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 sp 2 -iminosugar, whose preparation on a gram scale has been optimized, as the starting material. sp 2 -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.

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“…The gluco-configured glycosyl donor 13 , on his side, was prepared in eight steps on a 9 gram scale starting from 5-azido-5-deoxy-1,2-di- O -isopropylidene-α- d -glucofuranose 5 , 63 readily accessible from commercial d -glucurono-6,3-lactone (4 steps, 64% yield). 64 Reduction of the azide and carbonylation of the resulting vicinal aminodiol segment afforded the cyclic carbamate 12 .…”

“…61,62 Removal of the benzyl and isopropylidene groups by sequential catalytic (Pd/C) hydrogenation and acid hydrolysis, followed by conventional acetylation, provided the OGJ peracetate 11 (5 steps from 6, 18% overall yield, 2 grams of final compound per batch). The gluco-configured glycosyl donor 13, on his side, was prepared in eight steps on a 9 gram scale starting from 5-azido-5-deoxy-1,2-di-O-isopropylidene-α-D-glucofuranose 5, 63 readily accessible from commercial D-glucurono-6,3-lactone (4 steps, 64% yield). 64 Reduction of the azide and carbonylation of the resulting vicinal aminodiol segment afforded the cyclic carbamate 12.…”