The development of synthetic methods for the generation of complex molecules from readily available starting materials in an environmentally friendly manner benefits many areas of the health sciences, including those focused on the elucidation of biochemical pathways and the discovery of new pharmaceuticals. Catalysis by well-defined organometallic complexes offers a powerful approach to unlocking new chemical reactivity. The harnessing of this catalytic reactivity is in turn dependant on a firm understandin of the mechanistic aspects of a transformation. For example, transition metal catalysts often enable cross-coupilng reactivity by coupling arenes bearing activating or leaving groups with nucleophiles such as aryl boronic acids. Conversely, gold(III) catalysts offer the opportunity for direct C-H activation of simple arenes for subsequent functionalization. Compared to other transition metal catalyst systems that promote direct C-H activation however, the gold-catalyzed pathway offers mild and highly selective access to para-selective substitutions, but is significantly less understood. Defining the fundamental mechanisms involved in such a process is essential for fully harnessing the catalytic potential of gold in aryl C-H activation. Importanty, there is limited experimental evidence to support the apparent intermediacy of an arylgold(III) organometallic species. This gold-centered intermediate is a useful complement to that of other transition metals, as it can be accessed directly via para C-H activation to simple arenes such as toluene, potentially providing access to diverse para- substituted arene products. Through the development of a para-arylation of toluene, the goal of this research proposal is to isolate and characterize catalytically relevant arylgold intermediates and elucidate their potential for catalytic bond-forming reactivity. Spectroscopic techniques and x-ray crystallography will be used to elucidate the mechanistic processes involved in this approach. Ligand and substituent effects will also be probed to determine the kinetic and thermodynamic properties of the initial auration and subsequent reductive elimination mechanisms. The reactivity of the arylgold intermediate will also be investigated, with specific focus on the para arylation of toluene through a presumptive AuI/AuIII redox process. A set of competition experiments will also be aimed at elucidating the oxidative and reductive mechanisms involved in successive Au-C and C-C bond formation. This strategy, based on arylgold(III) intermediate isolation and characterization, will provide a convenient method for careful mechanistic study of gold catalysis, enabling the use of simple arenes as generic precursors to aryl electrophiles. Ultimately, such a process represents a complementary approach to other catalytic C-H activation platforms and offers access to a range of new, biologically relevant structures. Specifically, the para arylation method outlined in this proposal provides an important tool for probing protein-protein interactions in nature and for the development of a complementary and important structural class of molecules for use as medicines.

Public Health Relevance

In order to construct molecules that can be used (a) as medicines to treat chronic and infectious diseases, or (b) as probes for deciphering biological pathways, chemists must first develop synthetic methods to build these molecules. Catalysts offer an environmentally friendly manner of addressing this challenge by allowing access to complex, novel products from simple starting materials. This proposal seeks to mechanistically define how gold-based catalysts are able to transform some of natures cheapest and most abundant chemical building blocks, called arenes, into valuable products through a novel process that will enable the further development of alternative catalytic methods.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-A (09))
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Barski, Oleg
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University of California Berkeley
Schools of Arts and Sciences
United States
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Fracaroli, Alejandro M; Siman, Peter; Nagib, David A et al. (2016) Seven Post-synthetic Covalent Reactions in Tandem Leading to Enzyme-like Complexity within Metal-Organic Framework Crystals. J Am Chem Soc 138:8352-5