Ethyl enantioselective hydrogenation

Enantioselective hydrogenation Z-2-methyl-pent-2-enoic and Z-2-ethyl-hex-2-enoic acids occurred over alkaloid-modified Pd/SiOa as described in Table 2 Enantioselectivity was favoured by an increase in hydrogen pressure to 50 bar The enantiomeric excess of 27% in Z-2-methyl-pent-2-enoic acid hydrogenation was the highest value recorded in this study. 

One of the most interesting side reactions taking place during the enantioselective hydrogenation is the transesterification of the substrate or the reaction product. If the enantioselective hydrogenation of ethyl pyruvate was performed in methanol as a solvent the formation of methyl pyruvate and methyl lactate was observed. CD appeared to be an effective catalyst for the above transesterification reaction. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

The enantioselective hydrogenation of oc,p-unsaturated acids (or their esters) and a-ketoesters, mainly pyruvates, (Figure 1) is a subject of high industrial relevance in the pharmaceutical and agrochemical areas, considering the very different activity of pure enantiomers (1,2). However, the former reaction has been up to today less investigated, evidencing a lower enantioselectivity (maximum ee 38% in comparison to 90% for the ethyl pymvate) (3,4). 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

Torok B, Karoly F, Gerda S, Mihaly B (1997) Sonochemical enantioselective hydrogenation of ethyl pyruvate over platinum catalysts. Ultrason Sonochem 4(4) 301-304... 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Scheme 9.11 Enantioselective hydrogenation of ethyl pyruvate with platinum colloids stabilized by protonated-dihydrocinchonidine.

Scheme 9.12 Reusable aqueous suspension of Pt nanoparticles for enantioselective hydrogenation of ethyl pyruvate.

The Rh complex of the chiral Cj symmetry Josiphos 47 is also effective for the enantioselective hydrogenation of ethyl 3-oxobutanoate [27]. 

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. 

Enantioselective hydrogenation of prochiral ketones has rarely been studied in aqueous biphasic media. In addition to the chiral bisphosphonic acid derivatives of 1,2-cyclohexanediamine [130], the protonated 4,4 -, 5,5 -, and 6,6 -amino-methyl-substituted BINAP (diamBINAP 2HBr) ligands (Scheme 38.7) served as constituents of the Ru(II)-based catalysts in the biphasic hydrogenations of ethyl acetoacetate [131, 132]. These catalysts were recovered in the aqueous phase and used in at least four cycles, with only a marginal loss of activity and enantio-selectivity. 

As mentioned, the most studied reaction using these modified catalysts is the enantioselective hydrogenation of MP or ethyl pyruvate to the corresponding lactates using cinchona alkaloids... 

Cinchonidine promotes the enantioselective hydrogenation of ethyl pymvate even when the hydroxy group is O-methylated. This behavior supports the shape discrimination rather than the participation of a guiding group that is able to produce a second interaction. Nevertheless, it is also... 

Much work [42] has been devoted to cinchona alkaloid modified Pd and Pt catalysts in the enantioselective hydrogenation of a-keto esters such as ethyl pyruvate (Scheme 5.11). Optimal formulation and conditions include supported Pt, the inexpensive (—)-cinchonidine, acetic acid as solvent, 25 °C and 10-70 bar H2. Presently, the highest e.e. is 97.6% [to (R)-ethyl lactate]. 

In catalysis, adsorbed CO may retard some reactions such as olefin hydrogenation, fuel cell conversion, and enantioselective hydrogenation. For instance, Lercher and coworkers observed the deactivation of Pt/Si02 in the liquid-phase hydrogenation of crotonaldehyde, and ascribed this deactivation to the decomposition of crotonaldehyde on platinum surface to adsorbed CO [138]. Blaser and coworkers found that the addition of a small amount of formic acid decreases the rate of liquid-phase hydrogenation of ethyl pyruvate on cinchonidine-modified Pt/Al203 catalyst, which they explained as the decomposition of formic acid on the catalyst to adsorbed CO. Interestingly, the addition of acetic acid does not decrease the reaction rate, but whether acetic acid decomposes on the catalyst as formic acid does was not mentioned [139]. 

Enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified Pt/Al203 is an interesting system in heterogeneous catalysis [143-146], The key feature is that on cinchonidine-modified platinum, ethyl pyruvate is selectively hydrogenated to R-ethyl lactate, whereas on einchonine-modified platinum, S-ethyl pyruvate is the dominant product (Figure 16) [143]. 

In the present work, some promising results obtained with this kind of asymmetric heterogeneous catalyst, based on silica-supported Ni, Rh and Pt, chemically modified with chiral organotin compounds, are presented. The systems were tested in the enantioselective hydrogenation of ethyl pymvate, acetophenone and 3,4-dimethoxyacetophenone. The stabiUty of these catalysts was also studied to check if they could be reused. 

A typical probe molecule for enantioselective hydrogenation reactions (ethyl pym-vate) was chosen to test the performance of the chiral organometalUc catalysts prepared by SOMC/M techniques. 

Figure 6.18 Enantioselective hydrogenation of ethyl pyruvate on heterogeneous chiral catalysts. Activity as a function of time for the following catalysts ( ) Pt/(-)-MenSnBu3, ( ) Rh/ (-)-MenSnBu3 and (A) Ni/(-)-MenSnBu3. (Reproduced from Reference [45].)...

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). 

Recently, the enantioselective hydrogenation of ethyl pyruvate catalyzed by cinchona modified Pt/Al203 (ref. 1) was shown to be a ligand accelerated reaction (ref. 2). The rate of reaction for the fully modified system is more than 10 times faster than the racemic hydrogenation using unmodified catalyst. Under certain reaction conditions, this liquid phase hydrogenation exhibits a turn-over frequency of up to 50 s 1 (3.4 mol/kg-cat s). Emphasis until now has been directed at empirically increasing optical yields (ref. 3,4). 

We have identified reaction conditions where intrinsic kinetics can be obtained for the very fast enantioselective hydrogenation of ethyl pyruvate using a commercially available Pt/Al203 powder catalyst, modified with dihydrocinchonidine. We conclude that this is in pan due to i) the egg-shell structure of the catalyst, ii) the high turbulence achieved in the reactor and iii) the density and/or the viscosity of the solvent used. In solvents like ethyl pyruvate, liquid-solid transpon problems can arise. 

Most of the studies of Pt catalysts with cinchona alkaloids have focused on the hydrogenation of a-keto esters, especially ethyl pyruvate, as shown above, However, enantioselective hydrogenation of ketopantolactone and l-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione is attainable with a Pt catalyst modified by cinchonidine, giving the corresponding R alcohols with 92% ee and 91% ee, respectively (Scheme 1.40) [213]. These reactions can be performed with an S/C of up to 237,000 [213a],... 

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