ALKALOID SYNTHESIS USING ORGANORHODIUM CHEMISTRY

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The goals of this research proposal are the total synthesis of several members of the Amaryllidaceae alkaloid family, crinine, haemanthidine and pretazettine and the synthesis of the alkaloid dendrobine. Our plan centers around the further development of organorhodium chemistry in organic synthesis and the demonstration of the power and versatility of a new rhodium based olefin functionalization reaction which was recently discovered in our laboratories. The Amaryllidaceae alkaloids display a wide range of biological activity. Some members of the class have been shown to exhibit pronounced anti-bacterial and anti-fungal activity. Crinafoline and pretazettine have been shown to reduce the growth of cancer tumor cells. Pretazettine also shows antiviral activity. HAEMANthidine halts protein synthesis in eukaryotic cells by inhibiting the peptide bond formation step. The analgesic activity of galanthamine has been attributed to its resemblance to the morphine skeleton. Our approach to the synthesis of the Amaryllidaceae alkaloids will initially focus on the syntheses of the protein synthesis inhibitor, haemanthidine; crinine, which is thought to be a biosynthetic precursor to haemanthidine; and the antiviral alkaloid, pretazettine. Haemanthidine and crinine were both isolated from Crinum asiaticum. Their structures were determined by spectroscopic means and chemical transformations. Pretazettine was isolated from a variety of sources including Haemanthus natalensis and H. harrisiana application of our synthetic route to the synthesis of other biologically active Amaryllidaceae alkaloids is planned. Dendrobine is representative of a group of sesquiterpene lactone alkaloids, produced by the orchid species Dendrobium nobile, whose skeletal structure and pharmalogical properties are similar to those of the potent convulsant picrotoxin. The ornamental Chinese orchid from which Dendrobine was isolated was originally used to make the Chinese drug "Chin-Shih-Hu". Dendrobine has been shown to be effective in antidoting barbituate intoxication and it also shows beta-alanine and taurine antagonizing properties. Both the Amaryllidaceae alkaloids and Dendrobine provide ideal targets for investigating the scope of our new rhodium promoted olefin functionalization reaction sequence.