Continuous Flow Processes as an Enabling Tool for the Synthesis of Constrained Pseudopeptidic Macrocycles

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Process Chemistry

Background:

• Macrocyclic compounds are important in medicinal chemistry.
• Traditional batch synthesis of complex macrocycles can be inefficient and environmentally taxing.
• Developing scalable and sustainable synthetic methodologies is crucial.

Purpose of the Study:

• To develop a continuous flow methodology for preparing pseudopeptidic macrocycles.
• To optimize the macrocyclization process involving four coupled substitution reactions.
• To enhance productivity and reduce the environmental footprint of macrocycle synthesis.

Main Methods:

• Utilized a continuous flow reactor system for macrocyclization.
• Employed a specifically designed supported base to facilitate the reaction.
• Leveraged the template effect of bromide anions for efficient macrocycle formation.
• Investigated a four-step coupled substitution reaction sequence within the macrocyclization process.

Main Results:

• Achieved efficient, continuous production of pseudopeptidic macrocycles with the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold.
• Demonstrated a ca. 20-fold increase in productivity using flow protocols.
• Reduced the environmental impact by nearly two orders of magnitude compared to batch processes.
• Showcased the effectiveness of the supported base and bromide anion template effect at large scales.

Conclusions:

• Continuous flow methodology offers a highly efficient and scalable route for pseudopeptidic macrocycle synthesis.
• The developed method significantly improves productivity and sustainability in macrocycle preparation.
• This approach provides a greener alternative to conventional batch macrocyclization processes.