Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
J Am Chem Soc. 2022 Mar 9;144(9):3939-3948. doi: 10.1021/jacs.1c11921. Epub 2022 Feb 25.
Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Central to the success of this strategy is the use of a simple -acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes γ-C-H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C-H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymmetrization of -isobutyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of functionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules.
由于其独特的结构特征，应变的氨甲基环烷烃在药物化学中是一个经常出现的支架，这些结构特征赋予了它们一系列的生物性质。在这里，我们报告了钯催化的氨甲基环丙烷和环丁烷与芳基硼酸的对映选择性 C(sp)-H 芳基化反应。一系列天然的三级烷基胺基团能够作为单一非对映异构体，以优异的对映体比例引导 C-H 断裂，并在应变的环烷烃骨架上形成碳-芳基键。该策略的成功关键在于使用简单的 -乙酰氨基酸配体，它不仅控制对映选择性，而且还促进 γ-C-H 活化，而不是其他途径。对环钯化步骤的计算分析提供了对如何发生对映选择性 C-H 断裂的理解，并揭示了与我们之前关于 -异丁基三级烷基胺对映选择性去对称化工作不同的过渡态结构。这种简单而操作简单的方法简化了功能化氨甲基应变环烷烃的构建，我们相信它将在与生物活性小分子合成有关的学术和工业领域得到广泛应用。
