With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Gregory K. Friestad of the Chemistry Department at the University of Iowa. The project focuses on the development of new stereoselective methods to achieve asymmetric amine synthesis via free radical addition reactions. In particular, these studies will expand the scope and improve the efficiency of Mn-mediated radical additions, provide new methods for the construction of quaternary carbon stereocenters, and investigate asymmetric catalysis of radical additions to C=N bonds. A new radical addition approach to chiral amines, involving addition to the C=C bond of chiral enamides with subsequent stereoselective trapping by tandem bond constructions, will be studied.
This project will contribute to knowledge of the chemistry of radical addition reactions that generate chiral amines. Since chiral amines play crucial roles in pharmaceutical chemistry, these investigations are expected to have broad impact on research in the health sciences. This project will also provide important undergraduate, graduate and postdoctoral training in preparation for careers in health sciences research.
The Project Outcomes from CHE-0749850 are found in two general areas, educational outcomes and research outcomes. Educational outcomes under CHE-0749850 consist of successful training of graduate and undergraduate students to become independent in the design and execution of experiments, to become thoroughly versed in organic chemistry laboratory techniques, and to become proficient in professional communications including manuscript preparation and oral presentations. Specifically, the experimental activities were directed toward expanding the scope of asymmetric amine synthesis methods based on radical addition to C=N bonds, demonstrating applicability of these methods to significant synthetic problems, and developing a new radical-polar crossover coupling reaction of enamides. These research projects provided ideal pedagogy for preparing students to contribute their synthetic expertise to biomedical, materials science, and agricultural research; they have also proven to be strong preparation for academic career tracks. Two students were mentored through the successful completion of their PhD degree. A third student is in progress toward the PhD, and will have significant portions of her PhD thesis work supported of this award. Chairing a regional ACS meeting (MWRM 2009) also offered an opportunity to have a broader educational impact; 284 graduate students and 187 undergraduate students from around the Midwest attended this meeting, and many had the chance to present their science in a professional meeting for the first time. Research outcomes under CHE-0749850 are in the area of synthetic organic chemistry methodology, more specifically synthesis of chiral amines, and applications in total synthesis of biologically active compounds. Chiral a-branched amines are found in many biologically active synthetic targets, including natural products and designed pharmaceuticals. Often one of two mirror-image structures is the active compound in a pharmaceutical product, so it is crucial to be able to prepare the correct mirror image structure (asymmetric synthesis). In contrast to the chemistry of alcohols, the asymmetric synthesis of chiral amines has been slow to develop. We have been addressing this shortfall by developing new, more versatile reaction conditions for C–C bond constructions in asymmetric synthesis of amines. Our program offers a new approach: stereocontrolled free radical addition to C=N double bonds. We have developed a range of methods for novel radical additions to imino compounds, including silicon- and acetal-tethered additions, as well as intermolecular additions to N-acylhydrazones which exploit photolysis of Mn2(CO)10 to generate alkyl radicals from iodides, leading to a wide range of chiral amines. We have also demonstrated application of these new reactions to real-world synthesis problems (daunosamine, quinine, and tubulysins), which will encourage broader acceptance of these new synthetic tools among practitioners of organic chemistry. In terms of quantitative measures of the outcomes of this award, there have been six publications of original research in journal articles, as well as five book chapters reviewing progress in the research area.
