Greener Liquid-Phase Synthesis of Pseudoproline Dipeptide Building Blocks in Ethanol and Water

A sustainable synthetic strategy for Fmoc-protected pseudoproline dipeptides was developed to address the environmental and operational limitations of traditional solvent-intensive methods. By utilizing ethanol as solvent during cyclisation, activated ester formation, and coupling steps, this approach eliminates the need for hazardous conventional solvents while simplifying the overall process. The protocol consistently delivers pseudoproline dipeptides in high yields and with excellent purity, demonstrating that environmentally friendly modifications can maintain strong synthetic performance. In addition to its operational simplicity and scalability, the method significantly reduces solvent-related hazards, minimizes waste generation, and improves key green chemistry. This practical and versatile methodology provides a cleaner, more sustainable platform for the synthesis of pseudoproline-containing intermediates relevant to peptide and pharmaceutical manufacturing.