As part of an ongoing investigation for anticancer agents from natural resources, four plant extracts were determined to contain interesting bioactivity. These extracts were separated by chromatography to afford a number of bioactive compounds that were characterized by spectral analysis. Fractionation of the fruit extract of Cryptocarya crassifolia led to the isolation of two known flavonoids and two known cryptocaryalactones. Fractionation of the bark extract of the same plant also gave the same two cryptocaryalactones. All these compounds were weakly active in a cytotoxicity assay. Two new isoflavones were isolated from the roots of an Egyptian lotus plant, Lotus polyphyllos. Both compounds were characterized by UV, NMR, and mass spectroscopic analysis The methanol extract from the leaves and bark of a Brexiella sp. were found to display significant cytotoxic activity versus the A2780 mammalian cell line. Two highly active cardenolides, glucodigimetholide and xysmalogenin glucoside, were isolated and found to be responsible for the bioactivities. Both compounds were characterized by spectroscopic analysis and comparison to the known literature data. Two marine extracts were also investigated. The pyridoacridine alkaloids, amphimedine and neoampimedine, were isolated from the marine sponge Petrosia sp., and three bromo-tyrosine alkaloids were isolated from the marine sponge Porphyria flintae. The structures of these known compounds were all elucidated by comparison to literature data. Two 6-amino-glycoglycerolipids had been previously isolated from a marine algae species and shown to inhibit the activity of the enzyme Myt-1 kinase. These compounds and some related compounds were synthesized and their bioactivities against Myt1 kinase were determined. Two isotopically labeled paclitaxel analogs (2D, 19F) were prepared in preparation for studies of the tubulin-binding conformation of paclitaxel by REDOR NMR. A new macrocyclic A-nor-paclitaxel was also synthesized, and was found to have good cytotoxicity and improved tubulin-binding activity as compared with paclitaxel. / Ph. D.

The aim of this project was to develop a cascade approach towards perhydropyrrolo-[1,2-a]-quinolines and to apply this to the asymmetric synthesis of the gephyrotoxin alkoids. Chapters Two and Three outline the development of a synthetic route towards a range of cascade precursors, whilst Chapter Four outlines investigations into the enamine-Michael cascade. Central to understanding the cascade process was the discovery that the major product of the enamine-Michael cascade was the unusual tricyclic hydroquinium salt. This can subsequently be engaged in a diastereoselective inter- or intramolecular reduction to afford either a trans-perhydro-[1,2-a]-quinoline or a tetracyclic aminal in high overall yield depending on the C1 oxygen substituent.

This dissertation describes research into the synthesis of carbon nanotubes using traditional organic synthetic methods, as well as work on the fragmentation of β-hydroxy-α-diazoesters with a γ-hetero group and applications of their reactivity towards natural product synthesis. Carbon nanotubes are unique structures that can exhibit different electronic properties based on their chiral vector, and are a potential future source of semiconductors. Current methods of synthesis are unable to be adapted to commercial synthesis, providing the opportunity for the application of organic synthetic methods to generate them more uniformly and on a larger scale. The generation of tethered aldehyde ynoates and their utilization in 1,3-dipolar cycloadditions has been well developed by the Brewer group. Traditionally they have been generated from γ-siloxy-β-hydroxy-α-diazoesters, herein we explore utilizing an amino group as the fragmentation initializer. Additionally, application of the tethered aldehyde ynoate towards the synthesis of the natural products Demissidine and Aspidospermine are discussed.

Desde as primeiras civilizações, o ser humano se utiliza da diversidade química encontrada na natureza como parte do seu desenvolvimento e até mesmo sobrevivência. Dentre os produtos naturais, as plantas possuem destaque pela quantidade de candidatos a fármacos que chegam à fase final de estudos clínicos. Uma família de plantas de grande interesse é a Asteraceae, cujas plantas biossintetizam diferentes tipos de terpenos, poliacetilenos e substâncias fenólicas. Na busca por novas substâncias ativas, surgem as bibliotecas ou coleções de substâncias, extratos e frações que se tornaram uma das bases para a pesquisa das propriedades químicas e biológicas na indústria. Para a análise e conhecimento dessas bibliotecas são utilizadas técnicas analíticas no estado da arte, como a Cromatografia Líquida de Ultra Eficiência (do inglês, UHPLC), acoplada a Espectrômetros de Massas de Alta Resolução (do inglês, HRMS). Nesse trabalho foi desenvolvido um método analítico em CLAE-EM utilizando a abordagem metabolômica da impressão digital. Esse método foi otimizado utilizando ferramentas in silico e validado segundo padrões internacionais para validação bioanalítica, mostrando-se linear, seletivo, robusto, preciso e acurado para o que foi proposto. Esse método foi utilizado ao longo do processo de otimização para a extração de 244 diferentes espécies de Asteraceae, após a obtenção da melhor condição: 20 mg/mL de droga vegetal, proporção de etanol e água de 80% e tempo de extração de ultrassom de 15 min. A partir dessa condição, foram obtidos os extratos e construída assim a coleção denominada AsterLibII. Cento e vinte substâncias de origem natural isoladas pelo grupo de pesquisa AsterBioChem foram devidamente organizadas para compor a AsterLibI. As estruturas 2D obtidas a partir dessas substâncias, juntamente com mais de 8000 estruturas adicionais obtidas pela conversão de arquivos de levantamento bibliográfico, utilizando ferramentas computacionais, formaram a AsterLibIII. Os dados obtidos pela análise da AsterLibII por UHPLC-HRMS mostram a diversidade dos sinais que representam possíveis substâncias em uma faixa de polaridade de alta a média-baixa, não sendo facilmente interpretadas relações entre as amostras, devido à baixa sensibilidade de gráficos de dispersão e da correlação linear necessária para se obter a redução dimensional efetiva por PCA (Principal Component Analysis). Os modelos matemáticos utilizados tanto para a otimização do método analítico como para a obtenção da melhor condição para as bibliotecas se mostraram estatisticamente significativos e forneceram informações sobre as variáveis. Através das ferramentas analíticas e computacionais utilizadas, foi possível a construção de bibliotecas de produtos naturais promissoras para estudos biológicos e químicos, incluindo estudos voltados para modelos de desreplicação / From the begining, civilizations use the chemical diversity found in nature as part of their growing culture and knowledge, even to overcome disease. Among natural products, plants are most noticed because of their success in reaching the final stage of drug discovery. Asteraceae species are of great interest because of the chemical diversity and their dissemination in nature. The chemical compounds found in Asteraceae are terpenes, flavonoids, coumarins, polyacetylenes, benzofurans and phenylpropanoids. With regard to drug discovery, a new emerging approach is the construction of libraries, collections of extracts, compounds and fractions, which have become a fundamental tool for understanding biological and chemical properties, especially in industry. To perform library analysis towards knowledge, state-of-the-art techniques used are UHPLC and HRMS, mainly coupled. In this work, the development and validation of an analytical methodology using the metabolic fingerprint approach was carried out. After validation, the analytical method was considered linear, precise, robust, accurate and selective for the metabolomics analysis. The analytical method was applied together with response surface studies to obtain an efficient extraction condition that allowed to reach most of the chemical diversity. After that, 244 plant samples were extracted and AsterLibII was constructed. 120 natural compounds isolated by members of the AsterBioChem group were duly organized and became AsterLibI. Then, the 2D structures drawn from AsterLibI, along with about 8000 2D structures extracted and converted by computational means from the bibliographic search, became AsterLibIII. Graphical and mathematical analysis was performed on AsterlibII, although it was not easy to see patterns and continue the investigation of metabolites. This was due to the low sensitivity of the dispersion plots and the expected linear correlation to obtain a real dimensional reduction using Principal Component Analysis (PCA). The mathematical models used to understand the variables in the extraction and development of the method showed statistical significance and they were important to access information. Using analytical and computational tools, it was possible to construct libraries of natural products with great potential for biological and chemical studies, including dereplication studies

Thesis advisor: James P. Morken / This dissertation describes the first enantioselective 1,2-diboration of cis-substituted 1,3-dienes. In the presence of a platinum catalyst and TADDOL-derived phosphonite ligands, both 4,4-disubstituted and mono-cis-substituted 1,3-dienes undergo regioselective 1,2-diboration to afford the corresponding 1,2-diols upon oxidation in up to 98:2 er and high yield. By achieving enantioselective 1,2-diboration of 1,3-dienes, a new synthetic route to α-chiral (Z)-allylboronate reagents has been developed. In the presence of an aldehyde, these allyl bis(boronate) esters undergo highly diastereoselective allylboration reaction to afford enantioenriched 1,5-homoallylic alcohols bearing all-carbon quaternary centers or syn-propionate motifs. In the presence of 1,4-dicarbonyl compounds, the (Z)-allylboronates undergo a double allylation reaction to afford cyclohexanols with four contiguous stereocenters in good yield and moderate to excellent diastereoselectivity. The tandem diboration/double allylation has been applied to the total synthesis of pumilaside B aglyon, and the partial synthesis 1β-hydroxy arbusculin A and bromophycolide F. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: T. Ross Kelly / Total Synthesis is a field of Organic Chemistry that focuses on the construction of various compounds. These compunds can be known, such is the case in the synthesis of natural products like Lactonamycin, or they can be creations of the imagination, like the Molecular Motor. In both cases, this particular concentration of science involves a keen use of intellect as well as a substantial amount of creativity. / Thesis (BS) — Boston College, 2003. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Chemistry. / Discipline: College Honors Program.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Ligand-Controlled Site-Selective NHC–Cu-Catalyzed Protoboration of Monosubstituted Allenes. Site-selective proto–boryl additions to monosubstituted allenes promoted by NHC–Cu complexes are disclosed. Synthetically useful 1,1-disubstituted and Z-trisubstituted alkenylboron compounds are afforded in high efficiency (71%–92% yield) and site selectivity (88% to >98%) through proper choice of NHC ligands. Mechanistic study with the assistance of DFT calculations indicates that protonation of 2-boron-substituted allylcopper complex occurs through six-membered cyclic transition state. The utility of this protocol is demonstrated through application to fragment synthesis of an antibiotic macrolide natural product elansolid A. Chapter 2. Cu-Catalyzed Chemoselective Copper–Boron Additions to Monosubstituted Allenes Followed by Allyl Additions to Carbonyl Compounds. The first examples of catalytic generation of 2-boron-substituted allylcopper species and their in situ use for C–C bond formation are described. The reactions are performed in the presence of bisphosphine– or NHC–Cu complexes at 22 oC. High-value alcohol-containing alkenylboron compounds are provided in high efficiency (68–92% yield after oxidation) and stereoselectivity (88:12 to >98:2 dr). The reactions proceed with exclusive γ-addition mode through a cyclic six-membered transition state. Enantioselectivity can be achieved with chiral bisphosphine ligands in up to 97:3 enantiomeric ratio. Chapter 3. Chemo-, Site- and Enantioselective Copper–Boron Additions to 1,3-Enynes Followed by Site- and Diastereoselective Additions of the Resulting Allenylcopper Complexes to Aldehydes. Catalytic enantioselective multicomponent reactions involving 1,3-enynes, aldehydes and B2(pin)2 are described. The resulting products contain a primary C–B(pin) bond, as well as alkyne- and hydroxyl-substituted tertiary stereogenic centers. A critical feature is high enantioselectivity of the initial Cu–B addition to an alkyne-substituted terminal alkene. The key mechanistic issues are investigated by DFT calculations. Reactions are promoted in the presence of the Cu complex of an enantiomerically pure C1-symmetric bisphosphine and are complete in 8 h at ambient temperature. Products are generated in 66–94% yield (after oxidation or catalytic cross-coupling), 90:10 to >98:2 diastereomeric ratio, and 85:15–99:1 enantiomeric ratio. Aryl-, heteroaryl-, alkenyl-, and alkyl-substituted aldehydes and enynes are suitable substrates. Utility is demonstrated through catalytic alkylation and arylation of the organoboron compounds as well as applications to synthesis of fragments of tylonolide and mycinolide IV. Chapter 4. Multifunctional Alkenylboron Compounds through Single-Catalyst-Controlled Multicomponent Reactions and Their Applications in Scalable Natural Product Synthesis. A facile multicomponent catalytic process that begins with a chemo-, site- and diastereoselective copper–boron addition to a monosubstituted allene followed by addition of the resulting boron-substituted organocopper intermediate to an allylic phosphate, generating products that contain a stereogenic center, a monosubstituted alkene and an easily functionalizable Z-trisubstituted alkenylboron group in up to 89% yield with >98% branch selectivity and stereoselectivity and an enantiomeric ratio greater than 99:1. The copper-based catalyst is derived from a robust heterocyclic salt that can be prepared in multigram quantities from inexpensive starting materials and without costly column chromatography purification. The utility of the method is demonstrated through enantioselective synthesis of gram quantities of two natural products, rottnestol and herboxidiene/GEX1A. Chapter 5. Cu-Catalyzed Enantioselective Allyl and Propargyl 1,6-Conjugate Additions through 3,3’-Reductive Elimination. Catalytic enantioselective 1,6-conjugate additions of allyl-type nucleophiles promoted by NHC–Cu complexes are reported. Propargyl and 2-boron allyl 1,6-conjugate products are formed in high efficiency, diastereo- and enantioselectivity. The unique mechanistic feature is that the transformations proceed through Cu-catalyzed 3,3’-reductive elimination, that is unprecedented for copper catalysis. Further mechanistic study and application to complex molecule synthesis will be conducted. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Steven D. Bruner / Thesis advisor: Mary F. Roberts / The fuscachelins are a group of novel small molecule secondary metabolites produced by the thermophilic actinomycete <italic>Thermobifida fusca</italic>. A genome mining approach was employed to identify the fuscachelin nonribosomal peptide synthetase biosynthetic gene cluster in <italic>T. fusca</italic>. The peptide natural products were predicted to be siderophores, iron-scavenging small molecules. An assay guided fractionation approach was utilized to isolate the fuscachelins. Structure elucidation efforts employed nuclear magnetic resonance, mass spectrometric and chemical degradation techniques to determine the structure of the isolated compounds. Once the structure was known, a total synthesis was undertaken. The established synthetic route to the fuscachelins will allow for the facile development of custom-designed chemical tools for the further study of the fuscachelin biosynthetic enzymes and utilization proteins. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

nÃo hà / PrÃpolis, palavra de origem grega e significa a defesa da cidade. Usado na colmÃia para fechar frestas, garantindo a proteÃÃo contra microorganismos. Diversas propriedades foram relatadas terapeuticamente como: bactericida, fungicida, antivÃrus, antiinflamatÃria. As amostras de prÃpolis brasileiras podem ser classificados em 13 grupos, baseados nas caracterÃsticas fÃsico-quÃmicas e classificadas da seguinte maneira: cinco no Sul do Brasil (grupo 3), um no Sudeste (grupo 12) e seis no Nordeste (grupo 7). O trabalho teve como objetivo a investigaÃÃo fitoquÃmica de duas amostras de prÃpolis: uma de Alto Santo - Ceara e outra de Minas Gerais â Brasil, alÃm da determinaÃÃo da atividade biolÃgica e antioxidante. Da amostra de prÃpolis do CearÃ, foram identificados: triterpenos (lupeol, Ãcido canÃrico, lupenona e germanicona); flavonoides (quercetina, canferol, acacetina, 3-(4-metoxifenila) acrilato de 2(E)-2-metoxifenila-5-(5-hidroxi-3,7-dimetoxi-4-oxo-4H-cromen-2-ila). Da prÃpolis de Minas Gerais popularmente chamada de prÃpolis verde, obteve-se: Ãcido p-cumaric, Ãcido (E)-3-(3,4-dihidroxifenila) propenÃico e uma mistura dos Ãcidos: Ãcido (E)-3-(4-hidroxifenila) propenÃico, Ãcido 3-phenilpropanÃico e Ãcido 3-(4-hidroxifenila) propanÃico. Do lupeol obteve-se uma sÃrie de derivados, entre eles: o produto oxidado e os Ãsteres no carbono-3. Os compostos e os derivatives puros do lupeol foram identificados por mÃtodos espectroscÃpicos tais como IR, o RMN 1H e 13C CG/EM. Extrato de prÃpolis e compostos puros isolados foram avaliados para a atividade antioxidante usando o mÃtodo de captura de radical DPPH (2,2-difenila-1-picril-hidrazila) e os resultados mostraram a atividade muito boa para extratos e para os flavonÃides, os triterpenos mostraram uma atividade pequena. Do Ãleo essencial da prÃpolis de Minas Gerais, identificaram-se os constituintes classificados como monoterpenos oxigenados (0,3%), hidrocarbonetos sesquiterpenos (65,18%), sesquiterpenos oxigenados (23,64%), e derivados do Ãcido cinÃmico (6,17%). Foram identificados 24 constituintes, representando 97,7% do Ãleo, e os compostos principais definidos como: E-nelolidol (17,14%), E-cariofileno (13,38%) e selin-3,7(11)-dieno (10,35%) foram os mais abundantes. O Ãleo foi caracterizado com alta percentagem de hidrocarbonetos sesquiterpenos e sesquiterpenos oxigenados. A partir da prÃpolis de Minas Gerais, material de partida para a produÃÃo de pà liofilizado, produziu-se prÃpolis solÃvel em Ãgua, obtida de uma mistura com soluÃÃo de L-lisina e PVP. O liofilizado terà destino para testes biolÃgicos. / Propolis, word has the Greek origin, and means city defense. Used in the beehive to forbid openings, guaranteeing protection against microorganisms. Several therapeutically properties were reported such as: bactericidal, fungicidal, antivirus, anti-inflammatory. Brazilian propolis can be classified in 13 groups, based on the physical-chemistry characteristics classified as: five in the South of Brazil (group 3), one in Southeast (group 12) and six in the Northeast (group 7). The present work has a goal the phytochemical investigation of two samples of propolis: one from Alto Santo - Cearà and other from Minas Gerais - Brasil and determination of biological activity. From a sample of propolis of CearÃ, were identified: triterpenes (lupeol, acid canaric, lupenone and germanicone); flavonoids (kercetin, kanferol, acacetine, 3-(4-methoxyphenyl) acrilate of 2-(E)-2-methoxyphenil-5-(5-hydroxy-3,7-dimethoxy-4-oxo-4H-cromene-2-il). For the sample propolis of Minas Gerais popularly called âgreen propolisâ were identified p-cumaric acid, (E)-3-(3,4-dihidroxyphenyl) propenoic acid and a mixture of acid ones: (E)-3-(4-hydroxyphenyl) propenoic acid, 3-phenylpropanoic acid and 3-(4-hydroxiphenil) propanoic acid. From lupeol a serie of derivative were obtained including oxidation and esters at carbon-3. Pure compounds and lupeol derivatives were identified by spectroscopic methods such as IR, 1H and 13C NMR and MS. Propolis extracts and pure compounds were evaluated for scavenger activity using DPPH (2,2-diphenyl,1-picril-hidrazil) bioassay and results showed very good activity for extracts and for flavonoids where as triterpens showed a week activity. The essential oil of the propolis from Minas Gerais obtained by hydrodestillation process was analyzed by CG-MS techniques and composition was defined as: oxygenated monoterpenes (0,30%), hydrocarbons sesquiterpenes (65,18%), sesquiterpenes oxigenated (23,64%), and derivatives of the cinamic acid (6,17%). Twenty constituent were identified representing 97.7% and major compound defined as: E-nelolidol (17,14%), E-cariofilene (13,38%) and selin-3,7(11)-dien (10,35%). The oil was characterized with high percentage of hydrocarbons sesquiterpenes and oxygenated sesquiterpenes. The green propolis of Minas Gerais was used as material for the lyophilized drug production. From the propolis water soluble together with L-lysine and a polymer PVP was obtained a power and it is using for biological tests as anticancer agent.

Rhodococcus is a soil bacterium, member of the Actinobacteria, and a close relative of the prolific small molecule producer Streptomyces. Recent interest in Rhodococcus as an under investigated source of possible bioactive secondary metabolites is sparked by the discovery of many polyketide synthase and non-ribosomal peptide synthetase genes of unknown function from sequenced Rhodococcus genomes. Rhodococcus species strain MTM3W5.2 was recently shown to produce a strong inhibitory compound with activity against most strains of Rhodococcus and closely related genera. A goal of this investigation is to discover the gene(s) required to synthesize this inhibitory molecule. The engineered Rhodococcus transposon, pTNR, was used to generate random insertional mutations in the genome of MTM3W5.2. The transposon insertion sites for 8 non-producing mutants were cloned and sequenced. Genes that encode polyketide synthases usually form parts of large biosynthetic gene clusters responsible for the production of small polyketide molecules.