ACCESSING CHIRAL DIHYDRO- AND TETRAHYDROQUINAZOLINE-2,4-DIONES VIA [4+2]-CYCLOADDITIONS: FROM PIONEERING STUDIES TO ASYMMETRIC ORGANOCATALYZED SYNTHESES

Quinazoline-2,4-diones represent a prominent class of 5,6-fused-uracil derivatives which have attracted appreciable attention in the field of medicinal chemistry owing to their peculiar structure and multifaceted pharmacological profile. Within this heterocyclic class, the subdomain of chiral functionalized dihydro- and tetrahydroquinazoline derivatives, embedding in-cycle stereogenic elements, has emerged as an intriguing, yet underestimated, class of compounds, whose challenging structure and potential usefulness as drug-like pharmacophores has stimulated the development of versatile and efficient strategies toward their synthesis. After notable pioneering studies dating back to early 1980s, accessing these compounds in racemic format, substantial stagnation of innovative enantioselective synthesis procedures to access these ring systems occurred, thus precluding their exploitation in medicinal chemistry programmes. Quite recently, the implementation of asymmetric, organocatalytic strategies towards these products, and based on stepwise [4+2]-cycloadditions has renewed the interest toward this fascinating class of chiral compounds, possibly paving the way to the study of their biological activities in the years to come. This account highlights strategies to the chemical synthesis of chiral dihydro- and tetrahydroquinazoline-2,4-dione ring systems in both racemic and enantioenriched formats via [4+2]-cyclization between elusive uracil-based ortho-quinodimethane dienes and suitable dienophile components.