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Author: Subject: Pressing issue and a question
National Hazard

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Registered: 24-4-2009
Location: Portland, Oregon
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[*] posted on 22-1-2014 at 15:13
Pressing issue and a question

Hey everyone.

I am working with construction of (non-peptide) oligomers at work. The SPS resin I must use is the 2-chlorotrityl chloride resin. Unfortunately, our amino acid (the linker) comes Fmoc and Mtt protected (there are two amine groups, the amino acid is attached to the resin via the carboxyl group). The Fmoc group is no problem as it is not acid-labile, but we also need to remove the Mtt group at some point.

Unfortunately, CTC resin is very acid labile. There are ways to cleave the molecule off of the resin without touching Mtt, but I need to have the Mtt group cleaved off to give access to the amine group there.

I've come up with three possible solutions:

1) Figure out a way to remove the Mtt group without cleaving the molecule from the resin.

2) Cleave the Mtt group along with the CTC resin using HFIP (hexafluoroisopropanol). Re-couple with CTC resin and then attach the desired small molecule to the amine group using DIC/HOBt.

3) Cleave off both groups as with (2) and perform a solution-phase reaction using DCC/HOBt. Re-couple to CTC to purify the product (after filtering out the urea byproduct), wash and then cleave again.

The problem with (1) is that I doubt there's any possible way to cleave the Mtt group off without cleaving the entire thing from the CTC; it appears that CTC resin is very, very acid-labile. With (2), the problem is that the CTC resin might react with the free, Mtt-deprotected amine group and produce a major unwanted product. I think that a primary amine is a better nucleophile than the carboxylate anion (generated by reaction with Hunig's base from the free acid). With (3), the issue is that the molecule itself is a carboxylic acid, albeit a very large one compared to the small molecule (i.e. benzoic acid), so unwanted polymerization might occur.

I cannot use alternative protecting groups as these are the only ones we have and we do not have reagents to add protecting groups (i.e Boc2O). Also, I have to keep in mind that these reactions are on the sub-millimole scale, on the order of tens of micromoles.

EDIT: I've also thought of another solution; I've coupled this starting material to Rink amide resin before using DIC and HOBt. However, I got very low yields, and ended up switching to CTC.

But if there's no other way, I suppose I'll have to take that route, perhaps with an aminomethyl polystyrene resin. The issue there is that amide resins are very resistant to acid-treatment... Concentrated TFA seems to damage the desired product, so we use 0.1-1% TFA, at least for CTC resin.

[Edited on 22-1-2014 by Rich_Insane]

[Edited on 22-1-2014 by Rich_Insane]
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