Biocompatible metal-assisted C–C cross-coupling combined with biocatalytic chiral reductions in a concurrent tandem cascade

Abstract

In this study, we present a concurrent chemo/biocatalytic one pot reaction cascade by combining a metal (Pd/Cu) assisted Liebeskind–Srogl (L–S) coupling with an enantioselective enzymatic reduction for the production of chiral amines and alcohols. The latter transformation was realized by applying enantiocomplementary alcohol dehydrogenases from Lactobacillus kefir (R-selective) and Rhodococcus ruber (S-selective). Compatibility issues were solved by investigating first the L–S-coupling protocol in water at room temperature. Subsequently, we investigated two different biphasic systems and applied a biomimicking approach to separate enzyme-deactivating components. By using a lipophilic membrane in a smart reactor design, we were able to perform concurrent catalytic cascades with overall concentrations up to 100 mM substrate and to produce 1-phenylethylamine and several chiral alcohols in high yields (up to 81% over 2 steps) and enantiomeric purity ((+) and (−)-enantiomers both with 99% ee).