Busson, MJM; (2012) Towards Neocarzinostatin chromophore. Doctoral thesis , UCL (University College London).

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Abstract

Neocarzinostatin chromophore (NCS-C) was the first isolated member of the enediyne family, one of the most potent family of anticancer agents ever discovered. Neocarzinostatin (NCS or holo-NCS) is a 1 : 1 non-covalent complex of a very reactive nine-membered ring epoxydiyne chromophore (NCS-C) tightly bound to a protein, apo-NCS. Total syntheses of Myers and Hirama, and the work of Magnus and Caddick have shown the challenges involved in the synthesis of the Neocarzinostatin chromophore, and in particular its bicyclic epoxydiyne ring. This project thesis concerns evaluation of alternative approaches towards the synthesis of strained medium size rings, such as those in the Neocarzinostatin chromophore, using McMurry coupling and acyl radical chemistry. Chapter 1 provides an introduction to the field including a discussion of the mode of action of Neocarzinostatin and a detailed evaluation of previous approaches to the Neocarzinostatin chromophore. McMurry coupling and acyl radical chemistry are also reviewed, particularly with reference to their use in strained medium ring synthesis. Chapter 2 describes studies into aerobic hydroacylations of vinyl sulfonates in view of its application to the synthesis of NCS-C core. A broader range of aldehydes can now be used for the synthesis of β-ketosulfonates. Pentafluorophenol has been shown to have an inhibitory effect on hydroacylations of vinyl sulfonates and new conditions were developed to minimise this inhibitory effect. Preliminary mechanistic studies suggest that addition of acyl radicals to vinyl sulfonates is reversible. Chapter 3 includes studies on different approaches to key epoxydiyne synthon of Neocarzinostatin chromophore. Whilst zinc mediated coupling to give the key epoxydiyne synthon was capricious, sulphur ylide approach gave access to disubstituted propargylic epoxides in good yields. Proof of principle for the synthesis of the key epoxydiyne via this method is also described.

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