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New synthetic methodologies for the construction of pyrrolidine, piperidine and indolizidine systems


Part of this project makes use of a,b-unsaturated diazoketones as potential bifunctional intermediates to be applied in the quick and efficient synthesis of various alkaloids. Among these we can mention piperidine, indolizidine and pyrrolidine alkaloids. Specifically, this project aims the use of these intermediates in the divergent synthesis of several polyhydroxilated alkaloids and the total synthesis of preussine and barmumicine. The successful preparation of the polyhydroxilated alkaloids will allow us to evaluate them as inhibitors of glycosidases. The second part involves the synthesis of pumiliotoxine 209F using the chemistry of samarium diiodide. Pumiliotoxins (indolizidine alkaloids), homopumiliotoxins (quinolizidine alkaloids) and their congeners are a class of compounds isolated from the skin of some frogs from the Dendrobatidae, Mantellidae, Bufonidae, e Myobatrachidae families, possessing interesting pharmacologic activities (cardiotonic activity in low concentrations). Because of the big number of compounds among these toxins (about 100), synthetic methodologies that provide the preparation of these compounds (as well as analogues) in great amounts and in a fast and efficient way using common intermediates, are very important for application in chemical-biology. Since its introduction in organic chemistry the scope of transformations induced by SmI2 quickly grew up due its versatility and its application in numerous total syntheses of complex molecules have been described. Among the transformations mediated by SmI2, the formation of carbon-carbon bonds (C-C) are specially interesting given its ability to aggregate high molecular complexity in a single step due to the capacity SmI2 has to promote cascade reactions. This project proposes the preparation of the indolizidine alkaloid pumiliotoxina 209 F using SmI2 reagent in a concise approach that will also easily obtainable analogues in a few steps. (AU)

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Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ROSSET, ISAC G.; DIAS, RAFAEL M. P.; PINHO, VAGNER D.; BURTOLOSO, ANTONIO C. B. Three-Step Synthesis of (+)-Preussin from Decanal. Journal of Organic Chemistry, v. 79, n. 14, p. 6748-6753, JUL 18 2014. Web of Science Citations: 15.
BERNARDIM, BARBARA; BURTOLOSO, ANTONIO C. B. A two-step synthesis of the bioprotective agent JP4-039 from N-Boc-L-leucinal. Tetrahedron, v. 70, n. 20, p. 3291-3296, MAY 20 2014. Web of Science Citations: 6.
BURTOLOSO, ANTONIO C. B.; BERTONHA, ARIANE F.; ROSSET, ISAC G. Synthesis of Alkaloids: Recent Advances in the Synthesis of Phenanthroindolizidine Alkaloids. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 14, n. 2, p. 191-199, JAN 2014. Web of Science Citations: 16.
ROSSET, ISAC G.; BURTOLOSO, ANTONIO C. B. Preparation of Z-alpha,beta-Unsaturated Diazoketones from Aldehydes. Application in the Construction of Substituted Dihydropyridin-3-ones. Journal of Organic Chemistry, v. 78, n. 18, p. 9464-9470, SEP 20 2013. Web of Science Citations: 11.
BERNARDIM, BARBARA; LORDELLO, LEONARDO D.; BURTOLOSO, ANTONIO C. B. alpha,beta-Unsaturated Diazoketones as Versatile Building Blocks for the Synthesis of Hydroxylated Piperidines, Indolizidines and Quinolizidines. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 13, n. 17, p. 2099-2103, SEP 2013. Web of Science Citations: 8.
BURTOLOSO, ANTONIO C. B.; DIAS, RAFAEL M. P.; LEONARCZYK, IVES A. Sulfoxonium and Sulfonium Ylides as Diazocarbonyl Equivalents in Metal-Catalyzed Insertion Reactions. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, v. 2013, n. 23, p. 5005-5016, AUG 2013. Web of Science Citations: 44.
PINHO, VAGNER D.; PROCTER, DAVID J.; BURTOLOSO, ANTONIO C. B. SmI2-Mediated Couplings of a-Amino Acid Derivatives. Formal Synthesis of (-)-Pumiliotoxin 251D and (+/-)-Epiquinamide. ORGANIC LETTERS, v. 15, n. 10, p. 2434-2437, MAY 17 2013. Web of Science Citations: 21.
BERNARDIM, BARBARA; PINHO, VAGNER D.; BURTOLOSO, ANTONIO C. B. alpha,beta-Unsaturated Diazoketones as Platforms in the Asymmetric Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and Formal Synthesis of Pumiliotoxin 251D. Journal of Organic Chemistry, v. 77, n. 21, p. 9926-9931, NOV 2 2012. Web of Science Citations: 25.

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