xiv, 326 p. : ill. (some col.) / Tetra-ortho -substituted aryl naphthalenes (TOANs) are a motif of great importance, being present in biologically active natural products, chiral ligands, and building blocks relevant to materials science. The synthesis of sterically demanding and enantioenriched TOANs continues to be a challenge for current synthetic methods. Herein, we describe the highly effective synthesis of a variety of sterically demanding and enantioenriched TOANs through a rearrangement-based method. Our method utilizes a cyclopropyl carbinol moiety as the key rearrangement precursor. We have demonstrated that carbon-carbon coupling through a simple nucleophilic attack on a cyclopropyl indanone allows for very large aryl substrates to be added and rearranged. We discuss in detail the following: 1) the initial substrate-scope and proof-of-concept studies, 2) our progress in building the most sterically demanding TOANs to date, and 3) the asymmetric synthesis of TOANs through chiral transfer. This dissertation includes previously published and unpublished co-authored material. / Committee in charge: Michael M. Haley, Chairperson; Shih-Yuan Liu, Advisor; Darren W. Johnson, Member; Victoria J. DeRose, Member; Paul J. Wallace, Outside Member

Cyclopropanation of the unsaturated fatty acid moieties of membrane phospholipids is a commonly observed phenomenon in a number of bacterial systems. The cyclopropane fatty acids are usually synthesized during and after the transition from exponential growth to stationary phase, or under such environmental conditions as acidic culture pH, low oxygen tension or high salt concentrations. S-Adenosylmethionine, the ubiquitous methyl group donor, provides the methylene bridge carbon in the reaction catalyzed by cyclopropane fatty acid synthase. Also formed in the reaction is S-adenosylhomocysteine, a potent inhibitor of cyclopropane fatty acid synthase, which is degraded by S-adenosylhomocysteine nucleosidase. This work provides evidence for at least two modes of regulation of lactobacillic acid synthesis, the cyclopropane fatty acid formed from cis-vaccenic acid (cis-11,12-octadecenoic acid), in Lactobacillus piantarum.

The direct conversion of carbon–hydrogen bonds into valuable carbon-carbon and carbon-heteroatom bonds is a significant challenge to synthetic organic chemists. More than ever, chemists are employing Rh(III)-catalysts bearing cyclopentadienyl (Cp) ligands to transform otherwise inert C–H bonds. Furthermore, manipulating the sterics and electronics of the Cp ligand show significant impact on catalytic transformations. Our group has developed a library of CpˣRh(III)-precatalysts in hopes of enhancing known reactivity as well as discovering new C–H bond functionalizations. We have previously reported that N-enoxyphthalimides are a unique one-carbon component for the cyclopropanation of activated alkenes. In an effort to expand the scope to accessible alkenes, we have found a number of symmetrical unactivated alkenes undergo [2+1] annulation to afford intriguing spirocyclic cyclopropanes. Additionally, we have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols to furnish substituted cyclopropyl ketones. Notably, the traceless oxyphthalimide handle serves three functions: directing C–H activation, oxidation of Rh(III), and, collectively with the allylic alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes. Next, an artifact of previous cyclopropanation reactions leads to the formation of a Rh-π-allyl complex. Attempts at 1,1-carboamination of alkenes are made using alkenes and nitrenoid precursors toward the 3-component synthesis of allylic amines. Stoichiometric studies help elucidate the mechanism and challenges. Lastly, efforts toward 1,2-carboamination of alkenes initiated by sp³ C–H bond activation are made with two different reactivity manifolds. Isolation of reaction intermediates are discussed as well as providing viable paths toward valuable products.

The recent upsurge of degenerative diseases believed to be the result of oxidative stress has sparked an increased interest in utilizing the fundamental principles of physical organic chemistry to understand biological problems. Enzyme pathways can pose several experimental complications due to their complexity, therefore the small molecule probe approach can be utilized in an attempt understand the more complex enzyme mechanisms. The work described in this dissertation focuses on the use of N-cyclopropyl amines that have been used as probes to study the mechanism of monoamine oxidase (MAO) and cytochrome P-450 (cP-450). A photochemical model study of benzophenone triplet (3BP) with the MAO-B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and two of its derivatives, 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)-[trans-2-phenylcyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine is presented in Chapter 2. The barrier for ring opening of aminyl radical cations derived from N-cyclopropyl derivatives of tertiary amines (such as MPTP) is expected to be low. Reactions of 3BP with all three compounds are very similar. The results suggest that the reaction between benzophenone triplet and tertiary aliphatic amines proceed via a simple hydrogen atom transfer reaction. Additionally these model examinations provide evidence that oxidations of N-cyclopropyl derivatives of MPTP catalyzed by MAO-B may not be consistent with a pure SET pathway. The chemistry of N-cyclopropyl amines has been used to study the mechanism of amine oxidations by cP-450. Until recently, the rate constant for these ring opening reactions has not been reported. Direct electrochemical examinations of N-cyclopropyl-N-methylaniline showed that the radical cation undergoes a unimolecular rearrangement consistent with a cyclopropyl ring opening reaction. Examination of both the direct and indirect electrochemical data showed that the oxidation potential N-cyclopropyl-N-methylaniline to be +0.528 V (0.1 M Ag⁺/Ag), and rate constant for ring opening of 4.1 x 10⁴ s⁻¹. These results are best explained by two phenomena: (i) a resonance effect in which the spin and charge of the radical cation in the ring closed form is delocalized into the benzene ring hindering the overall rate of the ring opening reaction, and/or (ii) the lowest energy conformation of the molecule does not meet the stereoelectronic requirements for a ring opening pathway. Therefore a new series of spiro cyclopropanes were designed to lock the cyclopropyl group into the appropriate bisected conformation. The electrochemical results reported herein show that the rate constant for ring opening of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] are 3.5 x 10² s⁻¹ and 4.1 x 10² s⁻¹ with redox potentials of 0.3 V and 0.366 V respectively. In order to examine a potential resonance effect a derivative of N-methyl-N-cyclopropylaniline was synthesized to provide a driving force for the ring opening reaction thereby accelerating the overall rate of the ring opening pathway. The electrochemical results show that the rate constant for ring opening of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline to be 1.7 x 10⁸ s⁻¹ . The formal oxidation potential (E°OX) of this substrate was determined to be 0.53 V. The lowered redox potentials of 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] can be directly attributed to the electron donating character of the ortho alkyl group of the quinoline base structure of these spiro derivatives, and therefore the relative energy of the ring closed radical cations directly affects the rate of ring opening reactions. The relief of ring strain coupled with the formation of the highly resonance stabilized benzylic radical explains the rate increase for the ring opening reaction of 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline. / Ph. D.

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La base phosphazène ButP4 associée au thiophénol ou au bis (2-mercaptoéthyl) éther a été utilisée avec succès pour amorcer quantitativement la polymérisation anionique par ouverture de cycle des monomères cyclopropane-1,1-dicarboxylates de dialkyle. Pour des températures comprises entre 30 et 60°C dans le THF ou entre 30 et 100°C dans le toluéne, le mécanisme observé est celui d'une polymérisation anionique vivante qui conduit à des polymères présentant des indices de polymolécularité faibles et dont les Mn expérimentaux (mesurés par SEC et RMN 1H) sont en accord avec les valeurs théoriques. D'autres systèmes déamorçage comme le carbazole ou des composés possédant un proton acide associés à ButP4 conduisent également à des polymères bien définis. Une étude cinétique montre que l'ordre interne en monomère est égal à 1 sur l'ensemble de la gamme de conversion. Le système déamorçage thiophénol / ButP4 dans le THF présente une réactivité bien supérieure à celle du thiophénolate de sodium dans le DMSO qui est le système classique d'amorçage pour ce type de polymérisation. Différents agents de terminaison, comme l'acide chlorhydrique, le bromure d'allyle ou le bromure de propargyle, ont été utilisés pour terminer les réactions et ont conduit à l'obtention de polyméres hétérotéléchéliques. D'autres dérivés de cyclopropanes présentant des substituants variés ont également été examinés. Ces résultats ouvrent de très intéressantes perspectives dans la préparation d'architectures complexes comme des copolyméres à blocs, greffés ou en étoile. Les premières expériences de copolymérisation ont d'ailleurs été couronnées de succès. Afin d'obtenir de nouveaux canaux ioniques artificiels, différents monomères cyclopropane-1,1- dicarboxylates porteurs d'éthers-couronne ont été synthétisés. La polymérisation anionique par ouverture de cycle de ceux-ci a été étudiée en utilisant soit le thiophénolate de sodium soit le système thiophénol / ButP4 comme amorceur. Ces travaux ont également permis l'obtention d'un nouveau type de poly(éther-ester) qui s'est révélé intéressant comme perméabilisant membranaire. Les interactions des oligo(éther-ester)s avec des membranes modèles planes, des vésicules unilamellaires et des cellules ont été étudiées en collaboration avec des physiciens et des biologistes. Des résultats prometteurs en termes de transport d'ions ont été obtenus et sont présentés dans ce mémoire / The tetrameric phosphazene base ButP4 in association with thiophenol or bis(2-mercaptoethyl) ether has been successfully used in order to initiate the anionic ring-opening polymerization of di-n-alkyl cyclopropane-1,1-dicarboxylates. Well-defined monofunctional or difunctional polymers with a very narrow molecular weight distribution were obtained through a living process at temperatures between 30 and 60°C in THF or between 30 and 100°C in toluene. An excellent agreement is observed between theoretical and experimental Mn values (measured by SEC and by NMR). Other initiating systems such as carbazole or compounds with an acidic proton in association with ButP4 lead also to welldefined polymers. A kinetic study shows a first order with respect to the monomer concentration over the entire conversion range. The initiating system thiophenol / ButP4 in THF shows a much higher reactivity compared to the alkali metal thiophenolate which is the classical one. The living ends were reacted with different terminating agents such as hydrochloric acid, allyl and propargyl bromide thus leading to telechelic polymers. Other cyclopropane derivatives with various substituents have been also examined. These results open very exciting perspectives for the preparation of new architectures such as block and graft copolymers, star polymers. The first copolymer attempts were very successful. With the aim of designing new ion channel biomimics, cyclopropane-1,1-dicarboxylate monomers with crown-ethers substituents were synthesized. The anionic ring-opening polymerization of these monomers has been investigated using either sodium thiophenolate or thiophenol activated by ButP4. Moreover a new alternating poly(ether-ester) was obtained which is an interesting membrane permeabilizer. Its interaction with unilamellar vesicles, planar phospholipidic membranes and cells was studied in collaboration with biophysicists and biologists. Very promising results have been obtained

The thesis entitled ‘Studies of NIS Mediated Cyclopropane Ring Opening Reactions in Carbohydrate Chemistry’ is divided into four chapters. Chapter 1: Section 1: Efficient Synthesis of Fused Perhydrofuro[2,3-b]pyrans (and furans) by Ring Opening of 1,2-Cyclopropanated Sugar Derivatives. In this section a general and efficient methodology for the synthesis of carbohydrate derived perhydrofuro[2,3-b]pyrans (and furans) from the corresponding 1,2-cyclopropane carboxylates has been discussed. A wide range of linear-fused perhydrofuro[2,3-b]pyran or furan ring systems are encountered in a number of biologically active natural products. A few approaches are available for the construction of this kind of fused motifs which involve harsh reaction conditions and lengthy reaction sequence. The methodology utilizes the potential ability of cyclopropanated sugars to undergo N-iodosuccinimide (NIS) mediated electrophilic ring opening assisted by the pyran ring oxygen followed by intramolecular trapping of oxonium intermediate to generate the furan ring system. Cyclopropantion of tribenzyl glucal using methyl diazoacetate and catalytic amount of dirhodiumtetracetate furnished corresponding exo-1,2-cyclopropane carboxylate exclusively. To generate a nucleophile, cyclopropane carboxylate ester was reduced to the corresponding alcohol which upon treatment with NIS in CH3CN underwent ring opening followed by intramolecular ring closure to give the corresponding perhydro[2,3-b]furopyran along with an oxidized product. After various modifications we found that using CH2Cl2 as a solvent gave the expected perhydrofuropyran as the sole product in good yield (Scheme I). The stereochemistry of the product was established on the basis of 1H-1H NOESY experiment. There are many natural products that contain the perhydrofuro[2,3-b]furyl glycal core such as clerodin, jodrelline B and caryoptin, which show insect anti-feedant properties. With this in mind, the methodology has been successfully extended to the cyclopropanated tetrahydrofuran derivatives resulting in the synthesis of furofuryl glycal moiety (Scheme II). Scheme II Chapter 1: Section 2: Synthesis of Carbohydrate Derived Fused Perhydrofuro/pyrano[2,3-b]-γ-butyrolactones. In this section a general and efficient methodology for the synthesis of carbohydrate derived perhydrofuro/pyrano[2,3-b]-γ-butyrolactones has been discussed. The fusion of the γ-butyrolactone onto a substituted tetrahydrofuran/pyran ring makes a distinctive class natural diterpenoids. Representative members of this family include the marine diterpenoids norrisilide and miniolutelide A. In this chapter we describe a neutral and general method for the construction of perhydrofuro/pyrano[2,3-b]-γ-butyrolactones by NIS mediated ring opening of carbohydrate derived 1,2-cyclopropane carboxylic acids (Scheme III). Scheme III The present strategy is complementary to the existing methods and it is useful since it incorporates an additional chiral center in the molecule under milder conditions, which can be used for further transformations. Chapter 2: Ring Opening of Activated Cyclopropanes with NIS/NaN3: One-pot Synthesis of C-1 Linked Pseudo Disaccharides. Ring opening reactions of activated cyclopropanes have been widely used in organic synthesis. But they are restricted to only selected nucleophiles such as alcohol/ water, as most of the ring opening reactions need acidic activation. This chapter deals with studies of reactivity of various activated cyclopropanes with NIS as a neutral activator and sodium azide as a source of nitrogen nucleophile (Scheme IV). Scheme IV We have clearly demonstrated not only the importance of the donor-acceptor feature in the cyclopropanes in the electrophilic ring opening reaction, but also the selectivity in its functionality. Scheme V This methodology has been successfully utilized in a one-pot synthesis of C-1 linked pseudo-disaccharides from carbohydrate derived 1,2-cyclopropane carboxylates (Scheme V). Chapter 3: Synthesis of Unnatural C-2 Amino Acid Nucleosides Using NIS Mediated Ring Opening of 1,2-Cyclopropane Carboxylated Sugar Derivatives. In this chapter, we have efficiently demonstrated the utility of NIS mediated regioselective ring opening of carbohydrate derived donor-acceptor cyclopropanes for the synthesis of C-2 amino acid nucleosides. This leads to a new class of analogs of peptidyl nucleosides (Scheme VI). Scheme VI One of the advantageous factors is the attachment of nucleobase as well as generation of amino acid precursor in the same reaction which avoids lengthy reaction sequence. We have also shown the synthetic utility of our methodology to pyrimidine based furanosyl C-2 amino acid nucleosides which are of interest, since polyoxins having similar structural core exhibit antifungal activity (Scheme VII). Chapter 4: Attempts Towards the Synthesis of Carbohydrate Derived Spiro-perhydrofuropyrans Using NIS Mediated Cyclopropane Ring Opening Reaction. In this chapter we present various attempts to synthesize spiro-perhydrofuropyran/furans by ring opening of spiro-cylopropane derivatives and attempts towards stereoselective synthesis of spiro-cyclopropane carboxylates. Spiroacetal can be synthesized from the corresponding exo-cyclopropyl methanol, which can be obtained from the corresponding exo- cyclopropane carboxylate. The cyclopropyl carboxylate can be obtained from an exo- vinyl ether. Cyclopropanation of carbohydrate derived exo-glycal failed to give any selectivity under a variety of reaction conditions (Scheme VIII). Carbohydrate derived C1-unsaturated ester on cyclopropanation reaction using standard conditions (Pd(OAc)2/CH2N2) was found to be inert. The reaction under Simmons-Smith cyclopropanation conditions also gave similar results. Reduction of the ester part of the molecule to the corresponding alcohol was found to be helpful in the Simmon-Smith cyclopropanation reaction (CH2I2, Et2Zn) to obtain the corresponding exo-cyclopropane, but disappointingly without any selectivity (Scheme IX). In order to get exo-cyclopropane carboxylate with high stereoselectivity, we decided to use one of the hydroxyl group present in the molecule, as a chiral auxiliary. All the established methods for the diazoester formation failed to attach diazo ester at C-4 position (Scheme X). Scheme X (For structural formula pl see the pdf file)

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Microwave-Assisted Thermolysis of ortho-Substituted Aroylsilanes Marc Tremblay Master of Science Department of Chemistry University of Toronto 2008 The microwave-assisted thermolysis of ortho-substituted aroylsilanes has been investigated. When irradiated at 250ºC in DMSO or o‑dichlorobenzene for 10 minutes, aroylsilanes form siloxycarbenes that react following different pathways depending on the solvent and the structure of the starting material. It is shown that in the case of substrates having an O‑allyl or an O‑propargyl chain ortho to the acylsilane, cycloaddition occurs followed by a cascade ring opening to give respectively chroman‑4-one and chromen‑4-one derivatives in up to 66% yield. Among the major competitive pathways were the insertion of the siloxycarbene into allylic C–H bonds and decomposition of the acylsilane group to the corresponding aldehyde, followed by Claisen rearrangement.

Microwave-Assisted Thermolysis of ortho-Substituted Aroylsilanes Marc Tremblay Master of Science Department of Chemistry University of Toronto 2008 The microwave-assisted thermolysis of ortho-substituted aroylsilanes has been investigated. When irradiated at 250ºC in DMSO or o‑dichlorobenzene for 10 minutes, aroylsilanes form siloxycarbenes that react following different pathways depending on the solvent and the structure of the starting material. It is shown that in the case of substrates having an O‑allyl or an O‑propargyl chain ortho to the acylsilane, cycloaddition occurs followed by a cascade ring opening to give respectively chroman‑4-one and chromen‑4-one derivatives in up to 66% yield. Among the major competitive pathways were the insertion of the siloxycarbene into allylic C–H bonds and decomposition of the acylsilane group to the corresponding aldehyde, followed by Claisen rearrangement.