Master Organic Chemistry Reaction Guide

Sharpless Epoxidation

Description: The Sharpless Epoxidation is an enantioselective epoxidation of allylic alcohols.

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Notes: The Sharpless epoxidation only works for alkenes adjacent to an alcohol (CH2OH). The oxidant is t-butyl hydroperoxide, sometimes written (CH3)3C–OOH or abbreviated TBHP. The catalyst is titanium tetraisopropoxide, written Ti[Oi-Pr]or Ti[OCH(CH3)2]4. The additive that imparts chirality is diethyl tartrate (DET). Choosing (+) or (–) diethyl tartrate [full names: L-(+)-diethyl tartrate and D(–)-diethyl tartrate – one can omit the L or D without penalty] allows one to choose the major enantiomer that is formed in this reaction [see “Mechanism” section for specifics].

The major product can be predicted by use of a mnemonic (see below).

Examples:

2-examples

Notes: As far as the reagents are concerned, each of these examples just shows different ways of representing the key titanium catalyst and t-butyl hydroperoxide. The only difference is in the choice of diethyl tartrate (sometimes abbreviated DET) enantiomer.

Example 1 shows an epoxidation of an alkene drawn in the “side view” which clearly shows that using (–)-diethyl tartrate leads to epoxidation from the top face when the allylic alcohol is drawn in this orientation.

Example 2 shows that epoxidation only occurs on the alkene adjacent to CH2OH, the other alkene is untouched [BTW, this is because the OH coordinates to titanium]

Examples 3 and 4 show the major products formed with each of these alkenes, predicted by using the mnemonic (below).

Example 5 shows that no reaction occurs when an alkene without a neighbouring alcohol is used.

Mechanism: Without going into specific details, what happens in the Sharpless epoxidation is that the titanium binds to the allylic alcohol, t-butylhydroperoxide, and the tartate in such a way as to provide a chiral environment whereby one face of the alkene is preferentially exposed to the oxidant. The outcome of a Sharpless epoxidation can be predicted by using the following mnemonic. Placing the CH2OH group in the upper right hand quadrant, using (–)-DET will lead to epoxidation of the top face, whereas (+)-DET will lead to epoxidation of the bottom face.

3-mech

Notes: If you’re really interested in learning more about how this reaction works, along with many excellent examples, this handout by the Myers Group at Harvard University is phenomenal (as are their other handouts)


(Advanced) References and Further Reading:

  1. The first practical method for asymmetric epoxidation
    Tsutomu Katsuki and K. Barry Sharpless
    Journal of the American Chemical Society 1980, 102 (18), 5974-5976
    DOI:
    10.1021/ja00538a077
    This is a landmark paper in organic chemistry. Prof. K. Barry Sharpless (now at The Scripps Research Institute, La Jolla, CA), received the Nobel Prize for developing this reaction (now called the ‘Sharpless AE’), along with two others (the ‘Sharpless AD’ and ‘Sharpless AA’). As Prof. Sharpless describes, this reaction is simple, fairly robust, and can give very good yields of enantiopure products based very reliably. Tartrate salts (which are fairly inexpensive) are used to induce chirality.
  2. Catalytic asymmetric epoxidation and kinetic resolution: modified procedures including in situ derivatization
    Yun Gao, Janice M. Klunder, Robert M. Hanson, Hiroko Masamune, Soo Y. Ko, and K. Barry Sharpless
    Journal of the American Chemical Society 1987, 109 (19), 5765-5780
    DOI: 10.1021/ja00253a032
    Prof. Sharpless put a lot of work into ensuring that his reactions were robust, reliable and useful to the chemistry community. This paper describes an improvement to the original Sharpless AE from 1980; by using molecular sieves (zeolites commonly used to absorb water) in the reaction, the substrate scope, conversion, and EE’s are dramatically improved.
  3. ENANTIOSELECTIVE EPOXIDATION OF ALLYLIC ALCOHOLS: (2S,3S)-3-PROPYLOXIRANEMETHANOL
    Gordon Hill, K. Barry Sharpless, Christopher M. Exon, and Ronald Regenye
    Org. Synth. 1985, 63, 66
    DOI: 10.15227/orgsyn.063.0066
    The ultimate test of a reaction’s reliability is whether it can be reproduced independently. The Sharpless AE is therefore included in Organic Syntheses, a source of reliable and independently tested organic chemistry laboratory procedures.Due to the heavy interest in this reaction, a lot of work has gone into the mechanism of the Sharpless AE – this is just scratching the surface:Electronic and steric factors determining the asymmetric epoxidation of allylic alcohols by titanium-tartrate complexes (the Sharpless epoxidation)
  4. Karl Anker Joergensen, Ralph A. Wheeler, and Roald Hoffmann
    Journal of the American Chemical Society 1987, 109 (11), 3240-3246
    DOI:10.1021/ja00245a011Nobel Laureate Roald Hoffmann also explains the high EE’s encountered in the Sharpless AE using Frontier Molecular Orbital (‘FMO’) theory, the development of which he received a Nobel Prize for.
  1. Mechanism of asymmetric epoxidation. 1. Kinetics
    Scott S. Woodard, M. G. Finn, and K. Barry Sharpless
    Journal of the American Chemical Society 1991, 113 (1), 106-113
    DOI:10.1021/ja00001a018
    This paper investigates the Sharpless AE in detail and determines the rate constant of the reaction and the order of each reactant and the Ti catalyst.
  2. Mechanism of asymmetric epoxidation. 2. Catalyst structure
    G. Finn and K. Barry Sharpless
    Journal of the American Chemical Society 1991, 113 (1), 113-126
    DOI: 10.1021/ja00001a019
    In this paper, Profs. Sharpless and Finn use a variety of rigorous spectrometric techniques (multinuclear NMR, IR, MS etc.) to probe the actual structure of the active Ti catalyst in the Sharpless AE.

Comments

Comment section

2 thoughts on “Sharpless Epoxidation

  1. I always had the feeling that alkenes are little bit boring, but after reading all your post in this chapter I think they are quite beautifuul.

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