New Skeletal Editing Methods Advance Drug Discovery Chemistry
Three new chemical synthesis methods enable skeletal editing of molecular structures for drug discovery, including photochemical conversion of nitroarenes to azepines, enantioselective S-alkylation of sulfenamides, and O-to-N exchange in cyclic ethers.
Researchers have reported three novel skeletal editing strategies that enable the transformation of molecular scaffolds important for drug discovery chemistry. The methods offer new routes to synthesize nitrogen-containing heterocycles and chiral sulfur architectures commonly found in biologically active molecules.
A skeletal editing strategy based on DNA-encoded nitroarenes enables the direct conversion of benzene cores into valuable 3H-azepine scaffolds. This transformation is efficiently promoted by visible light in the presence of P(Oi-Pr)3, which serves as a reductant to generate reactive nitrene intermediates from the nitro group. Demonstrating broad substrate scope with applicability to pharmaceutical molecules, this protocol offers an efficient and versatile route to DNA-encoded 3H-azepine derivatives. It thus establishes a robust platform for skeletal diversification in DNA-encoded library synthesis.
A copper-catalyzed enantioselective S-alkylation of sulfenamides enabled by an amino-radical-transfer deboronation pathway has been developed. Chiral sulfilimines are obtained in high yields (up to 95%) and enantioselectivities (up to 98% ee) under mild conditions. An isomerizable bis(oxazoline) ligand bearing a bridging CH2 unit is identified as the key factor for both reactivity and stereoselectivity in the copper-catalyzed radical-relay coupling with sulfenamides. The method offers a general platform for accessing enantioenriched S(IV) architectures with aliphatic substituents and demonstrates strong potential for applications in medicinal chemistry. Various cyclic ring systems, which are important in drug discovery chemistry, were explored, including azetidine, tetrahydrofuran.
A R3P/ICH2CH2I-promoted O-to-N exchange of cyclic ethers has been reported. This strategy enables the direct conversion of widely available cyclic ethers─such as tetrahydrofuran and 1,4-dioxane─into nitrogen-containing heterocycles, structural motifs commonly found in biologically active molecules. The method exhibits broad compatibility with secondary and tertiary amines, delivering the corresponding products in moderate to good yields.