Investigation on Condensing Agents for Phosphinate Ester Formation with Nucleoside 5′-Hydroxyl Functions†
Investigation on Condensing Agents for Phosphinate Ester Formation with Nucleoside 5′-Hydroxyl Functions†
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核苷 5′-羟基官能团用于形成次膦酸酯的缩合剂的研究†
DOI：
10.1002/ejoc.200700528
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发表时间：
2008
影响因子：
2.8
通讯作者：
R. Strömberg
中科院分区：
文献类型：
--
作者：
A. Winqvist;R. Strömberg
研究了尿苷3′-脱氧-3 ′-C-亚甲基次膦酸酯与胸苷和鸟苷衍生物的缩合反应。对许多不同的缩合剂进行了比较，这些缩合剂包括新戊酰氯、三异丙基苯磺酰氯（TPS-Cl）、磷鎓和脲鎓衍生物、许多氯磷酸盐和双（2-氧代-3-恶唑烷基）次膦酰氯（OXP）。磷衍生物在亚甲基次膦酸酯的预活化期间产生缓慢缩合或氧化副反应（羟基苯并三唑衍生物）。特戊酰氯的偶联时间较长，并检测到竞争性5′-O-特戊酰化。TPS-Cl使产物快速缩合，但也使产物快速氧化。大多数氯磷酸盐与核苷组分的5′-O-磷酸化以及碱基磷酸化竞争。然而，2-氯-5，5-二甲基-2-氧代-1，3，2-二氧磷杂环己烷（DMOCP）以相当好的速率给出了二核苷亚甲基次膦酸酯的相当有效的形成。然而，使用该试剂，鸟嘌呤的O 6-保护可能变得必要，因为在延长的反应时间后，即使使用低浓度（60 mM）的DMOCP（2当量），也检测到痕量的O 6-磷酸化。次膦酸盐）。与DMOCP不同，双（2-氧代-3-恶唑烷基）次膦酰氯（OXP）可以以与次膦酸盐几乎等摩尔的量使用。在这样的条件下，OXP以与2当量的速率相当的速率给出几乎定量的缩合。的DMOCP，并且没有检测到副反应。我们也不能检测到OXP预活化的次膦酸盐的任何分解。亲核催化剂，比吡啶（N-甲基咪唑，碘化物和4-甲氧基吡啶），更强大，加速与OXP的反应，但在5′-OH组分的情况下，预活化导致活化的次膦酸酯的分解。（© Wiley-VCH Verlag GmbH & Co. KGaA，69451魏因海姆，德国，2008）
Condensation of a uridine 3′-deoxy-3′-C-methylenephosphinate with thymidine and guanosine derivatives to form methylenephosphinate esters was investigated. A number of different condensing agents were compared, and these include pivaloyl chloride, triisopropylbenzenesulfonyl chloride (TPS-Cl), phosphonium and uronium derivatives, numerous chlorophosphates and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP). The phosphonium derivatives gave slow condensations or oxidative side reactions (hydroxybenzotriazole derivatives) during preactivation of the methylenephosphinate. Pivaloyl chloride gave long coupling times, and competing 5′-O-pivaloylation was detected. TPS-Cl gave rapid condensation but also rapid oxidation of the product. Most chlorophosphates gave competing 5′-O-phosphorylation of the nucleoside component, as well as base phosphorylation. However, 2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (DMOCP) gave a rather efficient formation of dinucleoside methylenephosphinates at a decent rate. However, O6-protection of guanines could become necessary with this reagent, since upon extended reaction time traces of O6-phosphorylation were detected even with a low concentration (60 mM) of DMOCP (2 equiv. to phosphinate). Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP) can, unlike DMOCP, be used in nearly equimolar amounts to phosphinate. Under such conditions OXP gives virtually quantitative condensation at a rate comparable to that of 2 equiv. of DMOCP and with no side reactions detected. We could also not detect any decomposition of OXP-preactivated phosphinate. Nucleophilic catalysts, more powerful than pyridine (N-methylimidazole, iodide and 4-methoxypyridine), accelerated the reactions with OXP, but preactivation in the absence of the 5′-OH component led to decomposition of the activated phosphinate.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)