Ruthenium catalysts alcohol racemization

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. 

Kim and Park subsequently reported that ruthenium pre-catalyst 2 racemizes alcohols within 30 min at room temperature [53]. However, when combined with an enzyme (lipase) in DKR at room temperature, very long reaction times (1.3 to 7 days) were required, in spite of the fact that the enzymatic KR takes only a few hours (Scheme 5.24). Despite these compatibility problems, their results constituted an important improvement, since chemoenzymatic DKR could now be performed at ambient temperature to give high yields, which enables non-thermostable enzymes to be used. More recently, we communicated a highly efficient metal- and enzyme-catalyzed DKR of alcohols at room temperature (Scheme 5.24) [40, 54]. This is the fastest DKR of alcohols hitherto reported by the combination of transition metal and enzyme catalysts. Racemization was effected by a new class of very... 

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. 

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). 

By analogy, it seemed plausible that alcohol racemizations catalyzed by the same type of ruthenium complexes involve essentially the same mechanism (Fig. 9.11), in which the active catalyst is first generated by elimination of HC1 by the added base. This 16e complex subsequently abstracts two hydrogens from the alcohol substrate to afford an 18e complex and a molecule of ketone. Reversal of these steps leads to the formation of racemic substrate. 

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. 

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. 

Another ruthenium catalyst was used for the dynamic kinetic resolution of allylic alcohols [reaction (24)] by acylation yielding allylic acetates. Again a redox process should be responsible for the racemization. 

On the other hand, a chiral ruthenium catalyst, prepared from a chiral P/N ligand derived from L-proline, was applied in 2005 to the asymmetric isomerisation of racemic allylic alcohols via DKR. This new type of reaction was applicable to the asymmetric synthesis of muscone, as shown in Scheme 2.45. 

In 2006, Hulshof and colleagues reported the synthesis of a novel dinuclear ruthenium catalyst, bearing tetrafluorosuccinate and racemic BINAP ligands. This catalyst was applied to the DKR of various secondary alcohols in the presence of isopropyl butyrate as the acyl donor and Novozym 435 as the... 

Chiral phosphonous acid diester induces the kinetic resolution of racemic a-substituted y-unsaturated carboxylic acids through asymmetric protolac-tonization (Scheme 53) (130L2838). Dinamic kinetic resolution with Candida antartica lipase B and the ruthenium catalyst [RuCl(CO)2(T -C5Ph5)] of several homoallylic alcohols is applied in the key step to the synthesis of enantiomericaUy pure 5,6-dihydro-2ff-pyran-2-ones ( [13CEJ13859]). 

The first broadly applicable and highly practical type of DKR of alcohols in organic media was developed by the Backvall group [13, 14] by using the Shv6 ruthenium complex 14 as an efficient and enzyme-compatible metal-based redox catalyst for in situ racemization of alcohols. Notably, this (nonchiral) ruthenium catalyst does not require base and ketone additives for efficient racemization. This racemization... 

In 2006, Hulshof et ah reported the synthesis of a novel dinuclear ruthenium catalyst, bearing tetrafluorosuccinate and racemic BINAP ligands. This catalyst was applied to the DKR of various secondary alcohols in the presence of isopropyl butyrate as the acyl donor and Novozym 435 as the enzyme (Scheme 8.23). The activation of the ruthenium catalyst with K2CO3 was necessary. When the reaction was performed in the presence of the ketone corresponding to the substrate, it was complete within 10 hours with an excellent enantioselectivity, whereas, without this ketone, the complete reaction was achieved in 23 hours, also giving an excellent enantioselectivity. 

Chemoselective oxidation of a secondary alcohol moiety can be also performed with ruthenium catalysts with phenylindenyl Hgand. The selective oxidation of 1-phenylethanol to acetophenone from a mixture of phenylethanol isomers, without oxidizing the other isomer, can then be achieved (Scheme 29). In general, only the secondary alcohol moieties are oxidized and the catalyst can be used for the chemical separation of isomers or specific oxidation of highly functionalized molecules. The OKR of unactivated racemic alcohols with dioxygen of air as the hydrogen acceptor was effectively performed at room temperature with [(aqua)Ru(salen)] com-... 

Later, Shimada et al. reported a novel tandem oxidation-reduction reaction with a combination of two fnndamentally distinct Ru catalysts [13], By means of this strategy, the racemic secondary benzylic alcohols could be transformed efficiently into (R)-enantiomers (Scheme 9.10). This catalytic system, containing two different chiral ruthenium catalysts, provides an alternative to chiral secondary alcohol synthesis beyond direct raJuction or addition protocols. 

DKR of racemic 1-phenylethanol and other families of alcohols using a ruthenium dimeric catalyst as racemization agent. 

Immobilized and reusable ruthenium catalyst 13 oxovanadium compounds 14 and 15 as catalysts for the racemization of allylic alcohols. 

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