Chapter 1 contains a thorough overview of cobalt-catalyzed hydrogen atom transfer (HAT)-initiated alkene hydrofunctionalizations with special attention given to radical–polar crossover reactions. The chapter begins with a general mechanistic discussion of metal-hydride-initiated HAT radical reactions. A historical perspective on the origins of the field is then provided, including work by bioinorganic chemists, inorganic chemists, and seminal work by Mukaiyama. Key contributions from the Carreira, Shenvi, and Herzon labs are highlighted. The second half of Chapter 1 contains an exhaustive review of all published cobalt-catalyzed HAT-initiated radical–polar crossover alkene hydrofunctionalizations to date.Chapter 2 describes our lab’s strategy for developing a catalytic radical–polar crossover reaction under strong catalyst control. Direct conversion of tertiary allylic alcohols to epoxides or semipinacol rearrangement products could be achieved with judicious choice of cobalt(II) salen catalyst. Bifurcation of reaction pathways suggests the participation of electrophilic alkylcobalt(IV) intermediates. Evaluating the stereochemical outcomes of analogous bromohydrin expansions provided insight into which complexes promote the formation of alkylcobalt(IV) intermediates. Preliminary studies into solvent dependent radical–polar crossover hydrofunctionalizations of tertiary allylic alcohols bearing 1,1-disubstituted alkenes are described as well. In Chapter 3, efforts that led to the development of a catalytic asymmetric HAT radical–polar crossover hydroalkoxylation are summarized. Catalyst structure-activity relationships were revealed that lead to the synthesis of a series of novel scalemic cobalt(II) salen complexes containing extended aromatic systems. Our protocol proved successful for converting a variety of cyclic tertiary allylic alcohols to the corresponding epoxides with high levels of enantioselectivity. Analysis of thermodynamic parameters and arene properties suggest that stabilizing noncovalent cation–? interactions within the cobalt(II) salen catalyst are essential to asymmetric induction. Chapter 4 describes recent efforts by our lab to develop a catalytic radical¬–polar crossover variant of the Ritter reaction. Long-standing limitations to substrate scope within the field of cobalt-catalyzed HAT radical–polar crossover hydrofunctionalizations are discussed. Strategic ligand design facilitated the development of cobalt(II) salen complexes capable of efficiently engaging trisubstituted and tetrasubstituted alkenes to afford tert-alkyl acetamide products. Isotope labeling and excess water experiments identified that nucleophilic capture of electrophilic intermediates by water was competitive with the desired hydroamidation. Hydrogen evolution studies confirmed that formation of hydrogen gas is a competitive pathway that contributes to background consumption of oxidant and silane.

In Chapter One a review of the paxilline indole diterpene (PID) class of secondary metabolites is provided. The review introduces the paxilline indole diterpenes and describes defining structural and biosynthetic features. Thorough analysis of the prior synthetic art offers perspective that will contextualize the synthetic efforts described by our own lab in subsequent Chapters.

In Chapter Two a structure-goal and transform-based strategy to the paxilline indole diterpenes family of secondary metabolites is described. The pursuit of a tricarbocyclic subtarget led to the development of a new regioselective alkenylation of enoxysilanes and a radical-polar crossover polycyclization cascade. Our initial efforts in this area guided the application of a tether-controlled radical conjugate addition/aldol sequence to access the common pentacyclic core of the family. Realization of our strategy resulted in an 11-step synthesis of emindole SB, which is the simplest congener of the family.

In Chapter Three efforts focused on the extension of our strategy to the paxilline indole diterpenes are described. The insight provided by previous work from our lab guided the pursuit of a radical-polar crossover polycyclization cascade that enabled the preparation of a precursor to the tetracyclic terpenoid core of 11-ketopaspaline. A diastereoselective late-stage reduction of a ketal moiety delivered an undesired epimeric terpenoid core and thwarted a potential 14-step total synthesis of 11-ketopaspaline.

In Chapter Four a brief review of cobalt-catalyzed hydrofunctionalization of alkenes utilizing a radical-polar crossover reaction manifold initiated by a chemoselective hydrogen atom transfer is described. This body of research served as inspiration for the unexpected development of a chemoselective Ritter reaction. The formation of tert-alkyl acetamides from simple alkenes is achieved under mild conditions and in the presence of acid-sensitive functional groups. Efforts toward the hydrofunctionalization of monosubstituted alkenes via discreet organocobalt(III) and cationic organocobalt(IV) complexes is also described. Experiments aimed at elucidating the reaction mechanism indicated that radical intermediates are short-lived and relevant secondary organocobalt(III) complexes are plausible intermediates.

Research progress towards the total synthesis of A-74528 is described herein. Highlights of the synthetic route include: efforts towards an elaborated β–tetralone which was used to probe the feasibility of a radical 6-endo cyclization to construct ring A of A-74528, a successful tandem [1,4]-Brook/Benzyne Diels-Alder to construct a key tricyclic intermediate, and work towards the current synthetic approach which utilizes novel conditions discovered in our lab to promote a semi-pinacol rearrangement.

In Chapter 1, a thorough overview of the paxilline indoloterpenoids will be covered with an emphasis on the diterpene congeners. Their notable biological activities will be discussed, as well as their challenging structural features from a synthetic organic chemistry standpoint. A brief discussion on the biosynthetic origin of the natural product family is also provided. Prior synthetic art will then be discussed at length, with an emphasis on the terpene core, as knowledge of synthetic challenges intrinsic to this system has intimately guided the work discussed in Chapters 2 and 3.

Chapter 2 describes our lab’s efforts towards a total synthesis of (–)-nodulisporic acid C. Development of a key radical-polar crossover cascade and an enantioselective conjugate addition permitted expedient access the terpene core. Completion of the highly convergent synthesis was facilitated by an efficient, intermolecular ketone a-arylation between two complex fragments that required extensive optimization. Taken together, a 12-step, asymmetric synthesis of (–)- nodulisporic acid C was completed.

Chapter 3 describes recent efforts to elaborate on the utility of the key radical-polar crossover cyclization to access additional paxilline indole diterpene congeners, particularly flagship congener paxilline itself. Various strategies were assessed for transforming the original polycyclization product into the desired oxidation pattern. The lack of success in this endeavour forced a revision of the polycyclization substrate altogether. Proof of concept with this strategy has been demonstrated towards the core of paxilline.

In Chapter 4, a brief review of carbon-carbon bond forming processes enabled by hydrogen atom transfer is described. Our labs methodology expanding the radical-polar crossover cascade to a well-functioning annulation is then discussed. Highly decorated cyclohexanols, complementary to Diels-Alder adducts, were efficiently accessed. The methodology permitted a facile synthesis of labdane diterpene forskolin.

This dissertation communicates new methods in cyclopropane activation and hydrogen-atom-transfer-initiated alkene hydrofunctionalizations to access novel catalytic asymmetric reaction manifolds and challenging polyketide scaffolds. Chapter One delineates the discovery of the enterocin polyketide antibiotics and subsequent efforts to identify the biosynthetic origin of their intriguing architecture. A review of the synthetic efforts towards the enterocin polyketides demonstrates significant challenges associated with construction of their highly oxidized caged core. Chapter Two describes our efforts to synthesize deoxyenterocin utilizing a biomimetic aldol cascade strategy. Our attempts to build the core are thwarted, however, due to inherent instability observed in synthetic analogues of the putative biosynthetic octaketide precursor. In Chapter Three, a lack of synthetic technology to install bridgehead oxidation contained in the enterocin core is identified, and a propellane activation strategy to directly forge bis-bridgehead functionalization is devised. Successful implementation of an unexploited propellane activation mode enables difunctionalization of the bridged propellane bond.

Chapter Four describes the isolation, structure elucidation, and bioactivity studies of A-74528, an aromatic polyketide bearing a densely functionalized perhydrophenanthrene core. Identification of the biosynthetic gene cluster reveals an unusual polycyclization operative in the biosynthesis. The single reported synthetic effort towards A-74528 demonstrates that the biomimetic cascade proposed likely remains unfeasible. Our development of a route utilizing a hydrogen-atom-transfer (HAT) mediated semi-pinacol ring expansion provides access to a key tetracyclic intermediate for further elaboration to a key cyclopropanol substrate for investigation of an oxidative cleavage-induced radical cyclization cascade.

Chapter Five focuses on our laboratory’s development of the first catalytic asymmetric HAT-initiated alkene hydrofunctionalization. Identification of a cation-π interaction in the Co(salen) catalyst employed enables optimization to achieve a highly enantioselective hydroalkoxylation of alkenes.

This dissertation details the development of a synthetic route to the pleuromutilin diterpenes and the discovery of catalyst-controlled radical‒polar crossover reactions of allylic alcohols. Chapter one outlines the isolation and structure determination, biosynthesis, and antimicrobial activity of the pleuromutilins. Additionally, analysis of the unique chemistries and existing synthetic approaches to the mutilin diterpenoids is provided. Chapter two delineates our analysis of the pleuromutilin structure and execution of a new synthetic approach. Beginning with our early attempts to assemble the polycyclic architecture, the evolution of our strategy through three distinct phases is described. The culmination of these studies is a 16-step stereocontrolled synthesis of pleuromutilin, the shortest to date. Chapter three is comprised of relevant background to Markovnikov-selective radical hydrofunctionalization reactions and our laboratory’s studies on the radical‒polar crossover reactions of allylic alcohols. Our observation of previously unprecedented catalyst control over the radical‒polar crossover reactions of dialkyl(vinyl)carbinols is outlined.

The nodulisporic acids comprise a subclass of the paxilline indole diterpene family and express potent insecticidal activity. These natural products have been the targets of synthetic studies since their isolation due to their complex, polycyclic structures. Efficient assembly of these targets has necessitated the development of new chemical transformations to forge bonds otherwise incompatible with retrosynthetic disconnections. This thesis will describe the development of such chemical transformations, culminating in the synthesis of nodulisporic acid C in 12 steps longest linear sequence (LLS) from commercial material as well as the synthesis of an advanced intermediate en route to nodulisporic acid A. A convergent approach utilizing a late stage ketone α-arylation to unite the complex terpene and indenopyran fragments allowed for the brevity of the synthesis. Construction of the indenopyran was accomplished through a diastereo- and regioselective enyne cycloisomerization which afforded the desired stereochemistry and connectivity present in nodulisporic acids A and C. The strategy for the terpene fragment relied on a hydrogen atom transfer (HAT) initiated polycyclization of an α-disubstituted ketone. The synthesis of this intermediate required the selective functionalization of a ketone at the more substituted position to afford a 1,1-disubstituted alkene in an intermolecular fashion. The development of this transformation utilizing a formal ene reaction between an enoxy silane and a terminal alkyne in the presence of catalytic indium(III) bromide is also described herein. Importantly, this reaction is selective for the formation of quaternary centers even in the presence of other enolizable positions. The development of these new chemical transformations has allowed for efficient access to the most complex structural features of the nodulisporic acid family.

In Chapter One the isolation, biosynthesis, and bioactivity of the anthraquinone–

xanthone heterodimers is discussed. Additionally, a review of previous synthetic efforts

towards this class of natural products is provided, along with reported syntheses of related

anthraquinone- and xanthone-derived natural products.

Chapter Two discusses synthetic efforts towards the anthraquinone–xanthone

heterodimer natural products. This includes model system studies aimed at the construction

of the bicyclo[3.2.2]nonane core, as well as our first generation synthesis of the

benzocycloheptenone precursor. Our optimized route involves the development of an

iodine(III)-mediated arylation enol ethers, which allows for rapid construction of a key

intermediate in the synthesis. A Hauser–Kraus annulation–aldol reaction sequence enables

assembly of the bicyclo[3.2.2]nonane core, which is then carried on to complete the first total

synthesis of acremoxanthone A in 10 steps from commercial material.

xv

In Chapter Three an overview of previously reported methods for the alkenylation of

ketones is provided, followed by the development of the intermolecular In(III)-catalyzed

alkenylation of silyl enol ethers with alkynes. This reaction is demonstrated on a variety of

cyclic and acyclic substrates to provide the corresponding 2-siloxy-1,4-dienes, via a formal

ene reaction, or β,γ-unsaturated ketones. Additionally, mechanistic investigations are

discussed, including a proposed mechanism for the intermolecular formal ene reaction.