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Ascomycin ( 1a ), a macrolactam antifungal antibiotic disclosed by Arai in 1962, 1 was found to display immunosuppressive activity more than 2 decades later by Okuhara and coworkers at Fujisawa. 2 Ascomycin ( 1a ) and FK506 ( 1b ) bind to a peptidyl-prolyl-isomerase, FKBP, a necessary but insufficient condition for drug activity. Both FK506 and ascomycin exist as a mixture of slowly interconverting cis and trans amide rotamers. It has also been shown that only the trans amide rotamer binds to FKBP. 24-epi-Ascomycin ( 3 ), 24-oxo-22-norascomyin ( 9a ), and 22-norascomycin ( 9b ), obtained by semisynthesis from ascomycin, exist as single rotamers on the NMR time scale. Their synthesis and the biological consequences of this observation are discussed.

Ascomycin (1) is a close analogue of the immunosuppressant FK-506 (2) which differs slightly in the side chain at position 21 (ethyl vs allyl). Structurally unique ascomycin and FK-506 are the subjects of intense chemical research because of their application in organ transplantation and autoimmune disease. We have been interested in studying the effect of structural modification and conformational change on biological activity. This paper reports the fermentation and structural determination of ascomycin as well as the synthesis and structure confirmation of a series of pyrazole analogues (3 and 4) derived from ascomycin.