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. The key step was a ω‐transaminase‐catalysed regioselective monoamination of the diketone pentadecane‐2,6‐dione, which was obtained in a single step through the application of a 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.‐% N , N ‐dimethylformamide (DMF) or n ‐heptane the best results were obtained by employing two enantiocomplementary ω‐transaminases originating from Arthrobacter at 30–40 °C; under these conditions, conversions of more than 99 % and perfect stereocontrol ( ee > 99 %) were achieved. Diastereoselective chemical reduction (H 2 /Pd/C) of the biocatalytic product gave the target compound. The linear three‐step synthesis provided the natural product isosolenopsin in diastereomerically pure form ( ee > 99 %, dr = 99:1) with an overall yield of 64 %.