[Doane1]

Hey All,
I'm a college senior doing summer research and need some help/suggestions on some things.

Currently, as practice for synthesis of a similar compound, I am trying to methylate the amine of L-Serine using DMS and/or Iodomethane. In previous attempts, I was able to methylate the amine of L-Alanine by combining equal equivalents of L-Alanine methyl ester, DIPEA, and DMS dissolved in the minimal amount of dichloromethane. However, I'm hesitant to believe I'll get the same result with L-serine due to the fact that the OH group and amine group will be competing and will most likely both be methylated.

So, my question is, is there such a protecting group that I can use that will protect both the hydroxyl group and the carboxylic acid OH group and leave the amine unprotected for methylation?

The ultimate goal would be to produce N-Methyl-L-Serine from L-Serine. I do realize one can just purchase N-Methyl-L-Serine, but again, I'm trying to practice my techniques before attempting a similar synthesis of a much more expensive amino acid.

Thanks you much for all suggestions!

[discodermolide]

Hey All,
I'm a college senior doing summer research and need some help/suggestions on some things.

Currently, as practice for synthesis of a similar compound, I am trying to methylate the amine of L-Serine using DMS and/or Iodomethane. In previous attempts, I was able to methylate the amine of L-Alanine by combining equal equivalents of L-Alanine methyl ester, DIPEA, and DMS dissolved in the minimal amount of dichloromethane. However, I'm hesitant to believe I'll get the same result with L-serine due to the fact that the OH group and amine group will be competing and will most likely both be methylated.

So, my question is, is there such a protecting group that I can use that will protect both the hydroxyl group and the carboxylic acid OH group and leave the amine unprotected for methylation?


The ultimate goal would be to produce N-Methyl-L-Serine from L-Serine. I do realize one can just purchase N-Methyl-L-Serine, but again, I'm trying to practice my techniques before attempting a similar synthesis of a much more expensive amino acid.

Thanks you much for all suggestions!

I don't think you will O-methylate under these conditions

[herrhansen]

Did you get a mono methylation using this method?

[Doane1]

Well we only characterized using TLC and IR because currently our NMR and Mass Spec instruments are down, so I'm guessing we had a mix of mono and dimethylation.

[azmanam]

KOH and benzyl bromide (+ cat. Bu4NI might help) will benzylate the alcohol and form a benzyl ester.  Then you can N-methylate and use H2, Pd/C to deprotect both.

[Doane1]

Hey thats great! Thank you so much.

[nox]

KOH and benzyl bromide (+ cat. Bu4NI might help) will benzylate the alcohol and form a benzyl ester.  Then you can N-methylate and use H2, Pd/C to deprotect both.

What about silylation with TBS?

[Doc Oc]

KOH and benzyl bromide (+ cat. Bu4NI might help) will benzylate the alcohol and form a benzyl ester.  Then you can N-methylate and use H2, Pd/C to deprotect both.

I've actually used similar conditions to dibenzylate serine.  The alcohol, surprisingly, remained untouched.

The mono-methylation is a pain in the a.  Tried different reductive aminations as well as NaH/MeI of the Boc protected amine.  Not an easy transformation.

[orgopete]

I was skeptical of the O-benzylation in the presence of an amine. So, J-bone's report that this gives N-benzylation was not a surprise to me.

I would think a difficulty that might be experienced is that of any monomethylation reaction. They tend to give mixtures. If the prior alkylation of an aminoacid ester gave satisfactory yields of monomethylated aminoacid, I would just (close my eyes and) try it.

Otherwise, I might just diacylate or diacetylate and methylate the diacetyl serine. I wouldn't worry whether an ester formed in addition to the amide. It actually would be a good target. It would be a neutral compound and if you found loss of an acetyl group or unmethylated amide, it would be an easy compound to purify by chromatography. An acid catalyzed hydrolysis would give your N-methyl serine as its hydrochloride salt.