Synthesis of conformationally restricted cyclic hexadepsipeptides via direct amide cyclization

Ring closure by direct amide cyclization was used in the synthesis of 19-me mbered cyclic depsipeptides 27 (Schemes 1 and 3). The linear hexapeptide pr ecursors 4, containing the beta-hydroxy acid 3-hydroxy-2-phenylpropanoic ac id (Tro), and live alpha-amino acids of the type Aib, Gly, and Pro, were pr epared according to Scheme 2. The alpha,alpha-disubstituted alpha-amino aci d Aib was incorporated into the peptide chain via the azirine/oxazolone met hod, and Gly and Pro were introduced by using the TBTU/HOBt coupling method . The cyclic depsipeptides 27a-27f were obtained in reasanable-to-excellent yields (Scheme 3 and Table I).