DKR of Allylic Acetates

It has been demonstrated that the combination of metal-catalysed racemisation and enzymatic kinetic resolution is a powerful method for the synthesis of optically active compounds from racemic alcohols and amines. There are many metal complexes active for racemisation, but the conditions for enzymatic acylation often limit the application of the metal complexes to DKR. In the case of DKR of alcohols, complementary catalyst systems are now available for the synthesis of both (R)- and (5)-esters. Thus, (R)-esters can be obtained by the combination of an R-selective lipase, such as CAL-B or LPS, and a racemisation catalyst, whereas the use of an A-selective protease, such as subtilisin, at room temperature provides (5)-esters. The DKR of alcohols can be achieved not only for simple alcohols but also for those bearing various additional functional groups. The DKR of alcohols has also been applied to the synthesis of chiral polymers and coupled to tandem reactions, producing various polycyclic compounds. 

a number of robust racemisation catalysts has been developed which are stable even under aerobic conditions during DKR. Moreover, reusable catalyst systems that are stable under ambient conditions during DKR are now also available. Palladium nanoparticles embedded on various supports are common catalysts for amine racemisation, although there are some other catalysts, such as Raney nickel and Shvo-type ruthenium complexes. The DKR of amines is possible for aliphatic amines as well as for benzylic ones. Moreover, 

In order to compete with conventional processes for producing optically active compounds, the efficiencies of racemisation catalysts need to be enhanced substantially. In particular, the catalysts for the racemisation of amines need to be improved to enable DKR to proceed under ambient conditions. Besides the catalytic activity, recyclability is another essential factor for future catalysts. Simple reaction conditions that do not require restricted atmosphere and additives, such as bases and hydrogen mediators, should be also considered. Indeed, future racemisation catalysts should be more active, selective, environmentally benign, cheap and compatible with a broad range of enzymes under conditions suitable for industrial process. With further improvements in these factors, chemoenzymatic DKR processes should find use in the industrial synthesis of optically active products in the near future. 

Kirsch, Modern Organofluorine Chemistry, Wiley-VCH, Weinheim, 

Martin-Matute and J.-E. Backvall, Tetrahedron Asymmetry, 2006,17, 708-715. 

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The first example of chemoenzymatic DKR of allylic alcohol derivatives was reported by Williams et al. [37]. Cyclic allylic acetates were deracemized by combining a lipase-catalyzed hydrolysis with a racemization via transposition of the acetate group, catalyzed by a Pd(II) complex. Despite a limitation of the process, i.e. long reaction times (19 days), this work was a significant step forward in the combination of enzymes and metals in one pot Some years later, Kim et al. considerably improved the DKR of allylic acetates using a Pd(0) complex for the racemization, which occurs through Tt-allyl(palladium) intermediates. The transesterification is catalyzed by a lipase (Candida antarctica lipase B, CALB) using isopropanol as acyl acceptor (Scheme 5.19) [38]. 

In 1996, Williams and colleagues described the first examples of DKRs based on the use of a combination of enzymes and metal catalysts, which involved a lipase-palladium combination for the DKR of allyl acetates, and a... 

In 1996, Allen and Williams demonstrated that the DKR of allylic acetates could be accomplished through coupling palladium-catalysed racemisation and enzymatic hydrolysis of allylic acetates in buffer solution. However, the DKR under these conditions was limited to cyclohexenyl acetates to yield symmetrical palladium-allyl intermediates. Among them, 2-phenyl-2-cyclohexenyl acetate was the only substrate to have been resolved with good results (81% yield, 96% ee), as shown in Scheme 4.60. 

A novel approach was developed very recently by Kita et al. [15]. DKR of allylic alcohols was performed by combining a lipase-catalyzed acylation with a racemization through the formation of allyl vanadate intermediates. Excellent yields and enantioselectivities were obtained. An example is shown in Figure 4.4. A limitation with this approach for the substrates shown in Figure 4.4 is that the allylic alcohol must be equally disubstituted in the allylic position (R = R ) since C—C single bond rotation is required in the tertiary alkoxy intermediate. Alternatively, R or R can be H if the two allylic alcohols formed by migration of the hydroxyl group are enantiomers (e.g. cyclic allylic acetates). 

We discovered that cymene-ruthenium catalysts 3a-c were effective catalyst systems for facile DKR of secondary alcohols at 40 °C. This catalyst system was particularly useful for the DKR of allylic alcohols [18], which underwent smoothly at room temperature to provide the corresponding chiral acetates with excellent optical purities (Scheme 1.16). This work has for the first time demonstrated that DKR can be performed at room temperature. 

The Akai group S5nithesized (R)-imperanene by employing the DKR of allylic alcohol as the key step. In this synthesis, racemic alcohol intermediate rac-17 was converted to its enantiomeric acetate (S)-28 via the DKR, which was performed using lipase PS-IM and oxovanadium catalyst immobilized inside mesoporous silica (V-MPS). The target molecule of >99% ee was then obtained via four steps (Scheme 5.44) [66]. 

The chiral synthesis of allylic alcohols has been the focus of many research works due to the high versatility of these molecules in the preparation of many active com-poimds [58,82], Allen and Williams reported the first example of DKR of allylic alcohols via lipase-palladium catalyst coupling deracemization of cyclic allylic acetates [83]. However, the accumulation of secondary products, as well as the long reaction times required, limited the use of this strategy. 

In 2002, a novel aminocyclopentadienyl ruthenium chloride complex was introduced by Park s group involving a new mode of catalytic racemisation which allowed use of the more reactive isopropenyl acetate as an acyl donor and much less lipase. This catalytic system was particularly efficient for the DKR of various aliphatic or aromatic alcohols as shown in Scheme 4.9. Not only simple alcohols, but also functionalised alcohols such as allylic alcohols, alkynyl alcohols, diols, hydroxyl esters and chlorohydrins were successfully transformed into the corresponding chiral acetates. ... 

Scheme 4.61 Palladium-catalysed DKR of acyclic allylic acetates.

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]. 

In this case, a reaction temperature of 50°C was needed to increase the racemization rate of the substrate and achieve an efficient DKR. Ru catalyst 3a in combination with CAL-B or subtilin Carlsberg has been used to carry out the DKR of the allylic alcohol rac-49, which is a precursor of the pharmacologically important 2-arylpropionic acids. Bearing in mind that these two enzymes display opposite stereopreference, both enantiomers could be prepared. Scheme 57.12 shows the reaction conditions. DKR with CAL-B was conducted at 80°C to obtain an acceptable rate of product formation, the corresponding acetate (R)-50... 

DKR reactions were performed with lipase and Pd(PPh3)4 in the presence of dppf and 2-propanol in THF. 2-Propanol was used as an acyl acceptor. Various acyclic allyhc acetates were transformed to their corresponding allylic alcohols at room temperature in good yields and excellent optical purities (Table 16). 

In 2004, Krische and colleagues demonstrated that exposure of Morita-Baylis-Hillman acetates to tertiary phosphine catalysts in the presence of 4,5-dichlorophthalimide enabled regiospecific allylic substitution through a tandem Sn2 -Sn2 mechanism. Through the use of the chiral phosphine catalyst, (i )-Cl-MeO-BIPHEP, the racemic Morita-Baylis-Hillman acetate depicted in Scheme 2.108 was converted into the corresponding enantiomerically enriched allylic amination product, thus establishing the feasibility of DKR. 

The group also found that cymene ruthenium complexes, depicted in Scheme 4.6, were also active for the racemisation of alcohols in the presence of TEA. As shown in Scheme 4.6, a noticeable feature of these catalysts was their high activity towards allylic alcohols, since their DKR was possible even at room temperature by using PS-C and p-chlorophenyl acetate as the acyl donor. 

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