Total synthesis of clostrubin

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Natural Product Synthesis

Background:

• Clostrubin is a potent antibiotic identified in 2014, effective against methicillin- and vancomycin-resistant bacteria.
• Its complex pentacyclic polyphenol structure, featuring a fully substituted arene, presents a significant challenge for chemical synthesis.

Purpose of the Study:

• To report the first total synthesis of the natural product clostrubin.
• To develop an efficient synthetic route to access this challenging antibiotic structure.

Main Methods:

• A nine-step linear synthesis was designed, exploiting a desymmetrization strategy.
• Key reactions included Barton-Kellogg olefination for segment coupling and a photo-induced 6π electrocyclization for B ring construction.

Main Results:

• The first total synthesis of clostrubin was successfully accomplished.
• The synthetic route delivered 200 mg of clostrubin.
• The synthesis highlights novel strategies for constructing highly substituted aromatic systems.

Conclusions:

• The developed synthetic route provides access to clostrubin, a valuable antibiotic candidate.
• This work demonstrates the feasibility of synthesizing complex natural products with potential therapeutic applications.
• The synthetic methodology can be applied to the creation of related analogs for further drug discovery efforts.