Kinetically E-selective macrocyclic ring-closing metathesis.

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Macrocyclic compounds are vital in drug discovery, but their synthesis, particularly stereoselective E-olefin formation, is challenging.
• Existing ring-closing metathesis (RCM) methods often struggle with E-olefin selectivity or require material-intensive purification.
• The energetic favorability of E-alkenes can be compromised by adventitious olefin isomerization during synthesis.

Purpose of the Study:

• To develop a novel, stereoselective catalytic method for synthesizing macrocyclic E-olefins.
• To overcome the limitations of existing RCM techniques for accessing E-macrocyclic alkenes.
• To demonstrate the utility of the new method in synthesizing biologically relevant macrocyclic compounds.

Main Methods:

• Utilized dienes featuring an E-alkenyl-B(pinacolato) group as precursors for ring-closing metathesis.
• Employed a molybdenum monoaryloxide pyrrolide complex as the catalyst for the RCM reaction.
• Investigated the stereoselectivity and yield of the RCM reaction for macrocyclic E-olefin formation.

Main Results:

• Achieved stereoselective conversion of dienes to macrocyclic E-olefins with high E/Z ratios (>98/2).
• Obtained product yields of up to 73% using the molybdenum-based catalyst.
• Successfully synthesized biologically active macrocycles, including recifeiolide and pacritinib, demonstrating the method's practical utility.

Conclusions:

• The developed molybdenum-catalyzed RCM provides an efficient and highly stereoselective route to macrocyclic E-olefins.
• This method overcomes significant challenges in synthesizing E-macrocyclic alkenes, offering advantages over existing techniques.
• The approach is valuable for preparing complex pharmaceutical compounds, as exemplified by the synthesis of pacritinib at high substrate concentration.