Asymmetric Synthesis of a-Amino Acids

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate a-amino nitriles to provide a-amino acids (Scheme 1), was first reported in 1850 [1], This method has been applied on an industrial scale toward the synthesis of racemic a-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of a-amino acids [2]. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of a-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. 

Numerous asymmetric catalytic hydrogenations of carbon-nitrogen double bonds have been carried out. Some of the substrates used are oximes and hydrazones, but most of the reactions were carried out using Schiff s bases of ketones. a-Keto acids are precursors of a-amino acids in biosynthesis, and therefore a-keto acids have been used for the asymmetric syntheses of a-amino acids. ... 

Asymmetric Syntheses of a-Amino Acid and Peptide Derivatives... 

In 1961, Hiskey et al.(l) reported the successful asymmetric syntheses of a-amino acids. They demonstrated the synthesis of amino acids in 45-70% enantiomeric purity by catalytic hydrogenation of the Schiff bases prepared from a-keto acids and optically active a-methylbenzylamine followed by hydrogenolysis (Scheme 1). When (S)-amine was used, (S)-a-amino acid resulted. This is a highly stereoselective reaction. However, the authors did not discuss the steric course of the asymmetric hydrogenation process. 

A variety of chiral phase-transfer catalysts have been developed and successfully used in asymmetric syntheses of a-amino acids [19. 23, 24]. In 1984, researchers at Merck described the methylation of indanone 74 in the presence of the quaternized cinchona salt 75 as a chiral phase-transfer catalyst (Scheme 10.12) [66]. The alkylation product 76 was isolated in 92% ee and 95 % yield and subsequently elaborated into (-H)-indacrinone (77), which had previously only been prepared by resolution techniques. 

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. ... 

Asymmetric syntheses of (3- amino acids result from the addition of chiral enolates (399) to nitrone (400) via A-acyloxyiminium ion formation (642, 643). Regioselective convergence is obtained in the reactions of chiral boron- and titanium- enolates (399a,b), (401), and (402). This methodology was used in preparing four stereoisomers of a-methyl- 3-phenylalanine (403) in enantiomeric pure form (Scheme 2.179) (644). 

Kunz, H, Burgard, A, Schanzenbach, D, Asymmetric syntheses of p-amino acids with two new stereogenic centres at the a and p-positions, Angew. Chem. Int. Ed., 36, 386-387, 1997. 

Asymmetric alkylation of A-pro tec ted glycine ester 26 under phase-transfer catalysis conditions is the well-known method for the syntheses of a-amino acids [19]. Scheme... 

Reviews on phase-transfer catalysis for the syntheses of a-amino acids, (a) Ooi, T. and Maruoka, K. (2004) Asymmetric organocatalysis of structurally well-defined chiral quaternary ammonium fluorides. Acc. Chem. Res., 37, 526-533 (b) Maruoka, K. and Ooi, T. (2003) Enantioselective amino acid synthesis by chiral phase-transfer catalysis. Chem. Rev., 103, 3013-3028 (c) Ooi, T. and Maruoka, K. (2003) Enantioselective synthesis of a-amino acids by chiral phase-transfer catalysis. Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem.) 61, 1195-1206. 

Asymmetric electrophilic a-amination of carbonyl groups in syntheses of a-amino acids and A-heterocycles 04EJO1377. 

SCHEME 14.4. Asymmetric hydroformylation of aUcenes can provide versatile aldehydes which may be used for the Strecker syntheses of a-amino acids. 

Hanessian S, Bennani YL. Electrophilic amination and azi-dation of chiral a-alkyl phosphonamides asymmetric syntheses of a-amino a-alkyl phosphonic acids. Synthesis 1994 1272-1274. 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

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). 

For the synthesis of optically pure building blocks we mainly focused on the synthesis of protected noncoded (R)- and (S)-amino acids, as they can be synthesized reliably in enantiomerically pure form with a large variety of side chains using asymmetric hydrogenation of a-amino-a, 3-didehydroamino acids using cationic diphosphine rhodium catalysts.216,217 As a typical example of a reactophore we present a-alkynyl ketones, which is a representative bis-acceptor molecule. In Scheme 5 are depicted some of the many synthetic applications of acetylenic ketones in heterocyclic synthesis, which have great potential for combinatorial and parallel organic synthesis. 

The synthesis of a-amino acids has been carried out from a-keto acids by reductive aminadon using a platinum or palladium catalyst, mimicking their biosynthesis. Thus alanine, leucine, phenylalanine, " aspartic acid and glutamic acid - have been synthesized by reductive amination. When an optically active primary amine is used, asymmetric induction can proceed in the course of the reductive amination. 

In addition, the use of a whole-cell biocatalyst consisting of a racemase, hydantoi-nase, and carbamoylase allows a dynamic biocatalytic resolution. Besides resolution processes, asymmetric (bio-)catalytic concepts have been applied successfully on an industrial scale. The different types of asymmetric (bio-)catalytic syntheses of L-amino acids, based on the use of prochiral starting materials, are shown in Fig. 3. 

Some excellent reviews collect the early and recent literature with respect to typical complex-catalyzed reactions [5,6, 7, 8, 9,10,11,12]. Most of the water-soluble phosphines were synthesized by direct sulfonation of the phenyl group leading to mixtures of products. Sinou et al. [13] investigated the asymmetric hydrogenation of precursors of a-amino acids [ 14] and even of dehydropeptides... 

A more common strategy for stepwise asymmetric cyclopropanation is the use of chiral electrophiles. Meyers has used bicyclic lactams (c/. Scheme 3.19, 3.20) [145,146] as electrophilic auxiliaries in sulfur ylide cyclopropanations [147]. These auxiliaries, for reasons that are not entirely clear, are preferentially attacked from the a-face. After separation of the diastereomers, the amino alcohol auxiliary may be removed by refluxing in acidic methanol or reductively [145]. This methodology has been used in asymmetric syntheses of cw-deltamithrinic acid and dictyopterene C, illustrated in the inset of Scheme 6.40 [145]. 

Enamide ester, which is a useful synthetic intermediate for a variety of a-amino acids, can be prepared by means of the HWE reaction in the presence of TMG (3) or DBU [20,21]. In the synthesis of teicoplanin aglycon (80) reported by Evans et al. [22], one of the phenylalanine derivatives 79 was synthesized from the aldehyde 75. HWE reaction of aldehyde 75 with phosphonate 76 using TMG (3) in THF gave (Z)-enamide ester 77 in 99% yield. Asymmetric hydrogenation of 77 catalysed by rhodium(I) complex 78 (1 mol%) gave the phenylalanine ester 79 in 96% with 94% ee (Scheme 7.16). 

The use of optically resolved PTC catalysts for the synthesis of enantiomerically pure compounds is no doubt an attractive field. Asymmetric PTC has become an important tool for both laboratory syntheses and industrial productions of enantiomerically enriched compounds. Recently, Lygo and coworkers [207-216] reported a new class of Cinchona alkaloid-derived quaternary ammonium PTC catalysts, which have been applied successfully in the enantioselective synthesis of a-amino acids, bis-a-amino acids, and bis-a-amino acid esters via alkylation [207-213] and in the asymmetric epoxidation of a/p-unsaturated ketones [214-216]. 

Reviews on catalytic uses of DMAP and other 4-(dialkylamino)pyridines have appeared [9]. These bases are very efficient reagents for acylations, alkylations, silylations, phosphorylations, condensations, and transesterifications [ 10]. More recent applications of DMAP as a catalyst include a parallel synthesis of benzyl purine derivatives [11] and it has been employed as a base in the asymmetric synthesis of an amino acid via an auxiliary [12]. Uses of DMAP tethered to solid supports (of which one such example is commercially available) have been reviewed [10,13]. Such a system has recently been employed to synthesize multiple oligonucleotides linked end to end in tandem [14]. 

A variety of methods have been developed for the synthesis of a-amino acids. Here we describe two methods that are based on reactions we have studied before. In The Chemistry of... Asymmetric Syntheses of Amino Acids (WileyPLUS) we show methods to prepare a-amino acids in optically active form. Asymmetric synthesis is an important goal in a-amino acid synthesis due to the biological activity of the natural enantiomeric forms of a-amino acids, and due to the commercial relevance of products made by these routes. 

Glycosylamines, in particular the O-pivaloyl protected galactopyranosylamine 15 proved to be very efficient chiral templates in asymmetric Strecker (28) and Ugi syntheses (29) of a-amino acid derivatives. In both these processes the imines 16 formed from the galactosylamine 15 and aldehydes are the real chiral substrates. The N-galactosyl imines 16 of aromatic aldehydes can be synthesized from 15 and the aldehyde in n-pentane in the presence of molecular sieves (4A) and dried silica gel. Under these conditions anomerization of the imines can be prevented. The compounds 16 are isolated in crystalline form and contain less than 4% of the corresponding a-anomer. 

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