I am trying to couple the salicyl aldehyde to a Merrifield attached Thr, naturally after the tbu and Fmoc deprotection (performed with 80/10/10 TFA TIPS DCM, and piperidine, respectively).
After an overnight reaction in DCM/MeOH 1:1 with 1% AcOH and 5 eq of aldehyde, the ninhydrin test was striking positive.
I am currently undecided whether to try to protect the OH of the salicylaldehyde and repeat the oxazolidine formation under the same reaction conditions, or try to make it in AcOH/Py 1/1 mol:mol, as used in the Ser/Thr peptide ligation.
Would that be possible that the free OH of the aldehyde has disturbed somehow the reaction? And, if not, which could be the cause?
Thank you in advance for the guidance
Water in the reaction may be an issue as it is a byproduct. 4 A sieves are usually good but may be incovenient with the resin; alternatively you could switch to the dimethyl acetal of salicylaldehyde.
The mildly acidic free phenol may be providing anchimeric assistance contributing to the instability of your desired product; in which case protection may be necessary.
Dear Enric thank you for your answer
I have already tried to make sal. aldh. with the OH protected as Boc carbonic ester, which then should be cleaved upon base treatment although i still need to find out the conditions for such step. The matter even with this is the propensity of the N of the newly formed oxazolidine to exert a nucleophilic attack on the C=O of the ester, forming therefore the N boc protected oxazolidine ring, and which frees the OH. Is there any protection easily removable you would recommend me?
I'd probably try a TBS group first, hopefully the sterics won't be too bad.
Thank you Enric, i left the resin on 60 degrees overnight in AcOH/Py 1:1 and the nynidrin test is negative (light blue solution with yellowish breads agaist negative with darker blue solution with dark red breads visible at naked eye).
Anyway i will take it into account....how then the deprotection would be done? have u got any reference ?
Best Regards and thank youjavascript:
Phenolic TBS groups can be removed under mild conditions with Cs2CO3 in wet THF or with TBAF (1.1 eq.) in THF at room temperature. If epimerisation is giving you difficulties due to the basicity of TBAF then try NH4F in MeOH/H2O reflux.
My standard reference for protecting groups is the textbook "Greene's Protective Groups in Organic Synthesis", I have the 4th edition.
Hi Enric...last time i managed to make the oxazolidine synthesis on resin with unprotected sal. ald., though it took long reaction time and high concentration (best conditions being 50% solution of (AcOH/Py 1:1 mol:mol)/(sal. ald)), and now am seeking to improve the synthetic route....as mentioned i do not have yet that much experience in OH protection, and for this case i choose a TBDMS ether.....the protection went almost quantitative and provided the sterical hindrance of the protecting group does not impede the reaction, for the deprotection i would try DBU 1 eq in h20 acn 1:95....would you say it could work? or maybe i should make it at 60 degrees.....any advise? thank u for your interest (anyway i would try the deprotection in solution and allow the double of the time when making it on resin since i dont know any way to monitor it...so basically i would assume a similar kinetic between the two reaction in solution and in resin....)
DBU is probably overkill and constitutes quite harsh conditions. It should work well enough at room temperature. Sources of fluoride anion are the usual port of call for the deprotection of silyl ethers and the phenolic system is quite susceptible. I would go with TBAF in THF or DMF.
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