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大发现的发展。例如，新的强效药物的发现通常需要研究一些复杂化学结构的结构类似物。传统上，为了构建这些类似物，基本分子片段对在一系列化学步骤中连接起来，形成新的碳-碳(C-C)键。这增加了中间体的复杂性，直到得到所需的分子。然而，可获得的结构的多样性通常受到可用化学空间和获得所需化合物所需的时间/资源的限制，这为化学家构建未来药物的想象力限定了严格的边界。与传统的配对组装化学不同，该提议引入了一种新颖的可见光驱动过程，允许在单个化学步骤中对复杂分子片段进行多组分组装。在这个过程中形成了两个新的C-C键，其中一个是合成的多功能双键，对进一步的结构操作有用。这种化学是由膦盐史无前例的氧化还原生成磷叶立德引发的，在这一雄心勃勃的多组分C-C耦合中，它被用作化学碎片之间的关键。这种方法所需的温和条件将允许复杂的生物活性分子的快速修饰，产生无数用于创造新药的新的结构类似物。含有无处不在的官能团的复杂分子(即羧酸或醇/胺衍生物)甚至简单的SP3C-H键都将具有预期的反应活性，为未来的应用奠定了坚实的基础。我们方法的广泛应用将在制备一系列新型利拉胺类似物方面得到例证，利拉胺是一种廉价且容易获得的具有抗癌活性的分子，有可能为治疗具有挑战性的疾病提供新的强大的化疗药物。

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.