What is Rubottom Oxidation?
The reaction of silyl enol ethers with the epoxidation reagent m-chloroperbenzoic acid (m-CPBA) and then rearranged and hydrolyzed to form α-hydroxy ketones. It is a method for α-hydroxylation of carbonyl compounds.
In addition to m-CPBA, other oxidants (epoxidation reagents) such as oxygen, dimethyldioxypropane (DMDO), o-iodosylbenzoic acid, MoO5·Py·HMPA·(MoOPH) and Davis oxaziridine can also be used for this transformation. Davis oxaziridine is valuable for the preparation of optically active chiral reagents for the asymmetric α-hydroxylation of carbonyl compounds.
The Rubottom oxidation reaction is a powerful and versatile tool for the synthesis of α-hydroxy ketones. This transformation is required in the synthesis of many natural products, for example in the total synthesis of hispidospermidin and (±)-rishirilide B.
- Reagents: m-CPBA or other peroxyacid (such as Davis oxaziridine).
- Reactants: Silyl enol ethers.
- Products: α-Hydroxyketones.
- Reaction type: Oxidation reaction.
- Relatedreaction: Davis oxidation.
Fig 1. Rubottom oxidation reaction and its mechanism. [1,2]
Tips for Rubottom Oxidation
- Acyclic or cyclic silyl enol ethers can undergo this reaction.
- Silyl enol ethers can be efficiently prepared from the corresponding aldehydes/ketones.
- Post-treatment with acid or base can easily give α-hydroxycarbonyl compounds in high yields.
- If the reactants are susceptible to hydrolysis, the reaction can be carried out in a non-polar solvent.
Mechanism of Rubottom Oxidation
The enol ether double bond is epoxidized by peracid to form an epoxide. The release of the epoxide ring strain drives the rearrangement of the silyl migration to give a silylated α-hydroxy ketone, which is subsequently hydrolyzed to give the final α-hydroxy ketone.
Application Examples of Rubottom Oxidation
The α-hydroxy carbonyl unit is a recurring motif found in a variety of biologically active compounds, drugs, and synthetically useful intermediates, such as the antibiotics kjellmanianone, hamigeran A, and the antibacterial agent pramanicin. Therefore, Rubottom oxidation has a wide range of applications in organic synthesis, such as the synthesis of natural products, drug discovery, and the synthesis of functional materials such as polymers and catalysts.
- Example 1: Sara Meninno et al. found that commercially available and inexpensive magnesium monoperoxide (MMPP) was an effective oxidant for the first direct rubottom hydroxylation of α-substituted malonates, β-ketoesters, and β-ketoamides at room temperature in ethanol with NaHCO3 as an alkaline additive. Their work also demonstrated the feasibility of gram-scale oxidations. [3]
- Example 2: Hualing He et al. described a highly efficient catalytic asymmetric Rubottom-type oxidation reaction. Using m-CPBA as the oxidant and chiral calcium phosphate as the catalyst, a simple transformation led to the direct hydroxylation of N -Boc oxindoles and β-ketoesters with high yields (up to 99 %) and high enantiomeric enrichment (up to >99 % ee). This method has been successfully applied to the synthesis of pharmaceutically important 3-hydroxyoxindoles with excellent enantiomeric control. [4]
Fig 2. Synthetic examples via Rubottom oxidation reaction.
Related Products
References
- Rubottom, G. M., et al. Tetrahedron Letters, 1974, 15(49-50), 4319-4322.
- Li, J.J. Rubottom oxidation. In: Name Reactions. Springer, Cham. 2014, 527.
- Meninno, Sara, et al. European Journal of Organic Chemistry, 2021, 2021(11), 1758-1762.
- He, Hualing, et al. Chemistry–A European Journal, 2023, 29(10), e202203720.
