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Author: Subject: Synthesis of amino acid chlorides
Cactuar
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[*] posted on 25-7-2014 at 10:54
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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[*] posted on 25-7-2014 at 11:07


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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[*] posted on 25-7-2014 at 12:06


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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[*] posted on 25-7-2014 at 12:13


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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[*] posted on 25-7-2014 at 13:40


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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[*] posted on 25-7-2014 at 18:15


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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[*] posted on 27-7-2014 at 15:51


Quote: Originally posted by Chemosynthesis  
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


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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[*] posted on 28-7-2014 at 02:19


Quote: Originally posted by Cactuar  

Thank you! I even found FMoc-Ala-Cl has a CAS-number so I guess it has been isolated at some point.

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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[*] posted on 29-7-2014 at 11:59


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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[*] posted on 31-7-2014 at 01:20


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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[*] posted on 31-7-2014 at 09:21


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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[*] posted on 5-8-2014 at 18:18


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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