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

Reported herein is the synthesis of sialyl LewisX 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 reac-tion that has been evaluated both experimentally and by DFT calculations. The cyclization precursors are obtained from β-D-galactose pentaacetate in a 9-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.