Acceptor‐Reactivity‐Controlled Stereoconvergent Synthesis and Immunological Activity of a Unique Pentasaccharide from the Cell Wall Polysaccharide of Cutibacterium acnes C7

Abstract

Bacterial cell‐surface polysaccharides are involved in various biological processes and have attracted widespread attention as potential targets for developing carbohydrate‐based drugs. However, the accessibility of structurally well‐defined polysaccharide or related active oligosaccharide domains remains challenging. Herein, we describe an efficiently stereocontrolled approach for the first total synthesis of a unique pentasaccharide repeating unit containing four difficult‐to‐construct 1,2‐cis‐glycosidic linkages from the cell wall polysaccharide of Cutibacterium acnes C7. The features of our approach include: 1) acceptor‐reactivity‐controlled glycosylation to stereoselectively construct two challenging rare 1,2‐cis‐ManA2,3(NAc)2 (β‐2,3‐diacetamido‐2,3‐dideoxymannuronic acid) linkages, 2) combination use of 6‐O‐tert‐butyldiphenylsilyl (6‐O‐TBDPS)‐mediated steric shielding effect and ether solvent effect to stereoselectively install a 1,2‐cis‐glucosidic linkage, 3) bulky 4,6‐di‐O‐tert‐butylsilylene (DTBS)‐directed glycosylation to stereospecifically construct a 1,2‐cis‐galactosidic linkage, 4) stereoconvergent [2+2+1] and one‐pot chemoselective glycosylation to rapidly assemble the target pentasaccharide. Immunological activity tests suggest that the pentasaccharide can induce the production of proinflammatory cytokine TNF‐α in a dose‐dependent manner.