Total Synthesis of Peniterphenyls A and E

Area of Science:

• Marine Natural Products Chemistry
• Organic Synthesis
• Antiviral Drug Discovery

Background:

• Peniterphenyls A and E are marine natural products with potent anti-herpes simplex virus (HSV) activity.
• Their limited natural availability hinders detailed mechanistic studies and further investigation.
• Previous research suggests activity may involve interference with virus adsorption and host cell membrane fusion.

Purpose of the Study:

• To establish the first site-selective chemical total syntheses of peniterphenyls A and E.
• To provide a reliable and scalable synthetic route for obtaining these antiviral compounds.
• To facilitate further research into the mechanism of action of peniterphenyls A and E against HSV.

Main Methods:

• Development of a site-selective synthetic strategy utilizing nucleophilic aromatic substitution (S_NAr) and palladium-catalyzed C(sp²)-H/C(sp²)-H oxidative coupling.
• Employing a pivaloyl directing group to achieve efficient dibenzofuran core formation.
• Optimization of reaction conditions to control site-selectivity based on steric and electronic effects.

Main Results:

• Successful total synthesis of peniterphenyls A and E achieved.
• Peniterphenyl A synthesized in 4.5% overall yield over 13 steps.
• Peniterphenyl E synthesized in 2.3% overall yield over 12 steps.
• High site-selectivity in the palladium-catalyzed C-H activation step was demonstrated.

Conclusions:

• The developed synthetic route provides convenient access to peniterphenyls A and E from readily available materials.
• This synthesis overcomes the limitation of natural scarcity, enabling further biological evaluation.
• The efficient and site-selective methodology can be applied to the synthesis of related compounds for drug discovery.