UC Irvine

The bulk of this dissertation focuses upon the theme of hydrofunctionalization, or the addition of an X–H bond across a π-bond, in these cases a C–C double bond. This is an attractive method for forming new C–X and C–H bonds as hydrofunctionalization is highly atom economical. Additionally, hydrofunctionalization has the potential for stereoinduction either through substrate control or through the use of chiral catalysis. In this work, I will detail investigations of reactions involving both cases.

In Chapter 1, we developed a novel enantio- and regio-selective hydroamination of 1,3-dienes with pyrazoles. Through the use of a Pd precatalyst and a chiral bisphosphine ligand we were able to observe excellent yields, regioselectivities, and enantioselectivities for the formation of a number of allylic pyrazoles. In our mechanistic studies, we identified that the traditional Pd–H mechanism often proposed in olefin hydrofunctionalizations is not likely to be the operative mechanism. Instead, based on literature precedence and in agreement with observed mechanistic data, we favor a unique ligand-ligand hydrogen transfer mechanism (LLHT).

Chapter 2 details our studies of an enantioselective selenol-ene of styrenes. Styrene is a far less reactive coupling partner than those previously reported in other hydroselenation methodologies, but the use of a Rh precatalyst and a chiral bisphosphine ligand allow for Markovnikov-selective hydroselenation. Mechanistic studies identify a Rh–H resting state formed from oxidative addition to the Se–H bond of the selenol coupling partner.

In Chapter 3, we investigate the complementary anti-Markovnikov selenol-ene with alkenes. Instead of a metal catalyst, this reaction is promoted by blue LED irradiation and shows an extremely broad functional group tolerance. Mechanistic studies reveal diselenide as the photoactive species, which is actually a contaminant of selenol. Interestingly, both cyclic and acyclic substrates show a high preference for anti-addition of the Se- and H-atoms, giving rise to high diastereoselectivity. Experimental and computational mechanistic studies elucidate a mechanism involving a C-radical β to the selenide which shows a high preference for anti-addition due to delocalization of the transition state. We have coined this novel anti-selectivity for addition to a C-radical β to a selenide the "β-Selenium Effect".

The final chapter deviates from this theme of hydrofunctionalization. Collaborator Prof. Thomas Burke found that co-administration of STING and TLR agonists showed a significant synergistic anti-tumor effect in in vitro and in vivo models. However, these drugs cause deleterious global immune activation when administered intravenously, and thus only work for accessible tumors. I designed a co-drug featuring MSA-2 (benzothiophene oxobutanoic acid), a potent STING agonist, and resiquimod, a TLR-agonist approved for topical melanoma treatment. These drugs are connected by a linker featuring two motifs which are reported to undergo specific cleavage in tumors: a valine-citrulline motif, which is specifically cleaved by cathepsin B, an enzyme upregulated in the tumor microenvironment; and procysteine leaving group which is cleaved by reactive oxygen species present at high levels in the tumor microenvironment. In Chapter 4, I detail efforts towards the synthesis of this co-drug.