Copyright by Peter Andrew Webber 2008 The Dissertation Committee for Peter Andrew Webber Certifies that this is the approved version of the following dissertation: Studies Toward the Total Synthesis of Quinine Committee: Michael J. Krische, Supervisor Stephen F. Martin Philip D. Magnus Hung-wen Liu Sean Kerwin Studies Toward The Total Synthesis of Quinine by Peter Andrew Webber, B. S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May, 2008 Dedication To my wife, Erinn Webber, without her love and support this would not be possible. Acknowledgements I would like to thank Professor Michael J. Krische for allowing me the opportunity to work in his laboratory. During my graduate career, Professor Krische has provided an extremely stimulating environment which has led to my immense growth as a scientist. I am also extremely grateful to the members of the Krische group past and present for their support and memories, especially Regan Jones and Vanessa Williams for proofreading this dissertation. v Studies Toward the Total Synthesis of Quinine Publication No._____________ Peter Andrew Webber, Ph.D. The University of Texas at Austin, 2008 Supervisor: Michael J. Krische Quinine is an alkaloid natural product isolated from the bark of the cinchona tree. It has long served as a synthetic target due to its antimalarial properties. The total synthesis of quinine can be envisioned employing a recently developed catalytic enone cycloallylation methodology. This new process merges phosphine organocatalysis and transition metal catalysis. The pursuit of quinine details the first application of this novel method in organic synthesis. Herein, phosphine-catalyzed transformations of α,β-unsaturated compounds as well as a historical overview of the alkaloid target are thoroughly reviewed. The following chapters discuss both racemic and asymmetric approaches toward quinine, including the completion of a formal synthesis. Not only has the cycloallylation proved successful in this synthetic application, but this body of work has seen the development of many highly selective transformations. vi Table of Contents List of Tables ......................................................................................................... xi List of Figures...................................................................................................... xiii List of Schemes.................................................................................................... xiv Chapter 1 Historical Overview of Nucleophilic Organocatalysis via Conjugate Addition of Phosphines to α,β-Unsaturated Compounds...............................1 1.1 Introduction...............................................................................................1 1.2 Rauhut-Currier and Morita-Baylis-Hillman Reactions.............................2 1.2.1 Intramolecular Rauhut-Currier Reaction ......................................4 1.2.2 Synthetic Applications of the Intramolecular Rauhut-Currier Reaction ........................................................................................9 1.3 Modern Morita-Baylis-Hillman Applications.........................................10 1.3.1 Intermolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction ......................................................................................10 1.3.2 Intramolecular Phosphine-Catalyzed Morita-Baylis-Hillman Reaction ......................................................................................15 1.3.3 Asymmetric Morita-Baylis-Hillman Reaction............................19 1.3.4. Aza-Morita-Baylis-Hillman Reaction........................................23 1.3.5 Asymmetric Aza-Morita-Baylis-Hillman ...................................25 1.4 Expansion of Electrophilic Scope of Phosphine-Catalyzed Transformations of α,β-Unsaturated Acceptors..............................................................28 1.4.1 Phosphine-Catalyzed α-Allylation .............................................28 1.4.2 Phosphine-Catalyzed α-Alkylation.............................................31 1.4.3 Phosphine-Catalyzed α-Arylation ..............................................34 1.4.4 Other Phosphine-Catalyzed Transformation of α,β-Unsaturated Compounds .................................................................................36 1.5 Allylic Substitution of Morita-Baylis-Hillman Adducts ........................39 1.5.1 Tertiary Amine-Promoted Allylic Substitution ..........................40 1.5.2 Phosphine-Catalyzed Allylic Substitution ..................................43 1.6 Summary and Outlook ............................................................................52 1.7 References...............................................................................................53 vii Chapter 2 Historical Survey of Quinine.................................................................59 2.1 Introduction.............................................................................................59 2.2 Structural Determination.........................................................................61 2.3 The First Total Synthesis of Quinine......................................................64 2.4 Quinine Syntheses From Hoffman-La Roche.........................................66 2.4.1 Quinine via Benzylic Oxidation..................................................67 2.4.2 Quinine via Aminoepoxide Cyclization......................................68 2.4.3 Quinine via Stereoselective Carbonyl Reduction .......................68 2.4.4 Quinine via Lithiated Quinoline Aldehyde Addition..................69 2.5 Quinine via Novel Olefination Reactions...............................................70 2.6 The First Stereoselective Synthesis of Quinine ......................................71 2.7 Synthetic Approaches of the 21st Century ..............................................73 2.7.1 Synthetic Approach of Jacobsen.................................................73 2.7.2 Synthetic Approach of Kobayashi ..............................................74 2.7.3 Synthetic Approach of Williams.................................................76 2.8 Summary and Concluding Remarks .......................................................77 2.9 References...............................................................................................79 Chapter 3 Racemic Approach to Quinine ..............................................................82 3.1 First Generation Retrosynthetic Analysis ...............................................82 3.2 Cycloallylation Substrate Synthesis and Optimization...........................83 3.2.1 N-Tosyl Substrate Synthesis .......................................................83 3.2.2 Cycloallylation of N-Tosyl Substrate..........................................84 3.2.3 N-Trisyl Substrate Synthesis.......................................................85 3.2.4 Cycloallylation of N-Trisyl Substrate .........................................86 3.2.5 Additive Effect in Cycloallylation Optimization........................87 3.2.6 α,β-Unsaturated Acceptor in Cycloallylation Optimization.......90 3.3 Conjugate Reduction of Cycloallylation Adduct....................................91 3.4 Introduction of the Quinoline .................................................................96 3.5 Nucleophilic Epoxidation .......................................................................97 3.6 Aminoepoxide Cyclization .....................................................................99 3.6.1 Sulfonamide Deprotection ..........................................................99 viii 3.7 Second Generation Retrosynthetic Analysis.........................................101 3.8 Protecting Group Exchange ..................................................................102 3.9 Elaboration to Quinuclidine Cyclization ..............................................103 3.9.1 Epimerization in the Deprotection/Boc Protection Sequence...106 3.9.2 Epimerization in the Aldol/Dehydration Sequence ..................107 3.10 Allylic Alcohol Directed Epoxidation ................................................109 3.10.1 Vanadium-Catalyzed Epoxidation Mechanism Studies..........110 3.10.2 Ligand Effects in Vanadium-Catalyzed Epoxidation .............112 3.10.3 Optimization of Vanadium-Catalyzed Epoxidation ...............115 3.11 C7 Alcohol Deoxygenation Prior to Quinuclidine Formation............118 3.12 Quinuclidine Formation......................................................................120 3.12.1 Quinuclidine Formation in Previous Syntheses......................120 3.12.2 Quinuclidine Formation Optimization....................................120 3.13 C7 Alcohol Deoxygenation Following Quinuclidine Formation .......123 3.13.1 Regioselective C9 Alcohol Protection....................................123 3.13.2 Barton-McCombie C7 Alcohol Deoxygenation .....................124 3.13.3 Additional Alcohol Deoxygenations ......................................126 3.12.4 Deoxygenation via Nucleophilic Displacement at C7............128 3.13.5 Deoxygenation From MOM Ether..........................................133 3.14 Formal Synthesis.................................................................................134 3.14.1 Deoxygenation from N-Boc Series .........................................134 3.14.2 Deoxygenation from