Total Synthesis of (±)-Dhilirolide U

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Dhilirolides are a family of complex meroterpenoids with a densely functionalized pentacyclic skeleton.
• The specific biological activities and therapeutic potential of dhilirolides remain areas of active investigation.
• The intricate structure of dhilirolides presents significant synthetic challenges.

Purpose of the Study:

• To report the first total synthesis of (±)-dhilirolide U.
• To develop a synthetic strategy for constructing the characteristic bicyclo[3.2.1]octane fused to a γ-lactone motif found in dhilirolides.
• To establish a synthetic blueprint for accessing other members of the dhilirolide family.

Main Methods:

• A manganese(III)-mediated cyclization sequence was employed to initiate the construction of the pentacyclic core.
• A Payne-type rearrangement cascade was utilized to efficiently form the bicyclo[3.2.1]octane fused to a γ-lactone.
• Intramolecular nickel-catalyzed conjugate addition was key for installing vicinal quaternary carbon centers.
• Subsequent steps focused on building the tetrahydroisochromenone subunit to complete the target molecule.

Main Results:

• The total synthesis of (±)-dhilirolide U was successfully achieved.
• The key Mn(III)-mediated cyclization and Payne rearrangement cascade proceeded in high yields with excellent diastereocontrol.
• The intramolecular Ni-catalyzed conjugate addition effectively installed the challenging vicinal quaternary carbon centers.
• The synthetic route provided access to the highly decorated bicyclo[3.2.1]octane core structure.

Conclusions:

• The developed synthetic strategy provides a viable route to (±)-dhilirolide U.
• The methodology offers a versatile blueprint for the synthesis of diverse and complex dhilirolide meroterpenoids.
• This work expands the synthetic toolkit for accessing complex polycyclic natural products.