IL r it

Figure 10: Lipase-catalyzed acylation: the reaction depended on the counter anionic part of IL.

A mixed solvent system of an IL with organic solvent sometimes gave very nice results: Lundell21 reported that enhanced enantioselectivity was obtained when lipase-catalyzed acylation was carried out in a mixed solvent system of [emim][TFSI] with t-BuOMe (1:1), while poor enantioselectivity was recorded for that in the pure [emim][TFSI] solvent (Fig. 11).

Ganske and co-workers22a b reported that lipase-catalyzed acylation of a glucose derivative proceeded smoothly in a mixed solvent of [bmim][BF4] with t-BuOH, while no reaction took place in [bmim][BF4] (Fig. 12). These results taught us that a mixed solvent system of IL with organic solvent may be a good solution if the desired reaction did not take place in a pure IL solvent.

Modified enantioselectivity was reported if the reaction was carried out in an IL solvent instead of traditional organic solvent.23 For instance, Kazlauskas and Kim independently reported that the regioselectivity of lipase-catalyzed reaction was enhanced if the reaction was carried out in an IL solvent system (Fig. 13).7c24 Recently Wu and co-workers reported another chip of lipase-catalyzed reaction: a

Figure 11: Lipase-catalyzed reaction in a mixed solvent system using microwave reaction conditions at 80° C.

Lipase PS Pr^O^ QH H

Figure 11: Lipase-catalyzed reaction in a mixed solvent system using microwave reaction conditions at 80° C.

E>200. Microwave at BOX

Lipase PS Pr^O^ QH H

E>200. Microwave at BOX

Figure 12: Lipase-catalyzed regioselective esterification of glucose in a mixed solvent of IL with t-BuOH.

Figure 12: Lipase-catalyzed regioselective esterification of glucose in a mixed solvent of IL with t-BuOH.

CAL-B

,OAc

MeN^N^OMe

Me-fCfi,OMe

Figure 13: Enhanced regioselectivity of lipase-catalyzed acylation in IL solvent system.

significant enhanced enantioselectivity was obtained for Candida rugosa lipase-catalyzed acylation of ibuprofen in [bmim][BF4] compared to the isooctane solvent system (Fig. 14).25 Interestingly no enantioselectivity was obtained for [bmim][MeSO4], [bmim][OctylSO4], [(n-C6H13)3C14H29PN3], [Bu3MeP][OTs] or [mmim][MeSO4] solvent. These results clearly showed that appropriate choice of the IL is the key point of the reaction.

"npy

COOH

PrOH

[in-C8H13)aC14H2gP][N3],

Figure 14: Great diversity in enantioselectivity among IL solvent systems.

We investigated lipase-catalyzed acylation of 1-phenylethanol in the presence of various additives, in particular an IL additive using diisopropyl ether as solvent. Enhanced enantioselectivity was obtained when a BEG-based novel IL, i.e., imidazolium polyoxyethylene(10) cetyl sulfate, was added at 3-10 mol% vs. substrate in the Burkholderia cepacia lipase (lipase PS-C) catalyzed trans-esterification using vinyl acetate in diisopropyl ether or a hexane solvent system.5g

Recently Kim reported another very interesting salt-mediated activation of a lipase: lipase PS was mixed with the IL and resulted in "ionic liquid-coated lipase PS" which showed more enhanced enantioselectivity than commercial lipase PS-C in toluene, though no significant modification of the reaction rate was obtained.26 We discovered that lyophilization was essential to activate the lipase effectively by the IL. The novel IL [bdmim][cetyl-PEG10-sulfate] (IL1) worked as an excellent activator of lipase PS-catalyzed acetylation of various types of secondary alcohols using vinyl acetate as acyl donor in i-Pr2O solvent, while maintaining excellent enantioselectivity. More than 500- to 1000-fold acceleration was accomplished for some substrates (Fig. 15 and Table 1).27 On the contrary, previously established activation protocol such as PEG coating of a lipase could accelerate the reaction but caused no significant enhanced enantioselectivity; also using toluene as solvent sometimes provided enhanced enantios-electivity for some substrates, but other times caused a significant reduction in the reaction rate. Since similar activation was observed for CRL, we expect that the activation effect of IL1 might be general for various lipases. We believe this work not only represents a significant advance in the manner of preparation of optically active compounds using an enzymatic reaction but also provides a new aspect in the application of an IL for such a reaction. Since the present activation was significantly dependent on the substrate, we are also hoping that further optimization of the cationic part of the ILs may make it possible to apply the present protocol of lipase activation to various broader types of substrates.

IL1-PS Vinyl acetate

IL1:

Me-N7N+~Bu

Me o

0-S-^CH2CH20yC1sH33

o to

Figure 15: Results of activation effect by IL1-coating on the lipase PS-catalyzed enantioselective acylation.

Table 1

Typical examples of results of activation effect of IL1 coating on the lipase PS-catalyzed enantioselective acylation of (±)-1

Table 1

Typical examples of results of activation effect of IL1 coating on the lipase PS-catalyzed enantioselective acylation of (±)-1

Substrate

Ratea (above) and E value (below)

Specific activityb of IL1-PS vs. PS-C

Lipase PS

IL1-PS

OH (±)-1a

Rate: 65 E = 16

Rate: 1000 E > 200

15

OH NC^Js.,-

Rate: 100 E = 39

Rate: 9800 E = 40

98

(±)-1b

GOT""

Rate: 13 E > 200

Rate: 14 E > 200

1

(±)-1c

CD^

Rate: 1.0 x 10-2 E = 199

Rate: 11 E> 200

1100

(±)-1d

HO

Rate: 1.2 x 10-2 E> 200

Rate: 6 E > 200

500

(±)-1e

a Rate: mM h 1 mg (enzyme) 1. Rate was determined by GC analysis. b Specific activity was calculated by the rate of IL1-PS divided by that of PS-C.

a Rate: mM h 1 mg (enzyme) 1. Rate was determined by GC analysis. b Specific activity was calculated by the rate of IL1-PS divided by that of PS-C.

5. VARIOUS BIOTRANSFORMATIONS IN AN IONIC LIQUID SOLVENT SYSTEM

An IL solvent system is applicable to not only lipase but also other enzymes, though examples are still limited for lipase-catalyzed reaction in a pure IL solvent. But several types of enzymatic reaction or microbe-mediated reaction have been reported in a mixed solvent of IL with water. Howarth28 reported Baker's yeast reduction of a ketone in a mixed solvent of [bmim][PF6] with water (10:1) (Fig. 16). Enhanced enantioselectivity was obtained compared to the reaction in a buffer solution, while the chemical yield dropped.

Antibody-catalyzed aldol condensation was demonstrated in a [bmim][PF6] solvent system by Kitazume and co-workers29 (Fig. 17). They tested recyclable use of antibody catalyst in the solvent system and, very interestingly, found that the chemical yield was increased for the second cycle (89%) over the initial run (21%).

Figure 16: Baker's yeast reduction of ketones in a mixed solvent of IL with water.

Figure 16: Baker's yeast reduction of ketones in a mixed solvent of IL with water.

Figure 17: Antibody-mediated aldol reaction in IL solvent system.

Okrasa and co-workers reported an interesting combination reaction of glucose oxidase and peroxidase in a mixed solvent of [bmim][PF6] with water (Fig. 18). Asymmetric oxidation of sulfide was accomplished successfully in the reaction system.30

Griengl reported the first example of hydroxynitrile lyase-catalyzed cyanohydrin formation in a mixed solvent system of [bmim][BF4] and buffer (pH 3.7) (1:1) (Fig. 19).31a In the reaction, a mixed solvent system was essential, but excellent results were obtained.

Matsuda32 recently reported an elegant solution for using a delicate enzyme system in an IL solvent system (Fig. 20). The authors prepared Geotrichum candidum IFO5767 dried cell on water-absorbing polymer BL-100 and used

Figure 18: Glucose oxidase-mediated asymmetric oxidation of sulfide in IL

solvent system.

Figure 18: Glucose oxidase-mediated asymmetric oxidation of sulfide in IL

solvent system.

Figure 19: Enantioselective cyanohydrin formation using hydroxynitrile lyase in

IL solvent system.

Figure 19: Enantioselective cyanohydrin formation using hydroxynitrile lyase in

IL solvent system.

Figure 20: Use of IL as reaction medium for asymmetric reduction by

Geotrichum candidum.

Figure 20: Use of IL as reaction medium for asymmetric reduction by

Geotrichum candidum.

it for the asymmetric reduction of methyl ketones. The system made it possible to realize easy work-up and provided the corresponding alcohol with excellent enantioselectivity. Of interest was that the reactivity of the enzyme significantly depended on the counter anion of IL. The reaction proceeded smoothly in imidazolium PF6, BF4 or TFSI salt, while no reaction took place in imidazolium OTf, EtSO4, MeSO4 or NO3 salt as solvent. As reported in the reactions of lipases,14 20 nitric anion or sulfate anion might have a strong interaction with some parts of the enzyme protein, due to the highly nucleophilic nature of these anions, and caused deactivation of the enzyme activity.

Chiappe and co-workers33 reported chloroperoxide (CPO)-catalyzed oxidation in hydrophilic ILs as co-solvents (Fig. 21). The authors investigated the hydrophilic ILs on the activity of CPO and found that CPO showed a higher tolerance toward IL than organic solvent; good activity was obtained when the reaction was carried out in a mixed solvent of [mmim][Me2PO4] and buffer (pH 5.0) (1:1) rather than buffer solution.

CI i

O OH Chloroperoxidase (CPO) O

CI CI

CI CI

HjOa/KCI IL (30% v/v) in phosphate buffer

HjOa/KCI IL (30% v/v) in phosphate buffer

X=MeS04- H2P04" EtS04- CH3C02-MejPO«" Citr: HOC(CH2COOH)2COO"

X=MeS04- H2P04" EtS04- CH3C02-MejPO«" Citr: HOC(CH2COOH)2COO"

Figure 21: CPO-catalyzed chlorination in IL solvent system.

6. CONCLUDING REMARKS

There might be at least four advantages of the enzymatic reaction using an IL solvent system: (1) the purification process is very easy; (2) the reaction does not waste any water discarded with the organic solvent; (3) it is possible to use the enzyme repeatedly in this system; and (4) it is possible to activate the reaction using an IL-type supporting material. It is now completely established that ILs might be good candidates as the solvent of lipase-catalyzed reaction. However, we should consider the risk of using novel material. For example, Rogers warned that PF6 may be decomposed by moisture at higher temperature and produce toxic hydrogen fluoride.34a The authors also reported that cellulase was inhibited by the addition of [bmim][Cl]; chloride anion caused change of the folding pattern of the enzyme protein, which led to deactivation of the enzyme.34b However, imidazolium cation was reported to be easily degraded in the metabolism system.35 I believe that IL is superior to the conventional organic solvent if we try to create an enzymatic reaction under anhydrous conditions. To meet the challenge in chemistry of developing practical processes, the proper choice of a reaction medium is very important. Breakthroughs have sometimes come along with innovation of a reaction medium in chemical reactions and this is true even in enzymatic reactions. I hope this chapter may provide a hint for the reader's research.

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Future Directions in Biocatalysis Edited by Tomoko Matsuda © 2007 Elsevier B.V. All rights reserved.

Chapter 2

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