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

Several N-substituted nortropane and norgranatane derivatives were synthesised from tropinone and granatanone. The equilibrium distributions of the axial and equatorial N-invertomers of the free amine forms of the prepared products in methanol and their protonated forms (hydrochlorides) in water were studied by low-temperature and room-temperature NMR spectroscopy. Theoretical distributions in the gas phase, methanol and water solvents were calculated using DFT methods and compared with inverse gated 13C NMR experiments. DFT calculations provided results in reasonable agreement with experimental data. Equatorial invertomers dominated in N-tert-butyl- and N-benzylnortropinone, and the equatorial/axial ratio for N-ethyl- and N-phenethylnortropinone was close to 1. The axial invertomers dominated in all of the granatanone derivatives and the N-isopropyl- and N-phenylnortropane. Our experiments indicated that nitrogen protonation shifted the invertomer equilibrium towards equatorial forms. DFT calculations reproduced this effect for tropanes.

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