Synthetic studies towards biologically active heterocyclic alkaloids and their analogues

Nature is a rich source of biologically active secondary metabolites which are called Natural Products (NPs) that served as valuable pharmacophoric scaffolds for drug discovery as evidenced by the number of marketed drugs either derived or inspired from natural products NPs. Alkaloids are a major class of natural products containing at least one nitrogen atom and are secondary metabolites of organisms including plants, animals, bacteria, and fungi. However, the natural sources of these alkaloids are usually scarce and the isolation in copious quantities is difficult, limiting the further research of their bioactivities. Thus, it is particularly important to develop efficient and economical synthetic routes for their synthesis and derivatization to tap their medicinal potential fully. Among the natural alkaloids, pyrrole-imidazole alkaloids (PIA) and quinazolinone alkaloids attracted the utmost attention of synthetic chemists with their impressive broader biological activities for medicinal chemistry applications coupled with their paradoxically simplest structural cores that make up some of the most known complex NPs. Synthesis of PIAs, and quinazolinone alkaloids is a striking research area. In this thesis, we describe our own efforts towards the development of novel methodologies for the green synthesis of intermediates useful to access oroidin alkaloids and quinazolinone alkaloids along with their structural analogues. Chapter 1: Synthesis of 2-Substituted and 2,3-Disubstitutted imidazo[1,2-a]pyrimidines Towards the Synthesis of Oroidin and Its Analogues. Oroidin is a marine sponge-derived secondary metabolite and a parent alkaloid of a family of more than 200 of diverse pyrrole-imidazole alkaloids (PIAs) with broader biological activities including anticancer, antimalarial, antibacterial, channel blockers, antimuscarinic, antiserotogenic and antibiofouling activities. Structurally diverse oroidin and its analogues commonly have three parts: head, tail, and linker. In this study, we designed the synthesis of different oroidin analogues preserving the 2-aminoimidazole part of the head with diversified linkers and with substitutions on the imidazole head with an underlying aim to minimize the skeletal requirements by such as removing the tail or the linker to gain the same or enhanced activity of oroidin for medicinal chemistry applications. Chapter 2: Synthetic Studies Towards Vasicinone- A Pyrroloquinazolinone Alkaloid. Chapter 2 represents our modified synthetic approach of synthesizing chirally pure vasicinone by overcoming the drawbacks of our group’s previous approach by substituting the methyl or ethyl ester of the starting material to benzyl ester. This approach not only facilitates the one-pot synthesis of vasicinone with new end game in conjunction with the Dieckmann condensation of quinazolinone diester, but also reduces the step count of forming tricyclic diketone intermediate and reduces the need for using highly corrosive SOCl₂ to make the reaction greener and environmentally friendly. Chapter 3: Synthesizing Complex Quinazolinones by Utilizing Deoxyvasicinones. Chapter 3 describes the greener way of preparing the key synthetic intermediate of deoxyvasicinone with a future aim to elaborating it into complex quinazolinone alkaloids and analogues. For example, it can be converted into complex Peharmaline via acylation and Pictet-Spengler chemistry. The efforts towards this direction are described via C3 acylation of deoxyvasicinone with ethyl oxaloyl chloride and subsequent acid catalyzed annulation of the β-carboline core.