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

Abstract

The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine (1; R1 = R2= R3 = R4= Me) with alpha-hydroxycarboxylic 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 (to 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 HCI 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 alpha,alapha-disubstituted alpha-amino acids.