Axial chirality of 4-arylpyrazolo[3,4-b]pyridines. Conformational analysis and absolute configuration.

The stereodynamic behavior of a series of pyrazolo[3,4-b]pyridines was studied. The restricted rotations of the aryl substituent in position 4 of the heteroaromatic ring and of the benzoyl group in position 5 generated conformational enantiomers or conformational diastereoisomers depending on the local symmetry of the aryl substituent, with very high rotational barriers despite the absence of ortho-substituents. The energy barriers for the rotation of the 5-benzoyl group and the 4-aromatic ring were measured by dynamic NMR and rationalized by DFT calculations. When the aryl substituent at position 4 was 1-naphthyl, the resulting atropisomeric pair was resolved by means of enantioselective HPLC and the absolute configuration was determined by TD-DFT simulations of electronic circular dichroism spectra.