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.