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

Abstract

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 α-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_N2-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 α,β-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.

Fig. 1. Asymmetric construction of all-carbon quaternary stereocenters via enantioselective functionalizations of α-branched ketones.

a Asymmetric construction of quaternary stereocenters of activated ketones. b Asymmetric construction of quaternary stereocenters of α-branched cyclic ketones. c Unsaturation-enabled asymmetric Mannich reaction of α-branched acyclic ketones. d Asymmetric construction of acyclic quaternary stereocenters of α-alkynyl acyclic ketones.

Fig. 2. Substrate scope of α-alkynyl ketones.

Reactions were performed with 1 (0.2 mmol), 2a (0.22 mmol), CPA (S)-A9 (0.02 mmol), activated 4 Å MS (200 mg) in CCl₄ (2 mL) at room temperature. Isolated yields. Er values were determined by HPLC analysis on a chiral stationary phase.

Fig. 3. Substrate scope of allenamides.

Reactions were performed with 1a (0.2 mmol), 2 (0.22 mmol), CPA (S)-A9 (0.02 mmol), activated 4 Å MS (200 mg) in CCl₄ (2 mL) at room temperature. Isolated yields. Er values were determined by HPLC analysis on a chiral stationary phase.

Fig. 4. Control experiments.

a Reaction of α-alkenyl ketone substrate. b Reactions of α-alkyl ketone 4b, α-branched ynone 4c and β-ketoester 4d in this reaction. c Predicted pKa values of ketone substrates.

Fig. 5. Kinetic experiments.

a Relationship between the initial reaction rate and concentration of the CPA catalyst A7. b Relationship between the initial reaction rate and concentration of ketone 1a. c Relationship between the initial reaction rate and concentration of the allenamide 2a. d Relationship between the initial reaction rate and concentration of the amide additive 2a’. e KIE experiment of the α-H of ketone 1a. f Isomerization of 1a into allenyl ketone 1a’ and its reaction with allenamide 2a under the standard conditions.

Fig. 6. Investigation of the asymmetric induction mechanism.

a Nonlinear effect study. b Detection and characterization of the reaction intermediate. c Preparation of allyl phosphate of CPA A7 and its reaction with ketone 1a under the standard conditions. d Cross experiment of INT-A_2w. e Asymmetric reaction of allyl benzyl ether 6a with ketone 1a under the standard conditions.

Fig. 7. Proposed reaction mechanism and asymmetric transition state.

CPA catalyzed enolization of ketone as the rate-determining step and the conjugate addition with the α,β-unsaturated iminium as the enantio-determining step.

Fig. 8. Large-scale reaction and derivatizations of the chiral products.

a Gram-scale reaction. b Hydrogenation of 3a. c Cycloaddition of 3a with organic azide. d Hydrolysis and aldol reaction of 3a. e Reduction and cyclization of 3a.