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首页> 外文期刊>Chemistry: A European journal >Total Synthesis of (-)-Platensimycin by Advancing Oxocarbeniumand Iminium-Mediated Catalytic Methods
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Total Synthesis of (-)-Platensimycin by Advancing Oxocarbeniumand Iminium-Mediated Catalytic Methods

机译：氧碳和亚胺介导的催化方法全合成（-）-Platensimycin

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摘要

(-)-Platensimycin is a potent inhibitor of fatty acid synthase that holds promise in the treatment of metabolic disorders (e.g., diabetes and "fatty liver") and pathogenic infections (e.g., those caused by drug-resistant bacteria). Herein, we describe its total synthesis through a four-step preparation of the aromatic amine fragment and an improved stereocontrolled assembly of the ketolide fragment, (-)-platensic acid. Key synthetic advances include 1) a modified Lieben haloform reaction to directly convert an aryl methyl ketone into its methyl ester within 30 seconds, 2) an experimentally improved dialkylation protocol to form platensic acid, 3) a sterically controlled chemo- and diastereoselective organocatalytic conjugate reduction of a spiro-cyclized cyclohexadienone by using the trifluoroacetic acid salt of a-amino di-tert-butyl malonate, 4) a tetrabutylammonium fluoride promoted spiro-alkylative para dearomatization of a free phenol to assemble the cagelike ketolide core with the moderate leaving-group ability of an early tosylate intermediate, and 5) a bismuth(III)-catalyzed Friedel-Crafts cyclization of a free lactol, with LiClO_4 as an additive to liberate a more active oxocarbenium perchlorate species and suppress the Lewis basicity of the sulfonyloxy group. The longest linear sequence is 21 steps with an overall yield of 3.8% from commercially available eugenol.
机译：（-）-Platensimycin是有效的脂肪酸合酶抑制剂，在治疗代谢性疾病（例如糖尿病和“脂肪肝”）和病原性感染（例如由耐药细菌引起的感染）方面具有广阔的前景。在这里，我们描述了通过芳香胺片段的四步制备和酮化物片段（-）-戊酸的改进的立体控制组装而实现的全合成。关键的合成进展包括：1）改进的Lieben卤仿反应，可在30秒内将芳基甲基酮直接转化为甲酯; 2）实验上改进的二烷基化方案以形成膦酸; 3）立体控制的化学和非对映选择性有机催化共轭物还原α-氨基二叔丁基丙二酸酯的三氟乙酸盐制备螺环化环己二酮，4）氟化四丁基铵促进游离酚的螺环烷基化对脱芳香化反应，以使笼状酮环内酯与中等离去基团组装在一起早期甲苯磺酸酯中间体的能力，以及5）铋（III）催化的游离乳糖醇的Friedel-Crafts环化反应，并以LiClO_4作为添加剂来释放活性更高的氧碳碳鎓物种并抑制磺酰氧基的Lewis碱度。最长的线性序列为21个步骤，可从商购的丁香酚中获得3.8％的总收率。

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