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

Abstract

The solid-state structure of ( -) -a-lobeline hydrobromide has been determined by single crystal X-ray diffraction analysis. ( -)-a-Lobeline hydrobromide gives crystals belonging to the orthorhombic P2,2,2, space group, and at 298 K: a = 6.0100(3), b = 11.7177(4), c = 28.977(2) A, V = 2040.7(2), 2 = 4, R ( F ) = 0.030, and RJF) = 0.022. The (2R,6S,CBS)-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 phydroxyphenethyl residue exhibits a different conformation from that noted for the hydrochloride salt. 'H and 13C NMR spectroscopy for the hydrochloride salt dissolved in CD2C12 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 D20 and the free base in CDCI, also show axial N-methyl orientations. Conformational differences for the acetophenonyl and P-hydroxyphenethyl moieties were found in the two N-methyl epimers, as well as in the time-averaged salt (D20) and free base (CDCI,) structures. The putative bioactive conformation of the nicotine agonist was found to have a different acetophenonyl arm conformation than that found in both crystals. The nicotine agonist (2R,6S,CBS)-( -)-a-lobeline (( -)-2-[6-(fl-hydroxyphenethy1)-1 -methyl-2-piperidyl]acetophenone, 1) is a natural product isolated from LobeZia inflata L, and LobeZiaceae (Indian tobacco).' It is structurally related to the sedum alkaloid (2S,C,S)-( -)-sedamine [( -)-2-p-hydroxyphenethyl-1-methylpiperidine, 2].2 The hydrochloride salt of the lobelia alkaloid is utilized therapeutically as a respiratorystimulant. ' 1 2Paper 2/01019D

Enantioselective Access to Lobelia Alkaloids

“…To our surprise, an equilibrium was reached after 48 h, wherein we observed an equal mixture of the two isomers 1a and 1c , without further evolution. To our knowledge, this fact was not yet indicated for natural lobeline base itself, which was reported as a single product in CDCl 3 . Our own investigation of the 1 H NMR, in CDCl 3 , of natural lobeline base (obtained from the corresponding commercially available hydrochloride) indeed displayed, in the spectrum recorded immediately after extraction, only the isomer 1a but, after about 48 h, reached the same equilibrium observed for our synthetic product, i.e., an equal mixture of isomers 1a and 1c .…”

“…Lobeline 1a , is the main active alkaloid constituent of Lobelia inflata , a plant sometimes called “Indian tobacco” because it was initially used by Indians of North America as a tobacco substitute. The crude extract is toxic but has been widely recommended for treatment of respiratory illnesses such as asthma, bronchitis, pneumonia, and whooping cough.…”

History, chemistry and biology of alkaloids from Lobelia inflata

“…Indeed, the phenyl-2-ketoethyl and phenyl-2-hydroxyethyl groups could bind through hydrogen bonds to the receptors, even though the keto moiety has been reported to be a better hydrogen bond acceptor. 125 Many similar effects for nicotine 156 and lobeline 1, like tachycardia and hypertension, 126 anxiolytic activity 127 and improvement of learning and memory, 128 have been recorded. Contrary to 156, however, lobeline 1 does not increase locomotor activity 129 or produce conditioned place preference.…”

Lobeline Docking on AChBP and Nicotinic Receptors: Discriminating Importance of the Pocket Geometry and of the Ligand Configuration

“…The protonated (-)-lobeline ( Fig. 1a, (1R)-(-)-lobeline) is composed of a N-methyl piperidine ring in a chair conformation, to which are attached the phenyl-2-keto-ethyl and the phenyl-2(S)-hydroxyethyl substituents in positions 2 and 6 respectively [61]. In solution at physiological pH, the additional ammonium stereogenic centre allowed the formation of two potential diastereomers: the crystallographic structure of protonated lobeline in AChBP shows a syn-relation between the two substituting arms and the N-methyl group which occupies an axial position [8].…”