Chemoenzymatic dynamic kinetic resolution of primary amines

Area of Science:

• Organic Chemistry
• Biocatalysis
• Asymmetric Synthesis

Background:

• Chiral amines are crucial building blocks in pharmaceuticals and agrochemicals.
• Developing efficient methods for enantioselective synthesis of amine derivatives remains a significant challenge.
• Dynamic kinetic resolution (DKR) offers a powerful strategy to overcome equilibrium limitations in chiral resolutions.

Purpose of the Study:

• To develop an efficient and highly enantioselective process for the dynamic kinetic resolution of unfunctionalized primary amines.
• To combine ruthenium-catalyzed racemization with lipase-catalyzed acylation for DKR.
• To demonstrate the broad applicability of the developed method to various primary amines.

Main Methods:

• A one-pot procedure combining a ruthenium catalyst for racemization and a lipase enzyme for enantioselective acylation.
• Screening of various reaction conditions, including solvents, acyl donors, and catalysts, to optimize the DKR process.
• Analysis of reaction products using chiral High-Performance Liquid Chromatography (HPLC) to determine yield and enantiomeric excess (ee).

Main Results:

• The combined ruthenium-lipase system effectively resolved a diverse range of unfunctionalized primary amines.
• High yields (up to 99%) and excellent enantioselectivity (up to >99% ee) were achieved for the resulting amide products.
• The process demonstrated good functional group tolerance, allowing for the resolution of various amine substrates.

Conclusions:

• An efficient and versatile dynamic kinetic resolution of primary amines has been successfully developed.
• The combination of ruthenium-catalyzed racemization and lipase-catalyzed acylation provides a robust method for accessing enantiopure amides.
• This methodology offers a valuable tool for the asymmetric synthesis of chiral amine derivatives.