Asymmetric reduction using (R)-MeCBS and determination of absolute configuration of para-substituted 2-fluoroarylethanols

The asymmetric reduction of eight α-fluoroacetophenones has been investigated using (R)-MeCBS as a catalyst in various media. Based on a solvent screen, 1,2-dimethoxyethane, diethyl ether and dichloromethane were used in reductions of the α-fluoroacetophenones. The enantiomeric excess of the products depended on the solvent and the electronic character of the aromatic substituents. Higher enantioselectivity and less solvent dependency were observed in the reduction of substrates bearing electron donating substituents, whereas the opposite was the case for reduction of the substrates with electron withdrawing substituents. The (R)-2-fluoro-1-arylethanols were obtained with enantiomeric excesses in the range of 91–99% using 1,2-dimethoxyethane as a solvent. Six of the alcohols produced are new chemical entities. The absolute configurations of the (R)-2-fluoro-1-arylethanols were determined by circular dichroism using the exciton chirality method of the (S)-benzoate esters of the alcohols. The (S)-benzoate esters were obtained by lipase-catalysed resolution using Novozym 435.

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(R)-1-(4-(Benzyloxy)phenyl)-2-fluoroethanolC15H15FO2Ee = 97.0%[α]D25=-19.9 (c 0.60, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-1-(4-Bromophenyl)-2-fluoroethanolC8H8BrFOEe = 98.5%[α]D25=-32.3 (c 0.90, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethanolC9H8F4OEe = 93.0%[α]D25=-20.0 (c 0.70, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-2-Fluoro-1-(4-fluorophenyl)ethanolC9H11F2OEe = 99.0%[α]D25=-36.5 (c 0.60, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-2-Fluoro-1-(4-methxyphenyl)ethanolC9H11FO2Ee = 99.5%[α]D25=-38.5 (c 0.70, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-2-Fluoro-1-(4-nitrophenyl)ethanolC8H8FNO3Ee = 92.5%[α]D25=-17.7 (c 0.70, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-2-Fluoro-1-phenylethanolC8H9FOEe = 96.5%[α]D25=-64.4 (c 1.20, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(R)-4-(2-Fluoro-1-hydroxyethyl)benzonitrileC9H8FNOEe = 91.5%[α]D25=-27.1 (c 0.70, CHCl3)Source of chirality: asymmetric reductionAbsolute configuration: (R)

(S)-1-(4-(Benzyloxy)phenyl)-2-fluoroethyl benzoateC22H19FO3Ee = 99%[α]D25=-13.9 (c 1.00, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-1-(4-Bromophenyl)-2-fluoroethyl benzoateC15H12BrFO2Ee = 94%[α]D25=-49.5 (c 0.90, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-1-(4-Cyanophenyl)-2-fluoroethyl benzoateC16H12FNO2Ee = 90%[α]D25=-49.5 (c 0.90, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethyl benzoateC16H12F4O2Ee = 96%[α]D25=-40.3 (c 1.00, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-2-Fluoro-1-(4-fluorophenyl)ethyl benzoateC15H12F2O2Ee = 79%[α]D25=-23.3 (c 0.60, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-2-Fluoro-1-(4-methoxyphenyl)ethyl benzoateC16H15FO3Ee = 73%[α]D25=-15.0 (c 0.60, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-2-Fluoro-1-phenylethyl benzoateC15H13FO2Ee = 88%[α]D25=-42.2 (c 0.70, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)

(S)-2-Fluoro-1-(4-nitrophenyl)ethyl benzoateC15H12FNO4Ee = 94%[α]D25=-33.4 (c 0.70, CHCl3)Source of chirality: lipase resolutionAbsolute configuration: (S)