Fmoc-3-mGlu(OtBu)-OH | 1429504-34-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: Fmoc-3-mGlu(OtBu)-OH
• 英文别名: Fmoc-(2S,3R)-3-methylglutamic acid γ-tert-butyl ester；(2S,3R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-3-methyl-5-oxopentanoic acid；(2S,3R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid
• CAS: 1429504-34-6
• 化学式: C₂₅H₂₉NO₆
• 分子量: 439.508
• InChiKey: HYWKADVVVLDYEH-QRQCRPRQSA-N

物化性质

• 沸点：
  635.9±55.0 °C(Predicted)
• 密度：
  1.213±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Fmoc-gly-wang resin 、 O-(2-甲基-2-丙基)-N-{[(2-甲基-2-丙基)氧基]羰基}-D-丝氨酸 、 (2S)-2-(癸酰氨基)-3-(1H-吲哚-3-基)丙酸 、 Fmoc-3-mGlu(OtBu)-OH 、 O-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(N-(tert-butoxycarbonyl)formamido)phenyl)-4-oxobutanoyl)-N-((S)-2-azido-4-(tert-butoxy)-4-oxobutanoyl)-L-threonylglycine 、 Fmoc-L-天冬氨酸 beta-叔丁酯 、 Fmoc-D-丙氨酸 、 N-Fmoc-N'-Boc-L-鸟氨酸 、 N-Fmoc-N'-三苯甲基-D-天冬酰胺 在 哌啶 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Total Synthesis of Daptomycin by Cyclization via a Chemoselective Serine Ligation

  摘要：

  A total synthesis of daptomycin, the first natural product antibiotic launched in a generation, was achieved. This convergent synthesis relies on an efficient macrocyclization via a serine ligation to assemble the 31-membered cyclic depsipeptide. The difficult esterification by the nonproteinogenic amino acid kynurenine was accomplished via the esterification of a threonine residue by a suitably protected Trp ester, followed by ozonolysis. This synthesis provides a foundation and framework to prepare varied analogues of daptomycin to establish its structure-activity profile.

  DOI：

  10.1021/ja4012468
• 作为产物：
  描述：

  二乙基膦酰基乙酸叔丁酯 在 copper(l) iodide 、 Jones reagent 、 palladium 10% on activated carbon 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 乙醚 、 水 、 异丙醇 、 丙酮 、 mineral oil 为溶剂， 反应 3.67h， 生成 Fmoc-3-mGlu(OtBu)-OH
  参考文献：
  名称：

  由Fmoc保护的Garner醛高效合成和（2S，3R）-3-烷基和链烯基谷氨酸的对映体。

  摘要：

  （2S，3R）-3-烷基/烯基谷氨酸的6步对映选择性合成，包括具有生物意义的氨基酸（2S，3R据报道，针对Fmoc SPPS保护的）-3-甲基谷氨酸。总产量在52–65％之间。这些合成成功的关键是开发了高产率的两步合成Fmoc Garner醛，然后进行了Horner-Wadsworth-Emmons反应，以94％的产率得到了相应的Fmoc Garner的烯酸酯。探索了非对映选择性的1,4-二烷基铜酸锂加到Fmoc Garner的烯酸酯中。当使用二乙基铜酸锂和以前报道的将二烷基铜酸锂1，4-加到Boc或Cbz保护的Garner烯酸酯中的条件下，会发生明显的分解。通过对该反应的优化研究，得出了一系列可靠的条件，从而解决了先前报道的条件的缺点。在这种情况下，高度非对映选择性（大多数情况下> 20：1）1 二烷基/二烯基锂碳酸锂与Fmoc Garner烯酸酯的4加成反应以76-99％的产率实现。所得的1

  DOI：

  10.1007/s00726-020-02868-7

文献信息

• DAPTOMYCIN ANALOGUES AND A METHOD FOR THE PREPARATION OF DAPTOMYCIN OR A DAPTOMYCIN ANALOGUE
  申请人：THE UNIVERSITY OF HONG KONG

  公开号：US20150126707A1

  公开（公告）日：2015-05-07

  A method for the synthesis of daptomycin or a daptomycin analogue is carried out on a resin to form a linear precursor followed by a serine ligation macrocyclization in solution. Daptomycin analogues can differ from daptomycin by substitution of amino acids residues and/or deletion or addition of amino acid residues. Daptomycin analogues can include a different fatty acid in the side arm of the daptomycin analogue.

  一种合成达托霉素或达托霉素类似物的方法在树脂上进行，形成线性前体，然后在溶液中进行丝氨酸连接的大环化反应。达托霉素类似物可以通过替换氨基酸残基和/或删除或添加氨基酸残基与达托霉素不同。达托霉素类似物的侧链中可以包含不同的脂肪酸。
• Establishing the Structure–Activity Relationship of Daptomycin
  作者：Hoi Yee Chow、Kathy Hiu Laam Po、Kang Jin、Guanlin Qiao、Zhenquan Sun、Wenjie Ma、Xiyun Ye、Ning Zhou、Sheng Chen、Xuechen Li

  DOI：10.1021/acsmedchemlett.0c00175

  日期：2020.7.9

  of daptomycin analogues were synthesized, and the antimicrobial activities of the analogues were analyzed by several biological assays. From this study, we established a comprehensive structure–activity relationship of daptomycin which will lay the foundation for the further development of daptomycin-based antibiotics.

  达托霉素可有效治疗由耐抗生素的革兰氏阳性病原体引起的感染，包括耐甲氧西林的金黄色葡萄球菌（MRSA），耐万古霉素的肠球菌（VRE）和耐万古霉素的金黄色葡萄球菌（VRSA）。由于其对多重耐药细菌的独特作用机理，达托霉素提供了一种有吸引力的结构基序，可产生新的基于达托霉素的抗生素来对抗细菌耐药性问题。在这项研究中，我们使用了总合成方法来生产达托霉素类似物，其修饰类型和修饰位点多种多样。合成了五类达托霉素类似物，并通过几种生物学试验分析了该类似物的抗菌活性。通过这项研究，我们建立了达托霉素的全面结构-活性关系，这将为进一步开发基于达托霉素的抗生素奠定基础。
• Total Synthesis and Structural Establishment/Revision of Antibiotics A54145
  作者：Delin Chen、Hoi Yee Chow、Kathy Hiu Laam Po、Wenjie Ma、Emily Lok Yee Leung、Zhenquan Sun、Ming Liu、Sheng Chen、Xuechen Li

  DOI：10.1021/acs.orglett.9b01972

  日期：2019.7.19

  and the hydroxy-asparagine (HO-Asn) have been reported. We have developed efficient routes to obtain the fully protected l-MeO-Asp and l-HO-Asn building blocks compatible with Fmoc-SPPS, and a total synthesis of A54145 that enabled us to establish its structure, consisting of l-3S-HO-Asn and l-3R-MeO-Asp, revising the wrongly proposed structure of l-3S-MeO-Asp.

  A54145是一类结构类似于达托霉素的抗菌环脂肽家族。自1990年被发现以来，仅报道了甲氧基天冬氨酸（MeO-Asp）和羟基天冬酰胺（HO-Asn）的歧义结构。我们已经开发出有效的路线，以获得充分的保护升-MeO-Asp和升-总部-ASN建设与Fmoc-SPPS兼容块，这使我们能够建立其结构，由A54145的全合成升-3小号- HO-Asn和l -3 R -MeO-Asp，修改了错误提出的l -3 S -MeO-Asp结构。
• Solid-Phase Total Synthesis of Daptomycin and Analogs
  作者：Chuda Raj Lohani、Robert Taylor、Michael Palmer、Scott D. Taylor

  DOI：10.1021/acs.orglett.5b00043

  日期：2015.2.6

  An entirely solid-phase synthesis of daptomycin, a cyclic lipodepsipeptide antibiotic currently in clinical use, was achieved using a combination of α-azido and Fmoc amino acids. This methodology was applied to the synthesis of several daptomycin analogs, one of which did not contain kynurenine or the synthetically challenging amino acid (2S,3R)-methylglutamate yet exhibited an MIC approaching that of daptomycin.
• Methylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active against Resistant Pathogens
  作者：Hoi Yee Chow、Kathy Hiu Laam Po、Peng Gao、Pilar Blasco、Xiukun Wang、Congran Li、Lianwei Ye、Kang Jin、Kaichao Chen、Edward Wai Chi Chan、Xuefu You、Richard Yi Tsun Kao、Sheng Chen、Xuechen Li

  DOI：10.1021/acs.jmedchem.9b01957

  日期：2020.3.26

  Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including dapto-mycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.