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.