (±)-561 OMe TIPSO O O 47% yield, >99% ee OMe HO OMe 1) (PhO) P(O)N 2 3 DBU, PhCH3, 0 °C O OMe O N3 62% yield (2 steps) (–)-561 O NH (+)-563 OMe 49% yield (3 steps) (–)-562 OMe O 1) DMP, CH2Cl2, 0 °C 2) NaClO2, 2-methyl-2-butene NaH2PO4● H2O 3) H2, Pd/C, EtOAc 2) TBAF, THF HO O Pd(sparteine)Cl2 (–)-sparteine OMe 1) LiAH4, THF O OMe N 2) CH2O, NaBH3CN CH3CN O 52% yield (2 steps) (+)-Amurensinine (556) Me In 2007, Martin utilized a four-component reaction to rapidly access roelactamine 568 in a racemic fashion from piperonal 564. 91 The condensation of piperonal with methylamine provided an imine in situ that was then reacted sequentially with benzyl Grignard 566 and acid chloride 565 to furnish amide 567 (Scheme 4.59). Treatment of 567 with a concentrated 2:1 mixture of HCl:MeOH allowed the amide to undergo sequential cyclizations to produce roelactamine 568. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Scheme 4.59 Martin’s synthesis of roelactamine 568. O O Me O MgCl OAc + MeNH2 + Cl O 575 + OAc O O O 565 564 0 °C to 66 °C then –78 °C 566 51% yield OAc O O 567 O conc HCl/MeOH (2:1) O O O O O N O 71% yield OAc N THF, 3 Å MS Me (±)-Roelactamine (568) Finally, the first synthesis of a pavine alkaloid with C7 functionalization was reported by Nakagawa-Goto.92 From amine 569, which was prepared in three steps, amidation with carboxylic acid 570 using carbonyldiimidazole (CDI) provided amide 571 (Scheme 4.60). A Bischler–Napieralski reaction with POCl3 formed benzylisoquinoline 572. Treatment of 572 with methyl iodide delivered isoquinolinium salt 573. Subsequent reduction with NaBH4 to the enamine, followed by radical cyclization and removal of the benzyl group yielded (±)neocaryachine 574. Scheme 4.60 Nakagawa-Goto’s synthesis of neocaryachine 574. NH2 O OMe OMe Br BnO O CH2Cl2, 25 °C MeO 569 CDI CO2H + O POCl3 O O 91% yield 570 H N Br OMe CH3CN, 50 °C 60% yield 571 OBn 1) NaBH4, MeOH, –78 °C O 2) Bu3SnH, AIBN, PhMe 3) H2, Pd/C (5 mol %), EtOH, 20 °C O H O O MeI N O I 80 °C NMe O 77% yield Br 572 4.5. OMe OBn 14% yield (3 steps) Br 573 OMe OH 7 OMe NMe H (±)-Neocaryachine (574) OBn THIQ ALKALOIDS FROM THE SAFRAMYCIN FAMILY The saframycin family is the largest subclass of tetrahydroisoquinoline alkaloids, consisting of saframycins, safracins, ranieramycins, and ecteinascidins. The core structure of Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 576 Alkaloids (2002 – 2020) natural products in this family features the intricate pentacyclic skeleton, having five sixmembered rings condensed into the core scaffold (Figure 4.18). Well known for their potent anticancer/antitumor activities, natural products in this family have been popular targets in numerous synthetic endeavors. Figure 4.18 Core skeleton of THIQ alkaloids in the saframycin family. E A B N C D NH Pentacyclic skeleton Central piperazine subunit A and E rings are quinone/hydroquinone 4.5.1. SAFRAMYCIN ALKALOIDS 4.5.1.1. GENERAL STRUCTURE AND BIOSYNTHESIS The very first set of saframycins, namely safrmycins A–E, were isolated in 1977 from bacteria Streptomyces lavendulae.93 In the ensuing studies, four additional saframycins (F, G, H, and R) were isolated from the same species of bacteria,94 and later in 1988, it was disclosed that myxobacteria Myxococcus xanthus strain Mx x48 produced saframycins MX1 and MX2.95 In addition to the “natural” saframycins, six new saframycins (Y3, Yd-1, Yd-2, Ad-1, Y2b, and Y2b-d) were obtained by a directed biosynthesis through the supplementation of different amino acids.96 Among the currently known saframycin alkaloids, the shared structural motif is the amide side chain, which is appended on the B-ring at the C1 position (Figure 4.19). Additionally, the A-ring of all saframycins is in the quinone oxidation state, while the E-ring can be in various oxidation levels, ranging from phenol, hydroquinone, and quinone. The amino nitrile or carbinol amine functionality on the central piperazine subunit functions as a latent electrophilic iminium species, which can alkylate DNA, and is largely responsible for Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 577 Alkaloids (2002 – 2020) saframycins’ potent antitumor/antimicrobial activity. 97 Saframycins voided of a leaving group at C21 typically exhibit significantly lower biological activities.93 Figure 4.19 General structure and representative examples of saframycin alkaloids. OMe Me O O Me O Me A MeO N E N 1 N 21 Me O NH O NH COMe Saframycin A (575) : R1 = CN, X = H B (576) : R1 = H, X = H C (577) : R1 = H, X = OMe S (578) : R1 = OH, X = H R O R1 O R1 O X N MeO X 14 Me Saframycin Alkaloids OMe OMe Me HO Me O O O Me N N MeO OH OMe R1 NH O Me Me N Me O N MeO CN NH O NH2 O Me R1 O R2 Saframycin Mx1 (579) : R1 = OH Saframycin Y3 (581) : R1 = NH2, R2 = Me Mx2 (580) : R1 = H Yd-1 (582) : R1 = NH2, R2 = Et Early biochemical studies of saframycins were conducted via feeding/isotopelabelling experiments, and the results suggest that one alanine, one glycine, and two tyrosine derivatives constitute the backbone of saframycin A.98 By exploiting the cloned biosynthetic gene cluster and its sequence analysis, it was later proposed that the pentacyclic backbone is assembled by a nonribosomal peptide synthetase (NRPS).99 Specifically for saframycin A, the NRPS comprises three modules (SfmA, SfmB, and SfmC) in which the first two are responsible for the production of dipeptidyl intermediate A from alanine and glycine (Scheme 4.61A). As for the last module, intriguing multi-step transformations catalyzed by SfmC were discovered by Oikawa and coworkers in 2010.100 The notable domains in this module are a) the Pictet–Spengler reaction domain (PS) which catalyzes two successive Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 578 Alkaloids (2002 – 2020) Pictet–Spengler reactions to construct the bis-tetrahydroisoquinoline (bis-THIQ) intermediate, and b) the reduction domain (Red) which reduces the thioester intermediates and releases aldehyde precursors (B, E, and F) for following reactions. Interestingly, they also noted that the relatively less strict substrate specificity of the PS domain might allow for an incorporation of synthetic aldehydes into the core skeleton. Once the pentacycle is constructed, late-stage tailoring modifications, including hydroquinone oxidation, Nmethylation, and hydrolysis of the fatty acid chain proceed to afford Saframycin A.101 This thorough understanding of the biosynthetic mechanism serves as a foundation for future developments of a chemoenzymatic total synthesis of saframycin alkaloids and their related analogs (vide infra). Scheme 4.61 A. Domain organization of saframycin A NRPS. B. Proposed biosynthetic mechanism for the construction of saframycin A’s pentacyclic skeleton. a) Saframycin A nonribosomal peptide synthetase (NRPS): AL A C ACP Derivative of Tyr Gly Ala PCP C SfmA A PCP PS A SfmB PCP Red SfmC AL - acyl-coA ligase, ACP - acyl carrier protein, C - condensation, A - adenylation, PCP - peptidyl carrier protein, PS - Pictet-Spengler, Red - Reduction b) Proposed biosynthesis of saframycin A’s core PCP L–Alanine + H O A PCP O S PS A PCP O S Red SfmA SfmB S O HN SfmC Me Glycine O HN O Me SfmC B NH NH2 NH B O A Me C13H27 Me OH C OH D OMe OMe OMe OMe O Red SfmC H NH H N PS Red SfmC SfmC cyclization Me NH C NH H OH E OMe OH NH Me NH N MeO O F Me HO Me HO MeO Me H N C13H27 NH O SfmC Derivative of tyrosine OH OH NH G Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 4.5.1.2. TOTAL SYNTHESIS OF SAFRAMYCIN ALKALOIDS 579 After the publication of a comprehensive review by William in 2002,3 there have been only three reports detailing the synthesis of saframycin alkaloids, all targeted saframycin A. In 2011, Liu employed L-tyrosine as a chiral building block in the preparation of (–)-saframycin A (Scheme 4.62). 102 They commenced their synthetic studies by converting L-tyrosine methyl ester into the desired amino acid 584 in 12 steps and tetrahydroisoquinoline 583 in 11 steps, which served as the eastern and western portions of the natural product, respectively. Although the regioselectivity issue for mono-hydroxy phenol substrate is a common problem in the Pictet–Spengler cyclization reaction,103 they noted that the selectivity, in this case, can be controlled by carefully maintaining the reaction temperature at 0 °C with a slow addition of the aldehyde starting material, furnishing THIQ 583 in 86% yield. Scheme 4.62 Liu’s total synthesis of (–)-saframycin A 575. Me OTBS 11 steps MeO 583 CO2Me HO OTBS Br NH2 L-Tyrosine methyl ester 12 steps Me 36% yield (12 steps) MeO OTBS NH NHCbz O OH Me BOPCl, Et3N CH2Cl2, 23 °C TBSO CbzHN OTBS 3) TBAF, THF, 0 °C 4) TfOH, 23 °C MeO 71% yield (4 steps) 585 Br 584 OMe Me O Me HO Me Me O NHBoc OMe 1) HCOOH, THF H2O, 23 °C 2) DMP CH2Cl2, 23 °C OMe N MeO 88% yield OTBS NHBoc O NH Br 7 steps N OH O NH2 Me N 586 O N MeO 43% yield (7 steps) Me (–)-Saframycin A (575) O O NH O 9.7% overall yield 24 steps COMe With both halves in hand, they coupled them together to give the amide intermediate 585. Subsequent functional group manipulations and an intramolecular Pictet–Spengler cyclization with triflic acid (TfOH) afforded pentacycle 586. It is worth noting here that the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 580 Alkaloids (2002 – 2020) second Pictet–Spengler cyclization requires a bromine atom on the eastern half of the molecule to function as a blocking group and provide the correct regiochemical outcome for the cyclization. They further advanced this intermediate to the targeted natural product via a 7-step peripheral modification, concluding a 24-step total synthesis of (–)-saframycin A 575 in an overall 9.7% yield. Of note, the key synthetic strategy in this report is reminiscent of Corey’s approach to prepare the pentacyclic core of ecteinascidin and phthalascidin where an amide coupling is used to merge the western and eastern halves of the molecule.104 In 2018, Saito and coworkers published a racemic synthesis of saframycin A 575 (Scheme 4.63), which is a follow-up study to correct the stereochemistry at the C1 position of the western THIQ.105 The tricyclic lactam 587, which was prepared in 14 steps from commercially available material,106 first underwent reductive cleavage and Boc removal to provide hydroxymethyl isoquinoline 588. This compound served as a Pictet–Spengler substrate, and cyclization with allyl ethyl oxomalonate ester (589) delivered bis-THIQ 590. From this intermediate, the pentacyclic core 591 was constructed via the Swern oxidation of the primary alcohol to afford the aldehyde, which underwent ring-closure to generate the hemiaminal C-ring. By subjecting TMSCN to the same pot, the amino nitrile formation proceeded to furnish the desired product 591 in 82% yield over 2 steps. They subsequently performed a decarboxylation and stereoselective protonation to correctly install the stereochemistry at the C1 position of the western THIQ (592). In the final stage, the ethyl ester in 592 was converted to the pyruvamide through a 4-step sequence, consisting of a) LiBH4 reduction, b) Mitsunobu reaction with phthalimide, c) removal of phthalimide to reveal the free amine, and d) acylation of amine with pyruvic acid. Finally, selective Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 581 Alkaloids (2002 – 2020) demethylation and ceric ammonium nitrate (CAN) oxidation were performed to deliver (±)saframycin A 575 in an overall 27 steps for the longest linear sequence. Scheme 4.63 Saito’s total synthesis of saframycin A 575. Me OMe Me MeO OMe H Me MeO OMe Me N OMe HO 1) Boc2O, DMAP MeCN, 110 °C 2) NaBH4, EtOH, 25 °C MeO MeO O NH2 MeO 75% yield (3 steps) OMe 587 Me N H MeO MeO 78% yield 1:1 dr OMe R1 = CO2Et R2 = CO2Allyl H R1 R2 TFA, 25 °C OH 588 OMe NH N H OH Me MeO 1) (COCl)2, DMSO CH2Cl2, –78 °C; Et3N, –78 °C Me 2) TMSCN, ZnCl2 THF/CH2Cl2, 25 °C MeO OMe 82% yield (2 steps) H OMe Me N N MeO R1 R1 = CO2Et R2 = CO2Allyl R2 CN 591 590 OMe OMe Me 83% yield Me H N THF, 25 °C O Me MeO OMe Me O CN OEt 592 Me O N MeO 8% yield (6 steps) MeO N 6 steps N MeO Me O OMe Pd(PPh3)4 p-tolylSO2Na CO2Allyl 589 Me MeO MeO MeO OH EtO2C H Me 3) 1:2 TFA/CH2Cl2, 25 °C HN MeO OMe O O NH O COMe (±)-Saframycin A (575) The most recent total synthesis of saframycin A is a merger of chemical and biosynthesis.107 Based on the proposed nonribosomal peptide synthetase (NRPS) responsible for the construction of the pentacyclic skeleton (vide supra), Oikawa and Oguri specifically designed substrates that successfully participated in the SfmC-catalyzed multistep enzymatic conversion (Scheme 4.61). Once the core skeleton was obtained, they exploited chemical synthesis to further manipulate functional groups, and finally deliver not only saframycin A, but also Jorunnamycin A and N-Fmoc Saframycin Y3. This hybrid strategy is highly efficient and allows for a rapid access to the elaborated pentacyclic scaffolds only in a single day. 4.5.2. SAFRACIN ALKALOIDS Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 4.5.2.1. GENERAL STRUCTURE AND BIOSYNTHESIS 582 Isolated from Pseudomonas fluorescens,108 safracins are structurally similar to the saframycins, except for having a phenol E-ring instead of a quinone/hydroquinone (Figure 4.20). Optimization of the fermentation process of this bacteria resulted in a multikilogram isolation of cyanosafracin B, having a nitrile moiety at the C21 position, which served as an inexpensive precursor to prepare ecteinascidin 743 (Et-743), an anticancer drug.109 Biosynthetically, the pentacyclic core of safracins is believed to be assembled from one alanine, one glycine, and two functionalized tyrosine via the nonribosomal peptide synthetase (NRPS), resembling the mechanism reported for the saframycins.110 In the most recent study, Tang and coworkers essentially established the entire safracin biosynthetic pathway by investigating post-NRPS modifications. These include the A-ring oxidation, Nmethylation, and removal of the fatty acyl chain.111 Figure 4.20 General structure of safracin alkaloids. OMe HO A MeO N 1 N 21 Me 14 R1 NH O O N Me N MeO R1 NH O NH2 O NH2 Me Safracin Alkaloids 4.5.2.2. Me E Me O Me O Me HO OMe Me Safracin A (593) : R1 = H B (594) : R1 = OH TOTAL SYNTHESIS OF SAFRACIN ALKALOIDS Despite the extensive research in the area of safracin biosyntheses, to the best of our knowledge, there is still no report of a chemical total synthesis of any safracin alkaloid. Since the initial disclosure of efforts toward safracin A by Kubo and coworkers in 1995,112 not Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 583 Alkaloids (2002 – 2020) much progress has been reported. This could perhaps be attributed to the ample quantities of safracins obtained from the isolation process. 4.5.3. RENIERAMYCIN ALKALOIDS 4.5.3.1. GENERAL STRUCTURE AND BIOSYNTHESIS The general structure of renieramycins is highly similar to that of the saframycin alkaloids. The main difference is at the C1-position, where renieramycins possess an ester or alcohol functionality instead of an amide side chain found in the saframycins (Figure 4.21). Renieramycin alkaloids are typically isolated from marine organisms, such as different species of blue sponges and nudibranchs, collected in various parts of the world. Before 2002, only the structures of renieramycins A–G, I, cribrostatin 4 (or renieramycin H), and jorumycin were disclosed. However, in the past 20 years, more than 20 new renieramycins were reported.113 These new compounds are mostly artifacts resulting from the attempts to improve the stability of renieramycin alkaloids. In 2003–2004, the structures of renieramycins J–O, and Q–S were isolated from the Thai sponge Xestospongia sp. pretreated with potassium cyanide (KCN) by Saito, Suwanborirux, and coworkers.114 They found that the addition of KCN helps stabilizing the labile amino alcohol moiety via the conversion to a more stable amino nitrile and improves the isolated yields of renieramycins by approximately 100-fold. This developed isolation protocol also allowed for the discovery of minor components of renieramycins in Xestospongia sp., including renieramycins T–U which possess an ecteinascidinrenieramycin hybrid structure, 115 as well as renieramycin V which contains a sterol unit appended to the C14-position.116 Additionally, jorunnamycins A–C were isolated from the aqueous KCN-pretreated Jorunna funebris collected in Thailand.117 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 584 Figure 4.21 General structure and representative examples of renieramycin alkaloids. OMe OMe Me O O E N A N 21 1 O Me N Me 14 Me O R1 OR O R N O Me O H H O OH O Me H O Me OMe Me N MeO R2 1 O Renieramycin Alkaloids Me O X N MeO X Me HO Me Renieramycin H (602) Renieramycin A (595) : R1, R2 = H, X = OH (or Cribrostatin 4) E (596) : R1 = OH, R2 = H, X = H OMe G (597) : R1, R2 = O, X = H OH Me O 1 = CH COCH , X, R2 = H J (598) : R 2 3 N Me OH 1 2 2 M (599) : R = CN, R = H, X = H X N Me O X1 O (600) : R1 = CN, R2 = H, X = OH 2 N Me R R1 R (601) : R1 = CN, R2 = H, X = OMe Me O N X Me HO O Me MeO O O O H O O Me Renieramycin N (603) : R1 = CN, R2, X1= H, X2 = OH Q (604) : R1 = CN, R2 = H, X1, X2 = O Me Renieramycin T (606) : X = H U (607) : X = OH Me OMe O Me N Me O O O O H Me N MeO H H Me Me Me H Me Jorunnamycin A (608) : R = H C (609) : R = COEt H Renieramycin V (605) Me OMe OMe Me O Me O CN OR O H O Me N H Me CN Me O Me O O H N MeO H O OMe O OMe OH O Me N Me Me O O O N Me O O O MeO O Me H N O OH OMe Fennebricin A (612) Me HO O H Me O Me N Me Renieramycin X (611) OMe O N O Me Me N N N MeO O O Me Me Me Renieramycin W (610) MeO H CN H O Me O O H Me O CN H Me O N N MeO CN Me OH OAc Jorumycin (613) O Me H OH O CN OH Jorunnamycin B (614) The Saito and Concepcion groups later reported three novel renieramycin-type alkaloids, namely renieramycins W–Y, which were isolated from the KCN-pretreated Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 585 Alkaloids (2002 – 2020) Xestospongia sp. collected in the Philippines.118 Structurally, renieramycins W and X are the first to have tiglic acid ester functionality instead of the angelate ester or the alcohol. Most recently, Guo and coworkers successfully isolated and disclosed the structures of fennebricins A–D from the South China Sea nudibranch J. funebris.119 Biosynthetically, the core pentacyclic skeleton of renieramycins were also reported to be assembled through a non-ribosomal peptide synthetase (NRPS) pathway, similar to the NRPS system of saframycin A.120 Donia and coworkers recently discovered that there are three NRPS modules, namely, RenE, RenF, and RenK, which are responsible for the production of the renieramycin E core structure (Scheme 4.64A). The first two modules (RenK and RenE) promote the formation of aldehyde building block 615, while RenF catalyzes multi-step transformations to ultimately deliver pentacycle 617 (Scheme 4.64B). Of note, RenK module is missing an adenylation domain (A) consistent with the fact that renieramycin E is one amino acid shorter than saframycin A. Scheme 4.64 A. Domain organization of renieramycins NRPS. B. Proposed biosynthetic mechanism for the construction of renieramycin E’s pentacyclic skeleton. a) Renieramycins nonribosomal peptide synthetase (NRPS): AL C ACP PCP A C RenK PCP A PS RenE PCP Red RenF AL - acyl-coA ligase, ACP - acyl carrier protein, C - condensation, A - adenylation, PCP - peptidyl carrier protein, PS - Pictet-Spengler, Red - Reduction b) Proposed biosynthesis of renieramycin E’s core Me O HO A PCP O S O Me O O PCP Me NH derivative of tyrosine 615 O OH Me MeO 4.5.3.2. Me PS RenF angelic acid S H O RenK RenE Me HO OMe HO Me RenF 616 Me NH N MeO 617 OH O Me TOTAL SYNTHESIS OF RENIERAMYCIN ALKALOIDS O OH Me O Me Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 586 Alkaloids (2002 – 2020) In the past 20 years, chemical syntheses of renieramycins have been an active research area with a number of synthetic studies towards these molecules and >10 reports successfully preparing naturally occurring renieramycin alkaloids. The first total synthesis of (–)-cribrostatin 4 (602, aka renieramycin H) was disclosed by Danishefsky and coworkers in 2005 utilizing asymmetric reductions as key transformations to prepare both western and eastern halves of the molecule (Scheme 4.65).121 With the two enantioenriched fragments in hand, they convergently coupled them together through an amide coupling, followed by a “lynchpin Mannich” cyclization to deliver pentacycle 621. Of note, the stereochemistry at the C3 position is opposite to that existing in the saframycin-like backbone. Nonetheless, this is inconsequential because the targeted natural product has the C3=C4 benzylic olefin. Accordingly, the ketone functionality at the C4 position was reduced and subsequently eliminated, affording intermediate 622. Finally, the last steps of the total synthesis involves the adjustment of oxidation levels of the A- and E- rings, the installation of the ketone at C14, and the introduction of the angeloyl group. By first converting intermediate 622 to monoquinone 623, regioselective benzylic oxidation with SeO2 proceeded smoothly, followed by DMP oxidation and quinone reduction to generate bis-hydroquinone 624. Despite the difficulty met in their initial attempts to perform angelation on a similar substrate, they adjusted the A-ring oxidation state and were able to perform esterification on this specific intermediate using angeloyl chloride 625, followed by TBS deprotection to prepare 626. Selective air oxidation of the ring A hydroquinone eventually provided cribrostatin 4 (602) in 34 steps for the longest linear sequence from commercially available 2,3-dimethoxytoluene. They additionally noted that Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 587 Alkaloids (2002 – 2020) the high stability of the E-ring hydroquinone can be attributed to the presence of the C14 ketone, while the resting state of the A ring is in the quinone oxidation level. Scheme 4.65 Danishefsky’s total synthesis of (–)-cribrostatin 4 602. OMe OMe O OH Me 1) BOPCl, Et3N, CH2Cl2 2) DDQ, CH2Cl2/buffer (pH 7) BnO Me PMBO NH MeO OMe + BocMeN 3) DMP, 2,6-lutidine, CH2Cl2 HO2C 67% yield (3 steps) OBn H O 619 14 steps from 2,3-dimethoxytoluene 11 steps from 3-methylcatechol O O N 3 N MeO MeO OMe Me 1) NaBH4, THF/H2O 2) AcOH, Bu3SnH (Ph3P)2PdCl2, CH2Cl2 Me N N MeO 78% yield (3 steps) OMe 68% yield (3 steps) O OBn Me N Me O 14 N O OMe Me OTBS H HO 1) SeO2, dioxane 100 °C 2) DMP, CH2Cl2 Me 3) 10% Pd/C, H2 MeOH MeO Me 1) OH 625 Me Cl OTBS N N 77% yield (3 steps) O OBn OMe Me H O Me , CH2Cl2 2) AcOH, TBAF, THF 75% yield (2 steps) O OH 624 623 OMe OMe Me HO OH Me N N O 3) Fremy salt, KH2PO4 CH3CN/H2O H 622 O OMe 1) TBSOTf, Et3N, CH2Cl2 2) 5% Pd/C, H2, EtOAc Me OMe MeO 100 °C 59% yield “lynchpin Mannich” cyclization Me OH 621 OMe H O OBn BnO H O OBn MeO Me 620 3) CSA, benzene, 80 °C N HCO2H BocN OMe Me H 11 4 Me O Me OMe BnO O OMe 618 Me BnO Me H O O Me OH 1) PIFA CH3CN/H2O 2) Zn, AcOH Me 3) air, DMF MeO O 65% yield (3 steps) Me 626 Me HO O 4 3 N N O O Me H O OH O Me O Me Cribrostatin 4 (602) With a longstanding interest in the chemistry and biology of the THIQ antitumor antibiotics, the Williams laboratory also developed an asymmetric total synthesis of (–)cribrostatin 4 (602) (Scheme 4.66). 122 By exploiting a sequential asymmetric Staudinger/Pictet–Spengler cyclization reaction, which was first developed in a separate study,123 the b-lactam-fused THIQ 627 was prepared to serve as the western portion of the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 588 Alkaloids (2002 – 2020) molecule. On the other hand, the enantioenriched tyrosine derivative 628 was synthesized using chiral glycine template as a chiral auxiliary. The assembly of these two molecules was then performed through an acid chloride intermediate to provide amide 629 without detectable epimerization at the C13 position. Treatment of 629 with TBAF resulted in the removal of both the TBS and Fmoc protecting groups to give 630. Scheme 4.66 William’s total synthesis of (–)-cribrostatin 4 602. OMe OMe Bn OMe N Me TBSO O Me + NH MeO OBn OMe OMe (COCl)2, DMF 2,6-lutidine FmocMeN HO2C OBn Me CH2Cl2 627 628 17 steps from 2,6-dimethoxytoluene 15 steps from 2,6-dimethoxytoluene N MeO OBn OMe Me N MeO OBn OMe H 62% yield MeO OBn 1) Me 625 Me N N O OH 632 Cl O OBn Me H O 1) PdCl2, H2 (1 atm), EtOH 2) PIFA CH3CN/H2O 40% yield (2 steps) OMe Me HO Me , CH2Cl2 Me OMe H 631 H Me O N N O OMe MeO Me then NH4Cl 630 O 92% yield Me H OMe O OBn O THF OMe LiEt3BH THF, 0 °C Me O OBn HO Me HN 13 H TBAF 629 OMe HO Bn N O OMe Fmoc MeN 79% yield H Me TBSO Bn N O O Me 2) SeO2, dioxane, 85 °C MeO 3) DMP, CH2Cl2; then aq. Na2S2O3, THF N N O O Me H O OH O Me 34% yield (3 steps) O Me Cribrostatin 4 (602) Following this, the LiEt3BH reduction of b-lactam 630 initiated the cyclization/elimination cascade, which established the pentacyclic skeleton of cribrostatin 4. Although there are two possible pathways for this transformation, the authors postulated the formation of an o-quinone methide intermediate to be operative. Finally, the advancement of pentacycle 631 to cribostatin 4 consists of a) debenzylation with PdCl2, b) oxidation of both phenols to bisquinone 632 with PIFA, c) esterification to generate the angelated intermediate, Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 589 Alkaloids (2002 – 2020) and d) double oxidation to install a ketone functionality at the C14 position. It is worth noting here that the order of this sequence proves critical to the success of this synthesis, as Danishefsky previously found that the pentacyclic alcohol (deangelated cribrostatin 4) was highly unstable, and attempts to perform esterification on this particular intermediate all led to decomposition of the starting material.121 Overall, Williams and coworkers completed a 25-step (longest linear sequence) asymmetric total synthesis of (–)-cribostatin 4 (602), starting from commercially available 2,6-dimethoxytoluene. Within the same year, Zhu and coworkers described the third asymmetric total synthesis of (–)-cribrostatin 4 (602).124 The key synthetic strategy to access the pentacyclic skeleton (639) features a domino sequence, involving the formation of iminium ion 636, followed by b-elimination and Pictet–Spengler cyclization, which greatly resembles Williams’ strategy (Scheme 4.67). In Zhu’s case, the thiol group at the C4 position acts as a leaving group to unveil a,b-unsaturated iminium ion 638. This intermediate then underwent cyclization to form pentacycle 639 and its constitutional isomer, arising from the undesired regioselectivity, in 51% yield and 15% yield, respectively. The desired isomer (639) was transformed into cribrostatin 4 (602) following a similar strategy to previous syntheses, providing the natural product in the longest linear sequence of 26 steps from commercially available starting material. More recently, Saito reported a racemic total synthesis of cribrostatin 4 from commercial material.125 Instead of building the pentacyclic core from an amide coupling to join the two halves of the molecule, they completed the synthesis by employing diketopiperazine as a central building block and consequently constructing the B- and Drings to generate the pentacyclic framework. The endgame of this synthesis follows the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 590 Alkaloids (2002 – 2020) sequence reported by Williams.122 The Saito group also realized an alternative synthetic plan to cribrostatin 4 in 2015,126 where they slightly modified the order of transformations in the early stage to prepare the pentacyclic skeleton. With this improved strategy, they were able to perform reactions on larger scale and prepared 81 mg of cribrostatin 4 with 8.3% overall yield in addition to renieramycin I, which contains a methoxy substituent at the C14 position. Scheme 4.67 Zhu’s strategy to prepare the pentacyclic skeleton of (–)-cribrostatin 4 602. C6H13 OTBS C6H13 S AllylO OH MeO OH AllylO 1) Swern ox. Me N C6H13 OMe Me S O 2) TBAF AcOH, THF Me MeO NHAlloc + N OH 633 Me C6H13 OH NHAlloc H Me Me 635 N MeO OH 51% yield (3 steps) + 15% isomer O OBn N OH Me OMe NAlloc 637 N MeO OH O OBn Me OH 636 Me NAlloc MeO OH OMe AllylO S Me NAlloc 3) CH3SO3H O OBn O OBn AllylO OH NAlloc MeO C6H13 S H N 634 AllylO S AllylO OMe Me O OBn CH2Cl2 OH Me OH OMe O OBn 638 OH OMe OMe Me HO H OAllyl Me N N MeO OH Alloc H O OBn 639 Apart from cribrostatin 4 (or renieramycin H), renieramycin G (597) has also been a popular target, attracting interest from the group of Williams, Magnus, Zhu, Saito, Liu, and Yang to complete its total synthesis. In 2005, Williams and coworkers disclosed the first asymmetric total synthesis of renieramycin G along with another structurally similar natural product, jorumycin (613) (Scheme 4.68).127 They elegantly took advantage of the intrinsic symmetry of the molecule to prepare only one building block (640) that can be employed as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 591 Alkaloids (2002 – 2020) both the western and eastern fragments. The use of chiral glycine template 641 as a chiral auxiliary allows for the preparation of benzylated oxazinone 642 which can be further transformed into enantioenriched 1,3-cis-THIQ 643 over 10 steps and tyrosine derivative 644 over 5 steps. Scheme 4.68 William’s total synthesis of (–)-renieramycin G 597 and (–)-jorumycin 613. Ph CH2I O O 641 OMe OTBS NH MeO O 643 OAllyl NaHMDS, THF OBn Me 10 steps Ph BocN BocN MeO Me OMe Ph Ph 88% yield 640 MeO O Me OBn OMe 5 steps Me 93% yield MeO O Me TBSO Me OMe Fmoc HN MeO H OAllyl OMe OH Me 84% yield (3 steps) O OAllyl OMe Boc HN 3) HCO2H, THF, H2O N Me TBSO 1) piperidine, CH2Cl2 2) Boc2O, EtOH OH 644 OBn OMe OMe TBSO (COCl)2 DMF 2,6-lutidine CH2Cl2 NHFmoc OMe 642 OMe OAllyl N MeO H OAllyl O OAllyl 645 1) DMP 2) TBAF, 0 °C 3) TFA, CH2Cl2 anisole 4) HCHO, NaBH3CN 65% yield (4 steps) 646 OMe Me O O H Me 3 steps Me OMe Me H H N Me O 42% yield (3 steps) O O H O Me OMe (–)-Renieramycin G (597) OMe H OAllyl Me O O OAllyl 647 O Me N MeO Me N MeO OMe HO N O 5 steps H Me H 38% yield (5 steps) MeO O N O Me N OH OAc (–)-Jorumycin (613) The coupling of these two molecules via an acid chloride intermediate proceeded smoothly to deliver amide 645 in 93% yield. Fmoc removal with piperidine, reprotection of the free amine with a Boc protecting group, and selective removal of the TBS group were Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 592 Alkaloids (2002 – 2020) followed to provide alcohol 646. The pentacycle was then obtained after oxidation of the primary alcohol, formation of the carbinol amine, and Pictet–Spengler cyclization to construct the D-ring. Reductive amination afforded intermediate 647 that is a precursor to both (–)-renieramycin G (597) and (–)-jorumycin (613). Interestingly, the use of different protecting groups on the eastern nitrogen atom, which requires basic conditions for deprotection, resulted in the generation of the C3-epi variant (649) through epimerization (Scheme 4.69). They, nonetheless, successfully advanced this unexpected epimer to 3-epirenieramycin G and 3-epi-jorumycin for further biological evaluation studies. Scheme 4.69 William’s unexpected C3-epimerization toward the synthesis of 3-epirenieramycin G, and 3-epi-jorumycin. OMe Me O O H Me N 3 steps OMe OMe TBSO Me OMe Fmoc MeN N MeO H OAllyl OMe Me O OAllyl 648 1) HCO2H, THF H 2O 2) Swern oxid. 3) TBAF 0 °C; then MsOH 80% yield (3 steps) Me HO OMe H Me 51% yield (3 steps) O H O O Me H O N 3 Me OMe Me (–)-3-epi-597 N MeO OMe H OAllyl O N MeO TBSO Me O OAllyl Me O O 649 5 steps H Me H 27% yield (5 steps) MeO O N O Me N OH OAc (–)-3-epi-613 At the same time, Magnus independently developed racemic total syntheses of renieramycin G (597) and a lemonomycinone analog (Scheme 4.70).128 The A–B rings of both molecules were initially prepared through a modified Larock isoquinoline synthesis, followed by an addition at the C1 position, a reduction of the C3=C4 olefin, and a silylactivated amide coupling to deliver 1,3-cis-THIQ 650. This THIQ intermediate (650) then underwent cyclization, and functional group interconversion to thioaminal 651. At this stage, Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 593 Alkaloids (2002 – 2020) thioaminal 651 serves as a diverging point to access renieramycin G or lemonomycinone amide, where a lactam enolate alkylation with benzyl chloride 652 was performed for the synthesis of renieramycin G. This provided the undesired epimer of tetracycle 653 at the C13 position as a single diastereomer, which they were able to correct via a diastereoselective reprotonation with in situ trityl removal to deliver 654. Treatment of this intermediate (654) with AgBF4 then triggered cyclization to generate the D-ring in pentacycle 655. Finally, reductive amination, hydrogenolysis, ceric ammonium nitrate (CAN) oxidation, and esterification afforded racemic renieramycin G (597). In this same report, a lemonomycinone amide was also prepared by adapting this developed synthetic strategy. Scheme 4.70 Magnus’ total synthesis of renieramycin G 597. OMe OMe OH Me OMe NHBoc N MeO OBn 652 OTrt N OBn 84% yield (2 steps) 650 Cl MeO NBoc 1) Swern oxidation MeO 2) HSPh, p-TSA CH2Cl2, –5 to 5 °C O OBn H Me Me SPh 18-crown-6, KHMDS THF, –78 °C O OBn 98% yield 651 (±)-lemonomycinone amide 9 steps OMe OMe OMe Me PhS H 1) t-BuLi, THF, –78 °C; then BHT/THF OMe Boc 2) HCl/Et2O, 0 °C N 13 N MeO O OBn PhS H OMe Me 73% yield (2 steps) 653 H OBn O OBn OMe OMe OMe Me H H N H N MeO H OBn O OBn 655 Me O Me OMe 1) NaBH3CN, HCOH AcOH, MeOH 2) Pd(OH)2, MeOH, H2 O H Me 3) CAN, 6:1 CH3CN/H2O, –5 °C MeO 4) angeloyl chloride, CH2Cl2 25% yield (5 steps) PhCl 13 N 654 HO AgBF4 OMe Boc N MeO H OBn Me HO Me TrtO H N Me O N H O O O Me (±)-Renieramycin G (±)-597 O Me Zhu and coworkers disclosed the asymmetric total syntheses of (–)-reinieramycins G, M, (–)-jorunnamycin A, and (–)-jorumycin in 2009 (Scheme 4.71). 129 By employing Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 594 Alkaloids (2002 – 2020) aziridine as a lynchpin, they took a different approach to construct the pentacyclic skeleton. Instead of relying on the amide coupling to merge the western and eastern parts of the molecule, they exploited aziridine ring-opening to forge the desired pentacycle. Starting with a CuBr-mediated ring-opening of enantioenriched aziridine 657, which was prepared from a chiral pool starting material (N-trityl-L-serine methyl ester), the Boc-protected amino ester 658 was formed in 80% yield. Following Boc removal, the Pictet–Spengler cyclization of the free amine with formyl aziridine 659 and global benzylation were performed to afford the eastern THIQ building block (660). From here, another CuBr-promoted aziridine ringopening was utilized, and a sequence consisting of a debenzylation with in situ methylation and tandem Boc removal/Pictet–Spengler reaction delivered the key bis-THIQ (664). This intermediate was then subjected to two different synthetic sequences to prepare a variety of renieramycin alkaloids. First, conversion of the ester to the aldehyde and a Strecker reaction provided pentacycle 665. This intermediate can be further advanced to jorunnamycin A (608), renieramycin M (599), and jorumycin (613) over 2, 3, and 4 steps, respectively. On the other hand, renieramycin G (597) was obtained via a) an amide coupling to form pentacycle 666, b) hydrogenolysis with Pearlman’s catalyst, c) angelation of the primary alcohol, and c) DDQ oxidation of the bis-phenols. By exploiting the common strategy in the construction of the bis-THIQ pentacyclic scaffold, i.e., the amide coupling with subsequent elaboration of the C–E rings through Pictet–Spengler cyclization, the Liu group reported an asymmetric total synthesis of (–)renieramycin G (597).130 The use of L-tyrosine methyl ester as a chiral pool starting material, similar to their total synthesis of saframycin A (vide supra), allows for diastereocontrol in Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 595 Alkaloids (2002 – 2020) ensuing transformations which ultimately resulted in the successful preparation of enantiopure (–)-renieramycin G in 21 steps for the longest linear sequence. Scheme 4.71 Zhu’s total synthesis of (–)-renieramycins G 597, M 599, (–)-jorunnamycin A 608, and (–)-jorumycin 613. Me OMe OMe BocO 1) TFA, CH2Cl2 2) OMe BocN BocN Br CO2t-Bu 657 80% yield 656 CO2t-Bu BocN 83% yield CO2t-Bu 660 MeO OMe OMe 1) Pd(OH)2, HCHO MeOH, H2 Me BnO BnO H BocHN HO CO2t-Bu OBn OMe 1) LAH, THF 2) Swern oxid. H MeO 663 OH OBn 52% yield (2 steps) OMe H Me OMe O H Me OMe 2 steps H MeO H 665 N (–)-Jorunnamycin A (608) OMe 3 steps 4 steps O OMe O Me Me H H Me O O Me O Me N CN OH O CN OBn OH H Me N MeO Me O Me N 62% yield (3 steps) 664 OMe HO CO2t-Bu 3) TMSCN, ZnCl2 CH2Cl2 N H Me NH O H 662 MeO Me 2) TFA, CH2Cl2 OMe BnN O CuBr –78 to 23 °C Me Me MeO MeO MgBr 661 BnN 48% yield (3 steps) OMe BnO H OMe (PhO)2PO2H AcOH, Na2SO4 3) BnBr, K2CO3 NaI, DMF, 0 to 23 °C 658 Me BnO CHO 659 then CuBr, OMe BocN Me BocO Mg, LiCl, THF DIBAL, –10 °C; Me MeO OMe O O N O CN Me H O OH OAc Me N MeO O Me N N Me (–)-Jorumycin (613) (–)-Renieramycin M (599) OMe OMe 664 1) TFA, reflux 2) HATU, HOAt DIPEA, DMF 0 to 23 °C 90% yield (2 steps) OMe Me H H N Me N MeO H OH O OBn 666 1) Pd(OH)2, H2 MeOH 2) angelic acid Et3N, PhMe OMe Me HO Me O O 2,4,6-trichloro- MeO benzoyl chloride 3) DDQ, 9:1 acetone/H2O 50% yield (3 steps) H Me H N Me O N H O O O O Me Me (–)-Renieramycin G (–)-597 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 596 Alkaloids (2002 – 2020) After the disclosure of this report, the group extended this synthetic strategy to prepare 15 analogs of renieramycin G with varying groups at the angelate ester,131 15 analogs of jorumycin with varying groups at the primary alcohol, 132 as well as 3 additional stereoisomers of renieramycin G. 133 These analogs were biologically evaluated for their cytotoxic activities against multiple cancer cell lines. In 2011, Saito and coworkers reported the total synthesis of (±)-renieramycin G (Scheme 4.72),134 in which the synthetic strategy closely followed their previously reported pathway for the synthesis of saframycin B.135 From tricyclic lactam 667, they performed a Pictet–Spengler cyclization with diethoxyacetate, delivering pentacycle 668 in 76% yield, albeit with the opposite stereochemistry at the C1 position. By converting the pendent ester to the aldehyde 669, they were able to correct this stereochemical problem via a basemediated epimerization over a total of 6 steps. Finally, the racemic renieramycin G (597) was obtained by performing a reduction of the aldehyde to the alcohol, followed by debenzylation, CAN oxidation, and angelation. Scheme 4.72 Saito’s total synthesis of renieramycin G 597. OMe OH OH N Me OH (EtO)2CHCO2Et TMSOTf Me CH2Cl2, reflux MeO HN MeO H OMe O 76% yield H H N 1 O H OMe MeO Me H OBn O N 4 steps O 669 23% yield (4 steps) Me N MeO N H MeO O H Me Me O Me N 1 62% yield (6 steps) O 668 MeO OH 6 steps N OMe OBn Me H MeO EtO 667 Me Me MeO H H Me OMe Me MeO O O O Me H O Me (±)-renieramycin G (±)-597 O Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 597 Alkaloids (2002 – 2020) Most recently, Yang and coworkers accomplished the total syntheses of the renieramycin alkaloids by a unified strategy (Scheme 4.73).136 The key transformations to construct the pentacycle are not significantly different from previous reports (i.e., the amide coupling with subsequent formation of the C,D-rings) however, they were able to expediently prepare tyrosine derivatives 672 and 673 through the utilization of C–H functionalization methodology. Scheme 4.73 Yang’s strategy to assemble the pentacyclic core of renieramycin alkaloids. C–H arylation methodology to prepare amino ester: OMe Me OMe I Me + H Pd(TFA)2, Ag2CO3 CONHArF 2-picoline, TFA DCE, 100°C NPhth MeO OTBS OMe OTBS H Me CONHArF NPhth MeO 76% combined yield 671 670 H Me + NPhth MeO OH 672 CONHArF 673 4 steps from 2,6-dimethoxytoluene OMe 1) BF3•Et2O MeOH, 100 °C H Me 2) ethylenediamine CH2Cl2:MeOH 40 °C CO2Me NH2 MeO OH 674 77% yield (2 steps) OMe OMe Me 3 steps H CO2Me MeO OMe OH Me 3 steps OMe NH OTBS 674 OMe Me TBSO NH2 MeO OH Me 675 OBn H CO2H NHBoc MeO OTBS BOPCl Et3N CH2Cl2 0 °C Me OMe Boc HN N MeO H TBSO 90% yield HO O OBn 677 676 OMe Me HO OMe 4 steps 50% yield (4 steps) Me H H N Me OMe N MeO H OH O OBn 678 Inspired by Yu’s C–H arylation, they performed the coupling of alanine derivative 671 with aryl iodide 670.137 This reaction proceeded smoothly to provide a 76% combined Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 598 Alkaloids (2002 – 2020) yield of arylated products 672 and 673, which were transformed into the same amino ester 674 via the removal of the CONHArF directing group and phthalimide protecting group, respectively. Amino ester 674 was used to prepare both the western (675) and eastern (676) fragments of the renieramycin alkaloids. Treatment of 1,3-cis-THIQ 675 and Boc-protected amino acid 676 with BOPCl and Et3N provided amide product 677 in 90% yield. With 677 in hand, pentacycle 678 was obtained from DMP oxidation, removal of the phenolic TBS protecting groups, acid-promoted intramolecular Pictet–Spengler cyclization, and reductive amination. Subsequently, enantioenriched (–)-renieramycins, G, M, J, (–)-jorunnamycin A, and (–)-fennebricin A were prepared from this same pentacycle 678. Of note, this research represents the first asymmetric total syntheses of renieramycin J and fennebricin A. The recently isolated renieramycin T (606), which features a hybrid structure of ecteinascidin–renieramycin, was also a target for a total synthetic endeavor by Yokoya and Williams.138 By adapting the strategy used in their total synthetic studies of Et-743,139 they completed the synthesis of (–)-renieramycin T through the use of L-tyrosine as a chiral pool starting material (Scheme 4.74). Amide coupling of highly decorated THIQ 679 and Fmocprotected amino acid chloride 680, followed by swapping of amine protecting groups provided amide 681 in 89% overall yield. Removal of the acetonide, then Dess-Martin oxidation, and intramolecular Pictet–Spengler cyclization delivered pentacycle 682 in 75% yield over 4 steps. From this key intermediate, they performed several functional group manipulations to obtain phenol 683. This phenolic hydroxyl group was benzyl protected prior to the partial reduction of the central amide, cyanation of the in-situ generated iminium ion, and oxidation of the eastern phenol to afford mono-quinone 684. Finally, debenzylation with BCl3 and subsequent esterification with angeloyl chloride completed the total synthesis of Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 599 Alkaloids (2002 – 2020) renieramycin T (606). This natural product along with other compounds in this synthetic sequence were evaluated for their cytotoxicities and revealed to exhibit moderate activities against human cancer cell lines. Scheme 4.74 Yokoya’s and Williams’ total synthesis of (–)-renieramycin T 606. Me Me AllylO O TBS OMe Br O Me H Me + NH O COCl NHFmoc MeO O OTBS OBn 680 679 1) 2,6-lutidine CH2Cl2 AllylO 2) Et2NH, CH2Cl2 3) Boc2O, EtOH CH2Cl2 O O Me N N H Br O BnO H O O OBn 1) HCHO, MeCN, 2N HCl NaCH3CN, AcOH, 60 °C 2) Ac2O, DMAP Et3N, CH2Cl2 O 682 HO Me H N Me O H O CN OH 684 3) TBAF, THF 4) TFA, anisole CH2Cl2 75% yield (4 steps) O H O O OH O 1) BCl3, CH2Cl2 Me –78 °C, (CH3)5C6H H 2) angeloyl chloride DCE, 80 °C N N O O 60% yield (2 steps) 683 O 3) KCN, AcOH 4) Salcomine, O2 THF 42% yield (4 steps) Me O OH 1) BnBr, K2CO3 acetone, reflux 2) LiAlH2(OEt)2 THF, 0 °C Me OMe Me N N N OMe BnO Me H Me 74% yield (4 steps) O 681 AcO 3) Pd(PPh3)4, n-Bu3SnH AcOH, CH2Cl2 4) Raney Ni, H2 EtOH, 60 °C N O H O 89% yield (3 steps) 1) Dowex 50W-X8 MeOH 2) DMP oxidation OMe Me AllylO Me Br Boc HN OMe HO Me Me Me O Me O H CN Me O Me (–)-Renieramycin T (606) Seeking to develop an alternative strategy for the production of renieramycin T, Saito and coworkers applied the stereoselective decarboxylative reprotonation strategy previously discovered in the synthesis of saframycin A (Scheme 4.63, vide supra) in the context of this natural product.140 To this end, the group completed a formal synthesis of renieramycin T by concluding at intermediate 684 reported by Yokoya and Williams. The Chen group also achieved a total synthesis of (–)-renieramycin T in 2016.141 By mimicking the reported biosynthesis of Et-743, 142 they performed a Pictet–Spengler cyclization under a unique ternary solvent system (PhMe, CH2Cl2, and 2,2,2-trifluoroethanol) Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 600 Alkaloids (2002 – 2020) to construct the D-ring of bis-THIQ intermediate 687 (Scheme 4.75). Protection/deprotection chemistry was followed, then a Swern oxidation with a subsequent ZnCl2-promoted Strecker reaction eventually closed the C-ring, forming pentacycle 688 in 78% yield over 5 steps. With this intermediate in hand, they discovered that the chloroacetyl protecting group needed to be chemo- and regioselectively installed on the A-ring phenol (690) prior to oxidation and installation of the angeloyl group. Accordingly, they successfully prepared (–)-renieramycin T (606) in an additional 4 steps with 39% yield. Overall, this asymmetric total synthesis consists of 22 steps for the longest linear sequence, with a 6.2% overall yield from known starting materials. Apart from (–)-renieramycin T, the Chen group successfully prepared three other renieramycin-type alkaloids: (–)-jorunnamycin A, (–)-jorunnamycin C, and (–)jorumycin through this similar synthetic strategy.143 Scheme 4.75 Chen’s total synthesis of (–)-renieramycin T 606. Me MeO AllylO Me Me CHO NH2 MeO O O OH + NBoc 2.1:1:1 PhMe/CH2Cl2 /TFE, AcOH H OH OBn 4Å MS, (BnO)2PO2H 70 °C N O 64% yield H CN OBn 688 O 1) Pd(PPh3)4 Bu3SnH AcOH, CH2Cl2 2) HCHO,NaBH3CN AcOH, CH3CN/THF 3) BCl3, CH2Cl2 –78 °C Alloc N O O OBn Me HO HO Me N Me N O H O 80% yield (3 steps) CN OH OMe Cl Me 1) angelic acid 2,4,6-trichlorobenzoyl chloride O O Me N Me N O H O CN OH 690 687 78% yield (5 steps) O Et3N, toluene, 90 °C 2) CH3CN/aq. NaHCO3 56% yield (2 steps) OH Me H Me N Me O N O H CN Me O O 1) chloroacetic anhydride, pyridine 2) salcomine O2, CH3CN 70% yield (2 steps) 689 O OMe O 3) HCl, MeOH, 60 °C OH 4) Swern oxidation 5) TMSCN, ZnCl2, CH2Cl2 OMe Me AllylO Me H N H H NBoc OMe AllylO HO Me 686 685 AllylO 1) AllocCl, CH2Cl2/ aq. NaHCO3 2) AllylBr, Cs2CO3 NaI, CH3CN, 50 °C O Me (–)-Renieramycin T (606) Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 601 Alkaloids (2002 – 2020) Aiming to devise a complementary synthetic route to prepare bis-THIQ alkaloids that specifically avoids the Pictet–Spengler reaction, the Stoltz group completed a synthetic study toward jorumycin (613) via a two-part strategy, consisting of a cross-coupling reaction for the convergent construction of the requisite carbon-based skeleton and an enantioselective hydrogenation to install all of the key stereochemistry (Scheme 4.76).144 Specifically, we successfully exploited the N-oxide C–H functionalization developed by Fagnou and coworkers in the coupling of the eastern (692) and western (691) isoquinoline fragments. With the coupled product 693 in hand, the advancement of this intermediate to the bisisoquinoline hydrogenation precursor (694) was performed through isoquinoline oxidation/mono-N-oxide rearrangement, followed by the N–O bond cleavage and oxylmediated oxidation. Scheme 4.76 Stoltz’s total synthesis of (–)-jorunnamycin A 608 and (–)-jorumycin 613. Me MeO 1) MeReO3, H2O2 CH2Cl2; then Ac2O 2) Fe0, AcOH, 50 °C; then KF, 23 °C OMe OMe Me OTf N MeO Pd(OAc)2 OTBS P(t-Bu)2Me•HBF4 Me + N MeO O– OMe Me CsOPiv, Cs2CO3 PhMe, 130 ºC N N MeO 93% yield 692 691 Me + OMe Me Me OMe OMe N N Me MeO [Ir(cod)Cl]2 BTFM-xyliphos MeO O H2, TBAI 9:1 PhMe/AcOH 60 to 80 °C H Me H MeO H NH N H OMe OMe OH 694 O 695 OH recrystallized to >99% ee 83% yield, 88% ee OMe H Me H MeO O OMe Me O O 693 OMe MeO Me O N O Me N CN OH (–)-Jorunnamycin A (–)-608 Me O Ac2O, DMAP, MeCN; then, aq. AgNO3 45 °C 68% yield O H Me H MeO O N N OH OAc (–)-Jorumycin (–)-613 O Me OTBS 3) TEMPO, NHS, PhI(OAc)2, CH2Cl2; then p-TsOH•H2O 25% yield (3 steps) 1) aq. CH2O, NaBH(OAc)3, DCE 2) NCSac, HFIP, 0°C 3) Pd G3 dimer, AdBippyPhos CsOH•H2O, dioxane 4) Li(EtO)2AlH2, THF; then AcOH, KCN 5) DDQ, acetone, H2O 5% yield (5 steps) Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 602 Alkaloids (2002 – 2020) Another key transformation in this synthetic strategy is the sequential stereoselective hydrogenation to construct the pentacyclic scaffold of bis-THIQ molecules. The use of [Ir(cod)Cl]2 in conjunction with electron-poor Josiphos BTFM-xyliphos ligand was found to promote the desired hydrogenation-lactamization cascade, providing the pentacycle (695) as a single diastereomer in 83% yield, and with 88% ee. Furthermore, this intermediate was recrystallized from a slowly evaporating acetonitrile solution to enantiopurity. The relative and absolute stereochemistry of the product was confirmed via X-ray crystallographic analysis. The final stage of the synthesis consists of a 5-step sequence. First, reductive amination was employed to methylate the piperazinone N–H. Bis-chlorination of the A- and E-rings with N-chlorosaccharin (NCS) was then followed, and the subsequent C–O bond coupling provided a dihydroxylated compound. Lastly, partial reduction of the central lactam with cyanide trapping and DDQ oxidation delivered jorunnamycin A (608). Conversion of jorunnamycin A (608) into jorumycin (613) was achieved in one additional step, concluding the 16-step total synthesis. As a result of his unique approach, access to electronically modulated aromatic substitution patterns are readily attainable. 4.5.4. ECTEINASCIDIN ALKALOIDS 4.5.4.1. GENERAL STRUCTURE AND BIOSYNTHESIS The ecteinascidin alkaloids are known to be extremely potent antitumor agents, with Et-743 2 (Yondelis®) approved for clinical use for the treatment of advanced soft tissue sarcoma.145 Apart from other THIQ alkaloids, these agents are unique in their structure with the pentacyclic skeleton linked to a 10-membered lactone bridge through a benzylic sulfide linkage (Figure 4.22). Most ecteinascidin alkaloids contain an additional THIQ ring attached Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 603 Alkaloids (2002 – 2020) to the lactone bridge as a spirocycle, which is a key distinguishing feature from other THIQ natural product families. Figure 4.22 Ecteinascidin natural products. HO NH MeO O OMe OAcO S B A E H Me N HN O Me HO C D N O B A X E H Me O Me HO OAcO S R OMe NH N C D N R O O X Ecteinascidin 743 (184) : R = Me, X = OH Et 736 (700) : R = Me, X = OH 729 (696) : R = H, X = OH 722 (701) : R = H, X = OH 745 (697) : R = Me, X = H 759B (698) : R = Me, X = OH, S-oxide 770 (699) : R = Me, X = CN O NH2 OMe O Me HO OAcO S Me A R1 R2 N C D N Me Me A MeO OH Et 594 (702) : R1 = R2 = -OCH2O596 (703) : R1 = OMe, R2 = OH OMe Me HO OAcO S E H B O OH E H B N C D N R X Et 583 (704) : R = H, X = OH 597 (705) : R = Me, X = OH Early biosynthetic studies of the ecteinascidins revealed that tyrosine and cysteine are the two amino acid building blocks specifically for the synthesis of Et-743.146 More recently, with the advancement of next-generation sequencing technology, Sherman and coworkers exploited a meta-omic approach to identify the biosynthetic gene cluster responsible for the production of Et-743.147 In this study, three putative modules of nonribosomal peptide synthetase (NRPS) is reported to promote transformations for the construction of the pentacyclic core (Scheme 4.77). Similar to the NRPS system of saframycin A (vide supra), EtuA2 is a homologue of SfmC which iteratively incorporates two molecules of tyrosine derivatives into the core structure. After the reductive release, also through the EtuA2 module, the aldehyde intermediate undergoes cyclization to generate the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 604 Alkaloids (2002 – 2020) C ring. Hydrolysis of the pendent N-acyl moiety subsequently proceeds, and the 10membered lactone bridge is proposed to be assembled via the tailoring EtuO module. This produces Et-583 (704) as a late-stage intermediate, leading to other isolable ecteinascidins (Et-597, Et-596, and Et-594) and finally Et-743. Scheme 4.77 A. Domain organization of Et-743 NRPS. B. Proposed biosynthetic mechanism for the construction of Et-743’s pentacyclic skeleton. a) E7-743 nonribosomal peptide synthetase (NRPS): AL A C ACP PCP A C EtuA3 A PCP Red PS PCP PCP EtuA1 EtuA2 AL - acyl-coA ligase, ACP - acyl carrier protein, C - condensation, A - adenylation, PCP - peptidyl carrier protein, PS - Pictet-Spengler, Red - Reduction b) Proposed biosynthesis of Et-743’s core A EtuA1 EtuA3 EtuA2(Red) O HS H O OH S O O NH O NH derivative of tyrosine 706 O OH Me CnH2n+1 707 OH O O HS OH O OMe OAcO S OH Me OAcO S H N Me H N N MeO Me Et-743 (184) N O OH OH Et-596 (703) 4.5.4.2. Me Me HO O R OH Et-583: R = H (704) Et-597: R = Me (705) OMe O Me HO H N O O Me N MeO 710 OMe HO OAcO S NH2 O NH2 O Me N OH 709 H NH MeO O CnH2n+1 CnH2n+1 EtuO NH NH H MeO NH SH O Me HO Me Me Me derivative of tyrosine OMe OMe HO O MeO NH SH O 708 O OH Me O MeO EtuA2 NH EtuA2 O HS PS and Red Red EtuA2 NH2 H O PCP PS OH Et-594 (702) TOTAL SYNTHESIS OF ECTEINASCIDIN ALKALOIDS Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 605 Alkaloids (2002 – 2020) Approaches to the chemical syntheses of these natural products generally utilize electrophilic aromatic substitution strategies for construction of the THIQ motifs. After Corey’s seminal total synthesis of Et-743 184 in 1996, other groups have attempted to target this molecule and its congeners with distinct disconnections. 148 In 2002, Fukuyama and coworkers reported the second total synthesis of 184, envisioning key intermediate 711 to assemble the natural product scaffold through electrophilic aromatic substitution with the requisite oxidation state at the C4 position (Figure 4.23).149 Figure 4.23 Fukuyama’s synthetic strategy toward Et-743 184. HO NH MeO O Me OH H Me N O H 4 Me N Me N N O O O Me HO Me HO OAcO S OMe OMe O OH CN OAc 711 Et-743 (184) OMe OMOM Me BnO Me + NH2 O O OTBDPS 712 I BocHN CO2H 713 With two functionalized fragments 712 and 713, an Ugi four-component condensation reaction assembled intermediate 715 in high yield, which formed the diketopiperazine C-ring of the core in four subsequent steps (Scheme 4.78). After protection of the phenol and lactam nitrogen of 716, partial reduction of the carbonyl with NaBH4, and dehydration of the hemiaminal intermediate afforded the desired intermediate 717 for the Heck cyclization. Using 5 mol % of Pd2(dba)3 and 20 mol % of P(o-tol)3 ligand, an intramolecular Heck reaction proceeded smoothly to install the D-ring of the natural product scaffold 718 in 83% yield. After several functional group manipulations, the key aldehyde Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 606 Alkaloids (2002 – 2020) intermediate 719 then underwent hydrogenolysis of the benzyl ether to induce spontaneous cyclization and deliver the desired pentacycle 720. Scheme 4.78 Fukuyama’s total synthesis of Et-743 184. OMe NC MeO MOMO 714 Me acetaldehyde 712 + 713 Me PMPHN O HN Me MeOH, reflux OMe Boc Me 3) TFA, anisole 4) EtOAc, reflux N O OH 1) TBAF, THF 2) Ac2O, py., DMAP I O 90% yield Me OBn O OTBDPS Me O 72% yield (4 steps) O OAc 716 OMe 3) NaBH4, H2SO4 4) CSA, quinoline PhMe, reflux OMs Me N Boc I Pd2(dba)3 (5 mol %) P(o-tol)3 (20 mol %) O 78% yield (4 steps) Me N NEt3, CH3CN, reflux N O O 83% yield O OAc O O OAc 718 717 OBn O Me OMe Me OH Troc O O OH H Me Pd/C, H2 N THF, R.T. N O Me OMe Troc OAcO S H Me N Troc N O O SAc NH2 MeO OMe Me NH2•HCl HO NH MeO O 725 H N Me 2) AgNO3, CH3CN:H2O Me Me H N 89% yield (2 steps) O OMe HO OAcO S 1) NaOAc, EtOH N CN 723 HO HO Me Me AllylO 70% yield (3 steps) CN 722 NHAlloc OAcO S O 1) NH2NH2, CH3CN 2) TFA, TFE 3) Ac2O, py., DMAP O O 83% yield (3 steps) NHAlloc N O NHAlloc 721 Me O O CO2H AcS 720 OH H N 3) WSCD•HCl, DMAP, CN OAc OMe OH Troc O 719 AllylO 1) allyl bromide, i-Pr2NEt 2) K2CO3, MeOH N 84% yield CN OAc Me HO H N Boc N OMe BnO Me BnO OBn OMs Me I N OMe 1) MsCl, py. 2) Boc2O, DMAP NH O 715 Me OBn O Me N O O CN 724 O OH Et-743 (184) With the desired oxidation already in place at the C4 position, condensation of the alcohol with L-cysteine derivative 721 furnished ester 722, which smoothly formed the Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 607 Alkaloids (2002 – 2020) lactone bridge 723 under acidic conditions. A biomimetic transamination reaction afforded the α-ketolactone 724 to undergo a subsequent Pictet–Spengler reaction with 725 to install the third THIQ moiety. Generating the labile hemiaminal last with AgNO3 in CH3CN and H2O completed the natural product 184 in 93% yield. Since their completed total synthesis of 184 in 2002, Fukuyama and coworkers have revised their strategy to render its synthesis more efficient and practical.150 They instead envisioned accessing intermediate 728 from dihydropyrrole 727, assembled via a Heck reaction between amine 726 and enamide 727 (Scheme 4.79). Construction of the B-ring and the 10-membered lactone bridge would then proceed according to their initial synthetic strategy. With the functionalized fragments in hand, treatment of 726 with tert-butyl nitrite and BF3•OEt2 generated the diazonium salt in situ to undergo the key intermolecular Heck reaction with 727 in the presence of a palladium catalyst. Dihydroxylation of 728 and oxidative cleavage of the resulting 1,2-diol with H5IO6 formed dialdehyde intermediate 729, which could then be liberated by heating in m-xylene and trapped intramolecularly by the electron-rich arene to establish the THIQ B-ring and deliver 730. Substitution at the C1position of 731 was then elaborated to construct the 10-membered cyclic sulfide and access the natural product based on their previous synthetic strategy. Overall, the synthetic route to 184 was successfully shortened to 28 steps (as compared to 45 steps in their previous study) and 1.1% overall yield by efficiently constructing the B-ring. Other synthetic strategies to construct the THIQ B-ring of Et-743 (184) were reported in 2006, wherein Danishefsky and coworkers demonstrated a novel vinylogous Pictet– Spengler cyclization from an ortho-hydroxystyrene intermediate 732 (Scheme 4.80). 151 Treatment of 734 with DMDO then oxidized the C4 position, which produced ketone 736 as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 608 Alkaloids (2002 – 2020) the major product through either a concerted rearrangement or a 1,2-hydride migration from epoxide 735. After installation of the nitrile functionality, the MOM group was cleaved to reveal their final intermediate 738, which constituted a formal total synthesis of Et-743 (184). Scheme 4.79 Fukuyama’s revised total synthesis of Et-743 184. OMe OMe Me MOMO OBn BF3•OEt2, t-BuONO THF, –15 → 0 °C H then Pd2(dba)3, NaOAc CH3CN:THF, 0 °C → R.T. N H Me N + CO2Me N NH2 O O 1) OsO4, K3[Fe(CN)6] K2CO3, quinuclidine•HCl MeSO2NH2, t-BuOH, H2O, R.T. CO Me N 2 2) H5IO6, THF, 0 °C 81% yield (3 steps) O O O BnO 727 726 Me MOMO O Me 728 OMe OMe Me MOMO OH H OH N O CO2Me 1) H2, Pd/C, MeOH N HO 2) m-xylene, 120 °C; Red-Al, –42 → 60 °C O O OH H NHAlloc N Me 77% yield (3 steps) O 730 O 729 OMe OH Me NH2 Me MOMO OH H N 1) TFA, CF3CH2OH; PhMe, evaporation; Ac2O, py. 2) TFA, CH2Cl2 Me N O HS O O CN OAcO S Me H N O O 731 CN 724 NHAlloc HO NH MeO O OAcO S ref. 149 OMe Me HO Me H N N O O OH Et-743 (184) Me Me N 33% yield (3 steps) O OMe HO 3) (Ph3P)2PdCl2, AcOH n-Bu3SnH, CH2Cl2 O 721 3) H2NNH2•H2O, CH3CN N O CO2H AcS O 76% yield (2 steps) BnO Me Me 1) KCN, AcOH 2) EDCI•HCl, DMAP, CH2Cl2 Me MOMO Me Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 609 Scheme 4.80 Danishefsky’s formal total synthesis of Et-743 184. OMe OH OMe Me BnO OH O Me BocN CHF2CO2H, MgSO4 Me PhH, 100 °C Me N N N O H O O OBn O 1) TBSOTf, NEt3, CH2Cl2 2) Troc-Cl, TBAI, PhMe, 110°C O OBn 73% yield (4 steps) 733 OMe OMOM Troc DMDO Me MOMO O N N Troc NaCNBH3, 10 min. O O OBn 734 O OBn 736 735 OMe OMe MOMO 1) NaCNBH3 2) H2, Pd/C, EtOAc Me N 3) DIBAL, BuLi, THF, 0 °C 47% yield (3 steps) OH OH H 1) allyl bromide, i-Pr2NEt 2) KCN, AcOH 3) TFA, CH2Cl2, –20 °C N O O Troc O 737 Me AllylO Me HO Troc O 60% yield O N N O O OBn O Me N O Me BnO Me BnO OMOM N OMe OMe Me BnO Me Me 3) TBAF, CH2Cl2, 0 °C 4) MOM-Cl, i-Pr2NEt O 42–58% yield 732 O Me BnO 28% yield (3 steps) Me OH H N Troc N O O CN OH 738 On the other hand, Zhu and coworkers reported the total synthesis of Et-743 (184) by retrosynthetically disconnecting the molecule into four building blocks of similar size (Scheme 4.81).152 Synthesis of the D- and E-ring of 2 commenced with condensation of aldehyde 739 with phenylalanol 740, providing access to THIQ 741 in 84% yield as a single diastereomer. Masking the secondary amine as the N-allyloxycarbamate, followed by chemoselective protection of the alcohol and removal of the masked amino alcohol delivered 742. Assembly of this key intermediate with benzyl bromide 743 under CH3CN in the presence of triethylamine delivered two coupled products 744 and 745 that were isolated in 23% and 68% yield, respectively. The desired diastereomer 745 was carried forward to access the C-ring through a zinc chloride-catalyzed Strecker reaction that provided amino nitrile 746 as a single diastereomer. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 610 Scheme 4.81 Zhu’s total synthesis of ecteinascidin 770 699 and ecteinascidin 743 184. OMe OMe Me HO Me CHO O + NHBoc Me AcOH 3 Å MS H 2N 1) Alloc-Cl, NaHCO3 CH2Cl2 2) Allyl-Br, Cs2CO3, DMF H Me N Boc 7:1 CH2Cl2:TFE Me Me HO O 3) Ac2O, pyridine, DMAP CH2Cl2 4) TFA, CH2Cl2 HN 84% yield HO 739 HO 740 50% yield (4 steps) 741 OMe OMe OMe HO H A + D N Br CH3CN, 0 °C CO2Et 91% yield MOMO C N N Alloc O 71% yield (3 steps) O EtO2C 745 (68% yield) OMe MOMO Me 62% yield (4 steps) O O OH N Alloc N 2) EDCI, DMAP, CH2Cl2 N O SCAr3 TrocHN CN OAc O 749 O O Ar3SC OMe OMe Me HO OAcO S N Me O 1) AcOH, Zn 2) DBU aq. oxalic acid DMF:CH2Cl2 H Me Me O 751 Me NH O OMe OAcO S H N N 97% yield CN NH MeO Me AgNO3 CH3CN:H2O 92% yield O O Me HO O Me HO CN Et-770 (699) OMe Me HO OAcO S Me H N N O O 754 NaOAc, EtOH 753 SO3 752 49% yield (2 steps) HO Me N N NH2 HO H O CN MeO MeO N CHO N 64% yield (3 steps) Me HO OAcO S O O 750 1) TFA, TFE then Ac2O, pyridine DMAP, CH2Cl2 2) n-Bu3SnH, PdCl2(PPh3)2 AcOH, CH2Cl2 3) NaBH3CN, AcOH, HCHO NHTroc O NHTroc O CN 91% yield (2 steps) 748 Alloc N COOH O O 747 OH H Me 1) K2CO3, MeOH 95% yield Me AllylO OH H Me TFA CH2Cl2 CN OAc OMe OH Alloc N CN Me O N 746 AllylO Me AllylO 3) HF•H2O, CH3CN 4) DMP OMe CO2Et OAc O 1) LiBH4, MeOH THF, 0 °C 2) Ac2O, pyridine DMAP, CH2Cl2 OTBS Me 3) DMP then TMSCN, ZnCl2 O CO2Et OAc 744 (23% yield) Me Alloc NH O OMe 1) TBSCl, imidazole, DMF 2) K2CO3, MeOH N Alloc + NH O AllylO Me OH Me N 743 742 MOMO OH Me NEt3 O O AcO MOMO Me E H 2N Alloc OMOM Me AllylO AllylO Me AllylO OH Et-743 (184) Me Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 611 Alkaloids (2002 – 2020) After several oxidative manipulations to deliver aldehyde 747, cyclization under acidic conditions afforded 748 with concomitant removal of the MOM-protecting group. After installing the side chain at the C1 position to deliver 750, the 10-membered lactone bridge was installed from dissolving 750 in TFE containing 1% of TFA through in situ generation of an ortho-quinone methide followed by an intramolecular Michael addition to access the key C–S bond in 751. Following Corey’s protocol, installation of the final THIQ was accomplished via oxidation to the ketoester 753 and Pictet–Spengler cyclization with 754 to provide Et-770 (699) in 97% yield.148a Treatment of Et-770 with AgNO3 in a mixture of CH3CN and H2O provided Et-743 (184) in 92% yield. Within the same year, Zhu and coworkers reported a similar synthetic strategy for the total syntheses of Et-597 (705) and Et-583 (704), instead using phenol 755 to build the natural product scaffold through a sequence of aldol condensations followed by a Pictet–Spengler reaction (Scheme 4.82).153 Scheme 4.82 Zhu’s total synthesis of ecteinascidin 597 705 and ecteinascidin 583 704. OMe OMe OH O A E + MeO Me Si t-Bu Me D N OAc 74% yield NH2 O OAcO S Me Si t-Bu O N Et-583 (704) 757 Me NH2 O OMe Me HO Me H N Me N MeO OH 13 steps OAc OAcO S H Alloc 14 steps Me NH OH MeO OMe HO MeO N BocHN 756 755 Me OH Me MeMgCl, 576 THF Alloc then 577 CH2Cl2 BocHN O OH Me AllylO Me Me AllylO OH OH Et-597 (705) Recently, Ma and coworkers described the total synthesis of Et-743 and lurbinectedin through a convergent Pictet–Spengler coupling event of an elaborated tetrahydroisoquinoline Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 612 Alkaloids (2002 – 2020) and tyrosine derivative 758 (Scheme 4.83).154 Using the same intermediate 758 to construct both the western and eastern fragments of Et-743, a Pictet–Spengler reaction with benzyloxyacetaldehyde 759 and subsequent Boc-protection provided the western THIQ 760 in 83% overall yield. After oxidation of phenol 760 to quinone 761, a light-mediated C–H bond functionalization using blue LED light in THF allowed cyclization to deliver benzo[1,3]dioxole 762 in 83% yield. The formation of 762 could be scaled up to a multidecagram scale without compromising the yield. After protection of the phenol and oxidation of 762 to the aldehyde 763, an intermolecular Pictet–Spengler reaction with amino alcohol 758 provided cyclization product 764 as the major isomer in 67% yield. This key coupling event allowed efficient construction of the natural product scaffold to install four of the six rings in a single step. Oxidation of the hydroxymethyl group then prepared for a subsequent Strecker reaction to construct the amino nitrile 765. With decagram quantities of the hexacyclic intermediate 765, oxidation of the phenol with benzeneseleninic anhydride provided dihydroxy dienone 766, which underwent elimination and macrocyclization according to Corey’s one-pot procedure to obtain lactone 767.148a Finally, oxidation to the keto ester 753 and Pictet–Spengler reaction with phenethylamine 725 or tryptamine 768 followed by hydrolysis delivered either Et-743 (184) or lurbinectedin (769), respectively. 4.6. THIQ ALKALOIDS FROM THE NAPHTHYRIDINOMYCIN FAMILY 4.6.1. GENERAL STRUCTURE AND BIOSYNTHESIS Most alkaloids from the naphthyridinomycin family possess a hexacyclic skeleton, including four six-membered rings, a five-membered bridged ring, and an oxazolidine fragment (Figure 4.24). Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 613 Scheme 4.83 Ma’s total synthesis of ecteinascidin 743 184 and lurbinectedin 769. O OBn , AcOH 1) Me OH NH2 MeO OH 758 OH CH2OH 762 OBn O OMe OBn 2.7:1:1 PhMe:CH2Cl2:TFE Me 67% yield O OBn 87% yield (2 steps) 763 HN NBoc OH O OBn 764 Me AllylO OBn 3) (COCl)2, DMSO DIPEA, CH2Cl2 4) TFA, CH2Cl2 then TMSCN N Me 2) (PhSeO)2O CH2Cl2, –10 °C O OH O O OMe Me AllylO OAcO S Me 2) Tf2O, DMSO, –40 °C then DIPEA, then t-BuOH, 0 °C then (Me2N)2C=N-t-Bu then Ac2O 1) Pd(PPh3)4, n-Bu3SnH AcOH, CH2Cl2 H 2) N CHO Me N O N O 43% yield (2 steps) CN SO3 Me 752 767 then DBU, 0 °C then (CO2H)2 44% yield (2 steps) HO 1) MeO HO OMe O Me HO OAcO S Me NH3Cl O 725 OMe Me HO OAcO S Me H N 86% yield (2 steps) Me N O H O N Me 1) MeO MeO CN 753 OH Et-743 (184) N O O NH MeO NaOAc, EtOH 2) AgNO3 CH3CN:H2O O CN OH 766 NHAlloc 1) (R)-N-Alloc-S-Fm-Cys EDCI, DMAP, CH2Cl2 H N 765 O NH NH3Cl 768 N H NaOAc, EtOH 2) AgNO3 CH3CN:H2O Me N 79% yield (2 steps) CN OBn 76% yield (4 steps) O 1) BCl3, CH2Cl2 then TMSCN, –80 °C Me N O OMe AllylO H Me Me H OMe 1) HCHO, NaBH3CN AcOH, CH2Cl2 2) Allyl-Br, K2CO3 acetone, 65 °C 83% yield HO CHO O blue LED THF OBn 761 758, AcOH O CH2OH NBoc MeO 85% yield NBoc 2) (COCl)2, DMSO DIPEA, CH2Cl2 O H Me 1) K2CO3, BnBr acetone, 65 °C salcomine O2, CH3CN OBn 760 OBn NBoc O OH H Me CH2OH NBoc MeO 83% yield (2 steps) H Me 7:1 CH2Cl2:TFE 2) (Boc)2O, NEt3 CH2Cl2 O H Me 759 Me OMe NO HO H OAc S O H Me N 77% yield (2 steps) N O O OH Lurbinectedin (769) Me Me Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 614 Alkaloids (2002 – 2020) The A-ring can either be in the quinone or hydroquinone oxidation state. Members of this family are the naphthyridinomycin (591), cyanocyclines (592–593, 596), bioxalomycins (594–595), aclidinomycins (597–598), and dnacins (599–600). The biosynthesis of cyanocycline A was studied by Zmijewski and coworkers, where they discovered through feeding experiments that the core structure was assembled from tyrosine, methionine, glycine or serine, and ornithine. 155 Later in 2013, the Tang group analyzed the naphthyridinomycin gene cluster and proposed a pathway for the core formation via nonribosomal peptide synthetase (NRPS) NapL and NapJ modules.156 The completed biosynthetic pathway, especially how the five-membered bridged ring is formed in the core structure, however, still have not been fully elucidated in this study. Figure 4.24 Core skeleton of THIQ alkaloids in the naphthyridinomycin family and examples. NR O F N A B N E C B D NR N A N C Hexacyclic skeleton D E F O Quinone/hydroquinone A-ring Central piperazine subunit Oxazolidine moiety O O O Me H N H H Me NMe N R 2O O OH N H H NR N MeO OH R1 OH H O H Naphthyridinomycin (770) : R1 = OH, R2 = Me Bioxalomycin α1 (773) : R = H Cyanocycline A (771) : R1 = CN, R2 = Me Bioxalomycin α2 (774) : R = Me Cyanocycline F (772) : R1 = CN, R2 = H O HO CN Me OH N H H O H NMe N MeO OH CN OH Cyanocycline D (775) Me N OH H H MeO O H NMe N O H H N H H NMe N H 2N O R O H O R OH Dnacin A1 (778) : R = CN Aclindomycin A (776) : R = H Aclindomycin B (777) : R = OH Dnacin B1 (779) : R = OH Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 4.6.2. TOTAL SYNTHESIS OF NAPHTHYRIDINOMYCIN ALKALOIDS 615 Although no recent total synthesis of the naphthyridinomycin alkaloids have been reported, several approaches for the formal synthesis of these natural products have been explored.157 In 2007, Garner and coworkers disclosed an efficient synthetic approach toward the cyanocycline and bioxalomycin alkaloids harnessing their developed silver-catalyzed coupling reaction. 158 This key [C+NC+CC] coupling reaction provided rapid access to highly functionalized pyrrolidines which could be converted to the target in one-third of the total number of steps than previously reported total syntheses. The key coupling reaction was effected by combining aldehyde 780 and Oppolzer’s camphorsultam 781 in methyl acrylate solvent with 10 mol% AgOAc (Scheme 4.84). The [3+2] cycloaddition was proposed to proceed through a pre-TS model such as 782, in which the acrylate dipolarophile approaches the ylide from the least hindered endo-si face approach. The endo-selective asymmetric coupling allowed the construction of pyrrolidine 783 as a single diastereomer. To construct the rest of the natural product scaffold, 783 was subjected to hydrogenolysis to construct the lactam, and removal of the Boc group followed by a Pictet– Spengler reaction with benzyloxyacetaldehyde produced THIQ 784. After protection of the phenol, reduction with LiAlH4 released the chiral auxiliary and converted the carbamate to the required N-methyl group. Oxidation of the primary alcohol 785 allowed construction of the diazobicyclo[3.2.1]octane core followed by cyanide addition to deliver 786. Finally, the oxazolidine ring was constructed from reduction of 786 to the imine that was reacted with hot ethylene oxide in MeOH to afford the late-stage intermediate 787, a late-stage Fukuyama intermediate that was two steps away from the synthesis of cyanocycline A 771. 159 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 616 Alkaloids (2002 – 2020) Bioxalomycin b2 was known to be convertible from 771, demonstrating a formal synthesis of this natural product as well. Overall, the successful application of the asymmetric Agcatalyzed coupling reaction to install functionalized pyrrolidines allowed a rapid approach to this family of natural products. Scheme 4.84 Garner’s formal synthesis of cyanocycline A 771 and bioxalomycin b2 788. Me N + MeO NH2 S O OBn 780 MeO AgOAc (10 mol %) OO 1) H2, Pd/C, MeOH 2) CbzCl, DIPEA Me 3) TFA, CH2Cl2 4) BnOCH2CHO, AcOH 4 Å MS, CH2Cl2 42% yield (4 steps) OBn MeO O COXL OBn 1) BnBr, K2CO3, DMF, 60 °C 2) LiAlH4 THF, 0 °C Me 785 O 786 H N 19% yield (4 steps) H NMe ref. 159 N OH 787 CN OH H N MeO OMe N H H H NMe O O OBn OH 2) TMSCN, ZnCl2 OBn O MeO Ar 53% yield (2 steps) OBn Me Me CbzBnN NHBoc 1) Swern oxidation N H Me NH 784 1) Lawesson’s reagent PhH, reflux H 2) Raney-Ni Me acetone NMe 3) ethylene oxide N MeO MeOH, 60 °C 4) BCl3, CH2Cl2 CN OBn O Ag N H XL = Oppolzer’s L-camphorsultam OMeHN H H O OMeHN H H MeO 40% yield (2 steps) O 782 H N H Cbz NH OH S O 783 OMeHN H H MeO NHBoc Me 781 O N methyl acrylate 74% yield >20:1 dr OMe NH CbzBnN H NHBoc Me Me COXL MeO2C Me Me CHO CbzBnN MeO CN O OH Cyanocycline A (771) O O Me MeO H N H H NMe N H O O Bioxalomycin β2 (788) 4.7. THIQ ALKALOIDS FROM THE QUINOCARCIN FAMILY 4.7.1. GENERAL STRUCTURE AND BIOSYNTHESIS The quinocarcin family of THIQ alkaloids comprise quinocarcin 789, quinocarcinol 790, tetrazomine 791, lemonomycin 792, and aclidinomycins J–K (793–794). 160 These compounds are structurally similar, sharing a piperizinohydroisoquinoline motif, as well as Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 617 Alkaloids (2002 – 2020) a 3,8-diazobicyclo[3.2.1]octane core (Figure 4.25). Quinocarcin and tetrazomine possess an additional oxazolidine ring, while lemonomycin contains a 2,6-dideoxy-4-amino sugar (lemonose) that is rarely found in nature. Compounds within the quinocarcin family display varying levels of antitumor and antibiotic properties. In particular, quinocarcin has exhibited potent antitumor activity against a variety of tumor cell lines and its citrate salt (KW2152) had been in clinical trials in Japan.161 Figure 4.25 General skeleton of THIQ alkaloids in the quinocarcin family. O H B A N R D N C H O N NH Me O OMe N O H H N OH H Me N MeO R= O OH OR Lemonomycin (792) OH O Me NMe2 R H N MeO Me N Tetrazomine (791) O Me OH Quinocarcinol (790) HO OH H H OMe Quinocarcin (789) H Me N O OMe OH H N N 3,8-diazobicyclo[3.2.1]octane core N H H Me N Tetracyclic system OH O H O OH H H Aclidinomycin J (793): R = CO2H Aclidinomycin K (794): R = CH2OH OH OH In 2013, Oikawa and coworkers identified and analyzed the biosynthetic gene cluster (BGC) of quinocarcin and proposed its core assembly mechanism.162 There are five modules (Qcn12, 13, 15, 17, and 19) for quinocarcin non-ribosomal peptide synthetase (NRPS). Of these five modules, Qcn 17 and Qcn 19 are the two responsible for key C–C bond formations. Particularly for Qcn17 which contains Pictet–Spengler (PS) and reduction (RE) domains, this module is SfmC-like and promotes successive Pictet–Spengler/Mannich cyclizations to generate pyrrolidine-substituted tetra-hydroisoquinoline intermediate 799 (Scheme 4.85). Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 618 Alkaloids (2002 – 2020) The reductive release of this species affords an aldehyde, which spontaneously undergoes an intramolecular cyclization to furnish the C-ring of the quinocarcin scaffold (800). In addition to the quinocarcin biosynthetic core assembly mechanism, this study also investigated the biosynthetic pathway for SF-1739, which is a member of the naphthyridinomycin family of THIQ alkaloids. The authors concluded that the mechanisms for the core assembly of these THIQ-pyrrolidine alkaloids are essentially the same but start from amino acids with different substitution patterns on the aromatic portion. Scheme 4.85 Proposed biosynthetic mechanism for the construction of the quinocarcin core. A Qcn13, Qcn12 Qcn15 Qcn17(Red) O Me H O O NH2 m-tyrosine Me O S NH NH 4.7.2. H 2N N H H N NH OH 796 OR 797 S O PCP H N H H H S O NH OH N H O H H N PCP 798 NH C15H31 O NH Qcn17 4,5-dehydroarginine Qcn17 NH OR OH NH H 2N H O OR OH 795 C15H31 PS R= Me O O Red O Qcn17 OH PCP PS Me N H 799 OR OH OH OR 800 TOTAL SYNTHESIS OF QUINOCARCIN ALKALOIDS Toward the synthesis of (–)-quinocarcin (789), Myers and coworkers designed an extended approach of a previous strategy used by their lab to prepare (–)-saframycin A, involving a directed condensation of C- and N-protected ⍺-amino aldehydes.163 N-protected ⍺-amino aldehyde 801, comprising the A- and B-rings of the target, and C-protected ⍺-amino aldehyde 802 were subjected to condensation (Scheme 4.86). Without isolation, the product was treated with DBU to cleave the Fmoc group, then addition of methanolic HCN provided Strecker addition product 803. Treatment of 803 with trimethylsilyl cyanide and ZnCl2 in Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 619 Alkaloids (2002 – 2020) TFE resulted in the cyclization of the C- and D-rings, forming the tetracyclic core 804. Bismethylation, followed by oxidative cleavage of the olefinic side chain and Jones oxidation furnished acid 805. Debenzylation in BCl3 produced quinocarcin and its uncyclized precursor (DX-52-1) 806, and treatment with silver nitrate in aqueous methanol converted the mixture entirely to yield (–)-quinocarcin (789). Scheme 4.86 Myers’ total synthesis of (–)-quinocarcin 789. H A OH B TMS TMS O H NFmoc + H2N N 2) DBU then HCN/MeOH OBn 91% yield (2 steps) O 801 802 H 64% yield (3 steps) H NH 805 N TFE, 60 °C N OBn H H 804 O OH H BCl3 H N Me H CN OH 806 OH H AgNO3 N Me N MeOH, H2O N OMe N D C O O H H CN OBn OH 803 H CN OBn ZnCl2, TMSCN 46% yield OH Me N OMe CN N H CO2H N 1) Cs2CO3, Me2SO4 2) NaIO4, OsO4 3) Jones Reagent H CN 1) NaSO4, CH2Cl2 H CN 70% yield (2 steps) OMe O H (–)-Quinocarcin (789) In 2008, Zhu and coworkers reported the synthesis of (–)-quinocarcin through sequential ring cyclizations, and construction of the bridged bicycle by an intramolecular Mannich reaction using AgBF4.164 Selected as the A-ring scaffold, 3-hydroxybenzaldehyde 807 was converted to benzyl bromide 808 (Scheme 4.87). In the presence of Corey–Lygo’s phase-transfer catalyst (O-(9)-ally-N-(9’-anthracenylmethyl) cinchonidium bromide C6, 808 was used to alkylate N-(diphenylmethylene) glycine tert-butyl ester to produce 809 with >95% ee. A Pictet–Spengler reaction of ester 809 with benzoxyacetaldehyde 810 provided tetrahydroisoquinoline 811, comprising the A- and B-rings. Amine 812 was subsequently acylated with 813 to form THIQ 814. The ester moiety was selectively reduced before Swern oxidation to afford tricyclic hemiaminal 815 as a mixture of diastereomers. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) Scheme 4.87 Zhu’s total synthesis of (–)-quinocarcin 789. Br Br CHO OH OTBS 807 808 CHO Br 1) Ph2C=NCH2CO2t-Bu C6, CsOH●H2O CH2Cl2, —78°C CO2t-Bu NH2 91% yield 79% yield (3 steps) >95% ee B OH C6 NHCbz CO2Me HO2C NH 3) SOCl2, MeOH, reflux 74% yield (3 steps) OBn OMe 812 811 OMe O OBn TBSO 86% yield 2:3 dr 814 Br NCbz OH O OBn Br H TBSO H 88% yield or 62% yield (2 steps) 815 CHO H 1) (COCl)2, DMSO, –78 °C then Et3N, –78 to 0 °C H 2) TIPSOTf, Et3N, Et2O 3) AgBF4, THF N Cbz N OMe CrO3, aq. H2SO4 acetone, 0 °C H O OBn 71% yield 817 O CO2H Cbz N N H OMe 1) PhSH, Hf(OTf)4, CH2Cl2 2) EtSH,Hf(OTf)4, CH2Cl2 O OBn 81% yield 816 71% yield EtSH, Hf(OTf)4, CH2Cl2 or NCbz C N OMe OTBS OH Br N OMe H SEt H DMF, 0 to 23 °C 813 1) LiBH4, MeOH, Et2O 2) (COCl)2, DMSO, –78 °C then Et3N, –78 C to 0 °C N HATU, HOAt, DIPEA + OBn Br Br CO2Me NHCbz O N 809 CO2t-Bu 1) Boc2O, DIPEA, CH3CN 2) Me2SO4, Cs2CO3, acetone NH N CH2Cl2 OH Br A Br 810 OBn 4 Å MS, AcOH 2) THF/AcOH/H2O (1:1:1) 3) TBAF, THF, 0 °C Br 620 O OBn 818 1) Pd/C, H2 (1 atm), MeOH 2) HCHO, HCO2H, NaBH3CN H 3) Li/NH3 (l), THF then 2 N HCl N 83% yield (3 steps) N OMe OH H O Me H (–)-789 815 was then converted to amino thioether 816 in the presence of EtSH and Hf(OTf)4. The undesired diastereomer was recycled in the presence of PhSH and Hf(OTf)4, before subjecting the resulting compound to the previous thioether forming conditions again. A chemoselective Swern oxidation, silyl enol ether formation, and intramolecular Mannich reaction in the presence of silver tetrafluoroborate, an activator of the electrophile and nucleophile, led to a 5-endo-trig cyclization to furnish tetracyclic compound 817 with an exooriented aldehyde moiety. Jones oxidation of 817 followed by global deprotection, N- Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 621 Alkaloids (2002 – 2020) methylation, partial lactam reduction, and ring closure under acidic conditions produced (–)-quinocarcin (789). Harnessing a different approach toward the synthesis of (–)-quinocarcin, Stoltz and coworkers demonstrate the use of an aryne annulation reaction to assemble an isoquinoline precursor toward the THIQ moiety.165 Drawing from the synthetic strategy used by their group to synthesize (–)-lemonomycin (vide infra), Stoltz and coworkers began with the cyclization of a deprotonated oxidopyrazinium bromide 819 with the acrylamide of Oppolzer’s sultam 820 to deliver 821 with 99% ee (Scheme 4.88). Basic methanolysis on the desired diastereomeric product, followed by acylation with benzyloxyacetyl chloride 822 produced imide 823. Regioselective methanolysis at the lactam carbonyl was conducted with yttrium(III) triflate to produce enamine 824. The enamine and aryne precursor 825 were combined in the presence of tetra-n-butylammonium difluorotriphenylsilicate (TBAT) to generate isoquinoline 826. Two consecutive reductions produced separable THIQs, with desired diastereomer 827 as the major product obtained in 55% yield over two steps. After condensation to form the lactam, Pearlman’s catalyst was used to remove the two benzyl groups and methylate the unmasked amine to afford 828. Saponification of methyl ester 828, followed by partial reduction of the lactam and treatment of the resulting hemiaminal with a protic source resulted in ring closure to form the oxazolidine ring and afford (–)-quinocarcin (789). In a convergent approach toward the quinocarcin core, Ohno and coworkers employed a Sonogashira coupling and Au(I)-catalyzed intramolecular alkyne hydroamination to construct the scaffold of the THIQ core. 166 Bromoallene 830 was Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 622 Alkaloids (2002 – 2020) constructed from γ-butyrolactone 829 and treated with NaH to provide 2,5-cis-pyrrolidine 831 (Scheme 4.89). Further transformation produced pyrrolidine 832. Scheme 4.88 Stoltz’s total synthesis of (–)-quinocarcin 789. O Me Me Bn N O2S O 819 N 2) NaOMe, MeOH N Br CO2Me 1) N-Me-morpholine CH3CN, –20 °C O + HN Me BnO 69% yield Bn 60% yield OMe 825 NH MeO OBn 827 2) NaBH3CN, HCl MeOH, 0 °C N OMe MeO OBn O 55% yield (2 steps) 826 O MeO2C N OMe N THF, 40 °C TMS O 1) H2 (1 atm) Pd/C, THF Bn MeO2C Bn O O 823 TBAT + 824 H O MeO2C OTf NH O MeO Bn N BnO 821 N CH2Cl2, 40 °C N 93% yield MeO2C Y(OTf)3, MeOH CO2Me 822 CH2Cl2, 23 °C to reflux O 820 Cl DMAP, Et3N Bn HN 74% yield (2 steps) 99% ee BnO H 1) PhMe, 110 °C 2) CH2O (aq) H2 (1 atm) Pd(OH2)/C, MeOH 79% yield (2 steps) Me N N OMe O OH 828 1) LiOH•H2O THF/H2O H 2) Li, NH3 (l) –78 to –30 °C then 1 N HCl N 81% yield (2 steps) N OMe OH H O Me H (–)-789 Enantioenriched dihydrobenzofuran 834 was prepared from aryl iodide 833. A Sonogashira reaction was then utilized to couple building blocks 832 and 834 to produce coupled product 835. The Boc group was removed prior to Au(I)-catalyzed 6-endo-dig hydroamination using gold catalyst C7 to form the B-ring of the THIQ. Due to the instability of the enamine generated, the product was directly reduced with NaBH3CN without isolation to form secondary amine 836. Upon heating amine 836 in AcOH, condensation of the amine with one of the esters formed the diazobicyclo[3.2.1]octane core of intermediate 837. Treatment of 837 with CsCl enabled ring-opening of the dihydrobenzofuran moiety and subsequent methylation of the phenol generated compound 838. The alkyl halide was finally converted to the alcohol before cyclization to achieve (–)-789. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 623 Scheme 4.89 Ohno’s total synthesis of (–)-quinocarcin 789. 1) NaH, DMF • Br O O AcO OTBDPS 8 steps HO CO2Me 6 steps 2) TBAF, THF NHTs AcO 830 829 MeN TsN 95% yield (2 steps) OH 831 CO2Me 832 MeO2C I I Pd(PPh3)4, CuSO4 sodium ascorbate NHBoc CHO 833 O 92% yield 834 835 MeO2C NH CO2Me Me AcOH N N PhMe, 80 °C 96% yield O O H O 1) AgNO3, Et3N acetone/H2O (3:1) 50 °C H then CsCl, 60 °C 2) Me2SO4, Cs2CO3 H CO2Me H Me N N H OMe Cl 86% yield (2 steps) O 838 H Me N OMe 88% yield (3 steps) OH N 2) LiOH•H2O THF/H2O (2:1) 3) Li, NH3 (l), THF –78 to –30 °C 3) NaBH3(CN) 1 N HCl MeOH, 0 °C 1) BF3•Et2O SiCl4, 1,2-DCE O 837 836 1) TFA, CH2Cl2 2) C7 (20 mol %) 1,2-DCE CO2Me H N Me CO2Me NHBoc DMF/Et3N (3:2) O F N Me 832 8 steps (t-Bu)2P Au CN O SbF6 H C7 39% yield (3 steps) 4.7.3. (–)-Quinocarcin (789) TOTAL SYNTHESIS OF TETRAZOMINE In 2002, Williams and coworkers utilized a [1,3]-dipolar cycloaddition in the synthesis of antitumor antibiotic (–)-tetrazomine 791 and its analogues (Scheme 4.90).167 Starting with the ring-opening of aryl epoxide 839 using sodium azide, the resulting alcohol was protected and the azide was hydrogenated to afford amine 840. A nitro group was then installed ortho to the pre-existing methoxy group and subsequent hydrolysis of the trifluoroacetamide furnished primary amine 841. Alkylation of the amine with bromoacetaldehyde diethylacetal 842 provided secondary amine 843, which was acylated with 844 to produce amide 845. The nitro group was hydrogenated using PtO2, and the resulting aniline underwent acid-promoted cyclization to yield dihydroisoquinoline 846. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 624 Scheme 4.90 Williams’ total synthesis of (–)-tetrazomine 791. OEt Br 1) NaN3, acetone/H2O 2) NaH, THF then BnBr, KI NH2 O 3) Pd/C, H2, EtOH OMe OMe 82% yield (3 steps) 839 NH2 O2N OMe OBn 56% yield (2 steps) OEt OBn Fmoc N B MeO2CHN OMe H Me N Ra-Ni, EtOH O OBn 90% yield NMe 35% yield (2 steps) 5:1 dr CO2t-Bu N 1) (COCl)2, DMSO, –78 °C then Et3N, –78 to 23 °C Me 2) DBU, THF 3) NaBH4, EtOH N MeO2CHN OMe CO2t-Bu H N Me 48% yield (3 steps) O OH 40% yield (3 steps) O OH H H 2N N OMe 853 Cl Me CN OTIPS Me 1) TFA, 4 °C 2) 5% aq. HF, MeCN 2) DBU, CH2Cl2 CN OTIPS 72% yield (2 steps) 1:1 dr HO H OH H N O 3) AgOCOCF3, TFA, MeCN 4) Amberlyst Cl resin NH 26% yield (4 steps) 852 DMAP, CH2Cl2 N H N O NFmoc 851 TIPSO H OMe t-BuO H N 850 O 1) TIPSO 1) LiAlH3OEt, THF, 0 °C then KCN, AcOH 0 to 23 °C 2) TIPSCl, imidazole, THF 3) 2 M LiOH, THF, reflux N 1) NBS, CHCl3, 61 °C 2) t-butyl acrylate Et3N, 0 to 23 °C 849 H NH C O OBn H H2 (100 psi) 848 N H N CO2t-Bu N OMe 89% yield (3 steps) 847 H MeO2CHN 2) 6 N HCl, dioxane, 90 °C 3) MeOCOCl, py, CH2Cl2 Me 87% yield (3 steps) 846 OMe N O OBn 845 3) AgOCOCF3, TFAA TFA, ClCH2CH2Cl, 83 °C O OBn MeO2CHN Fmoc Me 1) pyrrolidine, MeCN 2) ICH2CN, DIPEA, THF N MeO2CHN OMe OMe 82% yield 843 A N O2N CH2Cl2 OMe 1) H2 (60 psi), PtO2 THF/EtOH (1:1) OEt 844 DMAP NH O2N 74% yield NFmoc Cl OEt OBn MeCN, 82 °C 841 Me O OEt K2CO3 2) 2 M LiOH THF/EtOH (1:1) 840 OEt t-BuO 842 1) KNO3, TFAA CH2Cl2, –20 °C N H • 2 HCl N OMe Me O (–)-Tetrazomine (791) Cyclization of amine 846 then proceeded by treatment with Ag(I)trifluoroacetate in the presence of TFA and TFAA to deliver allylic amine 847 through a speculated 6-exo-tet process. The amine 847 was then refluxed in chloroform with NBS to yield an iminium species that was treated with triethylamine and tert-butyl acrylate, producing ester 848 with 5:1 dr. Hydrogenation afforded 849, while the undesired diastereomer was epimerized and hydrogenated to produce the same product. Swern oxidation and treatment with DBU Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 625 Alkaloids (2002 – 2020) produced epimerized compound 850. Subsequent reduction followed by trapping of the resulting carbinolamine afforded the aminonitrile moiety. TIPS protection of the two primary alcohols followed by hydrolysis of the methyl carbamate afforded aniline 851. Acid chloride 852 was prepared in three steps and coupled with aniline 851 in the presence of DMAP. Subsequent cleavage of the Fmoc group with DBU afforded 853 with 1:1 dr, which were isolable and carried on separately. Treatment of aminonitrile 853 with silver trifluoroacetate induced cyclization to form the oxazolidine ring, and addition of Amberlyst ion-exchange resin (Cl– form) followed by filtration and lyophilization afforded tetrazomine 791. The other diastereomer of 853 was treated to the same steps to afford ent, epi-tetrazomine 791. In attempts to probe the biological activity of tetrazomine and its analogues, several novel analogues were prepared as shown in Scheme 4.91. Late-stage intermediate 854 was coupled to N-Fmoc-L-pipecolic acid chloride 855 followed by cleavage of the Fmoc and TIPS groups to afford both diastereomers 856 and 857 with 1:1 dr. Treatment of both isomers with AgOCOCF3 and TFA afforded two deoxytetrazomine analogs 858 and 859. Scheme 4.91 Williams’ synthesis of tetrazomine analogues. H Cl H N NH N NH N H N OMe Me H O • 2 HCl 858 + diastereomer 859 N H N + N O H CN OMe H Me NH N H N OH 857 Me H CN OMe OH H O HO H N 856 HO H 75–78% yield H HO H O 23% yield (2 steps) 1:1 dr 854 AgOCOCF3 TFA MeOH:H2O 855 DMAP, CH2Cl2 2) DBU, CH2Cl2 3) HF, CH3CN CN OTIPS OMe NFmoc Me N H 2N O 1) TIPSO Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 626 Alkaloids (2002 – 2020) To examine the interaction of tetrazomine 791 and analogues 858–859 with DNA cleavage, these compounds were incubated with a synthetic 32P-5’-end-labeled 45 bp duplex at pH 7 in phosphate buffer. While some analogues did not exhibit any DNA damage, tetrazomine 791 did display DNA cleavage in a non-sequence-specific manner. Additionally, all four oxazolidine and aminonitrile analogues were assayed against a Gram-(+) bacteria (Staphylococcus aureus) and a Gram-(–) bacteria (Klebsiella pneumoniae) via the disk diffusion method. Interestingly, deoxy compounds 858 and 859 displayed slightly better activity than either tetrazomine 791 or ent, epi-tetrazomine. 4.7.4. TOTAL SYNTHESIS OF LEMONOMYCIN While there have been reports toward the formal synthesis of lemonomycin,168 Stoltz and coworkers demonstrated a total synthesis of (–)-lemonomycin employing a stereoselective dipolar cycloaddition and diastereoselective Pictet–Spengler cyclization to form the tetracyclic compound. 169 Cyclization of deprotonated bromide salt 860 with Oppolzer’s sultam-derived acrylamide 861 provided bicycle 862 with high ee (Scheme 4.92). Enamide 862 was then converted to a silyl ether and treated with ICI to produce Ziodoenamide 863. Suzuki coupling with aryl boronic ester 864 provided aryl enamide 865 and subsequent hydrogenation and protection of the amine and phenol produced amide 866. Aminotriol 867 was accessed in three steps with 81% overall yield from simultaneous activation of the amide and protection of the phenol with Boc2O, reduction with NaBH4, and cleavage of the Boc and TIPS moieties using methanolic HCl. Aldehyde 868 was separately prepared in eight steps (not shown) for Pictet–Spengler reaction with aminotriol 867 to deliver THIQ 869. Hydrogenolytic cleavage of the Cbz group, Swern oxidation, and treatment with CAN ultimately provided (–)-lemonomycin 792. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 627 Scheme 4.92 Stoltz’s total synthesis of (–)-lemonomycin 792. HO Me Me Bn N Me O + HN O2S O 860 2) ICI, CH2Cl2, 0 °C Me Bn 862 B + HN TIPSO OMe Me O Me 863 69% yield OTs N Cbz 1) Boc2O, DMAP MeCN H 2) NaBH4, EtOH 3) HCl, MeOH O Me N MeO 81% yield (3 steps) OH + OH OH 867 868 HO OMe H N Cbz NH MeO OH O OH 2) (COCl)2, DMSO, Et3N –78 to 0 °C then HCl (aq) 3) CAN (aq), 0 °C Me OH O 869 Me Me NMe2 20% yield (3 steps) OH O 95% yield H N MeO Me NMe2 EtOH, 23 °C OH H N 1) H2, Pd/C, TFA, EtOH Me O O HO Me O Cbz NH2 866 OMe 63% yield (3 steps) O OMe H OH 3) KOTMS, MeCN HO HN MeO 1) H2 (1 atm), Pd/C TFA, EtOH 2) CbzCl, DMAP, MeCN 865 864 TIPSO OMe N Bn HN MeO OTs O Me Pd(PPh3)4, K2CO3 PhH, MeOH, 70 °C MeO Me 66% yield (2 steps) O Me Me OMe O N 1) TIPSOTf, CH2Cl2 2,6-lutidine Bn HN 72% yield (2 steps) 94% ee 861 TIPSO I N 2) NaBH4, EtOH N Br 1) N-Me-morpholine CH3CN, –20 °C (–)-Lemonomycin (792) OH Me OH O Me NMe2 Toward the synthesis of (–)-lemonomycin, Fukuyama and Kan and coworkers chose to couple the lemonose unit with the tetracyclic aglycon alkaloid subunit through a glycosidation reaction. 170 Oppolzer’s chiral auxiliary 870 was transformed to diketopiperazine 871 in four steps (Scheme 4.93). Diketopiperazine 871 was subjected to a Perkin condensation reaction with 872 to give Z-enamide 873, which was reduced and treated with TFA to produce cyclized product 874. Following several functional group transformations, the B-ring was constructed through a Pictet–Spengler reaction of 875 with cinnamaldehyde in the presence of CSA and TMSCN at 100 °C to deliver THIQ 876. A onepot conversion of 876 to aglycon alkaloid 877 was achieved through acetylation of the phenol Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 628 Alkaloids (2002 – 2020) group, ozonolysis, and subsequent reduction. Key intermediate 877 was coupled with functionalized lemonose 878 by treatment with TMSOTf and Drierite at –40 °C to deliver 879. After several functional group manipulations, exposure of primary alcohol 880 to Swern oxidation produced the geminal diol, and hemiaminal installation followed by CANmediated oxidation of the A-ring produced (–)-lemonomycin 792. Scheme 4.93 Fukuyama and Kan’s total synthesis of (–)-lemonomycin 792. Me Me OMe O Me Ph N SO2 N NBoc 4 steps O 872 O Me NBoc HN OMs O OMe 1) H2, Pd/C, quinoline, EtOH 2) NaBH4, MeOH, 0 °C Me 3) TFA, CH2Cl2, 0 to 20 °C 4) CbzCl, NaHCO3, CH2Cl2 MeO H H Me H OMs O 874 OTBDPS H H Me H OH 92% yield CN 1) Ac2O, pyridine 2) O3, CH2Cl2/MeOH, –78 °C Cbz 3) NaBH4, –78 °C N MeO 875 H N MeCN, 100 °C HN MeO OMe cinnamaldehyde CSA, TMSCN Cbz N 5 steps HN TMS OTBDPS OMe Cbz N 51% yield (4 steps) 873 96% yield OMs 871 870 MeO MeCN, –10 °C MeO O OMe t-BuOK, 4Å MS TMS + BocN Ph CHO H OH 84% yield (3 steps) CN 876 Ph OTBDPS TBDPSO OMe H Me H O + N Me H OAc CN OH 877 OTBS Me NMe2 CH2Cl2, –40 °C 3 steps H H H N N MeO H MOMO CN Me O N MeO H OAc O 86% yield 5:1 ⍺:β OTBS O OMe 1) (COCl)2, Et3N, DMSO –78 to 0 °C 2) 2 M HCl Me Me NMe2 880 Me NMe2 3) AgNO3, CH3CN/H2O 4) CAN, H2O, 0 °C MeO 879 OH H N H N OH O OH OH O CN Me HO 32% yield (4 steps) Cbz N OH OMe H TMSOTf, Drierite 878 Me H Me Cbz N MeO OMe F Me OH O Me NMe2 (–)-792 Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002 – 2020) 4.8 CONCLUSIONS 629 The THIQ natural products are one of the most prominent family of alkaloids that exhibit a diverse range of biological activity as well as structural complexity. It is noteworthy that from simple benzyl THIQ alkaloids to complex ecteinascidin THIQ natural products, all possess interesting biological properties and reactivity that are of great interest to synthetic, biological, and medicinal chemists. From 2002–2020, research in the total synthesis of THIQ alkaloids has advanced greatly, especially in the development of novel methodologies that enable creative synthetic approaches to these molecules. Not only do these modern chemical methods allow efficient chemical syntheses, but they also provide access to a library of natural product analogues to uncover more of their biological activity. Their challenging molecular architecture along with their important therapeutic effects will surely continue to drive research to develop novel reactions toward their chemical syntheses and uncover new biosynthetic pathways. As of yet, there are still several families of natural products of which their biosynthesis is not fully understood, and the chemical syntheses of some THIQ alkaloids have not yet been explored. Thus, this review hopefully serves as a guide for the recent developments in THIQ alkaloid chemistry, and also addresses some of the remaining challenges in the synthesis of this family of natural products for further medicinal and biological advancement. 4.9 (1) REFERENCES AND NOTES Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The Chemistry and Biology of Isoquinoline Alkaloids; Springer, 1985. Chapter 4 – Advances in the Total Synthesis of the Tetrahydroisoquinoline 630 Alkaloids (2002 – 2020) (2) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Chem. Rev. 2016, 116, 12369–12465. (3) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–1730. (4) Cassels, B. K. Nat. Prod. Commun. 2019, 14, 85–90. (5) Fahmy, N. M.; Al-Sayed, E.; El-Shazly, M.; Singab, A. N. Nat. Prod. 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(170) Yoshida, A.; Akaiwa, M.; Asakawa, T.; Hamashima, Y.; Yokoshima, S.; Fukuyama, T.; Kan, T. Chem. Eur. J. 2012, 18, 11192–11195. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 645 CHAPTER 5 Progress Toward the Total Synthesis of (+)-Cyanocycline A† 5.1 INTRODUCTION The tetrahydroisoquinoline (THIQ) alkaloids make up one of the largest groups of natural products with a wide range of structural diversity and biological activity. 1 In particular, THIQ alkaloids of the naphthyridinomycin family have long served as challenging synthetic targets due to their structural complexity and significant bioactivity as antibiotic and antitumor agents (Figure 5.1).2 Its congeners possess a hexacyclic carbon framework containing the THIQ core, a pyrrolidine-bridged ring, and a labile oxazolidine moiety as the F-ring. Members of this family include naphthyridinomycin (770), cyanocyclines (771–772, 775), bioxalomycins (773–774), aclindomycins (776–777), and dnacins (778–779). In 1982, cyanocycline A (771) was isolated from the fermentation broth of Streptomyces flavogriseus No. 49 that displayed significant antibiotic and antitumor activity.3 Cyanocycline A (771) possesses a caged, hexacyclic scaffold that is characterized by the aminonitrile moiety at C(22) in place of a carbinolamine or hydroxyl functionality ________________________________________________ † This research was performed in collaboration with Camila Suarez and Dr. Veronica Hubble. Early synthetic efforts were conducted by Dr. Eric Welin and Dr. Nick Hafeman. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 646 (Figure 5.2). Cyanocycline A (771) contains eight stereocenters, five of which are contiguous stereocenters centered on the piperidine E-ring. Three basic tertiary amines, a quinone, aminonitrile, and oxazolidine moieties are particularly distinguished functionalities of cyanocycline A that render this natural product a formidable synthetic challenge. Figure 5.1 General skeleton of THIQ alkaloids in the naphthyridinomycin family and examples. NR O F N A B C N E B D NR N C E N A Hexacyclic skeleton D F O Quinone/hydroquinone A-ring Central piperazine subunit Oxazolidine moiety O O O Me H N H H Me NMe N R 2O O OH N H H NR N MeO OH R1 OH H O H Naphthyridinomycin (770) : R1 = OH, R2 = Me Bioxalomycin α1 (773) : R = H Cyanocycline A (771) : R1 = CN, R2 = Me Bioxalomycin α2 (774) : R = Me Cyanocycline F (772) : R1 = CN, R2 = H O HO CN Me OH N H H O H NMe N MeO OH CN OH Cyanocycline D (775) Me O H N OH H O H NMe H N MeO O H H H NMe O R N N H 2N O H R OH Dnacin A1 (778) : R = CN Aclindomycin A (776) : R = H Aclindomycin B (777) : R = OH Dnacin B1 (779) : R = OH Figure 5.2. Structure of Cyanocycline A (771). O F N Me O H E 28 21 A MeO BH N C N Me D 22 O CN OH (+)-Cyanocycline A (771) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 647 The biosynthesis of cyanocycline A and related congeners was studied by Zmijewski and coworkers, where they discovered through feeding experiments that the core structure was assembled from tyrosine, methionine, glycine or serine, and ornithine.4 Later in 2013, the Tang group analyzed the naphthyridinomycin gene cluster and proposed a pathway for the core formation via nonribosomal peptide synthetase (NRPS) NapL and NapJ modules.5 The completed biosynthetic pathway, especially how the five-membered bridged ring is formed in the core structure, however, still have not been fully elucidated in this study. To date, only two completed syntheses of cyanocycline A have been reported by Evans and coworkers in 1986,6 and Fukuyama and coworkers in 1987.7 Both groups have later reported an asymmetric synthesis of (+)-cyanocycline A (771) utilizing a similar synthetic strategy, accomplishing the synthesis of the natural product in over 30 linear steps. 8,9 More recently, Garner and coworkers disclosed an efficient formal synthesis of cyanocycline A (771) and the bioxalomycin alkaloids harnessing their developed silvercatalyzed [C+NC+CC] coupling reaction (Scheme 4.83, vide supra). 10 Thus, the natural product scaffold was efficiently synthesized in one-third of the total number of steps than the previously reported total syntheses, constituting a formal synthesis of cyanocycline A (771) and bioxalomycin b2 (788). While these previously reported strategies pioneered the syntheses of the naphthyridinomycin alkaloids, they all feature electrophilic aromatic substitution chemistry for the construction of the THIQ core. Alternatively, we envision a novel, nonbiomimetic route to these alkaloids that could construct the natural product scaffold with high efficiency harnessing modern transition-metal catalysis. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 5.2 648 RETROSYNTHETIC ANALYSIS Inspired by our development of an asymmetric hydrogenation technology to reduce heteroaryl-substituted isoquinolines, we sought to target cyanocycline A (771) by a key global hydrogenation event of a pyrrole-substituted isoquinoline intermediate (Chapter 2– 3, vide supra). To this end, our first retrosynthetic analysis accessed cyanocycline A (771) by oxidation of arene 881 to afford the quinone, and aminonitrile formation via partial lactam reduction and cyanide trapping (Figure 5.3). To construct the piperidine E-ring, we envision a late-stage benzylic oxidation event of phenol 883 to generate an ortho-quinone methide intermediate 882 in situ, enabling cyclization of the pendent oxazolidine ring to afford the hexacyclic scaffold 881. Usage of highly reactive ortho-quinone methide intermediates for the construction of complex natural products have been precedented, including the total synthesis of a THIQ alkaloid Et-743 (184) reported by Corey and coworkers.11,12 Phenol 883 will be accessed from arene oxidation of THIQ 884, with reduction of the oxazoline ring to deliver the oxazolidine, which we anticipate will reduce from the more sterically accessible convex face. Oxazoline formation and cyclization of the secondary amine onto the pendent methyl ester of the pyrrolidine ring in 885 then delivers 884. THIQ 885 is then forged from a key asymmetric hydrogenation event of isoquinoline 886, utilizing our developed hydrogenation technology to sequentially reduce both the isoquinoline and pyrrole ring that could potentially enable cyclization to the amide as well.13 Finally, a cross-coupling event of two heterocyclic fragments 887 and 888 followed by allylic oxidation will afford the key hydrogenation precursor 886. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 649 Figure 5.3. Initial retrosynthetic analysis of (+)-cyanocycline A (771). O O O O N H Me N H Me H aminonitrile formation MeO OMe CN OH O H Me oxidation N MeO N OH (+)-Cyanocycline A (771) Me N HN H N H MeO O OH OMe 882 N H OMe H H MeO OMe N NH MeO2C H MeO OMe O OH Me N H NH MeO OMe OH N O OH oxazoline formation Me N cyclization asymmetric CO2Me hydrogenation Boc HO Me N N MeO OMe OH CO2Me Boc OH 886 cross-coupling 5.3 Me O OH 885 allylic oxidation N 884 HO Boc H Me reduction 883 Me N arene oxidation Me N MeO N O H Me H Me 881 OH HO O cyclization O benzylic oxidation HN Me HO OTf N MeO + X N OMe Me R 887 888 CO2Et FIRST GENERATION APPROACH First, we focused on forging the C(21)–C(28) bond of the natural product from two heterocyclic fragments (Figure 5.2). The synthesis of the isoquinoline fragment (887) utilizes aryne annulation methodology extensively developed in our lab, with applications in the total synthesis of jorumycin (Scheme 5.1).14 Our synthesis of isoquinoline triflate 887 began with an iridium-catalyzed borylation of 2,3-dimethoxytoluene 889, followed by oxidation and carbamate installation to deliver arene 890 in 79% overall yield. Silylation of the arene then proceeded through a carbamoyl-directed ortho-metalation event with nBuLi, then trapping with TMSCl to afford arene 891 in 93% yield. Next, the aryne Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 650 precursor was accessed from carbamate cleavage and triflation of the intermediary phenol to synthesize the silyl triflate 892 in 99% yield. Silyl aryl triflate 892 was then treated with cesium fluoride to generate the aryne intermediate in situ, which underwent aryne acylalkylation with in situ condensation to deliver 3-hydroxy-isoquinoline 893 in a range of 20–45% yield. Finally, triflation of isoquinoline 893 with trifluoromethanesulfonic anhydride provided the electrophilic coupling partner 887 in 94% yield. Scheme 5.1. Synthesis of the western isoquinoline fragment 887. Me [Ir(cod)OMe]2 (5 mol %) 3,4,7,8-tetramethylphenanthroline (10 mol %) B2pin2 (0.75 equiv), THF, 80 °C MeO then NMO, 80 °C then NEt3, i-PrNCO OMe 889 Me O MeO O MeO O TMS NHi-Pr 890 Me OMe MeO 99% yield Me OH N MeO OMe Me 893 methyl acetoacetate CsF, CH3CN, 80 °C TMS then aq. NH4OH, 60 °C OMe 20–45% yield 892 891 Me 93% yield OTf Et2NH, n-BuLi PhNTf2, THF, –78 °C TMEDA, TBSOTf, n-BuLi then TMSCl, Et2O, –78 °C OMe 79% overall yield Me NHi-Pr O OTf Tf2O, pyridine CH2Cl2, 0 °C 94% yield N MeO OMe Me 887 On the other hand, synthesis of the pyrrole fragment commenced from commercially available ethyl 1H-pyrrole-2-carboxylate 894 which underwent Vilsmeier– Haack formylation to deliver C3-substituted aldehyde 895 in 99% yield (Scheme 5.2).15 Treatment of 895 with Br2 installed the bromide 896 at the C2-position to serve as a functional handle for the key cross-coupling event. Then, subsequent N-methylation using dimethyl sulfate provided pyrrole 897 in 90% yield, which was then reduced with NaBH4 to afford alcohol 898.16 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 651 Scheme 5.2. Synthesis of the eastern pyrrole fragment 898. O O N H CO2Et dichloromethyl methyl ether AlCl3 (2 equiv) 1:1 CH2Cl2:MeNO2, –15 °C 894 Br2 N H CO2Et 895 99% yield CH2Cl2, 0 → 23 °C Br CO2Et N H 896 74% yield HO O (MeO)2SO2, K2CO3 NaBH4 Br CH3COCH3 N CO2Et Me 90% yield MeOH:CH2Cl2 Br CO2Et Me 99% yield 897 N 898 With the two coupling partners in hand, we then explored the first key crosscoupling event of heterocycles 887 and 898. We were inspired by Molander and coworkers’ report on a one-pot Miyaura borylation and Suzuki cross-coupling method between aryl and heteroaryl halides, which we envisioned could be applicable to our system.17 Thus, treatment of pyrrole 898 with XPhos Pd G2 catalyst, XPhos ligand, KOAc, and bis-boronic acid underwent Miyaura borylation to generate the boronic acid in situ, followed by addition of isoquinoline triflate 887 to effect a Suzuki cross-coupling event of the two heterocycles (Scheme 5.3). Scheme 5.3. One-pot Pd-catalyzed borylation/Suzuki cross-coupling reaction of heterocycles 887 and 898. Me HO OTf N MeO + Br N Me 1 equiv OMe Me 1.2 equiv CO2Et EtO XPhos-Pd-G2 (X mol %) XPhos (Y mol %) B2H4O4 (3 equiv) EtOH, KOAc (3 equiv), 80 °C Me then 887, K2CO3, 80 °C, 24 h MeO N N Me OMe Me 898 887 CO2Et 899 entry conditions results 1 X = 1 mol % Y = 2 mol % 13% yield of 899 44% conversion of 887 2 X = 5 mol % Y = 10 mol % 19% yield of 899 43% protodetriflation of 887 Initially, we observed that employing 1 mol % of the palladium catalyst afforded 13% yield of cross-coupled product 899, with concomitant expulsion of the hydroxyl group Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 652 and ethanol addition to the iminium generated (entry 1). Increasing the catalyst loading to 5 mol % afforded full conversion of isoquinoline triflate 887, but with only 19% yield of product 899 and 43% yield of protodetriflation observed (entry 2).18 Thus, we turned to other cross-coupling strategies to improve the convergent coupling of the two heterocyclic fragments. We next investigated Stille cross-coupling reactions to improve the key crosscoupling event. To this end, pyrrole 895 was protected with a Boc group instead to provide pyrrole 900 in 98% yield, followed by reduction of the aldehyde to deliver alcohol 901 in 99% yield (Scheme 5.4). Next, a-lithiation of the pyrrole directed by the Boc group was performed using LiTMP, and the generated lithiated species was trapped with Bu3SnCl to deliver the nucleophilic coupling partner 902 in 91% yield.19 Scheme 5.4. 2nd generation synthesis of pyrrole fragment 902. HO O O Boc2O, DMAP N H CO2Et 895 N CH2Cl2 CO2Et NaBH4 MeOH:CH2Cl2 Boc 98% yield 900 99% yield N CO2Et Boc 901 HO TMP, n-BuLi THF, –78 °C then Bu3SnCl Bu3Sn N CO2Et Boc 91% yield 902 With the revised pyrrole coupling partner 902, we then explored Stille crosscoupling conditions. Gratifyingly, employing Pd(PPh3)4 and CuTC as an additive produced the desired cross-coupled product 903 in 43% yield (Scheme 5.5, entry 1). 20 Further optimization of the reaction conditions using 1:1 equivalents of both partners, increased concentration, and extended reaction time improved the yield to 68% on a 2 mmol scale (entry 2). Having developed a convergent coupling reaction to access a highly Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 653 functionalized pyrrole-substituted isoquinoline 903, we were then poised to explore our key asymmetric hydrogenation step. Scheme 5.5. Stille cross-coupling of heterocycles 887 and 902. HO Me OTf N MeO HO + Bu3Sn OMe Me N Boc Y equiv X equiv CO2Et Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP (Z M), 25 °C MeO N CO2Et Boc OMe Me 903 902 887 N entry conditions results 1 X = 1.1 equiv Y = 1 equiv Z = 0.05 M, 2 h 43% yield 2 X = 1 equiv Y = 1 equiv Z = 0.06 M, 3 h 2 mmol scale 68% yield We first installed the hydroxymethyl functionality at the C1 position of the isoquinoline to assist directing the asymmetric hydrogenation.13 Allylic oxidation using SeO2 followed by reduction of the aldehyde intermediate with NaBH4 delivered isoquinoline 904 in 61% yield over 2 steps (Scheme 5.6). Then, we subjected isoquinoline 904 to our optimized asymmetric hydrogenation conditions using [Ir(cod)Cl]2, 4-methoxy3,5-dimethylphenyl-substituted (DMM) Josiphos ligand L7, TBAI, and 60 bar of H2. However, even after a reaction time of 42 hours at 80 °C, we mostly observed unreacted starting material, and 38% elimination of the C3-hydroxyl group on the pyrrole ring. Briefly surveying the 3,5-bis(trifluoromethyl)phenyl-substituted (BTFM) phosphine ligand L6 optimized for the jorumycin synthesis also resulted in poor conversion of isoquinoline 904 and expulsion of the hydroxyl group. Overall, having the alcohol oxidation state at the C3-position of the pyrrole ring proved to be incompatible with our Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 654 key hydrogenation reaction, prompting us to explore other functionalities that could be later utilized to install the oxazoline ring. Scheme 5.6. Key asymmetric hydrogenation of pyrrole-substituted isoquinoline 904. HO HO Me N N MeO CO2Et Boc OMe Me 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO Boc N OMe 61% yield over 2 steps 903 CO2Et N OH 904 Me [Ir(cod)Cl]2 (10 mol %) ligand (21 mol %), TBAI (60 mol %) H2 (60 bar) 9:1 THF:AcOH, 80 °C, 42 h Me X NH MeO 34% yield of unreacted SM 38% conversion to 905 CO2Et N OMe P(Ar)2 P(Xyl)2 Fe Boc Me L6: Ar = BTFM L7: Ar = DMM OH 905 Instead, we envisioned installing a methyl ester at the C3-position of the pyrrole fragment by subjecting pyrrole 900 to a Pinnick oxidation, accessing the carboxylic acid 906 (Scheme 5.7). Then, subsequent methylation of the acid delivered methyl ester 907 in 89% yield over 2 steps. From pyrrole 907, a-lithiation and stannylation conditions proceeded efficiently to deliver organostannane 908 in 90% yield. Having the methyl ester functionality at the C3-position serves not only to circumvent hydroxyl elimination pathways, but also to induce a stronger electron-withdrawing effect for pyrrole hydrogenation to be feasible. Scheme 5.7. 3rd generation synthesis of pyrrole fragment 908. O MeO2C HO2C N CO2Et Boc NaClO2, KH2PO4 sulfamic acid N 1,4-dioxane:H2O 906 MeO2C then Bu3SnCl 90% yield (MeO)2SO2, K2CO3 CH3COCH3 Boc 900 TMP, n-BuLi THF, –78 °C CO2Et Bu3Sn N Boc 908 CO2Et 89% yield over 2 steps N Boc 907 CO2Et Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 655 We then revisited the Stille cross-coupling of heterocyclic fragments 887 and 908 to advance to the key hydrogenation precursor (Scheme 5.8). We were pleased to see that we could even further optimize the Stille coupling to obtain a 96% yield of cross-coupled intermediate 909 employing 1:1 equivalents of both coupling partners. Further elaboration of the C1-substituent of the isoquinoline using the same oxidation sequence afforded the hydroxymethyl group 910 in an improved 75% yield over 2 steps. With a more efficient synthetic route to access hydrogenation precursor 910, we were poised to extensively investigate our key hydrogenation step. Scheme 5.8. Stille cross-coupling and synthesis of hydrogenation precursor 910. MeO2C Me MeO2C OTf N MeO + Bu3Sn OMe Me 1 equiv 887 N CO2Et Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP, 25 °C MeO Boc 1 equiv 96% yield 908 N N CO2Et Boc OMe Me 909 MeO2C 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO 75% yield over 2 steps N N OMe CO2Et Boc OH 910 First, we investigated iridium-catalyzed asymmetric hydrogenation conditions for the reduction of isoquinoline 910. Using optimized conditions for the jorumycin synthesis, we observed only a 40% yield of the THIQ product 911, but no trace of pyrrole hydrogenation after 42 hours at 80 °C (Scheme 5.9A).14 Instead, we observed Bocmigration product 912 from the protected nitrogen atom to the hydroxyl group, likely occurring due to the stronger electron-withdrawing effect of the pyrrole ring that enables Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 656 facile abstraction of the Boc group.21 Revealing the unprotected NH-pyrrole then impedes further hydrogenation presumably due to catalyst deactivation.22 Scheme 5.9. Key asymmetric hydrogenation attempts of isoquinoline 910. MeO2C A. Me N N MeO OMe CO2Et [Ir(cod)Cl]2 (10 mol %) OMe 911 + 9:1 THF:AcOH, 80 °C, 42 h MeO2C 40% conversion to THIQ 911 44% Boc-migrated pdt 912 OH 910 P(Ar)2 Me P(Xyl)2 Fe Me MeO2C Me N N MeO OMe Boc OH 910 CO2Et Ru(methylallyl)2(cod) (20 mol %) L12 (21 mol %), NEt3 (2 equiv) H2 (60 bar) i-PrOH, 80 °C, 42 h OMe CO2Et OBoc 912 MeO2C Me N X NH MeO 52% recovered SM 17% Boc-migrated pdt 912 N H N MeO L6: Ar = BTFM L12: Ar = Ph B. OH L6 (21 mol %), TBAI (60 mol %) H2 (60 bar) Boc CO2Et Boc NH MeO MeO2C Me N OMe CO2Et Boc OH 911 We also employed other asymmetric hydrogenation conditions, such as a ruthenium catalyst system developed by Kuwano and coworkers for the asymmetric hydrogenation of 2,3,5-trisubstituted pyrroles (Scheme 5.9B).23 However, we did not detect any reduction under the optimized Ru-catalyzed conditions, employing Ru(methylallyl)2(cod) and Phsubstituted Josiphos ligand L12, and instead recovered 52% of starting material and observed 17% yield of the Boc-migrated product 912.24 It became clear to us at this stage of the synthesis that the pyrrole ring was difficult to hydrogenate under these asymmetric hydrogenation conditions, and that hydrogenation precursor 910 was generally unreactive to undergo reduction. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 657 To better understand the reactivity of isoquinoline precursor 910 and whether the system can be reduced, we investigated heterogeneous hydrogenation conditions utilizing a variety of metal catalysts. Under 60 bars of H2 in AcOH, we observed mostly DHIQ intermediate 912 using 1 equivalent of PtO2, however we were pleased to see we could access the fully hydrogenated product 915 of both the isoquinoline and pyrrole rings (Scheme 5.10). Using Pd/C as catalyst afforded a range of byproducts, including both the Boc-protected and deprotected THIQ 911 and 913, respectively (entry 2). Gratifyingly, when using Rh/C as catalyst, we could now achieve 47% conversion of the fully hydrogenated intermediate 915, and additionally observe trace amounts of the cyclized product 916 from the secondary amine condensing onto the ethyl ester. Overall, Rh/C and PtO2 provided cleaner reaction profiles, but provided significant amounts of deprotected byproducts under acetic acid solvent and heat. We next investigated different solvents of the heterogeneous hydrogenation to suppress any deprotection pathways of the Boc group that impedes further hydrogenation (Scheme 5.11). Using 5% Rh/C and acetic acid as solvent, we observe 27% conversion to the fully hydrogenated intermediate 915 as well as the deprotected THIQ 913 and DHIQ 914 (entry 1). However, under less acidic solvents such as HFIP and TFE, there was no conversion to pyrrolidine 915, instead resulting in high levels of deprotected THIQ 913 and DHIQ 914 (entries 2 & 3). On the other hand, little conversion to the deprotected byproducts 913 and 914 was observed using PtO2 in less acidic solvents. Under TFE Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 658 solvent, hydrogenation to the pyrrolidine 915 occurred in 5% conversion, as well as 50% conversion to THIQ intermediate 911 (entry 6). Scheme 5.10. Heterogeneous hydrogenation investigation of isoquinoline 910.a MeO2C Me N Boc N MeO OMe heterogeneous hydrogenation conditions H2 (60 bar) CO2Et 911 – 916 AcOH, 60 → 80 °C, 42 h OH 910 entry conditions conversions 1 PtO2 (1 equiv) 9% 911 50% 913 9% 914 2 Pd/C (0.1 equiv) 29% 911 23% 913 24% 914 16% 915 3 Rh/C (0.1 equiv) 7% 913 15% 914 47% 915 trace 916 MeO2C MeO2C Me N NH MeO OMe R CO2Et Me NH MeO OMe OH MeO2C N H CO2Et Me NH MeO OMe OH 914 911, R = Boc 913, R = H N CO2Et Boc OH 915 MeO2C Me N Boc N MeO OMe O OH 916 [a] Reaction conditions: 0.01 mmol of 910 in 0.5 mL solvent. Relative levels of conversion determined by LC/MS analysis. Considering this trend, we further investigated the hydrogenation using PtO2 at ambient temperature. Under acidic solvents, significant levels of conversion to the deprotected DHIQ intermediate 914 were detected. However, we were pleased to see that Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 659 at ambient temperature using CHCl3 as solvent, we observed 53% conversion to fully hydrogenated intermediate 915 (Scheme 5.12, entry 4). Overall, key to the hydrogenation of both the isoquinoline and pyrrole ring was the suppression of deprotection pathways that results in byproducts 913 and 914 by using less acidic solvents and ambient temperature. Scheme 5.11. Investigation of solvent in heterogeneous hydrogenation of isoquinoline 910. MeO2C Me CO2Et N N MeO OMe heterogeneous hydrogenation conditions H2 (60 bar) Boc 911 – 915 solvent, 60 °C, 42 h OH 910 entry catalyst solvent conversions 1 5% Rh/C AcOH 27% 915 17% 913 34% 914 2 5% Rh/C HFIP >95% 913 3 5% Rh/C TFE 42% 911 50% 913 8% 914 4 PtO2 AcOH 80% 914 6% 915 5 PtO2 HFIP 9% 911 84% 913 7% 914 6 PtO2 TFE 50% 911 19% 914 27% 913 5% 915 MeO2C MeO2C Me N NH MeO OMe R OH 911, R = Boc 913, R = H CO2Et Me NH MeO OMe OH 914 MeO2C N H CO2Et Me N NH MeO OMe CO2Et Boc OH 915 [a] Reaction conditions: 0.01 mmol of 910 in 0.5 mL solvent. Relative levels of conversion determined by LC/MS analysis. Although we could achieve the fully hydrogenated intermediate 915 in 53% yield, the diastereoselectivity is low and isolated as a mixture of inseparable diastereomers.25 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 660 Moreover, in attempts to cyclize pyrrolidine 915 to the desired tetracycle 916 by hydrolyzing the ester, we observe competitive cyclization onto the methyl ester moiety at the C3-position of the pyrrolidine as well to deliver 917 (Scheme 5.13). Scheme 5.12. Investigation of solvent in heterogeneous hydrogenation of isoquinoline 910 at ambient temperature. MeO2C Me N N MeO OMe CO2Et heterogeneous hydrogenation conditions PtO2 (1 equiv), H2 (60 bar) Boc 911 – 915 solvent, 23 °C, 42 h OH 910 entry solvent conversions 1 AcOH 20% 915 80% 914 2 TFE 29% 911 17% 914 15% 913 8% 915 3 EtOH 46% SM 27% 911 13% 913 14% 914 4 CHCl3 18% 911 29% 914 53% 915 MeO2C MeO2C Me N NH MeO OMe R OH 911, R = Boc 913, R = H CO2Et Me NH MeO OMe OH 914 MeO2C N H CO2Et Me N NH MeO OMe CO2Et Boc OH 915 [a] Reaction conditions: 0.01 mmol of 910 in 0.5 mL solvent. Relative levels of conversion determined by LC/MS analysis. Considering the poor diastereoselectivity of the heterogeneous hydrogenation, competitive cyclization to the less strained tetracycle 917, and the inability to change the protecting group on the nitrogen atom from the cross-coupled intermediate, we considered Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 661 a different approach toward (+)-cyanocycline A (771) that would enable faster reduction and higher diastereoselectivity toward tetracycle 916. Scheme 5.13. Competitive cyclization of secondary amine on to esters at C3- and C5positions of the pyrrolidine ring. MeO2C Me N NH MeO OMe 5.4 Boc N CO2Et Me N LiOH THF:MeOH:H2O MeO Boc N MeO OMe O OH 916 CO2H Me + N OMe OH 915 Boc HO2C inseparable mixture O OH 917 SECOND GENERATION APPROACH To increase the diastereoselectivity of the global hydrogenation event, we considered installing a dearomatized dihydropyrrole fragment instead to enable facile reduction of the olefin. The ester adjacent to the nitrogen atom of the pyrrolidine ring would be brought in from chiral pool starting materials, which we envisioned would arise from glutamic acid derivatives. Thus, our revised retrosynthetic analysis of (+)-cyanocycline A (771) involves a different cross-coupling event of fragments 920 and 921 that switches the previously electrophilic partner of the isoquinoline fragment to a nucleophilic coupling partner (Figure 5.4). After allylic oxidation, global hydrogenation of intermediate 919 should be more efficient, as only the isoquinoline ring and the tetrasubstituted olefin of the dihydropyrrole ring are reduced to afford pyrrolidine 918. Synthesis of the dihydropyrrole fragment commences with commercially available (S)-pyroglutamic acid 922, which undergoes esterification and Boc-protection to afford lactam 923 (Scheme 5.14). Acylation of lactam 923 is then performed with LiHMDS and Mander’s reagent to install the methyl ester moiety at the C3-position to access lactam 924. Finally, treatment of 924 with 2,6-di-tert-butyl-4-methylpyridine and trapping the Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 662 generated enolate with Tf2O delivers vinyl triflate 921 in 51% yield. However, further attempts to optimize the yield of the triflation were unsuccessful due to the instability of intermediate 921. Figure 5.4. 2nd generation retrosynthetic analysis of (+)-cyanocycline A (771). O O O N O H Me N H Me H aminonitrile formation MeO OMe CN OH O H Me oxidation N MeO N OH (+)-Cyanocycline A (771) N N H MeO O OH OMe 881 882 H Me N H OMe N arene oxidation Me H MeO OMe O OH 883 H Me MeO OMe N N NH MeO2C Me H Boc NH OMe MeO2C Me N N MeO OMe OH OH 919 918 Me cross-coupling MeO2C X N MeO allylic oxidation + TfO CO2Me N OMe Me Boc 920 921 Scheme 5.14. Synthesis of dihydropyrrole coupling partner 921. 1) SOCl2, MeOH 0 → 23 °C O CO2H N H (S)-pyroglutamic acid 922 2) Boc2O, DMAP, NEt3 CH2Cl2 O 76% yield over 2 steps N CO2Me LiHMDS Mander’s reagent THF, –78 °C Boc 923 84% yield MeO2C MeO2C O N CO2Me 2,6-di-tert-butyl-4-methylpyridine; Tf2O 1,2-DCE, 0 → 23 °C TfO N Boc Boc 924 O OH O OH global CO2Me hydrogenation N MeO OH N cyclization 884 Boc Me oxazoline formation Me N MeO2C MeO2C H H Me reduction N MeO N O HN H OH H Me O benzylic oxidation O cyclization Me HN 20–51% yield 921 CO2Me Boc CO2Me Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 663 Conversion of the isoquinoline triflate 887 to a nucleophilic coupling partner was more challenging than anticipated. We first attempted Pd-catalyzed borylation conditions using B2pin2 and HBpin, but no conversion of starting material was observed (Scheme 5.15). 26 Using nickel-catalyzed borylation conditions developed by Molander and coworkers resulted in little conversion to the boronic acid 926, but mostly produced leftover starting material and protodetriflation.27 To our delight, Pd-catalyzed stannylation conditions inspired by Nechaev and coworkers gave smooth conversion of the isoquinoline triflate 887 to organostannane 927 in 77% yield.28 Scheme 5.15. Conversion of isoquinoline triflate 887 to a nucleophilic coupling partner. Me OTf N MeO PdCl2(dppf) (3 mol %) B2pin2 (3 equiv), NEt3 (3 equiv) 1,4-dioxane, 100 °C Me X Bpin N MeO OMe Me OMe Me 925 887 not observed Me OTf N MeO PdCl2(dppf) (3 mol %) HBpin (1.5 equiv), NEt3 (3 equiv) Me 1,4-dioxane, 80 °C MeO X Bpin N OMe Me OMe Me 925 887 not observed Me OTf N MeO NiCl2(dppf) (5 mol %) PPh3 (10 mol %) B2(OH)4 (5 equiv), DIPEA (3 equiv) EtOH, 80 °C Me X B(OH)2 N MeO OMe Me OMe Me 887 926 low conversion Me OTf N MeO OMe Me 887 Pd(PPh3)4 (10 mol %) Sn2Bu6 (1.1 equiv), LiCl (5 equiv) Me 1,4-dioxane, 100 °C MeO 77% yield SnBu3 N OMe Me 927 With both coupling partners in hand, we then explored Stille cross-coupling conditions of isoquinoline stannane 927 and vinyl triflate 921. Interestingly, using the same optimized conditions for the Stille coupling of isoquinoline triflate 887 and pyrrole stannane 908 resulted in a complex reaction profile of protodemetalation and Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 664 decomposition of the vinyl triflate 921 (Scheme 5.16, entry 1). When we explored other additives, we observed that adding LiCl that is known to accelerate the oxidative addition event of the vinyl triflate to palladium improved the yield to 64% (entry 2).29 Thus, using Pd(PPh3)4, CuI, LiCl, and 1:1 equivalents of both coupling partners, we could achieve cross-coupled product 928 by reversing the electronics of both fragments. Scheme 5.16. Cross-coupling of heterocycles 921 and 927 and synthesis of hydrogenation precursor. Me + N MeO MeO2C MeO2C SnBu3 TfO CO2Me N Stille coupling conditions Me conditions results 1 Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) NMP, 23 °C trace conversion to 928 protodemetallation of 927 decomposition of 921 2 Pd(PPh3)4 (5 mol %) CuI (1.2 equiv), LiCl (1.24 equiv) THF, 65 °C 64% yield of 928 MeO2C N N OMe Me 928 Boc 928 entry MeO2C MeO CO2Me OMe Me 921 927 Me N MeO Boc 1 equiv OMe Me 1 equiv N Boc CO2Me 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO 55% yield over 2 steps N N OMe CO2Me Boc OH 929 From cross-coupled intermediate 928, we could access the hydrogenation precursor 929 from allylic oxidation and subsequent reduction of the aldehyde intermediate, observing no deleterious pathways of oxidation of the dihydropyrrole ring and potential aromatization. However, due to the instability of vinyl triflate 921 that resulted in inconsistent yields of 20 to 51%, and to avoid undesired cyclization onto the methyl ester at the C3-position,30 we envisioned designing an elaborated dihydropyrrole fragment to enable a more convergent strategy for the two heterocycles. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 5.5 665 THIRD GENERATION APPROACH To this end, we considered installing the oxazoline ring onto the dihydropyrrole fragment (932) that maps directly onto ring F of the natural product. Not only would this reduce the number of subsequent steps from the global hydrogenation event to install the oxazoline ring, but would also impart a significant electron-withdrawing effect to enable reduction of the tetrasubstituted olefin (Figure 5.5). Moreover, we sought to utilize the oxazoline ring as a potential directing group for the cross-coupling with isoquinoline triflate 887 through either a Heck or a Pd-catalyzed concerted metalation deprotonation (CMD) reaction of the dihydropyrrole olefin.31 Such transformations using unactivated cyclic enamides are not well precedented, which we envision could be an opportunity for novel reaction development for the coupling of enamides and heteroaryl electrophiles.32 Synthesis of the oxazoline-appended dihydropyrrole 932 commences with lactam 923, which instead undergoes a dehydration event to access dihydropyrrole 933 (Scheme 5.17).33 Vilsmeier–Haack formylation using POCl3 in DMF affords aldehyde 934 in 70% yield, which is subjected to Pinnick oxidation to deliver carboxylic acid 935 in 76% yield. Then, amidation of 935 with ethanolamine and HATU reagent gives amide 936 in 80% yield that can be treated with DAST reagent at –78 °C to cleanly afford the oxazoline coupling partner 932 in 79% yield. With efficient access to dihydropyrrole fragment 932, we were then poised to explore the key cross-coupling event of isoquinoline triflate 887 and dihydropyrrole 932 without prefunctionalization of the olefin. First, a variety of Pd-catalyzed conditions were investigated based on precedent of direct C–H arylation reactions (Scheme 5.18).34 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 666 Figure 5.5. 3rd generation retrosynthetic analysis of (+)-cyanocycline A (771). O O O N O H Me N H Me H aminonitrile formation MeO OMe CN OH O H Me oxidation N MeO N OH (+)-Cyanocycline A (771) N N H MeO O OH OMe 881 HN H OH 882 N H OMe N arene oxidation Me H MeO OMe O OH 883 H N NH MeO2C Boc N O OH O Me global CO2Me hydrogenation N OMe Me Boc NH MeO OH N N MeO OMe OH 930 Me OTf OH CO2Me N + N MeO Boc 931 O allylic oxidation O OH N H cross-coupling N cyclization Me N N OMe N O Me N Boc OMe Me 932 887 Scheme 5.17. Synthesis of oxazoline dihydropyrrole coupling partner 932. OHC O N CO2Me Boc 923 LiBHEt3 PhMe, –78 °C Boc POCl3, DMF Boc 934 70% yield O HO2C CO2Me N Boc 935 76% yield CO2Me N CH2Cl2, 0 °C 933 73% yield 1,4-dioxane:H2O O N CH2Cl2, –78 °C 79% yield CO2Me N then TFAA, DIPEA DMAP, –78 → 23 °C NaClO2 2-methyl-2-butene NaH2PO4 DAST Me 884 O MeO H Me reduction N MeO N O H Me H H Me O benzylic oxidation O cyclization Me HN N Boc 932 CO2Me ethanolamine DIPEA, HATU CH2Cl2 80% yield HN HO N Boc 936 CO2Me CO2Me Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 667 After surveying a wide range of transition-metal catalysts, we were pleased to see that an initial reaction employing Pd(PPh3)4, phenanthroline as ligand, and Ag2CO3 as base gave trace conversion to product (entry 1). Surveying a variety of carbonate bases did not improve conversion to product 937, but Cs2CO3 in particular showed full consumption of starting material 932 to the hydrolyzed carboxylic acid (entry 2). Considering the unique reactivity of Cs2CO3, we hypothesized whether reducing the ester moiety to the alcohol to avoid hydrolysis of the substrate would activate the substrate toward cross-coupling. Thus, dihydropyrrole 932 was converted to the primary alcohol 938 via LiBH4 generated in situ.35 Scheme 5.18. Initial Pd-catalyzed CMD cross-coupling reaction of triflate 887 and dihydropyrrole 932. O O Me crosscoupling conditions + N MeO N N OTf N OMe Me 1 equiv Me N CO2Me N MeO Boc 1.5 equiv Boc OMe Me 932 887 CO2Me 937 entry conditions results 1 Pd(PPh3)4 (5 mol %) phenanthroline (15 mol %) Ag2CO3 (1 equiv), PhMe trace conversion to 937 mostly recovered SM 2 Pd(PPh3)4 (5 mol %) Cs2CO3 (3 equiv), PhMe hydrolysis of both 887 and 932 O O N N NaBH4, LiCl N Boc 932 CO2Me THF:EtOH 74% yield N Boc OH 938 Optimization of the Pd-catalyzed cross-coupling was then explored with triflate 887 and alcohol 938. To our delight, using P(t-Bu)3 as ligand and 1.0 equivalent of Cs2CO3 afforded a 10% NMR yield of cross-coupled intermediate 939 as a single isomer (Scheme 5.19, entry 1). Increasing the amount of base to 3.5 equivalents and diluting the Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 668 concentration to 0.04 M improved the yield to 25%, suggesting that a concerted metalation deprotonation (CMD) reaction pathway may be taking place over a Heck-type mechanism. 36 Yet, the reaction suffers from significant protodetriflation and homocoupling of isoquinoline triflate 887. Scheme 5.19. Optimization of Pd-catalyzed CMD cross-coupling reaction of triflate 887 and dihydropyrrole 938.a O O Me N OTf crosscoupling conditions + N MeO N N PhMe, 110 °C, 18 h Boc OH 1.5 equiv OMe Me 1 equiv Me N N MeO OMe Me 938 887 OH Boc 939 entry conditions results 1 Pd(OAc)2 (10 mol %), Pt-Bu3 (25 mol %) Cs2CO3 (1 equiv), PhMe (0.07 M) 10% yield 16% homocoupling 45% protodetriflation 2 Pd(OAc)2 (10 mol %), Pt-Bu3 (25 mol %) Cs2CO3 (3.5 equiv), PhMe (0.04 M) 25% yield 19% homocoupling 41% protodetriflation 3 Pd(OAc)2 (10 mol %), Pt-Bu3 (20 mol %) Cs2CO3 (3.5 equiv), CsOPiv (50 mol %) 11% yield 14% homocoupling 9% protodetriflation 4 Pd(OAc)2 (2.5 mol %), Pt-Bu3 (5 mol %) Cs2CO3 (3.5 equiv), CsOPiv (12.5 mol %) 36% yield 8% homocoupling 5% protodetriflation 5 Pd(OAc)2 (2.5 mol %), PPh3 (5 mol %) Cs2CO3 (3.5 equiv), CsOPiv (12.5 mol %) 34% yield 3% homocoupling 9% protodetriflation 6 Pd(OAc)2 (2.5 mol %), PCy3 (5 mol %) Cs2CO3 (3.5 equiv), CsOPiv (12.5 mol %) 47% yield 8% homocoupling 10% protodetriflation [a] Reaction conditions: 0.014 mmol of 887 in 0.34 mL solvent. Yields determined from crude 1H NMR using 1,3,5-trimethoxybenzene as standard. Employing CsOPiv as an additive that is known to be directly involved in the ratedetermining C–H bond cleavage/palladation event decreased the amount of protodetriflation and homocoupling byproducts, affording 939 in 11% yield.37 Lowering the catalyst loading to 2.5 mol % of palladium and 5 mol % of phosphine ligand also Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 669 significantly reduced the levels of homocoupling and protodetriflation while increasing the yield of 939 to 36% (entry 4). Finally, exploring more electron-deficient phosphine ligands such as PPh3 and PCy3 ultimately improved the yield of the cross-coupling to 47% while suppressing other undesired reaction pathways (entries 5 & 6). Efforts to continue improving the yield of this key cross-coupling reaction and access the hydrogenation precursor are currently ongoing. 5.6 CONCLUSION AND FUTURE DIRECTIONS Toward the total synthesis of (+)-cyanocycline A (771), we have developed a highly convergent strategy to cross-couple isoquinoline triflate 887 and dihydropyrrole 938 that installs four out of six rings of the natural product in a single transformation. With intermediate 939 in hand, we anticipate that oxidation of 939 will be relatively facile using previously employed oxidation conditions that installs the hydroxymethyl group at the C1position of the isoquinoline (Scheme 5.20). With hydrogenation precursor 931, a global hydrogenation event using PtO2 will be explored to access 930, which has already been demonstrated to reduce both the isoquinoline and pyrrole ring (e.g., 915). Due to the presence of one methyl ester substituent, cyclization of the secondary amine onto the ester should be selective to yield bicycle 884 with the oxazoline ring already in place. After arene oxidation to deliver phenol 883 which has been performed on a similar substrate in the jorumycin synthesis,14 benzylic oxidation of either oxazolidine 883 or the oxazoline will be extensively explored to generate an ortho-quinone methide intermediate 882 that enables cyclization of the pendent heterocycle to access the natural product scaffold 881. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 670 Finally, oxidation of the arene to the quinone and aminonitrile formation are both well precedented in previous syntheses of THIQ alkaloids to deliver (+)-cyanocycline A (771).2 Scheme 5.20. Proposed completion of (+)-cyanocycline A (771). O O N N oxidation Me N N OH Boc N MeO Me OMe Me OMe 939 O CO2Me N H Me cyclization H Boc NH MeO OMe OH 930 N OH Me N arene oxidation Me oxazoline reduction MeO H MeO OMe 882 N N O OH Me O OH O H Me H MeO OMe 881 Me 883 N OH H N OMe O HN Me H N 884 O HN H O OH O benzylic oxidation O O N Me OMe OH 919 N MeO hydrogenation Boc N MeO PtO2 H2 CO2Me N N O OH O N H Me Me H oxidation aminonitrile formation MeO O N Me N CN OH (+)-Cyanocycline A (771) In conclusion, we have developed a novel cross-coupling strategy of two heterocyclic fragments that installs all of the requisite carbon and nitrogen atoms of (+)cyanocycline A (771). Key to this reaction is an appended oxazoline ring on the dihydropyrrole fragment that enables deprotonation of the C(sp2)–H bond and palladation to couple with a functionalized isoquinoline triflate. Furthermore, extensive investigation into both the asymmetric hydrogenation and heterogeneous hydrogenation of a pyrrolesubstituted isoquinoline were explored to probe its reactivity and stereoselectivity. Although a variety of asymmetric hydrogenation conditions were not successful in reducing the pyrrole-substituted isoquinoline efficiently, we have developed a Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 671 hydrogenation method using PtO2 and 60 bar H2 at ambient temperature that enables the reduction of both the isoquinoline and pyrrole ring. We anticipate application of this technology to our most advanced intermediate to reduce a dearomatized dihydropyrrolesubstituted isoquinoline effectively. Efforts are currently underway to access this hydrogenation precursor toward the total synthesis of (+)-cyanocycline A (771). 5.7 EXPERIMENTAL SECTION 5.7.1 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. 38 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 flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and Oxford 600 MHz spectrometers and are reported relative to residual CHCl3 (δ = 7.26 ppm) or TMS (δ = 0.00 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ = 77.16 ppm), C6D6 (δ = 128.06 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 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 672 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 path-length cell. High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), or mixed ionization mode (MM: ESI-APCI+). Reagents were purchased from commercial sources and used as received unless otherwise stated. 5.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA Me [Ir(cod)OMe]2 (5 mol %) 3,4,7,8-tetramethylphenanthroline (10 mol %) B2pin2 (0.75 equiv), THF, 80 °C MeO then NMO, 80 °C then NEt3, i-PrNCO OMe Me O MeO 889 NHi-Pr O OMe 890 3,4-dimethoxy-5-methylphenyl isopropylcarbamate (890) Compound 890 was prepared according to literature procedure.14a In a nitrogen-filled glovebox, [Ir(cod)OMe]2 (22.3 mg, 0.034 mmol, 0.005 equiv) and 3,4,7,8-tetramethyl1,10-phenanthroline (15.9 mg, 0.067 mmol, 0.01 equiv) were dissolved in 5 mL THF and stirred for 30 min. Then, 2,3-dimethoxytoluene (1.00 mL, 6.73 mmol, 1 equiv) and B2Pin2 (1.28 g, 5.05 mmol, 0.75 equiv) were weighed into a 20 mL sealable microwave vial in the glovebox with a teflon-coated stir bar and 5 mL THF was added. Upon complete dissolution, the catalyst solution was transferred to the microwave vial, which was sealed prior to removing from the glovebox. The vial was then placed in a preheated 80 °C oil bath and stirred 48 h, at which time TLC (20% EtOAc in hexanes) revealed complete Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 673 conversion to a single borylated product. The vial was cooled to room temperature and the cap was removed. N-methylmorpholine-N-oxide (2.37 g, 20.2 mmol, 3 equiv) was added in a few small portions and the vial was resealed and returned to the 80 °C oil bath for 3 h, at which time TLC (20% EtOAc in hexanes) indicated complete oxidation to the intermediate phenol. NEt3 (4.7 mL, 33.7 mmol, 5 equiv) and isopropyl isocyanate (2.6 mL, 26.9 mmol, 4 equiv) were added at room temperature and the solution was stirred 16 h, at which time TLC (50% EtOAc/hex) indicated complete conversion to carbamate 890. 10% aq. Na2S2O3 was added to quench the remaining oxidant and citric acid hydrate (4.5 g, >3 equiv) was added to chelate the boron. This solution was stirred 1 h, and concentrated HCl was added 1 mL at a time until an acidic pH was achieved. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were then washed with aqueous K2CO3, dried over MgSO4 and concentrated. The product was purified by silica column chromatography (25% EtOAc in hexanes) to afford a colorless solid (1.35 g, 4.6 mmol, 79% yield); 1H NMR (400 MHz, CDCl3) δ 6.55 (d, J = 2.6, 1H), 6.52 (d, J = 2.8, 1H), 4.84 (d, J = 7.8 Hz, 1H), 3.88 (ddd, J = 16.1, 13.9, 7.6 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.24 (s, 3H), 1.23 (s, 3H), 1.21 (s, 3H); All characterization data match those reported. Me NHi-Pr O Me O MeO O TMS NHi-Pr TMEDA, TBSOTf, n-BuLi O MeO OMe 890 then TMSCl, Et2O, –78 °C OMe 891 3,4-dimethoxy-5-methyl-2-(trimethylsilyl)phenyl isopropylcarbamate (891) Compound 891 was prepared according to literature procedure.14a Carbamate 890 (17.30 g, 68.2 mmol, 1 equiv) was dissolved in Et2O (340 mL, 0.2 M) N,N,Nʹ,Nʹ- Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 674 tetramethylethylenediamine (TMEDA, 11.3 mL, 75.1 mmol, 1.1 equiv) was added and the solution was cooled to 0 °C before tert-butyldimethylsilyl triflate (TBSOTf, 17.25 mL, 75.1 mmol, 1.1 equiv) was added in a slow stream. The solution was stirred 10 min at 0 °C, removed from the ice bath and stirred at room temperature for 30 min. A second portion of TMEDA (41 mL, 273 mmol, 4 equiv) was added and the solution was cooled to –78 °C. n-Butyllithium (2.4 M, 114 mL, 274 mmol, 4 equiv) was added in a dropwise fashion through a flame-dried addition funnel over the course of 1 h, being sure to not let the temperature rise significantly. The resulting yellow suspension was stirred vigorously for 4 h at –78 °C, taking care not to let the temperature rise during the course of the reaction. Trimethylsilyl chloride (61 mL, 478 mmol, 7 equiv) was then added dropwise via addition funnel over the course of 30 min and the suspension was stirred at –78 °C for 30 min, then was removed from the dry ice bath and stirred at room temperature for 16 h. The reaction was quenched by the addition of 300 mL aqueous NH4Cl (30 mL saturated solution diluted to 300 mL) through an addition funnel, the first 50 mL of which were added dropwise, followed by the addition of the remainder in a slow stream. The aqueous phase was then further acidified by the addition of small portions of concentrated HCl until an acidic pH was achieved (~30 mL required). The layers were separated and the aqueous phase was extracted twice with Et2O. The combined organic phases were washed with saturated aqueous NH4Cl, dried over MgSO4 and concentrated. The product was purified by silica column chromatography (20 → 30% Et2O in hexanes) to afford a colorless solid (20.61 g, 63.3 mmol, 93% yield); 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 4.69 (d, J = 8.1 Hz, Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 675 1H), 3.96–3.85 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.23 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H), 0.30 (s, 9H); All characterization data match those reported. Me O MeO O TMS NHi-Pr Me OTf Et2NH, n-BuLi PhNTf2, THF, –78 °C TMS MeO OMe OMe 892 891 3,4-dimethoxy-5-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (892) Compound 892 was prepared according to literature procedure.14a Carbamate 891 (8.08 g, 24.8 mmol, 1 equiv) was dissolved in THF (100 mL, 0.25 M) and diethylamine (3.85 mL, 37.2 mmol, 1.5 equiv) was added and the solution was cooled to –78 oC. n-Butyllithium (2.5 M, 15 mL, 37.5 mmol, 1.5 equiv) was added slowly over the course of 15 min. The solution was stirred at that temperature for 30 min, then removed from its bath and stirred at 23 oC for 30 min. N-Phenyl triflimide (10.6 g, 29.8 mmol, 1.2 equiv) was added in one portion and the solution was stirred 30 min. A second portion of diethylamine (4.6 mL, 44.7 mmol, 1.8 equiv) was added and the solution was stirred 2 h. The solution was filtered through a 1 inch pad of silica gel with 50% Et2O in hexanes and concentrated. The product was purified by silica column chromatography (10% Et2O in hexanes) to afford a colorless oil (9.15 g, 24.6 mmol, 99% yield); 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 2.28 (d, J = 0.7 Hz, 3H), 0.38 (s, 9H); All characterization data match those reported. Me OTf methyl acetoacetate CsF, CH3CN, 80 °C Me MeO TMS then aq. NH4OH, 60 °C MeO OMe 892 7,8-dimethoxy-1,6-dimethylisoquinolin-3-ol (893) OH N OMe Me 893 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 676 Compound 893 was prepared according to literature procedure.14a Cesium fluoride (204 mg, 1.34 mmol, 2.5 equiv) was dissolved in acetonitrile (5.4 mL, 0.1 M) in a 20 mL microwave vial and water (9.7 μL, 0.537 mmol, 1.0 equiv) and methyl acetoacetate (58 μL, 0.537 mmol, 1.0 equiv) were added. Aryne precursor 892 (250 mg, 0.671 mmol, 1.25 equiv) was added neat via syringe, and the vial was placed in a preheated 80 °C oil bath. After 2 h, TLC revealed complete consumption of 892, so NH4OH (28–30%, 5.4 mL) was added in one portion. The vial was moved to a preheated 60 °C oil bath and stirred for 8 h. The solution was poured into brine inside a separatory funnel and the solution was extracted with EtOAc (2x 30 mL). The aqueous phase was brought to pH 7 by the addition of concentrated HCl and was extracted with EtOAc (2x 30 mL). The aqueous phase was discarded. The organic phase was then extracted with 2M HCl (5x 20 mL). The organic phase was checked by LCMS to confirm that all of product 893 had transferred to the aqueous phase and was subsequently discarded. The aqueous phase was then brought back to pH 7 by the addition of 100 mL 2M NaOH and was extracted with EtOAc (5x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated, providing product 893 as a yellow solid (56.9 mg, 0.243 mmol, 45% yield); 1 H NMR (400 MHz, CDCl3) δ 6.92 (d, J = 0.7 Hz, 1H), 6.51 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.03 (d, J = 0.7 Hz, 3H), 2.28 (d, J = 1.0 Hz, 3H); All characterization data match those reported. Me OH N MeO Tf2O, pyridine CH2Cl2, 0 °C Me OTf N MeO OMe Me OMe Me 893 887 7,8-dimethoxy-1,6-dimethylisoquinolin-3-yl trifluoromethanesulfonate (887) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 677 Compound 887 was prepared according to literature procedure.14a Isoquinoline 893 (2.60 g, 11.1 mmol, 1 equiv) was dissolved in CH2Cl2 (70 mL, 0.16 M) and pyridine (11.4 mL, 140.6 mmol, 12.7 equiv) was added and the solution was cooled to 0 °C. Trifluoromethanesulfonic anhydride (Tf2O, 3.00 mL, 17.8 mmol, 1.6 equiv) was added dropwise, causing the yellow solution to turn dark red. After 30 min TLC (10% EtOAc/hex) revealed complete conversion, so the reaction was quenched by the addition of saturated aqueous NaHCO3 (70 mL). The solution was stirred vigorously until bubbling ceased, at which time the layers were separated. The organic phase was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4 and concentrated. The product was purified by silica column chromatography (10% Et2O in hexanes) to afford a yellow oil (3.82 g, 10.5 mmol, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 1.0 Hz, 1H), 7.21 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.07 (d, J = 0.7 Hz, 3H), 2.44 (d, J = 1.0 Hz, 3H); All characterization data match those reported. O N H CO2Et dichloromethyl methyl ether AlCl3 (2 equiv) 1:1 CH2Cl2:MeNO2, –15 °C 894 N H CO2Et 895 Ethyl 4-formyl-1H-pyrrole-2-carboxylate (895) Compound 895 was prepared according to literature procedure.15 To a stirred solution of pyrrole 894 (20.0 g, 100 mmol, 1.0 equiv) in dry CH2Cl2 and MeNO2 (600 mL, 1:1) was added powdered AlCl3 (39.2 g, 144.4 mmol, 2 equiv) in portions. After stirring for 5 min, dichloromethyl methyl ether (98.0 g, 300 mmol, 1.2 equiv) was added dropwise at –15 °C over 10 minutes. The resulting mixture was stirred for 2 hours at –15 ºC. Upon full consumption of starting material determined by LCMS analysis, the mixture was quenched Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 678 with H2O (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was washed with saturated aq. NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was crystallized using 10% EtOAc in hexanes to afford pyrrole 895 as a green solid (35.61 g, 114.36 mmol, 99% yield); 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 9.74 (br s, 1H), 7.57 (dd, J = 3.3, 1.5 Hz, 1H), 7.33–7.32 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); All characterization data match those reported. O O Br2 N H CO2Et CH2Cl2, 0 → 23 °C Br 895 N H CO2Et 896 Ethyl 5-bromo-4-formyl-1H-pyrrole-2-carboxylate (896) A flame-dried round bottom flask was charged with pyrrole 895 (1.34 g, 8 mmol, 1.0 equiv) in DCM (70 mL) and cooled to 0 °C. A solution of Br2 (0.45 mL, 8.8 mmol, 1.1 equiv) in 10 mL DCM was then added dropwise, and the solution was stirred overnight at room temperature. After 18 hours, the reaction was quenched with saturated aqueous Na2S2O3 (35 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (20 → 30% EtOAc in hexanes) to afford pyrrole 896 as a yellow solid (1.96 g, 5.9 mmol, 74% yield); 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.28 (d, J = 2.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 184.8, 160.2, 125.8, 124.6, 114.9, 112.9, 61.7, 14.4; IR (Neat Film, NaCl) 3210, 2987, 1698, 1674, 1653, 1554, 1462, 1446, 1377, 1250, 1208, 1012, 847, 821, 773 cm–1; HRMS (ESI+) m/z calc’d for C8H9BrNO3 [M+H]+: 245.9760, found 245.9759. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 679 O O (MeO)2SO2, K2CO3 Br CO2Et N H Br CO2Et N CH3COCH3 Me 896 897 Ethyl 5-bromo-4-formyl-1-methyl-1H-pyrrole-2-carboxylate (897) A flame-dried round bottom flask was charged with pyrrole 896 (500 mg, 2 mmol, 1 equiv) and K2CO3 (1.4 g, 10.2 mmol, 5 equiv) in degassed acetone (20 mL, 0.1 M). Dimethyl sulfate (0.25 mL, 2.64 mmol, 1.3 equiv) was then added dropwise, and the reaction was stirred for 1 hour at room temperature. After full consumption of starting material by TLC analysis, the reaction was quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (10 → 20% EtOAc in hexanes) to afford pyrrole 897 as a pinkred solid (468 mg, 1.8 mmol, 90% yield); 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.42 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 185.0, 160.4, 126.1, 122.9, 119.4, 117.3, 61.0, 34.9, 14.4; IR (Neat Film, NaCl) 2978, 1713, 1668, 1651, 1469, 1442, 1369, 1352, 1293, 1281, 1242, 1203, 1081, 1036, 764, 739, 667 cm–1; HRMS (ESI+) m/z calc’d for C9H11BrNO3 [M+H]+: 259.9917, found 259.9921. HO O NaBH4 Br N CO2Et MeOH:CH2Cl2 Br N Me Me 897 898 CO2Et Ethyl 5-bromo-4-(hydroxymethyl)-1-methyl-1H-pyrrole-2-carboxylate (898) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 680 A flame-dried round bottom flask was charged with pyrrole 897 (436 mg, 1.7 mmol, 1 equiv) in 4:1 DCM:MeOH (13.6 mL:3.4 mL, 0.1 M total) and cooled to 0 °C. NaBH4 (190 mg, 5 mmol, 3 equiv) was then added to the flask, and the reaction was stirred for 30 minutes. After full consumption of starting material by TLC analysis, the reaction was quenched by adding citric acid monohydrate (714 mg, 2 equiv) and stirring rapidly for 10 minutes. The solution was then basified by the slow addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (10 → 20% EtOAc in hexanes) to afford pyrrole 898 as a yellow oil (440 mg, 1.68 mmol, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 4.50 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 123.9, 122.9, 117.5, 112.0, 60.3, 58.1, 34.8, 14.5; IR (Neat Film, NaCl) 3414, 2978, 2945, 2877, 1702, 1553, 1507, 1463, 1437, 1405, 1244, 1156, 1105, 1081, 1057, 999, 833, 759, 667 cm–1; HRMS (ESI+) m/z calc’d for C9H13BrNO3 [M+H]+: 262.0073, found 262.0080. HO Br Me N CO2Et OTf + N MeO Me OMe Me 898 887 XPhos Pd G2 (5 mol %) XPhos (10 mol %) B2(OH)4 (X equiv) KOAc, EtOH then 887, K2CO3, THF 80 °C, 24 h EtO Me N N MeO CO2Et Me OMe Me 899 Ethyl 5-(7,8-dimethoxy-1,6-dimethylisoquinolin-3-yl)-4-(ethoxymethyl)-1-methyl1H-pyrrole-2-carboxylate (899) This procedure was adapted from the method of Molander et al.17 In a flamedried µW vial was charged with XPhos Pd G2 catalyst (9.44 mg, 0.012 mmol, 5 mol %), XPhos ligand (11.4 g, 0.024 mmol, 10 mol %), bis-boronic acid (65 mg, 0.72 mmol, 3 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 681 equiv), KOAc (71 mg, 0.72 mmol, 3 equiv), and pyrrole 898 (63 mg, 0.24 mmol, 1 equiv). The vial was then sealed, and vacuum purged/refilled with N2 four times. Then, 0.14 M degassed EtOH (1.7 mL) was added, and heated to 80 °C for 1 to 2 hours until no starting material was observed. Upon full conversion of starting material, the vial was cooled to room temperature, and 1.8 M of degassed aq. K2CO3 solution (0.4 mL) was added to the vial. After stirring for 5 minutes, triflate 887 (105 mg, 0.29 mmol, 1.2 equiv) in 0.4 mL THF was added to the vial, then heated to 80 °C over 18 hours. The reaction vial was then cooled to room temperature, filtered over celite, and washed with EtOAc (2 x 1 mL). The crude reaction mixture was concentrated and directly purified by silica column chromatography (30% EtOAc in hexanes + 1% NEt3) to yield isoquinoline 899 as a brown oil (19 mg, 0.046 mmol, 19% yield); 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.37 (s, 1H), 7.10 (s, 1H), 4.34–4.24 (m, 4H), 4.01 (s, 3H), 4.00 (s, 3H), 3.95 (s, 3H), 3.52 (q, J = 7.0 Hz, 2H), 3.13 (s, 3H), 2.46 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 157.0, 151.0, 149.8, 141.5, 138.9, 137.7, 134.8, 124.1, 123.2, 121.6, 120.7, 120.1, 118.8, 65.4, 65.3, 60.9, 60.3, 59.9, 34.7, 27.3, 17.1, 15.5, 14.6; IR (Neat Film, NaCl) 2971, 2930, 2858, 2367, 1701, 1591, 1557, 1492, 1462, 1438, 1390, 1330, 1239, 1207, 1086, 1005, 907, 831, 765 cm–1; HRMS (ESI+) m/z calc’d for C24H31N2O5 [M+H]+: 427.2227, found 427.2240. O O Boc2O, DMAP N H 895 CO2Et CH2Cl2 N CO2Et Boc 900 1-(tert-butyl) 2-ethyl 4-formyl-1H-pyrrole-1,2-dicarboxylate (900) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 682 A flame-dried round bottom flask was charged with pyrrole 895 (2 g, 12 mmol, 1 equiv), DMAP (146 mg, 1.2 mmol, 10 mol %), and a magnetic stirring bar in DCM (5 mL, 2.4 M). A solution of Boc2O (2.9 g, 13.2 mmol, 1.1 equiv) in DCM (6 mL, 2 M) was then added dropwise, and stirred overnight at room temperature. Upon full consumption of the starting material, the crude reaction was quenched with 1 M HCl (10 mL) and extracted with Et2O (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (10 → 30% EtOAc in hexanes) to yield pyrrole 900 as a clear oil (3.1 g, 11.8 mmol, 98% yield); 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 1.61 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 185.1, 160.3, 147.5, 132.3, 127.7, 126.3, 117.0, 86.8, 61.6, 27.7, 14.3; IR (Neat Film, NaCl) 3127, 2981, 2812, 1766, 1731, 1687, 1560, 1417, 1371, 1340, 1281, 1225, 1152, 1112, 1074, 1012, 832, 774, 667 cm–1; HRMS (ESI+) m/z calc’d for N–H 900 C8H9NO3 [M+H]+: 168.0655, found 168.0656. O HO N Boc 900 CO2Et NaBH4 MeOH:CH2Cl2 N CO2Et Boc 901 1-(tert-butyl) 2-ethyl 4-(hydroxymethyl)-1H-pyrrole-1,2-dicarboxylate (901) A flame-dried round bottom flask was charged with pyrrole 900 (500 mg, 2 mmol, 1 equiv) in 4:1 DCM:MeOH (19 mL, 0.1 M total) and cooled to 0 °C. NaBH4 (213 mg, 5.6 mmol, 3 equiv) was then added in portions, and stirred for 30 minutes at room temperature. After full consumption of starting material by TLC analysis, the reaction was quenched by adding citric acid monohydrate (840 mg, 2 equiv) and stirred rapidly for 10 minutes. The Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 683 solution was then basified by the slow addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (20 → 30% EtOAc in hexanes) to afford pyrrole 901 as a clear oil (533 mg, 1.98 mmol, 99% yield); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 1.8 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 4.52 (d, J = 5.4 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.57 (s, 9H), 1.34 (t, J = 7.1 H, 3H); 13C NMR (100 MHz, CDCl3) δ 160.9, 148.3, 126.3, 124.2, 120.0, 119.9, 85.0, 61.1, 58.1, 27.8, 14.4; IR (Neat Film, NaCl) 3437, 2979, 2938, 2876, 1750, 1720, 1475, 1410, 1370, 1329, 1276, 1232, 1155, 1072, 1019, 980, 848, 831, 775 cm–1; HRMS (ESI+) m/z calc’d for N–H 901 C8H12NO3 [M+H]+: 170.0812, found 170.0808. HO HO N Boc 901 1-(tert-butyl) 2-ethyl CO2Et TMP, n-BuLi THF, –78 °C then Bu3SnCl Bu3Sn N CO2Et Boc 902 4-(hydroxymethyl)-5-(tributylstannyl)-1H-pyrrole-1,2- dicarboxylate (902) A flame-dried round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (TMP) (0.5 mL, 2.93 mmol, 2.05 equiv) in THF (5.4 mL, 0.26 M) and cooled to –78 °C. n-BuLi (2.5 M in hexanes, 1.2 mL, 2.93 mmol, 2.05 equiv) was then added dropwise, and stirred for 10 minutes at –78 °C, then 30 minutes at 0 °C. The solution was cooled again to –78 °C, and pyrrole 901 (385 mg, 1.43 mmol, 1 equiv) in THF (1.8 mL, 0.79 M) was added dropwise, and stirred for 20 minutes at –78 °C. Then, Bu3SnCl (0.78 mL, 2.86 mmol, 2 equiv) was added dropwise, and stirred for 4 hours as the cooling bath slowly warms to room temperature. After full consumption of starting material by TLC analysis, the reaction Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 684 was quenched with H2O (10 mL), extracted with Et2O (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (0 → 5% → 10% EtOAc in hexanes) to afford pyrrole 902 as a clear oil (726 mg, 1.3 mmol, 91% yield); 1H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.55 (s, 9H), 1.51–1.42 (m, 6H), 1.37–1.26 (m, 7H), 1.21 (t, J = 7.1 H, 3H), 1.13–1.05 (m, 5H), 0.88 (t, J = 7.3 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 161.3, 151.1, 141.4, 135.9, 129.2, 121.5, 84.9, 66.0, 60.9, 59.1, 29.3, 27.6, 27.4, 13.8, 12.3; IR (Neat Film, NaCl) 3448, 2955, 2927, 2870, 1727, 1550, 1477, 1463, 1369, 1321, 1236, 1206, 1158, 1073, 1043, 995, 847, 779, 667 cm–1; HRMS (ESI +) m/z calc’d for C25H46NO5Sn [M+H]+: 552.2419, found 552.2412. HO HO Me OTf N MeO + Bu3Sn N Boc OMe Me 887 1-(tert-butyl) CO2Et Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP (0.06 M), 25 °C MeO N CO2Et Boc OMe Me 902 2-ethyl N 903 5-(7,8-dimethoxy-1,6-dimethylisoquinolin-3-yl)-4- (hydroxymethyl)-1H-pyrrole-1,2-dicarboxylate (903) A flame-dried round bottom flask was charged with isoquinoline 887 (261 mg, 0.72 mmol, 1 equiv) and a magnetic stirring bar, and brought in a N2-filled glovebox. A solution of organostannane 902 (399 mg, 0.72 mmol, 1 equiv) in NMP (11.9 mL, 0.06 M) was then added to the flask, and stirred in the glovebox for 10 minutes at ambient temperature. Then, Pd(PPh3)4 (83 mg, 0.072 mmol, 10 mol %) was added, followed by addition of CuTC (150 mg, 0.79 mmol, 1.1 equiv). The flask was brought out of the glovebox and stirred for 2 hours at room temperature. Upon full consumption of starting material, the reaction was quenched with saturated aq. NaHCO3 (10 mL) and extracted with EtOAc (3 x 10 mL). The Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 685 combined organic phases were washed again with 5% aq. LiCl solution (2 x 10 mL), brine (10 mL), and dried over Na2SO4. The crude reaction was mixture was filtered, concentrated, and purified by silica column chromatography (20 → 40% EtOAc in hexanes) to yield isoquinoline 903 as a yellow solid (8.06 g, 30.6 mmol, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.33 (s, 1H), 6.96 (s, 1H), 4.52 (s, 1H), 4.43 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.11 (s, 3H), 2.44 (s, 3H), 1.49 (s, 9H), 1.36 (t, J = 7.1 H, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 157.2, 151.2, 150.0, 149.9, 140.6, 138.5, 136.1, 134.5, 126.4, 124.2, 123.9, 121.8, 119.9, 118.4, 85.8, 61.1, 60.9, 60.8, 60.3, 57.5, 27.5, 17.1, 14.6; IR (Neat Film, NaCl) 3391, 2978, 2934, 1763, 1717, 1596, 1558, 1492, 1448, 1393, 1370, 1331, 1282, 1220, 1154, 1078, 1005, 914, 845 cm–1; HRMS (ESI+) m/z calc’d for C26H33N2O7 [M+H]+: 485.2282, found 485.2310. HO HO Me N N MeO Boc CO2Et 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO OMe Me 2-ethyl N OMe 903 1-(tert-butyl) N CO2Et Boc OH 904 4-(hydroxymethyl)-5-(1-(hydroxymethyl)-7,8-dimethoxy-6- methylisoquinolin-3-yl)-1H-pyrrole-1,2-dicarboxylate (904) In a flame-dried µW vial was charged with SeO2 (105 mg, 0.95 mmol, 2 equiv) and a magnetic stir bar. The vial was vacuum purged/refilled with N2 three times. A solution of isoquinoline 903 (229 mg, 0.47 mmol, 1 equiv) in 1,4-dioxane (9.5 mL, 0.05 M) was then added to the vial, and heated to reflux for 2 hours. After full consumption of starting material observed by LCMS analysis, the vial was cooled to room temperature and the crude reaction mixture was filtered through celite, rinsing with EtOAc. The crude reaction was concentrated, then dissolved in 4:1 DCM:MeOH (4.7 mL, 0.1 M total). Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 686 NaBH4 (18 mg, 0.47 mmol, 1 equiv) was then added, and the reaction was stirred for 30 minutes at room temperature. After full conversion of the aldehyde intermediate observed by LCMS analysis, the reaction was quenched with citric acid monohydrate (199 mg, 0.95 mmol, 2 equiv) and water, and the solution was stirred rapidly for 10 minutes. The solution was then basified by the addition of saturated aq. NaHCO3 (10 mL), the layers were separated and the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was purified by silica column chromatography (40 → 50% EtOAc in hexanes) to yield isoquinoline 904 as a white solid (8.06 g, 30.6 mmol, 61% yield); 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.45 (s, 1H), 7.03 (s, 1H), 5.29 (s, 2H), 4.52 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 3.93 (s, 3H), 2.46 (s, 3H), 1.43 (s, 9H), 1.37 (t, J = 7.1 H, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 157.5, 151.0, 149.5, 149.3, 139.6, 138.8, 135.4, 134.5, 124.5, 124.3, 124.2, 119.8, 119.8, 118.1, 85.8, 64.8, 60.9, 60.9, 60.3, 57.5, 27.4, 17.1, 14.6; IR (Neat Film, NaCl) 3409, 2979, 2937, 2365, 1766, 1713, 1560, 1494, 1447, 1381, 1329, 1217, 1153, 1076, 1006, 911, 833, 734, 668 cm–1; HRMS (ESI+) m/z calc’d for C26H33N2O8 [M+H]+: 501.2231, found 501.2242. O N Boc 900 CO2Et 1) NaClO2, KH2PO4 sulfamic acid 1,4-dioxane:H2O 2) (MeO)2SO2, K2CO3 CH3COCH3 MeO2C N CO2Et Boc 907 1-(tert-butyl) 2-ethyl 4-methyl 1H-pyrrole-1,2,4-tricarboxylate (907) A flame-dried round bottom flask was charged with pyrrole 900 (1 g, 3.8 mmol, 1 equiv) in 1:1 1,4-dioxane:H2O (100 mL, 0.04 M total). The flask was then cooled to 0 °C, and sulfamic acid (2.18 g, 22 mmol, 6 equiv) was added in portions. A solution of NaClO2 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 687 (440 mg, 4.9 mmol, 1.3 equiv) and KH2PO4 (6.1 g, 44.9 mmol, 12 equiv) in 40 mL of H2O was then added dropwise via an addition funnel over 30 minutes. The flask was then removed from the ice bath and stirred overnight at room temperature. After full conversion of the starting material was observed, the reaction was extracted with EtOAc (3 x 20 mL). The organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then dissolved in sparged acetone (38 mL, 0.1 M). Solid K2CO3 (2.6 g, 18.7 mmol, 5 equiv) was added, then dimethyl sulfate (0.46 mL, 4.9 mmol, 1.3 equiv) was added dropwise. The reaction was stirred at room temperature until full consumption of the starting material was observed. The reaction was then quenched with saturated aq. NH4Cl (20 mL), extracted with EtOAc (3 x 10 mL), and the combined organic phases were dried over Na2SO4. The crude reaction mixture was then filtered, concentrated, and purified by silica column chromatography (5 → 10% EtOAc in hexanes) to yield pyrrole 907 as a clear oil (1.1 g, 3.38 mmol, 89% yield); 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.59 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 160.3, 147.6, 130.3, 126.4, 119.8, 117.4, 86.3, 61.4, 51.8, 27.7, 14.3; IR (Neat Film, NaCl) 3141, 2982, 2902, 2365, 1762, 1724, 1570, 1479, 1396, 1371, 1283, 1237, 1152, 1073, 997, 847, 776, 763, 567 cm–1; HRMS (ESI+) m/z calc’d for N–H 907 C9H12NO4 [M+H]+: 198.0761, found 198.0754. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A MeO2C 688 MeO2C N Boc 907 CO2Et TMP, n-BuLi THF, –78 °C then Bu3SnCl Bu3Sn N CO2Et Boc 908 1-(tert-butyl) 2-ethyl 4-methyl 5-(tributylstannyl)-1H-pyrrole-1,2,4-tricarboxylate (908) A flame-dried round bottom flask was charged with 2,2,6,6-tetramethylpiperidine (TMP) (0.19 mL, 1.1 mmol, 1.1 equiv) in THF (2.5 mL, 0.4 M) and cooled to –78 °C. nBuLi (2.5 M in hexanes, 0.48 mL, 1.2 mmol, 1.2 equiv) was then added dropwise, and stirred for 10 minutes at –78 °C, then 30 minutes at 0 °C. The solution was cooled again to –78 °C, and pyrrole 907 (297 mg, 1 mmol, 1 equiv) in THF (2.5 mL, 0.4 M) was added dropwise, and stirred for 20 minutes at –78 °C. Then, Bu3SnCl (0.3 mL, 1.1 mmol, 1.1 equiv) was added dropwise, and stirred for 4 hours as the cooling bath slowly warms to room temperature. After full consumption of starting material by TLC analysis, the reaction was quenched with H2O (10 mL), extracted with Et2O (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was then purified by silica column chromatography (0 → 2.5% → 5% EtOAc in hexanes) to afford pyrrole 908 as a clear oil (527 mg, 0.9 mmol, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 1.58 (s, 9H), 1.51–1.43 (m, 5H), 1.37–1.27 (m, 11H), 1.12–1.08 (m, 5H), 0.87 (t, J = 7.2 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 165.6, 160.6, 150.4, 150.0, 128.8, 126.6, 120.4, 85.9, 61.0, 51.6, 29.1, 27.6, 27.4, 13.9, 12.6; IR (Neat Film, NaCl) 2955, 2924, 2870, 1750, 1719, 1534, 1461, 1424, 1370, 1308, 1253, 1224, 1203, 1156, 1076, 1020, 848, 780, 667 cm–1; Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 689 HRMS (MM:ESI-APCI+) m/z calc’d for C26H46NO6Sn [M+H]+: 580.2368, found 580.2370. MeO2C Me MeO2C OTf N MeO OMe Me 887 + Bu3Sn N CO2Et Boc 908 Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP, 25 °C MeO N N CO2Et Boc OMe Me 909 1-(tert-butyl) 2-ethyl 4-methyl 5-(7,8-dimethoxy-1,6-dimethylisoquinolin-3-yl)-1Hpyrrole-1,2,4-tricarboxylate (909) A flame-dried round bottom flask was charged with isoquinoline 887 (198 mg, 0.54 mmol, 1 equiv) and a magnetic stirring bar, and brought in a N2-filled glovebox. A solution of organostannane 908 (319 mg, 0.54 mmol, 1 equiv) in NMP (9.3 mL, 0.06 M) was then added to the flask, and stirred in the glovebox for 10 minutes at ambient temperature. Then, Pd(PPh3)4 (63 mg, 0.054 mmol, 10 mol %) was added, followed by addition of CuTC (114 mg, 0.6 mmol, 1.1 equiv). The flask was brought out of the glovebox and stirred for 2 hours at room temperature. Upon full consumption of starting material, the reaction was quenched with saturated aq. NaHCO3 (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed again with 5% aq. LiCl solution (2 x 10 mL), brine (10 mL), and dried over Na2SO4. The crude reaction was mixture was filtered, concentrated, and purified by silica column chromatography (10 → 20% EtOAc in hexanes) to yield isoquinoline 909 as a yellow solid (265 mg, 0.52 mmol, 96% yield); 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.70 (s, 3H), 3.07 (s, 3H), 2.43 (s, 3H), 1.40 (s, 9H), 1.37 (t, J = 7.1 H, 3H); 13C NMR (100 MHz, CDCl3) δ 163.9, 160.0, 156.3, 151.3, 149.7, 147.5, 148.3, 140.0, 137.6, 134.2, 124.4, 124.3, 122.2, 121.7, 118.9, 85.8, 61.1, 60.9, 60.3, 51.5, Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 690 27.4, 17.0, 14.5; IR (Neat Film, NaCl) 2978, 2903, 2365, 1775, 1715, 1555, 1506, 1442, 1394, 1332, 1281, 1237, 1215, 1152, 1080, 1045, 1005, 834, 757 cm–1; HRMS (ESI+) m/z calc’d for C27H33N2O8 [M+H]+: 513.2231, found 513.2246. MeO2C MeO2C Me N N MeO CO2Et Boc 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO OMe Me 909 1-(tert-butyl) N N OMe CO2Et Boc OH 910 2-ethyl 4-methyl 5-(1-(hydroxymethyl)-7,8-dimethoxy-6- methylisoquinolin-3-yl)-1H-pyrrole-1,2,4-tricarboxylate (910) In a flame-dried µW vial was charged with SeO2 (115 mg, 1.03 mmol, 2 equiv) and a magnetic stir bar. The vial was vacuum purged/refilled with N2 three times. A solution of isoquinoline 909 (265 mg, 0.52 mmol, 1 equiv) in 1,4-dioxane (10 mL, 0.05 M) was then added to the vial, and heated to reflux for 2 hours. After full consumption of starting material observed by LCMS analysis, the vial was cooled to room temperature and the crude reaction mixture was filtered through celite, rinsing with EtOAc. The crude reaction was concentrated, then dissolved in 4:1 DCM:MeOH (5 mL, 0.1 M total). NaBH4 (20 mg, 0.52 mmol, 1 equiv) was then added, and the reaction was stirred for 30 minutes at room temperature. After full conversion of the aldehyde intermediate observed by LCMS analysis, the reaction was quenched with citric acid monohydrate (218 mg, 1.04 mmol, 2 equiv) and water, and the solution was stirred rapidly for 10 minutes. The solution was then basified by the addition of saturated aq. NaHCO3 (10 mL), the layers were separated and the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 691 purified by silica column chromatography (20 → 30% EtOAc in hexanes) to yield isoquinoline 910 as a white solid (207 mg, 0.39 mmol, 75% yield); 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 5.28 (d, J = 4.3 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.72 (s, 3H), 2.45 (s, 3H), 1.38–1.36 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 163.9, 160.0, 156.7, 151.2, 149.3, 148.5, 138.6, 138.4, 134.1, 124.5, 124.4, 122.7, 120.2, 118.7, 114.8, 86.6, 64.3, 61.2, 60.9, 51.6, 27.2, 17.0, 14.5; IR (Neat Film, NaCl) 3413, 2980, 2939, 2836, 2365, 1774, 1716, 1558, 1443, 1382, 1330, 1237, 1215, 1152, 1077, 1005, 905, 736, 668 cm–1; HRMS (ESI+) m/z calc’d for C27H33N2O9 [M+H]+: 529.2181, found 529.2199. MeO2C Me N N MeO OMe CO2Et Boc [Ir(cod)Cl]2 (10 mol %) L6 (21 mol %), TBAI (60 mol %) H2 (60 bar) MeO2C Me 9:1 THF:AcOH, 80 °C, 42 h NH MeO OMe OH CO2Et Boc OH 911 910 1-(tert-butyl) N 2-ethyl 4-methyl 5-(1-(hydroxymethyl)-7,8-dimethoxy-6- methylisoquinolin-3-yl)-1H-pyrrole-1,2,4-tricarboxylate (911) To an oven-dried 1-dram vial equipped with a stir bar and isoquinoline 910 (5 mg, 0.01 mmol, 1 equiv) was capped with a PTFE-lined septum and pierced with one 21 gauge green needle. The vial was then placed in a Parr bomb and brought into the glovebox, with the exception of the pressure gauge. A layer of plastic wrap and a rubber band were also brought in to seal the top of the bomb. In a nitrogen-filled glovebox, a solution of the BTFM-xyliphos ligand (SL-J008-2) (1.9 mg, 0.0021 mmol, 21 mol %) and [Ir(cod)Cl]2 (0.67 mg, 0.001 mmol, 10 mol %) in THF (0.45 mL per reaction) was prepared and allowed to stand for 10 minutes. Meanwhile, a solution of TBAI (2.2 mg, 0.006 mmol, 0.6 equiv) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 692 in AcOH (0.05 mL per reaction) was prepared in a 1-dram vial, and 0.05 mL of the solution was added to each reaction vial via a syringe. Afterwards, 0.45 mL of the homogeneous iridium catalyst solution was added to each reaction vial via a syringe. After re-capping the vials with caps equipped with needles, the reactions were placed in the bomb and the top was covered tightly with plastic wrap secured by a rubber band. The bomb was then removed from the glovebox, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was repeated two more times, before charging the bomb to 60 bar H2. The bomb was then placed in an oil bath and heated to 80 °C for 42 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3 (1 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organics layers were then dried over Na2SO4, and concentrated in vacuo. The crude reaction mixture was purified by silica column chromatography (50 → 75% EtOAc in hexanes + 1% NEt3) to yield isoquinoline 911 as a white solid (2 mg, 0.004 mmol, 40% yield); 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.48 (s, 1H), 4.83 (dd, J = 11.2, 3.6 Hz, 1H), 4.06 (dd, J = 11.1, 3.4 Hz, 1H), 3.84–3.82 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.24–3.18 (m, 1H), 2.70 (dd, J = 15.7, 11.2 Hz, 1H), 2.13 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.9, 160.0, 156.7, 151.2, 149.3, 148.5, 138.6, 138.4, 134.1, 124.5, 124.4, 122.7, 120.2, 118.7, 114.8, 86.6, 64.3, 61.2, 60.9, 51.6, 27.2, 17.0, 14.5; IR (Neat Film, NaCl) 2979, 2877, 2835, 2364, 1697, 1682, 1674, 1582, Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 693 1362, 1293, 1202, 1136, 1084, 1025, 911, 832, 775, 737, 667 cm–1; HRMS (ESI+) m/z calc’d for N–H 911 C22H29N2O7 [M+H]+: 433.1969, found 433.1985. MeO2C Me N N MeO OMe MeO2C [Ir(cod)Cl]2 (10 mol %) Boc CO2Et L6 (21 mol %), TBAI (60 mol %) H2 (60 bar) Me 9:1 THF:AcOH, 80 °C, 42 h OMe OH 4-methyl CO2Et OBoc 912 910 2-ethyl N MeO N H 5-(1-(((tert-butoxycarbonyl)oxy)methyl)-7,8-dimethoxy-6- methylisoquinolin-3-yl)-1H-pyrrole-2,4-dicarboxylate (912) To an oven-dried 1-dram vial equipped with a stir bar and isoquinoline 910 (5 mg, 0.01 mmol, 1 equiv) was capped with a PTFE-lined septum and pierced with one 21 gauge green needle. The vial was then placed in a Parr bomb and brought into the glovebox, with the exception of the pressure gauge. A layer of plastic wrap and a rubber band were also brought in to seal the top of the bomb. In a nitrogen-filled glovebox, a solution of the BTFM-xyliphos ligand (SL-J008-2) (1.9 mg, 0.0021 mmol, 21 mol %) and [Ir(cod)Cl]2 (0.67 mg, 0.001 mmol, 10 mol %) in THF (0.45 mL per reaction) was prepared and allowed to stand for 10 minutes. Meanwhile, a solution of TBAI (2.2 mg, 0.006 mmol, 0.6 equiv) in AcOH (0.05 mL per reaction) was prepared in a 1-dram vial, and 0.05 mL of the solution was added to each reaction vial via a syringe. Afterwards, 0.45 mL of the homogeneous iridium catalyst solution was added to each reaction vial via a syringe. After re-capping the vials with caps equipped with needles, the reactions were placed in the bomb and the top was covered tightly with plastic wrap secured by a rubber band. The bomb was then removed from the glovebox, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 694 repeated two more times, before charging the bomb to 60 bar H2. The bomb was then placed in an oil bath and heated to 80 °C for 42 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3 (1 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organics layers were then dried over Na2SO4, and concentrated in vacuo. The crude reaction mixture was purified by silica column chromatography (40% EtOAc in hexanes) to yield isoquinoline 912 as a white solid (2.1 mg, 0.004 mmol, 40% yield); (207 mg, 0.39 mmol, 44% yield); 1H NMR (400 MHz, CDCl3) δ 10.69 (br s, 1H), 9.43 (s, 1H), 7.46 (s, 1H), 7.16 (s, 1H), 5.70 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.91 (s, 3H), 2.35 (s, 3H), 1.52 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 160.7, 159.2, 155.3, 153.6, 151.7, 138.4, 128.0, 126.4, 121.8, 120.1, 116.7, 113.6, 108.6, 97.8, 82.9, 68.2, 60.9, 56.0, 51.7, 31.1, 27.9, 14.6, 9.9; IR (Neat Film, NaCl) 2975, 2900, 2364, 1787, 1715, 1555, 1510, 1442, 1394, 1337, 1281, 1240, 1215, 1170, 1080, 1058, 934, 830, 750 cm–1; HRMS (ESI+) m/z calc’d for C27H33N2O9 [M+H]+: 529.2181, found 529.2199. MeO2C MeO2C Me N N MeO OMe Boc CO2Et PtO2 (1 equiv) H2 (60 bar) AcOH, 60 °C, 42 h Me OMe OH 4-methyl CO2Et OH 914 910 2-ethyl NH MeO N H 5-(1-(hydroxymethyl)-7,8-dimethoxy-6-methyl-1,2- dihydroisoquinolin-3-yl)-1H-pyrrole-2,4-dicarboxylate (914) Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 695 To an oven-dried scintillation vial equipped with a stir bar and isoquinoline 910 (50 mg, 0.1 mmol, 1 equiv) was charged with PtO2 (21 mg, 0.1 mmol, 1 equiv). The reaction mixture was dissolved in AcOH (0.95 mL, 0.1 M), and was capped with a PTFE-lined septum and pierced with two 21 gauge green needles. The reaction vial was then placed in the bomb reactor, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was repeated two more times, before charging the bomb to 60 bar H2. The bomb was then placed in an oil bath and heated to 60 °C for 42 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3 (1 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organics layers were then dried over Na2SO4, and concentrated in vacuo. The crude reaction mixture was purified by silica column chromatography (20 → 40% EtOAc in hexanes) to yield isoquinoline 914 as a white solid (34 mg, 0.08 mmol, 80% yield); 1H NMR (400 MHz, CDCl3) δ 9.70 (br s, 1H), 7.32 (s, 1H), 6.79 (s, 1H), 6.42 (s, 1H), 5.96 (dd, J = 9.4, 3.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.75–3.69 (m, 1H), 3.63–3.56 (m, 1H), 2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.5, 160.7, 153.1, 151.6, 148.7, 132.1, 127.0, 124.0, 123.2, 121.5, 118.0, 117.6, 113.9, 81.4, 62.1, 61.0, 61.0, 60.2, 51.8, 27.8, 16.0, 14.5; IR (Neat Film, NaCl) 3483, 3264, 2978, 2938, 2251, 1712, 1697, 1572, 1477, 1462, 1369, 1327, 1258, 1200, 1117, 1076, 911, 766, 733 cm–1; HRMS (ESI+) m/z calc’d for C22H27N2O7 [M+H]+: 431.1813, found 431.1829. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A MeO2C MeO2C Me N N MeO OMe 696 Boc CO2Et PtO2 (1 equiv) H2 (60 bar) CHCl3, 23 °C, 42 h Me N NH MeO OMe OH OH 910 915 CO2Et Boc 1-(tert-butyl) 2-ethyl 4-methyl 5-(1-(hydroxymethyl)-7,8-dimethoxy-6-methyl-1,2,3,4tetrahydroisoquinolin-3-yl)pyrrolidine-1,2,4-tricarboxylate (915) To an oven-dried scintillation vial equipped with a stir bar and isoquinoline 910 (50 mg, 0.1 mmol, 1 equiv) was charged with PtO2 (21 mg, 0.1 mmol, 1 equiv). The reaction mixture was dissolved in CHCl3 (0.95 mL, 0.1 M), and was capped with a PTFE-lined septum and pierced with two 21 gauge green needles. The reaction vial was then placed in the bomb reactor, and the pressure gauge was quickly screwed in place and tightened. The bomb was charged to 5-10 bar H2 and slowly released. This process was repeated two more times, before charging the bomb to 60 bar H2, and stirred at room temperature for 42 hours. Then, the bomb was removed from the stir plate and the hydrogen pressure was vented. The reaction vials were removed from the bomb and each solution was basified by the addition of saturated aqueous K2CO3 (1 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organics layers were then dried over Na2SO4, and concentrated in vacuo. The crude reaction mixture was purified by silica column chromatography (1:1 DCM:EtOAc + 1% MeOH + 1% NEt3) to yield tetrahydroisoquinoline 915 as a colorless oil (24 mg, 0.04 mmol, 44% yield); Due to the inseparable nature of diastereomers and the poor diastereoselectivity of this reaction, the dr cannot be determined and only the major diastereomer is reported. 1H NMR (400 MHz, CDCl3) δ 6.73 (s, 1H), 5.14 (s, 1H), 5.03–5.00 (m, 1H), 4.57–4.52 (m, 1H), 4.34–4.25 (m, Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 697 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.55–3.48 (m, 1H), 3.25–3.14 (m, 1H), 3.06–2.99 (m, 1H), 2.68–2.58 (m, 2H), 2.51–2.36 (m, 2H), 2.23 (s, 3H), 1.45 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3, 150.4, 150.3, 133.4, 131.8, 126.0, 125.7, 83.6, 81.4, 64.3, 62.1, 61.5, 60.4, 60.0, 59.2, 54.9, 53.1, 31.7, 30.9, 28.6, 28.3, 28.1, 15.8, 14.2, 14.0; IR (Neat Film, NaCl) 3388, 2977, 2946, 2890, 2836, 2521, 1783, 1738, 1695, 1461, 1392, 1371, 1198, 1177, 1163, 1082, 910, 821, 736 cm–1; HRMS (ESI+) m/z calc’d for C27H41N2O9 [M+H]+: 537.2807, found 537.2825. MeO2C Me N NH MeO OMe Boc HO2C N CO2Et Boc Me N LiOH THF:MeOH:H2O N MeO OMe OH 915 916 Boc CO2H Me + N MeO OMe O OH inseparable mixture O OH 917 Tetracycle (916 + 917) In a flame-dried 1-dram vial was charged with tetrahydroisoquinoline 915 (4.6 mg, 0.009 mmol, 1 equiv) in 2:1 THF:H2O (0.3 mL, 0.03 M total). LiOH (1 mg, 0.043 mmol, 5 equiv) was then added to the vial, and heated to 50 °C for 1 hour. After full consumption of starting material observed by LC-MS analysis, the crude reaction mixture was directly purified using reverse-phase (C18) preparative HPLC (MeCN/0.1% TFA in water, 5.0 mL/min, monitor wavelength = 230 nm, 20–75% MeCN over 8 minutes, hold at 80% for 2 minutes. Product 916 and 917 has tR = 4.2 minutes). Yellow film, (1 mg, 0.002 mmol, 23% yield); Due to the inseparable nature of both cyclized products 916 and 917, we are unable to assign each structure, respectively, by 1H NMR (see Figure A6.51). However, we are confident that the two isomers are indeed two different cyclized products, as we observe Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 698 trace formations of both cyclized products with either the appended methyl (i.e., 916) or ethyl ester (i.e., 917) during this reaction by LC-MS analysis. 1) SOCl2, MeOH 0 → 23 °C O N H 922 CO2H 2) Boc2O, DMAP, NEt3 CH2Cl2 O N CO2Me Boc 923 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (921) A flame-dried round bottom flask was charged with (S)-pyroglutamic acid 922 (1 g, 7.7 mmol, 1 equiv) in MeOH (30 mL, 0.26 M) and cooled to 0 °C. Thionyl chloride (0.06 mL, 0.8 mmol, 0.1 equiv) was then added dropwise, and the mixture was allowed to warm up to room temperature and stirred for 24 hours. Upon full consumption of starting material, solid K2CO3 (790 mg, 9.2 mmol, 1.2 equiv) was added to the reaction mixture, and the resulting solution was filtered over celite. The crude reaction was then concentrated and carried forward to the next step. The crude reaction mixture was dissolved in DCM (7.7 mL, 1 M), and charged with DMAP (94 mg, 0.77 mmol, 0.1 equiv) and NEt3 (1 mL, 7.7 mmol, 1 equiv). Then, a solution of Boc2O (3.4 g, 15.4 mmol, 2 equiv) in DCM (2.7 mL, 2.9 M) was added dropwise, and the resulting reaction mixture was stirred for 18 hours at room temperature. Upon full consumption of starting material, the reaction was quenched with 1 N HCl (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (40 → 50% EtOAc in hexanes) to yield lactam 923 as a clear oil (1.4 g, 5.9 mmol, 76% yield); 1H NMR (400 MHz, CDCl3) δ 4.20 (dd, J = 8.2, 4.3 Hz, 1H), 3.70 (s, 3H), 3.60–3.30 (m, 2H), 2.30–1.75 (m, 2H), 1.40 (s, 9H); All characterization data match those reported.33 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 699 MeO2C O LiHMDS Mander’s reagent N CO2Me THF, –78 °C O N Boc Boc 923 924 CO2Me 1-(tert-butyl) 2,4-dimethyl (2S)-5-oxopyrrolidine-1,2,4-tricarboxylate (921) A flame-dried round bottom flask was charged with lactam 923 (535 mg, 2.2 mmol, 1 equiv) in THF (13 mL, 0.17 M) and cooled to –78 °C. A solution of LiHMDS (1 M in THF, 4.4 mL, 4.4 mmol, 2 equiv) was then added dropwise, and the mixture was stirred for 30 minutes at –78 °C. Mander’s reagent (0.21 mL, 2.64 mmol, 1.2 equiv) was then added dropwise, and the resulting solution was stirred for 1 hour. Upon full consumption of starting material, the reaction was quenched with saturated aq. NH4Cl (10 mL) at –78 °C, and the resulting solution was warmed to room temperature. The reaction mixture was extracted with EtOAc (3 x 10 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (20 → 50% EtOAc in hexanes) to yield lactam 924 as a clear oil (556 mg, 1.85 mmol, 84% yield) (dr = 1.5:1); [α]D25 –12.6 (c 0.99, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.67 (dd, J = 9.5, 2.6 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.67 (dd, J = 10.2, 9.0 Hz, 1H), 2.72 (ddd, J = 13.5, 10.2, 9.5 Hz, 1H), 2.57–2.51 (m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.5, 168.6, 167.9, 149.1, 84.4, 57.2, 53.2, 52.9, 48.5, 27.9, 25.4; IR (Neat Film, NaCl) 3470, 2978, 2955, 2345, 1795, 1741, 1652, 1458, 1437, 1394, 1370, 1312, 1293, 1265, 1253, 1024, 903, 771, 736 cm–1; HRMS (MM:ESI+) m/z calc’d for N–H-924 C8H11NO5 [M+H]+: 202.0710, found 202.0716. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A MeO2C MeO2C O 1-(tert-butyl) 700 N CO2Me 2,6-di-tert-butyl-4-methylpyridine; Tf2O 1,2-DCE, 0 → 23 °C TfO N Boc Boc 924 921 2,4-dimethyl CO2Me (S)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H- pyrrole-1,2,4-tricarboxylate (921) A flame-dried round bottom flask was charged with 2,6-di-tert-butyl-4methylpyridine (43 mg, 0.21 mmol, 2.1 equiv), and the flask was vacuum purged/refilled with N2 three times. A solution of lactam 924 (30 mg, 0.1 mmol, 1 equiv) in 1,2-DCE (0.5 mL, 0.2 M) was then added to the reaction mixture, stirred for 10 minutes, and cooled to 0 °C. Freshly distilled Tf2O (0.02 mL, 0.12 mmol, 1.2 equiv) was added dropwise at 0 °C, then the ice bath was removed and allowed to warm to room temperature over 3 hours. Upon full consumption of starting material, the reaction flask was cooled to 0 °C, and quenched with saturated aq. NaHCO3 (2 mL), and the resulting solution was warmed to room temperature. The reaction mixture was extracted with DCM (3 x 1 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (15 → 35% EtOAc in hexanes) to yield dihydropyrrole 921 as a colorless oil (22 mg, 0.05 mmol, 51% yield); [α]D25 –58.3 (c 1.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.73 (dd, J = 12.1, 4.1 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.19 (dd, J = 16.4, 12.1 Hz, 1H), 2.84 (dd, J = 16.4, 4.0 Hz, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.5, 162.8, 149.3, 145.5, 118.5 (q, J = 321.1 Hz), 99.6, 84.6, 57.8, 52.9, 51.9, 29.1, 28.0; 19 F NMR (282 MHz, CDCl3) δ –73.4; IR (Neat Film, NaCl) 2981, 2957, 2356, 2341, 1747, 1714, 1658, 1651, 1439, 1395, 1372, 1269, 1251, 1228, 1177, 1134, 907, 828, 767 cm–1; Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 701 HRMS (MM:ESI+) m/z calc’d for N–H-921 C9H10F3NO7S [M+H]+: 334.0203, found 334.0197. Me OTf N MeO Pd(PPh3)4 (10 mol %) Sn2Bu6 (1.1 equiv), LiCl (5 equiv) Me 1,4-dioxane, 100 °C MeO SnBu3 N OMe Me OMe Me 887 927 7,8-dimethoxy-1,6-dimethyl-3-(tributylstannyl)isoquinoline (927) In a flame-dried µW vial was charged with isoquinoline 887 (40 mg, 0.11 mmol, 1 equiv) and a magnetic stirring bar, and brought in a N2-filled glovebox. To the reaction vial was added LiCl (23 mg, 0.55 mmol, 5 equiv), Pd(PPh3)4 (13 mg, 0.01 mmol, 0.1 equiv), and then Sn2Bu6 (0.06 mL, 0.12 mmol, 1.1 equiv) dissolved in 1,4-dioxane (3.7 mL, 0.03 M). The reaction vial was then sealed and taken out of the glovebox and heated to 100 °C over 18 hours. Upon full consumption of starting material, the reaction flask was cooled to room temperature, and filtered over celite rinsing with EtOAc. The crude reaction mixture was directly purified by silica column chromatography (0 → 5% → 10% EtOAc in hexanes + 1% NEt3) to yield isoquinoline 927 as a clear oil (43 mg, 0.08 mmol, 77% yield); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.52 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.21 (s, 3H), 2.45 (s, 3H), 1.68–1.54 (m, 7H), 1.36 (h, J = 7.1 Hz, 6H), 1.16–1.09 (m, 5H), 0.89 (t, J = 7.2 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 156.7, 150.6, 148.1, 137.0, 134.0, 128.9, 128.7, 124.8, 115.1, 60.9, 60.3, 29.3, 27.7, 27.5, 17.1, 13.9, 10.0; IR (Neat Film, NaCl) 3052, 2952, 2923, 2843, 1616, 1572, 1555, 1474, 1433, 1394, 1368, 1326, 1241, 1144, 1117, 1080, 1002, 889, 683 cm–1; HRMS (ESI+) m/z calc’d for C25H42NO2Sn [M+H]+: 500.2258, found 500.2262. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A Me N MeO OMe Me 1 equiv 927 MeO2C MeO2C SnBu3 + TfO 702 N CO2Me Pd(PPh3)4 (5 mol %) CuI (1.2 equiv) LiCl (1.24 equiv) Me N THF, 65 °C Boc 1 equiv 921 N MeO CO2Me Boc OMe Me 928 1-(tert-butyl) 2,4-dimethyl (S)-5-(7,8-dimethoxy-1,6-dimethylisoquinolin-3-yl)-2,3dihydro-1H-pyrrole-1,2,4-tricarboxylate (928) In a flame-dried µW vial was charged with triflate 921 (18.7 mg, 0.045 mmol, 1 equiv) and a magnetic stirring bar, and brought in a N2-filled glovebox. To the reaction vial was added CuI (10 mg, 0.052 mmol, 1.2 equiv), LiCl (2.3 mg, 0.054 mmol, 1.24 equiv), and Pd(PPh3)4 (2.5 mg, 0.002 mmol, 0.05 equiv). Then, a solution of isoquinoline 927 (22 mg, 0.045 mmol, 1 equiv) in THF (0.5 mL, 0.1 M) was added to the reaction vial and sealed. The reaction vial was taken out of the glovebox and heated to 65 °C over 18 hours. Upon full consumption of starting material, the reaction was quenched with saturated aq. NaHCO3 (1 mL) and extracted with EtOAc (3 x 1 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was purified by silica column chromatography (40% EtOAc in hexanes + 1% NEt3) to yield isoquinoline 928 as a white solid (14 mg, 0.03 mmol, 64% yield); [α]D25 –99.5 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.36 (s, 1H), 4.91 (dd, J = 12.3, 5.0 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.83 (s, 3H), 3.47 (s, 3H), 3.33 (dd, J = 16.5, 12.3 Hz, 1H), 3.10 (s, 3H), 2.94 (dd, J = 16.5, 5.0 Hz, 1H), 2.42 (s, 3H), 1.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 171.3, 164.8, 156.2, 150.9, 149.7, 142.5, 137.3, 134.4, 124.1, 122.2, 118.7, 110.2, 81.9, 60.8, 60.5, 60.3, 60.2, 52.7, 51.3, 32.7, 27.7, 27.1, 17.0; IR (Neat Film, NaCl) 2950, 2597, 1744, 1703, 1641, 1591, 1556, 1483, 1442, 1394, 1330, 1236, 1176, Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 703 1147, 1118, 1006, 892, 768, 733 cm–1; HRMS (ESI+) m/z calc’d for C26H33N2O8 [M+H]+: 501.2231, found 501.2210. MeO2C MeO2C Me N N MeO CO2Me Boc Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO N N OMe OMe Me 928 1-(tert-butyl) 1) SeO2 1,4-dioxane, 110 °C CO2Me Boc OH 929 2,4-dimethyl (S)-5-(1-(hydroxymethyl)-7,8-dimethoxy-6- methylisoquinolin-3-yl)-2,3-dihydro-1H-pyrrole-1,2,4-tricarboxylate (929) In a flame-dried µW vial was charged with SeO2 (2.8 mg, 0.03 mmol, 1.5 equiv) and a magnetic stir bar. The vial was vacuum purged/refilled with N2 three times. A solution of isoquinoline 928 (8.4 mg, 0.02 mmol, 1 equiv) in 1,4-dioxane (0.5 mL, 0.04 M) was then added to the vial, and heated to reflux for 2 hours. After full consumption of starting material observed by LCMS analysis, the vial was cooled to room temperature and the crude reaction mixture was filtered through celite, rinsing with EtOAc. The crude reaction was concentrated, then dissolved in 4:1 DCM:MeOH (0.2 mL, 0.1 M total). NaBH4 (0.6 mg, 0.02 mmol, 1 equiv) was then added, and the reaction was stirred for 30 minutes at room temperature. After full conversion of the aldehyde intermediate observed by LCMS analysis, the reaction was quenched with citric acid monohydrate (8.4 mg, 0.04 mmol, 2 equiv) and water, and the solution was stirred rapidly for 10 minutes. The solution was then basified by the addition of saturated aq. NaHCO3 (1 mL), the layers were separated and the aqueous phase was extracted with DCM (3 x 1 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The crude reaction mixture was purified by silica column chromatography (40% EtOAc in hexanes) to yield Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 704 isoquinoline 929 as a white solid (4.8 mg, 0.01 mmol, 55% yield); [α]D25 –35.9 (c 0.75, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.43 (s, 1H), 5.53 (br s, 1H), 5.28 (s, 2H), 4.93 (dd, J = 12.0, 4.5 Hz, 1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.51 (s, 3H), 3.37 (dd, J = 16.6, 12.1 Hz, 1H), 2.99 (dd, J = 16.6, 4.5 Hz, 1H), 2.43 (s, 3H), 1.06 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 172.0, 164.7, 156.1, 150.9, 150.8, 149.3, 138.2, 134.1, 124.2, 120.4, 120.2, 110.5, 82.1, 64.2, 60.8, 60.6, 60.3, 60.2, 52.8, 51.4, 33.0, 27.7, 27.1, 17.0; IR (Neat Film, NaCl) 3362, 2946, 2928, 2903, 1751, 1736, 1700, 1637, 1560, 1466, 1436, 1387, 1328, 1236, 1175, 1154, 1013, 892, 763 cm–1; HRMS (ESI+) m/z calc’d for C26H33N2O9 [M+H]+: 517.2181, found 517.2195. O N Boc 923 CO2Me LiBHEt3 PhMe, –78 °C then TFAA, DIPEA DMAP, –78 → 23 °C CO2Me N Boc 933 1-(tert-butyl) 2-methyl (S)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (933) In a flame-dried round bottom flask was charged with lactam 923 (1 g, 4.1 mmol, 1 equiv) in PhMe (5.6 mL, 0.7 M) and cooled to –78 °C. A solution of LiBHEt3 (1M in PhMe, 4.5 mL, 4.5 mmol, 1.1 equiv) was then added dropwise to the reaction flask at –78 °C, and stirred for 1 hour. Upon full consumption of starting material by TLC analysis, DMAP (5 mg, 0.04 mmol, 0.01 equiv) and DIPEA (4 mL, 23 mmol, 5.7 equiv) was then added to the reaction mixture at –78 °C, followed by TFAA (0.7 mL, 4.9 mmol, 1.2 equiv) dropwise. The dry ice bath was then removed and allowed to warm to room temperature over 6 hours. Upon full consumption of the lactol, the reaction was quenched with H2O (10 mL), extracted with Et2O (3 x 10 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (5 → 10% EtOAc in Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 705 hexanes) to yield dihydropyrrole 933 as a clear oil (679 mg, 3 mmol, 73% yield) (rr = 1.1:1); 1H NMR (400 MHz, CDCl3) δ 6.65 (s, 1H), 4.96 (s, 1H), 4.59 (dd, J = 11.9, 5.4 Hz, 1H), 3.76 (s, 3H), 3.12–3.01 (m, 1H), 2.72–2.62 (m, 1H), 1.44 (s, 9H); All characterization data match those reported.33 OHC CO2Me N Boc 933 POCl3, DMF CH2Cl2, 0 °C N CO2Me Boc 934 1-(tert-butyl) 2-methyl (S)-4-formyl-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (934) In a flame-dried round bottom flask was charged with DMF (0.62 mL, 8 mmol, 4 equiv) and cooled to 0 °C. POCl3 (0.38 mL, 4 mmol, 2 equiv) was then added dropwise to the reaction flask, and stirred rapidly at 0 °C for 30 minutes. The reaction was diluted with DCM (11 mL, 0.18 M), and a solution of dihydropyrrole 933 (457 mg, 2 mmol, 1 equiv) in DCM (4.5 mL, 0.44 M) was added dropwise at 0 °C and stirred for 1 hour. Upon full consumption of starting material, the reaction flask was poured into a separatory funnel with ice-cold 2M NaOH (10 mL), extracted with DCM (3 x 10 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (20 → 30% EtOAc in hexanes) to yield dihydropyrrole 934 as a clear oil (357 mg, 1.4 mmol, 70% yield) (rr = 1.3:1); 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.54 (s, 1H), 4.80 (dd, J = 12.4, 5.1 Hz, 1H), 3.78 (s, 3H), 3.28–3.18 (m, 1H), 2.94–2.80 (m, 1H), 2.11 (s, 9H); All characterization data match those reported.35 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A OHC N CO2Me NaClO2 2-methyl-2-butene NaH2PO4 1,4-dioxane:H2O 706 HO2C N Boc Boc 934 935 CO2Me (S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-4,5-dihydro-1H-pyrrole-3carboxylic acid (935) In a flame-dried round bottom flask was charged with aldehyde 934 (1.7 g, 6.5 mmol, 1 equiv) in 3:1 1,4-dioxane:H2O (40 mL, 0.16 M total). To this solution was added NaH2PO4 (3.92 g, 32.7 mmol, 5 equiv) and 2-methyl-2-butene (2.8 mL, 26.2 mmol, 4 equiv), then NaClO2 (416 mg, 4.6 mmol, 0.7 equiv) was added in one portion and stirred for 18 hours at room temperature. Upon full consumption of starting material, the reaction was quenched with saturated aq. NaHCO3 (20 mL) and stirred for 30 minutes. The reaction mixture was washed with 1 M HCl (20 mL), extracted with EtOAc (3 x 10 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (20 → 70% EtOAc in hexanes + 1% AcOH) to yield dihydropyrrole 935 as a white solid (1.3 g, 4.94 mmol, 76% yield) (rr = 1.3:1); [α]D25 –41.7 (c 0.99, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 4.80 (dd, J = 12.2, 5.0 Hz, 1H), 3.78 (s, 3H), 3.29–3.17 (m, 1H), 2.91–2.83 (m, 1H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.0, 170.3, 150.5, 142.5, 109.6, 83.3, 59.5, 52.8, 32.3, 28.2; IR (Neat Film, NaCl) 2978, 2362, 1754, 1727, 1673, 1620, 1434, 1371, 1268, 1240, 1214, 1166, 1150, 1023, 921, 890, 836, 766, 753 cm–1; HRMS (ESI+) m/z calc’d for N–H-935 C7H9NO4 [M+H]+: 172.0604, found 172.0598. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 707 O HO2C N Boc 935 CO2Me ethanolamine DIPEA, HATU CH2Cl2 HN HO N CO2Me Boc 936 1-(tert-butyl) 2-methyl (S)-4-((2-hydroxyethyl)carbamoyl)-2,3-dihydro-1H-pyrrole1,2-dicarboxylate (936) In a flame-dried round bottom flask was charged with carboxylic acid 935 (469 mg, 1.73 mmol, 1 equiv) in DCM (35 mL, 0.05 M) and sparged with N2 for 10 minutes. To the resulting mixture was added DIPEA (0.45 mL, 2.6 mmol, 1.5 equiv) and ethanolamine (0.13 mL, 2.1 mmol, 1.2 equiv), and the reaction mixture was stirred for 15 minutes. HATU (798 mg, 2.1 mmol, 1.2 equiv) was then added in one portion, and stirred for 18 hours at room temperature. Upon full consumption of starting material, the reaction was filtered, concentrated, and directly purified by silica column chromatography (2 → 10% MeOH in DCM) to yield amide 936 as a white amorphous solid (435 mg, 1.4 mmol, 80% yield) (rr = 1.1:1); [α]D25 –51.4 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 6.65 (br s, 1H), 4.67 (dd, J = 12.2, 5.1 Hz, 1H), 3.74 (s, 3H), 3.69–3.67 (m, 2H), 3.43–3.41 (m, 2H), 3.29–3.11 (m, 1H), 2.89–2.77 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.6, 165.4, 151.0, 135.5, 113.8, 82.5, 62.1, 59.5, 52.6, 42.5, 34.2, 28.1; IR (Neat Film, NaCl) 3333, 3108, 2978, 2359, 1748, 1715, 1643, 1540, 1455, 1368, 1285, 1256, 1155, 1062, 975, 918, 848, 763, 679 cm–1; HRMS (ESI+) m/z calc’d for C14H23N2O6 [M+H]+: 315.1551, found 315.1560. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A O 708 O N HN DAST HO N Boc 936 CO2Me CH2Cl2, –78 °C N CO2Me Boc 932 1-(tert-butyl) 2-methyl (S)-4-(4,5-dihydrooxazol-2-yl)-2,3-dihydro-1H-pyrrole-1,2dicarboxylate (932) In a flame-dried round bottom flask was charged with amide 936 (389 mg, 1.24 mmol, 1 equiv) in DCM (11.3 mL, 0.11 M) and cooled to –78 °C. To this solution was added DAST (0.18 mL, 1.37 mmol, 1.1 equiv) dropwise at –78 °C, and stirred for 1 hour. Upon full consumption of starting material, the reaction was quenched with saturated aq. NaHCO3 (10 mL), extracted with DCM (3 x 5 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (100% EtOAc) to yield dihydropyrrole 932 as a colorless amorphous solid (290 mg, 0.98 mmol, 79% yield) (rr = 1.3:1); [α]D25 –38.4 (c 1.09, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 4.75 (dd, J = 12.1, 4.9 Hz, 1H), 4.26 (t, J = 9.2 Hz, 2H), 3.88 (t, J = 9.3 Hz, 2H), 3.75 (s, 3H), 3.35–3.22 (m, 1H), 2.96–2.86 (m, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.3, 161.6, 150.9, 135.4, 107.5, 82.5, 67.4, 58.8, 54.9, 52.7, 33.5, 28.3; IR (Neat Film, NaCl) 3127, 2976, 2877, 2364, 1754, 1715, 1660, 1610, 1478, 1370, 1328, 1263, 1163, 1046, 970, 905, 830, 762, 690 cm–1; HRMS (ESI+) m/z calc’d for C14H21N2O5 [M+H]+: 297.1445, found 297.1449. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A O 709 O N N NaBH4, LiCl N CO2Me THF:EtOH N Boc Boc 932 938 OH tert-butyl (S)-4-(4,5-dihydrooxazol-2-yl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole1-carboxylate (938) In a flame-dried round bottom flask was charged with NaBH4 (102 mg, 2.69 mmol, 3 equiv), LiCl (114 mg, 2.69 mmol, 3 equiv) in EtOH (3.7 mL, 0.24 M). The reaction flask was cooled to 0 °C, and stirred for 10 minutes. To the resulting mixture was added a solution of dihydropyrrole 932 (263 mg, 0.89 mmol, 1 equiv) in THF (3.7 mL, 0.24 M) dropwise at 0 °C. The ice bath was then removed and allowed to warm to room temperature over 18 hours. Upon full consumption of starting material, the reaction was quenched with H2O (5 mL), extracted with Et2O (3 x 5 mL), dried over Na2SO4, and concentrated. The crude reaction mixture was purified by silica column chromatography (10% MeOH in EtOAc) to yield dihydropyrrole 938 as a white solid (177 mg, 0.66 mmol, 74% yield); [α]D25 –118.9 (c 1.07, CHCl3); 1H NMR (400 MHz, CD3OD) δ 7.15 (s, 1H), 4.87 (s, 2H), 4.35–4.30 (m, 2H), 3.90–3.85 (m, 2H), 3.64–3.61 (m, 1H), 3.06–3.00 (m, 1H), 2.88–2.77 (m, 1H), 1.51 (s, 9H); 13C NMR (100 MHz, CD3OD) δ 164.6, 137.6, 109.3, 83.0, 68.6, 63.2, 61.2, 54.8, 33.4, 32.3, 28.5; IR (Neat Film, NaCl) 3258, 2976, 2933, 2878, 2357, 2330, 1708, 1653, 1476, 1455, 1430, 1369, 1307, 1240, 1164, 1048, 997, 825, 761 cm–1; HRMS (ESI+) m/z calc’d for C13H21N2O4 [M+H]+: 269.1496, found 269.1510. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 710 O Pd(OAc)2 (2.5 mol %) PCy3 (5 mol %) Cs2CO3 (3.5 equiv) CsOPiv (12.5 mol %) O Me N OTf N MeO + PhMe, 110 °C, 18 h N OMe Me 887 Boc OH N Me N N MeO 938 OH Boc OMe Me 939 tert-butyl (S)-4-(4,5-dihydrooxazol-2-yl)-5-(7,8-dimethoxy-1,6-dimethylisoquinolin-3yl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (939) In a flame-dried µW vial was charged with isoquinoline 887 (5 mg, 0.014 mmol, 1 equiv), dihydropyrrole 938 (5.5 mg, 0.02 mmol, 1.5 equiv) and a magnetic stirring bar, and brought in a N2-filled glovebox. In the glovebox, Cs2CO3 (15.6 mg, 0.05 mmol, 3.5 equiv) and CsOPiv (0.4 mg, 0.0017 mmol, 0.125 equiv) were weighed out and added to the reaction vial. A stock solution of the catalyst was prepared by adding Pd(OAc)2 (0.08 mg, 0.0003 mmol for each reaction vial, 2.5 mol %) and PCy3 (0.2 mg, 0.0007 mmol for each reaction vial, 5 mol %) dissolved in PhMe (0.34 mL for each reaction vial, 0.04 M) in a separate 1-dram vial. Upon complete dissolution of the catalyst, 0.34 mL of the solution was transferred to the reaction vial. The vial was then removed from the glovebox, and placed in an oil bath to stir for 18 hours at 110 °C. Upon full consumption of starting material, the reaction vial was cooled to room temperature, and filtered over celite. The crude reaction mixture was directly purified by silica column chromatography (1:1 DCM:EtOAc + 1% MeOH + 1% NEt3) to yield isoquinoline 939 as a yellow oil (3.1 mg, 0.006 mmol, 47% yield); [α]D25 –99.5 (c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 6.67 (s, 1H), 4.74–4.63 (m, 1H), 4.50 (dd, J = 9.8, 3.7 Hz, 1H), 4.42–4.36 (m, 1H), 4.27 (t, J = 9.3 Hz, 2H), 3.94 (s, 3H), 3.91 (t, J = 9.3 Hz, 2H), 3.89 (s, 3H), 3.17–3.12 (m, 1H), 3.03 (dd, J = 4.1, 1.5 Hz, 1H), 3.01 (s, 3H), 2.38 (s, 3H), 1.49 (s, 9H); 13C NMR (100 Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A 711 MHz, CDCl3) δ 164.7, 158.9, 156.4, 149.8, 148.2, 138.4, 137.4, 135.5, 122.4, 119.3, 108.7, 98.4, 81.8, 67.3, 66.1, 60.8, 60.3, 57.6, 54.9, 53.6, 28.4, 27.3, 26.8, 17.1; IR (Neat Film, NaCl) 3332, 2927, 1994, 1797, 1711, 1652, 1508, 1440, 1360, 1326, 1269, 1236, 1123, 1036, 1008, 902, 828, 749, 680 cm–1; HRMS (ESI+) m/z calc’d for C26H34N3O6 [M+H]+: 484.2442, found 484.2446. 5.8 REFERENCES AND NOTES (1) Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The Chemistry and Biology of Isoquinoline Alkaloids; Springer, 1985. (2) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev. 2008, 37, 2676–2690. (3) Hayashi, T.; Noto, T.; Nawata, Y.; Okazaki, H.; Sawada, M.; Ando, K. J. Antibiot. 1982, 35, 771–777. (4) a) Zmijewski, M. J. Jr.; Mikolajczak, M.; Viswanatha, V.; Hruby, V. J. J. Am. Chem. Soc. 1982, 104, 4969–4971; b) Zmijewski, M. J.; Palaniswamy, V. A.; Gould, S. J. J. Chem. Soc., Chem. Commun. 1985, 18, 1261–1262. (5) Pu, J.-Y.; Peng, C.; Tang, M.-C.; Zhang, Y.; Guo, J.-P.; Song, L.-Q.; Hua, Q.; Tang, G.-L. Org. Lett. 2013, 15, 3674–3677. (6) Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108, 2478–2479. (7) Fukuyama, T.; Li, L.; Laird, A. A.; Frank, R. K. J. Am. Chem. Soc. 1987, 109, 1587–1589. (8) Illig, C. R. Ph.D. Dissertation, Harvard University, Cambridge, MA, 1987. (9) Fukuyama, T. Adv. Heterocycl. Nat. Prod. Synth. 1992, 2, 189–249. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A (10) 712 a) Ümit Kaniskan, H.; Garner, P. J. Am. Chem. Soc. 2007, 129, 15460–15461; b) Garner, P.; Ümit Kaniskan, H.; Keyari, C. M.; Weerasinghe, L. J. Org. Chem. 2011, 76, 5283–5294. (11) Willis, N. J.; Bray, C. D. Chem. Eur. J. 2012, 18, 9160–9173. (12) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202–9203. (13) a) Kim, A. N.; Ngamnithiporn, A.; Welin, E. R.; Daiger, M. T.; Grünanger, C. U.; Bartberger, M. D.; Virgil, S. C.; Stoltz, B. M. ACS Catal. 2020, 10, 3241–3248; b) Kim, A. N.; Ngamnithiporn, A. Bartberger, M. D.; Stoltz, B. M. Chem. Sci. 2022, 13, 3227–3232. (14) a) Welin, E. R.; Ngamnithiporn, A.; Klatte, M.; Lapointe, G.; Pototschnig, G. M.; McDermott, M. S. J.; Conklin, D.; Gilmore, C. D.; Tadross, P. M.; Haley, C. K.; Negoro, K.; Glibstrup, E.; Grünanger, C. U.; Allan, K. M.; Virgil, S. C.; Slamon, D. J.; Stoltz, B. M. Science. 2019, 363, 270–275; b) Allan, K. M.; Hong, B. D.; Stoltz, B. M. Org. Biomol. Chem. 2009, 7, 4960–4964. (15) Warashina, T.; Matsuura, D.; Sengoku, T.; Takahashi, M.; Yoda, H.; Kimura, Y. Org. Process Res. Dev. 2019, 23, 614–618. (16) Protection of the aldehyde as the acetal resulted in low conversions, so we elected to reduce the aldehyde to the alcohol oxidation state. (17) Molander, G. A.; Trice, S. L.; Kennedy, S. M. J. Org. Chem. 2012, 77, 8678–8688. (18) Protection of the alcohol to circumvent expulsion of the hydroxyl group resulted in trace conversion of the pyrrole. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A (19) 713 Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. J. Org. Chem. 1981, 46, 157–164. (20) a) Reimann, C. E.; Ngamnithiporn, A.; Hayashida, K.; Saito, D.; Korch, K. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2021, 60, 17957–17962; b) Fürstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.; Nevado, C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2783–2875. (21) Xue, F.; Silverman, R. B. Tetrahedron Lett. 2010, 51, 2536–2538. (22) Hegedús, L.; Máthé, T. Appl. Catal., A 2002, 226, 319–322. (23) Kuwano, R.; Kashiwabara, M.; Ohsumi, M.; Kusano, H. J. Am. Chem. Soc. 2008, 130, 808–809. (24) Protection of the hydroxymethyl group to prevent the Boc-migration pathway resulted in no conversion of starting material. (25) Due to the low diastereoselectivity and inseparable nature of the diastereomers, the dr cannot be determined, however, we observe at least 4 diastereomers after isolation. (26) a) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman, J. W. Synthesis 2005, 4, 547–550; b) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164–168. (27) Molander, G. A.; Cavalcanti, L. N.; García-García, C. J. Org. Chem. 2013, 78, 6427–6439. (28) Gribanov, P. S.; Golenko, Y. D.; Topchiy, M. A.; Minaeva, L. I.; Asachenko, A. F.; Nechaev, M. S. Eur. J. Org. Chem. 2018, 2018, 120–125. Chapter 5 – Progress Toward the Total Synthesis of (+)-Cyanocycline A (29) 714 Casado, A. L.; Espinet, P.; Gallego, A. M. J. Am. Chem. Soc. 2000, 122, 11771– 11782. (30) Variation of the substituent at the C3-position of the dihydropyrrole was attempted to differentiate between the two ester functionalities but were unsuccessful, providing much lower yields of the triflation and Stille cross-coupling. (31) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848– 10849. (32) For examples of cyclic enamide cross-couplings, see: a) Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 43–46; b) Beng, T. K.; Langevin, S.; Braunstein, H.; Khim, M. Org. Biomol. Chem. 2016, 14, 830–834. (33) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem. 1999, 64, 6646–6652. (34) For examples of Pd-catalyzed C–H direct arylation reactions, see: a) Verrier, C.; Lassalas, P.; Théveau, L.; Quéguiner, G.; Trécourt, F.; Marsais, F.; Hoarau, C. Beilstein J. Org. Chem. 2011, 7, 1584–1601; b) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673–714; c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792–9826; d) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172–8174; e) Wang, L.; Carrow, B. P. ACS Catal. 2019, 9, 6821–6836. (35) Woo, G. H. C.; Kim, S.-H.; Wipf, P. Tetrahedron 2006, 62, 10507–10517. (36) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–1126. (37) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–16497. Appendix 5 – Synthetic Summary for Chapter 5 715 APPENDIX 5 Synthetic Summary for Chapter 5: Progress Toward the Total Synthesis of (+)-Cyanocycline A Appendix 5 – Synthetic Summary for Chapter 5 716 Scheme A5.1 Synthesis of the western isoquinoline fragment 887. [Ir(cod)OMe]2 (5 mol %) 3,4,7,8-tetramethylphenanthroline (10 mol %) B2pin2 (0.75 equiv), THF, 80 °C Me MeO Me 889 O MeO O TMS PhNTf2, THF, –78 °C MeO methyl acetoacetate CsF, CH3CN, 80 °C TMS then aq. NH4OH, 60 °C OMe 99% yield 20–45% yield 892 891 Me OH OTf Tf2O, pyridine N MeO OTf Et2NH, n-BuLi OMe Me 93% yield 890 Me NHi-Pr then TMSCl, Et2O, –78 °C OMe 79% overall yield Me TMEDA, TBSOTf, n-BuLi O MeO then NMO, 80 °C then NEt3, i-PrNCO OMe NHi-Pr O CH2Cl2, 0 °C OMe Me N MeO OMe Me 94% yield 887 893 Scheme A5.2 Synthesis of the eastern pyrrole fragment 898. CO2Et N H dichloromethyl methyl ether AlCl3 (2 equiv) O O Br2 1:1 CH2Cl2:MeNO2, –15 °C 894 N H 99% yield CO2Et CH2Cl2, 0 → 23 °C 895 N H 896 74% yield O HO (MeO)2SO2, K2CO3 CH3COCH3 Br NaBH4 Br N CO2Et Me 90% yield Br MeOH:CH2Cl2 Me 99% yield 897 CO2Et N 898 Scheme A5.3 2nd generation synthesis of pyrrole fragment 902. O HO O Boc2O, DMAP N H CO2Et 895 NaBH4 N CH2Cl2 Boc 98% yield 900 HO TMP, n-BuLi THF, –78 °C then Bu3SnCl 91% yield Bu3Sn N Boc 902 CO2Et CO2Et MeOH:CH2Cl2 99% yield N Boc 901 CO2Et CO2Et Appendix 5 – Synthetic Summary for Chapter 5 717 Scheme A5.4 Cross-coupling of heterocycles 887 and 902, and synthesis of hydrogenation precursor 904. HO HO Me OTf N MeO + Bu3Sn N CO2Et Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP (0.06 M), 25 °C MeO Boc OMe Me N CO2Et Boc OMe Me 68% yield 902 887 N 903 HO 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO CO2Et N Boc N OMe 61% yield over 2 steps OH 904 Scheme A5.5 3rd generation synthesis of pyrrole fragment 908. O HO2C NaClO2, KH2PO4 sulfamic acid N CO2Et MeO2C (MeO)2SO2, K2CO3 CO2Et N 1,4-dioxane:H2O Boc Boc 900 906 MeO2C CO2Et CH3COCH3 N 89% yield over 2 steps 907 Boc TMP, n-BuLi THF, –78 °C Bu3Sn then Bu3SnCl CO2Et N Boc 90% yield 908 Scheme A5.6 Stille cross-coupling and synthesis of hydrogenation precursor 910. MeO2C Me MeO2C OTf N MeO + Bu3Sn OMe Me 1 equiv 887 N CO2Et Pd(PPh3)4 (10 mol %) CuTC (1.1 equiv) Me NMP, 25 °C MeO Boc 1 equiv 96% yield 908 MeO2C 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO 75% yield over 2 steps N N OMe OH 910 Boc CO2Et N N OMe Me 909 Boc CO2Et Appendix 5 – Synthetic Summary for Chapter 5 718 Scheme A5.7 Hydrogenation attempts of isoquinoline 910. MeO2C Me MeO2C N OMe OMe L6 (21 mol %), TBAI (60 mol %) OH H2 (60 bar) 911 + 9:1 THF:AcOH, 80 °C, 42 h Boc N MeO CO2Et MeO2C 40% yield of THIQ 911 44% Boc-migrated pdt 912 OH Me 910 P(Ar)2 P(Xyl)2 Fe Me OMe OBoc 912 MeO2C MeO2C N OMe CO2Et Me PtO2 (1 equiv), H2 (60 bar) Boc N MeO N H N MeO L6: Ar = BTFM Me CHCl3, 23 °C, 42 h N NH MeO OMe 44% isolated yield OH 910 CO2Et Boc OH 915 Scheme A5.8 Synthesis of dihydropyrrole coupling partner 921. 1) SOCl2, MeOH 0 → 23 °C O CO2H N H (S)-pyroglutamic acid 922 2) Boc2O, DMAP, NEt3 CH2Cl2 O 76% yield over 2 steps N CO2Me LiHMDS Mander’s reagent THF, –78 °C Boc 923 84% yield MeO2C MeO2C O N CO2Me 2,6-di-tert-butyl-4-methylpyridine; Tf2O 1,2-DCE, 0 → 23 °C 924 TfO N Boc Boc 20–51% yield CO2Et Boc NH MeO [Ir(cod)Cl]2 (10 mol %) Me N 921 CO2Me CO2Et Appendix 5 – Synthetic Summary for Chapter 5 719 Scheme A5.9 Stannylation of isoquinoline triflate 887 and synthesis of dihydropyrrole hydrogenation precursor 929. Me OTf N MeO Pd(PPh3)4 (10 mol %) Sn2Bu6 (1.1 equiv), LiCl (5 equiv) Me 1,4-dioxane, 100 °C MeO OMe Me SnBu3 N OMe Me 77% yield 927 887 Me MeO2C SnBu3 + N MeO TfO MeO2C Pd(PPh3)4 (5 mol %) CuI (1.2 equiv) LiCl (1.24 equiv) CO2Me N OMe Me Boc 927 921 THF, 65 °C Me N Boc N MeO 64% yield OMe Me 928 MeO2C MeO2C Me N Boc N MeO CO2Me OMe Me 1) SeO2 1,4-dioxane, 110 °C Me 2) NaBH4 4:1 CH2Cl2:MeOH MeO N OMe 55% yield over 2 steps 928 CO2Me N Boc OH 929 Scheme A5.10 Synthesis of oxazoline dihydropyrrole coupling partner 932. OHC O N CO2Me Boc 923 LiBHEt3 PhMe, –78 °C then TFAA, DIPEA DMAP, –78 → 23 °C 73% yield CO2Me N Boc 933 CO2Me N 1,4-dioxane:H2O ethanolamine DIPEA, HATU CH2Cl2 Boc 935 76% yield O N DAST 79% yield N Boc 934 70% yield O HO2C NaClO2 2-methyl-2-butene NaH2PO4 CH2Cl2, –78 °C POCl3, DMF CH2Cl2, 0 °C N Boc 932 CO2Me 80% yield HN HO N Boc 936 CO2Me CO2Me CO2Me Appendix 5 – Synthetic Summary for Chapter 5 720 Scheme A5.11 Reduction of oxazoline 932 and Pd-catalyzed CMD cross-coupling of heterocycles 887 and 938. O O N N NaBH4, LiCl THF:EtOH CO2Me N Boc 74% yield N Boc OH 938 932 O O Me N OTf N MeO Pd(OAc)2 (2.5 mol %) PCy3 (5 mol %) Cs2CO3 (3.5 equiv) CsOPiv (12.5 mol %) + N OMe Me 1 equiv 887 Boc OH 1.5 equiv 938 PhMe, 110 °C, 18 h 47% yield N Me N N MeO OMe Me 939 Boc OH Appendix 6 – Spectra Relevant to Chapter 5 721 APPENDIX 6 Spectra Relevant to Chapter 5: Progress Toward the Total Synthesis of (+)-Cyanocycline A 11 10 Br O 896 N H 9 CO2Et 8 6 ppm 5 4 3 Figure A6.1 1H NMR (400 MHz, CDCl3) of compound 896. 7 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 722 Appendix 6 – Spectra Relevant to Chapter 5 723 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 896. 180 160 140 120 100 ppm 80 60 40 Figure A6.3 13C NMR (100 MHz, CDCl3) of compound 896. 20 11 10 Br O N 897 Me 9 CO2Et 8 6 ppm 5 4 3 2 Figure A6.4 1H NMR (400 MHz, CDCl3) of compound 897. 7 1 0 Appendix 6 – Spectra Relevant to Chapter 5 724 Appendix 6 – Spectra Relevant to Chapter 5 725 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 897. 180 160 140 120 100 ppm 80 60 40 Figure A6.6 13C NMR (100 MHz, CDCl3) of compound 897. 20 7 Br HO 898 Me N CO2Et 6 4 ppm 3 Figure A6.7 1H NMR (400 MHz, CDCl3) of compound 898. 5 2 1 Appendix 6 – Spectra Relevant to Chapter 5 726 Appendix 6 – Spectra Relevant to Chapter 5 727 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 898. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.9 13C NMR (100 MHz, CDCl3) of compound 898. 20 10 8 MeO Me MeO N 7 899 Me EtO N Me 6 5 ppm 4 3 Figure A6.10 1H NMR (400 MHz, CDCl3) of compound 899. CO2Et 2 1 Appendix 6 – Spectra Relevant to Chapter 5 728 Appendix 6 – Spectra Relevant to Chapter 5 729 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 899. 180 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.12 13C NMR (100 MHz, CDCl3) of compound 899. 20 10 10 O N 9 900 Boc CO2Et 7 6 ppm 5 4 3 Figure A6.13 1H NMR (400 MHz, CDCl3) of compound 900. 8 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 730 Appendix 6 – Spectra Relevant to Chapter 5 731 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 900. 180 160 140 120 100 ppm 80 60 40 Figure A6.15 13C NMR (100 MHz, CDCl3) of compound 900. 20 8 7 HO 901 Boc N CO2Et 6 4 ppm 3 Figure A6.16 1H NMR (400 MHz, CDCl3) of compound 901. 5 2 1 Appendix 6 – Spectra Relevant to Chapter 5 732 Appendix 6 – Spectra Relevant to Chapter 5 733 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 901. 170 160 150 140 130 120 110 13 100 90 ppm 80 70 60 50 40 30 20 Figure A6.18 C NMR (100 MHz, CDCl3) of compound 901. 10 9 8 Bu3Sn HO 902 Boc N 7 CO2Et 5 ppm 4 3 2 Figure A6.19 1H NMR (400 MHz, CDCl3) of compound 902. 6 1 0 Appendix 6 – Spectra Relevant to Chapter 5 734 Appendix 6 – Spectra Relevant to Chapter 5 735 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 902. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.21 13C NMR (100 MHz, CDCl3) of compound 902. 20 10 8 MeO Me 7 N 903 OMe Me HO 6 CO2Et 5 ppm 4 3 Figure A6.22 1H NMR (400 MHz, CDCl3) of compound 903. Boc N 2 1 Appendix 6 – Spectra Relevant to Chapter 5 736 Appendix 6 – Spectra Relevant to Chapter 5 737 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 903. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.24 13C NMR (100 MHz, CDCl3) of compound 903. 20 10 9 MeO Me 8 OMe OH N 904 HO CO2Et 6 5 ppm 4 3 Figure A6.25 1H NMR (400 MHz, CDCl3) of compound 904. 7 Boc N 2 1 Appendix 6 – Spectra Relevant to Chapter 5 738 Appendix 6 – Spectra Relevant to Chapter 5 739 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 904. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A6.27 13C NMR (100 MHz, CDCl3) of compound 904. 10 0 8 MeO2C 907 Boc N 7 CO2Et 5 ppm 4 3 Figure A6.28 1H NMR (400 MHz, CDCl3) of compound 907. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 740 Appendix 6 – Spectra Relevant to Chapter 5 741 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 907. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.30 13C NMR (100 MHz, CDCl3) of compound 907. 20 10 0 8 7 Bu3Sn MeO2C 908 Boc N CO2Et 6 4 ppm 3 2 Figure A6.31 1H NMR (400 MHz, CDCl3) of compound 908. 5 1 0 Appendix 6 – Spectra Relevant to Chapter 5 742 Appendix 6 – Spectra Relevant to Chapter 5 743 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 908. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.33 13C NMR (100 MHz, CDCl3) of compound 908. 20 10 8 7 MeO Me 909 OMe Me N MeO2C CO2Et 5 ppm 4 3 2 Figure A6.34 1H NMR (400 MHz, CDCl3) of compound 909. 6 Boc N 1 0 Appendix 6 – Spectra Relevant to Chapter 5 744 Appendix 6 – Spectra Relevant to Chapter 5 745 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 909. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.36 13C NMR (100 MHz, CDCl3) of compound 909. 20 10 8 MeO Me OMe 7 910 OH N MeO2C CO2Et 6 5 ppm 4 3 Figure A6.37 1H NMR (400 MHz, CDCl3) of compound 910. Boc N 2 1 Appendix 6 – Spectra Relevant to Chapter 5 746 Appendix 6 – Spectra Relevant to Chapter 5 747 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 910. 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.39 13C NMR (100 MHz, CDCl3) of compound 910. 20 10 9 MeO Me 8 OMe 911 OH NH MeO2C 7 Boc N 6 5 ppm 4 3 Figure A6.40 1H NMR (400 MHz, CDCl3) of compound 911. CO2Et 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 748 Appendix 6 – Spectra Relevant to Chapter 5 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 911. 749 11 10 MeO Me OMe 912 9 OBoc N MeO2C N H 8 7 6 ppm 5 4 3 Figure A6.42 1H NMR (400 MHz, CDCl3) of compound 912. CO2Et 2 1 Appendix 6 – Spectra Relevant to Chapter 5 750 Appendix 6 – Spectra Relevant to Chapter 5 751 Figure A6.43 Infrared spectrum (Thin Film, NaCl) of compound 912. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.44 13C NMR (100 MHz, CDCl3) of compound 912. 20 10 0 10 MeO Me 9 OMe 914 OH NH MeO2C 8 N H 7 6 ppm 5 4 3 Figure A6.45 1H NMR (400 MHz, CDCl3) of compound 914. CO2Et 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 752 Appendix 6 – Spectra Relevant to Chapter 5 753 Figure A6.46 Infrared spectrum (Thin Film, NaCl) of compound 914. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.47 13C NMR (100 MHz, CDCl3) of compound 914. 20 10 9 MeO Me 8 OMe 915 OH NH MeO2C Boc N 6 5 ppm 4 3 Figure A6.48 1H NMR (400 MHz, CDCl3) of compound 915. 7 CO2Et 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 754 Appendix 6 – Spectra Relevant to Chapter 5 755 Figure A6.49 Infrared spectrum (Thin Film, NaCl) of compound 915. c 180 160 140 120 13 100 ppm 80 60 40 Figure A6.50 C NMR (100 MHz, CDCl3) of compound 915. 20 8 7 MeO Me 6 O OH + MeO Me 5 inseparable mixture N Boc OMe 917 OH N 4 ppm O N Boc CO2H 3 2 Figure A6.51 1H NMR (400 MHz, CDCl3) of compounds 916 + 917. 916 OMe N HO2C 1 0 Appendix 6 – Spectra Relevant to Chapter 5 756 8 O MeO2C 924 Boc N 7 CO2Me 5 ppm 4 3 2 Figure A6.52 1H NMR (400 MHz, CDCl3) of compound 924. 6 1 0 Appendix 6 – Spectra Relevant to Chapter 5 757 Appendix 6 – Spectra Relevant to Chapter 5 758 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound 924. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A6.54 13C NMR (100 MHz, CDCl3) of compound 924. 20 10 8 TfO MeO2C 7 921 Boc N CO2Me 5 ppm 4 3 Figure A6.55 1H NMR (400 MHz, CDCl3) of compound 921. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 759 Appendix 6 – Spectra Relevant to Chapter 5 760 Figure A6.56 Infrared spectrum (Thin Film, NaCl) of compound 921. c 180 160 140 120 100 ppm 80 60 40 Figure A6.57 13C NMR (100 MHz, CDCl3) of compound 921. 20 Appendix 6 – Spectra Relevant to Chapter 5 -30 -40 -50 -60 -70 ppm -80 761 -90 -100 -110 Figure A6.58 19F NMR (282 MHz, CDCl3) of compound 921. c -120 10 9 MeO Me 927 8 OMe Me N 7 6 5 ppm 4 3 2 Figure A6.59 1H NMR (400 MHz, CDCl3) of compound 927. SnBu3 1 0 -1 Appendix 6 – Spectra Relevant to Chapter 5 762 Appendix 6 – Spectra Relevant to Chapter 5 763 Figure A6.60 Infrared spectrum (Thin Film, NaCl) of compound 927. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A6.61 13C NMR (100 MHz, CDCl3) of compound 927. 10 0 9 MeO Me 8 928 OMe Me N MeO2C CO2Me 6 5 ppm 4 3 Figure A6.62 1H NMR (400 MHz, CDCl3) of compound 928. 7 Boc N 2 1 0 Appendix 6 – Spectra Relevant to Chapter 5 764 Appendix 6 – Spectra Relevant to Chapter 5 765 Figure A6.63 Infrared spectrum (Thin Film, NaCl) of compound 928. c 180 160 140 120 100 ppm 80 60 40 Figure A6.64 13C NMR (100 MHz, CDCl3) of compound 928. 20 9 MeO Me 8 OMe 929 OH N MeO2C 7 CO2Me 6 5 ppm 4 3 Figure A6.65 1H NMR (400 MHz, CDCl3) of compound 929. Boc N 2 1 Appendix 6 – Spectra Relevant to Chapter 5 766 Appendix 6 – Spectra Relevant to Chapter 5 767 Figure A6.66 Infrared spectrum (Thin Film, NaCl) of compound 929. c 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.67 13C NMR (100 MHz, CDCl3) of compound 929. 20 10 9 HO2C 8 935 Boc N CO2Me 6 5 ppm 4 3 Figure A6.68 1H NMR (400 MHz, CDCl3) of compound 935. 7 2 1 Appendix 6 – Spectra Relevant to Chapter 5 768 Appendix 6 – Spectra Relevant to Chapter 5 769 Figure A6.69 Infrared spectrum (Thin Film, NaCl) of compound 935. c 180 170 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 Figure A6.70 13C NMR (100 MHz, CDCl3) of compound 935. 20 10 9 HO HN 8 O 936 Boc N CO2Me 7 5 ppm 4 3 Figure A6.71 1H NMR (400 MHz, CDCl3) of compound 936. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 770 Appendix 6 – Spectra Relevant to Chapter 5 771 Figure A6.72 Infrared spectrum (Thin Film, NaCl) of compound 936. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A6.73 13C NMR (100 MHz, CDCl3) of compound 936. 30 20 8 N 932 Boc N O 7 CO2Me 5 ppm 4 3 Figure A6.74 1H NMR (400 MHz, CDCl3) of compound 932. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 772 Appendix 6 – Spectra Relevant to Chapter 5 773 Figure A6.75 Infrared spectrum (Thin Film, NaCl) of compound 932. c 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 Figure A6.76 13C NMR (100 MHz, CDCl3) of compound 932. 30 20 8 N 938 Boc N O OH 7 5 ppm 4 3 Figure A6.77 1H NMR (400 MHz, CD3OD) of compound 938. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 774 Appendix 6 – Spectra Relevant to Chapter 5 775 Figure A6.78 Infrared spectrum (Thin Film, NaCl) of compound 938. c 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A6.79 13C NMR (100 MHz, CD3OD) of compound 938. 20 10 8 MeO Me O N 939 OMe Me N 7 Boc N OH 5 ppm 4 3 Figure A6.80 1H NMR (400 MHz, CDCl3) of compound 939. 6 2 1 Appendix 6 – Spectra Relevant to Chapter 5 776 Appendix 6 – Spectra Relevant to Chapter 5 777 Figure A6.81 Infrared spectrum (Thin Film, NaCl) of compound 939. c 160 150 140 130 120 110 100 90 ppm 80 70 60 50 40 30 20 Figure A6.82 13C NMR (100 MHz, CD3OD) of compound 939. 10 778 COMPREHENSIVE BIBLIOGRAPHY Abed Ali Abdine, R.; Hedouin, G.; Colobert, F.; Wencel-Delord, J. 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In 2016, the family also brought in a Havanese dog Daisy, who she considers as her little sister. Alexia grew up in Fairfax, VA, where she attended Thomas Jefferson High School for Science & Technology that started her passion for chemistry. She then went on to attend Princeton University, where she majored in chemistry and obtained a minor in music performance for flute. Her interest in organic chemistry quickly grew from taking classes taught by Professor Martin Semmelhack, Dr. Paul Reider, and Professor Abby Doyle, and had the pleasure of working in the laboratory of Professor Rob Knowles, focusing on the development of novel photocatalytic methodologies. From her experience in the Knowles group, she decided to pursue graduate school to further develop her academic career as a synthetic chemist. Upon completion of her undergraduate studies, Alexia moved back home to VA to be with family while commuting to Georgetown University as a postbaccalaureate researcher in Professor Tim Warren’s lab. At Georgetown, she worked on copper-catalyzed alkylation of unactivated sp3 C–H bonds, gaining immense experience in organometallic chemistry. In 2018, Alexia moved to Pasadena, CA to pursue her doctoral education at the California Institute of Technology. Under the guidance of Professor Brian Stoltz, her graduate work focused on asymmetric transition-metal catalysis and the total synthesis of complex alkaloids. Upon completion of her doctoral studies in May 2023, Alexia will stay around the LA area to begin her industrial career as a Process Development Scientist at Amgen in Thousand Oaks, CA.