Resolution of 1-phenylethanol

Lipases from C. antarctica and P. cepacia showed higher enantioselectivity in the two ionic liquids l-ethyl-3-methylimidazolium tetrafluoroborate and l-butyl-3-methylimidazolium hexafluoroborate than in THE and toluene, in the kinetic resolution of several secondary alcohols [49]. Similarly, with lipases from Pseudomonas species and Alcaligenes species, increased enantioselectivity was observed in the resolution of 1 -phenylethanol in several ionic liquids as compared to methyl tert-butyl ether [50]. Another study has demonstrated that lipase from Candida rugosa is at least 100% more selective in l-butyl-3-methylimidazolium hexafluoroborate and l-octyl-3-nonylimidazolium hexafluorophosphate than in n-hexane, in the resolution of racemic 2-chloro-propanoic acid [51]. 

The DKR of secondary alcohols can be efficiently performed via enzymatic acylation coupled with simultaneous racemization of the substrates. This method was first used by BackvaU for the resolution of 1-phenylethanol and 1-indanol [38]. Racemization of substrate 18 by a mthenium catalyst (Scheme 5.11) was combined with transesterification using various acyl donors and catalyzed by C.antarctica B Hpase. From aU the acyl donors studied, 4-chlorophenyl acetate was found to be the best. The desired product 19 was obtained in 80% yield and over 99% ee. 

Dynamic Kinetic Resolution of 1-Phenylethanol by Immobilized Lipase Coupled with In Situ Racemization over Zeolite Beta... 

An interesting innovation involves the use of isopropenyl acetate or acetic anhydride to accomplish irreversible acyl transfer63, as exemplified in the resolution of 1-phenylethanol (12) and the amino diol derivative 3- cr/ butyl-5-(2-hydroxyethyl)-2-oxazolidinone (14) ( ) ... 

The chiral TEMPO-derivative 87 has been shown to be an active catalyst for the oxidative kinetic resolution of 1-phenylethanol and derivatives. Catalyst loadings are in a practically very useful range (0.5-1 mol%) and hypochlorite is an attractive oxidant. Clearly, a more readily accessible catalyst would be desirable. In this respect, the Shi ketone 88 is advantageous. It must, however, be used in large excess and... 

There are a numerous amount of examples for optical resolutions through hydrolytic-enzyme-catalyzed esterifications13 and hydrolysis.14 Only selected reactions are shown in Figure 13-16. For example, in a large scale optical resolution of 1-phenylethanol by lipase (PS) with vinyl acetate, 67.5 Kg of (R)-1-phenylethanol was successfully synthesized with the flow system as shown in Figure 13 (a). 

A CLEA prepared from CaLB was recently shown to be an effective catalyst for the resolution of 1-phenylethanol and 1-tetralol in supercritical carbon dioxide in continuous operation [47]. Results were superior to those obtained with Nov 435 (CaLB immobilized on a macroporous acrylic resin) under the same... 

There are many reports of enzymatic catalysis in scC02 performing hydrolysis, oxidations, esterifications, and franr-esterification reactions. For example, the enzymatic kinetic resolution of 1-phenylethanol with vinyl acetate in scC02 using lipase from Candida antarctica B produces (R)-l-phenyethylacetate in >99% ee (i.e., enantiomeric excess, a measure of how much of one enantiomer is present as compared to the other), as shown in Figure 12.20. 

In this research the kinetic resolution of 1-phenylethanol catalyzed by commercially available immobilized lipase from CALB was assayed in non-aqueous conditions in SC-CO2 and IL/SC-CO2 systems with the aim of studying the enan-tioselectivity of Novozym 435. The influence of different reaction parameters, such as pressure, the acyl donor/alcohol molar ratio and different ILs, on the enantio-merically pure compound (R)-l-phenylethyl acetate formation via kinetic resolution of 1-phenylethanol was investigated. 

Therefore, the pressure effect on the enantioselectivity of commercially available immobilized CALB (Novozym 435) for the kinetic resolution of 1-phenylethanol was studied in non-aqueous SC-CO2. 

Figure 8.1 Pressure effect on the kinetic resolution of 1-phenylethanol, catalyzed by Immobilized CALB in SC-CO2 after five hours of reaction bars-dependence of the conversion on the pressure spots-pressure dependence of the enantiomeric excess for 1-phenylethanol.

The influence of different ILs, based on N, N dialkyUmidazolium cations as reaction media, on the enantioselectivity of commercially available immobilized lipase from CALB for the kinetic resolution of 1-phenylethanol was studied. Further, the performance of the enzymatic kinetic 1-phenylethanol resolution by CALB in the system [bmim][PF6]/SC-C02 was studied. 

Figure 8.4 Three different ILs [bmimjlPFs], [bmim][BF4] and [emim][NTf2] as reaction media for the enzymatic kinetic resolution of 1-phenylethanol by immobilized CALB after five and 24 hours of reaction.

Kinetic resolution of 1-phenylethanol catalyzed by CALB was carried out in the IL/SC-CO2 biphasic system. To prevent undesirable reactions and ensure better conversion of (R)-1-phenylethanol, [bmim][PF,5] was chosen for this kind of experiments. Because of the possible direct and indirect effects of the pressure on the activity of biocatalyst its influence was studied between 6 and 36.5 MPa. At aU conditions examined a biphasic reaction medium was attained, which is illustrated in Figure 8.5. The enzyme was suspended in the IL phase, where the reaction took place. The substrates and products resided largely in the supercritical phase, which was also the extractive phase. 

The extension of this method to the enzyme-catalyzed kinetic resolution of 1-phenylethanol by transesterification [Eq. (7)] was published by two groups nearly simultaneously (145,146). 

Different approaches have been developed to improve the activity of lipases in the kinetic resolution of 1-phenylethanol in ionic liquids. For example, Park and... 

Schofer SH, Kaftzik N, Wasserscheid P, Kragl U (2001) Enzyme catalysis in ionic liquids lipase catalysed kinetic resolution of 1-phenylethanol with improved enantioselectivity. Chem Commun 5 425-426... 

Shah S, Gupta MN (2007) Kinetic resolution of ( ) 1-phenylethanol in [Bmim][PFJ using high activity preparations of lipases. Bioorg Med Chem Lett 17 921-924... 

Hernindez-Femandez FJ, de los Rios AP, Tomis-Alonso F, G6mez D, Vfllora G (2007) Kinetic resolution of 1-phenylethanol integrated with separation of substrates and products by a supported ionic liquid membrane. J Chem Technol Biotechnol 82 190-195... 

Candida antarctica lipase B 2 Acylation of octan-l-ol and kinetic resolution of 1-phenylethanol using IL/SCCO2 81... 

In our group the kinetic resolution of 1-phenylethanol was investigated for a set of eight different lipases and two esterases in ten ionic liquids with MTBE as the reference [61],... 

Today, dynamic kinetic resolution of secondary alcohols by combination of enzymes with transition metal catalysts, originally developed by Williams and Backvall, are perhaps the best developed methods (33-36). Hitherto the most successful catalyst designs have been based on half-sandwich ruthenium complexes, of which the pentaphenylcyclopentadienyl ruthenium complex has been claimed as the currently best racemization catalyst. Racemization is then based on reversible conversion of the alcohol into the corresponding ketone (Fig. 21, A). The dynamic kinetic resolution of 1-phenylethanol with isopropenyl acetate in toluene in the presence of Novozym 435, performed in preparative scale, is a good example of the use of ruthenium complexes (35). Another thoroughly studied racemization method (Fig. 21, B) is based on the use of acidic resins or zeolites. Here the racemization takes place through prochiral sp car-benium ion by simultaneous elimination and addition of water (37). The use of... 

Racemization of the remnant substrate in a DKR process can be performed either spontaneously or by the employment of a chemo- or biocatalyst, which must be compatible with the reaction conditions used for the KR reaction. In the case of sec-alcohols, most of successful DKRs have been carried out by the use of ruthenium complex catalysts, soluble in the organic reaction media, which promote racemization through redox processes. The first examples describe the resolution of 1-phenylethanol (rac-1) by the combination of a rhodium catalyst (Rh2(OAc) ) with Pseudomonas fluorescens lipase [22], although more effective results were afforded by Backvall and coworkers [23], who developed the DKR of the same substrate and derivatives catalyzed by Candida antarctica lipase (CALB) and a ruthenium complex (Shvo s catalyst, 2 (Figure 14.2)), affording excellent conversions and enantiomeric excess (ee) values [24]. 

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