Construction of carbocycles via oxonium ylides generation and rearrangement: towards the synthesis of taxol.
PhD thesis, University of Glasgow.
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The diterpenoid natural product Taxol, first discovered in the late 1960’s, is one of the most important current drugs for the treatment of several cancers including breast and ovarian cancers. Although tremendous efforts towards its synthesis have been made in the last two decades, resulting in six elegant total syntheses, Taxol still constitutes a remarkable challenge for organic chemists due to its unique structural framework.
The high level of interest has spilled over to our laboratory, the purpose of this thesis was to develop an approach for the construction of medium-ring fused polycarbocyclic systems, which would then be applied to the synthesis of the sterically hindered eight-membered ring of the tricyclic core system of Taxol. Described herein is the continuation of efforts focused towards the access of fused medium-ring carbocycles by tandem catalytic oxonium ylide generation and rearrangement. The novel method in which intramolecular reaction of metal carbenoids with α-vinyl ethers and subsequent [2,3]-rearrangement of the cyclic oxonium ylide intermediates has been used as a powerful strategy to produce linearly fused bicyclic and tricyclic systems.
Following the success of our methodology, a key diazoketone intermediate was chosen to establish the viability of our strategy, before embarking on the total synthesis of Taxol. The efficient synthesis of the required diazoketone is discussed in detail, after the exploration of many different approaches. Finally, studies concerning the catalytic decomposition of the diazoketone towards the tricyclic core system of Taxol are presented.
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