Synthetic and Heterocyclic Chemistry Synthetic chemistry is the science of constructing complex molecules from simples ones. It is possible to divide it into two great landscapes: the total synthesis, where the synthetic chemists study how step by step it is possible to build a structure usually with biologically importance, and the methodologies which introduce new reactions. One might think that the synthetic chemistry is focused on C-H bond making therefore a huge mistake because synthetic chemistry doesn't look only to molecules built by carbon and hydrogen but also to heterocyclic compounds. Heterocyclic structures are organic compounds containing over carbon and hydrogen, heteroatoms too such as oxygen, sulfur or nitrogen in the framework of the ring structure that can show both aromatic and aliphatic properties. Heterocyclic chemistry is an inexhaustible resource of novel compounds and almost unlimited combinations of carbon, hydrogen and heteroatoms can be designed. These make compounds with the most diverse physical, chemical and biological properties available, so is very easy to guess the huge diffusion and importance of heterocyclic compounds. The examination of nature's favorite molecules reveals a striking preference for making carbon_heteroatom bonds rather than carbon_carbon bonds, surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon_heteroatom bonds. By the end of the second millennium, about approximately 20 millions of chemical compounds are been identified and to a large extend are heterocyclic. It is very easy to imagine the attention of the scientific community for this class of molecules and the efforts by the synthetic chemists to develop new procedures for their synthesis. The efforts by the synthetic chemist to synthesize new heterocycles structures, can be divided into two different strategies: the functionalization of heterocyclic frameworks and the synthesis of the functionalized ring starting from acyclic substrates. A fundamental aspect of heterocyclic chemistry is their reactivity, since the reactivity of the heteroatom influences the rest of the molecule, giving features completely different from the analogous carbon-hydrogen derivates. These features can be an advantage or a disadvantage at the same time, so the presence of the heteroatom in the ring framework is the heterocyclic chemistry's cornerstone, and these aspects will be explained during the thesis. As Corey said: ''Part of the charm of synthetic organic chemistry derives from the vastness of the intellectual landscape along several dimension. There is the almost infinite variety and number of possible target structures that lurk in the darkness, waiting to be made. The chemistry of heterocyclic compounds and methods for their synthesis form the bedrock of modern medicinal chemical and pharmaceutical research.'' The Marcantoni research group has been interested in both fields of the heterocycles synthesis: the functionalization of ring structures and the synthesis of heterocyclic rings staring from acyclic substrates. Regard to this, the research group has focused on the synthesis of biologically active heterocyclic scaffolds too. The study of the CeCl3.7H2O Lewis acid abilities in combination with Lewis acid activators such as NaI or CuI, as a promoter system in carbon-heteroatom bond forming reactions plays a key role as well. This thesis work is facing different aspects, as illustrated by the nature of the projects: the study of new approach to the synthesis of heterocycles from both the point of view; the functionalization of rings and the assembling starting from acyclic molecules promoted by CeCl3.7H2O Lewis acid; the synthesis of biologically active scaffolds. The first chapter is focused on the functionalization of heterocyclic structures with significant biological activity. In it, two projects are reported, the first describes the total synthesis of functionalized modified nucleoside LNA (Locked Nucleic Acid); in the second we have developed a new method for the sulfenylation of electron-rich aza-aromatics heterocycles promoted by CeCl3.7H2O Lewis acid in combination with NaI. The second chapter is concerns about the synthesis of heterocyclic structures starting from acyclic substrates. Herein three different projects are reported, each on with a new methodology promoted by CeCl3.7H2O Lewis acid system in combination with NaI or CuI. The third chapter was carried out in the the prof. T. J. Donohoe research group at the department of chemistry of the University of Oxford. Among the many research pursued by the Donohoe group, the work here described was a part of their project on the total synthesis of Microsclerodermins E. The Microsclerodermins are hexapeptide macrocyclic mulecules cointaining unusual aminoacid with significant biological activities. Microsclerodermins were isolated from natural sponges of waters of new Caledonia and Philippine by Bewley and Faulkner for the first time in 1994. Only one protocol of their total synthesis has been reported by Ma in 2003 and as shown by Ma work, one of the crucial steps of the synthesis is in the cyclization of the macrocyclic core, here is reported the total synthesis of a molecular model which mimics the cyclization of the unusual aminoacid residues to obtain the macrocyclic core. In every chapter will be presented an exhaustive explanation for each project, its synthetic importance and biological impact.
|Titolo:||Development of new Synthetic Methodologies aimed to poly-functionalize Heterocyclic Compounds having Biological Activity|
|Data di pubblicazione:||19-mar-2013|
|Appare nelle tipologie:||Tesi di dottorato (Pregresso)|