Ketone functionalized

The reactivity of achiral Ru compounds for the hydrogenation of functionalized ketones has not been extensively studied. RuCl2 P(C6H5)3 3 reduces y-keto carboxylic acid at 180 °C to the corresponding y-lactone (Eq. 2.15) [115]. Heterogeneous Ru/C catalyzes the atmospheric pressure hydrogenation of furfural in water at 25 °C [86]. Under such mild conditions, glucose is industrially converted to sorbitol (Eq. 2.16) [116]. At elevated temperature and pressure, tetramethyl-l,3-cyclobutanedione can be converted to a 98 2 diastereomer mixture of the diol (Eq. 2.17) [117]. 

In contrast, many chiral phosphine-metal complexes have been investigated in the enantioselective hydrogenation of functionalized ketones because of the synthetic significance of the corresponding alcoholic products [5]. A high catalytic activity and an excellent level of enantioselectivity have been achieved by means of chiral phosphine-Ru complexes, as shown below. The presence of a functional group dose to the carbonyl moiety effidently accelerates the reaction and also controls the stereochemical outcome. The heteroatom-metal interaction is supposed to effectively stabilize one of diastereomeric transition states and/or key intermediates in 

Excellent enantioselectivity is also attained by the BINAP-Ru method in hydrogenation of y-keto esters and o-acylbenzoic esters, giving y-lactones and o-phthalides, respectively [146,147]. 

CH2CI2 occurs 9.8-fold faster than that of the S isomer, and the equilibration between the enantiomeric substrates is 4.4-fold faster than hydrogenation of the slow-reacting S substrate. On the other hand, hydrogenation of racemic 3-acetyltetrahy-drofuran-2-one catalyzed by the cationic (l )-BINAP-RuCl()7 -C6H6) complex gives the 3S,ri syn) alcohol in up to 97% e.e. (Eq. 2.22) [120, 158bj. A similar result is obtained by use of a tetraMe-BITIANP-Ru complex [49]. 

BINAP-Ru complexes show an excellent enantioselectivity in the hydrogenation of a-, /3-, or y-amino, -hydroxy, and -alkoxy ketones. Thus, a-dialkylamino ketones are effectively converted by (S)-BINAP-RuCl2 complexes to the chiral /3-amino alcohols with up to 99% e.e. (Eq. 2.25) [119, 120]. A normally unreactive Ru diacetate complex may be used for the hydrogenation of a-dimethylaminoacetone [119]. With a trans-RuCl2 (R)-xylbinap (R)-daipen ((R,R)-20)/KOC(CH3)3 catalyst system, a variety of a- and /3-amino ketones are hydrogenated in high optical yields [114]. Thus, a-(dimethylamino)acetone is converted to the S amino alcohol in 92% e.e. with an S/C of 2000 under 8 atm H2, whereas a-(dimethylamino)acetophenone is converted to the R alcohol in 93% e.e. with the same catalyst. The reversed sense of 

In general, addition of weak acids increases the ee but the presence of water is detrimental. The modified catalyst has higher activity and a lower activation energy than unmodified Ni [10]. It is not clear yet, however, whether the enhanced rate is because of higher dispersion of the modified (corroded) Ni particles or because of a ligand acceleration effect. Note that Ni is thermodynamically unstable under ambient conditions in the presence of oxygen, a feature which complicates not only the application but also the reliable characterization of Ni catalysts. 

Variation of the stnicture of (/ ,/ )-tartaric acid revealed that two carboxyl groups and only one OH group are crucial for enantio-differentiation (Fig.l) [11]. 

The application range of modified Raney Ni has been extended to the enantio-selective hydrogenation of other -functionalized ketones such as y0-diketones (e. g. acetylacetone, 74% ee), 4-hydroxy-2-butanone and its methyl ether (68-70% ee), and ff-ketosulfones (67-71 % ee) [11]. 

There is no agreement yet about the mechanism of enantio-differentiation over the Ni-tartrate system. According to the model suggested by Japanese scientists 

Another proposal [25] assumes the formation of a six-membered ring intermediate via H-bonding interactions (Fig. 2). It is important that the substrate is present in the keto form on the metal surface as the enol form affords the opposite enantiomer in excess. Ni-tartrate, which is believed to interact with the substrate on the metal surface, is a poor modifier it is more probable that the sodium salt provides the high ee [13]. 

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One of the more important approaches to 1-azirines involves a similar base-induced cycloelimination reaction of a suitably functionalized ketone derivative (route c. Scheme 1). This reaction is analogous to route (b) (Scheme 1) used for the synthesis of aziridines wherein displacement of the leaving group at nitrogen is initiated by a -carbanionic center. An example of this cycloelimination involves the Neber rearrangement of oxime tosylate esters (357 X = OTs) to 1-azirines and subsequently to a-aminoketones (358) (71AHC-(13)45). The reaction has been demonstrated to be configurationally indiscriminate both syn and anti ketoxime tosylate esters afforded the same product mixture of a-aminoketones... 

Although this method is aot a geaeral procedure, bemg specific for ct-nitroketoues, k has several merits to avoid the use of toxic reageuts such as organodn compounds Functionalized ketones have been prepared by this denitration reaction, in which functionalized nitroalkanes are used as alkyl anion synthons For example, 3-nitropropanal ethylene acetal can be used as synthon of the 3-oxo-propyl anion and 1,4-dicarbonyl compounds are prepared, as shovm In Eq 7 88... 

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. 

BPPM Scheme 1.17) was used as catalyst [60]. The enantioselective hydrogenation of functionalized ketones was also efficiently achieved by a series of rhodium(I) aminophosphine- and amidophosphine-phosphinite complexes [61]. 

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]. 

Bppfoh and bppfa derivatives have been applied most successfully for the Rh-catalyzed hydrogenation of dehydro amino acid derivatives such as MAC (ee 97%) and of functionalized ketones [7]. The nature of the amino group has a significant effect on enantioselectivity and often also on activity, and is used to tailor the ligand for a particular substrate. Rh-bppfa complexes were among the first catalysts able to hydrogenate tetrasubstituted C=C bonds, albeit with relatively low activity (Table 25.2, entries 2.1-2.3). Ferrophos, one of the very few li-... 

Ferrocene-based complexes have some potential for the enantioselective reduction of ketones, but compared to other ligand classes this is relatively limited [3]. Rh complexes of bppfa, bophoz and josiphos are among the most selective catalysts for the hydrogenation of a-functionalized ketones (Table 25.9 Fig. 25.18, 30-32). Ru complexes of walphos and ferrotane are quite effective for... 

Rhodium-Catalyzed Enantioselective Hydrogenation of Functionalized Ketones... 

In this chapter, we will focus on the rhodium-catalyzed hydrogenation of functionalized ketones and the development of chiral phosphorous ligands for this process. Although there are other chiral phosphorous ligands which are effective for ruthenium-, iridium-, platinum-, titanium-, zirconium-, and palladium-catalyzed hydrogenation, they will not be discussed here. For details of these chemistries, the reader should refer to other chapters of this book. 

Rhodium-Catalyzed Enantioselective Hydrogenation of Functionalized Ketones 33.3.2.2 a,y-Diketoesters... 

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. 

This asymmetric catalytic reaction has found wide application in converting functionalized ketones to the corresponding secondary alcohols with high ee. A general illustration is given in Scheme 6-32. Five- to seven-membered chelate complexes, formed by the interaction of the Ru atom with carbonyl oxygen and a heteroatom X, Y, or Z may be the key intermediates that cause the high enantioselectivity in the reaction.67... 

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,... 

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