M.S. Arias

Structural and spectroscopic study of condensed piperidine bicyclanols. 3-Phenethyl-3-azabicyclo[3.2.1]octan-8-α-ol

Abstract The IR and 1 H and 13 C NMR spectra of 3-phenethyl-3-azabicyclo[3.2.1]octan-8-α-ol have been studied in several media, and its crystal structure has been determined by X-ray diffraction. The bicyclic system adopts a chair—envelope conformation with both OH and phenethyl groups in equatorial positions with respect to the piperidine ring. The existence of OH⋯N intermolecular hydrogen bonding in the solid state has been revealed by X-ray and IR data. The results obtained are compared with those previously found for the corresponding β-epimer.

Synthesis and structural study of 9-(2′-hydroxyethyl)-9-azabicyclo[3.3.1]nonan-3α-OL

Abstract The infrared, 1 H and 13 C NMR spectra of 9-(2′-hydroxyethyl)-9-azabicyclo[3.3.1] nonan-3α-ol (I) have been examined in several media. The crystal structure has been determined by X-ray diffraction. The bicycle system adopts in solid state a distorted double chair conformation, being the OH and 2′-hydroxyethyl group attached in axial position with respect to the piperidinol ring. In solution, by the contrary, the title compound adopts a preferred flattened chair-boat conformation with the piperidinol ring in a slight distorted boat form. The unambiguous assignment of all protons of the granatanine system, not described up to date, has been carried out.

Structural and conformational study of 9-(2′-hydroxyethyl)-9-azabicyclo[3.3.1]nonan-3β-ol

Abstract The infrared, 1H and 13C-NMR spectra of 9-(2′-hydroxyethyl)-9-azabicyclo[3.3.1]nonan-3β-ol (I) have been examined in several media. To assist in interpretation of the spectroscopic data, the crystal structure has been determined by X-ray diffraction. The bicyclic system adopts a flattened chair-chair conformation with OH and 2′-hydroxyethyl groups in equatorial and axial position with respect to the piperidinol ring. The crystal structure is stabilized by means of and intermolecular hydrogen bondings. In CDCl3 solution the title compound can be described as an equilibrium between two flattened chair-chair conformations through nitrogen inversion. A slight predominance of the form with the N-substituent axial with respect to the piperidine ring is suggested.

Synthesis and structural and conformational study of 3α-methoxycarbonyl-3β-(3′,4′,5′-trimethoxybenzamido)-N8-substituted nortropanes

Abstract Two 3α-methoxycarbonyl-3β-(3′,4′,5′-trimethoxybenzamido)-N8-substituted nortropanes have been synthesized and studied by IR, 1 H and 13 C NMR spectroscopy and the crystal structure of 3α-methoxycarbonyl-3β-(3′,4′,5′,-trimethoxybenzamido) tropane (IIa) has been determined by X-ray diffraction. The compounds studied display in deuterochloroform the same preferred conformation. The pyrrolidine and piperidine rings adopt a flattened N8 envelope and distorted chair conformation, puckered at N8 and markedly flattened at C3, with the N-substituent in equatorial position. This conformation seems to be governed by an intramolecular hydrogen bond. The crystal structure of IIa shows a complex hydrogen bonding network. Concerning the tropane skeleton, the X-ray results for IIa are quite similar to those found for compounds IIa,b in CDCl 3 solution. Some spectroscopy data of the precursor amidonitriles are also described.

Synthesis and structural study of tropane benzamines: Part III. N-(8-Isopropyl-nortropan-3-β-yl)-2-methoxy-4-amino-5-chlorobenzamide

Abstract N -(8-Isopropyl-nortropan-3-β-yl)-2-methoxy-4-amino-5-chlorobenzamide has been synthesized and its crystal and molecular structures determined by X-ray diffraction, IR, 1 H NMR and 13 C NMR methods. The pyrrolidine and piperidine rings adopt a flattened N-8 envelope and distorted chair conformation puckered at N-8, with the N -isopropyl substituent and the amido groups, respectively, in axial and equatorial position with respect to the piperidine ring. A great predominance in solution of the conformer observed in the solid state is proposed. The results obtained are compared with those previously found for the corresponding α-epimer.

Structural and conformational study of some N′-substituted benzoyl derivatives of the 3-β-amino-3-α-carbamoyl-N-8-substituted nortropanes

Abstract A series of substituted benzoyl derivatives of 3-β-amino-3-α-carbamoyl- N -8-substituted nortropanes has been synthesized and studied by IR, 1 H and 13 NMR spectroscopy, and the crystal structure of 3-α-carbamoyl-3-β- p -Chlorobenzamidotropane ( VIb ) has been determined by X-ray diffraction. The compounds studied display in deuterochloroform and deuteromethanol a chair-envelope conformation markedly flattened at C3 with the benzamido and carbamoyl groups in pseudo-equatorial and pseudo-axial positions respectively.

Synthesis and structural study of tropane benzamides: Part IV. N-(8-alkyl (or aralkyl) nortropan-3-β-yl)-3,4-5-trimethoxybenzamides

Abstract A series of N -(8-alkyl (or aralkyl) nortropan-3-β-yl)-3,4,5-trimethoxybenzamides have been synthesized and their molecular structures determined by 1 H-NMR and 13 C-NMR methods. The pyrrolidine and piperidine rings adopt a flattened N8 envelope and a slightly distorted chair conformation puckered at N8, with the N -substituent and the amido group at C3 position in the axial and equatorial positions, respectively, with respect to the piperidine ring.

Conformational study of 3-azabicyclo[3.3.1]nonan-9β-ol and 3-alkylderivatives

Abstract The conformational preferences of the 3-azabicyclo[3.3.1]nonan-9β-ol ( I ) and several 3-alkylderivatives have been studied by means of the molecular mechanics method (MM2, MM2′ and MMX programs). In all cases, the most stable conformer corresponds to a slightly flattened chair-chair conformation with the 3N-substituent in the β-disposition. According to the theoretical values: 1) the steric hindrance of the 3N-group is not very important in determining the energy differences between conformers; 2) the conformational inversion of the 3N-substituent is favoured by considering intramolecular hydrogen bond.

Comparative conformational study of α and β epimers of 3-phenethyl-3-azabicyclo [3.2.1]octan-8-ol with atropine and azaprophen

Abstract Conformational analysis of α(I) and β(II) epimers of 3-phenethyl-3-azabicyclo [3.2.1] octan-8-ol has been performed using the Molecular Mechanics Method (MM2). In both cases, the global minimum-energy conformer was the slight distorted chair form with the N-phenethyl group in equatorial position. The preferred conformation is in agreement with the form adopted in solid state and in solution in polar solvents. Higher energy differences between N-axial and N-equatorial conformations have been found with respect to tropine and 6-methyl-6-azabicyclo [3.2.1] octan-3-α-ol, the am i noalcohols components of atropine and azaprophen.

Synthesis and structural, conformational and pharmacological study of some esters derived from 3-β-hydroxytropan-3-α-carboxylic acid

Abstract A series of 3-β-hydroxy-3-α-alkoxycarbonyl tropanes has been synthesized and studied by IR, 1 H and 13 C NMR spectroscopy, and the crystal structure of ethyl-3-β-hydroxytropan-3-α-carboxylate ( VIb ) and phenethyl-3-β-hydroxytropan-3-α-carboxylate ( VIc ) have been determined by X-ray diffraction. The compounds studied display in chloroform- d the same preferred conformation. The pyrrolidine and piperidine rings adopt a flattened N8 envelope and a distorted chair conformation puckered at N8 and strongly flattened at C3, respectively, with the N -methyl and hydroxy groups in equatorial and pseudo-equatorial positions and the ester group in a pseudo-axial arrangement with respect to the piperidine ring. An intramolecular interaction between the hydroxy group and the nitrogen atom is proposed. However in CD 3 OD solution the intramolecular hydrogen bond is broken and the hydroxy and ester groups adopt a different relative disposition, more sterically favourable, decreasing the flattening of the piperidine ring. With regard to the tropane skeleton, these results are in close agreement with those found for compounds VIb and VIc in the crystalline state. The inhibitory effect of the title compounds on 3 H-GABA binding to a synaptosomal brain membranes is also reported.