Asymmetric syntheses of a-amino

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. 

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. 

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). 

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. 

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. 

Using the same catalyst system, Akiyama has demonstrated the catalytic asymmetric allenylation of a-amino ester 389 with propargylstannane 391 to synthesize allenic amine 392 in good yield and high enantiopurity (Scheme 5.2.87). 22... 

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

The asymmetric syntheses of p-amino alcohols have also been reported recently in the literaturef<>>f using chiral compound 2 as a starting material. 

Baer, K., Diickers, N., Hummel, W., and Groger, H., Expanding the apipUcation range of aldolases Novel asymmetric syntheses of a-methylat p-hydroxy a-amino acids and p-amino alcohols. ChemCatChem 2010,2 (8), 939-942. 

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

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). 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

A-Acido imines (R R"C = N —X=0) like /V-acyl (X = CR) /V-sulfonyl [X = S(R)=0]2-7 or /V-diphenylphosphinoylimines [X = P(C6H5)2]3 are masked inline derivatives of ammonia. Compared to the imines themselves these activated derivatives are better electrophiles showing less tendency to undergo undesired deprotonation rather than addition of organometal-lics1812 The apparent advantages of these compounds have been exploited for asymmetric syntheses of amines, amides, amino acids and /J-lactams1-8 I6. 

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

The (/ (-enantiomer of 5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has also been successfully used for asymmetric Strecker syntheses4In addition, the acetal protecting moiety of the auxiliary has been modified. No significant change in the Strecker syntheses of a-mcthylamino nitriles has been reported for these alternative auxiliaries50. 

Scheme 11 Asymmetric syntheses of 1,2-diamines with a-amino organometallic reagents...

M. Hirama u. S. Ito, Heterocycles 28, 1229-1247 (1989) . .Asymmetric Induction in the Intramolecular Conjugate Addition of y- or d-Carbamoyloxy-a,/ -unsaturated Esters. A New Method for Diastcreo-selective Amination and Divergent Syntheses of 3-Amino-2,3,6-trideoxyhcxoscs". 

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