Imperial College London

Henry Rzepa

Sharpless epoxidation converts a prochiral allylic alcohol into the
corresponding chiral epoxide with \> 90% enantiomeric
excess\[cite\]10.1021/jo00369a032\[/cite\],\[cite\]10.1021/jo00360a058\[/cite\].
Here is the first step in trying to explain how this magic is achieved.

![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/sharpless.svg "sharpless"){.aligncenter
.size-full .wp-image-8589 decoding="async" width="450"}

The scheme above shows how (achiral) prop-2-enol is converted using the
asymmetric catalyst (R,R)-diethyl tartrate  and *t*-butyl hydroperoxide
as oxidant into the (S)-chiral epoxide. The first step is to try to
construct a simple model for the reaction, and in this post I will start
by using one titanium as the core of the stage on which these actors
will perform. This is the ***mononuclear model***^†^. One can simply
envisage that a molecule of tartrate displaces two ^i^PrOH molecules
from Ti(O^i^Pr)~4~ in an ester exchange to form a
Ti(O^i^Pr)~2~(tartrate) complex. The remaining two iso-propanols are
then replaced by one molecule each of prop-2-enol and ^t^Bu-OOH. Now we
have the species Ti(OO^t^Bu)(O-CH~2~CH=CH~2~)(tartrate) as the starting
point from which a transition state for oxygen transfer to the alkene to
form the (S) epoxide (for R,R tartrate) can be
constructed (ωB97XD/6-311G(d,p)/SCRF=dichloromethane model).

<table class="aligncenter" data-border="1" data-align="center">
<colgroup>
<col style="width: 50%" />
<col style="width: 50%" />
</colgroup>
<tbody>
<tr class="odd">
<td><div id="attachment_8591" class="wp-caption aligncenter"
style="width: 220px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/sharpless-S.jpg"
title="sharpless-S" class="wp-image-8591" decoding="async"
aria-describedby="caption-attachment-8591"
onclick="jmolApplet([210,210],&#39;load wp-content/uploads/2012/12/sharpless-S-2113.390932.log;frame 31;set antialiasDisplay ON;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;&#39;,&#39;c1&#39;);"
width="210" />
<p>Mononuclear TS for S-epoxide. Click for 3D.</p>
</div></td>
<td><div id="attachment_8598" class="wp-caption aligncenter"
style="width: 220px">
<img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/sharpless-R.jpg"
title="sharpless-R" class="wp-image-8598" decoding="async"
aria-describedby="caption-attachment-8598"
onclick="jmolApplet([210,210],&#39;load wp-content/uploads/2012/12/sharpless-R-2113.392301.log;frame 31;set antialiasDisplay ON;vectors on;vectors 4;vectors scale 8.0;color vectors green;vibration 6;&#39;,&#39;c2&#39;);"
width="210" />
<p>Mononuclear TS for R-epoxide. Click for 3D.</p>
</div></td>
</tr>
<tr class="even">
<td colspan="2"><span style="font-size: small;">IRC for mononuclear
model showing oxygen atom transfer</span></td>
</tr>
<tr class="odd">
<td colspan="2"><img
src="http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/sharpless.gif"
title="sharpless" class="aligncenter size-full wp-image-8637"
loading="lazy" decoding="async" width="382" height="338" /></td>
</tr>
</tbody>
</table>

The transition state leading to
[(S)](http://hdl.handle.net/10.6084/m9.figshare.103175){target="_blank"
rel="noopener"} epoxide emerges as 0.86 kcal/mol higher in ΔG^‡^ than
the
[(R)](http://hdl.handle.net/10.6084/m9.figshare.103233){target="_blank"
rel="noopener"}, contrary to the experimental result where (S) is formed
with high specificity\[cite\]10.1021/jo00369a032\[/cite\]. Inspecting
the model, it is clear that the allylic alcohol substrate sits in a very
open pocket un-encumbered by any nearby groups (bottom right in the
animation above) and so the lack of π-facial selectivity is perhaps not
surprising.

To elaborate the model, I will turn to a crystal structure determined
for a Ti complex bearing a *t*-butyl peroxy
group\[cite\]10.1021/ja954308f\[/cite\], showing it to be a binuclear
complex^¶^ (magenta arrows indicate the peroxy groups) with bridging
oxygen atoms.^‡^

::: {#attachment_8601 .wp-caption .aligncenter style="width: 282px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/ZUKJIY.jpg "ZUKJIY"){.wp-image-8601
loading="lazy" decoding="async"
aria-describedby="caption-attachment-8601"
onclick="jmolApplet([210,210],'load wp-content/uploads/2012/12/ZUKJIY.mol;set antialiasDisplay ON;','c3');"
width="272" height="238"}

ZUKJIY. Click for 3D
:::

In the follow-up post,  we will see whether these binuclear models can
do better at explaining the enantioselectivity of the Sharpless
reaction.

------------------------------------------------------------------------

^†^ See [this
post](http://www.ch.imperial.ac.uk/rzepa/blog/?p=2300){target="_blank"
rel="noopener"} for an example of such "single-site" catalysis using Mg
or this article for an example using
silver\[cite\]10.1002/chem.201200547\[/cite\].

^¶^A binuclear Zn catalyst with similar oxy-bridges is used to
co-polymerise epoxides themselves with carbon
dioxide\[cite\]10.1021/ma300803b\[/cite\]. Many such binuclear complexes
are known.

^‡^ The other element for which a number of examples of such *t*-butyl
peroxy bonding are known is oddly enough,
lithium.\[cite\]10.1002/chem.200900746\[/cite\]

::: {#attachment_8632 .wp-caption .aligncenter style="width: 188px"}
![](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/MULVAQ.jpg "MUKVAQ"){.wp-image-8632
loading="lazy" decoding="async"
aria-describedby="caption-attachment-8632"
onclick="jmolApplet([210,210],'load wp-content/uploads/2012/12/MUKVAQ.cif;set antialiasDisplay ON;','c4');"
width="178" height="163"}

MUKVAQ. Click for 3D.
:::

------------------------------------------------------------------------

**Postscript:** Two lower energy conformations for the
[S](http://hdl.handle.net/10.6084/m9.figshare.103900){target="_blank"
rel="noopener"} and
[R](http://hdl.handle.net/10.6084/m9.figshare.103901){target="_blank"
rel="noopener"} transition states have been found, the latter being 1.6
kcal/mol lower in free energy. 

|                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| S                                                                                                                                                                                                                                                                         | R                                                                                                                                                                                                                                                              |
| ![S-new](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/S-new.jpg){.aligncenter .size-full .wp-image-8650 decoding="async" onclick="jmolApplet([210,210],'load wp-content/uploads/2012/12/Sharpless-S-2113.392948.log;frame 23;','c5');" width="200"} | ![R-new](http://www.ch.imperial.ac.uk/rzepa/blog/wp-content/uploads/2012/12/R-new.jpg){.aligncenter .wp-image-8651 decoding="async" onclick="jmolApplet([210,210],'load wp-content/uploads/2012/12/Sharpless-R-2113.395494.log;frame 23;','c6');" width="200"} |

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


Sharpless epoxidation converts a prochiral allylic alcohol into the corresponding chiral epoxide with &gt; 90% enantiomeric excess[cite]10.1021/jo00369a032[/cite],[cite]10.1021/jo00360a058[/cite]. Here is the first step in trying to explain how this magic is achieved.

Messaggi di Rogue Scholar

Why is the Sharpless epoxidation enantioselective? Part 1: a simple model.