Mk. Eberle et al., CYCLOSPORINE-A - REGIOSELECTIVE RING-OPENING AND FRAGMENTATION REACTIONS VIA THIOAMIDES - A ROUTE TO SEMISYNTHETIC CYCLOSPORINES, Journal of organic chemistry, 59(24), 1994, pp. 7249-7258
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).