SOLUTION-STATE AND SOLID-STATE STEREOCHEMISTRY OF (-)-ALPHA-LOBELINE HYDROCHLORIDE AND HYDROBROMIDE, A RESPIRATORY-STIMULANT DRUG

The solid-state structure of (-)-alpha-lobeline hydrobromide has been determined by single crystal X-ray diffraction analysis. (-)-alpha-Lobeline hydrobromide gives crystals belonging to the orthorhombic P2(1)2(1)2(1) space group, and at 298 K: a = 6.0100(3), b = 11.7177(4), c = 28.977(2) angstrom, V = 2040.7(2), Z = 4, R(F) = 0.030, and R(w)(F) = 0.022. The (2R,6S,C(beta)S)-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 beta-hydroxyphenethyl residue exhibits a different conformation from that noted for the hydrochloride salt. H-1 and C-12 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 beta-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.