Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States.
J Am Chem Soc. 2022 Aug 31;144(34):15549-15561. doi: 10.1021/jacs.2c04383. Epub 2022 Aug 17.
The C-H functionalization of silyl ethers via carbene-induced C-H insertion represents an efficient synthetic disconnection strategy. In this work, site- and stereoselective C(sp)-H functionalization at α, γ, δ, and even more distal positions to the siloxy group has been achieved using donor/acceptor carbene intermediates. By exploiting the predilections of Rh(-TCPTAD) and Rh(-2-Cl-5-BrTPCP) catalysts to target either more electronically activated or more spatially accessible C-H sites, respectively, divergent desired products can be formed with good diastereocontrol and enantiocontrol. Notably, the reaction can also be extended to enable desymmetrization of meso silyl ethers. Leveraging the broad substrate scope examined in this study, we have trained a machine learning classification model using logistic regression to predict the major C-H functionalization site based on intrinsic substrate reactivity and catalyst propensity for overriding it. This model enables prediction of the major product when applying these C-H functionalization methods to a new substrate of interest. Applying this model broadly, we have demonstrated its utility for guiding late-stage functionalization in complex settings and developed an intuitive visualization tool to assist synthetic chemists in such endeavors.
硅醚的 C-H 功能化通过卡宾诱导的 C-H 插入代表了一种有效的合成切断策略。在这项工作中，使用给体/受体卡宾中间体实现了对硅氧基α、γ、δ 位甚至更远位置的位点和立体选择性 C(sp)-H 功能化。通过利用 Rh(-TCPTAD)和 Rh(-2-Cl-5-BrTPCP)催化剂分别优先靶向更具电子活性或更具空间可及性的 C-H 位点，可以形成具有良好非对映选择性和对映选择性的不同目标产物。值得注意的是，该反应还可以扩展到实现手性硅醚的去对称化。利用本研究中广泛考察的底物范围，我们使用逻辑回归训练了一个机器学习分类模型，根据固有底物反应性和催化剂克服它的倾向来预测主要的 C-H 功能化位点。当将这些 C-H 功能化方法应用于感兴趣的新底物时，该模型可用于预测主要产物。广泛应用该模型，我们证明了其在复杂环境中引导后期功能化的实用性，并开发了一种直观的可视化工具，以协助合成化学家进行此类工作。
