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Dynamics and Catalytic Resolution of Selected Chiral Organolithiums Timothy Kum Beng University of Arkansas, Fayetteville

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Dynamics and Catalytic Resolution of Selected Chiral Organolithiums Timothy Kum Beng University of Arkansas, Fayetteville University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 12-2011 Dynamics and Catalytic Resolution of Selected Chiral Organolithiums Timothy Kum Beng University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Analytical Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Beng, Timothy Kum, "Dynamics and Catalytic Resolution of Selected Chiral Organolithiums" (2011). Theses and Dissertations. 212. http://scholarworks.uark.edu/etd/212 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. DYNAMICS AND CATALYTIC RESOLUTION OF SELECTED CHIRAL ORGANOLITHIUMS DYNAMICS AND CATALYTIC RESOLUTION OF SELECTED CHIRAL ORGANOLITHIUMS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By Timothy Kum Beng University of Buea Bachelor of Science in Chemistry, 2001 East Tennessee State University Master of Science in Chemistry, 2004 December 2011 University of Arkansas ABSTRACT One of the most important developments of the last decade has been the emergence of new methods to dynamically resolve racemic organolithiums using stoichiometric amounts of the chiral ligand. When this concept is implemented successfully, it obviates the need for covalently attached chiral auxiliary based methods, asymmetric deprotonation, and asymmetric synthesis of a precursor stannane as ways to access enantioenriched organolithium compounds for use in asymmetric synthesis. Since certain electrophiles consume the chiral ligand, it is desirable to render this process catalytic in the chiral ligand. As part of a larger study on the amenability of chiral organolithiums to a catalytic dynamic resolution, N-trimethylallyl-2-lithiopyrrolidine, N-Boc-2-lithiopiperidine, and the ethylene ketal of N-Boc-2-lithio-4-oxopiperidine were selected. The barriers to racemization and dynamic thermodynamic resolution (DTR) of these compounds were measured in the presence of various diamine ligands. Using the thermodynamic parameters to guide us, the catalytic dynamic resolution (CDR) was then investigated on both heterocycles at temperatures where racemization is much slower than resolution. Enantiomer ratios as high as 93:7 and 99:1 were achieved for N-trimethylallyl-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine respectively. The CDR of N-Boc-2-lithiopiperidine using our newly discovered ligands was applied to the highly enantioselective synthesis of several piperidine alkaloids and medicinal compounds such as conhydrine, anabasine, ropivacaine, coniine, pipecolic acid, pelletierine, epipinidinone, lupetidine, and epidihydropinidine. This dissertation is approved for Recommendation to the Graduate Council Dissertation Director: Dr. Robert E. Gawley Dissertation Committee: Dr. Bill Durham Dr. Neil Allison Dr. Matthias McIntosh Dr. Nan Zheng DISSERTATION DUPLICATION RELEASE I hereby authorize the University of Arkansas Libraries to duplicate this dissertation when needed for research and/or scholarship. Agreed Timothy Kum Beng Refused Timothy Kum Beng ACKNOWLEDGMENTS I thank my uncle, Mai Ntuh Thomas (deceased), for his moral support over the years, his willingness to sacrifice all of his savings in favor of a chance for me to pursue further studies. May his soul and those of his deceased wives rest in peace. I thank my adviser, Dr. Robert Gawley, for his encouragement and guidance through many challenging but rewarding experiments, his patience in dealing with an inexperienced laboratory student albeit with intimidating looks. I thank Drs. Neil Allison, Matt McIntosh, Nan Zheng, and Bill Durham for their willingness to serve on my graduate committee. I am very grateful to Dr. Peter Pulay for help in computational studies and analysis of kinetic data. I also thank visiting professors Dieter Seebach, Iain Coldham, Jonathan Clayden, Richmond Sarpong, Paul Williard, and Donna Blackmond for some helpful discussions. I heartily express my gratitude to Dr. Thomas Huang, Dr. Jeffrey Wardeska, and Ms Ellen Hagood for providing me with a home away from home in Johnson City, Tennessee during my demanding first year in the United States. I thank all the Gawley group members especially Abby for the helpful social and scientific discussions. I also thank Marv, KZ, Jerry, Dan, and Aaron for help in instrumentation. I appreciate the unwavering support from the special UB Chemistry class of 2001, Clarisse & Christian Muenyi, Christelle Kamga, Alain Talla, and Canisius Asimbong. It is with great pleasure that I recognize the assistance of my “mbongo-chobi”, Sarah Pursley and my step-daughter, Jasmine Elif for making life outside of the chemistry laboratory equally enjoyable. I love both of you. Finally, I give thanks to the almighty God for keeping me awake during sleepy moments. TABLE OF CONTENTS Page Chapter 1: Introduction 1.0 General background ................................................................................................... 1 1.1 Nucleophilic methods for generating chiral substituted nitrogen hetereocycles ....... 2 1.2 Electrophilic methods for inducing asymmetry in organolithiums............................ 4 1.2.1 Asymmetric deprotonation............................................................................. 6 1.2.2 Asymmetric substitution ................................................................................ 12 1.3 Racemization and configurational stability ............................................................... 19 1.4 Catalytic enantioselective deprotonation and catalytic dynamic resolution .............. 22 1.5 Statement of the problem ........................................................................................... 24 1.6 References .................................................................................................................. 25 Chapter 2: The Barriers to Enantiomerization and Dynamic Resolution of Selected α- aminoorganolithium Compounds 2.1 Introdu ction................................................................................................................ 30 2.2 Results and discussion: The case of N-Boc-2-lithiopiperidine 4 ............................... 33 2.2.1 Formation of N-Boc-2-lithiopiperidine.......................................................... 33 2.2.2 Configurational stability of 4 ......................................................................... 37 2.2.3 Racemization of 4 in the presence of TMEDA.............................................. 39 2.2.4 Kinetic order in TMEDA for racemization of 4 ............................................ 44 2.2.5 Dynamic thermodynamic resolution (DTR) of 4 ........................................... 48 2.2.6 Effect of [TMEDA] on dynamic resolution of 4 ........................................... 49 2.2.7 Effect of varying [6] on dynamic resolution of 4 .......................................... 53 2.2.8 Resolution of 4 in the presence of dilithiated diaminoalkoxide ligands ........ 55 2.2.9 Activation parameters for resolution of 4 ...................................................... 60 2.2.10 Effect of varying [10] on dynamic resolution of 4 ........................................ 63 2.2.11 Dynamic resolution of 4 in the presence of 10 and other achiral ligands...... 67 2.3 Summary and mechanistic hypotheses ...................................................................... 68 2.4 Activation parameters for resolution of the ethylene ketal of N-Boc-2-lithio-4- oxopiperidine 12 in the presence of 10 and TMEDA ................................................ 73 2.5 Activation parameters for racemization of 12 in the presence of TMEDA ............... 77 2.6 Enantiomerization of (S)-N-Boc-2-lithiopyrrolidine with (S,R)-6 ............................. 81 2.7 Dynamic thermodynamic resolution of 17 with 7 ..................................................... 83 2.8 Activation parameters for inversion of N-trimethylallyl-2-lithiopyrrolidine 20........ 86 2.9 Experimental Section ................................................................................................. 88 2.9.1 Kinetics of deprotonation of N-Boc-piperidine ............................................. 88 2.9.2 Tin-lithium exchange kinetics in the absence of a ligand .............................. 89 2.9.3 Configurational stability of 4 ......................................................................... 89 2.9.4 Racemization of 4 in the presence of TMEDA.............................................. 90 2.9.5 Kinetic order in TMEDA for racemization of 4 ............................................ 90 2.9.6 Dynamic thermodynamic resolution (DTR) of 4 ........................................... 91 2.9.7 Effect of [6] on dynamic resolution of 4........................................................ 91 2.9.8 Effect of [TMEDA] on dynamic resolution of 4 ........................................... 92 2.9.9 Progress of deprotonation of 11 ..................................................................... 92 2.9.10 Dynamic thermodynamic resolution of 12 in the presence of TMEDA ......... 93 2.9.11 Enantiomerization of S-12 in the presence of TMEDA .................................. 95 2.9.12 Synthesis of S-15............................................................................................
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