Tuberculosis (TB) is a serious infectious disease and global health threat. The persistence of TB globally is due to the hardiness of the bacterium Mycobacterium tuberculosis(Mtb), and the ability of Mtb to enter a dormant phase complicates the treatment. GlgE is a bacterial maltosyltransferase that catalyzes the elongation of a cytosolic, branched α-glucan. In Mtb inactivation of GlgE results in the rapid death of the organism due to a toxic accumulation of the maltosyl donor, maltose-1-phosphate (M1P), which suggests that GlgE is a fascinating target for inhibitor design. Cyclophellitol epoxides, aziridines, 1,6-epi-cyclophellitol cyclosulfate and derivatives of valienamine are reported as α-glucosidase inhibitors. Inspired by this we proposed to synthesize targets starting from maltose derivatives. 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 50% yield. Oxidation of the secondary alcohol using Moffatt oxidation followed by stereoselective addition of vinyl magnesium bromide afforded two diastereomeric separable dienes (9:1) in 70% yield. Intermolecular olefin metathesis of the desired diene using a first-generation Grubbs catalyst gave the carbasaccharide in 20% 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 inhibitor which will be tested for its inhibition activity against GlgE and various glycosidase enzymes.

Synthesis of non-covalent carbocyclic maltose derivative used as a potential inhibitor of Mycobacterium tuberculosis GlgE

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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