cyclotheonamide B | 129033-05-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: cyclotheonamide B
• 英文别名: Cyclotheonamid B；N-[(3S,7E,9S,12R,16S,19S)-12-benzyl-16-[3-(diaminomethylideneamino)propyl]-9-[(4-hydroxyphenyl)methyl]-2,6,11,14,15,18-hexaoxo-1,5,10,13,17-pentazabicyclo[17.3.0]docos-7-en-3-yl]acetamide
• CAS: 129033-05-2
• 化学式: C₃₇H₄₇N₉O₈
• 分子量: 745.836
• InChiKey: KVILZKPCTDRTNA-XRBZIDJVSA-N

物化性质

• 比旋光度：
  D23 -13.5° (c = 0.2 in methanol)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  54
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  268
• 氢给体数：
  8
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  L-鸟氨酸 在 palladium on activated charcoal 吗啉 、 4-二甲氨基吡啶 、 copper(II) carbonate 、 lithium hydroxide 、 四(三苯基膦)钯 、 正丁基锂 、 乙二胺四乙酸 、 茴香硫醚 、 氢气 、 silica gel 、 二异丁基氢化铝 、 碳酸氢钠 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 mercury dichloride 、 mercury(II) oxide 、 叔丁醇 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 201.23h， 生成 cyclotheonamide B
  参考文献：
  名称：

  Flexible and Convergent Total Synthesis of Cyclotheonamide B

  摘要：

  A convergent approach using two key intermediates, segment A [a L-proline-L-alpha-hydroxy-beta-homoarginine-D-phenylalanine (Pro-hArg-D-Phe) tripeptide] and segment B [a vinylogous L-tyrosine-L-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheonamide B (Scheme 1). The starting compound for the preparation of the hArg moiety 7, the predominant part of segment A, was N-alpha-(benzyloxycarbonyl)-N-omega , N(omega)'bis(tert-butyloxycarbonyl)-l-arginine methyl ester (15, Scheme 2), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a carboxylic acid anion equivalent. Coupling with properly protected Pro and D-Phe derivatives gave smoothly the desired Pro-hArg-D-Phe tripeptide derivative 24. The key feature of segment B, i.e., the L-tyrosine-derived alpha,beta-unsaturated gamma-amino acid 4, was prepared by a Wadsworth-Emmons olefination of the aldehyde 29 (Scheme 3) derived from N-(tert-butyloxycarbonyl), O-tert-butyl-L-tyrosine methyl ester (28). Selective N-(tert-butyloxycarbonyl) removal in the presence of the aryl tert-butyl ether present in the fully protected segment B, i.e., 32, was achieved by treatment with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield. Coupling of the key intermediates 24 and 34 using 2-(1H-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protected linear pentapeptide 35 in high yield (Scheme 4). Treatment of 35 with Pd(PPh3)(4)/morpholine resulted in simultaneous removal of the C-terminal allyl group and the N-terminal allyloxycarbonyl group to yield 36. Ring closure was effected under dilution conditions by treatment with TBTU/1-hydroxybenzotriazole/4-(dimethylamino and gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group with Dess-Rlartin periodinane (24 h, 40 degrees C) in the presence of tert-butyl alcohol gave 38, which was then subjected to O,N-deprotection with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.

  DOI：

  10.1021/jo961447m

文献信息

• A new synthesis of cyclotheonamide B via guanidination of ornithine
  作者：Deng Jingen、Hamada Yasumasa、Shioiri Takayuki

  DOI：10.1016/0040-4039(96)00270-5

  日期：1996.3

  A macrocyclic thrombin inhibitor, cyclotheonamide B (1, R=Ac) was synthesized via a new approach: guanidination of the ornithine-containing macrocyclic peptide (2). In comparison of various coupling reagents, pentafluorophenyl diphenylphosphinate (FDPP) gave the macrocyclic peptide (2) in good yield, and the configuration of the amino acid residue has been revealed to be important for the macrolactamization

  通过一种新方法合成了大环凝血酶抑制剂，环硫酰胺B（1，R = Ac）：含鸟氨酸的大环肽（2）的胍基化。与各种偶联剂相比，五氟苯基二苯基次膦酸酯（FDPP）以高收率得到大环肽（2），并且氨基酸残基的构型已被证明对于大内酰胺化很重要。
• [EN] ALPHA-KETOAMIDE DERIVATIVES AS INHIBITORS OF THROMBOSIS<br/>[FR] DERIVES DE L'ALPHACETOAMIDE UTILES COMME INHIBITEURS DE THROMBOSE
  申请人：CORVAS INTERNATIONAL, INC.

  公开号：WO1994021673A1

  公开（公告）日：1994-09-29

  (EN) $g(a)-Ketoamide derivatives, their pharmaceutically acceptable salts, compositions, diagnostic compositions and pharmaceutical compositions, which are useful for preventing or treating in a mammal a pathological condition characterized by thrombosis are described. $g(a)-Ketoamide derivatives, their pharmaceutically acceptable salts, compositions and diagnostic compositions, which are useful for $i(in vivo) imaging of thrombi in a mammal are also described. Methods of preventing or treating in a mammal a pathological condition characterized by thrombosis and methods of $i(in vivo) imaging of thrombi in a mammal are also disclosed.(FR) Cette invention porte sur des dérivés de l'$g(a)-cétoamide, leurs sels pharmacocompatibles, leurs composés, des préparations à des fins de diagnostic, et des préparations pharmaceutiques les contenant, qui s'avèrent utiles pour la prévention ou le traitement chez les mammifères d'états pathologiques se manifestant par des thromboses. L'invention porte également sur des dérivés de $g(a)-cétoamide, leurs sels pharmacocompatibles, composés, et préparations à des fins du diagnostic, qui s'avèrent utiles pour la visualisation $i(in vivo) des thromboses chez les mammifères, sur des méthodes de prévention et de traitement chez les mammifères d'états pathologiques se manifestant par des thromboses et des méthodes de visualisation $i(in vivo) de thrombus.

  该发明涉及以一种哺乳动物为对象，利用泪 enjoyment方法或者治疗导致血栓形成的病理状态的，涉及 tear g(a)-氨基酰离子药物以及其药用盐、复合物或诊断复合物的。本发明还涉及用于在哺乳动物体内实现血栓图像视觉化的技术。 描述了$g(a)-氨基酰胺衍生物及其药用可接受的盐、复合物、诊断复合物和制药复合物，这些化合物对于在哺乳动物中预防或治疗由血栓所导致的病理状态是有用的。以下是关于用于在哺乳动物中预防、治疗由血栓所导致的病理状态和体内外血栓图像视觉化的方法的描述。
• Total Synthesis of Cyclotheonamide B, a Facile Route towards Analogues
  作者：H Bastiaans

  DOI：10.1016/00404-0399(50)11539-

  日期：1995.8.14

  A flexible, convergent synthesis of Cyclotheonamide B (1b) was developed, starting from the constituent amino acids, using conventional benzyl-, t-butyl- and allyl-based protecting groups. By modification of the key intermediates, this approach allows the preparation of cyclotheonamide analogues.
• Maryanoff, Bruce E.; Greco, Michael N.; Zhang, Han-Cheng, Journal of the American Chemical Society, 1995, vol. 117, # 4, p. 1225 - 1239
  作者：Maryanoff, Bruce E.、Greco, Michael N.、Zhang, Han-Cheng、Andrade-Gordon, Patricia、Kauffman, Jack A.、Nicolaou、Liu, Aijun、Brungs, Peter H.

  DOI：——

  日期：——
• Reassignment of stereochemistry and total synthesis of the thrombin inhibitor cyclotheonamide B
  作者：Masahiko Hagihara、Stuart L. Schreiber

  DOI：10.1021/ja00042a053

  日期：1992.7