Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

Nitrogen and oxygen medium rings,
in particular nine-membered rings,
epitomize a unique area of chemical space that occurs in many natural
products and biologically appealing compounds. The scarcity of 8-
to 12-membered rings among clinically approved drugs is indicative
of the difficulties associated with their synthesis, principally owing
to the unfavorable entropy and transannular strain. We report here
a scandium triflate-catalyzed reaction that allows for a modular access
to a diverse collection of nine-membered ring heterocycles in a one-pot
cascade and with complete diastereocontrol. This cascade features
an intramolecular addition of an acyl group-derived enol to a α,β-unsaturated
carbonyl moiety, leading to N- and O-derived medium-ring systems.
Computational studies using the density functional theory support
the proposed mechanism. Additionally, a one-pot cascade leading to
hexacyclic chromeno­[3′,4′:2,3]­indolizino­[8,7-b]­indole architectures, with six fused rings and four contiguous
chiral centers, is reported. This novel cascade features many concerted
events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition,
1,3-sigmatropic rearrangement, Michael addition, and Pictet–Spengler
reaction among others. Phenotypic screening of the resulting oxazonine
collection identified chemical probes that regulate mitochondrial
membrane potential, adenosine 5′-triphosphate contents, and
reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising
approach for targeting cancer and metabolic disorders.