Multicomponent, Enantioselective Michael-Michael-Aldol-β-Lactonizations Delivering Complex β-Lactones

Area of Science:

• Organic Chemistry
• Catalysis
• Asymmetric Synthesis

Background:

• Tertiary amine Lewis bases are crucial in organic synthesis.
• Chiral β-lactones are valuable synthetic targets with diverse applications.
• Developing efficient multicomponent reactions for complex molecule synthesis is a key challenge.

Purpose of the Study:

• To develop a novel catalytic, enantioselective, three-component organocascade process.
• To synthesize complex bi- and tricyclic β-lactones.
• To explore the formation of multiple new bonds and stereocenters in a single operation.

Main Methods:

• Reaction of optically active tertiary amine Lewis bases with unsaturated acid chlorides.
• Utilizing a three-component strategy involving Michael-Michael-aldol-β-lactonization.
• Employing isothiourea catalysts for enantioselective synthesis and kinetic resolution.

Main Results:

• Formation of chiral α,β-unsaturated acylammonium salts as key intermediates.
• Successful synthesis of complex bi- and tricyclic β-lactones with up to four contiguous stereocenters.
• Achieved yields of 22-75% in the racemic series and 46% to quantitative with up to 94:6 er in the enantioselective series.
• Evidence for dynamic kinetic asymmetric transformation in optimizing tricyclic-β-lactone synthesis.

Conclusions:

• The described multicomponent, organocascade process is highly effective for constructing complex chiral β-lactones.
• The methodology offers a powerful route to molecules with multiple stereocenters and fused ring systems.
• Further optimization may enhance yields and enantioselectivity for specific targets.