Amino acids asymmetric synthesis

Very recently the Shibasaki group extended the range of application of their asymmetric two-center catalysts 31 to the synthesis of amino acid derivative intermediates for aeruginosin 298-A and analogs thereof [39]. Aeruginosin has a tetrapeptide-like structure and contains non-standard a-amino acids. The synthesis of the key intermediate (S)-20r, bearing a bulky substituent, is shown in Scheme 3.17 [39]. In the presence of the catalyst R,R) 31 the desired amino acid derivative (S)-20r was obtained in 80% yield and with 88% ee [39]. The catalyst 31, which is very stable under basic conditions, could be recovered in 80-90% yield and re-used efficiently [39]. 

Further great advances in the field of asymmetric alkylation reactions have been made by several groups working on chiral phase-transfer-catalyzed alkylation of glycinates (see also Section 3.1). A pioneer in this field is the O Donnell group [53, 54] who developed the first a-amino acid ester synthesis using this methodol-... 

There are two main routes for the production of D-amino acids chemical synthesis and enzymatic catalysis. As regards conventional chemical synthesis, unless asymmetrical starting compounds or catalysts are used, a mixture of the D- and L-stereoisomers is obtained in equal proportions. The racemic mixture is therefore optically inactive and the stereoisomers must be separated. The separation of the enantiomers by classical crystallization of diastereomeric salts is the most costly production step and in any case this method can only yield 50% of the desired enantiomer [3]. Enzymatic synthesis can solve the above problems, providing optical purity of the D-amino acid and a 100% yield, as well as mild, environment-friendly reaction conditions. 

Racemization of Amino Acids. The synthesis of (7 )-alanine was achieved starting from (S)-alanine via formation of the imidazoline with (S)-proline. This result can he explained in terms of epimerization and stereoselective protonation with asymmetric induction hy the chiral center originating from (S)-proline. 

Juaristi, E., Garcia-Barradas, O. Asymmetric addition of amines to a, 3-unsaturated esters and nitriles in the enantioselective synthesis of P-amino acids. Enantioselective Synthesis of. beta.-Amino Acids 1997, 139-149. 

Synthesis of Unsaturated a-Amino-acids Asymmetric Hydrogenation of Amino-acids Protection and Deprotection of Amino-acids Peptide Synthesis... 

SCHEME 31.32. The a- and (3-amino acid derivatives synthesis through an asymmetric hydrogen transfer. 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

G. M. Coppola andH. F. Asymmetric Synthesis Construction of Chiral Molecules Using Amino Acids, oBis N d y dn Sons, Inc., New York, 1987. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

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). 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

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

Asymmetric synthesis of a,a-disubstituted a-amino acids via an intramolecular Strecker synthesis using l,4-oxazin-3-one derivatives as key intermediates 97YGK982. 

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. ... 

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

An early success story in the field of catalytic asymmetric synthesis is the Monsanto Process for the commercial synthesis of l-DOPA (4) (see Scheme 1), a rare amino acid that is effective in the treatment of Parkinson s disease.57 The Monsanto Process, the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex, was introduced by W. S. Knowles and coworkers and has been in operation since 1974. This large-scale process for the synthesis of l-DOPA (4) is based on catalytic asymmetric hydrogenation, and its development can be... 

Another example of reagent-induced asymmetric synthesis is the enantioselective preparation of phosphoramides 6 by addition of dialkylzine reagents to A-diphenylphosphinoylimincs 4 in the presence of the enantiomerically pure 1,2-amino alcohols 5a or 5 b (diethylzinc does not add to A-silyl- or A-phenylimines)12. Phosphoramides 6 (crystalline solids) are obtained in moderate to good yield and good enantioselectivity. The latter can be enhanced by recrystallization. Acidic hydrolysis with dilute 3 M hydrochloric acid/tetrahydrofuran provides the corresponding amines 7 without any racemization. 

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. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

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