Chemoenzymatic synthesis of Tamsulosin†

Abstract

Several chemoenzymatic pathways have been developed for the stereoselective production of the drug tamsulosin. The interest in the exclusive synthesis of its (R)-enantiomer lies in the greater activity compared to that displayed by its (S)-counterpart for the treatment of kidney stones and benign prostatic hyperplasia disease. Using different types of biocatalysts such as lipases, alcohol dehydrogenases and transaminases, three complementary strategies have been studied to introduce chirality into a key synthetic precursor. The first approach involved the lipase-catalyzed kinetic resolution of a racemic amine precursor, although low conversions and selectivities were found. A second strategy consisted in the synthesis of a chiral alcohol intermediate through a bioreduction proccess catalyzed by ADHs, with the identification of stereocomplementary redox enzymes capable of producing both enantiomers. The (S)-alcohol, obtained with ADH-A from Rhodococcus ruber, was subsequently converted into the corresponding amine through a telescoped approach. Alternatively, transaminases were also employed for the biotransamination of the previously studied intermediate ketone, which led directly to the enantiopure (R)-amine in high yield. Finally, the active pharmaceutical ingredient was prepared in enantiopure form and in 49% overall yield from the ketone precursor by a two-step sequential transformation of the chiral amine building block. These findings highlight the importance and versatility of enzyme catalysis for the stereoselective synthesis of drugs.