APPROACH TO THE SPIROKETAL RINGS OF THE ALTOHYRTINS

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The altohyrtins comprise a newly-discovered class of potent cytotoxic macrolides of marine origin. The independently-isolated, and structurally identical, spongistatins have shown exceptional activity towards a variety of tumor types. Convergent synthetic assemblage of these natural products is our long term goal. Structurally unique, these compounds possess two separate spiroketal units, based on the 1,7-dioxaspiro[5.5]undecane ring system, which form the backbone of their molecular framework. Both of these spiroketals possess a methylenecarbonyl group attached to the C(2)-carbon. The synthetic design of these individual spiroketal ring systems will be the focus of our short term goals. The first objective of this research will be to develop a route to the basic spiroketal structure possessing a C(2) acetic acid appendage, for which an intramolecular 2-oxetanone ring opening strategy forms the basis. An oxocarbenium ion, generated by carbonyl-assisted ring cleavage of a 2-oxetanone ring, is to be trapped internally by a second carbonyl group to form a spiro-oxocarbenium ion. Reaction would terminate with nucleophilic addition of a silane-based reagent to this ion. Previous work by the investigator suggests that the dione precursor for spiroketal formation could be obtained by oxidative cleavage of a cyclopentene ring, and reacted in situ. The second objective will be to gain a thorough understanding of key aspects of stereocontrol in this reaction. The influence of substituents on the reactive conformation of the key spiro-oxocarbenium ion intermediate, as judged by the stereochemistry of reaction products, will be determined.