Synthesis of cyclosporine. Total syntheses of ‘cyclosporin A’ and ‘cyclosporin H’, two fungal metabolites isolated from the species Tolypocladium inflatum GAMS

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 -MeVal¹¹]cyclosporine ( 2 ).