Zirconocene mediated co-cyclisation reactions

Abstract

The novel work in this thesis covers three quite different areas of organozirconium chemistry.

The first is the synthesis of oxacycles by zirconocene mediated co-cyclisation, of which the literature contains few examples. 1,7-Enyne substrates based on alkoxyalkynes cyclise in good yield to provide tetrahydropyrans. The presence of an exocyclic, tethered alcohol functionality in the cyclised product allows a second, acid catalysed cyclisation to occur, providing a novel route to spiroketals.

In the second area, the feature peculiar to the zirconacycles prepared is a leaving group β to zirconium. In all cases, elimination of Zr-leaving group occurs to provide an alkene. Where the cyclisation substrates are 1,6-dienes or enynes prepared from dihydrofuran, cyclisation occurs despite the hindered nature of the enol ether double bond. Where the substrates are prepared from ethyl vinyl ether, the enol ether double bond is disubstituted, and a wider variety of 1,6-dienes and -enynes can be cyclised in yields of up to 89%. Chiral centres in the substrate often induce excellent diastereocontrol of the newly generated methyl group. The important feature of the cyclisation products is an exocyclic methylene group. As these methylene cyclopentanes are difficult to prepare from terminal alkyne substrates, our methodology provides an excellent route to these compounds. The cyclisation products are also monoalkyl zirconocenes, which we wished to functionalise further using carbenoid insertion chemistry. We have shown that ethoxy groups on zirconium inhibit carbenoid insertion, whereas chloride groups allow vinyl carbenoid insertions to occur in yields of up to 75%.

The third area of research was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo [4.3.0] nonane unit with four contiguous stereocentres. We prepared a co-cyclisation substrate which precedent suggested would provide only the desired diastereomer of the bicycle and a handle for introduction of the remainder of the natural product skeleton. Unfortunately, the co-cyclisation provided a mixture of products. Investigation was made into dihydro and despropyl analogues, which we hoped would provide single products on co-cyclisation. Although the synthesis was not completed, we have laid down groundwork which we hope will lead to a successful completion at a later stage.

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