New Multiple Bond-Forming Strategies for Organic Synthesis

Among the most important goals of modern synthetic chemistry is the facile construction of molecules that have relevant application in biological settings. Although historically most medicinal compounds have come from natural sources, contemporary drugs are commonly prepared by chemical synthesis. Several advantages result from the de novo construction of biologically active molecules including: 1) the prospective of generating structurally related analogues that may exhibit improved physiological properties; 2) the ability to prepare greater quantities of material; 3) the potential for discovering new methods for chemical synthesis that have application beyond the context in which they were first observed.Whether the end use of the compound is as a therapeutic agent, probe for elucidating biological pathways, or agriculturally beneficial material, the method for preparing the structure must be efficient. The demand for greener more atom-economical processes that maximize efficiency in terms of time, resources required, and waste generated per reaction constitutes a major driving force behind the investigation of new synthetic methods.This proposal seeks to develop a new paradigm for the construction of organic molecules. The proposed reactivity will produce biologically relevant products in an efficient manner by forming multiple bonds in a single operation. In addition, the key reagent that will effect this transformation is used in a catalytic fashion, such that a single molecule of reagent is capable of generating many molecules of the product, thereby minimising the waste generated during the course of the reaction. In order to illustrate the power of the innovative method to the synthetic community, upon establishing reactivity parameters, application to the synthesis of structurally complex, biologically relevant molecules will be undertaken.The research described is also expected to generate substantial new knowledge in a relatively unexplored area of organometallic chemistry. As such, there is vast opportunity for scientific discovery. This information will likely impact the way molecules are made in both the academic and industrial sectors.

The most direct impact of the proposed research will be to synthetic chemists. This includes both the international academic community, as well as the industrial sector (particularly global pharmaceutical and agrochemical corporations). In a wider sense, the impact that these two consumers of the research have on society (for example, discovering and developing new drugs) indicates that the potential reach of the proposal is truly broad. The direct users of this research in the synthetic chemistry community will be afforded a new tool for constructing complex molecules. The reaction paradigm described in the proposal allows for the facile preparation of a sub-structure that is common to many biologically active materials. In particular, agents that are active against cancer and influenza, compounds that act as insect anti-feedants, others that are potentially useful for the treatment of Alzheimer's disease, and a further compound that is a commercially available anti-depressant have all been identified as potentially accessible using the chemistry described in this proposal. The synthetic technology developed during the course of this undertaking will become available for use by the scientific community immediately upon dissemination of the results (see Impact Plan for further details). The broader influence found by utilising the newly discovered reactivity principles for the preparation of molecules relevant to society (such as pharmaceuticals and agrochemicals) is likely to be somewhat protracted (on the multi-year timescale) given the complexities associated with the widespread usage of such compounds (e.g. ensuring safety, etc.). Nevertheless, the potential gains for society are only expected to increase with time. The final products of the proposed research that must not be overlooked are the staff that will be trained under its auspices. The success of this grant application will fund a post-doctoral research associate to work with the P.I. and his group of Ph.D. students and undergraduate co-workers in the School of Chemistry at the University of Glasgow. The scientific training (including oral and written presentation skills) and problem solving abilities acquired by each of these individuals will provide an excellent platform for advancing to careers in academia or industry either in the UK, or internationally.