Qian Renzhe, Kalina Thomas, Horak Jeannie, Giberti Samuele, Forlani Giuseppe, Hammerschmidt Friedrich
Institute of Organic Chemistry, University of Vienna, Währingerstrasse 38, A-1090 Vienna, Austria.
Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, Eberhard-Karls-University Tübingen, Auf der Morgensstelle 8, 72076 Tübingen, Germany.
ACS Omega. 2018 Apr 24;3(4):4441-4452. doi: 10.1021/acsomega.8b00354. eCollection 2018 Apr 30.
Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding ()-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and -hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and ()-enantiomers (ee 92-99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ-pyrroline-5-carboxylate synthetase, and δ-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM.
外消旋的1-羟基-3-丁烯基膦酸酯、3-氯-1-羟基丙基膦酸酯和3-溴-1-羟基丙基膦酸酯，以及通过脂肪酶催化拆分相应的外消旋氯乙酸酯得到的相应（）-对映体，进行了官能团操作。这些操作包括臭氧分解、与叠氮酸和-羟基邻苯二甲酰亚胺的光延反应、肼衍生物的烷基化、邻苯二甲酰基的去除，随后进行分子内取代，以及整体脱保护，以得到吡咯烷-2-基膦酸、恶唑烷-3-基膦酸、恶唑烷-5-基膦酸、吡唑烷-3-基膦酸和1,2-恶嗪烷-3-基膦酸的外消旋体和（）-对映体（通过手性高效液相色谱法测定的对映体过量为92-99%）。对这些膦酸作为脯氨酸类似物和脯氨酸类似物抑制γ-谷氨酰激酶、δ-吡咯啉-5-羧酸合成酶和δ-吡咯啉-5-羧酸还原酶的能力进行了评估。只有后一种酶在浓度超过1 mM时被其中两种抑制。
