Concise Chemoenzymatic Three‐Step Total Synthesis of Isosolenopsin through Medium Engineering

Abstract

A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. In the key step, a ω-transaminase catalyzed the regioselective mono-amination of the diketone pentadecane-2,6-dione which was obtained in a single step via Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol% DMF or <i>n</i>-heptane best results were obtained employing two enantio-complementary ω-transaminases originating from <i>Arthrobacter</i> between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol (<i>ee</i> > 99%) were achieved. Diastereostelective chemical reduction (H₂/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form (<i>ee</i> > 99%, d.r. = 99:1) with an overall yield of 64%.