Synthetic Transformations of Sesquiterpene Lactones. 11.* Conjugates Based on Caffeine and Eudesmanolides with N -Contai
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SYNTHETIC TRANSFORMATIONS OF SESQUITERPENE LACTONES. 11.* CONJUGATES BASED ON CAFFEINE AND EUDESMANOLIDES WITH N-CONTAINING LINKERS
D. V. Reshetnikov,1 S. S. Patrushev,1,2 and E. E. Shults1*
8-(Aminoalkylamino)caffeine or 8-(piperazinyl)caffeine were formed in high yields by reacting 8-bromo- or 8-chlorocaffeine with linear and cyclic diamines using microwave-assisted organic synthesis. These amines were highly reactive in Michael reactions with sesquiterpene lactones containing active methylene groups. Conjugates with caffeine and eudesmanolide moieties bonded by a N-containing linker were synthesized. Keywords: caffeine, eudesmanolides, methylenelactones, Michael reaction. The alkaloid caffeine (1) is an available natural methylxanthine and an interesting lead compound for designing new derivatives with valuable biological activity and lower toxicity. It was used as a platform to synthesize agents to treat cancer of the lungs, liver, and breast and compounds enhancing stomach secretions and reducing the risk of developing gallstone disease [2]. Research on caffeine derivatives showed that compounds with various substituents in the C-8 position were antagonists of adenosine receptors [3, 4] and acetylcholine esterase [5, 6] and monoamine oxidase inhibitors [7]. 8-(2-Phenethyl)1,3,7-trimethylxanthine and 8-(phenoxymethyl)-1,3,7-trimethylxanthine were found to exhibit affinity for A1 and A2 adenosine receptors [8], confirming the hypothesis that modification of the caffeine C-8 substituent structure could lead to agents with increased affinity and selectivity for A1, A2A, A2B, or A3 adenosine receptors. 8-Aminocaffeine and 8-alkylmercaptocaffeine derivatives belong to this pharmacologically promising subclass [9]. The present article reports the regioselective synthesis of a series of eudesmane-xanthine conjugates using Michael reactions of diamino-substituted caffeine derivatives with eudesmane-type lactones, e.g., isoalantolactone (2), 4,15-epoxyisoalantolactone (3), and 3-hydroxyisoalantolactone (4). The presence of an activated methylene in lactones 2–4 enabled them to undergo Michael reactions. The nucleophiles were the N-nucleophiles 8-(aminoalkylamino)caffeine and 8-(piperazinyl)caffeine. The 8-aminocaffeine derivatives were prepared by heating 8-chlorocaffeine (5) with an excess (5 eq.) of an amine at 175–180°C [7] followed by workup with AcOH. Syntheses of caffeine diamino derivatives 6 and 7 by refluxing with an excess of ethylenediamine (8) or hexamethylenediamine (9) (5 mmol) and 2-bromocaffeine (10) in EtOH were previously reported [10]. In our hands, 6 and 7 were formed by reacting 8-chlorocaffeine (5) with diamines 8 and 9 (2 eq.) in 2-methoxyethanol using microwave-assisted organic synthesis (MAOS) (120°C, 3 h). Compounds 6 and 7 were isolated in 80–93% yields after column chromatography (Scheme 1). Their analytical characteristics were analogous to those in the literature [10]. This reaction also occurred readily with cyclic amines. The reaction of 8-halocaffeine 5 or 10 with piperazine (11) or mo
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