(3S)-3-hydroxyquinidine, the major biotransformation product of quinidine. Synthesis and conformational studies. X-Ray molecular structure of (3S)-3-hydroxyquinidine methanesuiphonate

Abstract

Hydroxyquinidine, the major metabolite of the Cinchona alkaloid quinidine, vvas prepared by synthetic chemical modification or microbial oxidation of quinidine. The structure of this metabolite has been demonstrated to be (3S)-3-hydroxyquinidine by 'H and 13C NMR, IR, UV and mass spectral analysis. Previously published comparisons of the 13C N M R spectra of 3-hydroxyquinidine and model compounds were used to establish the absolute stereochemistry of the metabolite (see ref. 8). This assignment has been verified by single-crystal X-ray analysis of ( 3 s ) -3hydroxyquinidine methanesulphonate. The gas-and solution-phase conformational preference of the metabolite derived from molecular modelling and NOE studies are compared with the conformation observed by X-ray crystallography.

CinchoniniumL-tartrate tetrahydrate

“…Compounds containing heterocyclic nitrogen systems are very important to mankind as they are often associated with substances that show physiological activity. In particular, naturally occurring alkaloids of the cinchona group have for a long time been used as antimalarial, antibacterial and cardioactive agents (Verpoorte et al, 1988;Carroll et al, 1991;Karle & Karle, 1992;Oleksyn & Serda, 1993;Chiou et al, 1996). Many factors can in¯uence the biological activity of these substances and the action mechanism is still not completely understood.…”

Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts in the One-Step Isomerisation of Cinchona Alkaloids to Δ3,10-Isobases

“…1. The alkene protons of =HC-Me from (Z)-and (E)-Δ 3,10 -isomers give two separate signals according to the literature data [12,13,25]. Determination of unconverted substrates can be possible from integration of peaks: =CH 2 protons (two doublets at ~4.90-5.10 ppm) or -CH= (multiplet at ~6.00 ppm).…”

“…This procedure was tested to find the optimal Literature data [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Oxidative cleavage [12][13][14][15] time for conversion of 1a or 2a to the isomers (Z/E)-3a or (Z/E)-4a. We monitored the ongoing conversion progress of substrates by taking micro-samples of the reaction mixture regularly, at 10-min intervals, which after extraction with diethyl ether in the presence of aqueous ammonia were analyzed by TLC (silica gel plates, methoxyethanol).…”

“…Two-step synthesis of the Δ 3,10 -isobases 3a,b and 4a,b, consisting of hydrogen halide addition and subsequent elimination by different bases has been elaborated [14-16, 20, 21]. However this way cannot be considered today as a modern preparative method by reason of poor atom economy, which is even poorer when additional stages of protection-deprotection of the hydroxy group must be performed [13,14] for prevention of the formation of isomers possessing an intramolecular ether bond between C9 and C10.…”

“…Δ 3,10 -Isobases were applied also as valuable intermediates for modification of the native structure [12] including the oxidative cleavage of the double bond [13][14][15][16].…”