A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-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 γ-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 M.; Schettini R.; Pierri G.; Marino M.L.; Izzo I.; De Riccardis F.; Bernardi L.; Sala G.D.. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1520-6904. - ELETTRONICO. - 85:11(2020), pp. 7476-7484. [10.1021/acs.joc.0c00880]

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

Bernardi L.;
2020

Abstract

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-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 γ-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.
2020
An Entry to Enantioenriched 3,3-Disubstituted Phthalides through Asymmetric Phase-Transfer-Catalyzed γ-Alkylation / Sicignano M.; Schettini R.; Pierri G.; Marino M.L.; Izzo I.; De Riccardis F.; Bernardi L.; Sala G.D.. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 1520-6904. - ELETTRONICO. - 85:11(2020), pp. 7476-7484. [10.1021/acs.joc.0c00880]
Sicignano M.; Schettini R.; Pierri G.; Marino M.L.; Izzo I.; De Riccardis F.; Bernardi L.; Sala G.D.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/787197
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