[Nescafe]

So,

I am in a bit of a pickle with my friend oxetane. I do not want it to open up, but it keeps on doing things I do not want it to do such as open up, polymerize etc. I have been gentle, careful and followed the procedures that are known to keep it intact. The story is, initially, I had a synthetic route where I had acid labile protecting groups, but, using acid opened up the ring. I used HCl and I know it is harsh but the acid labile groups were being resilient. Next, I planned a new route using base labile groups. Oxetane mainly behaves, but another part of the molecule does not behave well at all and does all sorts of rearrangements. So there is no way I can go this route with base labile protecting groups. I am more confident that I can handle the oxetane sensitivity to acid over the other part which is base labile (can not reveal entity unfortunately due to IP issues).

So, to ask a simple question, if you HAD to use an acid to remove let us say tert-butyl group or a boc without the oxetane opening up which condition would you use/recommend?

Thanks in advance,

Nescafe.

[discodermolide]

Find out exactly what acidic conditions lead to its survival. Use different mineral acids, different concentrations, use organic acids. Time, concentration, temperature, solvents etc.
Build up a picture of its stability. Otherwise you are shooting in the dark.

[Babcock_Hall]

IMO Discodermolide makes some very good points.  What about trifluoroacetic acid?

[Nescafe]

I just do not have much to work with but I understand what you are saying. TFA is a good idea for sure and probably the first I will try.

[C-hemCards]

Was the HCl anhydrous? Something like HCl in ether? If it was aqueous, give the anhydrous conditions a try. If you can simultaneously precipitate out the amine salt as it is deprotected, it will all but eliminate the oxetane rupture problem.

As stated above, TFA is a also good option. You could consider MsOH as well; I've had some luck with that in the past. ZnCl2 or ZnBr2 in CH2Cl2 can sometimes provide efficient Boc removal, but that reaction is usually feast or famine. Worth a try though.

[Nescafe]

Yes it was an anhydrous bottle of HCl in Dioxane 4.0M. I tried TFA and the ring stayed intact but I have a peptide, so both a carboxylic acid and an amine and I need to get rid of the TFA as my next step is peptide coupling and I do not want TFA to interfere. Azeotroping is not cutting it. I think I might have to use a resin, which do you recommend? I was thinking amberlyst-15, wash with water then ammonium hydroxide, will this elute the deprotonated acid as well or will the acid remain protonated due to the acidic nature of the resin?

Thanks,

Nescafe.

[C-hemCards]

Nearly all common resins are sulfonic acids tethered to a solid support, so you could just try a sulfonic acid and see how it does. With resins, you should really just filter them away and move on with the material crude, as that is the main benefit of a resin.

You may want to give the HCl conditions a try in different solvents, like Et2O, Bu2O or CH2Cl2.

[Nescafe]

So what you recommend is that I use this acidic resin, load my material and wash with MeOH/Water to get the TFA out, then Ammonium hydroxide? So once again I have H2N-------COOH.

1) Condition resin with MeOH/water
2) Load material with Methanol/water
3) Wash with methanol water to remove TFA
4) Wash with ammonium hydroxide to elute product
5) Vac of the ammonium hyroxide (What is the best way to make sure there is non left prior to proceeding to the coupling step as NH4OH could also interfere with coupling)
6) NMR the crude
7) Proceed with crude if all looks good?

Thanks!

Nescafe.

[C-hemCards]

I think I'm somewhat confused about your problems, but my experience using resins to deprotect a Boc group were to dissolve the substrate in a suitable solvent, add the resin, stir until rxn completion, filter off the resin, concentrate and move on.

I can't comment on whether your protocol will work well or not unfortunately, mainly because I don't know all of the details and I'm not an expert in oligopeptide chemistry. But, I do think you can find conditions to remove the Boc without nuking the oxetane. You just need to pay attention to the details of solvent, acid pka, scavenger, etc. Not saying that you haven't, but rather just be sure to make note of the small details, because they can really add up.

[Dan]

I think I'm somewhat confused about your problems, but my experience using resins to deprotect a Boc group were to dissolve the substrate in a suitable solvent, add the resin, stir until rxn completion, filter off the resin, concentrate and move on.

The issue here is that if your product has an amine it will be protonated and remain bound to the resin as the ammonium salt unless you release it by deprotonation - hence the ammonia elution.

I was thinking amberlyst-15, wash with water then ammonium hydroxide, will this elute the deprotonated acid as well or will the acid remain protonated due to the acidic nature of the resin?

You should recover the product as the net neutral Zwitterion following evaporation of the ammonia. I have purified amino acids this way before.

That said, your oxetane might not survive in ammonia. I would dissolve a few mg of the N-protected oxetane in ammonia and see if it is ok for a few hours (maybe overnight). It is worth checking it will not degrade at 40°C in aqueous ammonia as well so you know whether you can concentrate it at elevated temperature or not. I have no experience with oxetanes so this may be overly cautious

I think the suggestion of ethereal HCl is a good one - you used HCl/dioxane but the salt product may be soluble in dioxane. Also bear in mind that if that bottle of HCl/dioxane was old or not well kept, it would have been sopping wet.

Maybe instead of Boc, a fluoride-labile group would be better - I'm thinking 2-(trimethylsilyl)ethoxycarbonyl (Teoc).

[Nescafe]

Does anyone have a formula for how many grams of resin to use per gram of product? I cant seem to get the ratio right, either use too much which takes forever or too little which causes my product to elute with some TFA

[baum0372]

I had done a removal of a TFA salt of an amine, and using Amberlyst A21 in DCM (I believe 1-2g resin per 200mg product) I saw my solution go from cloudy to clear in about 2-3 minutes.  I let it stir for 10 minutes, then filtered through cotton/celite to remove resin and particulates from resin, and presto, pure product (the free amine).  In your case with your COOH, I'm not sure how your molecule will behave.  Anyways, weakly basic A21 resin might be a nice choice.