Role of the peri-effect in synthesis and reactivity of highly substituted naphthaldehydes: a novel backbone amide linker for solid-phase synthesis

Abstract

Handles (linkers) with an aldehyde functionality that permits the anchoring of substrates by reductive amination have, since their first report in the mid-1990s, become widely-used tools in solid-phase synthesis. In the synthesis of peptides, they allow anchoring of the growing peptide chain through a backbone amide, thus giving easy access to C-terminal modified or cyclic peptides. Recently, we described two new handles (NAL-1 and NAL-2) with dialkoxynaphthaldehyde core structures. Here, we describe the design, synthesis and properties of a novel trialkoxynaphthalene-based backbone amide linker (NAL-3). The NAL-3 handle is based on a trialkoxynaphthaldehyde (NALdehyde-3) that was synthesized in nine high-yielding steps from 3-methoxyphenylacetic acid in 51% overall yield. The naphthalene ring system was constructed using a regioselective methanesulfonic acid-catalyzed ring-closing reaction. The tetra-substituted naphthalene derivative 1,3,6-trimethoxynaphthalene-2-carbaldehyde (7) was selectively demethylated in the 1 position using BBr₃. The selectivity of this reaction is discussed, based on the crystal structures of reactant and product, 1-hydroxy-3,6-dimethoxy-naphthalene-2-carbaldehyde (8), and in the context of the peri-effect. The new handle was anchored to an aminomethylated poly(styrene) solid support, followed by assembly of a model dipeptide, then a study of the cleavage properties under acidic conditions was carried out. Surprisingly, the trialkoxynaphthaldehyde-based handle proved less acid-labile than the dialkoxynaphthaldehyde handles, and this fact is discussed with respect to handle design.