Abstract
Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014. This polyphenol possesses a fully substituted arene moiety on its pentacyclic scaffold, which poses a considerable challenge for chemical synthesis. Here we report the first total synthesis of clostrubin in nine steps (the longest linear sequence). A desymmetrization strategy is exploited based on the inherent structural feature of the natural product. Barton–Kellogg olefination forges the two segments together to form a tetrasubstituted alkene. A photo-induced 6π electrocyclization followed by spontaneous aromatization constructs the hexasubstituted B ring at a late stage. In total, 200 mg of clostrubin are delivered through this approach.
Highlights
Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014
An advanced olefin intermediate was constructed through Barton–Kellogg olefination, and a 6p electrocyclization promoted by ultraviolet light assembled the fully substituted B ring
N,N-dimethylformamide, triethylamine, N,N-diisopropylethylamine and chlorotrimethylsilane were distilled from calcium hydride and stored under an argon atmosphere
Summary
Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014. The potential of 1 as a lead compound for antibiotic development and its limited supply from natural sources stimulated us to launch a chemical synthesis programme immediately. We report the first total synthesis of clostrubin (1) from commercially available starting materials.
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