Ruthenium racemization

D KR of allylic alcohols can be also performed using ruthenium complexes for the racemization that occurs through hydrogen transfer reactions (vide infra) [16]. 

The research group of Backvall employed the Shvo s ruthenium complex (1) [21] for the racemization. This complex is activated by heat. For the KR they used p-chlorophenyl acetate as the acyl donor in combination with thermostable enzymes, such as CALB [20] (Figure 4.7). This was the first practical chemoenzymatic DKR affording acetylated sec-alcohols in high yields and excellent enantioselectivities. In the best case 100% conversion (92% isolated yield) with 99% ee was obtained. This method was subsequently applied to a variety of different substrates and it is employed (with a different ruthenium complex) by the Dutch company DSM for the large-scale production of (R)-phenylethanol [22]. 

Kim and Park subsequently reported that ruthenium precatalyst (2) racemizes alcohols svithin 30 minutes at room temperature [23]. However, when combined... 

Sheldon et al. have combined a KR catalyzed by CALB with a racemization catalyzed by a Ru(II) complex in combination with TEMPO (2,2,6,6-tetramethylpi-peridine 1-oxyl free radical) [28]. They proposed that racemization involved initial ruthenium-catalyzed oxidation of the alcohol to the corresponding ketone, with TEMPO acting as a stoichiometric oxidant. The ketone was then reduced to racemic alcohol by ruthenium hydrides, which were proposed to be formed under the reaction conditions. Under these conditions, they obtained 76% yield of enantiopure 1-phenylethanol acetate at 70° after 48 hours. 

Racemization of amines is difficult to achieve and usually requires harsh reaction conditions. Reetz et al. developed the first example of DKR of amines using palladium on carbon for the racemization and CALB for the enzymatic resolution [35]. This combination required long reaction times (8 days) to obtain 64% yield in the DKR of 1-phenylethylamine. More recently, Backvall et al. synthesized a novel Shvo-type ruthenium complex (S) that in combination with CALB made it possible to perform DKR of a variety of primary amines with excellent yields and enantioselectivities (Figure 4.13) [36]. 

Figure 6.3 Racemization of a secondary alcohol in the presence of a ruthenium hydrogen-transfer catalyst.

Scheme 5.11 Dynamic kinetic resolution of alcohol 18 by combination of enzymatic transesterification and ruthenium-catalyzed racemization.

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

In an effort directed at developing a racemization catalyst which works uniformly for all the substrates at room temperature, we designed and synthesized a novel aminocyclopentadienyl ruthenium chloride complex 5. The DKR of aromatic as well as aliphatic alcohols could be conducted at room temperature. In case of aromatic alcohols, the substituent effects were found insignificant in the DKR however, aromatic alcohols have comparatively faster conversion rates than their ahphatic counterparts. This is the first ever report of a catalyst... 

The (5 )-selective DKR of alcohols with subtilisin was also possible in ionic liquid at room temperature (Table 14). " In this case, the cymene-ruthenium complex 3 was used as the racemization catalyst. In general, the optical purities of (5 )-esters were lower than those of (R)-esters described in Table 5. 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

Interestingly, for the transformation of both the racemic 1-hydroxyalkanephosphonates 41 and 2-hydroxyalkanephosphonates 43 into almost enantiopure acetyl derivatives 42 and 44, respectively, a dynamic kinetic resolution procedure was applied. Pamies and BackvalP used the enzymatic kinetic resolution in combination with a ruthenium-catalysed alcohol racemization and obtained the appropriate O-acetyl derivatives in high yields and with almost full stereoselectivity (Equation 25, Table 5). It should be mentioned that lowering... 

Catalytic oxidant.1 In combination with N-methylmorpholine N-oxide (7,244) as the stoichiometric oxidant, this ruthenium compound can be used as a catalytic oxidant for oxidation of alcohols to aldehydes or ketones in high yield in CH2C12 at 25°. Addition of 4A molecular sieves is generally beneficial. Racemization is not a problem in oxidation of alcohols with an adjacent chiral center. Tetrabutylammonium perruthenate can also be used as a catalytic oxidant, but the preparation is less convenient. 

Ursini, C.V., Dias, G.H.M. and Rodrigues, J.A.R., Ruthenium-catalyzed reduction of racemic tricarbonyl( 7 -aryl ketonejchromium complexes using transfer hydrogenation a simple alternative to the resolution of planar chiral organometallics. J. Organomet. Chem., 2005,690, 3176. 

The enantioselective oxidative coupling of 2-naphthol itself was achieved by the aerobic oxidative reaction catalyzed by the photoactivated chiral ruthenium(II)-salen complex 73. 2 it reported that the (/ ,/ )-chloronitrosyl(salen)ruthenium complex [(/ ,/ )-(NO)Ru(II)salen complex] effectively catalyzed the aerobic oxidation of racemic secondary alcohols in a kinetic resolution manner under visible-light irradiation. The reaction mechanism is not fully understood although the electron transfer process should be involved. The solution of 2-naphthol was stirred in air under irradiation by a halogen lamp at 25°C for 24 h to afford BINOL 66 as the sole product. The screening of various chiral diamines and binaphthyl chirality revealed that the binaphthyl unit influences the enantioselection in this coupling reaction. The combination of (/f,f )-cyclohexanediamine and the (R)-binaphthyl unit was found to construct the most matched hgand to obtain the optically active BINOL 66 in 65% ee. 

Many different metal catalysts have been explored for racemization of secondary alcohols. Among them, ruthenium-based organometallic complexes have been most intensively tested as the racemization catalyst (Figure 1.1). 

These ruthenium catalysts catalyze the racemization of secondary alcohol through a dehydrogenation/hydrogenation cycle with or without releasing ketone as a byproduct (Scheme 1.5). Catalysts 6-9 display good activities at room temperature, while others show satisfactory activities at elevated temperatures. Catalyst 1, for example, requires a high temperature (70 °C) for dissociation into two monomeric species (la and lb) acting as racemization catalysts (Scheme 1.6). 

Most ruthenium catalysts except 8 and 9 are highly sensitive to oxygen or air and must be used under anaerobic conditions. The latter can be used under aerobic conditions. Currently, no rationale is available for explaining the difference in stability between these mthenium catalysts. In general, racemizations by these catalysts take place more rapidly with benzylic alcohols compared to non-benzylic or aliphatic alcohols. 

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