Stereoselective Preparation of Ceramide and Its Skeleton Backbone Modified Analogues via Cyclic Thionocarbonate Intermediates Derived by Catalytic Asymmetric Dihydroxylation of α,β-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)-α,β-unsaturated ester 5a−c as the chiral induction step, with the desired configurations in the products 1a−c, 2a, and 13 being generated by regioselective azide substitution at the α position of α,β-dihydroxyesters 6a−c via a cyclic thionocarbonate intermediate. Azido esters 10a−c are converted to the corresponding ceramides 1a−c 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, propargylic α-azido-β-hydroxyester 10a is converted to d-erythro-sphingosine 2a via simultaneous reduction of the triple bond, azido, and ester functional groups with LiAlH4, providing a highly concise and practical four-s...