Shinji Harada

This Account describes our research program on the development of lanthanide metal-catalyzed enantioselective Diels-Alder reactions of acid-labile siloxydienes. Although the siloxydienes-Danishefsky diene and heterocycle-fused derivativesare highly versatile synthetic building blocks, their inherent sensitivity to acidic conditions has limited the use of Lewis acid catalysis in asymmetric cycloadditions. We addressed this fundamental challenge by exploiting the unique properties of lanthanide metals-namely, their mild yet tunable Lewis acidity and tolerance for high coordination numbers-to develop ternary catalytic systems composed of lanthanide salts, chiral ligands, and amine bases. Through the systematic evolution of both the ligand architecture (from BINAMIDE to BINUREA to bisthiourea to hexadentate ImBpy-type ligands) and the metal center (Yb, Ho, and other lanthanides), we achieved highly enantioselective cycloadditions across a broad range of substrates, including Danishefsky-type dienes and novel heterocycle-fused siloxydienes. The synthetic utility of the presented methods has been demonstrated through the enantioselective total syntheses of natural products such as (-)minovincine, platyphyllide, and carbazomycins A and B, as well as the formal syntheses of pharmaceutical targets. Recently, the development of storable, crystalline helical lanthanide complexes has resulted in a practical and mechanistically well-defined catalytic platform, which is supported by luminescence spectroscopy and density functional theory calculations.