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

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

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

 -hydroxycarbonyl derivatives may: (a)suffer fragmentation via retro-aldol processes (b) undergo  -elimination of H 2 O (c) undergo further oxidation due to the enolic nature of the derived product.  -Diketone Synthesis Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, other examples with average yield of 59%

 -hydroxycarbonyl derivatives may: (a)suffer fragmentation via retro-aldol processes (b) undergo  -elimination of H 2 O (c) undergo further oxidation due to the enolic nature of the derived product.  -Diketone Synthesis Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, other examples with average yield of 59%

 -hydroxycarbonyl derivatives may: (a)suffer fragmentation via retro-aldol processes (b) undergo  -elimination of H 2 O (c) undergo further oxidation due to the enolic nature of the derived product.  -Diketone Synthesis Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, other examples with average yield of 59%

Garugamblin I Finney, N.S; More, J.D. Org. Lett. 2002, 4,

Garugamblin I Finney, N.S; More, J.D. Org. Lett. 2002, 4,

Mechanism of Oxidation

Comparative Analysis

 -Diketones do not react with IBX Why is IBX superior to other oxidants? 1.IBX is a slow and very mild oxidant. Heterogenous in EtOAc. Reaction time of 3 to 12 hours. Prevents over oxidation. S X R Starting material After work-up  -diketones are over oxidized by DMP: + DMP, 5 minutes

 -Diketones do not react with IBX Why is IBX superior to other oxidants? 1.IBX is a slow and very mild oxidant. Heterogenous in EtOAc. Reaction time of 3 to 12 hours. Prevents over oxidation. S X R Starting material After work-up  -diketones are over oxidized by DMP: + DMP, 5 minutes

 -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

 -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

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

Curcumin curcumin

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

Summary 1.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.

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

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