1-phenylethanol, resolution

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 8.6 Performance of the enzymatic kinetic 1-phenylethanol resolution over immobilized CALB in [bmim][PF6]/SC-C02 system at 313.15 K by varying the pressure bars-dependence of the conversion on the pressure spots-dependence of the enantiomeric excess on the pressure.

The IL/SC-CO2 media for 1-phenylethanol resolution, catalyzed by CALB, offers a number of advantages, such as high resolution yields, simple downstream processing, guarantying an enzyme overstabilization effect and exceptional enzyme enantioselectivity with no transformation of the not desired enantiomer, albeit apparently lower conversions were registered in this medium compared to the ones, obtained in SC-CO2. 

Figure 8.7 Acyl donor/alcohol molar ratio effect on the reaction of the enzymatic kinetic 1 -phenylethanol resolution by CALB in [bmimKPFel/SC-COz.

Later on the crucial role played by the solvent was enlightened in the protease-catalyzed resolution of racemic amines [26]. As shown in Table 1.3, the ratio of the initial rates of acylation of the (S)- and the (Ji)-enantiomers or racemic a-methyl-benzylamine (9) varied from nearly 1 in toluene to 7.7 in 3-methyl-3-pentanol. Similarly, the same authors found a significant solvent effect for the subtilisin-catalyzed transesterification of racemic 1-phenylethanol (10) using vinyl butyrate as acyl donor (Table 1.4 [27]). 

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]. 

In conclusion, both systems presented by both teams are rather competitive, even if the selectivity factors given by the system of Stoltz is better for a given set of substrates. In the case of 1-phenylethanol, Stoltz s system led to a 99% ee and s of 31, while in Sigman s procedure the resolution led to a 98.5% ee and s of 19. Both teams synthesized a range of model substrates that gave good ee s and good selectivity factors [44,45,49]. 

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. 

A different MS-based ee-assay makes use of a proline-derived mass-tagged acylating agent.95 In the course of derivatization it is necessary that some degree of kinetic resolution comes about. The sensitivity of the method was reported to be 10% ee. It can also be applied to the reaction of a prochiral compound lacking enantiotopic groups, as in the transformation of acetophenone to phenylethanol. 

Scheme 6.55 MW-assisted resolution of racemic 1 -phenylethanol via transesterification.

Heteroatom Oxidation, Dehydrogenation Electrooxidative kinetic resolution of rac alcohols mediated with a catalytic amount of an optically active A-oxyl was performed in an undivided cell at constant current conditions. A high enantiomeric purity for the recovered alcohol was found, which could be increased by electrolysis at lower temperatures. The optically active A-oxyl was recovered and used repeatedly without change in efficiency and selectivity [368]. Cyclovoltammetry with the A-oxyl (GR, 7S, 10/f)-4-oxo-2,2,7-trimethyl-10-isopropyl-l-azaspiro[5.5]undecane-A-oxyl as catalyst showed for rac-1-phenylethanol a highly enhanced catalytic... 

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

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

The empirical observation that (—)-sparteine 55 is necessary for catalysis implicates a base-promoted pathway in the mechanism. In the first step, a palladium alk-oxide is formed after alcohol binding, followed by p-hydride elimination of the alkoxide to yield a ketone product. On the basis of a kinetic study of the enantio-selective oxidation of 1-phenylethanol, it was revealed that (—)-sparteine plays a dual role in the oxidative kinetic resolution of alcohols, as a ligand on palladium and an exogeneous base " ... 

Figure 3. VCD and absorption spectra in the CH stretching region (a) a-phenylethanol, 0.074 M in ecu, path length O.IO cm, (b) (+)-a-phenylethyl isocyanate, 0.087 M in CCU, sample path length 0. IS cm. The time constant was 10 s, and the resolution was 6 cm. (Reproduced with the permission of North Holland Publishing Co., from ref. S9.)...

The infrared radiation caused by the heat of reaction of an enantioselective enzyme-catalyzed transformation can be detected by modern photovoltaic infrared (IT)-thermographic cameras equipped with focal-plane array detectors. Specifically, in the lipase-catalyzed enantioselective acylation of racemic 1-phenylethanol (20), the (K)- and (S)-substrates were allowed to react separately in the wells of microtiter plates, the (7 )-alcohol showing hot spots in the IR-thermographic images (113,114). Thus, enantioselective enzymes can be identified in kinetic resolution. However, quantification has not been achieved thus far by this method, which means that only those mutants can be identified which have E values larger than 100 (113-115). 

Biphasic systems consisting of ionic liquids and supercritical CO2 showed dramatic enhancement in the operational stability of both free and immobilized Candida antarctica lipase B (CALB) in the catalyzed kinetic resolution of rac- -phenylethanol with vinyl propionate at 10 MPa and temperatures between 120 and 150°C (Scheme 30) 275). Hydrophobic ionic liquids, [EMIM]Tf2N or [BMIM]Tf2N, were shown to be essential for the stability of the enzyme in the biotransformation. Notwithstanding the extreme conditions, both the free and isolated enzymes were able specifically to catalyze the synthesis of (J )-l-phenylethyl propionate. The maximum enantiomeric excess needed for satisfactory product purity (ee >99.9%) was maintained. The (S)-l-phenylethanol reactant was not esterified. The authors suggested that the ionic liquids provide protection against enzyme denaturation by CO2 and heat. When the free enzyme was used, [EMIM]Tf2N appeared to be the best ionic liquid to protect the enzyme, which... 

When the water-miscible ionic liquid [MMIM][MeS04] was used as a neat medium for the enzymatic transformations, however, poorer performance was observed. For the kinetic resolution of mc-l-phenylethanol by transesterification with vinyl acetate with a set of different lipases dispersed in the pure ionic liquid, it was found that [MMIM][MeS04] was among the poorest media for the enzymes (291). It has been recognized that some water-miscible ionic liquids in the pure form are denaturants (27), but, when they are used in the presence of excess water, their tendency to... 

In certain cases, especially for neutral substrates, the formation of covalent p,n-pairs, instead of salts, may be necessary to achieve optical resolution by crystallization. Suitable derivatives are esters of camphanic acid (1) or chrysanthemic acid (2) with racemic alcohols, or esters of menthol (3) and 1-phenylethanol (5) with racemic acids, or hydrazones of menthylhydrazine (4) with racemic aldehydes and ketones. 

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) ( ) ... 

Screening of eight lipases and two esterases 10 different ionic liquids Kinetic resolution of (R,S)-l-phenylethanol 44... 

The high thermostability of lipases in ionic liquids has stimulated research into kinetic resolutions at elevated temperatures [129]. The PsL-mediated acylation of 1-phenylethanol by vinyl acetate in [BMIm][ Tf2N] remained highly... 

Enzymatic resolution of racemic secondary alcohols by enantiomer-selective acylation gives optically pure compounds with up to 50% yield [332], When this method is coupled with the principle of dynamic kinetic resolution (see Section 1.4.1.5), the theoretical yield increases to 100%. Thus a reaction system consisting of an achiral transition-metal catalyst for racemization, a suitable enzyme, acetophenone, and an acetyl donor allows the transformation of racemic 1-phenylethanol to the R acetates with an excellent ee (Scheme 1.93) [333]. The presence of one equiv. of acetophenone is necessary to promote the alcohol racemization catalyzed by the... 

FIGURE 19 Effect of temperature on the chiral resolution of (a, c) 1-phenylethanol and (b, d) camphor on capillary containing the Chiralsil-nickel CSP (SFC). (From Ref. 94.)... 

The standard in the field was set with the following racemic resolution of secondary alcohols the transesterification of vinyl acetate to (S)-O-acetyl phenylethanol was catalyzed at room temperature by (isopropylamino)cyclopentadienylruthenium chloride and CALB with 97% yield and > 99% e.e. A reaction temperature of 25 °C, a reaction time of 30 h, and use of molecular sieve 4 A as a water trap, sodium carbonate as base, and vinyl acetate as acyl donor, are all major improvements over the previous state-of-the-art (Choi, 2002). 

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