Synthesis of beta-D-Galactosyl Ceramide Methylene Isostere

The methylene isostere of the glycosphingolipid beta-D-galactosyl N-palmitoyl C(18) ceramide has been synthesized by a linear reaction sequence starting from a beta-linked D-galactopyranosyl aldehyde. First, this sugar aldehyde was converted into a methylenephosphorane which in turn was coupled with N-Boc serinal acetonide. The double bond of the resulting olefin was reduced and the oxazolidine ring was cleaved and oxidized to give a C-glycosyl N-Boc alpha-amino butanal (three-carbon chain elongation). Then, an additional C(15) carbon chain was installed by addition of lithium 1-pentadecyne to the above glycosyl amino aldehyde. The syn/anti ratio (70:30) of the resulting mixture of amino alcohols was reversed (5:95) by an oxidation-reduction sequence to achieve the same stereochemistry as in the hydrophilic head of D-erythro-sphingosines. The major product was subjected to the reduction of the triple bond with LiAlH(4) to give the olefin with E geometry. Finally the N-amide group was installed by reaction with palmitoyl chloride and the O-benzyl protective groups of the sugar moiety were removed by treatment with lithium in liquid NH(3)-THF. The final product was characterized as the O-acetyl derivative.