Enzymatic resolution of hindered cyanohydrins, key precursors of muscarinic receptor antagonists

Enantiomerically pure 1-cycloalkyl-1-hydroxy-1-phenylcyanohydrins, key precursors in the synthesis of (S)-oxybutynin and other antimuscarinic agents, have been successfully prepared via lipase-catalyzed kinetic resolutions. Pseudomonas cepacia and Candida antarctica lipase B have shown excellent enantioselectivities in hydrolysis and acylation processes, depending on the substrate structure and the reaction conditions. Furthermore, molecular modeling of phosphonate transition state analogue for the C. antarctica lipase B enzymatic hydrolysis resolution step supports these facts, which were experimentally observed.

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(+)-(1-Cyano-1-cyclobutyl-1-phenylmethoxy)carbonylmethyl acetateC16H17NO4Ee = 70%[α]D20=+39 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed hydrolysisAbsolute configuration: (R)

(−)-1-Cyano-1-cyclobutyl-1-phenylmethyl hydroxyacetateC14H15NO3Ee = 99%[α]D20=-49 (c 0.12, CHCl3)Source of chirality: lipase-catalyzed hydrolysisAbsolute configuration: (S)

(+)-1-Cyano-1-cyclopentyl-1-phenylmethyl hydroxyacetateC15H17NO3Ee = 66%[α]D20=+13 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (S)

(+)-1-Cyano-1-cyclohexyl-1-phenylmethyl hydroxyacetateC16H19NO3Ee = 83%[α]D20=+7.5 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (S)

(−)-(1-Cyano-1-cyclopentyl-1-phenylmethoxy)carbonylmethyl butyrateC19H23NO4Ee = 64%[α]D20=-5 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)

(−)-(1-Cyano-1-cyclohexyl-1-phenylmethoxy)carbonylmethyl butyrateC20H25NO4Ee = 90%[α]D20=-6 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)

(−)-(1-Cyano-1-cyclopentyl-1-phenylmethoxy)carbonylmethyl decanoateC25H35NO4Ee = 92%[α]D20=-26 (c 0.15, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)

(−)-(1-Cyano-1-cyclohexyl-1-phenylmethoxy)carbonylmethyl decanoateC26H37NO4Ee = 72%[α]D20=-7 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)

(−)-(1-Cyano-1-cyclopentyl-1-phenylmethoxy)carbonylmethyl benzoateC22H21NO4Ee = 70%[α]D20=-6 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)

(−)-(1-Cyano-1-cyclohexyl-1-phenylmethoxy)carbonylmethyl benzoateC23H23NO4Ee = 96%[α]D20=-12 (c 0.10, CHCl3)Source of chirality: lipase-catalyzed acylationAbsolute configuration: (R)