91 デュオカルマイシン類の合成研究(口頭発表の部)

概要

論文の詳細を見る
Duocarmycins, A (1), C_1 (2), C_2 (4), B_1 (3) and B_2 (5) isolated from Streptomyces sp. by workers at Kyowa Hakko are novel antitumor antibiotics which are effective against murine lymphocytic leukemia P388 and murine sarcoma 180 in mice. Almost at the same time, isolation of two new antitumor antibiotics, pyrindamycin A and B, from the culture broth of Streptomyces sp. was reported by Meiji Seika, and these antibiotics were found to be identical with duocarmycin C_2 (4) and C_1 (2), respectively. The unique structural features of duocarmycins (pyrindamycins) resembling to the exceptionally potent antitumor antibiotic, (+)-CC-1065 (6), as well as their prominent antitumor activity distinguish these compounds as attractive targets for total synthesis. Aiming to make the synthesis of variety analogues of duocarmycin A possible, the synthetic scheme was studied in which the amide formation between the upper half of duocarmycin A with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid was examined after the functionalization for the crucial Ar_1-3-type Winstein cyclization. Thus, the N-boc-indoline derivative (13) prepared from 2-chloro-5-methoxy-nitrobenzene was converted to the 5-amino derivative (15) by nitration and reduction sequence. Introduction of the C1 unit into the C-4 position was achieved through the isatin derivative (17) by oxidative ring opening followed by methanolysis, affording the anthranilic acid methyl ester (21). The key Dieckmann cyclization of the diester (23) prepared by sequential alkylation of 21 with methyl 2-bromopropionate and formylation, gave a diastereomeric mixture of the tricyclic compounds (24a, b) which could be separated by preparative TLC. After hydrolysis of the less polar isomer (24a), the hydrochloride salt (30a) obtained was coupled with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid to give rise to the amide (31a). Mesylation of the primary alcohol followed by deprotection of the benzyl ether produced the phenol derivative (33a). This was finally converted to dl-duocarmycin A by treating with sodium hydride. Following the same sequence, preparation of dl-2-epi-duocarmycin A was accomplished starting from the more polar isomer (24b). The ^1H-NMR spectra of the synthetic dl-duocarmycin A was identical to that of the natural authentic sample.
天然有機化合物討論会の論文
1990-09-25

91 デュオカルマイシン類の合成研究(口頭発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク