Excellent Catalyst, Excellent ee – Jacobsen HKR, Asymmetric Catalysis in Organic Chemistry

Transition metal asymmetric catalysis to resolve a racemic mixture of terminal epoxides by reaction, due to diastereomeric transition states leading to differences in rates of reaction.

References:

J. Am. Chem. Soc. 2002, 124, 1307
https://doi.org/10.1021/ja016737l

J. Am. Chem. Soc. 2004, 126, 1360
https://doi.org/10.1021/ja038590z

Acc. Chem. Res. 2000, 33, 421
https://doi.org/10.1021/ar960061v

JACS 2009, 131, 4172
https://doi.org/10.1021/ja806151g

This is a truly excellent method for making hydroxyl stereocentre in high enantiomeric excess (ee) using asymmetric transition metal catalysis. The Jacobsen Hydrolytic Kinetic Resolution (HKR) takes a racemic, and importantly, terminal epoxide and opens it up in the least sterically hindered terminal position (primary centre vs. secondary centre). Using a chiral Lewis acid to activate the electrophile means that one of the enantiomers as part of the racemic mixture will bind more effectively to the catalyst, and react much more quickly than the other. Using water as a nucleophile will lead to the enantioenriched diol and also the (oppositely configured) enantioenriched epoxide left behind. These are very easily separable by standard flash column chromatography. It is also possible to use this method to install other nucleophiles such as azides.

The asymmetric catalyst used in these reactions is a chiral cobalt salen complex, for which both enantiomers are readily available.

Depending on what you require in your synthesis, you might want to vary the stoichiometry of the experiment that you use. If the enantiomeric excess of the epoxide left behind is your priority – add a little more than 0.5 equivalents of nucleophile. The reverse if you require the epoxideopened product as your priority for ee. In either scenario you make a sacrifice in yield in favour of enantiomeric excess, but if the Jacobsen HKR is an early step in your synthesis this is usually a good compromise.

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