Stereoselective Synthesis of Diazaheterocycles by Decarboxylative Asymmetric Allylic Alkylation Citation Sun, Alexander Wang (2019) Stereoselective Synthesis of Diazaheterocycles by Decarboxylative Asymmetric Allylic Alkylation. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/E2YS-GJ06. https://resolver.caltech.edu/CaltechTHESIS:05132019-140157302 Abstract The Stoltz group has developed transition-metal catalyzed methods to synthesize quaternary and tetrasubstituted stereocenters over the past fourteen years. Using iridium, palladium, copper, and nickel, the group has synthesized a myriad cyclic and acylic quaternary motifs of incredible synthetic and medicinal utility. This thesis presents several projects that further expand the scope of Pd-catalyzed decarboxylative allylic alkylation and examine its applications to the synthesis of medicinally important small molecules. The synthesis of chiral gem -disubstituted five-, six-, and seven-membered diazaheterocycles is presented. Their utility as building blocks for complex medicinal compounds is highlighted. Then, we explore the utility of gem-disubstituted heterocycles in the context of medicinal chemistry. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Heterocycle, allylic alkylation, allylation, palladium, quaternary center 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: Dervan, Peter B. (chair) Grubbs, Robert H. Davis, Mark E. Stoltz, Brian M. Defense Date: 19 April 2019 Funders: Funding Agency Grant Number NIH F30GM120836 Record Number: CaltechTHESIS:05132019-140157302 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05132019-140157302 DOI: 10.7907/E2YS-GJ06 Related URLs: URL URL Type Description https://doi.org/10.1039/C8SC03967D DOI Communication adapted for Chapter 1. ORCID: Author ORCID Sun, Alexander Wang 0000-0001-6639-4469 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 11513 Collection: CaltechTHESIS Deposited By: Alexander Sun Deposited On: 15 May 2019 18:53 Last Modified: 08 Nov 2023 00:39 Thesis Files Preview PDF - Final Version See Usage Policy. 31MB Repository Staff Only: item control page

STEREOSELECTIVE SYNTHESIS OF DIAZAHETEROCYCLES BY DECARBOXYLATIVE ASYMMETRIC ALLYLIC ALKYLATION Thesis by Alexander W. Sun In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2019 (Defended April 19, 2019) ii © 2019 Alexander W. Sun ORCID: 0000-0001-6639-4469 All Rights Reserved iii To mom & dad, for their unconditional love & support iv ACKNOWLEDGEMENTS Caltech is a special place. I’ve been incredibly fortunate to pursue my graduate studies here. Where else can one meet so many talented people from so many disciplines—chemistry, biology, engineering, physics, computer science, math—all just a short walk away? It’s been a pleasure to meet and learn from these true Techers. At Caltech, I met my amazing advisor, Professor Brian M. Stoltz; you may have heard Brian is a compassionate mentor, an affable person, and a brilliant chemist. This is all true. Thank you Brian, for all the time, effort, and support you’ve put into mentoring me over the past five years. It has been an honor to work in your research group. Additionally, thank you to the Caltech faculty and staff who have influenced my career path: thank you Professor Peter Dervan for chairing my committee and for allowing me to spend a summer in your research group. Thank you Professor Mark Davis and Professor Bob Grubbs for serving on my committee. Thank you Dr. Scott Virgil, Professor Sarah Reisman, Professor Greg Fu, and Professor Alison Ondrus, for your support and guidance throughout my graduate studies. Furthermore, I am very grateful for Dr. David VanderVelde and all his NMR assistance. Thank you Joe Drew, Agnes Tong, Alison Ross, and the entire CCE staff for maintaining the division. At Caltech, I met the many members of the Stoltz group; there are dozens (by my count, at least 110 Stoltz members) that I’ve interacted with over the years. Postdocs, visiting scholars, graduate students, undergraduates, even high schoolers. They are a truly talented group of chemists in which I’ve had great fortune to learn v from. Thank you all for being great labmates. Specifically, I’d like to acknowledge the following individuals in which I’ve collaborated with on projects or mentored as undergraduates/high schoolers: Dr. Marchello Cavitt, Stephan N. Hess, Dr. Brendan O’ Boyle, Dr. Gerit Pototschnig, Zachary P. Sercel, Ryan Dempsey, Yuanzhe Xie, and Angus Wu. The members of the Reisman, Fu, and Peters groups, who occupy the rest of the second and third floors of Schlinger (and the members of the Grubbs lab) have also been great people interact with and learn from. Apart from Caltech, I have many others to thank: My parents, for their love, support, and sacrifice without which I could not have progressed to where I am today. My undergraduate research advisors Professor David R. Tyler and Professor Amos B. Smith—their support and guidance have shaped the research path I’ve taken so far. Professor Neil K. Garg, for allowing me to work in his lab over a summer. Yoyo Luo, for her love and support throughout graduate school. The many students, faculty, and administrators of the UCLA-Caltech Medical Scientist Training Program, and especially the entering class of 2012—thank you for your support and friendship. Much of the chemistry in this thesis chemistry would not have happened in the absence of the individuals mentioned above, as well as many others—thank you. vi ABSTRACT The Stoltz group has developed transition-metal catalyzed methods to synthesize quaternary and tetrasubstituted stereocenters over the past fourteen years. Using iridium, palladium, copper, and nickel, the group has synthesized a myriad cyclic and acylic quaternary motifs of incredible synthetic and medicinal utility. This thesis presents several projects that further expand the scope of Pd-catalyzed decarboxylative allylic alkylation and examine its applications to the synthesis of medicinally important small molecules. The synthesis of chiral gem-disubstituted five-, six-, and seven-membered diazaheterocycles is presented. Their utility as building blocks for complex medicinal compounds is highlighted. Then, we explore the utility of gem-disubstituted heterocycles in the context of medicinal chemistry. vii PUBLISHED CONTENT AND CONTRIBUTIONS 1. Sun, A. Discussion Addendum for: Preparation of (S)-Tert-ButylPHOX and (S)-2Allyl-2-Methylcyclohexanone. Org. Synth. 2018, 95, 439–454. DOI: 10.15227/orgsyn.095.0439. A.W.S. led the writing of this review manuscript. 2. Sun, A. W.;‡ Hess, S. N.;‡ Stoltz, B. M. Enantioselective Synthesis of GemDisubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation. Chem. Sci. 2019, 10, 788–792. DOI: 10.1039/C8SC03967D. A.W.S. led project design, experimental work, data acquisition and analysis, and manuscript preparation. . viii TABLE OF CONTENTS Dedication ............................................................................................................................ iii Acknowledgements ............................................................................................................... iv Abstract ................................................................................................................................ vii Published Content and Contributions ................................................................................... vii Table of Contents ................................................................................................................ viii List of Figures ....................................................................................................................... xii List of Schemes ................................................................................................................. xxiii List of Tables ...................................................................................................................... xxv List of Abbreviations ......................................................................................................... xxvii CHAPTER 1 1 Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation 1.1 Introduction .................................................................................................................. 1 1.2 Piperazinone and Tetrahydropyrimidinones .................................................................. 4 1.3 Conclusions .................................................................................................... 15 1.4 Experimental Section ...................................................................................... 16 1.4.1 1.4.1.1 1.4.2 1.4.2.1 Materials and Methods ................................................................................... 16 Preparation of Known Compounds .................................................... 18 Experimental Procedures and Spectroscopic Data .......................................... 18 Procedures for the Synthesis of Piperazinone Allylic Alkylation Substrates .......................................................................................... 18 1.4.2.2 Procedures for the Synthesis of Tetrahydropyrimidinone Allylic Alkylation Substrates ........................................................................ 32 1.4.2.3 General Procedure Allylic Alkylation Optimization Screen ................ 44 1.4.2.4 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions ........................................................................................... 45 1.4.2.5 Experimental Procedures and Spectroscopic data for the Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Piperazinone Substrates ......................................................................................... 46 1.4.2.6 Experimental Procedures and Spectroscopic Data for the Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Tetrahydropyrimidinone Substrates ................................................... 56 ix 1.4.2.7 Experimental Procedure for the Gram Scale Decarboxylative Asymmetric Allylic Alkylation of Benzyl Tetrahydropyrimidinone 1.5e .......................................................................................................... 65 1.4.2.8 Experimental Procedures for the Transformations of Decarboxylative Allylic Alkylation Products ............................................................... 66 1.4.2.9 1.5 Determination of Enantiomeric Excess .............................................. 77 References and Notes ..................................................................................... 80 APPENDIX 1 Spectra Relevant to Chapter 1 89 APPENDIX 2 Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 203 A2.1 Introduction ................................................................................................. 203 A2.2 Conclusions .................................................................................................. 208 A2.3 Experimental Section .................................................................................... 209 A2.3.1 Materials and Methods .................................................................... 209 A2.3.2 Experimental Procedures and Spectroscopic Data ........................... 210 A2.3.3 Procedures for the Synthesis of Oxodiazepane Allylic Alkylation Substrates ........................................................................................ 211 A2.3.4 General Procedure for Allylic Alkylation Optimization Screen ........ 220 A2.3.5 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions ........................................................................ 220 A2.3.6 Experimental Procedures and Spectroscopic data for the PdCatalyzed Decarboxylative Asymmetric Allylic Alkylation of Oxodiazepane Substrates ................................................................ 221 A2.4 References and Notes ...................................................................... 225 APPENDIX 3 Spectra Relevant to Appendix 2 227 APPENDIX 4 Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones 254 A4.1 Introduction ................................................................................................. 254 A4.2 Synthesis of Cyclic Amino Acid Scaffolds .................................................... 258 A4.3 Decarboxylative Asymmetric Allylic Alkylation of Imidazolinones .............. 260 x A4.4 Conclusions .................................................................................................. 262 A4.5 Experimental Section .................................................................................... 263 A4.5.1 Materials and Methods .................................................................... 263 A4.5.2 Experimental Procedures and Spectroscopic Data ........................... 264 A4.5.2.1 Procedures for the Synthesis of Imidazolinone Allylic Alkylation Substrates ........................................................................................ 264 A4.5.2.2 General Procedure for Allylic Alkylation Optimization Screen ........ 271 A4.5.2.3 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions ....................................................................... 272 A4.5.2.4 Experimental Procedures and Spectroscopic data for the PdCatalyzed Decarboxylative Asymmetric Allylic Alkylation of Imidazolinone Substrates ................................................................ 272 A4.6 References and Notes ...................................................................... 274 APPENDIX 5 Spectra Relevant to Appendix 4 279 CHAPTER 2 gem-Disubstituted Morpholine Analogues of Linezolid 296 2.1 Introduction and Background ....................................................................... 296 2.2 Results .......................................................................................................... 298 2.3 Conclusions .................................................................................................. 307 2.4 Experimental Section .................................................................................... 308 2.4.1 Materials and Methods ................................................................................. 308 2.4.2 Experimental Procedures and Spectroscopic Data ........................................ 310 2.4.2.1 Determination of Absolute Configuration of 2.19a and 2.19b. ......... 310 2.4.2.2 Experimental Procedures for Biological Assays ................................ 315 2.4.2.3 Procedures and Spectroscopic Data for the Synthesis of Linezolid Analogues ....................................................................................... 317 2.4.2.4 Preparation of linezolid analogues via Cu-Catalyzed Ullman Coupling ......................................................................................... 323 2.5 References and Notes ................................................................................... 340 APPENDIX 6 Spectra Relevant to Chapter 2 346 xi APPENDIX 7 Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 384 A7.1 Introduction and Background ....................................................................... 384 A7.2 Conclusions .................................................................................................. 391 A7.3 Experimental Section .................................................................................... 391 A7.3.1 Materials and Methods .................................................................... 391 A7.3.2 Experimental Procedures and Spectroscopic Data ........................... 393 A7.3.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Tertiary Alcohol Allylic Alkylation Substrates and Corresponding Decarboxylative Alkylation Products .............. 393 A7.4 References and Notes ................................................................................... 413 Comprehensive Bibliography ............................................................................................. 790 Index .................................................................................................................................. 819 About the Author ............................................................................................................... 822 APPENDIX 8 Spectra Relevant to Chapter 7 417 xii LIST OF FIGURES CHAPTER 1 Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation Figure 1.1 Representative piperazine and piperazine-2-one pharmaceuticals and natural products ........................................................................................................... 4 Figure 1.2 Advantages of chiral gem-disubstituted piperazines .......................................... 5 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1 1 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 1.2 .................................... 64 Figure A1.3 13 Figure A1.4 1 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound 1.3b ................................. 66 Figure A1.6 13 Figure A1.7 1 Figure A1.8 Infrared spectrum (Thin Film, NaCl) of compound 1.3c ................................. 68 Figure A1.9 13 Figure A1.10 1 Figure A1.11 Infrared spectrum (Thin Film, NaCl) of compound 1.3d ................................. 70 Figure A1.12 13 Figure A1.13 1 Figure A1.14 Infrared spectrum (Thin Film, NaCl) of compound 1.3e .................................. 72 Figure A1.15 13 Figure A1.16 1 Figure A1.17 Infrared spectrum (Thin Film, NaCl) of compound 1.3f .................................. 74 Figure A1.18 13 Figure A1.19 1 Figure A1.20 Infrared spectrum (Thin Film, NaCl) of compound 1.3h ................................. 76 Figure A1.21 13 Figure A1.22 1 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 1.3i .................................. 78 Figure A1.24 13 Figure A1.25 1 Figure A1.26 Infrared spectrum (Thin Film, NaCl) of compound 1.3j ................................... 80 Figure A1.27 13 H NMR (400 MHz, CDCl3) of compound 1.2 ................................................ 63 C NMR (101 MHz, CDCl3) of compound 1.2 ............................................... 64 H NMR (400 MHz, CDCl3) of compound 1.3b .............................................. 65 C NMR (101 MHz, CDCl3) of compound 1.3b ............................................ 66 H NMR (400 MHz, CDCl3) of compound 1.3c .............................................. 67 C NMR (101 MHz, CDCl3) of compound 1.3c ............................................ 68 H NMR (400 MHz, CDCl3) of compound 1.3d .............................................. 69 C NMR (101 MHz, CDCl3) of compound 1.3d ............................................ 70 H NMR (400 MHz, CDCl3) of compound 1.3e ............................................. 71 C NMR (101 MHz, CDCl3) of compound 1.3e ............................................. 72 H NMR (400 MHz, CDCl3) of compound 1.3f ............................................... 73 C NMR (101 MHz, CDCl3) of compound 1.3f ............................................. 74 H NMR (400 MHz, CDCl3) of compound 1.3h .............................................. 75 C NMR (101 MHz, CDCl3) of compound 1.3h ............................................ 76 H NMR (400 MHz, CDCl3) of compound 1.3i ............................................... 77 C NMR (101 MHz, CDCl3) of compound 1.3i ............................................. 78 H NMR (400 MHz, CDCl3) of compound 1.3j ............................................... 79 C NMR (101 MHz, CDCl3) of compound 1.3j .............................................. 80 xiii Figure A1.28 1 Figure A1.29 Infrared spectrum (Thin Film, NaCl) of compound 1.3k .................................. 82 Figure A1.30 13 Figure A1.31 1 Figure A1.32 Infrared spectrum (Thin Film, NaCl) of compound 1.3l ................................... 84 Figure A1.33 13 Figure A1.34 1 Figure A1.35 Infrared spectrum (Thin Film, NaCl) of compound 1.3m ................................. 86 Figure A1.36 13 Figure A1.37 1 Figure A1.38 Infrared spectrum (Thin Film, NaCl) of compound 1.4a .................................. 88 Figure A1.39 13 Figure A1.40 1 Figure A1.41 Infrared spectrum (Thin Film, NaCl) of compound 1.4b .................................. 90 Figure A1.42 13 Figure A1.43 1 Figure A1.44 Infrared spectrum (Thin Film, NaCl) of compound 1.4c .................................. 92 Figure A1.45 13 Figure A1.46 1 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 1.4d .................................. 94 Figure A1.48 13 Figure A1.49 1 Figure A1.50 Infrared spectrum (Thin Film, NaCl) of compound 1.4e .................................. 96 Figure A1.51 13 Figure A1.52 1 Figure A1.53 Infrared spectrum (Thin Film, NaCl) of compound 1.4f ................................... 98 Figure A1.54 13 Figure A1.55 1 Figure A1.56 Infrared spectrum (Thin Film, NaCl) of compound 1.4h ................................ 100 Figure A1.57 13 Figure A1.58 1 Figure A1.59 Infrared spectrum (Thin Film, NaCl) of compound 1.4i ................................. 102 Figure A1.60 13 Figure A1.61 1 Figure A1.62 Infrared spectrum (Thin Film, NaCl) of compound 1.4j ................................. 104 Figure A1.63 13 Figure A1.64 1 Figure A1.65 Infrared spectrum (Thin Film, NaCl) of compound 1.4k ................................ 106 H NMR (400 MHz, CDCl3) of compound 1.3k .............................................. 81 C NMR (101 MHz, CDCl3) of compound 1.3k ............................................. 82 H NMR (400 MHz, CDCl3) of compound 1.3l ............................................... 83 C NMR (101 MHz, CDCl3) of compound 1.3l .............................................. 84 H NMR (400 MHz, CDCl3) of compound 1.3m ............................................. 85 C NMR (101 MHz, CDCl3) of compound 1.3m ............................................ 86 H NMR (400 MHz, CDCl3) of compound 1.4a .............................................. 87 C NMR (101 MHz, CDCl3) of compound 1.4a ............................................. 88 H NMR (400 MHz, CDCl3) of compound 1.4b .............................................. 89 C NMR (101 MHz, CDCl3) of compound 1.4b ............................................. 90 H NMR (400 MHz, CDCl3) of compound 1.4c .............................................. 91 C NMR (101 MHz, CDCl3) of compound 1.4c ............................................. 92 H NMR (400 MHz, CDCl3) of compound 1.4d .............................................. 93 C NMR (101 MHz, CDCl3) of compound 1.4d ............................................. 94 H NMR (400 MHz, CDCl3) of compound 1.4e .............................................. 95 C NMR (101 MHz, CDCl3) of compound 1.4e ............................................. 96 H NMR (400 MHz, CDCl3) of compound 1.4f ............................................... 97 C NMR (101 MHz, CDCl3) of compound 1.4f .............................................. 98 H NMR (400 MHz, CDCl3) of compound 1.4h .............................................. 99 C NMR (101 MHz, CDCl3) of compound 1.4h ........................................... 100 H NMR (400 MHz, CDCl3) of compound 1.4i ............................................. 101 C NMR (101 MHz, CDCl3) of compound 1.4i ............................................ 102 H NMR (400 MHz, CDCl3) of compound 1.4j ............................................. 103 C NMR (101 MHz, CDCl3) of compound 1.4j ............................................ 104 H NMR (400 MHz, CDCl3) of compound 1.4k ............................................ 105 xiv Figure A1.66 13 Figure A1.67 1 Figure A1.68 Infrared spectrum (Thin Film, NaCl) of compound 1.4l ................................. 108 Figure A1.69 13 Figure A1.70 1 Figure A1.71 Infrared spectrum (Thin Film, NaCl) of compound 1.4m ............................... 110 Figure A1.72 13 Figure A1.73 1 Figure A1.74 Infrared spectrum (Thin Film, NaCl) of compound 1.5a ................................ 112 Figure A1.75 13 Figure A1.73 1 Figure A1.74 Infrared spectrum (Thin Film, NaCl) of compound 1.5b ................................ 112 Figure A1.75 13 Figure A1.76 NOESY (400 MHz, CDCl3) of compound 1.5c .............................................. 113 Figure A1.77 1 Figure A1.78 Infrared spectrum (Thin Film, NaCl) of compound 1.5c ................................ 115 Figure A1.79 13 Figure A1.80 1 Figure A1.81 Infrared spectrum (Thin Film, NaCl) of compound 1.5d .................................. 82 Figure A1.82 13 Figure A1.83 1 Figure A1.84 Infrared spectrum (Thin Film, NaCl) of compound 1.5e .................................. 84 Figure A1.85 13 Figure A1.86 1 Figure A1.87 Infrared spectrum (Thin Film, NaCl) of compound 1.5f ................................... 86 Figure A1.88 13 Figure A1.89 1 Figure A1.90 Infrared spectrum (Thin Film, NaCl) of compound 1.5g .................................. 88 Figure A1.91 13 Figure A1.92 1 Figure A1.93 Infrared spectrum (Thin Film, NaCl) of compound 1.5h .................................. 90 Figure A1.94 13 Figure A1.95 1 Figure A1.96 Infrared spectrum (Thin Film, NaCl) of compound 1.5i ................................... 92 Figure A1.97 13 Figure A1.98 1 Figure A1.99 Infrared spectrum (Thin Film, NaCl) of compound 1.6a .................................. 94 Figure A1.100 13 C NMR (101 MHz, CDCl3) of compound 1.4k ........................................... 106 H NMR (400 MHz, CDCl3) of compound 1.4l ............................................. 107 C NMR (101 MHz, CDCl3) of compound 1.4l ............................................ 108 H NMR (400 MHz, CDCl3) of compound 1.4m ........................................... 109 C NMR (101 MHz, CDCl3) of compound 1.4m .......................................... 110 H NMR (400 MHz, CDCl3) of compound 1.5a ............................................ 111 C NMR (101 MHz, CDCl3) of compound 1.5a ........................................... 112 H NMR (400 MHz, CDCl3) of compound 1.5b ............................................ 111 C NMR (101 MHz, CDCl3) of compound 1.5b ........................................... 112 H NMR (400 MHz, CDCl3) of compound 1.5c ............................................ 114 C NMR (101 MHz, CDCl3) of compound 66 .............................................. 115 H NMR (400 MHz, CDCl3) of compound 1.5d .............................................. 81 C NMR (101 MHz, CDCl3) of compound 1.5e ............................................. 82 H NMR (400 MHz, CDCl3) of compound 1.5e .............................................. 83 C NMR (101 MHz, CDCl3) of compound 1.5f .............................................. 84 H NMR (400 MHz, CDCl3) of compound 1.5f ............................................... 85 C NMR (101 MHz, CDCl3) of compound 1.5g ............................................. 86 H NMR (400 MHz, CDCl3) of compound 1.5g .............................................. 87 C NMR (101 MHz, CDCl3) of compound 1.5h ............................................. 88 H NMR (400 MHz, CDCl3) of compound 1.5h .............................................. 89 C NMR (101 MHz, CDCl3) of compound 1.5i .............................................. 90 H NMR (400 MHz, CDCl3) of compound 1.5i ............................................... 91 C NMR (101 MHz, CDCl3) of compound 1.6a ............................................. 92 H NMR (400 MHz, CDCl3) of compound 1.6a .............................................. 93 C NMR (101 MHz, CDCl3) of compound 1.6b ............................................. 94 xv Figure A1.101 1 Figure A1.102 Infrared spectrum (Thin Film, NaCl) of compound 1.6b .................................. 96 Figure A1.103 13 Figure A1.104 1 Figure A1.105 Infrared spectrum (Thin Film, NaCl) of compound 1.6c .................................. 98 Figure A1.106 13 Figure A1.107 1 Figure A1.108 Infrared spectrum (Thin Film, NaCl) of compound 1.6d ................................ 100 Figure A1.109 13 Figure A1.110 1 Figure A1.111 Infrared spectrum (Thin Film, NaCl) of compound 1.6e ................................ 102 Figure A1.112 13 Figure A1.113 1 Figure A1.114 Infrared spectrum (Thin Film, NaCl) of compound 1.6f ................................. 104 Figure A1.115 13 Figure A1.116 1 Figure A1.117 Infrared spectrum (Thin Film, NaCl) of compound 1.6f ................................. 106 Figure A1.118 13 Figure A1.119 1 Figure A1.120 Infrared spectrum (Thin Film, NaCl) of compound 1.6g ................................ 108 Figure A1.121 13 Figure A1.122 1 Figure A1.123 Infrared spectrum (Thin Film, NaCl) of compound 1.6h ................................ 110 Figure A1.124 13 Figure A1.125 1 Figure A1.126 Infrared spectrum (Thin Film, NaCl) of compound 1.6i ................................. 112 Figure A1.127 13 Figure A1.128 1 Figure A1.129 Infrared spectrum (Thin Film, NaCl) of compound 1.8 .................................. 112 Figure A1.130 13 Figure A1.131 NOESY (400 MHz, CDCl3) of compound 1.9 ................................................ 113 Figure A1.132 1 Figure A1.133 Infrared spectrum (Thin Film, NaCl) of compound 1.10 ................................ 115 Figure A1.134 13 Figure A1.135 1 Figure A1.136 Infrared spectrum (Thin Film, NaCl) of compound 1.11 .................................. 82 Figure A1.137 13 Figure A1.138 1 H NMR (400 MHz, CDCl3) of compound 1.6b .............................................. 95 C NMR (101 MHz, CDCl3) of compound 1.6c ............................................. 96 H NMR (400 MHz, CDCl3) of compound 1.6c .............................................. 97 C NMR (101 MHz, CDCl3) of compound 1.6d ............................................. 98 H NMR (400 MHz, CDCl3) of compound 1.6d .............................................. 99 C NMR (101 MHz, CDCl3) of compound 1.6e ........................................... 100 H NMR (400 MHz, CDCl3) of compound 1.6e ............................................ 101 C NMR (101 MHz, CDCl3) of compound 1.6f ............................................ 102 H NMR (400 MHz, CDCl3) of compound 1.6f ............................................. 103 C NMR (101 MHz, CDCl3) of compound 1.6f ............................................ 104 H NMR (400 MHz, CDCl3) of compound 1.6f ............................................. 105 C NMR (101 MHz, CDCl3) of compound 1.6g ........................................... 106 H NMR (400 MHz, CDCl3) of compound 1.6g ............................................ 107 C NMR (101 MHz, CDCl3) of compound 1.6h ........................................... 108 H NMR (400 MHz, CDCl3) of compound 1.6h ............................................ 109 C NMR (101 MHz, CDCl3) of compound 1.6i ............................................ 110 H NMR (400 MHz, CDCl3) of compound 1.6i ............................................. 111 C NMR (101 MHz, CDCl3) of compound 1.8 ............................................. 112 H NMR (400 MHz, CDCl3) of compound 1.8 .............................................. 111 C NMR (101 MHz, CDCl3) of compound 1.9 ............................................. 112 H NMR (400 MHz, CDCl3) of compound 1.9 .............................................. 114 C NMR (101 MHz, CDCl3) of compound 1.10 ........................................... 115 H NMR (400 MHz, CDCl3) of compound 1.10 .............................................. 81 C NMR (101 MHz, CDCl3) of compound 1.11 ............................................. 82 H NMR (400 MHz, CDCl3) of compound 1.11 .............................................. 83 xvi Figure A1.139 Infrared spectrum (Thin Film, NaCl) of compound 1.12 .................................. 84 Figure A1.140 13 Figure A1.141 1 Figure A1.142 Infrared spectrum (Thin Film, NaCl) of compound 1.13 .................................. 86 Figure A1.143 13 Figure A1.144 1 Figure A1.145 Infrared spectrum (Thin Film, NaCl) of compound 1.14 .................................. 88 Figure A1.146 13 Figure A1.147 1 Figure A1.148 Infrared spectrum (Thin Film, NaCl) of compound 1.15 .................................. 90 Figure A1.149 13 Figure A1.150 1 Figure A1.151 Infrared spectrum (Thin Film, NaCl) of compound 1.15 .................................. 92 Figure A1.152 13 Figure A1.153 1 Figure A1.154 Infrared spectrum (Thin Film, NaCl) of compound 1.16 .................................. 94 Figure A1.155 13 Figure A1.156 Infrared spectrum (Thin Film, NaCl) of compound SI-3 ................................... 84 Figure A1.157 13 Figure A1.158 1 Figure A1.159 Infrared spectrum (Thin Film, NaCl) of compound SI-4 ................................... 86 Figure A1.160 13 Figure A1.161 1 Figure A1.162 Infrared spectrum (Thin Film, NaCl) of compound SI-5 ................................... 88 Figure A1.163 13 Figure A1.164 1 Figure A1.165 Infrared spectrum (Thin Film, NaCl) of compound SI-6 ................................... 90 Figure A1.166 13 C NMR (101 MHz, CDCl3) of compound 1.12 ............................................. 84 H NMR (400 MHz, CDCl3) of compound 1.12 .............................................. 85 C NMR (101 MHz, CDCl3) of compound 1.13 ............................................. 86 H NMR (400 MHz, CDCl3) of compound 1.13 .............................................. 87 C NMR (101 MHz, CDCl3) of compound 1.14 ............................................. 88 H NMR (400 MHz, CDCl3) of compound 1.14 .............................................. 89 C NMR (101 MHz, CDCl3) of compound 1.15 ............................................. 90 H NMR (400 MHz, CDCl3) of compound 1.15 .............................................. 91 C NMR (101 MHz, CDCl3) of compound 1.16 ............................................. 92 H NMR (400 MHz, CDCl3) of compound 1.16 .............................................. 93 C NMR (101 MHz, CDCl3) of compound SI-3 .............................................. 94 C NMR (101 MHz, CDCl3) of compound SI-3 .............................................. 84 H NMR (400 MHz, CDCl3) of compound SI-4 ............................................... 85 C NMR (101 MHz, CDCl3) of compound SI-4 .............................................. 86 H NMR (400 MHz, CDCl3) of compound SI-5 ............................................... 87 C NMR (101 MHz, CDCl3) of compound SI-5 .............................................. 88 H NMR (400 MHz, CDCl3) of compound SI-6 ............................................... 89 C NMR (101 MHz, CDCl3) of compound SI-6 .............................................. 90 APPENDIX 2 Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes Figure A2.1 Diazepines and diazepanes are medicinally important heterocycles ............. 117 Figure A2.2 gem-Disubstituted diazepanes can augment biological properties of small molecules .............................................................................................................................. 125 xvii APPENDIX 3 Spectra Relevant to Appendix 2 Figure A3.1 1 Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound A2S1 ............................... 170 Figure A3.3 13 Figure A3.4 1 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound A2S3 ............................... 172 Figure A3.6 13 Figure A3.7 1 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound A2S4 ............................... 174 Figure A3.9 13 Figure A3.10 1 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound A2.4f .............................. 176 Figure A3.12 13 Figure A3.13 1 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound A2.4g .............................. 178 Figure A3.15 13 Figure A3.16 1 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound A2.4h ............................. 180 Figure A3.18 13 Figure A3.19 1 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound A2.4i .............................. 182 Figure A3.21 13 Figure A3.22 1 Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound A2.4j .............................. 184 Figure A3.24 13 Figure A3.25 1 Figure A3.26 Infrared spectrum (Thin Film, NaCl) of compound A2.4l .............................. 186 Figure A3.27 13 Figure A3.28 1 Figure A3.29 Infrared spectrum (Thin Film, NaCl) of compound A2.5f .............................. 188 Figure A3.30 13 Figure A3.31 1 Figure A3.32 Infrared spectrum (Thin Film, NaCl) of compound A2.5g .............................. 190 Figure A3.33 13 Figure A3.34 1 Figure A3.35 Infrared spectrum (Thin Film, NaCl) of compound A2.5h ............................. 192 Figure A3.36 13 H NMR (400 MHz, CDCl3) of compound A2S1 ........................................... 169 C NMR (101 MHz, CDCl3) of compound A2S1 .......................................... 170 H NMR (400 MHz, CDCl3) of compound A2S3 ........................................... 171 C NMR (101 MHz, CDCl3) of compound A2S3 .......................................... 172 H NMR (400 MHz, CDCl3) of compound A2S4 ........................................... 173 C NMR (101 MHz, CDCl3) of compound A2S4 .......................................... 174 H NMR (400 MHz, CDCl3) of compound A2.4f .......................................... 175 C NMR (101 MHz, CDCl3) of compound A2.4f .......................................... 176 H NMR (400 MHz, CDCl3) of compound A2.4g .......................................... 177 C NMR (101 MHz, CDCl3) of compound A2.4g ......................................... 178 H NMR (400 MHz, CDCl3) of compound A2.4h .......................................... 179 C NMR (101 MHz, CDCl3) of compound A2.4h ......................................... 180 H NMR (400 MHz, CDCl3) of compound A2.4i ........................................... 181 C NMR (101 MHz, CDCl3) of compound A2.4i .......................................... 182 H NMR (400 MHz, CDCl3) of compound A2.4j ........................................... 183 C NMR (101 MHz, CDCl3) of compound A2.4j .......................................... 184 H NMR (400 MHz, CDCl3) of compound A2.4l ........................................... 185 C NMR (101 MHz, CDCl3) of compound A2.4l .......................................... 186 H NMR (400 MHz, CDCl3) of compound A2.5f .......................................... 187 C NMR (101 MHz, CDCl3) of compound A2.5f .......................................... 188 H NMR (400 MHz, CDCl3) of compound A2.5g .......................................... 189 C NMR (101 MHz, CDCl3) of compound A2.5g ......................................... 190 H NMR (400 MHz, CDCl3) of compound A2.5h .......................................... 191 C NMR (101 MHz, CDCl3) of compound A2.5h ......................................... 192 xviii Figure A3.37 1 Figure A3.38 Infrared spectrum (Thin Film, NaCl) of compound A2.5l .............................. 194 Figure A3.39 13 H NMR (400 MHz, CDCl3) of compound A2.5l ........................................... 193 C NMR (101 MHz, CDCl3) of compound A2.5l .......................................... 194 APPENDIX 4 Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones Figure A4.1 Biological important of disubstituted amino acids ........................................ 250 APPENDIX 5 Spectra Relevant to Appendix 4 Figure A5.1 1 Figure A5.2 Infrared spectrum (Thin Film, NaCl) of compound A4.8 ............................... 371 Figure A5.3 13 Figure A5.4 1 Figure A5.5 Infrared spectrum (Thin Film, NaCl) of compound A4.9 ............................... 373 Figure A5.6 13 Figure A5.7 1 Figure A5.8 Infrared spectrum (Thin Film, NaCl) of compound A4.11b .......................... 375 Figure A5.9 13 Figure A5.10 1 Figure A5.11 Infrared spectrum (Thin Film, NaCl) of compound A4.11d .......................... 377 Figure A5.12 13 Figure A5.13 1 Figure A5.14 Infrared spectrum (Thin Film, NaCl) of compound A4.11c ........................... 379 Figure A5.15 13 Figure A5.16 1 Figure A5.17 Infrared spectrum (Thin Film, NaCl) of compound A4.11e ........................... 381 Figure A5.18 13 Figure A5.19 1 Figure A5.20 Infrared spectrum (Thin Film, NaCl) of compound A4.10 ............................. 383 Figure A5.21 13 Figure A5.22 1 Figure A5.23 Infrared spectrum (Thin Film, NaCl) of compound A4.12b .......................... 385 Figure A5.24 13 H NMR (400 MHz, CDCl3) of compound A4.8 ............................................ 370 C NMR (101 MHz, CDCl3) of compound A4.8 ........................................... 371 H NMR (400 MHz, CDCl3) of compound A4.9 ............................................ 372 C NMR (101 MHz, CDCl3) of compound A4.9 ........................................... 373 H NMR (400 MHz, CDCl3) of compound A4.11b ....................................... 374 C NMR (101 MHz, CDCl3) of compound A4.11b ....................................... 375 H NMR (400 MHz, CDCl3) of compound A4.11d ........................................ 376 C NMR (101 MHz, CDCl3) of compound A4.11cd ..................................... 377 H NMR (400 MHz, CDCl3) of compound A4.11c ....................................... 378 C NMR (101 MHz, CDCl3) of compound A4.11c ....................................... 379 H NMR (400 MHz, CDCl3) of compound A4.11e ....................................... 380 C NMR (101 MHz, CDCl3) of compound A4.11e ....................................... 381 H NMR (400 MHz, CDCl3) of compound A4.10 .......................................... 382 C NMR (101 MHz, CDCl3) of compound A4.10 ......................................... 383 H NMR (400 MHz, CDCl3) of compound A4.12b ....................................... 384 C NMR (101 MHz, CDCl3) of compound A4.12b ....................................... 385 xix APPENDIX 6 Spectra Relevant to Chapter 2 Figure A6.1 1 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 2.5 .................................. 371 Figure A6.3 13 Figure A6.4 1 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 2.10 ................................ 373 Figure A6.6 13 Figure A6.7 1 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 2.12 ................................ 375 Figure A6.9 13 Figure A6.10 1 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 2.13 ................................ 377 Figure A6.12 13 Figure A6.13 1 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 2.14 ................................ 379 Figure A6.15 13 Figure A6.16 1 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 2.17 ................................ 381 Figure A6.18 13 Figure A6.19 1 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 2.18 ................................ 383 Figure A6.21 13 Figure A6.22 1 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 2.19a .............................. 385 Figure A6.24 13 Figure A6.25 1 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 2.19b .............................. 387 Figure A6.27 13 Figure A6.28 1 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 2.21 ................................ 389 Figure A6.30 13 Figure A6.31 1 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 2.22 ................................ 391 Figure A6.33 13 Figure A6.34 1 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 2.23 ................................ 393 Figure A6.36 13 H NMR (400 MHz, CDCl3) of compound 2.5 .............................................. 370 C NMR (101 MHz, CDCl3) of compound 2.5 ............................................. 371 H NMR (400 MHz, CDCl3) of compound 2.10 ............................................ 372 C NMR (101 MHz, CDCl3) of compound 2.10 ........................................... 373 H NMR (400 MHz, CDCl3) of compound 2.12 ............................................ 374 C NMR (101 MHz, CDCl3) of compound 2.12 ........................................... 375 H NMR (400 MHz, CDCl3) of compound 2.13 ............................................ 376 C NMR (101 MHz, CDCl3) of compound 2.13 ........................................... 377 H NMR (400 MHz, CDCl3) of compound 2.14 ............................................ 378 C NMR (101 MHz, CDCl3) of compound 2.14 ........................................... 379 H NMR (400 MHz, CDCl3) of compound 2.17 ............................................ 380 C NMR (101 MHz, CDCl3) of compound 2.17 ........................................... 381 H NMR (400 MHz, CDCl3) of compound 2.18 ............................................ 382 C NMR (101 MHz, CDCl3) of compound 2.18 ........................................... 383 H NMR (400 MHz, CDCl3) of compound 2.19a .......................................... 384 C NMR (101 MHz, CDCl3) of compound 2.19a ......................................... 385 H NMR (400 MHz, CDCl3) of compound 2.19b .......................................... 386 C NMR (101 MHz, CDCl3) of compound 2.19b ......................................... 387 H NMR (400 MHz, CDCl3) of compound 2.21 ............................................ 388 C NMR (101 MHz, CDCl3) of compound 2.21 ........................................... 389 H NMR (400 MHz, CDCl3) of compound 2.22 ............................................ 390 C NMR (101 MHz, CDCl3) of compound 2.22 ........................................... 391 H NMR (400 MHz, CDCl3) of compound 2.23 ............................................ 392 C NMR (101 MHz, CDCl3) of compound 2.23 ........................................... 393 xx Figure A6.37 1 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 2.24 ................................ 395 Figure A6.39 13 Figure A6.40 1 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 2.25 ................................ 397 Figure A6.42 13 Figure A6.43 1 Figure A6.44 Infrared spectrum (Thin Film, NaCl) of compound 2.26 ................................ 399 Figure A6.45 13 Figure A6.46 1 Figure A6.47 Infrared spectrum (Thin Film, NaCl) of compound 2.27 ................................ 401 Figure A6.48 13 Figure A6.49 1 Figure A6.50 Infrared spectrum (Thin Film, NaCl) of compound SI3a ................................ 403 Figure A6.51 13 Figure A6.52 1 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound SI4 .................................. 405 Figure A6.54 13 H NMR (400 MHz, CDCl3) of compound 2.24 ............................................ 394 C NMR (101 MHz, CDCl3) of compound 2.24 ........................................... 395 H NMR (400 MHz, CDCl3) of compound 2.25 ............................................ 396 C NMR (101 MHz, CDCl3) of compound 2.25 ........................................... 397 H NMR (400 MHz, CDCl3) of compound 2.26 ............................................ 398 C NMR (101 MHz, CDCl3) of compound 2.26 ........................................... 399 H NMR (400 MHz, CDCl3) of compound 2.27 ............................................ 400 C NMR (101 MHz, CDCl3) of compound 2.27 ........................................... 401 H NMR (400 MHz, CDCl3) of compound 2.27 ............................................ 402 C NMR (101 MHz, CDCl3) of compound SI3a ........................................... 403 H NMR (400 MHz, CDCl3) of compound SI4 .............................................. 404 C NMR (101 MHz, CDCl3) of compound SI4 ............................................. 405 CHAPTER 2 gem-Disubstituted Morpholine Analogues of Linezolid Figure 2.1 N-Heterocycles are valuable components of small molecule drugs. ............. 141 Figure 2.2 Substitution patterns of common saturated heterocycles found in small molecule drugs. ............................................................................................ 141 Figure 2.3 Biological properties altered by hypothetical gem-disubstitution of the antibiotic linezolid.. ..................................................................................... 141 Figure 2.4 Summary of oxazolidinone antibiotics .......................................................... 141 Figure 2.5 gem-Disubstituted linezolid analogues synthesized via Ullmann coupling. .. 141 Figure 2.6 Diastereomers of analogue 2.19. .................................................................. 141 APPENDIX 8 Spectra Relevant to Appendix 7 Figure A8.1 1 Figure A8.2 Infrared spectrum (Thin Film, NaCl) of compound A7.1 ............................... 531 Figure A8.3 13 Figure A8.4 1 Figure A8.5 Infrared spectrum (Thin Film, NaCl) of compound A7.2 ............................... 533 H NMR (500 MHz, CDCl3) of compound A7.1 ............................................ 530 C NMR (125 MHz, CDCl3) of compound A7.1 ........................................... 531 H NMR (500 MHz, CDCl3) of compound A7.2 ............................................ 532 xxi Figure A8.6 13 Figure A8.7 1 Figure A8.8 Infrared spectrum (Thin Film, NaCl) of compound A7.3 ............................... 535 Figure A8.9 13 Figure A8.10 1 Figure A8.11 Infrared spectrum (Thin Film, NaCl) of compound A7.5 ............................... 537 Figure A8.12 13 Figure A8.13 1 Figure A8.14 Infrared spectrum (Thin Film, NaCl) of compound A7.6a .............................. 539 Figure A8.15 13 Figure A8.16 1 Figure A8.17 Infrared spectrum (Thin Film, NaCl) of compound A7.6b ............................. 541 Figure A8.18 13 Figure A8.19 1 Figure A8.20 Infrared spectrum (Thin Film, NaCl) of compound A7.6c .............................. 543 Figure A8.21 13 Figure A8.22 1 Figure A8.23 Infrared spectrum (Thin Film, NaCl) of compound A7.6d ............................. 545 Figure A8.24 13 Figure A8.25 1 Figure A8.26 Infrared spectrum (Thin Film, NaCl) of compound A7.6d ............................. 547 Figure A8.27 13 Figure A8.28 1 Figure A8.29 Infrared spectrum (Thin Film, NaCl) of compound A7.6e ............................. 549 Figure A8.30 13 Figure A8.31 1 Figure A8.32 Infrared spectrum (Thin Film, NaCl) of compound A7.7a .............................. 551 Figure A8.33 13 Figure A8.34 1 Figure A8.35 Infrared spectrum (Thin Film, NaCl) of compound A7.7b ............................. 553 Figure A8.36 13 Figure A8.37 1 Figure A8.38 Infrared spectrum (Thin Film, NaCl) of compound A7.7c .............................. 555 Figure A8.39 13 Figure A8.40 1 Figure A8.41 Infrared spectrum (Thin Film, NaCl) of compound A7.7d ............................. 557 Figure A8.42 13 Figure A8.43 1 C NMR (125 MHz, CDCl3) of compound A7.2 ........................................... 533 H NMR (500 MHz, CDCl3) of compound A7.3 ............................................ 534 C NMR (125 MHz, CDCl3) of compound A7.3 ........................................... 535 H NMR (500 MHz, CDCl3) of compound A7.5 ............................................ 536 C NMR (125 MHz, CDCl3) of compound A7.5 ........................................... 537 H NMR (500 MHz, CDCl3) of compound A7.6a .......................................... 538 C NMR (125 MHz, CDCl3) of compound A7.6a ......................................... 539 H NMR (500 MHz, CDCl3) of compound A7.6b .......................................... 540 C NMR (125 MHz, CDCl3) of compound A7.6b ......................................... 541 H NMR (500 MHz, CDCl3) of compound A7.6c .......................................... 542 C NMR (125 MHz, CDCl3) of compound A7.6c ......................................... 543 H NMR (500 MHz, CDCl3) of compound A7.6d .......................................... 544 C NMR (125 MHz, CDCl3) of compound A7.6d ......................................... 545 H NMR (500 MHz, CDCl3) of compound A7.6d .......................................... 546 C NMR (125 MHz, CDCl3) of compound A7.6d ......................................... 547 H NMR (500 MHz, CDCl3) of compound A7.6e ......................................... 548 C NMR (125 MHz, CDCl3) of compound A7.6e ......................................... 549 H NMR (500 MHz, CDCl3) of compound A7.7a .......................................... 550 C NMR (125 MHz, CDCl3) of compound A7.7a ......................................... 551 H NMR (500 MHz, CDCl3) of compound A7.7b .......................................... 552 C NMR (125 MHz, CDCl3) of compound A7.7b ......................................... 553 H NMR (500 MHz, CDCl3) of compound A7.7c .......................................... 554 C NMR (125 MHz, CDCl3) of compound A7.7c ......................................... 555 H NMR (500 MHz, CDCl3) of compound A7.7d .......................................... 556 C NMR (125 MHz, CDCl3) of compound A7.7d ......................................... 557 H NMR (500 MHz, CDCl3) of compound A7.7e ......................................... 558 xxii Figure A8.44 Infrared spectrum (Thin Film, NaCl) of compound A7.7e ............................. 559 Figure A8.45 13 Figure A8.46 19 Figure A8.47 1 Figure A8.48 Infrared spectrum (Thin Film, NaCl) of compound A7.8 ............................... 562 Figure A8.49 13 Figure A8.50 1 Figure A8.51 Infrared spectrum (Thin Film, NaCl) of compound A7.9 ............................... 564 Figure A8.52 13 Figure A8.53 1 Figure A8.54 Infrared spectrum (Thin Film, NaCl) of compound A7.11 ............................. 566 C NMR (125 MHz, CDCl3) of compound A7.7e ......................................... 559 F vs 13C HSQC (376 MHz, CDCl3) of compound A7.8 ................................ 560 H NMR (500 MHz, CDCl3) of compound A7.8 ............................................ 561 C NMR (125 MHz, CDCl3) of compound A7.9 ........................................... 562 H NMR (500 MHz, CDCl3) of compound A7.9 ............................................ 563 C NMR (125 MHz, CDCl3) of compound A7.11 ......................................... 564 H NMR (500 MHz, CDCl3) of compound A7.11 .......................................... 565 xxiii LIST OF SCHEMES CHAPTER 1 Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation Scheme 1.1 Key Developments in Decarboxylative Allylic Alkylation Reactions ................ 8 Scheme 1.2 Existing approaches for gem-disubstituted piperazines and piperazinones ....... 9 Scheme 1.3 Comparison of routes to piperazin-2-one decarboxylative alkylation substrates. ....................................................................................................................... 10 Scheme 1.4 Synthetic approaches toward β2,2-amino acids using the allylic alkylation reaction ......................................................................................................... 11 Scheme 1.5 Product derivatization ................................................................................... 12 CHAPTER 2 gem-Disubstituted Morpholine Analogues of Linezolid Scheme 2.1 Synthesis of gem-disubstituted linezolid analogues via Cu-catalyzed Ullmann coupling ...................................................................................................... 146 Scheme 2.2 Synthesis of gem-disubstituted morpholines by benzoyl cleavage and reduction of morpholinone decarboxylative alkylation products ................................. 146 Scheme 2.3 Additional analogues synthesized by derivatization ..................................... 146 APPENDIX 2 Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes Scheme A2.1 Synthetic route toward diazepane DAAA substrates ..................................... 472 Scheme A2.2 Attempted synthesis of other medicinally relevant DAAA substrates ............ 475 APPENDIX 4 Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones Scheme A4.1 Synthetic methods for disubstituted amino acids .......................................... 472 Scheme A4.2 Transition metal catalyzed asymmetric allylic alkylation methods ............... 475 Scheme A4.3 Previous attempts toward the decarboxylative alkylation of cyclic amino acid scaffolds ................................................................................................................................. 476 Scheme A4.4 Routes toward a cyclic amino acid imidazolinone scaffold ........................... 476 xxiv Scheme A4.5 Synthesis of the imidazolinone DAAA substrate ............................................ 476 APPENDIX 7 Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols Scheme A7.1 Approaches toward tertiary α-hydroxy carbonyl compounds ..................... 472 Scheme A7.2 Unexpected formation of a tertiary alcohol .................................................. 475 Scheme A7.3 Mechanistic rationale for formation of isomeric tetralone products ............... 476 Scheme A7.4 Decarboxylative alkylation of a primary alcohol .......................................... 476 xxv LIST OF TABLES CHAPTER 1 Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation Table 1.1 Chiral α-disubstituted carbocycles/lactams accessible by decarboxylative allylic alkylation ...................................................................................................... 20 Table 1.2 Optimization of the reaction conditions ......................................................... 23 Table 1.3 Substrate scope exploration ............................................................................ 25 Table 1.4 Pd-catalyzed decarboxylative alkylation of tetrahydropyrimidin-2-ones. Scope of α-substituents ............................................................................................ 36 APPENDIX 2 Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes Table A2.1 Optimization studies on the DAAA of benzyl substrate A2.4a ..................... 117 Table A2.2 Oxodiazepane substrate scope exploration .................................................. 118 APPENDIX 4 Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones Table A4.1 Initial screening results on carbamate A4.11a ...................................... 143 Table A4.2 Initial screening results on methyl substrate A4.11b .............................. 144 Table A4.3 Initial Substrate Scope .................................................................... 145 CHAPTER 2 gem-Disubstituted Morpholine Analogues of Linezolid 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 7 Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols xxvi Table A7.1 Attempts to optimize reaction conditions for model substrate A7.3 ............. 432 Table A7.2 Investigation into reaction outcomes for isomeric tetralone A7.5 .................. 433 Table A7.3 Decarboxylative alkylation of α-hydroxyl dicarbonyl compounds ................ 434 xxvii LIST OF ABBREVIATIONS [α]D specific rotation at wavelength of sodium D line °C degrees Celsius Ac acetyl AcOH acetic acid APCI atmospheric pressure chemical ionization app apparent aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c concentration for specific rotation measurements (g/100 mL) ca. about (Latin circa) calc’d calculated cat catalytic CDI 1,1'-carbonyldiimidazole cm–1 wavenumber(s) CSA camphorsulfonic acid Cy cyclohexyl d doublet D deuterium dba dibenzylideneacetone xxviii DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DAAA decarboxylative asymmetric allylic alkylation DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIPEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine dmdba bis(3,5-dimethoxybenzylidene)acetone DME 1,2-dimethoxyethane DMF N,N-dimethylformamide 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 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) HMBC heteronuclear multiple bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide xxix 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 IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie KHMDS potassium hexamethyldisilazide L liter; ligand L* chiral ligand LDA lithium diisopropylamide LG leaving group lit. literature value m multiplet; milli m meta M metal; molar; molecular ion m/z mass to charge ratio Me methyl mg milligram(s) MHz megahertz min minute(s) MM mixed method mol mole(s) xxx mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves n nano N normal n-Bu butyl NBS N-bromosuccinimide NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance Ns 2-nitrobenzenesulfonyl Nu nucleophile o ortho p para Pd/C palladium on carbon Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline ligand pKa pK for association of an acid pmdba bis(4-methoxybenzylidene)acetone ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl Py pyridine q quartet R generic for any atom or functional group Ref. reference Rf retention factor s singlet or strong or selectivity factor sat. saturated xxxi SFC supercritical fluid chromatography t triplet t-Bu tert-butyl TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBAT tetrabutylammonium difluorotriphenylsilicate TBD 1,3,4-triazabicyclo[4.4.0]dec-5-ene TBHP tert-butyl hydroperoxide TBME tert-butyl methyl ether Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine 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 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1 CHAPTER 1 Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation† 1.1 INTRODUCTION AND BACKGROUND The catalytic decarboxylative allylic alkylation, originally reported by Tsuji and Saegusa in 1980,1,2 is a powerful transformation to effect C–C bond formation between an enolate precursor and an allyl group (Scheme 1.1A). However, an enantioselective version of the reaction was not developed until 2004 by the Tunge and Stoltz groups, who reported enantioselective alkylations of acyclic esters and cyclic allyl enol carbonates using DACH-Trost ligand and (S)-t-BuPHOX, respectively (Scheme 1.1B & C).3,4 In 2005, Trost reported a similar carbocyclic system, though using the ANDEN phenyl trost ligand to achieve high stereoselectivity.5,6 In an important advance, the Stoltz group in 2005 reported the DAAA of β-keto allyl esters, which significantly expanded the substrate scope of this Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 2 transformation; such bench stable ketoesters can be alkylated under mild basic conditions to afford a variety of decarboxylative alkylation substrates that would normally be difficult to access by other means (Scheme 1.1D).7 Scheme. 1.1 Key Developments in Decarboxylative Allylic Alkylation Reactions A. Tsuji’s Pd-catalyzed decarboxylative allylic alkylation (1980)X O O Pd(OAc)2 PPh3 O O THF >99% yield B. Tunge’s Pd-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) (2004)X O O Pd2(dba)3 (R,R)-DACH-phenyl Trost L O R O CH2Cl2, 25 °C R R R up to 94% yield up to 99% ee C. Stoltz’s Pd-catalyzed DAAA of cyclic allyl enol carbonates (2004)X O O Pd2(dba)3 (S)-t-Bu-PHOX O R O R THF, 25 °C up to 96% yield up to 92% ee D. Stoltz’s Pd-catalyzed DAAA of allyl β-keto esters (2005)X O R O O Pd2(dba)3 (S)-t-Bu-PHOX O R THF, 25 °C up to 88% ee Since these fundamental developments in asymmetric decarboxylative alkylation, numerous groups have further contributed to the expansion of this methodology to encompass a variety of acyclic and cyclic substrates.8,9 Summarized below in Table 1.1 are some of the many gem-disubstituted cyclic products that our laboratory has synthesized utilizing the DAAA reaction, highlighting the incredible versatility of this mild reaction.4,7,10–16 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 3 Table. 1.1 Chiral α-disubstituted carbocycles/lactams accessible by decarboxylative allylic alkylation R O O Pd/(S)-(CF3)3-t-BuPHOX R O O X n X = CH2, N n = 1, 2, 3, 4 O solvent, temp R O Et iBuO N Bn reference 10 reference 7 O reference 11 O CO2Me F reference 13 O BzN O MeO reference 13 reference 12 O N BzN BzN O R O Cl O NHBoc O Ph Me X Up to 99% yield Up to 99% ee reference 13 reference 13 CN Me BzN NBn Cl reference 15 O O O NHBoc Me BzN BzN O O reference 14 O NHBoc O BnO N O reference 14 reference 13 O O Me BzN N reference 11 N Bn S reference 11 reference 16 O reference 14 Despite the incredibly broad substrate scope of this reaction, there is still room for innovation, including novel medicinally relevant cyclic scaffolds, and the next frontier: acyclic scaffolds.17 In this chapter, we describe the extension of the DAAA reaction toward Boc-protected six-membered diazaheterocycles, including piperazinones and tetrahydropyrimidinones. Then, in the accompanying two appendices, we describe the DAAA of five and seven-membered diazaheterocycles. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.2 4 PIPERAZINONE and TETRAHYDROPYRIMIDINONE DAAA Nitrogen containing heterocycles are ubiquitous components of biologically active small molecules.18 For instance, piperazine, a representative diazaheterocycle, is the third most prevalent heterocycle in small molecule pharmaceuticals18 and can be found in bioactive molecules such as the antiviral natural product Herquline A,19 blockbuster psychiatric drug aripiprazole,20 and the HIV integrase inhibitor dolutegravir21,22 (as the oxidized counterpart, piperazin-2-one) (Fig. 1.1). Fig. 1.1 Representative piperazine and piperazine-2-one pharmaceuticals and natural products. O F NH O O H O H H Cl N N N H Herquline A aripiprazole F O N H O N Cl N N HO O H dolutegravir In the field of medicinal chemistry and fragment-based drug discovery, an emerging paradigm to enhance drug-like properties of small molecules involves reducing molecular flatness by incorporating chiral centers.23–27 This method of increasing molecular complexity can enhance binding affinity and specificity for a target, as receptor-ligand binding is often defined by three dimensional contacts.24 Furthermore, depending on the chemical composition of the chiral center, other properties such as metabolism, aqueous solubility, and cell-penetration may be optimized.23 The prevalence of piperazine in bioactive molecules makes it an excellent scaffold upon which to introduce chirality and increase molecular complexity. Chiral gem-disubstitution on any 5 of four carbon atoms in the piperazine ring could dramatically alter physicochemical Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles properties (Fig. 1.2). Despite this potential, there are no gem-disubstituted piperazines among the current 98 FDA approved piperazine-containing non-natural product derived drugs.28 Error! Reference source not found. In contrast, a significant number contain monosubstituted piperazines, which can be prepared through a variety of strategies,29–39 including cyclization of chiral precursors, enantioselective hydrogenation of pyrazines,32,33 palladium-catalyzed cyclizations,34–36 or asymmetric lithiation.37,38 Fig. 1.2 Advantages of chiral gem-disubstituted piperazines R1 N N R2 R3 R4 Increased molecular complexity5c Augmented properties: specificity, metabolism, solublity, permeability Absent in all 98 FDA-approved piperazine containing drugs6 gem-Disubstituted piperazine The dearth of piperazine gem-disubstitution in the pharmacopoeia highlights the significant challenge of installing fully substituted chiral centers into diazaheterocycles. The state of the art is perhaps best exemplified by the Bode laboratory’s extensive development of tin (SnAP) and silicon (SLAP) coupling reagents to generate spirosubstituted piperazines (Scheme 1.2A).40–42 However, this method is not yet enantioselective and involves potentially toxic tin reagents. Other non-enantioselective methods to synthesize gem-disubstituted piperazines include [4+2] cycloadditions of 1,2 diamines with propargyl alcohols developed by Rawal (Scheme 1.2B),34 and the ring expansion of oxetane spirocycles by Carreira (Scheme 1.2C).43 To our knowledge, the only method enabling the highly enantioselective synthesis of gem-disubstituted piperazines was published by our group in 2015.15Error! Reference source not found. We leveraged the Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 6 Scheme. 1.2 Existing approaches for gem-disubstituted piperazines and piperazinones A. Tin amine protocol (SnAP) coupling with ketones to form spiropiperazines (Bode) O R1 Boc N R2 NH2 SnBu3 NBoc n Cu(OTf)2 (10 mol %) R1 Boc N 2,6-lutidine (10 mol %) HFIP/MeCN R2 N H n NBoc n = 0, 1, 2 Currently not enantioselective B. Palladium catalyzed cyclization (Rawal) OBoc TsHN R3 R4 TsHN Ts N Pd2(dba)3 (3 mol %) DPEphos (3 mol %) R3 R4 N Ts CH2Cl2 2 examples Currently not enantioselective C. Oxetane ring expansion (Carreira) R6 R5N R5 N NR7 O TMSCN (1.5 equiv) R6 CN OTMS N R7 In(OTf)3 (7.5 mol %) MeCN 4 examples Up to 20:1 dr Currently not enantioselective D. Decarboxylative Asymmetric Allylic Alkylation (Stoltz 2015) O R8 O BzN O NR9 R9 = Bn or PMB Pd2(dba)3 (5 mol %) (S)-(CF3)3-t-BuPHOX (12.5 mol %) PhMe (0.014 M) 40 °C, 12 h O R8 BzN NR9 R8 = Me, Et, iBu, Bn, CH2OBn, Up to 96% ee Limited substrate scope Challenging substrate synthesis Difficult deprotection palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to synthesize chiral α,α-disubstituted N4-benzylated piperazin-2-ones (Scheme 1.2D). These piperazin2-ones could then be reduced into desirable chiral gem-disubstituted piperazines. However, we encountered two issues during the course of our attempts to utilize this method to synthesize disubstituted piperazines for medicinal chemistry purposes: first, the optimal nucleophilic benzyl-protected N4 significantly complicated substrate Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 7 synthesis via nucleophilic side reactions, leading to low yields of products. As a result, we failed to synthesize many desired substrates via standard enolate functionalization of the dicarbonyl precursor. Instead, we resorted to a low-yielding 5-step convergent sequence beginning from an amino acid (Scheme 1.3A). As a result, our substrate scope displayed limited functional group diversity. Second, noting that heterocycles such as piperidines, pyrollidines, and piperazines are prevalent in compounds of medicinal interest, we initiated a medicinal chemistry program to explore their utility in the context of cancer and infectious disease therapeutics. With a robust method of DAAA to generate chiral gem-disubstituted versions of medicinally relevant heterocycles, we initially sought to utilize our piperazinones15 in a collaboration with the Kurosu group at UTennessee to design novel C. dificile inhibitors. During this collaboration we worked with a N4-PMBprotected piperazin-2-one, in which we failed to remove the recalcitrant PMB group using a variety of common cleavage conditions that were orthogonal to the sensitive allyl functionality. Scheme 1.3. Comparison of routes to piperazin-2-one decarboxylative alkylation substrates. A. Previous route to allylic alkylation substrates (Stoltz 2015) O O R1 HO R1 O BzN NH2 O NBn R1 = i-butyl, Bn, CH2OBn D,L-amino acid 5 linear steps, 5-15% overall yield B. Streamlined route to allylic alkylation substrates (This research) O O O i. BzCl HN NBoc 1.1 BzN ii. Allyl cyanoformate 30% over two steps CO2Allyl Enolate functionalization NBoc 39-85% yield 1.2 R2 BzN CO2Allyl NBoc 1.3 8 The substrate-dependent drawbacks of our approach leave room for an improved Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles method to synthesize chiral disubstituted piperazines. In an effort to expand upon our group’s longstanding interest in transition-metal catalyzed allylic alkylation, we sought to identify an alternative protecting group that could overcome the aforementioned limitations by enabling both facile substrate synthesis and protecting group cleavage. After extensive explorations directed toward this goal, we were pleased to discover that replacing the N4-benzyl protecting group with a simple Boc (tert-butoxycarbonyl) protecting group addressed the issue of difficult substrate synthesis. Presumably, the electron-withdrawing Boc group attenuates the nucleophilicity of N4, enabling divergent access to a wider array of substrates 1.3 via enolate functionalization of dicarbonyl compound 1.2, which could be synthesized in only two steps from Boc-piperazinone 1.1 (Scheme 1.3B) With a streamlined approach toward a wide range of decarboxylative alkylation substrates, we began optimizing the reaction conditions: with model substrate 1.3m, conditions based on our previous report15 using 10 mol % (S)-(CF3)3-t-BuPHOX ligand and 4 mol % Pd2(pmdba)3 in 0.014 M toluene gave the product 3m in only 76% ee (Table 1.2, entry 1). Other commonly used allylic alkylation ligands such as (S)-t-BuPHOX (L2) and (S,S)-ANDEN-Ph Trost (L3) were tested, both giving suboptimal enantioselectivities (entries 2–3). We then examined the effect of solvent on the enantioselectivity (entries 4– 6), ultimately finding that 2:1 hexanes-toluene provided high yield and ee. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 9 Table 1.2 Optimization of the reaction conditionsa O NHBoc O BzN NHBoc O Pd2(pmdba)3 (4 mol %) L (10 mol %) O NBoc BzN NBoc Solvent (0.014 M) 40 °C, 12 h 1.3m 1.4m Entry Ligand Solvent Yield (%)b ee (%)c 1 2 3 4 5 6 L2 L2 L3 L1 L1 L1 Tol Tol Tol THF MTBE 2:1 Hex/Tol 75 70 83 — — 93 76 1 52 13 80 93 CF3 O O F3C P N P N O O NH HN PPh2 Ph2P CF3 (S)-L1 (S)-L2 (S,S)-L3 [a] Screens performed on a 0.04 mmol scale. [b] All reported yields are for isolated products. [c] The ee values were determined by chiral SFC analysis. Bz = benzoyl, Boc = tert-butoxycarbonyl, pmdba = bis(4-methoxybenzylidene)acetone Employing these satisfactory reaction conditions, we then explored the substrate scope of the decarboxylative alkylation of various N4-Boc protected piperazinones (Table 1.3). We first tested the α-monosubstituted piperazinone 1.3a, finding that typical conditions in a 0.033 M solution of toluene afforded the product 1.4a in high yield and enantioselectivity. Another monosubstituted piperazinone 1.4b with a N1-anisoyl protecting group, was also obtained in high yield and ee. Furthermore, replacement of the N4-Boc protecting group with Cbz (1.3c), and 2-chloro substitution of the allyl group (1.3d) similarly provided good results. 10 Next, we examined α,α-disubstituted substrates, finding that for the simple cases Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles of methyl substitution (1.3e, 1.3f), performing the reaction at 0.033 M concentration in toluene gave high yields and ee, with no improvement with the use of 2:1 hexanestoluene at 0.014 M concentration. The exception was N4-benzoyl protected substrate 1.3g, which in our previous work gave 52% ee in toluene; under our optimized conditions in 2:1 hexanes-toluene, the substrate gave an improved albeit modest ee of 70%. Larger substituents such as α-benzylated compound 1.3h or benzyloxymethyl ether 1.3i required the use of 2:1 hexanes-toluene to achieve high enantioselectivity. This unique mixedsolvent requirement was observed in all substituents other than methyl. A wide range of functional groups was tolerated: notably, the nitrile, ketone, and methylcarbamate substrates, which could not be accessed in our previously described efforts, gave high ee and yields (1.3j-m). Table 1.3. Substrate scope exploration. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O R3 O R1N O Pd2(dba)3 (4 mol %) (S)-(CF3)3-tBuPHOX (10 mol %) O NR2 R4 2:1 hexanes-toluene 40 °C 1.3a-n O NBoc BzN 1.4a[c]: R1 = Bz, 90% yield, 92% ee 1.4b[c]: R1 = An, 90% yield, 96% ee O Me NBoc Cl NBoc 1.4d[b,c] 85% yield 98% ee 1.4e[b,c] 90% yield 96% ee O O Ph AnN NBoc NBz NBoc 1.4g 80% yield 70% ee 1.4h[b] 70% yield 96% ee Me CN NBoc O NBoc 1.4i[b] 87% yield 92% ee NHCbz AnN AnN 1.4j 88% yield 97% ee OBn O O AnN O BzN 1.4f[b,c] 85% yield 96% ee O Me BzN NCbz Me R4 1.4a-n 1.4c[c] 75% yield 99% ee BzN AnN NR2 O BzN R3 R1N O O R1N 11 NBoc 1.4k 73% yield 97% ee O NHBoc BzN NBoc 1.4l 75% yield 92% ee NBoc 1.4m[b] 93% yield 93% ee [a] Conditions: piperazin-2-one 3 (1.0 equiv), Pd2(dba)3 (4 mol %), (S)-(CF3)3-tBuPHOX (10 mol %), in 2:1 hexanes/toluene (0.014 M) at 40 °C for 12-24 h. [b] Pd2(pmdba)3 (4 mol %) instead of Pd2(dba)3. [c] Toluene (0.033 M) instead of 2:1 hexanes/toluene. All reported yields are for isolated products. The ee values were determined by chiral SFC analysis. An = 4methoxybenzoyl, dba = dibenzylideneacetone. With the N-Boc piperazin-2-one substrates providing excellent results, we wondered whether an isomeric substrate class, the N-Boc tetrahydropyrimidin-2-ones (1.5), would perform similarly as well (Scheme 1.4c). The resulting α,α-disubstituted tetrahydropyrimidin-2-one products (1.6) are especially interesting as they may be hydrolyzed to afford valuable β2,2-amino acids (1.7), which are used in peptidomimetic therapeutics and in the design of unnatural peptides and proteins with unique secondary and tertiary structures.44–46 In fact, there is strong precedent for an allylic alkylation 12 approach toward β -amino acids. In 2018 the Shibasaki group described the Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 2,2 decarboxylative allylic alkylation of an N,O heterocycle to set the quaternary stereocenter, followed by N−O bond heterolysis to generate β2,2-amino acids (Scheme 1.4a).47 Later in 2018, Cossy and co-workers described a similar approach involving intermolecular allylic alkylation (Scheme 1.4b).48 Notably, the substrate scope for these two examples is limited to mostly α-benzylic and α-aryl compounds. If decarboxylative alkylation could be achieved with the versatile tetrahydropyrimidin-2-one scaffold, a broader range of chiral β2,2-amino acids might be accessible (Scheme 1.4c). Additionally, tetrahydropyrimidinones may be reductively transformed into hexahydropyrimidines, which are found in bioactive molecules such as the antibiotic hexetidine and the macrocyclic natural product verbamethine.49,50 Scheme 1.4. Synthetic approaches toward β2,2-amino acids using the allylic alkylation reaction A. Decarboxylative alkylation approach toward β2,2-amino acids (Shibasaki 2018)13a O R O O O Pd2(dmdba)3 OAllyl R R O Ph-ANDEN-Trost L BocN HO BocN Up to 94% ee R = Me, CH2Ar NHBoc O β-Amino Acid B. Allylic alkylation approach toward β2,2-amino acids (Cossy 2018)13b OAc O Ar O O Pd2(dba)3 Ar DACH-Ph Trost L Na2CO3 BocN Ar O HO BocN Up to 92% ee NHBoc O β-Amino Acid C. This Research: Decarboxylative alkylation of tetrahydropyrimidin-2-ones O R BzN O O OAllyl Conditions R BzN R Hydrolysis HO N Boc N Boc 1.5 1.6 O NHBoc 1.7 β-Amino Acid 13 Beginning our investigations with methyl substrate 1.5a (Table 1.4), we were Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles pleased to find that our optimized conditions in 2:1 hexanes-toluene furnished the desired decarboxylative alkylation product 1.6a in high yield and ee. The reaction proved amenable to a variety of α-substituents, including ethyl (1.6b), methyl ester (1.6c), 2chloroallyl (1.6d), and benzyl (1.6e). Furthermore, the reaction is scalable, with the benzyl substrate 1.5e giving good results in a 1 gram reaction. In contrast, the nitrile and benzyloxymethyl ether products 1.6f and 1.6g were isolated with reduced enantioselectivities. Pleasingly, the fluorine and propargyl substrates 1.5h and 1.5i performed well, and may serve as a precursor to a novel fluorinated β2,2-amino acid, or for biorthogonal click reactions, respectively. Table 1.4. Pd-catalyzed decarboxylative alkylation of tetrahydropyrimidin-2-ones. Scope of αsubstituents[a] Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O R5 O BzN O Pd2(pmdba)3 (S)-(CF3)3-tBuPHOX O R5 BzN 2:1 hexanes/toluene 40 °C N Boc 14 N Boc 1.6a–i 1.5a–i CO2Me O O O R5 BzN BzN N Boc 1.6c 67% yield 95% ee CN O O BzN BzN N Boc 1.6f 80% yield 74% ee O F BzN N Boc 1.6g 80% yield 87% ee 1.6e[b] 84% yield 95% ee 1.6d 85% yield 94% ee OBn Ph N Boc N Boc N Boc 5 1.6a: R = Me, 83% yield, 93% ee 5 6b: R = Et, 98% yield , 94% ee O Cl BzN BzN O BzN N Boc 1.6h 72% yield 92% ee N Boc 1.6i 75% yield 90% ee [a] Conditions: tetrahydropyrimidin-2-one 5 (1.0 equiv), Pd2(pmdba)3 (4 mol %), (S)-(CF3)3-tBuPHOX (10 mol %), in 2:1 hexanes/toluene (0.014 M) at 40 °C for 12-24 h. All reported yields are for isolated products. [b] Reaction performed with 1 gram of substrate 5e. The ee values were determined by chiral SFC analysis. Having demonstrated excellent results for the decarboxylative alkylation of piperazin-2-ones and tetrahydropyrimidin-2-ones, we began exploring their synthetic utility. In contrast to the relative difficulty of removing the N4-benzyl type protecting groups in our previous work, both Boc groups of 1.4m were easily removed by treatment with excess TFA to give aminopiperazinone 1.8 (Scheme 1.5a). With LiOH, the benzoyl group could be orthogonally removed to provide the free amide 1.9 (Scheme 1.5b). The amide 1.9 could then be reduced with LiAlH4 to the corresponding chiral aminopiperazine 1.10. To further illustrate the synthetic versatility realized by Bocdeprotection of N4, we hydrogenated the allyl olefin of methyl piperazinone 1.4e before cleaving the Boc group to obtain 1.11. We then applied Gaunt’s51 method of C−H carbonylation on the aliphatic amine of 1.11 to forge the fused β-lactam 1.12, which 15 bears resemblance to the core of various β-lactam antibiotics and β-lactamase inhibitors Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles (Scheme 1.5c). Lastly, we transformed four tetrahydropyrimidinone substrates, 1.6c-e and 1.6h, into their corresponding acyclic forms (Scheme 1.5d & e). Using a two-step protocol involving TFA-mediated Boc cleavage followed by saponification with LiOH, we successfully obtained the crude β2,2-amino acid (Scheme 1.5d); to facilitate silica gel chromatographic isolation, we chose to mask the free amine and carboxylic acid with Boc and benzyl groups, respectively, resulting in protected β2,2-amino acid 1.13. We note that in this four step sequence, we only performed one chromatographic separation to isolate the protected β-amino acid. In contrast, novel unprotected β2,2-amino acids 1.14–16 bearing pendant carboxylic acid, chloroallyl, and fluorine atom functional groups could be obtained directly by purification with reverse phase preparatory HPLC following the two-step deprotection sequence (Scheme 1.5e). Scheme 1.5. Product derivatization Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles a) NHBoc O 16 NH2 O TFA (20 equiv) BzN BzN CH2Cl2 73% yield NBoc NH 1.4m 1.8 b) NHBoc O BzN NHBoc LiAlH4 HN MeOH/H2O 92% yield NBoc NHBoc O LiOH 1.4m HN THF 63% yield NBoc NBoc 1.9 1.10 c) O O 1. Pd/C, H2 Me BzN 2. TFA, CH2Cl2 94% yield over 2 steps NBoc 1.4e BzN BzN CO (1 atm) AgOPiv, BQ toluene, 80 °C 55% yield NH 1.11 d) O Ph 1. TFA, CH2Cl2 2. LiOH, MeOH/H2O, 80 °C BzN 1.6e N 1.12 O Ph O BnO 3. Boc2O 4. BnBr, K2CO3, DMF 40% yield over 4 steps N Boc O Pd(OPiv)2 xantphos Me NH Boc 1.13 e) O R O 1. TFA, CH2Cl2 BzN 2. LiOH, MeOH/H2O, 80 °C N Boc R HO NH2 1.6c: R = CH2CH2CO2Me 1.14: R = CH2CH2CO2H, 46% yield 1.6d: R = 1.15: R = Cl 1.6h: R = F , 69% yield Cl 1.16[f]: R = F, 65% yield [a] Boc cleavage to the free amine. [b] Benzoyl cleavage and reduction to the piperazine. [c] Boc cleavage, allyl hydrogenation, and C−H carbonylation of the free amine. [d,e] hydrolysis and subsequent protection of the β2,2-amino acid. [f] KOH, 1:1 MeOH/H2O, rt; then, HCl, MeOH, rt. BQ = benzoquinone. Piv = pivalate. 1.3 CONCLUSIONS In summary, we have developed a decarboxylative asymmetric allylic alkylation reaction to synthesize unprecedented chiral α,α-disubstituted piperazin-2-ones and tetrahydropyrimidin-2-ones. This work represents a significant improvement upon existing technology, featuring ease of substrate synthesis, facile N4-Boc deprotection, and broader substrate scope. The resulting piperazinones can be transformed into 17 valuable chiral gem-disubstituted piperazines that are anticipated to provide stereodefined Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles access to new chemical space in drug discovery. Similarly, the tetrahydropyrimidinone scaffold could be hydrolyzed to provide access to corresponding protected and free β2,2amino acids. We anticipate this decarboxylative allylic alkylation protocol will find utility in the field of medicinal chemistry as well as in natural products synthesis. 1.4 EXPERIMENTAL SECTION 1.4.1 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. tert-Butyl 3oxopiperazine-1-carboxylate 1.1 was obtained from Combi-Blocks. Commercially obtained reagents were used as received. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar/Combi-Blocks 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) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, iodine on silica, ninhydrin, or KMnO4 staining. SiliaFlash P60 Academic Silica gel (particle size 0.040– 0.063 mm) was used for flash chromatography. 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. Reverse Phase Preparatory 18 HPLC was performed with a Teledyne ISCO ACCQPrep HP125 preparative liquid Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles chromatography system equipped with a RediSep Prep C18 5 µm column (20 x 250 mm). 1 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or CH3OH (δ 3.31 ppm). 13C 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 CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 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 water (δ 1.56 or 4.87 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 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). Stereochemistry is assigned by analogy to previous results.4,7,10,13,52,53 19 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.4.1.1 Preparation of Known Compounds Allyl cyanoformate was prepared according to the method of Weber.54 Phosphinooxazoline (PHOX) ligands (S)-L1, (S)-L2, and achiral GlyPhox were prepared by methods described in our previous work.4,55 Di-benzoylated allylic alkylation substrate 1.3g was prepared according to the method of Korch.15 Tris(4,4’- methoxydibenzylideneacetone)dipalladium(0) [Pd2(pmdba)3] was prepared according to the method of Ibers56 or Fairlamb.57 AgOPiv was prepared using Grubbs’ procedure.58 tert-Butyl ((phenylsulfonyl)methyl)carbamate and benzyl ((phenylsulfonyl)methyl)carbamate were prepared according to the method of Zwierzak or Dikshit.59,60 Benzyl 3-oxopiperazine-1-carboxylate was prepared according to the method of Batey.61 2-chloroallyl chloroformate was prepared according to the method of Stoltz.62 1.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 1.4.2.1 Procedures for the Synthesis of Piperazinone Allylic Alkylation Substrates O BzN NBoc tert-butyl 4-benzoyl-3-oxopiperazine-1-carboxylate. To a solution of tert-butyl 3oxopiperazine-1-carboxylate 1.1 (5.0 g, 24.9 mmol, 1 equiv) in THF (250 mL) at −78 °C was added dropwise nBuLi (11.4 mL, 2.4M solution in hexane, 27.5 mmol, 1.1 equiv) over 20 minutes. The resulting yellow solution was stirred for 10 min at −78 °C. Benzoyl chloride (3.48 mL, 30.0 mmol, 1.2 equiv) was then added dropwise at −78 °C, giving an 20 orange solution. The reaction was stirred for 2.5 h at −78 °C, quenched by addition of Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles saturated aqueous NH4Cl (100 mL), and diluted with ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was purified by silica gel flash column chromatography (10% →15% →20% EtOAc/hexanes) to give protected ketopiperazine as a white solid (3.2 g, 42.1% yield). Product identity was confirmed by comparison to previously reported characterization data.63 O O N MeO NBoc tert-butyl 4-(4-methoxybenzoyl)-3-oxopiperazine-1-carboxylate. To a solution of tertButyl 3-oxopiperazine-1-carboxylate (5.0 g, 24.9 mmol, 1 equiv) in THF (250 mL) at −78 °C was added dropwise nBuLi (11.4 mL, 2.4M solution in hexane, 27.5 mmol, 1.1 equiv) over 20 minutes. The resulting yellow solution was stirred for 10 min at −78 °C. Anisoyl chloride (4.1 mL, 30.0 mmol, 1.2 equiv) was then added dropwise at −78 °C, giving a bright orange solution. The reaction was stirred for 2 h at −78 °C, quenched by addition of saturated aqueous NH4Cl (100 mL), and diluted with ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was filtered through a plug of silica (1% →2% MeOH/CH2Cl2) to give crude 21 anisoyl protected ketopiperazine as a white foam, which was directly used without further Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles purification in subsequent acylation reactions with allyl cyanoformate. O BzN NCbz benzyl 4-benzoyl-3-oxopiperazine-1-carboxylate. To a solution of benzyl 3oxopiperazine-1-carboxylate61 (1.0 g, 4.3 mmol, 1.0 equiv) in THF (42 mL) at −78 °C was added dropwise nBuLi (1.96 mL, 2.4M solution in hexane, 4.7 mmol, 1.1 equiv) over 20 minutes. The solution was stirred for 10 min at −78 °C. Benzoyl chloride (0.595 mL, 5.1 mmol, 1.2 equiv) was then added dropwise at −78 °C, giving a light yellow solution. The reaction was stirred for 1 h at −78 °C, quenched by addition of saturated aqueous NH4Cl (50 mL), and diluted with ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was purified by silica gel flash column chromatography (33% EtOAc/hexanes) to give BzCbz-protected ketopiperazine SI-3 as a white solid (1.0 g, 70.0% yield); 1H NMR (500 MHz, CDCl3) δ 7.61 – 7.56 (m, 2H), 7.54 – 7.49 (m, 1H), 7.44 – 7.31 (m, 7H), 5.21 (s, 2H), 4.30 (s, 2H), 3.95 (dd, J = 6.8, 4.4 Hz, 2H), 3.83 (dd, J = 6.9, 4.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 172.8, 168.0, 167.6, 154.5, 136.0, 135.0, 132.3, 128.7, 128.5, 128.4, 128.3, 128.3, 68.0, 48.5, 43.3, 41.7, 41.4; IR (Neat Film, NaCl) 3386, 3063, 3033, 2954, 2894, 1706, 1600, 1584, 1498, 1449, 1422, 1394, 1367, 1302, 1231, 1177, 1162, 1123, 1060, 1028, 1010, 944, 857, 796, 765, 731, 22 699, 639, 612 cm ; HRMS (MM: ESI-APCI) m/z calc’d for C19H19N2O4 [M+H]+: Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles -1 339.1339, found 339.1338. O O BzN O NBoc 2-allyl 1-(tert-butyl) 4-benzoyl-3-oxopiperazine-1,2-dicarboxylate (1.2). To a solution of Bz-protected oxopiperazine (1.5 g, 4.9 mmol, 1.0 equiv) in THF (40 mL) at −78 °C was added LiHMDS (907 mg, 5.42 mmol, 1.10 equiv.) in THF (10mL) dropwise. The resulting orange reaction mixture was stirred for 15 min at −78 °C. Then, allyl cyanoformate (590 µL, 5.2 mmol, 1.05 equiv) was added dropwise at −78 °C, giving a yellow solution. After stirring for 1.5 h at −78 °C, the reaction was quenched with saturated aqueous NH4Cl (20 mL) and diluted with ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica. The silica-loaded crude mixture was purified by silica gel flash chromatography (10% → 20% EtOAc/hexanes) to give the allyl ester 1.2 as a white solid (1.3 g, 68% yield): 1H NMR (500 MHz, CDCl3) δ (a mixture of two rotamers) 7.59 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 5.92 (m, 1H), 5.44 – 5.07 (m, 3H), 4.84 – 4.57 (m, 2H), 4.28 – 3.61 (m, 4H), 1.43 (br s, 9H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 172.7, 166.9, 164.4, 154.1, 153.5, 134.6, 132.6, 131.0, 128.6, 128.4, 119.9, 119.4, 82.2, 82.0, z67.1, 62.7, 61.7, 43.2, 42.6, 41.5, 40.2, 29.4, 28.3; IR (Neat Film, NaCl) 2978 1746 1695 1600 1450 1393 1367 1310 1277 1231 1177 1158 23 1127 1088 1059 1009 958 861 794 770 728 694 623 cm ; HRMS (MM: ESI-APCI) m/z Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles -1 calc’d for C16H17N2O6 [(M-tBu)+H]+: 333.1081, found 333.1075. O O O N MeO O NBoc 2-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-3-oxopiperazine-1,2-dicarboxylate (1.3b). Following the procedure described for the preparation of 1.2, anisoyl protected oxopiperazine (1.0 g, 3.0 mmol, 1.0 equiv) was treated with LiHMDS (550 mg, 3.3 mmol, 1.1 equiv) and acylated with allyl cyanoformate (336 µL, 3.1 mmol, 1.05 equiv) to give, after purification by silica gel flash chromatography (Dry load SiO2, 18% EtOAc/hexanes), allyl ester 1.3b as a white solid (566 mg, 45% yield): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.61 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.91 (ddt, J = 16.4, 10.8, 5.8 Hz, 1H), 5.46–5.12 (m, 3H), 4.70 (s, 2H), 4.13–3.65 (m, 4H), 3.81 (s, 3H), 1.46 (m, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 171.9, 171.8, 167.0, 164.4, 164.2, 163.4, 154.0, 153.4, 131.4, 131.0, 126.3, 119.6, 119.2, 113.6, 82.0, 81.8, 66.9, 62.5, 61.6, 55.5, 43.3, 42.8, 41.5, 40.1, 28.2; IR (Neat Film, NaCl) 3384, 3060, 2978, 2843, 2568, 2049, 1732, 1605, 1580, 1513, 1456, 1372, 1258, 1088, 1059, 959, 844, 769, 736, 706, 634 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C21H27N2O7 [M+H]+: 419.1813, found 419.1815. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O 24 O BzN O NCbz 2-allyl 1-benzyl 4-benzoyl-3-oxopiperazine-1,2-dicarboxylate (1.3c). Following the procedure described for the preparation of 2, Cbz protected oxopiperazine (1.0 g, 3.0 mmol, 1.0 equiv) was treated with LiHMDS (544 mg, 3.3 mmol, 1.1 equiv) and acylated with allyl cyanoformate (331 µL, 3.1 mmol, 1.05 equiv) to give, after purification by silica gel flash chromatography (dry load SiO2, 20 → 25% EtOAc/hexanes), allyl ester 1.3a as a white solid (720 mg, 58% yield): 1H NMR (500 MHz, CDCl3) δ (a mixture of two rotamers) 7.65 – 7.56 (m, 2H), 7.56 – 7.46 (m, 1H), 7.46 – 7.28 (m, 7H), 5.87 (dtd, J = 47.5, 10.7, 5.4 Hz, 1H), 5.55 – 5.04 (m, 5H), 4.84 – 4.48 (m, 2H), 4.24 – 3.99 (m, 2H), 3.99 – 3.66 (m, 2H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 172.4, 172.3, 166.5, 164.0, 163.8, 154.8, 154.2, 135.7, 135.6, 134.4, 132.5, 130.9, 130.8, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.2, 128.1, 119.6, 119.5, 68.3, 68.2, 67.2, 67.1, 62.1, 61.9, 42.8, 42.3, 41.3, 40.8; IR (Neat Film, NaCl) 3386, 3064, 3033, 2955, 2897, 1746, 1713, 1694, 1651, 1600, 1584, 1498, 1450, 1417, 1368, 1304, 1278, 1229, 1195, 1178, 1160, 1124, 1088, 1061, 1014, 985, 951, 860, 794, 768, 729, 696, 675, 623 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C23H23N2O6 [M+H]+: 423.1551, found 423.1547. O O BzN O NBoc Cl 1-(tert-butyl) 2-(2-chloroallyl) 4-benzoyl-3-oxopiperazine-1,2-dicarboxylate (1.3d). Following the procedure described for the preparation of 1.2, benzoyl protected oxopiperazine (440 mg, 1.5 mmol, 1.0 equiv) was treated with LiHMDS (267 mg, 1.6 25 (235 mg, 1.5 mmol, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles mmol, 1.1 equiv) and acylated with 2-chloroallyl chloroformate 62 1.05 equiv) to give, after purification by silica gel flash chromatography (Dry load SiO2, 15% EtOAc/hexanes), 2-chloroallyl ester 1.3d as an off-white solid (431 mg, 70% yield): 1 H NMR (500 MHz, CDCl3): δ (a mixture of two rotamers) 7.59–7.54 (m, 2H), 7.50– 7.44 (m, 1H), 7.43–7.37 (m, 2H), 6.67 (m, 1H), 5.42–5.33 (m, 2H), 4.54 (m, 2H), 3.95– 3.89 (m, 2H), 3.72 (t, J = 5.2 Hz, 2H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (a mixture of two rotamers) 167.5, 167.3, 152.4, 152.2, 151.1, 151.0, 135.1, 134.9, 134.3, 131.3, 131.2, 128.5, 128.4, 128.0, 127.9, 126.7, 115.9, 115.7, 107.9, 107.6, 82.3, 82.2, 69.9, 69.8, 44.2, 43.1, 42.3, 41.7, 28.3; IR (Neat Film, NaCl) 3396, 3129, 3062, 2979, 2936, 2253, 1770, 1691, 1372, 1242, 1050, 987, 950, 922, 859, 839, 764, 731, 707, 647 cm-1; HRMS (MM: ESI-APCI) m/z calculated for C20H24ClN2O6 [M+H]+: 423.1317, found 423.1316. O Me O BzN O NBoc 2-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-2-methyl-3-oxopiperazine-1,2- dicarboxylate (1.3e). Sodium hydride (60% in mineral oil, 25 mg, 0.62 mmol, 1.2 equiv) was added to a solution of allyl ester 2 (200 mg, 0.52 mmol, 1.0 equiv) in THF (5 mL) at 0 °C. After stirring for 30 min at 0 °C, MeI (160 µL, 2.57 mmol, 5.0 equiv) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was 26 purified by silica gel flash chromatography (20% EtOAc/hexanes) to give methylated Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles allyl ester 3e as a colorless oil (180 mg, 85% yield): 1H NMR (400 MHz, CDCl3): δ 7.59 – 7.46 (m, 3H), 7.46 – 7.32 (m, 2H), 5.92 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.41 – 5.19 (m, 2H), 4.66 (d, J = 5.8 Hz, 2H), 4.24 – 4.09 (m, 1H), 4.05 – 3.90 (m, 2H), 3.81 – 3.64 (m, 1H), 1.84 (s, 3H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3): δ (a mixture of two rotamers) 172.5, 169.2, 168.0, 153.2, 134.8, 132.4, 131.5, 128.4, 128.0, 119.1, 82.7, 68.7, 66.9, 43.7, 40.9, 28.3, 21.5; IR (Neat Film, NaCl) 3384, 3064, 2980, 2939, 2876, 1962, 1766, 1694, 1600, 1584, 1451, 1394, 1368, 1306, 1270, 1232, 1206, 1164, 1096, 1060, 1032, 1016, 993, 968, 936, 854, 795, 770, 727, 696, 675, 633, 618 cm-1; HRMS (MM: ESI-APCI) m/z calculated for C16H19N2O4 [(M-Boc)+H]+: 303.1341, found 303.1339. O O Me O N MeO 2-allyl 1-(tert-butyl) O NBoc 4-(4-methoxybenzoyl)-2-methyl-3-oxopiperazine-1,2- dicarboxylate (1.3f). Following the procedure described for the preparation of 1.3e, anisoyl protected oxopiperazine 1.3b (120 mg, 0.29 mmol, 1.0 equiv) was treated with NaH (60% in mineral oil, 13 mg, 0.32 mmol, 1.1 equiv) and methylated with MeI (90 µL, 1.43 mmol, 5.0 equiv) to give, after purification by silica gel flash chromatography (dry load SiO2, 15% → 20% → 25% → 30% EtOAc/hexanes), methylated allyl ester 1.3f as a colorless oil (110 mg, 89% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 5.92 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.40 – 5.17 (m, 2H), 4.66 (d, J = 5.8 Hz, 2H), 4.15 – 4.02 (m, 1H), 4.02 – 3.87 (m, 2H), 3.83 (s, 3H), 3.80 – 3.67 (m, 1H), 1.84 (s, 3H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.8, 169.0, 27 168.1, 163.4, 153.2, 131.5, 131.0, 126.6, 119.0, 113.7, 82.6, 68.5, 66.8, 55.5, 43.8, 41.0, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 28.3, 21.6; IR (Neat Film, NaCl) 3081, 2978, 2938, 2842, 1766, 1702, 1604, 1579, 1512, 1460, 1394, 1368, 1308, 1287, 1259, 1235, 1208, 1169, 1114, 1095, 1060, 1021, 1004, 969, 933, 845, 789, 770, 733, 706, 648, 634 cm-1; HRMS (MM: ESI-APCI) m/z calculated for C18H21N2O7 [(M-tBu)+H]+: 377.1343, found 377.1339. O O Ph O N MeO 2-allyl 1-(tert-butyl) O NBoc 2-benzyl-4-(4-methoxybenzoyl)-3-oxopiperazine-1,2- dicarboxylate (1.3h). Following the procedure described for the preparation of 1.3e, anisoyl-protected allyl ester 1.3b (200 mg, 0.48 mmol, 1.0 equiv) was treated with potassium hydride (23 mg, 0.57 mmol, 1.2 equiv) and alkylated with benzyl bromide (170 µL, 1.43 mmol, 3.0 equiv) to give, after purification by silica gel flash chromatography (Dry load SiO2, 20% → 25% EtOAc/hexanes), the benzyl ester 1.3h as a colorless oil (100 mg, 41% yield) (Note: attempts using sodium hydride as a base failed to give conversion of starting material. Instead, potassium hydride resulted in conversion to the desired product.): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.52 (m, 2H), 7.42 – 7.23 (m, 3H), 7.11 (m, 2H), 6.92 – 6.75 (m, 2H), 5.97 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.50 – 5.17 (m, 2H), 4.87 – 4.57 (m, 2H), 3.86 (s, 3H), 3.79 – 3.56 (m, 4H), 2.95 (ddd, J = 13.3, 7.4, 3.0 Hz, 1H), 2.86 (br s, 1H), 1.55 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 172.1, 168.0, 167.4, 166.9, 163.4, 153.6, 153.4, 136.0, 135.3, 131.8, 131.3, 130.7, 128.8, 128.7, 128.4, 128.2, 127.8, 127.7, 127.5, 126.6, 119.4, 118.9, 113.7, 82.9, 81.8, 72.7, 67.0, 66.5, 55.6, 44.5, 43.0, 42.2, 41.4, 40.8, 28 40.0, 38.8, 28.5; IR (Neat Film, NaCl) 2978, 1764, 1698, 1604, 1512, 1496, 1455, 1394, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1366, 1307, 1282, 1256, 1196, 1155, 1078, 1020, 1000, 921, 844, 768 733, 704 cm-1; HRMS (MM: ESI-APCI) m/z calculated for C28H33N2O7 [M+H]+: 509.2282, found 509.2285. O OBn O BzN O NBoc 2-allyl 1-(tert-butyl) 4-benzoyl-2-((benzyloxy)methyl)-3-oxopiperazine-1,2- dicarboxylate (1.3i). Following the procedure described for the preparation of 1.3e, allyl ester 1.2 (150 mg, 0.39 mmol, 1.00 equiv) was treated with sodium hydride (17 mg, 0.42 mmol, 1.1 equiv) and alkylated with benzyl chloromethyl ether (107 µL, 0.77 mmol, 2.0 equiv) to give, after purification by silica gel flash chromatography (Dry load SiO2, 10% → 15% EtOAc/hexanes), benzyloxy methyl ether 1.3i as a colorless oil (50 mg, 55% yield BRSM): 1H NMR (500 MHz, CDCl3) δ (a mixture of two rotamers) 7.64 – 7.55 (m, 2H), 7.51 – 7.44 (m, 1H), 7.41 – 7.27 (m, 7H), 5.88 (ddt, J = 17.3, 10.4, 5.8 Hz, 1H), 5.40 – 5.17 (m, 2H), 4.74 – 4.47 (m, 4H), 4.38 (m, 1H), 4.17 (m, 1H), 4.08 – 3.84 (m, 4H), 1.42 (m, 9H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 173.0, 167.4, 167.2, 166.5, 153.6, 153.1, 141.0, 137.9, 137.5, 134.8, 132.4, 131.6, 131.1, 128.7, 128.7, 128.6, 128.4, 128.3, 128.0, 127.7, 127.6, 127.1, 119.5, 118.9, 82.7, 81.9, 73.9, 73.3, 72.6, 71.2, 71.1, 66.8, 65.4, 43.6, 43.4, 42.5, 41.7, 28.4, 28.3; IR (Neat Film, NaCl) 3528, 3064, 3031, 2978, 2934, 1762, 1694, 1600, 1496, 1453, 1394, 1366, 1314, 1270, 1231, 1205, 1161, 1094, 1055, 1014, 972, 941, 854, 795, 770, 730, 696, 674, 624 cm-1; HRMS (MM: ESI-APCI) m/z calculated for C24H25N2O7 [(M-tBu)+H]+: 453.1656, found 453.1649. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 29 NC O O O N MeO 2-allyl 1-(tert-butyl) O NBoc 2-(2-cyanoethyl)-4-(4-methoxybenzoyl)-3-oxopiperazine-1,2- dicarboxylate (1.3j). DBU (7.1 µL, 0.048 mmol, 0.10 equiv) was added to a solution of allyl ester 1.3b (200 mg, 0.478 mmol, 1.0 equiv) and acrylonitrile (94 µL, 1.43 mmol, 3.0 equiv) in DMF (2.4 mL) at room temperature. After stirring for 2 h at 70 °C and 24 h at 55 °C, additional DBU (14 µL, 0.1 mmol, 0.2 equiv) was added and the orange solution was maintained at 70 °C for 4 h. Then, additional DBU (21 µL, 0.143 mmol, 0.30 equiv) was added and the mixture was stirred at 70 °C for 3 h. After allowing the reaction mixture to cool to room temperature, the reaction was quenched with saturated aqueous NH4Cl (2 mL) and diluted with EtOAc (6 mL). The aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by flash chromatography (20% EtOAc/hexanes) to give the αcyanoethylated allyl ester 1.3j as a pale yellow oil (77.6 mg, 34% yield): 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 2H), 6.85 (d, J = 8.9 Hz, 2H), 5.92 (ddt, J = 17.2, 10.4 Hz, 5.9 Hz, 1H), 5.36 (dd, J = 17.2, 1.4 Hz, 1H), 5.29 (d, J = 10.5 Hz, 1H), 4.69 (d, J = 5.8 Hz, 2H), 4.25 (s, 1H), 4.06 (ddd, J = 13.1, 5.7, 3.1 Hz, 1H), 3.96 (ddd, J = 13.1, 8.6, 3.4 Hz, 1H), 3.83 (s, 3H), 3.64 – 3.49 (m, 1H), 2.77 (s, 2H), 2.49 (m, 1H), 2.44 – 2.31 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.7, 167.24, 166.3, 163.5, 153.4, 131.1, 126.2, 119.6, 119.1, 113.8, 82.9, 70.5, 67.3, 55.5, 43.9, 42.3, 29.8, 28.2, 12.8; IR (Neat Film, NaCl) 2978, 2249, 1760, 1694, 1604, 1579, 1512, 1462, 1394, 1368, 1311, 1258, 30 1160, 1018, 933, 846, 769, 737, 704 cm ; HRMS (MM: ESI-APCI): m/z calc’d for Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles -1 C24H30N3O7 [M+H]+: 472.2078, found 472.2078. O Me O O O N MeO 2-allyl 1-(tert-butyl) O NBoc 4-(4-methoxybenzoyl)-3-oxo-2-(3-oxobutyl)piperazine-1,2- dicarboxylate (1.3k). To a solution of allyl ester 1.3b (200 mg, 0.5 mmol, 1.0 equiv) and methyl vinyl ketone (80 µL, 0.96 mmol, 2.0 equiv) in acetone (2 mL) at room temperature was added DBU (7.1 µL, 0.05 mmol, 0.1 equiv). After stirring for 24 h at 55 °C, additional DBU (7.1 µL, 0.05 mmol, 0.1 equiv) was added and the orange solution was maintained at 55 °C for an additional 24 h. The reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was purified by silica gel flash column chromatography (33% EtOAc/hexanes) to afford the ketone 1.3k as a pale yellow oil (90 mg, 39% yield): 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 5.92 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.35 (dd, J = 17.2, 1.5 Hz, 1H), 5.26 (d, J = 10.4 Hz, 1H), 4.71 – 4.60 (m, 2H), 4.11 – 3.93 (m, 3H), 3.82 (s, 3H), 3.71 – 3.59 (m, 1H), 2.72 (q, J = 9.3, 8.1 Hz, 1H), 2.60 (dt, J = 9.6, 6.2 Hz, 3H), 2.10 (s, 3H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 207.8, 172.0, 167.9, 167.4, 163.4, 153.5, 131.5, 131.1, 126.6, 119.2, 113.7, 82.4, 70.6, 66.9, 55.5, 43.5, 42.1, 38.8, 29.8, 28.7, 28.3; IR (Neat Film, NaCl): 2977, 2934, 1761, 1704, 1604, 1512, 1456, 1394, 1367, 1312, 1257, 1199, 1168, 1090, 1018, 845, 768 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C25H33N2O8 [M+H]+: 489.2231, found: 489.2228. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O O NHCbz O N MeO 31 O NBoc 2-allyl 1-(tert-butyl) 2-((((benzyloxy)carbonyl)amino)methyl)-4-(4-methoxybenzoyl)3-oxopiperazine-1,2-dicarboxylate (1.3l). Following the procedure described for the preparation of 1.3m, anisoyl-protected allyl ester 1.3b (400 mg, 0.96 mmol, 1.0 equiv) was treated with Cs2CO3 (779 mg, 02.39 mmol, 2.5 equiv) and alkylated with benzyl ((phenylsulfonyl)methyl)carbamate59,60 (350 mg, 1.15 mmol, 2.5 equiv) to give, after purification by silica gel flash chromatography (Dry load SiO2, 10% → 15% → 20% EtOAc/hexanes), the aminomethyl allyl ester 1.3l as a white foam (300 mg, 54% yield): 1 H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.69 – 7.50 (m, 2H), 7.41 – 7.25 (m, 5H), 6.95 – 6.72 (m, 2H), 5.92 (ddt, J = 17.3, 10.4, 5.9 Hz, 1H), 5.49 – 4.96 (m, 5H), 4.85 – 4.53 (m, 2H), 4.27 – 3.87 (m, 5H), 3.83 (d, J = 14.6 Hz, 3H), 3.60 (d, J = 22.7 Hz, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 171.7, 167.3, 166.5, 163.4, 156.8, 153.7, 152.7, 136.4, 134.21, 132.5, 131.5, 131.2, 129.4, 129.3, 128.9, 128.6, 128.3, 126.5, 119.8, 119.3, 113.7, 83.1, 82.1, 71.4, 70.6, 68.3, 67.8, 67.0, 55.5, 45.0, 44.2, 43.7, 42.9, 41.9, 28.3; IR (Neat Film, NaCl) 3366, 2977, 1704, 1604, 1513, 1456, 1394, 1367, 1313, 1257, 1232, 1169, 1091, 1018, 1002, 845, 767, 698 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C30H36N3O9 [M+H]+: 582.2446, found 582.2438. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O 32 NHBoc O BzN O NBoc 2-allyl 1-(tert-butyl) 4-benzoyl-2-(((tert-butoxycarbonyl)amino)methyl)-3- oxopiperazine-1,2-dicarboxylate (1.3m). To a suspension of allyl ester 1.2 (200 mg, 0.5 mmol, 1.0 equiv) and tert-butyl ((phenylsulfonyl)methyl)carbamate59,60 (168 mg, 0.6 mmol, 1.2 equiv), in dichloromethane (2.5 mL) at room temperature was added Cs2CO3 (419 mg, 1.3 mmol, 2.5 equiv). After stirring for 3 h, saturated aqueous NH4Cl (1 mL) was added and the biphasic mixture was vigorously stirred for 20 min. The aqueous phase was extracted with dichloromethane (3 x 3 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was purified by silica gel flash column chromatography (15% EtOAc/hexanes) to give methylcarbamate allyl ester 1.3m as a white foam (202 mg, 76% yield): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.55 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 5.91 (ddt, J = 16.5, 10.4, 5.8 Hz, 1H), 5.34 – 5.27 (m, 2H), 4.96 (m, 1H), 4.66 (br s, 2H), 4.19 – 3.85 (m, 5H), 3.79 – 3.64 (m, 1H), 1.48 (s, 9H), 1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 172.4, 167.3, 166.8, 156.1, 153.6, 152.9, 134.9, 132.4, 131.7, 131.1, 128.3, 128.3, 119.6, 119.0, 83.1, 82.1, 79.9, 71.4, 70.6, 67.0, 44.3, 43.8, 43.2, 42.2, 41.6, 28.4, 28.3; IR (Neat Film, NaCl) 3386, 2978, 1760, 1698, 1601, 1505, 1451, 1394, 1367, 1314, 1232, 1203, 1164, 1092, 1067, 1012, 915, 854, 766, 730, 696 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C26H36N3O8 [M+H]+: 518.2497, found 518.2496. 33 Procedures for the Synthesis of Tetrahydropyrimidinone Allylic Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.4.2.2 Alkylation Substrates O HN N Boc tert-Butyl 4-oxotetrahydropyrimidine-1(2H)-carboxylate. A solution of 3- aminopropanamide hydrochloride (5 g, 40.1 mmol, 1.0 equiv), potassium hydroxide (3.38 g, 60.2 mmol, 1.5 equiv), and formaldehyde (37% in water, 5.97 mL, 80.3 mmol, 2.0 equiv) in ethanol (13 mL) was stirred at reflux for 4 h. The suspension was then maintained at 55 °C while triethylamine (5.5 mL, 40.1 mmol, 1 equiv) and di-tert-butyl dicarbonate (9.2 g, 42.1 mmol, 1.05 equiv) were added successively. The reaction was stirred for 2 h at 55 °C and then allowed to cool to ambient temperature. The precipitate was filtered off, the filtrate was concentrated under reduced pressure, and was then purified by silica gel flash chromatography (1 → 3% MeOH/CH2Cl2) to afford Bocprotected tetrahydropyrimidinone as a white solid (4.09 g, 51% yield over two steps): 1H NMR (500 MHz, CDCl3) δ 8.14 – 7.60 (m, 1H), 4.77 – 4.61 (m, 2H), 3.58 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 6.5 Hz, 2H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 171.5, 153.8, 153.4, 81.1, 54.8, 54.0, 40.4, 39.4, 31.4, 28.3; IR (Neat Film, NaCl) 3193, 2970, 1710, 1643, 1488, 1404, 1366, 1326, 1276, 1245, 1210, 1159, 1136, 1020, 949, 776 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C9H17N2O3 [M+H]+: 201.1234, found 201.1231. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 34 O BzN N Boc tert-Butyl 3-benzoyl-4-oxotetrahydropyrimidine-1(2H)-carboxylate. To a solution of tetrahydropyrimidinone (2.07 g, 10.4 mmol, 1.0 equiv) in THF (100 mL) at −78 °C was added n-butyllithium (2.2 M in hexanes, 4.94 mL, 10.9 mmol, 1.05 equiv) dropwise over 10 min. After stirring the solution at −78 °C for 20 min, benzoyl chloride (1.43 mL, 12.4 mmol, 1.2 equiv) was added dropwise at −78 °C. The reaction solution was stirred at −78 °C for 40 min, allowed to warm up to room temperature, and was then quenched with saturated aqueous NH4Cl (50 mL). The mixture was diluted with EtOAc (100 mL) and the aqueous phase was extracted with EtOAc (3 x 80 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (30% EtOAc/hexanes) to give Bz-protected tetrahydropyrimidinone as a white solid (2.72 g, 86% yield): 1H NMR (400 MHz, Chloroform-d) δ 7.55 (dt, J = 8.3, 1.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 5.28 (s, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.3, 170.7, 153.8, 135.0, 132.2, 128.4, 128.2, 81.7, 57.0, 40.4, 33.4, 28.3; IR (Neat Film, NaCl) 2978, 1698, 1480, 1450, 1408, 1367, 1304, 1266, 1239, 1141, 1015, 936, 863, 797, 700, 618 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C16H21N2O4 [M+H]+: 305.1496, found 305.1500. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O BzN 35 O O N Boc 5-Allyl 1-(tert-butyl) 3-benzoyl-4-oxotetrahydropyrimidine-1,5(2H)-dicarboxylate. To a solution of diisopropylamine (224 µL, 1.59 mmol, 1.2 equiv) in THF (3 mL) at −78 °C was added n-butyllithium (2.2 M in hexanes, 664 µL, 1.46 mmol, 1.1 equiv). The solution was maintained at −78 °C for 15 min and then cannulated over 10 min into a solution of Bz-protected tetrahydropyrimidine (404 mg, 1.33 mmol, 1.0 equiv) in THF (10 mL) at −78 °C. After stirring the solution at −78 °C for 25 min, allyl cyanoformate (156 µL, 1.46 mmol, 1.1 equiv) was added dropwise at −78 °C. The reaction mixture was maintained at −78 °C for 50 min and was then quenched with saturated aqueous NH4Cl (10 mL). The reaction mixture was diluted with EtOAc (10mL) and allowed to warm to room temperature. The aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (18 → 20 → 30% EtOAc/hexanes) to give re-isolated starting material (154 mg, 38% yield) and allyl ester as a white crystalline solid (310 mg, 60% yield, 97% yield based on recovered starting material): 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 5.95 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.37 (dq, J = 17.2, 1.5 Hz, 1H), 5.36 (m, 1H), 5.30 (dd, J = 10.4, 1.3 Hz, 1H), 5.17 (d, J = 12.6 Hz, 1H), 4.69 (d, J = 6.0 Hz, 2H), 4.27 (ddd, J = 13.7, 5.4, 1.2 Hz, 1H), 3.85 (dd, J = 13.7, 6.2 Hz, 1H), 3.63 (t, J = 5.7 Hz, 1H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.9, 167.8, 167.0, 153.4, 134.6, 132.5, 131.3, 128.7, 128.3, 119.7, 82.3, 67.0, 58.5, 50.1, 43.9, 28.3; IR (Neat Film, NaCl) 3406, 3064, 2978, 2935, 36 1714, 1601, 1480, 1450, 1416, 1369, 1287, 1148, 1072, 1017, 934 , 859, 796, 768, 736, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 703, 626 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H25N2O6 [M+H]+: 389.1707, found 389.1708. O Me BzN O O N Boc 1-(tert-butyl) 3-benzoyl-5-methyl-4-oxotetrahydropyrimidine-1,5(2H)-dicarboxylate (1.5a). To a solution of allyl ester (100 mg, 0.26 mmol, 1.0 equiv) in acetonitrile (2.6 mL) at 0 °C was added cesium carbonate (168 mg, 0.52 mmol, 2.0 equiv). After stirring the suspension for 30 min at 0 °C, methyl iodide (48 µL, 0.77 mmol, 3.0 equiv) was added. The reaction mixture was stirred for 3 h at 0 °C and diluted with saturated aqueous NH4Cl (2 mL) and EtOAc (2 mL). The aqueous phase was extracted with EtOAc (4 x 3 mL) and the combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The residue was purified by silica gel flash chromatography (15% EtOAc/hexanes) to give methylated allyl ester 1.5a as a colorless oil (100 mg, 95% yield): 1H NMR (500 MHz, CDCl3) δ (a mixture of two rotamers) 7.71 (d, J = 15.3 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 6.8 Hz, 2H), 5.96 (ddt, J = 16.6, 10.4, 6.0 Hz, 1H), 5.48 – 5.17 (m, 4H), 4.71 (d, J = 6.1 Hz, 2H), 4.43 (m, 1H), 3.38 (m, 1H), 1.49 (s, 9H), 1.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.2, 170.9, 170.7, 153.2, 135.0, 132.3, 131.3, 128.4, 128.2, 119.7, 82.1, 67.1, 58.9, 58.1, 52.8, 50.6, 50.3, 28.3, 19.3; IR (Neat Film, NaCl) 3406, 3065, 2980, 2939, 1714, 1602, 1450, 1423, 1369, 1288, 1251, 1162, 1134, 1104, 1028, 984, 938, 902, 857, 804, 765, 732, 697, 657, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C21H27N2O6 [M+H]+: 403.1864, found 403.1868. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O Et BzN 37 O O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-5-ethyl-4-oxotetrahydropyrimidine-1,5(2H)- dicarboxylate (1.5b). Following the procedure described for the preparation of 1.5a, allyl ester (200 mg, 0.52 mmol, 1.0 equiv) was treated with cesium carbonate (336 mg, 1.03 mmol, 2.0 equiv) and alkylated with ethyl iodide (124 µL, 1.54 mmol, 3.0 equiv) to give, after purification by silica gel flash chromatography (dry load SiO2, 15% EtOAc/hexanes), ethylated allyl ester 1.5b as a colorless oil (182 mg, 85% yield): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.70 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 5.95 (ddt, J = 16.6, 10.4, 6.0 Hz, 1H), 5.38 (dd, J = 17.2, 1.5 Hz, 1H), 5.31 (d, J = 10.3 Hz, 2H), 5.20 (d, J = 12.5 Hz, 1H), 4.70 (t, J = 5.5 Hz, 2H), 4.47 – 4.26 (m, 1H), 3.49 (d, J = 13.5 Hz, 1H), 1.96 (q, J = 7.5 Hz, 2H), 1.49 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 172.9, 170.4, 170.1, 169.8, 153.2, 135.0, 132.3, 131.2, 128.4, 128.2, 119.8, 81.9, 66.9, 57.9, 57.4, 56.7, 47.8, 47.4, 28.3, 26.4, 9.1; IR (Neat Film, NaCl) 2976, 1703, 1450, 1422, 1367, 1288, 1247, 1156, 1134, 1015, 942, 894, 802, 766, 718, 696 cm1 ; HRMS (MM: ESI-APCI): m/z calc’d for C22H29N2O6 [M+H]+: 417.2020, found 417.2019. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 38 CO2Me O BzN O O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-5-(3-methoxy-3-oxopropyl)-4- oxotetrahydropyrimidine-1,5(2H)-dicarboxylate (1.5c). To a suspension of allyl ester (100 mg, 0.26 mmol, 1.0 equiv) and potassium carbonate (178 mg, 1.29 mmol, 5.0 equiv) in acetone (1.0 mL) at room temperature was added methyl acrylate (47 µL, 0.52 mmol, 2.0 equiv). The reaction mixture was stirred for 3.5 h at 55 °C, allowed to cool to room temperature, and filtered through a cotton plug. The filter cake was washed with acetone (3 x 1 mL) and the combined organic phases were concentrated by under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (19% EtOAc/hexanes) to give pyrimidinone 1.5c as a colorless oil (101 mg, 83% yield): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.70 (br s, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 5.95 (ddt, J = 16.6, 10.3, 6.0 Hz, 1H), 5.38 (dd, J = 17.1, 1.6 Hz, 1H), 5.32 (d, J = 10.4 Hz, 1H), 5.25 (m, 2H), 4.70 (d, J = 6.0 Hz, 2H), 4.41 (m, 1H), 3.62 (s, 3H), 3.47 (m, 1H), 2.58 (ddd, J = 16.0, 9.5, 6.4 Hz, 1H), 2.46 – 2.33 (m, 1H), 2.21 (ddd, J = 10.0, 6.3, 3.2 Hz, 2H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.0, 172.9, 169.7, 153.1, 134.9, 132.4, 131.1, 128.4, 128.3, 120.1, 82.2, 67.2, 58.3, 57.6, 55.6, 51.9, 48.7, 48.2, 29.7, 28.3; IR (Neat Film, NaCl) 2978, 1704, 1423, 1368, 1248, 1153, 987, 803, 722, 696 cm1 ; HRMS (MM: ESI-APCI): m/z calc’d for C24H31N2O8 [M+H]+: 475.2075, found 475.2074. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O BzN O 39 Cl O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-5-(2-chloroallyl)-4-oxotetrahydropyrimidine-1,5(2H)dicarboxylate (1.5d). To a suspension of allyl ester (200 mg, 0.51 mmol, 1.0 equiv) and tetrabutylammonium iodide (17 mg, 0.05 mmol, 0.1 equiv), in THF (5.1 mL) at 0 °C was added NaH (60% in mineral oil, 25 mg, 0.62 mmol, 1.2 equiv). After stirring for 30 min at 0 °C, 2,3-dichloro-1-propene (95 µL, 1.02 mmol, 2 equiv) was added and the reaction mixture heated at 40 °C for 16 h. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (10% → 15% EtOAc/hexanes) to give 2-chloro-allyl allyl ester 1.5d as a colorless oil (140 mg, 59% yield): 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.6 Hz, 2H), 7.51 (s, 1H), 7.39 (t, J = 7.5 Hz, 2H), 6.07 – 5.90 (m, 1H), 5.71 – 5.48 (m, 1H), 5.33 (m, 4H), 5.03 (d, J = 12.5 Hz, 1H), 4.85 – 4.43 (m, 3H), 3.58 (mz, 1H), 3.32 (d, J = 15.1 Hz, 1H), 3.03 (d, J = 15f.1 Hz, 1H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.3, 169.9, 168.7, 153.4, 136.3, 134.9, 132.4, 131.2, 128.7, 128.2, 120.1, 118.8, 82.1, 67.7, 58.5, 57.8, 55.1, 47.7, 47.2, 41.0, 28.3; IR (Neat Film, NaCl) 2978, 1703, 1632, 1478, 1450, 1423, 1368, 1289, 1246, 1137, 902, 803, 721, 695, 633 cm-1; HRMS (MM: ESIAPCI): m/z calc’d for C23H28ClN2O6 [M+H]+: 463.1630, found 463.1641. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O BzN 40 Ph O O N Boc 5-Allyl 1-(tert-butyl) 3-benzoyl-5-benzyl-4-oxotetrahydropyrimidine-1,5(2H)- dicarboxylate (1.5e). To a solution of allyl ester (100 mg, 0.26 mmol, 1.0 equiv) in THF (2.6 mL) at room temperature was added sodium hydride (11 mg, 0.28 mmol, 1.1 equiv). After stirring for 15 min, benzyl bromide (37 µL, 0.31 mmol, 1.2 equiv) was added. The reaction mixture was maintained at room temperature for 22 h and at 55 °C for 24 h. The reaction was quenched with aqueous NH4Cl (2 mL) and diluted with EtOAc (2mL). The aqueous phase was extracted with EtOAc (3 x 3mL) and the combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (15% EtOAc/hexanes) to give benzylated allyl ester 1.5e as a colorless oil (94 mg, 76% yield): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.29 – 7.19 (m, 3H), 7.14 (dd, J = 7.4, 2.2 Hz, 2H), 5.95 (ddt, J = 16.6, 10.4, 6.0 Hz, 1H), 5.44 – 5.19 (m, 3H), 4.73 (m, 3H), 4.56 – 4.37 (m, 1H), 3.50 (d, J = 14.0 Hz, 1H), 3.33 (d, J = 13.9 Hz, 1H), 3.14 (d, J = 14.0 Hz, 1H), 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.1, 170.4, 169.3, 153.2, 135.0, 134.9, 132.4, 131.3, 130.9, 128.7, 128.7, 128.2, 127.5, 119.9, 81.9, 67.3, 58.0, 57.5, 57.3, 47.8, 47.2, 38.1, 28.3; IR (Neat Film, NaCl) 3063, 2978, 2935, 1704, 1602, 1479, 1451, 1418, 1368, 1287, 1251, 1152, 1093, 1002, 927, 902, 857, 804, 764, 727, 697, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H31N2O6 [M+H]+: 479.2177, found 479.2180. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 41 CN O BzN O O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-5-(2-cyanoethyl)-4-oxotetrahydropyrimidine- 1,5(2H)-dicarboxylate (1.5f). To a solution of allyl ester (100 mg, 0.26 mmol, 1.0 equiv) and acrylonitrile (34 µL, 0.52 mmol, 2.0 equiv) in acetonitrile (1.3 mL) at room temperature was added DBU (1.9 µL, 0.013 mmol, 0.05 equiv). After 22 h at room temperature, the reaction mixture was heated to 70 °C for 32 h, allowed to cool to room temperature, and treated with additional DBU (1.9 µL, 0.013 mmol, 0.05 equiv). After 2 h at 70 °C, the reaction mixture was allowed to cool to room temperature, directly concentrated onto silica gel, and purified by silica gel flash chromatography (22% EtOAc/hexanes) to give cyanoethylated pyrimidinone 1.5f as a colorless oil (71.5 mg, 63% yield): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 5.97 (ddt, J = 16.7, 10.3, 6.1 Hz, 1H), 5.41 (dd, J = 17.4, 1.5 Hz, 1H), 5.36 (d, J = 10.5 Hz, 1H), 5.28 (m, 2H), 4.74 (m, 2H), 4.41 (d, J = 13.8 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 2.72 (dt, J = 16.2, 7.9 Hz, 1H), 2.50 (dt, J = 16.6, 7.8 Hz, 1H), 2.20 (t, J = 7.9 Hz, 2H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.0, 169.4, 169.0, 153.1, 134.6, 132.7, 130.8, 128.4, 128.4, 120.6, 118.9, 82.6, 67.6, 67.6, 58.8, 57.9, 55.1, 49.0, 48.4, 29.2, 28.4, 13.6; IR (Neat Film, NaCl) 2979, 2250, 1698, 1450, 1423, 1369, 1286, 1250, 1155, 1030, 939, 857, 803, 718, 696, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C23H31N4O6 [M+NH4]+: 459.2238, found 459.2243. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 42 OBn O O BzN O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-5-((benzyloxy)methyl)-4-oxotetrahydropyrimidine1,5(2H)-dicarboxylate (1.5g). Following the procedure described for the preparation of 1.5a, allyl ester (200 mg, 0.52 mmol, 1.0 equiv) was treated with sodium hydride (29 mg, 0.72 mmol, 1.4 equiv) and alkylated with benzyl chloromethyl ether (127 µL, 0.93 mmol, 1.8 equiv) to give, after two rounds of purification by silica gel flash chromatography (dry load SiO2, 16 → 25% EtOAc/hexanes), BOM-alkylated allyl ester 1.5g as a colorless oil (57 mg, 22% yield): 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 8.3 Hz, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.41 – 7.24 (m, 7H), 5.94 (ddt, J = 16.5, 10.3, 6.0 Hz, 1H), 5.63 (d, J = 12.2 Hz, 1H), 5.43 – 5.25 (m, 2H), 4.95 (d, J = 12.4 Hz, 1H), 4.74 (dd, J = 13.0, 5.9 Hz, 1H), 4.70 – 4.36 (m, 4H), 4.07 (d, J = 9.2 Hz, 1H), 3.96 – 3.80 (m, 1H), 3.74 (d, J = 9.3 Hz, 1H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.2, 169.0, 168.7, 168.3, 153.6, 153.3, 137.5, 134.9, 132.2, 131.3, 131.0, 128.6, 128.1, 128.0, 127.7, 119.9, 119.7, 81.9, 73.9, 70.0, 67.1, 58.7, 57.9, 57.0, 47.0, 46.7, 28.3; IR (Neat Film, NaCl) 2978, 2360, 1704, 1453, 1418, 1368, 1290, 1248, 1153, 1128, 1072, 1003, 904, 857, 803, 735, 697, 633 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C28H33N2O7 [M+H]+: 509.2282, found 509.2279. O F O BzN O N Boc 43 3-benzoyl-5-fluoro-4-oxotetrahydropyrimidine-1,5(2H)- Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 5-allyl 1-(tert-butyl) dicarboxylate (1.5h). To a solution of allyl ester (100 mg, 0.257 mmol, 1.0 equiv) in THF (2.6 mL) at room temperature was added sodium hydride (11 mg, 0.28 mmol, 1.1 equiv). After stirring for 15 min, Selectfluor (109 mg, 0.31 mmol, 1.2 equiv) was added and the reaction mixture was stirred for 1.5 h at room temperature. The reaction was quenched with aqueous NH4Cl (2 mL) and diluted with EtOAc (2 mL). The aqueous phase was extracted with EtOAc (3 x 3 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated by reduced pressure onto silica gel. The residue was purified by silica gel flash chromatography (4:1 hexanes/EtOAc) to give fluorinated allyl ester 1.5h as a colorless oil (92 mg, 0.226 mmol, 88%); 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.67 (s, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 5.95 (ddt, J = 16.6, 10.3, 6.0 Hz, 1H), 5.63 – 5.07 (m, 4H), 4.88 – 4.77 (m, 1H), 4.75 (s, 1H), 4.43 (m, 1H), 3.99 (m, 1H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 172.4, 165.3, 164.4, 153.1, 133.8, 132.9, 130.5, 128.6, 128.5, 120.4, 89.3 (d, JCF = 192.9 Hz, appears as four peaks due to the presence of two rotamers and coupling with fluorine), 82.8, 67.8, 59.0, 58.4, 49.2, (d, JCF = 28.3 Hz), 48.4 (d, JCF = 27.3 Hz), 28.2; IR (Neat Film, NaCl) 2979, 2360, 1770, 1715, 1601, 1478, 1450, 1418, 1369, 1287, 1252, 1157, 1134, 1072, 1018, 907, 857, 829, 803, 764, 730, 695, 658, 633 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H27FN3O6 [M+NH4]+: 424.1878, found 424.1877. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O BzN 44 O O N Boc 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)tetrahydropyrimidine- 1,5(2H)-dicarboxylate 1.5i. To a solution of allyl ester (200 mg, 0.51 mmol, 1.0 equiv) in THF (5 mL) at 0 °C was quickly added sodium hydride (23 mg, 0.57 mmol, 1.1 equiv). After stirring at 0 °C for 30 minutes, propargyl bromide (111 µL, 1.03 mmol, 2 equiv) was added and the reaction mixture was heated to 50 °C. After three hours, more propargyl bromide (111 µL, 1.03 mmol, 2 equiv) was added and the reaction was allowed to continue for 16 h at 50 °C. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (50% CH2Cl2/hexanes → 70% CH2Cl2/hexanes → 20% EtOAc/hexanes) to afford the propargylated allyl ester 1.5i as a colorless oil (160 mg, 73% yield): 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 7.50 (d, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 5.96 (dd, J = 17.0, 10.6 Hz, 1H), 5.64 (dd, J = 12.4, 2.1 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 5.16 – 4.88 (m, 1H), 4.82 – 4.32 (m, 3H), 4.01 – 3.63 (m, 1H), 3.03 (d, J = 18.2 Hz, 1H), 2.71 (dd, J = 17.0, 2.7 Hz, 1H), 2.09 (t, J = 2.6 Hz, 1H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.3, 169.6, 168.6, 153.5, 134.9, 132.4, 131.2, 130.9, 128.6, 128.2, 120.0, 82.2, 78.8, 72.6, 67.5, 58.9, 58.2, 55.2, 48.2, 28.3, 23.0; IR (Neat Film, NaCl) 3280, 2978, 1704, 1600, 1479, 1450, 1422, 1368, 1287, 1245, 1155, 1140, 1073, 1016, 929, 904, 856, 803, 765, 733 695, 656 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C23H27N2O6 [M+H]+: 427.1864, found 427.1859. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.4.2.3 45 General Procedure for Allylic Alkylation Optimization Screen Optimization of Reaction Parameters NHBoc O O BzN NHBoc O Pd2(pmdba)3 (4 mol %) L (10 mol %) O NBoc BzN NBoc Solvent (0.014 M) 40 °C, 12 h 3m Entry 4m L Solvent Yield (%)b ee (%)c 76 1 L1 Tol 75 2 L2 Tol 70 1 3 L3 Tol 83 52 4 L1 THF – 13 5 L1 MTBE – 80 6 L1 2:1 Hex/Tol 93 93 CF3 O O F3C P N P N O O NH HN PPh2 Ph2P CF3 (S)-L1 (S)-L2 (S,S)-L3 [a] Screens performed on a 0.04 mmol scale. All reported yields are for isolated products. The ee values were determined by chiral SFC analysis. Bz = benzoyl, Boc = tert-butoxycarbonyl, pmdba = bis(4methoxybenzylidene)acetone In a nitrogen-filled glovebox, an oven-dried 1 dram vial was charged with Pd2(pmdba)3 (1.7 mg, 0.0015 mmol, 4 mol %), ligand (10 mol %), solvent (1 mL), and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then substrate 1.3m (20 mg, 0.04 mmol, 1.0 equiv) was added as a solution in solvent (1.8 mL, total concentration 0.014 M). The vial was sealed with a teflon cap and heated to 40 °C. When complete consumption of the starting material was observed by 46 thin layer chromatography, the reaction mixture was removed from the glovebox and Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the oxopiperazine 1.4m. 1.4.2.4 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions Please note The absolute configuration for all other products has been inferred by analogy.4,7,10,13,52,53 For respective SFC conditions, please refer to the section Determination of Enantiomeric Excess. In a nitrogen-filled glovebox, an oven-dried 1 dram vial or 20 mL scintillation vial was charged with Pd2(pmdba)3 or Pd2(dba)3 (4 mol %), (S)-(CF3)3-tBu-PHOX (10 mol %), hexane/toluene (2:1), and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then the substrate (1.0 equiv) was added as a solution in hexane/toluene (2:1, total concentration 0.014 M or 0.033 M). The vial was sealed with a teflon cap and heated to 40 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the desired oxopiperazine. 1.4.2.5 Experimental Procedures and Spectroscopic data for the Pd- Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Piperazinone Substrates Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 47 O BzN NBoc tert-butyl (S)-2-allyl-4-benzoyl-3-oxopiperazine-1-carboxylate (1.4a). Following the general procedure, allyl ester 3a (25 mg, 0.064 mmol, 1.0 equiv) in toluene (1.45 mL) was added to a solution of Pd2(dba)3 (2.3 mg, 0.0026 mmol, 4 mol %) and (S)-(CF3)3tBu-PHOX (3.8 mg, 0.0064 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (20% EtOAc/hexanes) gave monosubstituted oxopiperazine 1.4a as a yellow oil (21 mg, 90% yield, 92% ee). 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.64 – 7.46 (m, 3H), 7.41 (m, 2H), 5.83 (ddt, J = 17.2, 10.0, 7.3 Hz, 1H), 5.22 – 5.07 (m, 2H), 4.70 (m, 1H), 4.45 – 3.99 (m, 1H), 3.99 – 3.70 (m, 2H), 3.42 (m, 1H), 2.90 – 2.52 (m, 2H), 1.50 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 173.6, 170.6, 153.8, 135.3, 133.2, 132.2, 128.3, 128.3, 119.0, 81.3, 58.4, 44.5, 38.1, 37.2, 28.5. IR (Neat Film, NaCl) 2977, 2930, 1692, 1600, 1450, 1413, 1392, 1366, 1300, 1231, 1159, 1130, 1008, 973, 920, 856, 795, 762, 729, 696, 656 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H25N2O4 [M+H]+: 345.1809, found 345.1810; [α]D23.0 +49.5 (c 1.00, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD–H column, λ = 210 nm, tR (min): major = 3.741, minor = 2.682. O O N MeO tert-butyl NBoc (S)-2-allyl-4-(4-methoxybenzoyl)-3-oxopiperazine-1-carboxylate (1.4b). Following the general procedure, anisoyl-protected allyl ester 1.3b (15 mg, 0.036 mmol, 48 1.0 equiv) in toluene (0.6 mL) was added to a solution of Pd2(dba)3 (1.7 mg, 0.0014 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.8 mg, 0.0036 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (20% EtOAc/hexanes) gave monosubstituted oxopiperazine 1.4b as a light yellow oil (12 mg, 92% yield, 96% ee): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.60 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.85 (ddt, J = 17.1, 10.0, 7.3 Hz, 1H), 5.24 – 5.04 (m, 2H), 4.69 (m, 1H), 4.19 (m, 1H), 3.85 (m, 5H), 3.42 (m, 1H), 2.89 – 2.56 (m, 2H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.0, 170.6, 163.3, 153.9, 133.4, 131.2, 127.1, 118.9, 113.7, 81.3, 58.4, 55.6, 44.6, 38.3, 37.4, 28.5; IR (Neat Film, NaCl) 2976, 1694, 1605, 1512, 1462, 1416, 1366, 1315, 1257, 1234, 1170, 1130, 1003, 973, 842, 770 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H27N2O5 [M+H]+: 375.1914, found 375.1931; [α]D23.0 +41.7 (c 1.00, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD–H column, λ = 210 nm, tR (min): major = 4.708, minor = 3.998. O BzN NCbz benzyl (S)-2-allyl-4-benzoyl-3-oxopiperazine-1-carboxylate (1.4c). Following the general procedure, Cbz-protected allyl ester 1.3c (20 mg, 0.047 mmol, 1.0 equiv) in toluene (0.9 mL) was added to a solution of Pd2(dba)3 (2.2 mg, 0.0019 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (3.5 mg, 0.0047 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (20% EtOAc/hexanes) gave monosubstituted 49 oxopiperazine 1.4c as a colorless oil (15 mg, 83% yield, 99% ee): H NMR (500 MHz, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1 CDCl3) δ (a mixture of two rotamers) 7.62 – 7.46 (m, 3H), 7.44 – 7.29 (m, 7H), 5.79 (m, 1H), 5.16 (m, 4H), 4.83 (m, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 3.87 (m, 1H), 3.49 (m, 1H), 2.89 – 2.53 (m, 2H); 13C NMR (126 MHz, CDCl3) δ (a mixture of two rotamers) 173.5, 170.2, 154.7, 136.0, 135.2, 132.9, 132.3, 128.8, 128.6, 128.6, 128.4, 128.3, 119.3, 68.0, 58.4, 44.3, 39.6, 38.9, 37.2, 36.9; IR (Neat Film, NaCl) 3065, 2951, 1702, 1600, 1449, 1427, 1395, 1362, 1302, 1228, 1163, 1127, 1015, 975, 922, 796, 761,730, 697, 656 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H23N2O4 [M+H]+: 379.1652, found 379.1659; [α]D23.0 +66.0 (c 1.0, CHCl3); SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 4.873, minor = 6.748. O BzN NBoc Cl tert-butyl (S)-4-benzoyl-2-(2-chloroallyl)-3-oxopiperazine-1-carboxylate (1.4d). Following the general procedure, 2-chloroallyl ester 1.3d (20 mg, 0.047 mmol, 1.0 equiv.) in hexanes/toluene (2:1, 1.9 mL) was added to a solution of Pd2(pmdba)3 (2.1 mg, 0.0019 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.8 mg, 0.0047 mmol, 10 mol %) in hexanes/toluene (2:1, 1.5 mL). Purification by silica gel flash chromatography (15% EtOAc/hexanes) gave oxopiperazine 1.4d as a light yellow oil (15 mg, 85% yield, 98% ee). 1H NMR (400 MHz, CDCl3) δ (A mixture of two rotamers) 7.56 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 5.30 (s, 1H), 5.24 (s, 1H), 5.06 – 4.88 (m, 1H), 4.40 – 4.06 (m, 1H), 3.94 (m, 1H), 3.84 (m, 1H), 3.55 – 3.29 (m, 1H), 2.95 (dd, J = 13.1, 7.4 Hz, 2H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.5, 169.8, 153.7, 50 137.5, 135.3, 132.3, 128.4, 128.3, 116.8, 81.9, 57.0, 44.6, 41.8, 37.7, 28.4. IR (Neat Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Film, NaCl) 2977, 2359, 1694, 1635, 1456, 1418, 1394, 1367, 1284, 1232, 1200, 1158, 1007, 971, 892, 856, 796, 730, 696 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H24ClN2O4 [M+H]+: 379.1419, found 379.1416; [α]D23.1 +33.8 (c 1.00, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD–H column, λ = 254 nm, tR (min): major = 4.482, minor = 3.224. O Me BzN NBoc tert-butyl (S)-2-allyl-4-benzoyl-2-methyl-3-oxopiperazine-1-carboxylate (1.4e). Following the general procedure, methylated allyl ester 1.3e (23 mg, 0.057 mmol, 1.0 equiv) in toluene (1.2 mL) was added to a solution of Pd2(pmdba)3 (2.7 mg, 0.0023 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (3.7 mg, 0.0057 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (15% EtOAc/hexanes) gave disubstituted oxopiperazine 1.4e as a light yellow oil (17 mg, 85% yield, 96% ee). 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.46 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 5.81 – 5.67 (m, 1H), 5.17 – 5.13 (m, 1H), 5.12 (d, J = 1.1 Hz, 1H), 4.16 – 4.02 (m, 1H), 4.03 – 3.91 (m, 1H), 3.79 (ddd, J = 12.9, 9.0, 3.0 Hz, 1H), 3.53 (ddd, J = 14.1, 9.0, 2.8 Hz, 1H), 3.11 (m, 1H), 2.84 – 2.70 (m, 1H), 1.77 (s, 3H), 1.53 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 174.3, 172.8, 135.8, 133.1, 131.8, 128.3, 127.6, 119.5, 81.2, 67.3, 44.2, 42.7, 41.0, 28.6, 25.5; IR (Neat Film, NaCl) 3076, 2977, 2934, 1692, 1641, 16001,102, 1450, 1392, 1366, 1301, 1230, 1166, 1106, 1047, 1016, 955, 922, 852, 790, 757, 727, 695 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H27N2O4 [M+H]+: 359.1965, found 51 +6.5 (c 2.0, CHCl3); SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 359.1966; [α]D 22.8 AD-H column, λ = 210 nm, tR (min): major = 7.208, minor = 4.714. O O Me N MeO NBoc tert-butyl (S)-2-allyl-4-(4-methoxybenzoyl)-2-methyl-3-oxopiperazine-1-carboxylate (1.4f). Following the general procedure, anisoyl-protected allyl ester 1.3f (25 mg, 0.058 mmol, 1.0 equiv) in toluene (1.3 mL) was added to a solution of Pd2(pmdba)3 (2.5 mg, 0.0023 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (3.4 mg, 0.0058 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (20% EtOAc/hexanes) gave disubstituted oxopiperazine 1.4f as a light pink oil (19 mg, 86% yield, 96% ee). 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.53 (m, 2H), 6.99 – 6.82 (m, 2H), 5.86 – 5.67 (m, 1H), 5.23 – 5.04 (m, 2H), 4.01 (dddd, J = 33.5, 13.9, 5.8, 2.8 Hz, 2H), 3.85 (s, 3H), 3.74 (ddd, J = 12.7, 9.0, 2.8 Hz, 1H), 3.52 (ddd, J = 13.9, 9.0, 2.7 Hz, 1H), 3.20 (s, 1H), 2.80 (ddt, J = 14.0, 7.1, 1.2 Hz, 1H), 1.77 (s, 3H), 1.52 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.1, 172.4, 163.0, 153.9, 133.2, 130.6, 127.5, 119.4, 113.6, 81.2, 67.1, 55.5, 44.2, 42.8, 41.1, 28.6, 25.6; IR (Neat Film, NaCl) 3076, 2977, 2934, 1692, 1641, 16001,102, 1450, 1392, 1366, 1301, 1230, 1166, 1106, 1047, 1016, 955, 922, 852, 790, 757, 727, 695 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C21H29N2O5 [M+H]+: 389.2071, found 389.2083; [α]D22.0 +75.6 (c 2.9, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.370, minor = 4.278. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O 52 Me BzN NBz tert-butyl (S)-2-allyl-4-(4-methoxybenzoyl)-2-methyl-3-oxopiperazine-1-carboxylate (1.4g). Following the general procedure, di-Bz-protected allyl ester 1.3g (10 mg, 0.025 mmol, 1.0 equiv) in toluene (1.3 mL) was added to a solution of Pd2(dba)3 (0.9 mg, 0.00098 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.5 mg, 0.0025 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (20% EtOAc/hexanes) gave disubstituted oxopiperazine 1.4f as a colorless oil (8 mg, 89% yield, 70% ee). Product identity matched previously reported characterization data.4 SFC conditions: 10% MeOH, 2.5 mL/min, Chiralpak OJ-H column, λ = 254 nm, tR (min): major = 5.574, minor = 6.659. O O Ph N MeO NBoc tert-butyl (R)-2-allyl-2-benzyl-4-(4-methoxybenzoyl)-3-oxopiperazine-1-carboxylate (1.4h). Following the general procedure, benzylated allyl ester 1.3h (10 mg, 0.02 mmol, 1.0 equiv) in hexanes/toluene (2:1, 0.9 mL) was added to a solution of Pd2(pmdba)3 (0.86 mg, 0.00078 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.2 mg, 0.002 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). Purification by flash chromatography (5% → 10% → 15% EtOAc/hexanes) gave di-substituted oxopiperazine 1.4h as a colorless oil (7 mg, 77% yield, 96% ee): 1H NMR (400 MHz, CDCl3) δ (A mixture of two rotamers) 7.57 (t, J = 8.5 Hz, 2H), 7.29 (d, J = 5.7 Hz, 3H), 7.22 – 7.07 (m, 2H), 6.91 (d, J = 8.3 Hz, 2H), 5.82 (ddt, J = 17.0, 9.6, 7.1 Hz, 1H), 5.29 – 5.13 (m, 2H), 3.88 (m, 4H), 3.74 – 3.45 (m, 2H), 3.31 (m, 1H), 3.16 (d, J = 12.0 Hz, 2H), 2.98 – 2.57 (m, 2H), 1.57 (s, 9H); 13C 53 NMR (101 MHz, CDCl3) δ (A mixture of two rotamers) 172.7, 172.3, 172.0, 163.2, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 154.7, 153.4, 137.1, 136.4, 133.1, 132.6, 131.3, 130.4, 128.7, 128.5, 127.5, 127.2, 119.9, 119.7, 113.5, 82.2, 80.6, 71.7, 55.6, 43.6, 43.3, 42.9, 42.6, 41.8, 29.8, 28.9, 28.6; IR (Neat Film, NaCl) 2975, 1691, 1604, 1512, 1454, 1365,1309, 1282, 1258, 1167, 1104, 1077, 1021, 993, 925, 839, 768, 740, 704cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H33N2O5 [M+H]+: 465.2384, found 465.2390; [α]D23.4 +31.0 (c 0.47, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 7.471, minor = 5.802. O OBn BzN NBoc tert-butyl (R)-2-allyl-4-benzoyl-2-((benzyloxy)methyl)-3-oxopiperazine-1- carboxylate (1.4i). (Following the general procedure, benzyloxy methyl ether allyl ester 1.3i (25 mg, 0.049 mmol, 1.0 equiv) in hexanes/toluene (2:1, 3.0 mL) was added to a solution of Pd2(pmdba)3 (2.2 mg, 0.0020 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.9 mg, 0.0049 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). Purification by flash chromatography (15% EtOAc/hexanes) gave di-substituted oxopiperazine 1.4i as a colorless oil (20 mg, 87% yield, 92% ee): 1H NMR (500 MHz, CDCl3) δ (A mixture of two rotamers) 7.61 (dd, J = 8.2, 1.4 Hz, 2H), 7.51 – 7.43 (m, 1H), 7.38 – 7.26 (m, 7H), 5.72 (ddt, J = 17.6, 10.3, 7.4 Hz, 1H), 5.21 – 5.09 (m, 2H), 4.57 (t, J = 13.3 Hz, 3H), 4.32 – 3.63 (m, 5H), 3.25 – 2.93 (m, 1H), 2.60 (br s, 1H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 173.3, 172.5, 153.4, 135.6, 132.1, 131.9, 128.6, 128.3, 128.2, 127.9, 127.5, 120.0, 75.1, 74.2, 73.7, 70.6, 43.5, 38.5, 37.0, 28.6; IR (Neat Film, NaCl) 3064, 2976, 54 2931, 1692, 1601, 1474, 1452, 1392, 1365, 1317, 1286, 1251, 1232, 1164, 1102, 1062, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1016, 969, 924, 857, 730, 696, 671 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H33N2O5 [M+H]+: 465.2384, found 465.2388; [α]D23.8 –13.9 (c 0.33, CHCl3); SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 254 nm, tR (min): major = 3.737, minor = 4.398. CN O O N MeO tert-butyl NBoc (S)-2-allyl-2-(2-cyanoethyl)-4-(4-methoxybenzoyl)-3-oxopiperazine-1- carboxylate (1.4j). Following the general procedure, α-cyanoethylated allyl ester 1.3j (25 mg, 0.053 mmol, 1.0 equiv) in hexanes/toluene (2:1, 2.8 mL) was added to a solution of Pd2(dba)3 (1.9 mg, 0.0021 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (3.1 mg, 0.0053 mmol, 10 mol %) in hexanes/toluene (2:1, 1.0 mL). Purification by silica gel flash chromatography (dry load SiO2, 3:1 hexanes/EtOAc) gave oxopiperazine 1.4j as a colorless oil (20 mg, 88% yield, 97% ee): 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.79 (ddt, J = 16.6, 10.4, 7.5 Hz, 1H), 5.24 (d, J = 1.7 Hz, 1H), 5.20 (dd, J = 9.9, 1.9 Hz, 1H), 3.98 – 3.87 (m, 2H), 3.86 (s, 3H), 3.84 – 3.71 (m, 2H), 3.27 (m, 1H), 2.82 (m, 1H), 2.69 (dd, J = 13.8, 7.4 Hz, 1H), 2.47 (dt, J = 14.1, 7.4 Hz, 1H), 2.32 (t, J = 7.2 Hz, 2H), 1.53 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.4, 171.5, 163.4, 153.6, 132.0, 131.2, 127.0, 120.6, 119.1, 113.7, 82.0, 69.0, 55.6, 43.8, 43.2, 42.0, 32.3, 28.5, 13.1; IR (Neat Film, NaCl) 2976, 2933, 2359, 2247, 1694, 1605, 1579, 1512, 1456, 1366, 1281, 1258 1168, 1113, 1020, 974, 928, 843, 768, 614 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C23H30N3O5 [M+H]+: 428.2180, found 428.2182; 55 –4.3 (c 1.0, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak OD-H Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles [α]D 23.2 column, λ = 210 nm, tR (min): major = 6.049, minor = 5.143. O O Me O N MeO tert-butyl NBoc (S)-2-allyl-4-(4-methoxybenzoyl)-3-oxo-2-(3-oxobutyl)piperazine-1- carboxylate (1.4k). Following the general procedure, ketone 1.3k (25 mg, 0.051 mmol, 1.0 equiv) in hexanes/toluene (2:1, 2.2 mL) was added to a solution of Pd2(dba)3 (1.9 mg, .002 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (3.0 mg, 0.0051 mmol, 10 mol %) in hexanes/toluene (2:1, 1.5 mL). Purification by silica gel flash chromatography (dry load SiO2, 30% EtOAc/hexanes) gave ketone 1.4k as a pale yellow oil (17 mg, 73% yield, 97% ee); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 5.79 (ddt, J = 14.6, 9.4, 7.5 Hz, 1H), 5.18 (dd, J = 13.8, 1.9 Hz, 2H), 3.92 – 3.81 (m, 6H), 3.80 – 3.66 (m, 1H), 3.22 (s, 1H), 2.74 (dd, J = 13.8, 7.3 Hz, 1H), 2.72, (m, 1H), 2.50 – 2.27 (m, 3H), 2.13 (s, 3H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 207.5, 172.6, 172.4, 163.2, 132.8, 131.0, 127.3, 120.0, 113.6, 81.6, 69.5, 55.6, 43.9, 43.2, 39.1, 32.3, 30.0, 28.6, 24.8; IR (Neat Film, NaCl) 2975, 1694, 1605, 1512, 1456, 1392, 1366, 1282, 1258, 1168, 1113, 1062, 1019, 974, 923, 841, 768 cm-1; HRMS (MM: ESIAPCI): m/z calc’d for C24H33N2O6 [M+H]+: 445.2333, found 445.2335; [α]D23.2 +25.1 (c 0.97, CHCl3); SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 235 nm, tR (min): major = 9.712, minor = 10.434. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 56 NHCbz O O N NBoc MeO tert-butyl (R)-2-allyl-2-((((benzyloxy)carbonyl)amino)methyl)-4-(4-methoxybenzoyl)3-oxopiperazine-1-carboxylate (1.4l). Following the general procedure, aminomethyl allyl ester 3l (100 mg, 0.17 mmol, 1.0 equiv) in hexanes/toluene (2:1, 10 mL) was added to a solution of Pd2(dba)3 (6.3 mg, 0.0069 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (10 mg, 0.017 mmol, 10 mol %) in hexanes/toluene (2:1, 2 mL). Purification by silica gel flash chromatography (15% → 20% → 30% EtOAc/hexanes) gave di-substituted oxopiperazine 1.4l as a yellow oil (60 mg, 65% yield, 92% ee); 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.64 (t, J = 8.9 Hz, 2H), 7.44 – 7.23 (m, 5H), 6.89 (d, J = 8.5 Hz, 2H), 5.79 (dq, J = 16.8, 7.8 Hz, 1H), 5.32 – 4.93 (m, 5H), 4.31 – 3.97 (m, 1H), 3.95 – 3.64 (m, 7H), 3.64 – 3.45 (m, 1H), 3.45 – 2.87 (m, 1H), 2.64 (dd, J = 14.0, 7.3 Hz, 1H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.6, 172.3, 163.1, 156.4, 153.7, 136.6, 132.2, 131.1, 128.6, 128.4, 128.3, 127.3, 120.1, 113.6, 70.2, 67.0, 55.6, 46.9, 43.8, 43.2, 39.6, 28.6; IR (Neat Film, NaCl) 3357, 2975, 2361, 1694, 1605, 1512, 1456, 1366, 1317, 1283, 1255, 1169, 1094, 1061, 1020, 923, 841, 768, 699 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C29H36N3O7 [M+H]+: 538.2548, found 538.2543; [α]D22.8 +3.74 (c 2.0, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 280 nm, tR (min): major = 8.425, minor = 7.817. O NHBoc BzN NBoc 57 (R)-2-allyl-4-benzoyl-2-(((tert-butoxycarbonyl)amino)methyl)-3- Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles tert-Butyl oxopiperazine-1-carboxylate (1.4m). Following the general procedure, allyl ester 1.3m (100 mg, 0.19 mmol, 1.0 equiv) in hexanes/toluene (2:1, 8.0 mL) was added to a solution of Pd2(pmdba)3 (8.5 mg, 0.0077 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (11.4 mg, 0.019 mmol, 10 mol %) in hexanes/toluene (2:1, 4.0 mL). Purification by flash chromatography (15% EtOAc/hexanes) gave di-substituted oxopiperazine 1.4m as a pale yellow foam (85 mg, 93% yield, 93% ee): 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.61 (d, J = 7.6 Hz, 2H), 7.51 (tt, J = 7.5, 2.1 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 5.91 – 5.66 (m, 1H), 5.19 (d, J = 15.6 Hz, 2H), 4.73 (s, 1H), 4.09 – 3.72 (m, 5H), 3.67 (dd, J = 14.0, 7.0 Hz, 1H), 3.43 – 2.97 (m, 1H), 2.72 – 2.51 (m, 1H), 1.54 (s, 9H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) 172.9, 172.8, 155.7, 153.6, 135.8, 132.3, 131.9, 128.2, 128.0, 120.1, 81.2, 79.7, 70.5, 46.5, 43.7, 43.2, 39.4, 28.6, 28.5; IR (Neat Film, NaCl): = 3374, 2977, 1694, 1504, 1454, 1392, 1366, 1317, 1286, 1231, 1165, 1094, 1060, 1014, 921, 855, 765, 729, 696 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C25H36N3O6 [M+H]+: 474.2599, found: 474.2602; [α]D23.2 +2.7 (c 1.00, CH3Cl); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 254 nm, tR (min): major = 4.429, minor = 3.910. 1.4.2.6 Experimental Procedures and Spectroscopic Data for the Pd- Catalyzed Decarboxylative Tetrahydropyrimidinone Substrates Asymmetric Allylic Alkylation of Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O 58 Me BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-methyl-4-oxotetrahydropyrimidine-1(2H)- carboxylate (1.6a). Following the general procedure, methylated pyrimidinone 1.5a (15 mg, 0.037 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.0 mL) was added to a solution of Pd2(pmdba)3 (1.6 mg, 0.0015 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.2 mg, 0.0037 mmol, 10 mol %) in hexanes/toluene (2:1, 1.7 mL). Purification by silica gel flash chromatography (13% EtOAc/hexanes) gave α-methyl pyrimidinone 1.6a as a colorless oil (11 mg, 83% yield, 93% ee): 1H NMR (500 MHz, CDCl3) δ 7.57 – 7.46 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 5.78 (dq, J = 16.9, 8.0 Hz, 1H), 5.31 (d, J = 8.4 Hz, 1H), 5.25 – 5.09 (m, 3H), 3.69 (d, J = 13.8 Hz, 1H), 3.55 (m, 1H), 2.52 (m, 1H), 2.31 (dd, J = 13.9, 8.0 Hz, 1H), 1.51 (s, 9H), 1.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 176.8, 176.5, 173.9, 153.7, 135.6, 132.5, 132.1, 128.3, 127.9, 120.0, 81.8, 59.4, 59.0, 50.6, 49.7, 45.2, 41.0, 28.4, 22.4; IR (Neat Film, NaCl) 2976, 2932, 1698, 1426, 1367, 1286, 1246, 1136, 1027, 924, 858, 802, 750, 719, 695, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H27N2O4 [M+H]+: 359.1965, found 359.1963; [α]D23.2 – 25.7 (c 1.0, CHCl3); SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 254 nm, tR (min): major = 3.209, minor = 2.569. O Et BzN N Boc 59 (R)-5-allyl-3-benzoyl-5-ethyl-4-oxotetrahydropyrimidine-1(2H)- Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles tert-butyl carboxylate (1.6b). Following the general procedure, ethylated allyl ester 1.5b (15 mg, 0.036 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.0 mL) was added to a solution of Pd2(pmdba)3 (1.6 mg, 0.0014 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.1 mg, 0.0036 mmol, 10 mol %) in hexanes/toluene (2:1, 1.6 mL). Purification by silica gel flash chromatography (13% EtOAc/hexanes) gave α-ethyl tetrahydropyrimidinone 1.6b as a colorless oil (13 mg, 98% yield, 94% ee); 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.45 (m, 3H), 7.39 (t, J = 7.5 Hz, 2H), 5.87 – 5.62 (m, 1H), 5.48 – 5.24 (m, 1H), 5.20 – 5.03 (m, 3H), 3.75 (dd, J = 14.0, 1.4 Hz, 1H), 3.65 – 3.52 (m, 1H), 2.50 (dd, J = 14.2, 6.7 Hz, 1H), 2.27 (d, J = 16.1 Hz, 1H), 1.79 (dq, J = 14.9, 7.5 Hz, 1H), 1.68 (dq, J = 14.6, 7.4 Hz, 1H), 1.51 (s, 9H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 175.8, 174.1, 153.7, 135.8, 132.9, 132.0, 128.3, 128.0, 119.7, 81.7, 59.2, 58.8, 48.6, 48.0, 47.6, 39.1, 38.6, 28.7, 28.4, 8.4; IR (Neat Film, NaCl) 2976, 2927, 1698, 1426, 1367, 1286, 1263, 1246, 1136, 1017, 923, 859, 801, 738, 695, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C21H29N2O4 [M+H]+: 373.2122, found: 373.2122; [α]D22.2 –21.0 (c 1.0, CHCl3); SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak OJ-H column, λ = 254 nm, tR (min): major = 3.956, minor = 2.585. CO2Me O BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-(3-methoxy-3-oxopropyl)-4- oxotetrahydropyrimidine-1(2H)-carboxylate (1.6c). Following the general procedure, 60 methyl ester pyrimidinone 1.5c (15 mg, 0.032 mmol, 1.0 equiv) in hexanes/toluene (2:1, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.0 mL) was added to a solution of Pd2(pmdba)3 (1.2 mg, 0.0013 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.9 mg, 0.0032 mmol, 10 mol %) in hexanes/toluene (2:1, 1.3 mL). Purification by silica gel flash chromatography (15% EtOAc/hexanes) gave methyl ester 1.6c as a colorless oil (9.1 mg, 67% yield, 95% ee): 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 13.1, 7.2 Hz, 3H), 7.38 (t, J = 7.5 Hz, 2H), 5.73 (dq, J = 16.6, 7.4 Hz, 1H), 5.47 – 5.22 (m, 1H), 5.22 – 5.04 (m, 3H), 3.66 (m, 5H), 2.49 (dt, J = 12.9, 6.4 Hz, 1H), 2.37 (m, 2H), 2.31 – 2.19 (m, 1H), 2.14 – 1.91 (m, 2H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 175.2, 174.9, 173.9, 173.3, 153.5, 135.6, 132.1, 132.0, 128.4, 127.9, 120.3, 82.0, 59.2, 58.8, 51.1, 48.7, 47.7, 39.1, 38.8, 30.3, 28.9, 28.3; IR (Neat Film, NaCl) 2978, 1738, 1698, 1428, 1368, 1286, 1247, 1147, 925, 856, 802, 764, 696 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C23H31N2O6 [M+H]+: 431.2177, found 431.2173; [α]D23.1 +5.5 (c 0.9, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 5.591, minor = 6.372. O Cl BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-(2-chloroallyl)-4-oxotetrahydropyrimidine-1(2H)- carboxylate (1.6d). Following the general procedure, 2-chloropropenyl allyl ester 5d (20 mg, 0.049 mmol, 1.0 equiv) in hexanes/toluene (2:1, 3.0 mL) was added to a solution of Pd2(pmdba)3 (2.1 mg, 0.0020 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.9 mg, 0.0049 61 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). Purification by flash chromatography Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles (EtOAc/hexanes 15%) gave di-substituted oxopiperazine 1.6d as a yellow oil (17 mg, 94% yield, 94% ee); 1H NMR (400 MHz, CDCl3) δ (a mixture of two rotamers) 7.65 – 7.45 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 5.95 – 5.76 (m, 1H), 5.76 – 5.47 (m, 1H), 5.31 (d, J = 1.3 Hz, 1H), 5.30 – 5.16 (m, 2H), 4.92 (s, 1H), 4.05 (s, 1H), 3.61 (d, J = 14.0 Hz, 1H), 3.06 (d, J = 14.8 Hz, 1H), 2.69 – 2.55 (m, 1H), 2.45 (d, J = 14.5 Hz, 2H), 1.52 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 174.4, 173.9, 153.6, 137.5, 135.6, 132.1, 132.0, 128.3, 128.1, 120.8, 118.1, 82.0, 59.1, 48.2, 47.6, 46.6, 42.8, 42.3, 41.7, 28.4; IR (Neat Film, NaCl) 2977, 1698, 1630, 1478, 1426, 1368, 1286, 1246, 1140, 902, 802, 765, 724, 695, 636 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28ClN2O4 [M+H]+: 419.1732, found 419.1732; [α]D22.6 +22.2 (c 1.0, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 4.679, minor = 3.777. O Ph BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-benzyl-4-oxotetrahydropyrimidine-1(2H)- carboxylate (1.6e). Following the general procedure, benzylated allyl ester 1.5e (15 mg, 0.031 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.0 mL) was added to a solution of Pd2(pmdba)3 (1.4 mg, 0.0013 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.9 mg, 0.0031 mmol, 10 mol %) in hexanes/toluene (2:1, 1.2 mL). Purification by silica gel flash chromatography (13% EtOAc/hexanes) gave benzyl tetrahydropyrimidinone 1.6e as a 62 colorless oil (11.5 mg, 84% yield, 95% ee); H NMR (500 MHz, CDCl3) δ 7.58 – 7.49 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1 (m, 3H), 7.42 (t, J = 7.7 Hz, 2H), 7.31 – 7.24 (m, 3H), 7.20 (d, J = 7.2 Hz, 2H), 5.86 (dddd, J = 16.8, 10.2, 7.9, 6.6 Hz, 1H), 5.48 – 5.25 (m, 1H), 5.22 (d, J = 10.0 Hz, 1H), 5.21 – 5.14 (m, 1H), 4.87 (d, J = 11.9 Hz, 1H), 3.89 – 3.72 (m, 1H), 3.55 (d, J = 13.7 Hz, 1H), 3.37 – 3.21 (m, 1H), 2.80 – 2.68 (m, 1H), 2.65 (dd, J = 14.0, 6.6 Hz, 1H), 2.32 – 2.19 (m, 1H), 1.52 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 175.4, 173.9, 153.6, 136.1, 135.6, 132.6, 132.1, 131.0, 128.5, 128.3, 128.1, 127.1, 120.2, 81.9, 58.8, 49.5, 47.2, 46.5, 41.1, 40.6, 28.4; IR (Neat Film, NaCl) 2978, 2930, 2360, 1698, 1424, 1368, 1288, 1245, 1142, 1029, 924, 856, 802, 718, 696, 636 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C26H31N2O4 [M+H]+: 435.2278, found: 435.2274; [α]D22.1 –5.6 (c 1.0, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 4.096, minor = 4.670. CN O BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-(2-cyanoethyl)-4-oxotetrahydropyrimidine-1(2H)carboxylate (1.6f). Following the general procedure, cyanoethylated tetrahydropyrimidinone 1.5f (15 mg, 0.034 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.0 mL) was added to a solution of Pd2(pmdba)3 (1.2 mg, 0.0014 mmol, 4 mol %) and (S)(CF3)3-tBu-PHOX (2.0 mg, 0.0034 mmol, 10 mol %) in hexanes/toluene (2:1, 1.4 mL). Purification by silica gel flash chromatography (20% EtOAc/hexanes) gave 63 cyanoethylated tetrahydropyrimidinone 1.6f as a colorless oil (9.0 mg, 67% yield, 74% Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles ee): 1H NMR (500 MHz, CDCl3) δ 7.56 – 7.49 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 5.75 (dddd, J = 16.8, 10.2, 7.9, 6.6 Hz, 1H), 5.35 – 5.13 (m, 4H), 3.86 – 3.55 (m, 2H), 2.57 – 2.51 (m, 1H), 2.44 (dd, J = 10.0, 5.9 Hz, 2H), 2.32 (dd, J = 14.1, 8.0 Hz, 1H), 2.09 (dt, J = 14.6, 8.5 Hz, 1H), 1.96 (ddd, J = 14.3, 9.8, 6.2 Hz, 1H), 1.53 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.6, 173.7, 153.4, 135.4, 132.4, 131.2, 128.5, 127.8, 121.2, 119.2, 82.5, 59.4, 48.3, 47.7, 39.1, 31.0, 28.4, 12.6; IR (Neat Film, NaCl) 2977, 2931, 2248, 1694, 1601, 1478, 1427,1368, 1285, 1263, 1246, 1141, 1027, 926,901, 857, 802, 763, 721, 696, 636, cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N3O4 [M+H]+: 398.2074, found 398.2071; [α]D23.2 +10.0 (c 1.0, CHCl3); SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 3.148, minor = 4.927. O OBn BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-((benzyloxy)methyl)-4-oxotetrahydropyrimidine- 1(2H)-carboxylate (1.6g). Following the general procedure, allyl ester 1.5g (15 mg, 0.029 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.6 mL) was added to a solution of Pd2(pmdba)3 (1.3 mg, 0.0012 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.7 mg, 0.0029 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). Purification by flash chromatography (10 → 15% EtOAc/hexanes) gave di-substituted oxopiperazine 1.6g as a yellow oil (13 mg, 87% yield, 87% ee): 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.51 (m, 2H), 7.51 – 7.42 64 (m, 1H), 7.42 – 7.22 (m, 7H), 5.77 (ddt, J = 15.0, 10.3, 7.4 Hz, 1H), 5.54 – 5.49 (m, 1H), Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 5.28 – 5.10 (m, 2H), 5.06 (d, J = 12.1 Hz, 1H), 4.63 – 4.40 (m, 2H), 3.94 (m, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.75 (d, J = 8.9 Hz, 1H), 3.40 (d, J = 9.0 Hz, 1H), 2.42 (m, 2H), 1.50 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.7, 173.5, 153.6, 137.8, 135.5, 132.0, 128.6, 128.3, 128.2, 127.9, 127.7, 112.0, 81.8, 73.8, 58.8, 50.0, 46.9, 46.3, 38.6, 28.4; IR (Neat Film, NaCl) 2977, 2926, 2283, 1698, 1641, 1478, 1451, 1426, 1367, 1287, 1246, 1151, 1028, 906, 857, 801, 740, 697, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H32N2O5 [M+H]+: 465.2384, found 465.2378; [α]D23.4 +11.9 (c 0.67, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): major = 5.131, minor = 4.419. O F BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-fluoro-4-oxotetrahydropyrimidine-1(2H)- carboxylate (1.6h). Following the general procedure, fluorinated tetrahydropyrimidinone 1.5h (300 mg, 0.74 mmol, 1.0 equiv) in hexanes/toluene (2:1, 39 mL) was added to a solution of Pd2(pmdba)3 (24 mg, 0.022 mmol, 3 mol %) and (S)-(CF3)3-tBu-PHOX (35 mg, 0.059 mmol, 10 mol %) in hexanes/toluene (2:1, 15 mL). Purification by silica gel flash chromatography (15% EtOAc/hexanes) gave fluorinated tetrahydropyrimidinone 1.6h as a pale yellow oil (250 mg, 93% yield, 92% ee); 1H NMR (400 MHz, CDCl3) δ 65 7.59 (dd, J = 8.3, 1.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 5.82 (ddt, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles J = 14.9, 9.6, 7.2 Hz, 1H), 5.66 – 5.34 (m, 1H), 5.29 (s, 1H), 5.25 (d, J = 5.3 Hz, 1H), 5.24 – 5.13 (m, 1H), 4.13 – 3.72 (m, 2H), 2.81 (td, J = 14.3, 6.9 Hz, 1H), 2.67 (ddd, J = 22.4, 14.5, 7.6 Hz, 1H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 172.5, 168.23 (d, JCF = 23.6 Hz), 153.4, 134.3, 132.7, 129.7, 129.6, 128.5, 128.5, 128.3, 128.0, 121.4, 92.2 (d, JCF = 197.0 Hz, appears as four peaks due to the presence of two rotamers and coupling with fluorine), 82.4, 57.7, 49.4 (appears as four poorly resolved peaks due to the presence of two rotamers and coupling with fluorine), 38.2 (d, JCF = 22.8 Hz), 28.3; IR (Neat Film, NaCl) 2978, 1710, 1416, 1368, 1286, 1245, 1158, 1137, 906, 858, 801, 749, 723, 694, 662 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H24N2O4 [M+H]+: 363.1715, found: 363.1713; [α]D21.8 –28.6 (c 0.96, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 6.226, minor = 5.041. O BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)tetrahydropyrimidine- 1(2H)-carboxylate (1.6i). Following the general procedure, propargylated allyl ester 1.5i (20 mg, 0.047 mmol, 1.0 equiv) in hexanes/toluene (2:1, 2.8 mL) was added to a solution of Pd2(pmdba)3 (2.1 mg, 0.0019 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (2.8 mg, 0.0047 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). Purification by flash chromatography (EtOAc/hexanes 5% → 10% → 15%) gave propargyl 66 tetrahydropyrimidinone 1.6i as a yellow oil (15 mg, 83% yield, 90% ee): H NMR (400 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1 MHz, CDCl3) δ 7.58 (s, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 5.89 – 5.68 (m, 1H), 5.42 (s, 1H), 5.31 – 4.98 (m, 3H), 4.15 – 3.57 (m, 2H), 2.61 (dd, J = 16.9, 2.7 Hz, 2H), 2.42 (dd, J = 16.9, 2.7 Hz, 2H), 2.11 (t, J = 2.6 Hz, 1H), 1.54 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (a mixture of two rotamers) 174.3, 173.7, 153.6, 135.4, 132.2, 131.8, 128.3, 128.2, 120.6, 82.0, 79.6, 72.4, 59.3, 58.9, 48.2, 47.8, 40.1, 39.6, 28.4, 25.1; IR (Neat Film, NaCl) 3271, 2978, 2930, 1698, 1478, 1450, 1425, 1368, 1284, 1247, 1139, 1028, 927, 854, 802, 764, 720, 695, 635 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H27N2O4 [M+H]+: 383.1965, found 383.1973; [α]D23.0 +22.1 (c 0.47, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 4.769, minor = 4.399. 1.4.2.7 Experimental Procedure for the Gram Scale Decarboxylative Asymmetric Allylic Alkylation of Benzyl Tetrahydropyrimidinone 1.5e O Ph BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-benzyl-4-oxotetrahydropyrimidine-1(2H)- carboxylate (1.6e). In a nitrogen-filled glovebox, a 250 mL schlenk flask was charged with Pd2(pmdba)3 (69 mg, 0.063 mmol, 4 mol %), (S)-(CF3)3-tBu-PHOX (99 mg, 0.17 mmol, 8 mol %), hexane/toluene (2:1, 50 mL), and a magnetic stir bar. The flask was 67 stirred at ambient glovebox temperature (27 °C) for 30 min and then 1.5e (1g, 2.1 mmol, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.0 equiv) was added as a solution in hexane/toluene (2:1, 100 mL, total concentration 0.014M). The flask was sealed with a Kontes valve, removed from the glovebox, and heated to 40 °C for 16 h. The solution was concentrated under reduced pressure and purified by silica gel flash chromatography (15% EtOAc/hexanes) to give benzyl tetrahydropyrimidinone 1.6e as a yellow oil (780 mg, 87% yield, 95% ee); spectroscopic data vide supra. 1.4.2.8 Experimental Procedures for the Transformations of Decarboxylative Allylic Alkylation Products O NH2 BzN NH tert-butyl (R)-((2-allyl-4-benzoyl-3-oxopiperazin-2-yl)methyl)carbamate (1.8). Trifluoroacetic acid (114 µL, 1.5 mmol, 20 equiv) was added dropwise to a solution of methylcarbamate oxopiperazine 1.4m (35 mg, 0.07 mmol, 1.0 equiv) in CH2Cl2 (0.74 mL) at 0 °C. The reaction mixture was allowed to warm up to room temperature, stirred for 3 h and concentrated under reduced pressure. The residue was repeatedly taken up in CH2Cl2 (1.0 mL) and concentrated, four times. The crude residue was then purified by silica gel flash chromatography (10% MeOH/CH2Cl2) to yield deprotected oxopiperazine 1.8 as a pale yellow foam (27 mg, 73% yield); 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J = 68 8.0 Hz, 3H), 7.37 (t, J = 7.4 Hz, 2H), 5.66 (dd, J = 16.0, 8.8 Hz, 1H), 5.30 (d, J = 9.8 Hz, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1H), 5.25 (d, J = 16.8 Hz, 1H), 3.99 – 3.79 (m, 1H), 3.73 – 3.55 (m, 1H), 3.44 – 3.16 (m, 2H), 3.05 (d, J = 13.2 Hz, 1H), 2.89 (d, J = 11.6 Hz, 1H), 2.76 (dd, J = 14.0, 7.0 Hz, 1H), 2.45 (dd, J = 14.2, 7.1 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 173.7, 172.4, 135.5, 132.2, 129.7, 128.4, 128.0, 122.5, 62.0, 47.0, 43.5, 39.7, 38.1; IR (Neat Film, NaCl) 2976, 1682, 1470, 1282, 1203, 1135, 926, 836, 799, 722, 696 cm-1; HRMS (MM: ESIAPCI): m/z calc’d for C15H20N3O4 [M+H]+: 274.1550, found 274.1555; [α]D22.3 +15.1 (c 1.0, CHCl3). O NHBoc HN NBoc tert-butyl (R)-2-allyl-2-(((tert-butoxycarbonyl)amino)methyl)-3-oxopiperazine-1- carboxylate (1.9). LiOH monohydrate (2.5 mg, 0.06 mmol, 1.4 equiv) was added in one portion to a solution of methylcarbamate oxopiperazine 1.4m (20 mg, 0.04 mmol, 1.0 equiv) in methanol/water (1:1, 1.8 mL) at room temperature. The reaction mixture was stirred for 1 h, diluted with EtOAc (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous phase was extracted with EtOAc (3x3 mL) and the combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (hexanes/EtOAc 1:1) to yield lactam 1.9 as a white foam (14 mg, 92% yield): 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 5.72 (ddt, J = 17.2, 10.2, 7.4 Hz, 1H), 5.16 – 5.04 (m, 2H), 4.88 (t, J = 6.9 Hz, 1H), 4.26 – 3.91 (m, 1H), 3.82 (s, 1H), 3.60 (dd, J = 14.0, 5.9 Hz, 1H), 3.50 (s, 1H), 3.39 – 2.83 (m, 3H), 2.62 69 (s, 1H), 1.52 (s, 9H), 1.41 (s, 9H); C NMR (101 MHz, CDCl3) δ 172.7, 155.7, 153.9, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 13 132.7, 119.2, 81.2, 79.3, 69.1, 46.0, 43.1, 40.9, 38.9, 28.6, 28.5; IR (Neat Film, NaCl) 3337, 2977, 2360, 1698, 1520, 1367, 1243, 1168, 1085, 1058, 919, 866, 768, 733 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C18H32N3O5 [M+H]+: 370.2336, found 370.2337; [α]D21.9 –5.7 (c 1.0, CHCl3). NHBoc HN NBoc tert-butyl (S)-2-allyl-2-(((tert-butoxycarbonyl)amino)methyl)piperazine-1- carboxylate (1.10). To a solution of lactam 1.9 (50 mg, 0.14 mmol, 1 equiv) in THF (1.4 mL) at 0 °C was quickly added LAH (8 mg, 0.2 mmol, 1.5 equiv) in one portion. The mixture was stirred at room temperature and three portions of LAH (8 mg, 0.2 mmol, 1.5 equiv) were added over four hours until all starting material was consumed as determined by TLC analysis. The reaction mixture was then cooled to 0 °C and diluted with Et2O. H2O (40 µL), 15% aqueous NaOH (40 µL), and H2O (120 µL) were added successively at 0 °C. The mixture was stirred for 5 minutes at room temperature and then MgSO4 was added. The mixture was stirred for another 5 minutes at room temperature and then filtered over a pad of celite, rinsing with EtOAc. The solvent was concentrated under reduced pressure and the crude residue was purified by silica gel flash chromatography (MeOH/CH2Cl2, 1 → 2 → 4%) to afford piperazine 1.10 as a colorless oil (30 mg, 63% yield); 1H NMR (400 MHz, CDCl3) δ 5.84 – 5.66 (m, 1H), 5.28 – 5.01 (m, 3H), 3.75 (dd, J = 14.1, 5.6 Hz, 1H), 3.62 (dt, J = 13.6, 4.2 Hz, 1H), 3.35 (dd, J = 14.1, 7.3 Hz, 1H), 3.24 (ddd, J = 13.6, 9.8, 3.8 Hz, 1H), 3.02 – 2.91 (m, 1H), 2.85 (t, J = 11.1 Hz, 2H), 2.79 70 C NMR (101 MHz, Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles – 2.63 (m, 2H), 2.57 – 2.26 (m, 2H), 1.46 (s, 9H), 1.44 (s, 9H); 13 CDCl3) δ 156.8, 156.0, 133.1, 119.1, 80.6, 79.6, 59.9, 50.8, 46.2, 45.1, 42.3, 38.1, 28.6, 28.5; IR (Neat Film, NaCl) 3789, 3662, 3451, 3341, 3074, 2976, 2930, 2284, 1693, 1641, 1502, 1453, 1391, 1365, 1298, 1249, 1169, 1085, 996, 914, 859, 771 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C18H34N3O4 [M+H]+: 356.2544, found 356.2549; [α]D22.8 +5.3 (c 0.67, CHCl3). O Me BzN NH (S)-1-benzoyl-3-methyl-3-propylpiperazin-2-one 1.11. Piperazinone 1.4e (80 mg, 0.22 mmol, 1 equiv) was dissolved in MeOH (2.2 mL). The reaction flask was purged with Argon before adding Pd/C (10%, 24 mg, 0.022 mmol, 0.1 equiv). The flask was evacuated and filled with H2 three times, and then sparged with H2 for 5 minutes. The reaction was stirred at room temperature for 6 hours before being filtered through a pad of silica gel while rinsing with EtOAc. The crude hydrogenated product was then dissolved in CH2Cl2 (2.2 mL) and TFA (171 µL, 2.23 mmol, 10 equiv) was added. The reaction was stirred for 16 hours and then quenched with saturated aqueous NaHCO3 (5 mL). The solution was extracted with EtOAc (3x5 mL), dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude piperazinone was purified by silica gel flash chromatography (2.5 → 5% MeOH/CH2Cl2) to afford the desired product 1.11 (55 mg, 94% yield over two steps): 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.50 (m, 2H), 7.54 – 7.46 (m, 1H), 7.46 – 7.36 (m, 2H), 3.92 (ddd, J = 12.6, 5.4, 4.6 Hz, 1H), 3.81 (ddd, 71 J = 12.5, 6.7, 5.4 Hz, 1H), 3.32 – 3.18 (m, 2H), 1.92 (ddd, J = 13.6, 12.1, 4.7 Hz, 1H), Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.62 (ddd, J = 13.6, 12.2, 4.5 Hz, 1H), 1.42 (s, 3H), 1.54 – 1.23 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.7, 174.7, 136.4, 131.6, 128.3, 127.5, 61.2, 48.2, 41.2, 38.7, 25.0, 16.9, 14.5; IR (Neat Film, NaCl) 3331, 2960, 2872, 1681, 1600, 1448, 1378, 1284, 1202, 1176, 1152, 1112, 966, 794, 726, 694, 669 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C15H21N2O2 [M+H]+: 261.1598, found 261.1596; [α]D22.6 – 59.6 (c 1.35, CHCl3). O BzN N O (R)-4-benzoyl-6-propyl-1,4-diazabicyclo[4.2.0]octane-5,8-dione (1.12). To a 10 mL round-bottom flask was added Pd(OPiv)2 (3 mg, 0.0096 mmol, 0.1 equiv), AgOPiv58 (60 mg, 0.29 mmol, 3 equiv), Xantphos (6 mg, 0.0096 mmol, 0.1 equiv), and 1,4benzoquinone (21 mg, 0.19 mmol, 2 equiv). A solution of piperazine 1.11 (25 mg, 0.096 mmol, 1 equiv) in toluene (1 mL) was then added and the flask was evacuated and filled with carbon monoxide three times. The flask was then stirred at 80 °C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc, and filtered through celite while rinsing with additional EtOAc. The solvent was concentrated under reduced pressure onto silica gel and then purified by silica gel flash chromatography (2:1 hexanes/EtOAc) to provide the β-lactam 1.12 and as a light yellow oil (15 mg, 55% yield): 1H NMR (400 MHz, CDCl3) δ (5:1 ratio of desired product and an inseparable isomer resulting from insertion into another β-C−H) 7.56 – 7.51 (m, 3H), 7.46 – 7.40 (m, 2H), 4.51 (ddd, J = 14.0, 6.1, 2.9 Hz, 1H), 3.94 (ddt, J = 12.3, 10.8, 5.7 Hz, 1H), 3.78 – 3.67 (m, 1H), 3.40 (dddd, J = 12.3, 4.8, 2.8, 1.5 Hz, 1H), 3.27 – 3.10 (m, 72 2H), 1.98 (ddd, J = 14.2, 11.2, 5.5 Hz, 1H), 1.87 (ddd, J = 14.2, 11.0, 5.7 Hz, 1H), 1.59 – Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.40 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.2, 173.2, 169.1, 135.1, 132.6, 128.6, 128.3, 59.7, 46.7, 41.5, 39.7, 37.8, 17.7, 14.3; IR (Neat Film, NaCl) 3374, 2961, 1760, 1688, 1600, 1505, 1449, 1350, 1318, 1279, 1228, 1183, 1151, 1110, 963, 936, 796, 726, 694, 662 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C16H19N2O3 [M+H]+: 287.1390, found 287.1385; [α]D23.5 –12.8 (c 0.47, CHCl3). O Bn BnO BocHN (S)-2-benzyl-2-(((tert-butoxycarbonyl)amino)methyl)pent-4-enoic acid (1.13). To a solution of benzyl tetrahydropyrimidinone 1.6e (200 mg, 0.46 mmol, 1 equiv) in methylene chloride (4.6 mL) was added TFA (352 µL, 4.6 mmol, 10 equiv) dropwise at room temperature. The solution was stirred for 24 hours at room temperature and then quenched with aqueous NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (4 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in MeOH/H2O (1:1, 5 mL) and LiOH monohydrate (290 mg, 6.9 mmol, 15 equiv) was added. The reaction mixture was heated to 80 °C for 60 hours and then allowed to cool to room temperature. Then, NEt3 (77 µL, 0.55 mmol, 1.2 equiv) and Boc2O (110 mg, 0.51 mmol, 1.1 equiv) were added successively at room temperature. The reaction was stirred for 1 hour at room temperature and then acidified with 1 M HCl (4 mL). The solution was extracted with EtOAc (3 x 5 mL). The combined organic layers 73 were dried over Na2SO4. The crude Boc-protected β-amino acid was taken up in DMF Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles (2.3 mL). K2CO3 (95 mg, 0.69 mmol, 1.5 equiv) and BnBr (66 µL, 0.55 mmol, 1.2 equiv) were added at room temperature. The reaction was stirred at room temperature for 1 hour and then quenched with saturated aqueous NH4Cl. The solution was extracted with EtOAc (3 x 5 mL) and the combined organic layers were concentrated under reduced pressure and placed under high vacuum until trace DMF had evaporated. The residue was taken up in CH2Cl2, concentrated under reduced pressure onto silica gel and purified by silica gel flash chromatography (5 → 10% EtOAc/hexanes) to afford protected β2,2-amino acid 1.13 as a white solid (80 mg, 40% yield): 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.27 (m, 5H), 7.20 (dd, J = 4.9, 1.9 Hz, 3H), 7.10 – 6.93 (m, 2H), 5.92 – 5.75 (m, 1H), 5.18 – 5.04 (m, 4H), 4.96 – 4.81 (m, 1H), 3.34 (qd, J = 14.0, 6.5 Hz, 2H), 2.98 (d, J = 13.8 Hz, 1H), 2.86 (d, J = 13.8 Hz, 1H), 2.49 (ddt, J = 14.2, 6.7, 1.4 Hz, 1H), 2.31 (ddt, J = 14.2, 7.9, 1.1 Hz, 1H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 175.1, 156.1, 136.6, 135.6, 133.4, 130.2, 128.8, 128.6, 128.5, 128.4, 126.9, 119.2, 79.4, 66.8, 51.6, 44.1, 41.0, 38.8, 28.5; IR (Neat Film, NaCl) 3452, 3065, 3031, 2977, 2930, 1721, 1640, 1604, 1503, 1454, 1391, 1365, 1245, 1169, 1094, 1030z, 994, 917, 859, 776, 741, 700 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C25H32NO4 [M+H]+: 410.2326, found 410.2324; [α]D23.4 +3.47 (c 1.0, CHCl3). O OH O HO NH2 (R)-2-allyl-2-(aminomethyl)pentanedioic acid (1.14). To a solution of methyl ester tetrahydropyrimidinone 1.6c (140 mg, 0.325 mmol, 1 equiv) in CH2Cl2 (3.1 mL, 0.1 M) 74 was added TFA (250 µL, 3.25 mmol, 10 equiv) dropwise at room temperature. The Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles solution was stirred for 24 h at room temperature and then concentrated under reduced pressure. Remaining TFA was removed with by azeotroping with CH2Cl2 three times. The crude residue was dissolved in MeOH/H2O (1:1, 3.1 mL, 0.1 M) and LiOH monohydrate (205 mg, 4.89 mmol, 15 equiv) was added. The reaction mixture was heated to 80 °C for 16 h and then allowed to cool to room temperature. The reaction mixture was then acidified with 4 M HCl in dioxanes (~1 mL) until pH 1. Then, the solvent was concentrated under reduced pressure, resulting in precipitation of a white solid. A minimal amount of DMSO (~1 mL) was added to resolvate this precipitate. This solution was subjected to purification by reverse phase preparatory HPLC (0 → 40% MeCN/H2O gradient over 11 minutes, 20x250 mm C18 column, 25 mL/min flow rate) to yield β-amino acid 1.14 (30 mg, 46% yield) as a colorless oil. Note: HPLC fractions were spotted onto a silica TLC plate and eluted in (n-BuOH/H2O/EtOAc/AcOH, 1:1:1:1), then stained with ninhydrin to identify product-containing fractions. LC-MS was used to verify the fractions containing product. Note: HPLC H2O solvent contained 0.25% TFA. 1 H NMR (400 MHz, Methanol-d4) δ 5.88 – 5.68 (m, 1H), 5.32 – 5.13 (m, 2H), 3.18 – 2.99 (m, 2H), 2.51 (ddt, J = 14.4, 7.1, 1.3 Hz, 1H), 2.47 – 2.33 (m, 3H), 1.99 (td, J = 7.6, 1.3 Hz, 2H); 13C NMR (101 MHz, MeOD) δ 176.7, 176.6, 133.1, 120.6, 48.3, 43.5, 39.1, 29.38, 29.35; IR (Neat Film, NaCl) 2924, 1678, 1198, 1138 cm-1; HRMS (MM: ESIAPCI): m/z calc’d for C9H16NO4 [M+H]+: 202.1074, found 202.1075; [α]D22.7 –3.51 (c 1.0, MeOH). Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles O 75 Cl HO NH2 (S)-2-allyl-2-(aminomethyl)-4-chloropent-4-enoic acid (1.15). To a solution of chloroallyl tetrahydropyrimidinone 1.6d (30 mg, 0.072 mmol, 1 equiv) in CH2Cl2 (700 µL, 0.1 M) was added TFA (55 µL, 0.72 mmol, 10 equiv) dropwise at room temperature. The solution was stirred for 5 h at room temperature and then concentrated under reduced pressure. Remaining TFA was removed with by azeotroping with CH2Cl2 three times. The crude residue was dissolved in MeOH/H2O (1:1, 700 µL, 0.1 M) and LiOH monohydrate (45 mg, 1.07 mmol, 15 equiv) was added. The reaction mixture was heated to 80 °C for 16 h and then allowed to cool to room temperature. The reaction mixture was then acidified with 4 M HCl in dioxane (~1 mL) until pH 1. Then, the solvent was concentrated under reduced pressure, resulting in precipitation of a white solid. A minimal amount of DMSO (~1 mL) was added to resolvate this precipitate. This solution was subjected to purification by reverse phase preparatory HPLC (10 → 40% MeCN/H2O gradient over 11 minutes, 20x250 mm C18 column, 25 mL/min flow rate) to yield chloroallyl β-amino acid 1.15 (10 mg, 69% yield) as a colorless oil. Note: HPLC fractions were spotted onto a silica TLC plate and eluted in (n-BuOH/H2O/EtOAc/AcOH, 1:1:1:1), then stained with ninhydrin to identify product-containing fractions. LC-MS was used to verify the fractions containing product. Note: HPLC H2O solvent contained 0.25% TFA. 1H NMR (600 MHz, Methanol-d4) δ 5.84 (td, J = 17.2, 7.3 Hz, 1H), 5.40 (s, 2H), 5.28 – 5.18 (m, 2H), 3.29 (d, J = 13.5 Hz, 1H), 3.12 (d, J = 13.5 Hz, 1H), 2.94 (d, J = 15.1 Hz, 1H), 2.77 (d, J = 14.8 Hz, 1H), 2.57 (dd, J = 14.5, 7.0 Hz, 1H), 2.47 (dd, J = 14.5, 7.8 Hz, 1H); 13C NMR (101 MHz, MeOD) δ 176.6, 138.2, 133.1, 120.8, 118.7, 76 48.4, 44.2, 43.5, 39.6. Note: A H- C HMBC experiment revealed the chemical shift of Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1 13 the chiral quaternary carbon to be at 48.4 ppm, obscured by the CD3OD resonance. IR (Neat Film, NaCl) 2926, 1673, 1432, 1200, 1140, 900, 836, 800, 722 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C9H15ClNO2 [M+H]+: 204.0786, found 204.0787; [α]D22.5 –4.64 (c 0.67, MeOH). O F HO NH2 (S)-2-(aminomethyl)-2-fluoropent-4-enoic acid (1.16). To a solution of fluoro tetrahydropyrimidinone 1.6h (20 mg, 0.055 mmol, 1 equiv) in 1:1 MeOH/H2O (550 µL, 0.1 M) at room temperature was added KOH (31 mg, 0.55 mmol, 10 equiv). The cloudy solution became clear over seconds and was stirred for 5 min at room temperature until TLC analysis showed complete consumption of starting material. AcOH (~100 µL) was added to acidify the solution, which was then extracted with CH2Cl2 three times. The combined organic layers were dried with Na2SO4 and then concentrated under reduced pressure. HCl was generated in situ by adding AcCl (205 µL, 2.87 mmol, 52 equiv) dropwise to a separate 1 dram vial containing MeOH (550 µL) at 0 °C. This HCl solution was stirred for 5 min at 0 °C and was then transferred by pipette into a 1 dram vial containing the crude saponified residue. The reaction was stirred at rt for 2 h and was then concentrated under reduced pressure. The crude residue was dissolved in 1:1 H2O/MeCN (2.5 mL) and was then subjected to purification by reverse phase preparatory HPLC (0 → 40% MeCN/H2O gradient over 11 minutes, 20x250 mm C18 column, 25 mL/min flow rate) to yield fluoro β-amino acid 1.16 (5.0 mg, 65% yield) as a colorless 77 oil. Note: HPLC fractions were spotted onto a silica TLC plate and eluted in (nChapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles BuOH/H2O/EtOAc/AcOH, 1:1:1:1), then stained with ninhydrin to identify productcontaining fractions. LC-MS was used to verify the fractions containing product. Note: HPLC H2O solvent contained 0.25% TFA. 1H NMR (600 MHz, Methanol-d4) δ 5.80 (ddt, J = 17.3, 10.1, 7.2 Hz, 1H), 5.30 – 5.17 (m, 2H), 3.51 (dd, J = 26.1, 13.9 Hz, 1H), 3.38 – 3.32 (dd, J = 26.1, 13.9 Hz, 1H), 2.81 – 2.63 (m, 2H); 13C NMR (101 MHz, MeOD) δ 171.1 (d, JCF = 26.2 Hz), 130.7, 121.3, 95.0 (d, JCF = 190.2 Hz), 44.74 (d, JCF = 22.1 Hz), 40.44 (d, JCF = 22.1 Hz); IR (Neat Film, NaCl) 2924, 1674, 1422, 1202, 1141, 931, 798, 722 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C6H11NO2 [M+H]+: 148.0768, found 148.0770; [α]D22.5 –2.47 (c 0.33, MeOH). 78 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.4.2.9 Determination of Enantiomeric Excess Please note racemic products were synthesized according to the general procedure, using achiral GlyPHOX ligand instead of (S)-(CF3)3-tBu-PHOX.4,55 Entry Assay Conditions Retention time of major isomer (min) Retention time of minor isomer (min) %ee 3.741 2.682 92% NBoc SFC Chiralpak AD-H 15% iPrOH isocratic, 2.5 mL/min 4.708 3.998 96% NBoc SFC Chiralpak AD-H 15% iPrOH isocratic, 2.5 mL/min 4.873 6.748 99% NCbz SFC Chiralpak IC 30% iPrOH isocratic, 2.5 mL/min 4.482 3.224 98% NBoc Cl SFC Chiralpak AD-H 15% iPrOH isocratic, 2.5 mL/min SFC Chiralpak AD-H 7% iPrOH isocratic, 2.5 mL/min 7.208 4.714 96% SFC Chiralpak OJ-H 10% MeOH isocratic, 2.5 mL/min 5.574 6.659 70% SFC Chiralpak AD-H 10% iPrOH isocratic, 2.5 mL/min 5.370 4.278 96% SFC Chiralpak AD-H 15% iPrOH isocratic, 2.5 mL/min 7.471 5.802 96% Product O 1 BzN O 2 AnN O 3 BzN O 4 BzN O 5 Me BzN NBoc O 6 Me BzN NBz O 7 AnN NBoc O 8 Ph AnN NBoc 79 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Entry Product O 9 10 NBoc NBoc 11 Retention time of minor isomer (min) %ee SFC Chiralpak OJ-H 7% iPrOH isocratic, 2.5 mL/min 3.737 4.398 92% SFC Chiralpak OD-H 10% iPrOH isocratic, 2.5 mL/min 4.429 3.910 93% SFC Chiralpak OD-H 15% MeOH isocratic, 2.5 mL/min 8.425 7.817 92% SFC Chiralpak OD-H 15% iPrOH isocratic, 2.5 mL/min 6.049 5.143 97% SFC Chiralpak OD-H 7% iPrOH isocratic, 2.5 mL/min 9.712 10.434 97% NHBoc BzN O Retention time of major isomer (min) OBn BzN O Assay Conditions NHCbz AnN NBoc CN O 12 AnN NBoc O O 13 AnN NBoc 80 Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Entry Product O 14 Me N Boc 15 Retention time of minor isomer (min) 3.209 2.569 93% 3.956 2.585 94% SFC Chiralpak AD-H 10% iPrOH isocratic, 2.5 mL/min 5.591 6.372 95% SFC Chiralpak AD-H 10% iPrOH isocratic, 2.5 mL/min 4.679 3.777 94% SFC Chiralpak IC 20% iPrOH isocratic, 2.5 mL/min 4.096 4.670 95% SFC Chiralpak IC 30% iPrOH isocratic, 2.5 mL/min 3.148 4.927 74% SFC Chiralpak IC 20% iPrOH isocratic, 2.5 mL/min 5.131 4.419 87% SFC Chiralpak AD-H 10% iPrOH isocratic, 2.5 mL/min 4.769 4.399 90% SFC Chiralpak IC 10% iPrOH isocratic, 2.5 mL/min 6.226 5.041 92% SFC Chiralpak OJ-H 7% iPrOH isocratic, 2.5 mL/min BzN O Retention time of major isomer (min) Assay Conditions %ee Et BzN SFC Chiralpak OJ-H 7% iPrOH isocratic, 2.5 mL/min N Boc CO2Me O 16 BzN N Boc O 17 Cl BzN N Boc Ph O 18 BzN N Boc CN O 19 BzN N Boc OBn O 20 BzN N Boc O 21 BzN N Boc O 22 F BzN N Boc Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 1.5 (1) 81 REFERENCES AND NOTES Shimizu, I.; Yamada, T.; Tsuji, J. Palladium-Catalyzed Rearrangement of Allylic Esters of Acetoacetic Acid to Give γ,δ-Unsaturated Methyl Ketones. Tetrahedron Lett. 1980, 21, 3199–3202. (2) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. Facile Generation of a Reactive Palladium(II) Enolate Intermediate by the Decarboxylation of Palladium(II) .Beta.-Ketocarboxylate and Its Utilization in Allylic Acylation. J. Am. Chem. Soc. 1980, 102, 6381–6384. (3) Burger, E. C.; Tunge, J. A. Asymmetric Allylic Alkylation of Ketone Enolates: An Asymmetric Claisen Surrogate. Org. Lett. 2004, 6, 4113–4115. (4) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (5) Trost, B. M.; Xu, J. Regio- and Enantioselective Pd-Catalyzed Allylic Alkylation of Ketones through Allyl Enol Carbonates. J. Am. Chem. Soc. 2005, 127, 2846– 2847. (6) Trost, Cb.-C.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. New York 2006, No. 3, 28. (7) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Deracemization of Quaternary Stereocenters by Pd-Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β-Ketoesters. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. (8) Trost, B. M. Metal Catalyzed Allylic Alkylation: Its Development in the Trost Laboratories. Tetrahedron 2015, 71, 5708–5733. 82 James, J.; Jackson, M.; Guiry, P. Pd-Catalyzed Decarboxylative Asymmetric Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles (9) Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances. Adv. Synth. Cat. In Press. (10) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. (11) Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stoltz, B. M. Enantioselective Synthesis of α-Quaternary Mannich Adducts by Palladium-Catalyzed Allylic Alkylation: Total Synthesis of (+)-Sibirinine. J. Am. Chem. Soc. 2015, 137, 1040– 1043. (12) Hong, A. Y.; Krout, M. R.; Jensen, T.; Bennett, N. B.; Harned, A. M.; Stoltz, B. M. Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile Γ-Quaternary Acylcyclopentenes. Angew. Chem. Int. Ed. 2011, 50, 2756–2760. (13) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by PalladiumCatalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem. 2012, 4, 130–133. (14) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Enantioselective Synthesis of Dialkylated N -Heterocycles by Palladium-Catalyzed Allylic Alkylation. Org. Lett. 2015, 17, 1082–1085. (15) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-Ones and 83 Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles 54, 179–183. (16) Alexy, E. J.; Virgil, S. C.; Bartberger, M. D.; Stoltz, B. M. Enantioselective PdCatalyzed Decarboxylative Allylic Alkylation of Thiopyranones. Access to Acyclic, Stereogenic α-Quaternary Ketones. Org. Lett. 2017, 19, 5007–5009. (17) Alexy, E. J.; Zhang, H.; Stoltz, B. M. Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates. J. Am. Chem. Soc. 2018, 140, 10109–10112. (18) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. (19) Herquline A, produced by Penicillium herquei FKI-7215, exhibits anti-influenza virus properties: Bioscience, Biotechnology, and Biochemistry: Vol 81, No 1 (20) Grady, M. A.; Gasperoni, T. L.; Kirkpatrick, P. Aripiprazole. Nature Reviews Drug Discovery 2003, 2, 427. (21) Wang, H.; Kowalski, M. D.; Lakdawala, A. S.; Vogt, F. G.; Wu, L. An Efficient and Highly Diastereoselective Synthesis of GSK1265744, a Potent HIV Integrase Inhibitor. Org. Lett. 2015, 17, 564–567. (22) Ziegler, R. E.; Desai, B. K.; Jee, J.-A.; Gupton, B. F.; Roper, T. D.; Jamison, T. F. 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Angew. Chem. Int. Ed. 2018, 57, 7181–7185. 84 (23) Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Obika, S.; Hori, A.; Hase, Y.; et al. SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ Inhibitor. ACS Med. Chem. Lett. 2016, 7, 23–27. (24) Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.; Clemons, P. A.; Young, D. W. Route to Three-Dimensional Fragments Using Diversity-Oriented Synthesis. Proc. Natl. Acad. Sci.. 2011, 108, 6799–6804. (25) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry 2009, 52, 6752–6756. (26) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. Med. Chem. Commun. 2013, 4, 515–519. (27) Monteleone, S.; Fuchs, J. E.; Liedl, K. R. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and Sp3 Centers Enhance Target Selectivity. Frontiers in Pharmacology 2017, 8, 552. (28) Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; et al. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074– D1082. (29) Holl, R.; Schepmann, D.; Wünsch, B. Homologous Piperazine-Alcanols: Chiral Pool Synthesis and Pharmacological Evaluation. Med. Chem. Commun. 2012, 3, 673–679. 85 (30) Sudhakar, G.; Bayya, S.; Reddy, K. J.; Sridhar, B.; Sharma, K.; Bathula, S. R. Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Synthesis and Cytotoxicity of the Proposed Structure of Piperazirum, Its Stereoisomers and Analogues. Euro. J. Org. Chem. 2014, 1253–1265. (31) Chamakuri, S.; Jain, P.; Reddy Guduru, S. K.; Arney, J. W.; MacKenzie, K. R.; Santini, C.; Young, D. W. Synthesis of Enantiomerically Pure 6-SubstitutedPiperazine-2-Acetic Acid Esters as Intermediates for Library Production. J. Org. Chem. 2018. (32) Kuwano, R.; Ito, Y. Asymmetric Hydrogenation of 1,4,5,6-Tetrahydropyrazine-2(N-Tert-Butyl)Carboxamide Catalyzed by Trans-Chelating Chiral Diphosphine−Rhodium Complexes. J. Org. Chem. 1999, 64, 1232–1237. (33) Huang, W.-X.; Liu, L.-J.; Wu, B.; Feng, G.-S.; Wang, B.; Zhou, Y.-G. Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines Activated by Alkyl Halides. Org. Lett. 2016, 18, 3082–3085. (34) Montgomery, T. D.; Rawal, V. H. Palladium-Catalyzed Modular Synthesis of Substituted Piperazines and Related Nitrogen Heterocycles. Org. Lett. 2016, 18, 740–743. (35) Nakhla, J. S.; Wolfe, J. P. A Concise Asymmetric Synthesis of Cis-2,6Disubstituted N-Aryl Piperazines via Pd-Catalyzed Carboamination Reactions. Org. Lett. 2007, 9, 3279–3282. (36) Cochran, B. M.; Michael, F. E. Synthesis of 2,6-Disubstituted Piperazines by a Diastereoselective Palladium-Catalyzed Hydroamination Reaction. Org. Lett. 2008, 10, 329–332. 86 (37) McDermott, B. P.; Campbell, A. D.; Ertan, A. First Example of S-BuLi/(-)Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Sparteine-Mediated Chiral Deprotonation of a Piperazine and Proof of the Sense of Induction. Synlett 2008, 2008, 875–879. (38) Firth, J. D.; O’Brien, P.; Ferris, L. Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent. J. Am. Chem. Soc. 2016, 138, 651–659. (39) Gettys, K. E.; Ye, Z.; Dai, M. Recent Advances in Piperazine Synthesis. Synthesis 2017, 49, 2589–2604. (40) Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On the Origins of ThreeDimensionality in Drug-like Molecules. Future Medicinal Chemistry 2016, 8, 1753–1767. (41) Marson, C. M. Chapter Two - Saturated Heterocycles with Applications in Medicinal Chemistry. In Advances in Heterocyclic Chemistry; Scriven, E. F. V., Ramsden, C. A., Eds.; Heterocyclic Chemistry in the 21st Century; Academic Press, 2017; Vol. 121, pp 13–33. (42) Vo, C.-V. T.; Bode, J. W. Synthesis of Saturated N-Heterocycles. J. Org. Chem. 2014, 79, 2809–2815. (43) Ruider, S. A.; Müller, S.; Carreira, E. M. Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles. Angew. Chem. Int. Ed. 52, 11908–11911. (44) Weiner, B.; Szymański, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Recent Advances in the Catalytic Asymmetric Synthesis of β-Amino Acids. Chem. Soc. Rev. 2010, 39, 1656–1691. 87 (45) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I. Beta-Amino Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Acids: Versatile Peptidomimetics. Curr. Med. Chem. 2002, 9, 811–822. (46) Seebach, D.; Beck, A. K.; Bierbaum, D. J. The World of Beta- and GammaPeptides Comprised of Homologated Proteinogenic Amino Acids and Other Components. Chem. Biodivers. 2004, 1, 1111–1239. (47) Yu, J.-S.; Noda, H.; Shibasaki, M. Quaternary Β2,2-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid Phase Peptide Synthesis. Angew. Chem. Int. Ed. 2018, 57, 818–822. (48) Nascimento de Oliveira, M.; Arseniyadis, S.; Cossy, J. Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5-Ones: A Straightforward Access to Β2,2-Amino Acids. Chem. Eur. J. 2018, 24, 4810–4814. (49) Guggisberg, A.; Drandarov, K.; Hesse, M. Protoverbine, the Parent Member of a Class of Macrocyclic Spermine Alkaloids. Helvetica Chimica Acta 2000, 83, 3035–3042. (50) Drandarov, K.; Guggisberg, A.; Hesse, M. Asymmetric Syntheses of the Macrocyclic Spermine Alkaloids (−)-(S)-Protoverbine, (−)-(S)-Buchnerine, and Their Naturally Occurring Congenial Alkaloids. Helvetica Chimica Acta 2002, 85, 979–989. (51) Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki, K.; Gaunt, M. J. Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C−H Bonds in Aliphatic Amines. Angew. Chem. Int. Ed. 2017, 56, 11958–11962. 88 (52) Seto, M.; Roizen, J. L.; Stoltz, B. M. Catalytic Enantioselective Alkylation of Chapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Substituted Dioxanone Enol Ethers: Ready Access to C(α)-Tetrasubstituted Hydroxyketones, Acids, and Esters. Angew. Chem. 2008, 120, 6979–6982. (53) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Rapid Synthesis of an Electron-Deficient t-BuPHOX Ligand: Cross-Coupling of Aryl Bromides with Secondary Phosphine Oxides. Tetrahedron Lett. 2010, 51, 5550– 5554. (54) Childs, M. E.; Weber, W. P. Preparation of Cyanoformates. Crown Ether Phase Transfer Catalysis. J. Org. Chem. 1976, 41, 3486–3487. (55) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. A Facile and Modular Synthesis of Phosphinooxazoline Ligands. Org. Lett. 2007, 9, 2529–2531. (56) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. Chemistry of Dibenzylideneacetone-Palladium(0) Complexes: I. Novel Tris(Dibenzylideneacetone)Dipalladium(Solvent) Complexes and Their Reactions with Quinones. J. Organomet. Chem. 1999, 65, 253–266. (57) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Η2-Dba Complexes of Pd(0): The Substituent Effect in Suzuki−Miyaura Coupling. Org. Lett. 2004, 6, 4435–4438. (58) Endo, K.; Grubbs, R. H. Chelated Ruthenium Catalysts for Z-Selective Olefin Metathesis. J. Am. Chem. Soc. 2011, 133, 8525–8527. (59) Klepacz, A.; Zwierzak, A. An Expeditious One-Pot Synthesis of Diethyl N-Boc-1Aminoalkylphosphonates. Tetrahedron Lett. 2002, 43, 1079–1080. (60) Sikriwal, D.; Kant, R.; Maulik, P. R.; Dikshit, D. K. A Short Formal Synthesis of Three Epimers of Penmacric Acid. Tetrahedron 2010, 66, 6167–6173. 89 (61) Taylor, R. R. R.; Twin, H. C.; Wen, W. W.; Mallot, R. J.; Lough, A. J.; GrayChapter 1 – Enantioselective synthesis of gem-disubstituted N-Boc diazaheterocycles Owen, S. D.; Batey, R. A. Substituted 2,5-Diazabicyclo[4.1.0]Heptanes and Their Application as General Piperazine Surrogates: Synthesis and Biological Activity of a Ciprofloxacin Analogue. Tetrahedron 2010, 66, 3370–3377. (62) White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M. The Catalytic Asymmetric Total Synthesis of Elatol. J. Am. Chem. Soc. 2008, 130, 810–811. (63) Chollet, A.; Mori, G.; Menendez, C.; Rodriguez, F.; Fabing, I.; Pasca, M. R.; Madacki, J.; Korduláková, J.; Constant, P.; Quémard, A.; et al. Design, Synthesis and Evaluation of New GEQ Derivatives as Inhibitors of InhA Enzyme and Mycobacterium Tuberculosis Growth. Eur. J. Med. Chem. 2015, 101, 218–235. Appendix 1 – Spectra Relevant to Chapter 1 89 APPENDIX 1 Spectra Relevant to Chapter 1: Enantioselective Synthesis of gem-Disubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation Figure A1.1 1H NMR (500 MHz, CDCl3) of compound 1.2. Appendix 1 - Spectra Relevant to Chapter 1 90 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.2 Infrared spectrum (Thin Film, NaCl) of compound 1.2. Figure A1.3 13C NMR (126 MHz, CDCl3) of compound 1.2. 91 Figure A1.4 1H NMR (400 MHz, CDCl3) of compound 1.3b. Appendix 1 - Spectra Relevant to Chapter 1 92 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.5 Infrared spectrum (Thin Film, NaCl) of compound 1.3b. Figure A1.6 13C NMR (101 MHz, CDCl3) of compound 1.3b. 93 Figure A1.7 1H NMR (500 MHz, CDCl3) of compound 1.3c. Appendix 1 - Spectra Relevant to Chapter 1 94 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.8 Infrared spectrum (Thin Film, NaCl) of compound 1.3c. Figure A1.9 13C NMR (126 MHz, CDCl3) of compound 1.3c. 95 Figure A1.10 1H NMR (400 MHz, CDCl3) of compound 1.3d. Appendix 1 - Spectra Relevant to Chapter 1 96 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.11 Infrared spectrum (Thin Film, NaCl) of compound 1.3d. Figure A1.12 13C NMR (101 MHz, CDCl3) of compound 1.3d. 97 Figure A1.13 1H NMR (400 MHz, CDCl3) of compound 1.3e. Appendix 1 - Spectra Relevant to Chapter 1 98 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.14 Infrared spectrum (Thin Film, NaCl) of compound 1.3e. Figure A1.15 13C NMR (101 MHz, CDCl3) of compound 1.3e. 99 Figure A1.16 1 H NMR (400 MHz, CDCl3) of compound 1.3f. Appendix 1 - Spectra Relevant to Chapter 1 100 Appendix 1 - Spectra Relevant to Chapter 1 101 Figure A1.17 Infrared spectrum (Thin Film, NaCl) of compound 1.3f. Figure A1.18 13C NMR (101 MHz, CDCl3) of compound 1.3f. Figure A1.19 1H NMR (400 MHz, CDCl3) of compound 1.3h. Appendix 1 - Spectra Relevant to Chapter 1 102 Appendix 1 - Spectra Relevant to Chapter 1 103 Figure A1.20 Infrared spectrum (Thin Film, NaCl) of compound 1.3h. Figure A1.21 13C NMR (101 MHz, CDCl3) of compound 1.3h. Figure A1.22 1H NMR (500 MHz, CDCl3) of compound 1.3i. Appendix 1 - Spectra Relevant to Chapter 1 104 Appendix 1 - Spectra Relevant to Chapter 1 105 Figure A1.23 Infrared spectrum (Thin Film, NaCl) of compound 1.3i. Figure A1.24 13C NMR (126 MHz, CDCl3) of compound 1.3i. Figure A1.25 1H NMR (400 MHz, CDCl3) of compound 1.3j. Appendix 1 - Spectra Relevant to Chapter 1 106 Appendix 1 - Spectra Relevant to Chapter 1 107 Figure A1.26 Infrared spectrum (Thin Film, NaCl) of compound 1.3j. Figure A1.27 13C NMR (101 MHz, CDCl3) of compound 1.3j. Figure A1.28 1H NMR (400 MHz, CDCl3) of compound 1.3k. Appendix 1 - Spectra Relevant to Chapter 1 108 Appendix 1 - Spectra Relevant to Chapter 1 109 Figure A1.29 Infrared spectrum (Thin Film, NaCl) of compound 1.3k. Figure A1.30 13C NMR (101 MHz, CDCl3) of compound 1.3k. Figure A1.31 1H NMR (400 MHz, CDCl3) of compound 1.3l. Appendix 1 - Spectra Relevant to Chapter 1 110 Appendix 1 - Spectra Relevant to Chapter 1 111 Figure A1.32 Infrared spectrum (Thin Film, NaCl) of compound 1.3l. Figure A1.33 13C NMR (101 MHz, CDCl3) of compound 1.3l. Figure A1.34 1H NMR (400 MHz, CDCl3) of compound 1.3m. Appendix 1 - Spectra Relevant to Chapter 1 112 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.35 Infrared spectrum (Thin Film, NaCl) of compound 1.3m. Figure A1.36 13C NMR (101 MHz, CDCl3) of compound 1.3m. 113 Figure A1.37 1H NMR (400 MHz, CDCl3) of compound 1.4a. Appendix 1 - Spectra Relevant to Chapter 1 114 Appendix 1 - Spectra Relevant to Chapter 1 115 Figure A1.37 Infrared spectrum (Thin Film, NaCl) of compound 1.4a. Figure A1.39 13C NMR (101 MHz, CDCl3) of compound 1.4a. Figure A1.40 1 H NMR (400 MHz, CDCl3) of compound 1.4b. Appendix 1 - Spectra Relevant to Chapter 1 116 Appendix 1 - Spectra Relevant to Chapter 1 117 Figure A1.41 Infrared spectrum (Thin Film, NaCl) of compound 1.4b. Figure A1.42 13C NMR (101 MHz, CDCl3) of compound 1.4b. Figure A1.43 1 H NMR (400 MHz, CDCl3) of compound 1.4c. Appendix 1 - Spectra Relevant to Chapter 1 118 Appendix 1 - Spectra Relevant to Chapter 1 119 Figure A1.44 Infrared spectrum (Thin Film, NaCl) of compound 1.4c. Figure A1.45 13C NMR (101 MHz, CDCl3) of compound 1.4c. Figure A1.46 1H NMR (500 MHz, CDCl3) of compound 1.4d. Appendix 1 - Spectra Relevant to Chapter 1 120 Appendix 1 - Spectra Relevant to Chapter 1 121 Figure A1.47 Infrared spectrum (Thin Film, NaCl) of compound 1.4d. Figure A1.48 13C NMR (126 MHz, CDCl3) of compound 1.4d. Figure A1.49 1H NMR (500 MHz, CDCl3) of compound 1.4e. Appendix 1 - Spectra Relevant to Chapter 1 122 Appendix 1 - Spectra Relevant to Chapter 1 123 Figure A1.50 Infrared spectrum (Thin Film, NaCl) of compound 1.4e. Figure A1.51 13C NMR (126 MHz, CDCl3) of compound 1.4e. Figure A1.52 1H NMR (400 MHz, CDCl3) of compound 1.4f. Appendix 1 - Spectra Relevant to Chapter 1 124 Appendix 1 - Spectra Relevant to Chapter 1 125 Figure A1.53 Infrared spectrum (Thin Film, NaCl) of compound 1.4f. Figure A1.54 13C NMR (101 MHz, CDCl3) of compound 1.4f. Figure A1.55 1H NMR (400 MHz, CDCl3) of compound 1.4h. Appendix 1 - Spectra Relevant to Chapter 1 126 Appendix 1 - Spectra Relevant to Chapter 1 127 Figure A1.56 Infrared spectrum (Thin Film, NaCl) of compound 1.4h. Figure A1.57 13C NMR (101 MHz, CDCl3) of compound 1.4h. Figure A1.58 1H NMR (500 MHz, CDCl3) of compound 1.4i. Appendix 1 - Spectra Relevant to Chapter 1 128 Appendix 1 - Spectra Relevant to Chapter 1 129 Figure A1.59 Infrared spectrum (Thin Film, NaCl) of compound 1.4i. Figure A1.60 13C NMR (126 MHz, CDCl3) of compound 1.4i. Figure A1.61 1H NMR (400 MHz, CDCl3) of compound 1.4j. Appendix 1 - Spectra Relevant to Chapter 1 130 Appendix 1 - Spectra Relevant to Chapter 1 131 Figure A1.62 Infrared spectrum (Thin Film, NaCl) of compound 1.4j. Figure A1.63 13C NMR (101 MHz, CDCl3) of compound 1.4j. Figure A1.64 1H NMR (400 MHz, CDCl3) of compound 1.4k. Appendix 1 - Spectra Relevant to Chapter 1 132 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.65 Infrared spectrum (Thin Film, NaCl) of compound 1.4k. Figure A1.66 13C NMR (101 MHz, CDCl3) of compound 1.4k. 133 Figure A1.67 1H NMR (400 MHz, CDCl3) of compound 1. 4l. Appendix 1 - Spectra Relevant to Chapter 1 134 Appendix 1 - Spectra Relevant to Chapter 1 135 Figure A1.68 Infrared spectrum (Thin Film, NaCl) of compound 1.4l. Figure A1.69 13C NMR (101 MHz, CDCl3) of compound 1.4l. Figure A1.70 1H NMR (400 MHz, CDCl3) of compound 1.4m. Appendix 1 - Spectra Relevant to Chapter 1 136 Appendix 1 - Spectra Relevant to Chapter 1 137 Figure A1.71 Infrared spectrum (Thin Film, NaCl) of compound 1.4m. Figure A1.72 13C NMR (101 MHz, CDCl3) of compound 1.4m. Figure A1.73 1 H NMR (500 MHz, CDCl3) of compound 1.5a. Appendix 1 - Spectra Relevant to Chapter 1 138 Appendix 1 - Spectra Relevant to Chapter 1 139 Figure A1.71 Infrared spectrum (Thin Film, NaCl) of compound 1.5a. Figure A1.72 13C NMR (101 MHz, CDCl3) of compound 1.5a. Figure A1.73 1 H NMR (400 MHz, CDCl3) of compound 1.5b. Appendix 1 - Spectra Relevant to Chapter 1 140 Appendix 1 - Spectra Relevant to Chapter 1 141 Figure A1.74 Infrared spectrum (Thin Film, NaCl) of compound 1.5b. Figure A1.75 13 C NMR (101 MHz, CDCl3) of compound 1.5b. Figure A1.76 1H NMR (400 MHz, CDCl3) of compound 1.5c. Appendix 1 - Spectra Relevant to Chapter 1 142 Appendix 1 - Spectra Relevant to Chapter 1 143 Figure A1.77 Infrared spectrum (Thin Film, NaCl) of compound 1.5c. Figure A1.78 13C NMR (101 MHz, CDCl3) of compound 1.5c. Figure A1.79 1 H NMR (400 MHz, CDCl3) of compound 1.5d. Appendix 1 - Spectra Relevant to Chapter 1 144 Appendix 1 - Spectra Relevant to Chapter 1 145 Figure A1.80 Infrared spectrum (Thin Film, NaCl) of compound 1.5d. Figure A1.81 13C NMR (101 MHz, CDCl3) of compound 1.5d. Figure A1.82 1H NMR (400 MHz, CDCl3) of compound 1.5e. Appendix 1 - Spectra Relevant to Chapter 1 146 Appendix 1 - Spectra Relevant to Chapter 1 147 Figure A1.83 Infrared spectrum (Thin Film, NaCl) of compound 1.5e. Figure A1.84 13C NMR (101 MHz, CDCl3) of compound 1.5e. Figure A1.85 1H NMR (400 MHz, CDCl3) of compound 1. 5f. Appendix 1 - Spectra Relevant to Chapter 1 148 Appendix 1 - Spectra Relevant to Chapter 1 149 Figure A1.86 Infrared spectrum (Thin Film, NaCl) of compound 1.5f. Figure A1.87 13C NMR (101 MHz, CDCl3) of compound 1.5f. Figure A1.88 1H NMR (400 MHz, CDCl3) of compound 1.5g. Appendix 1 - Spectra Relevant to Chapter 1 150 Appendix 1 - Spectra Relevant to Chapter 1 151 Figure A1.89 Infrared spectrum (Thin Film, NaCl) of compound 1.6. Figure A1.90 13C NMR (101 MHz, CDCl3) of compound 1.5g. Figure A1.91 1H NMR (400 MHz, CDCl3) of compound 1.5h. Appendix 1 - Spectra Relevant to Chapter 1 152 Appendix 1 - Spectra Relevant to Chapter 1 153 Figure A1.92 Infrared spectrum (Thin Film, NaCl) of compound 1.5h. Figure A1.93 13C NMR (101 MHz, CDCl3) of compound 1.5h. Figure A1.94 1H NMR (400 MHz, CDCl3) of compound 1.5i. Appendix 1 - Spectra Relevant to Chapter 1 154 Appendix 1 - Spectra Relevant to Chapter 1 155 Figure A1.95 Infrared spectrum (Thin Film, NaCl) of compound 1.5i. Figure A1.96 13C NMR (101 MHz, CDCl3) of compound 1.5i. Figure A1.97 1H NMR (500 MHz, CDCl3) of compound 1.6a. Appendix 1 - Spectra Relevant to Chapter 1 156 Appendix 1 - Spectra Relevant to Chapter 1 157 Figure A1.98 Infrared spectrum (Thin Film, NaCl) of compound 1.6a. Figure A1.99 13C NMR (101 MHz, CDCl3) of compound 1.6a. Figure A1.100 1H NMR (400 MHz, CDCl3) of compound 1.6b. Appendix 1 - Spectra Relevant to Chapter 1 158 Appendix 1 - Spectra Relevant to Chapter 1 159 Figure A1.101 Infrared spectrum (Thin Film, NaCl) of compound 1.6b. Figure A1.102 13C NMR (101 MHz, CDCl3) of compound 1.6b. Figure A1.103 1H NMR (400 MHz, CDCl3) of compound 1.6c. Appendix 1 - Spectra Relevant to Chapter 1 160 Appendix 1 - Spectra Relevant to Chapter 1 161 Figure A1.104 Infrared spectrum (Thin Film, NaCl) of compound 1.6c. Figure A1.105 13C NMR (101 MHz, CDCl3) of compound 1.6c. Figure A1.106 1H NMR (400 MHz, CDCl3) of compound 1.6d. Appendix 1 - Spectra Relevant to Chapter 1 162 Appendix 1 - Spectra Relevant to Chapter 1 163 Figure A1.107 Infrared spectrum (Thin Film, NaCl) of compound 1.6d. Figure A1.108 13C NMR (101 MHz, CDCl3) of compound 1.6d. Figure A1.109 1H NMR (500 MHz, CDCl3) of compound 1.6e. Appendix 1 - Spectra Relevant to Chapter 1 164 Appendix 1 - Spectra Relevant to Chapter 1 165 Figure A1.110 Infrared spectrum (Thin Film, NaCl) of compound 1.6e. Figure A1.111 13C NMR (101 MHz, CDCl3) of compound 1.6e. Figure A1.112 1H NMR (500 MHz, CDCl3) of compound 1.6f. Appendix 1 - Spectra Relevant to Chapter 1 166 Appendix 1 - Spectra Relevant to Chapter 1 167 Figure A1.113 Infrared spectrum (Thin Film, NaCl) of compound 1.6f. Figure A1.114 13C NMR (101 MHz, CDCl3) of compound 1.6f. Figure A1.115 1H NMR (500 MHz, CDCl3) of compound 1.6f. Appendix 1 - Spectra Relevant to Chapter 1 168 Appendix 1 - Spectra Relevant to Chapter 1 169 Figure A1.116 Infrared spectrum (Thin Film, NaCl) of compound 1.6f. Figure A1.117 13C NMR (101 MHz, CDCl3) of compound 1.6f. Figure A1.118 1H NMR (400 MHz, CDCl3) of compound 1.6g. Appendix 1 - Spectra Relevant to Chapter 1 170 Appendix 1 - Spectra Relevant to Chapter 1 171 Figure A1.119 Infrared spectrum (Thin Film, NaCl) of compound 1.6g. Figure A1.120 13C NMR (101 MHz, CDCl3) of compound 1.6g. Figure A1.121 1H NMR (400 MHz, CDCl3) of compound 1.6h Appendix 1 - Spectra Relevant to Chapter 1 172 Appendix 1 - Spectra Relevant to Chapter 1 173 Figure A1.122 Infrared spectrum (Thin Film, NaCl) of compound 1.6h. Figure A1.123 13C NMR (101 MHz, CDCl3) of compound 1.6h. Figure A1.124 1H NMR (400 MHz, CDCl3) of compound 1.6i. Appendix 1 - Spectra Relevant to Chapter 1 174 Appendix 1 - Spectra Relevant to Chapter 1 175 Figure A1.125 Infrared spectrum (Thin Film, NaCl) of compound 1.6i. Figure A1.126 13C NMR (101 MHz, CDCl3) of compound 1.6i. Figure A1.127 1H NMR (400 MHz, CDCl3) of compound 1.8. Appendix 1 - Spectra Relevant to Chapter 1 176 Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.128 Infrared spectrum (Thin Film, NaCl) of compound 1.8. Figure A1.129 13C NMR (101 MHz, CDCl3) of compound 1.8. 177 Figure A1.130 1H NMR (400 MHz, CDCl3) of compound 1.9. Appendix 1 - Spectra Relevant to Chapter 1 178 Appendix 1 - Spectra Relevant to Chapter 1 179 Figure A1.131 Infrared spectrum (Thin Film, NaCl) of compound 1.9. Figure A1.132 13C NMR (101 MHz, CDCl3) of compound 1.9. Figure A1.133 1H NMR (400 MHz, CDCl3) of compound 1.10. Appendix 1 - Spectra Relevant to Chapter 1 180 Appendix 1 - Spectra Relevant to Chapter 1 181 Figure A1.134 Infrared spectrum (Thin Film, NaCl) of compound 1.10. Figure A1.135 13C NMR (101 MHz, CDCl3) of compound 1.10. Figure A1.136 1H NMR (400 MHz, CDCl3) of compound 1.11. Appendix 1 - Spectra Relevant to Chapter 1 182 Appendix 1 - Spectra Relevant to Chapter 1 183 Figure A1.137 Infrared spectrum (Thin Film, NaCl) of compound 1.11. Figure A1.138 13C NMR (101 MHz, CDCl3) of compound 1.11. Figure A1.139 1H NMR (400 MHz, CDCl3) of compound 1.12. Appendix 1 - Spectra Relevant to Chapter 1 184 Appendix 1 - Spectra Relevant to Chapter 1 185 Figure A1.140 Infrared spectrum (Thin Film, NaCl) of compound 1.12. Figure A1.141 13C NMR (101 MHz, CDCl3) of compound 1.12. Figure A1.142 1H NMR (400 MHz, CDCl3) of compound 1.13. Appendix 1 - Spectra Relevant to Chapter 1 186 Appendix 1 - Spectra Relevant to Chapter 1 187 Figure A1.143 Infrared spectrum (Thin Film, NaCl) of compound 1.13. Figure A1.144 13C NMR (101 MHz, CDCl3) of compound 1.13. Figure A1.145 1H NMR (400 MHz, CD3OD) of compound 1.14. Appendix 1 - Spectra Relevant to Chapter 1 188 Appendix 1 - Spectra Relevant to Chapter 1 189 Figure A1.146 Infrared spectrum (Thin Film, NaCl) of compound 1.14. Figure A1.147 13C NMR (101 MHz, CD3OD) of compound 1.14. Figure A1.148 1H NMR (600 MHz, CD3OD) of compound 1.15. Appendix 1 - Spectra Relevant to Chapter 1 190 Appendix 1 - Spectra Relevant to Chapter 1 191 Figure A1.149 Infrared spectrum (Thin Film, NaCl) of compound 1.15. Figure A1.150 13C NMR (101 MHz, CD3OD) of compound 1.15. Appendix 1 - Spectra Relevant to Chapter 1 Figure A1.151 1H-13C HMBC (CD3OD) of compound 1.15 192 Figure A1.152 1H NMR (600 MHz, CD3OD) of compound 1.16. Appendix 1 - Spectra Relevant to Chapter 1 193 Appendix 1 - Spectra Relevant to Chapter 1 194 Figure A1.153 Infrared spectrum (Thin Film, NaCl) of compound 1.16. Figure A1.154 13C NMR (101 MHz, CD3OD) of compound 1.16. Figure A1.155 1H NMR (500 MHz, CDCl3) of compound SI-3. Appendix 1 - Spectra Relevant to Chapter 1 195 Appendix 1 - Spectra Relevant to Chapter 1 196 Figure A1.156 Infrared spectrum (Thin Film, NaCl) of compound SI-3. Figure A1.157 13C NMR (126 MHz, CDCl3) of compound SI-3. Figure A1.158 1H NMR (500 MHz, CDCl3) of compound SI-4. Appendix 1 - Spectra Relevant to Chapter 1 197 Appendix 1 - Spectra Relevant to Chapter 1 198 Figure A1.159 Infrared spectrum (Thin Film, NaCl) of compound SI-4. Figure A1.160 13C NMR (126 MHz, CDCl3) of compound SI-4. Figure A1.161 1H NMR (400 MHz, CDCl3) of compound SI-5. Appendix 1 - Spectra Relevant to Chapter 1 199 Appendix 1 - Spectra Relevant to Chapter 1 200 Figure A1.162 Infrared spectrum (Thin Film, NaCl) of compound SI-5. Figure A1.163 13C NMR (101 MHz, CDCl3) of compound SI-5. Figure A1.164 1H NMR (400 MHz, CDCl3) of compound SI-6. Appendix 1 - Spectra Relevant to Chapter 1 201 Appendix 1 - Spectra Relevant to Chapter 1 202 Figure A1.165 Infrared spectrum (Thin Film, NaCl) of compound SI-6. Figure A1.166 13C NMR (101 MHz, CDCl3) of compound SI-6. Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 203 APPENDIX 2 Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes† A2.1 INTRODUCTION AND BACKGROUND Diazepanes and benzodiazepines are medicinally important seven-membered diazaheterocycles found in a variety of pharmaceuticals, including the eponymous benzodiazepine class of GABA agonists widely used as anxiolytics, sedatives, and pain relievers. These heterocycles exhibit a range of biological activities, having been tested in cancer therapeutics (BMS-214662) and marketed in FDA-approved drugs for the treatment of various conditions including allergies (Emedastine), hypertension (Bunazosin), and more recently, insomnia (Suvorexant) (Figure A2.1). Merck’s Suvorexant, which is the first orexin receptor antagonist of its class, is especially interesting as a mechanistically novel treatment for insomnia. Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 204 Figure A2.1 Diazepines and diazepanes are medicinally important heterocycles O O N NH R3N N Ph H 2N O R1 N N N S N S O O O R2 NC Benzodiazepines Sedative GABAergic anxiolytics BMS-214662 Anti-cancer Farnesyl transferrase inhibitor Bunazosin benign prostatic hyperplasia, hypertension, glaucoma alpha 1 antagonist OEt NPh O N Cl N N N N N N N N Suvorexant (Merck 2014) Insomnia treatment dual orexin receptor antagonist (DORA) O N N N N N Emedastine Antihistamine H1 receptor antagonist N H Selective dopamine D4 partial agonist While these diazepane-containing pharmaceuticals may occasionally contain chiral monosubstitutions, chiral gem-disubstitutions are absent. In fact, to our knowledge, there are no known stereoselective methods to generate chiral gem-disubstituted diazepanes. Such a method would be important, as there is increasing recognition of the correlation between three-dimensional complexity and drug-like properties. This increasing recognition is in part responsible for the resurgent interest in natural-product screening libraries.1 Thus, including more structurally complex gem-disubstituted diazepanes in the synthetic toolkit of medicinal chemistry would enable deeper structureactivity-relationship (SAR) studies of novel molecular space, potentially resulting in new small molecule drugs. Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 205 Figure A2.2 gem-Disubstituted diazepanes can augment biological properties of small molecules H N R3 N R1 R2 N H N R4 Unsubstituted diazepane Chiral disubstituted diazepane • Common in medicinal chemistry • No known synthetic methods • Greater sp3 complexity is associated with enhanced biological properties2 Here we report our preliminary investigations into the stereoselective synthesis of chiral gem-disubstituted oxo-diazepanes via the decarboxylative asymmetric allylic alkylation (DAAA) reaction. The resultant gem-disubstituted oxo-diazepanes can be reductively transformed into valuable chiral diazapanes. Our laboratory has extensively explored the utility of DAAA in generating all-carbon quaternary and tetrasubstituted centers; it has proven to be a robust method that tolerates an incredible range of substrates, from carbocyclic ketones to lactams to acyclic compounds. Oxodiazepane DAAA substrates can be synthesized beginning from Boc-piperidinone A2.1 (Scheme A2.1); Beckmann rearrangement2 of commercially available piperidinone A2.1 (<$0.50/gram) results in Boc-diazepanone A2.2, which can then be benzoylated and acylated to afford dicarbonyl compound A2.3. A2.3 then serves as a divergent point of entry into a variety of DAAA substrates. Scheme A2.1 Synthetic route toward diazepane DAAA substrates O N Boc A2.1 i. NH2OH NaOAc EtOH/H2O ii. TsCl K2CO3 82 °C O O O i. nBuLi, BzCl THF, -78 °C HN NBoc A2.2 ii. LHMDS, Allyl cyanoformate THF -78 °C O O BzN Base O R O BzN Electrophile NBoc A2.3 NBoc A2.4 Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 206 We chose the benzyl substrate A2.4a for initial optimizations (Table A2.1). Starting with conditions using (S)-(CF3)3-t-Bu-PHOX and 2:1 hexanes/toluene at 0.014 M concentration, which were based on our previous report,3 we were pleased to obtain the desired oxo-diazepane in 85% ee. Polar aprotic ethereal solvents (entries 1 and 2) proved inferior to less polar solvents such as methylcyclohexane. Ultimately, we found that conducting the reaction in methylcyclohexane provided the highest enantioselectivity at 89% ee (Entry 6). Table A2.1 Optimization studies on the DAAA of benzyl substrate A2.4a Ph O O BzN Ph O Pd2(pmdba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol%) O BzN Solvent, 0.014 M, 40 °C NBoc NBoc A2.5a A2.4a Entry Solvent ee (%) 1 THF 20 3 Dioxane 38 3 MTBE 70 4 Toluene 69 5 2:1 Hexanes/Toluene 85 6 MeCyclohexane 89 [a] Screens performed on a 0.04 mmol scale. [b] The ee values were determined by chiral SFC analysis. Bz = benzoyl, Boc = tert-butoxycarbonyl, pmdba = bis(4-methoxybenzylidene)acetone With optimal conditions in hand, we began exploring the oxodiazepane DAAA substrate scope (Table A2.2). In substrates A2.4i-k, we examined the electronic effect of the N1 protecting group, observing that anisoyl-protection yielded the product A2.5j with greater Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 207 ee than the para-CF3 and benzoyl versions A2.5i and A2.5k. The reaction is tolerant of a variety of functional groups such as chloroallyl (A2.5b), methyl ester (A2.5c), fluoro (A2.5e, A2.5g), carbamate (A2.5f), and alkyne (A2.5h), providing the desired products in ee’s up to 95% and yields up to >99%. Notably, the nitrile product A2.5d was obtained in a reduced 79% ee, suggesting that the seven-membered ring enables the nitrile functionality to adopt a conformation that interferes with the transition state of the reaction; this result contrasts with previous results using piperidinones and morpholinones in which high enantioselectivity was observed with the corresponding nitrile substrates.4,5 Table A2.2 Oxodiazepane substrate scope exploration O R O Pd2(dba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol%) O R1 N O R1 N MeCy, 0.014 M, 40 °C NBoc NBoc A2.4a-l A2.5a-l Cl CO2Me O CN O AnN O O AnN NBoc A2.5c A2.5d >99% yield 87% ee 96% yield 95% ee >99% yield 79% ee O O F A2.5e 83% yield 86% ee O Bn AnN BzN BzN NBoc NBoc NBoc A2.5b BocHN O F AnN AnN NBoc BzN R NBoc NBoc NBoc A2.5f A2.5g A2.5a A2.5h 76% yield 93% ee 84% yield 90% ee 84% yield 89% ee 44% yield 94% ee O Me BzN O Me O AnN NBoc O Me A2.5i A2.5j 91% ee 94% ee NBoc F3C Bn AnN N NBoc O NBoc A2.5k A2.5l 90% ee >99% yield 89% ee Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 208 [a] Conditions: oxodiazepane A2.4a-l (1.0 equiv), Pd2(dba)3 (4 mol %), (S)-(CF3)3-tBuPHOX (10 mol %), in methylcyclohexane (0.014 M) at 40 °C for 12-24 h. [b] Pd2(pmdba)3 (4 mol %) instead of Pd2(dba)3. All reported yields are for isolated products. The ee values were determined by chiral SFC analysis. An = 4-methoxybenzoyl, dba = dibenzylideneacetone. Unfortunately, attempts to synthesize other medicinally important seven-membered diazaheterocycle DAAA substrates using isomeric and benzo-fused intermediates such as A2.6 and A2.7 were unsuccessful. With A2.6, attempts at acylation to form the dicarbonyl intermediate resulted in degradation of the starting material. With A2.7, its corresponding enolate was unreactive and starting material was reisolated. Scheme A2.2 Attempted synthesis of other medicinally relevant DAAA substrates O LHMDS (1.1 equiv) BzN NBoc NBoc Degradation O O O BzN O BzN CNCO2Allyl (1.2 equiv) A2.6 O O O Cs2CO3/PhSO2CH2NHBoc BzN NBoc O R O NBoc BOMCl/NaH MeI/NaH A2.7 Unreactive We are currently exploring various product derivatizations and transformations, the results of which we hope will be published shortly. A2.2 CONCLUSIONS In summary, we report the enantioselective synthesis of unprecedented gem- disubstituted oxodiazepanes using the venerable Pd-catalyzed decarboxylative asymmetric allylic alkylation. The versatile (S)-(CF3)3-t-Bu-PHOX ligand performs well, Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 209 yielding products in ee’s ranging from 79-95%. These novel chiral diazepanes are anticipated to find utility in the design of novel diazepane-containing pharmaceuticals; their added three-dimensional complexity should enable access to new chemical space in the quest for new medicines. A2.3 EXPERIMENTAL SECTION A2.3.1 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. tert-Butyl 4-oxopiperidine1-carboxylate A2.1 was obtained from Combi-Blocks. Commercially obtained reagents were used as received. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar/Combi-Blocks 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) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, iodine on silica, ninhydrin, or KMnO4 staining. SiliaFlash P60 Academic Silica gel (particle size 0.040– 0.063 mm) was used for flash chromatography. 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. Reverse Phase Preparatory HPLC was performed with a Teledyne ISCO ACCQPrep HP125 preparative liquid chromatography system equipped with a RediSep Prep C18 5 µm column (20 x 250 mm). Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 1 210 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or CH3OH (δ 3.31 ppm). 13C 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 CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 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 water (δ 1.56 or 4.87 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 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). Stereochemistry is assigned by analogy to previous results. 4,6–10 A2.3.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes A2.3.3 211 Procedures for the Synthesis of Oxodiazepane Allylic Alkylation Substrates O HN NBoc tert-butyl 5-oxo-1,4-diazepane-1-carboxylate. Prepared according to a literature procedure, via Beckmann rearrangement.2 O BzN NBoc tert-butyl 4-benzoyl-5-oxo-1,4-diazepane-1-carboxylate. To a solution of tert-butyl 5oxo-1,4-diazepane-1-carboxylate (5 g, 1 equiv) in THF (230 mL, 0.1 M) at -78 °C was slowly added nBuLi (12.8 mL, 2.18 M, 1.2 equiv). The cloudy solution was allowed to warm up at ambient temperature until the solution became clear, at which point it was again cooled to -78 °C. Then, BzCl (3.52 mL, 1.3 equiv) was added and the reaction turned light orange over several minutes. The reaction was stirred for 1 h at -78 °C and was then quenched with sat. NH4Cl (aq), extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, concentrated onto SiO2. The silica-adsorbed crude product was purified by silica gel flash chromatography (20% acetone/hexanes) to afford the desired product in quantitative yield (7.43g); 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.49 – 7.41 (m, 1H), 7.41 – 7.32 (m, 2H), 4.03 – 3.96 (m, 2H), 3.71 (q, J = 6.1, 5.1 Hz, 4H), 2.82 – 2.75 (m, 2H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 175.6, 173.7, 154.5, 135.9, 131.7, 128.2, 127.9, 80.7, (47.7 and 47.10 appear as two peaks due to hindered rotation), 45.4, (41.6 and 41.0 appear as two peaks due to hindered rotation), 40.6, 28.3; IR (Neat Film, NaCl) 2976, 2932, 2251, 1682, 1599, 1582, 1450, Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 212 1422, 1392, 1366,1327, 1285, 1247, 1229, 1157, 1115, 1032, 1018, 976, 954, 915,862, 793,769, 729, 696, 647 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C17H26N3O4 [M+NH4]+: 336.1918, found 336.1912. O O Me O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-methyl-5-oxo-1,4-diazepane-1,6-dicarboxylate. To a solution of 6-allyl 1-(tert-butyl) 4-benzoyl-5-oxo-1,4-diazepane-1,6-dicarboxylate (240 mg, 1 equiv) in THF (6 mL, 0.1 M) at 0 °C was added NaH (60% in mineral oil, 26 mg, 1.1 equiv). The solution was stirred at 0 °C for 40 min and then MeI (186 uL, 5 equiv) was added. The reaction was heated to 45 °C for 16 h, then quenched with sat. NH4Cl (aq), and then extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated onto SiO2. The silica-adsorbed crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to afford the desired product in as a light yellow oil (200 mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.63 (m, 2H), 7.52 – 7.43 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 5.96 (ddt, J = 16.6, 10.4, 6.0 Hz, 1H), 5.40 (dq, J = 17.3, 1.5 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.73 (t, J = 6.2 Hz, 2H), 4.33 (s, 1H), 4.10 (d, J = 14.8 Hz, 1H), 3.64 (dt, J = 14.0, 3.4 Hz, 4H), 1.57 (s, 3H), 1.45 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ (174.5 and 174.1 appear as two peaks due to hindered rotation), 173.0, 171.7, (155.1 and 154.9 appear as two peaks due to hindered rotation), 135.7, 131.9, 131.1, 128.3, 128.2, 120.1, 81.1, 66.8, 57.6, (49.7 and 49.0 appear as two peaks due to hindered rotation), (47.0 and 46.0 appear as two peaks due to hindered rotation), 43.1, 28.4, 23.6. IR (Neat Film, NaCl) 2977, 1693, 1449, 1416, 1366, 1325, Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 213 1281, 1249, 1139, 1104, 1047, 983, 938, 768, 727, 694 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N2O6 [M+H]+: 417.2020, found 417.2010. O O O O N MeO NBoc 6-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6-dicarboxylate. To a solution of tert-butyl 4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1-carboxylate (1 g, 1.0 equiv) in THF (20 mL, 0.1 M total concentration) at −78 °C was added LiHMDS (528 mg, 1.1 equiv) in THF (9 mL) dropwise. The resulting light yellow reaction mixture was stirred for 15 min at −78 °C. Then, allyl cyanoformate (368 µL, 1.2 equiv) was added dropwise at −78 °C, giving a clear solution. After stirring for 1.5 h at −78 °C, the reaction was quenched with 1 M HCl (10 mL) and diluted with ethyl acetate (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and solid NaHCO3, decanted, and concentrated under reduced pressure onto silica. The silica-adsorbed crude mixture was purified by silica gel flash chromatography (10% → 20% EtOAc/hexanes) to give allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6-dicarboxylate as a clear oil (600 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.60 (m, 2H), 6.91 – 6.79 (m, 2H), 5.92 (ddt, J = 17.3, 10.4, 5.9 Hz, 1H), 5.42 – 5.20 (m, 2H), 4.77 – 4.56 (m, 2H), 4.40 – 3.92 (m, 4H), 3.82 (s, 5H), 3.58 – 3.24 (m, 1H), 1.46 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.1, 171.3, 167.6, 163.1, 154.6, 131.3, 131.2, 127.0, 119.4, 113.6, 81.1, 66.5, 55.9, 55.4, (47.7 and 46.7 appear as two peaks due to hindered rotation), Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 214 45.12, (43.3 and 42.8 appear as two peaks due to hindered rotation), 28.3. IR (Neat Film, NaCl) 2977, 1746, 1693, 1603, 1578, 1511, 1454, 1419, 1392, 1366, 1324, 1255, 1168, 1025, 995, 965, 842, 766 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N2O7 [M+H]+: 433.1969, found 433.1966. BocHN O O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-(((tert-butoxycarbonyl)amino)methyl)-5-oxo-1,4diazepane-1,6-dicarboxylate. A solution of A2.3 (200 mg, 1 equiv) and tert-butyl ((phenylsulfonyl)methyl)carbamate11,12 (162 mg, 1.2 equiv) in CH2Cl2 (2.5 mL, 0.2 M) was stirred for 5 min at rt. Then at room temperature was added Cs2CO3 (405 mg, 2.5 equiv). The reaction was stirred at rt for 30 min, then sat. aqueous NH4Cl (1 mL) was added and the biphasic mixture was vigorously stirred for 20 min. The aqueous phase was extracted with CH2Cl2 (3 x 3 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded crude reaction mixture was purified by automated silica gel flash chromatography (Teledyne ISCO) (10 → 40% acetone/hexanes) to give methylcarbamate allyl ester A2.4f as a white foam (200 mg, 76% yield): 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.71 (m, 2H), 7.59 – 7.46 (m, 1H), 7.40 (dd, J = 8.4, 7.0 Hz, 2H), 6.00 (ddt, J = 16.6, 10.3, 6.1 Hz, 1H), 5.51 – 5.25 (m, 2H), 5.17 (s, 1H), 4.81 – 4.62 (m, 2H), 4.36 (dd, J = 51.1, 15.8 Hz, 1H), 4.14 – 3.20 (m, 7H), 1.43 (d, J = 8.5 Hz, 18H); 13C NMR (101 MHz, CDCl3) δ (174.1 and 173.8 appear as two peaks due to hindered rotation), 172.7, (170.0 and 169.6 appear as two peaks due to hindered rotation), 155.9, (155.1 and 154.6 Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 215 appear as two peaks due to hindered rotation), 135.4, 132.2, 131.3, 128.5, 128.3, 120.2, 81.4, 79.5, 67.4, 62.6, 47.0, 46.8, 45.9, 43.2, 28.4, 28.4. IR (Neat Film, NaCl) 3457, 2977, 2934, 2253, 1704, 1600, 1503, 1450, 1417, 1392, 1367, 1325, 1283, 1248, 1158, 1042, 980, 913,77 860, 767, 729, 693, 663 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H37N3O8 [M+H]+: 532.2653, found 532.2664. Ph O O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-benzyl-5-oxo-1,4-diazepane-1,6-dicarboxylate (A2.4a). Sodium hydride (60% in mineral oil, 22 mg, 1.1 equiv) was added to a solution of allyl ester A2.3 (200 mg, 1.0 equiv) in THF (5 mL, 0.1 M) at 0 °C. After stirring for 30 min at 0 °C, BnBr (71 µL, 1.2 equiv) was added. The reaction mixture was heated to 50 °C and stirred for 16 h; at the 4 h mark, 2 equiv BnBr was added; at the 12 h mark, 2 equiv more BnBr was added. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. The silica-loaded residue was purified by silica gel flash chromatography (20% EtOAc/hexanes) to give benzylated allyl ester A2.4a as a white foam (130 mg, 53% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 2H), 7.55 – 7.46 (m, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.31 – 7.25 (m, 3H), 7.24 – 7.12 (m, 2H), 5.86 (tq, J = 22.8, 6.5 Hz, 1H), 5.38 (s, 1H), 5.36 – 5.27 (m, 1H), 4.63 (q, J = 6.3, 5.8 Hz, 2H), 4.12 (d, J = 15.1 Hz, 1H), 4.01 – 3.89 (m, 1H), 3.69 (q, J = 12.0, 9.6 Hz, 2H), 3.61 – 3.35 (m, 3H), Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 216 1.45 (s, 9H); 13C NMR (101 MHz, CDCl3) δ (174.3 and 174.0 appear as two peaks due to hindered rotation), (172.1 and 171.9 appear as two peaks due to hindered rotation), (170.8 and 170.2 appear as two peaks due to hindered rotation), (155.5 and 154.9 appear as two peaks due to hindered rotation), (135.6 & 135.5 appear as two peaks due to hindered rotation), 135.4, 132.0, (131.1 & 130.9 appear as two peaks due to hindered rotation), (130.7 & 130.5 appear as two peaks due to hindered rotation), 128.4, 128.4, 128.2, (127.4 & 127.3 appear as two peaks due to hindered rotation), (120.5 & 120.1 appear as two peaks due to hindered rotation), (81.2 & 80.9 appear as two peaks due to hindered rotation), (66.9 & 66.8 appear as two peaks due to hindered rotation), (62.5 & 62.1 appear as two peaks due to hindered rotation), (47.3 & 46.7 appear as two peaks due to hindered rotation), (46.2 & 45.7 appear as two peaks due to hindered rotation), (42.4 & 42.1 appear as two peaks due to hindered rotation), 42.0, 28.4. IR (Neat Film, NaCl) 3062, 3030, 2976, 2933, 1694, 1601, 1583, 1494, 1450, 1415, 1392, 1366, 1325, 1280, 1247, 1154, 1131, 1092, 1041, 1022, 980, 939, 867, 795, 767, 727, 703, 661 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C28H32N2O6 [M+H]+: 437.1707, found 437.1697. OMe O O O N MeO 6-allyl 1-(tert-butyl) NBoc 4-(4-methoxybenzoyl)-6-methyl-5-oxo-1,4-diazepane-1,6- dicarboxylate (A2.4j). To a solution of anisoyl allyl ester (200 mg, 1 equiv) and Cs2CO3 (301 mg, 2 equiv) in MeCN (4.6 mL, 0.1 M) was added MeI (143 uL, 5 equiv). The reaction was heated to 45 °C for 40 min and then quenched with aqueous NH4Cl (10 mL) Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 217 and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO) (0 → 90% EtOAc/hexanes) to give methylated allyl ester A2.4j as a clear oil (70 mg, 34% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.75 – 7.65 (m, 2H), 6.90 – 6.82 (m, 2H), 5.96 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.40 (dq, J = 17.2, 1.4 Hz, 1H), 5.36 – 5.29 (m, 1H), 4.71 (dddd, J = 14.2, 7.3, 4.4, 2.1 Hz, 2H), 4.27 – 4.15 (m, 1H), 4.14 – 4.04 (m, 1H), 3.83 (s, 3H), 3.76 (d, J = 13.6 Hz, 1H), 3.62 (dt, J = 13.9, 3.2 Hz, 2H), 3.56 – 3.46 (m, 1H), 1.60 – 1.55 (m, 3H), 1.44 (d, J = 17.8 Hz, 9H); 13C NMR (101 MHz, CDCl3) (173.9 & 173.6 appear as two peaks due to hindered rotation), 172.8, (172.0 & 171.8 appear as two peaks due to hindered rotation), 162.9, (155.1 & 154.9 appear as two peaks due to hindered rotation), 131.2, 131.2, 130.9, 127.5, (120.1 & 119.9 appear as two peaks due to hindered rotation), 113.6, 80.9, 66.7, 57.5, 55.4, (49.6 & 48.1 appear as two peaks due to hindered rotation), (47.1 & 46.1 appear as two peaks due to hindered rotation), 43.6, 28.3, 23.6. IR (Neat Film, NaCl) 2974, 2937, 1698, 1604, 1578, 1511, 1453, 1416, 1392, 1366, 1324, 1280, 1256, 1169, 1139, 1103, 1031, 1001, 983, 929, 840, 768, 733 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C23H30N2O7 [M+H]+: 447.2126, found 447.2128. O O O O N MeO NBoc Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 218 6-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-5-oxo-6-(prop-2-yn-1-yl)-1,4-diazepane1,6-dicarboxylate (A2.4h). Sodium hydride (60% in mineral oil, 25 mg, 1.1 equiv) was added to a solution of anisoyl allyl ester (250 mg, 1.0 equiv) in THF (5.8 mL, 0.1 M) at 0 °C. After stirring for 30 min at 0 °C, propargyl bromide (80% wt/wt in toluene, 125 µL, 2 equiv) was added. The reaction mixture was heated to 50 °C and stirred for 16 h, turning yellow in minutes. The reaction was quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0 → 50% acetone/hexanes) to give propargyl allyl ester A2.4h as a clear oil (220 mg, 81% yield). 1H NMR (500 MHz, Chloroform-d) δ 7.68 (dt, J = 11.9, 4.8 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.99 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.54 – 5.27 (m, 2H), 4.79 (dd, J = 14.0, 5.8 Hz, 2H), 4.33 – 3.96 (m, 3H), 3.82 (s, 4H), 3.78 – 3.56 (m, 1H), 3.48 (dt, J = 13.3, 3.1 Hz, 1H), 3.17 – 3.01 (m, 1H), 3.01 – 2.88 (m, 1H), 2.08 (t, J = 2.8 Hz, 1H), 1.42 (d, J = 14.3 Hz, 9H); 13C NMR (126 MHz, cdcl3) δ (173.7 & 173.2 appear as two peaks due to hindered rotation), (170.5 & 170.3 appear as two peaks due to hindered rotation), (169.7 & 169.2 appear as two peaks due to hindered rotation), 163.0, (155.5 & 154.9 appear as two peaks due to hindered rotation), 131.1, 131.0, 127.1, 120.2, 120.0, 113.5, (81.1 & 81.0 appear as two peaks due to hindered rotation), (78.9 & 78.6 appear as two peaks due to hindered rotation), 72.3, 67.3, (60.7 & 60.4 appear as two peaks due to hindered rotation), 55.4, (47.0 & 46.5 appear as two peaks due to hindered rotation), (46.1 & 46.0 appear as two peaks due to hindered rotation), 43.0, 28.3, (27.0 & 26.8 Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 219 appear as two peaks due to hindered rotation). HRMS (MM: ESI-APCI): m/z calc’d for C25H31N2O7 [M+H]+: 471. 2126, found 471.2130. O O O F O N MeO 6-allyl 1-(tert-butyl) NBoc 6-fluoro-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6- dicarboxylate (A2.4e). Sodium hydride (60% in mineral oil, 32 mg, 1.1 equiv) was added to a solution of anisoyl allyl ester (320 mg, 1.0 equiv) in THF (7.4 mL, 0.1 M) at 0 °C. After stirring for 30 min at rt, Selectfluor (315 mg 1.2 equiv) was added. The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction was quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0 → 50% acetone/hexanes) to give fluorinated allyl ester A2.4e as a clear oil (290 mg, 87% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.66 – 7.58 (m, 2H), 6.90 – 6.82 (m, 2H), 5.91 (ddt, J = 16.3, 10.9, 5.7 Hz, 1H), 5.42 – 5.32 (m, 1H), 5.29 (d, J = 9.6 Hz, 1H), 4.71 (dt, J = 21.0, 13.8 Hz, 3H), 4.52 – 4.40 (m, 1H), 4.39 – 4.19 (m, 2H), 3.94 (ddd, J = 21.1, 14.6, 9.4 Hz, 1H), 3.82 (s, 3H), 3.77 – 3.56 (m, 1H), 3.22 – 3.09 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.5, 169.6 (dd, J = 48.2, 25.4 Hz), 164.9 (d, J = 25.8 Hz), 163.4, 154.9, 131.2, 130.8, 126.0, 119.7, 113.8, 95.66 (dd, J = 205.6, 14.6 Hz), 81.4, 67.2, 55.5, 47.5 (dd, J = 109.0, 23.7 Hz), 47.1 Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 220 (d, J = 92.2 Hz), 43.3, 28.2. IR (Neat Film, NaCl) cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28FN2O7 [M+H]+: 451.1875, found 451.1877. A2.3.4 General Procedure for Allylic Alkylation Optimization Screen In a nitrogen-filled glovebox, an oven-dried 1 dram vial was charged with Pd2(pmdba)3 (4 mol %), ligand (10 mol %), solvent (1 mL), and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then substrate A2.4a (20 mg, 1.0 equiv) was added as a solution in solvent (1.8 mL, total concentration 0.014 M). The vial was sealed with a teflon cap and heated to 40 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the oxodiazepane A2.5a. A2.3.5 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions Please note The absolute configuration for all other products has been inferred by analogy.4,6–10 For respective SFC conditions, please refer to the section Determination of Enantiomeric Excess. In a nitrogen-filled glovebox, an oven-dried 1 dram vial or 20 mL scintillation vial was charged with Pd2(pmdba)3 or Pd2(dba)3 (4 mol %), (S)-(CF3)3-tBu-PHOX (10 mol %), methylcyclohexane, and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then the substrate (1.0 equiv) was added as Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 221 a solution in methylcyclohexane (total concentration 0.014 M). The vial was sealed with a teflon cap and heated to 40 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the desired oxopiperazine. A2.3.6 Experimental Procedures and Spectroscopic data for the PdCatalyzed Decarboxylative Asymmetric Allylic Alkylation of Oxodiazepane Substrates BocHN O BzN NBoc tert-butyl (S)-6-allyl-4-benzoyl-6-(((tert-butoxycarbonyl)amino)methyl)-5-oxo-1,4- diazepane-1-carboxylate (A2.5f). Following the general procedure, allyl ester A2.4f (53 mg, 1.0 equiv) in MeCy (1 mL) was added to a solution of Pd2(dba)3 (3.7 mg, 4 mol %) and (S)-(CF3)3-tBu-PHOX (5.9 mg, 10 mol %) in MeCy (7.1 mL). Purification by automated silica gel flash chromatography (0 → 50% EtOAc/hexanes) gave methyl carbamate oxodiazepane A2.5f as a white foam (37 mg, 76% yield, 93% ee). 1H NMR (400 MHz, Chloroform-d) δ 7.71 – 7.31 (m, 5H), 5.74 (ddt, J = 15.7, 10.5, 7.4 Hz, 1H), 5.21 – 5.05 (m, 2H), 4.38 (dd, J = 15.2, 5.3 Hz, 1H), 4.09 – 3.13 (m, 7H), 2.67 – 2.09 (m, 2H), 1.47 (d, J = 24.6 Hz, 18H); 13C NMR (101 MHz, CDCl3) δ (179.3 and 178.8 appear as two peaks due to hindered rotation), 174.5, 156.2, (155.9 and 155.0 appear as two peaks due to hindered rotation), 136.2, (132.5 and 132.0 appear as two peaks due to Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 222 hindered rotation), 131.7, 128.5, 127.7, 120.0, (81.3 and 81.1 appear as two peaks due to hindered rotation), 79.5, 54.7, 48.8, (47.2 and 46.7 appear as two peaks due to hindered rotation), 46.2, (42.6 and 41.1 appear as two peaks due to hindered rotation), (38.7 and 37.1 appear as two peaks due to hindered rotation), 28.5, 28.4. IR (Neat Film, NaCl) 2977, 1687, 1502, 1422, 1391, 1365, 1322, 1282, 1245, 1168, 978, 916, 753 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C26H37N3O6 [M+H]+: 488.2755, found 488.2747; [α]D23.2 –3.70 (c 1.85, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 5.684, minor = 4.539. O O N MeO NBoc tert-butyl (S)-6-allyl-4-(4-methoxybenzoyl)-5-oxo-6-(prop-2-yn-1-yl)-1,4-diazepane1-carboxylate (A2.5h). Following the general procedure, allyl ester A2.4h (70 mg, 1.0 equiv) in MeCy (1 mL) was added to a solution of Pd2(dba)3 (5.4 mg, 4 mol %) and (S)(CF3)3-tBu-PHOX (8.8 mg, 10 mol %) in MeCy (7.3 mL). Note: Reaction performed at 50 °C because no reaction occurred at 40 °C. Purification by automated silica gel flash chromatography (Teledyne ISCO, 0 → 40% acetone/hexanes) gave propargyl oxodiazepane A2.5h as a clear oil (28 mg, 44% yield, 94% ee); 1H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.2 Hz, 2H), 6.96 – 6.80 (m, 2H), 5.93 – 5.63 (m, 1H), 5.30 – 5.10 (m, 2H), 4.28 (d, J = 15.2 Hz, 1H), 3.83 (s, 7H), 3.50 (d, J = 11.6 Hz, 1H), 2.60 (dq, J = 30.2, 17.2, 16.6 Hz, 4H), 2.20 – 1.99 (m, 1H), 1.55 (d, J = 38.4 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 177.5, 174.6, 162.8, (155.6 & 155.2 appear as two peaks due Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 223 to hindered rotation), 132.1, 130.7, 127.9, 120.0, 113.7, (81.1 & 80.9 appear as two peaks due to hindered rotation), 80.5, 72.0, 55.5, 52.6, (49.1 & 46.9 appear as two peaks due to hindered rotation), 47.6, (43.0 & 42.33 appear as two peaks due to hindered rotation), (39.11 & 37.4 appear as two peaks due to hindered rotation), 28.5, (26.5 & 25.9 appear as two peaks due to hindered rotation). IR (Neat Film, NaCl) 3283, 2972, 2922, 1692, 1603, 1511, 1454, 1418, 1365, 1322, 1255, 1169, 1031, 980, 926, 839, 766, 670 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C24H31N2O5 [M+H]+: 427.2227, found 427.2238; [α]D22.1 –7.69 (c 1.0, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 11.163, minor = 10.615. Ph O BzN NBoc tert-butyl (S)-6-allyl-4-benzoyl-6-benzyl-5-oxo-1,4-diazepane-1-carboxylate (A2.5a). Following the general procedure, allyl ester A2.4a (42 mg, 1.0 equiv) in MeCy (1 mL) was added to a solution of Pd2(dba)3 (3.7 mg, 4 mol %) and (S)-(CF3)3-tBu-PHOX (6.0 mg, 10 mol %) in MeCy (6.2 mL). Purification by silica gel flash chromatography (0 → 20% EtOAc/hexanes) gave benzyl oxodiazepane A2.5a as a light pink oil (28 mg, 86% yield, 89% ee); 1H NMR (400 MHz, Chloroform-d) δ 7.56 – 7.40 (m, 3H), 7.40 – 7.32 (m, 2H), 7.32 – 7.19 (m, 3H), 7.19 – 7.00 (m, 2H), 5.88 (s, 1H), 5.26 – 5.07 (m, 2H), 4.26 – 4.03 (m, 1H), 3.94 (d, J = 15.4 Hz, 1H), 3.73 (d, J = 42.2 Hz, 1H), 3.54 (d, J = 15.3 Hz, 1H), 3.40 (s, 2H), 3.09 (dd, J = 61.0, 13.7 Hz, 1H), 2.94 – 2.34 (m, 3H), 1.48 (s, 10H); 13 C NMR (101 MHz, CDCl3) δ 179.1, 174.8, (156.0 & 155.3 appear as two peaks due to Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 224 hindered rotation), 136.6, 136.3, 133.0, 131.5, 130.8, 128.5, 128.4, 127.8, 127.1, (120.0 & 119.6 appear as two peaks due to hindered rotation), 80.8, (54.2 & 53.8 appear as two peaks due to hindered rotation), 49.1, 47.3, 46.8, (42.5 & 42.0 appear as two peaks due to hindered rotation), (41.4 & 40.3 appear as two peaks due to hindered rotation), 28.5. IR (Neat Film, NaCl) 3062, 2975, 2928, 1693, 1682, 1601, 1452, 1415, 1392, 1365, 1322, 1283, 1246, 1156, 1044, 978, 917, 865, 728, 697 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C27H33N2O4 [M+H]+: 449.2435, found 449.2429; [α]D22.4 +14.19 (c .66, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 3.572, minor = 2.789. O O F N MeO tert-butyl NBoc (S)-6-allyl-6-fluoro-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1- carboxylate (A2.5e). Following the general procedure, allyl ester A2.4e (45 mg, 1.0 equiv) in MeCy (1 mL) was added to a solution of Pd2(dba)3 (3.7 mg, 4 mol %) and (S)(CF3)3-tBu-PHOX (5.9 mg, 10 mol %) in MeCy (6.1 mL). Purification by automated silica gel flash chromatography (0 → 50% acetone/hexanes) gave fluorinated oxodiazepane A2.5e as a clear pink oil (45 mg, 83% yield, 86% ee); 1H NMR (400 MHz, Chloroform-d) δ 7.61 – 7.53 (m, 2H), 6.92 – 6.84 (m, 2H), 5.93 – 5.78 (m, 1H), 5.30 – 5.21 (m, 2H), 4.35 (t, J = 16.0 Hz, 1H), 4.22 – 4.02 (m, 2H), 3.96 – 3.85 (m, 1H), 3.84 (s, 3H), 3.40 – 3.19 (m, 2H), 2.94 – 2.78 (m, 1H), 2.71 – 2.48 (m, 1H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 173.9, 173.7, 163.1, 155.2, 131.0, 130.6, 127.1, 120.9, 113.8, Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 225 97.8 (dd, J = 193.7, 52.5 Hz), 81.1, 55.5, 49.8 (dd, J = 33.5, 23.3 Hz), (47.5 & 46.94 appear as two peaks due to hindered rotation), 43.2, 39.8 (dd, J = 32.1, 21.8 Hz), 28.3. IR (Neat Film, NaCl) 2977, 2932,1696, 1603,1578, 1511, 1448, 1413, 1366, 1327, 1256, 1169, 1152, 1029, 1000, 977, 923, 835, 766 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C21H28FN2O5 [M+H]+: 407.1977, found 407.1973; [α]D22.5 +46.99 (c 1.7, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 254 nm, tR (min): major = 2.692, minor = 3.253. A2.3.7 REFERENCES AND NOTES (1) Kearney, S. E.; Zahoránszky-Kőhalmi, G.; Brimacombe, K. R.; Henderson, M. J.; Lynch, C.; Zhao, T.; Wan, K. K.; Itkin, Z.; Dillon, C.; Shen, M.; et al. Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space. ACS Cent. Sci. 2018, 4, 1727–1741. (2) Ferreira, M. del R. R.; Cecere, G.; Pace, P.; Summa, V. Routes to HIV-Integrase Inhibitors: Efficient Synthesis of Bicyclic Pyrimidones by Ring Expansion or Amination at a Benzylic Position. Tetrahedron Lett. 2009, 50, 148–151. (3) Sun, A. W.; Hess, S. N.; Stoltz, B. M. Enantioselective Synthesis of GemDisubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation. Chem. Sci. 2019, 10, 788–792. (4) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by PalladiumCatalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem. 2012, 4, 130– 133. Appendix 2 – Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes 226 (5) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Enantioselective Synthesis of Dialkylated N -Heterocycles by Palladium-Catalyzed Allylic Alkylation. Org. Lett. 2015, 17, 1082–1085. (6) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (7) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Deracemization of Quaternary Stereocenters by Pd-Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β-Ketoesters. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. (8) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. (9) Seto, M.; Roizen, J. L.; Stoltz, B. M. Catalytic Enantioselective Alkylation of Substituted Dioxanone Enol Ethers: Ready Access to C(α)-Tetrasubstituted Hydroxyketones, Acids, and Esters. Angew. Chem. 2008, 120, 6979–6982. (10) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Rapid Synthesis of an Electron-Deficient t-BuPHOX Ligand: Cross-Coupling of Aryl Bromides with Secondary Phosphine Oxides. Tetrahedron Lett. 2010, 51, 5550– 5554. (11) Klepacz, A.; Zwierzak, A. An Expeditious One-Pot Synthesis of Diethyl N-Boc-1Aminoalkylphosphonates. Tetrahedron Lett. 2002, 43, 1079–1080. (12) Sikriwal, D.; Kant, R.; Maulik, P. R.; Dikshit, D. K. A Short Formal Synthesis of Three Epimers of Penmacric Acid. Tetrahedron 2010, 66, 6167–6173. Appendix 3 – Spectra Relevant to Appendix 2 227 APPENDIX 3 Spectra Relevant to Appendix 2: Decarboxylative Asymmetric Allylic Alkylation of gem-Disubstituted Diazepanes Figure A3.1 1H NMR (600 MHz, CDCl3) of compound A2S1. Appendix 3 - Spectra Relevant to Chapter 2 228 Appendix 3 - Spectra Relevant to Chapter 2 229 Figure A3.2 Infrared spectrum (Thin Film, NaCl) of compound A2S1. Figure A3.3 13C NMR (101 MHz, CDCl3) of compound A2S1. Figure A3.4 1H NMR (600 MHz, CDCl3) of compound A2S3. Appendix 3 - Spectra Relevant to Chapter 2 230 Appendix 3 - Spectra Relevant to Chapter 2 231 Figure A3.5 Infrared spectrum (Thin Film, NaCl) of compound A2S3. Figure A3.6 13C NMR (101 MHz, CDCl3) of compound A2S3. Figure A3.7 1H NMR (600 MHz, CDCl3) of compound A2S4. Appendix 3 - Spectra Relevant to Chapter 2 232 Appendix 3 - Spectra Relevant to Chapter 2 Figure A3.8 Infrared spectrum (Thin Film, NaCl) of compound A2S4. Figure A3.9 13C NMR (101 MHz, CDCl3) of compound A2S4. 233 Figure A3.10 1H NMR (600 MHz, CDCl3) of compound A2.4f. Appendix 3 - Spectra Relevant to Chapter 2 234 Appendix 3 - Spectra Relevant to Chapter 2 235 Figure A3.11 Infrared spectrum (Thin Film, NaCl) of compound A2.4f. Figure A3.12 13C NMR (101 MHz, CDCl3) of compound A2.4f. Figure A3.13 1H NMR (600 MHz, CDCl3) of compound A2.4g. Appendix 3 - Spectra Relevant to Chapter 2 236 Appendix 3 - Spectra Relevant to Chapter 2 237 Figure A3.14 Infrared spectrum (Thin Film, NaCl) of compound A2.4g. Figure A3.15 13C NMR (101 MHz, CDCl3) of compound A2.4g. Figure A3.16 1H NMR (600 MHz, CDCl3) of compound A2.4h. Appendix 3 - Spectra Relevant to Chapter 2 238 Appendix 3 - Spectra Relevant to Chapter 2 239 Figure A3.17 Infrared spectrum (Thin Film, NaCl) of compound A2.4h. Figure A3.18 13C NMR (101 MHz, CDCl3) of compound A2.4h. Figure A3.19 1H NMR (600 MHz, CDCl3) of compound A2.4i. Appendix 3 - Spectra Relevant to Chapter 2 240 Appendix 3 - Spectra Relevant to Chapter 2 241 Figure A3.20 Infrared spectrum (Thin Film, NaCl) of compound A2.4i. Figure A3.21 13C NMR (101 MHz, CDCl3) of compound A2.4i. Figure A3.22 1H NMR (600 MHz, CDCl3) of compound A2.4j. Appendix 3 - Spectra Relevant to Chapter 2 242 Appendix 3 - Spectra Relevant to Chapter 2 243 Figure A3.23 Infrared spectrum (Thin Film, NaCl) of compound A2.4j. Figure A3.24 13C NMR (101 MHz, CDCl3) of compound A2.4j. Figure A3.25 1H NMR (600 MHz, CDCl3) of compound A2.4l. Appendix 3 - Spectra Relevant to Chapter 2 244 Appendix 3 - Spectra Relevant to Chapter 2 245 Figure A3.26 Infrared spectrum (Thin Film, NaCl) of compound A2.4l. Figure A3.27 13C NMR (101 MHz, CDCl3) of compound A2.4l. Figure A3.28 1H NMR (600 MHz, CDCl3) of compound A2.5f. Appendix 3 - Spectra Relevant to Chapter 2 246 Appendix 3 - Spectra Relevant to Chapter 2 247 Figure A3.29 Infrared spectrum (Thin Film, NaCl) of compound A2.5f. Figure A3.30 13C NMR (101 MHz, CDCl3) of compound A2.5f. Figure A3.31 1H NMR (600 MHz, CDCl3) of compound A2.5g. Appendix 3 - Spectra Relevant to Chapter 2 248 Appendix 3 - Spectra Relevant to Chapter 2 249 Figure A3.32 Infrared spectrum (Thin Film, NaCl) of compound A2.5g. Figure A3.33 13C NMR (101 MHz, CDCl3) of compound A2.5g. Figure A3.34 1H NMR (600 MHz, CDCl3) of compound A2.5h. Appendix 3 - Spectra Relevant to Chapter 2 250 Appendix 3 - Spectra Relevant to Chapter 2 251 Figure A3.35 Infrared spectrum (Thin Film, NaCl) of compound A2.5h. Figure A3.36 13C NMR (101 MHz, CDCl3) of compound A2.5h. Figure A3.37 1H NMR (600 MHz, CDCl3) of compound A2.5l. Appendix 3 - Spectra Relevant to Chapter 2 252 Appendix 3 - Spectra Relevant to Chapter 2 253 Figure A3.38 Infrared spectrum (Thin Film, NaCl) of compound A2.5l. Figure A3.39 13C NMR (101 MHz, CDCl3) of compound A2.5l. Appendix 4 – Decarboxylative Alkylation of Imidazolinones 254 APPENDIX 4 Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones A4.1 INTRODUCTION AND BACKGROUND CO2H R1 H 2N R2 α-disubstituted amino acid Unnatural amino acids exhibit tremendous biological and chemical utility. They function as chemical intermediates and building blocks for peptide therapeutics, are heavily featured in biological studies of unnatural peptides and proteins, and are found in natural products1 (Figure A4.1). For example, alpha-disubstituted amino acids can alter peptide conformation and protein structure due increased conformational rigidity, thus serving as useful tools to probe the biological effects of protein structure.2,3 Because of their conformational effects and their enhanced resistance to chemical and enzymatic degradation, alpha-disubstituted amino acids are featured in a number of experimental peptide therapeutics.4–6 255 Appendix 4 – Decarboxylative Alkylation of Imidazolinones Figure A4.1 Biological important of disubstituted amino acids H N O N H H N H2N Me O O HO NH2 O prolyl-l-leucyl-glycinamide OH O MCCG 2-methyl-2-(carboxycyclopropyl) glycine glutamate receptor antagonist H 2N H N O Et N H Et H N O H O NH2 OH N O disubstituted analogue dopamine receptor modulator 10x more potent O H NH O O H 2N S OH altemicidin O Given the biological utility of disubstituted amino acids, researchers have developed myriad methods to synthesize chiral alpha-disubstituted amino acids. Here we cover just a few of the most prevalent strategies (Scheme A4.1); the interested reader is directed to a number of more comprehensive reviews.1,7–9 Classical approaches include enzymatic resolution of racemic mixtures, and installation of chiral auxiliaries. Seebach has pioneered the diastereoselective alkylation of cyclic oxazoline scaffolds, which are formed upon cyclization of an amino acid with a chiral aldehyde (Scheme A4.1A).10,11 The rigid cyclic structure enables highly diastereoselective alkylations; however, the substrate scope is limited by the availability of substituted amino acid precursors as well as the relatively harsh basic reaction conditions. In a modern twist on Seebach’s diastereoselective functionalization method Clayden recently developed an innovative Nto-C aryl migration strategy to generate alpha-arylated amino acids (Scheme A4.1B).12 Other popular chiral auxiliary strategies involve appending a removable chiral scaffold to either the carboxylic acid or the amine of an acyclic amino acid substrate, in the latter case forming a chiral Schiff base (Scheme A4.1C).13 256 Appendix 4 – Decarboxylative Alkylation of Imidazolinones In the realm of asymmetric catalysis, modern approaches include enantioselective Mannich reactions, Strecker reactions (Scheme A4.1D),14 phase transfer conditions (Scheme A4.1E)15,16 and allylic alkylation reactions (Scheme A4.2). Scheme A4.1 Synthetic methods for disubstituted amino acids A. Classical Method: Chiral Auxiliary/Diastereoselective Alkylation (Seebach) O O R Base Me O O Electrophile NH HO2C Hydrolysis Me Me NH2 NCbz Ph Ph R > 95% ee B. Diastereoselective Intramolecular Arylation (Clayden, Science 2018) O O MeN NMe Ar O HO2C R MeN THF rt N tBu Ar KHMDS R R NH2 N NHMe Ph Ar Up to >99% ee O C. Classical Method: Chiral Auxiliary CO2Me Me N CO2Me Base Me Me N Me Ar Electrophile Ph CO2Me Hydrolysis H 2N Me Ar > 98% ee Ph D. Catalytic Enantioselective Strecker Reaction (Shibasaki) R1 R2 N R2 Gd/L POPh2 HCN or TMSCn R1 CN NH2 up to 99% ee E. Asymmetric Phase Transfer Catalysis CO2tBu N Cl i. Chiral Cinchona Alkaloid Base/Electrophile Me R CO2tBu Me ii. Hydrolysis NH2 up to 87% ee The cyclic azlactone scaffold (Scheme A4.2A) is commonly used in asymmetric catalysis to generate functionalized precursors that can be hydrolyzed to provide chiral alpha-disubstituted amino acids.17,18 Transition metal catalyzed allylic alkylation approaches, pioneered by Trost and others, allow access to unique alpha-disubstituted amino acids containing a synthetically versatile allyl handle (Scheme A4.2A).19–21 257 Appendix 4 – Decarboxylative Alkylation of Imidazolinones However, these methods display limited substrate variation as the cyclic substrates are synthesized from existing amino acids. In a series of significant advances, mild allylic alkylation conditions using acyclic Schiff base scaffolds were recently developed Scheme A4.2B &C).22–24 Compared to previous acyclic strategies,25 these new developments feature broader substrate scope; however, their substrate variation is still limited by beginning from synthetically and commercially available amino acids. Scheme A4.2 Transition metal catalyzed asymmetric allylic alkylation methods A. Transition Metal Catalyzed Asymmetric Allylic Alkylation of Oxazolinones (Trost) O R R Pd or Mo Ligand O XX R O N N LHMDS, THF 65 °C Ph O O Hydrolysis OH NH2 Ph up to 99% ee OAc B. Cu/Ir and Cu/Pd Dual Catalysis (Zhang, Wang, 2017, 2018, JACS) N Ph CO2R R2 OCO2Me H 2N Cu/L R CO2R R R2 Ir/Phosphoramidite L Up to 99% ee, >20:1 dr C. Allylic Alkylation via Chiral Aldehyde Catalysis (Guo 2019, JACS) H2N CO2Et R R2 OAc Pd/Ar*CHO Catalyst ZnCl2, DBU Toluene R NH2 R2 CO2Et up to 87% yield up to 96% ee Substrate scope limited by starting material availability In the Stoltz laboratories, we previously attempted to optimize the DAAA of various oxazole and oxazolidine substrates (Scheme S4.3), which could theoretically be directly hydrolyzed to afford chiral amino acids.26 However, a series of conditions using Trost and PHOX ligands with various solvents resulted in low enantioselectivity. These poor results were consistent with our previous experience performing decarboxylative alkylation on lactone substrates. Furthermore, we believe the stabilized aromatic character of the prochiral decarboxylated intermediate contributes to the poor 258 Appendix 4 – Decarboxylative Alkylation of Imidazolinones enantioselectivity. Overcoming initial disappointments, we eventually identified a successful DAAA scaffold that when hydrolyzed, would result in a disubstituted amino acid. In the following section, we detail these efforts to significantly expand upon the substrate scope of chiral disubstituted amino acid synthesis via decarboxylative asymmetric allylic alkylation. Scheme A4.3 Previous attempts toward the decarboxylative alkylation of cyclic amino acid scaffolds A. Poor results from decarboxylative alkylation of an oxazole O O O Pd2dba3 (2.5 mol %) t-Bu-PHOX (6.5 mol %) Me O O THF 25 °C N O Me N Ph Ph 89% yield 2% ee B. Poor results from decarboxylative alkylation of an oxazolidine O Me O Pd2dba3 (4 mol %) (S)-CF3-t-Bu-PHOX (10 mol %) O O A4.2 NBoc Dioxane 60 °C O Me O NBoc 60% ee SYNTHESIS OF CYCLIC AMINO ACID SCAFFOLDS Scheme S4.4 Routes toward a cyclic amino acid imidazolinone scaffold A. Failed route toward imidazolinone A4.5 O O H2CO H 2N HN H2N NH A4.1 A4.5 B. Successful literature route toward imidazolinone A4.5 O NH2 H 2N O Benzaldehyde NaBH4 NHBn H 2N O H2CO HO A4.2 A4.3 C. More concise route toward Boc-imidazolinone A4.8 O N Boc A4.6 NH2OH, NaOAc H2O/EtOH (1:1) N NBn A4.1 NOH N Boc A4.7 TsCl K2CO3 DME:H2O (3:2) Reflux O HN NBoc A4.8 O 150 °C 0.7 torr hi-vac 6h O H2/Pd HN EtOH NBn A4.4 HN NH A4.5 Appendix 4 – Decarboxylative Alkylation of Imidazolinones 259 In light of our unsuccessful DAAA attempts with oxazole type scaffolds, we sought an alternative cyclic core; the imidazolinone core A4.5 (Scheme A4.4) is logically the next simplest scaffold on which to perform DAAA explorations, with hydrolysis ultimately yielding a chiral disubstituted amino acid. We thus sought to synthesize a model substrate based on the imidazolinone core. Initial attempts to cyclize glycinamide with formaldehyde (Scheme A4.4A) were unsuccessful. Looking to the literature, we found a multi-step patent route starting from glycinamide.27 Benzylation, followed by cyclization with formaldehyde affords hydroxyimidazolinone A4.3. Formaldehyde is then eliminated by heating under vacuum to yield benzyl-protected A4.4, with hydrogenolysis finally leading to imidazolinone A4.5. While this patent route proved reliable, we nevertheless sought a more concise route; Boc-azetidinone A4.6 is commercially available at <$1.25/gram, and Beckmann rearrangement would directly afford Bocimidazolinone A4.8. After screening a variety of conditions, we eventually found that Beckmann rearrangement of the oxime sulfonate under reflux provided the product A4.8 in rather low yields of around 20%. We are currently exploring other Beckmann rearrangement conditions to improve the yield. With Boc-imidazolinone A4.8 in hand, we next sought to synthesize the dicarbonyl compound A4.10, which would serve as a divergent point of entry to a variety of novel DAAA substrates. Benzoylation to give A4.9 was facile. However, acylation with allyl cyanoformate proved more difficult. At -78 °C, enolate formation by slowly adding a solution of A4.9 into a solution of LHMDS led to significant amounts of selfcleavage of the benzoyl protecting group, significantly lowering the yield of dicarbonyl 260 Appendix 4 – Decarboxylative Alkylation of Imidazolinones A4.10. Fortunately, performing the deprotonation at -114 °C, at which point the THF reaction solvent began to solidify, avoided degradation and afforded A4.10 in 90% yield. Scheme A4.5 Synthesis of the imidazolinone DAAA substrate O O i. Boc2O HN BzN NH ii. BzCl n-BuLi ii. CNCO2Allyl -96 °C NBoc A4.9 O O BzN NBoc A4.5 O i. LiHMDS THF, -114 °C R O BzN O NBoc O A4.11 A4.10 90% yield Divergent intermediate S4.10 significantly expands substrate scope A4.3 DECARBOXYLATIVE ASYMMETRIC ALLYLIC ALKYLATION OF IMIDAZOLINONES With dicarbonyl A4.10 in hand, we next synthesized a range of DAAA substrates. Using methyl and aminomethyl substrate A4.11a and A4.11b for initial optimization attempts, we found that in line with previous results on six and seven-membered diazaheterocycles, a nonpolar solvent mixture of 2:1 hexanes/toluene or 2:1 methylcyclohexane/toluene provided high enantioselectivity (Table A4.1, entries 2 & 3). In contrast, pure toluene resulted in lower ee (entry 1). To our delight, we achieved a 91% ee in our first screening attempt. O NHBoc O BzN NBoc O Pd2pmdba3 (4 mol %) (CF3)3-tBu-PHOX (10 mol %) O BzN Solvent (0.014 M) 40 °C A4.11a NBoc A4.12a Entry Solvent ee 1 Toluene 80 2 2:1 MeCy/Toluene 91 3 2:1 Hexanes/Toluene 91 Reactions performed on 10 mg scale NHBoc 261 Appendix 4 – Decarboxylative Alkylation of Imidazolinones With the methyl model substrate A4.11b, we found that (S)-(CF3)3-tBu-PHOX was the optimal ligand (Table A4.2, entry 3). ANDEN-Ph-Trost ligand in dioxane (entry 2) resulted in lowered enantioselectivity and longer reaction times; however, the entry should be repeated using 2:1 toluene/hexanes to provide a direct comparison to the other entries. While conducting the reaction at 40 °C resulted in higher enantioselectivity, the reaction was incomplete even after 72 hours, with significant amounts of starting material remaining. O Me O BzN NBoc Pd2pmdba3 (4 mol %) Ligand (10 mol %) O A4.11b Solvent (0.014 M) Temp O Me BzN NBoc A4.12b Entry Ligand Solvent Temp °C ee 1 (S)-(CF3)3-tBu-PHOX 2:1 Hexanes/Toluene 40 96a 2 (S,S)-ANDEN-Ph-Trost Dioxane 60 70a,b 2 (S)-(CF3)3-tBu-PHOX 2:1 Hexanes/Toluene 60 94 [a] Incomplete conversion after 72 h. [b] 0.5 M concentration. Reactions performed on 10 mg scale With these initial results in hand, we examined the DAAA of additional substrates (Table A4.3). The benzyl, benzyloxymethyl, and propargyl substrates A4.11c-d provided uniformly excellent ee. Yields will be determined in future larger scale reactions. 262 Appendix 4 – Decarboxylative Alkylation of Imidazolinones Table A4.3 Initial Substrate Scope O R O BzN NBoc Pd2pmdba3 (4 mol %) (CF3)3-tBu-PHOX (10 mol %) O R BzN 2:1 Hex/Tol Temp A4.11 O O O Ph BzN O OBn BzN NBoc NBoc A4.12 BzN NBoc A4.12c 60 °C: 94% ee, 12 h 40 °C: 98% ee, 36 h A4.12d A4.12e 40 °C: >99% ee 36 h 60 °C: 94% ee, 6 h O O Me BzN NBoc NHBoc BzN NBoc NBoc A4.12b 60°C: 94% ee, 12 h A4.12a 40°C: 91% ee, 4 h Reactions performed on 10 mg scale A4.4 CONCLUSIONS In summary, we report the enantioselective synthesis of unprecedented gem- disubstituted imidazolinones using the venerable Pd-catalyzed decarboxylative asymmetric allylic alkylation. The versatile (S)-(CF3)3-t-Bu-PHOX ligand performs well, yielding products in ee’s up to >99%. Future directions include further exploration of the substrate scope of this reaction and product transformations. These novel chiral imidazolinones are anticipated to find utility in the design of novel alpha-disubstituted amino acids. A4.5 EXPERIMENTAL SECTION A4.5.1 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 Appendix 4 – Decarboxylative Alkylation of Imidazolinones 263 by passage through an activated alumina column under argon. Boc-azetidinone S4.6 was obtained from Combi-Blocks. Commercially obtained reagents were used as received. Chemicals were purchased from Sigma Aldrich/Strem/Alfa Aesar/Combi-Blocks 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) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, iodine on silica, ninhydrin, or KMnO4 staining. SiliaFlash P60 Academic Silica gel (particle size 0.040– 0.063 mm) was used for flash chromatography. 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. Reverse Phase Preparatory HPLC was performed with a Teledyne ISCO ACCQPrep HP125 preparative liquid chromatography system equipped with a RediSep Prep C18 5 µm column (20 x 250 mm). 1 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or CH3OH (δ 3.31 ppm). 13C 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 CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 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 Appendix 4 – Decarboxylative Alkylation of Imidazolinones 264 solvent impurities of water (δ 1.56 or 4.87 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 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). Stereochemistry is assigned by analogy to previous results. 28–33 A4.5.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA A4.5.2.1 Procedures for the Synthesis of Imidazolinone Allylic Alkylation Substrates O HN NBoc tert-butyl 4-oxoimidazolidine-1-carboxylate (S4.8). Can be prepared by two separate procedures. Procedure A: To a solution of imidazolinone S4.527 (1.47 g, 1 equiv) in THF (170 mL, 0.1 M) was added NEt3 (2.38 mL, 1 equiv) followed by Boc2O (3.72 g, 1 equiv) portionwise. The solution was stirred for 4 h at rt and then concentrated. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0 → 20% MeOH/CH2Cl2) to provide S4.8 as a clear oil (2.5g, 79% yield). Procedure B: To a solution of Boc-azetidinone S4.6 (5 g, 1 equiv) in EtOH (60 mL, 0.25 M total Appendix 4 – Decarboxylative Alkylation of Imidazolinones 265 concentration) was added a solution of NaOAc (6.72 g, 2 equiv) and NH2OH-HCl (4.06 g, 2 equiv) in H2O (60 mL, 0.25 M total concentration). The solution was stirred at 50 °C for 2 h, and then extracted with CH2Cl2 (3x). The combined organic layers were backwashed with NaHCO3 (1x) dried over Na2SO4, concentrated, and then placed under high vacuum to remove AcOH. The crude oxime was then dissolved in 260 mL of 3:2 DME/H2O. K2CO3 (8.92 g, 2.5 equiv) and TsCl (5.9 g, 1.5 equiv) were added. The reaction was refluxed for 3 h until complete consumption of starting material was observed by TLC (5% MeOH/CH2Cl2). DME was concentrated off. The aqueous layer was extracted with EtOAc (6x). The combined organic layers were dried over Na2SO4 and concentrated. The crude imidazolinone was purified by automated silica gel flash chromatography (0 → 30% MeOH/CH2Cl2) to provide the Boc-imidazolinone S4.8. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 52.9 Hz, 1H), 4.76 (d, J = 11.0 Hz, 2H), 3.87 (d, J = 15.1 Hz, 2H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 172.1, 153.1, 152.7, 81.2, (59.0, 58.8 two peaks due to hindered rotation), (47.5, 47.0 two peaks due to hindered rotation), 28.4. O BzN NBoc tert-butyl 3-benzoyl-4-oxoimidazolidine-1-carboxylate (S4.9). S4.8 (1.4 g, 1 equiv) in THF (75 mL), 0.1 M at −78 °C was added dropwise nBuLi (3.61 mL, 2.5 M solution in hexane, 1.2 equiv). The resulting yellow solution was stirred for 5 min at −78 °C. Benzoyl chloride (1.14 mL, 1.3 equiv) was then added dropwise at −78 °C, giving a deep Appendix 4 – Decarboxylative Alkylation of Imidazolinones 266 yellow solution. The reaction was stirred for 10 min at −78 °C, quenched by addition of saturated aqueous NH4Cl, and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash column chromatography (0 → 80% EtOAc/hexanes) to give protected imidazolinone as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.61 (m, 2H), 7.61 – 7.51 (m, 1H), 7.48 – 7.39 (m, 2H), 5.29 (s, 2H), 4.17 (s, 2H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 168.6, 167.5, 152.6, 133.0, 132.7, 129.1, 128.0, 81.8, 61.8, 49.3, 28.4. IR (Neat Film, NaCl) 2979, 1763, 1708, 1476, 1448, 1410,1367, 1305, 1212, 1163, 1127, 894, 858, 767, 727, 704, 661 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C15H22N3O4 [M+NH4]+: 308.1605, found 308.1600. O O BzN NBoc O 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxoimidazolidine-1,5-dicarboxylate (A4.10). To a solution of LHMDS (1.52 g, 1.1 equiv) in THF (15 mL 0.1 M total concentration) was slowly added A4.9 (2.4 g, 1.0 equiv) in THF (68 mL, 0.1 M total concentration) at −114 °C. The resulting light orange reaction mixture (slurry/frozen) was stirred for 5 min at −114 °C. Then, allyl cyanoformate (368 µL, 1.2 equiv) was added dropwise at −114 °C, giving a light yellow solution. After stirring for 20 min at −96 °C, the reaction was quenched with 1 M HCl (10 mL) and diluted with ethyl acetate (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were Appendix 4 – Decarboxylative Alkylation of Imidazolinones 267 dried over anhydrous Na2SO4 and solid NaHCO3, decanted, and concentrated under reduced pressure The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0% → 80% EtOAc/hexanes) to give dicarbonyl A4.10 as a clear oil; 1H NMR (400 MHz, Chloroform-d) δ 7.65 – 7.57 (m, 2H), 7.57 – 7.51 (m, 1H), 7.42 (t, J = 7.8 Hz, 2H), 5.98 – 5.82 (m, 1H), 5.41 – 5.31 (m, 3H), 5.26 (dd, J = 15.2, 10.4 Hz, 1H), 4.80 – 4.63 (m, 2H), 1.52 (s, 4H), 1.46 (s, 4H); 13C NMR (101 MHz, CDCl3) δ (168.42, 168.20 two peaks due to hindered rotation), (165.70, 165.55 two peaks due to hindered rotation), (163.49, 163.24 two peaks due to hindered rotation), (152.14, 151.89 two peaks due to hindered rotation), 132.99, 132.63, (131.00, 130.94 two peaks due to hindered rotation), 129.18, 128.14, (119.79, 119.18 two peaks due to hindered rotation), (82.75, 82.61 two peaks due to hindered rotation), 67.16, 63.46, (63.01, 61.50 two peaks due to hindered rotation), (28.34, 28.23 two peaks due to hindered rotation). IR (Neat Film, NaCl) 2977, 1747, 1715, 1449, 1405, 1369,1302, 1250, 1167, 1135, 986, 938, 769, 725, 696, 668 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H26N3O6 [M+NH4]+: 392.1816, found 392.1822. O Me O BzN NBoc 5-allyl 1-(tert-butyl) O 3-benzoyl-5-methyl-4-oxoimidazolidine-1,5-dicarboxylate (A4.11b). Sodium hydride (60% in mineral oil, 32 mg, 1.2 equiv) was added to a solution of dicarbonyl A4.10 (250 mg, 1.0 equiv) in THF (6.7 mL, 0.1 M) at rt. After stirring for 30 min at rt, MeI (208 µL, 5 equiv) was added. The reaction mixture was stirred for 2 h. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica Appendix 4 – Decarboxylative Alkylation of Imidazolinones 268 gel flash chromatography (Teledyne ISCO, 0 → 50% acetone/hexanes) to give methyl allyl ester A4.11b as a clear oil; 1H NMR (400 MHz, Chloroform-d) δ 7.71 – 7.50 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 5.89 (dtt, J = 15.9, 10.3, 5.7 Hz, 1H), 5.46 – 5.15 (m, 4H), 4.80 – 4.50 (m, 2H), 1.81 (d, J = 21.1 Hz, 3H), 1.50 (s, 9H). 13C NMR (101 MHz, CDCl3) δ (168.6, 168.3 two peaks due to hindered rotation), 167.4, 167.2, (152.3, 152.2 two peaks due to hindered rotation), 132.9, 132.7, (131.2, 130.9 two peaks due to hindered rotation), 129.1, 128.1, (119.6, 119.0 two peaks due to hindered rotation), (82.6, 82.4 two peaks due to hindered rotation), (68.4, 68.2 two peaks due to hindered rotation), 67.1, (61.1, 61.0 two peaks due to hindered rotation), (28.3, 28.2 two peaks due to hindered rotation), (20.4, 19.8 two peaks due to hindered rotation); IR (Neat Film, NaCl) 2978, 1772, 1740, 1713, 1601, 1476, 1449, 1385,1369, 1304, 1244, 1161, 1123, 1066, 912, 858, 769, 732, 702, 667 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C20H28N3O6 [M+NH4]+: 406.1973, found 406.1975. O OBn O BzN NBoc 5-allyl 1-(tert-butyl) O 3-benzoyl-5-((benzyloxy)methyl)-4-oxoimidazolidine-1,5- dicarboxylate (A4.11d). Sodium hydride (60% in mineral oil, 32 mg, 1.2 equiv) was added to a solution of dicarbonyl A4.10 (250 mg, 1.0 equiv) in THF (6.7 mL, 0.1 M) at rt. After stirring for 30 min at rt, BOMCl (185 µL, 2 equiv) was added. The reaction mixture was stirred for 2 h. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude Appendix 4 – Decarboxylative Alkylation of Imidazolinones 269 product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0 → 40% acetone/hexanes) to give benzyloxymethyl allyl ester A4.11d as a clear oil; 1H NMR (400 MHz, Chloroform-d) δ 7.69 – 7.48 (m, 3H), 7.47 – 7.17 (m, 7H), 5.87 (dddt, J = 17.3, 10.4, 8.8, 5.8 Hz, 1H), 5.51 – 5.12 (m, 4H), 4.84 – 4.44 (m, 4H), 4.42 – 4.03 (m, 2H), 1.52 (s, 5H), 1.38 (s, 5H); 13C NMR (101 MHz, CDCl3) δ (168.5, 168.3 two peaks due to hinded rotation), (166.0, 165.7 two peaks due to hinded rotation), (165.3, 165.21 two peaks due to hinded rotation), (151.9, 151.5 two peaks due to hinded rotation), (137.7, 137.3 two peaks due to hindered rotation), 132.9, 132.7, (131.1, 130.8 two peaks due to hindered rotation), 129.2, (128.68, 128.5 two peaks due to hindered rotation), 128.1, 128.0, 127.9, (127.6 127.4 two peaks due to hindered rotation), (119.8, 119.2 two peaks due to hindered rotation), (82.5, 82.4 two peaks due to hindered rotation), 73.7, (72.0, 71.8 two peaks due to hindered rotation), (69.5, 69.0 two peaks due to hindered rotation), 67.0, 61.6, (28.4, 28.2 two peaks due to hindered rotation). IR (Neat Film, NaCl) 2975, 1771,1744, 1713, 1450, 1389, 1369,1308, 1236, 1158, 1068, 858, 795, 744, 696, 668 cm1 ; HRMS (MM: ESI-APCI): m/z calc’d for C27H34N3O7 [M+NH4]+: 512.2398, found 512.2395. O Ph O BzN NBoc 5-allyl 1-(tert-butyl) O 3-benzoyl-5-benzyl-4-oxoimidazolidine-1,5-dicarboxylate (A4.11c). Sodium hydride (60% in mineral oil, 32 mg, 1.2 equiv) was added to a solution of dicarbonyl A4.10 (250 mg, 1.0 equiv) in THF (6.7 mL, 0.1 M) at rt. After stirring for 30 min at rt, BnBr (169 µL, 2 equiv) was added. The reaction mixture was stirred for 5 h, turning cloudy in minutes. The reaction was quenched with aqueous NaHCO3 (10 mL) Appendix 4 – Decarboxylative Alkylation of Imidazolinones 270 and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 10 → 30% acetone/hexanes) to give benzyl allyl ester A4.11c as a clear oil; 1H NMR (400 MHz, Chloroform-d) δ 7.62 – 7.47 (m, 1H), 7.47 – 7.27 (m, 7H), 7.18 (ddd, J = 7.1, 5.3, 1.8 Hz, 2H), 5.92 (dddt, J = 17.2, 10.4, 7.9, 5.8 Hz, 1H), 5.44 – 5.19 (m, 3H), 5.16 (d, J = 7.0 Hz, 1H), 4.79 (ddt, J = 13.1, 5.7, 1.4 Hz, 1H), 4.74 – 4.59 (m, 2H), 4.40 (d, J = 7.0 Hz, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.67 – 3.49 (m, 1H), 1.56 (d, J = 2.8 Hz, 10H). 13C NMR (101 MHz, CDCl3) δ 168.3, 168.0, 166.7, 166.6, 166.26, 166.1, 152.1, 151.8, 134.8, 134.2, 132.8, 132.7, 131.3, 130.9, 130.3, 129.0, 128.8, 128.67, 128.0, 128.0, 127.9, 127.7, 119.7, 119.1, 82.9, 82.4, 72.9, 67.2, 61.3, 38.0, 37.2, 28.4, 28.4. IR (Neat Film, NaCl) 2977, 1770, 1712, 1602, 1449, 1393, 1294, 1230, 1147, 1074, 1009, 768, 701 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C26H32N3O6 [M+NH4]+: 482.2286, found 482.2284. O O BzN NBoc 5-allyl 1-(tert-butyl) O 3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)imidazolidine-1,5- dicarboxylate (A4.11e). Sodium hydride (60% in mineral oil, 32 mg, 1.2 equiv) was added to a solution of dicarbonyl A4.10 (250 mg, 1.0 equiv) in THF (6.7 mL, 0.1 M) at rt. After stirring for 15 min at rt, propargyl bromide (80% wt/wt in toluene, 252 µL, 4 equiv) was added. The reaction mixture was stirred for 1 h, turning light orange and cloudy in minutes. The reaction was quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, Appendix 4 – Decarboxylative Alkylation of Imidazolinones 271 decanted, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0 → 30% acetone/hexanes) to give propargyl allyl ester A4.11e as a clear oil; 1H NMR (400 MHz, Chloroform-d) δ 7.67 (dt, J = 8.5, 1.5 Hz, 2H), 7.61 – 7.51 (m, 1H), 7.51 – 7.34 (m, 2H), 5.86 (dtt, J = 17.3, 10.4, 5.8 Hz, 1H), 5.42 (dd, J = 18.4, 7.0 Hz, 1H), 5.37 – 5.18 (m, 3H), 4.82 – 4.48 (m, 2H), 3.46 (dd, J = 17.2, 2.7 Hz, 1H), 3.38 – 3.09 (m, 2H), 2.12 (dt, J = 5.4, 2.6 Hz, 1H), 1.49 (d, J = 20.7 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ 168.42, 168.17, 165.88, 165.83, 165.68, 165.59, 151.97, 151.53, 133.06, 132.52, 131.00, 130.69, 129.22, 128.13, 119.93, 119.35, 82.98, 82.76, 78.24, 77.57, 77.16, 72.37, 71.80, 71.13, 70.88, 67.36, 67.33, 62.01, 28.31, 28.20, 24.20, 23.29. IR (Neat Film, NaCl) 3280, 2977, 1771, 1746, 1713, 1601, 1449, 1391, 1370, 1295, 1228, 1151, 1058, 1018, 858, 790, 769, 739, 701, 665 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N3O6 [M+NH4]+: 430.1973, found 430.1969. A4.5.2.2 General Procedure for Allylic Alkylation Optimization Screen In a nitrogen-filled glovebox, an oven-dried 1 dram vial was charged with Pd2(pmdba)3 (4 mol %), ligand (10 mol %), solvent (1 mL), and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then substrate (10 mg, 1.0 equiv) was added as a solution in solvent (total concentration 0.014 M). The vial was sealed with a teflon cap and heated to 40 or 60 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the imidazolinone. 272 Appendix 4 – Decarboxylative Alkylation of Imidazolinones A4.5.2.3 General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions Please note The absolute configuration for all other products has been inferred by analogy.28–33 For respective SFC conditions, please refer to the section Determination of Enantiomeric Excess. In a nitrogen-filled glovebox, an oven-dried 1 dram vial or 20 mL scintillation vial was charged with Pd2(pmdba)3 or Pd2(dba)3 (4 mol %), (S)-(CF3)3-tBu-PHOX (10 mol %), 2:1 hexanes/toluene, and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then the substrate (10 mg, 1.0 equiv) was added as a solution in 2:1 hexanes/toluene (total concentration 0.014 M). The vial was sealed with a teflon cap and heated to 40 or 60 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the desired imidazolinone. A4.5.2.4 Experimental Procedures and Spectroscopic data for the PdCatalyzed Decarboxylative Asymmetric Imidazolinone Substrates O Ph BzN NBoc Allylic Alkylation of Appendix 4 – Decarboxylative Alkylation of Imidazolinones 273 tert-butyl (R)-5-allyl-3-benzoyl-5-benzyl-4-oxoimidazolidine-1-carboxylate (A4.12c). IR (Neat Film, NaCl) 2927, 1757, 1707,1389, 1367, 1295, 1167, 701, 660 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C25H29N2O4 [M+H]+: 421.2122, found 421.2108. O Me BzN NBoc tert-butyl (S)-5-allyl-3-benzoyl-5-methyl-4-oxoimidazolidine-1-carboxylate (A4.12b). Following the general procedure, allyl ester A4.11b (46 mg, 1.0 equiv) in 2:1 Hex/Tol (7.5 mL) was added to a solution of Pd2(pmdba)3 (5.2 mg, 4 mol %) and (S)-(CF3)3-tBuPHOX (7 mg, 10 mol %) in 2:1 Hex/Tol (1.0 mL). Reaction performed at 60 °C. Purification by automated silica gel flash chromatography (Teledyne ISCO, 0 → 20% acetone/hexanes) gave methyl imidazolinone A4.12b as a clear oil (94% ee); 1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), 5.70 (ddt, J = 17.3, 9.9, 7.5 Hz, 1H), 5.31 – 5.13 (m, 3H), 5.07 (dd, J = 13.8, 7.7 Hz, 1H), 3.16 (dd, J = 13.7, 7.8 Hz, 1H), 2.48 (ddd, J = 20.5, 13.6, 7.4 Hz, 1H), 1.76 – 1.40 (m, 13H); 13C NMR (101 MHz, CDCl3) δ 172.6, 168.7, 168.5, 152.7, 151.7, 133.2, 132.7, 132.1, 131.8, 129.0, 128.0, 120.4, 81.8, 81.3, 77.4, 66.1, 65.7, 60.8, 60.7, 41.3, 40.0, 28.5, 28.5, 23.6, 22.6; IR (Neat Film, NaCl) 3076, 2977, 2931, 1759, 1702, 1602,1477, 1449, 1388,1368, 1296, 1262,1227, 1168,1124, 1059, 997, 964, 928, 906, 879, 859, 823.08 95.51 792, 773, 732, 703, 661, 614 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H25N2O3 [M+H]+: 345.1809, found 345.1805. Appendix 4 – Decarboxylative Alkylation of Imidazolinones A4.6 (1) 274 REFERENCES AND NOTES Ohfune, Y.; Shinada, T. Enantio- and Diastereoselective Construction of α,αDisubstituted α-Amino Acids for the Synthesis of Biologically Active Compounds. Eur. J. Org. Chem. 2005, 2005 (24), 5127–5143. (2) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Control of Peptide Conformation by the Thorpe-Ingold Effect (Cα-Tetrasubstitution). Peptide Science 2001, 60 (6), 396–419. (2001)60:6<396::AID-BIP10184>3.0.CO;2-7. (3) Dehner, A.; Planker, E.; Gemmecker, G.; Broxterman, Q. B.; Bisson, W.; Formaggio, F.; Crisma, M.; Toniolo, C.; Kessler, H. Solution Structure, Dimerization, and Dynamics of a Lipophilic α/310-Helical, Cα-Methylated Peptide. Implications for Folding of Membrane Proteins. J. Am. Chem. Soc. 2001, 123 (27), 6678–6686. (4) Evans, M. C.; Pradhan, A.; Venkatraman, S.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Synthesis and Dopamine Receptor Modulating Activity of Novel Peptidomimetics of L-Prolyl-l-Leucyl-Glycinamide Featuring α,αDisubstituted Amino Acids. J. Med. Chem. 1999, 42 (8), 1441–1447. (5) Etienne, M. A.; Aucoin, J. P.; Fu, Y.; McCarley, R. L.; Hammer, R. P. Stoichiometric Inhibition of Amyloid β-Protein Aggregation with Peptides Containing Alternating α,α-Disubstituted Amino Acids. J. Am. Chem. Soc. 2006, 128 (11), 3522–3523. (6) Castro, V. I. B.; Carvalho, C. M.; Fernandes, R. D. V.; Pereira-Lima, S. M. M. A.; Castanheira, E. M. S.; Costa, S. P. G. Peptaibolin Analogues by Incorporation of Appendix 4 – Decarboxylative Alkylation of Imidazolinones 275 α,α-Dialkylglycines: Synthesis and Study of Their Membrane Permeating Ability. Tetrahedron 2016, 72 (7), 1024–1030. (7) Cativiela, C.; Díaz-de-Villegas, M. D. Recent Progress on the Stereoselective Synthesis of Acyclic Quaternary α-Amino Acids. Tetrahedron: Asymmetry 2007, 18 (5), 569–623. (8) Bera, K.; Namboothiri, I. N. N. Asymmetric Synthesis of Quaternary α-Amino Acids and Their Phosphonate Analogues. Asian J. Org. Chem. 2014, 3 (12), 1234– 1260. (9) Vogt, H.; Bräse, S. Recent Approaches towards the Asymmetric Synthesis of α,αDisubstituted α-Amino Acids. Org. Biomol. Chem. 2007, 5 (3), 406–430. (10) Fitzi, R.; Seebach, D. Resolution and Use in α-Amino Acid Synthesis of Imidazolidinone Glycine Derivatives. Tetrahedron 1988, 44 (17), 5277–5292. (11) Seebach, D.; Hoffmann, M. Preparation and Use in Amino Acid Synthesis of a New Chiral Glycine Derivative – (R)- and (S)-Tert-Butyl 2-Tert-Butyl-4-Methoxy2,5-Dihydroimidazole-1-Carboxylate (BDI). Eur. J. Org. Chem. 1998, 1998 (7), 1337–1351. (12) Leonard, D. J.; Ward, J. W.; Clayden, J. Asymmetric α-Arylation of Amino Acids. Nature 2018, 562 (7725), 105–109. (13) Meyer, L.; Poirier, J.-M.; Duhamel, P.; Duhamel, L. Chiral Auxiliaries with a Switching Center: New Tools in Asymmetric Synthesis. Application to the Synthesis of Enantiomerically Pure (R)- and (S)-α-Amino Acids. J. Org. Chem. 1998, 63 (23), 8094–8095. Appendix 4 – Decarboxylative Alkylation of Imidazolinones 276 (14) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. Catalytic Enantioselective Strecker Reaction of Ketoimines. J. Am. Chem. Soc. 2003, 125 (19), 5634–5635. (15) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. Practical Catalytic Enantioselective Synthesis of α,α-Dialkyl-α-Amino Acids by Chiral PhaseTransfer Catalysis. J. Am. Chem. Soc. 2000, 122 (21), 5228–5229. (16) Maruoka, K.; Ooi, T. Enantioselective Amino Acid Synthesis by Chiral PhaseTransfer Catalysis. Chemical Reviews 2003, 103 (8), 3013–3028. (17) de Castro, P. P.; Carpanez, A. G.; Amarante, G. W. Azlactone Reaction Developments. Chem. Eur. J. 2016, 22 (30), 10294–10318. (18) Serra, M.; Bernardi, E.; Marrubini, G.; Lorenzi, E. D.; Colombo, L. PalladiumCatalyzed Asymmetric Decarboxylative Allylation of Azlactone Enol Carbonates: Fast Access to Enantioenriched α-Allyl Quaternary Amino Acids. Eur. J. Org. Chem. 2019, 2019 (4), 732–741. (19) Trost, B. M.; Ariza, X. Catalytic Asymmetric Alkylation of Nucleophiles: Asymmetric Synthesis of α-Alkylated Amino Acids. Angew. Chem. Int. Ed. 1997, 36 (23), 2635–2637. (20) Trost, B. M.; Ariza, X. Enantioselective Allylations of Azlactones with Unsymmetrical Acyclic Allyl Esters. J. Am. Chem. Soc. 1999, 121 (46), 10727– 10737. (21) Trost, B. M.; Dogra, K. Synthesis of Novel Quaternary Amino Acids Using Molybdenum-Catalyzed Asymmetric Allylic Alkylation. J. Am. Chem. Soc. 2002, 124 (25), 7256–7257. Appendix 4 – Decarboxylative Alkylation of Imidazolinones 277 (22) Chen, L.; Luo, M.-J.; Zhu, F.; Wen, W.; Guo, Q.-X. Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective α-Allylic Alkylation of Amino Acid Esters. J. Am. Chem. Soc. 2019. (23) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,α-Disubstituted α-Amino Acids Bearing Vicinal Stereocenters. J. Am. Chem. Soc. 2018, 140 (6), 2080–2084. (24) Huo, X.; He, R.; Fu, J.; Zhang, J.; Yang, G.; Zhang, W. Stereoselective and SiteSpecific Allylic Alkylation of Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis. J. Am. Chem. Soc. 2017, 139 (29), 9819–9822. https://doi.org/10.1021/jacs.7b05460. (25) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. Synthesis of β-Substituted α-Amino Acids with Use of Iridium-Catalyzed Asymmetric Allylic Substitution. J. Org. Chem. 2003, 68 (16), 6197–6201. (26) 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.; et al. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17 (50), 14199–14223. (27) Pfeiffer, U.; Riccaboni, M. T.; Erba, R.; Pinza, M. A Short Synthesis of 4imidazolidinone. Liebigs Annalen der Chemie 1988, 1988 (10), 993–995. (28) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. Appendix 4 – Decarboxylative Alkylation of Imidazolinones 278 (29) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Deracemization of Quaternary Stereocenters by Pd-Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β-Ketoesters. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. (30) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. (31) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by PalladiumCatalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem. 2012, 4, 130–133. (32) Seto, M.; Roizen, J. L.; Stoltz, B. M. Catalytic Enantioselective Alkylation of Substituted Dioxanone Enol Ethers: Ready Access to C(α)-Tetrasubstituted Hydroxyketones, Acids, and Esters. Angew. Chem. 2008, 120 (36), 6979–6982. (33) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Rapid Synthesis of an Electron-Deficient t-BuPHOX Ligand: Cross-Coupling of Aryl Bromides with Secondary Phosphine Oxides. Tetrahedron Lett. 2010, 51, 5550– 5554. Appendix 5 – Spectra Relevant to Appendix 4 279 APPENDIX 5 Spectra Relevant to Appendix 4: Stereoselective Synthesis of α,α-Disubstituted Amino Acids via Decarboxylative Alkylation of Imidazolinones Figure A5.1 1H NMR (600 MHz, CDCl3) of compound A4.8 Appendix 5 - Spectra Relevant to Appendix 4 280 Appendix 5 - Spectra Relevant to Appendix 4 281 Figure A5.2 Infrared spectrum (Thin Film, NaCl) of compound A4.8 Figure A5.3 13C NMR (101 MHz, CDCl3) of compound A4.8 Figure A5.4 1H NMR (600 MHz, CDCl3) of compound A4.9. Appendix 5 - Spectra Relevant to Appendix 4 282 Appendix 5 - Spectra Relevant to Appendix 4 283 Figure A5.5 Infrared spectrum (Thin Film, NaCl) of compound A4.9. Figure A5.4 13C NMR (101 MHz, CDCl3) of compound A4.9 Figure A5.7 1H NMR (600 MHz, CDCl3) of compound A4.11b Appendix 5 - Spectra Relevant to Appendix 4 284 Appendix 5 - Spectra Relevant to Appendix 4 285 Figure A5.8 Infrared spectrum (Thin Film, NaCl) of compound A4.11b Figure A5.9 13C NMR (101 MHz, CDCl3) of compound A4.11b Figure A5.10 1H NMR (600 MHz, CDCl3) of compound A4.11d Appendix 5 - Spectra Relevant to Appendix 4 286 Appendix 5 - Spectra Relevant to Appendix 4 287 Figure A5.11 Infrared spectrum (Thin Film, NaCl) of compound A4.11d Figure A5.12 13C NMR (101 MHz, CDCl3) of compound A4.11d Figure A5.13 1H NMR (600 MHz, CDCl3) of compound A4.11c . Appendix 5 - Spectra Relevant to Appendix 4 288 Appendix 5 - Spectra Relevant to Appendix 4 289 Figure A5.14 Infrared spectrum (Thin Film, NaCl) of compound A4.11c Figure A5.15 13C NMR (101 MHz, CDCl3) of compound A4.11c Figure A5.16 1H NMR (600 MHz, CDCl3) of compound A4.11e Appendix 5 - Spectra Relevant to Appendix 4 290 Appendix 5 - Spectra Relevant to Appendix 4 Figure A5.17 Infrared spectrum (Thin Film, NaCl) of compound A4.11e Figure A5.18 13C NMR (101 MHz, CDCl3) of compound A4.11e 291 Figure A5.19 1H NMR (600 MHz, CDCl3) of compound A4.10 Appendix 5 - Spectra Relevant to Appendix 4 292 Appendix 5 - Spectra Relevant to Appendix 4 293 Figure A5.20 Infrared spectrum (Thin Film, NaCl) of compound A4.10 Figure A5.21 13C NMR (101 MHz, CDCl3) of compound A4.10 Figure A5.22 1H NMR (600 MHz, CDCl3) of compound A4.12b Appendix 5 - Spectra Relevant to Appendix 4 294 Appendix 5 - Spectra Relevant to Appendix 4 Figure A5.23 Infrared spectrum (Thin Film, NaCl) of compound A4.12b Figure A5.24 13C NMR (101 MHz, CDCl3) of compound A4.12b 295 296 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid CHAPTER 2 gem-Disubstituted Morpholine Analogues of Linezolid 2.1 Introduction Figure 2.1 N-Heterocycles are valuable components of small molecule drugs. C) Asymmetric alkylation of lactams to generate heterocycles bearing quaternary centers A) Examples of heterocycles common in biologically active molecules N N O N R1 R3 O N N [Pd2(pmdba)3] (S)-(CF3)3-tBuPHOX O N O R1 N toluene, 40°C R2 R3 N B) Examples of marketed pharmaceuticals containing heterocycles CO2Me N N Me Bz O Bz HN Bz N N 85% yield 99% ee MeO N N MeO NH O O O O R2 Bn O F Bz N 86% yield 96% ee 89% yield 91% ee N 92% yield 99% ee N N Imatinib (Gleevec) tyrosine kinase inhibitor O O N Bz Donepezil (Aricept) acetylcholine esterase inhibitor N LiOH H2O MeOH, 23°C 96% yield HN LiAlH4 Et2O, 35°C (91% yield) HN Traditionally, small molecule pharmaceuticals are rich in flat, aromatic motifs; however, studies have shown that increased sp3 character is associated with improved target specificity.1,2 One method of enhancing sp3 character in small molecule drugs involves incorporating saturated nitrogen heterocycles such as piperidine, piperazine, 297 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid pyrrolidine, and morpholine, which rank amongst the most common N-heterocycles in small molecule drugs (Figure 2.1A).3 Figure 2.2 Substitution patterns of common saturated heterocycles found in small molecule drugs a) Monosubstitution patterns of common saturated heterocycles found in small molecule drugs 1 42/72 5/72 14/72 N H 24/72 3/72 piperidine 13/37 6/37 15/37 23/37 N H pyrrolidine 1/59 H N 4/59 N H 7/59 piperazine 1/59 O 4/59 N H 7/59 morpholine b) Disubstitution patterns of common saturated heterocycles found in small molecule drugs 2 3/119 R R 20/119 R R N H R R 1/69 R N H 2/69 R H N O N H N H No disubstituted drugs The native sp3 complexity imparted by these saturated N-heterocycles can be further augmented by substituting the carbon atoms of the ring. Functionalizing these ring systems with carbon gem-disubstitutions—also termed quaternary centers—would potentially result in a number of improvements in the drug-like properties of such molecules, such as enhanced solubility, permeability, potency, and efficacy (Figure 2.1C). Interestingly however, a 2014 analysis found that a majority of piperidine and pyrrolidine-containing drugs contained one or more C-substitutions (Figure 2.2a).3 In contrast, gem-disubstituted heterocyclic drugs are relatively rare (Figure 2.2b). For example, an analysis of the drugbank.ca structural database reveals that of all 139 FDA approved non-natural product derived piperazine and morpholine-containing small molecule drugs, none contain a chiral gem-disubstituted piperazine or morpholine.4 And in 69 pyrrolidine containing drugs, only three chiral gem-disubstituted molecules exist. Only in the most common N-heterocycle, piperidine, are gem-disubstitutions more prevalent; out of 119 FDA approved piperidine-containing drugs, 23 are gem- 298 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid disubstituted. The dearth of gem-disubstituted heterocycles in the pharmacopeia is partially due to the difficulty of preparing such heterocycles in a high yielding, enantioselective manner. In recent years, however, powerful methods have been developed to enantioselectively synthesize gem-disubstituted heterocycles. For instance, our laboratory has pioneered the development of Pd-catalyzed decarboxylative asymmetric allylic alkylation methodologies to synthesize a range of gem-disubstituted lactams of ring size 5 to 7 (Figure 1c).5–8 Such lactams can be deprotected and reductively transformed into the corresponding gem-disubstituted N-heterocycles. While such gem-disubstituted heterocycles are rare in small molecule pharmaceuticals, they hold the potential to further enhance the drug-like properties of small molecules (Figure 2.3). Figure 2.3 Biological properties altered by hypothetical gem-disubstitution of the antibiotic linezolid. R1 R2 O C F N B F O Enhanced Properties Selectivity Polar Surface Area O N A O N O N O Metabolic Stability NHAc linezolid (Zyvox) 2.2 NHAc gem-disubstituted linezolid Results Given this potential, we sought to investigate the practical utility of gemdisubstituted heterocycles in bioactive small molecules. After surveying various Nheterocyclic drugs for cases in which physicochemical attributes could be improved upon heterocyclic gem-disubstitution, we selected the morpholine-containing oxazolidinone antibiotic Linezolid (Zyvox) (Figure 2.4). Approved by the FDA in 2001, Linezolid 299 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid inhibits bacterial ribosome assembly by binding to the 50S subunit of the ribosome.9 Linezolid and the recently approved oxazolidinone Tedizolid are important last resort antibiotics that are active against drug-resistant pathogens like methicillin-resistant Staphylococcus aureus (MRSA),10 vancomycin-resistant Enterococcus faecalis (VRE),11 and multi-drug resistant Mycobacterium tuberculosis (MDR-TB).12 Figure 2.4 Summary of oxazolidinone antibiotics F O N N N NH O N O N H N N F Me N O N O Linezolid (Pfizer 2000) F N O O O Me Me NH N N O NH Radezolid (Rib-X, In Development) • Member of the oxazolidinone class of antibiotics • Inhibits gram+ bacterial growth • Binds bacterial ribosome, preventing protein translation • Commonly treats pneumonia, skin & soft tissue infections • Bone marrow suppression major side effect Tedizolid (Merck, 2014) OH Because the bacterial and human mitochondrial ribosomes are highly homologous, oxazolidinone antibiotics bind a commonly conserved site and thus also inhibit mitochondrial protein synthesis (MPS).13,14 This off-target binding is thought to be responsible for the more significant side-effects of linezolid, including myelosuppression, hyperlactatemia, and peripheral neuropathy.15 Similarly, other ribosome-targeting antibiotics such as clindamycin and chloramphenicol also exhibit corresponding myelotoxic side effects.16,17 If a structure-activity-relationship (SAR) could be determined for linezolid’s mitochondrial binding ability, then new oxazolidinones could be designed with reduced MPS inhibition. In fact, reducing myelotoxic side effects while maintaining antibacterial potency is often cited as one of the greatest challenges in new oxazolidinone design.18 300 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Fortunately, the modular structure of oxazolidinones enables chemical modification of all three rings, A, B, and C, facilitating SAR studies for mitochondrial ribosome binding (Figure 2.3). Some patterns have already been emerged. In 2006, McKee identified several oxazolidinones that more potently inhibit MPS yet display MIC values comparable to that of linezolid (Table 2.1).19 In these cases, the morpholine ring was replaced with other heterocycles, suggesting the C-ring may be the greatest determinant of MPS inhibition. In spite of these initial results, there are no known reports of a potent oxazolidinone featuring reduced MPS inhibition. Table 2.1. MIC and MPS IC50 values for linezolid analogues MICa IC50b 2 12.8 1 0.95 4 1.7 2 4.2 2 0.83 F O N O N linezolid O F O O NH O N PNU-140693 O HO N O NH F N N O N O N PNU-108812 F N O O NH O MeHN N Eperezolid O F O O NH O N O O PNU-97786 NH [a] MIC (μg/mL) for S. aureus JC9213. [b] IC50 (μg/mL) for mitochondrial protein synthesis Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 301 We thus initiated a medicinal chemistry project seeking to modify the morpholine C-ring of linezolid with the goal of reducing MPS inhibition. Importantly, crystal structure studies note that the morpholine ring does not make significant interactions with the binding pocket, suggesting that the ring can be modified without compromising binding.20 Because increased molecular complexity is associated with reduced ligand promiscuity, we hypothesized that gem-disubstitution of the morpholine ring could potentially increase selectivity for the bacterial ribosome and reduce off-target side effects such as MPS inhibition (Figure 2.3). To test this hypothesis, we began by identifying a modular route to enable the synthesis of a library of gem-disubstituted linezolid analogs (Scheme 2.1). Cross-coupling of a gem-disubstituted morpholine with aryl halide 2.7 was identified as an efficient route. Thus, aryl halide 2.7 was synthesized by adapting a patent procedure.21 Briefly, (S)-epichlorohydrin (2.2) was coupled with 4chlorobenzaldehyde (2.1) and ammonia to give imine 3. To forge the oxazolidinone intermediate 2.5, imine 2.3 was then subjected to a base-catalyzed coupling reaction with carbamate 2.4,22 which itself was made by addition of benzyl chloroformate to 3fluoroaniline. Finally, imine hydrolysis, N-acetylation, and iodination provided the aryl iodide 2.7. 2.7 was cross-coupled under copper-catalyzed Ullmann conditions23 with a variety of gem-disubstituted morpholines resulting in linezolid analogues 2.12-2.19 (Figure 2.5). Notably, this synthetic route will facilitate future efforts to modify the C morpholine ring of linezolid. 302 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Scheme 2.1. Synthesis of gem-disubstituted linezolid analogues via Cu-catalyzed Ullmann coupling F H Cl H O O F Cl a 2.4 c, d N b N Cl O NHCbz OH 2.2 O 2.5 N (p-Cl)-C6H4 2.1 2.3 R1 R2 F O F N R I O O e N O 2.6 NH O F O N R O f N 2.7 AcHN C6H4-(p-Cl) 2.8 O O NH AcHN [a] (S)-epichlorohydrin, NH4OH (aq). THF, 40 °C, 12 h, 55% yield; [b] LiOt-Bu, CH2Cl2, rt to 40 °C, 87% yield; [c] 1N HCl, H2O/EtOAc; [d] Ac2O, CH2Cl2, 96% yield over 2 steps; [e] NIS, TFA, rt, 92% yield; f. Substituted morpholine 2.11a-p, CuBr (10 mol %), BINOL (20 mol %), K3PO4, DMF, 80 °C. Scheme 2.2. Synthesis of gem-disubstituted morpholines by benzoyl cleavage and reduction of morpholinone decarboxylative alkylation products O R BzN ii. LAH, THF, 50 °C, 2h O R i. LiOH/H2O, i-PrOH, rt HN O 2.10: R = Me, 90% yield 2.11: R = CH2OBn, 76% yield Two analogues 2.13 and 2.14 were prepared using substituted morpholines 2.10 and 2.11, which were synthesized via a decarboxylative alkylation protocol and subsequent deprotective and reductive transformations (Scheme 2.2).6 Other analogues including the gem-dimethyl compound 2.12 and spiro compounds 2.15-2.19 were prepared from commercially available di-substituted morpholines. We note that all analogs were synthesized as racemates. 303 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Figure 2.5. gem-Disubstituted linezolid analogues synthesized via Ullmann coupling F O Me Me F O N N O N O O 2.12 N Boc O N O 2.16 O Me F O Me NH F O N NH N O Me N O 2.13 O N Me O 2.17 N O O Me Me NH NH F O F O N N O BnO O O N O 2.14 N O 2.18 O O Me Me NH NH F O N O BocN 2.15 F O N N O O O O 2.19 N O O Me NH Me NH Additionally, analogues synthesized via Ullman coupling could be further derivatized (Scheme 2.3). Taking advantage of the versatile allyl handle of 2.13, hydroborationoxidation afforded hydroxyl analogue 2.20, which could be acetyl-protected to give analogue 2.21. Additionally, a Lemieux–Johnson oxidation provided the aldehyde intermediate, which was reductively aminated with dimethylamine to provide analogue 2.23. Catalytic hydrogenation afforded the reduced analogue 2.22. Similarly, the benzyloxy analogue 2.14 could also be hydrogenated using catalytic Pd(OH)2 on carbon to provide the hydroxyl analogue 2.24. Finally, Boc-spiro compound 2.16 was deprotected using HCl resulting in spiropiperidine 2.25; subsequent acetyl protection gave 2.26. Similarly, acid-catalyzed Boc-cleavage of 2.15 afforded spiropyrrolidine 2.27. 304 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Scheme 2.3. Additional analogues synthesized by derivatization F O Me Me O N N O O iii. AcCl, THF N O OR 2.20: R = H, 19% yield 2.21: R = Ac, 68% yield Me NH F Me O N O N F N N H2, Pd(OH)2/C O O 2.14 MeOH, rt N 88% yield ii. AcCl, THF N O O N NH F O N O N N HCl BocN O MeOH O Me NH O NHAc F O N 2.15 O N R 2.25: R = H, 32% yield 2.26: R = Ac, 77% yield Me 2.16 NHAc F O i. HCl, MeOH O O 2.24 F N N Boc O Me NH O NHAc F O HO O O 2.23 40% yield over two steps NH N O Me2N Me 83% yield N O 2.22 O F O N NHAc a, b c BnO O ii. NaBO3, H2O 2.13 O F O i. 9-BBN, THF N O HN N O 2.27 40% yield over 2 steps NHAc With a diverse set of gem-disubstituted linezolid analogues in hand, we proceeded with broth microdilution assays against S. aureus to determine minimum inhibitory concentration (MIC) values (Table 2.2). The initial three compounds, 2.12, 2.13, 2.24, were noticeably less potent than linezolid, suggesting that bulky alkyl di-substitution on the morpholino ring reduces activity. Similarly, bulky hydroxyl-substituted analogue 2.20 and protected alcohols 2.21 and 2.14 were also inactive. In contrast, hydroxyl analogue 2.25 retained a moderate amount of activity, displaying 48% growth inhibition at the maximal tested concentration of 16 µM. The amine-bearing derivatives, 2.23, 2.27, 2.17, 305 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid and 2.25, featuring methylamino, dimethyl amino, and spiroamine functionalities, were uniformly inactive up to 64 µM concentrations. Interestingly, when the basic nitrogen of 2.25 was masked as an amide as in 2.27, an 18% growth inhibition at the maximal tested concentration of 16 µM was achieved, suggesting that positively charged substituted morpholines are not tolerated. Finally, we were excited to observe increased growth inhibition when the spirofuran 2.18 and spirotetrahydropyran 2.19 analogues were tested, with 2.19 displaying the greatest potency of all analogues examined. Table 2.2. MIC values against ATCC 8235-4 (MSSA) or ATCC 43300 (MRSA) Compound Linezolid 2.12 2.13 2.22 2.20 2.21 2.14 2.24 MIC (μM) 4a,b 22a 32a 41a > 64a > 64b > 64b 16 uM: 48% inhib.b,d Compound MIC (μM) 2.23 2.27 2.17 2.25 2.26 2.18 2.19 2.19a 2.19b > 64b > 64b > 64b > 64b 16 uM: 18% inhib.b,d 16 uM: 65% inhib.b,d 16b 14b 22b [a] MIC: the lowest concentration of molecule preventing visible growth. [b] Tested against ATCC 43300 (MRSA). [c] Tested against ATCC 8235-4 (MSSA). [d] 16 μM was the maximal concentration tested. Since stereoisomers often exhibit differing biological activity, we used chiral HPLC to obtain both diastereomers of 2.19, and then assigned their absolute stereochemistry using vibrational circular dichroism (VCD) and optical rotation calculations, both of which were in agreement (Figure 2.6). Notably a eudysmic difference between the two diastereomers 2.19a and 2.19b was observed, with the more active diastereomer 2.19a displaying an MIC of 14 µM, roughly threefold less potent than linezolid (Table 2.2). 306 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Figure 2.6. Diastereomers of analogue 2.19. Absolute configuration of the spirocyclic stereocenter determined by both VCD and optical rotations (See Appendix 6 for details). O (S) F O (R) N F N O O O 2.19a N O O O N 2.19b O O Me Me NH NH We further investigated the bioactivity of 2.19a against other strains of S. aureus, determining the MIC values to be consistent against a range of MSSA and MRSA strains (Table 2.3). Table 2.3. MIC values of lead analogue 2.19a against various S. aureus strains Strain ATCC 8235-4 (MSSA) 43300 (MSSA) 29213 (MRSA) 25923 (MSSA) Linezolid MIC (uM) 2.19a MIC (μM) 4 4 4 4 12 12 12 12 We next examined the pharmacokinetic properties of 2.19a and 2.19b, determining most properties were slightly lower but comparable to that of linezolid (Table 2.4). For instance, 2.19a and 2.19b demonstrated slightly lower aqueous solubility and stability at low pH. Microsomal stability for was also lower than that of linezolid, perhaps due to the metabolic susceptibility of the tetrahydropyran ring. Initial safety data including cytotoxicity and cytochrome P450 isoform inhibition were satisfactory. One interesting difference was MPS inhibition, in which linezolid displayed a relatively potent 8 µM IC50. In contrast, 2.19a displayed an IC50 value of 30 µM. This finding correlates with the relative MIC values of linezolid and 2.19a; in this case, MPS inhibition is also roughly three-fold less potent, suggesting that the spirotetrahydropyran ring of 2.19a maintains moderate binding affinity to the bacterial ribosome while reducing inhibition of the mitochondrial ribosome. 307 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Table 4. Pharmacokinetic properties, inhibitory activity, and physicochemical properties Linezolid 2.19a 2.19b Aq. solubility (μg/mL) >67.47 >52.15 >48.89 Stability at gastric pH (% remaining 24h) 98% 94% 89% >216.8 170.0 128.3 Cytotoxicity EC50 (μM)b >30 > 30 > 30 CYP Inhibition (μM)c >100 >100 >100 MT Protein synthesis inhibition IC50 (μM)d 8.19 30 > 30 t1/2 microsomes (min)a [a] Metabolic stability performed with mouse liver microsomes [b] Cytotoxicity against HepG2 cells using CellTiter Glo [c] Measured against CYP1A2, 2C9, 2C19, 2D6, 3A4 [d] MitoBiogenesis In-Cell ELISA assay for COXI and SDH-A mitochondrial proteins 2.3 CONCLUSIONS In conclusion, we identified a gem-disubstituted morpholine analogue of linezolid bearing a spirotetrahydropyran substitution, 2.19a, that displays slightly reduced potency compared to linezolid against various S. aureus strains while also having reduced mitochondrial inhibition. These results contribute to the existing SAR of MPS inhibition (Table 2.1). Although the mitochondrial and bacterial ribosomes share homology, they have structural differences that may be exploited to design molecules with reduced selectivity for the mitochondrial ribosome.13 Our research further contributes to the body of data suggesting that the morpholine ring is a key structural component whose modification can reduce mitochondrial inhibition while maintaining bacterial ribosome inhibition. Continued efforts are needed to identify a molecule as potent as linezolid but with reduced MPS inhibition. This ability of gem-disubstituted heterocycles to alter selectivity for a target such as the bacterial ribosome highlights one of the many useful properties of heterocyclic substitution. Efforts such as those underway in our laboratory 308 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid to incorporate gem-disubstituted heterocycles into other small molecule scaffolds will undoubtedly shed light on the broader medicinal utility of gem-disubstituted heterocycles. 2.4 EXPERIMENTAL SECTION 2.4.1 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 Sigma Aldrich/Strem/Alfa Aesar/Combi-Blocks/Enamine/PharmaBlock and used as received. From Combi-Blocks: (S)-epichlorohydrin, 2,2-dimethylmorpholine. From Enamine: 1,8dioxa-4-azaspiro[5.5]undecane, tert-butyl 1-oxa-4,8-diazaspiro[5.5]undecane-8- carboxylate, 6-oxa-2,9-diazaspiro[4.5]decane, 2,6-dioxa-9-azaspiro[4.5]decane. From PharmaBlock: tert-butyl 8-oxo-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxylate. 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 or KMnO4 staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. 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. Reverse Phase Preparatory Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 309 HPLC was performed with a Teledyne ISCO ACCQPrep HP125 preparative liquid chromatography system equipped with a RediSep Prep C18 5 µm column (20 x 250 mm). 1 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or CH3OH (δ 3.31 ppm). 13C 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 CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 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 water (δ 1.56 or 4.87 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. 1 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or a Bruker Avance HD 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm) or CH3OH (δ 3.31 ppm). 13C 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 CDCl3 (δ 77.16 ppm) or CD3OD (δ 49.00 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 water (δ 1.56 or 4.87 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), 310 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 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 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). MIC values were obtained in collaboration with UCLA (P.L.B. and J.F.M.) and the CO-ADD. Pharmacokinetic data was obtained with WuXi AppTec, a contract research organization. 2.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA 2.4.2.1 Determination of Absolute Configuration of 2.19a and 2.19b. Ac N H N OH H N O O O O O O N ii. DBU, NEt3 O O 1,8-dioxa-4-azaspiro[5.5]undecane Purchased from Enamine LTD O Me i. Ph CDI, THF Me N Me Pd/C, H2 + SI1a O O O SI1b Diastereomers separated by preparative chiral HPLC MeOH/EtOAc (1:1) O SI2a H + N O O SI2b Ac2O, NEt3 CH2Cl2 O SI3a (S)-More potent Ac N O O SI3b (R)-Less potent Diastereomers SI1a and SI1b: To a solution of (S)-(−)-1-Phenylethanol (599 uL, 1.1 equiv) in THF (4.5 mL, 1M), was added CDI (794 mg, 1.1 equiv). The solution was stirred for 1 h at room temperature. Then NEt3 (686 uL, 1.1 equiv) and DBU (732 uL, 1.1 311 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid equiv) were added and the solution was stirred for 5 min. Then 1,8-dioxa-4azaspiro[5.5]undecane was added and the solution was stirred for 16 h before quenching with NH4Cl. Following extraction with EtOAc (3x10 mL) and backwashing with NaHCO3 (5 mL), the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (33% EtOAc:Hexanes). The diastereomers were then separated by chiral preparative HPLC (CHIRALPAK IC Column 20 x 150 mm), 30% iPrOH:Hexanes. The diastereomer SI1a which results in the more potent analogue 2.19a elutes first from the chiral column. H N H N O O O SI2a (S)-More potent O SI2b (R)-Less potent (R) and (S)-1,8-dioxa-4-azaspiro[5.5]undecane, enantiopure SI2a and SI2b: To a solution of carbamate SI1a or SI1b (460 mg, 1 equiv) in 1:1 EtOAc/MeOH (16 mL, 0.1 M) under nitrogen was added Pd/C (10%, 80 mg, 0.05 equiv). The reaction vessel was evacuated and filled with hydrogen three times and then left to stir for 12 h at room temperature. Following completion as determined by TLC, the reaction was filtered through celite, rinsed with EtOAc, and then concentrated to afford the enantiopure amines SI2a or SI2b, which were used in subsequent reactions without further purification. Ac N Ac N O O O SI3a (S)-More potent (R) and O SI3b (R)-Less potent (S)-1-(1,8-dioxa-4-azaspiro[5.5]undecan-4-yl)ethan-1-one (Acylated enantiomers SI3a and SI3b): To a solution of SI2a or SI2b in CH2Cl2 (5 mL, 0.1 M) was Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 312 added NEt3 (106 uL, 1.5 equiv) and Ac2O (53 uL, 1.1 equiv). The reaction was stirred at rt for 1 h and then purified by automated silica gel flash chromatography (Teledyne ISCO): MeOH/CH2Cl2 (0 → 30%) to afford the acylated amine SI3a or SI3b as a clear oil (65 mg, 65% yield); 1H NMR (400 MHz, Chloroform-d) δ 3.84 – 3.21 (m, 10H), 2.09 (d, J = 5.2 Hz, 3H), 1.88 – 1.48 (m, 4H); 13C NMR (101 MHz, CDCl3) δ (169.6 & 169.4 appear as two peaks due to hindered rotation), (71.1 & 70.9 appear as two peaks due to hindered rotation), (70.2 & 69.4 appear as two peaks due to hindered rotation), (68.5 & 68.4 appear as two peaks due to hindered rotation), (60.4 & 60.1 appear as two peaks due to hindered rotation), (51.1 & 41.7 appear as two peaks due to hindered rotation) (46.8 & 46.6 appear as two peaks due to hindered rotation), (30.9 & 29.8 appear as two peaks due to hindered rotation), (22.8 & 22.0 appear as two peaks due to hindered rotation), (21.2 & 21.11 appear as two peaks due to hindered rotation). IR: See VCD section; HRMS (MM: ESI-APCI) m/z calc’d for C10H21N2O3 [M+NH4]+: 217.1547, found 217.1552. [α]D22.7 –22.00 (c 1.0, CHCl3) for (S) ent. [α]D22.4 +17.38 (c 21.0, CHCl3) for (R) ent. Note: We elected to acylate these amines to facilitate absolute stereochemistry determination by both VCD and optical rotations. Method 1 – Vibrational Circular Dichroism (VCD) Experimental Protocol. Solutions of SI3a and SI3b (65 mg/mL) were prepared in CDCl3 and loaded into a front-loading SL-4 cell (International Crystal Laboratories) possessing BaF2 windows and 100 µm path length. Infrared (IR) and VCD spectra were acquired on a BioTools ChiralIR-2X VCD spectrometer as a one-hour block of 3120 scans for each enantiomer. A 15-minute acquisition of neat (+)-α-pinene control Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 313 (separate 75 µm BaF2 cell) yielded a VCD spectrum in agreement with literature spectra. IR and VCD spectra were background-corrected using a 5-minute block acquisition of the empty instrument chamber under gentle N2 purge. The resultant VCD spectra of SI3a and SI3b were enantiomer subtracted (half-difference). Computational Protocol. The arbitrarily chosen (R) enantiomer of compound SI3b was subjected to an exhaustive initial molecular mechanics-based conformational search (MMFF94 force field, 0.08 Å geometric RMSD cutoff, and 30 kcal/mol energy window) as implemented in MOE 2018.1 (Chemical Computing Group, Montreal, CA). All conformers retained the (R) configuration. All MMFF94 conformers were then subjected to geometry optimization, harmonic frequency calculation, and VCD rotational strength evaluation using density functional theory. All quantum mechanical calculations utilized the B3PW91 functional, cc-pVTZ basis, and implicit IEFPCM chloroform solvation model as implemented in the Gaussian 16 program system (Rev. B.01; Frisch et al., Gaussian, Inc., Wallingford, CT). Resultant harmonic frequencies were scaled by 0.98. All structurally unique conformers were Boltzmann weighted by relative free energy at 298.15 K. The predicted IR and VCD frequencies and intensities were convolved using Lorentzian line shapes (γ = 4 cm-1) and summed using the respective Boltzmann weights to yield the final predicted IR and VCD spectra of the (R) enantiomer of SI3b. The predicted VCD of the corresponding (S) enantiomer was generated by inversion of sign. From the agreement between the predicted and measured IR and VCD spectra in the useful range (1150-1325 cm-1; see below) the absolute configuration of the N-acylated derivative of the desired, more active spirocyclic amine tail group was established as (S). 314 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid Experimental (left) and computed (right) IR and VCD spectra for SI3a and SI3b. Method 2 – Optical Rotation (OR) Computational Protocol. The ensemble of unique B3PW91/cc-PVTZ conformers of the (R) enantiomer of SI3b generated in Method 1 above were subjected to optical rotation calculation at 589.0 nm using the B3LYP hybrid density functional, the large and diffuse 6-311++G(2df,2pd) basis set, and the IEFPCM implicit chloroform solvent model. From the computed B3PW91/cc-pVTZ free energies at 298.15 K and IEFPCM-B3LYP/631++G(2df,2pd) optical rotations, a Boltzmann-weighted OR value of +33.6° was determined for the (R)-configuration of the above N-acylated derivative. (Thus -33.6° for the (S) configuration). As the measured specific rotations (CHCl3 solvent, 22.7 °C, c = 1.0, 100 mm path length) were found to be +17.4° (less potent enantiomer) and -20.0° (more potent enantiomer) the OR-based assignment is therefore in accord with the VCD- Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 315 based assignment above (more active = (S), less active = (R). Individual free energies and optical rotational signatures are provided in the accompanying Microsoft Excel file. 2.4.2.2 Experimental Procedures for Biological Assays Broth microdilution method A (Performed by the CO-ADD) Samples were provided by the collaborator and stored frozen at -20 °C. Samples were prepared in DMSO and water to a final testing concentration of 32 µg/mL or 20 µM (unless otherwise indicated in the data sheet) and serially diluted 1:2 fold 8 times. Each sample concentration was prepared in 384-well plates, non-binding surface plate (NBS; Corning 3640) for each bacterial/fungal strain or Tissue-culture treated (TC-treated; Corning 3712/3764) black for mammalian cell types, all in duplicate (n=2), and keeping the final DMSO concentration to a maximum of 0.5% DMSO. All sample preparation was done using liquid handling robots. Whole cell growth inhibition assays against S. aureus ATCC 43300 MRSA were conducted as an 8-point dose response to determine the Minimum Inhibitory Concentration (MIC), in duplicate (n=2). All bacteria were cultured in Cation-adjusted Mueller Hinton broth (CAMHB) at 37 °C overnight. A sample of each culture was then diluted 40-fold in fresh broth and incubated at 37 °C for 1.5-3 h. The resultant mid-log phase cultures were diluted (CFU/mL measured by OD600), then added to each well of the compound containing plates, giving a cell density of 5Å~105 CFU/mL and a total volume of 50 µL. All the plates were covered and incubated at 37 °C for 18 h without shaking. Inhibition of bacterial growth was determined measuring absorbance at 600 nm (OD600), using a Tecan M1000 Pro monochromator plate reader. The percentage of growth inhibition was calculated for each well, using the negative control (media only) and Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 316 positive control (bacteria without inhibitors) on the same plate as references. The percentage of growth inhibition was calculated for each well, using the negative control (media only) and positive control (bacteria without inhibitors) on the same plate. The MIC was determined as the lowest concentration at which the growth was fully inhibited, defined by an inhibition ≥ 80%. In addition, the maximal percentage of growth inhibition is reported as DMax , indicating any compounds with partial activity. Broth microdilution method B (Performed by UCLA, P.L.B and J.F.M.) A broth microdilution method was used to estimate the MIC of synthesized compounds against Staphylococcus aureus ATCC 8235-4 (MSSA), 43300 (MSSA), 29213 (MRSA), and 25293 (MSSA). Compounds were diluted in Luria-Bertani (LB) broth to concentrations ranging from 4 µM to 22 µM (in 2 µM steps) in 96 well plates (100 µl per well). DMSO-treated wells (carrier-only) were used as negative controls, and linezolid-treated wells were used as positive controls. Wells at the edge of the plate were not used to avoid broth evaporation during incubation. Overnight cultures of S. aureus 8235-4 were diluted 1:200 in experimental plates, and plates were sealed with a plastic cover and tape. Inoculated plates were gently shaken (150 RPM) at 37 °C for 16hrs, at which point the optical density at 600nm (OD600) for each well was determined using an Epoch microplate spectrophotometer (BioTek Instruments). MIC was defined as the concentration at which at least 90% of S. aureus growth was inhibited, relative to DMSOtreated controls. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 2.4.2.3 317 Procedures and Spectroscopic Data for the Synthesis of Linezolid Analogues Cl OH N Cl (S)-1-chloro-3-((4-chlorobenzylidene)amino)propan-2-ol (2.3). To a solution of benzaldehyde (25 g, 1 equiv) in THF (180 mL, 1M) was added aqueous ammonia (28 wt %, 18 mL, 1.5 equiv). The mixture was stirred at rt for 20 min. Then, (S)-epichlorohydrin (13.9 mL, 1.0 equiv) was added. The reaction was stirred at 30 °C for 4 h, then at 40 °C for 12 h. with a reflux condenser attached. Then, another 18 mL aq. NH3 was added and stirring was continued at 40 °C for another 12 h. The solvent was concentrated under reduced pressure. 50 mL PhMe was added and then removed under reduced pressure to azeotrope remaining volatiles. The aqueous solution was then extracted with EtOAc (3x50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was recrystallized using hot hexanes, rinsed with hexanes, and isolated as white needles (22.7 g, 55% yield). Product identity matched previously reported characterization data.24 F H O N H O benzyl (3-fluorophenyl)carbamate (2.4). To a solution of 3-fluoroaniline (5 g, 1 equiv) and K2CO3 (7.46 g, 1.2 equiv) in THF at rt was added CbzCl (7 mL, 1.1 equiv). The Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 318 solution was stirred at rt for 5 h and then quenched with 200 mL sat. Na2CO3. The layers were separated and the organic layer was washed with Na2CO3 (2x). The combined aqueous layers were extracted with CH2Cl2 (4x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was triturated with hexanes at rt: after cooling at -20 °C, the white precipitate was isolated by filtration and used in the next step. Product identity matched previously reported characterization data.25 F O N O N Cl (S)-5-(((4-chlorobenzylidene)amino)methyl)-3-(3-fluorophenyl)oxazolidin-2-one (2.5). To a solution of carbamate 2.4 (4 g, 1 equiv) and LiOtBu (3.27 g, 2.5 equiv) in CH2Cl2 (22 mL, 0.75 M) was added a solution of imine 2.3 in CH2Cl2 (11 mL, 2.27 M). The reaction was refluxed for 16 h, and then allowed to cool to rt before being quenched with half saturated brine. The solution was extracted with CH2Cl2 (4x30 mL). Addition H2O and CH2Cl2 were added to clear emulsions formed in the separatory funnel. The combined organic layers were dried over Na2SO4, filtered over celite to remove suspended particles, and then concentrated under reduced pressure. The crude product was triturated by adding hot Et2O, which solvated the byproduct, but left the product unsolvated. The hot Et2O was allowed to cool to rt and then the product was isolated by filtration and rinsed with cold Et2O to provide the imine 2.5 as a white fluffy solid (4.73 g, 87% yield); 1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.62 (d, J = 8.3 Hz, Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 319 2H), 7.54 – 7.14 (m, 5H), 6.84 (td, J = 8.2, 2.5 Hz, 1H), 4.97 (dq, J = 8.9, 5.2 Hz, 1H), 4.29 – 4.04 (m, 2H), 4.04 – 3.79 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 163.21 (d, JCF = 245.0 Hz), 163.68, 154.45, 139.94 (d, JCF = 10.7 Hz), 137.44, 134.09, 130.35 (d, JCF = 9.4 Hz), 129.66, 129.10, 113.43 (d, JCF = 3.0 Hz), 110.85 (d, JCF = 21.2 Hz), 105.90 (d, JCF = 26.9 Hz), 71.90, 63.28, 48.27; IR (Neat Film, NaCl) 3746, 2360, 1748, 1646, 1614, 1495, 1456, 1405, 1224, 1195, 1168, 1087, 837 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C17H15FN2O2 [M+H]+: 333.0801, found 333.0803. [α]D22.7 –99.9 (c 2.0, CHCl3). F O N O NH O (S)-N-((3-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (2.6). To a solution of imine 2.5 in a 1:1 mixture of EtOAc/H2O (80 mL, 0.17 M) was added concentrated HCl (2.26 mL, 2 equiv). The reaction was stirred at rt for 5 h and then slowly quenched with NaHCO3(aq). Then, KOH was added until pH = 14. The solution was extracted with EtOAc (4x40 mL) and CH2Cl2 (4x40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with Et2O to afford crude amine, which was used in the next step without purification. To a solution of crude amine in CH2Cl2 (45 mL, 0.3 M) was added NEt3 (3.78 mL, 2 equiv) followed by Ac2O (2.55 mL, 2 equiv). The reaction was stirred for 2 h at rt and then quenched with H2O. Following extraction with EtOAc (3x20 mL) and drying with Na2SO4, the combined organic layers were concentrated under reduced pressure. The Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 320 crude product was dissolved in a minimal amount of hot CH2Cl2 and then Et2O was added. The solution was left overnight at -20 °C, resulting in crystallization of pure 2.6. The solid product (3.28 g, was isolated by filtration and rinsed with Et2O. Product identity matched previously reported characterization data. F I O N O NH O (S)-N-((3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (2.7). To a solution of (S)-N-((3-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (2.6) (2.9 g, 1 equiv) in TFA (12 mL, 1M) was added NIS (2.72 g, 1.05 equiv) portion-wise. The reaction was stirred for 1 h at rt. While stirring, the exothermic reaction turned pinked. Next, the TFA was concentrated off under reduced pressure. The crude mixture was diluted with Na2S2O3 (10%), and then KOH was added until pH = 14. Next the solution was diluted to ~700 mL volume with H2O. Extraction with CH2Cl2 (4x50 mL) and EtOAc (4x50 mL) was followed by drying with Na2SO4 and concentration of the combined organic layers under reduced pressure. The crude product was then purified by silica gel flash chromatography (5 → 10% MeOH/CH2Cl2) to afford the desired iodinated compound 2.7 (4 g, 92% yield). Product identity matched previously reported characterization data.27 BnO HN O 321 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 2-allyl-2-((benzyloxy)methyl)morpholine (2.11). Prepared according to literature procedure.6 Product identity matched previously reported characterization data.6 O Me BzN O 2-allyl-4-benzoyl-2-methylmorpholin-3-one.6 Prepared according to an adapted procedure from our publications:6,28 In the glove box, in a 100 mL Schlenck bomb, Pd(OAc) (2.7 mg, 0.005 equiv), GlyPHOX29,30 (16 mg, 0.02 equiv), and MTBE (5 mL) were added. The solution was stirred at rt for 30 min. Then, allyl 4-benzoyl-2-methyl-3oxomorpholine-2-carboxylate6 dissolved in 10 mL toluene was added. The reaction was heated to 60 °C for 5 h, at which time TLC analysis showed complete consumption of starting material. The solution was loaded onto a silica gel flash column and purified (10 → 20% EtOAc/Hexanes) to afford racemic 2-allyl-4-benzoyl-2-methylmorpholin-3-one as a white solid (620 mg, 98% yield). Product identity matched previously reported characterization data.6 Me HN O 2-allyl-2-methylmorpholine (10). To a solution of 2-allyl-4-benzoyl-2- methylmorpholin-3-one (620 mg, 1 equiv) in iPrOH (60 mL, 0.04 M) was added LiOHH2O (150 mg, 1.5 equiv) dissolved in H2O (16 mL, 0.15 M). The reaction was stirred at room temperature for 2 h and then concentrated into SiO2. The dry-loaded crude product was purified by silica gel flash chromatography (2.5 → 5% MeOH/CH2Cl2) to afford the deprotected lactam, which was carried onto the next step: 322 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid To a solution of deprotected lactam (370 mg, 1 equiv) in THF (24 mL, 0.1 M) was added LAH (271 mg, 3 equiv) portionwise at 0 °C. The reaction was then heated to 50 °C for 2 h. A Fieser workup was performed: the reaction was diluted with Et2O (12 mL) at 0 °C, then the following were slowly and sequentially added at 0 °C: 270 uL H2O, 270 uL 15% aq. NaOH, and lastly 800 uL H2O. The suspension was stirred at 0 °C for 15 min and then MgSO4 was added. The mixture was allowed to warm to rt and then filtered over celite, rinsing with EtOAc. The solvent was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (5 → 10% MeOH/CH2Cl2) to yield racemic 2.10 as a clear oil (305 mg, 90% yield over two steps); 1H NMR (600 MHz, Chloroform-d) δ 5.80 (dddd, J = 14.6, 12.9, 6.1, 3.8 Hz, 1H), 5.14 – 5.02 (m, 2H), 3.67 (dq, J = 5.7, 3.3, 2.7 Hz, 2H), 2.79 (q, J = 4.4, 4.0 Hz, 2H), 2.74 – 2.57 (m, 2H), 2.48 (dt, J = 12.1, 5.5 Hz, 1H), 2.21 (dt, J = 12.7, 5.9 Hz, 1H), 2.06 (d, J = 7.5 Hz, 1H), 1.26 – 1.10 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 133.6, 117.9, 72.1, 61.6, 54.3, 46.0, 41.7, 22.0; IR (Neat Film, NaCl) 3335, 3074,2973, 2938, 2868, 2818, 2741,2360, 1639, 1455, 1375, 1324, 1259, 1200, 1177, 1130, 1084, 997, 914, 852, 797, 750, 669 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C8H16NO [M+H]+: 142.1226, found 142.1229. O O NH BocN O LAH NH THF, 60 °C N 2-methyl-6-oxa-2,9-diazaspiro[4.5]decane (SI5). To a solution of tert-butyl 8-oxo-6oxa-2,9-diazaspiro[4.5]decane-2-carboxylate (100 mg, 1 equiv) in THF (3.9 mL, 0.1 M) at 0 °C was slowly added LAH (59 mg, 4 equiv). The reaction was stirred at 60 °C for 6 h and then allowed to cool to ambient temperature. A Fieser workup was performed: the 323 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid reaction was diluted two-fold with Et2O at 0 °C, then the following were slowly and sequentially added at 0 °C: 60 uL H2O, 60 uL 15% aq. NaOH, and lastly 180 uL H2O. The suspension was stirred at 0 °C for 15 min and then MgSO4 was added. The mixture was allowed to warm to rt and then filtered over celite, rinsing with EtOAc. The solvent was concentrated under reduced pressure. The crude product was used without further purification. Preparation of linezolid analogues via Cu-Catalyzed Ullman Coupling 2.4.2.4 H N F I O R CuBr (20 mol %) BINOL (20 mol %) O N O O Me NH F O R K3PO4, DMF, 80 °C 24-72 h R N O R N O O Me NH To a flame-dried one-dram vial equipped with a Teflon screw cap and a stir bar was added CuBr (0.1 - 0.3 equiv), BINOL (0.1 - 0.3 equiv), aryl iodide 2.7 (1 equiv), and K3PO4 (2 equiv). The vial was cycled into a glovebox and then DMF (0.2 M final concentration) was added to the vial, followed by the amine (2 equiv). The reaction was stirred at 80 °C for 24-72 hours until complete consumption of starting material was noted by LC-MS analysis. In some cases, conversion of the starting material stopped, at which point 0.2 equiv of CuBr and 0.2 equiv of BINOL was added to the reaction, which then proceeded to completion. The reaction was diluted with EtOAc and filtered through a plug of silica, rinsing with 10% MeOH/EtOAc. The solution was concentrated in vacuo until all DMF solvent was removed. The crude material was purified by by silica gel flash chromatography or reverse phase prep HPLC to afford the desired linezolid analog. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 324 F O N O O N O O Me NH N-(((S)-3-(3-fluoro-4-((S)-1,8-dioxa-4-azaspiro[5.5]undecan-4-yl)phenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.19a). Prepared according to the general procedure using: CuBr (2.3 mg, 0.016 mmol, 0.2 equiv), BINOL (4.5 mg, 0.016 mmol, 0.2 equiv), aryl iodide 2.7 (30 mg, 0.079 mmol, 1 equiv), K3PO4 (34 mg, 0.16 mmol, 2 equiv), enantiopure (S)-1,8-dioxa-4-azaspiro[5.5]undecane (SI2a) (18 mg, 0.16 mmol, 2 equiv), and 400 uL DMF. The crude residue was purified by silica gel flash chromatography (2 → 3 → 5% MeOH/CH2Cl2) to yield spirotetrahydropyran analogue 2.19a (8 mg, 28% yield) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 14.1, 2.6 Hz, 1H), 7.04 (ddd, J = 8.8, 2.6, 1.1 Hz, 1H), 6.88 (t, J = 9.1 Hz, 1H), 6.39 (t, J = 6.2 Hz, 1H), 4.76 (dddd, J = 8.8, 6.7, 5.5, 3.3 Hz, 1H), 4.00 (t, J = 9.0 Hz, 1H), 3.91 (t, J = 4.9 Hz, 2H), 3.85 – 3.77 (m, 1H), 3.74 (dd, J = 9.2, 6.7 Hz, 1H), 3.71 – 3.54 (m, 5H), 3.09 – 2.94 (m, 2H), 2.92 (s, 2H), 2.01 (s, 3H), 1.95 – 1.78 (m, 3H), 1.58 (dddd, J = 14.3, 11.4, 6.8, 2.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.6 (d, JCF = 246.5 Hz), 154.5, 136.9 (d, JCF = 9.0 Hz), 133.0 (d, JCF = 10.3 Hz), 119.2 (d, JCF = 4.0 Hz), 114.0 (d, J = 3.4 Hz), 107.6 (d, J = 26.1 Hz), 72.1, 71.7, 70.0, 68.7, 61.0, 56.9, 50.8, 47.8, 42.0, 31.0, 23.2, 22.4; IR (Neat Film, NaCl) 3312, 3073, 2953, 2846, 2244, 1748, 1660, 1517, 1486, 1446, 1416, 1374, 1324, 1279, 1225, 1196, 1097, 1044, 985, 910, 871, 809, 732, 674, 646 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H27FN3O5 [M+H]+: 408.1929, found 408.1909 [α]D22.7 –20.8 (c 1.5, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 325 F O N O O N O O Me NH N-(((S)-3-(3-fluoro-4-((R)-1,8-dioxa-4-azaspiro[5.5]undecan-4-yl)phenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.19b). Prepared according to the general procedure using: CuBr (2.3 mg, 0.016 mmol, 0.2 equiv), BINOL (4.5 mg, 0.016 mmol, 0.2 equiv), aryl iodide 2.7 (30 mg, 0.079 mmol, 1 equiv), K3PO4 (34 mg, 0.16 mmol, 2 equiv), enantiopure (R)-1,8-dioxa-4-azaspiro[5.5]undecane (SI2b) (18 mg, 0.16 mmol, 2 equiv), and 400 uL DMF. The crude residue was purified by silica gel flash chromatography (2 → 3 → 5% MeOH/CH2Cl2) to yield spirotetrahydropyran analogue 2.19b (10 mg, 32% yield) as a clear oil: 1H NMR (400 MHz, Chloroform-d) δ 7.43 (dd, J = 14.1, 2.6 Hz, 1H), 7.06 (ddd, J = 8.8, 2.7, 1.1 Hz, 1H), 6.91 (t, J = 9.1 Hz, 1H), 6.06 (t, J = 6.2 Hz, 1H), 4.76 (dddd, J = 8.9, 6.7, 5.8, 3.2 Hz, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.93 (t, J = 4.9 Hz, 2H), 3.81 (d, J = 11.7 Hz, 1H), 3.78 – 3.55 (m, 6H), 3.08 – 2.96 (m, 2H), 2.94 (s, 2H), 2.02 (s, 3H), 1.96 – 1.77 (m, 3H), 1.59 (dddd, J = 15.1, 12.8, 6.9, 2.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 171.1, 155.6 (d, J = 246.6 Hz), 154.3, 136.81 (d, J = 8.9 Hz), 133.06 (d, J = 10.4 Hz), 119.27 (d, J = 4.0 Hz), 113.99 (d, J = 3.5 Hz), 107.62 (d, J = 26.2 Hz), 71.9, 71.7, 70.0, 68.7, 60.9, 56.9, 50.8, 47.7, 42.1, 31.0, 23.3, 22.5; IR (Neat Film, NaCl) 3318, 3067, 2927, 2850, 1748, 1667, 1516, 1486, 1416, 1374, 1326, 1277, 1225, 1097, 939, 870, 815, 733 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H27FN3O5 [M+H]+: 408.1929, found 408.1932. [α]D22.7 +1.7 (c 1.0, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 326 F O N O O N O O NH N-(((5S)-3-(3-fluoro-4-(2,6-dioxa-9-azaspiro[4.5]decan-9-yl)phenyl)-2-oxooxazolidin5-yl)methyl)acetamide (2.18). Prepared according to the general procedure using: CuBr (7.5 mg, 0.052 mmol, 0.3 equiv), BINOL (15.0 mg, 0.052 mmol, 0.3 equiv), aryl iodide 2.7 (66 mg, 0.17 mmol, 1 equiv), K3PO4 (74 mg, 0.35 mmol, 2 equiv), 2,6-dioxa-9azaspiro[4.5]decane (50 mg, 0.35 mmol, 2 equiv), and 873 uL DMF. The crude residue was purified by reverse phase preparatory HPLC (0 → 100% MeCN/H2O gradient over 10 minutes, 30x250 mm C18 column, 60 mL/min flow rate) to yield spirotetrahydrofuran analogue 2.18 (35 mg, 51% yield) as a clear oil. Note: HPLC H2O solvent contained 0.25% TFA: 1H NMR (400 MHz, Chloroform-d) δ (Note TFA appears in the 1H and 13 C NMR) 7.41 (dd, J = 14.0, 2.6 Hz, 1H), 7.05 (ddd, J = 8.8, 2.6, 1.1 Hz, 1H), 6.92 (t, J = 9.0 Hz, 1H), 4.82 (dddd, J = 8.8, 6.4, 5.1, 3.6 Hz, 1H), 4.14 – 3.83 (m, 7H), 3.79 (dd, J = 9.3, 6.4 Hz, 1H), 3.75 – 3.65 (m, 2H), 3.03 (d, J = 5.2 Hz, 4H), 2.24 – 2.13 (m, 2H), 2.13 – 2.00 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 171.4, 155.6 (d, J = 246.6 Hz), 154.5, 136.4 (d, J = 9.0 Hz), 133.3 (d, J = 10.4 Hz), 119.1 (d, J = 4.0 Hz), 114.0 (d, J = 3.3 Hz), 107.6 (d, J = 26.1 Hz), 82.6, 75.5, 72.1, 67.6, 63.1, 57.9, 50.1, 47.7, 42.0, 36.4, 23.2; IR (Neat Film, NaCl) 3304, 3070, 2955, 2870, 1751, 1662, 1517, 1446, 1415, 1374, 1326, 1278, 1227, 1195, 1083, 1060, 992, 919, 731 cm-1; HRMS (MM: ESIAPCI) m/z calc’d for C19H25FN3O5 [M+H]+: 394.1773 found 394.1779. [α]D2.8 –5.54 (c 1.0, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 327 F O N O N O O NH (S)-N-((3-(4-(2,2-dimethylmorpholino)-3-fluorophenyl)-2-oxooxazolidin-5yl)methyl)acetamide (2.12). Prepared according to the general procedure using: CuBr (2.3 mg, 0.016 mmol, 0.2 equiv), BINOL (4.5 mg, 0.016 mmol, 0.2 equiv), aryl iodide 2.7 (30 mg, 0.079 mmol, 1 equiv), K3PO4 (34 mg, 0.16 mmol, 2 equiv), dimethyl morpholine (18 mg, 0.16 mmol, 2 equiv), and 400 uL DMF. The crude residue was purified by silica gel flash chromatography (2 → 3 → 5% MeOH/CH2Cl2) to yield dimethyl analogue 2.12 (8 mg, 28% yield) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 14.2, 2.6 Hz, 1H), 7.05 (ddd, J = 8.8, 2.6, 1.1 Hz, 1H), 6.88 (t, J = 9.1 Hz, 1H), 6.16 (t, J = 6.2 Hz, 1H), 4.76 (dddd, J = 8.9, 6.7, 5.7, 3.3 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.92 – 3.85 (m, 2H), 3.80 – 3.65 (m, 2H), 3.61 (dt, J = 14.7, 6.1 Hz, 1H), 3.01 – 2.93 (m, 2H), 2.81 (s, 2H), 2.02 (s, 3H), 1.34 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 171.2, 155.6 (d, JCF = 247.5 Hz), 154.45, 137.1 (d, JCF = 9.1 Hz), 132.71 (d, JCF = 10.1 Hz), 119.02 (d, JCF = 4.0 Hz), 114.03 (d, JCF = 4.0 Hz), 107.7 (d, JCF = 133.3 Hz), 72.0, 71.6, 61.4, 60.89, 60.86, 50.5, 47.8, 42.1, 24.8, 23.3; δ IR (Neat Film, NaCl) 3300, 2971, 1748, 1659, 1517, 1415, 1366, 1325, 1272, 1224, 1194, 1100, 987, 862, 752 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C18H25FN3O4 [M+H]+: 366.1824, found 366.1827 [α]D22.8 –5.60 (c 0.5, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 328 F O N O N O O NH N-(((5S)-3-(4-(2-allyl-2-methylmorpholino)-3-fluorophenyl)-2-oxooxazolidin-5yl)methyl)acetamide (2.13). Prepared according to the general procedure using: CuBr (9.1 mg, 0.064 mmol, 0.3 equiv), BINOL (18 mg, 0.064 mmol, 0.3 equiv), aryl iodide 2.7 (80 mg, 0.21 mmol, 1 equiv), K3PO4 (90 mg, 0.42 mmol, 2 equiv), methallyl morpholine 2.10 (60 mg, 0.42 mmol, 2 equiv), and 1.1 mL DMF. The crude residue was purified by reverse phase preparatory HPLC (50 → 70% MeCN/H2O gradient over 7 minutes, 30x250 mm C18 column, 60 mL/min flow rate) to yield methallyl analogue 2.13 (45 mg, 54% yield) as a light brown oil; 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 14.1, 2.6 Hz, 1H), 7.04 (dd, J = 8.8, 2.6 Hz, 1H), 6.90 (t, J = 9.1 Hz, 1H), 6.74 (t, J = 6.2 Hz, 1H), 5.93 – 5.78 (m, 1H), 5.17 – 5.07 (m, 2H), 4.85 – 4.75 (m, 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.91 (td, J = 4.6, 2.8 Hz, 2H), 3.81 – 3.59 (m, 3H), 3.05 – 2.95 (m, 2H), 2.90 (dd, J = 11.6, 1.1 Hz, 1H), 2.79 (dd, J = 11.6, 1.0 Hz, 1H), 2.66 (dd, J = 14.1, 7.1 Hz, 1H), 2.34 (ddt, J = 14.1, 7.5, 1.2 Hz, 1H), 2.07 (s, 3H), 1.29 (s, 3H): 13C NMR (101 MHz, CDCl3) δ 172.9 (C=O), 155.6 (d, JCF = 247.5 Hz), 154.9 (C=O), 137.1 (d, JCF = 8.1 Hz), 133.4, 132.5 (d, JCF = 10.1 Hz), 119.2 (d, JCF = 4.0 Hz), 118.3, 114.3 (d, JCF = 4.0 Hz), 107.9 (d, JCF = 26.3 Hz), 73.5, 72.0, 61.1, 59.7, 50.4, 47.9, 42.3, 41.5, 22.9, 22.4; δ IR (Neat Film, NaCl) 3300, 3077, 2976, 2822, 1752, 1662, 1546, 1517, 1486, 1445, 1415, 1377, 1326, 1269, 1222, 1196, 1172, 1086, 995, 918, 867, 817, 750, 703 cm-1; HRMS (MM: ESIAPCI) m/z calc’d for C20H27FN3O4 [M+H]+: 392.1980, found 392.1976 [α]D23.0 –4.55 (c 1.0, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 329 F O N O N O O NH N-(((5S)-3-(3-fluoro-4-(2-methyl-2-propylmorpholino)phenyl)-2-oxooxazolidin-5yl)methyl)acetamide (2.22). To a solution of methallyl analogue 2.13 (12 mg, 0.031 mmol, 1 equiv) in MeOH (300 uL, 0.1 M) was added Pd/C (10% wt/wt, 3.3 mg, 0.1 equiv). The reaction vial was evacuated and backfilled with H2 three times, and then sparged with H2 for 5 min. The reaction was stirred for 7 h and then the Pd/C was filtered off through a plug of celite, rinsing with EtOAc. The solution was concentrated under reduced pressure and purified by silica gel flash chromatography (2 → 5% MeOH/CH2Cl2) to yield the methyl-propyl analogue 2.22 as a clear oil (10 mg, 83% yield); 1H NMR (400 MHz, Chloroform-d) δ 7.41 (ddd, J = 14.2, 2.5, 0.9 Hz, 1H), 7.04 (ddq, J = 8.8, 2.6, 1.0 Hz, 1H), 6.89 (t, J = 9.1 Hz, 1H), 6.52 – 6.28 (m, 1H), 4.78 (dddd, J = 8.9, 6.6, 5.8, 3.2 Hz, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.86 (tdd, J = 11.6, 5.7, 4.3 Hz, 2H), 3.79 – 3.67 (m, 2H), 3.63 (dt, J = 14.7, 6.1 Hz, 1H), 3.05 – 2.92 (m, 2H), 2.83 (q, J = 11.5 Hz, 2H), 2.06 (s, 3H), 1.84 (ddd, J = 12.9, 10.3, 6.0 Hz, 1H), 1.55 – 1.31 (m, 3H), 1.29 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 155.6 (d, JCF = 246.7 Hz), 154.6, 137.2 (d, JCF = 8.8 Hz), 132.5 (d, JCF = 10.3 Hz), 119.1 (d, JCF = 4.2 Hz), 114.1 (d, JCF = 3.3 Hz), 107.8 (d, JCF = 26.3 Hz), 73.6, 71.9, 61.0, 60.1, 60.1, 50.4, 50.4, 47.8, 42.2, 39.6, 23.0, 22.0, 16.4, 14.8. IR (Neat Film, NaCl) 3297, 3074, 2957, 2872, 1753, 1659, 1517, 1485, 1448, 1414, 1377, 1326, 1278, 1226, 1195, Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 330 1101,1087, 994, 919, 867, 750 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H29FN3O4 [M+H]+: 394.2137, found 394.2147 [α]D22.0 –8.45 (c 0.7, CHCl3). HO F O N O N O O NH N-(((5S)-3-(3-fluoro-4-(2-(3-hydroxypropyl)-2-methylmorpholino)phenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.20). In a glovebox, to a solution of methallyl analogue 2.13 (20 mg, 0.051 mmol, 1 equiv) in THF (500 uL, 0.1 M), was added 9-BBN dimer (25 mg, 0.10 mmol, 2 equiv). The reaction was stirred for 3 h at ambient temperature amd then taken out of the glovebox. Then, a solution of NaBO3⋅4H2O in H2O (500 uL) was added and the mixture was stirred for 2 h before being concentrated down. The crude residue was purified by reverse phase preparatory HPLC (0 → 100% MeCN/H2O gradient over 10 minutes, 30x250 mm C18 column, 60 mL/min flow rate) to yield hydroxyl analogue 2.20 (4 mg, 19% yield) as a clear oil; 13C NMR (101 MHz, CDCl3) δ 172.0, 155.6 (d, J = 246.7 Hz), 154.6, 137.0 (d, J = 8.9 Hz), 132.7 (d, J = 10.4 Hz), 119.1 (dd, J = 4.1, 1.9 Hz), 114.1 (d, J = 3.3 Hz), 107.7 (d, J = 26.1 Hz), 73.6, 72.9, 71.9, 68.6, 63.4, 61.2, 61.1, 60.3, 60.3, 60.1, 60.1, 50.3, 50.2, 50.3, 47.8, 42.2, 34.8, 32.6, 26.3, 23.1, 22.2, 22.1, 21.4. IR (Neat Film, NaCl) 3314, 2937, 1783, 1747, 1666, 1517, 1486, 1416, 1379, 1223, 1168, 1100, 866, 820, 745, 667 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H29FN3O4 [M+H]+: 410.2086, found 410.2084 [α]D24.3 –6.35 (c 0.33, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 331 AcO F O N O N O O NH 3-(4-(4-((S)-5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)-2methylmorpholin-2-yl)propyl acetate (2.21). To a solution of hydroxyl analogue 2.20 (4 mg, 1 equiv) in CH2Cl2 (200 uL, 0.05 M) was added NEt3 (4 uL, 3 equiv) and AcCl (1 uL, 2 equiv). The solution was stirred at rt for 4 h, then concentrated, and purified by silica gel flash chromatography (3 → 5% MeOH/CH2Cl2) to give acetylated analogue 2.21 as a clear oil (3 mg, 68% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.42 (ddd, J = 14.2, 2.5, 0.9 Hz, 1H), 7.06 (dddt, J = 8.7, 2.7, 1.9, 1.0 Hz, 1H), 6.88 (t, J = 9.1 Hz, 1H), 6.11 (t, J = 6.3 Hz, 1H), 4.76 (dddd, J = 8.9, 6.6, 5.7, 3.2 Hz, 1H), 4.47 – 4.32 (m, 1H), 4.10 (td, J = 6.6, 5.2 Hz, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.88 – 3.80 (m, 2H), 3.76 – 3.66 (m, 2H), 3.65 – 3.58 (m, 1H), 2.97 (t, J = 4.9 Hz, 2H), 2.86 (d, J = 11.6 Hz, 1H), 2.80 (dd, J = 11.5, 1.6 Hz, 1H), 2.04 (d, J = 11.9 Hz, 6H), 1.86 (d, J = 6.7 Hz, 2H), 1.75 – 1.70 (m, 1H), 1.57 – 1.51 (m, 1H), 1.30 (d, J = 2.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.0, 171.2, 156.8, 154.4, 136.9 (dd, JCF = 12.6, 9.0 Hz), 132.8 (t, JCF = 10.5 Hz), 119.1 (t, JCF = 3.5 Hz), 114.0 (d, JCF = 3.3 Hz), 107.6 (d, JCF = 26.2 Hz), 73.0, 71.9, 68.7, 65.0, 61.1, 60.1, 50.3, 47.8, 42.1, 23.2, 22.6, 22.1, 21.1. IR (Neat Film, NaCl) 3311, 3063, 2962, 1747, 1667, 1516, 1415, 1371, 1222,1169, 1087, 1036, 919, 867, 803, 737, 703 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C22H31FN3O6 [M+H]+: 452.2191, found 452.2185 [α]D24.0 +3.67 (c .33, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 332 O H F O N O N O O NH N-(((5S)-3-(3-fluoro-4-(2-methyl-2-(2-oxoethyl)morpholino)phenyl)-2-oxooxazolidin5-yl)methyl)acetamide (SI4). To a solution of methallyl analogue 2.13 (54 mg, 1 equiv) in 2:1 THF/H2O (14 mL, 0.01 M) was added a solution of OsO4 in PhMe (87 uL, 0.079 M, 0.05 equiv) followed by NaIO4 (89 mg, 3 equiv) The reaction was stirred for 16 h at ambient temperature, and was then quenched with Na2S2O3. The mixture was extracted with EtOAc (5x) and the combined organic layers were dried over Na2SO4. The residue was purified by silica gel chromatography (10 → 20% → 30% MeOH/CH2Cl2) to yield dimethylamino analogue SI4 (15 mg, 94% yield) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 9.89 (t, J = 2.9 Hz, 1H), 7.42 (dd, J = 14.1, 2.6 Hz, 1H), 7.06 (ddd, J = 8.8, 2.6, 1.2 Hz, 1H), 6.89 (t, J = 9.1 Hz, 1H), 6.21 (t, J = 6.2 Hz, 1H), 4.76 (dddd, J = 8.9, 6.7, 5.7, 3.3 Hz, 1H), 4.07 – 3.78 (m, 3H), 3.78 – 3.56 (m, 3H), 3.10 – 3.02 (m, 2H), 3.02 – 2.89 (m, 2H), 2.82 (d, J = 11.7 Hz, 1H), 2.63 (dd, J = 15.4, 2.9 Hz, 1H), 2.02 (s, 3H), 1.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 201.9, 171.2, 155.7 (d, J = 246.5 Hz), 154.4, 136.4 (d, J = 9.1 Hz), 133.2 (d, J = 10.4 Hz), 119.3 (d, J = 3.9 Hz), 114.0 (d, J = 3.3 Hz), 107.6 (d, J = 26.1 Hz), 72.7, 72.0, 61.4, 60.0, 50.3, 49.5, 47.7, 42.0, 23.7, 23.2; IR (Neat Film, NaCl) 3316, 2937, 1748, 1659, 1517, 1415,1379,1279, 1225,1085, 868, 751 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C19H25FN3O5 [M+H]+: 394.1773, found 394.1770 [α]D25.3 +3.97 (c .47, CHCl3). Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 333 N F O N O N O O NH N-(((5S)-3-(4-(2-(2-(dimethylamino)ethyl)-2-methylmorpholino)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.23). To a solution of aldehyde SI4 (15 mg, 0.038 mmol, 1 equiv) in THF (400 uL, 0.1 M) was added dimethylamine (95 uL, 0.19 mmol, 5 equiv) and AcOH (2 uL, 0.038 mmol, 1 equiv). The solution was stirred for 5 min, and then NaBH(OAc)3 (16 mg, 0.076 mmol, 2 equiv) was added. The reaction was stirred for 3 h at ambient temperature, and was then concentrated onto SiO2. The silica loaded crude residue was purified by silica gel chromatography (10 → 20% → 30% MeOH/CH2Cl2) to yield dimethylamino analogue 2.23 (15 mg, 94% yield) as a clear oil; 1 H NMR (600 MHz, CDCl3) δ 7.41 (dt, J = 14.1, 2.8 Hz, 1H), 7.05 (dt, J = 9.0, 2.7 Hz, 1H), 6.86 (t, J = 9.1 Hz, 1H), 6.43 (t, J = 6.2 Hz, 1H), 4.76 (dtd, J = 9.3, 6.2, 3.4 Hz, 1H), 4.00 (t, J = 8.9 Hz, 1H), 3.84 (h, J = 6.8 Hz, 2H), 3.75 (dd, J = 9.1, 6.6 Hz, 1H), 3.68 (ddd, J = 14.6, 6.2, 3.4 Hz, 1H), 3.60 (dt, J = 14.6, 6.1 Hz, 1H), 3.02 – 2.92 (m, 4H), 2.86 (d, J = 11.6 Hz, 1H), 2.80 (d, J = 11.6 Hz, 1H), 2.66 (s, 6H), 2.46 – 2.38 (m, 1H), 2.01 (d, J = 8.8 Hz, 3H), 1.91 – 1.82 (m, 1H), 1.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.38, 155.62 (d, J = 246.1 Hz), 154.49, 136.54 (d, J = 9.1 Hz), 133.13 (d, J = 10.5 Hz), 119.19 (d, J = 4.0 Hz), 114.05 (d, J = 3.2 Hz), 107.60 (d, J = 26.3 Hz), 72.2, 72.0, 61.3, 60.1, 53.0, 50.25, 47.8, 43.2, 42.1, 31.3, 23.2, 22.3. IR (Neat Film, NaCl) 3250, 2924, 2270, 1750, 1669, 1554, 1517, 1484, 1413, 1381, 1325, 1278, 1226,1195, 1097, 993, 334 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 867,749, 674 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C21H32FN4O4 [M+H]+: 423.2402, found 423.2393 [α]D24.0 –3.59 (c 1.0, CHCl3). H N O F I CuBr (20 mol %) BINOL (20 mol %) O N R O O Me NH K3PO4, DMF, 80 °C 24-72 h F O R F O N N O BocN N O AcCl O NH MeOH, rt 1h O HN N O O NH N-(((5S)-3-(3-fluoro-4-(6-oxa-2,9-diazaspiro[4.5]decan-9-yl)phenyl)-2-oxooxazolidin5-yl)methyl)acetamide (2.27). Prepared according to the general procedure using: CuBr (2.3 mg, 0.016 mmol, 0.2 equiv), BINOL (4.5 mg, 0.016 mmol, 0.2 equiv), aryl iodide 2.7 (30 mg, 0.079 mmol, 1 equiv), K3PO4 (34 mg, 0.16 mmol, 2 equiv), 6-oxa-2,9diazaspiro[4.5]decane (38 mg, 0.16 mmol, 2 equiv), and 400 uL DMF. The crude residue was filtered through a silica column (2 → 3 → 5 → 10% MeOH/CH2Cl2) to yield a mixture of Boc-protected spirocyclic analogue 2.15 and starting material aryl iodide 2.7, which was carried forward to the next step: To 2.3 mL MeOH at 0 °C was added AcCl (230 uL), generating HCl in situ. This HCl solution was stirred for 5 min at 0°C and then transferred by syringe into a 20 mL scintillation vial containing Boc analogue 2.15. The reaction was stirred for 1 h at ambient temperature and then the solvent was concentrated under reduced pressure onto SiO2. The silica-loaded residue was purified by silica gel flash chromatography (5 → 10 → 20% MeOH/CH2Cl2) to yield spiropyrrolidine analogue 2.27 as a light yellow oil (12 mg, 40% yield over 2 steps). 1H NMR (400 MHz, CD3OD) δ 7.53 (dd, J = 14.5, 2.5 Hz, 1H), 7.19 (ddd, J = 8.8, 2.6, 1.0 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H), 4.83 – 4.73 (m, 1H), 4.12 (t, J = 9.0 Hz, 1H), 3.94 (dd, J = 5.4, 4.3 Hz, 2H), 3.80 (dd, J = 9.2, 6.3 Hz, 1H), 3.72 (dd, J = 12.6, 1.6 Hz, 1H), 3.56 (d, J = 5.0 Hz, 2H), 3.50 – 3.40 (m, 2H), 3.26 (d, J = 12.6 Hz, 1H), 3.17 (d, J = 11.8 Hz, 1H), 3.13 – Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 335 2.97 (m, 3H), 2.42 – 2.29 (m, 1H), 2.17 – 2.00 (m, 2H), 1.96 (s, 3H); 13C NMR (101 MHz, CD3OD) δ 174.1, 156.9 (d, J = 244.3 Hz), 156.6, 137.2 (d, J = 10.1 Hz), 135.5 (d, J = 10.6 Hz), 120.7 (d, J = 4.0 Hz), 115.5 (d, J = 3.0 Hz), 108.4 (d, J = 26.3 Hz), 82.2, 73.5, 63.5, 57.5, 52.6, 51.5, 49.2, 45.3, 43.1, 34.5, 22.4 (Note: A 1H-13C HSQC experiment revealed the chemical shift of a methylene carbon to be at 49.2 ppm, obscured by MeOD resonance); IR (Neat Film, NaCl) 3287, 2924, 2282, 1754, 1667, 1548, 1516, 1415, 1377, 1325, 1278, 1226, 1083, 989, 869, 751 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C19H26FN4O4 [M+H]+: 393.1933, found 393.1937 [α]D24.2 –3.78 (c 0.5, MeOH). F O N O N N O O NH N-(((5S)-3-(3-fluoro-4-(2-methyl-6-oxa-2,9-diazaspiro[4.5]decan-9-yl)phenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.17). Prepared according to the general procedure using: CuBr (2.3 mg, 0.2 equiv), BINOL (4.6 mg, 0.2 equiv), aryl iodide 2.7 (30 mg, 1 equiv), K3PO4 (34 mg, 2 equiv), 2-methyl-6-oxa-2,9-diazaspiro[4.5]decane (SI5) (25 mg, 2 equiv), and 400 uL DMF. The crude residue was purified by silica gel flash chromatography (5 → 10 → 20 MeOH/CH2Cl2) to yield N-methyl spiropyrrolidine analogue 2.17 (15 mg, 47% yield) as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 14.1, 2.6 Hz, 1H), 7.08 (ddd, J = 8.8, 2.6, 1.1 Hz, 1H), 6.90 (t, J = 9.0 Hz, 1H), 6.05 (t, J = 6.2 Hz, 1H), 4.77 (dddd, J = 8.9, 6.7, 5.9, 3.3 Hz, 1H), 4.02 (td, J = 9.0, 0.8 Hz, 1H), 3.95 – 3.81 (m, 2H), 3.79 – 3.66 (m, 2H), 3.60 (dt, J = 14.7, 6.1 Hz, 1H), 336 Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 3.25 (s, 1H), 3.11 (d, J = 11.6 Hz, 2H), 3.01 (t, J = 10.5 Hz, 5H), 2.66 (s, 3H), 2.20 (m, 2H), 2.02 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.1, 155.8 (d, J = 246.5 Hz), 154.4, 136.0 (d, J = 9.1 Hz), 133.6 (d, J = 10.4 Hz), 119.4 (d, J = 3.7 Hz), 114.0 (d, J = 3.4 Hz), 107.6 (d, J = 26.2 Hz), 81.7, 72.0, 63.4, 62.8, 57.84, 55.0, 50.4, 47.8, 42.4, 42.1, 35.4, 23.3; IR (Neat Film, NaCl) 3264, 2925, 2283, 1747, 1666, 1516, 1444, 1377, 1325, 1225, 1082, 869, 752 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H28FN4O4 [M+H]+: 407.2089, found 407.2095; [α]D24.8 –6.65 (c 1.0, MeOH). H N O F I O O Me NH K3PO4, DMF, 80 °C 24-72 h F O N O N Boc F O N CuBr (20 mol %) BINOL (20 mol %) O N R R N O O AcCl O MeOH, rt 1h N H NH N O O NH N-(((5S)-3-(3-fluoro-4-(1-oxa-4,8-diazaspiro[5.5]undecan-4-yl)phenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.25). Prepared according to the general procedure using: CuBr (2.1 mg, 0.015 mmol, 0.2 equiv), BINOL (4.2 mg, 0.015 mmol, 0.2 equiv), aryl iodide 2.7 (28 mg, 0.074 mmol, 1 equiv), K3PO4 (31 mg, 0.15 mmol, 2 equiv), tert-butyl 1-oxa-4,8-diazaspiro[5.5]undecane-8-carboxylate (38 mg, 0.15 mmol, 2 equiv), and 370 uL DMF. The crude residue was filtered through a silica column (40% MeCN/CH2Cl2) to yield a mixture of Boc-protected spirocyclic analogue 2.16 and starting material aryl iodide 2.7, which was carried forward to the next step: To 2.2 mL MeOH at 0 °C was added AcCl (220 uL), generating HCl in situ. This HCl solution was stirred for 5 min at 0°C and then transferred by syringe into a 20 mL scintillation vial containing Boc analogue 2.16. The reaction was stirred for 1 h at ambient temperature and then the solvent was concentrated under reduced pressure onto SiO2. The silica- Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 337 loaded residue was purified by silica gel flash chromatography (1 → 2 → 5 → 10 → 100% MeOH/CH2Cl2 with 1% NH4OH) to yield spiropiperidine analogue 2.25 as a light yellow oil (12 mg, 32% yield over two steps): 1H NMR (600 MHz, CD3OD) δ 7.51 (dd, J = 14.4, 2.5 Hz, 1H), 7.18 (ddd, J = 8.8, 2.6, 1.0 Hz, 1H), 7.06 (t, J = 9.2 Hz, 1H), 4.83 – 4.77 (m, 1H), 4.14 (t, J = 9.0 Hz, 1H), 3.98 (ddd, J = 11.4, 8.0, 3.2 Hz, 1H), 3.91 (ddd, J = 11.9, 5.0, 3.4 Hz, 1H), 3.88 – 3.80 (m, 2H), 3.56 (d, J = 5.1 Hz, 2H), 3.38 – 3.32 (m, 2H), 3.13 – 3.06 (m, 1H), 3.06 – 2.97 (m, 4H), 2.86 (d, J = 12.0 Hz, 1H), 2.20 – 2.14 (m, 1H), 2.14 – 2.01 (m, 1H), 1.97 (s, 3H), 1.81 – 1.76 (m, 1H), 1.63 (td, J = 13.7, 4.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.6 (d, J = 246.3 Hz), 154.6, 136.8 (d, J = 9.0 Hz), 133.0 (d, J = 10.4 Hz), 119.2 (d, J = 5.6 Hz), 114.0 (t, J = 3.8 Hz), 107.6 (d, J = 26.1 Hz), 72.1, 69.8, 60.9, 58.5, 50.7, 47.8, 46.13, 42.1, 31.6, 29.8, 23.3, 21.3; IR (Neat Film, NaCl) 3275, 2931, 2359, 1748, 1668, 1540, 1517, 1417, 1374, 1286, 1224, 1195, 1084, 867, 732 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H28FN4O4 [M+H]+: 407.2089, found 407.2080 [α]D25.2 –5.83 (c 0.8, CHCl3). F O N O N Ac N O O NH N-(((5S)-3-(4-(8-acetyl-1-oxa-4,8-diazaspiro[5.5]undecan-4-yl)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.26). To a solution of spiropiperidine 2.25 (12 mg, 1 equiv) in MeCN was added NEt3 (12 uL, 3 equiv) followed by DMAP (0.4 mg, 0.1 equiv), and then Ac2O (4 uL, 1.5 equiv). The reaction was stirred at rt for 2 h, concentrated, and then purified by silica gel flash chromatography (2 → 5 → 10% Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 338 MeOH/CH2Cl2) to afford acetylated analogue 2.26 as a clear oil (10 mg, 77% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.42 (dddd, J = 20.9, 14.2, 2.6, 1.6 Hz, 1H), 7.05 (ttd, J = 8.8, 2.6, 1.1 Hz, 1H), 6.94 – 6.82 (m, 1H), 6.34 – 6.17 (m, 1H), 4.86 (dd, J = 14.0, 6.1 Hz, 1H), 4.81 – 4.70 (m, 1H), 4.11 (ddd, J = 12.0, 8.9, 3.0 Hz, 1H), 4.05 – 3.82 (m, 2H), 3.82 – 3.43 (m, 6H), 3.23 – 2.64 (m, 5H), 2.15 – 2.05 (m, 3H), 2.02 (s, 3H), 1.89 – 1.83 (m, 1H), 1.74 – 1.66 (m, 2H), 1.60 – 1.50 (m, 1H); 13C NMR (101 MHz, CDCl3) δ (Note: multiple peaks observed due to the presence of rotamers) 171.2, 171.2, 169.9, 169.3, 156.9, 156.8, 154.5, 154.4, 136.8, 136.7, 136.7, 136.6, 136.4, 136.3, 133.5, 133.4, 132.9, 132.8, 119.4, 119.4, 119.2, 114.0, 114.0, 113.9, 107.7, 107.6, 107.5, 107.4, 107.3, 72.0, 71.9, 71.2, 70.8, 61.6, 61.3, 58.3, 56.5, 51.4, 51.1, 51.1, 50.3, 47.7, 47.3, 45.9, 45.8, 42.3, 42.1, 42.1, 42.1, 33.1, 33.0, 23.2, 21.7, 21.4, 20.9; IR (Neat Film, NaCl) cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C22H30FN4O5 [M+H]+: 449.2195, found 449.2193 [α]D24.4 –11.08 (c 0.7, CHCl3). F O N O BnO N O O NH N-(((5S)-3-(4-(2-allyl-2-((benzyloxy)methyl)morpholino)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.14). Prepared according to the general procedure using: CuBr (2.3 mg, 0.016 mmol, 0.2 equiv), BINOL (4.5 mg, 0.016 mmol, 0.2 equiv), aryl iodide 2.7 (30 mg, 0.079 mmol, 1 equiv), K3PO4 (34 mg, 0.16 mmol, 2 equiv), benzyloxy morpholine6 (18 mg, 0.16 mmol, 2 equiv), and 400 uL DMF. The crude residue was purified by silica gel flash chromatography (2 → 3 → 5% MeOH/CH2Cl2) to yield benzyloxy analogue 2.14 (8 mg, 28% yield) as a clear oil: 1H Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 339 NMR (400 MHz, CDCl3) δ 7.46 – 7.34 (m, 1H), 7.33 (d, J = 4.4 Hz, 3H), 7.33 – 7.23 (m, 1H), 7.04 (dd, J = 8.8, 1.8 Hz, 1H), 6.88 (t, J = 9.1 Hz, 1H), 6.29 (t, J = 6.1 Hz, 1H), 5.82 (ddt, J = 17.5, 10.3, 7.3 Hz, 1H), 5.15 – 5.04 (m, 2H), 4.76 (qd, J = 7.8, 6.6, 5.0 Hz, 1H), 4.56 (s, 2H), 4.05 – 3.49 (m, 7H), 3.06 – 2.87 (m, 4H), 2.77 (dt, J = 15.0, 7.5 Hz, 1H), 2.46 (dd, J = 14.3, 7.6 Hz, 1H), 2.01 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 171.4, 155.7 (d, J = 246.7 Hz), 154.5, 138.4, 137.0 (d, J = 9.0 Hz), 133.3, 132.9 (d, J = 10.3 Hz), 128.5, 127.8, 127.7, 119.3 (d, J = 4.0 Hz), 118.3, 114.0 (d, J = 3.3 Hz), 107.6 (d, J = 26.1 Hz), 74.9, 73.7, 72.0, 71.0, 61.4, 56.1, 50.5, 47.8, 42.1, 37.2, 23.2; IR (Neat Film, NaCl) 3288, 2921, 2364, 1749, 1654, 1516, 1416, 1373, 1324, 1274, 1224, 1103, 747 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C27H33FN3O5 [M+H]+: 498.2399, found 498.2393 [α]D22.6 –3.54 (c 1.0, CHCl3). F O N O HO N O O NH N-(((5S)-3-(4-(2-allyl-2-((benzyloxy)methyl)morpholino)-3-fluorophenyl)-2oxooxazolidin-5-yl)methyl)acetamide (2.24). In a 1 dram vial open to the air, benzyloxy analogue 2.14 (20 mg, 0.04 mmol, 1 equiv) was dissolved in MeOH (400 uL, 0.1M). Pd(OH)2/C (20 wt. %, 4.2 mg, 0.006 mmol, 0.15 equiv) was then added. The vial was then sealed with a septum cap and evacuated and filled using a balloon containing H2 three times. The solvent was then sparged with H2 for 5 min and stirred for 16 h until TLC analysis showed the starting material had been consumed. The Pd(OH)2/C was filtered off using a Celite plug and rinsed with EtOAc. The solvent was concentrated Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 340 under reduced pressure onto SiO2. The silica-loaded residue was purified by silica gel flash chromatography (2 → 3 → 10% MeOH/CH2Cl2) to yield hydroxyl analogue 2.24 (14 mg, 88% yield) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.42 (dt, J = 14.1, 2.4 Hz, 1H), 7.05 (dtd, J = 8.9, 2.4, 1.1 Hz, 1H), 6.90 (t, J = 9.1 Hz, 1H), 6.27 (t, J = 6.3 Hz, 1H), 4.77 (dddd, J = 8.9, 6.7, 5.6, 3.3 Hz, 1H), 4.01 (t, J = 9.0 Hz, 1H), 3.92 (t, J = 4.9 Hz, 2H), 3.79 – 3.70 (m, 2H), 3.74 – 3.63 (m, 2H), 3.61 (dt, J = 14.7, 6.0 Hz, 1H), 3.07 – 2.97 (m, 2H), 2.99 – 2.85 (m, 2H), 2.02 (s, 3H), 1.83 (ddd, J = 14.0, 11.6, 5.6 Hz, 1H), 1.60 (ddd, J = 14.0, 11.1, 5.8 Hz, 1H), 1.44 – 1.21 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.7 (d, J = 246.4 Hz), 154.5, 136.9 (d, J = 9.1 Hz), 133.1 (d, J = 10.4 Hz), 119.3 (d, J = 4.0 Hz), 114.0 (d, J = 2.5 Hz), 107.6 (d, J = 26.2 Hz), 75.3, 72.0, 64.8, 61.42, 55.4, 50.4, 47.8, 42.1, 35.3, 23.3, 16.4, 14.9; IR (Neat Film, NaCl) 3316, 2957, 1747,1659, 1547, 1516, 1416, 1375, 1268, 1229, 1090, 743 cm-1; HRMS (MM: ESI-APCI) m/z calc’d for C20H29FN3O5 [M+H]+: 410.2086, found 410.2086 [α]D22.3 –11.50 (c 1.0, CHCl3). 2.5 (1) REFERENCES AND NOTES Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52 (21), 6752–6756. (2) Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. Med. Chem. Commun. 2013, 4 (3), 515–519. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid (3) 341 Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57 (24), 10257–10274. (4) Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; et al. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074– D1082. (5) Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by PalladiumCatalysed Decarboxylative Allylic Alkylation of Lactams. Nature Chemistry 2012, 4 (2), 130–133. (6) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Enantioselective Synthesis of Dialkylated N -Heterocycles by PalladiumCatalyzed Allylic Alkylation. Org. Lett. 2015, 17 (5), 1082–1085. (7) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-Ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 54 (1), 179–183. (8) Sun, A. W.; Hess, S. N.; Stoltz, B. M. Enantioselective Synthesis of GemDisubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation. Chem. Sci. 2019, 10, 788–792. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid (9) 342 Swaney, S. M.; Aoki, H.; Ganoza, M. C.; Shinabarger, D. L. The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria. Antimicrobial Agents and Chemotherapy 1998, 42 (12), 3251–3255. (10) Ender, M.; McCallum, N.; Adhikari, R.; Berger-Bächi, B. Fitness Cost of SCCmec and Methicillin Resistance Levels in Staphylococcus Aureus. Antimicrob. Agents Chemother. 2004, 48, 2295–2297. (11) Gonzales, R. D.; Schreckenberger, P. C.; Graham, M. B.; Kelkar, S.; DenBesten, K.; Quinn, J. P. Infections Due to Vancomycin-Resistant Enterococcus Faecium Resistant to Linezolid. The Lancet 2001, 357 (9263), 1179. (12) Schecter, G. F.; Scott, C.; True, L.; Raftery, A.; Flood, J.; Mase, S. Linezolid in the Treatment of Multidrug-Resistant Tuberculosis. Clin Infect Dis 2010, 50 (1), 49–55. (13) Leach, K. L.; Swaney, S. M.; Colca, J. R.; McDonald, W. G.; Blinn, J. R.; Thomasco, L. M.; Gadwood, R. C.; Shinabarger, D.; Xiong, L.; Mankin, A. S. The Site of Action of Oxazolidinone Antibiotics in Living Bacteria and in Human Mitochondria. Molecular Cell 2007, 26 (3), 393–402. (14) Sharma, M. R.; Koc, E. C.; Datta, P. P.; Booth, T. M.; Spremulli, L. L.; Agrawal, R. K. Structure of the Mammalian Mitochondrial Ribosome Reveals an Expanded Functional Role for Its Component Proteins. Cell 2003, 115 (1), 97–108. (15) Narita, M.; Tsuji, B. T.; Yu, V. L. Linezolid-Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome. Pharmacotherapy 2007, 27, 1189–1197. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid (16) 343 Duewelhenke, N.; Krut, O.; Eysel, P. Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines. Antimicrob. Agents Chemother. 2007, 51, 54–63. (17) Li, C.-H.; Cheng, Y.-W.; Liao, P.-L.; Yang, Y.-T.; Kang, J.-J. Chloramphenicol Causes Mitochondrial Stress, Decreases ATP Biosynthesis, Induces Matrix Metalloproteinase-13 Expression, and Solid-Tumor Cell Invasion. Toxicol Sci 2010, 116 (1), 140–150. (18) Shaw, K. J.; Barbachyn, M. R. The Oxazolidinones: Past, Present, and Future. Ann. N. Y. Acad. Sci. 2011, 1241, 48–70. (19) McKee, E. E.; Ferguson, M.; Bentley, A. T.; Marks, T. A. Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones. Antimicrob. Agents Chemother. 2006, 50 (6), 2042–2049. (20) Ippolito, J. A.; Kanyo, Z. F.; Wang, D.; Franceschi, F. J.; Moore, P. B.; Steitz, T. A.; Duffy, E. M. Crystal Structure of the Oxazolidinone Antibiotic Linezolid Bound to the 50S Ribosomal Subunit. J. Med. Chem. 2008, 51 (12), 3353–3356. (21) Imbordino, R.; Perrault, W.; Reeder, M. Process for Preparing Linezolid. WO/2007/116284, October 19, 2007. (22) Yang, B.; Shi, L.; Wu, J.; Fang, X.; Yang, X.; Wu, F. Microwave-Assisted Expeditious Synthesis of 5-Fluoroalkyl-3-(Aryl/Alkyl)-Oxazolidin-2-Ones. Tetrahedron 2013, 69 (15), 3331–3337. (23) Mahy, W.; Leitch, J. A.; Frost, C. G. Copper Catalyzed Assembly of NAryloxazolidinones: Synthesis of Linezolid, Tedizolid, and Rivaroxaban. Eur. J. Org. Chem. 2016 (7), 1305–1313. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid (24) 344 McCarthy, J. R. A Convenient Synthesis of the Antibacterial Agent Linezolid. Tetrahedron Lett. 2015, 56 (49), 6846–6847. (25) Im, W. B.; Choi, S. H.; Park, J.-Y.; Choi, S. H.; Finn, J.; Yoon, S.-H. Discovery of Torezolid as a Novel 5-Hydroxymethyl-Oxazolidinone Antibacterial Agent. Eur. J. Med. Chem. 2011, 46 (4), 1027–1039. (26) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; et al. The Synthesis of N-Aryl-5(S)-Aminomethyl-2-Oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates. Org. Process Res. Dev. 2003, 7 (4), 533–546. (27) Spaulding, A.; Takrouri, K.; Mahalingam, P.; Cleary, D. C.; Cooper, H. D.; Zucchi, P.; Tear, W.; Koleva, B.; Beuning, P. J.; Hirsch, E. B.; et al. Compound Design Guidelines for Evading the Efflux and Permeation Barriers of Escherichia Coli with the Oxazolidinone Class of Antibacterials: Test Case for a General Approach to Improving Whole Cell Gram-Negative Activity. Bioorg. Med. Chem. Lett. 2017, 27, 5310–5321. (28) Marziale, A. N.; Duquette, D. C.; Craig, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst. Adv. Synth. Cat. 2015, 357, 2238–2245. (29) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126 , 15044–15045. Chapter 2 – gem-Disubstituted Morpholine Analogues of Linezolid 345 (30) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. A Facile and Modular Synthesis of Phosphinooxazoline Ligands. Org. Lett. 2007, 9, 2529–2531. Appendix 6 – Spectra Relevant to Chapter 2 346 APPENDIX 6 Spectra Relevant to Chapter 2: gem-Disubstituted Morpholine Analogues of Linezolid Figure A6.1 1H NMR (400 MHz, CDCl3) of compound 2.5 Appendix 6 - Spectra Relevant to Chapter 2 347 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.2 Infrared spectrum (Thin Film, NaCl) of compound 2.5 Figure A6.3 13C NMR (101 MHz, CDCl3) of compound 2.5 348 Figure A6.4 1H NMR (600 MHz, CDCl3) of compound 2.10. Appendix 6 - Spectra Relevant to Chapter 2 349 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.5 Infrared spectrum (Thin Film, NaCl) of compound 2.10. Figure A6.6 13C NMR (101 MHz, CDCl3) of compound 2.10. 350 Figure A6.7 1H NMR (400 MHz, CDCl3) of compound 2.12 Appendix 6 - Spectra Relevant to Chapter 2 351 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 2.12. Figure A6.9 13C NMR (101 MHz, CDCl3) of compound 2.12. 352 Figure A6.10 1 H NMR (400 MHz, CDCl3) of compound 2.13. Appendix 6 - Spectra Relevant to Chapter 2 353 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 2.13. Figure A6.12 13C NMR (101 MHz, CDCl3) of compound 2.13. 354 Figure A6.13 1 H NMR (400 MHz, CDCl3) of compound 2.14. Appendix 6 - Spectra Relevant to Chapter 2 355 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 2.14. Figure A6.15 13 C NMR (101 MHz, CDCl3) of compound 2.14. 356 Figure A6.16 1 H NMR (400 MHz, CDCl3) of compound 2.17. Appendix 6 - Spectra Relevant to Chapter 2 357 Appendix 6 - Spectra Relevant to Chapter 2 358 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 2.17 Figure A6.18 13 C NMR (101 MHz, CDCl3) of compound 2.17 Figure A6.19 1 H NMR (400 MHz, CDCl3) of compound 2.18. Appendix 6 - Spectra Relevant to Chapter 2 359 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.20 Figure A6.21 Infrared spectrum (Thin Film, NaCl) of compound 2.18 13 C NMR (101 MHz, CDCl3) of compound 2.18. 360 Figure A6.22 1 H NMR (400 MHz, CDCl3) of compound 2.19a. Appendix 6 - Spectra Relevant to Chapter 2 361 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 2.19a. Figure A6.21 13 C NMR (101 MHz, CDCl3) of compound 2.19a. 362 Figure A6.25 1 H NMR (400 MHz, CDCl3) of compound 2.19b. Appendix 6 - Spectra Relevant to Chapter 2 363 Appendix 6 - Spectra Relevant to Chapter 2 364 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 2.19b. Figure A6.27 13C NMR (101 MHz, CDCl3) of compound 2.19b. Figure A6.28 1 H NMR (400 MHz, CDCl3) of compound 2.21. Appendix 6 - Spectra Relevant to Chapter 2 365 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 2.21. Figure A6.30 13C NMR (101 MHz, CDCl3) of compound 2.21. 366 Figure A6.31 1H NMR (400 MHz, CDCl3) of compound 2.22. Appendix 6 - Spectra Relevant to Chapter 2 367 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 2.22. Figure A6.33 13C NMR (101 MHz, CDCl3) of compound 2.22. 368 Figure A6.34 1H NMR (600 MHz, CDCl3) of compound 2.23. Appendix 6 - Spectra Relevant to Chapter 2 369 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.35 Infrared spectrum (Thin Film, NaCl) of compound 2.23. Figure A6.36 13C NMR (101 MHz, CDCl3) of compound 2.23. 370 Figure A6.37 1H NMR (400 MHz, CDCl3) of compound 2.24. Appendix 6 - Spectra Relevant to Chapter 2 371 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.38 Infrared spectrum (Thin Film, NaCl) of compound 2.24. Figure A6.39 13C NMR (101 MHz, CDCl3) of compound 2.24. 372 Figure A6.40 1H NMR (600 MHz, CD3OD) of compound 2.25. Appendix 6 - Spectra Relevant to Chapter 2 373 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.41 Infrared spectrum (Thin Film, NaCl) of compound 2.25. Figure A6.42 13 C NMR (101 MHz, CDCl3) of compound 2.25. 374 Figure A6.43 1 H NMR (400 MHz, CDCl3) of compound 2.26. Appendix 6 - Spectra Relevant to Chapter 2 375 Appendix 6 - Spectra Relevant to Chapter 2 376 Figure A6.44 Infrared spectrum (Thin Film, NaCl) of compound 2.26. Figure A6.45 13 C NMR (101 MHz, CDCl3) of compound 2.26. Figure A6.46 1H NMR (400 MHz, CD3OD) of compound 2.27. Appendix 6 - Spectra Relevant to Chapter 2 377 Appendix 6 - Spectra Relevant to Chapter 2 378 Figure A6.47 Infrared spectrum (Thin Film, NaCl) of compound 2.27. Figure A6.48 13 C NMR (101 MHz, CD3OD) of compound 2.27. Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.49 HSQC of compound 2.27 revealing one peak obscured by CD3OD. 379 Figure A6.50 1 H NMR (400 MHz, CDCl3) of compound SI3a. Appendix 6 - Spectra Relevant to Chapter 2 380 Figure A6.51 13C NMR (101 MHz, CDCl3) of compound SI3a. Appendix 6 - Spectra Relevant to Chapter 2 381 Figure A6.52 1H NMR (400 MHz, CDCl3) of compound SI4. Appendix 6 - Spectra Relevant to Chapter 2 382 Appendix 6 - Spectra Relevant to Chapter 2 Figure A6.53 Infrared spectrum (Thin Film, NaCl) of compound SI4. Figure A6.54 13C NMR (101 MHz, CDCl3) of compound SI4. 383 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 384 APPENDIX 7 Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols A7.1 INTRODUCTION AND BACKGROUND Enantioenriched tertiary alcohols are valuable motifs found in myriad bioactive natural products and pharmaceuticals, such as the alkaloid chemotherapeutic (−)vinblastine1 and the neurotrophic sesquiterpene (+)-jiadifenin2 (Figure A7.1). Due to the molecular prevalence of chiral tertiary alcohols, diverse methods3 have been developed to enable the stereoselective α-hydroxylation of a wide range of carbonyl compounds, including acyclic compounds,4,5,6 oxindoles,7,8 pyrazolones,9 and cycloalkanones10 (Scheme A7.1). Aside from chiral oxidants such as oxaziridines introduced during Davis’s pivotal 1981 studies,11 α -hydroxylation methods can be broadly categorized under either transition metal catalysis or organic catalysis. In the realm of organic catalysis, a number of terminal oxidants have been coupled with structurally diverse chiral organic catalysts such BINOL-derived phosphoric acids,12 guanidine- bisureas,13,14,15 cinchona alkaloids,6,9 aminobenzamides,5 and photocatalysts composed of a bisoxazoline-diarylketone photosensitizer conjugate16 (Scheme A7.1a). Similarly, Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 385 numerous chiral transition metal complexes also facilitate -hydroxylation,3 including systems such as Cu-phenanthroline,17 Zr-Salen,10 and Ti-TADDOLato.18 Contrasting with these traditional enantioselective hydroxylation methods, in which the hydroxyl group is introduced in the enantiodetermining step, is a conceptually unique approach involving allylic alkylation of α -hydroxy compounds. In this case, alkylation of a prochiral hydroxyenolate would engender stereoselectivity. Of particular interest to our group were initial reports by Trost19,20 utilizing a Pd-catalyzed decarboxylative allylic alkylation protocol to synthesize protected tertiary α -hydroxy ketones and aldehydes (Scheme A7.1b). Trost found that depending on the choice of bisphosphine ligand, isomeric products A7.3 or A7.4 could be almost exclusively attained. Later, Trost21 again reported a decarboxylative alkylation approach toward the synthesis of MOM-protected tetralones (Scheme A7.1c). However, no examples of unprotected alcohols were shown. In a more recent 2017 advance, Zhang22 demonstrated that a dual catalyst system involving Trost’s Zn/ProPhenol system and an Ir catalyst could effect the C-alkylation of unprotected alcohols (Scheme A7.1d). It was hypothesized that the bidentate/ η 2 binding mode of the Zn catalyst reduced the nucleophilicity of the hydroxyl group, precluding O-allylation pathways. Most recently, Zhang8 utilized a single iridium-phosphoramidite catalyst in the asymmetric allylic alkylation of oxindoles, showing the Zn/ProPhenol partner was not needed. We wondered if subjecting similar tertiary alcohols to decarboxylative allylic alkylation conditions using a simple single catalyst system consisting of Pd-PHOX could likewise enable effective C-alkylation (Scheme A7.1e). Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 386 Scheme A7.1 Approaches toward tertiary α-hydroxy carbonyl compounds a) Traditional methods toward chiral alpha tertiary compounds O O Transition metal cat. or Organocatalyst R OH R Oxidant b) Decarboxylative alkylation of protected allyl enol carbonates (Trost) Pd/Trost L OCO2Allyl Ph O OR OR O Ph or OR Ph R = TBS, Bz, Ac c) Synthesis of protected chiral alpha tertiary hydroxylated tetralones (Trost) OCO2Allyl O OMOM Pd/Trost L R1 OMOM R1 85-96% ee d) Allylic alkylation of alpha hydroxy indanones (Zhang) R2 O OCO2Me O OH R2 Zn/ProPhenol OH R1 Ir/Phosphoramidite L R1 Up to 99% ee, >20:1 dr e) Decarboxylative alkylation of cyclic carbonyl compounds (this research) O O OH O X n O X = NBz, CH2 n = 1, 2, 3 Pd/L OH X n X = NBz, CH2 n = 1, 2, 3 Our investigations were stimulated by an unexpected result23 during the course of our studies on the decarboxylative allylic alkylation of N4-Boc piperazinones, in which we were pleased to obtain α-fluorinated substrate A7.1 via electrophilic fluorination of the 1,3 dicarbonyl precursor (Scheme A7.2). However, upon subjecting A7.1 to the optimized Pd-catalyzed alkylation conditions, the α-tertiary hydroxypiperazinone A7.2 was instead obtained in a moderate 50% yield and 77% ee. The presence of adventitious water could produce this unexpected result; if fluoride anion is eliminated during the course of the reaction, water could attack the resulting iminium species before allylation occurs. 387 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols To extend upon this finding, we began by exploring the decarboxylative alkylation of tetralone A7.3 (Table A7.1). Upon subjecting A7.3 to standard Pd-catalyzed decarboxylative alkylation conditions using electron-deficient PHOX ligand L1, a 5/1 mixture of the desired product A7.4a and the isomer A7.4b were obtained, both with low ee. In contrast, the more electron-rich PHOX ligand L2 increased the proportion of isomer A7.4b (1/3.6), with an improved ee of 68% for A7.4a. The bisphosphine ligands L3 and L4 provided even more of the isomer A7.4b, with ratios of 1/25 and 1/24, respectively. Interestingly, A7.4b was attained with an ee of 98% using L3. Scheme A7.2 Unexpected formation of a tertiary alcohol O O F BzN O NBoc O Pd2(dba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %) OH BzN 2:1 hexanes/toluene 40 °C NBoc A7.2 A7.1 50% yield 77% ee Table A7.1 Attempts to optimize reaction conditions for model substrate A7.3 O O OH Pd2(pmdba)3 (4 mol %) Ligand (10 mol %) O O OH OH O PhMe (0.033 M) temp, 12 h A7.4a A7.3 A7.4b No O-allylation observed X Entry Ligand Ratio A7.4a/4b (Yield %) a,b ee A7.4a (%) c ee A7.4b (%) 1 L1 5/1 (50) 40 10 2 L2 1/3.6 (61) 68 10 3 L3 1/25 (76) 1 98 4 L4 1/24 (75) 4 20 c 388 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols CF3 O O N P F3C N P CF3 (S)-L1 O (S)-L2 O O O NH HN NH HN PPh2Ph2P PPhPh 2 2P (S,S)-L3 (S,S)-L4 [a] Ratio determined by 400 MHz 1H NMR spectroscopy of the purified mixture. [b] Isolated yield for the mixture of A7.4a and A7.4b. [c] The ee values were determined by chiral SFC analysis. pmdba = bis(4-methoxybenzylidene)acetone We then subjected the isomeric tetralone substrate A7.5 to allylic alkylation conditions with ligands L1 and L3, achieving product ratios of 1.4/1 and <1/25, respectively (Table A7.2). Together, these results suggest there is an equilibration of Pdbound enolates leading to the observed ratios of products. Table A7.2 Investigation into reaction outcomes for isomeric tetralone A7.5 O O O OH Pd2(pmdba)3 (4 mol%) Ligand(10 mol%) O PhMe (0.033 M) rt, 12 h A7.5 Entry Ligand 1 2 OH OH O A7.4b A7.4a c Ratio A7.4a/4b (Yield a,b %) ee A7.4a (%) ee A7.4b (%) L1 1.4/1 (70) 86 1 L3 <1/25 (65) − 10 c [a] Ratio determined by 400 MHz 1H NMR spectroscopy of the purified mixture. [b] Isolated yield for the mixture of 4a and 4b. [c] The ee values were determined by chiral SFC analysis. We can rationalize these results with a relative rate argument considering the rate of alkylation versus equilibration of Pd-bound hydroxyenolates I and II (Scheme A7.3): If equilibration is faster than alkylation, as may be the case with electron rich ligands L3 and L4, then more of the isomer A7.4b should be formed as intermediate II is more stable both electronically and sterically. In contrast, if alkylation is faster than equilibration, as may be the case for the electron deficient PHOX ligand L1, then A7.3 should lead to proportionally more desired isomer A7.4a, and A7.5 should lead to more A7.4b. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 389 Scheme A7.3 Mechanistic rationale for formation of isomeric tetralone products O P OH CO2Allyl O N O Pd -CO2 A7.3 OH OH Pd/L A7.4a I P AllylO2C OH O OH Pd/L N OH Pd O O -CO2 A7.4b A7.5 II Thermodynamic As mixtures of isomeric products may be uniquely obtained in unsaturated αhydroxy systems such as tetralones, we elected to examine simpler carbocyclic substrates, beginning with cyclohexanone A7.6a (Table A7.3). Of the previously utilized ligands, the electron deficient L1 provided the best results, affording tertiary alcohol A7.7a in a moderate 70% ee. Similarly, a methallyl variant A7.7b and cycloheptanone A7.7c were also attained in modest ee. The cyclopentanone A7.7d was obtained in a disappointing 30% ee, suggesting significant influence of conformation on stereoselectivity. In contrast, we were excited to obtain the novel tertiary αhydroxypiperidinone A7.7e in 92% ee. Hydroxylactam A7.7e represents an oxidized derivative of the medicinally prevalent 3-hydroxypiperidine, which is found in pharmaceuticals like the chemotherapeutic vinblastine and the antihypertensive agent Benidipine.24 Unfortunately, a variety of other heterocyclic substrates including piperazinones, caprolactams, and pyrrolidines, were unreactive under these Pd-catalyzed conditions. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 390 Table A7.3 Decarboxylative alkylation of α-hydroxyl dicarbonyl compoundsa O O OH R1 N O Pd2(dba)3 (4 mol %) L1 (10 mol %) O R2 A7.6a-e O toluene (0.033 M) rt or 40 °C O OH A7.7a 85% yield d 70% ee O OH OH A7.7b b 84% yield d 75% ee O OH R1 N R2 A7.7a-e O HO A7.7c b 75% yield d 78% ee b OH BzN A7.7d 73% yield d 30% ee A7.7e b c 79% yield e 92% ee c [a] Reported yields are for the isolated products. [b] Reaction performed at rt. [c] Reaction performed at 40 °C. [d] ee value determined by chiral GC analysis. [e] ee value determined by chiral SFC analysis. dba = dibenzylideneacetone. Encouraged by these results, we next explored whether a primary hydroxyl group could be tolerated in the Pd-catalyzed decarboxylative alkylation conditions (Scheme A7.4). Our initial test substrate A7.8 was amenable using L3 to provide the desired primary hydroxyl product A7.9 in moderate yield and an ee of 93%. Unfortunately, a variety of other primary alcohol substrates including lactams, and carbocyclic motifs were either unreactive, or provided a low-yielding mixture of β-elimination and protonation products. 391 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols Scheme A7.4 Decarboxylative alkylation of a primary alcohol.a,b O OH O O O toluene (0.033 M) rt A7.8 OH Pd2(dba)3 (4 mol %) (S,S)-L3 (10 mol %) A7.9 63% yielda 93% eeb [a] Reported yield is for the isolated product. [b] ee value determined by chiral SFC analysis. A7.2 CONCLUSIONS In summary, we report initial results using the decarboxylative allylic alkylation reaction to synthesize chiral tertiary α-hydroxy compounds. While a novel tertiary hydroxypiperidinone was obtained in high ee, other carbocyclic compounds still require optimization with an appropriate catalyst-ligand combination. Nevertheless, this research provides proof of concept that Pd-catalysts are effective in the decarboxylative Calkylation of unprotected alcohol-containing substrates and can lead to high yield and high enantioselectivities in certain limited cases. A7.3 EXPERIMENTAL SECTION A7.3.1 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 Sigma Aldrich/Strem/Alfa Aesar/Combi-Blocks and used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Glove box manipulations were performed under a nitrogen atmosphere. Thin-layer Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 392 chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, iodine on silica, or KMnO4 staining. SiliaFlash P60 Academic Silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. 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. Automated silica gel flash chromatography was performed with a Teledyne ISCO CombiFlash EZ Prep system. 1 H NMR spectra were recorded on a Varian Inova 600 MHz or 500 MHz spectrometer or 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 Varian Inova 500 MHz spectrometer or 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 water (δ 1.56 or 4.87 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 an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 393 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). Stereochemistry is assigned by analogy to previous results.1 A7.3.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA A7.3.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Tertiary Alcohol Allylic Alkylation Substrates and Corresponding Decarboxylative Alkylation Products A) General Procedure for synthesis of allylic alkylation substrates using CeCl3-7H2O A solution of the β-ketoester (1 equiv) and CeCl3-7H2O (0.05 equiv) in iPrOH (0.1 M) was evacuated and filled with O2 three times. The solution was stirred at room temperature, changing color from light yellow to dark yellow/dark green over the course of the reaction. When TLC analysis showed the starting material had been completely consumed, the solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography to afford the desired alcohol. B) General Procedure for synthesis of allylic alkylation substrates using samarium(III) trifluoromethanesulfonate To an orange solution of iodine (0.02 equiv) and samarium (III) triflate (0.05 equiv) in a 1:5 mixture of H2O/THF (0.1 M) was added the β-ketoester substrate (1 equiv). The Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 394 solution was evacuated and filled with O2 three times, sparged with O2 for 5 minutes, and then allowed to stir until TLC analysis showed the starting material had been completely consumed. If the orange color faded to yellow, then another bolus of iodine was added iodine (0.02 equiv) as needed to restore the orange color. The reaction was then quenched with sodium thiosulfate and extracted with EtOAc (3x). NaCl was added to clear the emulsion formed during extraction. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure onto silica gel, and purified by silica gel flash chromatography to afford the desired alcohol. C) General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions Please note Racemic products were synthesized according to the general procedure, using achiral GlyPHOX ligand instead of a chiral ligand.3 The absolute configuration for all other products has been inferred by analogy.1 SFC and chiral GC conditions are listed at the end of the experimental procedure for each compound. In a nitrogen-filled glovebox, an oven-dried 1 dram vial or 20 mL scintillation vial was charged with Pd2(pmdba)3 or Pd2(dba)3 (4 mol %), ligand (10 mol %), toluene, and a magnetic stir bar. The vial was stirred at ambient glovebox temperature (27 °C) for 30 min and then the substrate (1.0 equiv) was added as a solution in toluene (total concentration 0.033 M). The vial was sealed with a teflon cap stirred at ambient temperature or at 40 °C. When complete consumption of the starting material was observed by thin layer chromatography, the reaction mixture was removed from the glovebox and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the desired tertiary hydroxyl product. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols O F 395 O BzN O NBoc 2-allyl 1-(tert-butyl) 4-benzoyl-2-fluoro-3-oxopiperazine-1,2-dicarboxylate (A7.1). Sodium hydride (60% in mineral oil, 11 mg, 0.28 mmol, 1.1 equiv) was added to a solution of 2-allyl 1-(tert-butyl) 4-benzoyl-3-oxopiperazine-1,2-dicarboxylate4Ref (100 mg, 0.26 mmol, 1.0 equiv) in THF (0.1 M) at 0 °C. After stirring for 30 min at 0 °C, Selectfluor (109 mg, 0.31 mmol, 1.2 equiv) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure onto silica gel. After purification by silica gel flash chromatography (Et2O/toluene 3% → 5%), the fluorinated ester A7.2 was isolated as a colorless oil (70 mg, 67% yield): 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.48 (m, 3H), 7.48 – 7.29 (m, 2H), 5.93 (ddt, J = 17.3, 10.4, 5.9 Hz, 1H), 5.46 – 5.21 (m, 2H), 4.84 – 4.63 (m, 2H), 4.21 (m, 1H), 4.15 – 3.92 (m, 2H), 3.83 (m, 1H), 1.49 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 171.7, 163.3 (d, JCF = 36 Hz), 162.5 (d, JCF = 29 Hz), 152.5, 133.8, 132.9, 130.9, 128.5, 128.2, 119.9, 95.4 (d, JCF = 227 Hz), 84.7, 67.7, 42.9, 41.2, 28.1; IR (Neat Film, NaCl) 3426, 3064, 2982, 2936, 1787, 1724, 1704, 1651, 1600, 1584, 1451, 1382, 1368, 1359, 1322, 1274, 1233, 1157, 1082, 1045, 1012, 993, 942, 849, 800, 774, 756, 725, 696, 624 cm-1; HRMS (MM: ESI-APCI) m/z calculated for [C20H27FN3O6] ([M+NH4]+): 424.1878, found 424.1865. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols O 396 OH BzN NBoc tert-butyl (R)-2-allyl-4-benzoyl-2-hydroxy-3-oxopiperazine-1-carboxylate (A7.2). Following general procedure B, fluorinated allyl ester A7.1 (10 mg, 0.025 mmol, 1.0 equiv) in hexanes/toluene (2:1, 1.3 mL) was added to a solution of Pd2(dba)3 (0.9 mg, 0.0098 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (1.5 mg, 0.0025 mmol, 10 mol %) in hexanes/toluene (2:1, 0.5 mL). The reaction was stirred at 40 °C for 16 h. Purification by flash chromatography (10 → 15% EtOAc/hexanes) gave hydroxypiperazinone A7.2 as a yellow oil (5 mg, 50% yield, 77% ee): 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.58 (m, 2H), 7.58 – 7.48 (m, 1H), 7.41 (dd, J = 8.3, 6.9 Hz, 2H), 5.74 (ddt, J = 17.5, 10.2, 7.4 Hz, 1H), 5.28 – 5.08 (m, 3H), 4.00 (t, J = 4.0 Hz, 2H), 3.86 (ddt, J = 11.0, 7.8, 3.9 Hz, 1H), 3.62 (dt, J = 13.9, 5.6 Hz, 1H), 3.2 (dd, J = 13.7, 7.2 Hz, 1H), 3.06 (dd, J = 13.7 fHz, 7.5 Hz, 1H), 1.54 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.3, 169.8, 154.5, 134.8, 132.2, 131.6, 128.4, 128.2, 120.4, 88.1, 82.6, 43.8, 42.4, 42.1, 28.5; IR (Neat Film, NaCl) 3375, 2978, 1714, 1600, 1513, 1394, 1368, 1253, 1172, 1028, 987, 833, 735 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C19H25N2O5 [M+H]+: 361.1758, found 361.1751; [α]D23.4 +5.2 (c 0.33, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 5.069, minor = 4.221. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols O 397 O OH O allyl 2-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (A7.3). Following general procedure B: to a solution of iodine (11 mg, 0.04 mmol, 0.02 equiv) and samarium (III) triflate (65 mg, 0.11 mmol, 0.05 equiv) in a 1:5 mixture of H2O/THF (24 mL) was added allyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (500 mg, 2.17 mmol, 1 equiv). The reaction was stirred for 72 h. Purification by silica gel flash chromatography (20 → 30% EtOAc/hexanes) afforded alcohol A7.3 as a clear oil (450 mg, 84% yield): 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 7.8, 1.6 Hz, 1H), 7.51 (ddd, J = 9.1, 6.6, 1.6 Hz, 1H), 7.32 (td, J = 7.2, 6.6, 1.6 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.80 (ddtd, J = 16.6, 11.0, 5.6, 1.5 Hz, 1H), 5.23 – 5.08 (m, 2H), 4.62 (d, J = 5.4 Hz, 2H), 4.39 (s, 1H), 3.10 (d, J = 5.6 Hz, 2H), 2.71 (ddd, J = 13.7, 6.0, 4.3 Hz, 1H), 2.24 (ddd, J = 13.6, 8.5, 6.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 194.5, 170.4, 144.0, 134.5, 131.1, Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 398 130.3, 129.0, 128.2, 127.2, 127.0, 118.7, 77.8, 66.4, 32.7, 30.2, 25.6; IR (Neat Film, NaCl) 3466, 3073, 3026, 2939, 1745 1689, 1649, 1602,1485, 1456, 1377, 1333, 1292, 1239, 1191, 1159, 1139, 1109, 1035, 996, 970, 944, 919, 806, 744, 690, 661 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for [C14H15O4] ([M+H]+): 247.0965, found 247.0965. O Diallyl O carbonate THF, NaH rt O O O OH O CeCl3/O2 O iPrOH 5 allyl 1-hydroxy-2-oxo-1,2,3,4-tetrahydronaphthalene-1-carboxylate (A7.5). To a suspension of NaH (60% in mineral oil, 684 mg, 17.1 mmol, 2.5 equiv) in THF (20 mL) at 0 °C was added 2-tetralone (1g, 6.84 mmol, 1 equiv) dropwise, producing a yellowgreen solution. The solution was stirred for 30 min at 0 °C before adding diallyl carbonate (1.47 mL, 10.3 mmol, 1.5 equiv) dropwise. The reaction was heated to reflux for 16 h, resulting in a dark orange-gold color. The reaction was quenched with aq. NH4Cl (20 mL) and then extracted with EtOAc (3x15 mL). The combined organic layers were dried with Na2SO4 and then concentrated under reduced pressure. Purification of the crude reaction mixture with silica gel flash chromatography (0 → 2.5 → 4% EtOAc/hexanes) afforded the intermediate allyl β-ketoester, which was then used in the following hydroxylation reaction following general procedure A: a solution of the βketoester (400 mg, 1.74 mmol, 1 equiv) and CeCl3-7H2O (32 mg, 0.087 mmol, 0.05 equiv) in iPrOH (17 mL, 0.1 M) was evacuated and filled with O2 three times. The solution was stirred for 6 h at room temperature, changing color from light yellow to dark Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 399 yellow over the course of the reaction. The solvent was removed under reduced pressure and the crude product was purified by silica gel Teledyne ISCO automated flash chromatography (0 → 50% Et2O/hexanes) to afford alcohol A7.5 as a clear oil (200 mg, 47% yield): 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.60 (m, 1H), 7.38 – 7.27 (m, 2H), 7.27 – 7.17 (m, 1H), 5.80 (ddt, J = 17.0, 10.6, 5.6 Hz, 1H), 5.23 – 5.16 (m, 1H), 5.15 (dq, J = 12.9, 1.6 Hz, 1H), 4.61 (t, J = 1.4 Hz, 1H), 4.60 – 4.57 (m, 2H), 3.40 – 3.27 (m, 1H), 3.14 – 2.99 (m, 2H), 2.74 – 2.59 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 206.9, 169.1, 136.0, 134.6, 130.9, 129.0, 128.0, 127.5, 126.5, 119.1, 79.8, 66.8, 34.6, 27.5; IR (Neat Film, NaCl) 3455, 3071, 3026, 2946, 1748, 1727, 1651, 1484, 1455, 1360, 1245, 1209, 1160, 1122, 1070, 1025, 990, 944, 749, 651 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for [C14H18NO4] ([M+NH4]+): 264.1230, found 264.1228. O OH OH O + 4a 4b Following general procedure B, tetralone A7.3 or A7.5 (20 mg, 0.081 mmol, 1 equiv) in toluene (2.0 mL) was added to a solution of Pd2(pmdba)3 (3.6 mg, 0.0032 mmol, 4 mol %) and ANDEN (S,S)-L3 (6.6 mg, 0.008 mmol, 10 mol %) or (S)-L1 (4.8 mg, 0.008 mmol, 10 mol %) in toluene (0.5 mL). Purification by silica gel flash chromatography (15% EtOAc/hexanes) gave α-tertiary tetralones A7.4a and A7.4b as a mixture, the ratio of which was determined by 1H NMR. Product identities of A7.4a and A7.4b were confirmed by comparison to previously reported characterization data. SFC conditions: 7% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): For 4b: major = 3.664, minor not detected. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 400 Note: Based on relative retention times, ANDEN (S,S)-L3 gives the opposite enantiomer of the product 4b compared to (S)-L1 and (S)-L2, [(S)-t-BuPHOX/(S)-CF3-t-BuPHOX]. O O OH O allyl 1-hydroxy-2-oxocyclohexane-1-carboxylate A7.6a. A solution of allyl 2- oxocyclohexane-1-carboxylate (1.7 g, 9.33 mmol, 1 equiv) and CeCl3-7H2O (173 mg, 0.47 mmol, 0.05 equiv) in i-PrOH (93 mL) was evacuated and filled with O2 three times. The solution was stirred for 1 hour at room temperature, changing color from clear to light pink over the course of the reaction. The solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (10 → Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 401 20% EtOAc/hexanes) to afford alcohol 6a as a clear oil (1.11 g, 60% yield): 1H NMR (400 MHz, CDCl3) δ 5.89 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.38 – 5.19 (m, 2H), 4.66 (dt, J = 5.8, 1.4 Hz, 2H), 4.35 (s, 1H), 2.71 – 2.59 (m, 2H), 2.55 (ddd, J = 14.1, 11.8, 6.1 Hz, 1H), 2.13 – 1.96 (m, 1H), 1.96 – 1.77 (m, 2H), 1.77 – 1.58 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 207.3, 169.8, 131.2, 119.4, 80.8, 66.5, 39.0, 37.8, 27.2, 22.1; IR (Neat Film, NaCl) 3780, 3458, 3087, 2947, 2869, 2668, 2403, 1727, 1649, 1452, 1425, 1374, 1337, 1311, 1247, 1207, 1132, 1116, 1094, 1054, 984, 937, 853, 817, 792, 714, 689, 618 cm-1; HRMS (MM: ESI-APCI) m/z calculated for [C10H18NO4] ([M+NH4]+): 216.1230, found 216.1232. O OH (R)-2-allyl-2-hydroxycyclohexan-1-one (A7.7a). Following general procedure B, ketoester A7.6a (15 mg, 0.076 mmol, 1.0 equiv) in toluene (1.8 mL) was added to a solution of Pd2(pmdba)3 (3.3 mg, 0.003 mmol, 4 mol %) and (S)-(CF3)3-tBu-PHOX (4.5 mg, 0.0076 mmol, 10 mol %) in toluene (0.5 mL). The reaction was stirred at ambient temperature for 16 h. Purification by flash chromatography (15% EtOAc/hexanes) gave α-hydroxycyclohexanone A7.7a as a yellow oil (10 mg, 85% yield, 70% ee): 1H NMR (400 MHz, CDCl3) δ 5.72 (ddt, J = 16.6, 10.6, 7.2 Hz, 1H), 5.16 – 5.06 (m, 2H), 3.95 (s, 1H), 2.59 (ddt, J = 14.0, 7.4, 1.1 Hz, 1H), 2.55 – 2.43 (m, 2H), 2.48 – 2.38 (m, 1H), 2.22 (dq, J = 13.0, 3.0 Hz, 1H), 2.16 – 2.05 (m, 1H), 1.89 – 1.56 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 213.7, 131.8, 118.9, 78.9, 41.9, 40.5, 38.4, 27.9, 22.7. IR (Neat Film, NaCl) 3475, 3073, 2939, 2864, 1711, 1639, 1441, 1379, 1309, 1242, 1156, 1128, 1078, 1047, 1000, 916, 681, 624 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C9H17NO2 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 402 [M+NH4]+: 172.1332, found 172.1328; [α]D23.0 –10.2 (c 1.0, CHCl3); Chiral GC conditions: Astec® CHIRALDEX G-TA column, 100 °C isotherm, tR (min): major = 29.288, minor = 36.310. O O OH O 2-methylallyl 1-hydroxy-2-oxocyclohexane-1-carboxylate (A7.6b). Note: While general procedure A using catalytic CeCl3-7H2O was successful, it led to a mixture that was more difficult to purify. Thus, we used general procedure B: to a solution of iodine (10 mg, 0.04 mmol, 0.02 equiv) and samarium (III) triflate (60 mg, 0.10 mmol, 0.05 equiv) in a 1:5 mixture of H2O/THF (24 mL) was added 2-methylallyl 2-oxocyclohexane- Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 403 1-carboxylateRef (400 mg, 2.0 mmol, 1 equiv). The reaction was stirred for 72 h. Purification by silica gel flash chromatography (1 → 2% Et2O/CH2Cl2) afforded alcohol A7.6b as a clear oil (240 mg, 55% yield): 1H NMR (400 MHz, CDCl3) δ 5.01 – 4.91 (m, 2H), 4.65 – 4.54 (m, 2H), 4.36 (s, 1H), 2.74 – 2.60 (m, 2H), 2.55 (ddd, J = 14.0, 11.7, 6.0 Hz, 1H), 2.04 (ddtd, J = 14.4, 6.4, 4.2, 3.8, 1.9 Hz, 1H), 1.94 – 1.76 (m, 2H), 1.74 (t, J = 1.2 Hz, 3H), 1.73 – 1.62 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 207.3, 169.9, 139.1, 114.0, 80.9, 69.2, 39.0, 37.7, 27.2, 22.1, 19.6; IR (Neat Film, NaCl) 3457, 3084, 2947, 2869, 1722, 1660, 1451, 1378, 1247, 1205, 1116, 1093, 1055, 991, 960, 907, 852, 814, 785, 686, 619 cm-1; HRMS (MM: ESI-APCI) m/z calculated for [C11H20NO4] ([M+NH4]+): 230.1387, found 230.1382. O OH (R)-2-hydroxy-2-(2-methylallyl)cyclohexan-1-one (A7.7b). Following general procedure C, alcohol A7.6b (15 mg, 0.071 mmol, 1.0 equiv) in toluene (1.6 mL) was added to a solution of [Pd2(pmdba)3] (3.1 mg, 0.0028 mmol, 4 mol %) and (S)-(CF3)3-tBuPHOX (4.2 mg, 0.0071 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (10% EtOAc/hexanes) gave alcohol A7.7b as a clear oil (10 mg, 84% yield, 75% ee): 1H NMR (400 MHz, CDCl3) δ 4.86 (dd, J = 2.1, 1.4 Hz, 1H), 4.73 (dd, J = 2.0, 1.0 Hz, 1H), 3.94 (s, 1H), 2.65 – 2.47 (m, 3H), 2.43 (dd, J = 13.8, 1.0 Hz, 1H), 2.24 (dq, J = 13.2, 3.1 Hz, 1H), 2.19 – 2.06 (m, 1H), 1.86 – 1.72 (m, 5H), 1.72 – 1.56 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 214.1, 141.0, 115.2, 79.5, 45.3, 41.4, 38.7, 28.2, 24.2, 23.0; IR (Neat Film, NaCl) 3482, 3073, 2941, 2865, 2358, 1709, 1644, 1452, 1376, 1308, 1250, 1197, 1154, 1130, 1103, 1069, 1015, 953, 893, 855, 654 cm-1; HRMS Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 404 (MM: ESI-APCI): m/z calc’d for [C10H20NO2] ([M+NH4]+): 186.1489, found 186.1482; [α]D23.3 –28.2 (c 0.33, CHCl3); Chiral GC conditions: Astec® CHIRALDEX G-TA column, 120 °C isotherm, tR (min): major = 11.639, minor = 13.805. O O HO O allyl 1-hydroxy-2-oxocycloheptane-1-carboxylate A7.6c. Following general procedure A: A solution of allyl 2-oxocycloheptane-1-carboxylate (500 mg, 2.55 mmol, 1 equiv) and CeCl3-7H2O (47 mg, 0.13 mmol, 0.05 equiv) in i-PrOH (25 mL) was stirred for 1 hour at room temperature, changing color from clear to yellow/golden-green over the course of the reaction. The crude product was purified by silica gel flash chromatography Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 405 (20% Et2O/hexanes) to afford alcohol A7.6c as a clear oil (340 mg, 63% yield): 1H NMR (500 MHz, CDCl3) δ 5.86 (ddt, J = 17.3, 10.4, 5.7 Hz, 1H), 5.37 – 5.14 (m, 2H), 4.61 (d, J = 5.8 Hz, 2H), 4.30 (d, J = 1.6 Hz, 1H), 2.93 (td, J = 12.0, 2.9 Hz, 1H), 2.56 (ddd, J = 11.7, 7.2, 2.2 Hz, 1H), 2.34 – 2.18 (m, 1H), 2.18 – 2.02 (m, 1H), 1.95 (tq, J = 6.3, 1.7 Hz, 1H), 1.88 – 1.72 (m, 2H), 1.46 (qdd, J = 8.1, 3.9, 2.3 Hz, 2H), 1.37 – 1.22 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 209.5, 170.3, 131.2, 119.2, 83.6, 66.5, 40.0, 34.5, 30.2, 27.2, 23.7; IR (Neat Film, NaCl) 3790, 3471, 2928, 2857, 2350, 1746, 1722, 1712, 1681, 1453, 1370, 1319, 1268, 1224, 1196, 1167, 1110, 1082, 1038, 992, 938 cm-1; HRMS (MM: ESI-APCI) m/z calculated for [C11H16O4] [M+H]+: 213.1121, found 213.1119. O HO (R)-2-allyl-2-hydroxycycloheptan-1-one (A7.7c). Following general procedure C, alcohol A7.6c (20 mg, 0.094 mmol, 1.0 equiv) in toluene (2.3 mL) was added to a solution of [Pd2(pmdba)3] (4.1 mg, 0.0038 mmol, 4 mol %) and (S)-(CF3)3-t-BuPHOX (5.6 mg, 0.0094 mmol, 10 mol %) in toluene (0.5 mL). Purification by flash chromatography (10% EtOAc/hexanes) gave alcohol A7.7c as a clear oil (12 mg, 75% yield, 78% ee): 1H NMR (400 MHz, CDCl3) δ 5.73 (ddt, J = 17.0, 10.3, 7.3 Hz, 1H), 5.19 – 4.95 (m, 2H), 3.83 (d, J = 1.5 Hz, 1H), 2.74 – 2.63 (m, 1H), 2.50 – 2.29 (m, 3H), 2.07 – 1.93 (m, 2H), 1.91 – 1.81 (m, 1H), 1.81 – 1.71 (m, 1H), 1.67 (ddt, J = 14.9, 10.8, 1.3 Hz, 1H), 1.51 – 1.31 (m, 2H), 1.31 – 1.17 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 215.6, 132.2, 118.9, 81.4, 44.7, 39.0, 36.8, 30.6, 27.4, 23.6; IR (Neat Film, NaCl) 3481, 3076, 2928, 2858, 2357, 1703, 1639, 1506, 1453, 1379, 1341, 1320, 1232, 1174, 1141, Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 406 1103, 1076, 1062,1043, 996, 947, 918, 839, 789, 671, 633 cm-1; HRMS (MM: ESIAPCI): m/z calc’d for [C10H17O2] [M+H]+: 169.1223, found 169.1224; [α]D23.8 –53.3 (c 1.0, CHCl3); Chiral GC conditions: Astec® CHIRALDEX G-TA column, 100 °C isotherm, tR (min): major = 38.348, minor = 37.356. O OH O O allyl 1-hydroxy-2-oxocyclopentane-1-carboxylate A7.6d. Following general procedure B, to a solution of iodine (15 mg, 0.06 mmol, 0.02 equiv) and samarium (III) triflate (89 mg, 0.15 mmol, 0.05 equiv) in a 1:5 mixture of H2O/THF (30 mL) was added allyl 2- Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 407 oxocyclopentane-1-carboxylate (500 mg, 2.97 mmol, 1 equiv). The reaction was stirred for 72 h. Purification by silica gel flash chromatography (20% EtOAc/hexanes) afforded alcohol A7.6d as a clear oil (200 mg, 36% yield): 1H NMR (400 MHz, CDCl3) δ 5.86 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.34 – 5.21 (m, 2H), 4.66 (ddt, J = 5.6, 2.7, 1.4 Hz, 2H), 3.74 (s, 1H), 2.56 – 2.35 (m, 3H), 2.09 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 213.3, 171.4, 131.1, 119.3, 79.9, 66.9, 35.9, 34.9, 18.5; IR (Neat Film, NaCl) 3473, 3088, 2965, 2893, 1758, 1737, 1649, 1447, 1403, 1363,1258, 1169, 1097, 1051, 982, 939,850, 817, 788, 649, 618 cm-1; HRMS (MM: ESI-APCI) m/z calculated for [C9H16NO4] [M+NH4]+: 202.1074, found 202.1069. O OH (R)-2-allyl-2-hydroxycyclopentan-1-one (A7.7d). Following general procedure C, alcohol A7.6d (40 mg, 0.22 mmol, 1.0 equiv) in toluene (4.5 mL) was added to a solution of [Pd2(dba)3] (7.7 mg, 0.0087 mmol, 4 mol %) and (S)-(CF3)3-t-BuPHOX (12.8 mg, 0.022 mmol, 10 mol %) in toluene (2.1 mL). Purification by flash chromatography (15 → 20% EtOAc/hexanes) gave alcohol A7.7d as a yellow oil (22 mg, 73% yield, 30% ee): 1H NMR (400 MHz, CDCl3) δ 5.79 (dddd, J = 16.9, 10.2, 8.1, 6.6 Hz, 1H), 5.31 – 5.08 (m, 2H), 2.46 (s, 1H), 2.41 – 2.17 (m, 4H), 2.17 – 2.06 (m, 1H), 2.06 – 1.75 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 219.4, 131.7, 120.1, 78.6, 40.4, 34.8, 34.6, 17.2; IR (Neat Film, NaCl) 3448, 3077, 2968, 2923, 2361, 1745, 1639, 1434, 1403, 1323, 1245, 1167, 1132, 1064, 1036, 998, 919, 839, 819, 752, 705, 630 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for [C8H16NO2] [M+NH4]+: 158.1176, found 158.1169; [α]D22.6 –19.8 (c 1.1, Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 408 CHCl3); Chiral GC conditions: Astec® CHIRALDEX G-TA column, 100 °C isotherm, tR (min): major = 18.666, minor = 23.348. O BzN O OH O allyl 1-benzoyl-3-hydroxy-2-oxopiperidine-3-carboxylate (A7.6e). Following general procedure B: to a solution of iodine (6.7 mg, 0.026 mmol, 0.02 equiv) and samarium (III) triflate (40 mg, 0.066 mmol, 0.05 equiv) in a 1:5 mixture of H2O/THF (15 mL) was added allyl 1-benzoyl-2-oxopiperidine-3-carboxylate (380 mg, 1.32 mmol, 1.0 equiv). The reaction was stirred for 6 days. Purification with silica gel flash chromatography (3:1 hexanes/EtOAc) afforded A7.6e as an off-white solid (243 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.65 (m, 2H), 7.53 – 7.46 (m, 1H), 7.42 – 7.35 (m, 2H), 5.96 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.39 (dq, J = 17.1, 1.4 Hz, 1H), 5.33 (dq, J = 10.3, 1.2 Hz, 1H), 4.75 (dt, J = 5.9, 1.3 Hz, 2H), 4.18 (s, 1H), 4.00 – 3.89 (m, 1H), 3.84 – 3.73 (m, Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 409 1H), 2.61 – 2.47 (m, 1H), 2.22 – 2.01 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 174.0, 172.1, 170.7, 134.9, 132.2, 130.9, 128.3, 128.2, 119.9, 76.9, 67.3, 46.7, 32.4, 19.3; IR (Neat Film, NaCl) 3459, 2954, 1747, 1682, 1600, 1478, 1450, 1393, 1270, 1178, 1141, 992, 947, 796, 727, 694, 662 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C16H18NO5 [M+H]+: 304.1179, found 304.1182; O OH BzN (R)-3-allyl-1-benzoyl-3-hydroxypiperidin-2-one (7e). Following general procedure C, α-hydroxylated allyl ester A7.6e (10 mg, 0.033 mmol, 1.0 equiv) in toluene (0.5 mL) was added to a solution of [Pd2(dba)3] (1.2 mg, 1.3 µmol, 0.040 equiv) and (S)-(CF3)3-t-BuPHOX (2.0 mg, 3.3 µmol, 0.10 equiv) in toluene (0.5 mL). The reaction was stirred at 40 °C for 16 h. Purification by flash chromatography (15% EtOAc/hexanes) gave α-hydroxy piperidinone A7.7e as a colorless oil (6.8 mg, 79% yield, 92% ee): 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.54 (m, 2H), 7.52 – 7.48 (m, 1H), 7.40 (t, J = 7.5 Hz, 2H), 5.87 (ddt, J = 17.4, 10.4, 7.1 Hz, 1H), 5.31 – 5.20 (m, 2H), 3.88 (dtd, J = 12.8, 4.7, 1.6 Hz, 1H), 3.84 – 3.74 (m, 1H), 3.31 (s, 1H), 2.66 (d, J = 7.2 Hz, 2H), 2.27 – 2.17 (m, 1H), 2.10 – 1.98 (m, 2H), 2.01 – 1.89 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 178.9, 174.6, 135.6, 132.1, 131.4, 128.5, 127.9, 120.3, 74.2, 47.4, 44.1, 33.1, 20.0; IR (Neat Film, NaCl) 3478, 2953, 1682, 1450, 1391, 1286, 1149, 1072, 998, 928, 795, 726, 694, 662 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for C15H18NO3 [M+H]+: 260.1281, found 260.1278; [α]D23.1 +9.7 (c 0.64, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OD-H column, λ = 210 nm, tR (min): major = 3.548, minor = 2.875. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols O 410 OH O O Allyl 2-(hydroxymethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (A7.8). To a solution of allyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (200 mg, 0.87 mmol, 1.0 equiv) in THF (1.6 mL) at 0 °C was added potassium bicarbonate (261 mg, 2.61 mmol, 3.0 equiv) and aqueous 37% formaldehyde (420 uL, 5.65 mmol, 6.5 equiv). The mixture was allowed to warm to room temperature and stirred for 3 h. Water (2 mL) was added and the mixture was extracted with CH2Cl2 (4 x 2 mL). The combined organic layers were dried over Na2SO4, decanted, and concentrated under reduced pressure. The Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 411 residue was taken up in THF and 1 drop of 1 M aqueous HCl was added. The solution was stirred for 20 minutes before being concentrated under reduced pressure onto silica gel and then purified by silica gel flash chromatography (20 → 25% EtOAc/hexanes) to give alcohol A7.8 as a clear oil (195 mg, 86% yield): 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 (td, J = 7.5, 1.4 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.28 – 7.17 (m, 1H), 5.88 – 5.68 (m, 1H), 5.22 – 5.08 (m, 2H), 4.62 (ddd, J = 5.3, 3.5, 1.6 Hz, 2H), 4.11 – 3.98 (m, 1H), 3.91 (dd, J = 11.4, 9.9 Hz, 1H), 3.42 – 3.28 (m, 1H), 3.10 – 2.89 (m, 2H), 2.45 (dt, J = 13.6, 4.4 Hz, 1H), 2.18 (ddd, J = 13.5, 10.9, 5.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 197.3, 171.0, 143.3, 134.2, 132.0, 131.4, 128.9, 127.9, 127.1, 118.4, 66.4, 66.0, 59.3, 29.2, 26.0; IR (Neat Film, NaCl) 3521, 3071, 3024, 2940,2881, 1731, 1681, 1650, 1600, 1455, 1414, 1354, 1315, 1268, 1239, 1185, 1137, 1086, 1048, 942, 805,787, 745, 689, 654 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for [C15H17O4] [M+H]+: 261.1121, found 261.1117. O OH Following general procedure C, alcohol A7.8 (52 mg, 0.20 mmol, 1.0 equiv) in toluene (4.0 mL) was added to a solution of [Pd2(dba)3] (7.3 mg, 0.008 mmol, 4 mol %) and (S,S)- ANDEN (L3) (16 mg, 0.02 mmol, 10 mol %) in toluene (2.0 mL). The reaction was stirred at ambient temperature for 16 h. Purification by flash chromatography (20 → 25% EtOAc/hexanes) gave primary alcohol A7.9 as a clear oil (27 mg, 63% yield, 92% ee): 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.32 (tdd, J = 7.8, 1.6, 0.9 Hz, 1H), 7.26 (m, 1H), 5.89 – 5.73 (m, 1H), 5.21 – Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols 412 5.09 (m, 2H), 3.77 – 3.63 (m, 2H), 3.20 – 3.07 (m, 1H), 2.92 (dt, J = 17.4, 4.6 Hz, 1H), 2.85 (dd, J = 8.5, 4.9 Hz, 1H), 2.58 – 2.46 (m, 1H), 2.35 (ddt, J = 13.9, 8.1, 1.1 Hz, 1H), 2.05 (ddd, J = 13.7, 11.5, 5.1 Hz, 1H), 1.93 (ddd, J = 13.8, 5.1, 3.9 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 204.0, 143.6, 133.9, 132.9, 131.6, 129.0, 127.9, 127.0, 119.2, 66.5, 49.2, 34.8, 28.0, 24.9. IR (Neat Film, NaCl) 3459, 3072, 2928, 1673, 1600, 1454, 1357, 1287, 1229, 1156, 1043, 997, 919, 793, 741 cm-1; HRMS (MM: ESI-APCI): m/z calc’d for [C14H17O4 ] [M+H]+: 217.1223, found 217.1214; [α]D22.9 +39.1 (c 1.00, CHCl3); SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak OJ–H column, λ = 210 nm, tR (min): major = 6.234, minor = 6.752. 413 Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols A7.4 (1) REFERENCES AND NOTES Kumar, A.; Patil, D.; Rajamohanan, P. R.; Ahmad, A. Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium Oxysporum Isolated from Catharanthus Roseus. PLOS ONE 2013, 8 (9), e71805. (2) Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. New Seco-PrezizaaneType Sesquiterpenes, Jiadifenin with Neurotrophic Activity and 1,2- Dehydroneomajucin from Illicium Jiadifengpi. J. Nat. Prod. 2002, 65 (4), 527– 531. (3) Smith, A. M. R.; Hii, K. K. (Mimi). Transition Metal Catalyzed Enantioselective α-Heterofunctionalization of Carbonyl Compounds. Chem. Rev. 2011, 111 (3), 1637–1656. (4) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. A Dynamic Kinetic Asymmetric Transformation in the α-Hydroxylation of Racemic Malonates and Its Application to Biologically Active Molecules. Angew. Chem. Int. Ed. 2009, 48 (4), 803–806. (5) Witten, M. R.; Jacobsen, E. N. A Simple Primary Amine Catalyst for Enantioselective α-Hydroxylations and α-Fluorinations of Branched Aldehydes. Org. Lett. 2015, 17 (11), 2772–2775. (6) Sim, S.-B. D.; Wang, M.; Zhao, Y. Phase-Transfer-Catalyzed Enantioselective αHydroxylation of Acyclic and Cyclic Ketones with Oxygen. ACS Catalysis 2015, 5 (6), 3609–3612. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols (7) 414 Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Lewis Acid-Catalyzed Enantioselective Hydroxylation Reactions of Oxindoles and βKeto Esters Using DBFOX Ligand. J. Am. Chem. Soc. 2006, 128 (51), 16488– 16489. (8) He, R.; Wu, S.; Tang, H.; Huo, X.; Sun, Z.; Zhang, W. Iridium-Catalyzed Enantioselective and Diastereoselective Allylation of Dioxindoles: A One-Step Synthesis of 3-Allyl-3-Hydroxyoxindoles. Org. Lett. 2018, 20 (19), 6183–6187. (9) Xue, F.; Bao, X.; Zou, L.; Qu, J.; Wang, B. Asymmetric Hydroxylation of 4Substituted Pyrazolones Catalyzed by Natural Cinchona Alkaloids. Advanced Synthesis & Catalysis 2016, 358 (24), 3971–3976. (10) Yang, F.; Zhao, J.; Tang, X.; Zhou, G.; Song, W.; Meng, Q. Enantioselective αHydroxylation by Modified Salen-Zirconium(IV)-Catalyzed Oxidation of β-Keto Esters. Org. Lett. 2017, 19 (3), 448–451. (11) Boschelli, D.; Smith, A. B.; Stringer, O. D.; Jenkins, R. H.; Davis, F. A. An Asymmetric Synthesis of (+)-Kjellmanianone. Tetrahedron Lett. 1981, 22 (44), 4385–4388. (12) Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. Chiral Brønsted Acid-Catalyzed Enantioselective α-Hydroxylation of β-Dicarbonyl Compounds. J. Am. Chem. Soc. 2009, 131 (13), 4562–4563. (13) Novacek, J.; Izzo, J. A.; Vetticatt, M. J.; Waser, M. Bifunctional Ammonium Salt Catalyzed Asymmetric α-Hydroxylation of β-Ketoesters by Simultaneous Resolution of Oxaziridines. Chem. Eur. J. 2016, 22 (48), 17339–17344. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols (14) 415 Lin, X.; Ruan, S.; Yao, Q.; Yin, C.; Lin, L.; Feng, X.; Liu, X. Kinetic Resolution of Oxaziridines via Chiral Bifunctional Guanidine-Catalyzed Enantioselective αHydroxylation of β-Keto Esters. Org. Lett. 2016, 18 (15), 3602–3605. (15) Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Iida, K.; Yamanaka, M.; Nagasawa, K. Origin of Stereocontrol in Guanidine-Bisurea Bifunctional Organocatalyst That Promotes α-Hydroxylation of Tetralone-Derived βKetoesters: Asymmetric Synthesis of β- and γ-Substituted Tetralone Derivatives via Organocatalytic Oxidative Kinetic Resolution. J. Am. Chem. Soc. 2015, 137 (5), 1909–1915. (16) Ding, W.; Lu, L.-Q.; Zhou, Q.-Q.; Wei, Y.; Chen, J.-R.; Xiao, W.-J. Bifunctional Photocatalysts for Enantioselective Aerobic Oxidation of β-Ketoesters. J. Am. Chem. Soc. 2017, 139 (1), 63–66. (17) Naganawa, Y.; Aoyama, T.; Kato, K.; Nishiyama, H. Cu(II)-Catalyzed Enantioselective α-Hydroxylation and α-Chlorination of β-Ketoesters with N,N,O-Tridentate Chiral Phenanthroline Ligand. ChemistrySelect 2016, 1 (9), 1938–1942. (18) Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Expanding the Scope of Asymmetric Electrophilic Atom-Transfer Reactions: Titanium- and RutheniumCatalyzed Hydroxylation of β-Ketoesters. PNAS 2004, 101 (16), 5810–5814. (19) Trost, B. M.; Xu, J.; Reichle, M. Enantioselective Synthesis of α-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates. J. Am. Chem. Soc. 2007, 129 (2), 282–283. Appendix 7 – Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols (20) 416 Trost, B. M.; Xu, J.; Schmidt, T. Ligand Controlled Highly Regio- and Enantioselective Synthesis of α-Acyloxyketones by Palladium-Catalyzed Allylic Alkylation of 1,2-Enediol Carbonates. J. Am. Chem. Soc. 2008, 130 (36), 11852– 11853. (21) Trost, B. M.; Koller, R.; Schäffner, B. Enantioselective Synthesis of Tertiary αHydroxyketones from Unfunctionalized Ketones: Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates. Angew. Chem. Int. Ed. 2012, 51 (33), 8290–8293. (22) He, R.; Liu, P.; Huo, X.; Zhang, W. Ir/Zn Dual Catalysis: Enantioselective and Diastereodivergent α-Allylation of Unprotected α-Hydroxy Indanones. Org. Lett. 2017, 19 (20), 5513–5516. (23) Sun, A. W.; Hess, S. N.; Stoltz, B. M. Enantioselective Synthesis of GemDisubstituted N-Boc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation. Chem. Sci. 2018. (24) Qi, X.; Chen, C.; Hou, C.; Fu, L.; Chen, P.; Liu, G. Enantioselective Pd(II)Catalyzed Intramolecular Oxidative 6- Endo Aminoacetoxylation of Unactivated Alkenes. J. Am. Chem. Soc. 2018, 140 (24), 7415–7419. Appendix 8 – Spectra Relevant to Appendix 7 417 APPENDIX 8 Spectra Relevant to Appendix 7: Decarboxylative Asymmetric Allylic Alkylation of Tertiary Alcohols Figure A8.1 1H NMR (400 MHz, CDCl3) of compound A7.1. Appendix 8 - Spectra Relevant to Appendix 7 418 Appendix 8 - Spectra Relevant to Appendix 7 419 Figure A8.2 Infrared spectrum (Thin Film, NaCl) of compound A7.1. Figure A8.3 13C NMR (101 MHz, CDCl3) of compound A7.1. Figure A8.4 1H NMR (400 MHz, CDCl3) of compound A7.2. Appendix 8 - Spectra Relevant to Appendix 7 420 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.5 Infrared spectrum (Thin Film, NaCl) of compound A7.2. Figure A8.6 13C NMR (101 MHz, CDCl3) of compound A7.2. 421 Figure A8.7 1H NMR (400 MHz, CDCl3) of compound A7.3. Appendix 8 - Spectra Relevant to Appendix 7 422 Appendix 8 - Spectra Relevant to Appendix 7 423 Figure A8.8 Infrared spectrum (Thin Film, NaCl) of compound A7.3. Figure A8.9 13C NMR (101 MHz, CDCl3) of compound A7.3. Figure A8.10 1H NMR (400 MHz, CDCl3) of compound A7.5. Appendix 8 - Spectra Relevant to Appendix 7 424 Appendix 8 - Spectra Relevant to Appendix 7 425 Figure A8.11 Infrared spectrum (Thin Film, NaCl) of compound A7.5. Figure A8.12 13C NMR (101 MHz, CDCl3) of compound A7.5. Figure A8.13 1H NMR (400 MHz, CDCl3) of compound A7.6a. Appendix 8 - Spectra Relevant to Appendix 7 426 Appendix 8 - Spectra Relevant to Appendix 7 427 Figure A8.14 Infrared spectrum (Thin Film, NaCl) of compound A7.6a. Figure A8.15 13C NMR (101 MHz, CDCl3) of compound A7.6a. Figure A8.16 1H NMR (400 MHz, CDCl3) of compound A7.6b. Appendix 8 - Spectra Relevant to Appendix 7 428 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.17 Infrared spectrum (Thin Film, NaCl) of compound A7.6b. Figure A8.18 13C NMR (101 MHz, CDCl3) of compound A7.6b. 429 Figure A8.19 1H NMR (500 MHz, CDCl3) of compound A7.6c. Appendix 8 - Spectra Relevant to Appendix 7 430 Appendix 8 - Spectra Relevant to Appendix 7 431 Figure A8.20 Infrared spectrum (Thin Film, NaCl) of compound A7.6c. Figure A8.21 13C NMR (126 MHz, CDCl3) of compound A7.6c. Figure A8.22 1H NMR (500 MHz, CDCl3) of compound A7.6d. Appendix 8 - Spectra Relevant to Appendix 7 432 Appendix 8 - Spectra Relevant to Appendix 7 433 Figure A8.23 Infrared spectrum (Thin Film, NaCl) of compound A7.6d. Figure A8.24 13C NMR (126 MHz, CDCl3) of compound A7.6d. Figure A8.25 1H NMR (400 MHz, CDCl3) of compound A7.6d. Appendix 8 - Spectra Relevant to Appendix 7 434 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.26 Infrared spectrum (Thin Film, NaCl) of compound A7.6d. Figure A8.27 13C NMR (101 MHz, CDCl3) of compound A7.6d. 435 Figure A8.28 1H NMR (400 MHz, CDCl3) of compound A7.6e. Appendix 8 - Spectra Relevant to Appendix 7 436 Appendix 8 - Spectra Relevant to Appendix 7 437 Figure A8.29 Infrared spectrum (Thin Film, NaCl) of compound A7.6e. Figure A8.30 13C NMR (101 MHz, CDCl3) of compound A7.6e. Figure A8.31 1H NMR (400 MHz, CDCl3) of compound A7.7a. Appendix 8 - Spectra Relevant to Appendix 7 438 Appendix 8 - Spectra Relevant to Appendix 7 439 Figure A8.32 Infrared spectrum (Thin Film, NaCl) of compound A7.7a. Figure A8.33 13C NMR (101 MHz, CDCl3) of compound A7.7a. Figure A8.34 1 H NMR (400 MHz, CDCl3) of compound A7.7b. Appendix 8 - Spectra Relevant to Appendix 7 440 Appendix 8 - Spectra Relevant to Appendix 7 441 Figure A8.35 Infrared spectrum (Thin Film, NaCl) of compound A7.7b. Figure A8.36 13 C NMR (101 MHz, CDCl3) of compound A7.7a. Figure A8.37 1H NMR (400 MHz, CDCl3) of compound A7.7c. Appendix 8 - Spectra Relevant to Appendix 7 442 Appendix 8 - Spectra Relevant to Appendix 7 443 Figure A8.38 Infrared spectrum (Thin Film, NaCl) of compound A7.7c. Figure A8.39 13C NMR (101 MHz, CDCl3) of compound A7.7c. Figure A8.40 1H NMR (400 MHz, CDCl3) of compound A7.7d. Appendix 8 - Spectra Relevant to Appendix 7 444 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.41 Infrared spectrum (Thin Film, NaCl) of compound A7.7d. Figure A8.42 13C NMR (101 MHz, CDCl3) of compound A7.7d. 445 Figure A8.43 1H NMR (400 MHz, CDCl3) of compound A7.7e. Appendix 8 - Spectra Relevant to Appendix 7 446 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.44 Infrared spectrum (Thin Film, NaCl) of compound A7.7e. Figure A8.45 13C NMR (101 MHz, CDCl3) of compound A7.7e. 447 Figure A8.46 1H NMR (400 MHz, CDCl3) of compound A7.8. Appendix 8 - Spectra Relevant to Appendix 7 448 Appendix 8 - Spectra Relevant to Appendix 7 449 Figure A8.47 Infrared spectrum (Thin Film, NaCl) of compound A7.8. Figure A8.48 13C NMR (101 MHz, CDCl3) of compound A7.8. Figure A8.49 1H NMR (400 MHz, CDCl3) of compound A7.9. Appendix 8 - Spectra Relevant to Appendix 7 450 Appendix 8 - Spectra Relevant to Appendix 7 Figure A8.50 Infrared spectrum (Thin Film, NaCl) of compound A7.9. Figure A8.51 13C NMR (101 MHz, CDCl3) of compound A7.9. 451 Figure A8.52 1H NMR (400 MHz, CDCl3) of compound A7.11. Appendix 8 - Spectra Relevant to Appendix 7 d 452 Appendix 8 - Spectra Relevant to Appendix 7 453 Figure A8.53 Infrared spectrum (Thin Film, NaCl) of compound A7.11. Figure A8.54 13C NMR (101 MHz, CDCl3) of compound A7.11. 454 COMPREHENSIVE BIBLIOGRAPHY Alexy, E. J.; Virgil, S. C.; Bartberger, M. D.; Stoltz, B. M. Enantioselective Pd-Catalyzed Decarboxylative Allylic Alkylation of Thiopyranones. Access to Acyclic, Stereogenic α-Quaternary Ketones. Org. Lett. 2017, 19, 5007–5009. Alexy, E. J.; Zhang, H.; Stoltz, B. M. Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates. J. Am. Chem. Soc. 2018, 140, 10109– 10112. Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Enantioselective Construction of Quaternary N-Heterocycles by PalladiumCatalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem. 2012, 4, 130– 133. 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.; et al. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17 (50), 14199–14223. Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. Bera, K.; Namboothiri, I. N. N. Asymmetric Synthesis of Quaternary α-Amino Acids and Their Phosphonate Analogues. Asian J. Org. Chem. 2014, 3 (12), 1234–1260. Boschelli, D.; Smith, A. B.; Stringer, O. D.; Jenkins, R. H.; Davis, F. A. An Asymmetric Synthesis of (+)-Kjellmanianone. Tetrahedron Lett. 1981, 22 (44), 4385–4388. Burger, E. C.; Tunge, J. A. Asymmetric Allylic Alkylation of Ketone Enolates: An Asymmetric Claisen Surrogate. Org. Lett. 2004, 6, 4113–4115. 455 Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki, K.; Gaunt, M. J. Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C−H Bonds in Aliphatic Amines. Angew. Chem. Int. Ed. 2017, 56, 11958–11962. Castro, V. I. B.; Carvalho, C. M.; Fernandes, R. D. V.; Pereira-Lima, S. M. M. A.; Castanheira, E. M. S.; Costa, S. P. G. Peptaibolin Analogues by Incorporation of α,αDialkylglycines: Synthesis and Study of Their Membrane Permeating Ability. Tetrahedron 2016, 72 (7), 1024–1030. Cativiela, C.; Díaz-de-Villegas, M. D. Recent Progress on the Stereoselective Synthesis of Acyclic Quaternary α-Amino Acids. Tetrahedron: Asymmetry 2007, 18 (5), 569–623. Chamakuri, S.; Jain, P.; Reddy Guduru, S. K.; Arney, J. W.; MacKenzie, K. R.; Santini, C.; Young, D. W. Synthesis of Enantiomerically Pure 6-Substituted-Piperazine-2Acetic Acid Esters as Intermediates for Library Production. J. Org. Chem. 2018. Chen, L.; Luo, M.-J.; Zhu, F.; Wen, W.; Guo, Q.-X. Combining Chiral Aldehyde Catalysis and Transition-Metal Catalysis for Enantioselective α-Allylic Alkylation of Amino Acid Esters. J. Am. Chem. Soc. 2019. Childs, M. E.; Weber, W. P. Preparation of Cyanoformates. Crown Ether Phase Transfer Catalysis. J. Org. Chem. 1976, 41, 3486–3487. Chollet, A.; Mori, G.; Menendez, C.; Rodriguez, F.; Fabing, I.; Pasca, M. R.; Madacki, J.; Korduláková, J.; Constant, P.; Quémard, A.; et al. Design, Synthesis and Evaluation of New GEQ Derivatives as Inhibitors of InhA Enzyme and Mycobacterium Tuberculosis Growth. Eur. J. Med. Chem. 2015, 101, 218–235. Cochran, B. M.; Michael, F. E. Synthesis of 2,6-Disubstituted Piperazines by a Diastereoselective Palladium-Catalyzed Hydroamination Reaction. Org. Lett. 2008, 10, 329–332. de Castro, P. P.; Carpanez, A. G.; Amarante, G. W. Azlactone Reaction Developments. Chem. Eur. J. 2016, 22 (30), 10294–10318. 456 Dehner, A.; Planker, E.; Gemmecker, G.; Broxterman, Q. B.; Bisson, W.; Formaggio, F.; Crisma, M.; Toniolo, C.; Kessler, H. Solution Structure, Dimerization, and Dynamics of a Lipophilic α/310-Helical, Cα-Methylated Peptide. Implications for Folding of Membrane Proteins. J. Am. Chem. Soc. 2001, 123 (27), 6678–6686. Ding, W.; Lu, L.-Q.; Zhou, Q.-Q.; Wei, Y.; Chen, J.-R.; Xiao, W.-J. Bifunctional Photocatalysts for Enantioselective Aerobic Oxidation of β-Ketoesters. J. Am. Chem. Soc. 2017, 139 (1), 63–66. Drandarov, K.; Guggisberg, A.; Hesse, M. Asymmetric Syntheses of the Macrocyclic Spermine Alkaloids (−)-(S)-Protoverbine, (−)-(S)-Buchnerine, and Their Naturally Occurring Congenial Alkaloids. Helvetica Chimica Acta 2002, 85, 979–989. Duewelhenke, N.; Krut, O.; Eysel, P. Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines. Antimicrob. Agents Chemother. 2007, 51, 54–63. Ender, M.; McCallum, N.; Adhikari, R.; Berger-Bächi, B. Fitness Cost of SCCmec and Methicillin Resistance Levels in Staphylococcus Aureus. Antimicrob. Agents Chemother. 2004, 48, 2295–2297. Endo, K.; Grubbs, R. H. Chelated Ruthenium Catalysts for Z-Selective Olefin Metathesis. J. Am. Chem. Soc. 2011, 133, 8525–8527. Etienne, M. A.; Aucoin, J. P.; Fu, Y.; McCarley, R. L.; Hammer, R. P. Stoichiometric Inhibition of Amyloid β-Protein Aggregation with Peptides Containing Alternating α,α-Disubstituted Amino Acids. J. Am. Chem. Soc. 2006, 128 (11), 3522–3523. Evans, M. C.; Pradhan, A.; Venkatraman, S.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Synthesis and Dopamine Receptor Modulating Activity of Novel Peptidomimetics of L-Prolyl-l-Leucyl-Glycinamide Featuring α,α-Disubstituted Amino Acids. J. Med. Chem. 1999, 42 (8), 1441–1447. 457 Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Η2-Dba Complexes of Pd(0): The Substituent Effect in Suzuki−Miyaura Coupling. Org. Lett. 2004, 6, 4435–4438. Ferreira, M. del R. R.; Cecere, G.; Pace, P.; Summa, V. Routes to HIV-Integrase Inhibitors: Efficient Synthesis of Bicyclic Pyrimidones by Ring Expansion or Amination at a Benzylic Position. Tetrahedron Lett. 2009, 50, 148–151. Firth, J. D.; O’Brien, P.; Ferris, L. Synthesis of Enantiopure Piperazines via Asymmetric Lithiation–Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent. J. Am. Chem. Soc. 2016, 138, 651–659. Fitzi, R.; Seebach, D. Resolution and Use in α-Amino Acid Synthesis of Imidazolidinone Glycine Derivatives. Tetrahedron 1988, 44 (17), 5277–5292. Gettys, K. E.; Ye, Z.; Dai, M. Recent Advances in Piperazine Synthesis. Synthesis 2017, 49, 2589–2604. Gonzales, R. D.; Schreckenberger, P. C.; Graham, M. B.; Kelkar, S.; DenBesten, K.; Quinn, J. P. Infections Due to Vancomycin-Resistant Enterococcus Faecium Resistant to Linezolid. The Lancet 2001, 357 (9263), 1179. Grady, M. A.; Gasperoni, T. L.; Kirkpatrick, P. Aripiprazole. Nature Reviews Drug Discovery 2003, 2, 427. Guggisberg, A.; Drandarov, K.; Hesse, M. Protoverbine, the Parent Member of a Class of Macrocyclic Spermine Alkaloids. Helvetica Chimica Acta 2000, 83, 3035–3042. He, R.; Liu, P.; Huo, X.; Zhang, W. Ir/Zn Dual Catalysis: Enantioselective and Diastereodivergent α-Allylation of Unprotected α-Hydroxy Indanones. Org. Lett. 2017, 19 (20), 5513–5516. He, R.; Wu, S.; Tang, H.; Huo, X.; Sun, Z.; Zhang, W. Iridium-Catalyzed Enantioselective and Diastereoselective Allylation of Dioxindoles: A One-Step Synthesis of 3-Allyl3-Hydroxyoxindoles. Org. Lett. 2018, 20 (19), 6183–6187. 458 Herquline A, produced by Penicillium herquei FKI-7215, exhibits anti-influenza virus properties: Bioscience, Biotechnology, and Biochemistry: Vol 81, No 1 Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika, S.; Hori, A.; Hase, Y.; et al. SAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ Inhibitor. ACS Med. Chem. Lett. 2016, 7, 23–27. Holl, R.; Schepmann, D.; Wünsch, B. Homologous Piperazine-Alcanols: Chiral Pool Synthesis and Pharmacological Evaluation. Med. Chem. Commun. 2012, 3, 673–679. Hong, A. Y.; Krout, M. R.; Jensen, T.; Bennett, N. B.; Harned, A. M.; Stoltz, B. M. RingContraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile Γ-Quaternary Acylcyclopentenes. Angew. Chem. Int. Ed. 2011, 50, 2756– 2760. Huang, W.-X.; Liu, L.-J.; Wu, B.; Feng, G.-S.; Wang, B.; Zhou, Y.-G. Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines Activated by Alkyl Halides. Org. Lett. 2016, 18, 3082–3085. Hung, A. W.; Ramek, A.; Wang, Y.; Kaya, T.; Wilson, J. A.; Clemons, P. A.; Young, D. W. Route to Three-Dimensional Fragments Using Diversity-Oriented Synthesis. Proc. Natl. Acad. Sci.. 2011, 108, 6799–6804. Huo, X.; He, R.; Fu, J.; Zhang, J.; Yang, G.; Zhang, W. Stereoselective and Site-Specific Allylic Alkylation of Amino Acids and Small Peptides via a Pd/Cu Dual Catalysis. J. Am. Chem. Soc. 2017, 139 (29), 9819–9822. Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,α-Disubstituted α-Amino Acids Bearing Vicinal Stereocenters. J. Am. Chem. Soc. 2018, 140 (6), 2080–2084. 459 Im, W. B.; Choi, S. H.; Park, J.-Y.; Choi, S. H.; Finn, J.; Yoon, S.-H. Discovery of Torezolid as a Novel 5-Hydroxymethyl-Oxazolidinone Antibacterial Agent. Eur. J. Med. Chem. 2011, 46 (4), 1027–1039. Imbordino, R.; Perrault, W.; Reeder, M. Process for Preparing Linezolid. WO/2007/116284, October 19, 2007. Ippolito, J. A.; Kanyo, Z. F.; Wang, D.; Franceschi, F. J.; Moore, P. B.; Steitz, T. A.; Duffy, E. M. Crystal Structure of the Oxazolidinone Antibiotic Linezolid Bound to the 50S Ribosomal Subunit. J. Med. Chem. 2008, 51 (12), 3353–3356. Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Lewis AcidCatalyzed Enantioselective Hydroxylation Reactions of Oxindoles and β-Keto Esters Using DBFOX Ligand. J. Am. Chem. Soc. 2006, 128 (51), 16488–16489. James, J.; Jackson, M.; Guiry, P. Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances. Adv. Synth. Cat. In Press. Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y. Synthesis of βSubstituted α-Amino Acids with Use of Iridium-Catalyzed Asymmetric Allylic Substitution. J. Org. Chem. 2003, 68 (16), 6197–6201. Kearney, S. E.; Zahoránszky-Kőhalmi, G.; Brimacombe, K. R.; Henderson, M. J.; Lynch, C.; Zhao, T.; Wan, K. K.; Itkin, Z.; Dillon, C.; Shen, M.; et al. Canvass: A CrowdSourced, Natural-Product Screening Library for Exploring Biological Space. ACS Cent. Sci. 2018, 4, 1727–1741. Klepacz, A.; Zwierzak, A. An Expeditious One-Pot Synthesis of Diethyl N-Boc-1Aminoalkylphosphonates. Tetrahedron Lett. 2002, 43, 1079–1080. 460 Klepacz, A.; Zwierzak, A. An Expeditious One-Pot Synthesis of Diethyl N-Boc-1Aminoalkylphosphonates. Tetrahedron Lett. 2002, 43, 1079–1080. Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-Ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 54, 179–183. Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-Ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 54 (1), 179–183. Kumar, A.; Patil, D.; Rajamohanan, P. R.; Ahmad, A. Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium Oxysporum Isolated from Catharanthus Roseus. PLOS ONE 2013, 8 (9), e71805. Kuwano, R.; Ito, Y. Asymmetric Hydrogenation of 1,4,5,6-Tetrahydropyrazine-2-(N-TertButyl)Carboxamide Catalyzed by Trans-Chelating Chiral Diphosphine−Rhodium Complexes. J. Org. Chem. 1999, 64, 1232–1237. Leach, K. L.; Swaney, S. M.; Colca, J. R.; McDonald, W. G.; Blinn, J. R.; Thomasco, L. M.; Gadwood, R. C.; Shinabarger, D.; Xiong, L.; Mankin, A. S. The Site of Action of Oxazolidinone Antibiotics in Living Bacteria and in Human Mitochondria. Molecular Cell 2007, 26 (3), 393–402. Leonard, D. J.; Ward, J. W.; Clayden, J. Asymmetric α-Arylation of Amino Acids. Nature 2018, 562 (7725), 105–109. Li, C.-H.; Cheng, Y.-W.; Liao, P.-L.; Yang, Y.-T.; Kang, J.-J. Chloramphenicol Causes Mitochondrial Stress, Decreases ATP Biosynthesis, Induces Matrix 461 Metalloproteinase-13 Expression, and Solid-Tumor Cell Invasion. Toxicol Sci 2010, 116 (1), 140–150. Lin, X.; Ruan, S.; Yao, Q.; Yin, C.; Lin, L.; Feng, X.; Liu, X. Kinetic Resolution of Oxaziridines via Chiral Bifunctional Guanidine-Catalyzed Enantioselective αHydroxylation of β-Keto Esters. Org. Lett. 2016, 18 (15), 3602–3605. Lovering, F. Escape from Flatland 2: Complexity and Promiscuity. Med. Chem. Commun. 2013, 4, 515–519. Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52 (21), 6752–6756. Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. Chiral Brønsted AcidCatalyzed Enantioselective α-Hydroxylation of β-Dicarbonyl Compounds. J. Am. Chem. Soc. 2009, 131 (13), 4562–4563. Mahy, W.; Leitch, J. A.; Frost, C. G. Copper Catalyzed Assembly of NAryloxazolidinones: Synthesis of Linezolid, Tedizolid, and Rivaroxaban. Eur. J. Org. Chem. 2016 (7), 1305–1313. Marson, C. M. Chapter Two - Saturated Heterocycles with Applications in Medicinal Chemistry. In Advances in Heterocyclic Chemistry; Scriven, E. F. V., Ramsden, C. A., Eds.; Heterocyclic Chemistry in the 21st Century; Academic Press, 2017; Vol. 121, pp 13–33. Maruoka, K.; Ooi, T. Enantioselective Amino Acid Synthesis by Chiral Phase-Transfer Catalysis. Chemical Reviews 2003, 103 (8), 3013–3028. Marziale, A. N.; Duquette, D. C.; Craig, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. An Efficient Protocol for the Palladium-Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst. Adv. Synth. Cat. 2015, 357, 2238–2245. 462 Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. Catalytic Enantioselective Strecker Reaction of Ketoimines. J. Am. Chem. Soc. 2003, 125 (19), 5634–5635. McCarthy, J. R. A Convenient Synthesis of the Antibacterial Agent Linezolid. Tetrahedron Lett. 2015, 56 (49), 6846–6847. McDermott, B. P.; Campbell, A. D.; Ertan, A. First Example of S-BuLi/(-)-SparteineMediated Chiral Deprotonation of a Piperazine and Proof of the Sense of Induction. Synlett 2008, 2008, 875–879. McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Rapid Synthesis of an Electron-Deficient t-BuPHOX Ligand: Cross-Coupling of Aryl Bromides with Secondary Phosphine Oxides. Tetrahedron Lett. 2010, 51, 5550–5554. McKee, E. E.; Ferguson, M.; Bentley, A. T.; Marks, T. A. Inhibition of Mammalian Mitochondrial Protein Synthesis by Oxazolidinones. Antimicrob. Agents Chemother. 2006, 50 (6), 2042–2049. Meyer, L.; Poirier, J.-M.; Duhamel, P.; Duhamel, L. Chiral Auxiliaries with a Switching Center: New Tools in Asymmetric Synthesis. Application to the Synthesis of Enantiomerically Pure (R)- and (S)-α-Amino Acids. J. Org. Chem. 1998, 63 (23), 8094–8095. Meyers, J.; Carter, M.; Mok, N. Y.; Brown, N. On the Origins of Three-Dimensionality in Drug-like Molecules. Future Medicinal Chemistry 2016, 8, 1753–1767. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Deracemization of Quaternary Stereocenters by Pd-Catalyzed Enantioconvergent Decarboxylative Allylation of Racemic β-Ketoesters. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. 463 Monteleone, S.; Fuchs, J. E.; Liedl, K. R. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and Sp3 Centers Enhance Target Selectivity. Frontiers in Pharmacology 2017, 8, 552. Montgomery, T. D.; Rawal, V. H. Palladium-Catalyzed Modular Synthesis of Substituted Piperazines and Related Nitrogen Heterocycles. Org. Lett. 2016, 18, 740–743. Naganawa, Y.; Aoyama, T.; Kato, K.; Nishiyama, H. Cu(II)-Catalyzed Enantioselective αHydroxylation and α-Chlorination of β-Ketoesters with N,N,O-Tridentate Chiral Phenanthroline Ligand. ChemistrySelect 2016, 1 (9), 1938–1942. Nakhla, J. S.; Wolfe, J. P. A Concise Asymmetric Synthesis of Cis-2,6-Disubstituted NAryl Piperazines via Pd-Catalyzed Carboamination Reactions. Org. Lett. 2007, 9, 3279–3282. Narita, M.; Tsuji, B. T.; Yu, V. L. Linezolid-Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome. Pharmacotherapy 2007, 27, 1189–1197. Nascimento de Oliveira, M.; Arseniyadis, S.; Cossy, J. Palladium-Catalyzed Asymmetric Allylic Alkylation of 4-Substituted Isoxazolidin-5-Ones: A Straightforward Access to Β2,2-Amino Acids. Chem. Eur. J. 2018, 24, 4810–4814. Novacek, J.; Izzo, J. A.; Vetticatt, M. J.; Waser, M. Bifunctional Ammonium Salt Catalyzed Asymmetric α-Hydroxylation of β-Ketoesters by Simultaneous Resolution of Oxaziridines. Chem. Eur. J. 2016, 22 (48), 17339–17344. Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Enantioselective Synthesis of Dialkylated N -Heterocycles by Palladium-Catalyzed Allylic Alkylation. Org. Lett. 2015, 17, 1082–1085. Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stoltz, B. M. Enantioselective Synthesis of αQuaternary Mannich Adducts by Palladium-Catalyzed Allylic Alkylation: Total Synthesis of (+)-Sibirinine. J. Am. Chem. Soc. 2015, 137, 1040–1043. 464 Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Iida, K.; Yamanaka, M.; Nagasawa, K. Origin of Stereocontrol in Guanidine-Bisurea Bifunctional Organocatalyst That Promotes α-Hydroxylation of Tetralone-Derived β-Ketoesters: Asymmetric Synthesis of β- and γ-Substituted Tetralone Derivatives via Organocatalytic Oxidative Kinetic Resolution. J. Am. Chem. Soc. 2015, 137 (5), 1909–1915. Ohfune, Y.; Shinada, T. Enantio- and Diastereoselective Construction of α,α-Disubstituted α-Amino Acids for the Synthesis of Biologically Active Compounds. Eur. J. Org. Chem. 2005, 2005 (24), 5127–5143. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. Practical Catalytic Enantioselective Synthesis of α,α-Dialkyl-α-Amino Acids by Chiral Phase-Transfer Catalysis. J. Am. Chem. Soc. 2000, 122 (21), 5228–5229. Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; et al. The Synthesis of NAryl-5(S)-Aminomethyl-2-Oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates. Org. Process Res. Dev. 2003, 7 (4), 533–546. Pfeiffer, U.; Riccaboni, M. T.; Erba, R.; Pinza, M. A Short Synthesis of 4-imidazolidinone. Liebigs Annalen der Chemie 1988, 1988 (10), 993–995. Qi, X.; Chen, C.; Hou, C.; Fu, L.; Chen, P.; Liu, G. Enantioselective Pd(II)-Catalyzed Intramolecular Oxidative 6- Endo Aminoacetoxylation of Unactivated Alkenes. J. Am. Chem. Soc. 2018, 140 (24), 7415–7419. Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. A Dynamic Kinetic Asymmetric Transformation in the α-Hydroxylation of Racemic Malonates and Its Application to Biologically Active Molecules. Angew. Chem. Int. Ed. 2009, 48 (4), 803–806. 465 Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Enantioselective Construction of αQuaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. Ruider, S. A.; Müller, S.; Carreira, E. M. Ring Expansion of 3-Oxetanone-Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles. Angew. Chem. Int. Ed. 52, 11908–11911. Schecter, G. F.; Scott, C.; True, L.; Raftery, A.; Flood, J.; Mase, S. Linezolid in the Treatment of Multidrug-Resistant Tuberculosis. Clin Infect Dis 2010, 50 (1), 49–55. Seebach, D.; Beck, A. K.; Bierbaum, D. J. The World of Beta- and Gamma-Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components. Chem. Biodivers. 2004, 1, 1111–1239. Seebach, D.; Hoffmann, M. Preparation and Use in Amino Acid Synthesis of a New Chiral Glycine Derivative – (R)- and (S)-Tert-Butyl 2-Tert-Butyl-4-Methoxy-2,5Dihydroimidazole-1-Carboxylate (BDI). Eur. J. Org. Chem. 1998, 1998 (7), 1337– 1351. Serra, M.; Bernardi, E.; Marrubini, G.; Lorenzi, E. D.; Colombo, L. Palladium-Catalyzed Asymmetric Decarboxylative Allylation of Azlactone Enol Carbonates: Fast Access to Enantioenriched α-Allyl Quaternary Amino Acids. Eur. J. Org. Chem. 2019, 2019 (4), 732–741. Seto, M.; Roizen, J. L.; Stoltz, B. M. Catalytic Enantioselective Alkylation of Substituted Dioxanone Enol Ethers: Ready Access to C(α)-Tetrasubstituted Hydroxyketones, Acids, and Esters. Angew. Chem. 2008, 120, 6979–6982. Sharma, M. R.; Koc, E. C.; Datta, P. P.; Booth, T. M.; Spremulli, L. L.; Agrawal, R. K. Structure of the Mammalian Mitochondrial Ribosome Reveals an Expanded Functional Role for Its Component Proteins. Cell 2003, 115 (1), 97–108. 466 Shaw, K. J.; Barbachyn, M. R. The Oxazolidinones: Past, Present, and Future. Ann. N. Y. Acad. Sci. 2011, 1241, 48–70. Shimizu, I.; Yamada, T.; Tsuji, J. Palladium-Catalyzed Rearrangement of Allylic Esters of Acetoacetic Acid to Give γ,δ-Unsaturated Methyl Ketones. Tetrahedron Lett. 1980, 21, 3199–3202. Sikriwal, D.; Kant, R.; Maulik, P. R.; Dikshit, D. K. A Short Formal Synthesis of Three Epimers of Penmacric Acid. Tetrahedron 2010, 66, 6167–6173. Sim, S.-B. D.; Wang, M.; Zhao, Y. Phase-Transfer-Catalyzed Enantioselective αHydroxylation of Acyclic and Cyclic Ketones with Oxygen. ACS Catalysis 2015, 5 (6), 3609–3612. Smith, A. M. R.; Hii, K. K. (Mimi). Transition Metal Catalyzed Enantioselective αHeterofunctionalization of Carbonyl Compounds. Chem. Rev. 2011, 111 (3), 1637– 1656. Spaulding, A.; Takrouri, K.; Mahalingam, P.; Cleary, D. C.; Cooper, H. D.; Zucchi, P.; Tear, W.; Koleva, B.; Beuning, P. J.; Hirsch, E. B.; et al. Compound Design Guidelines for Evading the Efflux and Permeation Barriers of Escherichia Coli with the Oxazolidinone Class of Antibacterials: Test Case for a General Approach to Improving Whole Cell Gram-Negative Activity. Bioorg. Med. Chem. Lett. 2017, 27, 5310–5321. Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I. Beta-Amino Acids: Versatile Peptidomimetics. Curr. Med. Chem. 2002, 9, 811–822. Sudhakar, G.; Bayya, S.; Reddy, K. J.; Sridhar, B.; Sharma, K.; Bathula, S. R. Synthesis and Cytotoxicity of the Proposed Structure of Piperazirum, Its Stereoisomers and Analogues. Euro. J. Org. Chem. 2014, 1253–1265. 467 Sun, A. W.; Hess, S. N.; Stoltz, B. M. Enantioselective Synthesis of Gem-Disubstituted NBoc Diazaheterocycles via Decarboxylative Asymmetric Allylic Alkylation. Chem. Sci. 2019, 10, 788–792. Swaney, S. M.; Aoki, H.; Ganoza, M. C.; Shinabarger, D. L. The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria. Antimicrobial Agents and Chemotherapy 1998, 42 (12), 3251–3255. Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. A Facile and Modular Synthesis of Phosphinooxazoline Ligands. Org. Lett. 2007, 9, 2529–2531. Taylor, R. R. R.; Twin, H. C.; Wen, W. W.; Mallot, R. J.; Lough, A. J.; Gray-Owen, S. D.; Batey, R. A. Substituted 2,5-Diazabicyclo[4.1.0]Heptanes and Their Application as General Piperazine Surrogates: Synthesis and Biological Activity of a Ciprofloxacin Analogue. Tetrahedron 2010, 66, 3370–3377. Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Control of Peptide Conformation by the Thorpe-Ingold Effect (Cα-Tetrasubstitution). Peptide Science 2001, 60 (6), 396– 419. (2001)60:6<396::AID-BIP10184>3.0.CO;2-7. Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Expanding the Scope of Asymmetric Electrophilic Atom-Transfer Reactions: Titanium- and RutheniumCatalyzed Hydroxylation of β-Ketoesters. PNAS 2004, 101 (16), 5810–5814. Trost, B. M. Metal Catalyzed Allylic Alkylation: Its Development in the Trost Laboratories. Tetrahedron 2015, 71, 5708–5733. Trost, B. M.; Ariza, X. Catalytic Asymmetric Alkylation of Nucleophiles: Asymmetric Synthesis of α-Alkylated Amino Acids. Angew. Chem. Int. Ed. 1997, 36 (23), 2635– 2637. Trost, B. M.; Ariza, X. Enantioselective Allylations of Azlactones with Unsymmetrical Acyclic Allyl Esters. J. Am. Chem. Soc. 1999, 121 (46), 10727–10737. 468 Trost, B. M.; Dogra, K. Synthesis of Novel Quaternary Amino Acids Using MolybdenumCatalyzed Asymmetric Allylic Alkylation. J. Am. Chem. Soc. 2002, 124 (25), 7256– 7257. Trost, B. M.; Koller, R.; Schäffner, B. Enantioselective Synthesis of Tertiary αHydroxyketones from Unfunctionalized Ketones: Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates. Angew. Chem. Int. Ed. 2012, 51 (33), 8290–8293. Trost, B. M.; Xu, J. Regio- and Enantioselective Pd-Catalyzed Allylic Alkylation of Ketones through Allyl Enol Carbonates. J. Am. Chem. Soc. 2005, 127, 2846–2847. Trost, B. M.; Xu, J.; Reichle, M. Enantioselective Synthesis of α-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates. J. Am. Chem. Soc. 2007, 129 (2), 282–283. Trost, B. M.; Xu, J.; Schmidt, T. Ligand Controlled Highly Regio- and Enantioselective Synthesis of α-Acyloxyketones by Palladium-Catalyzed Allylic Alkylation of 1,2Enediol Carbonates. J. Am. Chem. Soc. 2008, 130 (36), 11852–11853. Trost, Cb.-C.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. New York 2006, No. 3, 28. Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. Facile Generation of a Reactive Palladium(II) Enolate Intermediate by the Decarboxylation of Palladium(II) .Beta.Ketocarboxylate and Its Utilization in Allylic Acylation. J. Am. Chem. Soc. 1980, 102, 6381–6384. Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. Chemistry of Dibenzylideneacetone-Palladium(0) Complexes: I. Novel Tris(Dibenzylideneacetone)Dipalladium(Solvent) Complexes and Their Reactions with Quinones. J. Organomet. Chem. 1999, 65, 253–266. 469 Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. Vo, C.-V. T.; Bode, J. W. Synthesis of Saturated N-Heterocycles. J. Org. Chem. 2014, 79, 2809–2815. Vogt, H.; Bräse, S. Recent Approaches towards the Asymmetric Synthesis of α,αDisubstituted α-Amino Acids. Org. Biomol. Chem. 2007, 5 (3), 406–430. Wang, H.; Kowalski, M. D.; Lakdawala, A. S.; Vogt, F. G.; Wu, L. An Efficient and Highly Diastereoselective Synthesis of GSK1265744, a Potent HIV Integrase Inhibitor. Org. Lett. 2015, 17, 564–567. Weiner, B.; Szymański, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Recent Advances in the Catalytic Asymmetric Synthesis of β-Amino Acids. Chem. Soc. Rev. 2010, 39, 1656–1691. White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M. The Catalytic Asymmetric Total Synthesis of Elatol. J. Am. Chem. Soc. 2008, 130, 810–811. Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; et al. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074–D1082. Witten, M. R.; Jacobsen, E. N. A Simple Primary Amine Catalyst for Enantioselective αHydroxylations and α-Fluorinations of Branched Aldehydes. Org. Lett. 2015, 17 (11), 2772–2775. Xue, F.; Bao, X.; Zou, L.; Qu, J.; Wang, B. Asymmetric Hydroxylation of 4-Substituted Pyrazolones Catalyzed by Natural Cinchona Alkaloids. Advanced Synthesis & Catalysis 2016, 358 (24), 3971–3976. 470 Yang, B.; Shi, L.; Wu, J.; Fang, X.; Yang, X.; Wu, F. Microwave-Assisted Expeditious Synthesis of 5-Fluoroalkyl-3-(Aryl/Alkyl)-Oxazolidin-2-Ones. Tetrahedron 2013, 69 (15), 3331–3337. Yang, F.; Zhao, J.; Tang, X.; Zhou, G.; Song, W.; Meng, Q. Enantioselective αHydroxylation by Modified Salen-Zirconium(IV)-Catalyzed Oxidation of β-Keto Esters. Org. Lett. 2017, 19 (3), 448–451. Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. New Seco-Prezizaane-Type Sesquiterpenes, Jiadifenin with Neurotrophic Activity and 1,2-Dehydroneomajucin from Illicium Jiadifengpi. J. Nat. Prod. 2002, 65 (4), 527–531. Yu, J.-S.; Noda, H.; Shibasaki, M. Quaternary Β2,2-Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc-Based Solid Phase Peptide Synthesis. Angew. Chem. Int. Ed. 2018, 57, 818–822. Ziegler, R. E.; Desai, B. K.; Jee, J.-A.; Gupton, B. F.; Roper, T. D.; Jamison, T. F. 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. Angew. Chem. Int. Ed. 2018, 57, 7181–7185. 471 ABOUT THE AUTHOR Alexander W. Sun was born on May 1, 1990. He lived in Eugene, OR for 16 years, devoting most of his free time to swimming and water polo. Later on in high school, Alex became fascinated by organic synthesis, having been inspired both by the synthesis of aspirin during a routine laboratory course and an excellent organic chemistry course taught by Professor Gary O. Spessard. In 2008, Alex went on to attend the University of Oregon for his freshman year, undertaking his first research experience in the inorganic chemistry laboratory of Professor David R. Tyler. Seeking to explore a new environment, Alex spent his final three years of college at the University of Pennsylvania, majoring in Chemistry, Biochemistry, and Biology, while also submatriculating to obtain an M.Sc. in Chemistry. There, Alex further solidified his interest in organic chemistry by completing his master’s thesis on the synthesis of HIV-1 entry inhibitors in the research group of Professor Amos B. Smith, III. At Penn, in the Smith group, and surrounded by excellent mentors such as Professor Ponzy Lu, Alex became interested in the applications of organic chemistry to medicine, and decided to pursue an MD/PhD. In 2012, Alex joined the UCLA-Caltech MD/PhD program. During the summers, he worked in the groups of Professor Neil Garg and Professor Peter Dervan. Ultimately, Alex began doctoral studies with Professor Brian Stoltz, working on the synthesis and medicinal applications of chiral heterocycles. Following completion of his graduate studies, Alex will return to UCLA to finish the final two years of medical school, aiming to pursue residency with the continued goal of applying chemistry to medicine.