A General Strategy to Enantiomerically Pure Aliphatic and Olefinic Ketone Cyanohydrins by Stereoselective Alkylation of Umpoled Aldehyde Derivatives

Abstract

We present the first general synthesis of optically pure (R)- and (S)-ketone cyanohydrins with olefinic and aliphatic substituents. Consecutive condensations of POCl3 with pseudoephedrine (1) and racemic crotonaldehyde cyanohydrin (3, R = 1-propenyl) lead to the respective cyanohydrin phosphate 4c. Deprotonation, followed by highly stereoselective alkylation and a single chromatographic purification step, afford diastereomerically pure ketone cyanohydrin phosphates 5a−e. From these, enantiomerically pure tertiary cyanohydrins 6a−e can be obtained by mild Lewis acid-assisted hydrolysis. Pseudoephedrine is simultaneously recovered without loss of optical purity. The unsaturated alkylation products 5a−d are readily hydrogenated with diimide to aliphatic cyanohydrin phosphates 5f−i, which can be cleaved to furnish the free optically pure cyanohydrins 6f−i. Thus a broad variety of both saturated and unsaturated ketone cyanohydrins with R > Et becomes accessible in optically pure form for the first time. The free cyanohydrins are easily converted to optically pure α-branched α-hydroxy acids.