Highly Convenient Gram-Scale Solution-Phase Peptoid Synthesis and Orthogonal Side-Chain Post-Modification

Abstract

This paper describes the development of a highly convenient solution-phase methodology using volatile amines for the synthesis of b-, a,b-and a-tetrapeptoids, as an alternative to solid-phase technologies. Column chromatographic purifications are reduced to a minimum and the majority of the intermediates are purified by filtration and/or evaporation. The method is amenable to gram-scale synthesis of peptoids, and post-modification of a model peptoid by successive and selective ligations, using click thiol-ene coupling, and copper-catalysed azide-alkyne cycloaddition is demonstrated.There has been considerable interest in developing pseudopeptide oligomers with reduced complexity that are able to fulfill the functions of their natural peptide counterparts, without drawbacks such as low half-life and limited bioavailability. 2 Oligomers of N-substituted glycines, or a-peptoids, were developed in the early 1990s as a new type of simple peptidomimetic. They are characterised by resistance to proteases, rapid cellular uptake, a large potential for diversity and straightforward syntheses. 3 The first synthesis of oligomers of N-substituted balanines, or b-peptoids, followed later in the same decade. 4 In addition, we have recently communicated our initial studies on a new family of a,b-alternating peptoids. 5 Structurally, peptoids differ from peptides in that the side chains are attached to the amide nitrogen rather than to the a-or b-carbon. The peptoid backbone is therefore achiral and does not contain any amide protons. In spite of this, peptoids can still be driven to form secondary structures such as helices if a-chiral side chains are incorporated. 6 Peptoids have attracted significant interest and have been used in a number of important biological applications. 7The structural simplicity of the peptoids allows for their synthesis using a unique 'submonomer' protocol in which the peptoid residues are created directly on a growing chain, in an iterative manner. Highly efficient procedures have been developed for solid-phase synthesis of peptoids. However, our research project aimed at using b-and a,b-peptoids as scaffolds for multivalent ligand display 8 necessitates the development of efficient solution-phase methodologies which are able to provide large quantities of peptoids in a manner competitive with solid-phase synthesis. Accordingly, our published methodology for iterative solution-phase synthesis of peptoids (Scheme 1) has provided improvements, in terms of cost and time, compared to earlier techniques. 5Briefly, the peptoid residues are created in two steps by acylation of the N-terminus, followed by reaction of the acylated intermediate with an appropriate amine. By using tetrahydrofuran as the solvent for the acylation steps the formed ammonium salts precipitate, allowing for easy removal by filtration. Evaporation of the filtrate then furnishes the acylated intermediates in sufficiently high purity for direct use in the second step. Thus, only one chromatography operation per synthesised peptoid re...