Efficient Method for the Preparation of Peptoids (Oligo(N‐substituted glycines)) by Submonomer Solid‐Phase Synthesis.

Oligomers of N-substituted glycines, or “peptoids“, represent a new class of polymers (Figure 1) that are not found in nature, but are synthetically accessible and have been shown to possess significant biological activity and proteolytic stability.’ We present here an efficient, automated solid-phase method for the synthesis of oligo(N-substituted glycines) (NSGs) which is general for a wide variety of side-chain substituents and allows the rapid synthesis of molecules of potential therapeutic interest. The original method’ for the synthesis of oligomeric NSGs is analogous to standard solid-phase methods for peptide synthesis. Specifically, the carboxylate of Nu-Fmoc-protected (and sidechain-protected) NSGs is activated and then coupled to the secondary amino group of the resin-bound peptoid chain. Removal of the Fmoc group is then followed by addition of the next monomer. Thus, oligomeric NSGs have been treated as condensation homopolymers of N-substituted glycine. A disadvantage of this approach, however, is the necessity of preparing suitable quantities of a diverse set of protected N-substituted glycine monomers. In the method presented here, each N-substituted glycine monomer is assembled from two readily available “submonomers” in the course of extending the NSG polymer (Scheme I). Thus, oligomeric NSGs can also be considered to be alternating condensation copolymers of a haloacetic acid and a primary amine. As in the original method, the direction of polymer synthesis with the submonomers occurs in the carboxy to amino direction. The solid-phase assembly of each monomer, in the course of controlled polymer formation, eliminates the need for N*-protected monomers, as only reactive side-chain functionalities need to be protected. The a-haloacetyl submonomer is common to all cycles of chain extension. Moreover, each RNH2 submonomer is simpler in structure and many are commercially available; thus, oligo(NSG) synthesis is dramatically simplified. The preparation of NSG oligomers by the submonomer method2