Improving the performance of an acid-labile 4-hydroxymethyl phenoxyacetic acid (HMP) linker on resin and SynPhase grafted solid-supports.

A replacement of the acetic acid moiety by valeric acid within the 4-hydroxymethylphenoxyacetic acid (HMP) linker (Sheppard RC, Williams BJ. Acid-labile resin linkage agents for use in solid phase peptide synthesis. Int. J. Peptide Protein Res. 1982; 20: 451-454) significantly improved its performance in terms of loading capacity, yield and purity of the final products. The results indicated the spacer-linker combination and type of solid supports are important factors for solid-phase synthesis.

Comparative study of reductive amination reaction on 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid and its monomethoxy analog using the Multipin approach.

The 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid (Barany) linker and its monomethoxy analog were applied to the Multipin method of solid phase synthesis. A comparative assessment of reductive amination and cleavage of these linkers under conditions of multiple synthesis indicated that both were applicable to a broad range of primary amines including aniline and 4-nitroaniline. Apart from the greater lability of the dimethoxy version under TFA cleavage, there was no observable advantage of one linker over the other within the described experiment.