Acetamidocinnamic acid

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). 

Table 4. Asymmetric Hydrogenation of (Z)-2-Acetamidocinnamic Acid (6) to (f -At-Acetylphenylalanine (7)...

Chira.lHydrogena.tion, Biological reactions are stereoselective, and numerous dmgs must be pure optical isomers. Metal complex catalysts have been found that give very high yields of chiral products, and some have industrial appHcation (17,18). The hydrogenation of the methyl ester of acetamidocinnamic acid has been carried out to give a precusor of L-dopa, ie, 3,4-dihydroxyphenylalanine, a dmg used in the treatment of Parkinson s disease. 

The influence of the concentration of hydrogen in [BMIM][PFg] and [BMIM][BF4] on the asymmetric hydrogenation of a-acetamidocinnamic acid catalyzed by rhodium complexes bearing a chiral ligand has been investigated. FFydrogen was found to be four times more soluble in the [BFJ -based salt than in the [PFg] -based one. 

The cationic [Ir(cod)(bnda)](BF4) complex (bnda = 2,2 -diamno-l,l -binaphthyl), (336), catalyzes the enantioselective hydrogenation of (Z)-a-acetamidocinnamic acid to acetamidodihydrocinnamic... 

Brunner et al. attached chiral branches to non-chiral catalytically active sites. With the aim to influence the enantioselectivity of transition metal catalyzed reactions they synthesized several dendritically enlarged diphosphines such as 81 [101] (Fig. 29). In situ prepared catalysts from [Rh(cod)Cl]2and81 have been tested in the hydrogenation of (a)-N-acetamidocinnamic acid. After 20 hours at 20 bar H2-pressure (Rh/substrate ratio 1 50) the desired product was obtained with an enantiomer ratio of 51 49. 

A new class of phosphines (30) containing only an axial element of chirality (atropisomerism) has been made (253, 254). An in situ 1 1 rhodium/2,2-bis(diphenylphosphinomethyl)-1,1 -binaphthyl system (30a) hydrogenated a-acetamidocinnamic acid to a 54% ee (S) using 50 atm H2, the solvent not being recorded (253). The corresponding diphenyl-phosphinite system (30b) in toluene-acetone was particularly effective (76% ee) for hydrogenation (95 atm) of a-acetamidocinnamic and a-acet-amidoacrylic esters (254). 

In 1982, Yamashita reported the application of L-talopyranoside-based phos-phine-phosphinite ligand 165 (Fig. 27.15), and found that it induced low enan-tioselectivity (4.7-13% ee) in the hydrogenation of a-acetamidocinnamic acid [119]. Reetz introduced the phosphine-phosphonite ligand (151-153), which led to moderate enantioselectivity (52-88% ee) in the Rh-catalyzed hydrogenation of dimethyl itaconate [120]. The binaphthyl unit remained an essential element in the system. 

Fig. 41.4 Rhodium-catalyzed enantiomeric hydrogenation of a-acetamidocinnamic acid in the system [BMIM][SbF6]/iso-propanol system.

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%. 

Brunner et al. [26] synthesized and applied so-called dendrizymes in enan-tioselective catalysis. These catalysts are based on dendrimers which have a functionalized periphery that carries chiral subunits, (e.g. dendrons functionalized with chiral menthol or borneol ligands). The core phosphine donor atoms can be complexed to (transition) metal salts. The resultant dendron-enlarged 1,2-diphosphino-ethane (e.g. 16, see Scheme 17) Rh1 complexes were used as catalysts in the hydrogenation of acetamidocinnamic acid to yield iV-acetyl-phenylalanine (Scheme 17) [26]. A small retardation of the hydrogenation of the substrate was encountered, pointing to an effect of the meta-positioned dendron substituents. No significantly enantiomerically enriched products were isolated. However, a somewhat improved enantioselectivity (up to 10-11% e.e.) was... 

The same authors compared catalysts prepared from these precursors and [Ru(BINAP)Cl2]2 adsorbed on MCM-41 (with 26 and 37 A pores) and an amorphous mesoporous silica (with 68 A pores) all treated with combinations of SiPh2Cl2 and Si(CH2)3X (X = NH2, CO2H). Catalysts were also prepared in which the organometallic precursors were immobilized by entrapment into silica (using sol-gel techniques). This is one of the few studies in which the performance of chiral phosphine catalysts immobilized by covalent and noncovalent procedures are compared directly. The materials were examined as catalysts for the hydrogenation of sodium a-acetamidocinnamate and of a-acetamidocinnamic acid under similar conditions to those used for the catalysts on unmodified MCM-41. The catalysts... 

Ligand (349), water-soluble (350), and their (R)-enantiomers have been synthesized, and their Ru complexes used as catalysts (see also Section 5.5.3.2.5) for the asymmetric hydrogenation of methyl acetoacetate and (Z)-acetamidocinnamic acid. " The complex [Ru (5)-351 (OAc)2] and... 

With a rhodium complex catalyst containing a chiral ligand dispersed in [BMIM]SbFg, the enantioselective hydrogenation of a-acetamidocinnamic acid to (5)-phenylalanine was achieved with 64% enantiomeric excess 112). [RuCl2( S)-BINAP]2 NEt3 in [BMIM]BF4 for (5)-naproxen synthesis gave 80% ee from 2-(6-methoxy-2-naphthyl) acrylic acid and isopropyl alcohol 214). 

Enantioselective hydrogenation in ILs is of particular interest as it could provide a means for facile recycling of metal complexes of expensive chiral ligands. In their original study, Chauvin et al reported that [Rh (cod)(2)-(diop)][Pp6] catalyzed the enantioselective hydrogenation of oc-acetamidocinnamic acid to ( S)-phenylalanine with 64% ee, in a biphasic... 

Several bioconversion processes were developed to a production scale. These included the use of the precursors iranx-cirmamic acid by Cenex, df-acetamidocinnamic acid by... 

O-Acetamidocinnamic acid [5469-45-4] M 205.2, m 185-186° (2H2O), 190-191°(anhydr), 193-195°. Recrystd from H2O as the dihydrate and on drying at 100° it forms the anhydrous compound which is hygroscopic. Alkaline hydrolysis yields NH3 and phenylpyruvic acid. [Erlenmeyer and Friistuck A 284 47 1895). 

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