Application - Epoxidation in Reboxetine Synthesis

Reboxetine is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate.  It is being tested as a therapy for neuropathic pain.  The (S,S) enantiomer shown below is significantly more active than the racemate.  The racemate is much easier to make, however if you want the pure (S,S)-Reboxetine then a subsequent resolution would be necessary.  Since this is costly the manufacturer just manufactures and markets the racemate.



A key step in the synthesis of racemic Reboxetine is the epoxidation of cinnamly alcohol (1).


Reboxetine Epoxidation

Can you propose two possible ways to achieve this epoxidation?

A more atom economical synthesis would involve synthesizing the enantiopure epoxide instead.  One method to achieve this is the Sharpless Asymmetric Epoxidation.  The Sharpless asymmetric epoxidation utilizes diethyl tartrate as the chiral modifier, t-butylhydroperoxide as oxidant and Titanium(V) isopropoxide.  Epoxidation of cinnamyl alcohol proceeds with very high eneantioselectivity resulting in a 98% ee (enantiomeric excess).  

Reboxetine Sharpless Asymmetric Epoxidation

Do you recall what ee (enantiomeric excess means)?  What percent of (R,R) and (S,S) are made if the ee=98%?


What do you suppose would happen if diethyl (2S,3S)-tartrate were used instead?  What would the ee be then?