A novel asymmetric phase-transfer-catalyzed gamma-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary gamma-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide gamma-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

An Entry to Enantioenriched 3,3-Disubstituted Phthalides through Asymmetric Phase-Transfer-Catalyzed γ-Alkylation

Sicignano, Marina
Investigation
;
Schettini, Rosaria
Investigation
;
Pierri, Giovanni
Investigation
;
Izzo, Irene
Investigation
;
De Riccardis, Francesco
Investigation
;
Sala, Giorgio Della
Conceptualization
2020

Abstract

A novel asymmetric phase-transfer-catalyzed gamma-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary gamma-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide gamma-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4747802
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