Asymmetric Hydrogenations of Functionalized Ketones

One application of this hydrogenation with the structurally related 4,4-dimethyl-2, 3-furandione is shown in Equation 15.53. This a-ketoester undergoes hydrogenation with a neutral rhodium catalyst containing the bpm ligand shown in this equation with spectacularly high turnover numbers and good enantioselectivity. This product is used by Roche in the synthesis of pantothenic acid, a B-vitamin used for the synthesis of coenzyme 

This type of dynamic kinetic resolution has been conducted on a production scale by the Takasago Company. - [Ru(cymene)yj, in combination with Tol-BINAP, generates a catalyst for the hydrogenation of a p-keto ester containing an amidomethyl group on the central carbon (Equation 15.58). The product of this reaction is used for the synthesis of carbapanen antibiotics. This hydrogenation has been reported to be conducted on the scale of 50-120 tons per year. 

Other hydrogenations of p-keto esters are also conducted on production scales. MSC Technologies and Lanxess conduct these reactions with BINAP and a BIPHEP derivative as ligand. The reactions with BINAP typically occur with turnover numbers of 10,000-20,000 and frequencies of 12,000 h k 

Such dynamic kinetic resolutions can also be conducted on cyclic jS-keto esters. Two examples are shown in Equations 15.59 and 15.60. Such cyclic substrates contain a stereocenter at the carbon between the two carbonyl groups. Again, a dynamic kinetic resolution of these substrates by hydrogenation occurs selectively to form predominantly a single stereoisomer. This reaction occurs to form a 99 1 ratio of diaste-reomers and 93% enantioselectivity of the major diastereomer in the presence of a ruthenium-BINAP catalyst. The positions of the keto and ester functionalities can also be reversed. Reduction of the cyclic p-keto ester in Equation 15.60 generates, in this case, the cis diastereomer with high diastereoselectivity and enantioselectivity.  

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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. 

In contrast to their success in the asymmetric hydrogenation of functionalized ketones, BINAP-Ru catalysts fail to give good results with simple ketone because such substrates lack heteroatoms that enable the substrate to anchor strongly to the Ru metal. 

Figure 1.13. Asymmetric hydrogenation of functionalized ketones catalyzed by BINAP-Ru complexes.

Despite fruitful results of asymmetric hydrogenation of functionalized ketones, only limited examples have been reported for reaction of ketonic substrates with no functionality near the carbonyl group [1,162,254]. Transition-metal catalysts with a bidentate chiral phosphine, successfully used for functionalized ketones, are often ineffective for reduction of simple ketones in terms of reactivity and enantioselectivity [162b,c]. However, a breakthrough in this subject has been provided by the invention of a new chiral Ru catalyst system. 

Asymmetric reduction The ruthenium(II)-BINAP catalysts developed by Noyori s group in 1980s were the most successful for the asymmetric hydrogenation of functionalized ketones such as a-ketoesters, a-hydroxyketones and a-aminoketones because the second... 

Kitamura, M., Tokunaga, M., Ohkuma, T., Noyori, R. Convenient preparation of BINAP-ruthenium(ll) complexes for catalyzing the asymmetric hydrogenation of functionalized ketones. Tetrahedron Lett. 1991, 32, 4163-4166. 

Blanc, D., Henry, J.-C., Ratovelomanana-Vidal, V., and Genet, J.-P, Skewphos-RufB). An efficient catalyst for asymmetric hydrogenation of functionalized ketones. Tetrahedron Lett., 38, 6603, 1997. 

The asymmetric hydrogenation of functionalized ketones may also be performed in the presence of neutral Rh(I) complexes bearing 3.36 (R = c-CgHj j) as a ligand [114, 859,1136-1139]. (i )-Pantolactone 1.16 is obtained from 6.7 with a high enantiomeric excess by this method. Methyl glyoxylate (MeCOCOOMe) is also transformed into the corresponding (R)-alcohol. 

Ketone reductions. For the asymmetric hydrogenation of functionalized ketones, a team led by Noyori in Nagoya and Akutagawa in Tokyo introduced ruthenium(II) BINAP catalysts that produce excellent enantioselectivities for a number of functionalized ketones [69-75] (review [76] for a recent reference to a more reactive catalyst see ref. [77]). The topicity of the reduction is illustrated in Scheme... 

Kitamura M, Ohkuma T, Inoue S, Sayo N, Kumobayashi H, Akutagawa S, Ohta R, Takaya H, Noyori R. Homogeneous asymmetric hydrogenation of functionalized ketones. J. Am. Chem. Soc. 1988 110 629-631. 

Although Ru(OCOCH3)2(binap) exhibits excellent catalytic performance on asymmetric hydrogenation of functionalized olefins, it is feebly active for reaction of ketones. This failure is due to the property of the anionic ligands. Simple replacement of the carboxylate ligand by halides achieves high catalytic activity for reaction of functionalized ketones. 

The asymmetric hydrogenation of unfunctionalized ketones is a much more challenging task than that of functionalized ketones [3 j, 115]. Many chiral catalysts which are effective for functionalized ketones do not provide useful levels of enantioselectivity for unfunctio-nalized ketones, due to a lack of secondary coordination to the metal center. Zhang demonstrated the enantioselective hydrogenation of simple aromatic and aliphatic ketones using the electron-donating diphosphane PennPhos, which has a bulky, rigid and well-defined chiral backbone, in the presence of 2,6-lutidine and potassium bromide [36]. 

Keto Esters Asymmetric transfer hydrogenation of functionalized ketones is rare. However, an excellent optical yield is obtainable inreduction of methyl benzoylformate by using 2-propanol and with a catalyst system consisting of [RhCl(C6H]0)]2, (S,S)-DMDPEN, and KOH (Scheme 1.89) [313],... 

K. Evetraere, J.-F. Carpentier, A. Morteux, and M. Bulliard, N-Benzoyl-norephedrine derivatives as new, effident ligands for ruthenium-catalyzed asymmetric transfer hydrogenation of functionalized ketones, Tetrahedron Asymm. 1999, 10, 4083 4086. 

A considerable success has been realized for asymmetric hydrogenation of functionalized alkenes since the discovery of BINAP-Ru complexes in the mid-1980s [5]. The details are described in each of the following substrates, enamides, alkenyl esters and ethers, a,/3- and /3,y-unsaturated carboxylic acids, a,/3-unsaturated esters and ketones, and allylic and homoallylic alcohols. 

Unlike most rhodium homogeneous catalysts, the ruthenium(BlNAP) series is very effective for the asymmetric hydrogenation of functional ketones48. This leads to a number of experimental circumstances where the directing effect of substituents is brought into play. One of the most commonly used examples of asymmetric ketone hydrogenation is that of /1-keto esters. Diketone reduction with ruthenium[(5)-BINAP] demonstrates the high enantiomeric purity due to double asymmetric induction. 

As noted previously, one of the most dramatic advances in asymmetric hydrogenation over the past tu o decades has been the development of ruthenium catalysts for the hydrogenation of ketones. Tltese hydrogenations can be divided into the hydrogenation of "functionalized" ketones and "unfunctionalized" ketones. "Functionalized" ketones... 

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... 

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