Modular Synthesis of Neisseria meningitidis Lipooligosaccharide Inner Core Oligosaccharide Library to Identify Broadly Reactive Antigenic Epitopes

Neisseria meningitidis remains a global health threat and a leading cause of bacterial meningitis, with six serogroups responsible for most epidemic outbreaks. The inner core of its lipooligosaccharide (LOS) is highly conserved across serogroups and represents a promising target for a broad‐spectrum vaccine development. However, its exploration has been limited by the structural complexity of inner core and the lack of homogeneous oligosaccharide library for systematic antigenicity evaluation. Herein, we report the first total synthesis of a highly branched and sterically crowded inner core hexasaccharide via a strategically designed stereoconvergent [(2+3)+1] assembly approach. Central to this achievement is the rational tuning of glycosyl donor–acceptor reactivity, which enables the efficient construction of the sterically congested and challenging α‐Hep‐(1→5)‐Kdo glycosidic linkage. Additionally, a structurally defined 18‐membered library of inner core oligosaccharides was assembled by a modular synthesis approach. Glycan microarray screening with rabbit antisera raised against six epidemic serogroups suggests that three oligosaccharides exhibit broadly cross‐reactive antigenicity, which provides the candidate epitopes for the development of a broad‐spectrum meningococcal vaccine.