Synthesis of Chiral Organofluorines via Catalytic Asymmetric C-C Bond Formation with Fluoroenolates, Alkynes and Ynamides The ever-increasing demand for chiral compounds and the rapid rise of fluoroorganic pharmaceuticals call for the development of new synthetic methods that provide practical access to a wide variety of fluorinated chiral building blocks. The introduction of new strategies that allow control of the unique stability and reactivity patterns of fluorinated nucleophiles and electrophiles offers invaluable opportunities to streamline chemical syntheses of current and future fluoroorganic drugs. We will develop a method for asymmetric catalysis with fluorinated nucleophiles generated in-situ and under mild conditions from readily available trifluoroacetyl derived precursors. The feasibility and practicality of this approach are demonstrated with ample preliminary results obtained by a copper-bisoxazoline catalyzed reaction using aliphatic and aromatic aldehydes. Continued ligand development and the planned mechanistic investigations will further improve the enantioselectivity of this reaction and extend this methodology to a range of currently elusive fluorinated nucleophiles. Using bisoxazolidine ligands recently developed in our laboratories we have found an entry towards a practical catalytic asymmetric alkynylation of trifluoromethyl ketones. Further ligand and method development will go hand-in-hand with mechanistic studies and screening of promising reaction parameters. We have made substantial progress with this important reaction and this experience provides a unique opportunity to introduce ynamides and ynesulfonamides to catalytic C-C bond formation. Our preliminary investigations provide promising proof-of-concept results obtained with a tosylated ynamide and show that this research direction will provide unprecedented access to a diverse range of new versatile chiral building blocks. The planned catalyst and reaction developments will be guided by detailed mechanistic studies and lead to in-depth investigations of the scope and applications of the proposed methods. Our multifaceted efforts will introduce in-situ generated fluoroenolates to asymmetric catalysis (Aim 1), a practical method for the alkynylation of trifluoromethyl ketones (Aim 2), and catalytic enantioselective addition reactions with ynamides and derivatives thereof (Aim 3). Additional emphasis will be given to the synthetic use and reactions of the new building blocks that will be generated by the wide range of electrophiles and nucleophilic species made available during this work.

Public Health Relevance

Chiral fluoroorganic compounds have received increasing attention during the past decade due to their significant role in drug discovery. This steadily growing popularity stems from a variety of beneficial effects of the fluorine moiety on the pharmacological profiles of drugs;and it is therefore very important to develop synthetic routes towards new chiral building blocks, in particular if these lead to the emerging class of fluorinate pharmaceuticals. We aim to develop new catalytic methods for the asymmetric synthesis of a wide range of organofluorinated compounds which promise practical access to current and future drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM106260-01
Application #
8495556
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2013-09-10
Project End
2016-08-31
Budget Start
2013-09-10
Budget End
2016-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$337,287
Indirect Cost
$107,287
Name
Georgetown University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Zhang, Peng; Cook, Andrea M; Liu, Yang et al. (2014) Copper(I)-catalyzed nucleophilic addition of ynamides to acyl chlorides and activated N-heterocycles. J Org Chem 79:4167-73
Cook, Andrea M; Wolf, Christian (2014) Catalytic enantioselective nucleophilic addition of ynamides to aldehydes. Chem Commun (Camb) 50:3151-4