Racemization catalysts ruthenium catalyst

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. 

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. 

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. 

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. 

We reported the use of an indenyl ruthenium complex 2 as a racemization catalyst which did not produce ketones as the byproducts [17]. The metal catalyst requires a weak base like triethylamine and molecular oxygen to be activated. The DKR with 2 in combination with an immobilized PCL was carried out at a lower temperature (60°C) to afford good yields and high optical purities (Scheme 1.15). It is noteworthy that 2 does not require ketone as hydrogen mediator for racemization. 

In an effort directed at developing a racemization catalyst that works uniformly for a wide range of substrates at room temperature, we designed and synthesized a novel aminocyclopentadienyl ruthenium chloride complex 6 [25]. The DKR of... 

Kinetic resolutions, such as the ones discussed above, are limited to a 50% yield. Consequently, the undesired enantiomer needs to be recovered, racemized, and recycled, which makes the process more complex and leads to an increased solvent use. The obvious solution is to racemize the slow-reacting enantiomer in situ. With chiral alcohols, the racemization catalysts of choice are based on ruthenium (Figure 10.17). 

Racemic resolution of a-hydroxy esters was achieved with Pseudomonas cepacia lipase (PCL) and a ruthenium catalyst (for a list, see Figure 18.13) as well as 4-chlorophenyl acetate as an acyl donor in cyclohexane, with high yields and excellent enantiomeric excesses (Huerta, 2000) (Figure 18.14). Combining dynamic kinetic resolution with an aldol reaction yielded jS-hydroxy ester derivatives in very high enantiomeric excesses (< 99% e.e.) in a one-pot synthesis (Huerta, 2001). 

Enzymatic DKRs have also been applied in domino one-pot processes [97]. The combination of a lipase-catalyzed resolution with an intramolecular Diels-Alder reaction led to interesting building blocks for the synthesis of natural products such as compactin [98,99] or forskolin [100-102], A ruthenium catalyst is employed for the racemization of the slow reacting enantiomer of the starting material. The DKR with lipase B from C. antarctica delivered high enantiomeric excesses which could mainly be contained through the Diels-Alder reaction (Fig. 12). 

An example where a transition metal catalyst is used in combination with an enzyme has been described (Scheme 19.26).207 The racemic alcohol 50 was converted to the (A1)-acetate 51, using a ruthenium catalyst along with Novozym 435 (immobilized Lipase B from Candida antarctica), 3 equivalents of p-chlorophenylacetate in t-BuOH, and 1 equivalent of 1-indanone. The reaction yield was 81% with an optical purity of >99.5% ee. 

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. 

Fig. 9.5 Ruthenium complexes used as alcohol racemization catalysts.

One place to look for good alcohol racemization catalysts is in the pool of catalysts that are used for hydrogen transfer reduction of ketones. One class of complexes that are excellent catalysts for the asymmetric transfer hydrogenation comprises the ruthenium complexes of mono sulfonamides of chiral diamines developed by Noyori and coworkers [20, 21]. These catalysts have been used for the asymmetric transfer hydrogenation of ketones [20] and imines [21] (Fig. 9.9). 

Paetzold and Backvall [27] have reported the DKR of a variety of primary amines using an analog of the ruthenium complex 1 as the racemization catalyst and isopropyl acetate as the acyl donor, in the presence of sodium carbonate at 90 °C (Fig. 9.17). Apparently, the function of the latter was to neutralize traces of acid, e.g. originating from the acyl donor, which would deactivate the ruthenium catalyst. 

The method is of general applicability in the deracemization of secondary alcohols and amines and consists of a Upase-catalyzed irreversible acylation and in situ racemization of the non-reacted enantiomer catalyzed by a ruthenium catalyst. 

Deracemization of Hydroxy Acids by DKR (Hydrolytic Enzymes + Ruthenium-based Racemization Catalysts)... 

The use of the ruthenium catalysts is advantageous since it does not need the presence of a base as a co-catalyst. The presence of a base could induce racemization of the formed acetates by enoUzation. 

Scheme 13.2 Deracemization of a-hydroxy acids by DKR (hydrolytic enzymes + ruthenium-based racemization catalyst).

In the hydrogen transfer between propan-2-ol and acetophenone catalyzed by ruthenium catalyst L 2Ru(methallyl)2 (L 2 = chiral diphosphine ligand), Genet et al. observed racemization of a-methylbenzyl alcohol 63 formed as a final product (Scheme 12.8) [28]. 

Deracemization. Enzymatic acetylation of secondaiy benzylic alcohols under racemizing conditions using a ruthenium catalyst leads to chiral esters. 

DKR involves the combination of an enantioselective enzyme (often a hydro lytic enzyme such as a lipase) with a racemization catalyst (often a transition metal catalyst such as Shvo s ruthenium based catalyst and derivatives thereof) that is compatible with the enzyme. Under these conditions, both enantiomers of the starting material are converted to the product in yields and ee s that can approach 100%. 

Racemization catalyst (8 mol%) Ruthenium cymene complex EtaN... 

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