Racemization, amine-catalyzed

Scheme 19.13 Dynamic kinetic resolution of cyclic P-amino acid derivatives based on amine-catalyzed racemization and enzymatic oxazinone hydrolysis.

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]. 

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]). 

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). 

An elegant four-enzyme cascade process was described by Nakajima et al. [28] for the deracemization of an a-amino acid (Scheme 6.13). It involved amine oxidase-catalyzed, (i )-selective oxidation of the amino acid to afford the ammonium salt of the a-keto acid and the unreacted (S)-enantiomer of the substrate. The keto acid then undergoes reductive amination, catalyzed by leucine dehydrogenase, to afford the (S)-amino acid. NADH cofactor regeneration is achieved with formate/FDH. The overall process affords the (S)-enantiomer in 95% yield and 99% e.e. from racemic starting material, formate and molecular oxygen, and the help of three enzymes in concert. A fourth enzyme, catalase, is added to decompose the hydrogen peroxide formed in the first step which otherwise would have a detrimental effect on the enzymes. 

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

Backvall later demonstrated ruthenium-catalyzed racemization of a range of primary benzyhc amines using Shvd s dimeric catalyst in toluene at 100 °C [15]. 

Figure 13.3 Amine substrates tested in the SCRAM -catalyzed racemization.

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

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

This concept was also recently extended by Reetz et al. to the resolution of phenylethylamine [12]. In this case, an immobilised lipase and ethyl acetate as acyl donor are used the non-acylated (S)-enantiomer of the amine is racemized in situ by palladium on charcoal. After 8 days -the metal catalyzed racemization is again likely to he the rate-determining step - (/ )-A-acetyl-phenylethylamine is isolated in 64 % yield and 99 % enantiomeric excess. 

A-[Co(en)3l is not racemized in the presence of OH at high temperatures the observed loss of optical activity is associated with the formation of cis and trans [Co(en)2(OH)2] (164). This is in keeping with the observation that cis-[Co(en)2en(OH) (i.e., with one monodentate en ligand) in basic aqueous solution does not cyclize to form [Colenla] (165). In the presence of a large excess of free en, however, racemization is observed the rate is dependent on en concentration, and the complex exchanges ligands at about the same rate as racemization (164, 166). Carbon black catalyzed racemization follows the rate law V = Ai[Co(en)3 ]ads[OH ]ad8. where the concentrations refer to the amount of reactant adsorbed onto the surface of the catalyst, ki has a value of (9 1) X 10 M s at 25°C (167). An effect of [en] was observed but was attributed solely to the pH of the basic amine. The reaction on the surface of the catalyst was proposed to occur via the SnI(CB) mechanism. 

Kinetic resolution of ferrocene derivatives, mainly alcohols, had an important place during the early stage of stereochemical investigations of ferrocene derivatives. The reaction of (partially) resolved ferrocenylalkyl alcohols and amines with racemic 2-phenylbutyric acid anhydride (Korean s method) was the basis for the configurational assignment before the establishment of structures by X-ray crystallography [41]. There has been some debate on the reliability of the method [62, 63], and additional chirality information seems necessary for certainty. Recently, the kinetic resolution of 1-ferrocenylethanol by transesterification with vinyl acetate, catalyzed by a lipase from PseudomonasJluorescens, led to an enantiomeric excess of 90—96% of both enantiomers [64], opening new preparative aspects. 

In order to broaden the scope of the amine-catalyzed Michael addition, Yamaguchi examined the system of amine and alkali metal salt [2]. Although amine did not promote the addition of malonate to enones, the LiCl04-Et3N catalyst turned out to be effective. Optically active amines, however, gave racemic adducts. As an extension, the (S)-proline rubidium salt, (S)-21, was developed, which possessed a cation and an amine moiety in the same molecule [2, 22]. The catalyst (S)-21 in chloroform promoted the asymmetric addition of malonate to a wide range of enones and enals as exemplified by the reaction of... 

Enantioselective Acylation of Racemic Amines Catalyzed by Lipase from Burkholderia plantarii (E.C. 3.1.1.3)(63-6S ... 

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

Scheme 19.9 Dynamic kinetic resolution of a secondary amine based on ruthenium-catalyzed racemization and enzymatic acylation.

Synthetic highlight Diastereoselective production of rac-menthol from its aromatic precursor is achieved by site-selective isopropylation and diastereoselective hydrogenation to the all-trans racemate. Enantioselective allylic amine-enamine-imine rearrangement of an acyclic diene-allylic amine, catalyzed by an Rh(I)-(—)-BINAP complex, affords (—)-menthol the process has been scaled-up to production of 1,000 tons/year. 

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. 

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