An efficient synthesis of pyrrolo[2,1-c][1,4]benzodiazepine.: Synthesis of the antibiotic DC-81
An efficient synthesis of pyrrolo[2,1-c][1,4]benzodiazepine.: Synthesis of the antibiotic DC-81
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DOI：
10.1021/jo010043d
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发表时间：
2001-04-20
影响因子：
3.6
通讯作者：
Hsu, MH
中科院分区：
文献类型：
--
作者：
Hu, WP;Wang, JJ;Hsu, MH
吡咯 [2, 1-c][1, 4] 苯二氮卓类 (1)(PBD) 是一组由链霉菌属物种产生的强效、天然存在的抗肿瘤抗生素。 1 这些化合物的细胞毒性和抗肿瘤作用被认为是由 DNA 修饰引起的，DNA 修饰会抑制核酸合成并在细胞 DNA 中产生依赖于切除的单链和双链断裂。 2 这些抗生素已被提议与鸟嘌呤的 N2 共价结合，形成中性小沟加合物 (2)（方案 1）。 3 Tomaymycin (3)、交联剂 DSB-120 (4)、3d、4 和 DC-81 (5) 是 PBD 中最著名的示例（图 1）。这些化合物的合成方法已有报道； 4-6 然而，其中大多数都很乏味。例如，广泛使用的方法之一涉及使用氯化汞环化氨基二硫缩醛以得到亚胺产物（方案2）。然而，从L-脯氨酸（6）合成起始材料（2S）-吡咯烷-2-甲醛二乙基硫缩醛（7）需要六个步骤。 DC-81的这10步合成的总产率约为15-20%。 4, 6 最近，Wang 等人。报道了 DC-81 的全合成，经过 13 个步骤，产率 4%。 5b 在此，我们想报告一种非常短的路线和 PBD 类似物 DC-81 的高效合成。合成从用氯化亚锡还原取代的 2-硝基苯甲酸 (8) 6 开始，得到胺 10，产率 92%（方案 3）。所得胺10与三光气在THF中在回流下反应生成靛红酸酐(11)，收率极好(98％)。 7 在 120°C 下，化合物 11 在 DMSO 中与 L-脯氨酸偶联，生成双内酰胺 12，然后用 MOMCl 将酰胺转化为 N-(10-甲氧基甲基)-8-苄氧基-7-甲氧基吡咯并 [2, 1-c][1, 4]-苯二氮卓-5, 11-二酮 (13)，收率高。
Pyrrolo [2, 1-c][1, 4] benzodiazepines (1)(PBDs) are a group of potent, naturally occurring antitumor antibiotics produced by Streptomyces species. 1 The cytotoxic and antitumor effects of these compounds are believed to arise from modification of DNA, which leads to inhibition of nucleic acid synthesis and production of excision-dependent single-and double-strand breaks in cellular DNA. 2 These antibiotics have been proposed to covalently bond to N2 of guanine to form a neutral minor groove adduct (2)(Scheme 1). 3 Tomaymycin (3), cross-linker DSB-120 (4), 3d, 4 and DC-81 (5) are the best known examples of the PBDs (Figure 1). Synthetic approaches to these compounds have been reported; 4-6 however, most of them are tedious. For instance, one of the widely used methods involves the cyclization of amino dithioacetals using mercuric chloride to give the imine products (Scheme 2).Nevertheless, it takes six steps to synthesize the starting material,(2S)-pyrrolidine-2-carboxaldehyde diethyl thioacetal (7), from L-proline (6). The overall yield of this 10-step synthesis of DC-81 is about 15-20%. 4, 6 More recently, Wang et al. reported the total synthesis of DC-81 over 13 steps in 4% yield. 5b Herein we would like to report a very short route and efficient synthesis of PBD analogue, DC-81. The synthesis started with reduction of substituted 2-nitrobenzoic acid (8) 6 with stannous chloride to give amine 10 in 92% yield (Scheme 3). Reaction of the resulting amine 10 with triphosgene in THF under reflux generated isatoic anhydride (11) in excellent yield (98%). 7 Compound 11 was coupled to L-proline in DMSO at 120 C to produce dilactam 12, followed by conversion of the amide to N-(10-methoxymethyl)-8-benzyloxy-7-methoxypyrrolo [2, 1-c][1, 4]-benzodiazepine-5, 11-dione (13) with MOMCl in high yield.