Diastereoconvergent Negishi cross-coupling using functionalized cyclohexylzinc reagents

Area of Science:

• Organic Chemistry
• Catalysis
• Organometallic Chemistry

Background:

• Palladium-catalyzed cross-coupling reactions are crucial in organic synthesis.
• Achieving high diastereoselectivity in these reactions, especially with substituted cyclohexyl systems, remains a challenge.

Purpose of the Study:

• To develop highly diastereoselective palladium-catalyzed cross-coupling reactions.
• To investigate the influence of ligands and additives on stereoselectivity.
• To explore the scope with various substituted cyclohexylzinc reagents and coupling partners.

Main Methods:

• Utilized functionalized 2-, 3-, and 4-substituted cyclohexylzinc reagents.
• Employed palladium catalysis with Ruphos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl) as a ligand.
• Optimized reaction conditions using lithium chloride (LiCl) and N-ethylpyrrolidone (NEP) as additives.

Main Results:

• Achieved highly diastereoselective cross-coupling reactions under mild conditions.
• Demonstrated excellent stereoselectivity and good functional group tolerance.
• Confirmed the effectiveness of Ruphos ligand and LiCl/NEP additive system.

Conclusions:

• The developed method provides a robust route for diastereoselective synthesis of complex molecules.
• The stereoselectivity is rationalized by the equatorial positioning of the palladium moiety in the intermediate.
• This approach offers significant advantages for constructing stereochemically defined organic compounds.