Department of Chemistry, The City College of New York, 160 Convent Avenue, New York, New York 10031, USA.
Org Biomol Chem. 2016 Aug 7;14(29):7069-83. doi: 10.1039/c6ob01170e. Epub 2016 Jul 5.
Reaction of amide bonds in t-butyldimethylsilyl-protected inosine, 2'-deoxyinosine, guanosine, 2'-deoxyguanosine, and 2-phenylinosine with commercially available peptide-coupling agents (benzotriazol-1H-yloxy)tris(dimethylaminophosphonium) hexafluorophosphate (BOP), (6-chloro-benzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyClocK), and (7-azabenzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophospate (PyAOP) gave the corresponding O(6)-(benzotriazol-1-yl) nucleoside analogues containing a C-O-N bond. Upon exposure to bis(pinacolato)diboron and base, the O(6)-(benzotriazol-1-yl) and O(6)-(6-chlorobenzotriazol-1-yl) purine nucleoside derivatives obtained from BOP and PyClocK, respectively, underwent N-O bond reduction and C-N bond formation, leading to the corresponding C6 benzotriazolyl purine nucleoside analogues. In contrast, the 7-azabenzotriazolyloxy purine nucleoside derivatives did not undergo efficient deoxygenation, but gave unsymmetrical nucleoside dimers instead. This is consistent with a prior report on the slow reduction of 1-hydroxy-1H-4-aza and 1-hydroxy-1H-7-azabenzotriazoles. Because of the limited number of commercial benzotriazole-based peptide coupling agents, and to show the applicability of the method when such coupling agents are unavailable, 1-hydroxy-1H-5,6-dichlorobenzotriazole was synthesized. Using this compound, silyl-protected inosine and 2'-deoxyinosine were converted to the O(6)-(5,6-dichlorobenzotriazol-1-yl) derivatives via in situ amide activation with PyBroP. The O(6)-(5,6-dichlorobenzotriazol-1-yl) purine nucleosides so obtained also underwent smooth reduction to afford the corresponding C6 5,6-dichlorobenzotriazolyl purine nucleoside derivatives. A total of 13 examples were studied with successful reactions occurring in 11 cases (the azabenzotriazole derivatives, mentioned above, being the only unreactive entities). To understand whether these reactions are intra or intermolecular processes, a crossover experiment was conducted. The results of this experiment as well as those from reactions conducted in the absence of bis(pinacolato)diboron and in the presence of water indicate that detachment of the benzotriazoloxy group from the nucleoside likely occurs, followed by reduction, and reattachment of the ensuing benzotriazole, leading to products.
在商业上可用的肽偶联剂（苯并三唑-1H-氧基）三（二甲氨基膦）六氟磷酸盐（BOP）、（6-氯苯并三唑-1H-氧基）三吡咯烷基磷六氟磷酸盐（PyClocK）和（7-氮杂苯并三唑-1H-氧基）三吡咯烷基磷六氟磷酸盐（PyAOP）存在下，叔丁基二甲基硅基保护的肌苷、2'-脱氧肌苷、鸟苷、2'-脱氧鸟苷和 2-苯并肌苷的酰胺键发生反应，得到含有 C-O-N 键的相应的 O(6)-(苯并三唑-1-基)核苷类似物。在双(频哪醇)二硼和碱的作用下，分别从 BOP 和 PyClocK 获得的 O(6)-(苯并三唑-1-基)和 O(6)-(6-氯苯并三唑-1-基)嘌呤核苷衍生物经历 N-O 键还原和 C-N 键形成，导致相应的 C6 苯并三唑基嘌呤核苷类似物。相比之下，7-氮杂苯并三唑氧基嘌呤核苷衍生物没有经历有效的脱氧反应，而是生成了不对称核苷二聚体。这与先前关于 1-羟基-1H-4-氮杂和 1-羟基-1H-7-氮杂苯并三唑缓慢还原的报道一致。由于商业上可用的苯并三唑基肽偶联剂数量有限，并且为了展示在没有此类偶联剂时该方法的适用性，合成了 1-羟基-1H-5,6-二氯苯并三唑。使用该化合物，通过与 PyBroP 的原位酰胺活化，将硅基保护的肌苷和 2'-脱氧肌苷转化为 O(6)-(5,6-二氯苯并三唑-1-基)衍生物。所得的 O(6)-(5,6-二氯苯并三唑-1-基)嘌呤核苷也顺利还原，得到相应的 C6 5,6-二氯苯并三唑基嘌呤核苷衍生物。总共研究了 13 个实例，其中 11 个实例（上述氮杂苯并三唑衍生物）成功反应。为了了解这些反应是分子内还是分子间过程，进行了交叉实验。该实验的结果以及在没有双(频哪醇)二硼和在存在水的情况下进行的反应的结果表明，苯并三唑氧基基团可能从核苷上脱离，然后还原，再重新连接生成的苯并三唑，从而得到产物。
