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

An organolithium
addition–intramolecular α-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 α-amidoalkylation
step. The procedure is complementary to the intermolecular α-amidoalkylation
process, as opposite enantiomers are formed, and to the Pictet–Spengler
cyclization, which allows the formation of tertiary stereocenters.