Application of base cleavable safety catch linkers to solid phase library production

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Polymer Chemistry

Background:

• Solid-phase synthesis is crucial for creating compound libraries in drug discovery.
• Efficient cleavage of diverse functional groups from solid supports remains a challenge.
• Existing sulfone resins have limitations in cleavage speed and conditions.

Purpose of the Study:

• To develop a novel "Safety Catch" linker system for anchoring medicinal chemistry functional groups to amine resins.
• To investigate the cleavage efficiency and conditions of the new sulfide linker.
• To evaluate the application of this strategy in generating diverse compound libraries.

Main Methods:

• Anchoring functional groups (esters, carbamates, amines) to amine resins using sulfide "Safety Catch" linkers.
• Activating the linker with peracid followed by beta-elimination cleavage.
• Cleavage performed in gas phase or solution using secondary amines.
• Comparison of cleavage rates with existing sulfone resins (e.g., SEM).

Main Results:

• The sulfide "Safety Catch" linker system demonstrated significantly faster cleavage rates than other sulfone resins.
• Cleavage conditions were compatible with standard Fmoc deprotection protocols.
• Application to a medicinal chemistry library resulted in good yields and high purities of target compounds.
• The method successfully produced acids and primary, secondary, or tertiary amines.

Conclusions:

• The sulfide "Safety Catch" linker strategy provides an efficient and rapid method for solid-phase synthesis.
• This approach is versatile, accommodating various functional groups and cleavage products.
• The system's compatibility and efficiency make it highly suitable for medicinal chemistry library synthesis.