Solution- and solid-state stereochemistry of (–)-α-lobeline hydrochloride and hydrobromide, a respiratory-stimulant drug

Abstract

The solid-state structure of (–)-α-lobeline hydrobromide has been determined by single crystal X-ray diffraction analysis. (–)-α-Lobeline hydrobromide gives crystals belonging to the orthorhombic P2₁2₁2₁ space group, and at 298 K: a= 6.0100(3), b= 11.7177(4), c= 28.977(2)Å, V= 2040.7(2), Z= 4, R(F)= 0.030, and R_w(F)= 0.022. The (2R,6S,C_βS)-absolute configuration was determined from the effects of anomalous dispersion of the bromine atom. The N-methyl group exists in an axial configuration similar to that previously described for the hydrochloride salt. However, in the hydrobromide salt the β-hydroxyphenethyl residue exhibits a different conformation from that noted for the hydrochloride salt. ¹H and ¹³C NMR spectroscopy for the hydrochloride salt dissolved in CD₂Cl₂ shows axial- and equatorial-N-methyl solution-state diastereoisomers in the ratio ca. 5 : 1, respectively. The major contributors to the time-averaged structures of the salt in D₂O and the free base in CDCl₃ also show axial N-methyl orientations. Conformational differences for the acetophenonyl and β-hydroxyphenethyl moieties were found in the two N-methyl epimers, as well as in the time-averaged salt (D₂O) and free base (CDCl₃) structures. The putative bioactive conformation of the nicotine agonist was found to have a different acetophenonyl arm conformation than that found in both crystals.