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

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，为迄今未知的支架铺平了道路。最常见的有机催化反应是以醛为底物，醛的三种主要活化方式之一，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合成子的有力工具，但将两种或两种以上有机催化模式合并为级联反应使简单的非手性凝视材料能够快速转化为立体化学复杂的、对映体纯的产物。这些化合物在合成结构多样的天然产物和类药物分子的过程中起着多种中间体的作用。因此，有机级联催化的概念是天然产物合成的有力工具，能够模仿自然的有效生物合成途径。本提案中描述的研究对于开发第一个Ru-Im-SOMO有机催化级联及其在高效合成Secounega类高生物活性天然产物中的应用来说是一个具有挑战性的事业。在该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，这三个催化循环将合并为一个有机级联转化。最后，从市面上可买到的原料出发，短短九步即可完成杀菌剂病毒别塞卡宾和去甲卡宾的合成。考虑到病毒别塞卡宾的抗菌特性，这项工作的结果将对制药行业的药物发现和开发特别相关。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，并激励发现新类型的反应性、新的活化模式以及这些新反应性的结合，以发现前所未有的级联过程。

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.