Work

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

Year: 2017

Type: article

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 S N 2″ 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 -1 S,2 S -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.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.6b02801