The pyrrole-imidazole alkaloid family of natural products illustrates the diversity of topographically unique molecules with potent biological activities that can be found in the marine environment. Thus, great interest for this class of compounds has developed leading to new synthetic methodologies and tactics to build these complex secondary metabolites. The overall objectives of this research project include the total synthesis of the phakellins and phakellstatins. First, we revisited the strategy developed in our group for the total synthesis of (+)-dibromophakellstatin and utilized it for the synthesis of its naturally occurring enantiomer and congeners. Second, we proposed and studied a new and more concise approach to the phakellstatins and phakellins based on a key C-H insertion process developed by Du Bois. Attempts to streamline the first synthesis of (+)-dibromophakellstatin proved to be quite challenging. Shortcomings in the reproducibility of some parts of the original strategy precluded us from completing and making more efficient the synthesis of the natural enantiomer (-)-dibromophakellstatin. Fortuitously, our second generation approach though it presented itself as an efficient route to the phakellins and phakellstatins produced the undesired anti diastereomer of the key guanidine intermediate which precluded our study of the pivotal C-H insertion reaction.

The products of vanadium metal atom reactions with propene and some propene isotopomers (propene-d6 and propene-3,3,3-d3) are investigated using FT-IR matrix isolation. The major product from the condensation of V atoms with propene at elevated mole ratios is found to be propane (C3H8), the production of which is seen to increase as concentration of propene increases. Additionally a matrix isolated product formed after metal atom insertion into the C-H bond of propene at low propene mole ratios is isolated and identified. The location of the insertion site is identified as one of the methyl hydrogen carbon bonds. The structure of the product is identified as an allyl vanadium hydride complex, through a FT-IR matrix isolation study of propene isotopomers. It is also shown that this primary product acts as an intermediate in the formation of propane. A full mechanism for the proposed formation of propane from sacrificial hydrogenation is proposed and compared with the reported mechanism for the similar reaction involving ethene. The mechanistic identification of the hydrogenation of propene is shown as a generalization of the previous reaction involving ethene. Photochemistry of reactants and intermediates trapped in the matrix are investigated. Irradiation of matrices with several different UV-visible wavelength ranges indicate that no further chemistry occurs after formation of the matrix and further irradiation has no effect on intermediates or reactants. Additionally the reactivity of water with vanadium and propene under low propene concentration conditions is also studied. Results from this study show that under all conditions studied no incorporation of water into the propene molecule is found. / Thesis (Master, Chemistry) -- Queen's University, 2009-08-10 11:15:55.312

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Many commercialized medicinal compounds are analogs of chemicals isolated from sources found in nature (also called natural products). However, the natural sources of these chemicals, such as plants, fungi, or insects, only offer small quantities of these bioactive agents. Thus, it is typically desirable to find ways to synthesize these products and their analogs in large quantities using cost-effective methods that also minimize the impact on the environment. It is also important to develop strategies that expedite the process of modifying the natural products, which allows medicinal chemists to determine which functional groups are enhancing or deleterious to the bioactivity. In the Brewer lab, I have investigated organic reactions and methodologies with this aim - to find ways to efficiently break and form carbon-carbon bonds, and to utilize these reactions in the total synthesis of structurally related natural products. The total synthesis of natural products is often used to showcase a methodology's utility by applying it in a more complex structure. The Lewis acid-promoted fragmentation of γ-silyloxy-β-hydroxy-α-diazo esters to provide tethered aldehyde ynoates was discovered and developed in the Brewer lab. This methodology was extended to bicyclic systems, in which the ring-fusion bond fragmented as a way to afford 10-membered ring ynones and ynolides, which are traditionally challenging to synthesize. This work will exhibit how the fragmentation reaction that provided 10-membered ynolides has the potential to lend itself to the synthesis of several structurally related, bioactive natural products via a divergent total synthesis strategy. In addition, this dissertation will describe our discovery that modifying the diazo carbonyl precursor to a β-hydroxy-α-diazo ketone changes the course of the Lewis acid-promoted reaction. Rather than a fragmentation sequence, the compound is converted to a vinyl cation, which undergoes a rearrangement then a C-H insertion of a second vinyl cation intermediate. This transition metal-free rearrangement/C-H insertion reaction provided cyclopentenone products. The migratory aptitudes of non-equivalent substituents in the cationic rearrangement step will also be discussed. Finally, the disparate reactivities of vinyl cations derived from diazo ketone, diazo ester, and diazo amide precursors will be detailed from an experimental and computational perspective. The results underscore the fact that this rearrangement and C-H insertion reaction may eventually be an effective way to prepare complex cyclopentyl-containing structures, which are common motifs in biologically active natural products.

(-)-Kainic acid and its C-4 epimer, (+)-allokainic acid are parent members of a class of substituted pyrrolidines known as kainoids. They have been found to exhibit powerful biological properties, principally neuroexcitatory. Kainic acid has become especially important in the study of Alzheimer's disease, epilepsy, and other neurological disorders. The total syntheses of (-)-kainic acid and (+)-allokainic acid were achieved using (L)-glutamic acid as the starting material and the sole source of stereochemical induction. The key steps for these successful syntheses involve formation of the gamma-lactam core via rhodium (II) catalyzed intramolecular C-H insertion of the alpha-diazo-alpha-(phenylsulfonyl)acetamide intermediate and the stereoselective dephenylsufonylation. Pd(II)-catalyzed and oxygen promoted carbon-carbon bond formation methodologies using organoboronic reagents were developed. The first one is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles.This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. The second one is the formation of symmetric biaryls and dienes via oxidative dimerization of aryl and alkenyl boronic acids. These conditions utilized Pd(II) catalysts under an oxygen atmosphere with water as the solvent. The use of phase transfer catalysts promoted efficient and mild syntheses of a wide range of materials.

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.

Les alcaloïdes sont parmi les molécules naturelles les plus intéressantes pour leurs propriétés biologiques et médicinales. Parmi ceux-ci, les amaryllidacés et notamment la clivonine et ses analogues présentent de nombreuses propriétés peu étudiées et la synthèse de molécules de cette famille permettra des avancées dans ces études. Notre équipe s’intéresse particulièrement à cette molécule car sa synthèse pourrait se faire à partir d’une réaction de nitroso Diels-Alder énantiosélective qui est un sujet majeur de recherche dans notre laboratoire. Dans la suite de la synthèse, une deuxième étape clé doit faire intervenir une insertion C-H intramoléculaire. La réaction de nitroso Diels-Alder a été réalisée avec un excès énantiomérique de 96% et la synthèse a été poursuivie pour accéder à l’intermédiaire diazo clé, substrat de départ de l’insertion C-H. Cette dernière réaction n’a pas permis d’obtenir les produits escomptés en utilisant des catalyseurs commerciaux et une collaboration a été entamée avec le Pr Huw Davies pour pouvoir utiliser des catalyseurs plus élaborés. Les résultats de cette collaboration ne sont pas encore définitifs. Parallèlement, trois autres voies de synthèse de la clivonine ont été conçues et expérimentées, des variations de la synthèse originale, mais aucune n’a abouti. En revanche, une de ces synthèses nous a permis de découvrir une réactivité nouvelle des cycloadduits de nitroso Diels-Alder : en présence d’organolithiens, une réaction de β-fragmentation a lieu, suivie d’une addition, qui permet d’obtenir des composés monocycliques très fonctionnalisés avec une très bonne stéréosélectivité. Cette réaction et son étendue doivent encore être étudiées mais pourraient avoir des applications en synthèse totale. / Alkaloids are among the most interesting natural compounds because of their biological and medicinal properties. Among them amaryllidaceae alkaloids and especially clivonine and its analogues bear many under-studied properties and the synthesis of members of this family should allow more advances in this field. Our team is particularly interested in this target since its synthesis could be achieved starting from an enantioselective nitroso Diels-Alder reaction which is a major research topic of our group. Later in the synthesis a second key step would involve an intramolecular C-H insertion. The nitroso Diels-Alder reaction was performed with an enantiomeric excess of 96% and the synthesis was continued to access the key diazo intermediate, starting material for the C-H insertion step. This last reaction did not allow to access the desired products using commercially available catalysts and a collaboration was started with Pr Huw Davies in order to use more advanced catalysts. The final results of this collaboration are not available yet. Meanwhile three other synthetic routes for clivonine were designed and investigated as variants of the original strategy but none of them allowed access to clivonine. However one of those syntheses led to the discovery of a new reactivity of nitroso Diels-Alder cycloadducts: when exposed to organolithium reagents, a β-fragmentation occurs followed by an addition leading to highly fonctionnalized monocyclic products with high diastereoselectivity. This reaction and its scope need to be investigated further but may have applications in total synthesis.

Ce manuscrit expose différents développements méthodolgiques et leurs applications pour la synthèse de composés à visée anticancéreuse.Le premier chapitre décrit les travaux ciblant l’obtention d’analogues du TMC-95A, produit naturel inhibiteur du protéasome dont l’activité antitumorale a été démontrée. La formation de ces analogues passe par la synthèse d’intermédiaires tryptophanes hautement oxydés fonctionnalisés en position 7. Une première stratégie mettant en jeu une réaction d’insertion C-H nous a permis d’obtenir des oxindoles fluorés avec de bons rendements. Cependant, les difficultés rencontrées lors des étapes de déprotection et de réduction nous ont amenés à revoir notre approche synthétique. Une hétéroannulation de Larock a ensuite été envisagée pour la synthèse de tryptophanes fonctionnalisés, sans plus de succès. En revanche, nous avons été capables de mettre au point une réaction de fluoration oxydante régio- et chimiosélective du noyau indolique du tryptophane incorporé dans des tripeptides linéaires. Ainsi, des précurseurs avancés d’analogues du TMC-95A ont pu être obtenus.Dans un deuxième chapitre, nous nous sommes intéressés à la réactivité d’aziridines bicycliques dérivées de sulfamates, obtenues par aziridination intramoléculaire catalysée au cuivre en présence de réactifs de l’iode hypervalent. Nous avons ainsi pu montrer qu’il était possible d’en réaliser l’ouverture à l’aide de nucléophiles carbonés. Puis, les sulfamates cycliques à 7 chaînons obtenus peuvent également réagir avec des nucléophiles carbonés pour conduire à des amines polysubstituées. Enfin, des études préliminaires nous ont permis d’évaluer ces aziridines bicycliques comme précurseurs de dipoles-1,3 et ont conduit à la formation de composés à haute valeur ajoutée.Enfin, le dernier chapitre de ce manuscrit décrit les résultats obtenus pour la synthèse totale de produits naturels. Grâce à la méthodologie développée précédemment, nous avons pu synthétiser la spisulosine ES-285, produit naturel issu des palourdes comestibles de l’océan atlantique nord et dont l’activité antitumorale a été démontrée. La voie de synthèse mise au point permet de moduler la nature des nucléophiles introduits, permettant donc un accès rapide à de nouveaux composés, potentiellement plus actifs. Un analogue fluoré original de la spisulosine a ainsi pu être obtenu. Cette méthodologie a également été mise en œuvre pour la synthèse de molécules plus complexes, comme la monanchorine, un alcaloïde à guanidine polycyclique d’origine marine. Un précurseur avancé a ainsi pu être obtenu, mais il n’a malheureusement pas été possible de conclure la synthèse. / This manuscript exposes several synthetics methods and their applications for the preparation of new anti-cancer compounds.The first part describes our efforts toward the obtention of new analogs of TMC-95A, natural proteasome inhibitor, which antitumoral activity has already been shown. The formation of these compounds requires the synthesis of highly oxidized tryptophane substituted in position 7. An initial strategy involving a C-H insertion allowed us to obtain fluoro oxindoles in good yields. However, the encountered difficulties for the reduction and deprotection steps prompted us to rethink our strategy. A Larock heteroannulation has been considered for the synthesis of functionalized tryptophanes and was, unfortunately, unsuccessful. Nevertheless, we have been able to develop a regio- and chemoselctive oxidative fluoration of the trypthophane indolic core incorporated in tripeptides. Therefore, advanced precursors of TMC-95A analogs have been obtained.In the second part, the reactivity of bicyclic aziridines derived from sulfamates has been studied. These aziridines were obtained by copper catalyzed intramolecular aziridination in the presence of hypervalent iodine reagent. We were then able to demonstrate the possibility to perform nucleophilic ring opening of these bicyclic aziridines with carbon nucleophiles. The obtained 7 membered ring sulfamates were also submitted to nucleophilic ring opening with carbon nucleophiles to give acces to polysubstituted amines. Finally, preliminary studies allowed us to test these bicyclic aziridines as dipole-1,3 precursors and have led to the the formation of high value compounds.Finally, the last chapter describes the results we obtained for the total synthesis of natural products. Thanks to the methodology developed above, we were able to synthesize the spisulosine ES-285, natural product extracted from the north Atlantic clams and known to display antitumoral activity. The synthetic path allows us to change the nature of the nucleophile and gives rapidly access to new compounds, potentially more active. A new fluoro analog of the spisulosine has been obtained. This methodology has also been applied for the total synthesis more complex molecules, such as monachorin, a marine polycyclic guanidine alcaloïd. An advanced precursor has been synthesized, but we unfortunately weren’t able to finish the synthesis.

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).