Synthesis of cyclosporine. Total syntheses of ‘cyclosporin A’ and ‘cyclosporin H’, two fungal metabolites isolated from the species <i>Tolypocladium inflatum</i> G<scp>AMS</scp>

Abstract

Abstract The heptapeptide H‐MeBmt‐Abu‐Sar‐MeLeu‐Val‐MeLeu‐Ala‐OBzl ( 20 ) was synthesized for coupling with the previously described cyclosporine tetrapeptide sequence Boc‐ D ‐Ala‐MeLeu‐MeVal‐OH ( 21 ). The product of the coupling, the undecapeptide Boc‐ D ‐Ala‐MeLeu‐MeLeu‐MeVal‐MeBmt‐abu‐Sar‐MeLeu‐Val‐MeLeu‐Ala‐OBzl ( 22 ), was then deprotected and cyclized to cyclosporine ( 1 ). The tetrapeptide diastereoisomer Boc‐ D ‐ala‐MeLeu‐MeLeu‐ D ‐MeVAl‐OH ( 23 ) could also be used as a starting material to produce selectively the desired undecapeptide 22 . In this case, the N ‐methyl‐ D ‐valine unit, was selectively isomerized to the L‐from by using the appropriate condensing agent. The diastereoisomeric undecapeptide Boc‐ D ‐ala‐MeLeu‐MeLeu‐ D ‐MeVal‐MeBmt‐Abu‐Sar‐MeLeu‐Val‐MeLeuAla‐OBzl ( 24 ) was also synthesized starting from 21 by using the mixed pivalic anhydride method to selectively invert the configuration of the N ‐methyl‐ L ‐valine. The structure of the undecapeptide 24 was confirmed by deprotection and cyclization to ‘cyclosporin H’, a natural product known to have the structure [ D ‐MeVal 11 ]cyclosporine ( 2 ).