[ashford]

Hello,

What would be the different methods for racemic resolution of Limonene ?
Thanks for any help.

[sjb]

What methods of resolution do you know?

[ashford]

Here are the methods I know:
- You can switch to a diastereomer (This step is to my mind the most difficult in the case of limonene) to change the physical properties and then use either chromatography on column (difference of gravity property), or a solvent in which the diastereomers have different of solubility, or maybe use a fractional distillation…

- I think you can also use a reaction with a chiral reactive, which doesn’t have the same speed with the two enantiomers in order to separate them.

For further explanation:
The racemic solution of limonene is obtained by realizing Dies Alder reaction on methyl vinyl ketone followed by a Wittig reaction synthesis.

[discodermolide]

One way would be to hydroborate the terminal double bond, make a pair of diastereoisomeric esters, separate them and convert the ester back to the alcohol after separation then convert the alcohol back to a double bond.
Physical methods will not work on limonene itself.

[ashford]

Thanks a lot for your feedback.
Could you please confirm if my understanding is correct.
The limonene hydroborates into an alcohol transformed into an ester as shown in the file attached.
Can the 2 esters be separated through distallation ?
Then through a reduction we convert it back alcohol.
But how to convert back to double bond ?
Thanks for your help

[discodermolide]

The esters probably cannot be separated by distillation (too high a boiling point).
If for example you make a (+)-mandelic acid ester you will have a diastereoisomeric pair of esters. These may be crystalline, if not you will have to find a different acid that is crystalline as the limonene (alcohol) ester.
Anyway, assuming the mandelic acid ester is crystalline you need then to crystallise the esters apart by fractional crystallisation.
Having done that you must hydrolyse the ester back to the alcohol and then eliminate water to get the limonene back.

[ashford]

Concerning the hydroboration : Would it be better to use Dioxane dichloroborane (only the terminal bond is attacked) rather than BH3 as I saw from articles that both bonds are attacked when BH3 is used.

For the esterification you mean that we could use (+) - mandelic acid (if it’s appropriate for crystallisation) to get the 2 diastereoisomeric esters . Is that right ?
Could we use Ether as solvent for this fractional cristallisation ?

Got it about the hydrolysis. And then we use Calcium chloride to eliminate water.
Please find  below my understanding of the 2 first steps regarding reaction mechanism:

[discodermolide]

One point, you have missed out a carbon in your drawings.
Yes use (+) mandelic acid to get the diastereoisomeric esters. (+)-Mandelic acid was only an example, I have no ides if it will be suitable for this task.
Likewise, I have no idea if the esters will fractionally crystallise from ether.
The hydrolysis of an ester is a standard procedure un organic chemistry.

The resolution of enantiomers usually requires quite some experimentation to get the optimal salt or ester etc. Usually it takes several goes with different systems before you will find one that works.
You can separate diastereoisomeric esters by column chromatography orr MPLC.

There may be other ways of doing this resolution, the hydroboration was one that spontaneously popped into my head so a google search might help you find something else which may be easier, better or whatever!

[ashford]

Thanks a lot. Your feedback was very helpful.