Reações de carbociclização radicalar de orto e meta-iodobenzamidas derivadas de D-glicose visando à obtenção de macrolactamas, potenciais agentes bioativos

• Ano de defesa: 2008
• Autor(a) principal: Gleydson Daniel Pinto
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Ciclização radicalar; Produto bifenílico; Orto-e meta-iodoenzamidas; Reações químicas; Química farmacêutica; Processos quimicos; Farmácia
• Link de acesso: http://hdl.handle.net/1843/LFSA-7TBJES

Macrocyclic products often display remarkable biological activities. Among macrocycles with biological activities, there are macrolactams, as vicenistatin, pimecrolimus, rifampicin and others. In view of the potential applications of macrolactams and the synthetic challenge they present, the research group of Laboratório de Química Farmacêutica/Faculdade de Farmácia/UFMG in partnership with Departamento de Química/ICEx/UFMG (QF/DQ/UFMG) has been studied the Bu3SnH-mediated radical cyclization reactions to synthesize macrocycles, especially benzomacrolactams derived from carbohydrate. Carrying on this research program, it was planed the synthesis of four iodobenzamides derived from D-glucose: methyl 2,3-di-O-benzyl-4-O-(1-butenyl and 1-pentenyl)-6-deoxy-6-(2- and 3-iodobenzoylamino)-a-D-glucopyranosides. The reaction of the benzamides with Bu3SnH could to furnish 12-, 13- and 14-membered macrolactams by endo cyclization mode, that is the preferential mode in macrocyclizations. It was not possible to obtain the benzamides with 4-O-butenyl group because the sixth step was failure. The iodobenzamides methyl 2,3-di-O-benzyl-6-deoxy-6-(2- and 3-iodobenzoylamino)-4-O-(1-pentenyl)- a-D-glucopyranoside were obtained and submitted to Bu3SnH-mediated reactions in different conditions with variable concentration, addition time of the Bu3SnH/AIBN solution and solvent. Macrolactams were not isolated from any reaction. The ortho-benzamide led only to the hydrogenolysis product. A surprising amount of biphenyl compound, methyl 4-O-allyl-2,3-di-Obenzyl- 6-deoxy-6-(3-phenylbenzoylamino)-a-D-glucopyranoside, formed by addition of aryl radical to benzene, was isolated from the reaction carried out with benzene as solvent, very lowconcentration of the reagents and slow addition of the Bu3SnH/AIBN solution. The hydrogenolysis product, methyl 4-O-allyl-6-benzoylamino- 2,3-di-O-benzyl-6-deoxy-a-D-glucopyranoside, was isolated when benzene was the solvent, Bu3SnH/AIBN solution was added more rapidly and the dilution was lower. The hydrogenolysis product was also obtained from the reactions developed in cyclohexane and acetonitrile. The structures of the new compounds were elucidated by 1H and 13CNMR spectroscopy, DEPT, COSY, HMQC experiments and, in some cases, it was used HMBC and ESI-MS/MS. A radical addition-elimination process for the formation of the biphenyl compound and an explanation for the different outcomes for radical reactions of ortho- and metaiodobenzamides are presented. The ortho and meta-iodobenzamides, the products isolated from radical reactions and three intermediates were undergone to antibacterial and antifungal tests. The hydrogenolysis compound showed activity. The meta-iodobenzamide, the hydrogenolysis product and the biphenyl compound were submitted to anticancer test in National Cancer Institute, USA. The benzamide showed significant growth inhibition and was selected for five dose testing. The same three compounds were sent to tests of toxicity in mammalian cells and all were cytotoxic to at least one of the concentrations evaluated.