Conformational Pseudopolymorphism and Solid-State CPMAS NMR Studies for Determination of Solvent-Dependent Solution-State Conformational Preferences for (−)-Scopolamine Hydrobromide/Hydrochloride Salts

Abstract

Crystalline (−)-scopolamine hydrohalide (bromide and chloride) salts exist in two conformational families for the tropate ester moiety: the compact conformation (hydrates, phenyl ring underneath the scopine moiety), and the extended conformation (anhydrates, phenyl ring ca. antiperiplanar to oxiranyl O-atom). CPMAS 13C NMR solid-state spectra of anhydrates and hydrates are different. In both tertiary and quaternary scopolammonium salts, phenyl rings are immobile in compact conformation crystals having ca. 2.5 Å close lateral neighbors on both faces of the planar moiety. Phenyl rings undergo a π-flip in extended conformation crystals having ca. 3.0 Å close lateral neighbors on either face of the aromatic plane. Due to different OC−Cα−CH2OH dihedral angles [synperiplanar (eclipsed, in compact) and (+)-synclinal (gauche, in extended)], the methylol carbon chemical shifts of crystalline tertiary and quaternary scopolammonium salts and analogues are diagnostic markers for the tropate ester solid-state conformation [δCH2OH downfield from alkoxy δC(3) for extended conformations and upfield of δC(3) in compact conformations]. These solid-state model Δδ relationships were used to deconvolute weighted time-averaged chemical shifts in different solvents: e.g., one axial N-methyl scopolammonium bromide phenyl-ring face is solvent exposed in the compact conformation predominating in D2O medium, while both faces are solvent accessible in the extended major conformational contributor in CD2Cl2 solution.

Absolute configuration determination and conformational analysis of (−)‐(3S,6S)‐3α,6β‐diacetoxytropane using vibrational circular dichroism and DFT techniques

“…There has been a number of studies regarding the N-Me orientation of tropane alkaloids in solution, specially (2)scopolamine, showing that both dispositions can be present, depending on the specific structural characteristics of the molecule and the solvent that can stabilize one form or another. [18][19][20][21] In the case of 1, the conformational distribution can be divided in two groups, 1a-d and 1e-h, with equatorial and axial N-Me orientations, respectively, showing that approximately 82% of the conformational preference has the equatorial N-Me orientation. This preference can be easily explained considering axial-axial interactions that occur when the N-Me disposition is also axial, showing a distance of 2.3 Å between the N-methyl hydrogens and H2ax and/or H4ax.…”

DFT‐GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

“…Additionally, the conformational dependence of these differences is further supported by the CP‐MAS 13 C NMR spectra of related solids, in which important features arise when contrasted to the anisochronicity observed in the solution spectra of the free bases 15. While the sesquihydrate hydrobromide of 1 HBr and the hydrobromide of 2 , both packed in the compact conformation, show similar diastereotopic chemical shift differences as those found in solution (i.e.…”

“…While the sesquihydrate hydrobromide of 1 HBr and the hydrobromide of 2 , both packed in the compact conformation, show similar diastereotopic chemical shift differences as those found in solution (i.e. C‐6/C‐7 differences of 0.7 and 0.4 ppm for 1 in the solid and solution states, respectively, and C‐6/C‐7 differences of 0.9 and 0.5 ppm for 2 in the solid and solution states, respectively), the anhydrate in the extended conformation shows only unresolved C‐2/C‐4, C‐1/C‐5 and C‐6/C‐7 signals, clearly pointing toward a close relation between this anisochronicity and the compact conformation 15…”

“…A number of studies have dealt with the NMR properties of these compounds and their conformational preferences in the solid and solution states with great attention to the equatorial/axial ratio of the N ‐Me group either as free bases or as salts 5–16. The assignment of the 1 H and 13 C NMR spectra for both compounds have been recorded, discussed and corrected several times, and particular interest has arisen for solution measurements to the unusually large chemical shift differences of diastereotopic protons and carbons of the tropane squeleton (i.e.…”

Studies on the oxidative N-demethylation of atropine, thebaine and oxycodone using a FeIII-TAML catalyst

“…The naturally occurring alkaloids atropine (1), scopolamine (2) and cocaine (3) along with the opiate morphine (4) all contain a tertiary N-methylamine group (Fig. 1) and have been used for many centuries by humans as medicinal and psychoactive agents.…”