Stereochemistry of the N-methyl group in salts of tropane alkaloids

Glaser, Rainer; Peng, Qin; Perlin, Arthur S.

doi:10.1021/jo00245a009

Cited by 57 publications

(60 citation statements)

References 11 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As noted above, there is a dramatic change in the orientation of the Nmethyl group in protonated scopolamine from 95% axial N-methyl in aqueous medium to 95% equatorial N-methyl in CD,Cl,. 5 However, in the equatorial Nmethyl epimer, the nitrogen proton is disposed trans to the oxiranyl oxygen, and is thus sterically unable to participate in an internal H+-H. . .…”

Section: Resultsmentioning

confidence: 99%

NMR and molecular mechanics studies on the solution‐state conformation of (−)‐scopolamine free base

Glaser

1993

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

The NMR parameters of (-)-scopolamine free base in CDCl, determined by Sarazin et al. were used to reevaluate some of the stereochemicai conciusions recently reported by the authors. Similarly to the case with the protonated salt, the major contributor to the fast exchange ümit time-averaged sbucture of the free base bopate ester moiety appears to be the rotamer in which the phenyi and hydroxyl group are antipenplanar. Long-range heterondear coupling constants for the carboxyl carbon and also for the aromatic ipso carbon have been reassigned. Vicinal homoauclear coupling constants involving the methine proton and the two internaiiy diastereotopic protons in the (S)-CHCH,OH moiety have also been reassigned. Four conformadonal archetypes were caiculated by molecular mecbanics for the ( -)-(Ns,Ce-S)-scopoiamine free base equatoriai N-methyi diastereomer based on x-ray crystallographicaliy determined scopolamine structural analogues. The degree of aoisochronicity (and their relative shifts) exhibited by tbe internaiiy diastereotopic oxiranyl protons and carbons and the observation of NOE intensity enhancement of oxiranyi protons upon {H-aromatic} can be interpreted as arising from an interconverting profile of conformations at the fast exchange ümit. While a conformation similar to that of the soüd-state hydrobromide sesquihydrate salt appears to be a major contributor to the time-averaged structure, otber conformations can also play minor roles.

show abstract

Section: Resultsmentioning

confidence: 99%

NMR and molecular mechanics studies on the solution‐state conformation of (−)‐scopolamine free base

Glaser

1993

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, dissolution of 0.1 M (-)-scopolamine hydrobromide (la, lb) in CD2Cle showed a dramatic reversal of the isomer ratio (ca. 18 : 1 ratio of 2 versus 3, respectively) [12]. Doublet multiplicity for each of the two sets of externally diastereotopic methyl proton signals testified to the presence of two N-protonated species in the CD2C12 solution [12].…”

mentioning

confidence: 92%

“…Two drops of CF3CO2H were then added to the 2-mL NMR sample, and a slow exchange limit (SEL) ~3C NMR spectrum resulted that showed sharp lines of two protonated N-methyl diastereomeric species 6 46.86 (Ns, C~-S)-2 and 6 32.74 (Nr, C~-S)-3, in the ratio of ca. 1 : 18, respectively [12]. However, dissolution of 0.1 M (-)-scopolamine hydrobromide (la, lb) in CD2Cle showed a dramatic reversal of the isomer ratio (ca.…”

mentioning

confidence: 99%

“…. 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 protonated scopolamine appeared to be responsible for the dynamic nature of 1 in D20 solvent [12].…”

mentioning

confidence: 99%

“…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 protonated scopolamine appeared to be responsible for the dynamic nature of 1 in D20 solvent [12]. Two drops of CF3CO2H were then added to the 2-mL NMR sample, and a slow exchange limit (SEL) ~3C NMR spectrum resulted that showed sharp lines of two protonated N-methyl diastereomeric species 6 46.86 (Ns, C~-S)-2 and 6 32.74 (Nr, C~-S)-3, in the ratio of ca.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

1997

Self Cite

View full text Add to dashboard Cite

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...

show abstract

References

2015

Symmetry, Spectroscopy, and Crystallography

View full text Add to dashboard Cite

Stereochemistry of the N-methyl group in salts of tropane alkaloids

Cited by 57 publications

References 11 publications

NMR and molecular mechanics studies on the solution‐state conformation of (−)‐scopolamine free base

NMR and molecular mechanics studies on the solution‐state conformation of (−)‐scopolamine free base

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

References

Contact Info

Product

Resources

About