Modern drugs are highly functionalized molecules, and often these molecules are chiral. The most promising solution for production of these molecules has relied on an asymmetric catalytic process, especially catalytic asymmetric oxidation, which can introduce multi functional groups into the molecule. The long-term goal is to develop catalytic asymmetric oxidation processes which can create highly functionalized drugs at a useful level of selectivity and scalability. The objective of developing these catalysts is to provide reliable and easy access to make molecules previously unattainable in a simple manner. The key to success is proper molecular design of an oxidation catalyst. Catalytic selective oxidation can introduce oxygen, nitrogen, and halogen to the substrate catalytically and selectively. Guided by strong preliminary data, this hypothesis will be tested by pursuing four specific aims: 1) asymmetric construction of quaternary carbon using nitroso chemistry, 2) development of catalytic asymmetric nitroso hetero-Diels-Alder and related asymmetric cycloadditions, 3) asymmetric epoxidation and its kinetic resolution, and 4) asymmetric halogenation. All four approaches are innovative, because each of them is an unknown process which capitalizes on a totally new concept of catalyst design developed by our group using earlier NIH support. They also take advantage of a number of ligand libraries which are available in no other laboratory. The proposed research is significant, because it is expected to provide a fine toolbox of catalysts, which will make possible the provision of previously unattainable complex molecules needed to develop entirely new pharmacologic strategies in the future. Relevance to Public Health: This is an important area of organic synthesis that has potential applicability to efficiently strengthen drugs, ultimately including those for human beings. Finally, the projects described herein will provide excellent training for graduate students and postdoctoral associates in catalysis, experience that will prepare them well for independent research careers to contribute for public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM068433-07S1
Application #
8011916
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Hagan, Ann A
Project Start
2010-02-05
Project End
2011-01-31
Budget Start
2010-02-05
Budget End
2011-01-31
Support Year
7
Fiscal Year
2010
Total Cost
$92,046
Indirect Cost
Name
University of Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Wang, Chuan; Luo, Lan; Yamamoto, Hisashi (2016) Metal-Catalyzed Directed Regio- and Enantioselective Ring-Opening of Epoxides. Acc Chem Res 49:193-204
Nakashima, Erika; Yamamoto, Hisashi (2015) Continuous flow of nitroso Diels-Alder reaction. Chem Commun (Camb) 51:12309-12
Luo, Lan; Yamamoto, Hisashi (2015) Synthesis of virtually enantiopure aminodiols with three adjacent stereogenic centers by epoxidation and ring-opening. Org Biomol Chem 13:10466-70
Wang, Chuan; Yamamoto, Hisashi (2015) Gadolinium-Catalyzed Regio- and Enantioselective Aminolysis of Aromatic trans-2,3-Epoxy Sulfonamides. Angew Chem Int Ed Engl 54:8760-3
Wang, Chuan; Yamamoto, Hisashi (2015) Nickel-catalyzed regio- and enantioselective aminolysis of 3,4-epoxy alcohols. J Am Chem Soc 137:4308-11
Wang, Chuan; Yamamoto, Hisashi (2014) Tungsten-catalyzed asymmetric epoxidation of allylic and homoallylic alcohols with hydrogen peroxide. J Am Chem Soc 136:1222-5
Wang, Chuan; Yamamoto, Hisashi (2014) Tungsten-catalyzed regio- and enantioselective aminolysis of trans-2,3-epoxy alcohols: an entry to virtually enantiopure amino alcohols. Angew Chem Int Ed Engl 53:13920-3
Luo, Lan; Yamamoto, Hisashi (2014) Iron(II)-Catalyzed Asymmetric Epoxidation of Trisubstituted ?,?-Unsaturated Esters. European J Org Chem 2014:7803-7805
Wang, Chuan; Yamamoto, Hisashi (2014) Tungsten-catalyzed regioselective and stereospecific ring opening of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides. J Am Chem Soc 136:6888-91
Li, Zhi; Yamamoto, Hisashi (2013) Hydroxamic acids in asymmetric synthesis. Acc Chem Res 46:506-18

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