M. M. Mirzaeva

Crystal structure of indoline alkaloids kopsinilam, kopsinine, and the salts of the latter

Indoline alkaloids kopsinilam and kopsinine extracted from the plant Vinca erecta have been studied by X-ray crystallography; mono and double salts of the latter alkaloid also have been examined. Experimentally determined positions of Н atoms suggest sp3 hybridization of the indoline nitrogen atom N1 in the bases and the salts. Tetrahedral hybridization of the atom N1 in indoline alkaloids favors the formation of their double salts, what is unlikely for indole and indolinine alkaloids. In the halogen double salts there is an intramolecular Н bond between one of the protons of the NH2 group and the oxygen of the methoxycarbonyl group, that is absent in the mono salts and pure bases.

Crystal structure of pseudokopsinine and its salts

The X-ray diffraction study of an indoline alkaloid, pseudokopsinine, extracted from the plant Vinca erecta and its mono- and double salts is performed. The experimentally determined positions of Н atoms suggest the sp3 hybridization of the indoline nitrogen atom in the base and salts. The pseudokopsinine base and double salt have an intramolecular Н bond between the NH group proton and the ether oxygen atom of the methoxycarbonyl group, which is absent in the monosalt and the related indolines. The intermolecular Н bonds and/or the packing efficiency cause a conformational change in F and Е heterocycles in the indoline hetero framework of pseudokopsinine salts in comparison with that observed in the base.

Structure of 12-methoxyfluorocurarine

The crystal and molecular structures of quaternary salts and the quaternary base of 12-methoxynorfluorocurarine (vincanicine) that was isolated from the plant Vinca erecta were studied. The molecular structure, i.e., conformation, ring fusion, and absolute configuration (3S,7R,15S) of asymmetric centers, did not differ from that of norfluorocurarine. The carbonyl (C17=O) and N1H groups in the quaternary salts and base were mutually twisted and were involved in the crystal only in intermolecular H-bonds. The enol form in the zwitterionic alkaloid that existed in alkaline medium was observed in the crystal of 12-methoxynorfluorocurarine quaternary base.

Crystal structure of salts of indole alkaloid norfluorocurarine

Single crystal XRD is used to study the crystals of salts of indole alkaloid norfluorocurarine: hydrochloride recrystallized from absolute alcohol, dihydrate hydrochloride recrystallized from water, methochloride monohydrate recrystallized from water, solvate form of methochloride obtained from ethanol, and methobromide monohydrate. Intra- and intermolecular hydrogen bonds are analyzed in these crystals. The crystal structures of norfluorocurarine methochloride and methobromide monohydrates are isomorphic. In norfluorocurarine salts, the orientation of the carbonyl group is determined by the intramolecular C19=O…H-N1 hydrogen bond that is absent in the solvate form with ethanol.

Syntheses based on norfluorocurarine. 7. Reduction of norfluorocurarine and fluorocurarine by metallic sodium and sodium borohydride

Reduction of norfluorocurarine by sodium in EtOH formed deoxytetrahydronorfluorocurarine and tetrahydronorfluorocurarine. The latter was identical to the Wieland–Humlich 18-deoxyglycol. Reduction of norfluorocurarine by sodium borohydride in alkaline solution occurred with opening of rings C and E and formation of the new indole base 16-decarbmethoxyepistemmadenine. Reduction of fluorocurarine chloride or iodide by sodium borohydride formed the corresponding de-acetylretuline salts. The structures of the products were established by x-ray crystal structure analyses. Norfluorocurarine and representatives of the α-methylenindolenine series formed indoline derivatives upon reduction in acidic and neutral solutions; indole derivatives, in alkaline solution.

Syntheses based on norfluorocurarine. 5. NMR spectra of monomeric norfluorocurarine derivatives

NMR spectra of norfluorocurarine and seven of its derivatives were studied. The NMR spectral parameters were related to stereochemical features using molecular modeling by the semi-empirical AM1 approximation. The resulting steric characteristics of the molecules in solution agreed well with x-ray structure data. The only difference from the x-ray structure data was the ability of several substituents to rotate.

Syntheses based on norfluorocurarine. 2. Reduction and dehydrogenation products

The bisindole compound 2β,16α,2′β,16′β(H)-tetrahydronordihydrotoxiferine consisting of two diastereoisomeric deoxytetrahydronorfluorocurarine moieties was isolated from the reduction mixture of the alkaloid norfluorocurarine. 16-Deformyl-2,16,17,20-tetrahydro-20,21-dehydronorfluorocurarine was produced by dehydrogenation of norfluorocurarine; N(β)-methyldihydrodefluorocurarine, by hydrogenation of fluorocurarine. The structures of the synthesized compounds were established by x-ray structure analyses. The configurations of the asymmetric centers in 2β,16α,2′β,16′β(H)-tetrahydronordihydrotoxiferine were determined as 2S,3S,7R,15S,16R,2′S,3′S,7′R,15′S,16′S. Inversion to the R-configuration at the C15 center was observed in N(β)-methyldihydrodefluorocurarine whereas the configurations 3S and 7R were retained. Atom C2 adopted the S-configuration in 16-deformyl-2,16,17,20-tetrahydro-20,21-dehydronorfluorocurarine.

Syntheses based on norfluorocurarine. 3. Structures of (−)-norfluorocurarine, (±)-norfluorocurarine, and fluorocurarine

Structures of the alkaloids (−)-norfluorocurarine, its racemate (±)-norfluorocurarine from Vinca erecta, and fluorocurarine obtained by N(β)-methylation of (−)-norfluorocurarine were established by x-ray crystal structure analyses. The alkaloid crystallized with two molecules in the asymmetric unit for the first two crystals. The asymmetric unit of (±)-norfluorocurarine crystal consisted of two antipods. The asymmetric unit in the crystal of the last compound consisted of the N(β)-methylated cation and a hydroxide anion. The formation of bimolecular associates through intermolecular N–H…O H-bonds was typical of these crystal- line structures. An associate in the crystal structure of fluorocurarine involved two hydroxide anions.

Alkyl- and Acyl-Derivatives of Copsinine and Pseudocopsinine and Their Crystal Structures

Acyl- and alkyl-derivatives at the N1 and N4 atoms, respectively, of the indoline alkaloids copsinine (1) and pseudocopsinine (2), which were isolated from the plant Vinca erecta, were synthesized. Alkaloids 1 and 2 reacted with alkyl halides to give N4 substitution; with acetic anhydride, N1. In turn, N1-acyl-1 and -2 reacted with alkyl halides to bond the alkyl radical to the N4 position. Reaction products were identified using IR spectroscopy and HPLC-MS. Their structures were elucidated by X-ray crystal structure analyses (XSAs). The tetrahedral hybridization of N1 in the indoline alkaloids was favorable for forming their N1-acetyl derivatives, which is improbable in indole and α-methyleneindoline alkaloids.

Structure of 12-hydroxynorfluorocurarine, its hydrochloride, quaternary salts and a zwitterionic betaine

The crystal structures of 12-hydroxynorfluorocurarine (vincanidine) isolated from the plant Vinca erecta, its hydrochloride monohydrate, quaternary salts — chloromethylate and iodomethylate, and the quaternary base (zwitterionic betaine) have been studied. The asymmetric centers of the molecules have the 3S, 7R, 15S configuration. In all cases, the carbonyl group is in a twisted orientation with respect to the N1H group and participates in the intramolecular H-bond with this group. In crystals, the 12-hydroxy group is involved in intermolecular interactions. The quaternary base of 12-hydroxynorfluorocurarine contains a zwitterionic form of the alkaloid due to deprotonation of the 12-hydroxyl group. The packing in the crystal structure of 12-hydroxynorfluorocurarine and the quaternary base contains voids (19.8 % and 21.8 % of the total volume of the crystal cell, respectively) of the channel type along the c crystallographic axis.