Synthesis of 16-membered cyclic depsipeptides via direct amide cyclization

The 2,2-disubstituted 2H-azirin-3-amines 5 (3-amino-2H-azirines) were used as synthons for alpha,alpha-disubstituted a-amino acids in the preparation of 16-membered cyclic depsipeptides 13. The linear precursors containing fo ur alpha,alpha-disubstituted alpha-amino acids, the pentapeptides 12, were synthesized from beta-hydroxy acids 4 via the 'azirine/oxazolone method' (S cheme 2). The 16-membered cyclic depsipeptides 13 were prepared via 'direct amide cyclization' in good-to-excellent yields (Schemes 3 and 4). In addit ion to the desired cyclic monomer 13, which was obtained as the main produc t, the cyclodimer 14 could also be isolated. The cyclization conditions wer e investigated and found to be optimum with HCl in toluene at 100 degrees. The structure and conformation of the cyclic depsipeptide 13b was establish ed by X-ray crystallography.