Chemoenzymatic synthesis of piperoxan, prosympal, dibozane, and doxazosin

The synthesis of both enantiomers of 1,4-benzodioxan-2-carboxylic acid 1, a key synthetic intermediate for the therapeutic agents piperoxan, prosympal, dibozane, and doxazosin was achieved with good yields and high enantioselectivities via the Arthrobacter sp. lipase catalyzed kinetic resolution of ester (+/-)-17a. The influence of the co-solvents and the immobilization of the lipase upon kinetic resolution demonstrated that immobilized whole cells, in the presence of n-butanol as a co-solvent, resulted in the optimal resolution of the substrate (ee similar to 99%, E = 535) at 258 mmol (50 g/L) substrate concentration. (C) 2012 Elsevier Ltd. All rights reserved.