DKR of Amines

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]. 

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. 

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. 

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

Table 13.1 Jacobs DKR of amines with lipase, isopropyl acetate, and Pd/BaSO4.

Figure 11.4 Modified Backvall system for the DKR of amine substrates.

Scheme 4.32 DKR of amines using Pd on BaSO as a racemizing agent.

G. (2010) Switching from (R)- to (S)-selective chemoenzymatic DKR of amines involving sulfanyl radical-mediated racemization. Org. Biomol. Chem., 8 (18), 4165-4168. 

Another example of DKR of amines was reported by Kanerva s group in 2004. In this case, the DKR of the methyl esters of proline and pipecolic acid was based on the acylation of the secondary amino group of the amino esters with vinyl butanoate by Candida antarctica lipase A. Acetaldehyde, used as a racemising agent, was released in situ from vinyl butanoate in the presence of TEA, allowing proline and pipecolic add methyl esters to be acylated in the forms of highly enantiopure butanamides (Scheme 3.51). 

Scheme 4.42 DKR of amines with an analogue of Shvo s catalyst.

Today, a number of robust racemisation catalysts has been developed which are stable even under aerobic conditions during DKR. Moreover, reusable catalyst systems that are stable under ambient conditions during DKR are now also available. Palladium nanoparticles embedded on various supports are common catalysts for amine racemisation, although there are some other catalysts, such as Raney nickel and Shvo-type ruthenium complexes. The DKR of amines is possible for aliphatic amines as well as for benzylic ones. Moreover,... 

Scheme 8.69 Enz3Tnatic DKRs of amines with a palladium nanocatalyst.

Scheme 8.79 Enz5miatic DKR of amines with Raney nickel.

Scheme 8.80 Enzymatic DKR of amines with a zinc complex.

Scheme 9.7 DKRs of amines catalysed by enzyme catalysis and radical racemising...

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