康 · 学术 | Reaction of the Day No. 1495

转自：康龙化成

Stereoretentive Radical Cross-Coupling

Jiawei Sun,†1Jiayan He,†1Luca Massaro,†1David A. Cagan,1 Jet Tsien,1 Yu Wang,1 Flynn C. Attard,1 Jillian E. Smith,2 Jason S. Lee,2 Yu Kawamata,1 Phil S. Baran*1

1 Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, United States.

2 Automated Synthesis Facility, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA, 92037, United States.

—Nature. 2025

Recommended by Murong Xu_MC3

KEYWORDS: Stereoretentive, radical cross-coupling, Ni catalysis, Stereoselective (反应类型)sulfonylhydrazide(hetero)aryl halides (原料), aryl alkanes (产物), C(sp3)–C(sp2)(成键类型)

ABSTRACT: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.

a, Enantiospecific radical cross-coupling is widely viewed as challenging based on first principles. The design of chiral ligands for enantioconvergent radical cross-coupling is challenging and not as general as for the case of asymmetric hydrogenation.

b, Hypothesis and execution: enantiopure sulfonylhydrazides are the key to realize enantiospecific radical coupling

Scope and generality of

stereoretentive cross-coupling

Prof. Phil S. Baran et al have developed a stereoretentive, transition metal-catalyzed radical cross-coupling which has historically been regarded as a near-impossible transformation based on first principles. A simple solution is now disclosed using easily accessible enantioenriched sulfonylhydrazides as radical donors and an inexpensive, achiral Ni-catalyst. The realization of this longstanding challenge can be singularly attributed to the use of sulfonylhydrazide radical precursors for two reasons: (1) catalysis and reaction setup are simplified by removing exogenous redox-cycles and (2) a tethered diazene-Ni intermediate is presumably formed, as supported by calculations; loss of N2 drives C–C bond formation. A myriad of future directions, avenues for additional improvement, and applications in organic synthesis based on these findings can be envisioned.