Lessons from Natural Product Total Synthesis: Macrocyclization and Postcyclization Strategies

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Macrocyclic natural products are prevalent across all domains of life and are vital sources of therapeutic agents.
• Nature efficiently synthesizes macrocycles, but their chemical synthesis has historically been challenging due to entropic loss and ring strain.
• Advances in synthetic methodologies have significantly eased the 'macrocycle challenge,' enabling broader exploration of these structures.

Purpose of the Study:

• To review the current state of synthetic strategies for accessing macrocyclic natural products.
• To highlight recent advancements in macrocyclization reactions and their application in total synthesis.
• To explore the potential of macrocyclic compounds in expanding the chemical space for drug development.

Main Methods:

• Presentation of case studies involving total synthesis of diverse macrocyclic natural products.
• Utilized a variety of transformations, including classical macrolactonization/macrolactamization and metal-catalyzed reactions.
• Emphasized palladium-catalyzed C-C bond formation, alkene, and alkyne metathesis, as well as transannular gold and ruthenium catalysis.

Main Results:

• Demonstrated that macrocycle formation is no longer a primary limitation in total synthesis.
• Showcased the effectiveness of metal-catalyzed reactions, particularly metathesis, in constructing macrocyclic frameworks.
• Illustrated the utility of post-macrocyclization strategies, including dual-use functional groups and transannular reactions, for increasing molecular complexity.

Conclusions:

• The diminishing 'macrocycle challenge' allows for increased focus on post-cyclization modifications and complex molecule construction.
• Strategic design of cyclization precursors can streamline subsequent synthetic steps.
• Emerging catalytic methods, such as transannular gold and ruthenium catalysis, offer powerful tools for functionalizing macrocycles and accessing complex architectures.