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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 Often biologically & pharmacologically active Erythromycin A – antibiotic .

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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 • Often biologically & pharmacologically active • Erythromycin A – antibiotic

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

  4. 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

  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 • Subject the β-hydroxy carbonyl subunits to an asymmetric retro-aldol reaction • Ideal reagent requirements: stereoselective, wide substrate scope, fast reaction, good yield

  7. Applications in Nat. Prod. Research • Characterization of natural products by NMR • could be + or – absolute configuration • Mosher ester analysis can give absolute configuration • Advantages: • established, precedented • Disadvantages: • need enough material, need to have reactive alcohol for selective reaction, often unsuccessful on β-hydroxyketones and esters (elimination occurs)

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

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

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

  11. 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.

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

  13. Model Substrates Prepared (so far) • Methyleneβ-hydroxy esters, dimethylβ-hydroxy esters, β-hydroxyketone 2 1 3 4 5 6

  14. Reagent-Solvent Combinations • Screening reactions on substrates using various reagent-solvent combinations 2 1 3 ZnCl2 (DCM) ZnCl2 (MeOH, DCM, THF, CDCl3) NaOH (EtOH) HCl(EtOH) ZnCl2 (DCM) 4 5 6 ZnCl2 (MeOH, EtOH, DCM, THF, Tol, CH3CN) NaOH (EtOH) HCl (EtOH) BF3 (DCM, THF, Tol) ZnCl2 (DCM) NaOH (EtOH) HCl(EtOH) H3PO4 (EtOH) TNO•2H2O (CH3CN) NaOH (EtOH) HCl (EtOH) H3PO4 (EtOH) TNO•2H2O (CH3CN) GREEN = >10% R-A product BLUE = <10% R-A product BLACK = no R-A product

  15. Future Work • Hammett plots of aryl substituents • Effects of electron-withdrawing and electron-donating groups • Asymmetric ligands on retro-aldol reagents (chiral H3PO4 and N-oxides)

  16. Acknowledgments • Derksen Research Group: • Laura Brothers, Dr. Darren Derksen, Nikolai Zollinger • St. FX Chemistry Society

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