Catalyst-controlled regiodivergence and stereodivergence in formal cross-[4+2] cycloadditions: The unique effect of bismuth(III)

The [4+2] cycloaddition is crucial for constructing six-membered rings in pharmaceuticals and natural products. Cross-[4+2] cycloadditions offer greater product diversity than traditional diene-dienophile reactions due to multiple possible pathways. However, precise control over regio- and stereoselectivity for various isomers remains a great challenge. This study reports catalyst-controlled regiodivergent formal cross-cycloadditions of acyclic dienes and enones, significantly enhancing access to diverse pyrazole-fused spirooxindoles. Chiral phosphoric acid (CPA) catalysis enables endoselective [4+2] cycloadditions, while Bi(III) with a CPA ligand yields [2+4] products with high regio- and stereoselectivity. A Claisen rearrangement of the [2+4] adduct produces the exo-selective [4+2] product, further increasing stereochemical diversity and enabling the synthesis of six regio- and stereo-isomers from a single substrate set. DFT calculations reveal that Bi(III) reverses regioselectivity by repositioning reactants in the CPA pocket and stabilizing the enone oxygen's negative charge. In addition, product <b>3as</b> demonstrates therapeutic potential against triple-negative breast cancer, with an IC₅₀ of 8.5 μM in MDA-MB-453 cells.