Chemoenzymatic synthesis of levetiracetam and analogues

Abstract

Biocatalysts (enzymes and / or microorganisms) are widely used to create or resolve chiral centers, especially for drug synthesis. Levetiracetam (LEV), commercially known as Keppra®, is a chiral substance with anticonvulsant properties whose pharmacological activity is related to its (S) enantiomer. The increase of LEV usage over other anticonvulsant drugs is closely associated with its low occurrence of side effects. Several routes for LEV chemosynthetic production are reported in the literature. Most of them involve numerous synthetic steps, high-energy consumption, use of metal catalysts and low overall yields. On the other hand, this project aims to develop a chemoenzymatic route, with fewer steps, milder conditions and environmentally friendly reaction for the synthesis of LEV and analogues. The first step will focus on the synthesis of butanecyanohydrin from cyanosilylation of propanal, followed by the formation of halogenated compound. Different nitrogen heterocycles will replace the halogen atom to produce the starting materials for microbial enzymatic reactions. The main strategies to obtain the desired products, with high yields and enantioselectivity, will be the enzymatic selection and screening and use of ionic liquids as reaction medium.