Towards the synthesis of the IJK fragment of the marine polyether CTX3C.
PhD thesis, University of Glasgow.
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This thesis details the development of methods for the preparation and the functionalisation of cyclic enones, which may be utilised for the synthesis of marine polycyclic ether natural products. These metabolites are among the most complex and challenging toxins isolated so far.
The first chapter serves as an introduction to such complex natural products and describes their toxicology and biogenetic origins. A literature review of the advances made within the Clark group as well as in other laboratories toward the iterative and biomimetic synthesis of polycyclic ethers is also included with particular emphasis on the ciguatoxins. This is followed by a review of olefin metathesis and the use of ring-closing and ring-rearrangement metathesis reactions for the preparation of cyclic ethers.
Chapter 2 describes efforts towards the synthesis of seven- and eight-membered cyclic enones from commercially available carbohydrate derivatives. Cyclic ethers are prepared by ring closing metathesis of dienone precursors. The functionalisation of seven-membered system involves the utilisation of highly enantioselective reactions, such as copper-catalysed conjugate addition of dialkylzinc reagent and Tsuji-Trost allylation. The cyclisation of the dienone precursor of the eight-membered ring system proved to be problematic. In this case, the importance of the allylic substituent on the RCM reaction was demonstrated. Also, a two-directional approach to the IJK fragment of the marine polycyclic ether CTX3C was proposed. A reliable and relatively inexpensive synthetic pathway has been established to the first key intermediate. This latter was prepared in 1.6% overall yield over fourteen steps. Finally, the different options for the future work are discussed.
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