Stereochemistry of the N-Methyl Group in Salts of Tropane Alkaloids

¹H and ¹³C NMR slow exchange limit spectra of atropine sulfate/mesylate, homatropine hydrobromide, and benztropine mesylate solutions concur in showing that, at equilibrium, the equatoriakaxial N-CH₃ diastereomeric mixture was ca. 7:1 (D₂O) and ca. 18:1 (CD₂C1₂). A similar preponderance of equatorial N-CH₃ stereochemistry was observed for cocaine salts in both solvents (only equatorial isomer noted in D₂O ¹³C NMR spectrum, while ca. 18:1 equatoriakaxial ratio found in CD₂C1₂). The N-CH₃ orientation in scopolamine hydrobromide was strikingly solvent sensitive and underwent a reversal from an equatorial:axial N-CH₃ ratio of ca. 1:18 (D₂O) to ca. 18:1 (CD₂C1₂). Solid-state CP-MAS ¹³C NMR spectra of crystalline equatorial N-CH₃ (8s)-atropine sulfate and axial N-CH₃(9r)-scopolamine hydrobromide confirmed the stereochemical assignments for major and minor diastereomers in solution.