The group that joins the substrate to the resin bead is an essential part of solid phase synthesis. The linker is a specialised protecting group, in that much of the time, the linker will tie up a functional group, only for it to reappear at the end of the synthesis. The linker must not be affected by the chemistry used to modify or extend the attached compound. And finally the cleavage step should proceed readily and in a good yield. The best linker must allow attachment and cleavage in quantitative yield.
Carboxylic acid linkers
The first linking group used for peptide synthesis bears the name of the father of solid phase synthesis. Merrifield resin is cross-linked polystyrene functionalised with a chloromethyl group. The carbonyl group is attached by the nucleophilic displacement of the chloride with a cesium carboxylate salt in DMF. Cleavage to regenerate the carboxylic acid is usually achieved by hydrogen fluoride.
The second class of linker used for carboxylic acid is the Wang linker. This linker is generally attached to cross-linked polystyrene, TentaGel and polyacrylamide to form Wang resin. It was designed for the synthesis of peptide carboxylic acids using the Fmoc-protection strategy, and due to the activated benzyl alcohol design, the carboxylic acid product can be cleaved with TFA.
A more acid-labile form of the Wang resin has been developed. The SASRIN resin has the same structure as the Wang linker but with the addition of a methoxy group to stabilise the carbonium ion formed during acid catalysed cleavage.
