Total synthesis of all (-)-Agelastatin alkaloids

Area of Science:

• Marine natural products chemistry
• Organic synthesis
• Medicinal chemistry

Background:

• Pyrrole-imidazole alkaloids are a diverse class of marine natural products.
• Agelastatins are bioactive members with a unique tetracyclic structure.
• Their complex architecture presents a synthetic challenge and hints at unique biosynthetic pathways.

Purpose of the Study:

• To propose a hypothesis for the biogenesis of agelastatins.
• To achieve the first total syntheses of agelastatins C, D, E, and F.
• To develop a gram-scale synthesis of agelastatin A, guided by the biogenesis hypothesis.

Main Methods:

• Enantioselective total synthesis strategies.
• Development of novel annulation and carbohydroxylation reactions.
• Biomimetic approach inspired by proposed biosynthetic pathways.

Main Results:

• Successful concise enantioselective total syntheses of all known agelastatins.
• First-time synthesis of agelastatins C, D, E, and F.
• Gram-scale synthesis of agelastatin A, validating the biogenesis hypothesis and new reactions.

Conclusions:

• The study provides a plausible biosynthetic hypothesis for agelastatin formation.
• The developed synthetic methodologies enable access to complex marine alkaloids.
• This work expands the chemical space for exploring the biological activities of agelastatins.