[vioza]

Hi All!
I'm a little bit lost in understanding of the reaction. Please, *delete me*!
So here is a procedure: starting material is FmocCys(Trt)COOH, then Trt group is removed by TFA/TES. After that trimethylsilyl chloride is added to the reaction and refluxed for 2 hours. After the mixture is cooled to rt, acyl chloride is added followed by dropwise addition of triethylamine.
Is the silylation occurs only on carboxy group? or both SH and COOH are silylated?
How stable are silyl derivatives?
Desired compound is Fmoc-protected, s-acylated cysteine with free COOH group. Any ideas?

Thanks!

[Babcock_Hall]

Is the procedure above from a literature reference?  If so, would you give the citation?  Thanks.

[vioza]

Is the procedure above from a literature reference?  If so, would you give the citation?  Thanks.

Here it is:
TFA and TES were added to FmocCys(Trt)COOH in dichloromethane and mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue washed with toluene and evaporated. Then the solid was washed with hexane on the filter to remove the released triphenylmethane. The remaining solid was dissolved in dichloromethane, trimethylsilyl chloride was added and the mixture was heated to reflux (2hours). After cooling to rt acyl chloride was added, followed by dropwise addition of triethylamine solution (3 hours under argon). After the mixture had been stirred for one more hour, the solvent was evaporated and crude mixture was purified by flash chromatography.

[Dan]

Please give the citation, i.e. Journal name, publication year, page number

[vioza]

Please give the citation, i.e. Journal name, publication year, page number

Here it is:
Lumbierres, M., Palomo, J. M., Kragol, G., Roehrs, S., Müller, O. and Waldmann, H. (2005), Solid-Phase Synthesis of Lipidated Peptides. Chem. Eur. J., 11: 7405–7415. doi: 10.1002/chem.200500476
Procedure is page 7412

[baum0372]

If you take a look at equation 12 in the following link, they use TMSCl to protect a carboxylic acid and an amine for reaction with an acyl chloride.  Seems that the TMS protects the COOH group to prevent some side reactions such as mixed anhydride formation which could then react with a nucleophile (such as amine or thiol) which would essentially couple your starting materials together.  Because the TMS protected COOH is so labile, after the reaction, they can work it up in water to remove the TMS group.  In your case, they are protecting both the thiol and COOH, but the general strategy is the same.  Hope this helps.

DOI: 10.1002/047084289X.rc156.pub2

[vioza]

If you take a look at equation 12 in the following link, they use TMSCl to protect a carboxylic acid and an amine for reaction with an acyl chloride.  Seems that the TMS protects the COOH group to prevent some side reactions such as mixed anhydride formation which could then react with a nucleophile (such as amine or thiol) which would essentially couple your starting materials together.  Because the TMS protected COOH is so labile, after the reaction, they can work it up in water to remove the TMS group.  In your case, they are protecting both the thiol and COOH, but the general strategy is the same.  Hope this helps.

DOI: 10.1002/047084289X.rc156.pub2

Thank you for your comments! I was not sure when TMS deprotection step is happening, as there is no workup in the actual procedure, only chromatography of crude mixture...

[baum0372]

It would be my assumption that the acidic silica and residual water would quickly exchange with the TMS group to reform the COOH functionality.  Just my guess.  TMS on COOH I would suspect is very labile..

[Babcock_Hall]

TMS groups on phosphate esters or anhydrides are quite labile and are rapidly removed in the presence of water or an alcohol.

[kamiyu]

Yeah, TMS is very labile and I think the only useful/stable protection of its is acetylene.

I once protect carbazole with TMS (N-TMS), it just died in water.

I changed to tert-butyldimethylsilyl, it is much more stable.

[vioza]

Yeah, TMS is very labile and I think the only useful/stable protection of its is acetylene.

I once protect carbazole with TMS (N-TMS), it just died in water.

I changed to tert-butyldimethylsilyl, it is much more stable.

Thank you!
In this particular reaction do I have to wash final mixture with water? Or TMS will fall out on the column?