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

• Published in: Journal of organic chemistry 2019-06, Vol.84 (11), p.7372-7387
• Main Authors: Simard, Ryan D, Joyal, Mathieu, Gillard, Laura, Di Censo, Gianna, Maharsy, Wael, Beauregard, Janie, Colarusso, Pina, Patel, Kamala D, Prévost, Michel, Nemer, Mona, Guindon, Yvan
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b01075

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 reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from β-d-galactose pentaacetate in a nine-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.