Programmable meroterpene synthesis

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• The bicyclo[3.3.1]nonane core is prevalent in over 1000 natural products, exhibiting bioactivity against neurodegenerative diseases, infections, and cancer.
• Meroterpenes, natural products of mixed polyketide/terpenoid origin, are a significant source of bicyclo[3.3.1]nonane-containing compounds.

Purpose of the Study:

• To establish a general synthetic strategy for accessing bicyclo[3.3.1]nonane-containing natural products.
• To achieve the total synthesis of garsubellin A, a known enhancer of choline acetyltransferase.

Main Methods:

• Development of an abiotic annulation/rearrangement strategy.
• A 10-step total synthesis of garsubellin A was executed.
• Demonstration of a programmable assembly process for diverse meroterpene chemotypes.

Main Results:

• Successful 10-step total synthesis of garsubellin A.
• Validation of a versatile synthetic strategy for bicyclo[3.3.1]nonane derivatives.
• The strategy allows for the creation of multiple, diverse meroterpene chemotypes.

Conclusions:

• The developed synthetic strategy provides efficient access to the bicyclo[3.3.1]nonane scaffold.
• This approach facilitates the synthesis of biologically relevant meroterpenes.
• The programmable assembly offers a pathway to novel therapeutic agents.