Continuous kinetic resolution

Matsuda, T. and Watanabe, K. and Harada, T. and Nakamura, K. and Arita, Y. and Misumi, Y. and Ichikawa, S. and Ikariya, T. (2004). High-efFiciency and minimum-waste continuous kinetic resolution of racemie alcohols by using lipase in supercritical carbon dioxide. Chem. Commun., 20, 2286-2287. 

Fig. 9.29 Continuous kinetic resolution catalyzed by a CaLB CLEA in scC02.

Reetz et al. [39] carried out the continuous kinetic resolution of chiral alcohols using IL/scCOj biphasic systems with high enantioselectivity. In this approach, the racemic alcohol and the acylating agent were transported into the reactor nsing scCOj as the mobile phase. The basis of the proposed approach is that one of the enantiomers is esterified selectively by the lipase in the ionic liqnid and the mixture of products is continuously extracted with the scCO stream. The ester and unreacted alcohol were then separated downstream by controlled density reduction via variation of temperature and/or pressure of CO. The authors found that vinyl laureate, which is a cheap acylation agent, renders an ester less soluble than the unreacted alcohol, which allows an efficient recovery of the former compound. 

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 addition to Rh-catalysed hydroformylation, this special phase behaviour has been successfully applied to other continuous catalytic reactions - such as Ni-catalysed, enantioselective hydrovinylation [66] and the lipase-catalysed kinetic resolution and enantiomer separation of chiral alcohols [67]. 

The next step in the use of transfer hydrogenation catalysts for recycling of the unwanted enantiomer is the dynamic kinetic resolution. This is a combination of two reaction systems (i) the continuous racemization of the alcohol via hydrogen transfer and (ii) the enantioselective protection of the alcohol using a... 

Dynamic Kinetic Resolution Synthesis of a Fluorinated Amino Acid Ester Amide by a Continuous Process Lipase-mediated Ethanolysis of an Azalactone... 

Novozymes, a subtilisin produced by Bacillus licheniformis, was used by Chen et al ° to carry out a dynamic kinetic resolution of benzyl, butyl, or propyl esters of DL-phenylalanine, tyrosine, and leucine. The hydrolysis was performed at pH 8.5 in 2-methyl-2-propanol/water (19 1) and the freed L-amino acids precipitated. The key feature bringing about continual racemization of the remaining D-amino acid esters was the inclusion of 20 mmol 1 pyridoxal phosphate. 

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. 

A prominent example of chemoenzymatic catalysis in bio-organic chemistry is the dynamic kinetic resolution (DKR) of secondary alcohols (Scheme 9) [94, 95] and amines [96-99], In this process, a lipase is employed as an enantioselective acylation catalyst, and a metal-based catalyst ensures continuous racemization of the unreactive enantiomer. 

It is worth noting here that with two enzymes displaying opposite enantioselec-tivity it is possible to produce both enantiomers of the ester products. If the remaining alcohols can be continuously and rapidly racemized during the much slower acylation reaction, either the R- or S-esters can be obtained in high yields (>>5096) from reactions catalyzed by two hydrolases that display opposite enantio-preference. The combined process of racemization and simultaneous resolution, dynamic kinetic resolution (DKR), is described in Chapter 6. 

Control of the HPLC pump, the autosampler, and the MS is ensured by Masslynx 3.5 software. After optimization of the measurement conditions, a list of process measurements is setup (sample list), and the desired HPLC and MS steps are called upon. After a measurement, the ESI source is automatically brought to room temperature (shut down). Using 96-microtiter plates, 576 samples can be processed per measurement. The chromatograms are integrated by the software packages Quanlynx and Openlynx and exported as an Excel table. A macro is used to calculate the absolute intensities and therefore the ee and the conversion. The E values in kinetic resolution are automatically calculated with the formula of Sih [12]. Data processing is done with the Openlynx Browser. The overall process occurs continuously and enables analysis of up to 10000 samples per day, provided that the 8-channel multiplexed sprayer system is used [20b]. It is also possible to use 384-well micro titer plates. Systematic optimization is required for each new compound. 

In the kinetic resolution of chiral 1-substituted allylic alcohols, there clearly is benefit to be gained in the choice of tartrate ester used for the reaction. In these reactions, the efficiency of kinetic resolution increases as the size of the tartrate alkyl ester group increases. Data for DMT, DET, and DIPT are summarized below (see Table 6A.8 [6 J), and the trend shown there continues with the use of the crystalline dicyclohexyl and dicyclododecyl tartrates [4],... 

The only difference is that in conventional kinetic resolution the enantiomer (5)-substrate is left behind as unreacted starting material while in case of dynamic kinetic resolution the substrate is continuously isomerised during the resolution process, thus (R) and ( )-substrates are in equilibrium, which allows for the possibility of converting all starting materials of (A)-substrate into (A)-product. Several conditions should be applied and are reviewed in literature.21 For instance, Backvall et al20 used a combination of enzyme and transition metal complex (Ru-catalyst) to perform the DKR of a set of secondary alcohols. Depending on the substrate, the chemical yield was ranging from 60 to 88 % with more... 

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). 

Much activity continues to be centered around the preparation of enantioenriched epoxides using chiral Co(III)-, Mn(III)- and Cr(III)-salen complexes, particularly in the area of innovative methods. A recent brief review <02CC919> focuses on the synthesis, structural features, and catalytic applications of Cr(III)-salen complexes. In an illustrative example, Jacobsen and coworkers <02JA1307> have applied a highly efficient hydrolytic kinetic resolution to a variety of terminal epoxides using the commercially available chiral salen-Co(III) complex 1. For example, treatment of racemic m-chlorostyrene oxide (2) with 0.8 mol% of catalyst 1 in the presence of water (0.55 equiv) led to the recovery of practically enantiopure (> 99% ee) material in 40% yield (maximum theoretical yield = 50%). This method appears to be effective for a variety of terminal epoxides, and the catalyst suffered no loss of activity after six cycles. 

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