The discovery and development of new methods for the preparation and use of organic compounds has considerable impact upon how drugs are discovered and synthesized. One overall objective of this application is the development of catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds present in 84% of small-molecule drugs. Methods for the preparation of the subset of nitrogen heterocycles present in 59% of drugs are emphasized. Efficient syntheses of these compound classes will be accomplished by C-H functionalization methods. One example is stereoselective, catalytic two- and three-component C-H bond additions to C=O/C=N bonds to provide diverse amine and alcohol products that in situ can be transformed into more complex, drug-relevant heterocycles. New earth abundant Co(III) catalysts will be developed and studied for these transformations. Another example is efficient syntheses of diverse piperidines, the heterocycle class with the highest frequency of occurrence in drugs, by regio- and stereoselective elaboration of highly substituted 1,2-dihydropyridines generated in situ by one step C-H bond functionalization/electrocyclization cascades. New methods will also be achieved to prepare bridged and fused bicyclic and multicyclic piperidines, including pharmaceutical agents. Innovative new types of reactivity will be explored in C-H bond functionalization and subsequent transformations. These significant studies will enable the more rapid preparation of analogs in drug discovery efforts and reduced cost and waste in drug production due to; (1) the ubiquitous presence of C-H bonds in organic compounds, (2) the very high functional group compatibility of the Rh and Co catalysts used, and (3) the importance of the compound classes prepared. The second overriding objective is the development and use of potent and selective enzyme inhibitors discovered through substrate-based fragment approaches. Orally available inhibitors of cruzain, an essential protease of the parasite responsible for Chagas disease, have been developed as have near-IR quenched activity-based inhibitors of cathepsin S for imaging in vivo. The first inhibitors of Striatal-Enriched Phosphatase (STEP), a protein tyrosine phosphatase (PTP) implicated in a number of neurodegenerative diseases, including Alzheimer's disease (AD), will be advanced. Structure- based optimization will be carried out using the first x-ray structures of STEP inhibitor complexes. Reversible covalent inhibitors developed to recapitulate known physiological means of PTP regulation will also be advanced. This innovative platform for PTP inhibition has already resulted in compounds that reverse cognitive dysfunction in AD mouse models. The substrate fragment approach will also be applied to the increasingly prominent class of protein post-translational modification enzymes, the protein arginine deiminases (PADs), for which little inhibitor development has so far been carried out. This new and innovative approach has already resulted in PAD3 selective small molecule inhibitors and will be applied to the other PAD isozymes.
The discovery and development of new methods for the preparation and use of synthetic compounds has considerable impact upon how drugs are discovered and produced. This proposal describes powerful and general new C-H bond functionalization methods to efficiently prepare classes of compounds that predominate in drugs. New chemical approaches will also be applied to the discovery of small molecule inhibitors to challenging enzyme targets having essential physiological roles and relevance to human maladies.
|Chen, Shuming; Chan, Amy Y; Walker, Morgan M et al. (2018) ?-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions. J Org Chem :|
|Tjin, Caroline Chandra; Wissner, Rebecca F; Jamali, Haya et al. (2018) Synthesis and Biological Evaluation of an Indazole-Based Selective Protein Arginine Deiminase 4 (PAD4) Inhibitor. ACS Med Chem Lett 9:1013-1018|
|Boerth, Jeffrey A; Maity, Soham; Williams, Sarah K et al. (2018) Selective and synergistic cobalt(III)-catalyzed three-component C-H bond addition to dienes and aldehydes. Nat Catal 1:673-679|
|Hoang, Gia L; Ellman, Jonathan A (2018) Rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles. Tetrahedron 74:3318-3324|
|Halskov, Kim Søholm; Witten, Michael R; Hoang, Gia L et al. (2018) Rhodium(III)-Catalyzed Imidoyl C-H Activation for Annulations to Azolopyrimidines. Org Lett 20:2464-2467|
|Potter, Tyler J; Li, Yuantao; Ward, Michael D et al. (2018) RhIII-Catalyzed Synthesis of Isoquinolones and 2-Pyridones via Annulation of N-Methoxyamides and Nitroalkenes. European J Org Chem 2018:4381-4388|
|Walker, Morgan M; Chen, Shuming; Mercado, Brandon Q et al. (2018) Formation of Aminocyclopentadienes from Silyldihydropyridines: Ring Contractions Driven by Anion Stabilization. Angew Chem Int Ed Engl 57:6605-6609|
|Hoang, Gia L; Søholm Halskov, Kim; Ellman, Jonathan A (2018) Synthesis of Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-Azolo Imines and Dioxazolones. J Org Chem 83:9522-9529|
|Hoang, Gia L; Streit, Andrew D; Ellman, Jonathan A (2018) Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines. J Org Chem :|
|Potter, Tyler J; Ellman, Jonathan A (2017) Total Synthesis of (+)-Pancratistatin by the Rh(III)-Catalyzed Addition of a Densely Functionalized Benzamide to a Sugar-Derived Nitroalkene. Org Lett 19:2985-2988|
Showing the most recent 10 out of 17 publications