Synthesis of conformationally constrained amino acid and peptide derivatives

6-Benzylpiperazine-2,3,5-trione 5, a cyclic phenylalanine derivative, can be selectively and sequentially alkylated at N4, C6 and N1 to provide a range of conformationally constrained phenylalanine mimetics. Alkylation at C6, the α-carbon of the phenylalanine moiety is achieved under mild conditions and gives rise to Phe derivatives posessing a dialkylated α-carbon. Alkylation of piperazine 5 using methyl bromoacetate and ethyl bromopropionate gives access to peptoids 7 and 21 which are conformationally contrained Phe-Gly and Phe-Ala analogues respectively. The X-ray crystal structure of triallylated derivative 17 is also reported.