Synthesis of ( R)- and ( S)-Fmoc-Protected Diethylene Glycol Gamma PNA Monomers with High Optical Purity

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Polymer Science

Background:

• Peptide nucleic acids (PNAs) are DNA mimics with therapeutic potential.
• Optically pure PNA monomers are crucial for PNA synthesis.
• Existing synthetic routes can suffer from epimerization and low yields.

Purpose of the Study:

• To develop a robust and scalable synthetic route for optically pure, Fmoc-protected diethylene glycol-containing gamma-PNA monomers.
• To suppress epimerization during key synthetic steps.

Main Methods:

• Utilized 9-(4-bromophenyl)-9-fluorenyl as a temporary, safety-catch protecting group.
• Employed O-alkylation and reductive amination reactions.
• Assessed optical purity using 19F-NMR and HPLC.

Main Results:

• Achieved >99.5% enantiomeric excess (ee) for both (R)- and (S)-gamma-PNA monomers.
• Demonstrated excellent chemical yields in most synthetic steps.
• Developed a method suitable for large-scale monomer production without extensive chromatography.

Conclusions:

• The developed synthetic strategy provides a reliable method for producing high-purity gamma-PNA monomers.
• The use of the novel protecting group effectively prevents epimerization.
• This methodology facilitates large-scale manufacturing of PNA building blocks.