Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High...
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![Page 1: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/1.jpg)
Samuel L. BartlettHHMI Undergraduate Research Symposium
September 14th, 2011
“Practical and High Yielding Oxidation of -Hydroxyketones to -Diketones Using IBX”
![Page 2: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/2.jpg)
Importance of -diketonesA motif in biologically active compounds:
Useful in the Knovenagel Condensation:
Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596
![Page 3: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/3.jpg)
Importance of -diketonesA motif in biologically active compounds:
Useful in the Knovenagel Condensation:
Antonioletti, R.; Bovicelli, P.; Malancona S.Tetrahedron 2002, 58, 589-596
![Page 4: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/4.jpg)
-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%
![Page 5: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/5.jpg)
-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%
![Page 6: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/6.jpg)
-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%
![Page 7: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/7.jpg)
Garugamblin I
Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003
![Page 8: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/8.jpg)
Garugamblin I
Finney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003
![Page 9: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/9.jpg)
Mechanism of Oxidation
![Page 10: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/10.jpg)
Comparative Analysis
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-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
![Page 12: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/12.jpg)
-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
![Page 13: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/13.jpg)
-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
![Page 14: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/14.jpg)
-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
![Page 15: Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th, 2011 “Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones.](https://reader036.fdocuments.net/reader036/viewer/2022062322/56649cb15503460f94975a50/html5/thumbnails/15.jpg)
Scope of Reaction
Bartlett, S.L.; Beaudry, C.M. Manuscript submitted to J. Org. Chem.
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Curcumin
curcumin
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Current Limitations
1. Hetero-aromatic β-hydroxyketones have not been converted in high yield:
2. Loss of mass with low molecular weight diketones:
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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.
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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:
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AcknowledgementsProf. Chris Beaudry
The Beaudry Group
HHMI ProgramURISC ProgramCripps Scholarship
Cambridge Isotope Laboratories