Mycobacterium Tuberculosis (Mtb) GlgE is a glycoside hydrolase like phosphorylase essential for bacterial growth. The main function of the enzyme is to polymerize its substrate Maltose-1-Phosphate (M1P). In these studies, we explore the synthesis of mannose related cyclophellitol scaffolds in an attempt to create covalent inhibitors. (+)-Cyclophellitol has been shown to be a potent and selective mechanism based inhibitor of retaining α and β-glucosidases. For the mannose related cyclophellitol epoxide derivative, the synthetic strategy revolved on the glycosylation between ethyl (1S,4S,5S,6R)-4,5-Bis(benzyloxy)-6-hydroxycyclohex-2-enecarboxylate acceptor and 4-methylphenyl 2,3,4,6-tetrakis-O-(phenylmethyl)-1-thio-α-D-glucopyranoside donor, followed by subsequent ester reduction, epoxidation, and global deprotection to afford the target product. Similar strategy was adopted for the synthesis of the mannose related cyclophellitol aziridine derivative following substitution of the epoxide moiety for an aziridine. The acceptor was synthesized with an overall yield of 32% in six steps from D-xylose. The key transformations involved a zinc-mediated fragmentation of benzyl-protected methyl-5-deoxy-5-iodo-xylofuranoside, a highly diastereoselective indium-mediated coupling with ethyl-4-bromocrotonate, and finally a ring closing olefin metathesis to afford the acceptor. The glucoside donor building block was synthesized in three steps with an overall yield of 80%. These mannose derived cyclophellitol scaffolds will be tested and studied to determine their effectiveness as covalent inhibitors of Mtb GlgE.

Synthesis of mannose related cyclophellitol scaffolds

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