Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst–substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.

分子识别在酶-底物特异性，基因调节和疾病治疗中起关键作用。受酶促过程中分子识别能力的启发，我们寻求开发其在有机合成中的用途。在这里，我们证明了合成的铑基催化剂如何能够选择性地结合脱氢氨基酸残基以启动环肽的顺序和立体选择性合成。我们的实验和理论研究相结合，揭示了级联还原的基础，该级联还原发生在立体控制较高的情况下，且在大环周围的一个方向上发生。由于催化剂可以从肽上解离，因此加氢反应的C到N方向性是由催化剂-底物识别控制的，而不是由催化剂保持与大环结合的过程性机理控制的。