Synthesis of (-)-Melodinine K: A Case Study of Efficiency in Natural Product Synthesis
Synthesis of (-)-Melodinine K: A Case Study of Efficiency in Natural Product Synthesis
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DOI：
10.1021/acs.jnatprod.0c00310
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发表时间：
2020-08-28
影响因子：
5.1
通讯作者：
Andrade, Rodrigo B.
中科院分区：
文献类型：
--
作者：
Walia, Manish;Teijaro, Christiana N.;Andrade, Rodrigo B.
效率是现代天然产物合成中的关键组织原则。实际的标准包括时间，成本和综合目标所花费的努力，这些目标通过步数和规模进行跟踪。天然产物合成的执行，即其中所采用的每个反应的总和和同一性，福尔斯沿着化学（非生物）合成的连续体在一个极端上，接着是混合化学酶法，最后是生物（生物合成），承认第一个合成属于自然。起始材料还跨越接近目标的结构复杂性的连续体，其中一个极端是组成元素，其次是石油衍生的和“手性池”构建单元，以及复杂的天然产物（即，半合成（Semisynthesis）。在这里，我们详细介绍了我们的方法实现第一个合成（-）-melodinine K，一个复杂的双吲哚生物碱。本文报道了采用多米诺Michael/Mannich成环反应全合成（-）-他勃松宁和（-）-16-甲氧基他勃松宁。从非洲伏桑中分离出（-）-他勃松宁，并利用他勃松宁16-羟化酶进行战略性生物转化，以实现位点特异性C-H氧化，从而实现了可扩展的路线。仿生片段偶联反应采用Polonovski-Potier反应。随后的操作实现了目标。最后，我们讨论了天然产物合成的效率以及化学和生物技术如何定义合成前沿。
Efficiency is a key organizing principle in modern natural product synthesis. Practical criteria include time, cost, and effort expended to synthesize the target, which tracks with step-count and scale. The execution of a natural product synthesis, that is, the sum and identity of each reaction employed therein, falls along a continuum of chemical (abiotic) synthesis on one extreme, followed by the hybrid chemoenzymatic approach, and ultimately biological (biosynthesis) on the other, acknowledging the first synthesis belongs to Nature. Starting materials also span a continuum of structural complexity approaching the target with constituent elements on one extreme, followed by petroleum-derived and "chiral pool" building blocks, and complex natural products (i.e., semisynthesis) on the other. Herein, we detail our approach toward realizing the first synthesis of (-)-melodinine K, a complex bis-indole alkaloid. The total syntheses of monomers (-)-tabersonine and (-)-16-methoxytabersonine employing our domino Michael/Mannich annulation is described. Isolation of (-)-tabersonine from Voacanga africana and strategic biotransformation with tabersonine 16-hydroxylase for sitespecific C-H oxidation enabled a scalable route. The Polonovski-Potier reaction was employed in biomimetic fragment coupling. Subsequent manipulations delivered the target. We conclude with a discussion of efficiency in natural products synthesis and how chemical and biological technologies define the synthetic frontier.