Multicomponent reactions for DNA ‐encoded library construction: Scaffold diversity and reaction engineering strategies

Abstract DNA‐encoded libraries (DELs) enable large‐scale screening for hit identification, but accessing sp 3 ‐rich, three‐dimensional chemotypes beyond flat, aromatic scaffolds remains challenging. Multicomponent reactions (MCRs) assemble such complexity from simple building blocks in a single step, and reaction‐engineering strategies have extended on‐DNA MCR scope to previously incompatible transformations without compromising DNA integrity. This review summarizes these advances and highlights stereoselectivity and biological validation as key directions for future development of acyclic and on‐DNA MCR methodologies.