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 (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 (ee > 99 %, dr = 99:1) with an overall yield of 64 %. The alkaloid isosolenopsin was prepared in three steps. The optimised biocatalytic step used DMF as cosolvent and gave excellent conversion (up to > 99 %) and perfect regio‐ and stereoselectivity. After chemical reduction, isosolenopsin was obtained in diastereomerically pure form with more than 99 % ee.