The chromoprotein Neocarzinostatin (NCS) was the first isolated member of the so- called 'enediyne' class of antibiotics and was found to exhibit broad-spectrum antitumor activity. NCS was isolated in 1965 from the bacterium Streptomyces carzinostaticus and is made up of a 1:1 non-covalent complex of an extraordinarily reactive nine-membered ring epoxydiyne chromophore (NCS-C) tightly bound to a protein known as apo-NCS. The antitumor activity arises solely from the chromophore which acts as a DNA-cleaving agent initiated by radical hydrogen abstraction of a deoxyribose residue. The apoprotein protects, carries and delivers the chromophore offering potential as a novel, more selective drug delivery system. Our general strategy towards NCS-C involves the Michael addition of an epoxydiyne to a cyclopentenone followed by cyclisation via an aldol reaction. The enantioselective synthesis of the cyclopentenone fragment had already been synthesised within the group via enzyme-mediated kinetic resolution. The aim of this project is to report our current efforts to establish a general method for the synthesis of epoxydiynes in order to apply our own Michael/aldol sequence. Different routes to these epoxydiynes have been developed using a Sharpless asymmetric epoxidation. However, these have proven to be extremely difficult due to the formation of unstable intermediates which could not be processed to fully elaborated epoxydiynes. After considerable investigation, a concise and convergent approach to epoxydiynes was finally achieved on a multi-gram scale. This involves a diastereoselective addition of an allenyl zinc bromide to propargylic ketones/aldehydes followed by epoxide formation. This new protocol enables us to synthesise fully functionalised and stereochemically pure epoxydiynes including C-8 provides a very simple synthetic route to other functionalised epoxydiynes. Owing to the flexibility of our new method, epoxydiynes with different protecting groups can now be readily prepared enabling us to screen them in new Michael addition reaction studies
