Asymmetric hydrogeneation of cinnamic acid

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

Scheme 6.12 Asymmetric hydrogenation of cinnamic acid acetamidates.

Thus, G. Oehme et al. employed two types of polysoaps in the micellar catalytic asymmetric hydrogenation of cinnamic acid acetamidates as amino acid precursors [81, 82]. 

The first industrially interesting production of a chiral pharmaceutical with a chiral metal complex catalyst is the asymmetric hydrogenation of cinnamic acid derivatives to give L-DOPA, see Fig. 6.21. 

Table 5 Asymmetric hydrogenation of cinnamic and tiglic acid derivatives...

Enzymatic hydrogenations generate optically pure isomers attempts to initiate such processes are made on metal-catalyzed hydrogenations. Asymmetric hydrogenation can fill the need for asymmetric compounds of which only one enantiomorph is active, e.g., amino acids such as L-lysine, 1 (indispensable in animal feeds), L-phenylalanine, 2 (a sweet peptide component), L-dopa 3 (a drug for Parkinsonism), are required in the L-form for human or animal consumption. Consequently, most of the examples investigated are related to the asymmetric hydrogenation of acrylic acid or cinnamic acid derivatives. 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

Ruthenium complexes of (129) and (130)336 were investigated for the asymmetric hydrogenation of prochiral 2-R-propenoic acids (Scheme 62a) rhodium complexes of these ligands were used for hydrogenation of acetoamido-cinnamic acid methyl ester (Scheme 62c) and hydrogenation of acetophenone-benzylamine (Scheme 62b). The results obtained with these... 

Table 1 Asymmetric hydrogenation of (Z)-2-(acetamido) cinnamic acid, 2-(acetamido) acrylic acid and their methyl esters...

An asymmetric photosynthesis may be performed inside a crystal of -cinnamide grown in the presence of E-cinnamic acid and considered in terms of the analysis presented before on the reduction of crystal symmetry (Section IV-J). We envisage the reaction as follows The amide molecules are interlinked by NH O hydrogen bonds along the b axis to form a ribbon motif. Ribbons that are related to one another across a center of inversion are enantiomeric and are labeled / and d (or / and d ) (Figure 39). Molecules of -cinnamic acid will be occluded into the d ribbon preferentially from the +b side of the crystal and into the / ribbon from the — b side. It is well documented that E-cinnamide photodimerizes in the solid state to yield the centrosymmetric dimer tnixillamide. Such a reaction takes place between close-packed amide molecules of two enantiomeric ribbons, d and lord and / (95). It has also been established that solid solutions yield the mixed dimers (Ila) and (lib) (Figure 39) (96). Therefore, we expect preferential formation of the chiral dimer 11a at the + b end of the crystal and of the enantiomeric dimer lib at the —b end of the crystal. Preliminary experimental results are in accordance with this model (97). 

In asymmetric hydrogenation of olefins, the overwhelming majority of the papers and patents deal with hydrogenation of enamides or other appropriately substituted prochiral olefins. The reason is very simple hydrogenation of olefins with no coordination ability other than provided by the C=C double bond, usually gives racemic products. This is a common observation both in non-aqueous and aqueous systems. The most frequently used substrates are shown in Scheme 3.6. These are the same compounds which are used for similar studies in organic solvents salts and esters of Z-a-acetamido-cinnamic, a-acetamidoacrylic and itaconic (methylenesuccinic) acids, and related prochiral substrates. The free acids and the methyl esters usually show appreciable solubility in water only at higher temperatures, while in most cases the alkali metal salts are well soluble. 

Houpis, I.N., Patterson, L.E., Alt, C.A., Rizzo, J.R., Zhang, T.Y. and Haurez, M. S3mthesis of PPAR Agonist via Asymmetric Hydrogenation of a Cinnamic Acid derivative and Stereo-specific Displacement of (S)-2-Chloropropionic Acid. Org. Lett. 2005, 7, 1947-1950. 

Table I. Optical Yields for the Asymmetric Hydrogenation of a-(Acylamido)cinnamic Acid Derivatives Using Rhodium(I) Complexes Containing (NmenHCeHsJPC C P eHs ...

NMR spectroscopy has been used to study the species formed in solution by interaction of cinnamic acid derivatives with asymmetric hydrogenation catalysts. Such studies are necessarily limited to those species which accumulate in adequate concentration and have sufficiently long lifetimes for observation by NMR. In catalytic reactions as rapid as those described here, such complexes appear likely to be outside rather than in the operating catalytic cycle. ... 

In another example de Souza and Dupont studied the asymmetric hydrogenation of a-acetamido cinnamic acid and the kinetic resolution of ( )-methyl-3-hydroxy-2-methylenebutanoate with chiral Rh(I) and Ru(ii) complexes in [BMIM][BF4] and [BMIM][PFs] [106]. A special focus oftheir work was on the influence of H2 pressure on conversion. They determined the hydrogen solubility in the ionic liquid using... 

Biemer et al. reported the enantioselective behaviors of a Pd catalysts supported on specially prepared silica gels, which have been precipitated from Na silicate wiA HCl in the presence of optically active alkaloids sulfates of quinine (Q), quinidine (Qd ), cinchonine (Cn), or cinchonidine (Cnd). These catalysts proved to be active in the asymmetric hydrogenation of 2-methyl-cinnamic acid (Scheme 3.1.) . 

Asymmetric hydrogenation of a-acetamido cinnamic acid [Rh(PNNP)(NBD)], a chiral complex L-Phenylalanine Fiorini and Giongo (1979)... 

ChenW, SpindlerF, Pugin B, Nettekoven U (2013) ChenPhos highly modular P-stereogenic Cl-symmetric diphosphine ligands for the efficient asymmetric hydrogenation of a-substituted cinnamic acids. Angew Chem Intern Ed 52 8652-8656... 

Fig. 2.5 Substrate-catalyst complex in the asymmetric hydrogenation of a-alkyl cinnamic acids with Rh(TriFer) complex...

Fig. 2.6 Transition-state models for the asymmetric hydrogenation of a-substituted cinnamic acids catalysed by the (Sc. c.5Fc.5Fc.5p.5p)-Rh(TriFer) complex (reproduced from [35], with the permission of J. Wiley Sons Inc.)...

Asymmetric Hydrogenation.—The asymmetric hydrogenation of a-acylamino-acrylates and cinnamates using chiral rhodium(i) diphosphine complexes as catalysts is now established as one of the best methods for obtaining optically pure a-amino-acids (see previous reviews in this series). In the past year, some new chiral diphosphines have been added to the already considerable number of such ligands. A bis(diphenylphosphino)-derivative of pyrrolidine in conjunction with Rh can be used to hydrogenate a-acetamidocinnamates and itaconic acid with chiral inductions of 90%, whereas an Rh -diphos complex derived from natural tartaric acid effects the reduction of some a-acylaminoacrylic acids to natural (5)-a-acylamino-acids with optical yields of between 80 and 100%. ... 

In the asymmetric hydrogenation of the methyl ester of a-acetamido cinnamic acid, 3.24 cannot be observed by conventional NMR techniques. In situ PHIP-NMR studies in contrast do show two hydride signals at -19 and -2 ppm. Using a C-enriched substrate, the coupling between the asterisk-labeled carbon and the hydride at -2 ppm can also be observed. Based on the NMR data, the actual structure is concluded to be more like 3.25 than 3.24. 

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