Development of palladium-catalyzed alkene functionalization reactions with applications to the synthesis of novel anti-cancer compounds

The development of new practical oxidation reactions that produce nontoxic byproducts is a significant challenge facing chemists. Metal-catalyzed reactions are an attractive approach because of their ability to couple O2 reduction to catalyst regeneration. During the past 10 years, PdII has received a significant amount of attention in this area because of its ability to oxidize a wide range of organic substrates and employ O 2 as the sole stoichiometric oxidant. For example, the Sigman laboratory has previously developed catalyst systems for the aerobic PdII-catalyzed oxidation of alcohols and alkenes. Presented herein, is the use of one of these catalyst systems in the discovery of two new aerobic PdII-catalyzed alkene functionalization reactions, which have applications in the synthesis of small molecules active against breast cancer cells.;Initially, a PdII-catalyzed alkene hydroalkoxylation reaction, which in this case is the addition of an alcohol to a styrene derivative containing a phenol, was developed. Mechanistically the reaction was originally hypothesized to proceed via a Lewis acid catalyzed process. However, deuterium labeling experiments suggested a mechanistically distinct pathway that requires oxidation of the alcoholic solvent to generate a PdII-hydride intermediate that reacts with the alkene and proceeds to product via formation of an ortho-quinone methide intermediate.;Based upon the deuterium labeling studies, we proposed that an alcohol oxidation could be used to generate a PdII-alkyl intermediate from an alkene that does not contain a phenol. Subsequent transmetalation of this intermediate with an organometallic reagent and reductive elimination would generate a new carbon-carbon bond. Based upon this hypothesis, a new aerobic PdII-catalyzed reductive coupling of styrenes and organostannanes was developed that produces a variety of diarylmethine containing compounds.;Since many biologically active compounds contain diarylmethine functionality, several of the reductive coupling products were integrated into a screening library. One of the reductive coupling products, C-6, was found to be active against primary breast cancer tumor organoids using an innovated three-dimensional assay developed by Professor Bryan Welm's laboratory at the Huntsman Cancer Institute. The reductive coupling methodology was subsequently employed for structure activity relationship studies to identify the pharmacophore of C-6.