Solid-State Stereochemistry of (−)-Scopolamine Hydrobromide Sesquihydrate, a New Polymorph of the Anticholinergic Drug

Michel, A. G.; Drouin, Marc; Glaser, Rainer

doi:10.1002/jps.2600830413

Cited by 11 publications

(14 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Introductionmentioning

confidence: 89%

“…The structures of la [5] and the sesquihydrate pseudopolymorph lb [6] have recently been reported by Glaser and co-workers. Drawings la and lb, as well as all others to follow, depict actual twodimensional iconic projections [7] of the respective three-dimensional X-ray crystallographically deter- '0-4 II lb mined (or ab initio-calculated) structures [5,6]. The issue of polymorphism for scopolamine hydrobromide has not been adequately resolved in the United States Pharmacopoeia XXII [8], since only a maximum permissible 13% weight loss after drying at 105~ for 3 hr is specified, while no lower limit is stated [6].…”

Section: Introductionmentioning

confidence: 89%

“…The issue of polymorphism for scopolamine hydrobromide has not been adequately resolved in the United States Pharmacopoeia XXII [8], since only a maximum permissible 13% weight loss after drying at 105~ for 3 hr is specified, while no lower limit is stated [6]. Although the monographs mention a trihydrate [8], this has never been isolated (to the best of our knowledge), and crystallization from water affords only a sesquihydrate [6].…”

Section: Introductionmentioning

confidence: 98%

“…Drawings la and lb, as well as all others to follow, depict actual twodimensional iconic projections [7] of the respective three-dimensional X-ray crystallographically deter- '0-4 II lb mined (or ab initio-calculated) structures [5,6]. The issue of polymorphism for scopolamine hydrobromide has not been adequately resolved in the United States Pharmacopoeia XXII [8], since only a maximum permissible 13% weight loss after drying at 105~ for 3 hr is specified, while no lower limit is stated [6]. Although the monographs mention a trihydrate [8], this has never been isolated (to the best of our knowledge), and crystallization from water affords only a sesquihydrate [6].…”

Section: Introductionmentioning

confidence: 99%

“…7: 1 and 18 : 1 ratios of 4 : 5 in D20 and CD2C12, respectively) [12]. These solution-state diastereomerization reactions at the labile chirotopic and stereogenic nitrogen interconvert the two protonated N-methyl species via a prototropic shift/nitrogen inversion mechanism [12].The orientation of the N-methyl group is axial in both crystalline anhydrous (-)-Nr, C~-S)-scopolamine hydrobromide (la) [5] and in the (-)-(Nr, C~-S)-scopolamine hydrobromide sesquihydrate (lb) [6] The two N-methyl diastereomers of both scopolamine and atropine free bases were at the NMR fast exchange limit (FEL) for epimerization at nitrogen in ambient-temperature solutions of CDC13 solvent. 13C NMR spectroscopy unequivocally showed that the appropriate equatorial N-methyl diastereomers were the predominant contributors to the time-averaged spectral parameters for solutions of both alkaloid free bases [12].…”

mentioning

confidence: 98%

See 4 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

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

See 3 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

show abstract

References

2015

Symmetry, Spectroscopy, and Crystallography

View full text Add to dashboard Cite

DFT‐GIAO¹H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

Muñoz

Joseph‐Nathan

2010

Magnetic Reson in Chemistry

View full text Add to dashboard Cite

The relatively large chemical shift differences observed in the (1)H NMR spectra of the anticholinergic drugs (-)-scopolamine 1 and (-)-hyoscyamine 2 measured in CDCl(3) are explained using a combination of systematic/molecular mechanics force field (MMFF) conformational searches and gas-phase density functional theory (DFT) single point calculations, geometry optimizations and chemical shift calculations within the gauge including/invariant atomic orbital (GIAO) approximation. These calculations show that both molecules prefer a compact conformation in which the phenyl ring of the tropic ester is positioned under the tropane bicycle, clearly suggesting that the chemical shift differences are produced by the anisotropic effect of the aromatic ring. As the calculations fairly well predict these experimental differences, diastereotopic NMR signal assignments for the two studied molecules are proposed. In addition, a cursory inspection of the published (1)H and (13)C NMR spectra of different forms of 1 and 2 in solution reveals that most of them show these diastereotopic chemical shift differences, strongly suggesting a preference for the compact conformation quite independent of the organic or aqueous nature of the solvent.

show abstract

Solid-State Stereochemistry of (−)-Scopolamine Hydrobromide Sesquihydrate, a New Polymorph of the Anticholinergic Drug

Cited by 11 publications

References 11 publications

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

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

References

DFT‐GIAO¹H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

Contact Info

Product

Resources

About

Solid-State Stereochemistry of (−)-Scopolamine Hydrobromide Sesquihydrate, a New Polymorph of the Anticholinergic Drug

Cited by 11 publications

References 11 publications

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

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

References

DFT‐GIAO1H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine

Contact Info

Product

Resources

About

DFT‐GIAO¹H NMR chemical shifts prediction for the spectral assignment and conformational analysis of the anticholinergic drugs (−)‐scopolamine and (−)‐hyoscyamine