Bio-inspired approaches to accelerating metal ion-promoted reactions: enzyme-like rates for metal ion mediated phosphoryl and acyl transfer processes.

Intense efforts by many research groups for more than 50 years have been directed at biomimetic approaches to understand how enzymes achieve their remarkable rate accelerations. Nevertheless, it was noted in 2003 that, despite numerous efforts to design models for catalyzing the cleavage of such species as phosphate diesters, 'none of the several models so far described approaches the enormous catalytic efficiency of natural enzymes'. The same could be said for biomimetics of other enzymes promoting acyl or phosphoryl transfer reactions, particularly those mediated by metal ions such as Zn(II). Clearly other important factors were being overlooked or awaiting discovery. In this manuscript we describe two important effects that we have implemented to accelerate metal ion catayzed phosphoryl and acyl transfer reactions. The first of these relates to a medium effect where the polarity of the solution, as measured by dielectric constant, is reduced from that of water ( ε = 78) to values of 31.5 and 24.3 when the solvent is changed to methanol or ethanol. Among organic solvents these light alcohols are closest to water in terms of structure and properties as well as retaining important H-bonding properties. The second important effect involves a known but difficult to demonstrate mode of catalysis where the leaving group (LG) in a solvolysis reaction is accelerated as it becomes progressively poorer. In the cases described herein, the LG's propensity to depart from a substrate during the course of reaction is accelerated by coordination to a metal ion in a process known as leaving group assistance, or LGA. These two effects can each impart accelerations of 109-1017 for certain metal ion catalyzed reactions relative to the corresponding solvent, or base induced reactions. [ABSTRACT FROM AUTHOR]