Xu Yongzhuo, Wang Jiajia, Deng Guo-Jun, Shao Wen
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, P. R. China.
Chem Commun (Camb). 2023 Apr 4;59(28):4099-4114. doi: 10.1039/d3cc00439b.
The significance of chiral α-tertiary amines in medicinal chemistry and drug development has been unquestionably established in the last few decades. α-Tertiary amines are attractive structural motifs for natural products, bioactive molecules and pharmaceuticals and are preclinical candidates. Their syntheses have been the focus of intensive research, and the development of new methods has continued to attract more and more attention. In this review, we present the progress in the last decade in the development of synthetic methods for the assembly of chiral ATAs transition-metal catalysis. To date, the effective approaches in this area could be categorized into three strategies: enantioselective direct and indirect Mannich addition to ketimines; umpolung asymmetric alkylation of imine derivatives; and asymmetric C-N cross-coupling of tertiary alkyl electrophiles. Several related developing strategies for the synthesis of ATAs, such as hydroamination of alkenes, HAT amination approaches and the C-C coupling of α-aminoalkyl fragments, are also described in this article. These strategies have emerged as attractive C-C and C-N bond-forming protocols for enantioselective construction of chiral α-tertiary amines, and to some extent are complementary to each other, showing the prospect of application in medicinal chemistry and chemical biology.
在过去几十年里，手性α-叔胺在药物化学和药物开发中的重要性已得到明确确立。α-叔胺是天然产物、生物活性分子和药物中具有吸引力的结构基序，并且是临床前候选药物。它们的合成一直是深入研究的重点，新方法的开发也持续吸引着越来越多的关注。在本综述中，我们介绍了过去十年中用于构建手性α-叔胺（α-TAs）的合成方法在过渡金属催化方面的进展。迄今为止，该领域的有效方法可分为三种策略：对酮亚胺进行对映选择性直接和间接曼尼希加成；亚胺衍生物的极性翻转不对称烷基化；以及叔烷基亲电试剂的不对称碳-氮交叉偶联。本文还描述了几种用于合成α-TAs的相关发展策略，例如烯烃的氢胺化、氢原子转移（HAT）胺化方法以及α-氨基烷基片段的碳-碳偶联。这些策略已成为对映选择性构建手性α-叔胺的有吸引力的碳-碳和碳-氮键形成方案，并且在一定程度上相互补充，展现出在药物化学和化学生物学中的应用前景。
