Towards green, scalable peptide synthesis: leveraging DEG-crosslinked polystyrene resins to overcome hydrophobicity challenges.

Diethylene glycol dimethacrylate (DEG)-crosslinked polystyrene (PS) resin offers a promising alternative to traditional divinyl benzene (DVB)-PS resin for solid-phase peptide synthesis (SPPS), particularly for challenging sequences with hydrophobic or bulky amino acids. DEG-PS resin's reduced hydrophobicity and enhanced flexibility improve synthesis efficiency, yielding peptides up to 28 residues with higher purities and yields compared to DVB-PS. In various syntheses, DEG-PS outperformed DVB-PS resin, with higher purities and yields for challenging peptides such as ABC analogue (73.2%, 58.3% vs. 72.5%, 46.3%) and Thymosin (58.4%, 48.6% vs. 54.0%, 39.2%). In addition, DEG-PS resin effectively suppressed common side reactions, such as dipeptide formation, typically encountered with Wang PS-based resins. Incorporating green chemistry principles, DEG-PS enabled the synthesis of complex peptides with satisfactory results using environmentally friendly solvents and reagents. Three challenging peptides; β (34-42), Jung and Redemann (JR), and ABRF 1992 - were synthesized on DEG-PS resin, achieving purities of 41.4%, 41.0%, and 68.0%, and yields of 50.5%, 52.6%, and 56.2%, respectively. These findings highlight DEG-PS resin's advantages for classical, green, and automated SPPS, offering superior performance and scalability for industrial applications.