Divergent and programmable skeletal remodeling of complex macrocycles with a small method set

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• The bioactivity of macrocycles is highly dependent on their 3D structure.
• Modifying macrocyclic structures is challenging but crucial for drug discovery.

Purpose of the Study:

• To develop a systematic and programmable strategy for skeletal remodeling of large organic rings.
• To create a diverse library of macrocyclic analogs for potential therapeutic applications.

Main Methods:

• Utilized a central diversification platform (hub) based on macrocyclic olefins or dienes.
• Employed six key transformations including ring-opening/cross-metathesis, cross-metathesis, allylic substitution, alkene isomerization, ethenolysis, and ring-closing metathesis.
• The majority of transformations were catalytic and performed under mild conditions.

Main Results:

• Successfully generated fourteen analogs of the anti-cancer agent epothilone C.
• Demonstrated a divergent network of reactions from the diene hub.
• Achieved an average of three steps per analog synthesis from the diene hub.

Conclusions:

• The presented strategy offers a practical, efficient, and iterative approach for macrocycle skeletal remodeling.
• This method facilitates the rapid generation of diverse macrocyclic compounds.
• The approach is amenable to accessing analogs of biologically active molecules like epothilone C.