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 ∼99%, E = 535) at 258 mmol (50 g/L) substrate concentration.

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Diethylaminomethyl-1,4-benzodioxane [(S)-Piperoxan]C13H19NO2ee 93%[α]D25=-11.2 (c 0.5, CHCl3)Source of chirality: Enzymatic ResolutionAbsolute configuration: (S)

Piperidinomethyl-l,4-benzodioxane [(S)-Prosympal]C14H19NO2ee 90%[α]D25=-14.3 (c 0.25, CHCl3)Source of chirality: Enzymatic ResolutionAbsolute configuration: (S)

(l-Piperazinylmethyl)-1,4-benzodioxane [(S,S)-Dibozane]C22H26N2O4ee 94%[α]D25=-16.2(c 0.5, CHCl3)Source of chirality: Enzymatic ResolutionAbsolute configuration: (S,S)

(S)-N-Boc-(1,4-benzodioxane-2-carbonyl)piperazineC18H24N2O5ee 99%[α]D25=+51.5 (c 1, CHCl3)Source of chirality: Enzymatic ResolutionAbsolute configuration: (S)