Synthesis of conformationally restricted cyclic hexadepsipeptides via direct amide cyclization

Abstract

Ring closure by direct amide cyclization was used in the synthesis of 19-membered cyclic depsipeptides 27 (Schemes1 and 3). The linear hexapeptide precursors 4, containing the beta-hydroxy acid 3-hydroxy-2-phenylpropanoic acid (Tro), and five alpha-amino acids of the type Aib, Gly, and Pro, were prepared according to Scheme 2. The alpha,alpha-disubstituted alpha-amino acid Aib was incorporated into the peptide chain via the azirine/oxazolone method, and Gly and Pro were introduced by using the TBTU/HOBt coupling method. The cyclic depsipeptides 27a - 27f were obtained in reasonable-to-excellent yields (Scheme 3 and Table 1).