Synthese cyclischer Depsipeptide durch direkte Amid‐Cyclisierung: 12gliedrige Depsipeptide mit alternierender Sequenz von α‐Hydroxy‐ und α‐Aminosäuren

Synthesis of Cyclic Depsipeptides via Direct Amide Cyclization: Cyclic Depsipeptides with 12‐Ring Atoms and Alternating Sequence of α‐Hydroxy and α‐Amino Adds The reaction of 3‐(dimethylamino)‐2,2‐dimethyl‐2 H ‐azirine (1; R 1 = R 2 = R 3 = R 4 = Me) with α‐hydroxy‐carboxylic acids, followed by selective hydrolysis of the terminal dimethylamide group yields the dipeptide analogues 15a and 18b ( Schemes 3 and 4 ). After protection of the OH group (→ 16a and 19 , resp.), coupling with the C‐terminus‐protected derivatives 14 and 18a , respectively, by a modified 1,1′‐carbonyldiimidazole procedure followed by hydrolysis gives the linear depsipeptides 17c and 20 , respectively. Treatment with HCl gas in toluene at 100° leads to the cyclic depsipeptides 21 and 22 in very good yield. The two model reactions show that the ‘azirine/oxazolone‐method’, combined with the ‘direct amide cyclization’, is a versatile procedure for the synthesis of cyclic depsipeptides containing α,α‐disubstituted α‐amino acids.