A vital step in any efficient chemical synthesis of valuable, structurally complex, organic molecules is the step that couples elaborate fragments. When the atoms joined in a fragment-coupling step each posses 3-dimentional character, exhibiting chirality - the union is particularly challenging. The objective of the proposed researc is the development and validation of new methodologies for combining complex fragments of this type. Specifically, the proposed research will investigate the utility of bimolecular reaction of tertiary carbon radicals with carbon-centered electrophiles for fragment coupling and the construction of quaternary-carbon stereocenters. In addition, radical-based methods will be employed to access 1,4-dicarbonyl structural motifs that exhibit inverse polarity. Such chemical transformations are not commonly utilized in organic synthesis, yet hold untapped potential to address formidable challenges faced by the scientific community in constructing complex organic molecules. All of the methods to be developed under this fellowship will employ photoredox catalysis, and, as a result, will be particularly attractive for their low environmental impact and use of sustainable energy source, visible light. The developed methods will be utilized to generate a library of structural analogs of macrocarpal A, a natural product that exhibits anticancer activity. Antitumor studies will be performed in collaboration with Dr. David Horne to establish advanced structure-activity relationships. The developed body of knowledge should prove valuable in the discovery, and potentially production, of fine chemicals in the pharmaceutical, biotechnology, agricultural, and related industries.

Public Health Relevance

With over 1.6 million new cancer cases and nearly 600,000 cancer-related deaths each year, more efficient methods for the development of potential drug candidates are required. The proposed research will utilize renewable energy, visible light, to enable rapid access to libraries of small molecules possessing anticancer activity that will be used to establish structure-activity relationships, allowing for more efficient drug discovery process. The developed ideas will be applicable to the pharmaceutical, biotechnology, agricultural, and related industries.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31GM113494-01
Application #
8834139
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2015-07-01
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Tao, Daniel J; Slutskyy, Yuriy; Overman, Larry E (2016) Total Synthesis of (-)-Chromodorolide B. J Am Chem Soc 138:2186-9
Slutskyy, Yuriy; Overman, Larry E (2016) Generation of the Methoxycarbonyl Radical by Visible-Light Photoredox Catalysis and Its Conjugate Addition with Electron-Deficient Olefins. Org Lett 18:2564-7
Tao, Daniel J; Muuronen, Mikko; Slutskyy, Yuriy et al. (2016) Diastereoselective Coupling of Chiral Acetonide Trisubstituted Radicals with Alkenes. Chemistry 22:8786-90
Nawrat, Christopher C; Jamison, Christopher R; Slutskyy, Yuriy et al. (2015) Oxalates as Activating Groups for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling. J Am Chem Soc 137:11270-11273