engleski

Stereoselective synthesis of β,β-diaryl ketones with β-tetrasubstituted 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. The enantioselective Mannich-type reactions of isoindolinone-derived ketimines with carbon nucleophiles – α-azoesters, cyclohexenone, N- acetyl enamides and difluoroenoxysilanes – 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. Therefore, a chiral Brønsted acid-catalyzed stereoselective addition of ketones to benzophenone-ketimines for the construction of isoindolinone-derived β, β- diaryl ketones comprising quaternary stereogenic center is reported here. 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, β-quaternary 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 ; Stereoselectivity ; Stereoselective synthesis ; Diaryl ketones

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