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Phenolic Activation in Chiral Bronsted Acid-Catalyzed Intramolecular ?-Amidoalkylation Reactions for the Synthesis of Fused Isoquinolines.

ABSTRACT: An organolithium addition-intramolecular ?-amidoalkylation sequence on N-phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1'-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use of binol-derived N-triflylphosphoramides as catalysts are determinants to achieve reasonable levels of enantioselection, that is, up to 75% enantiomeric excess, in the ?-amidoalkylation step. The procedure is complementary to the intermolecular ?-amidoalkylation process, as opposite enantiomers are formed, and to the Pictet-Spengler cyclization, which allows the formation of tertiary stereocenters.

SUBMITTER: Aranzamendi E

PROVIDER: S-EPMC6641169 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Phenolic Activation in Chiral Brønsted Acid-Catalyzed Intramolecular α-Amidoalkylation Reactions for the Synthesis of Fused Isoquinolines.

Aranzamendi Eider E Sotomayor Nuria N Lete Esther E

ACS omega 20170616 6

An organolithium addition-intramolecular α-amidoalkylation sequence on <i>N</i>-phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1'-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use ...[more]

PMID: 31457610

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