(Principal Investigator's) The principal goal of this research program is to improve the efficiency by which relatively small organic compounds are synthesized. Large numbers of relatively small organic compounds are screened annually by the National Institutes of Health as a part of their mission to address specific public health concerns and to develop new therapeutic agents. For example, new therapeutic agents are constantly being developed and evaluated as effective agents to control and possibly to eradicate the HIV virus. The design and the reduction to practice of in vitro chemical syntheses of every small molecule in the NCI publication Chemical Structures of Interest to the Division of Cancer Treatment is critically dependent upon the availability of preparative synthetic methodology. Hence, procedures which decrease the effort required for in vitro chemical synthesis will assist the ongoing development and syntheses of physiologically active, small organic molecules. Synthetic efficiency of both naturally occurring and of non-naturally occurring analogs of small organic molecules will be improved through understanding of the precise details which control the key carbon-carbon bond forming reactions utilized in their preparation. The protocol utilized in this research project will be to complete a thorough structural analysis of common reactive intermediates which are utilized extensively in every synthetic organic chemistry laboratory. The structural results are obtained through a combination of techniques which include NMR spectroscopy, x-ray diffraction analysis and computational chemistry. The structural results manifest themselves as three dimensional pictures of aggregated species which have been shown by others to be reactive intermediates. The structural information will also be utilized to design synthetic methods and to explain, to control, and to predict the outcome of chemical reactions which are required to synthesize physiologically active compounds. Structural information will also be utilized to develop and to improve certain specific synthetic reagents for the asymmetric synthesis of organic chemicals. This research project is designed to complement the development of new synthetic reactions with a thorough understanding of the reaction processes themselves. Overall, a strict emphasis will be focused on those specific reactive species and reaction processes deemed most relevant to the development of synthetic organic chemistry used for the total synthesis of medicinal chemicals.
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