This dissertation describes the development of reaction methodologies that utilize unconventional building blocks. One major effort involves the development of a strategy to improve the practicality of the nickel-catalyzed Suzuki–Miyaura cross-coupling of amide electrophiles and a strategy for a base-mediated reduction of ketones to secondary alcohols. Furthermore, a one-pot reductive arylation of amides wherein two different nucleophiles are added to the amide carbonyl carbon is reported. This reaction, which proceeds by way of a sequential nickel-catalyzed Suzuki–Miyaura coupling and base-catalyzed reduction cascade process, directly converts amide starting materials to chiral secondary alkyl–aryl alcohol products. Finally, investigations into strained heterocyclic allenes are described. These studies detail the cyclic allene approach to the core of the manzamine alkaloid keramaphidin B, where the key step hinges on a cycloaddition of an azacyclic allene intermediate. Furthermore, the parameters controlling the regioselectivity of the Diels–Alder cycloaddition of heterocyclic allenes with a-pyrones is reported. Each of the methodologies presented is expected to expand the synthetic toolbox by leveraging unique reactivity.

This dissertation is divided into two projects concerning natural product synthesis and methodology development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.

Chapters One, Two, and Three focus on a particularly interesting and important class of indole-containing natural products called the akuammiline alkaloids. Specifically, Chapter One provides a historical overview of this family of compounds that ultimately demonstrates how these challenging structures, along with their encouraging pharmacological profiles, render them formidable synthetic targets that have been the subject of synthetic chemists’ efforts for the past decade.

Chapters Two and Three describe our lab’s own synthetic efforts to members of the akuammiline family: picrinine, strictamine, 2(S)-cathafoline, and aspidophylline A. Central to our approach was the use of modern variants of the classic Fischer indolization reaction to generate high levels of complexity and the cores of the natural products. Ultimately, these efforts culminated in the first total synthesis of picrinine, strictamine, and 2(S)-cathafoline, as well as an enantioselective, second-generation synthesis of aspidophylline A.

Chapter Four describes the development of the first Mizoroki–Heck cyclizations of amide derivatives. This work highlights the potential of amides, which were once thought to be unreactive due to their resonance stability, as building blocks to prepare complex structures. Through this method, various products containing quaternary centers can be formed.

This dissertation describes research pertaining to the synthesis of natural products and reaction methodology development. The synthesis of complex molecules remains a worthwhile pursuit as natural products and their derivatives are frequently a source of inspiration for new drugs. Additionally, the synthesis of complex molecules provides an avenue to test methodologies and develop novel strategies towards them. Reaction development enables the discovery of new reactivity and new disconnections to access complex small molecules more efficiently. Both total synthesis and reaction development continues to push the boundaries of synthetic organic chemistry. Chapter one offers a current perspective on the field of strained cyclic alkynes and allenes. Despite being validated over fifty years ago, strained cyclic alkynes and allenes have only recently been used to access complex small molecules. This chapter highlights recent methodologies and syntheses using strained arynes, allenes, and alkynes to generate complex products bearing stereodefined quaternary centers or generate products with multiple fused rings in high enantioenrichment. Chapter two describes the development of a methodology using strained cyclic alkynes and strained arynes to generate products bearing stereodefined quaternary stereocenters. Arynes and strained cyclic alkynes are highly electrophilic species and strategies to use these them in stereospecific reactions are limited. Accessing quaternary stereocenters remains a challenging, but important goal of synthetic chemistry. Specifically, the strategy pursued utilized enantioenriched enamines and arynes or cyclic alkynes to generate α-arylated or vinylated β-ketoesters in a stereospecific fashion. Chapter three describes the total synthesis of secologanin and strictosidine. Strictosidine is the last common biosynthetic precursor to all monoterpene indole alkaloids, which is a class of natural products with over three thousand compounds isolated to date. Presented here is a new strategy to access strictosidine enabled by a blend of both synthetic chemistry and biocatalysis. This strategy was then used to access aryne derivatives of strictosidine and a related natural product, strictosamide. The in situ generated arynes were trapped with dienes to access derivatives of these natural products. Chapter four describes the discovery of two homologous groups of pericyclase enzymes, which are enzymes that catalyze pericyclic reactions. Specifically, one group catalyzes a stereoselective hetero-Diels–Alder reaction and the other catalyzes an Alder-ene reaction, which was previously unknown in biology. A chemoenzymatic synthesis was utilized to access the substrate of the Diels–Alder reaction and Alder-ene reaction.

This dissertation encompasses several projects pertaining to natural product total synthesis, reaction methodology development, and kinetic studies. The total synthesis of natural products continues to be a fruitful area of research in organic chemistry. The successful completion of a total synthesis endeavor not only affirms ambitious route designs, but can also allow access to significant amounts of biologically-active compounds. Given that natural product structures inspire the development of new agrochemicals and pharmaceuticals, their syntheses are a worthwhile endeavor. Also, the development of new reaction methodologies and the understanding of fundamental reactivities of many intermediates remain important areas of research.

Chapter One offers a current perspective on the field of natural product total synthesis. Alhough historically viewed as a highly competitive field, several recent examples show the growing spirit of collaboration in total synthesis. By forming alliances with chemists in other fields, industries, or laboratories, total synthesis chemists have made many breakthroughs that would arguably not be possible if working independently.

Chapters Two and Three describe our laboratory’s total syntheses of several bioactive akuammiline alkaloids, including strictamine, 2(S)-cathafoline, akuammiline, -akuammigine, and 10-demethoxynorvincorine. Our strategic approach to the natural products focused on the use of a modern variant of a classic reaction, the Fischer indolization reaction, to install several rings and the common quaternary center found in each target. This strategy allowed for the first total syntheses of akuammilines bearing the methanoquinolizidine core and those that also bear vicinal quaternary centers. In addition, rearrangements of the methanoquinolizidine core were developed that allowed us to access pyrrolidinoindoline-containing akuammilines.

Chapter Four describes a series of kinetic studies used to determine the electrophilicity parameter of benzyne and related aryne intermediates. Arynes are a family of strained intermediates whose existence has been postulated for over 100 years. Recent advances have confirmed their existence and proven their synthetic utility. An advanced knowledge of their reactivity thus far has remained elusive. Our laboratory employed the diffusion clock method to measure the rates of reaction between several arynes and a variety of different nucleophilic reaction partners. The result allowed for the first quantification of the electrophilicity of these strained intermediates and should influence synthetic planning in the future.

Chapter Five includes a study in the development of reaction methodology. Utilizing a variant of the Fischer Indolization reaction, our laboratory discovered a general method for making aza-indoline structures. This methodology was applied in the synthesis of derivatives of akuammiline alkaloids and Alzheimer’s therapeutic molecules. In addition, a predictive computational model of reactivity was derived.

This dissertation describes the total syntheses of the indole diterpenoid natural products, tubingensin A & B. Central to the syntheses of these molecules was the use of heterocyclic aryne intermediates, which are highly reactive and can facilitate difficult bond formations. We describe the formation of vicinal quaternary centers using this methodology in what are some of the most stereochemically complex examples of aryne reactions.

Chapter One reviews the impact that indole diterpenoid natural products have had on chemical synthesis. This class of compounds has provided inspiration for the development of useful chemical methods and strategies. Natural products discussed include penitrem D, paspaline, emindole SB, dixiamycin B, and tubingensins A & B.

Chapter Two describes the total syntheses of (+)-tubingensin A. Vital to the success of the route was the use of heterocyclic aryne chemistry as well as a B-alkyl Suzuki–Miyaura reaction. The synthesis proceeded in only nine steps, longest linear sequence.

Chapter Three pertains to the synthesis of the more complex natural product, (–)- tubingensin B. The synthesis relied on a similar B-alkyl Suzuki–Miyaura reaction, a carbazolyne cyclization, and a radical cyclization to construct the core architecture of the molecule. The synthesis represented one of the biggest structural challenges addressed by heterocyclic aryne chemistry.

This study describes a facile nickel-catalyzed method to achieve the synthetically useful amination of aryl sulfamates and carbamates. This approach uses an air-stable Ni(II) precatalyst, which, when employed with a mild reducing agent, efficiently delivers aminated products in good yields. The scope of the method is broad with respect to both coupling partners. For instance, substrates with electron-donating and electron-withdrawing groups are tolerated, as well as those that possess ortho and para substituents. Furthermore, heteroaryl substrates may also be employed as coupling partners.

This dissertation features two projects concerning natural product synthesis and reaction development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.

Chapters One, Two, Three, and Four focus on an unusual variant of the Fischer indolization reaction and its application in the total synthesis of a particularly interesting class of indole alkaloids named the akuammilines. Specifically, Chapter One provides an overview of the so-called ‘interrupted Fischer indolization reaction’. This reaction is described from a methodological standpoint and is then evaluated in the context of akuammiline alkaloid total synthesis.

Chapters Two, Three, and Four describe enantioselective syntheses of various akuammiline alkaloids, in addition to several akuammiline alkaloid derivatives. Central to our approach was the development of modern variants of the classic Fischer indolization reaction to generate high levels of complexity. These efforts culminated in the first enantioselective total syntheses of (–)-aspidophylline A, (+)-strictamine, (–)-2(S)-cathafoline, (–)-pseudoakuammigine, (+)-akuammiline, (–)-10-demethoxyvincorine, and derivatives therein.

Chapters Five describes an application of the distortion/interaction model to a variety of mono and disubstituted benzynes and substituted indolynes. Chapter Six is focused on the development of a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates with b-ketoester-derived substrates. Our approach provides a general solution to the challenging problem of stereoselective b-ketoester arylation/alkenylation, with formation of a quaternary center with enantiomeric excess up to 96%.

This dissertation describes the total synthesis of tubingensin B and the development of two nickel-catalyzed methods. The two methodologies include the amination of aryl electrophiles in the green solvent 2-methyl-THF and the Suzuki–Miyaura coupling of aliphatic

amides via the activation of amide C–N bonds.

Chapter One highlights indole terpenoid natural products as the inspiration for the development of new synthetic methodologies and innovative strategies. This review showcases recent total syntheses of the natural products, penitrem D, emindole SB, paspaline, dixiamycin B, and tubingensins A and B.

Chapter Two pertains to the total synthesis of (–)-tubingensin B. Key steps of the synthesis involves a B-alkyl Suzuki–Miyaura reaction, a carbazolyne cyclization, and a radical cyclization to construct the core architecture of the molecule. Key to the synthesis of tubingensin B was the utilization of a heterocyclic aryne intermediate for the formation of a scaffold bearing vicinal quaternary centers. This synthesis illustrates the capability of aryne methodology in generating stereochemically complex structures.

Chapter Three describes the development of a green variant of a nickel-catalyzed amination reaction. As solvents comprise 85% of pharmaceutical waste, the use of a green solvent provides a considerable benefit for the potential application of the methodology to

industrial problems. We developed a method employing 2-Me-THF as a green solvent for the amination of aryl chlorides and sulfamates.

Chapter Four demonstrates the nickel-catalyzed Suzuki–Miyaura coupling of aliphatic amide derivatives. The methodology can be used to activate typically unreactive amide C–N bonds and, in turn, access an array of heterocyclic ketones.

This dissertation describes efforts in strained allene and alkyne methodology, as well as collaborative efforts at the interface of organic synthesis and bioengineering to construct complex molecules. Strained intermediates, though once only an intellectual curiosity, have proven to be useful synthetic building blocks in organic synthesis. This dissertation describes the expansion of cyclic allene chemistry to include (3+2) cycloadditions, as well as a greater understanding of the reactivities of nitrogen-containing analogs. Additionally, the use of strained alkyne intermediates to construct compounds relevant to materials chemistry is explained. Moreover, the synthesis of a key biosynthetic precursor for monoterpene indole alkaloids, as well as the combination of bioengineering and synthetic chemistry to access complex natural products, is described.

Chapter one describes the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, an synthetically underutilized strained intermediate. Our approach relies on the slow generation of 1,2-cyclohexadiene from its silyl triflate precursor and trapping using nitrone partners, allowing access to isoxazolidine products. Computational studies provide mechanistic insight into this reaction and explain the observed regio- and diastereoselectivity trends. Moreover, the manipulation of the isoxazolidine products demonstrates the utility of strained allene intermediates as synthetic building blocks.

Chapter two details an experimental and computational study of azacyclic allenes. This includes the synthesis of precursors to several substituted allenes, the trapping of the allenes in various cycloadditions, and explanations of the observed selectivities. Additionally, we demonstrate that stereochemical information can be transferred via an enantioenriched allene, and when taken in combination with the selectivities, highlights that azacyclic allenes can be harnessed as valuable synthetic building blocks for complex molecule synthesis.

Chapter three describes a modular approach towards polycyclic aromatic hydrocarbon (PAH) scaffolds. More specifically, we rely on strained alkyne and aryne intermediates to construct these PAH motifs. This study demonstrates underscore the importance of heterocyclic strained intermediates to prepare new organic materials.

Chapters four and five depict the synergy between chemical synthesis and bioengineering. More specifically, chapter four describes the discovery of an enzyme that can promote hydroalkoxylation reactions. Chapter five details the engineering of yeast enzymes to access an important monoterpene indole alkaloid building block, strictosidine, from its biosynthetic precursor, 8-hydroxygeraniol. Additionally, analysis and characterization of the shunt pathways present in this transformation are described.

Chapter six describes the development of a simple procedure to access 8-hydroxygeraniol. Our approach allows for large-scale production of this central biosynthetic precursor that should help enable biosynthetic studies to thousands of essential monoterpene indole alkaloids.