Synthesis of Natural Products and the Development of Synthetic Methodology: The Case Study of (-)-Atrop-abyssomicin C

During our attempt to follow the planned synthetic route to the naturally occurring antibiotic (-)-atrop-abyssomicin C, we encountered two shortcomings, which forced us to reconsider our tactics and find new methods to overcome the problems. These methods turned out to be of general applicability, as demonstrated later in total syntheses of two other natural products: (+)-allokainic acid and (-)-gabosine H. The paper provides a brief account of these endeavors

Synthesis of Natural Products and the Development of Synthetic Methodology: The Case Study of (-)-Atrop-abyssomicin C

During our attempt to follow the planned synthetic route to the naturally occurring antibiotic (-)-atrop-abyssomicin C, we encountered two shortcomings, which forced us to reconsider our tactics and find new methods to overcome the problems. These methods turned out to be of general applicability, as demonstrated later in total syntheses of two other natural products: (+)-allokainic acid and (-)-gabosine H. The paper provides a brief account of these endeavors

Biological Consequences of Tightly Bent DNA: The Other Life of a Macromolecular Celebrity

The mechanical properties of DNA play a critical role in many biological functions. For example, DNA packing in viruses involves confining the viral genome in a volume (the viral capsid) with dimensions that are comparable to the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein complexes (nucleosomes) in which DNA is tightly bent around protein spools. DNA is also tightly bent by many proteins that regulate transcription, resulting in a variation in gene expression that is amenable to quantitative analysis. In these cases, DNA loops are formed with lengths that are comparable to or smaller than the DNA persistence length. The aim of this review is to describe the physical forces associated with tightly bent DNA in all of these settings and to explore the biological consequences of such bending, as increasingly accessible by single-molecule techniques.Comment: 24 pages, 9 figure

Investigation of resin systems for improved ablative materials Final report, 19 Jun. 1964 - 31 Jul. 1965

Resin systems investigated for improving ablative materials for use with fluorine-containing liquid propellant system

MULTISCALE DYNAMIC MONTE CARLO / CONTINUUM MODELING OF DRYING AND CURING IN SOL-GEL SILICA FILMS

Modeling the competition between drying and curing processes in polymerizing films is of great importance to many existing and developing materials synthesis processes. These processes involve multiple length and time scales ranging from molecular to macroscopic, and are challenging to fully model in situations where the polymerization is non-ideal, such as sol-gel silica thin film formation. A comprehensive model of sol-gel silica film formation should link macroscopic flow and drying (controlled by process parameters) to film microstructure (which dictates the properties of the films). This dissertation describes a multiscale model in which dynamic Monte Carlo (DMC) polymerization simulations are coupled to a continuum model of drying. Unlike statistical methods, DMC simulations track the entire molecular structure distribution to allow the calculation not only of molecular weight but also of cycle ranks and topological indices related to molecular size and shape. The entire DMC simulation (containing 106 monomers) is treated as a particle of sol whose position and composition are tracked in the continuum mass transport model of drying. The validity of the multiscale model is verified by the good agreement of the conversion evolution of DMC and continuum simulations for ideal polycondensation and first shell substitution effect (FSSE) cases. Because our model allows cyclic and cage-like siloxanes to form, it is better able to predict the silica gelation conversion than other reported kinetic models. By studying the competition between molecular growth and cyclization, and the competition between mass transfer (drying) and reaction (gelation) on the drying process of the sol-gel silica film, we observe that cyclization delays gelation, shrinks the molecular size, increases the likelihood of skin formation, and leads to a molecular structure gradient inside the film. We also find that compared with a model with only 3-membered rings, the molecular structure is more complicated and the structure gradients in the films are larger with 4- membered rings. We expect that our simulation will allow better prediction of the formation of structure gradients in sol-gel derived ceramics and other nonideal multifunctional polycondensation products, and that this will help in developing procedures to reduce coating defects

Marine heterocyclic compounds that modulate intracellular calcium signals: Chemistry and synthesis approaches

Producción CientíficaIntracellular Ca2+ plays a pivotal role in the control of a large series of cell functions in all types of cells, from neurotransmitter release and muscle contraction to gene expression, cell proliferation and cell death. Ca2+ is transported through specific channels and transporters in the plasma membrane and subcellular organelles such as the endoplasmic reticulum and mitochondria. Therefore, dysregulation of intracellular Ca2+ homeostasis may lead to cell dysfunction and disease. Accordingly, chemical compounds from natural origin and/or synthesis targeting directly or indirectly these channels and proteins may be of interest for the treatment of cell dysfunction and disease. In this review, we show an overview of a group of marine drugs that, from the structural point of view, contain one or various heterocyclic units in their core structure, and from the biological side, they have a direct influence on the transport of calcium in the cell. The marine compounds covered in this review are divided into three groups, which correspond with their direct biological activity, such as compounds with a direct influence in the calcium channel, compounds with a direct effect on the cytoskeleton and drugs with an effect on cancer cell proliferation. For each target, we describe its bioactive properties and synthetic approaches. The wide variety of chemical structures compiled in this review and their significant medical properties may attract the attention of many different researchers.Ministerio de Ciencia e Innovación - (grant RTI2018-099298-B-100)Junta de Castilla y León - (grant VA294-P18

Functional materials synthesis by surface-supported chemistry

96 p.La química orgánica es un campo de investigación extremadamente maduro cuyos continuos avances han ido permitiendo la generación de materiales cada vez más refinados, caracterizados por fascinantes propiedades físicas y químicas. La aplicación de tales compuestos orgánicos nanoestructurados ha ido generando importantes impulsos al campo de la nanociencia. En los últimos 15 años se está desarrollando una nueva alternativa a la química convencional: la síntesis en superficies (¿on-surface synthesis¿, OSS) bajo condiciones de ultra alto vacío. Este nuevo planteamiento ha abierto nuevas puertas para la formación de nanoestructuras de carbono que no están al alcance de los métodos convencionales. Su aplicación para la síntesis de materiales orgánicos de baja dimensionalidad y con precisión atómica está mostrando un crecimiento en auge y tiene un enorme potencial para aplicaciones que incluyen nuevas tecnologías cuánticas.En esta tesis, este novedoso enfoque se aplica al crecimiento de diferentes tipos de materiales, seguido de una caracterización integral de las propiedades estructurales, químicas y electrónicas de los productos intermedios y finales. Para tal fin se ha utilizado principalmente la microscopía túnel de barrido a baja temperatura (4,3 K) en varios modos de medición, complementados con cálculos teóricos (DFT y métodos de partículas de sonda). En concreto se han estudiado los siguientes sistemas:(i) Química metal-orgánica, en la que se muestra la manera de controlar la estructura de enlace de tiolatos de oro y su estereoespecíficidad variando los parámetros de reacción en la superficie (recubrimiento y temperatura del sustrato).(ii) Química basada en pirenos. Usando moléculas de pireno funcionalizadas con alquinos, se investiga el efecto de los complejos metal-orgánicos descritos anteriormente en las reacciones de acoplamiento de alquinos. Los complejos metal-orgánicos no solo modifican el resultado de la reacción, sino que también reducen el umbral de la temperatura de activación, siendo por tanto un excelente ejemplo de síntesis en superficie de segundo orden (es decir, OSS del catalizador para dirigir nuevas reacciones de OSS). De otro lado, también se han utilizado pirenos funcionalizados con dos tipos de grupos funcionales distintos, como son los alquinos y átomos de Br. La presencia de ambos grupos funcionales permite nuevo abanico de reacciones que incluyen el tanto el acoplamiento de alquinos o el acoplamiento cruzado. El análisis de los productos resultantes y su abundancia tras tratamientos de calentamiento muestran una dominancia del acoplamiento de Glaser (acoplamiento de alquinos con pérdida de hidrógeno) como reacción inicial. Sin embargo, al utilizar un precursor no halogenado se observa una prevalencia de un acoplamiento sin pérdida de hidrógeno y una total ausencia de acoplamiento Glaser, evidenciando el papel crítico del Br en la reactividad de alquinos. Es importante destacar también que una comparación sistemática de las propiedades electrónicas de las diferentes estructuras de los productos ha permitido trazar importantes relaciones entre la estructura y las propiedades de los diversos tipos de acoplamientos entre pirenos.(iii) Química basada en aceno. Se ha estudiado la síntesis de acenos de gran tamaño, en concreto de heptaceno sobre Ag(001), a partir de precursores moleculares de tetrahidroheptaceno con y sin funcionalización adicional por átomos de Br. Se ha encontrado una variedad de productos intermedios que a menudo resultan de eventos de migración de hidrógeno. Sin embargo, el heptaceno es el producto final de los dos precursores y muestra un orbital LUMO completamente cargado. Centrándonos en los intermedios, se observa cómo dos átomos de carbono con hibridación sp3 en el segundo anillo de dihidroheptaceno son suficientes para causar el auto-desacoplamiento electrónico de la molécula y el sustrato. Se han investigado asimismo las señales magnéticas, evidenciadas en resonancias Kondo, asociadas a determinados escenarios de carga. Finalmente, utilizando precursores basados en acenos se ha explorado el impacto del sustrato en las reacciones de acoplamiento. En concreto se han utilizado superficies de Au(111) y Au(110), así como precursores de antraceno funcionalizados con halógenos y metilos. Sobre Au(111), una superficie atómicamente plana, se encuentran cinco tipos de productos covalentes, siendo el starphene con simetría de eje ternario el producto dominante. Por contra, sobre la superficie reconstruida de Au(110) 2×1, su simetría uniaxial promueve la formación de polímeros lineales no benzenoides.Esta tesis contribuye al campo de la ciencia de superficies, mostrando la posibilidad de sintetizar una variedad de nanomateriales novedosos basados en carbono mediante la síntesis en superficie, así como mediante la caracterización detallada sus propiedades. La comprensión de las propiedades físico-químicas de estos materiales avanzados es un paso de gran relevancia hacia sus futuras aplicaciones.The mature research field of conventional solution-based chemistry has allowed for a continuous generation of increasingly refined materials with amazing physical and chemical properties. This has contributed to great advances in the field of organic nanomaterials. The development of the recently revealed surface-supported synthesis under ultrahigh vacuum conditions has opened new doors for the formation of defect-free low-dimensional carbon nanostructures that are not achievable by conventional means. This new field, typically termed on-surface synthesis (OSS), is lately showing a booming growth that resonates with almost all the requirements for promising quantum size materials with tunable physicochemical properties.In this thesis, this novel approach is applied for the growth of a variety of materials, followed by a comprehensive characterization of the structural, chemical and electronic properties of the intermediates and end-products. This is achieved mainly by scanning tunneling microscopy operating at low temperature (4.3 K) in various measurement modes, assisted by theoretical calculations (DFT and probe particle methods). In particular, the following systems have been studied:(i) Metal-organic chemistry, in which the stereospecific coupling motif of gold thiolates is found to be controllable by varying the on-surface reaction parameters (i.e. coverage and substrate temperature).(ii) Pyrene-based chemistry. With alkyne-functionalized pyrene molecules, the impact of the presence of metal-organic complexes on alkyne coupling reactions is investigated. The complexes do not only modify the reaction outcome, but also reduce its activation temperature threshold, becoming an excellent example of second-order on-surface synthesis (i.e. OSS of catalyst to steer following OSS reactions). Secondly, pyrenes are used that are functionalized with alkynes and also Br atoms, allowing for alkyne homo- and cross-coupling reactions. The resulting products and their relative abundance are explored thoroughly after different annealing steps, revealing a dominant Glaser-coupling product upon heating. The absence of the latter when using non-halogenated precursor evidenced the role of Br in this coupling reaction. Importantly, a systematic comparison of the electronic properties of the different product structures has allowed drawing important structure-property relations with regard to the various inter-pyrene coupling motifs.(iii) Acene-based chemistry. The synthesis of higher acenes is studied, in particular heptacene on Ag(001), starting from tetrahydroheptacene molecular precursors with and without additional functionalization by Br atoms. A variety of stable reaction intermediates is found, often resulting from hydrogen migration events. However, heptacene is the end-product from the two precursors and displays a fully charged LUMO orbital. Focusing on the intermediates, two sp3-hybridized carbon atoms present at the second ring of dihydroheptacene are shown as sufficient self-decoupling factors. Magnetic Kondo fingerprints associated to specific charging scenarios are investigated. Finally, the impact of the surface structure on coupling reactions with acene-based precursors is then explored. More specifically, Au(111) and Au(110) surfaces, as well as anthracene precursors functionalized with halogen and methyls are used with this aim. On Au(111), the atomically flat surface, five covalent coupling motifs are found, with the 3-fold symmetric starphene showing the highest occurrence upon annealing. In contrast, on Au(110), being a 2×1 reconstructed surface, the uniaxial symmetry of the surface promotes the formation of mainly linear non-benzenoid polymers along the grooves of this substrate.This thesis contributes to the surface science field by showing the possibility to synthesize a variety of novel carbon-based nanomaterials using on-surface synthesis methods. The second main contribution is the detailed characterization of the produced materials using surface-sensitive techniques assisted by theoretical calculations. A deep understanding of the physicochemical properties of these materials is a crucial step forward towards their ultimately progressing applications.CFM; CSI

STUDIES ON SILICON NMR CHARACTERIZATION AND KINETIC MODELING OF THE STRUCTURAL EVOLUTION OF SILOXANE-BASED MATERIALS AND THEIR APPLICATIONS IN DRUG DELIVERY AND ADSORPTION

This dissertation presents studies of the synthetic processes and applications of siloxane-based materials. Kinetic investigations of bridged organoalkoxysilanes that are precursors to organic-inorganic hybrid polysilsesquioxanes are a primary focus. Quick gelation despite extensive cyclization is found during the polymerization of bridged silane precursors except for silanes with certain short bridges. This work is an attempt to characterize and understand some of the distinct features of bridged silanes using experimental characterization, kinetic modeling and simulation. In addition to this, the dissertation shows how the properties of siloxane- materials can be engineered for drug delivery and adsorption. The phase behavior of polymerizing mixtures is first investigated to identify the solutions that favor kinetic characterization. Microphase separation is found to cause gradual loss of NMR signal for certain initial compositions. Distortionless Enhancement by Polarization Transfer 29Si NMR is employed to identify the products of polymerization of some short-bridged silanes under no signal loss conditions. This technique requires knowing indirect 29Si-1H scalar coupling constants which sometimes cannot be measured due to second-order effects. However, the B3LYP density functional method with 6-31G basis set is found to predict accurate 29Si-1H coupling constants of organoalkoxysilanes and siloxanes. The scalar coupling constants thus estimated are employed to resolve non-trivial coupled NMR spectra and quantitative kinetic modeling is performed using the DEPT Si NMR transients. In order to investigate the role of the organic bridging group, the structural evolution of bridged and non-bridged silanes are compared using Monte Carlo simulations. Kinetic and simulation models suggest that cyclization plays a key role right from the onset of polymerization for bridged silanes even more than in non-bridged silanes. The simulations indicate that the carbosiloxane rings formed from short-bridged precursors slow down but do not prevent gelation. The tuning of siloxane-based materials for adsorption technologies are also discussed here. In the first example, antioxidant enzyme loading is investigated as a means to reduce oxidative stress generated by silica nanoparticle drug carriers. Materials are engineered for promising enzyme loading and protection from proteolysis. Second, the potential of copper sulfate impregnation to enhance adsorption of ammonia by silica is explored by molecular simulation

Functional materials synthesis by surface-supported chemistry

96 p.La química orgánica es un campo de investigación extremadamente maduro cuyos continuos avances han ido permitiendo la generación de materiales cada vez más refinados, caracterizados por fascinantes propiedades físicas y químicas. La aplicación de tales compuestos orgánicos nanoestructurados ha ido generando importantes impulsos al campo de la nanociencia. En los últimos 15 años se está desarrollando una nueva alternativa a la química convencional: la síntesis en superficies (¿on-surface synthesis¿, OSS) bajo condiciones de ultra alto vacío. Este nuevo planteamiento ha abierto nuevas puertas para la formación de nanoestructuras de carbono que no están al alcance de los métodos convencionales. Su aplicación para la síntesis de materiales orgánicos de baja dimensionalidad y con precisión atómica está mostrando un crecimiento en auge y tiene un enorme potencial para aplicaciones que incluyen nuevas tecnologías cuánticas.En esta tesis, este novedoso enfoque se aplica al crecimiento de diferentes tipos de materiales, seguido de una caracterización integral de las propiedades estructurales, químicas y electrónicas de los productos intermedios y finales. Para tal fin se ha utilizado principalmente la microscopía túnel de barrido a baja temperatura (4,3 K) en varios modos de medición, complementados con cálculos teóricos (DFT y métodos de partículas de sonda). En concreto se han estudiado los siguientes sistemas:(i) Química metal-orgánica, en la que se muestra la manera de controlar la estructura de enlace de tiolatos de oro y su estereoespecíficidad variando los parámetros de reacción en la superficie (recubrimiento y temperatura del sustrato).(ii) Química basada en pirenos. Usando moléculas de pireno funcionalizadas con alquinos, se investiga el efecto de los complejos metal-orgánicos descritos anteriormente en las reacciones de acoplamiento de alquinos. Los complejos metal-orgánicos no solo modifican el resultado de la reacción, sino que también reducen el umbral de la temperatura de activación, siendo por tanto un excelente ejemplo de síntesis en superficie de segundo orden (es decir, OSS del catalizador para dirigir nuevas reacciones de OSS). De otro lado, también se han utilizado pirenos funcionalizados con dos tipos de grupos funcionales distintos, como son los alquinos y átomos de Br. La presencia de ambos grupos funcionales permite nuevo abanico de reacciones que incluyen el tanto el acoplamiento de alquinos o el acoplamiento cruzado. El análisis de los productos resultantes y su abundancia tras tratamientos de calentamiento muestran una dominancia del acoplamiento de Glaser (acoplamiento de alquinos con pérdida de hidrógeno) como reacción inicial. Sin embargo, al utilizar un precursor no halogenado se observa una prevalencia de un acoplamiento sin pérdida de hidrógeno y una total ausencia de acoplamiento Glaser, evidenciando el papel crítico del Br en la reactividad de alquinos. Es importante destacar también que una comparación sistemática de las propiedades electrónicas de las diferentes estructuras de los productos ha permitido trazar importantes relaciones entre la estructura y las propiedades de los diversos tipos de acoplamientos entre pirenos.(iii) Química basada en aceno. Se ha estudiado la síntesis de acenos de gran tamaño, en concreto de heptaceno sobre Ag(001), a partir de precursores moleculares de tetrahidroheptaceno con y sin funcionalización adicional por átomos de Br. Se ha encontrado una variedad de productos intermedios que a menudo resultan de eventos de migración de hidrógeno. Sin embargo, el heptaceno es el producto final de los dos precursores y muestra un orbital LUMO completamente cargado. Centrándonos en los intermedios, se observa cómo dos átomos de carbono con hibridación sp3 en el segundo anillo de dihidroheptaceno son suficientes para causar el auto-desacoplamiento electrónico de la molécula y el sustrato. Se han investigado asimismo las señales magnéticas, evidenciadas en resonancias Kondo, asociadas a determinados escenarios de carga. Finalmente, utilizando precursores basados en acenos se ha explorado el impacto del sustrato en las reacciones de acoplamiento. En concreto se han utilizado superficies de Au(111) y Au(110), así como precursores de antraceno funcionalizados con halógenos y metilos. Sobre Au(111), una superficie atómicamente plana, se encuentran cinco tipos de productos covalentes, siendo el starphene con simetría de eje ternario el producto dominante. Por contra, sobre la superficie reconstruida de Au(110) 2×1, su simetría uniaxial promueve la formación de polímeros lineales no benzenoides.Esta tesis contribuye al campo de la ciencia de superficies, mostrando la posibilidad de sintetizar una variedad de nanomateriales novedosos basados en carbono mediante la síntesis en superficie, así como mediante la caracterización detallada sus propiedades. La comprensión de las propiedades físico-químicas de estos materiales avanzados es un paso de gran relevancia hacia sus futuras aplicaciones.The mature research field of conventional solution-based chemistry has allowed for a continuous generation of increasingly refined materials with amazing physical and chemical properties. This has contributed to great advances in the field of organic nanomaterials. The development of the recently revealed surface-supported synthesis under ultrahigh vacuum conditions has opened new doors for the formation of defect-free low-dimensional carbon nanostructures that are not achievable by conventional means. This new field, typically termed on-surface synthesis (OSS), is lately showing a booming growth that resonates with almost all the requirements for promising quantum size materials with tunable physicochemical properties.In this thesis, this novel approach is applied for the growth of a variety of materials, followed by a comprehensive characterization of the structural, chemical and electronic properties of the intermediates and end-products. This is achieved mainly by scanning tunneling microscopy operating at low temperature (4.3 K) in various measurement modes, assisted by theoretical calculations (DFT and probe particle methods). In particular, the following systems have been studied:(i) Metal-organic chemistry, in which the stereospecific coupling motif of gold thiolates is found to be controllable by varying the on-surface reaction parameters (i.e. coverage and substrate temperature).(ii) Pyrene-based chemistry. With alkyne-functionalized pyrene molecules, the impact of the presence of metal-organic complexes on alkyne coupling reactions is investigated. The complexes do not only modify the reaction outcome, but also reduce its activation temperature threshold, becoming an excellent example of second-order on-surface synthesis (i.e. OSS of catalyst to steer following OSS reactions). Secondly, pyrenes are used that are functionalized with alkynes and also Br atoms, allowing for alkyne homo- and cross-coupling reactions. The resulting products and their relative abundance are explored thoroughly after different annealing steps, revealing a dominant Glaser-coupling product upon heating. The absence of the latter when using non-halogenated precursor evidenced the role of Br in this coupling reaction. Importantly, a systematic comparison of the electronic properties of the different product structures has allowed drawing important structure-property relations with regard to the various inter-pyrene coupling motifs.(iii) Acene-based chemistry. The synthesis of higher acenes is studied, in particular heptacene on Ag(001), starting from tetrahydroheptacene molecular precursors with and without additional functionalization by Br atoms. A variety of stable reaction intermediates is found, often resulting from hydrogen migration events. However, heptacene is the end-product from the two precursors and displays a fully charged LUMO orbital. Focusing on the intermediates, two sp3-hybridized carbon atoms present at the second ring of dihydroheptacene are shown as sufficient self-decoupling factors. Magnetic Kondo fingerprints associated to specific charging scenarios are investigated. Finally, the impact of the surface structure on coupling reactions with acene-based precursors is then explored. More specifically, Au(111) and Au(110) surfaces, as well as anthracene precursors functionalized with halogen and methyls are used with this aim. On Au(111), the atomically flat surface, five covalent coupling motifs are found, with the 3-fold symmetric starphene showing the highest occurrence upon annealing. In contrast, on Au(110), being a 2×1 reconstructed surface, the uniaxial symmetry of the surface promotes the formation of mainly linear non-benzenoid polymers along the grooves of this substrate.This thesis contributes to the surface science field by showing the possibility to synthesize a variety of novel carbon-based nanomaterials using on-surface synthesis methods. The second main contribution is the detailed characterization of the produced materials using surface-sensitive techniques assisted by theoretical calculations. A deep understanding of the physicochemical properties of these materials is a crucial step forward towards their ultimately progressing applications.CFM; CSI