The utility of chemical synthesis in health-related research is closely tied to the efficient and selective construction of C-C bonds. Transition metal catalysis has introduced many C-C bond-forming transformations that would be challenging to accomplish via alternative means. Despite these advances, the general use of alkyl halides in catalytic, intermolecular C-C bond-forming reactions is limited to cross-coupling using stoichiometric organometallic reagents. This gap in reaction development limits the use of alkyl halides in C-C bond formation that would streamline drug synthesis and provide access to medicinally valuable functionalized small molecules. The long-term goal of this research is to introduce new catalytic C-C bond-forming reactions involving the direct coupling of alkyl electrophiles and widely available chemical feedstocks. The overall objective of this research is to develop new catalytic reactions of alkyl halides and alkenes or CO, including asymmetric variants. Synthetic studies and detailed experimental mechanistic analysis will be pursued to identify prevailing reaction pathways and avenues for further optimization. Our research is based on the central hypothesis that metal-catalyzed reactions involving hybrid organometallic-radical reactivity open the door to a wide variety of unique C-C bond-forming reactions. Transition-metal-promoted radical processes are well precedented, but the potential of this reactivity in organic synthesis is largely unrealized. Our initial work has demonstrated the power of this approach for accessing new catalytic transformations applicable to synthetically valuable carbo- and heterocycles. The rationale of the proposed research is that these fundamental C-C bond-forming reactions will enable new approaches to small molecule synthesis and facilitate access to a diverse array of functionalized compounds valuable in health-related research. This work involves three specific aims: (1) to develop intermolecular alkyl-Heck and carbonylative alkyl-Heck cross-couplings, (2) to perform detailed mechanistic investigations of alkyl-Heck processes, and (3) to develop enantioselective carbonylations of unactivated alkyl halides. Under the first aim, we will develop a general, intermolecular, catalytic coupling of unactivated alkyl halides and alkenes, providing a variety of valuable unsaturated products. In the second aim, we will study the reaction pathways involved in alkyl-Heck transformations to provide a mechanistic foundation for further reaction development. Under the third aim, we will develop a general catalytic asymmetric synthesis of carbonyl compounds via the carbonylation of alkyl electrophiles. We will extend this manifold to the enantioselective synthesis of ?-chiral esters, amides, and ketones. Our proposed research is innovative because it aims to develop new C-C bond-forming strategies using simple alkyl halides by harnessing unique organometallic-radical reactivity in palladium catalysis. These contributions are significant because they will offer practical, catalytic processes for the intermolecular formation of C-C bonds applicable to broad classes of small molecules valuable to the biomedical sciences.

Public Health Relevance

The proposed research is relevant to public health because it provides several synthetic methods for the efficient synthesis of functionalized small molecules of high biomedical importance. The challenge of rapidly accessing these structures is a significant barrier to health-related studies involving these compounds. Thus, we expect these synthetic tools to facilitate the development of next-generation small-molecule therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM107204-02
Application #
8847743
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2014-05-15
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kwiatkowski, Megan R; Alexanian, Erik J (2018) Nickel-Catalyzed Mizoroki-Heck-Type Reactions of Unactivated Alkyl Bromides. Angew Chem Int Ed Engl 57:16857-16860
Venning, Alexander R O; Kwiatkowski, Megan R; Roque Peña, Joan E et al. (2017) Palladium-Catalyzed Carbocyclizations of Unactivated Alkyl Bromides with Alkenes Involving Auto-tandem Catalysis. J Am Chem Soc 139:11595-11600
Roque Peña, Joan E; Alexanian, Erik J (2017) Cobalt-Catalyzed Silylcarbonylation of Unactivated Secondary Alkyl Tosylates at Low Pressure. Org Lett 19:4413-4415
Sargent, Brendon T; Alexanian, Erik J (2017) Cobalt-Catalyzed Carbonylative Cross-Coupling of Alkyl Tosylates and Dienes: Stereospecific Synthesis of Dienones at Low Pressure. J Am Chem Soc 139:12438-12440
Sargent, Brendon T; Alexanian, Erik J (2016) Palladium-Catalyzed Alkoxycarbonylation of Unactivated Secondary Alkyl Bromides at Low Pressure. J Am Chem Soc 138:7520-3
McMahon, Caitlin M; Renn, Matthew S; Alexanian, Erik J (2016) Manganese-Catalyzed Carboacylations of Alkenes with Alkyl Iodides. Org Lett 18:4148-50
Venning, Alexander R O; Bohan, Patrick T; Alexanian, Erik J (2015) Palladium-catalyzed, ring-forming aromatic C-H alkylations with unactivated alkyl halides. J Am Chem Soc 137:3731-4