近日，美国斯克里普斯研究所Phil S. Baran团队报道了可保持立体构型的自由基烷基-烷基交叉偶联反应。相关论文于2026年6月4日发表在《科学》杂志上。

由于存在竞争性的β-氢消除和自身偶联反应，以及自由基途径固有的较差立体控制能力，通过交叉偶联构建具有立体构型的C(sp³)-C(sp³)键仍颇具挑战。

研究组报道了一种可放大且可保持立体构型的自由基-自由基交叉偶联反应，该反应将两种不同的瞬态烷基自由基（分别源于富对映体的磺酰肼和非手性的一级及二级烷基卤化物）在无需手性配体、导向基团或外源氧化还原试剂的条件下实现偶联。

这种底物控制策略采用了一种镍催化的氧化还原中性体系，能够实现对二氮烯介导的自由基生成与卤原子转移的精确动力学匹配。该反应在多种哌啶和吡咯烷骨架结构上实现了80%至96%的对映体特异性以及合成有效产率（高达90%），同时兼容醚、游离胺、芳基卤化物、杂环、烯烃及其他敏感基序。机理研究支持通过笼内自由基回弹到镍中心来保持手性，随后经镍(I)-镍(III)介导的自由基捕获和还原消除完成反应。

附：英文原文

Title: Stereoretentive radical-based alkyl-alkyl cross-coupling

Author: Yu Wang, Jiawei Sun, Yin Li, David A. Cagan, Oliver T. Ring, Xin Zeng, Jet Tsien, Luca Massaro, Jillian E. Smith, Brandon J. Orzolek, Michael R. Collins, Yu Kawamata, Phil S. Baran

Issue&Volume: 2026-06-04

Abstract: The construction of stereogenic C(sp3)–C(sp3) bonds through cross-coupling remains a formidable challenge owing to competing β-hydride elimination and homocoupling as well as the poor inherent stereocontrol of radical pathways. In this work, we report a scalable stereoretentive radical-radical cross-coupling of two distinct, transient alkyl radicals, derived from enantioenriched sulfonylhydrazides and achiral primary and secondary alkyl halides, achieved without chiral ligands, directing groups, or exogenous redox agents. This substrate-controlled approach leverages a nickel-catalyzed, redox-neutral manifold, which enables precise kinetic matching of diazene-mediated radical generation and halogen atom transfer. The reaction produced enantiospecificities of 80 to 96% and synthetically useful yields (up to 90%) across diverse piperidine and pyrrolidine scaffolds while tolerating ethers, free amines, aryl halides, heterocycles, olefins, and other sensitive motifs. Mechanistic studies support caged radical rebound at nickel to preserve chirality, followed by nickel(I)-nickel(III)–mediated radical capture and reductive elimination.

DOI: aef6981

Source: https://www.science.org/doi/10.1126/science.aef6981