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...

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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
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container_issue 11
container_start_page 7372
container_title Journal of organic chemistry
container_volume 84
creator 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
description 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.
doi_str_mv 10.1021/acs.joc.9b01075
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title Synthesis of Sialyl LewisX Glycomimetics Bearing a Bicyclic 3‑O,4‑C‑Fused Galactopyranoside Scaffold
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