samuel l. bartlett hhmi undergraduate research symposium september 14 th, 2011 “practical and high...
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Samuel L. BartlettHHMI Undergraduate Research Symposium
September 14th, 2011
“Practical and High Yielding Oxidation of -Hydroxyketones to -Diketones Using IBX”
Importance of -diketonesA motif in biologically active compounds:
Useful in the Knovenagel Condensation:
Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596
Importance of -diketonesA motif in biologically active compounds:
Useful in the Knovenagel Condensation:
Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596
-hydroxycarbonyl derivatives may:
(a) suffer fragmentation viaretro-aldol processes
(b) undergo -elimination of H2O
(c) undergo further oxidation due to the enolic nature of the derived product.
-Diketone Synthesis
Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.
12 other examples with average yield of 59%
-hydroxycarbonyl derivatives may:
(a) suffer fragmentation viaretro-aldol processes
(b) undergo -elimination of H2O
(c) undergo further oxidation due to the enolic nature of the derived product.
-Diketone Synthesis
Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.
12 other examples with average yield of 59%
-hydroxycarbonyl derivatives may:
(a) suffer fragmentation viaretro-aldol processes
(b) undergo -elimination of H2O
(c) undergo further oxidation due to the enolic nature of the derived product.
-Diketone Synthesis
Smith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567.
12 other examples with average yield of 59%
Garugamblin I
Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003
Garugamblin I
Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003
Mechanism of Oxidation
Comparative Analysis
-Diketones do not react with IBXWhy 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
Startingmaterial
Afterwork-up
-diketones are over oxidized by DMP:
+ DMP, 5 minutes
-Diketones do not react with IBXWhy 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
Startingmaterial
Afterwork-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 Work1.Use IBX oxidation to form curcumin:
2.Explore the oxidation of hetero-aromatic -hydroxyketones:
3.Probe the reactivity of α-iodo-β-diketones:
AcknowledgementsProf. Chris Beaudry
The Beaudry Group
HHMI ProgramURISC ProgramCripps Scholarship
Cambridge Isotope Laboratories