Title

The Synthesis of Multicopper Oxidase Models

Document Type

Thesis

Publication Date

2010

Advisor

Brian Johnson, Biochemistry

Abstract

Multicopper oxidases are enzymes with a trinuclear arrangement of copper atoms that reduce O2 to H2O and oxidize substrate molecules in biological systems. Although much research has been conducted into the mechanism by which these enzymes reduce dioxygen, it has not been decidedly resolved. Using organic synthesis, models of the multicopper oxidase active site can be made to better understand the mechanism and intermediates involved in this reaction. By building various scaffold molecules that hold the copper ions, it may possible to isolate and characterize the oxygen-binding modes that best mimic the enzyme. The reactivity of the resulting complexes with O2 can be compared to that of the biological enzyme to test whether the model behaves similarly. Therefore, synthetic active site models can serve as tools to investigate the intermediates and mechanism by which multicopper oxidases function.

This thesis reports the synthesis of three previously unknown precursor molecules to the active site models. Through Grignard and alkyl lithium reactions, both 1,3,5-tris(3-trimethylsilylprop-2-ynyl)-2,4,6-triethylbenzene [1] and 2-(3-trimethylsilylprop-2-ynyl) pyridine [3] were synthesized. Removal of the TMS protecting groups from [1] resulted in the formation of 1,3,5-tris(2-propynyl)-2,4,6-triethylbenzene [2]. These molecules were characterized via 1H-NMR, 13C-NMR, and GC/MS analysis. "Click" chemistry reactions, combining alkynes and azides, are currently being investigated for their efficacy in forming the active site models from molecules [1]-[3].

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