Synthesis of Sialyl LewisX Glycomimetics Bearing a Bicyclic 3-O, 4-C-Fused Galactopyranoside Scaffold.

Reported herein is the synthesis of sialyl Lewis(x) analogues bearing a trans-bicyclo[4.4.0] dioxadecane-modified 3-O,4-C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position. This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from beta-D-galactose pentaacetate in a nine-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed formation of the acetylenic alpha-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.