Resolution of racemic amines via lipase-catalyzed benzoylation: Chemoenzymatic synthesis of the pharmacologically active isomers of labetalol

Lipase-catalyzed benzoylation of amines was shown to be feasible, in some cases with high enantioselectivity, and the best results were obtained using immobilized lipase from Candida antarctica (Novozym 435) and methyl benzoate as acyl donor in the presence of molecular sieves. The procedure was optimized for the resolution of (+/-)-1-methyl-3-phenylpropylamine, a key intermediate in the synthesis of antihypertensive drug labetalol, and the enantiopure (R)-benzamide was then converted into the pharmacologically active isomers of the drug. In comparison with the reported synthesis of chiral isomers of labetalol, this chemoenzymatic route offers the advantage in the lack of any chiral stoichiometric auxiliary.