Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th , 2011

1. “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones Using IBX” Samuel L. BartlettHHMI Undergraduate Research Symposium September 14th, 2011

2. A motif in biologically active compounds: Importance of -diketones Useful in the Knovenagel Condensation: Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596

3. Importance of -diketones A motif in biologically active compounds: Useful in the Knovenagel Condensation: Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596

4. -Diketone Synthesis • -hydroxycarbonyl derivatives may: • suffer fragmentation via • retro-aldol processes • (b) undergo -elimination of H2O • (c) undergo further oxidation due • to the enolic nature of the • derived product. 12 other examples with average yield of 59% Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.

5. -Diketone Synthesis • -hydroxycarbonyl derivatives may: • suffer fragmentation via • retro-aldol processes • (b) undergo -elimination of H2O • (c) undergo further oxidation due • to the enolic nature of the • derived product. 12 other examples with average yield of 59% Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.

6. -Diketone Synthesis • -hydroxycarbonyl derivatives may: • suffer fragmentation via • retro-aldol processes • (b) undergo -elimination of H2O • (c) undergo further oxidation due • to the enolic nature of the • derived product. 12 other examples with average yield of 59% Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.

7. Garugamblin I Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003

8. Garugamblin I Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003

9. Mechanism of Oxidation

10. Comparative Analysis

11. Why is IBX superior to other oxidants? • IBX is a slow and very mild oxidant. • Heterogenous in EtOAc. • Reaction time of 3 to 12 hours. • Prevents over oxidation. -Diketones do not react with IBX -diketones are over oxidized by DMP: Starting material After work-up + DMP, 5 minutes S X R

12. -Diketones do not react with IBX Why is IBX superior to other oxidants? • IBX is a slow and very mild oxidant. • Heterogenous in EtOAc. • Reaction time of 3 to 12 hours. • Prevents over oxidation. -diketones are over oxidized by DMP: Starting material After work-up + DMP, 5 minutes S X R

13. -Diketones react on silica gel Why is IBX superior to other oxidants? • 2. -diketones are reactive on standard silica gel columns. • Chromatographic purification leads to low mass recovery. • Lewis acidic silica gel may promote enolization and subsequent • reactions of -diketones. • The IBX protocol requires only simple filtration. IBX Swern DMP

14. -Diketones react on silica gel Why is IBX superior to other oxidants? • 2. -diketones are reactive on standard silica gel columns. • Chromatographic purification leads to low mass recovery. • Lewis acidic silica gel may promote enolization and subsequent • reactions of -diketones. • The IBX protocol requires only simple filtration. IBX Swern DMP

15. Scope of Reaction Bartlett, S.L.; Beaudry, C.M. Manuscript submitted to J. Org. Chem.

16. Curcumin curcumin

17. Current Limitations 1. Hetero-aromatic β-hydroxyketones have not been converted in high yield: 2. Loss of mass with low molecular weight diketones:

18. Summary • IBX is superior to other common oxidants for the transformation of • -hydroxyketones to -diketones. 2. IBX can be used to oxidize a wide variety of -hydroxyketones in excellent yield, including α-iodo substituted compounds.

19. 1.Use IBX oxidation to form curcumin: Future Work 2.Explore the oxidation of hetero-aromatic -hydroxyketones: 3.Probe the reactivity of α-iodo-β-diketones:

20. Prof.Chris Beaudry The Beaudry Group HHMI Program URISC Program Cripps Scholarship Acknowledgements Cambridge Isotope Laboratories