Enantioselective Hydrogenation of Ketoesters

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). 

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],... 

In recent years, much effort has been devoted to the enantioselective hydrogenation of yS-ketoesters, essentially using ruthenium-based catalysts. The aim of these reactions is to produce selectively enantiopure syn diols which are the key building blocks for the synthesis of inhibitors of HMG-coenzyme A reductase. Due to the availability of the AMPP ligands, and the reactivity of the rhodium catalysts based on them (notably the alkyl-substituted ones) towards ketonic sub-... 

Table 33.8 Enantioselective hydrogenation of a-fluoro-substituted / -ketoesters.

One of the important conclusions of the early attempts was that it is fruitful to place the functionality near an optically active support. Already in 1958, Isoda and coworkers reported for the first time the enantioselective hydrogenation with a Raney nickel catalyst modified with optically pure amino acids. Optical yields reported at that time were from low (2.5%) to moderate (36%) values (for references see [12]). Subsequently, in 1963, Izumi and coworkers [100] initiated an extended study of the modified Raney nickel system with TA. As a result of their initial researches, this system was the first heterogeneous chiral catalyst to give high enantioselectivities in the hydrogenation of / -ketoesters (95%) [101,102],... 

Figure 14.9 Two cycle mechanisms proposed for enantioselective hydrogenation of a-ketoesters on chirally modified platinum [66],...

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 16. Main features in enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified metal catalysts [ 143]. [Reproduced with permission of Elsevier from Baiker, A. J. Mol. Catal. A 1997,115, 473-493.]...

Enantioselective hydrogenation of p-ketoesters with monodentate ligands. Angew, Chem., Int. Ed., 43, 5066-5096. 

As a rule, synthetic chemists will consider only those new reactions and catalysts for preparative purposes where the enantioselectivity reaches a certain degree (e.g. >80%) and where both the catalyst and the technology are readily available. For heterogeneous catalysts this is not always the case because the relevant catalyst parameters are often unknown. It is therefore of interest that two types of modified Nickel catalysts are now commercially available a Raney nickel/tartrate/NaBr from Degussa [64] and a nickel powder/tartrate/NaBr from Heraeus [65, 66]. It was also demonstrated that commercial Pt catalysts are suitable for the enantioselective hydrogenation of a-ketoesters [30, 31]. With some catalytic experience, both systems are quite easy to handle and give reproducible results. 

The first transition metal catalysis using BINAP-ruthenium complex in homogeneous phase for enantioselective hydrogenation of P-ketoesters was developed by Noyori and co-workers [31]. Genet and co-workers described a general synthesis of chiral diphosphine ruthenium(II) catalysts from commercially available (COD)Ru(2-methylallyl)2 [32]. These complexes preformed or prepared in situ have been found to be very efficient homogeneous catalysts for asymmetric hydrogenation of various substrates such as P-ketoesters at atmospheric pressure and at room temperature [33]. 

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

S R ratio = 5 1) [22]. Yanada and Yoneda constructed the deazaflavinophane 26, which exhibits complete facial selectivity in its oxidation and reduction reactions, e.g. the reduction with NaBD to afford 27 [23], Belokon and Rozen-berg used scalemic 4-formyl-5-hydroxy[2.2]para-cyclophane (FHPC) 28 in the synthesis of a-ami-no acids (ee 45-98 %) [24], An alternative approach to FHPC was more recently reported by Hopf [25]. Other interesting advances in the area of chiral cyclophanes include the homochir-al [2.2]paracyclophane-derived amino acids 29 and 30 [26], as well as (5)-PHANEPHOS (31) [27], which has been shown to be an effective ligand for highly enantioselective Ru-catalyzed asymmetric hydrogenations of -ketoesters and... 

Figure 12 Schematic representation of the mechanism proposed for the enantioselective hydrogenation of a-ketoesters on cin-chonidine-modified platinum catalyst. The development of general methods for imparting enantioselectivity to regular heterogeneous catalysts promises to revolutionize the pharmaceutical and agrochemical industries ...

When we commenced our studies in 1995, perhaps the most intriguing aspect of the literature on the enantioselective hydrogenation of P-ketoesters over supported Ni catalysts was the critical dependence between enantiomeric excesses obtained and system variables such as temperature, concentration of modifier, time of modification, pH, etc [6, 7]. The underlying cause of this behaviour became evident when we discovered that the adsorption behaviour of enantiopure (7 ,J )-tartaric acid... 

Blaser HU, Jalett HP, Muller M, Studer M (1997) Enantioselective hydrogenation of a-Ketoesters using cinchona modified platinum catalysts and related systems. Catal Today 37 441... 

Taber and co-workers developed a convergent route to ( - )-432 based on the enantioselective hydrogenation of the p-ketoesters 629 and 630 over a ruthenium-BINAP catalyst, which introduced two of the required stereogenic centers with excellent enantioselectivity (ee 98%) (Scheme 83) 485). The products 631 and 632 were transformed into aldehyde 633 and phosphonium salt 634, respectively, after... 

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