Light-Driven Multicomponent C-C Couplings: New Avenues to Bioactive Molecules

合成化学是科学和技术的核心，并极大地促进了改变生活的重要发现的发展。例如，发现新的强效药物通常需要研究复杂化学结构的一些结构类似物。传统上，为了构建这些类似物，将基本分子片段对以一系列化学步骤连接以形成新的碳-碳（C-C）键。这提高了中间体的复杂性，直到获得所需的分子。然而，可获得的结构的多样性通常受到可用的化学空间和获得所需化合物所需的时间/资源的限制，为化学家构建未来药物的想象力定义了严格的界限。该提议引入了一种新颖的可视-光驱动过程，其允许在单个化学步骤中多组分组装复杂的分子片段。在此过程中形成了两个新的C-C键，其中一个是合成通用的双键，可用于进一步的结构操作。化学反应是由磷盐前所未有的氧化还原生成磷叶立德引发的，磷叶立德在这个雄心勃勃的多组分C-C偶联中用作化学片段之间的关键。这种方法所需的温和条件将允许快速修饰复杂的生物活性分子，产生无数新的结构类似物，用于创造新药。含有普遍存在的官能团的复杂分子（即羧酸或醇/胺衍生物）和甚至简单的sp3 C-H键将经历所需的反应性，为未来的应用定义了实质性的范围。我们的方法学的广泛应用将在制备一套新的leelamine类似物中举例说明，leelamine是一种廉价且容易获得的具有抗癌活性的分子，潜在地为治疗具有挑战性的疾病提供新的强效化疗剂。

Synthetic chemistry lays at the heart of Science and Technology and has greatly enabled the development of important life-changing discoveries. For instance, the discovery of novel powerful medicines generally requires the study of a number of structural analogues of complex chemical structures. Traditionally, to construct these analogues, pairs of elementary molecular fragments are connected in a sequence of chemical steps to form new carbon-carbon (C-C) bonds. This enhances the complexity of the intermediates until the desired molecule is achieved. However, the variety of structures accessible is generally limited by the chemical space available and the time/resources required to achieve the desired compound, defining strict boundaries to chemists' imagination for the construction of the medicines of tomorrow.In contrast to traditional pair assembly chemistry, this proposal introduces a novel visible-light driven process which allows the multicomponent assembly of complex molecular fragments in a single chemical step. Two new C-C bonds are formed in the process, one of which is a synthetically versatile double bond, useful moiety for further structure manipulation. The chemistry is triggered by an unprecedented redox generation of a phosphorus ylide from a phosphonium salt, which is used as a linchpin between the chemical fragments in this ambitious multicomponent C-C coupling. The mild conditions required for this methodology will allow the rapid modification of complex bioactive molecules, generating myriad novel structural analogues for the creation of new medicines. Complex molecules containing ubiquitous functional groups (i.e. carboxylic acids or alcohol/amine derivatives) and even simple sp3 C-H bonds would undergo the desired reactivity, defining a substantial scope for future applications.The wide application of our methodology will be exemplified in the preparation of a suite of novel analogues of leelamine, a cheap and readily available molecule with anti-cancer activity, potentially providing novel powerful chemotherapeutics for the treatment of a challenging illness.