A detailed scientific explanation of Fmoc-based solid-phase peptide synthesis (SPPS) — the method used to manufacture virtually all modern research and therapeutic peptides. Covers the historical development from Merrifield's original Boc chemistry to the modern Fmoc/tBu strategy, the chemistry of each step in the synthesis cycle (resin loading, Fmoc deprotection via piperidine-mediated beta-elimination, amino acid activation and coupling, washing), the role of resins and linkers (Wang, Rink amide, 2-chlorotrityl), coupling reagent chemistry (HATU, DIC/OxymaPure, carbodiimides), common side reactions (aspartimide formation, racemization, deletion sequences, aggregation), monitoring methods (Kaiser test, UV absorbance), TFA cleavage cocktails and scavenger selection, automation and microwave-assisted synthesis, the recent wash-free SPPS breakthrough reducing solvent waste by 95%, and practical considerations for difficult sequences.
Mar 10, 2026
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18 min read
SPPS
Fmoc
Solid Phase