Synthesis of Transition-State Inhibitors of Chorismate Utilizing Enzymes from Bromobenzene cis-1,2-Dihydrodiol

Xiao Kang Zhang, Feng Liu, William D. Fiers, Wen Mei Sun, Jun Guo, Zheng Liu, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

In order to survive in a mammalian host, Mycobacterium tuberculosis (Mtb) produces aryl-capped siderophores known as the mycobactins for iron acquisition. Salicylic acid is a key building block of the mycobactin core and is synthesized by the bifunctional enzyme MbtI, which converts chorismate into isochorismate via a SN2″ reaction followed by further transformation into salicylate through a [3,3]-sigmatropic rearrangement. MbtI belongs to a family of chorismate-utilizing enzymes (CUEs) that have conserved topology and active site residues. The transition-state inhibitor 1 described by Bartlett, Kozlowski, and co-workers is the most potent reported inhibitor to date of CUEs. Herein, we disclose a concise asymmetric synthesis and the accompanying biochemical characterization of 1 along with three closely related analogues beginning from bromobenzene cis-1S,2S-dihydrodiol produced through microbial oxidation that features a series of regio- and stereoselective transformations for introduction of the C-4 hydroxy and C-6 amino substituents. The flexible synthesis enables late-stage introduction of the carboxy group and other bioisosteres at the C-1 position as well as installation of the enol-pyruvate side chain at the C-5 position.

Original languageEnglish (US)
Pages (from-to)3432-3440
Number of pages9
JournalJournal of Organic Chemistry
Volume82
Issue number7
DOIs
StatePublished - Apr 7 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

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