N-Substituted Arylsulfonamides as Alternative Building Blocks in Peptoid and Peptide Synthesis

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Peptoids (oligo N-substituted glycines) are peptidomimetic oligomers showing attractive structural and pharmacological properties for the development of therapeutic candidates and molecular tools [1,2]. Compared to peptides, peptoids are resistant to proteases and show improved cell permeability [3,4]. Moreover, their synthesis is straightforward and the great chemical diversity that can be accessed with peptoids has prompted their use in combinatorial libraries. The submonomer method introduced by Zuckermann, et al. is the most frequently used approach to prepare peptoids [5]. This method is performed on solid support and involves iterative acylation and amination reactions to build up peptoid residues and generate oligomers after multiple rounds. A major advantage of this method is the large number of commercially available primary amines that allows the incorporation of an important chemical diversity. However, despite the great diversity of available primary amines, we observed that the number of submonomers bearing protected hydroxyl side chains is very limited. The very few that are commercially available are expensive. Protection of hydroxyl groups is recommended to avoid O-acylation during the acylation but the preparation of O-protected submonomers usually requires multistep synthesis or harsh conditions and they are recovered in low yields or often obtained as inconvenient gummy oils. To overcome these drawbacks and introduce interesting reactive or polar functionalities into peptoids, our strategy was to use amino alcohols as starting material and perform a two-step synthesis involving N-protection with an arylsulfonyl group followed by O-protection with tert-butyl to prepare fully protected submonomers. Then, the N-substituted arylsulfonamides could be used directly for the nucleophilic displacement step on solid support in the submonomer approach or for the synthesis of protected N-substituted glycines for the monomer approach (Figure 1).