Continuous-flow kinetic resolution

Table 9.4 Continuous-flow kinetic resolutions by Candida rugosa lipase (CrL) catalyzed hydrolysis (ranges between brackets indicate the interval of an investigated property). 

Boros, Z., Falus, P., Markus, M., Weiser, D., Olah, M., Hornyanszky, G., Nagy, J., and Poppe, L. (2013) How the mode of Candida antarctica lipase B immobilization affects the continuous-flow kinetic resolution of racemic amines at various temperatures. J. Mol. Catal. B Enzym., 85- 86, 119-125. doi 10.1016/j.molcatb.2012.09.004... 

Hellner, G., Boros, Z., Tomin, A., and Poppe, L. (2011) Novel sol-gel lipases by designed bioimprinting for continuous-flow kinetic resolutions. 

Kawakami, K., Ueno, M., Takei, T., Oda, Y., and Takahashi, R. (2012) Application of a Burkholderia cepacia lipase-immobilized silica monolith micro-bioreactor to continuous-flow kinetic resolution for transesterification of (R,S)-l-phenylethanol. 

Revisions of the continuous-flow method have been made to allow observations along the length of the flow tube rather than at right angles.5 This method, fast continuous flow, eliminates the dead time during which the reaction cannot be observed. Kinetic data can be extracted to a time resolution of nearly 10 p,s, but the mathematics is more complicated in this limit, because the mixing and chemical reaction occur on the same time scale. Rate constants nearly as large as the diffusion-controlled value have been determined in favorable cases.6... 

Apparently similar flowstream universal buffers have been developed by Alibrandi and others [128,129] for assessing kinetic parameters, such as the pH-dependent hydrolysis of acetylsalicylic acid. The pH-time curves are not as linear as in the SGA system. Other reports of continuous flow pH gradient spectrophotometric data have been described, with application to rank-deficient resolution of solution species, where the number of components detected by rank analysis is lower than the real number of components of the system [130]. The linear pH-time gradient was established in the flowstream containing 25 mM H3PO4 by the continuous addition of 100 mM Na3P04. 

Performing a systematic comparison of lipase-catalyzed kinetic resolutions of several seeondaiy aleohols in continuous flow mode (Figure 7) and shake flask batch mode using immobilized and non-mobilized lipases was reported by Csajagi and eo-workers [25]. The results indieated that immobilized as well as lyophilized powder forms of liphases can be effeetively used in eontinuous flow mode kinetie resolutions of raeemic alcohols in non-aqueous solvent systems. The produetivity of the lipases was higher in continuous flow reactors than in batch mode systems, whereas the enantiomer selectivities were similar. 

A novel continuous-flow SCCO2 process for the kinetic resolution of 1-phenyethanol enantiomers (Figure 30) using Novozym 435 immobilized enzyme from Candida antarctica was described by Matsuda et al. [51], The lipase enzyme, selectively acetylated the R)-alcohol component. A mixture of starting material and vinyl acetate was passed through the enzyme with supercritical carbon-dioxide (Figure 31). The reaction zone was pressurized and heated, so the reaction could be performed imder supercritical conditions, synthesizing the desired (i )-acetate with 99.7% ee. and 47% yield. 

To demonstrate the synthetic application of this methodology, the authors subsequently demonstrated its use for the preparative kinetic resolutions of a series of 2° alcohols, Table 24, whereby 20 ml solutions of each racemic alcohol were passed through the bioreactor (3.3 h) and found to afford analogous results to those obtained during the initial optimization experiments. The authors successfully demonstrated the use of immobilized and lyophilized enzymes within a continuous flow reactor, presenting a synthetically viable approach to the kinetic resolution of racemic alcohols. 

Reetz, M.T., W. Wiesenhofer, G. Francio and W. Leitner, Continuous Flow Enzymatic Kinetic Resolution and Enantiomer Separation Using Ionic Liquid/Supercritical Carbon Dioxide Media, Advanced Synthesis Catalysis, 345, 1221-1228 (2003). 

Kinetic resolution of chiral alcohols by selective esterification has also been performed in SCCO2 by several groups. A glass-immobilized lipase from Candida cylindracea was found to catalyze the stereoselective esterification of only the S isomer from racemic citronellol (Eq. (3)] in a continuous-flow reactor (78) ... 

Reetz MT, Wiesenhofer W, Francio G et al (2003) Continuous flow enzymatic kinetic resolution and enantiomer separation using ionic Uquid/supercritical carbon dioxide media. Adv Synth Catal 345 1221-1228... 

The separation of the products from the IL catalytic mixture can be performed in various cases by simple decanting and phase separation or by product distillation. In this respect, a continuous-flow process using toluene as extractant has been appHed for the selective Pd-catalyzed dimerization of methyl acrylate in ILs [136]. However, in cases where the products are retained in the IL phase, extraction with supercritical carbon dioxide can be used instead of classical liquid-liquid extractions that necessitate the use of organic solvents, which may result in cross-contamination of products. This process was successfully used in catalyst recycling and product separation for the hydroformylation of olefins employing a continuous-flow process in supercritical carbon dioxide-IL mixtures [137]. Similarly, free and immobilized Candida antarctica lipase B dispersed in ILs were used as catalyst for the continuous kinetic resolution of rac-l-phenylethanol in supercritical carbon dioxide at 120°C and 150°C and 10 Mpa with excellent catalytic activity, enzyme stability and enantioselectivity levels (Fig. 3.5-11). 

In the context of continuous-flow operations using SCCO2/ILS, it has to be mentioned that this concept has also been successfully applied to biocatalyzed reactions. Among others, Reetz et al. were able to demonstrate that kinetic resolution of alcohols is possible by lipase-catalyzed alcohol esterification in ILs and subsequent continuous extraction of the ester derivatives with SCCO2 [29]. For further information, see Chapter 8. 

Continuous-flow biphasic IL-SCCO2 has also been applied in biocatalysis. Thus enzymatic reactions including transesteriflcation [41], acylation [42], and kinetic resolution of enantiomers [43] have been reported. 

Acylations Carbon-coated magnetic Co-nanoparticles tagged with azabis (oxazoline)-Cu(II) complexes were utilized in a Cu(I)-catalyzed azide/alkyne cycloaddition (CuAAC), and the efficacy of the resulting nanomagnetic catalyst was tested in the kinetic resolution (KR) of racemic l,2-diphenylethane-l,2-diol via asymmetric monobenzoylation under batch conditions and in a continuous flow-type reactor [39]. 

Figure 9.3 Products of kinetic resolutions of the esters indicated by enzyme-catalyzed hydrolysis in continuous-flow mode [87. 90-95).

Figure 9.8 Hydrolase-catalyzed kinetic resolution of primary alcohols 21a-c by acylation in continuous-flow PBR.

Cu(I I )-azabis(oxazoline) complexes immobilized on magnetic Co/C nanoparticles kinetic resolution of l,2-diphenylethane-l,2-diol under batch and continuous-flow conditions. Chem. Mater., 22, 305—310. doi 10.1021/cm9019099... 

K., Dorko, Z., Urge, L., Darvas, F., and Poppe, L. (2010) Lipase-catalyzed kinetic resolution of 2-methylene-substituted cycloalkanols in batch and continuous-flow modes. Process Biochem., 45, 859-865. doi 10.1016/j.procbio.2010.02.006... 

Kinetic resolution of a precursor for myo-inositol phosphates under continuous flow conditions. J. Mol. Catal. B Enzym., 87, 139-143. doi 10.1016/j.molcatb.2012.11.006... 

L. S.M., Coelho, F., and de Souza, R.O.M.A. (2013) Kinetic resolution of 5H-pyrrolo[l,2-a]imidazol-7-ol, 6,7-dihydro under continuous flow conditions an intermediate for chi-... 

Silica bound chiral Co-salen complex (36) was synthesized and adapted to a continuous-flow reaction. The optical kinetic resolution of racemic epoxide (38) was successful to yield the desired triol (39) in good yield (36% conversion) and high enantiomeric excess (Scheme 7.31) [127]. A PASSflow microreactor consisting of Co-salen monolith (37) was used for the dynamic kinetic resolution of epibromohydrin (40). Three runs performed on the 1-mmol scale were completed and afforded (J )-(41) in 76-87% yield with constant enantiomeric purity of 91-93% ee [128]. 

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