DKR of Secondary Alcohols with Racemization Catalyst

However, the procedure has some drawbacks to overcome. First, it requires an elevated temperature (70 °C) for the activation of the racemization catalyst Such a high temperature is unacceptable for thermally less-stable enzymes. Second, the racemization proceeds through a mechanism including the release of ketone as a byproduct and thus the lowering of yield is inevitable. Third, PCPA used in an 

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The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

DKR of secondary alcohol is achieved by coupling enzyme-catalyzed resolution with metal-catalyzed racemization. For efficient DKR, these catalyhc reactions must be compatible with each other. In the case of DKR of secondary alcohol with the lipase-ruthenium combinahon, the use of a proper acyl donor (required for enzymatic reaction) is parhcularly crucial because metal catalyst can react with the acyl donor or its deacylated form. Popular vinyl acetate is incompatible with all the ruthenium complexes, while isopropenyl acetate can be used with most monomeric ruthenium complexes. p-Chlorophenyl acetate (PCPA) is the best acyl donor for use with dimeric ruthenium complex 1. On the other hand, reaction temperature is another crucial factor. Many enzymes lose their activities at elevated temperatures. Thus, the racemizahon catalyst should show good catalytic efficiency at room temperature to be combined with these enzymes. One representative example is subtilisin. This enzyme rapidly loses catalytic activities at elevated temperatures and gradually even at ambient temperature. It therefore is compatible with the racemization catalysts 6-9, showing good activities at ambient temperature. In case the racemization catalyst requires an elevated temperature, CALB is the best counterpart. 

DKR of Secondary Alcohols with Air-Stable Racemization Catalysts... 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

DKR requires two catalysts one for resolution and one for racemization. We and others have developed a novel strategy using enzyme as the resolution catalyst and metal as the racemization catalyst as shown in Scheme 1. The R-selecfive DKR can be achieved by combining a R-selective enzyme with a proper metal catalyst and its counterpart by the combination of the metal catalyst with a -selective enzyme. This strategy has been demonstrated to be applicable to the DKR of secondary alcohols, allylic esters, and primary amines. Among them, the DKR of secondary alcohols has been the most successful. 

Later, in a modification to the above system, we reported the use of an indenylruthenium complex 2 as a racemization catalyst for the DKR of secondary alcohols, which does not require ketones but a weak base hke triethylamine and molecular oxygen to be achvated. The DKR with 2 in combination with immobilized Pseudomonas cepacia lipase (PCL, trade name. Lipase PS-C ) was carried out at a lower temperature (60°C) and provided good yields and high optical purities (Table 2). This paved the way for the omission of ketones as... 

All the Ru-based racemization catalysts described earUer are air-sensitive and thus difficult to reuse. We found that a modified Ru complex 7 was air-stable and recyclable, in particular, in a polymer-supported form 8. The racemization of secondary alcohols with 7 took place equally well under both oxygen and argon atmospheres. The subsequent DKRs of several alcohols using 7 or 8 under aerobic... 

The first use of a metal catalyst in the DKR of secondary alcohols was reported by Williams et al. [7]. In this work, various rhodium, iridium, ruthenium and aluminum complexes were tested. Among them, only Rh2(OAc)4 and [Rh(cod)Cl]2 showed reasonable activity as the racemization catalyst in the DKR of 1-phenylethanol. The racemization occurred through transfer-hydrogenation reactions and required stoichiometric amounts of ketone as hydrogen acceptor. The DKR of 1-phenylethanol performed with Rh2(OAc)4 and Pseudomonas Jluore-scens lipase gave (R)-l-phenylethyl acetate of 98%e.e. at 60% conversion after 72 h. 

Following on from this initial publication of Backvall, many groups have reported on a variety of ruthenium-based systems for the DKR of secondary alcohols [9-17] mainly with the goal of eliminating the need for added base and ketone and reducing the reaction time by increasing the rate of racemization. Some examples of ruthenium complexes (1-8) which have been used as the racemization catalysts in these systems are depicted in Fig. 9.5. 

Some of these catalyze the smooth racemization of chiral secondary alcohols at room temperature. However, a major problem which needed to be solved in order to design an effective combination of ruthenium catalyst and lipase in a DKR of secondary alcohols was the incompatibility of many of the ruthenium catalysts and additives, such as inorganic bases, with the enzyme and the acyl donor. For example, the ruthenium catalyst may be susceptible to deactivation by the acetic acid generated from the acyl donor when it is vinyl acetate. Alternatively, any added base in the racemization system can catalyze a competing selective transesterification of the alcohol, resulting in a decrease in enantioselectivity. Consequently, considerable optimization of reaction protocols and conditions was necessary in order to achieve an effective DKR of secondary alcohols. 

In 2002, we reported that monomeric Ru catalyst 5 had a good racemization activity at room temperature and excellent compatibility with isopropenyl acetate [23]. We thus accomplished the first DKR of secondary alcohols, at room temperature by combining 5 with Novozym 435 or lipase PS-C in the presence of isopropenyl acetate (Scheme 5.15). A wide range of secondary alcohols including simple alcohols, allylic alcohols, alkynyl alcohols, diols, hydroxyl esters, and chlorohydrins were transformed to their acetates with good delds and excellent enantiomeric excesses in the DKR using 5 (Chart 5.12) [24]. 

The Fu group has reported the first nonenzymatic DKR of secondary alcohols [41]. In this DKR, a planar-chiral DMAP derivative ((+)-Cg-Phg-DMAP) as the resolution catalyst was coupled with a Ru complex 6 as the racemization catalyst in the presence of an acyl carbonate (Scheme 5.25). The DKR of simple secondary alcohols provided good )delds but lower enantiopurities compared to the enzymatic DKRs. It is noteworthy that the DKR of sterically more demanding substrates carr3dng a branched side chain (isopropyl or cyclopentyl) also provided similarly good results (Chart 5.25). 

Several chiral drugs were synthesized as examples of the synthetic applications of metalloenzymatic DKR. The Backvall group reported the synthesis of (S)-Me-imida-cloprid (15), an insect neurotoxin, including the DKR of secondary alcohol as the key step [63]. In this synthesis, to obtain enantiopure secondary alcohol (R)-13 as a key intermediate, the DKR of its racemic form was carried out with CAL-B (Novozym 435), Ru catalyst 6, and isopropenyl acetate as the acyl donor followed by hydrolysis. Then (R)-13 was converted to the target (98% ee) via two more steps in the overall 32% yield (Scheme 5.40). 

The KR of secondary alcohols by some hydrolytic enzymes has been well known. The combinations of these hydrolytic enzymes with racemization catalysts have been explored as the catalysts for the efficient DKR of the secondary alcohols. Up to now, lipase and subtilisin have been employed, respectively, as the R- and 5-selective resolution enzymes in combination with metal catalysts (Scheme 2). 

Other examples include OKR of racemic secondary alcohols (Scheme 25A), oxidative desymmetrizations of meso-diols, etc. The kinetic resolution is generally defined as a process where two enantiomers of a racemic mixture are transformed to products at different rates. Thus, one of the enantiomers of the racemate is selectively transformed to product, whereas the other is left behind. This method allows to reach a maximum of 50% yield of the enantiopure remaining sec-alcohol. To overcome this fim-itation, a modification of the method, namely dynamic kinetic resolution (DKR), was introduced. In this case, the kinetic resolution method is combined with a racemization process, where enantiomers are interconverted while one of them is consumed (e.g., by esterification. Scheme 25B). Therefore, a 100% theoretical yield of one enantiomer can be reached due to the constant equifibrium shift. In most of the proposed DKR processes, several catalytic systems, e.g., enzymes and transition-metal catalysts, work together. Both reactions (transfer hydrogenation of ketones and the reverse oxidation of secondary alcohols using ketone as a hydrogen acceptor) can be promoted by a catalyst. The process can involve a temporary oxidation of a substrate with hydrogen transfer to a transition-metal complex. 

It was found that the Ru catalyst 11 displayed a good racemization activity under household fluorescent light [37]. Its activity was comparable to those of 5 and 6. The DKR of simple secondary alcohols with 11 and Novozym 435 gave products of excellent enantiopurity with high yields (Scheme 5.21). 

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