Axial Chirality of 4‑Arylpyrazolo[3,4‑<i>b</i>]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.本研究对一系列吡唑并[3,4-b]吡啶（pyrazolo[3,4-b]pyridines）的立体动力学行为展开了探究。杂芳环4位芳基取代基与5位苯甲酰基的受限旋转，可依据芳基取代基的局部对称性生成构象对映体或构象非对映异构体；尽管不存在邻位取代基，但其旋转能垒极高。本研究通过动态核磁共振（dynamic NMR）测定了5位苯甲酰基与4位芳环的旋转能垒，并借助密度泛函理论（DFT）计算对其进行了合理化解析。当4位芳基取代基为1-萘基时，所得阻转异构对可通过对映选择性高效液相色谱（enantioselective HPLC）完成拆分，并通过电子圆二色谱（electronic circular dichroism）的含时密度泛函理论（TD-DFT）模拟确定了其绝对构型。