Total synthesis of pikromycin

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Natural Product Synthesis

Background:

• Pikromycin is the first isolated macrolide antibiotic, historically significant in antimicrobial research.
• Macrolide antibiotics are a crucial class of drugs, but their complex structures pose synthetic challenges.

Purpose of the Study:

• To achieve the first total synthesis of pikromycin.
• To develop a viable synthetic route for pikromycin and related macrolides.
• To demonstrate the utility of specific synthetic methodologies in complex molecule construction.

Main Methods:

• Retrosynthetic analysis dividing pikromycin into pikronolide (aglycon) and D-desosamine.
• Synthesis of the pikronolide aglycon utilizing asymmetric aldol reactions, Yamaguchi esterification, and ring-closing metathesis.
• Coupling of the synthesized aglycon with a D-desosamine derivative under Lewis acidic conditions.

Main Results:

• Successful total synthesis of pikromycin (6).
• Efficient synthesis of the pikronolide aglycon (6a).
• The synthetic strategy was also applied to the synthesis of narbomycin (5).

Conclusions:

• The total synthesis of pikromycin was successfully accomplished.
• The developed synthetic route provides a valuable method for constructing complex macrolide antibiotics.
• This work validates key synthetic reactions for macrolide synthesis.