Synthesis of heterocyclic scaffolds using reagentless techniques

This thesis focuses on the utilization of reagentless techniques, especially flow chemistry, for the synthesis of useful quantities of carbazole scaffolds and some of its derivatives. It also explores the potential biological activity of the scaffolds synthesised, as well as the scope of this type of new techniques in the synthesis of carbazole containing natural products, and the adaptation of this methodology to the synthesis of carbolines. Chapter 2 describes the development of a novel synthetic pathway for the synthesis of N-ethylated carbazoles using reagentless scaffolds, starting with readily commercially available haloanilines and boronic acids. Although each step of the synthesis is investigated, optimized and discussed separately, alhough the integrated methodology is all described together as a linear synthesis and total isolated yields are reported, as well as the possibility of scaling up the whole process for the continous production of carbazoles in gram scale. The data for the compound characterization is discussed and rationalized. Chapter 3 investigates the reactivation of the p53 gene when it suffers the Y220C mutation. Synthetic alternatives to PK083 analogues are explored, and 5 new candidates are sent to be tested in biological assays. The biological results of these new candidates are reported and the data is discussed. Also, computational docking is carried out using the Schrödinger interface Maestro to predict the acitivty of some of the scaffolds. Chapter 4 explores the adaptation of the methodology developed in Chapter 2 to synthesise a series of carbazole-based natural products, comparing the data to the previously published in the literature. Moreover, the adaptation of the method to the synthesis of carbolines is evaluated. Chapter 5 concludes the thesis and proposes possible future directions.