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

The combination of a gold(I) N-heterocyclic carbene complex and an ene-reductase (ERED) has made possible the synthesis of enantiopure beta,beta-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 alpha,beta-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. image