Synthesis of Enantiomerically Pure β‐Hydroxy Ketones via β‐Keto Weinreb Amides by a Condensation/Asymmetric‐Hydrogenation/Acylation Sequence

Abstract

An established route to enantiomerically pure β‐hydroxy ketones proceeds through the asymmetric hydrogenation of β‐keto esters, an ester/amide exchange, and the use of the resulting β‐hydroxy amide for the acylation of an organometallic compound. We shortened this route by showing that β‐keto Weinreb amides are hydrogenated with up to 99 % ee in the presence of [Me2NH2]+{[RuCl(S)‐BINAP]2(µ‐Cl)3}– (0.5 mol‐%) at room temp./5 bar. These Weinreb amides were prepared by seemingly obvious yet unprecedented condensations of lithiated N‐methoxy‐N‐methylacetamide with carboxylic chlorides (51–87 % yield). The resulting β‐hydroxy Weinreb amides were used for the acylation of organolithium and Grignard reagents. They thus gave enantiomerically pure β‐hydroxy ketones (28 examples). A selection of these compounds gave anti‐1,3‐diols after another C=O bond hydrogenation, or syn‐1,3‐diols by a Narasaka–Prasad reduction.