Total synthesis of (+)-chloriolide.

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• (+)-Chloriolide is a metabolite produced by the ascomycete fungus Chloridium virescens var. chlamydosporum.
• Macrolides are a class of natural products with diverse biological activities, often requiring complex synthetic strategies.
• Previous syntheses of (+)-chloriolide have been reported, but this study introduces a novel approach.

Purpose of the Study:

• To develop a new synthetic route to (+)-chloriolide utilizing an intramolecular Wittig olefination.
• To establish the first macrolide synthesis employing a ring-closing Wittig olefination of a stabilized phosphorus ylide with an ω-hemiacetal.
• To evaluate the cytotoxic and antimicrobial activities of the synthesized (+)-chloriolide.

Main Methods:

• A 16-step linear synthesis starting from cellulose to obtain levoglucosenone.
• Incorporation of a spacer derived from l-lactate to form an ω-hydroxyacetal.
• Utilized a phosphorus ylide (Ph3P=CCO) followed by acid and base treatment to induce spontaneous intramolecular Wittig olefination for macrolide ring closure.

Main Results:

• Successfully synthesized (+)-chloriolide in 65% yield via a novel intramolecular Wittig olefination.
• The synthesis did not require high-dilution conditions, simplifying the macrolide formation process.
• The synthetic (+)-chloriolide demonstrated moderate cytotoxicity against cancer cells but lacked antimicrobial activity against Staphylococcus aureus.

Conclusions:

• The study presents a groundbreaking method for macrolide synthesis using an intramolecular Wittig olefination of a stabilized phosphorus ylide bearing an ω-hemiacetal.
• This efficient synthesis provides a valuable route to (+)-chloriolide and potentially other complex macrolides.
• The biological evaluation indicates specific cytotoxic potential but no significant antimicrobial effects.