Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis

Zheng Liu, Feng Liu, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate. We report the design, synthesis, and biochemical evaluation of an inhibitor based on the putative transition state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge buildup at C-4 of chorismate in the TS as well as C-O bond formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side chain in chorismate with a stable C-linked propionate isostere. We developed a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps.

Original languageEnglish (US)
Pages (from-to)6545-6552
Number of pages8
JournalJournal of Organic Chemistry
Volume80
Issue number13
DOIs
StatePublished - Jul 2 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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