Scopolamine and atropine N-methyl diastereomer stability. Ab initio calculations on O-formylscopine and O-formyltropine model compounds

Robert Glaser, Vitaly Khutorsky, Michael Shokhen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Ab initio geometry optimizations at the RHF-21G basis set level were calculated forequatorial andaxial 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 theN-protonated tropanyl piperidine moiety pushes the smalleraxial N-proton closer toward the neighboring twoaxial C-H bonds compared with the analogous case for a bulkyaxial N-methyl. Increasedcis 1,3-diaxial interactions in theaxial N-methyl diastereomer destabilize this epimer in favor of theequatorial N-methyl counterpart [e.g., 2.121 kcal/mol lower energy for theequatorial N-methylO-formyltropineN-protonated diastereomer (12) than for theaxial epimer (13)]. Lower pyramidality at nitrogen in the free base maintains the relative stability of theequatorial N-methyl free base diastereomer (14) (1.120 kcal/mol more stable than theaxial free base15). A nonprotonated carbon atom at the apex of a three-membered ring fused to the 6,7-positions of theO-formyltropine skeleton results in severe transannular nonbonding steric interactions involving the neighboringequatorial N-methyl group inN-protonated16 (3.335 kcal/mol less stable than theaxial N-methyl epimer17, where these transannular interactions are reduced due to the smallerequatorial 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 neighboringequatorial N-methyl group inN-protonated18. These transannular interactions now become electrostatically attractive in theN-protonatedaxial N-methyl epimer19 (2.031 kcal/mol more stable than theequatorial epimer). Reduced pyramidality at nitrogen in theO-formylscopine free base reduces the repulsive transannular interaction with the neighboringequatorial N-methyl group compared to that in theN-protonated form. Lowered pyramidality also reduces thecis-1,3-diaxial interactions in theaxial N-methyl epimer, but the nitrogen lone pair is pushed close to the transannular oxygen lone pair as a result (theequatorial N-methyl free base20 is 3.870 kcal/mol more stable than theaxial epimer21). Theseab initio-calculated models ofO-formyltropines andO-formylscopineN-methyl diastereomeric protonated cations and free bases provide stereochemical insight into the relative stabilities of solution-state atropine and scopolamineN-methyl species previously observed by NMR spectroscopic methods.

Original languageEnglish
Pages (from-to)319-329
Number of pages11
JournalStructural Chemistry
Volume8
Issue number5
DOIs
StatePublished - 1 Oct 1997

Keywords

  • Ab initio
  • Atropine
  • NMR
  • Scopine
  • Scopolamine
  • Tropine
  • X-ray crystallography

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