Efficient Metal-Promoted Biomimetic Catalysis of Phosphoryl Transfer Reactions in Alcohols
Liu, C-Y Tony
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Understanding enzymatic reactions has many invaluable implications that could lead to useful pharmaceutical and commercial applications. Phosphoryl transfer reactions are perhaps the most prevalent chemical transformations in Nature. Phosphate esters are highly resistant to hydrolytic and nucleophilic degradation in the absence of catalysts, and enzymes that faciliate phosphoryl transfer reactions are among the most catalytically efficient enzymes in Nature. A common strategy for understanding enzyme catalysis involves designing small molecule enzyme mimics. Our approach is to focus on the reaction medium inside the enzyme active sites, which is generally accepted to be non-aqueous and have an effective dielectric constant like organic solvents. We find that by switching from water to light alcohols (methanol and ethanol), a dinuclear Zn(II) complex can accelerate the solvolytic cleavages of simple phosphate diesters (both DNA and RNA models) by 12 orders of magnitude relative to the background reactions. A series of detailed mechanistic investigations revealed that the catalyzed cleavage of phosphate diesters proceeds via a multi-step process. Furthermore, comparison between the catalysis observed in methanol and ethanol is provided. In addition, the rate-limiting step of the three-step catalytic process changes depending on the leaving groups of the substrates for the transesterification of a series of 2-hydroxylpropyl aryl phosphates promoted by 3.3:2Zn(II). The same dinuclear Zn(II) complex is also very efficient at catalyzing the methanolysis of a series of methyl aryl phosphates (DNA models). Additional catalysis through leaving group assistance was observed for methyl aryl phosphates that contain ortho-nitro and ortho-carbomethoxy substituents. To better understand the effectiveness of leaving group assistance in phosphoryl transfer reactions, we studied the solvolytic cleavage of a homologous set of phosphate mono-, di-, and triesters in methanol, and found that the reactions can be greatly accelerated solely through Cu(II)-promoted leaving group stabilization. Finally, to highlight the importance of the reaction medium, in the last chapter we present an unprecedented result whereby, in ethanol containing trace amounts of water, the same dinuclear Zn(II) catalyst can preferentially promote the hydrolysis of a DNA model substrate with catalytic efficacy that matches enzyme catalysis.