Oxa-conjugate additions

1. Oxetane vs. Dihydropyran Formation via a Transannular Oxa-conjugate Addition Stephen Houghton and Christopher N. Boddy* Department of Chemistry, Syracuse University Syracuse, NY 13244 Stereochemical assignment Possible mechanisms for oxetane formation Oxa-conjugate additions Laulimalide • Cytotoxic marine polyketide • Potential anticancer agent • Isolated from sponge in trace amounts • Likely from symbiotic bacteria on sponge • Epoxide is essential Transannular oxa-conjugate additions can be highly stereoselective Computational studies Biosynthetic origin of Dihydropyran is unclear Predict a stereoselective elimination and Eisomers cannot undergo oxa-conjugate addition Basic conditions are unreactive Cyclic carbonate J. Org. Chem., 1988, 53, 3644-3646 Pyran and cis olefin may form via a non-enzymatic method Pacific marine sponge Cacospongia mycofijiensis Syn carbonate is well aligned to undergo E2 elimination. cis triene generated through elimination Biological Activity • Stabilizes microtubules • Similar quantitatively to taxol • Binds to different site on tubulin polymer • Active on Taxol & epothilones A and B resistant cell lines 4 possible diastereomers Microtubules in two human osteosarcoma cells in interphase of the cell cycle. Microtubules are in red, chromatin is in blue, and centromeres are in green. desoxylaulimalide Test hypothesis with a model system How are most Cycloethers formed? Triene may access dihydropyran Synthesis of Macrocycle 1,2-diol type structure implicates epoxide opening mechanism Diols produce oxetanes monensin Epoxide opening does not explain all cycloethers trans oxetane Cis triene under Amberlyst conditions yields a new compound as shown by LC-MS which could be the dihydropyran cis triene laulimalide scytophycin C Michael addition may generate cycloethers Oxetane structure confirmed by 1H NMR, 13C NMR, HSQC, COSY, NOSEY, HMBC uncharacterized new compound Acknowledgements: The Boddy Research Group, Deborah Kerwood, Syracuse University Dept. of Chemistry