. An incredible diversity of transition metal-catalyzed methods has been developed around a small subset of elementary organometallic reactions. The overarching goal of our research program is to expand this tool box to include new organometallic mechanisms that can in turn be integrated into many new catalytic transformations to generate new organic structures. A central hypothesis of this proposal is that enforcing persistent coordinative-unsaturation in catalyst structures can enable unique organometallic mechanisms, such as in the transmetalation step common to all carbon- carbon and carbon-heteroatom cross-coupling reactions ? some of the most practiced reactions at all levels of pharmaceutical research. Our approach is inspired by the potential for substantial attractive van der Waals forces in large aliphatic groups, which we are able to incorporate into metal catalysts structures using large organophosphorus ligands. A primary focus of this work will be to understand the mechanisms of, and to leverage, an unusual series of transmetalation reactions we have observed with mixtures of low-coordinate palladium complexes and protic nucleophiles, such as organoboronic acids. These reactions can occur under very mild conditions even in the absence of strong base, which has been historically necessary in many cross-coupling reactions yet also compromises the compatibility with sensitive compounds. The unique influence of diamondoids, such as in tri(1-adamantyl)phosphine, in promoting this chemistry may reflect the large polarizability and dispersion forces manifested in large aliphatic molecules. In order to generalizing these aliphatic effects, we will concurrently pursue new, modular methods to construct congested C(sp3)?P bonds, which are common motifs in both catalytic structures and also many biologically active compounds. Furthermore, we will expand these aliphatic effects to promote historically challenging transmetalation and oxidative addition reactions in iron and copper catalysis, respectively, which are general problems that have hindered efforts hindered to develop more sustainable cross-coupling methods using abundant base metals Together the catalytic and organophosphorus synthetic efforts of this proposal will generate new biologically active molecular structures through novel carbon-element bond forming reactions.

Public Health Relevance

The project is relevant to the NIH's mission because it will develop new methods for the synthesis of pharmaceutically relevant organic molecules. Specifically, Pd-catalyzed cross- coupling reactions are widely utilized to prepare active pharmaceutical ingredients, and these proposed studies will expand the core structures accessible with this essential class of reaction. Additionally, studies of Fe- and Cu-catalyzed cross-coupling will be investigated as a strategy to improve the greenness and sustainability of chemical industry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM128902-02
Application #
9745378
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Lees, Robert G
Project Start
2018-07-15
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Graduate Schools
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08543