The Chemical Structure, Dynamics and Mechanisms Program in the Chemistry Division at the National Science Foundation supports Professor Andre Kutateladze of the University of Denver, for the development of new one-pot photo-protolytic oxametathesis reactions. The goal of this work is to use this type of photochemical reaction for what is known as "diversity-oriented synthesis," or DOS. The versatility and generality of this methodology will allow Dr. Kutateladze's group to access heretofore inaccessible carbon skeletons, giving rise to new organic molecules that can be rapidly screened for therapeutic activity. The work will also involve an innovative new method for rapid structure determination by NMR spectroscopy.
Broader impacts of the research include the multidisciplinary training opportunities for students, from organic synthesis to photochemistry and photophysics. Potential applications for the synthesized molecules in biology and medicine include new drug discovery at more rapid pace. Undergraduate participation in this research will be year-round, and Dr. Kutateladze is making a significant effort to attract students from underrepresented groups to his laboratory.
The primary thrust of this project is to introduce photoassisted synthesis into the toolbox of synthetic chemistry, especially in the area of high throughput synthetic methods, such as combinatorial synthesis and diversity-oriented synthesis. The field of organic chemistry needs new synthetic methodologies designed to rapidly access unprecedented molecular architectures. This is important for any area of chemistry, but particularly important for diversity-oriented synthesis, i.e. synthesis of collection of molecules which have very different structural characteristics to be exploited in various subfields of chemistry and outside of chemistry. Synthesis of novel polyheterocyclic compounds is particularly important in this context, as these compounds provide molecular core scaffolds for a number of applications, from material science to drug design and discovery. In this project supported by the NSF we have made several critical photosynthetic advances, with the two of them being most impactful: (a) photoprotolytic oxametathesis, where a photochemical cycloaddition reaction, which is not available in the ground state, is utilized with a subsequent deep cationic rearrangements to access unprecedented polycyclic oxygenated molecular architectures and (b) photoinduced intramolecular cycloadditions of photogenerated azaxylylenes – a new process, unprecedented in the literature, which provides access to nitrogen heterocycles with considerable saturation, i.e. extended three-dimensional structure. Three representative examples of rapid growth of complexity in just one photochemical step are shown. In sum, we have achieved success with the proposed photoassisted synthetic method development. The synthetic toolbox is considerably enriched as a result of this project. Another significant advance realized during the course of this work is of computational/theoretical nature. In order to aid in characterization of the synthesized complex polyheterocyclic molecules we have developed a new method for predicting NMR spin-spin coupling constants (NMR being the most informative solution structure method in organic chemistry). The method is more than twice as fast as the existing methods, and its accuracy is 2.5 times better than the existing state of the art, reaching 0.2 Hz rmsd. For non-crystallizable compounds, for which xray crystallographic structure determination is not an option, our new method for accurate NMR prediction is invaluable in deciphering the solution structures of polycyclic and polyheterocyclic molecules.
