Isothiourea-catalysed enantioselective [2,3]-sigmatropic rearrangements of allylic ammonium ylides : synthetic and mechanistic studies

Catalysis;Rearrangements (Chemistry);Thiourea;Ylides

West, Thomas H. ; Smith, Andrew David ; Smith, Andrew David

University:University of St Andrews

Department:Chemistry (School of)

关键词: Catalysis;    Rearrangements (Chemistry);    Thiourea;    Ylides;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/16675/ThomasWestPhDThesis.pdf?sequence=2&isAllowed=y

来源: DR-NTU

【 摘 要 】

The research in this thesis describes the development of an isothiourea-catalysed enantioselective [2,3]-rearrangement of allylic ammonium ylides, subsequent mechanistic and collaborative computationalstudies and the its application to the enantioselective synthesis of free α-amino esters.Chapter 1 aims to place this work in the context of the previous literature, highlighting a range ofstereoselective [2,3]-rearrangements of allylic ammonium ylides. Examples of catalytic stereoselective[2,3]-rearrangement of allylic ammonium ylides as well as state-of-the-art examples of organocatalyticenantioselective variants of the related [2,3]-Wittig rearrangement are discussed. The aims of thisresearch project are also set out.Chapter 2 describes the discovery and optimisation of the isothiourea-catalysed [2,3]-rearrangement of4-nitrophenyl ester quaternary ammonium salts (either isolated or generated in situ) to give a range ofsyn-α-amino acid derivatives in excellent yields (33-89%) and stereocontrol (up to >95:5 dr and >99%ee). This represents the first catalytic enantioselective variant of a [2,3]-rearrangement of allylicammonium ylides.Chapter 3 describes mechanistic studies. Reaction kinetic analysis by ¹⁹F NMR has allowed reactionprofiles to be built up, orders of each component to be determined and catalyst resting state to be probed.A catalytic intermediate has been observed; its constitution was proved unambiguously by¹³C and ¹⁵N isotopic labelling. Isotopic entrainment has proved the observed intermediate to be on-cycle andproductive towards catalysis. Competition kinetic isotope effects have provided detailed insight into the[2,3]-rearrangement step of the process. The effect of HOBt upon stereocontrol and the resting state ofthe catalyst have been probed through in situ¹⁹F NMR. Crossover experiments have given detailedinsight into the reversibility of each of the proposed catalytic steps. Collaborative computational workhas elucidated the origins of stereocontrol and has supported the experimentally proposed mechanism.Chapter 4 describes the application of this methodology to the enantioselective synthesis of free α-amino esters via [2,3]-rearrangement of N,N-diallyl allylic ammonium ylides. Enantio- andchemoselective [2,3]-rearrangement gave a range of N,N-diallyl α-amino esters, which could be readilyselectively mono- or bis-N-allyl deprotected. Bis-N-allyl deprotection gave a range of enantioenrichedfree α-amino esters. Selective mono-N-allyl deprotection was employed in the synthesis of afunctionalised piperidine motif.Chapter 5 summarises the work outlined in this thesis and draws conclusions, as well as giving insightinto potential future projects within the area.