For most of human history, precious metals such as gold, silver, and platinum were used as currency and jeweler. Beginning in the 20th century, with the onset of transition metal catalysis, chemists developed new methods to support industrial chemical synthesis. There are many notable examples, one is the Ziegler-Natta catalysts to perform olefin polymerization using titanium/aluminum-based systems. Another is the Fisher-Tropsch process to convert synthesis gas (CO/H2) into liquid hydrocarbons typically using cobalt, ruthenium, and iron. Also, the Haber-Bosch process where nitrogen and hydrogen gases are reacted in the presence of an iron catalyst to generate ammonia is a critically important process for the production of agricultural fertilizer worldwide. For precious transition metals such as gold, the first report of the metal being used in homogenous catalysis was in 1986. In this thesis, the application of gold homogenous into the synthesis of polycyclic carbocycles is being reported. This method was designed as a three-step one-pot sequence where an initial Diels-Alder reaction forms the first carbocycle with an embedded silyl enol ether moiety reactive to homogenous gold(I) catalysis. By selecting specific catalyst ligand and solvent conditions, selectivity between tri or steroid-like tetracycles was achieved via gold then Prins cyclizations or gold then Diels-Alder cyclizations. A combined total of 31 examples across 3 scopes was demonstrated using this divergent and modular strategy. This methodology aims to be applied in medicinal chemistry research in the synthesis of libraries of structurally related compounds baring resemblance to bioactive natural products. A related synthetic strategy was also used by our group in the total synthesis of salvinorin A. Initially isolated from Salvia divinorum in 1972, salvinorin A is trans neo-clerodane diterpene and was found to be a selective agonist of the kappa opioid receptor (κOR). This is unique compared to traditional morphine type opioids which are substrates of mu (μOR) and delta (δOR) opioid receptors. And as such, extensive work in medicinal chemistry has been published on utilizing salvinorin A as starting point towards the development of new analgesics. Our approach to synthesize salvinorin A centered around using a Diels-Alder reaction then gold cyclization to form the AB rings. The remaining C ring was formed via gold photoredox catalyzed radical cyclization, 1,2-addition of a furanyl organotitanium, and palladium catalyzed carbonylation. The formal synthesis of salvinorin A was completed in 21 steps by intercepting an intermediate in Hagiwara’s reported synthesis, and addition 3 steps would complete the total synthesis.

This thesis details the studies towards the total synthesis of the calyciphylline A-type Daphniphyllum alkaloids, with a particular focus on daphniyunnine D (23). Chapter 1 introduces these biologically and synthetically interesting polycyclic natural products and describes our designed approach towards their synthesis. Separate studies targeting the construction of two tricyclic ring systems have been developed. These provide rapid entry to synthetically versatile intermediates, allowing for the potential synthesis of numerous members of the alkaloid family. Chapter 2 describes the first study which focuses on the construction of the main tricyclic [6‒5‒7] ACD core 172 via a proton transfer/IMDAF reaction cascade as the main step. Large scale synthesis of the precursor to this cascade 164 has allowed for the successful investigation of an asymmetric variant giving rise to an enantioenriched adduct 104. Chapter 3 describes a novel design for the construction of the [7‒5‒5] DEF tricycle common to 100+ Daphniphyllum alkaloids. An IMPKR, double-bond migration, allylic oxygenation protocol was first validated on a model system and later applied in combination with the synthetic route developed in chapter 2 to achieve the construction of the [6‒5‒7‒5‒5] ACDEF pentacycle 249. Chapter 4 focuses on the construction of the piperidine ring B via an intramolecular gold-catalysed 6-exo-trig hydroalkylation. During the development of the route to daphniyunnine D, various intermediates were afforded which were further elaborated to provide appropriate cyclisation substrates for this study. Their synthesis combined with proof of principle experiments for the desired cyclisation conclude this dissertation work.

This thesis focuses upon pacidamycin, a member of the uridyl peptide antibiotics, a family of antibiotics which exhibit an, as yet, clinically unexploited mode of action, against MraY. The Goss group has previously demonstrated the ease of accessing N and C-termini analogues of pacidamycin utilizing precursor directed biosynthesis. The central diamino acid is key to pacidamycin's activity, yet little work has been carried out, to date, to investigate the SAR around this moiety. Particularly this thesis describes work toward generating pacidamycin analogues using the complementary tools of organic synthesis and biosynthesis. Chapter 1 introduces natural compounds and their importance in clinical use, provides a brief overview of the history of antibiotics and focuses on the urgent need for new antibiotics displaying new chemical architectures and possessing novel modes of action. This chapter also introduces uridyl peptide antibiotics and overviews the SAR studies around these unusual peptides, focusing on pacidamycin in particular. Diaminobutyric acid is central to these structures and a discussion of a selection of published methods to synthesis α, β-diaminobutyric acid (DABA) is also presented. Chapter 2 describes the synthesis of DABA and two analogues, in which the C-methyl moiety has been substituted by an ethyl or a cyclopropyl group. The mutasynthesis approach utilised in the attempt to generate novel pacidamycins and discussion around the results observes is also described. Chapter 3 demonstrates a three step one-pot reaction to access 1,3-disubstituted urea molecules. The chapter starts with a brief overview of previously established methods in the literature to access these useful molecules, and then moves towards a discussion about the reaction optimisation. The chapter also describes a family of analogues generated utilising this novel approach; and exploring the use of these analogues in the mutasynthesis of pacidamycin. In order to access the desired pacidamycin analogues with the modified diamino acid residue, it was determined that it is currently not possible to use a mutasynthesis approach, instead an approach of total synthesis needed to be employed. Chapter 4 describes this total synthesis. The C- terminal urea motif was generated using a novel 1-pot phosphine free route developed during this study. To access the central native (2S, 3S)- DABA, a variation of the route of Merino et al's via Garner's aldehyde was initially utilised. Subsequently, a shorter and more flexible approach from Soloshonok et al via a Ni (II) Schiff base complex of glycine was adopted. Unpublished results from the Goss group have shown that the 2',3'dihydroxy uridine analogues in pacidamycin conferred broader spectra of activity. Work towards the synthesis of these analogues has been conducted. The order of assembly of the peptide and the nucleoside fragments was in alignment with Boojamra et al's approach. If the de-protection chemistry had worked according to plan, this would have resulted with a synthesis that is at least 6 steps shorter and higher yielding then Boojamra's. The introduction in this chapter reports the various methods previously reported in the literature for the total synthesis of pacidamycin. A discussion about the current progress in the total synthesis highlighting the difficulties faced is also shown. Chapter 5 demonstrates utilising semi-synthesis as a useful tool to generate novel pacidamycins by applying a Pictet-Spengler reaction on pacidamycin 4. This chapter starts with an overview of this phosphate mediated Pictet-Spengler reaction. In addition, a discussion about the large-scale fermentation of Streptomyces coeruleorubidus, the wild type producer of pacidamycin, and the generation of pacidamycin analogues utilising a semi-synthesis approach is also presented. Chapter 6 describes the future work following on from this study building upon each of the above chapters.

Muamvatin (30) is a polypropionate natural product isolated from Siphonaria normalis by Ireland et al. in 1986. Muamvatin (30) is made from eight propionate units and contains an extraordinary trioxaadamantane ring system. This ring system exists in only one other naturally occurring polypropionate known as caloundrin B. Regarding the rare muamvatin trioxaadamantane ring system, it was hypothesized this ring system may not be formed via an enzymatic process and the actual natural product could be the linear precursor ent-71 which cyclizes to muamvatin (30) during isolation. The first total synthesis of muamvatin (30) by Paterson et al. confirmed its absolute and relative configuration, but the ambiguity regarding the origin of the trioxaadamantane ring system in this molecule remains unresolved. This work describes two approaches to make the linear precursor ent-71 from triol ketone 153. The carbon skeleton of muamvatin was synthesized through two iterative diastereoselective aldol reactions. In the first approach, “the thiopyran route”, the diene moiety of aldehyde 73 required protection to avoid reduction during desulfurization. Although use of the tircarbonyliron complex was successful, the trihydroxy ketone revealed upon desulfurization was unstable and spontaneously cyclized to bicyclic acetal 156. Molecular mechanics revealed that the relative configurations embedded in C3, C7, and C8 dramatically effected the stability of the corresponding bicyclic acetal. With that lesson learned, the fully assembled linear precursor 197 was made in our second approach “the acyclic route”. The oxidation state of the backbone oxygens were manipulated via an unusual chemoselective double Swern oxidation. Finally, revealing the sensitive 5-hydroxy-3,7,9-trione functionality formed the precursor 202. Efficient cyclization of precursor 202 and removal of the protecting group at C11-OH produced the desired natural product 30. The cyclization conditions tested on the linear precursor 202, suggested that although the cyclization to the trioxaadamantane is strongly favored thermodynamically, the process is very slow and unlikely to occur during the isolation process. Thus, formation of the trioxaadamantane ring system could be an enzyme-mediated process as was concluded for caloundrin B.

Intramolecular hydroamination represents a potentially general, simple strategy to access various nitrogen heterocycles. While important progress has been accomplished in recent years, six-membered ring formation via alkene hydroamination is typically difficult and limited to terminal alkenes, suggesting that only 2-methylpiperidines can be accessed reliably with current methods. As part of the Beauchemin group efforts on metal-free concerted hydroamination methods, the first part of this thesis describes the development of a Cope-type hydroamination-Meisenheimer rearrangement (CHMR) sequence that is applicable in inter- and intramolecular reactions. Data acquired from optimization on a difficult substrate (coniine) and the successful application of the CHMR sequence to the syntheses of N-norreticuline and 10-desbromoarborescidine are reported. The amination of alkenes is surprisingly scarcely used in the synthesis of complex alkaloids despite its potential for the construction of structurally challenging molecules while avoiding functional group interconversions. Hence, the second part of this thesis describes the studies on a novel amination sequence, consisting of an intermolecular Diels-Alder followed by an intramolecular hydroamination reaction, in the efforts towards the synthesis of biologically active and structurally complex Manzamine A. As such, the synthesis of the model substrates, including the development of a novel family of aminodienes, as well as the assessment of their reactivity towards [4+2] cycloadditions is reported.

This thesis describes the development of synthetic strategies towards the densely functionalised pyrrolidinone core of the polyene &beta;-lactone-&gamma;-lactam antibiotic oxazolomycin A. <strong>Chapter 1 The oxazolomycins</strong> The oxazolomycins, a unique class of biologically active molecules containing a spiro-fused β-lactone-γ-lactam ring system are introduced. The isolation, structural elucidation and biological properties of the oxazolomycins as well as those of the structurally related inthomycins are reviewed. <strong>Chapter 2 Previous syntheses</strong> The two total syntheses of neooxazolomycin and the synthetic approaches to the pyrrolidinone core of oxazolomycin A and KSM-2690 B are evaluated. <strong>Chapter 3 Project aims</strong> An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the pyrrolidinone core of oxazolomycin A are discussed. <strong>Chapter 4 Synthetic studies towards the pyrrolidinone core of oxazolomycin A</strong> The synthetic studies carried out towards the pyrrolidinone core of oxazolomycin A are described in detail. The preparation of an advanced intermediate containing the five chiral centres, four of which are contiguous, was achieved in twenty steps as a single diastereomer and as a single enantiomer. <strong>Chapter 5 Synthetic studies towards the middle fragment of oxazolomycin A</strong> A novel synthetic approach to the diene fragment contained in oxazolomycin A is reported. The formal synthesis of a dienyl iodide, in four fewer steps than previously reported was accomplished. <strong>Chapter 6 Conclusions and future work</strong> A summary of the synthetic work reported in this thesis and proposals for future study are presented. <strong>Chapter 7 Experimental</strong> Full experimental procedures and characterisation of compounds are reported. <strong>Chapter 8 References</strong> A complete list of citations employed in the previous seven chapters is provided.

This thesis firstly describes a synthesis of the natural product taurospongin A, a potent DNA polymerase beta inhibitor. Sharpless asymmetric dihydroxylation on olefin <b>E-1.60</b> followed by selective deoxygenation at C(2) via Barton‒McCombie reaction delivers the desired C(1)–C(10) carboxylic acid core. Subsequent esterification of the C(1)–C(10) fragment with C(1′)–C(25′) fatty acid furnishes the natural product in 13.5% yield. The structure of an unnamed natural product <b>2.14</b> isolated in 1974 is proven to be misassigned by previous studies within the Robertson group. As described in this thesis, two proposed structures A and B are obtained via total synthesis in order to reveal the identity of the natural product. A synthesis of key intermediate spirocycles <b>2.148</b> and <b>2.158</b> with desired trans- diol moiety is described by a dihydroxylation reaction on an electron deficient gamma-keto unsaturated acid with subsequent spirocyclisation reaction. Finally, methodology for generating high-value synthetic intermediates by an asymmetric, one-pot enzymatic di/polycarbonyl reduction is described. The concept of such methodology is first proven by the synthesis of (3R)-hydroxybutyl (3R)-hydroxybutanoate <b>3.20</b>. This thesis then describes substrate scope studies and corresponding stereochemical proof to provide more information about this methodology.

La formation de liaisons C-C constitue un sujet de recherche primordial en chimie organique. Parmitoutes les techniques existantes, la métathèse d’oléfines a constitué une véritable révolution, notamment grâceau développement de catalyseurs efficaces et tolérants vis-à-vis de bon nombre de groupements fonctionnels.Cette réaction a été envisagée ici sur trois cibles d’intérêt biologique : la diospongine A, la nhatrangine A et leberkeleyamide A.De nombreuses molécules naturelles bioactives appartiennent aux familles des 1,7-diarylheptanoïdes et1,9-diarylnonanoïdes. Issue de la première, la diospongine A a dévoilé des propriétés anti-ostéoporotiquesprometteuses. A l’inverse, aucun produit naturel 1,8-diaryloctanoïde n’a encore été rapporté. Désireux d’étudier lapotentielle activité de tels composés, plusieurs séries d’homologues de la diospongine A ont été synthétisées,impliquant la formation d’intermédiaires tétrahydropyraniques communs par cyclisation de Prins, suivi d’uneséquence métathèse croisée / oxydation de Wacker, permettant ainsi l’introduction de la diversité chimique.La nhatrangine A, récemment isolée de la cyanobactérie Lyngbya majuscula, a montré une potentielleactivité contre la lignée cancéreuse CoL-2. Aucune synthèse n’ayant encore été rapportée, quatre déconnectionsont ici été envisagées, impliquant respectivement une métathèse cyclisante, une métathèse croisée, une additionde Michael énantiosélective organocatalysée ou encore une alkylation diastéréosélective selon Myers commeétape clé. Toutes ces approches ont en commun l’utilisation d’une réaction de trans aldolisation. Un intermédiaireavancé a ainsi pu être synthétisé.Le berkeleyamide A, isolé du champignon Penicillium rubrum, est une molécule possédant une activitéinhibitrice micromolaire des enzymes MMP-3 et caspases-1, impliquées notamment dans la croissance descellules cancéreuses. Trois synthèses de ce composé sont déjà décrites dans la littérature, toutes démarrant dupool chiral. Deux approches « rétron » sont ici proposées, impliquant notamment une allylation diastéréosélectived’imine, une métathèse croisée et une cyclisation de type Heck. Le squelette carboné de la molécule a ainsi étéobtenu. / C-C bond formation constitutes a key research field of organic chemistry. Among all existing techniques, olefinmetathesis turned out to be a revolution, especially since efficient and functional groups tolerant catalysts havebeen developed. Herein, the application of this reaction has been considered to three targets of biological interest:diospongin A, nhatrangin A and berkeleyamide A.Numerous bioactive natural products belong to 1,7-diarylheptanoïd or 1,9-diarylnonanoïd families.Springing from the first one, diospongin A revealed promising anti-osteoporotic properties. Conversely, no naturalproduct from 1,8-diaryloctanoïds has been reported to date. Willing to study the potential activity of suchcompounds, several diospongin A homologues series have been synthesized, involving especially a Prinscyclisation for the formation of a common tetrahydropyran scaffold, followed by a cross metathesis / Wackeroxidation sequence, for the introduction of the chemical diversity.Nhatrangin A, recently isolated from the cyanobacteria Lyngbya majuscula, has showed a potentialactivity against the CoL-2 human cancer cell line. As no total synthesis of this molecule has been reported todate, four disconnections have been considered herein, respectively involving a ring closing metathesis, a crossmetathesis, an enantioselective organocatalysed Michael addition or a Myers diastereoselective alkylation as keystep. All these approaches have in common the use of a trans aldol reaction. An advanced intermediate has thusbeen obtained.Berkeleyamide A, isolated from the fungus Penicillium rubrum, possess a micromolar inhibitive activitytoward MMP-3 and caspases-1 enzymes, taking part in particular in cancer cells growth. Three total synthesis ofthis molecule have already been reported, all sharing to start from the chiral pool. Two “retron” approaches havebeen considered herein, involving especially an imine diastereoselective allylation, a cross metathesis and a Hecktype cyclisation. This led to the obtaining of the carbon backbone of the molecule.

Relatos sobre a toxicidade da fruta carambola (Averrhoa carambola) em pacientes com disfunção renal, com alguns desses pacientes chegando ao óbito, foram atribuídos a uma toxina denominada caramboxina, um aminoácido não peptídico derivado da fenilalanina, recentemente isolada por pesquisadores da Universidade de São Paulo. Com isso, este estudo foi planejado com o objetivo principal de investigar estratégias de síntese que permitiriam a síntese total da toxina. A partir do desenvolvimento inicial de uma rota sintética que empregou um aril-triflato para uma reação de acoplamento cruzado de Heck e a olefina acrilaldeído, que não se mostrou efetiva, outras rotas sintéticas foram planejadas empregando uma olefina derivada do aminoácido serina ou fazendo uso de produtos sintetizados durante o estudo, através de reações que conduzissem à molécula alvo. Apesar dos resultados negativos obtidos, a variação de estratégias permitiu maior compreensão acerca da síntese, além de contribuir para o estudo de diferentes metodologias. Entretanto, uma rota que fez uso da reação de acoplamento cruzado de Negishi com composto organozinco oriundo da serina como etapa chave, foi capaz de levar à síntese total da caramboxina, permitindo inclusive obter o produto assimétrico, conforme observado em análises de quantificação de enantiômeros. Com bons rendimentos na obtenção dos blocos de construção e na etapa chave de acoplamento, a rota exigiu dez etapas, desde os materiais de partida até a desproteção total, apresentando 33% de rendimento global, com boa reprodutibilidade e escalabilidade. Assim, com a obtenção da caramboxina sintética poderão ser respondidas várias lacunas, tanto em nível molecular (mecanismo de ação), quanto sobre seu possível metabolismo e farmacocinética / Reports on the toxicity of star fruit (Averrhoa Carambola) in patients with renal dysfunction, with some of them coming to death, were attributed to a toxin named caramboxin, a non-peptidic amino acid derived from phenylalanine, recently isolated by researchers from the University of São Paulo. Thus, this study was designed with the main objective of investigate strategies that would allow the total synthesis of the toxin. Starting from the initial development of a synthetic route that used an aryl-triflate for a cross coupling reaction of Heck with the olefin acrylaldehyde, which did not show effectiveness, other routes were planned using an olefin derived of the serine amino acid or making use of synthetized products obtained through the study, employing reactions that would lead to the target molecule. Despite the negative results, the variation of strategies allowed greater comprehension of the synthesis contributing to the study of different methodologies. However, a route that used the cross-coupling reaction of Negishi with an organozinc compound derived of serine as key step, led to the total synthesis of caramboxin including the obtention of the asymmetric product, as observed in enantiomers quantification analysis. With good yields for the building blocks and the cross-coupling key step the route required ten steps, from the starting materials to the total deprotection, exhibiting 33% of overall yield with good reproducibility and scalability. Thus, with the obtainment of synthetic caramboxin, will be possible to answer different gaps, both at the molecular level (mechanism of action) as well as on its possible metabolism and pharmacokinetics

Thesis advisor: Marc L. Snapper / Cyclobutadiene cycloadditions provide rapid access to rigid polycyclic systems with high strain energy and unusual molecular geometries. Further functionalization of these systems allows entry into unexplored chemical space. A tricarbonylcyclobutadiene iron complex on solid support enables exploration of these cycloadditions in a parallel format amenable to diversity oriented synthesis. Modeling of the cycloaddition transition states with density functional calculations provides a theoretical basis for analysis of the regioselectivity observed in generation of these substituted bicyclo[2.2.0]hexene derivatives. The high strain energy accessible in cyclobutadiene cycloadducts and their derivatives renders them useful synthons for access to medium-ring natural products through ring expansion. Torilin, a guaiane sesquiterpene isolated from extracts of the fruits of <italic>Torilis japonica</italic>, exhibits a range of biological activities including testosterone 5&alpha;-reductase inhibition, hKv1.5 channel blocking, hepatoprotective, anti-inflammatory and anti-cancer effects. These activities are reviewed and analyzed from the perspective of a common biochemical target. Tandem oxidation and acid-catalyzed rearrangement of a highly strained tetracyclo[5.3.0.0<super>1,5</super>.0<super>2,4</super>]decane in the presence of tetrapropylammonium perruthenate provides the bicyclo[5.3.0]decane core of this natural product with complete control of relevant stereochemistry. The complex precursor required for this rearrangement is rapidly accessed by cyclopropanation of an intramolecular cyclobutadiene cycloadduct. Synthetic studies are reported which provide preliminary access to 8-deoxytorilolone. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.