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The University of Southampton

Research project: Methylenecyclopropane Derivatives

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Cascade Radical Cyclisations of Methylenecyclopropane Derivatives

Cascade radical cyclisation reactions have proved to be very popular as a synthetic strategy as they allow the construction of several C-C bonds in one step and can provide elegant synthetic routes to complex polycyclic compounds and natural products. Our recent work in this area has focused on developing cascade radical cyclisations of methylenecyclopropane derivatives which provide entry to structures not otherwise readily accessible by radical cyclisations or other cascade sequences. Our initial work sought to establish the basic rules for cyclisation of methylenecyclopropane derived radicals, depending on the length of the radical tether. Thus, for example, we found that for simple alkyl radicals, methylenecyclopropylpropyl radicals (1, n = 1) underwent exclusive 5-exo cyclisation, followed by opening of the intermediate cyclopropylmethyl radical to give methylenecyclohexanes 2, whereas longer alkyl chains (n = 2,3) led to products from exo or endo cyclisation depending on substituents.

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Following these initial studies we have investigated a series of cascade cylisations with an additional radical acceptor tethered to the methylenecyclopropane unit. For example, radical 3 undergoes an initial 5-exo cyclisation onto the methylenecyclopropane unit, followed by opening of the resulting cyclopropyl methyl radical 4 to give 5 and further cyclisations (via 6) to give tricyclic products 7 and 8. This work has been extended to the cyclisation of 1,2 disubstituted methylenecyclopropane derivatives for the synthesis of cis-fused bicyclo-3.4.0-nonanes and bicyclo-4.4.0-decanes.

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In more recent work we have used a SmI2 initiated cascade of propargyl ether 9 which leads to bicyclic ether 10 with good stereoselectivity, and provides a short route to the monoterpenoid paeonilactone B. The stereoselectivity observed in the cyclisation, which was critically dependent on the presence of HMPA has been rationalised in terms of a chair-like transition state.

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This work is a surprisingly rare example of a radical cascade sequence initiated by a ketyl radical using SmI2 and the efficiency and high stereoselectivity of the cascade has encouraged us to investigate more demanding cascade sequences which should provide novel routes to complex polycyclic compounds.

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More recent work continues to focus on samarium iodide mediated cascade reaction processes e.g. of enone 11 which in one step gives the tetracyclic product 12.

Related research groups

Molecular Assembly, Function and Structure
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