Yttrium( <scp>III</scp> )‐Catalyzed Desymmetrization of 2‐Fluoro‐1,3‐indanediones via Allylation towards Chiral 3‐Hydroxyindanones Bearing Quaternary C–F Stereogenic Centers

Comprehensive Summary 3‐Hydroxyindanone represents one of the most valuable and privileged cyclic scaffolds in synthetic and medicinal chemistry, which widely exists in a variety of biologically active natural products and pharmaceutical lead molecules. Benefiting from its reactive hydroxyl and carbonyl functional groups, the 3‐hydroxyindanone skeleton also serves as a highly versatile synthetic building block for the modular construction of structurally complex fused and polycyclic ring systems, providing abundant opportunities for molecular diversification and drug molecular modification. Meanwhile, the introduction of fluorinated quaternary stereogenic centers has become a mature and powerful strategy in modern drug discovery. Fluorinated chiral architectures with quaternary C–F stereocenters can effectively optimize the lipophilicity, metabolic stability, and binding affinity of bioactive molecules, endowing them with unique and untapped pharmacological potential compared with their non‐fluorinated counterparts. Despite the tremendous advances in the synthetic chemistry of indanone derivatives and fluorinated chiral compounds, the catalytic asymmetric construction of enantiopure 3‐hydroxyindanones bearing quaternary C–F stereogenic centers remains a long‐standing and unaddressed challenge. The lack of reliable catalytic strategies severely restricts the further development and biological evaluation of such fluorinated chiral 3‐hydroxyindanones. To address this synthetic problem and continue our research interest in asymmetric catalysis and fluorine‐containing chiral heterocycle synthesis, we herein disclose the first example of catalytic asymmetric allylation for the desymmetrization of 2‐fluoro‐1,3‐indanediones, enabling the facile and efficient construction of chiral 3‐hydroxyindanones bearing quaternary C–F stereogenic centers. This newly developed yttrium(III)‐based catalytic system exhibits excellent synthetic performance and stereocontrol ability. A broad range of functionalized 2‐fluoro‐1,3‐indanedione substrates are well tolerated under mild reaction conditions, affording the target enantioenriched fluorinated 3‐hydroxyindanone products in high yields, excellent enantioselectivities, and exclusive diastereoselectivity (&gt;20 : 1 dr). Notably, this desymmetrization strategy not only provides a straightforward and unprecedented approach to forge challenging fluorinated quaternary stereocenters embedded in indanone skeletons but also offers a practical platform for the synthesis of novel fluorinated chiral drug candidates. We believe this work will enrich the synthetic methodology of fluorinated chiral cyclic compounds and provide new insights for the design and synthesis of fluorine‐modified bioactive molecules.