[Dan]

Hi all,

I've run into a synthetic problem, which perhaps someone has experience with.

Long story short: I have a short peptide that has 3 free amide/carbamate N-H groups that I want to protect. Ideally with fluoride-labile protecting groups; I cannot use strong base, acid or hydrogenolysis downstream. The alternative to protection is strategy redesign, which I am pursuing separately and do not want to discuss here (at least not now).

There is some precedent for silyl protection of the amide NH with e.g. TBS, but it is mainly applied to lactams - and mainly β-lactams, which are a different beast compared with linear amides. A preliminary experiment with my peptide (5 equiv TBSOTf/NEt₃) was not encouraging (~30% yield of a monosilylated peptide after chromatography, di- and trisilylated were not detected). Conversion appeared to be complete (TLC).

I will have a look at some other conditions along these lines, but if anybody has experience with either silylation of amides or protecting amide N-H groups, I'd be interested to hear about your experiences. I'm thinking about SEM, or maybe Teoc protection as options well.

[phth]

Stuff like NHBoc can come off with lewis acids, but that may be too harsh.  UV/microwave deprotrection might work.   Microwave deprotection of NHBoc in phosphate buffer works; it may not be what you're looking for, but I hope it helps.

[Dan]

Stuff like NHBoc can come off with lewis acids, but that may be too harsh.  UV/microwave deprotrection might work.   Microwave deprotection of NHBoc in phosphate buffer works; it may not be what you're looking for, but I hope it helps.

Maybe. I can also remove Boc with TMSOTf/lutidine, which may compatible with the molecule downstream.

[clarkstill]

How about Nosyl? I've recently had some success using (ortho)-nosyl it as a protecting group for a urea, and I can't imagine an amide would be all that different? Cleaves with NaSPh, which is probably a poor enough base not to mess with your other stuff?

Also, out of curiosity, does the TBS go on nitrogen or oxygen?

[Dan]

Also, out of curiosity, does the TBS go on nitrogen or oxygen?

Depends on the amide and the base used. According to the lit, usually N for aliphatic amides. I've seen examples of O-silylation of N-aryl amides using LDA though.

For my purposes, I don't mind (but a complicated mixture would be a pain).

Having had a dig through peptide literature, it seems this triple protection will be far from straightforward. Even permethylation of short peptides (which I assumed would be easy) appears to be a fairly complex problem in practice...