[Au]/[Ag]-catalysed expedient synthesis of branched heneicosafuranosyl arabinogalactan motif of Mycobacterium tuberculosis cell wall

Abstract

Emergence of multidrug-resistant and extreme-drug-resistant strains of Mycobacterium tuberculosis (MTb) can cause serious socioeconomic burdens. Arabinogalactan present on the cellular envelope of MTb is unique and is required for its survival; access to arabinogalactan is essential for understanding the biosynthetic machinery that assembles it. Isolation from Nature is a herculean task and, as a result, chemical synthesis is the most sought after technique. Here we report a convergent synthesis of branched heneicosafuranosyl arabinogalactan (HAG) of MTb. Key furanosylations are performed using [Au]/[Ag] catalysts. The synthesis of HAG is achieved by the repetitive use of three reactions namely 1,2-trans furanoside synthesis by propargyl 1,2-orthoester donors, unmasking of silyl ether, and conversion of n-pentenyl furanosides into 1,2-orthoesters. Synthesis of HAG is achieved in 47 steps (with an overall yield of 0.09%) of which 21 are installation of furanosidic linkages in a stereoselective manner.

A Versatile Synthesis of Pentacosafuranoside Subunit Reminiscent of Mycobacterial Arabinogalactan Employing One Strategic Glycosidation Protocol

“…The glycosidation between diol 8 and acceptor 32 was performed affording an inseparable mixture of pentasaccharides 35 . Earlier reports on the synthesis of pentasaccharide motifs indicated that the diastereomeric ratio would likely result from the C‐5 position of the aglycon due to its inherently more reactive nature compared with the C‐3‐OH . Temperature controlled glycosidations and reversing the addition sequence of glycosyl donor and acceptor did not improve the diastereoselectivity and, more frustratingly, the isomers could not be separated.…”

“…Now,t he stage was set for the gold/silver-catalysed glycosidation in a{ 2 2 + 1} fashion.T he glycosidation between diol 8 and acceptor 32 was performed affording an inseparable mixture of pentasaccharides 35.E arlier reports on the synthesis of pentasaccharidem otifs indicated that the diastereomericr atio would likely result from the C-5 position of the aglycon due to its inherently more reactive nature compared with the C-3-OH. [18,[21][22][23] Temperature controlled glycosidations and reversing the addition sequence of glycosyl donor and acceptor did not improvet he diastereoselectivity and, more frustratingly, the isomersc ould not be separated. Hence, sequential addition of the disaccharide was investigated and installation at the C-5 positionp rior to the C-3 positionw ould be beneficial because the mixtureo fc ompounds, if any,w as expected to be easy to purify.W ith this idea, orthoester 33 was saponified, monosilylated using 1.1 equivalent of TBDPS-Cl at 0 8Ca nd installation of the levulinoate protectionw as carried-out at the C-3 position to afford 36 in 61 %o ver three steps.…”

“…Nevertheless, synthesis of polylactosamine with 25‐saccharide residues by Ogawa and O ‐specific polysaccharide containing 24‐residues by Pozsgay were the conspicuous early efforts towards the synthesis of large oligomers. Of mycobacterial origin, mannose‐capped LAM fragment by Fraser–Reid, independent syntheses of docosaarabinofuranoside by Lowary and Ito, heneicosasaccharide (21‐residues) of LAM and AG syntheses by our group are some of the notable efforts in the literature that describe synthesis of large oligosaccharides. Lowary invoked salient features of trichloroacetamidates and thiotolyl donor chemistry, whereas Ito utilised thioglycosides for assembling the docosasaccharide .…”

Modular Synthesis of Nona‐Decasaccharide Motif from Psidium guajava Polysaccharides: Orthogonal One‐Pot Glycosylation Strategy

“…The regio‐ and stereochemical issues are major challenges during glycans synthesis, and results in a time‐consuming and tedious process for carbohydrate synthesis . Indeed, examples of the synthesis of long, branched, and complex carbohydrate chains with over 15 units are still limited . Therefore, development of efficient strategies for the assembly of long, branched, and complex carbohydrate sequences is direly needed and remains one of the most challenging tasks for synthetic chemists.…”

Expedient Synthesis of a Linear Nonadecaarabinofuranoside of the Mycobacterium tuberculosis Cellular Envelope

“…The synthesis of arabinan oligosaccharides has received considerable attention due to their immense significance in disease management. Several groups have attempted the synthesis of arabinan motifs; a large oligoarabinan with 22 Ara f units,, a henicosasaccharide fragment of AG, and a much larger fragment with 92 saccharide residues have been reported (Figure ).…”