A general organocatalyzed Michael-Michael cascade reaction generates functionalized cyclohexenes

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• β-dicarbonyl compounds are versatile Michael donors.
• Intermediates from Michael additions of unsaturated β-ketoesters can lead to complex reaction pathways.
• Developing selective cascade reactions is crucial for efficient synthesis.

Purpose of the Study:

• To develop a novel Michael-Michael cascade reaction for synthesizing cyclohexene products.
• To explore the use of cyclic and linear unsaturated β-ketoesters as substrates.
• To establish general reaction conditions for organocatalyzed cascade reactions.

Main Methods:

• Design of cyclic unsaturated β-ketoester substrates.
• Utilized diphenyl prolinol silyl ether as an organocatalyst.
• Optimized reaction conditions including solvent and additives.
• Investigated substrate scope with both cyclic and linear unsaturated β-ketoesters.

Main Results:

• Developed the first diphenyl prolinol silyl ether catalyzed Michael-Michael cascade reaction.
• Achieved efficient synthesis of cyclohexene products from various unsaturated β-ketoesters.
• Demonstrated that reaction conditions dictate cascade pathways and molecular scaffolds.
• Generated highly functionalized cyclohexenes with up to four stereocenters, high yield (up to 97%), diastereoselectivity (up to 32:1 dr), and enantioselectivity (up to 99% ee).

Conclusions:

• A general organocatalyzed Michael-Michael cascade reaction was established.
• The reaction provides a powerful single-step method for synthesizing complex cyclohexene derivatives.
• Reaction condition optimization allows access to different molecular scaffolds from the same substrate.