Efficient lipase-catalyzed kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles: application to an expedient synthesis of a statin intermediate

The kinetic resolution of 4-arylmethoxy-3-hydroxybutanenitriles was investigated by lipase-catalyzed transesterification in organic solvents. A high enantioselectivity was obtained via reaction with vinyl acetate in a mixed solvent (n-heptane/acetonitrile 1:1), which was catalyzed by the lipase from Artgribacter sp. A better selectivity was demonstrated when the number of substituents on the aryl ring increased. (S)-4-Arylmethoxy-3-hydroxybutanenitriles can be obtained with enantiomeric excesses of up to 98.0% by this method. Furthermore we have developed a novel route to synthesize tert-butyl (S)-6-benzyloxy-5-hydroxy-3-oxohexanoate, a key intermediate for the preparation of HMG-CoA reductase inhibitors (statins).

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(S)-4-Benzyloxy-3-hydroxybutanenitrileC11H13NO2Ee = 98.0% [by chiral HPLC][α]D20=-3.3 (c 3.3, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-4-(4-Chlorobenzyloxy)-3-hydroxybutanenitrileC11H12ClNO2Ee = 96.2% [by chiral HPLC][α]D20=-2.6 (c 3.2, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-4-(2,4-Dichlorobenzyloxy)-3-hydroxybutanenitrileC11H11Cl2NO2Ee = 96.1% [by chiral HPLC][α]D20=-0.6 (c 3.7, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-4-(4-Methlybenzyloxy)-3-hydroxybutanenitrileC12H15NO2Ee = 97.0% [by chiral HPLC][α]D20=-2.6 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (3S)

(S)-4-(4-Methoxybenzyloxy)-3-hydroxybutanenitrileEe = 96.3% [by chiral HPLC][α]D20=-1.8 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3S

(S)-4-(2,4,6-Trimethylbenzyloxy)-3-hydroxybutanenitrileEe = 92.7% [by chiral HPLC][α]D20=+3.0 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3S

(S)-4-(4-Fluorobenzyloxy)-3-hydroxybutanenitrileEe = 99.0% [by chiral HPLC][α]D20=-1.4 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3S

(R)-3-Acetyloxy-4-benzyloxy-3-hydroxybutanenitrileEe = 70.0% [by chiral HPLC][α]D20=+3.4 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-3-Acetyloxy-4-(4-chlorobenzyloxy)-3-hydroxybutanenitrileEe = 85.0% [by chiral HPLC][α]D20=+4.0 (c 5.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-3-Acetyloxy-4-(2,4-dichlorobenzyloxy)-3-hydroxybutanenitrileEe = 90.1% [by chiral HPLC][α]D20=+4.6 (c 4.5, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-3-Acetyloxy-4-(4-methylbenzyloxy)-3-hydroxybutanenitrileEe = 81.3% [by chiral HPLC][α]D20=+4.0 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-3-Acetyloxy-4-(4-methoxybenzyloxy)-3-hydroxybutanenitrileEe = 82.3% [by chiral HPLC][α]D20=+4.2 (c 5.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-3-Acetyloxy-4-(2,4,6-trimethylbenzyloxy)-3-hydroxybutanenitrileEe = 99.0% [by chiral HPLC][α]D20=+8.0 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

(R)-4-Acetyloxy-(4-fluorobenzyloxy)-3-hydroxybutanenitrileEe = 85.0% [by chiral HPLC][α]D20=+3.0 (c 3.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 3R

tert-Butyl (S)-6-(benzyloxy)-5-hydroxy-3-oxohexanoateEe = 98.0% [by chiral HPLC][α]D20=-13.6 (c 2.0, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: 5S