Tandem construction of biological relevant aliphatic 5-membered N-heterocycles

Abstract

Nature often uses cascade reactions in a highly stereocontrolled manner for assembly structurally diverse nitrogen-containing heterocyclic scaffolds, i.e. secondary metabolites, important for medicinal chemistry and pharmacy. Five-membered nitrogen-containing heterocycles as standalone rings, as well as spiro and polycyclic systems are pharmacophores of drugs approved in various therapies, i.a. antibacterial or antiviral, antifungal, anticancer, antidiabetic, as they target many key enzymes. Furthermore, a large number of pyrrolidine derivatives are currently considered as drug candidates. Cascade transformations, also known as domino or tandem reactions, offer straightforward methods to build N-heterocyclic libraries of the great structural variety desired for drawing SAR conclusions. The tandem transformations are often atom economic and time-saving because they are performed as the one-pot, so no need for purification after each 'virtual' step and the limited necessity of protective groups are characteristic for these processes. Thus, the same results as in classical multistep synthesis can be achieved at markedly lower costs and shorter time, which is in line with modern green chemistry rules. Great advantage of cascade reactions is often reflected in their high regio- and stereoselectivities, enabling the preparing of the heterocyclic compound better fitted to the expected target in cells. This review reveals the biological relevance of N-heterocyclic scaffolds based on saturated 5-membered rings since we showed a number of examples of approved drugs together with the recent biologically attractive leading structures of drug candidates. Next, novel cascade synthetic procedures, taking into account the structure of the reactants and reaction mechanisms, enabling to obtain biological-relevant heterocyclic frameworks with good yields and relatively high stereoselectivity, were reviewed and compared. The review covers the advances of designing biological active N-heterocycles mainly from 2018 to 2021, whereas the synthetic part is focused on the last 7 years.

Keywords: Biological activity; Cascade; Domino; Drug candidates; Mechanisms; Nitrogen heterocycles; Pyrrolidines.