Synthesis of Enantiomerically Pure [beta]-Hydroxy Ketones via [beta]-Keto Weinreb Amides by a Condensation/Asymmetric-Hydrogenation/Acylation Sequence

An established route to enantiomerically pure [beta]-hydroxy ketones proceeds through the asymmetric hydrogenation of [beta]-keto esters, an ester/amide exchange, and the use of the resulting [beta]-hydroxy amide for the acylation of an organometallic compound. We shortened this route by showing that [beta]-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 [beta]-hydroxy Weinreb amides were used for the acylation of organolithium and Grignard reagents. They thus gave enantiomerically pure [beta]-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.