Lakshman Mahesh K, Ngassa Felix N, Bae Suyeal, Buchanan Dennis G, Hahn Hoh-Gyu, Mah Heduck
Department of Chemistry, City College of CUNY, 138th Street at Convent Avenue, New York, New York 10031-9198, USA.
J Org Chem. 2003 Jul 25;68(15):6020-30. doi: 10.1021/jo030113b.
Single-electron oxidation of the carcinogenic hydrocarbon benzo[a]pyrene (BaP) is thought to result in a radical cation intermediate and this species has been proposed to cause alkylation at the nitrogens of the purine nucleobases. Although several different nucleoside adducts have been isolated as arising from this mode of metabolic activation, there are no selective, total syntheses of the stable exocyclic amino group adducts formed by the single-electron oxidation of any hydrocarbon with the purine 2'-deoxynucleosides to date. In this paper we disclose the synthesis of the model adducts N(6)-(1-pyrenyl)-2'-deoxyadenosine and N(2)-(1-pyrenyl)-2'-deoxyguanosine as well as the first synthesis of the carcinogen-linked nucleoside derivatives N(6)-(6-benzo[a]pyrenyl)-2'-deoxyadenosine and N(2)-(6-benzo[a]pyrenyl)-2'-deoxyguanosine via a palladium-mediated C-N bond formation. Two different coupling strategies were attempted: coupling of an aryl bromide with a suitably protected nucleoside and the coupling of an arylamine with a suitable halonucleoside. The former had somewhat limited applicability in that only N(6)-(1-pyrenyl)-2'-deoxyadenosine was prepared by this method; on the other hand, the latter was more general. However, there are noteworthy differences in the amination reactions at the C-6 and C-2 positions. Reactions at the C-6 resulted in the competing formation of a 1:2 amine-nucleoside adduct in addition to the desired monoaryl nucleoside. Such a dimer formation was not observed at the C-2. The C-2 adducts, however, displayed an interesting conformational behavior.
致癌性碳氢化合物苯并[a]芘（BaP）的单电子氧化被认为会产生一个自由基阳离子中间体，并且有人提出该物种会导致嘌呤核碱基的氮原子发生烷基化。尽管已经分离出几种不同的核苷加合物是由这种代谢活化模式产生的，但迄今为止，还没有通过任何碳氢化合物与嘌呤2'-脱氧核苷的单电子氧化形成的稳定环外氨基加合物的选择性全合成方法。在本文中，我们披露了模型加合物N(6)-(1-芘基)-2'-脱氧腺苷和N(2)-(1-芘基)-2'-脱氧鸟苷的合成，以及通过钯介导的C-N键形成首次合成致癌物连接的核苷衍生物N(6)-(6-苯并[a]芘基)-2'-脱氧腺苷和N(2)-(6-苯并[a]芘基)-2'-脱氧鸟苷。尝试了两种不同的偶联策略：芳基溴与适当保护的核苷的偶联以及芳基胺与适当卤代核苷的偶联。前者的适用性有些有限，因为通过这种方法仅制备了N(6)-(1-芘基)-2'-脱氧腺苷；另一方面，后者更具通用性。然而，在C-6和C-2位置的胺化反应存在值得注意的差异。在C-6处的反应除了所需的单芳基核苷外，还会竞争性地形成1:2的胺-核苷加合物。在C-2处未观察到这种二聚体的形成。然而，C-2加合物表现出有趣的构象行为。
