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). [cite journal
author = Strecker, A.
title = Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper
journal = Annalen der Chemie und Pharmazie
year = 1850
volume = 75
issue = 1
doi = 10.1002/jlac.18500750103
pages = 27–45] [cite journal
author = Strecker, A.
title = Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper (p )
journal = Annalen der Chemie und Pharmazie
year = 1854
volume = 91
issue = 3
doi = 10.1002/jlac.18540910309
pages = 349–351 ] 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. [Kendall, E. C.; McKenzie, B. F. "Organic Syntheses", Coll. Vol. 1, p.21 (1941); Vol. 9, p.4 (1929). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0021 Article] )] [Clarke, H. T.; Bean, H. J. "Organic Syntheses", Coll. Vol. 2, p.29 (1943); Vol. 11, p.4 (1931). ( [http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0029 Article] )]

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. [Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. "J. Am. Chem. Soc." 2003, "125(19)", 5634-5635. (DOI|10.1021/ja034980+)]

The traditional synthesis of Adolph Strecker from 1850 gives racemic α-amino nitriles, but recently several procedures utilizing asymmetric auxiliaries [ Davis, F. A. "et al." "Tetrahedron Lett." 1994, "35", 9351.] or asymmetric catalysts [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)] have been developed. [Duthaler, R. O. "Tetrahedron" 1994, "50", 1539-1650. (Review, DOI|10.1016/S0040-4020(01)80840-1)]

Reaction mechanism

The reaction mechanism for this reaction is sketched below. In part one aldehyde 1.1 reacts with ammonia in a nucleophilic addition to the hemiaminal 1.3 which attracts a proton to form iminium ion 1.5 by elimination of water. A second nucleophilic addition of the cyanide ion forms the aminonitrile 1.6.

In stage two a proton activates aminonitrile 2.1 for nucleophilic addition of two equivalents of water to intermediate 2.6 which eliminates ammonia and a proton to final product 2.7.

cope

An example of present-day use of the Strecker synthesis is a multikilogram scale synthesis of a valine derivative starting from "3-methyl-2-butanone" ["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.] :

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References

ee also

* Bucherer-Bergs reaction