Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/51883
Title: Reactivity and Applications of New Substrates for the Intermolecular Pauson-Khand Reaction: N-Boc-propargylamines and trifluoromethyl alkynes
Author: Aiguabella Font, Núria
Director: Riera i Escalé, Antoni
Keywords: Síntesi asimètrica
Prostaglandines
Reacció de Pauson-Khand
Compostos ciclopentànics
Alquins
Asymmetric synthesis
Prostaglandins
Pauson–Khand reaction
Five-membered-ring compounds
Alkynes
Issue Date: 7-Feb-2014
Publisher: Universitat de Barcelona
Abstract: [spa] La reacción de Pauson-Khand (PKR) es, formalmente, una cicloadición [2+2+1] que transcurre entre un alqueno, un alquino y una molécula de monóxido de carbono. Como producto de esta reacción, típicamente mediada o catalizada por un complejo de cobalto (0), se genera una ciclopentenona. Los compuestos ciclopentánicos son muy abundantes en la naturaleza, y presentan gran variedad estructural y funcional. Probablemente, dos de las familias de compuestos ciclopentánicos más conocidas son la de las prostaglandinas y la de los fitoprostanos. En los últimos años se ha descubierto que algunos de estos productos (o derivados) poseen propiedades altamente interesantes (como, por ejemplo, actividad antitumoral). La dificultad de aislarlos de fuentes naturales ha despertado un gran interés por desarrollar métodos eficientes para obtenerlos sintéticamente. Dado que estos productos comparten un anillo de ciclopentenona como elemento estructural, constituyen unos substratos ideales para ser sintetizados mediante una PKR. Durante la presente tesis se ha desarrollado una metodología para sintetizar prostaglandinas y fitoprostanos a partir del aducto de PK del norbornadieno y la N-Bocpropargilamina. La síntesis de dicho producto de partida puede realizarse de manera enantioselectiva, de modo que el producto final puede obtenerse, asimismo, de modo ópticamente enriquecido. Esta metodología se ha ensayado con la síntesis del éster metílico de un fitoprostano natural: el ácido 13-epi-12-oxo fitodienóico. Por otro lado, al inicio de esta tesis, no se había realizado nunca una PKR intermolecular con alquinos fluorados y considerando que las particulares propiedades esteroelectrónicas de estos productos podían influir de un modo interesante en la regioquímica de la reacción, decidimos estudiarlos en profundidad durante esta tesis. La principal conclusión que se ha obtenido es que los substituyentes fluorados siempre ocupan la posición alfa al carbonilo en las ciclopentenonas finales. En el caso de que el substituyente fluorado sea un trifluorometilo, se ha desarrollado una metodología que permite quitarlo para obtener los hasta ahora desconocidos regioisómeros de aductos de PK de alquinos terminales. También se ha desarrollado una metodología para realizar dichas PKRs de forma asimétrica y obtener los aductos ópticamente puros. Como aplicación de esta estrategia, se ha realizado una síntesis formal de la alfa-cuparenona, un sesquiterpeno natural.
[eng] The Pauson-Khand reaction (PKR) is, formally, a [2+2+1] cycloaddition involving an alkene, an alkyne and a carbon monoxide molecule, typically mediated or catalyzed by a cobalt (0) complex. The product of this reaction is a cyclopentenone. This reaction, discovered in 1973 by P. L. Pauson and I. U. Khand constitutes, nowadays, one of the most prominent methods for the synthesis of five-membered ring compounds. Regarding whether the alkene and the alkyne belong to the same molecule or are two different entities, we refer to the intra or intermolecular PKR, respectively. The intramolecular PKR has been the most extensively used one, since it allows the formation of complex polycyclic structures in very few synthetic steps and both the regio and stereoselectivity of the reaction are substrate-controlled. The intermolecular PKR has been traditionally less studied and exploited due to the limitations it presents. First of all, when the alkyne is internal and non-symmetrical the reaction may yield mixtures of regioisomers in different proportions depending on the electronic and steric properties of the substituents. If the reaction is carried out with a terminal alkyne, only one product is formed: the one that has the substituent alpha to the carbonyl in the final cyclopentenone. On the other hand, the reaction is very tolerant to different alkynes, but only tensioned and cyclic alkenes react satisfactorily, ethylene being an exception to this rule. Cyclopentanic compounds are very abundant in nature, and they present a great variety of structures and functions. Probably, two of the most well-known families of cyclopentanic compounds in nature are prostaglandins and phytoprostanes. Prostaglandins are generated by the action of cyclooxygenase (COX) on the fatty acids that come from the phospholipid bilayer. The most common substrate for this reaction cascade in the human body is arachidonic acid. In plants, a similar process occurs with linolenic acid as substrate and the family of phytoprostanes as product. The extremely interesting properties of these compounds, such as antitumor activity, along with the difficulty to isolate them from natural sources, has led to an increasing interest on finding simple and efficient methods to access them. The fact that these products share a cyclopentenone ring (or a derivative) as a structural feature makes them aperfect synthetic target for the PKR. During the present thesis, we have developed a methodology to synthesize prostaglandins and phytoprostanes from the PK adduct of norbornadiene and N-Bocpropargylamine. The synthesis of the aforementioned starting material can be carried out enantioselectively, so that the synthetic target can also be obtained as a single enantiomer. This methodology has been applied to the synthesis of a natural phytoprostane derivative: the methyl ester of 13-epi-12-oxo Phytodienoic acid. The introduction of fluorinated substituents in organic molecules is extremely interesting, since the presence of these functional groups modifies the chemical and physical properties of the molecules to which they are incorporated. Given that, at the beginning of this thesis, there were no precedents of the intermolecular PKR of fluorinated alkynes, and considering that the particular stereoelectronic properties of these products could have an interesting impact on the regiochemical outcome of the PKR, we decided to study them in this work. Our main conclusion has been that fluorinated substituents always occupy the alpha position to the carbonyl in the final cyclopentenone. This fact indicates that the steric bulk of fluorinated groups is larger than expected and overcomes its electronic properties (it is accepted that electron-donating groups prefer the alpha position in the final PK adduct, whereas electron-withdrawing groups prefer the beta position). Furthermore, in the case of trifluoromethyl alkynes, we have developed a methodology that allows to remove this group in order to obtain the previously unknown beta-substituted regiosiomers of PK adducts of terminal alkynes. We have also developed a methodology to carry out the synthesis of trifluoromethyl PK adducts enantioselectively. As an application of our methodology, we have developed a formal synthesis of alpha-cuparenone, a naturally occurring sesquiterpene.
URI: http://hdl.handle.net/2445/51883
Appears in Collections:Tesis Doctorals - Departament - Química Orgànica

Files in This Item:
File Description SizeFormat 
NAF_THESIS.pdf2.41 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.