Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units
Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units
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DOI：
10.1002/bip.10570
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发表时间：
2004-01-01
期刊：
影响因子：
2.9
通讯作者：
Fujii, N
中科院分区：
文献类型：
--
作者：
Otaka, A;Mitsuyama, E;Fujii, N
已经表明，天然存在的生物活性化合物（包括氨基酸）的氟化类似物通常表现出独特的生理活性。在种类繁多的含氟氨基酸中，具有取代磷酰基酯氧的二氟亚甲基（CF 2）单元的非水解性磷酸氨基酸在医药和生物领域中具有价值。我们已经从事合成这些类的不可水解的磷酸氨基酸对应于pTyr 3，pSer 4，和pThr 5与它们的掺入肽使用新开发的脱保护程序。本文综述了CF2取代的pThr模拟物的立体选择性合成和两步脱保护方法的发展。在上述合成研究的过程中，我们发现γ，γ-二氟-α，β-烯酸酯被有机铜试剂还原成γ-氟-β，γ-烯酸酯，然后将其应用于（Z）-氟烯烃二肽电子等排体的合成，所述（Z）-氟烯烃二肽电子等排体充当潜在的二肽模拟物，所述二肽模拟物具有与母体肽键的结构以及静电相似性。此外，有机铜介导的还原机制的调查导致其发展的SmI 2介导的方法向合成的氟烯烃电子等排体。(C)2004 Wiley Periodicals，Inc.
It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF2) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these c lasses of nonhydrolyzable phosphoainino acials corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF2-substituted pThr mimetics and development of a two-step deprotecting methodology for, the nonhydrolyzable catalogues are reviewed. In the course of the above synthetic study, we found that -gamma, gamma-difluoro-alpha, beta-enoates were reduced to gamma-fluoro-beta, gamma-enoates by organocopper reagents and then applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similaritv to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led its to development of a SmI2-mediated approach toward the synthesis of the fluoroalkene isosteres. (C) 2004 Wiley Periodicals, Inc.