Stereoselective C-Glycoside Formation with 2-O-Benzyl-4,6-O-benzylidene Protected 3-Deoxy Gluco- and Mannopyranoside Donors: Comparison with O-Glycoside Formation

Abstract

Unlike alcohols, the reaction of C-nucleophiles with 2-O-benzyl-4,6-O-benzylidene-protected gluco- and mannopyranosyl thioglycosides is highly stereoselective providing the α-C-glycosides in the gluco-series and the β-C-glycosides in the manno-series. Conformational analysis of nucleophilic attack of putative intermediate glycosyl oxocarbenium ions suggests that the observed selectivities for C-glycoside formation can be explained by preferential attack on the opposite face of the oxocarbenium to the C2-H2 bond and that eclipsing interactions with this bond are the main stereodetermining factor. It is argued that the steric interactions in the attack of alcohols (sp3-hybridized O) and of typical carbon-based nucleophiles (sp2 C) on oxocarbenium ions are very different, with the former being less severe, and thus that there is no a priori reason to expect O- and C-glycosylation to exhibit parallel stereoselectivities for attack on a given oxocarbenium ion.

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…The unexpected partial formation of the trans -fused tricyclic product from the cyclization reaction prompted the authors to suggest 19 that any intermediate oxocarbenium ion must be able to access the B 2,5 conformation consistent with an earlier suggestion from the same laboratory 18 and a subsequent one from the Bols group 16 (Scheme 3). …”

“…2) and advocated by Crich and coworkers in explanation of their experimental results (vide supra). 18–19 …”

The influence of acceptor nucleophilicity on the glycosylation reaction mechanism

“…71 For the weak C - and D -nucleophiles, which react in a highly selective β-manner, this latter pathway does not play a major role, and these nucleophiles attack the B 2,5 -oxocarbenium ion 16 selectively from the top face. 40,72 …”

Trifluoromethanesulfonate Anion as Nucleophile in Organic Chemistry

“…As reported previously, the cognate 4,6- O -benzylidene oxocarbenium ion does access the B 2,5 conformation 72 and is β-selective in its reactions with C-nucleophiles. 73 However, the evidence for the nucleophilicity of perchlorate toward cation-like electrophiles exceeds even that for triflate 26 suggesting the intermediacy of a α-glycosyl perchlorate in the triflate-free reaction. Indeed, glycosyl perchlorates were observed spectroscopically more than two decades before glycosyl triflates.…”