Strecker amino acid synthesis

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Strecker synthesis
Named after Adolph Strecker
Reaction type Substitution reaction
Identifiers
Organic Chemistry Portal strecker-synthesis
RSC ontology ID RXNO:0000207

The Strecker amino acid synthesis, also known simply as the Strecker synthesis, is a method for the synthesis of amino acids by the reaction of an aldehyde with ammonium chloride in the presence of potassium cyanide. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid.[1][2] The method is used commercially for the production of racemic methionine from methional.[3]

Strecker-Synthese Übersicht V3.svg

While usage of ammonium salts gives unsubstituted amino acids, primary and secondary amines also give substituted amino acids. Likewise, the usage of ketones, instead of aldehydes, gives α,α-disubstituted amino acids.[4]

Reaction mechanism[edit]

In the first part of the reaction, the carbonyl oxygen of an aldehyde is protonated, followed by a nucleophilic attack of ammonia to the carbonyl carbon. After subsequent proton exchange, water is cleaved from the iminium ion intermediate. A cyanide ion then attacks the iminium carbon yielding an aminonitrile.

Mechanism of the Strecker-Synthesis, part 1.

In the second part of the Strecker Synthesis the nitrile nitrogen of the aminonitrile is protonated, and the nitrile carbon is attacked by a water molecule. A 1,2-diamino-diol is then formed after proton exchange and a nucleophilic attack of water to the former nitrile carbon. Ammonia is subsequently eliminated after the protonation of the amino group, and finally the deprotonation of a hydroxyl group produces an amino acid.

Mechanism of the Strecker Synthesis.

One example of the Strecker synthesis is a multikilogram scale synthesis of an L-valine derivative starting from Methyl isopropyl ketone:[5][6]

Asymmetric Strecker reactions[edit]

Asymmetric Strecker reactions are well developed. By replacing ammonia with (S)-alpha-phenylethylamine as chiral auxiliary the ultimate reaction product was chiral alanine.[7]

Catalytic asymmetric Strecker reaction can be effected using thiourea-derived catalysts.[8] In 2012, a BINOL-derived catalyst was employed to generate chiral cyanide anion.[9]

Catalytic Asymmetric Strecker Synthesis.

History[edit]

The German chemist Adolph Strecker discovered the series of chemical reactions that produce an amino acid from an aldehyde or ketone.[10][11][12] Using ammonia or ammonium salts in this reaction gives unsubstituted amino acids. In the original Strecker reaction acetaldehyde, ammonia, and hydrogen cyanide combined to form after hydrolysis alanine. Using primary and secondary amines in place of ammonium was shown to yield N-substituted amino acids.[13]

The classical Strecker synthesis gives racemic mixtures of α-amino acids as products, but several alternative procedures using asymmetric auxiliaries[14] or asymmetric catalysts[15][16] have been developed.

The asymmetric Strecker reaction was reported by Harada in 1963.[17] The first asymmetric synthesis via a chiral catalyst was reported in 1996.[18]

Commercial syntheses of amino acids[edit]

Several methods exist to synthesize amino acids aside from the Strecker synthesis.[19][3]

The commercial production of amino acids usually relies on mutant bacteria that overproduce individual amino acids using glucose as a carbon source. Otherwise amino acids are produced by enzymatic conversions of synthetic intermediates. 2-Aminothiazoline-4-carboxylic acid is an intermediate in one industrial synthesis of L-cysteine. Aspartic acid is produced by the addition of ammonia to fumarate using a lyase.[3]

One of the oldest methods begins with the bromination at the α-carbon of a carboxylic acid. Nucleophilic substitution with ammonia then converts the alkyl bromide to the amino acid.[20]

References[edit]

  1. ^ Kendall, E. C.; McKenzie, B. F. Organic Syntheses, Coll. Vol. 1, p.21 (1941); Vol. 9, p.4 (1929). (Article)
  2. ^ Clarke, H. T.; Bean, H. J. Organic Syntheses, Coll. Vol. 2, p.29 (1943); Vol. 11, p.4 (1931). (Article)
  3. ^ a b c Karlheinz Drauz, Ian Grayson, Axel Kleemann, Hans-Peter Krimmer, Wolfgang Leuchtenberger, Christoph Weckbecker (2006), Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a02_057.pub2CS1 maint: Multiple names: authors list (link)
  4. ^ Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125(19), 5634–5635. (doi:10.1021/ja034980+)
  5. ^ A Concise Synthesis of (S)-N-Ethoxycarbonyl—methylvaline Jeffrey T. Kuethe, Donald R. Gauthier, Jr., Gregory L. Beutner, and Nobuyoshi Yasuda J. Org. Chem., 72 (19), 7469 -7472, 2007. doi:10.1021/jo7012862
  6. ^ The initial reaction product of 3-methyl-2butanone with sodium cyanide and ammonia is resolved by application of L-tartaric acid. The amino acid is isolated as its salt with dicyclohexylamine.
  7. ^ Jun Wang, Xiaohua Liu, Xiaoming Feng (2011). "Asymmetric Strecker Reactions". Chemical Reviews. doi:10.1021/cr200057t.CS1 maint: Uses authors parameter (link)
  8. ^ "Scaleable catalytic asymmetric Strecker syntheses of unnatural alpha-amino acids" doi:10.1038/nature08484 http://www.nature.com/nature/journal/v461/n7266/full/nature08484.html
  9. ^ "Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator" doi:10.1038/ncomms2216 http://www.nature.com/ncomms/journal/v3/n11/full/ncomms2216.html
  10. ^ Strecker, A. (1850). "Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper" [On the artificial formation of lactic acid and a new substance homologous to glycine]. Annalen der Chemie und Pharmacie. 75 (1): 27–45. doi:10.1002/jlac.18500750103.
  11. ^ Strecker, A. (1854). "Ueber einen neuen aus Aldehyd – Ammoniak und Blausäure entstehenden Körper" [On a new substance arising from acetaldehyde–ammonia [i.e., 1-aminoethanol] and hydrocyanic acid]. Annalen der Chemie und Pharmacie. 91 (3): 349–351. doi:10.1002/jlac.18540910309.
  12. ^ Strecker A (1850). "Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper". Justus Liebigs Annalen der Chemie. 75 (1): 27–45. doi:10.1002/jlac.18500750103.
  13. ^ Strecker A (1854). "Ueber einen neuen aus Aldehyd – Ammoniak und Blausäure entstehenden Körper". Justus Liebigs Annalen der Chemie. 91 (3): 349–51. doi:10.1002/jlac.18540910309.
  14. ^ Davis FA, Reddy RE, Portonovo PS (1994). "Asymmetric strecker synthesis using enantiopure sulfinimines: A convenient synthesis of α-amino acids". Tetrahedron Letters. 35 (50): 9351–9354. doi:10.1016/S0040-4039(00)78540-6.
  15. ^ Ishitani H, Komiyama S, Hasegawa Y, Kobayashi S (2000). "Catalytic Asymmetric Strecker Synthesis. Preparation of Enantiomerically Pure α-Amino Acid Derivatives from Aldimines and Tributyltin Cyanide or Achiral Aldehydes, Amines, and Hydrogen Cyanide Using a Chiral Zirconium Catalyst". Journal of the American Chemical Society. 122 (5): 762–6. doi:10.1021/ja9935207.
  16. ^ Huang J, Corey EJ (December 2004). "A new chiral catalyst for the enantioselective Strecker synthesis of alpha-amino acids". Organic Letters. 6 (26): 5027–9. doi:10.1021/ol047698w. PMID 15606127.
  17. ^ Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis Kaoru Harada Nature 200, 1201 (21 December 1963); doi:10.1038/2001201a0
  18. ^ Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide Mani S. Iyer,, Kenneth M. Gigstad,, Nivedita D. Namdev, and, Mark Lipton Journal of the American Chemical Society 1996 118 (20), 4910–4911 doi:10.1021/ja952686e
  19. ^ Duthaler RO (1994). "Recent developments in the stereoselective synthesis of α-aminoacids". Tetrahedron. 50 (6): 1539–1650. doi:10.1016/S0040-4020(01)80840-1.
  20. ^ McMurry J (1996). Organic chemistry. Pacific Grove, CA, USA: Brooks/Cole. p. 1064. ISBN 978-0-534-23832-2.

See also[edit]