Strecker amino acid synthesis

<h2 id="reaction-mechanism">Reaction mechanism</h2>
In the first part of the reaction process, the <a href="/facts/Carbonyl_group/KJ71bo3X">carbonyl</a> is converted to an <a href="/facts/Iminium_ion/eLFxYGI3">iminium</a>, to which a cyanide ion adds. First, the carbonyl oxygen of an <a href="/facts/Aldehyde/xSIRkW03">aldehyde</a> is protonated, followed by a <a href="/facts/Nucleophilic_addition/1HL9WlD6">nucleophilic attack</a> 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.

In the second part of the reaction process, the nitrile is <a href="/facts/Hydrolysis/JTvwIHPs">hydrolyzed</a>. 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 <a href="/facts/Amino_acid/WDxYwBny">amino acid</a>.

<h2 id="asymmetric-strecker-reactions">Asymmetric Strecker reactions</h2>
One example of the Strecker synthesis is a multikilogram scale synthesis of an <a href="/facts/L-valine/uTMLXBG4">L-valine</a> derivative starting from <a href="/facts/Methyl_isopropyl_ketone/qdnvDL3X">Methyl isopropyl ketone</a>:<a class="footnote-ref" id="fnref:5" href="#fn:5">5</a>

(CH3)2CHC(O)CH3 + HCN + NH3 → (CH3)2CHC(CN)(NH2)CH3 + H2O
The initial reaction product of 3-methyl-2butanone with <a href="/facts/Sodium_cyanide/CQfl206o">sodium cyanide</a> and <a href="/facts/Ammonia/MtLtJFtz">ammonia</a> is <a href="/facts/Chiral_resolution/tu0AIqGg">resolved</a> by application of <a href="/facts/L-tartaric_acid/GbRWxTz4">L-tartaric acid</a>. In contrast, asymmetric Strecker reactions require no resolving agent. By replacing ammonia with <a href="/facts/1-phenylethylamine/1WlQczGI">(S)-alpha-phenylethylamine</a> as <a href="/facts/Chiral_auxiliary/bn9wa27M">chiral auxiliary</a> the ultimate reaction product was chiral <a href="/facts/Alanine/fphQEdSc">alanine</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6">6</a>

Catalytic asymmetric Strecker reaction can be effected using <a href="/facts/Thiourea/69a3dfSc">thiourea</a>-derived <a href="/facts/Catalyst/LPBS7TQC">catalysts</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7">7</a> In 2012, a <a href="/facts/BINOL/Mkmm6zub">BINOL</a>-derived catalyst was employed to generate chiral cyanide anion (see figure).<a class="footnote-ref" id="fnref:8" href="#fn:8">8</a>

<h2 id="history">History</h2>
The German chemist <a href="/facts/Adolph_Strecker/IHICzsmW">Adolph Strecker</a> discovered the series of <a href="/facts/Chemical_reaction/GpqWlKrz">chemical reactions</a> that produce an <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> from an <a href="/facts/Aldehyde/xSIRkW03">aldehyde</a> or <a href="/facts/Ketone/BqQXpLo4">ketone</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9">9</a><a class="footnote-ref" id="fnref:10" href="#fn:10">10</a> Using ammonia or ammonium salts in this reaction gives unsubstituted amino acids. In the original Strecker reaction <a href="/facts/Acetaldehyde/QllLbSUe">acetaldehyde</a>, <a href="/facts/Ammonia/MtLtJFtz">ammonia</a>, and <a href="/facts/Hydrogen_cyanide/vNtA0Mxe">hydrogen cyanide</a> combined to form after hydrolysis <a href="/facts/Alanine/fphQEdSc">alanine</a>. Using primary and secondary amines in place of ammonium was shown to yield N-substituted amino acids.<a class="footnote-ref" id="fnref:11" href="#fn:11">11</a> 
The classical Strecker synthesis gives <a href="/facts/Racemic_mixture/STEagtrD">racemic mixtures</a> of α-amino acids as products, but several alternative procedures using asymmetric auxiliaries<a class="footnote-ref" id="fnref:12" href="#fn:12">12</a> or asymmetric catalysts<a class="footnote-ref" id="fnref:13" href="#fn:13">13</a><a class="footnote-ref" id="fnref:14" href="#fn:14">14</a> have been developed.
The asymmetric Strecker reaction was reported by Harada in 1963.<a class="footnote-ref" id="fnref:15" href="#fn:15">15</a> The first reported asymmetric synthesis via a <a href="/facts/Chiral_catalyst/5hJe37TL">chiral catalyst</a> was published in 1996.<a class="footnote-ref" id="fnref:16" href="#fn:16">16</a> However, this was retracted in 2023.<a class="footnote-ref" id="fnref:17" href="#fn:17">17</a>

<h2 id="commercial-syntheses-of-amino-acids">Commercial syntheses of amino acids</h2>
Several methods exist to synthesize amino acids aside from the Strecker synthesis.<a class="footnote-ref" id="fnref:18" href="#fn:18">18</a><a class="footnote-ref" id="fnref:19" href="#fn:19">19</a> 
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. <a href="/facts/2-Aminothiazoline-4-carboxylic_acid/7dJQQm7a">2-Aminothiazoline-4-carboxylic acid</a> is an intermediate in one industrial synthesis of L-<a href="/facts/Cysteine/kbqvUm6d">cysteine</a>. <a href="/facts/Aspartic_acid/9DFSFPa1">Aspartic acid</a> is produced by the addition of ammonia to <a href="/facts/Fumarate/VDecBfLQ">fumarate</a> using a lyase.<a class="footnote-ref" id="fnref:20" href="#fn:20">20</a>

<h2 id="see-also">See also</h2>
<ul><li><a href="/facts/Bucherer%25E2%2580%2593Bergs_reaction/TNCc7jlQ">Bucherer–Bergs reaction</a></li></ul>

<h2 id="references">References</h2>

<ol>
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<li id="fn:2">"a-Aminoisobutyric Acid". Organic Syntheses. 11: 4. 1931. doi:10.15227/orgsyn.011.0004. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></li>
<li id="fn:3">Drauz, Karlheinz; Grayson, Ian; Kleemann, Axel; Krimmer, Hans-Peter; Leuchtenberger, Wolfgang; Weckbecker, Christoph (2006). "Amino Acids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_057.pub2. ISBN 978-3-527-30673-2. <a href="978-3-527-30673-2" target="_blank">978-3-527-30673-2</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></li>
<li id="fn:4">Masumoto, Shuji; Usuda, Hiroyuki; Suzuki, Masato; Kanai, Motomu; Shibasaki, Masakatsu (May 2003). "Catalytic Enantioselective Strecker Reaction of Ketoimines". Journal of the American Chemical Society. 125 (19): 5634–5635. Bibcode:2003JAChS.125.5634M. doi:10.1021/ja034980+. PMID 12733893. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></li>
<li id="fn:5">Kuethe, Jeffrey T.; Gauthier, Donald R.; Beutner, Gregory L.; Yasuda, Nobuyoshi (September 2007). "A Concise Synthesis of (S)-N-Ethoxycarbonyl-α-methylvaline". The Journal of Organic Chemistry. 72 (19): 7469–7472. doi:10.1021/jo7012862. PMID 17713956. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></li>
<li id="fn:6">Wang, Jun; Liu, Xiaohua; Feng, Xiaoming (9 November 2011). "Asymmetric Strecker Reactions". Chemical Reviews. 111 (11): 6947–6983. doi:10.1021/cr200057t. PMID 21851054. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></li>
<li id="fn:7">Zuend, Stephan J.; Coughlin, Matthew P.; Lalonde, Mathieu P.; Jacobsen, Eric N. (October 2009). "Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids". Nature. 461 (7266): 968–970. Bibcode:2009Natur.461..968Z. doi:10.1038/nature08484. PMC 2778849. PMID 19829379. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778849" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778849</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></li>
<li id="fn:8">Yan, Hailong; Suk Oh, Joong; Lee, Ji-Woong; Eui Song, Choong (20 November 2012). "Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator". Nature Communications. 3 (1): 1212. Bibcode:2012NatCo...3.1212Y. doi:10.1038/ncomms2216. PMID 23169053. <a href="https://doi.org/10.1038%2Fncomms2216" target="_blank">https://doi.org/10.1038%2Fncomms2216</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></li>
<li id="fn:9">Strecker, Adolph (1850). "Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper". Annalen der Chemie und Pharmacie. 75 (1): 27–45. doi:10.1002/jlac.18500750103. <a href="https://zenodo.org/record/1427032" target="_blank">https://zenodo.org/record/1427032</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></li>
<li id="fn:10">Strecker, Adolph (1854). "Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper". Annalen der Chemie und Pharmacie. 91 (3): 349–351. doi:10.1002/jlac.18540910309. <a href="https://zenodo.org/record/1427060" target="_blank">https://zenodo.org/record/1427060</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></li>
<li id="fn:11">Strecker, Adolph (1854). "Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper". Annalen der Chemie und Pharmacie. 91 (3): 349–351. doi:10.1002/jlac.18540910309. <a href="https://zenodo.org/record/1427060" target="_blank">https://zenodo.org/record/1427060</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></li>
<li id="fn:12">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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></li>
<li id="fn:13">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. Bibcode:2000JAChS.122..762I. doi:10.1021/ja9935207. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></li>
<li id="fn:14">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. PMID 15606127. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></li>
<li id="fn:15">Harada, Kaoru (December 1963). "Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis". Nature. 200 (4912): 1201. Bibcode:1963Natur.200.1201H. doi:10.1038/2001201a0. PMID 14089910. S2CID 43857409. <a href="https://doi.org/10.1038%2F2001201a0" target="_blank">https://doi.org/10.1038%2F2001201a0</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></li>
<li id="fn:16">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. Bibcode:1996JAChS.118.4910I. doi:10.1021/ja952686e. PMID 24178715. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></li>
<li id="fn:17">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. 145 (27): 15016. Bibcode:2023JAChS.14515016I. doi:10.1021/jacs.3c03705. ISSN 0002-7863. <a href="https://doi.org/10.1021%2Fjacs.3c03705" target="_blank">https://doi.org/10.1021%2Fjacs.3c03705</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></li>
<li id="fn:18">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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></li>
<li id="fn:19">Drauz, Karlheinz; Grayson, Ian; Kleemann, Axel; Krimmer, Hans-Peter; Leuchtenberger, Wolfgang; Weckbecker, Christoph (2006). "Amino Acids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_057.pub2. ISBN 978-3-527-30673-2. <a href="978-3-527-30673-2" target="_blank">978-3-527-30673-2</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></li>
<li id="fn:20">Drauz, Karlheinz; Grayson, Ian; Kleemann, Axel; Krimmer, Hans-Peter; Leuchtenberger, Wolfgang; Weckbecker, Christoph (2006). "Amino Acids". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_057.pub2. ISBN 978-3-527-30673-2. <a href="978-3-527-30673-2" target="_blank">978-3-527-30673-2</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></li>
</ol>

Strecker amino acid synthesis open-in-new

Strecker amino acid synthesis