Enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation

The highly enantioselective synthesis of sterically hindered alpha-allyl-alpha-aryl oxindoles possessing an allcarbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of alpha-aryl-beta-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P, P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding alpha-allyl-alpha-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 alpha-aryl-beta-amido allyl ester substituted oxindoles showed that products containing bulky diortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted alpha-allyl-alpha-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.