Biomimetic Approach Toward Enterocin and Deoxyenterocin

Area of Science:

• Natural product synthesis
• Organic chemistry
• Medicinal chemistry

Background:

• Enterocin (vulgamycin) is a complex natural product known for its potent antibiotic activity.
• Its unique structure presents a significant challenge for total synthesis.
• Understanding its biosynthesis and developing synthetic routes are crucial for accessing novel antibiotics.

Purpose of the Study:

• To achieve the total synthesis of enterocin (vulgamycin).
• To explore biomimetic strategies for constructing the natural product's core structure.
• To develop alternative synthetic routes for efficient access to enterocin.

Main Methods:

• Synthesis of a linear polyketide precursor via an acyloin reaction.
• Introduction of a diazo group as a protecting group for enolizable ketones.
• Density Functional Theory (DFT) calculations to assess the feasibility of a biomimetic aldol addition cascade.
• Copper-catalyzed intramolecular cyclopropanation.
• Magnesium iodide (MgI2)-induced fragmentation to form the bicyclic core.

Main Results:

• A linear polyketide precursor resembling a biosynthetic intermediate was synthesized.
• The envisioned biomimetic aldol addition cascade was not achieved, with insights gained from DFT calculations.
• An alternative strategy involving Cu-catalyzed cyclopropanation and MgI2-induced fragmentation successfully installed the 2-oxabicyclo[3.3.1]nonane core.

Conclusions:

• The study highlights the challenges in biomimetic synthesis of complex natural products like enterocin.
• An effective alternative synthetic route was developed, showcasing the utility of Cu-catalyzed cyclopropanation and MgI2-induced fragmentation.
• This work provides valuable insights into the synthesis of enterocin and related compounds, potentially aiding in the development of new antibiotics.