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.

Transition metal catalyzed reactions are indispensable tools for the asymmetric construction of carbon–carbon bonds. Traditionally, cross-coupling reactions have relied on the use of aryl, vinyl or 1o alkyl electrophiles. Advances in asymmetric catalysis have permitted the use of 2o alkyl electrophiles in cross-coupling reactions allowing for the development of several stereoconvergent transformations. Herein, we report a complementary approach to asymmetric cross-coupling reactions by means of the development of stereospecific, nickel-catalyzed transformations of benzylic alcohol derivatives.

Our initial efforts were directed toward expanding upon a Kumada cross-coupling reaction of secondary benzylic ethers with methylmagnesium iodide previously reported by the Jarvo laboratory. We extended the scope of this reaction by developing conditions to enable the use of aryl Grignard reagents for the construction of enantioenriched triarylmethanes by stereospecific nickel-catalyzed cross-coupling of diaryl methanol derivatives. The reaction proceeds in high enantiospecificity and overall inversion. This methodology is used to prepare a single enantiomer of an anti-breast-cancer agent.

Further advances in our cross-coupling methodology are demonstrated in the development of a stereospecific Suzuki–Miyaura coupling of benzylic carbamates and pivolates with aryl- and heteroarylboronic esters. The reaction proceeds with selective inversion or retention at the electrophilic carbon depending on the nature of the ligand. Tricyclohexylphosphine ligand provides product with retention, while an NHC ligand provides product with inversion. The reaction proceeds in high enantiospecificity to afford either enantiomer of a variety of triarylmethanes.

Taking advantage of our growing expertise in nickel catalyzed reactions of secondary alkyl electrophiles, we designed the first alkyl Heck reaction with control of stereochemistry at the electrophilic carbon. Enantioenriched methylenecyclopentanes are synthesized by stereospecific, nickel-catalyzed Heck cyclizations of secondary benzylic ethers. The reaction proceeds in high yield and enantiospecificity for benzylic ethers of both π-extended and simple arenes. Ethers with pendant 1,2-disubstituted olefins form trisubstituted olefins with control of both absolute configuration and alkene geometry. The diastereoselective synthesis of a polycyclic furan is demonstrated.

In the final chapter of this work, we demonstrate a nickel-catalyzed generation of secondary benzylzinc reagents from 2-pyridyl carbinols that are phosphorylated in situ. A variety of benzylzinc reagents are formed in high yield, allowing for facile hydrogenolysis of 2-pyridyl carbinols. The utility of this transformation is highlighted in a high-yielding intramolecular addition of a secondary benzylzinc reagent to an α,β-unsaturated ester.

Construction of new C–C bonds between two fragments in syntheses of natural products and pharmaceutically relevant compounds have been accomplished through transition metal-catalyzed cross-coupling (XC) and, more recently, cross-electrophile coupling (XEC) reactions. Specifically, nickel, a more sustainable base metal, has become more prevalent and attractive for the development of new XEC reactions due to the ability of nickel to access more oxidation states compared to palladium, allowing for the possibility of both radical and polar reactivities. Furthermore, employing alkyl pseudohalides, for example, mesylates, as coupling partners has gathered increasing interest due to the accessibility to these pseudohalides from alkyl alcohols. Herein, development and mechanistic studies of reactions involving alkyl mesylates will be discussed.A halogenation reaction of alkyl alcohols with methylmagnesium halide reagents will be discussed (Chapter 2). While Grignard reagents are commonly considered carbon-based nucleophiles, initial mechanistic studies of the nickel-catalyzed XEC reaction of 1,3-dimesylates for the synthesis of cyclopropanes determined that the Grignard reagent, methylmagnesium iodide served as not only the reductant, but also the iodide source to convert the alkyl mesylates into alkyl iodides. We saw this as an opportunity to develop a new halogenation method. Therefore, we have developed a halogenation reaction of alkyl mesylates using Grignard reagents that proceeds rapidly at low temperatures, is tolerant of various functional groups, stereospecific, and occurs with inversion, and scalable. Next, the investigation of the recombination step between the nickel and radical intermediates following halogen atom abstraction in the nickel-catalyzed XEC reaction of 1,3-dimesylates, will be discussed (Chapter 3). After iodide formation by the Grignard reagent, it was proposed that halogen atom abstraction by the nickel catalyst at the secondary center forms a secondary alkyl radical species, which recombines with the nickel(I) species to yield an organonickel(II) intermediate. The lifetime of this secondary alkyl radical intermediate was investigated through the use of radical clock experiments. Inspired by the development of the XEC reaction of 1,3-dimesylates, we looked to develop new XEC reactions involving alkyl mesylates as coupling partners. First, development of an intramolecular nickel-catalyzed XEC reaction between alkyl mesylates and allylic gem-difluorides for the synthesis of vinyl fluoride-substituted cyclopropanes was accomplished (Chapter 4). The reaction was determined to be stereospecific, and possible mechanisms were proposed based on experimental mechanistic studies and DFT calculations. Finally, an intermolecular reductive methylation reaction of alkyl mesylates with methyl tosylate was developed (Chapter 5). This reaction allows for facile conversion of secondary alkyl alcohol derivatives into secondary methyl-bearing centers. Both reactions leverage the advantages of nickel catalysis and XEC reactions and build upon mechanistic understanding of previously developed reactions.

Metal-catalyzed reactions often allow access to reactivity that would be otherwise unavailable to researchers using more conventional synthetic methods. The Jarvo lab has worked to develop both stereoselective and stereospecific metal-catalyzed reactions that proceed with high stereochemical fidelity to produce synthetically useful products.

In Chapter 1 the enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl and aryl-alkylketimines. The synthetic transformation of one of the homopropargylic products via Sonogashira cross-coupling proceeds with high stereochemical fidelity.

In Chapter 2 work towards a deeper understanding of the mechanism of a previously disclosed stereospecific nickel-catalyzed cross-electrophile coupling of 2-aryl-4-chlorotetrahydropyrans to form cyclopropanes is described. Experiments were performed to determine the overall rate law of the reaction as well as the kinetic order of each reagent participating in the rate-determining step of the reaction.

In Chapter 3 work towards a new stereospecific nickel-catalyzed cross-electrophile coupling is described. Utilizing a strained 2-aryl-oxetane scaffold with a pendant chloride the stereospecific cross-electrophile coupling to form cyclopropanes.

The utility of synthetic methods depends greatly on the availability of the starting materials which they employ. This is especially true when reactions are intended to be applied for late-stage functionalization. Synthetic organic chemistry benefits from the development of methods that employ more readily available starting materials, and methods that convert these compounds into a less-readily available but more widely used derivatives. In this dissertation, readily available alcohols and amine derivatives are used as building blocks to access alkyl halides, and to forge carbon-carbon bonds in strained cyclopropane rings.First, propargylic amine derivatives used in a nickel-catalyzed domino cross electrophile coupling alkyne dicarbofunctionalization reaction will be discussed (Chapter 1). This method transforms 2-alkynyl-4-chloro-N-tosylpiperidines into vinyl cyclopropanes with a tetrasubstituted alkene and a pendant sulfonamide. Three carbon-carbon bonds are forged in this reaction, increasing molecular complexity by much in one step. We expanded the substrate scope, conducted mechanistic studies, and synthesized analogs of biologically active vinyl cyclopropanes. We proposed a bifurcated mechanism that diverges at a key allenylnickel species which is the result of propargylic oxidative addition. This method further advances metal-catalyzed domino reactions by serving as the first example of a domino reaction that involved a cross electrophile coupling as a discrete step combined with other carbon-carbon bond forming reactions. Next, aliphatic alcohols and sulfonates used in a halogenation method employing methyl Grignard reagents will be presented (Chapter 2). This reaction investigates an observation made in prior work, in which 1,3-diiodides were formed in situ from 1,3-dimesylates when a Grignard reagent was present. The substrate scope of the reaction is expanded to include alkyl alcohols and alkyl mesylates, and reaction conditions are modified to allow for the synthesis of both alkyl iodides and alkyl bromides. The halogenation reaction is established to work on gram-scale and to be stereospecific, giving inversion of configuration. This method showcases unusual reactivity of Grignard reagents that has not been explored in depth before. Lastly, aliphatic sulfonates and halides used in an electrochemical cross-electrophile coupling reaction to form alkyl and aryl cyclopropanes is discussed (Chapter 3). The substrate scope of the reaction is expanded to include pendant aryl groups with electron donating and electron withdrawing substituents, as well as entirely aliphatic groups. The reaction is established to be scalable and tolerant of moderate temperature and current changes.

Transition metal catalyzed reactions are ubiquitous in the realm of synthetic chemistry, allowing for the strategic construction of complex molecular frameworks of pharmaceuticals, natural products, and synthetic materials. Palladium-catalyzed cross-coupling reactions are part of the foundation of these transformations, insofar as they were recognized with the 2010 Nobel Prize in chemistry. Traditionally, these reactions have relied on aryl and vinyl electrophiles, whereas the alkyl counterparts have only recently begun to emerge in the literature. Nickel has been on the forefront of enantioconvergent alkyl cross-coupling reactions due to its propensity to undergo single electron chemistry. However, under special conditions, it has a unique ability to break strong carbon–oxygen bonds in a stereospecific manner, making research into its reactivity a valuable endeavor to the field of organometallic chemistry.

Chapter 1 describes the development of a stereospecific intramolecular alkyl-Heck cyclization of benzylic ethers. The reaction proceeds with inversion at the electrophilic carbon, for the synthesis of methylenecyclopentanes of both extended π-electron and simple aromatic systems. The enantioenriched products can be effectively derivatized to cyclic α-aryl ketones in good yields with good transfer of chirality. Avenues to expand the utility of this reaction have been identified and further studies are ongoing.

Chapter 2 discusses the development of nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides. An intermolecular reaction proceeds in high yields for primary benzylic esters for the synthesis of pharmacologically relevant diarylmethanes. The corresponding intramolecular cyclization proceeds under mild conditions, demonstrating the first example of a stereospecific cross-electrophile coupling of secondary benzylic esters. A variety of heterocyclic and functionalized substrates are tolerated under the reaction conditions.

Chapter 3 examines the development a regio- and stereoselective nickel-catalyzed hydroarylation of alkynes with arylboronic acids. The reaction is facilitated by propargyl carbamates as directing groups. The reaction is tolerant of a range of functional groups and heterocycles. Mechanistic studies reveal that the acidic protons of the arylboronic acid coupling partner serve as the origin of hydrogen. Furthermore, the synthesis of tamoxifen can be completed in two steps from a simple hydroarylation product.

The development of asymmetric transition-metal-catalyzed reactions has emerged as an important area of research in the past decade. Advances in the field are transforming the way chemists approach the construction of target compounds. This dissertation focuses on the expansion of stereospecific nickel-catalyzed reactions to synthesize small unnatural polyketide analogs, chiral long chain carboxylic acids, and highly substituted cyclopropanes. In the presence of an achiral nickel catalyst, a bidentate phosphine ligand, and a Grignard reagent, aryl-substituted tetrahydropyrans and tetrahydrofurans undergo a stereospecific ring-opening to afford acyclic polyketide analogs with complex stereoarrays and promising anti-cancer activity. Reactions proceed with inversion of stereochemistry at the benzylic position and are substrate controlled. Similarly, enantioenriched aryl-substituted lactones undergo a Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. The utility of this reaction was demonstrated in a two-step synthesis of an anti-dyslipidemia agent.

The nickel catalyst system was employed to develop the first stereospecific reductive cross-coupling reaction. 2-Aryl-4-chlorotetrahydropyrans undergo an intramolecular ring contraction to afford highly substituted cyclopropanes. The reactions proceed with retention at the benzylic center and inversion at the alkyl halide position. Vinyl-substituted tetrahydropyrans are also amenable substrates for this transformation and afford vinylcyclopropane products with excellent control of stereochemistry. This is the first reported reductive coupling between alkyl ethers and alkyl halides and provides a new, mild synthetic route to both aryl- and vinyl-substituted cyclopropanes.

Transition metal catalyzed cross-coupling reactions have become a staple of organic synthesis and are frequently the most practical strategy for the preparation of medicinal agents and fine chemicals. Catalysts based on the precious metal palladium are commonly used in cross-coupling reactions. Replacing palladium catalysts with nickel catalysts is an active area of research as such advances present significant benefits including increasing the sustainability of transformations and new mechanisms for control of stereochemistry in the construction of Csp3–Csp3 bonds.

In Chapter 1, a stereospecific nickel-catalyzed cross-coupling reaction of secondary benzylic ethers with a variety of aliphatic and aryl Grignard reagents is presented. The method is highly stereospecific and proceeds with inversion at the benzylic carbon. Products prepared by this method were subject to biological testing, and a thiophene-containing product was shown to selectively inhibit the growth of MCF-7 breast cancer cells.

In Chapter 2, mechanistic studies that provide insight into the mechanism of oxidative addition as well as the mechanisms of major side reactions, hydrogenolysis and β-hydride elimination, are presented. Experiments presented provide evidence that the mechanisms of cross-coupling, hydrogenolysis, and β-hydride elimination reactions all include a step of oxidative addition with inversion at the benzylic center. Hydrogenolysis was also shown to be stereospecific, proceeding with overall inversion at the stereogenic center.

In Chapter 3, the application of nickel-catalyzed cross-coupling reactions to the synthesis of either enantiomer of a bioactive triaryl methane from a single enantiomer of a precursor alcohol is presented. In the key cross-coupling step a Kumada protocol allows for cross-coupling with inversion at the benzylic carbon, while a Suzuki reaction allows for cross-coupling with retention.

Cross-coupling (XC) reactions have had a lasting impact on the way synthetic organic chemists approach bond construction. This is evident by the numerous industrial applications of XC methods and the 2010 Nobel prize awarded to Ei-ichi Negishi, Akira Suzuki, and Richard Heck. Palladium-catalyzed XC reactions have dominated the field and are now very well understood transformations. However, development of cross-electrophile coupling (XEC) reactions has moved slower than that of traditional XC reactions. XEC reactions offer attractive counterparts to traditional XC reactions as XEC reactions couple two electrophilic partners together, utilizing a widely accessible pool of halide and pseudohalide starting materials. Additionally, these transformations are commonly achieved using nickel catalysis, which offers practical advantages over the commonly used palladium catalysts. For example, nickel has a smaller carbon footprint associated with the mining of the metal making it a more sustainable alternative to precious metals such as palladium. Thus, the advancement of nickel-catalyzed XEC reactions will allow for the development of transformations that utilize readily accessible functional group motifs with sustainable base metal catalysis. Cyclopropane motifs are a common functional group found in pharmaceutical compounds and natural products. There are a variety of methods that synthesize cyclopropane motifs from either alkenes or diazo compounds including the Simmons–Smith reaction. However, there are few cyclopropanation methods that utilize simple C–O and C–N bonds as precursors. We foresaw nickel-catalyzed XEC reactions as a unique way to approach cyclopropane synthesis. Herein, a nickel-catalyzed XEC reaction of 1,3-dimesylates to access aryl- and alkylcyclopropanes is described. Additionally, by developing a mild set of reaction conditions, we foresaw the opportunity to develop a late-stage modification of medicinal agents such as statins. A zinc-mediated XEC reaction of 1,3-dimesylates for cyclopropane synthesis has also been described. Finally, domino reactions have become an attractive way to quickly build molecular complexity by undergoing multiple synthetic manipulations in a single step. Specifically, our lab foresaw the opportunity to build upon our previously developed nickel-catalyzed ring contraction of sulfonamides. Therefore, we have developed a domino XEC dicarbofuntionalization reaction of propargyl N-tosyl sulfonamides for cyclopropane synthesis. The rapid development of palladium-catalyzed XC methods was aided by mechanistic understanding of the various transformations. While mechanistic investigation of nickel-catalyzed XEC reactions has been performed, there are still key features involved in nickel catalysis that have yet to be addressed including the control of reactivity that the ligand imparts on the nickel catalyst. We foresaw the 4-halotetrahydropyrans (THP) as interesting model substrates for the study of ligand-based control of nickel-catalysts. Phosphine ligands were predicted to selectively engage the carbon–oxygen bond via a two-electron oxidative addition pathway to access a cyclopropane product. Conversely, nitrogen-based ligands were predicted to selectively engage the carbon–halogen bond in a one-electron oxidative addition pathway resulting in the reduced tetrahydropyran. Herein, a series of vinyl, naphthyl, and biphenyl THPs were examined with a series of phosphorous- and nitrogen-based ligands where two factors work in concert to determine chemoselectivity: the degree of C–O bond activation and the type of ligand employed.