PREPARATION OF [D-CYSTEINE]8-CYCLOSPORINE VIA INTRAMOLECULAR SULFUR TRANSFER-REACTION

Starting from [D-serine]8-cyclosporin (2) the diacetate 3 was prepared. This was treated with Lawesson's reagent. From the reaction mixture, three diacetylated thioamides were isolated in this order of increasing polarity: the 4,7-dithioamide 4a, the 7-thioamide 4b, and the 4-thioamide 4c. The acetate groups were hydrolyzed from all three compounds under basic conditions to give 5a-c. Treatment of 5b with tosyl chloride led to the dihydrothiazolobicyclosporin 6. Hydrolysis under acidic conditions yielded [D-cysteine]8-cyclosporin (7). This was converted to the 0,S-diacetate 8. A reductive desulfurization of 8 to the known acetylcyclosporin A (9) provided the stereochemical correlation between 7 and cyclosporin A (1).