Stereoselective synthesis of the 5′-hydroxy-5′-phosphonate derivatives of cytidine and cytosine arabinoside
Stereoselective synthesis of the 5′-hydroxy-5′-phosphonate derivatives of cytidine and cytosine arabinoside
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DOI：
10.1021/jo020483k
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发表时间：
2002-12-27
影响因子：
3.6
通讯作者：
Wiemer, DF
中科院分区：
文献类型：
--
作者：
Chen, XM;Wiemer, AJ;Wiemer, DF
胞苷和胞嘧啶阿拉伯糖苷 (ara-C) 的 (R)-和 (S)-5'-羟基 5'-膦酸酯衍生物 (ara-C) 均通过亚磷酸盐加成或路易斯酸介导的适当保护的 5'-核苷醛的氢膦酰化来制备。亚磷酸酯加成到被保护为 2',3'-丙酮化合物的胞嘧啶醛上，主要产生 5R 异构体，而亚磷酸酯加成到相应的 2',3'-双 TBS 衍生物上，则有利于 5'S 立体化学。相比之下，将亚磷酸酯添加到源自ara-C的2',3'-双TBS保护的醛中仅得到5R加合物。然而，TiCl4 介导的同一 ara-C 醛的氢膦酰化有利于 5'S 立体异构体的形成，比例为 2:1。一旦掌握了所有四种非对映体，这些化合物的立体化学就可以根据它们的光谱数据或从它们的O-甲基扁桃酸酯衍生物获得的数据来确定。膦酸酯和各种保护基团水解后，测试了四种 α-羟基膦酸作为核苷单磷酸激酶底物的能力及其对 K562 细胞的毒性。
Both the (R)- and (S)-5'-hydroxy 5'-phosphonate derivatives of cytidine and cytosine arabinoside (ara-C) have been prepared via phosphite addition or a Lewis acid mediated hydrophosphonylation of appropriately protected 5'-nucleoside aldehydes. Phosphite addition to a cytosine aldehyde protected as the 2',3'-acetonide gave predominately the 5R isomer, while phosphite addition to the corresponding 2',3'-bis TBS derivative favored the 5'S stereochemistry. In contrast, phosphite addition to the 2',3'-bis TBS protected aldehyde derived from ara-C gave only the 5R adduct. However, TiCl4-mediated hydrophosphonylation of the same ara-C aldehyde favored the 5'S stereoisomer by a 2:1 ratio. Once all four of the diastereomers were in hand, the stereochemistry of these compounds could be assigned based on their spectral data or that obtained from their O-methyl mandelate derivatives. After hydrolysis of the phosphonate esters and various protecting groups, the four alpha-hydroxy phosphonic acids were tested for their ability to serve as substrates for the enzyme nucleoside monophosphate kinase and for their toxicity to K562 cells.