Synthesis of Amino‐Acid–Nucleoside Conjugates

Representative derivatives of uridine-conjugate amino acids suitable protected for Fmoc solid-phase chemistry, have been prepared through efficient protocols using "click" reactions that include thio-ene radical reaction and copper-catalyzed azide alkyne cycloaddition (CuAAC). Several linkers between the amino acid and nucleoside units, including alkyl chains and a triazole ring, have been considered. Alkyl chains will keep flexibility to further allow the correct orientation of bisubstrate analogs and the triazole ring will promote additional interactions at the active sites of target enzymes. Also, a neutral surrogate of the pyrophosphate unit has been prepared through a Staudinger-Vilarrasa reaction as a key step. Neutral analogs are promising surrogates for avoiding troubles in cell-membrane permeability.