Among the classes of organic transformations, cycloaddition reactions constitute a powerful and versatile strategy for the rapid assembly of complex polycyclic scaffolds in a highly stereos elective fashion. A unique feature of this class of reactions resides in the possibility to alter the geometry and coordination number of the metal centre in order to increase the reactivity and selectivity of the process. Hence, the development of this strategy highlighted the opportunity to synthesize complex molecular architectures in a highly convergent and stereos elective manner using mild operating conditions, thereby improving the efficiency with respect to atom-economy and environmentally benign synthesis. Among the metal-catalysed carbocyclisation reactions, the Pauson-Khand (PK) methodology enables the straightforward construction of cyclopentenone derivatives from readily available synthons. Distinguishing feature of this reaction is the incorporation of a carbon monoxide unit into a polycyclic framework with the production of carbonyl systems that are amenable of further functionalisation. In this context, we performed a detailed computational analysis of the mechanism of the Rh-catalysed diastereoselective PK reaction. This study outlined the possibility to enhance the reactivity of 1,6-enynes towards the carbocyclisation through the incorporation of electron-withdrawing substituents on the alkyne terminus. Further experimental analysis revealed that the employment of a chlorine substituent on the alkyne moiety exerted a beneficial effect on the reactivity of 1,6-enynes and thereby provided a novel highly diastereoselective Rh-catalysed PK reaction at room temperature. The enhanced reactivity of chlorinated 1,6-enynes was subsequently exploited in the Rh-catalysed asymmetric PK reaction. A detailed optimisation study revealed that the electronic and geometric properties of iv chiral bisphosphine ligands exerted a remarkable influence on the reactivity of 1,6- enynes towards the carbocyclisation process. Hence, the synergic combination of chlorinated 1,6-enynes and SEGPHOS-type bisphosphine ligands allowed a highly enantioselective rhodium-catalysed PK reaction of substrates that are generally unreactive, such as 1,6-enynes bearing substituents on the alkene position. Hence, methodology expanded the synthetic potential of the PK reaction and moreover, provided a highly enantioselective construction of bicyclopentenone scaffolds under extremely mild operating conditions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:569158 |
| Date | January 2011 |
| Creators | Ricci, Paolo |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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