Decoding skeletal diversity and complexity: A biomimetic and photochemical remodeling strategy

Area of Science:

• Organic Synthesis
• Natural Product Chemistry
• Medicinal Chemistry

Background:

• Constructing complex three-dimensional polycyclic scaffolds from single precursors is a significant challenge in organic synthesis.
• Marine natural products often possess intricate structures with potential biological activities.

Purpose of the Study:

• To achieve a concise biomimetic synthesis of the marine natural product ocellatusone C.
• To develop a versatile platform for skeletal diversification of polycyclic scaffolds.
• To explore novel synthetic routes to complex molecular architectures.

Main Methods:

• Acid-triggered cascade reaction featuring a Dieckmann-type cyclization.
• Density functional theory (DFT) calculations and quasi-classical dynamics simulations.
• Skeletal reorganization via light-induced transformations and cross-coupling reactions.

Main Results:

• Successful concise biomimetic synthesis of ocellatusone C from tridachiahydropyrone.
• Generation of diverse [3.3.1] bicyclic analogs with broad functional group tolerance.
• Discovery of a light-induced skeletal reorganization for accessing elusive polycyclic architectures.
• Identification of significant antimalarial bioactivity in the synthesized compounds.

Conclusions:

• The developed biomimetic strategy provides an efficient platform for synthesizing complex polycyclic molecules.
• The study highlights the potential of these architecturally diverse systems as novel antimalarial drug leads.
• Mechanistic insights from DFT and dynamics simulations aid in understanding complex rearrangements.