Preparative resolution of bromocyclopropylcarboxylic acids

A general and efficient method for the preparative resolution of α- and β-bromocyclopropylcarboxylic acids has been developed. This protocol involves a sequence of two crystallizations with pseudo-enantiomeric amines, cinchonine, and cinchonidine, which yield both enantiomers of the acid in highly enriched form. Both alkaloids can be easily recovered and reused multiple times without any loss of efficacy.

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(1S,2R)-1-Bromo-2-methyl-2-phenylcyclopropane-1-carboxylic acidC11H11BrO2[α]D25 = +56.5 (c 0.22, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-methyl-2-(p-tolyl)cyclopropane-1-carboxylic acidC12H13BrO2[α]D25 = +66.0 (c 0.11, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-ethyl-2-phenylcyclopropane-1-carboxylic acidC12H13BrO2[α]D25 = +69.5 (c 0.12, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-methyl-2-(naphthalen-2-yl)cyclopropane-1-carboxylic acidC15H13BrO2[α]D25 = +108.2 (c 0.12, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-phenylcyclopropane-1-carboxylic acidC10H9BrO2[α]D25 = +166.0 (c 0.11, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-methyl-2-(m-tolyl)cyclopropane-1-carboxylic acidC12H13BrO2[α]D25 = +77.5 (c 0.10, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-(3,4-dimethylphenyl)-2-methylcyclopropane-1-carboxylic acidC13H15BrO2[α]D25 = +54.7 (c 0.17, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(1S,2R)-1-Bromo-2-(4-ethylphenyl)-2-methylcyclopropane-1-carboxylic acidC13H15BrO2[α]D25 = +69.8 (c 0.12, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

(S)-1-Bromo-2,2-diphenylcyclopropane-1-carboxylic acidC16H13BrO2[α]D25 = +110.3 (c 0.20, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (S)

(1S,2R)-1-Bromo-N,N-diethyl-2-methyl-2-phenylcyclopropane-1-carboxamideC15H20BrNO[α]D25 = +17.0 (c 0.19, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (1S,2R)-1-bromo-2-methyl-2-phenylcyclopropane-1-carboxylateC12H13BrO2[α]D25 = +34.6 (c 0.22, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (1S,2R)-1-bromo-2-methyl-2-(p-tolyl)cyclopropane-1-carboxylateC13H15BrO2[α]D25 = +42.6 (c 0.62, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (1R,2S)-1-bromo-2-ethyl-2-phenylcyclopropane-1-carboxylateC13H15BrO2[α]D25 = −30.9 (c 0.80, CH2Cl2)Source of chirality: cinchonidineAbsolute configuration: (1R,2S)

Methyl (1S,2R)-1-bromo-2-methyl-2-(naphthalen-2-yl)cyclopropane-1-carboxylateC16H15BrO2[α]D25 = +90.0 (c 0.60, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (1S,2R)-1-bromo-2-phenylcyclopropane-1-carboxylateC11H11BrO2[α]D25 = +122.4 (c 0.84, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (1R,2S)-1-bromo-2-methyl-2-(m-tolyl)cyclopropane-1-carboxylateC13H15BrO2[α]D25 = −30.2 (c 0.42, CH2Cl2)Source of chirality: cinchonidineAbsolute configuration: (1R,2S)

Methyl (1S,2R)-1-bromo-2-(3,4-dimethylphenyl)-2-methylcyclopropane-1-carboxylateC14H17BrO2[α]D25 = +35.4 (c 0.82, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (1S,2R)

Methyl (S)-1-bromo-2,2-diphenylcyclopropane-1-carboxylateC17H15BrO2[α]D25 = +85.6 (c 0.82, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (S)

(S)-2,2-Dibromo-1-methylcyclopropane-1-carboxylic acidC5H6Br2O2[α]D25 = +49.3 (c 0.13, CH2Cl2)Source of chirality: cinchonidineAbsolute configuration: (S)

Methyl (R)-2,2-dibromo-1-methylcyclopropane-1-carboxylateC6H8Br2O2[α]D25 = −62.0 (c 0.51, CH2Cl2)Source of chirality: cinchonineAbsolute configuration: (R)