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Polyketide Synthesis

Polyketide Synthesis. Derksen Research Group St. Francis Xavier University . Polyketides : What are they? . Secondary Metabolites Often Biologically & Pharmacologically active Erthromycin A. Polyketides : What are they? . Amphotericin B Peloruside A.

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Polyketide Synthesis

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  1. Polyketide Synthesis Derksen Research Group St. Francis Xavier University

  2. Polyketides: What are they? • Secondary Metabolites • Often Biologically & Pharmacologically active • Erthromycin A

  3. Polyketides: What are they? • Amphotericin B • Peloruside A

  4. Polyketide Preparation • Specific stereochemistry can be achieved by the use of chiral auxiliaries: ex. Evans’ Method: • Advantages: popular, well-established, versatile, pre-made auxiliaries available • Disadvantages: adds steps, chromatography required, need stoichiometric amounts of auxiliary

  5. Organocatalysis • ProlineAldol: • Advantages: cheap, catalytic, good enantiomeric excess, avoids use of toxic transition metals • Disadvantages: limited substrate scope, often poor diastereomeric ratio

  6. Our Approach • Synthesis of β-hydroxyketones • Base-catalyzed aldol addition • Advantages: very cheap, fairly quick, good yield • Disadvantages: racemic mixture, chromatography required • Reformatsky • Advantages: solvent free, very simple reaction, wide substrate scope • Disadvantages: chromatography required

  7. Our Approach (cont’d) • Stereoselective retro-aldol catalysis • Catalyst requirements: stereoselective, wide substrate scope, fast reaction, good yield

  8. Nature’s Precedent • Aldolases: catalytic aldol reaction • Fructose Bisphosphate • Isoenzymes: aldolaseA, aldolase B, aldolase C • fructose 1,6-bisphosphate into glyceraldehyde3- phosphate (GADP) and dihydroxyacetone phosphate (DHAP)

  9. Nature’s Precedent (cont’d) • Fructose Bisphosphate • fructose 1-phosphate into glyceraldehyde and DHAP

  10. Chemical Literature Precedent • Rapamycin • R106 • NSERC- review

  11. Our Progress • Significant product formed using NaOH and HCl as catalysts in ethanol

  12. Our Progress (cont’d) • Methylene substrates – how they’re made (solvent free Reformatsky), include rxns that didn’t work, product trace <5%

  13. Our Progress (cont’d) • Dimethyl substrates – no elimination, EW & ED groups

  14. Our Progress (cont’d) • X groups on Darren’s aldol product – results of having EW & ED groups on either side

  15. Summary • Results, which substrates/solvents/acid/base works best

  16. Mechanistic Insights • Positive Hypotheses (show picture of product) • Electron-donating groups on the carbonyl side encourage the retro-aldol products • Electron-withdrawing groups on the alcohol side encourage the retro-aldol products • Negative Hypotheses • Electron-withdrawing groups on the carbonyl side encourage elimination • Electron-donating groups on the alcohol side encourage elimination

  17. Future Work • Hammett Plots of aryl substituents • Catalyst screens with best substrate • Asymmetric ligands on catalysts (H3PO4 catalysts)

  18. Acknowledgments • St. Francis Xavier University • CFI • Merck-Frost • …

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