202339-50-2Relevant academic research and scientific papers
Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis
Liu, Zheng,Liu, Feng,Aldrich, Courtney C.
, p. 6545 - 6552 (2015)
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.
Total synthesis of (±)- and (+)-valienamine via a strategy derived from new palladium-catalyzed reactions
Trost, Barry M.,Chupak, Louis S.,Luebbers, Thomas
, p. 1732 - 1740 (2007/10/03)
A new strategy toward glycosidase inhibitors, represented by valienamine, which is such an inhibitor itself as well as a critical unit of pseudooligosaccharides that function this way, evolved from two newly developed palladium-catalyzed reactions. The applicability of a palladium(0)-catalyzed net regioselective cis-hydroxyamination derives from the reaction of vinyl epoxides with isocyanates. The utilization of a cocatalyst in this reaction is required in this case and may prove generally useful. A bidentate phosphate proved to be the most effective ligand. The requisite substrate was available via a Diels-Alder protocol and allowed the obtention of (±)-valienamine in only seven steps. The inability to perform the Diels-Alder reaction asymmetrically led to a different asymmetric synthesis of the pivotal epoxide intermediate in enantiomerically pure form, which derived from asymmetric palladium-catalyzed reactions. Using the desymmetrization of meso enedicarboxylates, the net equivalence of an asymmetric cis-hydroxycarboxylation led to the enantiomerically pure desired epoxide. (+)-Valienamine was available in 14 steps by this route.
