A unified strategy to ent-kauranoid natural products : total syntheses of (–)-maoecrystal Z, (–)-trichorabdal A, and (–)-longikaurin E

The diterpenoid constituents of the Isodon plants have attracted reasearchers interested in both their chemical structures and biological properties for more than a half-century. In recent years, the isolations of new members displaying previously unprecedented ring systems and highly selective biological properties have piqued interest from the synthetic community in this class of natural products.

Reported herein is the first total synthesis of such a recently isolated diterpenoid, (–)-maoecrystal Z. The principal transformations implemented in this synthesis include two highly diastereoselective radical cyclization reactions: a Sm^(II)-mediated reductive cascade cyclization, which forms two rings and establishes four new stereocenters in a single step, and a Ti^(III)-mediated reductive epoxide-acrylate coupling that yields a functionalized spirolactone product, which forms a core bicycle of maoecrystal Z.

The preparation of two additional ent-kauranoid natural products, (–)-trichorabdal A and (–)-longikaurin E, is also described from a derivative of this key spirolactone. These syntheses are additionally enabled by the palladium-mediated oxidative cyclization reaction of a silyl ketene acetal precursor that is used to install the bridgehead all-carbon quaternary stereocenter and bicyclo[3.2.1]octane present in each natural product. These studies have established a synthetic relationship among three architecturally distinct ent-kaurane diterpenoids and have forged a path for the preparation of interesting unnatural ent-kauranoid structural analogs for more thorough biological study.

The development of an asymmetric palladium-catalyzed conjugate addition and its application toward the total syntheses of taiwaniaquinoid natural products

The asymmetric synthesis of quaternary stereocenters remains a challenging problem in organic synthesis. Past work from the Stoltz laboratory has resulted in methodology to install quaternary stereocenters α- or γ- to carbonyl compounds. Thus, the asymmetric synthesis of β-quaternary stereocenters was a desirable objective, and was accomplished by engineering the palladium-catalyzed addition of arylmetal organometallic reagents to α,β-unsaturated conjugate acceptors.

Herein, we described the rational design of a palladium-catalyzed conjugate addition reactions utilizing a catalyst derived from palladium(II) trifluoroacetate and pyridinooxazole ligands. This reaction is highly tolerant of protic solvents and oxygen atmosphere, making it a practical and operationally simple reaction. The mild conditions facilitate a remarkably high functional group tolerance, including carbonyls, halogens, and fluorinated functional groups. Furthermore, the reaction catalyzed conjugate additions with high enantioselectivity with conjugate acceptors of 5-, 6-, and 7-membered ring sizes. Extension of the methodology toward the asymmetric synthesis of flavanone products is presented, as well.

A computational and experimental investigation into the reaction mechanism provided a stereochemical model for enantioinduction, whereby the α-methylene protons adjacent the enone carbonyl clashes with the tert-butyl groups of the chiral ligand. Additionally, it was found that the addition of water and ammonium hexafluorophosphate significantly increases the reaction rate without sacrificing enantioselectivity. The synergistic effects of these additives allowed for the reaction to proceed at a lower temperature, and thus facilitated expansion of the substrate scope to sensitive functional groups such as protic amides and aryl bromides. Investigations into a scale-up synthesis of the chiral ligand (S)-tert-butylPyOx are also presented. This three-step synthetic route allowed for synthesis of the target compound of greater than 10 g scale.

Finally, the application of the newly developed conjugate addition reaction toward the synthesis of the taiwaniaquinoid class of terpenoid natural products is discussed. The conjugate addition reaction formed the key benzylic quaternary stereocenter in high enantioselectivity, joining together the majority of the carbons in the taiwaniaquinoid scaffold. Efforts toward the synthesis of the B-ring are presented.

Studies toward the total synthesis of ritterazine B : the investigation of alkynylation reactions for use in the synthesis of the western fragment

The ritterazine and cephalostatin natural products have biological activities and structures that are interesting to synthetic organic chemists. These products have been found to exhibit significant cytotoxicity against P388 murine leukemia cells, and therefore have the potential to be used as anticancer drugs. The ritterazines and cephalostatins are steroidal dimers joined by a central pyrazine ring. Given that the steroid halves are unsymmetrical and highly oxygenated, there are several challenges in synthesizing these compounds in an organic laboratory.

Ritterazine B is the most potent derivative in the ritterazine family. Its biological activity is comparable to drugs that are being used to treat cancer today. For this reason, and the fact that there are no reported syntheses of ritterazine B to date, our lab set out to synthesize this natural product.

Herein, efforts toward the synthesis of the western fragment of ritterazine B are described. Two different routes are explored to access a common intermediate. An alkyne conjugate addition reaction was initially investigated due to the success of this key reaction in the synthesis of the eastern fragment. However, it has been found that a propargylation reaction has greater reactivity and yields, and has the potential to reduce the step count of the synthesis of the western fragment of ritterazine B.

The economics of hydro-meteorological disasters: approaching the estimation of the total costs

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Part I. Efforts directed towards the total synthesis of shionone. Part II. Conversion of estrone to androst-4-EN-3-ONE: a new method for activating the C-9 and C-10 positions of estrogenic steroids for substitution

Part I: An approach to the total synthesis of the triterpene shionone is described, which proceeds through the tetracyclic ketone i. The shionone side chain has been attached to this key intermediate in 5 steps, affording the olefin 2 in 29% yield. A method for the stereo-specific introduction of the angular methyl group at C-5 of shionone has been developed on a model system. The attempted utilization of this method to convert olefin 2 into shionone is described.

Part II: A method has been developed for activating the C-9 and C-10 positions of estrogenic steroids for substitution. Estrone has been converted to 4β,5β-epoxy-10β-hydroxyestr-3-one; cleavage of this epoxyketone using an Eschenmoser procedure, and subsequent modification of the product afforded 4-seco-9-estren-3,5-dione 3-ethylene acetal. This versatile intermediate, suitable for substitution at the 9 and/or 10 position, was converted to androst-4-ene-3-one by known procedures.

For the determination of iron (II) and total iron with 2,2'-dipyridyl in mineral waters. Reduction of iron (III) with ascorbic acid [Translation from: Zeitschrift fur Analytische Chemie 209 340-341, 1965]

The determination of bi- and trivalent iron in proximity, in mineral waters has gained in significance, on biological and technical grounds. This short paper describes the procedure of the determination of bivalent iron and total iron in a water sample.

New Catalytic Methods for the Preparation of Tryptophans and Pyrroloindolines: Total Synthesis of (+)-Naseseazines A and B and (–)-Aspergilazine A

Tryptophan and unnatural tryptophan derivatives are important building blocks for the total synthesis of natural products, as well as the development of new drugs, biological probes, and chiral small molecule catalysts. This thesis describes various catalytic methods for the preparation of tryptophan derivatives as well as their functionalization and use in natural product total synthesis.

Herein, the tandem Friedel–Crafts conjugate addition/asymmetric protonation reaction between 2-substituted indoles and methyl 2-acetamidoacrylate to provide enantioenriched trytophans is reported. This method inspired further work in the area of transition metal catalyzed arylation reactions. We report the development of the coppercatalyzed arylation of tryptamine and tryptophan derivatives. The utility of these transformations is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B. Further work on the development of a mild and general Larock indolization protocol to access unnatural tryptophans is also discussed.

Enantioselective Total Synthesis of Diketopiperazinecontaining Natural Products: (–)-Lansai B, (+)-Nocardioazines A and B, and (–)-Acetylapoaranotin

Diketopiperazine (DKP) motif is found in a wide range of biologically active natural products. This work details our efforts toward two classes of DKP-containing natural products.

Class one features the pyrroloindoline structure, derived from tryptophans. Our group developed a highly enantioselective (3 + 2) formal cycloaddition between indoles and acrylates to provide pyrroloindoline products possessing three stereocenters. Utilizing this methodology, we accomplished asymmetric total synthesis of three natural products: (–)-lansai B, (+)-nocardioazines A and B. Total synthesis of (–)-lansai B was realized in six steps, and featured an amino acid dimerization strategy. The total synthesis of (+)-nocardioazine B was also successfully completed in ten steps. Challenges were met in approaching (+)-nocardioazine A, where a seemingly easy last-step epoxidization did not prove successful. After re-examining our synthetic strategy, an early-stage epoxidation strategy was pursued, which eventually yielded a nine-step total synthesis of (+)-nocardioazine A.

Class two is the epidithiodiketopiperazine (ETP) natural products, which possesses an additional episulfide bridge in the DKP core. With the goal of accessing ETPs with different peripheral structures for structure-activity relationship studies, a highly divergent route was successfully developed, which was showcased in the formal synthesis of (–)-emethallicin E and (–)-haematocin, and the first asymmetric synthesis of (–)-acetylapoaranotin.

Total cross section measurements for ^3He(^3He, 2p)^4He at low energies

Precise measurements of the total reaction cross section for ³He(³He,2p)⁴He He have been made in the range of center-of-mass energies between 1100 keV and 80 keV. A differentially pumped gas target modified to operate with a limited quantity of the target gas was employed to minimize the uncertainties in the primary energy and energy straggle. Beam integration inside the target gas was carried out by a calorimetric device which measures the total energy spent in a heat sink rather than the total charge in a Faraday cup. Proton energy spectra have been obtained using a counter telescope consisting of a gas proportional counter and a surface barrier detector and angular distributions of these protons have been measured at seven bombarding energies. Cross section factors, S(E), have been calculated from the total cross sections and fitted to a linear function of energy over different ranges of energy. For E_cm < 500 keV

S(E_cm) = S₀ + S₁ E_cm

where S₀ = (5.0 ^+0.6_-0.4) MeV - barns and S₁ = (-1.8 ± 0.5) barns.

Efeito da Suplementação com L-arginina em subpopulações linfocitárias de ratos submetidos a esplenectomia total isolada ou combinada com autoimplante esplênico

A L-arginina é reconhecida como um nutriente de fundamental importância na resposta imune, apesar de seus efeitos serem, por vezes, considerados inconstantes. O autoimplante esplênico tem sido proposto como alternativa à esplenectomia total isolada, mas existem preocupações quanto à eficácia do restabelecimento da resposta imune, haja vista que o paciente pode permanecer com risco aumentado de desenvolvimento de infecção fulminante pós esplenectomia, mesmo após a regeneração morfológica do órgão. O objetivo deste estudo foi avaliar a participação da suplementação dietética com L-arginina em subpopulações linfocitárias no sangue, no baço e nos autoimplantes esplênicos de ratos submetidos a esplenectomia isolada ou combinada com autoimplante esplênico. Foram utilizados 42 ratos Sprague-Dawley machos, randomicamente distribuídos em seis grupos: 1 Controle operação simulada; 2 esplenectomia total; 3 esplenectomia total combinada com autoimplante esplênico; 4 Controle operação simulada, com suplementação de L-arginina; 5 esplenectomia total, com suplementação de L-arginina; e 6 esplenectomia total combinada com autoimplante esplênico, com suplementação de L-arginina. Os animais dos grupos 4, 5 e 6 receberam suplementação de L-arginina, uma vez ao dia, durante 15 dias anteriores a coleta sangüínea realizada imediatamente antes dos procedimentos operatórios (semanas 0 e 12). A dose utilizada foi de 1,0 g/kg/dia, administrada por via intragástrica em bolus. As avaliações foram realizadas por meio de hemograma e citometria de fluxo. A análise estatística utilizou testes paramétricos e nãoparamétricos, sendo p<0,05 considerado para a rejeição da hipótese nula. A suplementação com L-arginina acarretou elevação da contagem relativa e absoluta de neutrófilos periféricos, 12 semanas após a realização de esplenectomia total combinada com autoimplante esplênico. A esplenectomia total ocasionou diminuição da contagem relativa de linfócitos T totais, T CD4+ e T CD8β no sangue, mas a suplementação dietética com L-arginina evitou a diminuição do percentual de células T totais e T CD8β no sangue dos animais submetidos a autoimplante esplênico. Tanto a realização de autoimplante esplênico como a suplementação de L-arginina previnem a diminuição da subpopulação de linfócitos T CD4+ no sangue periférico, fato que usualmente ocorre após realização de esplenectomia total. Houve maior proliferação de células brancas / g de tecido nos autoimplante esplênico dos animais suplementados, porém a suplementação não influenciou a contagem de linfócitos T, T CD4+ e B de zona marginal de baço. A suplementação do aminoácido L-arginina após a realização de esplenectomia total combinada com autoimplante esplênico em ratos foi capaz de reverter alterações observadas em algumas das subpopulações linfocitárias, ocasionadas pela esplenectomia.

Studies Directed Toward the Total Synthesis of Germanicol

An approach to the synthesis of the pentacyclic triterpene germanicol is discussed.

Part I: Total yield measurements for the ^(21)Ne(α,n)^)(24)Mg reaction. Part II: A study of the ^(12)C(He,p)^(14)N reaction

PART I

The total cross-section for the reaction ²¹Ne(α, n)²⁴Mg has been measured in the energy range 1.49 Mev ≤ E_cm ≤ 2.6 Mev. The cross-section factor, S(O), for this reaction has been determined, by means of an optical model calculation, to be in the range 1.52 x 10¹² mb-Mev to 2.67 x 10¹² mb-Mev, for interaction radii in the range 5.0 fm to 6.6 fm. With S(O) ≈ 2 x 10¹² mb-Mev, the reaction ²¹Ne(α, n)²⁴Mg can produce a large enough neutron flux to be a significant astrophysical source of neutrons.

PART II

The reaction¹²C(³He, p)¹⁴N has been studied over the energy range 12 Mev ≤ E_lab ≤ 18 Mev. Angular distributions of the proton groups leading to the lowest seven levels in ¹⁴N were obtained.

Distorted wave calculations, based on two-nucleon transfer theory, were performed, and were found to be reliable for obtaining the value of the orbital angular momentum transferred. The present work shows that such calculations do not yield unambiguous values for the spectroscopic factors.

Produtividade Total dos Fatores: revisão da literatura e uma aplicação exploratória para a cultura do milho usando os dados dos censos agropecuários

Este trabalho pretende contribuir para o entendimento sobre a produtividade na agricultura brasileira, bem como propõe uma reflexão sobre o debate da produtividade total dos fatores. Para isso, buscou-se, antes de tudo, debater as medidas de produtividade, sobretudo as medidas de produtividade total dos fatores e, em seguida, apresentar estimativas da produtividade total na agricultura no Brasil e no mundo. Propõem-se também uma estimativa preliminar dessa metodologia para o cálculo da produtividade total dos fatores na cultura do milho através do índice de Tornqvist. O objetivo é, então, revisar a literatura teórica e empírica sobre a produtividade total dos fatores na agricultura e calcular as produtividades parciais e totais na cultura do milho para os estados brasileiros. Apesar da maior parte dos resultados encontrados no cálculo da produtividade total para a cultura do milho no Brasil não terem sido consistentes, a conclusão geral do levantamento bibliográfico foi que tanto a agricultura brasileira quanto a agricultura mundial, independente da metodologia utilizada, apresentou uma tendência ao crescimento da produtividade total dos fatores.