Solid Phase Synthesis of β-Peptoids: N-Substituted β-Aminopropionic Acid Oligomers

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Abstract
A solid-phase organic synthesis method has been developed for the preparation of N-substituted-β-aminopropionic acid oligomers or β-peptoids 1. Treatment of polymer-bound 4-(benzyloxy)benzyl acrylate 2 with primary amines afforded N-substituted β-alanines 3. Polymer loadings and product conversions were determined by direct cleavage of resin-bound materials and measurement by 1H NMR with an internal standard. The NMR method was used to establish loading of all resin-bound intermediates including acrylic acid. Acylation with acryloyl chloride followed by Michael addition of primary amines to the acrylamide allowed preparation of di-β-peptoids. By a linear set of seven reactions, trimeric N-benzyl-β-aminopropionic acid was prepared in 67% overall yield. Single-bead FT-IR microspectroscopy was used to acquire spectra of the resin bound mono-β-peptoids, di-β-peptoids, and acrylamide intermediates. A combinatorial library of defined mixtures of tri-β-peptoids was prepared by mixing equimolar amounts of the mono-β-peptoid resins and carrying them through two sequences of the acylation−Michael addition. The identity of a sample mixture was determined by LC−MS analysis of the cleavage product.