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Ethyl cyanohydroxyiminoacetate

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Ethyl cyanohydroxyiminoacetate
Names
Preferred IUPAC name Ethyl (2Z)-2-cyano-2-(hydroxyimino)acetate
Other names Oxyma
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.021.230 Edit this at Wikidata
EC Number
  • 223-351-3
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C5H6N2O3/c1-2-10-5(8)4(3-6)7-9/h9H,2H2,1H3/b7-4-Key: LCFXLZAXGXOXAP-DAXSKMNVSA-N
SMILES
  • CCOC(=O)/C(=N\O)/C#N
Properties
Chemical formula C5H6N2O3
Molar mass 142,11 g·mol
Appearance white powder
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). Infobox references
Chemical compound

Ethyl cyanohydroxyiminoacetate (oxyma) is the oxime of ethyl cyanoacetate and finds use as an additive for carbodiimides, such as dicyclohexylcarbodiimide (DCC) in peptide synthesis. It acts as a neutralizing reagent for the basicity or nucleophilicity of the DCC due to its pronounced acidity (pKa 4.60) and suppresses base catalyzed side reactions, in particular racemization.

Production

Ethyl cyanohydroxyiminoacetate is obtained in the reaction of ethyl cyanoacetate and nitrous acid (from sodium nitrite and acetic acid) in 87% yield.

Synthese von Hydroxyiminocyanessigsäureethylester
Synthese von Hydroxyiminocyanessigsäureethylester

Because of the rapid hydrolysis of the ester, the reaction should be carried out at pH 4.5, in buffered phosphoric acid the product can even be obtained in virtually quantitative yield.

The compound can be purified by recrystallization from ethanol or ethyl acetate.

Compared with the benzotriazole derivatives 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt) (which are widely used as peptide-linking reagents but are explosive), ethyl cyanohydroxyiminoacetate exhibits a markedly slowed thermal decomposition on heating.

Properties

Ethyl cyanohydroxyiminoacetate is a white solid which is soluble in many solvents common in the synthesis of peptides, such as dichloromethane or dimethylformamide (DMF). In crystalline form, the compound is present as an oxime, whereas it exists as a salt or in a strongly basic solution predominantly as a tautomeric nitrosoisomer in anionic form.

Applications

Owing to the simple preparative accessibility, the uncritical behavior at temperatures below 80 °C and in particular because of the high yields and the low racemization of the peptides obtained, ethyl cyanohydroxyiminoacetate has now become widely used as an additive in peptide syntheses.

Ethyl cyanohydroxyiminoacetate can be used as a coupling additive in the conventional peptide linking in solution, as in automated Merrifield synthesis on a solid-phase peptide synthesis, together with coupling reagents such as carbodiimides (for example dicyclohexylcarbodiimide (DCC)), diisopropylcarbodiimide (DIC) or the water-soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)).

Dipeptidsynthese mit Oxyma
Dipeptidsynthese mit Oxyma

For example, the stepwise liquid-phase synthesis of the dipeptide Z-L-Phg-L-Val-OMe yields the LL-product with 81-84% which is free from racemic DL dipeptide, using From N-protected Z-L-α-phenylglycine (with the benzyloxycarbonyl group, Z group) and L-valine methyl ester with the coupling reagent DIC and the additive ethyl cyanohydroxyiminoacetate.

More recently, a variety of derivatives of ethyl cyanohydroxyiminoacetate (Oxyma) have been developed as acylation reagents, such as Fmoc-oxyma for the transfer of the fluorenylmethoxycarbonyl protective group

Fmoc-Oxyma-Synthese
Fmoc-Oxyma-Synthese

or the coupling reagent COMU which is readily soluble as a dimethylmorpholine-uronium salt and which, like Oxyma, is superior to the standard additive HOBt for the suppression of racemization and acylation efficiency and is comparable to HOAt without presenting an explosion risk such as the benzotriazoles.

With water-soluble derivatives of ethyl cyanohydroxyiminoacetate (glyceroacetonide-oxyma) as additive and DIC as coupling reagent even in weakly basic aqueous solutions the linking of protected amino acids to oligopeptides is possible with a yield of 95% and a diastereomeric excess of> 99% using the model substances Z-L-Phg-OH and L-H-Pro-NH2.

Dipeptidsynthese mit Glyceroacetonid-Oxyma
Dipeptidsynthese mit Glyceroacetonid-Oxyma

In the coupling of amino acids, frequently occurring secondary reactions largely suppressed, which would be the formation of symmetrical acid anhydrides, racemization and epimerization and the cyclization to oxazolinones or - especially for dipeptides - to 2,5-diketopiperazines.

References

  1. ^ Subirós-Funosas, R.; Prohens, R.; Barbas, R.; El-Faham, A.; Albericio, F. (2009), "Oxyma: An efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion", Chem. Eur. J., vol. 15, no. 37, pp. 9394–9403, doi:10.1002/chem.200900614, PMID 19575348
  2. Conrad, M.; Schulze, A. (1909), "Über Nitroso-cyanessigsäure-Derivate", Chem. Ber. (in German), vol. 42, no. 1, pp. 735–742, doi:10.1002/cber.190904201117
  3. ^ Albericio, F.; Subirós-Funosas, R. (2012). "Ethyl 2-Cyano-2-(hydroxyimino)acetate". Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.rn01377. ISBN 978-0471936237.
  4. US 5166394, Breipohl, G. & König, W., "Coupling reagent for peptide synthesis", published 1992-11-2, assigned to Hoechst AG 
  5. ^ Subirós-Funosas, R.; Khattab, S.N.; Nieto-Rodriguez, L.; El-Faham, A.; Albericio, F. (2013), "Advances in acylation methodologies enabled by Oxyma-based reagents", Aldrichimica Acta, vol. 46, no. 1, pp. 21–41
  6. "Coupling Reagents Bachem" (PDF; 1,9 MB). Bachem.com. Global Marketing, Bachem Group. 2015. Retrieved 2016-10-10.
  7. El-Faham, A.; Al Marhoon, Z.; Abdel-Megeed, A.; Albericio, F. (2013), "OxymaPure/DIC: An Efficient Reagent for the Synthesis of a Novel Series of 4- Benzoyl Amino Acid Ester Derivatives", Molecules, vol. 18, no. 12, pp. 14747–14759, doi:10.3390/molecules181214747, PMC 6269765, PMID 24288002
  8. ^ Subirós-Funosas, R.; El-Faham, A.; Albericio, F. (2013). "Low-epimerization Peptide Bond Formation with Oxyma Pure: Preparation of Z-L-Phg-Val-OMe". Organic Syntheses. 90: 306–315. doi:10.15227/orgsyn.090.0306.
  9. El-Faham, A.; Albericio, F. (2011), "Peptide coupling reagents, more than a letter soup", Chem. Rev., vol. 111, no. 11, pp. 6557–6602, doi:10.1021/cr100048w, PMID 21866984
  10. Khattab, S.N.; Subirós-Funosas, R.; El-Faham, A.; Albericio, F. (2010), "Oxime Carbonates: Novel Reagents for the Introduction of Fmoc and Alloc Protecting Groups, Free of Side Reactions", Eur. J. Org. Chem., vol. 2010, no. 17, pp. 3275–3280, doi:10.1002/ejoc.201000028
  11. Wang, Q.; Wang, Y.; Kurosu, M. (2012), "A new Oxyma derivative for nonracemizable amide-forming reactions in water", Org. Lett., vol. 14, no. 13, pp. 3372–3375, doi:10.1021/ol3013556, PMC 3431018, PMID 22697488
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