Name: chiral control in sharpless epoxidation
Uploaded: 2023-04-30T18:28:41.000Z
Duration: 2 min 57 s
Channel: JoVE

Recall that epoxidation of alkenes by either peroxy acids or halohydrin cyclization follows syn addition and yields a racemic mixture of epoxides.
The formation of just one enantiomer in excess from alkenes can be achieved through a chiral catalyst, which favors epoxidation at only one facet of the alkene.
A chiral catalyst acts by lowering the activation energy for the formation of one enantiomer more than the other, leading to enantiomeric excess.
This forms the basis for Sharpless asymmetric epoxidation that converts allylic alcohols into chiral epoxy alcohols with very high enantioselectivity.
The reagents for Sharpless epoxidation include tert-butyl hydroperoxide or TBHP, titanium tetraisopropoxide, and a specific stereoisomer of diethyl tartrate or DET.
While TBHP acts as the oxidizing agent, titanium tetraisopropoxide and optically active DET combine and act as the chiral catalyst for the epoxidation.
The enantiomer of DET used in Sharpless epoxidation is either L-(+)-diethyl tartrate or D-(&#8722;)-diethyl tartrate.
For Sharpless epoxidation, the stereochemistry of the product depends on which enantiomer of DET used.
For instance, when trans-2-hexen-1-ol reacts with TBHP in the presence of titanium tetraisopropoxide and L-(+)-DET, the 2S,3S enantiomer of the product is obtained with 97% purity.
However, with D-(&#8722;)-DET, the other&#8212;2R,3R &#8212;enantiomer is obtained in excess.
The reaction mechanism involves rapid ligand exchange of titanium tetraisopropoxide with DET, TBHP, and the allylic alcohol, resulting in the clamping of the achiral alkene and oxidizing agent in a fixed stereochemical position.
Consequently, the epoxide oxygen is delivered from the same enantioface of the alkene, regardless of the substitution pattern.
When predicting the stereochemistry of the resulting epoxide, the alkene unit is oriented in the plane such that the hydroxymethyl substituent appears at the lower right position.
In this position, the titanium-(&#8722;)-DET complex delivers the epoxide oxygen to the top face of the alkene, and the titanium-(+)-DET complex delivers the oxygen to the bottom face of the alkene.

sharpless epoxidation

Sharpless Epoxidation

The conversion of allylic alcohols into epoxides using the chiral catalyst was discovered by K. Barry Sharpless and is known as Sharpless epoxidation. The use of a chiral catalyst enables the formation of one enantiomer of the product in excess. This chiral catalyst is mainly a chiral complex of titanium tetraisopropoxide and tartrate ester (specific stereoisomer). The stereoisomer used in the chiral catalyst dictates the formation of the enantiomer of the product. In other words, the use of L-(+)-diethyl tartrate leads to enantiomers having the epoxide ring below the plane, while with D-(&#8722;)-diethyl tartrate, to enantiomers with the epoxide ring above the plane. The high enantioselectivity of the reaction can be explained by considering the activation energies required for the reaction to proceed in the forward direction in the presence of the chiral catalyst. As shown in Figure 1, compared to the uncatalyzed reaction (blue curve), the activation energy of the reaction decreases dramatically with the addition of the chiral catalyst (red and green curves). Moreover, the activation energy for the formation of one enantiomer (red curve) is lowered more than that of another enantiomer (green curve), leading to the formation of one enantiomer in excess. Hence, Sharpless epoxidation reaction can be utilized for the synthesis of desired enantiomers of the product.
<img alt="Potential energy diagram with reaction coordinate, illustrating energy changes in a chemical reaction." src="/files/ftp_upload/12108/12108Figure%201.png" style="text-align: center; height: 300px;" data-altupdatedat="1761830439000" data-alt="Figure1" />
The stereochemistry of the product formed when any allylic alcohol is subjected to Sharpless epoxidation can be predicted by simply orienting the allylic alcohol molecule in a plane with the hydroxyl groups pointing towards the lower right corner, as shown in Figure 2. On this planar structure, D-(&#8722;)-diethyl tartrate delivers the oxygen from the top face of the alkene, making the epoxide formation feasible from above the plane, while L-(+)-diethyl tartrate delivers the oxygen from the bottom face of the alkene, thereby installing the epoxide ring from below the plane.
<img alt="Epoxidation process diagram with Ti-D-DET and Ti-L-DET complexes for alkene oxygen delivery." src="/files/ftp_upload/12108/12108Figure%202.svg" style="text-align: center; height: 300px;" data-altupdatedat="1761830439000" data-alt="Figure2" />

The conversion of allylic alcohols into epoxides using the chiral catalyst was discovered by K. Barry Sharpless and is known as Sharpless epoxidation. The ...

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Organic Chemistry

Unit 1

Ethers, Epoxides, Sulfides

KEY TERMS AND CONCEPTS

chiral control in sharpless epoxidation

Sharpless epoxidation is a chiral reaction that converts allylic alcohols into epoxides. It was discovered by K. Barry Sharpless. The reaction is useful because it can favor one enantiomer, or mirror-image product, over the other.

The key to this selectivity is a chiral catalyst. It is mainly a complex of titanium tetraisopropoxide and a tartrate ester with a specific stereoisomer, or 3D arrangement. The stereoisomer in the catalyst controls which enantiomer forms in excess.

Using L-(+)-diethyl tartrate leads to products with the epoxide ring below the plane. Using D-(−)-diethyl tartrate leads to products with the epoxide ring above the plane. This difference lets chemists choose the desired product orientation.

The selectivity can be understood by comparing activation energies, which are the energy barriers needed for a reaction to move forward. Without the catalyst, the barrier is higher. With the chiral catalyst, the barrier drops sharply, but one enantiomer still has a lower barrier than the other.

That unequal drop explains why one enantiomer forms in excess. As a result, Sharpless epoxidation is useful for making a chosen enantiomer of a product. The stereochemistry can also be predicted by placing the allylic alcohol in a plane with the hydroxyl group pointing toward the lower right corner. In that setup, D-(−)-diethyl tartrate delivers oxygen from the top face of the alkene, while L-(+)-diethyl tartrate delivers oxygen from the bottom face.

Chiral Control in Sharpless Epoxidation

structure and nomenclature of ethers

Ethers: Bonding, Types, and Naming

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Ethers can be cleaved into alkyl halides when heated with strong acids such as HBr and HI. This reaction is useful because ethers are usually unreactive in direct nucleophilic substitution. Their alkoxy groups are strong bases, so they are poor leaving groups. The acid cleavage happens in two substitution steps. First, the ether is converted into one alkyl halide and one alcohol. Then the alcohol reacts with excess HX acid to form a second alkyl halide. The reaction pathway depends on the...

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Why Stored Ethers Can Form Explosive Peroxides

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crown ethers

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Crown ethers are cyclic polyethers with several oxygen atoms arranged in a ring. Their ring shape gives them a crown-like form. Charles Pederson first synthesized the first crown ether at DuPont in 1967, and he later shared the 1987 Nobel Prize in Chemistry for that work. Crown ethers are named with the format x-crown-y. In this name, x is the total number of atoms in the ring, and y is the number of ether oxygen atoms. A common example is 18-crown-6. These molecules can bind specific alkali...

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Sharpless epoxidation is a chiral reaction that converts allylic alcohols into epoxides. It was discovered by K. Barry Sharpless. The reaction is useful because it can favor one enantiomer, or mirror-image product, over the other. The key to this selectivity is a chiral catalyst. It is mainly a complex of titanium tetraisopropoxide and a tartrate ester with a specific stereoisomer, or 3D arrangement. The stereoisomer in the catalyst controls which enantiomer forms in excess. Using...

acid-catalyzed ring-opening of epoxides

Epoxide Ring Strain and Acidic Opening

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base-catalyzed ring-opening of epoxides

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structure and nomenclature of thiols and sulfides

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preparation and reactions of sulfides

Sulfide Synthesis and Oxidation

Sulfides are sulfur compounds that contain two hydrocarbon groups attached to one sulfur atom. They are the sulfur analog of ethers, just as thiols are the sulfur analog of alcohols. Depending on the groups attached, sulfides may be symmetrical or asymmetrical. Symmetrical sulfides can be made by an S N 2 reaction. In this method, two equivalents of an alkyl halide react with one equivalent of sodium sulfide. Asymmetrical sulfides are prepared from thiols, an alkyl halide, and a base. This...

key terms and concepts

Learn how Sharpless epoxidation uses a chiral titanium-tartrate catalyst to form allylic alcohol epoxides and favor one enantiomer over another.

Chiral Control in Sharpless Epoxidation | JoVE K12

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Chiral Control in Sharpless Epoxidation

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