Stereoselective preparation of ceramide and its skeleton backbone modifiedanalogues via cyclic thionocarbonate intermediates derived by catalytic asymmetric dihydroxylation of alpha,beta-unsaturated ester precursors

A novel and efficient synthetic route to ceramide 1a and skeleton backbone modified ceramide analogues 1b,c is reported. The syntheses utilize osmium- catalyzed asymmetric dihydroxylation of (E)-alpha,beta -unsaturated ester 5 a-c as the chiral induction step, with the desired configurations in the pr oducts 1a-c, 2a, and 13 being generated by regioselective azide substitutio n at the alpha position of alpha,beta -dihydroxyesters 6a-c via a cyclic th ionocarbonate intermediate. Azido esters 10a-c are converted to the corresp onding ceramides la-e by a sequence of azide reduction, N-acylation, ester reduction (NaBH4/LiBr), and Birch reduction of the triple bond (Li, EtNH2). These seven-to eight-step syntheses afford the target compounds 1a-c with excellent stereocontrol and in 30-42% overall yields. Furthermore, propargy lic alpha -azido-beta -hydroxyester 10a is converted to D-erythro-sphingosi ne 2a via simultaneous reduction of the triple bond, azido, and ester funct ional groups with LiAlH4, providing a highly concise and practical four-ste p synthesis of this key naturally occurring sphingolipid. The L-erythro ste reoisomers are also available in high enantiomeric purity by the method des cribed herein.