An Expeditious Modular Hybrid Strategy for the Diversity-Oriented Synthesis of Lamellarins/Azalamellarins with Anticancer Cytotoxicity

A modular
hybrid strategy has been developed for the diversity-oriented
synthesis of lamellarins/azalamellarins. The common pentacyclic pyrrolodihydroisoquinoline
lactone/lactam core was formed via the Michael addition/ring closure
(Mi-RC) and the copper­(I) thiophene-2-carboxylate (CuTC)-catalyzed
C–O/C–N Ullmann coupling. Subsequent direct functionalization
at C1, DDQ-mediated C5C6 oxidation, and global deprotection
of all benzyl-type O- and N-protecting
groups furnished the desired lamellarins/azalamellarins. The late-stage
functionalization at C1 provided a handle to accommodate a wider scope
of functional groups as they need to tolerate only the DDQ oxidation
and global deprotection. Moreover, with the C1-H pyrrole
as the late-stage common intermediate, it was also possible to divergently
exploit not only its nucleophilic nature to react with some electrophilic
species but also some transition-metal-catalyzed cross-coupling reactions
(via the intermediacy of the C1-iodopyrrole) to incorporate diversity
at this position. Overall, this strategy simplifies the preparation
of lamellarins/azalamellarins; including the Mi-RC, these C1-structurally
diverse analogues could be prepared efficiently in 6–7 steps
from the easily accessed 1-acetoxymethyldihydroisoquinoline and β-nitrocinnamate.
Some selected azalamellarins were evaluated for their inhibitory effect
against HeLa cervical cancer cells. An acute induction of intrinsic
apoptosis was detected and may lead to growth suppression of or cytotoxicity
against cancer cells.