Aspartimide Formation and Its Prevention in Fmoc Chemistry Solid Phase Peptide Synthesis

Aspartimide formation remains a persistent challenge during Fmoc chemistry solid phase peptide synthesis. This review outlines various strategies to suppress base-mediated aspartimide formation, including the use of ester β-carboxyl protecting groups, non-ester-based β-carboxyl masking groups, and backbone-protecting groups. In addition, alternatives to the Fmoc group are explored that are cleavable under nonbasic conditions. The work discussed in this review highlights that the continued development of compatible and scalable tactics toward aspartimide prevention is essential for advancing peptide synthesis in both research and industry.