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Dihydropyran and oxetane formation via a transannular oxa-conjugate addition

Dihydropyran and oxetane formation via a transannular oxa-conjugate addition. Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007. Laulimalide. Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules

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Dihydropyran and oxetane formation via a transannular oxa-conjugate addition

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  1. Dihydropyran and oxetane formation via a transannular oxa-conjugate addition Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007

  2. Laulimalide • Cytotoxic marine polyketide • Potential anticancer agent, similar to Taxol • Stabilizes microtubules • Isolated from sponge in trace amounts • Insufficient material for clinical development Pacific marine sponge Cacospongia mycofijiensis Microtubules (green) during cell division

  3. Producing laulimalide • Engineering of a recombinant biosynthetic pathway • Produce macrocyclic precursors by fermentation • Several synthetic transformations will have to be validated • install the transannular dihydropyran • 2,3-Z olefin. • Provides new rapid and efficient strategy for total synthesis

  4. Proposal for biosynthetic origin of dihydropyran laulimalide scytophycin C Pyran and cis olefin may form via a non-enzymatic method

  5. Hypothesis tested using model system 8.2 kcal/mol more stable • Can we form dihydropyrans via transannular oxa-conjugate addition in 20-membered rings? • Is oxa-conjugate addition a stereoselective reaction? • Kinetic or thermodynamically controlled? Energy calculations: DFT B3LYP/6-G31 d p level

  6. Model Systemsynthesis

  7. 1,3-Diols are separable • Deprotection revealed 2 spots on TLC • Characterized by Rychnovshky method by preparing acetonides dr 1:1 anti syn

  8. Oxa-conjugate addition unexpected product • Highly strained trans oxetane is formed • Under basic conditions diols are not reactive syn diastereomer Single diastereomer Confirmed by COSY, HSQC, HMBC, NOESY 14.2 kcal/mol higher energy than dihydropyran Energy calculations: DFT B3LYP/6-G31 d p level

  9. Two possible mechanisms for oxetane formation • SN2 displacement • Elimination/addition • If SN2, anti diastereomer must produce cis oxetane

  10. Anti diastereomer also produces trans oxetane • Since inversion of stereochemisty is not observed cannot be SN2 displacement • Mechanism must be elimination, oxa-conjugate addition anti diastereomer 14.2 kcal/mol 13.3 kcal/mol higher energy than dihydropyran Energy calculations: DFT B3LYP/6-G31 d p level

  11. E1cB-like mechanism • Elimination is likely rate determining • Not reversible mechanism • Intermediate is not observed

  12. Cis triene may access dihydropyrans • Olefin geometry may play role in oxetane formation Energy calculations: DFT B3LYP/6-G31 d p level

  13. Cyclic carbonate produces cis triene • Cis triene is generated under basic conditions from both syn and anti diastereomers

  14. Cis triene produces new compound Amberlyst conditions yields a new compound as shown by LC-MS trans oxetane cis triene 4 hrs uncharacterized new compound

  15. Conclusions • Transannular oxa-conjugate addition can occur • High energy oxetane favored over low energy dihydropyran • Unusual regioselectivity of acid catalyzed oxa-conjugate addition • Regioselectivity could be attributed to olefin geometry of elimination (triene intermediate)

  16. Acknowledgements • Dr. Christopher Boddy • The Boddy lab members • Deborah Kerwood • Department of Chemistry • Syracuse University

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