BobHawson
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Methylation of 5-Hydroxytryptophan (5-HTP)
Hi,
Nice to be on the forum!
Anyone have any ideas on how to selectively methylate the 5 position of 5-HTP?
5-HTP
[2-amino-3- (5-hydroxy-1H-indol-3-yl) propanoic acid]
into
5-MeOTP?
[2-amino-3- (5-methoxy-1H-indol-3-yl) propanoic acid]
Would dimethyl sulfate methylate 5-Hydroxytryptophan at both hydroxy positions? One? Neither? If so, what would the product be called?
Thanks for the help folks.
BobHawson
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kclo4
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5-hydroxytrpytophan actually only has one Hydroxy group. The other one you are looking at is actually a carboxyl group. Notice the double bonded
oxygen next to it?
Read a bit about them here: http://en.wikipedia.org/wiki/Functional_group
The carboxyl group would possibly form a methyl ester, while you want a methyl ether, correct?
I think Sodium Methoxide could be used as the methylating agent. Although, I could be wrong.
Jee BobHawson, watcha gonna be doing with 5-MeO-Tryptaphan?
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smuv
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The amine, and the carboxyl group!
I did a quick scifiner search...nothing.
Amino acids can be protected as their copper(II) complex and their sidechains can subsequently be acylated; I have never seen this applied for
alkylation though.
[Edited on 12-10-2008 by smuv]
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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BobHawson
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Thanks for the tip kclo4, and a methyl ether is desired, yes.
Know of anywhere a procedure is given for using Sodium Methoxide (NaOCH3) in this way?
What could likely substitute for sodium methoxide, besides KOCH3?
BobHawson
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chemrox
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I think 5-meO-tryptophan is a better sleep aid than tryptophan and is sold as such. I seem to recall that 5-MeO-Tryptophan was sold as a sleep aid
during the tryptophan scare.
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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kclo4
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Interesting! Wouldn't mind obtaining 5-MeO-Tryptophan for that! I have the hardest time getting to sleep. I've contributed this to high histamines for
several reasons. Interestingly 4 pills of Diphenhydramine (75mg each) doesn't even begin to make me tired while all my friends claim that one knocks
them out.
This could help you with the MeO-tryptophan synthesis - http://www.erowid.org/archive/rhodium/chemistry/345tmb.p-cre...
Note that Sodium Methoxide is really dangerous!
Well.. all alkylating agents are also, but read the wiki about Methoxides and you'll know what i mean!
Oh.. are you sure it wasn't 5-Methoxytryptamine? I can find more info on that as a sleep aid then on the Tryptophan.
[Edited on 11-12-2008 by kclo4]
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smuv
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Chemrox I have never seen 5-meo-tryptophan otc. I believe you are getting it confused with melatonin, which is N-acetyl-(5-methoxy-tryptamine).
PS In my opinion melatonin is a placebo, but I take it anyways when I have trouble falling asleep...the placebo effect works 
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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BobHawson
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Thank you for the link klo4.
Found this on the same site, do you folks think substituting 5-hydroxytryptophan for 3,5-dimethoxy-4-hydroxy-benzaldehyde in this route would yield
5-methoxytryptophan?
Intuition says probably not, but that there's a possibility.
*
http://www.erowid.org/archive/rhodium/chemistry/345-tmb.html
3,4,5-trimethoxybenzaldehyde
10g 3,5-dimethoxy-4-hydroxy-benzaldehyde, 13.5g K2CO3 and 8.3g dimethylsulfate is dissolved in 80mL dry DMF, the solution is stirred for 2h and then
poured into 800mL ice/water, the product is filtered off and xtalised from cyclohexane.
All reactions gives over 80% yield after recrystallization.
*
BobHawson
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Nicodem
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| Quote: | Originally posted by BobHawson
Found this on the same site, do you folks think substituting 5-hydroxytryptophan for 3,5-dimethoxy-4-hydroxy-benzaldehyde in this route would yield
5-methoxytryptophan? |
What about learning some basic chemistry before hurting or poisoning yourself?
Sodium methoxide is not a methylating reagent. It is a base and nucleophile. For example, in the example you mention, it is used in an
S<sub>RN</sub>1 aromatic nucleophilic substitution which however is completely unrelated to O-methylation of 5-hydroxytryptophan
which is not really feasible without N-protection (the carboxylic group does not really need protection as the formed methyl ester is easily
cleaved, for example concurrently with N-deprotection).
PS: Please post beginners question in the Beginners section where I'm moving this thread. Else, if you prefer to post them in the Organic section just
add a few references to your thread opening post so that it will at least appear like you actually did some literature search before posting.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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BobHawson
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| Quote: | Originally posted by Nicodem
| Quote: | Originally posted by BobHawson
Found this on the same site, do you folks think substituting 5-hydroxytryptophan for 3,5-dimethoxy-4-hydroxy-benzaldehyde in this route would yield
5-methoxytryptophan? |
What about learning some basic chemistry before hurting or poisoning yourself?
Sodium methoxide is not a methylating reagent. It is a base and nucleophile. For example, in the example you mention, it is used in an
S<sub>RN</sub>1 aromatic nucleophilic substitution which however is completely unrelated to O-methylation of 5-hydroxytryptophan
which is not really feasible without N-protection (the carboxylic group does not really need protection as the formed methyl ester is easily
cleaved, for example concurrently with N-deprotection).
PS: Please post beginners question in the Beginners section where I'm moving this thread. Else, if you prefer to post them in the Organic section just
add a few references to your thread opening post so that it will at least appear like you actually did some literature search before posting.
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In the example mentioned, I was referring to the dimethylsulfate step, not the sodium methoxide one before it.
Also, I have searched for info on the o-methylation of 5-HTP, and could not find it!
So how would you get n-protection? And how would you get n-deprotection? And what would be an apt methylating agent?
BobHawson
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Nicodem
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Ah, yes dimethyl sulfate is a methylating reagent for phenols. I read you previous posts about using sodium methoxide more carefully than I read your
last one about dimethyl sulfate.
There are literally thousands of examples of phenol methylations in the literature. There are also general examples using dimethyl sulfate, methyl
iodide and diazomethane in Vogel or Organikum books. That you found nothing related to your problem is near to impossible unless you know not what to
search for.
It is N-protection, not "n-protection" (the "n-" prefix stands for something else, unrelated to nitrogen). There are many ways to
N-protect an amino acid and since I have no idea of what is available to you it makes no sense to search the literature for you. You could
check a review on protection group use, for example the book Protective groups in Organic Synthesis by T. Greene and see what is most
suitable for you.
Using diazomethane could be a way to skip N-protection since it should first O-methylate the carboxyl group and then the phenolic
group giving the 5-methoxytryptophane methyl ester which is easily hydrolysed. The next function to methylate would be the indole NH, but this too
slow to be of concern. But this is all guessing since there might be other side reactions.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Klute
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I would protect the amine by acylation (Ac2O, TsCl or even HCOOEt), and alkylate the phenol with trimethylphosphate/K2CO3, or anothe rlight
methylating agent, you don't want to methylate your amide (can happen with DMS and KOH).. Then hydrolyze off your amide with a dilute acid or base
reflux. You might want to form a ester before acylation just in case, doesn't take to long and should cause much looses. The ester will be hydrolyzed
at the same time as the (sulfo)amide.
Definitively check out the book Nicodem recommended, it is very complete and you have lots of options of selective deprotections!
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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zed
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I believe 5-Hydroxytryptophane should be easily methylated, without N-protection.
But, you might have to try it to find out. Here is the deal. React your 5-Hydroxytryptophane with 2 equivalents of potassium to form the
di-potassium salt.
Potassium methoxide might be a suitable reagent to accomplish this.
Once you have your di-potassium salt, react it with 2-equivalents of Methyl Iodide or some other methylating agent.
This should produce mainly, 5-Methoxytryptophane Methyl Ester. In my estimation, the alkali metal salts of a phenolic group and a carboxylic acid,
are going to be a lot more reactive to your methylating agent than the amino N-H is.
Shy about using your expensive 5-hydroxytryptophane in a real experiment? Try the experiment with Tyrosine. Tyrosine is cheap, cheap, cheap.
About $20.00 a Kilo. And, it is readily available. The same functional groups are present.
Since I'm pretty sure that I once read a paper describing the successful methylation
of the OH group of either tyrosine or tyramine, without N-protection, I'm relatively sure it can be done.
Of course, if what you really seek is Melatonin. This is all a waste of time. Someone in China wquld be happy to ship you a Kilo or so, for a few
hundred dollars.
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