Total Synthesis of Cyclotheonamides, Potent Inhibitors of Thrombin

凝血酶强效抑制剂环草酰胺的全合成

• 批准号: 04671303
• 负责人: HAMADA Yasumasa
• 金额: $ 1.34万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671303/
• 关键词: cyclotheonamide; inhibitor; thrombine; vinylogous tyrosine; alpha-keto arginine; 2,3-diaminopropionic acid; alphaケトアルギニン; 環境ペプチド; トロンビン阻害物質; E-ビニル-γ-アミノ酸; γ-ケト-β-アミノ酸

Cyclotheonamides(A and B), potent andselective inhibitor of the serine protease thrombine, were isolated fron a marine sponge of the genus Theonalla. They are cyclic pentapeptides containing two, so far umknown, amino acid components, a vinylogous tyrosine and alpha-keto arginine. We have undertaken total synthesis of the interesting cyclic peptides for evaluation of their biological activities.The preparation of the protected E-vinylogous tyrosine ester was carried out by a new one-pot reaction in high selectivity from the protected amino alclhol derived from D-tyrosine. The synthesis of the alpha-keto arginine was accomplished as alpha-hydroxy acid after homologation of L-arginine. The protected 2,3-diaminopropionic acid was synthesixed fron Z-L-asparagine according the lzumiya method.With the three unusual amino acids in hand, toral synthesis of cyclothenamide B was set out. The dipeptide, H-Dpr-Pro-OR, and tripeptide, Boc-alpha-hydroxyArg-the-vinylTyr-OH, were coupled with our method. Thus obtained pentapeptide after deprotection was cyclized with pentafluorophenyl diphenylphosphinate to give the cyclic precursor in high yield. Oxidation of the alpha-hydroxy acid moiety to alpha-keto acid one with Dess-Martin reagent furmished the cyclotheonamide B.

从Theonalla海绵中分离得到两种环辛酰胺类化合物（A和B），它们是丝氨酸蛋白酶凝血酶的选择性抑制剂。它们是环状五肽，含有两个迄今未知的氨基酸组分，乙烯基酪氨酸和α-酮基精氨酸。本文报道了一种新的高选择性的一锅反应，从D-酪氨酸衍生的保护氨基醇出发，合成了保护的E-乙烯基酪氨酸酯。α-酮基精氨酸的合成在L-精氨酸同系化后以α-羟基酸的形式完成。以Z-L-天冬酰胺为起始原料，按Izumiya法合成了保护的2，3-二氨基丙酸，并在此基础上，对环烯酰胺B的合成进行了初步探索。用我们的方法偶联了二肽H-Dpr-Pro-OR和三肽Boc-α-hydroxyArg-the-vinylTyr-OH。将脱保护后的五肽与二苯基次膦酸五氟苯基酯环化，以高产率得到环状前体。用戴斯-马丁试剂将α-羟基酸部分氧化为α-酮酸部分，得到环Theonamide B。

项目成果

Jingen Deng, Yasumasa Hamada, and Takayuki shioiri: "synthetic Studies of Cyclotheonamides, Cyclic Peptides from a Marine sponges." Peptide Chemistry. 72-75 (1992)

Jingen Deng、Yasumasa Hamada 和 Takayuki shioiri：“来自海洋海绵的环肽环草酰胺的合成研究”。

Jingen Deng Yasumasa Hamada Takayuki Shioiri: "Total Synthesis of Cyclotheonamide B" Angew.Chem.Int.Ed.Engl.,in preparation.(1994)

Jinen Deng Yasumasa Hamada Takayuki Shioiri：“Cyclotheonamide B 的全合成”Angew.Chem.Int.Ed.Engl.，准备中。(1994)

Jingen Deng Yasumasa Hamada Takayuki Shioiri: "Synthetic Studies of Cyclotheonamides,Cyclic Peptides from Marine sponges." Peptide Chemistry 1992. 72-73 (1992)

Jinen Deng Yasumasa Hamada Takayuki Shioiri：“来自海洋海绵的环肽环草酰胺的合成研究”。

Jingen Deng, Yasumasa Hamada, and Takayuki shioiri: "Total Synthesis of Cyclotheonamide B" Angew. Chem. Int. Ed. Engl.(in preparation).

Jinen Deng、Yasumasa Hamada 和 Takayuki shioiri：“Cyclotheonamide B 的全合成”Angew。

J.Deng,Y.Hamada,T.Shioiri: "Syuthetic Studies of Cycltheonamides,from a Masine Sporges" Peptide Chem:stry 1992. 72-73 (1992)

J.Deng、Y.Hamada、T.Shioiri：“来自马辛孢子的环草酰胺的合成研究”肽化学：stry 1992. 72-73 (1992)