Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis.
Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis.
复制标题
结核分枝杆菌水杨酸合酶 MbtI 的潜在过渡态抑制剂的立体控制合成
DOI：
10.1021/acs.joc.5b00455
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发表时间：
2015-07-02
期刊：
影响因子：
--
通讯作者：
Aldrich CC
中科院分区：
文献类型：
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作者：
Liu Z;Liu F;Aldrich CC
分枝杆菌素是由结核分枝杆菌 (Mtb) 产生的用于铁动员的小分子铁螯合剂（铁载体）。双功能水杨酸合酶 MbtI 通过将主要代谢物分支酸通过异分支酸转化为水杨酸来催化分枝杆菌素生物合成的第一步。我们报告了基于 MbtI 异分支酸酶部分反应的假定过渡态 (TS) 的抑制剂的设计、合成和生化评估。该抑制剂模拟了假设的 TS 中分支酸 C-4 处的电荷积累以及 C-6 处 C-O 键的形成。该抑制剂的另一个重要设计元素是用稳定的 C-连接丙酸等排体取代分支酸中不稳定的丙酮酸侧链。我们开发了一种高功能化环己烯抑制剂的立体控制合成方法，其特点是使用钛烯醇化物进行不对称羟醛反应、叔丁亚磺酰醛亚胺的非对映选择性格氏加成反应以及闭环烯烃复分解反应作为关键步骤。
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 build-up 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.