Selective epimerization and skeletal resection in the ascomycin framework: A study of the biological consequences of lactam rotamer selection

Article abstract of DOI:10.1016/0040-4020(96)00527-3

Ascomycin (1a), a macrolactam antifungal antibiotic disclosed by Arai in 1962, was found to display immunosuppressive activity more than 2 decades later by Okuhara and coworkers at Fujisawa. 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.