Total Synthesis of (-)-Psathyrin A Enabled by Radical Cyclization

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• (-)-psathyrin A is an antibacterial diterpene natural product.
• It possesses a complex 6/4/5/5 tetracyclic carbon skeleton with seven contiguous stereocenters.
• Three of these stereocenters are adjacent all-carbon quaternary centers, posing a significant synthetic challenge.

Purpose of the Study:

• To achieve the first enantioselective total synthesis of (-)-psathyrin A.
• To develop and apply novel synthetic methodologies for constructing complex natural products.
• To establish efficient routes for accessing molecules with challenging stereochemical features.

Main Methods:

• Enantioselective copper/NHC-catalyzed conjugate addition.
• Gold(I)-catalyzed Conia-ene reaction for bicyclic ring construction.
• Baran reductive olefin coupling (MHAT-initiated olefin-enone radical cyclization) for four-membered ring formation and third all-carbon quaternary center installation.

Main Results:

• Successful construction of the unique 6/4/5/5 tetracyclic carbon skeleton of (-)-psathyrin A.
• Establishment of seven contiguous stereocenters, including three adjacent all-carbon quaternary centers.
• Completion of the total synthesis in 19 steps, demonstrating the efficiency of the developed strategy.

Conclusions:

• The first enantioselective total synthesis of (-)-psathyrin A was achieved.
• The synthetic route showcases the power of modern catalytic methods, including copper, gold, and radical cyclizations.
• This work provides a viable pathway for the synthesis of (-)-psathyrin A and related complex diterpenoids.