[zilalti]

Hello all, I am a confused physical chemistry trying to do an organic synthesis but having a few problems. So I am working with this molecule http://www.dojindo.com/store/p/99-AB-NTA-free-acid.html and want to do a couple another molecule to the three acid groups (via a DCC coupling reaction) to form a triester. Before doing the DCC coupling reaction I guess I need protect the amine first.  My thought was to use boc-protection using boc anhydride. First of all if I do this is it OK to do it in water or DMSO as it’s the only solvents the molecule will dissolve in? Also in the process is it possible to protect the amine and not the carboxylic acids too? Finally if I do succeed in the Boc protection, how will I purify it given that the three carboxylic acid groups will readily stick to any column, or could I perhaps go ahead and do the second step without further purification? Thanks 

[clarkstill]

Hi,

You can certainly boc protect in water - this SI has a prep:

http://pubs.acs.org/doi/suppl/10.1021/ol0611191/suppl_file/ol0611191si20060525_032156.pdf

As for protecting the amine in the presence of the acids, this shouldn't be a problem at all; the acids are orders of magnitude less nucleophilic than the amine so shouldn't form any mixed anhydrides etc.

Purifying the compound looks pretty tricky, so I'd be tempted to take it on crude after protection. Unless you get lucky and the product is crystalline, I'd guess you're looking at using reverse-phase HPLC or an ion-exchange column.

Hope this helps.

[kriggy]

I thinkt it should be easy to separate on silica column when the non reacted compound will stick to the stationary phase.
Ion exchange could work too but I feel its very tricky to work with

[clarkstill]

Really? A tri-acid?

[kriggy]

The acid will stick on column but he wants the ester. If I understand the post

[clarkstill]

Ah yes, but I think we're purifying at different stages.  I was suggesting methods to purify after boc protection but prior to esterification.  I guess it may not be necessary, but it's always nice to work with purified material...

After that I agree the tri-ester should be trivial to column, and should separate well from the acids that preceded it.

[zilalti]

Thanks for the info guys, great help. I have gone ahead and tried doing the boc-protection in water, with no base but a little heating (to replicate the 35 C room temperature in the Indian lab the papers from). Ideally I would like to just go ahead and use the crude product in the next reaction. Am I right in thinking that once I remove the water on the rovap, any unreacted boc-anhydride will be evaporated too? I am just wondering if the NMR may show residual boc-anhydride and I won't be able to distinguish it from the boc attached the amine. Also it just occured to me that Boc Anhydrihyde isn't soluble in water so not sure how the reaction would proceed. Wouldn't it be better to add a little acetone or THF to the reaction mixture?

[zilalti]

Hi, Just wondering if someone could give me some further advice on this problem. So I have successfully boc-protected the amine of the triacid molecule (though I have some residual TEA in the product) and I am now trying to do a esterification on the three acid groups. I have tried to do a coupling reaction using DCC and the alcohol (3 eq of each with DMAP as a catalyst in DMF). Unfortunately when I do a TLC from the reaction nothing moves up the plate suggesting that the triester has not been formed. Am I right in thinking I should use 3 eq of the alcohol for the coupling reaction. I am wondering if there is something wierd going on when trying to form a triester and that I should perhaps use an excess of the alcohol to push the reaction towards the triester, or maybe I should heat a little. Any thoughts? Thanks

[Babcock_Hall]

Which alcohol?