Resolution, dynamic kinetic lipase-catalyzed

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]. 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

Chen, C.Y, Cheng, Y.C. and Tsai, S.W., Lipase-catalyzed dynamic kinetic resolution of (R,S)-fenoprofen thioester in isooctane. J. Chem. Technol. Biotechnol., 2002, 77, 699-705. 

The reversibility of hydrogen transfer reactions has been exploited for the racemi-zation of alcohols and amines. By coupling the racemization process with an enantioselective enzyme-catalyzed acylation reaction, it has been possible to achieve dynamic kinetic resolution reactions. The combination of lipases or... 

There are basically two approaches to the synthesis of enantiomerically pure alcohols (i) kinetic resolution of the racemic alcohol using a hydrolase (lipase, esterase or protease) or (ii) reduction mediated by a ketoreductase (KRED). Both of these processes can be performed as a cascade process. The first approach can be performed as a dynamic kinetic resolution (DKR) by conducting an enzymatic transesterification in the presence of a redox metal [e.g. a Ru(ll) complex] to catalyze in situ racemization of the unreacted alcohol isomer [11] (Scheme 6.1). We shall not discuss this type of process in any detail here since it forms the subject of Chapter 1. 

Hydrolase-catalyzed domino reactions incorporating a resolution and a subsequent cycloaddition reaction have been described [95-97]. This constitutes an attractive approach to complex synthetic intermediates. For example, the l-(3-methyl-2-furyl)]propanol roc-93 reacts with ethoxyvinyl methyl fumarate (94) catalyzed by Lipase LIP (from Pseudomonas aeruginosa) to furnish a dienophilic fumarate ester, which spontaneously undergoes an intramolecular Diels-Alder reaction with the furan moiety furnishing exclusively the syn-adduct, the oxabicy-clohexene 95 in excellent along with the remaining alcohol S-96 (Scheme 4.31) [95]. A similar approach has been used for a procedure that includes a series of domino reactions that includes dynamic kinetic resolution of the 3-vinylcyclohex-... 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

Akai S, Tanimoto K et al (2004) Lipase-catalyzed domino dynamic kinetic resolution of racemic 3-vinylcyclohex-2-en-l-ols/Intramolecular Diels-Alder reaction one-pot synthesis of optically active polysubstituted decalins. Angew Chem Int Ed 43 1407-1410... 

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. 

A completely different enzyme-catalyzed synthesis of cyanohydrins is the lipase-catalyzed dynamic kinetic resolution (see also Chapter 6). The normally undesired, racemic base-catalyzed cyanohydrin formation is used to establish a dynamic equilibrium. This is combined with an irreversible enantioselective kinetic resolution via acylation. For the acylation, lipases are the catalysts of choice. The overall combination of a dynamic carbon-carbon bond forming equilibrium and a kinetic resolution in one pot gives the desired cyanohydrins protected as esters with 100% yield [19-22]. 

Subsequently the groups of Williams [7] and Backvall [8] showed, in 1996 and 1997, respectively, that lipase-catalyzed transesterification of alcohols could be combined with transition metal-catalyzed racemization to produce an efficient dynamic kinetic resolution of chiral secondary alcohols (Fig. 9.2). 

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

Fig. 7 Dynamic kinetic racemate resolution via lipase-catalyzed enantioselective acylation.

Kellogg, Feringa and co-workers have achieved successful dynamic kinetic resolution reactions using cyclic hemiacetals as substrates[13, 14l The enzyme-catalyzed acetylation of 6-hydroxypyranone shown in Fig. 9-6 has been achieved with reasonable enantioselectivity with essentially complete conversion. The racemisation of the hemiacetal is presumed to proceed via reversible ring-opening of the pyranone1 1. The rate of reaction was found to greatly increase when the enzyme, lipase PS (Pseudomonas sp.) was immobilized on Hyflo Super Cell (HSC). 

Table 11.1-20). A very good illustration for the potential of enantiomer-differentiating acylation catalyzed by lipases is provided by the high-yield synthesis of a series of aromatic cyanohydrin acetates (la-g) from aldehydes, acetone cyanohydrin and vinyl acetate in the presence of Pseudomonas cepacia lipase and a basic anion-exchange resin in diisopropyl ether which proceeds under kinetic resolution coupled with in situ formation and racemization of the cyanohydrin representing a dynamic kinetic resolution. For further examples see Table 11.1-24. 

Table 11.1-24 lists lipase-catalyzed dynamic kinetic resolutions by different means. 4-Substituted oxazolin-5-ones racemize spontaneously by hydrolysis or alcoholysis caused by enolization to yield amino acid derivatives as outlined in the transformations (1), (2) and (3). Triethylamine may promote this type of transformations as... 

Table n.1-24. Lipase-catalyzed dynamic kinetic resolution (PCL Pseudomonas cepacia lipase, PPL pig pancreatic lipase, ANL Aspergillus n/ger lipase, MML Mucormieheilipase, CAL-B Candida antarctica B lipase, PSL Pseudomonas sp. lipase, PFL Pseudomoasfluorescens lipase, CAL Candida antarctica lipase, not specified). 

In reaction (25) racemization was realized by madelate racemase. However, this transformation is still a process carried out in two batches and therefore, not a dynamic kinetic resolution but certainly the starting point for further investigations by combining a lipase- and a second enzyme-catalyzed reaction in order to perform real dynamic kinetic resolution. 

M. T. Reetz, K. Schimossek, Lipase-catalyzed dynamic kinetic resolution of chiral amines use of palladium as the racemiza-tion catalyst, Chimia 1996, 50, 668. 

Dynamic Resolution. Lipase-catalyzed acyl transfer has become a well-established and popular method for the kinetic resolution of primary and secondary alcohols. In order to circumvent the limitations of kinetic resolution (i.e., a 50% theoretical yield of both enantiomers), several strategies have been developed, which achieve a more economic dynamic resolution process and allow the formation of a single stereoisomer as the sole product (for the theoretical background see Sect. 2.1.1). In contrast to compounds bearing a chiral center adjacent to an electron-withdrawing... 

Dynamic resolution of various sec-alcohols was achieved by coupling a Candida antarctica lipase-catalyzed acyl transfer to in-situ racemization based on a second-generation transition metal complex (Scheme 3.17) [237]. In accordance with the Kazlauskas rule (Scheme 2.49) (/ )-acetate esters were obtained in excellent optical purity and chemical yields were far beyond the 50% limit set for classical kinetic resolution. This strategy is highly flexible and is also applicable to mixtures of functional scc-alcohols [238-241] and rac- and mcso-diols [242, 243]. In order to access products of opposite configuration, the protease subtilisin, which shows opposite enantiopreference to that of lipases (Fig. 2.12), was employed in a dynamic transition-metal-protease combo-catalysis [244, 245]. 

Lipase-catalyzed dynamic kinetic resolution giving optically active cyanohydrins use of silica-supported ammonium hydroxide and porous ceramic-immobilized lipase. Tetrahedron, 64 (9), 2178-2183. 

M.L, and Mueller, T.N. (2006) Lipase/aluminum-catalyzed dynamic kinetic resolution of secondary alcohols. Angew. Chem. Int. Ed., 45 (39), 6567-6570. 

Zhou et al. combined the simultaneous dynamic kinetic resolution (DKR) of a secondary alcohol initiator with lipase-catalyzed ROP of s-CL. (R,5)-1-Phenyl-ethanol (PhE) was used as a model secondary alcohol and incorporated into PCL under DKR conditions using lipase CA and a Ru catalyst. A total of 75% of the PhE was incorporated as (R)-PhE-PCL with over 99% ee in 23 h at 75°C in toluene [149]. 

Wang, L, Cheng, Y., and Tsai, S.-W. (2004) Process modeling of the lipase-catalyzed dynamic kinetic resolution of (R, S)-suprofen 2, 2, 2-trifluoroethyl thioester in a hollow-fiher membrane. Bioprocess. Biosyst. Eng., 27 (1), 39-49. 

A third reason to use organic solvents is that other features of the reaction require it to be an acylation and not a hydrolysis. For example, some dynamic kinetic resolutions require an alcohol substrate because organometal-lic complexes racemize secondary alcohols, but not esters. The substrate must be an alcohol for the dynamic kinetic resolution to proceed. In another example, lipase- and esterase-catalyzed hydrolysis of amides to amines is too slow for practical use. However, the lipase-catalyzed acylation of amines in... 

Pamies, O. and BackvaU, J.-E. (2001). Efficient lipase-catalyzed kinetic resolution and dynamic kinetic resolution of beta-hydroxy nitriles. A route to useful precursors for gamma-amino alcohols. Adu. Synth. Catal., 343,726-731. 

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