Síntesi de nous polímers amb importants aplicacions mèdiques i industrials

Els dendrímers són un nou tipus de polímers que es caracteritzen per tenir una estructura tridimensional en forma ramificada com un arbre. La versatilitat d'aquests compostos i les seves aplicacions en camps tan diversos com la medicina o la indústria química, han despertat l'interés dels investigadors per poder sintetitzar-los amb materials assequibles i facilitar la seva producció comercial. Aquesta recerca s'ha centrat en l'obtenció d'un nou tipus de dendrímers.Los dendrímeros son un nuevo tipo de polímeros que se caracterizan por tener una estructura tridimensional en forma ramificada como un árbol. La versatilidad de estos compuestos y sus aplicaciones en campos tan diversos como la medicina o la industria química, han despertado el interés de los investigadores para poder sintetizarlos con materiales asequibles y facilitar su producción comercial. Esta investigación se ha centrado en la obtención de un nuevo tipo de dendrímeros

Reaccions d'addició de fosfinodiazoalcans i fosficarbens a dobles enllaços c=c i c=o : estudi mecanístic i aplicacions sintètiques /

Consultable des del TDXTítol obtingut de la portada digitalitzadaEn la present tesi doctoral s'han estudiat reaccions d'addició de fosfinodiazoalcans i fosfinocarbens, amb l'objectiu general d'explorar la seva reactivitat enfront d'olefines i aldehids. La versió asimètrica també ha estat considerada, tant pel que fa a la utilització de substrats com de reactius quirals. Els resultats d'aquests estudis s'han utilitzat per posar a punt mètodes sintètics per preparar diferents tipus de productes. En la primera part s'ha portat a terme un estudi comparatiu de la reactivitat i la selectivitat, respecte diazometà, de les cicloaddicions 1,3-dipolars de fosfinodiazoalcans a olefines quirals electrodeficients. S'ha observat que el diazometà és sempre més reactiu que el fosfinodiazoalcà considerat, i s'ha racionalitzat l'origen de la diferent reactivitat i diastereoselectivitat -facial observada en cada cas mitjançant càlculs teòrics. En una segona etapa s'ha dedicat a l'estudi de l'addició de [bis(diisopropilamino)fosfino](trimetilsilil)carbè a carbonils d'aldehids aromàtics, heteroaromàtics i alifàtics. En el cas de la reacció amb aldehids aromàtics i heteroaromàtics s'ha posat a punt la síntesi d'epòxids altament substituïts, amb bons rendiments i manera totalment estereoselectiva. Quan s'han usat aldehids alifàtics s'ha observat l'aparició d'una reacció competitiva, una addició de tipus [2+2], que després de passar per un intermedi oxafosfetènic que no s'aïlla, condueix a la formació de vinilfosfonamides. També s'ha estudiat la versió asimètrica de la reacció, utilitzant-se aldehids alifàtics quirals. D'aquesta manera s'han sintetitzat epòxids i vinilfosfonamides òpticament purs i de manera totalment diastereoselectiva. En una tercera part s'ha realitzat un estudi i una racionalització mitjançant càlculs teòrics de la reactivitat del carbè estudiat anteriorment enfront de benzaldehid i acetaldehid. En el cas de l'acetaldehid s'ha pogut explicar el comportament observat experimentalment, tant pel que fa a les dues reaccions competitives com pel que fa a l'estereoselectivitat de la reacció. En la quarta etapa s'ha abordat la síntesi i l'estudi de la reactivitat de nous aminofosfino(silil)diazocompostos quirals i dels seus carbens corresponents. En algun dels casos s'ha pogut sintetitzar un ciclopropà òpticament actiu i de manera totalment diastereoselectiva. Finalment es discuteix la síntesi i la reactivitat de [bis(dimetilamino)fosfino](trimetilsilil)-diazometà. La reacció d'aquest diazocompost amb aldehids condueix a la síntesi de derivats acetilèncis i de -hidroxifosfondiamides mitjançant una reacció iniciada per un atac nucleòfil del fòsfor al carboni carbonílic de l'aldehid. S'ha estudiat el mecanisme de la reacció i s'han realitzat reaccions complementàries que mostren el comportament ambifílic del diazocompost de partida i la seva enorme aplicabilitat sintètica.Addition reactions of phosphinodiazoalkanes and phosphinocarbenes to olefins and aldehydes have been studied in this doctoral thesis. The assymetric version of the reaction has also been considered, either by using chiral substrates or chiral reactants. The results of these studies have been used to set up new synthetic methods to prepare a variety of products. In the first chapter, a comparative study on the reactivity and selectivity of 1,3-dipolar cycloadditions of phosphinodiazoalkanes and diazomethane to chiral electron-deficient olefins has been carried out. Diazomethane has been shown to be more reactive than the considered phosphinodiazoalkanes. The origin of the different reactivity and of the -facial diastereoselectivity observed in all cases has been rationalized using theoretical calculations. The second chapter is devoted to the study of the addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene to the carbonyl group of aromatic, heteroaromatic and aliphatic aldehydes. When aromatic and heteroaromatic aldehydes have been used, highly substituted epoxides have been synthesized with good yields and in a total stereoselective manner. When aliphatic aldehydes have been used, a competitive reaction has been observed. This competitive reaction is a [2+2]-like addition that, after rearrangement of a transient oxaphosphetene that cannot be isolated, leads to the formation of vinylphosphonamides. The assymetric version of the reaction has also been studied by using chiral aliphatic aldehydes. In such a way, optically pure epoxides and vinylphosphonamides have been synthesized. A study and a rationale of the reactions considered in the previous chapter has been done in the third chapter using theoretical calculations. Benzaldehyde and acetaldehyde have been used as models. The reactivity referring to the two competitive reactions and the stereoselectivity observed when using acetaldehyde has been fully explained

Nous dendrímers quirals multifuncionals

Els dendrímers són (nano)arquitectures moleculars amb una mida i un nombre de grups terminals ben definits. Aquestes molècules tenen aplicacions potencials com a biomaterials, medicaments o hostes. En el present treball, s'ha dut a terme la síntesi d'uns nous dendrímers ciclobutànics quirals multifuncionals a través d'una estratègia convergent. Aquesta metodologia sintètica, que consisteix en la unió al nucli d'uns dendrons prèviament sintetitzats, condueix a dendrímers de pes molecular monodispers més fàcils de purificar. Al nostre laboratori s'han utilitzat, com a nuclis, benzens 1,3,5- trisubstituïts, mentre que, com a dendrons, s'han utilitzat un !,"- aminodiàcid ciclobutànic multifuncional i el tetrapèptid resultant de l'acoblament del !,"-aminodiàcid amb tres residus de GABA (àcid gamma-aminobutíric) convenientment funcionalitzats. Les propietats estructurals d'aquestes molècules i llurs possibles aplicacions en el camp dels nous materials estan sent estudiades.Dendrimers are highly-branched molecular (nano)architectures of well defined size and number of terminal groups. These molecules have potential applications as biomaterials, drugs or hosts. In the present work, new chiral multifunctional cyclobutane dendrimers have been synthesized through a convergent approach. This synthetic methodology, which consists in the attachment of pre-synthesized dendrons to the core, leads to dendrimers of monodisperse molecular weight which are easier to purify. In our laboratory 1,3,5-trisubstituted benzenes have been used as cores, whereas a multifunctional cyclobutane !,"-amino diacid and the tetrapeptide resulting from the coupling of the !,"-amino diacid an three conveniently protected GABA (gamma-aminobutiric acid) residues, have been used as dendrons. Structural properties of these molecules and their possible applications in the field of new materials are under study

Synthesis of Chiral Scaffolds Based on Polyfunctional Cyclobutane β-Amino Acids

Altres ajuts: Acord transformatiu CRUE-CSICChiral scaffolds have been synthesized through selective transformations from conveniently protected cyclobutane β-amino acids. The obtained derivatives present additional functional groups, such as hydroxyl, carboxyl, or carbon-carbon triple bond, linked to the amino acid core through a flexible C or C alkyl fragment. The resultant molecules are highly versatile to be used as chiral precursors for the production of polyfunctional chemical platforms. These can be suitable for the synthesis of complex molecules, through condensation reactions, such as peptide coupling, dehydration between a carboxylic acid and an alcohol, or click chemistry. To illustrate some of these possibilities, two hybrid tripeptides have been prepared as examples of their synthetic potential

Chiral Cyclobutane β-Amino Acid-Based Amphiphiles: Influence of Cis/Trans Stereochemistry on Solution Self-Aggregation and Recognition

Novel diastereomeric anionic amphiphiles based on the rigid cyclobutane β-amino acid scaffold have been synthesized and deeply investigated with the aim of generating new functional supramolecular architectures on the basis of the rational design of original amphiphilic molecules and the control of their self-assembly. The main interest has been focused on the effect that cis/trans stereochemistry exerts on their molecular organization and recognition. In diluted solutions, the relative stereochemistry mainly influences the headgroup solvation and anionic-charge stabilization, i.e., better stabilized in the cis diastereoisomer due to intramolecular hydrogen-bonding and/or charge-dipole interactions. This provokes differences in their physicochemical behavior (pKa, cmc, conductivity) as well as in the structural parameters of the spherical micelles formed. Although both diastereoisomers form fibers that evolve with time from the spherical micelles, they display markedly different morphology and kinetics of formation. In the lyotropic liquid crystal domain, the greatest differences are observed at the highest concentrations and can be ascribed to different hydrogen-bonding and molecular packing imposed by the stereochemical constraints. Remarkably, the spherical micelles of the two anionic surfactants show dramatically diverse enantioselection ability for bilirubin enantiomers. In addition, both the surfactants form heteroaggregates with bilirubin at submicellar concentrations but with a different expression of supramolecular chirality. This points out that the unlike relative configuration of the two surfactants influences their chiral recognition ability as well as the fashion in which chirality is expressed at the supramolecular level by controlling the molecular organization in both micellar aggregates and surfactant/bilirubin heteroaggregates. All these differential features can be appropriate and useful for the design and development of new soft materials with predictable and tunable properties and reveal the cyclobutane motif as a valuable scaffold for the preparation of new amphiphiles.We thank Jaume Caelles, in the SAXS-WAXS service at IQAC, for X-Ray measurements, and Imma Carrera for technical assistance in the surface tension measurements. Financial support from MINECO (grants CTQ2010-15408/BQU, CTQ2013-41514-P, and CTQ2013-43754-P) is gratefully acknowledged. Authors also thank the support from Generalitat de Catalunya (2014SGR358 and 2014SGR836).Peer reviewe

New chiral polyfunctional cyclobutane derivatives from (-)-verbenone: Possible surfactant behaviour

New enantiopure cyclobutane derivatives have been synthesized from a chiral precursor derived from (-)-verbenone. The cyclobutane moiety acts as a chiral platform to afford a γ-amino acid function in a branched side-chain containing an additional stereogenic centre as well as additional C6 or C16-alkyl chains linked to the ring by means of an amine or an amide function. One of these compounds, obtained as a 1:2 mixture with its TFA salt has been investigated, suggesting behaviour as a good surfactant and its critical micellar concentration has been determined. © 2013 Elsevier Ltd. All rights reserved.Imma Carrera is acknowledged for help in the measurement of surface tensions. Jaume Caelles from the SAXS-WAXS service at IQAC is acknowledged for the SAXS measurements. The authors thank financial support from Spanish Ministerio de Ciencia e Innovación (grant CTQ2010-15408/BQU and CTQ2010-14897) and Generalitat de Catalunya (grant 2009SGR-733 and 2009SGR-1331).Peer reviewe

Cyclobutane-based peptides/terpyridine conjugates : Their use in metal catalysis and as functional organogelators

Two new conjugates, hcptpyDP and hcptpyTP, of a terpyridine derivative incorporating artificial peptide moieties, have been synthesized and their use in the preparation of metal catalysts and organogelators has been investigated. Ru(II) complexes derived from these ligands showed electrochemical behavior and activity as catalysts in the epoxidation of olefins similar to that of Beller's catalyst. As organogelators, these conjugates were able to gelate a variety of solvents, from toluene to methanol, with satisfactory mgc (minimum gelation concentration) values. The presence of 4'-(4-carboxy)phenylterpyridine (hcptpy) moiety allows tuning the gelling properties and also influences the supramolecular self-assembling mode to produce chiral aggregates with respect to parent peptides DP and TP. In the case of the conjugates, π−π interactions provided by the aromatic moieties cooperate with inter-molecular hydrogen bonding between NH and CO in the amide groups. Further properties of peptide/terpyridine conjugates are under investigation in view of future applications

Preparació de blocs quirals per a nous agents de penetració cel·lular

Les membranes plasmàtiques protegeixen la cèl·lula d'invasions exògenes, fet que dificulta l'arribada de certs fàrmacs a les seves dianes terapèutiques intracel·lulars. En els últims anys, s'han desenvolupat diferents pèptids sintètics per internalitzar diferents molècules bioactives. Aquest article tracta de la síntesi en fase sòlida de dos pèptids tetradecamèrics híbrids mitjançant l'estratègia Fmoc/Boc. Aquests pèptids estan constituïts per un g-aminoàcid ciclobutànic i un residu de trans-g-amino-l-prolina funcionalitzat, enllaçats alternadament. Alguns d'aquests pèptids han donat bons resultats d'internalització en cèl·lules HeLa i en el paràsit leishmània, i es preveu realitzar un estudi en profunditat de les seves propietats de penetraci

Cyclobutane scaffold in bolaamphiphiles : Effect of diastereoisomerism and regiochemistry on their surface activity aggregate structure

Cationic bolaamphiphiles have been synthesized starting from meso cis- or chiral trans-1,2-difunctionalized cyclobutane derivatives. They include cis/trans pairs of diastereoisomers, of N- or C-centered bisamides. The goal of this work was to investigate the influence of stereochemistry and regiochemistry on their abilities as surfactants and self-assembly. Very large differences in surface coverage (2-fold), critical micellar concentration (cmc, up to 2 orders of magnitude), and aggregate structure (from lamellae to fibers) for the four molecules are remarkable due to regio- and stereochemistry differences. Computational calculations were carried out to rationalize the experimental findings and a new methodology has been developed to calculate the structure of these bolaamphiphiles at the surface. Although the four surfactants adopt a wicket-like conformation, for N-centered trans, the distance between polar heads is much larger than that for the other three molecules, as suggested by calculations. We have shown that the interplay between the regiochemistry and stereoisomerism, enhanced by rigidity of the cyclobutane ring, affects different physicochemical properties quite differently. That is, the cmc value is mainly governed by stereochemistry, with regiochemistry only modulating this value. On the other hand, regiochemistry definitely governs the morphology of the supramolecular aggregates (i.e., long fibers versus plates or spherical assemblies), with stereochemistry finely modulating their structural parameters. All these results must help in the rational design of new bolaamphiphiles with predictable properties and useful potential applications

Síntesi estereoselectiva de ciclobutan-1,2-diamines

En el present treball de màster s'ha dut a terme la síntesi estereoselectiva de ciclobutan-1,2-diamines protegides ortogonalment. S'han sintetitzat els quatre estereoisòmers de la ciclobutan-1,2-diamina partint d'un intermedi comú, l'àcid 2-metoxicarbonil-(1S,2R)-ciclobutan-1-carboxílic, del qual es disposen metodologies en el nostre grup de recerca per fer-ne la síntesi de manera enantioselectiva