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

  • View
    19

  • Download
    0

Embed Size (px)

DESCRIPTION

Practical and High Yielding Oxidation of - Hydroxyketones to -Diketones Using IBX . Samuel L. Bartlett HHMI Undergraduate Research Symposium September 14 th , 2011. A motif in biologically active compounds:. Importance of -diketones. Useful in the Knovenagel Condensation:. - PowerPoint PPT Presentation

Transcript

  • Samuel L. BartlettHHMI Undergraduate Research Symposium September 14th, 2011Practical 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:

    suffer fragmentation viaretro-aldol processes

    (b) undergo -elimination of H2O

    (c) undergo further oxidation due to the enolic nature of the derived product.

    -Diketone SynthesisSmith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567. 12 other examples with average yield of 59%

  • -hydroxycarbonyl derivatives may:

    suffer fragmentation viaretro-aldol processes

    (b) undergo -elimination of H2O

    (c) undergo further oxidation due to the enolic nature of the derived product.

    -Diketone SynthesisSmith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567. 12 other examples with average yield of 59%

  • -hydroxycarbonyl derivatives may:

    suffer fragmentation viaretro-aldol processes

    (b) undergo -elimination of H2O

    (c) undergo further oxidation due to the enolic nature of the derived product.

    -Diketone SynthesisSmith, A. B.; Levenberg, P.A. Synthesis 1981,7, 567. 12 other examples with average yield of 59%

  • Garugamblin IFinney, N.S; More, J.D. Org. Lett. 2002, 4, 3001-3003

  • Garugamblin IFinney, 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?IBX is a slow and very mild oxidant.Heterogenous in EtOAc.Reaction time of 3 to 12 hours.Prevents over oxidation.

    S X R

    StartingmaterialAfterwork-up-diketones are over oxidized by DMP:+ DMP, 5 minutes

  • -Diketones do not react with IBXWhy 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.

    S X R

    StartingmaterialAfterwork-up-diketones are over oxidized by DMP:+ DMP, 5 minutes

  • -Diketones react on silica gelWhy 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.

    IBXSwernDMP

  • -Diketones react on silica gelWhy 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.

    IBXSwernDMP

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

  • Curcumincurcumin

  • Current Limitations1. Hetero-aromatic -hydroxyketones have not been converted in high yield:2. Loss of mass with low molecular weight diketones:

  • SummaryIBX 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 -iodo substituted compounds.

  • Future Work1.Use IBX oxidation to form curcumin:2.Explore the oxidation of hetero-aromatic -hydroxyketones: 3.Probe the reactivity of -iodo--diketones:

  • AcknowledgementsProf. Chris Beaudry

    The Beaudry Group

    HHMI ProgramURISC ProgramCripps ScholarshipCambridge Isotope Laboratories

    *1.So Ive shown here a few biologically relevant -dikketones. I dont want to spend to much time talking about them in any detail, but I would like to point out the diversity of structure and biological role of these compounds. Its also worth noting that these compounds may exist as the enol or keto form in solution. Often both these forms are present in equilibrium.

    *1.So Ive shown here a few biologically relevant -dikketones. I dont want to spend to much time talking about them in any detail, but I would like to point out the diversity of structure and biological role of these compounds. Its also worth noting that these compounds may exist as the enol or keto form in solution. Often both these forms are present in equilibrium.

    *The 1,3-dioxygen framework of -diketones may be formed through the aldol coupling of an aldehyde and ketone, indeed over 17,000 examples of such a reaction appear on a scifinder search.*The 1,3-dioxygen framework of -diketones may be formed through the aldol coupling of an aldehyde and ketone, indeed over 17,000 examples of such a reaction appear on a scifinder search.*Its clear 1,3-dioxygen framework of -diketones may be formed through the aldol coupling of an aldehyde and ketone, indeed over 17,000 examples of such a reaction appear on a scifinder search. However, the subsequent oxidation reaction is, to our surprise, extremely under represented in the literature, one finds only 434 examples for the oxidation of -hydroxyketones to the corresponding -diketones with acidic -protons. It turns out we werent alone in our surprise at the lack of literature on this reaction. Smith studied this reaction in the 80s and postulated that the lack of literature information may be due to the expectation that -hydroxyketones may undergo retro aldol processes and elimination of water and that the -diketones formed may be further oxidized due to the enolic nature of these compounds. To summarize smiths work, he found the swern oxidation to be superior in yield to chromium based oxidations, however of the 13 substrates he tested, the average yield for swern conditions was around 60%.*Our interest in the oxidation of -hydroxyketones to -diketones arose from our labs work on the synthesis of garugamblin 1, we required an oxidation of the -hydroxyketone intermediate shown, after surveying a number of common oxidation conditions we found that they were all typically low yielding.*We found that Dess-Martin Periodinane (shown here), in both the absence and presence of sodium bicarbonate gave an unsatisfactory yield of 40%, swern gave 35, and TPAP, NMO gave a yield of less than 5%. It wasnt until we tried the IBX conditions described by Finney that we found a solution to this problem. These conditions provided a yield of 95%. I would just like to describe how convenient the IBX conditions are, one simply adds IBX (a solid) to a solution of -hydroxyketone in EtOAc straight out of the bottle, this mixture is refluxed at 77 degrees, upon completion by tlc the reaction mixture is simply filtered and concentrated to give pure -diketone product.*Id like to briefly cover the mechanism of this reaction:Nucleophilic attack of the hydroxyl group to the electrophilic iodine center followed by proton transfer and loss of water leads to the iodic ester intermediate shown at the bottom right corner, intramolecular proton abstraction by the oxide ligand leads to formation of the ketone product as well as an iodine (III) species.*So we wanted to investigate whether or not the trend we observed with the garugamblin 1 intermediate was common to the oxidation of other -hydroxyketones, we hoped to determine whether IBX provided superior yields in all cases. We compared the IBX protocol to two of the most common methods used for the transformation of -hydroxyketones to -diketones, the swern and DMP reactions, on 5 substrates. We discovered that IBX provided near quantitative yields independent of whether the hyrdoxyl group was benzyllic or aliphatic. For example the cyclohexanone para-nitrobenzaldehyde derived aldol shown here was oxidized to the desired -diketone in 99%. We found that IBX is superior for the oxidation of aromatic -hydroxyketones lacking substitution at the alpha position, as well as -hydroxyketones where the hydroxyl group is in aliphatic environments such as these two shown in the center. We were also delighted to find that IBX transforms -chloro--hydroxy ketones in high yield. The yields observed for DMP and swern conditions were often low to moderate respectively.*We wondered why the yields we observed were higher with IBX. For one, under our conditions the IBX oxidation is slow and mild. This is due to the fact that IBX is virtually insoluble in EtOAc. Reaction times for the IBX reaction range between 3 to 12 hours, this allows the experimentalist to stop the reaction before over oxidation of the desired -diketone occurs. Its our belief that the overoxidation of the desired product occurs relatively fast with DMP. *To test this hypothesis we subjected the -diketone shown to DMP conditions. Id like to draw your attention to the TLC plate shown at the right, the far left lane is -diketone alone, while the far right lane is the DMP, -diketone mixture after 5 minutes. As you can see there is evidence of new compounds formed by TLC. Also comparing the proton NMR of this mixture after work-up to the spectrum of the starting material we observe a number of peaks which we do not attribute to our -diketone, DMP, or its reduced byproducts. We interpret these two pieces of data to mean that DMP is over oxidizing the desired -diketone product.

    *Another reason we believe IBX has proven to be superior is that -diketones may react on silica gel columns. We have observed that chromatographic purification of diketones leads to lower mass recovery. It may be that the lewis acidic silica gel promotes enolization and reaction of diketones. The IBX protocol circumv