Aspartimide formation remains a persistent challenge in Fmoc solid phase peptide synthesis. This review surveys strategies to prevent aspartimide formation, covering protecting group design, backbone protection, and alternative deprotection approaches. Continued development of scalable, compatible tactics is key to advancing 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.