The proposed project will enable the catalytic, enantioselective fluorination of a range of organic substrate classes, including the synthesis of challenging, fully substituted fluorinated carbon stereocenters. The use of versatile, bifunctional thiourea catalysts should allow for a variety of substrate binding modes, enabling the use of a wide range of substrates and fluorinating reagents. The propensity of thiourea catalysts to bind to fluorinating agents will be evaluated via spectroscopic methods, providing insight into the strength and mode of reagent activation. Application of the catalyst/reagent combination to substrate classes such as aldehydes and ?-ketoesters will allow for the enantioselective synthesis of versatile fluorinated compounds. Combination of ?-ketoester fluorination with iminium catalysis will enable powerful domino transformations for the rapid assembly of molecular complexity. Proposed variation of the catalyst and fluorinating reagent will allow for the enantioselective fluorination of silyl ketene acetals, affording ?-fluorinated esters.

Public Health Relevance

Fluorinated organic compounds are ubiquitous in the pharmaceutical and agrochemical industries and represent a substantial proportion of compounds in the current pharmaceutical pipeline. The efficient, enantioselective formation of fluorinated sp3 carbon stereogenic centers represents a particular challenge in synthesis and prompts expansion of the scope of enantioselective fluorination. Herein, we describe the proposed use of chiral, bifunctional thiourea catalysts for the enantioselective fluorination of a variety of organic substrate classes and their downstream derivatization via domino reactions.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM109563-01
Application #
8647843
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02138