N,O-Bis-Fmoc (fluoren-9-ylmethoxycarbonyl) derivatives of N~-(2-hydroxy-4-methoxybenzyl)amino acids 5 are useful intermediates for the preparation of peptides with reversibly protected (tertiary) peptide bonds; their value in inhibiting interchain association during solid phase peptide synthesis is demonstrated.

2-Hydroxy-4-methoxybenzyl-amino acid residues inhibit interchain association in solid phase peptide synthesis. They are easily introduced through their N,O-bisFmoc derivatives. Preparation of a range of these derivatives is described.

Piperidine-mediated aspartimide and subsequent piperidide formation, during Fmoc-based synthesis of sensitive aspartyl ([3-tert-butyl ester, 0But)-containing peptides, is completely suppressed by the use of Hm b protection of the aspartyl amide bond.

Case studies of the solid‐phase synthesis of some ‘difficult sequences’ using continuous‐flow Fmoc‐polyamide techniques are presented. Solvent change and peptide side chain and backbone modification procedures recently found to reduce association effects are applied, and the results compared to syntheses under standard conditions.

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