Asymmetric hydrogenation functionalized ketones

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. 

Asymmetric hydrogenation of ketones which have a heteroatom close to the carbonyl group has been extensively studied because of the synthetic significance of the corresponding alcoholic products [1]. The presence of the functionality accelerates and directs asymmetric hydrogenation, probably through interaction with Lewis acidic metals that effectively stabilizes the transition state. In recent years, a high catalytic activity and an excellent level of enantioselectivity have been achieved by means of chiral phosphine-Rh and -Ru complexes. 

R. Noyori and T. Ohkuma, Asymmetric Catalysis by Architectural and Functional Molecular Engineering Practical Chemo- and Stereoselective Hydrogenation of Ketones , Angew. Chem. Int. Ed. Engl, 2001, 40, 40. 

The results clearly show that these novel ligands are able to form a suitable asymmetric enviromnent around the metal resulting in high asymmetric induction. Their catalytic potential has been demonstrated in the highly enantioselective Rh-catalyzed hydrogenation of itaconates and a-enamides and Ru-catalyzed hydrogenation of p-functionalized ketone. 

Noyori, R. and Okhuma, T. (2001) Asymmetric catalysis by architectural and functional molecular engineering practical chemo- and stereoselective hydrogenation of ketones. Angewandte Chemie-International Edition, 40 (1), 40-73. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Complexes containing one binap ligand per ruthenium (Fig. 3.5) turned out to be remarkably effective for a wide range of chemical processes of industrial importance. During the 1980s, such complexes were shown to be very effective, not only for the asymmetric hydrogenation of dehydroamino adds [42] - which previously was rhodium s domain - but also of allylic alcohols [77], unsaturated acids [78], cyclic enamides [79], and functionalized ketones [80, 81] - domains where rhodium complexes were not as effective. Table 3.2 (entries 3-5) lists impressive TOF values and excellent ee-values for the products of such reactions. The catalysts were rapidly put to use in industry to prepare, for example, the perfume additive citronellol from geraniol (Table 3.2, entry 5) and alkaloids from cyclic enamides. These developments have been reviewed by Noyori and Takaya [82, 83]. 

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. 

In summary, the asymmetric hydrogenation of olefins or functionalized ketones catalysed by chiral transition metal complexes is one of the most practical methods for preparing optically active organic compounds. Ruthenium and rhodium-diphosphine complexes, using molecular hydrogen or hydrogen transfer, are the most common catalysts in this area. The hydrogenation of simple ketones has proved to be difficult with metallic catalysts. However,... 

In Figure 13.19 we have shown a route to L-699,392 published by Merck involving three steps based on homogeneous catalysts, viz. two Heck reactions and one asymmetric hydrogen transfer reaction, making first an alcohol and subsequently a sulphide [21], Stoichiometric reductions for the ketone function have been reported as well [22] and the Heck reaction on the left-hand side can be replaced by a classic condensation reaction. L-699,392 is used in the treatment of asthma and related diseases. 

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. 

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

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]. 

The procedure for getting the polymer-bound ligands is very easy to reproduce. Three jS-functionalized aromatic ketones were successfully reduced to the corresponding alcohols by heterogeneous asymmetric hydrogen transfer reaction with formic acid-triethylamine azeotrope as the hydrogen donor. One of the product alcohols (19c) is an intermediate for the synthesis of optically active fluoxetine. 

Keto esters are the best functionalized ketone substrates for enan-tioselective hydrogenation. Esters of methyl, primary, secondary, and tertiary alcohols can be used to produce hydroxy esters in high yields, with up to 100% enantioselectivity (Scheme 49) (95). The fact that methyl 2, 2-dimethyl-3-oxobutanoate is hydrogenated in high chemical and optical yields with normal asymmetric orientation implies that the reaction does not necessarily involve the enol. 

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