Alanine asymmetric synthesis

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]. 

The imines of ( )-(l/ ,2/ ,5/ )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were highly successful as Michael donors in the asymmetric synthesis of 2,3-di-substituted glutamates. The chiral azaallyl anions derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 "C undergo addition to various ,/ -unsaturated esters with modest to high diastereoselectivities210,394. 

Abelian T., Chinchilla R., Galindo N., Guillena G., Najera C., Sansano J. M. Glycine and Alanine Imines As Templates for Asymmetric Synthesis of a-Amino Acids Eur. J. Org. Chem. 2000 2689-2697... 

Thus, a reversal of the diastereoseleetivity of the reaetion was observed if the enolate was prepared in the presenee of a lithiated base. The different behaviour of the base could be attributable to the geometry of the enolate. It was assumed that the use of KOH as a base would give predominantly the E enolate, whereas the Z enolate would be formed with a lithiated base such as LiN(TMS)2- This methodology was applied to the asymmetric synthesis of quaternary a-amino acids starting from an imino alaninate compound. 

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... 

The first 3,6-dialkoxy-2,5-dihydropyrazine used in asymmetric synthesis of amino acids 7 10 was the symmetrical derivative 2, derived from cyclo(L-Ala, L-Ala) (1). This dihydropyrazine can be prepared by direct condensation of the methyl ester of L-alanine and subsequent alkylation with trialkyloxonium tetrafluoroborate7. Although the condensation process results in partial racemization of the alanine moiety, recrystallization yields almost optically pure cyclo(L-Ala, L-Ala) (1). 

Recent developments regarding the utility of chiral amino acids in asymmetric synthesis of natural products were reported. Examples of such syntheses are the preparation of carbohydrates from (S)-glutamic acid 257), (S)-alanine 258), or (S)-threonine 259), and syntheses of alkaloids 260), terpenes 26I), peptide 262) derivatives, and toxines 263>. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

Reductive amination reactions of keto acids are performed with amino acid dehydrogenases. NAD-dependent leucine dehydrogenase from Bacillus sp. is of interest for the synthesis of (S)-fert.-leucine [15-17]]. This chiral compound has found widespread application in asymmetric synthesis and as a building block of biologically active substances. The enzyme can also be used for the chemoenzy-matic preparation of (S)-hydroxy-valine [18] and unnatural hydrophobic bran-ched-chain (S)-amino acids. NAD-dependent L-phenylalanine dehydrogenase from Rhodococcus sp. [19] has been used for the synthesis of L-homophenyl-alanine ((S)-2-Amino-4-phenylbutanoic acid) [9]. These processes with water-soluble substrates and products demonstrate that the use of coenzymes must not... 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

The use of proline methyl ester as a chiral auxiliary in the asymmetric synthesis of alanine is shown on the following page. The idea is to start with 2-oxopropanoic acid (pyruvic acid), which has the correct carbon skeleton, and replace tire oxygen on carbon 2 with an amino group and a hydrogen. This must be done in such a manner as to produce only the S-enantiomer of the amino acid, that is, L-alanine. This is accomplished by first attaching a chiral auxiliary, the methyl ester of L-proline, to the acid. In the critical step of the process, the catalytic hydrogenation, the chirality of the... 

An example of diastereoface differentiation is provided in an asymmetric synthesis of the dipeptide Ala-Ala [70]. The element of chirality is that of one of the alanine groups, and the faces are those of a Schiff base, > C=N—. The material undergoing a catalytic reduction is the isobutyl ester of the benzylamine Schiff base of N-pyruvoyl-(5)-alanine, 54. The ratio of R S (55) to S S dipeptide was 82 18 for an optical purity of 64%. 

An asymmetric synthesis of alanine itself is provided by the Grignard reaction of the benzylamine Schiff base, 57, of ( —)-menthyl glyoxylate, 56. The (S)-alanine, 58, was obtained with a 53% optical yield [71]. This yield could be influenced by another... 

Table 3 Solvent Effect in the Asymmetric Synthesis of Alanine Using Me (-) ...

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

Schdllkopf and cowoikers have pioneered the development of anions of another type of masked carboxylic acid derivative, i.e. bislactim ethers such as (159), derived from (5)-valine and glycine or alanine, for the asymmetric synthesis of amino acids. As shown in Scheme 78, compounds such as... 

Enamides can also be used as precursors for the asymmetric synthesis of amino acids via hydroformylation. Thus, asymmetric branched hydroformylation of vinylsuccinimide and vinylphthalimide upon further oxidation leads to, V-protccted amino carboxylic acids such as alanine. Branched products are obtained with high regioselectivities and good to high optical yields of up to 96% (see Table 7)125. 

Cyclic imines with glycine or alanine fragment as templates for asymmetric synthesis of a-amino acids 00EJO2689. 

Table II shows solvent effects in the asymmetric synthesis of alanine from pyruvic acid and (S)-a-methylbenzylamine( ). The optical purity of alanine decreases with increasing polarity of the solvent. In the case of the asymmetric synthesis of glutamic acid from a-keto glutaric acid and (S)-a-methylbenzylcimine, the configuration of the resulting glutamic acid was actually inverted by the use of polar solvents. The substrate appears to interact with the catalyst more strongly in a less polar than in a more polar solvent. Thus, the population of the chelated substrate is...

Allylation of the racemic alanine-derived azlactone 127 with racemic 3-aceto-xycyclohexene (126) using Trost L-1 as a ligand produced the allylated product 128 in 96 % yield with a 2.5 1 diastereomeric ratio. The enantiomeric excesses were 94 % and 92 % for the major and minor diastereomers. The reaction offers a good method of asymmetric synthesis of a-alkylated amino acid 129 [47]. 

An efficient asymmetric synthesis of a-amino acids has been described, having as its key step the stereoselective reduction of a carbon-nitrogen double bond in which the hydrogen atom addition is highly preferred from one diastereotopic face over the other. The sequence is shown for the synthesis of o-alanine. The optical purity observed is 96% in this instance, with optical yields of 92-97% reported for other amino acids prepared by this method. 

Basu, B. and Frejd, T. (1996) Catalytic asymmetric synthesis of bis-armed aromatic amino acid derivatives. Problems related to the synthesis of enantiomerically pure bis-methyl ester of the (5,5 )-p3nidine-2,6-diyl bis-alanine. Acta. Chem. Scand., 50, 316 22. 

However, it should be noted that the concept of carbohydrates as chiral synthons has always fascinated sugar chemists as the excellent 1972 review by Inch will attest 42). Thus in order to preserve historical perspective three antecedents for the use of sugars in asymmetric syntheses are noted in Scheme 1. First is Wolfrom s proof of the structure of (-t-)-alanine by synthesis from D-glucosamine 102). Second is the synthesis of the optically pure mandelic acid derivatives from 2,3-4,5-di-O-isopropylidene-fl/tfeAy o-D-arabinose (1) by Bonner (9), and third is Lemieux s synthesis of ethanol-l-d from diacetone glucose (6 a, Scheme 2) via the deuterated xylose (2) (57). 

Thus the overall result is C-alkylation of (5)-alanine with inversion. The method also works well in the asymmetric alkylation of glycine, as shown by the asymmetric synthesis of (5)-phosphonothricin (56), a naturally occurring herbicide.07] Note that the configuration at the tetrahedral phosphorus is irrelevant, since proton exchange in the phosphinic acid racemises this centre. 

Alanine dehydrogenase (AlaDH) has been coupled with lactate dehydrogenase (LDH) for the kinetic resolution of 3-fluoroalanine to the D-enantiomer and L-3-fluorolactic acid (Scheme 4.11). This approach represented the inverse counterpart to the LDH-AlaDH-cascade for the asymmetric synthesis of alanine from lactate as described above. As in the reverse system, internal cofactor regeneration was achieved, resulting in a redox-neutral process. D-3-Fluoroalanine and L-3-fluorolactic acid were obtained in 60% (ee = 88%) and 80% (ee>99%) yields, respectively. 

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of SchifI bases derived from a-amino-acid esters and good yields of /3-hydroxy-a-amino-acids are obtained. This type of compound is also prepared using the optically active imine (183) the t/trco-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88). The jS-hydroxy-a-amino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described. Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. L-Alanine, L-valine, and (S)-0,0-dimethyl-a-methyldopa have been used to prepare the heterocyclic intermediates (186), which give a range of amino-acids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187). ... 

Based on this model, the asymmetric synthesis of D-alanine was carried out. All the steps proceed in good yield and the amino acid obtained has an optical purity of 80%. Figure 2.8 outlines this synthesis. 

An interesting application of asymmetric synthesis afforded the in-danedione 2, from the trIketone 8 The use of aminoacids of the (S)-con-figuration such as L-proline and L-alanine as catalysts for the condensation gave optically active bicycllc intermediates 2 °f the (S)-configura-tion in yields of 60-85% with optical purity in the same range." ... 

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