New oxidative processes in organic chemistry and their synthetic applications
Creators: name: Zaccaria, Sabrina
Publisher: name: Università degli Studi di Napoli Federico II
Year: 2012

description: This PhD thesis focuses on the development of new oxidative processes mediated by transition metal oxo-species. In particular, new types of useful oxidative transformations involving the THF ring have been disclosed. In the first year of my PhD programme four novel C30 polyether bis-spiroketals, displaying selective cell killing effect on BT474 breast-derived cancer cell line, have been obtained from squalene through an unprecedented one-step, RuO4-catalysed, cascade process characterised by a tandem oxidative pentacyclization/double oxidative spiroketalization sequence. Preliminary studies indicate that the Ru-mediated spiroketalization steps proceed with retention of configuration at the forming spirocentres. A similarity with the oxidative behaviour of PCC has also been disclosed. Moreover a novel bis-iodurated polyether compound, based on an unprecedented tetra-THF backbone, has been isolated as a trace by-product of the oxidation of squalene. A bidirectional double oxidative bis-cyclization is invoked to explain the formation of this compound. The isolated substance was also successfully subjected to a double rearrangement-ring expansion to give a novel bis-THF-bis-THP compound. As part of our efforts toward the understanding of the oxidizing behavior of transition metal oxo-species, in the second year of my PhD programme PCC and the catalytic system PCC(cat.)/H5IO6 have been employed to oxidize mono- and poly-tetrahydrofuran compounds. Novel oxidative pathways have been disclosed. 2,2,5-trisubstituted THF rings lead to dicarbonyl compounds via oxidative cleavage of the C2-C3 bond. Cyclic enolethers appear to be intermediate species in this process. Oxidation of 2,2,5-trisubstituted alpha-keto-THF compounds proceeds with the oxidative cleavage of the C2(THF)-C=O bond to give 1,4-diketones possessing a degraded carbon backbone. Attack of the oxidant to 2,5-disubstituted THF rings leads to 1,4-diketones possessing the intact THF carbon framework. Oxidation of complex poly-THF substrates, embodying up to five THF rings, allows the access to novel poly-THF compounds via diastereoselective THF oxidation along the poly-THF backbone. The collected results provide a deeper comprehension of the reactivity of the PCC and also suggest a new mechanistic hypothesis of the PCC-mediated oxidative cleavage of alpha-hydroxy-THF compounds to g-lactones. The proposed mechanism well agrees with that reported for the oxidative cleavage of 8-hydroxy-neoisocedranol oxide by RuO4 and is in line with the similar oxidizing behaviour shown by these two oxo-species. The synthesis of racemic umbelactone, an antiviral natural butenolide metabolite, has also been carried out by using the developed chemistry. On the basis of this results, in the third year of my PhD programme, the first general synthesis of bis-alpha-acyloxy 1,4- and 1,5-diketones has been accomplished by CCP catalytic oxidative opening of bis acylated THF and THP diols, in turn synthesized by osmium- or ruthenium-catalyzed oxidative cyclization of 1,5- and 1,6-dienes. The overall sequence corresponds to the regioselective double ketoacyloxylation of the starting diene. To test the breadth of our methodology acylated cis-reticulatacin, a representative mono-THF Annonaceous acetogenin, has also been successfully oxidized with our procedure, thus opening the way to the preparation of new non-THF analogues of these active substances, to be used in biological assays. Moreover, among the conceivable synthetic uses the bis-alpha-acyloxy-1,5-dicarbonyl compounds obtained have been transformed into pyridine-based oxido pincer ligands or pyrazine dimethanol substances, leading to the discovery of unprecedented aromatization routes.
In addition the synthesis of nucleoside analogues possessing different base modifications has been carried out. The first general approach that allows either the synthesis of ring-expanded nucleosides (RENs), containing the unprecedented bis-alkylated imidazo[4,5-d][1,2, 6]oxadiazepine heterocyclic ring system, or the 2,6-dialkyl(aril)purine moiety has been developed. This method entails first of all the formation of a purine N1-oxide by treatment of the purine nucleoside with MeReO3 followed by addition of a Grignard reagent to the electrophilic C-6 carbon of the substrate. The reactivity of the C-6-substituted purine nucleosides towards a second Grignard reagent afforded new 4,5-disubstituted imidazo-nucleosides from which we obtained imidazo[4,5-d][1,2,6]oxadiazepine nucleosides, if treated with t-BuOOH, or 2,6-disubstituted purine nucleosides by treatment with Ac2O in pyridine. Using this procedure a small collection of ring-expanded nucleosides (RENs) has been synthesized and subjected to preliminary cytotoxicity tests on breast (MCF-7) and lung (A549) cancer cell lines. We are also synthesizing a collection of 2,6-disubstituted purine nucleosides to be subjected to biological assay.