Strecker amino acid synthesis explained

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 cyanide in the presence of ammonia. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid.^{[1] [2]} The method is used for the commercial production of racemic methionine from methional.

Primary and secondary amines also give N-substituted amino acids. Likewise, the usage of ketones, instead of aldehydes, gives α,α-disubstituted amino acids.^[3]

Reaction mechanism

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.

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.

Asymmetric Strecker reactions

One example of the Strecker synthesis is a multikilogram scale synthesis of an L-valine derivative starting from Methyl isopropyl ketone:^[4]

The initial reaction product of 3-methyl-2butanone with sodium cyanide and ammonia is resolved by application of L-tartaric acid. In contrast, asymmetric Strecker reactions require no resolving agent. By replacing ammonia with (S)-alpha-phenylethylamine as chiral auxiliary the ultimate reaction product was chiral alanine.^[5]

Catalytic asymmetric Strecker reaction can be effected using thiourea-derived catalysts.^[6] In 2012, a BINOL-derived catalyst was employed to generate chiral cyanide anion (see figure).^[7]

History

The German chemist Adolph Strecker discovered the series of chemical reactions that produce an amino acid from an aldehyde or ketone.^{[8] [9]} 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.^[9]

The classical Strecker synthesis gives racemic mixtures of α-amino acids as products, but several alternative procedures using asymmetric auxiliaries^[10] or asymmetric catalysts^{[11] [12]} have been developed.

The asymmetric Strecker reaction was reported by Harada in 1963.^[13] The first reported asymmetric synthesis via a chiral catalyst was published in 1996.^[14] However, this was retracted in 2023.^[15]

Commercial syntheses of amino acids

Several methods exist to synthesize amino acids aside from the Strecker synthesis.^[16]

The commercial production of amino acids, however, 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.

See also

• Bucherer–Bergs reaction

Notes and References

1. dl-Alanine . Organic Syntheses . 1929 . 9 . 4 . 10.15227/orgsyn.009.0004.
2. a-Aminoisobutyric Acid . Organic Syntheses . 1931 . 11 . 4 . 10.15227/orgsyn.011.0004 .
3. Masumoto . Shuji . Usuda . Hiroyuki . Suzuki . Masato . Kanai . Motomu . Shibasaki . Masakatsu . Catalytic Enantioselective Strecker Reaction of Ketoimines . Journal of the American Chemical Society . May 2003 . 125 . 19 . 5634–5635 . 10.1021/ja034980+ . 12733893.
4. Kuethe . Jeffrey T. . Gauthier . Donald R. . Beutner . Gregory L. . Yasuda . Nobuyoshi . A Concise Synthesis of (S)-N-Ethoxycarbonyl-α-methylvaline . The Journal of Organic Chemistry . September 2007 . 72 . 19 . 7469–7472 . 10.1021/jo7012862 . 17713956 .
5. Wang . Jun . Liu . Xiaohua . Feng . Xiaoming . Asymmetric Strecker Reactions . Chemical Reviews . 9 November 2011 . 111 . 11 . 6947–6983 . 10.1021/cr200057t . 21851054.
6. Zuend . Stephan J. . Coughlin . Matthew P. . Lalonde . Mathieu P. . Jacobsen . Eric N. . Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids . Nature . October 2009 . 461 . 7266 . 968–970 . 10.1038/nature08484 . 19829379 . 2778849 . 2009Natur.461..968Z .
7. Yan . Hailong . Suk Oh . Joong . Lee . Ji-Woong . Eui Song . Choong . Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator . Nature Communications . 20 November 2012 . 3 . 1 . 1212 . 10.1038/ncomms2216 . 23169053 . 2012NatCo...3.1212Y . free .
8. Strecker . Adolph . Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper . Annalen der Chemie und Pharmacie . 1850 . 75 . 1 . 27–45 . 10.1002/jlac.18500750103 .
9. Strecker . Adolph . Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper . Annalen der Chemie und Pharmacie . 1854 . 91 . 3 . 349–351 . 10.1002/jlac.18540910309 .
10. Davis . Franklin A. . Reddy . Rajarathnam E. . Portonovo . Padma S. . Asymmetric strecker synthesis using enantiopure sulfinimines: A convenient synthesis of α-amino acids . Tetrahedron Letters . December 1994 . 35 . 50 . 9351–9354 . 10.1016/S0040-4039(00)78540-6 .
11. Ishitani . Haruro . Komiyama . Susumu . Hasegawa . Yoshiki . Kobayashi . Shū . 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 . February 2000 . 122 . 5 . 762–766 . 10.1021/ja9935207 .
12. Huang . Jinkun . Corey . E. J. . A New Chiral Catalyst for the Enantioselective Strecker Synthesis of α-Amino Acids . Organic Letters . December 2004 . 6 . 26 . 5027–5029 . 10.1021/ol047698w . 15606127.
13. Harada . Kaoru . Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis . Nature . December 1963 . 200 . 4912 . 1201 . 10.1038/2001201a0 . 14089910 . 1963Natur.200.1201H . 43857409 . free .
14. Iyer . Mani S. . Gigstad . Kenneth M. . Namdev . Nivedita D. . Lipton . Mark . Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide . Journal of the American Chemical Society . January 1996 . 118 . 20 . 4910–4911 . 10.1021/ja952686e . 24178715.
15. Iyer . Mani S. . Gigstad . Kenneth M. . Namdev . Nivedita D. . Lipton . Mark . 2023-06-29 . Retraction of “Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide″ . Journal of the American Chemical Society . en . 10.1021/jacs.3c03705 . 0002-7863. free .
16. Duthaler . Rudolf O. . Recent developments in the stereoselective synthesis of α-aminoacids . Tetrahedron . January 1994 . 50 . 6 . 1539–1650 . 10.1016/S0040-4020(01)80840-1.