Cactuar
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Synthesis of amino acid chlorides
Hi! First post here!
I have studied organic chemistry but my knowledge of peptide synthesis is very limited.
I want to make an amino acid chloride and wonder which protecting group would be best to use. My previous attempts at di-boc:ing amines (also, these
were anilines) required quite harsh conditions like heating with KHMDS. Therefor I suspect that the carbamate will deactivate the amine enough to not
dimerize (unless heated). Does anyone know if there's any truth to this? My other thought was to use benzylidene since it has no protons.
Any input would be welcome. Thanks in advance!
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Brain&Force
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Do you mean  ? This may be of use.
http://chemwiki.ucdavis.edu/Organic_Chemistry/Carboxylic_Aci...
At the end of the day, simulating atoms doesn't beat working with the real things...
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Cactuar
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Sorry if I wasn't clear enough. I know how to make the acid chloride, what I want to know is what protecting group I should have on the nitrogen to
prevent dimerization.
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Chemosynthesis
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Never done it myself, but I have mostly seen Fmoc supplant t-boc in peptide synthesis. Apparently it is much superior.
http://www.peptideguide.com/protecting-groups-spps.html
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zed
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Um, way I remember......... Some of the guys had a discussion about N-acetylating aminoacids, via Acetyl Salicylic Acid (AKA Aspirin). Easy.
Converting the free acid to an acid-chloride thereafter, might require mild conditions. Benzoyl Chloride?
Maybe. I've always tried to strive for elegance. I have often failed. Most things are possible with enough dangerous and expensive reagents.
But, is there a simple, safe method?
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AvBaeyer
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Cactuar,
Amino acid chlorides can be made and were extensively used in the early days (pre-1940) of peptide synthesis. The problem was, as you have noted,
finding suitable amine protecting groups stable to acyl chloride formation but easy to remove without ripping apart the newly synthesized peptide.
Protection of the amino group can be done using most any acyl group (eg, benzoyl) or sulfonamide (eg p-tosyl) but these are very difficult to cleanly
remove. Alkoxycarbonyl groups such N-ethoxycarbonyl or Cbz would be more versatile as they are more easily removed than a regular acyl group and can
survive acid chloride formation. You might do well to consult Greenstein and Winitz, "Chemistry of the Amino Acids." Volume 2 has an extensive
discussion of coupling reactions including some information on amino acid chlorides.
AvB
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Cactuar
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Thank you! I even found FMoc-Ala-Cl has a CAS-number so I guess it has been isolated at some point.
Quote: Originally posted by AvBaeyer  | Cactuar,
Amino acid chlorides can be made and were extensively used in the early days (pre-1940) of peptide synthesis. The problem was, as you have noted,
finding suitable amine protecting groups stable to acyl chloride formation but easy to remove without ripping apart the newly synthesized peptide.
Protection of the amino group can be done using most any acyl group (eg, benzoyl) or sulfonamide (eg p-tosyl) but these are very difficult to cleanly
remove. Alkoxycarbonyl groups such N-ethoxycarbonyl or Cbz would be more versatile as they are more easily removed than a regular acyl group and can
survive acid chloride formation. You might do well to consult Greenstein and Winitz, "Chemistry of the Amino Acids." Volume 2 has an extensive
discussion of coupling reactions including some information on amino acid chlorides.
AvB |
Thank you very much. I'll try to get hold of the second volume and will try using Boc since I have it at hand.
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Chemosynthesis
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No problem! Hope even after the results come in you can look back and say we were helpful. Please keep us updated.
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Dr.Bob
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For most non automated synthesis, people use tBoc or Cbz groups on amino acids, but if you make the acid chloride, many amino acids either decompose
fairly quickly or racemize, which makes them less useful and hard to isolate. The solution for this is to either make the acid chloride (or fluoride
or bromide) in situ, where it reacts immediately, or better yet, use a less hard coupling technique like HBTU, DCC, EDC, CDI, TPA, or any of a dozen
amide forming reagents, some of which are used with HOBT as a catalyst/racemization minimizer. Fmoc amino acids are great for solid phase work, but
harder to use for normal solution phase chemistry. Normally, you only need one Boc on an amine to make it stable.
Alternatively, you can form an activated ester from some other reagents, like PFP-TFA, which makes perflourophenyl esters of acids, but that is harder
to come by. EDC, CDI, and HBTU are readily available, I think even on Ebay, but found in nearly any chem lab worldwide. If you show what the
reaction is that you are trying, someone here can likely tell you the best way to go.
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Rich_Insane
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I like the Fmoc group because deprotection is fairly simple with DBU or piperidine. However, I have only done solid phase synthesis. Is there a reason
you don't want to use DCC/HOBt or something like TSTU/HBTU/HATU etc?
The Boc group or maybe perhaps the Cbz group may be suitable for solution phase, no?
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Dr.Bob
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In solid phase removing the excess piperidine or similar base is easy from the de-Fmoc'd material. In solution, you now have deportected an amine
which you need to remove piperidine from, which is not very easy, given that both are polar amines. That is why people use Boc mostly for solution
phase and Fmoc almost only for solid phase, where removing the excess piperidine is trivial (wash with DCM). The boc deprot just involves treatment
with any acid, HCl (typically non-aqueous) and TFA being the most common. Both are volatile and the tBoc goes away as isobutylene and CO2, so all by
products are volatile, leaving the amine as the HCl salt if HCl is used, and you simply add one extra eq of TEA to the next step. I have done 100's
of those reactions, and Boc is great. Same for protecting acids as esters, tBu esters are a great thing, and they keep amino aids from racemizing.
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zed
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Hnnnh? I didn't assume you were going to synthesize peptides. Amino-acid Chlorides have other possible uses.
The Acid Chloride might be used to Alkylate the 3-position on an Indole ring, for instance.
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