Carbon-fluorine bond formation is a challenging chemical transformation, especially when used for the synthesis of arylfluorides. Simple molecules can be fluorinated with fluorination methods developed during the last 100 years, molecules of greater complexity, however, cannot. The current inability of chemists to efficiently make complex organic fluorides by late-stage fluorination often prevents research in diverse areas, such as drug development and molecular PET imaging. The proposed research addresses the chemical challenges of carbon-fluorine bond formation to synthesize functionalized arylfluorides. Our strategy for carbon-fluorine bond formation is based on organometallic chemistry. We proposed Pd- and Ag- mediated fluorination reaction of arylstannanes, arylboronic acids, and arylsilanes. Additionally we propose to develop transition metal fluoride complexes that react as electrophilic fluorination reagents using anionic fluoride as ultimate fluorine source. We further propose to synthesize four biologically active molecules via late-stage fluorination using our transition-metal mediated approach. A long-term-goal of our research is the application of our fluorination reactions to the synthesis of currently unavailable PET tracers for molecular imaging using positron-emission tomography. The application of the fluorination reactions to molecular imaging is beyond the scope of this grant proposal.

Public Health Relevance

Many of the most useful man-made molecules contain fluorine due to the unique, desired properties of fluorinated molecules. The current inability of chemists to make complex fluorinated molecules by late-stage fluorination often prevents research in diverse areas such as drug development and molecular PET imaging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088237-05
Application #
8601710
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-01-20
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$291,375
Indirect Cost
$113,175
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Brandt, Jochen R; Lee, Eunsung; Boursalian, Gregory B et al. (2014) Mechanism of Electrophilic Fluorination with Pd(IV): Fluoride Capture and Subsequent Oxidative Fluoride Transfer(.) Chem Sci 5:
Campbell, Michael G; Ritter, Tobias (2014) Late-stage formation of carbon-fluorine bonds. Chem Rec 14:482-91
Boursalian, Gregory B; Ngai, Ming-Yu; Hojczyk, Katarzyna N et al. (2013) Pd-catalyzed aryl C-H imidation with arene as the limiting reagent. J Am Chem Soc 135:13278-81
Mazzotti, Anthony R; Campbell, Michael G; Tang, Pingping et al. (2013) Palladium(III)-catalyzed fluorination of arylboronic acid derivatives. J Am Chem Soc 135:14012-5
Kamlet, Adam S; Neumann, Constanze N; Lee, Eunsung et al. (2013) Application of palladium-mediated (18)F-fluorination to PET radiotracer development: overcoming hurdles to translation. PLoS One 8:e59187
Sladojevich, Filippo; Arlow, Sophie I; Tang, Pingping et al. (2013) Late-stage deoxyfluorination of alcohols with PhenoFluor. J Am Chem Soc 135:2470-3
Furuya, Takeru; Kamlet, Adam S; Ritter, Tobias (2011) Catalysis for fluorination and trifluoromethylation. Nature 473:470-7
Powers, David C; Ritter, Tobias (2011) Palladium(III) in Synthesis and Catalysis. Top Organomet Chem 503:129-156
Tang, Pingping; Wang, Weike; Ritter, Tobias (2011) Deoxyfluorination of phenols. J Am Chem Soc 133:11482-4
Huang, Chenghong; Liang, Theresa; Harada, Shinji et al. (2011) Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids. J Am Chem Soc 133:13308-10

Showing the most recent 10 out of 17 publications