The proposed research project involves the development of a new synthetic method for the stereo- and regioselective functionalization of the allylic C-H bonds of homoallylic tosylates using quinoline-oxazoline- (quinox-) ligated Pd(0) catalysts. In preliminary experiments, allylic C-H bonds have been functionalized with alkyl-, vinyl-, and aryl boronic acid- and boronic ester nucleophiles at ambient temperature in isopropanol under basic conditions. This process is attractive because the functionalization of allylic C-H bonds using carbon- centered nucleophiles is an unsolved problem in organic synthesis. Boronate ester nucleophiles are cost effective, relatively non-toxic, and widely-available, making the synthesis of a diverse library of lead compound architectures possible. Mechanistically, the reaction is believed to involve oxidative addition into primary- and secondary homoallylic tosylates, followed by fast ?-hydride elimination to form a diene-Pd-H complex, and finally diene reinsertion to access the secondary allyl-Pd species to which boronate ester nucleophiles can be coupled. It is surprising that Pd-quinox complexes can promote oxidative addition into unactivated primary tosylates, since bulky, electron-rich phosphines were thought to be required in order to use Pd. The fact that the quinox ligands used in this reaction promote the oxidative addition of Pd(0) into unactivated secondary tosylates is especially remarkable because Pd was not previously known to undergo oxidative addition into such bonds (typically, a Ni catalyst is used). The ability to use secondary homoallylic tosylates as substrates is particularly useful because enantiomerically-enriched substrates can potentially transfer their chiral information to the C-H functionalization products. Alternatively, enantiomerically-enriched products may be accessd via asymmetric catalysis, since chiral quinox ligands are easily synthesized. Additional studies will explore the mechanism of oxidative addition (which may be stereo-retentive or stereo-invertive), the mechanism of ?- hydride elimination, and the importance of the electronic nature of the substrate olefin. Promising lead compounds that will be generated using this method, including the C-H functionalization products themselves and selected derivatives, will be tested for activity against primary patient MCF-7 breast cancer cells through collaborations established by the sponsoring investigator. The selectivity of the lead compounds against these cancer cells will be assessed by comparison to their activity against grossly normal MCF-10A cells.

Public Health Relevance

This research project investigates new metal-catalyzed reactions that combine cheap carbon-based starting materials into molecules of increased complexity. The details of how these reactions work will be investigated to help maximize their usefulness and uncover more new reactions. The molecules made using these reactions may be used to treat human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM099254-02
Application #
8499053
Study Section
Special Emphasis Panel (ZRG1-F04-D (20))
Program Officer
Barski, Oleg
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$52,190
Indirect Cost
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Stokes, Benjamin J; Liao, Longyan; de Andrade, Aline Mendes et al. (2014) A palladium-catalyzed three-component-coupling strategy for the differential vicinal diarylation of terminal 1,3-dienes. Org Lett 16:4666-9
Saini, Vaneet; Stokes, Benjamin J; Sigman, Matthew S (2013) Transition-metal-catalyzed laboratory-scale carbon-carbon bond-forming reactions of ethylene. Angew Chem Int Ed Engl 52:11206-20