35459-07-5Relevant academic research and scientific papers
Conformational control enabled by the fluorine gauche effect in a model of the β2-AR agonist salbutamol (Ventolin)
Teschers, Charlotte S.,Daniliuc, Constantin G.,Kehr, Gerald,Gilmour, Ryan
supporting information, p. 1 - 5 (2018/03/13)
The bronchodilator salbutamol adopts a characteristic gauche conformation about the ?O-C-C-N torsion angle. This topology is predicated on stabilizing stereoelectronic interactions of the type σ → σC-X*. X-ray crystallographic analysis of salbutamol also indicates that an intramolecular hydrogen bond reinforces this intuitive conformation (?O-C-C-N ≈ 60°). In this study, we demonstrate that single site OH → F substitution in model salbutamol systems preserves the gauche conformational preference by virtue of reinforcing hyperconjugative interactions of the type σC-H → σC-F* and σC-C → σC-N*. Since the amine remains fully protected throughout this conformational analysis, intramolecular hydrogen bonding can be discounted. Conformational mimesis is confirmed by NMR spectroscopy in solution, and also in the solid state.
