Total Synthesis of (-)-Platensimycin by Advancing Oxocarbenium- and Iminium-Mediated Catalytic Methods
Total Synthesis of (-)-Platensimycin by Advancing Oxocarbenium- and Iminium-Mediated Catalytic Methods
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DOI：
10.1002/chem.201400131
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发表时间：
2014-09-01
影响因子：
4.3
通讯作者：
Lear, Martin J.
中科院分区：
文献类型：
--
作者：
Eey, Stanley T. -C.;Lear, Martin J.
（-）-铂霉素是一种有效的脂肪酸合成酶抑制剂，有望用于治疗代谢紊乱（例如，例如，在一个实施例中，糖尿病和“脂肪肝”）和致病性感染（例如，例如，在一个实施例中，由耐药细菌引起的）。在此，我们描述了它的全合成通过四步制备的芳香胺片段和改进的立体控制组装的酮内酯片段，（-）-platensic酸。关键的合成进展包括1）在30秒内将芳基甲基酮直接转化成其甲酯的改良的Lieben卤仿反应，2）形成Platensic酸的实验改进的二烷基化方案，3）通过使用α-氨基丙二酸二叔丁酯的三氟乙酸盐对螺环化的环己二烯酮进行空间控制的化学和非对映体选择性有机催化共轭还原，4）四丁基氟化铵促进游离苯酚的螺烷基帕拉脱芳构化以组装笼状酮内酯核，其具有早期甲苯磺酸酯中间体的中等离去基团能力，和5）游离内半缩醛的铋（III）催化的Friedel-Crafts环化，其中LiClO 4作为添加剂以释放更活性的氧代碳鎓高氯酸盐物质并抑制磺酰氧基的刘易斯碱性。最长的线性序列为21步，从市售丁香酚的总产率为3.8%。
(-)-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 alpha-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 LiClO4 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.