{{short description|Method for the synthesis of amino acids}} {{Reactionbox |Name = Strecker synthesis |Type = Substitution reaction |NamedAfter = Adolph Strecker |Section3 = {{Reactionbox Identifiers |OrganicChemistryNamed = strecker-synthesis |RSC_ontology_id = 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 cyanide in the presence of ammonia. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid.<ref>{{cite journal |title=dl-Alanine |journal=Organic Syntheses |date=1929 |volume=9 |pages=4 |doi=10.15227/orgsyn.009.0004}}</ref><ref>{{cite journal |title=a-Aminoisobutyric Acid |journal=Organic Syntheses |date=1931 |volume=11 |pages=4 |doi=10.15227/orgsyn.011.0004 }}</ref> The method is used for the commercial production of racemic methionine from methional.<ref name=Ullmann/>

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Primary and secondary amines also give N-substituted amino acids. Likewise, the usage of ketones, instead of aldehydes, gives α,α-disubstituted amino acids.<ref>{{cite journal |last1=Masumoto |first1=Shuji |last2=Usuda |first2=Hiroyuki |last3=Suzuki |first3=Masato |last4=Kanai |first4=Motomu |last5=Shibasaki |first5=Masakatsu |title=Catalytic Enantioselective Strecker Reaction of Ketoimines |journal=Journal of the American Chemical Society |date=May 2003 |volume=125 |issue=19 |pages=5634–5635 |doi=10.1021/ja034980+ |pmid=12733893|bibcode=2003JAChS.125.5634M }}</ref>

==Reaction mechanism== In the first part of the reaction process, the carbonyl is converted to an iminium, to which a cyanide ion adds. First, 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 to form the iminium ion intermediate. A cyanide ion then attacks the iminium carbon yielding an aminonitrile.

400px|center|Mechanism of the Strecker-Synthesis, part 1.

In the second part of the reaction process, the nitrile is hydrolyzed. First, 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.

600px|center|Mechanism of the Strecker synthesis

==Asymmetric Strecker reactions== One example of the Strecker synthesis is a multikilogram scale synthesis of an L-valine derivative starting from methyl isopropyl ketone:<ref>{{cite journal |last1=Kuethe |first1=Jeffrey T. |last2=Gauthier |first2=Donald R. |last3=Beutner |first3=Gregory L. |last4=Yasuda |first4=Nobuyoshi |title=A Concise Synthesis of (''S'')-''N''-Ethoxycarbonyl-α-methylvaline |journal=The Journal of Organic Chemistry |date=September 2007 |volume=72 |issue=19 |pages=7469–7472 |doi=10.1021/jo7012862 |pmid=17713956 }}</ref> :{{chem2|(CH3)2CHC(O)CH3 + HCN + NH3 -> (CH3)2CHC(CN)(NH2)CH3 + H2O}} 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.<ref name=CR>{{cite journal |last1=Wang |first1=Jun |last2=Liu |first2=Xiaohua |last3=Feng |first3=Xiaoming |title=Asymmetric Strecker Reactions |journal=Chemical Reviews |date=9 November 2011 |volume=111 |issue=11 |pages=6947–6983 |doi=10.1021/cr200057t |pmid=21851054}}</ref>

[[File:Catalytic Asymmetric Strecker Synthesis-Nature Chem.tif|thumb|600px|Catalytic asymmetric Strecker synthesis. The catalyst 1a is based on chiral 1,1′-Bi-2-naphthol (BINOL), the "R" indicating the chirality. "Boc" is tert-Butyloxycarbonyl protecting group.]]

Catalytic asymmetric Strecker reaction can be effected using thiourea-derived catalysts.<ref>{{cite journal |last1=Zuend |first1=Stephan J. |last2=Coughlin |first2=Matthew P. |last3=Lalonde |first3=Mathieu P. |last4=Jacobsen |first4=Eric N. |title=Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids |journal=Nature |date=October 2009 |volume=461 |issue=7266 |pages=968–970 |doi=10.1038/nature08484 |pmid=19829379 |pmc=2778849 |bibcode=2009Natur.461..968Z }}</ref> In 2012, a BINOL-derived catalyst was employed to generate chiral cyanide anion (see figure).<ref>{{cite journal |last1=Yan |first1=Hailong |last2=Suk Oh |first2=Joong |last3=Lee |first3=Ji-Woong |last4=Eui Song |first4=Choong |title=Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator |journal=Nature Communications |date=20 November 2012 |volume=3 |issue=1 |page=1212 |doi=10.1038/ncomms2216 |pmid=23169053 |bibcode=2012NatCo...3.1212Y |doi-access=free }}</ref>

==History== The German chemist Adolph Strecker discovered the series of chemical reactions that produce an amino acid from an aldehyde or ketone.<ref name=Strecker1850>{{cite journal |last1=Strecker |first1=Adolph |title=Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper |journal=Annalen der Chemie und Pharmacie |date=1850 |volume=75 |issue=1 |pages=27–45 |doi=10.1002/jlac.18500750103 |url=https://zenodo.org/record/1427032 }}</ref><ref name=Strecker1854>{{cite journal |last1=Strecker |first1=Adolph |title=Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper |journal=Annalen der Chemie und Pharmacie |date=1854 |volume=91 |issue=3 |pages=349–351 |doi=10.1002/jlac.18540910309 |url=https://zenodo.org/record/1427060 }}</ref> 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.<ref name=Strecker1854/>

The classical Strecker synthesis gives racemic mixtures of α-amino acids as products, but several alternative procedures using asymmetric auxiliaries<ref>{{cite journal |last1=Davis |first1=Franklin A. |last2=Reddy |first2=Rajarathnam E. |last3=Portonovo |first3=Padma S. |title=Asymmetric strecker synthesis using enantiopure sulfinimines: A convenient synthesis of α-amino acids |journal=Tetrahedron Letters |date=December 1994 |volume=35 |issue=50 |pages=9351–9354 |doi=10.1016/S0040-4039(00)78540-6 }}</ref> or asymmetric catalysts<ref>{{cite journal |last1=Ishitani |first1=Haruro |last2=Komiyama |first2=Susumu |last3=Hasegawa |first3=Yoshiki |last4=Kobayashi |first4=Shū |title=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=Journal of the American Chemical Society |date=February 2000 |volume=122 |issue=5 |pages=762–766 |doi=10.1021/ja9935207 |bibcode=2000JAChS.122..762I }}</ref><ref>{{cite journal |last1=Huang |first1=Jinkun |last2=Corey |first2=E. J. |title=A New Chiral Catalyst for the Enantioselective Strecker Synthesis of α-Amino Acids |journal=Organic Letters |date=December 2004 |volume=6 |issue=26 |pages=5027–5029 |doi=10.1021/ol047698w |pmid=15606127}}</ref> have been developed.

The '''asymmetric Strecker reaction''' was reported by Harada in 1963.<ref>{{cite journal |last1=Harada |first1=Kaoru |title=Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis |journal=Nature |date=December 1963 |volume=200 |issue=4912 |pages=1201 |doi=10.1038/2001201a0 |pmid=14089910 |bibcode=1963Natur.200.1201H |s2cid=43857409 |doi-access=free }}</ref> The first reported asymmetric synthesis via a chiral catalyst was published in 1996.<ref>{{cite journal |last1=Iyer |first1=Mani S. |last2=Gigstad |first2=Kenneth M. |last3=Namdev |first3=Nivedita D. |last4=Lipton |first4=Mark |title=Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide |journal=Journal of the American Chemical Society |date=January 1996 |volume=118 |issue=20 |pages=4910–4911 |doi=10.1021/ja952686e |pmid=24178715|bibcode=1996JAChS.118.4910I }}</ref> However, this was retracted in 2023.<ref>{{Cite journal |last1=Iyer |first1=Mani S. |last2=Gigstad |first2=Kenneth M. |last3=Namdev |first3=Nivedita D. |last4=Lipton |first4=Mark |date=2023-06-29 |title=Retraction of "Asymmetric Catalysis of the Strecker Amino Acid Synthesis by a Cyclic Dipeptide″ |journal=Journal of the American Chemical Society |volume=145 |issue=27 |page=15016 |language=en |doi=10.1021/jacs.3c03705 |issn=0002-7863|doi-access=free |bibcode=2023JAChS.14515016I }}</ref>

==Commercial syntheses of amino acids== Several methods exist to synthesize amino acids aside from the Strecker synthesis.<ref>{{cite journal |last1=Duthaler |first1=Rudolf O. |title=Recent developments in the stereoselective synthesis of α-aminoacids |journal=Tetrahedron |date=January 1994 |volume=50 |issue=6 |pages=1539–1650 |doi=10.1016/S0040-4020(01)80840-1}}</ref><ref name=Ullmann/>

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.<ref name=Ullmann>{{Ullmann|first1=Karlheinz |last1=Drauz|first2=Ian|last2=Grayson|first3=Axel |last3=Kleemann |first4=Hans-Peter |last4=Krimmer |first5=Wolfgang |last5=Leuchtenberger |first6=Christoph |last6=Weckbecker |year=2006 |doi=10.1002/14356007.a02_057.pub2 |title=Amino Acids}}</ref>

==References== {{Reflist|2}}

==See also== * Bucherer–Bergs reaction

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Category:Multiple component reactions Category:Substitution reactions Category:Name reactions Category:Chemical synthesis of amino acids