engleski

Stereoselective synthesis of β,β-diaryl ketones with β-quaternary stereogenic center

Stereoselective synthesis of β, β-diaryl ketones with β-quaternary stereogenic center incorporated into isoindolinone moiety is described. Gem-diaryl-alkyl isoindolinone derivatives are key skeletons present in numerous naturally occurring and synthetic biologically active molecules. In this context, optically active isoindolinone-derived β, β- diaryl ketones show great potential as the synthetic intermediates of diarylalkyl- containing molecules due to the versatile transformations of the carbonyl and lactame group [1]. The enantioselective Mannich-type reactions of isoindolinone-derived ketimines with carbon nucleophiles – α-azoesters [2], cyclohexenone [3], N-acetyl enamides [4] and difluoroenoxysilanes [5] – provide a direct access to these compounds bearing a chiral quaternary stereogenic center. The main drawbacks of these methodologies are inherent restrictions for the construction of vicinal α, β-stereogenic centers, including the control of its diastereo- and enantioselectivity. Herein we report a chiral Brønsted acid- catalyzed stereoselective addition of ketones to N-acyl ketimines for the construction of isoindolinone-derived β, β-diaryl ketones comprising quaternary stereogenic center. Key to the success of this transformation is the generation of reactive N-acyl ketiminuim species in situ from 3-hydroxy isoindolinones under chiral phosphoric acid catalysis. The addition of enols provides products in excellent yields and enantioselectivities, including compounds with vicinal α, β- stereogenic centers. The stereochemical model of the chiral induction is proposed on the basis of the absolute configuration determined by the X-ray crystallographic analysis. Upon dehydration, N-acyl ketiminium ion forms an ion pair with the anion of the catalyst, thus blocking its si face. Enol approaches from re face of the electrophile, providing yielding products with in diastereo- and enantiomeric ratios.

β ; β-diaryl ketones ; stereoselective synthesis ; organocatalysis ; chiral Brønsted acids

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