The renascence of continuous-flow peptide synthesis – an abridged account of solid and solution-based approaches

Abstract

Within a decade of Merrifield's seminal description of solid-phase peptide synthesis, the synergies between solid-phase approaches and flow synthesis were noted by a number of groups. However, despite the various advantages flow brings to peptide synthesis, throughout the 1990s and 2000s, interest in the technique was overshadowed by microwave assisted approaches. However, the current expansion of flow technologies has reinvigorated interest in both solid-phase and solution-phase continuous-flow approaches for assembling peptides. This perspective traces the introduction and evolution of continuous-flow solid-phase synthesis from a practical aspect with a particular focus on solid supports, acylation protocols, and racemisation suppression. Practical aspects of solution-phase continuous-flow peptide synthesis are also considered with an evaluation of microreactor systems, coupling protocols, and fragment-based approaches for assembly of extended peptide units.