Asymmetric hydrogenation method

Besides the above-mentioned catalytic asymmetric hydrogenation method for preparing fluorine-containing compounds, other reactions such as asymmetric reduction of achiral fluorine-containing ketones are also feasible methods for preparing chiral fluorinated compounds. For example, the oxazabor-olidine system, which has been discussed in Chapter 6, can also be employed in the catalytic reduction of trifluoromethyl ketones. Scheme 8 40 depicts some examples.85... 

As the follow up to our studies in connection to the development of Ti-cat-alyzed cyanide additions to meso epoxides [4], we developed the corresponding catalytic enantioselective additions to imines [5]. A representative example is shown in Scheme 1 chiral non-racemic products maybe readily converted to the derived cx-amino acids (not available through catalytic asymmetric hydrogenation methods). In these studies, we further developed and utilized the positional optimization approach effected by examination of parallel libraries of amino acid-based chiral ligands (e.g., 1 and 2). Thus, the facile modularity of these ligands and their ease of synthesis were further exploited towards the development of a new catalytic enantioselective method that delivers various ar-... 

The food additive carnitine (25) is worthy of mention because it has a very close structural relationship to some beta blockers. It is also called vitamin BT. There are many potential routes to this compound, including an asymmetric hydrogenation method.234 236 The method is closely related to that used for Lipitor (Section 31.2.1). Reduction of 4-chloro-3-oxobutyrate provides the desired alcohol isomer. Ester hydrolysis and reaction with triethylamine affords 25. There are two other major approaches one relies on an asymmetric microbial oxidation (Scheme 31.22).237... 

Homogeneous catalytic asymmetric hydrogenation has become one of the most efficient methods for the synthesis of chiral alcohols, amines, a and (3-amino acids, and many other important chiral intermediates. Specifically, catalytic asymmetric hydrogenation methods developed by Professor Ryoji Noyori are highly selective and efficient processes for the preparation of a wide variety of chiral alcohols and chiral a-amino acids.3 The transformation utilizes molecular hydrogen, BINAP (2,2 -bis(diphenylphosphino)-l,l -binaphthyl) ligand and ruthenium(II) or rhodium(I) transition metal to reduce prochiral ketones 1 or olefins 2 to their corresponding alcohols 3 or alkanes 4, respectively.4... 

The studies have disclosed that the GABAb receptor affinity and antagonist effect of phaclofen resides in the (/f)-enan-tiomer. ° Zheng et al. explored the synthetic utility of the Rh-catalyzed asymmetric hydrogenation method as a key step in the enantioselective synthesis of (R)-phaclofen (Scheme 29.19). Enantioselective hydrogenation of... 

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). 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

Manufacture of rhodium precatalysts for asymmetric hydrogenation. Established literature methods used to make the Rh-DuPhos complexes consisted of converting (1,5-cyclooctadiene) acetylacetonato Rh(l) into the sparingly soluble bis(l,5-cyclooctadiene) Rh(l) tetrafluoroborate complex which then reacts with the diphosphine ligand to provide the precatalyst complex in solution. Addition of an anti-solvent results in precipitation of the desired product. Although this method worked well with a variety of diphosphines, yields were modest and more importantly the product form was variable. The different physical forms performed equally as well in hydrogenation reactions but had different shelf-life and air stability. 

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

By using a mixture of ethyl acetate and D2O as solvent for hydrogenation, up to 75% deuterium is incorporated in the reduced product.13 This result indicates that the role of water here is not only as a solvent. Research on asymmetric hydrogenation in an aqueous medium is still actively being pursued. The method has been applied extensively in the synthesis of various amino acid derivatives.14... 

Itoh, N., Nakamura, M., Inoue, K. and Makino, Y. (2007) Continuous production of chiral 1,3-butanediol using immobilized biocatalysts in a packed bed reactor promising biocatalysis method with an asymmetric hydrogen-transfer bioreduction. Applied Microbiology and Biotechnology, 75 (6), 1249-1256. 

Using Ir/MeO-Biphep/l2 catalyst system, a variety of substituted quinoline derivatives were hydrogenated in 95% yield and up to 96% ee. This method provided an efficient accesss to three naturally occurring alkaloids (Scheme 17).328 Ferrocene N, P ligand 108 is also effective for the asymmetric hydrogenation of quinolines with up to 92% ee.188a... 

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). 

The current research areas with ruthenium chemistry include the effective asymmetric hydrogenation of other substrates such as imines and epoxides, the synthesis of more chemoselective and enantioselective catalysts, COz hydrogenation and utilization, new methods for recovering and recycling homogeneous catalysts, new solvent systems, catalysis in two or three phases, and the replace-... 

Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds, and Ru-BINAP-catalyzed asymmetric hydrogenation of 2-arylacrylic acids has attracted a great deal of attention,11 as the chiral 2-arylpropionic acid products constitute an important class of nonsteroidal antiinflammatory drugs. 

Burk et al. reported an asymmetric hydrogenation catalyzed by [(Et-DuPhos)Rh]+ catalyst. Very high enantioselectivity was obtained. When R = z -Pr, the minor enantiomer could not be detected by chiral GC methods. The results are shown in Scheme 6-6.24... 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

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