Synthesis of Holomycin and Derivatives

Holomycin, 6-acetamido-5-oxo-4,5-dihydro-1,2-dithiolo[4,3-b]pyrrole (1a), and the 3-carboxylated derivative (1b) have been prepared by a ten-stage synthesis designed around two key reactions. Cyclization of 5-methoxalylamino-4-methoxycarbonyl-2-p-methoxyphenyl-2-methyl-1,3-dithiin (6) by base gave 7-hydroxy-4-methoxycarbonyl-2-p-methoxyphenyl-2-methyl-6-oxo-5,6-dihydro-1,3-dithiino[5,4-b]pyrrole (7) containing the required pyrrolinone ring. A contraction of the dithioketal 7-p-methoxybenzylamino-4-methoxycarbonyl-2-p-methoxyphenyl-2-methyl-6-oxo-5,6-dihydro-1,3-dithiino[5,4-b]pyrrole (9) afforded the cyclic enol disulfide 6-p-methoxybenzylamino-3-methoxycarbonyl-5-oxo-4,5-dihydro-1,2-dithiolo[4,3-b]pyrrole (10a). Further elaboration led to holomycin (1a) and the carboxy derivative 1b.