Thesis (Ph. D.)--University of Hong Kong, 1998. / Includes bibliographical references (leaves 188-198).

Thesis (Ph.D.)--Victoria University of Wellington, 2010. / Includes bibliographical references.

An array of different cyclopropanes have been synthesised, including the structurally simple 1-phenylcyclopropanol. These were synthesised in yields upwards of 60%, using the well published Kulinkovich reaction. From 1-phenylcyclopropanol, variations of the cyclopropane core structure were synthesised, creating species ideal for palladium cross coupling reactions, such as 1-phenylcyclopropyl methanesulfonate and 1-phenylcyclopropyl 4-methylbenzenesulfonate. These were formed in 50 and 60% yield respectively. Once obtained these cyclopropanes were used to perform Suzuki cross coupling reactions towards the formation of 1,1- diphenyl cyclopropane. Unfortunately, despite various attempts, the palladium cross coupling reactions were unsuccessful. The work did facilitate the discovery of a novel methodology for the synthesis of tetra substituted alkenes. Using similar methodology as that developed for the formation of 1- phenylcyclopropanol, a McMurry reaction was able to be performed on a number of different ketones. This reaction formed a wide array of different tetra-substituted alkenes with yields ranging from 20-99%, depending on the nature of the starting material. The method, involving the use of 9 equivalents of Grignard reagent and stoichiometric amounts of titanium isopropoxide, is a unique way of making low valent titanium in situ, as well as being homogeneous. Methodology for the formation of vinyl cyclopropanes containing an amide moiety has been developed, allowing a variety of different amines to be coupled to two different cyclopropanes. Once these species were synthesised, a palladium catalysed cyclisation, Heck reaction, carbonylation cascade was developed. This allowed the core cyclic structure of the stemona alkaloids to be obtained in a single reaction vessel with good yields of up to 52% depending on the amine used. The cascade was then applied to a fully substituted cyclic natural product core. However, the cascade reaction was unsuccessful. Efforts to alter the structure of the starting material, to remove the potentially hindering bromine, provided no improvement. It was established that the tetrakis(triphenylphosphine) palladium (0) catalyst used was too encumbered for insertion in to the sterically hindered starting material, which is likely to be causing the failure of the reaction.

The microbial oxidation of arenes to the corresponding cis-diols has been shown to be a convenient source of optically pure diols which can be used as synthons in asymmetric synthesis of complex, highly oxygenated molecules. The utility of such synthons has been demonstrated by the total synthesis of (-)- Specionin 1. A key transformation in this sequence is a low-temperature rearrangement of vinylcyclopropane 59 to diquinanes 61 and 62. Of additional merit is the development of an efficient preparation of enone 56 from cis arene diol 66. / Ph. D.

Nature’s biodiversity is complex and filled with beauty and wonder which are all observable on the macroscopic scale. This exquisiteness of nature’s intricacies are mirrored on the molecular level such that substances, large or small, are assembled to serve as signaling molecules, protective agents, and fundamental composites of higher-order frameworks for the operation and survival of life. Over the years, chemists have isolated and synthesized these molecules, known as natural products, to understand and evaluate their functions in biology and potential for medicinal applications. Although bioactive natural products demonstrate medicinal promise, poor pharmacological effects require further derivatization because semisynthesis is not sufficient to refine adverse pharmacokinetics. For some active molecules, isolation results in poor yields. In addition to small quantity isolation, many natural products, reflecting the immense complexity of biology itself, pose difficult synthetic challenges to organic chemists because of skeletal heterogeneity, stereochemical complexity, and substitution divergence. As a result of these synthetic obstacles to natural product utilization, improvements are needed in current chemical approaches, and new innovative methodologies for synthesis and chemical space exploration are necessary. Pharmaceutically relevant frameworks, natural products, and synthetic biologically active molecules are comprised of polycarbocyclic and heterocyclic scaffolds. Traditionally, cycloadditions, transannular transformations, and annulation reactions serve as powerful methods for polycyclic formation. In order to assemble diverse polycycles, donor-acceptor cyclopropanes are useful, versatile synthetic equivalents for C-C bond formations. By taking advantage of the strain within these unique, polarized systems, differing molecular architectures can be accessed directly to perform contemporary organic synthesis. Moreover, the donor-acceptor cyclopropanes initially utilized in these studies provided a fundamental basis for new methods to synthesize other relevant scaffolds. Unique, efficient, Lewis acid-catalyzed intramolecular cyclization strategies for the construction of functionalized polycycles using Friedel-Crafts-type alkylation sequences are presented to expand the reaction repertoire of the molecular architect. Generally, products were formed from commercially-available starting materials in high yields with broad scope. The methodologies were demonstrated to be modular, operationally simple, and amenable to different substitution patterns and functional groups to afford tetrahydroindolizines, heteroaromatic cyclohexenones, hydropyrido[1,2-a]indoles, pyrrolo[1,2-a]indoles, pyrrolo[3,2,1-ij]quinolines, pyrrolizines, and tetrahydrobenzo[ij]quinolizines. To demonstrate the utility of the methodologies devised, progress toward, (±)-rhazinicine, a natural product, is discussed. This dissertation is organized into six chapters: (1) an introduction, paradoxical stress and molecular strain’s utility in synthesis; (2) annulation reactions for the formation of heteroaromatic cyclohexenones; (3) hydropyrido[1,2-a]indole formation via an In(III)-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence; (4) tetrahydroindolizine formation and progress toward the total synthesis of (±)-rhazinicine (5) pyrrolo[1,2-a]indole synthesis using a Michael-type Friedel-Crafts cyclization approach; and (6) a versatile protocol for the intramolecular formation of functionalized pyrrolo[3,2,1-ij]quinolines.

Activated cyclopropanes have been extensively used in synthetic chemistry as precursors for cycloaddition reactions. The rationale behind this is their ability to undergo ring-opening when activated by a Lewis acid, this can be enhanced further by the presence of a carbocation stabilising group like electron-rich aromatics. The stabilised dipole formed after ring opening can be trapped with suitable electrophiles such as imines and aldehydes via a [3+2] cycloaddition reaction. This results in the synthesis of pyrrolidines and tetrahydrofurans in excellent yields but moderate diastereoselectivity. Similarly, 6-membered heterocycles can be formed via a [3+3] cycloaddition reaction of activated cyclopropanes with nitrones. Now to extend the scope of the methodology, a [3+3] dipolar cycloaddition has been developed using activated 2,3 disubstituted cyclopropane diesters to access a range of highly functionalised oxazines in moderate to good yields (50-75%) and with reasonable diastereoselectivity. The use of activated symmetrical disubstituted cyclopropanes afforded the desired oxazines in a regio- and diastereocontrolled manner, while the use of unsymmetrical cyclopropanes significantly reduced the diastereoselectivity of the reaction. The stereochemistry outcome of the reaction developed was determined by nOe analyses and X-ray diffraction structures could be recorded in some examples. A new methodology has also been developed to gain access to novel N-heterocyclic- and phenol- substituted cyclopropanes in one step from the corresponding cyclopropene via a conjugated addition.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Le présent mémoire a pour sujet le développement d’une méthode rapide et efficace vers la production d’allènes hautement substitués à partir de dérivés cyclopropaniques électrophiles énantioenrichis. L’avancement de méthodes synthétiques intéressantes pour la production asymétrique de ces dérivés de cyclopropane-1,1-diesters sera également présenté. Dans un premier temps, les différentes méthodes de synthèses des cyclopropanes activés seront abordées, ainsi que leur utilisation dans la préparation de molécules plus complexes. Par la suite, les techniques précédentes de préparation asymétrique des allènes seront introduites, démontrant ainsi la difficulté de leur accessibilité. Le développement d’une méthode fiable pour la synthèse de cyclopropane-1,1-diesters utilisant les ylures d’iodonium sera présenté. Finalement, l’accessibilité à plusieurs types d’allènes hautement substitués par l’utilisation de cuprates sera détaillée. Dans une seconde partie, il sera davantage question de l’accessibilité des cyclopropane-1,1-diesters énantioenrichis. Ces derniers sont d’un intérêt particulier, car ils constituent le point de départ de notre méthodologie précédente. Le développement d’une méthode pouvant être utilisée à grande échelle et à faible coût a donc été explorée. Les deux derniers chapitres présenteront donc les tentatives de générer ces cyclopropanes activés par résolution cinétique ou encore par l’hydrogénation asymétrique des cyclopropènes correspondants. / The subject of this present M.Sc. thesis is the developpement of an efficient and fast methodology toward the production of highly substituted allenes using enantioenriched cyclopropanes derivatives. The development of new synthetic methodologies in the production of these enantioenriched cyclopropan-1,1-diesters will be presented. First, the various methodologies for the preparation of activated cyclopropanes will be discussed along with their uses in the synthesis of more complex molecules. Then, the precedents in the field of asymmetric allenes synthesis will be introduced. The developpement of a viable method for the synthesis of cyclopropane-1,1-diesters using iodonium ylides will be presented. Finally, the accessibility of different highly substituted allenes by the used of cuprates will be detailed. In a second part, we will elaborate on the accessibility of the enantioenriched cyclopropane-1,1-diesters derivatives. These compounds are interesting, because they are used as starting materials in the previous methodology of allenes synthesis. This methodology has to be usable in large scale and at small cost. The last two chapters of this thesis will present the alternatives strategies for the preparation of these activated cyclopropanes by either kinetic resolution or the asymmetric hydrogenation of cyclopropenes.

Natural products and small molecules play a major role in drug development. However, using natural products as a source of medicine comes with many challenges, such as lack of natural abundance and difficulty in isolation. Consequently, synthetic organic chemistry is a solution in order to access these compounds in usable quantities. However, synthetic chemisty comes with its own challenges such as efficiency, chemoselectivity, stereoselectivity and enantioselectivity. Therefore, synthetic tools that addresses these challenges are required solve these limitations. This thesis discusses new methodologies using strained carbocycles (cyclopropanes and cyclopropenes) as the reactive subunit for the construction of different carbocyclic and heterocyclic compounds. The homo-Nazarov cyclization of alkenyl and heteroaryl cyclopropyl ketones was used in order to construct cyclohexenones, cyclohexenols, heteroaryl ring-fused cyclohexenones, dihydrofurans, furans and furanones in a mild and efficient manner. Benzofused heteroaromatic compounds were achieved via the Lewis acid-catalyzed cycloisomerization of cyclopropene-3,3-dicarbonyls and furan-3-carboxylates. These heteroaromatic compounds can be applied to medicinal chemistry and material science.