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Metabolic fate of t-BOC protected amine

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Limpet_Chicken

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The title says it all really, is the PH of stomach acid enough to deprotect a tert-butoxycarbonyl protected amine?

And what is the toxicity of the tBOC group and its fate metabolically speaking?
I am thinking of potential novel pro-drugs, that avoid going through the stage of a potentially verboten (but not by any means nescessarily, there are a whole crapload of active amines around obviously) amine via an isocyanate.

TFA cleavage of tBOC peptides leaves a t-Bu carbocation, which isn't going to be stable, so is this idea less genius than I originally thought? rapid metabolism to 2-methyl-propan-2-one or the equivalent propan-2-ol wouldn't be so bad, but I fancy it much less if it is going to form a nasty, reactive free radical that goes on to alkylate the shit out of the first thing it bumps into.

Predictions? tertiary carbocations are the most stable of the lot, ergo least aggressive alkylators, and if formed I would think are likely to react straight away with (mostly) H2O, metabolising to t-butanol, toxicological profile of tert-butanol isn't so bad, its metabolised to acetone, the small quantities of 'tone formed by an active dose of say N-tBOC-MDMA would be small and harmless.

Would a carbocation only be formed under anhydrous conditions? or is it possibly going to happen in vivo?

I don't want to bring this to synthesis discussion, so I won't give more than that very basic outline nescessary for the concept to be illustrated, hope that is ok.

Idea is sort of like that pthalimidopropiophenone that did the rounds a while back, I never tried any mind you, but similar concept, hopefully with less toxicity than the pthalimide leaving group (was it that bad?)
 
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Tertiary carbocation is more stable than primary or secondary, if a carbocation will form in a hydrous environment (I am not sure if it will) then it might be less inclined to alkylate the bejeesus out of the first thing it comes into contact with.

Bulky tBOC too, might be slower still to alkylate something other than the ever present H2O.

t-BuOH ain't too bad, breaks down into acetone and CO2.

Question is...will that bugger hydrolyse.
 
I'm hoping it will behave like an amide or ester, the carboxyl moiety gaining a hydroxyl group whilst the amine becomes protonated, ending up with the free amine and carboxylic acid.

BTW anyone know what is required for a carbamate to act as a muscle relaxer? now that would be hilarious, if one were to end up with a muscle-relaxant prodrug of MDxx by 'mistake'
 
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From what I remember of using t-Boc a common protocol used for deprotection was using a mixed aqueous/organic solution with some TFA or HCl. I believe the mechanism for deprotection was the same regardless of whether or not water was present, just that any t-Bu carbocation formed pretty much immediately turned into t-BuOH.

Unfortunately I think the rate of the deprotection changed very rapidly over the course of a pH unit or even less, going from virtually no reaction to complete in 15 minutes once you crossed the threshold. Unfortunately I can't remember what the concentration of acid was for the protocol.

You're best bet is probably to see if you can find some articles that detail the deprotection. I'm fairly certain there are some kinetic studies that have been done on it.
 
Hm, my mathematics skills are primary school at best, I think I will go with the tried and true 'suck it and see' approach.

I can't see it suddenly turning MDxx into anything hideously lethal, so why not, the proof of the pudding as they say, is in the eating.
 
Hmmm, I just had an idea.

Reading on the intoxicant properties of 2-methyl-butan-2-ol in this very forum....hmmm....what is its approximate duration of action? somewhere similar, to somewhat longer than that of MDMA, right?

Screw the tBOC protecting group and form the rearrangement product with tert-pentanol, so instead of hydrolysis to MDMA and t-BuOH, tweak it so one can take advantage of the breakdown product also, mmmmmm, nice relaxant built right into one's MDxx as a controlled release formulation of a sorts.

What think you people? is the carbamate likely to be active as a muscle relaxant in itself? that would be even jammier to pull off, a three for one triple action =D
 
um, the "muscle relaxant" property you are talking about is due to neuromuscular blockade via non-competitive inhibition of cholinesterase?
 
No, GABAergic, I haven't yet taken a look at the respective SAR of GABAergic vs cholinesterase inhibiting carbamates, but both do exist, look at the likes of methocarbamol, and carisoprodol
 
Screw the tBOC protecting group and form the rearrangement product with tert-pentanol, so instead of hydrolysis to MDMA and t-BuOH, tweak it so one can take advantage of the breakdown product also, mmmmmm, nice relaxant built right into one's MDxx as a controlled release formulation of a sorts.
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Heh, I already had this idea, posted it on this forum some time ago too... making a carbamate of an amphetamine and tert-pentanol - only I was thinking of ethylamphetamine, to get a nice smooth gabaergic stimulant.... but hey, the MDxx idea sounds good as well.

Another thing I was thinking back then was MD-amfechloral, to get a prodrug of MDA + chloral hydrate... or is that too far out :D
 
well if this could work i guess it might mitigate some of the excitotoxicity issues that come with stimulants.
 
I will report back as to weather it is active after bioassay, it should take around two weeks at the absolute most before it is done, I'm not exactly rolling in money.

I see no reason why it might not work, unless the stomach acid is not concentrated enough to deprotect the amine, although there are amidases that might oxidatively break down the amide, not sure yet if they give the amine though. You know what they say though about the proof of the pudding :)
 
Hehe neither can I :p

Although I am not, I admit, much of a fan of MDMA, the whole social-animal gushy huggy thing, its like trying to make me NT with a pill, although it doesn't quiet work, feels...not normal, if that makes sense.

But I can't see any reports of it having been done before, so somebody gotta do it, for the sake of science, y'know, honest guv=D
 
Limpet_Chicken said:
What think you people? is the carbamate likely to be active as a muscle relaxant in itself? that would be even jammier to pull off, a three for one triple action =D
Click to expand...

Hmm. I bet the carbamate will have some kind of activity on it's own, although unless administered parenterally I doubt you will be experiencing much of this activity... if stomach acid doesn't take care of the t-pentyloxycarbonyl then first-pass metabolism most likely will.
 
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