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 3as demonstrates therapeutic potential against triple-negative breast cancer, with an IC₅₀ of 8.5 μM in MDA-MB-453 cells.