Total synthesis of marinomycin A based on a direct dimerization strategy

Area of Science:

• Organic Chemistry
• Marine Natural Products
• Medicinal Chemistry

Background:

• (+)-Marinomycin A is a 44-membered macrodiolide with significant antitumor and antibiotic properties.
• It was isolated from the marine actinomycete Marinispora strain CNQ-140.
• The complex structure presents a significant synthetic challenge.

Purpose of the Study:

• To achieve the first asymmetric total synthesis of (+)-marinomycin A.
• To develop efficient and stereocontrolled methods for constructing the macrodiolide framework.
• To explore novel synthetic strategies for complex natural products.

Main Methods:

• Asymmetric epoxidation of a sigma-symmetrical dialkenyl carbinol to construct the hydroxy salicylate monomer.
• A highly convergent strategy for assembling the complex molecule.
• An unprecedented direct dimerization via sodium bis(trimethylsilyl)amide (NaHMDS)-promoted double transesterification.

Main Results:

• Successful asymmetric total synthesis of (+)-marinomycin A was accomplished.
• The stereocontrolled construction of the monomeric hydroxy salicylate was achieved.
• A novel and efficient direct dimerization method was developed and utilized.

Conclusions:

• The developed synthetic route provides access to (+)-marinomycin A.
• The key steps, including asymmetric epoxidation and direct dimerization, are valuable for synthesizing complex macrodiolides.
• This synthesis opens avenues for further biological evaluation and analog development.