Convergent Total Synthesis of (-)-Calidoustene

Area of Science:

• Organic Chemistry
• Natural Product Synthesis

Background:

• Sesterterpenoids are a class of natural products with diverse biological activities.
• The total synthesis of complex natural products presents significant challenges in stereocontrol and ring construction.

Purpose of the Study:

• To report the first total synthesis of the sesterterpenoid (-)-calidoustene.
• To develop and showcase novel synthetic methodologies for constructing complex polycyclic frameworks.

Main Methods:

• Stereoselective Michael/aldol cascade for trans-hydrindane backbone construction.
• Tandem Pummerer/Sakurai cyclization for bicyclo[3.2.1]octane framework establishment.
• Metallaphotoredox enone coupling and MHAT-initiated cyclization for C-ring formation.
• Late-stage functionalization including Cu-catalyzed desaturation and diimide reduction.

Main Results:

• Successful completion of the first total synthesis of (-)-calidoustene.
• Demonstration of a cascade reaction for efficient backbone construction.
• Establishment of a novel method for forging a congested bicyclic system.
• Efficient late-stage modifications to achieve the final target.

Conclusions:

• The developed synthetic route provides a viable pathway to (-)-calidoustene.
• The employed methodologies offer powerful tools for the synthesis of other complex natural products.
• This synthesis expands the accessibility of sesterterpenoids for further biological investigation.