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类作为底物，并以醛类的三种主要激活模式之一来区分，即铝、烯胺和SOMO（单占据分子轨道）激活。每种模式本身都是生成手性合成物的有力工具，但将两种或两种以上的有机催化模式合并到级联反应中，可以将简单的非手性起始材料快速转化为立体化学复杂的、对映体纯的产物。这些化合物在通往结构多样的天然产物和药物样分子的过程中充当多功能中间体。因此，有机级联催化的概念是天然产物合成的有力工具，能够模仿自然的高效生物合成途径。本提案所描述的研究代表了一项具有挑战性的事业，即开发第一个钌-铝- somo有机催化级联，并将其应用于高效合成高生物活性的Securinega类天然产物。在该项目的方法论开发阶段，必须独立建立三种不同催化循环的可行性。然后，三个催化循环将合并为有机级联转化。最后，以商业原料为原料，仅用9个步骤即可完成杀菌剂viroallosecurinine和norsecurinine的合成。鉴于viroallosecurinine的抗菌特性，这项工作的结果将与制药行业的药物发现和开发特别相关。此外，本研究将对不断发展的有机催化领域产生重大影响，并激发发现新型反应性，新的激活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.