Stereoselective Assembly of Complex Oligosaccharides Using Anomeric Sulfonium Ions as Glycosyl Donors

Abstract

The development of selectively protected monosaccharide building blocks that can reliably be glycosylated with a wide variety of acceptors is expected to make oligosaccharide synthesis a more routine operation. In particular, there is an urgent need for the development of modular building blocks that can readily be converted into glycosyl donors for glycosylations that give reliably high 1,2-cis-anomeric selectivity. We report here that 1,2-oxathiane ethers are stable under acidic, basic, and reductive conditions making it possible to conduct a wide range of protecting group manipulations and install selectively removable protecting groups such as levulinoyl (Lev) ester, fluorenylmethyloxy- (Fmoc) and allyloxy- (Alloc) carbonates, and 2-methyl naphthyl ethers (Nap). The 1,2-oxathiane ethers could easily be converted into bicyclic anomeric sulfonium ions by oxidization to sulfoxides and arylated with 1,3,5-trimethoxybenzene. The resulting sulfonium ions gave high 1,2-cis anomeric selectivity when glycosylated with a wide variety of glycosyl acceptors including properly protected amino acids, primary and secondary sugar alcohols and partially protected thioglycosides. The selective protected 1,2-oxathianes were successfully employed in the preparation of a branched glucoside derived from a glycogen-like polysaccharide isolated form the fungus Pseudallescheria boydii, which is involved in fungal phagocytosis and activation of innate immune responses. The compound was assembled by a latent-active glycosylation strategy in which an oxathiane was employed as an acceptor in a glycosylation with a sulfoxide donor. The product of such a glycosylation was oxidized to a sulfoxide for a subsequent glycosylation. The use of Nap and Fmoc as temporary protecting groups made it possible to install branching points.

Stereocontrolled 1,2-cis glycosylation as the driving force of progress in synthetic carbohydrate chemistry

“…39 This was certainly inspired by their earlier work on chiral auxiliaries and inherent drawbacks related to the necessity of obtaining pure enantiomeric substrates. Additional inspiration came from work by Turnbull et al .…”

Sulfonium Ions as Reactive Glycosylation Intermediates

“…4c) (14,15). They prepared β-sulfonium ion 14 by the action of trifluoromethanesulfonic anhydride (Tf 2 O), 1,3,5-trimethoxybenzene, and glycosyl sulfoxide 13 having the decalin structure.…”

Mechanism of Glycosylation of Anomeric Sulfonium Ions

“…11 The methodology was extended to a latent-active iterative glycosylation strategy for the stereoselective assembly of highly branched glycogen-like glycans that had been implicated in innate immune responses. 12 Bicyclic anomeric sulfonium ions can also be formed by arylation of 1,2-oxathiane ketals, which in turn, can easily be prepared from a thioglycoside (Scheme 1b). 13 …”