C–H Functionalization: Towards a More Sustainable Approach Using Cobalt and Application of Palladium to Total Synthesis of Natural Compounds

C–H bonds are ubiquitous in organic molecules and the major appeal of transition-metal catalyzed C–H activation is the possibility to functionalize any bond of a given molecule using simple and readily-available starting materials. Therefore, the development of new and efficient methodologies is required. In this thesis, it is presented a complete overview on the history and the various approaches available in C–H activation, as well as an in-depth look to the mechanisms at the base of this type of chemistry. Aim of this thesis was the development of novel C–H activation methodologies with first-row transition-metal, in particular using cobalt. For this reason, a detailed analysis of the modes of activation of cobalt will be presented bringing several different examples to follow the logic discussion and to demonstrate the pivotal role that this metal has taken in the last few years. We developed a C(sp2)–H alkenylation of biphenyl amines, incorporating the challenging non-reactive unactivated olefins with exclusive allylic selectivity on the distal ring of the biphenyl system. Several different functional groups are well-tolerated on both the aromatic rings and into the coupling partner. Moreover, we shed some light on the mechanism of this reaction by performing labelling studies, kinetic experiments and isolating a catalytic-competent organometallic intermediate. Having great success with the C(sp2)–H allylation we envisioned to develop a more challenging and under-represented C(sp3)–H functionalization. In particular, we decided to focus on the synthesis of valuable indolines through the amidation of unactivated C(sp3)–H bonds. We also became attracted by the application of C–H activation methodologies to the total synthesis of natural products. In particular, the purpose of transition-metal catalyzed C–H activation is to shorten the synthetic route and to carry out unusual and non-intuitive disconnections. In particular, at the University of Basel, we applied an intramolecular C(sp3)–H Pd-catalyzed arylation for the synthesis of Glionitrins and analogues, a family of unsymmetrical 2,5-epidithiodioxopiperazines with intriguing biological activity. We sought to find a divergent retrosynthetic plan in order to access to the whole class of derivatives of this family starting from inexpensive and readily-available amino acids. To better understand the mechanisms and reactivity of palladium in C–H activation, a detailed analysis will be presented bringing several different relevant examples. Moreover, application of these methodologies to total synthesis will be discussed in order to give the reader some insights and of this promising chemistry.