Chemoenzymatic total synthesis of rotigotine IRED-catalyzed reductive amination

A short and chemoenzymatic synthesis of rotigotine using an IR-36-M5 mutant is reported. Focusing on the residues that directly contact the 2-tetralone moiety, we applied structure-guided semi-rational design to obtain a double-mutant F260W/M147Y, which showed a good isolated yield and S -stereoselectivity >99% toward 2-aminotetralin synthesis. Furthermore, the utility of this biocatalytic protocol was successfully demonstrated in the enantioselective synthesis of rotigotine via enzymatic reductive amination as the key step. An engineered imine reductase (IRED) was developed specifically for 2-tetralone substrate, and utilized in the total synthesis of rotigotine.