Unlocking Diverse Asymmetric Three‐Component Reactions via Crowding Effects Within DNA Scaffolds

Asymmetric three-component reactions provide powerful access to chiral molecules bearing vicinal stereogenic centers, yet biocatalytic approaches remain underdeveloped. Here, we report a DNA-based catalytic platform that enables diverse asymmetric three-component reactions through substrate-binding-induced local steric crowding within a chiral DNA scaffold. Cooperative noncovalent interactions (NCIs) between DNA and multiple substrates spatially organize nucleophiles and electrophiles around activated enones, generating a crowded and confined catalytic environment that enhances stereocontrol. Using this strategy, six classes of nucleophiles and three electrophiles were employed to access a broad range of 1,2-difunctionalized products with high diastereo- and enantioselectivities. Notably, the approach enables previously unrealized asymmetric three-component aminohydration, fluorohydration, and carbohydration reactions using water as the nucleophile, as well as asymmetric three-component fluoroamination and carbofluorination reactions. In contrast, the corresponding two-component reactions examined in this study exhibit substantially lower enantioselectivities. Mechanistic experiments, spectroscopic studies, Hammett analysis, and computational investigations reveal that cooperative π-interactions, hydrogen bonding, and electrostatic interactions collectively preorganize all reactants within the DNA scaffold, thereby creating a more crowded and enzyme-like chiral environment for asymmetric induction. These findings establish DNA-based catalysis as a versatile platform for asymmetric multicomponent synthesis and introduce local steric crowding within programmable nucleic acid scaffolds as a general strategy for stereocontrol.