Acyl Phosphates: Biomimetic Reagents for Selective Acylation in Water

Acyl groups in biochemical reactions are activated as acyl adenylates; such intermediates are generated by a reaction with ATP. Acyl adenylates are mixed carboxylic-phosphoric anhydrides which are potentially useful as biomimetic reagents for acylation reactions in water. These species have been reported to be unstable and have been isolated without purification. Since the adenylate portion is necessarily complex because it originates from ATP, we reasoned that using a simple alkyl group in place of adenosine might allow the biomimetic process to proceed without the difficulties reported. Our laboratory has developed routes towards such acyl phosphate alkyl monoesters and we have used them for several applications. Such materials react rapidly and selectively with amines in order to produce amides. While reactions utilizing lanthanide ions allow for the selective monoacylation of diols through bis-dentate chelates of the lanthanide. However, the efficiency of diol acylation is limited due to significant hydrolysis of the phosphate reagent and the requirement of a stoichiometric amount of the lanthanide ion. Therefore, three distinct approaches towards improving the efficiency of lanthanide promoted acylation were investigated: addition of an inert co-solvent in an attempt to reduce hydrolysis, eliminating the stoichiometric requirement of the lanthanide by addition of MgII, and the development of immobilized lanthanides as catalysts for acylation. Finally, aminoacyl phosphates are biomimetically activated amino acids and in principle should function as peptide synthesis reagents. The stability and solubility of the activated materials in water presents an opportunity to perform aqueous peptide coupling; such a process is limited by the fact that common peptide coupling agents are either insoluble or unstable in water. Therefore, we investigated the reactions of aminoacyl phosphates with amino acid esters. We find that peptides form readily in buffered solutions, establishing a basis for a general protocol for aqueous amino acid coupling and could be adapted for applications such as solid phase peptide synthesis.Ph