Catalytic dicarbofunctionalization of unactivated alkenes offers a powerful method to create two carbon-carbon bonds simultaneously. Achievement of this objective offers to construct the cores of many biologically important molecules rapidly, concisely and cost-effectively. Our long-term goal is to devise and create such reactions by intercepting alkylmetal intermediates, generated in situ after the addition of organic halides to alkenes, with carbon nucleophiles. The development of these processes with simple unactivated alkenes has been shown to be exceptionally challenging, however, because of two key issues; slow migratory insertion of alkenes leading to the formation of cross-coupling products, and faster ?-H elimination from alkylmetal intermediates than transmetalation leading to the formation of Heck products. In the proposed research, we will implement three strategies to difunctionalize unactivated alkenes regioselectively with organic halides and organometallic reagents. First, we will introduce a strategy of Synergistic Bimetallic Cationic Catalysis, where cationic Ni(II) catalysts are generated in situ to address the key issues identified above. This process will enable us to perform regioselective ?,?-difunctionalization of unactivated alkenes located at the ?,?-position of carbonyl compounds. In our second strategy, we introduce the concept of Metallacycle Contraction Process, a reaction that harnesses the potential of alkylmetal intermediates to undergo ?-H elimination to contract a six-membered metallacycle to a five-membered metallacycle, and difunctionalizes unactivated alkenes at the unusual 1,3-position rather than the usual 1,2-position of alkenes. This unprecedented reaction allows us to create two new carbon-carbon bonds at the ?- and ?-positions of carbonyl compounds containing ?,?-alkenes. Third, our ultimate goal is to develop novel catalysts to modulate migratory insertion and ?-H elimination processes, and enable difunctionalization to proceed with simple alkenes without requiring a coordinating group. We present different catalytic conditions, which enable dicarbofunctionalization of alkenes lacking a coordinating group. The catalytic alkene dicarbofunctionalization reactions proposed and for which we have strong preliminary results are unique transformations that cannot be achieved with using other methodology.

Public Health Relevance

The goal of the proposed research is to design and create catalytic reactions that facilitate regioselective dicarbofunctionalization of unactivated alkenes. We will develop these transformations by intercepting alkylmetal species, formed after the addition of organic halides to alkenes, with organometallic reagents. This research program will invent new methods for rapidly constructing complex molecular motifs present in pharmaceuticals, bioactive molecules and drug targets, and will make significant impacts on the biomedical mission of the NIH.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM133438-02
Application #
9999602
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Yang, Jiong
Project Start
2019-09-01
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802