Asymmetric Pericyclic Transformations from Reactive Palladium Intermediates Citation Cusumano, Alexander Quinn (2024) Asymmetric Pericyclic Transformations from Reactive Palladium Intermediates. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/b0wn-wt67. https://resolver.caltech.edu/CaltechTHESIS:06222023-231753197 Abstract The Pd-catalyzed decarboxylative asymmetric allylic alkylation of enolate nucleophiles is a cornerstone of our groups’ efforts to develop methodologies that directly facilitate the synthesis of stereochemically complex molecular building blocks. This thesis first focuses on our efforts to deepen our mechanistic understanding of these transformations. We then employ our insights as a base from which we expand the scope of the decarboxylative asymmetric allylic alkylation reaction, as well as develop entirely novel reaction paradigms. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: asymmetric catalysis Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Fu, Gregory C. (chair) Goddard, William A., III Agapie, Theodor Stoltz, Brian M. Defense Date: 5 June 2023 Record Number: CaltechTHESIS:06222023-231753197 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:06222023-231753197 DOI: 10.7907/b0wn-wt67 Related URLs: URL URL Type Description https://doi.org/10.1021/jacs.0c06243 DOI Portions of article adapted for ch. 1 https://doi.org/10.1021/jacs.0c09575 DOI Portions of article adapted for ch. 2 https://doi.org/10.1021/acs.orglett.0c01441 DOI Related publications by author - see Published Content and Contributions no. 1 https://doi.org/10.1021/acs.joc.2c01693 DOI Related publications by author - see Published Content and Contributions no. 4 https://doi.org/10.1021/jacs.3c02104 UNSPECIFIED Related publications by author - see Published Content and Contributions no. 5 ORCID: Author ORCID Cusumano, Alexander Quinn 0000-0002-2914-2008 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 16131 Collection: CaltechTHESIS Deposited By: Alexander Cusumano Deposited On: 27 Jun 2023 22:14 Last Modified: 08 Nov 2023 00:39 Thesis Files PDF - Final Version See Usage Policy. 81MB Repository Staff Only: item control page

ASYMMETRIC PERICYCLIC TRANSFORMATIONS FROM REACTIVE PALLADIUM INTERMEDIATES Thesis by Alexander Quinn Cusumano In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2024 (Defended June 5, 2023) ii ã 2023 Alexander Quinn Cusumano ORCID: 0000-0002-2914-2008 iii To my loving parents iv ACKNOWLEDGEMENTS There are numerous people I wish to thank for their support, encouragement, mentorship, and friendship during my time in graduate school. The culmination of all of these interactions and memories has made this time a truly unique experience – one far more exhilarating and rewarding than I could have ever imagined. First, I have to thank Professor Brian Stoltz for his guidance, support, and unwavering enthusiasm over the past five years. Brian is an amazing scientist. He is always thinking outside the box, taking on hard challenges, and getting everyone else excited about chemistry. I also want to acknowledge how Brian is a role model of a PI. During my time in the Stoltz group, I have been continually impressed with his people skills – his patience, optimism, ability to foster scientific growth in his mentees, and his genuine investment in our personal development as young adults. Brian offers us an immense amount of freedom in our research directions and the types of challenges we wish to pursue. This level of autonomy allows us to explore our unique interests and define our own scientific identities, all while still benefiting from his support and guidance. I am extremely grateful to have had the opportunity to pursue doctoral studies in the Stoltz group. I would also like to thank Professor William (Bill) Goddard for being a second mentor to me on the fronts of theoretical and computational chemistry. Bill has unique insights, perspectives, and is always excited to talk about research. I have especially enjoyed taking and TA-ing the Ch120–CH121 series. The concepts we talked about and the intuitive picture of quantum mechanics painted from these courses has changed the way I think about chemistry at the deepest level. I would also like express my appreciation for the members of my thesis committee. In addition to being a supportive thesis chair, Professor Gregory Fu v was always there to offer professional advice and chemistry wisdom. From our chats about postdoc plans and grantsmanship to kinetic queries, Greg has been a phenomenal resource. I would also like to thank Professors Ryan Hadt, Theo Agapie, and Sarah Reisman for their support over the years. We are lucky at Caltech to have amazing staff that make everyone’s research possible. To that end, I am grateful for the plethora of help and guidance I have received over the years from Dr. Scott Virgil. I need to thank Dr. David VanderVelde, Dr. Mike Takase, and Dr. Mona Shahgholi for their expertise and assistance in NMR spectroscopy, X-ray crystallography, and mass spectrometry. Beth Marshall, Joe Drew, Alison Ross, and Tomomi Kano are all thanked for keeping everything in Schlinger running. I am lucky to have had a number of outstanding project partners during my time in the Stoltz group. The guidance of Dr. Eric Alexy and Dr. Tyler Fulton were critical when I first arrived. From teaching me laboratory techniques to offering big-picture career advice, their direction was treasured. I am thankful to Dr. Trevor Lohrey for all of the help with organometallic-related synthesis and questions, as well as insights on life as a postdoc. I have learned a ton from our conversations and had a great time working with Ni and Pd together. Working with Adrian Samkian and Zack Sercel on the synthesis of OSDAs has been a pleasure. I have also had the opportunity to work with Dr. Steven Sardini and Dr. Veronica Hubble on a variety of projects over the last years, all of which have been an awesome time (besides our “asymmetric” protonation). I am thankful for our “[4+2] team” – Kali Flesch, Ruby Chen, and Christian Strong – for being an amazingly supportive group in our efforts to hijack Pd enolates. Lastly, I am grateful for the opportunity to mentor Tianyi Zhang, an vi amazingly talented undergraduate, over the past two years. Tianyi continually impressed me with his intellect, fun personality, and ability to rapidly acquire and apply new skills. The Stoltz group is full of interesting characters that make coming to work each day that much more enjoyable. I got lucky to have an awesome cohort, with Alexia Kim, Zack Sercel, and Tyler Casselman (TC). Officer Kim has been the perfect hood-mate and partner on our bad boy police force over these 5 years. If you are reading this, I am sorry for the embarrassing photos in my defense. Thank you for putting up with me and blessing our bay with good tunes – sorry for the dances. Zack has been not only a source of encouragement, but also a great sounding board for wacky ideas, a fun project partner, and just a pleasure to talk to about life. Hopefully we get to cross paths again someday. TC was the addition to our cohort that we needed. From random fist-bumps when I looked stressed at my desk to hilarious one-liners, Tyler has been a great moral booster. I am also thankful for the following class, Melinda Chan and Ally Stanko. I need to thank Melinda for support and friendship over the years. I remember when we first met, you almost called the police because you didn’t have my number saved and I convinced you over text that you were being roped in to a cocaine smuggling ring in the Cats. Anyways, thank you for the Ting Ting workouts, letting me babysit Poo, and the life advice. Our group then rapidly expanded two classes of seven graduate students. Jay Barbor, Kali Flesch, Kevin Gonzales, Elliot Hicks, Farbod Moghadam, Samir Rezgui, and Adrian Samkian were all amazing additions to the group. The following year we were blessed with Ruby Chen, Ben Gross, Kim Sharp, Christian Strong, Camila Suarez, Marva Tariq, and Hao Yu. It was fun watching all of this new talent flood into the group as the size of our family grew dramatically. I am excited to see what our vii most recent class, Adrian de Almenara, Sydney Bottcher, Chloe Cerione, and Jonathan Farhi, will accomplish over the next few years. I am grateful for the talented group of postdocs I have overlapped with over the years. Dr. Stephen Sardini has been an awesome friend and project partner. Stephen is a talented chemist and has started and developed several exciting projects in his time in the Stoltz group. Thank you for helping me out whenever I got stuck and always pushing me to be a hard little worker. Dr. Veronica Hubble has been another key figure during my time in the Stoltz group. I remember chatting on the phone about Brian and research in the Stoltz group when you were considering pursuing a postdoc here. Fortunately, you decided to come to Caltech, and the rest is history. Dr. Melissa Ramirez has been an awesome addition to the group. Our conversations on academia, science, and life never failed to offer me a new perspective on things – this I value a ton. In addition to the former group members mentioned earlier, I have to give a special thanks to Dr. Chris Reimann for being a “fatherly” figure to me and Alexia when we were baby G1s. Thank you for always supporting us regardless of whatever wild situation in which we found ourselves. Long live “Bible Club.” My years prior to Caltech were formative. I am indebted to Professor Markus Etzkorn at UNC Charlotte for welcoming me into his research group during my high school years. Those early experiences introduced me to the exciting field that is organic chemistry, about which I have remained passionate ever since. Following this, I had the great fortune of working with Professor Joshua Pierce during my undergraduate years at NC State. His guidance and support (and patience) were crucial to my development as a young scientist and ultimately led to me pursuing graduate school. I would also especially like to thank Dr. viii Yasamin Moazami and the entirety of the Pierce group for being amazing mentors during these years. Lastly, I would like to extend my gratitude to my loving family, without whom none of this would be possible. My parents, and sister Nicki, have been an amazing support system every step of the way. To this day, without fail, I receive embarrassingly decorated “care packages” all the way from North Carolina for even the smallest of holidays. Thank you for always encouraging me to pursue my passions, and for the endless love. Of course, I have to thank my amazing girlfriend, Meagan Castañeda, for being by my side through this crazy journey. Meeting you was the best thing to happen to me during my time here. I am so lucky to have you and I am excited for the next steps in our life together. At last, mga anak natin Pingu, Koala, at Kokak – salamat sa support. ix ABSTRACT Research in the Stoltz group is centered around the development of novel tactics and strategies for the synthesis of complex organic molecules. The Pd-catalyzed decarboxylative asymmetric allylic alkylation of enolate nucleophiles is a cornerstone of our groups’ efforts to develop methodologies that directly facilitate the synthesis of stereochemically complex molecular building blocks. This thesis first focuses on our efforts to deepen our mechanistic understanding of these transformations. We then employ our insights as a base from which we expand the scope of the decarboxylative asymmetric allylic alkylation reaction, as well as develop entirely novel reaction paradigms. x PUBLISHED CONTENT AND CONTRIBUTIONS 1. Duquette, D. C.; Cusumano, A. Q.; Lefoulon, L.; Moore, J. T.; Stoltz, B. M. Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones. Org. Lett. 2020, 22, 4966–4969. DOI: 10.1021/acs.orglett.0c01441. A.Q.C. participated in manuscript preparation. 2. Cusumano, A. Q.; Stoltz, B. M.; Goddard, W. A. III. Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) Cross-Coupling. J. Am. Chem. Soc. 2020, 142, 13917–13933. DOI: 10.1021/jacs.0c06243. A.Q.C. carried out computational studies, experimental work, data analysis, and manuscript preparation. 3. Cusumano, A. Q.; Goddard, W. A. I.; Stoltz, B. M. The Transition Metal Catalyzed [π2s + π2s + s2s + s2s] Pericyclic Reaction: Woodward–Hoffmann Rules, Aromaticity, and Electron Flow. J. Am. Chem. Soc. 2020, 142, 19033–19039. DOI: 10.1021/jacs.0c09575. A.Q.C. carried out computational studies, data analysis, and manuscript preparation. 4. Zhang, T.; Cusumano, A. Q.; Hafeman, N. J.; Loskot, S. A.; Reimann, C. E.; Virgil, S. C.; Goddard, W. A. I.; Stoltz, B. M. Investigations of an Unexpected [2+2] Photocycloaddition in the Synthesis of (−)-Scabrolide A from Quantum Mechanics Calculations. J. Org. Chem. 2022, 87, 14115–14124. DOI: 10.1021/acs.joc.2c01693. A.Q.C. carried out computational studies, data analysis, and manuscript preparation. xi 5. Flesch, K. N.; Cusumano, A. Q.; Chen, P.-J.; Strong, C. S.; Sardini, S. R.; Du, Y. E.; Bartberger, M. D.; Goddard, W. A. I.; Stoltz, B. M. Divergent Catalysis: Catalytic Asymmetric [4+2] Cycloaddition of Palladium Enolates. J. Am. Chem. Soc. 2023. In press. DOI: 10.1021/jacs.3c02104. A.Q.C. carried out experimental work, computational studies, data analysis, and manuscript preparation. xii TABLE OF CONTENTS Dedication ...............................................................................................iii Acknowledgements ................................................................................. iv Abstract .................................................................................................. ix Published Content and Contributions ....................................................... x Table of Contents.................................................................................... xii List of Figures ......................................................................................... xvi List of Schemes ................................................................................... xxxv List of Tables ..................................................................................... xxxvii List of Abbreviations .......................................................................... xxxix CHAPTER 1 1 Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 1.1 1.2 1.3 1.4 1.5 1.6 Introduction .................................................................................................... 1 Computational Methods ................................................................................. 5 Results ............................................................................................................ 6 1.3.1 Oxidative Addition .............................................................................. 7 1.3.2 Decarboxylation ................................................................................ 13 1.3.3 C–C Bond Formation via Reductive Elimination ................................ 23 1.3.4 Complete Catalytic Cycle .................................................................. 35 1.3.5 Experiment and Discussion ............................................................... 39 Conclusions .................................................................................................. 43 Supporting Information ................................................................................. 46 1.5.1 General Computational Details ......................................................... 46 1.5.2 Initial Benchmarking ......................................................................... 49 1.5.3 Decarboxylation and Control Experiments ........................................ 52 1.5.4 Prediction of Enantioselectivity.......................................................... 53 1.5.5 Additional Notes ............................................................................... 57 1.5.6 Experimental Procedures and Spectroscopic Data ............................. 63 References and Notes ................................................................................... 67 xiii APPENDIX 1 Spectra Relevant to Chapter 1 CHAPTER 2 Analysis of the Pd [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 2.1 2.2 2.3 2.4 2.5 3.3 3.4 83 Introduction .................................................................................................. 83 Results and Discussion ................................................................................. 84 Conclusions .................................................................................................. 95 Supporting Information ................................................................................ 95 2.4.1 General Computational Details ......................................................... 95 2.4.2 NEVPT2/CASSCF Active Spaces and Results ..................................... 97 2.4.3 Additional Notes on NEVPT2/CASSCF Calculations ........................ 115 2.4.4 Discussion on Other Main Group Chelefuges ................................. 115 2.4.5 Exploring Exchange Coupling in Diradical Intermediate 30 ............ 117 2.4.6 Redox Innocence of the PHOX Ligand in the [π2s + π2s + σ2s + σ2s] Reaction .......................................................................................... 122 2.4.7 Nucleus Independent Chemical Shift (NICS) Calculations ............... 124 2.4.8 Intrinsic Bonding Orbital (IBO) Analysis .......................................... 125 References .................................................................................................. 126 CHAPTER 3 Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 3.1 3.2 80 136 Introduction ................................................................................................ 136 Results and Discussion ............................................................................... 138 3.2.1 Reaction Design and Optimization ................................................. 138 3.2.2 Proposed Mechanism ...................................................................... 143 3.2.3 Substrate Scope ............................................................................... 144 3.2.4 [4+2] Cycloaddition ........................................................................ 149 3.2.5 Catalyst Turnover ............................................................................ 152 3.2.6 Further Mechanism-based Developments ....................................... 153 3.2.7 Product Derivatizations ................................................................... 155 Conclusions ................................................................................................ 158 Supporting Information ............................................................................... 158 3.4.1 Materials and Methods .................................................................... 158 3.5 xiv 3.4.2 Experimental Procedures and Spectroscopic Data ....................... 160 3.4.3 Determination of Absolute and Relative Stereochemistry by VCD Spectroscopy ................................................................................... 262 3.4.4 2D NMR Analysis of Select Compounds ......................................... 287 3.4.5 General Computational Details ...................................................... 294 References and Notes ................................................................................. 303 APPENDIX 2 Spectra Relevant to Chapter 3 315 CHAPTER 4 537 Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.1 4.2 4.3 4.4 4.5 4.6 Introduction ................................................................................................ 537 Computational Methods ............................................................................. 539 Results and Discussion ............................................................................... 540 4.3.1 Step 1: Photoexcitation .................................................................... 541 4.3.2 Step 2: First C–C Bond Formation .................................................... 544 4.3.3 Step 3: Second C–C Bond Formation .............................................. 549 4.3.4 Complete Mechanism ..................................................................... 553 Conclusions ................................................................................................ 556 Supporting Information ............................................................................... 557 4.5.1 General Computational Details ....................................................... 557 References and Notes ................................................................................. 574 CHAPTER 5 586 Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 5.1 5.2 5.3 5.4 5.5 5.6 Introduction ................................................................................................ 586 Mechanism and Development ................................................................... 588 Substrate Scope ......................................................................................... 590 Product Transformations ............................................................................. 593 Conclusions ................................................................................................ 593 Supporting Information ............................................................................... 594 5.6.1 Materials and Methods .................................................................... 594 5.7 xv 5.6.2 Experimental Procedures and Spectroscopic Data ........................ 596 References and Notes ................................................................................. 639 APPENDIX 3 Spectra Relevant to Chapter 5 644 APPENDIX 4 Notebook Cross-Reference for New Compounds 753 ABOUT THE AUTHOR 757 xvi LIST OF FIGURES CHAPTER 1 Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) Cross-Coupling Figure 1.1 Figure 1.2 Figure 1.3 Figure 1.4 Figure 1.5 Figure 1.6 Figure 1.7 Figure 1.8 Figure 1.9 Figure 1.10 Figure 1.11 Figure 1.12 Figure 1.13 Figure 1.14 Figure 1.15 Pd-catalyzed Decarboxylative Asymmetric Allylic Alkylation ............ 2 Four classes of Pd0 allyl carboxylate oxidative addition....................... 8 Isomeric transition state for the anti-displacement-type oxidative addition ............................................................................................... 9 Relative free energies of constitutional isomers of h1– and h3–allyl Pd complexes from masked enolate synthons ........................................ 12 Experimentally-derived parameters for decarboxylation and decarboxylation pathways considered............................................... 14 Structures of rate-limiting transition states for decarboxylation .......... 19 Inner-sphere C–C bond forming transition states considered ............. 23 Reductive elimination from Pd enolate 13......................................... 25 Structures of the two lowest energy diastereomeric transition states of TS20 ................................................................................................... 26 Complete catalytic cycle for the inner-sphere allylic alkylation reaction ........................................................................................................... 36 Free energy profile of minimum energy pathway through full catalytic cycle ................................................................................................. 38 Conversion of 1 to (S)-2 under standard reaction conditions ............. 40 Effect of decarboxylation mechanism on downstream enantioselectivity .......................................................................................................... 41 Effect of solvation and ligand electronics on enantioselectivity ......... 43 Select frontier MOs of a model PtII complex highlighting potential hybridization of 2a’ and 3a’. ............................................................. 60 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1 1 H NMR (400 MHz, CDCl3) of compound 20 ................................... 81 Figure A1.2 Figure A1.3 xvii Infrared spectrum (Thin Film, NaCl) of compound 20 .................. 82 13 C NMR (100 MHz, CDCl3) of compound 20................................... 82 CHAPTER 2 Analysis of the Pd [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Figure 2.1 Figure 2.2 Figure 2.3 Figure 2.4 Figure 2.5 Figure 2.6 Figure 2.7 Figure 2.8 Figure 2.9 Figure 2.10 Figure 2.11 Figure 2.12 Figure 2.13 Figure 2.14 Figure 2.15 Figure 2.16 Figure 2.17 Figure 2.18 Figure 2.19 Figure 2.20 Figure 2.21 Figure 2.22 Figure 2.23 Figure 2.24 Seven-centered cyclic transition states in Pd catalysis. ...................... 84 Orbital correlation diagram for the [π2s + π2s + σ2s + σ2s] quasicheletropic reaction of diallyl sulfone .............................................. 86 Orbital correlation diagram for the pericyclic reaction of 26 to 28.... 90 FMO perspective of the [π2s + π2s + σ2s + σ2s] reaction ................. 91 IBO analysis the Pd [π2s + π2s + σ2s + σ2s] reaction ....................... 94 MCSCF active space orbitals and energies of complex 13. ................ 99 MCSCF active space orbitals and energies of complex TS20 ........... 100 MCSCF active space orbitals and energies of complex 19 ............... 101 MCSCF active space orbitals and energies of 23 ............................. 102 MCSCF active space orbitals and energies of TS27.......................... 103 MCSCF active space orbitals and energies of diradical 30 ............... 104 MCSCF active space orbitals and energies of TS28.......................... 105 MCSCF active space orbitals and energies of SO2 (24) .................... 106 MCSCF active space orbitals and energies of (s-cis)-1,5-hexadiene (25_cis) ............................................................................................ 107 MCSCF active space orbitals and energies of (s-trans)-1,5-hexadiene (25_trans) ........................................................................................ 108 MCSCF active space orbitals and energies of complex 26 ............... 109 MCSCF active space orbitals and energies of complex 27 ............... 110 MCSCF active space orbitals and energies of TS25.......................... 111 MCSCF active space orbitals and energies of TS26.......................... 112 MCSCF active space orbitals and energies of 28 ............................. 113 MCSCF active space orbitals and energies of 29 ............................. 114 Orbital correlation diagram for the ground-state symmetry-forbidden [π2s + π2s + σ2s + σ2s] extrusion of CO from hepta-1,6-dien-4-one ........................................................................................................ 116 Exchange coupling via IDDCI ......................................................... 121 Orbitals involved in the vertical transitions to the lowest energy singlet and triplet excited states at TS20. .................................................... 124 xviii CHAPTER 3 Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.1 Figure 3.2 Figure 3.3 Figure 3.4 Figure 3.5 Figure 3.6 Figure 3.7 Figure 3.8 Figure 3.9 Figure 3.10 Figure 3.11 Figure 3.12 Figure 3.13 Figure 3.14 Figure 3.15 Figure 3.16 Figure 3.17 Figure 3.18 Figure 3.19 Examples of chiral Pd enolate reactivity and proposed reaction ...... 137 General reactivity paradigm from Pd enolate 43 ............................. 139 Sacrificial additives to enable catalyst turnover and additive-free reaction with prenyl ester 40a ......................................................... 141 Eyring analysis of 41/49 product ratio for propylene and butylene tethered substrates 40a and 40f ....................................................... 147 Irreversibility of C–C bond formation and origins of enantioinduction in the [4+2] cycloaddition step............................................................ 151 Two lowest-energy pathways for catalyst turnover .......................... 153 KIE study and prenyl ester modification........................................... 154 Product derivatizations of [4+2] products........................................ 157 Three diastereomers 41a, 41q, and 41q’ to be compared to spectra computed from all eight possible stereoisomers .............................. 264 Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_endo-trans ................................................ 265 Overlayed experimental and calculated VCD spectra for 41a – assigned as ent-A_endo-trans ........................................................................ 265 Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_exo-trans................................................... 266 Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_endo-cis .................................................... 267 Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_exo-cis ...................................................... 268 Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_endo-trans ................................................ 269 Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_exo-trans................................................... 270 Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_endo-cis .................................................... 271 Overlayed experimental and calculated VCD spectra for 41q – assigned as ent-A_endo-cis ............................................................................ 271 Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_exo-cis ...................................................... 272 Figure 3.20 Figure 3.21 Figure 3.22 Figure 3.23 Figure 3.24 Figure 3.25 Figure 3.26 Figure 3.27 Figure 3.28 Figure 3.29 Figure 3.30 Figure 3.31 Figure 3.32 Figure 3.33 Figure 3.34 Figure 3.35 Figure 3.36 Figure 3.37 Figure 3.38 Figure 3.39 xix Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_endo-trans ................................................ 273 Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_exo-trans................................................... 274 Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_endo-cis .................................................... 275 Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_exo-cis ...................................................... 276 Overlayed experimental and calculated VCD spectra for 41q’ – assigned as ent-A_exo-cis .............................................................................. 276 Three diastereomers 41k, 41k’, and 41k’’ to be compared to spectra computed from all eight possible stereoisomers. ............................. 277 Experimental VCD and IR spectra for product 41k compared to computed spectra for B_endo-trans................................................. 278 Overlayed experimental and calculated VCD spectra for 41k – assigned as B_endo-trans............................................................................... 278 Experimental VCD and IR spectra for product 41k compared to computed spectra for B_exo-trans ................................................... 279 Experimental VCD and IR spectra for product 41k compared to computed spectra for B_endo-cis .................................................... 280 Experimental VCD and IR spectra for product 41k compared to computed spectra for B_exo-cis ...................................................... 281 Experimental IR spectrum for product 41k’ compared to computed spectra for isomers of B ................................................................... 282 Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_endo-trans................................................. 283 Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_exo-trans ................................................... 284 Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_endo-cis .................................................... 285 Overlayed experimental and calculated VCD spectra for 41k’’ – assigned as B_endo-cis ................................................................... 285 Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_exo-cis ...................................................... 286 1 H-1H COSY NMR spectrum of 41a (400 MHz, CDCl3) .................. 287 1 H-13C HSQC NMR spectrum of 41a (400 MHz, CDCl3) ................. 288 1 H-1H NOESY NMR spectrum of 41a (400 MHz, CDCl3). ............... 288 Figure 3.40 Figure 3.41 Figure 3.42 Figure 3.43 Figure 3.44 Figure 3.45 Figure 3.46 Figure 3.47 Figure 3.48 Figure 3.49 Figure 3.50 Figure 3.51 Figure 3.52 Figure 3.53 Figure 3.54 xx H- H COSY NMR spectrum of 41p (400 MHz, CDCl3) ............... 289 1 H-13C HSQC NMR spectrum of 41p (400 MHz, CDCl3) ................. 289 1 H-1H NOESY NMR spectrum of 41p (400 MHz, CDCl3) ................ 290 1 H-1H COSY NMR spectrum of 41q (400 MHz, CDCl3) .................. 290 1 H-13C HSQC NMR spectrum of 41q (400 MHz, CDCl3) ................. 291 1 H-1H NOESY NMR spectrum of 41q (400 MHz, CDCl3) ................ 291 1 H-1H COSY NMR spectrum of 41q’ (400 MHz, CDCl3) ................. 292 1 H-13C HSQC NMR spectrum of 41q’ (400 MHz, CDCl3) ................ 292 1 H-1H NOESY NMR spectrum of 41q’ (400 MHz, CDCl3) ............... 293 Relative free energies for various inner-sphere reductive elimination transition states from allyl (13), cinnamyl (116), and prenyl (117) complexes ...................................................................................... 293 Relative free energies for various proton transfer transition states from post-cycloaddition enolate 56 ......................................................... 298 Relative free energies for various proton transfer transition states from pre-cycloaddition enolate 55........................................................... 299 IBO analysis of N-detached inner-sphere mechanism and corresponding derived arrow-pushing mechanism .......................... 300 Computed pKa values of cationic π-allyl Pd complex 119 and ketones 49a and 41a. ................................................................................... 301 Comparison of internal versus external dienophile approach to both enantiotopic diene faces, select low energy conformers of TS31 and space filling models ......................................................................... 302 1 1 APPENDIX 2 Spectra Relevant to Chapter 3 Figure A2.1 Figure A2.2 Figure A2.3 Figure A2.4 Figure A2.5 Figure A2.6 Figure A2.7 Figure A2.8 Figure A2.9 Figure A2.10 1 H NMR (400 MHz, CDCl3) of compound 41a ............................. 316 Infrared spectrum (Thin Film, NaCl) of compound 41a ................ 317 13 C NMR (100 MHz, CDCl3) of compound 41a ............................ 317 1 H NMR (400 MHz, CDCl3) of compound 41b............................. 318 Infrared spectrum (Thin Film, NaCl) of compound 41b ................ 319 13 C NMR (100 MHz, CDCl3) of compound 41b ............................ 319 1 H NMR (400 MHz, CDCl3) of compound 41c ............................. 320 Infrared spectrum (Thin Film, NaCl) of compound 41c ................ 321 13 C NMR (100 MHz, CDCl3) of compound 41c ............................ 321 1 H NMR (400 MHz, CDCl3) of compound 41d............................. 322 Figure A2.11 Figure A2.12 Figure A2.13 Figure A2.14 Figure A2.15 Figure A2.16 Figure A2.17 Figure A2.18 Figure A2.19 Figure A2.20 Figure A2.21 Figure A2.22 Figure A2.23 Figure A2.24 Figure A2.25 Figure A2.26 Figure A2.27 Figure A2.28 Figure A2.29 Figure A2.30 Figure A2.31 Figure A2.32 Figure A2.33 Figure A2.34 Figure A2.35 Figure A2.36 Figure A2.37 Figure A2.38 Figure A2.39 Figure A2.40 Figure A2.41 Figure A2.42 Figure A2.43 Figure A2.44 Figure A2.45 Figure A2.46 Figure A2.47 xxi Infrared spectrum (Thin Film, NaCl) of compound 41d ............ 323 13 C NMR (100 MHz, CDCl3) of compound 41d ............................ 323 1 H NMR (400 MHz, CDCl3) of compound 41f ............................. 324 Infrared spectrum (Thin Film, NaCl) of compound 41f ................. 325 13 C NMR (100 MHz, CDCl3) of compound 41f ............................. 325 1 H NMR (400 MHz, CDCl3) of compound 41j.............................. 326 Infrared spectrum (Thin Film, NaCl) of compound 41j ................. 327 13 C NMR (100 MHz, CDCl3) of compound 41j ............................. 327 1 H NMR (400 MHz, CDCl3) of compound 41k ............................. 328 Infrared spectrum (Thin Film, NaCl) of compound 41k ................ 329 13 C NMR (100 MHz, CDCl3) of compound 41k ............................ 329 1 H NMR (400 MHz, CDCl3) of compound 41k’ ............................ 330 Infrared spectrum (Thin Film, NaCl) of compound 41k’ ............... 331 13 C NMR (100 MHz, CDCl3) of compound 41k’ ........................... 331 1 H NMR (400 MHz, CDCl3) of compound 41k’’ ........................... 332 Infrared spectrum (Thin Film, NaCl) of compound 41k’’ .............. 333 13 C NMR (100 MHz, CDCl3) of compound 41k’’ .......................... 333 1 H NMR (400 MHz, CDCl3) of compound 41l.............................. 334 Infrared spectrum (Thin Film, NaCl) of compound 41l ................. 335 13 C NMR (100 MHz, CDCl3) of compound 41l ............................. 335 1 H NMR (400 MHz, CDCl3) of compound 41m............................ 336 Infrared spectrum (Thin Film, NaCl) of compound 41m ............... 337 13 C NMR (100 MHz, CDCl3) of compound 41m ........................... 337 1 H NMR (400 MHz, CDCl3) of compound 41m’........................... 338 Infrared spectrum (Thin Film, NaCl) of compound 41m’ .............. 339 13 C NMR (100 MHz, CDCl3) of compound 41m’ .......................... 339 1 H NMR (400 MHz, CDCl3) of compound 41n............................. 340 Infrared spectrum (Thin Film, NaCl) of compound 41n ................ 341 13 C NMR (100 MHz, CDCl3) of compound 41n ............................ 341 1 H NMR (400 MHz, CDCl3) of compound 41o............................. 342 Infrared spectrum (Thin Film, NaCl) of compound 41o ................ 343 13 C NMR (100 MHz, CDCl3) of compound 41o ............................ 343 1 H NMR (400 MHz, CDCl3) of compound 41o’............................ 344 Infrared spectrum (Thin Film, NaCl) of compound 41o’ ............... 345 13 C NMR (100 MHz, CDCl3) of compound 41o’ ........................... 345 1 H NMR (400 MHz, CDCl3) of compound 41p............................. 346 Infrared spectrum (Thin Film, NaCl) of compound 41p ................ 347 Figure A2.48 Figure A2.49 Figure A2.50 Figure A2.51 Figure A2.52 Figure A2.53 Figure A2.54 Figure A2.55 Figure A2.56 Figure A2.57 Figure A2.58 Figure A2.59 Figure A2.60 Figure A2.61 Figure A2.62 Figure A2.63 Figure A2.64 Figure A2.65 Figure A2.66 Figure A2.67 Figure A2.68 Figure A2.69 Figure A2.70 Figure A2.71 Figure A2.72 Figure A2.73 Figure A2.74 Figure A2.75 Figure A2.76 Figure A2.77 Figure A2.78 Figure A2.79 Figure A2.80 Figure A2.81 Figure A2.82 Figure A2.83 Figure A2.84 xxii C NMR (100 MHz, CDCl3) of compound 41p ....................... 347 1 H NMR (400 MHz, CDCl3) of compound 41p’............................ 348 Infrared spectrum (Thin Film, NaCl) of compound 41p’ ............... 349 13 C NMR (100 MHz, CDCl3) of compound 41p’ ........................... 349 1 H NMR (400 MHz, CDCl3) of compound 41q............................. 350 Infrared spectrum (Thin Film, NaCl) of compound 41q ................ 351 13 C NMR (100 MHz, CDCl3) of compound 41q ............................ 351 1 H NMR (400 MHz, CDCl3) of compound 41q’............................ 352 Infrared spectrum (Thin Film, NaCl) of compound 41q’ ............... 353 13 C NMR (100 MHz, CDCl3) of compound 41q’ ........................... 353 1 H NMR (400 MHz, CDCl3) of compound 41r ............................. 354 Infrared spectrum (Thin Film, NaCl) of compound 41r ................. 355 13 C NMR (100 MHz, CDCl3) of compound 41r ............................ 355 1 H NMR (400 MHz, CDCl3) of compound 41s ............................. 356 Infrared spectrum (Thin Film, NaCl) of compound 41s ................. 357 13 C NMR (100 MHz, CDCl3) of compound 41s ............................ 357 1 H NMR (400 MHz, CDCl3) of compound 41t ............................. 358 Infrared spectrum (Thin Film, NaCl) of compound 41t ................. 359 13 C NMR (100 MHz, CDCl3) of compound 41t............................. 359 1 H NMR (400 MHz, CDCl3) of compound 41t’ ............................ 360 Infrared spectrum (Thin Film, NaCl) of compound 41t’ ................ 361 13 C NMR (100 MHz, CDCl3) of compound 41t’............................ 361 1 H NMR (400 MHz, CDCl3) of compound 41u............................. 362 Infrared spectrum (Thin Film, NaCl) of compound 41u ................ 363 13 C NMR (100 MHz, CDCl3) of compound 41u ............................ 363 1 H NMR (400 MHz, CDCl3) of compound D-41f ......................... 364 Infrared spectrum (Thin Film, NaCl) of compound D-41f ............. 365 13 C NMR (100 MHz, CDCl3) of compound D-41f......................... 365 2 H NMR (61 MHz, CHCl3) of compound D-41f ........................... 366 1 H NMR (400 MHz, CDCl3) of compound 44............................... 367 Infrared spectrum (Thin Film, NaCl) of compound 44 .................. 368 13 C NMR (100 MHz, CDCl3) of compound 44 .............................. 368 1 H NMR (400 MHz, CDCl3) of compound 40a ............................. 369 Infrared spectrum (Thin Film, NaCl) of compound 40a ................ 370 13 C NMR (100 MHz, CDCl3) of compound 40a ............................ 370 1 H NMR (400 MHz, CDCl3) of compound 40b............................. 371 Infrared spectrum (Thin Film, NaCl) of compound 40b ................ 372 13 xxiii Figure A2.85 C NMR (100 MHz, CDCl3) of compound 40b .......................372 1 Figure A2.86 H NMR (400 MHz, CDCl3) of compound 40c ............................. 373 Figure A2.87 Infrared spectrum (Thin Film, NaCl) of compound 40c ................ 374 Figure A2.88 13C NMR (100 MHz, CDCl3) of compound 40c ............................ 374 Figure A2.89 1H NMR (400 MHz, CDCl3) of compound 40d............................. 375 Figure A2.90 Infrared spectrum (Thin Film, NaCl) of compound 40d ................ 376 Figure A2.91 13C NMR (100 MHz, CDCl3) of compound 40d ............................ 376 Figure A2.92 1H NMR (400 MHz, CDCl3) of compound 40e ............................. 377 Figure A2.93 Infrared spectrum (Thin Film, NaCl) of compound 40e ................ 378 Figure A2.94 13C NMR (100 MHz, CDCl3) of compound 40e ............................ 378 Figure A2.95 1H NMR (400 MHz, CDCl3) of compound 40f ............................. 379 Figure A2.96 Infrared spectrum (Thin Film, NaCl) of compound 40f ................. 380 Figure A2.97 13C NMR (100 MHz, CDCl3) of compound 40f ............................. 380 Figure A2.98 1H NMR (400 MHz, CDCl3) of compound D-40f ......................... 381 Figure A2.99 Infrared spectrum (Thin Film, NaCl) of compound D-40f ............. 382 Figure A2.100 13C NMR (100 MHz, CDCl3) of compound D-40f......................... 382 Figure A2.101 2H NMR (61 MHz, CHCl3) of compound D-40f ........................... 383 Figure A2.102 1H NMR (400 MHz, CDCl3) of compound 40g ............................. 384 Figure A2.103 Infrared spectrum (Thin Film, NaCl) of compound 40g ................ 385 Figure A2.104 13C NMR (100 MHz, CDCl3) of compound 40g ............................ 385 Figure A2.105 1H NMR (400 MHz, CDCl3) of compound 40h............................. 386 Figure A2.106 Infrared spectrum (Thin Film, NaCl) of compound 40h ................ 387 Figure A2.107 13C NMR (100 MHz, CDCl3) of compound 40h ............................ 387 Figure A2.108 1H NMR (400 MHz, CDCl3) of compound 40i.............................. 388 Figure A2.109 Infrared spectrum (Thin Film, NaCl) of compound 40i ................. 389 Figure A2.110 13C NMR (100 MHz, CDCl3) of compound 40 .............................. 389 Figure A2.111 1H NMR (400 MHz, CDCl3) of compound 40j.............................. 390 Figure A2.112 Infrared spectrum (Thin Film, NaCl) of compound 40j ................. 391 Figure A2.113 13C NMR (100 MHz, CDCl3) of compound 40j ............................. 391 Figure A2.114 1H NMR (400 MHz, CDCl3) of compound 40k ............................. 392 Figure A2.115 Infrared spectrum (Thin Film, NaCl) of compound 40k ................ 393 Figure A2.116 13C NMR (100 MHz, CDCl3) of compound 40k ............................ 393 Figure A2.117 1H NMR (400 MHz, CDCl3) of compound 40l.............................. 394 Figure A2.118 Infrared spectrum (Thin Film, NaCl) of compound 40l ................. 395 Figure A2.119 13C NMR (100 MHz, CDCl3) of compound 40l ............................. 395 Figure A2.120 1H NMR (400 MHz, CDCl3) of compound 40m............................ 396 Figure A2.121 Infrared spectrum (Thin Film, NaCl) of compound 40m ............... 397 13 xxiv Figure A2.122 C NMR (100 MHz, CDCl3) of compound 40m ..................... 397 Figure A2.123 1H NMR (400 MHz, CDCl3) of compound 40n............................. 398 Figure A2.124 Infrared spectrum (Thin Film, NaCl) of compound 40n ................ 399 Figure A2.125 13C NMR (100 MHz, CDCl3) of compound 40n ............................ 399 Figure A2.126 1H NMR (400 MHz, CDCl3) of compound 40o............................. 400 Figure A2.127 Infrared spectrum (Thin Film, NaCl) of compound 40o ................ 401 Figure A2.128 13C NMR (100 MHz, CDCl3) of compound 40o ............................ 401 Figure A2.129 1H NMR (400 MHz, CDCl3) of compound 99............................... 402 Figure A2.130 Infrared spectrum (Thin Film, NaCl) of compound 99 .................. 403 Figure A2.131 13C NMR (100 MHz, CDCl3) of compound 99 .............................. 403 Figure A2.132 1H NMR (400 MHz, CDCl3) of compound 40p............................. 404 Figure A2.133 Infrared spectrum (Thin Film, NaCl) of compound 40p ................ 405 Figure A2.134 13C NMR (100 MHz, CDCl3) of compound 40p ............................ 405 Figure A2.135 1H NMR (400 MHz, CDCl3) of compound 40q............................. 406 Figure A2.136 Infrared spectrum (Thin Film, NaCl) of compound 40q ................ 407 Figure A2.137 13C NMR (100 MHz, CDCl3) of compound 40q ............................ 407 Figure A2.138 1H NMR (400 MHz, CDCl3) of compound 40r ............................. 408 Figure A2.139 Infrared spectrum (Thin Film, NaCl) of compound 40r ................. 409 Figure A2.140 13C NMR (100 MHz, CDCl3) of compound 40r ............................ 409 Figure A2.141 1H NMR (400 MHz, CDCl3) of compound 40s ............................. 410 Figure A2.142 Infrared spectrum (Thin Film, NaCl) of compound 40s ................. 411 Figure A2.143 13C NMR (100 MHz, CDCl3) of compound 40s ............................ 411 Figure A2.144 1H NMR (400 MHz, CDCl3) of compound 40t ............................. 412 Figure A2.145 Infrared spectrum (Thin Film, NaCl) of compound 40t ................. 413 Figure A2.146 13C NMR (100 MHz, CDCl3) of compound 40t............................. 413 Figure A2.147 1H NMR (400 MHz, CDCl3) of compound 40u............................. 414 Figure A2.148 Infrared spectrum (Thin Film, NaCl) of compound 40u ................ 415 Figure A2.149 13C NMR (100 MHz, CDCl3) of compound 40u ............................ 415 Figure A2.150 1H NMR (400 MHz, CDCl3) of compound 42............................... 416 Figure A2.151 Infrared spectrum (Thin Film, NaCl) of compound 42 .................. 417 Figure A2.152 13C NMR (100 MHz, CDCl3) of compound 42 .............................. 417 Figure A2.153 1H NMR (400 MHz, CDCl3) of compound 47............................... 418 Figure A2.154 Infrared spectrum (Thin Film, NaCl) of compound 47 .................. 419 Figure A2.155 13C NMR (100 MHz, CDCl3) of compound 47 .............................. 419 Figure A2.156 1H NMR (400 MHz, CDCl3) of compound 101............................. 420 Figure A2.157 Infrared spectrum (Thin Film, NaCl) of compound 101 ................ 421 Figure A2.158 13C NMR (100 MHz, CDCl3) of compound 101 ............................ 421 13 xxv Figure A2.159 H NMR (400 MHz, CDCl3) of compound 102........................ 422 Figure A2.160 Infrared spectrum (Thin Film, NaCl) of compound 102 ................ 423 Figure A2.161 13C NMR (100 MHz, CDCl3) of compound 102 ............................ 423 Figure A2.162 1H NMR (400 MHz, CDCl3) of compound 85............................... 424 Figure A2.163 Infrared spectrum (Thin Film, NaCl) of compound 85 .................. 425 Figure A2.164 13C NMR (100 MHz, CDCl3) of compound 85 .............................. 425 Figure A2.165 1H NMR (400 MHz, CDCl3) of compound 86............................... 426 Figure A2.166 Infrared spectrum (Thin Film, NaCl) of compound 86 .................. 427 Figure A2.167 13C NMR (100 MHz, CDCl3) of compound 86 .............................. 427 Figure A2.168 1H NMR (400 MHz, CDCl3) of compound D-86........................... 428 Figure A2.169 Infrared spectrum (Thin Film, NaCl) of compound D-86 .............. 429 Figure A2.170 13C NMR (100 MHz, CDCl3) of compound D-86 .......................... 429 Figure A2.171 2H NMR (61 MHz, CHCl3) of compound D-86............................. 430 Figure A2.172 1H NMR (400 MHz, CDCl3) of compound 87............................... 431 Figure A2.173 Infrared spectrum (Thin Film, NaCl) of compound 87 .................. 432 Figure A2.174 13C NMR (100 MHz, CDCl3) of compound 87 .............................. 432 Figure A2.175 1H NMR (400 MHz, CDCl3) of compound 93............................... 433 Figure A2.176 Infrared spectrum (Thin Film, NaCl) of compound 93 .................. 434 Figure A2.177 13C NMR (100 MHz, CDCl3) of compound 93 .............................. 434 Figure A2.178 1H NMR (400 MHz, CDCl3) of compound 88............................... 435 Figure A2.179 Infrared spectrum (Thin Film, NaCl) of compound 88 .................. 436 Figure A2.180 13C NMR (100 MHz, CDCl3) of compound 88 .............................. 436 Figure A2.181 1H NMR (400 MHz, CDCl3) of compound 89............................... 437 Figure A2.182 Infrared spectrum (Thin Film, NaCl) of compound 89 .................. 438 Figure A2.183 13C NMR (100 MHz, CDCl3) of compound 89 .............................. 438 Figure A2.184 1H NMR (400 MHz, CDCl3) of compound 90............................... 439 Figure A2.185 Infrared spectrum (Thin Film, NaCl) of compound 90 .................. 440 Figure A2.186 13C NMR (100 MHz, CDCl3) of compound 90 .............................. 440 Figure A2.187 1H NMR (400 MHz, CDCl3) of compound 91............................... 441 Figure A2.188 Infrared spectrum (Thin Film, NaCl) of compound 91 .................. 442 Figure A2.189 13C NMR (100 MHz, CDCl3) of compound 91 .............................. 442 Figure A2.190 1H NMR (400 MHz, CDCl3) of compound 92............................... 443 Figure A2.191 Infrared spectrum (Thin Film, NaCl) of compound 92 .................. 444 Figure A2.192 13C NMR (100 MHz, CDCl3) of compound 92 .............................. 444 Figure A2.193 1H NMR (400 MHz, CDCl3) of compound 96............................... 445 Figure A2.194 Infrared spectrum (Thin Film, NaCl) of compound 96 .................. 446 Figure A2.195 13C NMR (100 MHz, CDCl3) of compound 96 .............................. 446 1 xxvi Figure A2.196 H NMR (400 MHz, CDCl3) of compound 95......................... 447 Figure A2.197 Infrared spectrum (Thin Film, NaCl) of compound 95 .................. 448 Figure A2.198 13C NMR (100 MHz, CDCl3) of compound 95 .............................. 448 Figure A2.199 1H NMR (400 MHz, CDCl3) of compound 94............................... 449 Figure A2.200 Infrared spectrum (Thin Film, NaCl) of compound 94 .................. 450 Figure A2.201 13C NMR (100 MHz, CDCl3) of compound 94 .............................. 450 Figure A2.202 1H NMR (400 MHz, CDCl3) of compound 98............................... 451 Figure A2.203 Infrared spectrum (Thin Film, NaCl) of compound 98 .................. 452 Figure A2.204 13C NMR (100 MHz, CDCl3) of compound 98 .............................. 452 Figure A2.205 1H NMR (400 MHz, CDCl3) of compound 97............................... 453 Figure A2.206 Infrared spectrum (Thin Film, NaCl) of compound 97 .................. 454 Figure A2.207 13C NMR (100 MHz, CDCl3) of compound 97 .............................. 454 Figure A2.208 1H NMR (400 MHz, CDCl3) of compound 100............................. 455 Figure A2.209 Infrared spectrum (Thin Film, NaCl) of compound 100 ................ 456 Figure A2.210 13C NMR (100 MHz, CDCl3) of compound 100 ............................ 456 Figure A2.211 1H NMR (400 MHz, CDCl3) of compound D-100 ........................ 457 Figure A2.212 Infrared spectrum (Thin Film, NaCl) of compound D-100 ............ 458 Figure A2.213 13C NMR (100 MHz, CDCl3) of compound D-100 ........................ 458 Figure A2.214 2H NMR (61 MHz, CHCl3) of compound D-100........................... 459 Figure A2.215 1H NMR (400 MHz, CDCl3) of compound 103............................. 460 Figure A2.216 Infrared spectrum (Thin Film, NaCl) of compound 103 ................ 461 Figure A2.217 13C NMR (100 MHz, CDCl3) of compound 103 ............................ 461 Figure A2.218 1H NMR (400 MHz, CDCl3) of compound 107............................. 462 Figure A2.219 Infrared spectrum (Thin Film, NaCl) of compound 107 ................ 463 Figure A2.220 13C NMR (100 MHz, CDCl3) of compound 107 ............................ 463 Figure A2.221 1H NMR (400 MHz, CDCl3) of compound 105............................. 464 Figure A2.222 Infrared spectrum (Thin Film, NaCl) of compound 105 ................ 465 Figure A2.223 13C NMR (100 MHz, CDCl3) of compound 105 ............................ 465 Figure A2.224 1H NMR (400 MHz, CDCl3) of compound 106............................. 466 Figure A2.225 Infrared spectrum (Thin Film, NaCl) of compound 106 ................ 467 Figure A2.226 13C NMR (100 MHz, CDCl3) of compound 106 ............................ 467 Figure A2.227 1H NMR (400 MHz, CDCl3) of compound 113............................. 468 Figure A2.228 Infrared spectrum (Thin Film, NaCl) of compound 113 ................ 469 Figure A2.229 13C NMR (100 MHz, CDCl3) of compound 113 ............................ 469 Figure A2.230 1H NMR (400 MHz, CDCl3) of compound 104............................. 470 Figure A2.231 Infrared spectrum (Thin Film, NaCl) of compound 104 ................ 471 Figure A2.232 13C NMR (100 MHz, CDCl3) of compound 104 ............................ 471 1 xxvii Figure A2.233 H NMR (400 MHz, CDCl3) of compound 108.......................472 Figure A2.234 Infrared spectrum (Thin Film, NaCl) of compound 108 ................ 473 Figure A2.235 13C NMR (100 MHz, CDCl3) of compound 108 ............................ 473 Figure A2.236 1H NMR (400 MHz, CDCl3) of compound 109............................. 474 Figure A2.237 Infrared spectrum (Thin Film, NaCl) of compound 109 ................ 475 Figure A2.238 13C NMR (100 MHz, CDCl3) of compound 109 ............................ 475 Figure A2.239 1H NMR (400 MHz, CDCl3) of compound 110............................. 476 Figure A2.240 Infrared spectrum (Thin Film, NaCl) of compound 110 ................ 477 Figure A2.241 13C NMR (100 MHz, CDCl3) of compound 110 ............................ 477 Figure A2.242 1H NMR (400 MHz, CDCl3) of compound 111............................. 478 Figure A2.243 Infrared spectrum (Thin Film, NaCl) of compound 111 ................ 479 Figure A2.244 13C NMR (100 MHz, CDCl3) of compound 111 ............................ 479 Figure A2.245 1H NMR (400 MHz, CDCl3) of compound 112............................. 480 Figure A2.246 Infrared spectrum (Thin Film, NaCl) of compound 112 ................ 481 Figure A2.247 13C NMR (100 MHz, CDCl3) of compound 112 ............................ 481 Figure A2.248 1H NMR (400 MHz, CDCl3) of compound 49a ............................. 482 Figure A2.249 Infrared spectrum (Thin Film, NaCl) of compound 49a ................ 483 Figure A2.250 13C NMR (100 MHz, CDCl3) of compound 49a ............................ 483 Figure A2.251 1H NMR (400 MHz, CDCl3) of compound 49e ............................. 484 Figure A2.252 Infrared spectrum (Thin Film, NaCl) of compound 49e ................ 485 Figure A2.253 13C NMR (100 MHz, CDCl3) of compound 49e ............................ 485 Figure A2.254 1H NMR (400 MHz, CDCl3) of compound 49f ............................. 486 Figure A2.255 Infrared spectrum (Thin Film, NaCl) of compound 49f ................. 487 Figure A2.256 13C NMR (100 MHz, CDCl3) of compound 49f ............................. 487 Figure A2.257 1H NMR (400 MHz, CDCl3) of compound D-49f ......................... 488 Figure A2.258 Infrared spectrum (Thin Film, NaCl) of compound D-49f ............. 489 Figure A2.259 13C NMR (100 MHz, CDCl3) of compound D-49f......................... 489 Figure A2.260 2H NMR (61 MHz, CHCl3) of compound D-49f ........................... 490 Figure A2.261 1H NMR (400 MHz, CDCl3) of compound 49g ............................. 491 Figure A2.262 Infrared spectrum (Thin Film, NaCl) of compound 49g ................ 492 Figure A2.263 13C NMR (100 MHz, CDCl3) of compound 49g ............................ 492 Figure A2.264 1H NMR (400 MHz, CDCl3) of compound 49h............................. 493 Figure A2.265 Infrared spectrum (Thin Film, NaCl) of compound 49h ................ 494 Figure A2.266 13C NMR (100 MHz, CDCl3) of compound 49h ............................ 494 Figure A2.267 1H NMR (400 MHz, CDCl3) of compound 49i.............................. 495 Figure A2.268 Infrared spectrum (Thin Film, NaCl) of compound 49i ................. 496 Figure A2.269 13C NMR (100 MHz, CDCl3) of compound 49i ............................. 496 1 xxviii Figure A2.270 H NMR (400 MHz, CDCl3) of compound 83........................ 497 Figure A2.271 Infrared spectrum (Thin Film, NaCl) of compound 83 .................. 498 Figure A2.272 13C NMR (100 MHz, CDCl3) of compound 83 .............................. 498 Figure A2.273 1H NMR (400 MHz, CDCl3) of compound 84............................... 499 Figure A2.274 Infrared spectrum (Thin Film, NaCl) of compound 84 .................. 500 Figure A2.275 13C NMR (100 MHz, CDCl3) of compound 84 .............................. 500 Figure A2.276 1H NMR (400 MHz, CDCl3) of compound 59............................... 501 Figure A2.277 Infrared spectrum (Thin Film, NaCl) of compound 59 .................. 502 Figure A2.278 13C NMR (100 MHz, CDCl3) of compound 59 .............................. 502 Figure A2.279 1H NMR (400 MHz, CDCl3) of compound 63............................... 503 Figure A2.280 Infrared spectrum (Thin Film, NaCl) of compound 63 .................. 504 Figure A2.281 13C NMR (100 MHz, CDCl3) of compound 63 .............................. 504 Figure A2.282 1H NMR (400 MHz, CDCl3) of compound 64............................... 505 Figure A2.283 Infrared spectrum (Thin Film, NaCl) of compound 64 .................. 506 Figure A2.284 13C NMR (100 MHz, CDCl3) of compound 64 .............................. 506 Figure A2.285 1H NMR (400 MHz, CDCl3) of compound 65............................... 507 Figure A2.286 Infrared spectrum (Thin Film, NaCl) of compound 65 .................. 508 Figure A2.287 13C NMR (100 MHz, CDCl3) of compound 65 .............................. 508 Figure A2.288 1H NMR (400 MHz, CDCl3) of compound 66............................... 509 Figure A2.289 Infrared spectrum (Thin Film, NaCl) of compound 66 .................. 510 Figure A2.290 13C NMR (100 MHz, CDCl3) of compound 66 .............................. 510 Figure A2.291 1H NMR (400 MHz, CDCl3) of compound 67............................... 511 Figure A2.292 Infrared spectrum (Thin Film, NaCl) of compound 67 .................. 512 Figure A2.293 13C NMR (100 MHz, CDCl3) of compound 67 .............................. 512 Figure A2.294 1H NMR (400 MHz, CDCl3) of compound 68............................... 513 Figure A2.295 Infrared spectrum (Thin Film, NaCl) of compound 68 .................. 514 Figure A2.296 13C NMR (100 MHz, CDCl3) of compound 68 .............................. 514 Figure A2.297 1H NMR (400 MHz, CDCl3) of compound 114............................. 515 Figure A2.298 Infrared spectrum (Thin Film, NaCl) of compound 114 ................ 516 Figure A2.299 13C NMR (100 MHz, CDCl3) of compound 114 ............................ 516 Figure A2.300 1H NMR (400 MHz, CDCl3) of compound 69............................... 517 Figure A2.301 Infrared spectrum (Thin Film, NaCl) of compound 69 .................. 518 Figure A2.302 13C NMR (100 MHz, CDCl3) of compound 69 .............................. 518 Figure A2.303 1H NMR (400 MHz, CDCl3) of compound 70............................... 519 Figure A2.304 Infrared spectrum (Thin Film, NaCl) of compound 70 .................. 520 Figure A2.305 13C NMR (100 MHz, CDCl3) of compound 70 .............................. 520 Figure A2.306 1H NMR (400 MHz, CDCl3) of compound 75............................... 521 1 xxix Figure A2.307 Infrared spectrum (Thin Film, NaCl) of compound 75 ............ 522 Figure A2.308 13C NMR (100 MHz, CDCl3) of compound 75 .............................. 522 Figure A2.309 1H NMR (400 MHz, CDCl3) of compound 76............................... 523 Figure A2.310 Infrared spectrum (Thin Film, NaCl) of compound 76 .................. 524 Figure A2.311 13C NMR (100 MHz, CDCl3) of compound 76 .............................. 524 Figure A2.312 1H NMR (400 MHz, CDCl3) of compound 77............................... 525 Figure A2.313 Infrared spectrum (Thin Film, NaCl) of compound 77 .................. 526 Figure A2.314 13C NMR (100 MHz, CDCl3) of compound 77 .............................. 526 Figure A2.315 1H NMR (400 MHz, CDCl3) of compound 78............................... 527 Figure A2.316 Infrared spectrum (Thin Film, NaCl) of compound 78 .................. 528 Figure A2.317 13C NMR (100 MHz, CDCl3) of compound 78 .............................. 528 Figure A2.318 1H NMR (400 MHz, CDCl3) of compound 79............................... 529 Figure A2.319 Infrared spectrum (Thin Film, NaCl) of compound 79 .................. 530 Figure A2.320 13C NMR (100 MHz, CDCl3) of compound 79 .............................. 530 Figure A2.321 1H NMR (400 MHz, CDCl3) of compound 80............................... 531 Figure A2.322 Infrared spectrum (Thin Film, NaCl) of compound 80 .................. 532 Figure A2.323 13C NMR (100 MHz, CDCl3) of compound 80 .............................. 532 Figure A2.324 1H NMR (400 MHz, CDCl3) of compound 81............................... 533 Figure A2.325 Infrared spectrum (Thin Film, NaCl) of compound 81 .................. 534 Figure A2.326 13C NMR (100 MHz, CDCl3) of compound 81 .............................. 534 Figure A2.327 1H NMR (400 MHz, CDCl3) of compound 82............................... 535 Figure A2.328 Infrared spectrum (Thin Film, NaCl) of compound 82 .................. 536 Figure A2.329 13C NMR (100 MHz, CDCl3) of compound 82 .............................. 536 CHAPTER 4 Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Figure 4.1 Complete mechanism describing formation of unexpected product 124 from the intramolecular [2+2] photocycloaddition of enone 121 ...... 555 CHAPTER 5 Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles Figure 5.1 Asymmetric allylic alkylation of tetrasubstituted enolate nucleophiles xxx ...................................................................................................... 587 Figure 5.2 Computational studies and initial reaction development.................... 589 Figure 5.3 Substrate scope of branched-selective allylic alkylation ..................... 592 Figure 5.4 Branched allylic alkylation product derivatizations ............................ 593 APPENDIX 3 Spectra Relevant to Chapter 5 Figure A3.1 Figure A3.2 Figure A3.3 Figure A3.4 Figure A3.5 Figure A3.6 Figure A3.7 Figure A3.8 Figure A3.9 Figure A3.10 Figure A3.11 Figure A3.12 Figure A3.13 Figure A3.14 Figure A3.15 Figure A3.16 Figure A3.17 Figure A3.18 Figure A3.19 Figure A3.20 Figure A3.21 Figure A3.22 Figure A3.23 Figure A3.24 Figure A3.25 Figure A3.26 Figure A3.27 Figure A3.28 Figure A3.29 1 H NMR (400 MHz, CDCl3) of compound 160a ........................... 645 Infrared spectrum (Thin Film, NaCl) of compound 160a .............. 646 13 C NMR (100 MHz, CDCl3) of compound 160a .......................... 646 1 H NMR (400 MHz, CDCl3) of compound 160b........................... 647 Infrared spectrum (Thin Film, NaCl) of compound 160b .............. 648 13 C NMR (100 MHz, CDCl3) of compound 160b .......................... 648 1 H NMR (400 MHz, CDCl3) of compound 160c ........................... 649 Infrared spectrum (Thin Film, NaCl) of compound 160c .............. 650 13 C NMR (100 MHz, CDCl3) of compound 160c .......................... 650 1 H NMR (400 MHz, CDCl3) of compound 160d........................... 651 Infrared spectrum (Thin Film, NaCl) of compound 160d .............. 652 13 C NMR (100 MHz, CDCl3) of compound 160d .......................... 652 1 H NMR (400 MHz, CDCl3) of compound 160e ........................... 653 Infrared spectrum (Thin Film, NaCl) of compound 160e .............. 654 13 C NMR (100 MHz, CDCl3) of compound 160e .......................... 654 1 H NMR (400 MHz, CDCl3) of compound 160f ........................... 655 Infrared spectrum (Thin Film, NaCl) of compound 160f ............... 656 13 C NMR (100 MHz, CDCl3) of compound 160f ........................... 656 1 H NMR (400 MHz, CDCl3) of compound 160g ........................... 657 Infrared spectrum (Thin Film, NaCl) of compound 160g .............. 658 13 C NMR (100 MHz, CDCl3) of compound 160g .......................... 658 1 H NMR (400 MHz, CDCl3) of compound 160h........................... 659 Infrared spectrum (Thin Film, NaCl) of compound 160h .............. 660 13 C NMR (100 MHz, CDCl3) of compound 160h .......................... 660 1 H NMR (400 MHz, CDCl3) of compound 160i............................ 661 Infrared spectrum (Thin Film, NaCl) of compound 160i ............... 662 13 C NMR (100 MHz, CDCl3) of compound 160i ........................... 662 1 H NMR (400 MHz, CDCl3) of compound 160j............................ 663 Infrared spectrum (Thin Film, NaCl) of compound 160j ............... 664 Figure A3.30 Figure A3.31 Figure A3.32 Figure A3.33 Figure A3.34 Figure A3.35 Figure A3.36 Figure A3.37 Figure A3.38 Figure A3.39 Figure A3.40 Figure A3.41 Figure A3.42 Figure A3.43 Figure A3.44 Figure A3.45 Figure A3.46 Figure A3.47 Figure A3.48 Figure A3.49 Figure A3.50 Figure A3.51 Figure A3.52 Figure A3.53 Figure A3.54 Figure A3.55 Figure A3.56 Figure A3.57 Figure A3.58 Figure A3.59 Figure A3.60 Figure A3.61 Figure A3.62 Figure A3.63 Figure A3.64 Figure A3.65 Figure A3.66 xxxi C NMR (100 MHz, CDCl3) of compound 160j ..................... 664 1 H NMR (400 MHz, CDCl3) of compound 160k ........................... 665 Infrared spectrum (Thin Film, NaCl) of compound 160k .............. 666 13 C NMR (100 MHz, CDCl3) of compound 160k .......................... 666 1 H NMR (400 MHz, CDCl3) of compound 160l............................ 667 Infrared spectrum (Thin Film, NaCl) of compound 160l ............... 668 13 C NMR (100 MHz, CDCl3) of compound 160l ........................... 668 1 H NMR (400 MHz, CDCl3) of compound 160m ......................... 669 Infrared spectrum (Thin Film, NaCl) of compound 160m ............. 670 13 C NMR (100 MHz, CDCl3) of compound 160m ......................... 670 19 F NMR (282 MHz, CDCl3) of compound 160m ......................... 671 1 H NMR (400 MHz, CDCl3) of compound 160n........................... 672 Infrared spectrum (Thin Film, NaCl) of compound 160n .............. 673 13 C NMR (100 MHz, CDCl3) of compound 160n .......................... 673 19 F NMR (282 MHz, CDCl3) of compound 160n .......................... 674 1 H NMR (400 MHz, CDCl3) of compound 160o........................... 675 Infrared spectrum (Thin Film, NaCl) of compound 160o .............. 676 13 C NMR (100 MHz, CDCl3) of compound 160o .......................... 676 19 F NMR (282 MHz, CDCl3) of compound 160o .......................... 677 1 H NMR (400 MHz, CDCl3) of compound 160p........................... 678 Infrared spectrum (Thin Film, NaCl) of compound 160p .............. 679 13 C NMR (100 MHz, CDCl3) of compound 160p .......................... 679 19 F NMR (282 MHz, CDCl3) of compound 160p .......................... 680 1 H NMR (400 MHz, CDCl3) of compound 160p_linear................ 681 Infrared spectrum (Thin Film, NaCl) of compound 160p_linear ... 682 13 C NMR (100 MHz, CDCl3) of compound 160p_linear ............... 682 19 F NMR (282 MHz, CDCl3) of compound 160p_linear ............... 683 1 H NMR (400 MHz, CDCl3) of compound 160q_mixture ............ 684 1 H NMR (400 MHz, CDCl3) of compound 160q........................... 685 Infrared spectrum (Thin Film, NaCl) of compound 160q .............. 686 13 C NMR (100 MHz, CDCl3) of compound 160q .......................... 686 19 F NMR (282 MHz, CDCl3) of compound 160q .......................... 687 1 H NMR (400 MHz, CDCl3) of compound 158a ........................... 688 Infrared spectrum (Thin Film, NaCl) of compound 158a .............. 689 13 C NMR (100 MHz, CDCl3) of compound 158a .......................... 689 1 H NMR (400 MHz, CDCl3) of compound 158b........................... 690 Infrared spectrum (Thin Film, NaCl) of compound 158b .............. 691 13 xxxii Figure A3.67 C NMR (100 MHz, CDCl3) of compound 158b .................... 691 1 Figure A3.68 H NMR (400 MHz, CDCl3) of compound 158c ........................... 692 Figure A3.69 Infrared spectrum (Thin Film, NaCl) of compound 158c .............. 693 Figure A3.70 13C NMR (100 MHz, CDCl3) of compound 158c .......................... 693 Figure A3.71 1H NMR (400 MHz, CDCl3) of compound 158d........................... 694 Figure A3.72 Infrared spectrum (Thin Film, NaCl) of compound 158d .............. 695 Figure A3.73 13C NMR (100 MHz, CDCl3) of compound 158d .......................... 695 Figure A3.74 1H NMR (400 MHz, CDCl3) of compound 158e ........................... 696 Figure A3.75 Infrared spectrum (Thin Film, NaCl) of compound 158e .............. 697 Figure A3.76 13C NMR (100 MHz, CDCl3) of compound 158e .......................... 697 Figure A3.77 1H NMR (400 MHz, CDCl3) of compound 158f ........................... 698 Figure A3.78 Infrared spectrum (Thin Film, NaCl) of compound 158f ............... 699 Figure A3.79 13C NMR (100 MHz, CDCl3) of compound 158f ........................... 699 Figure A3.80 1H NMR (400 MHz, CDCl3) of compound 158g ........................... 700 Figure A3.81 Infrared spectrum (Thin Film, NaCl) of compound 158g .............. 701 Figure A3.82 13C NMR (100 MHz, CDCl3) of compound 158g .......................... 701 Figure A3.83 1H NMR (400 MHz, CDCl3) of compound 158h........................... 702 Figure A3.84 Infrared spectrum (Thin Film, NaCl) of compound 158h .............. 703 Figure A3.85 13C NMR (100 MHz, CDCl3) of compound 158h .......................... 703 Figure A3.86 1H NMR (400 MHz, CDCl3) of compound 158i............................ 704 Figure A3.87 Infrared spectrum (Thin Film, NaCl) of compound 158i ............... 705 Figure A3.88 13C NMR (100 MHz, CDCl3) of compound 158i ........................... 705 Figure A3.89 1H NMR (400 MHz, CDCl3) of compound 158j............................ 706 Figure A3.90 Infrared spectrum (Thin Film, NaCl) of compound 158j ............... 707 Figure A3.91 13C NMR (100 MHz, CDCl3) of compound 158j ........................... 707 Figure A3.92 1H NMR (400 MHz, CDCl3) of compound 158k ........................... 708 Figure A3.93 Infrared spectrum (Thin Film, NaCl) of compound 158k .............. 709 Figure A3.94 13C NMR (100 MHz, CDCl3) of compound 158k .......................... 709 Figure A3.95 1H NMR (400 MHz, CDCl3) of compound 158l............................ 710 Figure A3.96 Infrared spectrum (Thin Film, NaCl) of compound 158l ............... 711 Figure A3.97 13C NMR (100 MHz, CDCl3) of compound 158l ........................... 711 Figure A3.98 1H NMR (400 MHz, CDCl3) of compound 158m ......................... 712 Figure A3.99 Infrared spectrum (Thin Film, NaCl) of compound 158m ............. 713 Figure A3.100 13C NMR (100 MHz, CDCl3) of compound 158m ......................... 713 Figure A3.101 19F NMR (282 MHz, CDCl3) of compound 158m ......................... 714 Figure A3.102 1H NMR (400 MHz, CDCl3) of compound 158n........................... 715 Figure A3.103 Infrared spectrum (Thin Film, NaCl) of compound 158n .............. 716 13 xxxiii Figure A3.104 C NMR (100 MHz, CDCl3) of compound 158n ................... 716 Figure A3.105 19F NMR (282 MHz, CDCl3) of compound 158n .......................... 717 Figure A3.106 1H NMR (400 MHz, CDCl3) of compound 158o........................... 718 Figure A3.107 Infrared spectrum (Thin Film, NaCl) of compound 158o .............. 719 Figure A3.108 13C NMR (100 MHz, CDCl3) of compound 158o .......................... 719 Figure A3.109 19F NMR (282 MHz, CDCl3) of compound 158o .......................... 720 Figure A3.110 1H NMR (400 MHz, CDCl3) of compound 158p........................... 721 Figure A3.111 Infrared spectrum (Thin Film, NaCl) of compound 158p .............. 722 Figure A3.112 13C NMR (100 MHz, CDCl3) of compound 158p .......................... 722 Figure A3.113 19F NMR (282 MHz, CDCl3) of compound 158p .......................... 723 Figure A3.114 1H NMR (400 MHz, CDCl3) of compound 158q........................... 724 Figure A3.115 Infrared spectrum (Thin Film, NaCl) of compound 158q .............. 725 Figure A3.116 13C NMR (100 MHz, CDCl3) of compound 158q .......................... 725 Figure A3.117 19F NMR (282 MHz, CDCl3) of compound 158q .......................... 726 Figure A3.118 1H NMR (400 MHz, CDCl3) of compound 165a ........................... 727 Figure A3.119 Infrared spectrum (Thin Film, NaCl) of compound 165a .............. 728 Figure A3.120 13C NMR (100 MHz, CDCl3) of compound 165a .......................... 728 Figure A3.121 1H NMR (400 MHz, CDCl3) of compound 165b........................... 729 Figure A3.122 Infrared spectrum (Thin Film, NaCl) of compound 165b .............. 730 Figure A3.123 13C NMR (100 MHz, CDCl3) of compound 165b .......................... 730 Figure A3.124 1H NMR (400 MHz, CDCl3) of compound 165c ........................... 731 Figure A3.125 Infrared spectrum (Thin Film, NaCl) of compound 165c .............. 732 Figure A3.126 13C NMR (100 MHz, CDCl3) of compound 165c .......................... 732 Figure A3.127 1H NMR (400 MHz, CDCl3) of compound 165d........................... 733 Figure A3.128 Infrared spectrum (Thin Film, NaCl) of compound 165d .............. 734 Figure A3.129 13C NMR (100 MHz, CDCl3) of compound 165d .......................... 734 Figure A3.130 1H NMR (400 MHz, C6D6) of compound 165e ............................. 735 Figure A3.131 Infrared spectrum (Thin Film, NaCl) of compound 165e .............. 736 Figure A3.132 13C NMR (100 MHz, C6D6) of compound 165e ............................ 736 Figure A3.133 1H NMR (400 MHz, CDCl3) of compound 165f ........................... 737 Figure A3.134 Infrared spectrum (Thin Film, NaCl) of compound 165f ............... 738 Figure A3.135 13C NMR (100 MHz, CDCl3) of compound 165f ........................... 738 Figure A3.136 1H NMR (400 MHz, CDCl3) of compound 165g ........................... 739 Figure A3.137 Infrared spectrum (Thin Film, NaCl) of compound 165g .............. 740 Figure A3.138 13C NMR (100 MHz, CDCl3) of compound 165g .......................... 740 Figure A3.139 1H NMR (400 MHz, CDCl3) of compound L4 ............................... 741 Figure A3.140 Infrared spectrum (Thin Film, NaCl) of compound L4................... 742 13 xxxiv Figure A3.141 C NMR (100 MHz, CDCl3) of compound L4 ....................... 742 Figure A3.142 19F NMR (282 MHz, CDCl3) of compound L4............................... 743 Figure A3.143 31P NMR (121 MHz, CDCl3) of compound L4 .............................. 743 Figure A3.144 1H NMR (400 MHz, CDCl3) of compound L5 ............................... 744 Figure A3.145 Infrared spectrum (Thin Film, NaCl) of compound L5................... 745 Figure A3.146 13C NMR (100 MHz, CDCl3) of compound L5 .............................. 745 Figure A3.147 19F NMR (282 MHz, CDCl3) of compound L5............................... 746 Figure A3.148 31P NMR (121 MHz, CDCl3) of compound L5 .............................. 746 Figure A3.149 1H NMR (400 MHz, CDCl3) of compound L6 ............................... 747 Figure A3.150 Infrared spectrum (Thin Film, NaCl) of compound L6................... 748 Figure A3.151 13C NMR (100 MHz, CDCl3) of compound L6 .............................. 748 Figure A3.152 19F NMR (282 MHz, CDCl3) of compound L6............................... 749 Figure A3.153 31P NMR (121 MHz, CDCl3) of compound L6 .............................. 749 Figure A3.154 1H NMR (400 MHz, CDCl3) of compound L7 ............................... 750 Figure A3.155 Infrared spectrum (Thin Film, NaCl) of compound L7................... 751 Figure A3.156 13C NMR (100 MHz, CDCl3) of compound L7 .............................. 751 Figure A3.157 19F NMR (282 MHz, CDCl3) of compound L7............................... 752 Figure A3.158 31P NMR (121 MHz, CDCl3) of compound L7 .............................. 752 13 xxxv LIST OF SCHEMES CHAPTER 1 Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) Cross-Coupling Scheme 1.1 Scheme 1.2 Scheme 1.3 Free energy network from resting state 3 through decarboxylation .... 15 Relative energy of select h1– and h 3–allyl intermediates ................... 22 Various C–C bond forming pathways ................................................ 30 CHAPTER 3 Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Scheme 3.1 Proposed divergent catalytic cycle .................................................. 144 CHAPTER 4 Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Scheme 4.1 Scheme 4.2 Scheme 4.3 Scheme 4.4 Scheme 4.5 Scheme 4.6 Scheme 4.7 Scheme 4.8 Scheme 4.9 Photochemical [2+2] approach to scabrolide A .............................. 538 General four-step mechanism for the olefin/a,b-unsaturated carbonyl [2+2] photocycloaddition................................................................ 541 Photoexcitation of 3_S0 and conversion to reactive triplet diradical 121_3(nπ*) ....................................................................................... 543 Eight lowest energy reaction pathways from 121_3(ππ*) .................. 546 Predicted reactivity from diradical 126............................................ 550 Predicted reactivity from diradical 125............................................ 551 All four diastereomeric 5-exo-trig b-attack transition states and products ........................................................................................................ 562 All four diastereomeric 4-exo-trig b-attack transition states and products ........................................................................................................ 563 All diastereomeric products for 6-exo-trig α-attack (144–147), 6-endotrig β-attack (148–149), 5-endo-trig β-attack (150–151), and 5-exo-trig α-attack (152–155) .......................................................................... 564 xxxvi Scheme 4.10 Conformational influence on outcome post-ISC ....................... 565 Scheme 4.11 PESs generated from single point calculations along the BS-DFT IRC trajectories of 1126 to TS54 to 124 .................................................. 568 Scheme 4.12 Comparison of performance in relaxed surface scan of ring closure of diradical 1126 to form observed but undesired product 124 of various DFT functionals with respect to NEVPT2 ......................................... 570 Scheme 4.12 Comparison of performance in relaxed surface scan of ring closure of diradical 1125 to form observed but undesired product 120 of various DFT functionals with respect to NEVPT2 ......................................... 571 Scheme 4.12 Comparison of performance in relaxed surface scan of ring closure of diradical 1125 to form observed but undesired product 120 of various DFT functionals with respect to NEVPT2 ......................................... 571 xxxvii LIST OF TABLES CHAPTER 1 Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) Cross-Coupling Table 1.1 Table 1.2 Table 1.3 Table 1.4 Table 1.5 Table 1.6 Table 1.7 Table 1.8 Table 1.9 Table 1.10 Table 1.11 Qualitative comparison of relative free energy barrier heights along reductive elimination pathways.......................................................... 35 Comparison of geometric parameters obtained from geometry optimization with various functionals and basis sets .......................... 50 Decarboxylation barrier heights with geometries optimized in gas phase and with CPCM(THF) ......................................................................... 52 Decarboxylation barrier heights of complexes derived from the (R) enantiomer of 1 .................................................................................. 53 Comparison of relative free energies obtained across a variety of density functional methods............................................................................. 54 Comparison of relative free energies obtained at the DLPNO-CCSD(T) level of theory .................................................................................... 56 Optimization without D3 corrections (BP86) ..................................... 56 Optimization with B3LYP-D3............................................................. 57 Relative free energies (in kcal/mol) of isomeric oxidative addition transition states at various levels of theory .......................................... 59 Comparison of barrier heights to decarboxylation with the standard (S)t-BuPHOX and electron poor (S)-(CF3)3-t-BuPHOX ligands................. 61 Inner-sphere reductive elimination transition states with a-phenyl substrate ............................................................................................. 61 CHAPTER 2 Analysis of the Pd [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Table 2.1 Table 2.2 Calculation of spin exchange coupling constant (J) between spin centers in 1,4-diradical 30 ............................................................................ 119 TD-DFT vertical excitations at stationary points 13, TS20, and 19 ... 123 xxxviii CHAPTER 3 Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Table 3.1 Table 3.2 Optimization of [4+2] reaction conditions ....................................... 142 Substrate scope of the [4+2] reaction ............................................... 145 CHAPTER 4 Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Table 4.1 Table 4.2 Table 4.3 Table 4.4 Comparison of vertical excitation energies calculated at the 121_S0 with various state-averaging schemes....................................................... 560 Free energy barriers to C–C bond formation/cleavage from 1126...... 567 Partitioning of five lowest-energy conformers of singlet diradical 1126 between four outcomes based on picosecond-scale AIMD calculations ......................................................................................................... 572 Partitioning of five lowest-energy conformers of singlet diradical 1125 between four outcomes based on picosecond-scale AIMD calculations ......................................................................................................... 573 xxxix LIST OF ABBREVIATIONS [a]D specific rotation at wavelength of sodium D line ºC degrees Celsius Å Angstrom Aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bz benzoyl c concentration for specific rotation measurements calc’d calculated cm–1 wavenumer(s) d doublet D deuterium dba dibenzylideneacetone DMF N,N-dimethylformamide dr diastereomeric ratio ee enantiomeric excess equiv equivalent(s) xl ESI electrospray ionization Et ethyl EtOAc ethyl acetate G grams GC gas chromatography h hours HPLC high-performance liquid chromatography HRMS high-resolution mass spectrometry Hz hertz IPA isopropanol IR infrared (spectroscopy) J coupling constant (NMR), exchange coupling constant (diradicals) K Kelvin (absolute temperature) kcal kilocalorie KHMDS potassium hexamethyldisilazide L liter; ligand LDA lithium diisopropylamide m/z mass to charge ratio Me methyl mg milligram(s) MHz megahertz min minutes mol mole(s) xli n-Bu n-butyl NMR nuclear magnetic resonance Pd/C palladium on carbon Ph phenyl PHOX phosphinooxazoline (ligand) ppm parts per million R generic for any atom or functional groups SCF self-consistent field SFC supercritical fluid chromatography CHAPTER 1 Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 1.1 INTRODUCTION The construction of chiral all-carbon quaternary centers remains a forefront challenge in synthetic chemistry 1 Over the years, our group has pursued the development of the decarboxylative asymmetric allylic alkylation reaction as a practical entry into these highly sought-after structural motifs (Figure 1.1A). 2 This approach has proved fruitful in asymmetric synthesis,3 particularly in the early-stage preparation of chiral building blocks. However, our efforts to further extend the scope of these transformations have highlighted limitations of the current catalytic systems. 4 We recognize that a comprehensive mechanistic understanding is crucial in our ability to address these shortcomings and to realize general improvements. Owing to the interplay of several plausible inner- and outersphere processes (Figure 1.1B), the unification of a comprehensive, stereochemically complete mechanistic hypothesis has remained elusive for the Pd(PHOX) system. Determination of inner- or outer-sphere nucleophilic attack through observation of retention (outer-sphere) or inversion (inner-sphere) of stereochemistry when employing chiral cyclic allyl electrophiles is not applicable as such substitution patterns are not †This research was performed under the co-advisory of Prof. William A. Goddard III. Portions of this chapter have been reproduced with permission from Cusumano, A. Q.; Stoltz, B. M.; Goddard, W. A. III. J. Am. Chem. Soc. 2020, 142, 13917–13933. © 2020 American Chemical Society. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 2 tolerated by the system at hand. Surprisingly, allylic alkylation with the Pd(PHOX) system demonstrates remarkable tolerance to exogenous water, with reaction yields and enantioselectivity largely unaffected. 5 These results suggest that the presence of an unbound enolate with a conjugate acid pKa significantly higher than that of water is unlikely. Given the tolerance to water, an inner-sphere mechanism for C–C bond formation is generally invoked for the Pd(PHOX) system. Figure 1.1. (A) Original report of the decarboxylative asymmetric allylic alkylation of b-ketoesters by Stoltz.2a (B) Inner- and outer-sphere allylic alkylation. (C) Isolation of the catalyst resting state.5 (D) This research. A. Allylic alkylation of 𝛃-ketoesters to forge chiral all-carbon quaternary centers.2a Key building block O Me O Pd2(dba)3 (2 mol %) (S)-t-BuPHOX (6.25 mol %) O O O Me Ph2P THF, 25 ºC B. Outer- versus inner-sphere allylic alkylation. P N t-Bu 85% yield, 88% ee (±)-1 = N (S)-2 (S)-t-BuPHOX C. Mechanistic Developments.5 Resting state PdII outersphere Nu Nu (±)-1 Pd0 P Pd2(dba)3 (S)-t-BuPHOX N Pd = THF, < 25 ºC O Me O O PdII Nu D. This research. Decarboxylation Reductive Elimination P N P N Pd (±)-1 3 [X-ray] innersphere Pd (S)-2 O O Me O DLPNO-CCSD(T) & DFT Invesitgation Me O Origins of Enantioselectivity Mechanism of Decarboxylation Inner- versus outer-sphere Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 3 In contrast, mechanistic studies by Trost and coworkers with the bis-phosphine (R,R)-ANDEN-phenyl ligand on related substrates suggest alkylation occurs via an outersphere mechanism.6 As anticipated with an ionic outer-sphere mechanism, highly charge stabilized “soft” enolates perform well in these systems. 7 Unlike the outer-sphere conditions of Trost, the Pd(PHOX) catalytic manifold provides low levels of enantioselectivity with stabilized enolate nucleophiles,4,8 yet the Pd(PHOX) system excels with basic “hard” enolates, as well as substrates that contain heteroatoms.9 Key to the inner-sphere C–C bond formation hypothesis is the intermediacy of a square planar C- or O-bound PdII enolate complex. In our efforts to directly observe such a species, our group isolated a unique h1-allyl PdII carboxylate complex (3) from the reaction of Pd2(dba)3, (S)-t-BuPHOX, and b-ketoester 1 (Figure 1.1C). The carboxylate complex was determined to be the catalyst resting state, with decarboxylation as the ratelimiting process (k = 1.58 x 10–3 s–1 at 24 ºC, corresponding to a free energy barrier of 21.2 kcal/mol).5 In addition to experimental studies, our groups have turned to quantum mechanics (QM) calculations as a powerful tool to interrogate the mechanism of the stereoablative transformation of (±)-1 to (S)-2.10 These investigations focused on post-decarboxylation intermediates, and ultimately led to the discovery of a low energy pathway for inner-sphere C–C bond formation via a seven-centered cyclic reductive elimination transition state (Figure 1.1D). Analogous fully carbocyclic mechanisms have been proposed by Morken and Echavarren. 11 While these initial studies offer an invaluable knowledge base, the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 4 mechanism of decarboxylation and the precise origins of enantioinduction remained unclear. To address these questions, we returned to computational and experimental studies. During our group’s ongoing efforts to explore the mechanism, Sargent and coworkers reported an all-DFT-based investigation of the Pd(PHOX)-catalyzed transformation of 1 to 2. 12 Unfortunately, the computationally-derived barrier to decarboxylation was significantly less than that of experiment, with the rate-limiting step as an isomerization to a pre-decarboxylation intermediate. Nevertheless, other aspects of their study regarding decarboxylation and C–C bond formation corroborate our computational and experimental findings herein. Taken together, these studies bring an unprecedented level of clarity to the mechanism of the decarboxylative asymmetric allylic alkylation reaction. Herein, we outline a detailed QM investigation into each step of the reaction mechanism: oxidative addition, decarboxylation, and C–C bond formation, revealing a mechanistic picture that unites all current experimental observations, including enantioinduction, reaction rate, identity of the catalyst resting state, enolate cross-over, water tolerance, and solvent effects on the interplay between inner- and outer-sphere pathways in the PHOX system (Figure 1.1D). To provide useful insight into factors underlying enantiomeric selectivity, very high quantum mechanical accuracy is required. Given this, we use this study as an opportunity to compare the efficacy of various modern computational methods (density functional theory and localized coupled-cluster theory) in the context of asymmetric Pd0/PdII catalysis. Further experiments are carried out to explore the mechanistic hypotheses derived from the ab initio calculations. Lastly, we address the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 5 shortcomings of the present state-of-the-art catalyst systems and offer theory-based insight into future development. 1.2 COMPUTATIONAL METHODS Density functional theory (DFT) geometry optimizations, energy, vibrational frequency, and coupled-cluster calculations were performed using Orca version 4.1.2.13 Geometry optimizations were carried out with the BP86 generalized gradient approximation (GGA) functional14 with Becke-Johnson damped D3 dispersion corrections (herein referred to as D3).15 A mixed basis set was implemented, in which Pd is described by the small core LANL2TZ(f) basis set with the Hay–Wadt effective core potential (ECP),16 while the 6-31G(d) basis set was used on all other atoms. Key structures were optimized at various levels of theory and compared to crystallographic data to ensure that consistent results are obtained across multiple methodologies (see 1.5 Supporting Information for details). Triple-z quality single point calculations were carried out on all stationary points with a variety of density functionals, including BP86-D3,14 B3LYP-D3, 17 PBE0-D3, 18 M06,19 and DSD-BLYP-D320 with the def2-TZVP basis set21 on all atoms (including the small core ECP28MWB pseudopotential 22 on Pd). Corrections for solvation (THF or otherwise as specified) were carried out for single point calculations with the implicit Conductor-like Polarizable Continuum Model (CPCM). 23 Unless otherwise noted, all energies reported are G298 values from single point calculations at the M06/def2TZVP/CPCM(THF) level of theory on BP86-D3/LANL2TZ(f)–6-31G(d) optimized Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 6 geometries with thermodynamic corrections applied from frequency calculations obtained at the optimization level of theory. The Quasi-RRHO method is applied to correct for the breakdown of the harmonic oscillator approximation for low frequency vibrations.24 All stationary points are characterized by the appropriate number of imaginary vibrational modes (zero for optimized geometries and one for transition states). Intrinsic reaction coordinate (IRC) analyses were carried out to ensure all transition states connect the appropriate starting materials and products. Molecular illustrations were made from CLYview.25 Additional single point calculations were performed on all optimized structures with the domain based local pair natural orbital coupled-cluster (DLPNO-CCSD(T), “NormalPNO” settings unless otherwise noted) method as described by Neese and coworkers and as implemented in Orca (further details included in Supporting Information). 26 The cc-pVTZ basis set is used on all atoms in the DLPNO-CCSD(T) calculations, with the SK-MCDHF-RSC effective core potential27 on Pd. Throughout the text, free energies calculated from electronic energies at the DLPNO-CCSD(T)/ccpVTZ/CPCM(THF) level of theory are provided in brackets next to the DFT (M06/CPCM(THF)) values for comparison. 1.3 RESULTS Our investigation began with the experimental observation of the [(PHOX)Pd(h1- allyl)(RCO2)] complex (3) as the resting state of the catalyst (Figure 1.2). The structure of this unusual h1–allyl complex was previously confirmed by X-ray crystallography while Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 7 the solution phase behavior was studied by NMR spectroscopy.5 Importantly, 3 is competent in the reaction, and affords the ketone product 2 from b-ketoester 1 in similar yield and enantioselectivity to that obtained from the catalytic transformation. Kinetic studies revealed first order rate dependence of this process in 3,5 with an overall rate constant measured to be 1.58 x 10–3 s–1 (at 24 ºC in THF-d8). Given that loss of CO2 is the rate limiting step, the experimental ∆G‡ of decarboxylation is calculated to be 21.2 kcal/mol. 1.3.1 OXIDATIVE ADDITION To better understand the role of the catalyst resting state (3) in the overall mechanistic picture, we first sought to examine the mechanism of oxidative addition of allyl b-ketoester 1 to the Pd0(PHOX) precatalyst. Oxidative addition of allyl acetate to Pd0 complexes is generally represented as directly generating the [LnPd(h3-allyl)](OAc) ion pair in situ in a reversible fashion. 28 This prompted us to question whether oxidative addition proceeds through a unique mechanism in which 3 is yielded directly, or if an analogous [(PHOX)Pd(h3-allyl)]+(RCO2–) ion pair (4) is first formed followed by rapid equilibration to 3 (Figure 1.2A). While the stereoablative transformation employs racemic substrate (1), the chiral center is not directly involved but rather appended to the site of oxidative addition through freely rotatable bonds. Hence, we expect comparable energies of the diastereomeric transition states arising from both enantiomers of 1. Our initial explorations considered the (S) enantiomer of 1, but the relevant oxidative addition pathways were also evaluated for Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 8 (R)-1. A similar consideration is employed with regard to the orientation of the allyl fragment in the h3–bound form. Here, the prefix endo describes the h3–(allyl) conformer in which the apical carbon (i.e., C2) of the allyl group is cis to the t-Bu group of the PHOX ligand, and exo corresponds to the trans isomer. Experimentally the endo and exo isomers were found to be nearly identical in energy. Both endo and exo geometries will be considered. Unless otherwise stated, free energy comparisons are from the lowest energy conformer. Figure 1.2. (A) Four general classes of Pd0 allyl carboxylate oxidative addition mechanisms (B) Stereoretentive three-centered (TS1), seven-centered (TS2), and syn SN2’-like (TS3) transition states.a B. Stereoretantive mechanisms (TS1–TS3). A. Oxidative addition mechanisms considered. Resting state P P 3-coordinate (TS1) or pericyclic (TS2) N P Pd N O Pd O Me O O Me O O P N N Pd O Me O O 3 Pd TS1 ∆G‡ = 56.1 [63.2] TS2 ∆G‡ = 26.9 [31.6] O O Me O Me O O 5 SN2’ -like (TS3) or SN2 -like (TS4) O Me O O Stereoretentive mechanisms not operative O N P N Pd P Pd TS3 4 ∆G‡ = 21.6 [22.1] [a] Relative Gibbs free energies in kcal/mol (M06). Free energies derived from DLPNO-CCSD(T) calculations in brackets. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 9 Starting from olefin-bound Pd0(PHOX) complex 5, a variety of transition states that achieve C–O bond cleavage were considered (Figure 1.2A). Three- (TS1)29,30 and sevenmembered (TS2) cyclic transition states,31 as well as a syn conjugate displacement-type mechanism (TS3) afford barrier heights greater than that of the rate-limiting step (∆G‡ = 21.2 kcal/mol) (Figure 1.2B).5 Figure 1.3. Isomeric transition states for the anti displacement-type oxidative addition mechanisms.a P N P Pd O Me O O O Me O O (t-N)-5: 0.0 [0.0] N Pd (t-N)-TS4: 6.4 [4.8] Me O O O N P (t-N)-TS4 Pd 4: –1.0 [–5.8] P P N N Pd Pd O O O Me Me O O O (t-P)-5: 0.1 [0.7] (t-P)-TS4: 12.6 [11.2] (t-P)-TS4 [a] Relative Gibbs free energies in kcal/mol (M06). Free energies derived from DLPNO-CCSD(T) calculations in brackets. Endo h3–allyl 4 is 0.3 [0.4] kcal/mol higher in energy than its exo isomer depicted above. Analogous to TS3, an anti displacement-type mechanism (TS4) via electrophilic addition to Pd0 presents a substantially lower barrier than that of the other pathways Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 10 Comprehensive Quantum Mechanics Investigation considered (Figure 1.3). Unlike TS3, in which C–O bond breaking occurs through the filling of s*(C–O) by the olefin-based p(C–C) orbital, TS4 achieves the same overall result with direct overlap between s*(C–O) and the Pd d(x2–y2)-based HOMO. Isomeric transition states are possible, in which the displacement event occurs trans to either the nitrogen or phosphorus of the PHOX ligand. The abbreviations t-N and t-P refer to C–O bond breaking occurring trans to N and trans to P, respectively. Here, we assume free equilibration between the isomers of 5. Therefore, we consider the apparent barrier height to be that of the lowest energy transition state from the lowest energy isomer (t-N)-5. From the corresponding olefin-bound Pd precursors (5), we found a barrier height of 12.6 [11.2] kcal/mol for (t-P)-TS4. Interestingly, considerably lower energy pathways were obtained for displacements trans to nitrogen, with a barrier of 6.4 [4.8] kcal/mol for (t-N)-TS4. A similar energetic preference for displacement trans to nitrogen is observed across several DFT methods. Oxidative addition via these mechanisms leads directly to ion pair 4. Additionally, as anticipated by experiment, the energy of endo and exo isomers of 4 were found to be nearly identical, with the exo-isomer favored by 0.3 [0.4] kcal/mol. Henceforth, reference to TS4 will specifically refer to the lowest energy isomer, (t-N)-TS4. In summary, of the oxidative addition pathways considered, olefin binding, followed by anti displacement (TS4) affords the lowest barrier height by a considerable margin. The displacement is stereospecific to inversion of chirality with respect to that of the leaving group, whereas the pathways involving a three-centered transition state (TS1), Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 11 Comprehensive Quantum Mechanics Investigation a seven-membered pericyclic transition state (TS2), or a syn conjugate displacement (TS3) would be anticipated to retain the configuration of the carboxylate leaving group (when substitution is present on the allyl terminus). We emphasize that consideration of each mechanistic pathway is crucial in order to reliably interpret net inversion/retention of stereochemistry as a general mechanistic probe in the Tsuji–Trost reaction.32 Furthermore, the two lowest energy pathways (direct/anti and conjugate/syn displacement) directly afford ion pair 4 rather than 3 as the product of oxidative addition. These results suggest that the observed h1–allyl catalyst resting state (3) is not the direct product of oxidative addition but is generated through a subsequent equilibration from ion pair 4. Curious as to the magnitude of the difference in energy between h1–allyl 3 and ion pair 4, we compared the calculated free energies of the two isomeric complexes. In accord with experiment, [(PHOX)Pd(h1–allyl)(RCO2)] (3) is computed to be favored over the [(PHOX)Pd(h3–allyl)]+(RCO2–) ion pair (4) by 5.4 kcal/mol (Figure 1.4). Single point calculations with several other density functionals give rise to similar results (∆G = 4.6 to 9.3 kcal/mol), showing that this outcome is not an artifact of the DFT functional. In agreement with the DFT values, a difference in free energy of 5.2 kcal/mol favoring 3 over 4 is obtained at the DLPNO-CCSD(T) level of theory and is taken to be our reference value. Interestingly, this trend appears not to be due to an extraneous effect of the bketocarboxylate leaving group, but rather a general feature of the Pd(PHOX) system with allyl acetates. Control experiments have been previously reported by our group in which the allyl b-ketoester was replaced with allyl acetate to similar effect.5 The corresponding Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 12 Comprehensive Quantum Mechanics Investigation [(PHOX)Pd(h1–allyl)(OAc)] complex (6) was isolated and characterized by X-ray crystallography and solution-phase NMR spectroscopy. Accordingly, the difference in free energies between 6 and ion pair 7 was calculated to be 6.6 [6.0] kcal/mol, favoring the h1– allyl form (Figure 1.4). Figure 1.4. Relative free energies of constitutional isomers of h1– and h3–allyl Pd complexes from masked enolate synthons, and acetate for comparison.a 𝜷-ketoesters acetates enol carbonates P P N P Pd O Me O O Me O O N P 3 0.0 [0.0] Pd 4 5.4 [5.2] N Me P Me O O O O N Pd O Pd O N Me Pd O O O O O Me N P 6 0.0 [0.0] 7 6.6 [6.0] 8 9.7 [9.7] Pd 9 10.3 [12.2] [a] Relative Gibbs free energies in kcal/mol (M06). Free energies derived from DLPNO-CCSD(T) calculations in brackets. We then sought to explore these trends for the allyl enol carbonate substrate class,2b for which a crystal structure of the catalyst resting state has yet to be obtained. As with the b-ketocarboxylates, the corresponding h1–allyl carbonate complex (8) was predicted to be favored over the h3–allyl carbonate ion pair (9) (Figure 1.4). Calculations with the M06 density functional predict a 0.6 kcal/mol preference for the h1-allyl form, while DLPNOCCSD(T) theory refines the energy difference to 2.5 kcal/mol, still favoring the h1–allyl form. Accordingly, 31P NMR studies suggest the catalyst resting state may be an analogous h1–allyl complex.5 Taking experimental and theoretical results into account, we anticipate Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 13 Comprehensive Quantum Mechanics Investigation that the h1–allyl form similarly dominates the solution phase character of the catalyst resting state. Complexes 3, 4, 8, and 9, are constitutional isomers. Since the subsequent reaction yields identical Pd enolate intermediates, we note that the enol carbonate substrate is predicted to undergo a more exergonic reaction than the b-ketocarboxylate isomer by ca. 10 kcal/mol. While investigation into the mechanism of decarboxylation of the enol carbonates 8/9 lies outside the scope of this investigation, we postulate the following: If the resting state of the catalyst in the enol carbonate system is described by 8/9 (analogous to the carboxylates), and if the absolute energy of the barrier to decarboxylation is similar to that of 3, then a significantly higher reaction rate is anticipated. We therefore wish to highlight the design of the enolate synthon as one avenue by which future improvements to the reaction rate may be achieved. 1.3.2 DECARBOXYLATION We then sought to explore the mechanism through which decarboxylation occurs. Loss of CO2 was experimentally determined to be the rate-limiting step of catalyst turnover.4 Deriving inspiration from the canonical decarboxylation of b-ketocarboxylic acids, we explored analogous cases for a PdII b-ketocarboxylate (Figure 1.5). Two isomeric square pyramidal transition states may be envisioned: one in which the carboxylate group is apically bound to Pd (TS5), and another with an equatorially bound carboxylate (TS6). Alternatively, decarboxylation could occur through a Zwitterionic square planar complex wherein the ketone of the b-ketocarboxylate is coordinated to h1–allyl Pd (TS14) or the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 14 Comprehensive Quantum Mechanics Investigation analogous h1–allyl case (TS15). As noted previously, the minimum energy pathway through oxidative addition directly affords ion pair 4, rather than the catalyst resting state 3. To explore the interconnectivity between these intermediates, as well as our postulated decarboxylative pathways, we constructed the free energy network depicted in Scheme 1.1. Beginning from the product of oxidative addition, ion pair 4, the catalyst resting state (3) can be reached via square pyramidal intermediate 11 (a higher energy conformer of 3) with an overall effective barrier of 4.3 [5.0] kcal/mol and ∆G of –5.4 [–5.2] kcal/mol (Scheme 1.1). Figure 1.5. (A) Experimentally-derived parameters for decarboxylation. (B) Decarboxylation pathways considered. A. Experimental rate and corresponding barrier for rate-limiting decarboxylation. Resting state P CO2 N P = O Me O Hypothesized Pd enolate O Mechanism unknown Me kdecarbox. = 1.58 x10–3 s–1 O ∆G‡ = 21.2 kcal/mol 3 [X-ray]a N Pd Pd 13 B. Possible decarboxylation mechanisms. O O O O X O O X + R OX (X = H, Li, Na …) R O Me O CO2 R P N Pd O P O N Me O Pd TS5 TS6 O X O X O O X O O O + R O R O R CO2 P N Pd O O Me TS14 O Me O N P Pd TS15 O Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 15 Comprehensive Quantum Mechanics Investigation Scheme 1.1. Free energy network from resting state 3 to decarboxylation pathways.a Resting state O P N Pd O Me P 3 0.0 [0.0] P O Pd N O Pd N 10: 16.1 [16.9]b CO2 Me O P N O P N Pd TS12: 9.7 [10.2] Me O O O (Si)-13: 0.6 [5.4] TS5: 22.0 [26.8] Pathway 3 O O Pd TS8: 19.1 [20.7] TS7: 11.8 [12.5] TS11: 9.1 [7.5] Pathway 1 Me O O TS9: 18.9 [20.4] O O Me Me O O N 11: 6.2 [3.3] Me O O P CO2 Me N P Pd 4: 5.4 [5.2] O N Pd P TS15: 17.5 [23.3] Pd 14: 9.7 [17.0] TS13: 14.0 [16.3] TS10: 23.7 [28.1] Pathway 2 CO2 P N Pd O P Me O O 12: 12.7 [15.9] N Pd O O Me O TS14: 17.1 [22.0] P N Pd O Me (Re)-13: 0.2 [5.1] [a] Free energies in kcal/mol (M06) with energies derived from DLPNO-CCSD(T) calculations in brackets. Minimum energy pathways through decarboxylation colored with higher energy alternatives in grey. Lowest energy conformers depicted. We then turned our attention to decarboxylation. Transition states TS5 and TS6 require the square pyramidal precursors 10 and 11, respectively (Scheme 1.1). Sufficiently low energy pathways connecting the resting state (3) to 10 and 11 are found. Decarboxylation is observed only through transition states in which the carboxylate group is poised axially on the six-membered ring, whether it be in a boat ((boat)-TS5) or chair ((chair)-TS5). This may result from the C–CO2– s orbital experiencing enhanced overlap Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 16 Comprehensive Quantum Mechanics Investigation with the p* of the ketone when occupying an axial position. While the chair conformers dominate the equilibrium geometries of 10, both M06 and DLPNO-CCSD(T) methods predict decarboxylation through (boat)-TS5 to be lower in energy than (chair)-TS5 by 1.8 and 2.8 kcal/mol, respectively. An apparent ∆G‡ value of 22.0 [26.8] kcal/mol is calculated from resting state 3 to TS5. We will henceforth refer to this sequence as decarboxylative pathway 1. While the barrier to decarboxylation via TS5 is quite low with respect to 10 (5.9 [9.9] kcal/mol), decarboxylation directly from 11 (via TS6) is not observed. This result is not unexpected, since weak axial binding is generally observed in square planar d8 complexes (in the absence of p back bonding) by virtue of the filled, axially-oriented metalbased d(z2) orbital, here of slight Pd–O s* character. Considering the role of the PdII center as a Lewis acid in promoting the decarboxylation, the weak axial binding of the ketone carbonyl in 11 to the metal center results in a complex that is poorly predisposed to decarboxylation. Furthermore, the LUMO of the square planar/square pyramidal d8 complexes are largely of metal-based d(x2–y2) character. As such, compared to 11, the equatorially-bound carbonyl of 10 exhibits greater overlap with the Pd-based LUMO, allowing for more effective charge transfer to the electropositive metal center. This, combined with the greater positive partial charge of the Pd center in 10 due to the weakly bound axial carboxylate counterion, results in facile decarboxylation. Analogous to the highly charge-separated cyclic form of 10, we were intrigued to find an acyclic variant, 12, as a stable intermediate on the potential energy surface. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 17 Comprehensive Quantum Mechanics Investigation Calculations reveal 12 equilibrates with resting state 3 via TS11–11–TS12–4–TS13 (Scheme 1.1). The highest barrier is that of TS13 at 14.0 [16.3] kcal/mol, with 12 at 12.7 [15.9] kcal/mol higher in energy than 3. As with 10, decarboxylation from 12 may then occur with the carboxylate oriented axially in either a chair or boat conformer, with the chair being lowest in energy (TS14). From 12, a barrier height of 4.4 [6.1] kcal/mol through TS14 is found. With respect to resting state 3, the overall barrier to decarboxylation through this pathway is 17.1 [22.0] kcal/mol. As with TS5, decarboxylation through this route directly affords the h1–allyl O–bound Pd enolate (Re)-13 (a rotamer of (Si)-13). We will henceforth denote this sequence as decarboxylative pathway 2. We next envisioned the possibility for decarboxylation to occur directly from the [h3–(allyl)Pd(PHOX)]+(RCO2–) ion pair, 4. We will term this sequence decarboxylative pathway 3. In pathway 3, the overall barrier height through decarboxylation was found to be 17.5 [23.2] kcal/mol via the lowest energy conformer of TS15. Dissimilar to pathways 1 and 2, pathway 3 does not lead directly to (Re/Si)-13 but rather the h3–allyl isomer 14. The relevance of this detail becomes apparent below in the free energy networks through which C–C bond forming occurs (Scheme 1.3). Loss of CO2 is the overall rate determining step for pathways 1, 2, and 3. Of the three, we found pathway 2 to have the lowest barrier at 17.1 [22.0] kcal/mol; however, pathway 3 is comparable in energy, with a barrier height of 17.5 [23.2] kcal/mol, and the difference between these pathways is likely within the accuracy of DFT. Single point calculations with B3LYP-D3, PBE0-D3 and DSD-BLYP-D3 favor TS14 by 5.0, 2.0, and Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 18 Comprehensive Quantum Mechanics Investigation 0.4 kcal/mol, respectively. Moreover, DLPNO-CCSD(T) calculations favor TS14 by 1.2 kcal/mol. Thus, we suggest an energetic preference for pathway 2. However, both pathways 2 and 3 remain mechanistically relevant under the reaction conditions. As previously mentioned, NMR experiments determined the rate constant of decarboxylation of isolated 3 to be 1.58 x10–3 s–1 at 24 ºC, corresponding to ∆G‡ of 21.2 kcal/mol, which is consistent with the observed reaction time of a few hours. This experimental data affords an opportunity to compare the computational methods utilized in this study. Interestingly, all density functionals employed predict lower barriers than that of experiment. The most accurate values are obtained with the global hybrid PBE0-D3 and the spin-component-scaled double-hybrid DSD-BLYP-D3, with calculated barriers of 20.2 kcal/mol and 18.6 kcal/mol, respectively. The popular B3LYP-D3 density functional affords the least accurate ∆G‡ of 16.5 kcal/mol. With a barrier of 17.1 kcal/mol, M06 also overestimates the rate of decarboxylation. High-quality coupled-cluster calculations with DLPNO-CCSD(T) provide an accurate barrier height of 22.0 kcal/mol, within 1.0 kcal/mol of experiment. Employing “TightPNO” cutoff criteria refines this value to 21.9 kcal/mol. Since the dipole moment of TS15 (19.7 D) is large compared to that of TS5 (12.2 D) and TS14 (13.6 D) (with M06/CPCM(THF)) we investigated the effect of solvation on the relative free energy barriers of the three pathways. Experimentally, high yields and enantioselectivities are observed across a variety of non-polar aprotic solvents, while yields and enantioselectivities diminish in polar, aprotic solvents.4 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 19 Comprehensive Quantum Mechanics Investigation Figure 1.6. Structures of rate-limiting transition states for decarboxylation pathways 1–3 and apparent barriers as a qualitative function of solvation.a O O Me O O P N Pd P N O Pd O O Me O N P TS5 Pathway 1 TS14 Pathway 2 O Me O O Pd H TS15 Pathway 3 toluene (𝞮 = 2.4) Et2O (𝞮 = 4.3) THF (𝞮 = 7.3) DMF (𝞮 = 38.2) TS14 Pathway 2 15.4 16.5 17.1 17.9 TS15 Pathway 3 19.6 18.3 17.5 16.6 TS5 Pathway 1 21.9 22.0 22.0 22.0 TS16 – – 20.3b – Me O TS16 [a] Apparent barriers to decarboxylation (∆G‡ from 3). Free energies reported in kcal/mol, calculated with M06/def2-TZVP/CPCM(solvent) on gas phase geometries. [b] With respect to the corresponding b-ketoacid (16-H). Our initial efforts to assess solvent dependence focused on solvent effects from single point calculations using the implicit Conductor-like Polarizable Continuum Model (CPCM) for geometries optimized in the gas phase. As stated above, we found net barrier heights of 17.1, 17.5, and 22.0 kcal/mol in THF (e = 7.3) for decarboxylation pathways 2, 3, and 1, respectively. Control computation experiments were carried out in which Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 20 Comprehensive Quantum Mechanics Investigation optimizations of select intermediates were additionally carried out in THF (see 1.5 Supporting Information), yielding similar results but with an even greater preference for pathway 2. In addition to THF (e = 7.3), we compared the barrier heights of the three decarboxylative pathways in the less polar solvents toluene (e = 2.4) and diethyl ether (e = 4.3), along with the more polar DMF (e = 38.3). A clear trend arises in which a continuum with a reduced charge permittivity (e < 8) favors pathway 2 (TS14), while pathway 3 (TS15) is preferred in solvents with higher dielectric constants (e > 8) (Figure 1.6). Specifically, TS14 is 4.2 kcal/mol lower in energy than TS15 in toluene, compared to a ∆∆G‡ of 1.8 and 0.4 kcal/mol (favoring TS14) in Et2O and THF, respectively. In DMF, pathway 3 is predicted to be most favorable, with TS15 1.3 kcal/mol lower in energy than TS14. Furthermore, we found these trends to be a result of the simultaneous lowering of the barrier of TS14 and raising that of TS15 with decreasing solvent polarity. For example, ∆G‡ of decarboxylation through TS14 with M06/def2-TZVP/CPCM(toluene) was found to be 15.4 kcal/mol, compared to 17.1 kcal/mol in THF. Meanwhile, the barrier height to TS15 is 19.6 kcal/mol in toluene, compared to 17.5 kcal/mol in THF. In conclusion, less polar solvents afford greater selectivity for pathway 2 while lowering the overall barrier height to decarboxylation through this pathway. Since the polarizable continuum implicit solvation model considers electrostatics as the sole component of solute-solvent interaction, it may be inadequate to quantitatively capture all effects in the experimental solvent variations – particularly when comparing Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 21 Comprehensive Quantum Mechanics Investigation solutes with very different cavities. We expect the general trends to remain qualitatively consistent with these findings, and thus, valuable for considerations in future reaction development. Recently, a new CPCM model was developed and implemented in ORCA (versions 5 and above) that employs a polarization charge density made of spherical Gaussians, rather than point charges, spread over the surface of the solute cavity resulting in a smoother potential. For future investigations, we recommend the use of this improved Gaussian charge scheme (GCS) for geometry optimization and single-point energy evaluation. As racemic allyl b-ketoester 1 is employed in the stereoablative transformation, we carried out an analogous investigation from the other diastereomer of 3, derived for the (R)-1. A qualitatively similar situation is encountered (see 1.5 Supporting Information). Previous mechanistic studies found both the reaction yield and product enantioenrichment to be tolerant of super-stoichiometric equivalencies of water.5 This result formed the basis of evidence for an inner-sphere mechanism. Additionally, crossover experiments with deuterium labeling of both the allyl fragment and enolate were performed. Since nearly equal quantities of the crossed products were observed, the involvement of an outer-sphere mechanism in which a solvated free enolate is indifferent to attacking either the labeled or unlabeled h3–allyl complexes may be considered but is inconsistent with the water-stability of the system. These results may also be accommodated within the innersphere mechanistic hypothesis as well when considering the carboxylate/carbonate intermediates are sufficiently stable to undergo exchange prior to decarboxylation. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 22 Comprehensive Quantum Mechanics Investigation Scheme 1.2. Relative energy of select h1– and h3–allyl intermediates.a P N O Pd O Me O O O N P 3: 0.0 [0.0] Me O O N P Pd + O O 15 16 Pd 4: 5.4 [5.2] Me 15 + 16: 6.2 [9.6] [a] Relative Gibbs free energies in kcal/mol (M06). Free energies derived from DLPNO-CCSD(T) calculations in brackets. For the b-ketocarboxylate intermediate, this mechanism appears to take place. Comparing the difference in free energy between ion pair 4 and solvent separated ions 15 and 16, it is reasonable that free exchange between the carboxylate anion and Pd cation may occur at a rate superseding that of decarboxylation (Scheme 1.2). Both inner and outersphere mechanisms may thus accommodate the results of the crossover experiments. Therefore, under these conditions, the observation of enolate/allyl electrophile crossover is irrelevant to differentiation between the two mechanistic pathways. With regard to water tolerance, we compared the barrier heights to decarboxylation for the conjugate acid of b-ketocarboxylate 16 (16-H) via the canonical six-membered cyclic transition state to those of the Pd-catalyzed pathways mentioned above. With ∆G‡ = 20.3 [26.1] kcal/mol for TS16, the lowest apparent barriers to decarboxylation remain those involving the Pd catalyst (pathways 2 and 3). Furthermore, the lower pKa of 16-H compared to water (ca. 10 units) affords a low effective concentration 16-H, and thus, a substantially slower reaction than would be indicated from the relative ∆G‡ from 16-H is expected. This offers an explanation as to why, in the Pd(PHOX)-catalyzed systems, the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 23 Comprehensive Quantum Mechanics Investigation decarboxylated but non-alkylated starting material is not observed. Hence, the experimentally observed water tolerance is well explained for this system. 1.3.3 C–C BOND FORMATION VIA REDUCTIVE ELIMINATION Given post-decarboxylation Pd enolate intermediates 14, (Re)-13, and (Si)-13, we then sought to explore possible mechanisms for C(sp3)–C(sp3) bond formation. We further exploit this opportunity to revise and expand upon previous investigations in this area.10 Figure 1.7. Inner-sphere C–C bond forming transition states considered. C-bound enolate P N Pd Me O P C-bound enolate P N O Pd Me N P N Pd Pd O O Me Me TS17 TS18 (not observed) TS19 TS20 First, inner-sphere mechanisms are considered. We envisioned four unique classes of transition states through which reductive elimination may occur: (1) a three-membered ring transition state from a C–bound Pd enolate (TS17), (2) a five-membered cyclic transition state from a C–bound Pd enolate in which the carbon atom of the Pd enolate migrates to the distal carbon of the h1-allyl fragment (TS18), (3) a five-membered ring transition state from an O–bound Pd enolate in which the carbon atom of the enolate bonds with the proximal carbon of the h1-allyl fragment (TS19), and (4) a seven-membered cyclic transition state (TS20)33 (Figure 1.7). Previous investigation suggests the isomerization between oxygen and carbon-bound Pd enolates to be facile.10 Thus, we initially focused on evaluating the barrier to the C(sp3)–C(sp3) bond forming event. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 24 Comprehensive Quantum Mechanics Investigation Consistent with previous observations,10 three-centered transition state TS17 was calculated to be intractably high in energy, with an apparent barrier of 33.7 [46.4] kcal/mol. To determine whether a lower energy transition state could be found by expanding the ring size, we considered the vinylogous case of the 5-centered transition state (TS18). However, the planarity of the allyl fragment in the transition state mandates a still highly strained five-membered ring. Despite our best efforts, a transition state fitting this connectivity was never found on the PES, and any transformation similar would likely be intractably high in energy. Next, we turn our attention to an alternative five-membered cyclic transition state, TS19. Beginning from O–bound Pd enolate 13, the barrier to TS19 is found to be 32.6 [46.3] kcal/mol, and thus, likely not responsible for C–C bond formation. Lastly, we considered the fully expanded seven-membered cyclic transition state, TS20. Here, the seven-membered ring may adopt either a boat or chair conformer for both Re and Si faces of the enolate. Additionally, the six-membered ring of the cyclohexanone enolate fragment may adopt two unique half chair conformers, giving rise to eight total transition states to be considered (Figure 1.8). Here, bond formation from the Re and Si faces afford the S and R enantiomer of product, respectively. The prefixes chair/boat refer to the conformation of the seven-membered ring, and axial/equatorial denote the half chair geometry of the cyclic enolate (Figure 1.8A). Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 25 Comprehensive Quantum Mechanics Investigation Figure 1.8. (A) Reductive elimination from axial versus equatorial Pd enolate halfchairs. (B) Lowest energy chair and boat conformers for each diastereomeric sevencentered C–C bond forming transition state.a A. Axial versus equatorial attack from Pd enolate half-chairs. chair O twist-boat Me Me N O O Pd N Me P Me Pd Pd P P Axial attack (favored) O N Equatorial attack (disfavored) N Pd P B. Four lowest energy (axial attack) transition states. To (S)-2 [Major] O O N P Pd Me Me Me (Re)-13 O N P O Pd N P O Me Me Me (Re/chair)-TS20 ∆G‡rel = 0.0 [0.0] Pd O Me Me Me or (S)-2•Pd0(PHOX) (Re/boat)-TS20 ∆G‡rel = 3.6 [5.9] To (R)-2 [Minor] Me O O N P Pd Me Me (Si)-13 O O Me N P Pd Me Me (Si/chair)-TS20 ∆G‡rel = 2.1 [2.8] Me N P O Pd O Me Me or (R)-2•Pd0(PHOX) (Si/boat)-TS20 ∆G‡rel = 1.3 [1.9] [a] Relative free energies given in kcal/mol from final electronic energies at the M06/def2TZVP/CPCM(THF) level of theory with DLPNO-CCSD(T) values in brackets. For (Si/boat)-TS20, the DLPNO-CCSD(T) value was refined with TightPNO settings. Transition states that feature equatorial attack of the allyl fragment by the enolate half chair are all higher in energy than their axial counterparts by 0.4 to 1.5 kcal/mol. Henceforth, in our discussion the axial/equatorial suffix will be omitted with all references Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 26 Comprehensive Quantum Mechanics Investigation being to the favorable axial transition states. In comparison with the previously mentioned inner-sphere transition states, all eight of the seven-membered cyclic transition states (TS20) offer substantially lower barriers to C–C bond formation, with ∆G‡ ranging from 10.8 [18.5] to 15.1 [24.6] kcal/mol. Figure 1.9. Structures of the two lowest energy diastereomeric transition states of TS20.a O O N P Pd O Me Me (Re/chair)-TS20 ∆G‡rel = 0.0 [0.0] Me N P Me Pd O Me Me (Si/boat)-TS20 ∆G‡rel = 1.3 [1.9] [a] Relative free energies given in kcal/mol from final electronic energies at the M06/def2TZVP/CPCM(THF) level of theory with DLPNO-CCSD(T) values in brackets. Experimentally, the (S)- enantiomer of the t-BuPHOX ligand yields (S)-2-allyl-2methylcyclohexan-1-one ((S)-2) as the major product with 88% ee. At a reaction temperature of 25 ºC, this corresponds to an effective energetic difference of 1.6 kcal/mol between the enantiodetermining transition states. From O-bound Pd enolate (Si/Re)-13, we found the lowest energy difference between Re/Si diastereomeric transition states to be (Re/chair)-TS20 and (Si/boat)-TS20, with barrier heights of 10.8 and 12.1 kcal/mol, Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 27 Comprehensive Quantum Mechanics Investigation respectively (∆∆G‡ = 1.3 [1.9] kcal/mol) (Figure 1.8B). This initial result is in good agreement with the experimentally observed enantioselectivities. Because reliably obtaining relative energies within a sub-kcal/mol error from QM is challenging, we performed a variety of control calculational experiments. Single point calculations on the BP86-D3/LANL2TZ(f)-6-31G(d) optimized geometries were carried out with a suite of 15 density functionals, encompassing several classes of functionals. Electronic energies obtained at the DLPNO-CCSD(T) level of theory (with both NormalPNO and TightPNO settings) were employed for benchmarking. The four lower energy axial conformations of TS20 (Figure 1.8B) were also optimized with a subset of density functionals (with and without empirical dispersion corrections (D3)), followed by single point calculations as previously described (see 1.5 Supporting Information). All results from the control experiments correctly predict (Re/chair)-TS20 to be the overall lowest energy transition sate, with (Si/boat)-TS20 as the lowest energy pathway for the formation of the minor product (R)-2. Thus, we propose C–C bond formation via TS20 to be the enantiodetermining step in the decarboxylative asymmetric allylic alkylation reaction with the Pd(PHOX) catalyst (Figure 1.9). An investigation of a related system by our groups highlighted internal rearrangements of a Pd enolate as a potential mechanism by which product enantioselectivity is determined.10b Although outside the scope of that investigation, the authors noted that a subsequent equilibration between (Si/Re) enolates may be facile. Thus, a definite conclusion as to the origin of the enantioinduction was not drawn. Accordingly, we found a facile interconversion between (Si)-13 and (Re)-13, with a rotational barrier Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 28 Comprehensive Quantum Mechanics Investigation several kcal/mol lower in energy than that of C–C bond formation (TS24) (vide infra, Scheme 1.3). Therefore, the rate of kinetic quenching of intermediates (Si)-13 and (Re)-13 will not be sufficient to preserve any stereochemical induction of previous mechanistic steps. A similar conclusion was posited by McPherson and coworkers.12 Upon further examination, it becomes clear that in the case of the favored (Re)TS20 geometries, adverse interaction between the a-methyl substituent of the enolate fragment and the t-Bu group of the PHOX ligand is minimal compared to the analogous clash between the t-Bu group and the carbocyclic backbone of the enolate found in (Si)TS20. The four atoms ligating Pd, along with the two carbon termini of the newly forming s (C–C) bond, are nearly coplanar (Figure 1.9). In the Si transition states, the resulting steric clash between the ligand and substrate leads to a distorted chair/boat transition state as well as deviation from square planarity at the Pd center. We performed a control calculation in which the t-Bu group of the PHOX ligand was replaced with a hydrogen atom, followed by subsequent transition state optimization. The optimized (Si)-des-t-Bu transition state regained planarity resembling the favored (Re)-TS20 geometry. These results suggest that the steric interaction from the carbocyclic scaffold and the t-Bu group of the PHOX ligand, along with the accompanying distortion from square planarity, is the primary origin of enantioinduction. Although previous work suggests an inner-sphere mechanism to be prevalent, we do not discount the possibility that a competing outer-sphere mechanism is also present. In fact, with the Pd(PHOX) system, stabilized “soft” enolates generally remain competent in Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 29 Comprehensive Quantum Mechanics Investigation the reaction, albeit with substantially reduced enantioselectivities.4 In the canonical Tsuji– Trost allylic alkylation, differentiation between inner- and outer-sphere pathways is highly reliant on the nature of the nucleophile,34 with hard nucleophiles proceeding through innersphere attack and soft nucleophiles via outer-sphere mechanisms. As such, we hypothesize that the poor enantioselectivities observed with stabilized enolates are likely the result of a less selective outer-sphere mechanism dominating the C–C bond formation step. In an effort to continue the development of this methodology to include previously inaccessible substrate classes, we sought to explore the intricacies of the interplay between outer-sphere and inner-sphere mechanisms. From O–bound enolates (Si)-13 and (Re)-13, an associative displacement of the enolate by the olefin of the allyl fragment ((Si/Re)-TS21) directly affords 14 (as two inconsequential rotamers) (Scheme 1.3). Its noteworthy that 14 is also the product of decarboxylation through TS15 (decarboxylative pathway 3) (Scheme 1.1). As expected, in 14, bonding between the axial enolate oxygen and Pd is dominated by electrostatic attraction. Intermediate 14 presents a Pd–O bond length of 2.72 Å and Löwden bond order of 0.23, compared to the 2.08 Å Pd–O bond length and bond order of 0.60 as observed in (Re)-13. As such, disassociated ions 15 and 17 are comparable in free energy to 14. This was found to be the lowest energy entry into the outer-sphere mechanistic space (Scheme 1.3). Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 30 Comprehensive Quantum Mechanics Investigation Scheme 1.3. Various C–C bond forming pathways.a P P N Pd N Me Pd Me O O Me N P Pd N P O Me (Re/chair)-TS20 (Si)-TS22 (Re)-TS23: 16.6 [25.6] (Si)-TS23: 16.3 [25.9] P (Si/boat)-TS20 (Re)-TS22 (Re)-TS21: 14.2 [21.4] (Si)-TS21: 13.7 [22.4] (Re)-TS22: 14.1 [23.5] (Si)-TS22: 13.5 [25.0] 18 10.4 [16.0] Pd O 15 + 17 10.7 [20.7] O N (Si/boat)-TS20: 12.3 [25.8] (Re/chair)-TS20: 11.0 [23.6] TS24 5.3 [11.7] 14 9.7 [17.0] Me Me Pd O Me N 17 O (S)-19: –23.2 [–11.6] (R)-19: –23.2 [–13.5] N P Pd 15 P Me Pd P N Pd O Me (Re)-13: 0.2 [5.1] Outer-sphere P N Pd O (S)-19: –23.2 [–11.6] (R)-19: –23.2 [–13.5] (Si)-13: 0.6 [5.4] Inner-sphere [a] Free energies relative to 3 (in kcal/mol) obtained with M06/def2-TZVP/CPCM(THF), with energies derived from electronic energies at the DLPNO-CCSD(T)/cc-pVTZ/CPCM(THF) level of theory in brackets. Lowest energy conformers depicted. ∆∆G‡ refined to 1.9 kcal/mol with TightPNO settings. In considering C–C bond formation through an outer-sphere attack of enolate 17 on the [h3–(allyl)Pd(PHOX)]+ complex (15), we note that attack may occur either trans to N or P, from the Si or Re face of the enolate, in both enolate half chairs, and to either exo- or endo-allyl 15. Based on our previous findings, we considered only the enolate half chair which gives rise to the favored axial attack. Here, we found six of the eight hypothesized transition states for this outer-sphere process (TS22). Unlike the inner-sphere transition states TS20, which give rise to ∆∆G‡ of 1.3 [1.9] kcal/mol between the lowest energy diastereomeric transition states, the outer-sphere Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 31 Comprehensive Quantum Mechanics Investigation transition states afford reduced selectivity. From transition states (Si)-TS22 and (Re)-TS22, a ∆∆G‡ of 0.6 [1.4] kcal/mol was calculated. We note that the presence of numerous nearly degenerate rotameric transition states complicated obtaining accurate ∆∆G‡ for this pathway. In addition to reactivity at the π-allyl carbon termini, nucleophilic attack at the central carbon of the allyl fragment to afford palladacyclobutane species is known. 35 Previous experimental and computational studies find the mode of reactivity to be highly dependent on the s-donating/π-accepting nature of the ancillary ligand and the basicity of the nucleophile. Palladacyclobutane complexes have been proposed as mechanistic intermediates in palladium-mediated cyclopropanation reactions,36 as well as isolated and characterized by X-ray crystallography.37 Of relevance to this work, we considered that 15 and 17 may combine in such a way that the oxygen atom of 17 forms a covalent bond with the b carbon of the allyl fragment to afford metallacyclobutane 18. The C–C π orbitals of the enolate fragment are in potentially good overlap with the Pd–C s* of the allyl terminus. Thus, we envisioned intermediate 18 may be a competent precursor to the desired C–C bond formation via (Si/Re)-TS23. IRC analysis reveals (Si/Re)-TS23 directly connects metallacyclobutane 18 and the complexed ketone product (R/S)-19 on the potential energy surface without the intermittency of ion pair 15+17. Therefore, TS23 represents a C–C bond forming pathway unique to that of TS22. Complex 18 is well poised for reductive elimination to form 19. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 32 Comprehensive Quantum Mechanics Investigation The apparent barrier to this process (relative to enolate (Si)-13) is 16.4 [20.5] and 16.1 [20.8] kcal/mol for (Si)-TS23 and (Re)-TS23, respectively. From analysis of the free energy network encompassing Pd enolates (Si)-13, (Re)13, and 14, with the accompanying C–C bond forming pathways, the following conclusions are drawn: 1. Given facile rotation about the Pd–O and C–O s bonds in Pd enolates (Si)-13 and (Re)-13, preservation of stereochemical information through differentiation in energy between prior diastereomeric transition states should largely be erased. We found the rotational barrier from (Si)-13 to (Re)-13 to be 5.1 [6.6] kcal/mol (via TS24), whereas the minimum energy barrier to C–C bond formation is 10.8 [18.5] kcal/mol. Therefore, the rate of kinetic quenching of intermediates (Si)-13 and (Re)-13 will not be sufficient to preserve any stereochemical induction from previous mechanistic steps. However, this feature of the PES may be substrate specific and more extrapolated scaffolds may experience rotational barriers similar to or greater than that of C–C bond formation. 2. The mechanism through which decarboxylation of the b-ketoester occurs plays an important role in determining the predisposition for C–C bond formation to occur through either an inner or outer-sphere process. As previously mentioned, decarboxylation via TS5, TS14, and TS15, yield Pd enolates (Si)-13, (Re)-13, and 14, respectively. From (Re/Si)-13, direct C–C bond formation through the inner-sphere transition states (Re/chair)-TS20 or (Si/boat)-TS20 represent the lowest energy pathway to the product. From (Re/Si)-13, the apparent barrier height to C–C bond formation via an outer-sphere Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 33 Comprehensive Quantum Mechanics Investigation mechanism corresponds to the isomerization of (Re/Si)-13 to the axially-bound enolate 14 via (Re/Si)-TS21, as (Re/Si)-TS21 are found to be higher in energy than the outer-sphere C–C bond forming transition states (TS22). Therefore, decarboxylation through TS5 or TS14 (pathway 1 or 2) to directly afford (Re/Si)-13 carries a predisposition for innersphere C–C bond formation. Alternatively, decarboxylation via TS15 (pathways 3) directly leads to apical enolate 14. When this is the case, C–C bond formation through both inner and outer-sphere processes becomes highly competitive. From 14, the highest barrier to the outer-sphere mechanism is that of the outer-sphere C–C bond forming event (TS22). While the barrier heights for the inner-sphere C–C bond forming transition states are lower in energy than those of the outer-sphere mechanism, the Pd enolate must first undergo an isomerization from apically-bound 14 to square planar complexes (Re/Si)-13. In fact, the barrier heights of these isomerizations (via (Re/Si)-TS21) are comparable to that of the outer-sphere C–C bond formation. Therefore, less preference for the inner over outer-sphere mechanism is expected for the case in which decarboxylation proceeds through TS15 (pathway 3). Qualitatively similar results are obtained across a variety of density functional methods. 3. We previously discussed the effects of solvation on differentiating between decarboxylative pathways. We find that nonpolar solvents such as toluene impose a large preference for decarboxylation through the less polar TS14, while polar solvents result in preference for the more charge-separated TS15. Given the similarities in the free energies of the inner- and outer-sphere mechanisms, along with the experimentally observed solvent dependencies described in the literature, an analogous investigation into the solvent effects Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 34 Comprehensive Quantum Mechanics Investigation on differentiation of the inner- and outer-sphere mechanistic pathways was carried out. For the reasons described above, this investigation is qualitative in nature, highlighting the expected reactivity trends. First, we note the relative free energies between the low energy Pd enolates (Re/Si)13 and the transition states for their isomerization to 14 are independent of the continuum dielectric constant (Table 1.1). However, the barrier for C–C bond formation via innersphere TS20 demonstrates a dependence on solvent polarity in which less polar solvents afford reduced barrier heights. As anticipated, the generation of solvent separated ions 15 and enolate 17 from 14 becomes increasingly unfavorable with decreasing dielectric constant of the solvent. As the relative free energy of 15 and 17 increases dramatically in nonpolar solvents, the outer-sphere C–C bond formation from the separate ions via TS22 is anticipated to become less prevalent. In contrast, solvation in a continuum with a high dielectric constant favors the separate ions 15 and 17 over Pd enolate 14. The barriers to outer-sphere C–C bond formation also decrease, now favoring an outer-sphere mechanism from 14. Taken together with the results for solvent effects on decarboxylation, we conclude that in polar solvent, decarboxylation via TS15 is favored, affording intermediate 14. From 14, the minimum energy pathway to C–C bond formation is via a less enantioselective outer-sphere mechanism (TS22). Conversely, nonpolar solvents favor loss of CO2 through TS14, yielding enolate (Si)-13. Reductive elimination via the 7-membered pericyclic transition state TS20 then ensues. Given the sensitivity of relative barrier heights to changes in solvation, we highlight the need to consider both the mechanism of Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 35 Comprehensive Quantum Mechanics Investigation decarboxylation and that of the C–C bond forming pathways in determining the innersphere or outer-sphere mechanism to be more favorable. Table 1.1. Qualitative comparison of relative free energy barrier heights along reductive elimination pathways.a Intermediate PhMe Et2O THF DMF (Re)-13 0.6 0.5 0.5 0.4 (Si)-13 0.0 0.0 0.0 0.0 14 8.8 9.3 9.5 9.8 15 + 17 33.2 17.5 9.2 -0.5 (Re)-TS21 13.5 13.5 13.5 13.6 (Si)-TS21 14.1 14.1 14.1 14.1 (Re/chair)-TS20 9.5 10.3 10.8 11.5 (Si/boat)-TS20 10.9 11.7 12.1 12.7 (endo/Re/t-P)-TS22 14.9b 13.9b 13.3 12.6 (exo/Si/t-N)-TS22 16.0b 14.7b 13.9 12.9 (endo/Re/t-P)-TS23 19.8 17.8 16.6 15.1 (endo/Si/t-P)-TS23 19.1 17.2 16.1 14.8 [a] Relative free energies given in kcal/mol at the M06/def2-TZVP/CPCM(solvent) level of theory on geometries obtained in the gas phase. [b] Barrier less than free energy of separated ions 15 and 17. 1.3.4 COMPLETE CATALYTIC CYCLE Considering the findings for each step of the decarboxylative allylic alkylation reaction, we now construct a mechanistic picture that unites theoretical and experimental findings (Figure 1.10). First, the π-basic Pd0(PHOX) precatalyst coordinates to the olefin Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 36 Comprehensive Quantum Mechanics Investigation of the allyl b-ketoester starting material (1), followed by oxidative addition to form the [Pd(PHOX)(h3–allyl)]+(RCO2–) ion pair (4). Oxidative addition occurs trans to the nitrogen of the PHOX ligand via direct displacement of the carboxylate leaving group (TS4). Validation of this displacement-type mechanism supports the basis from which previous claims have been made using inversion/retention of stereochemistry as a probe for determination of inner versus outer-sphere mechanisms (when substitution on the allyl terminus is present).6,32 The mechanism of Bäckvall was found to be unlikely for these substrates.31 Furthermore, both enantiomers of the starting material have similar barriers to oxidative addition. This is in accordance with experimental evidence that a kinetic resolution of the allyl b-ketoester starting material is generally not observed to great extent.38 Figure 1.10. Complete catalytic cycle for the inner-sphere allylic alkylation reaction. O Me P O Me N Pd (S)-2 O Me O = O [XRD] 1. Oxidative Addition O O (±)-1 Resting state 5 P N P Pd Me O O N Pd O O Me N (S)-19 P O 4 3. Reductive Elimination (enantiodetermining) 2. Decarboxylation (rate-limiting) P N Pd O (Re)-13 Me O Pd CO2 3 Me O Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 37 Comprehensive Quantum Mechanics Investigation Ion pair 4 readily equilibrates to the more thermodynamically stable [Pd(PHOX)(h1–allyl)(RCO2)] complex (3). Experiment and computation agree in identifying 3 as the resting state of the catalyst. We further extend the analogous comparison to that of the enol carbonate substrate class (8/9). Given the equilibration between 3 and 4, along with the similar relative energies of the separated ions, we conclude that observation of crossover products in deuterium labeling experiments does not necessarily indicate an outer-sphere C–C bond forming mechanism, but rather is still accommodated within the inner-sphere mechanistic hypothesis.2 That is, charge-separated ion pairs may undergo facile anion exchange to afford the observed cross-products. Additionally, the pKb of the carboxylate/carbonate anions is such that quenching with water to render an inactive or decomposed species is not anticipated, in accordance with the observed water tolerance experiments.5 Subsequent loss of CO2 occurs through one (or more) of three unique decarboxylative transition states, each leading to a different Pd enolate intermediate. Our investigation determines that ion pair 4 (the initial product of oxidative addition) is a common intermediate along the two lowest energy pathways through decarboxylation. Therefore, the catalyst resting state (3) is best described as an off-cycle intermediate (Figure 1.11). In agreement with experiment, decarboxylation is determined here to be ratelimiting. Furthermore, the calculated rate of decarboxylation (4.65 x10–4 s–1, ∆G‡ = 21.9 kcal/mol) is in excellent agreement with that of experiment (1.58 x10–3 s–1; ∆G‡ = 21.2 kcal/mol).5 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 38 Comprehensive Quantum Mechanics Investigation Figure 1.11. Free energy profile of minimum energy pathway through full catalytic cycle (green) as well as pathway for equilibration to off-cycle resting state 3 (orange).a P Pd N P N P Pd N O O Me O TS14 17.1 [22.0] Rate-Limiting Step Pd O O Me O O Me O O 5 6.2 [11.1] Begin cycle TS4 12.7 [15.8] P P N Pd Pd O Me (Re/chair)-TS20 11.0 [23.6] Enantiodetermining Step 12 12.7 [15.9] TS12 9.7 [10.2] TS11 9.1 [7.5] ∆G‡obs N TS13 14.0 [16.3] O CO2 Me O O P 11 6.2 [3.3] P 3 0.0 [0.0] Resting State N Pd O Me O O Me O O O N P N Pd 4 5.4 [5.2] P N Pd (Si)-13 0.2 [5.1] O Me Pd Me O (S)-19 –23.2 [–13.5] [a] Note that decarboxylation is considered irreversible as CO2 is lost to reaction headspace/atmosphere. From the four-coordinate Pd enolates (Re/Si)-13, the most facile pathway to C–C bond formation is inner-sphere reductive elimination via a seven-membered pericyclic transition state (TS20). We establish that this C–C bond forming event is the enantiodetermining step (Figure 1.8). Calculated enantioselectivities agree with experiment and are assessed across a variety of computational methods. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 39 Comprehensive Quantum Mechanics Investigation We investigated the interplay of inner and outer-sphere mechanisms. In particular, we assess effects of solvation on the differentiation of these two processes. The highly enantioselective inner-sphere process is favored in nonpolar solvents, whereas the less selective outer-sphere mechanisms become increasingly relevant in polar solvents. The origin of this solvent dependence is two-fold. In addition to stabilization of charged intermediates encountered in the outer-sphere processes, we find that increasingly polar solvents favor decarboxylation via the formally charge-separated transition state TS15, leading directly to the square pyramidal enolate complex 14. Above, we discuss the implications of this in the context of a more facile entry into the outer-sphere mechanistic space. 1.3.5 EXPERIMENT AND DISCUSSION We then sought to experimentally evaluate the mechanistic predictions obtained in our computational investigation. In the case of a-methyl allyl enol carbonate 8, prior research reveals that the reaction rate is increased with the use of the more electron poor (S)-(CF3)3-t-BuPHOX ligand.39 While a similar trend for the analogous b-ketoester (1) may be anticipated, reaction time course studies reveal that the same rate enhancement is not observed (Figure 1.12). In fact, when the catalyst resting state (3), and both low energy transition states responsible for decarboxylation (TS14 and TS15) are re-optimized with the (S)-(CF3)3-t-BuPHOX ligand, the barrier to decarboxylation is calculated to be 22.2 kcal/mol (DLPNO-CCSD(T), TightPNO) — within error of the 21.9 kcal/mol (DLPNOCCSD(T), TightPNO) barrier height of the original system. This experiment further Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 40 Comprehensive Quantum Mechanics Investigation highlights the fidelity of the computational methods employed in this study in describing the reactivity trends in the catalytic system. Figure 1.12. Conversion of 1 to (S)-2 under standard reaction conditions.a 100 90 (S)-t-BuPHOX (S)-(CF3)3-t-BuPHOX 80 Conversion (%) 70 60 R 50 O 40 R 30 P N t-Bu 2 20 (S)-t-BuPHOX R=H R = CF3 (S)-(CF3)3-t-BuPHOX 10 0 0 50 100 150 200 250 300 Time (minutes) [a] Conversion as determined by GC-FID with respect to tetradecane internal standard. We prepared a-phenyl allyl b-ketoester substrate 20 to probe the interplay of inner and outer-sphere processes (Figure 1.13). Compared to a-methylated b-ketoester 1, the enolate derived from 20 experiences significant electronic stabilization through conjugation. As anticipated from the discussion provided above, as well as prior experimental trends, substrate 20 affords the desired product (S)-22 in 99% yield, however, in a modest 23% ee. It is worth noting that the reduction in enantioselectivity is likely not exclusively a consequence of steric interactions. A variety of sterically encumbered substrates, which do not provide significant electronic stabilization, such as the analogous a-t-Bu, a-Bn, a-prenyl, etc., compounds afford the corresponding allylic alkylation products in 82–91% ee.2,Error! Bookmark not defined. Furthermore, we compute a Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 41 Comprehensive Quantum Mechanics Investigation ∆∆G‡ of 1.3 kcal/mol between the enantiodetermining inner-sphere transition states derived from substrate 20 (corresponding to 80% ee at 25 ºC). These results suggest that an enantioselective inner-sphere pathway persists, however, under the standard reaction conditions, the less selective outer-sphere mechanisms dominate. Figure 1.13. Effect of decarboxylation mechanism on downstream enantioselectivity.a O O Ph O O O or O Ph Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.25 mol %) O Ph THF, 25 ºC, 12 h 20 21 From 20: 99% conv., 23% ee From 21: 99% conv., 15% ee (S)-22 [a] Enantiomeric excess determined by chiral SFC analysis. In addition to a-phenyl b-ketoester 20, the corresponding a-phenyl allyl enol carbonate (21) was also evaluated in the transformation (Figure 1.13). Interestingly, under identical conditions to those employed with b-ketoester 20, enol carbonate 21 affords (S)22 in a reduced 15% ee, compared to 23% ee as obtained starting from 20.8 After decarboxylation, both 20 and 21 share access to the same network of enolate intermediates (Scheme 1.3). However, by virtue of the differing mechanisms of decarboxylation, the point at which the intermediates derived from each substrate enter the post-decarboxylation mechanistic space is anticipated to vary. As prefaced by our computational investigation, this may lead to altered levels of product enantioenrichment due to the resulting predisposition for C–C bond formation to occur via inner- or outer-sphere mechanisms to varying extent (vida supra). Naturally, differences in enantioselectivities based on enolate Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 42 Comprehensive Quantum Mechanics Investigation synthon (i.e., b-ketoester versus enol carbonate) are expected to be increasingly pronounced in the case of stabilized enolates (20/21), for which an outer-sphere mechanism is readily accessible. These results highlight the importance in considering the effect of the mechanism of decarboxylation and subsequent behavior of enolate intermediates in the overall enantioselectivity of the transformation. With compound 20 in hand, we then sought to probe the effects of solvation and ligand electronics on observed enantioselectivity (Figure 1.14). As previously mentioned, the enantioselective inner-sphere pathway to C–C bond formation to (S)-22 is expected to be largely outcompeted by less selective outer-sphere mechanisms. Our computational investigations suggest that, for allyl b-ketoesters, inner-sphere mechanisms are favored by: (1) disfavoring the charge-separated intermediates required for an outer-sphere approach, and (2) favoring decarboxylative mechanisms that lead directly to h1–allyl square planar palladium enolates (i.e., via decarboxylation pathways 1 and 2). Calculations further predicted that this may be accomplished by utilizing nonpolar solvents, as well as through the installation of electron withdrawing groups on the PHOX ligand framework. Indeed, we observe an increase from 23 to 28% ee simply by implementing toluene (e = 2.4) in place of THF (e = 7.3) as the reaction solvent (entries 1–2, Figure 1.14). Utilizing the more electron poor (S)-(CF3)3-t-BuPHOX ligand in toluene (entry 3) and a 2:1 methylcyclohexane/toluene solvent mixture (e = 2.1), enantioselectivity was further enhanced to 32% and 36% ee, respectively (entries 3–4). Given the initial improvements from perturbations of ligand electronics and solvation alone, we suggest in silico high- Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 43 Comprehensive Quantum Mechanics Investigation throughput screening of ligands with different steric environments as a practical next step in future developmental efforts. Figure 1.14. Effect of solvation and ligand electronics on enantioselectivity. O Ph O O O Pd2(dba)3 (2.5 mol %) Ligand (6.25 mol %) Ph R Solvent, 25 ºC, 12 h Stablilized enolate 20 O (S)-22 P N Entry Ligand Solvent [𝝴] ee (%)a Yield 22 (%)b ∆Geqc R 1 2 3 4 (S)-t-BuPHOX (S)-t-BuPHOX (S)-(CF3)3-t-BuPHOX (S)-(CF3)3-t-BuPHOX THF [7.4] PhMe [2.4] PhMe [2.4] 2:1 MeCy/PhMe [2.1] 23 28 32 36 99 96 90 69d 1.8 24.0 31.0 35.2 (S)-t-BuPHOX R=H R = CF3 (S)-(CF3)3-t-BuPHOX 2 t-Bu Ph ∆Geq Pd O P N O P N + Ph N P = (S)-t-BuPHOX or (S)-(CF3)3-t-BuPHOX Pd [a] Determined by chiral SFC analysis. [b] Determined by 1H NMR with respect to 1,3,5trimethoxybenzene as an internal standard. [c] Change in free energy (in kcal/mol, 1 M standard state) from square pyramidal enolate to separated ions. [d] 34% of 20 remaining after 12 hours. 1.4 CONCLUSIONS We report a detailed quantum mechanics investigation into the three mechanistic steps (oxidative addition, decarboxylation, and reductive elimination) of the decarboxylative asymmetric allylic alkylation with the Pd(PHOX) catalyst system. Experiments were carried out to explore the mechanistic hypotheses derived from the ab initio calculations. Beginning with allyl b-ketoester 1, oxidative addition of Pd0(PHOX) proceeds through pre-coordination of the olefin of the allyl fragment of 1 (to give 5), followed by an SN2-like electrophilic addition to Pd to yield the [(PHOX)Pd(h3-allyl)]+(RCO2–) ion pair Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 44 Comprehensive Quantum Mechanics Investigation (4). Ion pair 4 then rapidly equilibrates to the catalyst resting state, [(PHOX)Pd(h1allyl)(RCO2)] (3). Complex 3 is best described as an off-cycle intermediate. Given the equilibration between 3 and 4, along with the similar relative energies of the separated ions, we corroborate that the results from our previously reported cross-over experiments are not necessarily indicative of an outer-sphere mechanism, but still are accommodated within the inner-sphere mechanistic hypothesis. From the catalyst resting state (3), we find three dominant pathways (1, 2, and 3) through which decarboxylation may occur. Each pathway leads to a unique palladium enolate with the ability for subsequent interconversion between the three. However, ensuing analysis of the C–C bond forming potential energy surface reveals that the enolates derived from pathways 1 and 2 are more predisposed to undergo an inner-sphere C–C bond formation via the seven-membered pericyclic transition state, TS20. On the other hand, decarboxylation via pathway 3 directly affords square pyramidal enolate 14 which may undergo a more facile dissociation and enter the outer-sphere mechanistic space. We predict relative barrier heights among the decarboxylative and C(sp3)–C(sp3) bond forming pathways to be highly solvent dependent. Decreasing solvent polarity favors inner-sphere processes by destabilizing the ionic intermediates of the outer-sphere mechanism, as well as promoting decarboxylation via Pathway 2. Decarboxylation is determined to be rate-limiting in accordance with experiment. Furthermore, the calculated decarboxylation rate constant in THF obtained with DLPNO-CCSD(T) (4.65x10–4 s–1; ∆G‡ = 21.9 kcal/mol) is in excellent agreement with that of experiment (1.58x10–3 s–1; ∆G‡ = Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 45 Comprehensive Quantum Mechanics Investigation 21.2 kcal/mol).4 In comparison, the DFT methods applied in this study all predict a rate constant 103–107 times larger in magnitude (∆G‡ = 12.5–18.9 kcal/mol) than experimentally observed. We considered several inner-sphere reductive elimination transition states. In accordance with previous research in our group, the seven-membered, doubly-vinylogous transition state (TS20)39 provides the lowest energy pathway to C–C bond formation in nonpolar solvents. We establish that the C(sp3)–C(sp3) bond forming event is the enantiodetermining step. Calculated ∆∆G‡ are in excellent agreement with experimentally observed enantioselectivities and are assessed across a variety of computational methods.40 A model is proposed for the origin of the enantioinduction. We also investigated outer-sphere processes, which we found to be competitive in barrier height with the inner-sphere reactions, albeit slightly less favorable. Unlike the inner-sphere transition states, however, severely degraded enantiocontrol is anticipated for outer sphere mechanisms. Additionally, enolate synthon design is highlighted as an area for future development. Herein, we compare the relative thermodynamics of catalyst resting states derived from different enolate precursors. From this, we suggest that in conjunction with catalyst design, the development of more activated masked enolates may achieve a desirable increase in reaction rate. With a complete mechanistic picture in hand, in silico development may now accompany ensuing experimental efforts. In order to evaluate the fidelity of the mechanistic hypotheses, a stabilized enolate equivalent (20) was employed as a probe for inner and outer-sphere competition. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 46 Comprehensive Quantum Mechanics Investigation Experimental results support the computation-based predictions in solvent trends as well as effects of ligand substitution. Furthermore, comparison between 20 and 21 demonstrates the intricacies in the equilibration of the palladium enolate intermediates as described herein. While a-methyl ketone 1 is employed throughout the majority of this study as a “standard” substrate, many of the experimentally observed trends mentioned throughout the text remain consistent amongst more highly decorated heterocyclic scaffolds alike. Thus, the conclusions presented herein are expected to serve as robust first-order approximations to a broad variety of substrate classes. Density functional theory and localized coupled-cluster theory are employed in this study. We find the DLPNO-CCSD(T) method of Neese et. al. highly effective in obtaining accurate barrier heights and thermodynamic relations.26 Thus, we recommend DLPNOCCSD(T) for routine use in future quantum mechanics-based investigations in asymmetric catalysis. These avenues of thought, coupled with the detailed mechanistic hypothesis presented herein, provide a powerful tool in addressing the current limitations and aiding in the future development of the decarboxylative asymmetric allylic alkylation reaction. 1.5 SUPPORTING INFORMATION 1.5.1 GENERAL COMPUTATIONAL DETAILS Density functional theory calculations All quantum mechanical calculations were performed with ORCA version 4.1 and 4.2.13 Unless otherwise noted, geometry optimizations were carried out with the BP86 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 47 Comprehensive Quantum Mechanics Investigation generalized gradient approximation (GGA) functional14 [Becke ’88 exchange functional paired with the Perdew ’86 correlation functional] with Becke–Johnson damped D3 dispersion corrections (henceforth referred to as D3).15 A mixed basis set was implemented, in which palladium is described by the small core LANL2TZ(f) basis set with the Hay Wadt effective core potential16 (ECP) [28 core electrons on Pd], and the 6-31G(d) basis set was used on all other atoms. Thermal corrections (at 298 K) were calculated from the unscaled vibrational frequencies at this level of theory. The Quasi-RRHO method was applied to correct for the breakdown of the harmonic oscillator approximation for low frequency vibrations.24 All stationary points are characterized by the appropriate number of imaginary vibrational modes (zero for optimized geometries and one for transition states). Intrinsic reaction coordinate (IRC) analyses were carried out to ensure all transition states connect the appropriate starting materials and products. Triple-ζ quality single point calculations were carried out on all stationary points with the BP86-D3, B3LYP-D3,17 PBE0-D3,18 M06,19 and DSD-BLYP-D320 functionals with the def2-TZVP basis set21 on all atoms (with the small core ECP28MWB pseudopotential22 on Pd). The Conductor-like Polarizable Continuum Model (CPCM)23 was employed in these single point calculations to include effects of solvation. Thermal corrections obtained at the previous level of theory are then applied to these electronic energies to obtain the reported free energies (G298). Calculated free energy changes are for a 1 M standard state at 25 ºC, apart from decarboxylation where CO2 is given a standard state of 1 atm. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 48 Comprehensive Quantum Mechanics Investigation These methods encompass a range of functional classes, including GGA (BP86D3), hybrid GGA (B3LYP-D3), non-empirical hybrid GGA (PBE0-D3), hybrid metaGGA (M06), and spin-component-scaled double hybrid (DSD-BLYP-D3), where effects from dispersion are accounted for either in parameterization or empirically with ad-hoc corrections. As the M06 density functional is parameterized to offer a suitable balance between transition metals and main group elements, we report these energies in the text of the manuscript. However, we encourage comparison of these results to those obtained with the other methods. The values obtained from all quantum mechanical calculations are included in the supporting excel file available online (https://pubs.acs.org/doi/10.1021/jacs.0c06243?ref=pdf). The resolution of identity (RI) and chain-of-spheres 40 (keyword = RIJCOSX) approximations were utilized for coulomb and exchange integrals, respectively, where applicable. Automatic generation of the auxiliary basis sets was employed (keyword = AutoAux). 41 The finest integration grid settings (Grid7, GridX9, NoFinalGrid) were utilized in all calculations. DLPNO-CCSD(T) Calculations Additional single point calculations were performed on all optimized structured with the domain based local pair natural orbital coupled-cluster (DLPNO-CCSD(T)) method as described by Neese et. al. and as implemented in ORCA.26 Here, we find the ccpVTZ basis set (with the corresponding cc-pVTZ/C and def2/J auxiliary basis sets), along with the small core SK-MCDHF-RSC effective core potential27 on Pd (i.e., the cc-pVTZPP main basis set with cc-pVTZ-PP/C and def2/J auxiliary basis sets) with the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 49 Comprehensive Quantum Mechanics Investigation “NormalPNO” cutoffs to offer an appropriate balance between cost and accuracy for routine use. As before, the CPCM(THF) was employed to account for effects of solvation. Thermal corrections obtained at the BP86-D3/LANL2TZ(f)–6-31G(d) are applied to the DLPNO-CCSD(T)/cc-pVTZ/CPCM(THF) electronic energies to afford the corresponding free energies. The “TightPNO” settings are employed to further refine correlation energy for comparison of select structures. Notes: § Similar results are obtained with the def2-TZVP basis set in control experiments, although we elected to employ Dunning’s cc-pVnZ family of basis sets for ease of basis set extrapolation with further calculations should the need arise. § “NormalPNO”: TCutPairs = 10–3, TCutDO = 1x10–2, TCutPNO = 3.33x10–7, TCutMKN = 10–3 § “TightPNO”: TCutPairs = 10–5, TCutDO = 5x10–3, TCutPNO = 1.00x10–7, TCutMKN = 10–3 § “TightPNO” settings may be employed, however, the computational cost increases dramatically. Thus, we have found an efficient approach is to perform routine single point calculations with “NormalPNO” cutoffs, then refine these values for key intermediates with the “TightPNO” settings. § When CPCM implicit solvation is employed (ORCA 4), the Hartree–Fock reference is optimized self-consistently with respect to the solvent reaction field, but the subsequent optimization of the cluster amplitudes is not. [An alternative is to apply ∆G(solv) from DFT calculations to a gas phase DLPNO-CCSD(T) energy.] Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 50 Comprehensive Quantum Mechanics Investigation 1.5.2 INITIAL BENCHMARKING We explore density functional and basis set dependence on the geometry optimization of the PdII resting state complex 3. These calculated geometries are then compared to that of the recently reported crystallographic structure (CCDC 695531) (Table 1.2).5 While slight discrepancies between crystallographic and solution phase structure may persist, we utilize this data as a reference point to which we may calibrate our methodology, as well as explore general trends in basis set and functional dependencies. Table 1.2. Comparison of geometric parameters obtained from geometry optimization with various functionals and basis sets.a Resting state P N Pd = O Me O O 3 Basis Set d1 [X-ray]b Functional Crystal XRD Pd–P Pd–N Pd–O Pd–C d1 MUEa MSE 2.189 2.133 2.136 2.055 4.687 - - LANL2DZ[Pd]/6-31G(d) BP86-D3 2.217 2.201 2.159 2.082 4.610 3.65 3.65 LANL2TZ [Pd]/6-31G(d) BP86-D3 2.213 2.192 2.151 2.082 4.618 3.12 3.12 LANL2TZ(f) [Pd]/6-31G(d) BP86-D3 2.206 2.148 2.107 2.067 4.598 1.83 0.38 def2-TZVP [all atoms] BP86-D3 2.182 2.136 2.111 2.070 4.632 1.25 -0.35 LANL2TZ(f) [Pd]/6-31G(d) PBE-D3 2.214 2.162 2.117 2.069 4.701 2.17 1.22 LANL2TZ(f) [Pd]/6-31G(d) TPSS-D3 2.217 2.154 2.101 2.071 4.673 2.50 0.75 LANL2TZ(f) [Pd]/6-31G(d) BLYP-D3 2.233 2.208 2.152 2.095 4.645 4.38 4.38 LANL2TZ(f) [Pd]/6-31G(d) B3LYP-D3 2.228 2.209 2.134 2.066 4.683 3.20 3.10 LANL2TZ(f) [Pd]/6-31G(d) B3PW-D3 2.204 2.145 2.088 2.045 4.586 2.13 -0.78 LANL2TZ(f) [Pd]/6-31G(d) PBE0-D3 2.211 2.150 2.086 2.040 4.673 2.60 -0.65 LANL2TZ(f) [Pd]/6-31G(d) TPSSh-D3 2.215 2.153 2.091 2.059 4.653 2.37 0.12 LANL2TZ(f) [Pd]/6-31G(d) wB97X-D3 2.226 2.179 2.097 2.033 4.612 2.75 -0.80 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 51 Comprehensive Quantum Mechanics Investigation LANL2DZ [Pd]/6-31G(d) B3LYP 2.278 2.234 2.133 2.079 5.102 5.43 5.28 [a] Geometric parameters (Pd–X bond lengths, and d1) given in angstrom (Å). MUE and MSE (excluding d1) given in pm. Optimization carried out beginning from the known X-ray crystal structure. [b] CCDC 695531 (ref. 5). From these controls, the following trends are observed: (1) Greatly reduced errors in Pd–X bond lengths with minimal increase in computational cost are obtained by employing the larger triple-ζ quality basis set with polarization functions, LANL2TZ(f), on Pd in place of the double-ζ (LANL2DZ) basis set. (2) The use of Becke-Johnson D3 damped dispersion corrections (-D3) in the optimization greatly aids in capturing perturbations of the ligand geometry arising from noncovalent interactions (see d1). (3) Density functionals constructed with the Lee–Yang–Parr correlation functional (BLYP, B3LYP) present elongated Pd–X bonds and are among the functionals with the highest MUEs. This trend has been previously described in the literature19 and has been attributed to the LYP functional underestimating correlation at the uniform electron gas (UEG) limit.42 Thus, for geometry optimization we employ the BP86 density functional with Becke– Johnson damped dispersion corrections (BP86-D3), with a mixed basis set comprised of the LANL2TZ(f) basis set on Pd with 6-31G(d) on all other atoms. We do not recommend the use of the B3LYP/LANL2DZ–6-31G(d) level of theory as is employed in select literature investigations. We believe more suitable geometries may be obtained with D3BJ dispersion Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 52 Comprehensive Quantum Mechanics Investigation corrections and triple-z basis sets with polarization functions on the metal center. Apart from B3LYP and BLYP, all other functionals evaluated perform comparably well. 1.5.3 DECARBOXYLATION AND CONTROL EXPERIMENTS In order to obtain accurate barrier heights for the rate determining decarboxylative step, geometry/transition state optimizations were also carried out with CPCM(THF) for comparison to the structures optimized in the gas phase (Table 1.3). Table 1.3. Decarboxylation barrier heights with geometries optimized in gas phase and with CPCM(THF).a Method (for (boat/ax)- (chair/ax)- (exo/chair/ax)- (boat/ax)- (chair/ax)- (exo/chair/ax)- TS5 (gas) TS14 (gas) TS15 (gas) TS5 (THF) TS14 (THF) TS15 (THF) 16.5 12.5 16.4 15.1 11.5 21.7 b 18.4 16.5 21.5 19.2 15.4 27.7 PBE0-D3 b 21.0 c 18.9 21.0 23.9 19.0 27.8 M06 22.0 17.1 17.5 21.8 15.2 19.8 DSD- d 20.6 18.6 19.0 22.5 17.1 24.1 26.8 22.0 23.2c 26.8 19.8 28.2 single point calculations) BP86-D3 B3LYP-D3 BLYP-D3 DLPNOe CCSD(T) [a] Comparison of barrier heights obtained across a variety of methods with geometries optimized in gas phase and with CPCM(THF). Barrier heights given in kcal/mol from “Method”/def2-TZVP– CPCM(THF)//BP86-D3/LANL2TZ(f)–6-31G(d) (with or without CPCM(THF)). [b] (chair/ax)-TS5. [c] (boat/ax)-TS14. [d] (exo/boat/ax)-TS15. [e] Single point with the cc-pVTZ basis set (with SK-MCDHFRSC pseudopotential on Pd; i.e., cc-pVTZ-PP), “NormalPNO” settings. For completeness, intermediates derived from the R enantiomer of starting material 1 were also investigated (Table 1.4). An analogous result was obtained. Note: Transition Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 53 Comprehensive Quantum Mechanics Investigation state geometries obtained with CPCM(THF) solvation were prone to an additional small imaginary vibrational mode (<5 cm-1) corresponding to a rocking of the ligand backbone. With the point charge CPCM scheme these were unable to be eliminated, however they bear no consequences on the final results. Table 1.4. Decarboxylation barrier heights of complexes derived from the (R) enantiomer of 1.a Method (chair/ax)-TS14_diast2 (exo/chair/ax)-TS15_diast2 BP86-D3 12.3 18.5 B3LYP-D3 16.7 24.8 PBE0-D3 21.0 25.5 M06 17.4 21.5 DSD-BLYP-D3 18.8 23.1 DLPNO-CCSD(T)b 21.6 27.7 [a] Barrier heights reported in kcal/mol from single point calculations with the listed functional/method, the def2-TZVP basis set on all atoms and CPCM(THF) on geometries obtained with BP86-D3/LANL2TZ(f)–6-31G(d). [b] Single point with the cc-pVTZ basis set (with SK-MCDHFRSC pseudopotential on Pd; i.e., cc-pVTZ-PP) and “NormalPNO” settings. 1.5.4 PREDICTION OF ENANTIOSELECTIVITY Given the challenge of calculating energies to within the sub-kcal/mol level of accuracy required for accurate prediction of reaction enantioselectivity, we chose to employ a variety of control experiments to assess the fidelity of our results. With geometries obtained at the BP86-D3/LANL2TZ(f)–6-31G(d) level, we began by evaluating single point energies with a variety of density functional methods (Table 1.5). These methods include generalized gradient approximation (GGA), meta-GGA, hybrid Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 54 Comprehensive Quantum Mechanics Investigation meta-GGA, range-separated hybrid GGA, and double hybrid functionals. Similar trends in relative free energies are obtained across each of the methods tested. Table 1.5. Comparison of relative free energies obtained across a variety of density functional methods.a BP86-D3 BLYP-D3 revPBE-D3 M06-L B3LYP-D3 B3LYP-D3b (Re/chair/ax)-TS20 0.0 0.0 0.0 0.0 0.0 0.0 (Re/boat/ax)-TS20 5.4 6.0 5.3 4.2 6.1 5.7 (Re/chair/eq)-TS20 1.6 2.2 1.7 1.4 2.0 1.9 (Re/boat/eq)-TS20 5.5 5.3 5.0 4.3 5.6 5.2 (Si/chair/ax)-TS20 2.0 2.4 1.9 1.8 2.8 2.6 (Si/boat/ax)-TS20 1.0 0.8 0.9 0.3 1.1 1.0 (Si/chair/eq)-TS20 4.2 5.0 4.1 3.7 5.0 4.9 (Si/boat/eq)-TS20 3.2 3.4 2.9 2.6 3.6 3.4 PBE0-D3 TPSSh-D3 M06 M06-2X wB97X-D3 mPW2PLYP-D (Re/chair/ax)-TS20 0.0 0.0 0.0 0.0 0.0 0.0 (Re/boat/ax)-TS20 5.2 5.9 3.6 4.3 6.1 5.1 (Re/chair/eq)-TS20 1.2 1.7 0.4 1.2 1.6 1.4 (Re/boat/eq)-TS20 5.6 5.8 4.0 4.4 5.8 5.8 (Si/chair/ax)-TS20 2.5 2.2 2.1 2.8 2.8 2.2 (Si/boat/ax)-TS20 1.5 1.0 1.3 1.0 0.9 1.9 (Si/chair/eq)-TS20 4.1 4.2 3.2 4.0 4.3 4.0 (Si/boat/eq)-TS20 3.5 3.3 2.8 2.8 3.0 4.1 PWPB95-D3 DSD-BLYP-D3 DSD-PBEP86-D3 (Re/chair/ax)-TS20 0.0 0.0 0.0 (Re/boat/ax)-TS20 5.5 5.1 5.0 (Re/chair/eq)-TS20 1.3 1.1 1.0 (Re/boat/eq)-TS20 5.5 5.6 5.6 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 55 Comprehensive Quantum Mechanics Investigation (Si/chair/ax)-TS20 2.4 2.2 2.1 (Si/boat/ax)-TS20 1.4 2.1 2.1 (Si/chair/eq)-TS20 3.9 3.8 3.6 (Si/boat/eq)-TS20 3.3 3.7 3.7 [a] Relative free energies reported in kcal/mol from single point calculations with the listed functional, the def2-TZVP basis set on all atoms and CPCM(THF) on geometries obtained with BP86-D3/LANL2TZ(f)–631G(d). [b] A mixed basis set consisting of LANL2TZ(f) on palladium and 6-311+G(d) on all other atoms utilized. Given the potentially significant role of noncovalent interactions in differentiating the energy between diastereomeric transition states, we sought to further refine our calculated ∆∆G‡ by employing single point calculations with domain based local pair natural orbital coupled-cluster theory (DLPNO-CCSD(T)) (Table 1.6). For these calculations, we employ the cc-pVTZ basis set on all atoms, with the SK-MCDHF-RSC relativistic effective core potential on palladium. Calculations are additionally carried out with the “TightPNO” criteria for the two lowest energy diastereomeric transition states found from calculations with the “NormalPNO” settings. Under standard conditions at 25 ºC, an enantiomeric excess of 88% is experimentally observed, corresponding to an apparent ∆∆G‡ of 1.6 kcal/mol. Comparing the relative energies of only the two lowest energy diastereomeric transition states with “NormalPNO” and “TightPNO” cutoffs affords a calculated ∆∆G‡ of 2.3 and 1.9 kcal/mol, respectively, corresponding to 96% ee and 92% ee. From a Boltzmann-weighted average over unique transition states (with “NormalPNO”), 94% ee is calculated. These results are Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 56 Comprehensive Quantum Mechanics Investigation in good agreement with experimentally obtained values, and thus highlight the efficacy of the DLPNO-CCSD(T) in the context of asymmetric catalysis. Table 1.6. Comparison of relative free energies obtained at the DLPNO-CCSD(T) level of theory.a DLNO-CCSD(T)b DLNO-CCSD(T) DLNO-CCSD(T) NormalPNO NormalPNO TightPNO (Re/chair/ax)-TS20 0.0 0.0 0.0 (Re/boat/ax)-TS20 6.6 5.9 – (Re/chair/eq)-TS20 1.4 1.0 – (Re/boat/eq)-TS20 6.6 6.1 – (Si/chair/ax)-TS20 3.0 2.8 – (Si/boat/ax)-TS20 2.2 2.3 1.9 (Si/chair/eq)-TS20 4.5 4.0 – (Si/boat/eq)-TS20 4.4 4.2 – [a] Relative free energies reported in kcal/mol with DLPNO-CCSD(T)/cc-pVTZ–CPCM(THF)//BP86D3/LANL2TZ(f)–6-31G(d). bUsing the def2-TZVP basis set on all atoms. Further controls were carried out in which transition state optimizations were carried out without D3 dispersion correction (Table 1.7), and with the B3LYP-D3 hybrid functional (Table 1.8). Both of these trials offer similar overall results to those obtained with BP86-D3 geometries. Table 1.7. Optimization without D3 corrections (BP86).a M06b DLNO-CCSD(T)c (Re/chair/ax)-TS20 0.0 0.0 (Re/boat/ax)-TS20 4.4 5.9 (Re/chair/eq)-TS20 1.6 2.2 (Re/boat/eq)-TS20 5.3 6.7 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 57 Comprehensive Quantum Mechanics Investigation (Si/chair/ax)-TS20 2.6 1.8 (Si/boat/ax)-TS20 1.7 2.7 (Si/chair/eq)-TS20 4.2 4.3 (Si/boat/eq)-TS20 3.5 5.0 [a] Relative free energies reported in kcal/mol with geometries obtained with BP86/LANL2DZ–631G(d). [b] Single point calculation with M06/def2-TZVP–CPCM(THF). [c] Single point calculation with DLPNO-CCSD(T)/cc-pVTZ–CPCM(THF) with “NormalPNO” settings. Table 1.8. Optimization with B3LYP-D3.a M06b DLNO-CCSD(T)c (Re/chair/ax)-TS20 0.0 0.0 (Re/boat/ax)-TS20 2.8 3.7 (Si/chair/ax)-TS20 1.7 1.9 (Si/boat/ax)-TS20 1.5 2.3 [a] Relative free energies reported in kcal/mol with geometries obtained with B3LYP-D3/LANL2DZ– 6-31G(d). The four lowest energy “axial” transition states were considered here. [b] Single point calculation with M06/def2-TZVP–CPCM(THF). [c] Single point calculation with DLPNO-CCSD(T)/ccpVTZ–CPCM(THF) with “NormalPNO” settings. 1.5.5 ADDITIONAL NOTES Facile interconversion between (Re)-13 and (Si)-13 A previous computational investigation into the reaction mechanism of a truncated system (beginning from enolate intermediates) highlights internal rearrangements of palladium enolates prior to C–C bond formation as a possible origin of enantioinduction.21 This hypothesis is dependent on kinetic quenching (rather than equilibration) of enolates (Re)-13 and (Si)-13 by their corresponding C–C bond forming events. However, the authors of that study recognize that a transition state leading to the facile equilibration of Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 58 Comprehensive Quantum Mechanics Investigation (Re/Si)-13 may exist, but do not explore further, leaving the origins of enantioinduction unresolved. In this investigation, a low energy transition state connecting (Re)-13 and (Si)13 on the PES is found (TS24, ∆G‡ ~ 5 kcal/mol). TS24 is significantly lower in energy than the next lowest transition states, which are those of C–C bond formation (TS20). Thus, enolates (Re)-13 and (Si)-13 are expected to be in thermal equilibrium. Hence, internal rearrangements of palladium enolates, followed by kinetic quenching via C–C bond formation, is not responsible for enantioinduction. Additional potentially lower energy transition states for the interconversion of (Re)13 and (Si)-13 likely persist, however are challenging to optimize given the flat nature of the PES and conformational flexibility of the enolate fragment. It is worth noting that highly decorated, sterically encumbered substrates may experience a barrier to enolate equilibration similar or greater in magnitude to that of C–C bond formation. Should this be the case, the mechanism of decarboxylation and/or choice of masked enolate synthon would play a large role in the resultant product enantioselectivity. The pathways, intermediates, and consideration described in this research provide a framework from which this would be evaluated. Trans Influence in Oxidative Addition Our investigations into the mechanism of oxidative addition reveal the lowest energy process for C–O bond cleavage to be that of an anti displacement-type of mechanism (Figure 1.3). The lowest energy conformer of four unique transition states are considered, in which displacement of the carboxylate leaving group occurs trans to either Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 59 Comprehensive Quantum Mechanics Investigation the nitrogen (t-N) or phosphorus (t-P) of the PHOX ligand, with either exo or endo approach of the allylic fragment. Table 1.9. Relative free energies (in kcal/mol) of isomeric oxidative addition transition states at various levels of theory.a BP86-D3 B3LYP-D3 PBE0-D3 M06 DLPNO-CCSD(T)b (exo/t-N)-TS4 0.0 0.0 0.0 0.0 0.0 (endo/t-N)-TS4 1.4 2.0 1.9 2.3 2.7 (exo/t-P)-TS4 5.9 7.6 7.3 7.5 9.3 (endo/t-P)-TS4 3.8 4.8 5.5 6.2 6.5 [a] Relative free energies reported in kcal/mol with geometries obtained with BP86-D3/LANL2TZ(f)– 6-31G(d). Single point calculation with def2-TZVP basis set on all atoms (def2-ECP on Pd) and CPCM(THF). [b] Single point calculation with DLPNO-CCSD(T)/cc-pVTZ/CPCM(THF) with “NormalPNO” settings. An energetic preference of 3.8–6.5 kcal/mol is found for the t-N transition states across the various levels of theory investigated (Table 1.9). While this may be in part due to steric interactions between the carboxylate leaving group and the phenyl rings of the triaryl phosphine ligand, we also consider electronic effects. In accordance with the anticipated trans influence, elongated Pd–X bond lengths trans to phosphorus are observed (Figure 1.3). As a hypothesis for the origins of the preference for t-N transition states, we consider the research of De Proft and co-workers,43 who provide a ligand-field-based rational for the trans influence in related square planar Pt(II) complexes. In brief, the authors suggest the repulsion between a strong trans ligand (T) and the ligand trans to T (L) arises from further hybridization (in unsymmetrical d8 complexes) between the occupied 2a’ and Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 60 Comprehensive Quantum Mechanics Investigation virtual 3a’ MOs (Figure 1.15) resulting in a net decrees in Pt–L s-bonding character, and thus, a longer bond length. Figure 1.15. Select frontier MOs of a model PtII complex highlighting potential hybridization of 2a’ and 3a’. 4a’ 3a’ X T Pt X L 2a’ 1a’ In the case of the (PHOX)Pd complexes, we consider this effect may play a role in the calculated preference for displacement trans to nitrogen. The reduced Pd–C(OCOR) bond length in the t-N transitions states should be conducive to enhanced overlap with the s*(C– O), thus, facilitating displacement of the carboxylate leaving group. Additional Computations for “Experiment and Discussion” Section of Manuscript Experimentally, it was determined that for b-ketoester substrate 1, employing the more electron poor (S)-(CF3)3-t-BuPHOX ligand in place of the standard (S)-t-BuPHOX ligand, with otherwise identical reaction conditions, did not result in a significant change in reaction rate. Computationally, an identical result was obtained. Henceforth, the suffix “_CF3” denotes structures that are re-optimized using the (R)-(CF3)3-t-BuPHOX ligand. The apparent barrier heights of the two lowest energy decarboxylation pathways (Pathways 2 and 3, see text) were then compared with both ligands at the DLPNO-CCSD(T) level of Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 61 Comprehensive Quantum Mechanics Investigation theory. Similar results are obtained with “NormalPNO” and “TightPNO” cutoffs (Table 1.10). Table 1.10. Comparison of barrier heights to decarboxylation with the standard (S)t-BuPHOX and electron poor (S)-(CF3)3-t-BuPHOX ligands.a TS14 TS15 TS14_CF3 TS15_CF3 NormalPNO 22.0 23.5 22.4 21.6 TightPNO 21.9 24.3 22.2 22.4 [a] Free energies reported in kcal/mol with geometries obtained with BP86-D3/LANL2TZ(f)–6-31G(d). Single point calculation with DLPNO-CCSD(T)/cc-pVTZ–CPCM(THF). In order to experimentally probe the interplay of inner- and outer-sphere mechanistic pathways, we prepared a-phenyl b-ketoester 20 as well as the corresponding enol carbonate 21. Highlighting the role of decarboxylative pathway on subsequent C–C bond formation, compounds 20 and 21 both yield a-phenyl product 22, however with differing degrees of enantioenrichment. In analogous fashion to intermediates derived from substrate 1 (R = Me), the corresponding set of seven-membered pericyclic inner-sphere C– C bond forming transition states (TS20_Ph) are considered. These initial results suggest that inner-sphere C–C bond formation for these a-phenyl enolates may give rise to a similar degree of product enantioenrichment as the a-methyl case (Table 1.11). Table 1.11. Inner-sphere reductive elimination transition states with a-phenyl substrate. Transition State G(rel) (Re/chair/axial)-TS20_Ph_i 0.0 Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 62 Comprehensive Quantum Mechanics Investigation (Re/chair/axial)-TS20_Ph_ii 1.3 (Re/boat/axial)-TS20_Ph_i 4.9 (Re/boat/axial)-TS20_Ph_ii 3.6 (Si/chair/axial)-TS20_Ph_i 4.1 (Si/chair/axial)-TS20_Ph_ii 4.1 (Si/boat/axial)-TS20_Ph_i 1.3 (Si/boat/axial)-TS20_Ph_ii 1.3 [a] Relative free energies reported in kcal/mol from the M06/def2-TZVP–CPCM(THF)//BP86D3/LANL2TZ(f)–6-31G(d) level of theory. Note that Re and Si exchange compared to TS20 with aMe groups due to the priority of the Ph substituent. 1.5.6 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA O O O PhB(OH)2 (1.1 equiv) Pb(OAc)4 (1.1 equiv) Hg(OAc)2 (0.11 equiv) O Ph O O 1.7/1 CHCl3/pyridine 40 ºC, 18 h 20 Allyl 2-oxo-1-phenylcyclohexane-1-carboxylate (20) Compound 20 was prepared in following literature precedent.44 To a flame dried flask equipped with a stir bar under a nitrogen atmosphere were added phenylboronic acid (1.46 g, 12.1 mmol, 1.10 equiv), lead(IV) acetate (5.34 g, 12.1 mmol, 1.10 equiv), and mercury(II) acetate (0.38 g, 1.21 mmol). The solids were dissolved in anhydrous chloroform (20 mL) and the solution was heated to 40 ºC. After one hour at 40 ºC, a solution of allyl 2oxocyclohexane-1-carboxylate2 (2.00 g, 11.0 mmol, 1.00 equiv) in pyridine (11.0 mL, 1.0 M) was added to the reaction, and stirring at 40 ºC was continued for 18 hours. Upon complete consumption of b-ketoester starting material, as determined by TLC (10% Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 63 Comprehensive Quantum Mechanics Investigation EtOAc/hexanes), the reaction mixture was let cool, then filtered through a plug of Celite® washing with chloroform. The combined organic phase was washed with aqueous H2SO4 (3 M, 20 mL). The resulting aqueous layer was extracted twice with chloroform (20 mL). The combined organic layer was once again washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and volatiles were removed in vacuo. The crude oil was purified by flash column chromatography (10% EtOAc/hexanes) to afford b-ketoester 20 (2.00 g, 70% yield) as a colorless oil, which solidifies to an amorphous solid upon refrigeration. 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.35 (m, 2H), 7.34 – 7.29 (m, 1H), 7.27 – 7.23 (m, 2H), 5.86 (ddt, J = 17.2, 10.5, 5.6 Hz, 1H), 5.25 – 5.17 (m, 2H), 4.65 (dq, J = 5.6, 1.5 Hz, 2H), 2.81 – 2.73 (m, 1H), 2.60 – 2.53 (m, 2H), 2.48 – 2.40 (m, 1H), 2.03 – 1.93 (m, 1H), 1.90 – 1.73 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 206.8, 171.1, 136.6, 131.6, 128.6, 128.0, 127.8, 118.6, 66.7, 66.1, 40.8, 35.2, 27.8, 22.1 IR (Neat Film, NaCl): 2989, 1714, 1434, 1214 cm–1. HRMS (MM: FD+): m/z calc’d for C16H18O3 [M]+: 258.1256, found 258.1265. O O R O O O or O R Pd2(dba)3 (2.5 mol %) Ligand (6.25 mol %) O R Solvent, 25 ºC General procedure for asymmetric allylic alkylation screening The procedure for the Pd-catalyzed dicarboxylic allylic alkylation is followed as described in our previous reports.2,Error! Bookmark not defined. In a nitrogen filled glovebox, an oven dried Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 64 Comprehensive Quantum Mechanics Investigation vial is charged with a stir bar, tris(dibenzylideneacetone)dipalladium(0) (2.28 mg, 2.50 µmol), and ligand (6.25 µmol). Solvent (1.0 mL) is added, and the catalyst stock solution is pre-stirred for 30 minutes at 25 ºC. To a separate vial equipped with a stir bar is added a solution of substrate (0.05 mmol) in solvent (1.0 mL, 0.05 M). To the solution of substrate is added 0.50 mL of the pre-stirred catalyst stock solution [1.25 µmol Pd2(dba)3, 3.13 µmol ligand]. The reaction vessel is then sealed with electrical tape and removed from the glovebox. Stirring is continued at 25 ºC for 12 hours (unless otherwise noted). Volatiles are then removed in vacuo and the product is purified by silica gel flash column chromatography or preparatory-scale TLC. O Me (S)-2 (S)-2-allyl-2-methylcyclohexan-1-one ((S)-2) Known compound – Spectral data matches that of prior literature reports.2,Error! Bookmark not defined. 1 H NMR (500 MHz, CDCl3): δ 5.69 (ddt, J = 16.2, 10.9, 7.4 Hz, 1H), 5.07 – 5.01 (m, 2H), 2.42 – 2.33 (m, 3H), 2.23 (dd, J = 13.8, 7.2 Hz, 1H), 1.91 – 1.67 (m, 5H), 1.64 – 1.55 (m, 1H), 1.07 (s, 3H). Note: Compound is moderately volatile, and care should be exercised when removing solvent in vacuo. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 65 Comprehensive Quantum Mechanics Investigation O Ph (S)-22 (S)-2-allyl-2-phenylcyclohexan-1-one ((S)-22) Known compound – Spectral data matches that of prior literature reports.45 1 H NMR (500 MHz, CDCl3): δ 7.35 (t, J = 7.7 Hz, 2H), 7.26 – 7.22 (m, 1H), 7.15 (d, J = 7.5 Hz, 2H), 5.44 (dddd, J = 17.0, 10.2, 7.9, 6.7 Hz, 1H), 4.92 (d, J = 10.2 Hz, 1H), 4.88 (d, J = 17.0 Hz, 1H), 2.67 (dq, J = 14.4, 3.0 Hz, 1H), 2.51 (dd, J = 14.0, 6.7 Hz, 2H), 2.44 (dd, J = 14.0, 8.0 Hz, 2H), 2.38 – 2.26 (m, 2H), 1.99 – 1.91 (m, 1H), 1.83 – 1.63 (m, 4H). SFC conditions: 5% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 3.31, major = 3.07. Racemic 22: From enol carbonate 21: Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 66 Comprehensive Quantum Mechanics Investigation From b-ketoester 20: From b-ketoester 20 with optimal conditions (entry 4 in Figure 1.14): Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 67 Comprehensive Quantum Mechanics Investigation 1.6 (1) REFERENCES AND NOTES (a) Trost, B. M.; Jiang, C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006, 3, 369–396. (b) Corey, E. J.; Guzman‐ Perez, A. The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters. Angew. Chem. Int. Ed. 1998, 37, 388–401. (2) (a) 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. (b) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (c) Ngamnithiporn, A.; Iwayama, T.; Bartberger, M. D.; Stoltz, B. M. Enantioselective Synthesis of Highly Oxygenated Acyclic Quaternary Center-Containing Building Blocks via Palladium-Catalyzed Decarboxylative Allylic Alkylation of Cyclic Siloxyketones. Chem. Sci. 2020, 11, 11068–11071. (d) Alexy, E. J.; Fulton, T. J.; Zhang, H.; Stoltz, B. M. PalladiumCatalyzed Enantioselective Decarboxylative Allylic Alkylation of Fully Substituted N-Acyl Indole-Derived Enol Carbonates. Chem. Sci. 2019, 10, 5996– 6000. (e) Lu, Y.; Goldstein, E. L.; Stoltz, B. M. Palladium-Catalyzed Enantioselective C(sp3)–C(sp3) Cross-Coupling for the Synthesis of (Poly)Fluorinated Chiral Building Blocks. Org. Lett. 2018, 20, 5657–5660. (f) Alexy, E. J.; Zhang, H.; Stoltz, B. M. Catalytic Enantioselective Synthesis of Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 68 Comprehensive Quantum Mechanics Investigation Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates. J. Am. Chem. Soc. 2018, 140, 10109–10112. (g) 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. (3) (a) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740– 751. (b) Pritchett, B. P.; Stoltz, B. M. Enantioselective Palladium-Catalyzed Allylic Alkylation Reactions in the Synthesis of Aspidosperma and Structurally Related Monoterpene Indole Alkaloids. Nat. Prod. Rep. 2018, 35, 559–574. (4) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17, 14199–14223. (5) Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Unusual Allylpalladium Carboxylate Complexes: Identification of the Resting State of Catalytic Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 69 Comprehensive Quantum Mechanics Investigation Enantioselective Decarboxylative Allylic Alkylation Reactions of Ketones. Angew. Chem. Int. Ed. 2009, 48, 6840–6843. Note that product enantioenrichment follows a linear correlation with PHOX ligand enantioenrichment. An error was found in a unit conversion (minutes to seconds) in the supporting information data. The correct rate in inverse seconds is k = 1.58 x 10–3 s–1. While this error was initially propagated it is minor and does not affect any subsequent conclusions. (6) Trost, B. M.; Xu, J.; Schmidt, T. Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Enol Carbonates. J. Am. Chem. Soc. 2009, 131, 18343–18357. (7) For review of classes of nucleophiles as well as mechanistic implications: (a) Trost, B. M.; Crawley, M. L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921–2944. Highlighting the challenge of employing “hard” ketone enolate nucleophiles: (b) Trost, B. M.; Schroeder, G. M. Palladium-Catalyzed Asymmetric Alkylation of Ketone Enolates. J. Am. Chem. Soc. 1999, 121, 6759–6760. For examples of stabilized ketone enolates with Trost system: (c) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Palladium-Catalyzed Asymmetric Allylic Alkylation of α-Aryl Ketones. Angew. Chem. Int. Ed. 2002, 41, 3492–3495. (d) Trost, B. M.; Radinov, R.; Grenzer, E. M. Asymmetric Alkylation of β-Ketoesters. J. Am. Chem. Soc. 1997, 119, 7879–7880. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 70 Comprehensive Quantum Mechanics Investigation (8) McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. High-Throughput Screening of the Asymmetric Decarboxylative Alkylation Reaction of Enolate-Stabilized Enol Carbonates. Synlett 2010, 11, 1712–1716. (9) (a) 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. (b) Sun, A. W.; Bulterys, P. L.; Bartberger, M. D.; Jorth, P. A.; O’Boyle, B. M.; Virgil, S. C.; Miller, J. F.; Stoltz, B. M. Incorporation of a Chiral Gem-Disubstituted Nitrogen Heterocycle Yields an Oxazolidinone Antibiotic with Reduced Mitochondrial Toxicity. Bioorg. Med. Chem. Lett. 2019, 29, 2686–2689. (c) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Enantioselective Synthesis of Dialkylated NHeterocycles by Palladium-Catalyzed Allylic Alkylation. Org. Lett. 2015, 17, 1082–1085. (d) 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 Palladium-Catalysed Decarboxylative Allylic Alkylation of Lactams. Nat. Chem 2012, 4, 130–133. (e) Bennett, N. B.; Duquette, D. C.; Kim, J.; Liu, W.-B.; Marziale, A. N.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Expanding Insight into Asymmetric Palladium-Catalyzed Allylic Alkylation of N-Heterocyclic Molecules and Cyclic Ketones. Chem.: Eur. J. 2013, 19, 4414–4418. (f) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 71 Comprehensive Quantum Mechanics Investigation Synthesis of α-Secondary and α-Tertiary Piperazin-2-Ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2015, 54, 179– 183. (g) Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Synthesis of Enantioenriched GemDisubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. Org. Lett. 2021, 23, 6348–6351. (h) Duquette, D. C.; Cusumano, A. Q.; Lefoulon, L.; Moore, J. T.; Stoltz, B. M. Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones. Org. Lett. 2020, 22, 4966–4969. (i) Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4-Diazepan-5-Ones. Org. Lett. 2019, 21, 9158–9161. (10) (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. The Inner-Sphere Process in the Enantioselective Tsuji Allylation Reaction with (S)-t-Bu-Phosphinooxazoline Ligands. J. Am. Chem. Soc. 2007, 129, 11876–11877. (b) Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. The Reaction Mechanism of the Enantioselective Tsuji Allylation: InnerSphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C– C Bond Formation. J. Am. Chem. Soc. 2012, 134, 19050–19060. (11) (a) Pérez-Rodríguez, M.; Braga, A. A. C.; de Lera, A. R.; Maseras, F.; Álvarez, R.; Espinet, P. A DFT Study of the Effect of the Ligands in the Reductive Elimination Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 72 Comprehensive Quantum Mechanics Investigation from Palladium Bis(Allyl) Complexes. Organometallics 2010, 29, 4983–4991. (b) Méndez, M.; Cuerva, J. M.; Gómez‐Bengoa, E.; Cárdenas, D. J.; Echavarren, A. M. Intramolecular Coupling of Allyl Carboxylates with Allyl Stannanes and Allyl Silanes: A New Type of Reductive Elimination Reaction? Chem. Eur. J. 2002, 8, 3620–3628. (c) Zhang, P.; Brozek, L. A.; Morken, J. P. Pd-Catalyzed Enantioselective Allyl−Allyl Cross-Coupling. J. Am. Chem. Soc. 2010, 132, 10686–10688. (12) McPherson, K. E.; Croatt, M. P.; Morehead, A. T. Jr.; Sargent, A. L. DFT Mechanistic Investigation of an Enantioselective Tsuji–Trost Allylation Reaction. Organometallics 2018, 37, 3791–3802. (13) (a) Neese, F. Software Update: The ORCA Program System, Version 4.0. Wiley Interdisciplinary Reviews: Computational Molecular Science 2018, 8, e1327. (b) Neese, F. The ORCA Program System. Wiley Interdisciplinary Reviews: Computational Molecular Science 2012, 2, 73–78. (14) (a) Perdew, J. P. Density-Functional Approximation for the Correlation Energy of the Inhomogeneous Electron Gas. Phys. Rev. B 1986, 33, 8822–8824. (b) Becke, A. D. Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Phys. Rev. A 1988, 38, 3098–3100. (15) (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 73 Comprehensive Quantum Mechanics Investigation 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32, 1456–1465. (c) Becke, A. D.; Johnson, E. R. A density-functional model of the dispersion interaction. J. Chem. Phys. 2005, 122, 154101. (d) Johnson, E. R.; Becke, A. D. A post-Hartree–Fock model of intermolecular interactions. J. Chem. Phys. 2005, 123, 024101. (e) Johnson, E. R.; Becke, A. D. 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The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 74 Comprehensive Quantum Mechanics Investigation Four M06-Class Functionals and 12 Other Functionals. Theor Chem Account 2008, 120, 215–241. (20) Kozuch, S.; Gruzman, D.; Martin, J. M. L. DSD-BLYP: A General Purpose Double Hybrid Density Functional Including Spin Component Scaling and Dispersion Correction. J. Phys. Chem. C 2010, 114, 20801–20808. (21) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (22) Andrae, D.; Häußermann, U.; Dolg, M.; Stoll, H.; Preuß, H. Energy-Adjusted ab Initio Pseudopotentials for the Second and Third Row Transition Elements. Theoret. Chim. Acta 1990, 77, 123–141. (23) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102, 1995–2001. (24) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chem. Eur. J. 2012, 18, 9955–9964. (25) Legault, C. Y. CYLView, 1.0b; Université de Sherbrooke, Canada, 2009; http://www.cylview.org. Note that solvent exposed surface plots were generated with Chimera: Petterson, E. F.; Goddard T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera – a visualization Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 75 Comprehensive Quantum Mechanics Investigation system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605– 1612. (26) (a) Riplinger, C.; Neese, F. An Efficient and near Linear Scaling Pair Natural Orbital Based Local Coupled Cluster Method. J. Chem. Phys. 2013, 138, 034106. (b) Riplinger, C.; Sandhoefer, B.; Hansen, A.; Neese, F. Natural Triple Excitations in Local Coupled Cluster Calculations with Pair Natural Orbitals. J. Chem. Phys. 2013, 139, 134101. (c) Riplinger, C.; Pinski, P.; Becker, U.; Valeev, E. F.; Neese, F. Sparse Maps—A Systematic Infrastructure for Reduced-Scaling Electronic Structure Methods. II. Linear Scaling Domain Based Pair Natural Orbital Coupled Cluster Theory. J. Chem. Phys. 2016, 144, 024109. (27) Peterson, K. A.; Figgen, D.; Dolg, M.; Stoll, H. Energy-Consistent Relativistic Pseudopotentials and Correlation Consistent Basis Sets for the 4d Elements Y–Pd. J. Chem. Phys. 2007, 126, 124101. (28) (a) Yamamoto, T.; Saito, O.; Yamamoto, A. Oxidative Addition of Allyl Acetate to Palladium(0) Complexes. J. Am. Chem. Soc. 1981, 103, 5600–5602. (b) Yamamoto, T.; Akimoto, M.; Saito, O.; Yamamoto, A. Interaction of Palladium(0) Complexes with Allylic Acetates, Allyl Ethers, Allyl Phenyl Chalcogenides, Allylic Alcohols, and Allylamines. Oxidative Addition, Condensation, Disproportionation, and π-Complex Formation. Organometallics 1986, 5, 1559– 1567. (c) Amatore, C.; Jutand, A.; Meyer, G.; Mottier, L. Evidence of the Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 76 Comprehensive Quantum Mechanics Investigation Reversible Formation of Cationic π-Allylpalladium(II) Complexes in the Oxidative Addition of Allylic Acetates to Palladium(0) Complexes. Chem.: Eur. J. 1999, 5, 466–473. (29) Ariafard, A.; Lin, Z. Understanding the Relative Easiness of Oxidative Addition of Aryl and Alkyl Halides to Palladium(0). Organometallics 2006, 25, 4030–4033 (30) Low, J. J.; Goddard, W. A. Theoretical Studies of Oxidative Addition and Reductive Elimination. 3. Carbon-Hydrogen and Carbon-Carbon Reductive Coupling from Palladium and Platinum Bis(Phosphine) Complexes. J. Am. Chem. Soc. 1986, 108, 6115–6128. (31) Grennberg, H.; Langer, V.; Bäckvall, J.-E. Structure and Reactivity of Cis- and Trans-Bis-[{5-Carbomethoxy-(1,2,3-η)-Cyclohexenyl}palladium]. Evidence for a (σ-Allyl)Palladium Intermediate in the Cis-Migration of Acetate from Palladium to Coordinated π-Allyl. J. Chem. Soc., Chem. Commun. 1991, 17, 1190–1192 (32) Trost, B. M.; Verhoeven, T. R. Allylic Substitutions with Retention of Stereochemistry. J. Org. Chem. 1976, 41, 3215–3216. (33) (a) Pérez-Rodríguez, M.; Braga, A. A. C.; de Lera, A. R.; Maseras, F.; Álvarez, R.; Espinet, P. A DFT Study of the Effect of the Ligands in the Reductive Elimination from Palladium Bis(Allyl) Complexes. Organometallics 2010, 29, 4983–4991. (b) Méndez, M.; Cuerva, J. M.; Gómez‐Bengoa, E.; Cárdenas, D. J.; Echavarren, A. M. Intramolecular Coupling of Allyl Carboxylates with Allyl Stannanes and Allyl Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 77 Comprehensive Quantum Mechanics Investigation Silanes: A New Type of Reductive Elimination Reaction? Chem. Eur. J. 2002, 8, 3620–3628. (c) Zhang, P.; Brozek, L. A.; Morken, J. P. Pd-Catalyzed Enantioselective Allyl−Allyl Cross-Coupling. J. Am. Chem. Soc. 2010, 132, 10686–10688. (34) (a) Trost, B. M.; Thaisrivongs, D. A. Strategy for Employing Unstabilized Nucleophiles in Palladium-Catalyzed Asymmetric Allylic Alkylations J. Am. Chem. Soc. 2008, 130, 14092–14093. (b) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Highly Enantioselective Palladium‐Catalyzed Alkylation of Acyclic Amides Angew. Chem. Int. Ed. 2008, 47, 1741–1744. (c) Trost, B. M.; Xu, J.; Schmidt, T. Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Enol Carbonates J. Am. Chem. Soc. 2009, 131, 18343–18357. (35) (a) Aranyos, A.; Szabó, K. J.; Castaño, A. M.; Bäckvall, J.-E. Central versus Terminal Attack in Nucleophilic Addition to (π-Allyl)Palladium Complexes. Ligand Effects and Mechanism. Organometallics 1997, 16, 1058–1064. (b) Szabó, K. J. Effects of the Ancillary Ligands on Palladium−Carbon Bonding in (h3−Allyl)Palladium Complexes. Implications for Nucleophilic Attack at the Allylic Carbons. Organometallics 1996, 15, 1128–1133. (c) Castaño, A. M.; Aranyos, A.; Szabó, K. J.; Bäckvall, J.-E. Nucleophilic Attack on (πAllyl)Palladium Complexes: Direction of the Attack to the Central or Terminal Carbon Atom by Ligand Control. Angew. Chem. Int. Ed. 1995, 34, 2551–2553. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 78 Comprehensive Quantum Mechanics Investigation (36) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. Cyclopropanation of Ester Enolates by π-Allylpalladium Chloride Complexes. J. Org. Chem. 1980, 45, 5193– 5196. (37) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Isolation and X-Ray Crystal Structure of a Palladacyclobutane: Insight into the Mechanism of Cyclopropanation. Angew. Chem. Int. Ed. 1995, 34, 100–102. (38) Note that in reference 2h a slight kinetic resolution was observed. (39) 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. (40) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree-Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree-Fock Exchange. Chemical Physics 2009, 356, 98–109. (41) Stoychev, G. L.; Auer, A. A.; Neese, F. Automatic Generation of Auxiliary Basis Sets. J. Chem. Theory Comput. 2017, 13, 554–562. (42) (a) Chéron, N.; Jacquemin, D.; Fleurat-Lessard, P. A Qualitative Failure of B3LYP for Textbook Organic Reactions. Phys. Chem. Chem. Phys. 2012, 14, 7170–7175. (b) Burke, K.; Perdew, J. P.; Ernzerhof, M. Why the Generalized Gradient Approximation Works and How to Go beyond It. International Journal of Quantum Chemistry 1997, 61, 287–293. Chapter 1 – Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A 79 Comprehensive Quantum Mechanics Investigation (43) Pinter, B.; Speybroek, V. V.; Waroquier, M.; Geerlings, P.; De Proft, F. trans effect and trans influence: importance of metal mediated ligand-ligand repulsion. Phys. Chem. Chem. Phys. 2013, 15, 17354–17365. (44) Akula, R.; Doran, R.; Guiry, P. J. Highly Enantioselective Formation of a-Allyl-aArylcyclopentanones via Pd-Catalysed Decarboxylative Asymmetric Allylic Alkylation. Chem. Eur. J. 2016, 22, 9938–9942. (45) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Palladium-Catalyzed Asymmetric Allylic Alkylation of α-Aryl Ketones. Angew. Chem. Int. Ed. 2002, 41, 3492–3495. Appendix 1 – Spectra Relevant to Chapter 1 80 APPENDIX 1 Spectra Relevant to Chapter 1: Mechanism of the Pd-catalyzed Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation 10 O O 20 Ph O 9 8 6 5 ppm 4 3 Figure A1.1. 1H NMR (400 MHz, CDCl3) of compound 20. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 81 Appendix 1 – Spectra Relevant to Chapter 1 82 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 20. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.3. 13C NMR (100 MHz, CDCl3) of compound 20. 0 CHAPTER 2 Analysis of the Pd [π2s + π2s + σ2s + σ2s] Pericyclic Reaction† 2.1 INTRODUCTION Selectivity in pericyclic reactions is a tangible manifestation of the quantum mechanical wave-like behavior of electrons. Bringing an acyclic system to a cyclic transition state introduces constructive/destructive interferences amongst the spatial wavefunctions of the component electrons, which are governed by orbital orthogonality requirements as prescribed by the Pauli principle. With proper constructive overlaps, the bond order of the transition state will match that of the reactant(s) and product(s) – i.e., net covalent bonding is maintained through the transition state. Alternatively, destructive interferences are incurred that do not allow for continual bonding – i.e., a covalent bonding interaction is lost, and the electronic configuration is that of a diradical. Several conceptual frameworks are commonly employed to analyze the nature of bonding in pericyclic transition states, though these are simply different projections of the same underlying physics. These tools include orbital and state correlation diagrams, frontier molecular orbital (FMO) theory, 1 the orbital phase continuity principle 2 in valence bonding wavefunctions, and the concept of transition state (anti)aromaticity.3 Pericyclic reactivity is also commonplace in organometallic systems.4 In fact, the elementary step responsible for enantioinduction in the inner-sphere asymmetric Tsuji †Performed under the co-advisory of Prof. William A. Goddard III. This chapter has been reproduced with permission from J. Am. Chem. Soc. 2020, 142, 19033–19039. © 2020 American Chemical Society. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 84 allylic alkylation is C–C bond formation through a synchronous, seven-membered pericyclic transition state (TS20) (Figure 2.1A).5 Since the original computational reports by our groups 6 and others, 7 the relationship between this class of seven-membered transition states to those of the canonical pericyclic reactions as described by Woodward and Hoffmann is underexplored. 8 Exemplifying the peculiar nature of the reaction, an analogous transformation in a system comprised of main group elements remains elusive.9 Given the key role of this seven-membered pericyclic process in asymmetric catalysis, we sought to delineate the underlying reactivity paradigm that enables this unique transformation (Figure 2.1B). Figure 2.1. Seven-centered cyclic transition states in Pd catalysis. A. Seven-membered transition state in C–C bond formation: B. This research: [𝛑2s + 𝛑2s + 𝛔2s + 𝛔2s] reactions. H 3P O N O N Pd Pd Me P Me P 13 t-Bu N = P N PPh2 H 3P N P H 3P H 3P Pd Pd H 3P X H 3P X X 26 (X = CH2) 27 (X = O) 19 TS25 (X = CH2) TS26 (X = O) 28 (X = CH2) 29 (X = O) Main group analog ∆G‡ = 10.8 kcal/mol ∆G = –22.5 kcal/mol Eight-electron pericyclic reaction O X S O (S)-t-BuPHOX 2.2 Facile Pd Pd TS20 O O Me 23 Symmetryforbidden O O S O S + O TS24 24 25 RESULTS AND DISCUSSION To obtain a general understanding of this bond forming event, we first examined an analogous system comprised of main group elements, namely the reaction of diallyl sulfone (23) to sulfur dioxide (24) and 1,5-hexadiene (25) (Figure 2.1B). If the geometry of the seven-membered cheletropic transition state (TS24) is constrained to match that of TS20, then a suprafacial relationship amongst the eight correlating orbitals with linear departure of the chelefuge is mandated. Thus, the transformation of 23 to 24 + 25 is designated [π2s Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 85 + π2s + s2s + s2s] and the reverse as [w2s + π2s + π2s + s2s]. With four suprafacial twoelectron terms, the ground-state pericyclic reaction of 23 to 24 + 25 is anticipated to be symmetry-forbidden by the generalized Woodward–Hoffmann rules.8 An identical conclusion is reached for chelefuges such as CO and N2 in the ground state.10 Given the low thermal barriers with which the Pd-catalyzed transformations proceed (∆G‡ = 10–20 kcal/mol),5 we became curious as to whether the transformation is similarly forbidden for a LnPd0-like chelefuge. To uncover the electronic origins that enable the transition metal-mediated pericyclic processes, we turned to ab initio Quantum Mechanics (QM) calculations. Calculations were carried out with the ORCA ab initio package (see 2.4. Supporting Information for full details). 11 Complete active space self-consistent field (CASSCF) theory is utilized to capture the multiconfigurational nature of the potential energy surface (PES), where the (8,8) active space is defined to be the eight valence electrons in eight correlating orbitals as described by orbital correlation diagrams. Dynamical correlation is accounted for via N-electron valence state perturbation theory12 (NEVPT2) single point calculations on the CASSCF wavefunctions. All geometry optimizations and frequency calculations were carried out with the triple-z quality def2-TZVP basis set13 on all atoms (with the small core ECP28MWB pseudopotential 14 on Pd, i.e., 18 explicit electrons including the 4s and 4p core electrons). For transition metal complexes with insignificant multiconfigurational character, geometries were obtained with density functional theory (DFT) (PBE0-D3(BJ)/def2-TZVP) 15 followed by CASSCF/NEVPT2 single point calculations with the def2-TZVPP basis set. Solvation was accounted for in single point Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 86 Figure 2.2. (A) Orbital correlation diagram for the [π2s + π2s + σ2s + σ2s] quasicheletropic reaction of diallyl sulfone.a (B) Symmetry-forbidden C–C bond formation from diallyl sulfone 23.b A. Orbital correlation diagram for the [𝛑2s + 𝛑2s + 𝛔2s + 𝛔2s] reaction of diallyl sulfone: Ground state symmetry-forbidden [𝛑2s + 𝛑2s + 𝛔2s + 𝛔2s] O O S O O S S 23 + O O 24 (hypothetical) 25 4b 4b 4a 2b [𝛑 C–C] 2a [𝛑 C–C] 3b 3b 3a 4a 2b 2b + + 1b [𝛑 C–C] 3a [𝛑 C–C] + + 2a [nS; 4s] 2b [S; px] 1b 2a 3a 1b 1a [𝛔 S–C] 2a 1b [𝛔 S–C] 1a 1a C. Electronic structure of diradical 30: B. Ground state reaction of 23 to 24 + 25: O S O X O O S O 23: 0.0 (0.0) |Φ# ⟩ + S O 3b 24 + 25: –10.2 (–7.0) Avoided crossing 4a 2b O O S TS27: 58.4 (47.1) O O S 30: 56.4 (49.7) O O |Φ# ⟩ 4b 3a 2b 3a 3a 1b 2a 1a 4b 4a 1b S 3b 2a 2b 1a TS28: 67.1 (51.2) [a] Select natural orbitals from the CAS(8,8) active space shown. [b] CASSCF-based free energy estimates in kcal/mol with the NEVPT2 corrected values in parentheses. calculation with the SMD model for THF.16 All energies reported are solvated free energies at 298.15 K. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 87 Beginning with main group analog diallyl sulfone (23), generation of symmetryadapted linear combinations of correlating valence orbitals under approximate C2 symmetry affords symmetric (a) and antisymmetric (b) sets of s/s *(C–S) and π/π*(C–C) orbitals (Figure 2.2A). Correlating these orbitals to those of the product implies an avoided crossing along the ground sate potential energy surface (PES) as the diabatic state describing 23, |Φ# ⟩, corresponds to a doubly excited state of the products. Likewise, a single transition state connecting 23 to 24 + 25 was not found on the CASSCF potential energy surface. Rather, a stepwise process involving singlet diradical intermediate 30 was found (Figure 2.2B).17 At this point, the ground state configuration interaction (CI) vector possesses nearly equal contributions of configurations |Φ% ⟩ and |Φ# ⟩ , leading to a diradical index d = 98.0% (Figure 2.2C). 18 Calculations with multireference iterative Difference Dedicated CI (IDDCI) theory provide d = 95.4% and a singlet/triplet exchange coupling constant (J) of 83 cm–1.19 In summary, the required crossing of the starting material (23) and product (24 + 25) diabatic ground states renders the concerted [π2s + π2s + s2s + s2s] reaction symmetry-forbidden. The ground state PES of 23 → 24 + 25 is characterized by a stepwise mechanism involving weakly coupled diradical 30, with an overall ∆G‡ of >50 kcal/mol — contrasting the low thermal barriers of Pd-catalyzed transformations (∆G‡ = 10–20 kcal/mol).5 Given this, we became curious as to whether the Pd-catalyzed transformation is similarly symmetry-forbidden, proceeding through a low energy diradical intermediate/state, or whether a unique set of symmetry elements describe the transformation that conserves orbital symmetry through the reaction. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 88 In order to probe this hypothesis, we first considered the case of a simplified bis(h1–allyl)PdII complex 26 (Figure 2.3A). Contrary to 23, we find a single low energy transition state (TS25), with ∆G‡ =13.4 kcal/mol, on the spin-restricted DFT (PBE0D3(BJ)/def2-TZVP) PES connecting 26 to 28 (Figure 2.3B). We obtain a similar result for (h1-allyl)PdII enolate 27. We find that the ground-state single-determinant wavefunction along the PES is stable with respect to symmetry breaking, suggesting a single closed-shell singlet (CSS) configuration is dominant. The existence of a saddle point smoothly connecting 26 to 28 on a PES derived from the CSS state of a single-determinant wavefunction points to the absence of an avoided crossing. Moreover, this suggests that simple DFT geometries should be reliable for these Pd complexes and will be used in the following. For comparison to the symmetry-forbidden transformation of 23 to 24 + 25, we construct the corresponding orbital correlation diagram for the conversion of 26 to 28 (Figure 2.3A). The four occupied correlating orbitals of starting complex 6 are identical in symmetry to those of diallyl sulfone 13 (two a and two b symmetry elements). However, unlike the products of the thermally-forbidden reaction (24 + 25), complex 28 maintains the symmetry of ground-state minimum 26. This is further evident in the composition of the ground-state CASSCF wavefunction at TS25, with weights of 0.86 and 0.02 for the dominant CSS configuration and second largest contributor, respectively. Note the absence of configurations corresponding Zwitterionic states or mixing of ground and doubly excited states describing a diradical configuration. Control experiments do not find evidence of redox noninnocence of the PHOX ligand scaffold. Thus, our calculations suggest the Pd Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 89 [π2s + π2s + s2s + s2s] reaction is symmetry-allowed. While introducing heteroatoms into the system formally lowers the symmetry, this has no effect on the underlying physics. Hence, the transformation of PdII enolate complex 27 to 29 is also symmetry-allowed in the ground-state (Figure 2.3B). The symmetry of the lone pair-like orbital of the chelefuge differentiates between the thermally-allowed and forbidden scenarios. In ground state SO2, the lone pair occupies a symmetric sp2 valence orbital (2a in Figure 2.2A), whereas in 8/9, this corresponds to the antisymmetric Pd-based d(x2–y2) orbital (2b in Figure 2.3A). Thus, the eight-electron seven-membered pericyclic transition is thermally-allowed in the case of Pd complexes 27, 29, and 13 by virtue of the parity of the d(x2–y2) orbital involved in s bonding with the organic scaffold (Figure 2.3C). 20 Other metal-based d orbitals can be included in this analysis but bear no consequence as these orbitals remain doubly occupied throughout the transformation. From the perspective of frontier molecular orbital (FMO) theory, the transformation is readily interpreted as the (in)ability of the chelefuge HOMO/donor to constructively interact with the antisymmetric LUMO/acceptor of the 1,5-hexadiene in the appropriate geometry (Figure 2.4A). If constructive overlap is achieved, then net bonding is preserved through the transition state and the reaction is symmetry-allowed.20a–b This is the case for the Pd-catalyzed transformation as the Pd-based d(x2–y2) HOMO of hypothetical L2Pd0 chelefuge s bonds with the diene in a suprafacial/antaranodal fashion, i.e., with phase inversion, constructively mixing with the diene LUMO (Figure 2.4A).21 This is not the case for the symmetric nucleophile lone pair orbitals of SO2 and CO.10 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 90 Figure 2.3. (A) Orbital correlation diagram for the pericyclic reaction of 26 to 28. Select natural orbitals of CAS(8,8) wavefunction shown. (B) Free energy changes and barriers (in kcal/mol). (C) Orbital topologies. A. Orbital correlation diagram for the [𝛑2s + 𝛑2s + 𝛔2s + 𝛔2s] reaction of bis-(𝝶1–allyl)PdII complex 26: y H 3P H 3P H 3P z x H 3P H 3P H 3P 26 Ground-state symmetry-allowed Pd Pd Pd 28 TS25 (4b) 4a (4a) 4b 2a [𝛑 C–C] 2b [𝛑 C–C] 3a (3a) 3b (3b) (2b) [nPd, 4d(x2–y2)] (4a) [Pd, 5s] (1a) [𝛔 C–C] (2a) [𝛑 C–C] 2b 2a (2b) (1b) 1a 1b 1a [𝛔 Pd–C] (2a) 1b [𝛔 Pd–C] (1a) B. The [𝛑2s + 𝛑2s + 𝛔2s + 𝛔2s] reaction of 6/7 to 8/9: H 3P H 3P H 3P Pd Pd H 3P H 3P 26 C. Relevant orbital topologies: TS25 Pd Pd H 3P O 27 H 3P (R) Pd O H 3P TS26 29 ∆G‡ = 13.8 (13.7); ∆G = –31.5 (–38.8) Suprafacial Antaranodal M 28 H 3P H 3P Pd Suprafacial Supranodal H 3P ∆G‡ = 13.4 (12.3); ∆G = –27.8 (–29.9) H 3P Chelefuge lone pair (R) [M = SO2, CO] [M = Ni, Pd, Pt] Approach: Linear Linear Antarafacial Antaranodal Antarafacial Supranodal Antarafacial Antaranodal Non-linear Non-linear Non-linear O [a] Free energies calculated using NEVPT2 electronic energies with thermal corrections and geometries from DFT (PBE0-D3(BJ)). Full DFT energies in parenthesis. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 91 Figure 2.4. (A) FMO perspective of the [π2s + π2s + σ2s + σ2s] reaction. (B) Relevant MOs from the CAS(8,8) active space that contribute to the aromaticity of TS25. (C) NICS analysis of TS25 (green and red spheres denote negative and positive NICS values).a A. Reactivity paradigm from FMOs: M Allowed Forbidden L R L R M M donor B. Elements of Craig–Möbius aromaticity in TS25: acceptor donor C. NICS analysis of TS25: –19.4 H 3P L Pd H 3P L acceptor +1.0 3.1 Å +0.5 4.7 Å HOMO L L HOMO –2 .0 [a] NICS values in ppm with sphere radius depicting magnitude of the shift (& = ()*++, )- / ). It is well understood that concerted, symmetry-allowed pericyclic reactions proceed through aromatic transition states.3 Thus, if the Pd [π2s + π2s + s2s + s2s] reaction of 26 to 28 is indeed symmetry-allowed, then TS25 should be aromatic in nature. From analysis of the active space MOs at TS25 we find elements of Craig–Möbius-like aromaticity within the s bonding framework.22 Of particular interest, the HOMO and HOMO–2 conform to a Möbius topology with the Pd d(x2–y2) generating a phase inversion and an odd number of nodes (1 and 3) along the ring (Figure 2.4B).23 To probe this suspected aromaticity, we Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 92 employ the Nucleus-Independent Chemical Shift (NICS) method of Schleyer and coworkers.24 A NICS(0) of –19.4 ppm is calculated at the geometric center of the sevenmembered ring of TS25, indicating aromaticity.25 Likewise, a positive NICS is found at various points along the external periphery. For enhanced visualization, the NICS at points along 2D grids are displayed in Figure 2.4C. A principal objective of our investigation is to relate electronic structure to intuitive concepts in chemical bonding. As such, we sought to explore whether the Pd-catalyzed [π2s + π2s + s2s + s2s] transformation could be properly described by valence bonding concepts such as the ubiquitous “arrow-pushing” formalism of Robinson and Ingold.26 Given the single-configurational nature of the ground state density, the concept of bond reorganization is addressed through analysis of Intrinsic Bonding Orbitals (IBOs) as described by Knizia and co-workers. 27 Previously, IBO analysis was implemented to highlight “electron flow” through transition states, discern between classes of mechanisms, and evaluate synchronicity of bond making/breaking in these events.27 Generation of IBOs proceeds through a Pipek–Mezey-style localization of Kohn–Sham orbitals where orbital charge contribution to an atomic center is measured by Intrinsic Atomic Orbital (IAO) charge.27a–b At no point in the localization are empirical concepts of valence bonding introduced, yet IBOs correspond well to two-center two-electron bonds (or lone pairs) as depicted in Lewis structures. IBOs of forming/breaking bonds at transition structures generally resemble three-center two-electron bonds describing the transformation of one localized bond to another. Hence, the progression of IBOs along a reaction coordinate offers a connection to the “arrow-pushing” formalism of Robinson and Ingold. So long as Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 93 the localized orbitals are adequately portrayed by a Lewis structure and the system is well described by a single reference wavefunction then there is utility in such analysis. IBO analysis was carried out with the full (PHOX)Pd enolate system (Figure 2.5). Four IBOs (12 ) undergo significant displacement along the intrinsic reaction coordinate (IRC) through 13→TS20→19.28 The first of these, 1. , corresponds to the localized π(C– C) bond of the enolate fragment, which smoothly progresses to encapsulate the density of the newly formed s(C–C) bond of the product. Likewise, 13 , 1/ , and 14 track the transformations of π(C–C) → π(C–C)’, s(Pd–C) → n(Pd; d(x2–y2)),29 and s(Pd–O) → π(C–O), respectively. Considering these transformations together reveals an intrinsic directionality to the evolution of the local orbitals in the Pd-catalyzed [π2s + π2s + s2s + s2s] reaction. Inspection of the relative magnitudes of net orbital displacement along the IRC further suggests synchronicity in the bond making/breaking events of the [π2s + π2s + s2s + s2s] process (Figure 2.5). In accord with the initial reports of Knizia and coworkers, we also find the localized IBOs obtained from the ground state densities closely resemble valence orbitals as portrayed in simple Lewis structures. Thus, tracking the net flow of electron density is carried out in the same valence bonding framework. The result is a mechanism described by the synchronous movement of valence bonding electron pairs, or more precisely, a first principles-derived “arrow-pushing” mechanism that accounts for the net change in bonding along the reaction coordinate in a chemically intuitive orbital basis (Figure 2.5).27b–c Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 94 Figure 2.5. IBO analysis the Pd [π2s + π2s + σ2s + σ2s] reaction. P N P P Me Pd N O Intrinsic Bonding Orbital (IBO) Analysis Pd Me Pd N O Me O P 19 N = (R)-t-BuPHOX 13 TS20 P Pd N P Pd N Pd N Me !! Me !! Me !! O P Pd N O P Me Pd N !! O P = Me O 19 O 12.0 0.7 10.0 Relative Energy (kcal/mol) 1 TS1 0.6 IBO 139 IBO 152 0.5 IBO 154 8.0 0.4 6.0 0.3 4.0 2 2.0 0.2 Orbital Change (e–) IRC IBO 137 0.1 0.0 0 0 10 20 30 40 50 60 Reaction Coordinate (bohr) [a] Note that the R enantiomer of the t-BuPHOX ligand employed. Select atoms omitted for clarity. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 2.3 95 CONCLUSIONS In conclusion, we find the Pd-catalyzed [π2s + π2s + s2s + s2s] reaction to be symmetry-allowed in the ground-state owing to phase inverting role of the Pd d(x2–y2) orbital in the s bonding framework of the transition state. Insights from this investigation are contextualized within the Woodward–Hoffmann rules, orbital correlation diagrams, and FMO theory. As with prototypical thermally-allowed pericyclic reactions, we find the Pd-catalyzed [π2s + π2s + s2s + s2s] reaction proceeds through an aromatic transition state. Lastly, we describe a first principles-derived “arrow-pushing” mechanism from analysis the transformation of IBOs along the reaction coordinate. These efforts highlight the connection between ab initio electronic structure calculations and empirical bonding concepts, thus, facilitating a natural conceptualization of chemical bonding in these unique systems. 2.4 SUPPORTING INFORMATION 2.4.1 GENERAL COMPUTATIONAL DETAILS All quantum mechanical calculations were performed with ORCA version 4.1 and 4.2.11 Geometries of open-shell species (TS27, 30, and TS28) and their precursors (23, 24 and 25) were optimized with complete active space self-consistent field (CASSCF) theory. The active space was defined as the correlating valence electrons and orbitals as obtained by the corresponding orbital correlation diagrams (see below). The triple-z quality def2TZVP basis set13 was used on all atoms. Further details on choice of active spaces are provided below. Results obtained via broken-symmetry density functional theory (BS-DFT) are provided below for comparison. For transition metal complexes with insignificant Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 96 multiconfigurational character (26, 27, TS25, TS26, 28, and 29), geometries were obtained from dispersion-corrected DFT. The PBE0 global hybrid density functional15 paired with Becke–Johnson damped D3 dispersion corrections (henceforth referred to as PBE0-D3(BJ)) and the def2-TZVP basis set on all atoms was employed. The small-core ECP28MWB pseudopotential14 was used on Pd (18 explicit electrons including the 4s and 4p core shells are defined). To account for dynamical correlation, N-electron valence state perturbation theory12 (NEVPT2) single point calculations were carried out on all stationary points (CASSCF and DFT geometries) from the corresponding CAS references. The strongly contracted variant of NEVPT2 was employed. Solvation was accounted for in these single point calculations with the SMD model for THF.16 In addition to single point calculations with NEVPT2/def2-TZVPP/SMD(THF), for the compounds that were optimized with PBE0-D3(BJ)/def2-TZVP, additional single point calculations were carried out with PBE0-D3(BJ)/def2-TZVP/SMD(THF) for comparison. Thermal corrections were obtained from the unscaled vibrational frequencies computed at the level of theory employed for geometry optimization. The Quasi-RRHO method 30 was applied to correct for the breakdown of the harmonic oscillator approximation in low frequency vibrations. For CASSCF and DFT calculations these frequencies were computed numerically and analytically, respectively. All stationary points were characterized by the appropriate number of imaginary vibrational modes (zero for optimized geometries and one for transition states). Intrinsic reaction coordinate (IRC) analyses were carried out to ensure all transition states connect saddle points to the Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 97 appropriate minima. Conformer searching was carried out manually and energies reported are from lowest energy conformers. All energies reported in the manuscript are free energies calculated at 298.15 K and at a 1 atm standard state. Applying thermal corrections obtained at the optimization level of theory to the single point electronic energies (and solvation free energies), final Gibbs free energies are accordingly: Gsolv = E(el)SP + ZPE + E(vib) + E(rot) + E(trans) + kbT – TS + ∆G(solv)SP The resolution of identity (RI) and chain-of-spheres 31 (keyword = RIJCOSX) approximations were utilized for coulomb and exchange integrals, respectively. Automatic generation of auxiliary basis sets was employed (keyword = AutoAux).32 [Note that in geometry optimization, frequency, and IRC calculations with CASSCF, the RI and COS approximations were not used as they are not implemented with analytical (nuclear) gradients in ORCA version 4.2.0]. The finest integration grid settings (Grid7, GridX9, NoFinalGrid) were utilized in all calculations. 2.4.2 NEVPT2/CASSCF ACTIVE SPACE RESULTS Unless otherwise specified, energies provided below are solvated CASSCF and NEVPT2 free energies (in Hartree) with the def2-TZVP basis set and SMD implicit solvation model for THF. Energies further refined with the def2-TZVPP basis set are provided in the text and supporting excel document (nearly identical results were obtained). Weights (Ci2) of the three configurations with the largest contributions to the ground state CI coefficient vector are provided. The notation [2200] corresponds to a configuration with double occupancy of the first and second MOs of the active space and zero occupancy of the third and fourth active space MOs. Unless otherwise noted, active space MOs are Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 98 depicted as the natural orbitals of the CAS wavefunction and are rendered with a contour value of 0.07. Active spaces were chosen to include the correlating valence orbitals as determined by the corresponding Woodward–Hoffmann orbital correlation diagrams.8 The active space may be localized to confirm the correct active space compositions. Unless otherwise specified, state-averaging was not employed, and results are that of the lowest energy singlet state. Occupancy numbers are provided in parentheses next to MO numbers. Orbital energy eigenvalues (from NEVPT2) are listed when the ordering of the active space MOs by occupancy number is different than the ordering by energies. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 99 Figure 2.6. MCSCF active space orbitals and energies of complex 13.a Ph Ph P Pd N O O Me t-Bu 13 CASSCF(8,8) -2022.394386 NEVPT2(8,8) -2030.146571 Weight Configuration 0.87749 [22220000] 0.02871 [21211010] 0.02357 [22020200] MO150 (1.98) MO151 (1.93) MO152 (1.93) MO153 (1.90) MO154 (0.10) MO155 (0.07) MO156 (0.07) MO157 (0.02) [a] Geometry taken from reference 5 (BP86-D3/LANL2TZ(f)[Pd],6-31G(d)). Energies above are CASSCF and NEVPT2 solvated electronic energies in Hartree. Orbital energy eigenvalues (by ascending MO) in eV: –0.5516, –0.4294, –0.2868, –0.3067, 0.1907, 0.3014, 0.3116, 0.9729. Isosurface level adjusted to 0.03 for ease of visualization. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 100 Figure 2.7. MCSCF active space orbitals and energies of TS20.a Ph Ph P Pd O N O Me t-Bu TS20 CASSCF(8,8) -2022.358794 NEVPT2(8,8) -2030.135158 Weight Configuration 0.85071 [22220000] 0.03808 [22202000] 0.00849 [22111100] MO150 (1.97) MO151 (1.94) MO152 (1.93) MO153 (1.85) MO154 (0.14) MO155 (0.10) MO156 (0.06) MO157 (0.02) [a] Geometry taken from reference 5 (BP86-D3/LANL2TZ(f)[Pd],6-31G(d)). Energies above are CASSCF and NEVPT2 solvated electronic energies in Hartree. Orbital energy eigenvalues (by ascending MO) in eV: –0.5101, –0.4084, –0.3196, –0.2322, 0.1617, 0.2167, 0.3781, 0.7215. Isosurface level adjusted to 0.04 for ease of visualization. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 101 Figure 2.8. MCSCF active space orbitals and energies of complex 19.a Ph Ph P Pd N O Me t-Bu O 19 CASSCF(8,8) -2022.420396 NEVPT2(8,8) -2030.191318 Weight Configuration 0.90785 [22220000] 0.02896 [22020200] 0.02830 [22202000] MO150 (1.98) MO151 (1.97) MO152 (1.93) MO153 (1.92) MO154 (0.09) MO155 (0.07) MO156 (0.02) MO157 (0.02) [a] Geometry taken from reference 5 (BP86-D3/LANL2TZ(f)[Pd],6-31G(d)). Energies above are CASSCF and NEVPT2 solvated electronic energies in Hartree. Orbital energy eigenvalues (by ascending MO) in eV: –0.6097, –0.4323, –0.4795, –0.3032, 0.2540, 0.2951, 0.7745, 0.5139. Isosurface level adjusted to 0.04 for ease of visualization. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Figure 2.9. MCSCF active space orbitals and energies of diallyl sulfone 23. O S O 23 CASSCF(8,8) -780.349971 NEVPT2(8,8) -782.106985 Weight Configuration 0.90106 [22220000] 0.03843 [22111100] 0.01005 [22202000] MO35 (1.98) MO36 (1.98) MO37 (1.98) MO38 (1.08) MO39 (0.92) MO40 (0.02) MO41 (0.02) MO42 (0.02) 102 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Figure 2.10. MCSCF active space orbitals and energies of TS27. O O S TS27 CASSCF(8,8) -780.258382 NEVPT2(8,8) -782.031183 Weight Configuration 0.68584 [22220000] 0.26002 [22202000] 0.01996 [22111100] MO35 (1.98) MO36 (1.98) MO37 (1.95) MO38 (1.44) MO39 (0.56) MO40 (0.05) MO41 (0.02) MO42 (0.02) 103 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Figure 2.11. MCSCF active space orbitals and energies of diradical 30. O O S 30 CASSCF(8,8) -780.261600 NEVPT2(8,8) -782.026896 Weight Configuration 0.52173 [22220000] 0.44492 [22202000] 0.00405 [12120101] MO35 (1.98) MO36 (1.98) MO37 (1.98) MO38 (1.08) MO39 (0.92) MO40 (0.02) MO41 (0.02) MO42 (0.02) 104 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction Figure 2.12. MCSCF active space orbitals and energies of TS28. O O S TS28 CASSCF(8,8) -780.244658 NEVPT2(8,8) -782.024561 Weight Configuration 0.61644 [22220000] 0.29502 [22202000] 0.04355 [22111100] MO35 (1.98) MO36 (1.98) MO37 (1.92) MO38 (1.33) MO39 (0.67) MO40 (0.08) MO41 (0.03) MO42 (0.02) 105 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 106 Figure 2.13. MCSCF active space orbitals and energies of SO2 (24). O S O 24 CASSCF(2,2) -547.345604 NEVPT2(2,2) -548.090971 Weight Configuration 0.98002 [20] 0.01998 [02] MO15 (1.96) MO16 (0.04) MO37 (1.92) MO38 (1.33) MO39 (0.67) MO40 (0.08) MO41 (0.03) MO42 (0.02) Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 107 Figure 2.14. MCSCF active space orbitals and energies of (s-cis)-1,5-hexadiene (25_cis).a 25_cis CASSCF(6,6) -233.022382 NEVPT2(6,6) -234.026032 Weight Configuration 0.91161 [222000] 0.03853 [211110] 0.01066 [220200] MO20 (1.98) MO21 (1.92) MO22 (1.92) MO38 (1.33) MO23 (0.08) MO24 (0.08) MO25 (0.02) MO42 (0.02) [a] Active space orbitals for compound 25_cis. (Not visible at isosurface printed above: MO23 and MO24 experience slight mixing with MO25 and MO20, respectively, such that the resulting orbital energy eigenvalue for MO23 is lower than that of the symmetric MO24 (0.2332 eV and 0.2374 eV). Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 108 Figure 2.15. MCSCF active space orbitals and energies of (s-trans)-1,5-hexadiene (25_trans). 25_trans CASSCF(6,6) -233.004232 NEVPT2(6,6) -234.022461 Weight Configuration 0.92057 [222000] 0.03724 [211110] 0.00985 [202200] MO20 (1.99) MO21 (1.92) MO22 (1.92) MO23 (0.08) MO24 (0.08) MO25 (0.00)* MO38 (1.33) MO42 (0.02) Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 109 Figure 2.16. MCSCF active space orbitals and energies of complex 26.a H 3P Pd H 3P 26 CASSCF(8,8) -1044.976965 NEVPT2(8,8) -1047.103294 Weight Configuration 0.88527 [22220000] 0.01649 [22111100] 0.01002 [21211010] MO46 (1.97) MO47 (1.95) MO48 (1.92) MO49 (1.92) MO50 (0.09) MO51 (0.07) MO52 (0.06) MO53 (0.02) [a] Active space orbitals for compound 26. Orbital energy eigenvalues (by ascending MO) in eV: – 0.4110, –0.4486, –0.3197, –0.3230, 0.1931, 0.2702, 0.3169, 0.6241. In this (low energy) conformation, the antisymmetric Pd–L s* and the antisymmetric C–C π* symmetry adapted linear combinations mix to give rise to MO50 and MO52. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 110 Figure 2.17. MCSCF active space orbitals and energies of complex 27.a H 3P Pd H 3P O 27 CASSCF(8,8) -1080.874182 NEVPT2(8,8) -1083.041153 Weight Configuration 0.88716 [22220000] 0.03125 [22111100] 0.02575 [20220020] MO46 (1.98) MO47 (1.94) MO48 (1.94) MO49 (1.91) MO50 (0.09) MO51 (0.07) MO52 (0.06) MO53 (0.01) [a] Active space orbitals for compound 27. Orbital energy eigenvalues (by ascending MO) in eV: – 0.5622, –0.3144, –0.4403, –0.3213, 0.1826, 0.2975, 0.2983, 0.9742. In this conformation, the h1allyl ligand C–C π orbitals are nearly coplanar and further mix with the Pd-based d(x2–y2) (MO48– MO51). If the active space is localized (Foster–Boys) the C–C π/π* and Pd–C s/s* may be separated for ease of interpretation. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 111 Figure 2.18. MCSCF active space orbitals and energies of TS25.a H 3P Pd H 3P TS25 CASSCF(8,8) -1044.936576 NEVPT2(8,8) -1047.082378 Weight Configuration 0.85693 [22220000] 0.01682 [22202000] 0.01094 [22111100] MO46 (1.96) MO47 (1.93) MO48 (1.92) MO49 (1.88) MO50 (0.13) MO51 (0.10) MO52 (0.10) MO53 (0.02) [a] Active space orbitals for compound TS25. Isosurface value adjusted to 0.04 for ease of visualization. Orbital energy eigenvalues (by ascending MO) in eV: –0.4443, –0.4016, –0.3064, – 0.2400, 0.1574, 0.2046, 0.3684, 0.5126. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 112 Figure 2.19. MCSCF active space orbitals and energies of TS26.a H 3P Pd H 3P O TS26 CASSCF(8,8) -1080.838314 NEVPT2(8,8) -1083.018807 Weight Configuration 0.86058 [22220000] 0.03715 [22202000] 0.00724 [22020200] MO46 (1.97) MO47 (1.94) MO48 (1.93) MO50 (0.13) MO51 (0.08) MO52 (0.06) MO49 (1.86) MO53 (0.02) [a] Active space orbitals for compound TS26. Isosurface value adjusted to 0.04 for ease of visualization. Orbital energy eigenvalues (by ascending MO) in eV: –0.5448, –0.4209, –0.3126, – 0.2783, 0.1404, 0.2406, 0.3519, 0.7700. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 113 Figure 2.20. MCSCF active space orbitals and energies of 28.a H 3P Pd H 3P 28 CASSCF(8,8) -1045.009114 NEVPT2(8,8) -1047.148494 Weight Configuration 0.88527 [22220000] 0.01649 [22111100] 0.01002 [21211010] MO46 (1.98) MO47 (1.97) MO48 (1.95) MO50 (0.08) MO51 (0.06) MO52 (0.02) MO49 (1.92) MO53 (0.01) [a] Active space orbitals for compound 28. Isosurface value adjusted to 0.04 for ease of visualization. Orbital energy eigenvalues (by ascending MO) in eV: –0.6193, –0.4392, –0.3288, –0.3509, 0.2247, 0.2579, 0.8061, 0.4683. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 114 Figure 2.21. MCSCF active space orbitals and energies of 29.a H 3P Pd H 3P O 29 CASSCF(8,8) -1080.909107 NEVPT2(8,8) -1083.101216 Weight Configuration 0.92253 [22220000] 0.02687 [22202000] 0.01400 [22020200] MO46 (1.98) MO47 (1.97) MO48 (1.95) MO49 (1.92) MO50 (0.08) MO51 (0.06) MO52 (0.02) MO53 (0.01) [a] Active space orbitals for compound 29. Isosurface value adjusted to 0.06 for ease of visualization. Orbital energy eigenvalues (by ascending MO) in eV: –0.6342, –0.4444, –0.3324, –0.5055, 0.2854, 0.2572, 0.8066, 0.4687. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 2.4.3 115 ADDITIONAL NOTES ON NEVPT2/CASSCF CALCULATIONS The frozen core approximation was not used in the NEVPT2 calculations (keyword: “! NoFrozenCore”). Solvated free energies include the cavitation, dispersion, structure (CDS) terms as calculated in the SMD model.16 Practical note to users: For efficiently converging active spaces with weakly correlated valence-bond-like orbitals (such as the C–C s/s*) in the starting complexes and products), we recommend use of the PMO virtual orbital optimization feature in ORCA. A standard procedure involved converging the MCSCF with an active space excluding the weakly correlating pair, localization of the internal space, locating the valence bond orbital of interest, then optimization of a corresponding virtual orbital (using the PMO methodology (RefMO)). Generally, expanding the active space to include the natural orbital-like pair affords smoothly convergence of the MCSCF. 2.4.4 DISCUSSION ON OTHER MAIN GROUP CHELEFUGES In our investigation of the [p2s + p2s + s2s + s2s] reaction, we employ diallyl sulfone (23) as a main group analog to bis(h1-allyl)Pd(PH3)2 complex 26. In addition to SO2, CO and N2 are also viable main group chelefuges. Thus, the [p2s + p2s + s2s + s2s] reactions of hepta-1,6-dien-4-one or diallyl isodiazene may be considered. For these scenarios, there are nine correlating valence orbitals – occupied by 10 valence electrons (see Chapter 3 of reference 8). Both reactions are similarly symmetry forbidden. As a representative example, the orbital correlation diagram for the reaction of hepta-1,6-dien4-one to CO and 1,5-hexadiene is provided below (Figure 2.22). In the general [p2s + p2s + s2s + s2a] reaction, we only consider linear departure/approach of the chelefuge due to Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 116 the geometric/steric constraints of the seven-membered transition state. An exception to this may be methylene carbene, which could possibly undergo the thermally allowed [p2s + p2s + s2s + s2a]/[w2a + p2s + p2s + s2s] reaction, i.e., with non-linear departure/approach of the carbene. Figure 2.22. Orbital correlation diagram for the ground state symmetry-forbidden [p2s + p2s + s2s + s2s] extrusion of CO from hepta-1,6-dien-4-one. O O 𝛔*C-O(A) O O 𝛔*C-C(A) O C 𝛔*C-O(S) 𝛑*C-C(A) 𝛑*C-C(S) 𝛑*C-C(A) 𝛑*C-C(S) O C 𝛑*C-O(A) O C O C nO (A) O 𝛔C-O(S) O O 𝛑C-C(A) 𝛑C-C(S) 𝛑C-C(A) 𝛑C-C(S) O C O C O C 𝛑C-O(A) O C 𝛔C-C(A) O O 𝛔C-C(S) 𝛔C-C(S) O C From the FMO perspective, it is important to note that the π systems of CO and N2 are of the correct symmetry to constructively interact with the diene LUMO (in its reactive conformer), but these π orbitals ultimately correlate to lone pairs on O (in CO) and N (in N2) and thus cannot serve as the “donor” in the donor-acceptor relationship. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 2.4.5 117 EXCHANGE COUPLING IN DIRADICAL INTERMEDIATE 30 The RI and COS integral approximations were not used in calculations evaluating exchange coupling. All computations were carried out in the gas phase. State averaging over the relevant singlet and triplet diradical states was employed in CASSCF calculations. Results obtained with the minimal (2,2) active space, i.e., including only the local spin centers, are provided for comparison. Hypothetical diradical species 30 is a metastable intermediate on the singlet CAS(8,8) and BS-DFT (56 = 0) potential energy surfaces. In the case of BS-DFT, the diradical was found as an intermediate regardless of choice of functional ((U)PBE0-D3(BJ), (U)PBE-D3(BJ), (U)M06-2X).33 Exchange coupling interaction may be described through the phenomenological Heisenberg–Dirac–van Vleck Hamiltonian34: 9:;<= = −2@ABC ABD 8 where ABC and ABD are “local” spin operators on spin sites E and F. J is defined as the exchange coupling constant. Thus, for the coupling of two spin-1/2 magnetic sites, J is expressed as: 1 @ = − (IJ − I% ) 2 where IJ and IL are the energies of the triplet- and singlet-coupled diradical states, respectively. When @ > 0, i.e., IJ < IL , the interaction is termed ferromagnetic. Likewise, @ < 0 implies an antiferromagnetic coupling of the two spins. As a consequence of a single determinant formulation, the broken-symmetry DFT solution of an open-shelled singlet state is a mixture of the 56 = 0 singlet and triplet states.35 Thus, calculation of exchange Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 118 coupling was performed after removal of spin contamination. The spin projection to the “true” singlet energy was carried out via the Yamaguchi equation36: IJ − IL = 2 (I − IDL ) 〈A 3 〉J − 〈A 3 〉DL J As such, the J values we report via BS-DFT are calculated as: @=− IJ − IDL 3 J − 〈A 〉DL 〈A 3 〉 Single point calculations with SA-CAS(8,8) on the CAS(8,8) PES initially suggest an antiferromagnetic coupling between the two spin-1/2 centers (J = –12.1 cm–1) of 30. However, inclusion of dynamical correlation via SC-NEVPT2, with the SA-CAS(8,8) reference, reveals a weak ferromagnetic coupling (J = 3.2 cm–1) (Table 2.1, entry 5). BSDFT single point calculations carried out on the CAS(8,8) geometry also suggest a singletcoupled diradical, with J = –38.9 cm–1. Conversely, DFT single point calculations at both the high spin and broken-symmetry (BS-)DFT-optimized geometries suggest ferromagnetism (Table 2.1, entries 9 and 10). Unsurprisingly, these data suggest the treatment of dynamical electron correlation is crucial in obtaining qualitatively meaningful results. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 119 Table 2.1. Calculation of spin exchange coupling constant (J) between spin centers in 1,4-diradical 30.a 3.05 Å O O Top view: Side view: = S 30 Entry No. Method J (cm–1) 1 SA-CAS(2,2) 59.1 2 SA-CAS(8,8) –12.1 3 SC-NEVPT2/SA-CAS(2,2) –14.1 4 FIC-NEVPT2/SA-CAS(2,2) –14.0 5 SC-NEVPT2/SA-CAS(8,8) 3.2 6 FIC-NEVPT2/SA-CAS(8,8) 7.0 7 IDDCIb 82.9 8 (U)PBE0-D3(BJ)c –38.9 9 (U)PBE0-D3(BJ)d 30.0 10 e 37.0 (U)PBE0-D3(BJ) [a] Unless otherwise noted, performed on the singlet CAS(8,8)/def2-TZVP geometry 30. All calculations above employ the def2-TZVP basis set on all atoms, no integral approximations, and are carried out in the gas phase. Pictured above are the two natural orbitals in the CAS(8,8) active space describing bonding and antibonding pairing in diradical 30. [b] IDDCI (see below) starting from the SA-CAS(2,2) wavefunction. [c] BS-DFT single point calculation on CAS(8,8)/def2-TZVP geometry. [d] Single point calculation on broken-symmetry ( 56 = 0 ) (U)PBE0-D3(BJ)/def2-TZVP optimized geometry. [e] Single point calculation on high spin (A = 1) (U)PBE0-D3(BJ)/def2-TZVP optimized geometry. For a more rigorous treatment of static and dynamic correlation, multireference calculations were carried out with the Iterative Difference Dedicated Configuration Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 120 Interaction (IDDCI) method. 37 The standard DDCI approach resembles that of an uncontracted MRCI (singles and doubles), where completely inactive double excitations are omitted. The reference states were defined to be the singlet and triplet diradical states. The state-averaged CAS(2,2) wavefunction was taken to be the initial orbitals. The results obtained with DDCI are highly depended on the choice of reference orbitals. To help alleviate this starting orbital dependence and generally obtain more accurate results, we employed the Iterative DDCI method (IDDCI) of Malrieu and coworkers.11b In IDDCI, an iterative MO improvement strategy is utilized in which a DDCI calculation is first converged, followed by construction of the state-averaged single-particle density matrix and diagonalization to give a set of new set of state-averaged natural orbital-like MOs. These MOs then serve as the starting orbital basis for a subsequent DDCI calculation. The process is repeated until self-consistency (i.e., the energies of the states stabilize). As implemented in the ORCA program, convergence of the calculated exchange coupling constant and state energies is achieved with the parameters Tsel = 1x10–11 (default 1x10–6) and Tpre = 1x10–4 (default 1x10–4). A sample input for the IDDCI calculation is provided below: ! def2-TZVP NoPop Grid7 NoFinalGrid ! MORead VeryTightSCF NoIter AllowRHF %base "SampleName" %moinp "SampleStart.gbw" %method FrozenCore fc_ewin end %mrci EWin -10,1000 CIType MRDDCI3 Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 121 Solver DIIS UseIVOs true Tsel 1e-11 Tpre 1e-5 AllSingles true DavidsonOpt none NatOrbIters 5 NewBlock 1 * NRoots 1 refs cas(2,2) end end NewBlock 3 * NRoots 1 refs cas(2,2) end end end * xyzfile 0 1 Sample.xyz Due to the rapid increase in computational cost with increase in the size of the active space, we elected to employ the (2,2) active space consisting of the two local magnetic orbitals. Calculations with the (8,8) active space were explored; however, it was found that convergence of the exchange coupling constant and state energies was not fully achieved with values of Tsel that yield a reasonable computational cost. Thus, we suggest the results obtained from the tightly converged (2,2) active space to be more robust. Note that the results are qualitatively similar regardless – both (2,2) and (8,8) active spaces afford J > 0. After five iterations, the IDDCI(2,2) method converges to an exchange coupling constant of 82.9 cm–1 (Figure 2.23). These results are in accord with that of NEVPT2(8,8) and BSDFT, suggesting a triplet ground state of diradical 30. In summary, the concerted ground state [p2s + p2s + s2s + s2s] reaction of diallyl sulfone 23 to SO2 (24) and 1,5-hexadiene (25) is symmetry forbidden. Owing to the triplet Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 122 ground state of diradical 30, the individual steps of the stepwise mechanism are formally spin forbidden — granted the singlet and triplet states are nearly degenerate (∆ET–S of ca. 0.5 kcal/mol) in the weakly coupled diradical. Figure 2.23. Exchange coupling via IDDCI.a [a] Convergence of exchange coupling and state energies via iterative MO optimization in DDCI (IDDCI). 2.4.6 REDOX INNOCENCE OF THE PHOX LIGAND The general Pd-catalyzed [p2s + p2s + s2s + s2s] pericyclic reaction is symmetry allowed without mandatory implication of ligand-based excited states/configurations. However, in the case of Pd(PHOX) complexes, we sought to evaluate whether the p system of the PHOX ligand is capable of facilitating the reductive elimination through ligandbased redox activity. First, we note that the ground state densities obtained with PBE0D3(BJ)/def2-TZVP are stable with respect to spin symmetry breaking. Thus, at the DFT level, the ground state along the reaction path 13 → TS20 → 19 is well represented as a Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 123 closed-shell singlet (CSS). Time-dependent density functional theory (TD-DFT) calculations were then carried out on stationary points 13, TS20, and 19 at the PBE0D3(BJ)/def2-TZVP/SMD(THF) level of theory. The TD-DFT calculations suggest no low energy excited states along the ground state PES. The lowest of these vertical transitions is that of the 3(M/L
L) at TS20, which is calculated to be nearly 1.0 eV (Table 2.2). All other excitations (M
M, L
M/L, etc.) are found to be > 2 eV. The PHOX p*-based LUMO (Figure 2.24) serves as a common acceptor in each of the lowest energy transitions in Table 2. These results suggest that redox contribution of the PHOX ligand along the ground state PES is likely trivial. Table 2.2. TD-DFT vertical excitations at stationary points 13, TS20, and 19.a 13 TS20 19 Excitation Energy (eV) Excitation Energy (eV) Excitation Energy (eV) Singlet L→L 1.463 M/L → L 1.401 MLCT 2.264 Triplet L→L 1.014 M/L → L 0.986 MLCT 1.941 [a] Lowest energy TD-DFT vertical excitations with PBE0-D3(BJ)/def2-TZVP/SMD(THF) and adapted triplets from the RKS reference. L = ligand, M = metal, M/L = mixed metal/ligand. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 124 Figure 2.24. Orbitals involved in the vertical transitions to the lowest energy singlet and triplet excited states at TS20. 1(M/L to L) = 1.40 eV 3(M/L to L) = 0.99 eV Pd/allyl/enolate-based HOMO 2.4.7 PHOX π*-based LUMO NUCLEUS INDEPENDENT CHEMICAL SHIFT CALCULATIONS Calculations of Nucleus Independent Chemical Shift (NICS) were carried out in order to probe the aromatic character of TS25. In this investigation, the formalism of Schleyer and coworkers is followed.24 Reported NICS values are the negative of the calculated isotropic chemical shift/shielding at the geometric center of the ring in question. These calculations were carried out with the NMR module in ORCA. Calculations of NICS were conducted in the gas phase at the PBE0-D3(BJ)/def2-TZVP level of theory. Gauge independent atomic orbitals (GIAO) were used and the relevant one-electron and twoelectron integrals were evaluated analytically and with the RIJK approximation, respectively. A ghost atom (“H:”, no nuclear charge nor electrons) was used to define a point in space at which shielding was to be determined. A highly contracted basis (and auxiliary basis) function was then assigned to the ghost atom. This procedure was used to ensure the proper grid points were assigned to the point in space without significantly perturbing the ground state density. Note that the results are independent of the chosen Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 125 exponent as long as the exponent is large. For example, the following would be added to the geometry block of an input file to define a point with cartesian coordinates (0.00, 1.00, 2.00): H: 0.00 1.00 2.00 newgto S 1 1 1000000 1 end newauxJKgto S 1 1 2000000 1 end At the PBE0-D3(BJ)/def2-TZVP level of theory, NICS values of –8.9 and 28.8 ppm were obtained for benzene and cyclobutadiene, respectively. These controls are in good agreement with literature values of –9.7 and 27.6 ppm (HF/6-31+G(d)).24 As described in the text, an NICS value of –19.4 ppm is found at the geometric center of the sevenmembered ring of TS25 (Figure 2.4C). A NICS value of –19.4 ppm reveals a significant diatropic ring current. Thus, TS25 is characterized as aromatic.25 2.4.8 INTRINSIC BONDING ORBITAL ANALYSIS Analysis of the net flow of electron density through the Pd-catalyzed [π2s + π2s + s2s + s2s] pericyclic reaction was carried out by Intrinsic Bonding Orbital (IBO) analysis.27 IBO analysis was carried out along the IRC describing 19
TS20
19. SCF densities were obtained at the M06/def2-TZVP/CPCM(THF) level of theory and on BP86D3(BJ)/LANL2TZ(f)[Pd]–6-31G(d) geometries, consistent with reference 5. Localization of the SCF density, frame alignment, and calculation of IBO displacement were carried out with the IBOView program. For further details of this procedure and additional discussion of the relevant theory, see the seminal reports of Knizia and coworkers.27 Note that results are largely independent of choice in density functional, and qualitatively identical results may be obtained with densities from an ab initio wavefunction method. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 2.5 (1) 126 REFERENCES AND NOTES Fukui, K. A Simple Quantum-Theoretical Interpretation of the Chemical Reactivity of Organic Compounds, in Molecular orbitals in chemistry, physics, and biology. A Tribute to R. S. Mulliken, (Eds,: Löwdin, P. O.; Pullman, B.), Academic Press, New York, 1964, 513–537. (2) Goddard, W. A. I. Orbital Phase Continuity Principle and Selection Rules for Concerted Reactions. J. Am. Chem. Soc. 1970, 92, 7520–7521. (3) For further discussion of aromaticity in pericyclic transition states, see: (a) Schleyer, P. von R.; Wu, J. I.; Cossío, F. P.; Fernández, I. Aromaticity in Transition Structures. Chem. Soc. Rev. 2014, 43, 4909–4921. (b) Dewar, M. J. S. Aromaticity and Pericyclic Reactions. Angew. Chem. Int. Ed. 1971, 10, 761–776. and references therein. (4) Such as three-centered reductive elimination and [2+2] cycloadditions in olefin metathesis. (5) (a) Cusumano, A. Q.; Stoltz, B. M.; Goddard III, W. A. Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) Cross-Coupling. J. Am. Chem. Soc. 2020, In-Press. (b) McPherson, K. E.; Croatt, M. P.; Morehead, A. T.; Sargent, A. L. DFT Mechanistic Investigation of an Enantioselective Tsuji–Trost Allylation Reaction. Organometallics 2018, 37, 3791– 3802. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction (6) 127 (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard III, W. A. The Inner-Sphere Process in the Enantioselective Tsuji Allylation Reaction with (S)-t-Bu-Phosphinooxazoline Ligands. J. Am. Chem. Soc. 2007, 129, 11876–11877. (b) Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard III, W. A. The Reaction Mechanism of the Enantioselective Tsuji Allylation: InnerSphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C– C Bond Formation. J. Am. Chem. Soc. 2012, 134, 19050–19060. (7) (a) Pérez-Rodríguez, M.; Braga, A. A. C.; de Lera, A. R.; Maseras, F.; Álvarez, R.; Espinet, P. A DFT Study of the Effect of the Ligands in the Reductive Elimination from Palladium Bis(Allyl) Complexes. Organometallics 2010, 29, 4983–4991. (b) Méndez, M.; Cuerva, J. M.; Gómez‐Bengoa, E.; Cárdenas, D. J.; Echavarren, A. M. Intramolecular Coupling of Allyl Carboxylates with Allyl Stannanes and Allyl Silanes: A New Type of Reductive Elimination Reaction? Chem. Eur. J. 2002, 8, 3620–3628. (c) Zhang, P.; Brozek, L. A.; Morken, J. P. Pd-Catalyzed Enantioselective Allyl−Allyl Cross-Coupling. J. Am. Chem. Soc. 2010, 132, 10686– 10688. (8) Woodward, R. B.; Hoffmann R.; The Conservation of Orbital Symmetry; Verlag Chemie GmbH (BRD) and Academic Press Inc. (USA), 1971. (9) Despite our best efforts, we are unable to find literature examples of an identical main group analog fitting ∆π = 0 and ∆s = 1 in this seven-membered geometry. (10) See Supporting Information for a discussion on N2 as a chelefuge. For examples of Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 128 reactivity of diazenes in cheletropic reactions, see Lemal, D. M.; McGregor, S. D. Dienes from 3-Pyrrolines. A Stereospecific Deamination. J. Am. Chem. Soc. 1966, 88, 1335–1336. (11) (a) Neese, F. Software Update: The ORCA Program System, Version 4.0. Wiley Interdisciplinary Reviews: Computational Molecular Science 2018, 8, e1327. (b) Neese, F. The ORCA Program System. Wiley Interdisciplinary Reviews: Computational Molecular Science 2012, 2, 73–78. (12) Angeli, C.; Cimiraglia, R.; Malrieu, J.-P. N-Electron Valence State Perturbation Theory: A Fast Implementation of the Strongly Contracted Variant. Chemical Physics Letters 2001, 350, 297–305. (b) Angeli, C.; Cimiraglia, R.; Malrieu, J.-P. N-Electron Valence State Perturbation Theory: A Spinless Formulation and an Efficient Implementation of the Strongly Contracted and of the Partially Contracted Variants. J. Chem. Phys. 2002, 117, 9138–9153. (13) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (14) Andrae, D.; Häußermann, U.; Dolg, M.; Stoll, H.; Preuß, H. Energy-Adjusted ab Initio Pseudopotentials for the Second and Third Row Transition Elements. Theoret. Chim. Acta 1990, 77, 123–141. (15) PBE0-D3: PBE0 hybrid density functional coupled with Becke–Johnson damped D3 dispersion correction. PBE0: (a) Adamo, C.; Barone, V. Toward Reliable Density Functional Methods without Adjustable Parameters: The PBE0 Model. J. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 129 Chem. Phys. 1999, 110, 6158–6170. D3(BJ): (b) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104. (c) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32, 1456–1465. (16) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. (17) Similar results were obtained with broken-symmetry DFT (see supporting information for details). We are unable to find a concerted closed-shell singlet [π2a + π2s + s2s + s2s] transition state. Additionally, singlet diradical 10 is in the boat conformation collapses to the corresponding cyclobutene. (18) Diradical index defined as described by Neese and coworkers, with d = 98.0% indicating of 98% diradical character. Here, c0 and cd are the factional contributions of the relevant bonding and antibonding configurations to the ground-state CI wavefunction. ST3 SU3 Q = 200R 3 ST + SU3 Herebian, D.; Wieghardt, K. E.; Neese, F. Analysis and Interpretation of MetalRadical Coupling in a Series of Square Planar Nickel Complexes: Correlated Ab Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 130 Initio and Density Functional Investigation of [Ni(LISQ)2] (LISQ=3,5-Di-TertButyl-o-Diiminobenzosemiquinonate(1-)). J. Am. Chem. Soc. 2003, 125, 10997– 11005. Note that through-bond coupling of 2b with s*(C–C) and 3a with s(C–C) gives rise to 2b being lower in energy than the symmetric 3a. For further discussion see: Stuyver, T.; Chen, B.; Zeng, T.; Geerlings, P.; De Proft, F.; Hoffmann, R. Do Diradicals Behave Like Radicals? Chem. Rev. 2019, 119, 11291–11351. (19) Calculated from singlet and triplet diradical references starting from state-averaged CASSCF orbitals. Further details and comparison with other methods are included in SI section. For the DDCI method, see: (a) Miralles, J.; Daudey, J.-P.; Caballol, R. Variational Calculation of Small Energy Differences. The Singlet-Triplet Gap in [Cu2Cl6]2−. Chem. Phys. Lett. 1992, 198, 555–562. (b) García, V. M.; Castell, O.; Caballol, R.; Malrieu, J. P. An Iterative Difference-Dedicated Configuration Interaction. Proposal and Test Studies. Chem. Phys. Lett. 1995, 238, 222–229. (c) García, V. M.; Reguero, M.; Caballol, R. Application of the Iterative DifferenceDedicated Configuration Interaction Method to the Determination of Excitation Energies in Some Benchmark Systems: Be, CH+, BH and CH2. Theor. Chem. Acc. 1997, 98, 50–56. As implemented in ORCA, we employ the uncontracted DDCI3 variant. (20) A similar effect was observed by Steigerwald and Goddard in studying the thermally allowed [2s + 2s] sigma bond metathesis of D2 by transition metal hydrides. (a) Steigerwald, M. L.; Goddard III, W. A. The 2s + 2s Reactions at Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 131 Transition Metals. 1. The Reactions of Deuterium with Dichlorohydrotitanium(1+) Ion (Cl2TiH+), Titanium Hydrogen Dichloride (Cl2TiH), and Scandium Hydrogen Dichloride (Cl2ScH). J. Am. Chem. Soc. 1984, 106, 308–311. (b) Steigerwald, M. L.; Goddard III, W. A. 2s + 2s Reactions at Transition Metals. Part 3. Dichlorotitanacyclopropane. The Structure and Reactivity of a Metallacyclopropane. J. Am. Chem. Soc. 1985, 107, 5027–5035. For further discussion on transition-metal enabled [2s + 2s], see (c) Mango, F. D.; Schachtschneider, J. H. Orbital Symmetry Restraints to Transition Metal Catalyzed [2+2] Cycloaddition Reactions. J. Am. Chem. Soc. 1971, 93, 1123–1130. For additional representative examples of transition-metal intervention in pericyclic reactions, see (d) Tantillo, D. J.; Hoffmann, R. Demoniac Intervention in the Thermal Electrocyclic Ring Opening of Cyclobutenes: Fe(CO)3 Complexation of Pericyclic Transition Structures. Helvetica Chimica Acta 2001, 84, 1396–1404. (e) Siebert, M. R.; Tantillo, D. J. Transition-State Complexation in PalladiumPromoted [3,3] Sigmatropic Shifts. J. Am. Chem. Soc. 2007, 129, 8686–8687. (f) Tantillo, D. J.; Hoffmann, R. Complicated Goings-On in the Metal-Manipulated Ring-Opening of Cyclobutene. J. Am. Chem. Soc. 2001, 123, 9855–9859. (g) Tantillo, D. J.; Carpenter, B. K.; Hoffmann, R. Disrotatory and Conrotatory Transition Structures for the Fe(CO)3-Templated Rearrangement of Methylenecyclopropane to Trimethylenemethane. Organometallics 2001, 20, 4562–4564. Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction (21) 132 LUMO as derived qualitatively for FMO analysis from two interacting three electron allyl fragments. (22) (a) Craig, D. P. A novel type of aromaticity. Nature 1958, 181, 1052–1053. (b) Zhu, C.; Luo, M.; Zhu, Q.; Zhu, J.; Schleyer, P. v R.; Wu, J. I.-C.; Lu, X.; Xia, H. Planar Möbius Aromatic Pentalenes Incorporating 16 and 18 Valence Electron Osmiums. Nature Communications 2014, 5, 3265. (c) An, K.; Shen, T.; Zhu, J. Craig-Type Möbius Aromaticity and Antiaromaticity in Dimetalla[10]Annulenes: A MetalInduced Yin-and-Yang Pair. Organometallics 2017, 36, 3199–3204. For a review on Möbius topologies, see (d) Rzepa, H. S. Möbius Aromaticity and Delocalization. Chem. Rev. 2005, 105, 3697–3715. (23) Hua, Y.; Zhang, H.; Xia, H.; Houk, K. N. Three Classes of π-Aromaticity 2020, submitted. Received as a personal communication. (24) (a) Schleyer, P. von R.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N. J. R. Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. J. Am. Chem. Soc. 1996, 118, 6317–6318. (b) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. von R. Nucleus-Independent Chemical Shifts (NICS) as an Aromaticity Criterion. Chem. Rev. 2005, 105, 3842–3888. (25) For use of NICS for determination of transition state aromaticity, see Jiao, H.; Schleyer, P. von R. Aromaticity of Pericyclic Reaction Transition Structures: Magnetic Evidence. J. Phys. Org. Chem. 1998, 11, 655–662. (26) (a) Ingold, C. K. Principles of an Electronic Theory of Organic Reactions. Chem. Rev. 1934, 15, 225–274. (b) Kermack, W. O.; Robinson, R. LI.—An Explanation Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 133 of the Property of Induced Polarity of Atoms and an Interpretation of the Theory of Partial Valencies on an Electronic Basis. J. Chem. Soc., Trans. 1922, 121, 427–440. (27) (a) Knizia, G. Intrinsic Atomic Orbitals: An Unbiased Bridge between Quantum Theory and Chemical Concepts. J. Chem. Theory Comput. 2013, 9, 4834–4843. (b) Knizia, G.; Klein, J. E. M. N. Electron Flow in Reaction Mechanisms—Revealed from First Principles. Angew. Chem. Int. Ed. 2015, 54, 5518–5522. (c) Klein, J. E. M. N.; Knizia, G. CPCET versus HAT: A Direct Theoretical Method for Distinguishing X–H Bond-Activation Mechanisms. Angew. Chem. Int. Ed. 2018, 57, 11913–11917. (28) Ishida, K.; Morokuma, K.; Komornicki, A. The Intrinsic Reaction Coordinate. An Ab Initio Calculation for HNC→HCN and H−+CH4→CH4+H−. J. Chem. Phys. 1977, 66, 2153–2156. (29) Final IBO at 2 is of d(x2–y2) parentage with π-back-bonding to the olefin observed. (30) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chem. Eur. J. 2012, 18, 9955–9964. (31) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree-Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree-Fock Exchange. Chem. Phys. 2009, 356, 98–109. (32) Stoychev, G. L.; Auer, A. A.; Neese, F. Automatic Generation of Auxiliary Basis Sets. J. Chem. Theory Comput. 2017, 13, 554–562. (33) For PBE see: (a) Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation Made Simple. Phys. Rev. Lett. 1996, 77, 3865–3868. For M06-2X Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 134 see (b) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor Chem Account 2008, 120, 215–241. (34) Heisenberg, W. Zur Theorie des Ferromagnetismus. Z. Physik 1928, 49, 619–636. (35) Neese, F. Definition of Corresponding Orbitals and the Diradical Character in Broken Symmetry DFT Calculations on Spin Coupled Systems. J. Phys. Chem. Solids 2004, 65, 781–785. (36) (a) Yamaguchi, K.; Takahara, Y.; Fueno, T. Ab-Initio Molecular Orbital Studies of Structure and Reactivity of Transition Metal-OXO Compounds. In Applied Quantum Chemistry; Smith, V. H., Schaefer, H. F., Morokuma, K., Eds.; Springer Netherlands: Dordrecht, 1986; pp 155–184. (b) Soda, T.; Kitagawa, Y.; Onishi, T.; Takano, Y.; Shigeta, Y.; Nagao, H.; Yoshioka, Y.; Yamaguchi, K. Ab Initio Computations of Effective Exchange Integrals for H–H, H–He–H and Mn2O2 Complex: Comparison of Broken-Symmetry Approaches. Chem. Phys. Lett. 2000, 319, 223–230. (c) Ferré, N.; Guihéry, N.; Malrieu, J.-P. Spin Decontamination of Broken-Symmetry Density Functional Theory Calculations: Deeper Insight and New Formulations. Phys. Chem. Chem. Phys. 2015, 17, 14375–14382. (37) (a) Miralles, J.; Castell, O.; Caballol, R.; Malrieu, J.-P. Specific CI Calculation of Energy Differences: Transition Energies and Bond Energies. Chem. Phys. 1993, 172, 33–43. For discussion on the iterative method (IDDCI) see: (b) García, V. M.; Chapter 2 – Analysis of the Pd-catalyzed [π2s + π2s + σ2s + σ2s] Pericyclic Reaction 135 Castell, O.; Caballol, R.; Malrieu, J. P. An Iterative Difference-Dedicated Configuration Interaction. Proposal and Test Studies. Chem. Phys. Lett. 1995, 238, 222–229. CHAPTER 3 Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates† 3.1 INTRODUCTION Enantioselective construction of all-carbon quaternary stereogenic centers represents a central and ongoing challenge in synthetic organic chemistry. 1 The asymmetric allylic alkylation of enolate nucleophiles serves as a powerful strategy for accessing such motifs.2 A unique aspect of the Pd-catalyzed allylic alkylation methods developed by our group is the inner-sphere reductive elimination from a chiral O-bound Pd enolate intermediate (32), yielding enantioenriched ketones (33) (Figure 3.1A). 3 , 4 This intermediate is generated catalytically from achiral or racemic enolate precursors, such as allyl enol carbonates5 and b-ketoesters6 (31). The Pd enolate is accessed in the absence of a base, under neutral conditions, and in a regiospecific fashion. Conversely, canonical conditions for enolate formation are plagued by regioselectivity challenges and typically require the use of a strong base or Lewis acid. Given the inherent advantages of Pd enolates, we sought to exploit their reactivity beyond simple allylic alkylations in more general asymmetric transformations. Highlighting the utility of this concept, our lab has demonstrated the enantioselective protonation of Pd enolates as a valuable strategy to access ketones with † This research was carried out with Flesch, K. N.; Chen, P.-J.; Strong, C. S. Portions of this chapter have been reproduced with permission from Stoltz, et al. J. Am. Chem. Soc. 2023. In press. © 2023 American Chemical Society. 137 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates tertiary stereocenters (34). 7 Building upon this success, we subsequently developed methods to construct quaternary centers via enantioselective conjugate additions8 (35) and intramolecular aldol reactions (36). 9 Taken together, these advances underscore the feasibility of employing Pd enolates as stereogenic nucleophiles. Figure 3.1. (A) Examples of chiral Pd enolate reactivity. (B) Lithium base-promoted intramolecular formal [4+2] cycloaddition. (C) Proposed asymmetric intramolecular [4+2] reaction. (D) Divergent catalytic cycle. A. Divergent reactivity from chiral Pd enolates. O R [Pd] O Pd O O Allylic R O R Alkylation CO2 31 33 32 [Pd] = Pd(PHOX) Chiral Enolate Protonation Conjugate Addition O R O H R Aldol Reaction O Ph NC CN OH 35 34 36 Employed in canonical enolate chemistry B. Racemic intramolecular formal [4+2] cycloaddition.10 Li O Me Me O O Formal [4+2] LiHMDS Me Me hexane/ether EtO2C 64% yield H EtO2C EtO2C (±)-37 D. Divergent Catalysis. 40a O O Me O Me (±)-39 38 C. This research. Me 2. Re-entry 41a G F Divergent Chemistry ([4+2] Cycloaddition) A Pd O Me CO2Bn 41a D Original B Cycle (Allylic Alkyation) X 40a H CO2Bn E 1. Exit C Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 138 In a unique example of enolate reactivity, Fukumoto and coworkers reported a formal [4+2] reaction from in situ generated conjugated lithium enolate 38, forging tricyclic adduct 39 in a racemic fashion (Figure 3.1B).10 We envisioned that an analogous asymmetric transformation would be tractable from a chiral, conjugated Pd enolate – derived from the decarboxylation of unsaturated b-ketoester 40a using an asymmetric ligand on Pd (Figure 3.1C). To realize this transformation, we sought to develop a conceptual framework based on our mechanistic understanding to expand the general utility of the Pd enolate. As such, we employed a strategy of divergent catalysis (Figure 3.1D), where deviation occurs at the common Pd enolate (i.e., C, Figure 3.1D, cf. Scheme 3.1, vide infra), allowing for desired alternative reactivity in the diverged cycle. Subsequent re-entry into the original catalytic cycle turns over the catalyst allowing regeneration of the Pd enolate. Applying this strategy of divergent catalysis, we developed a catalytic decarboxylative asymmetric intramolecular [4+2] cycloaddition from conjugated Pd enolates. Mechanistic studies including quantum mechanics calculations, Eyring analysis, and KIE studies offer insights into the reaction mechanism. This transformation enables access to tricyclic scaffolds bearing at least four contiguous stereocenters, at least one of which is quaternary. 3.2 RESULTS AND DISCUSSION 3.2.1 REACTION DESIGN AND OPTIMIZATION Employing unsaturated b-ketoester 42 as a precursor for conjugated Pd enolate 43, we hypothesized that the precedented allylic alkylation forming 44 could be interrupted by 139 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates a [4+2] cycloaddition to generate 45 (Figure 3.2A). Alkylation of the transposed enolate (45) would then turn over the catalyst and forge tricyclic product 46. Figure 3.2. (A) General reactivity paradigm from Pd enolate 43. (B) Computed substituent effects on the rate of C–C bond formation and successful application.a A. Desired reactivity of chiral Pd enolate 43. Allylic alkylation BnO2C O O O Pd2(dba)3 (S)-t-BuPHOX O N CO2Bn CO2 O Pd P BnO2C 42 43 44 Divergent catalysis Cycloadduct CO2Bn Ph2P O H O = N P N N t-Bu (S)-t-BuPHOX O Pd P H CO2Bn 45 46 B. Modulating barrier to reductive elimination. O O O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) O see TS29 toluene, 60 ºC CO2Bn CO2Bn kRed. Elim. > k[4+2] 42 44 98% yield, 84% ee N P R2 Pd O Me R1 Entry R1 R2 ∆G‡ krel (60 ºC) 1 2 H Ph H H 12.9 16.5 4.0 x 10–3 3 Me Me 21.6 1.7 x 10–6 1 Model system (TS29) R O O O Ph CO2Bn 47 Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) toluene, 120 ºC >99% conversion kRed. Elim. < k[4+2] R R * R = Ph/H O * H CO2Bn 48 Complex mixture [a] See 3.4 Supporting Information for computational details and discussion of other isomeric transition states. Yield determined by 1H NMR with respect to 1,3,5-trimethoxybenzene as internal standard. Enantiomeric excess determined by chiral SFC. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 140 Unfortunately, the rate direct allylic alkylation of enolate 43 supersedes the desired divergent reactivity. Treatment of b-ketoester 42 under our standard conditions produces ketone 44 in 98% yield and 84% ee (Figure 3.2B). This prompted us to redesign our exit strategy (Figure 3.1D). Increasing the rate of the cycloaddition through modification of the diene or dienophile could circumvent formation of premature allylic alkylation product 44 but would limit the generality of this transformation. Therefore, we sought to impede alkylation through modification of the allyl moiety. Computational investigation of a model system (TS29) suggested that introducing terminal substitution on the allyl group raises the barrier to reductive elimination, decreasing the rate of allylic alkylation (Figure 3.2B, see 3.4 Supporting Information for computational details).11 For example, phenyl substitution (entry 2, Figure 3.2B) slows the rate of inner-sphere reductive elimination by roughly three orders of magnitude. Inspired by these computational results, we explored the efficacy of cinnamyl ester substrate 47 in the transformation. In line with our hypothesis, the desired tricyclic core was observed (48), albeit as a complex mixture of isomers – hampering the synthetic utility. To this end, we sought to develop an alternative strategy for catalyst turnover that could potentially simplify the product outcomes. Building upon previous findings from our group, we sought to employ stoichiometric acidic additives for catalyst turnover. The exogenous acid serves the dual purpose of protonating the final enolate (analogous to 45) and turning over the catalyst by trapping the cinnamyl group. Addition of 3,5-dimethylphenol9 exclusively yielded undesired protonation product 49a along with aryl ether 50 (Figure 3.3A). To our delight, 141 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates replacing the phenol additive with 4-methylaniline afforded the desired endo [4+2] cycloadduct (41a) as a single diastereomer in 83% yield and 88% ee. Figure 3.3. (A) Sacrificial additives to enable catalyst turnover.a (B) Additive-free reaction with prenyl ester 40a.b A. Alternative catalyst turnover strategy. O O Ph O CO2Bn Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) O Ph CO2Bn 72% yield, 50% ee OAr 49a 47 O + 3 3,5-dimethylphenol (1 equiv) toluene, 60 ºC 50 (0.66 equiv) O O Ph O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) 4-methylaniline (1 equiv) toluene, 60 ºC CO2Bn 83% yield, 88% ee >20:1 dr 47 Ph + H CO2Bn NRAr 51 41a (0.78 equiv)a B. Additive-free catalyst turnover. O O Me O O Me Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) + toluene, 60 ºC CO2Bn 40a 83% yield, 87% ee >20:1 dr Me H CO2Bn 52 41a [Observed by 1H NMR]b [a] Equivalents includes mixture of branched and linear constitutional isomers, as well as doublealkylation of aniline. [b] Isoprene (52) observed in 0.94:1 ratio with 41a by 1H NMR (J Young tube, toluene-d8). Seeking to improve the reaction yield, the competency of b-ketoester 40a, derived from the commodity chemical prenyl alcohol, was explored. According to our computations, a substrate containing a di-substituted allyl fragment would be similarly effective in hindering premature allylic alkylation by increasing the barrier to reductive elimination (Figure 3.2B, entry 3). Perplexingly, while the desired tricyclic product was 142 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates generated in 73% isolated yield and 88% ee, no alkylated 4-methylaniline (analogous to 51) was observed as a byproduct. Table 3.1. Optimization of [4+2] reaction conditions.a O Me O O O Me O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) H + toluene, 60 ºC, 14 h CO2Bn H CO2Bn 40a BnO2C 41a 49a Entry Deviation from standard conditions Yield 41a (%)b ee 41a (%) Yield 49a (%)b ee 49a (%) 1 none 96 (83) 87 (87) – – 2 THF 86 81 – – 3 benzene 92 87 – – 4 1,4-dioxane 12 – 63 49 5 40 ºC 51 89 – – 6 (S)-(CF3)3-t-BuPHOX 12 89 66 62 7 (S)-(OMe)3-t-BuPHOX 40 88 26 65 8 4-methylaniline (1 equiv) 93 (73) 87 (88) – – 9 4-methylaniline (2 equiv) 78 87 – – 10 3,5-dimethylphenol (1 equiv) 0 – 100 71 R O P 2 O N R t-Bu (S)-t-BuPHOX P 2 N t-Bu R = CF3: (S)-(CF3)3-t-BuPHOX R = OMe: (S)-(OMe)3-t-BuPHOX [a] Conditions: 0.02 mmol 40a, 2.5 mol % Pd2(dba)3, 6.5 mol % ligand, in 1.0 mL of solvent (0.02 M). [b] Yields determined by 1H NMR with respect to 1,3,5-trimethoxybenzene as internal standard. Isolated yields on 0.2 mmol scale in parentheses. A control reaction excluding 4-methylaniline was carried out, and surprisingly, desired product 41a was formed in 83% yield and 87% ee (Figure 3.3B). This suggests that an alternative catalyst turnover mechanism is operative. Further NMR experiments revealed the stoichiometric evolution of isoprene (52) accompanying formation of product 41a. Intrigued by this unexpected finding and clean reaction profile, we pursued optimization of additive-free reaction conditions. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 143 The reaction proceeds in THF and benzene albeit in slightly diminished yield and enantioselectivity (entries 2–3, Table 3.1). Employing 1,4-dioxane as the solvent, protonation product 49a was obtained as the major product in 63% yield and 49% ee, while cycloadduct 41a was observed in only 12% yield (entry 4, Table 3.1). Lowering the temperature to 40 ºC slightly improved the ee to 89% at the cost of decreased conversion (entry 5, Table 3.1). Modification of the electronic properties of the PHOX ligand deleteriously impacted the product distribution (entries 6–7, Table 3.1). Phenol and aniline additives do not improve the reaction (entries 8–10, Table 3.1). Ultimately, optimized reaction conditions were determined to be additive-free with (S)-t-BuPHOX in toluene at 60 ºC. The reaction affords 41a, a bridged bicycle with a pendant fused ring, in 83% isolated yield and 87% ee. The transformation allows for the simultaneous construction of four contiguous stereocenters, including one all-carbon quaternary center. Gratifyingly, the reaction can be performed with reduced catalyst loading (0.625 mol %) on 1.0 mmol scale to afford 41a in 59% yield and 89% ee. The ability to efficiently construct these complex building blocks on scale highlights the synthetic utility of this transformation. 3.2.2 PROPOSED MECHANISM We sought to capitalize on these initial exciting results by constructing a mechanistic framework to inform rational design. Based on our lab’s prior investigations of Pd-catalyzed decarboxylative asymmetric allylic alkylation reactions, we propose that oxidative addition of Pd0 to b-ketoester 40a proceeds through complex 53 to afford the h1allyl carboxylate resting state 54 (Scheme 3.1).12 Rate-limiting decarboxylation ensues, affording O-bound Pd enolate 55.3,12 This chiral conjugated enolate then serves as the diene 144 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates in a [4+2] cycloaddition (TS30) with the pendant dienophile to form tricyclic enolate 56. Subsequent proton transfer would generate product 41a. Concomitant isoprene generation, followed by ligand exchange, allows for re-entry into the original catalytic cycle at 53. We posit that the formation of undesired ketone 49a arises from an off-cycle pathway, where catalyst turnover occurs prior to cycloaddition via premature proton transfer to 55. Scheme 3.1. Proposed divergent catalytic cycle. Undesired reaction pathways in grey. O O R Me O P N 3 Me P 52 40a Pd Ligand Exchange Me 5. Ligand Exchange Me 4. Proton Transfer N Me Pd H CO2Bn 41a CO2Bn R= Me O O R 57 52 O 1. Oxidative Addition O 40a 53 CO2Bn H P N P Divergent Chemistry O Pd P N O Original Catalytic Cycle R Me O P Me R O 58 56 N Pd O Me Me Me Me N Pd Me Pd 57 54 X Reductive Elimination 2. Decarboxylation (Rate-Limiting) BnO2C 49a N P Pd N P O Me Me TS30 3. Cycloaddition (Enantiodetermining) 3.2.3 Pd O CO2Bn Me Me CO2 Premature Proton Transfer 55 SUBSTRATE SCOPE With a working mechanistic hypothesis in hand, we sought to draw further mechanistic insights from substrate design, while simultaneously exploring limits of the reaction. Considering the inverse relationship between diene ring size and Diels–Alder 145 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Table 3.2. Substrate scope of the [4+2] reaction.a O Me O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) O toluene, 60 ºC R1 R2 R1 R2 n 40a-u O CO2R 40a H CO2R O 40i O CO2H O Me O Me O COPh CO2Bn H CO2Bn 40c 40j 41j (endo) 50% yield, 87% ee O O Me O O O H CO2Ph H CO2Ph H CO2Ph Me O CO2Ph H CO2Bn CO2Bn 40d 40k 41k (endo) 41k’ (exo) 41k’’ (other) 82% yield, 10.4:1.4:1 dr, 88% ee (endo) 41d (endo) 83% yield, 97% ee O Me O O Me O O H COPh 41c (endo) 65% yield, 65% ee Me O O 49i 80% yield, 7% ee 41i (endo) Me O O O H 2 O Me O Me O Me O CO2Mes CO2Bn 40e H CO2Bn 41e (endo) (not observed) 40l 41l (endo) 90% yield, 89% ee 49e 81% yield, 47% ee O Me O O H Me O O 4 O ONHP CO2Bn 40f O 41f (endo) 42% yield, 92% ee O 40g O H O 41g (endo) (not observed) H C(O)NHP O Me O CbzN 5 Me H CO2Bn H C(O)NHP 41m (endo) 41m’ (exo) 65% yield, 1.4:1 drb 62% ee (endo), 62% ee (exo) 40m 49f 45% yield, 51% ee O CO2Bn O CO2Bn O Me O H CO2Bn O Me Me O H CO2Mes CO2Bn O O 4 H CO2H (not observed) O H Me CO2H 41a (endo) 83% yield, 87% ee 41b (endo) 85% yield, 88% ee Me O O O Me O O 40b 3 49h 33% yield, 58% ee (not observed) O R = Et H H 41h (endo) 40h Me O R = Bn O Me O 41a-u Me O H O Me O n Product(s) Substrate O Product(s) Substrate O Me O CO2Bn 49g 74% yield, 56% ee N Cbz Me CO2Bn 40n H CO2Bn 41n (endo) 88% yield, 14.3:1 dr, 91% ee 146 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O O Me O O O 40o N O H O Me O O Me O CO2Bn 40t H CO2Bn 41p (endo) 81% yield, 28.4:1 drb, 72% ee 40p O Me O O O Me O H CO2Bn CO2Bn 40q H CO2Bn O * Me 40u H CO2Bn 41u (endo) 22% yield, >20:1 dr at *, 61% ee 41q (endo) 41q’ (exo) 92% yield, 1.6:1 dr 84% ee (endo), 29% ee (exo) O Me O H CO2Bn EtO H CO2Bn Me CO2Bn Me O EtO 41t (endo) 41t’ (exo) 89% yield, 2.6:1 drb 85% ee (endo), 72% ee (exo) Me O O Me O EtO H CO2Bn 41s (endo) 69% yield, 83% ee Me CO2Bn Me 40s O Me O Me CO2Bn O 41o (endo) 41o’ (exo) 92% yield, 1.1:1 dr 84% ee (endo), 79% ee (exo) O O N O O O Me O O O H O O O Me O N O O Me O CO2Bn Me 40r H Me CO2Bn 41r (endo) 47% yield, 89% ee [a] Conditions: 0.2 mmol 40a, 2.5 mol % Pd2(dba)3, 6.5 mol % ligand, in toluene (10 mL, 0.02 M), isolated yields, dr determined by 1H NMR analysis of reaction crude. [b] dr determined by isolated yields of endo/exo products. reaction rate 13 ,2, we explored whether this trend impacts the generality of our transformation. However, with cyclopentyl diene derived from enone 40c, a decrease in yield and ee, relative to six-membered parent substrate 40a, was noted (Table 3.2). In comparison to smaller ring sizes, seven-membered cyclic dienes require increased distortion energy to reach the desired transition state.13 Despite this, seven-membered ring substrate 40d leads to a high yield and improved ee. Thus, this transformation represents a powerful method to synthesize various challenging bicyclic cores. 147 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.4. Eyring analysis of 41/49 product ratio for propylene and butylene tethered substrates 40a and 40f.a O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) Me O O O Me O PhMe, temperature n + n H CO2Bn CO2Bn n H BnO2C 41a 41f 40a (n = 1) 40f (n = 2) 49a 49f 4.0 3.0 2.0 ln(11/19) ln(10/11) 1.0 0.0 -1.0 -2.0 Substrate n ∆∆H‡ (kcal/mol) ∆∆S‡ (eu) 40a 1 7±1 14 ± 3 40f 2 7±1 20 ± 2 -3.0 -4.0 2.2 2.4 2.6 2.8 3.0 3.2 1/T x 10 3 (K-1 ) T (ºC) 41a : 49a 41f : 49f 60 – 1.5 : 1.0 80 100 8.7 : 1.0 5.9 : 1.0 1.0 : 1.0 1.0 : 2.2 120 3.4 : 1.0 1.0 : 2.8 [a] All data points collected in triplicate, error bars and ranges reflect a 95% confidence interval.14 Reactions carried out on 0.02 mmol scale with product ratios determined by crude 1H NMR analysis. The dienophile tether length was subsequently modulated to test its influence on product distribution. The ethylene tethered substrate 40e yields solely the premature protonation product 49e, likely due to insurmountable developing ring strain in the cycloaddition transition state. In contrast to the propylene tethered substrate 40a, the Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 148 butylene tethered substrate 40f leads to a near equal distribution of cycloadduct 41f (42% yield) and prematurely protonation product 49f (45% yield). Following this trend, the pentylene tethered substrate 40g leads only to protonation product 49g. Rationalizing this phenomenon, we propose that lengthening the tether increases conformational flexibility and imposes a greater entropic penalty to the highly organized [4+2] transition state. In contrast, increased tether length is inconsequential to the protonation process, which does not involve the dienophile. Eyring analysis of product distributions from reactions of 40a and 40f further supports the hypothesis of an entropic preference for the formation of 49a/f over 41a/f (Figure 3.4). With 40a, cycloaddition (41a) is enthalpically favored (∆∆H‡ = 7 kcal/mol) but entropically disfavored (∆∆S‡ = 14 eu) over protonation (49a). As anticipated, increasing the tether length to four methylene units (40f) further increases the relative entropic penalty for cycloaddition (∆∆S‡ = 20 eu), while the differential enthalpy of activation remains similar (∆∆H‡ = 7 kcal/mol). Hence, entropy differences associated with tether length lead to the formation of differential amounts of undesired ketones 49a and 49f. We then surveyed the scope of functional groups that are tolerated in this reaction (Table 3.2). The cycloaddition does not proceed in the absence of a p-acceptor (40h), and carboxylic acid 40i exclusively affords undesired ketone 49i. To our delight, a variety of functional groups are compatible, including ethyl ester 10b, phenyl ketone 10j, phenyl ester 40k, mesityl ester 40l, N-hydroxyphthalimido (NHP) ester 40m, enecarbamate 40n, and N-acyl oxazolidinone 40o. Additionally, further conjugated cinnamic ester dienophile 40p Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 149 affords tetracycle 41p. These results demonstrate the ability to tolerate varying dienophile electronics, incorporate additional functional handles, and access alternate ring systems. The majority of the substrate scope is reflective of a stereospecific process, yielding only endo and exo diastereomers. We sought to exploit this property of the reaction to access other diastereomers of 41a by employing (Z)-olefin dienophile 40q. Gratifyingly, desired cycloadducts 41q (endo) and 41q’ (exo) are furnished in a 1.6:1 ratio with a 92% combined yield, in 84% and 29% ee, respectively. Further substitution patterns on the substrate were explored with the aim of increasing the stereochemical complexity of the products. Trisubstituted benzyl ester dienophile 40r furnished cycloadduct 41r, featuring two all-carbon quaternary centers, in 47% yield and 90% ee. b-Methyl (40s) and b-ethoxy (40t) a,b-unsaturated enones are also competent substrates, forging additional tetrasubstituted bridgehead stereocenters. Finally, we explored a-methyl substituted enone 40u. The corresponding product 41u was produced, bearing five contiguous stereocenters in >20:1 dr. In summary, the transformation described herein represents a versatile method for the preparation of a variety of enantioenriched polycyclic scaffolds. Inspired by these results, we sought to explore the origins of enantioinduction and the mechanism by which catalyst turnover is achieved. 3.2.4 [4+2] CYCLOADDITION In order to probe the origins of enantioinduction in the transformation, we first aimed to elucidate the enantiodetermining step in the catalytic cycle. We hypothesized that either the cycloaddition is irreversible and dictates the stereochemical outcome, or a Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 150 reversible [4+2] is coupled to a subsequent enantiodetermining step. First, we computationally evaluated the energetics of the [4+2] process. Cycloaddition directly from conjugated enolate 55 to transposed enolate 56 via TS30 is achieved with a ∆G‡ of 9.8 and ∆G of –22.3 kcal/mol (Figure 3.5A). The 32.1 kcal/mol barrier to the reverse process renders the cycloaddition step irreversible under the reaction conditions. Hence, our computations suggest that the cycloaddition step is enantiodetermining. To assess this hypothesis experimentally, reaction product 41a was converted to its corresponding prenyl enol carbonate 59. Under the standard reaction conditions, Pd0 undergoes oxidative addition to 59, and decarboxylation affords target common intermediate 56 (Figure 3.5B).5 When enantioenriched or racemic 59 is subjected to the reaction conditions, cycloadduct 41a is obtained in high yield and identical enantiopurity to that of the respective enol carbonate precursor (59) (Figure 3.5B). No stereochemical resolution in product 41a is observed from racemic enol carbonate 59, indicating that a post-cycloaddition process is not responsible for enantioinduction. In addition to verifying the irreversibility of the cycloaddition step, these experiments also support the viability of enolate 56 as an intermediate in the catalytic cycle (Scheme 3.1). Considering the [4+2] cycloaddition as the enantiodetermining process, the origin of enantioinduction in this step was investigated. As such, the lowest energy endo transition states giving rise to each enantiomer of 41a were evaluated (Figure 3.5C). The minimum energy pathway to each enantiomer of product features a transition state in which the dienophile tether is syn to the t-Bu group of the PHOX ligand – in accord with prior observations in inner-sphere allylic alkylation transition states.3,15 From this orientation, 151 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.5. (A) Computed barriers.a (B) Experimentally verifying irreversibility of the C–C bond formation. (C) Origins of enantioinduction in the [4+2] cycloaddition step. A. Thermodynamics of C–C bond formation. BnO2C BnO2C BnO2C ∆G‡forward = 9.8 N P Pd N O Me Pd P N O Me Pd P Me Me Me ∆G‡reverse = 32.1 Me TS30 Grel = 9.8 55 Grel = 0.0 O 56 Grel = –22.3 B. Enantioenrichment as readout of reversibility. Me O P Me O O 59 Me 52 O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) Me [4+2] step is irreversible and enantiodetermining 87 92 0 0 92 H CO2Bn H CO2Bn 41a 56 ee 59 (%) ee 41a (%) Yield 41a (%) 87 O Me toluene, 60 ºC H CO2Bn N Pd open back pocket C. Origins of enantioinduction (R = CO2Bn). sterically accessible face R Favored 6 6 4 4 5 O 5 N P External approach of dienophile (to 41a) Pd Me Me O 1 = 1 Me Me TS30 TS30 ∆G‡rel = 0.0 steric clash 4 Disfavored 6 R O Internal approach of dienophile (to ent-41a) steric clash N P Pd Me Me O TS31 ∆G‡rel = 1.6 6 5 4 5 1 Me = 1 Me TS31 [a] Gibbs free energies in kcal/mol. See supporting information in section 3.4 for details. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 152 the dienophile preferentially approaches the externally-exposed enantiotopic face of the diene to avoid steric clash between the benzyl ester and the phenyl groups of the PHOX ligand scaffold (Figure 3.5C). A 1.6 kcal/mol preference for external (TS30) over internal (TS31) approach is calculated, in accord with the experimentally observed 87% ee.16 The major enantiomer of product (41a) predicted by computations matches that of the major enantiomer obtained experimentally, as confirmed by vibrational circular dichroism (VCD) spectroscopy (see 3.4 Supporting Information for details). In summary, our investigations reveal C–C bond formation to be the enantiodetermining step, with enantioselectivity achieved by biasing external over internal dienophile approach (Figure 3.5). 3.2.5 CATALYST TURNOVER Our [4+2] transformation is rendered catalytic by a unique reduction of PdII to Pd0 that occurs concomitantly with formation of isoprene (52) and ketone 41a. This observation motivated computational investigations to elucidate the catalyst turnover mechanism. Of the numerous mechanisms explored, the minimum energy pathway involves isomerization of 56 to an N-detached p-allyl Pd species (60) and subsequent inner-sphere proton transfer (TS4) (Figure 3.6). Additionally, a pathway featuring outer-sphere proton transfer (TS5) was found to be highly competitive for catalyst turnover. These two processes present very similar free energy barriers of 22.3 and 22.4 kcal/mol, respectively, which are readily surmountable at 60 °C. A single favored pathway is not identified as the energy difference between the two mechanisms is within error of computations. In both pathways, subsequent ligand exchange of isoprene (52) for starting material 40a completes 153 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates the catalytic cycle. Analysis of Intrinsic Bonding Orbitals (IBOs) 17 along the reaction coordinate suggest these processes are best conceptualized as the transfer of a proton, rather than a hydride, to the Pd enolate (see 3.4 Supporting Information for details).18 Analogous mechanisms were found to be operative from pre-cycloaddition enolate 55, giving rise to premature protonation product 49a. Figure 3.6. Two lowest-energy pathways for catalyst turnover.a N-detached inner-sphere pathway BnO2C BnO2C BnO2C 3 P PdII P Me N O N t-Bu O Me O 3 H7 7 = P 8 N 8 d3,7 = 1.41 Å d7,8 = 1.38 Å Me t-Bu 60 Grel = 4.4 O PdII TS32 Grel = 22.3 O Pd0 O 61 Me Grel = –2.9 tBu 56 Grel = 0.0 BnO2C BnO2C O N P Me PdII 3 BnO2C O O Me t-Bu 62 Grel = 13.1 outer-sphere pathway N P 7 H O PdII O 9 = Me 3 7 O 9 t-Bu TS33 Grel = 22.4 N P 41a Pd0 t-Bu Me 57 Grel = –10.6 d3,7 = 1.55 Å d7,9 = 1.28 Å [a] Gibbs free energies in kcal/mol. See section 3.4 supporting information for details. 3.2.6 FURTHER MECHANISM-BASED DEVELOPMENTS While this method allows access to a variety of complex scaffolds, premature protonation remains an outstanding challenge we sought to address. As such, we aimed to leverage our mechanistic insights surrounding this process to inhibit byproduct formation. 154 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.7. (A) KIE study. (B) Prenyl ester modification. A. Leveraging kinetic isotope effect (KIE) to slow proton transfer.a O O CD3 O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) CD3 O 93% Db O D * D 64% Db + toluene, 60 ºC, 14 h H CO2Bn CO2Bn CO2Bn D-41f D-49f 66% yield, 91% ee, 1.6:1 dr at * 24% yield, 55% ee D-40f B. Modification of prenyl ester via cyclic and benzylic analogs.c O O O O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) OR toluene, 60 ºC, 14 h H CO2Bn CO2Bn CO2Bn 49f 41f Entry H + R Yield 41f (%) ee 41f (%) Yield 49f (%) ee 49f (%) (40f) 44 91 42 40 2d (63) 25 92 44 46 3 (64) 8 – 89 48 4 (65) 63 92 21 44 5 (66) 48 92 46 38 Ph (67) 14 94 86 60 Me 1 Me Ph 6e [a] Conditions: 0.20 mmol D-40f, 2.5 mol % Pd2(dba)3, 6.5 mol % ligand, in 10 mL of solvent (0.02 M). [b] Deuterium incorporation determined by HRMS. [c] Conditions: 0.02 mmol substrate, 2.5 mol % Pd2(dba)3, 6.5 mol % ligand, in 1.0 mL of solvent (0.02 M). Yield determined by 1H NMR with respect to 1,3,5-trimethoxybenzene as internal standard. [d] 21% of allylic alkylation product was also observed. [e] The corresponding benzylic diene was also observed (see 3.4 Supporting Information for details). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 155 To that end, we turned our attention to butylene tethered substrate 40f given its similar yield of desired 41f (44%) and byproduct 49f (42%). We envisioned favoring the formation of 41f by modification of the ancillary prenyl moiety. By introducing a kinetic isotope effect, we aimed to slow down the protonation processes. To our delight, employing hexa-deutero prenyl ester D-40f (Figure 3.7A) increases the yield of desired cycloadduct D-41f to 66%, with 91% ee.19 Next, cyclic analogs of the prenyl ester 40f were prepared (Figure 3.7B). At one extreme, seven-membered exocycle 66 affords a product distribution which closely mirrors that of parent substrate 40f (entry 5). Excitingly, contracting the ring by one methylene (65) shifts the distribution favorably toward 41f (entry 4, 3:1 ratio of 41f:49f). However, five- and four-membered exocycles (64 and 63), as well as acyclic bis-benzylic allylic ester 67, afford unfavorable product distributions. In summary, we find appropriate modification of the prenyl moiety to be effective in suppressing deleterious side reactions. This is particularly important as the ring system generated in this reaction is a scaffold relevant to natural product synthesis. 3.2.7 PRODUCT DERIVATIZATIONS To assess the utility of the asymmetric intramolecular [4+2] products, we started by altering the oxidation state of ketone 41a (Figure 3.8A) through a 1,2-reduction, which provided alcohol 68 in quantitative yield and in 1.5:1 dr. Subsequently, we explored ring expansion strategies to incorporate heteroatoms and to furnish different ring systems (Figure 3.8A). From ketone 41a, oxime condensation and subsequent Beckmann rearrangement afforded lactam 69 as a single isomer in 56% yield over two steps. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 156 Analogously, Baeyer–Villiger oxidation furnished lactone 70 in 41% yield as a single isomer. Furthermore, the tricyclic cycloaddition products closely resemble many members of the atisane family of diterpenoids (Figure 3.8B, 71-74). Therefore, reactions to further functionalize these scaffolds were explored. First, hydrogenolysis followed by persulfatemediated radical decarboxylation of 41f afforded ketone 75 in 27% yield over two steps.20 We were delighted to find that the exo-cyclic methylene motif presented in both crotogoudin (71) and campylopin (74) could be achieved through aldol condensations from both 75 and 41f to yield crotogoudin-like enone 76 in 41% yield and analogous enone 77 in 26% yield.21 Enone 77 can be further functionalized through dihydroxylation to furnish the primary and tertiary alcohol centers of the acochlearine (72) core in 13% yield and 10:1 dr (78). 22 A wider spectrum of natural product cores could also be accessed through oxidation at different sites of the tricyclic hydrocarbon backbone. For example, Riley oxidation of 41f provided diketone 79 in 50% yield,23 which can then be selectively monoprotected as acetal 80 in 41% yield.24 Further manipulations to the exposed ketone of 80 could yield spiramilactam B (73)-like oxidation patterns. To that end, directed C–H oxidation following an oxime condensation of 41f yielded oxime 81 in 30% yield. Deprotection of the oxime afforded the desired acetate on campylopin (74)-like tricycle 82 in 19% yield as a single diastereomer.25 Overall, derivatization of the Diels–Alder product 41f allowed access to four natural product-like motifs, demonstrating the potential of applying this transformation to asymmetric natural product syntheses. 157 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.8. (A) Oxidation state alterations, ring system adjustments, and heteroatom incorporation on 41a. (B) Reaction sequences to construct natural product-like cores. A. Reactivity of Diels–Alder product 41a. OH * 68 99% yield 1.5:1 dr at * NaBH4, MeOH 1,2-Reduction H CO2Bn O 1. NaOAc, NH2OH•HCl, MeOH 2. SOCl2, THF H N O H CO2Bn 69 56% yield H Beckmann Rearrangement CO2Bn 41a O O m-CPBA, NaHCO3, CH2Cl2 70 41% yield H Baeyer–Villiger Oxidation CO2Bn B. Construction of natural product-like cores from asymmetric Diels–Alder product 41f. O O O OH HO Me Me OH Me H OH O N N Me Me 71 Crotogoudin Me H CO2Bn i) HCO2Et, KHMDS toluene 41f AcO OH O 74 Campylopin O i) HCO2Et, KHMDS toluene ii) HCHO(aq), THF 76 41% yield 75 27% yield EtO2C O K2OsO4•2H2O NMO EtO2C O 78 13% yield 10:1 dr 77 26% yield BnO2C O O SeO2 HC(OMe)3 p-TsOH•H2O BnO2C O OMe OMe MeOH HOAc 80 41% yield 79 50% yield 1. NH2OH•HCl NaOAc, MeOH/H2O BnO2C N 2. PhI(OAc)2, Pd(OAc)2 AcOH, Ac2O AcO OAc BnO2C O K2CO3, NaHSO3 81 30% yield OH OH acetone, H2O ii) HCHO(aq), THF BnO2C O Me CHO 73 Spiramilactam B O 2. 2,4,6-collidine, (NH4)2S2O8, DMSO OH OH 72 Acochlearine 1. H2, Pd/C, MeOH O OH O MeOH/H2O AcO 82 19% yield > 20:1 dr Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 3.3 158 CONCLUSIONS We developed an asymmetric decarboxylative [4+2] cycloaddition employing a key catalytically-generated chiral Pd enolate intermediate – analogous to those implicated in inner-sphere allylic alkylation reactions. To enable this transformation, we first systematically modified the allyl moiety to disfavor undesired allylic alkylation. This allows the conjugated Pd enolate to engage in a [4+2] cycloaddition with a pendant dienophile. Computational and experimental analysis supports the role of C–C bond formation as the enantiodetermining step. Further computational investigation reveals that the catalyst turnover occurs through a proton transfer from the prenyl group directly to the transposed enolate, forming the desired product and releasing isoprene. Building upon these mechanistic insights, we were able to further favor the desired [4+2] cycloaddition over premature protonation for challenging substrates relevant to complex natural product synthesis. In summary, our approach of divergent catalysis serves as a powerful framework for rational design in asymmetric catalytic reactions. Studies applying this strategy more broadly in other synthetically relevant transformations are currently underway. 3.4 SUPPORTING INFORMATION 3.4.1 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. 26 Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 159 visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on a Bruker 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). 2H NMR spectra were recorded on a Bruker 400 MHz (61 MHz) spectrometer and are reported relative to residual CDCl3 (δ 7.26 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as the peaks appear as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of water (δ 1.56ppm), 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. 13C NMR spectra of deuterated compounds are complicated by the low intensity of peaks of deuteriumsubstituted carbon atoms. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. 160 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in Field Desorption (FD+) mode. Absolute stereochemical assignments were made by vibrational circular dichroism analysis for select compounds with related compounds assigned by analogy. Reagents were purchased from commercial sources and used as received unless otherwise stated. Ligands were prepared according to literature procedures.27 List of Abbreviations: ee – enantiomeric excess, SFC – supercritical fluid chromatography, TLC – thin-layer chromatography, IPA – isopropanol, VCD – vibrational circular dichroism. 3.4.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA Pd-Catalyzed Decarboxylative Cycloadditions General Procedure A: Asymmetric Pd-Catalyzed Decarboxylative Cycloadditions. O O Me O Me O CO2Bn R n 40 Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) PhMe, 60 ºC R n H CO2Bn 41 In a nitrogen filled glovebox, an oven-dried 20 mL vial was charged with a stir bar, Pd2(dba)3 (4.6 mg, 0.005 mmol, 2.5 mol %), (S)-t-BuPHOX (5.0 mg, 0.013 mmol, 6.5 mol %), and toluene (5 mL). The catalyst solution was stirred at 23 ºC for 20 min. A solution of substrate 40 (0.2 mmol, 1 equiv) in toluene (5 mL) was added to the vial. The resultant solution was then heated to 60 ºC for 14 h. The solution was then cooled to 23 ºC and concentrated under reduced pressure. The crude reaction mixture was loaded directly Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 161 onto a flash column and the product (41) was isolated by silica gel flash column chromatography. O H CO2Bn 41a benzyl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41a) Prepared from 40a following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (49.7 mg, 0.167 mmol, 83% yield, 87% ee). Absolute and relative stereochemistry were assigned by VCD (vida infra). 2D NMR studies independently confirm the relative stereochemistry (vida infra). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.31 (m, 5H), 5.14 (d, J = 1.6 Hz, 2H), 2.54 (dt, J = 18.8, 2.3 Hz, 1H), 2.51 – 2.47 (m, 2H), 2.21 (dddd, J = 10.6, 8.7, 7.2, 1.7 Hz, 1H), 2.14 – 2.04 (m, 3H), 1.86 (ddd, J = 13.0, 11.1, 6.8 Hz, 1H), 1.81 – 1.72 (m, 2H), 1.70 – 1.52 (m, 3H), 1.44 (ddt, J = 12.9, 10.9, 1.8 Hz, 1H), 1.22 (ddd, J = 13.9, 9.2, 4.9 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.1, 174.7, 136.0, 128.8, 128.5, 128.2, 66.7, 54.2, 47.5, 43.3, 41.3, 32.9, 29.1, 27.4, 26.5, 25.1, 22.6. IR (Neat Film, NaCl): 2947, 2873, 1726, 1455, 1267, 1160 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O3 [M]+: 298.1564, found 298.1576. Optical Rotation: [α]D21 –20.3 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.21, major = 5.30 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 162 O H CO2Et 41b ethyl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41b) Prepared from 40b following General Procedure A. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (39.9 mg, 0.169 mmol, 84% yield, 88% ee). 1 H NMR (400 MHz, CDCl3): δ 4.15 (q, J = 7.1 Hz, 2H), 2.55 (dt, J = 18.8, 2.6 Hz, 1H), 2.49 – 2.44 (m, 1H), 2.42 (d, J = 8.6 Hz, 1H), 2.23 – 2.14 (m, 1H), 2.15 – 2.04 (m, 3H), 1.91 – 1.71 (m, 3H), 1.71 – 1.52 (m, 3H), 1.50 – 1.40 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (dt, J = 9.2, 4.9 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.2, 174.9, 60.8, 54.2, 47.5, 43.3, 41.3, 32.9, 29.1, 27.4, 26.5, 25.1, 22.6, 14.4. IR (Neat Film, NaCl): 2947, 2873, 1725, 1270, 1170 cm–1. HRMS (MM: FD+): m/z calc’d for C14H20O3 [M]+: 236.1412, found 236.1415. Optical Rotation: [α]D21 –34.2 (c 1.00, CHCl3). Enantiomeric excess determined by converting ethyl ester to benzyl ester through saponification and Steglish esterification. SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.21, major = 5.30 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 163 O H CO2Bn 41c benzyl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-methanoindene-7-carboxylate (41c) Prepared from 40c following General Procedure A. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a colorless oil (37.0 mg, 0.130 mmol, 65% yield, 65% ee). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.29 (m, 5H), 5.13 (dd, J = 12.3, 7.9 Hz, 2H), 2.96 (t, J = 4.2, 1H), 2.92 (ddd, J = 5.2, 3.7, 1.4, 1H), 2.42 – 2.35 (m, 1H), 2.22 – 2.17 (m, 1H), 2.16 – 2.05 (m, 3H), 1.95 (ddtd, J = 12.9, 8.4, 5.1, 2.2 Hz, 1H), 1.90 – 1.80 (m, 2H), 1.66 (dt, J = 10.6, 1.6 Hz, 1H), 1.52 – 1.37 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 213.9, 173.3, 136.0, 128.8, 128.5, 128.3, 67.8, 66.6, 52.4, 48.5, 41.8, 40.6, 40.5, 32.2, 27.5, 22.1. IR (Neat Film, NaCl): 2960, 2358, 1739, 1164, 730, 668 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O3 [M]+: 284.1414, found 284.1407. Optical Rotation: [α]D21 +20.0 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 3.97, major = 4.33. O H CO2Bn 41d benzyl (3aR,7R,8S,8aR)-10-oxooctahydro-1H-3a,7-ethanoazulene-8-carboxylate (41d) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 164 Prepared from 40d following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (51.8 mg, 0.166 mmol, 83% yield, 97% ee). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.31 (m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 2.70 – 2.63 (m, 2H), 2.64 – 2.56 (m, 1H), 2.25 (ddd, J = 18.5, 2.0, 1.0 Hz, 1H), 2.08 (td, J = 10.5, 7.8 Hz, 1H), 2.03 – 1.94 (m, 1H), 1.93 – 1.79 (m, 3H), 1.78 – 1.60 (m, 4H), 1.59 – 1.43 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 215.7, 175.8, 136.0, 128.8, 128.5, 128.3, 66.7, 58.0, 50.2, 45.4, 41.0, 35.7, 33.6, 33.3, 32.0, 28.0, 21.8, 21.2. IR (Neat Film, NaCl): 2934, 2873, 1727, 1713, 1455, 1161 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M+H]+: 312.1720, found 312.1734. Optical Rotation: [α]D21 +21.4 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.70, major = 6.23. O H CO2Bn 41f benzyl (1S,2R,4aR,8aR)-4-oxooctahydro-2H-2,4a-ethanonaphthalene-1-carboxylate (41f). Prepared from 40f following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (26.3 mg, 0.084 mmol, 42% yield, 92% ee). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 165 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 2.47 (dt, J = 17.0, 2.8 Hz, 2H), 2.28 – 2.19 (m, 2H), 2.14 (ddd, J = 19.7, 3.8, 1.8 Hz, 1H), 2.01 (dddd, J = 11.8, 6.8, 4.5, 1.7 Hz, 1H), 1.87 (ddtd, J = 12.8, 4.5, 3.4, 1.6 Hz, 1H), 1.83 – 1.71 (m, 1H), 1.71 – 1.56 (m, 4H), 1.51 – 1.11 (m, 5H). 13 C NMR (100 MHz, CDCl3): δ 216.3, 174.5, 136.0, 128.7, 128.4, 128.2, 66.7, 49.8, 45.1, 40.5, 37.1, 30.9, 30.0, 28.9, 26.2, 25.6, 21.7, 21.1. IR (Neat Film, NaCl): 2928, 2856, 1721, 1170 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1720, found 312.1732. Optical Rotation: [α]D21 –15.5 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.70, major = 6.23. O H Ph O 41j (3aR,6R,7S,7aR)-7-benzoylhexahydro-3a,6-ethanoinden-4(1H)-one (41j) Prepared from 40j following General Procedure A. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a colorless oil (27.1 mg, 0.101 mmol, 50% yield, 87% ee). 1 H NMR (400 MHz, CDCl3): δ 7.97 – 7.94 (m, 2H), 7.61 – 7.56 (m, 1H), 7.51 – 7.46 (m, 2H), 3.42 (d, J = 8.5 Hz, 1H), 2.58 – 2.50 (m, 2H), 2.41 – 2.38 (m, 1H), 2.16 (ddd, J = 13.7, 11.1, 6.2 Hz, 1H), 2.08 – 1.87 (m, 4H), 1.82 – 1.74 (m, 1H), 1.70 – 1.50 (m, 4H), 1.25 (ddd, J = 14.0, 9.2, 5.1 Hz, 1H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 166 C NMR (100 MHz, CDCl3): δ 214.9, 201.0, 136.4, 133.4, 128.9, 128.5, 54.2, 49.4, 41.4, 40.8, 34.1, 28.9, 27.8, 26.5, 25.6, 22.7. IR (Neat Film, NaCl): 2945, 2871, 1720, 1677, 1447, 1217 cm-1. HRMS (MM: FD+): m/z calc’d for C18H20O2 [M]+: 268.1463, found 268.1463. Optical Rotation: [α]D21 –32.7 (c 1.00, CHCl3). SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 2.55, major = 3.40. O O O H CO2Ph H CO2Ph H CO2Ph 41k (endo-trans) 41k’ (exo-cis) 41k’’ (endo-cis) phenyl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41k, 41k’ and 41k’’) Prepared from 40k following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (47.2 mg, 0.166 mmol, 83% yield, 14.8:1.6:1.0 endo-trans/endo-cis/exo-trans, 88% ee (endo-trans)). Crude analysis by 1H NMR affords a 10.4:1.4:1.0 ratio of endo-trans/exotrans/endo-cis. The diastereomers were subsequently separated by preparative HPLC (15% IPA/hexanes, 25 mL/min, Chiralpak AD-H column) for independent characterization. Absolute and relative stereochemistry were assigned/confirmed by VCD where applicable (vida infra) in addition to 2D NMR. 41k (endo-trans): Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 167 H NMR (400 MHz, CDCl3): δ 7.41 – 7.34 (m, 2H), 7.25 – 7.20 (m, 1H), 7.09 – 7.04 (m, 2H), 2.70 (d, J = 8.7 Hz, 1H), 2.67 – 2.60 (m, 2H), 2.31 (dddd, J = 10.6, 8.8, 7.3, 1.7 Hz, 1H), 2.23 – 2.09 (m, 3H), 1.97 – 1.76 (m, 3H), 1.67 (ddddd, J = 13.5, 11.1, 9.0, 6.2, 4.5 Hz, 3H), 1.50 (ddt, J = 12.5, 10.6, 1.7 Hz, 1H), 1.31 – 1.17 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.8, 173.4, 150.7, 129.6, 126.0, 121.5, 54.2, 47.5, 43.4, 41.2, 32.9, 29.1, 27.3, 26.5, 25.0, 22.5. IR (Neat Film, NaCl): 2948, 2872, 1750, 1721, 1592, 1492, 1192, 1144 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O3 [M]+: 284.1412, found 284.1411. Optical Rotation: [α]D21 –16.7 (c 0.20, CHCl3). (single major enantiomer of 11j) SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.09, major = 6.08. 41k’ (exo-trans): 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.34 (m, 2H), 7.25 – 7.19 (m, 1H), 7.06 – 7.01 (m, 2H), 3.30 (dt, J = 12.0, 2.3 Hz, 1H), 3.08 (dt, J = 19.5, 2.8 Hz, 1H), 2.58 (h, J = 2.8 Hz, 1H), 2.47 – 2.33 (m, 2H), 2.21 (dt, J = 19.6, 2.4 Hz, 1H), 2.08 – 2.01 (m, 2H), 1.93 – 1.71 (m, 5H), 1.70 – 1.59 (m, 1H), 1.04 (ddd, J = 12.8, 11.4, 6.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.2, 171.8, 150.6, 129.6, 126.0, 121.7, 54.6, 45.8, 44.0, 40.1, 31.4, 28.4, 28.2, 27.0, 26.3, 21.8. IR (CDCl3 solution): 2951, 2870, 1751, 1717, 1194, 1163, 1146 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O3 [M]+: 284.1412, found 284.1417. 41k’’ (endo-cis): Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 168 H NMR (400 MHz, CDCl3): δ 7.43 – 7.36 (m, 2H), 7.27 – 7.22 (m, 1H), 7.12 – 7.07 (m, 2H), 2.76 – 2.67 (m, 1H), 2.58 (dt, J = 8.3, 1.7 Hz, 1H), 2.48 – 2.33 (m, 4H), 2.12 – 2.01 (m, 2H), 1.91 – 1.63 (m, 5H), 1.10 (ddd, J = 13.0, 11.2, 6.5 Hz, 1H), 1.01 (ddd, J = 12.4, 9.5, 2.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.1, 172.9, 150.9, 129.6, 126.1, 121.6, 53.8, 49.4, 46.0, 44.2, 32.7, 32.0, 28.6, 27.4, 22.6, 21.5. IR (CDCl3 solution): 2945, 2872, 1751, 1717, 1194, 1163, 1130 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O3 [M]+: 284.1412, found 284.1407. O H CO2Mes 41l mesityl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41l) Prepared from 40l following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (58.6 mg, 0.180 mmol, 90% yield, 89% ee). 1 H NMR (400 MHz, CDCl3): ) δ 6.87 (s, 2H), 2.75 (d, J = 8.8 Hz, 1H), 2.72 – 2.65 (m, 2H), 2.36 (dddd, J = 10.6, 8.9, 7.3, 1.6 Hz, 1H), 2.26 (s, 3H), 2.24 – 2.09 (m, 3H), 2.08 (s, 6H), 1.98 – 1.78 (m, 3H), 1.75 – 1.61 (m, 3H), 1.55 – 1.48 (m, 1H), 1.31 – 1.24 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.8, 172.8, 145.9, 135.6, 129.5, 129.5, 54.2, 47.4, 43.5, 41.3, 33.2, 29.2, 27.5, 26.5, 25.1, 22.6, 20.9, 16.4. IR (Neat Film, NaCl): 2946, 2873, 1747, 1723, 1485, 1458, 1189, 1137 cm–1. HRMS (MM: FD+): m/z calc’d for C21H26O3 [M]+: 326.1877, found 326.1886. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 169 Optical Rotation: [α]D21 –25.8 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.06, major = 4.33. O O H O NHP 41m (endo) 1,3-dioxoisoindolin-2-yl H O NHP 41m’ (exo) (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7- carboxylate (41m and 41m’) Prepared from 40m following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compounds as colorless oils (Endo: 37.7 mg, 0.106 mmol, 53% yield, 62% ee; Exo: 8.6 mg, 0.024 mmol, 12% yield, 62% ee). 41m (endo): 1 H NMR (400 MHz, CDCl3): δ 7.92 – 7.85 (m, 2H), 7.83 – 7.75 (m, 2H), 2.84 (dd, J = 8.7, 1.3 Hz, 1H), 2.71 (m, 1H), 2.64 (dt, J = 18.9, 2.5 Hz, 1H), 2.46 – 2.28 (m, 1H), 2.28 – 2.18 (m, 2H), 2.13 (m, 1H), 1.98 – 1.76 (m, 3H), 1.76 – 1.60 (m, 3H), 1.56 – 1.48 (m, 1H), 1.34 – 1.19 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.0, 171.4, 162.1, 135.0, 129.0, 124.2, 54.1, 44.8, 43.3, 41.0, 33.2, 28.9, 27.2, 26.4, 24.9, 22.4. IR (Neat Film, NaCl): 2948, 2873, 1782, 1742, 1718, 1466, 1362, 1185 cm–1. HRMS (MM: FD+): m/z calc’d for C20H19NO5 [M]+: 353.1263, found 353.1251. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 170 Optical Rotation: [α]D21 –0.2 (c 1.00, CHCl3). SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 4.03, major = 3.00 41m’ (exo): 1 H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 2.77 (tt, J = 3.9, 2.2 Hz, 1H), 2.73 (d, J = 8.4 Hz, 1H), 2.47 – 2.28 (m, 4H), 2.19 – 2.02 (m, 2H), 1.92 – 1.71 (m, 4H), 1.71 – 1.61 (m, 1H), 1.11 (ddd, J = 13.1, 11.2, 6.6 Hz, 1H), 1.08 – 0.95 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.2, 170.8, 162.1, 135.0, 129.1, 124.2, 53.7, 46.7, 46.0, 44.1, 32.9, 31.8, 28.4, 27.2, 22.5, 21.2. IR (Neat Film, NaCl): 2947, 2868, 1809, 1784, 1743, 1717, 1466, 1362, 1185 cm–1. HRMS (MM: FD+): m/z calc’d for C20H19NO5 [M]+: 353.1263, found 353.1261. Optical Rotation: [α]D21 –13.6 (c 0.81, CHCl3). SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 4.98, major = 4.29. O CbzN H CO2Bn 41n dibenzyl (3aR,4R,5R,7aS)-7-oxooctahydro-5,7a-(epiminomethano)indene-4,9- dicarboxylate (41n) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 171 Prepared from 40n following General Procedure A. Purification by flash column chromatography (0–40 % EtOAc/hexanes) afforded the title compound as a colorless oil (76.1 mg, 0.176 mmol, 88% yield, 14.3:1 endo/exo, 91% ee (endo)). 1 H NMR (400 MHz, CDCl3): δ 7.35 (dd, J = 7.1, 4.9 Hz, 10H), 5.21 – 5.07 (m, 4H), 4.90 – 4.74 (m, 1H), 3.49 (dd, J = 12.1, 5.8 Hz, 1H), 3.40 – 3.27 (m, 1H), 2.88 (t, J = 8.9 Hz, 1H), 2.66 – 2.42 (m, 2H), 2.30 (p, J = 9.3 Hz, 1H), 2.23 – 2.10 (m, 2H), 1.91 – 1.56 (m, 3H), 1.33 – 1.14 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 210.1, 209.7, 172.2, 154.4, 136.3, 135.5, 128.9, 128.7, 128.7, 128.4, 128.4, 128.4, 128.3, 128.2, 128.1, 67.6, 67.2, 55.9, 55.8, 50.4, 50.0, 48.8, 48.6, 45.7, 45.6, 42.6, 42.6, 41.7, 41.6, 29.0, 28.9, 24.1, 22.9. IR (Neat Film, NaCl): 3399, 2963, 2874, 2357, 1729, 1700, 1652, 1414, 1288, 1156, 1115, 748, 681 cm-1. HRMS (MM: FD+): m/z calc’d for C26H27NO5 [M]+: 433.1889, found 433.1874. Optical Rotation: [α]D21 –39.8 (c 0.75, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 9.19, major = 11.59. O O H O N O O 41o (endo) H O O N O 41o' (exo) 3-((3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carbonyl)oxazolidin-2-one (41o and 41o’) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 172 Prepared from 40o following General Procedure A. Purification by flash column chromatography (0–90 % EtOAc/hexanes) afforded the title compound as a colorless oil (51.2 mg, 0.185 mmol, 92% yield, 1.1:1 endo/exo (ratio from crude 1H NMR analysis), 84% ee (endo), 79% ee (exo)). 41o (endo): 1 H NMR (400 MHz, CDCl3): δ 4.43 (t, J = 8.1 Hz, 2H), 4.15 – 4.00 (m, 2H), 3.54 – 3.47 (m, 1H), 2.66 (ddd, J = 12.4, 8.3, 6.9 Hz, 1H), 2.52 – 2.25 (m, 4H), 1.92 – 1.68 (m, 5H), 1.67 – 1.53 (m, 2H), 1.08 (ddd, J = 12.9, 11.2, 6.4 Hz, 1H), 0.89 (tt, J = 12.3, 9.5 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.5, 173.8, 153.4, 62.1, 53.7, 48.3, 44.1, 44.0, 43.1, 33.8, 31.3, 28.7, 27.3, 22.8, 20.8. IR (Neat Film, NaCl): 2942, 2867, 1775, 1714, 1693, 1387, 1267, 1222, 1040 cm–1. HRMS (MM: FD+): m/z calc’d for C15H19NO4 [M]+: 277.1314, found 277.1321. Optical Rotation: [α]D21 –39.5 (c 1.00, CHCl3). SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.15, major = 5.17. 41o’ (exo): 1 H NMR (400 MHz, CDCl3): δ 4.43 (t, J = 8.1 Hz, 2H), 4.13 – 3.97 (m, 2H), 3.71 (d, J = 8.8 Hz, 1H), 2.59 – 2.41 (m, 2H), 2.35 (dd, J = 3.5, 2.3 Hz, 1H), 2.19 – 1.84 (m, 5H), 1.81 – 1.41 (m, 6H), 1.27 – 1.18 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.9, 174.6, 153.5, 62.13, 54.1, 45.6, 43.1, 41.2, 40.6, 34.5, 28.4, 27.3, 26.5, 25.3, 22.7. IR (Neat Film, NaCl): 2949, 2872, 1775, 1718, 1692, 1387, 1221,1040, 759 cm–1. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 173 HRMS (MM: FD+): m/z calc’d for C15H19NO4 [M]+: 277.1314, found 277.1317. Optical Rotation: [α]D21 –5.8 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 6.80, major = 6.38. O O H CO2Bn H CO2Bn 41p (endo) benzyl 41p’ (exo) (3R,4S,4aS,9aS)-1-oxo-1,2,3,4,4a,9-hexahydro-3,9a-ethanofluorene-4- carboxylate (41p and 41p’) Prepared from 40p following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compounds as colorless oils (Endo: 56.8 mg, 0.156 mmol, 78% yield, 72% ee; Exo: 2.0 mg, 5.48 µmol, 3% yield). 41p (endo): 1 H NMR (400 MHz, CDCl3): δ 7.28 – 7.20 (m, 5H), 7.14 – 7.05 (m, 4H), 5.13 (d, J = 2.4 Hz, 2H), 3.53 (dd, J = 9.4, 1.0 Hz, 1H), 3.16 (d, J = 15.7 Hz, 1H), 2.74 (dt, J = 9.3, 1.1 Hz, 1H), 2.61 (dt, J = 18.8, 2.4 Hz, 1H), 2.51 (ttd, J = 3.5, 2.2, 1.1 Hz, 1H), 2.31 (d, J = 15.8 Hz, 1H), 2.11 (ddd, J = 18.8, 3.5, 1.2 Hz, 1H), 1.70 – 1.56 (m, 2H), 1.54 – 1.45 (m, 1H), 1.42 – 1.34 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 214.0, 174.6, 142.3, 140.6, 135.8, 128.8, 128.6, 128.4, 127.3, 127.0, 125.5, 124.3, 67.1, 56.6, 47.8, 45.6, 42.1, 35.0, 33.2, 27.0, 24.8. IR (Neat Film, NaCl): 2942, 2869, 1726, 1457, 1164 cm-1. HRMS (MM: FD+): m/z calc’d for C23H22O3 [M+H]+: 346.1564, found 346.1571. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 174 Optical Rotation: [α]D21 +1.4 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 6.74, major = 6.28. 41p’ (exo): 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.34 (m, 5H), 7.24 (d, J = 7.1 Hz, 1H), 7.14 – 7.07 (m, 3H), 5.30 (d, J = 12.3 Hz, 1H), 5.25 (d, J = 12.3 Hz, 1H), 3.85 (d, J = 9.4 Hz, 1H), 3.46 (d, J = 14.7 Hz, 1H), 2.75 (d, J = 9.3 Hz, 1H), 2.69 – 2.65 (m, 1H), 2.44 (d, J = 14.9 Hz, 1H), 2.37 (dd, J = 18.7, 2.1 Hz, 1H), 2.19 (ddd, J = 18.6, 3.4, 2.1 Hz, 1H), 2.15 – 2.07 (m, 2H), 1.90 – 1.84 (m, 1H), 1.81 – 1.76 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 213.5, 174.0, 143.8, 142.7, 135.9, 128.8, 128.6, 128.4, 127.2, 126.6, 124.8, 122.5, 67.1, 56.4, 49.9, 48.3, 44.1, 35.3, 31.9, 27.5, 21.8. IR (Neat Film, NaCl): 2918, 1727, 1161 cm-1. HRMS (MM: FD+): m/z calc’d for C23H22O3 [M+H]+: 346.1569, found 346.1568. O O H CO2Bn H CO2Bn 41q (endo) 41q’ (exo) benzyl (3aR,6R,7S,7aS)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41q and 41q’) Prepared from 40q following General Procedure A. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (54.9 mg, 0.183 mmol, 92% yield, 1.6:1 endo/exo, 84% ee (endo), 29% ee (exo)). The endo (41q) and exo (41q’) diastereomers were subsequently separated by preparative TLC (25% Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 175 EtOAc/hexanes) for independent characterization. Absolute and relative stereochemistry were assigned/confirmed by VCD (see below). 41q (endo): 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.31 (m, 5H), 5.13 – 5.02 (m, 2H), 3.10 – 2.99 (m, 2H), 2.47 (h, J = 2.9 Hz, 1H), 2.36 – 2.21 (m, 2H), 2.15 (dt, J = 19.3, 2.3 Hz, 1H), 1.86 – 1.63 (m, 6H), 1.56 – 1.48 (m, 1H), 1.06 – 0.92 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 215.5, 172.9, 135.9, 128.7, 128.7, 128.5, 66.3, 54.4, 45.9, 44.0, 40.2, 31.4, 28.3, 28.1, 27.0, 26.4, 21.8. IR (Neat Film, NaCl): 2940, 2868, 1728, 1456, 1174, 1166, 1146 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O3 [M]+: 298.1564, found 298.1578. Optical Rotation: [α]D21 –32.4 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 5.44, major = 6.53. 41q’ (exo): 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.31 (m, 5H), 5.14 (d, J = 12.3 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 3.01 (ddd, J = 11.7, 3.3, 1.4 Hz, 1H), 2.46 (h, J = 3.3 Hz, 1H), 2.35 – 2.25 (m, 3H), 2.14 (tdd, J = 11.6, 7.9, 1.6 Hz, 1H), 2.07 – 1.94 (m, 2H), 1.88 – 1.69 (m, 3H), 1.63 – 1.57 (m, 1H), 1.47 – 1.34 (m, 2H), 1.16 (ddd, J = 13.9, 9.1, 5.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.5, 173.1, 136.0, 128.8, 128.5, 128.5, 66.3, 53.6, 45.4, 42.7, 41.2, 32.0, 26.4, 25.3, 24.4, 22.3, 21.8. IR (Neat Film, NaCl): 2946, 2847, 1720, 1457, 1154 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O3 [M]+: 298.1564, found 298.1578. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 176 Optical Rotation: [α]D21 –5.1 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 7.01, major = 7.42. O H BnO2C Me 41r benzyl (3aR,6R,7S,7aS)-7-methyl-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41r) Prepared from 40r following General Procedure A. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a colorless oil (29.4 mg, 0.094 mmol, 47% yield, 89% ee). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 2.49 – 2.38 (m, 2H), 2.32 (dt, J = 18.9, 2.8 Hz, 1H), 2.19 – 2.10 (m, 2H), 2.01 – 1.92 (m, 1H), 1.85 – 1.66 (m, 4H), 1.65 – 1.55 (m, 1H), 1.49 – 1.31 (m, 5H), 1.13 (ddd, J = 14.5, 9.1, 6.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 215.2, 177.8, 136.1, 128.7, 128.4, 128.0, 66.8, 54.37, 45.8, 44.7, 43.4, 37.3, 26.5, 24.4, 24.1, 22.7, 22.4, 20.8. IR (Neat Film, NaCl): 2951, 2875, 1723, 1454, 1239, 1212, 1106 cm-1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1725, found 312.1732. Optical Rotation: [α]D21 –15.3 (c 1.00, CHCl3). SFC conditions: 40% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 2.68, major = 3.51. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 177 O Me H CO2Bn 41s benzyl (3aR,6R,7R,7aR)-6-methyl-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41s) Prepared from 40s following General Procedure A. Purification by flash column chromatography (0–25% EtOAc/hexanes) afforded the title compound as a colorless oil (43.6 mg, 0.140 mmol, 69% yield, 83% ee). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.29 (m, 5H), 5.13 (d, J = 1.1 Hz, 2H), 2.86 (dd, J = 18.5, 3.5 Hz, 1H), 2.37 (dd, J = 8.8, 1.4 Hz, 1H), 2.29 – 2.15 (m, 1H), 2.15 – 2.04 (m, 1H), 2.01 – 1.70 (m, 3H), 1.84 (dd, J = 18.7, 1.4 Hz, 1H), 1.68 – 1.36 (m, 4H), 1.30 – 1.15 (m, 2H), 0.94 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 214.5, 174.9, 135.9, 128.8, 128.5, 128.5, 66.7, 54.2, 52.6, 47.0, 44.9, 38.0, 36.0, 28.7, 26.3, 26.0, 23.8, 22.8. IR (Neat Film, NaCl): 2949, 2873, 1750, 1498, 1454, 1384, 1324, 1155, 1114, 977, 754, 698, 678, 556 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1703, found 312.1720. Optical Rotation: [α]D21 –68.2 (c 0.75, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 10.23, major = 12.31. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O EtO H CO2Bn 178 O EtO 41t (endo) H CO2Bn 41t’ (exo) benzyl (3aR,6S,7R,7aR)-6-ethoxy-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41t and 41t’) Prepared from 40t following General Procedure A. Purification by flash column chromatography (0–50% EtOAc/hexanes) afforded the title compounds as colorless oils (Endo: 44.0 mg, 0.128 mmol, 64% yield, 85% ee; Exo: 17.0 mg, 0.050 mmol, 25% yield, 72% ee). Absolute and relative stereochemistry were assigned/confirmed by VCD (see below). 41t (endo): 1 H NMR (400 MHz, CDCl3): δ 7.38 – 7.28 (m, 5H), 5.16 (d, J = 1.5 Hz, 2H), 3.55 – 3.32 (m, 2H), 3.17 (dd, J = 18.5, 3.1 Hz, 1H), 2.86 (dd, J = 8.5, 1.5 Hz, 1H), 2.38 – 2.25 (m, 2H), 2.16 – 2.02 (m, 1H), 2.02 – 1.86 (m, 3H), 1.87 – 1.39 (m, 5H), 1.20 (ddd, J = 14.1, 9.1, 5.1 Hz, 1H), 1.03 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 210.8, 173.7, 136.0, 128.7, 128.4, 128.3, 78.2, 66.8, 58.0, 54.2, 51.9, 45.1, 45.1, 30.7, 28.8, 25.8, 24.8, 22.9, 15.8. IR (Neat Film, NaCl): 2944, 2875, 1726, 1458, 1390, 1320, 1282, 1153, 1110, 1039, 746, 700 cm–1. HRMS (MM: FD+): m/z calc’d for C21H26O4 [M]+: 342.1832, found 342.1826. Optical Rotation: [α]D21 –47.4 (c 0.75, CHCl3). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 179 SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.73, major = 5.13. 41t’ (exo): 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.28 (m, 5H), 5.19 (d, J = 1.1 Hz, 2H), 3.57 – 3.35 (m, 2H), 2.69 (dd, J = 7.8, 1.7 Hz, 1H), 2.60 – 2.47 (m, 1H), 2.47 – 2.44 (m, 2H), 2.39 (ddd, J = 12.5, 7.9, 6.9 Hz, 1H), 2.28 (ddd, J = 13.5, 9.4, 4.6 Hz, 1H), 1.92 – 1.78 (m, 3H), 1.77 – 1.66 (m, 1H), 1.67 – 1.58 (m, 1H), 1.11 (ddd, J = 11.3, 6.6, 3.7 Hz, 1H), 1.03 (t, J = 6.9 Hz, 3H), 0.89 (tt, J = 12.4, 9.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 211.5, 173.4, 136.0, 128.7, 128.4, 128.3, 66.9, 58.1, 54.1, 52.8, 47.5, 46.8, 31,0, 27.7, 26.5, 25.9, 23.1, 15.7. IR (Neat Film, NaCl): 2946, 1721, 1451, 1390, 1328, 1154, 1117, 767, 698 cm–1. HRMS (MM: FD+): m/z calc’d for C21H26O4 [M]+: 342.1833, found 342.1826. Optical Rotation: [α]D21 +1.8 (c 0.75, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 3.29, major = 4.04. O Me H CO2Bn 41u benzyl (3aR,6R,7S,7aR)-5-methyl-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (41u) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 180 Prepared from 40u following General Procedure A. Purification by flash column chromatography (0–25% EtOAc/hexanes) afforded the title compound as a colorless oil (13.6 mg, 0.044 mmol, 22% yield, 61% ee). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.32 (m, 5H), 5.14 (ddd, J = 17.8, 12.2 Hz, 2H), 2.61 (dd, J = 3.7, 2.1 Hz, 1H), 2.45 – 2.30 (m, 3H), 2.21 – 2.06 (m, 4H), 1.90 – 1.63 (m, 3H), 1.61 – 1.35 (m, 2H), 1.32 – 1.16 (m, 1H), 0.97 (d, J = 7.7 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 217.7, 174.8, 135.9, 128.7, 128.6, 128.5, 66.8, 54.2, 48.3, 46.9, 42.2, 38.1, 29.7, 28.9, 26.6, 24.1, 22.5, 15.8. IR (Neat Film, NaCl): 2943, 2873, 1718, 1455, 1197, 1171 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1725, found 312.1730. Optical Rotation: [α]D21 +10.9 (c 0.75, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 5.84, major = 5.43. O D H CO2Bn D-41f benzyl (1S,2R,4aR,8aR)-4-oxooctahydro-2H-2,4a-ethanonaphthalene-1-carboxylate3-d (D-41f) Prepared from D-40f following General Procedure A. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a colorless oil (41.3 mg, 0.132 mmol, 66% yield, 91% ee). 181 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.30 (m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1H), 2.51 – 2.41 (m, 1.6H), 2.36 – 2.10 (m, 2.7H), 2.02 (dddd, J = 11.8, 9.1, 5.3, 2.9 Hz, 1H), 1.91 – 1.83 (m, 1H), 1.82 – 1.71 (m, 1H), 1.70 – 1.55 (m, 4H), 1.52 – 1.11 (m, 5H). 13 C NMR (100 MHz, CDCl3): δ 216.4, 174.5, 136.0, 128.8, 128.4, 128.2, 77.5, 77.2, 76.8, 66.7, 49.9, 45.1, 40.5, 37.1, 31.0, 30.9, 30.8, 30.0, 28.9, 26.2, 25.6, 21.8, 21.2. *Partial deuteration complicates 13C NMR spectrum. Peaks are listed as they appear. 2 H NMR (61 MHz, CHCl3): δ 2.46, 2.14. *Trace D-exchanged water observed in spectrum. IR (Neat Film, NaCl): 2928, 2858, 1723, 1169 cm-1. HRMS (MM: FD+): m/z calc’d for C20H23DO3 [M+H]+: 313.1783, found 313.1795. Optical Rotation: [α]D21 –21.3 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 5.07, major = 6.38. O O O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) O CO2Bn PhMe, 60 ºC CO2Bn 98% yield, 84% ee 42 44 benzyl (S,E)-6-(1-allyl-2-oxocyclohex-3-en-1-yl)hex-2-enoate (44) Prepared from 42 (0.02 mmol) following General Procedure A. Purification by preparatory thin layer chromatography (25% EtOAc/hexanes) afforded the title compound as a colorless oil (10.1 mg, 0.0196 mmol, 98% yield, 84 % ee). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 182 H NMR (400 MHz, CDCl3): δ 7.40 – 7.29 (m, 5H), 6.97 (dt, J = 15.6, 6.9 Hz, 1H), 6.85 (dt, J = 10.1, 3.9 Hz, 1H), 5.91 (dt, J = 10.0, 2.0 Hz, 1H), 5.85 (dt, J = 15.7, 1.6 Hz, 1H), 5.69 (ddt, J = 16.6, 10.5, 7.3 Hz, 1H), 5.17 (s, 2H), 5.09 – 5.00 (m, 2H), 2.41 – 2.29 (m, 3H), 2.26 – 2.13 (m, 3H), 1.87 (t, J = 6.1 Hz, 2H), 1.63 – 1.23 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 202.9, 166.6, 149.6, 148.7, 136.3, 134.0, 129.0, 128.7, 128.3, 128.3, 121.4, 118.3, 66.2, 47.6, 39.1, 33.9, 32.9, 30.8, 23.1, 22.4. IR (Neat Film, NaCl): 2936, 2358, 1718, 1669, 1262, 992 cm–1. HRMS (MM: FD+): m/z calc’d for C22H26O3 [M]+: 338.1881, found 338.1877. Optical Rotation: [α]D21 –0.69 (c 0.62, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 14.49, major = 11.94. O OBn O 83 benzyl (E)-7-(1-(2-cyclobutylideneethyl)-2-oxocyclohex-3-en-1-yl)hept-2- enoateenoate (83) Prepared from 63 following General Procedure A, with the modification of being on 0.1 mmol scale. Purification by preparatory thin layer chromatography (20% EtOAc/hexanes) afforded the title compound as a clear oil (2.4 mg, 0.006 mmol, 6% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.29 (m, 5H), 6.99 (dt, J = 15.6, 6.9 Hz, 1H), 6.83 (dt, J = 10.0, 3.9 Hz, 1H), 5.92 – 5.81 (m, 2H), 5.17 (s, 2H), 5.01 – 4.92 (m, 1H), 2.67 – Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 183 2.54 (m, 3H), 2.40 – 2.30 (m, 2H), 2.27 – 1.99 (m, 4H), 1.96 – 1.82 (m, 3H), 1.63 – 1.49 (m, 3H), 1.49 – 1.36 (m, 3H), 1.32 – 1.13 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 203.6, 166.6, 150.1, 148.5, 143.1, 136.3, 129.1, 128.7, 128.3, 128.3, 121.1, 115.4, 66.2, 48.3, 34.1, 33.1, 32.3, 31.2, 30.8, 29.6, 28.8, 23.6, 23.2, 17.1. IR (Neat Film, NaCl): 2929, 1720, 1670, 1185 cm–1. HRMS (MM: FD+): m/z calc’d for C26H32O3 [M]+: 392.2351, found 392.2341. Ph Ph 84 (2-vinylprop-1-ene-1,3-diyl)dibenzene (84) Prepared from 67 following General Procedure A, with the modification of being on 0.1 mmol scale. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a colorless oil (6.5 mg, 0.03 mmol, 29% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.18 (m, 11.5H), 6.91 – 6.80 (m, 1.15H), 6.56 (ddd, J = 17.4, 10.8, 0.9 Hz, 0.15H), 6.45 (s, 1H), 5.42 – 5.33 (m, 1H), 5.19 – 5.13 (m, 1.15H), 5.11 – 5.06 (m, 0.15H), 3.90 (s, 0.3H), 3.73 (s, 2H). *Isolated as an apparent 1:0.15 mixture of alkene isomers. 13 C NMR (100 MHz, CDCl3): δ 140.5, 140.2, 139.9, 137.7, 137.5, 137.3, 134.2, 133.8, 131.8, 129.6, 128.9, 128.8, 128.7, 128.5, 128.2, 128.2, 127.3, 127.0, 126.2, 126.1, 116.4, 114.8, 40.3, 33.2. *Isolated as an apparent 1:0.15 mixture of alkene isomers. IR (Neat Film, NaCl): 3060, 3023, 2919, 1601, 1493, 1455, 1165, 1074 cm–1. 184 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates HRMS (MM: FD+): m/z calc’d for C17H16 [M]+: 220.1252, found 220.1257. Preparation of Unsaturated b-Ketoester Starting Materials General Procedure B: Horner–Wadsworth–Emmons Olefination O O Me O Me O R1 n O (EtO)2P (1.1 equiv) O R2 O NaH (1.1 equiv) THF, 0 ºC O Me O R1 85 O n Me R2 40 To a suspension of NaH (60% by weight in mineral oil, 1.1 equiv) in THF (0.5 M) at 0 ºC was dropwise added a solution of the appropriate phosphonate ester (1.1 equiv) in THF (1.0 M). Stirred at 0 ºC was continued for 30 minutes. To the reaction was then dropwise added a solution of aldehyde 85 (1.0 equiv) in THF (0.5 M). Upon complete consumption of starting material (as determined by TLC), the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The product (10) was purified by silica gel flash column chromatography. O Me O O Me CO2Bn 40a 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3-ene1-carboxylate (40a) Prepared from 85 and benzyl 2-(diethoxyphosphoryl)acetate 28 following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (0.410 g, 1.00 mmol, 67 % yield). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 185 H NMR (400 MHz, CDCl3): δ 7.38 – 7.29 (m, 5H), 6.98 (dt, J = 15.7, 6.9 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.02 (ddd, J = 10.1, 2.5, 1.5 Hz, 1H), 5.87 (dt, J = 15.6, 1.6 Hz, 1H), 5.31 – 5.24 (m, 1H), 5.17 (s, 2H), 4.58 (dt, J = 7.2, 1.0 Hz, 2H), 2.55 – 2.41 (m, 2H), 2.37 – 2.27 (m, 1H), 2.22 (qd, J = 7.3, 1.6 Hz, 2H), 1.97 – 1.86 (m, 2H), 1.77 – 1.69 (m, 4H), 1.67 (d, J = 1.4 Hz, 3H), 1.55 – 1.38 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 166.5, 149.3, 149.3, 139.7, 136.3, 129.4, 128.7, 128.3, 128.3, 121.5, 118.3, 66.2, 62.3, 57.0, 33.5, 32.7, 30.5, 25.8, 23.9, 23.2, 18.2. IR (Neat Film, NaCl): 3034, 2938, 1723, 1684, 1653, 1455, 1384, 1246, 1174, 1166 cm– 1 . HRMS (MM: FD+): m/z calc’d for C25H30O5 [M]+: 410.2088, found 410.2097. O Me O O Me CO2Et 40b 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3-ene1-carboxylate (40b) Prepared from 85 and ethyl 2-(diethoxyphosphoryl)acetate following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (0.291 g, 0.835 mmol, 47 % yield). 1 H NMR (400 MHz, CDCl3): δ 6.97 – 6.85 (m, 2H), 6.02 (ddd, J = 10.0, 2.6, 1.5 Hz, 1H), 5.81 (dt, J = 15.6, 1.6 Hz, 1H), 5.31 – 5.24 (m, 1H), 4.64 – 4.54 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 2.55 – 2.41 (m, 2H), 2.37 – 2.27 (m, 1H), 2.21 (qd, J = 7.3, 1.6 Hz, 2H), 1.98 – Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 186 1.87 (m, 2H), 1.78 – 1.69 (m, 4H), 1.68 (s, 3H), 1.55 – 1.37 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 166.8, 149.3, 148.5, 139.7, 129.4, 121.8, 118.3, 62.3, 60.3, 57.0, 33.5, 32.6, 30.5, 25.8, 23.9, 23.3, 18.2, 14.4. IR (Neat Film, NaCl): 2934, 1714, 1682, 1168 cm–1. HRMS (MM: FD+): m/z calc’d for C20H28O5 [M]+: 348.1937, found 348.1943. O Me O O Me CO2Bn 40d 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohept-3- ene-1-carboxylate (40d) Prepared from cyclohept-2-en-1-one following General Procedures B–D. Note that inseparable impurities plagued the b-ketoester and aldehyde intermediates. Fortunately, these intermediates could be brought through the sequence in sub-optimal purity to still afford the title compound 40d as a colorless oil (265 mg, 0.62 mmol, 3.2% yield from cyclohept-2-en-1-one) after a final purification by flash column chromatography (20% EtOAc/hexanes). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.30 (m, 5H), 6.97 (dt, J = 15.6, 6.9 Hz, 1H), 6.36 (ddd, J = 12.3, 5.5, 3.9 Hz, 1H), 5.98 (ddd, J = 12.3, 2.4, 1.4 Hz, 1H), 5.86 (dt, J = 15.6, 1.6 Hz, 1H), 5.28 (ddp, J = 8.6, 5.7, 1.4 Hz, 1H), 5.17 (s, 2H), 4.57 (d, J = 7.2 Hz, 2H), 2.47 – 2.27 (m, 3H), 2.19 (qd, J = 7.2, 1.6 Hz, 2H), 1.99 – 1.79 (m, 3H), 1.77 – 1.69 (m, 4H), 1.69 – 1.61 (m, 4H), 1.43 – 1.32 (m, 2H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 187 C NMR (100 MHz, CDCl3): δ 201.1, 172.9, 166.5, 149.3, 143.2, 139.7, 136.3, 131.6, 128.7, 128.3, 128.3, 121.5, 118.2, 66.2, 63.9, 62.2, 36.5, 32.6, 32.3, 31.2, 25.8, 24.3, 23.0, 18.2. IR (Neat Film, NaCl): 2927, 1720, 1686, 1453, 1162 cm–1. HRMS (MM: FD+): m/z calc’d for C26H32O5 [M]+: 424.2244, found 424.2241. O Me O O Me CO2Bn 40f 3-methylbut-2-en-1-yl (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2-oxocyclohex-3- ene-1-carboxylate (40f) Prepared from 86 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (15–20% EtOAc/hexanes) afforded the title compound as a colorless oil (652 mg, 1.54 mmol, 69% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.30 (m, 5H), 6.99 (ddd, J = 15.5, 7.3, 6.3 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.01 (d, J = 10.1 Hz, 1H), 5.85 (d, J = 15.6 Hz, 1H), 5.30 – 5.25 (m, 1H), 5.17 (s, 2H), 4.58 (d, J = 6.6 Hz, 2H), 2.55 – 2.40 (m, 2H), 2.36 – 2.26 (m, 1H), 2.24 – 2.16 (m, 2H), 1.96 – 1.86 (m, 2H), 1.77 – 1.65 (m, 7H), 1.47 (p, J = 7.4 Hz, 2H), 1.38 – 1.24 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.2, 171.6, 166.5, 149.7, 149.2, 139.4, 136.2, 129.2, 128.6, 128.2, 128.2, 121.1, 118.2, 66.0, 62.1, 56.9, 33.5, 32.0, 30.2, 28.4, 25.7, 24.2, 23.7, 18.1. IR (Neat Film, NaCl): 2932, 2861, 1722, 1684, 1653, 1456, 1263, 1181 cm–1. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 188 HRMS (MM: FD+): m/z calc’d for C26H32O5 [M]+: 424.2244, found 424.2247. O O CD3 O CD3 CO2Bn D-40f 3-(methyl-d3)but-2-en-1-yl-4,4,4-d3 (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2- oxocyclohex-3-ene-1-carboxylate (D-40f) Prepared from D-86 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (15–20% EtOAc/hexanes) afforded the title compound as a colorless oil (201 mg, 0.467 mmol, 48 % yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.30 (m, 5H), 6.99 (dt, J = 15.6, 6.9 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.01 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H), 5.85 (dt, J = 15.6, 1.5 Hz, 1H), 5.27 (t, J = 7.1 Hz, 1H), 5.17 (s, 2H), 4.58 (dd, J = 7.2, 1.7 Hz, 2H), 2.55 – 2.41 (m, 2H), 2.36 – 2.27 (m, 1H), 2.25 – 2.15 (m, 2H), 1.98 – 1.85 (m, 2H), 1.73 (ddd, J = 13.6, 11.2, 5.3 Hz, 1H), 1.51 – 1.42 (m, 2H), 1.37 – 1.25 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.7, 166.6, 149.8, 149.3, 139.4, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 118.4, 66.2, 62.3, 57.0, 33.6, 32.2, 30.3, 28.5, 24.3, 23.9. 2 H NMR (61 MHz, CHCl3): δ 1.69, 1.65. IR (Neat Film, NaCl): 2930, 1720, 1683, 1264, 1167 cm–1. HRMS (MM: FD+): m/z calc’d for C26H26D6O5 [M]+: 430.2621, found 430.2622. O Me O Me O CO2Bn 40g Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 189 3-methylbut-2-en-1-yl (E)-1-(8-(benzyloxy)-8-oxooct-6-en-1-yl)-2-oxocyclohex-3-ene1-carboxylate (40g) Prepared from 87 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (773 mg, 1.76 mmol, 65 % yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.29 (m, 5H), 6.99 (dt, J = 15.6, 6.9 Hz, 1H), 6.89 – 6.84 (m, 1H), 6.01 (ddd, J = 10.0, 2.5, 1.5 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.28 (ddp, J = 8.6, 5.7, 1.4 Hz, 1H), 5.17 (s, 2H), 4.63 – 4.53 (m, 2H), 2.55 – 2.40 (m, 2H), 2.36 – 2.26 (m, 1H), 2.19 (qd, J = 7.1, 1.6 Hz, 2H), 1.98 – 1.84 (m, 2H), 1.77 – 1.69 (m, 4H), 1.67 (s, 3H), 1.49 – 1.41 (m, 2H), 1.36 – 1.23 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 196.5, 171.7, 166.6, 150.1, 149.3, 139.5, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 118.4, 66.2, 62.2, 57.1, 33.7, 32.3, 30.3, 29.6, 27.8, 25.8, 24.4, 23.9, 18.2. IR (Neat Film, NaCl): 2929, 2858, 1721, 1684, 1654, 1456, 1264, 1168 cm–1. HRMS (MM: FD+): m/z calc’d for C27H34O5 [M]+: 438.2401, found 438.2396. O Me O O Me CO2Ph 40k 3-methylbut-2-en-1-yl (E)-2-oxo-1-(6-oxo-6-phenoxyhex-4-en-1-yl)cyclohex-3-ene-1carboxylate (40k) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 190 Prepared from 85 and benzyl 2-(diethoxyphosphoryl)acetate 29 following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (409 mg, 1.03 mmol, 57 % yield). 1 H NMR (400 MHz, CDCl3): δ 7.38 (t, J = 8.0 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 – 7.10 (m, 3H), 6.91 – 6.87 (m, 1H), 6.05 – 6.00 (m, 2H), 5.29 (tt, J = 7.1, 1.3 Hz, 1H), 4.61 (d, J = 7.1 Hz, 2H), 2.56 – 2.44 (m, 2H), 2.37 – 2.27 (m, 3H), 2.00 – 1.92 (m, 2H), 1.82 – 1.73 (m, 4H), 1.69 (s, 3H), 1.63 – 1.46 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 165.1, 150.9, 150.9, 149.3, 139.7, 129.5, 129.4, 125.8, 121.8, 121.1, 118.3, 62.4, 57.0, 33.6, 32.8, 30.5, 25.8, 23.9, 23.2, 18.2. IR (Neat Film, NaCl): 2930, 1732, 1684, 1652, 1458, 1245, 1195 cm–1. HRMS (MM: FD+): m/z calc’d for C24H28O5 [M]+: 396.1931, found 396.1945. O Me O O Me CO2Mes 40l 3-methylbut-2-en-1-yl (E)-1-(6-(mesityloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3- ene-1-carboxylate (40l) Prepared from 85 and mesityl 2-(diethoxyphosphoryl)acetate 30 following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (597 mg, 1.36 mmol, 76% yield). 1 H NMR (400 MHz, CDCl3): δ 7.17 (dt, J = 15.7, 6.8 Hz, 1H), 6.92 – 6.84 (m, 3H), 6.09 – 6.01 (m, 2H), 5.32 – 5.26 (m, 1H), 4.61 (d, J = 5.6 Hz, 2H), 2.57 – 2.43 (m, 2H), 2.39 – Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 191 2.27 (m, 3H), 2.26 (s, 3H), 2.09 (s, 6H), 2.01 – 1.92 (m, 2H), 1.79 (ddd, J = 13.6, 11.9, 4.8 Hz, 1H), 1.73 (s, 3H), 1.69 (s, 3H), 1.64 – 1.46 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 164.6, 150.7, 149.3, 146.0, 139.7, 135.3, 130.0, 129.4, 129.3, 120.7, 118.3, 62.4, 57.0, 33.6, 32.8, 30.5, 25.8, 23.9, 23.2, 20.9, 18.2, 16.4. IR (Neat Film, NaCl: 2920, 1733, 1684, 1458, 1248, 1192, 1140 cm–1. HRMS (MM: FD+): m/z calc’d for C27H34O5 [M]+: 438.2401, found 438.2401. O Me O Me O N Cbz CO2Bn 40n 1-benzyl 3-(3-methylbut-2-en-1-yl) (E)-3-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-4-oxo3,4-dihydropyridine-1,3(2H)-dicarboxylate (40n) Prepared from 88 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (20-30% EtOAc/hexanes) afforded the title compound as a colorless oil (181.3 mg, 0.332 mmol, 55% yield). 1 H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.44 – 7.28 (m, 10H), 6.94 (dt, J = 15.5, 6.8 Hz, 1H), 5.85 (dt, J = 15.7, 1.6 Hz, 1H), 5.42 – 5.21 (m, 4H), 5.17 (s, 2H), 4.67 – 4.51 (m, 3H), 3.71 (d, J = 13.6 Hz, 1H), 2.20 (q, J = 7.3 Hz, 2H), 2.07 – 1.92 (m, 1H), 1.69 – 1.58 (m, 1H), 1.71 (s, 3H), 1.66 (s, 3H), 1.49 – 1.40 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 190.5, 169.5, 166.4, 148.7, 142.7, 140.1, 136.2, 135.0, 129.0, 128.9, 128.7, 128.6, 128.4, 128.3, 121.7, 118.0, 106.5, 69.4, 66.2, 62.8, 55.3, 48.3, 32.4, 31.3, 25.8, 23.0, 18.2. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 192 IR (Neat Film, NaCl): 2938, 2338, 1726, 1676, 1604, 1456, 1388, 1303, 1201, 975 cm–1. HRMS (MM: FD+): m/z calc’d for C32H35NO7 [M]+: 545.2414, found 545.2408. O Me O O O Me O N O 40o 3-methylbut-2-en-1-yl (E)-2-oxo-1-(6-oxo-6-(2-oxooxazolidin-3-yl)hex-4-en-1- yl)cyclohex-3-ene-1-carboxylate (40o) Prepared from 85 and diethyl (2-oxo-2-(2-oxooxazolidin-3-yl)ethyl)phosphonate 31 following General Procedure B. Purification by flash column chromatography (0-80% EtOAc/hexanes) afforded the title compound as a colorless oil (275.1 mg, 0.706 mmol, 71% yield). 1 H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 15.6 Hz, 1H), 7.12 (dt, J = 15.4, 6.7 Hz, 1H), 6.87 (ddd, J = 7.8, 6.0, 3.9 Hz, 1H), 6.01 (dt, J = 10.3, 2.0 Hz, 1H), 5.28 (tt, J = 7.2, 1.3 Hz, 1H), 4.62 – 4.54 (m, 2H), 4.41 (dd, J = 8.5, 7.6 Hz, 2H), 4.11 – 4.02 (m, 2H), 2.55 – 2.40 (m, 2H), 2.38 – 2.25 (m, 3H), 2.00 – 1.86 (m, 2H), 1.82 – 1.69 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H), 1.50 (dtd, J = 17.3, 12.4, 7.6 Hz, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 165.3, 153.6, 150.9, 149.4, 139.6, 129.3, 120.5, 118.3, 62.3, 62.2, 57.0, 42.8, 33.4, 33.1, 30.3, 25.8, 23.9, 23.3, 18.2. IR (Neat Film, NaCl): 2927, 1774, 1724, 1684, 1636, 1385, 1359, 1222, 1042 cm–1. HRMS (MM: FD+): m/z calc’d for C21H27NO6 [M]+: 389.1838, found 389.1827. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O 193 Me O Me O CO2Bn Me 40r 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-5-methyl-6-oxohex-4-en-1-yl)-2- oxocyclohex-3-ene-1-carboxylate (40r) Prepared from 85 and benzyl 2-(diethoxyphosphoryl)propanoate 32 following General Procedure B. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a colorless oil (220 mg, 0.518 mmol, 29% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 6.87 (dddd, J = 10.1, 4.9, 3.0, 1.1 Hz, 1H), 6.78 (tq, J = 7.5, 1.5 Hz, 1H), 6.01 (ddd, J = 10.1, 2.5, 1.5 Hz, 1H), 5.31 – 5.24 (m, 1H), 5.18 (s, 2H), 4.58 (d, J = 6.9 Hz, 2H), 2.55 – 2.41 (m, 2H), 2.36 – 2.26 (m, 1H), 2.19 (qd, J = 7.5, 1.1 Hz, 2H), 1.98 – 1.87 (m, 2H), 1.85 (s, 3H), 1.79 – 1.69 (m, 4H), 1.67 (s, 3H), 1.53 – 1.37 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 168.0, 149.3, 142.3, 139.6, 136.5, 129.3, 128.6, 128.2, 128.1, 128.1, 118.3, 66.3, 62.3, 57.0, 33.7, 30.4, 29.2, 25.8, 23.9, 23.9, 18.2, 12.6. IR (Neat Film, NaCl): 2930, 1711, 1686, 1452, 1265, 1180 cm–1. HRMS (MM: FD+): m/z calc’d for C26H32O5 [M]+: 424.2250, found 424.2250. O Me O O Me Me CO2Bn 40s Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 3-methylbut-2-en-1-yl 194 (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-4-methyl-2- oxocyclohex-3-ene-1-carboxylate (40s) Prepared from 89 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (15–20–25% EtOAc/hexanes) afforded the title compound as a colorless oil (827.2 mg, 2.16 mmol, 64% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.28 (m, 5H), 6.98 (dt, J = 15.6, 6.8 Hz, 1H), 5.87 (dq, J = 2.7, 1.3 Hz, 1H), 5.86 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (tp, J = 7.1, 1.4 Hz, 1H), 5.16 (s, 2H), 4.64 – 4.51 (m, 2H), 2.52 – 2.36 (m, 2H), 2.28 – 2.14 (m, 3H), 1.98 – 1.83 (m, 5H), 1.72 (s, 4H), 1.67 (s, 3H), 1.54 – 1.34 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 195.9, 171.7, 166.5, 161.4, 149.3, 139.6, 136.3, 128.7, 128.3, 128.3, 126.1, 121.5, 118.4, 66.2, 62.3, 55.9, 33.5, 32.7, 30.2, 28.8, 25.8, 24.2, 23.3, 18.2. IR (Neat Film, NaCl): 3032, 2938, 1723, 1674, 1438, 1379, 1264, 1212, 1168, 1013, 741, 698 cm–1. HRMS (MM: FD+): m/z calc’d for C26H32O5 [M]+: 424.2235, found 424.2244. O Me O O EtO Me CO2Bn 40t 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-4-ethoxy-2- oxocyclohex-3-ene-1-carboxylate (40t) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 195 Prepared from 90 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (30% EtOAc/hexanes) afforded the title compound as a colorless oil (814.7 mg, 1.79 mmol, 88% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.28 (m, 5H), 6.98 (dt, J = 15.6, 6.8 Hz, 1H), 5.86 (dt, J = 15.7, 1.6 Hz, 1H), 5.34 (d, J = 1.2 Hz, 1H), 5.28 (dddt, J = 7.0, 5.6, 2.8, 1.4 Hz, 1H), 5.16 (s, 2H), 4.66 – 4.52 (m, 2H), 3.89 (qd, J = 7.1, 1.6 Hz, 2H), 2.61 (dddd, J = 17.9, 10.1, 4.9, 1.2 Hz, 1H), 2.46 – 2.27 (m, 2H), 2.21 (qd, J = 7.3, 1.6 Hz, 2H), 2.02 – 1.83 (m, 2H), 1.82 – 1.72 (m, 1H), 1.71 (s, 3H), 1.67 (s, 3H), 1.45 (dddd, J = 13.3, 11.2, 6.4, 2.7 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 195.8, 176.6, 171.8, 166.5, 149.4, 139.5, 136.3, 128.7, 128.3, 128.3, 121.4, 118.5, 102.3, 66.2, 64.5, 62.3, 56.0, 33.8, 32.7, 28.7, 26.6, 25.8, 23.3, 18.2, 14.3. IR (Neat Film, NaCl): 2939, 1721, 1655, 1608, 1446, 1380, 1314, 1242, 1190, 1026, 736 cm–1. HRMS (MM: FD+): m/z calc’d for C27H34O6 [M]+: 454.2349, found 454.2350. O Me Me O O Me CO2Bn 40u 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-3-methyl-2- oxocyclohex-3-ene-1-carboxylate (40u) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 196 Prepared from 91 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (1176.8 mg, 2.77 mmol, 71% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.26 (m, 5H), 6.98 (dt, J = 15.6, 6.8 Hz, 1H), 6.59 (ddt, J = 4.7, 3.1, 1.3 Hz, 1H), 5.87 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (tdq, J = 7.1, 2.8, 1.5 Hz, 1H), 5.17 (s, 2H), 4.57 (d, J = 6.7 Hz, 2H), 2.50 – 2.36 (m, 2H), 2.33 – 2.16 (m, 3H), 1.98 – 1.83 (m, 2H), 1.78 (q, J = 1.7 Hz, 3H), 1.77 – 1.64 (m, 1H), 1.72 (s, 3H), 1.67 (s, 3H) 1.61 – 1.34 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 197.0, 171.9, 166.5, 149.4, 143.8, 139.6, 136.3, 135.4, 128.7, 128.3, 128.3, 121.5, 118.3, 66.2, 62.2, 56.9, 33.6, 32.7, 30.9, 25.8, 23.6, 23.4, 18.2, 16.6. IR (Neat Film, NaCl): 2921, 1721, 1677, 1450, 1377, 1248, 1168, 728 cm–1. HRMS (MM: FD+): m/z calc’d for C26H32O5 [M]+: 424.2244, found 424.2244. O O O CO2Bn 42 allyl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3-ene-1-carboxylate (42) Prepared from 92 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (20–25% EtOAc/hexanes) afforded the title compound as a colorless oil (599.1 mg, 1.41 mmol, 46% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.26 (m, 5H), 6.98 (dt, J = 15.6, 6.9 Hz, 1H), 6.89 (dddd, J = 10.1, 4.8, 3.1, 1.0 Hz, 1H), 6.03 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 5.93 – 5.77 (m, Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 197 2H), 5.27 (dq, J = 17.2, 1.5 Hz, 1H), 5.21 (dq, J = 10.4, 1.3 Hz, 1H), 5.17 (s, 2H), 4.60 (dq, J = 5.6, 1.6 Hz, 2H), 2.57 – 2.42 (m, 2H), 2.39 – 2.27 (m, 1H), 2.22 (qd, J = 7.3, 1.6 Hz, 2H), 2.02 – 1.87 (m, 2H), 1.77 (ddd, J = 13.7, 11.7, 5.2 Hz, 1H), 1.57 – 1.40 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.0, 171.2, 166.5, 149.5, 149.1, 136.2, 131.7, 129.3, 128.7, 128.3, 128.3, 127.8, 127.1, 121.6, 118.7, 66.2, 65.9, 57.0, 33.4, 32.6, 30.3, 23.8, 23.2. IR (Neat Film, NaCl): 2937, 2357, 1723, 1684, 1456, 1262, 1165, 992 cm–1. HRMS (MM: FD+): m/z calc’d for C23H27O5 [M]+: 383.1871, found 383.1853. O O O Ph CO2Bn 47 cinnamyl 1-((E)-6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3-ene-1- carboxylate (47) Prepared from 93 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (569 mg, 1.24 mmol, 67% yield). 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.34 (m, 6H), 7.34 – 7.29 (m, 3H), 7.27 – 7.24 (m, 1H), 6.97 (dt, J = 15.6, 6.9 Hz, 1H), 6.89 (dddd, J = 10.1, 4.8, 3.1, 1.0 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.22 (dt, J = 15.9, 6.4 Hz, 1H), 6.04 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 5.86 (dt, J = 15.7, 1.6 Hz, 1H), 5.16 (s, 2H), 4.76 (dt, J = 6.4, 1.4 Hz, 2H), 2.56 – 2.45 (m, 2H), 2.37 – 2.28 (m, 1H), 2.22 (ddd, J = 7.4, 7.4, 1.6 Hz, 2H), 1.95 (ddt, J = 16.8, 7.9, 5.7 Hz, 2H), 1.78 (ddd, J = 13.7, 11.7, 5.0 Hz, 1H), 1.56 – 1.42 (m, 2H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 198 C NMR (100 MHz, CDCl3): δ 196.0, 171.4, 166.5, 149.5, 149.1, 136.2, 136.2, 134.7, 129.3, 128.7, 128.7, 128.3, 128.3, 126.8, 122.6, 121.6, 66.2, 65.9, 57.0, 33.4, 32.6, 30.3, 23.8, 23.2. IR (Neat Film, NaCl): 3034, 2942, 1718, 1700, 1684, 1247, 1166 cm–1 HRMS (MM: FD+): m/z calc’d for C29H30O5 [M]+: 458.2088, found 458.2082. O O O OBn 63 O 22-cyclobutylideneethyl (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2-oxocyclohex-3ene-1-carboxylatecarboxylate (63) Prepared from 94 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (5–60% EtOAc/hexanes) afforded the title compound as a colorless oil (354 mg, 0.81 mmol, 39.8% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.29 (m, 5H), 6.99 (dt, J = 14.9, 1.0 Hz, 1H), 6.91 – 6.84 (m, 1H), 6.02 (d, J = 1.2 Hz, 1H), 5.86 (d, J = 15.7 Hz, 1H), 5.24 – 5.13 (m, 3H), 4.51 – 4.41 (m, 2H), 2.75 – 2.62 (m, 4H), 2.56 – 2.39 (m, 2H), 2.36 – 2.27 (m, 1H), 2.25 – 2.16 (m, 2H), 2.02 – 1.84 (m, 4H), 1.73 (ddd, J = 13.6, 11.2, 5.3 Hz, 1H), 1.47 (p, J = 7.5 Hz, 2H), 1.40 – 1.23 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.6, 166.6, 149.8, 149.3, 148.8, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 114.0, 66.2, 62.3, 57.1, 33.6, 32.2, 31.2, 30.3, 29.6, 28.5, 24.3, 23.9, 17.1. IR (Neat Film, NaCl): 2945, 1722, 1687, 1446, 1169 cm–1. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 199 HRMS (MM: FD+): m/z calc’d for C27H32O5 [M]+: 436.2250, found 436.2222. O O O OBn 64 O 2-cyclopentylideneethyl (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2-oxocyclohex-3ene-1-carboxylate (64) Prepared from 95 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (1.40 g, 4.41 mmol, 38.9% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.28 (m, 5H), 6.99 (dt, J = 15.6, 6.9 Hz, 1H), 6.91 – 6.83 (m, 1H), 6.01 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.37 (tp, J = 7.0, 2.2 Hz, 1H), 5.17 (s, 2H), 4.60 – 4.53 (m, 2H), 2.56 – 2.39 (m, 2H), 2.37 – 2.15 (m, 7H), 1.98 – 1.85 (m, 2H), 1.78 – 1.54 (m, 5H), 1.53 – 1.41 (m, 2H), 1.40 – 1.22 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.7, 166.6, 151.1, 149.8, 149.3, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 113.8, 66.2, 63.7, 57.1, 33.9, 33.6, 32.2, 30.3, 29.0, 28.5, 26.4, 26.2, 24.3, 23.9. IR (Neat Film, NaCl): 2946, 1719, 1686, 1457, 1165 cm–1. HRMS (MM: FD+): m/z calc’d for C28H34O5 [M]+: 450.2406, found 450.2394. O O O OBn 65 O Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 2-cyclohexylideneethyl 200 (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2-oxocyclohex-3- ene-1-carboxylate (65) Prepared from 96 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (81 mg, 0.17 mmol, 32.9% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.27 (m, 5H), 6.99 (dt, J = 15.6, 6.9 Hz, 1H), 6.87 (dddd, J = 10.1, 5.2, 2.5, 1.1 Hz, 1H), 6.01 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.23 (tp, J = 7.3, 1.2 Hz, 1H), 5.17 (s, 2H), 4.59 (d, J = 7.2 Hz, 2H), 2.56 – 2.39 (m, 2H), 2.36 – 2.26 (m, 1H), 2.25 – 2.13 (m, 4H), 2.12 – 2.03 (m, 2H), 1.98 – 1.84 (m, 2H), 1.78 – 1.66 (m, 1H), 1.63 – 1.42 (m, 8H), 1.41 – 1.21 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.6, 166.6, 149.8, 149.3, 147.7, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 114.9, 66.2, 61.5, 57.0, 37.1, 33.6, 32.2, 30.4, 29.2, 28.5, 28.5, 27.9, 26.7, 24.3, 23.9. IR (Neat Film, NaCl): 2929, 2853, 1723, 1681, 1456, 1385, 1266, 1184 cm–1. HRMS (MM: FD+): m/z calc’d for C29H36O5 [M]+: 464.2563, found 464.2543. O O O OBn 66 O 2-cycloheptylideneethyl (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2-oxocyclohex-3ene-1-carboxylate (66) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 201 Prepared from 97 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (5–70% EtOAc/hexanes) afforded the title compound as a colorless oil (135 mg, 0.28 mmol, 30% yield). 1 H NMR (400 MHz, CDCl3): δ 7.43 – 7.29 (m, 5H), 6.99 (dt, J = 15.7, 6.9 Hz, 1H), 6.91 – 6.82 (m, 1H), 6.01 (ddd, J = 10.2, 2.6, 1.5 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (tt, J = 7.1, 1.3 Hz, 1H), 5.17 (s, 2H), 4.59 (d, J = 7.1 Hz, 2H), 2.57 – 2.39 (m, 2H), 2.36 – 2.16 (m, 7H), 1.98 – 1.84 (m, 2H), 1.73 (ddd, J = 13.6, 11.3, 5.2 Hz, 1H), 1.61 – 1.43 (m, 10H), 1.31 (dddd, J = 13.2, 11.8, 8.6, 6.2 Hz, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.7, 166.6, 149.8, 149.3, 149.0, 136.3, 129.4, 128.7, 128.3, 128.3, 121.2, 118.4, 66.2, 62.0, 57.0, 37.7, 33.6, 32.2, 30.4, 30.2, 29.8, 29.1, 28.9, 28.5, 27.3, 24.3, 23.9. IR (Neat Film, NaCl): 2919, 2361, 1722, 1682, 1651, 1443, 1234, 1187 cm–1. HRMS (MM: FD+): m/z calc’d for C30H38O5 [M]+: 478.2719, found 478.2716. O Ph O Ph O OBn 67 3-benzyl-4-phenylbut-2-en-1-yl O (E)-1-(7-(benzyloxy)-7-oxohept-5-en-1-yl)-2- oxocyclohex-3-ene-1-carboxylate (67) Prepared from 98 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (5–70% EtOAc/hexanes) afforded the title compound as a colorless oil (205 mg, 0.36 mmol, 39% yield). 202 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.24 (m, 9H), 7.23 – 7.17 (m, 2H), 7.09 (dd, J = 11.6, 7.3 Hz, 4H), 6.98 (dt, J = 15.6, 6.9 Hz, 1H), 6.89 – 6.80 (m, 1H), 6.02 (d, J = 10.1 Hz, 1H), 5.85 (d, J = 16.1 Hz, 1H), 5.51 (t, J = 7.2 Hz, 1H), 5.17 (s, 2H), 4.83 – 4.69 (m, 2H), 3.36 (s, 2H), 3.23 (s, 2H), 2.55 – 2.40 (m, 2H), 2.37 – 2.24 (m, 1H), 2.18 (q, J = 7.2 Hz, 2H), 2.00 – 1.85 (m, 2H), 1.75 (ddd, J = 13.5, 11.1, 5.2 Hz, 1H), 1.46 (p, J = 7.4 Hz, 1H), 1.38 – 1.22 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.2, 171.6, 166.6, 149.8, 149.3, 144.8, 139.0, 138.8, 136.3, 129.4, 129.3, 128.8, 128.7, 128.7, 128.5, 128.3, 128.3, 126.5, 126.4, 121.7, 121.3, 66.2, 61.9, 57.1, 42.9, 35.8, 33.6, 32.1, 30.3, 28.5, 24.3, 23.9. IR (Neat Film, NaCl): 3027, 2931, 1722, 1682, 1493, 1387, 1264, 1165 cm–1. HRMS (MM: FD+): m/z calc’d for C38H40O5 [M]+: 576.2876, found 576.2857. O O Me O Me O O P OEt Zn(OTf)2 (2.2 equiv) TMEDA (0.63 equiv) HO DBU (4 equiv) (1 equiv) OEt O Me O O THF, 23 ºC, 18 h Me OH O 85 O 40i (E)-6-(1-(((3-methylbut-2-en-1-yl)oxy)carbonyl)-2-oxocyclohex-3-en-1-yl)hex-2-enoic acid (40i)33 To a suspension of Zn(OTf)2 (6.6 mmol, 2.2 equiv) in THF (15 mL) was added (diethoxyphosphinyl)acetic acid (3 mmol, 1 equiv), followed by the addition of TMEDA (1.89 mmol, 0.63 equiv), DBU (12 mmol, 4 equiv), and then a solution of aldehyde 85 (3 mmol, 1 equiv) in THF (2 mL). The solution was stirred at 23 ºC for 18 h, and the reaction was diluted with 1 M HCl and extracted with dichloromethane (4x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 203 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Purification by silica gel flash column chromatography (35% EtOAc/hexanes with 3% AcOH) afforded the title compound as a white solid (137.4 mg, 0.43 mmol, 43% yield). 1 H NMR (400 MHz, CDCl3): δ 7.04 (dt, J = 15.7, 6.8 Hz, 1H), 6.93 – 6.84 (m, 1H), 6.03 (ddd, J = 10.2, 2.6, 1.5 Hz, 1H), 5.83 (dt, J = 15.6, 1.6 Hz, 1H), 5.28 (tp, J = 7.2, 1.4 Hz, 1H), 4.66 – 4.53 (m, 2H), 2.58 – 2.40 (m, 2H), 2.37 – 2.28 (m, 1H), 2.25 (qd, J = 7.3, 1.6 Hz, 2H), 1.98 – 1.87 (m, 2H), 1.80 – 1.68 (m, 1H), 1.73 (s, 3H), 1.68 (s, 3H), 1.61 – 1.37 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 171.6, 170.2, 151.4, 149.3, 139.7, 129.4, 120.8, 118.3, 62.4, 57.0, 33.5, 32.7, 30.5, 25.8, 23.9, 23.1, 18.2. IR (Neat Film, NaCl): 2929, 1725, 1694, 1424, 1384, 1236, 1171 cm–1. HRMS (MM: FD+): m/z calc’d for C18H24O5 [M]+: 320.1624, found 320.1636. O Me O O O Me NHP (2 equiv) DMAP (1.1 equiv) NEt3 (1.1 equiv) EDC•HCl (1.1 equiv) O Me O O O Me CH2Cl2, 23 ºC, 12 h NHP OH 40i 40m 3-methylbut-2-en-1-yl (E)-1-(6-((1,3-dioxoisoindolin-2-yl)oxy)-6-oxohex-4-en-1-yl)-2oxocyclohex-3-ene-1-carboxylate (40m)34 To a round bottom flask was added crude acid 40i (assumed quantitative yield from previous reaction, 1 mmol, 1 equiv), DMAP (1.1 mmol, 1.1 equiv), NHP (2 mmol, 2 equiv), dichloromethane (9.5 mL), and triethylamine (1.1 mmol, 1.1 equiv). EDC•HCl (1.1 mmol, 1.1 equiv) was then added under N2 atmosphere in a single portion, and the reaction was stirred vigorously at 23 ºC for 12 h. The reaction mixture was diluted with dichloromethane and washed with 0.5 N HCl, saturated aqueous NaHCO3, and brine. The combined organic 204 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (30–35% EtOAc/hexanes) afforded the title compound as a colorless oil (109.6 mg, 0.48 mmol, 24% yield over two steps). 1 H NMR (400 MHz, CDCl3): δ 7.96 – 7.84 (m, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 7.30 (dd, J = 15.8, 6.7 Hz, 1H), 6.89 (dddd, J = 10.1, 4.9, 3.0, 1.1 Hz, 1H), 6.10 (dt, J = 15.8, 1.6 Hz, 1H), 6.04 (ddd, J = 10.1, 2.5, 1.5 Hz, 1H), 5.29 (tdt, J = 5.7, 2.8, 1.4 Hz, 1H), 4.67 – 4.55 (m, 2H), 2.58 – 2.40 (m, 2H), 2.35 (m, 3H), 2.03 – 1.89 (m, 2H), 1.87 – 1.74 (m, 1H), 1.74 (s, 3H), 1.69 (d, J = 1.3 Hz, 3H), 1.66 – 1.45 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.2, 162.4, 162.2, 155.2, 149.3, 139.8, 134.8, 129.4, 129.1, 124.1, 118.3, 116.0, 62.4, 57.0, 33.5, 33.3, 30.6, 25.9, 23.9, 23.0, 18.3. IR (Neat Film, NaCl): 1771, 1744, 1682, 1185 cm–1. HRMS (MM: FD+): m/z calc’d for C26H27NO7 [M]+: 465.1788, found 465.1779. O t-Bu Me O Me O O 85 O P O O O OBn t-Bu O Me O O Me K3PO4 (2 equiv) MeCN, 0 to 25 ºC 40q CO2Bn 3-methylbut-2-en-1-yl (Z)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohex-3-ene1-carboxylate (40q) To a solution of benzyl 2-(bis(2-(tert-butyl)phenoxy)phosphoryl)acetate35 (890 mg, 1.80 mmol, 1.00 equiv) in MeCN (18 mL, 0.1 M) was added K2CO3 (783 mg, 3.69 mmol, 2.05 equiv). The reaction was cooled to 0 ºC and a solution of 85 (500 mg, 1.80 mmol, 1.00 equiv) in MeCN (18 mL, 0.1 M) was dropwise added. The reaction was gradually warmed 205 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates to 25 ºC and stirring was continued until consumption of 85 as determined by TLC (around 16 h). The reaction mixture was filtered through a plug of Celite® to remove solids and volatiles were removed in vacuo. Purification by flash column chromatography (0–40% EtOAc/hexanes) afforded the title compound as a colorless oil (482 mg, 1.17 mmol, 65 % yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 6.90 – 6.84 (m, 1H), 6.24 (dt, J = 11.5, 7.4 Hz, 1H), 6.01 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 5.83 (dt, J = 11.5, 1.7 Hz, 1H), 5.28 (ddp, J = 8.6, 5.7, 1.4 Hz, 1H), 5.15 (s, 2H), 4.59 (d, J = 7.2 Hz, 2H), 2.68 (qd, J = 7.4, 1.8 Hz, 2H), 2.53 – 2.41 (m, 2H), 2.35 – 2.26 (m, 1H), 1.98 – 1.87 (m, 2H), 1.79 – 1.71 (m, 4H), 1.67 (s, 3H), 1.52 – 1.37 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.4, 171.7, 166.2, 150.5, 149.3, 139.5, 136.3, 129.3, 128.7, 128.3, 128.3, 119.9, 118.4, 65.9, 62.3, 57.1, 33.4, 30.3, 29.4, 25.8, 24.2, 23.8, 18.2. IR (Neat Film, NaCl): 2918, 1714, 1447, 1178, 1161 cm–1. HRMS (MM: FD+): m/z calc’d for C25H30O5 [M]+: 410.2093, found 410.2108. O O Me O Ph3P Me O O Ph Me O O DCE, 60 ºC 3-methylbut-2-en-1-yl Me Ph O 85 O 40j (E)-2-oxo-1-(6-oxo-6-phenylhex-4-en-1-yl)cyclohex-3-ene-1- carboxylate (40j) (2-oxo-2-phenylethyl)triphenylphosphonium bromide36 (996 mg, 2.16 mmol, 1.2 equiv) was stirred in 26 mL of a 3:2 CH2Cl2/2 M aq. NaOH mixture for 30 minutes at 23 ºC. The layers were separated, and the aqueous layer was extracted twice with CH2Cl2. The Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 206 combined organic layers were washed with brine, dried over Na2SO4, filtered, and solvent was removed in vacuo. To a solution of this crude ylide in DCE (22 mL, 0.1 M) was added aldehyde 85 (500 mg, 1.80 mmol, 1 equiv). The reaction was stirred at 65 ºC for 36 hours. Upon complete consumption of 85, as determined by TLC, volatiles were removed in vacuo. Purification by flash column chromatography (30% EtOAc/hexanes) afforded the title compound as a colorless oil (330 mg, 0.867 mmol, 48% yield). 1 H NMR (400 MHz, CDCl3): δ 7.95 – 7.90 (m, 2H), 7.60 – 7.51 (m, 1H), 7.46 (tt, J = 6.8, 1.5 Hz, 2H), 7.02 (dt, J = 15.4, 6.7 Hz, 1H), 6.93 – 6.85 (m, 2H), 6.03 (ddd, J = 10.2, 2.6, 1.5 Hz, 1H), 5.30 – 5.25 (m, 1H), 4.59 (d, J = 7.1 Hz, 2H), 2.55 – 2.43 (m, 2H), 2.38 – 2.27 (m, 3H), 2.01 – 1.91 (m, 2H), 1.80 (ddd, J = 13.6, 12.0, 4.7 Hz, 1H), 1.72 (s, 3H), 1.67 (s, 3H), 1.63 – 1.47 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.3, 191.0, 171.6, 149.3, 149.1, 139.7, 138.1, 132.8, 129.4, 128.7, 128.7, 126.4, 118.3, 62.4, 57.0, 33.6, 33.2, 30.5, 25.8, 23.9, 23.4, 18.2. IR (Neat Film, NaCl): 2931, 1724, 1671, 1619, 1447, 1229, 1177 cm-1. HRMS (MM: FD+): m/z calc’d for C24H28O4 [M]+: 380.1988, found 380.1982. 207 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Br OAc O OAc O Me O (1.5 equiv) KHMDS (1.05 equiv) Me O OAc OAc Me BiCl3 Me O Me O benzene O 99 O (EtO)2P O O 18-crown-6 (1 equiv) THF, –78 to 45 ºC 100 O Me O O OBn (1.1 equiv) Me O Me O NaH (1.1 equiv) THF, 0 ºC CO2Bn 40p (2-((1-(((3-methylbut-2-en-1-yl)oxy)carbonyl)-2-oxocyclohex-3-en-1yl)methyl)phenyl)methylene diacetate (99) An oven dried round bottom flask was charged with KHMDS (837 mg, 4.20 mmol, 1.05 equiv), 18-crown-6 (1.06 g, 4.00 mmol, 1.0 equiv), and THF (21 mL). The mixture was cooled to –78 ºC and a solution of enone 100 (830 mg, 4.00 mmol, 1.0 equiv) in THF (10 mL) was added. The reaction mixture was stirred for 15 minutes then (2(bromomethyl)phenyl)methylene diacetate37 (1.86 g, 6.00 mmol, 1.5 equiv) was added in a minimal amount of THF (ca 5 mL). The solution was slowly warmed to 45 ºC and stirred for 14 h. Upon complete consumption of starting material (as determined by TLC), the solution was cooled to 23 ºC, diluted with a saturated aqueous solution of NH4Cl, and the reaction mixture was extracted thrice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (20–60% EtOAc/hexanes) afforded the title compound as a colorless oil (1.00 g, 2.33 mmol, 58% yield). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 208 H NMR (400 MHz, CDCl3): δ 7.87 (s, 1H), 7.58 – 7.52 (m, 1H), 7.30 – 7.24 (m, 2H), 7.21 – 7.16 (m, 1H), 6.88 – 6.82 (m, 1H), 6.07 (ddd, J = 10.1, 2.8, 1.3 Hz, 1H), 5.24 (ddq, J = 8.6, 5.7, 1.4 Hz, 1H), 4.56 (d, J = 7.2 Hz, 2H), 3.52 (d, J = 14.8 Hz, 1H), 3.45 (d, J = 14.8 Hz, 1H), 2.53 – 2.41 (m, 1H), 2.36 (dddd, J = 13.6, 4.9, 2.6, 1.3 Hz, 1H), 2.29 – 2.19 (m, 1H), 2.12 (s, 3H), 2.10 (s, 3H), 1.86 (ddd, J = 13.6, 10.4, 5.3 Hz, 1H), 1.73 (s, 3H), 1.67 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 195.4, 171.1, 168.8, 168.8, 149.6, 139.7, 135.5, 134.9, 131.5, 129.6, 129.5, 127.6, 127.2, 118.2, 88.4, 62.5, 58.2, 34.2, 30.2, 25.9, 24.1, 21.0, 21.0, 18.2. IR (Neat Film, NaCl): 2935, 1759, 1731, 1682, 1447, 1371, 1236, 1206 cm–1. HRMS (MM: FD+): m/z calc’d for C24H28O7 [M]+: 428.1835, found 428.1833. 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclohept-3- ene-1-carboxylate (40p) To a solution of diacetate 99 (500 mg, 1.17 mmol, 1 equiv) in benzene (11.7 mL, 0.1 M) was added bismuth chloride (38 mg, 0.12 mmol, 0.1 equiv). The reaction mixture was heated to 35 ºC for 3 hours. Upon cooling to 25 ºC, the reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted twice with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, and volatiles were removed in vacuo. The crude aldehyde was used directly in the subsequent Horner–Wadsworth–Emmons olefination. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 209 To a suspension of NaH (52 mg, 1.29 mmol, 60% by weight in mineral oil, 1.1 equiv) in THF (2.6 mL, 0.5 M) at 0 ºC was dropwise added a solution of benzyl 2(diethoxyphosphoryl)acetate28 (369 mg, 1.29 mmol, 1.1 equiv) in THF (1.3 mL, 1.0 M). Stirring at 0 ºC was continued for 30 minutes. To the reaction was then dropwise added a solution of the crude aldehyde in THF (2.4 mL, 0.5 M). Upon complete consumption of starting material (as determined by TLC), the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (230 mg, 0.502 mmol, 43% yield). 1 H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 15.7 Hz, 1H), 7.57 (dd, J = 7.5, 1.9 Hz, 1H), 7.44 – 7.31 (m, 5H), 7.27 – 7.17 (m, 3H), 6.85 – 6.80 (m, 1H), 6.40 (d, J = 15.7 Hz, 1H), 6.06 (ddd, J = 10.1, 2.9, 1.2 Hz, 1H), 5.28 – 5.21 (m, 3H), 4.56 – 4.49 (m, 2H), 3.57 (d, J = 14.3 Hz, 1H), 3.31 (d, J = 14.4 Hz, 1H), 2.51 – 2.39 (m, 1H), 2.30 – 2.16 (m, 2H), 1.82 – 1.70 (m, 4H), 1.65 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 195.1, 170.4, 166.7, 149.7, 143.2, 139.7, 136.7, 136.2, 134.7, 132.1, 130.0, 129.3, 128.7, 128.4, 128.3, 127.5, 126.8, 119.4, 118.2, 66.5, 62.5, 58.4, 35.4, 30.2, 25.9, 24.1, 18.2. IR (Neat Film, NaCl): 3028, 2927, 1720, 1686, 1629, 1168 cm–1. HRMS (MM: FD+): m/z calc’d for C29H30O5 [M]+: 458.2088, found 458.2086. 210 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O O t-Bu OBn (1.1 equiv) Me O O (EtO)2P Me O O Me O O NaH (1.1 equiv) THF, 0 ºC O 101 70% yield Me Cl N O Me O SPh Me O THF, –78 to 23 ºC CO2Bn CO2Bn 13% yield 102 40c 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclopentane1-carboxylate (102) Prepared from 101 and benzyl 2-(diethoxyphosphoryl)acetate28 following General Procedure B. Purification by flash column chromatography (15% EtOAc/hexanes) afforded the title compound as a colorless oil (1.40 g, 3.51 mmol, 70% yield). 1 H NMR (400 MHz, CDCl3): δ 7.76 (dt, J = 5.6, 2.7 Hz, 1H), 7.42 – 7.26 (m, 5H), 6.95 (dt, J = 15.6, 6.9 Hz, 1H), 6.16 (dt, J = 5.8, 2.2 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (tdq, J = 7.2, 2.9, 1.5 Hz, 1H), 5.16 (s, 2H), 4.59 (d, J = 7.1 Hz, 2H), 3.33 – 3.19 (m, 1H), 2.68 – 2.51 (m, 1H), 2.21 (qd, J = 7.3, 1.6 Hz, 2H), 1.99 (ddd, J = 13.7, 12.3, 4.5 Hz, 1H), 1.82 – 1.70 (m, 1H), 1.73 (s, 3H), 1.67 (s, 3H), 1.53 – 1.23 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 205.7, 170.6, 166.4, 163.9, 148.9, 139.6, 136.2, 132.4, 128.7, 128.4, 128.3, 121.7, 118.3, 66.2, 62.7, 58.0, 39.5, 34.0, 32.4, 25.9, 23.2, 18.2. IR (Neat Film, NaCl): 2932, 2356, 1715, 1263, 1164, 976, 754 cm–1. HRMS (MM: FD+): m/z calc’d for C24H28O5 [M]+: 396.1920, found 396.1931. 3-methylbut-2-en-1-yl (E)-1-(6-(benzyloxy)-6-oxohex-4-en-1-yl)-2-oxocyclopent-3- ene-1-carboxylate (40c) A flame dried round bottom flask was charged with i-Pr2NH (0.35 mL, 2.5 mmol, 1.25 equiv) and THF (8.0 mL, 0.25 M). The solution was cooled to –78 ºC and n-BuLi (0.96 mL, 2.4 mmol, 1.2 equiv) was added dropwise and the resultant solution was stirred for 30 211 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates min. Ketoester 102 (797 mg, 2.00 mmol, 1.0 equiv) in THF (8.0 mL, 0.25 M) was added dropwise and the mixture was stirred for 1 h. N-tert-Butylbenzenesulfinimidoyl chloride38 (560.9 mg, 2.6 mmol, 1.3 equiv) in THF (4.0 mL, 0.5 M) was added dropwise and the solution was slowly warmed to 23 ºC. Upon complete consumption of starting material (as determined by TLC), the reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with Et2O (25 mL x 3). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 0–40% EtOAc/Hexanes) to afford enone 40b as a colorless oil (100 mg, 0.25 mmol, 13% yield). 1 H NMR (400 MHz, CDCl3): δ 7.76 (dt, J = 5.6, 2.7 Hz, 1H), 7.42 – 7.26 (m, 5H), 6.95 (dt, J = 15.6, 6.9 Hz, 1H), 6.16 (dt, J = 5.8, 2.2 Hz, 1H), 5.85 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (tdq, J = 7.2, 2.9, 1.5 Hz, 1H), 5.16 (s, 2H), 4.59 (d, J = 7.1 Hz, 2H), 3.33 – 3.19 (m, 1H), 2.68 – 2.51 (m, 1H), 2.21 (qd, J = 7.3, 1.6 Hz, 2H), 1.99 (ddd, J = 13.7, 12.3, 4.5 Hz, 1H), 1.82 – 1.70 (m, 1H), 1.73 (s, 3H), 1.67 (s, 3H), 1.53 – 1.23 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 205.7, 170.6, 166.4, 163.9, 148.9, 139.6, 136.2, 132.4, 128.7, 128.4, 128.3, 121.7, 118.3, 66.2, 62.7, 58.0, 39.5, 34.0, 32.4, 25.9, 23.2, 18.2. IR (Neat Film, NaCl): 2932, 2356, 1715, 1263, 1164, 976, 754 cm–1. HRMS (MM: FD+): m/z calc’d for C24H28O5 [M]+: 396.1920, found 396.1931. H O O Me O O 100 O O Me (1.5 equiv) Et3N (0.1 equiv) DMF, 25°C Me O Me O O O (EtO)2P O Me O OBn (1.1 equiv) Me O NaH (1.1 equiv) THF, 0 ºC OBn 40e O Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 3-methylbut-2-en-1-yl 212 (E)-1-(5-(benzyloxy)-5-oxopent-3-en-1-yl)-2-oxocyclohex-3- ene-1-carboxylate (40e) To a solution of enone 100 (1.04 g, 5.00 mmol, 1.0 equiv) in DMF (10 mL, 0.5 M) at 25°C was added dropwise triethylamine (0.07 mL, 0.50 mmol, 0.1 equiv) followed by acrolein (0.50 mL, 7.50 mmol, 1.5 equiv). Upon consumption of starting material (as determined by TLC), the reaction mixture was diluted with water and extracted thrice with diethyl ether. The combined organic layers were washed with water followed by brine, dried over Na2SO4, and volatiles were removed in vacuo. The crude aldehyde was used directly in the subsequent Horner–Wadsworth–Emmons olefination. To a suspension of NaH (132 mg, 3.30 mmol, 60% by weight in mineral oil, 1.1 equiv) in THF (6 mL, 0.5 M) at 0 ºC was dropwise added a solution of benzyl 2-(diethoxyphosphoryl)acetate (945 mg, 3.30 mmol, 1.1 equiv) in THF (3.0 mL, 1.0 M). Stirred at 0 ºC was continued for 30 minutes. To the reaction was then dropwise added a solution of the crude aldehyde in THF (6.0 mL, 0.5 M). Upon complete consumption of starting material (as determined by TLC), the reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (10–20% EtOAc/hexanes) afforded the title compound as a colorless oil (490 mg, 1.24 mmol, 41% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.29 (m, 5H), 6.99 (dt, J = 15.7, 6.8 Hz, 1H), 6.93 – 6.84 (m, 1H), 6.03 (ddd, J = 10.1, 2.5, 1.5 Hz, 1H), 5.88 (dt, J = 15.6, 1.6 Hz, 1H), 5.27 (ddt, J = 7.2, 5.8, 1.4 Hz, 1H), 5.17 (s, 2H), 4.59 (d, J = 7.1 Hz, 2H), 2.56 – 2.41 (m, 2H), 2.38 – 2.13 (m, 3H), 2.08 – 1.81 (m, 3H), 1.73 (s, 3H), 1.67 (s, 3H). 213 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 C NMR (100 MHz, CDCl3): δ 196.0, 171.4, 166.4, 149.3, 148.9, 139.9, 136.2, 129.4, 128.7, 128.3, 121.5, 118.2, 66.2, 62.4, 56.6, 32.2, 30.7, 27.6, 25.8, 23.8, 18.2. IR (Neat Film, NaCl): 3032, 2934, 1737, 1681, 1445, 1384, 1265, 1175, 1137 cm–1. HRMS (MM: FD+): m/z calc’d for C24H28O5 [M]+: 396.1937, found 396.1926. Preparation of Aldehyde Precursors General Procedure C: Alkylation of b-Ketoesters Br O Me O O Me OEt n OEt KHMDS (1.05 equiv) 18-crown-6 (1 equiv) THF, –78 to 45 ºC R 100 O Me O O OEt R n OEt O Me 1M HCl(aq) Me O Me O acetone, 0 ºC R n O 85 An oven dried round bottom flask was charged with KHMDS (1.05 equiv), 18-crown-6 (1.0 equiv), and THF (0.2 M with respect to KHMDS). The mixture was cooled to –78 ºC and a solution of acyclated enone 100 (1.0 equiv) in THF (0.4 M) was added. The reaction mixture was stirred for 15 minutes and then the appropriate alkyl bromide (1.5 equiv) was added neat dropwise. The solution was slowly warmed to 45 ºC and stirred for 14 h. Upon complete consumption of starting material (as determined by TLC), the solution was cooled to 23 ºC, diluted with a saturated aqueous solution of NH4Cl and the reaction mixture was extracted thrice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude diethyl acetal which was used directly in the next step. A round bottom flask was charged with the crude acetal and acetone (0.5 M), then cooled to 0 ºC. Aqueous 1 M HCl (1:1 volume with respect to acetone) was added and stirring was continued for 1 h. Upon complete consumption of starting material (as determined by TLC), the reaction mixture was extracted with EtOAc (3x). The Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 214 combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography to afford the respective aldehyde product (85). O Me O Me O O 85 3-methylbut-2-en-1-yl 2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (85) Prepared from 100 and 4-bromo-1,1-diethoxybutane 39 following General Procedure C. Purification by flash column chromatography (25% EtOAc/hexanes) afforded the title compound as a colorless oil (1.81 g, 6.50 mmol, 49% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.5 Hz, 1H), 6.89 (dddd, J = 10.1, 4.4, 3.1, 1.1 Hz, 1H), 6.02 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 5.31 – 5.25 (m, 1H), 4.59 (d, J = 6.8 Hz, 2H), 2.55 – 2.43 (m, 4H), 2.39 – 2.30 (m, 1H), 2.02 – 1.94 (m, 1H), 1.89 (ddd, J = 12.5, 11.7, 4.5 Hz, 1H), 1.78 (dd, J = 11.6, 4.9 Hz, 1H), 1.73 (s, 3H), 1.71 – 1.59 (m, 5H) 13 C NMR (100 MHz, CDCl3): δ 202.2, 196.2, 171.5, 149.5, 139.7, 129.3, 118.3, 62.4, 57.0, 44.2, 33.2, 30.3, 25.8, 23.8, 18.2, 17.5. IR (Neat Film, NaCl): 2942, 1732, 1716, 1456, 1180 cm–1 HRMS (MM: FD+): m/z calc’d for C16H22O4 [M]+: 278.1518, found 278.1509. O Me O Me O O 86 3-methylbut-2-en-1-yl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (86) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 215 Prepared from 100 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (648 mg, 2.22 mmol, 38% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 6.91 – 6.84 (m, 1H), 6.01 (ddd, J = 10.1, 2.6, 1.6 Hz, 1H), 5.27 (tdq, J = 7.1, 2.8, 1.4 Hz, 1H), 4.58 (d, J = 7.1 Hz, 2H), 2.54 – 2.40 (m, 4H), 2.36 – 2.27 (m, 1H), 1.98 – 1.86 (m, 2H), 1.78 – 1.60 (m, 10H), 1.40 – 1.26 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.7, 149.4, 139.6, 129.3, 118.3, 62.3, 57.0, 43.7, 33.6, 30.4, 25.8, 24.3, 23.8, 22.5, 18.2. IR (Neat Film, NaCl): 2941, 1733, 1717, 1456, 1219 cm–1 HRMS (MM: FD+): m/z calc’d for C16H22O4 [M]+: 293.1747, found 293.1768. O O CD3 O CD3 O D-86 3-(methyl-d3)but-2-en-1-yl-4,4,4-d3 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1- carboxylate (D-86) Prepared from D-100 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (290 mg, 0.971 mmol, 42% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.01 (ddd, J = 10.1, 2.6, 1.6 Hz, 1H), 5.27 (t, J = 7.2 Hz, 1H), 4.58 (dd, J = 7.2, 1.8 Hz, 2H), 2.55 – 2.41 (m, 4H), 2.36 – 2.26 (m, 1H), 1.97 – 1.86 (m, 2H), 1.74 (ddd, J = 13.6, 11.6, 5.1 Hz, 1H), 1.68 – 1.60 (m, 2H), 1.40 – 1.24 (m, 2H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 216 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.7, 149.4, 139.4, 129.3, 118.4, 62.3, 57.0, 43.7, 33.6, 30.4, 24.3, 23.9, 22.5. 2 H NMR (61 MHz, CHCl3): δ 1.69, 1.65. IR (Neat Film, NaCl): 2941, 1726, 1682, 1238, 1186 cm–1 HRMS (MM: FD+): m/z calc’d for C17H18D6O4 [M]+: 298.2051, found 298.2052. O Me O O Me O 87 3-methylbut-2-en-1-yl 2-oxo-1-(6-oxohexyl)cyclohex-3-ene-1-carboxylate (87) Prepared from 100 and 6-bromo-1,1-diethoxyhexane39 following General Procedure C. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (838 mg, 2.73 mmol, 32% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.8 Hz, 1H), 6.90 – 6.85 (m, 1H), 6.01 (ddd, J = 10.0, 2.5, 1.5 Hz, 1H), 5.30 – 5.25 (m, 1H), 4.62 – 4.55 (m, 2H), 2.54 – 2.39 (m, 4H), 2.36 – 2.27 (m, 1H), 1.98 – 1.84 (m, 2H), 1.73 (t, J = 1.2 Hz, 4H), 1.69 – 1.59 (m, 5H), 1.39 – 1.24 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 202.8, 196.5, 171.7, 149.3, 139.5, 129.4, 118.4, 62.3, 57.1, 43.9, 33.6, 30.3, 29.6, 25.8, 24.4, 23.9, 21.9, 18.2. IR (Neat Film, NaCl): 2934, 2864, 1733, 1717, 1684, 1456, 1220 cm–1 HRMS (MM: FD+): m/z calc’d for C18H26O4 [M]+: 306.1831, found 306.1854. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O 217 O Ph O O 93 cinnamyl 2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (93) Prepared from 103 and 4-bromo-1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (10–25% EtOAc/hexanes) afforded the title compound as a colorless oil (0.607 g, 1.86 mmol, 49% yield). 1 H NMR (400 MHz, CDCl3): δ 9.74 (t, J = 1.5 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.35 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 6.91 (dddd, J = 10.1, 4.3, 3.1, 1.1 Hz, 1H), 6.63 (dt, J = 16.0, 1.4 Hz, 1H), 6.23 (dt, J = 15.8, 6.4 Hz, 1H), 6.05 (ddd, J = 10.1, 2.4, 1.7 Hz, 1H), 4.77 (dt, J = 6.5, 1.1 Hz, 2H), 2.57 – 2.45 (m, 4H), 2.42 – 2.32 (m, 1H), 2.05 – 1.98 (m, 1H), 1.93 (ddd, J = 13.2, 11.7, 5.1 Hz, 1H), 1.80 (ddd, J = 13.2, 11.1, 5.5 Hz, 1H), 1.73 – 1.63 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.1, 196.0, 171.3, 149.7, 136.2, 134.7, 129.2, 128.8, 128.3, 126.8, 122.7, 66.0, 57.1, 44.1, 33.3, 30.1, 23.8, 17.5. IR (Neat Film, NaCl): 2941, 1732, 1717, 1700, 1181, 734, 701 cm–1 HRMS (MM: FD+): m/z calc’d for C20H22O4 [M]+: 326.1513, found 326.1510. O Me O Me O N Bz O 88 1-benzyl 3-(3-methylbut-2-en-1-yl) 1,3(2H)-dicarboxylate (88) 4-oxo-3-(4-oxobutyl)-3,4-dihydropyridine- Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 218 Prepared from 104 and 4-bromo-1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (15–30% EtOAc/hexanes) afforded the title compound as a colorless oil (603.9 mg, 1.46 mmol, 60% yield). 1 H NMR (400 MHz, CDCl3): δ 9.73 (t, J = 1.4 Hz, 1H), 7.80 (s, 1H), 7.40 (d, J = 3.5 Hz, 5H), 5.27 (m, 4H), 4.61 (m, 3H), 3.78 (d, J = 13.6 Hz, 1H), 2.45 (tt, J = 6.8, 1.7 Hz, 2H), 2.03 – 1.90 (m, 1H), 1.72 (s, 3H), 1.67 (s, 3H), 1.70 – 1.60 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 201.6, 190.5, 169.4, 142.7, 140.1, 135.0, 129.0, 128.9, 128.6, 118.0, 106.5, 69.4, 62.8, 55.4, 48.2, 43.9, 31.1, 25.8, 18.2, 17.2. IR (Neat Film, NaCl): 2945, 2338, 1727, 1670, 1604, 1389, 1302, 1201, 932 cm–1. HRMS (MM: FD+): m/z calc’d for C23H27NO6 [M]+: 413.1838, found 413.1852. O Me O Me O Me O 89 3-methylbut-2-en-1-yl 4-methyl-2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (89) Prepared from 105 and 4-bromo-1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (25–50% EtOAc/hexanes) afforded the title compound as a colorless oil (1141.4 mg, 3.90 mmol, 78% yield). 1 H NMR (400 MHz, CDCl3): δ 9.74 (s, 1H), 5.87 (dt, J = 2.6, 1.2 Hz, 1H), 5.27 (tp, J = 7.1, 1.4 Hz, 1H), 4.58 (d, J = 7.2 Hz, 2H), 2.45 (ddd, J = 8.0, 4.8, 1.7 Hz, 4H), 2.29 – 2.18 (m, 1H), 1.92 (s, 3H), 2.00 – 1.84 (m, 2H), 1.72 (s, 3H), 1.67 (s, 3H), 1.79 – 1.54 (m, 3H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 219 C NMR (100 MHz, CDCl3): δ 202.2, 195.9, 171.7, 161.6, 139.6, 126.0, 118.3, 62.3, 56.0, 44.2, 33.2, 30.0, 28.7, 25.8, 24.2, 18.2, 17.5. IR (Neat Film, NaCl): 3426, 2936, 2730, 1725, 1672, 1637, 1440, 1380, 1348, 1311, 1272, 1233, 1214, 1177, 1104, 1050, 1016, 986, 939, 870, 842, 820, 776 cm–1. HRMS (MM: FD+): m/z calc’d for C17H24O4 [M]+: 292.1682, found 292.1669. O Me O Me O EtO O 90 3-methylbut-2-en-1-yl 4-ethoxy-2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (90) Prepared from 106 and 4-bromo-1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (30–40% EtOAc/hexanes) afforded the title compound as a colorless oil (653.2 mg, 2.03 mmol, 21% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.5 Hz, 1H), 5.34 (d, J = 1.1 Hz, 1H), 5.29 (tp, J = 7.2, 1.4 Hz, 1H), 4.66 – 4.53 (m, 2H), 3.86 (q, J = 7.18, 2H), 2.61 (dddd, J = 17.8, 10.3, 4.7, 1.3 Hz, 1H), 2.50 – 2.30 (m, 4H), 2.02 – 1.87 (m, 2H), 1.82 – 1.73 (m, 1H), 1.72 (s, 3H), 1.68 (s, 3H), 1.67 – 1.58 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 201.9, 195.5, 176.5, 171.5, 139.1, 118.1, 101.9, 64.3, 62.0, 55.7, 43.9, 33.1, 28.2, 26.3, 25.5, 17.9, 17.2, 13.9. IR (Neat Film, NaCl): 2939, 2728, 1723, 1659, 1608, 1447, 1380, 1315, 1242, 1179, 1108, 1027, 942, 816, 769 cm–1. HRMS (MM: FD+): m/z calc’d for C18H26O5 [M]+: 322.1790, found 322.1775. 220 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O Me O Me Me O O 91 3-methylbut-2-en-1-yl 3-methyl-2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (91) Prepared from 107 and 4-bromo-1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (15–20% EtOAc/hexanes) afforded the title compound as a colorless oil (1.14 g, 3.90 mmol, 70% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 6.64 – 6.57 (m, 1H), 5.27 (tt, J = 7.1, 1.4 Hz, 1H), 4.64 – 4.51 (m, 2H), 2.51 – 2.36 (m, 4H), 2.36 – 2.22 (m, 1H), 2.01 – 1.92 (m, 1H), 1.87 (m, 1H), 1.83-1.53 (m, 3H) 1.78 (s, 3H), 1.73 (s, 3H), 1.67 (d, J = 1.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 202.2, 196.9, 171.9, 143.9, 139.6, 135.3, 118.3, 62.2, 57.0, 44.2, 33.3, 30.7, 25.8, 23.5, 18.2, 17.7, 16.6. IR (Neat Film, NaCl): 3500, 2925, 2333, 1725, 1681, 1449, 1361, 1182 cm–1. HRMS (MM: FD+): m/z calc’d for C17H24O4 [M]+: 292.1680, found 292.1669. O O O O 92 allyl 2-oxo-1-(4-oxobutyl)cyclohex-3-ene-1-carboxylate (92) Prepared from allyl 2-oxocyclohex-3-ene-1-carboxylate 40 and 4-bromo-1,1- diethoxybutane39 following General Procedure C. Purification by flash column 221 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates chromatography (15–30% EtOAc/hexanes) afforded the title compound as a colorless oil (773.2 mg, 3.09 mmol, 21% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.4 Hz, 1H), 6.91 (dddd, J = 10.1, 4.4, 3.1, 1.1 Hz, 1H), 6.03 (dt, J = 10.1, 2.0 Hz, 1H), 5.86 (ddt, J = 17.1, 10.2, 5.6 Hz, 1H), 5.28 (dq, J = 17.2, 1.6 Hz, 1H), 5.22 (dq, J = 10.4, 1.3 Hz, 1H), 4.60 (dq, J = 5.4, 1.6 Hz, 2H), 2.58 – 2.43 (m, 4H), 2.43 – 2.30 (m, 1H), 2.07 – 1.95 (m, 1H), 1.91 (ddd, J = 13.2, 11.6, 5.2 Hz, 1H), 1.79 (ddd, J = 13.2, 10.9, 5.6 Hz, 1H), 1.75 – 1.56 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.1, 196.0, 171.2, 149.7, 131.7, 129.2, 118.7, 65.9, 57.1, 44.1, 33.1, 30.1, 23.7, 17.4. IR (Neat Film, NaCl): 2947, 2732, 1726, 1680, 1238, 1184 cm–1. HRMS (MM: FD+): m/z calc’d for C14H19O4 [M]+: 251.1281, found 251.1278. Br O Me O O 100 Me (1.5 equiv) KHMDS (1.05 equiv) O Me O O Me 18-crown-6 (1 equiv) THF, –78 to 45 ºC 40h 3-methylbut-2-en-1-yl 2-oxo-1-(pent-4-en-1-yl)cyclohex-3-ene-1-carboxylate (40h) Prepared from 100 and 5-bromopent-1-ene following General Procedure C (without hydrolysis step). Purification by flash column chromatography (0-20% EtOAc/hexanes) afforded the title compound as a colorless oil (93.8 mg, 0.34 mmol, 23% yield). 1 H NMR (400 MHz, CDCl3): δ 6.87 (dddd, J = 10.1, 4.8, 3.1, 1.1 Hz, 1H), 6.01 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 5.78 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.28 (tdq, J = 7.1, 2.9, 1.4 Hz, 1H), 5.00 (dq, J = 17.1, 1.6 Hz, 1H), 4.94 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 4.59 (dd, J = 7.2, 3.7 Hz, 1H), 4.64 – 4.53 (m, 2H), 2.57 – 2.41 (m, 2H), 2.38 – 2.24 (m, 2H), 2.12 – 2.01 (m, Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 222 2H), 2.00 – 1.86 (m, 2H), 1.77 – 1.69 (m, 1H), 1.73 (s, 3H), 1.68 (s, 3H), 1.51 – 1.28 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 196.5, 171.7, 149.3, 139.5, 138.4, 129.4, 118.4, 114.9, 62.2, 57.1, 34.2, 33.4, 30.3, 25.8, 24.0, 23.9, 18.2. IR (Neat Film, NaCl): 2928, 1726, 1683, 1440, 1383, 1186, 912 cm–1. HRMS (MM: FD+): m/z calc’d for C17H24O3 [M]+: 276.1725, found 276.1718. O Me O Me O O 101 3-methylbut-2-en-1-yl 2-oxo-1-(4-oxobutyl)cyclopentane-1-carboxylate (101) Prepared from 3-methylbut-2-en-1-yl 2-oxocyclopentane-1-carboxylate 41 and 4-bromo1,1-diethoxybutane39 following General Procedure C. Purification by flash column chromatography (20–25% EtOAc/hexanes) afforded the title compound as a colorless oil (1.86 g, 6.97 mmol, 87% yield). 1 H NMR (400 MHz, CDCl3): δ 9.74 (t, J = 1.4 Hz, 1H), 5.29 (tp, J = 7.3, 1.4 Hz, 1H), 4.59 (d, J = 7.2 Hz, 2H), 2.58 – 2.47 (m, 1H), 2.44 (tt, J = 7.0, 1.5 Hz, 2H), 2.44 – 2.36 (m, 1H), 2.31 – 2.18 (m, 1H), 2.11 – 1.85 (m, 4H), 1.74 (s, 3H), 1.68 (s, 3H), 1.67 – 1.48 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 214.8, 201.9, 171.0, 139.7, 118.2, 62.5, 60.4, 44.0, 38.0, 33.2, 33.0, 25.9, 19.8, 18.2, 17.6. IR (Neat Film, NaCl): 3456, 2954, 2724, 1745, 1721, 1446, 1406, 1384, 1154, 953 cm–1. HRMS (MM: FD+): m/z calc’d for C15H22O4 [M]+: 266.1525, found 266.1513. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O 223 O O O 96 2-cyclohexylideneethyl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (96) Prepared from 108 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–50% EtOAc/hexanes) afforded the title compound as a colorless oil (177 mg, 0.53 mmol, 25% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 1H), 6.93 – 6.83 (m, 1H), 6.02 (ddd, J = 10.1, 2.6, 1.6 Hz, 1H), 5.23 (tt, J = 7.2, 1.2 Hz, 1H), 4.60 (d, J = 7.2 Hz, 2H), 2.56 – 2.39 (m, 4H), 2.37 – 2.26 (m, 1H), 2.20 – 2.13 (m, 2H), 2.12 – 2.05 (m, 2H), 1.99 – 1.85 (m, 2H), 1.74 (ddd, J = 13.6, 11.7, 5.0 Hz, 1H), 1.64 (p, J = 7.5 Hz, 2H), 1.58 – 1.46 (m, 6H), 1.43 – 1.20 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.6, 149.3, 147.7, 129.4, 114.8, 61.5, 57.0, 43.7, 37.1, 33.6, 30.4, 29.2, 28.5, 27.9, 26.7, 24.3, 23.9, 22.5. IR (Neat Film, NaCl): 2929, 2858, 1731, 1446, 1170, 938 cm–1. HRMS (MM: FD+): m/z calc’d for C20H28O4 [M]+: 332.1988, found 332.1991. O O O O 95 2-cyclopentylideneethyl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (95) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 224 Prepared from 109 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (1.40 g, 4.40 mmol, 39% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 3H), 6.92 – 6.83 (m, 1H), 6.02 (ddd, J = 10.1, 2.6, 1.6 Hz, 1H), 5.41 – 5.32 (m, 1H), 4.64 – 4.50 (m, 2H), 2.56 – 2.39 (m, 4H), 2.37 – 2.20 (m, 5H), 1.99 – 1.83 (m, 2H), 1.80 – 1.57 (m, 7H), 1.45 – 1.22 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.7, 151.1, 149.4, 129.4, 113.8, 63.8, 57.0, 43.7, 33.9, 33.6, 30.4, 29.0, 26.4, 26.2, 24.3, 23.9, 22.5. IR (Neat Film, NaCl): 2947, 2725, 1729, 1697, 1456, 1356, 1215 cm–1. HRMS (MM: FD+): m/z calc’d for C19H26O4 [M]+: 318.1831, found 318.1809. O O O O 94 2-cyclobutylideneethyl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (94) Prepared from 110 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (649 mg, 2.13 mmol, 29% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 1H), 6.94 – 6.83 (m, 1H), 6.02 (ddd, J = 10.1, 2.6, 1.5 Hz, 1H), 5.20 (tp, J = 7.1, 2.3 Hz, 1H), 4.46 (ddt, J = 7.4, 2.3, 1.1 Hz, 2H), 2.69 (dt, J = 16.0, 8.4 Hz, 4H), 2.56 – 2.40 (m, 4H), 2.37 – 2.26 (m, 1H), 2.03 – 1.84 (m, 4H), 1.75 (ddd, J = 13.6, 11.6, 5.1 Hz, 1H), 1.64 (p, J = 7.5 Hz, 2H), 1.42 – 1.26 (m, 2H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 225 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.6, 149.4, 148.9, 129.4, 114.0, 62.3, 57.0, 43.7, 33.6, 31.2, 30.4, 29.6, 24.3, 23.9, 22.5, 17.1. IR (Neat Film, NaCl): 2941, 1726, 1681, 1446, 1387, 1240, 1171, 1103 cm–1. HRMS (MM: FD+): m/z calc’d for C18H24O4 [M]+: 304.1675, found 304.1677. O Ph O Ph O O 98 3-benzyl-4-phenylbut-2-en-1-yl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (98) Prepared from 111 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–60% Et2O/hexanes) afforded the title compound as a colorless oil (425 mg, 0.955 mmol, 18% yield). 1 H NMR (400 MHz, CDCl3): δ 9.73 (t, J = 1.7 Hz, 1H), 7.32 – 7.27 (m, 4H), 7.21 (tt, J = 7.5, 2.3 Hz, 2H), 7.15 – 7.03 (m, 4H), 6.90 – 6.82 (m, 1H), 6.02 (ddd, J = 10.2, 2.5, 1.6 Hz, 1H), 5.51 (d, J = 7.4 Hz, 1H), 4.83 – 4.70 (m, 2H), 3.36 (s, 2H), 3.24 (s, 2H), 2.54 – 2.24 (m, 5H), 2.00 – 1.86 (m, 2H), 1.77 (ddd, J = 13.6, 11.6, 5.1 Hz, 1H), 1.63 (p, J = 7.5 Hz, 2H), 1.44 – 1.22 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.5, 196.2, 171.6, 149.4, 144.8, 139.0, 138.8, 129.4, 129.3, 128.8, 128.7, 128.5, 126.5, 126.4, 121.7, 62.0, 57.0, 43.7, 42.9, 35.8, 33.6, 30.4, 24.3, 23.9, 22.5. IR (Neat Film, NaCl): 2923, 1723, 1684, 1493, 1451, 1386, 1231 cm–1. HRMS (MM: FD+): m/z calc’d for C29H32O4 [M]+: 444.2301, found 444.2300. 226 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O O O O 97 2-cycloheptylideneethyl 2-oxo-1-(5-oxopentyl)cyclohex-3-ene-1-carboxylate (97) Prepared from 112 and 5-bromo-1,1-diethoxypentane39 following General Procedure C. Purification by flash column chromatography (10–70% Et2O/hexanes) afforded the title compound as a colorless oil (349 mg, 1.01 mmol, 15% yield). 1 H NMR (400 MHz, CDCl3): δ 9.75 (t, J = 1.7 Hz, 1H), 6.91 – 6.84 (m, 1H), 6.02 (ddd, J = 10.1, 2.6, 1.6 Hz, 1H), 5.28 (tt, J = 7.1, 1.3 Hz, 1H), 4.60 (d, J = 7.1 Hz, 2H), 2.56 – 2.40 (m, 4H), 2.38 – 2.20 (m, 5H), 1.98 – 1.87 (m, 2H), 1.76 (ddd, J = 13.7, 12.0, 4.8 Hz, 1H), 1.65 (p, J = 7.5 Hz, 2H), 1.57 (q, J = 5.4 Hz, 4H), 1.50 (dt, J = 5.2, 2.4 Hz, 4H), 1.42 – 1.27 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 202.6, 196.4, 171.7, 149.4, 149.0, 129.4, 118.4, 62.1, 57.0, 43.7, 37.7, 33.6, 30.4, 30.2, 29.8, 29.1, 28.9, 27.3, 24.3, 23.9, 22.5. IR (Neat Film, NaCl): 2923, 2854, 1737, 1681, 1443, 1385, 1235, 1172 cm–1. HRMS (MM: FD+): m/z calc’d for C21H30O4 [M]+: 346.2144, found 346.2139. b-Ketoesters Synthesis General Procedure D: Prenyl b-ketoesters Synthesis through Acylation O O LDA (1.1 equiv), THF, –78 ºC R then, N O N –78 to 25 ºC Me Me O (1.2 equiv) R Me O O 100 Me Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 227 A flame dried round bottom flask was charged with iPr2NH (1.1 equiv) and THF (1.75 M). The solution was cooled to 0 ºC and n-BuLi (2.5 M in hexanes, 1.05 equiv) was added dropwise. The resultant solution was stirred for 30 min at 0 ºC. The corresponding cyclohexenone (1.0 equiv) in THF (1.25 M) was added dropwise and stirring was continued at 0 ºC for 30 minutes. The solution was cooled to –78 ºC, and the appropriate N-acyl imidazole (1.2 equiv) in THF (3.25 M) was added dropwise. After 2 h, the reaction was gradually warmed to 23 ºC and diluted with 2 M aqueous HCl until reaching a pH < 7. The reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to afford the corresponding acylated enone. O Me O O Me 100 3-methylbut-2-en-1-yl 2-oxocyclohex-3-ene-1-carboxylate (100) Prepared from 2-cyclohexen-1-one and 3-methylbut-2-en-1-yl 1H-imidazole-1- carboxylate 42 following General Procedure D. Purification by flash column chromatography (25% EtOAc/hexanes) afforded the title compound as a colorless oil (6.65 g, 31.9 mmol, 41% yield). 1 H NMR (400 MHz, CDCl3): δ 7.02 – 6.97 (m, 1H), 6.07 (dt, J = 10.2, 2.0 Hz, 1H), 5.37 – 5.32 (m, 1H), 4.65 (d, J = 7.1 Hz, 2H), 3.42 – 3.39 (m, 1H), 2.55 – 2.45 (m, 1H), 2.44 – 2.34 (m, 2H), 2.26 – 2.18 (m, 1H), 1.75 (s, 3H), 1.71 (s, 3H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 228 C NMR (100 MHz, CDCl3): δ 194.1, 170.2, 150.7, 139.6, 129.3, 118.4, 62.3, 53.6, 25.9, 25.8, 24.5, 18.2. IR (Neat Film, NaCl): 3033, 2934, 1736, 1682, 1447, 1387, 1302, 1233, 1159, 1123 cm– 1 HRMS (MM: FD+): m/z calc’d for C12H16O3 [M]+: 208.1099, found 208.1090. O O CD3 O CD3 D-100 3-(methyl-d3)but-2-en-1-yl-4,4,4-d3 2-oxocyclohex-3-ene-1-carboxylate (D-100) Prepared from 2-cyclohexen-1-one and 3-(methyl-d3)but-2-en-1-yl-4,4,4-d3 1H-imidazole1-carboxylate 43 following General Procedure D. Purification by flash column chromatography (25% EtOAc/hexanes) afforded the title compound as a colorless oil (1.00 g, 4.67 mmol, 37% yield). Note that 1.0 equiv of the N-acyl imidazole can be employed. 1 H NMR (400 MHz, CDCl3): δ 6.99 (dt, J = 10.0, 3.7 Hz, 1H), 6.06 (dt, J = 10.2, 2.1 Hz, 1H), 5.34 (t, J = 7.2 Hz, 1H), 4.65 (d, J = 7.2 Hz, 2H), 3.40 (dd, J = 9.7, 5.0 Hz, 1H), 2.54 – 2.44 (m, 1H), 2.44 – 2.32 (m, 2H), 2.22 (ddt, J = 13.7, 8.8, 3.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 194.1, 170.2, 150.7, 139.4, 129.3, 118.4, 62.3, 53.6, 25.8, 24.5. 2 H NMR (61 MHz, CHCl3): δ 1.72, 1.67. IR (Neat Film, NaCl): 2942, 1736, 1681, 1388, 1164 cm–1 HRMS (MM: FD+): m/z calc’d for C12H10D6O3 [M]+: 214.1476, found 214.1476. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O 229 O Ph O 103 cinnamyl 2-oxocyclohex-3-ene-1-carboxylate (103) Prepared from 2-cyclohexen-1-one and cinnamyl 1H-imidazole-1-carboxylate42 following General Procedure D. Purification by flash column chromatography (15–25% EtOAc/hexanes) afforded the title compound as a colorless oil (0.98 g, 3.82 mmol, 39% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.37 (m, 2H), 7.34 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 7.01 (dt, J = 10.3, 3.8 Hz, 1H), 6.67 (dt, J = 15.9, 1.3 Hz, 1H), 6.29 (dt, J = 15.9, 6.4 Hz, 1H), 6.09 (dt, J = 10.2, 2.0 Hz, 1H), 4.83 (d, J = 6.5 Hz, 2H), 3.47 (dd, J = 10.2, 4.9 Hz, 1H), 2.57 – 2.47 (m, 1H), 2.47 – 2.34 (m, 2H), 2.28 – 2.21 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 193.9, 169.9, 150.8, 136.3, 134.6, 129.3, 128.7, 128.2, 126.8, 122.9, 65.9, 53.6, 25.8, 24.5. IR (Neat Film, NaCl): 3024, 2940, 1734, 1676, 1304, 1223, 1157, 1123, 969 cm–1 HRMS (MM: FD+): m/z calc’d for C16H16NaO3 [M+Na]+: 279.0997, found 279.0983. O Me O Me O Me 107 3-methylbut-2-en-1-yl 3-methyl-2-oxocyclohex-3-ene-1-carboxylate (107) Prepared from 2-methylcyclohex-2-en-1-one44 and 3-methylbut-2-en-1-yl 1H-imidazole1-carboxylate42 following General Procedure D. Purification by flash column Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 230 chromatography (10–20% EtOAc/hexanes) afforded the title compound as a colorless oil (1.09 g, 4.90 mmol, 23% yield). 1 H NMR (400 MHz, CDCl3): δ 6.78 – 6.69 (m, 1H), 5.35 (tdq, J = 7.2, 2.9, 1.5 Hz, 1H), 4.65 (d, J = 7.2 Hz, 2H), 3.42 – 3.36 (m, 1H), 2.48 – 2.11 (m, 5H), 1.79 (d, J = 1.6 Hz, 3H), 1.75 (s, 3H), 1.70 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 194.7, 170.6, 145.5, 139.5, 135.4, 118.5, 62.2, 53.8, 26.3, 25.9, 24.6, 18.2, 16.2. IR (Neat Film, NaCl): 2925, 1736, 1676, 1449, 1381, 1249, 1151 cm–1. HRMS (MM: FD+): m/z calc’d for C13H18O3 [M]+: 222.1255, found 222.1251. O Me O O Me Me 105 3-methylbut-2-en-1-yl 4-methyl-2-oxocyclohex-3-ene-1-carboxylate (105) Prepared from 3-methylcyclohex-2-en-1-one and 3-methylbut-2-en-1-yl 1H-imidazole-1carboxylate42 following General Procedure D. Purification by flash column chromatography (10–20% EtOAc/hexanes) afforded the title compound as a colorless oil (2.95 g, 13.3 mmol, 17% yield). 1 H NMR (400 MHz, CDCl3): δ 5.91 (h, J = 1.4 Hz, 1H), 5.35 (tp, J = 7.1, 1.6 Hz, 1H), 4.65 (d, J = 7.2 Hz, 2H), 3.37 – 3.27 (m, 1H), 2.48 – 2.24 (m, 3H), 2.21 – 2.15 (m, 1H), 1.97 (s, 3H), 1.75 (d, J = 1.3 Hz, 3H), 1.70 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 193.9, 170.5, 163.0, 139.5, 126.0, 118.5, 62.3, 52.6, 29.5, 25.9, 25.7, 24.5, 18.2. 231 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates IR (Neat Film, NaCl): 2938, 1732, 1668, 1632, 1434, 1378, 1357, 1302, 1246, 1216, 1170, 1152, 1018 cm–1. HRMS (MM: FD+): m/z calc’d for C13H18O3 [M]+: 222.1257, found 222.1251. O Me O O Me EtO 106 3-methylbut-2-en-1-yl 4-ethoxy-2-oxocyclohex-3-ene-1-carboxylate (106) Prepared from 3-ethoxycyclohex-2-en-1-one and 3-methylbut-2-en-1-yl 1H-imidazole-1carboxylate42 following General Procedure D. Purification by flash column chromatography (25–30% EtOAc/hexanes) afforded the title compound as a colorless oil (2.84 g, 9.51 mmol, 19% yield). 1 H NMR (400 MHz, CDCl3): δ 5.38 (s, 1H), 5.37 – 5.32 (m, 1H), 4.72 – 4.59 (m, 2H), 3.91 (qd, J = 7.0, 2.3 Hz, 2H), 3.36 – 3.27 (m, 1H), 2.56 (ddd, J = 16.6, 6.2, 4.5 Hz, 1H), 2.47 – 2.27 (m, 2H), 2.24 – 2.08 (m, 1H), 1.75 (s, 3H), 1.70 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 194.0, 177.7, 170.6, 139.4, 118.5, 102.3, 64.6, 62.3, 52.5, 27.5, 25.9, 24.3, 18.2, 14.2. IR (Neat Film, NaCl): 2980, 2357, 1730, 1648, 1605, 1380, 1192, 1026, 668 cm–1. HRMS (MM: FD+): m/z calc’d for C14H20O4 [M]+: 252.1363, found 252.1356. O O N Bz NC OMe (1.15 equiv) LDA (1.2 equiv) THF, –78 ºC O O O OMe Zn0, prenol Me O O PhMe, 120 ºC N Bz N Bz 113 104 Me Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 232 1-benzyl 3-methyl 4-oxo-3,4-dihydropyridine-1,3(2H)-dicarboxylate (113) A flame dried round bottom flask was charged with i-Pr2NH (2.52 mL, 18.0 mmol, 1.2 equiv) and THF (167 mL, 0.1 M). The solution was cooled to –78 ºC and n-BuLi (7.20 mL, 18.0 mmol, 1.2 equiv) was added dropwise. The resultant solution was slowly warmed to 0 ºC over 1 h and then cooled to – 78 ºC. The LDA solution was added dropwise to a solution of 1-benzoyl-2,3-dihydropyridin-4(1H)-one45 (3.47 g, 15.0 mmol, 1.0 equiv) in THF (239 mL, 0.06 M) at –78 ºC. The resultant solution was stirred for 1 h. Then methyl cyanoformate (1.37 mL, 17.25 mmol, 1.15 equiv) was added dropwise. Upon complete consumption of starting material (as determined by TLC), the reaction was diluted with a saturated solution of NH4Cl and the product was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 20–30% EtOAc/Hexanes) to afford acylated enone 113 (1.17 g, 4.05 mmol, 27% yield). 1 H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 7.39 (d, J = 2.3 Hz, 5H), 5.40 (s, 1H), 5.28 (s, 1H), 4.39 (dd, J = 13.6, 8.9 Hz, 1H), 4.18 (dd, J = 13.6, 5.4 Hz, 1H), 3.76 (s, 3H), 3.51 (dd, J = 8.9, 5.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 187.8, 168.2, 143.6, 134.8, 129.1, 128.9, 128.8, 128.7, 106.8, 69.6, 52.9, 50.6, 44.4. IR (Neat Film, NaCl): 2952, 2332, 1734, 1670, 1601, 1388, 1293, 1213 cm–1. HRMS (MM: FD+): m/z calc’d for C15H15NO5 [M]+: 289.0950, found 289.0948. 1-benzyl 3-(3-methylbut-2-en-1-yl) 4-oxo-3,4-dihydropyridine-1,3(2H)-dicarboxylate (104) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 233 A flame dried round bottom flask equipped with a reflux condenser was charged with Zn0 dust (51.5 mg, 0.787 mmol, 0.2 equiv), acylated enone 113 (1.14 g, 3.40 mmol, 1.0 equiv), and toluene (19.7 mL, 0.2 M). To the stirred solution, prenyl alcohol was added neat (2.00 mL, 19.68 mmol, 5.0 equiv). The resultant solution was heated to reflux for 3 days. The solution was cooled to 23 ºC, filtered through a celite plug and eluted with CH2Cl2, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, 15–25% EtOAc/Hexanes) to afford acylated enone 104 (883 mg, 2.57 mmol, 65% yield). 1 H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.39 (m, 5H), 5.39 (s, 1H), 5.32 (tp, J = 7.3, 1.4 Hz, 1H), 5.27 (s, 2H), 4.65 (dd, J = 7.3, 2.9 Hz, 2H), 4.38 (dd, J = 13.6, 8.9 Hz, 1H), 4.17 (dd, J = 13.5, 5.4 Hz, 1H), 3.48 (dd, J = 9.1, 5.3 Hz, 1H), 1.74 (s, 3H), 1.69 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 187.9, 167.8, 143.5, 140.1, 134.9, 129.0, 128.9, 128.8, 128.7, 118.0, 106.9, 69.5, 62.8, 50.8, 44.5, 25.9, 18.2. IR (Neat Film, NaCl): 2965, 1727, 1676, 1599, 1388, 1293, 1209, 940 cm–1. HRMS (MM: FD+): m/z calc’d for C19H21HO5 [M]+: 343.1420, found 343.1420. 234 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates General Procedure E: Substituted b-Ketoesters Synthesis through Acylation42 O N N N N R O R HO (2.0 equiv) R THF/CH2Cl2, 0 to 25 °C O N O LDA (1.05 equiv), THF, 0 °C then, N R O R O O R R O N N O (1.0 equiv) R 100 –78 to 25 °C To a solution of di(1H-imidazol-1-yl)methanone (2.0 equiv) in THF (2.0 M) at 0 °C was added dropwise a solution of the corresponding alcohol (1.0 equiv) in CH2Cl2 (1.0 M). After 3 h, the reaction mixture was gradually warmed to 25 °C. Upon consumption of starting material (as determined by TLC), the reaction mixture was concentrated under reduced pressure then filtered through a silica plug and eluted with 50% EtOAc/Hexanes. The resulting solution was concentrated under reduced pressure. A flame dried round bottom flask was charged with iPr2NH (1.1 equiv) and THF (1.75 M). The solution was cooled to 0 ºC and n-BuLi (2.5 M in hexanes, 1.05 equiv) was added dropwise. The resultant solution was stirred for 30 min at 0 ºC. 2-cyclohexen-1-one (1.0 equiv) in THF (1.25 M) was added dropwise and stirring was continued at 0 ºC for 30 minutes. The solution was cooled to –78 ºC, and the corresponding crude 1H-imidazole-1carboxylate (1.2 equiv) in THF (3.25 M) was added dropwise. After 2 h, the reaction was gradually warmed to 23 ºC and diluted with 2 M aqueous HCl until reaching a pH < 7. The reaction mixture was extracted three times with EtOAc. The combined organic layers were Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 235 washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to afford the corresponding acylated enone. O O O 108 2-cyclohexylideneethyl 2-oxocyclohex-3-ene-1-carboxylate (108) Prepared from 2-cyclohexen-1-one and 2-cyclohexylideneethan-1-ol46 following General Procedure E, with the modification of 1.5 equiv of di(1H-imidazol-1-yl)methanone and 1.2 equiv of 2-cyclohexylideneethyl 1H-imidazole-1-carboxylate being used. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (535 mg, 2.15 mmol, 28% yield). 1 H NMR (400 MHz, CDCl3): δ7.04 – 6.95 (m, 1H), 6.07 (dt, J = 10.1, 2.0 Hz, 1H), 5.29 (tt, J = 7.2, 1.2 Hz, 1H), 4.67 (d, J = 7.2 Hz, 2H), 3.45 – 3.36 (m, 1H), 2.56 – 2.30 (m, 3H), 2.27 – 2.15 (m, 3H), 2.14 – 2.08 (m, 2H), 1.60 – 1.48 (m, 6H). 13 C NMR (100 MHz, CDCl3): δ 194.1, 170.2, 150.6, 147.5, 129.3, 115.0, 61.5, 53.6, 37.1, 29.2, 28.5, 27.9, 26.7, 25.8, 24.5. IR (Neat Film, NaCl): 2930, 2852, 1735, 1683, 1447, 1388, 1298, 1169, 1122 cm–1. HRMS (MM: FD+): m/z calc’d for C15H20O3 [M]+: 248.1412, found 248.1418. O O O 109 2-cyclopentylideneethyl 2-oxocyclohex-3-ene-1-carboxylate (109) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 236 Prepared from 2-cyclohexen-1-one and 2-cyclopentylideneethan-1-ol46 following General Procedure E. Purification by flash column chromatography (5–50% EtOAc/hexanes) afforded the title compound as a colorless oil (2.69 g, 11.46 mmol, 31.9% yield). 1 H NMR (400 MHz, CDCl3): δ 6.99 (dt, J = 10.1, 3.8 Hz, 1H), 6.07 (dt, J = 10.2, 2.0 Hz, 1H), 5.50 – 5.40 (m, 1H), 4.64 (dt, J = 7.2, 1.1 Hz, 2H), 3.45 – 3.37 (m, 1H), 2.57 – 2.15 (m, 8H), 1.75 – 1.58 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 194.1, 170.2, 151.2, 150.7, 129.3, 113.8, 63.8, 53.6, 34.0, 29.0, 26.4, 26.2, 25.8, 24.5. IR (Neat Film, NaCl): 2946, 2869, 1782, 1681, 1455, 1387, 1304, 1224, 1156 cm–1. HRMS (MM: FD+): m/z calc’d for C14H18O3 [M]+: 234.1256, found 234.1255. O O O 110 2-cyclobutylideneethyl 2-oxocyclohex-3-ene-1-carboxylate (110) Prepared from 2-cyclohexen-1-one and 2-cyclobutylideneethan-1-ol47 following General Procedure E. Purification by flash column chromatography (5–50% EtOAc/hexanes) afforded the title compound as a colorless oil (2.02 g, 9.19 mmol, 31.7% yield). 1 H NMR (400 MHz, CDCl3): δ 7.00 (dt, J = 10.1, 3.7 Hz, 1H), 6.07 (dt, J = 10.2, 2.0 Hz, 1H), 5.27 (tp, J = 6.9, 2.2 Hz, 1H), 4.53 (d, J = 7.2 Hz, 2H), 3.45 – 3.36 (m, 1H), 2.80 – 2.65 (m, 4H), 2.56 – 2.31 (m, 3H), 2.28 – 2.15 (m, 1H), 1.98 (p, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl3): δ 194.1, 170.1, 150.7, 148.9, 129.3, 114.1, 62.3, 53.6, 31.2, 29.6, 25.8, 24.5, 17.1. IR (Neat Film, NaCl): 2947, 1737, 1681, 1457, 1397, 1301, 1229, 1163, 1123 cm–1. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 237 HRMS (MM: FD+): m/z calc’d for C13H16O3 [M]+: 220.1099, found 220.1093. O Ph O Ph O 111 3-benzyl-4-phenylbut-2-en-1-yl 2-oxocyclohex-3-ene-1-carboxylate (111) Prepared from 2-cyclohexen-1-one and 3-benzyl-4-phenylbut-2-en-1-ol 48 following General Procedure E. Purification by flash column chromatography (5–50% EtOAc/hexanes) afforded the title compound as a colorless oil (1.96 g, 5.43 mmol, 21.3% yield). 1 H NMR (400 MHz, CDCl3): δ 7.33 – 7.25 (m, 4H), 7.24 – 7.18 (m, 2H), 7.17 – 7.07 (m, 4H), 7.03 – 6.97 (m, 1H), 6.08 (dt, J = 10.1, 2.0 Hz, 1H), 5.59 (tt, J = 7.1, 1.1 Hz, 1H), 4.86 – 4.80 (m, 2H), 3.48 – 3.35 (m, 3H), 3.26 (s, 2H), 2.55 – 2.32 (m, 3H), 2.30 – 2.15 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 193.9, 170.1, 150.7, 144.4, 139.0, 138.9, 129.3, 129.3, 128.9, 128.7, 128.5, 126.5, 126.4, 121.9, 62.0, 53.6, 42.9, 35.9, 25.8, 24.5. IR (Neat Film, NaCl): 3026, 2927, 1738, 1681, 1493, 1388, 1304, 1230, 1157, 1123 cm– 1 . HRMS (MM: FD+): m/z calc’d for C24H24O3 [M]+: 360.1725, found 360.17302. O O O 112 2-cycloheptylideneethyl 2-oxocyclohex-3-ene-1-carboxylate (112) 238 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Prepared from 2-cyclohexen-1-one and 2-cycloheptylideneethan-1-ol49 following General Procedure E. Purification by flash column chromatography (5–50% EtOAc/hexanes) afforded the title compound as a colorless oil (1.73 g, 5.43 mmol, 28.1% yield). 1 H NMR (400 MHz, CDCl3): δ 6.99 (dt, J = 10.0, 3.8 Hz, 1H), 6.07 (dt, J = 10.1, 2.0 Hz, 1H), 5.34 (tt, J = 7.1, 1.3 Hz, 1H), 4.66 (d, J = 7.0 Hz, 2H), 3.45 – 3.37 (m, 1H), 2.57 – 2.15 (m, 8H), 1.63 – 1.44 (m, 8H). 13 C NMR (100 MHz, CDCl3): δ 194.1, 170.2, 150.6, 148.8, 129.3, 118.5, 62.1, 53.6, 37.8, 30.2, 29.9, 29.1, 28.8, 27.3, 25.8, 24.5. IR (Neat Film, NaCl): 2923, 2853, 1736, 1681, 1442, 1388, 1300, 1231, 1155, 1122, 1076 cm–1. HRMS (MM: FD+): m/z calc’d for C26H22O3 [M]+: 262.1569, found 262.1577.Protonated Enone Byproducts O Me O O Me CO2Bn Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) O * 3,5-dimethylphenol (1 equiv) PhMe, 60 ºC 40a CO2Bn 49a benzyl (R,E)-6-(2-oxocyclohex-3-en-1-yl)hex-2-enoate (49a) In a nitrogen filled glovebox, an oven-dried 20 mL vial was charged with a stir bar, Pd2(dba)3 (0.46 mg, 0.50 µmol, 2.5 mol %), (S)-t-BuPHOX (0.50 mg, 1.3 µmol, 6.5 mol %), and toluene (0.5 mL). The catalyst solution was stirred at 23 ºC for 20 min. A solution of substrate 40a (8.2 mg, 0.020 mmol, 1 equiv) and 3,5-dimethylphenol (2.4 mg, 0.020 mmol, 1 equiv) in toluene (0.5 mL) was added to the vial. The resultant solution was then heated to 60 ºC for 14 h. The solution was then cooled to 23 ºC and concentrated under reduced Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 239 pressure. NMR analysis of the crude reaction mixture affords an NMR yield of 100% (with respect to 1,3,5-trimethoxybenzene as an internal standard). The sample was purified by preparatory TLC (25% EtOAc/hexanes) to afford 49a (71% ee). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 7.01 (dt, J = 15.7, 6.9 Hz, 1H), 6.92 (dddd, J = 10.1, 4.5, 3.5, 0.9 Hz, 1H), 5.98 (ddd, J = 10.1, 2.3, 1.7 Hz, 1H), 5.88 (dt, J = 15.6, 1.6 Hz, 1H), 5.17 (s, 2H), 2.46 – 2.34 (m, 2H), 2.32 – 2.20 (m, 3H), 2.09 (dqd, J = 13.3, 4.8, 1.0 Hz, 1H), 1.89 – 1.80 (m, 1H), 1.75 (dddd, J = 13.3, 11.0, 8.4, 5.8 Hz, 1H), 1.55 – 1.35 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 201.6, 166.6, 149.7, 149.6, 136.3, 129.7, 128.7, 128.3, 128.3, 121.4, 66.2, 46.5, 32.5, 29.0, 28.0, 25.6, 25.3. IR (Neat Film, NaCl): 2921, 1712, 1673, 1257 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O3 [M]+: 298.1569, found 298.1565. Optical Rotation: [α]D21 +3.5 (c 0.20, CHCl3). SFC conditions: 40% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 3.81, major = 4.34. O H CO2Bn 49d benzyl (R,E)-7-(2-oxocyclohex-3-en-1-yl)hept-2-enoate (49d) Isolated as a byproduct from the reaction of 40d to 41d as a colorless oil (10.4 mg, 0.0332 mmol, 17% yield, 67% ee). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 240 H NMR (400 MHz, CDCl3): δ 7.32 – 7.22 (m, 5H), 6.93 (dt, J = 15.7, 6.9 Hz, 1H), 6.53 (ddd, J = 12.0, 6.7, 4.0 Hz, 1H), 5.94 (ddd, J = 11.9, 2.5, 0.9 Hz, 1H), 5.80 (dt, J = 15.6, 1.6 Hz, 1H), 5.10 (s, 3H), 2.59 – 2.49 (m, 1H), 2.42 – 2.25 (m, 2H), 2.14 (tdd, J = 7.7, 4.8, 1.4 Hz, 2H), 1.90 – 1.48 (m, 5H), 1.44 – 1.29 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 205.7, 166.5, 149.6, 146.0, 136.2, 132.8, 128.6, 128.2, 128.2, 121.2, 66.0, 51.7, 32.4, 31.1, 29.9, 29.5, 25.8, 25.4. IR (Neat Film, NaCl): 2917, 1719, 1671, 1266, 1165 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1720, found 312.1734. Optical Rotation: [α]D21 –0.6 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 8.23, major = 7.63. O H CO2Bn 49e benzyl (S,E)-5-(2-oxocyclohex-3-en-1-yl)pent-2-enoate (49e) Isolated as the major byproduct from the reaction of 40e to 41e. Purification by flash column chromatography (0–45% EtOAc/hexanes) afforded the title compound as a colorless oil (46.1 mg, 0.16 mmol, 81% yield, 47% ee). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.28 (m, 5H), 7.01 (dt, J = 15.6, 6.9 Hz, 1H), 6.92 (dddd, J = 10.0, 4.4, 3.6, 1.0 Hz, 1H), 5.98 (dt, J = 10.0, 2.0 Hz, 1H), 5.90 (dt, J = 15.7, 1.6 Hz, 1H), 5.17 (s, 2H), 2.44 – 2.24 (m, 5H), 2.15 – 1.96 (m, 2H), 1.82 – 1.69 (m, 1H), 1.62 – 1.44 (m, 1H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 241 C NMR (100 MHz, CDCl3): δ 201.3, 166.5, 149.6, 149.4, 136.2, 129.7, 128.7, 128.3, 128.3, 121.6, 66.2, 45.9, 29.7, 28.2, 27.8, 25.4. IR (Neat Film, NaCl): 3032, 2932, 1719, 1675, 1455, 1386, 1265, 1171 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O3 [M]+: 284.1412, found 284.1407. Optical Rotation: [α]D21 +11.8 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AS-H column, l = 210 nm, tR (min): minor = 5.69, major = 6.54. O H CO2Bn 49f benzyl (R,E)-7-(2-oxocyclohex-3-en-1-yl)hept-2-enoate (49f) Isolated as a byproduct from the reaction of 40f to 41f as a colorless oil (28.1 mg, 0.090 mmol, 45% yield, 51% ee). Absolute stereochemistry proposed based on VCD analysis (vide infra). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.29 (m, 5H), 7.00 (dt, J = 15.6, 6.9 Hz, 1H), 6.90 (dddd, J = 10.0, 4.5, 3.5, 0.9 Hz, 1H), 5.97 (dt, J = 10.1, 2.0 Hz, 1H), 5.86 (dt, J = 15.6, 1.6 Hz, 1H), 5.17 (s, 2H), 2.42 – 2.33 (m, 2H), 2.29 – 2.18 (m, 3H), 2.08 (dqd, J = 13.3, 4.8, 0.9 Hz, 1H), 1.88 – 1.80 (m, 1H), 1.78 – 1.69 (m, 1H), 1.52 – 1.29 (m, 5H). 13 C NMR (100 MHz, CDCl3): δ 201.8, 166.6, 150.0, 149.5, 136.3, 129.6, 128.6, 128.3, 128.3, 121.2, 66.1, 46.6, 32.2, 29.0, 28.2, 27.9, 26.6, 25.2. IR (Neat Film, NaCl): 2927, 2859, 1716, 1675, 1652, 1262, 1172 cm–1 HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1725, found 312.1737. Optical Rotation: [α]D21 +4.1 (c 1.00, CHCl3). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 242 SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 7.77, major = 8.44. O D CO2Bn D-49f benzyl (R,E)-7-(2-oxocyclohex-3-en-1-yl-1-d)hept-2-enoate (D-49f) Isolated as a byproduct from the reaction of D-40f to D-41f as a colorless oil (14.9 mg, 0.0475 mmol, 24% yield, 55% ee). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 7.00 (dt, J = 15.6, 7.0 Hz, 1H), 6.91 (dddd, J = 10.1, 4.5, 3.5, 0.9 Hz, 1H), 5.97 (dddd, J = 10.0, 2.3, 1.6, 0.6 Hz, 1H), 5.86 (dt, J = 15.6, 1.6 Hz, 1H), 5.17 (s, 2H), 2.44 – 2.33 (m, 2H), 2.28 – 2.18 (m, 2.5H), 2.09 (ddt, J = 13.3, 5.8, 4.5 Hz, 1H), 1.87 – 1.70 (m, 2H), 1.53 – 1.27 (m, 5H). 13 C NMR (100 MHz, CDCl3): δ 201.9, 166.6, 150.0, 149.6, 129.7, 129.7, 128.7, 128.3, 128.3, 121.2, 66.2, 46.6, 32.3, 29.0, 28.9, 28.2, 27.9, 27.8, 26.7, 26.6, 25.3, 25.2. 2 H NMR (61 MHz, CHCl3): δ 2.25. IR (Neat Film, NaCl): 2929, 2857, 1714, 1697, 1267, 1174 cm-1. HRMS (MM: FD+): m/z calc’d for C20H23DO3 [M+H]+: 313.1783, found 313.1788. Optical Rotation: [α]D21 +5.8 (c 0.50, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 7.96, major = 8.67. O H CO2Bn 49g Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 243 benzyl (R,E)-8-(2-oxocyclohex-3-en-1-yl)oct-2-enoate (49g) Isolated as the major product from the reaction of 40g to 41g as a colorless oil (50.5 mg, 0.155 mmol, 77% yield, 56% ee). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.29 (m, 5H), 7.01 (dt, J = 15.6, 6.9 Hz, 1H), 6.91 (dddd, J = 10.0, 4.5, 3.5, 0.9 Hz, 1H), 5.97 (dt, J = 10.0, 2.0 Hz, 1H), 5.86 (dt, J = 15.6, 1.6 Hz, 1H), 5.17 (s, 2H), 2.45 – 2.33 (m, 2H), 2.30 – 2.16 (m, 3H), 2.09 (dqd, J = 14.5, 5.0, 0.9 Hz, 1H), 1.86 – 1.70 (m, 2H), 1.51 – 1.42 (m, 2H), 1.41 – 1.28 (m, 5H). 13 C NMR (100 MHz, CDCl3): δ 202.0, 166.7, 150.2, 149.5, 136.3, 129.7, 128.7, 128.3, 128.3, 121.1, 66.1, 46.6, 32.3, 29.3, 29.1, 28.0, 27.9, 26.8, 25.2. IR (Neat Film, NaCl): 2927, 2859, 1718, 1677, 1555, 1450, 1257, 1165 cm–1 HRMS (MM: FD+): m/z calc’d for C21H26O3 [M]+: 326.1877, found 326.1891. Optical Rotation: [α]D21 +7.0 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 9.70, major = 10.46. O H 49h 6-(pent-4-en-1-yl)cyclohex-2-en-1-one (49h) Isolated as the major product from the reaction of 40h to 41h as a colorless oil. Purification by flash column chromatography (0–15% EtOAc/hexanes) afforded the title compound as a colorless oil (11.0 mg, 0.067 mmol, 33% yield, 58% ee). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 244 H NMR (400 MHz, CDCl3): δ 6.91 (dddd, J = 10.1, 4.4, 3.5, 0.9 Hz, 1H), 5.97 (dt, J = 10.0, 2.1 Hz, 1H), 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01 (dq, J = 17.2, 1.8 Hz, 1H), 4.94 (dd, J = 10.1, 1.3 Hz, 1H), 2.45 – 2.24 (m, 3H), 2.16 – 1.98 (m, 2=3H), 1.95 – 1.69 (m, 2H), 1.55 – 1.31 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 202.0, 149.5, 138.8, 129.7, 114.7, 46.6, 34.0, 28.8, 27.9, 26.4, 25.2. IR (Neat Film, NaCl): 2925, 2859, 1677, 1639, 1456, 1387, 1215, 912 cm–1. HRMS (MM: FD+): m/z calc’d for C11H16O [M]+: 164.1201, found 164.1201. Optical Rotation: [α]D21 –111.5 (c 1.00, CHCl3). SFC conditions: 3% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 4.41, major = 4.11. O H CO2H 49i (E)-6-(2-oxocyclohex-3-en-1-yl)hex-2-enoic acid (49i) Isolated as the major product from the reaction of 40i to 41i as a colorless oil. Purification by flash column chromatography (35% EtOAc/hexanes with 3% AcOH) afforded the title compound as a white solid (33.2 mg, 0.16 mmol, 80% yield, 9% ee). 1 H NMR (400 MHz, CDCl3): δ 7.07 (dtd, J = 15.5, 7.0, 1.5 Hz, 1H), 6.97 – 6.87 (m, 1H), 5.98 (dq, J = 10.1, 1.9 Hz, 1H), 5.84 (dt, J = 15.6, 1.6 Hz, 1H), 2.49 – 2.35 (m, 2H), 2.34 – 2.19 (m, 3H), 2.16 – 2.04 (m, 1H), 1.92 – 1.81 (m, 1H), 1.81 – 1.70 (m, 1H), 1.63 – 1.48 (m, 2H), 1.48 – 1.35 (m, 1H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 245 C NMR (100 MHz, CDCl3): δ 201.7, 171.5, 151.9, 149.7, 129.7, 120.9, 46.5, 32.5, 29.0, 28.0, 25.5. IR (Neat Film, NaCl): 2928, 2857, 1731, 1454, 1155 cm–1 HRMS (MM: FD+): m/z calc’d for C12H17O3 [M]+: 209.1178, found 209.1168. Optical Rotation: [α]D21 2.2 (c 1.00, CHCl3). SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 3.30, major = 4.02 O H NHP O 49m 1,3-dioxoisoindolin-2-yl (E)-6-(2-oxocyclohex-3-en-1-yl)hex-2-enoate (49m) Isolated as a byproduct product from the reaction of 40m to 41m as a colorless oil. Purification by flash column chromatography (0–35% EtOAc/hexanes) afforded the title compound as a white solid (7.7 mg, 0.022 mmol, 11% yield). 1 H NMR (400 MHz, CDCl3): δ 7.89 (dd, J = 5.5, 3.1 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 (dt, J = 15.8, 6.9 Hz, 1H), 6.93 (dddd, J = 10.1, 4.5, 3.5, 1.0 Hz, 1H), 6.10 (dt, J = 15.8, 1.6 Hz, 1H), 5.99 (ddd, J = 10.0, 2.3, 1.7 Hz, 1H), 2.50 – 2.25 (m, 5H), 2.12 (m, 1H), 1.95 – 1.84 (m, 1H), 1.78 (m, 1H), 1.59 (m, 2H), 1.45 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 201.5, 162.5, 162.2, 155.6, 149.7, 134.9, 129.7, 129.1, 124.1, 115.9, 46.5, 33.2, 29.1, 28.1, 25.4, 25.3. IR (Neat Film, NaCl): 2931, 1770, 1745, 1673, 1466, 1360, 1186 cm–1. HRMS (MM: FD+): m/z calc’d for C20H19NO5 [M]+: 353.1263, found 353.1242. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates O 246 H Me CO2Bn 49r benzyl (R,E)-2-methyl-6-(2-oxocyclohex-3-en-1-yl)hex-2-enoate (49r) Isolated as a byproduct from the reaction of 40r to 41r as a colorless oil (23.2 mg, 0.0743 mmol, 37% yield, 59% ee). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.29 (m, 5H), 6.91 (dddd, J = 10.1, 4.5, 3.5, 0.9 Hz, 1H), 6.81 (td, J = 7.5, 1.5 Hz, 1H), 5.97 (dt, J = 10.0, 1.9 Hz, 1H), 5.18 (s, 2H), 2.45 – 2.34 (m, 2H), 2.32 – 2.17 (m, 3H), 2.09 (dqd, J = 13.4, 4.9, 1.0 Hz, 1H), 1.90 – 1.81 (m, 4H), 1.80 – 1.71 (m, 1H), 1.55 – 1.36 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 201.7, 168.1, 149.6, 142.7, 136.6, 129.7, 128.6, 128.2, 128.1, 127.9, 66.3, 46.6, 29.2, 29.0, 28.0, 26.2, 25.2, 12.6. IR (Neat Film, NaCl): 3033, 2932, 2861, 1710, 1677, 1256 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1725, found 312.1729. Optical Rotation: [α]D21 +8.6 (c 1.00, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 5.89, major = 6.22. O H CO2Bn EtO 49t benzyl (E)-6-(4-ethoxy-2-oxocyclohex-3-en-1-yl)hex-2-enoate (49t) Isolated as a byproduct from the reaction of 40t to 41t as a colorless oil (5.2 mg, 0.015 mmol, 8% yield, 45% ee). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 247 H NMR (400 MHz, CDCl3): δ 7.41 – 7.27 (m, 5H), 7.01 (dt, J = 15.6, 6.9 Hz, 1H), 5.87 (dt, J = 15.6, 1.6 Hz, 1H), 5.31 (s, 1H), 5.17 (s, 2H), 3.88 (qd, J = 7.1, 1.4 Hz, 2H), 2.41 (dd, J = 7.2, 5.3 Hz, 2H), 2.29 – 2.13 (m, 3H), 2.06 (dq, J = 13.2, 5.2 Hz, 1H), 1.86 (ddt, J = 13.3, 11.1, 5.2 Hz, 1H), 1.78 – 1.64 (m, 1H), 1.59 – 1.37 (m, 3H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 201.4, 176.9, 166.6, 149.7, 136.3, 128.7, 128.3, 128.3, 121.3, 102.3, 66.1, 64.4, 45.1, 32.5, 29.3, 28.2, 26.4, 25.7, 14.3. IR (Neat Film, NaCl): 2919, 1718, 1648, 1605, 1456, 1377, 1260, 1190, 732 cm–1. HRMS (MM: FD+): m/z calc’d for C21H26O4 [M]+: 342.1828, found 342.1826. Optical Rotation: [α]D21 –5.5 (c 0.34, CHCl3). SFC conditions: 15% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 10.17, major = 11.69. O Me H CO2Bn 49u benzyl (E)-6-(3-methyl-2-oxocyclohex-3-en-1-yl)hex-2-enoate (49u) Isolated as a byproduct from the reaction of 40u to 41u as a colorless oil (23.6 mg, 0.075 mmol, 37% yield, 46% ee). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.28 (m, 5H), 7.01 (dt, J = 15.5, 6.9 Hz, 1H), 6.71 – 6.63 (m, 1H), 5.88 (dt, J = 15.6, 1.6 Hz, 1H), 5.17 (s, 2H), 2.33 (ddq, J = 6.3, 4.8, 2.0 Hz, 2H), 2.29 – 2.19 (m, 3H), 2.10 – 2.01 (m, 1H), 1.88 – 1.77 (m, 1H), 1.76 (q, J = 1.7 Hz, 3H), 1.74 – 1.69 (m, 1H), 1.56 – 1.34 (m, 3H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 248 C NMR (100 MHz, CDCl3): δ 201.9, 166.6, 149.8, 144.5, 136.3, 135.3, 128.68, 128.3, 128.3, 121.3, 66.2, 46.6, 32.5, 29.2, 28.4, 25.7, 25.2, 16.3. IR (Neat Film, NaCl): 2925, 1718, 1670, 1455, 1262, 1172, 1013 cm–1. HRMS (MM: FD+): m/z calc’d for C20H24O3 [M]+: 312.1725, found 312.1721. Optical Rotation: [α]D21 –14.7 (c 0.35, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 7.18, major = 7.62. Product Derivatizations O OH NaBH4 (2 equiv) H CO2Bn 41a MeOH, 0 ˚C, 10 min H CO2Bn 68 benzyl (3aR,6R,7S,7aR)-4-hydroxyoctahydro-3a,6-ethanoindene-7-carboxylate (68) To a solution of ketone 41a (0.125 mmol, 1 equiv) in methanol (4.4 mL) was added NaBH4 (0.25 mmol, 2 equiv) at 0 ºC. The reaction was allowed to stir for 10 min at 0 ºC and then was diluted with water. The aqueous layer was extracted with dichloromethane (3x), and the combined organic layers were dried over Na2SO4. Concentration under reduced pressure afforded the title compound as a colorless oil (37.6 mg, 0.125 mmol, 99% yield). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.30 (m, 5H), 5.19 – 5.05 (m, 2H), 3.76 (dd, J = 8.9, 5.3 Hz, 0.4H, minor), 3.69 (dt, J = 8.9, 1.5 Hz, 0.6H, major), 2.35 – 2.24 (m, 1H), 2.15 – 1.95 (m, 2H), 1.95 – 1.83 (m, br, 1H), 1.83 – 1.56 (m, 6H), 1.53 – 1.23 (m, 5H), 1.15 – 1.01 (m, 1H). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 13 249 C NMR (100 MHz, CDCl3): δ 175.8, 175.6, 136.3, 128.6, 128.2, 128.2, 128.0, 128.0, 75.6, 70.3, 66.3, 66.3, 49.21, 48.1, 44.5, 44.2, 43.2, 36.8, 35.0, 34.9, 34.0, 30.5, 30.3, 30.1, 29.6, 29.0, 26.7, 26.3, 22.8, 22.8, 20.3. IR (Neat Film, NaCl): 3438, 3032, 2942, 2865, 1730, 1455, 1162 cm–1 HRMS (MM: FD+): m/z calc’d for C19H24O3 [M]+: 300.1725, found 300.1730. Optical Rotation: [α]D21 –31.1 (c 1.00, CHCl3). HO O N NaOAc (2.4 equiv) NH2OH•HCl (1.17 equiv) H CO2Bn 41a benzyl MeOH, reflux, 2 h H CO2Bn 114 (3aR,6R,7S,7aR,E)-4-(hydroxyimino)octahydro-3a,6-ethanoindene-7- carboxylate (114) To a stirred solution of ketone 41a (0.125 mmol, 1 equiv) in methanol (1.25 mL) was added NaOAc (0.3 mmol, 2.4 equiv), NH2OH•HCl (0.15 mmol. 1.17 equiv), and water (0.05 mL). The reaction was brought to reflux for 2 h and was subsequently cooled to 23 ºC and concentrated under reduced pressure. The crude mixture was then diluted with water and extracted with EtOAc (3x), washed with a saturated aqueous solution of NaHCO3 and brine, dried with Na2SO4, and concentrated under reduced pressure. The material was used in the next step without further purification assuming quantitative yield. 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.28 (m, 5H), 5.20 – 5.06 (m, 2H), 2.52 – 2.46 (m, 2H), 2.43 – 2.39 (m, 1H), 2.39 – 2.36 (m, 1H), 2.15 (dtd, J = 10.2, 8.2, 1.8 Hz, 1H), 2.07 (ddt, J = 11.9, 8.3, 4.1 Hz, 1H), 1.98 (ddd, J = 13.0, 11.0, 8.0 Hz, 1H), 1.82 – 1.71 (m, 3H), Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 250 1.67 (ddd, J = 10.9, 3.6, 1.8 Hz, 1H), 1.48 (dddd, J = 12.5, 7.8, 6.5, 3.7 Hz, 2H), 1.36 (dddd, J = 23.6, 11.1, 8.8, 2.6 Hz, 2H). 13 C NMR (100 MHz, CDCl3): δ 174.8, 165.4, 136.2, 128.7, 128.4, 128.2, 66.5, 48.2, 45.7, 44.4, 30.6, 29.2, 28.9, 28.1, 27.2, 25.5, 22.6. IR (Neat Film, NaCl): 2945, 1731, 1161 cm–1. HRMS (MM: FD+): m/z calc’d for C19H23NO3 [M]+: 313.1678, found 313.1676. Optical Rotation: [α]D21 –22.0 (c 0.37, CHCl3). HO N SOCl2 (5 equiv) O H N H THF, 0 ˚C, 3 h H CO2Bn 114 benzyl CO2Bn 69 (4R,5S,5aR,8aR)-2-oxooctahydro-1H-4,8a-ethanocyclopenta[b]azepine-5- carboxylate (69) To a solution of 114 (0.125 mmol, 1 equiv) in THF (1.25 mL) at 0 ºC was added a solution of SOCl2 (0.625 mmol, 5 equiv) in THF (0.23 mL). The reaction was stirred for 3 h at 0 ºC, followed by dilution with water. Aqueous solution NH4OH was added to the reaction mixture until neutral, and the aqueous layer was extracted with dichloromethane (3x). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (35% EtOAc/hexanes) afforded the title compound as a colorless oil (22 mg, 0.167 mmol, 56% yield over two steps). Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 1 251 H NMR (400 MHz, CDCl3): δ 7.41 – 7.27 (m, 5H), 6.67 (s, 1H, br), 5.15 (q, J = 12.3 Hz, 2H), 2.73 (dt, J = 18.1, 1.6 Hz, 1H), 2.62 (tdd, J = 9.9, 8.0, 1.4 Hz, 1H), 2.48 (dd, J = 18.4, 6.9 Hz, 1H), 2.40 – 2.32 (m, 2H), 2.29 – 2.16 (m, 1H), 1.95 (dtd, J = 12.7, 8.7, 2.2 Hz, 1H), 1.82 – 1.62 (m, 7H), 1.62 – 1.52 (m, 1H), 1.44 – 1.30 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 174.6, 174.2, 135.9, 128.8, 128.4, 128.3, 66.7, 59.9, 48.8, 48.5, 39.2, 33.3, 31.1, 29.8, 25.1, 23.3. IR (Neat Film, NaCl): 3182, 3055, 2934, 1727, 1648, 1456, 1398, 1167 cm–1. HRMS (MM: FD+): m/z calc’d for C19H23NO3 [M]+: 313.1678, found 313.1678. Optical Rotation: [α]D21 –5.5 (c 0.89, CHCl3). O O m-CPBA (1.2 equiv) NaHCO3 (2.9 equiv) H CO2Bn 41a benzyl CH2Cl2, 25 ˚C, 20 h O H CO2Bn 70 (4R,5S,5aR,8aR)-2-oxooctahydro-4,8a-ethanocyclopenta[b]oxepine-5- carboxylate (70) To a solution ketone 41a (37 mg, 0.13 mmol, 1 equiv) in CH2Cl2 (1.25 mL, 0.1 M) at 0°C was added NaHCO3 (30.8 mg, 0.37 mmol, 2.9 equiv). Subsequently, m-CPBA (31 mg, 0.15 mmol, 1.2 equiv) was added and the reaction was allowed to warm to 25 °C. Upon complete consumption of starting material (as determined by TLC), the reaction mixture was diluted with a saturated solution of Na2S2O3 and extracted with Et2O (3x). The combined organic layers were washed with a saturated solution of NaHCO3 followed by brine, dried over Na2SO4, and volatiles were removed in vacuo. Purification by preparatory 252 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates thin layer chromatography (30% EtOAc/hexanes) afforded the title compound as a clear oil (16 mg, 0.05 mmol, 41% yield). 1 H NMR (400 MHz, CDCl3): δ 7.43 – 7.29 (m, 5H), 5.22 – 5.10 (m, 2H), 2.97 (ddd, J = 19.0, 2.5, 1.4 Hz, 1H), 2.83 – 2.61 (m, 2H), 2.41 – 2.32 (m, 2H), 2.28 – 2.09 (m, 3H), 2.05 – 1.93 (m, 1H), 1.81 – 1.56 (m, 5H), 1.40 – 1.26 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 173.9, 172.9, 135.7, 128.8, 128.6, 128.3, 88.4, 66.9, 47.8, 46.5, 39.6, 39.1, 32.8, 30.4, 29.7, 24.9, 22.7. IR (Neat Film, NaCl): 2943, 2873, 1722, 1255, 1189, 1167 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O4 [M]+: 314.1518, found 314.1521. Optical Rotation: [α]D21 –15.8 (c 1.00, CHCl3). O O (NH4)2S2O8 (3 equiv) 2,4,6-collidine (3 equiv) H2 (1 atm), Pd/C DMSO, 60 ˚C, 2 h MeOH, 23 ºC, 18 h H CO2Bn O H CO2H 41f H 75 (2S,4aR,8aR)-octahydro-2H-2,4a-ethanonaphthalen-9-one (75) A vial containing ketone 41f (0.72 mmol, 1 equiv) and Pd/C (10 wt. % with 67% H2O, 0.072 mmol, 0.1 equiv) was evacuated and backfilled with H2. Methanol (1.06 mL) was subsequently added, and the reaction was stirred at 23 ºC overnight. The crude reaction mixture was filtered through a silica plug and concentrated under reduced pressure to afford the corresponding acid as a white solid, which was used without further purification. To a solution of the crude acid (0.62 mmol, 1 equiv) in DMSO (1.24 mL) was added (NH4)2S2O8 (1.86 mmol, 3 equiv) and 2,4,6-collidine (1.86 mmol, 3 equiv). The mixture was purged with N2 for 5 min and was subsequently sealed and heated to 60 ºC for 2 h with Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 253 stirring. The reaction mixture was diluted with dichloromethane, washed with brine (1x), and the aqueous layer was extracted with dichloromethane (3x). The combined organic layers were washed with brine (3x), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (15% EtOAc/hexanes) afforded the title compound as a white solid (30.2 mg, 0.167 mmol, 27% yield). 1 H NMR (400 MHz, CDCl3): δ 2.33 – 2.21 (m, 3H), 2.13 – 2.07 (m, 1H), 1.93 (dddd, J = 13.3, 10.6, 3.8, 2.8 Hz, 1H), 1.75 – 1.58 (m, 6H), 1.53 (dd, J = 13.6, 4.0 Hz, 1H), 1.47 – 1.38 (m, 2H), 1.38 – 1.28 (m, 1H), 1.27 – 1.17 (m, 1H), 1.17 – 1.05 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 218.6, 44.9, 43.9, 34.5, 34.1, 30.6, 29.0, 27.7, 25.9, 25.9, 21.8, 21.4. IR (Neat Film, NaCl): 2925, 1716 cm–1 HRMS (MM: FI+): m/z calc’d for C12H18O [M]+: 178.1358, found 178.1359. Optical Rotation: [α]D21 –59.9 (c 0.89, CHCl3). O 1. HCO2Et (71.4 equiv) KHMDS (28 equiv) PhMe, 70 ºC, 16 h H 75 2. HCHO(aq) THF, 50 ºC, 4 h O H 76 (2S,4aR,8aR)-10-methyleneoctahydro-2H-2,4a-ethanonaphthalen-9-one (76) To a solution of ketone 75 (0.056 mmol, 1 equiv) and ethyl formate (4 mmol, 71.4 equiv) in toluene (3.2 mL) was added a solution of KHMDS (0.5 M in toluene, 1.6 mmol, 28 equiv) at 23 ºC. The reaction mixture was stirred at 70 ºC for 16 h. Upon cooling to 0 ºC, THF (6.4 mL) and formalin (37% in water, 3.2 mL) was added, and then the reaction was heated to 50 ºC for 4 h. The reaction mixture was diluted with a saturated aqueous solution Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 254 of NH4Cl, extracted with EtOAc (3x), dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (30% EtOAc/hexanes, 2x) afforded the title compound as a yellow oil (4.4 mg, 0.023 mmol, 41% yield). 1 H NMR (400 MHz, CDCl3): δ 5.93 (d, J = 1.8 Hz, 1H), 5.15 (d, J = 1.8 Hz, 1H), 2.66 (p, J = 3.0 Hz, 1H), 2.39 – 2.19 (m, 1H), 1.98 (dddd, J = 13.2, 10.6, 3.9, 2.8 Hz, 1H), 1.81 – 1.61 (m, 6H), 1.51 – 1.42 (m, 2H), 1.41 – 1.31 (m, 2H), 1.23 – 1.15 (m, 2H), 1.11 (dt, J = 12.9, 3.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 205.3, 147.9, 116.3, 45.0, 36.1, 35.0, 34.7, 30.8, 29.0, 26.5, 26.0, 21.6, 21.3. IR (Neat Film, NaCl): 2926, 2859, 1708, 1630, 1464, 1449 cm–1 HRMS (MM: FD+): m/z calc’d for C13H18O [M]+: 190.1358, found 190.1353. Optical Rotation: [α]D21 –34.2 (c 0.29, CHCl3). O 1. HCO2Et (71.4 equiv) KHMDS (28 equiv) PhMe, 70 ºC, 16 h H CO2Bn 41f ethyl 2. HCHO(aq) THF, 50 ºC, 4 h O H CO2Et 77 (1S,2S,4aR,8aR)-3-methylene-4-oxooctahydro-2H-2,4a-ethanonaphthalene-1- carboxylate (77) To a solution of 41f (0.192 mmol, 1 equiv) and ethyl formate (13.71 mmol, 71.4 equiv) in toluene (11.1 mL) was added a solution of KHMDS (0.5 M in toluene, 5.49 mmol, 28 equiv) at 23 ºC. The reaction mixture was stirred at 70 ºC for 16 h. Upon cooling to 0 ºC, THF (22.2 mL) and formalin (37% in water, 11.1 mL) was added, and then the reaction was heated to 50 ºC for 4 h. The reaction mixture was diluted with a saturated aqueous solution Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 255 of NH4Cl, extracted with EtOAc (3x), dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (30% EtOAc/hexanes, 2x) afforded the title compound as a yellow oil (13.1 mg, 0.05 mmol, 26% yield). 1 H NMR (400 MHz, CDCl3): δ 5.99 (d, J = 1.7 Hz, 1H), 5.17 (d, J = 1.7 Hz, 1H), 4.21 – 4.01 (m, 2H), 3.04 (td, J = 3.1, 2.0 Hz, 1H), 2.27 (ddd, J = 14.2, 11.4, 5.4 Hz, 1H), 2.21 (dd, J = 6.8, 2.0 Hz, 1H), 2.01 (dddd, J = 11.6, 6.5, 4.4, 1.7 Hz, 1H), 1.92 – 1.75 (m, 3H), 1.73 – 1.65 (m, 2H), 1.56 – 1.50 (m, 1H), 1.47 – 1.31 (m, 2H), 1.29 – 1.16 (m, 6H). 13 C NMR (100 MHz, CDCl3): δ 203.7, 173.8, 144.3, 119.0, 60.8, 51.1, 45.0, 39.1, 37.2, 30.3, 28.9, 26.2, 25.8, 21.3, 21.1, 14.4. IR (Neat Film, NaCl): 2927, 2867, 1732, 1708, 1449, 1180 cm–1. HRMS (MM: FD+): m/z calc’d for C16H22O3 [M]+: 262.1569, found 262.1576. Optical Rotation: [α]D21 –3.9 (c 0.38, CHCl3). O HO K2OsO4·2H2O, NMO O HO acetone/H2O H CO2Et 77 ethyl H CO2Et 78 (1R,2S,4aR,8aR)-3-hydroxy-3-(hydroxymethyl)-4-oxooctahydro-2H-2,4a- ethanonaphthalene-1-carboxylate (78) A flame dried vial was charged with enone 77 (14.7 mg, 0.056 mmol, 1 equiv) and acetone (2.3 mL, 0.024 M) and water (0.6 mL, 0.094 M). NMO (50 wt. % in H2O) (23 µL, 0.112 mmol, 2 equiv) was added and the solution was cooled to 0 ºC. K2OsO4·2H2O (2.1 mg, 0.006 mmol, 0.1 equiv) was added to the solution. The resultant solution was slowly warmed to 23 ºC. Upon complete consumption of starting material (as determined by TLC), Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 256 the reaction was quenched with a saturated solution of Na2S2O3 and stirred for 30 min. The mixture was then diluted with CH2Cl2 and the product was extracted with CH2Cl2 (2 x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (50% EtOAc/hexanes) afforded the title compound as a colorless oil (2.1 mg, 0.007 mmol,13% yield, 10:1 dr). In the 1H NMR, peaks that correspond to the minor diastereomer closely resemble the major diastereomer. dr was determine through integration of 1H NMR peaks 2.69 ppm (major) and 2.96 ppm (minor). 1 H NMR (400 MHz, CDCl3): δ 4.15 (q, J = 7.1 Hz, 2H), 3.81 (dd, J = 11.8, 2.6 Hz, 1H), 3.54 (dd, J = 11.9, 2.7 Hz, 1H), 2.71 – 2.67 (m, 1H), 2.38 – 2.24 (m, 2H), 2.10 (d, J = 7.3 Hz, 1H), 1.94 – 1.64 (m, 7H), 1.47 – 1.18 (m, 9H). 13 C NMR (100 MHz, CDCl3): δ 218.4, 174.8, 75.8, 65.8, 61.0, 48.9, 45.4, 37.3, 37.2, 30.3, 28.3, 25.6, 22.5, 21.0, 14.3. IR (Neat Film, NaCl): 3468, 2930, 2355, 1716, 1197, 1033 cm–1. HRMS (MM: FD+): m/z calc’d for C16H24O5 [M]+: 296.1624, found 296.1619. Optical Rotation: [α]D21 2.1 (c 0.24, CHCl3). O O O SeO2 (1.2 equiv) AcOH, reflux, 19 h benzyl carboxylate (79) H CO2Bn H CO2Bn 41f 79 (1R,2S,4aR,8aR)-3,4-dioxooctahydro-2H-2,4a-ethanonaphthalene-1- Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 257 To a solution of 41f (0.064 mmol, 1 equiv) in glacial acetic acid (0.1 mL) was added SeO2 (0.077 mmol, 1.2 equiv). The reaction was brought to reflux for 19 h. After cooling to 23 ºC, the reaction mixture was filtered and concentrated under reduced pressure. The resulting crude mixture was dissolved in EtOAc and washed with water (5x), dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (30% EtOAc/hexanes) afforded the title compound as a yellow oil (10.4 mg, 0.031 mmol, 48% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.28 (m, 5H), 5.19 – 5.04 (m, 2H), 3.00 (m, 1H), 2.54 (dd, J = 6.4, 2.3 Hz, 1H), 2.40 (ddd, J = 14.6, 10.3, 6.9 Hz, 1H), 2.02 (m, 3H), 1.80 – 1.69 (m, 2H), 1.68 – 1.50 (m, 3H), 1.48 – 1.38 (m, 1H), 1.33 (dt, J = 13.4, 3.5 Hz, 1H), 1.29 – 1.15 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 198.7, 196.1, 173.2, 135.4, 128.8, 128.6, 128.4, 67.4, 49.9, 48.0, 46.3, 37.9, 30.2, 28.3, 25.5, 22.7, 20.5, 20.2. IR (Neat Film, NaCl): 2932, 2857, 1731, 1454, 1155 cm–1. HRMS (MM: FD+): m/z calc’d for C20H22O4 [M]+: 326.1518, found 326.1532. Optical Rotation: [α]D21 –49.2 (c 1.04, CHCl3). O O HC(OMe)3 (38 equiv) p-TsOH•H2O (1 equiv) MeO O MeO MeOH, 40 ºC, 19 h H CO2Bn H CO2Bn 79 80 benzyl (1R,2S,4aR,8aR)-3,3-dimethoxy-4-oxooctahydro-2H-2,4a-ethanonaphthalene1-carboxylate (80) 258 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates To a solution of diketone 79 (0.031 mmol, 1 equiv) in methanol (0.13 mL) was added HC(OMe)3 (1.2 mmol, 38 equiv) and p-TsOH•H2O (0.031 mmol, 1 equiv). The reaction was stirred for 19 h at 40 ºC, followed by dilution with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (4x), dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (30% EtOAc/hexanes) afforded the title compound as a yellow oil (4.7 mg, 0.013 mmol, 41% yield). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.29 (m, 5H), 5.26 (d, J = 12.3 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 3.20 (s, 3H), 3.06 (s, 3H), 2.93 (dt, J = 4.2, 2.2 Hz, 1H), 2.29 – 2.11 (m, 3H), 1.98 – 1.89 (m, 1H), 1.83 (dddd, J = 13.8, 11.4, 6.7, 2.4 Hz, 1H), 1.70 – 1.58 (m, 4H), 1.54 (d, J = 3.9 Hz, 1H), 1.31 (dd, J = 10.8, 2.4 Hz, 1H), 1.27 – 1.19 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 209.0, 173.5, 136.5, 128.6, 128.5, 128.2, 97.4, 66.4, 50.4, 48.8, 48.4, 45.5, 36.4, 34.9, 30.0, 29.1, 25.5, 23.1, 21.0, 21.0. IR (Neat Film, NaCl): 2933, 2855, 1736, 1449, 1172 cm–1 HRMS (MM: FD+): m/z calc’d for C22H28O5 [M]+: 372.1937, found 372.1931. Optical Rotation: [α]D21 –26.2 (c 0.42, CHCl3). HO O NaOAc (2.4 equiv) NH2OH•HCl (1.17 equiv) H CO2Bn MeOH, reflux, 3.5 h 41f benzyl AcO N N OAc Pd(OAc)2 (0.05 equiv) PhI(OAc)2 (3 equiv) H CO2Bn 1:1 AcOH/Ac2O 100 ˚C, 16 h H CO2Bn 81 (1S,2R,4aS,8aR,E)-5-acetoxy-4-(acetoxyimino)octahydro-2H-2,4a- ethanonaphthalene-1-carboxylate (81) Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 259 To a stirred solution of ketone 41f (0.096 mmol, 1 equiv) in methanol (0.93 mL) was added NaOAc (0.23 mmol, 2.4 equiv), NH2OH•HCl (0.111 mmol, 1.17 equiv), and water (0.033 mL). The reaction was brought to reflux for 3.5 h and was subsequently cooled to 23 ºC and concentrated under reduced pressure. The crude mixture was then diluted with water and extracted with EtOAc (3x), washed with a saturated aqueous solution of NaHCO3 and brine, dried with Na2SO4, and concentrated under reduced pressure. The crude oxime was dissolved in a 1:1 mixture of AcOH/Ac2O (0.78 mL). The reaction vessel was sealed and stirred at 23 ºC for 2 h. Pd(OAc)2 (0.0048 mmol, 0.05 equiv) and PhI(OAc)2 (0.288 mmol, 3 equiv) were subsequently added, and the reaction was heated to 100 ºC for 16 h. The reaction mixture was cooled to 23 ºC, filtered through a silica plug, and the filtrate was diluted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3 until not acidic, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (30% EtOAc/hexanes) afforded the title compound (81) as a yellow oil (12.3 mg, 0.0288 mmol, 30% yield over two steps). 1 H NMR (400 MHz, CDCl3): δ 7.43 – 7.27 (m, 5H), 5.31 – 5.20 (m, 1H), 5.20 – 5.02 (m, 2H), 2.62 (dt, J = 20.2, 3.5 Hz, 1H), 2.40 – 2.29 (m, 2H), 2.27 – 2.17 (m, 1H), 2.14 (s, 3H), 2.02 (s, 3H), 1.89 (m, 1H), 1.83 – 1.69 (m, 4H), 1.62 (t, J = 2.8 Hz, 2H), 1.46 – 1.28 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 173.9, 170.6, 170.4, 168.9, 135.9, 128.8, 128.5, 128.2, 71.7, 66.9, 49.6, 42.2, 39.1, 29.5, 28.9, 28.6, 26.9, 25.5, 23.0, 21.4, 20.2, 16.7. IR (Neat Film, NaCl): 2930, 1764, 1731, 1456, 1371, 1248, 1210 cm–1. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 260 HRMS (MM: FD+): m/z calc’d for C24H29NO6 [M]+: 427.1995, found 427.2017. Optical Rotation: [α]D21 –27.6 (c 1.00, CHCl3). AcO N O OAc OAc K2CO3 (0.45 equiv) NaHSO3 (3.5 equiv) H CO2Bn 81 benzyl MeOH, 23 ºC to reflux 9h H CO2Bn 82 (1S,2R,4aR,8aR)-5-acetoxy-4-oxooctahydro-2H-2,4a-ethanonaphthalene-1- carboxylate (82) To a solution of 81 (0.029 mmol, 1 equiv) in methanol (0.06 mL) in a loosely capped vial was added K2CO3 (0.013 mmol, 0.45 equiv) at 23 ºC in three portions over 6 h. NaHSO3 (0.1 mmol, 3.5 equiv) and water (0.06 mL) were subsequently added, and the vial was sealed and heated to 80 ºC for 3 h. The reaction mixture was diluted with CHCl3, rinsed with 1 M HCl, and the aqueous layer was extracted with CHCl3 (3x). The combined organic layers were neutralized with a saturated solution of NaHCO3, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by preparatory thin layer chromatography (35% EtOAc/hexanes) afforded the title compound as a colorless oil (1.8 mg, 0.0056 mmol, 19% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.30 (m, 5H), 5.19 – 5.06 (m, 3H), 2.48 (m, 1H), 2.41 (dt, J = 19.2, 2.8 Hz, 1H), 2.29 (dt, J = 6.9, 2.0 Hz, 1H), 2.16 – 2.04 (m, 3H), 1.98 (s, 3H), 1.94 – 1.89 (m, 1H), 1.87 – 1.79 (m, 3H), 1.78 – 1.73 (m, 1H), 1.71 (m, 2H), 1.46 – 1.29 (m, 3H). 13 C NMR (100 MHz, CDCl3): δ 212.2, 173.9, 170.2, 135.9, 128.8, 128.5, 128.3, 70.8, 66.9, 49.4, 48.5, 40.5, 37.9, 30.7, 29.0, 26.7, 25.8, 22.9, 21.3, 15.7. 261 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates IR (Neat Film, NaCl): 2928, 1781, 1375, 1246, 1173 cm–1. HRMS (MM: FD+): m/z calc’d for C22H26O5 [M]+: 370.1780, found 370.1774. Optical Rotation: [α]D21 –18.3 (c 0.18, CHCl3). Preparation of Additional Compounds Me O O KHMDS (1.0 equiv) 18-crown-6 (1.0 equiv) BF3•OEt2 (1.2 equiv) 41a N N O Me Me O H CO2Bn O O THF, –78 ºC, 2 h Me H CO2Bn 59 benzyl (3aR,6R,7S,7aR)-4-oxooctahydro-3a,6-ethanoindene-7-carboxylate (59)42 To a solution of KHMDS (40 mg, 0.20 mmol, 1.0 equiv) and 18-crown-6 (53 mg, 0.20 mmol, 1 equiv) in THF (2.0 mL) at –78 ºC was added a solution of 41a (60 mg, 0.20 mmol, 1 equiv). Stirring was continued at –78 ºC for 30 minutes, then a pre-mixed solution of 3methylbut-2-en-1-yl 1H-imidazole-1-carboxylate (43 mg, 0.24 mmol, 1.2 equiv) and boron trifluoride diethyl etherate (30 µL, 0.24 mmol, 1.2 equiv) in THF (1.2 mL) was added dropwise. After two additional hours of stirring at –78 ºC, EtOAc and saturated aqueous NH4Cl were added. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and solvent was removed in vacuo. The crude mixture was purified by silica gel flash column chromatography (0–40% EtOAc/hexanes) to afford enol carbonate 59 as a colorless oil (44 mg, 0.11 mmol, 55% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.29 (m, 5H), 5.70 (d, J = 6.8 Hz, 1H), 5.42 – 5.36 (m, 1H), 5.09 (d, J = 3.6 Hz, 2H), 4.65 (d, J = 7.3 Hz, 2H), 3.08 – 2.96 (m, 1H), 2.25 (d, J Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 262 = 5.6 Hz, 1H), 2.07 – 1.97 (m, 2H), 1.91 – 1.79 (m, 3H), 1.77 (s, 3H), 1.73 (s, 3H), 1.63 – 1.54 (m, 2H), 1.52 – 1.38 (m, 3H), 1.35 – 1.28 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 174.9, 155.6, 153.5, 140.6, 136.4, 128.7, 128.2, 128.0, 117.9, 112.8, 66.3, 65.3, 51.3, 48.1, 48.1, 35.5, 28.4, 28.4, 27.3, 25.9, 24.6, 22.8, 18.3. IR (Neat Film, NaCl): 2953, 2870, 1754, 1735, 1241, 1226, 1150 cm-1 HRMS (MM: FD+): m/z calc’d for C25H30O5 [M]+: 410.2093, found 410.2094. SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 3.05, major = 3.40. 4.4.3 DETERMINATION OF ABSOLUTE AND RELATIVE STEREOCHEMISTRY BY VCD SPECTROSCOPY Experimental Protocol: A solution of the compound of interest (50 mg/mL) in CDCl3 was loaded into a front-loading SL-4 cell (International Crystal Laboratories) possessing BaF2 windows and a 100 mm path length. Infrared (IR) and VCD spectra were acquired on a BioTools ChiralIR-2X VCD spectrometer as a set of 24 one-hour blocks (24 blocks, 3120 scans per block) in dual PEM mode. A 15-minute acquisition of neat (+)-α-pinene control yielded a VCD spectrum in agreement with literature spectra. IR and VCD spectra were background corrected using a 30-minute block IR acquisition of the empty instrument chamber under gentle N2 purge, and were solvent corrected using a 16-hour (16 blocks, 3120 scans per block) IR/VCD acquisition of CDCl3 in the same 100 μm BaF2 cell. The reported spectra represent the result of block averaging. Both enantiomers of compounds 41a, 41q, and 41q’ were prepared from the (S) and (R) enantiomers of the t-BuPHOX ligand. Data were collected for both enantiomers of Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 263 compounds at identical concentration and the final reported VCD spectra are the halfdifference of the spectra of the compounds derived from the (S) minus (R) enantiomer of ligand. Due to limited sample size, spectra of cycloadducts 41k’ and 41k’’ were collected at concentrations of 11.7 and 9.3 mg/mL, respectively. Computational Protocol: An arbitrarily chosen enantiomer of the compound of interest was subjected to an exhaustive initial molecular mechanics-based conformational search (OPLS_2005 force field, CHCl3 solvent, 10.0 kcal/mol cutoff, “Enhanced” torsional sampling) as implemented in MacroModel program. 50 The resulting ensemble of conformers was subsequently optimized using the B3PW91 functional, cc-pVTZ(-f) basis, and implicit PBF solvation model for chloroform using the Jaguar program.51 Harmonic frequencies computed at the B3PW91/cc-pVTZ(-f)/PBF(chloroform) level were scaled by 0.98. The resultant structurally unique conformers possessing all positive Hessian eigenvalues were Boltzmann weighted by relative free energy at 298.15 K. The predicted IR and VCD frequencies and intensities of the retained conformers were convolved using Lorentzian line shapes (γ = 4 cm-1) and summed using the respective Boltzmann weights to yield the final predicted IR and VCD spectra. The predicted VCD of the opposite enantiomer was generated by inversion of sign. 264 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates VCD Analysis for diastereomers 41a, 41p, and 41p’ Figure 3.9. Three diastereomers 41a, 41q, and 41q’ to be compared to spectra computed from all eight possible stereoisomers. O O Me O Me O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) PhMe, 60 ºC, 14 h CO2Bn H CO2Bn 11a 10a O Me O O O Me O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.5 mol %) + PhMe, 60 ºC, 14 h 10q CO2Bn H CO2Bn H CO2Bn 11q 11q’ Computed Stereoisomers O O O O H CO2Bn H CO2Bn H CO2Bn H CO2Bn A_endo-trans A_exo-trans A_endo-cis A_exo-cis O O O O H CO2Bn H CO2Bn H CO2Bn H CO2Bn entA_endo-trans entA_exo-trans entA_endo-cis entA_exo-cis 265 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.10. Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_endo-trans.a IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 -4 1000 1400 1300 -1 1200 1100 1000 cm -1 [a] Experimental IR spectrum in good agreement with computed spectrum. Experimental VCD spectrum for 41a is in excellent agreement with computed spectrum for ent-A_endo-trans. Figure 3.11. Overlayed experimental and calculated VCD spectra for 41a – assigned as ent-A_endo-trans. 4.0 Experimental VCD Noise Computed VCD 3.0 2.0 5 1.0 0.0 -1.0 -2.0 -3.0 -4.0 1400 1300 1200 cm -1 1100 1000 266 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.12. Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_exo-trans.a IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -1 -4 1400 1300 1200 1100 1000 cm -1 [a] A shift of –3 cm-1 along x-axis applied to computed spectra in fitting. Experimental data from 41a do not match computed data of A_exo-trans. 267 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.13. Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_endo-cis.a IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -4 1400 1300 -1 [a] Experimental data from 41a do not match computed data of A_endo-cis. 1200 cm -1 1100 1000 268 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.14. Comparison of experimental VCD and IR spectra for product 41a to computed spectra for A_exo-cis.a IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 -1 1000 -4 1400 1300 1200 1100 1000 cm -1 [a] A shift of –3 cm-1 along x-axis applied to computed spectra in fitting. Experimental data from 41a do not match computed data of A_exo-cis. 269 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.15. Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_endo-trans.a IR Spectra 0.4 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 5 2 0 0.3 Absorbance -2 -4 4 0.2 Computed VCD ent-Computed VCD 5 2 0.1 0 -2 0.0 1400 1300 1200 cm -1 1100 1000 -4 1400 1300 1200 1100 1000 cm -1 [a] A shift of +14 cm-1 along x-axis applied to computed spectra in fitting. The IR spectrum of 41q contains similar features to the calculated spectrum for A_endo-trans; however, the VCD spectrum displays large discrepancies at 1174, 1152, 1330, 1076, and 992 cm-1. 41q is not assigned as A_endotrans. 270 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.16. Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_exo-trans. IR Spectra 0.4 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 5 2 0 0.3 Absorbance -2 -4 4 0.2 Computed VCD ent-Computed VCD 5 2 0.1 0 -2 0.0 1400 1300 1200 cm -1 1100 1000 -4 1400 1300 1200 cm -1 [a] Experimental data from 41q do not match computed data of A_exo-trans. 1100 1000 271 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.17. Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_endo-cis. IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 -4 1000 1400 1300 -1 1200 1100 1000 cm -1 [a] A shift of +5 cm-1 along x-axis applied to computed spectra in fitting. The IR spectrum of 41q is in good agreement with that of the computed IR spectrum of A_endo-cis. Experimental VCD spectrum for 41q is in excellent agreement with computed spectrum for ent-A_endo-cis. Figure 3.18. Overlayed experimental and calculated VCD spectra for 41q – assigned as ent-A_endo-cis. 4.0 Experimental VCD Noise Computed VCD 3.0 2.0 5 1.0 0.0 -1.0 -2.0 -3.0 -4.0 1400 1300 1200 cm -1 1100 1000 272 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.19. Comparison of experimental VCD and IR spectra for product 41q to computed spectra for A_exo-cis.a IR Spectra 0.5 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 5 0.4 0 -2 Absorbance 0.3 -4 4 Computed VCD ent-Computed VCD 0.2 5 2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -4 1400 1300 -1 [a] Experimental data from 41q do not match computed data of A_exo-cis. 1200 cm -1 1100 1000 273 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.20. Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_endo-trans.a IR Spectra 0.8 VCD Spectra 3 Experimental IR Computed IR Experimental VCD Noise 2 0.7 5 1 0 0.6 -1 Absorbance 0.5 -2 -3 3 0.4 2 0.3 Computed VCD ent-Computed VCD 5 1 0.2 0 -1 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -3 -1 1400 1300 1200 1100 1000 cm -1 [a] The VCD spectrum was baseline-corrected with a shift of +7 cm-1 along y-axis. Experimental data from 41q’ do not match computed data of A_endo-trans. 274 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.21. Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_exo-trans.a IR Spectra 0.8 VCD Spectra 3 Experimental IR Computed IR Experimental VCD Noise 2 0.7 5 1 0 0.6 -1 Absorbance 0.5 -2 -3 3 0.4 2 0.3 Computed VCD ent-Computed VCD 5 1 0.2 0 -1 0.1 -2 0.0 1400 1300 1200 cm -1 1100 1000 -3 1400 1300 1200 1100 1000 cm -1 [a] The VCD spectrum of 41q’ was baseline-corrected with a shift of +7 cm-1 along y-axis. A shift of 15 cm-1 along x-axis applied to computed spectra in fitting. Experimental data from 41q’ do not match computed data of A_exo-trans. 275 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.22. Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_endo-cis.a IR Spectra 0.8 VCD Spectra 3 Experimental IR Computed IR Experimental VCD Noise 2 0.7 5 1 0 0.6 -1 Absorbance 0.5 -2 -3 3 0.4 2 0.3 Computed VCD ent-Computed VCD 5 1 0.2 0 -1 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -3 1400 1300 -1 1200 1100 1000 cm -1 [a] The VCD spectrum of 41q’ was baseline-corrected with a shift of +7 cm-1 along y-axis. Experimental data from 41q’ do not match computed data of A_endo-cis. 276 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.23. Comparison of experimental VCD and IR spectra for product 41q’ to computed spectra for A_exo-cis.a IR Spectra 0.8 VCD Spectra 3 Experimental IR Computed IR Experimental VCD Noise 2 0.7 5 1 0 0.6 -1 Absorbance 0.5 -2 -3 3 0.4 2 0.3 Computed VCD ent-Computed VCD 5 1 0.2 0 -1 0.1 -2 0.0 1400 1300 1200 cm 1100 -3 1000 1400 1300 -1 1200 1100 1000 cm -1 [a] The VCD spectrum of 41q’ was baseline-corrected with a shift of +7 cm-1 along y-axis. A shift of +7 cm-1 along x-axis applied to computed spectra in fitting. Experimental VCD spectrum for 41q’ is in good agreement with computed spectrum for ent-A_exo-cis. Figure 3.24. Overlayed experimental and calculated VCD spectra for 41q’ – assigned as ent-A_exo-cis. 2.0 Experimental VCD Noise Computed VCD 1.5 1.0 5 0.5 0.0 -0.5 -1.0 -1.5 -2.0 1400 1300 1200 cm -1 1100 1000 277 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.25. Three diastereomers 41k, 41k’, and 41k’’ to be compared to spectra computed from all eight possible stereoisomers. O O Me O O Me O Pd2(dba)3 (2.5 mol%) (S)-t-BuPHOX (6.5 mol%) O + + PhMe, 60 ºC, 14 h CO2Ph 40k H CO2Ph H CO2Ph H CO2Ph 41k 41k’ 41k’’ Computed Stereoisomers O O O O H CO2Ph H CO2Ph H CO2Ph H CO2Ph B_endo-trans B_exo-trans B_endo-cis B_exo-cis O O O O H CO2Ph H CO2Ph H CO2Ph H CO2Ph entB_endo-trans entB_exo-trans entB_endo-cis entB_exo-cis 278 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.26. Experimental VCD and IR spectra for product 41k compared to computed spectra for B_endo-trans.a IR Spectra 0.8 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 Absorbance 5 0.7 0.6 0 0.5 -2 0.4 -4 4 Computed VCD ent-Computed VCD 0.3 5 2 0.2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 -4 1000 1400 1300 -1 1200 1100 1000 cm -1 [a] Experimental IR spectrum in good agreement with computed spectrum. Experimental VCD spectrum for 41k is in excellent agreement with computed spectrum for B_endo-trans. Figure 3.27. Overlayed experimental and calculated VCD spectra for 41k – assigned as B_endo-trans. 4.0 Experimental VCD Noise Computed VCD 3.0 2.0 5 1.0 0.0 -1.0 -2.0 -3.0 -4.0 1400 1300 1200 cm -1 1100 1000 279 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.28. Experimental VCD and IR spectra for product 41k compared to computed spectra for B_exo-trans.a IR Spectra 0.8 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 Absorbance 5 0.7 0.6 0 0.5 -2 0.4 -4 4 Computed VCD ent-Computed VCD 0.3 5 2 0.2 0 0.1 -2 0.0 1400 1300 1200 cm -1 1100 1000 -4 1400 1300 1200 1100 1000 cm -1 [a] Experimental IR spectrum in good agreement with computed spectrum. However, VCD spectrum contain key sign mismatches in regions around 1400 and 1100 cm-1. Hence, 41k is not assigned as B_exo-trans. 280 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.29. Experimental VCD and IR spectra for product 41k compared to computed spectra for B_endo-cis.a IR Spectra 0.8 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 Absorbance 5 0.7 0.6 0 0.5 -2 0.4 -4 4 Computed VCD ent-Computed VCD 0.3 5 2 0.2 0 0.1 -2 0.0 1400 1300 1200 cm -1 1100 1000 -4 1400 1300 1200 1100 cm -1 [a] Experimental data do not match computed data and 41k is not assigned as B_endo-cis. 1000 281 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.30. Experimental VCD and IR spectra for product 41k compared to computed spectra for B_exo-cis.a IR Spectra 0.8 VCD Spectra 4 Experimental IR Computed IR Experimental VCD Noise 2 Absorbance 5 0.7 0.6 0 0.5 -2 0.4 -4 4 Computed VCD ent-Computed VCD 0.3 5 2 0.2 0 0.1 -2 0.0 1400 1300 1200 cm 1100 1000 -1 -4 1400 1300 1200 1100 1000 cm -1 [a] Experimental data do not match computed data and 41k is not assigned as B_exo-cis. Due to limited sample size (< 3 mg), useful VCD spectra of 41k’ were unable to be obtained. Enantiomeric series was assigned by analogy to the 41a, 41q and 41q’ series. The 1000–1500 cm-1 region of the IR spectra are still analyzed to support relative stereochemical assignments made by 2D NMR. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 282 Figure 3.31. Experimental IR spectrum for product 41k’ compared to computed spectra for B_endo-trans (top left), B_exo-trans (top right), B_endo-cis (bottom left), B_exo-cis (bottom right).a [a] The trans relationship is supported, in accord with 2D NMR data. In contrast to endo-cis and exocis, the computed IR spectra for both endo-trans and exo-trans are similar and do not offer key features for distinguishing the two. Given the trans stereochemistry, with 41k known as B_endo-trans, 41k’ is assigned as B_exo-trans with absolute stereochemistry assigned based on analogy to 41q’. 283 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.32. Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_endo-trans.a IR Spectra VCD Spectra 3 Experimental IR Computed IR 0.14 Experimental VCD Noise 2 1 5 0.12 0 Absorbance 0.10 -1 -2 0.08 -3 3 Computed VCD ent-Computed VCD 0.06 2 1 5 0.04 0 0.02 -1 -2 0.00 1400 1300 1200 cm -1 1100 1000 -3 1400 1300 1200 1100 cm -1 [a] Experimental data do not match computed data and 41k’’ is not assigned as B_endo-trans. 1000 284 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.33. Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_exo-trans.a IR Spectra VCD Spectra 3 Experimental IR Computed IR 0.14 Experimental VCD Noise 2 1 5 0.12 0 Absorbance 0.10 -1 -2 0.08 -3 3 Computed VCD ent-Computed VCD 0.06 2 1 5 0.04 0 0.02 -1 -2 0.00 1400 1300 1200 cm -1 1100 1000 -3 1400 1300 1200 1100 cm -1 [a] Experimental data do not match computed data and 41k’’ is not assigned as B_exo-trans. 1000 285 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.34. Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_endo-cis.a IR Spectra VCD Spectra 3 Experimental IR Computed IR 0.14 Experimental VCD Noise 2 1 5 0.12 0 Absorbance 0.10 -1 -2 0.08 -3 3 Computed VCD ent-Computed VCD 0.06 2 1 5 0.04 0 0.02 -1 -2 0.00 1400 1300 1200 cm 1100 -3 1000 1400 1300 -1 1200 1100 1000 cm -1 [a] Experimental IR spectrum is in agreement with the computed spectrum of B_endo-cis. Assignment of absolute stereochemistry is based the on the sign of the three most intense peaks in VCD spectrum, 1368, 1350, and 1085 cm-1. These match B_endo-cis, the same enantiomeric series as 41k. Figure 3.35. Overlayed experimental and calculated VCD spectra for 41k’’ – assigned as B_endo-cis. 2.0 Experimental VCD Noise Computed VCD 1.5 1.0 5 0.5 0.0 -0.5 -1.0 -1.5 -2.0 1400 1300 1200 cm -1 1100 1000 286 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.36. Experimental VCD and IR spectra for product 41k’’ compared to computed spectra for B_exo-cis.a IR Spectra VCD Spectra 3 Experimental IR Computed IR 0.14 Experimental VCD Noise 2 1 5 0.12 0 Absorbance 0.10 -1 -2 0.08 -3 3 Computed VCD ent-Computed VCD 0.06 2 1 5 0.04 0 0.02 -1 -2 0.00 1400 1300 1200 cm -1 1100 1000 -3 1400 1300 1200 1100 cm -1 [a] Experimental data do not match computed data and 41k’’ is not assigned as B_exo-cis. 1000 287 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 3.4.4 2D NMR ANALYSIS OF SELECT COMPOUNDS Figure 3.37. 1H-1H COSY NMR spectrum of 41a (400 MHz, CDCl3). Hc Hd Hb Hh Hj He 0.7 Hk 0.8 Hg O Hf Hd He Hi 0.9 1.0 Ha Hc BnO2C 1.1 1.2 1.3 Hb 1.4 1.5 1.7 1.8 1.9 2.0 Hb–Ha Hd–He 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.8 2.6 2.4 2.2 2.0 ppm 1.8 1.6 1.4 1.2 f1 (ppm) 1.6 Hb–Hf 288 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.38. 1H-13C HSQC NMR spectrum of 41a (400 MHz, CDCl3). 18 20 22 24 26 28 30 34 36 Hh Hk Hj Ha He BnO2C Hd 40 42 Hi Hd He 38 Hg O Hf Ha Hb f1 (ppm) 32 Hc Hc 44 46 Hb 48 50 2.8 2.6 2.4 2.2 2.0 ppm 1.8 1.6 1.4 1.2 Figure 3.39. 1H-1H NOESY NMR spectrum of 41a (400 MHz, CDCl3). 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.8 1.9 2.0 2.1 Hh Hj Hi Hd He BnO2C 2.4 2.2 2.0 1.8 ppm 1.6 1.4 2.3 Hg O Hf 2.6 2.2 Hk 1.2 2.4 2.5 Ha Hc 2.6 2.7 Hb 1.0 2.8 f1 (ppm) 1.7 Hd–Hf 289 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.40. 1H-1H COSY NMR spectrum of 41p (400 MHz, CDCl3). Hh/i Hh/i He Hd Hb Hc Ha 1.2 He–Hk 1.4 Hb–Hf Hc–Hf 1.6 1.8 Hc–Ha 2.0 Hb–Ha 2.2 Hi–Hh 2.6 He–Hd f1 (ppm) 2.4 Hd–Hc 2.8 Hh Hk Hj 3.0 Hg O Hf Hi Hd He 3.2 3.4 Ha Hc BnO2C 3.6 Hb 3.8 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 ppm 2.2 2.0 1.8 1.6 1.4 1.2 Figure 3.41. 1H-13C HSQC NMR spectrum of 41p (400 MHz, CDCl3). Hh Hj 20 Hk 22 Hg O Hf Hi Hd He BnO2C 24 Hj Hk Ha Hc 26 28 Hf Hb Hg 30 32 Hc 36 38 40 H b H 42 a 44 Hd H 46 e 48 50 52 3.6 3.4 3.2 3.0 2.8 2.6 ppm 2.4 2.2 2.0 1.8 1.6 1.4 f1 (ppm) 34 Hh Hi 290 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.42. 1H-1H NOESY NMR spectrum of 41p (400 MHz, CDCl3). Hk 1.0 Hg O Hf Hi Hd Hc–Hf Hc–Hg Ha–Hg Ha He Hc BnO2C 1.2 He–Hk 1.4 1.6 Hd–Hf Hb He–Hj Hb–Ha 1.8 Hc–Ha 2.0 2.2 Hh–Hi 2.4 Hd–Hc He–Hb f1 (ppm) Hh Hj 2.6 2.8 3.0 He–Hi 3.2 3.4 3.6 3.8 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 ppm 2.4 2.2 2.0 1.8 1.6 1.4 Figure 3.43. 1H-1H COSY NMR spectrum of 41q (400 MHz, CDCl3). 0.4 Hg O Hf He 0.6 Ha Hd Hc O O 0.8 Hb 1.0 Ph 1.2 1.4 1.6 1.8 Ha–Hc 2.0 Hc–Hb/d 2.2 2.4 Hc–Hb/d 2.6 2.8 3.0 3.2 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 3.4 f1 (ppm) Hb–Hf Hb–Hf/g 291 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.44. 1H-13C HSQC NMR spectrum of 41q (400 MHz, CDCl3). 18 Hg O Hf He 20 Ha Hd Hc O 22 24 Hb O Hf/g 26 Ph 28 32 34 f1 (ppm) 30 Hc 36 38 Hb Ha 40 42 Hd 44 He 46 48 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 0.8 Figure 3.45. 1H-1H NOESY NMR spectrum of 41q (400 MHz, CDCl3). 0.6 Hg O Hf He 0.8 Ha Hd 1.0 Hc O 1.2 Ph 1.4 Hc–Hf/g Hd–Hf 1.6 Ha–Hg 1.8 2.0 Hb–Ha 2.2 Hd–Hc 2.4 2.6 2.8 3.0 3.2 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 f1 (ppm) O Hb 292 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.46. 1H-1H COSY NMR spectrum of 41q’ (400 MHz, CDCl3). Hg O BnO2C 0.8 Ha He Hc Hd 1.0 1.2 Hb Hd–Hg 1.4 Hc–Hg 1.6 1.8 Hc–Ha,b,f 2.0 Hd–He 2.2 2.4 Hd–Hc 2.6 2.8 3.0 3.2 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 Figure 3.47. 1H-13C HSQC NMR spectrum of 41q’ (400 MHz, CDCl3). 18 Hg O Hf BnO2C He 20 Ha Hc Hd Hf Hg 22 24 Hb 26 28 30 Hc 34 36 38 40 He 42 Hd 44 Ha/b 46 48 50 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 f1 (ppm) 32 f1 (ppm) Hf 293 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.48. 1H-1H NOESY NMR spectrum of 41q’ (400 MHz, CDCl3). BnO2C He 1.1 Hg O Hf 1.2 1.3 Ha Hd Hc a H –H Hb c H –H g 1.4 1.5 g 1.6 1.7 1.8 1.9 2.1 Hc–Hf 2.2 Hd–Hb f1 (ppm) 2.0 Hd–He 2.3 2.4 Hd–Hc 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.2 3.4.5 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 GENERAL COMPUTATIONAL DETAILS General Notes All quantum mechanics calculations were carried out with the ORCA program.52 Geometry optimizations, harmonic frequency calculations, and single-point energy evaluations were carried out with density functional theory (DFT). The PBE0 functional53 paired with Becke–Johnson damped D4 dispersion corrections54, henceforth referred to as PBE0-D4, was used as it has proven a robust method for such systems in our prior studies.55 For geometry optimization and harmonic frequency calculations, Pd is described by the def2-TZVP basis set 56 and the ECP28MWB small-core (18 explicit valence electrons) quasi-relativistic pseudopotential,57 while C, H, N, and P are assigned the def2-SVP basis. Diffuse functions are added to oxygen (ma-def2-SVP). Herein, we refer to this composite Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 294 basis set as BS1. Geometry optimization and harmonic frequency calculations were carried out with the CPCM implicit solvation model for toluene (PhMe, e = 2.4). For all calculations employing CPCM, surface charges are described by the improved Gaussian charge scheme of Neese and coworkers with a scaled Van der Waals cavity (a = 1.2).58 All Hessians were computed analytically. Stationary points are characterized by the correct number of imaginary vibrational modes (zero for minima and one for saddle points). Intrinsic reaction coordinate (IRC) analysis confirms the nature of transition states. 59 Cartesian coordinates of all optimized structures are included as “.xyz” files are available online in a compressed in a zip file format. Electronic energies are further refined with single-point calculations employing the PBE0-D4 functional60 and the def2-TZVPP basis set on all atoms (with the ECP28MWB pseudopotential for Pd) with additional diffuse functions on O (ma-def2-TZVPP). This mixed basis is henceforth referred to as BS2. Solvation was accounted for with CPCM as mentioned above (PhMe, e = 2.4). Final Gibbs free energies were obtained by applying thermodynamic corrections obtained at the optimization level of theory to these refined electronic energies. Thermodynamic corrections from harmonic frequency calculations employ the quasi-ridged rotor harmonic oscillator approach to correct for the breakdown of the harmonic oscillator approximation at low vibrational frequencies.61 Note that free energies are adjusted to a 1 M standard state. The translational (Strans) and rotational entropy (Srot) contributions to the Gibbs free energy calculated for a complex in condensed phase are ca. 40–60% of the values obtained assuming an ideal gas. 62 As suggested in the literature, Strans and Srot obtained by ideal gas treatment are scaled by a factor of 0.5 to Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 295 obtain the final condensed phase values.63 Hence, the Gibbs free energy at 333.15 K is calculated as: 1 1 ∗ +,!"#$% = ()$,"#$% + /0( + (1234" + (2#1 + (%56 + 76 8 − 8 :;)$ + ;%56 + ;1234" + ;2#1 > 2 2 + ∆! @→∗ The resolution of identity (RI) and Chain-of-Spheres (COS) approximations are employed for efficient evaluation of Coulomb and exchange integrals, respectively.64 The def2/J auxiliary basis 65 is employed for all atoms except oxygen, for which a suitable auxiliary was obtained via the automatic generation algorithm in the ORCA program (keyword: AutoAux). 66 Very fine grid settings are employed in all calculations (optimization/frequency calculations: DefGrid2, single point calculations: DefGrid3). Conformer searching was carried out for each stationary point using the metadynamics-based CREST program (using GNF-FF) from the Grimme group. Duplicate conformers were removed, and low energy conformers were subsequently optimized and energies evaluated at the cheaper PBE0-D4/def2-TZVP (Pd), ma-def2-SVP (O), def2SVP/CPCM(PhMe)//PBE-D4/def2-TZVP (Pd), ma-def2-SV(P) (O), def2-SV(P) level of theory. The final low energy conformers were further optimized at the level of theory mentioned prior. Note that for enantiodetermining transition states (such as TS2 and TS3) conformer searching also explicitly includes rotation about the Pd–O–C–C(enolate) dihedral, consideration of s-cis and s-trans ester conformations, as well as all permutations of the considered stereochemical elements. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 296 Finally, conformational entropy 67 (entropy arising from multiple low energy thermally populated conformers) is accounted for by the mixture of components model of DeTar.68 Conformational entropy (Sconf) is defined as: !"#$% = −( ) *+ ln (*+ ) where *+ is the mole fraction (thermal population) of the ith conformer based on its relative free energy within the conformer ensemble. Given the computational demand for computing free energies for large ensembles of conformers, *+ was derived from the free energies initially computed during the conformer screening process (PBE0-D4/def2-TZVP (Pd), ma-def2-SVP (O), def2-SVP/CPCM(PhMe)//PBE-D4/def2-TZVP (Pd), ma-def2SV(P) (O), def2-SV(P)) ∗ 1%+$23 = 14#35 − 7!"#$% For the systems at hand, values of 7!"#$% (at 333.15 K) can be on the order of magnitude of a few kcal/mol. Comparison of Barrier Heights to Inner-sphere Reductive Elimination Employing cyclohexanone-derived Pd enolate as a model system (13, 116, 117), the barrier to inner-sphere reductive elimination was investigated while varying substitution on the allyl moiety (Figure 3.49). For further discussion on the seven-centered cyclic reductive elimination process, see Chapters 1–2. 297 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.49. Relative free energies for various inner-sphere reductive elimination transition states from allyl (13), cinnamyl (116), and prenyl (117) complexes.a Starting Enolate O N Pd P t-Bu O O Me N P Pd t-Bu Me Me N P Pd t-Bu O O O N P Pd t-Bu O N P Pd t-Bu O O Me (Si/chair)-TS20 Grel = 16.0 13 Grel = 0.0 (Si/boat)-TS20 Grel = 14.9 (Re/chair)-TS20 Grel = 12.9 O O O Me Me N O P Pd t-Bu Ph H H N O P Pd t-Bu Ph TS29a Grel = 22.4 TS29b Grel = 16.8 O Ph O Me N O P Pd t-Bu 116 Grel = 0.0 O Me O Starting Enolate O Me N O P Pd t-Bu Me TS29i Grel = 25.1 TS29j Grel = 23.8 Me TS29d Grel = 26.1 H N P Pd t-Bu O Ph Me TS29g Grel = 19.2 O Ph Me H TS29h Grel = 26.1 “Me down” (Re face) [Favored] “Me up” (Si face) [Disfavored] Me H O N P Pd t-Bu Ph N O P Pd t-Bu Me Me Me O H TS29f Grel = 21.4 O N P Pd O t-Bu Ph TS29c Grel = 16.5 H TS29e Grel = 21.9 (Re/boat)-TS20 Grel = 18.2 O O N H O P Pd t-Bu Ph Me N P Pd t-Bu Ph Me “Me down” (Re face) [Favored] “Me up” (Si face) [Disfavored] Starting Enolate N Pd P t-Bu “Me down” (Re face) [Favored] “Me up” (Si face) [Disfavored] O Me O O N Me O P Pd t-Bu Me N P Pd O t-Bu Me Me Me Me O N Pd P t-Bu O Me Me 117 Grel = 0.0 TS29k Grel = 21.6 TS29l Grel = 27.7 Me O O Me N O P Pd t-Bu Me N P Pd t-Bu O Me TS29m Grel = 28.5 TS29n Grel = 26.8 O Me Me Me O N P Pd t-Bu Me O TS29o Grel = 25.7 Me Me N P Pd t-Bu O Me Me Me TS29p Grel = 31.4 [a] Gibbs free energies in kcal/mol computed at the PBE0-D4/BS2/CPCM(PhMe)//PBE0D4/BS1/CPCM(PhMe) level of theory at 333.15 K. Mechanism of Catalyst Turnover Of all the sampled transition states, we found the outer-sphere and N-detached inner-sphere pathways to be highly competitive and lowest in energy. Additional transition states were 298 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates also explored, and the lowest energy pathway of each type of mechanism are shown in the following table. Figure 3.50. Relative free energies for various proton transfer transition states from post-cycloaddition enolate 56.a Starting Enolate Inner-Sphere Pathways Pd–H Transfer to Enolate BnO2C BnO2C Me O N P N P O Pd O O O H N P O Pd t-Bu TS34 Grel = 32.5 TS35 Grel = 45.2 Me N P O Pd t-Bu Me t-Bu BnO2C O Pd H H BnO2C TS36 Grel = 31.8 β-Hydride Elimination t-Bu Me 56 Grel = 0.0 BnO2C O BnO2C N Pd P Me t-Bu H O BnO2C O O P N Pd O N O Me P Me Pd t-Bu H H tBu TS37 Grel = 64.5 TS38 Grel = 55.6 TS39 Grel = ~29-30 [a] Gibbs free energies in kcal/mol computed at the PBE0-D4/BS2/CPCM(PhMe)//PBE0D4/BS1/CPCM(PhMe) level of theory at 333.15 K. Mechanism of Premature Protonation Analogous to the catalyst turnover mechanism, N-detached inner-sphere pathways were found to be lowest-energy for premature protonation. Of these transition states (TS40a and TS40b) that would yield enantiomeric protonation products, the lowest-energy TS40a provides the enantiomer consistent with the major reaction product. In addition, an outersphere pathway (TS41) was also found to be competitive. 299 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Figure 3.51. Relative free energies for various proton transfer transition states from pre-cycloaddition enolate 55.a Starting Enolate N-Detached Inner-Sphere Pathways Outer-Sphere Pathway R O N P O PdII t-Bu Me Me P N t-Bu 55 Grel = 0.0 O PdII O H P N Me TS40a Grel = 20.2 R O R t-Bu PdII O O H R N P Me PdII H O t-Bu Me TS40a Grel = 21.4 TS41 Grel = 23.4 [a] Gibbs free energies in kcal/mol computed at the PBE0-D4/BS2/CPCM(PhMe)//PBE0D4/BS1/CPCM(PhMe) level of theory at 333.15 K. 300 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Intrinsic Bonding Orbital (IBO) Analysis of Inner-sphere Proton Transfer IBO analysis along the reaction coordinate of the N-detached inner-sphere proton transfer to post-cycloaddition enolate confirms the role of prenyl as a proton source. Figure 3.52. IBO analysis of N-detached inner-sphere mechanism and corresponding derived arrow-pushing mechanism. BnO2C BnO2C BnO2C P = (S)-t-BuPHOX 2 2 2 P Pd O H7 9 N Me 60 3 P Pd O H7 9 8 N 3 3 8 P O H7 Pd 9 N Me Me TS32 N 8 Derived Arrow-Pushing Mechanism 61 BnO2C φ1 P Pd N O H Me BnO2C φ2 P N Pd O H Me Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 301 pKa Calculations and Thermodynamics of Outer-Sphere Proton Transfer The pKa values of the p-allyl Pd complex 118 and ketones were calculated, and the results verify that the proton transfers to both pre- and post-cycloaddition enolates are thermodynamically favorable. Figure 3.53. Computed pKa values of cationic p-allyl Pd complex 119 and ketones 49a and 41a. O P O Hb Hc N Pd Me Ha H CO2Bn BnO2C 41a 49a 118 Compound Proton pKa in water pKa in DMSO 118 Ha 20.0 19.5 49a Hb 30.1 30.3 41a Hc 31.3 30.8 P P N N Pd Pd Me H Me O O R H R 302 Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates Enantiodetermining [4+2] cycloaddition Figure 3.54. (A) Comparison of internal versus external dienophile approach to both enantiotopic diene faces. (B) Select low energy conformers of TS31 (allyl isomers not pictured). (C) Additional space-filling models for TS30 and TS31. A. External versus internal dienophile approach in pathways to 41a and (ent)-41a. TS leading to 41a TS leading to ent-41a (minor) R O N P Pd t-Bu O Me O N P Pd t-Bu Me R Me O R O N P Pd t-Bu O N P Pd t-Bu O Me Me Me TS30 TS42 ∆G‡rel = 6.4 kcal/mol TS31 ∆G‡rel = 1.6 kcal/mol TS43 ∆G‡rel = 3.5 kcal/mol [Lowest energy to ent-41a] B. Select low energy conformers of TS31: (Grel = 1.6 kcal/mol) (Grel = 2.3 kcal/mol) (Grel = 2.3 kcal/mol) C. 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The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 313 Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Account. 2008, 120, 215–241. (61) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chem. Eur. J. 2012, 18, 9955–9964. (62) Izato, Y.; Matsugi, A.; Koshi, M.; Miyake, A. A Simple Heuristic Approach to Estimate the Thermochemistry of Condensed-Phase Molecules Based on the Polarizable Continuum Model. Phys. Chem. Chem. Phys. 2019, 21, 18920–18929. (63) Finkelstein, A. V.; Janin, J. The Price of Lost Freedom: Entropy of Bimolecular Complex Formation. Protein Eng. Des. Sel. 1989, 3, 1–3. (64) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree-Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree-Fock Exchange. Chem. Phys. 2009, 356, 98–109. (65) Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057–1065. (66) Stoychev, G. L.; Auer, A. A.; Neese, F. Automatic Generation of Auxiliary Basis Sets. J. Chem. Theory Comput. 2017, 13, 554–562. (67) (a) Pracht, P.; Grimme, S. Calculation of Absolute Molecular Entropies and Heat Capacities Made Simple. Chem. Sci. 2021, 12, 6551–6568. (b) Gorges, J.; Grimme, S.; Hansen, A.; Pracht, P. Towards Understanding Solvation Effects on the Conformational Entropy of Non-Rigid Molecules. Phys. Chem. Chem. Phys. 2022, 24, 12249–12259. Chapter 3 – Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates (68) 314 (a) DeTar, D. F. Theoretical Ab Initio Calculation of Entropy, Heat Capacity, and Heat Content. J. Phys. Chem. A 1998, 102, 5128–5141. See also: (b) Guthrie, J. P. Use of DFT Methods for the Calculation of the Entropy of Gas Phase Organic Molecules: An Examination of the Quality of Results from a Simple Approach. J. Phys. Chem. A 2001, 105, 8495–8499. Appendix 2 – Spectra Relevant to Chapter 3 315 APPENDIX 2 Spectra Relevant to Chapter 3: Catalytic Asymmetric [4+2] Cycloaddition of Pd Enolates 10 41a H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.1. 1H NMR (400 MHz, CDCl3) of compound 41a. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 316 Appendix 2 – Spectra Relevant to Chapter 3 317 Figure A2.2. Infrared spectrum (Thin Film, NaCl) of compound 41a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.3. 13C NMR (100 MHz, CDCl3) of compound 41a. 0 10 41b H CO2Et O 9 8 6 5 ppm 4 3 Figure A2.4. 1H NMR (400 MHz, CDCl3) of compound 41b. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 318 Appendix 2 – Spectra Relevant to Chapter 3 319 Figure A2.5. Infrared spectrum (Thin Film, NaCl) of compound 41b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.6. 13C NMR (100 MHz, CDCl3) of compound 41b. 0 10 41c H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.7. 1H NMR (400 MHz, CDCl3) of compound 41c. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 320 Appendix 2 – Spectra Relevant to Chapter 3 321 Figure A2.8. Infrared spectrum (Thin Film, NaCl) of compound 41c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.9. 13C NMR (100 MHz, CDCl3) of compound 41c. 0 10 41d H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.10. 1H NMR (400 MHz, CDCl3) of compound 41d. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 322 Appendix 2 – Spectra Relevant to Chapter 3 323 Figure A2.11. Infrared spectrum (Thin Film, NaCl) of compound 41d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.12. 13C NMR (100 MHz, CDCl3) of compound 41d. 0 10 41f H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.13. 1H NMR (400 MHz, CDCl3) of compound 41f. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 324 Appendix 2 – Spectra Relevant to Chapter 3 Figure A2.14. Infrared spectrum (Thin Film, NaCl) of compound 41f. Figure A2.15. 13C NMR (100 MHz, CDCl3) of compound 41f. 325 10 41j H COPh O 9 8 6 5 ppm 4 3 Figure A2.16. 1H NMR (400 MHz, CDCl3) of compound 41j. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 326 Appendix 2 – Spectra Relevant to Chapter 3 Figure A2.17. Infrared spectrum (Thin Film, NaCl) of compound 41j. Figure A2.18. 13C NMR (100 MHz, CDCl3) of compound 41j. 327 10 41k H CO2Ph O 9 8 6 5 ppm 4 3 Figure A2.19. 1H NMR (400 MHz, CDCl3) of compound 41k. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 328 Appendix 2 – Spectra Relevant to Chapter 3 Figure A2.20. Infrared spectrum (Thin Film, NaCl) of compound 41k. Figure A2.21. 13C NMR (100 MHz, CDCl3) of compound 41k. 329 10 41k’ H CO2Ph O 9 8 6 5 ppm 4 3 2 Figure A2.22. 1H NMR (400 MHz, CDCl3) of compound 41k’ . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 330 Appendix 2 – Spectra Relevant to Chapter 3 331 Figure A2.23. Infrared spectrum (CDCl3 solution) of compound 41k’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.24. 13C NMR (100 MHz, CDCl3) of compound 41k’. 0 10 41k’’ H CO2Ph O 9 8 6 5 ppm 4 3 2 Figure A2.25. 1H NMR (400 MHz, CDCl3) of compound 41k” . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 332 Appendix 2 – Spectra Relevant to Chapter 3 333 Figure A2.26. Infrared spectrum (CDCl3 solution) of compound 41k’’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.27. 13C NMR (100 MHz, CDCl3) of compound 41k’’. 0 10 41l H CO2Mes O 9 8 6 5 ppm 4 3 2 Figure A2.28. 1H NMR (400 MHz, CDCl3) of compound 41l. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 334 Appendix 2 – Spectra Relevant to Chapter 3 335 Figure A2.29. Infrared spectrum (Thin Film, NaCl) of compound 41l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.30. 13C NMR (100 MHz, CDCl3) of compound 41l. 0 10 41m H C(O)NHP O 9 8 6 5 ppm 4 3 Figure A2.31. 1H NMR (400 MHz, CDCl3) of compound 41m. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 336 Appendix 2 – Spectra Relevant to Chapter 3 337 Figure A2.32. Infrared spectrum (Thin Film, NaCl) of compound 41m. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.33. 13C NMR (100 MHz, CDCl3) of compound 41m. 0 10 41m’ H C(O)NHP O 9 8 6 5 ppm 4 3 2 Figure A2.34. 1H NMR (400 MHz, CDCl3) of compound 41m’ . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 338 Appendix 2 – Spectra Relevant to Chapter 3 339 Figure A2.35. Infrared spectrum (Thin Film, NaCl) of compound 41m’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.36. 13C NMR (100 MHz, CDCl3) of compound 41m’. 0 CbzN 10 41n H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.37. 1H NMR (400 MHz, CDCl3) of compound 41n. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 340 Appendix 2 – Spectra Relevant to Chapter 3 341 Figure A2.38. Infrared spectrum (Thin Film, NaCl) of compound 41n. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.39. 13C NMR (100 MHz, CDCl3) of compound 41n. 0 O N H O O 10 41o O 9 8 6 5 ppm 4 3 Figure A2.40. 1H NMR (400 MHz, CDCl3) of compound 41o. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 342 Appendix 2 – Spectra Relevant to Chapter 3 343 Figure A2.41. Infrared spectrum (Thin Film, NaCl) of compound 41o. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.42. 13C NMR (100 MHz, CDCl3) of compound 41o. 0 O O 10 O O 41o’ N H 9 8 6 5 ppm 4 3 2 Figure A2.43. 1H NMR (400 MHz, CDCl3) of compound 41o’ . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 344 Appendix 2 – Spectra Relevant to Chapter 3 345 Figure A2.44. Infrared spectrum (Thin Film, NaCl) of compound 41o’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.45. 13C NMR (100 MHz, CDCl3) of compound 41o’. 0 10 41p H CO2Bn O 9 8 6 5 ppm 4 3 2 Figure A2.46. 1H NMR (400 MHz, CDCl3) of compound 41p. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 346 Appendix 2 – Spectra Relevant to Chapter 3 347 Figure A2.47. Infrared spectrum (Thin Film, NaCl) of compound 41p. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.48. 13C NMR (100 MHz, CDCl3) of compound 41p. 0 10 41p’ H CO2Bn O 9 8 6 5 ppm 4 3 2 Figure A2.49. 1H NMR (400 MHz, CDCl3) of compound 41p’ . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 348 Appendix 2 – Spectra Relevant to Chapter 3 349 Figure A2.50. Infrared spectrum (Thin Film, NaCl) of compound 41p’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.51. 13C NMR (100 MHz, CDCl3) of compound 41p’. 0 10 41q H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.52. 1H NMR (400 MHz, CDCl3) of compound 41q. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 350 Appendix 2 – Spectra Relevant to Chapter 3 351 Figure A2.53. Infrared spectrum (Thin Film, NaCl) of compound 41q. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.54. 13C NMR (100 MHz, CDCl3) of compound 41q. 0 10 41q’ H CO2Bn O 9 8 6 5 ppm 4 3 2 Figure A2.55. 1H NMR (400 MHz, CDCl3) of compound 41q’ . 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 352 Appendix 2 – Spectra Relevant to Chapter 3 353 Figure A2.56. Infrared spectrum (Thin Film, NaCl) of compound 41q’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.57. 13C NMR (100 MHz, CDCl3) of compound 41q’. 0 10 41r H Me CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.58. 1H NMR (400 MHz, CDCl3) of compound 41r. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 354 Appendix 2 – Spectra Relevant to Chapter 3 Figure A2.59. Infrared spectrum (Thin Film, NaCl) of compound 41r. Figure A2.60. 13C NMR (100 MHz, CDCl3) of compound 41r. 355 Me 10 41s H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.61. 1H NMR (400 MHz, CDCl3) of compound 41s. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 356 Appendix 2 – Spectra Relevant to Chapter 3 357 Figure A2.62. Infrared spectrum (Thin Film, NaCl) of compound 41s. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.63. 13C NMR (100 MHz, CDCl3) of compound 41s. 0 EtO 10 41t H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.64. 1H NMR (400 MHz, CDCl3) of compound 41t. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 358 Appendix 2 – Spectra Relevant to Chapter 3 359 Figure A2.65. Infrared spectrum (Thin Film, NaCl) of compound 41t. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.66. 13C NMR (100 MHz, CDCl3) of compound 41t. 0 EtO 10 41t’ H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.67. 1H NMR (400 MHz, CDCl3) of compound 41t’ . 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 360 Appendix 2 – Spectra Relevant to Chapter 3 361 Figure A2.68. Infrared spectrum (Thin Film, NaCl) of compound 41t’. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.69. 13C NMR (100 MHz, CDCl3) of compound 41t’. 0 Me 10 41u H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.70. 1H NMR (400 MHz, CDCl3) of compound 41u. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 362 Appendix 2 – Spectra Relevant to Chapter 3 363 Figure A2.71. Infrared spectrum (Thin Film, NaCl) of compound 41u. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.72. 13C NMR (100 MHz, CDCl3) of compound 41u. 0 D 10 D-41f H CO2Bn O 9 8 6 5 ppm 4 3 Figure A2.73. 1H NMR (400 MHz, CDCl3) of compound D-41f. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 364 Appendix 2 – Spectra Relevant to Chapter 3 365 Figure A2.74. Infrared spectrum (Thin Film, NaCl) of compound D-41f. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.75. 13C NMR (100 MHz, CDCl3) of compound D-41f. Appendix 2 – Spectra Relevant to Chapter 3 10 9 8 7 6 5 ppm 4 3 2.14 2.46 366 2 1 Figure A2.76. 2H NMR (61 MHz, CDCl3) of compound D-41f. 0 O 10 44 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.77. 1H NMR (400 MHz, CDCl3) of compound 44. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 367 Appendix 2 – Spectra Relevant to Chapter 3 368 Figure A2.78. Infrared spectrum (Thin Film, NaCl) of compound 44. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.79. 13C NMR (100 MHz, CDCl3) of compound 44. 0 O 10 O 40a O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.80. 1H NMR (400 MHz, CDCl3) of compound 40a. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 369 Appendix 2 – Spectra Relevant to Chapter 3 370 Figure A2.81. Infrared spectrum (Thin Film, NaCl) of compound 40a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.82. 13C NMR (100 MHz, CDCl3) of compound 40a. 0 O 10 O 40b O Me 9 CO2Et Me 8 6 5 ppm 4 3 Figure A2.83. 1H NMR (400 MHz, CDCl3) of compound 40b. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 371 Appendix 2 – Spectra Relevant to Chapter 3 372 Figure A2.84. Infrared spectrum (Thin Film, NaCl) of compound 40b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.85. 13C NMR (100 MHz, CDCl3) of compound 40b. 0 O 10 O 40c O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.86. 1H NMR (400 MHz, CDCl3) of compound 40c. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 373 Appendix 2 – Spectra Relevant to Chapter 3 374 Figure A2.87. Infrared spectrum (Thin Film, NaCl) of compound 40c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.88. 13C NMR (100 MHz, CDCl3) of compound 40c. 0 10 O O 40d O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.89. 1H NMR (400 MHz, CDCl3) of compound 40d. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 375 Appendix 2 – Spectra Relevant to Chapter 3 376 Figure A2.90. Infrared spectrum (Thin Film, NaCl) of compound 40d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.91. 13C NMR (100 MHz, CDCl3) of compound 40d. 0 O 10 O 40e O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.92. 1H NMR (400 MHz, CDCl3) of compound 40e. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 377 Appendix 2 – Spectra Relevant to Chapter 3 378 Figure A2.93. Infrared spectrum (Thin Film, NaCl) of compound 40e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.94. 13C NMR (100 MHz, CDCl3) of compound 40e. 0 O 10 O 40f O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.95. 1H NMR (400 MHz, CDCl3) of compound 40f. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 379 Appendix 2 – Spectra Relevant to Chapter 3 380 Figure A2.96. Infrared spectrum (Thin Film, NaCl) of compound 40f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.97. 13C NMR (100 MHz, CDCl3) of compound 40f. 0 O 10 O D-40f O 9 CO2Bn CD3 CD3 8 6 5 ppm 4 3 Figure A2.98. 1H NMR (400 MHz, CDCl3) of compound D-40f. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 381 Appendix 2 – Spectra Relevant to Chapter 3 382 Figure A2.99. Infrared spectrum (Thin Film, NaCl) of compound D-40f. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.100. 13C NMR (100 MHz, CDCl3) of compound D-40f. Appendix 2 – Spectra Relevant to Chapter 3 10 9 8 7 6 383 5 ppm 4 3 2 1 Figure A2.101. 2H NMR (61 MHz, CDCl3) of compound D-40f. 0 O 10 O 40g O Me CO2Bn 9 Me 8 6 5 ppm 4 3 Figure A2.102. 1H NMR (400 MHz, CDCl3) of compound 40g. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 384 Appendix 2 – Spectra Relevant to Chapter 3 385 Figure A2.103. Infrared spectrum (Thin Film, NaCl) of compound 40g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.104. 13C NMR (100 MHz, CDCl3) of compound 40g. 0 O 10 O 40h O 9 Me Me 8 6 5 ppm 4 3 Figure A2.105. 1H NMR (400 MHz, CDCl3) of compound 40h. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 386 Appendix 2 – Spectra Relevant to Chapter 3 387 Figure A2.106. Infrared spectrum (Thin Film, NaCl) of compound 40h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.107. 13C NMR (100 MHz, CDCl3) of compound 40h. 0 O 10 O 40i O Me 9 CO2H Me 8 6 5 ppm 4 3 Figure A2.108. 1H NMR (400 MHz, CDCl3) of compound 40i. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 388 Appendix 2 – Spectra Relevant to Chapter 3 389 Figure A2.109. Infrared spectrum (Thin Film, NaCl) of compound 40i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.110. 13C NMR (100 MHz, CDCl3) of compound 40i. 0 O 10 O 40j O O Ph Me 9 Me 8 6 5 ppm 4 3 Figure A2.111. 1H NMR (400 MHz, CDCl3) of compound 40j. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 390 Appendix 2 – Spectra Relevant to Chapter 3 391 Figure A2.112. Infrared spectrum (Thin Film, NaCl) of compound 40j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.113. 13C NMR (100 MHz, CDCl3) of compound 40j. 0 O 10 O 40k O Me 9 CO2Ph Me 8 6 5 ppm 4 3 Figure A2.114. 1H NMR (400 MHz, CDCl3) of compound 40k. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 392 Appendix 2 – Spectra Relevant to Chapter 3 393 Figure A2.115. Infrared spectrum (Thin Film, NaCl) of compound 40k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.116. 13C NMR (100 MHz, CDCl3) of compound 40k. 0 O 10 O 40l O Me 9 CO2Mes Me 8 6 5 ppm 4 3 Figure A2.117. 1H NMR (400 MHz, CDCl3) of compound 40l. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 394 Appendix 2 – Spectra Relevant to Chapter 3 395 Figure A2.118. Infrared spectrum (Thin Film, NaCl) of compound 40l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.119. 13C NMR (100 MHz, CDCl3) of compound 40l. 0 O 10 O 40m O O Me 9 ONHP Me 8 6 5 ppm 4 3 Figure A2.120. 1H NMR (400 MHz, CDCl3) of compound 40m. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 396 Appendix 2 – Spectra Relevant to Chapter 3 397 Figure A2.121. Infrared spectrum (Thin Film, NaCl) of compound 40m. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.122. 13C NMR (100 MHz, CDCl3) of compound 40m. 10 N Cbz O O 40n O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.123. 1H NMR (400 MHz, CDCl3) of compound 40n. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 398 Appendix 2 – Spectra Relevant to Chapter 3 399 Figure A2.124. Infrared spectrum (Thin Film, NaCl) of compound 40n. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.125. 13C NMR (100 MHz, CDCl3) of compound 40n. 0 O 10 O 40o O O N Me 9 Me O O 8 6 5 ppm 4 3 Figure A2.126. 1H NMR (400 MHz, CDCl3) of compound 40o. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 400 Appendix 2 – Spectra Relevant to Chapter 3 401 Figure A2.127. Infrared spectrum (Thin Film, NaCl) of compound 40o. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.128. 13C NMR (100 MHz, CDCl3) of compound 40o. 0 O 10 O Me 9 CH(OAc)2 99 O Me 8 6 5 ppm 4 3 Figure A2.129. 1H NMR (400 MHz, CDCl3) of compound 99. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 402 Appendix 2 – Spectra Relevant to Chapter 3 403 Figure A2.130. Infrared spectrum (Thin Film, NaCl) of compound 99. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.131. 13C NMR (100 MHz, CDCl3) of compound 99. 0 O 10 O 40p O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.132. 1H NMR (400 MHz, CDCl3) of compound 40p. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 404 Appendix 2 – Spectra Relevant to Chapter 3 405 Figure A2.133. Infrared spectrum (Thin Film, NaCl) of compound 40p. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.134. 13C NMR (100 MHz, CDCl3) of compound 40p. 0 10 O O 40q O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.135. 1H NMR (400 MHz, CDCl3) of compound 40q. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 406 Appendix 2 – Spectra Relevant to Chapter 3 407 Figure A2.136. Infrared spectrum (Thin Film, NaCl) of compound 40q. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.137. 13C NMR (100 MHz, CDCl3) of compound 40q. 0 O 10 O 40r O Me Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.138. 1H NMR (400 MHz, CDCl3) of compound 40r. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 408 Appendix 2 – Spectra Relevant to Chapter 3 409 Figure A2.139. Infrared spectrum (Thin Film, NaCl) of compound 40r. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.140. 13C NMR (100 MHz, CDCl3) of compound 40r. 0 Me 10 O O 40s O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.141. 1H NMR (400 MHz, CDCl3) of compound 40s. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 410 Appendix 2 – Spectra Relevant to Chapter 3 411 Figure A2.142. Infrared spectrum (Thin Film, NaCl) of compound 40s. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.143. 13C NMR (100 MHz, CDCl3) of compound 40s. 0 EtO 10 O O 40t O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.144. 1H NMR (400 MHz, CDCl3) of compound 40t. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 412 Appendix 2 – Spectra Relevant to Chapter 3 413 Figure A2.145. Infrared spectrum (Thin Film, NaCl) of compound 40t. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.146. 13C NMR (100 MHz, CDCl3) of compound 40t. 0 Me 10 O O 40u O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.147. 1H NMR (400 MHz, CDCl3) of compound 40u. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 414 Appendix 2 – Spectra Relevant to Chapter 3 415 Figure A2.148. Infrared spectrum (Thin Film, NaCl) of compound 40u. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.149. 13C NMR (100 MHz, CDCl3) of compound 40u. O 10 O 42 O 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.150. 1H NMR (400 MHz, CDCl3) of compound 42. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 416 Appendix 2 – Spectra Relevant to Chapter 3 417 Figure A2.151. Infrared spectrum (Thin Film, NaCl) of compound 42. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.152. 13C NMR (100 MHz, CDCl3) of compound 42. 0 O 10 O 47 O 9 CO2Bn Ph 8 6 5 ppm 4 3 Figure A2.153. 1H NMR (400 MHz, CDCl3) of compound 47. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 418 Appendix 2 – Spectra Relevant to Chapter 3 419 Figure A2.154. Infrared spectrum (Thin Film, NaCl) of compound 47. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.155. 13C NMR (100 MHz, CDCl3) of compound 47. 0 O 10 O 101 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.156. 1H NMR (400 MHz, CDCl3) of compound 101. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 420 Appendix 2 – Spectra Relevant to Chapter 3 421 Figure A2.157. Infrared spectrum (Thin Film, NaCl) of compound 101. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.158. 13C NMR (100 MHz, CDCl3) of compound 101. O 10 O 102 O Me 9 CO2Bn Me 8 6 5 ppm 4 3 Figure A2.159. 1H NMR (400 MHz, CDCl3) of compound 102. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 422 Appendix 2 – Spectra Relevant to Chapter 3 423 Figure A2.160. Infrared spectrum (Thin Film, NaCl) of compound 102. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.161. 13C NMR (100 MHz, CDCl3) of compound 102. 0 O 10 O 85 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.162. 1H NMR (400 MHz, CDCl3) of compound 85. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 424 Appendix 2 – Spectra Relevant to Chapter 3 425 Figure A2.163. Infrared spectrum (Thin Film, NaCl) of compound 85. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.164. 13C NMR (100 MHz, CDCl3) of compound 85. 0 O 10 O 86 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.165. 1H NMR (400 MHz, CDCl3) of compound 86. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 426 Appendix 2 – Spectra Relevant to Chapter 3 427 Figure A2.166. Infrared spectrum (Thin Film, NaCl) of compound 86. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.167. 13C NMR (100 MHz, CDCl3) of compound 86. 0 O 10 O D-86 O O 9 CD3 CD3 8 6 5 ppm 4 3 2 Figure A2.168. 1H NMR (400 MHz, CDCl3) of compound D-86. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 428 Appendix 2 – Spectra Relevant to Chapter 3 429 Figure A2.169. Infrared spectrum (Thin Film, NaCl) of compound D-86. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.170. 13C NMR (100 MHz, CDCl3) of compound D-86. Appendix 2 – Spectra Relevant to Chapter 3 10 9 8 7 6 430 5 ppm 4 3 2 1 0 Figure A2.171. 2H NMR (61 MHz, CHCl3) of compound D-86. O 10 O 87 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.172. 1H NMR (400 MHz, CDCl3) of compound 87. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 431 Appendix 2 – Spectra Relevant to Chapter 3 432 Figure A2.173. Infrared spectrum (Thin Film, NaCl) of compound 87. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.174. 13C NMR (100 MHz, CDCl3) of compound 87. 0 O 10 O 93 O O 9 Ph 8 6 5 ppm 4 3 Figure A2.175. 1H NMR (400 MHz, CDCl3) of compound 93. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 433 Appendix 2 – Spectra Relevant to Chapter 3 434 Figure A2.176. Infrared spectrum (Thin Film, NaCl) of compound 93. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.177. 13C NMR (100 MHz, CDCl3) of compound 93. 0 BnO N O 10 O O 88 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.178. 1H NMR (400 MHz, CDCl3) of compound 88. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 435 Appendix 2 – Spectra Relevant to Chapter 3 436 Figure A2.179. Infrared spectrum (Thin Film, NaCl) of compound 88. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.180. 13C NMR (100 MHz, CDCl3) of compound 88. 0 Me O 10 O 89 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.181. 1H NMR (400 MHz, CDCl3) of compound 89. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 437 Appendix 2 – Spectra Relevant to Chapter 3 438 Figure A2.182. Infrared spectrum (Thin Film, NaCl) of compound 89. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.183. 13C NMR (100 MHz, CDCl3) of compound 89. 0 EtO O 10 O 90 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.184. 1H NMR (400 MHz, CDCl3) of compound 90. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 439 Appendix 2 – Spectra Relevant to Chapter 3 440 Figure A2.185. Infrared spectrum (Thin Film, NaCl) of compound 90. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.186. 13C NMR (100 MHz, CDCl3) of compound 90. 0 Me O 10 O 91 O O Me 9 Me 8 6 5 ppm 4 3 Figure A2.187. 1H NMR (400 MHz, CDCl3) of compound 91. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 441 Appendix 2 – Spectra Relevant to Chapter 3 442 Figure A2.188. Infrared spectrum (Thin Film, NaCl) of compound 91. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.189. 13C NMR (100 MHz, CDCl3) of compound 91. 0 10 O 9 O 92 O O 8 6 5 ppm 4 3 Figure A2.190. 1H NMR (400 MHz, CDCl3) of compound 92. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 443 Appendix 2 – Spectra Relevant to Chapter 3 444 Figure A2.191. Infrared spectrum (Thin Film, NaCl) of compound 92. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.192. 13C NMR (100 MHz, CDCl3) of compound 92. 0 O 10 O 96 O 9 O 8 6 5 ppm 4 3 Figure A2.193. 1H NMR (400 MHz, CDCl3) of compound 96. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 445 Appendix 2 – Spectra Relevant to Chapter 3 446 Figure A2.194. Infrared spectrum (Thin Film, NaCl) of compound 96. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.195. 13C NMR (100 MHz, CDCl3) of compound 96. 0 O 10 O 95 O 9 O 8 6 5 ppm 4 3 Figure A2.196. 1H NMR (400 MHz, CDCl3) of compound 95. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 447 Appendix 2 – Spectra Relevant to Chapter 3 448 Figure A2.197. Infrared spectrum (Thin Film, NaCl) of compound 95. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.198. 13C NMR (100 MHz, CDCl3) of compound 95. 0 10 O O 94 O 9 O 8 6 5 ppm 4 3 Figure A2.199. 1H NMR (400 MHz, CDCl3) of compound 94. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 449 Appendix 2 – Spectra Relevant to Chapter 3 450 Figure A2.200. Infrared spectrum (Thin Film, NaCl) of compound 94. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.201. 13C NMR (100 MHz, CDCl3) of compound 94. 0 10 O O 98 O 9 O Bn Bn 8 6 5 ppm 4 3 Figure A2.202. 1H NMR (400 MHz, CDCl3) of compound 98. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 451 Appendix 2 – Spectra Relevant to Chapter 3 452 Figure A2.203. Infrared spectrum (Thin Film, NaCl) of compound 98. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.204. 13C NMR (100 MHz, CDCl3) of compound 98. 0 10 O O 97 O 9 O 8 6 5 ppm 4 3 Figure A2.205. 1H NMR (400 MHz, CDCl3) of compound 97. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 453 Appendix 2 – Spectra Relevant to Chapter 3 454 Figure A2.206. Infrared spectrum (Thin Film, NaCl) of compound 97. 220 200 180 160 140 120 ppm 100 80 60 40 20 Figure A2.207. 13C NMR (100 MHz, CDCl3) of compound 97. 0 10 O O 100 O 9 Me Me 8 6 5 ppm 4 3 Figure A2.208. 1H NMR (400 MHz, CDCl3) of compound 100. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 455 Appendix 2 – Spectra Relevant to Chapter 3 456 Figure A2.209. Infrared spectrum (Thin Film, NaCl) of compound 100. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.210. 13C NMR (100 MHz, CDCl3) of compound 100. 10 O O D-100 O 9 CD3 CD3 8 6 5 ppm 4 3 2 Figure A2.211. 1H NMR (400 MHz, CDCl3) of compound D-100. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 457 Appendix 2 – Spectra Relevant to Chapter 3 458 Figure A2.212. Infrared spectrum (Thin Film, NaCl) of compound D-100. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.213. 13C NMR (100 MHz, CDCl3) of compound D-100. Appendix 2 – Spectra Relevant to Chapter 3 10 9 8 7 6 459 5 ppm 4 3 2 1 0 Figure A2.214. 2H NMR (61 MHz, CHCl3) of compound D-100. 10 O O 103 O 9 Ph 8 6 5 ppm 4 3 Figure A2.215. 1H NMR (400 MHz, CDCl3) of compound 103. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 460 Appendix 2 – Spectra Relevant to Chapter 3 461 Figure A2.216. Infrared spectrum (Thin Film, NaCl) of compound 103. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.217. 13C NMR (100 MHz, CDCl3) of compound 103. 0 Me 10 O O 107 O 9 Me Me 8 6 5 ppm 4 3 Figure A2.218. 1H NMR (400 MHz, CDCl3) of compound 107. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 462 Appendix 2 – Spectra Relevant to Chapter 3 463 Figure A2.219. Infrared spectrum (Thin Film, NaCl) of compound 107. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.220. 13C NMR (100 MHz, CDCl3) of compound 107. 0 Me 10 O O 105 O 9 Me Me 8 6 5 ppm 4 3 Figure A2.221. 1H NMR (400 MHz, CDCl3) of compound 105. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 464 Appendix 2 – Spectra Relevant to Chapter 3 465 Figure A2.222. Infrared spectrum (Thin Film, NaCl) of compound 105. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.223. 13C NMR (100 MHz, CDCl3) of compound 105. 0 EtO 10 O O 106 O 9 Me Me 8 6 5 ppm 4 3 Figure A2.224. 1H NMR (400 MHz, CDCl3) of compound 106. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 466 Appendix 2 – Spectra Relevant to Chapter 3 467 Figure A2.225. Infrared spectrum (Thin Film, NaCl) of compound 106. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.226. 13C NMR (100 MHz, CDCl3) of compound 106. 0 BnO 10 N O O O 113 OMe 9 8 6 5 ppm 4 3 Figure A2.227. 1H NMR (400 MHz, CDCl3) of compound 113. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 468 Appendix 2 – Spectra Relevant to Chapter 3 469 Figure A2.228. Infrared spectrum (Thin Film, NaCl) of compound 113. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.229. 13C NMR (100 MHz, CDCl3) of compound 113. 0 BnO O 10 N O O 104 O 9 Me Me 8 6 5 ppm 4 3 Figure A2.230. 1H NMR (400 MHz, CDCl3) of compound 104. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 470 Appendix 2 – Spectra Relevant to Chapter 3 471 Figure A2.231. Infrared spectrum (Thin Film, NaCl) of compound 104. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.232. 13C NMR (100 MHz, CDCl3) of compound 104. O 10 O 108 O 9 8 6 5 ppm 4 3 Figure A2.233. 1H NMR (400 MHz, CDCl3) of compound 108. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 472 Appendix 2 – Spectra Relevant to Chapter 3 473 Figure A2.234. Infrared spectrum (Thin Film, NaCl) of compound 108. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.235. 13C NMR (100 MHz, CDCl3) of compound 108. 0 O 10 O 109 O 9 8 6 5 ppm 4 3 Figure A2.236. 1H NMR (400 MHz, CDCl3) of compound 109. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 474 Appendix 2 – Spectra Relevant to Chapter 3 475 Figure A2.237. Infrared spectrum (Thin Film, NaCl) of compound 109. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.238. 13C NMR (100 MHz, CDCl3) of compound 109. 0 10 O O 110 O 9 8 6 5 ppm 4 3 Figure A2.239. 1H NMR (400 MHz, CDCl3) of compound 110. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 476 Appendix 2 – Spectra Relevant to Chapter 3 477 Figure A2.240. Infrared spectrum (Thin Film, NaCl) of compound 110. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.241. 13C NMR (100 MHz, CDCl3) of compound 110. 0 O 10 O 111 O 9 Bn Bn 8 6 5 ppm 4 3 Figure A2.242. 1H NMR (400 MHz, CDCl3) of compound 111. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 478 Appendix 2 – Spectra Relevant to Chapter 3 479 Figure A2.243. Infrared spectrum (Thin Film, NaCl) of compound 111. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.244. 13C NMR (100 MHz, CDCl3) of compound 111. 0 O 10 O 112 O 9 8 6 5 ppm 4 3 Figure A2.245. 1H NMR (400 MHz, CDCl3) of compound 112. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 480 Appendix 2 – Spectra Relevant to Chapter 3 481 Figure A2.246. Infrared spectrum (Thin Film, NaCl) of compound 112. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.247. 13C NMR (100 MHz, CDCl3) of compound 112. 0 O 10 49a 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.248. 1H NMR (400 MHz, CDCl3) of compound 49a. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 482 Appendix 2 – Spectra Relevant to Chapter 3 483 Figure A2.249. Infrared spectrum (Thin Film, NaCl) of compound 49a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.250. 13C NMR (100 MHz, CDCl3) of compound 49a. 0 10 O H 49e 2 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.251. 1H NMR (400 MHz, CDCl3) of compound 49e. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 484 Appendix 2 – Spectra Relevant to Chapter 3 485 Figure A2.252. Infrared spectrum (Thin Film, NaCl) of compound 49e. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.253. 13C NMR (100 MHz, CDCl3) of compound 49e. 10 O H 49f 4 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.254. 1H NMR (400 MHz, CDCl3) of compound 49f. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 486 Appendix 2 – Spectra Relevant to Chapter 3 487 Figure A2.255. Infrared spectrum (Thin Film, NaCl) of compound 49f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.256. 13C NMR (100 MHz, CDCl3) of compound 49f. 0 10 O 4 D-49f D 9 CO2Bn 8 6 5 ppm 4 3 2 Figure A2.257. 1H NMR (400 MHz, CDCl3) of compound D-49f. 7 1 0 Appendix 2 – Spectra Relevant to Chapter 3 488 Appendix 2 – Spectra Relevant to Chapter 3 489 Figure A2.258. Infrared spectrum (Thin Film, NaCl) of compound D-49f. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.259. 13C NMR (100 MHz, CDCl3) of compound D-49f. Appendix 2 – Spectra Relevant to Chapter 3 11 10 9 8 7 6 490 5 ppm 4 3 2 1 0 Figure A2.260. 2H NMR (61 MHz, CHCl3) of compound D-49f. 10 O H 49g 5 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.261. 1H NMR (400 MHz, CDCl3) of compound 49g. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 491 Appendix 2 – Spectra Relevant to Chapter 3 492 Figure A2.262. Infrared spectrum (Thin Film, NaCl) of compound 49g. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.263. 13C NMR (100 MHz, CDCl3) of compound 49g. 10 O 49h H 3 9 8 6 5 ppm 4 3 Figure A2.264. 1H NMR (400 MHz, CDCl3) of compound 49h. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 493 Appendix 2 – Spectra Relevant to Chapter 3 494 Figure A2.265. Infrared spectrum (Thin Film, NaCl) of compound 49h. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A2.266. 13C NMR (100 MHz, CDCl3) of compound 49h. H 10 O 49i 4 CO2H 9 8 6 5 ppm 4 3 Figure A2.267. 1H NMR (400 MHz, CDCl3) of compound 49i. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 495 Appendix 2 – Spectra Relevant to Chapter 3 496 Figure A2.268. Infrared spectrum (Thin Film, NaCl) of compound 49i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.269. 13C NMR (100 MHz, CDCl3) of compound 49i. 0 O 10 83 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.270. 1H NMR (400 MHz, CDCl3) of compound 83. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 497 Appendix 2 – Spectra Relevant to Chapter 3 498 Figure A2.271. Infrared spectrum (Thin Film, NaCl) of compound 83. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.272. 13C NMR (100 MHz, CDCl3) of compound 83. 0 10 84 Ph Ph 9 8 6 5 ppm 4 3 Figure A2.273. 1H NMR (400 MHz, CDCl3) of compound 84. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 499 Appendix 2 – Spectra Relevant to Chapter 3 500 Figure A2.274. Infrared spectrum (Thin Film, NaCl) of compound 84. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.275. 13C NMR (100 MHz, CDCl3) of compound 84. 0 10 59 O H CO2Bn O O Me Me 9 8 6 5 ppm 4 3 Figure A2.276. 1H NMR (400 MHz, CDCl3) of compound 59. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 501 Appendix 2 – Spectra Relevant to Chapter 3 502 Figure A2.277. Infrared spectrum (Thin Film, NaCl) of compound 59. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.278. 13C NMR (100 MHz, CDCl3) of compound 59. 0 O O 63 10 O 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.279. 1H NMR (400 MHz, CDCl3) of compound 63. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 503 Appendix 2 – Spectra Relevant to Chapter 3 504 Figure A2.280. Infrared spectrum (Thin Film, NaCl) of compound 63. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.281. 13C NMR (100 MHz, CDCl3) of compound 63. 0 O O 10 O 64 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.282. 1H NMR (400 MHz, CDCl3) of compound 64. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 505 Appendix 2 – Spectra Relevant to Chapter 3 506 Figure A2.283. Infrared spectrum (Thin Film, NaCl) of compound 64. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.284. 13C NMR (100 MHz, CDCl3) of compound 64. 0 O 10 O O 65 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.285. 1H NMR (400 MHz, CDCl3) of compound 65. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 507 Appendix 2 – Spectra Relevant to Chapter 3 508 Figure A2.286. Infrared spectrum (Thin Film, NaCl) of compound 65. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.287. 13C NMR (100 MHz, CDCl3) of compound 65. 0 O 10 O O 66 9 CO2Bn 8 6 5 ppm 4 3 Figure A2.288. 1H NMR (400 MHz, CDCl3) of compound 66. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 509 Appendix 2 – Spectra Relevant to Chapter 3 510 Figure A2.289. Infrared spectrum (Thin Film, NaCl) of compound 66. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.290. 13C NMR (100 MHz, CDCl3) of compound 66. 0 O 10 O O 67 Bn 9 CO2Bn Bn 8 6 5 ppm 4 3 Figure A2.291. 1H NMR (400 MHz, CDCl3) of compound 67. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 511 Appendix 2 – Spectra Relevant to Chapter 3 512 Figure A2.292. Infrared spectrum (Thin Film, NaCl) of compound 67. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.293. 13C NMR (100 MHz, CDCl3) of compound 67. 0 10 68 H CO2Bn OH 9 8 6 5 ppm 4 3 Figure A2.294. 1H NMR (400 MHz, CDCl3) of compound 68. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 513 Appendix 2 – Spectra Relevant to Chapter 3 514 Figure A2.295. Infrared spectrum (Thin Film, NaCl) of compound 68. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.296. 13C NMR (100 MHz, CDCl3) of compound 68. 0 HO 10 114 H CO2Bn N 9 8 6 5 ppm 4 3 Figure A2.297. 1H NMR (400 MHz, CDCl3) of compound 114. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 515 Appendix 2 – Spectra Relevant to Chapter 3 516 Figure A2.298. Infrared spectrum (Thin Film, NaCl) of compound 114. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.299. 13C NMR (100 MHz, CDCl3) of compound 114. 0 O 69 10 H N H CO2Bn 9 8 6 5 ppm 4 3 Figure A2.300. 1H NMR (400 MHz, CDCl3) of compound 69. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 517 Appendix 2 – Spectra Relevant to Chapter 3 518 Figure A2.301. Infrared spectrum (Thin Film, NaCl) of compound 69. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.302. 13C NMR (100 MHz, CDCl3) of compound 69. 0 O 70 10 O H CO2Bn 9 8 6 5 ppm 4 3 Figure A2.303. 1H NMR (400 MHz, CDCl3) of compound 70. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 519 Appendix 2 – Spectra Relevant to Chapter 3 520 Figure A2.304. Infrared spectrum (Thin Film, NaCl) of compound 70. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.305. 13C NMR (100 MHz, CDCl3) of compound 70. 0 10 75 O 9 8 6 5 ppm 4 3 Figure A2.306. 1H NMR (400 MHz, CDCl3) of compound 75. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 521 Appendix 2 – Spectra Relevant to Chapter 3 522 Figure A2.307. Infrared spectrum (Thin Film, NaCl) of compound 75. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.308. 13C NMR (100 MHz, CDCl3) of compound 75. 0 10 76 O 9 8 6 5 ppm 4 3 Figure A2.309. 1H NMR (400 MHz, CDCl3) of compound 76. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 523 Appendix 2 – Spectra Relevant to Chapter 3 524 Figure A2.310. Infrared spectrum (Thin Film, NaCl) of compound 76. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.311. 13C NMR (100 MHz, CDCl3) of compound 76. 0 10 77 EtO2C O 9 8 6 5 ppm 4 3 Figure A2.312. 1H NMR (400 MHz, CDCl3) of compound 77. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 525 Appendix 2 – Spectra Relevant to Chapter 3 526 Figure A2.313. Infrared spectrum (Thin Film, NaCl) of compound 77. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.314. 13C NMR (100 MHz, CDCl3) of compound 77. 0 10 78 EtO2C O OH OH 9 8 6 5 ppm 4 3 Figure A2.315. 1H NMR (400 MHz, CDCl3) of compound 78. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 527 Appendix 2 – Spectra Relevant to Chapter 3 528 Figure A2.316. Infrared spectrum (Thin Film, NaCl) of compound 78. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.317. 13C NMR (100 MHz, CDCl3) of compound 78. 0 10 79 BnO2C O O 9 8 6 5 ppm 4 3 Figure A2.318. 1H NMR (400 MHz, CDCl3) of compound 79. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 529 Appendix 2 – Spectra Relevant to Chapter 3 530 Figure A2.319. Infrared spectrum (Thin Film, NaCl) of compound 79. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.320. 13C NMR (100 MHz, CDCl3) of compound 79. 0 10 80 9 OMe BnO2C O OMe 8 6 5 ppm 4 3 Figure A2.321. 1H NMR (400 MHz, CDCl3) of compound 80. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 531 Appendix 2 – Spectra Relevant to Chapter 3 532 Figure A2.322. Infrared spectrum (Thin Film, NaCl) of compound 80. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.323. 13C NMR (100 MHz, CDCl3) of compound 80. 0 10 81 AcO BnO2C N OAc 9 8 6 5 ppm 4 3 Figure A2.324. 1H NMR (400 MHz, CDCl3) of compound 81. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 533 Appendix 2 – Spectra Relevant to Chapter 3 534 Figure A2.325. Infrared spectrum (Thin Film, NaCl) of compound 81. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.326. 13C NMR (100 MHz, CDCl3) of compound 81. 0 10 82 AcO BnO2C O 9 8 6 5 ppm 4 3 Figure A2.327. 1H NMR (400 MHz, CDCl3) of compound 82. 7 2 1 0 Appendix 2 – Spectra Relevant to Chapter 3 535 Appendix 2 – Spectra Relevant to Chapter 3 536 Figure A2.328. Infrared spectrum (Thin Film, NaCl) of compound 82. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A2.329. 13C NMR (100 MHz, CDCl3) of compound 82. 0 CHAPTER 4 Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A † 4.1 INTRODUCTION The [2+2] photocycloaddition serves as a powerful tool for the construction of carbon–carbon and carbon–heteroatom bonds.1 The versatility of this transformation has led to numerous applications in the context of natural product synthesis,2 particularly as the four-membered cycloadducts can be further employed in ring expansion processes through strain-release and C–C bond activation.3 In our recent total synthesis of (–)-scabrolide A (119), we sought to construct the 7membered ring in the natural product through an oxidation/fragmentation sequence from cyclobutane 120. Intermediate 120 would be accessed through an intramolecular photochemical [2+2] cycloaddition of an enone with a pendant vinyl silane (121) – derived from 122 and 123 – to forge the [4–5] ring system (120) (Scheme 4.1A).4 Surprisingly, the desired [4–5] ring system (120) was not formed in this process; rather, a cis-fused [4–4] product 124 was produced as the exclusive product (Scheme 4.1B). The observed selectivity contrasts the “rule of five” generally attributed to enone-olefin cycloadditions, wherein the formation of five-membered rings is considered to be kinetically facile.5 As a consequence of the undesirable reactivity, three additional steps to protect and † This research was carried out with Zhang T. Y. Portions of this chapter have been reproduced with permission from Stoltz, et al. J. Org. Chem. 2022, 87, 14115–14124. © 2023 American Chemical Society. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 538 subsequently deprotect the isopropenyl olefin had to be incorporated into the synthesis. Rectifying the chemoselectivity of the [2+2] photocycloaddition from 121 would improve material throughput, support future synthetic efforts, and enable derivative-based biological studies.6 To explore this issue, we employ quantum mechanical calculations to understand the mechanism by which the unexpected product 124 is formed and uncover the origins of chemo- and diastereoselectivity. Scheme 4.1. Photochemical [2+2] approach to scabrolide A. A. Retrosynthetic approach to (–)-scabrolide A (119): HO O H Me O HO 1) Oxidative fragmentation 2) Tamao–Fleming O H Me H [2+2] Photocycloaddition SiMe2Ph O H O Me O 119 HO O Me 120 O H Me H SiMe2Ph 6 steps [Ref. 3] OH Me Me + Me O H O HO 121 B. Unexpected reactivity: HO HO Me H O SiMe2Ph Me O 123 H Me O HO H SiMe2Ph PhH, 23 ºC O H H O H O H H 120 124 Not Observed (desired) Observed (undesired) O OH 6-endo-trig versus 7-endo-trig O H O H O 7 Me OH Me 121_3(𝞹𝞹*) R + 3125 O 6 H R H H H Me O H H Me OH H O PhMe2Si C. This research: H O Me + O Me 121 O H Me hv (350 nm) O R CO2H 122 Me 3126 H Me OH Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.2 539 COMPUTATIONAL METHODS All quantum mechanics calculations were carried out with the Orca program. 7 Geometries were optimized by density functional theory (DFT) using the B3LYP functional8 paired with Grimme’s D4 dispersion correction9 and the def2-SV(P) basis set.10 Vibrational frequency calculations were carried out at the same level of theory for all stationary points to verify their nature as minima or saddle points and to obtain thermal Gibbs free energy corrections at 298 K. Intrinsic reaction coordinate (IRC) analysis was performed to confirm that transition states lead to the appropriate minima.11 Additional DFT single point calculations were carried out with the wB97M-V functional12 and the def2-TZVPP basis set with the SMD implicit solvation model for benzene. 13 Multiconfigurational single point calculations were carried out using complete active space self-consistent field (CASSCF) theory, with subsequent treatment of dynamical correlation by second order N-electron valence state perturbation theory (NEVPT2). 14 For stateaveraged calculations, the Nakano quasi-degenerate (QD) formulation was employed.15 These calculations employed the def2-TZVPP basis set with the SMD model for benzene. The (8,8) active space (eight electrons and eight orbitals) was chosen to contain the enone π system, the isopropenyl π/π* and the vinyl silane π/π*. The enone oxygen lone pair was included to obtain the (10,9) active space where nπ* states are relevant. Unless otherwise specified, final Gibbs free energies are NEVPT2/def2-TZVPP/SMD(benzene) electronic energies with thermodynamical corrections obtained from the optimization level of theory. For full computational details, see section 4.5. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.3 540 RESULTS AND DISCUSSION The mechanism of the enone-olefin [2+2] photocycloaddition has been the subject of numerous theoretical and experimental investigations.1b,16,17 The general mechanism begins with UVA irradiation to promote the n → π* excitation of a,b-unsaturated carbonyl 127 (Scheme 4.2, Step 1). The 1(nπ*) excited state undergoes intersystem crossing (ISC) primarily to the 3(ππ*) state (128_3(ππ*)) (El Sayed’s rule).18 Occupation of the antibonding π* orbital would then result in elongation of the C=O and C=C bonds. For conformationally flexible enones, the adiabatically relaxed 3(ππ*) state leads to a torsion about the a and b positions and typically becomes lower in energy than the 3(nπ*) state. Prior studies unambiguously determined that the first C–C bond formation occurs from triplet excited states,1b,17 preferentially from the 3(ππ*) state.16a For intermolecular cases, the ensuing C– C bond formation between the enone and olefin typically occurs via b-attack of the enone (Scheme 4.2, Step 2), i.e., an attack by the less stabilized spin center, to afford a triplet 1,4diradical (3129). Half-lives of the 1,4-triplet diradicals intermediates have been measured to range from 10 to 1,000 ns. 19 Subsequent ISC to the corresponding singlet diradical (1129) then enables either productive ring closure to form 131 or unproductive C–C scission to return to enone 127 (Scheme 4.2, Steps 3 and 4). Weedon and coworkers find that the intermediacy of a-radicals (sp2), such as 1129, tends to favor C–C bond scission, while ring closure is more likely with b-radicals (sp3), such as 1130.20 541 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Scheme 4.2. General four-step mechanism for the olefin/a,b-unsaturated carbonyl [2+2] photocycloaddition. O O 𝛃-attack 1. n → 𝛑* O R O excitation 𝛂 𝛃 127 CH2 128_3(𝞹𝞹*) 𝛂-attack 1. Photoexcitation + ISC 131 1129 O O H H R CH2 CH2 2. First bond formation O C–C scission ISC 3130 4.3.1 CH2 3129 R 2. ISC to 3(𝛑𝛑*) R R R O Ring closure ISC R R CH2 CH2 𝛕 = 10–1,000 ns 127 1130 3. ISC to singlet diradical 4. Second bond formation STEP 1: PHOTOEXCITATION The [2+2] photocycloaddition of enone 121 (Scheme 4.1B) is achieved upon irradiation with a standard UVA mercury vapor gas-discharge lamp (lmax ~ 350 nm). The initial singlet n → π* vertical excitation was calculated to be 3.96 eV (313 nm) (Scheme 4.3A) – in accord with known values for aliphatic cyclic enones.19b Energies of 3.73 and 4.01 eV were calculated for the vertical n → π* and π → π* excitations to the 3(nπ*) and 3 (ππ*) states, respectively, from the ground state minimum (121_S0) (Scheme 4.3C).21 The second lowest singlet excitation is significantly higher in energy at 7.45 eV and is of 1(ππ*) character.22 In accord with prior studies, the singlet n → π* excitation is accessible under UVA irradiation and is the excited state from which productive reactivity ensues. Despite our best efforts, pervasive root-flipping made adiabatic optimization on the 1 (nπ*) surface challenging. As such, we employed the optimized 3(nπ*) geometry as a surrogate for the 1(nπ*) minimum.23 The resulting adiabatic excitation energies of 3.34 and 3.37 eV (77.0 and 81.1 kcal/mol) are obtained for the 3(nπ*) and 1(nπ*) states, respectively. Apart from elongation of the C(2)–O(1) and C(3)–C(4) bonds, the 3(nπ*) geometry is Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 542 similar to that of the ground state enone (Scheme 4.3D). At the 121_1(nπ*) stationary point, the 3(ππ*) surface lies 4.8 kcal/mol above the 1(nπ*) surface. The 3(nπ*) is the lowest energy triplet state at the 121_S0 and 121_1(nπ*) stationary points (Scheme 4.3A); however, the adiabatic 3(ππ*) excitation energies of simple enones are typically lower than that of the 3 (nπ*) state. Although it has been hypothesized that for highly rigid, cyclic systems the 3 (ππ*) state may remain higher in energy,24 optimization of the 3(ππ*) state of 121 yields a total adiabatic excitation energy of 3.26 eV (75.2 kcal/mol), 1.8 kcal/mol lower than the 3 (nπ*) minimum despite the rigidity of the tricyclic core. Given its comparative thermodynamic favorability, we hypothesized that the 3(ππ*) surface can be readily accessed from the initially excited 1(nπ*) state and account for the subsequent C–C bond formation. Hence, we sought to further interrogate the interaction of the excited state surfaces. Beginning from the minimized 121_1(nπ*) geometry (still employing the 3(nπ*) minimum as a surrogate), the nuclear coordinates were relaxed with energies and forces obtained from the 3(ππ*) surface.25 Single point calculations at the QD-NEVPT2 level of theory were carried out at points along the optimization trajectory to plot the corresponding energies of the 1(nπ*), 3(nπ*), and 3(ππ*) surfaces. Moving along the reaction coordinate, the 3(ππ*) state energy decreases, with elongation of the C(2)–O(1) and C(3)–C(4) bonds and subsequent twisting along the C(2)–C(3)–C(4)–C(5) dihedral (Scheme 4.3D). The nπ* states increase in energy as a result of these distortions, with the 1(nπ*) crossing the 3(ππ*) surface at C(2)–O(1) and C(3)–C(4) bond lengths of 1.33 and 1.45 Å, respectively.26 Nonzero spin-orbit coupling (SOC) between the 1(nπ*) and 3(ππ*) states results in an avoided 543 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A crossing with a barrier (Ea) of 1.4 kcal/mol (Scheme 4.3B).27 In contrast to the 1(nπ*) to 3 (ππ*) crossing, ISC from the 1(nπ*) state to the 3(nπ*) state is symmetry-forbidden.18 Additionally, non-productive phosphorescence from the 3(nπ*) state to the closed-shell singlet ground state is symmetry-allowed and is anticipated to be rapid.18 In summary, an n → π* transition at 3.96 eV (313 nm) followed by ISC to the 3(ππ*) surface yields intermediate 121_3(ππ*) – which is 1.8 kcal/mol lower in energy than 121_3(nπ*) – poised to undergo the first C–C bond formation. Scheme 4.3. Photoexcitation of 121_S0 and conversion to reactive triplet diradical 121_3(nπ*). B. QD-NEVPT2 Surface Energies A. Excited State Potential Energy Surfaces 1(𝞹𝞹*) C. Select Natural Orbitals from the (10,9) Active Space 𝞹*) 1 (n 6.0 3(𝞹𝞹*) 3( 𝞹𝞹*) 4.0 Erel (kcal/mol) 1(n𝞹*) 4.01 eV 𝛑*4 (enone) 𝞹*) 1 (n 1.27 eV -2.0 3( 𝞹*) 3 (n 121_3(n𝞹*) Erel (eV) Ea 0.0 1.56 eV 121_ 1(n𝞹*) 3(n𝞹*) 𝞹*) 3 (n 2.0 -4.0 ∆G = 1.8 kcal/mol 121_3(𝞹𝞹*) 𝛑*3 (enone) 𝞹𝞹*) Ea = 1.4 kcal/mol n→𝛑* 𝛑→𝛑* D. Dihedral Torsion of 121_3(𝞹𝞹*) 0.79 eV Evert = 3.96 eV n → 𝞹* (313 nm) 121_1(n𝞹*) nO (enone) D(2,3,4,5) = 176º 3.73 eV 5 4 3 2 ISC Productive Non-productive S0 𝛑2 (enone) 121_3(𝞹𝞹*) 4 D(2,3,4,5) = 103º 5 3 2 𝛑1 (enone) 121_S0 Reaction Coordinate E. Forward Reaction OH Me z H O1 SiMe2Ph 2 3 4 x y O 5 H O 121_S0 Me * 1. Vertial excitation at 313 nm to 1(n𝞹*) 2. Geometric relaxation (C=O and C=C bond elongation) OH Me H O * SiMe2Ph OH 3. Crossing to 3(𝞹𝞹*) Me O H O 121_1(n𝞹*) 4. Rotation about C2-C3-C4-C5 dihedral Me H O SiMe2Ph Me O H O 121_3(𝞹𝞹*) Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.3.2 544 STEP 2: FIRST C–C BOND FORMATION Triplet diradical 121_3(ππ*) may then undergo C–C bond formation with either of the pendant olefins. A single reference approach such as DFT should provide a good description of the triplet surface where the lowest triplet state is well isolated from other excited states, as is the case for the 121_3(ππ*) (vide supra). Moreover, spin contamination is generally minor. As mentioned above, radical cyclizations during the first C–C bond formation may occur from either the a or b positions (Scheme 4.2, Step 2). In the analogous reaction between acrolein and ethylene, Houk and coworkers find a 3–4 kcal/mol preference for battack due to the greater stability of the resulting delocalized a-acyl radical.16a In the system at hand, b-attack may occur from the isopropenyl olefin in a 5-exo-trig fashion (TS44, TS45) or the vinyl silane in a 4-exo-trig (TS46, TS47) fashion, respectively (Scheme 4.4A). 28 The corresponding 5-endo-trig and 6-endo-trig cyclizations that give rise to spirocyclic 1,4-diradicals were also considered (see section 4.5). The cyclizations may occur from either the Re or Si face of the enone in conjunction with either face of the olefin (Schemes 4.7 and 4.8). In total, twelve diastereomeric transition states were considered for the b-attack mechanism. For reaction pathways involving a-attack, twelve diastereomeric transition states were similarly derived from approach to either face of the enone with the isopropenyl olefin in a 6-endo-trig (TS48, TS49) or 5-exo-trig cyclization (Scheme 4.7), or with the pendant vinyl silane in a 7-endo-trig (TS50, TS51) or 6-exo-trig cyclization (Scheme 4.9).29 All Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 545 diastereomeric transition states for α- and β-attack pathways were considered because the new stereocenters forged from the [2+2] photocycloaddition will be ablated during the ensuing synthetic transformations (oxidation and fragmentation, Scheme 4.1A). This causes diastereomeric diradicals – such as 3132 and 3133 (Scheme 4.4A) – to eventually give rise to the same [6–4–5] ring-containing synthetic intermediate. Therefore, only the chemoselectivity – not the diastereoselectivity – of the first C–C bond formation is relevant to the final synthetic outcome. Given the vast number of energetically accessible conformers for each of the 24 relevant diastereomeric transition states, pre-screening with DFT ((U)wB97M-V/def2TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P)) was carried out to efficiently eliminate high energy pathways. The eight most relevant pathways are discussed below (Scheme 4.4A) with additional discussion on alternative pathways in section 4.5. During the course of our synthetic planning, we envisioned that the system would preferentially undergo b-attack in a 5-exo-trig cyclization with the vinyl silane (TS44), forging the 5-membered ring of a desirable cycloaddition adduct (3132). Approach of the enone Si face to give 1,4-diradical intermediate 3132 is met with a barrier of 8.0 kcal/mol. The analogous 5-exo-trig transition state corresponding to approach of the Re face (TS45) was not found. Rather, diradical 3133 converts to 121_3(ππ*) via a stepwise mechanism from cycloheptyl diradical 3125 (Scheme 4.4B).30 546 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Scheme 4.4. Eight lowest energy reaction pathways from 121_3(ππ*).a A. Eight lowest energy reaction pathways from triplet diradical 121_3(𝛑𝛑*). 𝛃-attack on vinyl silane (5-exo-trig) 𝛂-attack on isopropenyl olefin (6-endo-trig) Desired O H 2C O H Predicted H O H R3Si O Me OH H 2C H O H O H R3Si O H Me OH Si-face Re-face H H O O H H H O R3Si Me OH O O H H O H SiR3 CH2 Me O Me OH H H O H Re-face Me OH O Me H CH2 Si face TS45 (Not Observed)b Grel = –11.9 O O H Me OH O O H O H Me H CH2 OH Me OH OH H 2C H H O H O H 2C O Me OH H O H Grel = –14.7 O H H O Me OH O R3Si 3135 Grel = 3.0 O Si-face H Si-face H 2C R3Si H O H H O Me OH O H H H O H SiR3 Me O O H Me OH Gibbs free energies (in kcal/mol) are calculated H H H O SiR3 O at Me OH H 3125 Grel = 0.0 SiR3 O H Me Bulky –SiMe2Ph group Me OH H H O Me TS52 Grel = 11.6 TS45 Not Observed (5-exo-trig) H 3137 Grel = –13.8 H O H SiR3 Me CH2 TS44 (5-exo-trig) H Me OH H H Me SiR3 O O H H O TS51 Grel = 7.4 H O H H Me OH H O Me OH SiR3 H O H H Me TS47 Grel = 14.0 Me [a] H O 3125 Grel = –13.6 B. 5-exo-trig Transition States O H H Me O H H O H SiR3 H Me OH Me OH H 3136 TS50 Grel = 8.0 H Me H Me H O H Re-face TS46 Grel = 5.2 H H O SiR3 H R3Si Re-face Me OH 𝛂-attack on vinyl silane (7-endo-trig) Me Grel = 1.4 Me Me OH CH2 3134 O Me OH Me SiR3 O H H H H O H TS49 Grel = 5.0 121_3(𝛑𝛑*) Grel = 0.0 H O H O Me O SiR3 H SiMe2Ph Re face 𝛃-attack on isopropenyl olefin (4-exo-trig) H H H H O H Si-face SiR3 H 3133 O SiR3 H Me OH H 3126 Grel = –15.6 TS48 Grel = 3.0 TS44 Grel = 8.0 H O Me Me 132 Grel = –8.7 H H SiR3 Me Me 3 H O H H H SiR3 CH2 the O Me OH 3133 Grel = 1.9 H NEVPT2/def2- TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. –SiR3 = SiMe2Ph. [b] All attempts to find a saddle point corresponding to TS45 ultimately lead to TS52 connecting 3125 to 3133. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 547 Prior studies suggest that bond formation occurs from the 3(ππ*) state rather than along the higher energy 3(nπ*) surface. Indeed, the 3(nπ*) state is found to lie 1.69 eV (39.0 kcal/mol) above the 3(ππ*) ground state triplet PES at the TS44 saddle point.31 At TS44, 3 (nπ*) character in the ground state triplet is negligible, contributing < 0.5% to the configuration interaction (CI) wavefunction. Surprisingly, a barrier of 5.2 kcal/mol was found for Re face b-attack in a 4-exotrig cyclization with the isopropenyl olefin (TS46), lower than that of the minimum energy 5-exo-trig pathway (TS44). Approaching from the Re face of the enone is favored (TS46), with a ∆G‡ to Si face approach of 14.0 kcal/mol (TS47) (Scheme 4.4A). Unlike the generation of cyclopentanes 3132 and 3133, the formation of both cyclobutane 1,4diradicals (3134 and 3135) is thermodynamically unfavorable, with a change in reaction free energy (∆G) of 1.4 and 3.0 kcal/mol, respectively. We then turned our attention to reaction pathways featuring a-attack of the triplet enone diradical. Productive C–C bond formation may occur through either a 6-endo-trig or 7-endo-trig radical cyclization from either the Re or Si face of the enone (Scheme 4.4).32 Barriers of 3.0 and 5.0 kcal/mol were found for 6-endo-trig cyclization from the Re (TS48) or Si face (TS49), respectively. Higher barriers were obtained for the 7-endo-trig cyclization at 8.0 and 7.4 kcal/mol for approach from the Re (TS50) or Si face (TS51), respectively. Triplet 1,4-diradical intermediates resulting from 6-endo-trig (3126) or 7endo-trig (3137) radical cyclization are lower in free energy than 121_3(ππ*) by at least 13 kcal/mol. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 548 In summary, the global minimum energy pathway for the first C–C bond formation from 121_3(ππ*) is via 6-endo-trig cyclization with the isopropenyl olefin to forge triplet diradical 3126. This process is accompanied by a ∆G‡ of 3.0 kcal/mol and a ∆G of –15.6 kcal/mol, relative to 121_3(ππ*). The transition state describing this minimum energy pathway (TS48) resides on the 3(ππ*) surface, with a vertical excitation energy of 1.96 eV (45.2 kcal/mol) to the 3(nπ*) state. At TS48, 3(nπ*) character in the ground state triplet is negligible, contributing < 0.5% to the CI wavefunction.33 Prior studies suggest that in photochemical [2+2] cycloadditions, the first C–C bond formation on the triplet surface occurs irreversibly (i.e., before ISC).1b,16 We found forward and reverse barriers to C–C bond formation along the minimum energy pathway to be 3.0 and 18.6 kcal/mol, with rate constants at 298.15 K of 3.9 x1010 s–1 and 1.4 x10–1 s–1, respectively. For simple enones, lifetimes of triplet 1,4-diradical intermediates derived from [2+2] photocycloadditions are on the scale of 10 to 1,000 ns, i.e., unimolecular decay rate constants are on the order of magnitude of 106 – 108 s–1.19 Thus, C–C bond formation through TS48 is irreversible, with the reverse process (k ~ 10–1 s–1) being outcompeted by ISC (k ~ 108 – 106 s–1). Meanwhile, productive bond formation (k ~ 1010 s–1) is anticipated to be more rapid than ISC, and thus, proceeds on the triplet surface. Still, we consider the effect of a competitive ISC. Starting from the 121_3(ππ*) geometry, optimization along the ground state singlet surface smoothly affords the closed-shell singlet starting material 121_S0. Hence, premature spin flip would lower the efficiency of the overall process but likely does not lead to undesired reactivity.16d Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.3.3 549 STEP 3: SECOND C–C BOND FORMATION The first ring closure generates a triplet 1,4-diradical, which was shown to be almost energetically degenerate with its singlet counterpart. The singlet-triplet gap for diradical 126 is calculated to be less than 1 kcal/mol, favoring anti-ferromagnetically coupled spins (Scheme 4.5).34 After ISC to the singlet 1,4-diradical surface, the system undergoes relaxation to a stable diradical intermediate or a C–C bond cleavage to re-form 121 (Scheme 4.5). We hypothesized that the partitioning between the two outcomes depends on the conformation of the 1,4-diradical at the point at which ISC occurs (Scheme 4.10).35 Starting from the triplet diradical geometries of low-energy conformers, relaxation of the nuclear coordinates on the broken-symmetry (MS = 0) DFT (BS-DFT)36,37 surface yields either singlet diradicals or enone 121. For diradical 126 (Scheme 4.5), five of the 14 lowest-energy conformers relaxed to enone 121 (including the globally lowest-energy conformer), which accounts for 70% of the Boltzmann-weighted population of conformers. As such, only 30% of the triplet diradical population will relax to stable singlet diradicals.38 Unlike multi-configurational methods (such as NEVPT2/CASSCF), singledeterminantal methods (such as BS-DFT) are unable to properly describe open-shell singlet states.36,39 Hence, we sought to compare the final energies calculated on the BS-DFT potential energy surface (PES) to those from the NEVPT2 surface. We found significant discrepancies in the BS-DFT and NEVPT2 PESs along the reaction coordinate of the second C–C bond formation (see section 4.5), with BS-DFT calculations favoring a later transition state than NEVPT2. Consequently, a more accurate barrier was derived from a Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 550 PES obtained by calculating NEVPT2 electronic energies along the BS-DFT intrinsic reaction coordinate (IRC) trajectory for the transition state in question. Scheme 4.5. Predicted reactivity from diradical 126. Predicted reactivity from 6-membered cyclic diradical 126 Me OH O O H H Me Me H O Me O Me H OH H O O Me H 121 Grel = –56.9 H Me OH H Me O H O O Me OH O H O Predicted H Me O Gibbs free energies (in H (S) Me H 124 Grel = –36.7 1TS54’ Grel = 3.9 Grel = 0.6 3126 1TS54 Grel = 1.8 Empirically observed Computationally predicted kcal/mol) O O R3Si Grel = 1.8 [a] H (S) 1TS54 121 Grel = –56.9 OH Me H 1126 Grel = 0.0 Me 124’ Grel = –32.1 O R3Si 1TS53 Grel = 3.7 (R) O R3Si 1TS54’ Grel = 3.9 Grel = 0.6 H H O R3Si 1126 G rel = 0.0 3126 H R3Si O (R) Me O R3Si O 1TS53 Grel = 3.7 H H R3Si O OH OH are Grel = –32.1 124’ 124 Grel = –36.7 calculated at the TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. –SiR3 = SiMe2Ph. NEVPT2/def2- Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 551 Scheme 4.6. Predicted reactivity from diradical 125. A. Predicted reactivity from 7-membered cyclic diradical 125 Me OH O H O SiR3 H H O O SiR3 H Me OH H O O Me OH H H H 3 3 O R3Si 121 Grel = –58.2 Grel ~ 0 H H O 1TS55 OH Me Me O Me O Me OH H (S) H O O 1125 Grel = 0.0 3125 G rel = 0.7 SiR3 O Me 1TS56’ Grel ~ 0 Me OH H O (S) H O Me Me O SiR3 H 120’ Grel = –55.3 H OH Me H O H 3 (R) O SiR3 H O (R) SiR3 H O Me O Me 1TS56 Grel ~ 0 120 Grel = –44.5 Grel = 0.7 3125 Grel ~ 0 1TS56 Grel ~ 0 1TS55 Grel = –44.5 120 1125 TS56’ Grel = 0.0 Grel = 0.0 121 Grel = -58.2 120’ Grel = –55.3 B. [2+2] Photocycloaddition with masked isoprenyl olefin HO Me H O HO SiMe2Ph Me H O H 3 3 1. hv (350 nm), PhH, 23 ºC 15 O H H Me O O 2. TiCp2Cl2, Mn0, collidine•HCl 1,4-CHD, THF, 23 ºC SiMe2Ph O H O Me 70% yield over 2 steps 138 Gibbs free energies OH 139 (1.7:1 dr at C(15)) [a] H 15 (in kcal/mol) are calculated at the TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. –SiR3 = SiMe2Ph. NEVPT2/def2- Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 552 From the relaxed singlet diradical geometry, the second C–C bond formation could then occur. For diradical 126, the formation of which is most facile during the first C–C bond formation (Scheme 4.4), the open-shell singlet PES for its lowest-energy conformer (Scheme 4.5) suggests that formation of the experimentally observed product 124 involves a barrier of 1.8 kcal/mol via 1TS54. This is significantly lower than the 3.9 kcal/mol barrier (1TS54’) for the formation of the corresponding diastereomer 124’ or the 3.7 kcal/mol barrier (1TS53) for the reversion back to enone 121. This is consistent with exclusive formation of product 6, as was observed experimentally.4 It was observed in the original synthesis of scabrolide A that protecting the isopropenyl olefin as an epoxide (138) afforded the desired [6–4–5] ring system as the R epimer at C(3) (139) (Scheme 4.6A). Analogously, we analyzed the open-shell singlet surface for diradical 125, which would lead to the desired but experimentally non-observed product 120 containing the [6–4–5] ring system with the same stereochemistry at C(3). Its precursor triplet diradical 3125 is generated via 7-endo-trig cyclization (TS50) of 121_3(ππ*) (Scheme 4.4A) and all of its low-energy conformers remained as stable singlet diradicals after ISC (with a singlet-triplet gap of less than 1.0 kcal/mol). NEVPT2 calculations suggest a highly flat open-shell singlet PES around the diradical geometry, with an approximately barrierless formation of target product 120 via 1TS56, or its diastereomer 120’ via 1TS56’, or re-formation of enone 121 via 1TS55 (Scheme 4.6B). The relative flat nature of the open-shell singlet PES introduces the possibility that dynamical effects might dictate the partitioning of reaction pathways from diradicals 1126 and 1125. Ergo, ab initio molecular dynamics (AIMD) simulations were performed, Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 553 beginning from optimized triplet-diradical geometries (see section 4.5). AIMD were carried out with the PBE functional, as our controlled studies found that omission of Hartree–Fock exchange leads to a more qualitatively correct open-shell singlet PES with respect to NEVPT2 as a reference (Schemes 4.12 and 4.13). For 1126, AIMD reveals an equal partitioning of low-energy conformers between substrate regeneration and product formation, which is qualitatively consistent with the distribution of outcomes from relaxation of nuclear coordinates of low-energy conformers along the broken-symmetry PES (Table 4.3). Similarly, AIMD trajectories suggest that the majority of the population of diradical 1125 terminate as the desired product 120, while <1% affords substrate 121 or diastereomer 120’ (Table 4.4). These results suggest that dynamic effects on the singlet surface are not significant and the aforementioned results from relaxation of nuclear coordinates after the ISC are reliable. In summary, our results demonstrate that if ISC from the triplet to the open-shell singlet surface affords a stable singlet diradical, then the second C–C bond formation (ring closure) will occur, albeit with variable efficiencies depending on the conformation of the singlet diradical. Equipped with this understanding, we hypothesized that the desired product 120 (or 120’) can be accessed, as long as formation of triplet diradical 3125 is favored during the first C–C bond formation. 4.3.4 COMPLETE MECHANISM As a result of these findings, we propose a mechanism that accounts for the chemo- and diastereoselectivity in the unexpected formation of 124 from enone 121 (Figure 4.1). The initial n → π* excitation followed by intersystem crossing (ISC) to the 3(ππ*) state Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 554 and geometric relaxation, characterized by twisting of the enone, affords triplet diradical 121_3(ππ*) (Scheme 4.3). From 121_3(ππ*), cyclizations can occur from a- or b-attack of the enone triplet diradical with either the pendant isopropenyl olefin or vinyl silane. Considering all modes of cyclization and Re/Si facial selectivity, a total of eight possible ring-closed products are relevant (Scheme 4.4A). From 121_3(ππ*) the most kinetically favorable of these pathways is a 6-endo-trig cyclization involving a-attack of the enone onto the isopropenyl olefin to give 3126, with ∆G‡ of 3.0 kcal/mol (TS48, Scheme 4.4A) and ∆∆G‡ of 4.4 kcal/mol (relative to the second lowest activation barrier). This initial C– C bond formation is thermodynamically favored by 15.6 kcal/mol. Experimentally derived excited state lifetimes for related 3(ππ*) 1,4-diradical intermediates range from 10 to 1,000 ns. As a result, the initial C–C bond formation is irreversible. ISC from 3126 affords the corresponding singlet 1,4-diradical 1126. Along the singlet surface, C–C bond cleavage to regenerate 121 or radical recombination to forge a second C–C bond may occur to form ring-closed species 124 or 124’. Given the flat nature of the singlet PES, the ultimate outcome of ISC was found to be influenced by the conformation of the triplet diradical prior to spin-flip. Relaxation to the ground state enone 121 was observed in a subset of conformers accounting for approximately 70% of the Boltzmann population of the conformer ensemble of 3126. For the conformers that persisted as singlet diradicals, radical recombination to forge experimentally observed product 124 is favored over formation of 124’ or 121 (Scheme 4.5). 555 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Figure 4.1. Complete mechanism describing formation of unexpected product 124 from the intramolecular [2+2] photocycloaddition of enone 121. HO Me O H SiMe2Ph 1. Excitation (n→𝛑*) Me O H HO Me 2. Crossing 1(n𝛑)→ 3(𝛑𝛑*) H O SiMe2Ph HO C–C bond formation 𝛂-attack via TS5 Me O O H O O H Me O SiMe2Ph HO Me H O H H H O PhMe2Si 124 3126 O Me 2. Ring closure via 1TS11 O 1(𝛑𝛑*) H Me 1. ISC H O 3(𝛑𝛑*) HO H 121_3(𝛑𝛑*) 121_S0 Me = 1(n𝛑*) O ∆E = 29.9 (1.30 eV) 2.29 Å SiMe2Ph TS48 TS50 Grel = 8.0 (0.35 eV) TS48 Grel = 5.2 (0.23 eV) H O 121_1(n𝛑*) 3(n𝛑*) Me Grel = 3.0 (0.13 eV) HO H Me to diradical 3125 O H Me 121_3(n𝛑*) O 121_3(𝛑𝛑*) ∆E = 17.3 Grel = 1.8 (0.08 eV) O PhMe2Si (0.75 eV) Grel = 0.0 (0.00 eV) 3126 ∆E = 18.2 (0.79 eV) Photoexcitation n→𝛑* at 313 nm (3.96 eV) H 1TS54 Grel = –15.6 (–0.68 eV) 1TS53 Grel = –12.5 (–0.54 eV) 1TS54 Productive Non-productive Grel = –14.4 (–0.62 eV) 1126 Grel = –16.2 (–0.70 eV) S0 HO Me O H O H HO Me Me H O SiMe2Ph O H O H Me H O SiMe2Ph 1/3126 1TS53 124 121_S0 [a] Relative free energies (in kcal/mol) calculated at the (QD-)NEVPT2/def2- TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. Relative energies in eV given in parentheses. Vertical excitation energies at selected stationary points are calculated with a stateaveraged wavefunction. 3(ππ*)/S0 intersection is not depicted. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.4 556 CONCLUSIONS We report a detailed quantum mechanics investigation of the mechanism of the intramolecular enone-olefin [2+2] photocycloaddition employed in our recent synthesis of (–)-scabrolide A (119). In our prior report, enone 121 was subjected to UV irradiation with the intent to forge a [6–4–5] ring system, which upon oxidative ring opening, would afford the fused [6–7] carbocyclic framework of (–)-scabrolide A (119). To our surprise, instead of forming the desired [6–4–5] ring scaffold (i.e., 120), 121 undergoes an unexpected cyclization to afford an undesired [6–4–4] ring system (i.e., 124). As a consequence of the undesirable reactivity, three additional synthetic steps to mask and subsequently reveal the isopropenyl olefin were incorporated into the synthesis. Our QM calculations reveal that the preferential formation of the [6–4–4] ring system is a result of a facile 6-endo-trig radical cyclization on the 3(ππ*) surface, outcompeting the alternative 7-endo-trig, 6-exo-trig, 5-exo/endo-trig, and 4-exo-trig pathways. Analysis of the open-shell singlet surfaces describing the hypothetical 1,4diradical intermediates post-ISC reveals that C–C bond formation by radical recombination is favorable in each case. Moreover, our study has showcased the practicality and accuracy of combining ab initio wavefunction methods (CASSCF/NEVPT2) with DFT in modeling multiconfigurational and multideterminental open-shell systems. This approach thus serves as a model for future computational endeavors aiming at real-world systems involving complex spin configurations. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.5 SUPPORTING INFORMATION 4.5.1 GENERAL COMPUTATIONAL DETAILS 557 All quantum mechanical calculations were performed with ORCA version 4.2.7 The resolution of identity (RI) and chain-of-spheres 40 approximations were utilized for Coulomb and exchange integrals, respectively, with the def2/J auxiliary basis set.41 Ultrafine integration grids were employed throughout (keywords: “Grid7 NoFinalGrid GridX9”). The CYLview and Chimera42 programs were used to generate graphical images in the main text. DFT Calculations: Unless otherwise noted, geometry optimizations were carried out with the B3LYP global hybrid generalized gradient approximation (GGA) functional8 with Grimme’s D4 dispersion corrections9 (henceforth referred to as B3LYP-D4) with the def2-SV(P) basis set10 on all atoms. For open-shell species, unrestricted Kohn–Sham orbitals were employed. Spin contamination is generally minor. Thermal corrections at 298.15 K were calculated from the unscaled vibrational frequencies at this level of theory. The Quasi-RRHO method was applied to correct for the breakdown of the harmonic oscillator approximation for low frequency vibrations. 43 All stationary points are characterized by the appropriate number of imaginary vibrational modes (zero for optimized geometries and one for transition states). Intrinsic reaction coordinate (IRC) analyses were carried out to ensure all transition states connect the appropriate starting materials and products.11 DFT electronic energies were further refined with the wB97M-V functional,12 def2-TZVPP basis set on all atoms, and the SMD implicit solvation model13 for benzene. Outlying charge corrections were included in the final solvated energies. Final Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 558 (DFT) Gibbs free energies were derived by applying thermodynamic corrections obtained at the optimization level of theory to these refined electronic energies. While these DFT energies are found to be reliable for high-spin (S = 1) intermediates where the nπ* and ππ* surfaces are well separated, multiconfigurational calculations (here, CASSCF/NEVPT2) are employed for a more rigorous description of the electronic structure. However, DFT remains a cost-effective tool for rapid evaluation/screening of conformers. Hence, calculations at the (U)wB97M-V/def2-TZVPP/SMD(benzene)//(U)-B3LYP-D4/def2SV(P) level of theory were employed for exploring reactivity along the triplet ππ* surface (see Schemes 4.7–4.9). CASSCF/NEVPT2 Calculations: CASSCF calculations were performed in order to properly describe the multiconfigurational nature of the system in regions of state crossings, as well as open-shell singlet intermediates. The active space is chosen to incorporate the necessary bonding/anti-bonding orbitals. For enone 121_S0, this affords a 10 electron in 9 orbital active space [enone π/π* orbitals, isopropyl π/π*, vinyl silane π/π*, carbonyl oxygen lone pair], henceforth abbreviated as (10,9). For intermediates where C– C bonds are formed from reactivity of these π systems, the corresponding C–C s/s* are included to maintain a consistent active space. The carbonyl oxygen lone pair of 121 and its subsequent intermediates is included only when necessary (i.e., describing nπ* states), as the lone pair is otherwise weakly correlated (occupation number > 1.999) leading to convergence issues. Additional dynamical correlation is recovered by subsequent NElectron Valence State Perturbation Theory14 (NEVPT2) calculations using the CASSCF wavefunction as a reference. For cases where state-averaged CASSCF wavefunctions are Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 559 employed, the quasi-degenerate formalism of Nakano15 (QD-NEVPT2) was employed, allowing for re-mixing of CI coefficients under the effect of dynamical correlation. Unless otherwise notes, all energies in the main text are relative Gibbs free energies in kcal/mol derived from electronic energies at the NEVPT2/def2-TZVPP/SMD(benzene) level of theory with thermodynamic corrections from the (U)B3LYP/def2-SV(P) optimization level. Excited State Surfaces in Scheme 4.3. The initial singlet n → π* vertical excitation energy of 3.96 eV (313 nm) was obtained from QD-NEVPT2-corrected CASSCF wavefunction with the (10,9) active space with averaging over two triplets (nπ* and ππ*) and three singlet states (closed-shell singlet (ground state), nπ*, and ππ*). Nearly identical results are obtained regardless of state averaging scheme employed (see Table 4.1). From the ground state closed-shell singlet (S0), the singlet n → π* (S1) and π → π* (S1) excitations are 3.96 and 7.45 eV, respectively (Table S1). Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 560 Table 4.1. Comparison of vertical excitation energies calculated at the 121_S0 with various state-averaging schemes.a State 2 triplets 2 singlets 3 singlets S0 – 0.00 [0.0] 0.00 [0.0] 2 triplets 3 singlets 0.00 [0.0] S1 – 4.01 [92.6] 3.99 [92.0] 3.96 [91.4] S2 – – 7.42 [171.2] 7.45 [171.7] T1 0.00 [0.0] – – 3.73 [85.9] T2 0.28 [6.6] – – 4.01 [92.4] [a] Calculations at the QD-NEVPT2/def2-TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory with the (10,9) active space at 121_S0. In order to calculate the energy difference between the 3(nπ*) and 3(ππ*) minima (i.e., 121_3(nπ*) and 121_3(ππ*)), single point calculations at the QD-NEVPT2/CASSCF level of theory with state averaging (3(nπ*) and 3(ππ*)) were carried out at the 121_3(nπ*) and 121_3(ππ*) stationary points. State averaging was employed as at 121_3(ππ*) the carbonyl oxygen lone pair is not significantly correlated in the ground-state triplet at 121_3(ππ*) (occupation number > 1.999). This results in convergence issues in orbital optimization when included in the active space. Accordingly, the lowest triplet state at 121_3(ππ*) does not contain significant 3(nπ*) character and is well described by a single configuration of ππ* character. Single point calculations with DFT ((U)wB97M-V/def2TZVPP/SMD(benzene)) also predict the 121_3(ππ*) minimum to be 1.8 kcal/mol lower in energy than 121_3(nπ*). An analogous strategy was employed when calculating the vertical excitation energies at the other relevant stationary points in Scheme 4.3 (121_3(ππ*)), scheme 4.4 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 561 (TS48), and when computing the vertical energy difference between 3(nπ*) and 3(ππ*) at C–C bond forming transition states. For computing the energy difference between stationary points with the same ground state (for example, ∆G‡ between 121_3(ππ*) and TS48, both with 3(ππ*) ground state), state-averaging is not employed. Additional Stereochemical Considerations In addition to the two 5-exo-trig b-attack pathways highlighted in the main discussion (TS44 and TS45 in Scheme 4.4), two additional diastereomeric pathways (TS57 and TS58) are possible (Scheme 4.7). These pathways present higher barriers and are not accessible given the estimated kinetics of ISC. Moreover, the ensuing ring closure (after ISC) of the diradical intermediates would forge highly strained trans [4–5] fused ring systems. Hence, even if triplet diradical intermediates 140 and 141 were formed, C–C bond scission after ISC is anticipated, reforming starting material 121_S0. In analogy to the discussion above, two additional diastereomeric 4-exo-trig battack transition states are possible (TS59 and TS60, Scheme 4.8). These pathways are high in energy relative to the minimum energy pathways (Scheme 4.4) and are not responsible for the observed reactivity. Moreover, the formation of the resulting cyclobutane-containing products is accompanied by a positive change in free energy. Hence, equilibration prior to ISC will preferentially reform 121_3(ππ*). Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 562 Scheme 4.7. All four diastereomeric 5-exo-trig b-attack transition states and products.a OH Me H O OH Me H O CH2 CH2 SiMe2Ph SiMe2Ph O H O H H O Me O Me TS44 OH Me H OH O Me H O CH2 SiMe2Ph SiMe2Ph O H O Me H 132 CH2 O ∆G‡ = 11.7 ∆G = –10.1 ∆G‡ = n/a ∆G = –12.1 H O Me H H 133 121_3(𝛑𝛑*) TS45 (not observed) OH Me H OH O Me H O CH2 CH2 SiMe2Ph SiMe2Ph O H O O Me H O Me H TS57 OH Me H H 140 O OH Me H O CH2 CH2 SiMe2Ph SiMe2Ph O H O O Me TS58 ∆G‡ = 14.2 ∆G = –9.0 H ∆G‡ = 16.8 ∆G = –7.1 H O Me H 141 [a] All diradicals are in the triplet spin state. Gibbs free energies in kcal/mol from the (U)wB97MV/def2-TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 563 Scheme 4.8. All four diastereomeric 4-exo-trig b-attack transition states and products. OH Me H OH OH Me H O CH2 CH2 Me O Me H O H O PhMe2Si O PhMe2Si 134 TS46 OH Me H OH O Me H O CH2 CH2 Me Me O 121_3(𝛑𝛑*) OH Me H O H O PhMe2Si O PhMe2Si TS47 135 H OH O Me H CH2 Me Me H O H 142 TS59 OH H OH O Me H O CH2 CH2 Me Me O H ∆G‡ = 16.2 ∆G = 0.8 O PhMe2Si O PhMe2Si Me ∆G‡ = 15.6 ∆G = 1.4 O CH2 O ∆G‡ = 11.8 ∆G = 0.2 O H O PhMe2Si O PhMe2Si TS60 143 ∆G‡ = 18.5 ∆G = 2.5 [a] All diradicals are in the triplet spin state. Gibbs free energies in kcal/mol from the (U)wB97MV/def2-TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 564 Scheme 4.9. All diastereomeric products for 6-exo-trig α-attack (144–147), 6-endotrig β-attack (148–149), 5-endo-trig β-attack (150–151), and 5-exo-trig α-attack (152–155).a 148 149 150 151 146 147 152 153 144 145 154 155 [a] All diradicals are in the triplet spin state. Gibbs free energies in kcal/mol from the (U)wB97MV/def2-TZVPP/SMD(benzene)//(U)B3LYP-D4/def2-SV(P) level of theory. While the formation of cross adducts is not experimentally observed, the free energy of triplet diradicals derived from 6-exo-trig a-attack (24–27), 6-endo-trig b-attack (28–29), 5-endo-trig b-attack (30–31), and 5-exo-trig a-attack (32–35) were evaluated for reference (Scheme 4.9). Wolf and Agosta have also previously found that substitution on the internal carbon of pendant olefins leads to “straight” adducts rather than crossed products.44 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 565 Open-shell Singlet Potential Energy Surfaces As the triplet diradical (such as 3126) undergoes a spin flip (ISC), whether it geometrically relaxes to the stable open-shell singlet diradical (such as 1126) or undergoes C–C bond cleavage back to the substrate 121 may be influenced by conformation (Scheme 4.10). Scheme 4.10. Conformational influence on outcome post-ISC.a 3126 126 126 121_S0 [a] Outcome of ISC would depend on the exact conformation of each conformer of triplet-spin diradical (3126). This led to a partitioning between geometry relaxation to a stable diradical (1126), or C–C bond cleavage to re-form substrate 121, as illustrated by the example of diradical 126. Unfortunately, a single Slater determinant, as is used in DFT, does not afford a proper spin eigenfunction for an open-shell singlet state. However, the broken-symmetry formalism may be employed to obtain an Ms = 0 wavefunction with a qualitatively correct character. While the resulting wavefunction is spin contaminated, the energy of the “pure” singlet state can be estimated by a variety of spin projection methods. Here, we employ that of Yamaguchi:45 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A "! − "" = 〈' # 〉 566 2 ("! − "$" ) # ! − 〈' 〉$" When applying this approach to calculate barriers for C–C bond formation/cleavage from the singlet diradical intermediates (1126, 1125, etc.), some spin-projected values resulted in barriers of < 0 kcal/mol (Table 4.2). This indicates that the broken-symmetry (BS) DFT PES may be qualitatively incorrect, i.e., stationary points on the BS-PES may not be stationary points on the true singlet surface. To test this, single point calculations with CASSCF/NEVPT2 were carried out along the IRC trajectories from the suspected saddle points (as obtained by BS-DFT) (Scheme 4.11). While BS-DFT predicts TS11 to be a stationary point between 18 and 6, the NEVPT2 PES reveals no well-defined saddle point, and hence, ∆E(el)‡ ~ 0.0 kcal/mol. While the relative energies along the BS-DFT PES are not necessarily accurate, the molecular geometries obtained along the IRC describing the simple C–C bond stretching/compressing should otherwise remain reliable. As such, a refined PES is derived from single point calculations with CASSCF/NEVPT2 carried out along the IRC trajectories from the saddle points as obtained by BS-DFT. ∆E(el) is then calculated from this new PES and thermodynamical corrections are applied accordingly to obtain free energy barriers (∆G‡). Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 567 Table 4.2. Free energy barriers to C–C bond formation/cleavage from 1126.a 3126 / 1126 TS53 121 TS54’ 124’ TS54 124’ 124 124’ 121 [a] Significant discrepancies between broken-symmetry DFT (BS-DFT), spin-projected BS-DFT, and QD-NEVPT2 calculations in the activation barrier for second C–C bond formation (TS54 and TS54’) and reversion to substrate (TS53), as illustrated by the example of diradical 126. Single-point energies were obtained using (U)B3LYP-D4/def2-SV(P) geometries at either the QD-NEVPT2/CASSCF/def2TZVPP/SMD(benzene) or (U)B3LYP-D4/def2-TZVPP/SMD(benzene) level of theory. For SP-BS-DFT, Yamaguchi’s formula for spin projection was applied. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 568 Scheme 4.11. PESs generated from single point calculations along the BS-DFT IRC trajectories of 1126 to TS54 to 124.a Me OH H O Me H 62 OH H O H H O H 46 Me O H H O 1126 62 Me H O R3Si O R3Si R3Si O OH Me 46 O Me TS54 124 Relative (electronic) Energy 10 0 -10 NEVPT2 -20 CASSCF -30 B3LYP-D4 -40 2.9 2.7 2.5 2.3 2.1 1.9 1.7 1.5 distance C(46) – C(62) (Å) [a] The CASSCF PES is included for comparison, but the NEVPT2 PES should be taken as reference. Considering the relatively flat nature of many of the open-shell singlet potential energy surfaces, we sought to explore by means of ab initio molecular dynamics (AIMD) simulations whether dynamic effects play a role in the final product distributions. For the system at hand, AIMD would not be practical at the CASSCF/NEVPT2 level. Constrained to DFT, we returned to the approach described above, now comparing the performance of a variety of functionals to NEVPT2 references. This was carried out for the ring closure step of diradicals 1126 (Scheme 4.12) and 1125 (Scheme 4.13). These results show that the PBE-D4 functional bears the best resemblance to the NEVPT2 potential energy surface. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 569 Employing the PBE-D4 functional, AIMD simulations were initiated from the lowest energy conformers (within a 1.0 kcal/mol window) of 3125 (Table 4.4) and 3126 (Table 4.3). AIMD simulations were propagated with a 1.0 fs timestep for up to 10 ps or until a bond formation/cleavage occurred. A Berendsen thermostat was employed with a time constant of 50 fs. Randomized initial velocities were set at 20 K, followed by a temperature ramp to 298 K. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 570 Scheme 4.12. Comparison of performance in relaxed surface scan of ring closure of diradical 1126 to form observed but undesired product 124 of various DFT functionals with respect to NEVPT2.a Me OH H O H Me 62 OH H O H O 1126 H R3Si O H 46 Me H O OH Me 46 O Me H O O R3Si TS54 62 Me H O R3Si 124 [a] Scans were performed from the lowest-energy conformer of 1126. All single point energies were calculated from each respective functional with the def2-TZVPP basis set and with the SMD(benzene) implicit solvation. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 571 Scheme 4.13. Comparison of performance in relaxed surface scan of ring closure of diradical 1125 to form observed but undesired product 120 of various DFT functionals with respect to NEVPT2.a Me OH H O H SiR3 Me OH H O H Me OH H O H 66 50 50 O H O O 1125 Me 50 66 SiR3 H O 66 SiR3 H O Me O Me TS56 120 [a] Scans were performed from the lowest-energy conformer of 1125. All single point energies were calculated from each respective functional with the def2-TZVPP basis set and with the SMD(benzene) implicit solvation. 572 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Table 4.3. Partitioning of five lowest-energy conformers of singlet diradical 1126 between four outcomes based on picosecond-scale AIMD calculations.a 1126 124’ 124 1126 121 124 124’ 121 [a] Percent remaining as diradical 1126, product 124 formation, diastereomer 124’ formation, and substrate 121 formation. AIMD calculations were performed at (U)PBE-D4/def2-SV(P) level of theory. 573 Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A Table 4.4. Partitioning of five lowest-energy conformers of singlet diradical 1125 between four outcomes based on picosecond-scale AIMD calculations.a 1125 120 120’ 1125 121 120 120’ 121 [a] Percent remaining as diradical 1125, product 120 formation, diastereomer 120’ formation, and substrate 121 formation. AIMD calculations were performed at (U)PBE-D4/def2-SV(P) level of theory. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 4.6 (1) 574 REFERENCES AND NOTES Initial reports: (a) Corey, E. J.; Bass, J. Dolf.; LeMahieu, Ronald.; Mitra, R. B. A Study of the Photochemical Reactions of 2-Cyclohexenones with Substituted Olefins. J. Am. Chem. Soc. 1964, 86, 5570–5583. (b) Eaton, P. E.; Hurt, W. S. Photodimerization of Cyclopentenone. Singlet or Triplet? J. Am. Chem. Soc. 1966, 88, 5038–5039. (c) Eaton, P. E. The Tricyclo[5.3.0.02,6]Decane System. The Photodimers of Cyclopentenone. J. Am. Chem. Soc. 1962, 84, 2344–2348. For broad reviews, see: (d) Crimmins, M. T. Synthetic Applications of Intramolecular Enone-Olefin Photocycloadditions. Chem. Rev. 1988, 88, 1453–1473. (e) Poplata, S.; Tröster, A.; Zou, Y.-Q.; Bach, T. Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions. Chem. Rev. 2016, 116, 9748–9815. (f) Crimmins, M. T.; Reinhold, T. L. Enone Olefin [2 + 2] Photochemical Cycloadditions. In Organic Reactions; John Wiley & Sons, Ltd, 2004; pp 297–588. For recent examples, see: (g) Ischay, M. A.; Ament, M. S.; Yoon, T. P. Crossed Intermolecular [2 + 2] Cycloaddition of Styrenes by Visible Light Photocatalysis. Chem. Sci. 2012, 3, 2807–2811. (h) Brimioulle, R.; and Bach, T. Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions. Science 2013, 342, 840–843. (i) Gravatt, C. S.; Melecio-Zambrano, L.; Yoon, T. P. Olefin-Supported Cationic Copper Catalysts for Photochemical Synthesis of Structurally Complex Cyclobutanes. Angew. Chem. Int. Ed. 2021, 60, 3989–3993. (j) Scholz, S. O.; Kidd, J. B.; Capaldo, L.; Flikweert, Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 575 N. E.; Littlefield, R. M.; Yoon, T. P. Construction of Complex Cyclobutane Building Blocks by Photosensitized [2 + 2] Cycloaddition of Vinyl Boronate Esters. Org. Lett. 2021, 23, 3496–3501. (k) Sherbrook, E. M.; Genzink, M. J.; Park, B.; Guzei, I. A.; Baik, M.-H.; Yoon, T. P. Chiral Brønsted Acid-Controlled Intermolecular Asymmetric [2 + 2] Photocycloadditions. Nat. Commun. 2021, 12, 5735. (2) Early example of use in synthesis: (a) Corey, E. J.; Mitra, R. B.; Uda, H. Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene. J. Am. Chem. Soc. 1964, 86, 485–492. For review see: (b) Iriondo-Alberdi, J.; Greaney, M. F. Photocycloaddition in Natural Product Synthesis. Eur. J. Org. Chem. 2007, 4801– 4815. (c) Bach, T.; Hehn, J. P. Photochemical Reactions as Key Steps in Natural Product Synthesis. Angew. Chem. Int. Ed. 2011, 50, 1000–1045. (d) Sarkar, D.; Bera, N.; Ghosh, S. [2+2] Photochemical Cycloaddition in Organic Synthesis. Eur. J. Org. Chem. 2020, 1310–1326. (e) Winkler, J. D.; Bowen, C. M.; Liotta, F. [2 + 2] Photocycloaddition/Fragmentation Strategies for the Synthesis of Natural and Unnatural Products. Chem. Rev. 1995, 95, 2003–2020. (3) Reviews of fragmentation strategies and tactics: (a) Namyslo, J.C.; Kaufman, D.E. The Application of Cyclobutane Derivatives in Organic Synthesis. Chem. Rev. 2003, 103, 1485–1538. (b) Murakami, M.; Ishida, N. Cleavage of Carbon–Carbon s-Bonds for Four-Membered Rings. Chem. Rev. 2021, 121, 264–299. (c) Wang, B.; Parea, M.A.; Sarpong, R. Transition Metal-Mediated C–C Single Bond Cleavage: Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 576 Making the Cut in Total Synthesis. Angew. Chem. Int. Ed. 2020, 59, 18898–18919. (d) Lee-Ruff, E.; Mladenova, G. Enantiomerically Pure Cyclobutane Derivatives and Their Use in Organic Synthesis. Chem. Rev. 2003, 103, 1449–1484. (4) Hafeman, N. J.; Loskot, S. A.; Reimann, C. E.; Pritchett, B. P.; Virgil, S. C.; Stoltz, B. M. The Total Synthesis of (−)-Scabrolide A. J. Am. Chem. Soc. 2020, 142, 8585– 8590. (5) (a) Srinivasan, Ramaswamy.; Carlough, K. H. Mercury(3P1) Photosensitized Internal Cycloaddition Reactions in 1,4-, 1,5-, and 1,6-Dienes. J. Am. Chem. Soc. 1967, 89, 4932–4936. (b) Liu, R. S. H.; Hammond, G. S. Photosensitized Cyclization of Myrcene: The Problem of Addition of Dienes to Alkenes. J. Am. Chem. Soc. 1964, 86, 1892–1893. For further discussion regarding the “Rule of Five” in the context of [2+2] photocycloadditions, see Bradley, S. A.; Bresnan, B. J.; Draper, S. M.; Geraghty, N. W. A.; Jeffares, M.; McCabe, T.; McMurry, T. B. H.; O’Brien, J. E. Photochemical [2 + 2] Cycloaddition Reactions of 6-Alkenyl-3Phenylcyclohex-2-En-1-Ones: Using Biradical Conformation Control to Account for Exceptions to the “Rule of Five.” Org. Biomol. Chem. 2011, 9, 2959. (6) (a) Sheu, J.-H.; Ahmed, A. F.; Shiue, R.-T.; Dai, C.-F.; Kuo, Y.-H. Scabrolides A−D, Four New Norditerpenoids Isolated from the Soft Coral Sinularia Scabra. J. Nat. Prod. 2002, 65, 1904–1908. (b) Thao, N. P.; Nam, N. H.; Cuong, N. X.; Quang, T. H.; Tung, P. T.; Dat, L. D.; Chae, D.; Kim, S.; Koh, Y.-S.; Kiem, P. V.; Minh, Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 577 C. V.; Kim, Y. H. Anti-Inflammatory Norditerpenoids from the Soft Coral Sinularia Maxima. Bioorg. Med. Chem. Lett. 2013, 23, 228–231. (7) (a) Neese, F. Software Update: The ORCA Program System, Version 4.0. Wiley Interdisciplinary Reviews: Computational Molecular Science 2018, 8, e1327. (b) Neese, F. The ORCA Program System. Wiley Interdisciplinary Reviews: Computational Molecular Science 2012, 2, 73–78. (8) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623–11627. (9) Caldeweyher, E.; Ehlert, S.; Hansen, A.; Neugebauer, H.; Spicher, S.; Bannwarth, C.; Grimme, S. A Generally Applicable Atomic-Charge Dependent London Dispersion Correction. J. Chem. Phys. 2019, 150, 154122. (10) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (11) Ishida, K.; Morokuma, K.; Komornicki, A. The Intrinsic Reaction Coordinate. An Ab Initio Calculation for HNC→HCN and H−+CH4→CH4+H−. J. Chem. Phys. 1977, 66, 2153–2156. (12) Mardirossian, N.; Head-Gordon, M. ωB97M-V: A Combinatorially Optimized, Range-Separated Hybrid, Meta-GGA Density Functional with VV10 Nonlocal Correlation. J. Chem. Phys. 2016, 144, 214110. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A (13) 578 Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. (14) (a) Angeli, C.; Cimiraglia, R.; Malrieu, J.-P. N-Electron Valence State Perturbation Theory: A Fast Implementation of the Strongly Contracted Variant. Chem. Phys. Lett. 2001, 350, 297–305. (b) Angeli, C.; Cimiraglia, R.; Malrieu, J.-P. N-Electron Valence State Perturbation Theory: A Spinless Formulation and an Efficient Implementation of the Strongly Contracted and of the Partially Contracted Variants. J. Chem. Phys. 2002, 117, 9138–9153. (15) When a state-averaged CASSCF wavefunction employed as a zeroth order reference, the Nakano quasi-degenerate formulation was used. (a) Nakano, H. Quasidegenerate Perturbation Theory with Multiconfigurational Self‐consistent‐ field Reference Functions. J. Chem. Phys. 1993, 99, 7983–7992. (b) Angeli, C.; Borini, S.; Cestari, M.; Cimiraglia, R. A Quasidegenerate Formulation of the Second Order N-Electron Valence State Perturbation Theory Approach. J. Chem. Phys. 2004, 121, 4043–4049. (16) (a) Wilsey, S.; González, L.; Robb, M. A.; Houk, K. N. Ground- and Excited-State Surfaces for the [2+2]-Photocycloaddition of α,β-Enones to Alkenes. J. Am. Chem. Soc. 2000, 122, 5866–5876. (b) Bertrand, C.; Bouquant, J.; Pete, J. P.; Humbel, S. Theoretical Description of [2+2] Photocycloadditions: Enone and Ethylene as a Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 579 Model of the Reactivity of Cycloenones. J. Mo. Struct. 2001, 538, 165–177. (c) Cucarull-González, J. R.; Hernando, J.; Alibés, R.; Figueredo, M.; Font, J.; Rodríguez-Santiago, L.; Sodupe, M. [2 + 2] Photocycloaddition of 2(5H)-Furanone to Unsaturated Compounds. Insights from First Principles Calculations and Transient-Absorption Measurements. J. Org. Chem. 2010, 75, 4392–4401. (d) Reguero, M.; Olivucci, M.; Bernardi, F.; Robb, M. A. Excited-State Potential Surface Crossings in Acrolein: A Model for Understanding the Photochemistry and Photophysics of a,b-Enones. J. Am. Chem. Soc. 1994, 116, 2103–2114. (17) (a) Lam, E. Y. Y.; Valentine, Donald.; Hammond, G. S. Mechanisms of Photochemical Reactions in Solution. XLIV. Photodimerization of Cyclohexenone. J. Am. Chem. Soc. 1967, 89, 3482–3487. (b) Ruhlen, J. L.; Leermakers, P. A. Photochemistry of Cyclopentenone in Various Media. J. Am. Chem. Soc. 1967, 89, 4944–4948. (c) Chapman, O. L.; Koch, T. H.; Klein, F.; Nelson, P. J.; Brown, E. L. Photochemical Transformations. XXV. Two Triplet Mechanisms in Photochemical Addition of 2-Cyclohexenones to 1,1- Dimethoxyethylene. J. Am. Chem. Soc. 1968, 90, 1657–1658. (d) Bauslaugh, P. G. Photochemical Cycloaddition Reactions of Enones to Alkenes; Synthetic Applications. Synthesis 1970, 287–300. For a review, see: (e) Schuster, D. I.; Lem, George.; Kaprinidis, N. A. New Insights into an Old Mechanism: [2 + 2] Photocycloaddition of Enones to Alkenes. Chem. Rev. 1993, 93, 3–22. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A (18) 580 (a) El‐Sayed, M. A. Spin—Orbit Coupling and the Radiationless Processes in Nitrogen Heterocyclics. J. Chem. Phys. 1963, 38, 2834–2838. (b) Baba, M. Intersystem Crossing in the 1nπ* and 1ππ* States. J. Phys. Chem. A 2011, 115, 9514–9519. (19) (a) Kaprinidis, N. A.; Lem, G.; Courtney, S. H.; Schuster, D. I. Determination of the Energies and Lifetimes of Triplet 1,4-Biradicals Involved in [2+2] Photocycloaddition Reactions of Enones with Alkenes Using Photoacoustic Calorimetry J. Am. Chem. Soc. 1993, 115, 3324–3325. (b) Schuster, D. I.; Dunn, D. A.; Heibel, G. E.; Brown, P. B.; Rao, J. M.; Woning, J.; Bonneau, R. Enone Photochemistry. Dynamic Properties of Triplet Excited States of Cyclic Conjugated Enones as Revealed by Transient Absorption Spectroscopy. J. Am. Chem. Soc. 1991, 113, 6245–6255. Here we assume a 1 M standard state of substrate. (20) Weedon, A. C., Enone photochemical cycloaddition in organic synthesis, in Synthetic Organic Chemistry, Horspool, W. M., Ed., Plenum Press, New York, 1984, chap. 2. (21) Similar results are obtained regardless of the state averaging scheme employed. (22) ∆EST(ππ*) is larger in magnitude than ∆EST(nπ*) as the overlap of the π/π* orbitals is greater than that of the n/π* orbitals. (23) The 3(nπ*) and 3(nπ*) minima are expected to be qualitatively similar in geometry. The similarity of their PES is highlighted in Scheme 4.3B. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A (24) 581 Schuster, D. I.; Woning, J.; Kaprinidis, N. A.; Pan, Y.; Cai, B.; Barra, M.; Rhodes, C. A. Photochemical and Photophysical Studies of Bicyclo[4.3.0]non-1(6)-en-2one. J. Am. Chem. Soc. 1992, 114, 7029–7034. (25) Root-flipping between 3(ππ*) and 3(nπ*) states complicates this matter. In order to approximate the diabatic surface obtained by relaxation of the nuclear coordinates of the 3(ππ*) state, the carbonyl oxygen lone pair is removed from the active space, rendering the 3(ππ*) state the lowest energy triplet state for the portion of the PES of interest. Starting from the 120_3(nπ*) minimum geometry, triplet state geometries were then relaxed at the CASSCF(8,8)/def2-SV(P) level of theory. Points along the optimization trajectory were then taken for analysis. (26) The crossing point is not rigorously the minimum energy crossing point, rather the approximate surface rather serves as an upper bound. (27) At the 3(ππ*)/1(nπ*) minimum energy crossing point, SOC creates an energy gap of ca. 1 kcal/mol between the adiabatic surfaces. (28) For β-attack, 2 diastereomeric transition states arise from each of 4-exo-, 5-endo-, 5-exo-, and 6-endo-trig cyclizations, as the pendant olefin of interest approaches the β-radical from either the Si or Re face of the enone. There are 2 more diastereomeric transition states for each of the 4-exo- and 5-exo-trig cyclizations, as the β-radical can approach the more substituted and prochiral carbon in the isopropenyl olefin and the vinyl silane from either of the diastereotopic faces of the olefin. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A (29) 582 For α-attack, 2 diastereomeric transition states arise from each of 5-exo-, 6-endo-, 6-exo-, and 7-endo-trig cyclizations, as the pendant olefin of interest approaches the β-radical from either the Si or Re face of the enone. There are 2 more diastereomeric transition states for each of the 5-exo- and 6-exo-trig cyclizations, as the α-radical can approach the more substituted and prochiral carbon in the isopropenyl olefin and the vinyl silane from either of the diastereotopic faces of the olefin. (30) No first-order saddle point exists describing TS45, not that the formation of 3133 is barrierless, but rather that the saddle structure that would have corresponded to TS45 maintains non-zero energy gradient until ultimately reaching TS52. In other words, bringing the vinyl silane olefin to the 3(ππ*) enone would more readily give rise to TS50. This is likely due to the steric congestion of forming vicinal tetrasubstituted centers in TS45. We note that there may be non-statistical dynamical affects that are not accounted for here – TS52 may be near an inflection point on a bifurcated PES which could lead to 3133 or 3125 from 3121. (31) The 3(nπ*) transition structure is different than that along the 3(ππ*) surface. However, the vertical excitation of ca. 40 kcal/mol at the 3(ππ*) saddle point highlights the significant divergence of the two surfaces at this region of the PES. (32) Similar reactivity has been proposed in intermolecular enone/olefine photocycloadditions. Bowman, R. M.; Calvo, C.; McCullough, J. J.; Rasmussen, P. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 583 W.; Snyder, F. F. Photoadditions of 2-Cyclohexenone Derivatives to Cyclopentene. Stereochemistry. J. Org. Chem. 1972, 37, 2084–2091. (33) Note that its <0.5% of QD-NEVPT2 wavefunction. (34) The vertical singlet-triplet gap was calculated at the same geometry optimized by (U)B3LYP-D4/def2-SV(P) on the open-shell singlet surface. Energy of the lowest singlet and triplet state was calculated with state-averaging using the QD-NEVPT2 method with an (8,8) active space. (35) Note the relative rates of ISC also depend on the geometry of the 1,4-diradical, with increasingly perpendicular valence orbitals giving rise to stronger SOC. Increased ionic character in the singlet state and decreasing distance between the two radical centers also serve to maximize SOC. See also: Carlacci, L.; Doubleday, C.; Furlani, T. R.; King, H. F.; McIver, J. W. Spin-Orbit Coupling in Biradicals. Ab Initio MCSCF Calculations on Trimethylene and the Methyl-Methyl Radical Pair. J. Am. Chem. Soc. 1987, 109, 5323–5329. (36) (a) Noodleman, L. Valence Bond Description of Antiferromagnetic Coupling in Transition Metal Dimers. J. Chem. Phys. 1981, 74, 5737–5743. (b) Noodleman, L.; Davidson, E. R. Ligand Spin Polarization and Antiferromagnetic Coupling in Transition Metal Dimers. Chem. Phys. 1986, 109, 131–143. (37) Broken symmetry energies were spin decontaminated following the approach of Yamaguchi and coworkers to approximate the energy of the pure singlet states. Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A (38) 584 Wagner, P. J.; Bucheck, D. J. Inefficiency and Reversibility in the Photodimerization of 2-Cyclopentenone. Can. J. Chem. 1969, 47, 713–714. (39) The single broken-symmetry determinant is not a proper spin eigenfunction of the '+ # operator. For addition discussion, see: Neese, F. Definition of Corresponding Orbitals and the Diradical Character in Broken Symmetry DFT Calculations on Spin Coupled Systems. J. Phys. Chem. Solids 2004, 65, 781–785. (40) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree-Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree-Fock Exchange. Chem. Phys. 2009, 356, 98–109. (41) Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057–1065. (42) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera—A Visualization System for Exploratory Research and Analysis. J. Comput. Chem. 2004, 25, 1605–1612. (43) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chem. Eur. J. 2012, 18, 9955–9964. (44) Wolff, S.; Agosta, W. C. Preparation of Derivatives of Tricyclo[4.2.0.01,4]Octane, Broken Window Compounds. J. Chem. Soc., Chem. Commun. 1981, 3, 118–120. (45) (a) Yamaguchi, K.; Takahara, Y.; Fueno, T. Ab-Initio Molecular Orbital Studies of Structure and Reactivity of Transition Metal-OXO Compounds. In Applied Quantum Chemistry; Smith, V. H., Schaefer, H. F., Morokuma, K., Eds.; Springer Chapter 4 – Quantum Mechanics Investigations of the [2+2] Photocycloaddition in the Synthesis of (–)-Scabrolide A 585 Netherlands: Dordrecht, 1986; pp 155–184. (b) Soda, T.; Kitagawa, Y.; Onishi, T.; Takano, Y.; Shigeta, Y.; Nagao, H.; Yoshioka, Y.; Yamaguchi, K. Ab Initio Computations of Effective Exchange Integrals for H–H, H–He–H and Mn2O2 Complex: Comparison of Broken-Symmetry Approaches. Chemical Physics Letters 2000, 319, 223–230. (c) Ferré, N.; Guihéry, N.; Malrieu, J.-P. Spin Decontamination of Broken-Symmetry Density Functional Theory Calculations: Deeper Insight and New Formulations. Phys. Chem. Chem. Phys. 2015, 17, 14375– 14382. CHAPTER 5 Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles.† 5.1 INTRODUCTION The construction of chiral all-carbon quaternary centers featuring vicinal tertiary stereocenters exemplifies a prevalent challenge in synthetic chemistry. We envisioned the transition metal-catalyzed branched-selective allylic alkylation of prochiral hard enolate nucleophiles as a promising strategy for accessing such motifs. However, a multitude of challenges must be overcome, including regioselectivity in enolate formation, and regio-, enantio-, and diastereoselectivity in the alkylation event.1 Ir catalyst systems have proven to be privileged for the branched-selective allylic alkylation of soft carbon nucleophiles.2 Extending this reactivity paradigm to hard, prochiral enolate nucleophiles has remained a challenge.3 To address this, Hartwig employed the in situ generation of Ba enolates to enable the branched-selective allylic alkylation of a-tetralone nucleophiles (156) (Figure 5.1A). 4 However, this approach is limited to select ketones due to the challenge of regioselective deprotonation. Related transformations are subject to similar constraints.5 The Pd-catalyzed decarboxylative allylic alkylation of b-ketoesters represents a general, regiospecific-at-nucleohile strategy for the asymmetric allylic alkylation of hard enolates (Figure 5.1B). 6 However, canonical Pd-catalyzed decarboxylative allylic alkylation † Unpublished research conducted with Dr. Stephen Sardini and Dr. Veronica Hubble Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 587 employing tetrasubstituted nucleophiles and substituted allyl esters (158a) gives rise to undesired regioselectivity, yielding linear alkylation products (159a) (Figure 5.1C).3,7 Figure 5.1. Asymmetric allylic alkylation of tetrasubstituted enolate nucleophiles. A. Ir-catalyzed branched-selective allylic alkylation of Ba enolates. O Ph O OCO2Me [Ir] (2 mol %) Me Me Ph Ba(Ot-Bu)2, THF, 5 ºC 156 (1.2 equiv) 83% yield 11:1 dr, 98% ee 157 B. Decarboxylative asymmetric allylic alkylation. O Me O O O Pd2(dba)3 (2.5 mol %) (S)-t-BuPHOX (6.25 mol %) Me O N Ph2P THF, 25 ºC 85% yield, 88% ee (±)-1 t-Bu (S)-t-BuPHOX (L1) (S)-2 C. Standard Pd-catalyzed decarboxylative allylic alkylation of substituted allyl esters.a O Me O O Ph O Pd2(dba)3 (2.5 mol %) (S,S)-DACH-phenyl (6.5 mol %) Ph THF, 60 ºC 95% yield, 28% ee >20:1 L/B 158a Me 159a Linear-selective D. This research: Branched-selective decarboxylative asymmetric allylic alkylation. Protonation O R1 R2 O O CO2 O R3 Pd R2 R3 R1 Up to 87% yield, >20:1 dr, 94% ee Regiospecific Branched-selective [a] Reaction conditions: 158a (0.05 mmol), Pd2(dba)3 (2.5 mol %), (S,S)-DACH-Ph (6.5 mol %), and THF (2 mL) at 60 ºC for 14 h. NMR yield determined with 1,3,5-trimethoxybenzene as an internal standard. Enantioselectivity measured by chiral SFC analysis. Aided by our prior mechanistic studies, we sought to favor the formation of branched products through the design of ligands that bias key interactions in the innersphere seven-membered reductive elimination transition state.8 Ultimately, we achieve a general approach to chiral all-carbon vicinal quaternary/tertiary stereocenters (Figure 5.1D). High diastereo- (>20:1) and enantioselectivity (>80% ee) are obtained, with the Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 588 majority of products featuring >20:1 branched/linear selectivity. Subsequent derivatization of these compounds highlights their utility as synthetic building blocks. 5.2 MECHANISM AND DEVELOPMENT We began our investigation by considering the inner-sphere transition states that lead to the formation of the desired branched (160a) and undesired linear (159a) products from b-ketoester 158a (Figure 5.2A). The two lowest energy transition states leading to linear (159a) and branched (160a) products are TS61 and TS62, respectively. Unfortunately, with the prototypical (S)-t-BuPHOX ligand (L1), linear TS61 is favored by 2.6 kcal/mol over its branched counterpart. Noting the proximity of the allyl substituent to the phenyl group of the PHOX backbone (red arrows in TS61 at top of Figure 5.2A), we explored di-ortho substitution of the ligand aryl groups as a means to disfavor TS61 by sterics.9 Accordingly, with (S)-Mes-t-BuPHOX (L2), TS62 now becomes favored over TS61 by 3.5 kcal/mol. Enantioselectivity of the branched product (160a) from inner-sphere reactivity is computed to remain high, with ∆∆G‡ between diastereomeric transition states of 2.4 and 3.9 kcal/mol with L1 and L2, respectively. Moreover, 2.5 and 1.2 kcal/mol preferences for the chair-like over the boat-like transition states ensures good diastereoselectivity. In summary, our preliminary in silico studies highlight that (1) ortho substitution of the ligand arenes will introduce a bias for the desired branched product (160a), and (2) a purely inner-sphere reaction will maintain both high diastereo- and enantioselectivity. 589 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles Figure 5.2. Computational studies and initial reaction development. B. Reaction optimization.b A. Mechanistic hypothesis.a O O Ar Me O N P Pd t-Bu O Ar Me Ar O O N Pd P t-Bu Ph O Pd2(dba)3 (2.5 mol %) ligand (6.5 mol %) TS61 TS62 Branch Transition State (to 160a) Exploit non-covalent interactions to favor TS62 TS61: (S)-t-BuPHOX (L1) TS61: (S)-Mes-t-BuPHOX (L2) Ar = Ar = ∆G‡rel (L) = 0.0 Me Me ∆G‡rel (L) = 3.5 ∆G‡rel (B) = 0.0 ∆G‡rel (B) = 2.6 Linear preferred Branched preferred Me Favorable Linear TS Disfavored Linear TS 158a Ph 160a (branched) 159a (linear) Entry Ligand Solvent Yield B:L dr % ee 1 2 3 4 5 (S)-t-BuPHOX (L1) (S)-t-BuPHOX (L1) (S)-(CF3)3-t-BuPHOX (L3) (S)-Mes-t-BuPHOX (L2) L4 L5 L6 L7 L7 THF PhMe PhMe PhMe PhMe 54 97 86 38 25 1 : 2.1 1 : 1.9 1 : 1.1 1.1 : 1 3.1 : 1 2.1 : 1 7.0 : 1 14 : 1 1.9 : 1 12 : 1 –12 65 80 6 68 PhMe PhMe PhMe PhMe 85 78 62 62 11 : 1 1.7 : 1 5.9 : 1 9.1 : 1 14 : 1 16 : 1 >20 : 1 >20 : 1 70 82 76 82 6 7 8 9c Ligand electronics L1 R =H CF3 L3 ortho-Substitution Ar = R CF3 O P 2 R N O Ar t-Bu P Ar F F Me L5 L4 N F OCF3 t-Bu L6 Potential edge–face interaction Me + Ar Linear Transition State (to 159a) O Ph solvent, 60 ºC O Me Me L7 Sterics to disrupt aryl positioning [a] Gibbs free energies in kcal/mol.10 [b] Reaction conditions: 158a (0.05 mmol), Pd2(dba)3 (2.5 mol %), ligand (6.5 mol %), and solvent (2 mL) at 60 ºC for 14 h. NMR yield determined with 1,3,5trimethoxybenzene as an internal standard. B:L and dr determined by crude 1H NMR analysis. Enantioselectivity measured by chiral SFC analysis. [c] Isolated yield from 0.1 mmol of 158a at 50 ºC. Encouraged by the prospect of rational ligand design as a means to affect branchedselective alkylation, we began our experimental investigations. As anticipated, subjecting b-ketoester 158a to standard reaction conditions with (S)-t-BuPHOX (L1) in THF afforded the undesired linear isomer (159a) as the major reaction product with a branched-to-linear ratio (B/L) of 1:2.1 (Figure 5.2B, entry 1). Surprisingly, the branched ketone (160a) was furnished in poor enantio- and diastereoselectivity. Our computational studies found that branched product formation from inner-sphere reductive elimination to proceed with both high enantio- and diastereoselectivity. Hence, we suspected a deleterious outer-sphere Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 590 mechanism to be competitive with said inner-sphere processes. To disfavor chargeseparated outer-sphere intermediates, a less polar solvent, such as toluene, and the electronpoor (S)-(CF3)3-t-BuPHOX (L3) ligand were explored. Under these conditions, the desired branched product is obtained in 86% yield, 80% ee, and an improved 14:1 dr (entries 2–3). As anticipated, regioselectivity remains poor, with a B/L ratio of 1:1.1. To improve branched-selectivity, (S)-Mes-t-BuPHOX (L2) from our in silico studies was explored; however, the electron rich nature of the ligand likely supports outer-sphere processes, affording 160a in 6% ee and 1.9:1 dr (entry 4). Hence, a series of ligands that keep ortho aryl substitution yet feature electron-withdrawing groups were evaluated (L4–L7, entries 5–8). Ultimately, o-trifluoromethylether-containing PHOX ligand L7 was found to be optimal for the branched-selective allylic alkylation of 158a, affording the desired product (160a) in 62% isolated yield, 82% ee, >20:1 dr, and in a 9.1:1 B/L ratio at 50 ºC in toluene (entry 9). 5.3 SUBSTRATE SCOPE With respect to the scope of the transformation, substrates that incorporate a,b- unsaturation led to a marked increase in the branched selectivity to 20:1 or greater (160b and 160c) (Figure 5.3). We were delighted to find the increasingly electron-rich enolate nucleophiles derived from synthetically useful vinylogous esters are well tolerated, affording the corresponding products (160d–160h) in generally good yield, >20:1 B/L, >20:1 dr, and 82–87% ee. Both ligands L6 and L7 perform well for the vinylogous ester substrate class. A vinylogous thioester was also explored, albeit reduced branched selectivity was observed (160i). a-Enaminone-containing product 160j was obtained in Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 591 lower yield but excellent diastereo- and enantioselectivity (>20:1 dr, 94% ee). We were excited to observe that aliphatic substituted allyl electrophiles are competent coupling partners. Crotyl alcohol-derived b-ketoester 158k affords enone 160k in 59% yield, 8.3:1 dr, and 73% ee, albeit with a diminished 2.5:1 B/L ratio. The reduction in branched selectivity likely arises from the smaller steric profile of the methyl substituent, making distinction between TS61 and TS62 more challenging. Employing a larger alkyl substituent restores branched-selectivity (160l). Additionally, a-fluoro enolate nucleophiles are highly competent substrates in this transformation. A variety of fluorinated tetrasubstituted/tertiary vicinal stereocenter-containing products (160m–160q) were furnished in generally good yield as predominantly a single isomer with high enantioselectivity (82–87% ee). Hence, the branched-selective decarboxylative allylic alkylation described herein represents a powerful strategy to access diverse, stereochemically rich building blocks. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 592 Figure 5.3. Substrate scope of branched-selective allylic alkylation.a O R2 O R3 O R1 O Pd2(dba)3 (2.5 mol%)b L7 (6.5 mol%) R2 R3 R1 PhMe, 50 ºC 158a–q 160a–q Substrate scope for branched-selective allylic alkylation forging quaternary centers O Me Ph O 160a 62% yield, 9.1:1 B/L >20:1 dr, 82% ee Me 160b 51% yield, 20:1 B/L >20:1 dr, 78% ee Et EtO 160e 70% yieldc, >20:1 B/L >20:1 dr, 87% ee O Me Ph O O N Me Ph O O Ph Me Me O OBn Me Me 160k 59% yieldc, 2.5:1 B/L 8.3:1 dr, 73% ee 160j 30% yieldd, 9.1:1 B/L >20:1 dr, 94% ee Ph 160h 70% yieldc, >20:1 B/L >20:1 dr, 82% ee Me 160i 87% yieldc, 7.5:1 B/L >20:1 dr, 78% ee Me BnO CN 160g 77% yieldc, >20:1 B/L >20:1 dr, 84% ee PhS Ph 160d 70% yield, >20:1 B/L >20:1 dr, 84% ee EtO 160f 42% yieldc, >20:1 B/L >20:1 dr, 84% ee Me EtO O CO2Me O Ph 160c 70% yield, >20:1 B/L >20:1 dr, 80% ee Ph EtO Me Me Ph O O O Ph 160l 35% yield, >20:1 B/L >20:1 dr, 82% ee Vicinal stereocenters containing C–F bonds O F Ph O F O Ph F Ph EtO 160m 71% yield, >20:1 B/L >20:1 dr, 85% ee 160o 80% yieldc,e, >20:1 B/L >20:1 dr, 87% ee 160n 75% yield, >20:1 B/L >20:1 dr, 82% ee O OBn O F Me 160p 48% yield, >20:1 B/L 14:1 dr, 84% ee F Me Me 160q 78% yieldd, 3.6:1 B/L 4.5:1 dr, 87% ee [a] Reaction conditions: 158 (0.1 mmol), Pd2(dba)3 (2.5 mol %), L7 (6.5 mol %), and toluene (4 mL) at 50 ºC for 14 h. [b] Pd2(pmdba)3 can be employed as a Pd source when dba is difficult to separate from desired product. [c] L6 employed (comparable performance between L7 and L6). [d] L3 employed. [e] Reaction carried out at 60 ºC. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 5.4 593 PRODUCT TRANSFORMATIONS Derivatization of allylic alkylation products showcases the synthetic utility of these building blocks. Stork–Danheiser ketone transposition of vinylogous ester 160d afforded g-substituted a,b-unsaturated ketone 161. Selective olefin hydrogenation of 160d smoothly furnishes vicinal stereocenter-containing product 162 in nearly quantitative yield. Wacker oxidation of the terminal olefin of 160c yielded ketone 163, now bearing a 1,4dioxygenation pattern. Figure 5.4. Branched allylic alkylation product derivatizations. O Me Ph Me Ph DIBAL-H, CH2Cl2, 0 ºC then, H2SO4, 23 ºC EtO 57% yield 160d O Me O 161 Ph O H2 (1 atm), Pd/C Me Et Ph MeOH, 23 ºC EtO 99% yield 160d O Me Ph EtO 162 O PdCl2, CuCl2 O2 (1 atm) Me DMF/H2O, 60 ºC 30% yield Me 160c 5.5 Ph Me O Me 163 CONCLUSIONS We report the development of a branched-selective Pd-catalyzed decarboxylative asymmetric allylic alkylation of hard enolate nucleophiles. Building on our prior studies on the inner-sphere seven-centered reductive elimination, we derive a set of design principles for rational ligand design that ultimately overturns the innate selectivity in prior systems. The transformation employs readily accessible b-ketoester precursors to furnish products containing vicinal all-carbon quaternary/tertiary stereocenters. Branched products Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 594 are obtained in up to 80% yield, >20:1 dr, and 87% ee. Studies further expanding the utility and scope of this transformation are underway and will be reported in due course. 5.6 SUPPORTING INFORMATION 5.6.1 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. 11 Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on a Bruker 400 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). 2H NMR spectra were recorded on a Bruker 400 MHz (61 MHz) spectrometer and are reported relative to residual CDCl3 (δ 7.26 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as the peaks appear as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of water (δ 1.56ppm), 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 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 595 silicon grease (δ 0.07 ppm), which do not impact product assignments. 13C NMR spectra of deuterated compounds are complicated by the low intensity of peaks of deuteriumsubstituted carbon atoms. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in Field Desorption (FD+) mode. Absolute stereochemical assignments were made by vibrational circular dichroism analysis for select compounds with related compounds assigned by analogy. Reagents were purchased from commercial sources and used as received unless otherwise stated. Ligands were prepared according to literature procedures.12 List of Abbreviations: ee – enantiomeric excess, SFC – supercritical fluid chromatography, TLC – thin-layer chromatography, IPA – isopropanol, VCD – vibrational circular dichroism, pmdba – bis(4-methoxybenzylidene)acetone. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 5.6.2 596 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation General Procedure A: Asymmetric Pd-Catalyzed Decarboxylative Allylic Alkylation. O R2 O O R1 R3 O Pd2(dba)3 (2.5 mol%) Ligand (6.5 mol%) PhMe, 50 ºC R2 R3 R1 158 160 In a nitrogen filled glovebox, an oven-dried 1 dram vial was charged with a stir bar, Pd2(dba)3 or Pd2(pmdba)3 (2.5 µmol, 2.5 mol %), ligand (0.0065 mmol, 6.5 mol %), and toluene (1.0 mL). The catalyst solution was stirred at 23 ºC for 20 min, then added to a solution of substrate 158 in toluene (3 mL) in a 2 dram vial. The reaction vial was then sealed with electrical tape, removed from the glovebox, and heated to 50 ºC for 14 h. The reaction mixture was let cool to ambient temperature, passed through a plug of silica gel, and concentrated under reduced pressure. The crude reaction mixture was loaded directly onto a flash column and the product (160) was isolated by silica gel flash column chromatography. O Me Ph 160a (S)-2-methyl-2-((S)-1-phenylallyl)cyclohexan-1-one (160a) Prepared from 158a (27.2 mg, 100 µmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–15% EtOAc/hexanes) afforded the title compound as a colorless oil (14.2 mg, 62.2 µmol, 62% yield, 9.1:1 B/L, >20:1 dr (B), 82% ee(B)). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 597 *Crude 1H NMR analysis reveals a B/L of 5.6:1 prior to chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.35 – 7.28 (m, 2H), 7.25 – 7.19 (m, 3H), 6.21 – 6.07 (m, 1H), 5.09 – 5.03 (m, 2H), 3.93 (d, J = 9.4 Hz, 1H), 2.56 – 2.32 (m, 2H), 2.10 – 1.98 (m, 2H), 1.87 – 1.62 (m, 3H), 1.35 – 1.24 (m, 1H), 0.98 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 215.0, 140.0, 136.6, 129.8, 128.2, 126.9, 117.2, 53.0, 52.5, 39.7, 37.4, 27.8, 21.1, 19.6. IR (Neat Film, NaCl): 3062, 3027, 2933, 2863, 1704, 1453, 1124 cm–1. HRMS (MM: EI+): m/z calc’d for C16H20O [M]+: 228.1514, found 228.1515. Optical Rotation: [α]D21 –25.1 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 3.59, major = 2.81. O Me Ph 160b (S)-6-methyl-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160b) Prepared from 158b (27.2 mg, 1.00 mmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–100% CH2Cl2/hexanes) afforded the title compound as a colorless oil (11.5 mg, 0.05 mmol, 51% yield, 20:1 B/L, >20:1 dr (B), 78% ee(B)). 1 H NMR (400 MHz, CDCl3): δ 7.32 – 7.17 (m, 5H), 6.84 (dt, J = 10.0, 3.9 Hz, 1H), 6.20 (dt, J = 16.8, 9.9 Hz, 1H), 5.91 (dt, J = 10.0, 2.1 Hz, 1H), 5.12 – 4.98 (m, 2H), 3.86 (d, J = Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 598 9.7 Hz, 1H), 2.56 – 2.46 (m, 1H), 2.40 – 2.29 (m, 1H), 1.85 (dt, J = 13.8, 5.7 Hz, 1H), 1.73 (ddd, J = 13.9, 7.3, 5.5 Hz, 1H), 1.10 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 203.0, 148.2, 140.8, 137.0, 129.8, 129.1, 128.1, 126.6, 117.4, 52.9, 48.8, 31.1, 23.4, 20.5. IR (Neat Film, NaCl): 3028, 2935, 2343, 2357, 1699, 1670, 1636, 1387, 1222, 695 cm–1. HRMS [M+H]+: m/z calc’d for C16H19O: 227.14359, found 227.14317. Optical Rotation: [α]D22 +39.0° (c 0.48, CHCl3). SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 4.45, major = 4.08. O Me Ph Me 160c (S)-3,6-dimethyl-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160c) Prepared from 158c (28.4 mg, 100 µmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–20% EtOAc/hexanes) afforded the title compound as a colorless oil (16.8 mg, 69.9 µmol, 70% yield, >20:1 B/L, >20:1 dr, 80% ee). 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.24 (m, 5H), 6.28 (dt, J = 16.8, 9.9 Hz, 1H), 5.83 (q, J = 1.4 Hz, 1H), 5.17 (dd, J = 10.0, 1.8 Hz, 1H), 5.11 (ddd, J = 16.8, 1.8, 0.9 Hz, 1H), 3.94 (d, J = 9.7 Hz, 1H), 2.51 – 2.42 (m, 1H), 2.37 – 2.28 (m, 1H), 1.98 (s, 3H), 1.92 (ddd, J = 13.8, 6.9, 5.4 Hz, 1H), 1.78 (ddd, J = 13.8, 7.0, 5.4 Hz, 1H), 1.16 (s, 3H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 599 C NMR (100 MHz, CDCl3): δ 202.8, 159.9, 141.0, 137.1, 129.8, 128.1, 126.5, 126.0, 117.4, 53.1, 47.5, 30.9, 28.3, 24.1, 20.8. IR (Neat Film, NaCl): 3062, 3028, 2969, 2932, 1663, 1637, 1452, 1377, 1213 cm–1. HRMS (MM: FD+): m/z calc’d for C17H20O [M]+: 240.1514, found 240.1522. Optical Rotation: [α]D21 +38.1 (c 1.00, CHCl3) SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, l = 210 nm, tR (min): minor = 2.95, major = 3.31. O Me Ph EtO 160d (S)-3-ethoxy-6-methyl-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160d) Prepared from 158d (31.4 mg, 100 µmol) following General Procedure A using Pd2(dba)3 and L7. Purification by flash column chromatography (0–40% EtOAc/hexanes) afforded the title compound as a colorless oil (18.8 mg, 70 µmol, 70% yield, >20:1 dr, 84% ee). Ligand L6 afforded identical results. 1 H NMR (400 MHz, CDCl3): δ 7.28 – 7.16 (m, 5H), 6.23 (dt, J = 16.8, 9.9 Hz, 1H), 5.23 (s, 1H), 5.12 (dd, J = 10.1, 1.8 Hz, 1H), 5.06 (ddd, J = 16.8, 1.9, 0.9 Hz, 1H), 3.90 (d, J = 9.7 Hz, 1H), 3.87 (dd, J = 7.0, 2.8 Hz, 1H), 3.83 (dd, J = 7.0, 2.7 Hz, 1H), 2.48 (ddd, J = 18.1, 7.0, 5.6 Hz, 1H), 2.44 – 2.34 (m, 1H), 1.87 (ddd, J = 13.4, 7.6, 5.6 Hz, 1H), 1.73 – 1.66 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.11 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 202.8, 175.5, 141.2, 137.1, 129.8, 128.1, 126.5, 117.4, 102.0, 64.3, 53.5, 47.5, 29.5, 26.1, 21.3, 14.3. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 600 IR (Neat Film, NaCl): 2942, 1647, 1611, 1377, 1190 cm–1. HRMS (MM: FD+): m/z calc’d for C18H22O2 [M]+: 270.1620, found 270.1628. Optical Rotation: [α]D21 –1.3 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 254 nm, tR (min): minor = 2.70, major = 3.25. O Et Ph EtO 160e (S)-3-ethoxy-6-ethyl-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160e) Prepared from 158e (34.4 mg, 104 µmol) following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (5–20% EtOAc/hexanes) afforded the title compound as a colorless oil (21.0 mg, 74 µmol, 70% yield, >20:1 dr, 87% ee). 1 H NMR (400 MHz, CDCl3): δ 7.26 – 7.21 (m, 4H), 7.19 – 7.13 (m, 1H), 6.26 (dt, J = 16.8, 10.1 Hz, 1H), 5.22 (s, 1H), 5.14 – 5.07 (m, 2H), 4.02 (d, J = 10.0 Hz, 1H), 3.86 – 3.78 (m, 2H), 2.47 – 2.33 (m, 2H), 1.96 – 1.74 (m, 3H), 1.50 (dq, J = 14.5, 7.4 Hz, 1H), 1.31 (t, J = 7.0 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 201.0, 175.2, 141.6, 137.0, 130.1, 128.0, 126.3, 117.3, 103.0, 64.2, 51.7, 50.7, 26.7, 26.3, 26.0, 14.3, 8.3. IR (Neat Film, NaCl): 2978, 2937, 1650, 1612, 1380, 1189 cm–1. HRMS (MM: ESI+): m/z calc’d for C19H25O2 [M+H]+: 285.1849, found 285.1859. Optical Rotation: [α]D21 +16.0 (c 1.00, CHCl3). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 601 SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 254 nm, tR (min): minor = 2.93, major = 3.50. O Ph EtO CO2Me 160f methyl 3-((R)-4-ethoxy-2-oxo-1-((S)-1-phenylallyl)cyclohex-3-en-1-yl)propanoate (160f) Prepared from 158f (38.2 mg, 98.9 µmol) following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (5–20% EtOAc/hexanes) afforded the title compound as a colorless oil (14.3 mg, 41.8 µmol, 42% yield, >20:1 dr, 84% ee). 1 H NMR (400 MHz, CDCl3): δ 7.26 – 7.20 (m, 4H), 7.18 – 7.13 (m, 1H), 6.25 (dt, J = 16.8, 10.1 Hz, 1H), 5.20 (s, 1H), 5.19 – 5.10 (m, 2H), 4.07 (d, J = 10.1 Hz, 1H), 3.86 – 3.77 (m, 2H), 3.63 (s, 3H), 2.52 – 2.33 (m, 3H), 2.25 (ddd, J = 16.3, 11.4, 4.8 Hz, 1H), 2.00 (ddd, J = 14.0, 11.5, 5.2 Hz, 1H), 1.95 – 1.79 (m, 3H), 1.31 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 200.2, 175.3, 174.3, 141.0, 136.2, 130.0, 128.0, 126.4, 117.9, 102.6, 64.2, 51.6, 51.0, 49.6, 28.3, 28.1, 27.0, 25.7, 14.1. IR (Neat Film, NaCl): 2980, 2946, 1737, 1643, 1610, 1381, 1191 cm–1. HRMS (MM: ESI+): m/z calc’d for C21H27O4 [M+H]+: 343.1904, found 343.1909. Optical Rotation: [α]D21 +24.6 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 254 nm, tR (min): minor = 2.54, major = 3.00. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 602 Ph O EtO CN 160g 3-((S)-4-ethoxy-2-oxo-1-((S)-1-phenylallyl)cyclohex-3-en-1-yl)propanenitrile (160g) Prepared from 158g (35.3 mg, 100 µmol) following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (23.9 mg, 77.2 µmol, 77% yield, >20:1 B/L, >20:1 dr, 84% ee). 1 H NMR (400 MHz, CDCl3): δ 7.29 – 7.23 (m, 2H), 7.19 (td, J = 7.8, 1.4 Hz, 3H), 6.23 (dt, J = 16.9, 10.1 Hz, 1H), 5.24 (s, 1H), 5.20 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 16.9 Hz, 1H), 3.97 (d, J = 9.9 Hz, 1H), 3.89 – 3.80 (m, 2H), 2.51 – 2.39 (m, 3H), 2.28 – 2.12 (m, 2H), 1.93 – 1.76 (m, 3H), 1.33 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.5, 175.8, 140.2, 135.8, 129.8, 128.3, 126.9, 120.4, 118.5, 102.6, 64.6, 51.0, 49.8, 29.3, 26.7, 25.7, 14.2, 12.1. IR (Neat Film, NaCl): 2980, 2937, 2246, 1643, 1606, 1381, 1190 cm–1. HRMS (MM: ESI+): m/z calc’d for C20H24O2N [M+H]+: 310.1802, found 310.1804. Optical Rotation: [α]D21 +13.1 (c 1.00, CHCl3). SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 254 nm, tR (min): minor = 2.06, major = 3.05. O Me Ph BnO 160h (S)-3-(benzyloxy)-6-methyl-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160h) Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 603 Prepared from 158h following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (0–40% EtOAc/hexanes) afforded the title compound as a colorless oil (23.4 mg, 0.704 mmol, 70% yield, >20:1 dr, 82% ee). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.32 (m, 5H), 7.30 – 7.24 (m, 4H), 7.19 (ddd, J = 8.4, 5.3, 2.2 Hz, 1H), 6.24 (dt, J = 16.8, 9.9 Hz, 1H), 5.37 (s, 1H), 5.12 (dd, J = 10.1, 1.9 Hz, 1H), 5.06 (d, J = 16.8 Hz, 1H), 4.87 – 4.80 (m, 2H), 3.92 (d, J = 9.7 Hz, 1H), 2.55 (dt, J = 18.1, 6.1 Hz, 1H), 2.45 (ddd, J = 18.1, 7.5, 5.6 Hz, 1H), 1.91 (ddd, J = 13.3, 7.6, 5.6 Hz, 1H), 1.73 (ddd, J = 13.7, 7.0, 5.6 Hz, 1H), 1.14 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 202.6, 175.0, 141.1, 137.0, 135.2, 129.8, 128.8, 128.7, 128.1, 128.0, 126.5, 117.5, 102.6, 70.5, 53.5, 47.6, 29.4, 26.1, 21.3. IR (Neat Film, NaCl): 2932, 1652, 1610, 1362, 1186 cm–1. HRMS (MM: FD+): m/z calc’d for C23H24O2 [M]+: 332.1776, found 332.1773. Optical Rotation: [α]D21 –5.0 (c 1.00, CHCl3). SFC conditions: 25% IPA, 2.5 mL/min, Chiralpak OD-H column, l = 254 nm, tR (min): minor = 4.10, major = 3.72. O Me Ph PhS 160i (S)-6-methyl-6-((S)-1-phenylallyl)-3-(phenylthio)cyclohex-2-en-1-one (160i) Prepared from 158i following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (0–40% EtOAc/hexanes) afforded the title compound as a colorless oil (29.2 mg, 0.873 mmol, 87% yield, 7.5:1 B/L, >20:1 dr, 78% ee). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 1 604 H NMR (400 MHz, CDCl3): δ 7.47 – 7.38 (m, 5H), 7.27 – 7.18 (m, 5H), 6.18 (dt, J = 16.8, 9.9 Hz, 1H), 5.37 (s, 1H), 5.11 (dd, J = 10.1, 1.9 Hz, 1H), 5.05 (d, J = 16.8 Hz, 1H), 3.91 (d, J = 9.7 Hz, 1H), 2.63 – 2.46 (m, 2H), 1.94 (ddd, J = 13.3, 7.7, 5.3 Hz, 1H), 1.78 (ddd, J = 13.7, 6.7, 5.2 Hz, 1H), 1.11 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 199.3, 164.0, 143.5, 140.9, 136.8, 135.6, 130.2, 129.9, 129.8, 128.1, 126.5, 120.3, 117.6, 53.3, 47.9, 31.0, 27.2, 21.3. IR (Neat Film, NaCl): 2927, 1650, 1579, 1212 cm–1. HRMS (MM: FD+): m/z calc’d for C22H22O2S [M]+: 334.1391, found 334.1392. Optical Rotation: [α]D21 –64.9 (c 1.00, CHCl3). SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 4.45, major = 4.08. O O N Me Ph 160j (S)-6-methyl-2-morpholino-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160j) Prepared from 158j following General Procedure A using Pd2(dba)3 and L3. Purification by preparatory TLC (10% acetone/toluene) afforded the title compound as a colorless oil (9.2 mg, 0.030 mmol, 30% yield, 9.1:1 B/L, >20:1 dr, 94% ee). 1 H NMR (400 MHz, C6D6): δ 7.18 – 7.16 (m, 3H), 7.14 – 7.08 (m, 2H), 7.06 – 7.01 (m, 1H), 6.13 (dt, J = 16.8, 9.9 Hz, 1H), 5.24 (t, J = 4.4 Hz, 1H), 4.98 – 4.90 (m, 2H), 3.90 (d, J = 9.6 Hz, 1H), 3.77 – 3.58 (m, 4H), 2.91 – 2.83 (m, 2H), 2.39 – 2.32 (m, 2H), 2.22 – 2.10 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 605 (m, 1H), 1.96 – 1.84 (m, 1H), 1.61 (dt, J = 13.8, 5.4 Hz, 1H), 1.33 (ddd, J = 13.8, 8.2, 5.6 Hz, 1H), 1.08 (s, 3H). 13 C NMR (100 MHz, C6D6): δ 198.3, 146.3, 141.1, 137.6, 130.0, 128.2, 126.8, 121.6, 117.2, 67.0, 53.4, 50.5, 49.4, 31.5, 22.0, 20.5. IR (Neat Film, NaCl): 3027, 2928, 2853, 1681, 1615, 1450, 1263, 1210, 1119 cm–1. HRMS (MM: ESI+): m/z calc’d for C20H27O2N [M+H]+: 312.1958, found 312.1961. Optical Rotation: [α]D21 +8.9 (c 0.90, CHCl3). SFC conditions: 30% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 280 nm, tR (min): minor = 3.89, major = 2.05. O Me Me Me 160k (S)-6-methyl-2-morpholino-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160k) Prepared from 158k (0.094 mmol) following General Procedure A using Pd2(pmdba)3 and L6. Purification by preparatory TLC (25% Et2O/hexanes) afforded the title compound as a colorless oil (10.0 mg, 0.056 mmol, 59% yield, 2.5:1 B/L, 9.0:1 dr, 73% ee). 1 H NMR (400 MHz, C6D6): δ 5.81 – 5.75 (m, 1.4H (linear + both branched)), 5.69 (ddd, J = 16.5, 10.7, 8.4 Hz, 0.9H (branched)), 5.62 – 5.53 (m, 0.4H (linear)), 5.39 – 5.29 (m, 0.4H (linear)), 5.08 – 4.95 (m, 2H (branched major + branched minor)), 2.75 – 2.63 (m, 0.9H(branched major)), 2.64 – 2.56 (m, 0.1H (branched minor)), 2.31 – 2.21 (m, 3.6H), 2.01 (ddd, J = 13.7, 7.3, 6.3 Hz, 1H), 1.95 – 1.87 (m, 5H), 1.76 – 1.58 (m, 3.3H), 1.06 (s, Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 606 1.2H(linear)), 0.99 (s, 2.7H(branched major)), 0.98 (s, 0.4H(branched minor)), 0.94 (d, J = 6.8 Hz, 2.7H(branched major)), 0.88 (d, J = 7.0 Hz, 0.4H(branched minor)). 13 C NMR (100 MHz, CDCl3): δ 204.0, 203.8, 160.5, 160.2, 140.4, 139.9, 126.8, 126.1, 125.8, 125.6, 125.5, 115.6, 115.4, 46.3, 46.0, 43.9, 41.6, 40.2, 33.8, 33.1, 31.9, 30.5, 29.8, 29.5, 28.4, 28.1, 28.0, 24.2, 24.1, 24.1, 21.9, 20.3, 18.1, 15.3, 14.4, 13.1. IR (Neat Film, NaCl): 2965, 2930, 1666, 1638, 1433, 1378, 1213 cm–1. HRMS (MM: FI+): m/z calc’d for C12H18O [M]+: 178.1358, found 178.1362. Optical Rotation: [α]D21 +2.3 (c 1.00, CHCl3). SFC conditions: 4% IPA, 2.5 mL/min, Chiralpak IC column, l = 210 nm, tR (min): minor = 7.16, major = 8.11. O OBn Me Me 160l (S)-6-methyl-2-morpholino-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160l) Prepared from 158l (0.105 mmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–20% EtOAc/hexanes) afforded the title compound as a colorless oil (10.6 mg, 0.037 mmol, 35% yield, >20:1 B/L, >20:1 dr, 82% ee). 1 H NMR (500 MHz, CDCl3): δ 7.35 – 7.28 (m, 4H), 7.28 – 7.23 (m, 1H), 5.79 (s, 1H), 5.67 (dt, J = 16.9, 9.9 Hz, 1H), 5.19 – 5.10 (m, 2H), 4.47 (d, J = 2.4 Hz, 2H), 3.57 – 3.40 (m, 2H), 2.97 (ddd, J = 9.4, 7.4, 5.6 Hz, 1H), 2.37 – 2.17 (m, 2H), 2.08 – 1.97 (m, 1H), 1.91 (s, 3H), 1.70 – 1.61 (m, 2H), 1.02 (s, 3H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 607 C NMR (101 MHz, CDCl3): δ 202.7, 159.9, 138.6, 136.0, 128.3, 127.5, 127.4, 125.9, 118.5, 72.8, 70.6, 48.1, 45.1, 29.7, 28.0, 24.1, 20.9. IR (Neat Film, NaCl): 3026, 2918, 1665, 1453, 1214, 1096 cm–1. HRMS (MM: ESI+): m/z calc’d for C19H24O2 [M]+: 284.1766, found 284.1776. Optical Rotation: [α]D21 +33.2 (c 1.05, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 3.77, major = 2.81. O F Me 160m (S)-2-fluoro-2-((S)-1-phenylallyl)cyclohexan-1-one (160m) Prepared from 158m (28.6 mg, 103 µmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–15% EtOAc/hexanes) afforded the title compound as a colorless crystalline solid (17.1 mg, 73.6 µmol, 71% yield, >20:1 B/L, >20:1 dr, 85% ee) as well as a fraction (1.5 mg, 6.5 µmol, 6% yield) containing mixed E/Z linear isomers with trace of the major diastereomer of the branched isomer. Overall yield: 18.6 mg, 80.1 µmol, 77% yield, 13:1 B/L, >20:1 dr (B), 85% ee (B)). *Crude 1H NMR analysis reveals a B/L of 12.5:1 prior to chromatography. 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.24 (m, 5H), 6.18 (ddd, J = 17.1, 10.3, 8.8 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 5.08 (d, J = 17.1 Hz, 1H), 3.88 (dd, J = 32.4, 8.8 Hz, 1H), 2.71 – 2.63 (m, 1H), 2.54 – 2.45 (m, 1H), 2.06 – 1.98 (m, 1H), 1.86 – 1.68 (m, 5H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 608 *Trace isolated peaks of minor diastereomer (<5%) observed as 5.26 – 5.19 (m, 2H), 2.88 – 2.75 (m, 2H), 2.43 – 2.30 (m, 2H). Others overlap with major diastereomer. 13 C NMR (100 MHz, CDCl3): δ 207.5 (d, JC–F = 18.2 Hz), 137.9, 135.3 (d, JC–F = 5.4 Hz), 129.6 (d, J = 2.6 Hz), 128.8, 127.5, 117.9, 100.7 (d, JC–F = 194.8 Hz), 53.1 (d, JC–F = 20.0 Hz), 40.3, 36.7 (d, JC–F = 21.7 Hz), 27.8, 22.2 (d, JC–F = 9.1 Hz). 19 F NMR (282 MHz, CDCl3): δ –166.45 (d, J = 32.5 Hz). IR (Neat Film, NaCl): 2948, 1724, 1454, 1047 cm–1. HRMS (MM: EI+): m/z calc’d for C15H17OF [M]+: 232.1263, found 232.1259. Optical Rotation: [α]D21 –23.3 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 3.23, major = 2.65. O F Ph (S)-2-fluoro-2-((S)-1-phenylallyl)cyclohexan-1-one (160n) Prepared from 158n (27.0 mg, 98.4 µmol) following General Procedure A using Pd2(pmdba)3 and L7. Purification by flash column chromatography (0–20% EtOAc/hexanes) afforded the title compound as a colorless oil (17.1 mg, 74.3 µmol, 75% yield, >20:1 B/L, >20:1 dr, 82% ee). 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.27 (m, 5H), 6.95 – 6.90 (m, 1H), 6.23 (ddd, J = 17.0, 10.1, 8.7 Hz, 1H), 6.06 (dddd, J = 10.0, 4.0, 2.8, 1.3 Hz, 1H), 5.11 (d, J = 10.1 Hz, 1H), 4.96 (d, J = 17.0 Hz, 1H), 3.67 (dd, J = 31.1, 8.7 Hz, 1H), 2.58 – 2.38 (m, 2H), 2.19 – 2.07 (m, 1H), 2.00 – 1.92 (m, 1H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 609 C NMR (100 MHz, CDCl3): δ 195.6 (d, JC–F = 17.2 Hz), 149.0, 138.5, 135.3 (d, JC–F = 5.5 Hz), 129.2 (d, JC–F = 2.8 Hz), 128.9, 128.2, 127.6, 118.0, 97.4 (d, JC–F = 194.5 Hz), 53.0 (d, JC–F = 20.2 Hz), 31.2 (d, JC–F = 22.1 Hz), 25.1 (d, JC–F = 11.3 Hz). 19 F NMR (282 MHz, CDCl3): –168.84 (d, J = 31.5 Hz). IR (Neat Film, NaCl): 3031, 2922, 1695, 1489, 1452, 1425, 1383, 1219, 1060 cm–1. HRMS (MM: EI+): m/z calc’d for C15H15OF [M]+: 230.1107, found 230.1113. Optical Rotation: [α]D21 +41.1 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 4.74, major = 3.92. O F Ph EtO 160o (R)-3-ethoxy-6-fluoro-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160o) Prepared from 158o (31.8 mg, 100 µmol) following General Procedure A using Pd2(dba)3 and L6. Purification by flash column chromatography (5–20% EtOAc/hexanes) afforded the title compound as a colorless oil (21.9 mg, 79.8 µmol, 80% yield, >20:1 dr, 87% ee). 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.26 (m, 5H), 6.36 – 6.22 (m, 1H), 5.35 – 5.32 (m, 1H), 5.13 (d, J = 10.2 Hz, 1H), 4.97 (d, J = 17.0 Hz, 1H), 3.92 (q, J = 7.1 Hz, 2H), 3.71 (dd, J = 29.7, 8.5 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.45 – 2.36 (m, 1H), 2.16 – 2.03 (m, 1H), 1.94 – 1.85 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 194.4 (d, JC–F = 18.1 Hz), 194.3, 175.6 (d, JC–F = 1.6 Hz), 138.8, 135.4 (d, JC–F = 5.6 Hz), 129.3 (d, JC–F = 2.5 Hz), 128.8, 127.5, 117.8, 100.8, 96.4 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 610 (d, JC–F = 191.3 Hz), 65.1, 53.3 (d, JC–F = 20.8 Hz), 29.3 (d, JC–F = 23.5 Hz), 27.2 (d, JC–F = 11.0 Hz), 14.2. 19 F NMR (282 MHz, CDCl3): δ –168.60– –168.67 (m, 1F). IR (Neat Film, NaCl): 2981, 2938, 1672, 1603, 1379, 1243, 1193 cm–1. HRMS (MM: ESI+): m/z calc’d for C17H20O2F [M+H]+: 275.1442, found 275.1440. Optical Rotation: [α]D21 –11.2 (c 0.70, CHCl3). SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 254 nm, tR (min): minor = 2.25, major = 2.58. O OBn O F OBn F + Me Me 160p 160p_linear (R)-6-((S)-1-(benzyloxy)but-3-en-2-yl)-6-fluoro-3-methylcyclohex-2-en-1-one (160p) Prepared from 158p (36.0 mg, 108 µmol) following General Procedure A using Pd2(dba)3 and L7. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the branched product (160p) as a colorless oil (14.8 mg, 51.3 µmol, 48% yield, 14.3:1 dr, 84% ee) and the (Z)-linear product (160p_linear) also as a colorless oil (2.9 mg, 10.1 µmol, 9% yield, >20:1 Z/E, 53% ee)). Overall yield: 17.7 mg, 61.4 µmol, 57% yield, 5.1:1 B/L, >16.1 dr (B), 84% ee (B)). *Crude 1H NMR analysis reveals a B/L of 5.6:1 and a dr (B) of 12.9:1 prior to chromatography. In the tabulated NMR data for 160p, the minor diastereomer is denoted. 160p: Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 1 611 H NMR (400 MHz, CDCl3): δ 7.36 – 7.27 (m, 5H), 5.88 – 5.74 (m, 2H), 5.34 – 5.24 (m, 0.15H(minor)), 5.17 (dd, J = 10.3, 1.7 Hz, 1H), 5.12 (d, J = 17.8 Hz, 1H), 4.50 (s, 2H), 4.45 (d, J = 11.8 Hz, 0.07H(minor)), 4.34 (d, J = 11.7 Hz, 0.07H(minor)), 3.76 (dd, J = 9.8, 6.7 Hz, 1H), 3.65 (dd, J = 9.6, 6.3 Hz, 0.07H(minor)), 3.52 (ddd, J = 9.8, 5.6, 0.9 Hz, 1H), 2.99 (ddt, J = 21.4, 9.2, 6.1 Hz, 1H), 2.91 – 2.82 (m, 0.07H(minor)), 2.53 – 2.33 (m, 3H), 2.26 – 2.14 (m, 1H), 1.96 (s, 3H), 1.93 (s, 0.19H(minor)). 13 C NMR (100 MHz, CDCl3): δ 194.0 (d, JC–F = 17.9 Hz), 162.3, 138.2, 133.8 (d, JC–F = 4.6 Hz), 128.5, 127.8, 127.7, 125.1, 119.1, 95.6 (d, JC–F = 185.9 Hz), 73.3, 69.7 (d, JC–F = 5.7 Hz), 47.1 (d, JC–F = 21.4 Hz), 30.6 (d, JC–F = 22.7 Hz), 29.6 (d, JC–F = 9.5 Hz), 24.2. 19 F NMR (282 MHz, CDCl3): δ –167.64 – –167.85 (m). IR (Neat Film, NaCl): 2923, 1681, 1633, 1104 cm–1. HRMS (MM: FD+): m/z calc’d for C18H21O2F [M]+: 289.1604, found 289.1590. Optical Rotation: [α]D21 –34.2 (c 1.00, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 4.59, major = 3.43. 160p_linear: 1 H NMR (400 MHz, CDCl3): δ 7.37 – 7.27 (m, 5H), 5.89 – 5.80 (m, 2H), 5.66 (dddt, J = 11.2, 8.4, 6.9, 1.5 Hz, 1H), 4.54 – 4.48 (m, 2H), 4.13 – 4.08 (m, 1H), 4.09 – 4.00 (m, 1H), 2.68 – 2.49 (m, 2H), 2.48 – 2.30 (m, 2H), 2.28 – 2.09 (m, 2H), 1.94 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 194.3 (d, JC–F = 17.9 Hz), 162.8, 138.3, 130.6, 128.6, 128.0, 127.8, 125.5 (d, JC–F = 4.5 Hz), 124.9, 93.9 (d, JC–F = 183.0 Hz), 72.5, 65.8, 32.1 (d, JC–F = 23.8 Hz), 31.6 (d, JC–F = 22.9 Hz), 29.2 (d, JC–F = 9.0 Hz), 24.3. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 19 612 F NMR (282 MHz, CDCl3): δ –161.29 – –161.59 (m). IR (Neat Film, NaCl): 2917, 1682, 1631, 1072 cm–1. HRMS (MM: FD+): m/z calc’d for C18H21O2F [M]+: 289.1604, found 289.1597. Optical Rotation: [α]D21 –5.3 (c 0.30, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak OJ-H column, l = 210 nm, tR (min): minor = 6.68, major = 5.86. O F Me Me 160q (R)-3-ethoxy-6-fluoro-6-((S)-1-phenylallyl)cyclohex-2-en-1-one (160q) Prepared from 158q (23.3 mg, 103 µmol) following General Procedure A using Pd2(pmdba)3 and L3. Purification by flash column chromatography (5–20% Et2O/hexanes) afforded the title compound as a colorless oil (14.7 mg, 80.8 µmol, 78% yield, >20:1 dr, 87% ee). For further characterization, the mixture of isomers was subsequently purified by C18 reverse-phase preparatory HPLC (40–65% MeCN/H2O) to afford the major diastereomer of 160q as a single isomer. *Compound 160q was found to be volatile, avoid excessive exposure to high vacuum. Yields are corrected for trace Et2O in sample after purification.* 1 H NMR (400 MHz, CDCl3): δ 5.93 – 5.83 (m, 2H), 5.10 – 5.01 (m, 2H), 2.91 – 2.74 (m, 1H), 2.47 (dt, J = 18.9, 5.6 Hz, 1H), 2.36 (dt, J = 19.0, 6.5 Hz, 1H), 2.29 – 2.18 (m, 2H), 1.97 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 613 C NMR (100 MHz, CDCl3): 194.3 (d, JC–F = 18.0 Hz), 162.0, 137.5, 125.4, 116.5, 95.8 (d, JC–F = 184.7 Hz), 40.29 (d, JC–F = 21.9 Hz), 30.5, 29.8, 29.5, 29.3, 29.2, 29.1, 14.2 (d, JC–F = 5.7 Hz). 19 F NMR (282 MHz, CDCl3): δ –168.13– –168.31 (m, 1F). IR (Neat Film, NaCl): 2919, 2849, 1681, 1633, 1434, 1380, 1225 cm–1. HRMS (MM: FI+): m/z calc’d for C11H15OF [M]+: 182.1107, found 182.1107. Optical Rotation: [α]D21 –32.3 (c 0.40, CHCl3). SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak IC column, l = 254 nm, tR (min): minor = 4.76, major = 5.45. Synthesis of b-ketoester substrates (158a–158q) General Procedure B: Alkylation of b-ketoesters. O R1 O O K2CO3 (2 equiv) electrophile (2 equiv) OR2 acetone, 50 ºC R3 O OR2 R1 165a–xx 158a–q To a solution of b-ketoester 165 (1 equiv) in acetone (0.5 M) is added anhydrous K2CO3 (2 equiv), followed by the relevant electrophile (2 equiv). The reaction is heated to 50 ºC and stirring is continued until complete consumption of starting material is observed (typically 24–36 h). The reaction mixture is then filtered, and volatiles are removed in vacuo. Purification by flash silica gel column chromatography affords the desired alkylated b-ketoester. O Me O O 158a Ph Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 614 cinnamyl 1-methyl-2-oxocyclohexane-1-carboxylate (158a) Prepared from cinnamyl 2-oxocyclohexane-1-carboxylate and methyl iodide following General Procedure B. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (0.458 g, 1.39 mmol, 84% yield). 1 H NMR (600 MHz, CDCl3): δ 7.45 – 7.36 (m, 2H), 7.36 – 7.30 (m, 2H), 7.30 – 7.22 (m, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.26 (dt, J = 15.9, 6.5 Hz, 1H), 4.81 (ddd, J = 12.8, 6.4, 1.2 Hz, 1H), 4.77 (ddd, J = 12.8, 6.4, 1.2 Hz, 1H), 2.57 – 2.52 (m, 1H), 2.51 – 2.43 (m, 2H), 2.06 – 1.98 (m, 1H), 1.79 – 1.61 (m, 3H), 1.53 – 1.44 (m, 1H), 1.33 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 208.3, 173.0, 136.2, 135.0, 128.8, 128.4, 126.8, 126.6, 65.9, 57.4, 40.8, 38.4, 27.6, 22.8, 21.4. IR (Neat Film, NaCl): 2938, 1714, 1453 (m), 1142 (m), 961 (m) cm–1. HRMS (MM: FD+): m/z calc’d for C17H20O3 [M]+: 272.1412, found 272.1410. O Me O O Ph 158b cinnamyl 1-methyl-2-oxocyclohex-3-ene-1-carboxylate (158b) Prepared from cinnamyl 2-oxocyclohex-3-ene-1-carboxylate (prepared following General Procedure D and used crude) and methyl iodide following General Procedure B. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (0.48 g, 1.78 mmol, 23% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.27 (m, 5H), 6.92 (dddd, J = 10.1, 4.4, 3.3, 1.0 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 6.3 Hz, 1H), 6.07 (ddd, J = 10.1, 2.4, 1.7 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 615 Hz, 1H), 4.83 – 4.70 (m, 2H), 2.57 – 2.43 (m, 2H), 2.40 – 2.30 (m, 1H), 1.92 (ddd, J = 14.6, 8.9, 5.2 Hz, 1H), 1.42 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 197.0, 172.6, 149.6, 136.3, 134.5, 129.0, 128.8, 128.3, 126.8, 122.8, 65.9, 53.6, 33.5, 23.8, 20.8. IR (Neat Film, NaCl): 3025, 1731, 1681, 1250, 1096 cm–1. HRMS (MM: FD+): m/z calc’d for C17H18O3 [M]+: 270.1256, found 270.1259. O Me O O Me Ph 158c cinnamyl 1,4-dimethyl-2-oxocyclohex-3-ene-1-carboxylate (158c) Prepared from 165a and methyl iodide following General Procedure B. Purification by flash column chromatography (15% EtOAc/hexanes) afforded the title compound as a colorless oil (0.65 g, 2.1 mmol, 63% yield). 1 H NMR (600 MHz, CDCl3): δ 7.37 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 7.4 Hz, 2H), 7.28 – 7.23 (m, 1H), 6.61 (d, J = 15.8 Hz, 1H), 6.23 (dt, J = 15.8, 6.4 Hz, 1H), 5.92 (s, 1H), 4.81 – 4.70 (m, 2H), 2.51 (dt, J = 13.3, 4.8 Hz, 1H), 2.48 – 2.39 (m, 1H), 2.25 (dt, J = 19.0, 5.3 Hz, 1H), 1.94 (s, 3H), 1.92 – 1.86 (m, 1H), 1.41 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.7, 172.8, 161.7, 136.3, 134.3, 128.7, 128.2, 126.8, 125.7, 122.9, 65.8, 52.5, 33.3, 28.7, 24.3, 20.5. IR (Neat Film, NaCl): 3026, 2935, 1731, 1668, 1448, 1253 cm–1. HRMS (MM: ESI+): m/z calc’d for C18H23O3Na [M+Na]+: 307.1305, found 307.1308. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles O Me O O EtO 616 Ph 158d cinnamyl 4-ethoxy-1-methyl-2-oxocyclohex-3-ene-1-carboxylate (158d) Prepared from 165b and methyl iodide following General Procedure B. Purification by flash column chromatography (10–50% EtOAc/hexanes) afforded the title compound as a colorless oil (0.65 g, 2.1 mmol, 63% yield). 1 H NMR (400 MHz, CDCl3): δ 7.38 – 7.25 (m, 5H), 6.62 (d, J = 15.9 Hz, 1H), 6.24 (dt, J = 15.9, 6.3 Hz, 1H), 5.37 (s, 1H), 4.82 – 4.72 (m, 2H), 3.90 (q, J = 7.0 Hz, 2H), 2.61 – 2.47 (m, 2H), 2.38 (dt, J = 17.1, 5.3 Hz, 1H), 1.88 (ddd, J = 13.7, 8.5, 5.2 Hz, 1H), 1.43 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.9, 176.7, 172.9, 136.3, 134.3, 128.7, 128.2, 126.8, 123.0, 101.9, 65.8, 64.6, 52.6, 31.9, 26.6, 20.7, 14.2. IR (Neat Film, NaCl): 2980, 2942, 1731, 1656, 1606, 1377, 1250, 1195 cm–1. HRMS (MM: FD+): m/z calc’d for C19H22O4 [M]+: 314.1518, found 314.1516. O Et O O EtO Ph 158e cinnamyl 4-ethoxy-1-ethyl-2-oxocyclohex-3-ene-1-carboxylate (158e) Prepared from 165b and ethyl iodide following General Procedure B. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (0.458 g, 1.39 mmol, 84% yield). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 1 617 H NMR (400 MHz, CDCl3): δ 7.38 – 7.35 (m, 2H), 7.33 – 7.29 (m, 2H), 7.27 – 7.23 (m, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.24 (dt, J = 15.8, 6.3 Hz, 1H), 5.36 (s, 1H), 4.77 (dd, J = 6.3, 1.4 Hz, 2H), 3.93 – 3.84 (m, 2H), 2.64 (dddd, J = 17.9, 9.8, 5.0, 1.2 Hz, 1H), 2.45 (dt, J = 13.3, 5.0 Hz, 1H), 2.36 (dt, J = 17.9, 5.0 Hz, 1H), 2.13 – 2.01 (m, 1H), 1.93 (ddd, J = 13.3, 9.6, 5.2 Hz, 1H), 1.83 (dq, J = 13.9, 7.5 Hz, 1H), 1.33 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.0, 176.7, 171.8, 136.4, 134.3, 128.7, 128.2, 126.8, 123.1, 102.3, 65.7, 64.5, 56.5, 27.9, 27.1, 26.6, 14.2, 9.2. IR (Neat Film, NaCl): 3025, 2979, 2938, 1728, 1659, 1603, 1446, 1378, 1235, 1186 cm– 1 . HRMS (MM: ESI+): m/z calc’d for C20H25O4 [M+H]+: 329.1747, found 329.1747. O O O EtO Ph CO2Me 158f cinnamyl 4-ethoxy-1-(3-methoxy-3-oxopropyl)-2-oxocyclohex-3-ene-1-carboxylate (158f) Prepared from 165b and methyl acrylate following General Procedure B. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (0.48 g, 1.24 mmol, 75% yield). 1 H NMR (400 MHz, CDCl3): δ 7.39 – 7.35 (m, 2H), 7.34 – 7.29 (m, 2H), 7.28 – 7.23 (m, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 6.3 Hz, 1H), 5.36 (s, 1H), 4.82 – 4.72 (m, 2H), 3.88 (qd, J = 7.1, 2.0 Hz, 2H), 3.65 (s, 3H), 2.64 – 2.53 (m, 1H), 2.49 – 2.36 (m, 4H), Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 618 2.33 – 2.25 (m, 1H), 2.13 (ddd, J = 13.9, 10.0, 6.1 Hz, 1H), 1.95 – 1.87 (m, 1H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 195.4, 176.6, 173.7, 171.5, 136.3, 134.6, 128.7, 128.2, 126.8, 122.8, 102.2, 66.0, 64.7, 55.4, 51.8, 29.8, 29.0, 28.9, 26.4, 14.2. IR (Neat Film, NaCl): 2946, 1737, 1731, 1659, 1651, 1606, 1246, 1192 cm–1. HRMS (MM: ESI+): m/z calc’d for C22H27O6 [M+H]+: 387.1802, found 387.1806. O O O EtO Ph CN 158g cinnamyl 1-(2-cyanoethyl)-4-ethoxy-2-oxocyclohex-3-ene-1-carboxylate (158g) Prepared from 165b and acrylonitrile following General Procedure B. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (349 mg, 0.987 mmol, 59% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 – 7.27 (m, 5H), 6.64 (d, J = 15.9 Hz, 1H), 6.23 (dt, J = 15.9, 6.5 Hz, 1H), 5.38 (s, 1H), 4.85 – 4.74 (m, 2H), 3.96 – 3.86 (m, 2H), 2.65 – 2.39 (m, 5H), 2.31 – 2.13 (m, 2H), 2.01 – 1.94 (m, 1H), 1.35 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 194.8, 176.9, 171.0, 136.1, 135.2, 128.8, 128.4, 126.8, 122.3, 119.8, 102.2, 66.4, 64.9, 55.1, 30.0, 29.4, 26.4, 14.2, 13.4. IR (Neat Film, NaCl): 2981, 2939, 1730, 1651, 1605, 1381, 1186 cm–1. HRMS (MM: EI+): m/z calc’d for C21H23O4N [M]+: 353.1629, found 353.1627. O Me O O BnO 158h Ph Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 619 cinnamyl 4-(benzyloxy)-1-methyl-2-oxocyclohex-3-ene-1-carboxylate (158h) Prepared from 165c and methyl iodide following General Procedure B. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (179 mg, 0.475 mmol, 57% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.26 (m, 10H), 6.63 (d, J = 15.9 Hz, 1H), 6.25 (dt, J = 15.9, 6.3 Hz, 1H), 5.52 (s, 1H), 4.89 (s, 2H), 4.83 – 4.72 (m, 2H), 2.65 (dddd, J = 17.6, 9.8, 4.5, 1.1 Hz, 1H), 2.56 – 2.41 (m, 2H), 1.92 (ddd, J = 12.8, 8.8, 4.7 Hz, 1H), 1.44 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.7, 176.4, 172.8, 136.3, 135.0, 134.4, 128.9, 128.8, 128.7, 128.2, 128.0, 126.8, 123.0, 102.5, 70.8, 65.9, 52.6, 31.9, 26.6, 20.7. IR (Neat Film, NaCl): 3027, 2935, 1730, 1659, 1607, 1251, 1189, 1170 cm–1. HRMS (MM: ESI+): m/z calc’d for C24H24O4 [M]+: 376.1675, found 376.1665. O Me O O Ph PhS 158i cinnamyl 1-methyl-2-oxo-4-(phenylthio)cyclohex-3-ene-1-carboxylate (158i) Prepared from 165d and methyl iodide following General Procedure B. Purification by flash column chromatography (5–30% EtOAc/hexanes) afforded the title compound as a colorless oil (232 mg, 0.853 mmol, 62% yield). 1 H NMR (400 MHz, CDCl3): δ 7.46 – 7.27 (m, 10H), 6.62 (d, J = 15.9 Hz, 1H), 6.24 (dt, J = 15.9, 6.3 Hz, 1H), 5.52 (s, 1H), 4.81 (dd, J = 12.9, 6.3 Hz, 1H), 4.73 (dd, J = 13.0, 6.3 Hz, 1H), 2.73 – 2.64 (m, 1H), 2.59 – 2.46 (m, 2H), 2.01 – 1.93 (m, 1H), 1.41 (s, 3H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 620 C NMR (100 MHz, CDCl3): δ 193.3, 172.5, 165.9, 136.2, 135.5, 134.3, 130.3, 129.9, 128.6, 128.1, 127.8, 126.7, 122.7, 119.9, 65.8, 52.8, 33.6, 27.6, 20.4. IR (Neat Film, NaCl): 2934, 1729, 1655, 1577, 1303, 1250, 1167, 1108 cm–1. HRMS (MM: FD+): m/z calc’d for C23H22O3S [M]+: 378.1290, found 378.1293. O O N Me O O Ph 158j cinnamyl 1-methyl-3-morpholino-2-oxocyclohex-3-ene-1-carboxylate (158i) Prepared from 165e and methyl iodide following General Procedure B. Purification by flash column chromatography (15–50% EtOAc/hexanes) afforded the title compound as a colorless oil (0.43 g, 1.24 mmol, 81% yield). 1 H NMR (400 MHz, C6D6): δ 7.14 – 7.10 (m, 2H), 7.09 – 6.99 (m, 3H), 6.36 (d, J = 15.9 Hz, 1H), 6.00 (dt, J = 15.9, 6.4 Hz, 1H), 5.17 (ddd, J = 4.9, 3.5, 1.0 Hz, 1H), 4.56 (ddd, J = 12.9, 6.5, 1.4 Hz, 1H), 4.50 (ddd, J = 12.8, 6.3, 1.4 Hz, 1H), 3.67 (ddd, J = 11.2, 6.4, 3.0 Hz, 1H), 3.58 (ddd, J = 11.2, 6.4, 2.9 Hz, 1H), 2.91 (ddd, J = 11.5, 6.3, 2.9 Hz, 1H), 2.47 – 2.30 (m, 4H), 1.92 – 1.81 (m, 1H), 1.53 – 1.46 (m, 1H), 1.45 (s, 3H). 13 C NMR (100 MHz, C6D6): δ 192.8, 172.4, 146.9, 136.5, 134.7, 128.9, 128.6, 126.9, 123.0, 121.8, 66.9, 65.6, 54.4, 50.2, 33.3, 22.7, 20.9. IR (Neat Film, NaCl): 2936, 2856, 1736, 1730, 1692, 1613, 1448 cm–1. HRMS (MM: ESI+): m/z calc’d for C21H26O4N [M+H]+: 356.1856, found 356.1867. O Me O O Me 158k Me Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 621 (E)-but-2-en-1-yl 1,4-dimethyl-2-oxocyclohex-3-ene-1-carboxylate (158k) Prepared from 165g and methyl iodide following General Procedure B. Purification by flash column chromatography (5–25% EtOAc/hexanes) afforded the title compound as a colorless oil (0.29 g, 1.30 mmol, 55% yield). 1 H NMR (400 MHz, CDCl3): δ 5.89 (s, 1H), 5.74 (dqt, J = 15.3, 6.5, 1.2 Hz, 1H), 5.57 – 5.47 (m, 1H), 4.56 – 4.47 (m, 2H), 2.51 – 2.37 (m, 2H), 2.28 – 2.19 (m, 1H), 1.94 (s, 3H), 1.90 – 1.82 (m, 1H), 1.70 (d, J = 6.5 Hz, 3H), 1.37 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 196.9, 172.8, 161.6, 131.4, 125.8, 124.8, 65.9, 52.4, 33.3, 28.7, 24.3, 20.4, 17.9. IR (Neat Film, NaCl): 3027, 2938, 2917, 1730, 1679, 1636, 1440, 1250 cm–1. HRMS (MM: ESI+): m/z calc’d for C13H18O3Na [M+Na]+: 245.1148, found 245.1159. O Me OBn O O Me 158l (Z)-4-(benzyloxy)but-2-en-1-yl 1,4-dimethyl-2-oxocyclohex-3-ene-1-carboxylate (158l) Prepared from 165f and methyl iodide following General Procedure B. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (361 mg, 1.1 mmol, 73% yield). 1 H NMR (500 MHz, CDCl3): δ 7.39 – 7.31 (m, 1H), 7.31 – 7.26 (m, 1H), 5.88 (q, J = 1.5 Hz, 1H), 5.80 (dtt, J = 11.2, 6.2, 1.4 Hz, 1H), 5.70 – 5.59 (m, 1H), 4.72 – 4.59 (m, 2H), 4.11 (ddd, J = 6.3, 1.6, 0.8 Hz, 1H), 2.47 (dt, J = 13.2, 5.1 Hz, 1H), 2.43 – 2.35 (m, 1H), Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 622 2.24 (dt, J = 18.9, 5.2 Hz, 1H), 1.94 (d, J = 1.4 Hz, 1H), 1.87 (ddd, J = 13.2, 8.3, 5.1 Hz, 1H), 1.37 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.6, 172.7, 161.6, 138.1, 131.2, 128.6, 127.9, 127.8, 126.4, 125.6, 72.6, 65.8, 61.1, 52.4, 33.2, 28.7, 24.3, 20.3. IR (Neat Film, NaCl): 3031 (m), 2933 (m), 1731 (s), 1681 (s), 1454 (m), 1214 (m) cm–1. HRMS (MM: ESI+): m/z calc’d for C20H24O4Na [M+Na]+: 351.1567, found 351.1565. O R1 O OR2 O Selectfluor (1.1 equiv) TiCl4 (0.1 equiv) MeCN, 23 ºC R1 F O OR2 General Procedure C: Fluorination of b-ketoesters. To a solution of b-ketoester (1 equiv) in anhydrous acetonitrile (0.2 M) at 23 ºC is added neat titanium(IV) chloride (0.1 equiv). After 5 minutes, Selectfluor® was added in one portion. The reaction mixture is stirred at 23 ºC until complete consumption of starting material as observed by TLC (typically 2 hours). Water is then added, and the reaction mixture is extracted three times with Et2O. The combined organic layers was washed with saturated aqueous brine, dried over anhydrous sodium sulfate, and volatiles were removed in vacuo. The crude reaction mixture was purified by silica gel flash column chromatography to yield the desired a-fluoro-b-ketoester. O F O O Ph 158m cinnamyl 1-fluoro-2-oxocyclohexane-1-carboxylate (158m) Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 623 Prepared from cinnamyl 2-oxocyclohexane-1-carboxylate following General Procedure C. Purification by flash column chromatography (5–40% EtOAc/hexanes) afforded the title compound as a colorless oil (0.80 g, 2.9 mmol, 75% yield). 1 H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 7.3 Hz, 2H), 7.37 – 7.29 (m, 2H), 7.29 – 7.26 (m, 1H), 6.70 (d, J = 15.9 Hz, 1H), 6.29 (dt, J = 15.9, 6.6 Hz, 1H), 4.89 (d, J = 6.5 Hz, 2H), 2.81 – 2.69 (m, 1H), 2.67 – 2.56 (m, 1H), 2.57 – 2.40 (m, 1H), 2.25 – 2.11 (m, 1H), 1.99 – 1.82 (m, 4H). 13 C NMR (100 MHz, CDCl3): δ 201.9 (d, JC–F = 20.0 Hz), 166.9 (d, JC–F = 24.9 Hz), 136.0, 135.6, 128.8, 128.5, 126.9, 121.9, 96.6 (d, JC–F = 197.2 Hz), 66.9, 39.7, 36.2 (d, JC–F = 21.7 Hz), 26.7, 21.0 (d, JC–F = 5.7 Hz). 19 F NMR (282 MHz, CDCl3): δ –160.82 (ddd, J = 21.5, 13.5, 5.1 Hz, 1F). IR (Neat Film, NaCl): 2943, 1731, 1457, 1281 cm–1 HRMS (MM: FD+): m/z calc’d for C16H17O3F [M]+: 276.1162, found 276.1165. O F O O Ph 158n cinnamyl 1-fluoro-2-oxocyclohex-3-ene-1-carboxylate (158n) Prepared from cinnamyl 2-oxocyclohex-3-ene-1-carboxylate (prepared following General Procedure D and used crude) following General Procedure C. Purification by flash column chromatography (0–20% EtOAc/hexanes) afforded the title compound as a colorless oil (0.54 g, 2.0 mmol, 50% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.37 (m, 2H), 7.35 – 7.30 (m, 2H), 7.30 – 7.26 (m, 1H), 7.10 (dt, J = 10.2, 4.0 Hz, 1H), 6.69 (d, J = 15.9 Hz, 1H), 6.27 (dt, J = 15.8, 6.5 Hz, Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 624 1H), 6.18 (dq, J = 10.2, 2.0 Hz, 1H), 4.94 – 4.84 (m, 2H), 2.72 – 2.58 (m, 3H), 2.48 – 2.39 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 188.9 (d, J = 18.7 Hz), 167.0 (d, J = 25.9 Hz), 151.9, 135.9, 135.4, 128.7, 128.4, 127.7, 126.8, 121.8, 92.9 (d, J = 194.8 Hz), 66.8, 31.3 (d, J = 22.5 Hz), 23.3 (d, J = 7.2 Hz). 19 F NMR (282 MHz, CDCl3): δ –164.30 (dd, J = 22.8, 12.5 Hz). IR (Neat Film, NaCl): 3027, 2940, 1759, 1693, 1265 cm–1. HRMS (MM: FD+): m/z calc’d for C16H15O3F [M]+: 274.1005, found 274.1004. O F O O Ph EtO 158o cinnamyl 4-ethoxy-1-fluoro-2-oxocyclohex-3-ene-1-carboxylate (158o) Prepared from 165b following General Procedure C. Purification by flash column chromatography (0–25% EtOAc/hexanes) afforded the title compound as a colorless oil (0.16 g, 0.50 mmol, 31% yield). 1 H NMR (400 MHz, CDCl3): δ 7.42 – 7.35 (m, 2H), 7.36 – 7.27 (m, 2H), 7.31 – 7.22 (m, 2H), 6.68 (d, J = 15.9 Hz, 1H), 6.28 (dd, J = 16.0, 6.2 Hz, 1H), 5.46 (s, 1H), 4.94 – 4.85 (m, 2H), 3.97 (q, J = 7.1 Hz, 2H), 2.72 – 2.53 (m, 3H), 2.44 – 2.33 (m, 1H), 1.38 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 188.6 (d, JC–F = 18.9 Hz), 178.2, 167.7 (d, JC–F = 26.0 Hz), 136.1, 135.3, 128.7, 128.4, 126.9, 122.0, 101.0, 92.3 (d, JC–F = 193.6 Hz), 66.8, 65.3, 29.7 (d, JC–F = 23.0 Hz), 25.7 (d, JC–F = 6.0 Hz), 14.2. 19 F NMR (282 MHz, CDCl3): δ –163.76 – –163.93 (m). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 625 IR (Neat Film, NaCl): 2983, 2943, 1765, 1666, 1599, 1382, 1264 cm–1 HRMS (MM: ESI+): m/z calc’d for C18H19O4FNa [M+Na]+: 341.1148, found 341.1158. O OBn O F O Me 158p (Z)-4-(benzyloxy)but-2-en-1-yl 1-fluoro-4-methyl-2-oxocyclohex-3-ene-1-carboxylate (158p) Prepared from 165f following General Procedure C. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (0.39 g, 1.2 mmol, 75% yield). 1 H NMR (400 MHz, CDCl3): δ 7.38 – 7.27 (m, 5H), 6.00 (s, 1H), 5.89 – 5.82 (m, 1H), 5.73 – 5.66 (m, 1H), 4.79 (d, J = 6.7 Hz, 2H), 4.51 (s, 2H), 4.13 (d, J = 6.2 Hz, 2H), 2.63 – 2.33 (m, 4H), 2.03 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 188.5 (d, JC–F = 18.6 Hz), 167.4 (d, JC–F = 25.8 Hz), 164.6, 138.1, 132.1, 128.6, 128.0, 127.9, 125.6, 124.7, 92.2 (d, JC–F = 194.0 Hz), 72.7, 65.8, 62.0, 31.1 (d, JC–F = 22.5 Hz), 28.0 (d, JC–F = 6.5 Hz), 24.7. 19 F NMR (282 MHz, CDCl3): δ –165.21 (dd, J = 26.4, 12.0 Hz). IR (Neat Film, NaCl): 2914, 1764, 1681, 1627, 1264, 1088 cm–1 HRMS (MM: ESI+): m/z calc’d for C19H22O4F [M+H]+: 333.1502, found 333.1491. O F O O Me Me 158q (E)-but-2-en-1-yl 1-fluoro-4-methyl-2-oxocyclohex-3-ene-1-carboxylate (158q) Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 626 Prepared from 165g following General Procedure C. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (326 mg, 1.44 mmol, 60% yield). 1 H NMR (400 MHz, CDCl3): δ 6.00 (s, 1H), 5.87 – 5.77 (m, 1H), 5.58 (dtq, J = 15.0, 6.7, 1.7 Hz, 1H), 4.64 (ddt, J = 6.7, 2.5, 1.2 Hz, 2H), 2.65 – 2.49 (m, 3H), 2.43 – 2.33 (m, 1H), 2.03 (s, 3H), 1.72 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 188.7 (d, JC–F = 18.6 Hz), 167.4 (d, JC–F = 25.7 Hz), 164.5, 132.8, 124.7, 124.1, 92.3 (d, JC–F = 194.1 Hz), 67.0, 31.2 (d, JC–F = 22.5 Hz), 28.2 (d, JC–F = 6.8 Hz), 24.6, 18.0. 19 F NMR (282 MHz, CDCl3): δ –165.04 (d, J = 22.2 Hz). IR (Neat Film, NaCl): 3029, 2940, 1760, 1681, 1631, 1436, 1271, 1263, 1019 cm–1. HRMS (MM: ESI+): m/z calc’d for C12H15O3FNa [M+Na]+: 249.0897, found 249.0901. O LDA (2 equiv) + R1 (2.2 equiv) O O N N OR2 THF, 0 to 23 ºC R1 O OR2 (1 equiv) General Procedure D: b-ketoester synthesis through ketone acylation. A flame dried round bottom flask was charged with iPr2NH (2.2 equiv) and THF (1.75 M). The solution was cooled to 0 ºC and n-BuLi (2.5 M in hexanes, 2.1 equiv) was added dropwise. The resultant solution was stirred for 30 min at 0 ºC. The corresponding cyclohexenone (2.0 equiv) in THF (1.25 M) was added dropwise and stirring was continued at 0 ºC for 30 minutes. The solution was cooled to –78 ºC, and the appropriate N-acyl imidazole (1.0 equiv) in THF (3.25 M) was added dropwise. After 2 h, the reaction was Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 627 gradually warmed to 23 ºC and diluted with 2 M aqueous HCl until reaching a pH < 7. The reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography to afford the corresponding acylated enone. O O O Ph Me 165a cinnamyl 4-methyl-2-oxocyclohex-3-ene-1-carboxylate (165a) Prepared from 3-methylcyclohex-2-en-1-one and cinnamyl 1H-imidazole-1-carboxylate following General Procedure D. Purification by flash column chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (5.5 g, 20.3 mmol, 51% yield). 1 H NMR (600 MHz, CDCl3): δ 7.42 – 7.36 (m, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.29 – 7.19 (m, 1H), 6.67 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.8, 6.4 Hz, 1H), 5.94 (d, J = 1.5 Hz, 1H), 4.82 (d, J = 6.4 Hz, 2H), 3.46 – 3.28 (m, 1H), 2.49 – 2.25 (m, 4H), 2.25 – 2.17 (m, 1H), 1.97 (d, J = 1.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 193.7, 170.2, 163.1, 136.3, 134.5, 128.7, 128.2, 126.8, 126.0, 123.0, 65.8, 52.7, 29.6, 25.6, 24.5. IR (Neat Film, NaCl): 3026, 2935, 1737, 1666, 1445, 970 cm–1. HRMS (MM: ESI+): m/z calc’d for C17H18O3Na [M+Na]+: 293.1148, found 293.1152. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles O 628 O O Ph EtO 165b cinnamyl 4-ethoxy-2-oxocyclohex-3-ene-1-carboxylate (165b) Prepared from 3-ethoxycyclohex-2-en-1-one following General Procedure D. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (2.13 g, 7.09 mmol, 35% yield). 1 H NMR (400 MHz, CDCl3): δ 7.41 – 7.37 (m, 2H), 7.32 (tt, J = 6.5, 1.0 Hz, 2H), 7.28 – 7.23 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.29 (dt, J = 15.9, 6.4 Hz, 1H), 5.40 (s, 1H), 4.82 (dd, J = 6.4, 1.4 Hz, 2H), 3.96 – 3.88 (m, 2H), 3.41 – 3.36 (m, 1H), 2.62 – 2.52 (m, 1H), 2.48 – 2.33 (m, 2H), 2.25 – 2.15 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3): δ 193.6, 177.6, 170.2, 136.2, 134.3, 128.6, 128.1, 126.7, 122.9, 102.1, 65.8, 64.6, 52.4, 27.4, 24.2, 14.1. IR (Neat Film, NaCl): 2980, 2942, 1736, 1654, 1602, 1380, 1192 cm–1. HRMS (MM: FD+): m/z calc’d for C18H20O4 [M]+: 300.1362, found 300.1353. O O O BnO Ph 165c cinnamyl 4-(benzyloxy)-2-oxocyclohex-3-ene-1-carboxylate (165c) Prepared from 3-(benzyloxy)cyclohex-2-en-1-one following General Procedure D. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (0.79 g, 2.2 mmol, 22% yield). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 1 629 H NMR (400 MHz, CDCl3): δ 7.42 – 7.27 (m, 10H), 6.68 (d, J = 15.9 Hz, 1H), 6.29 (dt, J = 15.9, 6.4 Hz, 1H), 5.54 (s, 1H), 4.91 (d, J = 2.5 Hz, 2H), 4.83 (dd, J = 6.4, 1.3 Hz, 2H), 3.41 (dd, J = 9.0, 5.0 Hz, 1H), 2.65 (ddd, J = 17.5, 6.4, 5.0 Hz, 1H), 2.56 – 2.46 (m, 1H), 2.41 (dtd, J = 13.7, 8.7, 5.0 Hz, 1H), 2.23 (ddt, J = 13.5, 6.6, 5.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 193.6, 177.3, 170.1, 136.2, 134.7, 134.4, 128.8, 128.7, 128.6, 128.1, 127.9, 126.7, 122.9, 102.8, 70.8, 65.8, 52.4, 27.4, 24.2. IR (Neat Film, NaCl): 3030, 2942, 1736, 1657, 1603, 1362, 1186, 1150 cm–1. HRMS (MM: FD+): m/z calc’d for C23H22O4 [M]+: 362.1518, found 362.1510. O O O Ph PhS 165d cinnamyl 2-oxo-4-(phenylthio)cyclohex-3-ene-1-carboxylate (165d) Prepared from 3-(phenylthio)cyclohex-2-en-1-one following General Procedure D. Purification by flash column chromatography (10–60% EtOAc/hexanes) afforded the title compound as a colorless oil (1.59 g, 4.36 mmol, 44% yield). *trace 3-(phenylthio)cyclohex-2-en-1-one coeluted with 165d. The material can be carried through alkylation and separated without issue* 1 H NMR (400 MHz, CDCl3): δ 7.49 – 7.37 (m, 8H), 7.34 – 7.25 (m, 2H), 6.66 (d, J = 15.9 Hz, 1H), 6.27 (dt, J = 15.9, 6.3 Hz, 1H), 5.53 (s, 1H), 4.81 (dd, J = 6.4, 1.4 Hz, 2H), 3.41 (dd, J = 9.3, 4.9 Hz, 1H), 2.75 – 2.66 (m, 1H), 2.62 – 2.51 (m, 1H), 2.50 – 2.36 (m, 1H), 2.32 – 2.25 (m, 1H). 13 C NMR (100 MHz, CDCl3): δ 190.2, 169.9, 167.5, 136.3, 135.6, 134.5, 130.5, 130.1, 128.7, 128.2, 127.7, 126.8, 122.9, 120.1, 65.9, 52.9, 28.6, 26.1. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 630 IR (Neat Film, NaCl): 3054, 2939, 1736, 1656, 1576, 1300, 1167, 1146 cm–1. HRMS (MM: FD+): m/z calc’d for C22H20O3S [M]+: 364.1133, found 364.1133. O O O N O Ph 165e cinnamyl 3-morpholino-2-oxocyclohex-3-ene-1-carboxylate (165e) Prepared from 2-morpholinocyclohex-2-en-1-one 13 following General Procedure D. Purification by flash column chromatography (30–60% EtOAc/hexanes) afforded the title compound as a colorless oil (1.34 g, 3.92 mmol, 33% yield). 1 H NMR (400 MHz, C6D6): δ 7.16 – 7.13 (m, 2H), 7.10 – 6.98 (m, 3H), 6.43 (d, J = 15.9 Hz, 1H), 6.12 (dt, J = 15.9, 6.4 Hz, 1H), 5.22 (t, J = 4.5 Hz, 1H), 4.71 – 4.61 (m, 2H), 3.64 – 3.56 (m, 4H), 3.28 (dd, J = 9.6, 4.6 Hz, 1H), 2.67 – 2.55 (m, 4H), 2.20 – 2.12 (m, 1H), 2.02 (dq, J = 17.5, 4.9, 4.3 Hz, 1H), 1.81 – 1.65 (m, 2H). 13 C NMR (100 MHz, C6D6): δ 190.4, 169.7, 146.5, 136.7, 134.5, 128.8, 128.2, 127.0, 124.3, 123.4, 66.9, 65.6, 55.2, 50.3, 26.0, 23.6. IR (Neat Film, NaCl): 3024, 2953, 2854, 1736, 1685, 1610, 1448, 1262, 1118 cm–1. HRMS (MM: ESI+): m/z calc’d for C20H24O4N [M+H]+: 342.1700, found 342.1710. O OBn O O Me 165f (Z)-4-(benzyloxy)but-2-en-1-yl 4-methyl-2-oxocyclohex-3-ene-1-carboxylate (165f) Prepared from 3-methylcyclohex-2-en-1-one and (Z)-4-(benzyloxy)but-2-en-1-yl 1Himidazole-1-carboxylate following General Procedure D. Purification by flash column Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 631 chromatography (20% EtOAc/hexanes) afforded the title compound as a colorless oil (5.5 g, 20.3 mmol, 51% yield). *Due to difficult separation, the NMR contains signals associated with the starting material. However, this can be used in the next step without consequence.* 1 H NMR (600 MHz, CDCl3): δ 7.41 – 7.32 (m, 4H), 7.32 – 7.27 (m, 1H), 5.91 (t, J = 1.5 Hz, 1H), 5.86 – 5.78 (m, 1H), 5.76 – 5.63 (m, 1H), 4.72 (dd, J = 6.6, 1.3 Hz, 2H), 4.51 (s, 2H), 4.13 (dd, J = 6.2, 1.5 Hz, 2H), 3.40 – 3.21 (m, 1H), 2.48 – 2.25 (m, 5H), 2.25 – 2.14 (m, 1H), 2.05 – 1.96 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ 193.6, 170.2, 163.1, 138.1, 131.2, 128.6, 127.9, 127.8, 126.5, 126.0, 72.6, 65.8, 61.1, 52.6, 29.5, 25.6, 24.5. IR (Neat Film, NaCl): 3457, 3031, 2936, 1738, 1667, 1453 cm–1. HRMS (MM: ESI+): m/z calc’d for C19H22O4Na [M+Na]+: 337.1410, found 337.1415. O O O Me Me 165g (E)-but-2-en-1-yl 4-methyl-2-oxocyclohex-3-ene-1-carboxylate (165g) Prepared from 3-methylcyclohex-2-en-1-one following General Procedure D. Purification by flash column chromatography (20–40% EtOAc/hexanes) afforded the title compound as a colorless oil (1.98 g, 9.49 mmol, 63% yield). 1 H NMR (400 MHz, CDCl3): δ 5.92 (q, J = 1.4 Hz, 1H), 5.84 – 5.74 (m, 1H), 5.63 – 5.54 (m, 1H), 4.58 (dt, J = 6.5, 1.1 Hz, 2H), 3.32 (dd, J = 9.6, 5.1 Hz, 1H), 2.45 – 2.27 (m, 3H), 2.21 – 2.16 (m, 1H), 1.97 (s, 3H), 1.71 (dq, J = 6.5, 1.2 Hz, 3H). 632 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 C NMR (100 MHz, CDCl3): δ 193.8, 170.2, 163.0, 131.7, 126.0, 124.9, 66.0, 52.6, 29.5, 25.6, 24.5, 17.9. IR (Neat Film, NaCl): 3027, 2941, 1737, 1671, 1632, 1439, 1166, 1153 cm–1. HRMS (MM: ESI+): m/z calc’d for C12H16O3Na [M+Na]+: 231.0992, found 231.1000. CF3 CF3 PH + O N Br R 2 CuI (15 mol%) DMEDA (1.1 equiv) Cs2CO3 (3.0 equiv) O PhMe, 130 ºC, 24 h N P (1.3 equiv) R tBu 2 tBu General Procedure E: Preparation of Novel (S)-t-BuPHOX Ligands. A flame-dried 3-neck round-bottom flask attached to a reflux condenser under nitrogen atmosphere was charged with CuI (0.15 equiv). Anhydrous toluene (0.03 M) was added followed by DMEDA (1.1 equiv), and the reaction mixture was stirred at ambient temperature for 20 minutes. To the pre-stirred catalyst solution was added the requisite aryl bromide (1.0 equiv), Cs2CO3 (3.0 equiv), and the aryl phosphine (1.3 equiv). Minimal additional toluene was added to rinse any solids off the sides of the flask. The reaction mixture was heated to reflux (ca. 130 °C) and stirred for a minimum of 21 h. Upon completion, the reaction mixture was cooled to ambient temperature, filtered through a pad of celite, and washed with CH2Cl2. The filtrate was concentrated and purified by flash silica gel column chromatography. CF3 CF3 O P + O R Br 2 H (1.8 equiv) Ph2SiH2 O PhMe, 130 ºC, 24 h P N tBu CF3 CuI (15 mol%) DMEDA (1.1 equiv) Cs2CO3 (3.8 equiv) R 2 O O 140 ºC 24 to 48 h N tBu General Procedure F: Preparation of Novel (S)-t-BuPHOX Ligands. P R 2 N tBu Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 633 A flame-dried 3-neck round-bottom flask attached to a reflux condenser under nitrogen atmosphere was charged with CuI (0.15 equiv). Anhydrous toluene (0.03 M) was added followed by DMEDA (1.1 equiv), and the reaction mixture was stirred at ambient temperature for 20 minutes. To the pre-stirred catalyst solution was added aryl bromide (1.0 equiv), Cs2CO3 (3.8 equiv), and aryl phosphine oxide (1.8 equiv). Minimal additional toluene was added to rinse any solids off the sides of the flask. The reaction mixture was heated to reflux (ca. 130 °C) and stirred for a minimum of 21 h. Upon completion, the reaction mixture was cooled to ambient temperature, filtered through a pad of celite, and washed with CH2Cl2. The filtrate was concentrated and purified by flash silica gel column chromatography. The isolated phosphine oxide was placed in an oven-dried vial along with a magnetic stir bar and degassed using an Argon balloon for 10 min. Ph2SiH2 (1.2 mL, 6.5 mmol, 7.0 equiv) was added to the reaction vial, which fully dissolved the phosphine oxide residue. The reaction vial was then placed in a pre-heated oil bath at 140 °C and stirred until complete reduction of phosphine oxide (typically 24–120 h). Once complete as determined by 31P NMR, the reaction was cooled to ambient temperature adsorbed onto silica gel then purified by flash silica gel column chromatography. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 634 CF3 O F P N 2 F t-Bu L4 (S)-2-(2-(bis(2,6-difluorophenyl)phosphaneyl)-5-(trifluoromethyl)phenyl)-4-(tertbutyl)-4,5-dihydrooxazole (L4) Prepared from bis(2,6-difluorophenyl)phosphane (190 mg, 0.74 mmol, 1.2 equiv) following General Procedure E. Purification by flash column chromatography (0–50% CH2Cl2/hexanes) afforded the title compound as a white solid (67 mg, 0.13 mmol, 20% yield). *Note: Ullmann coupling using the aryl phosphine oxide does not yield any product. 1 H NMR (300 MHz, CDCl3): δ 8.23 (dd, J = 4.4, 2.0 Hz, 1H), 7.61 – 7.50 (m, 1H), 7.42 – 7.26 (m, 3H), 6.83 (qd, J = 7.8, 2.3 Hz, 4H), 4.30 (dd, J = 10.1, 8.5 Hz, 1H), 4.13 (t, J = 8.7 Hz, 1H), 3.94 (dd, J = 10.1, 8.9 Hz, 1H), 0.69 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 165.8 (td, J = 9.0, 3.7 Hz), 163.3 (td, J = 9.0, 4.1 Hz), 161.2 (d, J = 4.9 Hz), 140.9 (d, J = 28.6 Hz), 133.1, 132.1, 131.6 (dt, J = 28.6, 10.9 Hz), 130.5 (qd, J = 33.2, 1.6 Hz), 128.0, 126.4 (q, J = 3.7 Hz), 126.2 – 126.0 (m), 125.3, 122.6, 119.8, 114.7 – 113.3 (m), 111.9 – 111.2 (m), 68.9, 33.5, 25.8. 31 P NMR (121 MHz, CDCl3): δ –55.81 – –56.51 (m). 19 F NMR (282 MHz, CDCl3): δ –62.83 – –62.88 (m, 3F), –100.06 – –100.19 (m, 1F), – 100.24 – –100.34 (m, 1F), –100.43 – –100.54 (m, 1F), –100.58 – –100.70 (m, 1F). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 635 IR (Neat Film, NaCl): 3080, 2958, 2907, 2870, 1657, 1607, 1574, 1454, 1326, 1228, 1176, 1131, 1083, 986, 784 cm–1. HRMS (MM: ESI+): m/z calc’d for C26H21NOF7P [M]+: 527.12490, found 527.12391. Optical Rotation: [α]D21 +18.1° (c 0.10, CHCl3) CF3 O P N 2 Me t-Bu L5 (S)-4-(tert-butyl)-2-(2-(di-o-tolylphosphaneyl)-5-(trifluoromethyl)phenyl)-4,5dihydrooxazole (L5) Prepared from di-o-tolylphosphane (240 mg, 1.1 mmol, 1.3 equiv) following General Procedure E. Purification by flash column chromatography (0–30% EtOAc/hexanes) afforded the title compound as a tan solid (130 mg, 0.27 mmol, 31% yield). 1 H NMR (400 MHz, CDCl3): δ 8.21 (t, J = 2.7 Hz, 1H), 7.51 (dd, J = 8.1, 2.0 Hz, 1H), 7.26 – 7.16 (m, 4H), 7.11 – 6.97 (m, 3H), 6.73 – 6.64 (m, 2H), 4.13 (dd, J = 10.1, 8.5 Hz, 1H), 4.04 (t, J = 8.3 Hz, 1H), 3.94 (dd, J = 10.1, 8.3 Hz, 1H), 2.38 (dd, J = 4.1, 1.7 Hz, 6H), 0.70 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 161.61, 143.48 – 143.01 (m), 142.75 (d, J = 27.4 Hz), 142.31 (d, J = 28.0 Hz), 135.93 – 135.60 (m), 134.81, 133.49, 133.26, 133.05, 130.85, 130.53, 130.25 (d, J = 4.9 Hz), 128.90 (d, J = 15.1 Hz), 126.81 (dq, J = 11.3, 3.7 Hz), 126.38 (d, J = 16.2 Hz), 125.30, 122.59, 68.63, 33.76, 25.79, 21.48, 21.25. 31 P NMR (121 MHz, CDCl3): δ –20.8 (s). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 19 636 F NMR (282 MHz, CDCl3): δ –62.8 (s). IR (Neat Film, NaCl): 3056, 2957, 2867, 2356, 1653, 1471, 1454, 1341, 1324, 1169, 1130, 1079, 970 cm–1. HRMS (MM: ESI+): m/z calc’d for C28H29NOF3P [M+H]+: 483.19389, found 483.19472. Optical Rotation: [α]D22 –55.4 ° (c 0.28, CHCl3). CF3 O P N 2 F t-Bu L6 (S)-2-(2-(bis(2-fluorophenyl)phosphaneyl)-5-(trifluoromethyl)phenyl)-4-(tert-butyl)4,5-dihydrooxazole (L6) Prepared from bis(2-fluorophenyl)phosphine oxide (408 mg, 1.7 mmol, 1.8 equiv) following General Procedure F. Purification by flash column chromatography (0–50% EtOAc/hexanes) afforded the title compound as a white solid (408 mg, 0.81 mmol, 85% yield). 1 H NMR (500 MHz, CDCl3): δ 8.28 (t, J = 2.8 Hz, 1H), 7.59 (dd, J = 8.2, 2.0 Hz, 1H), 7.41 – 7.32 (m, 2H), 7.20 (dd, J = 8.2, 3.0 Hz, 1H), 7.11 – 7.02 (m, 4H), 6.88 – 7.84 (m, 1H), 6.82 – 6.77 (m, 1H), 4.26 (dd, J = 10.1, 8.6 Hz, 1H), 4.12 (t, J = 8.6 Hz, 1H), 4.00 (dd, J = 10.1, 8.6 Hz, 1H), 0.74 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 165.7 (dd, J = 17.9, 16.1 Hz), 163.5 – 163.0 (m), 161.3, 141.6 (d, J = 29.5 Hz), 135.0 – 134.8 (m), 134.7 – 134.4 (m), 132.3 (d, J = 21.8 Hz), 131.4 Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 637 (dd, J = 25.3, 8.3 Hz), 131.0 (d, J = 33.2 Hz), 127.0 (q, J = 3.7 Hz), 126.7 (t, J = 3.5 Hz), 125.2, 124.8 (dd, J = 9.7, 3.3 Hz), 124.4 – 123.7 (m), 122.5, 68.9, 33.7, 25.8. 31 P NMR (121 MHz, CDCl3): δ –32.10 (t, J = 63.2 Hz). 19 F NMR (282 MHz, CDCl3): δ –62.90 (s, 3F), –103.64 – –103.88 (m, 1), –103.88 – – 104.11 (m, 1F). IR (Neat Film, NaCl): 3069, 2956, 2357, 1654, 1469, 1324, 1170, 1132, 1081, 756 cm–1. HRMS (MM: ESI+): m/z calc’d for C26H23NOF5P [M+H]+: 491.14374, found 491.14451. Optical Rotation: [α]D22 –20.5° (c 0.73, CHCl3). CF3 O P N 2 OCF3 t-Bu L7 (S)-2-(2-(bis(2-(trifluoromethoxy)phenyl)phosphaneyl)-5-(trifluoromethyl)phenyl)4-(tert-butyl)-4,5-dihydrooxazole (L7) Prepared from bis(2-(trifluoromethoxy)phenyl)phosphine oxide (700 mg, 1.9 mmol, 1.8 equiv) following General Procedure F. Purification by flash column chromatography (0– 50% EtOAc/hexanes) afforded the title compound as a tan solid (632 mg, 0.99 mmol, 94% yield). 1 H NMR (300 MHz, CDCl3): δ 8.25 – 8.23 (m, 1H), 7.62 – 7.50 (m, 1H), 7.45 – 7.37 (m, 2H), 7.31 – 7.27 (m, 2H), 7.20 – 7.14 (m, 2H), 7.03 (dd, J = 8.2, 2.7 Hz, 1H), 6.90 – 6.74 (m, 2H), 4.21 (dd, J = 10.2, 8.5 Hz, 1H), 4.12 (t, J = 8.2 Hz, 1H), 3.98 (dd, J = 10.2, 7.8 Hz, 1H), 0.71 (s, 9H). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 13 638 C NMR (101 MHz, CDCl3): δ 161.24, 151.82 (dd, J = 27.3, 19.9 Hz), 141.42 (d, J = 30.8 Hz), 135.41 (d, J = 2.8 Hz), 135.00, 134.49, 133.09 (d, J = 23.3 Hz), 131.50, 131.18, 130.94, 130.85, 130.66, 130.45 (d, J = 17.5 Hz), 130.23, 129.78 (d, J = 21.2 Hz), 128.00, 127.86 (d, J = 1.3 Hz), 126.95 – 126.41 (m), 125.16, 124.33 (d, J = 3.0 Hz), 122.45, 121.76 (d, J = 3.0 Hz), 119.60, 119.27 – 119.01 (m), 116.60, 69.01, 33.82, 25.66. 31 P NMR (121 MHz, CDCl3): δ –27.4 (m). 19 F NMR (282 MHz, CDCl3): δ –56.5 (s, 6F), –62.9 (s, 3F). IR (Neat Film, NaCl): 3062, 2964, 2870, 2363, 2342, 1653, 1472, 1326, 1251, 1216, 1200, 1168, 1160, 1128, 1081 cm–1. HRMS (MM: ESI+): m/z calc’d for C28H23NO3F9P [M+H]+: 623.12718, found 623.12455. Optical Rotation: [α]D21 –20.3 ° (c 1.48, CHCl3). Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 5.7 (1) 639 REFERENCES AND NOTES Junk, L.; Kazmaier, U. The Allylic Alkylation of Ketone Enolates. ChemistryOpen 2020, 9, 929–952. (2) (a) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Iridium-Catalyzed Diastereo-, Enantio-, and Regioselective Allylic Alkylation with Prochiral Enolates. ACS Catal. 2016, 6, 6207–6213. (b) Qu, J.; Helmchen, G. Applications of Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in Target-Oriented Synthesis. Acc. Chem. Res. 2017, 50, 2539–2555. (c) Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account. Synlett 2018, 29, 2481–2492. (d) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions. Chem. Rev. 2019, 119, 1855–1969. (e) Moghadam, F. A.; Hicks, E. F.; Sercel, Z. P.; Cusumano, A. Q.; Bartberger, M. D.; Stoltz, B. M. Ir-Catalyzed Asymmetric Allylic Alkylation of Dialkyl Malonates Enabling the Construction of Enantioenriched All-Carbon Quaternary Centers. J. Am. Chem. Soc. 2022, 144, 7983–7987. (3) Trost, B. M.; Schroeder, G. M. Palladium-Catalyzed Asymmetric Allylic Alkylation of Ketone Enolates. Chem. Eur. J. 2005, 11, 174–184. (4) Chen, W.; Chen, M.; Hartwig, J. F. Diastereo- and Enantioselective IridiumCatalyzed Allylation of Cyclic Ketone Enolates: Synergetic Effect of Ligands and Barium Enolates. J. Am. Chem. Soc. 2014, 136, 15825–15828. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles (5) 640 (a) Chen, J.-P.; Peng, Q.; Lei, B.-L.; Hou, X.-L.; Wu, Y.-D. Chemo- and Regioselectivity-Tunable Pd-Catalyzed Allylic Alkylation of Imines. J. Am. Chem. Soc. 2011, 133, 14180–14183. (b) Braun, M.; Laicher, F.; Meier, T. Diastereoselective and Enantioselective Palladium-Catalyzed Allylic Substitution with Nonstabilized Ketone Enolates. Angew. Chem. Int. Ed. 2000, 39, 3494–3497. (c) Yu, F.-L.; Bai, D.-C.; Liu, X.-Y.; Jiang, Y.-J.; Ding, C.-H.; Hou, X.-L. PdCatalyzed Allylic Alkylation of Gem-Alkyl,Aryl-Disubstituted Allyl Reagents with Ketones: Diastereoselective Construction of Vicinal Tertiary and Quaternary Carbon Centers. ACS Catal. 2018, 8, 3317–3321. (d) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. Highly Regio-, Diastereo-, and Enantioselective PdCatalyzed Allylic Alkylation of Acyclic Ketone Enolates with Monosubstituted Allyl Substrates. J. Am. Chem. Soc. 2007, 129, 7718–7719. (6) (a) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (b) 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. (c) Ngamnithiporn, A.; Iwayama, T.; Bartberger, M. D.; Stoltz, B. M. Enantioselective Synthesis of Highly Oxygenated Acyclic Quaternary Center-Containing Building Blocks via Palladium-Catalyzed Decarboxylative Allylic Alkylation of Cyclic Siloxyketones. Chem. Sci. 2020, 11, 11068–11071. (d) Alexy, E. J.; Fulton, T. J.; Zhang, H.; Stoltz, B. M. Palladium- Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 641 Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Fully Substituted N-Acyl Indole-Derived Enol Carbonates. Chem. Sci. 2019, 10, 5996– 6000. (e) Lu, Y.; Goldstein, E. L.; Stoltz, B. M. Palladium-Catalyzed Enantioselective C(sp3)–C(sp3) Cross-Coupling for the Synthesis of (Poly)Fluorinated Chiral Building Blocks. Org. Lett. 2018, 20, 5657–5660. (f) 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. (g) 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. (7) (a) Reaction conditions: 158a (0.05 mmol), Pd2(dba)3 (2.5 mol %), (S,S)-DACHPh (6.5 mol %), and THF (2 mL) at 60 ºC for 14 h. (b) An analogous result was found by Wolfe and coworkers: Bornowski, E. C.; Hinds, E. M.; White, D. R.; Nakamura, Y.; Wolfe, J. P. Pd-Catalyzed Alkene Difunctionalization Reactions of Enolates for the Synthesis of Substituted Bicyclic Cyclopentanes. Org. Process Res. Dev. 2019, 23, 1610–1630. (8) (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. The Inner-Sphere Process in the Enantioselective Tsuji Allylation Reaction with (S)-t-Bu-Phosphinooxazoline Ligands. J. Am. Chem. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles 642 Soc. 2007, 129, 11876–11877. (b) Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. The Reaction Mechanism of the Enantioselective Tsuji Allylation: InnerSphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C– C Bond Formation. J. Am. Chem. Soc. 2012, 134, 19050–19060. (c) Cusumano, A. Q.; Stoltz, B. M.; William A. Goddard, III. Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)–C(sp3) CrossCoupling. J. Am. Chem. Soc. 2020, 142, 13917–13933. (d) McPherson, K. E.; Croatt, M. P.; Morehead, A. T.; Sargent, A. L. DFT Mechanistic Investigation of an Enantioselective Tsuji–Trost Allylation Reaction. Organometallics 2018, 37, 3791–3802. (9) For an example of the use of ligand sterics to influence regioselectivity in Pdcatalyzed allylic alkylation, see: (b) Yang, M.-H.; Orsi, D. L.; Altman, R. A. Ligand-Controlled Regiodivergent Palladium-Catalyzed Decarboxylative Allylation Reaction to Access α,α-Difluoroketones. Angew. Chem. Int. Ed. 2015, 54, 2361–2365. (10) Free energies at the PBE0-D4/def2-TZVPP/SMD(PhMe)//PBE-D4/def2- TZVP[Pd], ma-def2-SVP[O], def2-SV(P) level of theory at 333.15 K. Chapter 5 – Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles (11) 643 Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (12) 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. (13) Tobias, M. A.; Strong, J. G.; Napier, R. P. Preparation of 2-substituted 2cyclohexen-1-ones J. Org. Chem. 1970, 35, 1709–1711. APPENDIX 3 Spectra Relevant to Chapter 5: Development of a Branched-selective Asymmetric Allylic Alkylation of Hard Pd-Enolate Nucleophiles Ph 160a Me 10 O 9 8 6 5 ppm 4 3 Figure A3.1. 1H NMR (400 MHz, CDCl3) of compound 160a. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 645 646 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.2. Infrared spectrum (Thin Film, NaCl) of compound 160a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.3. 13C NMR (100 MHz, CDCl3) of compound 160a. 0 Ph 160b Me 10 O 9 8 6 5 ppm 4 3 Figure A3.4. 1H NMR (400 MHz, CDCl3) of compound 160b. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 647 648 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.5. Infrared spectrum (Thin Film, NaCl) of compound 160b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.6. 13C NMR (100 MHz, CDCl3) of compound 160b. 0 Me 10 Me Ph 160c O 9 8 6 5 ppm 4 3 Figure A3.7. 1H NMR (400 MHz, CDCl3) of compound 160c. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 649 650 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.8. Infrared spectrum (Thin Film, NaCl) of compound 160c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.9. 13C NMR (100 MHz, CDCl3) of compound 160c. 0 10 EtO Me Ph 160d O 9 8 6 5 ppm 4 3 Figure A3.10. 1H NMR (400 MHz, CDCl3) of compound 160d. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 651 652 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.11. Infrared spectrum (Thin Film, NaCl) of compound 160d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.12. 13C NMR (100 MHz, CDCl3) of compound 160d. 0 10 EtO Et Ph 160e O 9 8 6 5 ppm 4 3 Figure A3.13. 1H NMR (400 MHz, CDCl3) of compound 160e. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 653 654 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.14. Infrared spectrum (Thin Film, NaCl) of compound 160e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.15. 13C NMR (100 MHz, CDCl3) of compound 160e. 0 EtO 10 Ph 160f O 9 CO2Me 8 6 5 ppm 4 3 Figure A3.16. 1H NMR (400 MHz, CDCl3) of compound 160f. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 655 656 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.17. Infrared spectrum (Thin Film, NaCl) of compound 160f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.18. 13C NMR (100 MHz, CDCl3) of compound 160f. 0 EtO 10 Ph 160g O CN 9 8 6 5 ppm 4 3 Figure A3.19. 1H NMR (400 MHz, CDCl3) of compound 160g. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 657 658 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.20. Infrared spectrum (Thin Film, NaCl) of compound 160g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.21. 13C NMR (100 MHz, CDCl3) of compound 160g. 0 BnO 10 Me Ph 160h O 9 8 6 5 ppm 4 3 Figure A3.22. 1H NMR (400 MHz, CDCl3) of compound 160h. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 659 660 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.23. Infrared spectrum (Thin Film, NaCl) of compound 160h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.24. 13C NMR (100 MHz, CDCl3) of compound 160h. 0 PhS 10 Me Ph 160i O 9 8 6 5 ppm 4 3 Figure A3.25. 1H NMR (400 MHz, CDCl3) of compound 160i. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 661 662 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.26. Infrared spectrum (Thin Film, NaCl) of compound 160i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.27. 13C NMR (100 MHz, CDCl3) of compound 160i. 0 O 10 N Me 160j O Ph 9 8 6 5 ppm 4 3 Figure A3.28. 1H NMR (400 MHz, C6D6) of compound 160j. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 663 664 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.29. Infrared spectrum (Thin Film, NaCl) of compound 160j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.30. 13C NMR (100 MHz, C6D6) of compound 160j. 0 Me 10 Me Me 160k O 9 8 6 5 ppm 4 3 Figure A3.28. 1H NMR (400 MHz, CDCl3) of compound 160k. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 665 666 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.32. Infrared spectrum (Thin Film, NaCl) of compound 160k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.33. 13C NMR (100 MHz, CDCl3) of compound 160k. 0 Me 10 Me 160l O OBn 9 8 6 5 ppm 4 3 Figure A3.34. 1H NMR (400 MHz, CDCl3) of compound 160l. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 667 668 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.35. Infrared spectrum (Thin Film, NaCl) of compound 160l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.36. 13C NMR (100 MHz, CDCl3) of compound 160l. 0 10 F Me 160m O 9 8 6 5 ppm 4 3 Figure A3.37. 1H NMR (400 MHz, CDCl3) of compound 160m. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 669 670 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.38. Infrared spectrum (Thin Film, NaCl) of compound 160m. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.39. 13C NMR (100 MHz, CDCl3) of compound 160m. 671 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.40. 19F NMR (282 MHz, CDCl3) of compound 160m. 10 F Me 160n O 9 8 6 5 ppm 4 3 Figure A3.41. 1H NMR (400 MHz, CDCl3) of compound 160n. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 672 673 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.42. Infrared spectrum (Thin Film, NaCl) of compound 160n. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.43. 13C NMR (100 MHz, CDCl3) of compound 160n. 0 674 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.44. 19F NMR (282 MHz, CDCl3) of compound 160n. EtO 10 F Ph 160o O 9 8 6 5 ppm 4 3 Figure A3.45. 1H NMR (400 MHz, CDCl3) of compound 160o. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 675 676 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.46. Infrared spectrum (Thin Film, NaCl) of compound 160o. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.47. 13C NMR (100 MHz, CDCl3) of compound 160o. 0 677 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.48. 19F NMR (282 MHz, CDCl3) of compound 160o. Me F 10 160p O OBn 9 8 6 5 ppm 4 3 Figure A3.49. 1H NMR (400 MHz, CDCl3) of compound 160p. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 678 679 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.50. Infrared spectrum (Thin Film, NaCl) of compound 160p. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.51. 13C NMR (100 MHz, CDCl3) of compound 160p. 0 680 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.52. 19F NMR (282 MHz, CDCl3) of compound 160p. Me F 10 160p O OBn 9 7 6 5 ppm 4 3 2 Figure A3.53. 1H NMR (400 MHz, CDCl3) of compound 160p_linear. 8 1 0 Appendix 3 – Spectra Relevant to Chapter 5 681 682 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.54. Infrared spectrum (Thin Film, NaCl) of compound 160p_linear. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.55. 13C NMR (100 MHz, CDCl3) of compound 160p_linear. 683 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.56. 19F NMR (282 MHz, CDCl3) of compound 160p_linear. Me F 10 160q O Me 9 7 6 5 ppm 4 3 2 Figure A3.57. 1H NMR (500 MHz, CDCl3) of compound 160q (mixture). 8 1 0 Appendix 3 – Spectra Relevant to Chapter 5 684 Me F 10 160q O Me 9 8 6 5 ppm 4 3 2 Figure A3.58. 1H NMR (400 MHz, CDCl3) of compound 160q. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 685 686 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.59. Infrared spectrum (Thin Film, NaCl) of compound 160q. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.60. 13C NMR (100 MHz, CDCl3) of compound 160q. 0 687 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.61. 19F NMR (282 MHz, CDCl3) of compound 160q. O O 158a O 10 Me 9 Ph 8 6 5 ppm 4 3 2 Figure A3.62. 1H NMR (600 MHz, CDCl3) of compound 158a. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 688 689 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.63. Infrared spectrum (Thin Film, NaCl) of compound 158a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.64. 13C NMR (100 MHz, CDCl3) of compound 158a. 0 Me 10 O O 165b O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.65. 1H NMR (400 MHz, CDCl3) of compound 158b. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 690 691 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.66. Infrared spectrum (Thin Film, NaCl) of compound 158b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.67. 13C NMR (100 MHz, CDCl3) of compound 158b. 0 Me 10 O Me O 158c O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.68. 1H NMR (600 MHz, CDCl3) of compound 158c. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 692 693 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.69. Infrared spectrum (Thin Film, NaCl) of compound 158c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.70. 13C NMR (100 MHz, CDCl3) of compound 158c. 0 EtO 10 O O O 158d Me 9 Ph 8 6 5 ppm 4 3 Figure A3.71. 1H NMR (400 MHz, CDCl3) of compound 158d. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 694 695 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.72. Infrared spectrum (Thin Film, NaCl) of compound 158d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.73. 13C NMR (100 MHz, CDCl3) of compound 158d. 0 EtO 10 O O O 158e Et 9 Ph 8 6 5 ppm 4 3 2 Figure A3.74. 1H NMR (400 MHz, CDCl3) of compound 158e. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 696 697 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.75. Infrared spectrum (Thin Film, NaCl) of compound 158e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.76. 13C NMR (100 MHz, CDCl3) of compound 158e. 0 EtO 10 O 9 CO2Me O 158f O Ph 8 6 5 ppm 4 3 Figure A3.77. 1H NMR (400 MHz, CDCl3) of compound 158f. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 698 699 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.78. Infrared spectrum (Thin Film, NaCl) of compound 158f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.79. 13C NMR (100 MHz, CDCl3) of compound 158f. 0 10 EtO O CN O 158g O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.80. 1H NMR (400 MHz, CDCl3) of compound 158g. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 700 701 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.81. Infrared spectrum (Thin Film, NaCl) of compound 158g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.82. 13C NMR (100 MHz, CDCl3) of compound 158g. 0 BnO 10 O O O 158h Me 9 Ph 8 6 5 ppm 4 3 2 Figure A3.83. 1H NMR (400 MHz, CDCl3) of compound 158h. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 702 703 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.84. Infrared spectrum (Thin Film, NaCl) of compound 158h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.85. 13C NMR (100 MHz, CDCl3) of compound 158h. 0 PhS 10 O O O 158i Me 9 Ph 8 6 5 ppm 4 3 Figure A3.86. 1H NMR (400 MHz, CDCl3) of compound 158i. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 704 705 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.87. Infrared spectrum (Thin Film, NaCl) of compound 158i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.88. 13C NMR (100 MHz, CDCl3) of compound 158i. 0 O 10 N O O 9 O 158j Me Ph 8 6 5 ppm 4 3 Figure A3.89. 1H NMR (400 MHz, C6D6) of compound 158j. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 706 707 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.90. Infrared spectrum (Thin Film, NaCl) of compound 158j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.91. 13C NMR (100 MHz, C6D6) of compound 158j. 0 Me O O 158k Me 10 O 9 Me 8 6 5 ppm 4 3 2 Figure A3.92. 1H NMR (400 MHz, CDCl3) of compound 158k. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 708 709 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.93. Infrared spectrum (Thin Film, NaCl) of compound 158k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.94. 13C NMR (100 MHz, CDCl3) of compound 158k. 0 Me 10 O Me O 158l O 9 OBn 8 6 5 ppm 4 3 Figure A3.95. 1H NMR (400 MHz, CDCl3) of compound 158l. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 710 711 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.96. Infrared spectrum (Thin Film, NaCl) of compound 158l. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.97. 13C NMR (100 MHz, CDCl3) of compound 158l. -20 10 O F O 158m O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.98. 1H NMR (400 MHz, CDCl3) of compound 158m. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 712 713 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.99. Infrared spectrum (Thin Film, NaCl) of compound 158m. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.100. 13C NMR (100 MHz, CDCl3) of compound 158m. 714 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.101. 19F NMR (282 MHz, CDCl3) of compound 158m. 10 O F O 158n O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.102. 1H NMR (400 MHz, CDCl3) of compound 158n. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 715 716 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.103. Infrared spectrum (Thin Film, NaCl) of compound 158n. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.104. 13C NMR (100 MHz, CDCl3) of compound 158n. 717 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.105. 19F NMR (282 MHz, CDCl3) of compound 158n. EtO 10 O F O 158o O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.106. 1H NMR (400 MHz, CDCl3) of compound 158o. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 718 719 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.107. Infrared spectrum (Thin Film, NaCl) of compound 158o. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.108. 13C NMR (100 MHz, CDCl3) of compound 158o. 720 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.109. 19F NMR (282 MHz, CDCl3) of compound 158o. Me 10 O F O 158p O 9 OBn 8 6 5 ppm 4 3 2 Figure A3.110. 1H NMR (400 MHz, CDCl3) of compound 158p. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 721 722 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.111. Infrared spectrum (Thin Film, NaCl) of compound 158p. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.112. 13C NMR (100 MHz, CDCl3) of compound 158p. 723 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.113. 19F NMR (282 MHz, CDCl3) of compound 158p. Me 10 O F O 158q O 9 Me 8 6 5 ppm 4 3 2 Figure A3.114. 1H NMR (400 MHz, CDCl3) of compound 158q. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 724 725 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.115. Infrared spectrum (Thin Film, NaCl) of compound 158q. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.116. 13C NMR (100 MHz, CDCl3) of compound 158q. 726 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.117. 19F NMR (282 MHz, CDCl3) of compound 158q. Me 10 O O 165a O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.118. 1H NMR (400 MHz, CDCl3) of compound 165a. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 727 728 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.119. Infrared spectrum (Thin Film, NaCl) of compound 165a. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.120. 13C NMR (100 MHz, CDCl3) of compound 165a. -20 10 EtO O O 165b O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.121. 1H NMR (400 MHz, CDCl3) of compound 165b. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 729 730 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.122. Infrared spectrum (Thin Film, NaCl) of compound 165b. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.123. 13C NMR (100 MHz, CDCl3) of compound 165b. 10 BnO O O 9 165c O Ph 8 6 5 ppm 4 3 2 Figure A3.124. 1H NMR (400 MHz, CDCl3) of compound 165c. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 731 732 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.125. Infrared spectrum (Thin Film, NaCl) of compound 165c. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.126. 13C NMR (100 MHz, CDCl3) of compound 165c. PhS 10 O O 165d O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.127. 1H NMR (400 MHz, CDCl3) of compound 165d. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 733 734 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.128. Infrared spectrum (Thin Film, NaCl) of compound 165d. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.129. 13C NMR (100 MHz, CDCl3) of compound 165d. O 10 N O 165e O O 9 Ph 8 6 5 ppm 4 3 2 Figure A3.130. 1H NMR (400 MHz, C6D6) of compound 165e. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 735 736 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.131. Infrared spectrum (Thin Film, NaCl) of compound 165e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.132. 13C NMR (100 MHz, C6D6) of compound 165e. 0 Me 10 O O 165f O 9 OBn 8 6 5 ppm 4 3 2 Figure A3.133. 1H NMR (400 MHz, CDCl3) of compound 165f. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 737 738 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.134. Infrared spectrum (Thin Film, NaCl) of compound 165f. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.135. 13C NMR (100 MHz, CDCl3) of compound 165f. -20 10 Me O 9 O 165g O Me 8 6 5 ppm 4 3 2 Figure A3.136. 1H NMR (400 MHz, CDCl3) of compound 165g. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 5 739 740 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.137. Infrared spectrum (Thin Film, NaCl) of compound 165g. 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.138. 13C NMR (100 MHz, CDCl3) of compound 165g. F 10 F 2 P CF3 L4 N 9 t-Bu O 8 6 5 ppm 4 3 Figure A3.139. 1H NMR (400 MHz, CDCl3) of compound L4. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 741 742 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.140. Infrared spectrum (Thin Film, NaCl) of compound L4. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.141. 13C NMR (100 MHz, CDCl3) of compound L4. -20 743 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.142. 19F NMR (282 MHz, CDCl3) of compound L4. 100 80 60 40 20 ppm 0 -20 -40 Figure A3.143. 31P NMR (121 MHz, CDCl3) of compound L4. -60 10 Me 2 P CF3 L5 N 9 t-Bu O 8 6 5 ppm 4 3 Figure A3.144. 1H NMR (400 MHz, CDCl3) of compound L5. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 744 745 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.145. Infrared spectrum (Thin Film, NaCl) of compound L5. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.146. 13C NMR (100 MHz, CDCl3) of compound L5. 0 746 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.147. 19F NMR (282 MHz, CDCl3) of compound L5. 200 180 160 140 120 100 80 ppm 60 40 20 0 -20 Figure A3.148. 31P NMR (121 MHz, CDCl3) of compound L5. -40 10 F 2 P CF3 L6 N 9 t-Bu O 8 6 5 ppm 4 3 Figure A3.149. 1H NMR (400 MHz, CDCl3) of compound L6. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 747 748 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.150. Infrared spectrum (Thin Film, NaCl) of compound L6. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.151. 13C NMR (100 MHz, CDCl3) of compound L6. 0 749 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.152. 19F NMR (282 MHz, CDCl3) of compound L6. 200 180 160 140 120 100 80 ppm 60 40 20 0 -20 -40 Figure A3.153. 31P NMR (121 MHz, CDCl3) of compound L6. -60 10 OCF3 2 P CF3 L7 N 9 t-Bu O 8 6 5 ppm 4 3 Figure A3.154. 1H NMR (400 MHz, CDCl3) of compound L7. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 5 750 751 Appendix 3 – Spectra Relevant to Chapter 5 Figure A3.155. Infrared spectrum (Thin Film, NaCl) of compound L7. 220 200 180 160 140 120 100 ppm 80 60 40 20 0 Figure A3.156. 13C NMR (100 MHz, CDCl3) of compound L7. -20 752 Appendix 3 – Spectra Relevant to Chapter 5 20 0 -20 -40 -60 -80 ppm -100 -120 -140 -160 -180 Figure A3.157. 19F NMR (282 MHz, CDCl3) of compound L7. 200 180 160 140 120 100 80 ppm 60 40 20 0 -20 Figure A3.158. 31P NMR (121 MHz, CDCl3) of compound L7. -40 APPENDIX 4 Notebook Cross-Reference for New Compounds. Appendix 4 – Notebook Cross-Reference for New Compounds 754 Table A4.1 Notebook cross-reference for Chapter 3. Compound Notebook Ref. 40a AQC3-189 40b AQC5-245 40c KNF-2-145 40d AQC4-33 40e CS-I-153 40f AQC4-274 40g AQC3-213 40h KNF-2-219 40i RC-I-99 40j AQC4-109 40k AQC3-263 40l AQC3-277 40m RC-I-75 40n KNF-3-033 40o KNF-2-207 40p AQC4-55 40q AQC3-281 40r AQC4-67 40s KNF-1-287 40t KNF-2-157 40u ED-2-043 41a AQC3-291 41b AQC5-251 41c KNF-2-151 41d AQC4-35_p1 41f AQC4-19_p1 41j AQC4-117 41k AQC3-265B_p4 41k’ AQC3-265B_p3 41k” AQC3-265B_p1 41l AQC3-287 41m RC-I-181A 41m’ RC-I-181A Compound 41n 41o 41o’ 41p 41p’ 41q 41r 41s 41t 41t’ 41u 42 44 47 49a 49e 49f 49g 49h 49i 63 64 65 66 67 68 69 70 75 76 77 78 79 Notebook Ref. KNF-3-043-B KNF-2-221A KNF-2-221B AQC4-61 AQC4-181_p2 AQC3-275_p2 AQC4-69_p1 KNF-1-295 KNF-2-161_A KNF-2-161_B KNF-2-229_C KNF-1-289 KNF-1-293 AQC3-137 AQC3-229 CS-I-163 AQC4-19_p2 AQC4-21 KNF-3-031 RC-I-119A CS-I-225 CS-I-223 CS-I-183 CS-I-271 CS-I-257 RC-I-111 RC-I-129 CS-I-51 RC-II-35 RC-II-39 RC-II-41 KNF-3-177 RC-I-301 Appendix 4 – Notebook Cross-Reference for New Compounds 80 81 82 83 84 85 86 87 89 90 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 RC-II-67 RC-II-65 RC-II-77 CS-I-229 CS-I-279 AQC3-187 AQC3-201 AQC3-203 KNF-1-283 KNF-2-155 KNF-1-275-B AQC3-129 CS-I-217 CS-I-215 CS-I-179 CS-I-267 CS-I-249 AQC4-159 AQC3-183 KNF-2-121 KNF-2-123 AQC3-117 KNF-2-155 KNF-1-279 KNF-2-147 ED-2-035 CS-I-175 CS-I-203 CS-I-207 CS-I-237 CS-I-253 KNF-2-283 RC-I-113 D-40f D-41f D-49f D-86 D-100 755 AQC4-143 AQC4-153_p1 AQC4-153_p2 AQC4-139 AQC4-133 Appendix 4 – Notebook Cross-Reference for New Compounds 756 Table A4.2 Notebook cross-reference for Chapter 5. Compound Notebook Ref. 158a SRS-II-294 158b AQC5-65 158c SRS-III-128 158d AQC5-47 158e AQC5-193 158f AQC5-173 158g AQC5-235 158h AQC5-117 158i AQC5-115 158j AQC6-87 158k AQC6-123 158l SRS-III-31 158m AQC5-41 158n AQC5-67 158o AQC5-153 158p AQC5-103 158q AQC5-125 160a AQC5-265 160b VH-II-197 160c AQC5-271 160d AQC5-143 160e AQC5-201 160f AQC5-181 160h AQC5-145 160i AQC5-147 160j AQC6-147 160k AQC6-151 160l AQC6-151 160m AQC5-267 160n AQC5-269 160o AQC5-171 160p AQC5-257_p1 160p_linear AQC5-107B_p2 160q AQC6-145_p1 Compound 165a 165b 165c 165d 165e 165f 165g L4 L5 L6 L7 Notebook Ref. SRS-III-16 AQC5-37 AQC5-111 AQC5-109 AQC6-83 SRS-III-30 AQC6-113 VH-II-264 VH-II-195 VH-II-281 VH-II-291 757 ABOUT THE AUTHOR Alexander Quinn Cusumano was born in St. Petersburg, Florida on June 7th, 1997 to Dave and Dale Cusumano. After 10 years in Florida, Alex, his parents, and his younger sister Nicki moved to Charlotte, North Carolina. His interest in organic chemistry began in high school after carrying out research in the lab of Professor Markus Etzkorn at the University of North Carolina at Charlotte. In the fall of 2014, Alex started attending North Carolina State University in Raleigh, North Carolina as a chemistry major. While an undergraduate at NCSU, he conducted research under the advisory of Professor Joshua Pierce regarding the development of methods for the synthesis of functionalized heterocycles in the context of natural product synthesis. With the continued support and guidance from Dr. Pierce, his passion for academic research was solidified, leading him to continue his studies in graduate school. Upon completion of his studies at NCSU, Alex moved to Pasadena, California to pursue graduate studies at the California Institute of Technology under the advisory of Professor Brian Stoltz, with additional guidance from Professor William A. Goddard III. His research focused on the development of novel asymmetric transformations, with an emphasis on transition-metal catalysis and computational chemistry. Upon completion of his Ph.D. at Caltech in June 2023, Alex will continue to broaden his research horizons with a postdoctoral appointment under the guidance of Professor Abigail Doyle at the University of California at Los Angeles.