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.[3]
Primary and secondary amines also give N-substituted amino acids. Likewise, the usage of
ketones, instead of aldehydes, gives α,α-disubstituted amino acids.[4]
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:[5]
Catalytic asymmetric Strecker reaction can be effected using thiourea-derived
catalysts.[7] In 2012, a
BINOL-derived catalyst was employed to generate chiral cyanide anion (see figure).[8]
History
The German chemist
Adolph Strecker discovered the series of
chemical reactions that produce an
amino acid from an
aldehyde or
ketone.[9][10] 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.[10]
The classical Strecker synthesis gives
racemic mixtures of α-amino acids as products, but several alternative procedures using asymmetric auxiliaries[11] or asymmetric catalysts[12][13] have been developed.
The asymmetric Strecker reaction was reported by Harada in 1963.[14] The first reported asymmetric synthesis via a
chiral catalyst was published in 1996.[15] However, this was retracted in 2023.[16]
Commercial syntheses of amino acids
Several methods exist to synthesize amino acids aside from the Strecker synthesis.[17][3]
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.[3]
^Davis, Franklin A.; Reddy, Rajarathnam E.; Portonovo, Padma S. (December 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.
^Ishitani, Haruro; Komiyama, Susumu; Hasegawa, Yoshiki; Kobayashi, Shū (February 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): 762–766.
doi:
10.1021/ja9935207.
^Huang, Jinkun; Corey, E. J. (December 2004). "A New Chiral Catalyst for the Enantioselective Strecker Synthesis of α-Amino Acids". Organic Letters. 6 (26): 5027–5029.
doi:
10.1021/ol047698w.
PMID15606127.
^Iyer, Mani S.; Gigstad, Kenneth M.; Namdev, Nivedita D.; Lipton, Mark (January 1996). "Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide". Journal of the American Chemical Society. 118 (20): 4910–4911.
doi:
10.1021/ja952686e.
PMID24178715.
^Duthaler, Rudolf O. (January 1994). "Recent developments in the stereoselective synthesis of α-aminoacids". Tetrahedron. 50 (6): 1539–1650.
doi:
10.1016/S0040-4020(01)80840-1.