Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14850, United States.
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States.
J Am Chem Soc. 2022 Jan 26;144(3):1187-1197. doi: 10.1021/jacs.1c09412. Epub 2022 Jan 11.
The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
“神奇甲基”效应，即在引入单个甲基基团后，生物活性化合物的效力显著提高，这是药物化学家在药物发现过程中采用的一种简单而强大的策略。尽管取得了重大进展，但能够实现结构复杂的药物分子选择性 C(sp)-H 甲基化的方法仍然非常有限。在这项工作中，我们通过电化学氧化，揭示了一种用于保护胺（即酰胺、碳酸酯和磺酰胺）α-甲基化的模块化、高效和选择性策略。基于经典的 Shono 氧化反应，我们的机理分析指导了改进的电化学方案的开发，该方案具有广泛的反应范围、高官能团兼容性和操作简单性。重要的是，该反应体系适用于含有在药用活性化合物中常见碱性氮基团的复杂靶标进行后期功能化。当与有机锌介导的 C-C 键形成相结合时，我们的方案能够直接对各种胺衍生物进行甲基化，包括那些之前已经探索过“神奇甲基”效应的化合物。因此，这种合成策略避免了目前获得此类化合物所需的多步合成，有可能加速药物发现的努力。
