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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.

Abstract: The first chapter of this thesis describes the development of a general method for indirectly effecting radical carbocyclization of an alkyl chain onto an aromatic ring. This process involves a Birch reductive alkylation of aromatic tert-butyl esters, chromium(VI)-mediated oxidation and radical cyclization. The cyclized products are easily oxidized to the corresponding cross-conjugated ketones via Saegusa oxidation. Addition of organolithium or Grignard reagents and treatment with bismuth trichloride affords aromatized benzo-fused carbocycles. The second chapter describes a method for converting Morita-Baylis-Hillman acetates into unusual seven-membered heterocycles containing both nitrogen and sulfur. N-Deprotection of the MBH acetates and trapping with CS2 affords the desired 2-thioxo-1,3-thiazepines. In a modification of this process, when the original nitrogen is substituted with a carbon chain, an azepine derivative is generated. The ring closures occur by intramolecular conjugate displacement. The last chapter of this thesis describes synthetic studies towards the marine antibiotic alkaloid, marinopyrrole B. Due to the difficulty of bromination of the pyrrole system, it is known that marinopyrrole B cannot be directly made from marinopyrrole A. Our plan was based on brominating the bottom pyrrole at an early stage and constructing the top pyrrole ring later. Previous studies towards the core structure of marinopyrrole A suggested that the Paal-Knorr reaction is an ideal method for construction of the top ring. Preparation of the precursor for the Paal-Knorr reaction was planned via an intermolecular conjugate displacement between a densely halogenated pyrrole and a Morita-Baylis-Hillman carbonate. However, this approach was unsuccessful and further studies are in hand.

The critically important nature of radical and radical ion mechanisms in biology and chemistry continues to be recognized as our understanding of these unique transient species grows. The work presented herein demonstrates the versatility of kinetic studies for understanding the elementary chemical reactions of radicals and radical ions. Chapter 2 discusses the use of direct ultrafast kinetics techniques for investigation of crucially important enzymatic systems; while Chapter 3 demonstrates the value of indirect competition kinetics techniques for development of synthetic methodologies for commercially valuable classes of compounds. The mechanism of decay for aminyl radical cations has received considerable attention because of their suspected role as intermediates in the oxidation of tertiary amines by monoamine oxygenases and the cytochrome P450 family of enzymes. Radical cations are believed to undergo deprotonation as a key step in catalysis. KIE studies performed by previous researchers indicate N,N-dimethylaniline radical cations deprotonate in the presence of the bases acetate and pyridine. By studying the electrochemical kinetics of the reaction of para substituted N,N-dimethylaniline radical cations with acetate anion, we have produced compelling evidence to the contrary. Rather than deprotonation, acetate reacts with N,N-dimethylaniline radical cation by electron transfer, generating the neutral amine and acetoxyl radical. Transport properties of reactants and solvent polarity changes were investigated and confirmed not to influence the electrochemical behavior forming the basis for our mechanistic hypothesis. To reconcile our conclusion with earlier results, KIEs were reinvestigated electrochemically and by nanosecond laser flash photolysis. Rather than a primary isotope effect (associated with C-H bond cleavage), we believe the observed KIEs are secondary, and can be rationalized on the basis of a quantum effect due to hyperconjugative stabilization in aromatic radical cations during an electron transfer reaction. Product studies performed by constant potential coulometry indicate N,N-dimethylaniline radical cations are catalytic in carboxylate oxidations. Collectively, our results suggest that aminyl radical cation deprotonations may not be as facile as was previously thought, and that in some cases, may not occur at all. Interest in design and synthesis of selenium containing heterocycles stems from their ability to function as antioxidants, anti-virals, anti-inflammatories, and immunomodulators. To establish synthetic feasibility of intramolecular homolytic substitution at selenium for preparation of selenocycles, we set out to determine what factors influence cyclization kinetics. A series of photochemically labile Barton and Kim esters have been syntheisized and employed as radical precursors. The effect of leaving radical stability on kinetics has been investigated through determination of rate constants and activation parameters for intramolecular homolytic substitution of the corresponding radicals via competition experiments. Notable leaving group effects on measured kinetic parameters show more facile reactions for radical precursors with more stable leaving radicals. Moreover, cyclizations to form six-membered (as opposed to five- membered) ring systems exhibited order of magnitude decreases in rate constants for a given leaving radical. Our results are congruent with expectations for radical cyclizations trends for the varied experimental parameters and suggest homolytic substitution affords a convenient means for synthesis of selenocycles.

I. Maintaining high standards of science training is important for pharmacy graduates to practice knowledgeably, responsibly, and confidently. Instrumentation and resource constraints are maximal in the pharmaceutical analysis laboratory due to the nature of the experiments that need to be conducted and the need to provide as much individualized learning experience as possible. Therefore, the 1st year PharmD students perform the laboratory exercises in subgroups, rotating each week in three tri-weekly cycles. Although this arrangement optimizes space, instrument and resources utilization, it creates inevitable educational gaps related to each subgroup's experiment. More specifically, there are gaps with the lectures' progress and the necessary pre-laboratorial instruction for each experiment. Therefore, online instructional tutorials and technique-demos as well as accompanying online quizzes were prepared and delivered through a secure course-website. Each student had to view the tutorials and pass the quizzes before coming to the laboratory. In addition, virtual laboratories were designed as an additional aid for some experiments. As shown by student surveys, these changes were well-received and improved many aspects of this class. II. Most cancer mortality results after it has metastasized from its primary growth site and spread to remote sites. Metastasis is a complex succession of events that the cancer cell manages to accomplish as the disease progresses. One necessary step is the breakdown of the physical barriers, such as endothelial basal membrane and extra-cellular matrix. In order to achieve this, cancer cells express heparanase, a beta-endoglucuronidase that breaks down the glycan part of heparan sulfate, which is a basic constituent of these physical barriers. Amino-sugars have been shown to inhibit this type of carbohydrate-processing enzymes by virtue of their transition state mimicry. Since the substrate of heparanase carries acidic moieties, its inhibitors also carry acidic groups. Few efficient synthetic routes are available for the synthesis of sugar amino-acids. The feasibility of the use of an unprecedented intramolecular SN2’Mitsunobu reaction and alpha-aminomethyl radical cyclizations is explored for the synthesis of alpha- and beta- sugar amino-acids respectively.

This thesis summarizes research conducted toward total syntheses of a perhydronapthalene-containing C20 quassinoid, chapparrinone (3), and perhydrindan-containing C19 quassinoids, the polyandranes (4). In the project directed toward chaparrinone, methodology to prepare perhydnaphthalenes via 6-heptynyl radical cyclizations was studied. It was revealed that electron-deficient alkynyl radicals cyclized more efficiently than electron-rich counterparts. Radicals partitioned approximately 2:1 to give trans- and cis-perhydronaphthylenes. When the conformation of the radical cyclization precursor was constrained by a pre-installed D-ring (see 123 in Scheme 3.36), exclusive trans-perhydronaphthalene (124) formation was observed. This research resulted in preparation of a BCDE ring system (124) from benzoate 83 in 12 steps and 7.0% overall yield. In the approach to polyandranes (4), a cyclopropyl radical fragmentation was used to avoid an unwanted secondary free radical cyclization. As a result, the trans-perhydroindan substructure 223 was efficiently prepared in 9 steps from starting material 144. A strategy of double Eschenmoser-Claisen rearrangement was used to construct the D-ring and introduce the quaternary carbon at C(10). As a result, the BCDE ring system (204) of the polyandranes (4) was prepared in 13 steps from 144 in 4.7% overall yield.

This thesis describes research directed toward a synthesis of (5R)- and (5S)-polyandrane. The polyandranes are members of the quassinoid family of natural products isolated from plants of the Simaroubaceae family. Many members of the quassinoid family of natural products have elicited interest due to their medicinal properties, especially bruceantin. Synthetic interest in quassinoids has resulted in publication of numerous total syntheses including the polyandranes and bruceantin. Our approach for the synthesis of the polyandranes revolves around preparation of a tricyclic intermediate containing a trans-perhydroindan substructure as the first key intermediate. Preparation of the tricyclic intermediate, first carried out in a model system, incorporates a 5-exo-dig radical cyclization as the key bond-forming reaction. Implementation of the chemistry developed in the model system to substrates with the correct C11 oxidation state, results in an unexpected tetracyclic product. A radical clock is incorporated into the system to circumvent tetracycle formation. The second major goal is formation of the D ring. Studies toward D ring formation include an ene cyclization, a radical cyclization, and a Tsuji-Trost cyclization.

The formation of silylstannyl dienes from 1,6-diynes was first reported by our former research group members. These dienes are fascinating molecules as they exhibit helical chirality. However, monocyclic dienes are known to undergo fast helical isomerization. For our main goal of making a unidirectional helical polyolefin, a diene in which this helical isomerization is completely frozen is necessary. A bicylic motif was designed to obtain such a system by slowing down this isomerization. The chemistry of these silylstannyl dienes was unexplored. We probed the Stille coupling reactions of these compounds with various electrophiles. A new protocol for the Stille coupling which used 2 mol% Pd(MeCN)2Cl2, 4 mol% AsPh3 and 8 mol% CuI in DMF at room temperature was found to be effective for several difficult substrates. Using these conditions, iodobenzene, bromotrimethylsilyl acetylene, benzyl bromide and 1,4-diiodobenzene were efficiently coupled. Synthesis of a polyolefin was attempted by coupling of a silylstannyl diene with its iodide derivative under the same conditions. However, instead of the expected tetraene, a rearranged product was observed which presumably was formed via a 1,7 -hydrogen shift. The Palladium-catalyzed addition of silylstannane reagents to alkynes is known to be a synthetically useful reaction. The tolerance of a sensitive functionality like epoxide iii had not been reported before. We examined the addition of Bu3SnSiMe3 to epoxyalkynes and found that the desired addition product was formed in excellent yields. Such products can be subjected to the well-known Ti(III)-mediated epoxide opening-radical cyclization. The reaction presumably occurs via radical formation followed by an addition-elimination sequence to give the expected product. This reaction affords five-membered carbo- and heterocyclic compounds. The presence of the vinyl-TMS group at the terminal provides a potentially useful alcohol. Similarly epoxyalkynes undergo Pd-catalyzed distannation followed by Ti(III) mediated reaction to give cyclic alcohols with vinylstannane, which is more reactive than the corresponding vinyl vinylsilane. The application of this addition-elimination reaction was expected for the formation of four-membered carbocyclic compounds. However, the radical formed by epoxide opening abstracts the vinyl hydrogen via a 6-membered transition state and an internal alkyne was obtained.

An efficient and generally applicable method for the synthesis of 3,6-disubstituted 1,2-dithiins has been developed. The method involves the use of tert-butyl mercaptan for its regio- and stereoselective 1,4-bis-addition to 1,4-disubstituted 1,3-butadiynes. Deprotection of the tert-butyl group and formation of the 1,2-dithiin ring are accomplished in a single operational step by treatment of the thiol adducts with iodine, N-iodosuccinimide, or N-bromosuccinimide, providing a variety of 3,6-disubstituted 1,2-dithiin compounds in good to excellent yields. A mild and efficient procedure for the reduction of sulfoxides to thioethers has also been established. Activation of the sulfoxides in situ by treatment with acetic anhydride followed by reduction with zinc metal affords their corresponding thioethers in high yields. The first total synthesis of thiarubrine C, a DNA-cleaving natural 1,2-dithiin, has been realized in 9 steps from readily available 2,4-hexadiyne-1,6-diol. Preliminary studies on its DNA-cleavage have revealed its ability to cleave DNA in the presence of a thiol, oxygen, and trace of a metal ion, thus suggesting the generation of hydroxyl radical and its involvement as part of the mechanism for DNA-cleavage. A method to achieve (alkoxycarbonylamino)methyl radical cyclization using phenyl selenides as precursors has been established. The preparation of phenyl selenides involves the efficient formation of a carbon-nitrogen bond from the corresponding alcohol by the use of the Mitsunobu reaction and the tin-lithium exchange of the organostannane intermediate followed by quenching with diphenyl diselenide. The above radical cyclization has been applied to the total synthesis of a Nitraria alkaloid, sibirine. The preparation of the phenyl selenide precursor, 3-(t-butyldimethylsiloxy)-2-$\{3\sp\prime$- (N-(carbomethoxy)-N-phenylselanylmethylamino) $\}$propyl-1-phenylsulfonylcyclohexene, involves the use of the Suzuki coupling reaction of an alkenyl bromide and a protected amine-containing alkylborane as a key step. The radical cyclization directly provides the 2-azaspiro (5.5) undecane skeleton of sibirine with high regio-and stereoselectivity when a vinyl sulfone is used as the radical acceptor. This total synthesis of sibirine is achieved in 12 steps from 1,3-cyclohexanedione.