Amino acids from ketones

STRECKER Aminoacid synthesis Synthesis of a-amino acids from aldehydes or ketones via cyanohydnns... 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

One of the most valuable and widely used applications of C=N bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from a-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

Adlington RM, Baldwin JE, Catterick D, Pritchard GJ (1997) A versatile approach to pyrimidin-4-yl substituted alpha-amino acids from alkynyl ketones the total synthesis of L-lathyrine. Chem Commun 1757-1758... 

Studies on the transamination reaction between f-butyl esters of optically active amino acids and methyl pyruvate were carried out, as shown in Scheme 7. The resulting iminodicarboxylic acid (16) was partially hydrolyzed and then oxidized with f-butyl hypochlorite to form alanine. The oxidation is a generally applicable one, and the optical purity of alanine is high (50-70%). Similar asymmetric transamination between an (S)-amino acid and ketones was carried out. Catalytic hydrogenation of the Schiff s bases prepared from a-keto acid esters and amino acid esters was carried out, and a substituent and temperature effect observed (de 40-70%). ... 

The liver takes up alanine and other amino acids from the blood and converts the nitrogen to urea and the carbons to glucose and ketone bodies, which are released into the blood and oxidized by tissues for energy. 

Another synthesis of (2R,2 71)-(+)-Z/zreo-methyl-phenidate hydrochloride (1) using an enantiomerically pure starting material, u-pipecolic acid (15), was reported by Perel et al. (Scheme Enantiomerically pure D-pipecolic acid (15) was obtained in 57% yield by recrystallization of diastereomeric tartrate salt, followed by the separation of the desired amino acid from tartaric acid by ion-exchange chromatography. D-Pipecolic acid (15) was protected with a BOC group to afford M-BOC-n-pipecoUc acid (16) in 97% yield. The key amino ketone (18 ... 

However, soluble metal chiral complex catalysts are better, even though ketone hydrogenation under these conditions is more difficult to run than olefin hydrogenation. Notable achievements have been made using Rh and Ru metals. Phosphine ligands are often used, which contain either an asymmetric alkyl group have the phosphorous atom as the asymmetric center, or have an axial element of chirality (atropisomerism) . Other chiral ligands commonly used are derived from amino acids, from L-hydroxyproline and from ferrocene. 

Pillai developed the 2 -nitrobenzhydryl PS resin [20] (8, NBH resin) as an a-substituted nitrobenzyl Hnker. The NBH resin was prepared from o-nitrobenzoyl chloride and 1% cross-Hnked PS resin by Friedel-Crafts acylation and ketone reduction (Scheme 17.7). Photolysis of single amino acids from the NBH resin... 

The Strecker [1] and Bucherer-Bergs [2] reactions are the most important strategies and powerful tools for the synthesis of a-amino acids from a carbonyl compound and cyanide. The classical first approach uses ammonium hydroxide and potassium cyanide to obtain the corresponding aminonitrile compound 1, whereas the second one is a four-component condensation between an aldehyde or ketone derivative reacting with potassium cyanide and ammonium carbonate as source of ammonia and carbon dioxide affording hydan-toin componnds 2 [3], In both cases, final hydrolysis would deliver the corresponding o,a-disubstituted a-amino acid derivatives 3 (Scheme 10.1) [4],... 

Unblocked amino acid chloromethyl ketones are prepared by reaction of benzyloxycarbonyl blocked derivatives with HBr in HOAc, trifluoroaoetic acid, or by hydrogenation. The hydrogenolysis procedure can lead to difficulty in some cases since the chlorine is also susceptible to hydrogenolysis. " A very useful method for the synthesis of chloromethyl ketone derivatives of amino acids utilizes the ready removal of the f-butyloxycarbonyl (Boc) group with hydrochloric acid (Scheme 1). In one step the chloromethyl ketone moiety is generated from the diazomethyl ketone and the protecting group is removed. ... 

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