Asymmetric hydrogenation enantioselectivity

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... 

The chiral (R)-bcnzazepine derivative 20 is a key intermediate in the synthesis of a non-peptide AVP V2-agonist. Efficient production of this intermediate was thus required, and this has been achieved by highly enantioselective asymmetric hydrogenation of the easily made acids 18 (E and Z) and 19, using Ru(II) complex catalysts <00CHIR425>. 

Following Wilkinson s discovery of [RhCl(PPh3)3] as an homogeneous hydrogenation catalyst for unhindered alkenes [14b, 35], and the development of methods to prepare chiral phosphines by Mislow [36] and Horner [37], Knowles [38] and Horner [15, 39] each showed that, with the use of optically active tertiary phosphines as ligands in complexes of rhodium, the enantioselective asymmetric hydrogenation of prochiral C=C double bonds is possible (Scheme 1.8). 

A chiral zw a-metallocene triflate complex catalyzes the Diels-Alder cycloaddition reaction between an oxazolidinone-based dienophile and cyclopentadiene [206]. Triflate in titanocene and zirconocene complexes is labile [207,208] and thus the polarity of solvent influences the reactivity and enantioselectivity. Asymmetric hydrogenation of imines and enamines catalyzed by chiral aw a-titanocene catalyst provides amines with high enantioselectivity [209,210]. 

The resolution of racemic secondary allyl alcohols can be performed in the presence of certain ruthenium chiral catalysts through enantioselective asymmetric hydrogenation [811, 881], Chiral poisoning also works in such kinetic resolutions. For example, hydrogenation of 2-cyclohexenol under ( )-binap-Ru catalysis in the presence of (II , 25)-ephedrine 1.61 (10 equiv) provides unreacted (J )-2-cydo-hexenol in 95% ee after 60% conversion [857],... 

Magnetically recoverable heterogenized nanoparticle supported chiral Ru complexes were obtained and used in highly enantioselective asymmetric hydrogenation of aromatic ketones (Hu et al., 2005). The catalysts can be recycled by magnetic decantation and used for asymmetric hydrogenation for up to 14 times without loss of activity and enantioselectivity. 

The complex does not involve any direct metal coordination but operates through weak interactions with functional groups and relies only on the formation of three hydrogen bonds. The Ir complex (26), (Ar = (3,5)-(Bu02C6H3, X = 6-Me), is the precatalyst for 0 the enantioselective asymmetric hydrogenation of aromatic ketones by H2 in EtOH to... 

Catalytic asymmetric hydrogenation was one of the first enantioselective synthetic methods used industrially (82). 2,2 -Bis(diarylphosphino)-l,l -binaphthyl (BINAP) is a chiral ligand which possesses a Cg plane of symmetry (Fig. 9). Steric interactions prevent interconversion of the (R)- and (3)-BINAP. Coordination of BINAP with a transition metal such as mthenium or rhodium produces a chiral hydrogenation catalyst capable of inducing a high degree of enantiofacial selectivity (83). Naproxen (41) is produced in 97% ee by... 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

Both reactions were carried out under two-phase conditions with the help of an additional organic solvent (such as iPrOH). The catalyst could be reused with the same activity and enantioselectivity after decantation of the hydrogenation products. A more recent example, again by de Souza and Dupont, has been reported. They made a detailed study of the asymmetric hydrogenation of a-acetamidocin-namic acid and the kinetic resolution of methyl ( )-3-hydroxy-2-methylenebu-tanoate with chiral Rh(I) and Ru(II) complexes in [BMIM][BF4] and [BMIM][PFg] [55]. The authors described the remarkable effects of the molecular hydrogen concentration in the ionic catalyst layer on the conversion and enantioselectivity of these reactions. The solubility of hydrogen in [BMIM][BF4] was found to be almost four times higher than in [BMIM][PFg]. 

Although the asymmetric hydrogenation of itaconic acid derivatives is a potential synthetic approach to many useful product [105], lower enantioselectivities are often reported. In contrast with other catalysts, f-Bu-BisP, Ad-BisP, t-Bu-MiniPHOS, BIPNOR 27, and Brown s ligand 25 gave high to almost perfect ees in the hydrogenation of these substrates (Scheme 23) [101]. 

The Rh(I)-catalyzed asymmetric hydrogenation of dimethyl 1-benzoyloxy-ethenephosphonate 2 using f-Bu-BisP as the chiral ligand gave the corresponding (S)-product in 88% ee (Scheme 27) [120], enantioselectivity being comparable to those observed by Burk et al. [121]. 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

Pd metals immobilized on SBA-15 and NaY were applied as catalysts in the synthesis of amino alcohol. These catalysts afford a high level of enantioselectivity in the asymmetric hydrogenation of a-keto alcohol to corresponding amino alcohol. The large peilladium metal exhibited higher catalytic activity and enantioselectivity than well dispersed one over porous supports in the hydrogenation. 

The hydrogenation of a cinnamate was also investigated as a first step to determine kinetics and finally to come to a quantitative determination of kinetic models and parameters in asymmetric catalysis [64]. The enantiomeric excess of enantioselective catalytic hydrogenations is known to be dependent on pressure, chiral additives and mixing. Such dependences are often due to kinetics, demanding appropriate studies. 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

The modifier in these cases seems to generate enantioselective sites at the metal surface and helps the molecule to adsorb in a preferred fashion so that the formation of only one stereo- product is possible. There are several milestones that have contributed to this state-of-the-art technology. Discovery of Wilkinson s catalyst led to the feasibility of asymmetric hydrogen transfer with the aid of an optically active Wilkinson-type catalyst for L-DOPA (Monsanto s anti-Parkinson disease drug) synthesis (Eqn. (21)). 

The asymmetric hydrogenation of C=N (Eqn. (23)), in contrast with C=0 and C=C bonds, is much less developed. Hexahydrowoquinoline was used as its phosphoric acid salt. Iridium-ferrocenyl complexes were found to be sati.sfactory. After optimisiation, Meyer et al. (1997) were able to realize an enantioselectivity of 89% ee. 

BITIANP, were tested as ruthenium ligands for the asymmetric hydrogenation of various olefinic substrates. The results collected in Scheme 8.8 show that these novel ligands were able to induce high enantioselectivities of up to 94% ee. ... 

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