A. Developing high valent metal mediated functionalization of aromatic C–H bonds to form new C–Y bonds.

Our goal is to develop novel metal-catalyzed synthetic methods that directly functionalize aromatic C–H bonds with different reagents to form C–Y bonds. This goal is based on my previous work at the University of Chicago . We have demonstrated that gold(III) species can catalyze the direct functionalizations of aromatic C–H bonds with electron-deficient alkynes and alkenes under mild conditions. We have also extended this work to intramolecular reactions of arenes with epoxides, primary alcohol triflate and sulfonate esters. However, the mechanism of this reaction is still not clear. Based on our results, we suggest that the intermediates of these reactions are arylgold(III) species. I propose to utilize this “Ar-M” species to i) react with an alkyl esters or halides in an SN2 manner different from Friedel-Crafts process; ii) react with different halides via a palladium(or other metals)-catalyzed process to generate coupling products; iii) form C-N/O bonds by using different reagents. Another proposed research direction is to efficiently functionalize heterocycles or fused-cyclic aromatic structures; most of these molecules represent core structures in many pharmaceutical compounds and natural products. We are also interested in exploring other high-valent metal complexes to catalyze this reaction. The mechanism of these kinds of reactions will be investigated.

B. Developing new catalytic systems to activate inert C-O bonds.

Coupling reaction is one of the most useful methods to form C-C or C-X bonds in advanced organic synthesis. With the use of organic halides or triflates as the substrates, the new C-C bond is easily built with different reagents through different procedures, including Heck reaction, Sonogashira coupling, etc. Recently Fu and his coworkers reported that the alkyl halides could undergo a similar process with the sp2-C halides. However, these types of reactions also have several drawbacks: i) most halides are not environmentally benign; ii) halides are not readily available; iii) most of these reactions need over one equivalent of specific base to remove the acid generated from the reaction. These drawbacks limit the application of coupling reactions in industry.

One of my aims is to use an alcohol/phenol ester or ether instead of halides/triflates in the coupling reaction so that the coupling reaction can demonstrate much broader prospective in chemical industry. Very recently, two examples were reported by different groups to realize the coupling reaction of phenyl tosylates with methyl ethers. Based on my research, I propose to develop new catalytical systems to activate inert C-O bonds. Metal ions such as the main group metals, early transition metals, and rare earth metals have good oxophilicity. In the solution, these ions can bond the oxygen atoms in C-O bonds. They will activate C-O bonds by the redistribution of the electronic density on the C-O bonds. I propose that low-valent metal catalysts (Pd(0) and Ni(0))can be oxiditively added by the activated C-O bonds to generate the high-valent metal intermediates, which will couple with different reagents. In these reactions, the starting materials are readily available from ketones, aldehydes, alcohols or phenols. The byproducts (like acetates or methoxides) may serve as bases to neutralize the acids generated in the coupling procedure. I plan to start this field from the phenyl sulfonate or acetate esters.

The discovery of new catalysts for activation of the inert C-O bonds is also exciting. It allows the construction of various molecules starting from simple materials like phenols and ketones in several simple steps. This methodology offers a unique opportunity to effectively couple alkenyl/aryl groups with different organic reagents to synthesize diverse compounds in mild conditions.

C. transfering O atoms from common oxidants such as O2 and H2O2 to C-H bonds or C=C bonds.

Transition-metal-catalyzed oxidative reactions are important processes in organic synthesis, biological systems and industrial applications. The development of new catalytic oxidative systems using economic and environmentally benign oxidants such as dioxygen (O2) and hydrogen peroxide (H2O2) is particularly attractive. In spite of extensive efforts in the past, there is still a long way to realize this ultimate goal, posing a critical challenge to the chemical community.

The aim of this proposed research is to prepare and isolate coordination-unsaturated low-valent transition metal compounds with the use of strong electron-donating and sterically bulky ligands. The oxygenated high-valent transition metal species will be generated by subsequent treatment of these low-valent transition metal compounds (like silver(I) compounds) with O2 or other oxidants in organic solvents. The reactivity of the oxygenated complexes towards olefins and other substrates will then be evaluated. Electron-donating ligand sets will be employed in our study to promote generation and stabilization of high-valent states of transition metal ions like silver(II) or silver(III).

Very recently, a series of copper(II/III), Pd(II) complexes was prepared and the formation of novel copper/palladium superoxo or bis(μ-oxo) complexes were observed with the use of different ligands. These complexes were extensively used in the oxygen atom transfer system. I propose that using our designed ligands can realize the oxygen transfer and increase the efficiency of the catalysts.

D. Transtion-metal-catalyzed CO2 activation .

Carbon dioxide is one of the most important carbon resources, existng widly in nature. CO2 has sepcial transformation cycle in nature and is closely relative to biological activities. CO2 can be regarded as a non-toxic, abundant, economic, and easily available "green" carbon resource. The application of CO2 by human being is almost always based on its physical properties, namely its inert chemical properties. The major obstacle is the thermodynamically low energy and relatively high activative energy. At present, there are four kinds of methods for the transformation of carbon dioxide. They are: a) using dihydrogen, unsaturated compounds, small-ring compounds, organometallic reagents and other high-energy starting materials reacting with carbon dioxide, which is the majority of methods at present and in future; b) selecting low-energy compounds as the target products such as arganic carbonate esters; c) in an equilibrium involving CO2, removing one or more products from the system to increase the conversion of CO2; d) utility of other kinds of energy such as light and electricity. Among these methods, transition metal involved activation of CO2 has attracted more and more attention in the recent years. Transtion metals can not only activate CO2 in an efficient pathway, but also coinstantaneously activate other unsaturated compounds such as alkenes, alkynes, dienes, allenes, and dihydrogen. Therefore, from simple starting materials, many important chemical reagents can be synthesized efficiently, such as acids, esters, lactones and so on. The transition-metal-catalyzed CO2 activation has wide potential applications in organic synthesis and chemical industry.

E. Improving the efficiency of alkylation anticancer chemotherapies by evaluation of small molecule inhibitors for human AGT

A. SPECIFIC AIMS: i) to design and synthesize small molecule inhibitors for the human AGT protein (hAGT); (ii) to assess the in vitro and in vivo effects of these inhibitors by using a crosslinking technique as a biochemical assay; (iii) to develop new drugs/codrugs to treat tumor cells by inactivating the hAGT before administration of alkylating chemotherapeutic agents.