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

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.