Synthesis of Camptothecin and Analogs Employing Novel Domino Recation

采用新型多米诺骨牌反应合成喜树碱及其类似物

• 批准号: 08557120
• 负责人: IHARA Masataka
• 金额: $ 4.61万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08557120/
• 关键词: Camptothecin; Dimino Reaction; Intramolecular Double Michael Reaction; Enamine Annulation; Intramolecular Diels-Alder Reaction; Topoisomerase I Inhibitor; Polycyclic Compounds; Hyeterocyclic Compounds; 分子内ディールス・アルダー反応; 抗がん剤; 全合成; 立体選択的合成; インドー

The antitumor alkaloid camptothecin has attracted much attention over the years since its isolation in 1966. Camptothecin has a long, rich history as a potential anticancer agent, and it has recently reemerged as one of the most important lead compounds among the antitumor natural products. Several syntheses of camptothecin have accomplished, resulting in the development of numerous new synthetic strategies and methodologies. Camptothecin proved to be a rather difficult target as is event by the length of many of the early syntheses.We have investigated in order to develop a new and effective synthesis of camptothecin and analogs. First, we succeeded in the synthesis of the racemate of camptothecin using the enamine annulation method, which was developed by us. Using this method l0-methoxy and l0-hydroxycamptothecins were prepared. Shortening steps of this strategy was further studied and a domino reaction, double enamine annelation reaction, was devised.Domino reactions forming multip … More le bonds in a stereo- and regio-selective manner by one procedure is one of the most ideal process in organic synthesis. The domino reaction is also called as cascade and tandem reaction. As the result of the further investigations, we could developed several types of domino reactions, which are useful for natural products synthesis. One of them is the intramolecular double Michael reaction. Thus, treatment of an indole derivative having an alpha, beta-unsaturated ester function at the C-2 position and an unsaturated amide group at the C-3 position with TBSOTf in the presence of triethylamine provided the indoloquinolizidine derivative. Tacamonine, an indole alkaloid, having important biological activities was straightforwardly synthesized by this method. The indoloquinolizidine derivative prepared by the intramolecular double Michael reaction could be converted into camptotecin analogs.Recently, the a, b, c, d part of camptothecin was directly constructed by the intramolecular Diels-Alder reaction of a 1-azadiene. It is expected that a facile synthesis of camptothecin and analogs would be accomplished by this methodology. Less

抗肿瘤生物碱喜树碱自1966年分离以来，多年来一直受到人们的广泛关注。喜树碱作为一种潜在的抗肿瘤药物有着悠久的历史，近年来又重新成为抗肿瘤天然产物中最重要的先导化合物之一。喜树碱的几个合成已经完成，导致许多新的合成策略和方法的发展。喜树碱是一个相当困难的目标，因为许多早期合成的长度是事件。我们已经研究，以发展一个新的和有效的喜树碱及其类似物的合成。首先，我们采用自行开发的烯胺成环法成功地合成了喜树碱外消旋体。用此方法制备了10-甲氧基和10-羟基喜树碱。进一步研究了该方法的简化步骤，设计了一种多米诺反应--双烯胺加成反应， ...更多信息 通过一个步骤以立体选择性和区域选择性的方式分离键是有机合成中最理想的方法之一。多米诺骨牌反应也被称为级联和串联反应。通过进一步的研究，我们可以开发出几种类型的多米诺反应，这对天然产物的合成是有用的。其中之一是分子内双迈克尔反应。因此，在三乙胺存在下，用TBSOTf处理在C-2位具有α，β-不饱和酯官能团和在C-3位具有不饱和酰胺基团的吲哚衍生物，得到吲哚并喹嗪衍生物。用该方法直接合成了具有重要生物活性的吲哚生物碱他坎替。通过分子内双Michael反应制备的吲哚并喹嗪衍生物可转化为喜树碱类似物，最近，通过α 1-氮二烯的分子内Diels-Alder反应直接构建喜树碱的a，B，c，d部分。预期通过该方法可实现喜树碱及其类似物的简易合成。少

项目成果

Y. Tokunaga: "1, 3-Dipolar Cycloaddition of 1-Carboxynitrone : Different Stereoselectivity Caused by Salt Effect" Tetrahedron Lett.3734. 6157-6160 (1996)

Y. Tokunaga：“1-羧基硝酮的 1, 3-偶极环加成：盐效应引起的不同立体选择性”Tetrahedron Lett.3734。

M.Toyota, M.Hirota, Y.Nichikawa, K.Fukumoto, and M.Ihara: "Palladium-Ctalyzed Intramolecular Allylic Alkylation Reaction in Marine Natural Product Synthesis-Enanitoselective Synthesis of (+) -Methyl Pedrate, a Key Intermediate in Synthese of Mycalamides"

M.Toyota、M.Hirota、Y.Nichikawa、K.Fukumoto 和 M.Ihara：“海洋天然产物合成中的钯催化分子内烯丙基烷基化反应 - 对映选择性合成 ( )-Pedrate 甲酯，这是合成中的关键中间体

H.Nemoto, M.Yoshida, K.Fukumoto and M.Ihara: "A Novel Strategy for the Enantioselective Synthesis of the Steroidal Framework Using Cascade Ring Expansion Reactions of Small Ring Systems-Asymmetric Total Synthesis of (+) -Equilenin" Tetrahedron Letters. 40

H.Nemoto、M.Yoshida、K.Fukumoto 和 M.Ihara：“利用小环系统的级联环扩展反应对映选择性合成甾体框架的新策略 - ( ) -马烯雌酮的不对称全合成”四面体字母。

井原正隆 他1名: "Natural Product Reports" The Royal Society of Chemistry, 16 (1997)

Masataka Ihara 和其他 1 人：“天然产物报告”英国皇家化学学会，16 (1997)

井原正隆 他2名: "Construction by Bicyclo〔2.2.2〕octane Ring System via Homoallyl-Homoallyl Radical Rearrangement" Tetrahdron Letters. 40・8. 1551-1554 (1999)

Masataka Ihara 和另外 2 人：“通过高烯丙基-高烯丙基自由基重排构建双环〔2.2.2〕辛烷环系统”Tetrahdron Letters 40・8（1999）。