Pushing the limits of solid-phase peptide synthesis with continuous flow

© 2018 Georg Thieme Verlag. All rights reserved. Since its invention by Bruce Merrifield, solid-phase peptide synthesis has conventionally been performed in batch reactors. With systems created by Atherton, Dryland, and Sheppard in the 1980s, flow-chemistry techniques began to be applied to enhance solid-phase peptide synthesis, improving mixing and enabling time-resolved monitoring of Fmoc removal. Here, we review the history of flow-chemical techniques for solid-phase peptide synthesis, advances in solid supports that make flow chemistry on the solid phase feasible, the rationale behind using flow chemistry for amino acid activation, and other techniques for synthesizing peptides in flow, including the use of solid-supported coupling reagents and soluble macromolecular supports. Advantages of flow-chemistry techniques for both solid- and liquid-phase peptide synthesis include precise control of reagent heating and chiral integrity of incorporated amino acids, improvements in amino acid coupling times, and in-process detection of problematic peptide sequences.