Organocatalysis using Bifunctional Aminoboronic Acids – Application to the Asymmetric Aldol Reaction

Abstract

The organocatalytic iminium activation strategy acting cooperatively with a Lewis acidic group has been applied to the development of a novel generation of proline-based aminoboronic acid catalysts.
Key steps for their synthesis included (-)-sparteine mediated asymmetric deprotonation of N-Boc-pyrrolidine, copper(I) catalysed borylation of alkylhalides and catalysed hydroboration of alkenes. The evaluation of the first proline-based aminoboronic acids is described in the context of organocatalysed aldol reactions between p-nitrobenzaldehyde and acetone. Enhanced reactivity and enantioselectivity observed in the presence of a boronate ester analogue of the catalyst resulted in further examination regarding the role of the esterification diol in these organocatalytic reactions. Notably, 11B NMR studies have been assessed, allowing the evaluation of different diols in terms of stability and Lewis acid tuning, and plausible identification of the catalytic species present.
The feasibility of the catalyst under optimised reaction conditions was demonstrated in the aldol reaction of different substrates. Extended mechanistic studies lead to the proposal of a catalytic cycle in which a highly organised transition state plays a key role for both the reactivity and enantioselectivity observed. Finally, strategies employed to further examine both reactivity and asymmetric induction of the free boronic acid catalyst are discussed, examing the carbon length chain between the secondary amine moiety and the boronic acid group of the catalyst.