Neighbouring group participation vs. addition to oxacarbenium ions: studies on the synthesis of mycobacterial oligosaccharides

Abstract

Neighbouring group participation is frequently used to control the stereoselectivity of chemical reactions. Herein, we investigate the use of neighbouring group participation for the synthesis of disaccharides incorporating the mycobacterial sugar methylthioxylose. A bicyclic thioglycoside was activated by methylation to generate a methylsulfonium group that would act both as the anomeric leaving group, and also provide the methylsulfide group in the product. Model reactions indicated that the bicyclic intermediate would also act as a participating group to direct the acceptor alcohol to the lower alpha-face of the sugar. While the key sulfonium intermediate could be detected in the reaction mixture, the glycosylation reaction proceeded with moderate stereoselectivity, apparently via an S(N)1-type mechanism. Density functional theory calculations were used to compare our methylthioxylose sulfonium ion with a trans-decalin-like sulfonium ion described by Boons and co-workers to be an alpha-directing participating group (J. Am. Chem. Soc. 2005, 127, 12090). Our studies show that even where a bicyclic sulfonium ion can be detected in the reaction mixture, caution should be applied before invoking it as an intermediate on the reaction pathway.

Sulfonium Ions as Reactive Glycosylation Intermediates

“…Although sulfonium ions of furanosides 58 have been used for the 1,2-cis selective glycosylation, the stereoselectivity of the thusobtained disaccharide 60 was moderate (α:β = 5:1) (Scheme 8). In this case, it was proposed that sulfonium ions work as a precursor of the glycosyl cation (oxonium ion), which is the real intermediate of glycosylation (24).…”

“…The "superdisarmed" donor is less reactive than the typical "disarmed" donor, which has 2,3,4,6-tetra-O-benzoyl protecting groups, because the 3,4,6-O-tribenzoyl work as electron-withdrawing groups and the 2-O-benzyl group does not work as a neighboring group (23). Turnbull and co-workers have already reported sulfonium ions of furanosides by the direct method using MeOTf (24).…”

The intriguing dual-directing effect of 2-cyanobenzyl ether for a highly stereospecific glycosylation reaction

“…On the other hand, neighbouring hydroxyl groups of the donor could show influence on the anomeric preference through their protecting substituents, many of which were routinely exploited in various glycosylation methods, such as 2-O-ester-type [8][9][10] or 2-O-picolyl-type [11][12][13] for 1,2-trans glycosylation, and several sulfide auxiliaries [14][15][16][17][18] as well as intramolecular aglycon delivery IAD-type 19,20 for 1,2-cis glycosylation reactions.…”

Chemical Biology: What is Its Role in Drug Discovery?

“…The use of the NPPOC photolabile protecting group in the synthesis of glycopyranosides has been explored (Yi et al, 2009) and the synthesis of pseudooligosacchasrides using cross-metathesis methods (Ronchi et al, 2009) and pseudodisaccharides based on neamine have also been described (Pang et al, 2009). Several studies on the control of glycosylation reactions have also been reported (Belen Cid et al, 2009;Xiaoning Li et al, 2009;Stalford et al, 2009). Studies towards the synthesis of C-glycosyl amino acids have been described using C-glycosyl 2-iodopropanes and the chiral auxiliary camphorsultam glyoxylic oxime ester (Bragnier et al, 2009).…”