Henry Rzepa's Blog

Sharpless epoxidation converts a prochiral allylic alcohol into the corresponding chiral epoxide with > 90% enantiomeric excess[1],[2]. Here is the first step in trying to explain how this magic is achieved.

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 ⁱPrOH molecules from Ti(OⁱPr)₄ in an ester exchange to form a Ti(OⁱPr)₂(tartrate) complex. The remaining two iso-propanols are then replaced by one molecule each of prop-2-enol and ^tBu-OOH. Now we have the species Ti(OO^tBu)(O-CH₂CH=CH₂)(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).

Mononuclear TS for S-epoxide. Click for 3D.	Mononuclear TS for R-epoxide. Click for 3D.
IRC for mononuclear model showing oxygen atom transfer

The transition state leading to (S) epoxide emerges as 0.86 kcal/mol higher in ΔG^‡ than the (R), contrary to the experimental result where (S) is formed with high specificity[1]. 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[3], showing it to be a binuclear complex^¶ (magenta arrows indicate the peroxy groups) with bridging oxygen atoms.^‡

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 for an example of such “single-site” catalysis using Mg or this article for an example using silver[4].

^¶A binuclear Zn catalyst with similar oxy-bridges is used to co-polymerise epoxides themselves with carbon dioxide[5]. 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.[6]

MUKVAQ. Click for 3D.

Postscript: Two lower energy conformations for the S and R transition states have been found, the latter being 1.6 kcal/mol lower in free energy. 

S	R