Rockerflame
Harmless
Posts: 1
Registered: 24-11-2009
Member Is Offline
Mood: No Mood
|
|
D-labelled glycine methyl ester synthesis?
Hi,
anyone got some ideas about the synthesis of
NH2-CD2-CO2-CH3
|
|
|
bbartlog
International Hazard
Posts: 1139
Registered: 27-8-2009
Location: Unmoored in time
Member Is Offline
Mood: No Mood
|
|
Looks like reversing the labeling would be easier (ND2-CH2-CO2-CD3), at least to my novice eyes; but maybe that wouldn't serve your purpose.
[Edited on 25-11-2009 by bbartlog]
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
Start from D-labelled acetic acid (CD3CO2D), which should be commercially available (I assume you have access, theres not much you can do with
D-labelled stuff without an institution with lots of machines... which consequently has funds for this sort of thing). Then you have to find a way to
get your ester and amine on there...
I'd suggest HVZ, quench with ethanol (as opposed to water, to form the ethyl ester (CD2ClCO2Et) of the chloroacetyl chloride (CD2ClCOCl; use excess
phosphorus to make sure this is what you have...)... then you have to get that alpha chlorine to an amino group; plenty of methods for this
transformation, just choose one that won't hydrolyse your ester; gabriel synthesis followed by "workup" (i.e. formation of the free amine) with
hydrazine in (sub?)stoichiometric quantities should be ok, but this assumes the imide is attacked in preference to your ester - something you'll have
to check.
Hope this is of some help to you 
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
From methyl glycinate:
-Install N-CBZ protecting group (or other, probably Bz is better - non enolizable)
-Form lithium enolate (with LDA in THF) and quench with D2O. Would have to do this more than once to achieve high % labelling.
-Hydrogenolyze CBZ
Cheaper to buy 13C-glycine from sigma. =) only $140/g
[Edited on 26-11-2009 by Arrhenius]
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
I should have checked prices before commmenting. D-labelled compounds are admittedly something I've never really looked at, for lack of use without
aforementioned large expensive machines. An obvious point that is probably implied but not said, is that when forming the enolate, you need to add
protected glycinate ester to an excess of strong base (LDA is most appropriate I suspect, LiH may be fine also) to prevent Claisen condensation.
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
The limited solubility of metal hydrides makes it difficult to quantitatively form the enolate, hence a lithium amide is more effective. I think one
would find that the Claisen product is quite minimal at -78ºC. An Aldol reaction is far more energetically favorable, and hence goes to completion
upon warming to rt.
For instance, this OrgSyn prep uses t-butoxide in refluxing t-butanol.
So, yes, adding the ester to the LDA is the correct order of addition, but probably doesn't matter much anyhow.
Clearly an amateur is uninterested in 2H labelled compounds... so I'll assume you're ready to have a look at the 1H-NMR (a little crazy around 3ppm,
probably) to determine product purity 
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
Arrhenius - you are right regarding the claisen is slow at -78C, at which temperature is necessary/ideal to use LDA at (and the key point I missed
when I made my last post...). I just want to make sure that I'm not misunderstanding you when you mention the Aldol reaction - you mean in general,
and not in this specific preparation (as we are only dealing with an ester...)?
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
I mean Aldol reaction in the sense of an enolate reacting specifically with an aldehyde electrophile.
I suggested this as a facile method to deuterate the molecule, but I don't think it would be terribly effective. It sounds fine, and D2O is cheap,
but I'm not sure - when forming a second enolate - whether the deuterium or hydrogen will be abstracted. I'm inclined to think there will be a slight
preference for the hydrogen (call me an idiot, but a deuterated molecule is metabolised slower in the body).
Depending on the % labelling required (usually 100%), one would have to form the enolate MANY times (% = e^n, or something like that). Perhaps not
ideal
|
|
|
not_important
International Hazard
Posts: 3873
Registered: 21-7-2006
Member Is Offline
Mood: No Mood
|
|
Seems to me that if the enolate formation is about the same chance for H and D, then every time you went through the enolate-quench cycle you'd
replace about half the remaining Hs, so the number of steps N is found by (allowable fraction of H) > 1/2^N. Thus 1 ppt H means 10 cycles, 14 for
> 100 ppm, 20 for 1 ppm.
hmmm ... as an alternative, how about starting with dimethyl malonate, catalysed H-D exchange of both methylene hydrogens - swamp them with D2O or
MeOD plus a bit of strong base, form the monoamide from that, then Hofman rearrangement. You'll lose some ester to hydrolysis, but a NaHCO3 wash (in
D2O?) will snag the free acid; the starting materials are cheap so real high yields aren't that necessary. The methylene Hs come off a lot easier
than those of prot-NH-CH2-CO2Me, and as it's an exchange rather than an enolate quench a higher replacement can be obtained in a step.
[Edited on 29-11-2009 by not_important]
|
|
|
DJF90
International Hazard
Posts: 2266
Registered: 15-12-2007
Location: At the bench
Member Is Offline
Mood: No Mood
|
|
http://en.wikipedia.org/wiki/Kinetic_isotope_effect
I wrote out a massive reply but it was lost as I tried to post it... the above link summarises what I wanted to say quite nicely, and even goes into
more detail.
[Edited on 29-11-2009 by DJF90]
|
|
|
Nicodem
Super Moderator
Posts: 4230
Registered: 28-12-2004
Member Is Offline
Mood: No Mood
|
|
It always bemuses me how such lazy questions always end up being used and abused for reinventing the wheel. What is wrong with checking the
literature for the answer? It is supposed to be the first thing a scientist is supposed to do.
alpha-Dideuterated methyl glycinate hydrochloride is made by the esterification of alpha-dideterated glycine which itself is made by treating glycine
with barium hydroxide or some other base in D2O. There are several papers and patents on the topic and I'm not even going to waste my time citing
them. Besides, if a more original route is needed, then hydrogenating a solution of methyl nitroacetate in MeOD or D2O with an inert cosolvent might
do. An equivalent of an acid, preferably a deuterated one, should be present because methyl glycinate is not very stable in its free base state.
Methyl nitroacete is a carbon acid and as such it fairly rapidly undergoes proton exchange with protic solvents, and if this is D2O or MeOD, then you
get O2N-CD2-COOMe which after hydrogenation gives H2N-CD2-COOMe. Surely there must be some example of methyl nitroacetate hydrogenation in the
literature.
…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!
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
