Preparation of enantiomerically pure N-heterocyclic amino alcohols by enzymatic kinetic resolution

The synthesis of both enantiomers of N-benzyl-3-hydroxypyrrolidine and N-benzyl-3-hydroxypiperidine via enzymatic kinetic resolution of the corresponding racemic esters is described. Various commercially available hydrolases were studied as biocatalysts in native and immobilized form. The best results were obtained with lipases PS, AK, CAL-B and with protease Alcalase, which were active and selective for the kinetic resolutions of racemic esters (E > 100). Under optimized reaction conditions, highly enantiomerically enriched (up to 99.5% ee) resolution products were obtained. Lipase and protease showed opposite enantiopreference on the esters, allowing the preparation of both enantiomers of the target compounds. Semi-continuous reactions in column reactors with immobilized biocatalysts were also performed with high enantioselectivities. Inversion of the configuration at C(3) of N-benzyl-3-hydroxypyrrolidine was quantitatively effected in a short number of steps.

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(R)-N-Benzyl-3-hydroxypirrolidineC11H15NOee >99.5% on Chiralcel OJ HPLC column[α]D20 = +3.9 (c 0.5, MeOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (R)

(R)-N-Benzyl-3-hydroxypiperidineC12H17NOee >99.5% on Chiralcel OJ HPLC column[α]D20 = −13.4 (c 0.5, MeOH)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (R)