Stereochemistry of 2,3-dimethyl analogues of the reversed ester of pethidine and related compounds: examples of vicinal diaxial methyl groups in 2,3-dimethylpiperidine derivatives

Abstract

The configurations and preferred solute conformations of three diastereoisomeric forms of 1,2,3-trimethyl-4-phenylpiperidin-4-ol, isolated from the product of reaction between 1,2,3-trimethyl-4-piperidone and phenyl-lithium, are established from n.m.r. and other data as α, c-2-Me, c-3-Me, r-4-OH; β, t-2-Me, c-3-Me, r-4-OH (both eq-4-Ph chairs), and γ, c-2-Me, t-3-Me, r-4-OH (boat in CDCl₃). Hydrochlorides of all three isomeric forms of corresponding acetates and propionates have preferred eq-4-Ph chair conformations in CDCl₃. In cases of the γ-ester and γ-piperidin-4-ol hydrochlorides and the γ-piperidin-4-ol base in (CD₃)₂SO, avoidance of the 2,3-dimethyl γ-gauche interaction appears to be a determinant conformational factor. Isomeric potency rankings of the propionate esters in animal antinociceptive tests are γ > α > β.