Stereoselective Synthesis of Fluorescent α‐Amino Acids Containing Oxine (8‐Hydroxyquinoline) and Their Peptide Incorporation in Chemosensors for Divalent Zinc.
Stereoselective Synthesis of Fluorescent α‐Amino Acids Containing Oxine (8‐Hydroxyquinoline) and Their Peptide Incorporation in Chemosensors for Divalent Zinc.
复制标题
含 Oxine（8-羟基喹啉）的荧光 α-氨基酸的立体选择性合成及其在二价锌化学传感器中的肽掺入。
DOI：
10.1002/chin.199907211
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
B. Imperiali
中科院分区：
文献类型：
--
作者：
G. Walkup;B. Imperiali
开发用于检测离子种类的荧光化学传感器一直是许多研究者关注的焦点。在继续寻找新的传感分子的过程中，工程配体在水溶液中表现出选择性和强烈的二价金属结合是至关重要的。2,3根据这些标准，我们试图在合成结构中利用天然存在的肽或蛋白质的通常无与伦比的金属结合特性。为了突出这种方法的通用性，我们为Zn (II)（基于锌指结构域）5,6和Cu (II)（基于血清白蛋白的氨基末端Cu （II）和Ni （II）结合结构域）制备了选择性化学传感器。最近，我们已经开始将这些和其他溶液型化学传感试剂连接到水溶剂化的树脂上，将它们转化为可再生装置。在这种情况下，相对较大尺寸的锌（II）荧光传感器（25个残基）阻碍了具有明确组成的传感材料的生产。为了使成功的Zn （II）传感器所需的肽基组分的尺寸最小化，我们开发了用于固相肽合成的新残基，这些残基含有众所周知的配体氧（8-羟基喹啉）的高亲和力，双齿金属结合功能；该化合物及其衍生物历来被用作锌（II）， 8以及其他几种阳离子的荧光指示剂。我们现在报道了(S)-2-氨基- nr -9-氟酰甲氧羰基-3-（氧-2-基）丙酸（Fmoc-2Oxn-OH, 1）和(S)-2-氨基- nr -9-氟酰甲氧羰基-3-（氧-5-基）丙酸（Fmoc-5Oxn-OH, 2）的合成，以及这些残基在短肽（7个残基）中的结合，能够报告亚微摩尔水平的锌（II）。方案1概述了以Myers伪麻黄碱甘氨酸酰胺烷基化10,11为关键立体反应步骤合成1的方法。以市售的8-羟基-2-甲基喹啉(3)为原料，通过苯酚作为苯磺酸酯的保护，然后进行自由基溴化，分两步制备溴化物4。选择假麻黄碱甘氨酸酰胺(5)的（R， R）-(-)对映体进行烷基化反应，以得到具有l构型的R-氨基酸衍生物6作为主要的非对映体。一般来说，为了在1-3小时内完成在0℃下进行的反应，使用了2个等量的5个等量的溴4，没有尝试确定烷基化反应的非对映选择性，但分离的收率高达89%，在> 95%，经1H NMR测定。6的碱性水解使r -氨基酸从苯磺酸酯和伪麻黄碱助剂中分离出来，然后将新释放的r -胺作为9-芴基甲氧羰基（Fmoc）衍生物进行保护，产率为1，收率为90%，ee为95%。13
The development of fluorescent chemosensors for the detection of ionic species has been a focus for many researchers. 1 In the continuing search for new sensing molecules, engineering ligands which exhibit selective and avid divalent metal binding in aqueous solution is critical. 2, 3 In light of these criteria, we have sought to harness within synthetic constructs the often unsurpassed metal-binding properties of naturally occurring peptides or proteins. 4 Highlighting the versatility of this approach, we have prepared selective chemosensors for both Zn (II)(based on the zinc finger domains) 5, 6 and for Cu (II)(based on the amino-terminal Cu (II) and Ni (II) binding domains of the serum albumins). 7 More recently, we have begun to convert these and other solution-based chemosensing reagents to regenerable devices by attaching them to water-solvated resins. In this context, the relatively large size of our Zn (II) fluorosensors (25 residues) is prohibitive to the production of sensing materials with well-defined composition. Toward the goal of minimizing the size of the peptidyl component required for a successful Zn (II) sensor, we have developed new residues for solid-phase peptide synthesis that contain the high-affinity, bidentate metal-binding functionality of the well-known ligand oxine (8-hydroxyquinoline); this compound and its derivatives have historically found use as fluorometric indicators of Zn (II), 8 as well as several other cations. 9 We now report the syntheses of (S)-2-amino-NR-9-fluorenylmethoxycarbonyl-3-(oxine-2-yl) propionic acid (Fmoc-2Oxn-OH, 1) and (S)-2-amino-NR-9-fluorenylmethoxycarbonyl-3-(oxine-5-yl) propionic acid (Fmoc-5Oxn-OH, 2), as well as the incorporation of these residues in short peptides (7 residues) capable of reporting sub-micromolar levels of Zn (II).The synthesis of 1, employing the Myers pseudoephedrine glycinamide alkylation10, 11 in the key stereogenic step, is outlined in Scheme 1. Starting from commercially available 8-hydroxy-2-methylquinoline (3), bromide 4 was prepared in two steps via protection of the phenol as the benzenesulfonate ester, followed by free radical bromination. The (R, R)-(-) enantiomer of pseudoephedrine glycinamide (5) was chosen for alkylations in order to yield as the major diastereomer the R-amino acid derivative 6 possessing the L-configuration. 12 In general, 2 equiv of 5 per equiv of bromide 4 were used in order to drive the reactions to completion within 1-3 h when conducted at 0 C. No attempt was made to determine the diastereoselectivity of the alkylation reaction, yet isolated yields of 6 as high as 89% were achieved, in> 95% de as determined by 1H NMR. Basic hydrolysis of 6 to free the R-amino acid from the benzenesulfonate ester and pseudoephedrine auxiliary, followed by protection of the newly liberated R-amine as the 9-fluorenylmethoxycarbonyl (Fmoc) derivative, provided 1 in 90% yield and> 95% ee. 13