Ethyl cyanohydroxyiminoacetate

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Ethyl cyanohydroxyiminoacetate
Ethyl cyanohydroxyiminoacetate.svg
Names
Preferred IUPAC name
Ethyl (2Z)-2-cyano-2-(hydroxyimino)acetate
Other names
Oxyma
Identifiers
3D model (JSmol)
ECHA InfoCard 100.021.230 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • CCOC(=O)/C(=N\O)/C#N
Properties
C5H6N2O3
Molar mass 142,11 g·mol −1
Appearancewhite powder
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1]

Contents

Production

Ethyl cyanohydroxyiminoacetate is obtained in the reaction of ethyl cyanoacetate and nitrous acid (from sodium nitrite and acetic acid) in 87% yield. [2]

Synthese von Hydroxyiminocyanessigsaureethylester Hydroxyiminocyanessigsaureethylester Synthese.svg
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. [3]

The compound can be purified by recrystallization from ethanol [3] or ethyl acetate. [4]

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. [1]

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. [5]

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. [1] [5] [6]

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) [7] or the water-soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI)). [8]

Dipeptidsynthese mit Oxyma Dipeptidsynthese mit Oxyma.svg
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. [8]

More recently, a variety of derivatives of ethyl cyanohydroxyiminoacetate (Oxyma) have been developed as acylation reagents, [9] such as Fmoc-oxyma for the transfer of the fluorenylmethoxycarbonyl protective group [10]

Fmoc-Oxyma-Synthese Synthese von Fmoc-Oxyma.svg
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. [5]

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. [11]

Dipeptidsynthese mit Glyceroacetonid-Oxyma Dipeptidsynthese mit Glyceroacetonid-Oxyma.svg
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.

Related Research Articles

<span class="mw-page-title-main">Oxime</span> Organic compounds of the form >C=N–OH

In organic chemistry, an oxime is an organic compound belonging to the imines, with the general formula RR’C=N−OH, where R is an organic side-chain and R' may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds. Amidoximes are oximes of amides with general structure R1C(=NOH)NR2R3.

<span class="mw-page-title-main">Dipeptide</span> Shortest peptide molecule, containing two amino acids joined by a single peptide bond

A dipeptide is an organic compound derived from two amino acids. The constituent amino acids can be the same or different. When different, two isomers of the dipeptide are possible, depending on the sequence. Several dipeptides are physiologically important, and some are both physiologically and commercially significant. A well known dipeptide is aspartame, an artificial sweetener.

<span class="mw-page-title-main">Peptide synthesis</span> Production of peptides

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis in living organisms occurs in the opposite direction.

<span class="mw-page-title-main">Carbodiimide</span> Class of organic compounds with general structure RN=C=NR

In organic chemistry, a carbodiimide is a functional group with the formula RN=C=NR. On Earth they are exclusively synthetic, but in interstellar space the parent compound HN=C=NH has been detected by its maser emissions.

<span class="mw-page-title-main">Carbonyldiimidazole</span> Chemical compound

1,1'-Carbonyldiimidazole (CDI) is an organic compound with the molecular formula (C3H3N2)2CO. It is a white crystalline solid. It is often used for the coupling of amino acids for peptide synthesis and as a reagent in organic synthesis.

<span class="mw-page-title-main">Hydroxybenzotriazole</span> Chemical compound

Hydroxybenzotriazole is an organic compound that is a derivative of benzotriazole. It is a white crystalline powder, which as a commercial product contains some water. Anhydrous HOBt is explosive.

<span class="mw-page-title-main">Pseudoproline</span>

Pseudoproline derivatives are artificially created dipeptides to minimize aggregation during Fmoc solid-phase synthesis of peptides.

Bioconjugation is a chemical strategy to form a stable covalent link between two molecules, at least one of which is a biomolecule.

<span class="mw-page-title-main">Benzotriazole</span> Chemical compound

Benzotriazole (BTA) is a heterocyclic compound with the chemical formula C6H5N3. Its five-membered ring contains three consecutive nitrogen atoms. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and triazole. This white-to-light tan solid has a variety of uses, for instance, as a corrosion inhibitor for copper.

<i>N</i>-Hydroxysuccinimide Chemical compound

N-Hydroxysuccinimide (NHS) is an organic compound with the formula (CH2CO)2NOH. It is a white solid that is used as a reagent for preparing active esters in peptide synthesis. It can be synthesized by heating succinic anhydride with hydroxylamine or hydroxylamine hydrochloride.

<span class="mw-page-title-main">HATU</span> Chemical compound

HATU is a reagent used in peptide coupling chemistry to generate an active ester from a carboxylic acid. HATU is used along with Hünig's base, or triethylamine to form amide bonds. Typically DMF is used as solvent, although other polar aprotic solvents can also be used.

<span class="mw-page-title-main">1-Hydroxy-7-azabenzotriazole</span> Chemical compound

1-Hydroxy-7-azabenzotriazole (HOAt) is a triazole used as a peptide coupling reagent. It suppresses racemization that can otherwise occur during the reaction.

<span class="mw-page-title-main">1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide</span> Chemical compound

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide is a water-soluble carbodiimide usually handled as the hydrochloride.

The Steglich esterification is a variation of an esterification with dicyclohexylcarbodiimide as a coupling reagent and 4-dimethylaminopyridine as a catalyst. The reaction was first described by Wolfgang Steglich in 1978. It is an adaptation of an older method for the formation of amides by means of DCC (dicyclohexylcarbodiimide) and 1-hydroxybenzotriazole (HOBT).

2,5-Diketopiperazine is an organic compound with the formula (NHCH2C(O))2. The compound features a six-membered ring containing two amide groups at opposite positions in the ring. It was first compound containing a peptide bond to be characterized by X-ray crystallography in 1938. It is the parent of a large class of 2,5-Diketopiperazines (2,5-DKPs) with the formula (NHCH2(R)C(O))2 (R = H, CH3, etc.). They are ubiquitous peptide in nature. They are often found in fermentation broths and yeast cultures as well as embedded in larger more complex architectures in a variety of natural products as well as several drugs. In addition, they are often produced as degradation products of polypeptides, especially in processed foods and beverages. They have also been identified in the contents of comets.

<span class="mw-page-title-main">HBTU</span> Chemical compound

HBTU is a coupling reagent used in solid phase peptide synthesis. It was introduced in 1978 and shows resistance against racemization. It is used because of its mild activating properties.

<span class="mw-page-title-main">PyAOP reagent</span> Chemical compound

PyAOP is a coupling reagent used in solid phase peptide synthesis. It is a derivative of the HOAt family of coupling reagents. It is preferred over HATU, because it does not side react at the N-terminus of the peptide. Compared to the HOBt derivates, PyAOP are more reactive due to the additional nitrogen.

Hydroxylamine-<i>O</i>-sulfonic acid Chemical compound

Hydroxylamine-O-sulfonic acid (HOSA) or aminosulfuric acid is the inorganic compound with molecular formula H3NO4S that is formed by the sulfonation of hydroxylamine with oleum. It is a white, water-soluble and hygroscopic, solid, commonly represented by the condensed structural formula H2NOSO3H, though it actually exists as a zwitterion and thus is more accurately represented as +H3NOSO3−. It is used as a reagent for the introduction of amine groups (–NH2), for the conversion of aldehydes into nitriles and alicyclic ketones into lactams (cyclic amides), and for the synthesis of variety of nitrogen-containing heterocycles.

<i>N</i>-Hydroxyphthalimide Chemical compound

N-Hydroxyphthalimide is the N-hydroxy derivative of phthalimide. The compound can be utilized as a catalyst for oxidation reactions, in particular for the selective oxidation with molecular oxygen under mild conditions.

<span class="mw-page-title-main">HCTU</span> Chemical compound

HCTU is an aminium coupling reagent used in peptide synthesis. It is analogous to HBTU. The HOBt moiety has a chlorine in the 6 position which improves reaction rates and the synthesis of difficult couplings

References

  1. 1 2 3 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. 1 2 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. 1 2 3 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-[2-(2-Acetylaminophenyl)-2-oxo-acetylamino] Benzoyl Amino Acid Ester Derivatives", Molecules, vol. 18, no. 12, pp. 14747–14759, doi: 10.3390/molecules181214747 , PMC   6269765 , PMID   24288002
  8. 1 2 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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