Counteranion-Controlled Unprecedented Diastereo- and Enantioselective Tandem Formal Povarov Reaction for Construction of Bioactive Octahydro-Dipyrroloquinolines

The asymmetric inverse-electron-demand
hetero-Diels–Alder
(IEHDA) reactions of imines and dienophiles have emerged as an attractive
tool for derivatizing optically active complex azaheterocycles. In
comparison, such reactions involving iminium ions remain great challenges
because of low association of iminium ions with neutral catalytic
centers. To overcome this, we report a metal-phosphate-catalyzed asymmetric
tandem hydroamination/formal Povarov reaction of secondary aminoalkynes
via a chiral counteranion-controlled iminium ion intermediate strategy.
Critical to the success of this challenging strategy was chiral phosphate
as an ion pair to achieve counteranion-controlled asymmetric reaction
of in situ-generated iminium ions. This method enables a convenient,
powerful, and atom-economical access to tetracyclic octahydro-dipyrroloquinoline
frameworks bearing multiple contiguous stereogenic centers in good
yields with diastereo- and enantioselectivities, from acyclic starting
materials, and the catalyst loadings could be as low as 1 mol %. The
asymmetric cross-coupling reaction of different aminoalkynes has further
been demonstrated with good results. Furthermore, this methodology
was applied to enantioselective synthesis of incargranine B aglycone
epimer in only two steps. The reaction is demonstrated to proceed
through a stepwise process for formal Povarov reaction.