Synthesis of New Trans Double-Bond Sphingolipid Analogues: Δ4,6 and Δ6 Ceramides

Unsaturation was introduced at Δ4,6 and Δ6 of the sphingoid chain of naturally occurring ceramide 1 via a β-keto sulfoxide (12) and sulfone (18) derived from N-Boc-l-serine methyl ester acetonide (9), affording two novel ceramide analogues, (2S,3R)-2-octanoylamidooctadeca-(4E,6E)-diene-1,3-diol (2) and (2S,3R)-2-octanoylamidooctadec-(6E)-ene-1,3-diol (3). After C-alkylation of 12 with (E)-1-bromo-2-tetradecene (8), a trans double bond was installed by elimination of PhS(O)H, providing conjugated dienone oxazolidine 13. Reaction of 18 with 8, followed by desulfonation (Al(Hg)), afforded keto-oxazolidine 20, which bears a (E)-Δ6 double bond. The syntheses of analogues 2 and 3 from ketones 13 and 20, respectively, were completed by the following sequence of reactions:  diastereoselective reduction (NaBH4/CeCl3 or DIBAL-H), hydrolysis of the oxazolidine ring, liberation of the amino group, and installation of the N-amide group.