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Studies on the synthesis of stable-isotope-labeled amino acids canying functional group and their conformational analysis

带官能团的稳定同位素标记氨基酸的合成及其构象分析研究

基本信息

批准号：
13640544
负责人：
OBA Makoto
金额：
$ 2.24万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Recently, the combination of stable isotope labeling and advanced multidimensional NMR spectroscopy has become more promising method for determining the overall and local structures of proteins in solution. In particular, the regio-and stereoselectively isotope-labeled amino acids are excellent probes for collecting precise structural information such as the side-chain conformations about specific residues. We have recently explored the methods for stereoselective deuteration of only one of the diastereotopic methyl groups and methylene protons of amino acid side-chains. However, investigation of amino acids carrying a functional group in the side chain, such as lysine, arginine, serine, cystein, aspartic acid, and so on, remains untouched despite their importance in protein function. In the present work, we investigated the regio-and stereoselective deuterium labeling of such amino acids. The representative results are as follows.1. Asymmetric synthesis of (2S,3S,4R,5R)-[2,3,4,5-D_4]o … More rnithine was examined. The chirally deuterated 3-aminopropanal was prepared by a catalytic deuteration of an unsaturated -γ-lactone derived from L-glutamic acid followed by several functional group interconversions. Condensation of the obtained deuterium-labeled 3-aminopropanal with a chiral glycine template afforded unsaturated ornithine. The dehydroornithine was then subjected to a catalytic deuteration followed by deprotection to give the L-[2,3,4,5-D_4]ornithine.2. Synthesis of L-[5,5,6,6-D_4]lysine starting from L-pyroglutamic acid was investigated. One carbon homologation of the side chain was carried out by cyanation of deuterated 5-iodonorvaline prepared from L-pyroglutamic acid. Catalytic deuteration of the obtained cyanide followed by the standard deprotection procedure afforded L-[5,5,6,6-D_4]lysine.3. Synthesis of a novel 3,4-didehydropyroglutamate derivative in which the carboxylic group is protected as an ABO ester was examined. Some reactions of the obtained unsaturated pyroglutamate template such as dihydroxylation, Michael addition, and some cycloadditions were found to take place in a stereospecific manner. Catalytic deuteration of the olefin followed by acidic hydrolysis gave (2S,3S,4R)-[3,4-D_2]glutamic acid. Less

近年来，稳定同位素标记技术与先进的多维核磁共振技术相结合，已成为确定蛋白质整体和局部结构的一种新方法。特别是，区域和立体选择性同位素标记的氨基酸是很好的探针，用于收集精确的结构信息，如特定残基的侧链构象。我们最近探索了立体选择性氘化的方法，只有一个非对映异构体的甲基和氨基酸侧链的亚甲基质子。然而，尽管在蛋白质功能中具有重要性，但对在侧链中携带功能基团的氨基酸，如赖氨酸、精氨酸、丝氨酸、半胱氨酸、天冬氨酸等的研究仍然未受影响。在目前的工作中，我们研究了区域和立体选择性氘标记的氨基酸。代表性结果如下。1.（2S，3S，4 R，5 R）-[2，3，4，5-D_4]o的不对称合成 ...更多信息检查鸟氨酸。由L-谷氨酸衍生的不饱和-γ-内酯经催化氘代反应，再经几个官能团相互转化，得到手性氘代3-氨基丙醛。氘标记的3-氨基丙醛与手性甘氨酸模板缩合得到不饱和鸟氨酸。脱氢鸟氨酸再经催化氘代、脱保护得到L-[2，3，4，5-D_4]鸟氨酸。以L-焦谷氨酸为原料合成L-[5，5，6，6-D_4]赖氨酸。以L-焦谷氨酸为原料，通过氘代5-碘正缬氨酸的氰化反应，实现了侧链的一碳同系化。将所得氰化物催化氘化，然后进行标准脱保护程序，得到L-[5，5，6，6-D_4]赖氨酸。研究了一种新型的3，4-二脱氢焦谷氨酸酯衍生物的合成，其中羧基被保护为ABO酯。所得的不饱和焦谷氨酸模板的一些反应，如双羟基化，迈克尔加成，和一些环加成被发现发生在立体特异性的方式。烯烃经催化氘代后酸解得（2S，3S，4 R）-[3，4-D_2]谷氨酸。少