MW SYSTEMATIC STUDY OF ALKALOIDS: THE DISTORTED TROPANE OF SCOPOLINE

Abstract

Tropane alkaloids have diverse pharmacological uses and are well-known for their neurostimulant activity. Previous structure-activity-relationship established correlations between bioactivity and several aspects of ligand conformation and stereochemistry, including delicate intramolecular effects like nitrogen inversion$^{a}$. We have initiated a series of structural studies on tropane alkaloids$^{b}$, aimed to discerning their intrinsic stereochemical properties using rotational spectroscopy in supersonic jets$^{c}$. Here we extend these studies to the epoxytropanes, initially motivated to interrogate the influence of the epoxy group on nitrogen inversion and ring conformation. The rotational spectrum evidences a single structure in the gas phase, providing a first description of the (three ring) structurally-distorted tropane in scopoline. The determined rotational parameters of scopoline reveal the structural consequences of the intramolecular cyclation of scopine, which breaks the original epoxy group and creates a new ether bridge and a 7$\beta$-hydroxytropane configuration. The hydroxyl group further stabilizes the molecule by an $O-H \cdots N$ intramolecular hydrogen bond, which, in turn, forces the N-methyl group to the less stable axial form$^{b}$. The experimental work was supported by ab initio and DFT calculations.\\ $^{a}$ i) S.Singh, \emph{Chem. Rev.} 100, 925 (2000); ii) A. Krunic, D. Pan, W.J. Dunn III, S.V.S. Miariappan, \emph{Bioorg. & Med. Chem.} 17, 811 (2009).\\ $^{b}$ E.J. Cocinero, A. Lesarri, P. Ecija, J.-U. Grabow, J.A. Fernandez, F. Casta\~{n}o, \emph{Phys. Chem. Chem. Phys.} 12, 6076 (2010).\\ $^{c}$ E.J. Cocinero, A. Lesarri, P. Ecija, J.-U. Grabow, J.A. Fernandez, F. Casta\~{n}o, \emph{Phys. Chem. Chem. Phys.} 12, 12486 (2010).