In solid phase peptide synthesis, a linker is a molecule that connects the solid phase (a beaded resin support) to the growing peptide chain. The linker is often permanently attached to the solid phase, but carries a transient covalent bond to the peptide (typically its C-terminus) that can be cleaved after completion of the synthesis to release the peptide. Cleavage can take place under various conditions depending on the linker type and result in different C-terminal functionalities of the released peptide, e.g. amides, carboxylic acids, esters, lactams, etc. Linkers that do not attach via the C-terminus do also exist.
Examples
+ Linker First reported use C-Terminal outcome Protecting group chemistry Stability to deprotection conditions Typical cleavage conditions Merrifield 1963 Carboxylic acid Boc Unstable in neat TFA Anhydrous HF Rink Amide 1987 Amide Fmoc Stable to 20% piperidine 95% TFA in dichloromethane Wang 1973 Carboxylic acid Fmoc Stable to 20% piperidine 50-95% TFA in dichloromethane Sieber 1987 Amide Fmoc Stable to 20% piperidine 1-5% TFA in dichloromethane 4-(Hydroxymethyl)benzoic acid 1981 Carboxylic acid, amide, ester, lactam, etc. (depends on cleavage conditions) Fmoc Stable to 20% piperidine (diketopiperazine formation risk after deprotection of 2nd amino acid) Nucleophilic base o-Nitrobenzyl 1975 Amide Fmoc Stable to TFA and 20% piperidine UV light
References