A stereocontrolled, efficient synthetic route to bioactive sphingolipids: Synthesis of phytosphingosine and phytoceramides from unsaturated ester precursors via cyclic sulfate intermediates

An efficient and highly enantioselective method for the preparation of D-ri bo- and L-lyxophytosphingosines (1a,b, respectively) and phytoceramides (2a ,b) has been developed. The key steps in the syntheses are as follows: (i) osmium-catalyzed asymmetric dihydroxylation of 4-O-protected (E)-alpha,beta -unsaturated ester 5 (generated by dihydroxylation of 1-hexadecene, follow ed by oxidation to the aldehyde and Horner-Wadsworth-Emmons olefination), ( ii) conversion to cyclic sulfate intermediate 7, and (iii) regioselective a lpha -azidation of 7. Reduction of 4-O-protected 2-azido ester 8 via alpha -azidolactone 9 afforded phytosphingosine 1a. Staudinger reduction of the a zido group of 8, followed by in situ N-acylation in aqueous media and reduc tion of the ester functionality with NaBH4/LiBr, provided phytoceramide 28. By using a similar approach, phytosphingosine Ib was synthesized. D-erythr o-4,5-Dihydrosphingosine 1c and D-erythro-4,5-dihydroceramide 2c were synth esized in high yield from 1-hexadecanol via cyclic sulfate intermediate 15. The desired configurations at C-2, C-3, and C-4 of the sphingoid chain can be accessed readily by the route described here.