Racemization ruthenium catalysts

A chiral, non-racemic ruthenium catalyst for asymmetric olefin metathesis. 

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. 

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. 

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. 

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. 

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. 

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. 

When an enantiomerically pure catalyst is used in the directed hydrogenation of a racemic reactant then the enantiomers will react at intrinsically different rates since the transition states are diastereomeric. With some rhodium and ruthenium catalysts the difference [expressed as a selectivity factor S = k(fast)/k(slow)] is > 10 which makes the process synthetically useful. This is the case for all the x-hydroxyalkylacrylates described in Section 2.5.1.1.1. when complexes based on rhodium(DiPAMP)+ are employed as catalysts. The procedure is operationally simple in that the reaction is run to the point where the enantiomeric excess of recovered reactant is ca. 95% (57-65 % reaction) and the hydrogenation is then stopped. The starting material and product arc separated after removal of the catalyst. Similar results are obtained for a-hydro-xyalkyl-39, x-amidoalkyl-40 and a-carboxyalkylacrylatcs41 (entries 1-3, in the table below). 

An elegant combination of monomers with the components of a dynamic kinetic resolution (DKR) permitted the conversion of a racemic diol into a polymer consisting of enantioenriched units that could be recovered by polymer hydrolysis [28]. Diol 5 and achiral diester 6 were combined with a well-known system of lipase and ruthenium catalyst (see Chapters 4 and 5 for more on this). The esterification of the free hydroxyl groups is very selective (for the R) configuration) but as the polymerization proceeds, the (S) stereocentres are racemized. Upon 92% conversion of the hydroxy groups and hydrolysis of the polymer, an enantioenriched sample of the diol was obtained that contained essentially none of the (S,S)-isomer. 

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... 

In 2001, Takahashi et al. [204] described the first Ru-catalyzed asymmetric allylic substitutions. The planar-chiral cydopentadienyl-mthenium complexes led to branched aUylation products with enantiosdectivities of up to 97% ee. Some years later, they showed that such complexes serve as effective catalysts for the kinetic resolution of racemic allyhc carbonates such as 200 in AAAs. The absolute configurations of the recovered carbonates and the alkylation products such as 201 were shown to depend on the substituent on the cyclopentadienyl group at the 4-position of the ruthenium catalyst (Scheme 12.98) [205]. 

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... 

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