Peptide-directed solid-phase reductive amination

Abstract

We report an integrated solid-phase reductive amination/solid-phase fragment condensation (SPFC) strategy for the replacement of amide bonds in peptide sequences with the aminomethylene Ψ[CH₂–NH] amide isostere. N-Fmoc-protected C-terminal peptide α-amino aldehydes were prepared and condensed with the N-terminus of peptide sequences assembled on 2-chlorotrityl chloride (CLTR) resin, followed by efficient imine reduction under mild conditions. Epimerization at the reacting α-amino aldehyde was below 10%, typically in the range of 1–7%. Cleavage from the resin under mild acidic conditions afforded peptides in which native amide bonds were selectively replaced by Ψ[CH₂–NH] linkages. In addition, this methodology enables the preparation of suitably protected Ψ[CH₂–NH]-containing peptide fragments that are compatible with further solid-phase, fragment-based, or convergent peptide synthesis and modification strategies. The methodology constitutes a general and versatile tool for selective peptide backbone modification with relevance to the development of peptides and peptidomimetics with improved properties and applications in drug design.