Diastereodivergent Asymmetric [3+2] Cyclization of Chromone Derivatives with γ-Hydroxyenones

Abstract

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.

Keywords

Diastereodivergent synthesis / Organocatalysis / Asymmetric catalysis / Diastereoselectivity / 3-Tetrahydrofuran-chromone / Chromone derivatives / γ-Hydroxyenones / DFT calculation

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2026 SIOC, CAS, Shanghai, & WILEY-VCH GmbH