Diastereodivergent Asymmetric [3+2] Cyclization of Chromone Derivatives with <i>γ</i> ‐Hydroxyenones ^†

Comprehensive Summary The successful development of the organocatalyzed asymmetric [3+2] cyclization of chromone derivatives with γ‐hydroxyenones has enabled the efficient synthesis of 3‐tetrahydrofuran‐chromones featuring three contiguous stereogenic centers. This reaction proceeds with excellent efficiency, delivering high yields (up to 98%), diastereoselectivities (up to 95 : 5 dr), and enantioselectivities (up to 99% ee). Notably, a diastereodivergent transformation is achieved by treating the initial cycloadduct with DBU, which triggers a sequence of retro‐Michael reaction, C–C bond rotation, and intramolecular cyclization to afford the thermodynamically more stable diastereomer. DFT calculations support this mechanistic pathway, identifying the ring‐closing step as the rate‐determining transition state and confirming the overall exothermic nature of the transformation. The protocol enables access to four stereoisomers and represents the diastereodivergent synthesis of 3‐tetrahydrofuran‐chromones, providing a library of compounds for biological activity screening. Furthermore, synthetic transformations of the products were performed to enhance the synthetic effectiveness of the protocol. This work advances asymmetric catalysis by offering a versatile approach to complex chiral heterocycles with tunable stereochemistry.