Encouraging progress in the ω-aspartylation of complex oligosaccharides as a general route to β-N-linked glycopolypeptides

Abstract

Described herein is a method for the joining of complex peptides to complex oligosaccharides via an N-linkage. The ω-aspartylation is conducted by coupling fully deprotected glycosylamine with a peptide containing a unique thioacid at the ω-aspartate carboxyl. In the presence of HOBT, under conditions that, in principle, allow for oxidation, complex components are combined in encouraging yields to produce structurally and stereochemically defined N-linked glycopolypeptides wherein the carbohydrate domain can be quite complex. Various mechanisms for oxidative coupling are proposed.

Figure 1

Merger of glycan and peptide domains through aspartylation; undesired base-induced aspartimide formation.

Figure 2

Proposed base-free amide β-asparagine linkage through interception of a thio-FCMA (formimidate carboxylate mixed anhydride) intermediate.

Figure 3

Thioacid peptides 7–13.

Figure 4

Oligosaccharides 14–17.

Figure 5

Possible mechanisms for HOBT-mediated oxidation.