Carbon-13 Magnetic Resonance: the Stereochemistry of Pharmacologically Active 1,2,5-Trimethyl-4-phenyl-piperidine Derivatives

Abstract

The carbon-13 magnetic resonance spectra of three diastereoisomers of 1,2,5-trimethyl-4-phenylpiperidin-4-ol and their esters and corresponding hydrochlorides have been determined in deuterochloroform and/or dimethylsulfoxide-d6. Chemical shifts observed support the configurations t-2-Me, c-5-Me (γ), c-2-Me, t-5-Me (β), and c-2-Me, c-5-Me, r-4-OH (α) for the isomers specified in parentheses. Chair conformations are preferred for γ (eq-Ph) and β (ax-Ph) piperidinols while the α-form favors a skew-boat. Evidence is presented for conformational changes in the α- and β-forms after N-protonation. The γ- and β-esters have conformations similar to the parent 4-piperidinols while the α-acetate base and hydrochloride prefer chair conformations but with different 4-phenyl orientations (base ax-Ph, HCl eq-Ph).