Otaka Akira, Mitsuyama Etsuko, Watanabe Junko, Watanabe Hideaki, Fujii Nobutaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Biopolymers. 2004;76(2):140-9. doi: 10.1002/bip.10570.
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 (CF(2)) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids 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 CF(2)-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues 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 similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led us to development of a SmI(2)-mediated approach toward the synthesis of the fluoroalkene isosteres.
研究表明，包括氨基酸在内的天然生物活性化合物的氟化类似物通常具有独特的生理活性。在种类繁多的含氟氨基酸中，具有二氟亚甲基（CF(2)）单元取代磷酸酯氧的不可水解磷酸氨基酸在医学和生物学领域具有重要价值。我们致力于合成这些对应于pTyr 3、pSer 4和pThr 5的不可水解磷酸氨基酸，并使用新开发的脱保护程序将它们掺入肽中。本文综述了CF(2)取代的pThr模拟物的立体选择性合成以及不可水解类似物的两步脱保护方法的开发。在上述合成研究过程中，我们发现γ,γ-二氟-α,β-烯酸酯可被有机铜试剂还原为γ-氟-β,γ-烯酸酯，然后应用于（Z）-氟烯烃二肽类似物的合成，这些类似物可作为与母体肽键具有结构和静电相似性的潜在二肽模拟物。此外，对有机铜介导还原反应的机理研究使我们开发出一种SmI(2)介导的合成氟烯烃类似物的方法。
