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Topic: hydrolysis of methylester in the presence of Fmoc  (Read 474 times)

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Offline kriggy

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hydrolysis of methylester in the presence of Fmoc
« on: May 03, 2022, 07:40:53 AM »
Hi there,

I have Fmoc-Lys(Boc)-OMe and I want to get rid of the methylester. Is there a way to do it without removing fmoc? I know you can remove fmoc with NaOH in organic solvents so im looking for something milder. K2CO3 maybe?

thanks

Offline Babcock_Hall

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #1 on: May 03, 2022, 09:51:08 AM »
That does not look easy.  This is not a well thought-out idea, but what about using an esterase enzyme in a mixed solvent?  The fourth edition of Wuts and Greene has stuff on pp. 551-2 and 558-9.  The authors mention something about thermitase being compatible with FMOC.  Reissmann and Greiner 1992 Int J Pep Protein Research 40, 110.  Pig liver esterase is another enzyme that comes up in this section of the book.

This section of the book also mentions methods to remove methyl esters from FMOC-protected amino acids, but I wonder whether the BOC group would stand up to AlCl3/DMA.

Offline kriggy

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #2 on: May 03, 2022, 09:58:11 AM »
Thank you.
I will look into it but I dont think im gonna run any enzyme stuff because we dont have experience with it since I can just deprotect with NaOH and then add fmoc again but I wanted to avoid this just because its wasteful approach.

Offline Babcock_Hall

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #3 on: May 03, 2022, 10:00:25 AM »
I sometimes see people use 2 equivalents of LiOH, but I don't know whether or not it is preferable to NaOH or KOH.

Offline rolnor

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Offline Babcock_Hall

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #5 on: May 03, 2022, 12:07:37 PM »
Hi Rolnor,

Thank you; this looks useful.  This reference looks familiar did you (or did someone else--maybe wildfyr) post this some time back?

Offline Babcock_Hall

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #6 on: May 04, 2022, 02:11:17 PM »
Hi Kriggy,

On page 44 of the fourth edition of Greene and Wuts there is a method for removing methyl esters from amino acids protected with CBZ, BOC, or FMOC.  Yields of the 5-oxazolidinone intermediates were 25-90% (some BOC-protected amino acid esters gave low yields).  These were hydrolyzed using sodium bicarbonate in water/methanol at reflux for 5-10 minutes.  I believe that this two-step procedure removed the FMOC group in the second step, something that Greene's book did not indicate.  This sounds like a good method to hydrolyze a methyl ester in the presence of the CBZ protecting group, but it is not suitable for your application.
Allevi P, Anastasia M 2003 Tet. Lett. 44:7663-7665 doi:10.1016/j.tetlet.2003.08.028
« Last Edit: May 04, 2022, 02:42:25 PM by Babcock_Hall »

Offline BobfromNC

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #7 on: May 12, 2022, 05:10:51 PM »
You can always try one of the methods of LiI in pyridine or another high BP solvent to remove the methyl as methyl iodide.  These work, but are not pleasant to do or workup, and suffer poor yields.   Better to plan better from the start, but not always possible.   I have had to do that method, and it worked well enough.

Offline rolnor

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Re: hydrolysis of methylester in the presence of Fmoc
« Reply #8 on: May 13, 2022, 01:01:42 AM »
Hi Rolnor,

Thank you; this looks useful.  This reference looks familiar did you (or did someone else--maybe wildfyr) post this some time back?

Possibly, it does come up now and then.

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