Total Synthesis of (-)-Lasonolide A

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• Lasonolides are novel polyketides exhibiting significant in vitro anti-cancer activity.
• The complex structure of lasonolide A presents a synthetic challenge.

Purpose of the Study:

• To develop a formal synthesis of lasonolide A.
• To establish a convergent synthetic strategy for lasonolide A.
• To investigate and control selectivity in Ru-catalyzed alkene-alkyne coupling.

Main Methods:

• Convergent synthesis utilizing two complex fragments.
• Ruthenium-catalyzed alkene-alkyne coupling reaction.
• Enzyme-catalyzed dynamic kinetic reduction of a β-ketoester.

Main Results:

• Successful formal and subsequent total synthesis of lasonolide A.
• Demonstrated control over linear vs. branched product selectivity in Ru-catalyzed coupling through substrate modification.
• Engineered enzyme achieved high enantioselectivity in β-ketoester reduction.

Conclusions:

• The developed synthetic route provides access to lasonolide A.
• The study advances the understanding and application of Ru-catalyzed coupling reactions.
• Enzyme engineering offers a powerful tool for stereoselective synthesis.