Nucleobase-Functionalized 7-Deazaisoguanine and 7-Deazapurin-2,6-diamine Nucleosides: Halogenation, Cross-Coupling, and Cycloaddition.

The functionalization in position-7 of 7-deazaisoguanine and 7-deazapurin-2,6-diamine ribo- and 2'-deoxyribonucleosides by halogen atoms (chloro, bromo, iodo), and clickable alkynyl and vinyl side chains for copper-catalyzed and copper-free cycloadditions is described. Problems arising during the synthesis of the 7-iodinated isoguanine ribo- and 2'-deoxyribonucleosides were solved by the action of acetone. The impact of side chains and halogen atoms on the p K a values and hydrophobicity of nucleosides was investigated. Halogenated substituents increase the lipophilic character of nucleosides in the order Cl < Br < I and decrease the p K values of protonation. Photophysical properties (fluorescence, solvatochromism, and quantum yields) of azide-alkyne click adducts bearing pyrene as sensor groups were determined. Pyrene fluorescence was solvent-dependent and changed according to the linker lengths. Excimer emission was observed in dioxane for the long linker adduct. Bioorthogonal inverse-electron-demanding Diels-Alder cycloadditions (iEDDA) were conducted on the electron-rich vinyl groups of 7-deazaisoguanine and 7-deazapurin-2,6-diamine nucleosides as dienophiles and 3,6-dipyridyl-1,2,4,5-tetrazine as diene. The initially formed complex reaction mixture of isomers could be easily oxidized with iodine in tetrahydrofuran (THF)/pyridine leading to single aromatic tetrazine adducts within a short time and in excellent yields.