Rapid sp³-Enriched Scaffold Generation via a Selective Aziridine Amide Ring-Opening Reaction

Sp(3)-enriched small molecules play a critical role in developing drug candidates. While designing analogues with greater sp(3) character, a methodology utilizing a less explored cyclic-aziridine amide ring-opening reaction to generate sp(3)-enriched scaffolds has been developed and reported. This methodology enables rapid access to substructures with higher fsp(3) values, attracting greater attention within the past few decades. The reaction exhibits a wide reaction scope, featuring a highly sterically hindered phenolic ether, thiophenolic ethers, protected aniline formations, and aliphatic/heteroaromatic ring-containing aziridine amides as substrates. Additionally, this reaction provides access to congested tertiary ether formations through regioselective transformation, applicable to an extensive range of drug discovery targets, construction of complex small molecules, and natural product syntheses. The scaffolds developed show improved physicochemical properties.