New synthetic pathways to polyfluoroalkyl-containing amino- and hydroxy acids with potential biological activity

这个为期一年的项目旨在完成我的团队与伊戈尔一世团队的长期成功合作。Gerus和Ivan S.来自乌克兰科学院的康德拉托夫在基辅。该项目的重点是开发新的氟化氨基酸和羟基酸作为天然氨基酸的潜在生物电子等排体，并研究氟化基团对此类分子行为的影响。将氟或多氟烷基引入生物相关有机分子中是一种有效的方法，用于对重要性质如偶极矩、碱性/酸性、亲脂性进行特定改性，从而改变化学反应性和生物活性。例如，在过去几年中合成了许多含氟氨基酸，其中一些由于其作为某些酶的可逆或自杀抑制剂、作为用于分子结构研究的方便的19 F NMR探针和作为肽合成的结构单元的潜在药用用途而引起了特别的兴趣。在第一个资助期内，我们研究了（i）三氟甲基化吡喃酮与不同亲二烯体的Diels-Alder反应，以合成新的含三氟甲基的芳香族氨基酸和（ii）2-氨基-5-三氟甲基吡喃酮的催化氢化，作为制备新的氟化氨基酸和羟基酸的基础。继续我们在这一领域的研究，我们将开发立体选择性途径对5-聚氟烷基脯氨酸类似物被用作空间固定的肽类似物。另一个目标是制备和研究多官能氟化结构单元，其可用于合成在战略位置上带有氟原子或氟化基团的脯氨酸、谷氨酰胺、鸟氨酸等的不同类似物。我们还将完成我们在生物学感兴趣的氟化GABA类似物领域的研究。最后，我们将制备和研究含三氟甲氧基的氨基酸，这是很少探索，但预计将是感兴趣的生物有机化学，特别是肽建模，由于其极其亲脂的特性。

This one-year project is designed to finalize the long-lasting successful collaboration of my group with the group of Igor I. Gerus and Ivan S. Kondratov from the Academy of Sciences of Ukraine in Kiev. The project focuses on the development of new fluorinated amino- and hydroxy acids as potential bioisosteres of natural amino acids and on the investigation of the influence of fluorinated groups on the behavior of such molecules. The introduction of fluorine or polyfluoroalkyl groups into bio-relevant organic molecules is an efficient method for the specific modification of important properties such as dipole moment, basicity/acidity, lipophilicity, and hence of the chemical reactivity and biological activity. By way of example, many fluorine-containing amino acids were synthesized during past years and some of them have attracted particular interest owing to their potential medicinal utility as reversible or suicide inhibitors of certain enzymes, as convenient 19F NMR probes for molecular structure investigations and as building blocks for peptide synthesis. In the first funding period we investigated (i) Diels-Alder reactions of trifluoromethylated pyrones with different dienophiles in order to synthesize new trifluoromethyl containing aromatic amino acids and (ii) the catalytic hydrogenation of 2-amino-5-trifluoromethylpyrones as the basis for the preparation of new fluorinated amino- and hydroxy acids. Continuing our investigations in this field, we will develop stereoselective pathways towards 5-polyfluoroalkyl proline analogs to be used as sterically fixed peptide analogs. Another goal is the preparation and investigation of polyfunctional fluorinated building blocks, which can be applied for the synthesis of different analogs of proline, glutamine, ornithine, etc. bearing fluorine atoms or fluorinated groups in strategic positions. We are also going to finalize our studies in the field of fluorinated GABA analogs of biological interest. Finally we will prepare and investigate trifluoromethoxy containing amino acids, which are scantily explored but are expected to be of interest for bioorganic chemistry, particularly for peptide modeling due to its extremely lipophilic character.