Free radical cyclization methodology has been used extensively in synthesis for manipulation of complex molecules such as alkaloids, terpenes, carbohydrates, peptides and nucleic acids. The methodology has emerged as a result of work by physical organic chemists who determined rate constants for the most common radical reactions used in organic synthesis. A novel route to cyclic imines based on 5-exo radical cyclization was explored. The radical precursors were imines prepared from allylamine and readily available a-phenylselenenyl ketones. The synthesis of conformationally constrained bicyclic nucleosides is also reported using 5-exo and 6-exo cyclizations of hexenyl and heptenyl radicals in thymidine nucleosides. The nucleosides were incorporated in a 15mer antisense oligonucleotide via solid-phase oligonucleotide synthesis. The AONs with the modifications were tested for target affinity and stability and compared with the well known LNA modified AONs. The thesis discusses the unique qualities of these novel molecules and presents them as potential candidates for antisense therapeutic agents. Keeping up with the theme of intramolecular carbon-carbon bond formation, microwave induced carbodechalcogenation of chalcogenoanhydrides was explored. Poor generality in these reactions made us turn to transition metal catalysis for Sonogashira cross-coupling reactions using alkyl aryl and diaryl tellurides as coupling partners.

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Radical chemistry is a crucial tool to organic chemists. Recent trends in the field have been directed towards the development of photocatalysts capable of generating a radical through a renewable source like sunlight using a single electron transfer mechanism. The use of Au2dppm2Cl2, having a stronger reducing potential, allows an expansion of the reactivity to those achieved by iridium and ruthenium catalysts.1 The focus of this thesis is axed on the development of Au2dppm2Cl2 as an efficient photoredox catalyst for a tandem one-pot catalysis and its application in a dual catalytic system. The use of Au2dppm2Cl2 in a dual catalysis for the synthesis of β-amino acids was undertaken. The problems encountered over the course of the investigation showed an insufficient oxidation potential of the photoredox catalyst in addition to the facile homolytic cleavage of the C-halogen bond under UV light. However, this shows great promise for the achievement of beta amino acids using solely organocatalysis. The development of a tandem one-pot radical cyclization for the synthesis of fused- carbocycles, which are frequently encountered scaffolds in diterpenoid natural products, is reported. The initial experiments were conducted on a model substrate, enabling the verification of the proposed hypothesis. The success of this methodology was then applied to various substrates affording the desired fused 5 membered rings in good yields. These reactions show tremendous potential in the field of total synthesis for the rapid access of complex molecular structures. (1) Revol, G.; McCallum, T.; Morin, M.; Gagosz, F.; Barriault, L. Angew. Chem. Int. Ed. 2013, 52, 13342.

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The development of the interrupted Nazarov cyclization of allenyl vinyl ketones is presented. The intermediate oxyallyl cation, derived from an allenyl vinyl ketone, may be trapped efficiently by a divergent array of nucleophilic species generating functionalized cyclopent-2-enone products. Allenyl vinyl ketones are also a versatile source of cyclic molecules via a tandem reaction sequence terminated via reaction with acyclic dienes, cyclic dienes, aza-heterocycles, electron-rich alkenes, or styrenes by the formation of an additional ring by a [4 + 3] and/or [3 + 2] cyclization or by the formation of one additional carbon-carbon bond. The bicyclic compounds generated by these processes are densely substituted, and would be difficult to access as succinctly in other ways. The products of these interrupted Nazarov reactions generally reflect excellent regio- and stereoselectivity in the trapping reaction. In some instances, equilibrating conditions were shown to enhance the proportion of one product at the expense of another or to provide a different carbon skeleton. This process appears fairly general, and can be conducted with unsubstituted or alkyl, aromatic, or heteroaromatic allenyl vinyl ketones. The exceptional affinity of allenyl vinyl ketones to undergo interrupted Nazarov reactions is likely a result of the increased longevity of the intermediate oxyallyl cation, due in part to the increased resonance stabilization provided by the allene unit. The high regioselectivity noted in the trapping process was computationally and experimentally confirmed to be a result of a localization of the positive charge in the intermediate oxyallyl cation. The application of this recently developed methodology towards the synthesis of the natural product (+)-roseadione is also described. The tandem Nazarov/[4 + 3] cascade of allenyl vinyl ketones provides a unique manner in which to access the tricyclic core of this cyclooctanoid natural product, a molecule which, to date, has never been synthesized.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. These compounds have interesting anticancer and anti-HIV properties as well as other biological activities making them highly attractive synthetic targets. We report a stereodivergent, asymmetric total synthesis of (−)-clusianone in six steps from commercial materials. We have implemented a challenging cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms. Mechanistic studies point to the unique ability of formic acid to mediate the cyclization forming the clusianone framework. We also present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via palladium-catalyzed dearomative conjunctive allylic alkylation (DCAA). These efficient palladium-catalyzed protocols construct the [3.3.1]-bicyclic PPAP core in a single step from their stable aromatic precursors. The first syntheses of 13,14-didehydroxyisogarcinol and garcimultiflorone A stereoisomers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastereoselective cationic oxycyclizations enabled asymmetric syntheses of (−)-6-epi-13,14-didehydroxyisogarcinol and (+)-30-epi-13,14-didehydroxyisogarcinol. A similar strategy enabled production of the meso-derived isomers (±)-6,30-epi-13,14-didehydroxyisogarcinol and (±)-6,30-epi-garcmultiflorone A. A convenient strategy for gram scale synthesis of these stereoisomers was developed utilizing diastereomer separation at a later stage in the synthesis that minimized the number of necessary synthetic operations to access all possible stereoisomers. Finally, we report cationic rearrangements of dearomatized acylphloroglucinols leading to the formation of unprecedented PPAP scaffolds. A novel type A [3.3.1]-bicyclic PPAP was produced as a major product and the structure confirmed by X-ray crystallographic analysis. A novel [3.3.1]-bicyclolactone was also produced utilizing an alternative substrate. Efforts will be described to determine the scope of these rearrangements and type A-selective cyclizations. / 2018-08-09T00:00:00Z

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No description available.

An iterative protocol is a highly efficient strategy for the generation of large, complex molecules that has been applied in many different subfields of organic synthesis. The use of a tandem or cascade reaction is also an effective approach for the rapid introduction of molecular complexity into a system since the number of steps requiring independent optimization is greatly reduced. With the aim of creating new synthetic strategies to efficiently gain access to stereochemically complex small molecules, we envisioned the use of short iterative protocols to prepare reactive oligomers to which a diverse range of cascade cyclization processes could be applied. In an attempt to minimize reaction optimization and chromatographic purification steps during the development of our small molecule precursors, we first developed an iterative synthesis based on a conjugate addition/reduction sequence that has allowed us to access a diverse series of oligo-vinyl ether intermediates. Significantly, both the addition and reduction steps proceed in near-quantitative yield, and reaction co-products can be removed without column chromatography. At the same time, most of our vinyl ether intermediates are stable to silica gel, and so analytically pure samples can be prepared when desired. Except for when very sterically demanding substrates are employed as electrophiles, the intermediates are isolated as single geometrical isomers. We also developed an improved synthesis of a previously intractable class of alkynoate starting materials (4-aryl-2-butynoates) to ensure a diverse range of easily accessible monomeric building blocks were available for our use. With this effective iterative route in hand, we have several interesting small molecule targets at our disposal. We first applied our iterative route to synthesize oxygen-containing analogues of juvenile hormone III. These mono- and bis-vinyl ethers are currently undergoing biological testing (in collaboration with Dr. Steve Perlman and Dr. Michael Horst), and early results show promise as ecologically degradable insect control agents. We also developed an unprecedented 6-endo/5-exo radical cascade reaction across bis-vinyl ethers which proceeds in good yield, high diastereoselectivity, and excellent regiochemical control. This reaction represents the first cascading radical cyclization ever reported for a bis-vinyl ether system and validates our iterative approach to molecular complexity. / Graduate

Les composés oxygénés de faible poids moléculaire présentent un fort intérêt en chimie des parfums. Un grand nombre d’odorants contiennent un ou plusieurs cycles au sein de leur structure. Ce travail de thèse est dédié au développement de nouvelles carbocyclisations intramoléculaires de dérivés d’éthers d’énol catalysées par des (super)acides de Lewis. L’étude s’intéresse à la réactivité bivalente des alcools (bis)allyliques portant une fonction alkoxy. Dans ce contexte, la réactivité de la fonction éther d’énol en présence d’un alcool allylique a été développée en présence d’acides de Lewis et de Brønsted comme catalyseurs. En l’occurrence, une chimiodivergence contrôlée par le substrat a été démontrée pour des précurseurs dérivés de différents types d’éthers d’énol. Ainsi, des cyclopenténones ont été formées par électrocyclisation catalysée par le triflate de bismuth(III). Ou alors, des cétones insaturées α-oxygénées ou soufrées ont été obtenues par activation préferentielle de l’éther d’énol en présence de l’acide ptoluènesulfonique. Une étude mécanistique a été effectuée mettant en avant la différence entre la catalyse par acides de Lewis et de Brønsted ainsi que l’influence de l’acidité du catalyseur. Il a été possible de contrôler la chimiodivergence par le catalyseur dans le cas des dérivés du phenyl vinyl sulfure. Deux produits différents ont été obtenus à partir d’un seul substrat de départ en utilisant des systèmes catalytiques robustes et peu onéreux. La plupart des nouveaux composés présentent des notes olfactives intéressantes. En outre, l’électrocyclisation catalysée par le triflate de bismuth a été appliquée à la synthèse de la rotundone, un odorant naturel à la note typique du poivre. / Oxygenated low molecular weight compounds are of particular interest in fragrance chemistry. A large number of odorants present one or more rings within their structure. This work is dedicated to the development of novel intramolecular carbocyclizations of enol ether derivatives catalyzed by Lewis (super)acids. The study turns around the dual reactivity of alkoxy-substituted bis(allylic) alcohols. In this context, the behavior of the enol ether function in the presence of an allylic alcohol has been elaborated under Lewis and Brønsted acid-catalysis. Hereby, a pronounced substrate-controlled chemodivergence as demonstrated for precursors derived from different types of enol ethers. Either, cyclopentenones were formed by electrocyclization under bismuthIII triflate catalysis, or a skeletal rearrangement after preferential activation of the enol ether in the presence of p-toluenesulfonic led to α-oxygenated or αsulfenylated unsaturated ketones. Mechanistic studies have been performed and the difference between Lewis and Brønsted acid-catalysis as well as the influence of the catalyst acidity have been highlighted. The chemodivergence could be tuned by the nature of the catalyst in the case of phenyl vinyl sulfide derivatives. Two different products were obtained from a single and easily accessible starting material using robust, air- and water-compatible catalytic systems. Most of the new compounds presented interesting olfactory notes. The developed bismuthIII triflate-catalyzed electrocyclization was further applied to the total synthesis of the natural pepper odorant rotundone.