Amines, DKR

The Backvall group applied the amine DKR methodology to the synthesis of nor-sertraline [67] (Scheme 5.45), which is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. In the first step, the DKR of racemic amine rac-29 was performed with CAL-B (Novozym 435) and dimeric Ru catalyst 12 to obtain the enantiomeric amide (R)-30 (99% ee). The (R)-amide was converted via several chemical steps to tiie target (99% ee) with an overall 28% 5deld. 

Racemization of amines is difficult to achieve and usually requires harsh reaction conditions. Reetz et al. developed the first example of DKR of amines using palladium on carbon for the racemization and CALB for the enzymatic resolution [35]. This combination required long reaction times (8 days) to obtain 64% yield in the DKR of 1-phenylethylamine. More recently, Backvall et al. synthesized a novel Shvo-type ruthenium complex (S) that in combination with CALB made it possible to perform DKR of a variety of primary amines with excellent yields and enantioselectivities (Figure 4.13) [36]. 

A very elegant approach has been developed by Kanerva et al. DKR of N-hetrocyclic a-amino esters is achieved using CAL-A [54]. Racemization occurs when acetaldehyde is released in situ from the acyl donor. In this case aldehyde-catalyzed racemization of the product cannot occur (Figure 4.28). This is one of the few examples reported for DKR of secondary amines (For a recent example see the above text and Ref. [38]). 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

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 DKR of amine is more challenging compared to that of secondary alcohol since no metal catalysts have been known for the efficient racemizahon of amine. Reetz et al. reported for the first time the DKR of amine, in which 1-phenylethylamine was resolved by the combination of lipase and palladium (Scheme 4). In this procedure, CALB and Pd/C were employed as the combo catalysts. However, the DKR required a very long reaction time (8 days) at 50-55°C and provided a poor isolated yield (60%). Recently, an improved procedure using Pd on alkaline earth salts as the racemizahon catalyst was reported by Jacobs et al. " The DKR reachons were performed at 70°C for 24-72 h and 75-88% yields were obtained with 99% or greater enanhomeric excess. 

Recently, Backvall et al. reported that a p-methoxy derivative of dirutheitium complex 1 racemizes benzyl amines at 90-100°C in toluene and the DKRs using it were achieved successfully (Scheme 5). More than ten benzylic amines were transformed to the corresponding amides with good yields and high ee. ... 

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. 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

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. 

DKR of Primary Amines with a Recyclable Palladium Nanocatalyst 149... 

A heterogeneous and recyclable palladium catalyst, Pd/A10(OH), is excellent for the racemization of primary amines. We have demonstrated successful DKR of various primary amines by combining the palladium catalyst and a lipase to produce the corresponding (/ )-acetamides in high yields and in high optical purities. Tables 4.3 and 4.4 show the results of the DKR of benzyhc and aliphatic primary amines. 

DKR for the Synthesis of Esters, Amides and Acids Using Lipases Table 4.4 DKR of various aliphatic amines... 

DKR of Amines by Biocatalysis and In Situ Free-radical-mediated Racemization 153... 

Another possible mechanism for the racemization of amino acid esters involves the in situ, transient, formation of Schiff s bases by reaction of the amine group of an amino acid ester with an aldehyde. Using this approach, DKR of the methyl esters of proline 5 and pipecolic acid 6 was achieved using lipase A from C. ant-arclica as the enantioselective hydrolytic enzyme and acetaldehyde as the racemiz-ing agent (Scheme 2.4). Interestingly, the acetaldehyde was released in situ from vinyl butanoate, which acted as the acyl donor, in the presence of triethylamine. The use of other reaction additives was also investigated. Yields of up to 97% and up to 97% e.e. were obtained [6]. 

Scheme 2.26 DKR of chiral amines using CALB and a ruthenium catalyst.

Similarly, CALB has been used in combination with a palladium/alkaline earth metal-based racemization catalyst to effect a DKR on the benzylic amine 56e (Scheme 2.27). The (R)-amide 57e was obtained in very good yield and excellent optical purity. Several other substrates also underwent the reaction [29],... 

Kim et al. have developed a practical procedure for the DKR of primary amines illustrated by substrate 56c (Scheme 2.28). They employed a supported palladium nanocatalyst as the racemization catalyst and commercially available CALB as the enantioselective catalyst for acylation of the amine using ethyl methoxyacetate as the acyl donor. High yields and enantiomeric excesses were achieved [30]. 

Scheme 2.30 DKR of secondary amine 61 using a novel iridium catalyst.

Scientists at Huddersfield University in collaboration with Avecia have developed a DKR process involving the combination of immobilized Candida rugosa lipase and an iridium-based racemization catalyst (Scheme 2.30). By using carbonate 62 as the acyl donor, the racemic secondary amine 61 was converted to the corresponding carbamate (R)-63 in high yield and enantiomeric excess [32]. 

In order to obtain a commercially viable process it is necessary to racemize the unwanted amine enantiomer, preferably in situ in a so-called DKR. The paUadium-on-charcoal-catalyzed racemization of amines was first reported by Murahashi et al. [23] and was later combined with Upase-catalyzed acylation, to afford a DKR, by Reetz [24] and others [25]. We were able to achieve a DKR of a-methyl benzyl-amine by performing the hpase-catalyzed acylation in the presence of a palladium nanoparticle catalyst (Scheme 6.10). 

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