Two dialkoxynaphthalene aldehydes as backbone amide linkers for solid-phase synthesis

Two new solid-phase handles for backbone amide anchoring based on regioisomeric dialkoxynaphthalene aldehydes (NALdehydes) were synthesized in five convenient steps from the corresponding commercially available dihydroxynaphthalenes. The two NALdehydes were coupled to an aminomethyl polystyrene support, the first monomer attached by efficient reductive amination, and the secondary amine acylated to form naphthalene amide linker (NAL-1 and NAL-2) anchoring. After on-resin synthesis, release of peptides was effected with TFA/H2O (95:5), TFA/DCM (50:50), or low TFA concentrations. The properties of the NAL handles were evaluated in the solid-phase synthesis of a series of peptides, in which NAL-2 showed the best cleavage properties.