Synthesis of Pyrene and Benzo[a]pyrene Adducts at the Exocyclic Amino Groups of 2‘-Deoxyadenosine and 2‘-Deoxyguanosine by a Palladium-Mediated C−N Bond-Formation Strategy

• Published in: Journal of organic chemistry Vol. 68; no. 15; pp. 6020 - 6030
• Main Authors: Lakshman, Mahesh K, Ngassa, Felix N, Bae, Suyeal, Buchanan, Dennis G, Hahn, Hoh-Gyu, Mah, Heduck
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25-07-2003
• Subjects: Amines - chemistry; Benzo(a)pyrene - analogs & derivatives; Benzo(a)pyrene - chemical synthesis; Benzo(a)pyrene - chemistry; Carbohydrates. Nucleosides and nucleotides; Catalysis; Chemistry; Deoxyguanosine - chemistry; DNA Adducts; Exact sciences and technology; Indicators and Reagents; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Palladium; Preparations and properties; Pyrenes - chemical synthesis; Pyrenes - chemistry; Arylation; Amine; Amination; Pyrene derivatives; Aromatic compound; Palladium; NMR spectrometry; Deoxyribonucleoside; Ultraviolet spectrometry; Chemical synthesis; Chemical coupling; Halogen Organic compounds
• DOI: 10.1021/jo030113b
• EISSN: 1520-6904
• ISSN: 0022-3263

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.