Filippo De Simone
The increasing progress in medicinal chemistry and chemical biology requires more versatile synthetic strategies for the generation of libraries of active compounds and theirs analogues. A wide range of biologically active natural and synthetic compounds contain a complex polycyclic heterocyclic scaffold as core structure. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. The goal of my PhD thesis was the development of a new catalytic cyclization reaction – the formal homo-Nazarov reaction. Starting from cyclopropanes as the smallest carbocycles, we were able to build-up complex carbocyclic and heterocyclic molecules, including alkaloid natural products. This thesis is divided in three main chapters, introduction, formal homo-Nazarov reaction and cyclization reactions of aminocyclopropanes. In the introductory part, the electronic properties and synthetic approaches to generate cyclopropanes are first described. Next, important examples of annulation and cyclization reactions involving cyclopropanes are discussed, pointing out the importance of activating and/or polarizing substituents on the three member ring. The second chapter of this thesis is dedicated to the development of a new catalytic method for the cyclization of vinyl cyclopropyl ketones –the formal homo-Nazarov cyclization. Optimization of the catalytic conditions is described, as well as extension of the substrate scope to a wide range of heterocycles and carbocycles. The reaction mechanism is then investigated using kinetic, labeling and trapping experiments. The results of these investigations indicate a stepwise mechanism through carbocationic intermediates. Moreover, the influence of an additional polarizing ester substituent on the cyclopropane is discussed, as well as the resulting scope extension. Finally, a first example of asymmetric induction for the catalytic formal homo-Nazarov cyclization using chiral Lewis acid catalysts is presented. The third chapter reports the extension of the catalytic homo-Nazarov cyclization to aminocyclopropanes. The reaction occurs under mild conditions and highly diastereoselective cyclizations are obtained via an acyliminium intermediate generated through opening of the cyclopropane. The presented methodology allowed an excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners. The utility of the developed methodology is demonstrated by the generation of two different polycyclic scaffolds of natural products starting from a common intermediate. Based on this method, a formal total synthesis of the Aspidosperma alkaloid aspidospermidine is presented. The scope and limitations of our methodology are presented on an extended range of aryl- and vinyl- cyclopropyl ketones bearing indole, pyrrole, pyran, benzofuran or thiophene groups as electron-rich aryl or alkene substituents, and cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane. Finally, the versatility of our cyclization method is demonstrated by its successful application in the total synthesis of the natural alkaloid goniomitine, accomplished in 13 linear steps with an overall yield of 11%. The availability of goniomitine and several of its analogues in significant amount allowed the first studies of the bioactivity of this class of alkaloids, which displayed only low cytotoxicity (IC50: 15-123 µM).
EPFL2012
