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Organocatalytic stereoselective synthesis of β,β- diaryl ketones with β-tetrasubstituted stereogenic center

Organocatalytic stereoselective synthesis of β, β- diaryl ketones with β-tetrasubstituted 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 tetrasubstituted 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 benzophenone-ketimines for the construction of isoindolinone-derivedβ, β-diaryl ketones comprising tetrasubstituted stereogenic center. Key to the success of this transformation is the generation of reactive N-acyl ketiminuim species in situ from 3-hydroxy isoindolinones mediated by (R)-TRIP catalyst (Scheme 1). A broad range of ketimines and ketones afforded isoindolinone derivatives comprisingβ-tetrasubstituted center of chirality in high yields and enantioselectivities. The methodology was successfully employed in the construction of α, β- vicinal stereogenic centers in high diastereomeric and enantiomeric ratios. The mechanism of stereochemical induction will also be discussed.

Organocatalysis ; Stereoselective synthesis ; β, β-diaryl ketones

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