NMR and molecular mechanics studies on the solution‐state conformation of (−)‐scopolamine free base

Abstract

The NMR parameters of (-)-scopolamine free base in CDCl, determined by Sarazin et al. were used to reevaluate some of the stereochemicai conciusions recently reported by the authors. Similarly to the case with the protonated salt, the major contributor to the fast exchange ümit time-averaged sbucture of the free base bopate ester moiety appears to be the rotamer in which the phenyi and hydroxyl group are antipenplanar. Long-range heterondear coupling constants for the carboxyl carbon and also for the aromatic ipso carbon have been reassigned. Vicinal homoauclear coupling constants involving the methine proton and the two internaiiy diastereotopic protons in the (S)-CHCH,OH moiety have also been reassigned. Four conformadonal archetypes were caiculated by molecular mecbanics for the ( -)-(Ns,Ce-S)-scopoiamine free base equatoriai N-methyi diastereomer based on x-ray crystallographicaliy determined scopolamine structural analogues. The degree of aoisochronicity (and their relative shifts) exhibited by tbe internaiiy diastereotopic oxiranyl protons and carbons and the observation of NOE intensity enhancement of oxiranyi protons upon {H-aromatic} can be interpreted as arising from an interconverting profile of conformations at the fast exchange ümit. While a conformation similar to that of the soüd-state hydrobromide sesquihydrate salt appears to be a major contributor to the time-averaged structure, otber conformations can also play minor roles.

Enantiomeric differentiation of atropine/hyoscyamine by 13C NMR spectroscopy and its application to Datura stramonium extract

“…1). The carbon numbering of atropine followed that of Glaser (1993) and it was in agreement with Leete et al ., (1975). The chemical shift assignment of aromatic carbons C13 and C14 was achieved using lanthanide shift reagents (LSR).…”

Positive Identification of the Principal Component of a White Powder as Scopolamine by Quantitative One‐Dimensional and Two‐Dimensional NMR Techniques

“…There is a significant number of NMR investigations in the literature addressing scopolamine structure (26–42) that permit direct comparisons between our measured NMR parameters and previously published values. We have made several such comparisons for our chemical shift and J H,H measurements, and have presented them in table form.…”

Scopolamine and atropineN-methyl diastereomer stability.Ab initio calculations onO-formylscopine andO-formyltropine model compounds

“…13C NMR spectroscopy unequivocally showed that the appropriate equatorial N-methyl diastereomers were the predominant contributors to the time-averaged spectral parameters for solutions of both alkaloid free bases [12]. The four crystallographically found archetypical conformations for scopolamine free base have recently been discussed by Glaser [15].The finding of different relative stabilities of scopolamine equatorial and axial N-methyl diastereomers in various solvents or as a function of nitrogen protonation provided the impetus to undertake the ab initio calculations described below. …”

“…Ethano-bridged free base models 14,15 [equatorial N-methyl 14 calculated to be 1.120 kcal/mol lower than axial N-methyl 15, --~ ~(eqMe) versus 101.3 ~ e~(axMe), and 103.9 ~ ~(eqMe) versus --~ ~(axMe); lone pair position not determined]. The corresponding two O-formyltropine N-methyl diastereomeric free base models (14,15) were also studied.…”

“…The corresponding two O-formyltropine N-methyl diastereomeric free base models (14,15) were also studied. Conversion of the N-protonated cationic models to those of the free bases did not change the relative stability of the equatorial N-methyl free base diastereomer versus its axial counterpart.…”