Solid-phase synthesis of substituted guanidines using a novel acid labile linker

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Solid-phase synthesis is a powerful technique for generating chemical libraries.
• Developing efficient linkers is crucial for expanding the scope of solid-phase synthesis.
• Guanidine motifs are prevalent in biologically active molecules.

Purpose of the Study:

• To develop and characterize a novel acid-labile linker for solid-phase synthesis of substituted guanidines.
• To demonstrate the utility of the linker through high-yielding reactions with diverse amines.
• To showcase the linker's capability in constructing complex guanidine libraries.

Main Methods:

• Development of an acid-labile linker designed for solid-phase synthesis.
• Pyrazole displacement reactions utilizing structurally diverse aliphatic and aromatic amines.
• Acid-catalyzed cleavage using trifluoroacetic acid/water mixture for final product release.
• Mitsunobu N-alkylation for subsequent modifications.

Main Results:

• The novel linker facilitates high-yielding pyrazole displacement reactions.
• Substituted guanidines were obtained in high purity (80-95%) and good isolated yields (50-95%).
• Successful synthesis of an 880-member library of trisubstituted arylguanidines was achieved, demonstrating linker versatility.

Conclusions:

• The developed acid-labile linker is a valuable tool for the efficient solid-phase synthesis of diverse guanidines.
• The linker's robustness and compatibility with subsequent reactions like Mitsunobu alkylation are confirmed.
• This methodology significantly advances the construction of guanidine-based compound libraries for potential therapeutic applications.