C-H functionalisation reactions aim for the selective cleavage of C-H bonds, and formation of a new carbon or heteroatom bond, often with the use of a transition metal catalyst. These reactions offer potential for functionalisation of hydrocarbons in fewer steps than conventional methods, and with high atom efficiency. They are therefore a subject of intense research in organic synthesis. Carbon-heteroatom bond forming reactions are particularly sought after, and useful in the efficient synthesis of many biologically significant groups such as oxazolidinone rings, 1,2 or 1,3 amino alcohols and amino acid analogues. An efficient, cheap and robust method for C-H amination would also be adaptable to varied syntheses of important large molecules. The necessity for complex and efficient transformations with a minimal number of steps means that heteroatom ring closures are also attractive and widely used reactions in such large molecule syntheses. The nitroso group is a highly reactive species which is normally generated in situ by oxidation of a hydroxylamine, for carbon-nitrogen bond forming reactions including the nitroso Heteroatomic Diels Alder reaction, nitroso ene reaction, and nitroso aldol reaction. Nitroso group reactions often show high stereo- and regioselectivity, and have formed key components of the syntheses of important biological molecules. Enantioselectivive protocols for the nitroso-ene reaction and, to a lesser extent, the nitroso HDA reaction, are poorly developed, however, and the range of available intramolecular nitroso reactions is limited. We aimed to establish efficient single-step intermolecular C-H amination reactions, to give 1,2 and 1,3 heteroatom functionalised molecules, and to develop the capacity for enantioselective induction in this reaction, if possible. Having synthesised a model set of unsaturated hydroxycarbamates, we identified a suitable system for nitroso generation, using a catalytic metal and stoichiometric oxidant. This resulted in in situ generation of cyclised product, with the olefin functionality intact. This cyclisation was then optimised and used to obtain a range of new heterocycles. The possibility of enantioselective induction via chiral catalysts was explored, as well as catalytic systems to increase the stereoselectivity of the reaction. In summary, a cheap, novel and reliable method was developed for formation of oxazolidinone rings from unsaturated hydroxycarbamates using an original intramolecular nitroso ene reaction, and a range of unsaturated heterocycles were synthesised in fairly good yields. Distereoselectivity of the nitroso ene cyclisations was optimised. However, to-date, we were unable to develop an enantioselective varient of the reaction. Several related aminations, as well as transformations of N-hydroxyoxazolidinone products, were also attempted during the project.

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T11:13:03Z (GMT). No. of bitstreams: 1 Melgar_GliseidaZelayaran_D.pdf: 8992583 bytes, checksum: 4cacbcdc703a19bccdf5bea13368488a (MD5) Previous issue date: 2008 / Resumo: Em 1995 Miao e colaboradores relataram o isolamento da estavamicina (1), um novo produto natural, membro da família dos pirrolocetoindanos, a partir de uma cultura líquida de Streptomyses sp., isolada de uma amostra de terra coletada na Índia. A estavamicina contém uma interessante subestrutura hexahidroindeno de fusão de anel trans com 5 centros estereogênicos, uma cadeia lateral que contém outros 2 centros estereogênicos, um álcool dialílico, três duplas ligações e um resíduo de carboxilato de sódio. Apresenta atividade inibidora moderada contra a ligação do fator de transcrição EBV BZLF1 com o DNA com um valor de IC50 = 50 mM.O fragmento C11-C26 (206), contendo o grupo pirrol e 5 centros estereogênicos da estavamicina, foi preparado a partir do (R)-3-hidroxi-2-metilpropionato de metila, após uma sequência de reações, que envolveu 14 etapas (rota linear mais longa) e um rendimento global de 7%. As principais características incluem a preparação de uma imida a,b-insaturada utilizando a reação de Horner-Wadsworth-Emmons, a reação de olefinação de Takai, o acoplamento cruzado de Stille, seguido da cicloadição intramolecular de Diels-Alder que fornece dois adutos bicíclicos, sendo o majoritário correspondente ao produto desejado (para os casos de R = (R)-Bn e R = H). A última etapa foi a preparação da lactona tricíclica seguida da abertura utilizando o 2-lítio-N-MEM-pirrol.O fragmento C1-C6 (235) foi preparado a partir do 3-hidroxi-pentanodioato de dietila, após uma seqüência de reações, que envolveu 7 etapas e um rendimento global de 11,5%. As principais características incluem a elegante reação de transesterificação por quebra de simetria, redução do ácido com borana seguida por oxidação de swern e olefinação utilizando o procedimento modificado de Stork-Wittig.Em conseqüência, a rota de obtenção dos fragmentos C1-C6 e C11-C26 aqui descrita é, em princípio, prontamente aplicável para a preparação da estavamicina e análogos que eventualmente pudessem apresentar atividade farmacológica destacada. / Abstract: Epstein-Barr virus (EBV) is a human herpes virus that infects lymphocytes and epithelial cells. Is has been estimated that this virus infects a large part of the world¿s population. In 1995, stawamycin (1), a new natural product from the pyrroloketoindane family was isolated by Miao et. al from a liquid culture of Streptomyces sp, and displayed moderate inhibitory activity against the binding of the EBV BZLF1 transcription factor to DNA with IC50 = 50 mM in a DNA binding assay. Stawamycin has a trisubstituted trans-fused bicyclo[4.3.0]nonane substructure containing five stereogenic centres and a side chain that contains two stereogenic centres at C3 and C9 (absolute configuration not determined), a doubly allylic alcohol and a sodium carboxylate residue. To determine the relative configurations between C3 and C9, to establish the absolute configuration of stawamycin, and to provide material for further biological studies as well as access to novel analogues, we initiated a study towards the synthesis of this very interesting compound. We wish to describe here our successful efforts towards the preparation of the C1¿C6 as well as the C11¿C26 carbocyclic fragment of stawamycin. The bicyclo[4.3.0]nonane (C11¿C26) fragment of stawamycin has been prepared by a sequence involving 14 steps (7% overall yield) from methyl (R)-(-)-3-hydroxy-2- methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction between a vinyl iodide and a vinyl stannane followed by an intramolecular Diels¿Alder cycloaddition reaction to give the desired adduct as the major isomer. The best result was obtained with the use of a triene bearing an achiral oxazolidinone in the presence of Et2AlCl to promote the IMDA cycloaddition reaction. The last step was an preparation of the tricyclic lactone followed by the opening by means of the 2-lítio-N-MEM-pirrol.The (C1¿C6) fragment of stawamycin has been prepared from diethyl-3- hydroxypentanedioate by a sequence which involved a symmetry breaking reaction of a cyclic anhydride, followed by the formation of a Z-vinyliodide employing a Stork-Wittig procedure. / Doutorado / Quimica Organica / Doutor em Ciências