Carbocations in action. Design, synthesis, and evaluation of a highly acid-sensitive naphthalene-based backbone amide linker for solid-phase synthesis.

The design, synthesis, and properties of an extremely acid-labile backbone amide linker based on a regiospecifically substituted tetraalkoxy naphthaldehyde core are presented. This handle enables cleavage of peptide backbone amides (secondary amides) off a solid support using as little as 0.5% TFA in CH2Cl2. This proceeds without cleavage of tert-butyl ethers and tert-butyl esters. The design is based on a DFT study that predicted the most stabile alkoxy-substituted methyl naphthyl carbocation. [structure: see text]