Synthesis and separation of diastereomers of ribonucleoside 5′-(α-P-borano)triphosphates
Synthesis and separation of diastereomers of ribonucleoside 5′-(α-P-borano)triphosphates
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DOI：
10.1021/jo972002g
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发表时间：
1998-08-21
影响因子：
3.6
通讯作者：
Shaw, BR
中科院分区：
文献类型：
--
作者：
He, KH;Hasan, A;Shaw, BR
核苷硼烷磷酸盐，其中一个磷酸氧被硼烷基团取代，是天然存在的核苷酸的等离子和等电子类似物。硼代磷酸酯也是硫代磷酸酯和甲基膦酸酯的生物化学上重要的同系物。我们开发了一种方便的一锅法合成核糖核苷（A，U，G和C）5 '-（α-P-硼基）三磷酸组。用8-氯-4H-1，3，2-苯并二氧磷杂环己-4-酮对2 ′，3 ′-保护的核糖核苷进行磷酸化，得到5 ′-亚磷酸酯中间体2，其在焦磷酸盐存在下进行原位取代，得到环状中间体β-2，β-3-二氧代-β-1-核糖核苷酰基环三磷酸3。用胺硼烷络合物立即氧化化合物3产生核糖核苷5 '-（α-β-硼烷基）环三磷酸4。随后化合物4与水反应，然后与氢氧化铵反应，得到粗产物，为核糖核苷5 ′-（α-β-硼烷基）三磷酸6的非对映异构体混合物。使用离子交换色谱以30-45%的总产率分离纯化合物6。通过反相HPLC实现核糖核苷5 '-（α-β-硼基）三磷酸6的两种非对映异构体的分离。
Nucleoside boranophosphates, in which one of the phosphate oxygens is replaced by a borane group, are isoionic and isoelectronic analogues of naturally occurring nucleotides. Boranophosphates also are biochemically important congeners of phosphorothioates and methylphosphonates. We have developed a convenient one-pot method to synthesize the set of ribonucleoside (A, U, G, and C) 5'-(alpha-P-borano)triphosphates. Phosphitylation of the 2',3'-protected ribonucleoside with 8-chloro-4H-1,3,2-benzodioxaphosphorin-4-one gives the 5'-phosphite intermediate 2 which undergoes in situ substitution in the presence of pyrophosphate to give the cyclic intermediate, P-2,P-3-dioxo-P-1-ribonucleosidylcyclotriphosphate 3. Immediate oxidation of compound 3 with amine borane complex results in ribonucleoside 5'-(alpha-P-borano)cyclotriphosphate 4. Subsequent reaction of compound 4 with water followed by ammonium hydroxide yields the crude product as a diastereomeric mixture of ribonucleoside 5'-(alpha-P-borano)triphosphate 6. Pure compound 6 is isolated in 30-45% overall yield using ion-exchange chromatography. The separation of two diastereomers of ribonucleoside 5'-(alpha-P-borano)triphosphate 6 is achieved by reverse phase HPLC.