CYCLOSPORINE-A - REGIOSELECTIVE RING-OPENING AND FRAGMENTATION REACTIONS VIA THIOAMIDES - A ROUTE TO SEMISYNTHETIC CYCLOSPORINES

Cyclosporin A (1a) served as the starting material for the semisynthet ic preparation of a variety of novel cyclosporins. Acetylcyclosporin A (2) was treated with Lawesson's reagent. From the reaction mixture, t hree novel acetylated thioamides were isolated: the 4,7-bis(thioamide) 3a, the 7-thioamide 3b, and the 4-thioamide 3c. The acetylated produc ts 3a-c were hydrolyzed to the known thioamides 4a-c, respectively. Th e 7-thioamide 3b was alkylated to give the S-benzyl thioamidate 5b. A regioselective ring opening reaction at the activated site was induced by treating 5b under acidic conditions giving the 7,8-seco-cyclospori n 7a. The (R)-alanine moiety was replaced by (R)-phenylalanine via the Edman degradation product 7e giving 7f. Removal of the protecting gro ups led to 7h. This was cyclized to [(R)-phenylalanine](8)-cyclosporin (1b). The N-protected 7,8-seco-cyclosporin 7i was reduced to the alde hyde 7j, homologated (7k), and deprotected to give 7m. This was cycliz ed to the vinylogous cyclosporin 8a. Similarly,:the 4,5-seco-cyclospor in 9c was prepared and converted via several steps (9d-h) to the vinyl ogous cyclosporin 8b. Finally, under acidic conditions, the dibenzyl b is(thioamidate) 5a underwent a fragmentation reaction to give the octa peptide 10a and the tripeptide 11a. The octapeptide 10a was coupled wi th a different tripeptide (11d) to 9i and cyclized via 9j-k to the [(S )-phenylalanine](7)-cyclosporin (1c).