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