The Wang ester linker can be cleaved with ammonia to generate primary carboxamide, but this is
a difficult reaction, that is very slow with sterically hundred amino acids such as valine.
A prolonged treatment with ammonia could lead to a racemisation of chiral peptides.
Chemists developed a linking group that would generate carboxamide in mild acidic conditions.
The first developed was the methylbenzhydrylamine (MBHA) linker on polystyrene for improved
synthesis of peptides using the Boc protection strategy. Sieber developed a new linker with
greater acid lability. He used a xanthenyl derivate. The acid-labile 9-xanthenyl group has
been used to protect the amide group of asparagine and glutamine.
As the xanthenyl group is less acid-labile than Boc, an additional –OCH2- group was introduced between the anchor and polystyrene to increase acid-lability.
An other acid-labile linker was developed in the same time. The rink linker is now preferred for generating primary carboxamide on solid phase. The greater acid sensitivity in this linker is a consequence of the two additional electron donating methoxy group. In the generation of primary carboxamide, the starting material is attached to the linker as a carboxylic acid and after synthetic modification is cleaved from the resin with TFA.
The use of Rink resin to produce carboxamide following TFA-catalysed cleavage.
