Synthesis of conformationally restricted cyclic pentadepsipeptides via direct amide cyclization

The 2,2-disubstituted 2H-azirin-3-amines 6 (3-amino-2H-azirines) were used as building blocks for alpha,alpha -disubstituted alpha -amino acids in the preparation of 16-membered cyclic depsipeptides 14. The linear precursors containing four alpha,alpha -disubstituted alpha -amino acids, the peptapep tides 13, were synthesized starting with beta -hydroxy acids 5 via the 'azi rine/oxazolone method'. The cyclic depsipeptides 14 were formed via 'direct amide cyclization' and the influence of several factors on this cyclizatio n was investigated in the following way: (a) using the same composition of alpha,alpha -disubstituted alpha -amino acids, but changing their respectiv e positions in the peptide chain; (b) using different C-terminal alpha,alph a -disubstituted alpha -amino acids in the peptide chain; (c) using differe nt beta -hydroxy acids; and (d) using different diastereoisomers of the pep tides. (C) 2001 Elsevier Science Ltd. All rights reserved.