Allylic rearrangement

Stereocenter

Organic chemistry

Combinatorial chemistry

Kinetic resolution

Stereochemistry

Enantioselective synthesis

Catalysis

Lewis acids and bases

Chemistry

Chemoselectivity

1,3-Dipolar cycloaddition

Pyrrolidine

Cycloaddition

Ylide

Bifunctional

Azomethine ylide

ACS Catalysis

We designed bifunctional 4-pyrrolidinopyridines as powerful Lewis base catalysts. The catalyst structure features a 4-hydroxy-2-(hydroxydiphenylmethyl)pyrrolidine-1-formyl group at the pyridine's C3 site and a chiral side arm at the C2 position of the p-pyrrolidine ring. An operationally simple three-step synthetic route allows for efficient and economical catalyst preparation. In comparison with other Lewis bases, the catalyst exhibits excellent efficiency and stereoselectivity in the asymmetric (3 + 2) cycloaddition of allylic N-ylide generated in situ from a pyrazolone-derived Morita–Baylis–Hillman carbonate, providing a powerful platform for the construction of chiral spiropyrazolone derivatives. The reaction mechanism was thoroughly studied. Control experiments and DFT calculations illustrated the origin of the chemoselectivity and the stereocontrol model. H-bonding is crucial for the control of enantioselectivity and diastereoselectivity. The catalyst was also successfully applied in other reactions, such as an acylative dynamic kinetic resolution to synthesize a chiral phthalidyl ester, including the prodrug Talmetacin.

Design and Application of Chiral Bifunctional 4-Pyrrolidinopyridines: Powerful Catalysts for Asymmetric Cycloaddition of Allylic <i>N</i>-Ylide

Design and Application of Chiral Bifunctional 4-Pyrrolidinopyridines: Powerful Catalysts for Asymmetric Cycloaddition of Allylic N-Ylide