Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China.
State Key Laboratory and Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, PR China.
Nat Commun. 2024 Jun 18;15(1):5181. doi: 10.1038/s41467-024-49223-y.
Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N-acyl groups play a decisive role in the reaction activity.
肽醛是各种生物系统中必不可少的关键生物分子，这就不断推动着人们去开发高效的合成方法。在此，我们开发了一种无金属、简便且生物兼容的策略，用于直接电化学合成非天然肽醛。这种电氧化方法通过 C‒N 键的断裂实现了一步和原子经济性的开环反应，从而实现了同脯氨酸特异性肽的多样化，并扩大了底物范围，包括各种大小的酰胺、酯和环状胺。该电合成方案的显著效果为使用简洁的合成序列和无外消旋条件，高效地修饰和组装线性和大环肽奠定了基础。此外，实验和密度泛函理论（DFT）计算的结合表明，不同的 N-酰基在反应活性中起着决定性的作用。
