Revisiting Hetero‐Diels–Alder Reactions in Organic Synthesis: Insights Into the Construction of Natural Products and Bioactive Molecular Architectures

ABSTRACT The hetero‐Diels–Alder (HDA) reaction stands out as a powerful and versatile synthetic strategy, particularly in the formation of six‐membered heterocycles. This reaction, a variation of the classical Diels–Alder process, enables the efficient construction of heterocyclic structures, offering exceptional control over regio‐ and stereoselectivity. Its ability to incorporate various heteroatoms, such as sulfur, makes it invaluable in the synthesis of a broad range of natural products and pharmacologically active molecules. The review provides an in‐depth exploration of different HDA reactions, including those involving aza, oxa, and nitroso dienophiles, as well as those employing heteroatoms. It also examines the synthesis of cyclic hydrazines and the reaction's role in functionalizing diene‐containing natural products like thebaine, colchicine, and steroids. Further, the review highlights the total synthesis of bioactive compounds, such as pyrroles, spiropyrrolidone derivatives, and dihydrocoumarins, underscoring the reaction's significance in the production of complex and bioactive molecules. By exploring its applications in nature and its diverse functionalization capabilities, this reaction emerges as an indispensable tool in the design and development of complex, bioactive compounds with significant therapeutic potential.