Modern drugs are highly functionalized molecules, and often these molecules are chiral. In the pharmaceutical industry, single chiral drugs constitute over half the total drug market, and the key components in 9 of the top 10 drugs are chiral. The biomedical importance of chiral compounds has spurred intense research efforts by leading laboratories. The most promising solution for production of these molecules has relied on asymmetric catalytic processes, especially catalytic asymmetric oxidation, which can introduce multi-functional groups into the molecule. The long term goal of the project 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. In this renewal proposal, we outline plans for the development and use of new oxidation catalysts for enantioselective synthesis of multi-functional molecules. Unlike traditional transition metal-based catalysts, the catalysts being developed and studied in this program are organic molecules or contain non-harmful metals. These transition metal-free catalysts are not only of a fundamental interest, but also of industrial importance, since harmful transition metals are undesirable in pharmaceutical drugs. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. Mechanistic, crystallographic, and computational studies will provide an understanding of the catalytic processes and steer the development of more effective catalysts. Catalytic selective oxidation can introduce oxygen, nitrogen, or a halogen to the substrate catalytically and selectively. Our specific major aim is asymmetric epoxidation. The investigations of this reaction are expected to lead to the development of broadly useful asymmetric oxidation catalysis methodologies that will impact many facets of chemical synthesis. Additionally, the effort will provide excellent training in synthetic methodology development to undergraduate, graduate, and postdoctoral students interested in a research career in the pharmaceutical industry or academia Modified Specific Aim Catalytic enantioselective oxidation is an extremely important process for the drug industry. This is clear because the most bioactive molecules have highly functionalized structures. Simple olefins and carbonyl compounds are the most attractive starting materials available to the synthetic chemist, easily accessible in large quantities and in many varieties. Nature achieves highly specific syntheses of complex substances through the uniquely selective oxidation by enzyme catalysts starting from these simple compounds. While there are currently many broadly useful methods for catalytic asymmetric reduction, there are far fewer of these catalytic asymmetric techniques for oxidation. It should be noted that selective oxidation catalysis represents more formidable challenges than does for selective reduction catalysis, not the least of which is the thermodynamic instability of ligands under oxidative conditions. Although recently there has been progress in this important area, it is not yet sufficient. We propose herein catalytic oxidation which can introduce oxygen and sulfur into substrates chemo-, regio-, and enantioselectively to provide simple entry to the synthesis of highly functionalize complex molecules that have heretofore been known. Thus, our contribution here is expected to provide a set of new and general chiral oxidation catalysts for pharmaceutical laboratories and drug industries.
The specific aim of the next funding period is asymmetric epoxidation.
The aim i s divided into two parts: (1) vanadium, hafnium, and zirconium catalysts for epoxidation and their application to epoxidation- cyclization cascades;and (2) iron-based catalysts for asymmetric epoxidation and C-H oxidation and activation. These catalysts are significant in their representation as simple, benign ways to promote enantioselective epoxidation reactions. Overall, the proposed work will not only lead to an efficient synthetic route for selective oxidations, but, more importantly, will result in the development of methodology that should prove to be of general value to medicinal chemistry. The proposed project will include syntheses of several simple bioactive molecules to demonstrate how our catalysts work. The actual utility of the methods, of course, is much broader. It is also expected that what is learned will be equally applicable to the development of new oxidation catalysts of other systems. The proposed 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 previous 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.

Public Health Relevance

This is an important area of organic synthesis that has the potential ability to efficiently strength drugs, ultimately including those for human beings. Finally the projects described will provide excellent training for undergraduate, graduate, and postdoctoral students in catalysis, which will prepare them well for independent careers contributing to public health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Chicago
Schools of Arts and Sciences
United States
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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
Yamamoto, Hisashi (2013) Ten years of research in Chicago. Tetrahedron 69:

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