Reliable assignment of absolute configuration of chiral amines based on the analysis of 1H NMR spectra of their CFTA amide diastereomers

Applications of the CFTA method, a new and reliable procedure for the determination of the absolute configuration of chiral primary amines, are described in detail. In addition to the very high reactivity of CFTA chloride, the stable anti-periplanar conformers of CFTA amides, associated with the chiral structure of fluorine atom on a stereogenic center, are the key factors that make the technique of using 1H NMR analysis of the CFTA diastereomers very reliable. In particular, this method is useful for the determination of the absolute stereochemistry of isotopically multi-labeled amino acid derivatives.

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N-[(R)-2-(3,3-Dimethyl)butyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC16H21FN2O[α]D29=-2.6 (c 1.5, MeOH)Source of chirality: (R)-2-(3,3-dimethyl)butylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,2′R)

N-[(R)-2-(3,3-Dimethyl)butyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC16H21FN2O[α]D27=-21.7 (c 2.0, MeOH)Source of chirality: (R)-2-(3,3-dimethyl)butylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,2′R)

N-[(1R,2S,4R)-Bornyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC20H25FN2O[α]D29=-14.8 (c 1.1, MeOH)Source of chirality: (1R,2S,4R)-bornylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,1′R,2′S,4′R)

N-[(1R,2S,4R)-Bornyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC20H25FN2O[α]D28=-24.3 (c 1.1, MeOH)Source of chirality: (1R,2S,4R)-bornylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′R,2′S,4′R)

N-[(1R,2S,3S)-Isopinocampheyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC20H25FN2O[α]D28=+24.5 (c 1.1, MeOH)Source of chirality: (1R,2S,3S)-isopinocampheylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,1′R,2′S,3′S)

N-[(1R,2S,3S)- Isopinocampheyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC20H25FN2O[α]D28=+19.0 (c 1.0, MeOH)Source of chirality: (1R,2S,3S)-isopinocampheylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′R,2′S,3′S)

N-[(S)-1-Phenylethyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC18H17FN2O[α]D27=-88.9 (c 1.2, MeOH)Source of chirality: (S)-1-phenylethylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,1′S)

N-[(S)-1-Phenylethyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC18H17FN2O[α]D26=-89.6 (c 1.6, MeOH)Source of chirality: (S)-1-phenylethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-(p-Nitrophenyl)ethyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC18H16FN3O3[α]D28=-77.5 (c 1.1, MeOH)Source of chirality: (S)-1-(p-nitrophenyl)ethylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,1′S)

N-[(S)-1-(p-Nitrophenyl)ethyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC18H16FN3O3[α]D27=-118.9 (c 1.4, MeOH)Source of chirality: (S)-1-(p-nitrophenyl)ethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonylethyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC14H15FN2O3[α]D25=+1.2 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonylethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(R)-1-Methoxycarbonylpropyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC15H17FN2O3[α]D25=+0.8 (c 1.0, CHCl3)Source of chirality: (R)-1-methoxycarbonylpropylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′R)

N-[(S)-1-Methoxycarbonyl-2-methylpropyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC16H19FN2O3[α]D25=+2.8 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-2-methylpropylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonyl-2,2-dimethylpropyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC17H21FN2O3[α]D25=-15.4 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-2,2-dimethylpropylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonyl-3-methylbutyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC17H21FN2O3[α]D25=-1.1 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-3-methylbutylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonyl-4-thiapentyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC16H19FN2O3S[α]D25=+21.7 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-4-thiapentylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-2-Benzyloxycarbonyl-1-methoxycarbonylethyl]-(R)-2-cyano-2-fluoro-p- tolylacetamideC22H21FN2O5[α]D25=+48.1 (c 1.0, CHCl3)Source of chirality: (S)-2-benzyloxycarbonyl-1-methoxycarbonylethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-3-Ethoxycarbonyl-1-methoxycarbonylpropyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC18H21FN2O5[α]D25=+2.7 (c 1.0, CHCl3)Source of chirality: (S)-3-ethoxycarbonyl-1-methoxycarbonylpropylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(1S,2R)-1-Methoxycarbonyl-2-benzyloxypropyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC22H23FN2O4[α]D25=+9.3 (c 1.0, CHCl3)Source of chirality: (1S,2R)-1-methoxycarbonyl-2-benzyloxypropylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S,2′R)

N-[(S)-1-Methoxycarbonyl-2-phenylethyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC20H19FN2O3[α]D25=-41.2 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-2-phenylethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonyl-2-(3-indolyl)ethyl]-(R)-2-cyano-2-fluoro-p-tolylacetamideC22H20FN3O3[α]D25=+51.8 (c 1.0, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-2-(3-indolyl)ethylamine and (R)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2R,1′S)

N-[(S)-1-Methoxycarbonyl-4-methylpentyl]-(S)-2-cyano-2-fluoro-p-tolylacetamideC18H23FN2O3[α]D27=-42.2 (c 0.91, CHCl3)Source of chirality: (S)-1-methoxycarbonyl-4-methylpentylamine and (S)-2-cyano-2-fluoro-p-tolylacetic acidAbsolute configuration: (2S,2′S)