What Is Sharpless Asymmetric Epoxidation?
The Sharpless asymmetric epoxidation (SAE) was developed by K. Barry Sharpless and coworkers in 1980. The SAE transforms a prochiral or racemic allylic alcohol into a chiral 2,3-epoxy alcohol (glycidol) with high enantiomeric excess (typically >90% ee). It provides a highly reliable, predictable, and broadly applicable method for the enantioselective epoxidation of primary and secondary allylic alcohols. Its profound impact on the synthesis of complex chiral molecules was recognized with the 2001 Nobel Prize in Chemistry awarded to Sharpless.
The core catalytic system consists of:
- Titanium Source: Ti(O-iPr)4 (titanium tetra(isopropoxide)) is the most commonly used titanium reagent to form the active chiral complex.
- Chiral Tartrate Ligand: Diethyl tartrate (DET) or diisopropyl tartrate (DIPT), in either enantiomeric form, supplies the chirality. Choice of ligand and its enantiomer controls the absolute configuration of the epoxide.
- Oxidant (Oxygen Donor): tert-Butyl hydroperoxide (t-BuOOH) is the standard oxidant. Other hydroperoxides can work in special cases, but t-BuOOH is preferred for reproducibility.
- Substrate: An allylic alcohol (primary or secondary) — the free OH coordinates to titanium and directs the approach of the oxidant.
- Solvent: Non-protic, dry solvents are used—commonly dichloromethane or toluene. Reactions are run under anhydrous conditions.
- Related Reactions: Jacobsen–Katsuki epoxidation, Shi epoxidation.
- Tips:
a) The enantiomer of the tartrate ester employed dictates the face of the allylic double bond to which oxygen is delivered. The famous "Sharpless Mnemonic" states: With L-(+)-DET, the oxygen adds from the bottom face when the substrate is drawn with the alcohol chain in the southwest quadrant. The reverse is true for D-(-)-DET.
b) Temperature: Often run at low temperature (e.g., −20 °C to 0 °C) to improve enantioselectivity and control reaction rate.
Fig 1. Sharpless asymmetric epoxidation and its mechanism. [1]
Mechanism of Sharpless Asymmetric Epoxidation
- Pre-activation and Complex Formation: Titanium isopropoxide reacts with the chiral tartrate ligand, displacing isopropanol molecules. This forms a chiral, dimeric titanium-bis(μ-tartrate) complex. The allylic alcohol substrate then coordinates to titanium via its hydroxyl group, displacing another alkoxide. The presence of molecular sieves is critical here, as water hydrolyzes Ti(O-iPr)4 to inactive, polymeric TiO2 species.
- Organization and Transition State: The active catalyst is a dimeric structure where two titanium centers are bridged by two tartrate ligands. The tartrate framework creates a chiral pocket. The allylic alcohol and TBHP coordinate to the same titanium center. The peroxide aligns for nucleophilic attack on the olefin, a process orchestrated by the tartrate's ester carbonyls, which likely activate the peroxide via hydrogen bonding. The geometry forces the largest substituent on the olefin (typically trans to the alcohol) away from the tartrate backbone, directing the peroxide attack from the less hindered, enantioface.
- Oxygen Transfer and Release: The [2,3]-sigmatropic rearrangement-like transition state leads to oxygen transfer from the peroxide to the olefin, forming the epoxide with simultaneous release of tert-butanol. The chiral epoxide product is then displaced by new molecules of allylic alcohol and TBHP, continuing the catalytic cycle.
Application Examples of Sharpless Asymmetric Epoxidation
Sharpless asymmetric epoxidation is ubiquitous in natural product and complex-molecule synthesis. Enantioenriched epoxy alcohols are versatile intermediates — they can be opened regio- and stereoselectively to install 1,2-diols, amino alcohols, or other functional arrays. Typical application areas include synthesis of prostaglandins and related polyoxygenated lipids, construction of polyol fragments in polyketide and macrolide natural products, and building blocks for pharmaceuticals and agrochemicals.
- Example 1: In the total synthesis route of (+)-Nivetetracyclate A reported by Michel Blitz et al., the intermediate allyl alcohol 19 was successfully converted to epoxide 20 with 93% ee through the Sharpless asymmetric epoxidation reaction. [2]
- Example 2: Shin-ichiro Yoshizawa et al. used the Sharpless-Katsuki asymmetric epoxidation reaction and the Sharpless asymmetric dihydroxylation reaction to construct the octahydroisochromene skeleton, and further incorporated it into SARS 3CL protease inhibitors. [3]
Fig 2. Synthetic examples via Sharpless asymmetric epoxidation.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 497-500.
- Blitz, Michel, et al. Organic Letters 21.3 (2019): 785-788.
- Yoshizawa, Shin-ichiro, et al. Bioorganic & medicinal chemistry 28.4 (2020): 115273.
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