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 omega-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 omega-transaminases originating from Arthrobacter at 30-40 degrees 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%.