The development of novel routes to stereochemically and structurally complex targets of biological interest remains of paramount importance. New strategies, bond disconnections, and catalysts that exploit standard functional groups in innovative ways each contribute to the overall goal of increased scope and efficiency, and decreased time and cost. Catalysis, the use of substoichiometric amounts of reagent, without the need for covalent attachment or pretreatment, carries with it the promise of greener, more efficient, more selective methods for synthesis. This proposal seeks to develop novel methods to use traditional functional groups in non-traditional ways, accessing hitherto unavailable bond disconnection strategies in an effort to greatly expand our toolkit. In the context of this research, we will apply these breakthroughs in order to prepare stermocurtisine and cephalomysin, two members of a family of biologically active agents whose activity spans from anti-fungal to anti-angiogenic and antitumor. We have further developed techniques for the selective and green synthesis of new amide bonds, ubiquitous functional groups in chemistry and biology. The specific goals of this research are as follows: 1) develop the catalytic enantioselective intermolecular Stetter reaction;2) explore cascade catalysis using simple precursors to generate densely functionalized products;3) pursue the rapid total synthesis of a variety of biologically important molecules using this approach;4) investigate the redox chemistry of 1-reducible aldehydes using nucleophilic carbenes. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.
Project Narrative One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize complex frameworks using easily accessible precursors with high efficiency.
|White, Nicholas A; Ozboya, Kerem E; Flanigan, Darrin M et al. (2014) Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via N-Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes. Asian J Org Chem 3:442-444|
|Hsieh, Sheng-Ying; Wanner, Benedikt; Wheeler, Philip et al. (2014) Stereoelectronic basis for the kinetic resolution of N-heterocycles with chiral acylating reagents. Chemistry 20:7228-31|
|White, Nicholas A; Rovis, Tomislav (2014) Enantioselective N-heterocyclic carbene-catalyzed ?-hydroxylation of enals using nitroarenes: an atom transfer reaction that proceeds via single electron transfer. J Am Chem Soc 136:14674-7|
|White, Nicholas A; DiRocco, Daniel A; Rovis, Tomislav (2013) Asymmetric N-heterocyclic carbene catalyzed addition of enals to nitroalkenes: controlling stereochemistry via the homoenolate reactivity pathway to access ?-lactams. J Am Chem Soc 135:8504-7|
|Lathrop, Stephen P; Rovis, Tomislav (2013) A photoisomerization-coupled asymmetric Stetter reaction: application to the total synthesis of three diastereomers of (-)-cephalimysin A. Chem Sci 4:|
|Zhao, Xiaodan; Glover, Garrett S; Oberg, Kevin M et al. (2013) SNAr-Derived Decomposition By-products Involving Pentafluorophenyl Triazolium Carbenes. Synlett 24:|
|DiRocco, Daniel A; Oberg, Kevin M; Rovis, Tomislav (2012) Isolable analogues of the Breslow intermediate derived from chiral triazolylidene carbenes. J Am Chem Soc 134:6143-5|
|DiRocco, Daniel A; Rovis, Tomislav (2012) Catalytic asymmetric ýý-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis. J Am Chem Soc 134:8094-7|
|DiRocco, Daniel A; Noey, Elizabeth L; Houk, K N et al. (2012) Catalytic asymmetric intermolecular Stetter reactions of enolizable aldehydes with nitrostyrenes: computational study provides insight into the success of the catalyst. Angew Chem Int Ed Engl 51:2391-4|
|Zhao, Xiaodan; DiRocco, Daniel A; Rovis, Tomislav (2011) N-heterocyclic carbene and Brønsted acid cooperative catalysis: asymmetric synthesis of trans-?-lactams. J Am Chem Soc 133:12466-9|
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