This proposal addresses Broad Challenge Area (06) Enabling Technologies and Specific Challenge Topic 06-GM-109 Green chemistry and engineering for drug discovery, development, and production. Development of chemical methodologies and tools to promote green chemistry and engineering innovation into drug discovery, development, and production. Selective oxidation reactions are among the most important classes of reactions in chemical synthesis. Molecular oxygen is the least expensive and most environmentally benign chemical oxidant available, yet it is virtually never used in drug development and production because aerobic oxidation reactions typically exhibit poor reaction selectivity and present insurmountable safety hazards. The project described in this proposal will build upon recent advances in metal-catalyzed reactivity and innovations in reaction engineering in order to achieve safe and scalable methods for use of molecular oxygen as a selective oxidant in pharmaceutical synthesis. Flow-reactor technology provides a means to translate small-scale aerobic oxidation reactions, many of which have been reported in the recent literature, into large-scale pharmaceutical processes. The design, construction and testing of operational flow reactors will be performed in collaboration with scientists and engineers at Eli Lilly (Indianapolis, IN), and this work will target the development of reactors compatible with both homogeneous and heterogeneous reaction solutions. These reactors will be used for systematic investigation of factors (catalyst identity, temperature, pressure, flow-rate, etc.) that enable effective translation of results obtained from small-scale, batch reactions into successful flow-based processes. Initial studies will focus on palladium-catalyzed methods for aerobic alcohol oxidation, which have been the focus of considerable synthetic and mechanistic investigation by the PI and his group over the past 10 years. The results of these studies should be applicable to the entire scope of aerobic oxidation reactions that have been reported in recent years, including methods for carbon-nitrogen bond formation, allylic acetoxylation and C-H bond functionalization reactions. The expanding scope of selective aerobic oxidation reactions suggests that this project will play an important role in promoting """"""""green chemistry"""""""" in large-scale production of pharmaceuticals. Once the flow reaction methods are established, they will be used to achieve two synthetically useful tandem transformations that build upon flow-based aerobic alcohol oxidations: (1) convergence of racemic secondary alcohols into their enantiomerically pure form via sequential aerobic alcohol oxidation/enantioselective ketone hydrogenation, and (2) the conversion of alcohols to (chiral) amines via sequential aerobic alcohol oxidation/(enantioselective) reductive amination reactions. In the both classes of reactions, oxidation reactions with O2 and reduction reactions with H2 will be performed in flow.

Public Health Relevance

Molecular Oxygen is the most abundant and environmentally benign oxidant available for chemical synthesis;however, fundamental challenges limit its utility in pharmaceutical synthesis. The proposed research will implement innovative chemistry (new catalytic methods) and engineering (flow-reactor technology) strategies to overcome this limitation, thereby enabling widespread use of a new environmentally benign (""""""""green"""""""") method for the development and production of pharmaceuticals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-BCMB-P (58))
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Schwab, John M
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Mannel, David S; Stahl, Shannon S; Root, Thatcher W (2014) Continuous Flow Aerobic Alcohol Oxidation Reactions Using a Heterogeneous Ru(OH) x /Al2O3 Catalyst. Org Process Res Dev 18:1503-1508
Ryland, Bradford L; Stahl, Shannon S (2014) Practical aerobic oxidations of alcohols and amines with homogeneous copper/TEMPO and related catalyst systems. Angew Chem Int Ed Engl 53:8824-38
Diao, Tianning; Wadzinski, Tyler J; Stahl, Shannon S (2012) Direct Aerobic ?, ?-Dehydrogenation of Aldehydes and Ketones with a Pd(TFA)(2)/4,5-Diazafluorenone Catalyst(). Chem Sci 3:887-891
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