Total synthesis of branimycin: an evolutionary approach

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Branimycins are a class of macrolactone antibiotics with potential therapeutic applications.
• The total synthesis of complex natural products is crucial for drug discovery and development.
• Previous synthetic routes to branimycin or its analogs have not been reported.

Purpose of the Study:

• To achieve the first total synthesis of the macrolactone antibiotic branimycin.
• To develop and optimize synthetic strategies for constructing the branimycin core structure.
• To establish a reliable method for assembling the polyketide side chain and macrolactone ring.

Main Methods:

• The synthesis employed a key disconnection strategy, separating the molecule into a cis-dehydrodecalone core and a polyketide side chain.
• Five different approaches were explored for constructing the dehydrodecalone core, utilizing various chiral elements and ring-closing methodologies.
• The chosen route involved organometallic desymmetrization of diepoxynaphthalene, followed by vinyl iodide addition and Michael addition for side chain incorporation.

Main Results:

• The first total synthesis of branimycin was successfully accomplished.
• A robust synthetic route was established, starting from diepoxynaphthalene and culminating in the target molecule.
• Key intermediates, including epoxy ketone 107 and the assembled core-side chain adduct, were synthesized and characterized.

Conclusions:

• The successful total synthesis of branimycin provides a foundation for further biological evaluation and analog development.
• The developed synthetic methodology, particularly the organometallic strategies, can be applied to the synthesis of other complex macrolactones.
• This work highlights the power of modern synthetic organic chemistry in accessing challenging natural products.