UC Irvine

Methodology for the synthesis of enantioenriched compounds is critical to the discovery of new pharmaceuticals. To access single enantiomers of biologically relevant molecules for evaluation, the Jarvo laboratory has developed both enantiospecific and enantioselective reactions. Herein, we report the development of transition metal-catalyzed methodology to generate diarylalkanes and homopropargylic sultams in high enantiomeric excess.

Diaryl sulfides and 1,1-diarylalkanes are known to exhibit a wide variety of therapeutic applications, including treatment of breast cancer. These compound classes were synthesized for biological evaluation against a range of cancer cell lines. Heteroaromatic diaryl thioethers were prepared by the reaction of sulfenyl chlorides with arylzinc bromides, while enantioenriched 1,1-diarylalkanes were synthesized through the nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents. Several lead compounds were identified that selectively inhibited breast cancer cell proliferation in the low micromolar range. In particular, a diarylalkane containing a thiophene moiety exhibited selective activity against a triple-negative breast cancer line.

Stereospecific nickel-catalyzed cross-coupling methodology has also been applied to the synthesis of tubulin-binding diarylethane derivatives. Upon evaluation for inhibition of tubulin polymerization, the (S)-enantiomer of a trimethoxyphenyl-containing diarylethane exhibited higher levels of tubulin disruption than the (R)-enantiomer. These results show proof of concept that enantioenriched diarylethanes exhibit marked differences in tubulin-binding activity.

We developed a different type of nickel-catalyzed reaction for the stereospecific ring-opening of O-heterocycles in order to provide acyclic alcohols with controlled formation of a new C–C bond. Aryl-substituted tetrahydropyrans underwent nickel-catalyzed Kumada coupling reactions with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. A furan-substituted lactone underwent a Negishi cross-coupling reaction to provide the corresponding carboxylic acid in high enantiospecificity. Biological evaluation of the products identified several lead compounds with selective activity against a triple-negative breast cancer line.

In the final Chapter of this dissertation, we describe the synthesis of enantioenriched homopropargylic α-chiral sulfonamides via the enantioselective silver-catalyzed propargylation of N-sulfonyl ketimines. This reaction proceeded in high yield and excellent enantiomeric excess, and was compatible with a wide variety of diaryl and alkyl ketimines. Synthetic transformations of homopropargylic products via enyne ring-closing metathesis and reduction reactions proceeded with high stereochemical fidelity. Both allenyl and propargyl borolane reagents could be used to obtain propargylic products, most consistent with a mechanism involving transmetallation of the silver catalyst with the borolane reagent.