Development of the First Ruthenium-Iminium-SOMO Organocatalytic Cascade and Its Application in Total Synthesis of the Highly Bioactive Natural Products Viroallosecurinine and Norsecurinine

第一个钌-亚胺-SOMO有机催化级联的研制及其在高生物活性天然产物Viroallosecurinine和Norsecurinine全合成中的应用

• 批准号: 238839157
• 负责人: Dr. Dominik Hager
• 金额: --
• 依托单位: Frick Chemistry Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/238839157?language=en
• 关键词: Development; First; Ruthenium; Iminium; SOMO

Organocatalysis has become a tremendously important field of organic chemistry over the past decades. Small molecules can catalyze a variety of different transformations in an asymmetric manner, paving the way to hitherto unknown scaffolds. The most common organocatalytic reactions utilize aldehydes as substrates, and are distinguished by one of three major activation modes of aldehydes, namely iminium, enamine, and SOMO (single occupied molecular orbital) activation. Each mode per se is a powerful tool to generate chiral synthons, but the merger of two or more organocatalytic modes to cascade reactions enables the rapid conversion of simple achiral staring materials into stereochemically complex, enantiomerically pure products. These compounds serve as versatile intermediates en route to structurally diverse natural products and drug-like molecules. Thus, the concept of organocascade catalysis is a powerful tool for natural product synthesis, able to imitate Nature's efficient biosynthetic pathways. The research described in this proposal represents a challenging enterprise for the development of the first ruthenium-iminium-SOMO organocatalytic cascade, and its application in the efficient synthesis of highly bioactive natural products of the Securinega class. In the methodology development phase of this project, the viability of three different catalytic cycles will have to be established independently. Then, the three catalytic cycles will be merged to an organocascade transformation. Finally, the short synthesis of the bactericides viroallosecurinine and norsecurinine will be completed in just nine synthetic steps from commercially available starting material.Given the antibacterial properties of viroallosecurinine, the results of this work will be particularly relevant for drug discovery and development within the pharmaceutical industry. In addition, this research will impact significantly on the growing field of organocatalysis, and inspire the discovery of new types of reactivity, novel modes of activation and the marriage of these new reactivities for the discovery of unprecedented cascade processes.

在过去的几十年里，有机催化已经成为有机化学中一个非常重要的领域。小分子可以以不对称的方式催化各种不同的转化，为迄今为止未知的支架铺平了道路。最常见的有机催化反应利用醛作为底物，并且通过醛的三种主要活化模式之一区分，即亚胺、烯胺和SOMO（单占据分子轨道）活化。每种模式本身都是产生手性手性配体的有力工具，但是两种或更多种有机催化模式的级联反应的合并使得简单的非手性起始材料能够快速转化为立体化学复杂的对映体纯产物。这些化合物作为多功能中间体，可用于合成结构多样的天然产物和药物样分子。因此，有机级联催化的概念是天然产物合成的有力工具，能够模仿自然界的有效生物合成途径。该提案中描述的研究代表了第一个单铵盐-亚胺-SOMO有机催化级联的开发及其在一叶叶姜类高生物活性天然产物的有效合成中的应用的挑战性企业。在本项目的方法学开发阶段，必须独立确定三种不同催化循环的可行性。然后，三个催化循环将合并为一个有机级联转化。最后，从市售的起始原料出发，通过9个合成步骤完成了杀真菌剂病毒别一叶碱和去甲一叶碱的短合成。鉴于病毒别一叶碱的抗菌特性，这项工作的结果将特别适用于制药工业中的药物发现和开发。此外，这项研究将对日益增长的有机催化领域产生重大影响，并激发发现新型反应性，新型活化模式以及这些新反应性的婚姻，以发现前所未有的级联过程。