Bifunctional iminophosphoranes as catalysts for enantioselective prototrophic shifts

This thesis describes investigations into the application of the bifunctional iminophosphorane (BIMP) catalyst previously developed in the Dixon group to new transformations in superbase catalysis. Chapter 2 summarises the development of the enantioselective [1,3]-prototropic shifts of β,γ-unsaturated cyclohexenones into their chiral conjugated counterparts. The reaction proceeds via an initial rapid and reversible deprotonation followed by a rate- and stereo-determining protonation at the γ-position of the extended enolate which occurs in up to 99% ee and up to 99% yield. The reaction was found to be broadly applicable to a range of β,γ-unsaturated cyclohexenones synthesised from Hagemann’s ester and, by tuning the catalyst’s basicity and hydrogen-bond donor ability, the transformation could be carried out on more challenging substrates synthesised by [Co]-catalysed Diels-Alder reactions. The products were derivatised further while maintaining enantiopurity, we also demonstrated the transformation’s relevance to a key building block of (−)-reserpine and (−)-penitrem D. The mechanistic aspects of the reaction were probed by both deuterium labelling experiments as well as computational work in collaboration with Prof. Robert Paton and Dr. Luis Simón. Adhering to the same theme, chapter 3 describes the development of a novel BIMP catalysed strain release concept to synthesise chiral cyclopropanes. By strategic placement of an electron withdrawing group on a cyclopropene ring, γ-deprotonation occurs readily and the consequential extended enolate protonates asymmetrically at the α-position mirroring the prototropic shift of β,γ-unsaturated cyclohexenones. The reaction occurs rapidly with high levels of selectivity (up to 99% ee) and is applicable to a range of carbonyl species including esters and amides and, by tuning the catalyst scaffold, ketones. By structural modification of the cyclopropene as well as the iminophosphorane the transformation’s applicability to the synthesis of pyrethroid-type molecules such as permethrin was demonstrated.