Total Synthesis of (±)-Nisamycin

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Antibiotic Synthesis

Background:

• Manumycin-type antibiotics, including nisamycin, are a class of natural products with potential therapeutic applications.
• The complex structures of these antibiotics present significant synthetic challenges.
• Developing efficient and convergent synthetic routes is crucial for accessing these compounds and their analogs.

Purpose of the Study:

• To develop a highly convergent synthesis of the m-C7N-antibiotic nisamycin.
• To establish a synthetic strategy applicable to other manumycin-type antibiotics.
• To explore novel methodologies for constructing the polyene side chains.

Main Methods:

• A three-step sequence was employed to construct the epoxyquinol core.
• Organozirconocene-mediated synthesis was utilized for the eastern polyene side chain.
• Stille coupling reactions were used to introduce the southern polyene side chain.

Main Results:

• A convergent synthesis of nisamycin was successfully developed.
• The methodology proved effective for constructing the polyene side chains, including for asukamycin.
• The synthesis provided access to TIPS-protected nisamycin, readily convertible to the natural product.

Conclusions:

• The developed synthetic route is efficient and convergent for nisamycin.
• This strategy is adaptable for synthesizing other members of the manumycin antibiotic family.
• Novel organozirconocene and Stille coupling methods facilitate the construction of complex polyene side chains.