Prescription drugs are a vital modality in our national healthcare infrastructure. It is therefore crucial that the research, development and manufacture of active pharmaceutical ingredients (APIs) remain a top priority ensuring that patients have immediate access to medications. Nitrogen heterocycles constitute a significant portion of all US FDA approved small molecule prescription drugs. Of those heterocycles, the six-membered piperidine ring is present in the largest percentage of pharmaceuticals containing nitrogen. Piperidines are most likely to be substituted at N1 or C4 with 1,4-disubstituted rings accounting being the most common. Despite the variety of chemical methods available to access sparsely functionalized piperidines, the asymmetric synthesis of highly substituted piperidines remains a significant challenge in chemical synthesis. The molecular structures of those APIs can have complex spatial arrangements of the constituent elements. The spatial orientation of the atoms, called stereochemistry, can affect the physiological properties of the API. Additionally, the stereochemistry adds complexity to the synthesis and ultimately cost to make the API. Therefore, new and efficient chemical methods are continually needed to ensure sufficient quantities of prescription drugs are available for affordable prices. The mentioned shortcomings necessitate fundamental research in the stereo-controlled construction of multi-substituted nitrogen heterocycles to meet the continual healthcare demand for new pharmaceutical agents. The over-arching goal of this proposal is to develop asymmetric cyclization reactions for the synthesis of bioactive nitrogen heterocyclic motifs found in natural products and APIs. To achieve that broad object, we have preliminary data to support the specific aims of the project in which we will: 1) Investigate intramolecular carbon-carbon bond formation for the asymmetric synthesis of multi-substituted piperidines; 2) Probe the reactive nature of underdeveloped electrophilic carbon reactive intermediates to trigger intramolecular cyclization events; 3) Design and execute the chemical syntheses of polycyclic nitrogen heterocycles with pharmaceutical potential. The synthetic and mechanistic aspects of these new asymmetric chemical reactions will be probe using a variety of spectroscopic techniques. In addition to having meaningful impact on biomedical research, this project will provide training to undergraduate and graduate students in the laboratory methods of synthetic organic chemistry in the state of Mississippi. !
Public Health Statement. Prescription drugs are an essential therapeutic resource to our national health care infrastructure. There are many scientific, economic and regulatory factors in developing new prescription drugs and bringing them to market. This research will reduce the economic burden on patients and healthcare stakeholders through the development of new chemical reactions that will create prescription drugs using more efficient and less expensive methods. !