11.10 : 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.