Lipase-catalyzed domino Michael–aldol reaction of 2-methyl-1,3-cycloalkanedione and methyl vinyl ketone for the synthesis of bicyclic compounds

ABSTRACT

Synthesis of bicyclic compounds was achieved via a lipase-catalyzed, stereoselective, domino Michael–aldol reaction of 2-methyl-1,3-cycloalkanedione and methyl vinyl ketone. Appropriate reaction conditions, including the type of enzyme, solvent, and temperature, were determined. In addition, the effects of solvent polarity and addtives were investigated. The reaction proceeded in the presence of lipase AS in a solution of 20% acetone in dimethylsulfoxide (DMSO) at 10 °C for 8 days, followed by the addition of p-toluenesulfonic acid (TsOH) to afford bicyclic compounds in 51–83% yields with moderate stereoselectivity. Although this domino Michael–aldol reaction showed only moderate stereoselectivity, even with the acid-supported enhancement of the reaction, these results represent potential new applications for lipase.

GRAPHICAL ABSTRACT

KEYWORDS:

• Bicyclic compound
• biocatalyst
• domino reaction
• lipase
• Michael–aldol reaction

Acknowledgment

We thank Meito Sangyo Co, Novozymes A/S and Amano Enzyme Inc. for their generous donation of lipase.