Kedarcidin, isolated from the actinomycete strain, was identified as a 1:1 complex of an apoprotein and a nine-membererd ring enediyne chromophore. It exhibits potent in vivo antitumor activity and also shows pronounced activity against Gram-positive bacteria. The structural complexity of the kedarcidin chromophore, as well as its unique mode of action, makes it a challenging and fascinating target for the total synthesis. The structure of chromophore was originally assigned by Leet et al. in 1993. In 1997, we found that the kedarcidin chromophore has the β-azatyrosyl moiety, instead of the α-amino acid form. Consequently, the absolute configuration of the chromophore was also revised. In 2007, Myers and co-workers synthesized the revised mold of the chromophore and proposed the C10 epi compound (1) as the proper structure of chromophore. Herein, we report the successfull synthesis of the protected aglycon of kedarcidin chromophore 10. In our earlier work, we have succeeded in constructing the multicyclic diyne ansamacrolide, possessing the entire carbon skeleton of the kedarcidin chromophore aglycon. However, introduction of the C8-C9 epoxide was unsuccessful due to the transannular steric hindrance of the ansa-bridge. Therefore, an alternative synthetic strategy is required for the construction of the nine-membered epoxy diyne core. Our successful new strategy involves the C5-C6 cyclization of 11 which has the C8-C9 epoxide and a reductive olefination of the C4-C5 diol derivative 33. Synthesis was initiated by an etherification of newly prepared five-membered ring moiety 16, which possesses the proposed configuration at C10, with a pyridine moiety 4. Sonogashira coupling with an alkyne moiety 15 and subsequent macrolactonization gave 30 as a single atoropisomer. An amide formation with a naphtoate moiety 6 afforded 31. The nine-membered ring formation at C5-6 position via CeCl_3/LiHMDS mediated cydization protocol gave the nine-membered diyne 9 with the entire carbon skelton of the kedarcidin aglycon. To complete the synthesis of the protected aglycon 10, the reductive elimination of C4-5 dioxy functionalities was established. p-Trifluoromethylbenzoate and mesylate were chosen as the diol derivative. Selective deprotection of TES ether and mesylation followed by the formation of p-trifluoromethylbenzoate ester gave 33 as the suitable precoursor for C4-5 olefination. The Sml_2mediated reductive olefination smoothly proceeded to give the protected aglycon 10 as a sole product. Possible reduction of epoxide was not observed. As described, we achieved the total synthesis of the protected aglycon of kedarcidin chromophore 10 for the first time.
