The palladium(II)-catalyzed oxidative macrocyclization of bis(vinylboronate esters) is demonstrated as an efficient method for the synthesis of macrocyclic dienes. The macrocyclization reactions feature mild conditions due to a palladium(II) catalytic cycle which obviates the need for a high energy oxidative addition step of standard palladium(0) catalytic cycles. Instead, this oxidative coupling is promoted by chloroacetone as a terminal re-oxidant in the catalytic cycle. An extension of the oxidative coupling/macrocyclization strategy is highlighted where molecular oxygen may be used in place of chloroacetone as the terminal re-oxidant. Homocoupling reactions of vinylboronate esters served as a template to screen reaction conditions for this method. From these experiments, multiple reaction conditions gave the oxidative homocoupling product in high yield. These reaction conditions were successfully applied to the oxidative macrocyclization of a bis(vinylboronate ester) using molecular oxygen as a re-oxidant.

Syntheses of strained cyclic dienes were accomplished via the palladium(II)-catalyzed oxidative cyclizations of terminal bis(vinylboronate esters). The reactions generated strained (E,E)-1,3-dienes that underwent spontaneous 4π-electrocyclizations to form bicyclic cyclobutenes. Formation of the cyclobutenes is driven by strain in the medium-ring (E,E)-1,3-diene intermediates. Thermal ring openings of the cyclobutenes give (Z,Z)-1,3-diene products, again for thermodynamic reasons. These results are in contrast with typical acyclic trans-3,4-dialkyl cyclobutenes, which favor outward torquoselective ring-openings to give (E,E)-1,3-dienes. DFT calculations verified the thermodynamic versus kinetic control of the reactions and kinetic studies are in excellent agreement with the calculated energy changes.

Investigations on the transannular Pauson-Khand reaction are also highlighted. The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2+2+1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Our successful transannular Pauson-Khand reaction required a cyclic enyne incorporating one short three-membered linker chain and a rigid aryl linker in the backbone of the long linker chain. This rigidity of the aryl linker is proposed to facilitate the transannular [2+2+1] cyclization. Computational studies revealed that transannular Pauson-Khand reactions are thermodynamically favored for cyclic enynes featuring a long linker of at least 5 carbons, but with smaller chains the reactions are thermodynamically disfavored. Experimental studies show that long linking chains with more than 5 members are required to prevent to steric interactions between the dicobalt hexacarbonyl moiety and the linking chain to allow the reaction to be kinetically favored.

The final part of this work highlights progress towards the total synthesis of (+)-kingianin A. This natural product was isolated as a racemic mixture from the bark of Endiandra kingiana and is an inhibitor of antiapoptotic protein Bcl-Xl, highlighting its potential use in cancer treatments. Its structure is proposed to arise from an intermolecular Diels-Alder dimerization reaction of bicyclo[4.2.0]octadiene fragments derived from an 8π/6π-electrocyclization cascade. Although two total syntheses of (±)-kingianin A have been reported, an enantioselective synthesis has not been achieved and is the purpose of this study. This synthetic route begins from L-(+)-dimethyl tartrate, a cheap and commercially available starting material, and aims to follow a biomimetic synthetic pathway featuring a substrate controlled diastereoselective palladium(II)-catalyzed oxidative cyclization and 8π/6π-electrocyclization cascade. Although the feasibility of this cascade pathway has not yet been realized, key synthetic transformations to install the requisite carbocyclic framework of (+)-kingianin A have been discovered, paving the way for future investigations on the palladium(II)-catalyzed coupling/electrocyclization cascade and completion of the synthesis.

Chapter one describes a [2+2+1+1] reaction for the synthesis of quinones from alkynes. Cobalt octacarbonyl, in a mechanism reminiscent of the Pauson-Khand reaction, combines two equivalents of an alkyne with two equivalents of carbon monoxide via a series of insertions and reductive eliminations, to form a quinone. In theory, this reaction provides rapid access to complicated quinone structures. Unfortunately, a competing [2+2+2] reaction which is catalyzed by cobalt to give benzene derivatives out competes the desired reaction, and high yields were never achieved. Chapter two details the investigation of three different intramolecular cyclization reactions which endeavor to take advantage of the unique reactivity of vinyl ethers. Using complex vinyl ether substrates synthesized by methods previously described by our group, these reactions should provide easy access to relatively complex fused ring systems. The chapter primarily focuses on the [2+2] cycloaddition of vinyl ethers with both ketenes and ketene iminium ions, which yield cyclobutanone products. Also described is the investigation into the nucleophilic attack of epoxides by vinyl ethers. Although perfectly sound from a mechanistic perspective, as born out by intermolecular examples, the challenge of performing these intramolecular reactions remains the incompatibility of vinyl ethers with certain necessary reaction conditions. Chapter three describes the synthesis of a metal carbene complex using gold and an analog of the 5’-cap of mRNA; the first such example to be synthesized via in situ generation of a carbene at the C8 position of guanosine. The only previous example was generated via an oxidative addition with platinum under extreme conditions. In our example we use extremely mild conditions which suggest the possibility of forming such a complex with mRNA oligonucleotides, and perhaps even in vivo. Such reactivity of mRNA is unprecedented and could lead to interesting pharmaceutical possibilities.

Transition metal-mediated synthesis and functionalization of macrocycles were investigated. A novel synthetic strategy was discovered to build macrocyclic enynes; vic-dibromo tetrasubstituted alkenes were utilized as highly effective protected alkyne groups in selective ene-ene ring closing metathesis reactions of (E)-dibromotrienes. Macrocyclic enynes with varied sizes and functionality were synthesized in excellent yields by facile Zn-promoted deprotection of (E)-dibromodiene rings. The new strategy circumvented high catalyst loadings and reaction condition restrictions; thus, was proven superior to traditional alkyne protection methods employing dicobalt octacarbonyl complexations. Cyclic enynes were obtained in a more step-economic and efficient manner compared to classical SN2 ring closing processes. The reactivity and utility of enyne rings were showcased by platinum(II)-catalyzed transannular cyclopropanations.

The first dicobalt hexacarbonyl-promoted transannular [4+2] cycloaddition reactions were demonstrated. Optimized cycloadditions for macrocyclic dicobalt-dienyne complexes afforded target tricyclic scaffolds in a more effective manner than thermal transannular Diels-Alder reactions of metal-free dienyne rings. Further, dicobalt hexacarbonyl complexes of unactivated dienophiles underwent intermolecular room temperature-[4+2] cycloadditions with unactivated dienes leading to products that are inaccessible by thermal Diels-Alder reactions. Cycloaddition reactions of complexes were highly selective; [4+2] reaction adducts were obtained stereospecifically and competing Pauson-Khand reactions were not detected.

Functionalizations of enyne macrocycles through intermolecular and transannular reactions of their corresponding dicobalt complexes were studied. Novel complex polycycles were prepared by intramolecular and intermolecular [2+2+2], [2+2+1+1], [2+2+1] cycloadditions. The chemoselectivity of dicobalt-promoted cycloadditions was altered by varying the promoter and solvents utilized. The first transannular Pauson-Khand reaction was discovered. The novel synthetic method was optimized and structural requirements for reaction substrates were investigated.

A method is reported for synthesis of synthetically-valuable borylated pyridines via a Lewis acid promoted C-H activation approach. The transformation involves BF3 or BH3 Lewis-acid precomplexation followed by Ir-catalyzed borylation. The method’s development was guided by computational studies, culminating in the development of a reaction with several advantages over existing methods, including enhanced reactivity, improved regioselectivity, novel formation of trifluoroborate salts and an operationally simple purification procedure. During the reaction discovery process, we also devised a convenient and rapid synthesis of isotopically enriched 10B-pinacolborane, which was used to probe the reaction mechanism.

The synthesis and screening of various π-base ligands for use in a copper-promoted coupling reaction of alcohols and vinyl boronates are also highlighted. While alkenes and alkynes are frequently used as π–bond ligands in transition-metal promoted reactions, allenes have long been underutilized for this purpose despite possessing excellent π–bond donor characteristics. Several alkynes and allenes were synthesized and tested as π–bond ligands in a copper-mediated oxidative vinyl ether synthesis. Cyclonona-1,2-diene was identified as an ideal allene additive for the reaction.

Next, building upon our previous work on palladium-catalyzed oxidative couplings of vinyl boronates, we describe our efforts towards translating this chemistry to a nickel-catalyzed manifold. Central to the success of this new method was the serendipitous discovery that nitroarenes act as a terminal oxidant for nickel, enabling the synthesis of biaryls and butadienes. To the best of our knowledge, this is the first example of nitroarenes used as oxidants in a nickel-catalyzed coupling reaction.

The final part of this work chronicles the design and synthesis of a new class of carbon-monoxide releasing molecules. While carbon monoxide is a pervasive environmental toxin, it’s also an endogenously-produced, essential signaling molecule in all vertebrates. In order to better study the physiological effects of CO, we synthesized molecules which are activated by the presence of genetically programmable β-galactosidase enzyme. This chapter represents an important first step towards the realization of a useful biochemical tool and perhaps even a unique therapeutic compound.

Chapters one and two focus on the effect of allenes as π-ligands on copper-promoted coupling reactions. While there are many examples showcasing alkenes and alkynes as π-bond additives in transition-metal reactions, allenes have no precedent as π-bond ligands, despite the similarities to alkenes and alkynes. The added benefit provided by allenes was observed in several different copper-mediated cross-coupling reactions. Chapter two will discuss the π-ligands role in these reactions through mechanistic studies.

Chapter three described a method for preparing substituted 1,3-dienes and [n]dendralenes. These privileged products are accessed through palladium(II)-catalyzed oxidative homocoupling of alkynes and internal vinyl boronate esters. The method is extremely mind and offers a wide range of functional group tolerance. A minor modification to the oxidative protocol conditions allows the synthesis of [3]dendralenes through palladium(0)-catalyzed cross-coupling of alkynes and vinyl triflates. The utility of the diene products in synthesis will also be highlighted.

Chapter four will highlight the synthesis of cyclic triynes for use in the transannular hexadehydro-Diels–Alder reaction. The hexadehydro-Diels–Alder reaction has recently reemerged as a powerful way of accessing benzyne intermediates through an intramolecular [4+2] cycloaddition of an alkyne and a diyne. While there exists numerous examples for the intramolecular hexadehydro-Diels–Alder reaction, the transannular case has yet to be explored. Efforts towards understanding how ring strain effects the hexadehydro-Diels–Alder reaction will be discussed.

These studies describe the use of the redox-active 1,1'-diamidoferrocene ligand on uranium and group 5 metals. A novel terminal uranium-imide complex was synthesized using the bulky 2,6-dimesitylphenyl imide substituent as support. Although the uranium-imide was shown to be sterically accessible through the accommodation of another 2,6-dimesitylphenyl amide group, further reactivity was not seen, with the exception of sulfur. Electron transfer between the iron contained in the 1,1'-diamidoferrocene ligand and group 5 metals was more apparent than with uranium. A control reaction between ferrocene and niobium pentachloride suggested the formation of ferrocenium via electron transfer from iron to niobium. The use of a reduced tantalum and niobium precursors is required for coordination by 1,1'-diamidoferrocene ligands to prevent side reactions.

The studies reported in this dissertation illustrate a few selected examples of using density functional theory (DFT) calculations to investigate various aspects of iridium-catalyzed reactions and ring-opening of bicyclic cyclobutene rings. These computational predictions not only reproduce and explain experimental results and offer insights to reaction mechanisms, but also provide theoretical models to predict reactivity, regio- and stereoselectivities.

Chapter 1 is a review surveying the literature of iridium-catalyzed borylation reactions. Emphasis is placed on iridium-catalyzed borylation of alkenes and arenes. In particular, I discuss the history leading up to the current catalyst systems for iridium-catalyzed borylation reactions, and regioselectivity of borylation for a number of different substrates. Despite the large amount of work on iridium-catalyzed borylation reactions, this review shows that there is still much to be understood regarding the origins of observed regioselectivities.

Chapters 2 and 3 describe theoretical investigations of Ir(III)-catalyzed borylation reactions. The origins of regioselectivities observed in the borylation of pyridine are discussed in Chapter 2. The high selectivity for borylation at the 3- and 4- position of pyridine is attributed to the formation of a Lewis acid-base complex between pyridine and either boron species or iridium species in solution. The origins of regioselectivities for the iridium-catalyzed borylation of substituted arenes and 5-membered heterocycles are discussed in Chapter 3. The distortion/interaction model was employed to understand the origins of the selectivities in these reactions. Computations revealed that regioselectivity is mainly controlled by differences in the interaction energies between the iridium catalyst and arene carbon.

Chapter 4 illustrates a theoretical study of ring-opening in strained, trans-substituted cyclobutenes. The torquoselectively preferred outward ring-opening products are unable to form due to ring strain inherent in 9- and 10-membered macrocyclic (E,E)-1,3-dienes. As a result of this study, I propose a general methodology for stereoselective synthesis of macrocyclic (Z,Z)-1,3-dienes termed strain-induced thermal selectivity (SITS).

The effect of pi ligands, 3-hexyne and 1,2-cyclononadiene, in the Chan-Lam modification of the Ullmann reaction was investigated. Reaction conditions were optimized to give the highest yields in this copper(II) mediated oxidative coupling of boronic acids and arylamines. Pyridine proved to be a more efficient base than triethylamine for the substrates screened. It was found that 3-hexyne and 1,2-cyclononadiene had a beneficial effect on most of the substrates screened. The yields ranged from modest to excellent. A small self-ligating effect from olefin-substituted phenyl boronic acids was observed.

The unique characteristics of 1,2-dienes have proven to be a dynamic and ever growing field of study in organic chemistry. Allenes have been manipulated into a myriad of transformations, and have offered their unique characteristics to a number of fields of study. Chapter 1 discusses a phosphine catalyzed annulation between allenoates and alkenes to form cyclohexenes. In Chapter 2 the new phosphine catalyzed β'-Addition of a Pronucleophile to an allenoate is examined. Chapter 3 presents the development of a proline derived phosphine catalyst and its application in asymmetric synthesis of dihydropyrroles. A review on allene complexes with transition metals is presented in Chapter 4. Chapter 5 explores the effect of allene ligands upon copper, and subsequent copper-mediated vinyl ether synthesis.