Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/102991
Title: Intermolecular Pauson-Khad reaction: study of the regioselectivity, photochemistry of the adducts and synthetic applications
Author: Khaizourane, Héléa
Director: Riera i Escalé, Antoni
Keywords: Reaccions d'addició
Reacció de Pauson-Khand
Addition reactions
Pauson-Khand reaction
Issue Date: 11-Mar-2016
Publisher: Universitat de Barcelona
Abstract: [eng] The Pauson-Khand reaction (PKR), introduced by Pauson and Khand in 1973, is an efficient method to access the synthesis of five-membered rings in one single step. This reaction is a transition metal-mediated [2+2+1] carbocyclisation between an alkyne, an alkene and carbon monoxide (CO). It forms a cyclopentenone where two new asymmetric centres would be created if the alkene is disubstituted. This reaction is commonly mediated by a cobalt complex such as Co2(CO)8. In the intermolecular PKR, when the synthesis involves terminal alkynes, the reaction is highly regioselective affording a single cyclopentenone with the substituent in a to the carbonyl group. However, the regiochemical outcomes of the PKR of unsymmetrical internal alkynes are difficult to predict since it can afford two regioisomers, a/f3. The first objective of the doctoral thesis was to better understand and predict the regioselectivity of the intermolecular PKR. We have successfully carried out a study using a full set of aliphatic alkynes bearing sterically similar but electronically different substituents. Indeed, the influence of the electronic effects over the regioselectivity of the intermolecular PKR of aliphatic alkynes has been predicted by theoretical calculations of the alkyne. Thus, when substituents bearing more electronegative atom than the carbon, -I groups yielded tofi —regioisomer with a remarkably high regioselectivity. While a less electronegative atom than the carbon inverted the regioselectivity toward the a-regioisomer. The computational NBO charges around the carbon of the alkyne and at its a-position indicated that the polarization of alkyne was inductively mediated from the heteroatom. Thus, the alkyne polarization of the substituents in a-position of the alkynes can alone qualitatively predict the regiochemical outcome of the PKR. The results were published in Journal of Organic Chemistry,2014, 79, 10999-11010. The second objective of the thesis was devoted to find synthetic applications of the adducts of the intermolecular PKR. The methodology was applied to the synthesis of natural products and phenanthrene derivatives. The intermolecular PKR of internal alkynes proved to be the best method to synthesize the rac-sarkomycin methyl ester (anti-cancer drug). Thus, the fastest total synthesis of the rac-sarkomycin methyl ester was achieved in 2-pot reaction and 15 % overall yield and will be submitted to publication. A new pathway was undertaken to obtain methyl jasmonate (frangance) from intermolecular PKR of unsymmetrical alkynes or terminal alkyne. The first pathway used the PKR of unsymmetrical alkyne where our model to predict the regioselectivity was employed. It revealed that even the formed adduct gave the opposite isomer that we would expect, the computational NBO charges correlated well the experimental outcome. The second pathway was carried out with the PKR of terminal alkyne. Our preliminary results allowed us to identify that the Claisen-Johnson rearrangement used as key step could be applied in the synthesis of the methyl jasmonate. In the third objective, synthetic applications of intermolecular PKR of symmetrical alkynes toward photochemical transformations were undertaken from diaryl and heterocyclic alkynes. The electrocyclisation reaction of the PKRs of disubstituted aryl alkynes could be optimised affording a new access to phenanthrene derivatives. This photochemical reaction induced the formation of two possible atropoisomers which by the steric hindrance of the PK adducts imposed by its substituents afforded a mixture of twisted isomers assimilated to helicene- like family. The PKR of bis(dimethyl phenyl) and bis(trimethyl phenyl) alkynes and norbornene were optimised affording excellent yields and times of reaction. The results were published in European Journal of Organic Chemistry, 2012, 30, 6058–6063. The reactivity of heterocyclic alkynes such as pyridyl and thiophenyl motifs regarding the PKR and photochemical reactions were studied. While the pyridyl motif did not afford the PK adduct, for the first time, PK adduct of the bis (dimethyl thiophenyl) alkyne successfully gave the reversible photoswitch reaction even the PKR gave low yield.
[cat] La reacció de Pauson-Khand (PKR) descoberta durant l'any 1971 per P. L. Pauson i I. U. Khand, és formalment una cicloaddició [2+2+1] entre un alquè, un alquí i una molècula de monòxid de carboni típicament mediada o catalitzada per un complex de cobalt, generalment Co2(CO)8. En la PKR intermolecular quan falquí és terminal, la regioselectivitat és fàcil de determinar i només dóna un regioisòmer amb el substituent en a de l'adducte. Però, els resultats de la regioselectivitat son difícilment previsibles quan s'utilitzen alquins interns, i s'obtenen unes mescles de a i [3 regioisòmers en proporcions variables. El primer objectiu d'aquesta tesi va ser l'estudi de la regioselectivitat de la PKR intermolecular amb una varietat d' alquins interns amb substituents amb diferents propietats electròniques per un lloc i per altre lloc una cadena alifàtica. Es va establir una relació entre els canvis electrònics d'alquins asimètrics i els resultats de la regioselectivitat dels adductes de PKR de manera experimental i computacional. Els resultats van ser publicats al Journal of Organic Chemisty 2014, 79, 10999-11010. El segon objectiu de la tesi va ser la recerca d' aplicacions sintètiques dels adductes de la PKR intermolecular a la síntesi de productes naturals com l'èster metílic de la rac-sarcomicina (medicament contra el càncer) sintetitzat en només 4 passos i un rendiment global de 15%. Una nova via es va plantejar per obtenir l'èster metílic del jasmonat (fragància) mitjançant una reacció de PK intermolecular d'alquí terminal i una reacció de Claisen-Johnson que montren bons resultats preliminars. En el tercer objectiu, es van dur a terme aplicacions sintètics de la reacció de PK intermolecular d'alquins simètrics d'arílics i heterocíclics mitjançant transformacions fotoquímiques. Per primera vegada, el adducte PK del bis(dimetil tiofenil) alquí va donar amb èxit la reacció fotoreversible tot i que la PKR va donar baix rendiment. La reacció d'electrociclació dels adductes de PK d'alquins disubstuïts arílics es va poder optimitzada amb bons rendiments i temps de reacció donant un nou accés a derivats de fenantrens torçats quirals. Els resultats van ser publicats en l'European Journal of Organic Chemisty, 2012, 30, 6058-6063.
URI: http://hdl.handle.net/2445/102991
Appears in Collections:Tesis Doctorals - Departament - Química Orgànica

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