Chemical Synthesis of a Highly Branched Hexasaccharide Fragment from <i>Bordetella pertussis</i> Lipooligosaccharide

An expedient synthesis of a core hexasaccharide fragment from <i>Bordetella pertussis</i> lipooligosaccharide has been achieved via a linear glycosylation strategy. Multiple challenges met in the synthesis include the stereoselective formation of two 1,2-<i>cis</i>-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-<i>O</i>-acyl group and the stereocontrolling effect of the 6-<i>O</i>-<i>tert</i>-butyldiphenylsilyl group were utilized for the synthesis of the desired 1,2-<i>cis</i>-gluco- and 1,2-<i>cis</i>-2-aminoglucoside moieties, respectively. The 2,7-branched heptoside structure was constructed through a 2-<i>O</i> and then 7-<i>O</i> 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 <b>1</b>, carrying an aminopropyl linker at the reducing end, can be covalently conjugated to a carrier protein for further immunological investigations.