[(1E,3S,4R,5S,8R,9E,12S,14S)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-8-ethyl-5-hydroxy-14-methoxy-14-[(2R,3S,5R)-3-methoxy-5-methyl-6-oxooxan-2-yl]-2,4,10,12-tetramethyl-7-oxotetradeca-1,9-dien-3-yl] (2S)-1-formylpiperidine-2-carboxylate | 686773-65-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: [(1E,3S,4R,5S,8R,9E,12S,14S)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-8-ethyl-5-hydroxy-14-methoxy-14-[(2R,3S,5R)-3-methoxy-5-methyl-6-oxooxan-2-yl]-2,4,10,12-tetramethyl-7-oxotetradeca-1,9-dien-3-yl] (2S)-1-formylpiperidine-2-carboxylate
• CAS: 686773-65-9
• 化学式: C₄₂H₆₈ClNO₁₀
• 分子量: 782.456
• InChiKey: GHKXGBGDMDKVSJ-ZJWSYRQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  54
• 可旋转键数：
  20
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  138
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  甲醇 、 吡美莫司 以66%的产率得到
  参考文献：
  名称：

  氨基酸区域有修饰的新孢子霉素衍生物——5,6-脱氢孢子霉素的合成，生物活性和X射线晶体结构

  摘要：

  Abstractmagnified imageThe immunomodulatory macrolide ascomycin (1a) inhibits T‐cell activation via binding to macrophilin‐12 and inhibition of the phosphatase calcineurin. Its structural analogs pimecrolimus and tacrolimus have recently become available as the first novel topical treatments of atopic dermatitis since the introduction of topical corticosteroids in the 1950s. This stimulated the search for novel derivatives with an improved biological profile. Though several derivatives of 1a are known, only a few derivatives with modifications on the amino acid moiety are available because of the chemical inaccessibility of this region. To this end, we present here a new approach using a photochemical reaction as the key step. Thus, irradiation of ascomycin (1a) led to mixtures of the methoxy products 2a and 8, the cleavage product 4a, the but‐1‐enyl derivative 7, and the oxazolidinone 9 depending on the solvent. The selectivity of the reaction was improved to furnish 2a or 9 in preparatively useful yields. The mechanism and scope of the reaction were investigated. Starting from 2a, several analogs featuring novel modifications on the amino acid moiety, which are not easily accessible through routine methods, were synthesized in a few steps. Further, using the photoreaction key intermediates with potential for broader modifications on the amino acid moiety were synthesized, and their utility was exemplified by the synthesis of vinylpipecolic acid and vinylproline analogs. An interesting photochemical cleavage of the amide bond in the derivatives of ascomycin (1a) is presented. The structural and conformational features of the new analogs together with the X‐ray crystal structure of 5,6‐dehydroascomycin (6a) are presented, and their biological activities are discussed. Of all the derivatives, 6a showed the best activities in in vitro and in vivo models of allergic contact dermatitis whilst showing a lower risk of immunosuppression.

  DOI：

  10.1002/hlca.200800436

文献信息

• New Derivatives of Ascomycin with Modifications in the Amino Acid Region - Synthesis and Biological Activities, and X-Ray Crystal Structure of 5,6-Dehydroascomycin
  作者：Murty A. R. C. Bulusu、Peter Waldstätten、Thomas Tricotet、Christophe Rochais、Andrea Steck、Markus Bacher、Gerhard Schulz、Josef G. Meingassner、Peter Hiestand、Gerhard Zenke、Walter Schuler、Trixie Wagner

  DOI：10.1002/hlca.200800436

  日期：2009.5

  Abstractmagnified imageThe immunomodulatory macrolide ascomycin (1a) inhibits T‐cell activation via binding to macrophilin‐12 and inhibition of the phosphatase calcineurin. Its structural analogs pimecrolimus and tacrolimus have recently become available as the first novel topical treatments of atopic dermatitis since the introduction of topical corticosteroids in the 1950s. This stimulated the search for novel derivatives with an improved biological profile. Though several derivatives of 1a are known, only a few derivatives with modifications on the amino acid moiety are available because of the chemical inaccessibility of this region. To this end, we present here a new approach using a photochemical reaction as the key step. Thus, irradiation of ascomycin (1a) led to mixtures of the methoxy products 2a and 8, the cleavage product 4a, the but‐1‐enyl derivative 7, and the oxazolidinone 9 depending on the solvent. The selectivity of the reaction was improved to furnish 2a or 9 in preparatively useful yields. The mechanism and scope of the reaction were investigated. Starting from 2a, several analogs featuring novel modifications on the amino acid moiety, which are not easily accessible through routine methods, were synthesized in a few steps. Further, using the photoreaction key intermediates with potential for broader modifications on the amino acid moiety were synthesized, and their utility was exemplified by the synthesis of vinylpipecolic acid and vinylproline analogs. An interesting photochemical cleavage of the amide bond in the derivatives of ascomycin (1a) is presented. The structural and conformational features of the new analogs together with the X‐ray crystal structure of 5,6‐dehydroascomycin (6a) are presented, and their biological activities are discussed. Of all the derivatives, 6a showed the best activities in in vitro and in vivo models of allergic contact dermatitis whilst showing a lower risk of immunosuppression.