Total synthesis of isoneoantimycin

Area of Science:

• Natural Product Chemistry
• Organic Synthesis
• Medicinal Chemistry

Background:

• Antimycins are antifungal metabolites from Streptomyces bacteria.
• Neoantimycins, ring-expanded analogues, regulate oncogenic proteins GRP78/BiP and K-Ras.
• Isoneoantimycin, lacking a macrolide core, is a minor metabolite of neoantimycin.

Purpose of the Study:

• To achieve the total synthesis of isoneoantimycin.
• To assign the stereochemistry of isoneoantimycin.
• To facilitate structure-activity relationship studies of neoantimycins.

Main Methods:

• Total synthesis utilizing chiral-pool building blocks.
• Stereochemical assignment based on presumed similarity to neoantimycin biosynthesis.
• Spectroscopic data comparison between synthetic and natural isoneoantimycin.

Main Results:

• Successful synthesis of isoneoantimycin with the (1S,2R,5S,6S,14R,15R,17S) configuration.
• Verification of the presumed stereochemistry of natural isoneoantimycin.
• Confirmation that isoneoantimycin is the first reported antimycin antibiotic without a macrolide core.

Conclusions:

• The total synthesis and stereochemical assignment of isoneoantimycin were achieved.
• The stereochemistry of natural isoneoantimycin was confirmed to be (1S,2R,5S,6S,14R,15R,17S).
• This synthesis provides a foundation for future structure-activity studies of neoantimycins and their analogues.