Assessing biocatalysis for the synthesis of optically active tetrahydropyrazolo[1,5-α]pyrimidines (THPPs) as novel therapeutic agents

•Enzymatic screening to identify the potential application of biocatalysis to therapeutically relevant substrates: tetrahydropyrazolo[1,5-α]pyrimidines.•CAL-B-catalyzed enantioselective biotransformations: kinetic resolution of chiral substrates with asymmetric centres located far from the catalytic centre.•Proof of concept for process optimization: screening of bio-based co-solvents.

Enantiomerically pure THPPs are useful pharmacological agents in relevant therapeutic areas such as tuberculosis, osteoporosis and hepatitis C. Typically resolved by preparative chiral HPLC, in this work the catalytic approach – via hydrolase-catalyzed kinetic resolution – has been demonstrated for the first time. After biocatalytic successful proof-of-concept, future opportunities for protein engineering and process set-up appear.

Graphical abstractBiocatalysis takes over. Enantiomerically pure THPPs are useful pharmacological agents in relevant therapeutic areas such as tuberculosis, osteoporosis and hepatitis C. Typically resolved by preparative chiral HPLC, in this work the catalytic approach – via hydrolase-catalyzed kinetic resolution – has been demonstrated for the first time. After biocatalytic successful proof-of-concept, future opportunities for protein engineering and process set-up appear.Figure optionsDownload full-size imageDownload as PowerPoint slide