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New Tools for Organic Synthesis and Natural Product Characterization

New Tools for Organic Synthesis and Natural Product Characterization. Christina LeGay Derksen Research Group St. Francis Xavier University . Polyketides : What are they? . Secondary metabolites – Generally found in bacteria and fungi Often biologically & pharmacologically active

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New Tools for Organic Synthesis and Natural Product Characterization

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  1. New Tools for Organic Synthesis and Natural Product Characterization Christina LeGay Derksen Research Group St. Francis Xavier University

  2. Polyketides: What are they? • Secondary metabolites – Generally found in bacteria and fungi • Often biologically & pharmacologically active • Erythromycin A – antibiotic

  3. Polyketides: More Examples • Amphotericin B – antifungal drug • Peloruside A – antimitotic agent

  4. The Aldol Reaction • Carbon-carbon bond forming reaction • Two carbonyl compounds, usually a ketone and an aldehyde • Product is a β-hydroxy carbonyl • “Aldol” because product contains an aldehyde and an alcohol

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

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

  7. Nature’s Precedent • Aldolases: catalytic aldol reaction • Fructose bisphosphatealdolase – catalyzes reversible reaction

  8. Chemical Literature Precedent • Rapamycin: immunosuppressant drug (G.S.K) • retro-aldol in presence of ZnCl2 catalyst Luengo, J.; Konialian, A.; Holt, D. Tet. Lett. 1993, 34, 991-994.

  9. Chemical Literature Precedent • R106-1: potent & abundant antifungal agent (E.L.) • retro-aldol optimized in presence of TNO•2H2O Rodriguez, M.; Zweifel, M. Tet. Lett.1996, 37, 4301-4304.

  10. Our Approach: Asymmetric Catalysis • Subject the β-hydroxy carbonyl subunits to asymmetric retro-aldol catalysis • Ideal catalyst requirements: stereoselective, wide substrate scope, fast reaction, good yield

  11. Applications in Nat. Prod. Research • Our procedure could potentially use mass spec to determine absolute configuration: • Chiral catalysts used: react stereoselectively • Compare outcome to model reactions • Example:

  12. Proof of Concept • Retro-aldol observed using NaOH and HCl as catalysts in ethanol • fast reaction, retro-aldol products are major

  13. Preliminary results • Show screening reactions with best yield

  14. Honours Project Proposal • Construct Hammett plots of aryl substituents • Examine the effects of electron-withdrawing and electron-donating groups • Determine reaction mechanism using Lewis acid or Lewis base catalysts

  15. Long Term Goals • Use catalysts with Asymmetric ligands • Determine effects of ligands on retro-aldol • Ex. chiral H3PO4 and N-oxide catalysts • -draw binol on phosphorous • -chiral noxide

  16. Acknowledgments • Derksen Research Group: • Laura Brothers, Darren Derksen, Nikolai Zollinger • CFI

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