Enantioselective hydrogenation of ketones

The groups of Marinetti and Genet have shown that several bisphosphetane-derived ligands (58, 59, 61) form effective Ru-based catalysts for the hydrogena- 

Finally, the group of Zhou has recently published the first Pd-catalyzed enantiomeric reduction of ketones using Me-DuPhos [197]. By performing the reaction in TFE, a series of a-phthalimido ketones 140 were reduced in high yield and 75-92% ee, albeit at high catalyst loadings (SCR 50), reaction times (12 h) and pressures (13.7 atm). This procedure was extended to include ketones 134 (R=Ph, R = Et), 139 (Ar=Ph), and 141. 

Enantiomerically pure amines are extremely important building blocks for biologically active molecules, and whilst numerous methods are available for their preparation, the catalytic enantioselective hydrogenation of a C=N bond potentially offers a cheap and industrially viable process. The multi-ton synthesis of (S)-metolachlor fully demonstrates this [108]. Although phospholane-based ligands have not proven to be the ligands of choice for this substrate class, several examples of their effective use have been reported. 

Indeed, the imine intermediate 142 in the synthesis of metolachlor has been reduced in 97% ee using an iridium complex of the phospholane-containing ligand 55 [80]. 

A trons-[RuCl2(diphosphine)(l,2-diamine)] complex with (R,R)-Et-DuPhos and (R,R)-l,2-diaminocyclohexane as the ligand combination has been found to be effective for the hydrogenation of imine 143, with up to 94% ee being obtained under the standard basic conditions employed for this catalytic system [198]. Unfortunately, the optimum combination of chiral diphosphine and diamine was found to be substrate-dependent, with only 40% ee being obtained for 2-methylquinoxaline 144 with Et-DuPhos. 

Homogeneous enantioselective hydrogenation of ketones has been first carried out with the ionic complexes of Schrock and Osborn using chiral phosphines like BMPP, EMPP, DIOP, etc., but the optical yields were rather low. By preparing the catalyst with the same chiral phosphines in situ, the optical selectivity (which is determined in this case by the covalent and ionic complexes present simultaneously) was improved considerably. RhClP2 and RhPa type intermediates are regarded to be responsible for this effect. 

Many of the chiral bidentate phosphines synthesized in the last years have also been tested for enantioselective ketone reduction. Some of the results achieved are compiled in Table 2. The influence of phosphine structure on optical selectivity and catalytic activity is considerable, but a reliable correlation could not yet be found. It seems that chiral bidentate 6w(diphenyl)phosphines, like prophos forming 5-membered chelate rings with the rhodium atom and used with great success for the hydrogenation of dehydroaminoacids, are not suitable for ketone reduction because of very low reaction rates. 

Optical selectivity in these reactions is obviously strongly depending also on the structure of the substrate. It has been generally observed that enantioselectivity is higher in the case of alkyl-aryl ketones than with dialkyl ketones. 

First results with polymer-supported rhodium(I) chiral diphosphine complexes were published by Ohkubo, but the optical selectivity reported was rather moderate (7.7% e.e.). Chiral ruthenium catalysts have also been successfully used, and the results were compiled in a review published in 1981.  

Only little information is available on asymmetric ketone reduction using hydrogen transfer. With secondary alcohols or indoline as hydrogen donors, optical yields up to 9.9% were obtained in the presence of H4Ru4(CO)8[(-)DIOP]2 as a catalyst. Iridium compounds like [Ir(C0D)(PPEI)] C104 proved to be more enantioselective in the presence of Reducing propiophenone 30% e.e. was observed at 50% 

Polymer-supported Ru precatalysts were prepared from the polymeric chiral 

2- diamines and the RUCI2/BINAP complex [116]. Polymer-supported chiral 1,2-diamines were prepared by using either a polymer-reaction method or a polymerization method [117]. The polymer-reaction method involved the reaction of chiral 

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L = P(CH3)3 or CO, oxidatively add arene and alkane carbon—hydrogen bonds (181,182). Catalytic dehydrogenation of alkanes (183) and carbonylation of bensene (184) has also been observed. Iridium compounds have also been shown to catalyse hydrogenation (185) and isomerisation of unsaturated alkanes (186), hydrogen-transfer reactions, and enantioselective hydrogenation of ketones (187) and imines (188). 

Chitosan (Fig. 27) was deposited on sihca by precipitation. The palladium complex was shown to promote the enantioselective hydrogenation of ketones [80] with the results being highly dependent on the structure of the substrate. In the case of aromatic ketones, both yield and enantioselectiv-ity depend on the N/Pd molar ratio. Low palladium contents favored enan-tioselectivity but reduced the yield. Very high conversions were obtained with aliphatic ketones, although with modest enantioselectivities. More recently, the immobilized chitosan-Co complex was described as a catalyst for the enantioselective hydration of 1-octene [81]. Under optimal conditions, namely Co content 0.5 mmolg and 1-octene/Co molar ratio of 50, a 98% yield and 98% ee were obtained and the catalyst was reused five times without loss of activity or enantioselectivity. 

Whereas general activities and selectivities for hydrogenations of ketones are similar to those of aldehydes, one big difference exists between the two. The hydrogenation of prochiral ketone carbonyls produces chiral carbons. Over symmetrical catalysts, racemic alcohols are formed however, over unsymmet-rical surfaces, enantioselectivity may occur. Enantioselective hydrogenations of ketones is an increasingly active research held and is covered in Chapter 3. Here we discuss that aspect of stereoselectivity associated with ring systems. 

The concerted delivery of protons from OH and hydride from RuH found in these Shvo systems is related to the proposed mechanism of hydrogenation of ketones (Scheme 7.15) by a series of ruthenium systems that operate by metal-ligand bifunctional catalysis [86]. A series of Ru complexes reported by Noyori, Ohkuma and coworkers exhibit extraordinary reactivity in the enantioselective hydrogenation of ketones. These systems are described in detail in Chapters 20 and 31, and mechanistic issues of these hydrogenations by ruthenium complexes have been reviewed [87]. 

The enantioselective hydrogenation of ketones which have two heteroatoms on both sides of the carbonyl group tends to give lower enantioselectivity due to the competitive interaction of the functionalities with the catalyst. The extent depends... 

The asymmetric synthesis of allenes via enantioselective hydrogenation of ketones with ruthenium(II) catalyst was reported by Malacria and co-workers (Scheme 4.11) [15, 16]. The ketone 46 was hydrogenated in the presence of iPrOH, KOH and 5 mol% of a chiral ruthenium catalyst, prepared from [(p-cymene) RuC12]2 and (S,S)-TsDPEN (2 equiv./Ru), to afford 47 in 75% yield with 95% ee. The alcohol 47 was converted into the corresponding chiral allene 48 (>95% ee) by the reaction of the corresponding mesylate with MeCu(CN)MgBr. A phosphine oxide derivative of the allenediyne 48 was proved to be a substrate for a cobalt-mediated [2 + 2+ 2] cycloaddition. 

The Rh complex of PennPhos (XIII) is a good catalyst for highly enantioselective hydrogenation of ketones, and acetophenone (99) was hydrognated to. vcc-phenethyl alcohol (100) with 95% ee in 97% yield in the presence of 2,6-lutidine as an important additive [63]. 

An interesting asymmetric activation of Ru complexes for enantioselective hydrogenation of ketones has been observed [65], Hydrogenation of 2,4,4-trimethyl-2-cyclohexenone using racemic RuCl2 (tolbmap)(dmf)n, (5,5)-DPEN and KOH (1 1 2) afforded the alcohol 107 with 95% ee in 100% yield. When (R)-TolBINAP and (S,S)-DPEN were used, the alcohol 107 with 96% ee was obtained. On the other hand, only... 

Mikami, M., Korenaga, T., Ohkuma, T., and Noyori, R. 2000. Asymmetric activation/ deactivation of racemic Ru catalysis for highly enantioselective hydrogenation of ketonic substrates. Angew. Chem. Int. Ed., 39, 3707-3710. 

Fig. 6.23. Use of temporary auxiliary in the enantioselective hydrogenation of ketones which enhances the enantioselectivity to nearly 100% enantiomeric excess.

Scheme 9.11 Programmed assembly of MOCP 18 for immobilization of Noyori s catalyst and the enantioselective hydrogenations of ketones.

Scheme 10.2 The Orito reaction enantioselective hydrogenation of ketone over CD- or CN-modified Pd/C...

Another example worth mentioning is catalytic enantioselective hydrogenation of ketones. This reaction over non-chiral catalysts when a ketone contains a prochiral center produces racemic mixtures of optical isomers. The kinetics of 1 -phenyl-1,2-propanedione hydrogenation was studied in the presence of a chiral modifier -natural alkaloid cinchonidine (Figure 7.7)... 

Additional catalyst development identified the positive effect of 1,2-diamines as additives in the (BlNAP)Ru(OAc)2-catalyzed enantioselective hydrogenations of ketones [24], This discovery ultimately led to the synthesis of a class of (diphosphine) Ru(diamine)X2 (X = H, halide) compounds [25] (Figure 4.1) which have emerged as some of the most active and selective hydrogenation catalysts ever reported [26]. Mechanistic studies by Noyori [14] and Morris [27] have established bifunctional hydrogen transfer to substrate from the cis Ru-H and N-H motifs and identified the importance of ruthenium hydridoamido complexes for the heterolytic splitting of H2. This paradigm allows prediction of the absolute stereochemistry of the chiral alcohols produced from these reachons. 

Table 3. Enantioselective Hydrogenation of Ketones in Different Solvents...

Scheme 7.12 Ru-catalysed enantioselective hydrogenation of ketones (27) and P-keto...

Complexes of primary and secondary amines can serve as reactive ligands. For example, 1,2-diamines have acted in a hybrid fashion on catalysts for enantioselective hydrogenation of ketones and imines, serving a role in both controlling structure and delivering the hydrogen to the ketone or imine, as shown schematically in Figure 2.38. " ... 

Leyssens, T. Peeters, D. Harvey, J. N. Origin of enantioselective hydrogenation of ketones by RuH2(diphosphine)(diamine) catalysts A theoretical study. Organometallics 2008, 27, 1514-1523. 

Both (RJi) and (S,S) enantiomers of ethylenebis(rf-tetrahydroindenyl)titanium difluoride (EBTHI)TiF2, were developed by Buchwald et al. and used in many efficient enantioselective hydrogenations of ketones [15] and imines [16]. The utility of this process was demonstrated in the enantio- and diastereo-selective preparation of sertraline according to Scheme 7.2. The enantioselectivity and yield in this reaction ranged between 90 and 96% e.e. and 40-50%, respectively. The yield is based on the racemic 5, and amounts to 76-96% when based on the (4S)-enantiomer. Workup in this reaction requires chromatographic separation of (15,45 )-1, from the (4i )-ketone 4. Later, in Sect. 7.5.4, we shall discuss an independent research project that resulted in the efficient recycling of the wrong enantiomer of this ketone. 

In more complicated cases of kinetic modeling, not only enantioselectivity, but also regioselectivity should be considered. In catalytic enantioselective hydrogenation of ketones such as 1-phenyl-1,2-propanedione, a range of products can be formed (Fig. 7.19)... 

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