New Synthesis-Enabling Reactions and Reaction Cascades for the Discovery and Production of Potential Anti-Cancer Compounds

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Alongside the surgeon's knife and radiotherapy, chemotherapy is one of the most effective weapons especially on inoperable and aggressive cancers such as small cell lung cancer. To date there are still many more cancers than effective medicines and there remains the need for effective anti-cancer treatments that are both selective and potent. The majority of the existing drugs in clinical use are of natural origin or are man made analogues of these natural products. These (often) cytotoxic natural products are employed by the host organism as a means of self-defense and over millennia have evolved to be both potent and selective in their modes of action against predators. An excellent example is paclitaxel [taxol] first isolated from the pacific yew tree and currently used in the treatment of lung, ovarian and breast cancers. If the natural product can be harvested on scale and in a sustainable fashion, or be created by fermentation techniques in the laboratory, then an effective marketable drug can be developed. When this is not possible the only remaining option is to manufacture through the process of chemical synthesis. However, these target molecules often possess such complex three dimensional structures that the traditional, one-step, one-pot chemical synthesis approaches become so lengthy that only milligram quantities can be obtained. This problem maybe overcome by the strategic implementation of new synthesis enabling reactions and reaction cascades into chemical routes from appropriate and readily available starting materials. These can allow the construction of the complex target molecules in around 15 steps, compared with 30-40 steps using traditional approaches. Accessing complex molecules in around 15 steps means that these molecules (and libraries of analogues) may now be made at speed and possibly on gram scale. In addition, large quantities of late stage intermediates resembling in part the natural product can be accessed and converted into libraries of structurally simplified natural product analogues. Such synthesis capability may allow thorough biological evaluation for the first time and the creation of powerful structure / activity relationships that can be fed back into the synthesis cycle, potentially resulting in compounds with enhanced biological activity, and eventually lead to attractive drug candidates. Our group has been engaged over the past 3 years in the discovery and development of new asymmetric catalysts, new powerful catalyst-enabled synthetic methodology and most relevant to this proposal, new catalyst and multi-catalyst enabled reaction cascade sequences. Reaction cascades are powerful in synthesis as they allow a series of bond-forming reactions to occur in a single vessel / thus building complexity and maximizing efficiency. By judicious choice of starting materials and catalysts, advanced intermediates can be created in one efficient operation. During the five year Fellowship we wish to significantly expand the lines of research opened up by these preliminary studies, develop new catalyst enabled synthetic methodology and reaction cascades, and apply the findings to the total synthesis of a number of complex bioactive alkaloid natural products. For the first three years of the fellowship we wish to develop new chemistry and strategies leading to the short and effective stereoselective total synthesis of both daphniyunnine D and manzamine A (and their analogues for biological evaluation and the development of SAR).