STUDIES ON THE SYNTHESIS OF ANTITUMOR PYRROLOIMINOQUINONE MARINE ALKALOIDS

抗肿瘤吡咯亚氨基醌海洋生物碱的合成研究

• 批准号: 09680571
• 负责人: IWAO Masatomo
• 金额: $ 1.86万
• 依托单位: NAGASAKI UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680571/
• 关键词: MARINE NATURAL PRODUCTS; PYRROLOIMINOQUINONE; MAKALUVAMINES; VEIUTAMINE; ANTITUMOR COMPOUNDS; INDOLE; LITHIATION; ピロロイミノキノン; 海洋アルカロイド

Pyrroloiminoquinone marine alkaloids have received considerable attention due to their potential antitumor activity. In this reserch project we have developed new and efficient methods for both construction and functionalization of pyrroloiminoquinone nucleus based mainly upon directed lithiation strategy.Thus, 1-triisopropylsily-6-methoxygramine was chlorinated at 4-position of the indole ring via directed lithiation followed by a reaction with hexachloroethane. The chlorinated gramine was converted to 1-protected-6-methoxytryptamine derivatives by conventional procedure. The tryptamines were cyclized to the key tricyclic 7-methoxy- 1, 3, 4, 5 -tetrahydropyrrolo[4, 3, 2- de] quinolincs by aryne-mediated cyclization. The Fremy's salt or salcomine-catalyzed oxidation of the tricyclic compounds produced the 7-methoxy-pyrroloiminoquinones, which were converted to the pyrroloiminoquinone marine alkaloids makaluvamines A, D, 1, and K by the reactions with ammmonium chloride or tyramine hydrochloride (Tetrahedron, 1998, 54, 8999).Next, the 6-selective functionalization of 1, 3, 4, 5-tetrahydropyrrolo[4, 3, 2-de] quinoline nucleus has been developed via N-Boc-directed lithiation. By using this method, the first total synthesis of veiutamine, a new type of pyrroloiminoquinone marine alkaloid bearing a p-hydroxybenzyl substituent at C-6 position has been achieved. This procedure is useful for the synthesis of a number of 6-substituted pyrroloiminoquinone marine alkaloid analogues, which are essential for structure-activity relationshiip studies of this type of potential antitumor compounds (Tetrahedron Letters, 1999, 40, 1713).

吡咯亚氨基醌类海洋生物碱因其潜在的抗肿瘤活性而受到广泛关注。在本研究项目中，我们开发了新的和有效的方法来构建和功能化的吡咯亚氨基醌核主要基于直接锂化策略，即1-三异丙基硅基-6-甲氧基芦竹碱通过直接锂化在吲哚环的4-位上进行氯化，然后与六氯乙烷反应。用常规方法将氯代芦竹碱转化为1-保护基-6-甲氧基色胺衍生物。通过芳炔介导的环化反应，色胺被环化为关键的三环7-甲氧基-1，3，4，5 -四氢吡咯并[4，3，2- de]喹啉。三环化合物经Fremy盐或Salcomine催化氧化生成7-甲氧基-吡咯亚氨基醌，再与氯化铵或酪胺盐酸盐反应生成吡咯亚氨基醌海洋生物碱Makaluvamines A、D、1和K（Tetrahedron，1998，54，8999）。接下来，已经通过N-Boc-定向锂化开发了1，3，4，5-四氢吡咯并[4，3，2-de]喹啉核的6-选择性官能化。利用该方法首次实现了6位含对羟基苄基取代基的新型吡咯亚氨基醌类海洋生物碱维鲁塔明的全合成。该方法可用于合成许多6-取代的吡咯并亚氨基醌海洋生物碱类似物，其对于这类潜在抗肿瘤化合物的结构-活性关系研究是必不可少的（Tetrahedron Letters，1999，40，1713）。

项目成果

Y.MOro-oka, T.Fukuda, M.Iwao: "The First Total Synthesis of Veiutamine, A New Type of Pyrroiminoquinone Marine Alkaloids" Tetrahedron Letters. Vol.40, No.9. 1713-1716 (1999)

Y.MOro-oka、T.Fukuda、M.Iwao：“首次全合成 Veiutamine，一种新型吡咯亚氨基醌海洋生物碱”四面体字母。

Y.Moro-oka,T.Fukuda,M.Iwao: "The first total synthesis of Veiutamine, a new type of pyrroloiminoquinone marine alkaloid"Tetrahedron Letters. 40・9. 1713-1716 (1999)

Y.Moro-oka、T.Fukuda、M.Iwao：“新型吡咯亚氨基醌海洋生物碱 Veiutamine 的首次全合成”Tetrahedron Letters 40・9 (1999)。

M.Iwao,O.Motoi,T.Fukuda,F.Ishibashi: "New Synthetic Approach to Pyrroloimoquinone Marine Alkaloids. Total Synthesis of Makalivamines A,D,I,and K." Tetrahedron. 54・31. 8999-9010 (1998)

M.Iwao、O.Motoi、T.Fukuda、F.Ishibashi：“吡咯并醌海洋生物碱的新合成方法。Makalivamines A、D、I 和 K 的全合成”54・31。 ）

M.Iwao, O.Motoi, T.Fukuda, F.Ishibashi: "New Synthetic Approach to Pyrroloiminoquinone Marine Alkaloids. Total Synthesis of Makaluvamines A, D, I, and K" Tetrahedron. Vol.54, No.31. 8999-9010 (1998)

M.Iwao、O.Motoi、T.Fukuda、F.Ishibashi：“吡咯亚氨基醌海洋生物碱的新合成方法。Makaluvamines A、D、I 和 K 的全合成”四面体。