Evaluation of Several Routes to Advanced Pregabalin Intermediates: Synthesis and Enantioselective Enzymatic Reduction Using Ene-Reductases

Abstract

This publication describes the evaluation of four synthetic routes to the advanced pregabalin (Lyrica) intermediate 7. Asymmetric reduction of (E)-7 with an ene-reductase (OPR1 from Lycopersicon esculentum) gave a saturated cyanoester intermediate 5 with the desired S stereocenter in >99% ee. OPR1 also catalyzed the reduction of (Z)-7 to (S)-5, but with lower conversion and selectivity.

Enantioselective Copper‐Catalyzed Radical Ring‐Opening Cyanation of Cyclopropanols and Cyclopropanone Acetals

“…[2] Among them, enantiomerically enriched β-carbonyl nitriles are particularly prominent targets, because they can be transformed into γ-lactams and γamino acids, which are widely used as anti-depressant agents and selective agonists of GABA (γ-aminobutyric acids) receptors ( Figure 1). [3] A variety of methods have been established for asymmetric synthesis of β-carbonyl nitriles, including lewis acid-catalyzed conjugate hydrocyanation of α,βunsaturated compounds, [4] enzyme catalyzed bioreduc-tion of cyanoacrylates, [5] and nickel-catalyzed crosscoupling of α-halonitriles with organozinc reagents. [6] Despite these progresses, exploration of efficient approaches to access the chiral β-carbonyl nitriles is still in strong demand.…”

Development and Scale-up of an Organocatalytic Enantioselective Process to Manufacture (S)-Pregabalin

“…In addition, the best methods of resolution of Pregabalin gave only 25-30% yields. [1][2][3][4] Therefore, the present method, that provides (S)-1 in 65% yield is competitive when benchmarked against resolution. Considering that all the reagents could be sourced at cheap price and the solvents and catalysts recycled, this is a cost efficient and competitive method for the large scale manufacture of (S)-1.…”

A Rapid and High‐Throughput Assay for the Estimation of Conversions of Ene‐Reductase‐Catalysed Reactions

“…Even though the performances of these biocatalysts in terms of stereoselectivity are often close to optimal from the very first stages of the investigations, there is still some room for improvement as far as other relevant aspects of their synthetic application are concerned. For example, in different cases the tolerance shown by ERs to high substrate/product concentrations,2b–c as well as the specific activity toward selected target substrates,2d, 5 are inadequate for large‐scale applications.…”