Biomedical subjects

Anatoly M Belostotskii

Publications and source records attributed to Anatoly M Belostotskii.

4 recordsLinked to original sources

PubMed2004

N-inversion-associated conformational dynamics is unusually rapid in morphine alkaloids.

(13)C DNMR studies of codeine and sinomenine (derivatives of N-Me morphinan) indicated that N-inversion-C-N rotation (NIR) is unusually fast for these substituted piperidines when compared with other N-Me piperidines. Since only broadening, but no signal splitting, was reached at low temperatures and the difference of chemical shifts (Delta delta) for individual conformers with the equatorially and axially oriented N-Me substituent was unavailable, the limits of the NIR barrier for these amines were determined by line shape analysis using Delta delta values provided by ab initio calculations. On the basis of the comparison of experimentally determined (13)C NMR chemical shifts for tropane conformers with the ones calculated at different theory levels for this N-Me piperidine, the B3LYP/6-31G(p)/GIAO level was chosen as a sufficiently accurate method for calculations of Delta delta. By this new "semiempirical" procedure of line shape analysis the NIR barrier for the studied morphinans lies within a 25-27 kJ mol(-1) (6.0-6.5 kcal mol(-1)) range. A low NIR barrier for morphine alkaloids is supposed to be an important factor in the activation of morphine receptor.

Alkaloids↗

PubMed2003

Conformational dynamics in nitrogen-fused azabicycles.

Using molecular mechanics (MM3 force field)-based methodology, conformational dynamics have been studied for 1-azabicyclo[2.2.0]hexane, 1-azabicylo[3.3.0]octane, and 1-azabicylo[4.4.0]decane. Obtained conformational schemes describe the flexibity of these parent azabicyles as well as permit us to estimate conformational mobility in related N-fused systems. Quantum mechanics ab initio calculations have been used in order to check the reliability of molecular mechanics-provided estimates of relative energy of conformers. The previous dynamic NMR (DNMR) data have been reinterpreted for some polycyclic alkaloids.

Journal Article↗

PubMed2002

Nitrogen inversion in cyclic amines and the bicyclic effect.

The hitherto unsolved problem of the origin of the unusually high nitrogen inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the sigma-orbitals of the C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).

Journal Article↗

PubMed2002

Crowded piperidines with intramolecularly hydrogen-bonded nitrogen: synthesis and conformation study.

2,2,6,6-Tetramethyl substituted piperidines with a beta-branched N-alkyl substituent were synthesized by the photoreaction of N-Me precursors with ketones. The main conformation features of these sterically-hindered amines (established by NMR and IR spectroscopy) are a ring in the chair form, an eclipsed conformation for the N-substituent and an intramolecular OH...N bond. High barriers for the geminal substituent topomerization were measured for these piperidines at different temperatures by means of line-shape analysis of the temperature-dependent 13C and 1H NMR spectra. An MM3-derived conformation scheme indicated that, for one of the studied analogues, the rotation of the N-substituent determines a slow topomerization rate. A new mechanism of nitrogen inversion--a concerted hydrogen-bond dissociation/nitrogen inversion process--is considered for hydrogen-bonded amines.

Hydrogen Bonding↗