Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach

Area of Science:

• Organic Chemistry
• Catalysis
• Asymmetric Synthesis

Background:

• Catalytic enantioselective methods often show limited scope with sterically or electronically demanding substrates.
• Expanding existing asymmetric reactions to new substrates is a significant challenge in synthetic chemistry.

Purpose of the Study:

• To develop a systematic workflow to enhance the applicability and reliability of asymmetric conjugate additions.
• To adapt copper-catalyzed alkylzirconium additions for sterically demanding α,β-unsaturated ketones.

Main Methods:

• Utilized quantitative structure-selectivity relationships (QSSRs) for modified phosphoramidite ligand design.
• Employed iterative model construction and ligand synthesis, evaluating 20 chiral ligands.
• Investigated copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles.

Main Results:

• Successfully adapted the copper-catalyzed reaction for sterically demanding linear enones, including those with tert-butyl β-substituents.
• Achieved high yields (up to 99%) and enantioselectivity (up to 95% ee) across 20 diverse examples.
• Demonstrated tolerance for common functional groups in both nucleophiles and electrophiles.

Conclusions:

• The developed workflow broadens the scope of copper-catalyzed asymmetric conjugate addition reactions.
• The modified ligands and systematic approach enable the use of challenging substrates, enhancing synthetic utility.