Hydrogenation of -2-acetamidocinnamic acid

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). 

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... 

The cyclobutane derivative (55) gave an optical yield of 91% in the hydrogenation of a-acetamidocinnamic acid. The catalyst was here prepared in situ from [RhCl(l,5-hexadiene)]2. The corresponding 1,2-derivative of cyclopentane gave an optical yield of only 73% and the cyclopropane and cyclohexane derivatives gave 15% and 36% respectively.235 [RhCl(cod)2] in presence of the norbomadiene-based ligand NORPHOS (56) gave up to 96% optical yields with a-acetamidocinnamic acid as substrate.236... 

Diphosphine ligands derived from 2,2 -diamino-l,l -binaphthyP together with the somewhat simpler compounds, l,2-bis(diphenylphosphino)-cyclohexane, -butane, and -l-cyclohexylethane, " have also been utilized in such reductions and give excellent chiral inductions with some substrates. A novel cationic ferrocenyl-phosphine-Rh complex has been found to catalyse the hydrogenation of or-acetamidocinnamic acids in optical yields of around 80% reductions of the corresponding acrylates using this catalyst give lower optical yields. 

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)...

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... 

The insolubilized DIOP catalyst (34) was found to be rather ineffective for the asymmetric hydrogenation of oleflnic substrates the hydrogenation of a-ethyl-styrene proceeded readily but gave (-)-R-2-phenylbutane with an optical purity of only 1.5%. Methyl atropate was hydrogenated to (+)-S-methylhydratropate (2.5% ee). The soluble DIOP catalyst gave 15 and 17% ee, respectively, for the same reductions. The optical purity of the products was lower when recovered insolubilized catalyst was used. There was no reduction of a-acetamidocinnamic acid in ethanol-benzene with the insolubilized catalyst, presumably due to the hydrophobic nature of the polymer support causing it to shrink in hydroxylic solvents. 

Chiral rhodium-DuPHOS complexes are highly efficient catalyst for the enantioselective hydrogenation of enamides. One drawback of these catalysts is that they are easily oxidised and inert conditions are required for optimal results. The methyl- and ethyl substituted Rh-DuPHOS compounds, 3a and 3b, have been successfully applied in the reduction of a-acetamidocinnamic acids in [C4Ciim][PF6], Scheme 3.7.[7,39] While activities and selectivities are slightly lower compared to the homogeneous reaction in 2-propanol, the ionic liquid-immobilised catalyst is less prone to oxidation and recycling is feasible at least three times. 

Enantioselective Hydrogenation. (R,5 )-CAMPHOS has been employed in combination with rhodium(I) to reduce alkene carbon-carbon double bonds. Thus, the Rh(I) complex formed from (R,5 )-CAMPHOS and [Rh(cyclooctene)2Cl]2 in toluene-EtOH-EtsN solution catalyzes the hydrogenation (1 atm H2, 20 °C) of atropic acid and of ct-acetamidocinnamic acid. The... 

A mmetric hydrogenation catalyzed by palladium deposited on simpler synthetic polypeptides, homopolymers of a-amino acids or their derivatives, was studied by Beamer, Belding and Pickling (5, (5). In the hydrogenation in ethanol of a-meth-ylcinnamic acid [ J] and of a-acetamidocinnamic acid [4] to give 2-methyl-3-phenyl-propanoic acid [5] and phenylalanine, respectively, the predominant optical antipodte was found much dependent on the secondary conformation of the polypeptide (Table 1). 

The synthesis of carbohydrate-phosphinites was, however, unexpectedly successful. The preparation was much easier than that of the phosphanes. The products could be obtained in crystalline state and were less sensitive to oxidation by air. Their thermal stability was high and drying could be done in vacuum up to 100 °C without decomposition. The rhodium(I) chelate of methyl 4,6-O-benzyli-dene-2,3-bis(0-diphenylphosphino)-a-D-glucopyranoside led to 75% ee (S)-N-acetyl-phenylalanine 2a on hydrogenation of (Z)-2-acetamidocinnamic acid la (Fig. 2) [6],... 

In 1978 we tried to establish contacts with an industrial partner, which were realized by talks with Dr. Lohmann, at that time head of the research department of the VEB ISIS-Chemie, Zwickau. Earlier it was a Kommanditgcscllschaff with government participation but was later converted into a nationalized state-run plant with the status of a VEB ( Volkseigener Betrieb , i.e., a firm owned by the people), a typical state-owned plant in the former GDR. The company was interested in producing L-dopa and we saw a good opportunity for an industrial process using the asymmetric hydrogenation of O-functionalized derivatives of (Z)-2-acetamidocinnamic acid 1 a with our catalysts as shown in Fig. 4. 

Formation of a a-alkylrhodium by insertion of an alkene into a Rh—H bond is a key step in homogeneous asymmetric hydrogenation of alkenes by Rh(I) catalysts. Such intermediates are characterized using multinuclear NMR both in hydrogenation of (Z)-a-acetamidocinnamate by [Rh(Ph2 PCH2 CHj PPhj)] and in the asymmetric hydrogenation of a-benzamidocinnamic acid or its methyl ester by (R,R)-l,2-bis(o-methoxy-phenylphenylphosphino)ethane complexes of Rh(I) . 

More effective, with an ee of 35%, was the hydrogenation of the azlactone of the 2-acetamidocinnamic acid, into D-(+)-A-acetylphenyl-alanine, 6. ... 

Beamer et al. used Pd-polymer catalysts in the hydrogenation of the C=C bonds in 2-acetamidocinnamic acid to iV-acetylphenylalanine (Scheme 3.5.) and 2-methylcinnamic acid to 2-methyl-3-phenylpropanoic acid (Scheme 3.8.). The results are in Table 3.2. 

Scheme 1.3 Hydrogenation of 2-a-acetamidocinnamic acid. The numbers refer to the ee of 12.

Thermodynamic stability of M—C bond in water has raised questions about lifetimes of intermediates in the aqueous organometallic catalytic cycles. From deuterium-labeling experiments (Eq. 6.3), Sinou and coworkers have concluded that the protonation of the M—C bond can occur readily. When the reduction of (Z)-acetamidocinnamic acid methyl ester was performed under hydrogen in a two-phase system (Et0Ac-D20) in the presence of the catalyst [Rh(cod)Cl]2- - TPPTS [tris-(OT-sulfonato-phenyl)phosphine], regioselective... 

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