Synthesis of Pharmaceutically Active Heterocycles and Lipid Targets: Novel Rearrangements and Methods for Carbon-Heteroatom Bond Formation

The pharmaceutical industry faces considerable challenges, not only from an R and D standpoint, but also politically and fiscally. Politically, governments around the world are trying to contain costs, and these costs are constantly the subject of intense scrutiny, with the real risk that the public health is suffering the consequences. Therefore, as scientists, we are called to innovate processes and help with witty and affordable solutions. In particular, as synthetic organic chemists, we are called to use imagination and expertise to bring new attractive organic transformations or bright improvements of existing processes, in order to maintain active and alive the real engine of innovation: research. Both from an academic and industrial point of view, new approaches for the achievement of synthetic fragments, moieties or targets are constantly required in a straightforward but brilliant fashion. For our part, we decided to investigate some of the most recurrent topics in organic chemistry and provide new synthetic ideas. This work has been divided into three main chapters, which incorporate topics such as the synthesis of biologically interesting lipid targets and pharmaceutically relevant heterocyclic structures. Therefore we put in place the search for new methods aimed at the formation of new carbon-carbon and carbon-heteroatom bonds. We addressed concerns about the quest for selectivity in the formation of these bonds, providing stereo-, chemo- and regioselective synthetic solutions. Specifically, the work described in Chapters 1 and 2 was carried out from January 2011 to January 2013 in the laboratories of Prof. Marcantoni at the University of Camerino, and focuses on the formation of new C-C and C-heteroatom bonds for the construction of more complex heterocyclic and lipid structures, mainly involving cerium (III) salts as Lewis acids and organometallic compounds. The results presented in the third chapter were achieved from February 2013 to December 2013 under the guidance of Dr. Jeremy T. Starr at Pfizer's Worldwide Research and Development Center in Groton, Connecticut, USA. Chapter 3 was dedicated to the study and the development of new applications of a novel thermal rearrangement of propargyl amine N-oxides, powerful acyclic precursors for the achievement of more interesting heterocyclic structure. As a proof of the validity of the method, and given the particular interest of heterocycles in medicinal chemistry, synthesis of Celebrex®, a drug commercialized by Pfizer, was carried out. The author wishes to thank Prof. Enrico Marcantoni, for his guidance and for the valuable expertise continuously provided. All the people who have been part of the group over the years, for friendship and helpful discussions. Dr. Jeremy T. Starr for extraordinarily mentoring the author and for the warm welcome in his great and highly qualified group. My family and my dad for making me the person I am.