New Tools for Organic Synthesis and Natural Product Characterization

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 • Erthromycin A – antibiotic

3. Polyketides: What are they? • Amphotericin B – antifungal drug • Peloruside A – antimitotic agent

4. Polyketide Preparation • 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. Ideal Catalysis • Subject the polyketide subunits to Asymmetric retro-aldol catalysis • Catalyst requirements: stereoselective, wide substrate scope, fast reaction, good yield

7. Applications • Characterization of Natural Products by NMR • could be + or – absolute confirmation • compare to standard • Mosher ester analysis can give absolute configuration • Advantage: established, precedental • Disadvantage: need enough material!, needs to have reactive alcohol for selective reaction • Our procedure could use Mass Spec to determine absolute configuration • Brasilinolide A degradation

8. Our Approach • Synthesis of model polyketide subunits: β-hydroxyketones and esters • Base-catalyzed aldol addition • Advantages: very cheap, fairly quick, good yield • Disadvantages: chromatography required • Reformatsky • Advantages: solvent free, very simple reaction, wide substrate scope • Disadvantages: chromatography required

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

10. Chemical Literature Precedent • Rapamycin: immunosuppressant drug • retro-aldol in presence of ZnCl2 catalyst “Studies on the Chemistry of Rapamycin: Novel Transformations under Lewis-Acid Catalysis," Luengo et al, Tetrahedron Letters (34,6,pp.991-994, 1993).

11. Chemical Literature Precedent • R106-1: potent & abundant antifungal agent • retro-aldol optimized in presence of TNO•2H2O "Trimethylamine N-oxide: A Novel Reagent for the Promotion of the Retro-Aldol Reaction of R106-1 (LY295337)," Rodriguez and Zweifel, Tetrahedron Letters (37,25,pp.4301-4304, 1996).

12. Proof of Concept • Significant product formed using NaOH and HCl as catalysts in ethanol • effective retro-aldol catalysts, very fast reaction, large yield

13. Our Progress • Methyleneβ-hydroxy esters

14. Our Progress (cont’d) • Dimethylβ-hydroxy esters

15. Our Progress (cont’d) • Dimethylβ-hydroxy esters

16. Our Progress (cont’d) • β-hydroxyketone: aldol adduct

17. Mechanistic Insights • Groups encouraging Retro-Aldolproducts (desired): • Groups encouraging Elimination products (undesired):

18. Summary • Results, which substrates/solvents/acid/base works best

19. Future Work • Hammett Plots of aryl substituents • Catalyst screens with best substrate • Asymmetric ligands on catalysts (H3PO4 catalysts)

20. Acknowledgments • St. Francis Xavier University • CFI • Merck-Frost

21. References