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Stephen F. Martin - One of the best experts on this subject based on the ideXlab platform.

Robert Glaser - One of the best experts on this subject based on the ideXlab platform.

  • Crystallization of a Racemate Affords a P21 Chiral Crystal Structure: Asymmetric Unit of Two Opposite Handed Molecules Simulates Achiral P21/n Packing via Pseudosymmetry
    Crystal Growth & Design, 2011
    Co-Authors: Avital Steinberg, Itzhak Ergaz, Rubén A. Toscano, Robert Glaser
    Abstract:

    A racemic mixture consisting of a secondary ammonium salt (±)-(1RS,3SR,4RS)-1-phenyl-cis-3,4-n-butano-5,6-dihydro-1H-2,5-Benzoxazocine hydrochloride (1) crystallized as a “false conglomerate” of crystals in the monoclinic system, Sohncke space group P21 with two molecules of opposite handedness in the asymmetric unit and at 295(2) K: a = 10.224(2) A, b = 13.969(2) A, c = 12.724(2) A, β = 98.996(2)°, V = 1794.9(5) A3, Z = 4, and Z′ = 2. The cis-3,4-n-butano-5,6-dihydro-1H-2,5-Benzoxazocine fused-ring skeletons are approximately enantiotopic and exhibit pseudoinversion and pseudo-n-glide relationships. These noncrystallographic symmetries enable space filling in the chiral crystal structure to resemble that of a higher order achiral P21/n apparent space group (Z = 4, Z′ = 1). The secondary ammonium salt molecules crystallize in patterns influenced by a complex blend of N−H···Cl, C−H···Cl, C−H···O, and C−H···Ar interactions that seem to be responsible for different conformational twists of the phenyl rings i...

  • Solution- and Solid-State NMR Studies of Eight- and Nine-Membered Medium Ring Cis-Cycloalkene Stereochemistry
    Annual Reports on NMR Spectroscopy, 2005
    Co-Authors: Robert Glaser, Itzhak Ergaz, Ganit Levi-ruso, Dror Shiftan, Artem Novoselsky, Shimona Geresh
    Abstract:

    Solution-state 13C and 1H nuclear magnetic resonance (NMR) spectroscopy (including nuclear overhauser effect studies); density functional theory quantum mechanical conformational modeling (and resultant calculations of 13C shielding constants and JHH spin–spin coupling constants) were combined with solid-state cross-polarization/magic angle spinning 13C-NMR spectroscopy of samples whose structures are known by X-ray crystallography to help unravel the extra complications present in cis-cyclooctene and cis-cyclononene medium ring stereochemical investigations. The stereochemistry of medium rings is considerably more complicated than that of the common rings (five to seven members) due to the presence of chiral conformations. An achiral cycloalkane conformation has only two sub-types: a reference conformation and a ring-inverted (inverso) conformation in which corresponding torsion angles exhibit sign-inverted values. The reference and its ring-invertomer lose their structural degeneracy and become diastereomeric when axial and equatorial substituents on a stereogenic ring atom in one conformation exchange their orientations in the other. The reference and ring-inverted structures of chiral conformations (e.g. those for cis-cyclooctene) represent a pair of reference/inverso enantiomers. Chiral conformations of heteroatom substituted cis-cyclooctenes result in the formation of two pairs of enantiomers differing in the directionality (tropicity) of the heteroatom vis-a-vis the double bond (i.e. a reference/inverso pair and a reversed tropicity diastereomeric retro/retro-inverso pair). Labeling of a ring atom in a chiral conformation cis-cyclooctene with a single substituent makes that ring atom stereogenic. This causes all four of these isomers to be diastereomeric, and each now has an enantiomeric partner. The theoretical possibility of stereochemically labeled chiral medium rings having diastereomeric conformational subtypes, differing in the stereogenic elements of ring chirality and/or substituent tropicity, was shown to exist in practice for some of the 2,5-Benzoxazocine and 2,6-benzoxazonine skeletons reported in this study. These were characterized by both solution- and solid-state NMR spectroscopy together with X-ray crystallography.

  • Solution- and Solid-State Structures of N-Desmethylnefopam Hydrochloride, a Metabolite of the Analgesic Drug
    Journal of pharmaceutical sciences, 1993
    Co-Authors: Robert Glaser, Shimona Geresh, David Donnell, Marc Drouin, Jeanine Blumenfeld, Nobuyuki Sugisaka, André Mlchel
    Abstract:

    The solid-state structure of (+/-)-N-desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single-crystal X-ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 0.025. The Benzoxazocine ring of crystalline 1 is twisted into the boat-flattened (chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo-type ring position, whereas the O atom and NCH2Ar occupy sterically hindered positions between "boat" and "chair" regions. Dissolution of BfC crystalline 1 in CD2Cl2 solvent affords a dynamic conformational equilibrium (involving the putative twist-chair-flattened (chair) conformer) as shown by line broadening and weighted time-averaged vicinal coupling constants [-OCH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1) degrees O-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the BfC conformation is the major contributor to time-averaged structure.

  • NMR studies on conformational and N-configurational interconversion in 3-methyl derivatives of the non-narcotic analgesic drug nefopam
    Magnetic Resonance in Chemistry, 1993
    Co-Authors: Robert Glaser, Jeanine Blumenfeld, Shimona Geresh
    Abstract:

    Two different N-configurations and two different eight-membered ring conformations were found in the diastereomeric crystalline (1R,3S)/(1S,3R)- and (1S,3R)/(1S,3S)-3-methylnefopam hydrochloride salts. 1H and 13C NMR spectroscopy showed that both crystalline epimers undergo N-configurational and eight-membered ring conformational equilibria on dissolution in a solvent (e.g. CD2Cl2). Observation of N-H proton vicinal coupling in both the solution-state major and minor species for each epimer signifies slow exchange limit kinetic regimes for N-configurational interconversion via a prototropic shift-nitrogen inversion. Since previous studies have shown 2,5-Benzoxazocine ring inversion to be unfavourable, the finding of weighted time-average vicinal coupling constants for the OCH(CH3)CH2NH(CH3)CH2 moiety is interpreted in terms of a fast exchange limit (and in some cases fast magnetic site exchange broadening) kinetic regime for eight-membered ring conformational change. For each C-3 epimer; a quantitative estimation was made for the 2n = 4 solution-state diastereomeric forms resulting from the two stereogenic elements of N-configuration and ring conformation. Comparisons were made with the parent nefopam hydrochloride, N-desmethylnefopam hydrochloride metabolite and the nefopam methiodide quaternary ammonium salt.

Caterina Ercolani - One of the best experts on this subject based on the ideXlab platform.

James J. Sahn - One of the best experts on this subject based on the ideXlab platform.

Shimona Geresh - One of the best experts on this subject based on the ideXlab platform.

  • Solution- and Solid-State NMR Studies of Eight- and Nine-Membered Medium Ring Cis-Cycloalkene Stereochemistry
    Annual Reports on NMR Spectroscopy, 2005
    Co-Authors: Robert Glaser, Itzhak Ergaz, Ganit Levi-ruso, Dror Shiftan, Artem Novoselsky, Shimona Geresh
    Abstract:

    Solution-state 13C and 1H nuclear magnetic resonance (NMR) spectroscopy (including nuclear overhauser effect studies); density functional theory quantum mechanical conformational modeling (and resultant calculations of 13C shielding constants and JHH spin–spin coupling constants) were combined with solid-state cross-polarization/magic angle spinning 13C-NMR spectroscopy of samples whose structures are known by X-ray crystallography to help unravel the extra complications present in cis-cyclooctene and cis-cyclononene medium ring stereochemical investigations. The stereochemistry of medium rings is considerably more complicated than that of the common rings (five to seven members) due to the presence of chiral conformations. An achiral cycloalkane conformation has only two sub-types: a reference conformation and a ring-inverted (inverso) conformation in which corresponding torsion angles exhibit sign-inverted values. The reference and its ring-invertomer lose their structural degeneracy and become diastereomeric when axial and equatorial substituents on a stereogenic ring atom in one conformation exchange their orientations in the other. The reference and ring-inverted structures of chiral conformations (e.g. those for cis-cyclooctene) represent a pair of reference/inverso enantiomers. Chiral conformations of heteroatom substituted cis-cyclooctenes result in the formation of two pairs of enantiomers differing in the directionality (tropicity) of the heteroatom vis-a-vis the double bond (i.e. a reference/inverso pair and a reversed tropicity diastereomeric retro/retro-inverso pair). Labeling of a ring atom in a chiral conformation cis-cyclooctene with a single substituent makes that ring atom stereogenic. This causes all four of these isomers to be diastereomeric, and each now has an enantiomeric partner. The theoretical possibility of stereochemically labeled chiral medium rings having diastereomeric conformational subtypes, differing in the stereogenic elements of ring chirality and/or substituent tropicity, was shown to exist in practice for some of the 2,5-Benzoxazocine and 2,6-benzoxazonine skeletons reported in this study. These were characterized by both solution- and solid-state NMR spectroscopy together with X-ray crystallography.

  • Solution- and Solid-State Structures of N-Desmethylnefopam Hydrochloride, a Metabolite of the Analgesic Drug
    Journal of pharmaceutical sciences, 1993
    Co-Authors: Robert Glaser, Shimona Geresh, David Donnell, Marc Drouin, Jeanine Blumenfeld, Nobuyuki Sugisaka, André Mlchel
    Abstract:

    The solid-state structure of (+/-)-N-desmethylnefopam hydrochloride (1), a metabolite of the analgesic drug, was determined by single-crystal X-ray diffraction analysis. Compound 1 gave crystalline prisms belonging to the orthorhombic Pcab space group, and at ambient temperature (293 K), a = 9.939(2), b = 14.479(1), c = 20.148(3) A, V = 2899.5(8) A3, Z = 8, R(F) = 0.045, and Rw(F) = 0.025. The Benzoxazocine ring of crystalline 1 is twisted into the boat-flattened (chair) [BfC] conformation, the phenyl ring resides in a relatively sterically unhindered exo-type ring position, whereas the O atom and NCH2Ar occupy sterically hindered positions between "boat" and "chair" regions. Dissolution of BfC crystalline 1 in CD2Cl2 solvent affords a dynamic conformational equilibrium (involving the putative twist-chair-flattened (chair) conformer) as shown by line broadening and weighted time-averaged vicinal coupling constants [-OCH2CH2N- segment] in the 1H NMR spectrum. The solution-state weighted time-averaged 50(1) degrees O-CH2-CH2-N dihedral angle, calculated by the R-ratio method, shows that the BfC conformation is the major contributor to time-averaged structure.

  • NMR studies on conformational and N-configurational interconversion in 3-methyl derivatives of the non-narcotic analgesic drug nefopam
    Magnetic Resonance in Chemistry, 1993
    Co-Authors: Robert Glaser, Jeanine Blumenfeld, Shimona Geresh
    Abstract:

    Two different N-configurations and two different eight-membered ring conformations were found in the diastereomeric crystalline (1R,3S)/(1S,3R)- and (1S,3R)/(1S,3S)-3-methylnefopam hydrochloride salts. 1H and 13C NMR spectroscopy showed that both crystalline epimers undergo N-configurational and eight-membered ring conformational equilibria on dissolution in a solvent (e.g. CD2Cl2). Observation of N-H proton vicinal coupling in both the solution-state major and minor species for each epimer signifies slow exchange limit kinetic regimes for N-configurational interconversion via a prototropic shift-nitrogen inversion. Since previous studies have shown 2,5-Benzoxazocine ring inversion to be unfavourable, the finding of weighted time-average vicinal coupling constants for the OCH(CH3)CH2NH(CH3)CH2 moiety is interpreted in terms of a fast exchange limit (and in some cases fast magnetic site exchange broadening) kinetic regime for eight-membered ring conformational change. For each C-3 epimer; a quantitative estimation was made for the 2n = 4 solution-state diastereomeric forms resulting from the two stereogenic elements of N-configuration and ring conformation. Comparisons were made with the parent nefopam hydrochloride, N-desmethylnefopam hydrochloride metabolite and the nefopam methiodide quaternary ammonium salt.