Preparation of a-Amino Acids

Problem 21.2 Synthesize leucine, (CH,),CHCH,CH(NH,)COO, by (a) Hell-Volhard-Zelinsky reaction (Section 16.3) followed by ammonolysis. (b) Gabriel synthesis, (c) phthalimidomalonic ester synthesis, (d) reductive amination of a keto acid, (e) Strecker synthesis (addition of NH, HCN to RCH=0), (/) acetylaminomalonic ester. 

Use ester rather than acid to prevent conversion of anion to phthalimide. 

In the presence of NH, an aminonitrile is formed instead of a cyanohydrin. (/) HjCfCOOEOj HON=C(COOEt)j AcNHCH(COOEt)  

Problem 21.3 Write structural formulas for compounds (A) through (C) and classify the reactions. 

Problem 21.4 Outline the preparation of (a) methionine from acrolein by the Strecker synthesis (Problem 21.2(e)), (b) glutamic acid by the phthalimidomalonic ester synthesis (Problem 21.2(c)].  

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Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) The a-halo acids obtained by halogenation of carboxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of a-amino acids is displacement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. 

Chiral cyclic /V,D-acetals of glyoxal and their use for preparation of a-amino acids 98SL449. 

A particularly useful variation of this reaction uses cyanide rather than HCN. a-Amino nitriles can be prepared in one step by the treatment of an aldehyde or ketone with NaCN and NH4CI. This is called the Strecker synthesisand it is a special case of the Mannich reaction (16-15). Since the CN is easily hydrolyzed to the acid, this is a convenient method for the preparation of a-amino acids. The reaction has also been carried out with NH3-I-HCN and with NH4CN. Salts of primary and secondary amines can be used instead of NH to obtain N-substituted and N,N-disubstituted a-amino nitriles. Unlike 16-51, the Strecker synthesis is useful for aromatic as well as aliphatic ketones. As in 16-51, the Me3SiCN method has been used 64 is converted to the product with ammonia or an amine. ... 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Ketoximes and oximes of 2-oxo-acids are hydrogenated to amines by [CoH(CN)5]3-. The latter reaction allows the preparation of a-amino-acids by reductive amination of 2-oxo-acids in aqueous ammonia. At 40-50 °C and 70 bar H2 the yields are ca. 90% [146]. 

Kubryk, M. and Hansen, K.B. Apphcation of the Asymmetric Hydrogenation of Enamines to the Preparation of a Amino Acid Pharmacophore. Tetrahedron Asymmetry 2006,17, 205-209. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

The solid-phase synthesis of a-amino acids via alkaloid-catalyzed alkylation has been investigated by the O Donnell group [64, 65]. The solid-phase based synthetic approach is particularly useful for rapid preparation of a-amino acids for combinatorial application. The concept of this solid-phase synthetic approach, which comprises three key steps, is shown in Scheme 3.22 (for formation of (R) enantiomers). First, solid-phase bound glycine, 51, is converted into its benzophenone imine de-... 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

Note There are several ways to prepare Schollkopf s alkylated lactam ether substrates (for the preparation of a-amino acids) that do not imvolve the foregoing standard lithiation/alkylation procedures. Such variants are exemplified here. 

In summary, the stereoselective formation of the a-azido carboximides (S)-7 by means of electrophilic azide transfer to the JV-acyloxazolidinones 5 leads to a new class of very versatile protected amino acids which can be easily tranformed into free amino acids (or peptides). This methodology, in contrast to the preparation of a-amino acids by means of alkylation of chiral glycine enolates9, also provides access to arylglycines and hindered amino acid derivatives such as tcrt-alkylglycines. 

The mixed anhydride method is analogously and conveniently applied to the preparation of a-amino acids (60) from malonic acid half-esters (59 equations 38 and 39). - ... 

Preparation of a-amino acid amides of aromatic amines (111) is easily conducted as a one-pot procedure by the modified Curtius reaction of aromatic carboxylic acids with DPPA, followed by reaction with iV-protected a-amino acids (equation 44). By this method, -t-butoxycarbonyl-L-leucine p-nitroanilide, which serves as a substrate for leucine aminopeptidase after deblocking of its r-butoxycar-bonyl group, has been efficiently prepared from p-nitrobenzoic acid and -r-butoxycarbonyl-L-leucine. 

A more general method for preparation of a-amino acids is the amidomalonate synthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by 5 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to yield an a-amino acid. For example, aspartic acid can be prepared from ethyl bromoacetate, BrCH2C02Et ... 

Jang and co-workers reported on the development of an enantioselective radical addition reaction to glyoxylate oxime ether for the preparation of a-amino acids under mild reaction conditions with chiral quaternary ammonium salts of hypophosphorous acid in aqueous media.26 The newly prepared chiral quaternary ammonium hypophosphites are inexpensive, less toxic than metal-containing compounds and the reaction conditions and workup are mild and simple (Table 7.2). It is also important to note that chiral quaternary hypo-phosphites are recyclable without altering their performance. The... 

Aller, E., Buck, R.T., Drysdale, M.J., Ferris, L., Haigh, D., Moody, C.J., Pearson, N.D., and Sanghera, J.B., N-H Insertion reaction of rhodium carbenoids. Part 1. Preparation of a-amino acid and a-aminophosphonic acid derivatives, J. Chem. Soc., Perkin Trans. 1, 2879, 1996. 

Scheme 1.10 Preparation of a amino acids from protected glyceraldehyde.

There is only one previous comprehensive review of the electrophilic animation of carbanions 2 shorter reviews3 9 and reviews limited to particular reagents, substrates, or products have appeared animation with haloamines,10 sulfonylhydroxylamines,11 oxaziridines,12 oximes,13 diazonium salts,14,15 diazo compounds,16 activated azo compounds,17 azides,18-23 and nitridomanganese(V) reagents 24,25 animation of enolates 26-30 and the preparation of a-amino acids by electrophilic animation.31-34... 

Carboxylic acid derivatives that have a-substituents can exist as chiral compounds. The resolution of the enantiomers of such compounds is a useful process, leading to the preparation of a-amino acids, a-hydroxy adds and other a-substituted carboxylic acids and their derivatives in enantiomerically enriched form. In addition, the racemization of such compounds can be achieved by a deprotonation/reprotonation sequence, as shown in Fig. 9-13. 

One of the most common substrates is vinyl acetate, leading to 2-acetoxypropanal with up to 98% ee125 if the reaction is carried out in the presence of orthoformate. Vinyl propionate and vinyl benzoate can also be used (see Table 7)75,167. All these substrates are prostereogenic building blocks, e.g, as precursors for the asymmetric preparation of a-amino acids, such as threonine. 

Yields are usually less good on ammonolysis of simple halo aliphatic acids and then a large excess of ammonia appears desirable. Cheronis and Spitz-mueller516 found adding ammonium carbonate assisted formation of primary amino acids and gave directions for preparation of a-amino acids with 2-6 carbon atoms details are illustrated in the following example. 

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