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Synthesis and biological activity evaluation of new spiro-pyranoquinoline and pyranocoumarin analogues

By Βασιλική Παντελέων

Abstract

In the present thesis a number of new spiro-substituted pyranocoumarins and pyranoquinolinones have been designed and synthesized. The conformation analysis of the new molecules, their antioxidant activity and their interaction with β-amyloid peptide have been studied. The pyranobenzopyran-2-ones bearing a spiro cyclopentane, cyclohexane and cycloheptane ring were synthesized from 8-acetyl-7-hydroxycoumarin, upon reaction with the suitable cyclic ketone in the presence of pyrrolidine, to yield the corresponding spiro-4-oxodihydropyranocoumarins. After reduction of the ketone carbonyl and dehydration of the resulting carbinol, the target olefins were obtained and were then converted into the corresponding cis-diols. The spiro-adamantane analogue was synthesized through condensation of 7-hydroxycoumarin and 2-chloro-2-ethynyladamantane, followed by thermal rearrangement of the resulting ether. The angular isomer was isolated and converted to the corresponding cis-diol. The pyranoquinolin-2-ones bearing a spiro cyclopentane, cyclohexane and cycloheptane ring were prepared from 2-hydroxy-5-nitroacetophenone, that by a procedure similar to the one mentioned above, was converted to key indermediates spiroacetamidobenzopyranes. The corresponding adamantane analogue was prepared from 4-acetamido-3-nitrophenol. The nitroacetamidobenzopyranes were subsequently converted to the corresponding iodonitrobenzopyranes, which underwent coupling with acrylic acid, reduction of the nitro group and cyclization, to yield the spiropyranoquinolin-2-ones and then, the corresponding cis-diols. For the synthesis of the 4-hydroxycoumarin analogues, 2,6-dihydroxyacetophenone reacted with the suitable cyclic ketone, the hydroxyl group of the resulting spiro benzopyran-4-one was mesylated, and then the ketone was converted to the corresponding benzopyrane. Upon hydrolysis of the mesylate, the resulting phenols reacted with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) and after cyclization yielded the 4-hydroxycoumarines. The spiroadamantane derivatives were synthesized from 2,4-dihydroxyacetophenone through reaction with 2-chloro-2-ethynyladamantane, followed by thermal rearrangement of the resulting ether. The corresponding diols were prepared by syn-hydroxylation of the intermediate above mentioned mesylates, protection of the diol through acetal formation, reaction with Meldrum’s acid and deprotection. For the synthesis of the 4-hydroxypyranoquinolin-2-ones, the intermediate spiro acetamidobenzopyranes were converted to the corresponding 6-amino-5-derivatives, which yielded the nitrobenzopyranes after diazotization and reduction of the amino group. Reduction of the nitro group, condensation with diethyl malonate and cyclization of the resulting amide, gave the spiro 4-hydroxypyranoquinolin-2-ones. The corresponding diols were prepared by syn-hydroxylation of the intermediate spiro 5-nitrobenzopyranes, protection of the diol through formation of the acetal, reduction of the nitro group, condensation with diethyl malonate, cyclization of the resulting amide and deprotection. The conformation of the pyran ring of the new spiro-substituted cis-diols, was investigated using 1D and 2D NMR spectral data and molecular mechanic calculations.

Topics: Πυρανοκουμαρίνες, Πυρανοκινολίνες, Διαμόρφωση, Σάρωση ελευθέρων ριζών, 1,1-διφαινυλο-2-πικρυλοϋδραζυλο ρίζα, Pyranocoumarines, Pyranoquinolines, Conformation, Radical scavenging effect, 1,1-diphenyl-2-picrylhydrazyl (DPPH)
Publisher: National and Kapodistrian University of Athens
Year: 2006
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