Cyclosporin 4,7-bis(thioamide) | 139050-41-2

• 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: Cyclosporin 4,7-bis(thioamide)
• 英文别名: cyclo[Abu-Sar-N(Me)thionoLeu-Val-N(Me)Leu-thionoAla-D-Ala-N(Me)Leu-N(Me)Leu-N(Me)Val-N(Me)Bmt(E)]；(6S,9S,12S,15S,18S,21R,24S,27S,30S,33S)-6-ethyl-9-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,10,13,16,19,21,24,28-nonamethyl-15,18,27,33-tetrakis(2-methylpropyl)-12,30-di(propan-2-yl)-23,32-bis(sulfanylidene)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,26,29-nonone
• CAS: 139050-41-2
• 化学式: C₆₂H₁₁₁N₁₁O₁₀S₂
• 分子量: 1234.76
• InChiKey: WXHOPLWYCKWXJL-CGLBZJNRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  309
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  Cyclosporin 4,7-bis(thioamide) 在 盐酸 、 sodium hydroxide 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 0.75h， 生成 Val-MeLeu-Ala-thiocarboxylic acid S-benzyl ester
  参考文献：
  名称：

  Cyclosporin A: Regioselective Ring Opening and Fragmentation Reactions via Thioamides. A Route to Semisynthetic Cyclosporins

  摘要：

  Cyclosporin A (1a) served as the starting material for the semisynthetic preparation of a variety of novel cyclosporins. Acetylcyclosporin A (2) was treated with Lawesson's reagent. From the reaction mixture, three novel acetylated thioamides were isolated: the 4,7-bis(thioamide) 3a, the 7-thioamide 3b, and the 4-thioamide 3c. The acetylated products 3a-c were hydrolyzed to the known thioamides 4a-c, respectively. The 7-thioamide 3b was alkylated to give the S-benzyl thioamidate 5b. A regioselective ring opening reaction at the activated site was induced by treating 5b under acidic conditions giving the 7,8-seco-cyclosporin 7a. The (R)-alanine moiety was replaced by (R)-phenylalanine via the Edman degradation product 7e giving 7f. Removal of the protecting groups led to 7h. This was cyclized to [(R)-phenylalanine](8)-cyclosporin (1b). The N-protected 7,8-seco-cyclosporin 7i was reduced to the aldehyde 7j, homologated (7k), and deprotected to give 7m. This was cyclized to the vinylogous cyclosporin 8a. Similarly,:the 4,5-seco-cyclosporin 9c was prepared and converted via several steps (9d-h) to the vinylogous cyclosporin 8b. Finally, under acidic conditions, the dibenzyl bis(thioamidate) 5a underwent a fragmentation reaction to give the octapeptide 10a and the tripeptide 11a. The octapeptide 10a was coupled with a different tripeptide (11d) to 9i and cyclized via 9j-k to the [(S)-phenylalanine](7)-cyclosporin (1c).

  DOI：

  10.1021/jo00103a015
• 作为产物：
  描述：

  O-acetyl-cyclosporin A 在 劳森试剂 、 sodium methylate 作用下， 以 甲醇 、 xylene 为溶剂， 反应 3.0h， 生成 Cyclosporin 4,7-bis(thioamide)
  参考文献：
  名称：

  Cyclosporin A: Regioselective Ring Opening and Fragmentation Reactions via Thioamides. A Route to Semisynthetic Cyclosporins

  摘要：

  Cyclosporin A (1a) served as the starting material for the semisynthetic preparation of a variety of novel cyclosporins. Acetylcyclosporin A (2) was treated with Lawesson's reagent. From the reaction mixture, three novel acetylated thioamides were isolated: the 4,7-bis(thioamide) 3a, the 7-thioamide 3b, and the 4-thioamide 3c. The acetylated products 3a-c were hydrolyzed to the known thioamides 4a-c, respectively. The 7-thioamide 3b was alkylated to give the S-benzyl thioamidate 5b. A regioselective ring opening reaction at the activated site was induced by treating 5b under acidic conditions giving the 7,8-seco-cyclosporin 7a. The (R)-alanine moiety was replaced by (R)-phenylalanine via the Edman degradation product 7e giving 7f. Removal of the protecting groups led to 7h. This was cyclized to [(R)-phenylalanine](8)-cyclosporin (1b). The N-protected 7,8-seco-cyclosporin 7i was reduced to the aldehyde 7j, homologated (7k), and deprotected to give 7m. This was cyclized to the vinylogous cyclosporin 8a. Similarly,:the 4,5-seco-cyclosporin 9c was prepared and converted via several steps (9d-h) to the vinylogous cyclosporin 8b. Finally, under acidic conditions, the dibenzyl bis(thioamidate) 5a underwent a fragmentation reaction to give the octapeptide 10a and the tripeptide 11a. The octapeptide 10a was coupled with a different tripeptide (11d) to 9i and cyclized via 9j-k to the [(S)-phenylalanine](7)-cyclosporin (1c).

  DOI：

  10.1021/jo00103a015

文献信息

• Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity
  作者：Dieter Seebach、Soo Y. Ko、Horst Kessler、Matthias Köck、Michael Reggelin、Peter Schmieder、Malcolm D. Walkinshaw、J. Jakob Bölsterli、Dorian Bevec

  DOI：10.1002/hlca.19910740833

  日期：1991.12.11

  The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O-atoms and/or the hydroxy O-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins

  环孢菌素A（CsA）与Lawesson试剂在不同条件下的反应产生了各种硫代环孢菌素，其中MeBmt残基的羰基O原子和/或羟基O原子被S原子取代。通过NMR光谱确定S原子的位置，并通过NMR光谱和X射线结晶学研究产物的构象。一些硫代环孢菌素显示出有趣的构象性质。而一个构象强烈CDCL支配为环孢素A 3，两种构象异构A和B，在一个比58:42被发现为[ 1 ψ 2，CS–NH] CsA。广泛的NMR研究（包括新的2D和3D异核技术）和使用ROE效应的受限MD计算表明，主要构象异构体A与CsA相同，而次要构象异构体B在Sar 3和MeLeu 4残基之间包含一个顺式肽键。[ 4 ψ 5，CSNH; 7 ψ 8，CS-NH]的CsA表现出非常相似的结晶的CsA的构象。然而，在该二硫代类似物中不存在D-Ala 8 N H，MeLeu 6 Coγ-转H键。MeBmt 1也不同侧链构象，二硫构象显示出强MeBmt
• Cyclosporin A: Regioselective Ring Opening and Fragmentation Reactions via Thioamides. A Route to Semisynthetic Cyclosporins
  作者：Marcel K. Eberle、Anne-Marie Jutzi-Eme、Francois Nuninger

  DOI：10.1021/jo00103a015

  日期：1994.12

  Cyclosporin A (1a) served as the starting material for the semisynthetic preparation of a variety of novel cyclosporins. Acetylcyclosporin A (2) was treated with Lawesson's reagent. From the reaction mixture, three novel acetylated thioamides were isolated: the 4,7-bis(thioamide) 3a, the 7-thioamide 3b, and the 4-thioamide 3c. The acetylated products 3a-c were hydrolyzed to the known thioamides 4a-c, respectively. The 7-thioamide 3b was alkylated to give the S-benzyl thioamidate 5b. A regioselective ring opening reaction at the activated site was induced by treating 5b under acidic conditions giving the 7,8-seco-cyclosporin 7a. The (R)-alanine moiety was replaced by (R)-phenylalanine via the Edman degradation product 7e giving 7f. Removal of the protecting groups led to 7h. This was cyclized to [(R)-phenylalanine](8)-cyclosporin (1b). The N-protected 7,8-seco-cyclosporin 7i was reduced to the aldehyde 7j, homologated (7k), and deprotected to give 7m. This was cyclized to the vinylogous cyclosporin 8a. Similarly,:the 4,5-seco-cyclosporin 9c was prepared and converted via several steps (9d-h) to the vinylogous cyclosporin 8b. Finally, under acidic conditions, the dibenzyl bis(thioamidate) 5a underwent a fragmentation reaction to give the octapeptide 10a and the tripeptide 11a. The octapeptide 10a was coupled with a different tripeptide (11d) to 9i and cyclized via 9j-k to the [(S)-phenylalanine](7)-cyclosporin (1c).