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A carbon-13 trifluoromethyl group within an amino acid

A carbon-13 trifluoromethyl group within an amino acid - Chemistry Forum

A carbon-13 trifluoromethyl group within an amino acid - Chemistry Forum. Discuss chemical reactions, chemistry.


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  #1  
Old 08-05-2003, 04:57 PM
David Naugler
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Default A carbon-13 trifluoromethyl group within an amino acid



Hi,

I'm interested in finding a way to put a carbon-13 labeled
trifluoromethyl group into an alpha amino acid, i.e., any amino acid
that is homologous to a natural amino acid, for instance isoleucine.
This question relates to a previous thread regarding the use of
azobis(isobutyronitrile) for the free radical telomerization of
ethylene with CCl4.

Fluorine is almost isosteric with hydrogen and so amino acids that are
fluorinated somewhere on the aliphatic or aromatic side chains can be
incorporated into proteins using conventional expression systems
without loss of protein structure or activity. The expression system
is set up using a minimal media and the fluorinated amino acid as the
sole amino acid source. Biology is not perturbed by carbon-13.

A carbon-13 trifluoromethyl group would give a strong NMR signal in a
carbon - flourine heteronuclear correlation experiment. Incorporated
within a large protein, such a hetcor experiment could be TROSYfied
for line shape improvement. At this stage, I need to be somewhat vague
about the NMR pulse program details, since, as far as I know, this
work has not been done before, because as far as I know, carbon-13
labeled trifluoromethyl amino acids are as yet unknown. In addition,
for membrane proteins, it is possible to play NMR relaxation games
with flourine using paramagnetic solutes like O2 to gain knowlege of
protein structure, topology and immersion depth.

There are a paucity of carbon-13 precursors to start such a project.
Carbon-13 labeled carbon tetrachloride is one available precursor that
is sold for a price of several hundred dollars per gram.
Azobis(isobutyronitrile) can be used to initiate the free radical
telomerization of ethylene with carbon-13 labeled CCl4. Done neat with
an excess of ethylene, telomerization would give a distribution of
chain lengths. Done with stoichiometric ratios and in an inert solvent
like maybe hexane might optimize for the production of
1,1,1,3-tetrachloropropane. A lone aliphatic chlorine can be displaced
as HCl to give a double bond that in turn can be reduced or oxidized
to a carboxylate, or perhaps replaced by NH2.

Under rather extreme conditions the chlorines of a (carbon-13 labeled)
trichloromethyl group can be replaced by fluorine using antimony
trifluoride say, to give the desired NMR labeled group.

My question relates to what would be the most efficient synthetic
route to some amino acid labeled with a carbon-13 trifluoromethyl
group using the above chemistry. Rather than using ethylene, why not
start with some off the shelf synthetic alpha amino acid that has an
olefinic side chain? Do the above chemistry and we're done. Except
that the above chemistry is rather extreme and we would need to do
protection and deprotection of the carboxyl and amino groups. Maybe we
could start with some olefinic nitrile which could be hydrolized down
to a carboxylate and maybe the lone Cl replaced with NH2. However, I
have no feel for free radical chemistry and I do not know the extent
to which free radical CCl3 would add to ester carbonyl or nitrile or
whatever. Does one need to do Huckel MO calculations to calculate
radical electon densities in order to predict the outcome of a
proposed free radical reaction?

Given the free radical chemistry of CCl4, it would be extremely
helpful if members of this newsgroup could suggest synthetic
approaches to any carbon-13 trifluoromethyl labeled amino acid. I
thank you and science thanks you. Any comments, suggestions or caveats
would be appreciated.

-dgn
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  #2  
Old 08-07-2003, 06:34 PM
Scot.Orb@cts.com
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Default A carbon-13 trifluoromethyl group within an amino acid

[Only registered users see links. ] wrote:


Hi David,

there is a summary of synthetic methods at
[Only registered users see links. ]
which you might find useful.


Must disagree with that. F is isosteric with O, not H


It is perturbed by monofluoroacetate however. If you make anything
which metabolises to acetate, you will stop the Kreb Cycle.







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