Novel Approaches in the Synthesis of Natural and Synthetic Fused Aza-Polycycles Toward the Development of New Bioactive Compounds

The purpose of this chapter is to review and discuss the literature that has covered the most recent and highly impact researches related with the total synthesis of alkaloids and synthetic products classified as aza-polycycles. After a general introduction, our chapter will be devoted to the recent aspects developed for the stereoselective synthesis of three main aza-polycycles: First, we will refer to the novel synthetic strategies for the preparation of selected pyrrolo[2,1-a]isoquinoline alkaloids and their synthetic derivatives that have included the pharmacophores of known bioactive natural products (nuevamine, jantimine, crispine, and cryptaustoline). In the second place, our interest will focus on methods developed to control the stereochemistry of the C-1 center in the synthesis of 1-phenethyl-1,2,3,4-tetrahydroisoquinoline alkaloids, mainly those ones isolated from Dysoxylum lenticellare: (+)-dysoxyline, (+)-colchiethanamine, (+)-colchiethine, and (+)-homolaudanosine. Then, we will describe the current protocols for the synthesis of aporphine and homoaporphine alkaloids, highlighting and putting in perspective the role of 1-phenethyltetrahydroisoquinolines in the biosynthesis of homoaporphines and how this approach could be taken into account in the future development of strategies for the preparation of analogues to these alkaloids. In the final section, the chemistry of β-carbolines, a group of naturally occurring indole alkaloids that are prevalent in Harmala species but also exist in several marine tunicates, will be analyzed in terms of the methods developed for the total synthesis of these structures, including complete saturated and unsaturated compounds containing one or more chiral center. Additionally, challenging synthetic derivatives that have shown biomedical applications will also be incorporated. We have chosen these aza-polycycles as the main topic for this chapter due to their widely known biological activities and the pharmacological potential of the new derivatives to be discovered, which make them attractive targets for the development of novel approaches for their total synthesis that here we discuss. Besides the synthetic aspects and to increase the practical usefulness of our chapter, in each section we have also included a short, but comprehensive, summary of the diverse biological activities reported and studied for these natural structures in the 2010–2015 period.