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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 Christina LeGay Derksen Research Group St. Francis Xavier University
Polyketides: What are they? • Secondary metabolites • Often biologically & pharmacologically active • Erythromycin A – antibiotic
Polyketides: More Examples • Amphotericin B – antifungal drug • Peloruside A – antimitotic agent
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
Organocatalysis • ProlineAldol: • Advantages: cheap, catalytic, good enantiomeric excess, avoids use of toxic transition metals • Disadvantages: limited substrate scope, often poor diastereomeric ratio
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
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)
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:
Nature’s Precedent • Aldolases: catalytic aldol reaction • Fructose bisphosphatealdolase – catalyzes reversible reaction
Chemical Literature Precedent • Rapamycin: immunosuppressant drug • retro-aldol in presence of ZnCl2 catalyst Luengo, J.; Konialian, A.; Holt, D. Tet. Lett. 1993, 34, 991-994.
Chemical Literature Precedent • R106-1: potent & abundant antifungal agent • retro-aldol optimized in presence of TNO•2H2O Rodriguez, M.; Zweifel, M. Tet. Lett.1996, 37, 4301-4304.
Proof of Concept • Retro-aldol observed using NaOH and HCl as catalysts in ethanol • Effective retro-aldol catalysts, fast reaction, good yield (elimination products reduced)
Model Substrates Prepared (so far) • Methyleneβ-hydroxy esters, dimethylβ-hydroxy esters, β-hydroxyketone (aldol adduct) 2 1 3 4 5 6
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
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)
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
BicyclicProline Analogs • Recently completed synthesis • Being examined for use in prolinealdol catalysis and as enzyme inhibitors
Acknowledgments • DerksenResearch Group: • Laura Brothers, Darren Derksen, Nikolai Zollinger • Russell Wyeth: StFX Biology (Nudibranchs) • Greg McCullagh, Michael Gerhartz • Lori Graham: StFX Biology (Assistance with Level II organisms, pathogens)