The development of powerful new methods for the generation of carbon-carbon bonds has an impact on a wide array of disciplines that require the synthesis of organic compounds (e.g., biological chemistry, pharmaceutical chemistry, and biology); transition metals can catalyze carbon-carbon bond-forming processes, such as cross-couplings of organic electrophiles and nucleophiles, that would otherwise be difficult or impossible to achieve. Furthermore, because the two mirror-image isomers (enantiomers) of a molecule generally have different biological activity due to the handedness of the molecules of life (e.g., peptides, DNA, RNA, and carbohydrates), there is a need in the biomedical community to efficiently generate compounds in stereoisomerically pure form. This research program is directed at addressing both of these challenges. During the next grant period, a largely unexplored dimension of cross-coupling reactions will be investigated: processes that employ alkyl electrophiles as substrates. Efforts will focus on the development of versatile catalysts, including chiral catalysts, for a wide range of powerful bond-forming processes. Such reactions have the potential to simultaneously generate a carbon-carbon bond and to define up to two new stereocenters. Mechanistic studies will play an important role in this project, since an improved understanding of metal-based reactivity will facilitate catalyst development. This research program offers an opportunity to have a substantial impact on synthetic chemistry, as well as to enrich our understanding of once-unexpected chemical reactivity.

Public Health Relevance

The development of efficient new chemical processes will have a substantial impact on a wide array of biomedical disciplines that require the synthesis of organic compounds (e.g., biological chemistry, pharmaceutical chemistry, and biology). This project is focused on the discovery of new methods for the synthesis of carbon-carbon bonds (which form the backbone of organic molecules) and for the control of the chirality ('handedness') of compounds, which can be central to biological activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM062871-19
Application #
9608749
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
2001-04-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
19
Fiscal Year
2019
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Wang, Zhaobin; Bachman, Shoshana; Dudnik, Alexander S et al. (2018) Nickel-Catalyzed Enantioconvergent Borylation of Racemic Secondary Benzylic Electrophiles. Angew Chem Int Ed Engl 57:14529-14532
Wang, Zhaobin; Yin, Haolin; Fu, Gregory C (2018) Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins. Nature 563:379-383
Choi, Junwon; Fu, Gregory C (2017) Transition metal-catalyzed alkyl-alkyl bond formation: Another dimension in cross-coupling chemistry. Science 356:
Mu, Xin; Shibata, Yu; Makida, Yusuke et al. (2017) Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling. Angew Chem Int Ed Engl 56:5821-5824
Kalek, Marcin; Fu, Gregory C (2017) Caution in the Use of Nonlinear Effects as a Mechanistic Tool for Catalytic Enantioconvergent Reactions: Intrinsic Negative Nonlinear Effects in the Absence of Higher-Order Species. J Am Chem Soc 139:4225-4229
Fu, Gregory C (2017) Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes. ACS Cent Sci 3:692-700
Schmidt, Jens; Choi, Junwon; Liu, Albert Tianxiang et al. (2016) A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters. Science 354:1265-1269
Zuo, Zhiwei; Cong, Huan; Li, Wei et al. (2016) Enantioselective Decarboxylative Arylation of ?-Amino Acids via the Merger of Photoredox and Nickel Catalysis. J Am Chem Soc 138:1832-5
Ziegler, Daniel T; Fu, Gregory C (2016) Catalytic Enantioselective Carbon-Oxygen Bond Formation: Phosphine-Catalyzed Synthesis of Benzylic Ethers via the Oxidation of Benzylic C-H Bonds. J Am Chem Soc 138:12069-72
Chu, Crystal K; Liang, Yufan; Fu, Gregory C (2016) Silicon-Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles. J Am Chem Soc 138:6404-7

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