Methyl -2-acetamidocinnamate

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

As enantioselective hydrogenations of prochiral substrates are undoubtedly the most common applications of chiral diphosphine ligands, a broad screening of our ligands was undertaken with some commonly used standard substrates. As substrates for the hydrogenation of C=C double bonds dimethyl itaconate (DlMl), methyl 2-acetamidoacrylate (MAA), methyl acetamidocinnamate (MAC) as an a-amino acid precursor, and ethyl (Z)-3-acetamidobutenoate ( 3-ENAM1DE) as a p-amino acid precursor were chosen (see Eig. 1.4.5). 

Asymmetric hydrogenation of (Z)-methyl acetamidocinnamate with rhodium chiral diphosphine complexes Mesh MSR Abdallah et al. [37]... 

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],...

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. 

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. 

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. 

Borner reported the synthesis of pyrophosphites 149 with chiral binaphthyl substituents [118]. The results showed that the Hg-binaphthyl unit was the best for the Rh-catalyzed hydrogenation of methyl (Z)-2-acetamidocinnamate (48% ee) and dimethyl itaconate (70% ee). 

Pizzano and Suarez described a convenient preparation of a series of new chiral phosphine-phosphites based on the easy demethylation of o-anisyl phosphines [124]. Rh-156a complex was found to be the most effective catalyst for the hydrogenation of dimethyl itaconate (99.6% ee), whereas 155b and 156a induced >99% ee in the hydrogenation of methyl N-2-acetamidocinnamate. Reetz... 

Salzer et al. prepared a set of planar-chiral diphosphine ligands based on the arene chromium tricarbonyl backbone (Fig. 36.3) [21]. The straightforward four-step synthetic route allowed the preparation of 20 ligands of this family. These ligands were tested in Ru- and Rh-catalyzed enantioselective hydrogenation of various substrates, including the standard C=C substrates (dimethyl itaconate, methyl-2-acetamidocinnamate, methyl-2-acetamidoacrylate) as well as MEA-imine (l-(methoxymethyl)ethylidene-methylethylaniline) and ethyl pyruvate. Moderate conversions and ee-values were obtained. 

Fig. 36.8 ee-values obtained in the Rh-catalyzed hydrogenation of methyl-2-acetamidocinnamate, plotted against the ligand ratio (the ratio (L1 + L2)/Rh always remains 2). 

Reaction using ligand 4 a, substrate methyl-a-acetamidocinnamate ... 

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