The basic objectives of this application are the explanation, development and application of tandem cycloaddition and cyclization reaction of the nitroalkene functional group. The program is divided into two major sections with specific aims but unified in the common theme of new reaction chemistry. The goals of the first section are to expand the scope of the tandem intermolecular [4+2]/intramolecular [3+2]-cycloaddition by investigation of structural modification in diene, dipolarophile, connecting tether and dienophile. New chiral dienophiles, based on chiral enol ethers and enamines will be developed. The second stage of developmental studies will involve modification of substrates to allow for various ring sizes to be accommodated. Reconstruction of the basic substrate will also allow for a spiro-mode annulation allowing for construction of nitrogen bearing quaternary asymmetric centers. A significant subgoal in the developmental section Is the invention of a new reaction combining the ready construction of cyclic nitronic esters with their expected potential as acceptors in radical cyclization reactions. This amalgamation is expected to dramatically expand the potential of the nitroalkene cycloaddition reaction by providing access to compounds not readily available by the tandem cycloaddition sequence. Many different radical precursors will be explored. The goal of the second section is the demonstration of the synthetic potential of the tandem cycloaddition and cyclization methodology. The basic polycyclic subunits constructed by these reactions bear a significant structural homology to many different families of alkaloid natural products. The methodological development in the first section is guided by the structural and functional requirements posed by many of these natural compounds. The ability to prepare, in optically active form, representatives of the pyrrolizidine, melodinus, sceletium, amaryllidaceae, hasubanan, cephalotaxus and erythrina families of alkaloids is illustrated. To accomplish this, the versatility of the reaction will be tested in functional competability and structural virtuosity. Although an admittedly ambitious undertaking, the longer term goal of the project is to provide mild, efficient and general methods for the synthesis of multifunctional polycyclic compounds in non-racemic form.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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University of Illinois Urbana-Champaign
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United States
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Denmark, Scott E (2018) Organic Synthesis: Wherefrom and Whither? (Some Very Personal Reflections). Isr J Chem 58:61-72
Denmark, Scott E; Matesich, Zachery D; Nguyen, Son T et al. (2018) Catalytic Nucleophilic Allylation Driven by the Water-Gas Shift Reaction. J Org Chem 83:23-48
Ibrahim, Malek Y S; Denmark, Scott E (2018) Selective extraction of supported Rh nanoparticles under mild, non-acidic conditions with carbon monoxide. J Mater Chem A Mater 6:18075-18083
Thomas, Andy A; Zahrt, Andrew F; Delaney, Connor P et al. (2018) Elucidating the Role of the Boronic Esters in the Suzuki-Miyaura Reaction: Structural, Kinetic, and Computational Investigations. J Am Chem Soc 140:4401-4416
Tao, Zhonglin; Robb, Kevin A; Panger, Jesse L et al. (2018) Enantioselective, Lewis Base-Catalyzed Carbosulfenylation of Alkenylboronates by 1,2-Boronate Migration. J Am Chem Soc 140:15621-15625
Barraza, Scott J; Denmark, Scott E (2018) Synthesis, Reactivity, Functionalization, and ADMET Properties of Silicon-Containing Nitrogen Heterocycles. J Am Chem Soc 140:6668-6684
Ibrahim, Malek Y S; Denmark, Scott E (2018) Palladium/Rhodium Cooperative Catalysis for the Production of Aryl Aldehydes and Their Deuterated Analogues Using the Water-Gas Shift Reaction. Angew Chem Int Ed Engl 57:10362-10367
Böse, Dietrich; Denmark, Scott E (2018) Investigating the Enantiodetermining Step of a Chiral Lewis Base Catalyzed Bromocycloetherification of Privileged Alkenes. Synlett 29:433-439
Tao, Zhonglin; Robb, Kevin A; Zhao, Kuo et al. (2018) Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes. J Am Chem Soc 140:3569-3573
Barraza, Scott J; Denmark, Scott E (2017) Unexpected Rearrangement of 2-Bromoaniline under Biphasic Alkylation Conditions. Synlett 28:2891-2895

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