Stereoretentive radical-based alkyl-alkyl cross-coupling

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Constructing stereogenic C(sp3)-C(sp3) bonds via cross-coupling is challenging due to competing side reactions and poor stereocontrol in radical pathways.
• Existing methods often require chiral ligands or directing groups, limiting their scope and efficiency.

Purpose of the Study:

• To develop a scalable and stereoretentive method for radical-radical cross-coupling of distinct alkyl radicals.
• To achieve high enantiospecificity in C(sp3)-C(sp3) bond formation without relying on chiral auxiliaries or exogenous redox agents.

Main Methods:

• Utilized enantioenriched sulfonylhydrazides and achiral alkyl halides as radical precursors.
• Employed a nickel-catalyzed, redox-neutral manifold for controlled radical generation and cross-coupling.
• Investigated mechanistic pathways involving diazene-mediated radical generation and halogen atom transfer.

Main Results:

• Achieved stereoretentive radical-radical cross-coupling with enantiospecificities ranging from 80% to 96%.
• Obtained synthetically useful yields up to 90% for diverse piperidine and pyrrolidine scaffolds.
• Demonstrated tolerance for various functional groups including ethers, amines, aryl halides, and olefins.

Conclusions:

• The substrate-controlled approach enables efficient and stereospecific formation of C(sp3)-C(sp3) bonds.
• Caged radical rebound at nickel is proposed to preserve chirality during the cross-coupling process.
• The developed method offers a valuable tool for synthesizing complex chiral molecules with high fidelity.