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Hydroacylation and C-N Coupling Reactions. Mechanistic Studies and Application in the Nucleoside Synthesis

by Marcé Villa, Patricia

Abstract (Summary)
The PhD work Hydroacylation and C-N coupling Reactions. Mechanistic Studies and Application in the Nucleoside Synthesis tackle two different objectives, a) developing new methods of synthesis of nucleosides (introduction, and chapters 1 and 2) and b) to carry out a mechanistic study of the intermolecular hydroacylation and hydroiminoacylation reaction with and cationic rhodium complexes (chapter 3). Concerning the synthesis nucleosides, in chapter 1 we have explored new methods of synthesis of 2,3-dideoxynucleosides and isonucleosides using a palladium or copper catalyzed C-N coupling reaction, aiming to overcome the stereoselectivity problems of the glycosylation reaction. The synthesis of the iodo-vinyl derivatives required as starting materials has been tried by different procedures, all of them unsuccessful. Finally, the coupling reaction has been explored in 1-iodo-glucal derivatives. Palladium catalysts were unsuccessful in coupling with benzimidazol used as model of purinic bases. Copper catalysts provided very low conversions. However, the oxidative addition of 1-iodo-glucal to palladium was proved and it was also observed that the reaction with aniline proceeds. That, suggest that the problem is in the steps involving the benzimidazol. In chapter 2, it has been developed a new method of synthesis of carbocyclic nucleosides using and enantioselective intramolecular hydroacylation reaction as a key step. This reaction leaded to the 3-hydroxymethyl-cyclopentanones in good yields and excellent enantioselectivities. When (S,S)-Me-Duphos was used the 3S-cyclopentanone was obtained, in contrast whether the (R,R)-Me-Duphos was employed the reaction proceed giving the opposite enantiomer. In both cases. The reduction of the ketone can be carried out in a stereoselective way using a hydroxyl-assited reduction with NaBH(OAc)3. Alternatively, the diastereomeric mixture obtained by a direct reduction can be resolved by using a DKR process using a combined enzyme/Ru complex catalytic system. A Mitsunobu reaction has allowed finally to link adenine to the cyclopentane moiety. In the third chapter, the mechanism of both cationic and neutral rhodium catalyst precursors in the hydroiminoacylation of alkenes was studied. The oxidative addition step was studied using both NMR and DFT techniques. Using the neutral complex, this step is a thermodynamically favoured process, as demonstrated by the isolation of the stable complex. Furthermore, DFT calculations showed the existence of an agostic intermediate on the route to the C-H activation product. In the cationic system, the oxidative addition reaction was shown by DFT calculations to be an endothermic process, hence un-favoured. This was in agreement with the NMR experiments, in which an oxidative addition product was only detected in the presence of a chloride source. Furthermore, the transition states involved in both systems were identified using DFT calculations, which proved that the presence of chloride not only stabilize the oxidative addition product but also lower the energy barrier of the overall process. Using the neutral system, it was identified the coupling product still coordinated to rhodium, which is in an enamine tautomeric form. After removal of the coupling product the stable complex [Rh(?-Cl)(PPh3)2]2 was formed. This species was reported as a precursor for the oxidative addition step, from which the catalytic cycle can start again. However in the cationic system, the system did not yield any stable rhodium species and quickly evolved towards decomposition.
This document abstract is also available in Spanish.
Bibliographical Information:

Advisor:Castillón Miranda, Sergio

School:Universitat Rovira i Virgili

School Location:Spain

Source Type:Master's Thesis

Keywords:departament de química analítica i orgànica

ISBN:

Date of Publication:05/23/2008

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