Synthesis of cyclooctyne-sulfamates by the Nicholas cyclisation

Area of Science:

• Organic Chemistry
• Click Chemistry
• Chemical Synthesis

Background:

• Strain-promoted azide-alkyne cycloaddition (SPAAC) is a key bioconjugation technique.
• Cyclooctyne derivatives are essential reagents for SPAAC.
• Developing novel, stable, and reactive cyclooctyne scaffolds is crucial for advancing bioconjugation.

Purpose of the Study:

• To explore the Nicholas cyclisation as a synthetic method for cyclooctyne-sulfamates.
• To evaluate the stability and reactivity of monocyclic and benzene-fused cyclooctyne-sulfamates in SPAAC.
• To understand the structural and electronic factors influencing the performance of these SPAAC reagents.

Main Methods:

• Synthesis of cyclooctyne-sulfamates using Nicholas cyclisation.
• Preparation of Co2(CO)6-complexes for stabilization and characterization.
• Cobalt deprotection to yield free cyclooctynes.
• Kinetic studies of SPAAC reactions with benzyl azide.
• Density Functional Theory (DFT) calculations for theoretical analysis.

Main Results:

• Successfully synthesized monocyclic and benzene-fused cyclooctyne-sulfamates via Nicholas cyclisation.
• The monocyclic cyclooctyne-sulfamate (SNO-Me2) demonstrated stability and efficient SPAAC reactivity (k = 0.0163 M-1 s-1).
• Benzene-fused analogues (B-SNO, B-SNO-Me2) exhibited kinetic instability.
• DFT calculations elucidated the impact of benzene-fusion and methyl groups on stability and reactivity.

Conclusions:

• Nicholas cyclisation is a viable method for preparing cyclooctyne-sulfamate SPAAC reagents.
• Monocyclic cyclooctyne-sulfamates are promising for SPAAC applications due to their stability and reactivity.
• Benzene-fusion significantly compromises the stability of these cyclooctyne derivatives.
• Structural modifications like propargylic methylation influence the overall performance of SPAAC reagents.