Stereocontrolled Synthesis of α‐3‐Deoxy‐d‐manno‐oct‐2‐ulosonic Acid (α‐Kdo) Glycosides Using C3‐p‐Tolylthio‐Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides

Abstract

Abstract3‐Deoxy‐d‐manno‐oct‐2‐ulosonic acid (Kdo) is an eight‐carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α‐Kdo glycosides with a C3‐p‐tolylthio‐substituted Kdo phosphite donor. The presence of the p‐tolylthio group enhanced the reactivity, suppressed the formation of elimination by‐products (2,3‐enes), and provided complete α‐stereocontrol. A variety of Kdo α‐glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p‐tolylthio group can be efficiently removed by free‐radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one‐pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5‐branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8‐branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.