1 / 18

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.

zofia
Download Presentation

Polyketide Synthesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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 • …

More Related