Determination of the N-methyl stereochemistry in tropane and granatane derivatives in solution: a computational and NMR spectroscopic study

Determination of the N-invertomer stereochemistry in N-substituted nortropanones and norgranatanones using computational and NMR methods

“…Direct NoD-NMR methods [45] for water or methanol solutions (e.g., ROESY technique) did not provide useful information due to interferences from the non-deuterated solvent, low sample solubility and fast rate of invertomer interchange. Therefore, we used proven methods based on 13 C NMR combined with verified DFT calculations [40]. To probe the behaviour of these amino ketones in aqueous environments including the potential involvement of protonated amine forms in aldol and other reactions in aqueous media [44], we also included the N-invertomer equilibriums in the corresponding hydrochlorides.…”

“…In addition, reportedly a more accurate but much more computationally demanding B3LYP/6-311++G(3d,3p) level of theory was included for comparison for these particular structures. This basis set was chosen due to the satisfactory results obtained for the investigation of the N-methyl invertomer distributions for tropanes and granatanes [40]. All of the electronic structure calculations were performed using the GAUSS-IAN 09 suite of programs.…”

“…We used a proven approach used by Sturm [26] and by us [40] for the N-methyl analogues based on integration of signals in inverse gated 13 C NMR experiments. The 13 C NMR spectra of some of the free amines 1 and 2 in methanol at -90 8C and many amines 1 and 2 hydrochlorides in water at room temperature exhibited separate signals for both N-invertomers (Tables 4 and 5).…”

“…The equatorial/axial invertomer ratio for deuterotropinone deuterochloride in D 2 O was determined to be 4.2 based on NMR spectra to be 4.2 [39]. Recently, we have determined the differences in the invertomer preferences for the N-methyl derivatives of tropane and granatane in polar solvents [40]. X-ray diffraction revealed the N-benzyl group in equatorial position in N-benzylnortropinone aldols [41] and aldol tosylhydrazone [21].…”

Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis

“…In contrast, N-methyl-9-azabicyclo [3.3.1]-nonane, the core scaffold of GAs, appears in considerably fewer alkaloid metabolites ( Figure 1). The bicyclic core structures of TAs and GAs differ by only one carbon atom, yet this difference alters the conformational preferences of each of the core skeletons [7]. Furthermore, the presence or absence of a single carbon atom in the core rings of TAs and GAs alters their chemical and pharmacological activities.…”