July 01, 2022, 08:07:23 PM
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Topic: Conditions for a BOC-protected NHS-ester coupling to an amine  (Read 387 times)

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Offline Babcock_Hall

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We have a BOC-protected amino acid, in which the carboxylic acid is in the form of an active ester with N-hydroxysuccinimide.  We wish to couple to a free amine, in which the C-terminus is protected as the tertiary-butyl ester.  We have been searching the literature for conditions.  We found about 30 reactions via SciFinder, plus one other from a previous search, of which most were in the patent literature.  DMF shows up a good deal as the solvent, but I have also seen THF and DCM.  The biggest puzzle is the presence and the amount of tertiary amine base which is present more often than not (triethylamine, DIPEA, or N-methylmorpholine being employed in most instances).  In some instances, the amine was used as a hydrochloride or hydrobromide salt, but this is not stated clearly in every example.  In one instance in which the hydrobromide salt was used, there was a 4.67 mole excess of TEA present.  There might have been traces of acetic acid left in this particular example, but I am not sure.

My main question is whether or not we should include a tertiary amine base.  A nonnucleophilic base would be unlikely to do harm, but I am not sure if will do any good (unless we have some acid as an impurity.   My second question is the choice of solvent.  I am inclined to go with DMF but am open to other ideas.  I may try a search with slightly more relaxed criteria later.  Thanks for any ideas.

Offline Babcock_Hall

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #1 on: April 18, 2022, 02:15:49 PM »
I am still going through reaction conditions from the literature.  Most examples use a hydrochloride salt of the amine.  Perhaps the reason for excess base is to pull the deprotonation toward completion.  Right now I am leaning toward not using any additional base, using DMF as the solvent, and working up with several 5% LiCl washes, followed by a brine wash.  The aqueous washes should remove DMF and also remove the N-hydroxysuccinimide by-product.
« Last Edit: April 18, 2022, 05:28:55 PM by Babcock_Hall »

Offline Babcock_Hall

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #2 on: April 18, 2022, 08:09:28 PM »
I have been advised to add 2-3 equivalents of base.  It has also been suggested to use 0.5 M HCl followed by saturated sodium bicarbonate as part of the work-up.  The idea is to remove unreacted starting materials.

Offline rolnor

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #3 on: April 19, 2022, 02:11:54 AM »
I have never added base. The leaving group is not acidic so it seems non important?
I would try just mix the reactants, it should be straightforward. If they use DMF its probably for solubility reasons, you can use any anhydrous solvent.

Offline kriggy

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #4 on: April 19, 2022, 06:03:39 AM »
I did this reaction few days ago: I used excess of OSu ester and triethylamine. Worked wonders, full conversion. I did thos reaction in the past as well and seems they are somehow worse without base.

Offline Babcock_Hall

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #5 on: April 19, 2022, 09:04:05 AM »
Kriggy,

How much excess?  I have seen a slight excess of one or the other reagent, but I need to double-check this.

Offline Babcock_Hall

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Re: Conditions for a BOC-protected NHS-ester coupling to an amine
« Reply #6 on: April 19, 2022, 01:09:23 PM »
Someone at ChemPros (Reddit) noted a slight increase in yield in the presence of base.  We will use a little.  Right now I plan to model our synthesis after:
https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01852
We will substitute in a 5% citric acid wash for the 1 N HCl wash, which is essentially wildfyr's suggestion.  My estimate and a quick search in Ford and Moore's indispensable book suggests that the pH should be near 2 for citric acid.  Acetic acid at 1 M would be another choice.
« Last Edit: April 19, 2022, 03:19:07 PM by Babcock_Hall »

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