SOLID-PHASE SYNTHESIS OF BETA-PEPTOIDS - N-SUBSTITUTED BETA-AMINOPROPIONIC ACID OLIGOMERS

A solid-phase organic synthesis method has been developed for the prep aration of N-substituted-beta-aminopropionic acid oligomers or beta-pe ptoids 1. Treatment of polymer-bound 4-(benzyloxy)benzyl acrylate 2 wi th primary amines afforded N-substituted beta-alanines 3. Polymer load ings and product conversions were determined by direct cleavage of res in-bound materials and measurement by H-1 NMR with an internal standar d. The NMR method was used to establish loading of all resin-bound int ermediates including acrylic acid. Acylation with acryloyl chloride fo llowed by Michael addition of primary amines to the acrylamide allowed preparation of di-beta-peptoids. By a linear set of seven reactions, trimeric N-benzyl-beta-aminopropionic acid was prepared in 67% overall yield. Single-bead FT-IR microspectroscopy was used to acquire spectr a of the resin bound mono-beta-peptoids, di-beta-peptoids, and acrylam ide intermediates. A combinatorial library of defined mixtures of tri- beta-peptoids was prepared by mixing equimolar amounts of the mono-bet a-peptoid resins and carrying them through two sequences of the acylat ion-Michael addition. The identity of a sample mixture was determined by LC-MS analysis of the cleavage product.