Synthesis of Macrocyclic Structures by Intramolecular Photoclick Reaction

Area of Science:

• Organic Chemistry
• Chemical Synthesis
• Macrocyclic Chemistry

Background:

• Macrocycles are crucial in various fields, including medicine and materials science.
• Efficient synthesis of medium- to large-sized macrocycles remains a synthetic challenge.
• Strain-promoted azide-alkyne cycloaddition (SPAAC) offers a bioorthogonal approach to cyclization.

Purpose of the Study:

• To develop an efficient method for synthesizing medium- to large-sized macrocycles.
• To explore the utility of photo-SPAAC reactions for macrocyclization.
• To investigate sequential SPAAC-photo-SPAAC reactions for macrocycle synthesis.

Main Methods:

• Photo-SPAAC cyclization of bifunctional linear molecules containing a cyclopropenone-caged dibenzocyclooctyne and an azide group.
• SPAAC-photo-SPAAC reaction sequence involving monobifunctional dibenzocyclooctadiyne or bis-dibenzocyclooctynes with bis-azides.
• Density Functional Theory (DFT) analysis of SPAAC cyclization pathways.

Main Results:

• Photo-SPAAC reactions afforded macrocycles with 18- to 51-membered rings in high to quantitative yields.
• High effective molarity was observed for bifunctional cyclooctyne-azide linear molecules in both solution and neat states.
• SPAAC-photo-SPAAC sequences successfully produced macrocycles with 17- to 34-membered rings in high yields, with minimal dimeric byproducts in some cases.

Conclusions:

• Photo-SPAAC is a powerful tool for the efficient synthesis of diverse medium- to large-sized macrocycles.
• The developed methods offer high yields and control over macrocycle formation.
• These reactions represent a significant advancement in macrocyclic chemistry, applicable to various synthetic challenges.