35 (-)-マデュロペプチンクロモフォアの全合成と構造改訂(口頭発表の部)

Maduropeptin, an extremely potent antitumor agent, was isolated from the groth filtrate of Actinomadura madurae. It was identified as a 1:1 complex of an acidic carrier apoprotein (32kDa) and 9-membered ring enediyne chromophore, which showed selective DNA strand scission such as 5'-TCTT/3'-AGAA and 5'-TCTC/3'-AGAG. The chromophore (1), isolated as a methanol adduct, possesses a labile 9-membered diyne core, a macrolactam ansa0bridge and an aminosugar moieties. The protected aglycon 4 had been synthesized as reported on 49^<th> symposium on the chemistry of natural products. Here we report the total synthesis of the (-)-maduropeptin chromophore and its structure revision. The glycosyl donor 3 was synthesized from known lactone 5, which was derived from L-serine according to Nicolaou's procedure, in two steps. Glydocylation of the C9 tertiary hydroxyl group of 2, which was derived from 4 in 4 steps, in CH_2Cl_2 using TMSOTf as a Lewis acid proceeded smoothly to afford axial glycoside 9 in 40% yield. Removal of two benzoyl groups and all TES groups of 9 led to completion of the total synthesis of 1. However, the ^1H and ^<13>C NMR spectra of synthetic 1 were found to differ from those of the natural product. In consequence, the proposed structure of the natural chromophore of maduropeptin was revised as structure 1', which possesses the antipodal madurosamine moiety. Stereoselective glycosylation using enantiomeric sugar moiety ent-3, which was derived from D-serine, was conducted under the similar conditions (30% yield based on 50% recovery of 2). Deprotection of all protecting groups of 10 afforded the desired chromophore 1'. The ^1H and ^<13>C NMR spectra, as well as HRMS and NOE correlations, were in good agreement to those of the natural product. Thus, the first total synthesis and structure revision of (-)-maduropeptin chromophore were accomplished.