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.
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.
|Stokes, Benjamin J; Bischoff, Amanda J; Sigman, Matthew S (2014) Pd(Quinox)-Catalyzed Allylic Relay Suzuki Reactions of Secondary Homostyrenyl Tosylates via Alkene-Assisted Oxidative Addition. Chem Sci 5:2336-2339|
|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|
|Stokes, Benjamin J; Opra, Susanne M; Sigman, Matthew S (2012) Palladium-catalyzed allylic cross-coupling reactions of primary and secondary homoallylic electrophiles. J Am Chem Soc 134:11408-11|