Scopolamine and atropineN-methyl diastereomer stability.Ab initio calculations onO-formylscopine andO-formyltropine model compounds

Abstract

Ab initio geometry optimizations at the RHF/3-2tG basis set level were calculated for equatorial and axial N-methyl diastereomers of O-formyltropine and O-formylscopine esters and other model compounds. These optimized geometries were then utilized as input for single-point energy calculations using the higher level RHF/6-31G* basis set to afford a more precise estimation of the total energies and atomic charges. Ethano bridge "pinching" of the N-protonated tropanyl piperidine moiety pushes the smaller axial N-proton closer toward the neighboring two axial C--H bonds compared with the analogous case for a bulky axial N-methyl. Increased cisl,3-diaxial interactions in the axial N-methyl diastereomer destabilize this epimer in favor of the equatorial N-methyl counterpart [e.g., 2.121 kcal/mol lower energy for the equatorial N-methyl O-formyltropine N-protonated diastereomer (12) than for the axial epimer (13)]. Lower pyramidality at nitrogen in the free base maintains the relative stability of the equatorial N-methyl free base diastereomer (14) (1.120 kcal/mol more stable than the axial free base 15). A nonprotonated carbon atom at the apex of a three-membered ring fused to the 6,7-positions of the O-formyltropine skeleton results in severe transannular nonbonding steric interactions involving the neighboring equatorial N-methyl group in N-protonated 16 (3.335 kcal/mol less stable than the axial N-methyl epimer 17, where these transannular interactions are reduced due to the smaller equatorial N--H proton). Oxygen atom occupation of the apex of a similar fused three-membered ring retains the same severe transannular nonbonding steric interactions involving the neighboring equatorial N-methyl group in N-protonated 18. These transannular interactions now become electrostatically attractive in the N-protonated axial N-methyl epimer 19 (2.031 kcal/mol more stable than the equatorial epimer). Reduced pyramidality at nitrogen in the O-formylscopine free base reduces the repulsive transannular interaction with the neighboring equatorial N-methyl group compared to that in the N-protonated form. Lowered pyramidality also reduces the cis-l,3-diaxial interactions in the axial N-methyl epimer, but the nitrogen lone pair is pushed close to the transannular oxygen lone pair as a result (the equatorial N-methyl free base 20 is 3.870 kcal/mol more stable than the axial epimer 21). These ab initio-calculated models of O-formyltropines and O-formylscopine N-methyl diastereomeric protonated cations and free bases provide stereochemical insight into the relative stabilities of solution-state atropine and scopolamine N-methyl species previously observed by NMR spectroscopic methods.KEY WORDS: Scopolamine; atropine; scopine; tropine; ab initio; X-ray crystallography; NMR. . It was reasoned that the root of this confusion resulted from a very broadened low-intensity 6 33 N-CH 3 signal (width at half-height W1/2 = 55 Hz) in D20 which could be buried in the baseline noise of a low-S/N spectrum [12]. The relatively low 7.55 pK~ value of pro...

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.…”

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

“…Scopolamine has two stereogenic chirotopic 6 atoms: the relatively stereostable α-carbon and the stereolabile nitrogen. The important role of cis 1,3-diaxial interactions involving the equatorial N- methyl with the oxiranyl oxygen or the axial N- methyl with the piperidinyl-ring axial protons was recently studied by ab initio molecular modeling techniques …”