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首页> 外文期刊>Chemistry: A European journal >Exercises in pyrrolidine chemistry: Gram scale synthesis of a Pro-Pro dipeptide mimetic with a polyproline type II helix conformation
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Exercises in pyrrolidine chemistry: Gram scale synthesis of a Pro-Pro dipeptide mimetic with a polyproline type II helix conformation

机译：吡咯烷化学中的练习：克级合成具有脯氨酸II型螺旋构象的Pro-Pro二肽模拟物

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摘要

A practical and scalable synthesis of a Fmoc-protected tricyclic dipeptide mimetic (6), that is, a 1,4-diaza-tricyclo-[8.3.0~(3, 7)]-tridec-8-ene derivative resembling a rigidified di-L-proline in a polyproline type II (PPII) helix conformation, was developed. The strategy is based on a Ru-catalyzed ring-closing metathesis of a dipeptide (4) prepared by PyBOP coupling of cis-5-vinylproline tert-butylester (2) and trans-N-Boc-3-vinylproline (rac-3) followed by chromatographic diastereomer separation. Building block 2 was prepared from L-proline in six steps via electrochemical C5-methoxylation, cyanation and conversion of the nitrile into a vinyl substituent. Building block rac-3 was prepared in five steps exploiting a Cu-catalyzed 1,4-addition of vinyl-MgBr to a 2,3-dehydroproline derivative in the key step. In the course of the investigation subtle dependencies of protecting groups on the reactivity of the 2,3- and 2,5-disubstituted pyrrolidine derivatives were observed. The configuration and conformational preference of several intermediates were determined by X-ray crystallography. The developed synthesis allows the preparation of substantial amounts of 6, which will be used in the search for new small molecules for the modulation of protein-protein interactions involving prolin-rich motifs (PRDs).
机译：一种实用且可扩展的Fmoc保护的三环二肽模拟物（6）的合成方法，即类似于刚性化的1,4-二氮杂-三环-[8.3.0〜（3，7）]-tridec-8-ene衍生物开发了聚脯氨酸II型（PPII）螺旋构象的di-L-脯氨酸。该策略基于Ru催化的二肽（4）的闭环复分解反应，该复分解反应是通过PyBOP偶联顺式5-乙烯基脯氨酸叔丁酯（2）和反式-N-Boc-3-乙烯基脯氨酸（rac-3）制备的然后进行色谱非对映体分离。由L-脯氨酸通过电化学C5-甲氧基化，氰化和腈转化为乙烯基取代基的六步制备结构单元2。分五个步骤制备了结构单元rac-3，该步骤在关键步骤中利用了Cu催化的乙烯基-MgBr的1,4-加成反应生成2,3-脱氢脯氨酸衍生物。在研究过程中，观察到保护基对2，3-和2，5-二取代的吡咯烷衍生物的反应性的细微依赖性。通过X射线晶体学测定几种中间体的构型和构象偏好。发达的合成方法可以制备大量的6，这些分子将用于寻找新的小分子来调节涉及富脯氨酸基序（PRD）的蛋白质-蛋白质相互作用。

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