Fluorinated nucleosides, especially the analogues with fluorine atom(s) in the ribose ring, have been known to exert potent biological activities. The first part of this dissertation was aimed at developing oxidative desulfurization-fluorination and reductive desulfonylation-fluorination methodologies toward the synthesis of 2'-mono and/or 2',2'-difluoro pyrimidine nucleosides from the corresponding 2'-arylthiopyrimidine precursors. Novel oxidative desulfurization-difluorination methodology was developed for the synthesis of α,α-difluorinted esters from the corresponding α-arylthio esters, wherein the arylthio group is present on a secondary internal carbon. For the reductive desulfonylation studies, cyclic voltammetry was utilized to measure the reduction potentials at which the sulfone moiety of substrates can be cleaved. The 5-bromo pyrimidine nucleosides and 8-bromo purine nucleosides act as crucial intermediates in various synthetic transformations. The second part of the present dissertation was designed to develop a novel bromination methodology using 1,3-dibromo-5,5-dimethylhydantoin (DBH). Various protected and deprotected pyrimidine and purine nucleosides were converted to their respective C5 and C8 brominated counterparts using DBH. The effect of Lewis acids, solvents, and temperature on the efficiency of bromination was studied. Also, N-bromosuccinimide (NBS) or DBH offered a convenient access to 8-bromotoyocamycin and 8-bromosangivamycin. Third part of this research work focuses on the design and synthesis of 6-N-benzylated derivatives of 7-deazapurine nucleoside antibiotics, such as tubercidin, sangivamycin and toyocamycin. Target molecules were synthesized by two methods. First method involves treatment of 7-deazapurine substrates with benzylbromide followed by dimethylamine-promoted Dimroth rearrangement. The second method employs fluoro-diazotization followed by SNAr displacement of the 6-fluoro group by a benzylamine. The 6-N-benzylated 7-deazapurine nucleosides showed type-specific inhibition of cancer cell proliferation at micromolar concentrations and weak inhibition of human equilibrative nucleoside transport protein (hENT1). In the fourth part of this dissertation, syntheses of C7 or C8 modified 7-deazapurine nucleosides, which might exhibit fluorescent properties, were undertaken. 8-Azidotoyocamycin was synthesized by treatment of 8-bromotoyocamycin with sodium azide. Strain promoted click chemistry of 8-azidotoyocamycin with cyclooctynes gave the corresponding 8-triazolyl derivatives. Alternatively, 7-benzotriazolyl tubercidin was synthesized by iodine catalyzed CH arylation of tubercidin with benzotriazole.

Este trabalho apresenta: 1) Duas revisões bibliográficas sendo uma sobre a síntese de α-ceto-tioésteres e -ésteres e a outra sobre a decomposição de sulfóxidos e sulfonas sulfeniladas; 2) Investigações prévias indicando a viabilidade da decomposição térmica e a estabilidade relativa dos derivados bissulfenilados de tioésteres de diferentes estados de oxidação Ia-e, obtidos a partir do α-ceto-tioéster; 3) O estudo de síntese de precursores de α-ceto-tioésteres II e α-ceto-ésteres III, a saber: α - metilsulfonil- α - metiltio tioésteres IVa-c, -éster V e α, α - dimetiltio - ésteres VIa-c; 4) Decomposição térmica de α-metilsulfonil-α-metiltio-tioésteres Iva, b e c e -éster V sintetizados aos α-ceto-tioésteres e ésteres correspondentes, pelo emprego do método elaborado anteriormente por Wladislaw e col. e sugestão do mecanismo da mesma. A síntese de α metilsulfonil α metiltio tiopropionato de etila (Ivb), foi efetuada a partir do ácido α-cloro propiônico através de quatro passos reacionais, a saber: sulfenilação por substituição, oxidação à sulfona , tioesterificação e sulfenilação pelo emprego de NaH/MeS02SMe em DMSO. A obtenção do α - benzil - α - metilsulfonil - α - metiltio - tioacetato de etila (Ivc) foi efetuada a partir de ácido α-cloro acético através de reações de sulfenilação por substituição oxidação à sulfona tioesterificação alquilação com brometo de benzila e NaH em DMSO e, finalmente, a sulfenilação que só foi possível com o emprego de N-metiltioftalimida. A síntese de α-metilsulfonil-α-metiltio-propionato de etila (V) foi efetuada a partir do α-metilsulfonil malonato VIIa pelo eemprego do método de descarbetoxilação sulfenilativa usando 1,4 diazabiciclo [2,2,2] octano (DABCO) em tolueno sob refluxo e MeSO2SMe. Os compostos VIIa,b e c foram preparados a partir dos malonatos de dietila alquil - substituidos, seguido de sulfenilação e oxidação à sulfona. É de interesse a inédita reação de α - metilsulfonil fenilmalonato de dietila (VIIb), com DABCO em benzeno sob refluxo e MeSO2SMe, que conduziu à dessulfonilação sulfenilativa fornecendo o α - metiltio - fenilmalonato de dietila. É apresentada uma discussão mecanística tanto sobre descarbetoxilação, como sobre dessulfonilação sulfenilativas. A síntese de α,α-dimetiltio-ésteres VIa-c foi efetuada pela reação de sulfenilação com descarboxilação dos mono-ácidos malônicos correspondentes. O acompanhamento da descarboxilação e experimentos de deuteração permitiram esclarecer a sequência dos passos reacionais nestas novas reações. Cabe ressaltar que são compostos ainda não descritos na literatura os precursores IVa, IVb, IVc, V e Vib e 11 intermediários envolvidos nas reações efetuadas. Os resultados apresentados neste trabalho, além de importância sintética, trazem uma contribuição para a Química de Compostos Orgânicos de Enxofre. / This work presents: 1) Two literature reviews, one about the synthesis of α-keto thioesters and esters and the other on the decomposition of sulfenylated sulfoxides and sulfones; 2) Previous investigations indicating the viability of thermal decomposition and the relative stability of the dithioderivatives of different oxidation states Ia-e,which were obtained from the α-keto thioester; 3) The study of synthesis of α-keto thioesters II and esters III precursors, which are the following: α-methylsulfonyl-α-methylthio-thioesters IVa-c and -ester V, and α, α - dimethylthio esters VIa-c; 4) Thermal decomposition of the synthesized α - methylsulfonyl- α -methylthio- thioesters Iva,b e c and ester V, to the corresponding α-keto thioesters and α-keto ester, through the method developed by Wladislaw et al., with the suggestion of the mechanism. α-Methylsulfonyl-α-methylthio ethyl thiopropionate (Ivb) was synthesized from α-chloro-propionic acid in four steps: sulfenylative substitution, oxidation to sulfone, thioesterification and sulfenylation using NaH/MeSO2SMe in DMSO. α-Benzyl-α-methylsulfonyl-α-methylthio ethyl thioacetate (,i>Ivc) was obtained from α-chloro acetic acid through the following steps: sulfenylative substitution, oxidation to sulfone, thioesterification, alkylation with benzylbromide and NaH in DMSO, and finally, the sulfenylation which was successful only with the use of N-methylthiophtalimide. α-Methylsulfonyl-α-methylthio ethyl propionate (V) was synthesized through the sulfenylative decarbethoxylation of α methylsulfonyl diethyl malonate VIIa employing DABCO (1,4-diazabicyclo [2.2.2.]octane), in refluxing toluene, and MeSO2Sme. The compounds VIIa,b e c were obtained by the alkylation of malonates, followed by sulfenylation and oxidation to sulfones. An interesting and novel reaction, the sulfenylative desulfonylation, was observed when α-methylsulfonyl phenyldiethyl malonate (VIIb) was treated with DABCO, in refluxing benzene and MeSO2SMe, which led to the α-methylthio diethyl malonate. A mechanistic discussion about the sulfenylative decarbethoxylation and sulfenylative desulfonylation is presented. α, α-dimethylthio esters VIa-c were synthesized by sulfenylation and decarboxylation of the corresponding malonic half-esters. The sequence of the steps of this new reaction could be determined by deuteration experiments and by following the evolution of CO2. The precursors IV, IVb, IVc, V e Vib and 11 intermediates were unknown compounds. This work, besides the synthetical importance, presents some contribution to the Organosulfur Chemistry.

Este trabalho apresenta: 1) Duas revisões bibliográficas sendo uma sobre a síntese de α-ceto-tioésteres e -ésteres e a outra sobre a decomposição de sulfóxidos e sulfonas sulfeniladas; 2) Investigações prévias indicando a viabilidade da decomposição térmica e a estabilidade relativa dos derivados bissulfenilados de tioésteres de diferentes estados de oxidação Ia-e, obtidos a partir do α-ceto-tioéster; 3) O estudo de síntese de precursores de α-ceto-tioésteres II e α-ceto-ésteres III, a saber: α - metilsulfonil- α - metiltio tioésteres IVa-c, -éster V e α, α - dimetiltio - ésteres VIa-c; 4) Decomposição térmica de α-metilsulfonil-α-metiltio-tioésteres Iva, b e c e -éster V sintetizados aos α-ceto-tioésteres e ésteres correspondentes, pelo emprego do método elaborado anteriormente por Wladislaw e col. e sugestão do mecanismo da mesma. A síntese de α metilsulfonil α metiltio tiopropionato de etila (Ivb), foi efetuada a partir do ácido α-cloro propiônico através de quatro passos reacionais, a saber: sulfenilação por substituição, oxidação à sulfona , tioesterificação e sulfenilação pelo emprego de NaH/MeS02SMe em DMSO. A obtenção do α - benzil - α - metilsulfonil - α - metiltio - tioacetato de etila (Ivc) foi efetuada a partir de ácido α-cloro acético através de reações de sulfenilação por substituição oxidação à sulfona tioesterificação alquilação com brometo de benzila e NaH em DMSO e, finalmente, a sulfenilação que só foi possível com o emprego de N-metiltioftalimida. A síntese de α-metilsulfonil-α-metiltio-propionato de etila (V) foi efetuada a partir do α-metilsulfonil malonato VIIa pelo eemprego do método de descarbetoxilação sulfenilativa usando 1,4 diazabiciclo [2,2,2] octano (DABCO) em tolueno sob refluxo e MeSO2SMe. Os compostos VIIa,b e c foram preparados a partir dos malonatos de dietila alquil - substituidos, seguido de sulfenilação e oxidação à sulfona. É de interesse a inédita reação de α - metilsulfonil fenilmalonato de dietila (VIIb), com DABCO em benzeno sob refluxo e MeSO2SMe, que conduziu à dessulfonilação sulfenilativa fornecendo o α - metiltio - fenilmalonato de dietila. É apresentada uma discussão mecanística tanto sobre descarbetoxilação, como sobre dessulfonilação sulfenilativas. A síntese de α,α-dimetiltio-ésteres VIa-c foi efetuada pela reação de sulfenilação com descarboxilação dos mono-ácidos malônicos correspondentes. O acompanhamento da descarboxilação e experimentos de deuteração permitiram esclarecer a sequência dos passos reacionais nestas novas reações. Cabe ressaltar que são compostos ainda não descritos na literatura os precursores IVa, IVb, IVc, V e Vib e 11 intermediários envolvidos nas reações efetuadas. Os resultados apresentados neste trabalho, além de importância sintética, trazem uma contribuição para a Química de Compostos Orgânicos de Enxofre. / This work presents: 1) Two literature reviews, one about the synthesis of α-keto thioesters and esters and the other on the decomposition of sulfenylated sulfoxides and sulfones; 2) Previous investigations indicating the viability of thermal decomposition and the relative stability of the dithioderivatives of different oxidation states Ia-e,which were obtained from the α-keto thioester; 3) The study of synthesis of α-keto thioesters II and esters III precursors, which are the following: α-methylsulfonyl-α-methylthio-thioesters IVa-c and -ester V, and α, α - dimethylthio esters VIa-c; 4) Thermal decomposition of the synthesized α - methylsulfonyl- α -methylthio- thioesters Iva,b e c and ester V, to the corresponding α-keto thioesters and α-keto ester, through the method developed by Wladislaw et al., with the suggestion of the mechanism. α-Methylsulfonyl-α-methylthio ethyl thiopropionate (Ivb) was synthesized from α-chloro-propionic acid in four steps: sulfenylative substitution, oxidation to sulfone, thioesterification and sulfenylation using NaH/MeSO2SMe in DMSO. α-Benzyl-α-methylsulfonyl-α-methylthio ethyl thioacetate (,i>Ivc) was obtained from α-chloro acetic acid through the following steps: sulfenylative substitution, oxidation to sulfone, thioesterification, alkylation with benzylbromide and NaH in DMSO, and finally, the sulfenylation which was successful only with the use of N-methylthiophtalimide. α-Methylsulfonyl-α-methylthio ethyl propionate (V) was synthesized through the sulfenylative decarbethoxylation of α methylsulfonyl diethyl malonate VIIa employing DABCO (1,4-diazabicyclo [2.2.2.]octane), in refluxing toluene, and MeSO2Sme. The compounds VIIa,b e c were obtained by the alkylation of malonates, followed by sulfenylation and oxidation to sulfones. An interesting and novel reaction, the sulfenylative desulfonylation, was observed when α-methylsulfonyl phenyldiethyl malonate (VIIb) was treated with DABCO, in refluxing benzene and MeSO2SMe, which led to the α-methylthio diethyl malonate. A mechanistic discussion about the sulfenylative decarbethoxylation and sulfenylative desulfonylation is presented. α, α-dimethylthio esters VIa-c were synthesized by sulfenylation and decarboxylation of the corresponding malonic half-esters. The sequence of the steps of this new reaction could be determined by deuteration experiments and by following the evolution of CO2. The precursors IV, IVb, IVc, V e Vib and 11 intermediates were unknown compounds. This work, besides the synthetical importance, presents some contribution to the Organosulfur Chemistry.