Molecules containing carbon fluorine bonds are industrially prevalent as approximately 30% of all agrochemicals and 20% of all pharmaceuticals contain fluorine. The incorporation of fluorine into pharmaceuticals can enhance lipophilicity, bioavailability, metabolic stability, and can alter the strength of a compound's interaction with a target protein. For example, the highly successful drugs Lipitor (hypercholesterolemia), Ciprobay (antibiotic), and Risperdal (antipsychotic) boast an aryl fluorine bond. Additionally, the radioactive isotope 18F is widely used for molecular positron emission tomography (PET) in oncology imaging. While fluorine has widespread use, the traditional methods to incorporate it into an aromatic framework generally require harsh reaction conditions that do not tolerate many functional groups. Because of these restrictions, strategically advantageous late-stage approaches are generally abandoned, and the desired fluorine atoms are introduced into aromatics at an early synthetic stage. Catalysis, however, enables mild reaction conditions and selective transformations by providing lower energy pathways for the conversion of reactants into products. Specifically, transition metal-catalyzed cross-coupling reactions-the joining of two fragments by way of a metal catalyst-are widespread in modern synthesis. By selection of the correct ligand, Pd has been shown to catalyze Ar-F bond formation, albeit with limited substrate scope. The reaction is believed to proceed though a Pd(0)/Pd(II) catalytic cycle and mechanistic studies revealed that reductive elimination is the problematic step. Decreasing the electron density of the metal center (or formal oxidation) is known to accelerate reductive elimination. This proposal aims at developing several bulky monophosphine ligands that contain a ferrocene unit to reversibly control the electron density on the catalytically metal center, allowing for mil and specific Ar-F bond formation.

Public Health Relevance

Fluorine atoms are key components in many pharmaceuticals; however, incorporating them is generally difficult and requires harsh reaction conditions. This proposal develops a mild and selective method to introduce fluorine into a variety of molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM108092-02
Application #
8840037
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Barski, Oleg
Project Start
2014-04-15
Project End
2017-04-14
Budget Start
2015-04-15
Budget End
2016-04-14
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
Sather, Aaron C; Buchwald, Stephen L (2016) The Evolution of Pd0/PdII-Catalyzed Aromatic Fluorination. Acc Chem Res 49:2146-2157
Sather, Aaron C; Lee, Hong Geun; De La Rosa, Valentina Y et al. (2015) A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides. J Am Chem Soc 137:13433-8
Sather, Aaron C; Lee, Hong Geun; Colombe, James R et al. (2015) Dosage delivery of sensitive reagents enables glove-box-free synthesis. Nature 524:208-11