Ethyl pyruvate, enantioselective hydrogenation

In order to reveal the importance of the basic quinuclidine N and the OH group of CD in the enantioselection, the efficiency of CD as chiral modifier of Pt was compared to those of some CD derivatives (Table 3). Two typical trifluoromethyl ketones, 1 and 4, were hydrogenated in an apolar solvent and in acetic acid. Data on ethyl pyruvate 9 hydrogenation are also schown in Table 3 for comparison. 

An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

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.

Recently, platinum nanoparticles protected by N,N-dimethyl-N-cetyl-N-(2-hydro-xyethyl)ammonium chloride salt and modified with cinchonidine were investigated in the enantiomeric hydrogenation of ethyl pyruvate in pure biphasic liquid-liquid (water/substrate) media at room temperature [139]. For the first time, the aqueous phase containing Pt(0) nanocatalysts with an average size of 2.5 nm could be reused for successive hydrogenations, and with a total conversion of activity and enantioselectivity in (R)-(+)-ethyl lactate up to 55% (Scheme 9.12). 

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

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. 

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... 

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]. 

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].)...

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],... 

Later studies by Blaser et al. revealed that the enantioselectivities as well as the rates of hydrogenation for a-keto esters are increased by hydrogenation in acetic acid. In the hydrogenation of ethyl pyruvate the best results (93-95% ee) were obtained in ace-... 

Minder et al. studied various modifiers containing a nitrogen base for the enantioselective hydrogenation of ethyl pyruvate.223,224 Up to 82% ee with (R)-l-(l-naphthyl)ethylamine and up to 75% ee with (/ )-2-( 1 -pyrrolidinyl)-1 -(1 -naphthyl)-ethanol as modifiers were achieved in the hydrogenation of ethyl pyruvate to (R)-ethyl lactate over Pt-Al203 in acetic acid. 

The Pt-catalyzed enantioselective hydrogenation of ethyl pyruvate to (/ )-ethyl lactate was considerably faster (by a factor of 3-3.5) in supercritical ethane than in the conventional apolar solvent toluene, whereas the enantioselectivity was unaffected. Complete catalyst deactivation was observed in C02, which was shown by FTIR to be due to the reduction of C02 to CO via reverse water gas shift reaction. The catalyst could be regenerated by exposing it to ambient air, while hydrogen treatment was less efficient. This is the first evidence to the limitation of catalytic hydrogenations over Pt metals in supercritical C02. 

Enantioselective hydrogenation of ethyl pyruvate in supercritical and conventional solvents... 

Several zeolites have been used as supports for cinchona modified Pt in the enantioselective hydrogenation of a-ketoesters such as ethyl pyruvate ... 

ESMS was employed to identify reactive intermediates in the enantioselective hydrogenation of ethyl pyruvate on Pt-alumina, Pt black, and Pt black+alumina catalysts modified by dihydrocinchonidine in acetic acid [56]. The ESMS spectra of the raw product revealed a large number of species which fell into four groups (1) dihydrocinchonidine and its hydrogenated derivatives (2) the adducts of ethyl pyruvate and its oligomers (3) (R)-ethyl lactate, the product of the enantioselective hydrogenation, and its adducts and (4) oxonium compounds formed from alumina. The latter most likely play a decisive role in the development of the chiral environment of the catalyst surface. As suggested by the authors, these oxonium cations could make the so-called electrostatic catalysis [57],based on electrostatic acceleration, possible. 

---