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A Powerful Enantioselective Organocatalytic Approach to the Total Synthesis of
Madangamine Alkaloids

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Closing in on a powerful therapeutic

Cytotoxins, compounds toxic to cells, abound in nature as one organism's way to protect itself against another. Scientists investigated the synthesis of a newly discovered family of these that could help protect people against cancer.

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Humankind's use of cytotoxins abounds, with examples ranging from beauty treatments to natural pesticides to various disease therapies. Madangamines, a novel group of pentacyclic (containing five rings) cytotoxic alkaloids from marine sponges, are gaining growing attention for their ability to kill cancer cells. To date, six members have been isolated and named madangamine A to F. However, synthesis is a complex multi-step pathway involving numerous reactions. Total synthesis (complete synthesis of an organic molecule from precursors) and industrial-scale production would provide important new weapons in the battle against cancer. This provided the impetus behind the EU-funded project 'A powerful enantioselective organocatalytic approach to the total synthesis of madangamine alkaloids' (POWORMAD). All madangamines discovered so far have the same tricyclic core consisting of ABC rings. The project explored two synthetic strategies, fast and efficient ways to synthesise the common tricyclic core and similarly easy ways to build the other macrocyclic rings that are fundamental to biological activity. Scientists started with madangamine D, as the saturated macrocycle D necessary for the synthesis of madangamine D can be made from several different reaction pathways. Synthesis of madangamine D requires over 20 synthesis phases, including many with enantioselective formation of certain products. This means that two compounds of identical chemical formula but different chemical structure must be distinguished and only one included in the reaction. The difficulty and complexity of the reactions has made the total synthesis of this molecule quite elusive. The project combined catalysis, total synthesis and structure elucidation. Researchers successfully carried out numerous synthetic steps that brought them to the threshold of the madangamine D molecule. Its first total synthesis will be a milestone in the history of organic synthetic chemistry and open a door to a novel natural way to stop cancer cells in their tracks. POWORMAD has made an important contribution to the realisation of that event.

Keywords

Cytotoxins, cancer, alkaloids, madangamine, total synthesis, enantioselective, tricyclic core, macrocycle

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