Strecker amino acid synthesis
The Strecker amino acid synthesis, devised by Adolph Strecker, is a series of chemical reactions that synthesize an amino acid from an aldehyde (or ketone).[1][2][3] The aldehyde is condensed with ammonium chloride in the presence of potassium cyanide to form an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino-acid.[4][5] In the original Strecker reaction acetaldehyde, ammonia, and hydrogen cyanide combined to form after hydrolysis alanine.
While usage of ammonium salts gives unsubstituted amino acids, primary and secondary amines also successfully give substituted amino acids. Likewise, the usage of ketones, instead of aldehydes, gives α,α-disubstituted amino acids.[6]
The traditional synthesis of Adolph Strecker from 1850 gives racemic α-amino nitriles, but recently several procedures utilizing asymmetric auxiliaries[7] or asymmetric catalysts[8][9] have been developed.[10]
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[edit] Reaction mechanism
The reaction mechanism for this reaction is sketched below. In part one the carbonyl oxygen of an aldehyde 1.1 is protonated followed by a nucleophilic attack of ammonia to the carbonyl carbon. The hydroxyl group of the intermediate 1.2 abstracts a proton while the ammonium group releases one. Water is cleaved from the intermediate 1.3 and an iminium ion 1.4 is formed. A cyanide ion attacks to the iminium carbon yielding an aminonitrile 1.5.
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| Strecker synthesis part I |
In the second part of the Strecker Synthesis the nitrile nitrogen of the aminonitrile 2.1 is protonated and the nitrile carbon is attacked by a water molecule. The intermediate 2.2 abstracts one proton and releases another. A 1,2-diamino diol 2.3 is formed after a nucleophilic attack of water to the former nitrile carbon. Ammonia is cleaved due the protonation of the amino group and finally the deprotonation of one of the two hydroxyl groups produces a carboxylic group and an amino acid 2.4 is formed.
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| Strecker synthesis part II |
[edit] Asymmetric Strecker reactions
The asymmetric Strecker reaction was poineered by Kaoru Harada in 1963. [11] [12]. By replacing ammonia with (S)-alpha-phenylethylamine as chiral auxiliary the ultimate reaction product was chiral alanine. The first asymmetric synthesis via a chiral catalyst was reported in 1996 [13]
[edit] Scope
An example of present-day use of the Strecker synthesis is a multikilogram scale synthesis of an L-valine derivative starting from 3-methyl-2-butanone[14] [15]:
[edit] References
- ^ Strecker, A. (1850). "Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper". Annalen der Chemie und Pharmazie 75 (1): 27–45. doi:10.1002/jlac.18500750103.
- ^ Strecker, A. (1854). "Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper (p )". Annalen der Chemie und Pharmazie 91 (3): 349–351. doi:10.1002/jlac.18540910309.
- ^ Shibasaki, M.; Kanai, M.; Mita, K. Org. React. 2008, 70, 1. (doi:10.1002/0471264180.or070.01)
- ^ Kendall, E. C.; McKenzie, B. F. Organic Syntheses, Coll. Vol. 1, p.21 (1941); Vol. 9, p.4 (1929). (Article)
- ^ Clarke, H. T.; Bean, H. J. Organic Syntheses, Coll. Vol. 2, p.29 (1943); Vol. 11, p.4 (1931). (Article)
- ^ Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125(19), 5634-5635. (doi:10.1021/ja034980+)
- ^ Davis, F. A. et al. Tetrahedron Lett. 1994, 35, 9351.
- ^ Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122(5), 762-766. (doi:10.1021/ja9935207)
- ^ Huang, J.; Corey, E. J. Org. Lett. 2004, 6(26), 5027-5029. (doi:10.1021/ol047698w)
- ^ Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (Review, doi:10.1016/S0040-4020(01)80840-1)
- ^ Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis Kaoru Harada Nature 200, 1201 (21 December 1963); doi:10.1038/2001201a0
- ^ Asymmetric Strecker Reactions Jun Wang, Xiaohua Liu, Xiaoming Feng 2011 Chemical Reviews Article ASAP doi:10.1021/cr200057t
- ^ 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
- ^ 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
- ^ 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.
