Chiral Primary Amine Catalyzed Asymmetric α‐Benzylation with In Situ Generated ortho‐Quinone Methides

Abstract

A dual activation strategy integrating primary amine catalysis and Lewis base activation has been developed for an asymmetric α-benzylation reaction. Enamines derived from β-ketocarbonyls could react effectively with in situ generated ortho-quinone methides under Lewis base activation in asymmetric α-benzylation of β-ketocarbonyls and α-branched aldehydes. The approach enables the creation of acyclic all-carbon quaternary stereocenters with excellent enantioselectivities and good activity.

Asymmetric catalytic construction of fully substituted carbon stereocenters using acyclic α-branched β-ketocarbonyls: the “Methyl Rule” widely exists

“…Enamines derived from β-ketocarbonyls could react effectively with in situ generated ortho-quinone methides under Lewis base activation, affording products with acyclic all-carbon quaternary stereocenters with excellent ee values (Scheme 44). 49 In 2018, Meggers and co-workers developed an elegant electricity-driven chiral Lewis acid catalysis for the oxidative crosscoupling of 2-acyl imidazoles with silyl enol ethers, which include products that bear all-carbon quaternary stereocenters.…”

Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine

“…Thus, extensive efforts have been made to develop a method for the formation of acyclic all-carbon quaternary stereocenters. 6,[23][24][25][26][27][28][29][30][31][32][33][34] The utilization of an enolate is one of the most powerful methods for the construction of acyclic all-carbon quaternary stereocenters. Effective methods that use the nucleophilicity of enolates have been reported.…”

Asymmetric Retro-Claisen Reaction by Synergistic Chiral Primary Amine/Palladium Catalysis

“…When the β-ketoester substrate 1r was employed to react with the carbonate 2a under standard conditions, no desired retro-Claisen cleavage product was detected. Not unexpectedly, the reaction provided a single α-benzylation adduct 3ra in 72% yield and >99% ee after acyl protection of the free phenol moiety (Scheme , I) …”

“…Not unexpectedly, the reaction provided a single αbenzylation adduct 3ra in 72% yield and >99% ee after acyl protection of the free phenol moiety (Scheme 2, I). 14 To evaluate the practicality of the current reaction, we performed a 1 mmol scale with β-diketone 1a and 2f in the presence of only 10 mol % of primary amine catalyst and 1 mol % of Pd catalyst. The desired product was obtained in 75% yield and 97% ee with a prolonged reaction time (Scheme 2, II).…”