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Results and Discussion

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Epoxidations and Hydroperoxidations of α,β-Unsaturated Ketones

Part of the book series: Springer Theses ((Springer Theses))

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Abstract

Simple cyclic enones have generally been omitted within the vast majority of studies on the asymmetric epoxidation of α,β-unsaturated ketones. Thus, we decided to focus on these challenging cyclic substrates as a departure point before extending the methodology to different types of α,β-unsaturated ketones.

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Notes

  1. 1.

    Yield determined by GC with an internal standard method.

  2. 2.

     Catalyst system [(R,R)-DPEN ⋅ (S)-TRIP] exhibited low catalytic efficiency also with other 3-substituted 2-cyclohexenones; i.a. (2R,3S)-3-benzyl-2,3-epoxycyclohexanone (48m) was obtained in 35% yield and 86:14 er and (2R,3S)-3-isopropyl-2,3-epoxycyclohexanone (48i) in 36% yield and 89.5:10.5 er, respectively.

  3. 3.

    [(R,R)-DPEN ⋅ TFA] and [(R,R)-DPEN ⋅ (S)-TRIP] were tested, but gave inferior results (~40% conversion, 80:20 and 93:7 er, respectively).

  4. 4.

    The relative configuration was assigned by NOE analysis.

  5. 5.

    Racemate was obtained with alkaline hydrogen peroxide in methanol with 98:2 dr.

  6. 6.

    One-pot syntheses of epoxide 84 starting from diketone 82 are possible in the presence of catalyst [67 ⋅ 2 TCA] but have not been optimized.

  7. 7.

    Racemate was obtained with alkaline hydrogen peroxide in methanol with 94:6 dr from racemic enone 83.

  8. 8.

    This is in accordance with our observation that 2-cyclopentenone (46r) dimerizes in the presence of the catalytic salt [13 ⋅ 2 TFA] as detected by GC–MS and ESI-MS.

  9. 9.

    This trend had previously been observed with the six-membered ring analogues.

  10. 10.

    [13 ⋅ 3 TCA] was chosen instead of [13 ⋅ 2 TCA] since a 3:1 acid/9-amino(9-deoxy)epiquinine ratio seemed to have a beneficial effect on the catalyst activity (Table 4.22, entry 6 versus 7).

  11. 11.

    Determined by GC-MS.

  12. 12.

    The sterically demanding 9-amino(9-deoxy)epiquinine (13) catalyst may somewhat shield the α-position and thus hinder α-protonation in favour of competing γ-protonation.

  13. 13.

     Determined by GC–MS.

  14. 14.

     Deng and co-workers reported identical substrate scope limitations in their [13 ⋅ 3 TFA]-catalyzed asymmetric alkylperoxidation of α,β-unsaturated ketones with TBHP and related oxidants.

  15. 15.

    Iso-46v was detected in the crude product mixture prior to treatment with base. Deconjugation was also noticed in the reaction of 2-cycloheptenone (46s), yet only to a negligible extent (~1%).

  16. 16.

    The same two-step protocol was applied to 2-cycloheptenone (46s). Yet, the yield was not significantly improved to compensate for the loss of enantioselectivity (96.5:3.5 er).

  17. 17.

    Density functional theory (DFT) computation at the B3LYP/6-31G* level of theory (Vacuum) was performed using Spartan’08 Windows from Wavefunction, Inc.

  18. 18.

    Due to the incompatibility of the reaction conditions of the hydroperoxidation and the hydrogenation, this transformation was carried out in a stepwise fashion simply interrupted by an aqueous work-up alike in the epoxidation protocol.

  19. 19.

    We discovered a catalytic effect of the eight-membered ring peroxide 117 on the reductive cleavage of 2,3-epoxycyclooctanone 48v which is to date unknown in nature. Full conversion to 3-hydroxycyclooctanone 124d was achieved within 10 min at ambient temperature albeit once again with erosion of optical purity.

  20. 20.

    Density functional theory (DFT) computation at the B3LYP/6-31G* level (Vacuum) was performed using Spartan ‘08 Windows from Wavefunction, Inc.

  21. 21.

    Initially formed refers to the epoxide fraction which is formed directly under the reaction conditions, and not through conversion of the corresponding peroxyhemiketal to the epoxide while treating the crude mixture with base (NaOH).

  22. 22.

    Enantiomeric ratios were determined after converting the peroxyhemiketals to the corresponding epoxides.

  23. 23.

    The reaction catalyzed by [(R,R)-DPEN ⋅ (S)-TRIP] supposedly proceeds in an analogous fashion.

  24. 24.

    pK a(H2O2) 11.8, for comparison: pK a(quinuclidine) 11.1, pK a(i-PrNH2) 10.7, pK a(benzyl amine) 9.34, pK a(quinoline) 4.85.

  25. 25.

    pK a(2,3-diaminobutane, rac.) 10.00, 6.91.

  26. 26.

    Alternatively, a cross-over experiment could have been carried out by mixing a peroxyhemiketal with a different enone substrate under reaction condition in the absence of H2O2.

  27. 27.

    In particular for reactions conducted at elevated temperatures of 50 °C or higher.

  28. 28.

    DFT calculations were performed using Spartan′08 Windows from Wavefunction, Inc.

  29. 29.

    Due to a change in priority of the substituent attached to the β-carbon, compounds 46h-m formally undergo attack from the re(β)-face in the presence of catalyst [13 ⋅ 2 TFA], although in practice there is no change in facial selectivity.

  30. 30.

    Cyclic enones 46g,h and l were prepared by Martin through the same route.

  31. 31.

    Cyclic enones 46v-x were prepared in collaboration with Wang.

  32. 32.

    Despite several reruns, we were not able to reproduce the diastereoselectivity of >12:1 (threo/erythro) reported by the Kessar group.

  33. 33.

    Suzuki–Miyaura reaction of boronic diacid 157 with 2,4,6-triisopropylphenyl bromide afforded poor yields of the dicoupling product.

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    Corinna Reisinger

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Reisinger, C. (2012). Results and Discussion. In: Epoxidations and Hydroperoxidations of α,β-Unsaturated Ketones. Springer Theses. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28118-1_4

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