6 Neothramycinの化学的研究

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Neothramycin is a new antitumor antibiotic isolated from a culture filtrate of Streptomyces No. MC916-C4, and exhibits a marked prolongation-effect in the survival period of mice implanted with leukemia L-1210 cells. We report here the structure established on the basis of spectral data, chemical degradations and total synthesis. In an aqueous solution, neothramycin exists as a mixture of two isomers, neothramycins A and B (1a and 1b, C_<13>H_<14>N_2O_4). A mixture of the corresponding O-alkylneothramycins A and B are easily obtained either from neothramycin A or B by simple treatment with anhydrous alcohols. Alkaline hydrolysis of butylneothramycin A (3a) with Ba(OH)_2-saturated aqueous solution afforded 4-hydroxy-5-methoxyanthranilic acid identical with synthetic one. Treatment of 3a with phenyldiazomethane followed by mild hydrolysis with 0.01N HCl-dioxane (1: 1 in volume) gave a mixture of O-benzylneothramycins A and B. It was oxidized with KMnO_4 in acetone to afford a compound (5). Acid hydrolysis of 5 with HCl at 105℃ gave a slightly racemized mixture of L-glutamic acid hydrochloride From the results of the chemical degradations and the PMR data (Table 1), the absolute structures of 1a and 1b were elucidated as (3S,11aS)- and (3R,11aS)-2,3,5,11a-tetrahydro-3,8-dihydroxy-7-methoxy-5-oxo-1H-pyrrolo[2,1-c][1,4]benzodiazepine, respectively. A total synthesis of neothramycin was designed to approach by a new route different from that of anthramycin. Thus, neothramycin has been synthesized starting from vanillic acid (6) through 7-step procedure (Fig. 2), in which the key stage involves ring formation of the 1,4-benzodiazepine with retention of the absolute configuration.
天然有機化合物討論会の論文
1976-09-20

6 Neothramycinの化学的研究

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