β,β‐Disubstituted Alkan‐2‐ones from Propargylic Alcohols Combining a Meyer‐Schuster Rearrangement and Asymmetric Alkene Bioreduction

Abstract

The combination of a gold(I) N‐heterocyclic carbene complex and an ene‐reductase (ERED) has made possible the synthesis of enantiopure β,β‐disubstituted ketones in a one‐pot concurrent approach. The protocol consists of the Meyer‐Schuster rearrangement of racemic propargylic tertiary alcohols using [1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene]‐[bis(trifluoromethanesulfonyl)‐imide]gold(I) (IPrAuNTf₂), followed by an asymmetric alkene reduction of the α,β‐unsaturated ketone intermediate using the Zymomonas mobilis ERED (NCR‐ERED). The chemoenzymatic cascade was optimised with a model substrate, where E/Z‐isomers both generated the (R)‐ketone, which was rationalised using in silico molecular docking experiments. The cascade was then applied towards the production of a series of (R)‐4‐substituted‐alkan‐2‐ones in enantiopure form in a straightforward manner.