Unexpected stability of aryl β-N-acetylneuraminides in neutral solution: Biological implications for sialyl transfer reactions

Article abstract of DOI:10.1021/ja042280e

A reagent panel comprised of seven aryl β-D-N-acetylneuraminides was synthesized and then used to probe the mechanisms of nonenzymatic hydrolysis. These reactions proceeded via four independent pathways: (1) acid-catalyzed hydrolysis of the neutral molecule; (2) acid-catalyzed hydrolysis of the anionic form, or its kinetic equivalent spontaneous hydrolysis of the neutral form; (3) spontaneous hydrolysis of the anionic form; and (4) a base-promoted pathway. The pH-independent spontaneous hydrolysis of 4-nitrophenyl α-D-N- acetylneuraminide (5) occurs at a rate that is over 100 times faster than that of the corresponding reaction of 4-nitrophenyl β-D-N-acetylneuraminide (4a). Spontaneous hydrolyses of four aryl β-D-N-acetylneuraminides displayed a β_Ig value of -1.24 ± 0.16 (pH = 8.1, T = 100 °C), and at a pH value of 1.0 (50 °C), all seven panel members gave a β_Ig value of 0.14 ± 0.08. The aqueous ethanolyses of 4a and 5 gave similar products and displayed sensitivity parameters (m) in a standard Winstein-Grunwald analysis of -0.04 ± 0.01 and ± 0.23 ± 0.02, respectively. These results, plus the activation parameters calculated for the spontaneous hydrolyses of the anionic forms of 5 (ΔH? = 116 ± 2 kJ mol^-1 and ΔS? = 27 ± 4 J mol^-1 K^-1) and 4a (ΔH? = 138 ± 3 kJ mol^-1 and ΔS? = 59 ± 8 J mol ^-1 K^-1), are inconsistent with anomeric carboxylate assistance occurring during the hydrolysis reactions, and the likely cause for the enhanced reactivity of 5 in comparison to that of 4a is an increase in ground-state steric strain.