Enantioselective hydrogenation reactions

Efficient enantioselective asymmetric hydrogenation of prochiral ketones and olefins has been accompHshed under mild reaction conditions at low (0.01— 0.001 mol %) catalyst concentrations using rhodium catalysts containing chiral ligands (140,141). Practical synthesis of several optically active natural... 

Another important example of an enantioselective reaction mediated by a chiral catalyst is the hydrogenation of 3-substituted 2-acetamidoacrylic acid derivatives. 

As mentioned in Sect. 2.2, phosphine oxides are air-stable compounds, making their use in the field of asymmetric catalysis convenient. Moreover, they present electronic properties very different from the corresponding free phosphines and thus may be employed in different types of enantioselective reactions, m-Chloroperbenzoic acid (m-CPBA) has been showed to be a powerful reagent for the stereospecific oxidation of enantiomerically pure P-chirogenic phos-phine-boranes [98], affording R,R)-97 from Ad-BisP 6 (Scheme 18) [99]. The synthesis of R,R)-98 and (S,S)-99, which possess a f-Bu substituent, differs from the precedent in that deboranation precedes oxidation with hydrogen peroxide to yield the corresponding enantiomerically pure diphosphine oxides (Scheme 18) [99]. 

The variation of enantioselectivities with temperature and pressure was investigated. The effects of these two factors are very substrate dependent and difficult to generalize even in a single substrate serie. However, it seems that enantioselectivities are shghly better at 25-40 °C than at lower temperatures (0 °C or less). The stereoselectivity can be inverted for specific alkenes (formation of the S or R enantiomer preferentially). For several substrates, the reactions tend to proceed to completion with optimal ee s when performed at lower hydrogen pressure (2 bar) instead of 50 bar (Fig. 13). Pronoimced variation of enantioselectivities with hydrogen concentration in solution may indicate the presence of two (or even more) different mechanisms which happen to give opposite enantiomers for some substrates. 

Table 3), Enantioselective reaction was of order 0 7 in hydrogen by the initial rate method (over the range 2 to 50 bar, 293 K, cinchonine modifier) and 0 2 in pyruvate (0 1 to 3.0 M, 293 K, 10 bar pressure, cinchonine modifier) Enantiomeric excess was independent of reactant concentrations within these ranges Reactions exhibited self-poisoning so that complete conversion was not achieved within 20 h reaction time. As the quantity of cinchonine modifier added to the catalyst was increased from zero to 1 gram per gram so the... 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

Other enantioselective reactions performed by microwave heating include asymmetric Heck reactions (Scheme 6.53 a) [109] and ruthenium-catalyzed asymmetric hydrogen-transfer processes (Scheme 6.53 b) [110]. 

The BINAP-Ru(II)-catalyzed enantioselective hydrogenation of f>-keto esters is used for the synthesis of a wide range of important natural and man-made compounds [1-4, 48] some examples of these are listed in Figure 32.10, wherein chiral centers created by the enantioselective reaction are labeled with R or S. 

Nature uses enantioselective transfer hydrogenation to reduce metabolites, for example pyruvate to give (S)-lactic acid and 2-ketoglutarate to give (S)-2-hydroxy -glutarate. The reaction is reversible and the equilibrium position depends on the concentration of the species. The enzyme catalysts are named dehydrogenases, and they employ a soluble cofactor or hydride acceptor called NAD(P) in its oxi-... 

Chemical catalysts for transfer hydrogenation have been known for many decades [2e]. The most commonly used are heterogeneous catalysts such as Pd/C, or Raney Ni, which are able to mediate for example the reduction of alkenes by dehydrogenation of an alkane present in high concentration. Cyclohexene, cyclo-hexadiene and dihydronaphthalene are commonly used as hydrogen donors since the byproducts are aromatic and therefore more difficult to reduce. The heterogeneous reaction is useful for simple non-chiral reductions, but attempts at the enantioselective reaction have failed because the mechanism seems to occur via a radical (two-proton and two-electron) mechanism that makes it unsuitable for enantioselective reactions [2 c]. 

Fig. 35.4 Outline mechanism for the rhodium-catalyzed enantioselective transfer hydrogenation reaction.

Brunner, Leitner and others have reported the enantioselective transfer hydrogenation of alpha-, beta-unsaturated alkenes of the acrylate type [50]. The catalysts are usually rhodium phosphine-based and the reductant is formic acid or salts. The rates of reduction of alkenes using rhodium and iridium diamine complexes is modest [87]. An example of this reaction is shown in Figure 35.8. Williams has shown the transfer hydrogenation of alkenes such as indene and styrene using IPA [88]. 

Scheme 6-30 shows that the halogen-containing complexes RuX2 (BINAP) are excellent catalysts With an S/C of over 103 or even 104, the enantioselective hydrogenation of methyl 3-oxobutanoate can still proceed well in methanol. The yield of the enantioselective reaction is almost 100%. 

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