Racemization 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]. 

Jacobs et al. have found that the efficiency of the Pd-catalyzed racemization of amines can be improved by using Pd immobilized on supports such as BaS04, CaC03, or BaC03. The racemization was combined with a KR catalyzed by CALB affording enantiopure acetylated benzylamines in high yields [37]. 

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. 

Racemizations are not limited to alcohols indeed, some racemizations of amines have also been reported [121]. 

Scheme 2.29 Racemization of amine 59 via addition of thiyl radicals.

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). 

The racemization of amines is more difficult than that of alcohols owing to the more reactive nature of the intermediate (imine vs. ketone). Thus, imines readily undergo reaction with a second molecule of amine and/or hydrogenoly-... 

Fig. 9.14 Side reactions in metal-catalyzed racemization of amines.

A chemical reaction is carried out between the racemate and an optically active form (either laevo-or dextro-) of a substance capable of reacting with the racemate. This other optically active compound is usually derived from a natural source. To resolve the racemates of amines (or other bases) and alcohols, for example, use may be made of the naturally occurring d-tartaric acid (from wine tartar). The reaction with amines gives salts and esters are formed with alcohols. For the resolution of racemates of acids, use is frequently made of alkaloids such as quinine or stiychnine extracted from plants in which each of these alkaloids is present in an optically active form. The racemate mixture forms two diastereoisomers (compounds that are stereoisomers of each other, but are not enantiomers) of a derivative, with the optically active reagent used. If the... 

In addition to the proline polymers, polymers containing N-carboxymethyl-L-valine (Snyder et al., 1972), A -()3-hydroxyethyl)-D-propylenediaminotetraacetic acid (Humbel et al., 1970 Bemauer et al., 1971), L-histidine (Guette et al., 1978), and iV-benzyl-L-leucine (Tsuchida et al., 1976) have been used to separate racemates of amines and amino acids. 

While many heterogeneous catalysts and some homogenous catalytic complexes are known to racemize optically active scc-alcohols via corresponding ketones [18, 19], there is little precedence for the racemization of amines [20, 21]. Moreover, most of them do not meet industrial criteria for turn over number (TON), price of the catalyst, loading capacity of the catalyst or reaction conditions, in particular when high temperatures are required. 

On the other hand, the racemization of amines is more difficult compared to that of alcohols. Several metal systems based on palladium (Pd), Ru, nickel (Ni), cobalt (Co), and Ir have been employed as the racemization catalysts. Pd-based catalysts include Pd/C, Pd/BaSO, and Pd/A10(0H). They are readily available but require higher temperatures for satisfactory racemization. So they should be coupled with thermostable enzymes such as Novozym 435 for the successful DKR. A possible mechanism for the Pd-catalyzed racemization of amine is described in Scheme 5.5. The racemization occurs via reversible dehydrogenation/hydrogena-tion steps including an imine intermediate. The imine intermediate can react with starting material to afford a secondary amine as the byproduct. The deamination of substrate and byproduct are also possible at elevated temperature. In case the... 

The coupling of enzyme-catalyzed resolution with metal-catalyzed racemization constitutes a powerful DKR methodology for the synthesis of enantioenriched alcohols, amines, and amino acids. In many cases, the metalloenzymatic DKRs provide high yields and excellent enantiopurities, both approaching 100%, and thus provide useful alternatives to the chemical catalytic asymmetric reactions employing transition metals (complexes) or organocatalysts. The wider applications of a metalloenzymatic DKR method, however, are often limited by the low activity, narrow substrate specificity, or modest enantioselectivity of the enzyme employed. The low activities of metal-based catalysts, particularly in the racemization of amines and amino acids, also limit the wider applications of DKR. It is expected that fm-ther efforts to overcome these limitations with the developments of new enzyme-metal combinations will make the metalloenzymatic DKR more attractive as a tool for asymmetric synthesis in the future. 

More recently, Backvall and coworkers have described a very effective catalyst for the racemization of amines highly dispersed Pd nanoparticles supported in the large pores of silica-based mesocellular foam (MCF) [104]. This catalyst proved to be a more robust catalyst in amine racemization than any other catalysts reported before and is completely compatible with CALB activity. 

Ruthenium-based catalyst employed in the racemization of amines. 

As in the case of sec-alcohols, ruthenium complex has also been investigated as a catalyst in the racemization of primary amines. In fact, Shvo s complex 2 (Figure 14.3) was employed by the Backvall s group as the catalyst of the racemization of amines under transfer hydrogenation conditions [105]. However, temperatures up to 110 °C were required for amine racemization, incompatible with the lipase resolution, and furthermore, side products were formed in the medimn and a hydrogen source was needed. To avoid these drawbacks, the racemization at high temperature was carried out after a first lipase-catalyzed KR, followed by a second KR process, and a hydrogen source such as 2,4-dimethylpentan-3-ol was employed. 

Overall, compared to chemical methods, these one-pot biocatal5dic cascades enable "green" racemization of amines and amino acids under mild reachon conditions. 

Koszelewski, D., et al. Enzymatic racemization of amines catalyzed by enantiocomple-mentary co-transaminases. Chem. Eur.., 2011.17(1) 378-383. 

Metal-catalyzed racemization of amines generally takes place via reversible dehydrogenation-hydrogenation steps through imine intermediates (Scheme 57.21). During this process, and facilitated by the elevated temperatures required for racemization, the imine intermediate can undergo side reactions (condensation with an amine molecule, hydrolysis, etc.), which could lower the yield of the amide and make it difficult to isolate. 

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