Racemization catalysts

For the cycloaddition reaction in Scheme 4.6 it was found that 3-bromocam-phor, for example, can bind selectively to one enantiomer of the complex [12] and that if the reaction was performed in the presence of the racemic catalyst 8 and 3-bromocamphor, cis-3 was isolated with up to 80% ee compared to 95% ee for the reaction catalyzed by (J )-8b. 

For an efficient enzymatic DKR the following requirements must be fulfilled (i) the KR must be very selective ( > 20) (ii) the racemization must be fast (at least 10 times faster than the enzyme-catalyzed transformation of the slow reacting enantiomer, krac >10 kent-s) (hi) the racemization catalyst must not react with the product of the reaction (iv) the KR and the racemization must be compatible under the same reaction conditions. 

In 1994, Wang et al. reported the DKR of amino acid derivatives by using pyridoxal 5-phosphate as the racemization catalyst [51]. The enzyme employed to catalyze the... 

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. 

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. 

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). 

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... 

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. 

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 DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

Scheme 5.8 DKR of a secondary alcohol using an acidic zeolite racemization catalyst in conjunction with CALB. The zeolite was encapsulated using an Lb L method in order to overcome the incompatibility of the two catalysts.

Scheme 5.9 DKR using Shvo s catalyst as racemization catalyst and immobilized lipase TL to yield...

These new generation catalysts have been applied to the asymmetric activation of an inactive racemic metal compound by a non-racemic enantiopure ligand, called a vitamer (Scheme 20a). In contrast, a racemic catalyst can interact with an enantiopure chiral poison (asymmetric... 

In the contemporary production of enantiopure compounds this feature is highly appreciated. Currently, kinetic resolution of racemates is the most important method for the industrial production of enantiomerically pure compounds. This procedure is based on chiral catalysts or enzymes, which catalyze conversion of the enantiomers at different rates. The theoretical yield of this type of reaction is only 50%, because the unwanted enantiomer is discarded. This generates a huge waste stream, and is an undesirable situation from both environmental and economic points of view. Efficient racemization catalysts that enable recycling of the undesired enantiomer are, therefore, of great importance. 

Another interesting issue is the possibility of creating optically active compounds with racemic catalysts. The term chiral poisoning has been coined for the situation where a chiral substance deactivates one enantiomer of a racemic catalyst. Enantiomerically pure (R,R)-chiraphos rhodium complex affords the (iS )-methylsuccinate in more than 98% ee when applied in the asymmetric hydrogenation of a substrate itaconate.109 An economical and convenient method... 

In contrast to chiral poisoning, the concept of chiral activation has also emerged recently. An additional activator selectively or preferentially activates one enantiomer of the racemic catalyst, resulting in much faster reaction, and gives products with high ee. 

The formal view. The formal view is much simpler. The racemic catalysts have a twofold axis and therefore C2-symmetry. Both sites of the catalysts will therefore preferentially co-ordinate to the same face (be it re or si) of propene. Both sites will show the same enantiospecificity the twofold axis converts one site in the other one. Subsequently, insertion will lead to the same enantiomer. According to the definition of Natta, this means that isotactic polymer will be formed. If the chain would move from one site to the other without insertion of a next molecule of propene, it will continue making the same absolute configuration at the branched carbon atom. Hence, no mistake occurs when this happens. 

Procedure 1 Synthesis of the Amine Racemization Catalyst Pentamethylcyclopentadienyliridium(III) Iodide Dimer... 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Saunders et al. reported the DKR system for secondary alcohols using Cp lr complexes bearing a NHC ligand as racemization catalysts [47]. As shown in Scheme 5.15, the reaction of racemic 1-phenylethanol with isopropenyl acetate in the presence of catalyst 22 (0.1mol% Ir) and Novozyme 435 at 70 °C for 8h gave... 

Enantiomer-selective deactivation of racemic catalyts by a chiral deactivator affects the enantiomer-selective formation of a deactivated catalyst with low catalytic activity (Scheme 8.2). Therefore, it is crucial for a chiral deactivator to interact with one enantiomer of a racemic catalyst (Scheme 8.2a). As the chiral deactivator does not interact with the other enantiomer of racemic catalyst, the enantiomeri-cally enriched product can be obtained. Therefore, the level of enantiomeric excess (% ee) could not exceed that attained by the enantiopure catalyst. On the other hand, nonselective complexation of a chiral deactivator would equally and simultaneously deactivate both catalyst enantiomers, thereby yielding a racemic product (Scheme 8.2b). Although this strategy tends to use excess chiral poison relative to the amount of catalyst, it offers a significant advantage in reducing cost and synthetic difficulty since readily available racemic catalysts and often inexpensive chiral poisons are used. 

ASYMMETRIC ACTIVATION AND DEACTIVATION OF RACEMIC CATALYSTS (a) Aldol reaction... 

Combination of the asymmetric activation and asymmetric deactivation protocols as asymmetric activation/deactivation can be achieve the difference in catalytic activity between the two enantiomers of racemic catalysts can be maximized through selective activation and deactivation of enantiomeric catalyst, respectively (Scheme 8.15). 

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