Development of Stereoselective Iridium-Catalyzed Allylic Alkylation Methods

Citation

Shockley, Samantha Elizabeth (2018) Development of Stereoselective Iridium-Catalyzed Allylic Alkylation Methods. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/S93J-6P85. https://resolver.caltech.edu/CaltechTHESIS:05302018-124410879

Abstract

The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. Historically, our group’s interest has centered on palladium-catalyzed allylic alkylation, though recently effort has moved to include the study of iridium catalysts. This thesis presents four related projects, all unified by the use of enantioselective iridium-catalyzed allylic alkylation to construct highly-congested C–C bonds.

First, the development of the first diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form vicinal tertiary and all-carbon quaternary stereodyads with alkyl-substituted allylic electrophiles is described. Next, the first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) nucleophile is presented, representing a rare example of umpolung strategy in iridium-catalyzed allylic alkylation. Additionally, the application of a MAC reagent in the first highly enantioselective iridium-catalyzed allylic alkylation to provide access to products bearing an allylic all-carbon quaternary stereocenter is detailed. The use of the MAC nucleophile enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. Finally, the first enantioselective transition metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is presented.

Item Type:

Thesis (Dissertation (Ph.D.))

Subject Keywords:

Iridium, allylic alkylation, catalytic, stereoselective

Degree Grantor:

California Institute of Technology

Division:

Chemistry and Chemical Engineering

Major Option:

Chemistry

Thesis Availability:

Public (worldwide access)

Research Advisor(s):

Stoltz, Brian M.

Thesis Committee:

Reisman, Sarah E. (chair)
Grubbs, Robert H.
Dervan, Peter B.
Stoltz, Brian M.

Defense Date:

25 May 2018

Funders:

Funding Agency	Grant Number
NIH	F31 GM120804

Record Number:

CaltechTHESIS:05302018-124410879

Persistent URL:

https://resolver.caltech.edu/CaltechTHESIS:05302018-124410879

DOI:

10.7907/S93J-6P85

Related URLs:

URL	URL Type	Description
https://doi.org/10.1021/acscatal.6b01886	DOI	Review article adapted for Prologue and Chapter 1
https://doi.org/10.1002/anie.201609960	DOI	Communication adapted for Chapter 1
https://doi.org/10.1021/acs.orglett.7b00449	DOI	Communication adapted for Chapter 2
https://doi.org/10.1002/anie.201707015	DOI	Communication adapted for Chapter 3
https://doi.org/10.1002/anie.201804820	DOI	Communication adapted for Chapter 4
https://doi.org/10.1021/ol5031537	DOI	Communication adapted for Appendix 8
https://doi.org/10.1021/acs.oprd.5b00169	DOI	Review article adapted for Appendix 8
https://doi.org/10.1016/j.tetlet.2017.07.022	DOI	Communication adapted for Appendix 11

ORCID:

Author	ORCID
Shockley, Samantha Elizabeth	0000-0001-5682-8569

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No commercial reproduction, distribution, display or performance rights in this work are provided.

ID Code:

10974

Collection:

CaltechTHESIS

Deposited By:

Samantha Shockley

Deposited On:

01 Jun 2018 18:27

Last Modified:

08 Nov 2023 00:39

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DEVELOPMENT OF STEREOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION METHODS Thesis by Samantha Elizabeth Shockley In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2018 (Defended May 25, 2018) ii © 2018 Samantha E. Shockley ORCID: 0000-0001-5682-8569 All Rights Reserved iii To my dad iv ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Brian Stoltz, for his constant support during my graduate education. I know that it is not a given to have an advisor that you respect and like as both a person and a scientist, and I feel very fortunate to have found this in Brian and to have had the opportunity to work in his lab. Brian’s ability to simultaneously be there for his students as well as give them latitude to explore and become independent scientists has made him an incredible mentor. I would also like to sincerely thank the chair of my committee, Professor Sarah Reisman, for all of her help over the past five years with research questions, the Women in Chemistry Committee, and job advice. The Stoltz group is very lucky to have her as a second advisor and her lab as coworkers. In addition, I am deeply appreciative of the insightful questions into my research and the valuable career advice the rest of my thesis committee, Professors Bob Grubbs and Peter Dervan, have given me over my graduate career. I would not have made it to Caltech without the mentorship and encouragement of my previous advisors. I very grateful for the support of my undergraduate research advisor, Professor Richard Jordan, particularly his patience to go line by line over all my writing and his persistent willingness to meet and discuss chemistry. I am also indebted to my Fulbright grant advisor, Professor Martin Banwell, who gave me the opportunity to join his lab and pursue a project of my choosing. I need to thank all of the excellent Caltech staff for making my PhD possible. Specifically, Dr. Scott Virgil for all of his help with instrumentation and not laughing me out of his office when I told him I needed to prepHPLC every single compound in v a methods paper. Additionally, Dr. David VanderVelde for hiring me as GLA and helping with many of the structural assignments discussed herein. As well as, Dr. Mike Takase and Larry Henling for their patience and assistance with obtaining X-ray diffraction data, Dr. Mona Shahgholi and Naseem Torian for their tireless work with mass spectrometry data, and Rick Gerhart and Jeff Groseth for repairing everything I broke in graduate school. Finally, I would like to thank Joe Drew, Agnes Tong, Alison Ross, and the rest of the graduate support staff for keeping everything running so well in the CCE department. During my time at Caltech, I have been extremely lucky to have had excellent project partners. First, I would like to thank Jeff Holder for letting me jump on his project as a first year and putting up with my hysterical panicked calls about breaking instruments. Next, none of the work on iridium-catalyzed allylic alkylation presented in this thesis would have been possible without the early work of Corey Reeves and Boger Liu, who were great mentors in passing the projects down to me. Finally, I have been incredibly lucky to have worked with Caleb Hethcox on many of the projects presented herein. Even when our chemistry was invariably failing, coming to work was always enjoyable. I cannot imagine a better mentor, coworker, or best friend. I was fortunate to have mentored three students during my time in the Stoltz group. Their fresh enthusiasm for chemistry was often much needed in the depths of my PhD, and for that, I would like to sincerely thank Netgie Laguerre, Bridget Garrity, and Winston Odom for working with me. I look forward to following their, what am sure will be successful, careers in chemistry. I am very thankful for all of the members, past and present, of the Stoltz lab who have made the group an enjoyable place to come every day. Specifically, I could vi not have asked for a better place to work than the Small Office, whose unique culture has always kept things entertaining, especially the Small Office members of Nick O’Connor, Kelly Kim, Christopher Haley, Doug Duquette, Lukas Hilpert, Jared Moore, David Schuman, and Justin Hilf. I am particularly indebted to Nick and Christopher for all of their mentorship when I joined the lab and Kelly for her friendship and willingness to put up with my constant nagging to stop hoarding. Additionally, I would like to thank Beau Pritchett for what can only be described of as being my life coach, but in all seriousness, who I very much respect. Finally, I need to thank my hoodmate of four years, Austin Wright, for tolerating my neurotic cleanliness and persistent need to pick up his half of the hood. Finally, I would like to thank my friends and family who made my graduate degree possible. Sherrie Xie and Erin Britton for being incredible friends, always being there to talk, and game to travel anywhere. Nik Thompson for his love, unwavering support as my biggest cheerleader, and incredible patience with me, even extending back to the early days of college problem sets. Lastly, my mom, dad, and brother who may not have understood why I would want to be in chemistry graduate school, but were always there to support and help me in any way they could. I am forever appreciative of all of the lunches packed, homework checked, science fair project help, rides to school when I missed the bus for the hundredth time, care packages, trips to cook for me during finals, and cards to celebrate my tiny milestones, amongst everything else you always selflessly did. I would never have made it to or through graduate school without you – I love you! The work presented in this thesis would not have been possible without the continued support of all these people and many others not specifically mentioned by name. To each of them, I am deeply grateful. vii ABSTRACT The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. Historically, our group’s interest has centered on palladium-catalyzed allylic alkylation, though recently effort has moved to include the study of iridium catalysts. This thesis presents four related projects, all unified by the use of enantioselective iridium-catalyzed allylic alkylation to construct highlycongested C–C bonds. First, the development of the first diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form vicinal tertiary and all-carbon quaternary stereodyads with alkyl-substituted allylic electrophiles is described. Next, the first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) nucleophile is presented, representing a rare example of umpolung strategy in iridium-catalyzed allylic alkylation. Additionally, the application of a MAC reagent in the first highly enantioselective iridium-catalyzed allylic alkylation to provide access to products bearing an allylic all-carbon quaternary stereocenter is detailed. The use of the MAC nucleophile enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. Finally, the first enantioselective transition metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is presented. viii PUBLISHED CONTENT AND CONTRIBUTIONS 1. Shockley, S. E.;‡ Holder, J. C.;‡ Stoltz, B. M. “A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H.” Org. Lett. 2014, 16, 6362–6365. DOI: 10.1021/ol5031537. S.E.S participated in designing second generation synthetic routes, experimental work, data acquisition and analysis, and manuscript preparation. 2. Holder, J. C.; Shockley, S. E.; Wiesenfeldt, M. P.; Shimizu, H.; Stoltz, B. M. “Preparation of dihydrooxazole) (S)-tert-ButylPyOx and methylcyclohexanone.” Preparation Org. Synth. ((S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5 of 2015, (R)-3-(4-chlorophenyl)-392, 247–266. DOI: 10.15227/orgsyn.092.0247. S.E.S. participated in reaction optimization, experimental work, data acquisition and analysis, and manuscript preparation. 3. Shockley, S. E.; Holder, J. C.; Stoltz, B. M. “Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Cyclic Electrophiles.” Org. Process Res. Dev. 2015, 19, 974–981. DOI: 10.1021/acs.oprd.5b00169. S.E.S. led the writing of the review manuscript. 4. Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. “Iridium-Catalyzed Diastereo-, Enantio-, and Regioselective Allylic Alkylation with Prochiral Enolates.” ACS Catal. 2016, 6, 6207– 6213. DOI: 10.1021/acscatal.6b01886. S.E.S. participated in the writing of the review manuscript. ix 5. Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. “Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride.” Angew. Chem. Int. Ed. 2016, 55, 16092– 16095. (Highlighted in Synfacts 2017, 13, 0167). DOI: 10.1002/anie.201609960. S.E.S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 6. Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. “Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents.” Org. Lett. 2017, 19, 1527– 1529. DOI: 10.1021/acs.orglett.7b00449. S.E.S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 7. Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. “Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy.” Tetrahedron Lett. 2017, 58, 3341–3343. DOI: 10.1016/j.tetlet.2017.07.022. S.E.S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 8. Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. “Enantioselective Synthesis of Acyclic αQuaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation.” Angew. Chem. Int. Ed. 2017, 56, 11545–11548. (Highlighted in Synfacts 2017, 13, 1192). DOI: 10.1002/anie.201707015. S.E.S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. x 9. Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. “Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation.” Angew. Chem. Int. Ed. 2018, doi: 10.1002/anie.201804820. S.E.S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 10. Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. “Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account.” Manuscript submitted. S.E.S. participated in the writing of the review manuscript. xi TABLE OF CONTENTS Dedication ............................................................................................................................ iii Acknowledgements ............................................................................................................... iv Abstract ................................................................................................................................ vii Published Content and Contributions .................................................................................. viii Table of Contents .................................................................................................................. xi List of Figures ...................................................................................................................... xix List of Schemes ................................................................................................................. xxxv List of Tables ................................................................................................................... xxxvii List of Abbreviations ........................................................................................................... xliii PROLOGUE Iridium-Catalyzed Allylic Alkylation 1 P.1 Introduction ..................................................................................................... 1 P.2 References and Notes ....................................................................................... 4 CHAPTER 1 Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 5 1.1 Introduction ..................................................................................................... 5 1.2 Background to Diastereo-, Enantio-, and Regioselective Iridium-Catalyzed Allylic Alkylation with Prochiral Enolates ......................................................... 7 1.2.1 Iridium Catalyst-Controlled Processes ............................................................... 7 1.2.1.1 Acyclic Nucleophiles .......................................................................... 7 1.2.1.2 Cyclic Nucleophiles .......................................................................... 10 1.2.2 Dual Catalyst-Controlled Processes ................................................................ 15 1.3 Reaction Optimization .................................................................................. 19 1.4 Substrate Scope Exploration ........................................................................... 21 1.5 Product Transformations ................................................................................ 26 1.6 Conclusions ................................................................................................... 27 1.7 Experimental Section ...................................................................................... 28 1.7.1 1.7.1.1 1.7.2 Materials and Methods ................................................................................... 28 Preparation of Known Compounds .................................................... 29 Experimental Procedures and Spectroscopic Data .......................................... 30 xii 1.7.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Tetralone Substrates ........................................................................... 30 1.7.2.2 Additional Optimization of Reaction Parameters ............................... 36 1.7.2.3 General Procedure for Optimization Reactions (Table 1.1 & 1.4) ...... 37 1.7.2.4 General Procedure for the Iridium-Catalyzed Allylic Alkylation ......... 37 1.7.2.5 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products ............................................................................................ 40 1.7.2.6 Experimental Procedures and Spectroscopic Data for the Product Transformations of Allylic Alkylation Products ................................... 50 1.7.2.7 1.8 Determination of Enantiomeric Excess ............................................... 56 References and Notes ..................................................................................... 58 APPENDIX 1 Spectra Relevant to Chapter 1 62 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 116 A2.1 General Experimental ................................................................................... 117 A2.1.1 X-Ray Crystal Structure Analysis of Allylic Alkylation Product 58e ................ 117 A2.1.2 X-Ray Crystal Structure Analysis of Triol 63 .................................................. 125 A2.1.3 X-Ray Crystal Structure Analysis of Diol 64 .................................................. 133 CHAPTER 2 140 Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 2.1 Introduction and Background ....................................................................... 140 2.2 Reaction Optimization ................................................................................. 142 2.3 Substrate Scope Exploration .......................................................................... 143 2.4 Conclusions .................................................................................................. 146 2.5 Experimental Section .................................................................................... 147 2.5.1 2.5.1.1 2.5.2 Materials and Methods ................................................................................. 147 Preparation of Known Compounds .................................................. 148 Experimental Procedures and Spectroscopic Data ........................................ 149 2.5.2.1 General Procedure for the Synthesis of Electrophiles ....................... 149 2.5.2.2 Spectroscopic Data for the Synthesis of Electrophiles ....................... 150 2.5.2.3 General Procedure for Optimization Reactions (Table 2.1) .............. 151 2.5.2.4 General Procedure for the Iridium-Catalyzed Allylic Alkylation ....... 152 2.5.2.5 Procedure for the Preparatory Scale Reaction .................................. 153 xiii 2.5.2.6 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products .......................................................................................... 154 2.5.2.7 2.6 Determination of Enantiomeric Excess ............................................. 162 References and Notes ................................................................................... 164 APPENDIX 3 Spectra Relevant to Chapter 2 168 CHAPTER 3 201 Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.1 Introduction and Background ....................................................................... 201 3.2 Reaction Optimization ................................................................................. 203 3.3 Mechanistic Insights ..................................................................................... 204 3.4 Substrate Scope Exploration .......................................................................... 206 3.5 Product Transformations ............................................................................... 210 3.6 Conclusions .................................................................................................. 211 3.7 Experimental Section .................................................................................... 212 3.7.1 Materials and Methods ................................................................................. 212 3.7.1.1 3.7.2 Preparation of Known Compounds .................................................. 214 Experimental Procedures and Spectroscopic Data ........................................ 214 3.7.2.1 Representative Procedures for the Synthesis of Electrophiles ............ 214 3.7.2.1.1 Representative Procedure #1: Oxidative Heck Reaction ..... 214 3.7.2.1.2 Representative Procedure #2: Reduction & Acylation ......... 215 3.7.2.2 Spectroscopic Data for the Synthesis of Electrophiles ....................... 216 3.7.2.3 General Procedure for Optimization Reactions (Table 3.1) .............. 222 3.7.2.4 General Procedure for the Enantioenriched Carboxylic Acid Synthesis ......................................................................................... 223 3.7.2.5 Spectroscopic Data for the Enantioenriched Carboxylic Acids ......... 224 3.7.2.6 Experimental Procedures and Spectroscopic Data for the One-pot Syntheses of Carboxylic Acid Derivatives ........................................ 233 3.7.2.7 Experimental Procedures and Spectroscopic Data for the Product Transformations of α-Quaternary Ester 82 ........................................ 239 3.7.2.8 3.8 Determination of Enantiomeric Excess ............................................. 242 References and Notes ................................................................................... 244 APPENDIX 4 Spectra Relevant to Chapter 3 249 xiv APPENDIX 5 X-Ray Crystallography Reports Relevant to Chapter 3 A5.1 318 General Experimental ................................................................................... 319 A5.1.1 X-Ray Crystal Structure Analysis of Carboxylic Acid 77h .............................. 319 CHAPTER 4 325 Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via IridiumCatalyzed Allylic Alkylation 4.1 Introduction and Background ....................................................................... 325 4.2 Reaction Optimization ................................................................................. 327 4.3 Substrate Scope Exploration .......................................................................... 329 4.4 Product Transformations ............................................................................... 334 4.5 Conclusions .................................................................................................. 335 4.6 Experimental Section .................................................................................... 336 4.6.1 Materials and Methods ................................................................................. 336 4.6.1.1 Key Considerations .......................................................................... 337 4.6.1.2 Preparation of Known Compounds .................................................. 338 4.6.2 Experimental Procedures and Spectroscopic Data ........................................ 338 4.6.2.1 General Procedure for the Synthesis of Electrophiles ....................... 338 4.6.2.2 Spectroscopic Data for the Synthesis of Electrophiles ....................... 339 4.6.2.3 General Procedure for Optimization Reactions (Table 4.1) .............. 340 4.6.2.4 General Procedure for the Iridium-Catalyzed Allylic Alkylation ....... 341 4.6.2.5 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products .......................................................................................... 342 4.6.2.6 Experimental Procedures and Spectroscopic Data for the Product Transformations of Allylic Alkylation Products ................................. 355 4.6.2.7 4.7 Determination of Enantiomeric Excess ............................................. 261 References and Notes ................................................................................... 363 APPENDIX 6 Spectra Relevant to Chapter 4 369 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4 429 A7.1 A7.1.1 General Experimental ................................................................................... 430 X-Ray Crystal Structure Analysis of Bis-Nitrile 97c ........................................ 431 xv A7.2 References and Notes ................................................................................... 440 CHAPTER 5 441 Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 5.1 Introduction .................................................................................................. 441 5.2 Synthesis of Vicinal Tertiary and All-Carbon Quaternary Stereocenters via Enantio- and Diastereoselective Iridium-Catalyzed Allylic Alkylation ........... 445 5.2.1 Cyclic Nucleophiles ..................................................................................... 445 5.2.2 Acyclic Nucleophiles ................................................................................... 449 5.2.3 Alkyl-Substituted Electrophiles ...................................................................... 450 5.3 Umpoled Iridium-Catalyzed Allylic Alkylation Reactions ............................. 454 5.3.1 Tertiary Allylic Stereocenters ........................................................................ 455 5.3.2 Quaternary Allylic Stereocenters .................................................................. 457 5.4 Synthesis of Vicinal All-Carbon Quaternary Centers via Enantioselective Iridium-Catalyzed Allylic Alkylation ............................................................. 462 5.5 Conclusions and Future Outlook .................................................................. 464 5.6 References and Notes ................................................................................... 466 APPENDIX 8 471 A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)Taiwaniaquinone H A8.1 Introduction ................................................................................................. 471 A8.2 Background to the Stoltz Group’s Enantioselective Palladium-Catalyzed Conjugate Addition Chemistry ..................................................................... 474 A8.2.1 Introduction to Asymmetric Transition Metal-Catalyzed Conjugate Addition Chemistry .................................................................................................... 474 A8.2.2 Initial Discoveries ........................................................................................ 475 A8.2.3 Further Reaction Development ..................................................................... 479 A8.2.4 Mechanistic Hypothesis ................................................................................ 483 A8.2.5 Heterocyclic Acceptors ............................................................................... 487 A8.3 Retrosynthetic Analysis ................................................................................ 488 A8.4 First Generation Route ................................................................................. 489 A8.5 Second Generation Route ............................................................................ 493 A8.6 Conclusions ................................................................................................. 498 A8.7 Experimental Section ................................................................................... 489 A8.7.1 Materials and Methods ................................................................................. 498 A8.7.1.1 Preparation of Known Compounds .................................................. 499 xvi A8.7.2 Experimental Procedures and Spectroscopic Data ........................................ 500 A8.7.2.1 General Procedure and Spectroscopic Data for the Synthesis of Resorcinol Pivaloyl Esters ................................................................ 500 A8.7.2.2 General Procedure and Spectroscopic Data for the Synthesis of Borylated Arenes ............................................................................. 502 A8.7.2.3 General Procedure and Spectroscopic Data for the Synthesis of Boronic Acid Analogues ............................................................................... 505 A8.7.2.4 General Procedure and Spectroscopic Data for the Asymmetric Palladium-Catalyzed Conjugate Addition of Arylboronic Acids ....... 508 A8.7.2.5 Procedures and Spectroscopic Data for Synthetic Intermediates ...... 511 A8.7.2.6 Determination of Enantiomeric Excess ............................................. 520 A8.7.2.7 Hammett Plot Data .......................................................................... 521 A8.8 References and Notes ................................................................................... 521 APPENDIX 9 Spectra Relevant to Appendix 8 529 APPENDIX 10 X-Ray Crystallography Reports Relevant to Appendix 8 577 A10.1 A10.1.1 General Experimental ................................................................................... 578 X-Ray Crystal Structure Analysis of Undesired Tricycle 203 .......................... 578 APPENDIX 11 Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 589 A11.1 Introduction and Background ....................................................................... 589 A11.2 Reaction Development ................................................................................. 591 A11.3 Conclusions .................................................................................................. 593 A11.4 Experimental Section .................................................................................... 594 A11.4.1 Materials and Methods ................................................................................. 594 A11.4.1.1 A11.4.2 Preparation of Known Compounds .................................................. 596 Experimental Procedures and Spectroscopic Data ........................................ 596 A11.4.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Allylic Alkylation Substrates ............................................................ 596 A11.4.2.2 General Procedure for the Asymmetric Palladium-Catalyzed Allylic Alkylation ....................................................................................... 599 xvii A11.4.2.3 Spectroscopic Data for the Asymmetric Palladium-Catalyzed Allylic Alkylation Products ......................................................................... 600 A11.4.2.4 General Procedure for Spirocyclic Formation ................................. 602 A11.4.2.5 Spectroscopic Data for Spirocyclic Compounds ............................. 602 A11.4.2.6 Determination of Enantiomeric Excess ............................................ 604 A11.5 References and Notes ................................................................................... 604 APPENDIX 12 Spectra Relevant to Appendix 11 607 APPENDIX 13 Progress Toward the Synthesis of (+)-Isopalhinine A 626 A13.1 Introduction and Background ....................................................................... 626 A13.2 Iridium-Catalyzed Allylic Alkylation Route ................................................... 627 A13.3 Palladium-Catalyzed Allylic Alkylation Route with A Masked Stabilized Lactam Enolate ............................................................................................. 636 A13.4 Piperidone Palladium-Catalyzed Allylic Alkylation Route ............................. 640 A13.5 Diastereoselective Route .............................................................................. 643 A13.6 Future Directions and Proposed Late-Stage Chemistry to Access (+)-Isopalhinine A ......................................................................................... 647 A13.7 Conclusions .................................................................................................. 649 A13.8 Experimental Section .................................................................................... 650 A13.8.1 Materials and Methods ................................................................................. 650 A13.8.1.1 A13.8.2 Preparation of Known Compounds .................................................. 651 Experimental Procedures and Spectroscopic Data ........................................ 652 A13.8.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.2 ......................................... 652 A13.8.2.2 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.3 ......................................... 663 A13.8.2.3 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.4 ......................................... 671 A13.8.2.4 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.5 ......................................... 677 A13.8.2.5 A13.9 Determination of Enantiomeric Excess ............................................. 681 References and Notes ................................................................................... 683 APPENDIX 14 Spectra Relevant to Appendix 13 687 xviii APPENDIX 15 Notebook Cross-Reference for New Compounds 739 Comprehensive Bibliography ............................................................................................. 759 Index .................................................................................................................................. 788 About the Author ............................................................................................................... 791 xix LIST OF FIGURES PROLOGUE Iridium-Catalyzed Allylic Alkylation Figure P.1 Challenges of enantio- and diastereoselective iridium-catalyzed allylic alkylation ......................................................................................................... 3 CHAPTER 1 Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride Figure 1.1 Enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reactions ........................................................................................................... 6 Figure 1.2 Select natural products bearing alkyl-substituted vicinal tertiary and quaternary stereocenters .................................................................................................... 7 Figure 1.3 Product transformations of allylic alkylation products 54 and 58a .................. 27 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1 1 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 54 ..................................... 64 Figure A1.3 13 Figure A1.4 1 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound epi-54 ............................... 66 Figure A1.6 13 Figure A1.7 1 Figure A1.8 Infrared spectrum (Thin Film, NaCl) of compound 55 ..................................... 68 Figure A1.9 13 Figure A1.10 1 Figure A1.11 Infrared spectrum (Thin Film, NaCl) of compound 56b ................................... 70 Figure A1.12 13 Figure A1.13 1 Figure A1.14 Infrared spectrum (Thin Film, NaCl) of compound 56c ................................... 72 Figure A1.15 13 Figure A1.16 1 Figure A1.17 Infrared spectrum (Thin Film, NaCl) of compound 56e ................................... 74 Figure A1.18 13 Figure A1.19 1 H NMR (400 MHz, CDCl3) of compound 54 ................................................. 63 C NMR (101 MHz, CDCl3) of compound 54 ................................................ 64 H NMR (400 MHz, CDCl3) of compound epi-54 ........................................... 65 C NMR (101 MHz, CDCl3) of compound epi-54 .......................................... 66 H NMR (400 MHz, CDCl3) of compound 55 ................................................. 67 C NMR (101 MHz, CDCl3) of compound 55 ................................................ 68 H NMR (400 MHz, CDCl3) of compound 56b ............................................... 69 C NMR (101 MHz, CDCl3) of compound 56b .............................................. 70 H NMR (400 MHz, CDCl3) of compound 56c ............................................... 71 C NMR (101 MHz, CDCl3) of compound 56c .............................................. 72 H NMR (400 MHz, CDCl3) of compound 56e ............................................... 73 C NMR (101 MHz, CDCl3) of compound 56e .............................................. 74 H NMR (400 MHz, CDCl3) of compound 56g ............................................... 75 xx Figure A1.20 Infrared spectrum (Thin Film, NaCl) of compound 56g ................................... 76 Figure A1.21 13 Figure A1.22 1 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 56h ................................... 78 Figure A1.24 13 Figure A1.25 1 Figure A1.26 Infrared spectrum (Thin Film, NaCl) of compound 56k ................................... 80 Figure A1.27 13 Figure A1.28 1 Figure A1.29 Infrared spectrum (Thin Film, NaCl) of compound 58a ................................... 82 Figure A1.30 13 Figure A1.31 1 Figure A1.32 Infrared spectrum (Thin Film, NaCl) of compound 58b ................................... 84 Figure A1.33 13 Figure A1.34 1 Figure A1.35 Infrared spectrum (Thin Film, NaCl) of compound 58c ................................... 86 Figure A1.36 13 Figure A1.37 1 Figure A1.38 Infrared spectrum (Thin Film, NaCl) of compound 58d ................................... 88 Figure A1.39 13 Figure A1.40 1 Figure A1.41 Infrared spectrum (Thin Film, NaCl) of compound 58e ................................... 90 Figure A1.42 13 Figure A1.43 1 Figure A1.44 Infrared spectrum (Thin Film, NaCl) of compound 58f .................................... 92 Figure A1.45 13 Figure A1.46 1 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 58g ................................... 94 Figure A1.48 13 Figure A1.49 1 Figure A1.50 Infrared spectrum (Thin Film, NaCl) of compound 58h ................................... 96 Figure A1.51 13 Figure A1.52 1 Figure A1.53 Infrared spectrum (Thin Film, NaCl) of compound 58i .................................... 98 Figure A1.54 13 Figure A1.55 1 Figure A1.56 Infrared spectrum (Thin Film, NaCl) of compound 58j .................................. 100 Figure A1.57 13 C NMR (101 MHz, CDCl3) of compound 56g .............................................. 76 H NMR (400 MHz, CDCl3) of compound 56h ............................................... 77 C NMR (101 MHz, CDCl3) of compound 56h .............................................. 78 H NMR (400 MHz, CDCl3) of compound 56k ............................................... 79 C NMR (101 MHz, CDCl3) of compound 56k .............................................. 80 H NMR (400 MHz, CDCl3) of compound 58a ............................................... 81 C NMR (101 MHz, CDCl3) of compound 58a .............................................. 82 H NMR (400 MHz, CDCl3) of compound 58b ............................................... 83 C NMR (101 MHz, CDCl3) of compound 58b .............................................. 84 H NMR (400 MHz, CDCl3) of compound 58c ............................................... 85 C NMR (101 MHz, CDCl3) of compound 58c .............................................. 86 H NMR (400 MHz, CDCl3) of compound 58d ............................................... 87 C NMR (101 MHz, CDCl3) of compound 58d .............................................. 88 H NMR (400 MHz, CDCl3) of compound 58e ............................................... 89 C NMR (101 MHz, CDCl3) of compound 58e .............................................. 90 H NMR (400 MHz, CDCl3) of compound 58f ................................................ 91 C NMR (101 MHz, CDCl3) of compound 58f ............................................... 92 H NMR (400 MHz, CDCl3) of compound 58g ............................................... 93 C NMR (101 MHz, CDCl3) of compound 58g .............................................. 94 H NMR (400 MHz, CDCl3) of compound 58h ............................................... 95 C NMR (101 MHz, CDCl3) of compound 58h .............................................. 96 H NMR (400 MHz, CDCl3) of compound 58i ................................................ 97 C NMR (101 MHz, CDCl3) of compound 58i ............................................... 98 H NMR (400 MHz, CDCl3) of compound 58j ................................................ 99 C NMR (101 MHz, CDCl3) of compound 58j ............................................. 100 xxi Figure A1.58 1 Figure A1.59 Infrared spectrum (Thin Film, NaCl) of compound 58k ................................. 102 Figure A1.60 13 Figure A1.61 1 Figure A1.62 Infrared spectrum (Thin Film, NaCl) of compound 61 ................................... 104 Figure A1.63 13 Figure A1.64 1 Figure A1.65 Infrared spectrum (Thin Film, NaCl) of compound 62 ................................... 106 Figure A1.66 13 Figure A1.67 1 Figure A1.68 Infrared spectrum (Thin Film, NaCl) of compound 63 ................................... 108 Figure A1.69 13 Figure A1.70 1 Figure A1.71 Infrared spectrum (Thin Film, NaCl) of compound 64 ................................... 110 Figure A1.72 13 Figure A1.73 1 Figure A1.74 Infrared spectrum (Thin Film, NaCl) of compound 65 ................................... 112 Figure A1.75 13 Figure A1.76 NOESY (400 MHz, CDCl3) of compound 65 ................................................. 113 Figure A1.77 1 Figure A1.78 Infrared spectrum (Thin Film, NaCl) of compound 66 ................................... 115 Figure A1.79 13 H NMR (400 MHz, CDCl3) of compound 58k ............................................. 101 C NMR (101 MHz, CDCl3) of compound 58k ............................................ 102 H NMR (400 MHz, CDCl3) of compound 61 ............................................... 103 C NMR (101 MHz, CDCl3) of compound 61 .............................................. 104 H NMR (400 MHz, CDCl3) of compound 62 ............................................... 105 C NMR (101 MHz, CDCl3) of compound 62 .............................................. 106 H NMR (400 MHz, CDCl3) of compound 63 ............................................... 107 C NMR (101 MHz, CDCl3) of compound 63 .............................................. 108 H NMR (400 MHz, CDCl3) of compound 64 ............................................... 109 C NMR (101 MHz, CDCl3) of compound 64 .............................................. 110 H NMR (400 MHz, CDCl3) of compound 65 ............................................... 111 C NMR (101 MHz, CDCl3) of compound 65 .............................................. 112 H NMR (400 MHz, CDCl3) of compound 66 ............................................... 114 C NMR (101 MHz, CDCl3) of compound 66 .............................................. 115 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Figure A2.1 X-ray crystal structure of allylic alkylation product 58e ................................. 117 Figure A2.2 X-ray crystal structure of triol 63 ................................................................... 125 Figure A2.3 X-ray crystal structure of diol 64 ................................................................... 133 CHAPTER 2 Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents Figure 2.1 Iridium-catalyzed allylic alkylation strategies ................................................ 141 APPENDIX 3 Spectra Relevant to Chapter 2 Figure A3.1 1 H NMR (400 MHz, CDCl3) of compound 69c ............................................. 169 xxii Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound 69c ................................. 170 Figure A3.3 13 Figure A3.4 1 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound 70e ................................. 172 Figure A3.6 13 Figure A3.7 1 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound 70f .................................. 174 Figure A3.9 13 Figure A3.10 1 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound 70g ................................. 176 Figure A3.12 13 Figure A3.13 1 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound 71a ................................. 178 Figure A3.15 13 Figure A3.16 1 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound 71b ................................. 180 Figure A3.18 13 Figure A3.19 1 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound 71c ................................. 182 Figure A3.21 13 Figure A3.22 1 Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound 71d ................................. 184 Figure A3.24 13 Figure A3.25 1 Figure A3.26 Infrared spectrum (Thin Film, NaCl) of compound 71e ................................. 186 Figure A3.27 13 Figure A3.28 1 Figure A3.29 Infrared spectrum (Thin Film, NaCl) of compound 71f .................................. 188 Figure A3.30 13 Figure A3.31 1 Figure A3.32 Infrared spectrum (Thin Film, NaCl) of compound 71g ................................. 190 Figure A3.33 13 Figure A3.34 1 Figure A3.35 Infrared spectrum (Thin Film, NaCl) of compound 71h ................................. 192 Figure A3.36 13 Figure A3.37 1 Figure A3.38 Infrared spectrum (Thin Film, NaCl) of compound 71i .................................. 194 Figure A3.39 13 C NMR (101 MHz, CDCl3) of compound 69c ............................................ 170 H NMR (400 MHz, CDCl3) of compound 70e ............................................. 171 C NMR (101 MHz, CDCl3) of compound 70e ............................................ 172 H NMR (400 MHz, CDCl3) of compound 70f .............................................. 173 C NMR (101 MHz, CDCl3) of compound 70f ............................................. 174 H NMR (400 MHz, CDCl3) of compound 70g ............................................. 175 C NMR (101 MHz, CDCl3) of compound 70g ............................................ 176 H NMR (400 MHz, CDCl3) of compound 71a ............................................. 177 C NMR (101 MHz, CDCl3) of compound 71a ............................................ 178 H NMR (400 MHz, CDCl3) of compound 71b ............................................. 179 C NMR (101 MHz, CDCl3) of compound 71b ............................................ 180 H NMR (400 MHz, CDCl3) of compound 71c ............................................. 181 C NMR (101 MHz, CDCl3) of compound 71c ............................................ 182 H NMR (400 MHz, CDCl3) of compound 71d ............................................. 183 C NMR (101 MHz, CDCl3) of compound 71d ............................................ 184 H NMR (400 MHz, CDCl3) of compound 71e ............................................. 185 C NMR (101 MHz, CDCl3) of compound 71e ............................................ 186 H NMR (400 MHz, CDCl3) of compound 71f .............................................. 187 C NMR (101 MHz, CDCl3) of compound 71f ............................................. 188 H NMR (400 MHz, CDCl3) of compound 71g ............................................. 189 C NMR (101 MHz, CDCl3) of compound 71g ............................................ 190 H NMR (400 MHz, CDCl3) of compound 71h ............................................. 191 C NMR (101 MHz, CDCl3) of compound 71h ............................................ 192 H NMR (400 MHz, CDCl3) of compound 71i .............................................. 193 C NMR (101 MHz, CDCl3) of compound 71i ............................................. 194 xxiii Figure A3.40 1 Figure A3.41 Infrared spectrum (Thin Film, NaCl) of compound 71j .................................. 196 Figure A3.42 13 Figure A3.43 1 Figure A3.44 Infrared spectrum (Thin Film, NaCl) of compound 71k ................................. 198 Figure A3.45 13 Figure A3.46 1 Figure A3.47 Infrared spectrum (Thin Film, NaCl) of compound 71l .................................. 200 Figure A3.48 13 H NMR (400 MHz, CDCl3) of compound 71j .............................................. 195 C NMR (101 MHz, CDCl3) of compound 71j ............................................. 196 H NMR (400 MHz, CDCl3) of compound 71k ............................................. 197 C NMR (101 MHz, CDCl3) of compound 71k ............................................ 198 H NMR (400 MHz, CDCl3) of compound 71l .............................................. 199 C NMR (101 MHz, CDCl3) of compound 71l ............................................. 200 CHAPTER 3 Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Figure 3.1 Synthesis of allylic all-carbon quaternary stereocenters via enantioselective iridium-catalyzed allylic alkylation ............................................................... 202 Figure 3.2 One-pot transformations to α-quaternary carboxylic acid derivatives ........... 210 Figure 3.3 Product transformations of α-quaternary ester 82.......................................... 211 APPENDIX 4 Spectra Relevant to Chapter 3 Figure A4.1 1 Figure A4.2 Infrared spectrum (Thin Film, NaCl) of compound 73 ................................... 251 Figure A4.3 13 Figure A4.4 1 Figure A4.5 Infrared spectrum (Thin Film, NaCl) of compound 74 ................................... 253 Figure A4.6 13 Figure A4.7 1 Figure A4.8 Infrared spectrum (Thin Film, NaCl) of compound 76c ................................. 255 Figure A4.9 13 Figure A4.10 1 Figure A4.11 Infrared spectrum (Thin Film, NaCl) of compound 76f .................................. 257 Figure A4.12 13 Figure A4.13 1 Figure A4.14 Infrared spectrum (Thin Film, NaCl) of compound 76g ................................. 259 Figure A4.15 13 Figure A4.16 1 Figure A4.17 Infrared spectrum (Thin Film, NaCl) of compound 76h ................................. 261 H NMR (400 MHz, CDCl3) of compound 73 ............................................... 250 C NMR (101 MHz, CDCl3) of compound 73 .............................................. 251 H NMR (400 MHz, CDCl3) of compound 74 ............................................... 252 C NMR (101 MHz, CDCl3) of compound 74 .............................................. 253 H NMR (400 MHz, CDCl3) of compound 76c ............................................. 254 C NMR (101 MHz, CDCl3) of compound 76c ............................................ 255 H NMR (400 MHz, CDCl3) of compound 76f .............................................. 256 C NMR (101 MHz, CDCl3) of compound 76f ............................................. 257 H NMR (400 MHz, CDCl3) of compound 76g ............................................. 258 C NMR (101 MHz, CDCl3) of compound 76g ............................................ 259 H NMR (400 MHz, CDCl3) of compound 76h ............................................. 260 xxiv Figure A4.18 13 Figure A4.19 1 Figure A4.20 Infrared spectrum (Thin Film, NaCl) of compound 76i .................................. 263 Figure A4.21 13 Figure A4.22 1 Figure A4.23 Infrared spectrum (Thin Film, NaCl) of compound 76k ................................. 265 Figure A4.24 13 Figure A4.25 1 Figure A4.26 Infrared spectrum (Thin Film, NaCl) of compound 77b ................................. 267 Figure A4.27 13 Figure A4.28 1 Figure A4.29 Infrared spectrum (Thin Film, NaCl) of compound 77c ................................. 269 Figure A4.30 13 Figure A4.31 1 Figure A4.32 Infrared spectrum (Thin Film, NaCl) of compound 77d ................................. 271 Figure A4.33 13 Figure A4.34 1 Figure A4.35 Infrared spectrum (Thin Film, NaCl) of compound 77e ................................. 273 Figure A4.36 13 Figure A4.37 1 Figure A4.38 Infrared spectrum (Thin Film, NaCl) of compound 77f .................................. 275 Figure A4.39 13 Figure A4.40 1 Figure A4.41 Infrared spectrum (Thin Film, NaCl) of compound 77g ................................. 277 Figure A4.42 13 Figure A4.43 1 Figure A4.44 Infrared spectrum (Thin Film, NaCl) of compound 77h ................................. 279 Figure A4.45 13 Figure A4.46 1 Figure A4.47 Infrared spectrum (Thin Film, NaCl) of compound 77i .................................. 281 Figure A4.48 13 Figure A4.49 1 Figure A4.50 Infrared spectrum (Thin Film, NaCl) of compound 77j .................................. 283 Figure A4.51 13 Figure A4.52 1 Figure A4.53 Infrared spectrum (Thin Film, NaCl) of compound 77k ................................. 285 Figure A4.54 13 Figure A4.55 HMBC (400 MHz, CDCl3) of compound 77k ................................................ 286 C NMR (101 MHz, CDCl3) of compound 76h ............................................ 261 H NMR (400 MHz, CDCl3) of compound 76i .............................................. 262 C NMR (101 MHz, CDCl3) of compound 76i ............................................. 263 H NMR (400 MHz, CDCl3) of compound 76k ............................................. 264 C NMR (101 MHz, CDCl3) of compound 76k ............................................ 265 H NMR (400 MHz, CDCl3) of compound 77b ............................................. 266 C NMR (101 MHz, CDCl3) of compound 77b ............................................ 267 H NMR (400 MHz, CDCl3) of compound 77c ............................................. 268 C NMR (101 MHz, CDCl3) of compound 77c ............................................ 269 H NMR (400 MHz, CDCl3) of compound 77d ............................................. 270 C NMR (101 MHz, CDCl3) of compound 77d ............................................ 271 H NMR (400 MHz, CDCl3) of compound 77e ............................................. 272 C NMR (101 MHz, CDCl3) of compound 77e ............................................ 273 H NMR (400 MHz, CDCl3) of compound 77f .............................................. 274 C NMR (101 MHz, CDCl3) of compound 77f ............................................. 275 H NMR (400 MHz, CDCl3) of compound 77g ............................................. 276 C NMR (101 MHz, CDCl3) of compound 77g ............................................ 277 H NMR (400 MHz, CDCl3) of compound 77h ............................................. 278 C NMR (101 MHz, CDCl3) of compound 77h ............................................ 279 H NMR (400 MHz, CDCl3) of compound 77i .............................................. 280 C NMR (101 MHz, CDCl3) of compound 77i ............................................. 281 H NMR (400 MHz, CDCl3) of compound 77j .............................................. 282 C NMR (101 MHz, CDCl3) of compound 77j ............................................. 283 H NMR (400 MHz, CDCl3) of compound 77k ............................................. 284 C NMR (101 MHz, CDCl3) of compound 77k ............................................ 285 xxv Figure A4.56 1 Figure A4.57 Infrared spectrum (Thin Film, NaCl) of compound 78b ................................. 288 Figure A4.58 13 Figure A4.59 1 Figure A4.60 Infrared spectrum (Thin Film, NaCl) of compound 78c ................................. 290 Figure A4.61 13 Figure A4.62 1 Figure A4.63 Infrared spectrum (Thin Film, NaCl) of compound 78e ................................. 292 Figure A4.64 13 Figure A4.65 1 Figure A4.66 Infrared spectrum (Thin Film, NaCl) of compound 79a ................................. 294 Figure A4.67 13 Figure A4.68 1 Figure A4.69 Infrared spectrum (Thin Film, NaCl) of compound 79b ................................. 296 Figure A4.70 13 Figure A4.71 1 Figure A4.72 Infrared spectrum (Thin Film, NaCl) of compound 79f .................................. 298 Figure A4.73 13 Figure A4.74 HMBC (400 MHz, CDCl3) of compound 79f ................................................ 299 Figure A4.75 1 Figure A4.76 Infrared spectrum (Thin Film, NaCl) of compound 82 ................................... 301 Figure A4.77 13 Figure A4.78 1 Figure A4.79 Infrared spectrum (Thin Film, NaCl) of compound 83 ................................... 303 Figure A4.80 13 Figure A4.81 1 Figure A4.82 Infrared spectrum (Thin Film, NaCl) of compound 84 ................................... 305 Figure A4.83 13 Figure A4.84 1 Figure A4.85 Infrared spectrum (Thin Film, NaCl) of compound 85 ................................... 307 Figure A4.86 13 Figure A4.87 1 Figure A4.88 Infrared spectrum (Thin Film, NaCl) of compound 86 ................................... 309 Figure A4.89 13 Figure A4.90 1 Figure A4.91 Infrared spectrum (Thin Film, NaCl) of compound 88 ................................... 311 Figure A4.92 13 Figure A4.93 1 H NMR (400 MHz, CDCl3) of compound 78b ............................................. 287 C NMR (101 MHz, CDCl3) of compound 78b ............................................ 288 H NMR (400 MHz, CDCl3) of compound 78c ............................................. 289 C NMR (101 MHz, CDCl3) of compound 78c ............................................ 290 H NMR (400 MHz, CDCl3) of compound 78e ............................................. 291 C NMR (101 MHz, CDCl3) of compound 78e ............................................ 292 H NMR (400 MHz, CDCl3) of compound 79a ............................................. 293 C NMR (101 MHz, CDCl3) of compound 79a ............................................ 294 H NMR (400 MHz, CDCl3) of compound 79b ............................................. 295 C NMR (101 MHz, CDCl3) of compound 79b ............................................ 296 H NMR (400 MHz, CDCl3) of compound 79f .............................................. 297 C NMR (101 MHz, CDCl3) of compound 79f ............................................. 298 H NMR (400 MHz, CDCl3) of compound 82 ............................................... 300 C NMR (101 MHz, CDCl3) of compound 82 .............................................. 301 H NMR (400 MHz, CDCl3) of compound 83 ............................................... 302 C NMR (101 MHz, CDCl3) of compound 83 .............................................. 303 H NMR (400 MHz, CDCl3) of compound 84 ............................................... 304 C NMR (101 MHz, CDCl3) of compound 84 .............................................. 305 H NMR (400 MHz, CDCl3) of compound 85 ............................................... 306 C NMR (101 MHz, CDCl3) of compound 85 .............................................. 307 H NMR (400 MHz, CDCl3) of compound 86 ............................................... 308 C NMR (101 MHz, CDCl3) of compound 86 .............................................. 309 H NMR (400 MHz, CDCl3) of compound 88 ............................................... 310 C NMR (101 MHz, CDCl3) of compound 88 .............................................. 311 H NMR (400 MHz, CDCl3) of compound 89 ............................................... 312 xxvi Figure A4.94 Infrared spectrum (Thin Film, NaCl) of compound 89 ................................... 313 Figure A4.95 13 Figure A4.96 1 Figure A4.97 Infrared spectrum (Thin Film, NaCl) of compound 90 ................................... 315 Figure A4.98 13 Figure A4.99 1 Figure A4.100 Infrared spectrum (Thin Film, NaCl) of compound 91 ................................... 317 Figure A4.101 13 C NMR (101 MHz, CDCl3) of compound 89 .............................................. 313 H NMR (400 MHz, CDCl3) of compound 90 ............................................... 314 C NMR (101 MHz, CDCl3) of compound 90 .............................................. 315 H NMR (400 MHz, CDCl3) of compound 91 ............................................... 316 C NMR (101 MHz, CDCl3) of compound 91 .............................................. 317 APPENDIX 5 X-Ray Crystallography Reports Relevant to Chapter 3 Figure A5.1 X-ray crystal structure of carboxylic acid 77h ............................................... 319 CHAPTER 4 Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via IridiumCatalyzed Allylic Alkylation Figure 4.1 State-of-the-art in the enantioselective synthesis of vicinal all-carbon quaternary centers via transition metal-catalyzed allylic alkylation ................................ 326 Figure 4.2 Product transformations of allylic alkylation products ................................... 335 APPENDIX 6 Spectra Relevant to Chapter 4 Figure A6.1 1 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 93 ................................... 371 Figure A6.3 13 Figure A6.4 1 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 95a ................................. 373 Figure A6.6 13 Figure A6.7 1 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 95b ................................. 375 Figure A6.9 13 Figure A6.10 1 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 95d ................................. 377 Figure A6.12 13 Figure A6.13 1 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 95e ................................. 379 Figure A6.15 13 H NMR (400 MHz, CDCl3) of compound 93 ............................................... 370 C NMR (101 MHz, CDCl3) of compound 93 .............................................. 371 H NMR (400 MHz, CDCl3) of compound 95a ............................................. 372 C NMR (101 MHz, CDCl3) of compound 95a ............................................ 373 H NMR (400 MHz, CDCl3) of compound 95b ............................................. 374 C NMR (101 MHz, CDCl3) of compound 95b ............................................ 375 H NMR (400 MHz, CDCl3) of compound 95d ............................................. 376 C NMR (101 MHz, CDCl3) of compound 95d ............................................ 377 H NMR (400 MHz, CDCl3) of compound 95e ............................................. 378 C NMR (101 MHz, CDCl3) of compound 95e ............................................ 379 xxvii Figure A6.16 1 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 95f .................................. 381 Figure A6.18 13 Figure A6.19 1 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 95g ................................. 383 Figure A6.21 13 Figure A6.22 1 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 96b ................................. 385 Figure A6.24 13 Figure A6.25 1 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 96c ................................. 387 Figure A6.27 13 Figure A6.28 1 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 96f .................................. 389 Figure A6.30 13 Figure A6.31 1 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 97a ................................. 391 Figure A6.33 13 Figure A6.34 1 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 97b ................................. 393 Figure A6.36 13 Figure A6.37 1 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 97c ................................. 395 Figure A6.39 13 Figure A6.40 1 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 97d ................................. 397 Figure A6.42 13 Figure A6.43 1 Figure A6.44 Infrared spectrum (Thin Film, NaCl) of compound 97e ................................. 399 Figure A6.45 13 Figure A6.46 1 Figure A6.47 Infrared spectrum (Thin Film, NaCl) of compound 97f .................................. 401 Figure A6.48 13 Figure A6.49 1 Figure A6.50 Infrared spectrum (Thin Film, NaCl) of compound 97g ................................. 403 Figure A6.51 13 Figure A6.52 1 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound 97h ................................. 405 H NMR (400 MHz, CDCl3) of compound 95f .............................................. 380 C NMR (101 MHz, CDCl3) of compound 95f ............................................. 381 H NMR (400 MHz, CDCl3) of compound 95g ............................................. 382 C NMR (101 MHz, CDCl3) of compound 95g ............................................ 383 H NMR (400 MHz, CDCl3) of compound 96b ............................................. 384 C NMR (101 MHz, CDCl3) of compound 96b ............................................ 385 H NMR (400 MHz, CDCl3) of compound 96c ............................................. 386 C NMR (101 MHz, CDCl3) of compound 96c ............................................ 387 H NMR (400 MHz, CDCl3) of compound 96f .............................................. 388 C NMR (101 MHz, CDCl3) of compound 96f ............................................. 389 H NMR (400 MHz, CDCl3) of compound 97a ............................................. 390 C NMR (101 MHz, CDCl3) of compound 97a ............................................ 391 H NMR (400 MHz, CDCl3) of compound 97b ............................................. 392 C NMR (101 MHz, CDCl3) of compound 97b ............................................ 393 H NMR (400 MHz, CDCl3) of compound 97c ............................................. 394 C NMR (101 MHz, CDCl3) of compound 97c ............................................ 395 H NMR (400 MHz, CDCl3) of compound 97d ............................................. 396 C NMR (101 MHz, CDCl3) of compound 97d ............................................ 397 H NMR (400 MHz, CDCl3) of compound 97e ............................................. 398 C NMR (101 MHz, CDCl3) of compound 97e ............................................ 399 H NMR (400 MHz, CDCl3) of compound 97f .............................................. 400 C NMR (101 MHz, CDCl3) of compound 97f ............................................. 401 H NMR (400 MHz, CDCl3) of compound 97g ............................................. 402 C NMR (101 MHz, CDCl3) of compound 97g ............................................ 403 H NMR (400 MHz, CDCl3) of compound 97h ............................................. 404 xxviii Figure A6.54 13 Figure A6.55 1 Figure A6.56 Infrared spectrum (Thin Film, NaCl) of compound 97j .................................. 407 Figure A6.57 13 Figure A6.58 1 Figure A6.59 Infrared spectrum (Thin Film, NaCl) of compound 97k ................................. 409 Figure A6.60 13 Figure A6.61 1 Figure A6.62 Infrared spectrum (Thin Film, NaCl) of compound 97l .................................. 411 Figure A6.63 13 Figure A6.64 1 Figure A6.65 Infrared spectrum (Thin Film, NaCl) of compound 101 ................................. 413 Figure A6.66 13 Figure A6.67 1 Figure A6.68 Infrared spectrum (Thin Film, NaCl) of compound 102 ................................. 415 Figure A6.69 13 Figure A6.70 1 Figure A6.71 Infrared spectrum (Thin Film, NaCl) of compound 103 ................................. 417 Figure A6.72 13 Figure A6.73 HSQC (400 MHz, CDCl3) of compound 103 ................................................ 418 Figure A6.74 HMBC (400 MHz, CDCl3) of compound 103 ................................................ 419 Figure A6.75 NOESY (400 MHz, CDCl3) of compound 103 ............................................... 420 Figure A6.76 1 Figure A6.77 Infrared spectrum (Thin Film, NaCl) of compound 104 ................................. 422 Figure A6.78 13 Figure A6.79 NOESY (400 MHz, CDCl3) of compound 104 ............................................... 423 Figure A6.80 1 Figure A6.81 Infrared spectrum (Thin Film, NaCl) of compound 105 ................................. 425 Figure A6.82 13 Figure A6.83 NOESY (400 MHz, CDCl3) of compound 105 ............................................... 426 Figure A6.84 1 Figure A6.85 Infrared spectrum (Thin Film, NaCl) of compound 106 ................................. 428 Figure A6.86 13 C NMR (101 MHz, CDCl3) of compound 97h ............................................ 405 H NMR (400 MHz, CDCl3) of compound 97j .............................................. 406 C NMR (101 MHz, CDCl3) of compound 97j ............................................. 407 H NMR (400 MHz, CDCl3) of compound 97k ............................................. 408 C NMR (101 MHz, CDCl3) of compound 97k ............................................ 409 H NMR (400 MHz, CDCl3) of compound 97l .............................................. 410 C NMR (101 MHz, CDCl3) of compound 97l ............................................. 411 H NMR (400 MHz, CDCl3) of compound 101 ............................................. 412 C NMR (101 MHz, CDCl3) of compound 101 ............................................ 413 H NMR (400 MHz, CDCl3) of compound 102 ............................................. 414 C NMR (101 MHz, CDCl3) of compound 102 ............................................ 415 H NMR (400 MHz, CDCl3) of compound 103 ............................................. 416 C NMR (101 MHz, CDCl3) of compound 103 ............................................ 417 H NMR (400 MHz, CDCl3) of compound 104 ............................................. 421 C NMR (101 MHz, CDCl3) of compound 104 ............................................ 422 H NMR (400 MHz, CDCl3) of compound 105 ............................................. 424 C NMR (101 MHz, CDCl3) of compound 105 ............................................ 425 H NMR (400 MHz, CDCl3) of compound 106 ............................................. 427 C NMR (101 MHz, CDCl3) of compound 106 ............................................ 428 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4 Figure A7.1 X-ray crystal structure of bis-nitrile 97c ......................................................... 431 xxix CHAPTER 5 Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Figure 5.1 Stoltz group contributions to palladium-catalyzed allylic alkylation methodology and application in natural product total synthesis .................... 442 Figure 5.2 Stereodyad-containing natural products as inspiration for the development of novel iridium-catalyzed allylic alkylation technology ................................... 443 Figure 5.3 Timeline for the development of iridium-catalyzed allylic alkylation prior to the Stoltz group’s entry into the field .................................................................. 444 Figure 5.4 Select examples of diverse product transformations of enantio- and diastereoselective iridium-catalyzed allylic alkylation products 137 ............. 454 Figure 5.5 Iridium-catalyzed allylic alkylation strategies ................................................ 455 Figure 5.6 Limitations in enantioselective iridium-catalyzed allylic alkylation prior to 2017 ......................................................................................................... 457 Figure 5.7 Enantioselective synthesis of acyclic α-quaternary esters 82 and amides 84 ..................................................................................................... 462 Figure 5.8 Product derivatizations of iridium-catalyzed allylic alkylation products 157 bearing vicinal all-carbon quaternary centers ............................................... 464 APPENDIX 8 A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)Taiwaniaquinone H Figure A8.1 Taiwaniaquinoid natural products ................................................................ 472 Figure A8.2 Stoltz group conjugate addition chemistry as inspiration for revised retrosynthetic analysis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) ............................................................................................................. 473 Figure A8.3 Linear relationship of catalyst ee to product ee ............................................. 484 Figure A8.4 Proposed catalytic cycle for the asymmetric conjugate addition of arylboronic acids to cyclic enones catalyzed by the combination of Pd(OCOCF3)2 and (S)-tBuPyOx (L14) ............................................................................................... 486 Figure A8.5 Calculated transition states and effect of α’-substituents on enantioselectivity .......................................................................................... 487 Figure A8.6 Planned retrosynthesis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) ............................................................................................................. 489 Figure A8.7 Hammett plot of log10(er) vs σp for select boronic acids in the palladiumcatalyzed conjugate addition reaction .......................................................... 490 xxx APPENDIX 9 Spectra Relevant to Appendix 8 Figure A9.1 1 Figure A9.2 Infrared spectrum (Thin Film, NaCl) of compound 169b ............................... 531 Figure A9.3 13 Figure A9.4 1 Figure A9.5 Infrared spectrum (Thin Film, NaCl) of compound 169c ............................... 533 Figure A9.6 13 Figure A9.7 1 Figure A9.8 Infrared spectrum (Thin Film, NaCl) of compound 169d ............................... 535 Figure A9.9 13 Figure A9.10 1 Figure A9.11 Infrared spectrum (Thin Film, NaCl) of compound 169e ............................... 537 Figure A9.12 13 Figure A9.13 1 Figure A9.14 Infrared spectrum (Thin Film, NaCl) of compound 169f ................................ 539 Figure A9.15 13 Figure A9.16 1 Figure A9.17 Infrared spectrum (Thin Film, NaCl) of compound 197 ................................. 541 Figure A9.18 13 Figure A9.19 1 Figure A9.20 Infrared spectrum (Thin Film, NaCl) of compound 198 ................................. 543 Figure A9.21 13 Figure A9.22 1 Figure A9.23 Infrared spectrum (Thin Film, NaCl) of compound 199 ................................. 545 Figure A9.24 13 Figure A9.25 1 Figure A9.26 Infrared spectrum (Thin Film, NaCl) of compound 202 ................................. 547 Figure A9.27 13 Figure A9.28 1 Figure A9.29 Infrared spectrum (Thin Film, NaCl) of compound 203 ................................. 549 Figure A9.30 13 Figure A9.31 1 Figure A9.32 Infrared spectrum (Thin Film, NaCl) of compound 205 ................................. 551 Figure A9.33 13 Figure A9.34 1 Figure A9.35 Infrared spectrum (Thin Film, NaCl) of compound 206 ................................. 553 Figure A9.36 13 H NMR (500 MHz, CDCl3) of compound 169b ........................................... 530 C NMR (125 MHz, CDCl3) of compound 169b .......................................... 531 H NMR (500 MHz, CDCl3) of compound 169c ........................................... 532 C NMR (125 MHz, CDCl3) of compound 169c .......................................... 533 H NMR (500 MHz, CDCl3) of compound 169d ........................................... 534 C NMR (125 MHz, CDCl3) of compound 169d .......................................... 535 H NMR (500 MHz, CDCl3) of compound 169e ........................................... 536 C NMR (125 MHz, CDCl3) of compound 169e .......................................... 537 H NMR (500 MHz, CDCl3) of compound 169f ............................................ 538 C NMR (125 MHz, CDCl3) of compound 169f ........................................... 539 H NMR (500 MHz, CDCl3) of compound 197 ............................................. 540 C NMR (125 MHz, CDCl3) of compound 197 ............................................ 541 H NMR (500 MHz, CDCl3) of compound 198 ............................................. 542 C NMR (125 MHz, CDCl3) of compound 198 ............................................ 543 H NMR (500 MHz, CDCl3) of compound 199 ............................................. 544 C NMR (125 MHz, CDCl3) of compound 199 ............................................ 545 H NMR (500 MHz, CDCl3) of compound 202 ............................................. 546 C NMR (125 MHz, CDCl3) of compound 202 ............................................ 547 H NMR (500 MHz, CDCl3) of compound 203 ............................................. 548 C NMR (125 MHz, CDCl3) of compound 203 ............................................ 549 H NMR (500 MHz, CDCl3) of compound 205 ............................................. 550 C NMR (125 MHz, CDCl3) of compound 205 ............................................ 551 H NMR (500 MHz, CDCl3) of compound 206 ............................................. 552 C NMR (125 MHz, CDCl3) of compound 206 ............................................ 553 xxxi Figure A9.37 1 Figure A9.38 Infrared spectrum (Thin Film, NaCl) of compound 207 ................................. 555 Figure A9.39 13 Figure A9.40 1 Figure A9.41 Infrared spectrum (Thin Film, NaCl) of compound 208 ................................. 557 Figure A9.42 13 Figure A9.43 1 Figure A9.44 Infrared spectrum (Thin Film, NaCl) of compound 209 ................................. 559 Figure A9.45 13 Figure A9.46 19 Figure A9.47 1 Figure A9.48 Infrared spectrum (Thin Film, NaCl) of compound 210 ................................. 562 Figure A9.49 13 Figure A9.50 1 Figure A9.51 Infrared spectrum (Thin Film, NaCl) of compound 211 ................................. 564 Figure A9.52 13 Figure A9.53 1 Figure A9.54 Infrared spectrum (Thin Film, NaCl) of compound 212 ................................. 566 Figure A9.55 13 Figure A9.56 1 Figure A9.57 Infrared spectrum (Thin Film, NaCl) of compound 213 ................................. 568 Figure A9.58 13 Figure A9.59 1 Figure A9.60 Infrared spectrum (Thin Film, NaCl) of compound 214 ................................. 570 Figure A9.61 13 Figure A9.62 1 Figure A9.63 Infrared spectrum (Thin Film, NaCl) of compound 215 ................................. 572 Figure A9.64 13 Figure A9.65 1 Figure A9.66 Infrared spectrum (Thin Film, NaCl) of compound 216 ................................. 574 Figure A9.67 13 Figure A9.68 1 Figure A9.69 Infrared spectrum (Thin Film, NaCl) of compound 217 ................................. 576 Figure A9.70 13 H NMR (500 MHz, CDCl3) of compound 207 ............................................. 554 C NMR (125 MHz, CDCl3) of compound 207 ............................................ 555 H NMR (500 MHz, CDCl3) of compound 208 ............................................. 556 C NMR (125 MHz, CDCl3) of compound 208 ............................................ 557 H NMR (500 MHz, CDCl3) of compound 209 ............................................. 558 C NMR (125 MHz, CDCl3) of compound 209 ............................................ 559 F vs 13C HSQC (376 MHz, CDCl3) of compound 209 ................................. 560 H NMR (500 MHz, CDCl3) of compound 210 ............................................. 561 C NMR (125 MHz, CDCl3) of compound 210 ............................................ 562 H NMR (500 MHz, CDCl3) of compound 211 ............................................. 563 C NMR (125 MHz, CDCl3) of compound 211 ............................................ 564 H NMR (500 MHz, CDCl3) of compound 212 ............................................. 565 C NMR (125 MHz, CDCl3) of compound 212 ............................................ 566 H NMR (500 MHz, CDCl3) of compound 213 ............................................. 567 C NMR (125 MHz, CDCl3) of compound 213 ............................................ 568 H NMR (500 MHz, CDCl3) of compound 214 ............................................. 569 C NMR (125 MHz, CDCl3) of compound 214 ............................................ 570 H NMR (500 MHz, CDCl3) of compound 215 ............................................. 571 C NMR (125 MHz, CDCl3) of compound 215 ............................................ 572 H NMR (500 MHz, CDCl3) of compound 216 ............................................. 573 C NMR (125 MHz, CDCl3) of compound 216 ............................................ 574 H NMR (500 MHz, CDCl3) of compound 217 ............................................. 575 C NMR (125 MHz, CDCl3) of compound 217 ............................................ 576 APPENDIX 10 X-Ray Crystallography Reports Relevant to Appendix 8 Figure A10.1 X-ray crystal structure of undesired tricycle 203 ........................................... 578 xxxii APPENDIX 11 Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy Figure A11.1 Strategy and inspiration for the catalytic enantioselective synthesis of all-carbon quaternary spirocycles .................................................................................. 591 APPENDIX 12 Spectra Relevant to Appendix 11 Figure A12.1 1 Figure A12.2 Infrared spectrum (Thin Film, NaCl) of compound 218a ............................... 609 Figure A12.3 13 Figure A12.4 1 Figure A12.5 Infrared spectrum (Thin Film, NaCl) of compound 218b ............................... 611 Figure A12.6 13 Figure A12.7 1 Figure A12.8 Infrared spectrum (Thin Film, NaCl) of compound 218c ............................... 613 Figure A12.9 13 Figure A12.10 1 Figure A12.11 Infrared spectrum (Thin Film, NaCl) of compound 219a ............................... 615 Figure A12.12 13 Figure A12.13 1 Figure A12.14 Infrared spectrum (Thin Film, NaCl) of compound 219b ............................... 617 Figure A12.15 13 Figure A12.16 1 Figure A12.17 Infrared spectrum (Thin Film, NaCl) of compound 219c ............................... 619 Figure A12.18 13 Figure A12.19 1 Figure A12.20 Infrared spectrum (Thin Film, NaCl) of compound 220a ............................... 621 Figure A12.21 13 Figure A12.22 1 Figure A12.23 Infrared spectrum (Thin Film, NaCl) of compound 220b ............................... 623 Figure A12.24 13 Figure A12.25 1 Figure A12.26 Infrared spectrum (Thin Film, NaCl) of compound 220c ............................... 625 Figure A12.27 13 H NMR (400 MHz, CDCl3) of compound 218a ........................................... 608 C NMR (101 MHz, CDCl3) of compound 218a .......................................... 609 H NMR (400 MHz, CDCl3) of compound 218b ........................................... 610 C NMR (101 MHz, CDCl3) of compound 218b .......................................... 611 H NMR (400 MHz, CDCl3) of compound 218c ........................................... 612 C NMR (101 MHz, CDCl3) of compound 218c .......................................... 613 H NMR (400 MHz, CDCl3) of compound 219a ........................................... 614 C NMR (101 MHz, CDCl3) of compound 219a .......................................... 615 H NMR (400 MHz, CDCl3) of compound 219b ........................................... 616 C NMR (101 MHz, CDCl3) of compound 219b .......................................... 617 H NMR (400 MHz, CDCl3) of compound 219c ........................................... 618 C NMR (101 MHz, CDCl3) of compound 219c .......................................... 619 H NMR (400 MHz, CDCl3) of compound 220a ........................................... 620 C NMR (101 MHz, CDCl3) of compound 220a .......................................... 621 H NMR (400 MHz, CDCl3) of compound 220b ........................................... 622 C NMR (101 MHz, CDCl3) of compound 220b .......................................... 623 H NMR (400 MHz, CDCl3) of compound 220c ........................................... 624 C NMR (101 MHz, CDCl3) of compound 220c .......................................... 625 xxxiii APPENDIX 14 Spectra Relevant to Appendix 13 Figure A14.1 1 Figure A14.2 1 Figure A14.3 13 Figure A14.4 1 Figure A14.5 13 Figure A14.6 1 Figure A14.7 13 Figure A14.8 1 Figure A14.9 13 Figure A14.10 1 Figure A14.11 13 Figure A14.12 1 Figure A14.13 13 Figure A14.14 1 Figure A14.15 13 Figure A14.16 1 Figure A14.17 13 Figure A14.18 1 Figure A14.19 13 Figure A14.20 1 Figure A14.21 13 Figure A14.22 1 Figure A14.23 13 Figure A14.24 1 Figure A14.25 13 Figure A14.26 1 Figure A14.27 1 Figure A14.28 13 Figure A14.29 1 Figure A14.30 13 Figure A14.31 1 Figure A14.32 1 Figure A14.33 1 Figure A14.34 13 Figure A14.35 1 Figure A14.36 13 H NMR (400 MHz, CDCl3) of compound 226 ............................................. 688 H NMR (400 MHz, CDCl3) of compound 233 ............................................. 689 C NMR (101 MHz, CDCl3) of compound 233 ............................................ 690 H NMR (400 MHz, CDCl3) of compound 234 ............................................. 691 C NMR (101 MHz, CDCl3) of compound 234 ............................................ 692 H NMR (400 MHz, CDCl3) of compound 235 ............................................. 693 C NMR (101 MHz, CDCl3) of compound 235 ............................................ 694 H NMR (400 MHz, CDCl3) of compound 238 ............................................. 695 C NMR (101 MHz, CDCl3) of compound 238 ............................................ 696 H NMR (400 MHz, CDCl3) of compound 240 (LG = Cl) ............................. 697 C NMR (101 MHz, CDCl3) of compound 240 (LG = Cl) ............................. 698 H NMR (400 MHz, CDCl3) of compound 241 ............................................. 699 C NMR (101 MHz, CDCl3) of compound 241 ............................................ 700 H NMR (400 MHz, CDCl3) of compound 243 ............................................. 701 C NMR (101 MHz, CDCl3) of compound 243 ............................................ 702 H NMR (400 MHz, CDCl3) of compound 244 ............................................. 703 C NMR (101 MHz, CDCl3) of compound 244 ............................................ 704 H NMR (400 MHz, CDCl3) of compound 245 ............................................. 705 C NMR (101 MHz, CDCl3) of compound 245 ............................................ 706 H NMR (400 MHz, CDCl3) of compound 247 ............................................. 707 C NMR (101 MHz, CDCl3) of compound 247 ............................................ 708 H NMR (400 MHz, CDCl3) of compound 248 ............................................. 709 C NMR (101 MHz, CDCl3) of compound 248 ............................................ 710 H NMR (400 MHz, CDCl3) of compound 249 ............................................. 711 C NMR (101 MHz, CDCl3) of compound 249 ............................................ 712 H NMR (400 MHz, CDCl3) of compound 256 ............................................. 713 H NMR (400 MHz, CDCl3) of compound 257 ............................................. 714 C NMR (101 MHz, CDCl3) of compound 257 ............................................ 715 H NMR (400 MHz, CDCl3) of compound 258 ............................................. 716 C NMR (101 MHz, CDCl3) of compound 258 ............................................ 717 H NMR (400 MHz, CDCl3) of compound 259 ............................................. 718 H NMR (400 MHz, CDCl3) of compound 260 ............................................. 719 H NMR (400 MHz, CDCl3) of compound 261 ............................................. 720 C NMR (101 MHz, CDCl3) of compound 261 ............................................ 721 H NMR (400 MHz, CDCl3) of compound 262 ............................................. 722 C NMR (101 MHz, CDCl3) of compound 262 ............................................ 723 xxxiv Figure A14.37 1 Figure A14.38 13 Figure A14.39 1 Figure A14.40 1 Figure A14.41 13 Figure A14.42 1 Figure A14.43 13 Figure A14.44 1 Figure A14.45 1 Figure A14.46 13 Figure A14.47 1 Figure A14.48 13 Figure A14.49 1 Figure A14.50 13 Figure A14.51 1 Figure A14.52 13 Figure A14.53 1 Figure A14.54 13 Figure A14.55 1 H NMR (400 MHz, CDCl3) of compound 263 ............................................. 724 C NMR (101 MHz, CDCl3) of compound 263 ............................................ 725 H NMR (400 MHz, CDCl3) of compound 274 ............................................. 726 H NMR (400 MHz, CDCl3) of compound 275 ............................................. 727 C NMR (101 MHz, CDCl3) of compound 275 ............................................ 728 H NMR (400 MHz, CDCl3) of compound 276 ............................................. 729 C NMR (101 MHz, CDCl3) of compound 276 ............................................ 730 H NMR (400 MHz, CDCl3) of compound 277 ............................................. 731 H NMR (400 MHz, CDCl3) of compound 280 ............................................. 732 C NMR (101 MHz, CDCl3) of compound 280 ............................................ 733 H NMR (400 MHz, CDCl3) of compound 281 ............................................. 734 C NMR (101 MHz, CDCl3) of compound 281 ............................................ 735 H NMR (400 MHz, CDCl3) of compound 282 ............................................. 736 C NMR (101 MHz, CDCl3) of compound 282 ............................................ 737 H NMR (400 MHz, CDCl3) of compound 291 ............................................. 738 C NMR (101 MHz, CDCl3) of compound 291 ............................................ 739 H NMR (400 MHz, CDCl3) of compound 295 ............................................. 740 C NMR (101 MHz, CDCl3) of compound 295 ............................................ 741 H NMR (400 MHz, CDCl3) of compound 296 ............................................. 742 xxxv LIST OF SCHEMES PROLOGUE Iridium-Catalyzed Allylic Alkylation Scheme P.1 Asymmetric transition metal-catalyzed allylic alkylation ................................... 2 Scheme P.2 Asymmetric iridium-catalyzed allylic alkylation ............................................... 2 CHAPTER 1 Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride Scheme 1.1 First report of diastereo- and enantioselective iridium-catalyzed allylic alkylation ......................................................................................................... 8 Scheme 1.2 Allylic alkylation of acyclic β-ketoesters by Stoltz ............................................. 9 Scheme 1.3 Allylic alkylation with acyclic α-alkoxy ketones by Hartwig ........................... 10 Scheme 1.4 Counterion-assisted iridium-catalyzed allylic alkylation of azlactones by Hartwig .......................................................................................................... 11 Scheme 1.5 Cation control of diastereoselectivity in iridium-catalyzed allylic alkylation of a) 5H-oxazol-4-ones 20 and b) 5H-thiazol-4-ones 24 by Hartwig ................... 12 Scheme 1.6 Allylic alkylation of a) bicyclic β-ketoesters 27 and b) monocyclic β-ketoesters 30 by Stoltz .................................................................................................... 13 Scheme 1.7 Allylic alkylation of extended enolates by Stoltz ............................................. 14 Scheme 1.8 Allylic alkylation of non-stabilized enolates by Hartwig ................................. 15 Scheme 1.9 Dual catalyst-promoted allylic alkylation of aldehydes by Carreira ................. 15 Scheme 1.10 Proline-derived dual catalysis by Carreira ....................................................... 16 Scheme 1.11 Diastereoablative allylic alkylation of 46 by Stoltz .......................................... 17 Scheme 1.12 Bimetallic dual catalytic allylic alkylation by Zhang ....................................... 18 CHAPTER 2 Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents Scheme 2.1 Preparatory scale reaction ............................................................................ 146 CHAPTER 5 Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Scheme 5.1 Enantio- and diastereoselective iridium-catalyzed allylic alkylation of cyclic nucleophiles 128 .......................................................................................... 448 xxxvi Scheme 5.2 Iridium-catalyzed allylic alkylation/Cope rearrangement sequence ............... 448 Scheme 5.3 Enantio- and diastereoselective iridium-catalyzed allylic alkylation of acyclic nucleophiles 134 .......................................................................................... 449 Scheme 5.4 Enantio- and diastereoselective iridium-catalyzed allylic alkylation with crotyl chloride (57) ................................................................................................. 453 Scheme 5.5 First report of MAC reagent 67c in an asymmetric transition-metal catalyzed reaction ........................................................................................................ 457 Scheme 5.6 Enantioselective synthesis of acyclic α-quaternary carboxylic acids 153....... 461 Scheme 5.7 Synthesis of vicinal all-carbon quaternary centers 157 via enantioselective iridium-catalyzed allylic alkylation ............................................................... 463 APPENDIX 8 A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)Taiwaniaquinone H Scheme A8.1 Stoltz group retrosynthesis of (+)-dichroanone (159) ..................................... 472 Scheme A8.2 Asymmetric transition metal-catalyzed conjugate addition ........................... 475 Scheme A8.3 Initial Stoltz group asymmetric palladium-catalyzed conjugate addition with (S)-t-BuPyOx (L14) ....................................................................................... 476 Scheme A8.4 Necessity of water in developed asymmetric palladium-catalyzed conjugate addition ........................................................................................................ 480 Scheme A8.5 Synthesis of acetyl conjugate addition product 169b .................................... 491 Scheme A8.6 Unexpected cyclization of phenolic intermediate ......................................... 492 Scheme A8.7 Synthesis of para-bromo conjugate addition product 169d ........................... 495 Scheme A8.8 Isopropenyl cross-coupling ........................................................................... 496 Scheme A8.9 Synthesis of key intermediate 169f ............................................................... 497 APPENDIX 13 Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.1 Initial retrosynthetic analysis of (+)-isopalhinine A (221) via iridium-catalyzed allylic alkylation of endocyclic 1,3-dicarbonyl nucleophile 225 ................... 628 Scheme A13.2 Synthesis of alkyl-substituted electrophile 226 .............................................. 628 Scheme A13.3 Efforts to synthesize endocyclic 1,3-dicarbonyl nucleophiles ........................ 629 Scheme A13.4 Revised retrosynthetic analysis of (+)-isopalhinine A (221) via iridium-catalyzed allylic alkylation of lactone nucleophile 238 ................................................ 632 Scheme A13.5 Synthesis of lactone nucleophile 238 ............................................................ 632 Scheme A13.6 Attempts to advance bicycle 241 to key spirocyclic intermediate 223 .......... 635 xxxvii Scheme A13.7 Retrosynthetic analysis of (+)-isopalhinine A (221) via palladium-catalyzed allylic alkylation of masked stabilized lactam enolate 253 ............................ 637 Scheme A13.8 Synthesis of spirocyclic intermediate 263 via palladium-catalyzed allylic alkylation ..................................................................................................... 639 Scheme A13.9 Attempted alkylations of spirocyclic enone 263 ............................................ 640 Scheme A13.10 Retrosynthetic analysis of (+)-isopalhinine A (221) via palladium-catalyzed allylic alkylation of piperidone 272 .............................................................. 641 Scheme A13.11 Attempts to advance benzyl-protected piperidone 273 ................................. 642 Scheme A13.12 Attempts to advance Boc-protected piperidone 279 ..................................... 643 Scheme A13.13 Retrosynthetic analysis of (+)-isopalhinine A (221) via diastereoselective alkylation/allylation sequence ...................................................................... 644 Scheme A13.14 Attempts at diastereoselective functionalization ............................................ 644 Scheme A13.15 Requisite propyl chain as a nitrogen protecting group .................................. 645 Scheme A13.16 Non-strong base route to RCM precursor 298 ............................................... 646 Scheme A13.17 Attempts to advance β-ketolactam 296 ......................................................... 646 Scheme A13.18 Proposed route to (+)-isopalhinine A (221) from alkylated spirocycle 223 .... 648 Scheme A13.19 Alternative acyl anion equivalents ................................................................ 649 xxxviii LIST OF TABLES CHAPTER 1 Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride Table 1.1 Optimization of reaction parameters .............................................................. 20 Table 1.2 Substrate scope exploration ............................................................................ 23 Table 1.3 Substrate scope limitations ............................................................................. 25 Table 1.4 Additional optimization of reaction parameters .............................................. 36 Table 1.5 Determination of enantiomeric excess ............................................................ 57 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Table A2.1 Crystal data and structure refinement for allylic alkylation product 58e ........ 117 Table A2.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 58e. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ............................................................................. 118 Table A2.3 Bond lengths [Å] and angles [°] for 58e ........................................................ 119 Table A2.4 Anisotropic displacement parameters (Å x 10 ) for 58e. The anisotropic 2 3 displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 123 Table A2.5 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 58e .......................................................................................................... 124 Table A2.6 Crystal data and structure refinement for triol 63 .......................................... 125 Table A2.7 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 63. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ..................................................................................................... 126 Table A2.8 Bond lengths [Å] and angles [°] for 63 .......................................................... 128 Table A2.9 Anisotropic displacement parameters (Å x 10 ) for 63. The anisotropic 2 3 displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 130 Table A2.10 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 63 ........................................................................................................... 131 Table A2.11 Crystal data and structure refinement for diol 64 .......................................... 133 xxxix Table A2.12 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 64. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ..................................................................................................... 135 Table A2.13 Bond lengths [Å] and angles [°] for 64 .......................................................... 135 Table A2.14 Anisotropic displacement parameters (Å x 10 ) for 64. The anisotropic 2 3 displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 138 Table A2.15 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 64 ........................................................................................................... 139 CHAPTER 2 Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents Table 2.1 Optimization of reaction parameters .................................................. 143 Table 2.2 Electrophile substrate scope ............................................................. 144 Table 2.3 Electrophile substrate scope limitations ............................................... 145 Table 2.4 Determination of enantiomeric excess ................................................ 162 CHAPTER 3 Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Table 3.1 Optimization of reaction parameters ............................................................ 204 Table 3.2 Electrophile isomers ..................................................................................... 205 Table 3.3 Aryl substituent substrate scope .................................................................... 207 Table 3.4 Non-aryl substituent substrate scope ............................................................. 208 Table 3.5 Substrate scope limitations ........................................................................... 209 Table 3.6 Determination of enantiomeric excess .......................................................... 242 APPENDIX 5 X-Ray Crystallography Reports Relevant to Chapter 3 Table A5.1 Crystal data and structure refinement for carboxylic acid 77h ....................... 319 Table A5.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 77h. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ............................................................................. 321 Table A5.3 Bond lengths [Å] and angles [°] for 77h ........................................................ 321 xl Table A5.4 2 3 Anisotropic displacement parameters (Å x 10 ) for 77h. The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 323 Table A5.5 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 77h ......................................................................................................... 323 CHAPTER 4 Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via IridiumCatalyzed Allylic Alkylation Table 4.1 Optimization of reaction parameters ............................................................ 328 Table 4.2 Nucleophile substrate scope ......................................................................... 330 Table 4.3 Electrophile substrate scope .......................................................................... 331 Table 4.4 Substrate scope limitations ........................................................................... 333 Table 4.5 Determination of enantiomeric excess .......................................................... 361 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1 Crystal data and structure refinement for bis-nitrile 97c ................................ 432 Table A7.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 97c. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ............................................................................. 433 Table A7.3 Bond lengths [Å] and angles [°] for 97c ........................................................ 434 Table A7.4 Anisotropic displacement parameters (Å x 10 ) for 97c. The anisotropic 2 3 displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 437 Table A7.5 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 97c .......................................................................................................... 438 Table A7.6 Torsion angles [°] for 97c ............................................................................. 439 CHAPTER 5 Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Table 5.1 Development of conditions for the iridium-catalyzed allylic alkylation reaction of cyclic nucleophiles forming tertiary and all-carbon quaternary stereocenters ................................................................................................ 446 xli Table 5.2 Optimization of iridium-catalyzed allylic alkylation reaction of alkyl-substituted electrophile 53 ............................................................................................. 451 Table 5.3 Optimization of the enantioselective synthesis of acyclic α-quaternary carboxylic acid derivatives 73 ...................................................................... 459 APPENDIX 8 A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)Taiwaniaquinone H Table A8.1 Scope of arylboronic acid and enone conjugate acceptors ........................... 478 Table A8.2 Effect of additives on reaction rate, yield, and enantioselectivity ................... 481 Table A8.3 Expanded substrate scope with improved reaction conditions ...................... 483 Table A8.4 Asymmetric conjugate addition of arylboronic acids to heterocyclic conjugate acceptors ...................................................................................................... 488 Table A8.5 Identification of a suitable conjugate addition system ................................... 494 Table A8.6 Determination of enantiomeric excess .......................................................... 520 Table A8.7 Data for Hammett analysis of enantioselectivity for select boronic acids ...... 521 APPENDIX 10 X-Ray Crystallography Reports Relevant to Appendix 8 Table A10.1 Crystal data and structure refinement for undesired tricycle 203 ................... 578 Table A10.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 203. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ............................................................................. 580 Table A10.3 Bond lengths [Å] and angles [°] for 203 ........................................................ 581 Table A10.4 Anisotropic displacement parameters (Å x 10 ) for 203. The anisotropic 2 3 displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ....................................................................................................... 584 Table A10.5 4 2 3 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 203 ......................................................................................................... 585 Table A10.6 Torsion angles [°] for 203 ............................................................................. 586 Table A10.7 Hydrogen bonds for 203 [Å and °]................................................................ 588 xlii APPENDIX 11 Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy Table A11.1 Enantioselective palladium-catalyzed allylic alkylations with substrates bearing a masked methyl vinyl ketone ...................................................................... 592 Table A11.2 One-pot synthesis of spirocyclic compounds ................................................ 593 Table A11.3 Determination of enantiomeric excess .......................................................... 604 APPENDIX 13 Progress Toward the Synthesis of (+)-Isopalhinine A Table A13.1 Optimization of the iridium-catalyzed allylic alkylation of model endocyclic 1,3-dicarbonyl nucleophile 233 ................................................................... 631 Table A13.2 Optimization of the iridium-catalyzed allylic alkylation of lactone 238 ........ 634 Table A13.3 Optimization of protecting groups for the palladium-catalyzed allylic alkylation reaction ........................................................................................ 638 Table A13.4 Determination of enantiomeric excess .......................................................... 681 APPENDIX 15 Notebook Cross-Reference for New Compounds Table A15.1 Notebook cross-reference for compounds in Chapter 1 ........................... 768 Table A15.2 Notebook cross-reference for compounds in Chapter 2 ........................... 771 Table A15.3 Notebook cross-reference for compounds in Chapter 3 ........................... 773 Table A15.4 Notebook cross-reference for compounds in Chapter 4 ........................... 777 Table A15.5 Notebook cross-reference for compounds in Appendix 8 ........................ 780 Table A15.6 Notebook cross-reference for compounds in Appendix 11 ....................... 783 Table A15.7 Notebook cross-reference for compounds in Appendix 13 ....................... 784 xliii LIST OF ABBREVIATIONS [α]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 CBS Corey–Bakshi–Shibata catalyst CDI 1,1'-carbonyldiimidazole cm–1 wavenumber(s) cod 1,5-cyclooctadiene Cp cyclopentadienyl CSA camphorsulfonic acid xliv Cy cyclohexyl d doublet D deuterium DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBDMH 1,3-dibromo-5,5-dimethylhydantoin DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCAA decarboxylative allylic alkylation DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIBAL diisobutylaluminum hydride DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine dmdba bis(3,5-dimethoxybenzylidene)acetone DMDO dimethyldioxirane 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) EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess EI+ electron impact equiv equivalent(s) ESI electrospray ionization xlv Et ethyl EtOAc ethyl acetate EWG electron withdrawing group FAB fast atom bombardment g gram(s) GC gas chromatography gCOSY gradient-selected correlation spectroscopy h hour(s) HG-II Hoveyda-Grubbs catalyst 2nd generation HMBC heteronuclear multiple bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy HSQC heteronuclear single quantum correlation Hz hertz hν light i-Pr isopropyl i.e. that is (Latin id est) IBX 2-iodoxybenzoic acid IPA isopropanol, 2-propanol Ipc diisopinocampheyl IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie KHMDS potassium hexamethyldisilazide L liter; ligand L* chiral ligand xlvi 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 MAC masked acyl cyanide Me methyl mg milligram(s) MHz megahertz min minute(s) MM mixed method mol mole(s) MOM methoxymethyl acetal mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves n nano N normal n-Bu butyl nbd norbornadiene NBS N-bromosuccinimide Nf perfluorobutanesulfonyl fluoride NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance Ns 2-nitrobenzenesulfonyl Nu nucleophile xlvii o ortho p para Pd/C palladium on carbon Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline ligand Pin 2,3-dimethylbutane-2,3-diol (pinacol) Piv trimethylacetyl, pivaloyl pKa pK for association of an acid pMBz 4-methoxy-benzoyl pmdba bis(4-methoxybenzylidene)acetone ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl Proton sponge 1,8-bis(dimethylamino)naphthalene Py pyridine q quartet R generic for any atom or functional group RCM ring-closing metathesis Red-Al sodium bis(2-methoxyethoxy)aluminium hydride Ref. reference Rf retention factor s singlet or strong or selectivity factor sat. saturated SFC supercritical fluid chromatography t triplet t-Bu tert-butyl TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide xlviii TBAT tetrabutylammonium difluorotriphenylsilicate TBD 1,3,4-triazabicyclo[4.4.0]dec-5-ene TBDPS tert-butyldiphenylsilyl TBHP tert-butyl hydroperoxide TBME 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 TIPS triisopropylsilyl TLC thin-layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl 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 λ wavelength µ micro Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1 CHAPTER 1 Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride† 1.1 INTRODUCTION The synthesis of singular all-carbon quaternary stereocenters has been a longstanding challenge in the synthetic community.1 Significant progress in this area over the past few decades has recently shifted the forefront of investigation toward the more difficult task of constructing vicinal stereodyads bearing at least one quaternary stereocenter. This nascent field is beset with difficulties not only arising from the increased sterics in the bond-forming event, but also the additional requirement of diastereocontrol. Among the available methodologies tailored for this challenge, 2 , 3 iridium-catalyzed allylic alkylations represent some of the most selective strategies, yet remain underdeveloped.4 † This work was performed in collaboration with Dr. J. Caleb Hethcox. Portions of this chapter have been reproduced with permission from Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. Angew. Chem. Int. Ed. 2016, 55, 16092–16095 © 2016 Wiley-VCH and Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. ACS Catal. 2016, 6, 6207–6213 © 2016 American Chemical Society. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 2 Figure 1.1 Enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reactions a) Prior Art: Vicinal Tertiary and Quaternary Stereocenters • Five reports • No alkyl-substituted electrophiles O O OCO 2Me R [IrL*] R b) Prior Art: Alkyl-Substituted Electrophiles • Four examples • No all-carbon quaternary stereocenters OCO 2Me R O OMe/H Ph Ph H/Ph [IrL*] Ph/H R O R = H, Et, or OBn OMe/H c) This Research: • Vicinal tertiary and quaternary stereocenters • Alkyl-substituted electrophile • Commercially available electrophile O O Cl EWG R [IrL*] R EWG The first diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation was disclosed by Takemoto in 2003 and remained the sole report of such a transformation for a decade. 5 Of the eleven published accounts of enantio- and diastereoselective iridium-catalyzed allylic alkylation since, 6,7,8 only five reports provide access to vicinal tertiary and all-carbon quaternary stereocenters.6 However, none of these protocols tolerate the use of alkyl-substituted electrophiles (Figure 1.1a). Conversely, the four singular examples employing alkyl-substituted electrophiles in two published papers fail to enable construction of all-carbon quaternary stereocenters (Figure 1.1b).7 While these protocols provide access to valuable chiral synthons, a wide variety of synthetic targets require the installation of alkyl-substituted stereodyads between neighboring tertiary and quaternary carbon atoms (Figure 1.2). To the best of our knowledge, no transition metal-catalyzed process allows for the preparation of this Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 3 desired motif. Herein, we describe the first method for the iridium-catalyzed synthesis of alkyl-substituted vicinal tertiary and all-carbon quaternary stereocenters via allylic alkylation of prochiral enolates (Figure 1.1c). Figure 1.2 Select natural products bearing alkyl-substituted vicinal tertiary and quaternary stereocenters. HO O O H H O O O O H ligularone (1) 1.2 BACKGROUND REGIOSELECTIVE O OH H crinipellin B (2) TO elisabethin A (3) DIASTEREO-, IRIDIUM-CATALYZED ALLYLIC ENANTIO-, AND ALKYLATION WITH PROCHIRAL ENOLATES A more detailed description of the twelve diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation methods5–8 previously disclosed at the time we began this investigation is discussed vide infra. 1.2.1 IRIDIUM CATALYST-CONTROLLED PROCESSES 1.2.1.1 Acyclic Nucleophiles Takemoto reported the first diastereo-, enantio-, and regioselective iridiumcatalyzed allylic alkylation reaction, wherein an iridium complex of bidentate chiral phosphite L1 and [Ir(cod)Cl]2 catalyzes the reaction of glycinate nucleophile 4 and arylsubstituted allylic phosphates 6 (Scheme 1.1).5 The corresponding branched products 7 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 4 and 9 bearing vicinal tertiary and trisubstituted stereocenters are afforded in moderate to excellent yields with good to excellent enantioselectivities, albeit with moderate diastereoselectivities. Takemoto also found that simply by employing either KOH or LiHMDS, the diastereomeric ratio can be inverted in order to preferentially access either diastereomer (7 versus 9); this synthetically useful phenomenon has yet to be reported again. Scheme 1.1 First report of diastereo- and enantioselective iridium-catalyzed allylic alkylation Ar Ph 50% KOH (300 mol %) toluene, 0 °C Ph OK N 5 Ph O P N CO2t-Bu OP(O)(OEt)2 5 examples 77–97% yield 68:32–82:18 dr 94–97% ee Ot-Bu Ph 6 [Ir(cod)Cl] 2 (10 mol %) (R a )-L1 (20 mol %) Ar Ph Ph N CO2t-Bu 7 O O SEt 4 (R a )-L1 Ar Ph LiHMDS (300 mol %) THF, 0 °C Ph Ot-Bu N OLi 8 6 OP(O)(OEt)2 [Ir(cod)Cl] 2 (10 mol %) (R a )-L1 (20 mol %) 5 examples 78–84% yield 87:13–90:10 dr 85–96% ee Ar Ph Ph N CO2t-Bu 9 The different behavior of the bases is believed to be the result of contrasting enolate geometry; the hypothesis being that KOH predominately gives the E-enolate 5 and LiHMDS instead forms the Z-enolate 8. This observation illuminates the additional challenge that acyclic, prochiral nucleophiles present in contrast to cyclic nucleophiles in diastereo- and enantioselective allylic alkylation chemistry. In acyclic cases, the enolate geometry must be selectively controlled in addition to the facial approach of the Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 5 nucleophile. This combination of challenges has resulted in significantly fewer reports of acyclic, prochiral enolate nucleophiles as compared to cyclic, prochiral nucleophiles. A decade after Takemoto’s report, our group disclosed the second report of an iridium-catalyzed allylic alkylation of acyclic enolates in 2013 (Scheme 1.2).6a Like Takemoto, we found chelation of the enolate with a metal cation, specifically lithium, to be crucial to the diastereoselectivity as bases lacking a chelating metal cation (i.e., DABCO) provide significantly lower selectivity. By deprotonating ketoesters 10 with LiOt-Bu prior to introduction of the electrophile, products 12 bearing vicinal tertiary and all-carbon quaternary stereocenters can be obtained in moderate to excellent selectivities with the use of a catalyst derived from [Ir(cod)Cl]2 and Me-THQphos (L2). While a majority of the cinnamyl carbonates 11 proceed with a high degree of regioselectivity (>90:10), we found that the use of electron-deficient aryl-substituted electrophiles 11 (e.g., R = C6H5NO2 or C6H5CF3) lead to a decrease in selectivity (50:50–86:14). Scheme 1.2 Allylic alkylation of acyclic β-ketoesters by Stoltz O [Ir(cod)Cl] 2 (2 mol %) (R,R a )-L2 (4 mol %) LiOt-Bu (200 mol %) TBD (10 mol %) O Ar OEt R1 10 R 1 = alkyl, benzyl, propargyl, F, Cl + R2 OCO 2Me 21 examples 78–95% yield 11 2 R = aryl, heteroaryl, alkenyl 50:50–95:5 branched/linear 6:1–20:1 dr 91–99% ee N P N O (R,R a )-L2 N R2 R1 CO2Et Ar THF, 25 °C O O N H TBD 12 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 6 In 2016, Hartwig found that acyclic α-alkoxy ketones 13 undergo selective allylic alkylation reactions with allyl carbonates 14 in the presence of preformed metallacyclic iridium complex 15, LiHMDS, and CuBr (Scheme 1.3).7a In these reactions, the geometry of the acyclic enolate, formed by deprotonation with the lithium base, is controlled by chelation to a copper(I) salt. Interestingly, the identity of the cation associated with the base is also found to play an integral role in achieving high diastereoselectivities, with KHMDS providing much lower selectivities than LiHMDS. The exact nature of this cation dependence is unknown. It is also worth noting that the scope of this reaction permits the use of crotyl carbonates, albeit in lower diastereoselectivities (ca. 7:1 dr). This is one of only two reports of alkyl-substituted electrophiles in a diastereoselective iridium-catalyzed allylic alkylation. Scheme 1.3 Allylic alkylation with acyclic α-alkoxy ketones by Hartwig O OR 2 Ar Ph R1 13 R 1 = aryl, heteroaryl R 2 = Me, MOM, MEM, PMB O 15 (2 mol %) LiHMDS (200 mol %) CuBr (200 mol %) + R3 OCO 2Me 14 R 3 = aryl, heteroaryl, alkenyl, methyl O R3 Ir P O Me N Ar THF, 5 °C R 1 OR 2 23 examples 71–99% yield 6:1–20:1 dr 88–99% ee 16 Ar * Ar BF 4 15 Ar = 2-Napthyl 1.2.1.2 Cyclic Nucleophiles In 2013, Hartwig published the first example of a diastereoselective iridiumcatalyzed allylic alkylation of cyclic, prochiral nucleophiles (Scheme 1.4).8a In this report, vicinal tertiary and tetra-substituted stereodyads are created via the allylic alkylation of azlactones 18 with aryl- and alkenyl-substituted allylic carbonates 11 in the Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 7 presence of catalytic amounts of achiral silver phosphate 17, 3 Å molecular sieves, and an iridium catalyst generated in situ from [Ir(cod)Cl]2 and ligand L3. Through a series of control experiments, the authors were able to determine that both the phosphate and methyl carbonate anions, but not the silver cation, are key to the high reaction diastereoselectivity (up to >20:1 dr). The counteranions are presumed to deprotonate and control the facial attack of the nucleophile while the silver cation is believed to sequester chloride and promote the formation of the active metallacyclic iridium catalyst. Scheme 1.4 Counterion-assisted iridium-catalyzed allylic alkylation of azlactones by Hartwig t-Bu Ar O P t-Bu O O P O OAg N O Ar t-Bu (R,R,R a )-L3 t-Bu 17 Ar = 2-MeO-C6H 4 [Ir(cod)Cl] 2 (2 mol %) O N O + R1 (R,R,R a )-L3 (4 mol %) 17 (8 mol %) R1 R2 OCO 2Me Ph 18 11 R 1 = 1° or 2° alkyl, Bn R 2 = aryl, heteroaryl, alkenyl toluene, 23 °C 15 examples 68–96% yield 7:1–20:1 dr 80–99% ee R2 N O O Ph 19 This counterion strategy did not prove fruitful in the iridium-catalyzed allylic alkylation of substituted 5H-oxazol-4-ones 20 or 5H-thiazol-4-ones 24 (Scheme 1.5).8b Application of the previously developed conditions to the reaction of 5H-oxazol-4-ones 20 with cinnamyl carbonates failed to yield desired allylic alkylation products 23 (Scheme 1.5a). The yields were improved by examining a number of organic and inorganic bases in combination with silver phosphate 17. However, it was not until a substoichiometric amount of diethyl zinc, allylic acetate 21, and preformed catalyst 22 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 8 were used in place of the silver phosphate that good diastereoselectivities were achieved (up to 18:1 dr). The authors propose that the addition of diethyl zinc leads to the formation of zinc enolate aggregates ranging from dimers to tetramers, which in turn impart facial selectivity to the prochiral nucleophile. Scheme 1.5 Cation control of diastereoselectivity in iridium-catalyzed allylic alkylation of a) 5Hoxazol-4-ones 20 and b) 5H-thiazol-4-ones 24 by Hartwig a) O N O R1 22 (2 mol %) R1 + Et 2Zn (60 mol %) R2 OAc PMP 20 21 R 1 = 1° or 2° alkyl R 2 = aryl, heteroaryl CPME, 23 °C R2 15 examples 80–94% yield 6:1–18:1 dr 98–99% ee O O N PMP O 23 Ir P Me N b) O S N R3 22 (2 mol %) R3 + OBoc Ph 24 25 R 3 = 1° alkyl, Bn R 4 = aryl, heteroaryl dioxane, 23 °C 14 examples 75–96% yield 6:1–13:1 dr 98–99% ee Ar Ar 22 Mg(Ni-Pr 2)2 (60 mol %) R4 O * O R4 S N Ar = 2-MeO-C6H 4 Ph 26 Application of the optimal conditions developed for 5H-oxazol-4-ones 20 using diethyl zinc does not afford a diastereoselective reaction (1.3:1 dr) with substituted 5Hthiazol-4-ones 24 (Scheme 1.5b). Instead, the authors achieved diastereoselectivity using a magnesium enolate formed from magnesium bis(diisopropyl)amide. The aggregation states of magnesium enolates, which are generally thought to be higher order aggregates than that of the corresponding zinc enolates, are believed to be responsible for the difference in diastereoselectivity. The authors also found that tert-butyl carbonate electrophiles 25 further improve the diastereoselectivities (up to 13:1 dr) for this nucleophile class. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 9 In 2013, our group pioneered the discovery of diastereo- and enantioselective iridium-catalyzed allylic alkylation chemistry of cyclic enolates for the formation of vicinal tertiary and all-carbon quaternary stereocenters (Scheme 1.6).6b Initial investigations involving tetralone 27 revealed that a wide variety of aryl- and heteroarylsubstituted allylic carbonates 28 react to provide products 29 with high yields and stereoselectivities (Scheme 1.6a). The use of Me-THQphos (L2) as the chiral ligand and LiBr as a stoichiometric additive were found to be critical in attaining high selectivity. We postulate that LiBr results in lithium enolate aggregates, similar to those proposed by Hartwig.8b In further investigations, we found that reactions involving various monocyclic substrates 30 afford the corresponding products 31 with similarly high yields and selectivities to those of the tetralone-based nucleophiles (Scheme 1.6b). Of note, the use of electron-deficient aryl-substituted electrophiles leads to an erosion in regioselectivity (50:50 to 71:29 branched/linear) in reactions of bicyclic nucleophiles. Scheme 1.6 Allylic alkylation of a) bicyclic β-ketoesters 27 and b) monocyclic β-ketoesters 30 by Stoltz [Ir(cod)Cl] 2 (2 mol %) (R,R a )-L2 (4 mol %) TBD (10 mol %) LiBr (100 mol %) a) O O OMe + R 27 OCO 2Me 28 R = aryl, heteroaryl, alkenyl O O OR X + Ph OCO 2Me n 30 X = CH2, O, NBn R = alkyl n = 0 or 1 31 R CO2Me THF, 20 °C 9 examples 90–99% yield 50:50–95:5 branched/linear 8:1–20:1 dr 90–99% ee [Ir(cod)Cl] 2 (2 mol %) (R,R a )-L2 (4 mol %) TBD (10 mol %) LiBr (100 mol %) b) O THF, 20 °C 6 examples 85–99% yield 85:15–93:7 branched/linear 8:1–20:1 dr 97–99% ee 29 O Ph X CO2R n 32 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 10 Studies toward substrate scope expansion of this reaction led to the successful allylic alkylation of extended enolates derived from unsaturated β-ketoester 33 (Scheme 1.7).6e Though the yields and selectivities were generally found to be lower than the corresponding saturated analogs (vide supra), allylic alkylation at the α-carbon atom of the extended enolate was achieved to provide products 35 bearing an additional olefin for further functionalization of the molecule. Scheme 1.7 Allylic alkylation of extended enolates by Stoltz O [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %) TBD (10 mol %) O X OR + Ar OCO 2Me n 33 X = CH2, NBn n = 0 or 1 34 O Ar X CO2R THF, 20 °C n 8 examples 40–99% yield 11:1–20:1 branched/linear 1.2:1–5:1 dr 79–98% ee (major diastereomer) 62–91% ee (minor diasteromer) 35 In 2013, Hartwig found that non-stabilized enolates 36 undergo selective iridiumcatalyzed allylic alkylation reactions to form vicinal tertiary and all-carbon quaternary stereocenters using preformed iridium complex 22 and BaOt-Bu (Scheme 1.8).6d In all cases, products 37 are afforded with excellent enantioenrichment (>98% ee), and even simple cyclohexanone derivatives provide good selectivity for allylic alkylation of the corresponding thermodynamic enolate. This protocol is currently the only reported set of conditions for cyclic nucleophiles that is not limited to softer enolate equivalents (e.g., malonates and β-ketoesters). Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 11 Scheme 1.8 Allylic alkylation of non-stabilized enolates by Hartwig O O 22 (2 mol %) R1 + Ba(Ot-Bu) 2 (120 mol %) R2 OCO 2Me 11 36 R 2 = aryl or alkenyl R 1 = alkyl, aryl, benzyl, OMe R2 R1 THF, 5 °C 22 examples 78–95% yield 6:1–20:1 dr 95–99% ee 37 1.2.2 DUAL CATALYST-CONTROLLED PROCESSES Methodology that allows for the selective synthesis of all four branched stereoisomers from one set of starting materials is highly sought after in the field of allylic alkylation. However, controlling the facial selectivity of both the nucleophile and the electrophile is a daunting task for a single catalyst.9 Thus, the use of two catalysts has been required to achieve stereodivergence. Scheme 1.9 Dual catalyst-promoted allylic alkylation of aldehydes by Carreira O R1 H OH + 38 39 R 1 = aryl or alkyl R 2 = aryl or heteroaryl O H R2 Me R1 H DCE, 25 °C R2 Me [Ir(cod)Cl] 2 (3 mol %) L4 (10 mol %) (R a )-L5 (12 mol %) Cl3CCO2H (50 mol %) 19 examples 42–86% yield 4:1–20:1 dr >99% ee 40 H 2N N O P N O N L4 (R a )-L5 In 2013, Carreira disclosed the first dual catalytic allylic alkylation to construct vicinal tertiary and all-carbon quaternary stereocenters via the use of cinchona alkaloidderived primary amine L4 and phosphoramidite ligand L5 (Scheme 1.9).6c With the 12 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride appropriate combination of enantiomers of ligand L5 and pseudo-enantiomers of L4, functionalized aldehyde 40, or any of the three other corresponding stereoisomers, can be obtained with little erosion of selectivity due to mismatched catalysts from aldehyde 38 and branched alcohol 39. The authors propose that the lack of an apparent mismatched pair of catalysts likely arises from a high degree of planarity between the two chiral intermediates in the carbon–carbon bond-forming event. During the course of reaction optimization, the authors discovered that an acid co-catalyst is extremely important for high stereoselectivity, with trichloroacetic acid being optimal. This pioneering study set the foundation for future work using the powerful combination of enamine and iridium catalysis. Scheme 1.10 Proline-derived dual catalysis by Carreira Ar Ar N H OTMS (S)-L6 Ar = 3,5-(CF3)2-Ph O Ar H [Ir(cod)Cl] 2 (3 mol %) (S a )-L5 (12 mol %) (R)-L6 (10 mol %) (MeO)2PO 2H (75 mol %) or Cl3CCO2H (50 mol %) DCE, 25 °C R 41 23 examples 73–86% yield 5:1–20:1 dr >99% ee O OH R H 42 R =alkyl, NPhth, or OBn + [Ir(cod)Cl] 2 (3 mol %) (S a )-L5 (12 mol %) (S)-L6 (10 mol %) (MeO)2PO 2H (75 mol %) or Cl3CCO2H (50 mol %) DCE, 25 °C Ar 43 23 examples 60–76% yield 3.5:1–13:1 dr >99% ee O Ar H R 44 In a second-generation protocol, Carreira utilized proline-derived amine L6 for the formation of vicinal tertiary stereocenters (Scheme 1.10).8c While seemingly simpler from a steric perspective, this transformation in fact produces a number of additional challenges; specifically, both the starting material and allylic alkylation products are potential electrophiles for aldol processes, and the products are susceptible to 13 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride epimerization. Nevertheless, the authors found that the appropriate selection of the enantiomers of L5 and L6 allows for the full complement of stereoisomers to be accessed with good to excellent selectivity. Unlike with the cinchona alkaloid-derived catalyst L4 (Scheme 1.9), a significant mismatched pair of catalysts is observed (7:1 dr mismatched versus 20:1 dr matched). In this work, the authors found dimethyl hydrogen phosphate to be the optimal acid co-catalyst (42, R = alkyl). In a follow-up study, the authors reported that this method tolerates α-heteroatoms (42, R = NPhth or OBn) in similarly high yields and selectivities, though trichloroacetic acid is required as the co-catalyst.8d Scheme 1.11 Diastereoablative allylic alkylation of 46 by Stoltz CF3 O PAr 2 N O Ph 91% yield, 8:1 dr O Ph i-Pr Ar = 4-CF3-Ph (S)-L7 (12.5 mol %) Pd 2dba3 (5 mol %) TBAT (120 mol %) allyl methyl carbonate (120 mol %) THF, 25 °C 45 Ph PAr 2 N O Ph CO2CH2CH2TMS 46 Me Me Ar = 4-CF3-Ph i-Pr (R)-L8 (12.5 mol %) Pd 2dba3 (5 mol %) TBAT (120 mol %) allyl methyl carbonate (120 mol %) O Ph THF, 25 °C 85% yield, 18:1 dr 47 available via Scheme 1.6 87% yield 20:1 dr >99% ee Our group has developed a two-step procedure for the divergent synthesis of various stereoisomers of cyclohexanone derivatives (Scheme 1.11).6b Trimethylsilyl ethyl ester 46 is readily accessible via the aforementioned iridium-catalyzed allylic alkylation (Scheme 1.6). The use of the two pseudo-enantiomeric phosphinooxazoline (PHOX) ligands L7 and L8 allows for a fluoride-triggered diastereoablative palladium-catalyzed allylic alkylation, delivering either 45 or 47 selectively. While there is a significant difference in selectivities between the two pathways (8:1 dr mismatched versus 18:1 dr 14 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride matched), both palladium-catalyzed allylic alkylation products are obtained in good yields with no loss in enantioselectivity. Finally, in 2016, Zhang developed a bimetallic dual catalysis strategy for the stereodivergent allylic alkylation of α-hydroxyketones 49 using a chiral iridium complex derived from phosphoramidite L9 and a chiral zinc–ProPhenol (L10) species.7b This method does not require the use of an exogenous base and a range of α-hydroxyl-γ,δunsaturated ketones 48/51 containing vicinal stereocenters can be accessed in good yields and stereoselectivities utilizing this protocol. Moreover, with the appropriate combination of L9 and L10 enantiomers, any stereoisomer of product can be constructed with the dual catalytic strategy; however, a significant mismatched pair of catalysts is observed (15:1 dr matched versus 6:1 dr mismatched). Scheme 1.12 Bimetallic dual catalytic allylic alkylation by Zhang O Ph Ar H OH 48 [Ir(cod)Cl] 2 (2 mol %) [Ir(cod)Cl] 2 (2 mol %) (S,S,S a )-L9 (4 mol %) (R,R,R a )-L9 (4 mol %) Et 2Zn (5 mol %) Et 2Zn (5 mol %) O (R,R)-L10 (6 mol %) 4Å MS, THF, 25 °C OH Ar 7 examples 81–94% yield 5:1–20:1 dr >97% ee + OCO 2Me R 49 4Å MS, THF, 25 °C 21 examples 67–96% yield 3:1–18:1 dr >93% ee 50 R = alkyl, aryl, or alkenyl Ph O P N Ph O Ph (R,R,R a )-L9 O (R,R)-L10 (6 mol %) Ph HO Ph N OH (R,R)-L10 N Ph OH Ph Ar H OH 51 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1.3 15 REACTION OPTIMIZATION Based on the precedent from the aforementioned reports of diastereo-, enantio-, and regioselective iridium-catalyzed allylic alkylation, our studies commenced with an exploration of the efficacy of additives, leaving groups, bases, and ligands on the selectivity of the reaction between α-carboxymethyl tetralone (52) and crotyl electrophile 53. Using our previously reported conditions for iridium-catalyzed allylic alkylations with cinnamyl-derived electrophiles as a starting point,6a,b the reactivity of tetralone 52 was first investigated with crotyl carbonate in the presence of catalytic phosphoramidite L2·½[Ir(cod)Cl]2 and either LiBr (Table 1.1, entry 1),6a LiOt-Bu (entry 2),6b or a combination of LiBr and LiOt-Bu (entry 3). Unfortunately, while these conditions result in excellent conversion and good diastereoselectivity, low levels of regioselectivity were observed. As our earlier work on cinnamyl-derived electrophiles revealed that the regioselectivity improved as carbocation stability increased (i.e., increasingly electronrich aromatic cinnamyl derivatives),6b we reasoned that the poor regioselectivity in this case was likely due to the minimal stabilization of the carbocation afforded by the methyl substituent of 53. Specifically, we hypothesized that the attenuated carbocation stability could be effecting slow equilibration between diastereomers of the iridium π-allyl complex, translating into diminished regioselectivity. Previous reports have proposed that LiCl may facilitate the equilibration leading to increased regio- and enantioselectivity,10 but we noted little improvement in selectivity with the use of LiCl as compared to LiBr (entry 4). We subsequently turned our attention to the nature of the leaving group on the electrophile. We envisioned that switching from crotyl methyl carbonate to crotyl Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 16 chloride would render the anions in solution congruent and perhaps make the effect of the chloride anions more pronounced. To our delight, regioselectivity is dramatically improved with the use of crotyl chloride, albeit with diminished diastereoselectivity (entry 5). Table 1.1 Optimization of reaction parametersa LG 53 O O [Ir(cod)Cl] 2 (2 mol %) O O L (4 mol %), TBD (10 mol %) + OMe THF (0.1M), 25 °C, 18 h CO 2Me 52 CO 2Me 55 54 Base (200 mol %) Additive (mol %) LG 52: 53 Yield 54+55 (%)b 54: 55 c dr of 54 c ee of 54 (%)d L2 – LiBr (100) OCO2Me 2:1 100 55:45 6.4:1 – L2 LiOt-Bu – OCO2Me 2:1 85 34:66 5.3:1 – L2 LiOt-Bu LiBr (100) OCO2Me 2:1 100 45:55 6.8:1 – – Entry L 1 2 3 4 L2 LiOt-Bu LiCl (100) OCO2Me 2:1 69 50:50 7.2:1 5 L2 LiOt-Bu LiCl (100) Cl 2:1 94 86:14 4.8:1 – 6 L2 proton sponge LiCl (100) Cl 2:1 100 93:7 7.9:1 66 7 L9 proton sponge LiCl (100) Cl 2:1 79 69:31 2.4:1 – 8 L5 proton sponge LiCl (100) Cl 2:1 91 52:48 1.5:1 – 9 L11 proton sponge LiCl (100) Cl 2:1 46 95:5 6.0:1 96 10 L11 proton sponge – Cl 2:1 trace – – – 11 L11 proton sponge LiCl (400) Cl 2:1 78 94:6 6.7:1 97 12 L11 proton sponge LiCl (400) Cl 1:1 55 95:5 5.3:1 98 13 L11 proton sponge LiCl (400) Cl 1:2 76 >95:5 5.3:1 85 N R O O P N O P N O Ph O Ph P N O (S,S,S a )-L9 N TBD N R R = H: (S,S a )-L2 R = Ph: (S,S a )-L11 N H N (S a )-L5 proton sponge [a] Reactions performed on 0.1 mmol scale. [b] 1H NMR yield based on internal standard of the mixture of diastereomers. [c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined by chiral SFC analysis. [e] TBD = 1,3,5triazabicyclo[4.4.0]dec-5-ene, proton sponge = 1,8-bis(dimethylamino)naphthalene. Previous work demonstrating the marked effect of bases on regio- and diastereoselectivity in iridium-catalyzed allylic alkylations prompted an extensive Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 17 exploration of bases (see Section 1.7.2.2, Table 1.4).5–8 We found that the use of proton sponge in place of LiOt-Bu afforded the desired branched product 54 with high regioselectivity (93:7, 54:55) and diastereoselectivity (7.9:1 dr), though in a modest 66% enantiomeric excess (entry 6). A brief study of ligand frameworks (entries 7–9) 11 revealed 3,3’-diphenyl-phosphoramidite L11 to be optimal. Using L11, allylic alkylation product 54 is obtained in excellent enantioselectivity (96% ee) with comparable regioand diastereoselectivities to L2, though in considerably lower yield (46%, entry 9). Efforts to increase the yield revealed super-stoichiometric levels of LiCl to be both essential and correlative to the conversion (entries 10 and 11). Ultimately, we found that the combination of catalytic phosphoramidite L11·½ [Ir(cod)Cl]2, 200 mol % proton sponge, and 400 mol % LiCl deliver product 54 in 78% yield (entry 11) with an exceptional branched to linear ratio (94:6, 54:55), diastereoselectivity (6.7:1 dr), and enantioselectivity (97% ee). Finally, it should be noted that we observed optimal conversion and selectivity using a 2:1 nucleophile to electrophile ratio; however, the nucleophile and electrophile stoichiometry can be varied (1:1 or 1:2) without dramatically affecting reaction conversion or selectivity, rendering the reaction synthetically practical (entries 12 and 13). Moreover, the excess equivalent of nucleophile can be re-isolated during purification. 1.4 SUBSTRATE SCOPE EXPLORATION With the optimized conditions identified, we explored the substrate scope of this diastereo-, enantio-, and regioselective allylic alkylation reaction (Table 1.2). Generally, the process is tolerant of a wide range of substituents and functionality on both the arene Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 18 and ester groups. We found that increasing the size of the ester moiety (–CO2Me, –CO2Et, –CO2i-Pr) results in formation of the corresponding products 54, 58a, and 58b in increasingly improved regio- and diastereoselectivity but moderately diminished yields. As a balance between yield and selectivity, we moved forward in our investigation using α-carboxyethyl tetralone derivatives. Moreover, we were pleased to find that a (2trimethylsilyl)ethyl substrate undergoes allylic alkylation to provide 58c with good selectivity, albeit in modest yield. Alkylation product 58c may undergo subsequent fluoride-triggered allylic alkylation mediated by palladium to provide either diastereomer of the bis-alkylation product with catalyst control.12 We sought to further examine the scope of the reaction by exploring the diversity of substitution permitted on the tetralone aromatic ring. Gratifyingly, a wide variety of both electron-donating and withdrawing groups are tolerated at varying positions, though an electronic effect was noted on enantioselectivity. We observed that substrates bearing electron-donating groups (MeO–, Me2N–) at the 6-position give products 58d and 58e with slightly diminished enantioselectivity (84–86% ee). Conversely, substrates with electron-withdrawing groups (7-MeO–, 7-NO2–, 6-Br–) afford the corresponding products 58f, 58g, and 58h in excellent enantioselectivity (94–98% ee). Additionally, 5,7dimethyl-substituted tetralone 58i is furnished in comparable selectivity to unsubstituted α-carboxyethyl tetralone 58a. In all examples, good regio- and diastereoselectivity is observed. Furthermore, during the course of our investigations we found that the βketoester moiety is crucial to the reaction. Substrates with this functionality replaced with either a nitrile or ketone provide the corresponding products 58j and 58k in decreased selectivities. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 19 Table 1.2 Substrate scope explorationa [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L11 (4 mol %) O + R O TBD (10 mol %), LiCl (400 mol %) proton sponge (200 mol %) EWG R Cl EWG THF (0.1 M), 25 °C, 18 h 57 52, 56a–k O 54, 58a–k O O O CO2Me CO2Et 74% (74%) yield b 93:7 b:l c 6:1 dr c 96% ee d 58a 58b 58c 71% (56%) yield 93:7 b:l 8.9:1 dr 96% ee 58% (55%) yield 95:5 b:l 17.5:1 dr 96% ee 37% (27%) yield 95:5 b:l 12.1:1 dr 89% ee 54 CO2i-Pr O O O O MeO O2N CO2Et CO2Et CO2Et Me 2N MeO 58e e 58f 46% (46%) yield 93:7 b:l 5.4:1 dr 86% ee 68% (68%) yield 90:10 b:l 7.6:1 dr 94% ee O O O CO2Et CO2Et 58g 58d 65% (55%) yield 92:8 b:l 5.8:1 dr 84% ee CO2Et CO2(CH2)2TMS 94% (82%) yield 90:10 b:l 15.5:1 dr 93% ee O CN C(O)Me Br 58h 58i 78% (63%) yield 92:8 b:l 10.4:1 dr 98% ee 66% (52%) yield 94:6 b:l 10.9:1 dr 96% ee 58j >99% (95%) yield 90:10 b:l 5.1:1 dr 52% ee 58k 32% (23%) yield 85:15 b:l 1.7:1 dr 65% ee [a] Reactions performed on 0.2 mmol scale with 2:1 nucleophile/electrophile. [b] 1H NMR yield based on internal standard of the mixture of diastereomers; combined isolated yield of branched and linear products given in parentheses. [c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined by chiral SFC or HPLC analysis. [e] Absolute stereochemistry determined via single-crystal X-ray analysis. A broader investigation of the substrate scope reveals additional limitations of the catalytic system (Table 1.3). Foremost, no allylic alkylation is observed with alkylsubstituted allylic chloride derivatives other than crotyl chloride (57). With respect to limitations on the nucleophile substrate scope, altering the saturated ring size (e.g., a benzosuberone-derived nucleophile) or employing a 2-tetralone-derived nucleophile Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 20 leads to products 60a and 60b in significantly diminished diastereo- and regioselectivities. Additionally, bicyclic nucleophiles containing fused heterocycles give products 60c and 60d in decreased yields. Use of a chromanone-based nucleophile affords allylic alkylation product 60e with no diastereocontrol. Furthermore, we observed that monocyclic nucleophiles, including lactones, lactams, and piperidones, afford the corresponding products 60f, 60g, 60h, 60i, and 60j in only modest yields. Morever, with respect to linear nucleophiles, we noted minimal or no conversion to product when a quaternary stereocenter is formed in the allylic alkylation reaction (e.g., 60k, 60l, and 60m), and in the case of propargyl 60m, we hypothesize that the alkyne functionality leads to catalyst poisoning. However, we did observe excellent reactivity for αhalogenated linear nucleophiles, which reacted to give products 60n and 60o in high yield and regioselectivity, though inconsistent diastereo- and enantioselectivities. Finally, we were interested to find that in contrast to the case with a tetralone-derived nucleophile, exchanging the β-ketoester moiety for a nitrile on a linear nucleophile gave product 60p in excellent yields and selectivities. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 21 Table 1.3 Substrate scope limitationsa [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L11 (4 mol %) O O TBD (10 mol %), LiCl (400 mol %) proton sponge (200 mol %) EWG + Cl EWG THF (0.1 M), 25 °C, 18 h 57 59a–p 60a–p O O CO2Me MeO 2C O N O CO2Me 60a b CO2Me O 60b b 60c b 60d 79% yield 78:22 b:l d 1.2:1 dr d 90% yield 67:33 b:l 2:1 dr trace yield 50% yield >95:5 b:l 1.4:1 dr O O O O c O CO2Me CO2Me O 60e t-BuO b trace yield 86:14 b:l 1.1:1 dr 60f b 60g 56% yield 81:19 b:l 3.3:1 dr b 7% yield – b:l 3.9:1 dr O CO2Et 60m b 19% yield 90:10 b:l 2:1 dr CO2Me N Bn 60h 60j b O CO2Et MeO 60k CO2Et 51% yield 90:10 b:l 5.2:1 dr O BocN CO2Me b 47% yield 86:14 b:l 5.1:1 dr O O 60i CO2Me e NC CO2Et 60l 49% yield 83:17 b:l 3.6:1 dr no reaction 53% (46%) yield 91:9 b:l 4.5:1 dr 4% ee f O O O Cl CO2Et F CO2Et CN 60n 60o 60p 96% (93%) yield >95:5 b:l 29:1 dr 85% ee 95% (47%) yield >95:5 b:l 3.5:1 dr 38% ee 91% yield 90:10 b:l >20:1 dr b [a] Reactions performed on 0.2 mmol scale with 2:1 nucleophile/electrophile. [b] Reaction performed with (S,Sa)-L2. [c] 1H NMR yield based on internal standard of the mixture of diastereomers; combined isolated yield of branched and linear products given in parentheses. [d] Determined by 1H NMR analysis of the crude reaction mixture. [e] Reaction performed with 1:1.1 nucleophile/electrophile, 400 mol % proton sponge, and 0.5 M THF. [f] Determined by chiral SFC or HPLC analysis. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1.5 22 PRODUCT TRANSFORMATIONS To demonstrate the synthetic utility of this method, we carried out a number of transformations on allylic alkylation products 54 and 58a (Figure 1.3). We found that the addition of allylmagnesium chloride proceeds smoothly to furnish alcohol 61 in 71% yield as a single diastereomer. In a two-step protocol, addition of allyl Grignard with subsequent ring-closing metathesis allows rapid access to tricycle 62 bearing three contiguous stereocenters in 58% yield over two steps. The resultant cyclohexene moiety undergoes diastereoselective dihydroxylation to provide triol 63 bearing five contiguous stereocenters in 59% yield. Both the ester and the ketone functionalities of 58a can be reduced to provide 1,3-diol 64 in 43% yield. Dihydroxylation of the pendant olefin of 58a proceeds with concomitant lactonization to provide highly functionalized γ-butyrolactone 65 in 65% yield. Functionalized γ-butyrolactone moieties are highly prevalent and estimated to be present in about 10% of all natural products. 13 Additionally, Corey– Chaykovsky epoxidation proceeds smoothly, furnishing 66 in 82% yield. Notably, all six of these derivatizations proceed with excellent diastereoselectivity to facilitate the synthesis of at least three contiguous stereocenters, demonstrating the ease with which complexity can be added to these high-value products. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 23 Figure 1.3 Product transformations of allylic alkylation products 54 and 58aa HO HO CO2Et CO2Et 61 62 a a,b O OH O OH f a–c CO2R HO CO2Et CO2Et 54 or 58a 66 e O O 63 d (X-ray) OH O OH OH 65 64 (X-ray) [a] allylmagnesium chloride, THF, –78 °C, 71% yield. [b] HG-II, CH2Cl2, 81% yield. [c] K2OsO4, NMO, THF/H2O, 59% yield. [d] DIBAL, THF, –78 °C, 43% yield. [e] K2OsO4, NMO, THF/H2O, 65% yield. f) Me3S(O)I, NaH, DMSO, 82% yield. 1.6 CONCLUSIONS In summary, we have developed the first enantioselective transition-metal- catalyzed allylic alkylation reaction forming vicinal tertiary and all-carbon quaternary stereocenters between prochiral enolates and an alkyl-substituted electrophile. Critical to the success of this new reaction is the identity and ubiquity of the chloride counterion in addition to the use of proton sponge, the combination of which affords excellent regioand enantioselectivities along with good yields and diastereoselectivities. Additionally, a number of transformations were carried out on the alkylation products to demonstrate the value of this method in rapidly accessing highly functionalized, stereochemically rich polycyclic scaffolds. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1.7 EXPERIMENTAL SECTION 1.7.1 MATERIALS AND METHODS 24 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. Commercially obtained reagents were used as received. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4, or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Preparatory HPLC was performed with an Agilent 1200 Series HPLC equipped with two Agilent Zorbax RX-sil silica columns (9.4 x 250 mm) in series. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak AD-H column (4.6 mm x 25 cm) in series with a Chiralpak AD column (4.6 mm x 25 cm) or a Chiralpak IC column (4.6 mm x 25 cm), all obtained from Daicel Chemical Industries, Ltd. with visualization at 254 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak IC column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 254 nm. 1H NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 25 and are reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of benzene (δ 7.36 ppm), water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESIAPCI+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as: [α]DT (concentration in g/100 mL, solvent). 1.7.1.1 Preparation of Known Compounds Previously reported methods were used to prepare ligands (S,Sa)-L2,11a,14 (S,Sa)L11,11a,14 and (Sa)-L915 as well as starting materials 52,16 56a,16 56f,17 56d,18 56i,19 and 56j.20 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 26 1.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 1.7.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Tetralone Substrates O O O Isopropyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56b). A solution of methyl ester 5216 (0.75 g, 3.7 mmol, 1 equiv), Bu2SnO (0.091 g, 0.37 mmol, 0.1 equiv), and IPA (15 mL) was heated under reflux for 72 h then concentrated onto silica and purified by silica gel flash column chromatography (3% Et2O/hexanes) to give isopropyl ester 56b (1:1 mixture of enol/keto isomers) as a colorless oil (0.62 g, 72% yield): 1H NMR (400 MHz, CDCl3) δ 12.56 (s, 0.5H), 8.05 (ddd, J = 7.8, 1.5, 0.6 Hz, 0.5H), 7.81 – 7.77 (m, 0.5H), 7.49 (td, J = 7.8, 1.5 Hz, 0.5H), 7.35 – 7.23 (m, 2H), 7.20 – 7.14 (m, 0.5H), 5.14 (dp, J = 17.1, 6.2 Hz, 1H), 3.56 (dd, J = 10.5, 4.7 Hz, 0.5H), 3.13 – 2.93 (m, 1H), 2.81 (dd, J = 8.6, 6.9 Hz, 1H), 2.60 – 2.52 (m, 1H), 2.53 – 2.43 (m, 0.5H), 2.35 (ddt, J = 13.5, 5.7, 4.7 Hz, 0.5H), 1.32 (d, J = 6.3 Hz, 3H), 1.28 (dd, J = 6.3, 2.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.6, 172.5, 170.0, 165.0, 143.8, 139.5, 133.9, 132.0, 130.5, 130.3, 128.9, 127.8, 127.5, 127.0, 126.7, 124.4, 97.5, 69.0, 68.2, 54.9, 27.9, 27.8, 26.5, 22.2 (2C), 21.9, 21.9, 20.7; IR (Neat Film, NaCl) 3070, 3027, 2980, 2937, 2847, 1736, 1687, 1644, 1618, 1571, 1454, 1384, 1322, 121, 1214, 1106, 1084, 949, 831, 770, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H17O3 [M+H]+: 233.1172, found 233.1174. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride O 27 O O TMS 2-(Trimethylsilyl)ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56c). A solution of LiHMDS (1.83 g, 10.9 mmol, 2 equiv) in THF (20 mL) was added dropwise to a solution of 1-tetralone (0.804 g, 5.50 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. After 1.5 h at –78 °C, a solution of 2-(trimethylsilyl)ethyl 1H-imidazole-1carboxylate (1.39 g, 6.55 mmol, 1.2 equiv) in THF (5 mL) was then added. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 1à5% Et2O/hexanes, 30 min) to provide ester 56c (3:1 mixture of enol/keto isomers) as a colorless oil (0.40 g, 25%): 1H NMR (400 MHz, CDCl3) δ 12.57 (s, 0.75H), 8.08 (dd, J = 7.8, 1.4 Hz, 0.25H), 7.83 (dd, J = 7.8, 1.4 Hz, 0.75H), 7.52 (td, J = 7.8, 1.4 Hz, 0.25H), 7.39 – 7.24 (m, 2H), 7.23 – 7.16 (m, 0.75H), 4.41 – 4.14 (m, 2H), 3.61 (dd, J = 10.3, 4.7 Hz, 0.25H), 3.14 – 2.97 (m, 0.5H), 2.83 (dd, J = 8.9, 6.6 Hz, 1.5H), 2.64 – 2.57 (m, 1.5H), 2.56 – 2.47 (m, 0.25H), 2.38 (m, 0.25H), 1.24 – 0.99 (m, 2H), 0.10 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 193.4, 173.1, 170.5, 165.1, 155.5, 143.8, 139.5, 134.0, 131.9, 131.0, 130.2, 128.9, 127.9, 127.5, 127.0, 126.7, 124.4, 97.2, 66.2, 63.8, 62.9, 54.8, 27.9, 27.8, 26.5, 20.7, 17.7, 17.5, 17.5, –1.3, –1.39, –1.41; IR (Neat Film, NaCl) 3071, 3028, 2954, 2898, 2846, 1739, 1689, 1644, 1620, 1571, 1454, 1394, 1355, 1325, 1270, 1212, Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 28 1175, 1133, 1084, 859, 837, 769 cm-1; HRMS (FAB+) m/z calc’d for C16H23O3Si [M+H]+: 291.1417, found 291.1421. O O OEt Me 2N Ethyl 6-(dimethylamino)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56e). To a suspension of NaH (0.98 g, 29 mmol, 3.7 equiv, 60 wt %) in THF (10 mL) was added diethyl carbonate (1.9 mL, 16 mmol, 2 equiv). The reaction mixture was brought to reflux at which point a solution of 6-(dimethylamino)-3,4-dihydronaphthalene-1(2H)-one (1.5 g, 7.9 mmol, 1 equiv) in THF (10 mL) was added dropwise via addition funnel over 15 min. The reaction mixture was heated to reflux for an additional 18 h then allowed to cool to ambient temperature, whereupon it was quenched with conc. AcOH (10 mL) and diluted with Et2O (30 mL). The organic layer was washed with brine (5 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 10à20% EtOAc/hexanes, 30 min) to provide dimethylamine 56e (keto isomer) as a tan solid (1.36 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.0 Hz, 1H), 6.60 (dd, J = 9.0, 2.6 Hz, 1H), 6.36 (d, J = 2.6 Hz, 1H), 4.32 – 4.12 (m, 2H), 3.52 (dd, J = 10.2, 4.7 Hz, 1H), 3.06 (s, 6H), 2.99 – 2.83 (m, 2H), 2.44 (m, 1H), 2.29 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 191.4, 171.2, 153.8, 145.9, 130.1, 128.5, 120.8, 110.6, 109.3, 61.2, 54.5, 40.2, 28.6, 26.8, 14.4; IR (Neat Film, NaCl) 2935, 1735, 1660, 1593, 1521, 1449, 1372, 1308, 1197, 1121, 1084, 923 cm-1; HRMS (FAB+) m/z calc’d for C15H20NO3 [M+H]+: 262.1443, found 262.1473. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride O O2N 29 O OEt Ethyl 7-nitro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56g). A solution of LiHMDS (1.8 g, 11 mmol, 2.1 equiv) in THF (20 mL) was added dropwise to a solution of 7-nitro-3,4-dihydronaphthalene-1(2H)-one (1.0 g, 5.2 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. The reaction was stirred for 1.5 h at –78 °C, whereupon ethyl cyanoformate (0.61 g, 6.2 mmol, 1.2 equiv) was added. The resulting reaction mixture was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (8% EtOAc/hexanes) to provide nitroarene 56g (enol isomer) as a colorless solid (114 mg, 8%): 1H NMR (400 MHz, CDCl3) δ 12.45 (s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (dt, J = 8.3, 1.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 2.66 (dd, J = 8.8, 6.9 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.4, 162.5, 147.3, 146.3, 131.6, 128.5, 125.0, 119.6, 98.9, 61.2, 28.0, 20.2, 14.4; IR (Neat Film, NaCl) 2996, 2962, 2907, 2858, 1755, 1648, 1514, 1401, 1344, 1270, 1252, 1216, 1068, 1027, 907, 806, 745 cm-1; HRMS (FAB+) m/z calc’d for C13H14NO5 [M+H]+: 264.0872, found 264.0871. Please note that a minor amount of keto isomer is present in the spectra, which does not impact the characterization. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride O 30 O OEt Br Ethyl 6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56h). A solution of LiHMDS (1.8 g, 11 mmol, 2.1 equiv) in THF (20 mL) was added dropwise to a solution of 6-bromo-3,4-dihydronaphthalene-1(2H)-one16 (1.2 g, 5.2 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. The reaction was stirred for 1.5 h at –78 °C, whereupon ethyl cyanoformate (0.61 g, 6.2 mmol, 1.2 equiv) was added. The resulting reaction mixture was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 5à20% EtOAc/hexanes, 30 min) to provide bromide 56h (4:1 mixture of enol/keto isomers) as a tan solid (0.63 g, 41%): 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 0.8H), 7.90 (d, J = 8.3 Hz, 0.2H), 7.64 (d, J = 8.3 Hz, 0.8H), 7.46 – 7.38 (m, 1.2H), 7.33 (dd, J = 2.0, 1.0 Hz, 0.8H), 4.27 (p, J = 7.0 Hz, 2H), 3.58 (dd, J = 10.0, 4.7 Hz, 0.2H), 3.09 – 2.90 (m, 0.4H), 2.78 (dd, J = 8.9, 6.7 Hz, 1.6H), 2.62 – 2.52 (m, 1.6H), 2.53 – 2.27 (m, 0.4H), 1.34 (t, J = 7.1 Hz, 2.4H), 1.29 (t, J = 7.1 Hz, 0.6H); 13C NMR (101 MHz, CDCl3) δ 192.5, 172.7, 170.0, 164.2, 145.4, 141.4, 131.8, 130.7, 130.6, 130.0 129.9, 129.6, 129.3, 129.1, 126.0, 124.9, 97.4, 61.6, 60.8, 54.4, 27.7, 27.5, 26.3, 20.5, 14.4, 14.3; IR (Neat Film, NaCl) 2979, 2958, 2902, 2848, 1740, 1689, 1645, 1616, 1588, 1558, 1479, 1406, 1377, 1267, 1214, 1195, 1096, 1025, 845, 829, 758 cm-1; HRMS (FAB+) m/z calc’d for C13H14BrO3 [M+H]+: 297.0126, found 297.0134. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride O 31 O 2-Acetyl-3,4-dihydronaphthalen-1(2H)-one (56k). To a suspension of NaH (0.49 g, 21 mmol, 2 equiv, 60 wt %) in EtOAc (2 mL) cooled to 0 °C, a solution of 1-tetralone (1.5 g, 10 mmol, 1 equiv) in toluene (0.5 mL) was added dropwise. After H2 evolution ceased, the resulting solution was heated to 40 °C for 3 h. The reaction mixture was then allowed to cool to ambient temperature, whereupon it was quenched with MeOH (5 mL), poured onto H2O (20 mL), neutralized with conc. HCl, and extracted with CH2Cl2 (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give ketone 56k (enol isomer) as a pale yellow solid (0.51 g, 26%): 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.7, 1.4 Hz, 1H), 7.40 (td, J = 7.7, 1.4 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.20 (dq, J = 7.7, 0.7 Hz, 1H), 2.87 (dd, J = 8.5, 6.3 Hz, 2H), 2.68 – 2.59 (m, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.0, 177.0, 140.9, 132.0, 131.2, 127.7, 127.0, 126.0, 106.1, 28.4, 24.1, 22.9; IR (Neat Film, NaCl) 3061, 2940, 2893, 2838, 1598, 1567, 1414, 1354, 1294, 1213, 1156, 1079, 1033, 974, 902, 788, 737, 548 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H13O2 [M+H]+: 189.0910, found 189.0908. Please note that the exchangeable enol proton was not observed in the 1H NMR spectrum. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1.7.2.2 32 Additional Optimization of Reaction Parameters Table 1.4 Additional optimization of reaction parametersa O O N OMe N N H O O TBD 52 CO 2Me [Ir(cod)Cl] 2 (2 mol %) L (4 mol %), TBD (10 mol %) + Cl CO 2Me + 54 THF (0.1 M), 25 °C, 18 h 55 57 Entry L Base Additive Solvent 1 L2 quinoline LiCl THF 94:6 4.6:1 2 L2 pyridine LiCl THF 89:11 7.2:1 54: 55b dr of 54b 3 L2 triethylamine LiCl THF 86:14 4.5:1 4 L2 isoquinoline LiCl THF 89:11 11.3:1 5 L2 N-methylimidazole LiCl THF 80:20 3.0:1 6 L2 N-methylmorpholine LiCl THF 89:11 6.0:1 7 L2 N-methylpiperidine LiCl THF 89:11 5.1:1 8 L2 2,4,6-tri-tert-butylpyridine LiCl THF 89:11 4.0:1 9 L2 sym-collidine LiCl THF 93:7 5.0:1 10 L2 proton sponge LiCl THF 92:8 8.3:1 11 L11 proton sponge LiCl THF 94:6 6.7:1 12 L11 proton sponge CsCl THF nr nr 13 L11 proton sponge TBAC THF nr nr 14 L11 proton sponge CuCl THF 88:12 6.8:1 15 L11 proton sponge LiCl TBME 80:20 7.7:1 16 c L11 proton sponge LiCl toluene 95:5 6.7:1 4.5:1 17 L11 proton sponge LiCl dioxane 83:17 18 L11 proton sponge LiCl cyclohexane nr nr 19 L11 proton sponge LiCl CH2Cl2 78:22 1.8:1 Ph O P N O O P N O (S,S,S a )-L2 (S,S,S a )-L11 Ph [a] Reactions performed with 0.1 mmol of 53, 0.2 mmol of 52, 0.2 mmol of base, and 0.4 mmol of additive. [b] Determined by 1H NMR analysis of the crude reaction mixture. [c] Trace conversion. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 1.7.2.3 33 General Procedure for Optimization Reactions (Table 1.1 & 1.4) In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (1.3 mg, 0.0020 mmol, 2 mol %), ligand L (0.0040 mmol, 4 mol %), TBD (1.4 mg, 0.010 mmol, 10 mol%), and THF (0.5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with base, additive, tetralone 52 (0.20 mmol), and THF (0.25 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by 0.25 mL of a solution of crotyl electrophile 53 (0.2 M in THF). The vial was sealed and stirred at 25 °C. After 18 h, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc. The crude mixture was concentrated and dimethyl maleate (0.050 mmol in 0.5 mL CDCl3) was added. The NMR yield (measured in reference to dimethyl maleate δ 6.28 ppm (s, 2H)), regioselectivity (branched product to linear product: 54:55), and diastereoselectivity were determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (10% Et2O/hexanes) to afford the combined branched (54/epi-54) and linear (55) products as an inseparable mixture. The major diastereomer (54) was isolated by preparatory HPLC (2% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm) and analyzed by chiral SFC (3% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 254 nm). 1.7.2.4 General Procedure for the Iridium-Catalyzed Allylic Alkylation Please note that the absolute configuration was determined only for compound 58f via x-ray crystallographic analysis. The absolute configuration for all other products Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 34 has been inferred by analogy. For respective HPLC and SFC conditions, please refer to Table 1.5. Methyl (S)-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (54). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (S,Sa)-L11 (4.9 mg, 0.0080 mmol, 4 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with proton sponge (86 mg, 0.40 mmol, 200 mol %), tetralone 52 (82 mg, 0.40 mmol, 200 mol %), LiCl (34 mg, 0.80 mmol, 400 mol %), and THF (0.5 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by a solution of crotyl chloride 57 (18 mg, 0.20 mmol, 100 mol %) in THF (0.5 mL). The vial was sealed and stirred at 25 °C. After 18 h, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc. The crude mixture was concentrated and dimethyl maleate (0.10 mmol in 0.5 mL CDCl3) was added. The NMR yield (74%, measured in reference to dimethyl maleate δ 6.28 ppm (s, 2H)), regioselectivity (branched product to linear product, b:l = 93:7), and diastereoselectivity (dr = 6:1) were determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (10% Et2O/hexanes) to give the isolated yield of the branched and linear products (38.0 mg, 74% combined yield). The diastereomers were separated by preparatory HPLC (2% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm). Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 35 O CO2Me Major diastereomer 54 was isolated as a colorless oil: 96% ee; [α]D25 –48.5 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (ddd, J = 7.9, 1.5, 0.5 Hz, 1H), 7.45 (td, J = 7.4, 1.5 Hz, 1H), 7.30 (ddt, J = 7.3, 6.9, 1.1 Hz, 1H), 7.20 (dtt, J = 7.6, 1.3, 0.7 Hz, 1H), 5.82 (ddd, J = 17.0, 10.2, 8.9 Hz, 1H), 5.12 – 4.97 (m, 2H), 3.64 (s, 3H), 3.28 – 3.09 (m, 2H), 2.90 (ddd, J = 17.4, 4.9, 3.0 Hz, 1H), 2.43 (ddd, J = 13.7, 4.7, 3.0 Hz, 1H), 2.22 (ddd, J = 13.7, 12.3, 4.9 Hz, 1H), 1.15 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 194.3, 171.2, 143.4, 139.1, 133.6, 132.7, 128.9, 128.2, 126.8, 116.6, 61.2, 52.5, 43.5, 27.8, 26.3, 16.6; IR (Neat Film, NaCl) 3073, 2951, 2850, 1732, 1688, 1600, 1454, 1434, 1290, 1241, 1220, 993, 917, 746 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H19O3 [M+H]+: 259.1329, found 259.1329; SFC conditions: 3% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 5.170, minor = 5.968. O CO 2Me Minor diastereomer epi-54 (which was inseparable from major diastereomer 54) was isolated as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 7.9, 1.4 Hz, 1H), 7.46 (td, J = 7.5, 1.5 Hz, 1H), 7.34 – 7.27 (m, 1H), 7.23 – 7.16 (m, 1H), 5.98 (ddd, J = 17.2, 10.3, 7.8 Hz, 1H), 5.12 – 5.00 (m, 2H), 3.65 (s, 3H), 3.27 – 3.05 (m, 2H), 2.97 – 2.85 (m, 1H), 2.45 (dddd, J = 19.3, 13.7, 4.7, 3.2 Hz, 1H), 2.17 – 2.10 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 194.5, 171.3, 143.3, 139.9, 133.6, 132.7, 128.8, 128.2, 126.8, 116.2, 61.2, 52.5, 42.5, 28.5, 26.3, 15.0; IR (Neat Film, NaCl) 3072, Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 36 2951, 1734, 1686, 1601, 1453, 1438, 1289, 1240, 1219, 1000, 917, 808, 746 cm-1. HRMS (MM: ESI-APCI+) m/z calc’d for C16H19O3 [M+H]+: 259.1329, found 259.1332. Please note that the provided spectra for epi-54 reflect the inseparable mixture of epi-54 and 54, while the tabulated NMR data is for only epi-54. O CO2Me Linear isomer 55 was isolated as a colorless oil: 23% ee; [α]D25 –5.2 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.06 (m, 1H), 7.60 – 7.47 (m, 1H), 7.36 (tdd, J = 7.8, 1.3, 0.6 Hz, 1H), 7.29 – 7.23 (m, 1H), 5.68 – 5.56 (m, 1H), 5.56 – 5.40 (m, 1H), 3.73 (s, 3H), 3.19 – 3.08 (m, 1H), 2.97 (dt, J = 17.3, 4.9 Hz, 1H), 2.71 (ddt, J = 7.2, 2.5, 1.2 Hz, 2H), 2.57 (dt, J = 13.8, 4.9 Hz, 1H), 2.26 – 2.13 (m, 1H), 1.71 (dq, J = 6.4, 1.2 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 195.3, 172.3, 143.5, 133.6, 132.1, 129.8, 128.9, 128.2, 126.9, 125.7, 57.8, 52.6, 37.7, 30.5, 26.0, 18.2; IR (Neat Film, NaCl) 2918, 2850, 1732, 1689, 1601, 1434, 1263, 1236, 1086, 973, 944, 802, 743 cm-1. HRMS (MM: ESI-APCI+) m/z calc’d for C16H19O3 [M+H]+: 259.1329, found 259.1324; HPLC conditions: 1% IPA, 1 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 19.785, minor = 24.041. 1.7.2.5 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products O CO2Et Ethyl (S)-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (58a). Product 58a was prepared according to the general procedure and isolated by Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 37 preparatory TLC (10% Et2O/hexanes) to give the isolated yield of the branched and linear products (30.3 mg, 56% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (2% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 96% ee; [α]D25 –44.3 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 7.5, 1.5 Hz, 1H), 7.44 (td, J = 7.5, 1.5 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.19 (d, J = 7.5 Hz, 1H), 5.84 (ddd, J = 17.0, 10.2, 8.8 Hz, 1H), 5.20 – 4.96 (m, 2H), 4.24 – 3.95 (m, 2H), 3.26 – 3.08 (m, 2H), 2.89 (ddd, J = 17.4, 4.7, 3.0 Hz, 1H), 2.41 (ddd, J = 13.7, 4.7, 3.0 Hz, 1H), 2.21 (ddd, J = 13.7, 12.3, 4.7 Hz, 1H), 1.19 – 1.09 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 194.4, 170.7, 143.2, 139.1, 133.5, 132.9, 128.8, 128.1, 126.7, 116.5, 61.4, 60.8, 43.4, 28.1, 26.3, 16.6, 14.2; IR (Neat Film, NaCl) 3073, 2978, 2938, 1729, 1693, 1639, 1600, 1454, 1290, 1237, 1220, 1019, 909, 746, 652 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H21O3 [M+H]+: 273.1485, found 273.1493; SFC conditions: 3% MeOH, 3.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 4.539, minor = 5.113. O CO2i-Pr Isopropyl (S)-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2carboxylate (58b). Product 58b was prepared according to the general procedure and isolated by preparatory TLC (8% EtOAc/hexanes) to give the isolated yield of the branched and linear products (31.3 mg, 55% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (2% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 96% ee; Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 38 [α]D25 –61.5 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 7.9, 1.4 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.37 – 7.22 (m, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.86 (ddd, J = 17.1, 10.2, 8.8 Hz, 1H), 5.12 – 4.92 (m, 3H), 3.23 – 3.11 (m, 1H), 3.11 – 2.98 (m, 1H), 2.89 (ddd, J = 17.5, 5.1, 2.9 Hz, 1H), 2.39 (ddd, J = 13.7, 4.8, 2.9 Hz, 1H), 2.20 (ddd, J = 13.7, 12.2, 5.0 Hz, 1H), 1.18 (dd, J = 6.6, 5.3 Hz, 6H), 1.02 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 194.6, 170.4, 143.0, 139.2, 133.3, 133.2, 128.7, 128.0, 126.7, 116.5, 69.0, 60.6, 43.4, 28.5, 26.3, 21.8, 21.6, 16.7; IR (Neat Film, NaCl) 3073, 2979, 2936, 1724, 1694, 16001, 1456, 1374, 1288, 1244, 1220, 1179, 1144, 1105, 915, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H23O3 [M+H]+: 287.1642, found 287.1650; HPLC conditions: 1% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 10.378, minor = 11.179. O CO2CH2CH2TMS 2-(Trimethylsilyl)ethyl (S)-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4tetrahydronaphthalene-2-carboxylate (58c). Product 58c was prepared according to the general procedure and isolated by preparatory TLC (5% Et2O/hexanes) to give the isolated yield of the branched and linear products (18.3 mg, 27% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (1% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 89% ee; [α]D25 –46.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.0, 1.5 Hz, 1H), 7.44 (td, J = 8.0, 1.5 Hz, 1H), 7.29 (t, J = 8.0, 1H), 7.19 (d, J = 8.0, 1H), 5.84 (ddd, J = 17.0, 10.2, 8.8 Hz, 1H), 5.15 – 5.00 (m, 2H), 4.23 – 4.03 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 39 (m, 2H), 3.26 – 3.02 (m, 2H), 2.88 (ddd, J = 17.4, 4.9, 2.9 Hz, 1H), 2.40 (ddd, J = 13.7, 4.7, 2.9 Hz, 1H), 2.21 (ddd, J = 13.6, 12.3, 4.9 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H), 0.89 (dd, J = 9.3, 8.1 Hz, 2H), –0.03 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 194.4, 171.0, 143.3, 139.2, 133.5, 133.0, 128.8, 128.2, 126.7, 116.5, 63.9, 60.8, 43.5, 28.2, 26.3, 17.4, 16.6, –1.5 (3C); IR (Neat Film, NaCl) 3074, 2955, 2899, 1727, 1693, 1601, 1454, 1289, 1251, 1220, 1141, 1041, 918, 860, 837, 746, 695 cm-1; HRMS (FAB+) m/z calc’d for C20H28O3SiNa [M+Na]+: 367.1706, found 367.1720; HPLC conditions: 1% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 9.018, minor = 9.737. O CO2Et MeO Ethyl (S)-2-((S)-but-3-en-2-yl)-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate (58d). Product 58d was prepared according to the general procedure and isolated by preparatory TLC (8% Et2O/hexanes) to give the isolated yield of the branched and linear products (33.0 mg, 55% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (7% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 84% ee; [α]D25 –12.3 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 1H), 6.81 (ddd, J = 8.8, 2.6, 0.7 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 5.82 (ddd, J = 17.1, 10.2, 8.8 Hz, 1H), 5.12 – 4.97 (m, 2H), 4.20 – 3.99 (m, 2H), 3.84 (s, 3H), 3.26 – 3.08 (m, 2H), 2.84 (ddd, J = 17.4, 4.9, 3.0 Hz, 1H), 2.39 (ddd, J = 13.6, 4.7, 2.9 Hz, 1H), 2.17 (ddd, J = 13.7, 12.4, 4.9 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H), 1.12 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.0, Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 40 170.8, 163.7, 145.9, 139.2, 130.7, 126.5, 116.4, 113.5, 112.3, 61.4, 60.6, 55.6, 43.3, 27.7, 26.7, 16.5, 14.3; IR (Neat Film, NaCl) 3075, 2964, 2935, 2849, 1727, 1681, 1600, 1494, 1446, 1354, 1253, 1217, 1094, 1022, 917, 854, 824 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H23O4 [M+H]+: 303.1591, found 303.1583; HPLC conditions: 1% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 23.903, minor = 29.498. O CO2Et Me 2N Ethyl (S)-2-((S)-but-3-en-2-yl)-6-(dimethylamino)-1-oxo-1,2,3,4tetrahydronaphthalene-2-carboxylate (58e). Product 58e was prepared according to the general procedure and isolated by preparatory TLC (10% EtOAc/hexanes) to give the isolated yield of the branched and linear products (29.0 mg, 46% combined yield). The major diastereomer was isolated as a colorless solid by preparatory HPLC (10% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 86% ee; [α]D25 +8.5 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.9 Hz, 1H), 6.59 (dd, J = 9.0, 2.6 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 5.82 (ddd, J = 17.1, 10.2, 8.7 Hz, 1H), 5.15 – 4.96 (m, 2H), 4.10 (ddq, J = 41.7, 10.8, 7.1 Hz, 2H), 3.31 – 3.12 (m, 2H), 3.04 (s, 6H), 2.78 (ddd, J = 17.1, 4.8, 3.0 Hz, 1H), 2.36 (ddd, J = 13.4, 4.6, 3.0 Hz, 1H), 2.13 (ddd, J = 13.4, 12.5, 4.8 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.1, 171.2, 153.6, 145.5, 139.5, 130.5, 121.9, 116.1, 110.5, 109.2, 61.2, 60.5, 43.2, 40.2 (2C), 27.4, 26.9, 16.4, 14.3; IR (Neat Film, NaCl) 3078, 2935, 1725, 1666, 1595, 1520, 1446, 1370, 1293, 1221, Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 41 1196, 1125, 1025, 912, 813 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H26NO3 [M+H]+: 316.1907, found 316.1912; HPLC conditions: 3% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 24.809, minor = 33.026. O MeO CO2Et Ethyl (S)-2-((S)-but-3-en-2-yl)-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate (58f). Product 58f was prepared according to the general procedure and isolated by preparatory TLC (8% Et2O/hexanes) to give the isolated yield of the branched and linear products (41.0 mg, 68% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (2% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 94% ee; [α]D25 –76.8 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.8 Hz, 1H), 5.84 (ddd, J = 17.0, 10.2, 8.9 Hz, 1H), 5.12 – 4.95 (m, 2H), 4.20 – 4.02 (m, 2H), 3.83 (s, 3H), 3.17 – 3.04 (m, 2H), 2.83 (ddd, J = 17.2, 5.0, 2.9 Hz, 1H), 2.39 (ddd, J = 13.6, 4.6, 2.9 Hz, 1H), 2.19 (ddd, J = 13.7, 12.2, 5.0 Hz, 1H), 1.22 – 1.09 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 194.4, 170.7, 158.3, 139.0, 135.7, 133.6, 129.9, 122.0, 116.4, 109.6, 61.3, 60.5, 55.5, 43.4, 28.4, 25.4, 16.6, 14.1; IR (Neat Film, NaCl) 3075, 2963, 2936, 2838, 1728, 1688, 1609, 1497, 1463, 1419, 1329, 1279, 1232, 1175, 1143, 1034, 920, 881, 819 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H23O4 [M+H]+: 303.1591, found 303.1583; HPLC conditions: 1% EtOH/hexanes, 1 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 42 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 17.216, minor = 14.519. O O2N CO2Et Ethyl (S)-2-((S)-but-3-en-2-yl)-7-nitro-1-oxo-1,2,3,4-tetrahydronaphthalene-2carboxylate (58g). Product 58g was prepared according to the general procedure and isolated by preparatory TLC (20% EtOAc/hexanes) to give the isolated yield of inseparable branched and linear products (52.0 mg, 82% combined yield): 93% ee; [α]D25 –53.5 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3, major diastereomer) δ 8.86 (d, J = 2.5 Hz, 1H), 8.27 (dd, J = 8.4, 2.5 Hz, 1H), 7.39 (dt, J = 8.7, 0.9 Hz, 1H), 5.81 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H), 5.23 – 4.99 (m, 2H), 4.25 – 3.97 (m, 2H), 3.24 (dddd, J = 18.1, 12.3, 4.8, 1.1 Hz, 1H), 3.13 – 2.96 (m, 2H), 2.46 (ddd, J = 13.9, 4.8, 2.7 Hz, 1H), 2.24 (ddd, J = 13.9, 12.4, 4.9 Hz, 1H), 1.21 – 1.12 (m, 6H); 13C NMR (101 MHz, CDCl3, major diastereomer) δ 192.4, 170.2, 149.7, 147.2, 138.5, 133.8, 130.3, 127.2, 123.4, 117.2, 61.8, 60.8, 43.6, 27.9, 26.7, 16.6, 14.2; IR (Neat Film, NaCl) 3079, 2979, 2938, 1727, 1698, 1612, 1526, 1421, 1347, 1218, 1181, 1018, 931, 740 cm-1; HRMS (FAB+) m/z calc’d for C17H20NO5 [M+H]+: 318.1341, found 318.1333; HPLC conditions: 5% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 14.901, minor = 13.808. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 43 O CO2Et Br Ethyl (S)-6-bromo-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2carboxylate (58h). Product 58h was prepared according to the general procedure and isolated by silica gel flash column chromatography (5% Et2O/hexanes) to give the isolated yield of the branched and linear products (44.0 mg, 63% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (0.8% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 98% ee; [α]D25 –32.7 (c 2.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.42 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.40 – 7.35 (m, 1H), 5.81 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H), 5.11 – 4.98 (m, 2H), 4.20 – 3.99 (m, 2H), 3.25 – 3.02 (m, 2H), 2.85 (ddd, J = 17.6, 4.9, 2.8 Hz, 1H), 2.40 (ddd, J = 13.7, 4.8, 2.9 Hz, 1H), 2.19 (ddd, J = 13.8, 12.3, 4.9 Hz, 1H), 1.20 – 1.12 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 193.6, 170.5, 144.9, 138.9, 131.8, 131.7, 130.2, 129.8, 128.7, 116.8, 61.6, 60.7, 43.5, 28.0, 26.1, 16.6, 14.3; IR (Neat Film, NaCl) 3074, 2977, 2936, 1728, 1690, 1587, 1444, 1353, 1279, 1235, 1218, 1182, 1144, 1018, 910, 838, 670 cm-1; HRMS (EI+) m/z calc’d for C17H19O3Br [M]+: 350.0518, found 350.0491; SFC conditions: 3% MeOH/hexanes, 3.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 9.330, minor = 8.616. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 44 O CO2Et Ethyl (S)-2-((S)-but-3-en-2-yl)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2carboxylate (58i). Product 58i was prepared according to the general procedure and isolated by preparatory TLC (9% EtOAc/hexanes) to give the isolated yield of the branched and linear products (31.0 mg, 52% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (1.5% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 96% ee; [α]D25 –35.1 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 2.0 Hz, 1H), 7.22 – 7.08 (m, 1H), 5.85 (ddd, J = 17.0, 10.2, 8.9 Hz, 1H), 5.18 – 4.94 (m, 2H), 4.20 – 3.86 (m, 2H), 3.18 – 3.08 (m, 1H), 2.92 (ddd, J = 16.9, 11.6, 5.0 Hz, 1H), 2.81 (ddd, J = 17.7, 5.6, 3.0 Hz, 1H), 2.45 (ddd, J = 13.8, 4.9, 3.0 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H), 2.15 (ddd, J = 13.8, 11.5, 5.5 Hz, 1H), 1.17 – 1.10 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 194.9, 170.7, 139.2, 138.7, 136.4, 136.0, 135.8, 132.9, 126.0, 116.4, 61.3, 60.2, 42.9, 27.1, 23.3, 21.0, 19.3, 16.5, 14.2; IR (Neat Film, NaCl) 3075, 2976, 2935, 1730, 1688, 1611, 1477, 1445, 1375, 1286, 1236, 1222, 1163, 1139, 1020, 919, 884 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H25O3 [M+H]+: 301.1798, found 301.1801; HPLC conditions: 1% IPA/hexanes, 1 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 9.599, minor = 10.926. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 45 O CN (R)-2-((S)-but-3-en-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbonitrile (58j). Product 58j was prepared according to the general procedure and isolated by preparatory TLC (17% EtOAc/hexanes) to give the isolated yield of the branched and linear products (43.0 mg, 95% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (4% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 52% ee; [α]D25 +11.4 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.45 – 7.32 (m, 1H), 7.29 – 7.25 (m, 1H), 5.91 (ddd, J = 17.0, 10.3, 8.0 Hz, 1H), 5.17 (dt, J = 10.3, 1.1 Hz, 1H), 5.05 (dt, J = 17.1, 1.2 Hz, 1H), 3.27 – 2.89 (m, 3H), 2.43 (ddd, J = 7.1, 5.3, 3.4 Hz, 2H), 1.22 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 190.3, 142.4, 137.1, 134.6, 130.7, 129.0, 128.9, 127.6, 118.5, 118.1, 53.0, 39.8, 28.5, 25.2, 15.3; IR (Neat Film, NaCl) 2975, 2930, 1693, 1600, 1454, 1292, 1223, 1158, 1096, 992, 927, 904, 788, 741 cm-1; HRMS (FAB+) m/z calc’d for C15H16ON [M+H]+: 226.1232, found 226.1240; HPLC conditions: 2% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 24.027, minor = 26.658. O C(O)Me (R)-2-acetyl-2-((S)-but-3-en-2-yl)-3,4-dihydronaphthalen-1(2H)-one (58k). Product 10k was prepared according to the general procedure and isolated by preparatory TLC (9% EtOAc/hexanes) to give the isolated yield of the branched and linear products (11.0 Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 46 mg, 23% combined yield). The major diastereomer was isolated as a colorless oil by preparatory HPLC (4% EtOAc/hexanes, two Agilent Zorbax RX-sil silica columns in series; flow rate = 15 mL/min; λ = 254 nm): 65% ee; [α]D25 –43.3 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (dt, J = 8.0, 0.9 Hz, 1H), 7.47 (td, J = 7.5, 1.5 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.19 (dtt, J = 7.7, 1.2, 0.6 Hz, 1H), 5.64 (ddd, J = 17.0, 10.2, 8.8 Hz, 1H), 5.27 – 4.94 (m, 2H), 3.46 – 3.32 (m, 1H), 3.16 (dddt, J = 17.4, 12.6, 4.7, 1.1 Hz, 1H), 2.84 (ddd, J = 17.4, 5.0, 2.7 Hz, 1H), 2.47 (ddd, J = 13.5, 4.7, 2.7 Hz, 1H), 2.12 – 2.06 (m, 1H), 2.09 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 204.7, 196.8, 144.2, 138.3, 134.1, 132.8, 129.0, 128.0, 126.7, 116.5, 68.4, 42.6, 26.9, 25.9, 24.7, 16.3; IR (Neat Film, NaCl) 3076, 2971, 2937, 1708, 1674, 1599, 1446, 1359, 1295, 1231, 1208, 1120, 995, 912, 781, 754, 737 cm-1; HRMS (FAB+) m/z calc’d for C16H19O2 [M+H]+: 243.1385, found 243.1381; HPLC conditions: 1% EtOH/hexanes, 1 mL/min, Chiralpak AD then AD-H column, λ = 254 nm, tR (min): major = 11.271, minor = 11.944. 1.7.2.6 Experimental Procedures and Spectroscopic Data for the Transformations of Allylic Alkylation Products HO CO2Et Ethyl (1R,2S)-1-allyl-2-((S)-but-3-en-2-yl)-1-hydroxy-1,2,3,4tetrahydronaphthalene-2-carboxylate (61). Allylmagnesium chloride (0.065 mL, 0.11 mmol, 1.1 equiv, 1.7 M in THF) was added dropwise to a solution of ethyl ester 58a (27 mg, 1.0 mmol, 1 equiv) in THF (0.5 mL) at –78 °C. The mixture was stirred at –78 °C for Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 47 4 h, whereupon the reaction was quenched with a saturated NH4Cl aqueous solution (1 mL). The aqueous layer was then extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (9% Et2O/hexanes) to give alcohol 61 as a colorless oil (31 mg, 71% yield): [α]D25 +27.3 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m, 1H), 7.20 – 7.14 (m, 2H), 7.10 – 7.02 (m, 1H), 5.99 (ddd, J = 17.1, 10.2, 8.5 Hz, 1H), 5.65 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 4.98 – 4.85 (m, 2H), 4.85 – 4.76 (m, 1H), 4.68 (ddd, J = 17.1, 1.9, 1.0 Hz, 1H), 4.33 – 4.19 (m, 2H), 4.01 (s, 1H), 2.94 – 2.86 (m, 2H), 2.72 (ddt, J = 8.6, 7.0, 0.8 Hz, 1H), 2.52 – 2.30 (m, 3H), 2.21 – 2.12 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 142.0, 140.7, 134.1, 133.7, 127.9, 126.7, 126.3, 125.5, 117.5, 114.7, 76.6, 61.1, 56.4, 47.2, 41.2, 25.2, 23.3, 16.7, 14.4; IR (Neat Film, NaCl) 3492, 3075, 2978, 2930, 2853, 1732, 1694, 1640, 1455, 1376, 1267, 1213, 1026, 914, 766, 732, 665 cm-1; HRMS (FAB+) m/z calc’d for C20H27O3 [M+H]+: 315.1960, found 315.1954. HO CO2Et Ethyl (4bR,8S,8aS)-4b-hydroxy-8-methyl-5,8,9,10-tetrahydrophenanthrene8a(4bH)-carboxylate (62). A solution of bis-olefin 61 (4.0 mg, 0.013 mmol, 1 equiv), Hoveyda-Grubbs Catalyst-II (1.4 mg, 2.6 µmol, 0.2 equiv), and CH2Cl2 (0.5 mL) was stirred at ambient temperature for 18 h, whereupon the reaction mixture was concentrated under reduced pressure. The crude residue was purified by preparatory TLC (9% Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 48 EtOAc/hexanes) to give tricycle 62 as a colorless oil (3.0 mg, 81% yield): [α]D25 +7.9 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.46 (m, 1H), 7.22 – 7.16 (m, 2H), 7.13 – 7.06 (m, 1H), 5.82 (ddt, J = 10.1, 5.1, 2.6 Hz, 1H), 5.56 (ddt, J = 10.1, 2.6, 1.8 Hz, 1H), 3.96 (qd, J = 7.1, 1.0 Hz, 2H), 3.36 (ddt, J = 18.0, 3.8, 2.6 Hz, 1H), 3.09 – 2.96 (m, 1H), 2.96 – 2.78 (m, 2H), 2.70 – 2.57 (m, 1H), 2.49 – 2.38 (m, 1H), 2.28 – 2.11 (m, 1H), 1.12 (d, J = 7.6 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 140.0, 136.0, 130.6, 129.6, 127.9, 126.3, 125.1, 124.1, 70.5, 60.0, 52.2, 36.8, 36.4, 26.4, 25.5, 16.2, 14.2; IR (Neat Film, NaCl) 3488, 3019, 2972, 2934, 1727, 1715, 1451, 1368, 1293, 1251, 1177, 1027, 887, 761, 694 cm-1; HRMS (FAB+) m/z calc’d for C18H23O3 [M+H]+: 287.1647, found 287.1637. Please note that the exchangeable hydroxy proton was not observed in the 1H NMR spectrum. OH OH HO CO2Et Ethyl (4bR,6R,7S,8R,8aS)-4b,6,7-trihydroxy-8-methyl-5,6,7,8,9,10hexahydrophenanthrene-8a(4bH)-carboxylate (63). A solution of olefin 62 (18 mg, 0.058 mmol, 1 equiv), K2OsO4 (1.0 mg, 2.8 µmol, 0.05 equiv), N-methylmorpholine Noxide (11 mg, 0.093 mmol, 1.6 equiv), and THF/H2O (3:1, 0.2 mL) was stirred at ambient temperature for 18 h, whereupon the reaction was quenched with saturated Na2S2O3 aqueous solution (1 mL). The aqueous layer was then extracted with EtOAc (5 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (17% EtOAc/hexanes) to give triol 63 as a colorless oil (11 mg, 59% yield): [α]D25 +3.8 (c Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 49 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.19 (td, J = 7.4, 1.5 Hz, 1H), 7.16 – 7.05 (m, 2H), 4.26 (q, J = 3.3 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 3.74 (dd, J = 11.0, 3.5 Hz, 1H), 3.70 – 3.56 (m, 1H), 3.06 – 2.92 (m, 3H), 2.78 (dd, J = 14.6, 3.0 Hz, 1H), 2.61 – 2.44 (m, 1H), 2.24 – 2.05 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.9, 139.4, 136.9, 129.6, 128.4, 125.8, 123.8, 73.0, 72.7, 70.5, 60.4, 56.1, 37.3, 35.3, 25.9, 25.1, 13.9, 12.3; IR (Neat Film, NaCl) 3284, 2970, 2928, 1723, 1452, 1382, 1259, 1234, 1189, 1103, 1054, 1020, 867, 834, 763, 722 cm-1; HRMS (MM: ESI-APCI–) m/z calc’d for C18H24O5Cl [M+Cl]–: 355.1318, found 355.1326. Please note that two of the exchangeable hydroxy protons were not observed in the 1H NMR spectrum. OH OH (1R,2R)-2-((S)-But-3-en-2-yl)-2-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (64). DIBAL (0.071 mL, 0.40 mmol, 4 equiv) was added dropwise to a solution of ethyl ester 58a (27 mg, 1.0 mmol, 1 equiv) in THF (0.6 mL) at –78 °C. The mixture was stirred at –78 °C for 6 h, whereupon the reaction was quenched with a saturated Rochelle’s salt aqueous solution (1 mL) and stirred for 18 h at ambient temperature. The aqueous layer was then extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (20% EtOAc/hexanes) to give diol 64 as a colorless oil (10 mg, 43% yield): [α]D25 +105.7 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.44 (m, 1H), 7.24 – 7.18 (m, 2H), 7.11 (ddd, J = 5.5, 2.4, 1.2 Hz, 1H), Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 50 6.30 (ddd, J = 17.2, 10.1, 9.1 Hz, 1H), 4.99 (ddd, J = 10.1, 2.1, 0.6 Hz, 1H), 4.90 (ddd, J = 17.3, 2.1, 0.9 Hz, 1H), 4.80 (d, J = 7.3 Hz, 1H), 3.81 (dd, J = 11.3, 5.5 Hz, 1H), 3.59 (dd, J = 11.4, 3.7 Hz, 1H), 2.91 – 2.66 (m, 2H), 2.65 – 2.57 (m, 2H), 2.19 (bs, 1H), 1.75 (ddd, J = 13.8, 7.2, 6.5 Hz, 1H), 1.64 – 1.50 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 144.5, 138.9, 135.9, 128.4, 127.3, 127.0, 126.5, 115.1, 75.3, 67.3, 43.7, 39.8, 25.8, 25.7, 15.5; IR (Neat Film, NaCl) 3404, 3069, 3020, 2932, 1634, 1602, 1455, 1417, 1374, 1268, 1217, 1191, 1045, 991, 913, 774, 741, 641 cm-1; HRMS (FAB+) m/z calc’d for C15H19O2 [(M+H)–H2]+: 231.1385, found 231.1385. Please note that a minor amount of epimeric product is present in the 1H NMR spectrum. OO O OH (3S,4R)-5-(Hydroxymethyl)-4-methyl-3',4,4',5-tetrahydro-1'H,2H-spiro[furan-3,2'naphthalene]-1',2-dione (65). A solution of methyl ester 54 (20.0 mg, 0.077 mmol, 1 equiv), K2OsO4 (3.0 mg, 0.0081 mmol, 0.11 equiv), N-methylmorpholine N-oxide (15 mg, 0.12 mmol, 1.6 equiv), and THF/H2O (3:1, 0.4 mL) was stirred at ambient temperature for 12 h, whereupon a second addition of K2OsO4 and N-methylmorpholine N-oxide was added and the reaction was stirred for an additional 24 h. The reaction was quenched with saturated Na2S2O3 aqueous solution (1 mL). The aqueous layer was then extracted with EtOAc (5 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (33% EtOAc/hexanes) to give lactone 65 as a colorless oil (13 mg, 65% yield): [α]D25 +7.0 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 51 δ 8.07 (dd, J = 7.9, 1.4 Hz, 1H), 7.52 (td, J = 7.5, 1.5 Hz, 1H), 7.38 – 7.31 (m, 1H), 4.26 (ddd, J = 10.5, 5.6, 2.4 Hz, 1H), 4.01 (ddd, J = 12.8, 7.0, 2.5 Hz, 1H), 3.82 (dt, J = 12.4, 6.0 Hz, 1H), 3.59 (dq, J = 10.5, 7.0 Hz, 1H), 3.47 – 3.34 (m, 1H), 2.98 (dt, J = 17.0, 3.8 Hz, 1H), 2.32 – 2.25 (m, 2H), 1.94 (t, J = 6.7 Hz, 1H), 1.03 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.6, 173.5, 144.0, 134.4, 131.8, 129.0, 128.8, 127.2, 84.3, 62.9, 57.7, 36.1, 25.6, 25.3, 10.8; IR (Neat Film, NaCl) 3444, 2928, 2851, 1760, 1682, 1599, 1455, 1308, 1239, 1217, 1166, 1094, 1056, 1021, 914, 759, 733, 656 cm-1; HRMS (FAB+) m/z calc’d for C15H17O4 [M+H]+: 261.1127, found 261.1129. NOE correlation: OO H O H OH H NOE O CO2Et Ethyl (1R,2S)-2-((S)-but-3-en-2-yl)-3,4-dihydro-2H-spiro[naphthalene-1,2'-oxirane]2-carboxylate (66). (CH3)3SOI (35 mg, 0.17 mmol, 1.7 equiv) and NaH (5.0 mg, 0.15 mmol, 1.5 equiv, 60 wt %) were dissolved in DMSO (1.5 mL). The mixture was stirred for 20 min at ambient temperature, whereupon a solution of ketone 58a (27 mg, 0.10 mmol, 1 equiv) in DMSO (1.0 mL) was added. The resulting solution was stirred for an additional 18 h. H2O (2.0 mL) was then added to the reaction mixture and the aqueous layer was extractd with EtOAc (3 x 5 mL). The organic layer was washed with H2O (5.0 mL) and brine (5.0 mL), dried over Na2SO4, and concentrated under reduced pressure. Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 52 The crude residue was purified by preparatory TLC (3% Et2O/hexanes) to give epoxide 66 as a colorless oil (23 mg, 82% yield): [α]D25 +10.4 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.15 (m, 3H), 7.15 – 7.07 (m, 1H), 6.07 (ddd, J = 17.1, 10.3, 8.1 Hz, 1H), 4.93 (ddd, J = 10.2, 1.9, 0.8 Hz, 1H), 4.74 (ddd, J = 17.1, 2.0, 1.1 Hz, 1H), 4.29 – 4.06 (m, 2H), 3.01 – 2.94 (m, 1H), 2.98 (d, J = 5.1 Hz, 1H), 2.93 – 2.82 (m, 1H), 2.82 – 2.71 (m, 1H), 2.62 (d, J = 5.1 Hz, 1H), 2.35 (ddd, J = 14.0, 8.2, 5.7 Hz, 1H), 2.09 (ddd, J = 14.2, 6.9, 5.5 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ; 173.4, 140.9, 138.2, 136.4, 127.8, 127.4, 126.8, 123.4, 115.1, 61.0, 59.1, 56.5, 51.9, 40.2, 28.0, 26.2, 15.8, 14.4; IR (Neat Film, NaCl) 3073, 2977, 2938, 1723, 1489, 1456, 1368, 1296, 1255, 1233, 1213, 1134, 1096, 1025, 915, 760 cm-1; HRMS (FAB+) m/z calc’d for C18H21O3 [(M+H)–H2]+: 285.1491, found 285.1487. Please note that the relative stereochemistry of 16 has been assigned via analogy to 11 and 14. 1.7.2.7 Determination of Enantiomeric Excess O EWG R1 + OCO 2Me THF (0.1 M), 25 °C, 18 h 52, 56a–k O [Rh(CO) 2Cl]2 (10 mol %) NaH (110 mol %) R1 EWG rac-54, rac-58 Please note racemic products (rac-54, rac-58) were synthesized as follows: in a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Rh(CO)2Cl]2 (10 mol %) and but-3-en-2-yl methyl carbonate (140 mol %) in THF. Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with tetralone 52, 56a–k (100 mol %), NaH (110 mol %), and THF. The pre-formed catalyst solution (vial A) was then transferred to vial B and the vial was sealed and stirred at 25 °C. After 18 h, the vial was removed from the glove box and filtered through celite, Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 53 rinsing with EtOAc to give the crude racemic product. The residue was purified as in the general procedure for the Ir-catalyzed allylic alkylation. Table 1.5 Determination of enantiomeric excess Entry Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee SFC Chiralpak AD-H 3% MeOH isocratic, 3.5 mL/min 5.170 5.968 96% 19.785 24.041 23% CO2Me HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 4.539 5.113 96% CO2Et SFC Chiralpak AD-H 3% MeOH isocratic, 3.5 mL/min 10.378 11.179 96% CO2i-Pr HPLC Chiralpak AD then AD-H 1% EtOH/hexanes isocratic, 1 mL/min 9.018 9.737 89% CO2CH2CH2TMS HPLC Chiralpak AD then AD-H 1% EtOH/hexanes isocratic, 1 mL/min 23.903 29.498 84% CO2Et HPLC Chiralpak AD then AD-H 1% EtOH/hexanes isocratic, 1 mL/min 24.809 33.026 86% CO2Et HPLC Chiralpak AD then AD-H 3% EtOH/hexanes isocratic, 1 mL/min Product O 1 CO2Me O 2 O 3 O 4 O 5 O 6 MeO O 7 Me 2N Chapter 1 – Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride Entry Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee 17.216 14.519 94% CO2Et HPLC Chiralpak AD then AD-H 1% EtOH/hexanes isocratic, 1 mL/min 14.901 13.808 93% CO2Et HPLC Chiralpak AD then AD-H 5% EtOH/hexanes isocratic, 1 mL/min 9.330 8.616 98% CO2Et SFC Chiralpak AD-H 3% MeOH isocratic, 3.5 mL/min 9.599 10.926 96% CO2Et HPLC Chiralpak IC 1% IPA/hexanes isocratic, 1 mL/min 24.027 26.658 52% CN HPLC Chiralpak AD then AD-H 2% EtOH/hexanes isocratic, 1 mL/min 11.271 11.944 65% C(O)Me HPLC Chiralpak AD then AD-H 1% EtOH/hexanes isocratic, 1 mL/min Product O MeO 8 O 9 O2N O 10 Br O 11 O 12 O 13 1.8 (1) 54 REFERENCES AND NOTES (a) Douglas, C. 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(19) Paolo, B.; Diego, V.; Giampietro, B.; Roberto, S. U.S. Patent, 166800 A1, Sept. 4, 2003. (20) Ankner, T.; Fridén-Saxin, M.; Pemberton, N.; Seifert, T.; Grøtli, M.; Luthman, K.; Hilmersson, G. Org. Lett. 2010, 12, 2210–2213. Appendix 1 – Spectra Relevant to Chapter 1 58 APPENDIX 1 Spectra Relevant to Chapter 1: Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 10 9 8 6 5 ppm 4 3 Figure A1.1 1H NMR (400 MHz, CDCl3) of compound 54 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 59 Appendix 1 – Spectra Relevant to Chapter 1 60 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 54 200 180 160 140 120 100 ppm 80 60 40 Figure A1.3 13C NMR (101 MHz, CDCl3) of compound 54 20 0 10 9 8 7 5 ppm 4 3 Figure A1.4 1H NMR (400 MHz, CDCl3) of compound epi-54 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 61 Appendix 1 – Spectra Relevant to Chapter 1 62 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound epi-54 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.6 13C NMR (101 MHz, CDCl3) of compound epi-54 0 10 9 8 7 5 ppm 4 3 Figure A1.7 1H NMR (400 MHz, CDCl3) of compound 55 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 63 Appendix 1 – Spectra Relevant to Chapter 1 64 Figure A1.8 Infrared spectrum (Thin Film, NaCl) of compound 55 200 180 160 140 120 100 ppm 80 60 40 Figure A1.9 13C NMR (101 MHz, CDCl3) of compound 55 20 0 10 9 8 6 5 ppm 4 3 Figure A1.10 1H NMR (400 MHz, CDCl3) of compound 56b 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 65 Appendix 1 – Spectra Relevant to Chapter 1 66 Figure A1.11 Infrared spectrum (Thin Film, NaCl) of compound 56b 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.12 13C NMR (101 MHz, CDCl3) of compound 56b 0 16 14 12 8 6 ppm 4 2 Figure A1.13 1H NMR (400 MHz, CDCl3) of compound 56c 10 0 -2 Appendix 1 – Spectra Relevant to Chapter 1 67 Appendix 1 – Spectra Relevant to Chapter 1 68 Figure A1.14 Infrared spectrum (Thin Film, NaCl) of compound 56c 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.15 13C NMR (101 MHz, CDCl3) of compound 56c 0 10 9 8 6 5 ppm 4 3 Figure A1.16 1H NMR (400 MHz, CDCl3) of compound 56e 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 69 Appendix 1 – Spectra Relevant to Chapter 1 70 Figure A1.17 Infrared spectrum (Thin Film, NaCl) of compound 56e 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.18 13C NMR (101 MHz, CDCl3) of compound 56e 0 13 12 11 10 8 7 ppm 6 5 4 Figure A1.19 1H NMR (400 MHz, CDCl3) of compound 56g 9 3 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 71 Appendix 1 – Spectra Relevant to Chapter 1 72 Figure A1.20 Infrared spectrum (Thin Film, NaCl) of compound 56g 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.21 13C NMR (101 MHz, CDCl3) of compound 56g 0 14 13 12 11 10 8 7 ppm 6 5 4 Figure A1.22 1H NMR (400 MHz, CDCl3) of compound 56h 9 3 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 73 Appendix 1 – Spectra Relevant to Chapter 1 74 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 56h 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.24 13C NMR (101 MHz, CDCl3) of compound 56h 0 10 9 8 6 5 ppm 4 3 Figure A1.25 1H NMR (400 MHz, CDCl3) of compound 56k 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 75 Appendix 1 – Spectra Relevant to Chapter 1 76 Figure A1.26 Infrared spectrum (Thin Film, NaCl) of compound 56k 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.27 13C NMR (101 MHz, CDCl3) of compound 56k 0 10 9 8 6 5 ppm 4 3 Figure A1.28 1H NMR (400 MHz, CDCl3) of compound 58a 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 77 Appendix 1 – Spectra Relevant to Chapter 1 78 Figure A1.29 Infrared spectrum (Thin Film, NaCl) of compound 58a 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.30 13C NMR (101 MHz, CDCl3) of compound 58a 0 10 9 8 6 5 ppm 4 3 Figure A1.31 1H NMR (400 MHz, CDCl3) of compound 58b 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 79 Appendix 1 – Spectra Relevant to Chapter 1 80 Figure A1.32 Infrared spectrum (Thin Film, NaCl) of compound 58b 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.33 13C NMR (101 MHz, CDCl3) of compound 58b 0 10 9 8 7 5 ppm 4 3 Figure A1.34 1H NMR (400 MHz, CDCl3) of compound 58c 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 81 Appendix 1 – Spectra Relevant to Chapter 1 82 Figure A1.35 Infrared spectrum (Thin Film, NaCl) of compound 58c 200 180 160 140 120 100 ppm 80 60 40 Figure A1.36 13C NMR (101 MHz, CDCl3) of compound 58c 20 0 10 9 8 6 5 ppm 4 3 Figure A1.37 1H NMR (400 MHz, CDCl3) of compound 58d 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 83 Appendix 1 – Spectra Relevant to Chapter 1 84 Figure A1.38 Infrared spectrum (Thin Film, NaCl) of compound 58d 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.39 13C NMR (101 MHz, CDCl3) of compound 58d 0 10 9 8 6 5 ppm 4 3 Figure A1.40 1H NMR (400 MHz, CDCl3) of compound 58e 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 85 Appendix 1 – Spectra Relevant to Chapter 1 86 Figure A1.41 Infrared spectrum (Thin Film, NaCl) of compound 58e 200 180 160 140 120 100 ppm 80 60 40 Figure A1.42 13C NMR (101 MHz, CDCl3) of compound 58e 20 0 10 9 8 6 5 ppm 4 3 Figure A1.43 1H NMR (400 MHz, CDCl3) of compound 58f 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 87 Appendix 1 – Spectra Relevant to Chapter 1 88 Figure A1.44 Infrared spectrum (Thin Film, NaCl) of compound 58f 200 180 160 140 120 100 ppm 80 60 40 Figure A1.45 13C NMR (101 MHz, CDCl3) of compound 58f 20 0 10 9 8 6 5 ppm 4 3 Figure A1.46 1H NMR (400 MHz, CDCl3) of compound 58g 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 89 Appendix 1 – Spectra Relevant to Chapter 1 90 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 58g 200 180 160 140 120 100 ppm 80 60 40 Figure A1.48 13C NMR (101 MHz, CDCl3) of compound 58g 20 0 10 9 8 6 5 ppm 4 3 Figure A1.49 1H NMR (400 MHz, CDCl3) of compound 58h 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 91 Appendix 1 – Spectra Relevant to Chapter 1 92 Figure A1.50 Infrared spectrum (Thin Film, NaCl) of compound 58h 200 180 160 140 120 100 ppm 80 60 40 Figure A1.51 13C NMR (101 MHz, CDCl3) of compound 58h 20 0 10 9 8 6 5 ppm 4 3 Figure A1.52 1H NMR (400 MHz, CDCl3) of compound 58i 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 93 Appendix 1 – Spectra Relevant to Chapter 1 94 Figure A1.53 Infrared spectrum (Thin Film, NaCl) of compound 58i 200 180 160 140 120 100 ppm 80 60 40 Figure A1.54 13C NMR (101 MHz, CDCl3) of compound 58i 20 0 10 9 8 6 5 ppm 4 3 Figure A1.55 1H NMR (400 MHz, CDCl3) of compound 58j 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 95 Appendix 1 – Spectra Relevant to Chapter 1 96 Figure A1.56 Infrared spectrum (Thin Film, NaCl) of compound 58j 200 180 160 140 120 100 ppm 80 60 40 Figure A1.57 13C NMR (101 MHz, CDCl3) of compound 58j 20 0 10 9 8 6 5 ppm 4 3 Figure A1.58 1H NMR (400 MHz, CDCl3) of compound 58k 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 97 Appendix 1 – Spectra Relevant to Chapter 1 98 Figure A1.59 Infrared spectrum (Thin Film, NaCl) of compound 58k 200 180 160 140 120 100 ppm 80 60 40 Figure A1.60 13C NMR (101 MHz, CDCl3) of compound 58k 20 0 10 9 8 6 5 ppm 4 3 Figure A1.61 1H NMR (400 MHz, CDCl3) of compound 61 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 99 Appendix 1 – Spectra Relevant to Chapter 1 100 Figure A1.62 Infrared spectrum (Thin Film, NaCl) of compound 61 200 180 160 140 120 100 ppm 80 60 40 Figure A1.63 13C NMR (101 MHz, CDCl3) of compound 61 20 0 10 9 8 6 5 ppm 4 3 Figure A1.64 1H NMR (400 MHz, CDCl3) of compound 62 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 101 Appendix 1 – Spectra Relevant to Chapter 1 102 Figure A1.65 Infrared spectrum (Thin Film, NaCl) of compound 62 200 180 160 140 120 100 ppm 80 60 40 Figure A1.66 13C NMR (101 MHz, CDCl3) of compound 62 20 0 10 9 8 6 5 ppm 4 3 Figure A1.67 1H NMR (400 MHz, CDCl3) of compound 63 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 103 Appendix 1 – Spectra Relevant to Chapter 1 104 Figure A1.68 Infrared spectrum (Thin Film, NaCl) of compound 63 200 180 160 140 120 100 ppm 80 60 40 Figure A1.69 13C NMR (101 MHz, CDCl3) of compound 63 20 0 10 9 8 6 5 ppm 4 3 Figure A1.70 1H NMR (400 MHz, CDCl3) of compound 64 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 105 Appendix 1 – Spectra Relevant to Chapter 1 106 Figure A1.71 Infrared spectrum (Thin Film, NaCl) of compound 64 200 180 160 140 120 100 ppm 80 60 40 Figure A1.72 13C NMR (101 MHz, CDCl3) of compound 64 20 0 10 9 8 6 5 ppm 4 3 Figure A1.73 1H NMR (400 MHz, CDCl3) of compound 65 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 107 Appendix 1 – Spectra Relevant to Chapter 1 108 Figure A1.74 Infrared spectrum (Thin Film, NaCl) of compound 65 200 180 160 140 120 100 ppm 80 60 40 Figure A1.75 13C NMR (101 MHz, CDCl3) of compound 65 20 0 4.4 {4.26,2.28} 4.2 3.8 3.6 ppm 3.4 3.2 Figure A1.76 NEOSY (400 MHz, CDCl3) of compound 65 4.0 3.0 2.8 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Appendix 1 – Spectra Relevant to Chapter 1 109 f1 (ppm) 10 9 8 6 5 ppm 4 3 Figure A1.77 1H NMR (400 MHz, CDCl3) of compound 66 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 110 Appendix 1 – Spectra Relevant to Chapter 1 111 Figure A1.78 Infrared spectrum (Thin Film, NaCl) of compound 66 200 180 160 140 120 100 ppm 80 60 40 Figure A1.79 13C NMR (101 MHz, CDCl3) of compound 66 20 0 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 112 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1: Stereoselective Iridium-Catalyzed Allylic Alkylation Reactions with Crotyl Chloride 113 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.1 GENERAL EXPERIMENTAL X-ray crystallographic analysis was obtained from the Caltech X-Ray Crystallography Facility using a Bruker D8 Venture Kappa Duo Photon 100 CMOS diffractometer. A2.1.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF ALLYLIC ALKYLATION PRODUCT 58e O CO2Et Me 2N The alkylation product 58e (86% ee) was recrystallized by slow evaporation of hexanes to provide crystals suitable for X-ray analysis, m.p. = 67 – 69 °C. Figure A2.1 X-ray crystal structure of allylic alkylation product 58e Table A2.1 Crystal data and structure refinement for allylic alkylation product 58e Empirical formula C19 H25 N O3 Formula weight 315.40 Temperature 100(2) K Wavelength 1.54178 Å 114 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Crystal system Monoclinic Space group P21 Unit cell dimensions a = 7.5983(10) Å a = 90°. b = 6.1333(8) Å b = 99.411(4)°. c = 18.493(3) Å g = 90°. Volume 850.2(2) Å3 Z 2 Density (calculated) 1.232 Mg/m3 Absorption coefficient 0.661 mm-1 F(000) 340 Crystal size 0.240 x 0.230 x 0.080 mm3 Theta range for data collection 2.422 to 79.330°. Index ranges -9<=h<=8, -7<=k<=7, -23<=l<=23 Reflections collected 26025 Independent reflections 3636 [R(int) = 0.0411] Completeness to theta = 67.679° 99.6 % Absorption correction Semi-empirical from equivalents Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3636 / 1 / 212 Goodness-of-fit on F2 1.094 Final R indices [I>2sigma(I)] R1 = 0.0271, wR2 = 0.0727 R indices (all data) R1 = 0.0274, wR2 = 0.0730 Absolute structure parameter 0.07(3) Extinction coefficient n/a Largest diff. peak and hole 0.132 and -0.164 e.Å-3 4 2 Table A2.2 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters (Å x 3 10 ) for 58e. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) _____________________________________________________________________ O(1) O(2) O(3) 7683(1) 3598(1) 2465(1) 7250(2) 7112(2) 3836(2) 2322(1) 1929(1) 2155(1) 22(1) 22(1) 26(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 115 N(1) 7877(2) 5287(2) 5723(1) 22(1) C(1) 6891(2) 5855(2) 2615(1) 18(1) C(2) 5657(2) 4176(2) 2162(1) 19(1) C(3) 5859(2) 1974(2) 2564(1) 21(1) C(4) 5385(2) 2122(2) 3330(1) 21(1) C(5) 6371(2) 3931(2) 3774(1) 19(1) C(6) 6627(2) 3825(2) 4533(1) 20(1) C(7) 7579(2) 5444(2) 4976(1) 19(1) C(8) 8254(2) 7234(2) 4615(1) 21(1) C(9) 8014(2) 7309(2) 3861(1) 20(1) C(10) 7074(2) 5687(2) 3423(1) 19(1) C(11) 7366(2) 3305(2) 6073(1) 25(1) C(12) 8987(2) 6890(2) 6164(1) 23(1) C(13) 3720(2) 4979(2) 2090(1) 19(1) C(14) 1805(2) 8046(3) 1784(1) 26(1) C(15) 1022(2) 7841(3) 986(1) 34(1) C(16) 6100(2) 3994(3) 1368(1) 23(1) C(17) 4726(2) 2647(3) 886(1) 27(1) C(18) 3647(2) 3362(3) 300(1) 34(1) C(19) 7958(2) 3021(3) 1358(1) 30(1) _____________________________________________________________________ Table A2.3 Bond lengths [Å] and angles [°] for 58e _____________________________________________________ O(1)-C(1) O(2)-C(13) O(2)-C(14) O(3)-C(13) N(1)-C(7) N(1)-C(12) N(1)-C(11) C(1)-C(10) C(1)-C(2) C(2)-C(3) C(2)-C(13) C(2)-C(16) C(3)-C(4) C(3)-H(3A) 1.2222(17) 1.3416(18) 1.4618(16) 1.2044(18) 1.3659(18) 1.4557(18) 1.4589(18) 1.480(2) 1.5442(18) 1.537(2) 1.5374(18) 1.5650(19) 1.521(2) 0.9900 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3)-H(3B) C(4)-C(5) C(4)-H(4A) C(4)-H(4B) C(5)-C(6) C(5)-C(10) C(6)-C(7) C(6)-H(6) C(7)-C(8) C(8)-C(9) C(8)-H(8) C(9)-C(10) C(9)-H(9) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C) C(12)-H(12A) C(12)-H(12B) C(12)-H(12C) C(14)-C(15) C(14)-H(14A) C(14)-H(14B) C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(16)-C(17) C(16)-C(19) C(16)-H(16) C(17)-C(18) C(17)-H(17) C(18)-H(18A) C(18)-H(18B) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(13)-O(2)-C(14) C(7)-N(1)-C(12) C(7)-N(1)-C(11) 0.9900 1.5042(19) 0.9900 0.9900 1.388(2) 1.4074(19) 1.4096(19) 0.9500 1.4236(19) 1.376(2) 0.9500 1.4032(19) 0.9500 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.505(2) 0.9900 0.9900 0.9800 0.9800 0.9800 1.505(2) 1.535(2) 1.0000 1.322(2) 0.9500 0.9500 0.9500 0.9800 0.9800 0.9800 116.82(11) 120.26(11) 119.66(12) 116 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(12)-N(1)-C(11) O(1)-C(1)-C(10) O(1)-C(1)-C(2) C(10)-C(1)-C(2) C(3)-C(2)-C(13) C(3)-C(2)-C(1) C(13)-C(2)-C(1) C(3)-C(2)-C(16) C(13)-C(2)-C(16) C(1)-C(2)-C(16) C(4)-C(3)-C(2) C(4)-C(3)-H(3A) C(2)-C(3)-H(3A) C(4)-C(3)-H(3B) C(2)-C(3)-H(3B) H(3A)-C(3)-H(3B) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(5)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(6)-C(5)-C(10) C(6)-C(5)-C(4) C(10)-C(5)-C(4) C(5)-C(6)-C(7) C(5)-C(6)-H(6) C(7)-C(6)-H(6) 119.10(12) 121.63(12) 121.71(12) 116.66(11) 109.99(11) 108.68(11) 108.76(11) 111.84(12) 106.93(11) 110.60(11) 112.21(12) 109.2 109.2 109.2 109.2 107.9 112.26(11) 109.2 109.2 109.2 109.2 107.9 120.11(13) 119.48(12) 120.38(12) 121.95(12) 119.0 119.0 N(1)-C(7)-C(6) N(1)-C(7)-C(8) C(6)-C(7)-C(8) C(9)-C(8)-C(7) C(9)-C(8)-H(8) C(7)-C(8)-H(8) C(8)-C(9)-C(10) C(8)-C(9)-H(9) C(10)-C(9)-H(9) C(9)-C(10)-C(5) 121.49(12) 121.09(12) 117.41(13) 120.20(13) 119.9 119.9 122.17(13) 118.9 118.9 118.13(13) 117 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(9)-C(10)-C(1) C(5)-C(10)-C(1) N(1)-C(11)-H(11A) N(1)-C(11)-H(11B) H(11A)-C(11)-H(11B) N(1)-C(11)-H(11C) H(11A)-C(11)-H(11C) H(11B)-C(11)-H(11C) N(1)-C(12)-H(12A) N(1)-C(12)-H(12B) H(12A)-C(12)-H(12B) N(1)-C(12)-H(12C) H(12A)-C(12)-H(12C) H(12B)-C(12)-H(12C) O(3)-C(13)-O(2) O(3)-C(13)-C(2) O(2)-C(13)-C(2) O(2)-C(14)-C(15) O(2)-C(14)-H(14A) C(15)-C(14)-H(14A) O(2)-C(14)-H(14B) C(15)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(14)-C(15)-H(15A) C(14)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(14)-C(15)-H(15C) H(15A)-C(15)-H(15C) 119.25(12) 122.60(12) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 124.23(13) 124.53(13) 111.23(11) 110.68(13) 109.5 109.5 109.5 109.5 108.1 109.5 109.5 109.5 109.5 109.5 H(15B)-C(15)-H(15C) C(17)-C(16)-C(19) C(17)-C(16)-C(2) C(19)-C(16)-C(2) C(17)-C(16)-H(16) C(19)-C(16)-H(16) C(2)-C(16)-H(16) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(16)-C(17)-H(17) 109.5 109.29(13) 111.13(11) 112.17(12) 108.0 108.0 108.0 125.47(16) 117.3 117.3 118 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 119 C(17)-C(18)-H(18A) 120.0 C(17)-C(18)-H(18B) 120.0 H(18A)-C(18)-H(18B) 120.0 C(16)-C(19)-H(19A) 109.5 C(16)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(16)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 _____________________________________________________________ Table A2.4 Anisotropic displacement parameters 2 3 (Å x 10 ) for 58e. The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ O(1) 19(1) 17(1) 32(1) 2(1) 6(1) -3(1) O(2) 14(1) 16(1) 35(1) 1(1) 1(1) 1(1) O(3) 16(1) 21(1) 41(1) 4(1) 3(1) -3(1) N(1) 22(1) 16(1) 28(1) 1(1) 6(1) -1(1) C(1) 11(1) 13(1) 30(1) 2(1) 4(1) 1(1) C(2) 14(1) 15(1) 28(1) 0(1) 2(1) -1(1) C(3) 17(1) 13(1) 32(1) -1(1) 2(1) -1(1) C(4) 18(1) 14(1) 32(1) 2(1) 3(1) -4(1) C(5) 12(1) 14(1) 31(1) 1(1) 4(1) 1(1) C(6) 15(1) 14(1) 31(1) 2(1) 6(1) -1(1) C(7) 14(1) 15(1) 28(1) 0(1) 5(1) 3(1) C(8) 17(1) 14(1) 32(1) 1(1) 3(1) -2(1) C(9) 14(1) 14(1) 32(1) 3(1) 3(1) -1(1) C(10) 12(1) 15(1) 29(1) 2(1) 3(1) 0(1) C(11) 28(1) 17(1) 31(1) 3(1) 9(1) 2(1) C(12) 21(1) 19(1) 29(1) -2(1) 3(1) 0(1) C(13) 16(1) 16(1) 24(1) -1(1) 2(1) -1(1) C(14) 16(1) 20(1) 39(1) -1(1) 0(1) 3(1) C(15) 27(1) 33(1) 40(1) 1(1) -7(1) 5(1) C(16) 19(1) 21(1) 28(1) -1(1) 6(1) -2(1) C(17) 25(1) 27(1) 30(1) -4(1) 6(1) -3(1) C(18) 30(1) 41(1) 31(1) -3(1) 3(1) -3(1) 120 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(19) 22(1) 32(1) 38(1) -5(1) 10(1) 1(1) _____________________________________________________________________ 4 2 3 Table A2.5 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 58e ________________________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(3A) 5075 886 2276 25 H(3B) 7106 1463 2599 25 H(4A) 4085 2369 3292 26 H(4B) 5673 719 3588 26 H(6) 6146 2627 4762 24 H(8) 8872 8379 4895 26 H(9) 8500 8499 3631 24 H(11A) 6078 3077 5938 37 H(11B) 7674 3450 6606 37 H(11C) 8003 2057 5909 37 H(12A) 10166 6934 6015 35 H(12B) 9116 6485 6683 35 H(12C) 8427 8330 6092 35 H(14A) 1857 9604 1927 31 H(14B) 1030 7281 2084 31 H(15A) 1819 8539 688 52 H(15B) -147 8555 894 52 H(15C) 886 6296 854 52 H(16) 6079 5497 1156 27 H(17) 4624 1157 1013 33 H(18A) 3705 4841 153 41 H(18B) 2815 2397 25 41 H(19A) 7954 1474 1490 45 H(19B) 8840 3797 1712 45 H(19C) 8266 3172 866 45 ____________________________________________________________________ 121 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.1.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF TRIOL 63 OH OH HO CO2Et Triol 63 was recrystallized by slow evaporation of benzene to provide crystals suitable for X-ray analysis, m.p. = 111 – 115 °C. Figure A2.2 X-ray crystal structure of triol 63 Table A2.6 Crystal data and structure refinement for triol 63 Empirical formula C28.63 H34.63 O5 Formula weight 458.70 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Hexagonal Space group P6522 Unit cell dimensions a = 21.3194(5) Å a = 90°. b = 21.3194(5) Å b = 90°. c = 18.6055(6) Å g = 120°. Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 122 Volume 7323.6(4) Å3 Z 12 Density (calculated) 1.305 Mg/m3 Absorption coefficient 0.695 mm-1 F(000) 3108 Crystal size .2 x .1 x .1 mm3 Theta range for data collection 2.393 to 58.098°. Index ranges -22<=h<=20, -22<=k<=22, -20<=l<=20 Reflections collected 60463 Independent reflections 3412 [R(int) = 0.0731] Completeness to theta = 67.679° 78.2 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7514 and 0.6563 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3412 / 1 / 283 Goodness-of-fit on F2 1.110 Final R indices [I>2sigma(I)] R1 = 0.0803, wR2 = 0.1889 R indices (all data) R1 = 0.1100, wR2 = 0.2084 Absolute structure parameter 0.03(8) Extinction coefficient n/a Largest diff. peak and hole 0.290 and -0.263 e.Å-3 4 Table A2.7 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x10 ) for 63. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ O(1A) 7920(2) 7040(3) 6808(2) 56(1) O(2A) 9307(3) 7800(3) 6495(3) 58(1) O(3A) 9815(2) 6894(2) 5959(2) 43(1) O(4A) 7565(3) 6012(4) 4758(3) 83(2) O(5A) 7359(4) 5007(4) 5298(3) 109(3) C(1A) 7758(4) 6774(4) 6067(3) 55(2) 123 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(2A) C(3A) C(4A) C(5A) C(6A) C(7A) C(8A) C(9A) C(10A) C(11A) C(12A) C(13A) C(14A) C(15A) C(16A) C(17A) C(18A) C(1) C(2) C(3) C(4) C(5) C(6) C(1DA) C(2DA) C(3DA) C(4DA) C(5DA) 7774(4) 7206(4) 6454(4) 6399(5) 5726(6) 5634(7) 6225(7) 6913(5) 7009(4) 8356(4) 9097(4) 9114(3) 8537(3) 8628(4) 7550(4) 7152(6) 6414(7) 5200(6) 5804(6) 6326(6) 4612(8) 3968(7) 5251(7) 7650(90) 8300(80) 8570(40) 8180(80) 7520(80) 6048(4) 5535(4) 5377(7) 6008(7) 5959(9) 6481(12) 7100(9) 7191(6) 6657(6) 7356(4) 7469(4) 6767(4) 6184(4) 5516(4) 5710(5) 4621(7) 4137(6) 5125(5) 5643(6) 6241(6) 6693(6) 6673(5) 7315(7) 9370(50) 9420(50) 9070(70) 8680(50) 8630(60) 6049(3) 6597(4) 6424(5) 6139(4) 6069(5) 5755(7) 5525(5) 5601(4) 5911(4) 5609(4) 5797(3) 5770(3) 6252(3) 6272(4) 5293(4) 4606(5) 4612(5) 3686(4) 4044(4) 3681(5) 3992(5) 4078(5) 4077(5) 5020(80) 5190(40) 4760(80) 4160(70) 4000(60) 52(2) 63(2) 91(4) 83(3) 125(6) 136(7) 109(5) 81(3) 70(3) 57(2) 48(2) 42(2) 44(2) 63(2) 63(2) 137(6) 113(4) 76(3) 80(3) 91(3) 95(3) 88(3) 100(4) 520(40) 520(40) 520(40) 520(40) 520(40) C(6DA) 7260(40) 8980(70) 4420(100) 520(40) C(1DB) 9660(90) 9170(100) 4740(60) 410(30) C(2DB) 10280(80) 9850(100) 4720(70) 410(30) C(3DB) 10570(30) 10170(40) 4060(110) 410(30) C(4DB) 10240(80) 9820(80) 3430(60) 410(30) C(5DB) 9620(80) 9140(70) 3450(60) 410(30) C(6DB) 9330(50) 8810(40) 4110(100) 410(30) _____________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Table A2.8 Bond lengths [Å] and angles [°] for 63 _____________________________________________________ O(1A)-C(1A) 1.466(7) O(2A)-C(12A) 1.438(8) O(3A)-C(13A) 1.425(7) O(4A)-C(16A) 1.176(10) O(5A)-C(16A) 1.344(11) O(5A)-C(17A) 1.472(10) C(1A)-C(10A) 1.514(10) C(1A)-C(11A) 1.519(10) C(1A)-C(2A) 1.566(11) C(2A)-C(3A) 1.541(10) C(2A)-C(16A) 1.543(10) C(2A)-C(14A) 1.549(9) C(3A)-C(4A) C(4A)-C(5A) C(5A)-C(6A) C(5A)-C(10A) C(6A)-C(7A) C(7A)-C(8A) C(8A)-C(9A) C(9A)-C(10A) C(11A)-C(12A) C(12A)-C(13A) C(13A)-C(14A) C(14A)-C(15A) C(17A)-C(18A) C(1)-C(1)#1 C(1)-C(2) C(2)-C(3) C(3)-C(3)#1 C(4)-C(6) C(4)-C(5) C(5)-C(5)#2 C(6)-C(6)#2 C(1DA)-C(2DA) C(1DA)-C(6DA) C(2DA)-C(3DA) 1.499(12) 1.504(14) 1.392(14) 1.410(14) 1.35(2) 1.36(2) 1.386(13) 1.382(12) 1.516(9) 1.514(9) 1.527(9) 1.531(10) 1.384(14) 1.341(15) 1.378(13) 1.379(13) 1.331(18) 1.353(15) 1.363(15) 1.365(19) 1.36(2) 1.3900 1.3900 1.3900 124 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3DA)-C(4DA) C(4DA)-C(5DA) C(5DA)-C(6DA) C(1DB)-C(2DB) C(1DB)-C(6DB) C(2DB)-C(3DB) C(3DB)-C(4DB) C(4DB)-C(5DB) C(5DB)-C(6DB) C(16A)-O(5A)-C(17A) O(1A)-C(1A)-C(10A) O(1A)-C(1A)-C(11A) C(10A)-C(1A)-C(11A) O(1A)-C(1A)-C(2A) C(10A)-C(1A)-C(2A) C(11A)-C(1A)-C(2A) C(3A)-C(2A)-C(16A) C(3A)-C(2A)-C(14A) C(16A)-C(2A)-C(14A) C(3A)-C(2A)-C(1A) C(16A)-C(2A)-C(1A) C(14A)-C(2A)-C(1A) C(4A)-C(3A)-C(2A) C(3A)-C(4A)-C(5A) C(6A)-C(5A)-C(10A) C(6A)-C(5A)-C(4A) C(10A)-C(5A)-C(4A) C(7A)-C(6A)-C(5A) 1.3900 1.3900 1.3900 1.390(3) 1.3900 1.3900 1.3900 1.3900(12) 1.3900 117.2(8) 105.6(5) 105.8(6) 114.3(7) 106.6(6) 112.1(7) 111.8(6) 108.7(6) 110.6(6) 111.2(5) 106.8(6) 109.0(7) 110.5(6) 113.0(7) 115.3(8) 117.2(13) 120.3(12) 122.5(8) 123.1(14) C(6A)-C(7A)-C(8A) 119.2(11) C(7A)-C(8A)-C(9A) 120.4(14) C(10A)-C(9A)-C(8A) 120.7(12) C(9A)-C(10A)-C(5A) 119.3(8) C(9A)-C(10A)-C(1A) 121.6(9) C(5A)-C(10A)-C(1A) 119.0(9) C(12A)-C(11A)-C(1A) 112.5(6) O(2A)-C(12A)-C(13A) 111.1(5) O(2A)-C(12A)-C(11A) 109.2(6) C(13A)-C(12A)-C(11A) 111.9(6) 125 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 126 O(3A)-C(13A)-C(12A) 110.2(5) O(3A)-C(13A)-C(14A) 110.5(5) C(12A)-C(13A)-C(14A) 112.2(5) C(13A)-C(14A)-C(15A) 110.3(5) C(13A)-C(14A)-C(2A) 110.6(6) C(15A)-C(14A)-C(2A) 116.1(6) O(4A)-C(16A)-O(5A) 121.7(7) O(4A)-C(16A)-C(2A) 126.8(9) O(5A)-C(16A)-C(2A) 111.4(8) C(18A)-C(17A)-O(5A) 108.7(8) C(1)#1-C(1)-C(2) 119.8(5) C(1)-C(2)-C(3) 120.2(7) C(3)#1-C(3)-C(2) 120.0(5) C(6)-C(4)-C(5) 121.4(10) C(4)-C(5)-C(5)#2 119.2(6) C(4)-C(6)-C(6)#2 119.5(7) C(2DA)-C(1DA)-C(6DA)120.0 C(3DA)-C(2DA)-C(1DA)120.0 C(2DA)-C(3DA)-C(4DA)120.00(6) C(3DA)-C(4DA)-C(5DA)120.0 C(4DA)-C(5DA)-C(6DA)120.0 C(5DA)-C(6DA)-C(1DA)120.00(6) C(2DB)-C(1DB)-C(6DB) 120.00(11) C(3DB)-C(2DB)-C(1DB) 120.00(5) C(4DB)-C(3DB)-C(2DB) 120.00(6) C(5DB)-C(4DB)-C(3DB) 120.00(12) C(4DB)-C(5DB)-C(6DB) 120.00(8) C(5DB)-C(6DB)-C(1DB) 120.00(9) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 y,x,-z+2/3 #2 x,x-y+1,-z+5/6 2 3 Table A2.9 Anisotropic displacement parameters (Å x10 ) for 63. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] _____________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ 127 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(1A) 51(3) O(2A) 60(3) O(3A) 35(3) O(4A) 97(5) O(5A) 115(5) C(1A) 40(4) C(2A) 40(4) C(3A) 46(5) C(4A) 34(5) C(5A) 41(6) C(6A) 56(7) C(7A) 72(8) C(8A) 86(8) C(9A) 85(7) C(10A) 51(5) C(11A) 54(5) C(12A) 49(4) C(13A) 33(4) C(14A) 37(4) C(15A) 51(5) C(16A) 33(4) C(17A) 105(9) C(18A) 129(10) C(1) 121(8) C(2) 136(9) C(3) 115(8) C(4) 177(12) C(5) 132(9) 88(4) 59(3) 45(3) 137(5) 73(4) 94(6) 73(5) 77(5) 139(10) 157(10) 253(17) 300(20) 231(15) 147(9) 128(8) 79(5) 58(5) 56(4) 46(4) 47(5) 93(7) 133(10) 92(8) 92(7) 110(8) 106(8) 91(8) 81(6) 40(2) 61(3) 45(2) 36(3) 49(3) 34(3) 31(3) 37(4) 54(5) 46(5) 59(6) 75(8) 64(6) 48(5) 38(4) 46(4) 40(4) 31(3) 36(3) 77(5) 40(5) 59(6) 64(6) 49(4) 38(4) 58(5) 57(6) 60(5) -17(3) -10(3) 2(2) -23(3) -30(3) -17(4) -14(3) -16(4) -20(6) -45(6) -80(9) -109(11) -71(8) -40(5) -34(5) 2(4) 2(3) -4(3) -6(3) -3(4) -22(5) -52(6) -17(5) 11(5) -5(5) -16(5) -8(5) -9(5) -8(2) -5(2) 1(2) -14(3) 24(3) -9(3) 3(3) 5(3) 8(4) -13(4) -29(5) -54(7) -44(6) -28(4) -11(4) -1(4) -1(3) 0(3) 0(3) 12(4) 4(3) 13(6) -16(6) 0(5) -8(5) -17(5) -21(7) -8(6) 43(3) 32(3) 17(2) 74(4) -21(4) 36(4) 19(4) 9(4) 8(5) 46(6) 71(9) 127(12) 119(10) 86(7) 51(6) 39(4) 29(4) 16(3) 12(3) 13(4) 15(4) -26(8) 16(8) 79(7) 95(7) 59(7) 99(9) 60(6) C(6) 131(9) 146(11) 46(5) -9(7) -15(6) 87(9) _____________________________________________________________________ 4 2 3 Table A2.10 Hydrogen coordinates (x 10 ) and isotropic displacement parameters (Å x 10 ) for 63 _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(1A) 7550 6986 7001 84 128 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(2A) H(3A) H(3AA) H(3AB) H(4AA) H(4AB) H(6A) H(7A) H(8A) H(9A) H(11A) H(11B) H(12A) H(13A) H(14A) H(15A) H(15B) H(15C) H(17A) H(17B) H(18A) H(18B) H(18C) H(1) H(2) H(3) H(4) H(5) 8992 9776 7212 7338 6162 6247 5320 5172 6168 7313 8255 8358 9445 9015 8634 8599 8251 9091 7272 7414 6293 6279 6157 4846 5860 6738 4613 3533 7554 6578 5083 5752 5201 4990 5549 6417 7465 7616 7221 7808 7802 6589 6383 5337 5147 5645 4964 4363 3825 3852 4400 4724 5589 6584 6270 6242 6789 6237 6610 7071 6856 6072 6245 5698 5316 5440 5107 5675 5444 5274 6740 5793 6561 6476 4216 4534 5022 4180 4636 3933 4532 3921 3873 4016 88 65 76 76 109 109 150 163 131 97 69 69 57 51 52 94 94 94 164 164 169 169 169 91 96 110 113 106 H(6) H(1DA) H(2DA) H(3DA) H(4DA) H(5DA) H(6DA) H(1DB) H(2DB) H(3DB) 5686 7468 8562 9005 8353 7259 6817 9471 10503 10983 7320 9607 9679 9096 8442 8370 8953 8948 10084 10630 4014 5309 5591 4874 3877 3595 4311 5182 5145 4047 120 622 622 622 622 622 622 495 495 495 129 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(4DB) 10431 10040 2986 495 H(5DB) 9399 8904 3023 495 H(6DB) 8919 8358 4121 495 _____________________________________________________________________ A2.1.3 X-RAY CRYSTAL STRUCTURE ANALYSIS OF DIOL 64 OH OH Diol 64 was recrystallized in boiling heptane to provide crystals suitable for X-ray analysis, m.p. = 97 – 99 °C. Figure A2.3 X-ray crystal structure of diol 64 Table A2.11 Crystal data and structure refinement for diol 64 Empirical formula C15 H20 O2 Formula weight 232.31 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P21 Unit cell dimensions a = 8.0972(3) Å a = 90°. 130 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 b = 6.3583(2) Å b = 105.4260(10)°. c = 12.5999(4) Å g = 90°. Volume 625.33(4) Å3 Z 2 Density (calculated) 1.234 Mg/m3 Absorption coefficient 0.630 mm-1 F(000) 252 Crystal size .1 x .1 x .1 mm3 Theta range for data collection 3.639 to 79.259°. Index ranges -10<=h<=10, -8<=k<=8, -15<=l<=16 Reflections collected 20029 Independent reflections 2647 [R(int) = 0.0449] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2647 / 3 / 163 Goodness-of-fit on F2 1.085 Final R indices [I>2sigma(I)] R1 = 0.0296, wR2 = 0.0677 R indices (all data) R1 = 0.0312, wR2 = 0.0687 Absolute structure parameter 0.04(8) Extinction coefficient n/a Largest diff. peak and hole 0.144 and -0.158 e.Å-3 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 131 4 Table A2.12 Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters (≈Å x 3 10 ) for 64. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ C(1) 8395(2) 5246(3) 8290(1) 13(1) C(2) 6809(2) 3826(3) 8166(1) 14(1) C(3) 6586(2) 2540(3) 7101(1) 15(1) C(4) 6321(2) 3872(3) 6062(1) 18(1) C(5) 7576(2) 5670(3) 6196(1) 15(1) C(6) 7795(2) 6715(3) 5269(1) 18(1) C(7) 8956(2) 8347(3) 5356(2) 20(1) C(8) 9945(2) 8942(3) 6391(2) 21(1) C(9) 9737(2) 7927(3) 7319(2) 18(1) C(10) 8540(2) 6317(3) 7239(1) 14(1) O(1) 8491(2) 6779(2) 9145(1) 15(1) O(2) 8701(2) 1051(2) 9217(1) 18(1) C(11) 7204(2) 2296(3) 9154(2) 16(1) C(12) 5173(2) 5063(3) 8245(2) 16(1) C(13) 4829(2) 7173(3) 7629(2) 21(1) C(14) 3580(2) 3725(3) 7913(2) 19(1) C(15) 2772(2) 2878(3) 8592(2) 23(1) _____________________________________________________________________ Table A2.13 Bond lengths [Å] and angles [°] for 64 _____________________________________________________ C(1)-O(1) 1.440(2) C(1)-C(10) 1.521(2) C(1)-C(2) 1.543(2) C(1)-H(1) 1.0000 C(2)-C(3) 1.541(2) C(2)-C(11) 1.545(2) C(2)-C(12) 1.566(2) C(3)-C(4) 1.525(2) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(4)-C(5) 1.509(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(4)-H(4A) C(4)-H(4B) C(5)-C(6) C(5)-C(10) C(6)-C(7) C(6)-H(6) C(7)-C(8) C(7)-H(7) C(8)-C(9) C(8)-H(8) C(9)-C(10) C(9)-H(9) O(1)-H(1O) O(2)-C(11) O(2)-H(2O) C(11)-H(11A) C(11)-H(11B) C(12)-C(14) C(12)-C(13) C(12)-H(12) C(13)-H(13A) C(13)-H(13B) C(13)-H(13C) C(14)-C(15) C(14)-H(14) C(15)-H(15A) C(15)-H(15B) O(1)-C(1)-C(10) 0.9900 0.9900 1.396(2) 1.400(2) 1.385(3) 0.9500 1.389(3) 0.9500 1.384(3) 0.9500 1.395(2) 0.9500 0.93(2) 1.432(2) 0.91(2) 0.9900 0.9900 1.508(2) 1.537(3) 1.0000 0.9800 0.9800 0.9800 1.322(3) 0.9500 0.9500 0.9500 110.31(13) O(1)-C(1)-C(2) C(10)-C(1)-C(2) O(1)-C(1)-H(1) C(10)-C(1)-H(1) C(2)-C(1)-H(1) C(3)-C(2)-C(1) C(3)-C(2)-C(11) C(1)-C(2)-C(11) C(3)-C(2)-C(12) C(1)-C(2)-C(12) 110.47(13) 115.37(14) 106.7 106.7 106.7 107.46(13) 108.58(14) 107.34(13) 114.66(14) 113.27(15) 132 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-C(2)-C(12) C(4)-C(3)-C(2) C(4)-C(3)-H(3A) C(2)-C(3)-H(3A) C(4)-C(3)-H(3B) C(2)-C(3)-H(3B) H(3A)-C(3)-H(3B) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(5)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(6)-C(5)-C(10) C(6)-C(5)-C(4) C(10)-C(5)-C(4) 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(10) C(8)-C(9)-H(9) C(10)-C(9)-H(9) 105.21(13) 114.18(14) 108.7 108.7 108.7 108.7 107.6 112.78(14) 109.0 109.0 109.0 109.0 107.8 118.84(16) 119.89(15) 121.27(15) 121.68(17) 119.2 119.2 119.20(17) 120.4 120.4 119.79(18) 120.1 120.1 121.30(17) 119.3 119.3 C(9)-C(10)-C(5) C(9)-C(10)-C(1) C(5)-C(10)-C(1) C(1)-O(1)-H(1O) C(11)-O(2)-H(2O) O(2)-C(11)-C(2) O(2)-C(11)-H(11A) C(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(2)-C(11)-H(11B) 119.13(16) 118.63(15) 122.16(15) 107.5(19) 115.1(17) 112.54(14) 109.1 109.1 109.1 109.1 133 134 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(11A)-C(11)-H(11B) 107.8 C(14)-C(12)-C(13) 108.99(15) C(14)-C(12)-C(2) 111.98(15) C(13)-C(12)-C(2) 116.67(15) C(14)-C(12)-H(12) 106.2 C(13)-C(12)-H(12) 106.2 C(2)-C(12)-H(12) 106.2 C(12)-C(13)-H(13A) 109.5 C(12)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 C(12)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 C(15)-C(14)-C(12) 125.79(17) C(15)-C(14)-H(14) 117.1 C(12)-C(14)-H(14) 117.1 C(14)-C(15)-H(15A) 120.0 C(14)-C(15)-H(15B) 120.0 H(15A)-C(15)-H(15B) 120.0 _____________________________________________________________ Table A2.14 Anisotropic displacement parameters (Å 2 3 x 10 ) for 14. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] _____________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ C(1) 15(1) 11(1) 13(1) -1(1) 2(1) 1(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) O(1) 14(1) 16(1) 19(1) 15(1) 18(1) 23(1) 20(1) 17(1) 14(1) 17(1) 11(1) 12(1) 18(1) 13(1) 20(1) 21(1) 20(1) 18(1) 14(1) 13(1) 14(1) 16(1) 16(1) 16(1) 16(1) 18(1) 24(1) 18(1) 15(1) 14(1) 1(1) -1(1) -1(1) 0(1) 1(1) 4(1) 1(1) -1(1) 1(1) -3(1) 2(1) 1(1) 2(1) 3(1) 4(1) 9(1) 8(1) 5(1) 4(1) 2(1) -1(1) 0(1) -3(1) 3(1) 2(1) 1(1) -3(1) -1(1) 2(1) 0(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 135 O(2) 18(1) 11(1) 21(1) 1(1) 0(1) 2(1) C(11) 18(1) 12(1) 16(1) 2(1) 3(1) 1(1) C(12) 17(1) 14(1) 16(1) 0(1) 4(1) -1(1) C(13) 18(1) 16(1) 29(1) 4(1) 6(1) 3(1) C(14) 17(1) 17(1) 21(1) -2(1) 3(1) -1(1) C(15) 20(1) 19(1) 31(1) 0(1) 9(1) -1(1) _____________________________________________________________________ Table A2.15 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 103) for 64 _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(1) 9423 4319 8540 16 H(3A) 7615 1651 7174 18 H(3B) 5590 1591 7016 18 H(4A) 6441 2964 5448 22 H(4B) 5141 4443 5864 22 H(6) 7130 6296 4560 21 H(7) 9075 9051 4715 24 H(8) 10761 10042 6462 25 H(9) 10423 8336 8024 21 H(1O) 9470(30) 6480(50) 9710(20) 52(8) H(2O) 8500(30) -340(30) 9040(20) 42(8) H(11A) 7369 3113 9843 19 H(11B) 6210 1351 9090 19 H(12) 5343 5400 9042 19 H(13A) 4478 6913 6834 32 H(13B) 5875 8025 7814 32 H(13C) 3914 7925 7847 32 H(14) 3117 3469 7149 22 H(15A) 3189 3093 9363 28 H(15B) 1773 2054 8308 28 _____________________________________________________________________ Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 136 CHAPTER 2 Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents† 2.1 INTRODUCTION AND BACKGROUND Since the first report of an asymmetric iridium-catalyzed allylic alkylation in 1997,1 the technology has been widely developed for normal reactivity patterns between electrophilic π-allyl species and nucleophilic enolate equivalents, organometallic reagents, or heteroatoms (Figure 2.1a, left).2 However, the application of an umpolung strategy to stitch together a formally electrophilic group and a π-allyl cation via enantioselective iridium-catalyzed allylic alkylation remains underexplored (Figure 2.1a, right).3 To date, only two examples of reverse-polarity nucleophiles in iridium-catalyzed allylic alkylation have been reported (Figure 2.1b). In 2008, Helmchen showed that the extensively explored malononitrile nucleophile can operate as a methoxy carbonyl synthon with the † This work was performed in collaboration with Dr. J. Caleb Hethcox. Portions of this chapter have been reproduced with permission from Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. Org. Lett. 2017, 19, 1527– 1529 © 2017 American Chemical Society. 137 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents subsequent application of an oxidative degradation process (Figure 2.1b, left). 4 More recently, Carreira disclosed the use of formaldehyde N,N-dialkylhydrazone as a formyl anion equivalent in iridium-catalyzed allylic alkylation reactions (Figure 2.1b, right). 5 Herein, we describe the first use of an acyl cyanide equivalent in asymmetric iridiumcatalyzed allylic alkylation, which formally serves as the addition of carbon monoxide (Figure 2.1c, left). Figure 2.1 Iridium-catalyzed allylic alkylation strategies a) Iridium-Catalyzed Allylic Alkylation Strategies δ− R O δ+ Ar O δ− X δ− R δ+ Ar δ+ R δ+ Ar δ+ Ar Umpolung (2 reports) Standard (>60 reports) b) Prior Art: Umpolung Strategy Iridium-Catalyzed Allylic Alkylation O O NC N CN MeO H Helmchen 4 Carreira5 H N H c) This Research: Use of an Umpoled Masked Acyl Cyanide (MAC) Reagent O OR NC CN MAC reagent NC OMOM O ref 7,8 NC Ar X Ar X = OH, NR 2, OR As part of our ongoing research program to develop iridium-catalyzed allylic alkylation methods, 6 we became interested in exploring the reactivity of masked acyl cyanide (MAC) reagents as reverse-polarity nucleophiles with π-allyl electrophiles. Following reaction with an electrophile, these umpoled synthons, developed by Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 138 Yamamoto and Nemoto,7 can be unmasked to reveal a transient acyl cyanide intermediate, which can be further transformed into a carboxylic acid, amide, or ester.7,8 We envisioned that the novel application of MAC reagents to iridium-catalyzed allylic alkylation chemistry could provide access to highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives, which are otherwise difficult to prepare (Figure 1c, right).9 2.2 REACTION OPTIMIZATION Preliminary studies focused on the identification of a suitable protecting group for MAC nucleophile 67 in order to achieve the allylic alkylation reaction. Using our previously reported conditions for iridium-catalyzed allylic alkylations with cinnamylderived electrophiles as a starting point,6a we found that the reaction of either silyl ether 67a or acetate 67b with cinnamyl carbonate (68) furnishes desired products 69a and 69b, respectively, albeit in low yields (Table 2.1, entries 1 and 2). However, the use of methoxymethyl ether 67c provides allylic alkylation product 69c in 64% yield (entry 3). Moreover, we were pleased to find that product 69c can be obtained with excellent enantioselectivity (95% ee), obviating the need for further optimization beyond that of conversion. Of note, as in our prior investigations on iridium-catalyzed allylic alkylation,6a LiBr was found to improve the regioselectivity of the allylic alkylation reaction – the use of 200 mol % (in comparison to 100 mol % as utilized in our previous report6a) provides consistently higher yields of desired branched product 69. Efforts to increase the reaction conversion revealed that altering the nucleophile to electrophile ratio from 1:2 to 2:1 improves the yield to 77% with no erosion of enantioselectivity (entries 4 and 5). We observed that extending the reaction time from 18 139 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents to 48 hours provides product 69c in a now synthetically useful 85% yield and 97% ee (entry 6). Ultimately, we found that treatment of a mixture (2:1) of nucleophile 67c to electrophile 68 with a combination of catalytic Ir(cod)Cl·L2 (4 mol %) and LiBr (200 mol %) at 60 °C delivers allylic alkylation product 69c in a high 86% yield with an exceptional 96% enantioselectivity in only 18 hours (entry 7). Table 2.1 Optimization of reaction parametersa LiBr (200 mol %) [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %), TBD (10 mol %) OR + NC Ph OCO 2Me CN NC OR NC Ph THF (0.1 M), 18 h 67a–c 69a–c 68 Entry R 67: 68 Temp (°C) 1 TBS (67a) 1:2 2 Ac (67b) 1:2 3 MOM (67c) 4 Yield (%)b ee (%)c 23 24 – 23 19 – 1:2 23 64 95 MOM (67c) 1:1 23 50 96 5 MOM (67c) 2:1 23 77 96 6d MOM (67c) 2:1 23 85 97 7 MOM (67c) 2:1 60 86 96 O P N O (S,S a )-L2 [a] Reactions performed on 0.1 mmol scale. [b] 1H NMR yield based on internal standard. [c] Determined by chiral HPLC analysis. [d] Reaction run for 48 h. [e] TBD = 1,3,5-triazabicyclo[4.4.0]dec-5-ene. 2.3 SUBSTRATE SCOPE EXPLORATION With the optimized conditions identified, the substrate scope of the enantioselective umpolung reaction was explored (Table 2.2). Our investigation began by probing the effects of electronics on reaction yield and selectivity. Gratifyingly, we observed that para-substituted aryl electrophiles bearing both electron-withdrawing (–Br, –CF3, –F) and electron-donating (–OMe) groups furnish products 71a–d with consistently excellent enantioselectivities (>95% ee). While products 71a (–Br) and 71d (–OMe) are obtained in high yield (>94% yield), diminished yields (58% and 69% yield, 140 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents respectively) are observed for the more electron-poor products 71b (–CF3) and 71c (–F). Further examination of electrophile electronics revealed that meta-Cl-substituted 71e, as well as poly-alkoxylated 71f and 71g, are each furnished in good yields (>81%) and high enantioselectivities (92–98% ee), despite varying electronics. Studies involving sterically demanding substrates showed that products 71h (–2-Np) and 71i (–ortho-Me) can be provided with good selectivities (92% and 89% ee, respectively), albeit in moderate yields (41% and 65%, respectively). Additionally, we were pleased to discover that pyridine 71j, furan 71k, and thiophene 71l are each afforded with excellent enantioselectivities (90–96% ee) and in moderate to high yields (73–94%). Table 2.2 Electrophile substrate scopea LiBr (200 mol %) [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %), TBD (10 mol %) OMOM + NC R OCO 2Me CN NC NC Br NC OMOM NC 94% yield 96% ee c THF (0.1 M), 60 °C, 18 h 70a–l OMOM 71a NC b 71b NC OMOM NC NC OMOM NC F d 58% yield 96% ee NC OMOM NC CF3 OMOM NC 71a–l NC OMOM NC NC NC Cl O OMOM O OMe 71c 71d 71e 71f 69% yield 96% ee 95% yield 95% ee 85% yield 92% ee 90% yield 96% ee NC OMOM NC NC OMOM NC NC OMOM NC NC OMOM NC O MeO OMOM R 67c NC NC S N OMe OMe 71g 71h 71i 71j 71k 71l 81% yield 98% ee 41% yield 92% ee 65% yield 89% ee 74% yield 90% ee 73% yield 96% ee 94% yield 93% ee [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC or SFC analysis. [d] Reaction run for 36 h at 50 °C. 141 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents A broader investigation of the substrate scope revealed limitations of the developed catalytic system (Table 2.3). Foremost, alkenyl substitution is not tolerated on allylic electrophile 70 and leads to significantly diminished yields and enantioselectivities, as is observed in the formation of iso-propenyl 71m, cyclohexyl 71n, and propenyl 71o. Additionally, a propargyl-substituted electrophile does not give desired product 71q in the allylic alkylation reaction, likely due to catalyst poisioning by binding of the alkyne to the metal source. Finally, the optimized reaction conditions fail to provide synthetically useful yields or high regioselectivities when alkyl-substituted allylic electrophiles are employed (e.g., 71q–u). Table 2.3 Electrophile substrate scope limitationsa LiBr (200 mol %) [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %), TBD (10 mol %) OMOM + NC R THF (0.1 M), 60 °C, 18 h 70m–u OMOM NC NC NC R 67c NC OCO 2Me CN OMOM NC OMOM NC NC OMOM NC NC 71m–u OMOM NC NC OMOM NC Ph 71m 50% yield b 59% ee c NC OMOM NC 71n 42% yield d NC OMOM NC 71o 71p 71q trace yield trace yield no reaction NC OMOM NC NC OMOM NC MeO 2CO 71r 71s 71t 71u no reaction trace yield poor b:l trace yield poor b:l no reaction [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC or SFC analysis. [d] 1H NMR yield based on internal standard. 142 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents To demonstrate the synthetic utility of this method, a preparatory scale (4 mmol) reaction was performed (Scheme 2.1). Using cinnamyl carbonate (68), both the yield and enantioselectivity of the reaction are unchanged from those obtained at 0.1 mmol scale. Scheme 2.1 Preparatory scale reaction [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %) TBD (10 mol %) LiBr (200 mol %) OMOM + NC Ph 67c 2.4 OCO 2Me CN 68 THF (0.1 M), 60 °C, 18 h gram scale 86% yield, 95% ee NC OMOM NC Ph 69c CONCLUSIONS In summary, we have developed the first enantioselective iridium-catalyzed allylic alkylation reaction of masked acyl cyanide (MAC) reagents. The umpolung strategy showcased in this reaction diverges from the normal reactivity patterns employed in all but two of the previously reported iridium-catalyzed allylic alkylations and is the first report of a carbon monoxide synthon in iridium-catalyzed allylic alkylation. Critical to the success of this new reaction is the identity of the methoxymethyl protecting group on the MAC reagent. The developed methodology proceeds with moderate to excellent yields (up to 95%) and high levels of enantioselectivity (up to 98% ee) on up to gram scale for a wide range of aryl- and heteroaryl-substituted allylic electrophiles. Furthermore, MAC adducts bearing resemblance to compound 4c have been transformed into acids, amides, and esters by unmasking the alkoxy malononitrile moiety.7,8 Thus, this methodology serves as an entry to enantioenriched vinylated α-aryl carbonyl derivatives. 143 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 2.5 EXPERIMENTAL SECTION 2.5.1 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. Commercially obtained reagents were used as received. Chemicals were purchased from Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Sigma Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4 or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak IC column (4.6 mm x 25 cm) or a Chiralpak AD column (4.6 mm x 25 cm), both obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak IC-3 column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. 1H NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 144 Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of benzene (δ 7.36 ppm), water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as: [α]DT (concentration in g/100 mL, solvent). 2.5.1.1 Preparation of Known Compounds Previously reported methods were used to prepare ligand (S,Sa)-L210 as well as starting materials 67a–c, 11 68, 12 70a,11 70b,11 70c, 13 70d, 14 70h,10b 70i,14 70j, 15 70k, 16 70l.12 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 2.5.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 2.5.2.1 General Procedure for the Synthesis of Electrophiles 145 OCO 2Me Cl (E)-3-(3-Chlorophenyl)allyl methyl carbonate (70e). To a solution of methyl (E)-3-(3chlorophenl)prop-2-enoate17 (1.4 g, 7.0 mmol, 1 equiv) in Et2O (28 mL) at –78 °C was added DIBAL (3.0 g, 21 mmol, 3 equiv) dropwise. The resulting reaction mixture was stirred at –78 °C for 2.5 h, whereupon the reaction was quenched with a saturated aqueous Rochelle’s salt solution (10 mL). The cooling bath was then removed and the reaction was stirred for 18 h at ambient temperature. The aqueous layer was extracted with CH2Cl2 (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was then dissolved in CH2Cl2 (10 mL) and cooled to 0 °C. Pyridine (1.7 mL, 21 mmol, 3 equiv) was added followed by methyl chloroformate (0.81 mL, 11 mmol, 1.5 equiv) dropwise. The resulting solution was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched with the addition of 1 M HCl (10 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (5% EtOAc/hexanes) to give carbonate 70e as a colorless oil (1.0 g, 63% yield): 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.37 (m, 1H), 7.30 – 7.23 (m, 3H), 6.69 – 6.60 (m, 1H), 6.32 (dt, J = 15.9, 6.3 Hz, 1H), 4.81 (dd, J = 6.3, 1.4 Hz, 2H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.7, 138.0, 134.7, 133.2, 130.0, 128.3, Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 146 126.7, 125.0, 124.2, 68.1, 55.1; IR (Neat Film, NaCl) 3010, 2956, 2856, 1748, 1594, 1567, 1442, 1377, 1261, 1091, 1078, 962, 791, 777, 682 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H11ClO3 [M]+: 226.0397, found 226.0398. 2.5.2.2 Spectroscopic Data for the Synthesis of Electrophiles OCO 2Me O O (E)-3-(Benzo[d][1,3]dioxol-5-yl)allyl methyl carbonate (70f). Carbonate 70f was prepared from methyl (2E)-3-(1,3-benzodioxol-5-yl)acrylate 18 according to the general procedure and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless solid (0.79 g, 48% yield): 1H NMR (400 MHz, CDCl3) δ 6.93 (d, J = 1.6 Hz, 1H), 6.83 (ddd, J = 7.9, 1.6, 0.5 Hz, 1H), 6.79 – 6.73 (m, 1H), 6.60 (dt, J = 15.7, 1.3 Hz, 1H), 6.12 (dt, J = 15.7, 6.6 Hz, 1H), 5.96 (s, 2H), 4.76 (dd, J = 6.6, 1.3 Hz, 2H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.8, 148.2, 147.9, 134.9, 130.6, 121.8, 120.7, 108.4, 106.0, 101.3, 68.7, 55.0; IR (Neat Film, NaCl) 3003, 2956, 2895, 2781, 1747, 1504, 1491, 1446, 1384, 1355, 1252, 1194, 1126, 1103, 1039, 933, 863, 791 cm-1; HRMS (FAB+) m/z calc’d for C12H12O5 [M]+: 236.0685, found 236.0674. MeO OCO 2Me MeO OMe (E)-Methyl (3-(3,4,5-trimethoxyphenyl)allyl) carbonate (70g). Carbonate 70g was prepared from methyl 3,4,5-trimethoxycinnamate 19 according to the general procedure and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 147 colorless oil (1.2 g, 65% yield): 1H NMR (400 MHz, CDCl3) δ 6.65 – 6.56 (m, 3H), 6.21 (dt, J = 15.8, 6.5 Hz, 1H), 4.78 (dd, J = 6.5, 1.3 Hz, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.8, 153.4, 138.4, 135.0, 131.8, 122.0, 103.9, 68.5, 61.1, 56.2, 55.0; IR (Neat Film, NaCl) 2999, 2956, 2840, 1748, 1583, 1508, 1452, 1420, 1339, 1265, 1128, 1010, 941, 850, 792 cm-1; HRMS (FAB+) m/z calc’d for C14H18O6 [M]+: 282.1103, found 282.1114. 2.5.2.3 General Procedure for Optimization Reactions (Table 2.1) In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (1.3 mg, 0.0020 mmol, 2 mol %), ligand (S,Sa)-L2 (1.8 mg, 0.0040 mmol, 4 mol %), TBD (1.4 mg, 0.010 mmol, 10 mol%), and THF (0.5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with LiBr (17 mg, 0.20 mmol, 200 mol %), MAC nucleophile 67 (0.20 mmol), and THF (0.25 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by 0.25 mL of a solution of cinnamyl carbonate 68 (0.4 M in THF). The vial was sealed and stirred at the specified temperature. After 18 or 48 h, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc. The crude mixture was concentrated and 1,2,4,5-tetrachloro-3-nitrobenzene (0.10 mmol in 0.5 mL CDCl3) was added. The NMR yield (measured in reference to 1,2,4,5-tetrachloro-3-nitrobenzene δ 7.74 ppm (s, 1H)) was determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (15% EtOAc/hexanes) to afford product 69, which was analyzed by chiral HPLC (1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm). Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 2.5.2.4 148 General Procedure for the Iridium-Catalyzed Allylic Alkylation Please note that the absolute configuration of product 69c was assigned by conversion to (R)-2-phenylbutanoic acid.20 All other products (71a–l) were assigned by analogy. For respective HPLC and SFC conditions, please refer to Table 2.4. NC OMOM NC (R)-2-(Methoxymethoxy)-2-(1-phenylallyl)malononitrile (69c). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (S,Sa)-L2 (3.7 mg, 0.0080 mmol, 4 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with LiBr (35 mg, 0.40 mmol, 200 mol %), MAC nucleophile 67c (50 mg, 0.40 mmol, 200 mol %), and THF (0.5 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by a solution of cinnamyl carbonate 68 (38 mg, 0.20 mmol, 100 mol %) in THF (0.5 mL). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc. The crude mixture was concentrated and the resulting residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give the product 69c as a colorless oil (41 mg, 85% yield): 95% ee; [α]D25 –41.3 (c 2.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.32 (m, 5H), 6.29 (ddd, J = 16.9, 10.3, 8.6 Hz, 1H), 5.53 – 5.38 (m, 2H), 5.06 – 4.94 (m, 2H), 3.97 – 3.91 (m, 1H), 3.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 134.4, 131.5, 129.6, 129.1, 128.9, Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 149 122.7, 112.7, 112.7, 96.5, 69.9, 58.4, 57.4; IR (Neat Film, NaCl) 3065, 3033, 2961, 2904, 2851, 2244, 1750, 1496, 1455, 1420, 1267, 1217, 1164, 1109, 1053, 1033, 967, 940, 791, 732, 700 cm-1; HRMS (FAB+) m/z calc’d for C14H15N2O2 [M+H]+: 243.1131, found 243.1134; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 12.831, minor = 17.466. 2.5.2.5 Procedure for the Preparatory Scale Reaction NC OMOM NC (R)-2-(Methoxymethoxy)-2-(1-phenylallyl)malononitrile (69c). In a nitrogen-filled glove box, a solution of [Ir(cod)Cl]2 (106 mg, 0.16 mmol, 2 mol %), ligand (S,Sa)-L2 (145 mg, 0.32 mmol, 4 mol %), TBD (110 mg, 0.79 mmol, 10 mol %) in THF (20 mL) was stirred at 25 °C. After 10 minutes, the catalyst mixture was added to a mixture of LiBr (0.69 g, 7.9 mmol, 200 mol %), MAC nucleophile 67c (1 g, 7.9 mmol, 200 mol %), and THF (20 mL) followed by cinnamyl carbonate 68 (0.76 g, 4.0 mmol, 100 mol %). The flask was removed from the glove box and stirred at 60 °C. After 18 h, the crude reaction mixture was concentrated and the resulting residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give the product 69c as a colorless oil (0.82 g, 86% yield): 95% ee, spectroscopic data vide supra. Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 2.5.2.6 150 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products NC OMOM NC Br (R)-2-(1-(4-Bromophenyl)allyl)-2-(methoxymethoxy)malononitrile (71a). Product 71a was prepared according to the general procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) to give a colorless oil (60 mg, 94% yield): 96% ee; [α]D25 –44.3 (c 3.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m, 2H), 7.32 – 7.28 (m, 2H), 6.23 (ddd, J = 16.9, 10.3, 8.6 Hz, 1H), 5.55 – 5.38 (m, 2H), 5.05 – 4.96 (m, 2H), 3.92 (d, J = 8.6 Hz, 1H), 3.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 133.4, 132.1, 131.3, 130.9, 123.4, 123.2, 112.6, 112.5, 96.6, 69.5, 57.8, 57.5; IR (Neat Film, NaCl) 3013, 2934, 2242, 1488, 1404, 1274, 1216, 1163, 1108, 1034, 1010, 967, 939, 826, 762 cm-1; HRMS (FAB+) m/z calc’d for C14H13BrO2N2 [M]+: 320.0160, found 320.0155; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 15.852, minor = 11.623. NC OMOM NC CF3 (R)-2-(Methoxymethoxy)-2-(1-(4-(trifluoromethyl)phenyl)allyl)malononitrile (71b). Product 71b was prepared according to the general procedure and isolated by preparatory TLC (5% EtOAc/hexanes, plate eluted three times) to give a pale yellow oil (36 mg, 58% Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 151 yield): 96% ee; [α]D25 –25.2 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 6.27 (ddd, J = 16.9, 10.3, 8.7 Hz, 1H), 5.57 – 5.41 (m, 2H), 5.09 – 4.96 (m, 2H), 4.02 (d, J = 8.7 Hz, 1H), 3.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.4, 131.5, 131.1, 130.6, 130.2, 125.9 (q, J = 3.9 Hz), 125.3, 123.6, 122.6, 112.5, 112.4, 96.7, 69.4, 58.0, 57.6; IR (Neat Film, NaCl) 2962, 2906, 2835, 2245, 1751, 1618, 1445, 1417, 1445, 1417, 1327, 1269, 1218, 1166, 1127, 1069, 943, 840, 792 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H12F3N2O2 [(M+H)–H2]–: 309.0851, found 309.0849; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 10.681, minor = 8.223. NC OMOM NC F (R)-2-(1-(4-Fluorophenyl)allyl)-2-(methoxymethoxy)malononitrile (71c). Product 71c was prepared according to the general procedure and isolated by preparatory TLC (9% EtOAc/hexanes, plate eluted two times) to give a colorless oil (37 mg, 69% yield): 96% ee; [α]D25 –35.9 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.32 (m, 2H), 7.15 – 7.02 (m, 2H), 6.25 (ddd, J = 16.9, 10.3, 8.5 Hz, 1H), 5.57 – 5.35 (m, 2H), 5.11 – 4.94 (m, 2H), 3.95 (d, J = 8.5 Hz, 1H), 3.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 161.9, 131.5, 131.4, 131.2, 130.2 (d, J = 3.5 Hz), 122.9, 116.1, 115.9, 112.7, 112.6, 96.6, 69.8 (d, J = 1.6 Hz), 57.5 (d, J = 9.2 Hz); IR (Neat Film, NaCl) 3085, 2964, 2847, 2242, 1606, 1511, 1415, 1281, 1230, 1164, 1108, 1053, 968, 940, 798, 766 cm-1; HRMS (ESI+) m/z calc’d for C14H14N2O2F [M+H]+: 261.1039, found 261.1033; HPLC conditions: 1% Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 152 IPA, 1 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 11.712, minor = 8.971. NC OMOM NC OMe (R)-2-(Methoxymethoxy)-2-(1-(4-methoxyphenyl)allyl)malononitrile (71d). Product 71d was prepared according to the general procedure and isolated by silica gel flash column chromatography (5–10% EtOAc/hexanes) to give a colorless oil (52 mg, 95% yield): 95% ee; [α]D25 –51.8 (c 2.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.26 (ddd, J = 16.9, 10.3, 8.5 Hz, 1H), 5.61 – 5.34 (m, 2H), 5.08 – 4.94 (m, 2H), 3.91 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.1, 131.7, 130.8, 126.3, 122.3, 114.3, 112.82, 112.78, 96.5, 70.1, 57.6, 57.4, 55.4; IR (Neat Film, NaCl) 3005, 2962, 2939, 2905, 2838, 2244, 2052, 1890, 1610, 1584, 15112, 1459, 1305, 1252, 1216, 1182, 1162, 1107, 1031, 937, 834, 783, 765, 625 cm-1; HRMS (FAB+) m/z calc’d for C15H17N2O3 [M+H]+: 273.1239, found 273.1227; SFC conditions: 3% IPA, 3.5 mL/min, Chiralpak IC-3 column, λ = 210 nm, tR (min): major = 6.831, minor = 5.267. Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents NC 153 OMOM NC Cl (R)-2-(1-(3-Chlorophenyl)allyl)-2-(methoxymethoxy)malononitrile (71e). Product 71e was prepared according to the general procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) to give a colorless oil (47 mg, 85% yield): 92% ee; [α]D25 –38.5 (c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.28 (m, 4H), 6.23 (ddd, J = 16.9, 10.3, 8.7 Hz, 1H), 5.57 – 5.40 (m, 2H), 5.08 – 4.97 (m, 2H), 3.92 (d, J = 8.7 Hz, 1H), 3.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 136.4, 134.7, 130.8, 130.2, 129.9, 129.3, 127.8, 123.3, 112.6, 112.4, 96.6, 69.5, 57.9, 57.5; IR (Neat Film, NaCl) 3069, 2962, 2849, 2832, 2244, 1751, 1596, 1576, 1478, 1436, 1418, 1277, 1217, 1164, 1109, 111055, 1032, 967, 940, 884, 797, 760, 730, 713, 690 cm-1; HRMS (ESI+) m/z calc’d for C14H14N2O2Cl [M+H]+: 277.0744, found 277.0715; SFC conditions: 3% IPA, 3.5 mL/min, Chiralpak IC-3 column, λ = 210 nm, tR (min): major = 3.846, minor = 3.428. NC OMOM NC O O (R)-2-(1-(Benzo[d][1,3]dioxol-5-yl)allyl)-2-(methoxymethoxy)malononitrile (71f). Product 71f was prepared according to the general procedure and isolated by silica gel flash column chromatography (5–10% EtOAc/hexanes) to give a colorless oil (51 mg, 90% yield): 96% ee; [α]D25 –40.6 (c 3.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.91 – 6.78 (m, 3H), 6.20 (ddd, J = 16.9, 10.3, 8.5 Hz, 1H), 5.99 (s, 2H), 5.51 – 5.37 (m, 2H), 154 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 5.03 (d, J = 1.4 Hz, 2H), 3.86 (d, J = 8.5 Hz, 1H), 3.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 148.2, 148.1, 131.5, 127.9, 123.5, 122.5, 112.7, 109.7, 108.7, 101.5, 96.6, 70.0, 58.1, 57.5; IR (Neat Film, NaCl) 3081, 2972, 2902, 2352, 1505, 1488, 1446, 1368, 1251, 1238, 1164, 1108, 1039, 967, 934, 864, 817, 800, 763 cm-1; HRMS (ESI+) m/z calc’d for C15H15N2O4 [M+H]+: 287.1032, found 287.1039; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 24.142, minor = 19.686. NC OMOM NC MeO OMe OMe (R)-2-(Methoxymethoxy)-2-(1-(3,4,5-trimethoxyphenyl)allyl)malononitrile (71g). Product 71g was prepared according to the general procedure and isolated by silica gel flash column chromatography (20% EtOAc/hexanes) to give a colorless oil (54 mg, 81% yield): 98% ee; [α]D25 –28.2 (c 3.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 2H), 6.23 (ddd, J = 16.8, 10.3, 8.5 Hz, 1H), 5.55 – 5.35 (m, 2H), 5.11 – 4.94 (m, 2H), 3.87 (m, 7H), 3.85 (s, 3H), 3.46 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 153.4, 138.5, 131.3, 129.7, 122.6, 112.8, 112.7, 106.6, 96.5, 69.9, 61.0, 58.5, 57.5, 56.3; IR (Neat Film, NaCl) 2941, 2840, 244, 1591, 1509, 1463, 1418, 1333, 1245, 1163, 1127, 1034, 1007, 950, 925, 840, 771, 719 cm-1; HRMS (ESI+) m/z calc’d for C17H21N2O5 [M+H]+: 333.1450, found 333.1450; HPLC conditions: 7% IPA, 1.0 mL/min, Chiralpak AD column, λ = 210 nm, tR (min): major = 17.062, minor = 12.809. 155 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents NC OMOM NC (R)-2-(Methoxymethoxy)-2-(1-(naphthalen-1-yl)allyl)malononitrile (71h). Product 71h was prepared according to the general procedure and isolated by preparatory TLC (9% Et2O/hexanes, plate eluted two times) to give a colorless oil (24 mg, 41% yield): 92% ee; [α]D25 –30.9 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.11 (dt, J = 8.5, 1.0 Hz, 1H), 7.95 – 7.86 (m, 2H), 7.81 (dd, J = 7.4, 1.2 Hz, 1H), 7.60 (ddd, J = 8.6, 6.8, 1.5 Hz, 1H), 7.57 – 7.49 (m, 2H), 6.38 (ddd, J = 16.7, 10.3, 8.2 Hz, 1H), 5.57 – 5.43 (m, 2H), 5.05 – 4.92 (m, 3H), 3.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 134.1, 132.2, 132.1, 130.8, 129.6, 129.3, 126.9, 126.6, 126.1, 125.3, 122.8, 122.7, 113.10, 112.72, 96.5, 70.1, 57.5, 51.6; IR (Neat Film, NaCl) 3051, 2960, 2926, 2851, 2244, 1708, 1398, 1215, 1162, 1106, 1030, 960, 925, 783 cm-1; HRMS (ESI+) m/z calc’d for C18H17N2O2 [M+H]+: 293.1290, found 293.1263; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 15.134, minor = 10.197. NC OMOM NC (R)-2-(Methoxymethoxy)-2-(1-(o-tolyl)allyl)malononitrile (71i). Product 71i was prepared according to the general procedure and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) to give a colorless oil (33 mg, 65% yield): 89% ee; [α]D25 –68.7 (c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.48 (m, 1H), 7.28 – Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 156 7.19 (m, 3H), 6.22 (ddd, J = 16.9, 10.2, 8.2 Hz, 1H), 5.50 – 5.35 (m, 2H), 5.06 – 4.98 (m, 2H), 4.34 (dd, J = 8.2, 1.0 Hz, 1H), 3.45 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 137.4, 133.1, 132.0, 131.2, 128.6, 128.1, 126.6, 122.5, 113.0, 112.8, 96.5, 69.8, 57.5, 53.0, 20.3; IR (Neat Film, NaCl) 3023, 2958, 2360, 2243, 1748, 1640, 1603, 1489, 1445, 1382, 1264, 1164, 1109, 1034, 943, 846, 792, 748, 654 cm-1; HRMS (FAB+) m/z calc’d for C15H17N2O2 [M+H]+: 257.1290, found 257.1280; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 16.719, minor = 9.761. NC OMOM NC N (R)-2-(Methoxymethoxy)-2-(1-(pyridin-3-yl)allyl)malononitrile (71j). Product 71j was prepared according to the general procedure and isolated by silica gel flash column chromatography (25% acetone/hexanes) to give a pale yellow oil (36 mg, 74% yield): 90% ee; [α]D25 –30.8 (c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.63 (dd, J = 4.7, 1.7 Hz, 2H), 7.78 (dddd, J = 8.0, 2.3, 1.6, 0.5 Hz, 1H), 7.35 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 6.27 (ddd, J = 16.9, 10.3, 8.7 Hz, 1H), 5.63 – 5.39 (m, 2H), 5.06 – 4.97 (m, 2H), 4.00 (d, J = 8.7 Hz, 1H), 3.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.1, 150.4, 136.7, 130.4, 130.3, 123.8, 123.7, 112.5, 112.3, 96.7, 69.4, 57.5, 56.0; IR (Neat Film, NaCl) 2963, 2943, 2905, 2833, 2244, 1751, 1718, 1590, 1577, 1480, 1419, 1430, 1271, 1217, 1164, 1109, 2055, 1028, 970, 941, 848, 817, 756, 714 cm-1; HRMS (FAB+) m/z calc’d for C13H14N3O2 [M+H]+: 244.1086, found 244.1083; HPLC conditions: 20% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 13.161, minor = 23.457. Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents NC 157 OMOM NC O (R)-2-(1-(Furan-2-yl)allyl)-2-(methoxymethoxy)malononitrile (71k). Product 71k was prepared according to the general procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) to give a colorless oil (34 mg, 73% yield): 96% ee; [α]D25 –44.9 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.53 – 6.34 (m, 2H), 6.14 (dddd, J = 16.9, 10.2, 8.5, 0.8 Hz, 1H), 5.58 – 5.43 (m, 2H), 5.10 – 4.94 (m, 2H), 4.16 (d, J = 8.5 Hz, 1H), 3.48 (d, J = 0.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 147.4, 143.5, 129.1, 123.5, 112.4, 112.3, 111.0, 110.4, 96.6, 68.9, 57.5, 52.4; IR (Neat Film, NaCl) 3125, 2091, 2964, 2942, 2905, 2833, 2245, 1499, 1444, 14222, 1270, 1217, 1164, 1109, 1030, 922, 797, 743 cm-1; HRMS (ESI+) m/z calc’d for C12H13N2O3 [M+H]+: 233.0926, found 233.0948; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 13.297, minor = 10.761. NC OMOM NC S (S)-2-(Methoxymethoxy)-2-(1-(thiophen-2-yl)allyl)malononitrile (71l). Product 71l was prepared according to the general procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) to give a colorless oil (49 mg, 98% yield): 93% ee; [α]D25 –40.3 (c 2.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 5.1, 1.2 Hz, 1H), 7.20 (ddd, J = 3.6, 1.2, 0.7 Hz, 1H), 7.08 (dd, J = 5.2, 3.6 Hz, 1H), 6.21 (ddd, J = 16.8, 10.2, 8.6 Hz, 1H), 5.59 – 5.48 (m, 2H), 5.09 (d, J = 1.7 Hz, 2H), 4.31 (dd, J = 8.6, 158 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 0.8 Hz, 1H), 3.52 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 135.7, 131.3, 128.3, 127.1, 126.9, 123.0, 112.5, 112.4, 96.7, 69.8, 57.6, 54.0; IR (Neat Film, NaCl) 3090, 2963, 2904, 2833, 2245, 2079, 1639, 1433k 1365, 1270, 1238, 1216, 1162, 1108, 1029, 922, 856, 839, 704 cm-1; HRMS (ESI+) m/z calc’d for C12H13N2O2S [M+H]+: 249.0698, found 249.0703; SFC conditions: 3% IPA, 3.5 mL/min, Chiralpak IC-3 column, λ = 210 nm, tR (min): major = 5.289, minor = 4.010. 2.5.2.7 Determination of Enantiomeric Excess Please note racemic products were synthesized using racemic L2. Table 2.4 Determination of enantiomeric excess Entry Product NC Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 12.831 17.466 95 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 15.852 11.623 96 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 10.681 8.223 96 OMOM NC 1 NC Assay Conditions OMOM NC 2 Br NC OMOM NC 3 CF3 159 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 11.712 8.971 96 SFC Chiralpak IC-3 3% IPA isocratic, 3.5 mL/min 6.831 5.267 95 SFC Chiralpak IC-3 3% IPA isocratic, 3.5 mL/min 3.846 3.428 92 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 24.142 19.686 96 HPLC Chiralpak AD 7% IPA isocratic, 1 mL/min 17.062 12.809 98 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 15.134 10.197 92 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 16.719 9.761 89 OMOM NC NC 4 F OMOM NC NC 5 OMe OMOM NC NC 6 Cl OMOM NC NC 7 O O NC OMOM NC 8 OMe MeO OMe NC OMOM NC 9 NC NC 10 OMOM 160 Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents Entry Product NC Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak IC 20% IPA isocratic, 1 mL/min 13.161 23.457 90 HPLC Chiralpak IC 1% IPA isocratic, 1 mL/min 13.297 10.761 96 SFC Chiralpak IC-3 3% IPA isocratic, 3.5 mL/min 5.289 4.010 93 OMOM NC 11 N NC 12 OMOM NC O NC 13 OMOM NC S 2.6 REFERENCES AND NOTES (1) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025–8026. (2) For select reviews of asymmetric iridium-catalyzed allylic alkylation, see: (a) Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675–691; (b) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169–208; (c) Liu, W.-B.; Xia, J. B.; You, S.-L. Top. Organomet. Chem. 2012, 38, 155–208; (d) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. ACS Catal. 2016, 6, 6207–6213. (3) Nucleophilic additions of methylene imines to iridium π-allyl complexes have been accomplished via an umpoled strategy. However, the reactions deliver products Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 161 resembling those of standard iridium-catalyzed allylic alkylation of enolates, see: Su, Y.-L.; Li, Y.-H.; Chen, Y.-G.; Han, Z.-Y. Chem. Commun. 2017, 53, 1985–1988. (4) Förster, S.; Tverskoy, O.; Helmchen, G. Synlett 2008, 18, 2803–2806. (5) Breitler, S.; Carreira, E. M. J. Am. Chem. Soc. 2015, 137, 5296–5299. (6) (a) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626–10629; (b) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298–17301; (c) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. J.; Tran, K.; Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 5234–5237; (d) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem. Int. Ed. 2016, 55, 16092–16095. (7) (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990, 55, 4515–4516; (b) Nemoto, H.; Li, X.; Ma, R.; Suzuki, I.; Shibuya, M. Tetrahedron Lett. 2003, 44, 73–75; (c) Nemoto, H.; Kawamura, T.; Miyoshi, N. J. Am. Chem. Soc. 2005, 127, 14546–14547; (d) Nemoto, H.; Ma, R.; Kawamura, T.; Kamiya, M.; Shibuya, M. J. Org. Chem. 2006, 71, 6038–6043; (e) Nemoto, H.; Kawamura, T.; Kitasaki, K.; Yatsuzuka, K.; Kamiya, M.; Yoshioka, Y. Synthesis 2009, 1694–1702. (8) (a) Kociołek, K.; Leplawy, M. T. Synthesis 1977, 778–780; (b) Kubota, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991, 56, 7195–7196; (c) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya, M. Tetrahedron 2000, 56, 1463–1468; (d) Yamatsugu, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2009, 65, 6017–6024; (e) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050–16053; (f) Yang, K. S.; Rawal, V. H. J. Am. Chem. Soc. 2014, 136, Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 162 16148–16151; (g) Kagawa, N.; Nibbs, A. E.; Rawal, V. H. Org. Lett. 2016, 18, 2363–2366. (9) (a) Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690–4691; (b) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180–17181; (c) Yan, S.-S.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.; Dai, L.-X.; Hou, X.-L. Angew. Chem. Int. Ed. 2005, 44, 6544–6546; (d) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am. Chem. Soc. 2007, 129, 7718–7719; (e) Lundin, P. M., Esquivias, J.; Fu, G. C. Angew. Chem. Int. Ed. 2009, 48, 154–156; (f) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264–1266; (g) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7442–7445; (h) Poremba, K. E.; Lee, V. A.; Sculimbrene, B. R. Tetrahedron 2014, 70, 5463–5467; (i) Liu, Y.; Virgil, S. C.; Grubbs, R. H.; Stoltz, B. M. Angew. Chem. Int. Ed. 2015, 54, 11800–11803. (10) (a) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076–2082; (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2012, 134, 4812–4821. (11) (a) Nemoto, H.; Li, X.; Ma, R.; Suzuki, I.; Shibuya, M. Tetrahedron Lett. 2003, 44, 73–75; (b) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050–16053. (12) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9, 3949–3952. (13) Trost, B. M.; Miller, J. R.; Hoffman, C. M. Jr. J. Am. Chem. Soc. 2011, 133, 8165– 8167. Chapter 2 – Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 163 (14) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–15165. (15) Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266–3268. (16) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005, 7, 1093–1096. (17) Cao, W.; Liu, X.; Peng, R.; He, P.; Lin, L.; Feng, X. Chem. Commun. 2013, 49, 3470–3472. (18) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Torviso, R.; Pomilio, N.; Moltrasio, G. Y. Tetrahedron, 2012, 68, 913–921. (19) Nguyen, B. H.; Perkins, R. J.; Smith, J. A.; Moeller, K. D. J. Org. Chem. 2015, 80, 11953–11962. (20) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L. Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532–8533. Appendix 3 – Spectra Relevant to Chapter 2 164 APPENDIX 3 Spectra Relevant to Chapter 2: Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents 10 9 8 7 5 ppm 4 3 Figure A3.1 1H NMR (400 MHz, CDCl3) of compound 69c 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 165 Appendix 3 – Spectra Relevant to Chapter 2 166 Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound 69c 200 180 160 140 120 100 ppm 80 60 40 Figure A3.3 13C NMR (101 MHz, CDCl3) of compound 69c 20 0 10 9 8 7 5 ppm 4 3 Figure A3.4 1H NMR (400 MHz, CDCl3) of compound 70e 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 167 Appendix 3 – Spectra Relevant to Chapter 2 168 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound 70e 200 180 160 140 120 100 ppm 80 60 40 Figure A3.6 13C NMR (101 MHz, CDCl3) of compound 70e 20 0 10 9 8 7 5 ppm 4 3 Figure A3.7 1H NMR (400 MHz, CDCl3) of compound 70f 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 169 Appendix 3 – Spectra Relevant to Chapter 2 170 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound 70f 200 180 160 140 120 100 ppm 80 60 40 Figure A3.9 13C NMR (101 MHz, CDCl3) of compound 70f 20 0 10 9 8 6 5 ppm 4 3 Figure A3.10 1H NMR (400 MHz, CDCl3) of compound 70g 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 171 Appendix 3 – Spectra Relevant to Chapter 2 172 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound 70g 200 180 160 140 120 100 ppm 80 60 40 Figure A3.12 13C NMR (101 MHz, CDCl3) of compound 70g 20 0 10 9 8 6 5 ppm 4 3 Figure A3.13 1H NMR (400 MHz, CDCl3) of compound 71a 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 173 Appendix 3 – Spectra Relevant to Chapter 2 174 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound 71a 200 180 160 140 120 100 ppm 80 60 40 Figure A3.15 13C NMR (101 MHz, CDCl3) of compound 71a 20 0 10 9 8 6 5 ppm 4 3 Figure A3.16 1H NMR (400 MHz, CDCl3) of compound 71b 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 175 Appendix 3 – Spectra Relevant to Chapter 2 176 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound 71b 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.18 13C NMR (101 MHz, CDCl3) of compound 71b 0 10 9 8 6 5 ppm 4 3 Figure A3.19 1H NMR (400 MHz, CDCl3) of compound 71c 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 177 Appendix 3 – Spectra Relevant to Chapter 2 178 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound 71c 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.21 13C NMR (101 MHz, CDCl3) of compound 71c 0 10 9 8 6 5 ppm 4 3 Figure A3.22 1H NMR (400 MHz, CDCl3) of compound 71d 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 179 Appendix 3 – Spectra Relevant to Chapter 2 180 Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound 71d 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.24 13C NMR (101 MHz, CDCl3) of compound 71d 0 10 9 8 6 5 ppm 4 3 Figure A3.25 1H NMR (400 MHz, CDCl3) of compound 71e 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 181 Appendix 3 – Spectra Relevant to Chapter 2 182 Figure A3.26 Infrared spectrum (Thin Film, NaCl) of compound 71e 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.27 13C NMR (101 MHz, CDCl3) of compound 71e 0 10 9 8 6 5 ppm 4 3 Figure A3.28 1H NMR (400 MHz, CDCl3) of compound 71f 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 183 Appendix 3 – Spectra Relevant to Chapter 2 184 Figure A3.29 Infrared spectrum (Thin Film, NaCl) of compound 71f 200 180 160 140 120 100 ppm 80 60 40 Figure A3.30 13C NMR (101 MHz, CDCl3) of compound 71f 20 0 10 9 8 6 5 ppm 4 3 Figure A3.31 1H NMR (400 MHz, CDCl3) of compound 71g 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 185 Appendix 3 – Spectra Relevant to Chapter 2 186 Figure A3.32 Infrared spectrum (Thin Film, NaCl) of compound 71g 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.33 13C NMR (101 MHz, CDCl3) of compound 71g 0 10 9 8 6 5 ppm 4 3 Figure A3.34 1H NMR (400 MHz, CDCl3) of compound 71h 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 187 Appendix 3 – Spectra Relevant to Chapter 2 188 Figure A3.35 Infrared spectrum (Thin Film, NaCl) of compound 71h 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.36 13C NMR (101 MHz, CDCl3) of compound 71h 0 10 9 8 6 5 ppm 4 3 Figure A3.37 1H NMR (400 MHz, CDCl3) of compound 71i 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 189 Appendix 3 – Spectra Relevant to Chapter 2 190 Figure A3.38 Infrared spectrum (Thin Film, NaCl) of compound 71i 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.39 13C NMR (101 MHz, CDCl3) of compound 71i 0 10 9 8 6 5 ppm 4 3 Figure A3.40 1H NMR (400 MHz, CDCl3) of compound 71j 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 191 Appendix 3 – Spectra Relevant to Chapter 2 192 Figure A3.41 Infrared spectrum (Thin Film, NaCl) of compound 71j 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.42 13C NMR (101 MHz, CDCl3) of compound 71j 0 10 9 8 6 5 ppm 4 3 Figure A3.43 1H NMR (400 MHz, CDCl3) of compound 71k 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 193 Appendix 3 – Spectra Relevant to Chapter 2 194 Figure A3.44 Infrared spectrum (Thin Film, NaCl) of compound 71k 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.45 13C NMR (101 MHz, CDCl3) of compound 71k 0 10 9 8 6 5 ppm 4 3 Figure A3.46 1H NMR (400 MHz, CDCl3) of compound 71l 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 195 Appendix 3 – Spectra Relevant to Chapter 2 196 Figure A3.47 Infrared spectrum (Thin Film, NaCl) of compound 71l 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.48 13C NMR (101 MHz, CDCl3) of compound 71l 0 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 197 CHAPTER 3 Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation† 3.1 INTRODUCTION AND BACKGROUND The field of enantioselective iridium-catalyzed allylic alkylation has flourished in the twenty years since the seminal report by Helmchen.1 Over these two decades, the substrate scope with respect to the nucleophile has expanded significantly to encompass a vast array of both carbon2 and heteroatom3 nucleophiles.4 Conversely, the scope of the electrophiles has remained largely unchanged, being limited to those that produce products bearing a tertiary allylic stereocenter (Figure 3.1a, left).5 Despite the synthetic community’s longstanding interest in the synthesis of enantioenriched quaternary stereocenters as well as the development of other transition metal-catalyzed processes to access all-carbon quaternary allylic stereocenters,6,7,8 iridium-catalyzed allylic alkylation † This work was performed in collaboration with Dr. J. Caleb Hethcox. Portions of this chapter have been reproduced with permission from Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. Angew. Chem. Int. Ed. 2017, 56, 11545–11548 © 2017 Wiley-VCH. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 198 reactions that furnish products possessing such a stereocenter remain conspicuously absent from the literature (Figure 3.1a, right). Figure 3.1 Synthesis of allylic all-carbon quaternary stereocenters via enantioselective iridiumcatalyzed allylic alkylation a) Limitations in Enantioselective Iridium-Catalyzed Allylic Alkylation [L*Ir] [L*Ir] R2 R1 R Nu all reports R Nu Nu R1 R 2 zero reports b) This Research R2 OMOM NC CN R1 O i. [IrL*] δ + OCO 2Me ii. H +, HX δ X R1 R 2 X = OH, OR, NR 2 As part of our ongoing program in developing iridium-catalyzed allylic alkylation technology and our continued interest in the catalytic, asymmetric synthesis of quaternary stereocenters,9 we were attracted to this unmet challenge. Moreover, we imagined that an umpolung strategy iridium-catalyzed allylic alkylation reaction of a trisubstituted allylic electrophile with a masked acyl cyanide (MAC) nucleophile would not only give rise to products containing an enantioenriched allylic all-carbon quaternary stereocenter, but also provide access to highly valuable acyclic α-quaternary carboxylic acid derivatives (i.e., acids, esters, amides) upon unmasking of the MAC functionality (Figure 3.1b). 9e,10 However, success of this strategy hinged upon the implementation of a trisubstituted allylic electrophile, which was predicted to be unreactive in an enantioselective iridiumcatalyzed allylic alkylation reaction. It is known that the reaction rates of these processes decrease with increasing substitution on the olefin of the electrophile.5,11,12 Herein, we Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 199 discuss the unlocking of this heretofore unreactive class of electrophiles to achieve the first example of an enantioselective iridium-catalyzed allylic alkylation reaction forming a quaternary stereocenter at the allylic position. 3.2 REACTION OPTIMIZATION Preliminary studies focused on identifying a combination of ligand and additive to promote the reaction of MAC 67c and trisubstituted allylic electrophile 72 (Table 3.1). Application of our standard conditions for iridium-catalyzed allylic alkylation reactions of [Ir(cod)Cl]2, L2, and LiBr return only starting material (Table 3.1, entry 1).9a,e A brief ligand screen revealed that while ligand L9 also results in no reaction (entry 2), the phosphoramidite L5 developed by Carreira provides desired product 73 in 13% yield with a moderate 79% ee (entry 3).3b Attempts to further increase yield and selectivity via an extensive evaluation of additives known to promote iridium-catalyzed allylic alkylations proved ineffective.2–4,9 As we hypothesized that the oxidative addition process is slow for trisubstituted allylic electrophiles, we reasoned that the inclusion of a strong Lewis acid would facilitate the ionization of the carbonate during the insertion event, leading to improved reactivity of these recalcitrant electrophiles. Toward this end, we substituted LiBr for triethylborane and were pleased to find that the yield nearly triples and the enantioselectivity rises to 93% ee (entry 4).13 Upon varying the stoichiometry of nucleophile 67c to electrophile 72, we observed a dramatic increase in yield to 74% with no erosion of enantioselectivity (entry 5). Ultimately, we discovered that exposure of a mixture (1:2) of MAC 67c and trisubstituted allylic electrophile 72 affords MAC adduct 73 in nearly quantitative yield and in 94% ee (entry 6). Of note, excess electrophile 72 is Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 200 not consumed and can be recovered following the iridium-catalyzed allylic alkylation reaction. Table 3.1 Optimization of reaction parametersa [Ir(cod)Cl] 2 (2 mol %) OMOM + NC CN L (4.2 mol %), TBD (10 mol %) Ph OCO 2Me 67c THF (0.1 M), 60 °C, 18 h NC OMOM NC Ph 73 72 Entry L 1:2 Additive (200 mol %) Yield (%)b ee (%)c 1 L2 2:1 LiBr 0 – 2 L9 2:1 LiBr 0 – 3 L5 2:1 LiBr 13 79 4 L5 2:1 BEt 3 34 93 5 L5 1:1.2 BEt 3 74 92 6 L5 1:2 BEt 3 99 94 O P N O O P N O (S,S a )-L2 (S,S,S a )-L9 Ph Ph O P O N (S a )-L5 [a] Reactions performed on 0.1 mmol scale. [b] 1H NMR yield based on internal standard. [c] Determined by chiral HPLC analysis. [d] TBD = 1,3,5-triazabicyclo[4.4.0]dec-5-ene. 3.3 MECHANISTIC INSIGHTS During the course of our optimization studies, we discovered both the surprising necessity of the guanidine base TBD as well as the importance of electrophile stereochemistry in our newly developed reaction. Though previously reported conditions for the use of L5 in iridium-catalyzed allylic alkylations do not require a base additive,14 we found the inclusion of TBD during the catalyst prestir to be critical to the success of the reaction. TBD is included with ligands L2 and L9 to form an active iridicycle catalyst; however, Carreira has demonstrated that ligand L5 does not form an iridicycle.14 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 201 Thus, we hypothesize that TBD may be serving as either a placeholder ligand to prevent the formation of an inactive catalyst or as a base to promote the formation of an active, novel iridicycle.2a,c Additionally, we noted that use of the E-trisubstituted allylic electrophile was required, as Z-olefin isomer 74 led to markedly decreased yield and selectivity (Table 3.2). We rationalize this difference in reactivity via the preferred conformation of the reactants. Whereas 72 may exist in a planar conformation, the phenyl group of 74 likely prefers to rotate out of plane to alleviate A1,3 strain (Table 3.2, bottom). In adopting this perpendicular conformation, the phenyl ring has now increased the sterics above and below the olefin as well as become σ-withdrawing rather than πdonating. Finally, neither a kinetic nor a dynamic kinetic resolution occurs under the reaction conditions with the use of terminal olefin rac-75 (Table 3.2). Table 3.2 Electrophile isomersa BEt 3 (200 mol %) [Ir(cod)Cl] 2 (2 mol %) (S a )-L5 (4.2 mol %), TBD (10 mol %) OMOM + NC CN NC 72, 74, or 75 OMOM NC THF (0.1 M), 60 °C, 18 h Ph 73 67c OCO 2Me Ph Ph OCO 2Me OCO 2Me 72 99% yield b 94% ee c Ph 74 (±)-75 18% yield 16% ee 99% yield 1% ee OCO 2Me 74 OCO 2Me 74 [a] Reactions performed with 67c (0.1 mmol) and 72, 74, or 75 (0.2 mmol). [b] 1H NMR yield based on internal standard. [c] Determined by chiral HPLC analysis. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.4 202 SUBSTRATE SCOPE EXPLORATION Before substrate scope exploration commenced, we identified an additional opportunity for innovation. We imagined that hydrolysis of the MAC functionality of product 73 could be performed in the same reaction vessel as the iridium-catalyzed allylic alkylation reaction to provide direct access to the corresponding carboxylic acid in a onepot, two-step procedure.10 Moreover, we envisioned that these carboxylic acid products would be amenable to purification by a simple acid/base extraction. To this end, we subjected the crude allylic alkylation mixture to hydrolysis with 6M HCl at 80 °C and were pleased to find that pure carboxylic acid 77a is obtained after an aqueous work-up with no need for column chromatography (Table 3.3). With the optimized protocol in hand, we first explored the effect of substitution on the aryl moiety of electrophile 76 (Table 3.3). We were pleased to find that parasubstitution was well tolerated to provide acids 77b–f in consistently high enantioselectivities, though electron-rich substrates provide decreased yields. Metasubstituted products 77g and 77h are obtained in similarly high enantioselectivites (92% and 87% ee, respectively), and bulky naphthyl-substituted acid 77i is furnished in 92% ee, albeit in a moderate 66% yield. Further exploration of steric effects using methylsubstituted derivatives demonstrates that while a single meta-substituent is tolerated to access 77j in 68% yield with 93% ee, the bis-meta-substituted derivative 77k is afforded in a drastically lower 32% yield but with good enantioselectivity (85% ee). Finally, we discovered that ortho-substitution is not tolerated and only starting material is recovered from the reaction. 203 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Table 3.3 Aryl substituent substrate scopea i. BEt 3 (200 mol %) [Ir(cod)Cl] 2 (2 mol %) (S a )-L5 (4.2 mol %), TBD (10 mol %) THF (0.1 M), 60 °C, 18 h OMOM NC Ar + CN OCO 2Me 77 72, 76 O O HO HO Ar ii. 6 M HCl (0.05 M), 80 °C, 18 h 67c O O O HO HO HO Cl F F 3C O HO O HO OH 77a 77% yield b 95% ee c 77c 77d 77e 77f 90% yield 90% ee 83% yield 92% ee 65% yield 94% ee 51% yield 95% ee O O HO O HO Br 77g e 69% yield 92% ee d 77b 80% yield 93% ee O HO O HO HO O HO NO 2 g 77h f 77i 93% yield 87% ee 66% yield 92% ee 77j g 68% yield 93% ee 77k g 77l 32% yield 85% ee 0% yield –% ee [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC or SFC analysis. [d] Electrophile 76f used as the bis-carbonate which was deprotected during hydrolysis. [e] Reaction run for 48 h. [f] Absolute stereochemistry determined via single crystal X-ray analysis, the absolute stereochemistry of all other compounds has been assigned by analogy. [g] Reaction performed with double catalyst loading. With the general trends in reactivity corresponding to aryl substitution elucidated, we next turned our attention to the scope of the reaction with respect to the alkyl moiety of the electrophile (Table 3.4). We found that extension of the alkyl chain leads to decreased yields with ethyl-substituted 79a and n-butyl-substituted 79b able to be isolated in 61% and 14% yield, respectively, though both are obtained in similarly excellent enantioselectivities. Furthermore, branched-substituted electrophiles are unreactive and only starting material is recovered in attempts to prepare isopropylsubstituted 79c. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 204 Table 3.4 Non-aryl substituent substrate scopea R2 OMOM NC CN i. BEt 3 (200 mol %) [Ir(cod)Cl] 2 (4 mol %) (S a )-L5 (8.4 mol %), TBD (20 mol %) THF (0.1 M), 60 °C, 18 h R1 + OCO 2Me O HO R1 R 2 ii. 6 M HCl (0.05 M), 80 °C, 18 h 67c 79 78 O O HO O HO O HO Et HO n-Bu O HO O HO i-Pr Ph 79a 61% yield 92% ee c b 79b 79c 14% yield 95% ee 0% yield –% ee 79d/e 79f 79g trace yield –% ee 32% yield 3% ee 63% yield [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC or SFC analysis. We then moved to explore the necessity of the aryl functionality. We hypothesized that cyclohexyl- and cyclohexenyl-substituted electrophiles 78d and 78e would mimic the steric bulk of the phenyl moiety of 76a when interacting with the chiral catalyst, but we found that only trace products 79d and 79e are observed under our reaction conditions (Table 3.4). Use of bis-n-alkyl-substituted electrophile 78f provides the corresponding acid 79f in moderate yield, though no enantioselectivity is observed. Finally, we were pleased to find that prenyl methyl carbonate (78g) is a competent electrophile furnishing acid 79g in 63% yield. A wider exploration into the scope of this novel transformation revealed additional limitations of the catalytic system (Table 3.5). Foremost, while furan- and thiophene-substituted allylic electrophiles are well tolerated in the iridium-catalyzed allylic alkylation reaction, the heteroaromatic functionality on the allylic alkylation product is not amenable to the hydrolysis conditions and thus trace 81a and 81b are recovered. Moreover, alkenyl substitution is not permitted on allylic electrophile 80, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 205 likely due to its ability to bind to the iridium catalyst, and no conversion to propargylderived 81c is observed. Additionally, only trace conversion to hydroxymethyl 81d is noted when corresponding TBS-protected allylic electrophile 80d is employed. A trifluoromethyl group in place of the methyl substituent on the electrophile shuts down the allylic alkylation reaction entirely, as does the use of a bulky branched geranylderived electrophile, resulting in no isolation of 81e and 81f, respectively. Also, use of a tethered allylic electrophile (e.g., tetralone 80g) does not afford corresponding bicyclic product 81g. Finally, we found that a tetrasubstituted allylic electrophile was able to yield allylic alkylation product 81h, albeit in a modest 11% yield. Table 3.5 Substrate scope limitationsa R2 OMOM NC CN + R1 OCO 2Me R3 67c i. BEt 3 (200 mol %) [Ir(cod)Cl] 2 (4 mol %) (S a )-L5 (8.4 mol %), TBD (20 mol %) THF (0.1 M), 60 °C, 18 h O HO R1 R 2 ii. 6 M HCl (0.05 M), 80 °C, 18 h 81 80 O O HO R3 O HO O HO HO OH O S Ph 81a 81b 81c 81d decomposition decomposition no reaction trace yield O O HO HO O O HO HO CF3 81e 81f 81g no reaction no reaction no reaction [a] Reactions performed on 0.2 mmol scale. [b] 1H NMR yield based on internal standard. 81h 11% yield b Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.5 206 PRODUCT TRANSFORMATIONS As MAC adducts can be transformed to essentially any carboxylic acid derivative,10 we endeavored to develop additional one-pot transformations to access both α-quaternary esters and amides. Gratifyingly, we found that alkanolysis of the crude MAC alkylation product with either methanol or allyl alcohol provides methyl ester 82 and allyl ester 83 in 88% and 74% yield, respectively (Figure 3.2). Similarly, aminolysis provides access to both tertiary amide 84 in 61% yield and secondary amide 85 in 63% yield. Figure 3.2 One-pot transformations to α-quaternary carboxylic acid derivativesa O O MeO 82 NC Cl O b a OMOM 83 Cl NC O N H d 85 O Cl Cl c N 84 Cl [a] i. CSA, AcOH/DME, 60 °C, 6 h, ii. MeOH, Et3N, –40 °C → 23 °C, 18 h, 88% yield; [b] i. CSA, AcOH/DME, 60 °C, 6 h, ii. allyl alcohol, Et3N, 0 °C → 23 °C, 18 h, 74% yield; [c] CSA, AcOH/DME, 60 °C, 6 h, ii. pyrrolidine, Et3N, –40 °C → 23 °C, 18 h, 61% yield; [d] i. CSA, AcOH/DME, 60 °C, 6 h, ii. allyl amine, Et3N, 0 °C → 23 °C, 18 h, 63% yield. In order to demonstrate the synthetic utility of the enantioenriched α-quaternary carboxylic acid derivatives, a series of transformations were performed to access a diverse array of chiral building blocks starting from ester derivative 82 (Figure 3.3). Hydrogenation of olefin 82 delivers ethyl-substituted 86 in 97% yield. Alcohol 87 is accessed via reduction of the ester moiety in 73% yield. Dihydroxylation of the pendant Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 207 olefin proceeds with concomitant lactonization to furnish γ-butyrolactone 88 in 82% yield as a mixture (1:1) of diastereomers. Finally, ozonolysis furnishes aldehyde 89 in moderate yield. Figure 3.3 Product transformations of α-quaternary ester 82a O HO MeO a b 86 87 Cl O Cl MeO 82 O Cl O O MeO H 89 d c O Cl OH Cl 88 [a] Pd/C, H2 (balloon), EtOAc, 23 °C, 18 h, 97% yield; [b] DIBAL, Et2O, 0 °C, 2 h, 73% yield; [c] K2OsO4, NMO, THF/H2O (4:1), 23 °C, 18 h, 82% yield (1:1 dr); [d] i. O3, NaHCO3, MeOH/CH2Cl2 (1:5), –78 °C, 0.5 h, ii. DMS, –78 °C→ 23 °C, 18 h, 50% yield. 3.6 CONCLUSIONS In conclusion, we have developed the first synthesis of all-carbon quaternary allylic stereocenters via enantioselective iridium-catalyzed allylic alkylation. The unprecedented combination of triethylborane and a catalyst prepared from [Ir(cod)Cl]2, L5, and TBD was used to coerce reactivity from a once poorly reactive class of trisubstituted allylic electrophiles. Furthermore, the use of a single masked acyl cyanide nucleophile facilitates the one-pot syntheses of enantioenriched α-quaternary acids, esters, and amides. The protocol is tolerant of a wide range of substitution on the aryl moiety to provide the corresponding products in good yields and excellent enantioselectivities. This methodology is critical in laying the groundwork for the future development of Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 208 technology to access vicinal quaternary centers via iridium-catalyzed allylic alkylation of prochiral nucleophiles. 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. Commercially obtained reagents were used as received. Chemicals were purchased from Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Sigma Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4, or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak IC column (4.6 mm x 25 cm) or a Chiralpak AD-H column (4.6 mm x 25 cm), both obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak AD-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Preparatory HPLC was performed with an Agilent 1200 Series HPLC equipped with a Viridis SFC 2-Ethylpyridine 5 µm column (4.6 x 250 mm). 1H Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 209 NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of benzene (δ 7.36 ppm), water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as [α]DT (concentration in g/100 mL, solvent). 210 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.7.1.1 Preparation of Known Compounds Previously reported methods were used to prepare ligands (S,Sa)-L22c,15 and (Sa)- L516 as well as starting materials 67c,10b,17 72,18 75,18 76a,19 76b,20 76d,18 76e,18 76j,18 76l,18 78a,18 78d,18 and 78f18. 3.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 3.7.2.1 Representative Procedures for the Synthesis of Electrophiles 3.7.2.1.1 Representative Procedure #1: Oxidative Heck Reaction21 OMe O O H Methyl (E)-3-(4-formylphenyl)but-2-enoate (90). To a solution of (4- formylphenyl)boronic acid (0.75 g, 5.0 mmol, 1 equiv), Pd(OAc)2 (23 mg, 0.10 mmol, 0.02 equiv), dppp (62 mg, 0.15 mmol, 0.03 equiv) in acetone (8 mL) was added methyl crotonate (1.1 mL, 10.0 mmol, 2 equiv) followed by trifluoroacetic acid (0.12 mL, 1.5 mmol, 0.3 equiv). The resulting slurry was heated under reflux for 48 h, whereupon the reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (5% EtOAc/hexanes) to give carbonate 90 as a colorless oil (0.17 g, 17% yield): 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.97 – 7.78 (m, 2H), 7.74 – 7.58 (m, 2H), 6.22 (q, J = 1.3 Hz, 1H), 3.80 (s, 3H), 2.62 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 191.8, 167.0, 154.4, 148.2, 136.5, 130.1, 127.1, 119.0, 51.5, 18.1; IR (Neat Film, NaCl) 2950, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 211 2839, 1704, 1631, 1605, 1434, 1349, 1273, 1214, 1171, 1036, 828 cm-1; HRMS (FAB+) m/z calc’d for C12H13O3 [M+H]+: 205.0865, found 205.0860. 3.7.2.1.2 Representative Procedure #2: Reduction & Acylation OCO 2Me F (E)-3-(4-Fluorophenyl)but-2-en-1-yl methyl carbonate (76c). To a solution of methyl (E)-3-(4-fluorophenyl)but-2-enoate22 (0.30 g, 1.6 mmol, 1 equiv) in THF (3.1 mL) at –78 °C was added DIBAL (0.85 mL, 4.8 mmol, 3 equiv) dropwise. The resulting reaction mixture was stirred at –78 °C for 2.5 h, whereupon the reaction was quenched with a saturated aqueous Rochelle’s salt solution (5 mL). The cooling bath was then removed and the reaction was stirred for 18 h at ambient temperature. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was then dissolved in CH2Cl2 (6.4 mL) and cooled to 0 °C. Pyridine (1.1 mL, 13 mmol, 8.3 equiv) was added followed by methyl chloroformate (0.28 mL, 3.7 mmol, 2.3 equiv) dropwise. The resulting solution was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched with the addition of 1 M HCl (5 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (5% EtOAc/hexanes) to give carbonate 76c as a colorless solid (0.14 g, 38% yield): 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 2H), 7.05 – 6.96 (m, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 212 2H), 5.87 (tq, J = 7.0, 1.4 Hz, 1H), 4.84 (dd, J = 7.1, 0.8 Hz, 2H), 3.80 (s, 3H), 2.11 (dd, J = 1.4, 0.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.7, 161.3, 156.0, 140.2, 138.6 (d, J = 3.3 Hz), 127.6 (d, J = 8.0 Hz), 120.7 (d, J = 1.3 Hz), 115.4, 115.1, 65.0, 55.0, 16.5; IR (Neat Film, NaCl) 2961, 1896, 1742, 1649, 1589, 1468, 1442, 1379, 1334, 1252, 1110, 994, 960, 945, 825, 794 cm-1; HRMS (FAB+) m/z calc’d for C12H13FO3 [M]+: 224.0849, found 224.0850. 3.7.2.2 Spectroscopic Data for the Synthesis of Electrophiles OCO 2Me (Z)-methyl (3-phenylbut-2-en-1-yl) carbonate (74). Carbonate 74 was prepared from ethyl (Z)-3-phenylbut-2-enoate23 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.18 g, 49% yield): 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.18 (m, 5H), 5.76 – 5.68 (m, 1H), 4.58 (dd, J = 7.2, 1.1 Hz, 2H), 3.79 (s, 3H), 2.13 (q, J = 1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.8, 143.8, 140.3, 128.4, 127.8, 127.6, 120.5, 65.8, 54.8, 25.6; IR (Neat Film, NaCl) 3023, 2956, 1748, 1494, 1441, 1382, 1350, 1263, 1024, 944, 792, 765, 702 cm-1; HRMS (FAB+) m/z calc’d for C12H15O3 [M+H]+: 207.1021, found 207.1011. OCO 2Me MeO 2CO (E)-3-(4-(((Methoxycarbonyl)oxy)methyl)phenyl)but-2-en-1-yl methyl carbonate (76f). Carbonate 76f was prepared from 90 according to Representative Procedure #2 and Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 213 isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless solid (0.11 g, 46% yield): 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (m, 4H), 5.98 – 5.88 (m, 1H), 5.15 (s, 2H), 4.85 (dd, J = 7.0, 0.9 Hz, 2H), 3.802 (s, 3H), 3.795 (s, 3H), 2.13 – 2.10 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 156.0, 155.9, 142.8, 140.6, 134.7, 128.5, 126.3, 121.2, 69.4, 65.0, 55.1, 55.0, 16.4; IR (Neat Film, NaCl) 2959, 1754, 1443, 1385, 1333, 1288, 958, 909, 794, 731 cm-1; HRMS (FAB+) m/z calc’d for C15H18O6 [M]+: 294.1103, found 294.1098. OMe O Br Methyl (E)-3-(3-bromophenyl)but-2-enoate (91). Ester 91 was prepared from (3bromophenyl)boronic acid according to Representative Procedure #1 and isolated by silica gel flash column chromatography (3% EtOAc/hexanes) as a colorless oil (0.54 g, 42% yield): 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.59 (m, 1H), 7.51 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.31 – 7.26 (m, 1H), 6.14 (q, J = 1.3 Hz, 1H), 3.78 (d, J = 1.2 Hz, 3H), 2.57 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.1, 154.3, 144.4, 132.1, 130.2, 129.6, 125.1, 122.8, 117.9, 51.4, 18.1; IR (Neat Film, NaCl) 3062, 2948, 1719, 1631, 1558, 1435, 1346, 1274, 1191, 1168, 1037, 869, 785, 688 cm-1; HRMS (FAB+) m/z calc’d for C11H12O2Br [M+H]+: 255.0021, found 255.0020. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 214 OCO 2Me Br (E)-3-(3-Bromophenyl)but-2-en-1-yl methyl carbonate (76g). Carbonate 76g was prepared from 91 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.47 g, 78% yield): 1 H NMR (400 MHz, CDCl3) δ 7.54 (t, J = 1.8 Hz, 1H), 7.40 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.32 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.22 – 7.14 (m, 1H), 5.96 – 5.88 (m, 1H), 4.88 – 4.76 (m, 2H), 3.81 (s, 3H), 2.12 – 2.08 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 155.93, 144.65, 139.74, 130.68, 129.96, 129.18, 124.64, 122.65, 122.08, 64.84, 55.02, 16.38; IR (Neat Film, NaCl) 2955, 1748, 1590, 1558, 1442, 1376, 1332, 1263, 946, 789, 690 cm-1; HRMS (FAB+) m/z calc’d for C12H13O3Br [M]+: 284.0048, found 284.0073. OCO 2Me NO 2 (E)-Methyl (3-(3-nitrophenyl)but-2-en-1-yl) carbonate (76h). Carbonate 76h was prepared from methyl (E)-3-(3-nitrophenyl)but-2-enoate20 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) as a colorless oil (0.47 g, 78% yield): 1H NMR (400 MHz, CDCl3) δ 8.26 (t, J = 2.0 Hz, 1H), 8.14 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 7.73 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.10 – 5.91 (m, 1H), 4.88 (dt, J = 6.9, 0.8 Hz, 2H), 3.82 (s, 3H), 2.18 (dd, J = 1.4, 0.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.9, 148.5, 144.1, 138.7, 131.9, 129.4, 123.6, 122.5, 121.0, 64.7, 55.1, 16.4; IR (Neat Film, NaCl) Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 215 3108, 3026, 2969, 2868, 1750, 1530, 1443, 1384, 1353, 1279, 1096, 994, 949, 930, 876, 788, 736, 682 cm-1; HRMS (FAB+) m/z calc’d for C12H14O5N [M+H]+: 252.0872, found 252.0884. OCO 2Me (E)-methyl (3-(Naphthalen-2-yl)but-2-en-1-yl) carbonate (76i). Carbonate 76i was prepared from methyl (E)-3-(naphthalen-2-yl)but-2-enoate24 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.26 g, 51% yield): 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.77 (m, 4H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 7.52 – 7.42 (m, 2H), 6.12 – 6.05 (m, 1H), 4.92 (dq, J = 7.0, 0.7 Hz, 2H), 3.82 (s, 3H), 2.29 – 2.22 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 156.0, 140.9, 139.7, 133.4, 133.0, 128.3, 128.0, 127.7, 126.4, 126.1, 124.9, 124.3, 121.3, 65.2, 55.0, 16.5; IR (Neat Film, NaCl) 3057, 2952, 1752, 1740, 1596, 1467, 1442, 1382, 1248, 997, 941, 818, 794, 740 cm-1; HRMS (FAB+) m/z calc’d for C16H16O3 [M]+: 256.1100, found 256.1095. OCO 2Me (E)-3-(3,5-Dimethylphenyl)but-2-en-1-yl methyl carbonate (76k). Carbonate 76k was prepared from methyl (E)-3-(3,5-dimethylphenyl)but-2-enoate 25 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 216 EtOAc/hexanes) as a colorless oil (0.32 g, 86% yield): 1H NMR (400 MHz, CDCl3) δ 7.02 (dt, J = 1.6, 0.8 Hz, 2H), 6.93 (td, J = 1.6, 0.8 Hz, 1H), 5.96 – 5.82 (m, 1H), 4.84 (dd, J = 7.0, 0.8 Hz, 2H), 3.80 (s, 3H), 2.31 (d, J = 0.7 Hz, 6H), 2.15 – 2.06 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 156.0, 142.6, 141.5, 137.9, 129.4, 123.9, 120.4, 65.1, 54.9, 21.5, 16.5; IR (Neat Film, NaCl) 2956, 2918, 2862, 1748, 1601, 1443, 1376, 1335, 1262, 944, 905, 849, 792, 699 cm-1; HRMS (FAB+) m/z calc’d for C14H18O3 [M]+: 234.1256, found 234.1252. OCO 2Me (E)-Methyl (3-phenylhept-2-en-1-yl) carbonate (78b). Carbonate 78b was prepared from ethyl (E)-3-phenylhept-2-enoate 26 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.31 g, 58% yield): 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.27 (m, 5H), 5.89 – 5.71 (m, 1H), 4.84 (d, J = 7.0 Hz, 2H), 3.80 (s, 3H), 2.73 – 2.46 (m, 2H), 1.41 – 1.24 (m, 4H), 1.06 – 0.73 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 156.0, 146.6, 142.0, 128.4, 127.6, 126.6, 121.1, 65.0, 55.0, 31.2, 30.2, 22.7, 14.0; IR (Neat Film, NaCl) 3034, 2957, 2872, 1748, 1644, 1599, 1493, 1444, 1378, 1344, 1262, 1129, 941, 792, 766, 698 cm-1; HRMS (FAB+) m/z calc’d for C15H20O3 [M]+: 248.1412, found 248.1424. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 217 OCO 2Me (E)-Methyl (4-methyl-3-phenylpent-2-en-1-yl) carbonate (78c). Carbonate 78c was prepared from ethyl (E)-4-methyl-3-phenylpent-2-enoate 27 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.17 g, 17% yield): 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 3H), 7.11 – 7.02 (m, 2H), 5.61 (td, J = 7.0, 1.3 Hz, 1H), 4.46 (dd, J = 7.0, 0.8 Hz, 2H), 3.75 (s, 3H), 2.66 – 2.54 (m, 1H), 1.03 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 155.8, 154.0, 139.7, 128.5, 128.2, 127.3, 117.8, 66.1, 54.8, 36.0, 21.5; IR (Neat Film, NaCl) 2961, 2872, 1749, 1492, 1442, 1263, 942, 792, 771, 703 cm-1; HRMS (FAB+) m/z calc’d for C14H19O3 [M+H]+: 235.1334, found 235.1344. OCO 2Me (E)-3-(Cyclohex-1-en-1-yl)but-2-en-1-yl methyl carbonate (78e). Carbonate 78e was prepared from ethyl (E)-3-(cyclohex-1-en-1-yl)but-2-enoate 28 according to Representative Procedure #2 and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.25 g, 73% yield): 1H NMR (400 MHz, CDCl3) δ 6.00 – 5.92 (m, 1H), 5.68 – 5.55 (m, 1H), 4.79 (d, J = 7.0 Hz, 2H), 3.78 (s, 3H), 2.16 (ddd, J = 12.0, 5.9, 3.7 Hz, 4H), 1.85 (d, J = 1.1 Hz, 3H), 1.73 – 1.49 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 156.0, 141.2, 137.0, 126.0, 116.8, 65.5, 54.9, 26.1, 25.8, 23.0, 22.3, 14.1; IR (Neat Film, NaCl) 2929, 2859, 1749, 1638, 1443, 1263, 1119, 940, 792 cm-1; HRMS (FAB+) m/z calc’d for C12H18O3 [M]+: 210.1256, found 210.1252. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.7.2.3 218 General Procedure for Optimization Reactions (Table 3.1) NC OMOM NC (S)-2-(Methoxymethoxy)-2-(2-phenylbut-3-en-2-yl)malononitrile (73). In a nitrogenfilled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (1.3 mg, 0.0020 mmol, 2 mol %), ligand (Sa)-L5 (2.5 mg, 0.0042 mmol, 4.2 mol %), TBD (1.4 mg, 0.010 mmol, 10 mol %), and THF (0.5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with MAC nucleophile 67c (0.10 mmol or 0.20 mmol, as specified), THF (0.5 mL), and the Lewis acid additive (200 mol %). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 72 (0.20 mmol, 0.10 mmol, or 0.12 mmol, as specified). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc. The crude mixture was concentrated and 1,2,4,5-tetrachloro-3-nitrobenzene (0.10 mmol in 0.5 mL CDCl3) was added. The NMR yield (measured in reference to 1,2,4,5-tetrachloro-3-nitrobenzene δ 7.74 ppm (s, 1H)) was determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (15% EtOAc/hexanes) to afford MAC adduct product 73 as a colorless oil. For the purposes of characterization, product 73 was further purified by preparatory HPLC (20% EtOAc/hexanes, Viridis SFC 2-Ethylpyridine 5 µm column, flow rate = 1.5 mL/min; λ = 230 nm): 94% ee (entry 9); [α]D25 +11.7 (c 0.07, CHCl3) (entry 9); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.54 (m, 2H), 7.42 – 7.32 (m, 3H), 6.51 (dd, J = 17.4, 11.0 Hz, 1H), 5.59 – 5.34 (m, 2H), 5.02 (s, 2H), 3.42 (s, 3H), 1.84 (s, 3H); Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 13 219 C NMR (101 MHz, CDCl3) δ 138.3, 137.6, 129.0, 128.57, 238.55, 128.3, 125.2, 119.2, 112.8, 112.7, 96.7, 73.9, 57.5, 52.8, 20.9; IR (Neat Film, NaCl) 3062, 2957, 2896, 2242, 2189, 1750, 1492, 1445, 1358, 1268, 1161, 1108, 1030, 930, 751, 698 cm-1; HRMS (ESI+) m/z calc’d for C15H17N2O2 [M+H]+: 257.1290, found 257.1313; HPLC conditions: 1% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 13.303, minor = 17.243. 3.7.2.4 General Procedure for the Enantioenriched Carboxylic Acid Synthesis Please note that the absolute configuration was determined only for compound 77h via x-ray crystallographic analysis. The absolute configuration for all other products has been inferred by analogy. For respective HPLC and SFC conditions, please refer to Table 3.6. O HO (S)-2-Methyl-2-phenylbut-3-enoic acid (77a). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (Sa)-L5 (4.9 mg, 0.0084 mmol, 4.2 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with MAC nucleophile 67c (25 mg, 0.20 mmol, 100 mol %), THF (1 mL), and BEt3 (400 µL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 72 (83 mg, 0.40 mmol, 200 mol %). The vial was sealed and stirred at 60 °C. After 18 h or 48 h, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 220 the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated. The crude material was heated at 80 °C in 6M HCl (4 mL) for 18 h. Whereupon, the reaction mixture was cooled to 0 °C and basified with 6M NaOH (4.5 mL). The aqueous layer was extracted with CH2Cl2 (4 x 8 mL). The combined organic layers were washed with 2M NaOH (8 mL). The combined aqueous layers were acidified with concentrated HCl, extracted with CH2Cl2 (4 x 8 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C to give the product 77a as a colorless solid (27 mg, 77% yield): 95% ee; [α]D25 +13.5 (c 1.3, CHCl3); HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 12.198, minor = 11.426. Characterization data match those reported in the literature.29 Please note Compounds 77i, 77j, 77k, and 79a–g were prepared at the same concentration with double catalyst loadings. 3.7.2.5 Spectroscopic Data for the Enantioenriched Carboxylic Acids O HO Cl (S)-2-(4-Chlorophenyl)-2-methylbut-3-enoic acid (77b). Product 77b was prepared according to the general procedure to give a pale yellow oil (33 mg, 80% yield): 93% ee; [α]D25 +8.1 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.24 (m, 4H), 6.38 (dd, J = 17.5, 10.7 Hz, 1H), 5.44 – 5.16 (m, 2H), 1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.4, 141.1, 140.1, 133.3, 128.7, 128.3, 116.1, 53.3, 23.3; IR (Neat Film, NaCl) 3089, 2987, 2645, 2539, 1705, 1493, 1400, 1282, 1097, 1014, 928, 826, 755 cm-1; HRMS Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 221 (FAB+) m/z calc’d for C11H12O2Cl [M+H]+: 211.0526, found 211.0528; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 15.642, minor = 14.104. O HO F (S)-2-(4-Fluorophenyl)-2-methylbut-3-enoic acid (77c). Product 77c was prepared according to the general procedure to give a pale yellow oil (35 mg, 90% yield): 90% ee; [α]D25 +3.4 (c 1.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.19 (m, 2H), 7.05 (t, J = 8.7 Hz, 2H), 6.39 (dd, J = 17.5, 10.7 Hz, 1H), 5.42 – 5.14 (m, 2H), 1.67 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.6, 163.2, 160.7, 140.4, 138.3 (d, J = 3.4 Hz), 128.5 (d, J = 8.1 Hz), 115.9, 115.5, 115.3, 53.2, 23.5; IR (Neat Film, NaCl) 3088, 2987, 2924, 2642, 1704, 1603, 1510, 1462, 1412, 1277, 1234, 1165, 928, 833, 816, 735 cm-1; HRMS (FAB+) m/z calc’d for C11H12FO2 [M+H]+: 195.0833, found 195.0841; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 15.499, minor = 13.811. O HO F 3C (S)-2-Methyl-2-(4-(trifluoromethyl)phenyl)but-3-enoic acid (77d). Product 77d was prepared according to the general procedure to give a pale yellow oil (41 mg, 83% yield): Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 222 92% ee; [α]D25 –2.2 (c 2.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.60 (dt, J = 8.1, 0.8 Hz, 2H), 7.45 (dt, J = 8.3, 0.8 Hz, 2H), 6.38 (dd, J = 17.5, 10.7 Hz, 1H), 5.48 – 5.09 (m, 2H), 1.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 179.0, 146.6, 139.7, 129.6, 130.0, 129.5, 127.2, 125.6 (q, J = 3.7 Hz), 122.8, 116.6, 53.7, 29.9, 23.4; IR (Neat Film, NaCl) 2926, 2649, 1707, 1618, 1413, 1328, 1277, 1167, 1126, 1081, 1016, 930, 940 cm-1; HRMS (FAB+) m/z calc’d for C12H12O2F3 [M+H]+: 245.0789, found 245.0794; SFC conditions: 2% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 13.592, minor = 15.745. O HO (S)-2-Methyl-2-(p-tolyl)but-3-enoic acid (77e). Product 77e was prepared according to the general procedure to give a pale yellow oil (24 mg, 63% yield): 94% ee; [α]D25 +4.6 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.01 (m, 4H), 6.40 (dd, J = 17.5, 10.7 Hz, 1H), 5.59 – 5.08 (m, 2H), 2.34 (s, 3H), 1.64 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 181.0, 140.7, 139.8, 137.0, 129.3, 126.6, 115.4, 53.3, 23.3, 21.1; IR (Neat Film, NaCl) 2986, 1702, 1636, 1512, 1457, 1412, 1276, 1191, 1132, 1077, 1020, 925, 815, 730 cm-1; HRMS (ESI-) m/z calc’d for C12H13O2 [M-H]-: 189.0916, found 189.0903; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 15.393, minor = 14.288. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 223 O HO OH (S)-2-(4-(Hydroxymethyl)phenyl)-2-methylbut-3-enoic acid (77f). Product 77f was prepared according to the general procedure and isolated by preparatory TLC (30% acetone/hexanes) to give a colorless soild (21 mg, 51% yield): 95% ee; [α]D25 +3.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.33 (q, J = 8.2 Hz, 4H), 6.37 (dd, J = 17.5, 10.7 Hz, 1H), 5.39 – 5.10 (m, 2H), 4.57 (s, 2H), 1.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.1, 143.2, 140.4, 136.4, 128.8, 127.2, 115.8, 53.6, 45.9, 23.4; IR (Neat Film, NaCl) 2985, 2927, 2642, 1703, 1636, 1512, 1460, 1268, 1182, 1076, 926, 836, 731, 683 cm-1; HRMS (FAB+) m/z calc’d for C12H15O3 [M+H]+: 207.1021, found 207.1025; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 15.258, minor = 14.667. O HO Br (S)-2-(3-Bromophenyl)-2-methylbut-3-enoic acid (77g). Product 77g was prepared according to the general procedure to give a pale yellow oil (35 mg, 69% yield): 92% ee; [α]D25 –2.6 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 1.9 Hz, 1H), 7.41 (ddd, J = 7.6, 1.9, 1.2 Hz, 1H), 7.29 – 7.18 (m, 2H), 6.35 (dd, J = 17.5, 10.7 Hz, 1H), 5.42 – 5.09 (m, 2H), 1.65 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 179.7, 145.0, 139.8, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 224 130.5, 130.2, 129.9, 125.5, 122.8, 116.4, 53.5, 23.3; IR (Neat Film, NaCl) 2987, 2644, 1705, 1593, 1566, 1475, 1413, 1280, 1129, 1070, 997, 928, 785, 760, 700 cm-1; HRMS (ESI-) m/z calc’d for C11H10O2Br [M-H]-: 252.9864, found 252.9864; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 15.217, minor = 14.439. O HO NO 2 (S)-2-Methyl-2-(3-nitrophenyl)but-3-enoic acid (77h). Product 77h was prepared according to the general procedure to give a colorless solid (41 mg, 93% yield): 87% ee; [α]D25 +94.5 (c 3.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.22 (t, J = 2.0 Hz, 1H), 8.15 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.69 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 6.38 (dd, J = 17.5, 10.7 Hz, 1H), 5.59 – 5.11 (m, 2H), 1.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 179.6, 148.5, 144.7, 139.2, 133.3, 129.6, 122.5, 122.1, 117.2, 53.7, 23.4; IR (Neat Film, NaCl) 3089, 2988, 2924, 2641, 1707, 1530, 1351, 1276, 1106, 929, 808, 738, 688 cm-1; HRMS (FAB+) m/z calc’d for C11H12O4N [M+H]+: 222.0766, found 222.0769; HPLC conditions: 3% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 24.060, minor = 20.907. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 225 O HO (S)-2-Methyl-2-(naphthalen-2-yl)but-3-enoic acid (77i). Product 77i was prepared according to the general procedure to give a pale yellow oil (30 mg, 66% yield): 92% ee; [α]D25 +7.8 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.72 (m, 4H), 7.55 – 7.39 (m, 3H), 6.52 (dd, J = 17.5, 10.7 Hz, 1H), 5.57 – 5.11 (m, 2H), 1.77 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.9, 140.5, 140.0, 133.3, 132.5, 128.3, 128.2, 127.6, 126.3, 126.2, 125.3, 125.2, 116.0, 53.9, 23.4; IR (Neat Film, NaCl) 3057, 2984, 1701, 1506, 1458, 1411, 1274, 1182, 1128, 1102, 925, 856, 816, 747 cm-1; HRMS (FAB+) m/z calc’d for C15H14O2 [M]+: 226.0994, found 226.0992; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 28.272, minor = 24.870. O HO (S)-2-Methyl-2-(m-tolyl)but-3-enoic acid (77j). Product 77j was prepared according to the general procedure to give a pale yellow oil (26 mg, 68% yield): 93% ee; [α]D25 +5.2 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.04 (m, 4H), 6.40 (dd, J = 17.5, 10.7 Hz, 1H), 5.45 – 5.08 (m, 2H), 2.44 – 2.20 (m, 3H), 1.65 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.2, 142.7, 140.6, 138.3, 128.5, 128.1, 127.3, 123.7, 115.6, 53.6, 23.3, 21.7; IR (Neat Film, NaCl) 2984, 2923, 2648, 1703, 1606, 1459, 1411, 1275, 1178, 1127, 1002, 926, 785, 703 cm-1; HRMS (FAB+) m/z calc’d for C12H15O2 [M+H]+: 191.1072, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 226 found 191.1074; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 13.800, minor = 12.388. O HO (S)-2-(3,5-Dimethylphenyl)-2-methylbut-3-enoic acid (77k). Product 77k was prepared according to the general procedure and isolated by preparatory TLC (30% acetone/hexanes) to give a colorless oil (13 mg, 32% yield): 85% ee; [α]D25 –40.6 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 8.5 Hz, 3H), 6.42 (dd, J = 17.4, 10.6 Hz, 1H), 5.45 – 5.08 (m, 2H), 2.33 (s, 6H), 1.65 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.5, 142.8, 140.8, 138.1, 129.0, 124.4, 115.3, 53.6, 23.3, 21.6; IR (Neat Film, NaCl) 2983, 2919, 2639, 1700, 1602, 1411, 1279, 1125, 923, 848, 708 cm-1; HRMS (FAB+) m/z calc’d for C13H17O2 [M+H]+: 205.1229, found 205.1233; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 11.107, minor = 10.064. Please note an HMBC has been included due to the low intensity of the carbonyl 13 C shift at δ 180.5. O HO Et (S)-2-Ethyl-2-phenylbut-3-enoic acid (79a). Product 79a was prepared according to the general procedure and isolated by preparatory TLC (30% acetone/hexanes) to give a Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 227 colorless oil (23 mg, 61% yield): 92% ee; [α]D25 +17.4 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.22 (m, 5H), 6.36 (dd, J = 17.7, 10.9 Hz, 1H), 5.35 (d, J = 10.7 Hz, 1H), 5.09 (d, J = 17.6 Hz, 1H), 2.36 – 2.00 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 180.1, 141.3, 139.1, 128.4, 127.6, 127.2, 116.9, 58.0, 29.4, 9.4; IR (Neat Film, NaCl) 3060, 2970, 2928, 2636, 1702, 1495, 1448, 1407, 1381, 1261, 1083, 924, 761, 700 cm-1; HRMS (FAB+) m/z calc’d for C12H15O2 [M+H]+: 191.1072, found 191.1071; HPLC conditions: 1.5% IPA, 1.0 mL/min, two Chiralpak AD-H columns in series, λ = 210 nm, tR (min): major = 46.253, minor = 47.271. O HO n-Bu (S)-2-Phenyl-2-vinylhexanoic acid (79b). Product 79b was prepared according to the general procedure and isolated by preparatory TLC (30% acetone/hexanes) to give a colorless oil (6 mg, 14% yield): 95% ee; [α]D25 –106.0 (c 0.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.29 (m, 5H), 6.38 (dd, J = 17.6, 10.9 Hz, 1H), 5.32 (dd, J = 10.9, 0.9 Hz, 1H), 5.06 (dd, J = 17.6, 0.9 Hz, 1H), 2.28 – 1.98 (m, 2H), 1.44 – 1.14 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.4, 141.6, 139.7, 128.4, 127.5, 127.1, 116.6, 57.5, 36.5, 27.0, 23.4, 14.1; IR (Neat Film, NaCl) 2956, 2920, 2851, 1734, 1706, 1466, 1378, 1260, 1098, 925, 800, 722, 700 cm-1; HRMS (FAB+) m/z calc’d for C14H19O2 [M+H]+: 219.1385, found 219.1291; SFC conditions: 5% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 10.646, minor = 11.952. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 228 O HO Ph (R)-2-Methyl-2-phenethylbut-3-enoic acid (79f). Product 79f was prepared according to the general procedure and isolated by preparatory TLC (33% acetone/hexanes) to give a colorless oil (13 mg, 32% yield): 3% ee; [α]D25 –12.1 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.04 (m, 5H), 6.10 (dd, J = 17.6, 10.7 Hz, 1H), 5.21 (dd, J = 14.0, 3.3 Hz, 2H), 2.60 (dt, J = 11.0, 4.9 Hz, 2H), 2.33 – 1.79 (m, 2H), 1.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 182.0, 142.0, 140.9, 128.54, 128.49, 126.1, 114.7, 48.7, 41.1, 31.2, 20.7; IR (Neat Film, NaCl) 3026, 2927, 1702, 1496, 1454, 1380, 1264, 1097, 925, 748, 700 cm-1; HRMS (FAB+) m/z calc’d for C13H17O2 [M+H]+: 267.1385, found 267.1376; HPLC conditions: 2% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 18.485, minor = 14.652. Please note an HMBC has been included due to the low intensity of the carbonyl 13C shift at δ 182.0. O HO 2,2-Dimethylbut-3-enoic acid (79g). Product 79g was prepared according to the general procedure to give a colorless oil (15 mg, 63% yield). Characterization data match those reported in the literature.30 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.7.2.6 229 Experimental Procedures and Spectroscopic Data for the One-pot Syntheses of Carboxylic Acid Derivatives O MeO Cl Methyl (S)-2-(4-chlorophenyl)-2-methylbut-3-enoate (82). In a nitrogen-filled glove box, to a scintillation vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (13 mg, 0.02 mmol, 2 mol %), ligand (Sa)-L5 (25 mg, 0.042 mmol, 4.2 mol %), TBD (14 mg, 0.10 mmol, 10 mol %), and THF (5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another scintillation vial (vial B) was charged with MAC nucleophile 67c (126 mg, 1.0 mmol, 100 mol %), THF (5 mL), and BEt3 (2.0 mL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 76b (480 mg, 2.0 mmol, 200 mol %). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box and the reaction mixture was concentrated under reduced pressure. To the vial of crude MAC adduct equipped with a stir bar and septum cap was added 1:1 AcOH/DME (2 mL, 0.5 M) and CSA (0.26 g, 1.1 mmol, 1.1 equiv) under a nitrogen atmosphere. The reaction was heated to 60 °C for 6 h, whereupon the reaction mixture was cooled to ambient temperature, diluted with anhydrous MeOH (2.8 mL), and cooled to –40 °C. A solution of 1:1 MeOH/Et3N (5.6 mL, 20.1 equiv of Et3N) was added dropwise over 10 min. The reaction mixture was allowed to warm to ambient temperature over 18 h, whereupon the reaction was slowly quenched with saturated NH4Cl aqueous solution (5 mL). The aqueous layer was then extracted with CH2Cl2 (3 x 10 mL) and the Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 230 combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give methyl ester 82 as a colorless oil (0.20 g, 88% yield): [α]D25 +1.5 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 – 6.99 (m, 4H), 6.35 (dd, J = 17.5, 10.7 Hz, 1H), 5.48 – 5.00 (m, 2H), 3.70 (s, 3H), 1.62 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.0, 142.0, 140.6, 132.9, 128.7, 128.1, 115.6, 53.5, 52.7, 23.7; IR (Neat Film, NaCl) 2986, 2952, 1734, 1637, 1493, 1459, 1246, 1181, 1123, 1098, 1014, 926, 828, 757 cm-1; HRMS (FAB+) m/z calc’d for C12H13ClO2 [M+]+: 224.0604, found 224.0621. O O Cl Allyl (S)-2-(4-chlorophenyl)-2-methylbut-3-enoate (83). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (Sa)-L5 (4.9 mg, 0.0084 mmol, 4.2 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with MAC nucleophile 67c (25 mg, 0.20 mmol, 100 mol %), THF (1 mL), and BEt3 (400 µL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 76b (96 mg, 0.40 mmol, 200 mol %). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 231 To the vial of crude MAC adduct equipped with a stir bar and septum cap was added 1:1 AcOH/DME (0.4 mL, 0.5 M) and CSA (51 mg, 0.22 mmol, 1.1 equiv) under a nitrogen atmosphere. The reaction was heated to 60 °C for 6 h, whereupon the reaction mixture was cooled to ambient temperature, diluted with allyl alcohol (0.4 mL), and cooled to 0 °C. A solution of 1:1 Et3N/allyl alcohol (1.1 mL, 20.4 equiv of Et3N) was added dropwise over 10 min. The reaction mixture was allowed to warm to ambient temperature over 18 h, whereupon the reaction was slowly quenched with saturated NH4Cl aqueous solution (5 mL). The aqueous layer was then extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C. The crude residue was purified by preparatory TLC (8% EtOAc/hexanes) to give allyl ester 83 as a colorless oil (37 mg, 74% yield): [α]D25 +0.4 (c 2.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.12 (m, 4H), 6.36 (dd, J = 17.5, 10.7 Hz, 1H), 5.85 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.38 – 5.02 (m, 4H), 4.61 (dt, J = 5.6, 1.4 Hz, 2H), 1.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 174.1, 142.0, 140.6, 132.9, 131.9, 128.6, 128.1, 118.5, 115.6, 65.9, 53.5, 23.6; IR (Neat Film, NaCl) 3089, 2985, 2930, 2857, 1900, 1734, 1638, 1493, 1236, 1177, 1122, 1097, 1014, 926, 828, 756 cm-1; HRMS (FAB+) m/z calc’d for C14H16O2Cl [M+H]+: 251.0839, found 251.0842. 232 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation O N Cl (S)-2-(4-Chlorophenyl)-2-methyl-1-(pyrrolidin-1-yl)but-3-en-1-one (84). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (Sa)-L5 (4.9 mg, 0.0084 mmol, 4.2 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with MAC nucleophile 67c (25 mg, 0.20 mmol, 100 mol %), THF (1 mL), and BEt3 (400 µL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 76b (96 mg, 0.40 mmol, 200 mol %). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated. To the vial of crude MAC adduct equipped with a stir bar and septum cap was added 1:1 AcOH/DME (0.4 mL, 0.5 M) and CSA (51 mg, 0.22 mmol, 1.1 equiv) under a nitrogen atmosphere. The reaction was heated to 60 °C for 6 h, whereupon the reaction mixture was cooled to ambient temperature, diluted with CH2Cl2 (0.4 mL), and cooled to –40 °C. A solution of 1:1 pyrrolidine/CH2Cl2 (0.67 mL, 20.4 equiv of pyrrolidine) was added dropwise over 10 min then Et3N (0.57 mL, 4.1 mmol, 20.4 equiv). The reaction mixture was allowed to warm to ambient temperature over 18 h, whereupon the reaction was slowly quenched with saturated NH4Cl aqueous solution (5 mL). The aqueous layer was then extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 233 at 0 °C. The crude residue was purified by preparatory TLC (30% acetone/hexanes) to give amide 84 as a colorless oil (32 mg, 61% yield): [α]D25 –49.5 (c 1.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 2H), 7.21 – 7.14 (m, 2H), 6.45 (dd, J = 17.4, 10.7 Hz, 1H), 5.27 (dd, J = 10.7, 0.8 Hz, 1H), 5.10 (dd, J = 17.4, 0.8 Hz, 1H), 3.63 – 3.47 (m, 2H), 2.98 (dt, J = 10.6, 6.3 Hz, 1H), 2.52 (dt, J = 10.6, 6.7 Hz, 1H), 1.78 – 1.62 (m, 2H), 1.64 – 1.55 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 172.1, 143.2, 139.7, 132.5, 129.0, 127.6, 115.5, 54.3, 47.52, 47.44, 28.4, 26.5, 23.5; IR (Neat Film, NaCl) 2928, 2873, 1742, 1627, 1491, 1396, 1228, 1185, 1096, 1012, 921, 829, 723 cm-1; HRMS (FAB+) m/z calc’d for C15H19ClNO [M+H]+: 264.1155, found 264.1154. O N H Cl (S)-N-allyl-2-(4-chlorophenyl)-2-methylbut-3-enamide (85). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (Sa)-L5 (4.9 mg, 0.0084 mmol, 4.2 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with MAC nucleophile 67c (25 mg, 0.20 mmol, 100 mol %), THF (1 mL), and BEt3 (400 µL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 76b (96 mg, 0.40 mmol, 200 mol %). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 234 To the vial of crude MAC adduct equipped with a stir bar and septum cap was added 1:1 AcOH/DME (0.4 mL, 0.5 M) and CSA (51 mg, 0.22 mmol, 1.1 equiv) under a nitrogen atmosphere. The reaction was heated to 60 °C for 6 h, whereupon the reaction mixture was cooled to ambient temperature, diluted with allyl amine (0.4 mL), and cooled to 0 °C. A solution of 1:1 Et3N/allyl amine (1.1 mL, 20.4 equiv of Et3N) was added dropwise over 10 min. The reaction mixture was allowed to warm to ambient temperature over 18 h, whereupon the reaction was slowly quenched with saturated NH4Cl aqueous solution (5 mL). The aqueous layer was then extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C. The crude residue was purified by preparatory TLC (30% EtOAc/hexanes) to give allyl amide 85 as a colorless oil (31 mg, 63% yield): [α]D25 +10.2 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.17 (m, 4H), 6.29 (dd, J = 17.4, 10.6 Hz, 1H), 5.90 – 5.75 (m, 1H), 5.64 (s, 1H), 5.33 (dd, J = 10.6, 0.8 Hz, 1H), 5.20 – 5.03 (m, 3H), 3.96 – 3.82 (m, 2H), 1.67 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 174.1, 142.0, 141.8, 134.1, 133.1, 128.9, 128.8, 116.6, 116.5, 54.3, 42.3, 24.6; IR (Neat Film, NaCl) 3341, 3085, 2983, 2931, 1739, 1658, 1520, 1493, 1414, 1270, 1096, 1014, 922, 827, 725, 657 cm-1; HRMS (FAB+) m/z calc’d for C14H17NOCl [M+H]+: 250.0999, found 250.0991. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.7.2.7 235 Experimental Procedures and Spectroscopic Data for the Product Transformations of α-Quaternary Ester 82 O MeO Cl Methyl (S)-2-(4-chlorophenyl)-2-methylbutanoate (86). To a solution of olefin 82 (13 mg, 0.056 mmol, 1 equiv) in EtOAc (1 mL) was added Pd/C (2.5 mg, 20% w/w). The reaction mixture was sparged with a hydrogen gas (balloon) for 5 minutes and then stirred under a hydrogen atmosphere for 18 h, whereupon the reaction was filtered through celite with EtOAc (5 mL) and concentrated under reduced pressure at 0 °C to give alkyl 86 as a colorless oil (12 mg, 97% yield): [α]D25 +3.6 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.15 (m, 4H), 3.67 (s, 3H), 2.31 – 1.80 (m, 2H), 1.53 (s, 3H), 0.83 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.5, 142.4, 132.6, 128.6, 127.7, 52.3, 50.4, 32.0, 22.2, 9.2; IR (Neat Film, NaCl) 2970, 2880, 1731, 1493, 1457, 1383, 1307, 1238, 1147, 1096, 1012, 824, 756, 720 cm-1; HRMS (FAB+) m/z calc’d for C12H16O2Cl [M+H]+: 227.0839, found 227.0840. HO Cl (S)-2-(4-Chlorophenyl)-2-methylbut-3-en-1-ol (87). DIBAL (0.029 mL, 0.16 mmol, 3 equiv) was added dropwise to a solution of methyl ester 82 (13 mg, 0.056 mmol, 1 equiv) in Et2O (1.0 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h, whereupon the reaction was quenched with a saturated Rochelle’s salt aqueous solution (1 mL) and stirred for 18 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 236 h at ambient temperature. The aqueous layer was then extracted with CH2Cl2 (3 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C. The crude residue was purified by preparatory TLC (25% acetone/hexanes) to give alcohol 87 as a colorless oil (8 mg, 73% yield): [α]D25 +11.0 (c 0.4, CHCl3). Characterization data match those reported in the literature.31 O O Cl OH (3S)-3-(4-Chlorophenyl)-4-hydroxy-3-methyldihydrofuran-2(3H)-one (88). To a solution of olefin 82 (24 mg, 0.10 mmol, 1 equiv) in THF/H2O (4:1, 1 mL) was added K2OsO4 (4.0 mg, 0.010 mmol, 0.1 equiv) and N-methylmorpholine N-oxide (19 mg, 0.16 mmol, 1.6 equiv). The reaction mixture was stirred for 18 h, whereupon the reaction was quenched with sodium sulfite (10 mg, 0.079 mmol, 0.79 equiv) and diluted with water (0.5 mL). The aqueous layer was then extracted with EtOAc (3 x 5 mL) and the combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure at 0 °C. The crude residue was purified by preparatory TLC (30% acetone/hexanes) to give lactone 88 as a colorless oil (19 mg, 82% yield, 1:1 dr): [α]D25 –115.6 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.26 (m, 4H), 4.58 (dd, J = 4.4, 2.8 Hz, 0.5H), 4.54 (dd, J = 10.2, 4.5 Hz, 0.5H), 4.35 – 4.31 (m, 0.5H), 4.28 – 4.20 (m, 1H), 4.16 (dd, J = 10.1, 2.8 Hz, 0.5H), 1.66 (s, 1.5H), 1.57 (s, 1.5H); 13C NMR (101 MHz, CDCl3) δ 178.4, 178.1, 138.4, 134.4, 134.0, 133.9, 129.6, 129.4, 129.3, 127.8, 76.5, 76.2, 71.8, 71.6, 53.2, 52.8, 22.3, 18.5; IR (Neat Film, Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 237 NaCl) 3448, 2976, 2929, 1761, 1496, 1384, 1218, 1178, 1096, 1072, 1014, 982, 927, 737, 688 cm-1; HRMS (FAB+) m/z calc’d for C11H12O3Cl [M+H]+: 227.0475, found 227.0481. O MeO O H Cl Methyl (R)-2-(4-chlorophenyl)-2-methyl-3-oxopropanoate (89). A solution of olefin 82 (10 mg, 0.045 mmol, 1 equiv) and NaHCO3 (1.0 mg, 0.011 mmol, 0.25 equiv) in MeOH/ CH2Cl2 (1:5, 2.6 mL) was cooled to –78 °C. Ozone was bubbled through the reaction mixture for 0.5 h, whereupon the reaction mixture was sparged with N2 and dimethyl sulfide (0.10 mL, 0.14 mmol, 3 equiv) was added. The cooling bath was then removed and the reaction was stirred for 18 h at ambient temperature. The reaction mixture was concentrated under reduced pressure at 0 °C and the crude residue was purified by preparatory TLC (17% Et2O/hexanes) to afford aldehyde 89 as a colorless oil (5.0 mg, 50% yield): [α]D25 +9.1 (c 0.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.41 – 7.33 (m, 2H), 7.22 – 7.13 (m, 2H), 3.81 (s, 3H), 1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 196.2, 171.8, 134.8, 134.5, 129.5, 128.5, 61.7, 53.1, 18.0; IR (Neat Film, NaCl) 2992, 2954, 2845, 2726, 1721, 1596, 1494, 1455, 1252, 1122, 1096, 1013, 911, 823, 758, 718 cm-1; HRMS (FAB+) m/z calc’d for C11H12ClO3 [M+H]+: 227.0475, found 227.0479. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 3.7.2.8 Determination of Enantiomeric Excess Please note racemic products were synthesized using racemic L5. Table 3.6 Determination of enantiomeric excess 238 239 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 15.258 14.667 95% HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 15.217 14.439 92% HPLC Chiralpak AD–H 3% IPA isocratic, 1 mL/min 24.060 20.907 87% HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 28.272 24.870 92% HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 13.800 12.388 93% HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 11.107 10.064 85% HPLC two Chiralpak AD–H in series 1.5% IPA isocratic, 1 mL/min 46.253 47.271 92% O HO 7 OH O HO 8 Br O HO 9 NO 2 O HO 10 O HO 11 O HO 12 O 13 HO Et 240 Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee SFC Chiralpak AD–H 5% IPA isocratic, 2.5 mL/min 10.646 11.952 95% HPLC Chiralpak AD–H 2% IPA isocratic, 1 mL/min 18.485 14.652 3% O 14 HO n-Bu O 15 HO Ph 3.8 REFERENCES AND NOTES (1) Janssen, J. 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Lett. 2005, 7, 1255–1258; (b) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 15604–15605; (c) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2010, 49, 8370–8374; (d) Hojoh, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2017, 139, 2184–2187. (9) (a) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298– 17301; (b) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626–10629; (c) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.; Stoltz, B. M. J. Am. Chem. Soc. 2016, 138, 5234–5237; (d) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem. Int. Ed. 2016, 55, 16092–16095; (e) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Org. Lett. 2017, 19, 1527–1529. (10) (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990, 55, 4515–4516; (b) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050–16053. (11) (a) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 8136–8147; (b) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 14968–14981. Chapter 3 – Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 243 (12) One report of a trisubstituted allylic electrophile in an enantioselective iridiumcatalyzed allylic alkylation had been disclosed, but the products bear a tertiary allylic stereocenter: Chen, M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55, 11651–11655. (13) To the best of our knowledge, only one report of a borane additive (Ph3B) in iridium-catalyzed allylic alkylation reactions had been disclosed: Yamashita, Y.; Gopalarathnam, A.; Hartwig J. F. J. Am. Chem. Soc. 2007, 129, 7508–7509. (14) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603– 3606. (15) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076–2082. (16) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Org. 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Appendix 4 – Spectra Relevant to Chapter 3 245 APPENDIX 4 Spectra Relevant to Chapter 3: Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.1 1H NMR (400 MHz, CDCl3) of compound 73 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 246 Appendix 4 – Spectra Relevant to Chapter 3 247 Figure A4.2 Infrared spectrum (Thin Film, NaCl) of compound 73 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A4.3 13C NMR (101 MHz, CDCl3) of compound 73 20 10 0 -10 10 9 8 7 5 ppm 4 3 Figure A4.4 1H NMR (400 MHz, CDCl3) of compound 74 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 248 Appendix 4 – Spectra Relevant to Chapter 3 249 Figure A4.5 Infrared spectrum (Thin Film, NaCl) of compound 74 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.6 13C NMR (101 MHz, CDCl3) of compound 74 0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A4.7 1H NMR (400 MHz, CDCl3) of compound 76c 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 250 Appendix 4 – Spectra Relevant to Chapter 3 251 Figure A4.8 Infrared spectrum (Thin Film, NaCl) of compound 76c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.9 13C NMR (101 MHz, CDCl3) of compound 76c 10 0 -10 10 9 8 6 5 ppm 4 3 Figure A4.10 1H NMR (400 MHz, CDCl3) of compound 76f 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 252 Appendix 4 – Spectra Relevant to Chapter 3 253 Figure A4.11 Infrared spectrum (Thin Film, NaCl) of compound 76f 200 180 160 140 120 100 ppm 80 60 40 Figure A4.12 13C NMR (101 MHz, CDCl3) of compound 76f 20 0 10 9 8 6 5 ppm 4 3 Figure A4.13 1H NMR (400 MHz, CDCl3) of compound 76g 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 254 Appendix 4 – Spectra Relevant to Chapter 3 255 Figure A4.14 Infrared spectrum (Thin Film, NaCl) of compound 76g 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.15 13C NMR (101 MHz, CDCl3) of compound 76g 0 10 9 8 6 5 ppm 4 3 Figure A4.16 1H NMR (400 MHz, CDCl3) of compound 76h 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 256 Appendix 4 – Spectra Relevant to Chapter 3 257 Figure A4.17 Infrared spectrum (Thin Film, NaCl) of compound 76h 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.18 13C NMR (101 MHz, CDCl3) of compound 76h 0 10 9 8 6 5 ppm 4 3 Figure A4.19 1H NMR (400 MHz, CDCl3) of compound 76i 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 258 Appendix 4 – Spectra Relevant to Chapter 3 259 Figure A4.20 Infrared spectrum (Thin Film, NaCl) of compound 76i 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.21 13C NMR (101 MHz, CDCl3) of compound 76i 0 10 9 8 6 5 ppm 4 3 Figure A4.22 1H NMR (400 MHz, CDCl3) of compound 76k 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 260 Appendix 4 – Spectra Relevant to Chapter 3 261 Figure A4.23 Infrared spectrum (Thin Film, NaCl) of compound 76k 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.24 13C NMR (101 MHz, CDCl3) of compound 76k 0 10 9 8 6 5 ppm 4 3 Figure A4.25 1H NMR (400 MHz, CDCl3) of compound 77b 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 262 Appendix 4 – Spectra Relevant to Chapter 3 263 Figure A4.26 Infrared spectrum (Thin Film, NaCl) of compound 77b 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.27 13C NMR (101 MHz, CDCl3) of compound 77b 0 10 9 8 6 5 ppm 4 3 Figure A4.28 1H NMR (400 MHz, CDCl3) of compound 77c 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 264 Appendix 4 – Spectra Relevant to Chapter 3 265 Figure A4.29 Infrared spectrum (Thin Film, NaCl) of compound 77c 200 180 160 140 120 100 ppm 80 60 40 Figure A4.30 13C NMR (101 MHz, CDCl3) of compound 77c 20 0 10 9 8 6 5 ppm 4 3 Figure A4.31 1H NMR (400 MHz, CDCl3) of compound 77d 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 266 Appendix 4 – Spectra Relevant to Chapter 3 267 Figure A4.32 Infrared spectrum (Thin Film, NaCl) of compound 77d 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.33 13C NMR (101 MHz, CDCl3) of compound 77d 0 10 9 8 6 5 ppm 4 3 Figure A4.34 1H NMR (400 MHz, CDCl3) of compound 77e 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 268 Appendix 4 – Spectra Relevant to Chapter 3 269 Figure A4.35 Infrared spectrum (Thin Film, NaCl) of compound 77e 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.36 13C NMR (101 MHz, CDCl3) of compound 77e 0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.37 1H NMR (400 MHz, CDCl3) of compound 77f 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 270 Appendix 4 – Spectra Relevant to Chapter 3 271 Figure A4.38 Infrared spectrum (Thin Film, NaCl) of compound 77f 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.39 13C NMR (101 MHz, CDCl3) of compound 77f 10 0 -10 10 9 8 6 5 ppm 4 3 Figure A4.40 1H NMR (400 MHz, CDCl3) of compound 77g 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 272 Appendix 4 – Spectra Relevant to Chapter 3 273 Figure A4.41 Infrared spectrum (Thin Film, NaCl) of compound 77g 200 180 160 140 120 100 ppm 80 60 40 Figure A4.42 13C NMR (101 MHz, CDCl3) of compound 77g 20 0 10 9 8 6 5 ppm 4 3 Figure A4.43 1H NMR (400 MHz, CDCl3) of compound 77h 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 274 Appendix 4 – Spectra Relevant to Chapter 3 275 Figure A4.44 Infrared spectrum (Thin Film, NaCl) of compound 77h 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.45 13C NMR (101 MHz, CDCl3) of compound 77h 0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.46 1H NMR (400 MHz, CDCl3) of compound 77i 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 276 Appendix 4 – Spectra Relevant to Chapter 3 277 Figure A4.47 Infrared spectrum (Thin Film, NaCl) of compound 77i 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A4.48 13C NMR (101 MHz, CDCl3) of compound 77i 20 10 0 -10 10 9 8 6 5 ppm 4 3 Figure A4.49 1H NMR (400 MHz, CDCl3) of compound 77j 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 278 Appendix 4 – Spectra Relevant to Chapter 3 279 Figure A4.50 Infrared spectrum (Thin Film, NaCl) of compound 77j 200 180 160 140 120 100 ppm 80 60 40 Figure A4.51 13C NMR (101 MHz, CDCl3) of compound 77j 20 0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.52 1H NMR (400 MHz, CDCl3) of compound 77k 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 280 Appendix 4 – Spectra Relevant to Chapter 3 281 Figure A4.53 Infrared spectrum (Thin Film, NaCl) of compound 77k 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.54 13C NMR (101 MHz, CDCl3) of compound 77k 10 0 -10 Figure A4.55 HMBC (400 MHz, CDCl3) of compound 77k 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 f2 (ppm) {1.66,180.21} 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 4 – Spectra Relevant to Chapter 3 282 f1 (ppm) 10 9 8 6 5 ppm 4 3 Figure A4.56 1H NMR (400 MHz, CDCl3) of compound 78b 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 283 Appendix 4 – Spectra Relevant to Chapter 3 284 Figure A4.57 Infrared spectrum (Thin Film, NaCl) of compound 78b 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.58 13C NMR (101 MHz, CDCl3) of compound 78b 0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.59 1H NMR (400 MHz, CDCl3) of compound 78c 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 285 Appendix 4 – Spectra Relevant to Chapter 3 286 Figure A4.60 Infrared spectrum (Thin Film, NaCl) of compound 78c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.61 13C NMR (101 MHz, CDCl3) of compound 78c 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.62 1H NMR (400 MHz, CDCl3) of compound 78e 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 287 Appendix 4 – Spectra Relevant to Chapter 3 288 Figure A4.63 Infrared spectrum (Thin Film, NaCl) of compound 78e 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.64 13C NMR (101 MHz, CDCl3) of compound 78e 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.65 1H NMR (400 MHz, CDCl3) of compound 79a 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 289 Appendix 4 – Spectra Relevant to Chapter 3 290 Figure A4.66 Infrared spectrum (Thin Film, NaCl) of compound 79a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A4.67 13C NMR (101 MHz, CDCl3) of compound 79a 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.68 1H NMR (400 MHz, CDCl3) of compound 79b 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 291 Appendix 4 – Spectra Relevant to Chapter 3 292 Figure A4.69 Infrared spectrum (Thin Film, NaCl) of compound 79b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A4.70 13C NMR (101 MHz, CDCl3) of compound 79b 20 10 0 -10 10 9 8 6 5 ppm 4 3 Figure A4.71 1H NMR (400 MHz, CDCl3) of compound 79f 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 293 Appendix 4 – Spectra Relevant to Chapter 3 294 Figure A4.72 Infrared spectrum (Thin Film, NaCl) of compound 79f 200 180 160 140 120 100 ppm 80 60 40 Figure A4.73 13C NMR (101 MHz, CDCl3) of compound 79f 20 0 7.5 7.0 6.5 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 Figure A4.74 HMBC (400 MHz, CDCl3) of compound 79f 6.0 2.5 2.0 1.5 {1.41,181.74} 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 4 – Spectra Relevant to Chapter 3 295 f1 (ppm) 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.75 1H NMR (400 MHz, CDCl3) of compound 82 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 296 Appendix 4 – Spectra Relevant to Chapter 3 297 Figure A4.76 Infrared spectrum (Thin Film, NaCl) of compound 82 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.77 13C NMR (101 MHz, CDCl3) of compound 82 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.78 1H NMR (400 MHz, CDCl3) of compound 83 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 298 Appendix 4 – Spectra Relevant to Chapter 3 299 Figure A4.79 Infrared spectrum (Thin Film, NaCl) of compound 83 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.80 13C NMR (101 MHz, CDCl3) of compound 83 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.81 1H NMR (400 MHz, CDCl3) of compound 84 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 300 Appendix 4 – Spectra Relevant to Chapter 3 301 Figure A4.82 Infrared spectrum (Thin Film, NaCl) of compound 84 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A4.83 13C NMR (101 MHz, CDCl3) of compound 84 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.84 1H NMR (400 MHz, CDCl3) of compound 85 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 302 Appendix 4 – Spectra Relevant to Chapter 3 303 Figure A4.85 Infrared spectrum (Thin Film, NaCl) of compound 85 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.86 13C NMR (101 MHz, CDCl3) of compound 85 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.87 1H NMR (400 MHz, CDCl3) of compound 86 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 304 Appendix 4 – Spectra Relevant to Chapter 3 305 Figure A4.88 Infrared spectrum (Thin Film, NaCl) of compound 86 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.89 13C NMR (101 MHz, CDCl3) of compound 86 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.90 1H NMR (400 MHz, CDCl3) of compound 88 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 306 Appendix 4 – Spectra Relevant to Chapter 3 307 Figure A4.91 Infrared spectrum (Thin Film, NaCl) of compound 88 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.92 13C NMR (101 MHz, CDCl3) of compound 88 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A4.93 1H NMR (400 MHz, CDCl3) of compound 89 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 3 308 Appendix 4 – Spectra Relevant to Chapter 3 309 Figure A4.94 Infrared spectrum (Thin Film, NaCl) of compound 89 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A4.95 13C NMR (101 MHz, CDCl3) of compound 89 10 0 -10 10 9 8 6 5 ppm 4 3 Figure A4.96 1H NMR (400 MHz, CDCl3) of compound 90 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 310 Appendix 4 – Spectra Relevant to Chapter 3 311 Figure A4.97 Infrared spectrum (Thin Film, NaCl) of compound 90 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.98 13C NMR (101 MHz, CDCl3) of compound 90 0 10 9 8 6 5 ppm 4 3 Figure A4.99 1H NMR (400 MHz, CDCl3) of compound 91 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 312 Appendix 4 – Spectra Relevant to Chapter 3 313 Figure A4.100 Infrared spectrum (Thin Film, NaCl) of compound 91 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.101 13C NMR (101 MHz, CDCl3) of compound 91 0 Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 314 APPENDIX 5 X-Ray Crystallography Reports Relevant to Chapter 3: Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives via Iridium-Catalyzed Allylic Alkylation Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 A5.1 315 GENERAL EXPERIMENTAL X-ray crystallographic analysis was obtained from the Caltech X-Ray Crystallography Facility using a Bruker D8 Venture Kappa Duo Photon 100 CMOS diffractometer. A5.1.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF CARBOXYLIC ACID 77h O HO NO 2 Carboxylic acid 77h (87% ee) was recrystallized by slow evaporation of CH2Cl2 to provide crystals suitable for X-ray analysis. Figure A5.1 X-ray crystal structure of carboxylic acid 77h Table A5.1 Crystal data and structure refinement for carboxylic acid 77h Empirical formula C11 H11 N O4 Formula weight 221.21 Temperature 200(2) K Wavelength 1.54178 Å 316 Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 Crystal system Monoclinic Space group P21 Unit cell dimensions a = 7.3561(3) Å a= 90° b = 6.7600(3) Å b= 94.5940(10)° c = 10.9461(5) Å g = 90° Volume 542.57(4) Å3 Z 2 Density (calculated) 1.354 Mg/m3 Absorption coefficient 0.879 mm-1 F(000) 232 Theta range for data collection 4.051 to 72.406°. Index ranges -9<=h<=9, -8<=k<=8, -13<=l<=13 Reflections collected 24109 Independent reflections 2132 [R(int) = 0.0427] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2132 / 1 / 146 Goodness-of-fit on F2 1.315 Final R indices [I>2sigma(I)] R1 = 0.0495, wR2 = 0.1336 R indices (all data) R1 = 0.0497, wR2 = 0.1346 Absolute structure parameter 0.08(5) Extinction coefficient n/a Largest diff. peak and hole 0.312 and -0.539 e.Å-3 317 Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A5.2 Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 77h. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ C(1) 6927(3) 5263(3) 4602(2) 32(1) C(2) 7734(2) 5232(3) 5795(2) 30(1) C(3) 6640(2) 5267(3) 6762(2) 27(1) C(4) 4752(2) 5328(3) 6510(2) 33(1) C(5) 3969(2) 5364(3) 5309(2) 35(1) C(6) 5062(3) 5332(3) 4329(2) 34(1) C(7) 7495(2) 5394(3) 8089(2) 33(1) C(8) 7573(4) 7595(4) 8448(2) 52(1) C(9) 9331(3) 4360(5) 8210(2) 51(1) C(10) 10884(3) 5180(9) 8624(2) 86(2) C(11) 6291(2) 4290(3) 8935(2) 33(1) O(1) 6125(2) 2390(3) 8666(1) 46(1) O(2) 5572(2) 5042(3) 9776(1) 49(1) N(1) 8117(3) 5216(4) 3590(2) 47(1) O(3) 9753(2) 5210(6) 3825(2) 84(1) O(4) 7426(3) 5157(6) 2546(2) 81(1) _____________________________________________________________________ Table A5.3 Bond lengths [Å] and angles [°] for 77h _____________________________________________________ C(1)-C(6) 1.381(3) C(1)-C(2) 1.390(2) C(1)-N(1) 1.466(3) C(2)-C(3) 1.380(2) C(3)-C(4) 1.395(2) C(3)-C(7) 1.538(2) C(4)-C(5) 1.392(3) Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 C(5)-C(6) 1.391(3) C(7)-C(9) 1.517(3) C(7)-C(11) 1.527(2) C(7)-C(8) 1.539(3) C(9)-C(10) 1.318(4) C(11)-O(2) 1.210(2) C(11)-O(1) 1.321(3) N(1)-O(3) 1.210(3) N(1)-O(4) 1.214(3) C(6)-C(1)-C(2) 123.08(18) C(6)-C(1)-N(1) 118.68(17) C(2)-C(1)-N(1) 118.25(17) C(3)-C(2)-C(1) 119.26(16) C(2)-C(3)-C(4) 118.74(16) C(2)-C(3)-C(7) 120.38(14) C(4)-C(3)-C(7) 120.72(15) C(5)-C(4)-C(3) 121.17(17) C(6)-C(5)-C(4) 120.45(17) C(1)-C(6)-C(5) 117.31(17) C(9)-C(7)-C(11) 106.08(18) C(9)-C(7)-C(3) 110.51(16) C(11)-C(7)-C(3) 109.42(14) C(9)-C(7)-C(8) 114.1(2) C(11)-C(7)-C(8) 109.22(15) C(3)-C(7)-C(8) 107.45(17) C(10)-C(9)-C(7) 125.3(4) O(2)-C(11)-O(1) 122.7(2) O(2)-C(11)-C(7) 124.49(19) O(1)-C(11)-C(7) 112.85(17) O(3)-N(1)-O(4) 122.26(19) O(3)-N(1)-C(1) 118.91(17) O(4)-N(1)-C(1) 118.82(19) _____________________________________________________________ 318 319 Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A5.4 Anisotropic displacement parameters (Å2x 103) for 77h. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] _____________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ C(1) 38(1) 32(1) 26(1) -1(1) 2(1) 1(1) C(2) 29(1) 34(1) 28(1) 0(1) 1(1) 0(1) C(3) 30(1) 25(1) 27(1) 1(1) 1(1) -1(1) C(4) 30(1) 34(1) 35(1) 1(1) 4(1) 1(1) C(5) 29(1) 34(1) 41(1) 3(1) -5(1) -1(1) C(6) 40(1) 28(1) 32(1) -2(1) -8(1) 1(1) C(7) 31(1) 42(1) 26(1) 0(1) 3(1) -4(1) C(8) 72(2) 48(1) 36(1) -7(1) 6(1) -24(1) C(9) 33(1) 91(2) 30(1) 16(1) 4(1) 5(1) C(10) 32(1) 176(5) 49(1) 35(2) -6(1) -14(2) C(11) 33(1) 39(1) 26(1) 2(1) 1(1) 2(1) O(1) 62(1) 37(1) 42(1) 0(1) 22(1) -4(1) O(2) 60(1) 51(1) 38(1) -7(1) 22(1) 5(1) N(1) 50(1) 67(1) 26(1) 2(1) 4(1) 5(1) O(3) 40(1) 176(3) 36(1) 0(1) 9(1) 5(1) O(4) 66(1) 151(3) 25(1) -7(1) -1(1) 12(1) _____________________________________________________________________ Table A5.5 Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 77h _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(2) 9023 5188 5942 36 H(4) 3987 5347 7168 40 H(5) 2680 5410 5158 42 H(6) 4546 5355 3505 40 320 Appendix 5 – X-Ray Crystallography Reports Relevant to Chapter 3 H(8A) 8291 8322 7880 78 H(8B) 8145 7730 9284 78 H(8C) 6333 8135 8410 78 H(9) 9363 3012 7967 62 H(10A) 10911 6525 8877 103 H(10B) 11978 4427 8671 103 H(1) 5466 1842 9160 69 _____________________________________________________________________ Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 321 CHAPTER 4 Enantioselective Synthesis Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation† 4.1 INTRODUCTION AND BACKGROUND The enantioselective preparation of singular all-carbon quaternary stereocenters has been a persistent challenge in the synthetic community and a topic of great interest to our research group. 1 However, due to significant progress in this area over recent decades, 2 the more formidable challenge of constructing vicinal all-carbon quaternary centers has become the forefront of investigation. A limited number of organic 3 and transition metal-catalyzed4,5 methods for the enantioselective preparation of vicinal allcarbon quaternary stereocenters have been reported, 6 with enantioselective transition metal-catalyzed allylic alkylation strategies remaining underexplored. † This work was performed in collaboration with Dr. J. Caleb Hethcox. Portions of this chapter have been reproduced with permission from Hethcox, J. C.;‡ Shockley, S. E.;‡ Stoltz, B. M. Angew. Chem. Int. Ed. 2018, doi: 10.1002/anie.201804820 © 2018 Wiley-VCH. 322 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation In 2011, Trost reported an enantioselective palladium-catalyzed allylic alkylation of oxindoles to provide reverse prenylated products containing a homoallylic quaternary stereocenter vicinal to an all-carbon quaternary center (Figure 4.1a).5a,b In 2014, Ooi5c and Zhang5d each disclosed examples of enantio- and diastereoselective palladiumcatalyzed allylic alkylation reactions to form cyclic products bearing vicinal all-carbon quaternary stereocenters (Figure 4.1b). To date, these three methods represent the only enantioselective transition metal-catalyzed allylic alkylation protocols for the synthesis of vicinal all-carbon quaternary centers7,8 – none of these reports provide access to acyclic products. Figure 4.1 State-of-the-art in the enantioselective synthesis of vicinal all-carbon quaternary centers via transition metal-catalyzed allylic alkylation a) Previous Report: Enantioselective Synthesis of Vicinal Quaternary Centers Trost (2011) R2 O R2 [PdL*] + BocO N up to 90% yield up to >99% ee R1 O N R1 b) Previous Reports: Enantio- and Diastereoselective Synthesis of Vicinal Quaternary Stereocenters Ooi (2014) CN Ar O CO2Et + O [PdL*] R up to 99% yield up to >20:1 dr up to 99% ee O [PdL*] R up to 98% yield up to 11:1 dr up to 98% ee NsN Ar CN NsN CO2Et R Zhang (2014) CN Ar O EWG + O Ar EWG O CN R c) This Research: Enantioselective Synthesis of Vicinal Quaternary Centers with Prochiral Electrophile R3 R1 NC [IrL*] + CN R2 OCO 2Me NC R1 NC R2 R3 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 323 Recently, our group reported the first iridium-catalyzed allylic alkylation method to allow for the synthesis of highly enantioenriched allylic quaternary stereocenters. 9 Given that iridium-catalyzed allylic alkylation is well known to facilitate the synthesis of vicinal stereocenters (3°/3° and 3°/4°),10 we hypothesized that we could utilize our newly developed technology to prepare vicinal all-carbon quaternary centers, with the use of appropriately designed nucleophiles. 11 Herein, we discuss the first enantioselective transition metal-catalyzed allylic alkylation to form acyclic products bearing vicinal allcarbon quaternary centers (Figure 4.1c). 4.2 REACTION OPTIMIZATION Preliminary studies focused on identifying a suitable catalyst system to promote the reaction of nucleophile 92 and trisubstituted allylic electrophile 72 (Table 4.1). In designing our optimal nucleophile for the allylic alkylation reaction, we imagined that methylmalononitrile (92) would mimic both the acidity and steric bulk of the previously utilized masked acyl cyanide (MAC) nucleophile9 (Figure 1C, R1 = OMOM) as well as provide versatile functional handles for derivatizations of product 93. We were pleased to find that our hypothesis was valid, and when utilizing our optimized conditions for the iridium-catalyzed allylic alkylation of MAC reagents9 with nucleophile 92, product 93 is obtained in nearly quantitative yield, though in only a moderate 73% ee (Table 4.1, entry 1). In an effort to improve the enantioselectivity of the transformation we investigated a range of basic additives, as bases have been reported to have a pronounced effect on selectivity in allylic alkylation reactions.12 While addition of LiOt-Bu provided only a slight enhancement in enantioselectivity to 81% ee (entry 2), we were delighted to find Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 324 that the amine base DABCO affords product 93 in 92% yield and an excellent 95% ee (entry 3). At this time, the specific role of DABCO remains unknown; however, due to the additive’s drastic effect on enantioselectivity, we hypothesize that DABCO allows for increased equilibration between diastereomers of an iridium π-allyl complex by slowing the rate of nucleophilic attack.13,14 Moreover, while we observed the highest yield for the allylic alkylation reaction using a 1:2 nucleophile to electrophile ratio, the nucleophile and electrophile stoichiometry can be varied (1:1 or 2:1) without affecting reaction selectivity, though yields are diminished (entries 4 and 5). Of note, excess electrophile 72 is unable to be quantitatively recovered as a competing elimination reaction takes place to form a diene byproduct. Table 4.1 Optimization of reaction parametersa Base (200 mol %) BEt 3 (200 mol %) [Ir(cod)Cl]2 (2 mol %) (S a )-L5 (4 mol %), TBD (10 mol %) NC CN + OCO2Me Ph 92 NC NC THF (0.1 M), 60 °C, 18 h Ph 93 72 Entry Nuc:Elec 1 2 Base Yield (%)b ee (%)c 1:2 – >99 73 1:2 LiOt-Bu >99 81 3 1:2 DABCO 92 95 4 1:1 DABCO 67 95 5 2:1 DABCO 41 94 O P N O (S a )-L5 [a] Reactions performed on 0.1 mmol scale. [b] 1H NMR yield based on internal standard. [c] Determined by chiral SFC analysis. [d] TBD = 1,3,4-triazabicyclo[4.4.0]dec-5-ene, DABCO = 1,4-diazabicyclo[2.2.2]octane. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 4.3 325 SUBSTRATE SCOPE EXPLORATION With the optimal conditions identified (Table 4.1, entry 3), we explored the substrate scope for this new transformation. With respect to nucleophile 94, the process is tolerant of a wide variety of substituted malononitrile derivatives (Table 4.2). Specifically, we were pleased to find that increasing the steric bulk on the nucleophile results in formation of the corresponding ethyl-substituted 95a and benzyl-substituted 95b products in only slightly decreased yields (76% and 69%, respectively) and no significant loss in enantioselectivity. Interestingly, phenyl-substituted nucleophile 94c gives full conversion to the linear product (105, Section 4.6.2.5) in the allylic alkylation reaction rather than branched product 95c. Additionally, olefinic substituents on the nucleophile are tolerated under the reaction conditions provided the olefin is at least di-substituted; allylsubstituted 94d returns only starting material in the allylic alkylation reaction while methallyl-substituted product 95e can be prepared in 33% yield with 92% ee and prenylsubstituted product 95f can be constructed in an excellent 92% yield with 96% ee. We reason that increased olefin substitution decreases the affinity of the olefin to bind to the catalyst,15 thus leading to increased yields. Furthermore, we were delighted to discover that carbonyl-containing product 95g can be obtained in a moderate 52% yield with an excellent 96% ee. Finally, fluorinated product 95h can be accessed in a moderate 50% yield with 91% ee. 326 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Table 4.2 Nucleophile substrate scopea DABCO (200 mol %) BEt 3 (200 mol %) [Ir(cod)Cl]2 (2 mol %) (S a )-L5 (4 mol %), TBD (10 mol %) R + NC CN Ph OCO2Me 92, 94a–g NC NC 93 Ph 93, 95a–g Et NC NC Ph 89% yield 95% ee c NC THF (0.1 M), 60 °C, 18 h 72 NC Bn NC NC Ph b Ph NC NC Ph NC Ph 95a 95b 95c 76% yield 95% ee 69% yield 93% ee 0% yield –% ee Ph 95d d 0% yield –% ee O CF3 NC NC NC NC NC NC NC NC Ph R NC Ph Ph Ph 95e 95f 95g 95h 33% yield 92% ee 92% yield 96% ee 52% yield 96% ee 50% yield 91% ee [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral SFC. [d] 99% conversion by 1H NMR to linear product 105. Pleased to find the reaction amenable to a range of nucleophilic substrates, we sought to further examine the scope of the transformation by exploring the diversity of substitution permitted on trisubstituted allylic electrophile 96 (Table 4.3). Gratifyingly, we observed that a series of para-substituted allylic electrophiles bearing both electrondonating (–p-Me, –p-OMe) and withdrawing groups (–p-Ph, –p-F) on the aromatic ring furnish the corresponding products 97a–d in consistently excellent enantioselectivities (>94% ee) when subjected to the reaction conditions utilizing methylmalononitrile (92) as the nucleophile. In evaluating the effect of meta-substitution, we found that products 97e–h (–m-Me, –m-Cl, –m-NO2, 2-Np) can be obtained with similarly high enantiocontrol (>93% ee). Generally, we noted that electron-rich electrophiles (i.e., 96a, 327 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 96b, 96e) provide the corresponding allylic alkylation products in slightly diminished yields (67–80% versus 84–99%) as compared to electron-poor electrophiles (i.e., 96c, 96d, 96f, 96g). At this time, ortho-substitution (i.e., –o-Me) is not tolerated under the reaction conditions and no conversion to product 97i is observed. However, we were pleased to discover that the reaction is amenable to bis-alkyl-substitution on the allylic electrophile allowing for access to product 97j in 65% yield and 84% ee as an inseparable mixture (1:1.5) of branched and linear isomers. Additionally, reverse prenylation can be effected to produce achiral product 97k in 61% yield. Finally, extension of the alkyl chain on the allylic electrophile to an ethyl group leads to a decreased yield with 97l isolated in 50% yield but with no loss in selectivity (96% ee). Table 4.3 Electrophile substrate scopea DABCO (200 mol %) BEt 3 (200 mol %) [Ir(cod)Cl]2 (2 mol %) R2 CN NC + R1 NC (S a )-L5 (4 mol %), TBD (10 mol %) NC OCO2Me R1 R 2 THF (0.1 M), 60 °C, 18 h 92 97a–l 96a–l NC NC NC NC NC NC NC NC NC NC NC NC MeO Ph 97a 80% yield 96% ee c b F Cl d 97b 97c 70% yield 96% ee >99% yield 95% ee 97d 97e 97f 99% yield 94% ee 67% yield 95% ee 99% yield 99% ee NC NC NC NC NC NC NC NC NC NC NC NC Et Ph NO 2 97g 97h 97i 97j 84% yield 93% ee 93% yield 95% ee 0% yield –% ee 65% yield 84% ee e 97k 97l 61% yield –% ee 50% yield 96% ee [a] Reactions performed on 0.2 mmol scale. [b] Isolated yield. [c] Determined by chiral HPLC or SFC. [d] Absolute stereochemistry determined by single-crystal X-ray analysis; the absolute stereochemistry of all other compounds was assigned by analogy. [e] Isolated as an inseparable mixture (1:1.5) of linear to branched product. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 328 A deeper investigation into the scope of this novel transformation revealed the limits of the catalytic system (Table 4.4). Foremost, Lewis basic functionalities are not tolerated on nucleophile 98 or electrophile 99, thus low yields or no reactivity was observed in the formation of thiophene 100a, furan 100b, ketone 100d, alkyne 100f, pyridine 100k, and thiophene 100l. Moreover, branched substitution on the nucleophile is not permitted in the allylic alkylation reaction as isopropyl-substituted 98 (R1 = i-Pr) returns only starting material. Additionally, drastically altering the pKa of nucleophile 98 shuts down the reaction, as seen with ester-functionalized 100e (R1 = CO2Et). Also, adding significant steric bulk to nucleophile 98 leads to low to no conversion to product (e.g., 100g, 100h). Furthermore, to date, only functionalized-malononitrile nucleophiles have been successful utilized in the reported allylic alkylation reaction, despite studies into other bis-electron-withdrawing group-functionalized nucleophiles (e.g., 1,3-diketone 100j) and unfunctionalized malononitrile (100i). Of note, para-trifluoromethylsubstituted allylic alkylation product 100m can be isolated in a good 75% yield, however the enantiomeric excess could not be determined due to inseparable enantiomers by HPLC and SFC; though we hypothesize that the value would be consistently high as with other electrophile substrates (Table 4.3). With respect to substitution on the electrophile, replacement of the aryl moiety with an alkyl group leads to minimal to no yield of allylic alkylation products 100n, and 100o. Use of a cyclic allylic electrophile does not afford corresponding bicyclic product 100p. Finally, despite the interest and value in the corresponding products (100q and 100r), due to difficulty of substrate preparation, a trifluoromethyl-substitute malononitrile nucleophile and halogen-substituted malononitriles were not explored in the newly developed allylic alkylation reaction. 329 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Table 4.4 Substrate scope limitationsa DABCO (200 mol %) BEt 3 (200 mol %) [Ir(cod)Cl]2 (2 mol %) R1 NC CN + R2 98 OCO2Me NC NC R2 R3 100a–r Ph O NC NC NC NC R1 THF (0.1 M), 60 °C, 18 h 99 S 100a (S a )-L5 (4 mol %), TBD (10 mol %) R3 NC O NC NC O NC NC NC NC TMS OEt NC b 100b 100c 100d 100e 100f 48% yield c 89% ee 18% yield no reaction no reaction 27% yield OTBS NPth 23% yield NC NC NC NC NC O H NC NC NC NC NC O S N 100g 100h 100i 100j 100k 100l 35% yield no reaction 16% yield no reaction trace yield no reaction NC NC NC NC NC NC NC NC NC CF3 NC X NC NC F 3C 100m 75% yield –% ee d 100n 100o 100p 100q 100r trace yield trace yield no reaction not studied not studied [a] Reactions performed on 0.2 mmol scale. [b] 1H NMR yield based on internal standard. [c] Determined by chiral HPLC or SFC. [d] Isolated yield. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 4.4 330 PRODUCT TRANSFORMATIONS With the general reactivity trends for the allylic alkylation reaction explored, we sought to demonstrate the utility of these sterically congested products (Figure 4.2). Though hydrogenation of the olefin in allylic alkylation product 93 using palladium catalysis proved problematic due to competing reduction of the nitrile groups, we found that treatment of 93 with Wilkinson’s catalyst under a hydrogen atmosphere chemoselectively reduces the olefin to furnish 101 in 92% yield. Additionally, ozonolysis of olefin 93 proceeds smoothly to give enantioenriched aldehyde 102 in 93% yield,16 wherein the aldehyde moiety can serve as a valuable functional handle for further manipulation (e.g., reductive aminations, allylations, and olefinations). Allylic alkylation product 95f was subjected to a two-step ozonolysis/aldol condensation process to deliver a densely functionalized, enantioenriched cyclopentene (106, Section 4.6.2.6) in 43% yield, which can then undergo diastereoselective hydration of the bis-nitrile functionality to provide amide 103 in 1:11 dr. Chiral cyclopentenes have been demonstrated to be key building blocks in a number of complex molecule total syntheses. 17 Finally, enantioenriched lactone 104 bearing vicinal all-carbon quaternary stereocenters can be accessed in 65% yield and 1:2.5 dr from allylic alkylation product 93 via ozonolysis followed by reductive quenching. The transformations forming products 103 and 104 showcase that the diastereotopic nitrile functionalities of the allylic alkylation products are amenable to diastereoselective differentiation to afford vicinal all-carbon quaternary stereocenters, which are otherwise difficult to prepare. 331 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Figure 4.2 Product transformations of allylic alkylation products NC R = Me R = Me NC a Ph 101 NC NC NC b O Ph 102 R NC Ph 93, 95f O NC O e R = Me Ph c,d R = CH 2CH 2C(O)Me O O H 2N NC Ph 104 103 [a] RhCl(PPh3)3, H2 (balloon), benzene, 23 °C, 18 h, 92% yield; [b] O3, pyridine, CH2Cl2, –78 °C, 4 min, 93% yield; [c[ i. O3, pyridine, CH2Cl2, –78 °C, 4 min, ii. p-TsOH, benzene, reflux, 18 h, 47% yield; [d[ NaOH, EtOH/H2O (1:1), 60 °C, 18 h, 38% yield, 1:11 dr; [e] i. O3, MeOH, –78 °C, 0.5 h, ii. NaBH4, 0 °C, 3 h, 65% yield, 1:2.5 dr. 4.5 CONCLUSIONS In conclusion, we have developed the first enantioselective transition metal- catalyzed allylic alkylation reaction for the preparation of acyclic products bearing vicinal all-carbon quaternary centers. Key to the success of this new reaction is the use of DABCO in combination with triethylborane and our unique catalyst prepared from [Ir(cod)Cl]2, (Sa)-L5, and TBD. The developed method proceeds with moderate to excellent yields and high levels of enantioselectivity for a wide range of substitution on both the malononitrile-derived nucleophile and the trisubstituted allylic electrophile. Furthermore, the allylic alkylation products can be transformed by chemo- and diastereoselective methods to a number of highly valuable, densely functionalized building blocks, including those containing vicinal all-carbon quaternary stereocenters. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 4.6 EXPERIMENTAL SECTION 4.6.1 MATERIALS AND METHODS 332 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. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4, or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak OJ column (4.6 mm x 25 cm) or a Chiralpak AD-H column (4.6 mm x 25 cm), both obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak OJ–H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. 1H NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 333 Some reported spectra include minor solvent impurities of water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), acetone (δ 2.17 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESIAPCI+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as: [α]DT (concentration in g/100 mL, solvent). 4.6.1.1 Key Considerations All synthesized reagents (i.e., (Sa)-L5, 92, 72, 94, and 96) were dried over P2O5 and drierite in a vacuum desiccator under vacuum overnight before use in the iridiumcatalyzed allylic alkylation reaction. THF was taken directly from an activated alumina column under argon and used immediately to eliminate the possibility of peroxides. Mesitylene or 1,2,4,5-tetrachloro-3-nitrobenzene were used as the internal standard for determining 1H NMR yields. Prolonged storage of electrophiles 72 and 96 at room temperature under an air atmosphere results in the formation of an unidentified impurity; storage in a –30 °C freezer allows for prolonged storage. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 4.6.1.2 334 Preparation of Known Compounds Previously reported methods were used to prepare ligand (Sa)-L5 18 as well as starting materials 92,19 72,20 94a,21 94b,19 94c,22 94d,23 94e,24 94f,24 94g, 25 94h,26 96a,27 96d,9 96e,27 96g,9 96h,9 96i,27 96j,27 96k,28 and 96l.27 4.6.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 4.6.2.1 Representative Procedures for the Synthesis of Electrophiles OCO2Me MeO (E)-3-(4-Methoxyphenyl)but-2-en-1-yl methyl carbonate (96b). To a solution of methyl (E)-3-(4-methoxyphenyl)but-2-enoate29 (0.21 g, 1.0 mmol, 1 equiv) in THF (6.0 mL) at –78 °C was added DIBAL (0.62 mL, 3.0 mmol, 3.5 equiv) dropwise. The resulting reaction mixture was stirred at –78 °C for 2.5 h, whereupon the reaction was quenched with a saturated aqueous Rochelle’s salt solution (10 mL). The cooling bath was then removed and the reaction was stirred for 18 h at ambient temperature. The aqueous layer was extracted with CH2Cl2 (3 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was dissolved in CH2Cl2 (4.0 mL) and cooled to 0 °C. Pyridine (0.64 mL, 8.3 mmol, 8.3 equiv) was added followed by methyl chloroformate (0.20 mL, 2.3 mmol, 2.3 equiv) dropwise. The resulting solution was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with the addition of 1 M HCl (5 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 20 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 335 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (5% EtOAc/hexanes) to give carbonate 96b as a colorless solid (0.13 g, 53% yield): 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.92 – 5.82 (m, 1H), 4.84 (dd, J = 7.2, 0.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 2.16 – 2.05 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 159.4, 156.0, 140.7, 134.9, 127.1, 119.1, 113.8, 65.2, 55.4, 54.9, 16.4; IR (Neat Film, NaCl) 2958, 2832, 1753, 1740, 1440, 1381, 1336, 1249, 1028, 942, 819, 798 cm-1; HRMS (FAB+) m/z calc’d for C13H16O3 [M]+•: 236.1049, found 236.1053. 4.6.2.2 Spectroscopic Data for the Synthesis of Electrophiles OCO2Me Ph (E)-3-([1,1'-Biphenyl]-4-yl)but-2-en-1-yl methyl carbonate (96c). Carbonate 96c was prepared from methyl (E)-3-([1,1'-biphenyl]-4-yl)but-2-enoate 30 according to the representative procedure and isolated by silica gel flash column chromatography (5% EtOAc/hexanes) as a colorless oil (0.17 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 19.6 Hz, 4H), 7.51 – 7.41 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 6.00 (td, J = 7.0, 1.4 Hz, 1H), 4.88 (dq, J = 7.0, 0.8 Hz, 2H), 3.81 (s, 3H), 2.17 (dt, J = 1.3, 0.7 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 156.0, 141.4, 140.7, 140.7, 140.6, 128.9, 127.5, 127.1, 126.4, 120.8, 65.1, 55.0, 16.4; IR (Neat Film, NaCl) 3032, 2968, 1750, 1740, 1441, 1408, 1340, 1245, 992, 943, 827, 794, 759, 689 cm-1; HRMS (FAB+) m/z calc’d for C18H18O3 [M]+•: 282.1256, found 282.1253. 336 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation OCO2Me Cl (E)-3-(3-Chlorophenyl)but-2-en-1-yl methyl carbonate (96f). Carbonate 96f was prepared from methyl (E)-3-(3-chlorophenyl)but-2-enoate 31 according to the representative procedure and isolated by silica gel flash column chromatography (10% EtOAc/hexanes) as a colorless oil (0.43 g, 88% yield): 1H NMR (400 MHz, CDCl3) δ 7.38 (q, J = 1.5 Hz, 1H), 7.30 – 7.22 (m, 3H), 5.92 (ddt, J = 6.9, 5.6, 1.4 Hz, 1H), 4.84 (dq, J = 7.0, 0.8 Hz, 2H), 3.81 (s, 3H), 2.10 (dt, J = 1.4, 0.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.9, 144.4, 139.8, 134.4, 129.7, 127.8, 126.3, 124.2, 122.0, 64.9, 55.0, 16.4; IR (Neat Film, NaCl) 2957, 1748, 1594, 1564, 1443, 1377, 1333, 1268, 1172, 1102, 997, 948, 906, 884, 782, 691 cm-1; HRMS (FAB+) m/z calc’d for C12H13ClO3 [M]+•: 240.0553, found 240.0564. 4.6.2.3 General Procedure for Optimization Reactions (Table 4.1) NC NC Ph (S)-2-Methyl-2-(2-phenylbut-3-en-2-yl)malononitrile (93). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (1.3 mg, 0.0020 mmol, 2 mol %), ligand (Sa)-L5 (2.0 mg, 0.004 mmol, 4 mol %), TBD (1.4 mg, 0.010 mmol, 10 mol %), and THF (0.5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with nucleophile 92 (0.10 mmol or 0.20 mmol, as specified), THF (0.5 mL), and the base additive (0 or 200 mol %). The preformed catalyst solution (vial A) was then transferred to vial B followed immediately by Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 337 carbonate 72 (0.20 mmol, 0.10 mmol, or 0.20 mmol, as specified). The vial was sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box concentrated under reduced pressure. To the crude reaction mixture was added 1,2,4,5-tetrachloro-3nitrobenzene (0.10 mmol in 0.5 mL CDCl3). The NMR yield (measured in reference to 1,2,4,5-tetrachloro-3-nitrobenzene δ 7.74 ppm (s, 1H)) was determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (15% Et2O/hexanes, eluted twice) to afford allylic alkylation product 3 as a pale yellow oil. 4.6.2.4 General Procedure for the Iridium-Catalyzed Allylic Alkylation Please note that the absolute configuration was determined only for compound 97c via X-ray crystallographic analysis. The absolute configuration for all other products has been inferred by analogy. For respective HPLC and SFC conditions, please refer to Table S1. NC NC Ph (S)-2-Methyl-2-(2-phenylbut-3-en-2-yl)malononitrile (93). In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (Sa)-L5 (4.0 mg, 0.008 mmol, 4 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol %), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with nucleophile 92 (18 mg, 0.20 mmol, 100 mol %), THF (1 mL), DABCO (45 mg, 0.40 mmol, 200 mol %), and BEt3 (400 µL, 1M in hexanes). The pre-formed catalyst solution (vial A) was then transferred to vial B followed immediately by carbonate 72 (83 mg, 0.40 mmol, 200 mol %). The vial was Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 338 sealed and stirred at 60 °C. After 18 h, the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (15% Et2O/hexanes, eluted twice) to afford allylic alkylation product 93 as a pale yellow oil (37 mg, 89% yield): 95% ee; [α]D25 +32.9 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.52 (m, 2H), 7.44 – 7.33 (m, 3H), 6.49 (dd, J = 17.3, 11.0 Hz, 1H), 5.63 – 5.31 (m, 2H), 1.80 (s, 3H), 1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 139.2, 138.3, 128.7, 128.6, 128.1, 119.0, 116.1, 116.0, 49.4, 41.9, 21.8, 21.5; IR (Neat Film, NaCl) 3095, 3062, 2992, 2951, 2247, 1749, 1639, 1600, 1496, 1447, 1417, 1386, 1270, 1217, 1165, 1102, 1074, 1031, 1003, 937, 802, 751, cm-1; HRMS (ESI+) m/z calc’d for C14H14N2 [M]+•: 210.1157, found 210.1156; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.832, minor = 4.594. 4.6.2.5 Spectroscopic Data for the Iridium-Catalyzed Allylic Alkylation Products NC Et NC Ph (S)-2-Ethyl-2-(2-phenylbut-3-en-2-yl)malononitrile (95a). Allylic alkylation product 95a was prepared according to the general procedure and isolated by preparatory TLC (100% toluene, eluted twice) to give a pale yellow oil (34 mg, 76% yield): 95% ee; [α]D25 +19.0 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.51 (m, 2H), 7.45 – 7.31 (m, 3H), 6.51 (dd, J = 17.3, 11.0 Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 5.40 (d, J = 17.3 Hz, 1H), 1.90 – 1.72 (m, 5H), 1.27 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 139.6, Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 339 138.7, 128.6, 128.5, 128.2, 118.7, 115.2, 115.1, 49.9, 49.7, 27.7, 22.0, 10.7; IR (Neat Film, NaCl) 3094, 3061, 2959, 2931, 2874, 2244, 1730, 1640, 1600, 1496, 1461, 1446, 1416, 1382, 1271, 1175, 1074, 1031, 1002, 937, 793, 750, 701 cm-1; HRMS (ESI+) m/z calc’d for C15H17N2 [M+H]+: 225.1392, found 225.1395; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.378, minor = 4.088. NC Bn NC Ph (S)-2-Benzyl-2-(2-phenylbut-3-en-2-yl)malononitrile (95b). Allylic alkylation product 95b was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a pale yellow oil (39 mg, 69% yield): 93% ee; [α]D25 +11.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.62 (m, 2H), 7.51 – 7.29 (m, 8H), 6.64 (dd, J = 17.3, 11.0 Hz, 1H), 5.60 (d, J = 11.0 Hz, 1H), 5.47 (d, J = 17.2 Hz, 1H), 3.07 – 2.90 (m, 2H), 1.93 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 139.4, 138.5, 132.6, 130.5, 128.9, 128.7, 128.7, 128.6, 128.3, 119.1, 114.9, 114.7, 50.6, 50.3, 39.6, 22.1; IR (Neat Film, NaCl) 3092, 3063, 3034, 2990, 2927, 2245, 1957, 1884, 1810, 1748, 1602, 1498, 1456, 1446, 1416, 1383, 1270, 1212, 1159, 1110, 1080, 1032, 1004, 938, 766, 749 cm-1; HRMS (FAB+) m/z calc’d for C20H19N2 [M+H]+: 287.1548, found 287.1553; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 10.960, minor = 11.727. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation NC 340 Ph Ph NC (E)-2-Phenyl-2-(3-phenylbut-2-en-1-yl)malononitrile (105). Linear allylic alkylation product SI-1 was prepared according to the general procedure in 99% conversion by 1H NMR yield but was inseparable from unreacted electrophile 72. 105 was prepared via an alternate route for verification and characterization. In a nitrogen-filled glove box, to a 1 dram vial equipped with a stir bar was added Pd(PPh3)4 (11 mg, 0.01 mmol, 0.1 mol %), nucleophile 94c (21 mg, 0.15 mmol, 1.5 equiv), electrophile 72 (21 mg, 0.10 mmol, 1.0 equiv), and THF (1 mL). The reaction was stirred for 18 h whereupon the vial was removed from the glove box, transferred to a 20 mL vial with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (20% Et2O/hexanes, eluted twice) to afford 105 as a colorless crystalline solid (23 mg, 43% yield): 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.28 (m, 10H), 5.75 (td, J = 7.8, 1.5 Hz, 1H), 3.23 – 3.01 (m, 2H), 1.95 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 143.8, 142.6, 131.7, 130.1, 129.8, 128.5, 128.0, 126.1, 126.1, 117.2, 115.0, 42.5, 42.0, 16.6; IR (Neat Film, NaCl) 3062, 3032, 2983, 2930, 2246, 1599, 1494, 1451, 1383, 1277, 1027, 861, 756, 692 cm-1; HRMS (FAB+) m/z calc’d for C19H17N2 [M+H]+: 273.1292, found 273.1387. NC NC Ph (S)-2-(2-methylallyl)-2-(2-phenylbut-3-en-2-yl)malononitrile (95d). Allylic alkylation product 95d was prepared according to the general procedure and isolated by preparatory Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 341 TLC (100% toluene, eluted twice) to give a pale yellow oil (17 mg, 33% yield): 92% ee; [α]D25 +26.0 (c 0.94, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.45 – 7.32 (m, 3H), 6.54 (dd, J = 17.3, 11.0 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 5.11 (t, J = 1.4 Hz, 1H), 5.01 (p, J = 1.0 Hz, 1H), 2.50 – 2.35 (m, 2H), 1.91 (dd, J = 1.6, 0.8 Hz, 3H), 1.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 139.4, 138.5, 137.9, 128.7, 128.6, 128.3, 119.1, 118.7, 115.4, 115.2, 50.4, 47.6, 41.5, 23.2, 22.0; IR (Neat Film, NaCl) 3085, 2988, 2242, 1747, 1650, 1496, 1445, 1416, 1381, 1264, 1072, 1004, 910, 792, 750, 698 cm-1; HRMS (FAB+) m/z calc’d for C17H19N2 [M+H]+: 251.1548, found 251.1539; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.138, minor = 3.923. NC NC Ph (S)-2-(3-Methylbut-2-en-1-yl)-2-(2-phenylbut-3-en-2-yl)malononitrile (95e). Allylic alkylation product 95e was prepared according to the general procedure and isolated by preparatory TLC (5% Et2O/hexanes, eluted twice) to give a colorless oil (49 mg, 92% yield): 96% ee; [α]D25 +7.87 (c 6.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.47 – 7.31 (m, 3H), 6.54 (dd, J = 17.3, 11.0 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 5.34 – 5.24 (m, 1H), 2.46 (qd, J = 14.1, 7.6 Hz, 2H), 1.84 (s, 3H), 1.78 (d, J = 1.4 Hz, 3H), 1.60 (d, J = 1.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 140.4, 139.6, 138.7, 128.6, 128.5, 128.1, 118.7, 115.3, 115.3, 115.2, 49.6, 48.9, 32.7, 26.1, 21.9, 18.4; IR (Neat Film, NaCl) 3089, 2987, 2926, 2242, 1497, 1446, 1416, 1383, Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 342 1004, 935, 838, 750, 700 cm-1; HRMS (FAB+) m/z calc’d for C18H21N2 [M+H]+: 265.1705, found 265.1709; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.095, minor = 4.061. O NC NC Ph (S)-2-(3-oxobutyl)-2-(2-phenylbut-3-en-2-yl)malononitrile (95f). Allylic alkylation product 95f was prepared according to the general procedure and isolated by preparatory TLC (20% Et2O/hexanes, eluted twice) to give a colorless oil (28 mg, 52% yield): 96% ee; [α]D25 +16.8 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.53 (m, 2H), 7.46 – 7.30 (m, 3H), 6.50 (dd, J = 17.2, 10.9 Hz, 1H), 5.54 (d, J = 11.0 Hz, 1H), 5.41 (d, J = 17.2 Hz, 1H), 2.86 – 2.75 (m, 2H), 2.19 (s, 3H), 2.17 – 1.97 (m, 2H), 1.82 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.1, 139.2, 138.2, 128.7, 128.6, 128.1, 119.1, 115.0, 114.9, 49.8, 47.7, 40.0, 30.2, 27.8, 21.8; IR (Neat Film, NaCl) 3094, 3061, 2991, 2957, 2246, 1721, 1640, 1601, 1582, 1496, 1446, 1418, 1370, 1288, 1215, 1170, 1118, 1080, 1032, 1002, 938, 754, 702 cm-1; HRMS (FAB+) m/z calc’d for C17H19N2O [M+H]+: 267.1497, found 267.1499; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 5.022, minor = 7.267. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 343 CF3 NC NC Ph (S)-2-(2-Phenylbut-3-en-2-yl)-2-(3,3,3-trifluoropropyl)malononitrile (95g). Allylic alkylation product 95g was prepared according to the general procedure and isolated by preparatory TLC (100% toluene, eluted twice) to give a colorless oil (29 mg, 50% yield): 91% ee; [α]D25 +16.6 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.32 (m, 5H), 6.50 (dd, J = 17.2, 10.9 Hz, 1H), 5.59 (d, J = 11.0 Hz, 1H), 5.44 (d, J = 17.2 Hz, 1H), 2.57 – 2.39 (m, 2H), 2.12 – 1.93 (m, 2H), 1.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.8, 137.7, 128.87, 128.86, 127.9, 125.7 (q, J = 276.4 Hz), 119.5, 114.3, 114.1, 49.9, 47.5, 31.7, 31.3 (q, J = 30.3 Hz), 27.1 (q, J = 3.4 Hz); IR (Neat Film, NaCl) 3096, 3063, 2992, 2928, 2242, 1496, 1447, 1400, 1318, 1257, 1157, 1089, 1046, 940, 845, 752, 701, 624 cm-1; HRMS (ESI+) m/z calc’d for C16H15F2N2 [M]+•: 292.1187, found 292.1173; SFC conditions: 1% IPA, 3.0 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 1.651, minor = 1.868. NC NC (S)-2-Methyl-2-(2-(p-tolyl)but-3-en-2-yl)malononitrile (97a). Allylic alkylation product 97a was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a pale yellow oil (36 mg, 80% yield): 96% ee; [α]D25 +48.7 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.39 (m, 2H), 7.23 – 7.16 (m, 2H), 6.48 (dd, J = 17.3, 11.0 Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 5.40 (d, J = Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 344 17.3 Hz, 1H), 2.35 (s, 3H), 1.77 (s, 3H), 1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.44, 138.42, 136.2, 129.3, 128.0, 118.8, 116.2, 116.1, 49.2, 42.0, 21.8, 21.5, 21.1; IR (Neat Film, NaCl) 3094, 2992, 2953, 2925, 2247, 1748, 1682, 1639, 1614, 1515, 1454, 1416, 1383, 1268, 1198, 1102, 1074, 1019, 937, 825, 804, 774 cm-1; HRMS (ESI+) m/z calc’d for C15H16N2 [M]+•: 224.1314, found 224.1306; SFC conditions: 1% IPA, 3.0 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.658, minor = 4.375. NC NC MeO (S)-2-(2-(4-Methoxyphenyl)but-3-en-2-yl)-2-methylmalononitrile (97b). Allylic alkylation product 97b was prepared according to the general procedure and isolated by preparatory TLC (20% Et2O/hexanes, eluted twice) to give a pale yellow oil (34 mg, 70% yield): 96% ee; [α]D25 +25.4 (c 2.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.42 (m, 2H), 6.95 – 6.88 (m, 2H), 6.47 (dd, J = 17.3, 11.0 Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 5.39 (d, J = 17.3 Hz, 1H), 3.82 (s, 3H), 1.77 (s, 3H), 1.65 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.5, 138.5, 131.0, 129.4, 118.7, 116.2, 116.1, 113.9, 55.4, 49.0, 42.1, 21.7, 21.6; IR (Neat Film, NaCl) 2998, 2934, 2832, 2242, 1609, 1514, 1458, 1298, 1257, 1188, 1029, 932, 832, 808, 774 cm-1; HRMS (FAB+) m/z calc’d for C15H15ON2 [(M+H)–H2]+: 239.1184, found 239.1198; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 5.019, minor = 5.890. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 345 NC NC Ph (S)-2-(2-([1,1'-Biphenyl]-4-yl)but-3-en-2-yl)-2-methylmalononitrile (97c). Allylic alkylation product 97c was prepared according to the general procedure and isolated by preparatory TLC (20% Et2O/hexanes, eluted twice) to give a colorless crystalline solid (58 mg, 99% yield): 95% ee; [α]D25 +42.3 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.32 (m, 9H), 6.53 (dd, J = 17.3, 10.9 Hz, 1H), 5.58 (d, J = 10.9 Hz, 1H), 5.46 (d, J = 17.3 Hz, 1H), 1.84 (s, 3H), 1.71 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 141.3, 140.1, 138.2, 138.1, 129.0, 128.5, 127.8, 127.24, 127.21, 119.1, 116.1, 116.0, 49.3, 41.9, 21.8, 21.5; IR (Neat Film, NaCl) 3059, 3032, 2992, 2952, 2247, 1749, 1488, 1450, 1416, 1386, 1267, 1214, 1168, 1102, 1076, 1007, 937, 842, 766, 749, 698 cm-1; HRMS (FAB+) m/z calc’d for C20H18N2 [M]+•: 286.1470, found 286,1466; SFC conditions: 1% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 43.531, minor = 40.798. NC NC F (S)-2-(2-(4-fluorophenyl)but-3-en-2-yl)-2-methylmalononitrile (97d). Allylic alkylation product 97d was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a colorless oil (45 mg, 99% yield): 94% ee; [α]D25 +23.5 (c 3.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 9.0, 5.1 Hz, 2H), 7.09 (dd, J = 9.1, 8.3 Hz, 2H), 6.46 (dd, J = 17.3, 11.0 Hz, 1H), 5.55 (d, Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 346 J = 11.0 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 1.78 (s, 3H), 1.67 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6 (d, J = 249.0 Hz), 138.1, 135.1 (d, J = 3.3 Hz), 130.1, 130.0, 119.3, 115.9 (d, J = 10.2 Hz), 115.6 (d, J = 21.4 Hz), 49.1, 42.0, 21.7, 21.7; IR (Neat Film, NaCl) 3074, 2993, 2247, 1752, 16001, 1509, 1453, 1416, 1386, 1239, 1170, 1097, 1014, 936, 838, 820, 782, 643 cm-1; HRMS (ESI+) m/z calc’d for C14H13FN2 [M]+•: 228.1063, found 228.1036; HPLC conditions: 3% IPA, 1 mL/min, Chiralpak OJ column, λ = 210 nm, tR (min): major = 22.493, minor = 29.003. NC NC (S)-2-Methyl-2-(2-(m-tolyl)but-3-en-2-yl)malononitrile (97e). Allylic alkylation product 97e was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a colorless oil (30 mg, 67% yield): 95% ee; [α]D25 +29.8 (c 1.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.33 (m, 2H), 7.32 – 7.22 (m, 1H), 7.17 (ddt, J = 7.4, 1.4, 0.7 Hz, 1H), 6.48 (dd, J = 17.3, 11.0 Hz, 1H), 5.53 (d, J = 11.0 Hz, 1H), 5.42 (d, J = 17.3 Hz, 1H), 2.38 (d, J = 0.8 Hz, 3H), 1.78 (s, 3H), 1.66 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 139.1, 138.4, 138.3, 129.2, 128.7, 128.5, 125.1, 118.8, 116.1, 116.0, 49.2, 41.8, 21.8, 21.8, 21.4; IR (Neat Film, NaCl) 3092, 2992, 2951, 2924, 2246, 1638, 1606, 1588, 1492, 1454, 1417, 1384, 1250, 1162, 1106, 1042, 1002, 937, 794, 766, 705 cm-1; HRMS (ESI+) m/z calc’d for C15H17N2 [M+H]+: 225.1392, found 225.1387; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 2.897, minor = 3.290. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 347 NC NC Cl (S)-2-(2-(3-Chlorophenyl)but-3-en-2-yl)-2-methylmalononitrile (97f). Allylic alkylation product 97f was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a pale yellow oil (48 mg, 99% yield): 99% ee; [α]D25 +3.2 (c 3.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.43 (m, 2H), 7.40 – 7.30 (m, 2H), 6.43 (dd, J = 17.3, 10.9 Hz, 1H), 5.58 (d, J = 11.0 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 1.78 (s, 3H), 1.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 141.4, 137.6, 134.7, 129.9, 128.8, 128.5, 126.2, 119.6, 115.8, 115.7, 49.3, 41.7, 21.7, 21.4; IR (Neat Film, NaCl) 3071, 2992, 2957, 2247, 1880, 1752, 1637, 1594, 1571, 1478, 1458, 1414, 1261, 1217, 1168, 1094, 999, 938, 885, 811, 739, 695 cm-1; HRMS (ESI+) m/z calc’d for C14H13ClN2 [M]+•: 244.0767, found 244.0773; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.255, minor = 4.955. NC NC NO 2 (S)-2-Methyl-2-(2-(3-nitrophenyl)but-3-en-2-yl)malononitrile (97g). Allylic alkylation product 97g was prepared according to the general procedure and isolated by preparatory TLC (25% Et2O/hexanes) to give a pale yellow solid (43 mg, 84% yield): 93% ee; [α]D25 +38.6 (c 2.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.41 (t, J = 2.1 Hz, 1H), 8.25 (ddd, J Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 348 = 8.3, 2.2, 1.0 Hz, 1H), 7.98 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 6.50 (dd, J = 17.2, 10.9 Hz, 1H), 5.66 (d, J = 11.0 Hz, 1H), 5.46 (d, J = 17.2 Hz, 1H), 1.85 (s, 3H), 1.73 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 148.3, 141.8, 136.9, 134.1, 129.8, 123.7, 123.3, 120.5, 115.4, 115.3, 49.4, 41.7, 21.7, 21.3; IR (Neat Film, NaCl) 3093, 2994, 2957, 2927, 2248, 1749, 1534, 1455, 1418, 1379, 1351, 1266, 1218, 1107, 1002, 942, 906, 854, 812, 795, 739, 721, 688 cm-1; HRMS (ESI+) m/z calc’d for C14H13N2O2 [M]+•: 255.1008, found 255.0983; HPLC conditions: 6% IPA, 1 mL/min, Chiralpak AD– H column, λ = 210 nm, tR (min): major = 12.542, minor = 11.851. NC NC (S)-2-Methyl-2-(2-(naphthalen-2-yl)but-3-en-2-yl)malononitrile (97h). Allylic alkylation product 97h was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a colorless oil (48 mg, 93% yield): 95% ee; [α]D25 +57.9 (c 3.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.2 Hz, 1H), 7.93 – 7.80 (m, 3H), 7.70 (dd, J = 8.8, 2.1 Hz, 1H), 7.57 – 7.49 (m, 2H), 6.60 (dd, J = 17.3, 10.9 Hz, 1H), 5.60 (d, J = 11.0 Hz, 1H), 5.46 (d, J = 17.3 Hz, 1H), 1.91 (s, 3H), 1.70 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.4, 136.5, 132.9, 132.8, 128.6, 128.3, 127.8, 127.5, 127.0, 126.7, 125.4, 119.2, 116.1, 116.0, 49.6, 41.8, 21.8 (2C); IR (Neat Film, NaCl) 3060, 2992, 2950, 2246, 1748, 1637, 1598, 1507, 1453, 1416, 1386, 1277, 1194, 1164, 1130, 1103, 999, 937, 902, 859, 819, 779, 747, 666 cm-1; HRMS (ESI+) m/z calc’d for C18H17N2 [M+H]+: 261.1392, found 261.1378; SFC conditions: 4% Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 349 IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 11.637, minor = 13.691. NC NC Ph (R)-2-Methyl-2-(3-methyl-5-phenylpent-1-en-3-yl)malononitrile (97j). Allylic alkylation product 97j was prepared according to the general procedure and isolated by preparatory TLC (20% Et2O/hexanes, eluted twice) to give a pale yellow oil (31 mg, 65% yield as a 1:1.5 mixture of linear to branched products): 84% ee; [α]D25 +17.0 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 – 7.06 (m, 13.5H), 5.80 (dd, J = 17.3, 10.8 Hz, 1.5H), 5.48 (dd, J = 10.8, 0.5 Hz, 1.5H), 5.30 (dd, J = 17.4, 0.6 Hz, 1.5H), 5.19 – 5.11 (m, 1H), 2.70 (dd, J = 8.9, 6.7 Hz, 2.5H), 2.57 (dq, J = 7.7, 0.7 Hz, 2H), 2.54 – 2.40 (m, 3H), 2.34 (ddd, J = 8.6, 6.4, 1.1 Hz, 2H), 1.94 (ddd, J = 10.3, 6.8, 5.6 Hz, 3H), 1.71 – 1.67 (m, 3H), 1.64 (s, 4.5H), 1.55 (s, 3H), 1.30 (s, 4.5H); 13C NMR (101 MHz, CDCl3) δ 143.7, 141.4, 141.1, 137.0, 128.7, 128.5, 128.4, 126.4, 126.1, 120.5, 116.3, 115.8, 115.7, 115.3, 46.2, 41.8, 41.5, 38.7, 37.4, 34.2, 31.8, 30.9, 23.8, 20.5, 17.1, 16.9; IR (Neat Film, NaCl) 3087, 3064, 3028, 2989, 2930, 2864, 2247, 1949, 1871, 1812, 1638, 1604, 1497, 1453, 1418, 1385, 1277, 1179, 1104, 1074, 1030, 1002, 936, 751, 714, 699, 624 cm-1; HRMS (ESI+) m/z calc’d for C16H19N2 [M+H]+: 239.1548, found 239.1530; SFC conditions: 0.1% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 7.621, minor = 7.163. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 350 NC NC 2-Methyl-2-(2-methylbut-3-en-2-yl)malononitrile (97k). Allylic alkylation product 97k was prepared according to the general procedure and isolated by preparatory TLC (20% Et2O/hexanes, eluted twice) to give a colorless oil (18 mg, 61% yield): 1H NMR (400 MHz, CDCl3) δ 5.92 (dd, J = 17.2, 10.8 Hz, 1H), 5.45 – 5.04 (m, 2H), 1.68 (s, 3H), 1.35 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 138.8, 118.2, 115.8, 42.9, 41.2, 22.9, 20.6; IR (Neat Film, NaCl) 3095, 2981, 2941, 2885, 2248, 1643, 1459, 1419, 1383, 1176, 1155, 1112, 998, 934, 735, 688 cm-1; HRMS (ESI+) m/z calc’d for C9H11N2 [(M+H)–H2]+: 147.0922, found 147.0945. NC NC Ph Et (S)-2-Methyl-2-(3-phenylpent-1-en-3-yl)malononitrile (97l). Allylic alkylation product 97l was prepared according to the general procedure and isolated by preparatory TLC (15% Et2O/hexanes, eluted twice) to give a colorless oil (23 mg, 50% yield): 96% ee; [α]D25 +30.4 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.46 (m, 2H), 7.46 – 7.29 (m, 3H), 6.19 (ddd, J = 17.6, 11.3, 0.7 Hz, 1H), 5.69 (d, J = 11.3 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 2.50 (dqd, J = 14.3, 7.2, 0.7 Hz, 1H), 2.15 (dq, J = 14.4, 7.2 Hz, 1H), 1.60 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 134.8, 134.7, 129.8, 128.58, 128.57, 121.2, 116.3, 116.1, 54.4, 42.6, 26.4, 21.9, 9.1; IR (Neat Film, NaCl) 3094, 3061, 2981, 2944, 2884, 2246, 1638, 1601, 1496, 1448, 1414, 1382, 1180, 1161, 1083, 1002, 940, 751, 704 cm-1; HRMS (FAB+) m/z calc’d for C15H17N2 [M+H]+: Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 351 225.1392, found 225.1377; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 3.270, minor = 4.727. 4.6.2.6 Experimental Procedures and Spectroscopic Data for the Product Transformations of Allylic Alkylation Products NC NC Ph (S)-2-Methyl-2-(2-phenylbutan-2-yl)malononitrile (101). In a nitrogen-filled glove box, to a 1 dram vial equipped with a stir bar was added olefin 93 (25 mg, 0.12 mmol, 1 equiv), RhCl(PPh3)3 (11 mg, 0.012 mmol, 10 mol %) and benzene (1.2 mL). The reaction mixture was removed from the glove box, sparged with hydrogen (balloon) for 5 minutes, and stirred under a hydrogen atmosphere for 18 h, whereupon the reaction was concentrated under reduced pressure. The crude residue was purified by preparatory TLC (20% EtOAc/hexanes) to give alkyl 101 as a colorless oil (23 mg, 92% yield): [α]D25 +16.6 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.31 (m, 5H), 2.58 – 2.46 (m, 1H), 1.94 (dq, J = 13.6, 7.2 Hz, 1H), 1.65 (d, J = 0.9 Hz, 3H), 1.56 (s, 3H), 0.83 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 136.9, 128.7, 128.3 (2C), 116.3, 116.3, 47.3, 43.3, 29.5, 21.2, 20.5, 8.8; IR (Neat Film, NaCl) 3059, 2979, 2943, 2885, 2245, 1602, 15001, 1451, 1391, 1192, 1164, 1098, 1030, 806, 774, 741, 702, 662 cm-1; HRMS (ESI+) m/z calc’d for C14H16N2 [M]+•: 212.1314, found 212.1291. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 352 NC NC O Ph (S)-2-Methyl-2-(1-oxo-2-phenylpropan-2-yl)malononitrile (102). A solution of olefin 93 (40.0 mg, 0.19 mmol, 1 equiv) and pyridine (0.038 mL, 0.48 mmol, 2.5 equiv) in CH2Cl2 (2.0 mL) was cooled to –78 °C. Ozone was bubbled through the resulting solution for 4 min, whereupon the reaction mixture was sparged with O2, warmed to ambient temperature, and diluted with CH2Cl2 (5.0 mL). The reaction mixture was washed with saturated aqueous NaHCO3 (5 mL) and the aqueous layer was further extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were washed with 1 M HCl (5 mL), brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure to give aldehyde 102 as a colorless solid (37 mg, 93% yield): [α]D25 –46.9 (c 2.1, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.55 – 7.45 (m, 3H), 7.41 – 7.30 (m, 2H), 1.88 (s, 3H), 1.70 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.9, 131.1, 130.2, 129.6, 128.9, 115.3, 115.2, 58.3, 37.4, 21.4, 16.3; IR (Neat Film, NaCl) 3033, 3063, 2985, 2954, 2832, 2720, 2249, 1726, 1498, 1448, 1395, 1376, 1262, 1190, 1172, 1080, 923, 869, 764, 703 cm-1; HRMS (ESI+) m/z calc’d for C13H12N2O [M]+•: 212.0950, found 212.0948. NC O NC Ph (S)-4-Acetyl-2-methyl-2-phenylcyclopent-3-ene-1,1-dicarbonitrile (106). A solution of olefin 95f (42 mg, 0.16 mmol, 1 equiv) and pyridine (0.031 mL, 0.39 mmol, 2.5 equiv) in CH2Cl2 (2.0 mL) was cooled to –78 °C. Ozone was bubbled through the resulting solution for 4 min, whereupon the reaction mixture was sparged with O2, warmed to Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 353 ambient temperature, and diluted with CH2Cl2 (5.0 mL). The reaction mixture was washed with saturated aqueous NaHCO3 (5 mL) and the aqueous layer was further extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were washed with 1 M HCl (5 mL), brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was dissolved in benzene (10 mL) and p-toluenesulfonic acid (30.0 mg, 0.16 mmol, 1 equiv) was added. The resulting solution was stirred at ambient temperature for 0.5 h and then heated under reflux for 18 h, whereupon the reaction mixture was cooled to ambient temperature and diluted with Et2O (10 mL). Saturated aqueous NaHCO3 (10 mL) was added to the resulting solution and allowed to stir for 5 min. The organic layer was then separated and washed further with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (33% acetone/hexanes) to give enone 106 as a colorless oil (19 mg, 47% yield over two steps): [α]D25 –27.3 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.36 (m, 5H), 6.91 (dd, J = 2.2, 1.2 Hz, 1H), 3.56 (dd, J = 16.7, 1.2 Hz, 1H), 3.39 (dd, J = 16.7, 2.1 Hz, 1H), 2.48 (s, 3H), 1.82 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.6, 145.4, 140.5, 138.8, 129.5 (d, J = 2.6 Hz), 126.3, 114.7, 114.4, 61.4, 45.7, 42.2, 26.8, 23.6; IR (Neat Film, NaCl) 3063, 2978, 2934, 2249, 1676, 1629, 1499, 1446, 1371, 1335, 1267, 1098, 1026, 953, 896, 764, 699 cm-1; HRMS (FAB+) m/z calc’d for C16H15ON2 [M+H]+: 251.1184, found 251.1197. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation O 354 O H 2N NC Ph (1S,2S)-4-acetyl-1-cyano-2-methyl-2-phenylcyclopent-3-ene-1-carboxamide (103). A solution of bis-nitrile 106 (19 mg, 0.074 mmol, 1 equiv), NaOH (10 mg, 0.25 mmol, 3.4 equiv) in EtOH/H2O (1:1, 1.0 mL) was heated to 60 °C for 18 h, whereupon the resulting mixture was cooled to ambient temperature and diluted with EtOAc (5 mL). The solution was washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparatory TLC (50% acetone/hexanes) to give amide 103 as a colorless oil (7.5 mg, 38% yield, 1:11 dr): [α]D25 +4.4 (c 1.2, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 5H), 6.65 (dd, J = 2.3, 1.1 Hz, 1H), 5.76 (s, 2H), 3.71 (dd, J = 17.0, 2.3 Hz, 1H), 3.22 (dd, J = 17.0, 1.1 Hz, 1H), 2.44 (s, 3H), 1.58 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.4, 165.9, 146.5, 141.9, 129.8, 129.0, 127.4, 124.9, 120.6, 60.5, 59.0, 39.2, 26.9, 21.4; IR (Neat Film, NaCl) 3338, 3201, 3062, 2980, 2929, 2854, 2242, 1732, 1694, 1673, 1604, 1498, 1446, 1371, 1338, 1259, 1102, 1046, 913, 767. 734, 702 cm-1; HRMS (FAB+) m/z calc’d for C16H17O2N2 [M+H]+: 269.1290, found 269.1282. Please note that the NMR data listed is for the major diastereomer, though both diastereomers can be seen in the NMR spectra in a 1:11 ratio. Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 355 Stereochemical Assignment: No NOE H 2N O H H O NC There is an NOE between the bottom allylic proton (blue) and the methyl group, but not the phenyl group and the top allylic proton (red), leading us to believe that it exists in the conformer below Ph NOE NH 2 O Ph H CN H There is a HMBC between the bottom proton (blue) and the amide; thus we believe that the amide is on the top face which provides a great angle for coupling as opposed to if the amide were in the equatorial position, which would be approaching 90 ° O NC O Ph (3R,4S)-3,4-dimethyl-2-oxo-4-phenyltetrahydrofuran-3-carbonitrile (104). A solution of olefin 93 (100.0 mg, 0.48 mmol, 1 equiv) in MeOH (5.0 mL) was cooled to –78 °C. Ozone was bubbled through the reaction mixture for 0.5 h, whereupon the resulting solution was sparged with O2 and NaBH4 (0.80 mg, 2.1 mmol, 4.4 equiv) was added. The reaction was then warmed to 0 °C and stirred for 3 h. The reaction mixture was quenched with the addition of 1 M HCl (5 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (20% acetone/hexanes) to give lactone 104 as a colorless solid (66 mg, 65% yield, 1:2.5 dr): [α]D25 +21.3 (c 3.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.33 (m, 3H), 7.26 – 7.23 (m, 2H), 4.78 (dt, J = 9.1, 0.8 Hz, 1H), 4.50 (d, J = 9.1 Hz, 1H), 1.74 (d, J = 0.8 Hz, 3H), 1.33 (s, 3H); 13C NMR (101 MHz, Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 356 CDCl3) δ 171.7, 138.7, 129.6, 128.5, 125.6, 117.7, 74.6, 49.6, 49.0, 27.1, 18.9; IR (Neat Film, NaCl) 2979, 2930, 2355, 2242, 1783, 1498, 1445, 1381, 1279, 1172, 1092, 1012, 764, 699 cm-1; HRMS (ESI+) m/z calc’d for C13H13NO2 [M]+•: 215.0946, found 215.0966. Please note that the NMR data listed is for the major diastereomer. NOE correlation: O O CN NOE Ph 357 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 4.6.2.7 Determination of Enantiomeric Excess Please note racemic products were synthesized using racemic L5. Table 4.5 Determination of enantiomeric excess Entry Product NC 1 NC Ph NC 2 Et NC Ph NC 3 Bn NC Ph 4 NC NC Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.832 4.594 95% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.378 4.088 95% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 10.960 11.727 93% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.138 3.923 92% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.095 4.061 96% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 5.022 7.267 96% Ph 5 NC NC Ph O 6 NC NC Ph 358 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee SFC Chiralpak OJ–H 1% IPA isocratic, 3.0 mL/min 1.651 1.868 91% SFC Chiralpak OJ–H 1% IPA isocratic, 3.0 mL/min 3.658 4.375 96% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 5.019 5.890 96% SFC Chiralpak OJ–H 1% IPA isocratic, 2.5 mL/min 43.531 40.798 95% HPLC Chiralpak OJ 3% IPA isocratic, 1 mL/min 22.493 29.003 94% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 2.897 3.290 95% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.255 4.955 99% CF3 7 NC NC Ph NC NC 8 NC NC 9 MeO NC NC 10 Ph NC NC 11 F NC NC 12 NC NC 13 Cl 359 Chapter 4 – Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak AD–H 6% IPA isocratic, 1 mL/min 12.542 11.851 93% SFC Chiralpak OJ–H 4% IPA isocratic, 2.5 mL/min 11.637 13.691 95% SFC Chiralpak OJ–H 0.1% IPA isocratic, 2.5 mL/min 7.621 7.163 84% SFC Chiralpak OJ–H 3% IPA isocratic, 2.5 mL/min 3.270 4.727 96% NC NC 14 NO 2 NC NC 15 NC NC 16 Ph NC 17 4.7 (1) NC Et REFERENCES AND NOTES For select reviews, see: (a) Douglas, C. 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Appendix 6 – Spectra Relevant to Chapter 4 365 APPENDIX 6 Spectra Relevant to Chapter 4: Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.1 1H NMR (400 MHz, CDCl3) of compound 93 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 366 Appendix 6 – Spectra Relevant to Chapter 4 367 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 93 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.3 13C NMR (101 MHz, CDCl3) of compound 93 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A6.4 1H NMR (400 MHz, CDCl3) of compound 95a 7.0 2.0 1.5 1.0 0.5 0.0 Appendix 6 – Spectra Relevant to Chapter 4 368 Appendix 6 – Spectra Relevant to Chapter 4 369 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 95a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.6 13C NMR (101 MHz, CDCl3) of compound 95a 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A6.7 1H NMR (400 MHz, CDCl3) of compound 95b 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 370 Appendix 6 – Spectra Relevant to Chapter 4 371 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 95b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.9 13C NMR (101 MHz, CDCl3) of compound 95b 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.10 1H NMR (400 MHz, CDCl3) of compound 95d 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 372 Appendix 6 – Spectra Relevant to Chapter 4 373 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 95d 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.12 13C NMR (101 MHz, CDCl3) of compound 95d 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.13 1H NMR (400 MHz, CDCl3) of compound 95e 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 374 Appendix 6 – Spectra Relevant to Chapter 4 375 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 95e 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.15 13C NMR (101 MHz, CDCl3) of compound 95e 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.16 1H NMR (400 MHz, CDCl3) of compound 95f 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 376 Appendix 6 – Spectra Relevant to Chapter 4 377 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 95f 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.18 13C NMR (101 MHz, CDCl3) of compound 95f 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 f1 (ppm) 4.5 4.0 3.5 3.0 Figure A6.19 1H NMR (400 MHz, CDCl3) of compound 95g 7.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 6 – Spectra Relevant to Chapter 4 378 Appendix 6 – Spectra Relevant to Chapter 4 379 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 95g 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.21 13C NMR (101 MHz, CDCl3) of compound 95g 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.22 1H NMR (400 MHz, CDCl3) of compound 96b 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 380 Appendix 6 – Spectra Relevant to Chapter 4 381 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 96b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.24 13C NMR (101 MHz, CDCl3) of compound 96b 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.25 1H NMR (400 MHz, CDCl3) of compound 96c 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 382 Appendix 6 – Spectra Relevant to Chapter 4 383 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 96c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.27 13C NMR (101 MHz, CDCl3) of compound 96c 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.28 1H NMR (400 MHz, CDCl3) of compound 96f 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 384 Appendix 6 – Spectra Relevant to Chapter 4 385 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 96f 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.30 13C NMR (101 MHz, CDCl3) of compound 96f 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.31 1H NMR (400 MHz, CDCl3) of compound 97a 7.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 6 – Spectra Relevant to Chapter 4 386 Appendix 6 – Spectra Relevant to Chapter 4 387 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 97a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.33 13C NMR (101 MHz, CDCl3) of compound 97a 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.34 1H NMR (400 MHz, CDCl3) of compound 97b 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 388 Appendix 6 – Spectra Relevant to Chapter 4 389 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 97b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.36 13C NMR (101 MHz, CDCl3) of compound 97b 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.37 1H NMR (400 MHz, CDCl3) of compound 97c 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 390 Appendix 6 – Spectra Relevant to Chapter 4 391 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 97c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.39 13C NMR (101 MHz, CDCl3) of compound 97c 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.40 1H NMR (400 MHz, CDCl3) of compound 97d 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 392 Appendix 6 – Spectra Relevant to Chapter 4 393 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 97d 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.42 13C NMR (101 MHz, CDCl3) of compound 97d 20 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.43 1H NMR (400 MHz, CDCl3) of compound 97e 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 394 Appendix 6 – Spectra Relevant to Chapter 4 395 Figure A6.44 Infrared spectrum (Thin Film, NaCl) of compound 97e 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.45 13C NMR (101 MHz, CDCl3) of compound 97e 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.46 1H NMR (400 MHz, CDCl3) of compound 97f 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 396 Appendix 6 – Spectra Relevant to Chapter 4 397 Figure A6.47 Infrared spectrum (Thin Film, NaCl) of compound 97f 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.48 13C NMR (101 MHz, CDCl3) of compound 97f 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.49 1H NMR (400 MHz, CDCl3) of compound 97g 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 398 Appendix 6 – Spectra Relevant to Chapter 4 399 Figure A6.50 Infrared spectrum (Thin Film, NaCl) of compound 97g 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.51 13C NMR (101 MHz, CDCl3) of compound 97g 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.52 1H NMR (400 MHz, CDCl3) of compound 97h 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 400 Appendix 6 – Spectra Relevant to Chapter 4 401 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound 97h 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.54 13C NMR (101 MHz, CDCl3) of compound 97h 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.55 1H NMR (400 MHz, CDCl3) of compound 97j 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 402 Appendix 6 – Spectra Relevant to Chapter 4 403 Figure A6.56 Infrared spectrum (Thin Film, NaCl) of compound 97j 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.57 13C NMR (101 MHz, CDCl3) of compound 97j 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.58 1H NMR (400 MHz, CDCl3) of compound 97k 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 404 Appendix 6 – Spectra Relevant to Chapter 4 405 Figure A6.59 Infrared spectrum (Thin Film, NaCl) of compound 97k 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.60 13C NMR (101 MHz, CDCl3) of compound 97k 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.61 1H NMR (400 MHz, CDCl3) of compound 97l 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 406 Appendix 6 – Spectra Relevant to Chapter 4 407 Figure A6.62 Infrared spectrum (Thin Film, NaCl) of compound 97l 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.63 13C NMR (101 MHz, CDCl3) of compound 97l 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.64 1H NMR (400 MHz, CDCl3) of compound 101 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 408 Appendix 6 – Spectra Relevant to Chapter 4 409 Figure A6.65 Infrared spectrum (Thin Film, NaCl) of compound 101 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.66 13C NMR (101 MHz, CDCl3) of compound 101 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.67 1H NMR (400 MHz, CDCl3) of compound 102 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 410 Appendix 6 – Spectra Relevant to Chapter 4 411 Figure A6.68 Infrared spectrum (Thin Film, NaCl) of compound 102 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.69 13C NMR (101 MHz, CDCl3) of compound 102 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.70 1H NMR (400 MHz, CDCl3) of compound 103 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 412 Appendix 6 – Spectra Relevant to Chapter 4 413 Figure A6.71 Infrared spectrum (Thin Film, NaCl) of compound 103 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 Figure A6.72 13C NMR (101 MHz, CDCl3) of compound 103 20 10 0 -10 10.0 9.0 7.0 6.0 5.0 4.0 f2 (ppm) 3.0 2.0 Figure A6.73 HSQC (400 MHz, CDCl3) of compound 103 8.0 1.0 0.0 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 6 – Spectra Relevant to Chapter 4 414 f1 (ppm) 8.0 7.5 7.0 6.0 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 2.5 Figure A6.74 HMBC (400 MHz, CDCl3) of compound 103 6.5 {3.69,165.73} 2.0 1.5 1.0 0.5 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 Appendix 6 – Spectra Relevant to Chapter 4 415 f1 (ppm) 7.5 7.0 6.5 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 {3.68,1.58} Figure A6.75 NOESY (400 MHz, CDCl3) of compound 103 6.0 {3.73,1.58} 2.5 2.0 1.5 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 Appendix 6 – Spectra Relevant to Chapter 4 416 f1 (ppm) 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.76 1H NMR (400 MHz, CDCl3) of compound 104 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 417 Appendix 6 – Spectra Relevant to Chapter 4 418 Figure A6.77 Infrared spectrum (Thin Film, NaCl) of compound 104 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.78 13C NMR (101 MHz, CDCl3) of compound 104 10 0 -10 9.5 9.0 8.5 8.0 7.0 6.5 6.0 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 2.5 Figure A6.79 NOESY (400 MHz, CDCl3) of compound 104 7.5 2.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 419 f1 (ppm) 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.80 1H NMR (400 MHz, CDCl3) of compound 105 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 420 Appendix 6 – Spectra Relevant to Chapter 4 421 Figure A6.81 Infrared spectrum (Thin Film, NaCl) of compound 105 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.82 13C NMR (101 MHz, CDCl3) of compound 105 10 0 -10 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 4.0 f2 (ppm) 3.5 3.0 2.5 Figure A6.83 NOESY (400 MHz, CDCl3) of compound 105 7.0 {5.78,7.37} {3.18,5.79} 2.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 422 f1 (ppm) 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A6.84 1H NMR (400 MHz, CDCl3) of compound 106 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 4 423 Appendix 6 – Spectra Relevant to Chapter 4 424 Figure A6.85 Infrared spectrum (Thin Film, NaCl) of compound 106 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A6.86 13C NMR (101 MHz, CDCl3) of compound 106 10 0 -10 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 425 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4: Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.1 426 GENERAL EXPERIMENTAL Low-temperature diffraction data (φ-and ω-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu K radiation (λ = 1.54178 Å) from an IµS micro-source for the α structure of compound 97c. The structure was solved by direct methods using SHELXS 1 and refined against F2 on all data by full-matrix least squares with SHELXL-2016 2 using established refinement techniques. 3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). All disordered atoms were refined with the help of similarity restraints on the 1,2- and 1,3-distances and displacement parameters as well as enhanced rigid bond restraints for anisotropic displacement parameters. Compound 97c crystallizes in the tetragonal space group I41 with half a molecule in the asymmetric unit. The molecule is located near a crystallographic 2fold rotation axis and is disordered by the rotation. The phenyl moiety was disordered over four positions, two of which are pairwise related to the other two by the 2-fold rotation. This requires a number of SADI restraints during refinement. We note that a Bayesian analysis of the Friedel pairs (performed using the "Bijvoet-Pair Analysis" routine of PLATON) confirms the absolute stereochemical assignment based on the Flack x. The output of this analysis gives: Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 427 Bayesian Statistics Student_T Nu 99 Select Pairs 752 Theta_Min .. 5.23 Theta_Max ..74.45 P2(true).... 1.000 P3(true).... 0.999 P3(rac-twin) 0.8E-03 P3(false) ..0.8E-08 G .......... 2.0938 G (su) ..... 0.4726 Hooft y .... -0.5(2) A7.1.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF BIS-NITRILE 97c NC NC Ph Bis-nitrile 97c (95% ee) was recrystallized from boiling hexane to provide crystals suitable for X-ray analysis. Figure A7.1 X-ray crystal structure of bis-nitrile 97c 428 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1 Crystal data and structure refinement for bis-nitrile 97c Empirical formula C20 H18 N2 Formula weight 286.36 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Tetragonal Space group I41 Unit cell dimensions a = 10.0971(4) Å a= 90°. b = 10.0971(4) Å b= 90°. c = 15.5215(7) Å g = 90°. Volume 1582.44(14) Å3 Z 4 Density (calculated) 1.202 Mg/m3 Absorption coefficient 0.545 mm-1 F(000) 608 Crystal size 0.600 x 0.150 x 0.150 mm3 Theta range for data collection 5.226 to 74.482°. Index ranges -12<=h<=12, -12<=k<=12, -17<=l<=19 Reflections collected 10160 Independent reflections 1590 [R(int) = 0.0381] Completeness to theta = 67.679° 99.6 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.5549 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1590 / 823 / 256 Goodness-of-fit on F2 1.044 Final R indices [I>2sigma(I)] R1 = 0.0422, wR2 = 0.1227 R indices (all data) R1 = 0.0433, wR2 = 0.1248 Absolute structure parameter -0.6(3) Extinction coefficient n/a Largest diff. peak and hole 0.211 and -0.114 e.Å-3 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 429 Table A7.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 97c. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ C(11) 4978(4) 4611(3) 4288(2) 41(1) C(12) 3831(6) 4487(6) 4770(4) 50(1) C(13) 3815(16) 4637(13) 5665(6) 44(2) C(14) 4960(20) 4930(50) 6109(3) 47(3) C(15) 6113(19) 5045(15) 5612(9) 58(3) C(16) 6135(6) 4925(6) 4736(4) 50(1) C(21) 5150(20) 4990(50) 7046(10) 44(3) C(22) 4028(19) 5180(30) 7561(12) 58(4) C(23) 4064(18) 5150(30) 8460(12) 68(4) C(24) 5262(18) 4980(40) 8853(12) 63(5) C(25) 6388(16) 4750(30) 8376(10) 69(4) C(26) 6337(17) 4800(30) 7479(10) 54(3) C(21A) 4840(30) 4910(40) 7104(13) 43(5) C(22A) 3718(19) 4470(30) 7512(12) 47(4) C(23A) 3681(18) 4450(20) 8410(11) 57(4) C(24A) 4750(30) 4830(40) 8896(17) 56(6) C(25A) 5830(20) 5330(30) 8484(15) 57(4) C(26A) 5890(20) 5390(30) 7587(15) 52(4) C(1) 5012(4) 4373(4) 3312(3) 45(1) C(2) 6410(11) 3889(10) 3042(7) 52(2) C(3) 6731(6) 2674(6) 2858(5) 78(2) C(4) 3908(17) 3438(17) 3046(13) 70(5) C(5) 4782(5) 5744(4) 2825(3) 51(1) C(6) 3509(14) 6450(11) 3020(8) 65(3) C(7) 5866(16) 6713(17) 3030(10) 50(2) N(1) 6596(5) 7446(5) 3232(4) 78(1) C(8) 4876(5) 5491(6) 1886(3) 64(1) N(2) 5010(30) 5250(20) 1173(3) 100(6) _____________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3 Bond lengths [Å] and angles [°] for 97c _____________________________________________________ C(11)-C(12) 1.385(7) C(11)-C(16) 1.396(7) C(11)-C(1) 1.534(6) C(12)-C(13) 1.398(11) C(12)-H(12) 0.9500 C(13)-C(14) 1.380(16) C(13)-H(13) 0.9500 C(14)-C(15) 1.400(16) C(14)-C(21) 1.467(18) C(15)-C(16) 1.366(14) C(15)-H(15) 0.9500 C(16)-H(16) 0.9500 C(21)-C(26) 1.390(17) C(21)-C(22) 1.397(17) C(22)-C(23) 1.396(17) C(22)-H(22) 0.9500 C(23)-C(24) 1.366(18) C(23)-H(23) 0.9500 C(24)-C(25) 1.376(16) C(24)-H(24) 0.9500 C(25)-C(26) 1.394(15) C(25)-H(25) 0.9500 C(26)-H(26) 0.9500 C(21A)-C(22A) 1.374(19) C(21A)-C(26A) 1.384(19) C(22A)-C(23A) 1.395(17) C(22A)-H(22A) C(23A)-C(24A) C(23A)-H(23A) C(24A)-C(25A) C(24A)-H(24A) C(25A)-C(26A) C(25A)-H(25A) C(26A)-H(26A) C(1)-C(4) C(1)-C(2) 0.9500 1.37(2) 0.9500 1.36(2) 0.9500 1.395(18) 0.9500 0.9500 1.518(16) 1.551(11) 430 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 C(1)-C(5) C(2)-C(3) C(2)-H(2) C(3)-H(3A) C(3)-H(3B) C(4)-H(4A) C(4)-H(4B) C(4)-H(4C) C(5)-C(8) C(5)-C(6) C(5)-C(7) C(6)-H(6A) C(6)-H(6B) C(6)-H(6C) C(7)-N(1) C(8)-N(2) C(12)-C(11)-C(16) C(12)-C(11)-C(1) C(16)-C(11)-C(1) C(11)-C(12)-C(13) C(11)-C(12)-H(12) C(13)-C(12)-H(12) C(14)-C(13)-C(12) C(14)-C(13)-H(13) C(12)-C(13)-H(13) C(13)-C(14)-C(15) C(13)-C(14)-C(21) C(15)-C(14)-C(21) 1.594(6) 1.301(10) 0.9500 0.9500 0.9500 0.9800 0.9800 0.9800 1.482(7) 1.501(13) 1.503(15) 0.9800 0.9800 0.9800 1.091(15) 1.141(9) 116.9(3) 122.6(4) 120.5(4) 122.5(8) 118.8 118.8 120.7(9) 119.7 119.7 116.0(5) 127.6(17) 115.9(18) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(14)-C(15)-H(15) C(15)-C(16)-C(11) C(15)-C(16)-H(16) C(11)-C(16)-H(16) C(26)-C(21)-C(22) C(26)-C(21)-C(14) C(22)-C(21)-C(14) C(23)-C(22)-C(21) 123.8(11) 118.1 118.1 120.1(9) 119.9 119.9 116.1(14) 126(2) 118(2) 123.3(16) 431 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 C(23)-C(22)-H(22) 118.3 C(21)-C(22)-H(22) 118.3 C(24)-C(23)-C(22) 118.1(16) C(24)-C(23)-H(23) 121.0 C(22)-C(23)-H(23) 121.0 C(23)-C(24)-C(25) 120.9(15) C(23)-C(24)-H(24) 119.5 C(25)-C(24)-H(24) 119.5 C(24)-C(25)-C(26) 120.0(15) C(24)-C(25)-H(25) 120.0 C(26)-C(25)-H(25) 120.0 C(21)-C(26)-C(25) 121.3(13) C(21)-C(26)-H(26) 119.3 C(25)-C(26)-H(26) 119.3 C(22A)-C(21A)-C(26A) 119.6(19) C(21A)-C(22A)-C(23A) 119.1(16) C(21A)-C(22A)-H(22A) 120.5 C(23A)-C(22A)-H(22A) 120.5 C(24A)-C(23A)-C(22A) 121.7(17) C(24A)-C(23A)-H(23A) 119.1 C(22A)-C(23A)-H(23A) 119.1 C(25A)-C(24A)-C(23A) 118(2) C(25A)-C(24A)-H(24A) 120.8 C(23A)-C(24A)-H(24A) 120.8 C(24A)-C(25A)-C(26A) 121(2) C(24A)-C(25A)-H(25A) 119.5 C(26A)-C(25A)-H(25A) 119.5 C(21A)-C(26A)-C(25A) 119.8(18) C(21A)-C(26A)-H(26A) 120.1 C(25A)-C(26A)-H(26A) 120.1 C(4)-C(1)-C(11) 110.4(8) C(4)-C(1)-C(2) 113.5(9) C(11)-C(1)-C(2) 109.7(6) C(4)-C(1)-C(5) 107.7(7) C(11)-C(1)-C(5) 109.2(3) C(2)-C(1)-C(5) 106.2(5) C(3)-C(2)-C(1) 125.7(8) C(3)-C(2)-H(2) 117.1 432 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 433 C(1)-C(2)-H(2) 117.1 C(2)-C(3)-H(3A) 120.0 C(2)-C(3)-H(3B) 120.0 H(3A)-C(3)-H(3B) 120.0 C(1)-C(4)-H(4A) 109.5 C(1)-C(4)-H(4B) 109.5 H(4A)-C(4)-H(4B) 109.5 C(1)-C(4)-H(4C) 109.5 H(4A)-C(4)-H(4C) 109.5 H(4B)-C(4)-H(4C) 109.5 C(8)-C(5)-C(6) 109.6(7) C(8)-C(5)-C(7) 105.9(7) C(6)-C(5)-C(7) 105.8(8) C(8)-C(5)-C(1) 107.9(4) C(6)-C(5)-C(1) 116.2(5) C(7)-C(5)-C(1) 111.0(8) C(5)-C(6)-H(6A) 109.5 C(5)-C(6)-H(6B) 109.5 H(6A)-C(6)-H(6B) 109.5 C(5)-C(6)-H(6C) 109.5 H(6A)-C(6)-H(6C) 109.5 H(6B)-C(6)-H(6C) 109.5 N(1)-C(7)-C(5) 174.5(14) N(2)-C(8)-C(5) 176(2) _____________________________________________________________ Table A7.4 Anisotropic displacement parameters (Å2x 103) for 97c. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] _____________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ C(11) 47(2) 43(2) 34(2) 1(1) 1(1) 4(2) C(12) 42(2) 67(3) 43(2) 2(3) 5(2) 2(3) C(13) 53(3) 48(5) 32(3) 2(3) 8(2) 3(3) C(14) 65(3) 39(7) 37(2) 1(4) 6(5) 7(3) C(15) 55(3) 62(8) 58(4) -15(4) -8(3) -3(4) C(16) 49(2) 56(3) 46(3) -3(3) 4(2) -5(3) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 434 C(21) 56(8) 31(5) 44(5) -5(6) 10(5) 1(8) C(22) 63(9) 67(8) 45(6) 1(6) 4(5) -1(8) C(23) 80(9) 83(9) 40(6) -1(6) 9(6) -2(10) C(24) 85(10) 69(10) 36(6) -5(6) 11(6) -3(10) C(25) 82(9) 89(9) 36(5) -11(4) 5(5) -14(8) C(26) 64(8) 72(8) 26(4) -3(4) 3(4) -7(7) C(21A) 64(10) 47(10) 18(6) -10(7) 4(7) 2(9) C(22A) 51(8) 55(9) 36(6) 0(5) 5(5) 7(7) C(23A) 64(9) 69(10) 37(6) -11(6) 5(6) 5(7) C(24A) 75(11) 58(11) 35(8) -3(6) 2(7) -2(8) C(25A) 71(10) 63(10) 38(7) 1(7) -4(7) -4(9) C(26A) 64(10) 46(8) 46(7) 1(7) 4(6) -3(9) C(1) 48(2) 47(2) 39(2) -5(2) 4(2) -2(1) C(2) 66(3) 41(4) 49(3) -11(3) 19(2) -3(3) C(3) 82(3) 66(3) 86(4) -8(3) 32(3) 0(3) C(4) 79(7) 73(8) 57(6) -24(5) 15(5) -25(6) C(5) 57(2) 59(2) 37(3) 2(2) -3(2) -2(2) C(6) 91(5) 51(6) 53(3) 21(3) 18(3) 17(3) C(7) 67(4) 48(3) 36(4) -1(3) -2(3) 2(3) N(1) 86(3) 62(2) 84(3) -4(2) 7(2) -12(2) C(8) 64(3) 84(3) 45(3) 4(2) 0(2) -21(3) N(2) 100(3) 164(18) 35(2) -7(4) 8(4) -60(11) _____________________________________________________________________ Table A7.5 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 103) for 97c _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(12) 3024 4292 4482 61 H(13) 3007 4534 5971 53 H(15) 6925 5212 5901 70 H(16) 6940 5055 4430 60 H(22) 3202 5331 7286 70 H(23) 3277 5256 8789 81 H(24) 5318 5012 9463 76 H(25) 7201 4562 8658 83 H(26) 7131 4701 7157 65 435 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 H(22A) H(23A) H(24A) H(25A) H(26A) H(2) H(3A) H(3B) H(4A) H(4B) H(4C) H(6A) H(6B) H(6C) 2977 2893 4744 6561 6643 7091 6082 7615 3973 3049 3988 3559 3364 2773 4171 4179 4738 5645 5751 4536 1995 2467 3256 3848 2607 7361 6462 5988 7187 8693 9506 8813 7309 3009 2883 2698 2428 3172 3368 2805 3644 2738 57 68 67 69 62 62 93 93 104 104 104 98 98 98 Table A7.6 Torsion angles [°] for 97c ________________________________________________________________ C(16)-C(11)-C(12)-C(13) -1.3(8) C(1)-C(11)-C(12)-C(13) 176.6(7) C(11)-C(12)-C(13)-C(14) 1(3) C(12)-C(13)-C(14)-C(15) -1(5) C(12)-C(13)-C(14)-C(21) -173(4) C(13)-C(14)-C(15)-C(16) 3(5) C(21)-C(14)-C(15)-C(16) 175(3) C(14)-C(15)-C(16)-C(11) -3(3) C(12)-C(11)-C(16)-C(15) 2.5(9) C(1)-C(11)-C(16)-C(15) -175.4(8) C(13)-C(14)-C(21)-C(26) 154(3) C(15)-C(14)-C(21)-C(26) -18(6) C(13)-C(14)-C(21)-C(22) -22(6) C(15)-C(14)-C(21)-C(22) 166(3) C(26)-C(21)-C(22)-C(23) -1(3) C(14)-C(21)-C(22)-C(23) 175(4) C(21)-C(22)-C(23)-C(24) 2(3) C(22)-C(23)-C(24)-C(25) -4(4) C(23)-C(24)-C(25)-C(26) 5(4) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 C(22)-C(21)-C(26)-C(25) 2(3) C(14)-C(21)-C(26)-C(25) -174(4) C(24)-C(25)-C(26)-C(21) -4(3) C(26A)-C(21A)-C(22A)-C(23A) -3(3) C(21A)-C(22A)-C(23A)-C(24A) -2(3) C(22A)-C(23A)-C(24A)-C(25A) 6(5) C(23A)-C(24A)-C(25A)-C(26A) -4(5) C(22A)-C(21A)-C(26A)-C(25A) 4(3) C(24A)-C(25A)-C(26A)-C(21A) -1(4) C(12)-C(11)-C(1)-C(4) -25.7(9) C(16)-C(11)-C(1)-C(4) 152.2(8) C(12)-C(11)-C(1)-C(2) -151.5(6) C(16)-C(11)-C(1)-C(2) 26.4(6) C(12)-C(11)-C(1)-C(5) 92.6(5) C(16)-C(11)-C(1)-C(5) -89.6(5) C(4)-C(1)-C(2)-C(3) -20.9(15) C(11)-C(1)-C(2)-C(3) 103.2(11) C(5)-C(1)-C(2)-C(3) -138.9(9) C(4)-C(1)-C(5)-C(8) -62.4(9) C(11)-C(1)-C(5)-C(8) 177.7(4) C(2)-C(1)-C(5)-C(8) 59.5(6) C(4)-C(1)-C(5)-C(6) 61.1(11) C(11)-C(1)-C(5)-C(6) -58.8(8) C(2)-C(1)-C(5)-C(6) -177.0(8) C(4)-C(1)-C(5)-C(7) -178.0(10) C(11)-C(1)-C(5)-C(7) 62.1(7) C(2)-C(1)-C(5)-C(7) -56.1(8) ________________________________________________________________ A7.2 REFERENCES AND NOTES (1) Sheldrick, G. M. Acta Cryst. 1990, A46, 467–473. (2) Sheldrick, G. M. Acta Cryst. 2015, C71, 3–8. (3) Müller, P. Crystallography Reviews 2009, 15, 57–83. 436 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 437 CHAPTER 5 Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary† 5.1 INTRODUCTION To enable our ongoing research program focused on the synthesis of complex natural products, we became intested in developing robust methods for the synthesis of stereochemically rich building blocks containing quaternary stereocenters. As a result, our group has developed a range of technologies for the enantioselective preparation of all-carbon quaternary stereocenters. 1 Perhaps most notably, we reported a general asymmetric palladium-catalyzed allylic alkylation method to provide access to a wide variety of products 109 bearing a homoallylic quaternary stereocenter (Figure 5.1, top).2 Over the past decade, we have expanded this methodology to a broad array of substrates 107 3 and applied this chemistry to facilitate expedient total syntheses of a variety of † Portions of this chapter have been reproduced from Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. Manuscript submitted. 438 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary natural products, including (–)-cyanthiwigin F (110),4 (+)-dichroanone (111),5 and (+)sibirinine (112, Figure 5.1, bottom).6 Figure 5.1 Stoltz group contributions to palladium-catalyzed allylic alkylation methodology and application in natural product total synthesis Stoltz Group Palladium-Catalyzed Allylic Alkylation (2004–present) Homoallylic Quaternary Stereocenters Nuc R4 + LG L* [PdL*] OR R4 Nuc O R4 O Pd R1 R3 R1 R2 R3 R4 O R2 108 109 107 prochiral Enantioselective O Select Synthetic Applications O OH H O N O H O O (–)-cyanthiwigin F (110) (+)-dichroanone (111) (+)-sibirinine (112) Despite its extensive substrate tolerance, our palladium-catalyzed allylic alkylation technology is limited to the synthesis of isolated stereocenters. Thus, to date, this methodology is not amenable to the direct preparation of vicinal stereocenters, which are found in a variety of synthetic targets such as ligularone (1), crinipellin B (2), and elisabethin A (3, Figure 5.2, top). Inspired by these diverse and numerous stereodyadcontaining natural products, we sought to expand our stereoselective allylic alkylation research program to include iridium-catalyzed processes that do enable the construction of such vicinal stereocenters 114 (Figure 5.2, bottom). 439 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Figure 5.2 Stereodyad-containing natural products as inspiration for the development of novel iridium-catalyzed allylic alkylation technology Select Natural Products Inaccessible via Palladium-Catalyzed Allylic Alkylation HO O O H H O O O O H O OH H ligularone (1) crinipellin B (2) elisabethin A (3) Stoltz Group Initial Planned Iridium-Catalyzed Allylic Alkylation Vicinal 4°/3° Stereocenters (Unreported as of 2013) [IrL*] + R2 R1 113 EWG EWG R3 R2 R3 R1 108 114 prochiral Regioselective Enantioselective Diastereoselective While the aforementioned palladium-catalyzed allylic alkylation has been under exploration since the 1960s,7 iridium-catalyzed allylic alkylation is a relatively new area of research. Takeuchi reported the first example of iridium-catalyzed allylic alkylation in 1997 using malonate nucleophiles 115, demonstrating that iridium catalysts can provide high branched selectivity (branched to linear ratio, b:l) in contrast to palladium catalysts that favor the synthesis of linear products (Figure 5.3a).8,9 Shortly thereafter, Helmchen reported that the reaction could be rendered enantioselective with the inclusion of chiral phosphinooxazoline ligand L12 (Figure 5.3b).10 In 2003, Takemoto disclosed the first report of a diastereoselective iridium-catalyzed allylic alkylation reaction, wherein prochiral nucleophiles 120 were utilized to form vicinal trisubstituted and tertiary stereocenters 122 (Figure 5.3c, top).11 It was then a decade later before the next report of diastereoselective iridium-catalyzed allylic alkylation was disclosed, which this time 440 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary enabled the preparation of vicinal tertiary and tetra-substituted stereocenters 125 (Figure 5.3c, bottom).12 Figure 5.3 Timeline for the development of iridium-catalyzed allylic alkylation prior to the Stoltz group’s entry into the field a) First Report of Iridium-Catalyzed Allylic Alkylation Takeuchi (1997) + NaCH(CO 2Me) 2 R [Ir(cod)Cl] 2 (2 mol %) P(OPh) 3 (4 mol %) R 115 OAc 116 MeO2C O THF, reflux CO2Me N P(Ar) 2 117 70–100% yield 93:7–100:0 b:l Regioselective b) First Enantioselective Iridium-Catalyzed Allylic Alkylation Helmchen (1997) Ar = 4-(CF3 )C6H 4 (S)-L12 NaCH(CO 2Me) 2 [Ir(cod)Cl] 2 (2 mol %) (S)-L12 (4 mol %) 115 + OAc Ar 118 R MeO2C SEt THF, reflux 93–100% yield 62:38–99:1 b:l 78–95% ee O CO2Me P 119 O Regioselective Enantioselective (R a )-L1 c) First Diastereoselective Iridium-Catalyzed Allylic Alkylations Takemoto (2003) Ph Ph 120 N CO2t-Bu Ar Ar t-BuO 2C O P N + KOH (aq), THF, 0 °C OPO(OEt)2 Ar [Ir(cod)Cl] 2 (10 mol %) (R a )-L1 (20 mol %) 121 63–97% yield 100:1 b:l 94–97% ee 2:1–4:1 dr Ph N O Ar Ph 122 Ar = 2-MeO-C6H 4 Regioselective Enantioselective Diastereoselective (R,R,R a )-L3 Hartwig (2013) t-Bu O 123 R O N O O Ph OCO 2Me 69–93% yield 94–99% ee 7:1–20:1 dr 125 O P R Ar N 3 Å MS, PhMe, 23 °C + 124 t-Bu O O Ph Ar [Ir(cod)Cl] 2 (2 mol %) (R,R,R a )-L3 (4 mol %) 17 (8 mol %) t-Bu OAg t-Bu 17 Regioselective Enantioselective Diastereoselective Despite these seminal reports, when our group entered the field in 2013, there were no examples of an iridium-catalyzed allylic alkylation reaction to form a single all- Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 441 carbon quaternary stereocenter, let alone a stereodyad containing an all-carbon quaternary stereocenter. 13 Therefore, we were highly intrigued by the possibility of developing new iridium-catalyzed allylic alkylation technology that would allow for the preparation of sterically congested enantioenriched quaternary stereocenters, and thus potentially open the door to the synthesis of a range of new natural product targets (Figure 5.2, top). 5.2 SYNTHESIS OF VICINAL TERTIARY AND ALL-CARBON QUATERNARY STEREOCENTERS VIA ENANTIO- AND DIASTEREOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION 5.2.1 CYCLIC NUCLEOPHILES14,15 In our quest to develop the first iridium-catalyzed allylic alkylation reaction to form vicinal tertiary and all-carbon quaternary stereocenters, we initially selected cyclic prochiral enolates as our nucleophiles in order to obviate the need to control enolate geometry during the allylic alkylation reaction.1,16 Thus, our preliminary exploration into this research area commenced with tetralone 27. We rapidly found that the standard phosphoramidite ligands L13 and L9, which were at the time typically utilized in iridium-catalyzed allylic alkylation with enolate equivalents, were not amenable to the synthesis of a quaternary stereocenter, as neither provided high levels of diastereoselectivity (Table 5.1, entries 1 and 2). Inspired by the work of the You group on the allylic alkylation of heterocycles,17 we evaluated the effect of MeTHQPhos (L2) as the ligand and found that it provided product 127 with a high degree of regio-, diastereo-, and enantioselectivity (entry 3). 442 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Table 5.1 Development of conditions for the iridium-catalyzed allylic alkylation reaction of cyclic nucleophiles forming vicinal tertiary and all-carbon quaternary stereocentersa O [Ir(cod)Cl] 2 (2 mol %) O OMe O Ph L (4 mol %), TBD (10 mol %) + Ph 27 OCO 2Me THF, 20 °C CO2Me 126 127 Entry L Additive (X mol %) b:lb drb ee (%)c 1 L13 NaH (200) >95:5 1:1 99 2 L9 NaH (200) >95:5 1:2 32 3 L2 NaH (200) 95:5 >20:1 98 4 L2 – 80:20 11:1 96 5 L2 LiCl (100) 88:12 14:1 98 6 L2 LiBr (100) 95:5 >20:1 >99 Ph O Ph O P N O O P N O P N O Ph Ph (S,S,R a )-L13 (S,S,S a )-L9 (R,R a )-L2 [a] Reactions performed with 0.1 mmol of 126, 0.2 mmol of 27 in THF (0.1M) and allowed to proceed to complete consumption of 126. [b] Determined by 1H NMR and UHPLC-MS analysis of the crude mixture. [c] Determined by chiral HPLC analysis of the major diastereomer. [d] TBD = 1,3,5-triazabicyclo[4.4.0]dec-5-ene. At this point in our optimization efforts, we realized that the reaction conditions could be simplified if the exogenous base was removed and the carbonate leaving group was instead relied on as the stoichiometric base required for enolate formation. Toward this end, sodium hydride was excluded from the reaction, but we observed diminished selectivity (Table 5.1, entry 4). Previous literature reports documented the beneficial effects of halide salts on selectivity in iridium-catalyzed allylic alkylation reactions.18 When this strategy was explored in our reaction conditions, LiCl provided only minor enhancement in selectivity (entry 5). However, LiBr led to a pronounced enhancement in Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 443 both conversion and selectivity, providing us with our optimized reaction conditions (entry 6). Upon investigating the substrate scope of the developed transformation, we found the reaction amenable to a wide variety of substitution on both the allylic electrophile and the nucleophile (Scheme 5.1).14 Though, as a general trend, branched regioselectivity increases with greater carbocation stability on the allylic electrophile, thus electron-rich aromatics 129 (R2 = EDG–Ar) provide higher branched to linear ratios. Additionally, the reaction is not limited to aryl substitution on the allylic electrophile, as both heteroaryl and alkenyl substitution provide the corresponding products in good yields and selectivities (e.g., 131a). A key limitation to this initial report is that alkyl-substituted allylic electrophiles are not tolerated and instead proceed with poor conversions and selectivities. With respect to nucleophile 128, we found that the aryl ring of tetralone 27, used as the optimization substrate, could be removed without diminishing reactivity or stereoselectivity of the reaction (e.g., as seen in products 131b and 131c). Finally, we observed that unsaturated nucleophiles 128 are tolerated, allowing for access to products bearing a 1,5-diene (e.g., 131d) for subsequent functionalization, though the addition of LiBr was not required in these reactions.15 444 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Scheme 5.1 Enantio- and diastereoselective iridium-catalyzed allylic alkylation of cyclic nucleophiles 128 O [Ir(cod)Cl] 2 (2 mol %) (R,R a )-L2 (4 mol %) TBD (10 mol %) LiBr (100 mol %) O OR1 + R2 R2 X CO2R 1 n OCO 2Me THF, 20 °C n X O 128 129 130 Select examples O O O Ph O Ph Ph CO2Me CO2Me CO2Me CO2Et O a 131a 131b 131c 131d 92% yield 95:5 b:l 10:1 dr 90% ee 85% yield 93:7 b:l 8:1 dr 99% ee 88% yield 90:10 b:l 16:1 dr 98% ee 99% yield >20:1 b:l 2:1 dr 95% ee [a] Reaction performed with (S,Sa)-L2 without LiBr. Upon further optimization, we found that the reactions of unsaturated nucleophiles (e.g., 132) progressed with a higher degree of selectivity when LiOt-Bu was utilized as a base additive in place of LiBr.15 These allylic alkylation conditions followed by a subsequent thermal Cope rearrangement, allow unsaturated compounds 132 to formally undergo allylic alkylation at the γ-position to produce comounds such as 35 with a high degree of enantioselectivity (Scheme 5.2). Scheme 5.2 Iridium-catalyzed allylic alkylation/Cope rearrangment sequence MeO 2C 1. [Ir(cod)Cl] 2 (2 mol %) (R,R a )-L2 (4 mol %) TBD (10 mol %) LiOt-Bu (120 mol %) THF (0.1 M), 20 °C CO2Me + X 132 OCO 2Me Ar n 124 MeO 2C CO2Me Ar 2. toluene, 100 °C 12 examples 72–97% yield 90–97% ee X n 133 γ-allylic alkylation product 445 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 5.2.2 ACYCLIC NUCLEOPHILES19 In looking to expand our iridium-catalyzed allylic alkylation reaction from cyclic enolate nucleophiles to acyclic variants, we fortuitously discovered that our conditions for cyclic nucleophiles provide satisfactory reactivity and selectivity for acyclic nucleophile 134 (Scheme 5.3). With further optimization though, we ultimately found LiOt-Bu to be the optimal additive as it led to shorter reaction times. With respect to the substrate scope of this transformation, we again observed that reaction regioselectivity is directly affected by the electronics of the aryl functionality on allylic electrophile 135, however, enantio- and diastereoselectivities remain consistently excellent. Moreover, heteroaryl-substituted allylic electrophiles are tolerated, as are various substituents at the α-position of acyclic β-ketoester nucleophile 134. However, in contrast to the cyclic variants, we noted pronounced decreases in the diastereomeric ratio of product 136 when ketone 134 was not an aryl ketone (e.g., 136a versus 136d). Scheme 5.3 Enantio- and diastereoselective iridium-catalyzed allylic alkylation of acyclic nucleophiles 134 [Ir(cod)Cl] 2 (2 mol %) O (R,R a )-L2 (4 mol %), TBD (10 mol %) O R1 OR 3 R4 OCO 2Me THF, 25 °C R2 R1 R 2 CO2R 3 135 134 R4 O LiOt-Bu (200 mol %) + 136 Select examples OMe Br O O Ph Ph CO2Et O Ph Bn CO2Et Ph CO2Et O Ph Cy CO2Et 136a 136b 136c 136d 85% yield 99:1 b:l >20:1 dr 99% ee 98% yield 86:14 b:l 19:1 dr 99% ee 99% yield 90:10 b:l 13:1 dr 99% ee 92% yield 92:8 b:l 4:1 dr 96% ee Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 446 5.2.3 ALKYL-SUBSTITUTED ELECTROPHILES20 After disclosing methods for the synthesis of vicinal tertiary and all-carbon quaternary stereocenters using cyclic,14 acyclic,19 and extended enolate15 nucleophiles in iridium-catalyzed allylic alkylation, we noted that none of these protocols tolerated the use of alkyl-substituted electrophiles. In fact, at the time, no transition metal-catalyzed process enabled the construction of an alkyl-substituted stereodyad between neighboring tertiary and quaternary carbon atoms. Realizing that many synthetic targets require the installation of this specific stereodyad, we became intrigued with the possibility of further developing our enantio- and diastereoselective iridium-catalyzed allylic alkylation chemistry to allow for the use of allylic electrophiles bearing an sp3-hybridized substituent. Based on our prior efforts in optimizing iridium-catalyzed allylic alkylation reactions, we anticipated that we would need to explore new combinations of additives and ligands in order to effect selectivity in the reaction between tetralone nucleophile 52, utilized in our seminal report14 (Table 5.1), and alkyl-substituted electrophile 53 (Table 5.2). Indeed, when we employed our previously reported conditions for cyclic or acyclic nucleophiles,14,19 we observed excellent yields and good diastereoselectivities but poor branched to linear ratios (Table 5.2, entries 1 and 2). Given the trends established in our earlier work where regioselectivity increases with increasing carbocation stability of the iridium π-allyl cation, these findings were not surprising as the methyl group is less stabilizing than an aryl substituent. We hypothesized that decreasing carbocation stability results in slow equilibration between iridium π-allyl diastereomers. Thus, we sought to employ LiCl as an additive, which has been proposed to facilitate iridium π-allyl 447 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary equilibration and therefore improve regio- and enantioselectivity in iridium-catalyzed allylic alkylation reactions.18 While we did not see a marked effect by adding LiCl alone (entry 3), we postulated that by rendering all anions in solution congruent, the effect of the chloride additive would be more pronounced. This hypothesis led us to replace the methyl carbonate leaving group of crotyl electrophile 53 with chloride, and in doing so we noted a significant increase in reaction regioselectivity, though the diastereoselectivity was now only moderate (entry 4). Table 5.2 Optimization of iridium-catalyzed allylic alkylation reaction of alkyl-substituted electrophile 53a R O [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L (4 mol %) TBD (10 mol %) O + OMe LG CO 2Me THF, 25 °C 52 O P N O O 53 R R = H: (S,S a )-L2 R = Ph: (S,S a )-L11 54 Entry L Base (200 mol %) Additive (mol %) LG Yield (%)b b:l c drc ee (%)d 1 L2 – LiBr (100) OCO2Me 100 55:45 6.4:1 – 2 L2 LiOt-Bu – OCO2Me 85 34:66 5.3:1 – 3 L2 LiOt-Bu LiCl (100) OCO2Me 69 50:50 7.2:1 – 4 L2 LiOt-Bu LiCl (100) Cl 94 86:14 4.8:1 – 5 L2 proton sponge LiCl (100) Cl 100 93:7 7.9:1 66 6 L11 proton sponge LiCl (100) Cl 46 95:5 6.0:1 96 7 L11 proton sponge LiCl (400) Cl 78 94:6 6.7:1 97 [a] Reactions performed on 0.1 mmol of 53, 0.2 mmol of 52 in THF (0.1 M) for 18 h. [b] 1H NMR yield of the mixture of diastereomers based on internal standard. [c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined by chiral SFC analysis. [e] Proton sponge = 1,8-bis(dimethylamino)naphthalene. We next sought to improve the diastereoselectivity of the reaction by investigating additional bases other than LiOt-Bu, as we had found in our prior work that bases had a significant effect on selectivity.14,15,19 After an extensive screen of bases, we Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 448 identified that the bulky amine base, proton sponge, allowed our transformation to proceed in good yield, regio- and diastereoselectivity, but poor enantioselectivity (entry 5). In order to increase the enantioselectivity of our desired reaction, we moved to employ bulkier phosphoramidite ligand L11, which led to excellent enantioselectivity, though at the expense of yield (entry 6). Ultimately, we discovered that we could improve the reaction yield, with no effect on selectivity, by increasing the amount of the inexpensive LiCl additive to 400 mol % (entry 7). This extensive fine-tuning of reaction parameters is included here as an illustrative example of how altering one reaction partner (e.g., the substituent on the electrophile) in an iridium-catalyzed allylic alkylation reaction necessitates complete reoptimization of the system. The optimized conditions allow for a wide range of substituted tetralone nucleophiles 56 to undergo a highly selective iridium-catalyzed allylic alkylation reaction with crotyl chloride (57, Scheme 5.4). However, at this time, the nucleophile scope is limited to β-ketoester-based tetralones. We postulate that this limitation is due to both pKa restrictions of the nucleophile that prevent the use of tetralones bearing other αelectron withdrawing groups (e.g., nitrile, ketone; 58j versus 54) as well as the necessity of sp2-hybridized bulk at the carbonyl α’ position to induce selectivity. With respect to the electrophile, longer chain alkyl-substituted electrophiles result in diminished yields and selectivities, likely due to increased sterics. Limitations aside, this transformation represents the first transition metal-catalyzed allylic alkylation reaction forming vicinal tertiary and all-carbon quaternary stereocenters between prochiral enolates and an alkylsubstituted electrophile.20 We envision that with further exploration of new catalytic 449 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary systems that the substrate scope of this transformation can be expanded to additional alkyl-substituted electrophiles in the future. Scheme 5.4 Enantio- and diastereoselective iridium-catalyed allylic alkylation reactions with crotyl chloride (57) [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L11 (4 mol %) TBD (10 mol %) LiCl (400 mol %) proton sponge (200 mol %) O EWG + Cl R THF, 25 °C 56 57 O R EWG 12 examples 37–95% yield 1.7:1–17.5:1 dr 52–98% ee 58 Select examples O O O O2N CO2Me CO2Me CN 58g 58i 58j 82% yield 90:10 b:l 15.5:1 dr 93% ee 52% yield 94:6 b:l 10.9:1 dr 96% ee 95% yield 90:10 b:l 5.1:1 dr 52% ee In order to demonstrate the synthetic utility of our enantio- and diastereoselective iridium-catalyzed allylic alkylation methodology, we carried out series of product transformations on allylic alkylation products 137 (Figure 5.4). Notably, all of these derivatizations proceed with excellent diastereoselectivity to facilitate the synthesis of complex building blocks, demonstrating the ease with which complexity can be added to these high-value products. 450 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Figure 5.4 Select examples of diverse product transformations of enantio- and diastereoselective iridium-catalyzed allylic alkylation products 137a Ph EtO 2C O EtO 2C Ph O O Ph Ph H EtO 2C O Ph 138 139 140 a b c O Ph R CO2Et 137 d e f O O O OH OH O HO CO2Et CO2Et 63 OH 66 65 [a] pyrrolidine, AcOH, t-BuOMe, reflux, 95% yield; [b] Co2(CO)8, CH2Cl2, then Me3NO⋅2H2O, >20:1 dr, 99% yield; [c] HGII (10 mol %), CH2Cl2, 40 °C, 96% yield; [d] i) allylmagnesium chloride, THF, –78 °C, 71% yield, ii) HG-II, CH2Cl2, 81% yield, iii) K2OsO4, NMO, THF/H2O, 59% yield; [e] Me3S(O)I, NaH, DMSO, 82% yield; [f] K2OsO4, NMO, THF/H2O, 65% yield. 5.3 UMPOLED IRIDIUM-CATALYZED ALLYLIC ALKYLATION REACTIONS After four years of expanding the limits of enantio- and diastereoselective iridium-catalyzed allylic alkylation, we became aware of another limitation in the field. Specifically, we noted that over the past two decades of iridium-catalyzed allylic alkylation research since the seminal report,8 the technology had been widely developed for standard reactivity patterns between electrophilic π-allyl species and nucleophilic enolate equivalents (141), carbanion equivalents (142), or heteroatoms (143, Figure 451 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 5.5a).13,21 However, the application of an umpolung strategy in iridium-catalyzed allylic alkylation to stitch together two formally electrophilic species remained underexplored (144, Figure 5.5b, left). At the time, only two examples of reverse-polarity nucleophiles had been reported for this chemistry, 22 though neither were in the carboxylic acid oxidation state which would allow for direct access to either enantioenriched amides, esters, or carboxylic acids. Figure 5.5 Iridium-catalyzed allylic alkylation strategies a) Standard Iridium-Catalyzed Allylic Alkylation δ− R R δ− X δ− δ+ δ+ Ar Ar δ+ Ar 141 142 143 O b) Umpolung Strategy Iridium-Catalyzed Allylic Alkylation via MAC Reagent O δ+ X OR δ+ Ar 144 NC H+ CN 67 O O 145 146 NC 5.3.1 TERTIARY ALLYLIC STEREOCENTERS23 With this gap in the literature noted we set forth to develop an iridium-catalyzed allylic alkylation method for accessing carboxylic acid derivatives and we identified masked acyl cyanide (MAC) reagents 67 as potential nucleophiles (Figure 5.5b, left). These MAC reagents which were developed by Nemoto and Yamamoto, and popularized by Rawal, can expel an equivalent of cyanide when exposed to acid therefore allowing them to function as acyl cyanide nucleophiles (145, Figure 5.5b, right). 24 As acyl cyanides are highly electrophilic, the MAC reagent truly functions as a carbon monoxide Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 452 synthon (146). Thus, we envisioned that if the MAC reagent could react with an iridiumπ allyl species to generate an alkylation product, we could use extensive literature precedent to unmask the MAC adduct and further transform the transient acyl cyanide to carboxylic acid derivatives 144 upon treatment with heteroatom nucleophiles (e.g., H2O, RNH2, ROH).24,25 As a result, the MAC reagent would function as each an amide, ester, and carboxylic acid synthon. Employing our previously disclosed conditions for the iridium-catalyzed allylic alkylation of cyclic nucleophiles to form vicinal tertiary and all-carbon quaternary stereocenters,14 we were able to rapidly establish that the MAC reagent was a competent nucleophile in the iridium-catalyzed reaction given the judicious choice of protecting group on the hydroxyl moiety. Specifically, we found that a methyoxymethyl (MOM) group (67c) was required in order to access products 71 in high yields (Scheme 5.5). We hypothesize that this protecting group is optimal due to its small steric profile as well as its potential to coordinate and be activated by the LiBr additive. Using these optimized conditions, we discovered that a range of cinnamyl-derived electrophiles, including heteroaryl-substituted allylic electrophiles, react in high yields and excellent enantioselectivities in up to gram scale to provide allylic alkylation products 71, which are amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carboxylic acid derivatives.23 453 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Scheme 5.5 First report of MAC reagent 67c in an asymmetric transition-metal catalyzed reaction [Ir(cod)Cl] 2 (2 mol %) (S,S a )-L2 (4 mol %) TBD (10 mol %) LiBr (200 mol %) OMOM + NC Ar OCO 2Me CN OMOM NC NC X THF, 60 °C 124 67c O ref 24, 25 Ar Ar 71 12 examples 58–95% yield 89–96% ee 148 X = OH, NR 2, OR Select examples NC OMOM NC NC OMOM NC NC OMOM NC NC MeO NC N OMe Br OMOM OMe 71a 71g 71i 71j 94% yield 96% ee 81% yield 98% ee 65% yield 89% ee 74% yield 90% ee 5.3.2 QUATERNARY ALLYLIC STEREOCENTERS26 After having developed the iridium-catalyzed allylic alkylation chemistry for MAC nucleophile 67c, 23 we sought to further leverage the utility of the MAC reagents to access an even more challenging class of compounds – acyclic α-quaternary carbonyl derivatives. However, our proposed allylic alkylation strategy had one major caveat, namely, enantioenriched quaternary allylic stereocenters had never been synthesized via iridium-catalyzed allylic alkylation reactions (Figure 5.6).27 Figure 5.6 Limitations in enantioselective iridium-catalyzed allylic alkylation prior to 2017 [L*Ir] [L*Ir] R1 R Nu R 149 all reports R2 Nu zero reports Nu R1 R 2 150 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 454 Over the past twenty years, enantioselective iridium-catalyzed allylic alkylation reactions have been exclusively limited to those synthesizing tertiary allylic stereocenters 149 (Figure 5.6, left).13,21 In contrast, use of a 1,1-disubstituted π-allyl to forge quaternary allylic stereocenters 150 was unreported (Figure 5.6, right). In order to access such a geminal-disubstituted π-allyl species, a trisubstituted allylic electrophile would need to be utilized; however, this class of electrophile was predicted to be unreactive in iridiumcatalyzed allylic alkylation chemistry. Literature reports have demonstrated that the reaction rates of these processes decrease with increasing substitution on the olefin of the electrophile. 28 Therefore, we anticipated that our preliminary experiments into this research area would focus on identifying a method in which to unlock reactivity from a heretofore unreactive trisubstituted allylic electrophile 72 (Table 5.3). As we anticipated, application of our standard conditions for the iridiumcatalyzed allylic alkylation of cyclic nucleophiles failed to invoke reactivity from trisubstituted allylic electrophile 72, instead returning starting material (Table 5.3, entry 1). We rationalized that we would need to explore other phosphoramidite ligand frameworks in order to identify a more reactive catalyst (entries 2 and 3). Ultimately, we identified that phosphoramidite L5, developed by Carreira, was uniquely effective in providing desired product 73, though in only modest yield (entry 3).29 In an effort to increase the yield and selectivity of the transformation, we performed an extensive investigation into alternative additives that have proven successful in promoting iridiumcatalyzed allylic alkylation reactions. However, it was not until we identified the necessity of a strong Lewis acid co-catalyst to promote oxidative addition via facilitating the ionization of the carbonate leaving group from allylic electrophile 72 that we saw 455 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary improved reactivity. Specifically, we discovered that the addition of Lewis acidic triethylborane to the reaction provided access to desired product 73 in nearly triple the conversion and excellent enantioselectivity (entry 4). Finally, we found that we could further improve reaction yield by altering the nucleophile to electrophile stoichiometry such that an excess of electrophile is present (entry 5). Of note, the E-olefin isomer of allylic electrophile 72 is required, as the Z-trisubstituted allylic electrophile gave significantly decreased yields and selectivities. Table 5.3 Optimization of the enantioselective synthesis of products 73 bearing allylic quaternary stereocenters [Ir(cod)Cl] 2 (2 mol %) L (4.2 mol %), TBD (10 mol %) OMOM + NC CN Ph 67c OCO 2Me NC OMOM NC THF, 60 °C Ph 73 72 Entry L 67c:72 Additive (200 mol %) Yieldb ee (%)c 1 L2 2:1 LiBr 0 – 2 L9 2:1 LiBr 0 – 3 L5 2:1 LiBr 12 79 4 L5 2:1 BEt 3 34 93 5 L5 1:2 BEt 3 99 94 O P N O (S,S a )-L2 Ph O P N O Ph (S,S,S a )-L9 O P O N (S a )-L5 [a] Reactions performed on 0.1 mmol scale. [b] 1 H NMR yield based on internal standard. [c] Determined by chiral HPLC analysis. While optimizing the reaction parameters for this novel transformation, we noted the importance of the guanidine base, 1,3,5-triazabicyclo[4.4.0]dec-5-ene (TBD), on reactivity. Typically, TBD is utilized as a substoichiometric base additive to promote the Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 456 formation of an active iridicycle catalyst. 30 However, Carreira has reported that phosphoramidite L5 does not form an iridicycle and thus a base additive is not required when employing this ligand in iridium-catalyzed allylic alkylation reactions. 31 We postulate that in the case of our developed reaction, TBD may be serving as a labile placeholder ligand to prevent the formation of an inactive catalyst or as a base to promote the formation of a novel active iridicycle. In looking to how this new reaction could be even further improved, we envisioned that hydrolysis of the MAC functionality of allylic alkylation product 152 could be carried out in the same reaction vessel as the iridium-catalyzed reaction to provide direct access to the corresponding carboxylic acid in a one-pot, two-step procedure (Scheme 5.6).25e Moreover, we hypothesized that carboxylic acid products 153 could be isolated in high purify after a simple acid/base work up alone, with no need for column chromatography. We were pleased to find that our hypothesis was valid and with our optimized conditions a range of acyclic α-quaternary carboxylic acids 153 were prepared with varying substitution at the α-position. Specifically, both electron withdrawing and donating groups are well tolerated at the para and meta positions of the aryl substituent on electrophile 151, though diminished yields are observed for bis-metasubstituted arenes and no reactivity is observed with ortho-substituted aryl groups. With respect to the alkyl substituent (R), lengthening the n-alkyl group beyond an ethyl moiety results in poor yields, as does the use of branched alkyl substituents. Also of note, bisalkyl-substituted allylic electrophiles do not currently fare well in this chemistry (cf., 79f). 457 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Scheme 5.6 Enantioselective synthesis of acyclic α-quaternary carboxylic acids 153 [Ir(cod)Cl] 2 (2 mol %) (S a )-L5 (4.2 mol %) TBD (10 mol %) BEt 3 (200 mol %) R OMOM OMOM NC O NC R + NC Ar CN 67c OCO 2Me 6 M HCl HO 80 °C THF, 60 °C Ar 152 151 R 153 11 examples 51–93% yield 85–95% ee Select examples O HO O HO O HO O HO Et Ph O2N 77e 77h 79a 79f 65% yield 94% ee 93% yield 87% ee 61% yield 92% ee 32% yield 3% ee As MAC adducts can be transformed into essentially any carboxylic acid derivative, we sought to develop additional one-pot methods to access α-quaternary esters and amides.25e Toward this end, we were pleased to find that MAC adduct 154 could be advanced in a one-pot fashion to a variety of esters (e.g., 82), as well as amides (e.g., 84) in moderate to high yields following cleavage of the MOM group and interception of the transient acyl cyanide by the appropriate nucleophile (Figure 5.7). 458 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary Figure 5.7 Enantioselective synthesis of acyclic α-quaternary esters 82 and amides 84 O i. CSA, AcOH/DME ii. MeOH, Et 3N MeO (88% yield) NC OMOM 82 Cl NC 154 Cl O i. CSA, AcOH/DME ii. pyrrolidine, Et 3N N (61% yield) 84 5.4 Cl SYNTHESIS OF VICINAL ALL-CARBON QUATERNARY CENTERS VIA ENANTIOSELECTIVE IRIDIUM-CATALYZED ALLYLIC ALKYLATION32 Noting that our preparation of enantioenriched α-quaternary carboxylic acid derivatives progresses through intermediate 152, bearing vicinal tetra-substituted and quaternary centers, led us to imagine that we could utilize this iridium-catalyzed allylic alkylation methodology to synthesize highly congested vicinal all-carbon quaternary centers. In designing a nucleophile for this desired reaction, we postulated that the most facile reaction development would be achieved if the malononitrile functionality of the previously utilized MAC nucleophile 67c was kept intact and the α-substitution were not more sterically demanding than the MOM group. Indeed, our previously reported conditions for the synthesis of α-quaternary carboxylic acid derivatives using MAC reagent 67c translated directly to the reaction of methylmalononitrile (155, R1 = Me) with trisubstituted allylic electrophile 156, though the enantioselectivity was low (Scheme 5.7). As our early work demonstrated that basic additives have pronounced effects on 459 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary selectivity, we explored the effect of base on our current reaction. Ultimately, DABCO was revealed to be uniquely effective for this transformation, providing products 157 bearing vicinal all-carbon quaternary centers in moderate to good yields and excellent enantioselectivities for a variety of substituted malononitrile nucleophiles 155 and trisubstituted allylic electrophiles 156. At this time, we believe that the DABCO increases the enantioselectivity of the transformation by allowing for increased equilibration between diastereomers of an iridium π-allyl complex by slowing the rate of nucleophilic attack.18,33 Scheme 5.7 Synthesis of vicinal all-carbon quaternary centers 157 via enantioselective iridiumcatalyzed allylic alkylation [Ir(cod)Cl]2 (2 mol %) (S a )-L5 (4 mol %) TBD (10 mol %) BEt 3 (200 mol %) R1 NC DABCO (200 mol %) R2 + Ar CN 155 OCO2Me NC P N O NC THF, 60 °C 156 O R1 Ar R2 (S a )-L5 157 18 examples 33–99% yield 84–99% ee Select examples NC NC NC NC NC NC NC Ph NC Ph Cl Ph 93 95f 97f 97j 89% yield 95% ee 92% yield 96% ee 99% yield 99% ee 65% yield 84% ee As we are inspired and driven by the application of our methods in complex molecule synthesis, we sought to demonstrate the feasibility of chemoselective manipulation of allylic alkylation product 157 (Figure 5.8). The olefin functionality of 460 Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 157 can either be chemoselectively reduced or oxidized via ozonolysis. Furthermore, multistep procedures can be utilized to prepare densely-functionalized compounds bearing two contiguous all-carbon quaternary stereocenters, such as 103 and 104. Figure 5.8 Product derivatizations of iridium-catalyzed allylic alkylation products 157 bearing vicinal all-carbon quaternary centersa NC R1 = Me R1 = Me NC a Ph 101 NC b NC NC O Ph R1 102 NC Ar R2 157 O NC e O c,d O R1 = Me Ph R1 = CH 2CH 2C(O)Me 104 O H 2N NC Ph 103 [a] RhCl(PPh3)3, H2 (balloon), benzene, 23 °C, 18 h, 92% yield; [b] O3, pyridine, CH2Cl2, –78 °C, 4 min, 93% yield; [c] i. O3, pyridine, CH2Cl2, –78 °C, 4 min, ii. p-TsOH, benzene, reflux, 18 h, 47% yield; [d] NaOH, EtOH/H2O (1:1), 60 °C, 18 h, 38% yield, 1:11 dr; [e] i. O3, MeOH, –78 °C, 0.5 h, ii. NaBH4, 0 °C, 3 h, 65% yield, 1:2.5 dr. 5.5 CONCLUSIONS AND FUTURE OUTLOOK Building on our group’s longstanding interest in the synthesis of enantioenriched quaternary stereocenters, we have sought to expand the limits of iridium-catalyzed allylic alkylation chemistry to encompass the synthesis of sterically congested all-carbon quaternary stereocenters. Initially, we focused on the development of enantio- and diastereoselective iridium-catalyzed allylic alkylation technology for the construction of vicinal tertiary and all-carbon quaternary stereocenters. Our work has enabled the use of both cyclic and acyclic nucleophiles, as well as alkyl-substituted allylic electrophiles in this methodology. We then shifted our attention to umpolung strategy iridium-catalyzed allylic alkylation chemistry and developed MAC reagents as nucleophiles. Continued Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 461 study of the umpolung chemistry led to the synthesis of allylic quaternary stereocenters via the use of trisubstituted allylic electrophiles in conjunction with a Lewis acid cocatalyst. Most recently, we have discovered iridium-catalyzed allylic alkylation technology that provides access to vicinal all-carbon quaternary centers. Despite these advances by our group, as well as beautiful work from other groups in the area,13,21 this emerging field is not without limitations. While there have been extensive advances to widen the substrate scope with respect to the nucleophile partner, the allylic electrophile remains largely limited to aryl- and alkenyl-substitution, aside from our reported method for the use of crotyl chloride as an electrophile.20 Most importantly though, no general method for iridium-catalyzed allylic alkylation exists. As demonstrated vide supra, even minor changes to either the nucleophile or electrophile partner necessitate complete reoptimization of the reaction parameters. Ideally, a single catalyst system will be developed in the future which enables highly selective iridiumcatalyzed allylic alkylation reactions for any combination of nucleophile and electrophile. In looking forward, we envision that the field will shift its attention to the development of enantio- and diastereoselective iridium-catalyzed allylic alkylation for the synthesis of vicinal all-carbon quaternary stereocenters; a highly challenging motif to access that has also become a holy grail for many other areas of synthetic methodology. We hope that our recent work on the synthesis of vicinal quaternary centers will inspire and enable these studies. Ultimately, we look forward to a time when the broader synthetic community embraces iridium-catalyzed allylic alkylation as an enabling and reliable technology for the synthesis of complex targets. Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 5.6 462 REFERENCES AND NOTES (1) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751. (2) Behena, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17, 14199–14223. (3) For select examples, see: (a) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2013, 52, 6718–6721; (b) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Angew. Chem. Int. 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Synthesis 2009, 2076–2082; (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2012, 134, 4812–4821. (18) (a) Bartels, B.; Helmchen, G. Chem. Commun. 1999, 741–742; (b) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529–3532; (c) Polet, D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K.; Chem. Eur. J. 2006, 12, 3596–3609. (19) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298– 17301. (20) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem. Int. Ed. 2016, 55, 16092–16095. (21) For selected reviews of asymmetric iridium-catalyzed allylic alkylation, see: (a) Helmchen, G.; Dahnz, A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675−691; (b) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169−208; (c) Liu, W.-B.; Xia, J. B.; You, S.-L. Top. Organomet. Chem. 2011, 38, 155−208. (22) (a) Förster, S.; Tverskoy, O.; Helmchen, G. Synlett 2008, 2803−2806; (b) Breitler, S.; Carreira, E. M. J. Am. Chem. Soc. 2015, 137, 5296−5299. (23) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Org. Lett. 2017, 19, 1527–1529. (24) (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990, 55, 4515−4516; (b) Nemoto, H.; Li, X.; Ma, R.; Suzuki, I.; Shibuya, M. Tetrahedron Lett. 2003, 44, Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 465 73−75; (c) Nemoto, H.; Kawamura, T.; Miyoshi, N. J. Am. Chem. Soc. 2005, 127, 14546−14547; (d) Nemoto, H.; Ma, R.; Kawamura, T.; Kamiya, M.; Shibuya, M. J. Org. Chem. 2006, 71, 6038−6043; (e) Nemoto, H.; Kawamura, T.; Kitasaki, K.; Yatsuzuka, K.; Kamiya, M.; Yoshioka, Y. Synthesis 2009, 1694−1702; (f) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050–16053; (g) Yang, K. S.; Rawal, V. H. J. Am. Chem. Soc. 2014, 136, 16148– 16151; (h) Kagawa, N.; Nibbs, A. E.; Rawal, V. H. Org. Lett. 2016, 18, 2363–2366. (25) (a) Kociołek, K.; Leplawy, M. T. Synthesis 1977, 778−780; (b) Kubota, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991, 56, 7195−7196; (c) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya, M. Tetrahedron 2000, 56, 1463−1468; (d) Yamatsugu, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2009, 65, 6017−6024; (e) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050−16053; (f) Yang, K. S.; Rawal, V. H. J. Am. Chem. Soc. 2014, 136, 16148−16151; (g) Kagawa, N.; Nibbs, A. E.; Rawal, V. H. Org. Lett. 2016, 18, 2363−2366. (26) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2017, 56, 11545–11548. (27) At the time of publication, a singular example of an iridium-catalyzed allylic alkylation reaction producing a product bearing an allylic all-carbon stereocenter has been reported with 11% yield and 21% ee: Onodera, G.; Watabe, K.; Matsubara, M.; Oda, K.; Kezuka, S.; Takeuchi, R. Adv. Synth. Catal. 2008, 350, 2725–2732. Chapter 5 – Stereoselective Iridium-Catalyzed Allylic Alkylation in the Stoltz Laboratory: A Summary 466 (28) (a) Madrahimov, S. T.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 8136–8147; (b) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 14968–14981. (29) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 3139–3143. (30) For examples of the formation of active iridicycles, see: (a) Jiang, X.; Beiger, J. J.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 87–90; (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J. Am. Chem. Soc. 2012, 134, 4812–4821. (31) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603– 3606. (32) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Angew. Chem. Int. Ed. 2018, doi: 10.1002/anie.201804820. (33) DABCO has been previously utilized in iridium-catalyzed allylic alkylation leading to higher yields but slower rates of reaction, see: B. P. Bondzic, A. Farwick, J. Liebich, P. Eilbracht, Org. Biomol. Chem. 2008, 6, 3723–3731. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 467 APPENDIX 8 A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H† A8.1 INTRODUCTION First isolated in 1995, the taiwaniaquinoid natural products are a family of tricyclic diterpenoids with a unique [6,5,6]-abeo-abietane skeleton (158–164, Figure A8.1). 1 Since their isolation, the taiwaniaquinoids have attracted significant attention from the synthetic community, resulting in a multitude of total and formal syntheses.2 Interest in these compounds stems from their reported biological activity,3 in addition to their unique architecture containing a benzylic quaternary stereocenter. Due to the limited number of methodologies capable of installing benzylic quaternary stereocenters, only four catalytic, enantioselective syntheses of taiwaniaquinoids have been published to date.2e,m,q,t † This work was performed in collaboration with Dr. Jeffrey C. Holder. Portions of this chapter have been reproduced with permission from Shockley, S. E.;‡ Holder, J. C.;‡ Stoltz, B. M. Org. Lett. 2014, 16, 6362– 6365 © 2014 American Chemical Society and Shockley, S. E.; Holder, J. C.; Stoltz, B. M. Org. Process Res. Dev. 2015, 19, 974–981 © 2015 American Chemical Society. 468 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Figure A8.1 Taiwaniaquinoid natural products H O O O O OMe (+)-taiwaniaquinone H (158) OMe (+)-taiwaniaquinone G (160) CHO H HO O OH (+)-dichroanone (159) CHO H O O O OH (+)-dichroanal B (161) O OH HO OR (+)-taiwaniaquinone A (R = H) (162) (+)-taiwaniaquinone F (R = Me) (163) OMe (+)-taiwaniaquinol B (164) Our laboratory has a longstanding interest in the development of methods for the enantioselective synthesis of quaternary stereocenters and the application of these technologies to the synthesis of natural product targets. In 2006, our group reported the first catalytic, enantioselective total synthesis of (+)-dichroanone (159) via enantioselective palladium-catalyzed allylic alkylation (Scheme A8.1).2e This work featured a linear synthetic sequence, elaborating palladium-catalyzed allylic alkylation product 166 to bicyclic enone 165 by Wacker oxidation and subsequent aldol condensation. The final ring was appended by another aldol condensation, and a novel series of oxidations provided the natural product in only 11 steps. Scheme A8.1 Stoltz group retrosynthesis of (+)-dichroanone (159) O O O O OH (+)-dichroanone (159 ) 165 166 469 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H In 2011, the Stoltz group disclosed the first enantioselective palladium-catalyzed conjugate addition methodology to form quaternary stereocenters in high yields and enantioselectivities (Figure A8.2, top).4 Following this report, we recognized that the βaryl ketone motif found in these conjugate addition products 169 mapped onto the scaffold of the taiwaniaquinoid terpene natural products, and we envisioned that a more convergent synthesis of these natural products could be achieved by employing β-aryl ketone 170 as the key intermediate (Figure A8.2, bottom). This modified retrosynthetic analysis facilitates a highly convergent, catalytic, enantioselective key step that brings together 13 of the 19 carbon atoms of the taiwaniaquinoid tricyclic core, including the quaternary stereocenter, in a single chemical transformation. Herein, we discuss the rational design of high-yielding and highly enantioselective conjugate addition reactions of arylboronic acids that facilitate the catalytic, enantioselective formal synthesis of (+)taiwaniaquinone H (158) and (+)-dichroanone (159) in >99% ee. Figure A8.2 Stoltz group conjugate addition chemistry as inspiration for revised retrosynthetic analysis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) O N O (HO)2B R + N O t-Bu (S)-t-BuPyOx (L14) Pd(OCOCF 3)2 R 167 168 169 O R O O OR R = Me, (+)-taiwaniaquinone H (158) R = H, (+)-dichroanone (159) 170 470 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H A8.2 BACKGROUND TO THE STOLTZ GROUP’S ENANTIOSELECTIVE PALLADIUM-CATALYZED CONJUGATE ADDITION CHEMISTRY A8.2.1 INTRODUCTION TO ENANTIOSELECTIVE TRANSITION METALCATALYZED CONJUGATE ADDITION CHEMISTRY Enantioselective conjugate addition has become a powerful synthetic tool for the assembly of structurally complex molecules. 5 Recently, new developments in this transformation have served as solutions to the persistent challenge of the catalytic, enantioselective synthesis of all-carbon quaternary stereocenters (Scheme A8.2). 6 To date, copper catalysis has dominated the field of enantioselective conjugate addition, however, these copper-catalyzed methods require the use of highly reactive organometallic reagents (e.g., diorganozinc, 7 triorganoaluminum, 8 and organomagnesium 9 reagents). Thus, these reactions typically necessitate rigorously anhydrous reaction conditions and often operate at cryogenic temperatures. Alternatively, chiral rhodium catalysts in combination with air-stable, easily handled organoboron reagents have been shown to produce a wide array of conjugate addition adducts in very high yield and enantiomeric excess.10,11,12 Although extremely effective, these rhodium catalysts are expensive, air-sensitive, and many of the most widely used precatalysts are not commercially available. Additionally, rhodium-catalyzed conjugate additions to form quaternary stereocenters require boroxine or tetraarylborate reagents rather than widely available arylboronic acids. Furthermore, large excesses of the boron reagents are necessary to drive the reactions to completion. These factors diminish the appeal of such rhodium-catalyzed methods in complex molecule synthesis where custom aromatic units are often desired and thus the arene material is of high value.8,13 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 471 Scheme A8.2 Enantioselective transition metal-catalyzed conjugate addition O chiral transition metal complex + R1 R2 O M R3 172 171 organometallic reagent = organomagnesium, -zinc -aluminum, -boron R1 R3 R2 173 transition metal = Cu, Rh, Pd Palladium-catalyzed conjugate addition reactions are less developed than those using copper and rhodium but offer significant advantages. For example, palladiumcatalyzed conjugate addition reactions utilize commercially available, air-stable, and functional group-tolerant boron nucleophiles. Furthermore, the reactions are typically not sensitive to water or oxygen. Together, these features comprise an operationally simple and robust transformation.14 At the time the Stoltz group began our work in this area, there were only examples of the enantioselective synthesis of tertiary stereocenters in the palladium literature and a single report of the synthesis of quaternary stereocenters, albeit as a racemate.15 It was not until our report in 2011 that a palladium-derived catalyst was employed to construct an enantioenriched quaternary stereocenter via conjugate addition methodology.4a Subsequent to our studies, similar palladium-catalyzed conjugate additions to forge quaternary stereocenters were reported by Minnaard and de Vries16 as well as Stanley.17 A8.2.2 INITIAL DISCOVERIES Our initial studies involved the enantioselective conjugate addition of arylboronic acids to β-substituted carbocyclic enones to generate benzylic all-carbon quaternary stereocenters.4a We began these efforts by investigating the reaction of 3- 472 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H methylcyclohexen-2-one (167) with phenylboronic acid (174, Scheme A8.3). Building on the precedent for bidentate, dinitrogen ligands in conjugate addition chemistry,15,18 we found that a catalyst formed in situ from the combination of Pd(OCOCF3)2 and the chiral pyridinooxazoline ligand, (S)-t-BuPyOx (L14), 19 proved effective in forming βquaternary ketone product 175 in high yield and enantioselectivity. Many other ligands were examined in the course of our studies but none provided the high selectivities observed with t-BuPyOx (L14). Further optimization revealed that polar, coordinating solvents hindered the reaction while non-polar solvents provided higher conversions and superior enantioinduction. Ultimately, we found that 1,2-dichloroethane allowed for the fastest reaction times (12–24 h) with minimization of side product formation. Furthermore, we were pleased to find that the amount of phenylboronic acid could be reduced to 1.1 equivalents with no detrimental effect on the reactivity other than increased reaction times. Scheme A8.3 Initial Stoltz group enantioselective palladium-catalyzed conjugate addition with (S)-tBuPyOx (L14) O O B(OH) 2 + (1.1 equiv) 167 174 L3 (6 mol %) Pd(OCOCF 3)2 (5 mol %) ClCH2CH2Cl 60 °C, 12 h (99% yield, 93% ee) O N Ph N L14 175 t-Bu (S)-t-BuPyOx Based on control studies, we found the reaction to be insensitive to adventitious moisture and air atmosphere as neither the high yield nor enantioselectivity were impacted upon addition of water (up to 10 equivalents) and no improvements were noted under inert gas atmospheres. Therefore, the reactions may be conducted under ambient Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 473 air in screw-top vials without the need for purification or distillation of any commercially obtained materials. Moreover, the optimal chiral ligand, (S)-t-BuPyOx (L14), can be expediently prepared on relatively large scale in two steps from readily available starting materials.20 Gratifyingly, a wide range of arylboronic acids and enones undergo highly enantioselective reactions under the developed conditions (Table A8.1). With respect to the nucleophile scope, para-substituted arylboronic acids are well tolerated. Alkylsubstituted arylboronic acids react with good yields and enantioselectivities to give products such as 4-methyl- and 4-ethyl-substituted ketones 177a and 177b. However, we noted a distinct electronic trend on selectivity, wherein electron-rich nucleophiles tend to furnish more modest yields and enantioselectivities (177c, 177d, and 177h). Conversely, arylboronic acids bearing electron-withdrawing substituents produce ketone products in excellent enantioselectivities. Specifically, the electron-poor substitution can include carbonyl (177e), trifluoromethyl (177f) or halide (177g) functional groups. Additionally, reactions involving meta-substituted nucleophiles fare well with alkyl (177i), ester (177j), halide (177k), or even nitro groups (177l) on the arylboronic acid. Notably, substituents at the 2-position of the arylboronic acid result in slower reactions and furnish diminished yields of the ketone products in low enantioselectivity (e.g., 2-methylphenylboronic acid results in 13% of its corresponding product in 22% ee). These ortho-arylboronic acid substrates react with higher yields and enantioselectivities in the palladium-catalyzed conjugate addition manifold described by Minnaard and de Vries.16b 474 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Table A8.1 Scope of arylboronic acid and enone conjugate acceptorsa O R + O L14 (6 mol %) Pd(OCOCF 3)2 (5 mol %) B(OH) 2 R ClCH2CH2Cl 40–80 °C, 12–24 h n 176 O n 168 O 177 O O O O Et 177a 99% yield 87% ee c b O OBn OMe 177b 177c 177d 177e 90% yield 85% ee 96% yield 74% ee 58% yield 69% ee 99% yield 96% ee O O O O O O CF3 F OTBS 177f 177g 177h 177i 177j 99% yield 96% ee 84% yield 92% ee 52% yield 82% ee 99% yield 91% ee 91% yield 95% ee O O O O O Cl NO 2 177k 177l 177m 177n 177o 55% yield 96% ee 40% yield 92% ee 84% yield 91% ee 85% yield 93% ee 96% yield 92% ee O O O O O Ph BnO 177p 177q 177r 177s 177t 95% yield 91% ee 74% yield 91% ee 86% yield 79% ee 68% yield 88% ee 65% yield 91% ee [a] Reactions performed with arylboronic acid (0.50 mmol), cycloalkenone (0.25 mmol), Pd(OCOCF3)2 (5 mol %), and L14 (6 mol %) in ClCH2CH2Cl (1 mL) at 60 °C for 12 h. [b] Isolated yield. [c] Determined by chiral HPLC. Cyclic enones of different ring sizes, and with a range of β-substitution, react to afford enantioenriched β-quaternary ketone products (Table A8.1). Cyclohexanone products bearing both linear (177o–q) and branched β-substituents (177r and 177s) as Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 475 well as functionalized side chains (177t) are formed in good to excellent yields and selectivity from their corresponding substituted Michael acceptors. Moreover, altering the ring size has no deleterious effect on reactivity and furnishes products with five- (177m) or seven-membered (177n) cycloalkanones in high yields and enantioselectivity. To the best of our knowledge, this represents the first example of a single catalyst system that successfully constructs quaternary stereocenters via enantioselective conjugate addition to 5-, 6-, and 7-membered enones. A8.2.3 FURTHER REACTION DEVELOPMENT Following our initial communication of the construction of quaternary stereocenters by enantioselective palladium-catalyzed conjugate addition,4a we sought to further generalize the substrate scope, reduce the catalyst loading, and lower the reaction temperature.4b While we noted that the addition of water had no deleterious effect in our initial report, we did not consider adventitious water to be a crucial component. Thus, it came as a surprise when attempts to perform the reaction on large scale failed to fully convert enone 167 to product ketone 175. We rationalized that, on small scale, the moisture in the air and on the glassware provided sufficient water to drive the reaction to completion, however, on larger scale this trace moisture was insufficient. Analysis of the balanced equation for the overall transformation indicated that the addition of water is necessary to achieve catalyst turnover (Scheme A8.4). Thus, we found that the addition of 5 equivalents of water to the reaction mixture restored the reactivity when performing reactions on multi-gram scale. To date, reactions as large as 35 mmol scale have been successfully conducted. 476 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Scheme A8.4 Necessity of water in developed enantioselective palladium-catalyzed conjugate addition O O B(OH) 2 + 167 H + + H 2O 174 Ph 175 HO B(OH) 2 178 Examination of deuterium incorporation in the product ketone supported our hypothesis of water’s role in catalyst turnover. In reactions performed with deuterium oxide in place of water, we found significant deuterium incorporation at the α-methylene position of the carbonyl. This observation was true in reactions run to low conversion as well. These experiments, in combination with the scalability problems encountered without water as an additive, suggested that water is the reagent assisting turnover, rather than the boron nucleophile (Scheme A8.4). Based on literature reports detailing palladium-catalyzed conjugate addition employing cationic or dicationic precatalysts possessing weakly coordinating anions (PF6¯, SbF6¯, BF4¯, etc.),14 we sought to evaluate the effect of salt additives on the reaction rate with the hope of achieving milder reaction conditions (Table A8.2). At 40 °C, with no additives, the addition of phenylboronic acid to 3-methylcyclohexenone (167) is very slow and rarely goes to full conversion before the catalyst decomposes. At this same temperature, we observed that the addition of strongly coordinating anions (e.g., chloride, entry 1) shutdown the reaction while sodium salts with weakly coordinating anions greatly enhanced the reaction rate, albeit with diminished enantioselectivity (e.g., NaPF6, entry 2). Other additives required extended reaction times (e.g., (n-Bu)4NPF6, entry 3). A larger examination of salt additives containing weakly Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 477 coordinating counterions revealed that NH4PF6 gave the optimal combination of short reaction time with minimized loss of enantioselectivity (entry 4). We posit that these additives alter the catalyst resting state and result in a larger percentage of dissolved palladium species in the catalytic cycle. Table A8.2 Effect of additives on reaction rate, yield, and enantioselectivitya PhB(OH) 2 (2 equiv) L14 (6 mol %) Pd(OCOCF 3)2 (5 mol %) O Ph H 2O (5 equiv) additive (30 mol %) ClCH2CH2Cl, 40 °C 167 Entry O 175 ee (%)c Additive Time (h) Yield (%)b 1 NaCl 24 trace – 2 NaPF 6 6 97 87 3 (n-Bu)4NPF 6 24 98 90 4 NH 4PF 6 12 96 91 [a] Reactions performed with phenylboronic acid (0.5 mmol), 167 (0.25 mmol), NH4PF6 (30 mol %), water (5 equiv), Pd(OCOCF3)2 (5 mol %), and L14 (6 mol %) in ClCH2CH2Cl (1 mL) at 40 °C. [b] GC yield utilizing tridecane standard. [c] Determined by chiral HPLC. Incorporation of the optimized additives (5 equivalents water, 30 mol % NH4PF6) into the reaction conditions allowed for reactions to be conducted at decreased temperatures (23–40 °C) and significantly broadened the substrate scope. Many of the previously studied substrates that contained temperature-sensitive functionalities (e.g., silyl ethers) or groups that may react with trace palladium(0) formed by off-cycle pathways (e.g., arylbromides) afforded higher desired product yields under the modified conditions. For example, ketones 177k, 181a, 177l, and 181b were obtained in nearly double the yield under the new conditions (Table A8.3). Furthermore, at 40 °C the combination of additives allowed catalyst loadings of only 2.5 mol % of palladium and 3 mol % of ligand for most reactions. Moreover, the additives facilitated the reactions of Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 478 two new substrate classes: (1) β-acyl cyclic enones and (2) arylboronic acids containing nitrogen substituents. We were pleased to note that β-acyl enone substrates provided access to enantioenriched 1,4-dicarbonyl compounds, with only the olefin insertion process forming the quaternary stereocenter observed (181c–f), as opposed to the isomeric insertion products that would afford tertiary stereocenters. We also observed that aniline-derived boronic acid substrates protected with a trifluoroacetyl group did not poison the catalyst and allowed for the synthesis of heteroatom-substituted products (181e, 181g–j). 479 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Table A8.3 Expanded substrate scope with improved reaction conditionsa Pd(OCOCF 3)2 (5 mol %) L3 (6 mol %) NH 4PF 6 (30 mol %) H 2O (5 equiv) O B(OH) 2 + n R2 O ClCH2CH2Cl 40–60 °C, 12 h R1 176, 179 168, 180 O Ar n R1 177, 181 O O O Cl Br NO 2 177k 181a 177l 181b 55% yield, 97% ee 96% yield, 96% ee 44% yield, 86% ee 84% yield, 84% ee 40% yield, 92% ee 81% yield, 91% ee 32% yield, 77% ee 70% yield, 77% ee O O F O O NHCOCF 3 Cl O O 181c 85% yield 96% ee c b O O O 181d 181e 181f 66% yield 92% ee 73% yield 91% ee 72% yield 93% ee O O O OMe O F 3C NH NH NH O NH O F 3C O F 3C CF3 181g 181h 181i 181j 98% yield 89% ee 75% yield 88% ee 93% yield 90% ee 60% yield 92% ee [a] Blue font: reported yield and ee of the product in the absence of NH4PF6 and water, with reactions performed at 60 °C. Red font: yield and ee of the product with additives. Conditions: reactions were performed with arylboronic acid (1.0 mmol), cycloalkenone (0.5 mmol), NH4PF6 (30 mol %), water (5 equiv), Pd(OCOCF3)2 (5 mol %), and L14 (6 mol %) in ClCH2CH2Cl (2 mL) at 40 °C. [b] Isolated yield. [c] Determined by chiral HPLC. A8.2.4 MECHANISTIC HYPOTHESIS Studies have been conducted to elucidate the catalytic cycle active in our enantioselective conjugate addition chemistry.4b A range of Lewis and π-acidic metal salts were substituted for palladium with no product observed, signifying that palladiumcatalyzed conjugate addition is not a Lewis acid-catalyzed process. The reaction proceeds Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 480 in the presence of mercury drops, which would poison a heterogeneous catalyst, indicating that a soluble complex likely catalyzes the reaction. Furthermore, a nonlinear effect study supported the action of a single, monomeric ML-type catalyst as the kinetically relevant species (Figure A8.3).21 The linear relationship between catalyst ee and product ee argues against the kinetic relevance of palladium/ligand dimers in solution, as opposed to some catalysts that are known to aggregate in reservoirs.15,22 Figure A8.3 Linear relationship of catalyst ee to product ee Density functional theory (DFT) calculations, performed in collaboration with the Houk laboratory, support the cationic catalytic cycle shown in Figure A8.4.4b, 23 We postulate that the active catalyst is a cationic palladium(II) hydroxide species, which are known to undergo rapid transmetallation with arylboronic acids without added base.24 We envision that arylpalladium 183 forms by transmetallation of the arylboronic acid with cationic catalyst 182. Substrate association via the carbonyl yields an equilibrating mixture of carbonyl-bound complex 184 and olefin-bound complex 185. C-bound enolate 188 is the initial product of alkene insertion into the aryl C–Pd bond. Notably, this Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 481 insertion is calculated to be both the enantiodetermining and turnover-limiting step of the catalytic cycle. Subsequent isomerization to O-bound tautomer 187 followed by protonation affords the product ketone and regenerates the catalyst (182).25 This proposed mechanism was experimentally substantiated by a recent collaboration with the Zare laboratory in which arylpalladium cation 183 and enone complex 184/185 were identified by DESI-MS monitoring of the reaction mixture.26 No intermediates occurring after the predicted turnover-limiting step were observed. The observation of enone-arylpalladium complex 184 for a variety of arylboronic acid substrates led us to hypothesize that complex 184 may be the resting state. The enantiodetermining alkene insertion step involves a four-membered cyclic transition state, with the lowest energy diastereomer calculated to be transition state 186a, which leads to the observed (R)-product. Diastereomer 186a is the most stable as the bulky t-Bu group on the ligand points away from the substrate. Analysis of the effects of substituents on the ligand at the 4-position of the oxazoline revealed that replacing the t-Bu functionality with smaller groups, such as i-Pr, i-Bu, or Ph, significantly reduced the selectivity. If instead the oxazoline is substituted at the 5-position practically no enantioselectivity is afforded. Electronic perturbation of the pyridine moiety of the ligand did not erode enantioselectivity, though rates were greatly changed. Therefore, enantioselectivity is primarily attributed to the ligand/substrate steric interactions. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 482 Figure A8.4 Proposed catalytic cycle for the enantioselective conjugate addition of arylboronic acids to cyclic enones catalyzed by the combination of Pd(OCOCF3)2 and (S)-t-BuPyOx (L14) O B(OH) 2 N Ph 175 N 174 Pd HO protonation transmetallation L 182 H 2O N N N O Pd N Pd O N L N L Pd 183 L Ph Ph 167 187 188 N N Pd N H Pd N Pd 186a coordination N OO N O O carbopalladation 185 O 184 turnover-limiting and enantioselectivity-determining step Transition state calculations suggested that stereocontrol predominantly arises from the repulsion of the α’-methylene hydrogens on the cyclohexenone substrate with the ligand (Figure A8.5). In the disfavored diastereomeric transition state (186b), these atoms are only 2.3 Å apart and thus incur a significant energetic penalty. Consequently, replacing the CH2 group with an oxygen atom (e.g., lactone 189, Figure A8.5) decreases the energy difference between the two diastereomeric transition states and leads to an observed decrease in enantioselectivity from 93% ee to 57% ee. Of note, α,β-unsaturated lactone substrates afford high enantioselectivity in the enantioselective palladiumcatalyzed conjugate addition described by Minnaard and de Vries.16a Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 483 Figure A8.5 Calculated transition states and effect of α’-substituents on enantioselectivity OO N H N Pd 186a favored transition state Effect of α'-substituent on enantioselectivity: O O H O H Ph Ph 175 189 93% ee 57% ee 186b disfavored transition state A8.2.5 HETEROCYCLIC ACCEPTORS We wished to extend our conjugate addition methodology to the synthesis of stereochemically complex heterocyclic molecules. We found that the palladium-catalyzed conjugate addition of arylboronic acids to chromones and 4-quinolones delivered tertiary stereocenters in high yield and enantioselectivities across multiple heterocyclic scaffolds with a wide range of arylboronic acids (Table A8.4).4c While chromones 27 , 28 and 4quinolones29 have been successfully employed in rhodium-catalyzed conjugate addition, to our knowledge, these are the first examples of enantioselective transition metalcatalyzed conjugate additions to chromones and 4-quinolones using either palladium catalysis or arylboronic acid nucleophiles.30 Overall, a total of 38 adducts were prepared in moderate to excellent yield and high enantioselectivity. Furthermore, the stability of the reaction components to air and moisture affords unprecedented functional group tolerance. Thus, heterocyclic products 484 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H bearing heterocyclic substitution (192c), free phenolic groups (192d), and N-substituted arenes (192b and 192f) could be obtained via the conjugate addition methodology. Table A8.4 Enantioselective conjugate addition of arylboronic acids to heterocyclic conjugate acceptorsa O B(OH) 2 + R1 R2 O O R1 ClCH2CH2Cl 60 °C, 12 h X 190 L14 (6 mol %) Pd(OCOCF 3)2 (5 mol %) NH 4PF 6 (30 mol %) H 2O (5 equiv) X 191 R2 192 O O O O O OMe O NH(COCF 3) 192a 91% yield 94% ee c b O O N Cbz N Cbz HO O O Ac 192b 192c 192d 80% yield 95% ee 70% yield 83% ee 77% yield 93% ee O NH(COCF 3) O OMe N Cbz N Cbz CO2Me OMe 192e 192f 192g 192h 50% yield 80% ee 45% yield 85% ee 50% yield 85% ee 34% yield 60% ee [a] Reactions performed with arylboronic acid (0.50 mmol), heterocyclic acceptor (0.25 mmol), NH4PF6 (30 mol %), water (5 equiv), Pd(OCOCF3)2 (5 mol %), and L14 (6 mol %) in ClCH2CH2Cl (1 mL) at 60 °C for 12 h. [b] Isolated yield. [c] Determined by chiral HPLC. A8.3 RETROSYNTHETIC ANALYSIS The formal synthesis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) provided an optimal forum for demonstrating the breadth and generality of our aforementioned palladium-catalyzed conjugate addition chemistry. Our preliminary Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 485 strategic disconnections of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) involved late stage introduction of the gem-dimethyl functionality and oxidation of the Cring of enone 193 to the quinone (Figure A8.6).31,2f In turn, the B-ring of tricycle 193 was envisioned to be established through ortho-formylation of phenol 194 and subsequent aldol condensation. Finally, we anticipated that the all-carbon quaternary stereocenter could be constructed by enantioselective palladium-catalyzed conjugate addition of 3methyl-2-cyclohexenone (167) with an appropriate arylboronic acid 195.4 Figure A8.6 Planned retrosynthesis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) O O A B OR 2 C O OR 3 R 3 = Me, (+)-taiwaniaquinone (158) 193 R 3 = H, (+)-dichroanone (159) OR 2 O O R1 OR 2 R1 194 (HO)2B + 167 195 OR 2 A8.4 FIRST GENERATION ROUTE We first selected para-acetylphenylboronic acid 199 (Scheme A8.5) as our conjugate addition substrate. In our previous work we noted that electron-withdrawing substituents at the para-position of the arylboronic acid often afforded highly enantioenriched β-quaternary ketone products.4 A plot of the enantiomeric ratio versus the Hammett value (σp) for a variety of para-substituted phenylboronic acids demonstrates a strong positive linear correlation, R2 = 0.92 (Figure A8.7). 32 The positive value of ρ Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 486 (0.81) suggests that the difference in energy between the diastereomeric transition states leading to the enantiomeric (S) and (R) products increases as the boronic acid becomes increasingly electron deficient. Thus, the best selectivity in the conjugate addition reaction is achieved with electron-withdrawing substituents in the para-position. Therefore, we chose to mask the isopropyl group as a methyl ketone to achieve a selective conjugate addition reaction. Figure A8.7 Hammett plot of log10(er) vs σp for select boronic acids in the palladium-catalyzed conjugate addition reaction 1.8 p−CF 3 1.7 p−Cl p−Ac 1.6 10 log (er) 1.5 p−Br p−H 1.4 p−F 1.3 1.2 p−Et p−iPr p−Me 1.1 1 −0.2 −0.1 0 0.1 0.2 σ 0.3 0.4 0.5 0.6 p 2 y = 0.8058x + 1.3096 R =0.92 Access to para-acetylphenylboronic acid 199 began with acylation of 2,6dihydroxyacetophenone (196) with pivaloyl chloride to provide arene 197 (Scheme A8.5). Installation of the boryl substituent was accomplished through an iridiumcatalyzed C–H borylation. 33 This reaction provided pinacol boronate ester 198 as the exclusive product in 89% yield. Empirically, we identified that protecting the metahydroxyl substituents with pivalate groups allowed for the highest yields in this borylation chemistry. After exhaustive exploration of deprotection conditions, we found 487 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H that treatment with diethanolamine and subsequent acid-catalyzed hydrolysis of the transesterified intermediate afforded arylboronic acid 199 in 92% yield.34 Boronic acid 199 was treated with 3-methyl-2-cyclohexenone (167) in the presence of Pd(OCOCF3)2, (S)-t-BuPyOx (L14), and NH4PF6 at 50° C to afford enantioenriched ketone 169b in 93% yield and 94% ee.4b Scheme A8.5 Synthesis of acetyl conjugate addition product 169b O HO O OH N PivO PivCl, DMAP, NEt 3 OPiv CH2Cl2, 0 °C → 23 °C (94% yield) OPiv BPin (89% yield) 197 O PivO OPiv 198 Pd(OCOCF 3)2 (S)-t-BuPyOx (L14) NH 4PF 6, H 2O 3-methyl-2-cyclohexenone (167) O OPiv O ClCH2CH2Cl, 50 °C 2. 0.1 M HCl, CH2Cl2, 23 °C (92% yield, 2 steps) PivO THF, 60 °C 196 1. diethanolamine, EtOAc O N [Ir(cod)OMe] 2 B 2pin 2 B(OH) 2 199 (93% yield, 94% ee) OPiv 169b With ketone 169b in hand, we turned our attention to the installation of the final carbon of the tricyclic core and completion of the B-ring. Regrettably, attempts to formylate arene 169b were unsuccessful. We rationalized that the sterically congested environment surrounding the arene C–H bonds prohibited installation of a functional group handle. Moreover, deprotection of the hydroxyl groups of ketone 169b was not facile, and required treatment with LiSEt to cleanly remove both pivaloyl groups and afford what we predicted to be resorcinol 200 (Scheme A8.6). Though HRMS data matched the molecular formula of desired resorcinol 200, the 1H NMR spectra did not 488 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H match that of a typical β-quaternary ketone conjugate addition product. We suspected that an unproductive cyclization may have occurred and sought to crystallize derivatives of ketone 202 to confirm the new structure by single crystal X-ray diffraction. Bromination and methylation of compound 202 provided bromoarene 203 as a white crystalline solid. As we suspected, a cyclization had occurred and the structure proved to be [3.2.1]bicycle 203. Thus, we were able to properly assign the structures of cyclization product 202 and arene bromination adduct 203. This X-ray structure also confirms the absolute stereochemistry imparted in enantioselective conjugate addition reactions of arylboronic acids to cyclic conjugate acceptors facilitated by the catalyst derived from the combination of (S)-t-BuPyOx (L14) and Pd(OCOCF3)2. Scheme A8.6 Unexpected cyclization of phenolic intermediatea O 1.DBDMH a CH2Cl2, 23 °C LiSEt O OH DMF, 0 °C O OPiv O 169b O Br OMe 2. CH3I, Cs2CO3 (CH3)2CO, 23 °C O 200 OH 201 OMe (not observed) (not observed) OPiv OH LiSEt O DMF, 0 °C HO (95% yield) OH 202 Br 1.DBDMH CH2Cl2, 23 °C 2. CH3I, Cs2CO3 (CH3)2CO, 23 °C (42% yield, 2 steps) OMe O HO OMe 203 (X-ray) [a] DBDMH = 1,3-dibromo-5,5-dimethylhydantoin Cyclizations of β-aryl ketones to form [3.2.1] bicycles are rare; the few other reports of this transformation require treatment with strong Lewis35 or Brønsted acids36 at elevated temperatures. These reactions presumably operate via an electrophilic aromatic substitution mechanism. While it is possible that our noted cyclization proceeds through a Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 489 similar mechanism, we did not observe cyclization with substrates bearing protected phenols, which suggests that the hydroxyl group or phenoxide may be involved in the cyclization mechanism. This observation led us to propose that this unexpected cyclization may instead occur through a carbonyl ene or lithium phenoxide aldol reaction pathway. A8.5 SECOND GENERATION ROUTE As we were unable to functionalize ketone 169b without causing the undesired cyclization, we decided to redesign the arylboronic acid substrate and began examining alternative conjugate addition reactions. Removing the acetyl group would obviate the need to differentiate the benzylic carbonyl from the cyclic ketone while installing the requisite isopropyl group in the first-generation conjugate addition product 169b. We envisioned that a para-halogenated arylboronic acid derivative would allow for facile installation of the isopropyl group via cross-coupling chemistry. Additionally, based on our Hammett plot analysis, we posited that the para-halide would serve as a necessary para-electron-withdrawing group to impart high enantioselectivity in the palladium/L14 conjugate addition chemistry (Figure A8.7).4 Gratifyingly, we found that use of these boronic acids furnished products bearing para-iodo (169c), para-bromo (169d), and para-chloro (169e) arenes in high enantioselectivity and moderate to high yields (Table A8.5). 490 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Table A8.5 Identification of a suitable conjugate addition systema O L14 (6 mol %) Pd(OCOCF 3)2 (5 mol %) NH 4PF 6 (30 mol %) H 2O (5 equiv) (HO)2B + O R ClCH2CH2Cl 50 °C, 72 h 167 R 169 168 O O O OMe OPiv OPiv O 169a 169b OMe trace product O 169c OPiv 93% yield 94% ee c b 42% yield 92% ee O O OPiv 169d Br OPiv 98% yield >99% ee I OPiv OPiv 169e Cl OPiv 94% yield >99% ee 169f OMe 85% yield 85% ee d [a] Reactions performed with boronic acid (1.5 equiv), 167 (1 equiv), NH4PF6 (30 mol %), water (5 equiv), Pd(OCOCF3)2 (5 mol %), and L14 (6 mol %) in ClCH2CH2Cl at 50 °C for 12 h. [b] Isolated yield. [c] Determined by chiral HPLC or SFC. We consequently pursued a revised approach to the natural products via bromoarene 169d, selected both for its superior reactivity in palladium-catalyzed conjugate addition chemistry and facile cross-coupling ability. To access this intermediate, 2-bromoresorcinol 204 was converted to para-bromophenyl boronic acid derivative 207 in 73% yield over four steps (Scheme A8.7). Subsequent catalytic, enantioselective conjugate addition furnished ketone 169d in 98% yield and >99% ee. 491 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Scheme A8.7 Synthesis of para-bromo conjugate addition product 169d Br HO Br OH PivO PivCl, DMAP, NEt 3 CH2Cl2, 0 °C → 23 °C Br PivO OPiv BPin (95% yield) (95% yield) 205 Br PivO OPiv 206 Pd(OCOCF 3)2 (S)-t-BuPyOx (L14) NH 4PF 6, H 2O 3-methyl-2-cyclohexenone (167) O OPiv ClCH2CH2Cl, 50 °C 2. 0.1 M HCl, CH2Cl2, 23 °C (82% yield, 2 steps) N [Ir(cod)OMe] 2 B 2pin 2 THF, 60 °C 204 1. diethanolamine, EtOAc N OPiv B(OH) 2 207 Br (98% yield, >99% ee) OPiv 169d Having installed the quaternary stereocenter, we next sought to append the isopropyl group. Attempts to directly cross-couple an isopropyl zinc reagent with bromide 169d gave an inseparable mixture of iso- and n-propyl products.37 The steric hindrance of the nearby pivaloyl groups thwarted our attempts to cross couple 169d with isopropenyl organometallic regents, but we ultimately achieved success using Molander’s protocol for Suzuki-Miyaura couplings of potassium isopropenyltrifluoroboronate salts.38 Our optimized conditions (170 °C, 1 h, microwave) gave a crude mixture of both cross coupled product and mono-deprotected cross coupled product that could be stirred with tetrabutylammonium hydroxide to furnish isopropenyl phenol 208 in 70% yield (Scheme A8.8). Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 492 Scheme A8.8 Isopropenyl cross-coupling O O OPiv Br 169d OPiv BF 3K Pd(OAc) 2, K 2CO3 dioxane:H2O (9:1) 170 °C, µwave, 1 h then Bu 4NOH dioxane/H2O (9:1) OH 208 OPiv (70% yield) With a route to mono-deprotected arene 208 established, we turned our efforts once more toward the formation of the B-ring. However, despite the successful removal of one pivaloyl group, the system proved resistant to a number of metal and non-metal mediated ortho-formylations, directed ortho-metalations, and halogenations, regardless of protection of the ketone. We speculate that the failure of these efforts may again be attributed to the formidable steric environment of the arene C–H bonds. Recognizing that significant steric hindrance would prevent the formation of the B-ring, we sought to diminish the steric environment of the arene by reductive removal of the free phenol. Activation of phenol 208 by exposure to excess perfluorobutanesulfonyl fluoride led to the generation of nonaflate 209 in 80% yield (Scheme A8.9). Subsequent hydrogenation with Pd/C simultaneously cleaved the nonaflate and reduced the isopropenyl functionality to afford isopropyl arene 210 in 72% yield. 39 Finally, the pivaloyl group was replaced with a methyl group by one pot deprotection and methylation with LiSEt and Me2SO4 to provide ketone 169f in 83% yield. With the less substituted arene 169f in hand, we believed that the necessary tricycle could now be readily formed by ortho-formylation. 493 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H Scheme A8.9 Synthesis of key intermediate 169f O O O NfF, DMAP OH ONf Et 3N, CH2Cl2, 23 °C 208 OPiv H 2 (1 atm), Pd/C Et 3N, MeOH, 65 °C (80% yield) 209 (72% yield) OPiv 210 OPiv O O LiSEt, DMF/THF 0 °C → 45 °C Ref. 2t then Me 2SO4, 45 °C (83% yield) 169f OMe >99% ee O OR R = Me, (+)-taiwaniaquinone H (158) R = H, (+)-dichroanone (159) Concurrent with our synthetic efforts, Qin and coworkers reported a formal total synthesis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) via enantioselective conjugate addition of (4-isopropyl-3-methyloxyphenyl)boronic acid to 3-methyl-2cyclohexenone (167) in 85% yield and 85% ee (169f, Table A8.5) using the catalyst developed in our laboratory.2t,4a However, Qin was unable to optimize the conjugate addition substrates to achieve yields or enantioselectivities over 85%. This result aligns well with our Hammett plot analysis; the determined linear relationship predicts an enantioselectivity of 88% for the electron-donating isopropyl group (Figure A8.7). Moreover, this study demonstrated that our common intermediate 169f could be further transformed into the taiwaniaquinoid tricyclic skeleton by ortho-formylation followed by aldol condensation. Therefore, our synthesis of ketone 169f in >99% ee constitutes a formal synthesis of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) in the highest reported enantioselectivity to date. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H A8.6 494 CONCLUSIONS In summary, we have completed the formal catalytic, enantioselective total syntheses of (+)-taiwaniaquinone H (158) and (+)-dichroanone (159) in 35% overall yield, starting from commercially available 2-bromoresorcinol (204). Investigation of electronic effects of arylboronic acid substituents on enantioselectivity enabled the rational design of a highly enantioselective reaction that furnished established intermediate 169f in exceptionally high yield and enantioselectivity. Additionally, an unexpected cyclization to form a [3.2.1] bicycle permitted the unambiguous determination of the absolute stereochemistry of the quaternary stereocenter installed by the palladium/L14-catalyzed conjugate addition reaction by X-ray diffraction analysis. A8.7 EXPERIMENTAL SECTION A8.7.1 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. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar and used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 495 quenching or p-anisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. 1H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or (CH3)2SO (δ 2.50 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CDCl3 (δ 77.16 ppm), (CD3)2SO (δ 39.52 ppm) or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, app = apparent. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from an Agilent 6200 Series TOF with Agilent G1978A Multimode source in mixed ionization mode (MultiMode ESI/APCI) or from a JEOL JMS-600H in fast atom bombardment (FAB+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as [α]DT (concentration in g/100 mL, solvent). A8.7.1.1 Preparation of Known Compounds Previously reported methods were used to prepare ligand (S)-t-BuPyOx (L14).20b Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 496 A8.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA A8.7.2.1 General Procedure and Spectroscopic Data for the Synthesis of Resorcinol Pivaloyl Esters O PivO OPiv 2-Acetyl-1,3-phenylene bis(2,2-dimethylpropanoate) (197). An oven-dried 1 L roundbottom flask was charged with a magnetic stir bar, 2,6-dihydroxyacetophenone (10 g, 65.7 mmol, 1 equiv) and DMAP (800 mg, 6.57 mmol, 10 mol %). The flask was evacuated under vacuum and back-filled three times with argon. The solids were suspended in CH2Cl2 (450 mL), and NEt3 (23 mL, 165 mmol, 2.5 equiv) was added, at which time the solution became homogenous and a transparent, pale yellow color was observed. The reaction solution was cooled to 0 °C in an ice/water bath and pivaloyl chloride (17 mL, 138 mmol, 2.1 equiv) was added via mechanical syringe pump addition over the course of 2 h. Slow addition is essential to maintain an internal temperature of less than 5 °C and minimize formation of side products. Upon complete addition, the ice/water bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the starting material was consumed by TLC analysis (30% acetone/hexanes, stain p-anisaldehyde), and the reaction mixture was quenched with sat. NH4Cl (aq, 300 mL). The mixture was diluted with CH2Cl2 (400 mL) and transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined organic extracts were washed with 1M HCl (3 x 100 mL) and brine (1 x 100 mL), dried over Mg2SO4 and concentrated under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (150 g silica gel, eluent: 20% Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 497 acetone/hexanes) to afford pivaloyl 197 as a white, crystalline solid (19.73 g, 94% yield): 1 H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 8.3 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 2.45 (s, 3H), 1.32 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 198.7, 176.4, 147.9, 130.4, 128.6, 120.1, 39.2, 31.7, 27.1; IR (Neat Film, NaCl): 3487, 3395, 2976, 2936, 2874, 1755, 1705, 1611, 1576, 1478, 1457, 1397, 1368, 1274, 1251, 1233, 1117, 1101 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C18H23O5 [M-H]-: 319.1551, found 319.1542. Br PivO OPiv 2-Bromo-1,3-phenylene bis(2,2-dimethylpropanoate) (205). White, crystalline solid (3.77 g, 95% yield): 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 1.40 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 175.8, 149.9, 128.0, 120.9, 111.4, 39.6, 27.4; IR (Neat Film, NaCl): 2971, 2934, 2972, 1762, 1586, 1479, 1460, 1396, 1365, 1274, 1254, 1233, 1093, 1031, 884 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C16H25BrNO4 [M+NH4]+: 374.0961, found 374.0960. Cl PivO OPiv 2-Chloro-1,3-phenylene bis(2,2-dimethylpropanoate) (211). White, crystalline solid (7.57 g, 98% yield): 1H NMR (500 MHz, CDCl3) δ 7.28 (t, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 1.40 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 175.8, 148.4, 127.0, 121.0, 121.0, 39.3, 27.1; IR (Neat Film, NaCl): 2970, 2935, 2874, 1765, 1749, 1583, 1478, Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 498 1463, 14552, 1397, 1368, 1273, 1259, 1235, 1112, 1033 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C16H25ClNO4 [M+NH4]+: 330.1467, found 330.1472. I PivO OPiv 2-Iodo-1,3-phenylene bis(2,2-dimethylpropanoate) (212). White, crystalline solid (14.0 g, 96% yield): 1H NMR (500 MHz, CDCl3) δ 7.35 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 1.42 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 175.9, 152.9, 129.5, 120.0, 88.0, 39.5, 27.5; IR (Neat Film, NaCl): 2972, 2873, 1755, 1583, 1479, 1451, 1396, 1367, 1274, 1244, 1218, 1095, 1029, 967, 941, 886 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C16H20IO4 [M-H]-: 403.0412, found 403.0413. A8.7.2.2 General Procedure and Spectroscopic Data for the Synthesis of Borylated Arenes O PivO OPiv O B O 2-Acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-phenylene bis(2,2- dimethylpropanoate) (198). In a nitrogen-filled glove box, a 500 mL round-bottom flask with a Kontes valve was charged with a stir bar, arene 197 (16.02 g, 50.0 mmol, 1.0 equiv), B2Pin2 (9.5 g, 37.5 mmol, 0.75 equiv), [Ir(cod)(OMe)]2 (33 mg, 0.05 mmol, 0.1 mol %), and tetramethylphenanthroline (24 mg, 0.10 mmol, 0.2 mol %). The solids were Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 499 suspended in THF (50 mL), and the flask was sealed and removed from the glove box. The reaction mixture was stirred in an oil bath heated at 60 °C for 45 h, at which time the reaction was complete by TLC analysis (20% acetone/hexanes, p-anisaldehyde stain). The reaction mixture was cooled to ambient temperature and filtered through a silica gel plug (50 g silica gel, eluent: acetone), and concentrated under reduced pressure. The crude reaction mixture was further purified by silica gel flash chromatography (200 g silica gel, eluent: 20% acetone/hexanes) to afford borylated 198 as an amorphous offwhite solid (19.85 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 2H), 2.43 (s, 3H), 1.33 (s, 12H), 1.32 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 198.8, 176.5, 147.3, 131.0, 126.0, 120.1, 84.6, 39.2, 31.5, 27.2, 25.0; IR (Neat Film, NaCl): 3509, 2981, 2935, 1766, 1707, 1482, 1459, 1405, 1396, 1354, 1331, 1259, 1212, 1147 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C24H39BNO7 [M+NH4]+: 463.2850, found 463.2852. Br PivO OPiv O B O 2-Bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-phenylene bis(2,2- dimethylpropanoate) (206). Amorphous off-white solid (2.04 g, 96% yield): 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 2H), 1.39 (s, 18H), 1.32 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 175.8, 149.5, 129.8, 126.6, 114.9, 84.6, 39.5, 27.4, 25.0; IR (Neat Film, NaCl): 2977, 1764, 1600, 1479, 1397, 1389, 1364, 1329, 1274, 1211, 1141, 1094, 1036 cm-1; Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 500 HRMS (MultiMode ESI/APCI+) m/z calc’d for C22H36BBrNO6 [M+NH4]+: 499.1850, found 499.1834. Cl PivO OPiv O B O 2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-phenylene bis(2,2- dimethylpropanoate) (213). Amorphous off-white solid (9.01 g, 99% yield): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 2H), 1.38 (s, 18H), 1.33 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 175.9, 148.1, 128.6, 126.8, 124.1, 84.6, 39.4, 27.3, 23.0; IR (Neat Film, NaCl): 2977, 2935, 2873, 1763, 1605, 1480, 1404, 1365, 1326, 1270, 1213, 1145, 1121, 1094, 1036 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C22H36BClNO6 [M+NH4]+: 455.2355, found 455.2358. I PivO OPiv O B O 2-Iodo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-phenylene bis(2,2- dimethylpropanoate) (214). Amorphous off-white solid (12.5 g, 95% yield): 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 2H), 1.41 (s, 18H), 1.32 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 175.9, 152.6, 131.2, 125.7, 92.3, 84.6, 39.5, 27.5, 25.0; IR (Neat Film, NaCl): 2974, 2935, 2873, 1761, 1598, 1549, 1480, 1463, 1395, 1360, 1330, 1274, 1209, 1142, Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 501 1094, 1034, 965, 900, 848 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C22H32BFIO6 [M+F]-: 549.1321, found 549.1337. A8.7.2.3 General Procedure and Spectroscopic Data for the Synthesis of Boronic Acid Analogues O PivO OPiv B(OH) 2 (4-Acetyl-3,5-bis(pivaloyloxy)phenyl)boronic acid (199). A 250 mL round-bottom flask was charged with a stir bar and pinacol boronate ester 198 (8.65 g, 19.27 mmol, 1.0 equiv). The solid was dissolved in EtOAc (250 mL), and diethanolamine (2.35 mL, 24.10 mmol, 1.25 equiv) was added with vigorous stirring. (Note: a glass pipette was cut to have a wide bore, and this wide-bored pipet was used to add the viscous diethanolamine.) Upon addition of diethanolamine, a white precipitate formed. This suspension was stirred vigorously for a further 4 h at ambient temperature, at which time the mixture was concentrated under reduced pressure. The crude white semi-solid reaction residue was suspended in Et2O (300 mL) and stirred vigorously for 30 min. The suspension was then cooled to –20 °C in a freezer overnight. The white solid was collected by vacuum filtration, and the compound was washed with additional portions of Et2O (3 x 50 mL). The collected white solid (7.38 g) was suspended in 0.5 M HCl (200 mL) and stirred vigorously. CH2Cl2 (ca. 50 mL) was added until the solid fully dissolved. The biphasic mixture was stirred for 12 h with extreme vigor. The mixture was then subjected to continuous extraction with boiling CH2Cl2 (300 mL) for 6 h. The combined organic Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 502 extracts were concentrated in vacuo and dried under high vacuum to afford boronic acid 199 as an off-white, flaky solid (6.45 g, 92% yield over two steps): 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 2H), 2.19 (s, 3H), 1.08 (s, 18H); 13C NMR (125 MHz, acetone-d6) δ 198.5, 176.7, 148.1, 138.0, 131.2, 126.2, 39.5, 31.7, 27.2; IR (Neat Film, NaCl): 3446, 2975, 2359, 1751, 1700, 1653, 1635, 1558, 1540, 1480, 1456, 1407, 1340, 1247, 1100, 1038 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C18H29BNO7 [M+NH4]+: 381.2068, found 381.2061. Br PivO OPiv B(OH) 2 (4-Bromo-3,5-bis(pivaloyloxy)phenyl)boronic acid (207). Please note 2 M H2SO4 and THF were used in place of 0.5 M HCl and CH2Cl2, a continuous extraction was not required. Off-white, flaky solid (11.0 g, 82% yield over two steps): 1H NMR (500 MHz, DMSO-d6) δ 7.50 (s, 2H), 1.40 (s, 18H); 13C NMR (125 MHz, DMSO-d6) δ 175.3, 148.6, 135.6, 126.3, 112.8, 38.8, 26.8; IR (Neat Film, NaCl): 3454, 3364, 2976, 2937, 2874, 1755, 1733, 1736, 1480, 1454, 1426, 1365, 1342, 1271, 1218, 1137, 1108, 1038 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C16H22BBr2O6 [M+Br]-: 477.9918, found 477.9923. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 503 Cl PivO OPiv B(OH) 2 (4-Chloro-3,5-bis(pivaloyloxy)phenyl)boronic acid (215). Please note 2 M H2SO4 and THF were used in place of 0.5 M HCl and CH2Cl2, a continuous extraction was not required. Off-white, flaky solid (3.50 g, 86% yield over two steps): 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 2H), 1.34 (s, 18H); 13C NMR (100 MHz, DMSO-d6) δ 175.3, 147.2, 134.8, 126.3, 121.5, 38.8, 26.7; IR (Neat Film, NaCl): 3377, 2980, 1753, 1735, 1639, 1480, 1463, 1428, 1366, 1342, 1280, 1139, 1113, 1089 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C16H22BCl2O6 [M+Cl]-: 390.0928, found 390.0936. I PivO OPiv B(OH) 2 (4-Iodo-3,5-bis(pivaloyloxy)phenyl)boronic acid (216). Please note 2 M H2SO4 and THF were used in place of 0.5 M HCl and CH2Cl2, a continuous extraction was not required. Off-white, flaky solid (4.82 g, 94% yield over two steps): 1H NMR (500 MHz, DMSO-d6) δ 7.37 (s, 2H), 1.37 (s, 18H); 13C NMR (125 MHz, DMSO-d6) δ 175.4, 152.0, 136.5, 125.2, 92.0, 38.8, 27.0; IR (Neat Film, NaCl): 3369, 2975, 1759, 1735, 1395, 1360, 1277, 1095, 1034, 904 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C16H22BClIO6 [M+Cl]-: 482.0284, found 482.0296. 504 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H A8.7.2.4 General Procedure and Spectroscopic Data for the Enantioselective Palladium-Catalyzed Conjugate Addition of Arylboronic Acids O OPiv O OPiv (R)-2-Acetyl-5-(1-methyl-3-oxocyclohexyl)-1,3-phenylene bis(2,2- dimethylpropanoate) (169b). A 20 mL screw-top vial was charged with a stir bar, Pd(OCOCF3)2 (25 mg, 0.075 mmol, 2.5 mol %), (S)-t-BuPyOx (18 mg, 0.099 mmol, 3 mol %), NH4PF6 (145 mg, 0.99 mmol, 30 mol %), and the solids were dissolved in 1,2dichloroethane (2 mL) and stirred at ambient temperature for 5 min. Not all solids dissolved at this time. A 100 mL round bottom flask was charged with a stir bar, boronic acid 19 (1.20 g, 3.30 mmol, 1.1 equiv), and 1,2-dichloroethane (10 mL), and stirred at ambient temperature. The catalyst solution was filtered through a pipet plugged with a Kimwipe and added to the suspension of boronic acid in one portion. 3methylcyclohexen-2-one (340 µL, 3.00 mmol, 1.0 equiv) and water (270 µL, 15 mmol, 5 equiv) were added by syringe and the flask was stirred in an oil bath heated to 50 °C for 72 h. When the starting material was consumed as determined by TLC analysis (10% acetone/hexanes, p-anisaldehyde stain), the mixture was cooled to ambient temperature and filtered through a plug of silica gel (eluent: CH2Cl2) and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (200 g silica gel, eluent gradient: 5% acetone/hexanes to 10% acetone/hexanes) to afford conjugate addition product 169b as a colorless oil (1.19 g, 93% yield): 94% ee; [α]25D –36.1° (c 1.85, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.91 (s, 2H), 2.77 (d, J = 14.1 Hz, 1H), 2.42 (s, 4H), 2.33 (t, J = 6.8 Hz, 2H), 2.12 (s, 1H), 1.99 – 1.84 (m, 2H), 1.82 – 1.71 (m, Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 505 1H), 1.32 (s, 21H);13C NMR (125 MHz, CDCl3) δ 210.4, 198.5, 176.4, 151.3, 148.0, 126.5, 117.5, 52.8, 43.0, 40.8, 39.2, 37.6, 31.5, 28.9, 27.2, 27.1, 27.1, 22.0; IR (Neat Film, NaCl): 3404, 2973, 2937, 2874, 1758, 1708, 1620, 1562, 1480, 1408, 1397, 1257, 1095 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C25H34NaO6 [M+Na]+: 453.2248, found 453.2234; HPLC conditions: 5% IPA, 1.0 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 6.454, minor = 6.227. O OPiv Br OPiv (R)-2-Bromo-5-(1-methyl-3-oxocyclohexyl)-1,3-phenylene bis(2,2- dimethylpropanoate) (169d). Please note 1.5 equiv of boronic acid were employed. Colorless solid (4.57 g, 98% yield): >99% ee; [α]25D –34.5° (c 1.41, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.93 (s, 2H), 2.76 (d, J = 14.1 Hz, 1H), 2.44 (d, 14.1 Hz, 1H), 2.33 (t, J = 6.7 Hz, 2H), 2.19 – 2.06 (m, 1H), 1.98 – 1.85 (m, 2H), 1.80 – 1.74 (m, 1H), 1.40 (s, 18H), 1.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 210.2, 175.8, 149.8, 149.0, 118.4, 108.9, 53.0, 42.8, 40.8, 39.6, 37.7, 28.8, 27.4, 22.1; IR (Neat Film, NaCl): 2973, 2936, 2874, 1763, 1713, 1601, 1571, 1480, 1463, 1408, 1397, 1365, 1272, 1227, 1096, 1037, 894 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C23H35BrNO5 [M+NH4]+: 484.1693, found 484.1693; HPLC conditions: 20% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 5.795, minor = 6.232. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 506 O OPiv Cl OPiv (R)-2-Chloro-5-(1-methyl-3-oxocyclohexyl)-1,3-phenylene bis(2,2- dimethylpropanoate) (169e). Please note 1.5 equiv of boronic acid were employed. Colorless solid (0.74 g, 94% yield): >99% ee; [α]25D –38.9° (c 2.59, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.95 (s, 2H), 2.76 (d, J = 14.1 Hz, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.32 (t, J = 6.7 Hz, 2H), 2.15 – 2.06 (m, 1H), 1.98 – 1.84 (m, 2H), 1.82 – 1.71 (m, 1H), 1.38 (s, 18H), 1.30 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 210.3, 175.7, 148.2, 147.8, 118.4, 118.3, 52.8, 42.6, 40.6, 39.3, 37.5, 28.7, 27.2, 21.9; IR (Neat Film, NaCl): 2972, 2936, 2874, 2256, 1763, 1713, 1607, 1574, 1479, 1413, 1397, 1352, 1316, 1272, 1227, 1050, 1038, 895, 734 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C23H35ClNO5 [M+NH4]+: 440.2198, found 440.2197; SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak AS-H column, λ = 210 nm, tR (min): major = 5.393, minor = 6.285. O OPiv I OPiv (R)-2-Iodo-5-(1-methyl-3-oxocyclohexyl)-1,3-phenylene bis(2,2-dimethylpropanoate) (169c). Please note 1.5 equiv of boronic acid were employed. Colorless solid (0.40 g, 42% yield): 92% ee; [α]25D –29.2° (c 4.47, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.87 (s, 2H), 2.75 (d, J = 14.1 Hz, 1H), 2.42 (d, 14.1 Hz, 1H), 2.30 (t, J = 6.8 Hz, 2H), 2.12 – 2.06 (m, 1H), 1.92 – 1.85 (m, 2H), 1.77 – 1.72 (m, 1H), 1.40 (s, 18H), 1.28 (s, 3H); 13C Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H NMR (125 MHz, CDCl3) δ 507 210.4, 175.9, 152.7, 150.4, 117.6, 85.0, 52.8, 42.7, 40.7, 39.4, 37.5, 28.7, 27.4, 22.0; IR (Neat Film, NaCl): 2972, 2936, 2873, 1759, 1711, 1598, 1560, 1480, 1461, 1396, 1368, 1314, 1271, 1226, 1098, 1036, 938, 914, 894, 754, 733 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C23H35INO5 [M+NH4]+: 532.1554, found 532.1567; HPLC conditions: 20% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 6.130, minor = 7.008. A8.7.2.5 Procedures and Spectroscopic Data for Synthetic Intermediates OH O HO OH (R)-1-(1,3,9-Trihydroxy-5-methyl-6,7,8,9-tetrahydro-5H-5,9methanobenzo[7]annulen-2-yl)ethanone (202). A 250 mL round-bottom flask was charged with a stir bar, flame-dried under vacuum, back-filled with argon, and charged with THF (25 mL). The solution was cooled to 0 °C in an ice/water bath and ethanethiol (0.890 mL, 12.5 mmol, 2.7 equiv) was added via syringe. n-BuLi (2.5 M solution in hexanes, 5.5 mL, 13.75 mmol, 2.97 equiv) was added dropwise, and a white precipitate was observed at the completion of the addition. DMF (25 mL) was added until the solution became homogenous and clear. The solution was allowed to stir at 0 °C for 30 min. A flame-dried, 25 mL conical flask was charged with ketone 169b (1.99 g, 4.62 mmol, 1 equiv) and DMF (10 mL). The ketone solution was transferred via cannula to the cooled, freshly-prepared solution of LiSEt dropwise over 10 min. The ice/water bath was removed and the reaction was allowed to stir and warm to ambient temperature over 30 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 508 min, at which time the starting material was consumed as determined by TLC analysis (20% EtOAc/hexanes, p-anisaldehyde stain). The reaction was quenched by addition of sat. NH4Cl solution (aq, 50 mL), diluted with CH2Cl2 (200 mL) and water (200 mL) and transferred to a separatory funnel. 1M HCl (aq) was added until the aqueous layer was pH 2–4. The aqueous layer was extracted with CH2Cl2 (5 x 50 mL) and the combined organic extracts were washed with water (7 x 50 mL), brine (1 x 50 mL), dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography (90 g silica gel, eluent gradient: 10% EtOAc/hexanes to 20% EtOAc/hexanes) to afford tricycle 202 as a pale yellow oil (1.15 g, 95% yield): [α]25D – 19.0° (c 0.26, CHCl3); 1H NMR (500 MHz, CDCl3) δ 13.30 (s, 1H), 8.30 (s, 1H), 6.23 (d, J = 1.9 Hz, 1H), 2.71 (s, 3H), 2.58 (bs, 1H), 2.12 (ddd, J = 9.5, 2.9, 2.2 Hz, 1H), 2.01– 1.89 (m, 1H), 1.76 – 1.59 (m, 3H), 1.48 – 1.32 (m, 2H), 1.31 (s, 3H), 1.03 – 0.81 (m, 1H); 13 C NMR (125 MHz, CDCl3) δ 204.9, 165.8, 156.1, 154.4, 118.8, 109.1, 102.4, 82.3, 59.0, 45.7, 35.4, 34.5, 33.2, 22.9, 21.4; IR (Neat Film, NaCl): 3338, 2934, 2867, 1641, 1588, 1435, 1375, 1324, 1270, 1243, 1124, 1055, 1027, 973, 839 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C15H19O4 [M+H]+: 263.1278, found 263.1272. Br OH O HO OH (R)-1-(4-Bromo-1,3,9-trihydroxy-5-methyl-6,7,8,9-tetrahydro-5H-5,9methanobenzo[7]annulen-2-yl)ethanone (217). A 50 mL, flame-dried, round-bottom flask was charged with a stir bar, tricycle 202 (110 mg, 0.419 mmol, 1 equiv) and Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 509 dibromodimethylhydantoin (151 mg, 0.461 mmol, 1.1 equiv). The flask was evacuated under vacuum and back-filled with argon, and the solids were dissolved in CH2Cl2 (5 mL) and stirred at ambient temperature. After 30 min, an aliquot was partitioned between EtOAc (1 mL) and sat. Na2S2O3 (aq, 1 mL), and the organic layer was subjected to LCMS analysis, where no starting material was observed. The red-colored reaction was quenched by the addition of 20% Na2S2O3 solution (aq, 20 mL) and stirred vigorously for 3 h, until the orange/red color was no longer observed. The mixture was partitioned between CH2Cl2 (20 mL) and water (20 mL) and transferred to a separatory funnel. 1M HCl was added until the aqueous layer was pH 3. The aqueous layer was extracted with CH2Cl2 (5 x 25 mL) and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (12 g silica gel, eluent gradient: 10% EtOAc/hexanes to 25% EtOAc/hexanes) to afford bromo arene 217 as a yellow, semi-crystalline solid (92 mg, 66% yield): [α]25D –20.8° (c 1.26, CHCl3); 1H NMR (500 MHz, CDCl3) δ 13.37 (s, 1H), 9.10 (s, 1H), 2.74 (s, 3H), 2.55 (s, 1H), 2.22 (ddd, J = 9.7, 3.0, 2.2 Hz, 1H), 1.93 (ddd, J = 11.2, 6.2, 3.0 Hz, 1H), 1.75 – 1.64 (m, 4H), 1.61 (s, 3H), 1.35 (td, J = 13.0, 5.5 Hz, 1H), 0.96 – 0.80 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 204.5, 154.3, 151.9, 120.2, 110.2, 109.9, 97.9, 81.4, 59.1, 48.8, 34.4, 33.1, 33.0, 24.6, 21.6; IR (Neat Film, NaCl): 3381, 2936, 2852, 1631, 1566, 1415, 1373, 1326, 1274, 1233 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C15H16BrO4 [M-H]-: 339.0237, found 339.0230. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 510 Br OMe O HO OMe (R)-1-(4-Bromo-9-hydroxy-1,3-dimethoxy-5-methyl-6,7,8,9-tetrahydro-5H-5,9methanobenzo[7]annulen-2-yl)ethanone (203). A flame-dried 20 mL vial was charged with a stir bar, bromo-diphenol 217 (92 mg, 0.270 mmol, 1 equiv), Cs2CO3 (194 mg, 0.595 mmol, 2.2 equiv), and acetone (5 mL). The vial was stirred under argon atmosphere at ambient temperature, and methyl iodide (0.037 mL, 0.595 mmol, 2.2 equiv) was added in one portion. The yellow reaction slurry was stirred for 40 h at ambient temperature, at which time the color had faded to a white slurry and the starting material was consumed as determined by TLC analysis (20% EtOAc/hexanes, panisaldehyde stain). The reaction was quenched with sat. NH4Cl solution (aq, 5 mL) and stirred for 12 h at ambient temperature. The reaction was diluted with EtOAc (10 mL) and water (10 mL), and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic extracts were washed with water (2 x 10 mL) and brine (1 x 10 mL), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (12 g silica gel, eluent gradient 10% EtOAc/hexanes to 20% EtOAC/hexanes) to afford 203 as a clear oil that solidified to an amorphous white solid upon standing (62 mg, 63% yield): [α]25D –5.8° (c 0.73, CHCl3); 1H NMR (500 MHz, CDCl3) δ 3.81 (s, 3H), 3.80 (s, 3H), 2.56 (s, 3H), 2.24 (dt, J = 10.1, 2.5 Hz, 1H), 1.84 – 1.71 (m, 2H), 1.71 – 1.61 (m, 4H), 1.60 (s, 3H), 1.35 (td, J = 12.9, 5.8 Hz, 1H), 0.81 – 0.67 (m, 1H).13C NMR (125 MHz, CDCl3) δ 201.8, 153.9, 151.0, 148.1, 135.9, 130.5, Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 511 108.9, 79.7, 63.9, 63.1, 58.6, 48.0, 36.7, 33.2, 32.6, 25.1, 21.6; IR (Neat Film, NaCl): 3429, 2938, 2853, 1704, 1642, 1590, 1450, 1382, 1323, 1237, 1120, 1077 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C17H22BrO4 [M+H]+: 369.0696, found 369.0690. O OH OPiv (R)-3-Hydroxy-5-(1-methyl-3-oxocyclohexyl)-2-(prop-1-en-2-yl)phenyl pivalate (208). Four 20 mL microwave vials were each charged with a stir bar, ketone 169d (0.594 g, 1.27 mmol, 1 equiv), potassium isopropenyltrifluoroborate (281 mg, 1.91 mmol, 1.25 equiv), K2CO3 (263 g, 1.91 mmol, 1.5 equiv), PPh3 (33 mg, 0.127 mmol, 10 mol %), and Pd(OAc)2 (14 mg, 0.0635 mmol, 5 mol %), and capped with a microwave septum top. The vials were evacuated with vacuum and back-filled with argon three times. The solids were suspended in degassed dioxane/H2O (9:1 ratio, 20 mL) before the reaction was stirred in the microwave reactor for 1 h at 170 °C on very high absorbance mode. The mixture was cooled to ambient temperature and filtered through a plug of silica gel (eluent: EtOAc) and concentrated under reduced pressure to afford a brown oil. A 100 mL round-bottom flask was charged with the combined crude reaction residues, a stir bar, Bu4NOH (4.7 mL, 7.15 mmol, 2.4 equiv), and dioxane/H2O (9:1 ratio, 50 mL). The reaction was stirred at ambient temperature for 10 h, at which point the starting material was consumed as determined by TLC analysis (20% EtOAc/hexanes, panisaldehyde stain). The reaction was quenched with sat. NH4Cl (aq, 25 mL) and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 100 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 512 mL), and the combined organic extracts were washed with brine (1 x 100 mL), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (50 g silica gel, eluent gradient: 10% EtOAc/hexanes to 20% EtOAc/hexanes) to afford isopropenyl 208 as a yellow oil (1.23 g, 70% yield over 2 steps): [α]25D –37.4° (c 1.26, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.79 (d, J = 1.8 Hz, 1H), 6.53 (d, J = 1.8 Hz, 1H), 5.52 (s, 1H), 5.43 (s, 1H), 5.04 (s, 1H), 2.79 (d, J = 14.1 Hz, 1H), 2.41 (d, J = 14.1 Hz, 1H), 2.32 (t, J = 6.7 Hz, 2H), 2.14 – 2.08 (m, 1H), 2.00 (s, 3H), 1.91 – 1.84 (m, 2H), 1.83 – 1.73 (m, 1H), 1.31 (s, 9H), 1.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 211.0, 176.8, 152.9, 149.1, 148.7, 138.1, 121.3, 119.3, 111.9, 110.3, 53.2, 42.8, 40.9, 39.2, 37.8, 29.0, 27.3, 23.6, 22.2; IR (Neat Film, NaCl): 3418, 3083, 2970, 2874, 1712, 1620, 1480, 1414, 1368, 1316, 1278, 1230, 1122, 1073, 1035, 1017, 943, 901, 758 cm-1; HRMS (MultiMode ESI/APCI-) m/z calc’d for C21H27O4 [M-H]-: 343.1915, found 343.1926. O ONf OPiv (R)-5-(1-Methyl-3-oxocyclohexyl)-3-(perfluorobutoxy)-2-(prop-1-en-2-yl)phenyl pivalate (209). A 15 mL, flame-dried, round-bottom flask was charged with a stir bar, phenol 208 (165 mg, 0.479 mmol, 1 equiv) and DMAP (3 mg, 0.024 mmol, 5 mol%). The flask was evacuated under vacuum and back-filled with argon three times. The solids were dissolved in CH2Cl2 (5 mL), and NEt3 (1.34 mL, 9.58 mmol, 20 equiv) was added. Perfluorobutanesulfonyl fluoride (1.72 mL, 9.58 mmol, 20 equiv) was then added Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 513 dropwise and the resulting solution was stirred at ambient temperature for 18 h, at which time the starting material was consumed as determined by TLC analysis (30% EtOAc/hexanes, p-anisaldehyde stain). The mixture was washed with water (10 mL) and brine (10 mL), and the organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (9 g silica gel, gradient: 10% EtOAc/hexanes) to afford nonaflate 209 as a colorless oil (0.2694 g, 80% yield): [α]25D –22.1° (c 1.31, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 1.8 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 5.39 (t, J = 1.2 Hz, 1H), 5.00 (t, J = 1.2 Hz, 1H), 2.76 (d, J = 14.0 Hz, 1H), 2.47 (d, J = 14.0 Hz, 1H), 2.35 (t, J = 6.8 Hz, 2H), 2.19 – 2.05 (m, 1H), 2.00 (s, 3H), 1.99 – 1.87 (m, 2H), 1.86 – 1.74 (m, 1H), 1.32 (s, 9H), 1.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 210.1, 176.7, 149.5, 149.5, 147.3, 135.1, 129.6, 120.3, 120.3, 117.0, 116.4, 114.3, 109.9, 108.0, 52.9, 42.9, 40.8, 39.2, 37.6, 28.8, 27.2, 23.1, 22.0; 19F (376 MHz, CDCl3) δ -80.94 (t, J = 9.9 Hz, 3F), -109.86 (t, J = 14.0 Hz, 2F), -121.04 – -120.86 (m, 2F), -126.04 (dt, J = 13.9, 13.5, 4.9 Hz, 2F). IR (Neat Film, NaCl): 2971, 2877, 1759, 1720, 1649, 1623, 1553, 1482, 1427, 1353, 1240, 1200, 1145, 1107, 1032, 1011, 985, 944, 922 cm-1. HRMS (FAB+) m/z calc’d for C25H28F9O6S [M+H]+: 627.1457, found 627.2216. O OPiv (R)-2-Isopropyl-5-(1-methyl-3-oxocyclohexyl)phenyl pivalate (210). A 25 mL Schlenk flask was charged with a stir bar, nonaflate 209 (62.1 mg, 0.110 mmol, 1 equiv), 10% Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 514 Pd/C (62.1 mg, equal weight to that of the nonaflate), Et3N (38 µL, 0.276 mmol, 2.5 equiv), and MeOH (5 mL). The reaction mixture was degassed then back-filled with H2 gas (1 atm) using Schlenk technique. The flask was sealed and stirred in an oil bath heated to 65 °C for 11 h. The mixture was cooled to ambient temperature, filtered through a silica gel plug (10 g silica gel, eluent: EtOAc) and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (9 g silica gel, eluent: 5% EtOAc/hexanes) to afford pivaloyl 209 as a colorless oil (26.4 mg, 72% yield): [α]25D –41.4° (c 1.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.2, 2.1 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 3.13 (p, J = 6.9 Hz, 1H), 2.84 (d, J = 14.1 Hz, 1H), 2.45 (d, J = 14.2 Hz, 1H), 2.33 (t, J = 6.7 Hz, 2H), 2.19 – 2.12 (m, 1H), 1.99 – 1.84 (m, 2H), 1.84 – 1.70 (m, 1H), 1.41 (s, 9H), 1.32 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 211.4, 177.2, 148.6, 146.5, 138.0, 126.5, 123.3, 119.5, 53.2, 42.6, 40.9, 39.3, 37.9, 29.3, 27.4, 27.1, 23.0, 22.9, 22.2; IR (Neat Film, NaCl): 2963, 2872, 1750, 1714, 1619, 1504, 1462, 1410, 1365, 1276, 1229, 1160, 1120, 1055, 1030, 932, 904 cm-1; HRMS (MultiMode ESI/APCI+) m/z calc’d for C21H34NO3 [M+NH4]+: 348.2533, found 348.2518. O OMe (R)-3-(4-Isopropyl-3-methoxyphenyl)-3-methylcyclohexane-1-one (169f). A 25 mL round bottom flask was charged with a stir bar, flame-dried under vacuum, back-filled with argon, and charged with THF (2 mL). The solution was cooled to 0 °C in an Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 515 ice/water bath and ethanethiol (57 µL, 0.787 mmol, 10 equiv) was added via syringe. nBuLi (2.5 M solution in hexanes, 322 µL, 0.802 mmol, 10.2 equiv) was added dropwise, and a white precipitate was observed at the completion of the addition. The solution was allowed to stir at 0 °C for 1 h. A flame-dried 15 mL conical flask was charged with pivaloyl 210 (26.0 mg, 0.079 mmol, 1 equiv) and DMF (1 mL). The ketone solution was transferred via cannula to the cooled, freshly-prepared solution of LiSEt dropwise over 5 min. The ice/water bath was removed and the reaction was stirred in an oil bath heated to 45 °C for 6 h, at which time the starting material was consumed as determined by TLC analysis (30% EtOAc/hexanes, p-anisaldehyde stain). Me2SO4 (112 µL, 1.185 mmol, 15 equiv) was added to the reaction mixture and stirred at 45 °C for an additional 15 min, at which time the reaction was complete as determined by TLC analysis (30% EtOAc/hexanes, p-anisaldehyde stain). The reaction was quenched with NH4OH (aq, 5 mL) and stirred at 45 °C for another 15 min then diluted with H2O (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried with MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography (9 g silica gel, eluent: 2.5% EtOAc/hexanes) to afford key intermediate 169f as a colorless oil (17.0 mg, 83 % yield): [α]25D –60.4° (c 1.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H) 3.82 (s, 3H), 3.26 (p, J = 6.9 Hz, 1H), 2.87 (d, J = 14.2 Hz, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.31 (t, J = 6.8 Hz, 2H), 2.20 – 2.14 (m, 1H), 1.93 – 1.82 (m, 2H), 1.72 – 1.62 (m, 1H), 1.33 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 211.8, 156.8, 146.1, 134.9, 126.1, 117.8, 108.3, 55.5, 53.4, 43.0, 41.0, 38.3, 30.1, 26.6, 22.8, 22.2; IR (Neat Film, NaCl): 2958, 2869, 1713, 1611, 1573, 1504, 1462, 1409, 1350, 1305, 1254, 1240, 1164, Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 516 1092, 1038, 920 cm-1; HRMS (FAB+) m/z calc’d for C17H24O2 [M]+: 260.1776, found 260.1782. A8.7.2.6 Determination of Enantiomeric Excess Please note racemic products were synthesized using racemic i-Pr-PyOx. Table A8.6 Determination of enantiomeric excess Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak AD-H 5% IPA in hexanes isocratic, 1.0 mL/min 6.454 6.227 94 HPLC Chiralpak IC 20% IPA in hexanes isocratic, 1.0 mL/min 5.795 6.232 >99 SFC Chiralpak AS-H 3% IPA in hexanes isocratic, 2.5 mL/min 5.393 6.285 >99 HPLC Chiralpak IC 20% IPA in hexanes isocratic, 1.0 mL/min 6.130 7.008 92 O OPiv O 1 OPiv O OPiv 2 Br OPiv O OPiv 3 Cl OPiv O OPiv 4 I OPiv 517 Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H A8.7.2.7 Hammett Plot Data4a,b Table A8.7 Data for Hammett analysis of enantioselectivity for select boronic acids phenylboronic acid p-Et p-Me p-H p-F p-Cl p-Ac p-CF3 p-Br p-iPr A8.8 (1) σp 2 ee3 er log10(er) -0.15 -0.17 0 0.06 0.23 0.50 0.54 0.23 -0.15 85 87 92 92 95 96 96 12 14 24 24 39 49 49 1.1 1.2 1.4 1.4 1.6 1.7 1.7 REFERENCES AND NOTES (a) Majetich, G.; Shimkus, J. 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Chem. Soc. 2006, 128, 5628–5629; (c) Shintani, R.; Hayashi, T. Org. Lett. 2011, 13, 350–352. (13) A paper describing the use of Rh·OlefOX (olefin-oxazoline) complex provided a single example of a phenylboronic acid addition to 3-methylcyclohexen-2-one (e.g., 167 + 174 à 175). However, ketone 175 was isolated in only 36% yield and 85% ee, see: Hahn, B. T.; Tewes, F.; Fröhlich, R.; Glorius, F. Angew Chem. Int. Ed. 2010, 49, 1143–1146. (14) For review articles, see: (a) Gutnov, A. Eur. J. Org. Chem. 2008, 4547–4554; (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M. Synthesis 2007, 1279–1300. (15) Lin, S.; Lu, X. Org. Lett. 2010, 12, 2536–2539. (16) (a) Gottumukkala, A. L.; Matcha, K.; Lutz, M.; de Vries, J. G.; Minnaard, A. J. Chem.–Eur. J. 2012, 18, 6907–6914; (b) Buter, J.; Moezelaar, R.; Minnaard, A. J. Org. Biomol. Chem. 2014, 12, 5883–5890. (17) Kadam, A. A.; Ellern, A.; Stanley, L. M. Org. Lett. 2017, 15, 4062–4065. (18) (a) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651–9653; (b) Lin, S.; Lu, X. Tetrahedron Lett. 2006, 47, 7167–7170. (19) Brunner, H.; Obermann, U. Chem. Ber. 1989, 122, 499–507. (20) (a) Shimizu, H.; Holder, J. C.; Stoltz, B. M. Beilstein J. Org. Chem. 2013, 9, 1637– 1642; (b) Holder, J. C.; Shockley, S. E.; Wiesenfeldt, M. P.; Shimizu, H.; Stoltz, B. M. Org. Synth. 2015, 92, 247–266. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 523 (21) Guillaneux, D.; Zheo, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430–9439. (22) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130–2138. (23) All calculations were performed with Gaussian 03. Frisch, M. J.; et al. Gaussian 03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004. (24) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116–2119. (25) Our initial hypothesis concerning the reaction mechanism was well informed by the seminal work of Miyaura, see: Nishitaka, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004, 23, 4317–4324. (26) Boeser, C. L.; Holder, J. C.; Taylor, B. L. H.; Houk, K. N.; Stoltz, B. M.; Zare, R. N. Chem. Sci. 2015, 6, 1917–1922. (27) (a) Chen, J.; Chen, J.; Lang, F.; Zhang, X.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. J. Am. Chem. Soc. 2010, 132, 4552–4553; (b) Han, F.; Chen, G.; Zhang, X.; Liao, J. Eur. J. Org. Chem. 2011, 2928–2931; (c) Korenaga, T.; Hayashi, K.; Akaki, Y.; Maenishi, R.; Sakai, T. Org. Lett. 2011, 13, 2022–2025. (28) For a recent example, see: He, Q.; So, C. M.; Bian, Z.; Hayashi, T.; Wang, J. Chem. Asian J. 2015 10, 540–543. (29) (a) Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Org. Lett. 2005, 7, 5317– 5319; (b) Zhang, X.; Chen, J.; Han, F.; Cun, L. Liao, J. Eur. J. Org. Chem. 2011, 1443–1446. Appendix 8 – A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 524 (30) For an isolated example of a palladium-catalyzed non-enantioselective conjugate addition to a chromone, see: Huang, S.-H.; Wu, T.-M.; Tsai, F.-Y. Appl. Organomet. Chem. 2010, 24, 619–624. (31) Reetz, M. T.; Westermann, J.; Steinbach, R. J. Chem. Soc. Chem. Commun. 1981, 237–239. (32) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195. Red crosses in Figure A8.7 are interpolated from the linear least square regression using the known Hammett values (σp) for para-Br and para-iPr. (33) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390–391. (34) Sun, J.; Perfetti, M. T.; Santos, W. L. J. Org. Chem. 2011, 76, 3571–3575. (35) Johnston, M. D.; Shapiro, B. L.; Shapiro, M. J.; Proulx, T. W.; Godwin, A. D.; Pearce, H. L. J. Am. Chem. Soc. 1975, 97, 542–554. 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Appendix 9 – Spectra Relevant to Appendix 8 525 APPENDIX 9 Spectra Relevant to Appendix 8: A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H 10 9 8 6 5 ppm 4 3 Figure A9.1 1H NMR (500 MHz, CDCl3) of compound 169b 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 526 Appendix 9 – Spectra Relevant Appendix 8 527 Figure A9.2 Infrared spectrum (Thin Film, NaCl) of compound 169b 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.3 13C NMR (125 MHz, CDCl3) of compound 169b 0 10 9 8 6 5 ppm 4 3 Figure A9.4 1H NMR (500 MHz, CDCl3) of compound 169c 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 528 Appendix 9 – Spectra Relevant Appendix 8 529 Figure A9.5 Infrared spectrum (Thin Film, NaCl) of compound 169c 220 200 180 160 140 120 100 ppm 80 60 40 Figure A9.6 13C NMR (125 MHz, CDCl3) of compound 169c 20 0 10 9 8 6 5 ppm 4 3 Figure A9.7 1H NMR (500 MHz, CDCl3) of compound 169d 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 530 Appendix 9 – Spectra Relevant Appendix 8 531 Figure A9.8 Infrared spectrum (Thin Film, NaCl) of compound 169d 220 200 180 160 140 120 100 ppm 80 60 40 Figure A9.9 13C NMR (125 MHz, CDCl3) of compound 169d 20 0 10 9 8 6 5 ppm 4 3 Figure A9.10 1H NMR (500 MHz, CDCl3) of compound 169e 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 532 Appendix 9 – Spectra Relevant Appendix 8 533 Figure A9.11 Infrared spectrum (Thin Film, NaCl) of compound 169e 220 200 180 160 140 120 100 ppm 80 60 40 Figure A9.12 13C NMR (125 MHz, CDCl3) of compound 169e 20 0 10 9 8 6 5 ppm 4 3 Figure A9.13 1H NMR (500 MHz, CDCl3) of compound 169f 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 534 Appendix 9 – Spectra Relevant Appendix 8 535 Figure A9.14 Infrared spectrum (Thin Film, NaCl) of compound 169f 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.15 13C NMR (125 MHz, CDCl3) of compound 169f 0 10 9 8 6 5 ppm 4 3 Figure A9.16 1H NMR (500 MHz, CDCl3) of compound 197 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 536 Appendix 9 – Spectra Relevant Appendix 8 537 Figure A9.17 Infrared spectrum (Thin Film, NaCl) of compound 197 220 200 180 160 140 120 100 ppm 80 60 40 Figure A9.18 13C NMR (125 MHz, CDCl3) of compound 197 20 0 10 9 8 6 5 ppm 4 3 Figure A9.19 1H NMR (500 MHz, CDCl3) of compound 198 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 538 Appendix 9 – Spectra Relevant Appendix 8 539 Figure A9.20 Infrared spectrum (Thin Film, NaCl) of compound 198 220 200 180 160 140 120 100 ppm 80 60 40 Figure A9.21 13C NMR (125 MHz, CDCl3) of compound 198 20 0 10 9 8 6 5 ppm 4 3 Figure A9.22 1H NMR (500 MHz, CDCl3) of compound 199 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 540 Appendix 9 – Spectra Relevant Appendix 8 541 Figure A9.23 Infrared spectrum (Thin Film, NaCl) of compound 199 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.24 13C NMR (125 MHz, CDCl3) of compound 199 0 13 12 11 10 8 7 ppm 6 5 4 Figure A9.25 1H NMR (500 MHz, CDCl3) of compound 202 9 3 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 542 Appendix 9 – Spectra Relevant Appendix 8 543 Figure A9.26 Infrared spectrum (Thin Film, NaCl) of compound 202 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.27 13C NMR (125 MHz, CDCl3) of compound 202 0 10 9 8 6 5 ppm 4 3 Figure A9.28 1H NMR (500 MHz, CDCl3) of compound 203 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 544 Appendix 9 – Spectra Relevant Appendix 8 545 Figure A9.29 Infrared spectrum (Thin Film, NaCl) of compound 203 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.30 13C NMR (125 MHz, CDCl3) of compound 203 0 10 9 8 6 5 ppm 4 3 Figure A9.31 1H NMR (500 MHz, CDCl3) of compound 205 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 546 Appendix 9 – Spectra Relevant Appendix 8 547 Figure A9.32 Infrared spectrum (Thin Film, NaCl) of compound 205 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.33 13C NMR (125 MHz, CDCl3) of compound 205 0 10 9 8 6 5 ppm 4 3 Figure A9.34 1H NMR (500 MHz, CDCl3) of compound 206 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 548 Appendix 9 – Spectra Relevant Appendix 8 549 Figure A9.35 Infrared spectrum (Thin Film, NaCl) of compound 206 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.36 13C NMR (125 MHz, CDCl3) of compound 206 0 10 9 8 6 5 ppm 4 3 Figure A9.37 1H NMR (500 MHz, CDCl3) of compound 207 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 550 Appendix 9 – Spectra Relevant Appendix 8 551 Figure A9.38 Infrared spectrum (Thin Film, NaCl) of compound 207 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.39 13C NMR (125 MHz, CDCl3) of compound 207 0 10 9 8 6 5 ppm 4 3 Figure A9.40 1H NMR (500 MHz, CDCl3) of compound 208 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 552 Appendix 9 – Spectra Relevant Appendix 8 553 Figure A9.41 Infrared spectrum (Thin Film, NaCl) of compound 208 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.42 13C NMR (125 MHz, CDCl3) of compound 208 0 10 9 8 6 5 ppm 4 3 Figure A9.43 1H NMR (500 MHz, CDCl3) of compound 209 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 554 Appendix 9 – Spectra Relevant Appendix 8 555 Figure A9.44 Infrared spectrum (Thin Film, NaCl) of compound 209 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.45 13C NMR (125 MHz, CDCl3) of compound 209 0 -70 -80 {-80.94,117.01} -100 ppm -110 -120 Figure A9.46 19F vs 13C HSQC NMR (376 MHz, CDCl3) of compound 209 -90 {-109.86,114.29} -130 {-121.04,109.85} 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 9 – Spectra Relevant to Appendix 8 556 f1 (ppm) 10 9 8 6 5 ppm 4 3 Figure A9.47 1H NMR (500 MHz, CDCl3) of compound 210 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 557 Appendix 9 – Spectra Relevant Appendix 8 558 Figure A9.48 Infrared spectrum (Thin Film, NaCl) of compound 210 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.49 13C NMR (125 MHz, CDCl3) of compound 210 0 10 9 8 6 5 ppm 4 3 Figure A9.50 1H NMR (500 MHz, CDCl3) of compound 211 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 559 Appendix 9 – Spectra Relevant Appendix 8 560 Figure A9.51 Infrared spectrum (Thin Film, NaCl) of compound 211 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.52 13C NMR (125 MHz, CDCl3) of compound 211 0 10 9 8 6 5 ppm 4 3 Figure A9.53 1H NMR (500 MHz, CDCl3) of compound 212 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 561 Appendix 9 – Spectra Relevant Appendix 8 562 Figure A9.54 Infrared spectrum (Thin Film, NaCl) of compound 212 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.55 13C NMR (125 MHz, CDCl3) of compound 212 0 10 9 8 6 5 ppm 4 3 Figure A9.56 1H NMR (500 MHz, CDCl3) of compound 213 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 563 Appendix 9 – Spectra Relevant Appendix 8 564 Figure A9.57 Infrared spectrum (Thin Film, NaCl) of compound 213 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.58 13C NMR (125 MHz, CDCl3) of compound 213 0 10 9 8 6 5 ppm 4 3 Figure A9.59 1H NMR (500 MHz, CDCl3) of compound 214 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 565 Appendix 9 – Spectra Relevant Appendix 8 566 Figure A9.60 Infrared spectrum (Thin Film, NaCl) of compound 214 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.61 13C NMR (125 MHz, CDCl3) of compound 214 0 10 9 8 6 5 ppm 4 3 Figure A9.62 1H NMR (500 MHz, CDCl3) of compound 215 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 567 Appendix 9 – Spectra Relevant Appendix 8 568 Figure A9.63 Infrared spectrum (Thin Film, NaCl) of compound 215 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.64 13C NMR (125 MHz, CDCl3) of compound 215 0 10 9 8 6 5 ppm 4 3 Figure A9.65 1H NMR (500 MHz, CDCl3) of compound 216 7 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 569 Appendix 9 – Spectra Relevant Appendix 8 570 Figure A9.66 Infrared spectrum (Thin Film, NaCl) of compound 216 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.67 13C NMR (125 MHz, CDCl3) of compound 216 0 13 12 11 10 8 7 ppm 6 5 4 Figure A9.68 1H NMR (500 MHz, CDCl3) of compound 217 9 3 2 1 0 Appendix 9 – Spectra Relevant Appendix 8 571 Appendix 9 – Spectra Relevant Appendix 8 572 Figure A9.69 Infrared spectrum (Thin Film, NaCl) of compound 217 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.70 13C NMR (125 MHz, CDCl3) of compound 217 0 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 573 APPENDIX 10 X-Ray Crystallography Reports Relevant to Appendix 8: A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 A10.1 574 GENERAL EXPERIMENTAL X-ray crystallographic analysis was obtained from the Caltech X-Ray Crystallography Facility using a Bruker D8 Venture Kappa Duo Photon 100 CMOS diffractometer. A10.1.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF UNDESIRED TRICYCLE 203 Br OMe O HO OMe Undesired tricycle 203 was recrystallized by slow evaporation of CH2Cl2 and hexanes to provide crystals suitable for X-ray analysis. Figure A10.1 X-ray crystal structure of undesired tricycle 203 Table A10.1 Crystal data and structure refinement for undesired tricycle 203 Empirical formula C17 H23 Br O5 Formula weight 387.26 Temperature 100 K Wavelength 0.71073 Å 575 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 Crystal system Monoclinic Space group C121 Unit cell dimensions a = 18.8295(9) Å a= 90°. b = 7.8451(4) Å b= 95.208(2)°. c = 11.4443(5) Å g = 90°. Volume 1683.56(14) Å3 Z 4 Density (calculated) 1.528 Mg/m3 Absorption coefficient 2.464 mm-1 F(000) 800 Crystal size 0.43 x 0.42 x 0.29 mm3 Theta range for data collection 1.787 to 48.826°. Index ranges -39<=h<=39, -16<=k<=16, -22<=l<=24 Reflections collected 78240 Independent reflections 16574 [R(int) = 0.0370] Completeness to theta = 25.000° 99.8 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.5777 and 0.4462 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 16574 / 1 / 299 Goodness-of-fit on F2 0.966 Final R indices [I>2sigma(I)] R1 = 0.0256, wR2 = 0.0521 R indices (all data) R1 = 0.0344, wR2 = 0.0538 Absolute structure parameter 0.0289(17) Extinction coefficient n/a Largest diff. peak and hole 0.653 and -0.707 e.Å-3 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 576 Table A10.2 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 203. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ Br(1) 2611(1) 10106(1) 9689(1) 15(1) O(1) 3623(1) 7401(1) 8867(1) 14(1) O(2) 3898(1) 5319(1) 6487(1) 32(1) O(3) 2081(1) 4751(1) 5906(1) 15(1) O(4) 746(1) 6695(1) 5256(1) 15(1) C(1) 1792(1) 8548(1) 7722(1) 10(1) C(2) 2444(1) 8611(1) 8398(1) 10(1) C(3) 2985(1) 7448(1) 8188(1) 10(1) C(4) 2858(1) 6206(1) 7328(1) 10(1) C(5) 2190(1) 6066(1) 6697(1) 10(1) C(6) 1663(1) 7235(1) 6896(1) 9(1) C(7) 883(1) 7289(1) 6423(1) 11(1) C(8) 433(1) 6312(1) 7261(1) 15(1) C(9) 584(1) 6889(1) 8542(1) 17(1) C(10) 655(1) 8831(1) 8680(1) 17(1) C(11) 1110(1) 9610(1) 7757(1) 12(1) C(12) 734(1) 9187(1) 6539(1) 13(1) C(13) 4140(1) 8608(2) 8543(1) 21(1) C(14) 3440(1) 4958(1) 7122(1) 14(1) C(15) 3422(1) 3280(1) 7728(1) 21(1) C(16) 2247(1) 5220(2) 4744(1) 23(1) C(17) 1200(1) 11532(1) 7918(1) 21(1) O(5) 4353(1) 8297(2) 5398(1) 43(1) _____________________________________________________________________ Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 Table A10.3 Bond lengths [Å] and angles [°] for 203 _____________________________________________________ Br(1)-C(2) 1.8906(8) O(1)-C(3) 1.3713(9) O(1)-C(13) 1.4310(12) O(2)-C(14) 1.2111(12) O(3)-C(5) 1.3751(10) O(3)-C(16) 1.4412(14) O(4)-H(4A) 0.70(4) O(4)-C(7) 1.4158(11) C(1)-C(2) 1.3921(11) C(1)-C(6) 1.4044(11) C(1)-C(11) 1.5333(11) C(2)-C(3) 1.4041(11) C(3)-C(4) 1.3893(12) C(4)-C(5) 1.3969(11) C(4)-C(14) 1.5033(12) C(5)-C(6) 1.3859(11) C(6)-C(7) 1.5183(10) C(7)-C(8) 1.5397(13) C(7)-C(12) 1.5231(12) C(8)-H(8A) 0.98(2) C(8)-H(8B) 0.949(19) C(8)-C(9) 1.5366(14) C(9)-H(9A) 1.035(18) C(9)-H(9B) 1.01(2) C(9)-C(10) 1.5357(16) C(10)-H(10A) 0.98(2) C(10)-H(10B) C(10)-C(11) C(11)-C(12) C(11)-C(17) C(12)-H(12A) C(12)-H(12B) C(13)-H(13A) C(13)-H(13B) C(13)-H(13C) C(14)-C(15) 0.906(18) 1.5458(13) 1.5417(13) 1.5262(13) 0.993(18) 0.961(15) 0.92(2) 0.98(2) 0.932(18) 1.4899(15) 577 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) C(17)-H(17A) C(17)-H(17B) C(17)-H(17C) O(5)-H(5A) O(5)-H(5B) C(3)-O(1)-C(13) C(5)-O(3)-C(16) C(7)-O(4)-H(4A) C(2)-C(1)-C(6) C(2)-C(1)-C(11) C(6)-C(1)-C(11) C(1)-C(2)-Br(1) C(1)-C(2)-C(3) C(3)-C(2)-Br(1) O(1)-C(3)-C(2) O(1)-C(3)-C(4) C(4)-C(3)-C(2) C(3)-C(4)-C(5) C(3)-C(4)-C(14) C(5)-C(4)-C(14) O(3)-C(5)-C(4) O(3)-C(5)-C(6) 0.97(3) 0.95(2) 1.00(2) 1.02(2) 0.97(2) 0.84(3) 0.96(2) 0.93(2) 1.19(2) 0.83(4) 0.93(8) 114.67(7) 112.54(9) 108(4) 119.34(7) 131.62(7) 108.83(6) 122.18(6) 119.90(7) 117.73(6) 122.13(7) 117.87(7) 119.80(7) 120.65(7) 119.20(7) 120.09(7) 118.31(7) 122.49(7) C(6)-C(5)-C(4) C(1)-C(6)-C(7) C(5)-C(6)-C(1) C(5)-C(6)-C(7) O(4)-C(7)-C(6) O(4)-C(7)-C(8) O(4)-C(7)-C(12) C(6)-C(7)-C(8) C(6)-C(7)-C(12) C(12)-C(7)-C(8) 119.20(7) 108.75(7) 120.90(7) 130.12(7) 114.47(7) 111.11(7) 112.59(7) 109.45(7) 100.13(6) 108.47(7) 578 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 C(7)-C(8)-H(8A) C(7)-C(8)-H(8B) H(8A)-C(8)-H(8B) C(9)-C(8)-C(7) C(9)-C(8)-H(8A) C(9)-C(8)-H(8B) C(8)-C(9)-H(9A) C(8)-C(9)-H(9B) H(9A)-C(9)-H(9B) C(10)-C(9)-C(8) C(10)-C(9)-H(9A) C(10)-C(9)-H(9B) C(9)-C(10)-H(10A) C(9)-C(10)-H(10B) C(9)-C(10)-C(11) H(10A)-C(10)-H(10B) C(11)-C(10)-H(10A) C(11)-C(10)-H(10B) C(1)-C(11)-C(10) C(1)-C(11)-C(12) C(12)-C(11)-C(10) C(17)-C(11)-C(1) C(17)-C(11)-C(10) C(17)-C(11)-C(12) C(7)-C(12)-C(11) C(7)-C(12)-H(12A) C(7)-C(12)-H(12B) C(11)-C(12)-H(12A) 110.3(9) 100.8(11) 108.1(15) 112.54(7) 111.3(9) 113.4(11) 112.7(10) 107.0(11) 102.1(15) 113.37(8) 107.8(11) 113.4(12) 108.4(13) 109.6(12) 111.74(8) 108.0(17) 110.9(12) 108.2(12) 108.71(7) 100.11(7) 107.17(7) 117.14(8) 111.74(8) 111.01(8) 102.47(6) 110.7(10) 108.1(9) 111.6(10) C(11)-C(12)-H(12B) H(12A)-C(12)-H(12B) O(1)-C(13)-H(13A) O(1)-C(13)-H(13B) O(1)-C(13)-H(13C) H(13A)-C(13)-H(13B) H(13A)-C(13)-H(13C) H(13B)-C(13)-H(13C) O(2)-C(14)-C(4) O(2)-C(14)-C(15) 112.1(9) 111.5(14) 108.7(14) 112.7(11) 109.0(12) 105.4(18) 106.8(17) 113.8(16) 120.71(9) 122.24(9) 579 580 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 C(15)-C(14)-C(4) 117.05(8) C(14)-C(15)-H(15A) 106.0(16) C(14)-C(15)-H(15B) 108.4(13) C(14)-C(15)-H(15C) 110.2(13) H(15A)-C(15)-H(15B) 102(2) H(15A)-C(15)-H(15C) 120(2) H(15B)-C(15)-H(15C) 109.7(18) O(3)-C(16)-H(16A) 112.2(11) O(3)-C(16)-H(16B) 110.1(12) O(3)-C(16)-H(16C) 102.7(17) H(16A)-C(16)-H(16B) 111.1(18) H(16A)-C(16)-H(16C) 110(2) H(16B)-C(16)-H(16C) 110.8(19) C(11)-C(17)-H(17A) 113.8(12) C(11)-C(17)-H(17B) 105.1(16) C(11)-C(17)-H(17C) 114.3(10) H(17A)-C(17)-H(17B) 103.5(19) H(17A)-C(17)-H(17C) 102.8(16) H(17B)-C(17)-H(17C) 117.1(19) H(5A)-O(5)-H(5B) 108(5) _____________________________________________________________ Table A10.4 Anisotropic displacement parameters (Å2x 103) for 203. The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] _____________________________________________________________________ U11 U22 U33 U23 U13 U12 _____________________________________________________________________ Br(1) O(1) O(2) O(3) O(4) C(1) C(2) C(3) C(4) C(5) 16(1) 9(1) 24(1) 15(1) 12(1) 9(1) 10(1) 8(1) 8(1) 9(1) 16(1) 19(1) 30(1) 14(1) 20(1) 10(1) 11(1) 12(1) 12(1) 11(1) 13(1) 15(1) 44(1) 14(1) 11(1) 10(1) 9(1) 10(1) 12(1) 10(1) -6(1) 2(1) 12(1) -5(1) -3(1) 0(1) -1(1) 1(1) 1(1) -1(1) 0(1) -3(1) 22(1) 1(1) -2(1) 1(1) 1(1) 0(1) 1(1) 1(1) -2(1) -1(1) 12(1) 1(1) 1(1) 1(1) -1(1) 0(1) 1(1) 1(1) 581 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 C(6) 7(1) 12(1) 9(1) 0(1) 0(1) 1(1) C(7) 8(1) 16(1) 10(1) 0(1) 0(1) 1(1) C(8) 10(1) 20(1) 16(1) 2(1) 1(1) -2(1) C(9) 14(1) 25(1) 14(1) 4(1) 3(1) -3(1) C(10) 12(1) 25(1) 14(1) -2(1) 4(1) 2(1) C(11) 10(1) 13(1) 13(1) 0(1) 2(1) 4(1) C(12) 10(1) 16(1) 13(1) 2(1) 0(1) 4(1) C(13) 11(1) 26(1) 26(1) 1(1) -1(1) -6(1) C(14) 10(1) 16(1) 16(1) 0(1) 2(1) 3(1) C(15) 21(1) 15(1) 29(1) 4(1) 4(1) 6(1) C(16) 22(1) 33(1) 15(1) -8(1) 4(1) 1(1) C(17) 22(1) 14(1) 26(1) -3(1) 0(1) 6(1) O(5) 34(1) 31(1) 66(1) 17(1) 12(1) 2(1) _____________________________________________________________________ Table A10.5 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 10 3) for 203 _____________________________________________________________________ x y z U(eq) _____________________________________________________________________ H(4A) 730(20) 5810(50) 5270(40) 110(14) H(8A) 504(8) 5090(30) 7183(13) 18(3) H(8B) -34(10) 6580(30) 6933(16) 24(4) H(9A) 199(10) 6480(30) 9068(15) 23(4) H(9B) 1018(11) 6250(30) 8880(17) 27(5) H(10A) 863(11) 9080(30) 9475(18) 33(5) H(10B) 216(9) 9320(20) 8589(16) 24(4) H(12A) H(12B) H(13A) H(13B) H(13C) H(15A) H(15B) H(15C) H(16A) H(16B) 213(9) 947(8) 4561(12) 4005(10) 4233(10) 3716(14) 2962(11) 3523(11) 2770(12) 1930(11) 9400(20) 9770(20) 8430(30) 9790(30) 8410(20) 2520(40) 2800(30) 3430(30) 5560(30) 6120(30) 6506(16) 5920(13) 9001(19) 8697(17) 7769(16) 7310(20) 7559(18) 8598(19) 4724(17) 4436(18) 21(4) 12(3) 37(5) 34(5) 23(4) 53(7) 34(5) 35(5) 36(6) 31(5) Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 582 H(16C) 2168(13) 4320(30) 4360(20) 43(6) H(17A) 1378(10) 11860(30) 8703(18) 29(5) H(17B) 737(13) 11970(30) 7840(20) 42(6) H(17C) 1619(10) 12150(30) 7333(18) 32(5) H(5A) 4075(17) 7470(50) 5340(30) 76(10) H(5B) 4760(40) 8000(110) 5030(90) 114 _____________________________________________________________________ Table A10.6 Torsion angles [°] for 203 ________________________________________________________________ Br(1)-C(2)-C(3)-O(1) -1.53(11) Br(1)-C(2)-C(3)-C(4) 173.23(6) O(1)-C(3)-C(4)-C(5) 172.81(7) O(1)-C(3)-C(4)-C(14) -4.40(12) O(3)-C(5)-C(6)-C(1) 179.12(8) O(3)-C(5)-C(6)-C(7) 5.42(14) O(4)-C(7)-C(8)-C(9) 178.38(7) O(4)-C(7)-C(12)-C(11) -164.95(7) C(1)-C(2)-C(3)-O(1) -176.65(8) C(1)-C(2)-C(3)-C(4) -1.89(12) C(1)-C(6)-C(7)-O(4) 150.32(7) C(1)-C(6)-C(7)-C(8) -84.20(8) C(1)-C(6)-C(7)-C(12) 29.65(9) C(1)-C(11)-C(12)-C(7) 40.37(8) C(2)-C(1)-C(6)-C(5) -3.86(12) C(2)-C(1)-C(6)-C(7) 171.06(7) C(2)-C(1)-C(11)-C(10) -84.97(11) C(2)-C(1)-C(11)-C(12) C(2)-C(1)-C(11)-C(17) C(2)-C(3)-C(4)-C(5) C(2)-C(3)-C(4)-C(14) C(3)-C(4)-C(5)-O(3) C(3)-C(4)-C(5)-C(6) C(3)-C(4)-C(14)-O(2) C(3)-C(4)-C(14)-C(15) C(4)-C(5)-C(6)-C(1) C(4)-C(5)-C(6)-C(7) 162.89(9) 42.84(14) -2.18(12) -179.38(8) -176.12(8) 3.18(12) -84.34(12) 95.72(11) -0.15(12) -173.85(8) Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 C(5)-C(4)-C(14)-O(2) C(5)-C(4)-C(14)-C(15) C(5)-C(6)-C(7)-O(4) C(5)-C(6)-C(7)-C(8) C(5)-C(6)-C(7)-C(12) C(6)-C(1)-C(2)-Br(1) C(6)-C(1)-C(2)-C(3) C(6)-C(1)-C(11)-C(10) C(6)-C(1)-C(11)-C(12) C(6)-C(1)-C(11)-C(17) C(6)-C(7)-C(8)-C(9) C(6)-C(7)-C(12)-C(11) C(7)-C(8)-C(9)-C(10) C(8)-C(7)-C(12)-C(11) C(8)-C(9)-C(10)-C(11) C(9)-C(10)-C(11)-C(1) C(9)-C(10)-C(11)-C(12) C(9)-C(10)-C(11)-C(17) C(10)-C(11)-C(12)-C(7) C(11)-C(1)-C(2)-Br(1) C(11)-C(1)-C(2)-C(3) C(11)-C(1)-C(6)-C(5) C(11)-C(1)-C(6)-C(7) C(12)-C(7)-C(8)-C(9) C(13)-O(1)-C(3)-C(2) C(13)-O(1)-C(3)-C(4) C(14)-C(4)-C(5)-O(3) C(14)-C(4)-C(5)-C(6) 98.44(12) -81.50(11) -35.38(12) 90.10(11) -156.05(9) -170.04(6) 4.85(12) 89.61(8) -22.54(9) -142.58(9) 50.99(10) -42.94(8) 42.10(11) 71.66(8) -43.70(11) -47.37(10) 60.01(9) -178.18(8) -72.96(8) 4.07(13) 178.96(8) -179.21(8) -4.29(9) -57.35(9) -83.51(11) 101.63(10) 1.06(12) -179.64(8) C(16)-O(3)-C(5)-C(4) -91.05(10) C(16)-O(3)-C(5)-C(6) 89.68(10) C(17)-C(11)-C(12)-C(7) 164.77(8) ________________________________________________________________ 583 Appendix 10 – X-Ray Crystallography Reports Relevant to Appendix 8 584 Table A10.7 Hydrogen bonds for 203 [Å and °] _____________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) _____________________________________________________________________ O(4)-H(4A)...O(5)#1 0.70(4) 2.11(4) 2.7707(15) 158(5) C(12)-H(12A)...O(2)#2 0.993(18) 2.577(18) 3.5655(12) 173.5(14) C(13)-H(13B)...Br(1) 0.98(2) 2.963(19) 3.4746(12) 113.5(13) C(16)-H(16B)...O(4) 0.97(2) 2.54(2) 3.1572(13) 121.7(15) O(5)-H(5A)...O(2) 0.83(4) 2.18(4) 2.8176(15) 133(3) O(5)-H(5B)...O(5)#3 0.93(8) 1.80(7) 2.678(3) 155(8) _____________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1/2,y-1/2,-z+1 #2 x-1/2,y+1/2,z #3 -x+1,y,-z+1 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 585 APPENDIX 11 Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy† A11.1 INTRODUCTION AND BACKGROUND The widespread prevalence of spirocycles in biologically active molecules has inspired the development of many methods for the synthesis1 and, more recently, the enantioselective synthesis 2 of this motif. During the course of our ongoing efforts in natural product synthesis, the preparation of an enantioenriched spirocyclic cyclohexenone derivative bearing both an all-carbon quaternary stereogenic spirocenter as well as a 1,4-dicarbonyl moiety spanning the spirocenter was required. This goal was challenging not only due to the difficulties in constructing 1,4-dicarbonyls,3 but also due to the inherent challenges of enantioselectively synthesizing an all-carbon quaternary stereocenter.4 As the enantioselective synthesis of all-carbon quaternary stereocenters via † This work was performed in collaboration with Dr. J. Caleb Hethcox. Portions of this chapter have been reproduced with permission from Shockley, S. E.;‡ Hethcox, J. C.;‡ Stoltz, B. M. Tetrahedron Lett. 2017, 58, 3341–3343 © 2017 Elsevier Ltd. Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 586 palladium-catalyzed allylic alkylation has been developed extensively by our group,5 we envisioned that rapid entry to the spirocyclic cyclohexenone framework could be achieved if the olefin was disconnected via a ring-closing metathesis reaction (RCM) and the resultant α-quaternary carbonyl derivative could be synthesized asymmetrically via our allylic alkylation methodology (Figure A11.1a). In addition to the application to our own synthetic endeavor, we imagined that this strategy would be amenable to the synthesis of a wide array of all-carbon quaternary spirocyclic compounds, such as acorenone, laurencenone B, and α-chamigrene (Figure A11.1b). 6 However, this plan hinged on the challenging use of bromomethyl vinyl ketone as an alkylating reagent. Nucleophilic addition to bromomethyl vinyl ketone can be problematic due to the three electrophilic positions on the molecule, which include positions for Michael addition, 1,2-addition, and SN2 displacement (Figure A11.1c, left). As a solution to this issue, Funk has developed the use of 6-(bromomethyl)-4H-1,3-dioxin as a bromomethyl vinyl ketone surrogate (Figure A11.1c, left). 7 Following alkylation, the dioxin functionality of this reagent can be unmasked under thermal conditions to release formaldehyde and reveal the latent enone. Therefore, we envisioned that we could obviate the challenges of using bromomethyl vinyl ketone by utilizing Funk’s dioxin reagent in our planned strategy (Figure A11.1c, right). However, the use of a substrate bearing such a bulky substituent with Lewis basic oxygens had not yet been explored in our palladium-catalyzed allylic alkylation chemistry. 587 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy Figure A11.1. Strategy and inspiration for the catalytic enantioselective synthesis of all-carbon quaternary spirocycles a) Planned strategy for spirocycle synthesis O O DCAA RCM X X O O O O O X O alkylation O X O O + Br O b) Select spirocyclic natural products Cl O O acorenone laurencenone B α-chamigrene c) Bromomethyl vinyl ketone surrogate δ+ O δ+ O O X O O O DCAA; Δ X O O Br δ+ A11.2 O δ+ Br O REACTION DEVELOPMENT We fortuitously discovered that the standard conditions developed by our group for palladium-catalyzed allylic alkylation reactions were adaptable to this new substrate class (Table A11.1). The use of a catalyst prepared from Pd2(pmdba)3 and (S)-(CF3)3-tBu-PHOX (L15) provided access to a variety of dioxin-substituted allylic alkylation products in consistently high yields and enantioselectivities. Cyclohexanone 219a was obtained in 91% yield and 83% ee. Moreover, tetralone 219b was afforded in similarly 588 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy high yield and selectivity, and we were pleased to find that lactam 219c could be accessed in an excellent 95% yield and 99% ee. Based on these results in combination with the previously established trends in our palladium-catalyzed allylic alkylation methodology,5 we infer that the masked methyl vinyl ketone substituent should be broadly applicable to all of the ring systems tolerated in this chemistry. Table A11.1 Enantioselective palladium-catalyzed allylic alkylations with substrates bearing a masked methyl vinyl ketonea CF 3 O O N (4-CF3-C6H 4)2P O O t-Bu X O O 218a–c O L15 (12.5 mol %) Pd 2(pmdba)3 (5 mol %) X O solvent (0.1 M), 18 h 219a–c O O O O BzN O O O O O O 219a b 219b b 219c c 91% yield 82% ee 95% yield 99% ee 91% yield d 83% ee e [a] Reactions performed on 0.2 mmol scale. [b] Performed using THF at 23 °C. [c] Performed using toluene at 40 °C. [d] Isolated yield. [e] Determined by chiral HPLC or SFC. With the feasibility of utilizing substrates bearing a masked methyl vinyl ketone functionality in our allylic alkylation chemistry established, we moved to demonstrate the ease with which this strategy can provide access to the desired spirocyclic compounds. Though the masked methyl vinyl ketone synthon has been shown to provide access to bridged and fused bicyclic systems,7 to the best of our knowledge, the utility of this reagent for the synthesis of spirocycles has yet to be demonstrated. We were pleased to 589 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy find that the planned thermal unmasking/RCM sequence proceeded smoothly in a single reaction vessel (Table A11.2). In this procedure, dioxin 219 is unmasked via heating in toluene at 180 °C for one hour, whereupon the reaction is cooled to 60 °C and a solution of Hoveyda-Grubbs second-generation catalyst is introduced to complete the annulation. Using this newly developed protocol, spirocyclic cyclohexenones 220a, 220b, and 220c were obtained in good to excellent yields, thus demonstrating the viability of this strategy for the synthesis of enantioenriched spirocycles. Table A11.2 One-pot synthesis of spirocyclic compoundsa O O X i. toluene, 180 °C, 1 h X O ii. HG-II, 60 °C, 18 h O 219a–c 220a–c O O O O 220a 93% yield b O O BzN O 220b 220c 77% yield 53% yield [a] Reactions performed on 0.1 mmol scale. [b] Isolated yield. A11.3 CONCLUSIONS In summary, we have demonstrated that substrates bearing a bulky, highly oxygenated methyl vinyl ketone surrogate can be utilized in an enantioselective palladium-catalyzed allylic alkylation reaction. The resulting allylic alkylation products are obtained in high yields and selectivities with neither the increased sterics nor the added Lewis basic oxygen atoms adversely affecting reactivity. Furthermore, we 590 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy developed a one-pot unmasking/RCM procedure showcasing that these allylic alkylation products can be easily advanced to enantioenriched spirocycles bearing both an allcarbon quaternary stereogenic spirocenter as well as a 1,4-dicarbonyl functionality spanning the spirocenter. This simple two-step strategy is amenable to the synthesis of a range of enantioenriched spirocyclic natural products. A11.4 EXPERIMENTAL SECTION A11.4.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Commercially obtained reagents were used as received. Chemicals were purchased from Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Sigma Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4, or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak IC column (4.6 mm x 25 cm) or Chiralpak AD-H column (4.6 mm x 25 cm), both obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Analytical SFC was performed with a Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 591 Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak OJ-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. 1H NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of benzene (δ 7.36 ppm), water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESIAPCI+). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell, and are reported as: [α]DT (concentration in g/100 mL, solvent). Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy A11.4.1.1 592 Preparation of Known Compounds Previously reported methods were used to prepare ligand (S)-L15 8 and 6(bromomethyl)-4H-1,3-dioxin7. A11.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA A11.4.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Allylic Alkylation Substrates O O O O O Allyl 1-((4H-1,3-dioxin-6-yl)methyl)-2-oxocyclohexane-1-carboxylate (218a). Allyl 2oxocyclohexane-1-carboxylate9 (0.20 g, 1.1 mmol, 1 equiv), K2CO3 (0.76 g, 5.5 mmol, 5 equiv), and 6-(bromomethyl)-4H-1,3-dioxin7 (0.30 g, 1.7 mmol, 1.5 equiv) were dissolved in acetone (5 mL). The resulting reaction mixture was heated under reflux for 18 h, whereupon the reaction was cooled to ambient temperature, filtered through celite with acetone (10 mL), and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (15% EtOAc/hexanes) to give ester 218a as a colorless oil (0.26 g, 84% yield): 1H NMR (400 MHz, CDCl3) δ 5.83 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.31 – 5.12 (m, 2H), 4.89 – 4.80 (m, 2H), 4.66 (t, J = 2.6 Hz, 1H), 4.57 – 4.48 (m, 2H), 4.14 – 4.09 (m, 2H), 2.76 (dt, J = 15.0, 1.6 Hz, 1H), 2.56 (dt, J = 13.9, 3.2 Hz, 1H), 2.43 – 2.25 (m, 2H), 2.24 – 2.16 (m, 1H), 2.01 – 1.89 (m, 1H), 1.82 – 1.63 (m, 2H), 1.56 (dddd, J = 17.0, 12.4, 8.4, 4.4 Hz, 1H), 1.36 (ddd, J = 13.9, 12.2, 4.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 206.4, 170.4, 150.3, 131.6, 118.8, 100.8, 90.3, 65.9, 63.7, 59.8, 40.9, 38.8, 35.7, 27.5, 22.3; IR (Neat Film, NaCl) 3083, 2944, 2867, Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 593 2796, 1715, 1682. 1648, 1451, 1372, 1314, 1175, 1092, 990, 927, 847, 761 cm-1; HRMS (FAB+) m/z calc’d for C15H19O5 [M+H]–H2: 279.1232, found 279.1224. O O O O O Allyl 2-((4H-1,3-dioxin-6-yl)methyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2- carboxylate (218b). Allyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate9 (0.60 g, 2.8 mmol, 1 equiv), Cs2CO3 (1.6 g, 5.0 mmol, 1.8 equiv), and 6-(bromomethyl)-4H-1,3dioxin7 (0.55 g, 3.1 mmol, 1.1 equiv) were dissolved in DMF (19 mL). The resulting reaction mixture was heated to 70 °C for 18 h, whereupon the reaction was cooled to ambient temperature, poured into H2O (40 mL), and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give ester 218b as a pale yellow oil (0.65 g, 71% yield): 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 7.9, 1.4 Hz, 1H), 7.47 (td, J = 7.5, 1.5 Hz, 1H), 7.34 – 7.27 (m, 1H), 7.21 (dd, J = 7.6, 1.2 Hz, 1H), 5.80 (ddt, J = 17.2, 10.5, 5.5 Hz, 1H), 5.27 – 5.06 (m, 2H), 4.93 (s, 2H), 4.83 (t, J = 2.6 Hz, 1H), 4.56 (dq, J = 5.6, 1.6 Hz, 2H), 4.20 (dt, J = 2.6, 1.3 Hz, 2H), 3.22 – 3.07 (m, 1H), 3.01 – 2.73 (m, 3H), 2.64 (dt, J = 13.9, 4.6 Hz, 1H), 2.23 – 2.11 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 194.2, 170.8, 150.5, 143.3, 133.6, 132.0, 131.6, 128.9, 128.3, 126.8, 118.3, 101.4, 90.5, 66.0, 64.0, 56.8, 38.4, 30.5, 26.1; IR (Neat Film, NaCl) 2929, 2852, Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 594 1730, 1688, 1600, 1453, 1371, 1313, 1294, 1232, 1172, 1093, 987, 950, 846, 744 cm-1; HRMS (FAB+) m/z calc’d for C19H19O5 [M+H]–H2: 327.1232, found 3267.1223. O O BzN O O O Allyl 3-((4H-1,3-dioxin-6-yl)methyl)-1-benzoyl-2-oxopiperidine-3-carboxylate (218c). Allyl 1-benzoyl-2-oxopiperidine-3-carboxylate5e (0.20 g, 0.70 mmol, 1 equiv), Cs2CO3 (0.41 g, 1.3 mmol, 1.8 equiv), and 6-(bromomethyl)-4H-1,3-dioxin7 (0.14 g, 0.77 mmol, 1.1 equiv) were dissolved in DMF (5 mL). The resulting reaction mixture was heated to 70 °C for 18 h, whereupon the reaction was cooled to ambient temperature, poured into H2O (40 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (25% EtOAc/hexanes) to give ester 218c as a pale yellow oil (0.13 g, 49% yield): 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.66 (m, 2H), 7.53 – 7.42 (m, 1H), 7.42 – 7.33 (m, 2H), 5.99 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.49 – 5.28 (m, 2H), 5.05 – 4.93 (m, 2H), 4.78 (dt, J = 3.0, 1.5 Hz, 1H), 4.72 (ddt, J = 6.0, 1.7, 0.8 Hz, 2H), 4.20 (dq, J = 2.7, 1.2 Hz, 2H), 3.94 – 3.66 (m, 2H), 2.98 – 2.87 (m, 1H), 2.74 – 2.62 (m, 1H), 2.50 – 2.33 (m, 1H), 2.14 – 1.92 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 175.1, 171.4, 171.3, 150.0, 135.9, 131.9, 131.5, 128.3, 128.1, 119.8, 101.7, 90.7, 66.9, 64.0, 55.3, 46.5, 39.3, 30.3, 20.6; IR (Neat Film, NaCl) 2934, 2856, 1732, 1678, 1448, 1371, 1272, 1231, Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 595 1170, 1145, 1090, 985, 939, 845, 721, 694, 647 cm-1; HRMS (FAB+) m/z calc’d for C21H24O6N [M+H]+: 386.1604, found 386.1619. A11.4.2.2 General Procedure for the Asymmetric Palladium-Catalyzed Allylic Alkylation O O O (S)-2-((4H-1,3-Dioxin-6-yl)methyl)-2-allylcyclohexan-1-one (219a). In a nitrogen-filled glove box, to a 1 dram vial equipped with a stir bar was added Pd2(pmdba)3 (11 mg, 0.01 mmol, 5 mol %), ligand (S)-L1 (13 mg, 0.025 mmol, 12.5 mol %), and THF (2 mL). The resulting mixture was stirred at 25 °C for 30 min, whereupon substrate 218a (56 mg, 0.20 mmol, 1 equiv) was added. The vial was sealed, removed from the glove box, and stirred at 25 °C. After 18 h, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparatory TLC (10% EtOAc/hexanes) to give allyl 219a as a colorless oil (43 mg, 91% yield): 83% ee; [α]D25 –13.1 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.66 (ddt, J = 16.5, 10.6, 7.3 Hz, 1H), 5.09 – 4.99 (m, 2H), 4.95 (d, J = 5.4 Hz, 1H), 4.88 (d, J = 5.4 Hz, 1H), 4.68 (t, J = 2.6 Hz, 1H), 4.26 – 4.11 (m, 2H), 2.58 – 2.45 (m, 2H), 2.39 – 2.28 (m, 3H), 2.18 (d, J = 14.5 Hz, 1H), 1.84 (tdd, J = 6.7, 3.4, 1.6 Hz, 1H), 1.79 – 1.69 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 213.9, 151.5, 134.0, 118.4, 100.7, 90.4, 63.9, 51.0, 39.5, 39.4, 39.0, 36.8, 27.3, 21.0; IR (Neat Film, NaCl) 3391, 3074, 2924, 2854, 2795, 1705, 1681, 1638, 1445, 1372, 1311, 1196, 1172, 1124, 1093, 1021, 990, 911, 847, 755, 640 cm-1; HRMS (FAB+) m/z calc’d for C14H19O3 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 596 [M+H]–H2: 235.1334, found 235.1341; HPLC conditions: 3% IPA, 1.0 mL/min, Chiralpak AD–H column, λ = 210 nm, tR (min): major = 7.066, minor = 7.722. A11.4.2.3 Spectroscopic Data for the Asymmetric Palladium-Catalyzed Allylic Alkylation Products Please note that the absolute configurations of 219a–c were determined by analogy.5e,g For respective HPLC conditions, please refer to Table A11.3. O O O (S)-2-((4H-1,3-Dioxin-6-yl)methyl)-2-allyl-3,4-dihydronaphthalen-1(2H)-one (219b). Product 219b was prepared according to the general procedure to give a colorless oil (52 mg, 91% yield): 82% ee; [α]D25 +0.254 (c 2.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 7.8, 1.4 Hz, 1H), 7.47 (td, J = 7.5, 1.5 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.27 – 7.19 (m, 1H), 5.79 (dddd, J = 17.0, 10.3, 7.8, 7.0 Hz, 1H), 5.17 – 5.00 (m, 2H), 5.00 – 4.88 (m, 2H), 4.74 (t, J = 2.6 Hz, 1H), 4.21 (dt, J = 2.5, 1.2 Hz, 2H), 3.02 (dd, J = 7.2, 5.5 Hz, 2H), 2.69 (dq, J = 14.3, 1.3 Hz, 1H), 2.55 (ddt, J = 14.1, 7.0, 1.3 Hz, 1H), 2.34 – 2.27 (m, 1H), 2.27 – 2.21 (m, 1H), 2.11 (ddt, J = 6.0, 4.8, 3.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 200.5, 151.5, 143.2, 133.9, 133.2, 132.0, 128.8, 128.2, 126.7, 118.7, 100.8, 90.4, 64.0, 47.8, 39.6, 38.8, 30.4, 25.3; IR (Neat Film, NaCl) 3072, 3004, 2929, 2859, 2794, 1677, 1600, 1454, 1432, 1371, 1289, 1225, 1193, 1172, 1093, 1023, 989, 918, 847, 742 cm-1; HRMS (FAB+) m/z calc’d for C18H19O3 [M+H]–H2: 283.1334, found Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 597 283.1338; HPLC conditions: 4% IPA, 1.0 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 29.702, minor = 23.387. O BzN O O (S)-3-((4H-1,3-Dioxin-6-yl)methyl)-3-allyl-1-benzoylpiperidin-2-one (219c). Product 219c was prepared according to the general procedure (toluene used in place of THF, reaction mixture heated to 40 °C) to give a pale yellow oil (66 mg, 95% yield): 99% ee; [α]D25 +11.4 (c 3.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.31 (m, 5H), 5.76 (dddd, J = 17.1, 10.3, 7.7, 6.9 Hz, 1H), 5.21 – 5.09 (m, 2H), 5.06 – 4.98 (m, 2H), 4.74 (td, J = 2.7, 0.8 Hz, 1H), 4.23 (ddd, J = 2.6, 1.7, 0.8 Hz, 2H), 3.91 – 3.67 (m, 2H), 2.76 (dtd, J = 14.3, 1.7, 0.9 Hz, 1H), 2.59 (ddt, J = 13.8, 6.9, 1.3 Hz, 1H), 2.31 (ddt, J = 13.8, 7.7, 1.1 Hz, 1H), 2.15 – 2.09 (m, 1H), 2.04 – 1.95 (m, 3H), 1.93 – 1.83 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 177.1, 175.6, 151.2, 136.7, 133.3, 131.5, 128.2, 127.8, 119.6, 101.2, 90.6, 64.1, 47.0 (2C), 43.5, 41.7, 30.0, 20.0; IR (Neat Film, NaCl) 3346, 3072, 2945, 2868, 2795, 1678, 1600, 1477, 1449, 1386, 1372, 1286, 1150, 1172, 1092, 1023, 990, 919, 846, 792, 725, 696 cm-1; HRMS (FAB+) m/z calc’d for C20H24NO4 [M+H]+: 342.1705, found 342.1714; SFC conditions: 5% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 210 nm, tR (min): major = 11.165, minor = 10.427. Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy A11.4.2.4 598 General Procedure for Spirocyclic Formation O O (S)-Spiro[5.5]undec-9-ene-1,8-dione (220a). To a sealed Biotage microwave vial, allyl 219a (24 mg, 0.10 mmol, 1 equiv) and toluene (0.7 mL) were added. The reaction mixture was heated to 180 °C for 1 h, whereupon the reaction was cooled to 60 °C and a solution of Hoveyda-Grubbs 2nd generation catalyst (6.3 mg, 0.010 mmol, 0.10 equiv) in toluene (0.3 mL) was added. The reaction mixture was then stirred an additional 18 h at 60 °C, cooled to ambient temperature, and directly purified by preparatory TLC (15% EtOAc/hexanes) to give spirocycle 220a as a colorless oil (17 mg, 93% yield): [α]D25 –1.4 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.81 (dt, J = 10.1, 4.1 Hz, 1H), 5.99 (dt, J = 10.0, 2.1 Hz, 1H), 2.84 (ddt, J = 18.8, 4.4, 1.4 Hz, 1H), 2.80 – 2.71 (m, 1H), 2.47 – 2.32 (m, 4H), 1.95 – 1.73 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 212.3, 197.4, 146.0, 129.5, 51.5, 45.7, 38.2, 38.1, 33.7, 27.7, 20.8; IR (Neat Film, NaCl) 3037, 2936, 2865, 1705, 1678, 1446, 1424, 1387, 1252, 1135, 736 cm-1; HRMS (FAB+) m/z calc’d for C11H15O2 [M+H]+: 179.1072, found 179.1078. A11.4.2.5 Spectroscopic Data for Spirocyclic Compounds O O (S)-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalen]-3-ene-1',5-dione (220b). Product 220b was prepared according to the general procedure to give a colorless oil (18 mg, 77% yield) after preparatory TLC (15% EtOAc/hexanes): [α]D25 –1.5 (c 1.2, CHCl3); Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 1 599 H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 7.8, 1.4 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.40 – 7.30 (m, 1H), 7.26 – 7.20 (m, 1H), 6.91 – 6.77 (m, 1H), 6.10 (dt, J = 10.3, 2.1 Hz, 1H), 3.09 – 2.89 (m, 3H), 2.82 (d, J = 16.2 Hz, 1H), 2.50 – 2.38 (m, 2H), 2.27 – 2.02 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 199.2, 197.4, 145.6, 142.7, 133.9, 130.8, 129.5, 128.9, 128.5, 127.2, 47.7, 44.6, 32.5, 32.3, 25.0; IR (Neat Film, NaCl) 3034, 2926, 2858, 1683, 1601, 1455, 1388, 1250, 1224, 1157, 946, 750 cm-1; HRMS (FAB+) m/z calc’d for C15H15O2 [M+H]+: 227.1072, found 227.1074. O BzN O (S)-2-benzoyl-2-azaspiro[5.5]undec-9-ene-1,8-dione (220c). Product 220c was prepared according to the general procedure to give a colorless oil (15 mg, 53% yield) after preparatory TLC (40% EtOAc/hexanes): [α]D25 +29.7 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.32 (m, 5H), 6.87 (ddd, J = 10.2, 5.0, 3.3 Hz, 1H), 6.06 (dt, J = 10.1, 2.1 Hz, 1H), 3.91 – 3.74 (m, 2H), 3.09 (dt, J = 18.9, 3.0 Hz, 1H), 2.96 (d, J = 16.1 Hz, 1H), 2.59 (dd, J = 16.2, 1.3 Hz, 1H), 2.49 (ddt, J = 18.9, 5.0, 1.6 Hz, 1H), 2.09 – 1.95 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 196.4, 177.0, 175.1, 145.8, 135.8, 131.9, 129.2, 128.5, 127.6, 47.1, 47.0, 46.4, 34.8, 32.5, 19.3; IR (Neat Film, NaCl) 2949, 1679, 1449, 1388, 1281, 1151, 919, 729, 694, 665 cm-1; HRMS (FAB+) m/z calc’d for C17H18O3N [M+H]+: 284.1287, found 284.1277. 600 Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy A11.4.2.6 Determination of Enantiomeric Excess Please note racemic products were synthesized using Pd(PPh3)4 in place of Pd2(pmdba)3 and (S)-L15. Table A11.3 Determination of enantiomeric excess Entry Product Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak AD-H 3% IPA isocratic, 1 mL/min 7.066 7.722 83 HPLC Chiralpak IC 4% IPA isocratic, 1 mL/min 29.702 23.387 82 SFC Chiralpak OJ-H 5% IPA isocratic, 2.5 mL/min 11.165 10.427 99 O 1 O O O 2 O O O BzN 3 O O A11.5 (1) REFERENCES AND NOTES For reviews on the synthesis of spirocycles, see: (a) Krapcho A. P. Synthesis 1974, 383–419; (b) Sannigrahi, M. Tetrahedron 1999, 55, 9007–9071; (c) Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K.; Tetrahedron 2006, 62, 779– Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 601 828; (d) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165– 193; (e) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558–2573; (f) D’yakonov, V. A.; Trapeznikova, O. A.; de Meijere, A.; Dzhemilev, U. M. Chem. Rev. 2014, 114, 5775–5814. (2) For reviews on the enantioselective synthesis of spirocycles, see: (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060–1074; (b) Franz, A. K.; Hanhan, N. V.; Ball-Jones, N. R. ACS Catal. 2013, 3, 540–553; (c) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol. Chem. 2012, 10, 5165–5181; (d) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003–3025; (e) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F., III. ACS Catal. 2014, 4, 743–762. (3) (a) Arason, K. M.; Bergmeier, S. C. Org. Prep. Proced. Int. 2002, 34, 337–366; (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546– 11560. (4) For reviews on the synthesis of quaternary stereocenters, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. USA 2004, 101, 5363–5367; (b) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593–4623; (c) Quasdorf. K. W.; Overman, L. E. Nature 2014, 516, 181–191; (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388–401; (e) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001, 40, 4591–4597; (f) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396; (g). Liu, Y.; Han. S.-J.; Liu, W.-B., Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751. (5) (a) Craig, R. A., II.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Org. Lett. 2015, 17, 5160–5163; (b) Numajiri, Y.; Jiménez-Osés, G.; Appendix 11 – Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 602 Wang, B.; Houk, K. N.; Stoltz, B. M. Org. Lett. 2015, 17, 1082–1085; (c) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz. B. M. Angew. Chem. Int. Ed. 2013, 52, 6718–6721; (d) Bennett, N. B.; Duquette, D. C.; Kim, J.; Liu, W.-B.; Marziale, A. N.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2013, 19, 4414–4418; (e) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2012, 4, 130–133; (f) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17, 14199–14223; (g) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045. (6) Smith, L. K.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 9907–9933. (7) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2002, 124, 754–755. (8) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 5550–5554. (9) Mohr, J. T.; Behenna, D. C.; Harned, A. M. Stoltz, B. M. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. Appendix 12 – Spectra Relevant to Appendix 11 603 APPENDIX 12 Spectra Relevant to Appendix 11: Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via an Enantioselective Allylic Alkylation Strategy 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.1 1H NMR (400 MHz, CDCl3) of compound 218a 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 604 Appendix 12 – Spectra Relevant Appendix 11 605 Figure A12.2 Infrared spectrum (Thin Film, NaCl) of compound 218a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.3 13C NMR (101 MHz, CDCl3) of compound 218a 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.4 1H NMR (400 MHz, CDCl3) of compound 218b 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 606 Appendix 12 – Spectra Relevant Appendix 11 607 Figure A12.5 Infrared spectrum (Thin Film, NaCl) of compound 218b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.6 13C NMR (101 MHz, CDCl3) of compound 218b 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.7 1H NMR (400 MHz, CDCl3) of compound 218c 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 608 Appendix 12 – Spectra Relevant Appendix 11 609 Figure A12.8 Infrared spectrum (Thin Film, NaCl) of compound 218c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.9 13C NMR (101 MHz, CDCl3) of compound 218c 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.10 1H NMR (400 MHz, CDCl3) of compound 219a 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 610 Appendix 12 – Spectra Relevant Appendix 11 611 Figure A12.11 Infrared spectrum (Thin Film, NaCl) of compound 219a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.12 13C NMR (101 MHz, CDCl3) of compound 219a 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.13 1H NMR (400 MHz, CDCl3) of compound 219b 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 612 Appendix 12 – Spectra Relevant Appendix 11 613 Figure A12.14 Infrared spectrum (Thin Film, NaCl) of compound 219b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.15 13C NMR (101 MHz, CDCl3) of compound 219b 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.16 1H NMR (400 MHz, CDCl3) of compound 219c 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 614 Appendix 12 – Spectra Relevant Appendix 11 615 Figure A12.17 Infrared spectrum (Thin Film, NaCl) of compound 219c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.18 13C NMR (101 MHz, CDCl3) of compound 219c 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.19 1H NMR (400 MHz, CDCl3) of compound 220a 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 616 Appendix 12 – Spectra Relevant Appendix 11 617 Figure A12.20 Infrared spectrum (Thin Film, NaCl) of compound 220a 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.21 13C NMR (101 MHz, CDCl3) of compound 220a 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.22 1H NMR (400 MHz, CDCl3) of compound 220b 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 618 Appendix 12 – Spectra Relevant Appendix 11 619 Figure A12.23 Infrared spectrum (Thin Film, NaCl) of compound 220b 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.24 13C NMR (101 MHz, CDCl3) of compound 220b 10 0 -10 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 2.5 Figure A12.25 1H NMR (400 MHz, CDCl3) of compound 220c 7.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 12 – Spectra Relevant Appendix 11 620 Appendix 12 – Spectra Relevant Appendix 11 621 Figure A12.26 Infrared spectrum (Thin Film, NaCl) of compound 220c 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 40 30 20 Figure A12.27 13C NMR (101 MHz, CDCl3) of compound 220c 10 0 -10 622 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A APPENDIX 13 Progress Toward the Synthesis of (+)-Isopalhinine A† A13.1 INTRODUCTION AND BACKGROUND The Lycopodium alkaloids are family of complex, polycyclic, bioactive molecules that have been the subject of intense synthetic efforts over the past fifty years.1 In 2013, a novel Lycopodium alkaloid, (+)-isopalhinine A (221, Scheme A13.1), was isolated containing an unprecedented (5/6/6/6/7) pentacyclic scaffold comprised of a densely functionalized isotwistane core containing vicinal all-carbon quaternary stereocenters appended to a 1-azabicyclo[4.3.1]decane moiety. 2 The complex architecture of (+)isopalhinine A (221) has piqued the interest of the synthetic community, however, despite one report toward the isotwistane core,3 the natural product has yet to succumb to total synthesis. Herein, we detail our progress toward (+)-isopalhinine A (221) via a series of evolving strategies unified by the late-stage synthesis of the isotwistane core and the early construction of the functionalized nitrogen-containing heterocycle. † Portions of this work were performed in collaboration with Dr. J. Caleb Hethcox. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.2 623 IRIDIUM-CATALYZED ALLYLIC ALKYLATION ROUTE Our initial retrosynthetic analysis of (+)-isopalhinine A (221) began with disconnection of the caging architecture by C–N bond cleavage of the bridging propyl chain, followed by rupture of the central isotwistane core, which would be formed via an intramolecular Diels–Alder cycloaddition, to provide spirocycle 222 (Scheme A13.1). Spirocycle 222 would in turn be prepared by enolate formation and subsequent hemiaminal formation via the addition of an acyl anion equivalent into spirocyclic lactam 223. Intramolecular aldol condensation and redox manipulation would then lead back to functionalized β-ketolactam 224. Enantioenriched 224 would be generated from βketolactam 225 and allylic electrophile 226, which would require the development of novel stereoselective iridium-catalyzed allylic alkylation technology as both the use of alkyl-substituted allylic electrophile 226 and endocyclic 1,3-dicarbonyl nucleophile 225 in iridium-catalyzed allylic alkylation chemistry is unprecedented in the literature. This synthetic strategy would enable rapid access to (+)-isopalhinine A (221) in as few as fourteen steps from 225 and 226. 624 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.1 Initial retrosynthetic analysis of (+)-isopalhinine A (221) via iridium-catalyzed allylic alkylation of endocyclic 1,3-dicarbonyl nucleophile 225 H O BnO OH N N-alkylation O HO OBn O OH Bn N MOMO O acyl anion addition O NBn [4+2] 221 MOMO MOMO 222 (+)-isopalhinine A 223 O BnO TBSO aldol condensation O NBn TBSO oxidation Ir-catalyzed allylic alkylation NBn O 225 OCO 2Me O OBn 224 226 We began our explorations into this initial synthetic plan with the synthesis of proposed iridium-catalyzed allylic alkylation substrates 225 and 226. The preparation of allylic electrophile 226 proceeded via known allylic alcohol 230, which was synthesized in three steps and 40% overall yield from commercially available 4-pentyn-1-ol (227, Scheme A13.2). 4,5 Subsequent acylation with methyl chloroformate afforded requisite alkyl-substituted allylic electrophile 226 in 89% yield.6 Scheme A13.2 Synthesis of alkyl-substituted electrophile 226 OH n-BuLi (CH2O)n BnBr, TBAI, KH HO BnO THF, 0 °C → 23 °C 227 THF, –78 °C → 23 °C (67% yield) BnO (70% yield) 228 229 O Red-Al Cl BnO OH Et 2O, 0 °C → 23 °C (86% yield) 230 OMe BnO OCO 2Me pyridine, CH2Cl2 0 °C → 23 °C (89% yield) 226 625 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Synthesis of proposed endocyclic 1,3-dicarbonyl nucleophile 225 proved more challenging. While we were able to rapidly access allylated β-ketolactam 233 from Bocβ-alanine (231, Scheme A13.3a),7 we were unable to prepare desired alkyl-substituted nucleophile 225 (Scheme A13.3b). In our attempt to synthesize desired 225 we explored a variety of approaches including C-alkylation and Knoevenagel condensation/reduction sequences of β-ketolactam 232, cyclization of β-ketoester 234, as well as ozonolysis/reduction of allylated β-ketolactam 233, but all routes were met with failure. Scheme A13.3 Efforts to synthesize endocyclic 1,3-dicarbonyl nucleophiles a) Synthesis of allylated nucleophile BocHN O 1. EDC•HCl, CH2Cl2 Meldrum's acid 0 °C → 23 °C O OH 231 O NBoc 2. EtOAc, reflux allyl iodide K 2CO3 DMSO, 23 °C O 232 (95% yield) NBoc O 233 (37% yield) b) Attempts to synthesize requisite nucleophile X O O OTBS BocHN alkylation O OMe cyclization TBSO O NBoc 234 OTBS NBoc O O 232 OTBS Knoevenagel condensation reduction O 225 O ozonolysis reduction NBoc O 233 Unable to synthesize desired alkyl-substituted nucleophile 225, we decided to instead explore the proposed iridium-catalyzed allylic alkylation reaction of alkylsubstituted electrophile 226 with allyl-substituted nucleophile 233, postulating that we could subsequently perform redox manipulations on allylic alkylation product 235 in Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 626 order to intercept our original synthetic plan (Table A13.1). Our prior work on iridiumcatalyzed allylic alkylation reactions with crotyl chloride primed us for the challenges involved in the use of alkyl-substituted electrophiles like 226. 8 Specifically, we anticipated poor regioselectivity in the allylic alkylation reaction as a result of the minimal stabilization of the allyl carbocation afforded by the alkyl substituent of 226, in addition to poor reactivity due to the steric bulk of the alkyl group. Therefore, we hypothesized that we would need to explore novel ligand and additive combinations in the iridium-catalyzed allylic alkylation reaction in order to achieve both a selective and high yielding transformation. We began our studies employing our previously explored conditions for the iridium-catalyzed allylic alkylation of cinnamyl-derived electrophiles. 9 Unsurprisingly, we observed that the reaction proceeded with poor branched selectivity, instead favoring the synthesis of the undesired linear product (Table A13.1, entry 1). Though base additives have been shown to play an important role in the selectivity of iridiumcatalyzed allylic alkylations,8,9,10 an extensive investigation of bases proved unsuccessful in promoting branched selectivity in the reaction (entries 2–5). Turning our attention to the ligand, we found that the use of Alexakis ligand L16, instead of Me-THQphos (L2), in combination with LiBr or DABCO as additives, reversed the regioselectivity of the transformation to favor the synthesis of desired branched product 235 (entries 6 and 9). However, poor conversions (15% combined yield of branched and linear products, entry 9) and our inability to separate the branched and linear isomers by column chromatography led us to terminate our studies on endocyclic 1,3-dicarbonyl 627 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A nucleophiles in order to identify a more suitable nucleophile for the iridium-catalyzed allylic alkylation reaction. Table A13.1 Optimization of the iridium-catalyzed allylic alkylation of endocyclic 1,3-dicarbonyl nucleophile 233a NBoc + OBn [Ir(cod)Cl] 2 (2 mol %) TBD (10 mol %) L (4 mol %) O BnO OCO 2Me O THF (0.1M), 23 °C, 18 h NBoc O 233 O 226 235 Entry L Additive (200 mol %) b:lb O P N O 1 L2 LiBr 30:70 2 L2 LiOtBu 27:73 3 4 5 L2 L2 L2 DABCO DMAP NEt 3 39:61 12:88 28:72 6 L16 LiBr 64:36 7 L16 LiOtBu 34:66 8 L16 Cs2CO 3 27:73 9 10 11 L16 L16 L16 DABCO DMAP 63:37 25:75 29:71 NEt 3 (R,R a )-L2 O P N Ph O Ar Ar = 2-MeO-C6H 4 (R,R,R a )-L16 [a] Reactions performed on 0.2 mmol scale with 2:1 nucleophile/electrophile. [b] Determined by TOF LCMS analysis of the crude reaction mixture. [c] TBD = 1,3,5-triazabicyclo[4.4.0]dec-5-ene. In a revised retrosynthetic analysis of (+)-isopalhinine A (221), we envisioned that we could employ lactone nucleophile 238, in place of β-ketolactam 225, in the proposed iridium-catalyzed allylic alkylation reaction of alkyl-substituted electrophile 226 (Scheme A13.4). Preserving our endgame strategy, allylic alkylation product 237 would then undergo lactamization to intercept key intermediate 236 from our original retrosynthesis (Scheme A13.1). We hypothesized that the similarity between lactone 238 and our group’s previously explored β-ketoester nucleophiles9,11 would allow for a more facile optimization of the iridium-catalyzed allylic alkylation reaction. 628 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.4 Revised retrosynthetic analysis of (+)-isopalhinine A (221) via iridium-catalyzed allylic alkylation of lactone nucleophile 238 H O O OH N BnO O lactamization O Scheme A13.1 Ir-catalyzed allylic alkylation O O NR RO O HO O BnO O 221 238 OCO 2Me 236 (+)-isopalhinine A BocHN O 237 BocHN OBn 226 To explore this idea, we synthesized lactone nucleophile 238 (Scheme A13.5). A Masamune-Claisen reaction of Boc-β-alanine (231) afforded β-ketoester 239 in 99% yield. Subsequent alkylation gave silyl ether 234, which was then exposed to TBAF to effect deprotection and cyclization in order to provide lactone 238 in 91% yield. Scheme A13.5 Synthesis of lactone nucleophile 238 O O BocHN CDI, MgCl 2 KO 2CCH2COMe OH THF, 23 °C 231 BocHN (69% yield) O BocHN (91% yield) O O TBAF THF, 23 °C OTBS OTBS NaH, NaI DME, 0 °C → 85 °C 239 O OMe 234 Br OMe (99% yield) O O BocHN 238 With lactone nucleophile 238 in hand, we turned to explore its reactivity in the proposed iridium-catalyzed allylic alkylation reaction (Table A13.2). Due to early difficulties in isolating branched allylic alkylation product 237 in high purity, we were prompted to discover that γ-butyrolactone allylic alkylation product 237 could be elaborated to α-quaternary lactam derivative 241 in a one-pot fashion upon treatment with trifluoracetic acid. Unlike lactone 237, branched lactam 241 is separable from its linear isomer and is merely the hemiacetal of key intermediate 236 (Scheme A13.4). Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 629 With respect to the optimization of the allylic alkylation reaction, our group’s previously reported conditions for the iridium-catalyzed allylic alkylation of crotyl chloride8 (Table A13.2, entry 1), poorly reactive allylic electrophiles 12 (entry 2), and β-ketoester nucleophiles9 (entry 3), all afforded poor selectivities when applied to our desired transformation. After extensive exploration of ligands and base additives, we found that the bulkier Feringa ligand L17 in combination with DABCO gave desired lactam 241 in excellent yield, regio- and enantioselectivity, though poor diastereoselectivity (entry 5). We believe that the diastereoselectivity of this transformation can potentially be further improved by exploring dual catalytic systems.13 Of note, linear β-ketoester 234 (Scheme A13.5) was also explored in the iridium-catalyzed allylic alkylation reaction with electrophile 240; however, the best results were observed using the same optimized conditions for lactam substrate 238 (Table A13.2, entry 5) and while the regioselectivity and yields were high (91:9 b:l, 94% yield), the diastereoselectivity was poor (1.2:1 dr) and all isomers were inseparable by column chromatography. 630 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Table A13.2 Optimization of the iridium-catalyzed allylic alkylation of lactone 238a BnO O O LG O + BocHN OBn [Ir(cod)Cl] 2 (2 mol %) L (4 mol %) TBD (10 mol %) O O 238 O THF (0.1 M), 60 °C, 18 h OBn O TFA/CH2Cl2 (1:1) 240 NH 23 °C, 3h O HO 237 241 BocHN Entry a L Base (200 mol %) Additive (mol %) LG Yield (%)b b:l c drc ee (%)d 1 L11 proton sponge LiCl (400) Cl 87 87:13 1.4:1 68 2 L5 – BEt 3 (200) OCO2Me 49 31:69 1.2:1 – 3 L2 – LiBr (200) OCO2Me 11 13:87 1.1:1 – 4 L17 – LiBr (200) OCO2Me 50 57:43 1.0:1 – 5 L17 DABCO – OCO 2Me 79 99:1 1.5:1 96 R O P N O Ph O P N O R R = H: (S,S a )-L2 R = Ph: (S,S a )-L11 O Ph P N O Ph Ph (S a )-L5 (S,S,S a )-L17 [a] Reactions performed on 0.1 mmol scale with 2:1 nucleophile/electrophile. [b] 1H NMR yield based on internal standard. [c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined via chiral HPLC. [e] TBD = 1,3,5triazabicyclo[4.4.0]dec-5-ene. We next turned our attention to the advancement of bicyclic hemiacetal 241 to spirocyclic enone 223 (Scheme A13.6), which would set the stage for the pivotal acyl anion addition. Toward this end, we performed a Wacker oxidation of pendant olefin 241 (Scheme A13.6, top). However, despite a variety of conditions, we observed cyclization of the hemiacetal moiety into the nascent ketone of 242 forming new unstable hemiacetal 243, which readily dehydrated to dihydrofuran 244. In an effort to circumvent this undesired reactivity, we instead oxidized hemiacetal 241 to aldehyde 245 using Dess– Martin periodinane prior to the Wacker oxidation (Scheme A13.6, middle). Unfortunately, Wacker product 246 suffered an undesirable intramolecular aldol reaction in situ, delivering undesired 5-membered aldol product 247. Lastly, we discovered that 631 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A we could perform a directed reduction of hemiacetal 241 using the hydroxyethyl group of the opened hemiacetal to access diol 248 (Scheme A13.6, bottom). Subsequent selective oxidation of the primary alcohol afforded aldehyde 249. To our disappointment, attempts to perform a Wacker oxidation on aldehyde 250 proved unsuccessful. It is likely that protection of the primary alcohol and/or amide is required for the Wacker oxidation to proceed. Scheme A13.6 Attempts to advance bicycle 241 to key spirocyclic intermediate 223 OBn O2 (1 atm) PdCl 2, CuCl2 - H 2O O O O NBn NH O HO 242 OBn O HO O CH2Cl2, 23 °C 243 244 (minor, unstable) (major) 223 desired OBn HO H O2 (1 atm) PdCl 2, CuCl2 NH MOMO O OBn O DMP NH O OBn (46% yield) O NH O HO O OBn OBn O O dioxane/H2O (7:1), 23 °C NH OBn O O O dioxane/H2O (7:1), 23 °C NH O O 241 NH O O O 245 O 246 247 OBn O NaBH 4 MeOH, 23 °C (44% yield) HO 248 O O MeCN, 23 °C (40% yield) OBn O2 (1 atm) PdCl 2, CuCl2 O IBX NH HO OBn NH O HO dioxane/H2O (7:1), 23 °C NH O HO 249 250 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.3 632 PALLADIUM-CATALYZED ALLYLIC ALKYLATION ROUTE USING A MASKED STABILIZED LACTAM ENOLATE Concurrent with our efforts to develop an iridium-catalyzed allylic alkylation approach to (+)-isopalhinine A (221), an alternate route to the natural product relying on a palladium-catalyzed allylic alkylation was explored (Scheme A13.7). Maintaining the endgame strategy from the iridium-catalyzed allylic alkylation route (Scheme A13.1), this alternate retrosynthetic analysis leads through the same disconnects to spirocyclic intermediate 223, which in this approach would be synthesized via an α-alkylation and diastereoselective reduction of the corresponding ketone of acetal 251. Cyclic enone 251 would then arise from the ozonolysis and aldol condensation enantioenriched lactam 252, which in turn would result from an enantioselective palladium-catalyzed decarboxylative allylic alkylation of substrate 253. The key advantage to this alternate route is the elimination of the need to control diastereoselectivity in the allylic alkylation reaction, which was the main challenge in the aforementioned iridium-catalyzed allylic alkylation route. Moreover, the tertiary stereocenter of the vicinal tertiary and quaternary stereodyad set in the iridium-catalyzed allylic alkylation pathway was to be ablated later in the synthesis in the formation of cyclohexadiene 222 (Scheme A13.1 and Scheme A13.7), and therefore our efforts to achieve a diastereoselective reaction were ultimately unnecessary. 633 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.7 Retrosynthetic analysis of (+)-isopalhinine A (221) via palladium-catalyzed allylic alkylation of masked stabilized lactam enolate 253 H O BnO OH N N-alkylation O HO OBn O OH MOMO NPG NPG MOMO 223 O ozonolysis aldol condensation O NPG NPG OO O O 251 Pd-catalyzed allylic alkylation O O NPG O reduction MOMO 222 (+)-isopalhinine A O alkylation O [4+2] 221 O O acyl anion addition 252 O 253 At the time we began our studies into this palladium-catalyzed route, the Stoltz group had previously examined the palladium-catalyzed decarboxylative alkylation of enolate-stabilized enol carbonates for the synthesis of all-carbon quaternary stereocenters14 as well as developed the asymmetric palladium-catalyzed decarboxylative allylic alkylation of lactams to reach quaternary N-heterocycles, specifically lactams, in high enantioselectivies.15 However, enolate-stabilized lactams such as 253 had yet to be explored in our palladium-catalyzed allylic alkylation chemistry. As such, we utilized easy-to-access model substrate 254 in order to explore the effects of protecting groups on yield and selectivity in our desired allylic alkylation reaction (Table A13.3). Through a series of optimization studies, we found that the nature of both the nitrogen (Table A13.3a) and ketone (Table A13.3b) protecting groups play pivotal roles on the enantioselectivity of the palladium-catalyzed decarboxylative alkylation of enolatestabilized lactam 253. Ultimately, we determined that protecting the amide nitrogen of model lactam 256 with a para-methoxy-benzoyl group (pMBz) and the ketone 634 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A functionality as a gem-dimethyl-dioxane moiety allowed us to access corresponding product 257 in the highest enantioselectivity (93% ee) and a moderate 46% yield. Table A13.3 Optimization of protecting groups for the palladium-catalyzed allylic alkylation reaction a ) Optimization of Lactam Protecting Group O Et O O NR O Pd 2(dba)3 (5 mol %) (S)-(CF3)3-t-BuPHOX L15 (12.5 mol %) Et O NR O hexane/toluene (2:1), 35 °C, 18 h O O 255 254 Entry R Conversion (%) 1 Bz 42 48 2a Bn 4-MeO-Bz 3,4,5-triMeO-Bz 4-MeO-benzenesulfonyl 7 29 75 86 79 87 62 61 63 53 3 4 5 6 Boc ee (%) b ) Optimization of Ketone Protecting Group O O Et O O Pd 2(dba)3 (5 mol %) (S)-(CF3)3-t-BuPHOX L15 (12.5 mol %) N O OMe O Et O O N O hexane/toluene (2:1), 35 °C, 18 h OMe O (46% yield, 93% ee) 256 257 [a] Reaction performed in cyclohexane. Having completed these optimization efforts, we moved to pursue the preparation of synthetically relevant substrate 260 for the proposed palladium-catalyzed allylic alkylation reaction (Scheme A13.8). Protected lactam 258 can be accessed in three steps from Boc-β-alanine (231). Subsequent acylation and allylation provided desired allylic alkylation substrate 260. Of note, iridium-catalyzed allylic alkylation was required for the allylation of 259, as we found that all attempts to allylate extremely sterically demanding 259 using standard methods resulted in returned starting material or deprotection of the starting material. Treatment of 260 with Pd(PPh3)4 afforded racemic product rac-261 in a 635 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A high 84% yield. Unfortunately, attempts to render the allylic alkylation reaction enantioselective utilizing our optimization conditions from model system 257 (Table A13.3) resulted in only modest enantioselectivities and yields, likely due to the now increased steric bulk around the reactive site. Additional studies into alternate palladiumcatalyzed allylic alkylation systems, specifically those utilizing Trost ligands known to tolerate more sterically encumbered substrates, 16 also showed poor reactivity. Nonetheless, we were pleased to find that we could advance rac-261 through an ozonolysis and an acid-catalyzed aldol reaction to provide desired spirocyclic enone 263. Scheme A13.8 Synthesis of spirocyclic intermediate 263 via palladium-catalyzed allylic alkylationa O 3 steps O 1. LiHMDS, THF, –78 °C N O BocHN O O OH OMe O O 2. methallyl Manders, –60 °C O 258 allyl methyl carbonate [Ir(cod)Cl] 2 (2 mol %) rac-L2 (4 mol %) LiBr (200 mol %), TBD (10 mol %) O O THF, 23 °C 259 Pd(PPh 3)4 (5 mol %) or Pd 2(pmdba)3 (5 mol %) (S)-(CF3)3-t-BuPHOX L15 (10.5 mol %) O O NpMBz O NpMBz O hexanes/toluene (0.03 M), 35 °C O (90% yield) NpMBz O (80% yield) 231 O O (84% yield, rac) (trace yield, 24% ee) 260 261 O O O O i. O 3, CH2Cl2, –78 °C ii. PPh 3, –78 °C → 23 °C (82% yield) p-TsOH•H 2O, MgSO 4 O NpMBz O O 262 toluene, reflux (53% yield) NpMBz O O 263 [a] pMBz = 4-MeO-Bz We next attempted to alkylate spirocyclic enone 263 in order to obtain α’alkylated intermediate 267 (Scheme A13.9). To our dismay, early efforts to directly alkylate or allylate 263 proved unsuccessful, likely due to the sterically hindered 636 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A neopentyl nature of the intermediate enolate, as well as the possibility of competitive γfunctionalization. We also found that forming silyl enol ether 266 was not fruitful, and were thus unable to explore alternate alkylation strategies. Scheme A13.9 Attempted alkylations of spirocyclic enone 263 O O O NpMBz O O NpMBz ii. 264 or allyl iodide –78 °C → 23 °C O R i. LiHMDS THF, –78 °C 263 BnO I 264 O O 265 OBn OTMS O O TMSCl, NEt 3 MeCN, 23 °C NpMBz O i. KOt-Bu or TBAT or MeLi ii. 264 O O NpMBz O O 266 A13.4 267 PIPERIDONE PALLADIUM-CATALYZED ALLYLIC ALKYLATION ROUTE In light of our inability to achieve a highly enantioselective palladium-catalyzed allylic alkylation using enolate-stabilized lactam substrate 253 (Section A13.3), we chose to investigate a modified palladium-catalyzed allylic alkylation route that employed a class of substrates already known to be successful in our group’s methodology: piperidones (Scheme A13.10).17 In this revised retrosynthetic analysis of (+)-isopalhinine A (221), the N-alkylation and intramolecular Diels–Alder disconnects of the previous routes remain, however [4+2] substrate 222 is now the result of an acyl anion addition into imine 268, which would arise from a late-stage oxidation of piperidine 269. Similar to the previous palladium-catalyzed allylic alkylation route, enone 269 would be formed 637 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A via ozonolysis and aldol condensation of diene 270. We envisioned that ether 270 would be prepared by diastereoselective reduction of enantioenriched piperidone 271, which would be formed via enantioselective palladium-catalyzed decarboxylative allylic alkylation of substrate 272. Scheme A13.10 Retrosynthetic analysis of (+)-isopalhinine A (221) via palladium-catalyzed allylic alkylation of piperidone 272 H O BnO OH N N-alkylation O HO OBn O OH MOMO NPG acyl anion addition N 222 (+)-isopalhinine A 268 O ozonolysis MOMO 269 alkylation MOMO MOMO aldol condensation oxidation [4+2] 221 NR O O reduction Pd-catalyzed allylic alkylation O O NR N R MOMO 270 O 271 N R 272 We first explored the feasibility of this revised plan by investigating the reactivity of benzyl-protected piperidone 273 (Scheme A13.11). Acylation and alkylation afforded allylic alkylation substrate 274, which we were pleased to find smoothly underwent the proposed palladium-catalyzed decarboxylative allylic alkylation to afford corresponding product 275 in excellent 93% yield and good 82% ee. Of note, product 275 is the incorrect enantiomer to access (+)-isopalhinine A (221), however, the challenges of preparing the requisite (R)-L15 led us to explore the early chemistry of this route using the easy-to-access 275. Subsequent diastereoselective reduction of ketone 275 using CBS catalyst delivered alcohol 276 in a 9:1 dr. We found that while we were able to protect the hydroxyl group to give 277, we were unable reveal the masked bis-carbonyl motif via 638 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A ozonolysis of diene 277. Realizing that the basic nitrogen of 277 was likely problematic in the ozonolysis reaction, we directed efforts toward investigating alternative protecting groups for piperidone 273, ultimately selecting a Boc group. Scheme A13.11 Attempts to advance benzyl-protected piperidone 273 O N Bn 1. NaH, diallyl carbonate THF, 0 °C → 23 °C O 2. methallyl bromide, K 2CO3 TBAI, acetone, 50 °C O O O THF, 23 °C N Bn (23% yield) 273 Pd 2(dba)3 (5 mol %) (S)-t-BuPHOX L18 (10.5 mol %) N Bn (93% yield, 82% ee) 275 274 (S)-CBS catalyst (20 mol %) BH 3•SMe2 (200 mol %) NBn CH 2Cl 2, 0 °C (59% yield, 9:1 dr) HO 276 NBn CH 2Cl 2, 0 °C (74% yield) O ozonolysis MOMBr, DIPEA NBn O MOMO MOMO 277 278 Boc-protected piperidone 279 performed similarly to benzyl-protected analogue 273 in the palladium-catalyzed decarboxylative allylic alkylation reaction, providing product 281 in 73% yield and 90% ee (Scheme A13.12). However, the CBS reduction of ketone 281 to give hydroxy 282 proceeded in significantly diminished yields and a now moderate 4:1 dr. Moreover, despite exploring a variety of conditions, efforts to either protect alcohol 282 or perform an ozonolysis were not successful. Given these difficulties and our concern with successfully performing the proposed selective late-stage oxidation to access imine 262 (Scheme A13.10), we elected to conclude explorations into this route. 639 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.12 Attempts to advance Boc-protected piperidone 279 O N Boc 279 1. NaH, diallyl carbonate THF, 0 °C → 23 °C O O O 2. methallyl bromide, K 2CO3 TBAI, acetone, 50 °C Pd 2(dba)3 (5 mol %) (S)-(CF3)3-t-BuPHOX L15 (10.5 mol %) O THF (0.05 M), 23 °C N Boc (17% yield) N Boc (73% yield, 90% ee) 281 280 O ozonolysis NBoc O (S)-CBS catalyst (20 mol %) BH 3•SMe2 (200 mol %) HO NBoc CH 2Cl 2, 0 °C (33% yield, 4:1 dr) 283 HO 282 protection NBoc BzO 284 A13.5 DIASTEREOSELECTIVE ROUTE While working to develop an enantioselective route to key spirocyclic intermediate 223, we wondered whether we could carry out a rapid, diastereoselective synthesis of 223 that would enable the preparation of large quantities of the compound for the purposes of exploring the proposed late-stage chemistry (Scheme A13.13). Toward this end, we envisioned that spirocyclic intermediate 223 could arise from an alkylation and ring closing metathesis of unmasked dioxin 285,18 which would now be the result of a diastereoselective alkylation/allylation sequence of hydroxy lactam 286. 640 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.13 Retrosynthetic analysis of (+)-isopalhinine A (221) via diastereoselective alkylation/allylation sequence H O BnO OH N N-alkylation O HO OBn O OH NR1 MOMO O acyl anion addition O NR1 [4+2] 221 R 2O R 2O 222 (+)-isopalhinine A RCM O diastereoselective alkylation O O 223 O NR1 NR1 alkylation allylation R 2O R 2O 285 286 In the forward direction, we began our studies with known β-ketolactam 232 (Scheme A13.14). Reduction of the ketone functionality with sodium borohydride followed by protection of the resultant hydroxyl group gave silyl ether 287 in 70% yield. Disappointingly, attempts to allylate or alkylate lactam 287 returned only deprotected starting material. Scheme A13.14 Attempts at diastereoselective functionalization O i. LiHMDS, THF, –78 °C NBoc ii. allyl bromide –78 °C → 23 °C O NBoc 1. NaBH 4, CH2Cl2 /AcOH (9:1) 0 °C → 23 °C 2. TBDPSCl, imidazole CH2Cl2, 23 °C O 232 (70% yield) TBDPSO O O 289 O NBoc Br 288 TBDPSO 287 O i. LiHMDS, THF, –78 °C O ii. 288, –78 °C → 23 °C O NBoc TBDPSO 290 641 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Realizing that we would need to replace the Boc group of lactam 287 with a basestable protecting group in order to promote functionalization, we considered alkylating lactam 291 with the requisite hydroxypropyl tether required for the proposed late-stage N-alkylation event (Scheme A13.13). Unfortunately, despite significant efforts to Nalkylate lactam 291, we observed only elimination of the iodide on the alkylating reagent or elimination of the silyl ether of 291 to form an enamide (Scheme A13.15). Scheme A13.15 Requisite propyl chain as a nitrogen protecting group O 264 O I 3M HCl/EtOAc NBoc N NH 0 °C → 23 °C TBDPSO O OBn (66% yield) 287 TBDPSO 291 alkylation OBn TBDPSO 292 To circumvent the issues we were observing with functionalizing lactam 287, we explored an alternative route to RCM precursor 298 that did not require the use of strong base, but would instead rely on a diastereoselective Tsuji reaction18a (Scheme A13.16). In this synthetic sequence, secondary amine 293 is acylated with 294 to give amide 295 in 76% yield. Subsequent Dieckmann condensation delivered functionalized β-ketolactam 296 in a moderate 50% yield. 642 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Scheme A13.16 Non-strong base route to RCM precursor 298 O N H 294 OH HO O EDCI, DMAP, NEt 3 O HO O OMe HO CH2Cl2, 23 °C N (76% yield) 293 O 296 O O OPG O O O N O (52% yield) 295 O O NaO OMe allyl alcohol, 23 °C O O O O OPG diastereoselective Tsuji reaction O O O N N PGO PGO 297 298 We were disappointed to find that attempts to advance β-ketolactam 296 to Tsuji substrate 297 were unsuccessful (Scheme A13.17). Specifically, we found that we could only reduce ketone 296 in low yields using sodium borohydride (Scheme A13.17, top). Efforts to protect the resultant hydroxy group resulted in retro Dieckmann products of 296 (Scheme A13.17, middle), as did attempts to alkylate 296 with dioxin 28818 (Scheme A13.7, bottom). Scheme A13.17 Attempts to advance β-ketolactam 296 O NaBH 4 O O N OH N OPG N OH THF, 23 °C HO (low yield) O 299 O O protection O N O O OH O O 296 300 O O 288, K 2CO3 acetone, 55 °C O O O O 301 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.6 643 FUTURE DIRECTIONS AND PROPOSED LATE-STAGE CHEMISTRY TO ACCESS (+)-ISOPALHININE A Should additional efforts enable access to key spirocyclic intermediate 223 via any of the aforementioned routes, the proposed late-stage chemistry to synthesize (+)isopalhinine A (221) is detailed in Scheme A13.18. Enone 223 will be converted to desired cyclohexadiene 302 by enolization and trapping with chloromethyl methyl ether. Diastereoselective addition of an acrolein-derived acyl anion equivalent (e.g., 303) to the amide functionality of 302 by approach of the anion over the olefinic group (i.e., α-face attack) will then provide Diels–Alder substrate 304 upon revealing the carbonyl group by desilylation and cyanide extrusion. Such masked acyl-anion additions to lactams have ample precedent in the literature,19 and we anticipate that the keto aminal (e.g., 222a) will likely be stable to subsequent manipulation, potentially as the free hydroxyl.20 If the need arises, we anticipate protecting hemiaminal 222a as a BOM ether (222b), or alternatively, reducing to the α-amidocarbonyl system (i.e., 222c). From spirocycle 222, an intramolecular diastereoselective [4+2] Diels–Alder cycloaddition will furnish the isotwistane core of (+)-isopalhinine A (221) to yield 305.21 The diastereoselectivity of the IMDA is controlled by the tethering of the dienophile to the top face of the spirocycle. Cleavage of the benzyl residues will occur via transfer hydrogenolysis (note: BOM cleavage would occur here if 305b is employed) to yield aminoalcohol 306. 22 Subsequent N-alkylation via an iridium-catalyzed “borrowing hydrogen”-type alkylation will install the final ring. 23 Finally, removal of remaining MOM group with acid will deliver (+)-isopalhinine A (221). If we are confronted with stability issues that require the use of ketone 307b, a late-stage oxidation (e.g., with 644 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A K2Fe(CN)6/NaHCO3/H2O, 24 O2/SiO2/H2O, 25 MnO2, 26 NaOMe/O2/H2O 27 ) will be employed to install the aminal group and reach (+)-isopalhinine A (221). Scheme A13.18 Proposed route to (+)-isopalhinine A (221) from alkylated spirocycle 223 OBn CN OBn O MOMO i-Pr2NEt, MOMCl O MOMO 223 MOMO 302 304 BnO TBAF H O R Bn N MOMO O R Bn N toluene, Δ THF 2. Et 3SiH TFA H MOMO 222a: R = OH 222b: R = OBOM 222c: R = H HO OBn MOMO OH OH N R toluene, 110 °C HO O O N HCl THF O HO HO 221 307a: R = OH [O] 307b: R = H (+)-isopalhinine A MOMO H N 306a: R = OH 306b: R = H H H R Pd/C 305a: R = OH 305b: R = OBOM 305c: R = H [Cp*IrCl 2]2, NaHCO 3 O cyclohexene MOMO 1. BOMCl i-Pr2NEt OTBS OH Bn N MOMO Et 2O –78 → 0 °C NBn MOMO NC OTBS LiHMDS O CH2Cl2 NBn BnO 303 Preliminary studies have been undertaken to investigate the proposed acyl anion addition chemistry in model systems. While the addition of aryl-functionalized silyl cyanohydrins into lactams is known,19 acrolein-derived silyl cyanohydrin, such as 303, additions have yet to be explored. Our early studies indicated that γ-addition of acrolein equivalent 303 is a competitive pathway. As such, we anticipate that future studies into this addition chemistry will involve alternative silyl cyanohydrins, especially those with masked olefins28 (e.g., 308 or 310) or electronic biases for α-addition (e.g., 31229), that 645 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A will preclude γ-addition (Scheme A13.19). In the case of masked olefin equivalents, following addition, the olefin functionality of 222 can then be exposed by mesylation and elimination of the primary alcohol in addition product 313.30 Scheme A13.19 Alternative acyl anion equivalents S OTMS TBSO CN 308 S S S TBSO 309 310 OMOM • 311 312 BnO 308 1. LiHMDS, Et 2O –78 → 0 °C MOMO HO BnO O R Bn N 2. TBAF, THF 313 A13.7 OMe CN MOMO 1. MsCl, pyridine CH2Cl2 2. KOH, TBAB CH2Cl2 MOMO 222 O R Bn N MOMO CONCLUSIONS In summary, we have detailed our efforts toward the total synthesis of (+)- isopalhinine A (221) including routes featuring an iridium-catalyzed allylic alkylation of an alkyl-substituted electrophile, a palladium-catalyzed allylic alkylation of an enolatestabilized lactam, a palladium-catalyzed allylic alkylation of a piperidone, and a diastereoselective alkylation/allylation sequence. Each of these routes to (+)-isopalhinine A (221) preserve the endgame strategy discussed in Section A13.6, wherein variants of key spirocycle 223 is imagined to be advanced to the natural product. Future studies may include further optimization of the iridium-catalyzed allylic alkylation reaction of Section A13.2 using dual metal catalysis and alternative alkylation methods of palladiumcatalyzed allylic alkylation intermediate 263 of Section A13.3. The successful completion of this work would represent the first total synthesis of (+)-isopalhinine A (221). 646 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.8 EXPERIMENTAL SECTION A13.8.1 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. Commercially obtained reagents were used as received. Chemicals were purchased from Aldrich/Strem/Alfa Aesar/Oakwood Chemicals and used as received. Sigma Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer chromatography (TLC) and preparatory TLC was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, KMnO4, or panisaldehyde staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak AD-H column (4.6 mm x 25 cm), Chiralpak AD column (4.6 mm x 25 cm), or a Chiralpak OJ column (4.6 mm x 25 cm), all obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak OJ-H column (4.6 mm x 25 cm) or Chiralpak AS-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. 1H NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer or a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer or a Varian Inova 500 MHz spectrometer and are Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 647 reported relative to residual CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of benzene (δ 7.36 ppm), water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). A13.8.1.1 Preparation of Known Compounds Previously reported methods were used to prepare ligands (R,R,Ra)-L16 31 and (S,S,Sa)-L17. 32 (S)-L18 was purchased from Sigma Aldrich. For the preparation of ligands L2, L5, L11, and L15, see chapter or appendix where initially disclosed. Literature procedures were used to prepare known compounds 228–230,4,5 232,7 239,33 264,34 287,35 293.36 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 648 A13.8.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA A13.8.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.2 BnO OCO 2Me (E)-6-(Benzyloxy)hex-2-en-1-yl methyl carbonate (226). Pyridine (2.8 mL, 34 mmol, 3.0 equiv) was added to a solution of alcohol 2304,5 (2.4 g, 11 mmol, 1.0 equiv) in CH2Cl2 (100 mL) at 0 °C, followed by addition of methyl chloroformate (1.3 mL, 17 mmol, 1.5 equiv) dropwise. The resulting solution was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with the addition of 1 M HCl (20 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give carbonate 226 as a colorless oil (2.7 g, 89% yield): 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.28 (m, 5H), 5.91 – 5.72 (m, 1H), 5.60 (dtt, J = 15.5, 6.5, 1.4 Hz, 1H), 4.56 (dq, J = 6.4, 1.0 Hz, 2H), 4.49 (s, 2H), 3.78 (s, 3H), 3.47 (t, J = 6.4 Hz, 2H), 2.17 (q, J = 7.1 Hz, 2H), 1.71 (dq, J = 8.3, 6.5 Hz, 2H). O NBoc O Tert-butyl 3-allyl-2,4-dioxopiperidine-1-carboxylate (233). To a solution of βketolactam 2327 in DMSO (50 mL) was added potassium carbonate (2.6 g, 19 mmol, 1.0 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 649 equiv) followed by allyl iodide (1.6 mL, 17 mmol, 0.9 equiv). The resulting solution was stirred for 18 h at ambient temperature, whereupon the reaction mixture was directly purified by silica gel flash column chromatography (30–50% EtOAc/hexanes) to give allyl 233 as a tan oil (1.8 g, 37% yield): 1H NMR (400 MHz, CDCl3) δ 5.90 (ddtd, J = 17.1, 10.2, 7.0, 1.0 Hz, 1H), 5.23 – 4.96 (m, 2H), 4.62 – 4.39 (m, 1H), 3.88 – 3.68 (m, 1H), 3.61 – 3.42 (m, 1H), 2.80 – 2.41 (m, 4H), 1.55 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 202.5, 166.6, 151.6, 135.5, 117.3, 84.4, 60.7, 39.7, 38.1, 28.1, 27.56. O BocHN O OMe OTBS Methyl 5-((tert-butoxycarbonyl)amino)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3- oxopentanoate (234). To a suspension of NaH (2.8 g, 82 mmol, 1.2 equiv, 60% in mineral oil) in DME (300 mL) was added a solution of β-ketoester 23933 (17 g, 71 mmol, 1.0 equiv) in DME (100 mL) followed by a solution of (2-bromoethoxy)(tertbutyl)dimethylsilane (19 g, 78 mmol, 1.1 equiv) and sodium iodide (5.4 g, 36 mmol, 0.5 equiv) in DME (50 mL). The resulting solution was heated under reflux for 18 h, then cooled to ambient temperature, filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (20–80% EtOAc/hexanes) to give silyl ether 234 as a pale orange oil (20 g, 69% yield): 1H NMR (400 MHz, CDCl3) δ 4.97 (s, 1H), 3.78 – 3.67 (m, 4H), 3.61 (td, J = 6.0, 1.7 Hz, 2H), 3.37 (q, J = 5.9 Hz, 2H), 2.93 – 2.64 (m, 2H), 2.13 – 1.99 (m, 2H), 1.42 (s, 9H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 205.3, 170.1, 155.9, 79.4, 60.5, 55.5, 52.6, 42.4, 35.2, 31.1, 28.5, 26.0, 18.4, -5.3. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 650 OBn O NBoc O Tert-butyl (S)-3-allyl-3-((S)-6-(benzyloxy)hex-1-en-3-yl)-2,4-dioxopiperidine-1- carboxylate (235). Please note Absolute and relative stereochemistry were not determined, and the structure is drawn by analogy to previous work.9 A general procedure for the optimization reactions (Table A13.1) is as follows. In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (2.7 mg, 0.0040 mmol, 2 mol %), ligand (0.0080 mmol, 4 mol %), TBD (2.8 mg, 0.020 mmol, 10 mol%), and THF (1 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with additive (0.40 mmol, 200 mol %), nucleophile 233 (103 mg, 0.40 mmol, 2.0 equiv), and THF (1 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by carbonate 226 (53 mg, 0.20 mmol, 1.0 equiv). The vial was sealed and stirred at 23 °C. After 18, the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The regioselectivity was determined by TOF LCMS (PMM_10min_50-80 ACN-AcOH). The crude mixture was purified by silica gel flash column chromatography (5–20% EtOAc/hexanes) to give allylic alkylation product 235 as a colorless oil and an inseparable mixture of branched and linear isomers: 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.05 (m, 5H), 5.74 – 5.41 (m, 2H), 5.36 – 4.91 (m, 4H), 4.46 (d, J = 4.7 Hz, 2H), 3.93 – 3.62 (m, 2H), 3.49 – 3.33 (m, 2H), 2.70 – 2.44 (m, 6H), 2.03 (q, J = 7.3 Hz, 1H), 1.62 (dt, J = 8.7, 6.6 Hz, 2H), 1.54 (s, 9H); 13C NMR (101 MHz, 651 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A CDCl3) δ 207.9, 207.6, 207.3, 172.0, 152.1, 138.7, 135.5, 132.2, 128.5, 127.7, 123.7, 119.8, 83.8, 73.0, 69.7, 64.2, 42.0, 41.3, 40.4, 39.3, 29.4, 29.3, 28.1. O O O BocHN Tert-butyl (3-oxo-3-(2-oxotetrahydrofuran-3-yl)propyl)carbamate (238). To a solution of silyl ether 234 (7.6 g, 19 mmol, 1.0 equiv) in THF (200 mL) was added TBAF (25 mL, 25 mmol, 1.3 equiv). The resulting solution was stirred at ambient temperature for 7 h, whereupon the reaction mixture was concentrated onto silica gel under reduced pressure and purified by silica gel flash column chromatography (50–70% EtOAc/hexanes) to give lactone 238 as a pale pink oil (4.4 g, 91% yield): 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 1H), 4.46 – 4.24 (m, 2H), 3.80 – 3.66 (m, 1H), 3.52 – 3.27 (m, 2H), 3.27 – 3.09 (m, 1H), 2.95 – 2.69 (m, 2H), 2.32 (dddd, J = 13.3, 9.3, 7.9, 5.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 201.9, 172.5, 155.8, 79.5, 67.5, 52.2, 42.7, 35.1, 28.4, 23.8. BnO Cl (E)-(((6-Chlorohex-4-en-1-yl)oxy)methyl)benzene (240, LG = Cl). To a solution of Nchlorosuccinimide (1.9 g, 14 mmol, 1.5 equiv) in CH2Cl2 (40 mL) at 0 °C was added dimethyl sulfide (1.3 mL, 17 mmol, 1.9 equiv) dropwise over 5 min. A solution of alcohol 2304,5 (1.9 g, 9.3 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was then added and the resulting solution was stirred at 0 °C for 2 h, whereupon the mixture was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 652 the addition of H2O (20 mL), and the aqueous layer was extracted with Et2O (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (5% EtOAc/hexanes) to provide chloride 240 as a pale yellow oil (1.7 g, 83% yield): 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.26 (m, 5H), 5.82 – 5.72 (m, 1H), 5.66 – 5.58 (m, 1H), 4.50 (s, 2H), 4.02 (dd, J = 7.1, 1.0 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 2.25 – 2.07 (m, 2H), 1.81 – 1.61 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 138.6, 135.5, 128.5, 127.8, 127.7, 126.5, 73.1, 69.6, 45.5, 29.0, 28.9. OBn O NH O HO (3aS,7aR)-3a-((S)-6-(Benzyloxy)hex-1-en-3-yl)-7a-hydroxyhexahydrofuro[3,2c]pyridin-4(2H)-one (241). Please note Absolute and relative stereochemistry were not determined, and the structure is drawn by analogy to previous work.9 A general procedure for the optimization reactions (Table A13.2) is as follows. In a nitrogen-filled glove box, to a 1 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (1.3 mg, 0.0020 mmol, 2 mol %), ligand (0.0040 mmol, 4 mol %), TBD (1.4 mg, 0.010 mmol, 10 mol %), and THF (0.5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another 1 dram vial (vial B) was charged with additive (0.20 or 0.40 mmol, 200 or 400 mol %), lactone nucleophile 238 (52 mg, 0.20 mmol, 2.0 equiv), and THF (0.5 mL). The pre-formed catalyst solution (vial A) was then transferred to vial B followed by electrophile 240 (0.10 mmol, 1.0 equiv). The vial was sealed and stirred at 60 °C. After 18 h, the vial was Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 653 removed from the glove box and concentrated under reduced pressure to give lactone allylic alkylation product 237. To crude 237 was added TFA/CH2Cl2 (1:1, 1 mL) and the resulting solution was stirred for 3 h, whereupon NEt3/CH2Cl2 (1:1, 1 mL) was added. The resulting solution was stirred for 18 h, whereupon brine (1 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and 1,2,4,5-tetrachloro-3-nitrobenzene (0.10 mmol in 0.5 mL CDCl3) was added. The NMR yield (measured in reference to 1,2,4,5tetrachloro-3-nitrobenzene δ 7.74 ppm (s, 1H)) was determined by 1H NMR analysis of the crude mixture. The residue was purified by preparatory TLC (50% acetone/hexanes) to afford hemiacetal 241 as an inseparable mixture of diastereomers. The major diastereomer was isolated by preparatory HPLC (reverse phase, MeCN/H2O, C18 column): 96% ee; 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.27 (m, 5H), 5.75 – 5.49 (m, 2H), 5.21 – 4.91 (m, 2H), 4.48 (s, 2H), 4.04 – 3.94 (m, 1H), 3.70 (dddd, J = 16.7, 9.9, 8.3, 7.1 Hz, 1H), 3.53 – 3.28 (m, 3H), 3.22 – 3.07 (m, 1H), 2.69 – 2.41 (m, 3H), 2.39 – 2.11 (m, 3H), 1.89 (dd, J = 13.6, 4.9 Hz, 1H), 1.67 (tdd, J = 10.6, 7.1, 4.2 Hz, 2H), 1.51 – 1.38 (m, 1H), 1.24 (ddt, J = 17.0, 8.8, 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 174.4, 173.9, 140.2, 139.4, 138.8, 138.7, 128.5, 128.5, 127.9, 127.8, 127.7, 127.6, 118.3, 116.4, 103.4, 103.3, 73.1, 72.9, 70.4, 69.8, 65.6, 65.1, 59.4, 58.9, 48.2, 47.2, 38.3, 38.3, 35.7, 33.9, 32.0, 30.6, 28.4, 27.6, 27.6, 26.5; HPLC conditions: 8% IPA, 1.0 mL/min, Chiralpak AD–H column, λ = 210 nm, tR (min): major = 21.087, minor = 21.876. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 654 OBn O O HO NH O (3R,3aS,7aS)-3-(3-(Benzyloxy)propyl)-2-hydroxy-2-methyltetrahydro-7a,3a(epoxyethano)furo[3,2-c]pyridin-4(5H)-one (243). To a solution of hemiacetal 241 (13 mg, 0.036 mmol, 1.0 equiv) in dioxane/H2O (7:1, 0.5 mL) was added PdCl2 (1.0 mg, 0.0056 mmol, 0.16 equiv) and copper(I) chloride (3.6 mg, 0.036 mmol, 1.0 equiv). The resulting solution was sparged with oxygen (balloon) and stirred under an oxygen atmosphere for 4 h, whereupon the reaction mixture was filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (30% acetone/hexanes) to provide 243 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H), 6.03 (s, 1H), 4.49 (d, J = 2.4 Hz, 2H), 4.25 (td, J = 8.6, 6.8 Hz, 1H), 3.86 (td, J = 8.3, 3.8 Hz, 1H), 3.57 – 3.40 (m, 2H), 3.21 (dp, J = 6.8, 2.9 Hz, 2H), 2.95 (s, 1H), 2.45 (ddd, J = 13.5, 6.7, 3.9 Hz, 1H), 2.23 (dt, J = 13.4, 8.5 Hz, 1H), 2.17 (s, 1H), 2.16 – 2.07 (m, 2H), 1.96 (ddd, J = 13.5, 8.2, 5.4 Hz, 2H), 1.78 (dq, J = 8.6, 3.4, 2.1 Hz, 5H), 1.53 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.4, 138.7, 128.5, 127.9, 127.6, 115.1, 104.8, 73.1, 70.6, 67.2, 54.9, 53.5, 37.9, 35.3, 31.1, 30.7, 29.9, 28.7, 28.2, 23.6. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 655 OBn O NH O O (3aS,7aS)-3-(3-(benzyloxy)propyl)-2-methyl-6,7-dihydro-7a,3a(epoxyethano)furo[3,2-c]pyridin-4(5H)-one (244). Olefin 244 was isolated as a byproduct in the synthesis and/or purification of 243. The amount of olefin 244 was found to increase when the crude reaction mixture of 243 was subjected to reduced pressure: 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.27 (m, 5H), 6.06 (d, J = 5.4 Hz, 1H), 4.47 (s, 2H), 4.01 (ddd, J = 8.4, 5.3, 2.9 Hz, 1H), 3.78 – 3.67 (m, 1H), 3.42 (t, J = 6.4 Hz, 2H), 3.31 – 3.12 (m, 2H), 2.34 (dt, J = 13.5, 2.9 Hz, 1H), 2.26 – 2.19 (m, 3H), 1.83 (s, 3H), 1.71 (td, J = 8.4, 4.5 Hz, 4H), 0.99 – 0.69 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 207.2, 173.8, 152.8, 138.6, 128.5, 127.8, 114.7, 106.2, 73.0, 69.8, 66.9, 64.5, 37.9, 34.46, 31.1, 29.5, 20.7, 11.6. OBn O NH O O 2-((S)-3-((S)-6-(Benzyloxy)hex-1-en-3-yl)-2,4-dioxopiperidin-3-yl)acetaldehyde (245). To a solution of hemiacetal 241 (56 mg, 0.16 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added Dess–Martin periodinane (83 g, 0.20 mmol, 1.2 equiv). The resulting solution was heated in a sealed vial to 50 °C for 2.5 h, whereupon the reaction mixture was cooled to ambient temperature, diluted with Et2O, sequentially washed with 10% aqueous Na2S2O3/saturated aqueous NaHCO3 mixture (1:1, 10 mL) and brine (20 mL), dried over Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 656 Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (50% EtOAc/hexanes then 50% acetone/hexanes) to provide 245 as a colorless oil (26 mg, 46% yield): 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 7.36 – 7.27 (m, 5H), 6.45 (d, J = 14.5 Hz, 1H), 5.49 (ddt, J = 43.8, 16.9, 10.0 Hz, 1H), 5.19 (td, J = 10.3, 1.7 Hz, 1H), 5.10 – 5.02 (m, 1H), 4.46 (s, 3H), 3.74 (dtd, J = 12.0, 5.5, 2.6 Hz, 1H), 3.63 (dtd, J = 14.2, 6.4, 3.6 Hz, 1H), 3.57 – 3.47 (m, 1H), 3.42 (dddd, J = 8.7, 7.3, 3.5, 2.2 Hz, 3H), 3.37 – 3.15 (m, 2H), 3.01 – 2.81 (m, 1H), 2.74 – 2.59 (m, 1H), 2.46 (ddd, J = 12.2, 10.0, 2.3 Hz, 1H), 1.75 – 1.60 (m, 3H), 1.45 – 1.16 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 207.6, 207.2, 199.9, 173.8, 173.1, 138.5, 136.6, 136.4, 128.5, 127.8, 127.7, 119.9, 119.2, 89.5, 73.0, 72.9, 69.7, 59.9, 59.3, 50.6, 50.4, 49.2, 38.9, 37.9, 36.7, 36.5, 28.0, 27.9, 26.9, 25.9. OBn HO H O NH O O (7R,7aS)-7-(3-(Benzyloxy)propyl)-9-hydroxydihydro-5H-4a,7a(epoxyethano)cyclopenta[c]pyridine-1,6(2H,7H)-dione (247). To a solution of aldehyde 245 (39 mg, 0.11 mmol, 1.0 equiv) in dioxane/H2O (7:1, 1.5 mL) was added PdCl2 (2.0 mg, 0.011 mmol, 0.1 equiv) and copper(I) chloride (11 mg, 0.11 mmol, 1.0 equiv). The resulting solution was sparged with oxygen (balloon) and stirred under an oxygen atmosphere for 18 h, whereupon the reaction mixture was filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (75% acetone/hexanes) Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 657 to provide 247 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 0.9 Hz, 5H), 5.55 (d, J = 6.1 Hz, 1H), 4.53 – 4.45 (m, 4H), 3.55 – 3.40 (m, 4H), 3.20 (dt, J = 7.7, 4.0 Hz, 3H), 2.88 – 2.75 (m, 1H), 2.66 – 2.41 (m, 3H), 2.33 (t, J = 6.7 Hz, 1H), 2.22 – 2.07 (m, 2H), 1.92 (ddd, J = 13.8, 8.8, 5.4 Hz, 1H), 1.88 – 1.70 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 175.8, 138.5, 128.4, 127.8, 127.6, 116.1, 107.0, 99.8, 72.9, 70.4, 55.0, 38.2, 37.8, 35.8, 28.5, 27.9, 27.6, 24.7. OBn O NH HO HO (3S,4S)-3-((S)-6-(Benzyloxy)hex-1-en-3-yl)-4-hydroxy-3-(2-hydroxyethyl)piperidin2-one (248). Please note Relative stereochemistry was not confirmed. To a solution of hemiacetal 241 (25 mg, 0.072 mmol, 1.0 equiv) in MeOH (1 mL) was added NaBH4 (8.0 mg, 0.22 mmol, 3.0 equiv). The resulting solution was stirred for 18 h, whereupon the reaction was quenched with a saturated aqueous solution of sodium citrate (1 mL) and extracted with EtOAc (3 x 5 mL), washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (33% acetone/hexanes) to provide hydroxy 248 as a colorless oil (11 mg, 44% yield): 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H), 5.99 (ddd, J = 17.3, 8.6, 2.6 Hz, 1H), 5.85 – 5.67 (m, 1H), 5.27 – 5.04 (m, 2H), 4.48 (d, J = 3.0 Hz, 2H), 4.03 (ddd, J = 23.5, 7.0, 4.3 Hz, 1H), 3.94 – 3.64 (m, 2H), 3.58 – 3.39 (m, 3H), 3.26 (dddd, J = 14.5, 11.7, 6.9, 4.0 Hz, 1H), 2.70 (dtd, J = 9.4, 6.0, 2.6 Hz, 1H), 2.16 – 1.98 (m, 3H), 1.94 – 1.82 (m, 1H), 1.81 – 1.65 (m, 2H), 1.44 (ddt, J = 13.8, 10.5, 7.7 Hz, 2H); 13C NMR (101 MHz, Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 658 CDCl3) δ 176.4, 176.3, 140.5, 138.7, 138.7, 138.6, 128.5, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6, 118.3, 117.6, 73.0, 72.9, 71.4, 70.9, 70.4, 70.3, 59.5, 59.4, 52.5, 52.1, 47.7, 46.4, 38.0, 37.8, 37.3, 33.9, 28.9, 27.9, 27.8, 26.7, 26.1, 24.9. OBn O NH O HO 2-((3S,4S)-3-((S)-6-(Benzyloxy)hex-1-en-3-yl)-4-hydroxy-2-oxopiperidin-3yl)acetaldehyde (249). To solution of alcohol 248 (10 mg, 0.029 mmol, 1.0 equiv) in MeCN (1 mL) was added IBX (25 mg, 0.089 mmol, 3.0 equiv). The resulting solution was stirred for 18 h, whereupon the reaction mixture was filtered through celite, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (44% acetone/hexanes) to provide aldehyde 249 as a colorless oil (4.0 mg, 40% yield): 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 7.36 – 7.28 (m, 5H), 5.45 (dt, J = 16.9, 10.1 Hz, 1H), 5.20 (ddd, J = 11.4, 10.1, 1.8 Hz, 1H), 5.07 (dddd, J = 17.0, 12.4, 1.8, 0.6 Hz, 1H), 4.47 (s, 3H), 3.83 – 3.72 (m, 1H), 3.66 (ddd, J = 6.2, 4.6, 2.5 Hz, 1H), 3.61 – 3.48 (m, 1H), 3.48 – 3.37 (m, 3H), 3.33 (dd, J = 18.9, 5.4 Hz, 1H), 3.02 – 2.83 (m, 1H), 2.75 – 2.61 (m, 1H), 2.51 – 2.40 (m, 1H), 1.75 – 1.63 (m, 2H), 1.54 – 1.14 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 207.5, 206.9, 199.9, 199.8, 173.7, 172.9, 138.6, 136.6, 136.4, 128.5, 127.9, 127.8, 127.72, 127.71, 119.9, 119.2, 73.0, 72.9, 69.8, 69.7, 60.0, 59.4, 50.7, 50.6, 50.5, 49.4, 38.9, 38.0, 36.8, 36.6, 28.0, 27.9, 27.0, 26.0. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.8.2.2 659 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.3 O O Et O O N O O OMe Allyl 7-ethyl-9-(4-methoxybenzoyl)-3,3-dimethyl-8-oxo-1,5-dioxa-9azaspiro[5.5]undecane-7-carboxylate (256). To a solution of LiHMDS (0.89 g, 5.4 mmol, 1.1 equiv) in THF (20 mL) at –78 °C was added a solution of protected lactam 295 (1.6 g, 4.9 mmol, 1.0 equiv) in THF (20 mL). The resulting mixture was stirred for 2 h at –78 °C, whereupon allyl chloroformate (0.59 g, 5.4 mmol, 1.1 equiv) was added dropwise. The reaction mixture was stirred for 3 h at –78 °C followed by an additional 18 h at –50 °C. The reaction was quenched with the addition of brine (20 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL), washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (35% EtOAc/hexanes) to provide acylated295 as a colorless oil (0.70 g, 34% yield). To a solution of acylated-295 (0.20 g, 0.48 mmol, 1.0 equiv) in acetone (5 mL) was added potassium carbonate (0.33 g, 2.4 mmol, 5.0 equiv) and ethyl iodide (0.39 mL, 4.8 mmol, 10.0 equiv). The resulting solution was stirred for 18 h at ambient temperature, whereupon the mixture was filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (50% EtOAc/hexanes) to provide ethyl 256 as a colorless oil (36 mg, 17% yield): 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.71 (m, 2H), 6.95 – 6.75 (m, 2H), 6.09 – 5.82 (m, Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 660 1H), 5.51 – 5.19 (m, 2H), 4.86 – 4.60 (m, 2H), 3.82 (s, 4H), 3.79 – 3.40 (m, 6H), 2.74 (dt, J = 14.6, 5.2 Hz, 1H), 2.46 – 2.08 (m, 3H), 1.20 (s, 3H), 1.02 (t, J = 7.4 Hz, 3H), 0.76 (s, 3H). Et O O N O O OMe (R)-7-Allyl-7-ethyl-9-(4-methoxybenzoyl)-3,3-dimethyl-1,5-dioxa-9azaspiro[5.5]undecan-8-one (257). In a nitrogen-filled glove box, to a 1 dram vial equipped with a stir bar was added Pd2(dba)3 (3.7 mg, 0.0040 mmol, 5 mol %), (S)-L15 (5.2 mg, 0.010 mmol, 12.5 mol %), and hexanes/toluene (2:1, 2.7 mL). The resulting solution was stirred at 25 °C for 10 min, whereupon substrate 256 (36 mg, 0.081 mmol, 1.0 equiv) was added. The vial was sealed and stirred at 35 °C for 18 h, whereupon the vial was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (30% EtOAc/hexanes) to provide allylic alkylation product 257 as a colorless solid (7.4 mg, 46% yield): 93% ee; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.23 – 6.00 (m, 1H), 5.18 – 4.93 (m, 2H), 3.83 (s, 3H), 3.77 – 3.56 (m, 4H), 3.43 (ddd, J = 11.7, 5.2, 2.6 Hz, 2H), 2.91 – 2.59 (m, 3H), 2.30 (ddd, J = 14.5, 8.5, 7.3 Hz, 1H), 2.15 – 1.98 (m, 1H), 1.93 (dt, J = 14.4, 7.4 Hz, 1H), 1.20 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H), 0.77 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.8, 175.3, 162.4, 136.5, 130.1, 128.9, 116.5, 113.6, 100.3, 70.4, 56.8, 55.5, 41.5, 33.2, 29.9, 25.2, 23.7, 22.5, 20.1, 9.1; SFC conditions: 3% MeOH, 3.0 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 18.627, minor = 4.817. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A O 661 O N O O OMe 9-(4-Methoxybenzoyl)-3,3-dimethyl-1,5-dioxa-9-azaspiro[5.5]undecan-8-one (258). To a solution of 2327 (45 g, 210 mmol, 1.0 equiv) in toluene (300 mL) was added paratoluenesulfonic acid (2.0 g, 11 mmol, 0.05 equiv) and 2,2-dimethyl-1,3-propanediol (33 g, 320 mmol, 1.5 equiv). The resulting solution was heated under reflux for 18 h with azeotropic removal of water via Dean–Stark trap, whereupon the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was purified by recrystallization from boiling EtOAc to give the protected ketone-232 (23 g, 54% yield). To a solution of protected ketone-232 (1.5 g, 7.5 mmol, 1.0 equiv) in THF (25 mL) was added NEt3 (1.6 mL, 11.3 mmol, 1.5 equiv), 4-dimethylaminopyridine (0.91 g, 0.75 mmol, 0.1 equiv), and para-anisoyl chloride (1.3 mL, 9.8 mmol, 1.3 equiv). The resulting solution was stirred at ambient temperature for 18 h, whereupon the mixture was filtered through celite, rinsing CH2Cl2, and concentrated under reduced pressure. The crude reside was purified by silica gel flash column chromatography (20% acetone/hexanes) to afford protected lactam 258 as a white solid (1.3 g, 54% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.82 – 3.75 (m, 2H), 3.55 (s, 4H), 2.92 (t, J = 1.0 Hz, 2H), 2.35 – 2.21 (m, 2H), 1.00 (d, J = 6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6, 170.6, 162.9, 130.9, 127.6, 113.6, 96.4, 70.8, 55.5, 43.3, 41.9, 30.3, 30.2, 22.6, 22.6. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A O O O 662 O N O O OMe 2-Methylallyl 9-(4-methoxybenzoyl)-3,3-dimethyl-8-oxo-1,5-dioxa-9azaspiro[5.5]undecane-7-carboxylate (259). To a solution of LiHMDS (1.1 g, 6.6 mmol, 1.1 equiv) in THF (40 mL) at –78 °C was added a solution of protected lactam 258 (2.0 g, 6.0 mmol, 1.0 equiv) in THF (40 mL). The resulting mixture was stirred for 2 h at –78 °C, whereupon methallyl chloroformate (0.83 g, 6.6 mmol, 1.1 equiv) was added dropwise. The reaction mixture was stirred for 2 h at –78 °C followed by an additional 18 h at –60 °C. The reaction was quenched with the addition of brine (20 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 40 mL), washed with brine (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (20–40% EtOAc/hexanes) to provide acylated 259 as a colorless foam (2.1 g, 80% yield): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 5.12 – 4.92 (m, 2H), 4.77 – 4.55 (m, 2H), 4.27 (d, J = 2.2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.83 (s, 4H), 3.81 – 3.67 (m, 2H), 3.63 – 3.43 (m, 3H), 2.55 (ddd, J = 13.8, 12.5, 5.9 Hz, 1H), 2.28 (ddt, J = 13.8, 4.5, 2.4 Hz, 1H), 1.79 (d, J = 0.6 Hz, 3H), 1.07 (s, 3H), 0.93 (s, 3H). Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A O O O 663 O N O O OMe 2-Methylallyl 7-allyl-9-(4-methoxybenzoyl)-3,3-dimethyl-8-oxo-1,5-dioxa-9azaspiro[5.5]undecane-7-carboxylate (260). In a nitrogen-filled glove box, to a 2 dram vial (vial A) equipped with a stir bar was added [Ir(cod)Cl]2 (31 mg, 0.046 mmol, 2 mol %), rac-L2 (42 mg, 0.093 mmol, 4 mol %), TBD (32 mg, 0.23mmol, 10 mol %), and THF (5 mL). Vial A was stirred at 25 °C (ca. 10 min) while another a 100 mL round bottom flask was charged with β-ketoamide 259 (1.0 g, 2.3 mmol, 1.0 equiv), LiBr (0.40 g, 4.6 mmol, 2.0 equiv), and THF (15 mL). The pre-formed catalyst solution (vial A) was then transferred to the round bottom flask followed by allyl methyl carbonate (0.40 g, 3.5 mmol, 1.5 equiv). The flask was removed from the glove box, placed under an argon atmosphere, and stirred at ambient temperature for 3.5 h, whereupon the reaction mixture was filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to afford allylated 260 (0.98 g, 90% yield): 1H NMR (400 MHz, CDCl3) δ 7.81 – 7.71 (m, 2H), 6.89 – 6.78 (m, 2H), 6.00 (dddd, J = 16.8, 10.1, 7.7, 6.5 Hz, 1H), 5.14 – 5.02 (m, 2H), 4.97 (td, J = 4.3, 3.6, 2.2 Hz, 2H), 4.69 – 4.50 (m, 2H), 3.80 (s, 3H), 3.79 – 3.68 (m, 2H), 3.68 – 3.56 (m, 2H), 3.48 (ddd, J = 21.8, 11.4, 2.6 Hz, 2H), 3.06 – 2.90 (m, 2H), 2.78 (dt, J = 14.6, 4.9 Hz, 1H), 2.24 (ddd, J = 14.6, 10.3, 5.8 Hz, 1H), 1.76 (s, 3H), 1.20 (s, 3H), 0.76 (s, 3H). Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A O 664 O N O O OMe (R)-7-Allyl-9-(4-methoxybenzoyl)-3,3-dimethyl-7-(3-methylbut-3-en-1-yl)-1,5-dioxa9-azaspiro[5.5]undecan-8-one (rac-261). In a nitrogen-filled glove box, to a 100 mL round bottom flask equipped with a stir bar was added Pd(PPh3)4 (46 mg, 0.040 mmol, 0.05 equiv), substrate 260 (0.37 g, 0.79 mmol, 1.0 equiv), and toluene (20 mL). The flask was removed from the glove box, placed under an argon atmosphere, and stirred at 35 °C for 18 h, whereupon the reaction mixture was filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to afford allylic alkylation product rac-261 (0.29 g, 84% yield): 24% ee; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.52 (m, 2H), 6.90 – 6.78 (m, 2H), 6.12 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.11 – 4.94 (m, 2H), 4.83 (ddd, J = 10.4, 2.4, 1.3 Hz, 2H), 3.83 (s, 4H), 3.70 (dd, J = 18.9, 11.6 Hz, 2H), 3.55 (ddd, J = 12.6, 10.3, 6.0 Hz, 1H), 3.46 (ddd, J = 11.7, 3.9, 2.5 Hz, 2H), 2.92 – 2.69 (m, 3H), 2.69 – 2.49 (m, 2H), 2.21 (ddd, J = 14.6, 10.2, 6.5 Hz, 1H), 1.72 (d, J = 0.6 Hz, 3H), 1.23 (s, 3H), 0.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 175.9, 174.7, 162.5, 143.1, 136.8, 130.7, 128.4, 116.6, 115.9, 113.5, 99.6, 70.4, 56.9, 55.5, 41.4, 41.0, 36.8, 29.9, 24.7, 23.9, 22.6, 20.2; SFC conditions: 3% MeOH, 3.0 mL/min, Chiralpak AS–H column, λ = 210 nm, tR (min): major = 11.875, minor = 10.765. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 665 O O O O N O O OMe (R)-2-(9-(4-Methoxybenzoyl)-3,3-dimethyl-8-oxo-7-(3-oxobutyl)-1,5-dioxa-9azaspiro[5.5]undecan-7-yl)acetaldehyde (262). A solution of olefin 261 (20 mg, 0.047 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was cooled to –78 °C. Ozone was bubbled through the reaction mixture for 0.5 h, whereupon the reaction mixture was sparged with N2 and triphenylphosphine (25 mg, 0.094 mmol, 2.0 equiv) was added. The cooling bath was then removed and the reaction was stirred for 1.5 h at ambient temperature. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by silica gel flash column chromatography (40% EtOAc/hexanes) to afford aldehyde 262 as a colorless oil (17 mg, 82% yield): 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.67 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, 3H), 3.83 (s, 4H), 3.78 – 3.61 (m, 5H), 3.42 (ddd, J = 11.9, 7.3, 2.6 Hz, 2H), 3.20 (d, J = 15.8 Hz, 1H), 3.11 (dd, J = 16.0, 2.6 Hz, 1H), 2.96 (d, J = 15.9 Hz, 1H), 2.81 (dd, J = 16.1, 2.1 Hz, 1H), 2.48 (qdd, J = 14.6, 6.9, 5.6 Hz, 2H), 2.21 (s, 3H), 1.16 (s, 3H), 0.77 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 206.4, 199.1, 174.2, 173.9, 162.8, 130.8, 127.6, 113.5, 98.4, 70.4, 56.2, 55.4, 46.3, 45.1, 41.2, 31.8, 29.6, 23.4. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 666 O O O N O O OMe 14-(4-Methoxybenzoyl)-3,3-dimethyl-1,5-dioxa-14-azadispiro[5.0.57.46]hexadec-10ene-9,13-dione (263). To a solution of bis-carbonyl 262 (20 mg, 0.046 mmol, 1.0 equiv) in toluene (2 mL) was added para-toluenesulfonic acid monohydrate (1 mg, 0.0046 mmol, 0.1 equiv) and MgSO4 (20 mg, 100 wt %). The resulting slurry was heated to 100 °C for 0.5 h, whereupon the mixture was cooled to ambient temperature, filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude reside was purified by preparatory TLC (40% acetone/hexanes) to afford enone 263 as a colorless oil (10 mg, 53% yield): 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.36 (m, 2H), 6.89 (ddd, J = 10.2, 5.8, 2.5 Hz, 1H), 6.84 – 6.76 (m, 2H), 6.08 – 5.98 (m, 1H), 3.81 (s, 3H), 3.77 – 3.54 (m, 4H), 3.45 (ddd, J = 11.7, 4.1, 2.5 Hz, 2H), 3.12 – 2.76 (m, 4H), 2.58 (dt, J = 14.7, 5.9 Hz, 1H), 2.35 (ddd, J = 14.6, 8.3, 6.1 Hz, 1H), 1.18 (s, 3H), 0.78 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 197.0, 175.9, 174.2, 162.8, 145.5, 130.3, 129.1, 127.4, 113.7, 98.5, 70.8, 70.7, 56.5, 55.5, 41.6, 39.6, 30.1, 29.4, 23.3, 22.2, 20.0. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.8.2.3 667 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.4 O O O N Bn Allyl 1-benzyl-3-(2-methylallyl)-4-oxopiperidine-3-carboxylate (274). To a solution of NaH (2.2 g, 66 mmol, 2.5 equiv, 60% in mineral oil) in THF (24 mL) at 0 °C was added a solution of 1-benzyl-4-piperidone (5 g, 26 mmol, 1.9 equiv) in THF (10 mL) over 15 min. The resulting mixture was warmed to ambient temperature, diallyl carbonate (5.7 mL, 40 mmol, 1.5 equiv) was added, and the solution was stirred for an additional 18 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 mL) and acidified (pH = 4) with 1 M HCl. The aqueous layer was extracted with EtOAc (3 x 40 mL), washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (20% EtOAc/hexanes) to provide acylated-274 as a colorless oil (2.5 g, 35% yield). To a solution of acylated-274 (0.10 g, 0.37 mmol, 1.0 equiv) in acetone (5 mL) was added potassium carbonate (0.10 g, 0.73 mmol, 2.0 equiv), tetrabutylammonium iodide (14 mg, 0.037 mmol, 0.1 equiv), and methallyl bromide (0.074 mL, 0.73 mmol, 2.0 equiv). The resulting solution was heated to 50 °C for 18 h, whereupon the reaction mixture was cooled to ambient temperature, filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to afford functionalized Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 668 piperidone 274 as a colorless oil (78 mg, 65% yield): 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.18 (m, 6H), 5.89 (ddt, J = 17.3, 10.4, 5.8 Hz, 1H), 5.44 – 5.16 (m, 2H), 4.80 (s, 1H), 4.71 – 4.56 (m, 3H), 3.72 – 3.54 (m, 2H), 3.49 (dd, J = 11.6, 2.7 Hz, 1H), 3.09 – 2.91 (m, 1H), 2.84 (ddd, J = 15.3, 11.8, 6.6 Hz, 1H), 2.64 (dd, J = 13.9, 0.9 Hz, 1H), 2.46 – 2.34 (m, 3H), 2.29 (d, J = 11.6 Hz, 1H), 1.66 (t, J = 1.1 Hz, 3H). O N Bn (S)-3-Allyl-1-benzyl-3-(2-methylallyl)piperidin-4-one (275). In a nitrogen-filled glove box, to a 250 mL round bottom flask equipped with a stir bar was added Pd2(dba)3 (81 mg, 0.088 mmol, 2.5 mol %), (S)-L18 (85 mg, 0.22 mmol, 6.25 mol %), and THF (110 mL). The resulting solution was stirred at 25 °C for 10 min, whereupon substrate 274 (1.2 g, 3.5 mmol, 1.0 equiv) was added. The flask was sealed and stirred at ambient temperature. After 18, the flask was removed from the glove box and filtered through a pad of silica, rinsing with EtOAc, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (8% EtOAc/hexanes) to provide allylic alkylation product 275 as a colorless oil (7.4 mg, 46% yield): 82% ee; 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.21 (m, 5H), 5.75 – 5.58 (m, 1H), 5.12 – 4.95 (m, 2H), 4.84 (dq, J = 2.9, 1.5 Hz, 1H), 4.68 (dq, J = 2.0, 0.9 Hz, 1H), 3.68 – 3.47 (m, 2H), 2.78 (dddd, J = 8.4, 6.4, 3.1, 1.5 Hz, 1H), 2.69 – 2.56 (m, 4H), 2.53 – 2.45 (m, 2H), 2.46 – 2.36 (m, 2H), 1.68 (t, J = 1.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 212.3, 142.1, 138.7, 133.9, 128.9, 128.5, 127.4, 118.3, 115.3, 62.4, 62.3, 53.5, 52.3, 42.3, 39.54, 38.9, Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 669 24.6; HPLC conditions: 1% EtOH, 1.0 mL/min, Chiralpak OJ column, λ = 210 nm, tR (min): major = 10.113, minor = 8.486. NBn HO (3S,4R)-3-Allyl-1-benzyl-3-(2-methylallyl)piperidin-4-ol (276). Please note Relative stereochemistry was not confirmed. To a solution of ketone 275 (0.50 g, 1.8 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at 0 °C was added (S)-CBS (1 M, 0.35 mL, 0.35 mmol, 0.2 equiv) followed by BH3•DMS (2 M, 1.8 mL, 3.5 mmol, 2.0 equiv). The resulting solution was stirred for 1.5 h, whereupon the reaction was quenched with MeOH (5 mL) and a saturated aqueous sodium citrate solution (10 mL) then warmed to ambient temperature and stirred for an additional 15 min. The aqueous layer was extracted with Et2O (3 x 30 mL), dried over Mg2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (20% EtOAc/hexanes) to afford alcohol 276 as an inseparable mixture (9:1) of diastereomers and a colorless oil (0.50 g, 59% yield): 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.31 (m, 5H), 5.98 (ddt, J = 17.4, 9.8, 7.5 Hz, 1H), 5.19 – 5.07 (m, 2H), 4.90 (dd, J = 2.6, 1.4 Hz, 1H), 4.80 (dd, J = 2.6, 1.1 Hz, 1H), 3.62 (t, J = 6.9 Hz, 1H), 3.53 (d, J = 13.0 Hz, 1H), 3.34 (d, J = 13.1 Hz, 1H), 2.63 – 2.42 (m, 2H), 2.42 – 2.32 (m, 1H), 2.29 (d, J = 13.3 Hz, 1H), 2.21 – 2.00 (m, 2H), 1.82 (t, J = 1.1 Hz, 3H), 1.80 – 1.69 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 144.1, 139.1, 135.6, 133.4, 132.8, 129.2, 128.7, 128.6, 128.3, 127.1, 126.7, 117.9, 115.2, 62.9, 42.7, 30.1, 26.0, 25.7. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 670 NBn MOMO (3S,4R)-3-Allyl-1-benzyl-4-(methoxymethoxy)-3-(2-methylallyl)piperidine (277). To a solution of alcohol 276 (70 mg, 0.25 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at 0°C was added DIPEA (0.065 mL, 0.38 mmol, 1.5 equiv) and bromomethyl methyl ether (0.040 mL, 0.49 mmol, 2.0 equiv). The resulting mixture was stirred for 3 h, whereupon the reaction was quenched with a saturated aqueous NaHCO3 solution (5 mL) and the aqueous layer was extracted with EtOAc (3 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to afford ether 277 as a colorless oil (61 mg, 74% yield): 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.13 (m, 5H), 5.88 (dddt, J = 27.1, 17.3, 10.1, 7.4 Hz, 1H), 5.15 – 4.99 (m, 2H), 4.97 – 4.84 (m, 1H), 4.78 – 4.68 (m, 2H), 4.65 (dd, J = 7.7, 6.9 Hz, 1H), 3.59 – 3.41 (m, 2H), 3.39 (d, J = 1.1 Hz, 4H), 2.75 – 2.30 (m, 4H), 2.30 – 1.89 (m, 5H). O O O N Boc 3-Allyl 1-(tert-butyl) 3-(2-methylallyl)-4-oxopiperidine-1,3-dicarboxylate (280). To a solution of NaH (4.2 g, 130 mmol, 2.5 equiv, 60% in mineral oil) in THF (45 mL) at 0 °C was added a solution of 1-Boc-4-piperidone (10.0 g, 50.2 mmol, 1.0 equiv) in THF (20 mL) over 15 min. The resulting mixture was warmed to ambient temperature, diallyl Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 671 carbonate (11 mL, 75 mmol, 1.5 equiv) was added, and the solution was stirred for an additional 18 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (30 mL) and acidified (pH = 4) with 1 M HCl. The aqueous layer was extracted with EtOAc (3 x 60 mL), washed with brine (60 mL), dried over Na2SO4, and concentrated under reduced pressure. To a solution of the crude residue in acetone (60 mL) was added potassium carbonate (14 g, 104 mmol, 2.0 equiv), tetrabutylammonium iodide (0.96 g, 2.6 mmol, 0.1 equiv), and methallyl chloride (10.0 mL, 104 mmol, 2.0 equiv). The resulting solution was heated to 45 °C for 18 h, whereupon the reaction mixture was cooled to ambient temperature, filtered through a pad of silica, rinsing with acetone, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10–20% EtOAc/hexanes) to afford functionalized piperidone 280 as a colorless oil (2.9 g, 17% yield over 2 steps): 1H NMR (400 MHz, CDCl3) δ 5.90 (ddt, J = 17.2, 10.3, 5.9 Hz, 1H), 5.39 – 5.20 (m, 2H), 4.88 (t, J = 1.7 Hz, 1H), 4.74 (dp, J = 2.9, 1.0 Hz, 1H), 4.68 – 4.57 (m, 3H), 4.32 – 4.06 (m, 1H), 3.34 – 3.18 (m, 1H), 3.09 (d, J = 13.7 Hz, 1H), 2.78 – 2.67 (m, 2H), 2.55 – 2.41 (m, 2H), 1.75 (t, J = 1.1 Hz, 1H), 1.71 (t, J = 1.1 Hz, 3H), 1.51 (d, J = 2.1 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 208.8, 203.8, 169.6, 154.4, 141.8, 140.2, 131.2, 119.1, 115.7, 80.3, 66.1, 60.8, 51.6, 38.9, 28.3, 23.7. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 672 O N Boc Tert-butyl (S)-3-allyl-3-(2-methylallyl)-4-oxopiperidine-1-carboxylate (281). In a nitrogen-filled glove box, to 1 dram vial equipped with a stir bar was added Pd2(dba)3 (12 mg, 0.013 mmol, 2.5 mol %), (S)-L15 (17 mg, 0.033 mmol, 6.25 mol %), and THF (10 mL). The resulting solution was stirred at 25 °C for 10 min, whereupon substrate 280 (0.18 g, 0.52 mmol, 1.0 equiv) was added. The flask was sealed and stirred at ambient temperature for 18 h, whereupon the flask was removed from the glove box and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (8% EtOAc/hexanes) to provide allylic alkylation product 81 as a colorless oil (0.11 g, 73% yield): 90% ee; 1H NMR (400 MHz, CDCl3) δ 5.68 (dddd, J = 17.0, 10.3, 7.9, 6.8 Hz, 1H), 5.19 – 4.95 (m, 2H), 4.86 (s, 1H), 4.70 (d, J = 1.0 Hz, 1H), 3.95 – 3.35 (m, 4H), 2.71 – 2.19 (m, 6H), 1.66 (d, J = 0.7 Hz, 3H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 154.9, 141.2, 132.9, 119.1, 115.8, 80.5, 52.9, 41.3, 39.1, 38.3, 31.7, 28.5, 24.5, 22.8, 14.3; HPLC conditions: 0.9% EtOH, 1.0 mL/min, Chiralpak AD & AD–H columns in series, λ = 210 nm, tR (min): major = 11.319, minor = 11.808. NBoc HO Tert-butyl (3S,4R)-3-allyl-4-hydroxy-3-(2-methylallyl)piperidine-1-carboxylate (282). Please note Relative stereochemistry was not confirmed. To a solution of ketone 281 (83 mg, 0.28 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at 0 °C was added (S)-CBS (1 M, Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 673 0.057 mL, 0.057 mmol, 0.2 equiv) followed by BH3•DMS (2 M, 0.35 mL, 0.70 mmol, 2.0 equiv). The resulting solution was stirred for 7 h, whereupon a second aliquot of BH3•DMS (2 M, 0.10 mL, 0.20 mmol, 0.7 equiv) was added. The reaction was stirred for an additional 3.5 h, quenched with MeOH (5 mL) and a saturated aqueous sodium citrate solution (10 mL), then warmed to ambient temperature and stirred for an additional 15 min. The aqueous layer was extracted with Et2O (3 x 10 mL), dried over Mg2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (30% EtOAc/hexanes) to afford alcohol 282 as an inseparable mixture (4:1) of diastereomers and a colorless oil (83 mg, 33% yield): 1H NMR (400 MHz, CDCl3) δ 6.20 – 5.85 (m, 1H), 5.23 – 5.06 (m, 2H), 5.03 – 4.94 (m, 1H), 4.86 (s, 1H), 4.04 – 3.13 (m, 2H), 3.01 – 2.84 (m, 2H), 2.43 – 2.19 (m, 3H), 2.01 (d, J = 13.7 Hz, 1H), 1.89 – 1.79 (m, 3H), 1.56 (q, J = 2.3, 1.8 Hz, 11H); 13C NMR (101 MHz, CDCl3) δ 155.2, 143.4, 134.3, 118.4, 118.2, 115.8, 115.6, 42.4, 41.9, 37.5, 29.7, 28.8, 28.4, 25.4, 25.4. A13.8.2.4 Experimental Procedures and Spectroscopic Data for the Synthesis of Synthetic Intermediates in Section A13.5 O NH TBDPSO 4-((Tert-butyldiphenylsilyl)oxy)piperidin-2-one (291). To a solution of 3 M HCl/EtOAc (0.5 mL) at 0 °C was added 28735 (0.10 g, 0.22 mmol, 1.0 equiv). The resulting mixture was stirred for 1 h, whereupon the reaction was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (35– Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 674 100% acetone/hexanes) to afford deprotected lactam 291 as a colorless solid (51 mg, 66% yield): 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.32 (m, 10H), 7.17 (s, 1H), 4.15 (p, J = 4.9 Hz, 1H), 3.69 – 3.42 (m, 1H), 3.27 – 2.99 (m, 1H), 2.41 (dd, J = 4.8, 1.6 Hz, 2H), 1.74 (q, J = 5.7 Hz, 2H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.9, 135.7, 135.7, 133.7, 133.4, 129.9, 129.9, 127.8, 127.8, 65.8, 40.5, 37.8, 29.9, 26.9, 19.1. O O HO O 3-(Allyloxy)-3-oxopropanoic acid (294). A solution of Meldrum’s acid (20.0 g, 0.14 mmol, 1.0 equiv) in allyl alcohol (40 mL) was heated under reflux for 18 h, whereupon the reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was dissolved in MeOH (60 mL), aqueous ammonia (50%, 7 mL) was added, the resulting solution was stirred for 15 min, and then concentrated under reduced pressure. The crude residue was washed with hexanes/Et2O (1:1, 2 x 15 mL), dissolved in H2O (20 mL) and acidified with 1 M HCl. The aqueous layer was extracted with Et2O (3 x 30 mL), washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give acid 294 as a colorless solid (13.0 g, 65% yield). O HO N OMe O O O Allyl 3-((3-hydroxypropyl)(3-methoxy-3-oxopropyl)amino)-3-oxopropanoate (295). To a solution of amino alcohol 29336 (2.0 g, 12 mmol, 1.0 equiv), 4- Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 675 dimethylaminopyridine (0.15 g, 1.2 mmol, 0.1 equiv), NEt3 (4.5 mL, 32 mmol, 2.6 equiv) in CH2Cl2 (24 mL) at 0 °C was added acid 294 (2.3 g, 16 mmol, 1.3 equiv) followed by EDCI•HCl (3.1 g, 16 mmol, 1.3 equiv) portionwise. The resulting solution was stirred for 18 h, whereupon the reaction was quenched with 1 M HCl (pH < 7), extracted with CH2Cl2 (3 x 20 mL), washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford β-ketoamide 295 as a colorless oil (2.7 g, 76% yield): 1H NMR (400 MHz, CDCl3) δ 6.02 – 5.76 (m, 1H), 5.47 – 5.13 (m, 2H), 4.63 (ddtt, J = 4.8, 3.8, 2.5, 1.2 Hz, 2H), 3.89 – 3.18 (m, 7H), 2.64 (td, J = 7.1, 4.4 Hz, 1H), 2.06 – 1.44 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 172.6, 171.3, 167.7, 131.5, 119.2, 118.9, 66.3, 66.2, 66.1, 58.2, 52.3, 45.8, 43.9, 42.1, 41.4, 40.9, 33.2, 32.3, 31.1, 30.2. OH O O O N O Allyl 1-(3-hydroxypropyl)-2,4-dioxopiperidine-3-carboxylate (296). To allyl alcohol (35 mL) was added Na metal (0.67 g, 29 mmol, 2.1 equiv) followed by β-ketoamide 295 (4.0 g, 14 mmol, 1.0 equiv). The resulting solution was heated under reflux for 18 h, whereupon the reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was dissolved in H2O (30 mL) and the aqueous layer was extracted with EtOAc (3 x 30 mL). The aqueous layer was then acidified with 6 M HCl and extracted with 10% isopropanol/CH2Cl2 (3 x 30 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography to afford β-ketolactam 296 as a Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 676 yellow oil (1.9 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 5.99 (ddt, J = 17.2, 10.5, 5.5 Hz, 1H), 5.50 – 5.41 (m, 1H), 5.28 (dt, J = 10.5, 1.4 Hz, 1H), 4.81 (dt, J = 5.5, 1.5 Hz, 2H), 4.03 (p, J = 6.1 Hz, 3H), 3.57 (q, J = 6.0, 5.6 Hz, 4H), 3.46 – 3.37 (m, 2H), 2.67 (t, J = 6.9 Hz, 2H). 677 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.8.2.5 Determination of Enantiomeric Excess Please note racemic products for palladium-catalyzed allylic alkylations were synthesized using Pd(PPh3)4. Racemic products for iridium-catalyzed allylic alkylations were synthesized using racemic L2. Table A13.4 Determination of enantiomeric excess Entry Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee HPLC Chiralpak AD-H 8% IPA isocratic, 1.0 mL/min 21.087 21.876 96% NBz SFC Chiralpak OJ-H 3% MeOH isocratic, 3.0 mL/min 19.747 22.731 48% NBn SFC Chiralpak OJ-H 5% MeOH isocratic, 3.0 mL/min 7.012 5.589 29% SFC Chiralpak OJ-H 3% MeOH isocratic, 3.0 mL/min 20.272 24.437 62% SFC Chiralpak OJ-H 1% MeOH isocratic, 3.0 mL/min 27.715 25.961 61% Product OBn O 1 NH O HO O Et 2 O O Et 3 O O O Et 4 O O N O OMe O Et 5 O O OMe N O O OMe OMe 678 Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A Entry Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee SFC Chiralpak OJ-H 5% MeOH isocratic, 3.0 mL/min 15.378 17.679 63% SFC Chiralpak OJ-H 1% MeOH isocratic, 3.0 mL/min 3.062 4.057 53% SFC Chiralpak OJ-H 3% MeOH isocratic, 3.0 mL/min 18.627 4.817 93% SFC AS-H 3% MeOH isocratic, 3.0 mL/min 11.875 10.765 24% HPLC Chiralpak OJ 1% EtOH isocratic, 1.0 mL/min 10.113 8.486 82% HPLC Chiralpak AD & AD-H in series 0.9% EtOH isocratic, 1.0 mL/min 11.319 11.808 90% Product OMe Et O 6 O N O S O O Et 7 O NBoc O O Et 8 O O N O OMe O O 9 O N O OMe O O 10 N Bn O 11 N Boc Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A A13.9 (1) 679 REFERENCES AND NOTES (a) Ma, X.; Gang, D. 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(14) McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett 2010, 1712–1716. (15) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chem. 2012, 4, 130–133. (16) Trost, B. M. Tetrahedron 2015, 71, 5708–5733. (17) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17, 14199–14223. (18) (a) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Tetrahedron Lett. 2017, 58, 3341– 3343; (b) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2002, 124, 754–755. Appendix 13 – Progress Toward the Synthesis of (+)-Isopalhinine A 681 (19) (a) Hünig, S.; Schäfer, M.; Schweeberg, W. Chem. Ber. 1993, 126, 191–204; (b) Wiedner, S. D.; Vedejs, E. Org. Lett. 2010, 12, 4030–4033. 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Appendix 14 – Spectra Relevant to Appendix 13 683 APPENDIX 14 Spectra Relevant to Appendix 13: Progress Toward the Synthesis of (+)-Isopalhinine A 10 9 8 7 5 ppm 4 3 Figure A14.1 1H NMR (400 MHz, CDCl3) of compound 226 6 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 684 10 9 8 6 5 ppm 4 3 Figure A14.2 1H NMR (400 MHz, CDCl3) of compound 233 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 685 200 180 160 120 100 ppm 80 60 Figure A14.3 13C NMR (101 MHz, CDCl3) of compound 233 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 686 10 9 8 6 5 ppm 4 3 Figure A14.4 1H NMR (400 MHz, CDCl3) of compound 234 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 687 200 180 160 120 100 ppm 80 60 Figure A14.5 13C NMR (101 MHz, CDCl3) of compound 234 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 688 10 9 8 6 5 ppm 4 3 Figure A14.6 1H NMR (400 MHz, CDCl3) of compound 235 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 689 200 180 160 120 100 ppm 80 60 Figure A14.7 13C NMR (101 MHz, CDCl3) of compound 235 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 690 10 9 8 6 5 ppm 4 3 Figure A14.8 1H NMR (400 MHz, CDCl3) of compound 238 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 691 200 180 160 120 100 ppm 80 60 Figure A14.9 13C NMR (101 MHz, CDCl3) of compound 238 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 692 10 9 8 6 5 ppm 4 3 Figure A14.10 1H NMR (400 MHz, CDCl3) of compound 240 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 693 220 200 180 140 120 100 ppm 80 60 Figure A14.11 13C NMR (101 MHz, CDCl3) of compound 240 160 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 694 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A14.12 1H NMR (400 MHz, CDCl3) of compound 241 7.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 14 – Spectra Relevant Appendix 13 695 210 200 190 180 170 160 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 Figure A14.13 13C NMR (101 MHz, CDCl3) of compound 241 150 40 30 20 10 0 -10 Appendix 14 – Spectra Relevant Appendix 13 696 10 9 8 6 5 ppm 4 3 Figure A14.14 1H NMR (400 MHz, CDCl3) of compound 243 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 697 200 180 160 120 100 ppm 80 60 Figure A14.15 13C NMR (101 MHz, CDCl3) of compound 243 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 698 10 9 8 6 5 ppm 4 3 Figure A14.16 1H NMR (400 MHz, CDCl3) of compound 244 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 699 200 180 160 120 100 ppm 80 60 Figure A14.17 13C NMR (101 MHz, CDCl3) of compound 244 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 700 10 9 8 6 5 ppm 4 3 Figure A14.18 1H NMR (400 MHz, CDCl3) of compound 245 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 701 220 200 180 140 120 100 ppm 80 60 Figure A14.19 13C NMR (101 MHz, CDCl3) of compound 245 160 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 702 10 9 8 6 5 ppm 4 3 Figure A14.20 1H NMR (400 MHz, CDCl3) of compound 247 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 703 200 180 160 120 100 ppm 80 60 Figure A14.21 13C NMR (101 MHz, CDCl3) of compound 247 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 704 10 9 8 6 5 ppm 4 3 Figure A14.22 1H NMR (400 MHz, CDCl3) of compound 248 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 705 200 180 160 120 100 ppm 80 60 Figure A14.23 13C NMR (101 MHz, CDCl3) of compound 248 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 706 10 9 8 6 5 ppm 4 3 Figure A14.24 1H NMR (400 MHz, CDCl3) of compound 249 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 707 200 180 160 120 100 ppm 80 60 Figure A14.25 13C NMR (101 MHz, CDCl3) of compound 249 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 708 10 9 8 6 5 ppm 4 3 Figure A14.26 1H NMR (400 MHz, CDCl3) of compound 256 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 709 10 9 8 6 5 ppm 4 3 Figure A14.27 1H NMR (400 MHz, CDCl3) of compound 257 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 710 200 180 160 120 100 ppm 80 60 Figure A14.28 13C NMR (101 MHz, CDCl3) of compound 257 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 711 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A14.29 1H NMR (400 MHz, CDCl3) of compound 258 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 14 – Spectra Relevant Appendix 13 712 210 200 190 180 170 160 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 Figure A14.30 13C NMR (101 MHz, CDCl3) of compound 258 150 40 30 20 10 0 -10 Appendix 14 – Spectra Relevant Appendix 13 713 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A14.31 1H NMR (400 MHz, CDCl3) of compound 259 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 14 – Spectra Relevant Appendix 13 714 10 9 8 6 5 ppm 4 3 Figure A14.32 1H NMR (400 MHz, CDCl3) of compound 260 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 715 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A14.33 1H NMR (400 MHz, CDCl3) of compound 261 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 14 – Spectra Relevant Appendix 13 716 200 180 160 120 100 ppm 80 60 Figure A14.34 13C NMR (101 MHz, CDCl3) of compound 261 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 717 10 9 8 6 5 ppm 4 3 Figure A14.35 1H NMR (400 MHz, CDCl3) of compound 262 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 718 220 200 180 140 120 100 ppm 80 60 Figure A14.36 13C NMR (101 MHz, CDCl3) of compound 262 160 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 719 10.5 10.0 9.5 9.0 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 f1 (ppm) 4.0 3.5 3.0 Figure A14.37 1H NMR (400 MHz, CDCl3) of compound 263 7.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 14 – Spectra Relevant Appendix 13 720 210 200 190 180 170 160 140 130 120 110 100 90 f1 (ppm) 80 70 60 50 Figure A14.38 13C NMR (101 MHz, CDCl3) of compound 263 150 40 30 20 10 0 -10 Appendix 14 – Spectra Relevant Appendix 13 721 10 9 8 6 5 ppm 4 3 Figure A14.39 1H NMR (400 MHz, CDCl3) of compound 274 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 722 10 9 8 6 5 ppm 4 3 Figure A14.40 1H NMR (400 MHz, CDCl3) of compound 275 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 723 200 180 160 120 100 ppm 80 60 Figure A14.41 13C NMR (101 MHz, CDCl3) of compound 275 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 724 10 9 8 6 5 ppm 4 3 Figure A14.42 1H NMR (400 MHz, CDCl3) of compound 276 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 725 200 180 160 120 100 ppm 80 60 Figure A14.43 13C NMR (101 MHz, CDCl3) of compound 276 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 726 10 9 8 6 5 ppm 4 3 Figure A14.44 1H NMR (400 MHz, CDCl3) of compound 277 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 727 10 9 8 6 5 ppm 4 3 Figure A14.45 1H NMR (400 MHz, CDCl3) of compound 280 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 728 200 180 160 120 100 ppm 80 60 Figure A14.46 13C NMR (101 MHz, CDCl3) of compound 280 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 729 10 9 8 6 5 ppm 4 3 Figure A14.47 1H NMR (400 MHz, CDCl3) of compound 281 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 730 200 180 160 120 100 ppm 80 60 Figure A14.48 13C NMR (101 MHz, CDCl3) of compound 281 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 731 10 9 8 6 5 ppm 4 3 Figure A14.49 1H NMR (400 MHz, CDCl3) of compound 282 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 732 200 180 160 120 100 ppm 80 60 Figure A14.50 13C NMR (101 MHz, CDCl3) of compound 282 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 733 10 9 8 6 5 ppm 4 3 Figure A14.51 1H NMR (400 MHz, CDCl3) of compound 291 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 734 200 180 160 120 100 ppm 80 60 Figure A14.52 13C NMR (101 MHz, CDCl3) of compound 291 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 735 10 9 8 6 5 ppm 4 3 Figure A14.53 1H NMR (400 MHz, CDCl3) of compound 295 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 736 200 180 160 120 100 ppm 80 60 Figure A14.54 13C NMR (101 MHz, CDCl3) of compound 295 140 40 20 0 Appendix 14 – Spectra Relevant Appendix 13 737 10 9 8 6 5 ppm 4 3 Figure A14.55 1H NMR (400 MHz, CDCl3) of compound 296 7 2 1 0 Appendix 14 – Spectra Relevant Appendix 13 738 Appendix 15 – Notebook Cross-Reference for New Compounds 739 APPENDIX 15 Notebook Cross-Reference for New Compounds The following notebook cross-reference provides the file name for all original spectroscopic data obtained for new compounds presented within this thesis. The information is organized by chapter or appendix and sequentially by compound number. All 1H NMR, 13C NMR, as well as 19F NMR and any two-dimensional NMR data, if applicable, are electronically stored on the Caltech NMR laboratory server (mangia.caltech.edu, most typically under the usernames ‘sshockle’, ‘chethcox’, or ‘jholder’) and on the Stoltz group server. Electronic copies of all IR spectra can also be found on the Stoltz group server. All laboratory notebooks are stored in the Stoltz group archive. 740 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.1 Notebook cross-reference for compounds in Chapter 1 Compound 1H NMR 13C NMR IR JCH-III-163BpHPLC-fract2 JCH-III-163BpHPLC-fract2 JCH-III-155A -pHPLC-fract3 (major-diast) SES-IX-Me_ester_ minor_dr SES-IX-Me_ester_ minor_dr SES-IX-Me_Esterminor-dr JCH-III-163BpHPLC-fract3 JCH-III-163BpHPLC-fract3 JCH-III-155A -pHPLC-fract3 (linear) SES-VIII-235 -pTLC SES-VIII-235 -pTLC SES-VIII-235 -pTLC SES-IX-199-isco2 -fract3 SES-IX-199-isco2 -fract3 SES-IX-199 OEt SES-IX-233B -fract1-redo SES-IX-233B -fract1-redo SES-IX-233B -fract1 OEt SES-IX-237A -fract1 SES-IX-237A -fract1 SES-IX-237A -fract1 OEt SES-IX-237B -repurified SES-IX-237B -repurified SES-IX-237B -fract1 JCH-III-131 -p_2 JCH-III-131 -p_2 ch3131p Chemical Structure O 54 CO2Me O epi-54 CO 2Me O 55 CO2Me O O 56b O O O 56c O TMS O O 56e Me 2N O 56g O O2N O O 56h Br O 56k O 741 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-IX-197A-d1 SES-IX-197A-d1 SES-IX-229B SES-IX-243A-d1 SES-IX-243A-d1 SES-IX-245 SES-IX-239D-d1 SES-IX-239D-d1 SES-IX-239D JCH-III-217B-d1 -dry-real JCH-III-217B-d1 -dry-real SES-IX-239F-d1 SES-IX-239G-d1 SES-IX-239G-d1 SES-IX-239G JCH-III-217A-d1 JCH-III-217A-d1 JCH-III-217A-d1 SES-IX-239J -HPLC-1 SES-IX-239J -HPLC-1 SES-IX-239J SES-IX-239I-d1 SES-IX-239I-d1 SES-IX-239I JCH-III-217D-d1-dry JCH-III-217D-d1-dry SES-IX-239H-d1 O 58a CO2Et O 58b CO2i-Pr O 58c CO2CH2CH2TMS O 58d CO2Et MeO O 58e CO2Et Me 2N O 58f MeO CO2Et O 58g O2N CO2Et O 58h CO2Et Br O 58i CO2Et 742 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-IX-239K-d1 SES-IX-239K-d1 SES-IX-239K-d1 JCH-III-173F-2&3 JCH-III-173F-2&3 JCH-III-173F JCH-III-249 JCH-III-249 JCH-III-249 JCH-III-253 JCH-III-253 JCH-III-253 JCH-III-267-fract1 JCH-III-267-fract1 JCH-III-267 JCH-III-255 JCH-III-255 JCH-III-255 JCH-III-243p JCH-III-243p JCH-III-243 SES-IX-269 -repurified SES-IX-269 -repurified SES-IX-269 O 58j CN O 58k C(O)Me 61 HO CO2Et HO 62 CO2Et OH OH 63 HO CO2Et OH 64 OH OO O 65 OH O 66 CO2Et 743 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.2 Notebook cross-reference for compounds in Chapter 2 Compound Chemical Structure NC 1H NMR 13C NMR IR SES-IX-275-fract1 SES-IX-275-fract1 JCH-IV-139 SES-X-179A-fract1 SES-X-179A-fract1 SES-X-179A SES-X-179C-fract1 SES-X-179C-fract1 SES-X-179C SES-X-183B SES-X-183B-fract1 SES-X-183B JCH-IV-189A JCH-IV-189A JCH-IV-163B JCH-IV-197B -fract3 JCH-IV-197B -fract3 JCH-IV-163C JCH-IV-217A JCH-IV-217A JCH-IV-217A SES-X-185C-fract1 JCH-IV-163A JCH-IV-163A OMOM NC 69c OCO 2Me 70e Cl OCO 2Me 70f O O MeO 70g OCO 2Me MeO OMe NC OMOM NC 71a Br NC OMOM NC 71b CF3 NC OMOM NC 71c F NC OMOM NC 71d OMe 744 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR JCH-IV-189B JCH-IV-189B JCH-IV-189B JCH-IV-189D JCH-IV-189D JCH-IV-189D JCH-IV-189C JCH-IV-189C JCH-IV-189C JCH-IV-217B JCH-IV-217B JCH-IV-217B JCH-IV-189E JCH-IV-189E JCH-IV-163D SES-X-169H -fract2 SES-X-169H -fract2 SES-X-169H JCH-IV-131B JCH-IV-131B JCH-IV-131B SES-X-169G SES-X-169G SES-X-169G OMOM NC NC 71e Cl OMOM NC NC 71f O O NC OMOM NC 71g MeO OMe OMe NC OMOM NC 71h NC OMOM NC 71i NC OMOM NC 71j N NC 71k OMOM NC O NC 71l OMOM NC S 745 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.3 Notebook cross-reference for compounds in Chapter 3 Compound Chemical Structure NC 13C NMR IR JCH-VI-35prepHPLC JCH-VI-35prepHPLC JCH-V-131A JCH-V-93-fract1 JCH-V-93-fract1 JCH-V-93 SES-XI-131B SES-XI-131B SES-XI-131B SES-XI-67Cfract1 SES-XI-67Cfract1 SES-XI-67C SES-XI-109Ifract1 SES-XI-109Ifract1 SES-XI-109I SES-XI-59Afract1 SES-XI-59Afract1 SES-XI-59A JCH-V-185B JCH-V-185B JCH-V-185B SES-XI-109Gfract1 SES-XI-109Gfract1 SES-XI-109G OMOM NC 73 1H NMR 74 OCO 2Me OCO 2Me 76c F OCO 2Me 76f OCO 2Me OCO 2Me 76g Br OCO 2Me 76h NO 2 OCO 2Me 76i 76k OCO 2Me 746 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR JCH-V-155B JCH-V-155B JCH-V-155B JCH-V-155C JCH-V-155C JCH-V-155C SES-XI-103BA SES-XI-103BA SES-XI-103B JCH-V-175D JCH-V-175D JCH-V-175D SES-XI-197AA-top SES-XI-197AA-top SES-XI-197A SES-XI-115C SES-XI-115C SES-XI-115C JCH-V-155E JCH-V-155E JCH-V-155E SES-XI-155GA SES-XI-155GA SES-XI-155H O HO 77b Cl O HO 77c F O HO 77d F 3C O HO 77e O HO 77f OH O HO 77g Br O HO 77h NO 2 O HO 77i 747 Appendix 15 – Notebook Cross-Reference for New Compounds 1H NMR 13C NMR IR JCH-V-155D JCH-V-155D JCH-V-155D 77k SES-XI-155Afract1-conc SES-XI-155Afract1-conc SES-XI-155Afract1 78b SES-XI-71Bfract1 SES-XI-71Bfract1 SES-XI-71B Compound Chemical Structure O HO 77j O HO OCO 2Me 78c OCO 2Me JCH-VI-35fract1-bottom JCH-VI-35fract1-bottom JCH-VI-35 78e OCO 2Me JCH-V-263fract1 JCH-V-263fract1 JCH-V-263 Et SES-XI-155Dfract1 SES-XI-155Dfract1 JCH-V-155J n-Bu SES-XI-179Cfract2 SES-XI-179Cfract2 JCH-V-155K SES-XI-119Jfract1 SES-XI-119Jfract1 JCH-V-155O O 79a HO O 79b HO O 79f HO Ph 748 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-XI-149fract2 SES-XI-149fract2 SES-XI-149fract2 JCH-V-297-2fract4 JCH-V-297-2fract4 JCH-V-297 SES-XI-147fract4 SES-XI-147fract4 SES-XI-147fract4 JCH-V-299-2fract1 JCH-V-299-2fract1 JCH-V-299 JCH-V-255 JCH-V-255 JCH-V-255 JCH-VI-19fract2-dry JCH-VI-19fract2-dry JCH-VI-19 JCH-VI-27fract2 JCH-VI-27fract2 JCH-VI-27 SES-XI-61Dfract1 SES-XI-61Dfract1 SES-XI-61D SES-XI-105Ifract1 SES-XI-105Ifract1 SES-XI-105I O MeO 82 Cl O O 83 Cl O N 84 Cl O N H 85 Cl O MeO 86 Cl O O 88 Cl OH O MeO O H 89 Cl OMe 90 O O H OMe O 91 Br 749 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.4 Notebook cross-reference for compounds in Chapter 4 Compound Chemical Structure 1H NMR 13C NMR IR SES-XII-43A SES-XII-43A JCH-VI-179fract1 SES-XII-193C SES-XII-95Bfract1 SES-XII-95Dfract1 SES-XII-95Dfract1 SES-XII-83Bfract1 SES-XII-153Bfract1 SES-XII-153Bfract1 SES-XII-151C JCH-VI-183Bfract1 JCH-VI-183Bfract1 JCH-VI-183B SES-XII-95Cfract1 SES-XII-95Cfract1 SES-XII-83Cfract2 SES-XII-185Afract1 SES-XII-185Afract1 SES-XII-185A JCH-VII-33Afract1 JCH-VII-33Afract1 JCH-VII-33A NC 93 NC Ph NC 95a Et NC Ph NC 95b SES-XII-83Afract2 Bn NC Ph NC 95d NC Ph 95e NC NC Ph O 95f NC NC Ph CF3 95g NC NC Ph OCO2Me 96b MeO 750 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure OCO2Me 96c 1H NMR 13C NMR IR JCH-VII-33Bfract1 JCH-VII-33Bfract1 JCH-VII-33B JCH-VI-293Cfract1 JCH-VI-293Cfract1 JCH-VI-293C SES-XII-167Bfract1 SES-XII-167Bfract1 JCH-VI-279E SES-XII-191Bfract1-redo SES-XII-191Bfract1-redo SES-XII-191Bredo SES-XII-191Afract1 SES-XII-191Afract1 SES-XII-191A JCH-VI-277Ffract1 JCH-VI-277Ffract1 JCH-VI-275H SES-XII-97Cfract1 SES-XII-97Cfract1 SES-XII-97Cfract1 SES-XII-187Dfract1 SES-XII-187Dfract1 SES-XII-187D SES-XII-157Afract1 SES-XII-157Afract1 SES-XII-155A Ph OCO2Me 96f Cl NC NC 97a NC NC 97b MeO NC NC 97c Ph NC NC 97d F NC NC 97e NC NC 97f Cl NC NC 97g NO 2 751 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-XII-97Dfract1 SES-XII-97Dfract1 SES-XII-97Dfract1 SES-XII-193Bfract1 SES-XII-193Bfract1 SES-XII-195A SES-XII-193Afract1 SES-XII-193Afract1 SES-XII-193Aair SES-XII-97Gfract1 SES-XII-97Gfract1 SES-XII-97Gfract1 SES-XII-197fract1 SES-XII-197fract1 SES-XII-197 JCH-VII-61 JCH-VII-61 JCH-VII-61 JCH-VII-75fract1 JCH-VII-75fract1 JCH-VII-75 JCH-VI-215top JCH-VI-215top JCH-VI-115fract2 JCH-VII-37fract1 JCH-VII-37fract1 JCH-VII-37 NC NC 97h NC NC 97j Ph NC 97k NC NC 97l NC Ph Et NC 101 NC Ph NC 102 NC O Ph O NC 103 NC Ph O NC O 104 Ph NC 105 NC Ph Ph 752 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.5 Notebook cross-reference for compounds in Appendix 8 Compound Chemical Structure 1H NMR 13C NMR IR JCH-X-167 JCH-X-167 JCH-X-167 SES-III-85-fract2 SES-III-85-fract2 SES-Piv Iodo CA SES-II-119-fract2 & SES-II-143-fract1 SES-II-119-fract2 & SES-II-143-fract1 SES-BromoPiv CA SES-1-119 chiralcharc SES-1-119 chiralcharc SES-chloro Piv CA SES-III-129fract1 SES-III-129fract1/2 SES-Qins Intermediate JCH-V-125 & JCH-X-bispiv_13C JCH-V-125 & JCH-X-bispiv_13C JCH-V-125 & JCH-X-bispiv_13C JCH-X-165Bpin JCH-X-165Bpin JCH-X-165Bpin JCH-Acyl B(OH)2 & JCH-X-167 JCH-Acyl B(OH)2 & JCH-X-167 JCH-Acyl B(OH)2 & JCH-X-167 O OPiv 169b O OPiv O OPiv 169c I OPiv O OPiv 169d Br OPiv O OPiv 169e Cl OPiv O 169f OMe O 197 PivO OPiv O PivO OPiv 198 O B O O PivO OPiv 199 B(OH) 2 753 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR JCH-X-189A JCH-X-189A JCH-X-189A JCH-tricycle & JCH-X-215-A JCH-tricycle & JCH-X-215-A JCH-tricycle & JCH-X-215-A SES-II-125 SES-II-125 SES-Bromo Piv SES-II-127-crystals SES-II-127-crystals SES-Bromo PivBPin SES-III-65 SES-III-65 SES-Bromo PivB(OH)2 SES-II-17-fract2 SES-II-17-fract2 SES-isopropenyl MonoPiv SES-III-109 -fract1 SES-III-109 -fract1/2 SES-Nf Piv isopropenyl SES-III-127B -fract1 SES-III-127B -fract1 SES-monopiv isopropyl OH 202 O HO OH Br OMe 203 O HO OMe Br 205 PivO OPiv Br PivO OPiv 206 O B O Br PivO OPiv 207 B(OH) 2 O OH 208 OPiv O ONf 209 OPiv O 210 OPiv 754 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-1-137 SES-1-137 SES-chloroPiv SES-1-203 SES-1-203 SES-Piv Iodo SES-II-91 SES-II-91 SES-Piv Chloro BPin SES-1-205 SES-1-205 SES-Piv Iodo BPin SES-II-79 SES-II-79 SES-ChloroPiv B(OH)2 SES-1-207Bsolid SES-1-207Bsolid SES-Piv Iodo B(OH)2 Cl 211 PivO OPiv I 212 PivO OPiv Cl PivO OPiv 213 O B O I PivO OPiv 214 O B O Cl PivO OPiv 215 B(OH) 2 I PivO OPiv 216 B(OH) 2 755 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.6 Notebook cross-reference for compounds in Appendix 11 Compound Chemical Structure O 1H NMR 13C NMR IR SES-XI-207 -fract2 SES-XI-207 -fract2 SES-XI-207 SES-XI-213pTLC SES-XI-213pTLC JCH-VI-39A (mislabeled) JCH-VI-41pTLC JCH-VI-41pTLC JCH-VI-41 SES-XI-215A SES-XI-215A SES-XI-215A SES-XI-215B SES-XI-215B SES-XI-215B SES-XI-217C SES-XI-217C SES-XI-217C JCH-VI-45Afract1 JCH-VI-45Afract1 JCH-VI-45A JCH-VI-43B JCH-VI-43B JCH-VI-43B JCH-VI-45Cfract1 JCH-VI-45Cfract1 JCH-VI-45C O O 218a O O O O O 218b O O O O BzN O 218c O O O 219a O O O 219b O O O BzN 219c O O O 220a O O 220b O O 220c BzN O 756 Appendix 15 – Notebook Cross-Reference for New Compounds Table A15.7 Notebook cross-reference for compounds in Appendix 13 Compound 226 Chemical Structure BnO OCO 2Me 1H NMR 13C NMR IR SES-III-287-fract1 – – SES-III-293 -fract1 SES-III-293 -fract1 – SES-V-153-fract1 SES-V-153-fract1 – SES-V-41 -fract3 SES-V-41 -fract3 – SES-V-275 -fract1-redo SES-V-275 -fract1-redo – SES-V-251-fract1 SES-V-251-fract1 – SES-VIII-129 -fract1 SES-VIII-129 -fract1 – SES-XI-249FprepHPLC-fract2 SES-XI-249FprepHPLC-fract2 – SES-VI-131135-fract2 SES-VI-131135-fract2 – O 233 NBoc O O 234 O OMe BocHN OTBS OBn O 235 NBoc O BnO O O 237 O BocHN O O O 238 BocHN 240 LG = Cl BnO Cl OBn O 241 NH O HO OBn O 243 O HO O NH 757 Appendix 15 – Notebook Cross-Reference for New Compounds Compound Chemical Structure 1H NMR 13C NMR IR SES-VI-121 -fract1 SES-VI-121 -fract1 – SES-VI-219 -fract3 SES-VI-219 -fract3 – SES-VI-215 -prepB SES-VI-215 -prepB – JCH-V-35-fract3 JCH-V-35-fract3 SES-XI-15 -bottom SES-XI-239 -fract1 & SES-XI-21-fract2 SES-XI-21 -fract2 – SES-VII-209 -pTLC-middle – – SES-VII-223 -rac-fract1 SES-VII-223 -rac-fract1 – SES-XI-255 -fract2 & JCH-VI-91 SES-XI-255 -fract2 & JCH-VI-91 JCH-VI-91 OBn O 244 NH O O OBn O 245 NH O O OBn HO H O 247 NH O O OBn O 248 NH HO HO OBn O 249 NH O HO O O 256 Et O NpMBz O O Et O NpMBz O 257 O O 258 O N O O OMe 758 Appendix 15 – Notebook Cross-Reference for New Compounds Compound 1H NMR 13C NMR IR SES-XI-257 -fract1 – – SES-VII-263 -redo-fract2 – – NpMBz SES-XI-283 -fract1 SES-XI-283 -fract1 SES-XI-283 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Res. 2014, 47, 2558–2573. 788 INDEX γ γ-butyrolactone ................................................................................................ 26, 211, 464, 632 π π-allyl ........................................................... 3, 19, 140, 141, 164, 328, 366, 450, 454, 458, 463 A acyclic.......................................... 7–11, 201, 202, 326, 327, 335, 449, 450, 457, 460–426, 465 aldol ................................. 16, 334, 464, 472, 489, 493, 497, 627, 628, 634, 636, 637, 639, 641 alkyne ...................................................................................................................... 24, 145, 332 C carbocation ...................................................................................................... 19, 447, 450, 630 carbon monoxide ................................................................................................... 141, 146, 455 carboxylic acid ............... 201, 202, 206, 210, 223, 224, 233, 249, 318, 319, 455, 456, 460–462 CBS ................................................................................................................ 641–643, 673, 676 chelation/chelating ............................................................................................................... 9, 10 cocatalyst ........................................................................................................... 16, 17, 458, 465 Cope ...................................................................................................................................... 448 Corey–Chaykovsky ................................................................................................................... 26 counterion .................................................................................................................. 11, 27, 481 cyanohydrin ................................................................................................................... 648, 686 cyclopentene .................................................................................................................. 334, 464 D DABCO .............................. 9, 328, 330, 331, 333, 335, 341, 366, 463, 470, 630, 631, 633, 634 decarboxylative .............................................................................................. 636, 637, 641, 642 Dieckmann..................................................................................................................... 645, 646 Diels–Alder ............................................................................................................ 627, 640, 647 dihydroxylation ................................................................................................................ 26, 210 789 E enolate ............................ 1, 2, 7–10, 12–15, 140, 165, 445, 446, 449, 450, 452, 454, 627, 636, 637, 640, 649 epoxidation .............................................................................................................................. 26 G Grignard ................................................................................................................................... 26 H hemiacetal.............................................................................. 632, 634, 635, 657, 658, 659, 661 heteroaryl/heteroaromatic....................................................... 9–13, 15, 146, 208, 447, 449, 456 hydrogenation ........................................................................................................ 210, 334, 496 hydrolysis ....................................................................................................... 206–208, 460, 491 I iridicycle ........................................................................................................ 204, 205, 460, 470 K Knoevenagel........................................................................................................................... 629 L lactam .............. 24, 592, 627, 632, 633, 636–638, 640, 643–645, 647–649, 663, 665, 666, 678 lactamization.................................................................................................................. 631, 632 lactonization .................................................................................................................... 26, 211 Lewis acid ...................................................................................... 203, 222, 458, 459, 465, 483 M methyl vinyl ketone ........................................................................................................ 592, 593 Michael .......................................................................................................................... 479, 590 O one-pot........................................................................... 210, 211, 233, 460, 461, 593, 594, 632 790 ozonolysis .............................................................. 211, 334, 464, 629, 636, 637, 639, 641–643 P palladium ................. 1, 17, 18, 22, 325, 326, 334, 441–443, 467, 472–477, 479–481, 483–490, 493, 494, 498, 508, 528, 590–593, 599, 600, 636–642, 649, 681 piperidine ......................................................................................................................... 36, 640 piperidone ........................................................................ 24, 640–643, 649, 671, 672, 674, 675 poison ...................................................................................................................... 24, 482, 484 preparatory scale ............................................................................................................ 146, 153 prochiral............................................................... 2, 7–10, 12, 27, 212, 326, 442, 443, 445, 452 propargyl .............................................................................................................. 9, 24, 145, 209 proton sponge .............................................................. 20, 21, 23, 25, 27, 36, 38, 451–453, 634 R rhodium ................................................................................................................. 474, 475, 487 ring-closing metathesis/RCM .................................................... 26, 590, 591, 593, 594, 644–646 S silver .................................................................................................................................. 11, 12 steric/sterically........................... 3, 5, 11, 16, 144, 205, 206, 208, 327, 329, 332, 334, 445, 452, 456, 462, 464, 465, 485, 491, 495, 496, 593, 630, 638, 639 T triethylborane ................................................................................................. 203, 211, 335, 459 W Wacker................................................................................................................... 472, 634, 635 791 ABOUT THE AUTHOR Samantha Elizabeth Shockley was born in Birmingham, Alabama on February 6th, 1990 to Susan and Edward Shockley. Sam grew up in Gainesville, Florida with her older brother Matthew Shockley. In the fall of 2008, Sam moved to Chicago, Illinois to attend the University of Chicago. Despite her initial intention to study Egyptology, she graduated with B.S. degrees in chemistry and biochemistry and a B.A. in biology. While in college, she performed undergraduate research on zirconocene-catalyzed C–H functionalization under the guidance of Professor Richard Jordan. Following her undergraduate education, Sam moved to Canberra, Australia to conduct a yearlong U.S. Fulbright research grant at the Australian National University in the laboratory of Professor Martin Banwell. During this time, she investigated the design and synthesis of lipophilic analogues of lamellarin W. Upon returning to the States, Sam moved to Pasadena, California to pursue her doctoral studies at the California Institute of Technology with Professor Brian Stoltz. Her graduate work has focused on the development of enantioselective transition metal catalysis and natural product total synthesis. Upon completion of her doctoral research in May 2018, Sam will begin her professional career as a medicinal chemist at Merck, South San Francisco.