This thesis describes investigations directed towards developing a novel synthetic route to the natural products perophoramidine and the communesins, with particular emphasis placed on the formation of the two vicinal all-carbon quaternary centres contained in these molecules. Chapter 1 introduces perophoramidine and the communesin group of natural products and explains how they are related to the calycanthaceous alkaloids. The isolation of perophoramidine and the communesins is outlined and their biosynthesis is discussed. Specific structural features of these natural products are highlighted before established synthetic strategies are reviewed. Chapter 1 concludes by proposing a novel synthetic route for the synthesis of perophoramidine and the communesins that involves a Claisen rearrangement in the indolo[2,3-b]quinoline system as a key step. Chapter 2 describes model studies on the proposed Claisen rearrangement in an attempt to form a quaternary centre in the indolo[2,3-b]quinoline system. These initial studies did not result in the generation of the desired quaternary centre. However, a detailed understanding of the reactions that occur leads to the design of a new model substrate. Chapter 3 describes studies on the revised model system that result in the formation of the desired quaternary centre using a Claisen rearrangement. The differences between the two systems are discussed before an investigation into the scope of the rearrangement is described. Chapter 3 concludes by describing an investigation into a protecting group strategy that would by required with this synthetic route. Chapter 4 describes investigations into the formation of the second vicinal quaternary centre using a model system. The synthetic routes investigated lead to two separate methods for the formation of the desired quaternary centre. Chapter 5 describes investigations into the effect a C-10 substituent has on the Claisen rearrangement. Additionally, an asymmetric version of the Claisen rearrangement is examined. Chapter 5 culminates in the preparation of an intermediate relevant to an asymmetric synthesis of the communesins.

O presente trabalho divide-se em três capítulos: Capítulo I - Nova síntese de ?-xiloidona: rearranjo de Claisen em hidroxinaftoquinonas; Capítulo II - Síntese e estudo de reatividade de promissores núcleos heteroaromáticos subexplorados pela química medicinal; Capítulo III - Análise computacional de similaridade e propriedades físico-químicas dos núcleos heterocíclicos do capítulo II. O capítulo I descreve uma nova rota para a síntese de ?-xiloidona, um produto natural relacionado ao lapachol, subexplorado pela química medicinal. Esta rota é baseada no rearranjo propargílico de Claisen, a partir da reação de lausona com 3-cloro-3- metilbutino sob catálise de CuCl2/I2.Este capítulo também descreveu a síntese de um derivado furano naftoquinoidal, o qual pode ser utilizado como precursor de ?- duniona, via rearranjo de Claisen aril-alílico. Além da realização desta metodologia substituindo o 3-cloro-3-metilbutino por cinco diferentes alcinos. Este novo processo ofereceu como vantagens principais o menor custo dos catalisadores empregados, os rendimentos melhorados e o reduzido número de etapas reacionais em relação as rotas descritas na literatura para obtenção de?-xiloidona. O Capítulo II apresenta o desenvolvimento de métodos sintéticos novos e eficazes para 3 núcleos heterocíclicos (naftiridinona, pirazolopiridinona e dihidropirrolopirazinona) pouco explorados pela química medicinal porém com potencial para descoberta de fármacos. Buscando abranger metodologias orientadas pela diversidade, neste capítulo foi realizado um estudo preliminar de reatividade destes núcleos frente diferentes abordagens, tanto frente métodos diretos de arilação quanto metodologias clássicas de modificação de anéis aromáticos. Além disso, no capítulo III foram realizados estudos de similaridade para a obtenção de padrões estruturais que possam ser aplicados em programas de descoberta de fármacos assim como o estudo de propriedades físico-químicas dos núcleos do capítulo II. Todo este trabalho permitiu desenvolver 10 moléculas inéditas na literatura, bem como novas metodologias para a síntese de compostos previamente descritos. / The present work is divided in two chapters: Chapter I - New synthesis of ? - xiloidone: Claisen rearrangement of hydroxynaphthoquinones; Chapter II - Synthesis and reactivity study of promising heteroaromatic coresunderstudied by medicinal chemistry; Chapter III - Similarity and physic-chemical properties analysis of the heterocyclic cores from chapter II. Chapter I describes a newsynthetic route to?- xiloidona, which isa natural product related to lapachol and understudied by medicinal chemistry. This route is based on propargyl Claisen rearrangement from the reaction of lawsone and 3-chloro-3- methylbutynemediated by CuCl2/I2. This chapter also describes the synthesis of a furan derivative which can be used as?- dunnione precursor. Also this methodology had been applied replacing the 3-chloro- 3-methyllbutynefor five different alkynes. This new process is associated with lower cost, improved yields and reduced number of reaction steps when compared to the literature. The chapter II aimed at the development of synthetic methods to obtain 3 heterocyclic cores(naphthyridinone, pyrazolopyridinoneand dihydropyrrolopyrazinone)with drug discovery potential but also understudied by medicinal chemistry. Diversity-oriented methodologies had been performedresulting in a reactivity study of these cores across severalsynthetic approaches. Furthermore, the chapter III described the similarity studies that were conducted aiming to obtain structural patterns that can be applied in drug discovery programs. This work describes the development of 10 non-published molecules as well as new methodologies for the synthesis of these previously described compounds.

Thesis advisor: Shih-Yuan Liu / This dissertation describes progress in the field of polycyclic boron- nitrogen-containing systems, especially for potential application in organic-based optoelectronic devices and hydrogen storage materials. The replacement of a BN unit for a CC unit organic compounds (BN/CC isosterism) can have a profound effect on the electronic structure and even function of a given molecular topology without changing its physical structure very much. Direct comparison between a BN-containing molecule and its direct all-carbon analogue is crucial to establishing the origin of these differences. The synthesis and optoelectronic characterization of boron- nitrogen-containing analogues of naphthalene, anthracene, and tetracene are disclosed. Also examined herein is the aromatic Claisen rearrangement applied to an azaboryl allyl ether. Finally, the chemistry of saturated BN heterocycles, including an iridium-catalyzed transfer dehydrogenation method for synthesizing BN-fused azaborines. Also disclosed is the actual application of these cyclic amine-boranes in supplying hydrogen for a proton exchange membrane (PEM) fuel cell. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The Johnson-Claisen rearrangement is a valuable method for the formation of new carbon-carbon bonds, however the rearrangement suffers from high reaction temperatures and prolonged reaction times. On the basis of previous research into substituent-induced rate enhancements of the Claisen rearrangement, we aimed to reduce the severity of the Johnson-Claisen conditions by applying this reaction to allylic cyanohydrins. Application of the standard Johnson-Claisen conditions (excess of orthoester and catalytic protic acid) to allylic cyanohydrins resulted in their decomposition to a,b- unsaturated aldehydes. The anticipated d-ethoxycarbonyl-a,b-unsaturated nitriles were formed in trace amounts. Subsequent optimisation of this reaction has allowed a practical entry into a,b- unsaturated nitriles in reasonable yields, however high reaction temperatures were necessary for an efficient conversion. Clearly, a change of approach was desired; we have since discovered that mixed orthoesters derived from allylic alcohols undergo methanol elimination in the presence of triisobutylaluminium (TIBAL) at room temperature to form mixed ketene acetals. TIBAL then promotes immediate Claisen rearrangement of these intermediates, and subsequent reduction of the ester products to yield, g,d- unsaturated primary alcohols in a convenient one-pot procedure, with yields ranging from 52-81% and with a range of functional group tolerance.

The work described herein is directed towards the Claisen rearrangements and [3+2] cycloaddition reaction of pyridine N-oxide systems. The pyridine N-oxide molecule is a very versatile and useful synthetic intermediate for the construction of more complex pyridines. Chapter 1 contains a review of work carried out within the group towards Claisen rearrangement of benzene-type systems. The acid catalysed rearrangement of these systems affords a high degree of regioselectivity. A literature survey of the [3+2] cycloaddition reaction of both aliphatic nitrones and aromatic N-oxides with various dipolarophiles is also included. Access to many stereochemically pure products demonstrates that the [3+2] cycloaddition has become a very important ring-forming reaction. Chapter 2 describes development of two Claisen rearrangement precursors and their subsequent attempted Claisen rearrangement is outlined. Chapter 3 details the construction of a range of 3-substituted pyridine N-oxides. Their attempted intermolecular cycloaddition, by thermal means and at high pressure, with mono- and di-activated dipolarophiles is described. Chapter 4 outlines attempts towards and the final synthesis of the ester cycloaddition precursors. Attempted intramolecular [3+2] cycloaddition of these substrates both thermally and under high pressure is summarised. Chapter 5 describes approaches towards [3+2] cycloaddition precursors that contain mono- and di-activated dienophiles. The synthesis of a variety of 3-substituted pyridines is detailed.

O presente trabalho divide-se em três capítulos: Capítulo I - Nova síntese de ?-xiloidona: rearranjo de Claisen em hidroxinaftoquinonas; Capítulo II - Síntese e estudo de reatividade de promissores núcleos heteroaromáticos subexplorados pela química medicinal; Capítulo III - Análise computacional de similaridade e propriedades físico-químicas dos núcleos heterocíclicos do capítulo II. O capítulo I descreve uma nova rota para a síntese de ?-xiloidona, um produto natural relacionado ao lapachol, subexplorado pela química medicinal. Esta rota é baseada no rearranjo propargílico de Claisen, a partir da reação de lausona com 3-cloro-3- metilbutino sob catálise de CuCl2/I2.Este capítulo também descreveu a síntese de um derivado furano naftoquinoidal, o qual pode ser utilizado como precursor de ?- duniona, via rearranjo de Claisen aril-alílico. Além da realização desta metodologia substituindo o 3-cloro-3-metilbutino por cinco diferentes alcinos. Este novo processo ofereceu como vantagens principais o menor custo dos catalisadores empregados, os rendimentos melhorados e o reduzido número de etapas reacionais em relação as rotas descritas na literatura para obtenção de?-xiloidona. O Capítulo II apresenta o desenvolvimento de métodos sintéticos novos e eficazes para 3 núcleos heterocíclicos (naftiridinona, pirazolopiridinona e dihidropirrolopirazinona) pouco explorados pela química medicinal porém com potencial para descoberta de fármacos. Buscando abranger metodologias orientadas pela diversidade, neste capítulo foi realizado um estudo preliminar de reatividade destes núcleos frente diferentes abordagens, tanto frente métodos diretos de arilação quanto metodologias clássicas de modificação de anéis aromáticos. Além disso, no capítulo III foram realizados estudos de similaridade para a obtenção de padrões estruturais que possam ser aplicados em programas de descoberta de fármacos assim como o estudo de propriedades físico-químicas dos núcleos do capítulo II. Todo este trabalho permitiu desenvolver 10 moléculas inéditas na literatura, bem como novas metodologias para a síntese de compostos previamente descritos. / The present work is divided in two chapters: Chapter I - New synthesis of ? - xiloidone: Claisen rearrangement of hydroxynaphthoquinones; Chapter II - Synthesis and reactivity study of promising heteroaromatic coresunderstudied by medicinal chemistry; Chapter III - Similarity and physic-chemical properties analysis of the heterocyclic cores from chapter II. Chapter I describes a newsynthetic route to?- xiloidona, which isa natural product related to lapachol and understudied by medicinal chemistry. This route is based on propargyl Claisen rearrangement from the reaction of lawsone and 3-chloro-3- methylbutynemediated by CuCl2/I2. This chapter also describes the synthesis of a furan derivative which can be used as?- dunnione precursor. Also this methodology had been applied replacing the 3-chloro- 3-methyllbutynefor five different alkynes. This new process is associated with lower cost, improved yields and reduced number of reaction steps when compared to the literature. The chapter II aimed at the development of synthetic methods to obtain 3 heterocyclic cores(naphthyridinone, pyrazolopyridinoneand dihydropyrrolopyrazinone)with drug discovery potential but also understudied by medicinal chemistry. Diversity-oriented methodologies had been performedresulting in a reactivity study of these cores across severalsynthetic approaches. Furthermore, the chapter III described the similarity studies that were conducted aiming to obtain structural patterns that can be applied in drug discovery programs. This work describes the development of 10 non-published molecules as well as new methodologies for the synthesis of these previously described compounds.

Synthetic approaches towards linear fused carbon rings have been developed over the last decades due to their high interest as compounds with potential antibiotic activity and as organic electronics. The application of a novel iterative route towards linear fused carbon ring systems could provide a versatile new mode of access to complex substituted ring systems. Studies have previously demonstrated the use of an allylation-double Claisen-RCM sequence to build fused carbon rings (C). In this thesis we described our work to expand the use of this methodology by developing milder reaction conditions that could be applied to a wider range of compounds. This novel methodology was applied towards the synthesis of benzodifuran compounds (D). Our work was extended by developing, for the first time, a mixed Fries-Claisen rearrangement strategy which furnishes template (F), a key intermediate in the synthesis of pyranonaphthoquinones (G). Our work culminated in a new approach to the pyranonaphthoquinone natural products eleutherin (H) and isoeleutherin (I). [Figures missing from abstract].

The dissertation describes Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement and the design and development of cationic 1,3-diaza-Claisen rearrangement. Our previous work has shown that isocyanates react with azanorbornenes and azabicyclo[2.2.2]octenes under thermal conditions to afford zwitterionic intermediates that undergo a thermal 1,3-diaza-Claisen rearrangement to give both ureas and isoureas. However, some azanorbornenes and azabicyclooctenes failed to rearrange or proceeded in low yields. To address these challenging substrates for the thermal 1,3-diaza-Claisen rearrangement, we have developed a Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement. Interestingly, under Pd0-catalyzed condition, both isocyanates with electron-withdrawing groups and isocyanates without electron-withdrawing groups react with azanorbornenes and azabicyclo[2.2.2]octenes to provide ureas as the only products in high yields. More importantly, the reactions that failed under thermal conditions were all successful under Pd0-catalysis. In addition to azanorbornenes and azabicyclo[2.2.2]octenes, other ring systems were also investigated. Pd0 catalysis has broadened the scope of tertiary allylic amines that react with isocyanates to afford 1,3-diaza-Claisen rearrangement products. In the presence of p-TsCl and NEt3, allylaminopropyl benzyl ureas were initially dehydrated to form protonated carbodiimides whose presence was confirmed by the infrared absorption frequency at 2100 cm-1 which is the characteristic band of -N=C=N-; then the in situ generated protonated carbodiimides were poised for further cationic 1,3-diaza-Claisen rearrangement to afford synthetically challenging guanidines. The effect of acid on the rearrangement was ascertained by the fact that no rearrangement product was observed by simply heating free base carbodiimide 3.10 in benzene at reflux. Other dehydration reagents, such as Tf2O, Ts2O, MsCl were also investigated, and none of them provide satisfactory results. A selection of allyamino benzyl ureas with different tether length, substituents, or in varied ring systems, were synthesized to explore the scope of this methodology. This methodology works best at allylaminopropyl benzyl ureas, and the substituents on the benzyl group does not seem to affect the reaction rate in a significant way.

Among Nature’s creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes make them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Total synthesis of sesquiterpenes acorenols, chamigrenes, and laurokamurene B; and Enantiospecific synthesis of ABC-ring system of A-nor and abeo pentacyclic triterpenes” describes the studies directed towards the total synthesis of the sesquiterpenes mentioned in the title and exploratory studies towards triterpenoids. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. The sesquiterpenes acorenols, containing an interesting spiro[4.5]decane carbon framework, was first isolated in 1970 by the research group of Tomita from the wood of Juniperus rigida. Recently, in 2003, Braun and coworkers reported the isolation of epi α- and epi β-acorenols along with α- and β-acorenols from the sandal wood oil Santalum spicatum. Total synthesis of all the four acorenols has been described in the first part of the first chapter of the thesis. Initially, a model study has been carried out for the spirocyclopentannulation of cyclohexanone employing a combination of Ireland ester Claisen rearrangement and ring closing metathesis reaction to furnish methyl 4-methylspiro[4.5]dec-3-en-1-carboxylate. The same methodology has been extended for the total synthesis of all the four acorenols starting from cyclohexane-1,4-dione via cis and trans isomers of methyl 4-methyl-8-methylene-spiro[4.5]dec-3-ene-1-carboxylate. Total synthesis of β-chamigrene, γ-chamigrene and laurencenone C, containing spiro[5.5]undecane carbon framework, has been described in the second part of the first chapter. As a model study, cyclohexanone has been transformed into 1,5,5-trimethylspiro-[5.5]undec-4-en-3-one employing a combination of Ireland ester Claisen rearrangement and intramolecular type-II carbonyl ene reactions. The methodology has been extended to chamigrenes starting from cyclohexane-1,4-dione via methyl 2-(1-isopropenyl-4-oxocyclo-hexyl)-2-methylpropanoate and 5,5-dimethyl-1,9-ismethylenespiro[5.5]undecan-3-ol. The marine sesquiterpenes laurokamurenes were first isolated in 2006 by Mao and Guo from Laurencia okamurai Yamada. First total synthesis of (±)-laurokamurene B has been described in the first part of the second chapter. To begin with Ireland ester Claisen rearrangement of but-2-enyl 2-methylpropionate furnished methyl 2,2,3-trimethylpent-4-enoate, which was then transformed into 4,5,5-trimethyl-3-(4-methylphenyl)hepta-1,6-dien-3-ol. RCM reaction followed by reductive deoxygeneation transformed 4,5,5-trimethyl-3-(4-methylphenyl)hepta-1,6-dien-3-ol into (±)-laurokamurene B. Subsequently, an enantioselective total synthesis of (+)-laurokamurene B has been accomplished. Stereoselective hydrogenation of methyl campholenoate furnished methyl 2-[(1S,3S)-2,2,3-trimethyl-cyclopent-1-yl]acetate, which was then transformed into (+)-laurokamurene B via degradation of the two carbon side chain and introduction of the aryl moiety, which established the absolute configuration of laurokamurenes. The third chapter deals with the enantiospecific generation of ABC-ring system of A-nor and abeo 4(3 → 2) tetra and pentacyclic triterpenes. To begin with (R)-carvone was identified as B-ring of ABC-ring system of A-nor and abeo tetra and pentacyclic triterpenes, as the absolute configuration at the C-5 position of the targets correlate to the stereo centre of carvone, and isopropenyl group can serve as the C-4 carbon of the targets along with the two gem-dimethyl groups. A lithium liquid ammonia mediated cyclisation of δ,ε-unsaturated esters was employed for the construction of the A ring and an RCM reaction was opted for the construction of the C ring. (R)-Carvone has been converted into 2-(1-ethoxyethoxy)-1,3,7,7-tetramethylbicyclo[4.3.0]non-3-en-8-ol via lithium liquid ammonia mediated cyclisation of methyl 2-(1-ethoxyethoxy)-6-isopropenyl-1,3-dimethylcyclohex-3-enyl]acetate, which was then transformed into 4-methoxymethoxy-2,5,5,9-tetramethyltricyclo[7.4.0.02,6]tridec-11-en-8-one via the RCM reaction of 3,4-bisallyl-8-methoxymethoxy-4,6,9,9-tetramethylbicyclo-[4.3.0]nonan-3-one. The strategy has been further extended to the synthesis of 4-methylene-2,5,5,9-tetramethyltricyclo[7.4.0.02,6]tridec-11-en-8-one, which contains the ABC ring system of abeo 4(3→2) tetra and pentacyclic triterpenes.

Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements. Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system. From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1. A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity. / Graduate