Tuberculosis (TB) is an infectious disease that is one of the top 10 causes of death around the world. Emergence of multi drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) has made the treatment of TB more difficult. The increasing resistance of Mycobacterium tuberculosis (Mtb) towards current drugs creates the need to identify new drug targets. We are focusing on Mtb GlgE, a glycoside hydrolase-like phosphorylase that catalyzes the addition of maltose to maltooligosaccharides. To inhibit GlgE we designed and synthesized a carbasugar inhibitor structurally related to maltose. To synthesize the inhibitor, we produced a benzylated maltose thioglycoside using reported chemistry. The anomeric position of maltose was deprotected by N-bromosuccinimide to generate a free reducing end in 91% yield. The reducing sugar was olefinated by Wittig chemistry in 50% yield. Moffatt oxidation of the alcohol at the 6-position afford a ketone which was further subjected to a stereoselective addition reaction using vinyl magnesium bromide to afford diastereisomeric dienes (9:1) in 78% yield. Ring closing metathesis of the desired epimer resulted in a cyclohexene adduct. Acetyl protection of the free hydroxyl followed by a 1,3-sigmatropic rearrangement resulted in the desired isomeric cyclohexene. The deprotection of acetyl was followed by a Furukawa-Simmons-Smith cyclopropanation. To complete the synthesis, aromatic nucleophilic substitution using 1,3,5-triflurobenzene followed by deprotection of the benzyl groups yielded the target inhibitor. Evaluation of the inhibitory activity is ongoing.

Synthesis of a cyclopropyl-containing mechanism-based glycoside hydrolase inhibitor

2019 Spring National Meeting

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