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

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).