Synthesis of Both Enantiomers of Diastereomeric 4‐Fluoro‐4,5‐Dihydroceramides

Abstract

Abstract Two diastereomeric enantiopure 4‐fluoro‐4,5‐dihydroceramides with the natural D ‐ erythro configuration at the 2‐ and 3‐carbon atoms have been synthesized in an enantioselective eleven‐step sequence. The key step of the synthesis was a diastereoselective asymmetric Sharpless dihydroxylation of ethyl trans ‐4‐fluorooctadec‐2‐enoate ( 8 ) with AD‐mix‐β to afford the D ‐ erythro arrangement. The diastereomers of the other enantiomeric series were synthesized analogously with the use of AD‐mix‐α. In all cases, the nitrogen heteroatom was introduced into the 2‐position by regio‐ and stereoselective ring opening of cyclic sulfates 13 and 14 with azide. Staudinger reduction, acylation of the intermediary formed amino group, chromatographic separation of the diastereomers and chemoselective reduction of the ester functionality with sodium borohydride in the presence of methanol afforded both title compounds in an enantiopure form. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)