Synthesis of ceramide analogues having the C(4)-C(5) bond of the long-chain base as part of an aromatic or heteroaromatic system

Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl ceramide analogues 2 and 3. The first route involve s the addition of an aryllithium or a heteroaryllithium reagent (7a or 25a, respectively) to the L-serine-derived aldehyde 4, followed by hydrolysis o f the oxazolidine, liberation of the amino group, and N-acylation. The seco nd route, which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting with 3-bromobenzaldehyde, utilizes a Heck. r eaction to afford (E)-alpha,beta -unsaturated ester 16, then osmium-catalyz ed asymmetric dihydroxylation for the introduction of the desired chirality at C-2 and C-3. Regioselective alpha -azidation of alpha -O-nosyl-beta -hy droxyester 18 with sodium azide, followed by LiAlH4 reduction of the azido and ester groups and N-acylation, complete the synthesis of arylceramide an alogue 2.