Many biologically active compounds are chiral, and more than 50% of today's top-selling drugs are marketed as single enantiomers. The high and ever-increasing demand for enantiopure compounds requires constant progress in asymmetric synthesis. In particular, the development of new catalysts continues to be crucial. Chiral bisoxazolidines with a rigid C2-symmetric scaffold have very promising applications in asymmetric catalysis. This new class of N,O-donor ligands will be applied in challenging enantioselective carbon-carbon bond formation reactions.
With this award, the Organic Synthesis: Methodology and Organometallic Program is supporting the research of Professor Christian Wolf of the Department of Chemistry at Georgetown University. Professor Wolf's research is aimed at the development of new chiral bisoxazolidine ligands for asymmetric catalysis. Studies to elucidate the mechanism of bisoxazolidine-catalyzed reactions and efforts to fine-tune the catalytic efficiency and asymmetric induction of this class of ligands will be undertaken. The successful development of new asymmetric catalysts is expected to provide new tools for the synthesis of complex chiral target molecules. This will have an impact on the pharmaceutical, food, and agricultural industries.
Christian Wolf, Georgetown University, Washington, DC 20057 Chirality is a key property of numerous biologically active compounds that exist as mirror images called enantiomers. Many pharmaceuticals, agrochemicals, flavors, fragrances, and nutrients, are chiral, and more than 50% of today’s blockbuster drugs including Lipitor, Zocor, Plavix, and Nexium are sold as single enantiomers. The high and ever-increasing demand for enantiomerically pure compounds requires constant progress and innovative approaches that lead to the discovery of new synthetic methodology. The ability of academic and industrial labs to produce drugs and other important chiral compounds is based on the availability of efficient synthetic tools. With this NSF award, the Wolf research group has used so-called bisoxazolidine catalysts, which were invented by the same laboratory, to develop a variety of catalytic enantioselective reactions, including aldol-type reactions, radical reactions and nucleophilic additions. These reactions are important because they provide practical access to versatile chiral building blocks that can be used to produce key precursors of some of the biologically active compounds mentioned above, as shown in Figures 1 and 2. For example, an efficient access to a chiral 1,3-diamino-2-propanol motif that leads to new drug candidates with substantial promise for the treatment of tuberculosis, Alzheimer’s disease and nosocomial infections caused by Gram-positive bacteria that are resistant to common antibiotics has been developed. The study of the properties of bisoxazolidines, in particular mechanistic analysis of their mode of action and the investigation of the transition metal binding capabilities, have been important milestones in these efforts. The Wolf laboratory has thus (1) developed synthetic methods that can be used to generate important drug precursors with higher yields and in fewer steps than previously reported procedures and (2) discovered new carbon-carbon bond forming reactions that provide unprecedented access to novel multifunctional compounds. Together with the ubiquity of chiral compounds in medicine, nanomaterials and other fields, these findings will facilitate the making of both known and new chemical entities with various applications. Most noteworthy, however, is the emphasis in the Wolf laboratory on the synthesis of precursors of current and emerging pharmaceuticals which is likely to impact drug discovery and development programs. In addition to the general practical utility, many of the synthetic venues developed with this award provide both economic and environmental advantages over previously known protocols due to waste reduction and reduced energy consumption. One of the bisoxazolidine catalysts has been patented and is now commercially available. The successful transition of this invention from the research laboratory through patent and publication processes to the commercial stage underscores the significance and impact of this work. The results of this project including experimental procedures, detailed optimization studies, mechanistic findings, and full characterization of all new chemicals produced have been published in peer-reviewed, prestigious international journals. In addition, the PI and the students presented the research outcomes at various scientific seminars, meetings and conferences. These research efforts have involved graduate, undergraduate and high school students including minorities who have received in-depth training in a wide range of synthetic and analytical techniques and found opportunities to participate in interdisciplinary research projects. In addition, an elective course aimed at preparing students and postdoctoral fellows for their future careers, a local synthesis symposium that provides a unique stage for new and experienced students to present and discuss their work, and the integration of research and teaching initiatives have been incorporated to provide fruitful training grounds for future scientists.
