Freiria, Marta; (2003) Novel rhodium (I)-catalysed tandem hydrosilylation-intramolecular aldol reaction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis focuses on the study of the scope and generality of a novel atom efficient intramolecular transition metal catalysed tandem reductive-aldol cyclisation as a general stereoselective route for the preparation of carbocyclic rings from 6-oxo-2-hexenoates and related homologues. The thesis is divided into three major sections. The introductory review is divided into two sections. The first of these presents a general overview covering the significance of biologically active carbocyclic nucleosides and their previous asymmetric synthesis, with special attention devoted to asymmetric methods for the construction of the carbocyclic moiety. In a second section, some recent developments in the intermolecular reductive aldol reaction and related transformations for the preparation of carbocycles are described. The second chapter opens with a preliminary study on the optimisation of the hydrosilylation-intramolecular aldol reaction conditions that lead to the best yields and levels of stereocontrol. The results of screening a series of silanes and rhodium catalysts was effectuated and revealed several features of interest. Subsequent sections then describe the synthesis of the cyclisation precursors, comprising the development of a simple atom efficient route to 5,5-disubstituted-6-oxo-2-hexenoates. The scope of our novel methodology was then investigated, with special emphasis in the influence of the substitution pattern on reactivity and selectivity as well as in the tolerance of heteroatomic substituents. The feasibility of larger ring sizes was also assessed, as was the possibility of replacing the aldehyde functionality in the substrate by alternative electrophiles. The related hydroboration- intramolecular aldol reaction was then investigated and a variety of alternative catalysts containing a transition metal other than rhodium were evaluated. This section is followed by some mechanistic investigations and a detailed discussion on the mechanism and the stereochemical outcome of this transformation. Finally, the generality of the method was evaluated in the synthesis of the carbocyclic moiety of two biologically active carbocyclic nucleosides. The concluding section provides a formal description of the experimental results and procedures together with appropriate references.

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