[uglepik]

I'm attempting to protect secondary amines on solid-phase using Boc2O (4 eq in DCM) and a reaction time of 2 days.

After that I have attempted to cleave my compound from a 2-chlorotrityl resin using 5% TFA in DCM, which I think should NOT take off the bocs.

However, it doesn't seem to work very well, as my MS-peaks make very little sense.

Does anyone have any experience with boc-protection of secondary amines? And with subsequent mild cleavage where the bocs are supposed to stay on? How do you go about this?

Thanks!

[Honclbrif]

What type of ionization are you using? BOC is also thermally labile (comes of at ~100°) and ESI usually has a hot enough source temp to remove it. Every time I've done an LC-MS on a BOC protected amine (BOC is there by NMR) I always see the -BOC species as the major peak, frequently there is no +BOC peak observed.

Modification: If you're doing LC-MS on a BOC protected species, check for an m/z = 57 (t-butyl cation) peak that coelutes with the -BOC peak. Its indirect evidence that the BOC was there, but fell off during ionization.

[uglepik]

What type of ionization are you using? BOC is also thermally labile (comes of at ~100°) and ESI usually has a hot enough source temp to remove it. Every time I've done an LC-MS on a BOC protected amine (BOC is there by NMR) I always see the -BOC species as the major peak, frequently there is no +BOC peak observed.

We're using ESI and as you say, usually boc-groups come off to some extent. However, my experience is that it is only a fraction that falls off and that the "complete" molecule is usually seen with -boc peaks lagging behind it. With these experiements, the peaks I do get, usually make very little sense and cannot be attributed to anything rational.

[enahs]

I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....

[Honclbrif]

I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....

I was thinking this too, but wanted to get the MS thing out of the way

[uglepik]

I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....

To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.

Which conditions did you use to remove your secondary bocs with TFA/DCM?

[enahs]

I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....

To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.

Which conditions did you use to remove your secondary bocs with TFA/DCM?

15%. ~12 grams of product went to completion in less then 20 minutes.

[uglepik]

I have had great success using TFA in DCM to REMOVE BOC from secondary amine..!!! So that is probably your problem....

To remove boc from at least a primary amine you usually employ relatively large concentrations of TFA (95%) while what I use is 5%. I believe that it should be possible to cleave the still protected compound from a 2-chlorotrityl resin using mild cleavage conditions. I have done this before with tBu protection groups (on glutamic acids) and they stayed on after mild cleavage wheras they are removed by 95% TFA. I would expect at least primary boc's to behave the same way - however with secondary bocs I am not sure.

Which conditions did you use to remove your secondary bocs with TFA/DCM?

15%. ~12 grams of product went to completion in less then 20 minutes.

Ouch!

[CPfeif]

I see this thread is almost a year old now, however I will share my thoughts/experience anyway...

I am a graduate student who works in the field of peptidomimetics and has a lot of experience working with Boc protected proline-type derivatives on solid support.

In my experience, there is no way around cleaving Boc protecting groups when cleaving from 2-Cl-Trt resin. tBu esters are more sluggish and can sometimes be retained when cleaving from this resin though it is essentially a race.

I suggest two possible solutions to this issue:

The first should be obvious in that a more acid-stable protecting group such as CBz may be able to be used in place of the Boc group.

The second is a little less obvious - use a more acid-labile resin! I suggest Sieber Amide resin (sold by Novabiochem and a few other companies) which is cleaved by only 1% TFA in DCM. I have personally used this resin to successfully cleave a molecule with Boc protecting groups intact.

Best,

CPfeif