High-throughput organic synthesis of bicyclic diketopiperazines 1, beta-turn mimetics, is described. Starting from Merrifield resin-bound piperazine-2-carboxylic acid, first two (R-4 and R-5) Side chains are introduced via the Petasis reaction and subsequent amide bond formation. Unblocking the a-amino group of piperazine-2-carboxylic acid, Boc-N-protected alpha-amino acid coupling and deprotection followed by cyclative cleavage introduces the remaining R-2 and R-1 side chains. (C) 2000 Elsevier Science Ltd. All rights reserved.