Synthesis of 3-Amino Acids

FIGURE 22.21 Aziactone synthesis of a dehydroamino acid derivative. 

What alkyl halides would you use to prepare the following a-amino acids by the amidomalonate method  

Another method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is preparedby treatment of pyruvic acid with ammonia in the presence of NaBH4. 

As described in Section 18.6, the reaction proceeds throngh formation of an intermediate imine that is then reduced. 

The synthesis of an a-amino acid from an achiral precursor by either of the methods just described yields a racemate, with equal amounts of S and R enantiomers. To use an amino acid in the laboratory synthesis of a naturally occurring protein, however, the pure S enantiomer must be obtained. 

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemate into its pure enantiomers (Section 5.8). A more efficient approach, however, is to use an enantioselective synthesis to prepare only the desired S enantiomer directly. As discussed in the Chapter 14 Lagniappe, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that unsymmetrical environment, the substrate may be more open to reaction on one side than on another, leading to an excess of one enantiomeric product over another. 

In the presence of primary amides, aldehydes can be directly carbonylated into amino acids  

Pino [164] has shown that the rather drastic reaction conditions (100 to 150 under 200 to 300 bar) initially used by H. Wakanatsu were not necessary good (or even better) results are obtainable under much milder conditions 70 to 100 °C under 100 to 150 bar. 

The reaction mechanism has been studied by P. Pino [164] and is summarized here  

It is not at present possible to know which of the elementary steps A and/or B are actually followed both are possible. 

The intermediacy of the gem amido-alcohol has recently been demonstrated by Ajinomoto [165], who succeeded in preparing oxazolones starting from such an amido-alcohol in anhydrous medium  

There is an abundant supply of L-enantiomers of most of the coded amino acids. These are made available through large-scale fermentative production in most cases, and also through processing of protein hydrolysates. The early sections of this chapter cover this aspect, However, laboratory synthesis methods are required for the provision of most of the other natural amino acids and for all other amino acids, so the main part of this chapter deals with established syntheses. 

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Glycine is the simplest member of a large and very important class of compounds, the a-amino-carboxylic acids. TTiere are many different methods available for the synthesis of amino-acids, but glycine can be readily prepared by the action of an excess of ammonia on chloroacetic acid ... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Alternatively, various 4-substituted derivatives have been prepared via synthesis of amino acid (68) by reaction of the anion formed from protected glycine and an appropriately substituted Schiff base. 

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

Biotransformations are carried out by either whole cells (microbial, plant, or animal) or by isolated enzymes. Both methods have advantages and disadvantages. In general, multistep transformations, such as hydroxylations of steroids, or the synthesis of amino acids, riboflavin, vitamins, and alkaloids that require the presence of several enzymes and cofactors are carried out by whole cells. Simple one- or two-step transformations, on the other hand, are usually carried out by isolated enzymes. Compared to fermentations, enzymatic reactions have a number of advantages including simple instmmentation reduced side reactions, easy control, and product isolation. 

SCHdLLKOPF Amino acid synthesis Asymmetric synthesis of amino acids from dihydropyraaines... 

This group was used to protect the nitrogen of glycine in a synthesis of amino acids. ... 

Assimilatory nitrate reduction Conversion of nitrate to reduced forms of nitrogen, generally ammonium, for the synthesis of amino acids and proteins. 

One of the oldest methods for the synthesis of amino acids dates back to the nineteenth century and is simply a nucleophilic substitution in which ammonia reacts with an a-halo carboxylic acid. 

Among other reactions proceeding with the retention of the heterocyclic nucleus may be noted the synthesis of amino acids of the isoxazole series from isoxazole-5-aldehydes/ the successful extension of the Schmidt reaction to 3-acylisoxazoles, and the synthesis of various polycyclic heterocycles, e.g. 101 102, involving the isoxa-... 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

Auxotrophic mutant lack one or more enzymes involved in the synthesis of amino acids (such as tyrosine). This prevents accumulation of the amino acid and thus avoids feedback inhibition of enzymatic steps in the L-phenylalanine pathway. 

The asymmetric synthesis of amino acids via the addition of allyl and 2,3-dimethyl-2-bulenyl organometallics to ( — )-8-phenylmenthyl A-methoxyiminoacetate (14) was examined12. The results show that both allyl- and 2,3-dimethyl-2-butenylzinc bromide provide good stercocontrol. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

Figure 6.9 Chemoenzymatic synthesis of amino acids via desymmetrization of malonates.

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

Figure 10.1. Schematic diagram showing inhibition of synthesis of amino acids a) single chain inhibition occurs when enzyme controlling committed step (S ) is inhibited by increasing concentrations of product AAj b) branched chain inhibition of by increased concentration of AA2 occurs at a post-branching step (sj), while permitting continued production of product of other branch (AAj). In general, each step is controlled by a single enzyme.

Macko, S.A., Fogel, M.L., Hare, P.E. and Hoering, T.C. 1987 Isotopic fractionation ofnitrogen and carbon in the synthesis of amino acids by microorganisms. Chemical Geology (Isotope Geoscience Section) 65 79-92. 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

Another elegant example of a highly atom efficient process is the use of palladium-cataly.sed amidocarbonylation for the one-step synthesis of amino acid derivatives from an aldehyde, CO, and an amide (Eqn. (10)) (Beller et al., 1997, 1999). 

This version of the Curtius rearrangement has been applied to the synthesis of amino acid analogs and structures containing amino acids. Several m-2-aminocyclopropane carboxylate esters were prepared by selective hydrolysis of cyclopropane-1,2-dicarboxylates, followed by reaction with DPPA.267... 

Another method for the synthesis of amino-acid amides entails the conversion of N-( 1 -benzotriazolylcarbonyl) amino acids with amines in anhydrous or aqueous systems C1101... 

Formation of the very unstable dehydroalanine derivatives A p-dimethylaminophe-nyl- and Af-p-nitrophenyhnethylenedehydroalanine methyl ester could only be verified by -NMR. Because of Michael-type reactions with cuprates, the iV-arylmethylenedehy-droalanine methyl esters have been applied as building blocks in the synthesis of amino acids.[18]... 

Interaction of Ni11 ions with amino acids is also important for asymmetric synthesis of amino acids. A convenient large-scale asymmetric synthesis of enantiometrically pure trans-cinnamyl-glycine and -o-alanine via reaction of cinnamyl halides with Ni11 complexes of a chiral Schiff base of glycine and alanine has been elaborated.1711 Similar procedures have been applied to other amino acids as well.1712... 

W Kwapiszewski, J Kolwas. Synthesis of amino acid derivatives of benzocaine. III. Preparation of N-(N -N -dimethylaminoacyl)-benzocaines. Acta Polon Pharm 34 377-382, 1977. 

Synthesis of Amino Acid Analogs. J. Amer. chem. Soc. 77, 1 (1955). 

Hydroxynitrile lyases (HNLs or oxynitrilases) catalyze C—C bond-forming reactions between an aldehyde or ketone and cyanide to form enantiopure cyanohydrins (Figure 1.15), which are versatile building blocks for the chiral synthesis of amino acids, hydroxy ketones, hydroxy acids, amines and so on [68], Screening of natural sources has led to the discovery of both... 

Arthur L. Weber (1998), now working at the Seti Institute of the Ames Research Center at Moffett Field, reports the successful synthesis of amino acid thioesters from formose substrates (formaldehyde and glycolaldehyde) and ammonia synthesis of alanine and homoserine was possible when thiol catalysts were added to the reaction mixture. On the basis of his experimental results, Weber (1998) suggests the process shown in Fig. 7.10 to be a general prebiotic route to amino acid thioesters. 

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