Organocatalysis Empowers Synthesis of Rare D- and L-glycero-L-Heptopyranosyl Thioglycosides

Abstract

D- and L-glycero-L-Heptopyranosyl residues are essential structural motifs in glycans and glycoconjugates, yet they remain challenging to obtain from natural sources. Herein, we disclose an efficient protocol for synthesizing D- and L-glycero-L-heptopyranosyl thioglycosides, which are recognized as powerful glycosyl donors. Our strategy pivots on a C1-to-C5 switch strategy, commencing from readily accessible allyl α-C-glycosides. The key transformations include a DBU-catalyzed anomerization of easily available α-C-glycosylethanals, an imidazolidinone-catalyzed α-oxyamination of the aldehydes to install a chiral hydroxy group with high selectivity, and a decarboxylative transformation of the resulting uronic acids into the target thioglycosides. We found that the efficiency of the anomerization step is significantly influenced by the electronic nature of the protecting groups and the conformation of a sugar ring. Intriguingly, the stereoselectivity of the key oxyamination step was found to be independent of the catalyst's chirality. To demonstrate the practical application of this protocol, we synthesized three distinct thioglycosides, including 6-O-methyl-D-glycero-L-gluco-heptopyranosyl thioglycoside, L-glycero-L-galacto-heptopyranosyl thioglycoside and L-glycero-L-manno-heptopyranosyl thioglycoside from the corresponding allyl α-C-glycosides. The ready access to these glycosyl donors paves the way for synthesizing biologically relevant targets, such as Campylobacter jejuni NCTC11168 capsular oligosaccharides, septacidin/spicamycin-type nucleosides, and their analogues.

Keywords

D-/L-glycero-L-Heptopyranoses / Anomerization / Organocatalysis / β-C-Glycosylethanals / Campylobacter jejuni / Rare sugars / Oligosaccharide synthesis / C-Glycosides

RIGHTS & PERMISSIONS

2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH