Convergent gold-catalyzed synthesis of a partially protected MTX-capped octasaccharide motif of Mycobacterium tuberculosis lipoarabinomannan

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death from a single infectious agent worldwide. The emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) strains has further compounded the need for effective intervention strategies and rapid diagnostic approaches. One of the striking features of Mtb is its remarkably thick and waxy cell wall characterized by the presence of arabinogalactan (AG), lipoarabinomannan (LAM), peptidoglycan and mycolic acids. Further, arabinose and galactose residues in AG and LAM occur in the furanose form whereas the mannose occurs in the pyranose form. The terminal mannose-cap region of Mtb LAM contains the unusual 5-deoxy-5-methylthio-D-Xylf (MTX) residue, a rare sugar that shields mannose caps from recognition by host immune receptors. The presence of MTX moiety in the terminal portion poses a significant synthetic challenge while assembling the LAM fragments. In this endeavour, we have developed a convergent strategy for the synthesis of the terminal octasaccharide moiety using silver-assisted gold-catalyzed glycosylations. A key feature of this approach is the late-stage installation of the methylthio functionality enabling the synthetic flexibility and versatility.