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 pKa values and hydrophobicity of nucleosides was investigated. Halogenated substituents increase the lipophilic character of nucleosides in the order Cl < Br < I and decrease the pK 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.