Chemical Synthesis of a Highly Branched Hexasaccharide Fragment from Bordetella pertussis Lipooligosaccharide

Abstract

An expedient synthesis of a core hexasaccharide fragment from Bordetella pertussis lipooligosaccharide has been achieved via a linear glycosylation strategy. Multiple challenges met in the synthesis include the stereoselective formation of two 1,2-cis-glycosidic linkages and the construction of sterically crowded 2,7- and 3,4-disubstituted heptoside subunits. Substituent-directing glycosylation approaches such as the remote participation effect of the 6-O-acyl group and the stereocontrolling effect of the 6-O-tert-butyldiphenylsilyl group were utilized for the synthesis of the desired 1,2-cis-gluco- and 1,2-cis-2-aminoglucoside moieties, respectively. The 2,7-branched heptoside structure was constructed through a 2-O and then 7-O glycosylation sequence. More importantly, the key 3,4-branched framework was established through a 3 + 1 + 1 + 1 assembly method that involved the sequential coupling of the trisaccharide alcohol with three monosaccharide building blocks, ultimately forming the entire molecular skeleton. The obtained hexasaccharide 1, carrying an aminopropyl linker at the reducing end, can be covalently conjugated to a carrier protein for further immunological investigations.