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 α,α-disubstituted α-amino acids in the preparation of 16-membered cyclic depsipeptides 14. The linear precursors containing four α,α-disubstituted α-amino acids, the pentapeptides 13, were synthesized starting with β-hydroxy acids 5 via the ‘azirine/oxazolone method’. The cyclic depsipeptides 14 were formed via ‘direct amide cyclization’ and the influence of several factors on this cyclization was investigated in the following way: (a) using the same composition of α,α-disubstituted α-amino acids, but changing their respective positions in the peptide chain; (b) using different C-terminal α,α-disubstituted α-amino acids in the peptide chain; (c) using different β-hydroxy acids; and (d) using different diastereoisomers of the peptides.