Enzymatic transesterification of pharmacologically interesting β-aminocycloalkanol precursors

Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E ≫ 200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.

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(1S,2R)-2-PhthalimidocyclopentanolC13H13NO3Ee >99% (HPLC, Chiralpak AS)[α]D20=-3.6 (c 0.50, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (1S,2R)

(1R,2S)-2-Phthalimido-1-acetoxycyclopentaneC15H15NO4Ee >99% (HPLC, Chiralpak AS)[α]D20=+8.8 (c 0.50, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (1R,2S)

(1S,2R)-2-PhthalimidocyclohexanolC14H15NO3Ee >99% (HPLC, Chiralcel OD)[α]D20=-11.5 (c 0.50, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (1S,2R)

(1S,2R)-2-Phthalimido-1-acetoxycyclohexaneC16H17NO4Ee >99% (HPLC, Chiralcel OD)[α]D20=-12.0 (c 0.50, CHCl3)Source of chirality: Enzymatic resolutionAbsolute configuration: (1R,2S)