What Is Sharpless Asymmetric Dihydroxylation?
Olefins can undergo enantioselective dihydroxylation in the presence of chiral ligands containing dihydrogen compounds of natural cinchona alkaloids quinine and quinidine and osmium tetroxide to form highly optically active vicinal diol compounds. This reaction is called the Sharpless asymmetric dihydroxylation or Sharpless AD reaction. In this reaction, the most typical chiral ligands are (DHQ)2-PHAL (derived from dihydroquinine) and (DHQD)2-PHAL (derived from dihydroquinidine).
The chiral ligand and osmium tetroxide are both catalytic, and potassium ferrocyanide is a stoichiometric oxidant. These reaction components are mixed in proportion as necessary for the convenient asymmetric dihydroxylation commercial reagents AD-mix-α [containing (DHQ)2-PHAL] and AD-mix-β [containing (DHQD)2-PHAL].
The photosensitive vicinal diols derived by Sharpless dihydroxylation are generally key synthetic intermediates for organic synthesis. Therefore, the reaction has been widely used in asymmetric synthesis, such as the key intermediates of the insect hormone (+)-exo-brevicomin and the anticancer drug camptothecin.
- Reactants: Osmium tetroxide (OsO4), chiral ligand (e.g., (DHQD)2-PHAL or (DHQ)2-PHAL), oxidant (e.g., K3Fe(CN)6 or N-methylmorpholine N-oxide (NMO)).
- Products: Alkenes.
- Reaction type: Oxidation reaction.
- Related reaction: Upjohn dihydroxylation.
- Experimental tips:
In Sharpless asymmetric dihydroxylation of different olefins, trans olefins are reactive more than cis olefins; Double bonds with electrons are more reactive than electronless double bonds in polyene compounds; For olefins with triple bonds, double bonds are reactive more than triple bonds.
Fig 1. Sharpless asymmetric dihydroxylation reaction and its mechanism. [1]
Mechanism of Sharpless Asymmetric Dihydroxylation
The catalytic mechanism of the Sharpless dihydroxylation reaction is still unclear. As determined by the kinetics of E J Corey et al, Sharpless asymmetric dihydroxylation reactions follows a two-stage oxidation process: (1) rapid, reversible formation of the olefin-Os(VIII) π-d complex and (2) slow rearrangement to the [3 + 2] cycloaddition transition state. [2] However, Sharpless et al. proposed another mechanism using the addition of the olefin bond [2 + 2] to the complex OsO4, as well as the interaction between the substrate and the L-shaped binding pocket. The assumption generally believed is that the chiral ligand is first complexed with OsO4 to produce a chiral N-OsO4 complex; this complex is enantioselective dihydroxylated with the olefin.
Stereoselectivity of Sharpless Asymmetric Dihydroxylation
The stereoselectivity of this reaction can be predicted according to the following rules. The steric effect of the ligand is the reason for the excellent stereoselectivity of the reaction. The substituents on the double bond of the olefin are arranged according to the relative volume (L, M and S are large, medium and small groups respectively) as shown in Fig 1. The ligand (DHQD)2-PHAL gives the dihydroxylation product from the top of the double bond (β-plane); the ligand (DHQ)2-PHAL gives the dihydroxylation product in the opposite direction (α-plane). Table 1 shows the results of asymmetric dihydroxylation of some olefins for reference.
Table 1. Selectivity of Sharpless AD reaction of some alkenes.
Application Examples of Sharpless AD Reaction
- Example 1: In the key step of the total synthesis of nhatrangin A, α,β-unsaturated esters were passed through Sharpless asymmetric dihydroxylation (AD-mix-β) to give the respective diols yielding 89.9% and ee rate being 98%. [3]
- Example 2: Sharpless asymmetric dihydroxylation can be employed to efficiently produce various natural products including alkaloids, lactones, amino acids etc. The figure below shows the application of Sharpless asymmetric dihydroxylation in the total synthesis of chelonin B. [4]
Fig 2. Synthetic examples via Sharpless asymmetric dihydroxylation reaction.
Related Products
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| 600-13-5 | 2-Butenoicacid,2-chloro-,(E)-(9ci) | Inquiry | |
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| 17102-64-6 |  | trans,trans-2,4-Hexadien-1-ol | Inquiry |
| 2497-21-4 |  | 4-Hexen-3-one | Inquiry |
| 565-62-8 |  | 3-Methyl-3-penten-2-ol | Inquiry |
| 818-59-7 |  | Methyl 2-pentenoate | Inquiry |
| 15790-88-2 | Methyl trans-2-pentenoate | Inquiry | |
| 924-50-5 |  | Methyl 3-Methyl-2-Butenoate | Inquiry |
| 110-44-1 |  | Sorbic Acid | Inquiry |
| 13419-69-7 |  | trans-2-Hexenoic acid | Inquiry |
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 493-496.
- Corey, E. J., et al. Journal of the American Chemical Society, 1996, 118(2), 319-329.
- Kamal, Ahmed, et al. Organic & Biomolecular Chemistry, 2013, 11(27), 4442-4448.
- Heravi, Majid M., et al. Tetrahedron: Asymmetry, 2017, 28(8), 987-1043.
