Astarita, Anna (2010) Nuove strategie sintetiche per C-glicosidi ad attività antivirale e antitumorale. [Tesi di dottorato] (Unpublished)


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Item Type: Tesi di dottorato
Resource language: Italiano
Title: Nuove strategie sintetiche per C-glicosidi ad attività antivirale e antitumorale
Date: 29 November 2010
Number of Pages: 161
Institution: Università degli Studi di Napoli Federico II
Department: Chimica organica e biochimica
Scuola di dottorato: Scienze chimiche
Dottorato: Scienze chimiche
Ciclo di dottorato: 23
Coordinatore del Corso di dottorato:
Iesce, Maria
Date: 29 November 2010
Number of Pages: 161
Keywords: C-glicosidi, glicosilfurani, ossigeno singoletto
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Date Deposited: 02 Dec 2010 07:57
Last Modified: 30 Apr 2014 19:44
DOI: 10.6092/UNINA/FEDOA/8156

Collection description

Carbohydrates are very important molecules because they are involved in many biological processes. Among the others remarkable interest is devoted to natural or synthetic C-glycosides owing to their pharmacological properties and higher stability than the O-analogues. Hence, the design of new synthetic procedures for this compound class is a field of organic chemistry continuously explored. Generally, the synthetic methodology for glycosides consists of a coupling reaction between a glycosyl-donor and a suitable acceptor in the presence of a Lewis acid. When this approach fails, a different strategy is based on transformations of a pre-existent residue into the aglycone target through suitable and selective reactions. Within this frame a novel recent approach employs furans as pre-existent aglycones and the dye-sensitized photooxygenation as the starting reaction in the construction of the desired target. The strategy, based on the reactivity of the thermally unstable intermediate endoperoxides, has been used for the synthesis of new functionalized C-glycosides, in particular pyridazine and pyrazoline C-nucleosides as well as new exo-glycals, all compounds of pharmacological and synthetic interest. A peculiarity of glycosylfuran endoperoxides is the rearrangement to O-glycosides with the migration of the sugar moiety and retention of configuration at anomeric carbon. This Baeyer-Villiger-type mechanism is a reaction rarely observed in other furan endoperoxides. The aim of this thesis has been to explore novel applications of this strategy. In a first phase investigation has been directed to verify the 1O2 reactivity towards 2,5-diglycosyl furans and to use the procedure for the synthesis of new 1,1’-linked disaccharides separated by a functionalized spacer of 4 or 5 atoms. These derivatives are of interest because they are structurally related to disaccharides mimetics of the Sialyl Lewis X (sLeX), a tetrasaccharide involved in the initial step of inflammation response. The novel 2,5-diglycosylfurans have been prepared by two successive coupling reactions. The photooxygenation has led quantitatively to O-glycosides via the corresponding endoperoxides. The use of asymmetrically substituted diglycosyl furans and theoretical calculations have evidenced that the sugar migration is promoted by steric effects. Competition between two sugars depends on C1/C2 configurations, and at a lesser extent on C1/C4 configurations; hence the migratory aptitude follows the order glucose>galactose>mannose. These factors are overcome by crowded protecting groups as benzyl. Both Baeyer-Villiger rearranged products can also be obtained starting from 2-glycosyfurans bearing encumbered arylmethyl substituents at 5 position. Reduction of the endoperoxides with Et2S at -20 °C provides a stereoselective access to 1,1’-linked C-diglycosides separated by a spacer of 4 atoms, namely an -unsaturated 1,4-dicarbonyl function with trans-configuration due to the rapid isomerization of the corresponding cis-derivatives. In order to get a deeper insight in the effect of substituents on the fate of glycosylfuran endoperoxides a novel 2-sugar furan bearing a methoxycarbonyl function at the 5-position, selected as representative electron-withdrawing substituent, has been prepared and photooxygenated. The electronic nature of the substituent does not affect the [4+2] cycloaddition of electrophilic singlet oxygen to the furan, but it dramatically influences the reaction course by promoting, in addition to the expected O-glycoside, a thermal rearrangement of the endo-peroxide to a C-nucleoside bis-epoxide, previously not observed. The aglycone in this product is structurally related to (+)-crotepoxide, a known antitumoral drug. Reduction of the endoperoxide by classical treatment with Et2S gives the corresponding enedione quantitatively. This compound by basic catalysis rearranges to a spironucleoside which is the first example of this compound class. In addition to the versatility of the reaction products (furan endoperoxides), photooxygenation has the advantage to be an environmentally friendly oxidation system since it is based on solar light, atmospheric oxygen and an atoxic dye. A drawback is the use of halogenated solvents. Therefore, in order to improve the synthetic process, stimulated by the use of potentially hydrophilic glycosyl compounds, investigation has been directed to the dye-sensitized photooxygenation of simple furans in green solvents such as water and ionic liquids. The nature of solvents does not influence the addition mode of singlet oxygen to the heterocycle which undergoes [4+2] cycloaddition even when singlet oxygen has a low life-time (in water), evidently owing to the high reactivity of furan system. Instead it has a role in the fate of the furan endoperoxides. Due to the polarity and nucleophilic nature of the solvent, endo-peroxide decomposition leads mainly to enediones and/or 2(5H)-furanones (from furans with at least one hydrogen at -position) and epoxides (from arylsubstitued furans). The results appear particularly promising due to the mild conditions and the high selectivity in obtaining compounds as enediones and 2(5H)-furanones of considerable synthetic and biological interest. The use of water as solvent does not affect the reaction of the deprotected 2-glucosylfuran which gives the corresponding O-glycoside quantitatively. This compound exhibits retention of configuration at the anomeric carbon, but the double bond in the trans configuration An interesting, albeit preliminary, result has been obtained in the field of synthesis and reactivity of furans. Indeed, bis-furyl sugars have been obtained by acid-catalysed glycosidation of nucleophilic furans and appropriately protected glycosyl donors . The achievement of these derivatives in high yields encourages to investigate on the possibility of using them as precursors of rare and/or not-easily accessible monosaccharides. In conclusion, new important results have been obtained not only in the field of glycosides, but also in the field of heterocycles, namely synthesis and reactivity of furans. Moreover promising applications of the dye-sensitized photooxygenation of furans under green conditions have been evidenced.


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