A novel 1,3-dipolar cycloaddition strategy towards securinine and virosecurinine

This thesis describes the development of a novel synthetic route towards the Securinega alkaloids, securinine 1 and virosecurinine 2. The key reaction in this innovative approach is the l,3-dipolar cycloaddition between pyridinium stabilised ylides 169 and γ,δ-unsaturated butenolides 142, to form spirocyclic dihydropyridines 168 as single diastereoisomers. The Introduction chapter introduces the Securinega alkaloids and describes previous syntheses of securinine 1. This section also reports on developments in the field of l,3-dipolar cycloaddition chemistry, with particular emphasis on the cycloadditions of pyridinium stabilised ylides 169. Cycloadditions of γ,δ -unsaturated butenolides 142 with azomethine and other ylides are also described. The Results and Discussion section describes investigations which were conducted towards the total synthesis of securinine 1 and virosecurinine 2. A number of routes to γ,δ -unsaturated butenolides 191 were evaluated and are discussed. The optimum route was found to be a three step procedure from propargyl alcohols 193, via Johnson-Claisen rearrangement to 13- allenic esters, which were hydrolysed and then cyclised under transition metal catalysis. γ,δ -unsaturated butenolides 191 were then employed in l,3-dipolar cycloaddition reactions with pyridinium stabilised ylides 169. Dihydropyridines 168 formed in the cycloaddition step were found to be unstable and as such, strategies for the stabilisation of these compounds are discussed. Reduction afforded stable intermediates 229 prompting investigation to deliver intermediates that could be used to carry out the remaining cyclisation required for the synthesis of tetracyclic structures. Attempts at a variety of such ring closing reactions are described, the most advanced intermediates being committed to an intramolecular Heck reaction. Finally, expansion of the scope of the key cycloaddition reaction is described and opportunities for further developments are discussed. The Experimental section describes all procedures which were used to synthesise compounds disclosed in this thesis. Full spectroscopic data and characterisation is also provided. The Appendices include some relevant XRD, NMR and MS data for clarity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo