1 / 18

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 .

zilya
Download Presentation

New Tools for Organic Synthesis and Natural Product Characterization

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. 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: Asymmetric Catalysis • Subject the β-hydroxy carbonyl subunits to asymmetric retro-aldol catalysis • Ideal catalyst 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 confirmation • 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 catalysts 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 catalyst 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 catalysts in ethanol • fast reaction, elimination products reduced

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

  14. Catalyst-Solvent Combinations • Screening reactions on substrates using various catalyst-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 = sig. R-A product BLUE = trace 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 catalysts (chiral H3PO4 and N-oxide catalysts)

  16. Independent Research: In Progress • Nudibranchs (sea slugs) utilize chemicals from their environment for camouflage and defense • Four sets of predator-prey (nudibranch/food source) relationships that are being investigated

  17. BicyclicProline Analogs • Recently completed synthesis • Being examined for use in prolinealdol catalysis and as enzyme inhibitors

  18. Acknowledgments • DerksenResearch Group: • Laura Brothers, Darren Derksen, Nikolai Zollinger • Biofouling Research Group • Russell Wyeth: StFX Biology (Nudibranchs) • Greg McCullagh, Michael Gerhartz • Lori Graham: StFX Biology (Assistance with Level II organisms, pathogens)

More Related