Cascade synthetic strategies opening access to medicinal-relevant aliphatic 3- and 4-membered N-heterocyclic scaffolds

Abstract

Cascade reactions are often ‘employed’ by nature to construct structurally diverse nitrogen-containing heterocycles in a highly stereoselective fashion, i.e., secondary metabolites important for pharmacy. Nitrogen-containing heterocycles of three- and four-membered rings, as standalone and bicyclic compounds, inhibit different enzymes and are pharmacophores of approved drugs or drug candidates considered in many therapies, e.g. anticancer, antibacterial or antiviral. Domino transformations are in most cases in line with modern green chemistry concepts due to atom economy, one-pot procedures often without use the protective groups, time-saving and at markedly lower costs than multistep transformations. The tandem approaches can help to obtain novel N-heterocyclic scaffolds, functionalized according to structural requirements of the target in cells, taking into account the nature of functional group and stereochemistry. On the other hand cascade strategies allow to modify small N-heterocyclic rings in a systematic way, which is beneficial for structure-activity relationship (SAR) analyses. This review is focused on the biological relevance of the N-heterocyclic scaffolds with smaller 3- and 4-membered rings among approved drugs and leading structures of drug candidates. The cascade synthetic strategies offering N-heterocyclic scaffolds, at relatively good yields and high stereoselectivity, are discussed here. The review covers mainly years from 2015 to 2021.