title: Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis.
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.
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, Minnesota 55455, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, Minnesota 55455, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, Minnesota 55455, United States.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D053138:Cyclohexenes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008190:Lyases / Q000737:chemistry*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D017262:Siderophores / Q000096:biosynthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D053138:Cyclohexenes; D017262:Siderophores; D013452:Sulfonium Compounds; D008190:Lyases; C022620:salicylate synthetase