Catalytic C-C bond forming reactions have revolutionized the discovery and synthesis of small molecules in academia and industry, but the full potential of transition-metal catalysis is now frequently limited by the need for pre-formed organometallic reagents. Few such reagents are commercially available because their synthesis is not trivial and many of the reagents have limited stability. These limitations have consequences for drug discovery and biochemistry because many potentially important molecules are not made when they are deemed too time consuming to access. One potential solution to this problem is the replacement of nucleophilic organometallic reagents with electrophiles, such as organic halides, which are bench stable and plentiful. This program's long-term goals are the development of new catalytic reactions that couple two or more electrophiles as well as the illumination of the factors which control selectivity and reactivity in these reductive coupling reactions. In the proposed grant, reductive alternatives will be developed for two of the most important types of C-C bond forming reactions: cross-coupling and conjugate addition. The guiding mechanistic hypothesis for this work is that the single-electron chemistry of first-row transition metals will enable the coupling of two electrophiles by allowing multiple oxidative additions to occur at a single metal center. Although radical intermediates are almost certainly involved, these transition-metal catalyzed reactions can be tuned through choice of metal and ligand. Thus, the reactions developed will provide a complementary reactivity to the better studied two-electron processes of other metals. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop direct reductive cross-coupling reactions that form Csp3- Csp2 bonds from simple organic halides or pseudohalides and better understand the mechanism of the transformation;(2) create direct reductive coupling methods that form Csp3-Csp3 bonds;and, (3) extend the concept of reductive coupling to include the coupling of organic halides with carbon monoxide, alkenes, and alkynes. Under each aim a promising catalyst system has been discovered in the applicant's laboratory that will become the basis for the development of several general methods. The approach is innovative because it focuses on the development of new reactions that completely avoid intermediate organometallic reagents. Strategies to overcome the challenges of cross-selectivity and reactivity have been identified that have previously prevented progress. By investigating reactions with different mechanisms, the proposed research presents the opportunity for dramatic improvements in critical C-C bond-forming reactions as well as new bond constructions that were not previously possible. The proposed research is significant because it is expected to expand the number of molecules that can be rapidly made from commercially available materials. In the long run, this expansion of readily accessible molecular diversity will enable discoveries in molecular biology and pharmacology that will directly impact human health.

Public Health Relevance

The new coupling reactions proposed in this application do not require specialized techniques or the exclusion of air, empowering those in the health sciences, even those with limited chemistry experience, to synthesize needed molecules themselves. The proposed research is relevant to public health and the mission of the NIH because it is from this expanded, diversified pool that tomorrow's drugs and molecular probes will be discovered.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097243-03
Application #
8458158
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$283,276
Indirect Cost
$99,926
Name
University of Rochester
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Everson, Daniel A; Buonomo, Joseph A; Weix, Daniel J (2014) Nickel-catalyzed cross-electrophile coupling of 2-chloropyridines with alkyl bromides. Synlett 25:233-238
Zhao, Yang; Weix, Daniel J (2014) Nickel-catalyzed regiodivergent opening of epoxides with aryl halides: co-catalysis controls regioselectivity. J Am Chem Soc 136:48-51
Everson, Daniel A; Weix, Daniel J (2014) Cross-electrophile coupling: principles of reactivity and selectivity. J Org Chem 79:4793-8
Biswas, Soumik; Weix, Daniel J (2013) Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides. J Am Chem Soc 135:16192-7
Shrestha, Ruja; Dorn, Stephanie C M; Weix, Daniel J (2013) Nickel-catalyzed reductive conjugate addition to enones via allylnickel intermediates. J Am Chem Soc 135:751-62
Everson, Daniel A; Jones, Brittany A; Weix, Daniel J (2012) Replacing conventional carbon nucleophiles with electrophiles: nickel-catalyzed reductive alkylation of aryl bromides and chlorides. J Am Chem Soc 134:6146-59
Wotal, Alexander C; Weix, Daniel J (2012) Synthesis of functionalized dialkyl ketones from carboxylic acid derivatives and alkyl halides. Org Lett 14:1476-9