抄録
C-1027 is a potent antitumor chromoprotein antibiotic. It is composed of an apoprotein and a labile 9-membered enediyne chromophore 1. The C-1027 chromophore 1 quickly aromatizes via Masamune-Bergman cyclization at ambient temperature, generating p-benzyne biradical 2 that exerts its biological activity by abstracting hydrogen from DNA. The chemical instability and the complex architecture distinguish 1 as a challenging target for the total synthesis. We report a total synthesis of the protected aglycon and the chromophore 1. A key feature of our syntheis is construction of the nine-membered enediyne from the nine-membered diyne via the reductive olefination of vicinal diol derivative. First, we examined the reductive olefination in the presence of a benzoxazine moiety and synthesis of the protected aglycon 15. As shown in Scheme 2, the adequately protected benzoxazine moiety 9 was condensed with readily prepared nine-membered diyne 4. The product 10 was converted to 13, which is the suitable precursor of the reductive olefination. The reduction of 13 with samarium iodide was successful to afford the protected aglycon 15 via dehydration of hemiacetal using a mesylation-elimination sequence. Then, we attempted the total synthesis of 1. Highly diastereoselective glycosylation under Schmidt conditions enabled preparation of 23 (Scheme 4). The reductive olefination of 23 and subsequent dehydration also worked well to give the protected chromophore 24. Finally, formation of 1 was confirmed by ESI-MS (HRMS) after global deprotection with TBAF.
