Panigrahi Nihar R, Khan Shahrukh M, Arora Paramjit S
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States.
J Am Chem Soc. 2025 Jul 23;147(29):25682-25691. doi: 10.1021/jacs.5c07242. Epub 2025 Jul 14.
Peptide synthesis is a highly optimized process that has led to the production of new classes of therapeutics and materials. The process of peptide synthesis is straightforward: commercially available, orthogonally protected amino acids can be linked on the solid phase using highly efficient coupling agents. However, the simplicity of peptide synthesis masks a significant drawback of the current method: it is highly wasteful and utilizes a solvent that is facing restrictions on its use. A catalyst that allows solid phase synthesis of peptides in benign solvents without requirement for excess reagents and protected amino acids would have a significant impact. Here, we describe the development of a small molecule catalyst for peptide synthesis. The catalyst design incorporates redox recycling of diselenide and phosphine with air as the ultimate oxidant and phenylsilane as the ultimate reductant. The catalyst affords efficient coupling of amino acids in the solution and solid phase. Significantly, the catalyst functions with acetonitrile, bypassing the need for DMF. The current effort builds on mechanistic analysis of reaction rates and intermediates in our prior work which led to a hydrogen bonding catalyst: [Handoko; ; Panigrahi, N. R.; Arora, P. S. 2022, 144, 3637-3643]. Here, we significantly simplified earlier designs to afford an easily accessible small molecule catalyst.
肽合成是一个高度优化的过程,已促成了新型治疗药物和材料的产生。肽合成过程很简单:市售的、正交保护的氨基酸可使用高效偶联剂在固相上连接。然而,肽合成的简单性掩盖了当前方法的一个重大缺点:它非常浪费,且使用的一种溶剂的使用正面临限制。一种能够在良性溶剂中进行肽的固相合成、无需过量试剂和保护氨基酸的催化剂将产生重大影响。在此,我们描述了一种用于肽合成的小分子催化剂的开发。该催化剂设计结合了二硒化物和膦的氧化还原循环,以空气作为最终氧化剂,苯基硅烷作为最终还原剂。该催化剂能在溶液和固相中实现氨基酸的高效偶联。重要的是,该催化剂可在乙腈中发挥作用,无需使用N,N-二甲基甲酰胺(DMF)。目前的工作基于我们之前对反应速率和中间体的机理分析,该分析促成了一种氢键催化剂:[汉多科;;帕尼格拉希,N.R.;阿罗拉,P.S. 2022,144,3637 - 3643]。在此,我们大幅简化了早期设计,以提供一种易于获取的小分子催化剂。