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April 13, 2016

Classics in Organic Chemistry, Part II

Filed under: Classics in Organic Chemistry — sankirnam @ 4:04 pm

The next post in this series is about a reaction known as the “Shi Epoxidation”. This was first reported in 1997 by Prof. Yian Shi at Colorado State University, and has since been refined many times and is now an important component of the synthetic chemist’s toolkit. As mentioned in the paper, this method complements the other asymmetric epoxidation methods in the literature nicely. The Sharpless AE (asymmetric epoxidation), which was one of the first truly robust and reproducible asymmetric synthetic methods to be reported, works best with allylic alcohols, and while there are several ways to asymmetrically epoxidize cis-olefins, trans-olefins remained a major challenge until the development of the Shi epoxidation.

When broken down into its constituent conceptual components, this reaction is very simple to understand.shi_epoxidation_1The terminal oxidant is Oxone, a triple salt containing potassium peroxysulfate (KHSO5), and the species 1 is the catalyst that actually does the epoxidation. When mixed with Oxone, the ketone functionality in 1 is converted to a dioxirane, which is the species that does the actual epoxidation. And since 1 is chiral, it will also do a facially selective epoxidation, in essence, an asymmetric epoxidation!shi_epoxidation_2Oxidation with dioxiranes is well-established in the chemical literature. DMDO (dimethyldioxirane) is readily generated from mixtures of acetone and Oxone, and the chemistry of this was explored by Prof. Waldemar Adam. The breakthrough here is that instead of using a simple symmetric ketone like acetone and making DMDO in situ, one can use a chiral ketone and make a chiral dioxirane. The nice thing about the ketone 1 is that it can be made relatively easily and is derived from D-fructose (which is inexpensive and readily available) by ketalization (acetone, HClO4, 0 °C, 53%) and oxidation (PCC, rt, 93%). The enantiomer is also accessible from L-sorbose, although that requires more synthetic steps.shi_epoxidation_3So that’s the broad picture of this reaction, and one can readily see why this gained popularity. It is an asymmetric synthetic method that complements others in the literature, and the chiral ketone catalyst can be readily prepared from inexpensive starting materials. In fact, it is commercially available. This is also one of the early instances of organocatalysis, and it is unfortunate that Shi did not use the term in any of his early papers – he could have gotten credit as one of the pioneers of this field of chemistry. Shi only started using the term “organocatalytic” in his papers much later, after the field of organocatalysis had been kickstarted by MacMillan, Barbas, and List.

One of the drawbacks with the Shi epoxidation is that it does not work very well with cis-olefins, but that is why this is complementary to other methods – this works very well with trans-olefins, and there are other methods that work just fine for cis-olefins. There are more details and nuances that can be discussed here as well. The first is that in the initial publication, the epoxidation is not catalytic with respect to chiral ketone 1. Shi had to use 3 equivalents of the ketone, as he and his coworkers observed that it decomposed very rapidly under the reaction conditions (pH 7-8). Those were initially chosen to minimize the background reaction (oxidation of the olefin by Oxone, giving a racemic product). It was also proposed that the ketone catalyst 1 was decomposing under the oxidative conditions through a Baeyer-Villiger reaction. It was then found that increasing the pH to 10.5 by using a K2CO3 buffer allowed the ketone catalyst to become longer-lived, thus enabling a catalytic process by slowing down the Baeyer-Villiger oxidation and improving the nucleophilicity of Oxone in the reaction medium. The implication is that the pH needs to be carefully controlled during this reaction, necessitating the use of syringe pumps to slowly add buffer or base in order to maintain the pH. Shi has also done a lot more work in this area, trying to improve the lifetime, scope, and generality of the reaction, as well as trying to asymmetrically epoxidize trisubstituted olefins, which is still a long-standing challenge.

Further information can be found in the links above, or in the references below:

  1. Shi Epoxidation – Organic Chemistry Portal
  2. Shi epoxidation – Wikipedia
  3. Oxidations with Dioxirane
  4. Murray, R. W.; Singh, M. Org. Synth. 199774, 91 (Example of a procedure for doing epoxidation with DMDO)
  5. Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 198922, 205 (Review on dioxiranes)
  6. Murray, R. W. Chem. Rev. 198989, 1187 (Review on dioxiranes)
  7. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997119, 11224 (First full article by Shi)
  8. Wong, O. A.; Shi, Y. Chem. Rev. 2008108, 3958 (Review on organocatalytic asymmetric epoxidation methods, including an in-depth discussion on the applications of Shi’s method)
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