New eras of catalysis: Towards the development of pseudotransition metal organocatalysts for metal-free cross-coupling transformations

过渡金属催化的交叉偶联转化是药物开发中不可缺少的 和药物化学，允许在极其复杂的分子中获得无数的键连接 设置。尽管其力量强大，但对过渡金属催化的持续依赖带来了许多挑战。为 例如，药物合成中最紧迫的挑战是与贵族有关的极端成本 形成这些贵重、高性能催化剂的金属(例如，Ru、Rh、Pd、Pt和Ir)。此外，过渡- 由于金属的元素毒性，它们受到严格的监管，这给上游带来了巨大的成本 将药物推向市场的合成阶段。最后，继续依赖过渡金属催化 是不可持续的，受到全球已知矿藏原材料迅速枯竭的威胁，而且 供应链中断。因此，对于温和和普遍的键形成的替代策略的发展是 对于制药和药物化学的持续生产力来说，这是必要的。 有机催化是传统过渡金属催化的一种有吸引力的替代品，很容易被利用 可获得、廉价、实用的小分子催化剂。一种有机催化剂的鉴定 模仿过渡金属催化剂行为的能力形成了一种理想的方法；先验的，这样的策略 将是“即插即用”，在保留交叉耦合的本质的同时，仅调用催化剂身份的改变 传统上用于交叉偶联化学的合作伙伴。如果成功，这种方法将解决每个 前面列举的挑战。 这项计划的目标是设计、合成和开发一系列“假金属”有机催化剂。 以促进大量的催化交叉偶联转化。这些催化剂被称为假金属到 反映了它们模拟过渡金属催化剂的经典断键和成键行为的能力。 具体地说，这项研究计划详细说明了邻二硫代醌作为假金属有机催化剂的发展， 在合理设计、结构-活动-关系、计算模型和假设的原则指导下， 驱动型实验。我们的初步计算结果将我们引向邻二硫代苯二酚，这是由于中性 吉布斯自由能预测这些支架被氧化插入到几种S键类型中。在这项研究中， 严谨的机理和表征研究将描述有机催化剂固有的关键原理 物种形成和相关的基本步骤，以化学计量研究、线性自由能关系为特征 分析和催化中间体表征。在丰富的机械论理解的指导下，我们将 通过一系列交叉偶联转化考察这些有机催化剂的合成能力， 包括C-N、C-O、C-SF5和N-CF3键形成的例子。总体而言，这项研究将建立一个新的 可持续的、可获得的交叉偶联化学的范例，并将对医学做出重大贡献 有机合成方面的研究、药物开发和基础知识。

Transition-metal catalyzed cross-coupling transformations are indispensable to pharmaceutical development and medicinal chemistry, allowing access to innumerable bond connections in extremely complex molecular settings. Despite its power, continued reliance on transition-metal catalysis poses many challenges. For example, a most pressing challenge in pharmaceutical synthesis is the extreme cost associated with the noble metals that form these precious, high-powered catalysts (e.g., Ru, Rh, Pd, Pt, and Ir). Furthermore, transition- metals are treated with strict regulation due to their elemental toxicity, imparting significant cost in the upstream synthetic stages of delivering a drug to the marketplace. Finally, continued reliance on transition-metal catalysis is unsustainable, threatened by the rapid depletion of raw materials at known global deposits and consistent supply-chain disruptions. Thus, the development of alternative strategies for mild and general bond formation is necessary for continued productivity in pharmaceutical and medicinal chemistry. Organocatalysis is an attractive surrogate to traditional transition-metal catalysis, leveraging readily accessible, inexpensive, and practical small molecules as catalysts. The identification of an organocatalyst with the ability to mimic the behavior of a transition-metal catalyst forms an ideal approach; a priori, such a strategy would be “plug and play,” invoking only a change in catalyst identity while preserving the nature of cross-coupling partners traditionally utilized in cross-coupling chemistry. If successful, this approach would address each of the challenges previously enumerated. The goal of this proposal is to design, synthesize, and develop a series of “pseudometal” organocatalysts to facilitate a vast array of catalytic cross-coupling transformations. These catalysts are termed pseudometal to reflect their ability to mimic the classical bond-breaking and bond-forming behavior of transition-metal catalysts. Specifically, this research plan details the development of ortho-dithioquinones as pseudometal organocatalysts, guided by principles of rational design, structure-activity-relationships, computational modeling, and hypothesis- driven experimentation. Our preliminary computational results direct us to ortho-dithioquinones due to the neutral Gibbs free energies predicted for oxidative insertion of these scaffolds into several s-bond types. In this research, rigorous mechanistic and characterization studies will profile the key principles inherent to organocatalyst speciation and the associated elementary steps, featuring stoichiometric studies, linear free-energy relationship analyses, and catalytic intermediate characterization. Guided by a rich mechanistic understanding, we will examine the synthetic capabilities of these organocatalysts through a series of cross-coupling transformations, including examples of C–N, C–O, C–SF5, and N–CF3 bond formation. Overall, this research will establish a new paradigm for sustainable, accessible cross-coupling chemistry, and will significantly contribute to medical research, pharmaceutical development, and fundamental knowledge in organic synthesis.