Glycoside hydrolases (GH) are hydrolytic enzymes involved in a large array of biological phenomena. Inhibiting the GH activity varies the glycosylation or catabolism of glycans, making the GH inhibitors highly potent drugs. An important class of GH inhibitors in glycobiology are the carbasugars as some of these pseudosaccharides may mimic the transition state (TS) of the catalysed reaction while others may mimic the Michaelis complex. 1-Aminocarbasugars are thought to mimic charge development in the TS by incorporating a basic nitrogen atom in place of C(1)-O. There are well known examples of this class of compounds such as Acarbose, vogliobose, validamine, valienamine which show inhibitory activity against different α-GHs. Inspired by this we proposed to synthesize the 4-alpha-glucoside of validamine and valienamine starting from commercially available reducing sugar maltose. Our synthesis started with a β-thiomaltoside which was treated with N-bromosuccinimide to obtain a maltose hemiacetal in 90% yield. Then Wittig olefination was performed to obtain the vinyl glycoside in 55% yield. Oxidation of the secondary alcohol using Moffatt oxidation followed by stereoselective addition of vinyl magnesium bromide afforded two diastereomeric separable dienes (4:1) in 70% yield. Intramolecular ring closing metathesis of the desired diene using a first generation Grubbs catalyst gave the carbasaccharide in 25% yield. The tertiary alcohol of the pseudodisaccharide was then converted to carbamate and subjected to an Ichikawa rearrangement to give protected maltosyl valienamine analog in 60% yield. Then subsequent deprotection of these derivatives afforded the desired compounds which will be evaluated for inhibition activity against Streptomyces coelicolor (Sco) which belongs to the GH13 Carbohydrate Active EnZyme (CAZy) family.

Stereoselective synthesis of a 4-alpha-glucoside of validamine and valienamine as potential inhibitors of hydrolase-like enzyme Streptomyces coelicolor GlgEI

ACS Spring Meeting 2021

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