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The University of Southampton
Chemistry

Research project: Oxidative Cyclisation: Total Syntheses of Acetogenins

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Annonaceous acetogenins have attracted huge interest due to their exceptional cytotoxicity towards cancer cells (IC50 values µM–sub nM). Our aim has been to develop selective oxidative cyclisation strategies for the synthesis of the mono-THF, adjacent bis-THF and non-adjacent bis-THF subclasses of acetogenins. We have completed total syntheses of 7 acetogenins including mebranacin, cis-sylvaticin and cis-reticulaticin-10-one.

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Project Overview

Our synthesis of cis-solamins illustrates the efficiency of the oxidative cyclisation approach to these cis-2,5-disubstituted mono-THF acetogenins. The methodological theme explored the selectivity of oxidative cyclisation mediated by the permanganate ion, and allowed us to avoid the use of hydroxyl protecting groups in the fragment assembly stages for the synthesis of cis-solamin.

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A number of synthetic acetogenins and acetogenin analogues have been evaluated for cytotoxic, haemolytic activity, and Complex I inhibition. We also discovered that cis-solamin and other mono-THF compounds exist in nature as mixtures of diastereoisomers, which are tetra-epimeric within the THF diol motif (Collaboration with Prof. Figadere and Prof. Chapman). Although many research groups have isolated these types of compounds from natural sources, it was only through our total syntheses that we have uncovered this fact.

Current projects focus on stereochemical assignment of the diepomuricanins, which are bis-epoxide containing acetogenins and putative biosynthetic precursors to solamin and cis-solamins. Another aspect of this project is the application of permanganate-mediated oxidative cyclisation to the synthesis of novel acetogenin analogues, which will undergo biological evaluation for anti-tumor and insecticidal activity.

Related research groups

Organic Chemistry: Synthesis, Catalysis and Flow

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