A-Acetylphenylalanine

Reduction in the presence of methanolic sodium methoxide produces the corresponding A -acetylphenylalanine methyl ester as the final product. °° ° Enzymatic resolution of A -acetylphenylalanine methyl ester then gives phenylalanine in high enantiomeric purity. Magnesium in methanol has also been used to produce nearly quantitative yields of the M-acetylphenylalanine methyl ester without isolation of the intermediate saturated oxazolone. ° ... 

In these 1968 papers, the substrates to be hydrogenated were a-ethylstyrene, a-methoxystyrene, a-phenylacrylic acid, itaconic acid, etc. The hydrogenation of dehydroamino acid derivatives entered the literature with the papers of Kagan and co-workers [59, 60] and Knowles et al. [61]. Actually, the hydrogenation of (Z)-c -acetamidocinnamic acid to give A-acetylphenylalanine (eq. (3)) became the most frequently studied test system for the evaluation of new catalysts. 

Asymmetric hydrogenation of a-amidoacrylic acids and related olefins has been reported to proceed with high enantioselectivity in the presence of chiral ferrocenyl-phosphine-rhodium catalysts. Both ferrocenylmonophosphines [21, 24, 58] and ferrocenylbisphosphines [17, 59, 60] can produce A -acetylphenylalanine with >80 /o ee in the rhodium-catalyzed hydrogenation of a-acetoaminocinnamic acid or its esters (Scheme 2-42). The high selectivity is ascribed mainly to a characteristic structure of the olefinic substrate that has an amido group at the proper position... 

Pavlov et al. studied the hydrogenation of 2-acetamidocinnamic acid 1 into A-acetylphenylalanine 2 at atmospheric pressure and a temperature range of 50-70°C (Scheme 3.5.) using a cholesteric liquid crystal (cholesteryl tridecanoate, Me(CH2)i iCOO-Cholesteryl). 

Another approach is to build up a polymer network aroimd a complex. Pavlov et al. studied a chiral liquid crystal matrix, in which the Wilkinson catalyst, [RhCl(PPh3)3] was embedded in cholesteryltridecanoate and catalyzed the enantioseleetive hydrogenation of 2-acetamidocinnamic acid into A-acetylphenylalanine with an ee of 60% (see details in Chapter 3). 

The toxins of many members of the fungal genus Al-ternaria produce phytotoxins of these, many [such as AM-toxin I (18)] are peptides. The fungal pathogen Alternaria mali on apples produce necrotic lesions on the leaves, shoots, and fruits of susceptible cultivars (Natori et al, 1981). Alternaria kikuchiana, which causes black spot disease on the Japanese pear (Pyrus serotina) produces phytotoxins which are based on A -acetylphenylalanine and a Cio fatty acid (Harbome, 1986). 

Many of the most useful applications of enzymes in asymmetric synthesis involve kinetic resolution and an example is the hydrolysis of ( )-A -acetylphenylalanine methyl ester (43) with a-chymotrypsin to give the (S)-acid (44) and the unchanged (/ )-ester (45). Very often, as in this case, we can make use of either of the two products once they have been resolved by a further simple non-asymmetric chemical step (here hydrolysis of (45) to give the (/ )-acid). 

Details of the first stereoselective hydrogenation in ionic liquids were published by the group of Chauvin [68], who reported the enantioselective hydrogenation of the enamide a-acetamidocinnamic acid in the biphasic system [BMIM][SbF6]/ iPrOH (ratio 3 8) catalyzed by [Rh(cod) (-)-diop ][PF6]. The reaction afforded (S)-N-acetylphenylalanine in 64% enantiomeric excess (ee) (Fig. 41.4). The product was easily and quantitatively separated and the ionic hquid could be recovered, while the loss of rhodium was less than 0.02%. 

The reaction was monitored by H-NMR. When complete conversion was obtained, the solvent was removed and the crude reaction was filtered through a short silica gel column using t-butyl methyl ether as eluent. The resulting solution was concentrated using a rotatory evaporator to give N-acetylphenylalanine methyl ester in quantitative yield as a white solid. 

From the fore gut of Laccophilus minutus, a Bacillus pumilus strain was isolated which produced maculosin, the diketopiperazine formed from proline and tyrosine [103] 24, phenyl malonate 25, N-acetylphenylalanine 26, N-acetyl-tryptophane 27 and 3,4-dihydroxybenzoic acid [ 103]. Maculosin which has also been isolated from several microorganisms and sponges shows phytotoxic and cytotoxic properties [103], 3,4-dihydroxybenzoic acid shows antioxidant properties and was already found in pygidial defensive glands of several dytis-cid beetles. 

Muller et al.understand better the role of tyrosine in the structure and biological function of MDH. Resolution of the protein absorption spectrum, using iV-acetylphenylalanine ethyl ester in dioxane and A-acetyltyrosine ethyl ester in dioxane or 0.1 M phosphate buffer to model the effect of the local environments of the chromophoric groups, indicated that both the pig and the... 

Traditional commercial requirements for L-phenylalanine have been small (less than 50 ton/a) and had been satisfied by the use of aminoacylase to resolve chemically synthesised DL-N-acetylphenylalanine. However with the advent of aspartame as a high intensity sweetener a very big derived demand for L-phenylalanine was generated. As a result a number of companies began to develop bioconversion and fermentation processes to produce L-phenylalanine. 

Although the standard amidocarbonylation reaction involves an aldehyde and an amide, benzyl chloride can be used as the reactant. The amidocarbonylation of benzyl chloride was first reported by Wakamatsu eta/, in 1976 using Co2(CO)8 as catalyst precursor. This process was revisited by de Vries et al. in 1996 and iV-acetylphenylalanine 8 was obtained in 82% yield under the optimized conditions (Scheme 2)." Since the Co-catalyzed amidocarbonylation is carried out in the presence of CO and H2, formylation of benzyl chloride takes place first to form phenylacetalde-hyde in situ. In this particular case, as Scheme 2 illustrates, A-acetylenamine 10 is formed as intermediate, followed by the chelation-controlled HCo(CO)4 addition to give alkyl-Co intermediate II. Insertion of CO to the carbon-Co bond of II, forming acyl-Co complex 12, followed by hydrolysis affords 8 and regenerates active Co catalyst species. 

Willner et al. also prepared fulgimide-modified (through lysine nitrogen) a-chy-motrypsin 30, with nine fulgimide molecules in one protein. 311 The modified protein was active towards esterification of N-acetylphenylalanine in cyclohexane. Together with the bioimprinting technique of the substrate, the rate of esterification could be accelerated by irradiation with UV light. 

The glycine-derivative radical generated by this process was found to react with a benzyl radical, which was generated from toluene under similar reaction conditions. Thus, irradiation of a solution of N-acetylglycine ethyl ester and toluene in acetone led to the formation of DL-N-acetylphenylalanine ethyl ester (70),... 

The evidence for involvement of an acyl intermediate comes from the fact that pepsin catalyzes the exchange of between free carboxyl groups of acyl amino acids (products) and water 126, 127). This is fully discussed by Knowles 108) and Fruton 46). Attempts to trap putative acyl enzymes have failed so far. Furthermore, Shkarenkova et al. 128) showed that is rapidly incorporated from H2 into an active site carboxyl group of pepsin in the absence of an acyl amino acid, and that the rate of loss from labelled pepsin is similar to the pepsin-catalyzed rate of exchange with acetylphenylalanine. The 0-exchange experiments, therefore, do not require the formation of an acyl intermediate. With this in mind Knowles proposed a mechanism for pepsin-catalyzed reactions 108) which involves a covalent amino intermediate but not an acyl intermediate. 

Hydrogenation of MAC catalyzed by a homogeneous Rh catalyst to give R and S enantiomers of N-acetylphenylalanine methyl ester. 

N-acetylphenylalanine methyl ester during MAC hydrogenation in methanol solvent [C. R. Landis and J. Halpern, J. Am. Chem. Soc., 109 (1987) 1746]. The DI-PAMP coordinates to the rhodium through the phosphorus atoms and leaves plenty of space around the Rh cation for other molecules to bind and react. The unique feature of this system is that the chirality of the DIPAMP ligand induces the high stereoselectivity of the product molecules. An analogous nonchiral ligand on the Rh cation produces a catalyst that is not enantioselective. 

FIGURE 13.6, Scattering curves for the host and guest molecules in a / -cyclodextrin (host) - 2iV-acetylphenylalanine methyl ester (guest) complex. Data for the host (J cyclodextrin) are indicated by solid lines, and for the guest (the methyl ester) by broken lines. The guest is somewhat disordered in the channel provided by the more ordered structure of the crystallized host (Ref. 24). 

To the methods of preparation cited by Gillespie and Snyder the following may be added the reduction of phenylpyruvic acid in alcoholic-ammoniacal solution with hydrogen in the presence of platinum catalyst and the reduction of a-acetaminocinnamic acid with hydrogen in the presence of platinum followed by hydrolysis of the resulting acetylphenylalanine. ... 

A very simple C2-symmetric diphosphine 10 was prepared by Bosnich and Fryzuck in 1977 [33]. Hydrogenation of AT-acetyldehydrophenylalanine gaveN-acetylphenylalanine with an ee close to 99%. The authors proposed that the asymmetric induction originated from the twist conformation of the chelate ring X or 8 configuration), locked by the diequatorial orientation of the two methyl substituents. 

Chiral complexes of Rh supported on AI2O3, AgCl, or BaS04, cellulose, or silica gel afford insoluble catalysts that hydrogenate (Z)-a-/V-acetamidocinnamic acid to N-acetylphenylalanine with 79% e.e. (e.e. = enantiomeric excess) in aqueous NaOH,... 

The 100 e.v. yield for the radiolytic degradation of the peptide bond, as measured in terms of G( NH3) after mild hydrolysis, has been determined for a variety of aliphatic, aromatic and sulfur-containing amino acids in the N-acetyl form. These data are summarized in Table I. In the case of the aliphatic series, we note that the length of the side-chain has relatively little effect on the yield of main-chain degradation. The effect of the aromatic groups of acetylphenylalanine and of acetyltyrosine is to quench in part the yields of those reactions that lead to formation of amide ammonia. The sulfur moiety of methionine on the other hand appears to be relatively ineffective in quenching such reactions. 

The hydroxyl group of both isomers forms hydrogen bonds equally with secondary hydroxyl groups of a-CyD. Another example of a crystalline complex with a racemic compound is the j8-CyD complex with flurbiprofen. In the crystal, two j8-CyD molecules form a head-to-head dimer and a pair of (R)- and (S)-flurbiprofen is packed in the barrel-like cavity (Fig. 7.25A) [163]. In contrast, an excess of (S)-isomer was detected in the j8-CyD complex with racemic fenoprofen [157]. j8-CyD molecules form a same dimer structure in the crystal of the complex with each isomer, but the arrangement of guest molecules in the dimer cavity differs between the two crystals. Two (H)-isomer molecules are included in the head-to-head mode (Fig. 7.25B) while the head-to-tail arrangement is observed in the (S)-isomer complex (Fig. 7.25C) [158]. In fS-CyD complexes with N-acetylphenylalanine, the L-isomer is disordered in the dimer cavity while two molecules of D-isomer are included in a head-to-head mode [177]. 

---