title: 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 BBr(3). 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.
authors.affiliation: Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Pittelkow
authors.forename: Ulrik
authors.initials: U
authors.lastname: Boas
authors.forename: Mikkel
authors.initials: M
authors.lastname: Jessing
authors.forename: Knud J
authors.initials: KJ
authors.lastname: Jensen
authors.forename: Jørn B
authors.initials: JB
authors.lastname: Christensen
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000577:Amides; D009281:Naphthalenes