Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003, USA.
Department of Process Research and Development, Institution Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, NJ 07065, USA.
Angew Chem Int Ed Engl. 2022 Nov 25;61(48):e202213315. doi: 10.1002/anie.202213315. Epub 2022 Oct 26.
Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non-canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.
脱羟氨酸（Dha）的自由基加成反应是一种很有吸引力的、模块化的策略，可以用来开发用于药物发现的非典型肽类似物。先前关于肽和蛋白质中 Dha 残基的自由基加成反应的研究表明，该方法具有出色的官能团兼容性，但立体选择性的缺乏限制了该方法的合成实用性。在这里，我们通过使用手性镍催化剂来控制 Dha 在寡肽上的自由基加成的立体选择性，从而解决了这一挑战。该条件可以适应各种伯和仲亲电试剂，将聚乙二醇、生物素、卤代标记、疏水性和亲水性侧链引入肽中。该反应的特点是催化剂控制，可以在很大程度上克服基于底物的立体化学结果控制，从而对短肽进行修饰。我们预计，发现手性镍配合物可以赋予催化剂控制，从而允许快速对具有非天然侧链的肽进行后期修饰。
