Three-Step Catalytic Asymmetric Total Syntheses of 13-Methyltetrahydroprotoberberine Alkaloids

(S,R)-N-PINAP
was identified to be the chiral ligand for highly enantioselective
CuI-catalyzed reaction of tetrahydroisoquinolines (THIQs), alkynes,
and 2-bromobenzaldehyde derivatives. This enables us to accomplish
the first asymmetric total synthesis of 12 natural 13-methyltetrahydroprotoberberine
(13-MeTHPB) alkaloids in only three catalytic steps with 47–64%
overall yields. In addition, the Pd-catalyzed reductive Heck cyclization
was successfully extended to three Pd-catalyzed domino reactions (Heck/Suzuki,
Heck/Sonogashira, and Heck/Heck), which greatly expands the synthetic
utility of this catalytic strategy and allows expeditious access to
13-substituted tetrahydroprotoberberines for further bioactivity evaluation.