Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

Abstract

A simple and efficient method for the stereoselective synthesis of nojirimycin α-C-glycoside derivatives has been developed using a bicyclic carbamate-type sp2-iminosugar, whose preparation on a gram scale has been optimized, as the starting material. sp2-iminosugar O-glycosides or anomeric esters serve as excellent precursors of acyliminium cations, which can add nucleophiles, including C-nucleophiles. The stereochemical outcome of the reaction is governed by stereoelectronic effects, affording the target α-anomer with total stereoselectivity. Thus, the judicious combination of C-allylation, carbamate hydrolysis, cross-metathesis, and hydrogenation reactions provides a very convenient entry to iminosugar α-C-glycosides, which have been transformed into N,C-biantennary derivatives by reductive amination or thiourea-forming reactions. The thiourea adducts undergo intramolecular cyclization to bicyclic iminooxazolidine iminosugar α-C-glycosides upon acid treatment, broadening the opportunities for molecular diversity. A preliminary evaluation against a panel of commercial glycosidases validates the approach for finely tuning the inhibitory profile of glycomimetics.