Lipoarabinomannan (LAM) from the Mycobacterium
tuberculosis cell envelope represents important targets
for the development of
new therapeutic agents against tuberculosis, which is a deadly disease
that has plagued mankind for a long time. However, the accessibility
of long, branched, and complex lipoarabinomannan over 100-mer remains
a long-standing challenge. Herein, we report the modular synthesis
of mannose-capped lipoarabinomannan 101-mer from the M. tuberculosis cell wall using a one-pot assembly
strategy on the basis of glycosyl ortho-(1-phenylvinyl)benzoates
(PVB), which not only accelerates the modular synthesis but also precludes
the potential problems associated with one-pot glycosylation with
thioglycosides. Shorter sequences including 18-mer, 19-mer, and 27-mer
are also synthesized for in-depth structure–activity relationship
biological studies. Current synthetic routes also highlight the following
features: (1) streamlined synthesis of various linear and branched
glycans using one-pot orthogonal glycosylation on the combination
of glycosyl N-phenyltrifluoroacetimidates, glycosyl ortho-alkynylbenzoates, and glycosyl PVB; (2) highly stereoselective
construction of 10 1,2-cis-arabinofuranosyl linkages
using 5-O-(2-quinolinecarbonyl)-directing 1,2-cis-arabinofuranosylation via a hydrogen-bond-mediated aglycone
delivery strategy; and (3) convergent [(18 + 19) × 2 + 27] one-pot
synthesis of the 101-mer LAM polysaccharide. The present work demonstrates
that this orthogonal one-pot glycosylation strategy can highly streamline
the chemical synthesis of long, branched, and complex polysaccharides.