Activation of acyl phosphate monoesters by lanthanide ions: Towards biomimetic acylation

Acyl phosphates, the mixed anhydrides of carboxylic and phosphoric acids, have critical roles in many biochemical processes. Monoesters of acyl phosphates are involved in biochemical acylation, most notably the aminoacylation of tRNA via aminoacyl-adenylates. Since they are soluble in water and hydrolyze with half-lives of more than 100 hours in neutral solution, they are intriguing as potential biomimetic acylating agents. This lack of reactivity towards oxygen-centered nucleophiles is despite the fact that their most important biochemical role is the acylation of the 3′-terminal hydroxyls of tRNA. Therefore, we sought to develop methods for the specific activation of acyl phosphate monoesters towards functional groups that model the 3′ terminal hydroxyls of tRNA. We chose benzoyl methyl phosphate (BMP) for these studies since its reactions can be followed by UV spectroscopy. We find that lanthanides are excellent and selective catalysts for the reactions of BMP.; The hydrolysis of BMP is accelerated 5000 fold with 0.001 M europium, while 1 M magnesium ion accelerates the hydrolysis less than 50 fold. Kinetic analysis of the lanthanide-catalyzed hydrolysis reveals that a 1:1 lanthanide-BMP chelate forms and reacts rapidly with hydroxide at the carbonyl ( K₁ = 400 M−1 and k = 4 × 10−3s−1, pH 7). The rate constant for the hydroxide dependence of the europium catalyzed process (1.9 × 104 M−1s−1), is 105 times larger than for the metal-free reaction.; Lanthanides are excellent catalysts for the reaction of BMP with diols. Ethylene glycol and cis-1,2-cyclopentanediol react faster than water, with relative second order rate constants of 170, 46, and 1, for the two diols and water respectively. Adenosine is of particular interest due to its position at the 3′ terminus of tRNA. We find that it reacts rapidly with BMP to give monoacylation of the 2′ or 3′-OH at a rate that is 104 times faster than hydrolysis.; I propose that the reaction involves a ternary intermediate in which a lanthanide ion forms a bidentate connection with the oxygens of the carbonyl and phosphate of the acyl phosphate and also with the nucleophilic diol, resulting in reduced entropy of activation for the substitution.