Stereoselectivity of macrocyclic ring-closing olefin metathesis

Area of Science:

• Organic Chemistry
• Catalysis
• Macromolecular Chemistry

Background:

• Macrocyclic compounds are important in pharmaceuticals and materials science.
• Ring-closing metathesis (RCM) is a powerful tool for macrocycle synthesis.
• Controlling stereochemistry in RCM, particularly E/Z ratios, remains a challenge.

Purpose of the Study:

• To investigate the synthesis of 14-membered lactones via macrocyclic RCM.
• To determine the factors influencing the E/Z stereochemistry of the resulting lactones.
• To elucidate the mechanistic basis for the observed stereochemical outcomes.

Main Methods:

• Macrocyclic ring-closing olefin metathesis was employed using a specific ruthenium catalyst (catalyst 3).
• The reaction was performed with varying R groups (auxiliaries) and initial alkene stereochemistries.
• Kinetic studies were conducted to analyze the reaction mechanism and product formation over time.

Main Results:

• The synthesis successfully produced 14-membered lactones with high efficiency.
• A high E/Z ratio of the lactone product was consistently observed, irrespective of the auxiliary or initial alkene stereochemistry.
• Kinetic analysis revealed that secondary metathesis reactions drive the product towards its thermodynamic E/Z ratio.

Conclusions:

• Ruthenium catalyst 3 is effective for synthesizing 14-membered lactones via macrocyclic RCM.
• The high E/Z selectivity is a result of product isomerization driven by secondary metathesis.
• This study provides insights into controlling stereochemistry in macrocyclic metathesis reactions.