The metathesis reaction between two alkenes represents a powerful tool for the formation of carbon-carbon bonds, which has led to profound synthetic applications in a large variety of biologically active target structures. The corresponding carbonyl-olefin metathesis reaction enables direct carbon-carbon bond construction, however, currently available synthetic methods are severely limited by harsh reaction conditions or require the use of stoichiometric metal alkylidene complexes as reagents. To date, no protocol of general synthetic utility for catalytic carbonyl-olefin metathesis exists. The objective of the proposed research program is to identify a chemical strategy that enables the catalytic carbonyl-olefin metathesis and related carbocyclization reactions based on inexpensive and earth-abundant transition metals. A distinctive feature of this new methodology is that it will provide a general and modular protocol for the synthesis of a large variety of cyclic motifs incorporated in many ubiquitous chemical scaffolds and biologically active complex molecules. Additionally, this new approach enables carbonyl-olefin metathesis reactions under mild reaction conditions with high functional group tolerance. In particular, highly functionalized carbocycles which all constitute core components of pharmacophores with a wide array of biological activities, will be directly accessible in a single transformation. Such carbocycles include cyclopentenes, cyclohexenes, furans, pyrans, pyridines and their analogs, indenes, napthalenes, spirocyclic, polycyclic as well as biaryl building blocks. The utility of these new carbocyclization reactions catalyzed by earth-abundant transition metals will be demonstrated by enabling the synthesis of biologically active target structures from simple, and readily available starting materials. The compounds prepared within this research program will be incorporated into the compound library maintained by the Center for Chemical Genomics (CCG) at the University of Michigan and become part of high-throughput screening (HTS) approaches for biological research and novel drug discovery projects. In summary, the research proposed will establish the first general, catalytic carbonyl-olefin metathesis reaction employing earth-abundant transition metals as a new tool for direct carbon-carbon bond construction which is expected to have wide implications for the area of complex molecule synthesis.
The proposed research is relevant to public health because the development of new catalytic methods described is expected to ultimately enable efficient synthetic access to human medicines and biologically active natural products relying on environmentally benign and inexpensive reagents. The project is relevant to the part of NIH's mission that includes the development of fundamental knowledge which will help improve and ultimately protect human health.
|Watson, Rebecca B; Schindler, Corinna S (2018) Iron-Catalyzed Synthesis of Tetrahydronaphthalenes via 3,4-Dihydro-2H-pyran Intermediates. Org Lett 20:68-71|
|McAtee, Christopher C; Ellinwood, Duncan C; McAtee, Rory C et al. (2018) Functionalized Cyclopentanes via Sc(III)-Catalyzed Intramolecular Enolate Alkylation. Tetrahedron 74:3306-3313|
|Ludwig, Jacob R; Watson, Rebecca B; Nasrallah, Daniel J et al. (2018) Interrupted carbonyl-olefin metathesis via oxygen atom transfer. Science 361:1363-1369|
|Groso, Emilia J; Golonka, Alexander N; Harding, Ryan A et al. (2018) 3-Aryl-2,5-Dihydropyrroles via Catalytic Carbonyl-Olefin Metathesis. ACS Catal 8:2006-2011|
|McAtee, Christopher C; Riehl, Paul S; Schindler, Corinna S (2017) Polycyclic Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl-Olefin Metathesis. J Am Chem Soc 139:2960-2963|
|Ludwig, Jacob R; Phan, Susan; McAtee, Christopher C et al. (2017) Mechanistic Investigations of the Iron(III)-Catalyzed Carbonyl-Olefin Metathesis Reaction. J Am Chem Soc 139:10832-10842|
|Ludwig, Jacob R; Schindler, Corinna S (2017) Lewis Acid Catalyzed Carbonyl-Olefin Metathesis. Synlett 28:1501-1509|