近日，美国斯克里普斯研究所Phil S. Baran团队研究了立体伸缩自由基交叉耦合。该项研究成果发表在2025年4月22日出版的《自然》杂志上。

自由基最早是由Gomberg在120多年前发现的，Kochi在20世纪70年代首次证明了自由基的交叉偶联。与广泛使用的极性交叉偶联化学形成C（sp²）-C（sp²）键相比，自由基交叉偶联在应用于饱和体系的偶联时是有利的，因为所采用的条件温和，与单电子化学相关的化学选择性增强。事实上，在交叉偶联中使用无处不在的碳基片段（羧酸、醇、胺、烯烃等）的能力大大简化了对各种复杂分子的访问。尽管有这些优点，但涉及自由基的对映体特异性偶联反应尚不清楚，并且由于其近乎瞬时的外消旋化（皮秒时间尺度），通常被认为具有挑战性。

因此，控制自由基交叉偶联的立体化学结果只能在个案的基础上使用定制的手性配体或在附近立体中心的指导下以非对映选择性的方式实现。研究组展示了如何利用易于获得的富对映体磺酰肼和低负载的廉价非手性镍催化剂来首次解决这一棘手的挑战，从而实现富对映烷基片段和（杂）芳基卤化物之间的对映体特异性、立体保留的自由基交叉偶合，而无需外源氧化还原化学或手性配体。计算支持了一种独特的含镍二氮烯过渡态与由N₂损失驱动的C-C键形成的中间体。

附：英文原文

Title: Stereoretentive radical cross-coupling

Author: Sun, Jiawei, He, Jiayan, Massaro, Luca, Cagan, David A., Tsien, Jet, Wang, Yu, Attard, Flynn C., Smith, Jillian E., Lee, Jason S., Kawamata, Yu, Baran, Phil S.

Issue&Volume: 2025-04-22

Abstract: Free radicals were first discovered over 120 years ago by Gomberg1 and the first radical cross-couplings demonstrated by Kochi in the 1970’s.2 In contrast to widely employed polar cross-coupling chemistry to forge C(sp2)–C(sp2) bonds (Suzuki, Negishi, Kumada, etc.), radical cross-coupling is advantageous when applied to the coupling of saturated systems due to the mild conditions employed and enhanced chemoselectivity associated with single electron chemistry. Indeed, the ability to employ ubiquitous carbon-based fragments (carboxylic acids, alcohols, amines, olefins, etc.) in cross-coupling has dramatically simplified access to a variety of complex molecules.3-9 Despite these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be challenging due to their near-instantaneous racemization (picosecond timescale).10 As a result, controlling the stereochemical outcome of radical cross-coupling can only be achieved on a case-by-case basis using bespoke chiral ligands11 or in a diastereoselective fashion guided by nearby stereocenters.12 Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni-catalyst can be enlisted to solve this vexing challenge for the first time thereby enabling enantiospecific, stereoretentive radical cross-coupling between enantioenriched alkyl fragments and (hetero)aryl halides without exogenous redox chemistry or chiral ligands. Calculations support the intermediacy of a unique Ni-bound diazene-containing transition state with C–C bond formation driven by loss of N2.

DOI: 10.1038/s41586-025-09011-0

Source: https://www.nature.com/articles/s41586-025-09011-0