Synthesis of 2-aryloxypropanoic acids analogues of clofibric acid and assignment of the absolute configuration by 1H NMR spectroscopy and DFT calculations

A new set of optically active 2-aryloxypropanoic acids has been synthesized through a simple strategy, in good yields and excellent enantiomeric excesses. Their absolute configuration was assigned by means of a NMR-based approach consisting of the derivatization of the carboxylic acids with ethyl mandelate and the comparison of the chemical shifts of the obtained diastereomers. The effectiveness of such an approach has been tested against a larger set of chiral α-substituted-carboxylic acids and by performing high level density functional theory (DFT) calculations on a set of low energy conformations for each diastereomeric derivative. The employed computational procedure has enabled us to find a semiquantitative relationship between the experimental NMR data and the theoretically calculated energy gaps which confirms the theoretical foundations of the NMR strategy and allows to understand when and why it is most likely to fail.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(R)-2-(4-Chlorophenoxy)propanoic acidC9H9ClO3Ee = 98%[α]D = +41.9 (c 1.2, CH3OH)Source of chirality: (S)-ethyl lactateAbsolute configuration: (R)

(R)-2-[(6-Chloroquinolin-2-yl)oxy]propanoic acidC12H10ClNO3Ee = 99%[α]D = +110.7 (c 2.0, CHCl3)Source of chirality: (S)-ethyl lactateAbsolute configuration: (R)

(R)-2-(1,3-Benzothiazol-2-yloxy)propanoic acidC10H9NO3SEe = 98%[α]D = +35.9 (c 2.0, CH3OH)Source of chirality: (S)-ethyl lactateAbsolute configuration: (R)

(R)-2-(1-Naphthyloxy)propanoic acidC13H12O3Ee = 99%[α]D = −61.3 (c 1.8, CHCl3)Source of chirality: (S)-ethyl lactateAbsolute configuration: (R)