De novo synthesis of a methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide

A general strategy toward the synthesis of C-ketosides of N-acetylneuramini c acid (Neu5Ac) has been developed and successfully applied to the synthesi s of methylene-bridged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2. The key str ategic element of this novel approach is a stereoselective, 6-exo-trig sele ctive, electrophilic cyclization of the appropriate open chain precursor 4 by means of phenylselenyl triflate. The open chain precursor was formed by the addition of lithiated iodide 18 accessible from D-galactose to open cha in aldehyde 5a obtained from n-glucono-delta -lactone by chain elongation. Subsequent C-1-incorporation using Tebbe-reagent? formation of a cyclic car bonate, and deprotection of the two isopropylidene ketals afforded tetrol 4 which, upon treatment with phenylselenyl triflate, was stereoselectively c yclized in a B-exo-trig selective manner. A selena-Pummerer rearrangement, oxidation, and esterification readily led to methyl ester 37 which, after d eacetylation, could be regioselectively tetrabenzoylated with benzoyl cyani de. Triflate activation of the axial hydroxyl group in 40 and nucleophilic displacement by azide ion with inversion of configuration afforded azide 41 , which was reduced with hydrogen and Pearlman's catalyst. Concomitant remo val of the benzyl ethers and subsequent saponification of all ester moietie s successfully completed the de novo synthesis of the desired methylene bri dged Neu5Ac-alpha-(2,3)-Gal C-disaccharide 2.