Activation of glycosyl methylpropiolates by TfOH.

Activation of glycosyl methylpropiolates by TfOH was investigated. Armed and superarmed glycosyl donors can be activated by use of 0.2 equivalent TfOH whereas 1.0 equivalent of TfOH was required for the activation of the disarmed glycosyl donors. All the glycosidations gave very good yields. The method is suitable for synthesis of glycosides and disaccharides and it may result in the hydrolysis of the interglycosidic bond if the sugar at the non-reducing end is armed or superarmed. These problems are not seen when gold-catalyzed activation procedures are invoked for the activation of glycosyl alkynoates.

Glycosyl Vinylogous Carbonates as Glycosyl Donors by Metal-Free Activation.

Synthesis of glycoconjugates employs a glycosylation reaction wherein an electrophile and a nucleophile known as a glycosyl donor and an aglycon, respectively, are involved. Glycosyl donors often contain a leaving group at the anomeric carbon that upon reaction with activator(s) results in a highly reactive electrophilic species reported as an oxycarbenium ion contact pair that will then be attacked by the aglycon. Therefore, identification of the correct glycosyl donor and activation protocol is essential for the synthesis of all glycoconjugates. Recently identified [Au]/[Ag]-catalyzed activation of ethynylcyclohexyl glycosyl carbonates is one such versatile method for the synthesis of glycosides, oligosaccharides, and glycoconjugates. In this work, stable glycosyl vinylogous carbonates were identified to undergo glycosidation in the presence of a sub-stoichiometric quantity of TfOH. The reaction is fast and suitable for donors containing both C2-ethers and C2-esters. Donors positioned with C2-ethers resulted in anomeric mixtures with greater selectivity toward 1,2-cis glycosides, whereas those with C2-esters gave 1,2-trans selective glycosides. The versatility of the method is demonstrated by conducting the glycosylation with more than 25 substrates. Furthermore, the utility of the glycosyl vinylogous carbonate donors is demonstrated with the successful synthesis of the branched pentaarabinofuranoside moiety of the Mycobacterium tuberculosis cell wall.

Synthesis of the hyper-branched core tetrasaccharide motif of chloroviruses.

Chemical synthesis of complex oligosaccharides, especially those possessing hyper-branched structures with one or multiple 1,2-cis glycosidic bonds, is a challenging task. Complementary reactivity of glycosyl donors and acceptors and proper tuning of the solvent/temperature/activator coupled with compromised glycosylation yields for sterically congested glycosyl acceptors are among several factors that make such syntheses daunting. Herein, we report the synthesis of a semi-conserved hyper-branched core tetrasaccharide motif from chloroviruses which are associated with reduced cognitive function in humans as well as in mouse models. The target tetrasaccharide contains four different sugar residues in which l-fucose is connected to d-xylose and l-rhamnose via a 1,2-trans glycosidic bond, whereas with the d-galactose residue is connected through a 1,2-cis glycosidic bond. A thorough and comprehensive study of various accountable factors enabled us to install a 1,2-cis galactopyranosidic linkage in a stereoselective fashion under [Au]/[Ag]-catalyzed glycosidation conditions en route to the target tetrasaccharide motif in 14 steps.

Silver-assisted gold-catalyzed formal synthesis of the anticoagulant Fondaparinux pentasaccharide.

Clinically approved anti-coagulant Fondaparinux is safe since it has zero contamination problems often associated with animal based heparins. Fondaparinux is a synthetic pentasaccharide based on the antithrombin-binding domain of Heparin sulfate and contains glucosamine, glucuronic acid and iduronic acid in its sequence. Here, we show the formal synthesis of Fondaparinux pentasaccharide by performing all glycosidations in a catalytic fashion for the first time to the best of our knowledge. Designer monosaccharides were synthesized avoiding harsh reaction conditions or reagents. Further, those were subjected to reciprocal donor-acceptor selectivity studies to guide [Au]/[Ag]-catalytic glycosidations for assembling the pentasaccharide in a highly convergent [3 + 2] or [3 + 1 + 1] manner. Catalytic and mild activation during glycosidations that produce desired glycosides exclusively, scalable route to the synthesis of unnatural and expensive iduronic acid, minimal number of steps and facile purifications, shared use of functionalized building blocks and excellent process efficiency are the salient features.

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

Oligosaccharides are involved in a myriad of biological phenomena. Many glycobiological experiments can be undertaken if homogenous and well-defined oligosaccharides are accessible. Mycobacterial cell walls contain arabinogalactan as one of the major constituents that is challenging for chemical synthesis. Therefore, the major aim of this investigation is to synthesise a major oligosaccharide portion of the arabinogalactan. The pentacosafuranoside (25mer) synthesis involved installation of several arabinofuranosidic linkages through neighbouring group participation for 1,2-trans linkages and oxidation-reduction strategy for the 1,2-cis Araf. A strategically placed n-pentenyl moiety at the reducing end enables ligation of biomolecular probes through celebrated cross metathesis or thiol-ene click reactions. Several linear and branched oligosaccharides were synthesised ranging from trisaccharide to pentadecasaccharide during this endeavour. Synthesis of pentacosasaccharide was accomplished in 77 steps with 0.0012 % overall yield. These oligosaccharides are envisioned to be excellent probes for understanding disease biology thereby facilitating discovery of novel antitubercular agents, vaccines and/or diagnostics.

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

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.