11.10
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.…
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-(−)-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-(−)-DET, the other—2R,3R —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-(−)-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.
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Q1: What is Sharpless epoxidation and why is it useful?
Sharpless epoxidation converts allylic alcohols into chiral epoxy alcohols with very high enantioselectivity using a chiral catalyst. Unlike standard epoxidation methods that produce racemic mixtures, this reaction selectively forms one enantiomer in excess, enabling synthesis of desired stereoisomers with exceptional purity and control.
Q2: What are the three main reagents used in Sharpless epoxidation?
The three essential reagents are tert-butyl hydroperoxide (TBHP), which acts as the oxidizing agent; titanium tetraisopropoxide, which combines with tartrate ester to form the chiral catalyst; and a specific stereoisomer of diethyl tartrate (DET), either L-(+) or D-(−), which provides the chiral environment for selective epoxidation.
Q3: How does a chiral catalyst enable selective epoxide formation?
A chiral catalyst lowers the activation energy for forming one enantiomer more than the other, creating an energy difference that favors production of one stereoisomer in excess. This differential activation energy is the basis for achieving high enantioselectivity and enantiomeric excess in Sharpless epoxidation reactions.
Q4: How does the choice of DET enantiomer affect product stereochemistry?
The stereoisomer of diethyl tartrate used determines which face of the alkene receives the epoxide oxygen. L-(+)-DET delivers oxygen to the bottom face, forming epoxides with the ring below the plane, while D-(−)-DET delivers oxygen to the top face, producing epoxides with the ring above the plane.
Q5: How can you predict the stereochemistry of a Sharpless epoxidation product?
Orient the allylic alcohol molecule in a plane with the hydroxyl group pointing toward the lower right corner. Then apply the DET enantiomer rule: D-(−)-DET delivers oxygen from above, while L-(+)-DET delivers oxygen from below, determining the final epoxide ring position and stereochemistry.
Q6: What is the role of titanium tetraisopropoxide in Sharpless epoxidation?
Titanium tetraisopropoxide undergoes rapid ligand exchange with diethyl tartrate, tert-butyl hydroperoxide, and the allylic alcohol substrate. This exchange creates a chiral titanium-tartrate complex that clamps the alkene and oxidizing agent in a fixed stereochemical position, enabling highly selective stereoselective oxygen delivery to the substrate.
Q7: Why does Sharpless epoxidation produce higher purity enantiomers than standard epoxidation?
Standard epoxidation methods like peroxy acid oxidation or halohydrin cyclization follow syn addition and yield racemic mixtures with equal amounts of both enantiomers. Sharpless epoxidation uses a chiral catalyst that preferentially stabilizes one enantiomer's transition state, producing one stereoisomer in significant excess with very high purity.