Morpholine, a strong contender for Fmoc removal in solid-phase peptide synthesis

Area of Science:

• Organic Chemistry
• Peptide Synthesis
• Green Chemistry

Background:

• Solid-phase peptide synthesis (SPPS) commonly uses piperidine for Fmoc removal.
• Piperidine use can lead to side reactions like diketopiperazine and aspartimide formation.
• There is a need for greener and safer reagents in SPPS.

Purpose of the Study:

• To evaluate morpholine as a greener alternative to piperidine for Fmoc removal in SPPS.
• To assess the efficiency and selectivity of morpholine in Fmoc deprotection.
• To compare the purity of peptides synthesized using morpholine versus piperidine.

Main Methods:

• Fmoc removal using 50%-60% morpholine in dimethylformamide (DMF).
• Synthesis of somatostatin as a model peptide.
• Analysis of peptide purity and side-product formation.

Main Results:

• Morpholine efficiently removed Fmoc in SPPS.
• Morpholine minimized diketopiperazine and aspartimide formation.
• Somatostatin synthesized with morpholine showed comparable purity to that synthesized with piperidine.

Conclusions:

• Morpholine is a viable and greener alternative for Fmoc removal in SPPS.
• Morpholine-based Fmoc removal offers improved selectivity and reduced side reactions.
• This method supports the development of more sustainable peptide synthesis protocols.