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The Anti Selective Aldol Addition of Ketones to Aldehydes Via N-Amino Cyclic

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The Anti Selective Aldol Addition of Ketones to Aldehydes Via N-Amino Cyclic The Anti Selective Aldol Addition of Ketones to Aldehydes via N-Amino Cyclic Carbamate Chiral Auxiliaries and the Asymmetric Total Synthesis of (+)- and (-)- Mefloquine Hydrochloride by John Derrick Knight Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Don M. Coltart, Co-Supervisor ___________________________ Steven W. Baldwin, Co-Supervisor ___________________________ Jiyong Hong ___________________________ Dewey G. McCafferty Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 ABSTRACT The Anti Selective Aldol Addition of Ketones to Aldehydes via N-Amino Cyclic Carbamate Chiral Auxiliaries and the Asymmetric Total Synthesis of (+)- and (-)- Mefloquine Hydrochloride by John Derrick Knight Department of Chemistry Duke University Date:_______________________ Approved: ___________________________ Don M. Coltart, Co-Supervisor ___________________________ Steven W. Baldwin, Co-Supervisor ___________________________ Jiyong Hong ___________________________ Dewey G. McCafferty An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the Graduate School of Duke University 2012 Copyright by John Derrick Knight 2012 Abstract In the first part of this dissertation, the first asymmetric anti selective aldol addition of a ketone-derived donor that is independent of the structure of the ketone is described. This transformation is facilitated by the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Under certain conditions, this transformation not only exhibits near perfect anti selectivity and enantioselectivity but also does so via thermodynamic control. Simple manipulation of the reaction conditions allows for the O-benzylation of the prepared aldol products and the subsequent removal of the ACC auxiliary to give the β-benzyloxy ketone. Both symmetric and asymmetric ketones can be utilized, and aldol products that would otherwise be difficult if not impossible to prepare via conventional methods are able to be prepared. The second part of this dissertation describes the asymmetric total synthesis of (+)- and (-)-mefloquine hydrochloride, a potent antimalarial compound. The synthesis is based on an ACC-mediated asymmetric Darzens reaction between a α-chloro ketone and a quinoline-based aldehyde. This novel methodology gives a highly enantioenriched epoxide that can be further functionalized to prepare both enantiomers of the antimalarial drug. iv Dedicated to my parents – this accomplishment would have never occurred without their efforts in raising a son who was prepared to go far in life v Contents Abstract .......................................................................................................................................... iv List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................ x List of Schemes ............................................................................................................................ xii Acknowledgements .................................................................................................................... xv 1. N-Amino Cyclic Carbamate Hydrazones and Their Use in an Anti-Selective Asymmetric Aldol Reaction. ....................................................................................................... 1 1.1 N-Amino Cyclic Carbamate (ACC) Auxiliaries ........................................................ 1 1.1.1 Carbon-Carbon Bond Formation ........................................................................... 1 1.1.2 Ketone-Based Chiral Auxiliaries ............................................................................ 2 1.1.3 N-Amino Cyclic Carbamate Chiral Auxiliaries ................................................... 5 1.1.4 Computational Studies of ACC Hydrazones [13] ............................................... 9 1.1.5 Further Examination of Alkylation Chemistry .................................................. 14 1.2 The Aldol Reaction ...................................................................................................... 16 1.2.1 The Aldol Addition ................................................................................................ 16 1.2.2 Ketone-Based Aldol Additions Using Boron Enolates ..................................... 20 1.2.3 SAMP/RAMP Aldol Reactions ................................................................................ 24 1.2.4 Organocatalytic Aldol Additions ............................................................................ 27 1.3 ACC-Mediated Aldol Reaction ................................................................................. 31 1.3.1 Synthesis of ACC 1.13 ............................................................................................ 31 1.3.2 Initial Experiments ................................................................................................. 34 vi 1.3.3 Preliminary Mechanistic Studies ......................................................................... 40 1.3.4 Stability of Syn and Anti Aldol Products ............................................................ 44 1.3.5 Auxiliary Removal and O-Protection .................................................................. 46 1.3.6 Unsymmetrical Ketone Systems .......................................................................... 51 1.3.7 Enolizable Aldehydes and Ketones ..................................................................... 54 1.4 Conclusion .................................................................................................................... 55 1.5 Experimental Section .................................................................................................. 56 2. Asymmetric Total Synthesis of (+)- and (-)-Mefloquine Hydrochloride from N-Amino Cyclic Carbamate (ACC) Hydrazones ..................................................................................... 92 2.1 Malaria & Mefloquine Hydrochloride ........................................................................ 92 2.1.1 Malaria ........................................................................................................................ 92 2.1.2 Treatment of Malaria ................................................................................................ 95 2.1.3 Mefloquine .................................................................................................................. 97 2.1.4 Prior Syntheses of Mefloquine Hydrochloride ................................................... 100 2.1.5 Single Enantiomer Drugs ....................................................................................... 106 2.2 Asymmetric Darzens Reaction of α-Chloro Ketones .............................................. 108 2.2.1 The Darzens Reaction ............................................................................................. 108 2.2.2 Asymmetric Darzens Reactions of α-Halo Ketones with Aldehydes .............. 111 2.4 Efforts Towards the Synthesis of (+)-Mefloquine Hydrochloride ......................... 115 2.4.1 Purpose ..................................................................................................................... 115 2.4.2 Initial Reactions ....................................................................................................... 116 2.4.3 Initial ACC-Mediated Darzens Reactions and Stereochemical Outcome ....... 120 vii 2.4.4 Stereochemical Model ............................................................................................. 125 2.4.5 Subsequent Reactions ............................................................................................. 128 2.4.6 Baeyer-Villiger and Further Reactions ................................................................. 132 2.4.7 Azido-Wittig Olefination and Cyclization ........................................................... 136 2.4.8 Completion of Synthesis ......................................................................................... 139 2.5 Synthesis of (-)-Mefloquine Hydrochloride .............................................................. 141 2.6 Sharpless Modification to the Synthetic Route of (+)-Mefloquine Hydrochloride ............................................................................................................................................... 142 2.7 Conclusion ..................................................................................................................... 143 2.8 Experimental Section ................................................................................................... 144 Appendix – X-Ray Crystallography Data .............................................................................. 165 Bibliography .............................................................................................................................. 171 Biography ................................................................................................................................... 180 viii List of Tables Table 1. Initial alkylation of 3-pentanone using ACC
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