Palladium‐Catalyzed Enantioselective Cyclization of 1,6‐Enynes through Intramolecular Chlorine Transfer as a Novel Strategy for Asymmetric Halopalladation

Abstract

Palladium-catalyzed enantioselective cyclization of enynes has contributed significantly to the construction of chiral cyclic molecules. In contrast, the catalytic asymmetric cyclization involving halopalladation remains an unresolved challenge with the inevitable disturbance of the halide ions. Herein, an intramolecular chlorine transfer strategy is used to accomplish the enantioselective chloropalladation cyclization of 1,6-enynes. This reaction provides a redox-neutral approach to a variety of chiral α-chloromethylene-γ-butyrolactones with excellent E selectivity and enantioselectivity. The precisely controlled coordination of palladium with both the in situ generated nucleophilic species and the monodentate phosphoramidite ligand is crucial for enantioselectivity.

Recent advances in Pd-catalyzed asymmetric cyclization reactions

“…A novel chlorine transfer strategy for the facile synthesis chiral α-chloromethylene-γ-butyrolactones 514 via the enantioselective chloropalladation cyclization of 1,6-enynes 513 was accomplished by the group of Jiang in 2022 (Scheme 119). 237 The authors found that the substrate bearing the quinoline group may poison the palladium catalyst, thus completely inhibiting this transformation. The steric bulk of the substituents had a considerable effect on both the yield and the enantioselectivity, as ortho substituents resulted in lower yields and ee values.…”

Oxygen-, Nitrogen-, and Sulfur-Containing Heterocycles: Recent Advances in De Novo Synthesis and Prospect

“…41 In 2022, we applied an intramolecular chlorine transfer strategy in palladium-catalyzed enantioselective cyclization of 1,6-enynes to access a variety of chiral α-chloromethylene-γbutyrolactones with excellent E selectivity and high enantioselectivity (Scheme 23). 42 Excess halide ions lead to saturated coordination [PdX 4 ] 2− species, which will block the coordination of palladium with chiral ligands, so that high enantioselectivity of enynes by halopalladation progress is undeveloped. Our group proposed a general endogenous halogen transfer strategy that halide preinstalled on the substrate and controllably released and sequentially transferred.…”

Asymmetric Palladium-Catalyzed Aminochlorination of Unactivated Alkenes

“…Indeed, when 10 equiv of CaCl 2 was added into a solution of ( L1 )­PdCl 2 in deuterium chloroform, there was no free L1 observed in the mixture, whereas the addition of the same amount of Bu 4 NCl showed an obvious dissociation of L1 from the palladium center, thereby inhibiting the reaction (Figure ). Solvent screening indicated that polar solvents, such as acetonitrile and 1,4-dioxane, in which CaCl 2 has a solubility better than that in chlorobenzene, decreased the enantioselectivity (entries 10 and 11). These observations indicate that the palladium catalyst is indeed deactivated by chloride anions, and NCS as an electrophilic chlorination reagent was essential for the asymmetric chlorination.…”