Synthesis of non-natural monoterpene indole alkaloid scaffolds using plant-derived iridoid pools

Monoterpene indole alkaloids (MIAs) are privileged natural products characterized by their sp3-rich terpenoid frameworks and nitrogen-containing alkaloid scaffolds. To date, more than 4000 MIAs have been reported. However, most MIAs are biosynthesized from tryptamine and secologanin, which fundamentally restricts the accessible chemical space. Herein, we report the synthesis of non-natural polycyclic MIA-like compounds employing a diversity-enhanced extract strategy using iridoid-containing plants (Cornus officinalis and Gardenia jasminoides) in combination with a series of indole alkylamines. This approach enables the collective transformation of complex iridoid pools into alkaloid-like scaffolds possessing ring connectivities and scaffold topologies that differ from those typically observed in naturally occurring MIAs. Chemoinformatic analysis using uniform manifold approximation and projection and tree-based manifold approximation and projection demonstrates that the synthesized compounds occupy a chemical space distinct from that of naturally occurring MIAs. Consistent with this result, Tanimoto similarity analysis reveals a low average similarity score (0.19) relative to natural MIAs, supporting the structural differentiation of the generated scaffolds from currently known natural MIAs. Biological evaluation of the resulting chemical library identifies several nonpolycyclic compounds exhibiting modest anti-inflammatory activity, illustrating the potential of structurally differentiated MIA-like scaffolds for future biological studies. Monoterpene indole alkaloids (MIAs) are valuable natural products with sp3-rich terpenoid frameworks and nitrogen-containing alkaloid scaffolds, but their structural diversity is largely shaped by canonical strictosidine-based biosynthesis from tryptamine and secologanin. Here, the authors report a diversity-enhanced extract strategy that transforms plant-derived iridoid pools with a series of indole alkylamines to generate structurally diverse, non-natural MIA-like scaffolds and expand the accessible chemical space surrounding natural MIAs.