Asymmetric construction of acyclic quaternary stereocenters via direct enantioselective additions of α-alkynyl ketones to allenamides

Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. Here the authors show an efficient chiral phosphoric acid catalyzed direct asymmetric addition of alpha-alkynyl acyclic ketones with allenamides to produce acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities: Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. However, development of highly efficient asymmetric catalytic methods for the construction of these privileged motifs represents a longstanding challenge in organic synthesis. Herein, an efficient chiral phosphoric acid catalyzed direct asymmetric addition of alpha-alkynyl acyclic ketones with allenamides has been developed, furnishing the acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities. Extensive and detailed experimental mechanistic studies were performed to investigate the mechanism of this reaction. Despite a novel covalent allyl phosphate intermediate was found in these reactions, further studies indicated that a S(N)2-type mechanism with the ketone nucleophiles is not very possible. Instead, a more plausible mechanism involving the elimination of the allyl phosphate to give the alpha,beta-unsaturated iminium intermediate, which underwent the asymmetric conjugate addition with the enol form of ketone nucleophiles under chiral anion catalysis, was proposed. In virtue of the fruitful functional groups bearing in the chiral products, the diverse derivatizations of the chiral products provided access to a wide array of chiral scaffolds with quaternary stereocenters.

Automated summary

Acyclic quaternary stereocenters are commonly found in biologically active natural products and pharmaceuticals. The development of an efficient chiral phosphoric acid catalyzed direct asymmetric addition method has allowed for the synthesis of acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities. The mechanism of this reaction involves a novel covalent allyl phosphate intermediate and asymmetric conjugate addition under chiral anion catalysis. Extensive experimental studies have provided access to a wide array of chiral scaffolds with quaternary stereocenters.