Stereoretentive radical cross-coupling.

Abstract

Free radicals were first discovered more than 120 years ago by Gomberg¹ and the first radical cross-couplings demonstrated by Kochi in the 1970s (ref. ²). In contrast to widely used polar cross-coupling chemistry to forge C(sp²)-C(sp²) bonds (such as Suzuki, Negishi and Kumada), radical cross-coupling is advantageous when applied to the coupling of saturated systems because of the mild conditions used and enhanced chemoselectivity associated with single-electron chemistry. The ability to use ubiquitous carbon-based fragments (such as carboxylic acids, alcohols, amines and olefins) in cross-coupling has greatly simplified access to various complex molecules^3-9. Apart from these advantages, enantiospecific coupling reactions involving free radicals are unknown and generally believed to be challenging because of their near-instantaneous racemization (picosecond timescale)¹⁰. As a result, controlling the stereochemical outcome of radical cross-coupling can be achieved only on a case-by-case basis using bespoke chiral ligands¹¹ or in a diastereoselective fashion guided by nearby stereocentres¹². Here we show how readily accessible enantioenriched sulfonylhydrazides and low loadings of an inexpensive achiral Ni catalyst can be used to solve this challenge, 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.