Concise Chemoenzymatic Three Step Total Synthesis of Isosolenopsin Through Medium Engineering.

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 -heptane best results were obtained employing two enantio-complementary ω-transaminases originating from between 30-40 °C; under these conditions conversions of >99% and perfect stereocontrol ( > 99%) were achieved. Diastereostelective chemical reduction (H/Pd/C) of the biocatalytic product gave the target compound. The linear three step synthesis provided the natural product isosolenopsin in diastereomerically pure form ( > 99%, d.r. = 99:1) with an overall yield of 64%.