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 SN2-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.
Highlights
Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals
Since the diverse transformations of the alkynyl groups and their weak ability to activate the α-position of carbonyl compounds due to the high s character of alkynyl groups[65,66], we started our study by employing racemic α-alkynyl ketone 1a as the model substrate
When the reaction between 1a and allenamide 2a was investigated under the catalysis of chiral phosphoric acids (CPA) A1 (10 mol%) in CCl4 at ambient temperature, the desired product 3a bearing an all-carbon quaternary stereocenter was exclusively generated in 61% yield with 71:29 enantiomeric ratio, without detecting the potential α’- or γregioisomers (Table 1, entry 1)
Summary
Acyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. When the reaction between 1a and allenamide 2a was investigated under the catalysis of CPA A1 (10 mol%) in CCl4 at ambient temperature, the desired product 3a bearing an all-carbon quaternary stereocenter was exclusively generated in 61% yield with 71:29 enantiomeric ratio (er), without detecting the potential α’- or γregioisomers (Table 1, entry 1).
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