Acetamidocinnamates

Figure C2.7.4. Catalytic cycle for hydrogenation of methyl-(Z)-a-acetamidocinnamate tire rate constants were measured at 298 K S is solvent [8],...

Figure C2.7.5. Pathways for tire hydrogenation of metliyl-(Z)-a-acetamidocinnamate catalysed by a rhodium comolex witli a chiral diohosohine lieand S is solvent 181.

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. 

To establish the most advantageous conditions for production of L-phenylalanine from acetamidocinnamic add using two micro-organisms the following factors were investigated pH, amino donor and ratio of two enzyme activities. 

Table 8.7 The most important process conditions for the production of L-phenylalanine by direct fermentation precursor addition, phenylpyruvic add (PPA) bloconversion, acetamidocinnamic add (ACA).

Encapsulated rhodium complexes were prepared from Rh-exchanged NaY zeolite by complexation with (S)-prolinamide or M-tert-butyl-(S)-prolinamide [73,74]. Although these catalysts showed higher specific activity than their homogeneous counterparts in non-enantioselective hydrogenations, the hydrogenation of prochiral substrates, such as methyl (Z)-acetamidocinnamate [73] or ( )-2-methyl-2-pentenoic acid [74], led to low... 

For example, the hydrogenation of methyl (Z)-a-acetamidocinnamate gives a chiral product when conducted in the presence of a chiral diphosphine catalyst. The enantiomeric excess data for micro-reactor and batch operation are in line when performed imder similar conditions [169]. A very high reproducibility of determining data on enantiomeric excess was reported [170]. In addition, the ee distribution was quite narrow 90% of aU ee data were within 40-48% [170]. 

Conjugated Alkene Hydrogenation Investigated in Micro Reactors Cas/liquid reaction 19 [CL 19) Hydrogenation of Z-(a)-acetamidocinnamic methyl ester... 

Scheme 8.5 Hydrogenation of methyl a-acetamidocinnamate with S/P ligands derived from carbohydrates.

Other S/P ligands derived from carbohydrates and depicted in Scheme 8.5 were found by Khiar et al. to be efficient catalysts for the rhodium-catalysed methyl ot-acetamidocinnamate hydrogenation, leading to protected (5)-phe-nylalanine in a quantitative yield and with an enantioselectivity of 92% ee. On the other hand, the use of 2-phosphinite tert-butyl-thioarabinoside as the ligand afforded the corresponding (2 )-isomer in 92% ee. 

In some cases an alternative sequence involving addition of hydrogen at rhodium prior to complexation of the alkene may operate.11 The phosphine ligands serve both to provide a stable soluble complex and to adjust the reactivity at the metal center. The a-bonded intermediates have been observed for Wilkinson s catalyst12 and for several other related catalysts.13 For example, a partially hydrogenated structure has been isolated from methyl a-acetamidocinnamate.14... 

An especially important case is the enantioselective hydrogenation of a-amidoacrylic acids, which leads to a-aminoacids.29 A particularly detailed study has been carried out on the mechanism of reduction of methyl Z-a-acetamidocinnamate by a rhodium catalyst with a chiral diphosphine ligand DIPAMP.30 It has been concluded that the reactant can bind reversibly to the catalyst to give either of two complexes. Addition of hydrogen at rhodium then leads to a reactive rhodium hydride and eventually to product. Interestingly, the addition of hydrogen occurs most rapidly in the minor isomeric complex, and the enantioselectivity is due to this kinetic preference. 

Fig. 5.4. Schematic mechanism for enantioselective hydrogenation of methyl acetamidocinnamate (MAC) over a cationic ruthenium catalyst. Reproduced...

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). 

Although the latter product is a solvated mononuclear [Rh(MeOH)2(diphos)]+ cation, in the solid state it is isolated as a binuclear complex of formula [Rh2 (diphos)2](BF4)2, in which each rhodium center is bonded to two phosphorus atoms of a chelating bis(diphenylphosphino)ethane ligand, and to a phenyl ring of the bis(diphenylphosphino)ethane ligand of the other rhodium atom. This dimer reverts to a mononuclear species on redissolving. The mechanism of hydrogenation of the prochiral alkene methyl(Z)-a-acetamidocinnamate, studied in detail by Halpern [31], is depicted in Scheme 1.7. 

In addition to direct DuPhos and BPE analogues, several other ligands containing five-membered phosphacycles have been reported (Fig. 24.6). As early as 1991, non-C2-symme trie phospholane-containing phosphines 37-39 were reported by Brunner and Limmer [7]. These were prepared by base-induced addition of the secondary phospholane to the appropriate diphenylphosphino-substi-tuted olefin. As for the symmetrical 3,4-disubstituted bisphospholanes, enantios-electivities for the Rh-catalyzed reduction of a-acetamidocinnamate were poor. 

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