Photochemical reactions are attractive for drug discovery because they enable the synthesis of unusual, strained molecular frameworks that cannot be synthesized by other methods. Nevertheless, pharmaceutical companies rarely take advantage of photochemical synthesis because the need for specialized photochemical equipment is an impractical impediment and because very few methods to control the stereochemistry of photochemical reactions exist. Therefore, the structures of the molecules that are produced by photochemical synthesis have essentially not been examined as possible drug candidates. Our laboratory has pioneered a new approach to photochemical synthesis that uses convenient, readily available sources of visible light (e.g., household lightbulbs, ambient sunlight) in order to make photochemical synthesis accessible to medicinal chemists for the first time. This Proposal has two parallel objectives:
Aim 1. The development of strategies to control the stereochemistry of photochemical reactions.
Aim 2. The development of a novel mechanism of photochemical activation with visible light. These methods are powerful, robust, and simple to perform on large, industrially relevant scales. Thus, the research described in this proposal will significantly impact both the academic chemistry community and the broader community of medicinal chemists who require new methods of molecule construction to discover the next generation of life-saving drugs.

Public Health Relevance

The activity, selectivity, and potency of a drug is determined by its molecular structure. Thus if a compound cannot be synthesized, its potential as a drug candidate cannot be assessed. We are developing new photochemical reactions that produce unique molecular architectures, with the hopes that the ability to efficiently assemble these structures might facilitate the discovery of the next generation of life-saving drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095666-08
Application #
9380341
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2010-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Amador, Adrian G; Sherbrook, Evan M; Lu, Zhan et al. (2018) A general protocol for radical anion [3 + 2] cycloaddition enabled by tandem Lewis acid photoredox catalysis. Synthesis (Stuttg) 50:539-547
Reed, Nicholas L; Herman, Madeline I; Miltchev, Vladimir P et al. (2018) Photocatalytic Oxyamination of Alkenes: Copper(II) Salts as Terminal Oxidants in Photoredox Catalysis. Org Lett 20:7345-7350
Miller, Zachary D; Lee, Byung Joo; Yoon, Tehshik P (2017) Enantioselective Crossed Photocycloadditions of Styrenic Olefins by Lewis Acid Catalyzed Triplet Sensitization. Angew Chem Int Ed Engl 56:11891-11895
Lin, Shishi; Lies, Shane D; Gravatt, Christopher S et al. (2017) Radical Cation Cycloadditions Using Cleavable Redox Auxiliaries. Org Lett 19:368-371
Pitre, Spencer P; Scaiano, Juan C; Yoon, Tehshik P (2017) Photocatalytic Indole Diels-Alder Cycloadditions Mediated by Heterogeneous Platinum-Modified Titanium Dioxide. ACS Catal 7:6440-6444
Pitre, Spencer P; Yoon, Tehshik P; Scaiano, Juan C (2017) Titanium dioxide visible light photocatalysis: surface association enables photocatalysis with visible light irradiation. Chem Commun (Camb) 53:4335-4338
Yoon, Tehshik P (2016) Photochemical Stereocontrol Using Tandem Photoredox-Chiral Lewis Acid Catalysis. Acc Chem Res 49:2307-2315
Blum, Travis R; Miller, Zachary D; Bates, Desiree M et al. (2016) Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer. Science 354:1391-1395
Scholz, Spencer O; Farney, Elliot P; Kim, Sangyun et al. (2016) Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates. Angew Chem Int Ed Engl 55:2239-42
Amador, Adrian G; Sherbrook, Evan M; Yoon, Tehshik P (2016) Enantioselective Photocatalytic [3 + 2] Cycloadditions of Aryl Cyclopropyl Ketones. J Am Chem Soc 138:4722-5

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