Asymmetric Synthesis of Functionalised Pyrrolidines and their Application in Total Synthesis Christopher James Maddocks Doctor of Philosophy University of York Department of Chemistry December 2020 Abstract The intramolecular aza-Michael reaction has been used effectively in the synthesis of nitrogen heterocycles, with several efforts made in recent years to do so asymmetrically. The selection of the Michael acceptor can play an important role in both the rate and enantioselectivity of the reaction. The research in this thesis demonstrates how the use of a chiral phosphoric acid can catalyse the intramolecular asymmetric aza-Michael reaction of a protected amine with an α,β- unsaturated thioester. The scope of the reaction was demonstrated in the synthesis of 2,2- and 3,3-spirocyclic pyrrolidines in high yields and enantioselectivity (Scheme 1). The synthesis of an unsubstituted pyrrolidine provided the core of two natural products (R)- bgugaine and (R)-irnidine and both succumbed to total synthesis. (R)-Bgugaine was synthesized in a 33% overall yield in 6 steps while (R)-irnidine was synthesized for the first time in an overall yield of 18% over 6 steps. Scheme 1. Asymmetric synthesis of spirocyclic pyrrolidines Scheme 2. Total synthesis of (R)-bgugaine and (R)-irnidine 1 Contents Abstract ...................................................................................................................................... 0 Contents ..................................................................................................................................... 2 List of Figures ............................................................................................................................. 5 List of Schemes........................................................................................................................... 6 List of Tables ............................................................................................................................ 10 Acknowledgements .................................................................................................................. 11 Declaration ............................................................................................................................... 12 1. Introduction – The Enantioselective Synthesis of Pyrrolidines ........................................... 13 1.1. Pyrrolidines in pharmaceuticals .................................................................................... 13 1.2. Chiral pool synthesis ..................................................................................................... 15 1.3. Chiral auxiliaries ............................................................................................................ 16 1.4. Chiral lithium amide bases ............................................................................................ 19 1.5. Asymmetric transition metal catalysis .......................................................................... 22 1.5.1. Intermolecular cyclisation...................................................................................... 23 1.5.2. Intramolecular cyclisation ...................................................................................... 27 1.6. Asymmetric organocatalysis ......................................................................................... 30 1.6.1. Intermolecular cyclisation...................................................................................... 30 1.6.2. Intramolecular cyclisation ...................................................................................... 33 1.7. Asymmetric intramolecular aza-Michael reactions ...................................................... 35 2. Asymmetric synthesis of spirocyclic pyrrolidines ................................................................ 43 2.1. Comparison of the Michael acceptor reactivity ........................................................... 48 2.1.1. HPLC determination of enantiomeric ratio ........................................................... 53 2.2. Scope of the reaction for 3,3-disubstitution................................................................. 56 2.3. Scope of the reaction for 2,2-disubstitution................................................................. 59 2.4. Synthesis of an unsubstituted pyrrolidine .................................................................... 69 2.5. Functionalisation of pyrrolidines .................................................................................. 74 2.5.1. Transesterification and confirmation of stereochemistry ..................................... 74 2.5.2. Cbz de-protection .................................................................................................. 76 2.6. Summary of results ....................................................................................................... 78 2 3. Expanding the methodology ............................................................................................... 80 3.1. Di-fluorinated pyrrolidines ............................................................................................ 80 3.1.1. Previous route ........................................................................................................ 81 3.1.2. Synthesis of 2,2-difluoro precursors ...................................................................... 86 3.1.3. Synthesis of 3,3-difluoro precursors ...................................................................... 89 3.2. Methyl substitution on Michael acceptor .................................................................... 92 3.3. Summary of results ....................................................................................................... 96 4. Total Synthesis of Natural Products ..................................................................................... 97 4.1. Wittig route ................................................................................................................. 102 4.2 Liebeskind-Srogl coupling route .................................................................................. 104 4.2.1 Alcohol deoxygenation ......................................................................................... 106 4.2.2 Dithiolane synthesis .............................................................................................. 110 4.2.3 Wolff-Kishner reduction ....................................................................................... 111 4.3. Summary of results ..................................................................................................... 116 5. Desymmetrisation of Prochiral Amines ............................................................................. 117 5.1. Synthesis of Precursors ............................................................................................... 122 5.2. Asymmetric Cyclisation .............................................................................................. 123 5.2.1 Determination of stereochemistry ....................................................................... 129 6. Conclusions ........................................................................................................................ 132 7. Future work ........................................................................................................................ 134 8. Experimental ...................................................................................................................... 136 General Experimental ........................................................................................................ 136 Screening of Michael acceptors in the intramolecular aza-Michael reaction ................... 136 Synthesis of 3,3-disubstituted precursors ......................................................................... 145 Synthesis of 2,2-disubstituted precursors ......................................................................... 154 Asymmetric cyclisation of 3,3-disubstituted pyrrolidines ................................................. 174 Asymmetric cyclisation of 2,2-disubstituted pyrrolidines ................................................. 179 Asymmetric cyclisation of unsubstituted pyrrolidines ...................................................... 188 Determination of the absolute stereochemistry ............................................................... 192 Cbz deprotection ................................................................................................................ 193 Synthesis of fluorinated amines ........................................................................................ 194 Michael acceptor methyl substitution ............................................................................... 199 3 Total Syntheses of Irnidine and Bgugaine ......................................................................... 201 Desymmetrisation procedures .......................................................................................... 217 9 Appendices .......................................................................................................................... 221 9.1. HPLC data for cyclised compounds ............................................................................. 221 10. Abbreviations ................................................................................................................... 242 11. References ......................................................................................................................