Chemoenzymatic synthesis and biological evaluation of enantiomerically enriched 1-(β-hydroxypropyl)imidazolium-and triazolium-based ionic liquids

Article abstract of DOI:10.3762/bjoc.9.56

Racemic 1-(β-hydroxypropyl)azoles were prepared by solvent-free direct regioselective ring opening of 1,2-propylene oxide with imidazole or 1,2,4-triazole. Lipase-catalyzed transesterification of alcohols with vinyl acetate resulted in kinetic enantiomers resolution. Separated (S)-enantiomers of (+)-1-(1H-imidazol-1-yl)propan-2-ol and (+)-1-(1H-1,2,4-triazol-1-yl)propan-2- ol were quaternized with alkyl bromides or iodides, yielding novel optically active ionic liquids. Racemic salts were tested against a wide range of microorganisms.

Full text of DOI:10.3762/bjoc.9.56

Chemoenzymatic synthesis and biological
evaluation of enantiomerically enriched
1-(β-hydroxypropyl)imidazolium- and
triazolium-based ionic liquids
Paweł Borowiecki*, Małgorzata Milner-Krawczyk and Jan Plenkiewicz
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 516–525.
Warsaw University of Technology, Faculty of Chemistry,
Noakowskiego St. 3, 00-664 Warsaw, Poland
doi:10.3762/bjoc.9.56
Received: 30 November 2012
Accepted: 15 February 2013
Published: 12 March 2013
Email:
Paweł Borowiecki* - pawel_borowiecki@onet.eu
* Corresponding author
Associate Editor: J. N. Johnston
Keywords:
© 2013 Borowiecki et al; licensee Beilstein-Institut.
License and terms: see end of document.
antibiotics; antifungal agents; double derivatization; enzyme catalysis;
ionic liquids
Abstract
Racemic 1-(β-hydroxypropyl)azoles were prepared by solvent-free direct regioselective ring opening of 1,2-propylene oxide with
imidazole or 1,2,4-triazole. Lipase-catalyzed transesterification of alcohols with vinyl acetate resulted in kinetic enantiomers resolu-
tion. Separated (S)-enantiomers of (+)-1-(1H-imidazol-1-yl)propan-2-ol and (+)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol were quater-
nized with alkyl bromides or iodides, yielding novel optically active ionic liquids. Racemic salts were tested against a wide range of
microorganisms.
Introduction
Aromatic heterocycles play a crucial role in medicinal chem- logical requirements, therefore, its presence in active substances
istry [1,2]. More than half of all known drugs contain at least is very desirable. Imidazole rings are also frequently present in
one heterocyclic component. Novel biologically active com- antibacterial [6-8], antifungal [9-13], antiparasitic [14,15], anti-
pounds are often designed as analogues of endogenous ligands cancer [16,17] and antiaggregatory [18] preparations.
that are vital to biochemical processes. Since most of these
substances are comprised of heterocycles, such rings by default In turn, many 1,2,4-triazole derivatives exhibit antimicrobial
become core structures of the newly designed therapeutically [19,20], antifungal [21], antitumor [22], analgesic [23], anti-
active compounds.
inflammatory [24], psychoactive [25-27], anticonvulsant [28],
diuretic [29], and anti-HIV [30] activity. 1,2,4-Triazole deriva-
Many biomolecules (e.g., vitamins, amino acids, purines, alka- tives also represent the most important group of herbicides and
loids) containing an imidazole ring [3-5] meet the relevant bio- fungicides [31].
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Beilstein J. Org. Chem. 2013, 9, 516–525.
In recent years growing attention has been focused on imida- pyl)azoles as a key step. We have shown that this attempt is
zole- and 1,2,4-triazole-derived ionic liquids (ILs), as well as simple and allows the preparation of new types of optically
their chiral derivatives (CILs). CILs have become a subject of active ionic liquids. Inhibitory activity of the newly synthesized
intensive study since their potential as catalysts for asymmetric CILs was tested towards gram-negative and gram-positive
induction [32-34], as supplements for influencing reaction ste- bacteria and fungi.
reoselectivity [35], as chiral solvents in stereoselective polymer-
Results and Discussion
ization [36], as chiral phase for gas chromatography [37], or as
Synthesis and enzymatic resolution of the
N-2-hydroxypropylazoles
chiral differentiating solvents for spectroscopic investigations
[38,39] is far from being exhausted. CILs can also act as a tool
for organizing the structure of solid polymeric electrolytes
(SPE), playing the triple role as plasticizer, solvent for the ions,
and medium. Most of the described optically active ILs are
prepared from easily accessible natural chiral substrates [40].
The use of ILs in so-called “green chemistry”, as for example
solvents in inorganic or organic syntheses or as a replacement
for many hazardous and volatile organic solvents, raises the
question about the toxicity of newly designed compounds.
Therefore, it is crucial to select the least toxic ILs with good
chemical properties that can be used in industrial processes
[41]. Moreover, a number of current studies have demonstrated
the potential of certain ionic liquids to exhibit excellent antimi-
In this paper we report the synthesis of racemic 1-(1H-imidazol-
1-yl)propan-2-ol and 1-(1H-1,2,4-triazol-1-yl)propan-2-ol and
the procedure for lipase-catalyzed kinetic separation of their
enantiomers. These enantiomers can be used as chiral synthons
for new drugs, pesticides or task-specific ionic liquids. The
1-(β-hydroxypropyl)-imidazole (±)-3a and -triazole (±)-3b used
in this study were prepared as racemic mixtures according to the
method described by Yus and co-workers [46] (Scheme 1).
Next, these compounds were used as a new type of substrate in
lipase-catalyzed transesterification, yielding both enantiomers
with good optical purity.
crobial activity, raising the possibility that ionic liquids could The syntheses of the secondary alcohols (±)-3a and (±)-3b were
find application as biocidal agents in the control of microor- accomplished by the addition of imidazole (2a) or 1,2,4-tria-
ganism growth [42-45].
zole (2b) to 1,2-propylene oxide (1) under solvent-free condi-
tions. The epoxide ring-opening reactions were carried for 24 h
Herein, we report the results of our investigation on the at elevated temperature (32 °C) and resulted in the formation of
chemoenzymatic synthesis of new chiral ionic liquids the appropriate alcohols (±)-3a and (±)-3b in high yields
using enzyme-catalyzed kinetic resolution of 1-(β-hydroxypro- (Scheme 1).
Scheme 1: Synthesis of optically active ILs. Reagents and conditions: (i) 1,2-propylene oxide (1.1 equiv), 32 °C, 24 h; (ii) vinyl acetate (5 equiv),
Novozyme SP 435, 2-methyl-2-butanol, rt, 48 h, magnetic stirrer; (iii) vinyl acetate (5 equiv), enzyme, 2-methyl-2-butanol/MTBE (methyl tert-butyl
ether), rt, 250 rpm; (iv) RX (3 equiv), Δ, dry CH3CN.
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Beilstein J. Org. Chem. 2013, 9, 516–525.
In the next step, the influence of crucial parameters in enzyme- neering". After testing several solvents for lipase-catalyzed
catalyzed reactions such as the type and quantity of the biocata- acetylation of (±)-3a and (±)-3b with vinyl acetate, we deter-
lyst and solvent on the enantiomers resolution was investigated. mined the following order of their utility as the reaction media:
The aim was to achieve a conversion close to 50% and 99% ee MTBE ~ 2-methyl-2-butanol > acetone > 1,4-dioxane >> aceto-
for the slow-reacting substrates and product enantiomers. Four nitrile. Further optimization revealed that MTBE and 2-methyl-
different lipases, i.e., two native (Amano PS, Amano AK) and 2-butanol are unsurpassed, not only from the viewpoint of sub-
two immobilized enzymes (Novozym SP 435, Amano PS-IM), strate solubility and reactivity, but also due to the highest enan-
were chosen for the transesterification studies. The screenings tiomeric excesses of the separated enantiomers. Results of the
were performed with a 5-fold molar excess of vinyl acetate as lipase-catalyzed transesterification of the racemic (±)-3a are
an irreversible acyl donor at ambient temperature. The selec- summarized in Table 1.
tion of a proper solvent is a significant factor in biocatalysis
[47,48], since solvents are able to change the activity [49-51] The experiments demonstrated that the reaction proceeded
and enantioselectivity [52-54] of an enzyme. Conformational particularly efficiently when Amano AK or Amano PS-IM were
changes in the enzyme structure under the influence of solvent used. These enzymatic preparations also gave excellent reac-
can even invert the substrate specificity and the enzyme–sub- tion enantioselectivities (Table 1, entries 3–5 and 11–13, E >>
strate affinity [55]. The ability to control the direction of an 200). Particularly, Amano AK was characterized by very high
enzymatic reaction and its specificity in a nonaqueous environ- selectivity (Table 1, entry 3, E = 584) toward the acetate (+)-6a
ment has resulted in the development of so-called "solvent engi- formation, which was enantiomerically pure (>99% ee) when
Table 1: Lipase-catalyzed resolution of racemic 1-(1H-imidazol-1-yl)propan-2-ol (±)-3a.
Entry Enzyme
Solvent
MTBEe
t (h)
Conv.a (%)
Product
eeb (%)
Ec
Yieldd (%)
alcohol
ester
41
97
95
56
1
20
30
32
98
Amano PS
2
alcohol
ester
46
99
43
67
2-methyl-2-butanole 26
103
alcohol
ester
88
>99
97
62
3
MTBEe
5
47
41
45
584
419
492
alcohol
ester
70
>99
95
90
4
5
Amano AK
2-methyl-2-butanole 22
2-methyl-2-butanolf 43
alcohol
ester
80
>99
94
91
alcohol
ester
97
73
95
79
6
MTBEe
1.5
7
57
59
30
53
57
26
23
41
16
17
alcohol
ester
98
68
53
73
7
MTBEf
alcohol
ester
40
93
99
64
8
Novozym SP 435
2-methyl-2-butanole
7
alcohol
ester
82
73
70
62
9
2-methyl-2-butanolf 11
2-methyl-2-butanolf 12
alcohol
ester
92
68
40
60
10
alcohol
ester
64
99
98
75
11
12
13
MTBEf
3
4
5
39
46
38
386
254
368
alcohol
ester
82
98
66
95
Amano PS-IM
MTBEf
alcohol
ester
60
>99
86
88
2-methyl-2-butanolf
aConversion was calculated from the enantiomeric excess of the starting material (ees) and the product (eep) according to the formula: conv. =
ees/(ees + eep). bDetermined by HPLC analysis by using a Chiralcel OD-H column. cCalculated according to Chen et al. [56], by using the equation:
E = ln[(1 − conv.)(1 − ees)]/ln[(1 − conv.)(1 + ees)]. dIsolated yield after column chromatography. eConditions: (±)-3a 300 mg, lipase 100 mg, solvent
3 ml, vinyl acetate 1 g (5 equiv), 250 rpm at rt. fConditions: (±)-3a 300 mg, lipase 50 mg, solvent 3 ml, vinyl acetate 1 g (5 equiv), 250 rpm at rt.
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Beilstein J. Org. Chem. 2013, 9, 516–525.
the reaction was arrested close to 45% conversion. In turn, tion catalyzed by Amano PS-IM, which was much faster than
conversion exceeding 57% was beneficial for high optical that catalyzed by native Amano PS. The reaction enantio-
purity of the remaining alcohol (+)-5a (Table 1, entries 6 and 7, selectivities were fairly good (E = 20–56) for all of the tested
>97% ee).
lipases except Novozyme SP 435, which showed very high
activity but low stereoselectivity (E = 6).
In the lipase-catalyzed acetylation of alcohol (±)-3b the best
results were achieved with native Pseudomonas fluorescens The racemic acetyl esters (±)-4a and (±)-4b used for determina-
lipase (Amano AK) suspended in 2-methyl-2-butanol (Table 2, tion of the enantiomeric configurations were prepared in good
entry 5, E = 56). As shown in the Table 2, the reaction time isolated yields by lipase-catalyzed esterification of the appro-
required for about 50% substrate conversion varied from 5 h for priate 1-(β-hydroxypropyl)azole (±)-3a or (±)-3b with vinyl
Amano PS-IM in MTBE (Table 2, entry 8) to 132 h for the least acetate as the acyl donor (Scheme 1). The enzyme-catalyzed
active enzyme, i.e., native Amano PS in 2-methyl-2-butanol syntheses of acetylated standards were used, since the conven-
(Table 2, entry 2).
tional esterification procedure of (±)-3a and (±)-3b (with Ac2O,
pyridine and DMAP) gave low yields (ca. 25%) of the acetates.
Generally, similar to acetylation of (±)-3a, the highest reaction
rates for (±)-3b were observed with Amano PS-IM in MTBE.
Determination of the stereochemistry of alco-
As usual, the optical purities of the acetate, as well as of the hols (+)-5a and (+)-5b
remaining alcohol, were dependent on the enzyme used and the The absolute configurations of the alcohols (+)-5a and (+)-5b,
conversion rate. For example, with Amano AK the reaction obtained by lipase-catalyzed transesterification of the race-
reached 37% conversion after 30 h giving product (+)-6b in mates (±)-3a and (±)-3b, were determined by the modified
90% ee (Table 2, entry 4), and after 49 h the stereochemical Mosher’s method as described by Riguera et al [57]. This ap-
course reached 54% conversion yielding the slower reacting proach consists of comparing the differences between 1H NMR
enantiomer (+)-5b with high enantiomeric excess (Table 2, chemical shifts recorded for the diastereomeric esters prepared
entry 5, 98% ee). The highest optical purity for (+)-6b (90% ee) from the separated enantiomers of the alcohols (+)-5a or (+)-5b
and the shortest reaction time (10 h) were obtained by the reac- and (R)- and (S)-enantiomers of methoxyphenylacetic acid
Table 2: Lipase-catalyzed resolution of racemic 1-(1H-1,2,4-triazol-1-yl)propan-2-ol (±)-3b.
Entry Enzyme
Solvent
t (h)
Conv.a (%)
Product
eeb (%)
Ec
Yieldd (%)
alcohol
ester
57
84
77
87
1
MTBEe
65
40
39
20
27
Amano PS
2
alcohol
ester
56
88
85
73
2-methyl-2-butanole
132
alcohol
ester
63
89
97
97
3
MTBEe
12
30
49
41
37
54
33
33
56
alcohol
ester
54
90
93
97
4
5
Amano AK
2-methyl-2-butanole
2-methyl-2-butanole
alcohol
ester
98
85
93
97
alcohol
ester
49
59
82
98
6
7
MTBEe
7
8
45
40
6
6
Novozym SP
435
alcohol
ester
40
60
95
93
2-methyl-2-butanole
alcohol
ester
74
84
76
87
8
9
MTBEf
5
47
41
25
36
Amano PS-IM
alcohol
ester
62
90
98
77
2-methyl-2-butanolf
10
aConversion was calculated from the enantiomeric excess of the starting material (ees) and the product (eep) according to the formula conv. =
ees/(ees + eep). bDetermined by HPLC analysis by using Chiralcel OD-H column. cCalculated according to Chen et al. [56], by using the equation:
E = ln[(1 − conv.)(1 − ees)]/ln[(1 - conv.)(1 + ees)]. dIsolated yield after column chromatography. eConditions: (±)-3a 300 mg, lipase 100 mg, solvent
3 ml, vinyl acetate 1 g (5 equiv), 250 rpm at rt. fConditions: (±)-3a 300 mg, lipase 50 mg, solvent 3 ml, vinyl acetate 1 g (5 equiv), 250 rpm at rt.
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Beilstein J. Org. Chem. 2013, 9, 516–525.
Scheme 2: Conversion of (+)-5a and (+)-5b into MPA esters 9a, 9b and 10a, 10b.
(MPA, Mosher reagent) (Scheme 2). The utility of this method
applied to secondary alcohols possessing heterocyclic azole
rings has been demonstrated by us previously [58].
The absolute configuration of the substrate is deduced by inter-
pretation of the signs of the ΔδRS values, by using an empirical
model that assumes that in MPA esters of secondary alcohols,
the most representative conformer has the methoxy group of
MPA, the carbonyl group, and a proton bonded to the stere-
Figure 1: Model for the configurational correlation of MPA esters 9a,
9b and 10a, 10b.
ogenic center of the alcohol in the same plane.
to significant differences in chemical shifts (δ = 0.91 ppm),
especially in the case of the imidazolium derivatives 9a and
10a. Comparison of the 1H NMR spectra of these two species
for this particular alcohol (+)-5a shows that the phenyl ring of
the chiral auxiliary reagent projects its magnetic anisotropy
strongly toward the H(2’) proton in the (S)-derivative 9a, while
the same proton in the (R)-MPA ester 10a remains unaffected.
The opposite phenomenon is observed for methyl group protons
H(8’), which are shielded in (R)-MPA derivatives 10a due to
the strength and direction of the anisotropic effect, while in (S)-
MPA ester 9a they are unaffected. Similarly, information
gained from 1H NMR spectra of both species of triazolic
alcohol, 9b and 10b, defined (+)-5b as having (S)-configura-
tion (see the lower part of the Figure 2).
The differences in the chemical shifts (ΔδRS) observed in the
spectra of the esters prepared from the chiral auxiliaries [(R)-
and (S)-MPA acids, respectively], were calculated separately
for the protons attached to the carbon atoms situated on both
sides of the chirality center, as shown by the following equa-
tions:
The signs of these parameters bear the information necessary Synthesis of chiral ionic liquids
for the configurational assignment, since they indicate the rela- In the final step, the appropriate chiral intermediates (S)-(+)-1-
tive position of L1/L2, with respect to the anisotropic group (1H-imidazol-1-yl)propan-2-ol ((+)-5a) or (S)-(+)-1-(1H-1,2,4-
(phenyl group of MPA). The positive value of ΔδRS, which triazol-1-yl)propan-2-ol ((+)-5b) and various alkyl halides were
corresponds to the signal of the protons of the substituent L1, reacted in dry acetonitrile. The quaternization of the N-3 atom
and the negative sign for the protons L2 indicate an (S)-configu- of imidazole and that of N-4 of the 1,2,4-triazole ring of the
ration for the enantiomers of both types of investigated alco- derivatives, provided salts (+)-7a–h and (+)-8a–f in >81% and
hols (+)-5a and (+)-5b according to Figure 1. The 1H NMR >78% isolated yields, respectively (Table 3). With the excep-
spectra recorded for the resulting diastereomeric derivatives tion of (+)-8a–c and (+)-8e–f, which are exceedingly viscous
(Figure 2) confirmed the results of the above equations.
liquids (gums), all of the chiral hydroxy-functionalized imida-
zolium and one of the triazolium salts are liquid at room
The chiral environment provided by the derivatizing agent temperature. Final products were characterized by 1H,
(MPA) covalently associated with the respective alcohol leads 13C NMR and FTIR spectroscopy as well as high-resolution
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Beilstein J. Org. Chem. 2013, 9, 516–525.
Figure 2: The 1H NMR spectra of the derivatives of two unreacted chiral alcohols (+)-5a (top) and (+)-5b (bottom). Symbols marked in green repre-
sent protons shielded by the phenyl ring of chiral auxiliary (MPA); blue labels stand for unaffected protons.
electrospray ionization mass spectrometry (HRMS–ESI). Their select the most promising compounds for further determination
structures were found to be spectroscopically well–defined, of minimal inhibitory concentrations (MICs) by the broth dilu-
which was further confirmed by elemental analyses. For the tion method (Table 5). In turn, the antifungal activity was tested
purpose of biological tests, the racemic mixtures all of salts by the agar dilution method. The results are listed in Table 6.
presented in Table 3 were synthesized.
The antimicrobial and antifungal activities of tested CILs are
Antimicrobial activity of racemic ionic liquids
significantly dependent on the alkyl chain length, as was
Antibacterial and antifungal activities of the synthesized demonstrated in numerous previous studies [59]. The high toxi-
racemic CILs were evaluated against a wide range of microor- city of CILs was noted for CILs with alkyl-chain substituents of
ganisms. The studies were conducted on three strains of gram- 10–16 carbon atoms (Table 4 and 5). Moreover, the chemical
negative bacteria, two strains of gram-positive bacteria, and nature of the cationic head group influenced the overall toxicity
eight strains of fungi. For the preliminary screening of bacteria of the CILs, which is in good agreement with several previous
and yeasts we used the agar diffusion test (Table 4) in order to studies [60]. The imidazolium CILs exhibited visibly stronger
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Beilstein J. Org. Chem. 2013, 9, 516–525.
Table 3: Synthesis of chiral imidazolium (+)-7a–h and triazolium ILs (+)-8a–f.
Entry
IL
R
X
t (h)
T (°C)
Yield (%)
[α]Da
1
2
3
4
5
6
7
8
(+)-7a
(+)-7b
(+)-7c
(+)-7d
(+)-7e
(+)-7f
(+)-7g
(+)-7h
C3H7
Br
Br
Br
Br
I
96
96
96
96
96
96
96
96
65
92
93
94
82
92
92
86
81
+23.6
+25.3
+17.2
+15.4
+16.3
+15.8
+14.2
+11.4
C3H5
65
C4H9
80
C5H11
C7H15
C10H21
C12H25
C16H33
82
82
I
82
I
120
120
I
9
(+)-8a
(+)-8b
(+)-8c
(+)-8d
(+)-8e
(+)-8f
C3H7
Br
Br
Br
Br
I
48
48
48
48
48
48
65
65
80
82
82
82
98
94
90
78
87
92
+18.8
+15.6
+17.7
+15.4
+10.2
+8.5
10
11
12
13
14
C3H5
C4H9
C5H11
C7H15
C10H21
I
aSpecific rotation; c solution in chloroform (c 1.0).
Table 4: Growth inhibition halo (cm) for the racemic imidazolium and triazolium CILs (25 mM).
E. coli
ATCC 8739
G(−)
S. typhimurium
ATCC 14028
G(−)
P. aeruginosa
ATCC 9027
G(−)
B. subtilis
ATCC 6633
G(+)
S. aureus
ATCC 6538
G(+)
C. albicans
ATCC 10231
yeast
CIL
R
(±)-7a
(±)-7d
(±)-7e
(±)-7f
C3H7
–
–
–
–
–
–
–
–
+
C5H11
C7H15
C10H21
–
–
–
–
–
1.20 ± 0.00
1.40 ± 0.00
1.03 ± 0.04
1.23 ± 0.04
1.05 ± 0.00
1.10 ± 0.00
1.20 ± 0.00
2.30 ± 0.00
1.73 ± 0.04
2.80 ± 0.00
(±)-8a
(±)-8d
(±)-8e
(±)-8f
C3H7
–
–
–
–
–
–
C5H11
C7H15
C10H21
–
–
–
–
–
–
–
–
–
–
1.00 ± 0.00
1.25 ± 0.07
–
1.30 ± 0.14
1.25 ± 0.07
1.08 ± 0.04
1.90 ± 0.14
1.18 ± 0.04
–: No inhibition; +: total growth inhibition
Table 5: The MIC (mM) values for the racemic imidazolium and triazolium CILs.
E. coli
ATCC 8739
G(−)
S. typhimurium
ATCC 14028
G(−)
P. aeruginosa
ATCC 9027
G(−)
B. subtilis
ATCC 6633
G(+)
S. aureus
ATCC 6538
G(+)
C. albicans
ATCC 10231
yeast
CIL
R
(±)-7f
(±)-7g
(±)-7h
C10H21
C12H25
C16H33
0.5
0.3
0.2
0.4
0.5
0.5
>9.5
1.6
0.5
0.5
0.2
0.2
0.3
0.3
0.3
0.1
0.3
9.0
(±)-8f
C10H21
1.7
4.8
5.5
3.0
0.5
0.9
antibacterial and antifungal activity than triazolium CILs of the tested compounds could still be observed, with the
(Tables 4–6). However, the filamentous fungi displayed high strongest toxicity demonstrated by CILs with an alkyl chain
tolerance towards the tested CILs. Nevertheless, the relation substituent of 12 carbon atoms (Table 6). This high tolerance of
between the alkyl chain substituent and the antifungal activity filamentous fungi against CILs could be explained by the ability
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Beilstein J. Org. Chem. 2013, 9, 516–525.
Table 6: Antifungal activity (% of control) of the racemic imidazolium and triazolium CILs (1mM).
F. oxysporum F. sambucinum F. culmorum A. brasiliensis C. coccodis
P. infestans
MP 324
P. infestans
MP 1320
CIL
R
MF 5
MF 1
MF 18
ATCC 16404 MC 1
(±)-7a C3H7
89.97 ± 0.00 99.60 ± 0.88
98.38 ± 0.81 100.78 ± 0.78 98.70 ± 1.67
101.32 ± 1.02 92.89 ± 1.18 96.71 ± 1.58
82.73 ± 0.66 89.92 ± 5.47 96.55 ± 1.24
68.40 ± 1.00 91.55 ± 0.68 99.54 ± 1.76
66.78 ± 3.68 87.20 ± 0.72 93.73 ± 1.97
98.81 ± 3.76 93.00 ± 7.87
99.49 ± 5.01 104.17 ± 7.04
90.65 ± 2.14 59.29 ± 3.20
113.32 ± 3.17 99.43 ± 4.21
88.21 ± 6.76 85.02 ± 5.16
(±)-7d C5H11 90.12 ± 5.10 96.56 ± 3.82
(±)-7e C7H15 110.20 ± 4.01 87.55 ± 8.03
(±)-7f C10H21 59.70 ± 5.12 63.00 ± 1.45
(±)-7g C12H25 47.58 ± 7.08 61.33 ± 1.50
(±)-7h C16H33 74.35 ± 11.65 94.53 ± 3.72
74.13 ± 8.51 93.66 ± 2.96 103.10 ± 45.34 92.77 ± 2.65 91.87 ± 2.28
(±)-8a C3H7
95.16 ± 3.07 102.28 ± 0.76
99.19 ± 2.04 98.40 ± 3.45 101.30 ± 1.67
105.29 ± 2.64 93.31 ± 1.60 97.53 ± 6.64
95.58 ± 2.78 104.12 ± 1.58 99.82 ± 3.43
92.64 ± 7.14 98.65 ± 3.12 104.59 ± 2.59
101.58 ± 2.37 91.20 ± 6.68
112.05 ± 0.00 93.05 ± 24.81
104.63 ± 7.64 92.64 ± 4.45
93.47 ± 2.87 95.58 ± 4.82
(±)-8d C5H11 94.65 ± 3.43 93.89 ± 5.06
(±)-8e C7H15 105.10 ± 2.32 98.39 ± 5.47
(±)-8f C10H21 77.35 ± 5.95 73.58 ± 5.28
of fungal cultures to change their cell biochemistry (resulting in
an altered pattern of secondary metabolites) in response to CILs
[61].
Supporting Information
Supporting Information File 1
Complete experimental procedures and characterization
data.
Conclusion
Lipase-catalyzed kinetic enantiomeric separation of 1-(1H-
imidazol-1-yl)propan-2-ol (±)-3a proceeded with excellent
enantioselectivity, exceeding E = 500, in a short reaction time
(5 h), by using a native enzymatic preparation from
Pseudomonas fluorescens (Amano AK) as biocatalyst. In turn,
after many trials we found that the kinetic separation of enan-
tiomers of 1-(1H-1,2,4-triazol-1-yl)propan-2-ol (±)-3b with
various tested lipases was less efficient than that of (±)-3a.
Resolution of (±)-3b proceeded with good yield, but the enan-
tiomeric excess of the slower reacting enantiomer (alcohol
(+)-5b) was less than 98%. The faster reacting ester (+)-6b
barely reached 90% ee. Nevertheless, the procedure presented
here is simple and efficient, and, after some additional optimi-
zation, can be readily extended to other substrates of this type.
According to 1H NMR investigations, the slower reacting enan-
tiomers of the alcohols (+)-5a and (+)-5b possess (S)-configura-
tion. This assignment is in good agreement with Kazlauskas’s
rule [62,63], where in lipase-catalyzed esterification of second-
ary alcohols the (R)-ester and (S)-alcohol enantiomers are
obtained. The imidazolic and triazolic chiral salts derived from
alcohols (S)-(+)-5a and (S)-(+)-5b were obtained in high to
excellent isolated yields. The core structures of these salts were
modified by using, for quaternization reaction, haloalkanes or
haloalkenes with various chain lengths. Their antibacterial and
antifungal properties were evaluated by three different methods.
Some of these compounds exhibited biological activity that was
significantly dependent on the alkyl chain length, with consider-
ably high toxicity of the substituents with 10–16 carbon atoms.
The imidazolium salts revealed stronger antibacterial activity
than their triazolium analogues.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-56-S1.pdf]
Acknowledgements
The project was co-financed by The European Regional Devel-
opment Fund under The Innovative Economy Operational
Programme 2007–2013: “Biotransformations for Pharmaceu-
tical and Cosmetic Industry” POIG.01.03.01-00-158/09. These
studies were partially supported by the Warsaw University of
Technology, Faculty of Chemistry. In addition, we would like
to thank Dominika Brzezińska, M. Sc. for participating in the
biological investigations.
References
1. Broughton, H. B.; Watson, I. A. J. Mol. Graphics Modell. 2004, 23,
51–58. doi:10.1016/j.jmgm.2004.03.016
2. Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Discovery Dev. 2005, 8,
723–740.
3. Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409–424.
doi:10.2174/1389557053544047
4. De Luca, L. Curr. Med. Chem. 2006, 13, 1–23.
doi:10.2174/0929867310607010001
5. Du, H.; He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965–992.
doi:10.1055/s-2006-939720
6. Khabnadideh, S.; Rezaei, Z.; Khalafi-Nezhad, A.; Bahrinajafi, R.;
Mohamadia, R.; Farrokhroz, A. A. Bioorg. Med. Chem. Lett. 2003, 13,
2863–2865. doi:10.1016/S0960-894X(03)00591-2
7. Khan, M. S.; Siddiqui, S. A.; Siddiqui, M. S. R. A.; Goswami, U.;
Srinivasan, K. V.; Khan, M. I. Chem. Biol. Drug Des. 2008, 72,
197–204. doi:10.1111/j.1747-0285.2008.00691.x
523

Beilstein J. Org. Chem. 2013, 9, 516–525.
8. Atia, A. J. K. Molecules 2009, 14, 2431–2446.
29.Shah, M. H.; Mhasalkar, M. Y.; Patki, V. M.; Deliwala, C. V.;
doi:10.3390/molecules14072431
Sheth, U. K. J. Pharm. Sci. 1969, 58, 1398–1401.
doi:10.1002/jps.2600581123
9. Lennon, I. C.; Ramsden, J. A. Org. Process Res. Dev. 2005, 9,
110–112. doi:10.1021/op049838n
30.Kirschberg, T. A.; Balakrishnan, M.; Huang, W.; Hluhanich, R.;
Kutty, N.; Liclican, A. C.; McColl, D. J.; Squires, N. H.; Lansdon, E. B.
Bioorg. Med. Chem. Lett. 2008, 18, 1131–1134.
10.Rossello, A.; Bertini, S.; Lapucci, A.; Macchia, M.; Martinelli, A.;
Rapposelli, S.; Herreros, E.; Macchia, B. J. Med. Chem. 2002, 45,
4903–4912. doi:10.1021/jm020980t
doi:10.1016/j.bmcl.2007.11.127
11.Hori, K.; Sakaguchi, A.; Kudoh, M.; Ishida, K.; Aoyama, Y.; Yoshida, Y.
Chem. Pharm. Bull. 2000, 48, 60–64. doi:10.1248/cpb.48.60
12.Fringuelli, R.; Schiaffella, F.; Bistoni, F.; Pitzurra, L.; Vecchiarelli, A.
Bioorg. Med. Chem. 1998, 6, 103–108.
31.Yu, S.; Chai, X.; Hu, H.; Yan, Y.; Guan, Z.; Zou, Y.; Sun, Q.; Wu, Q.
Eur. J. Med. Chem. 2010, 45, 4435–4445.
doi:10.1016/j.ejmech.2010.07.002
32.Zhou, W.; Xu, L.-W.; Qiu, H.-Y.; Lai, G.-Q.; Xia, C.-G.; Jiang, J.-X.
Helv. Chim. Acta 2008, 91, 53–59. doi:10.1002/hlca.200890012
33.Lee, J. W.; Shin, J. Y.; Chun, Y. S.; Jang, H. B.; Song, C. E.; Lee, S.
Acc. Chem. Res. 2010, 43, 985–994. doi:10.1021/ar9002202
34.Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111, 3508–3576.
doi:10.1021/cr1003248
doi:10.1016/S0968-0896(97)10016-5
13.Norman, S. M.; Bennett, R. D.; Poling, S. M.; Maier, V. P.;
Nelson, M. D. Plant Physiol. 1986, 80, 122–125.
doi:10.1104/pp.80.1.122
14.Saadeh, H. A.; Mosleh, I. M.; El-Abadelah, M. M. Molecules 2009, 14,
2758–2767. doi:10.3390/molecules14082758
35.Shen, Z.-L.; Zhou, W.-J.; Liu, Y.-T.; Ji, S.-J.; Loh, T.-P. Green Chem.
2008, 10, 283–286. doi:10.1039/b717235d
15.Mukherjee, A.; Kumar, S.; Seth, M.; Bhaduri, A. P.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1989, 28B,
391–396.
36.Biedroń, T.; Kubisa, P. J. Polym. Sci., Part A: Polym. Chem. 2005, 43,
3454–3459. doi:10.1002/pola.20863
16.Bellina, F.; Cauteruccio, S.; Borsotti, P.; Taraboletti, G.; Monti, S.;
Giavazzi, R.; Rossi, R. EJC Suppl. 2006, 4, 12–13.
doi:10.1016/S1359-6349(06)70033-7
37.Rizvi, S. A. A.; Shamsi, S. A. Anal. Chem. 2006, 78, 7061–7069.
doi:10.1021/ac060878u
38.Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron Lett. 2008, 49,
1249–1252. doi:10.1016/j.tetlet.2007.12.024
17.Bellina, F.; Cauteruccio, S.; Monti, S.; Rossi, R.
Bioorg. Med. Chem. Lett. 2006, 16, 5757–5762.
39.Joshi, M. D.; Anderson, J. L. RSC Adv. 2012, 2, 5470–5484.
doi:10.1039/c2ra20142a
doi:10.1016/j.bmcl.2006.08.087
18.Manley, P. W.; Allanson, N. M.; Booth, R. F. G.; Buckle, P. E.;
Kuzniar, E. J.; Lad, N.; Lai, S. M. F.; Lunt, D. O.; Tuffin, D. P.
J. Med. Chem. 1987, 30, 1588–1595. doi:10.1021/jm00392a011
19.Castagnolo, D.; Radi, M.; Dessì, F.; Manetti, F.; Saddi, M.;
Meleddu, R.; De Logu, A.; Botta, M. Bioorg. Med. Chem. Lett. 2009,
19, 2203–2205. doi:10.1016/j.bmcl.2009.02.101
40.Poterała, M.; Plenkiewicz, J. Tetrahedron: Asymmetry 2011, 22,
294–299. doi:10.1016/j.tetasy.2011.01.024
41.Wood, N.; Stephens, G. Phys. Chem. Chem. Phys. 2010, 12,
1670–1674. doi:10.1039/b923429b
42.Hough-Troutman, W. L.; Smiglak, M.; Griffin, S.; Reichert, W. M.;
Mirska, I.; Jodynis-Liebert, J.; Adamska, T.; Nawrot, J.; Stasiewicz, M.;
Rogers, R. D.; Pernak, J. New J. Chem. 2009, 33, 26–33.
doi:10.1039/b813213p
20.Zhang, F.-F.; Gan, L.-L.; Zhou, C.-H. Bioorg. Med. Chem. Lett. 2010,
20, 1881–1884. doi:10.1016/j.bmcl.2010.01.159
21.Rezaei, Z.; Khabnadideh, S.; Pakshir, K.; Hossaini, Z.; Amiri, F.;
Assadpour, E. Eur. J. Med. Chem. 2009, 44, 3064–3067.
doi:10.1016/j.ejmech.2008.07.012
43.Gilmore, B. F. Ionic Liquids: Applications and Perspectives.
Kokorin, A., Ed.; InTech: New York, 2011; pp 587–604.
44.Ventura, S. P.; de Barros, R. L.; Sintra, T.; Soares, C. M.; Lima, A. S.;
Coutinho, J. A. Ecotoxicol. Environ. Saf. 2012, 83, 55–62.
doi:10.1016/j.ecoenv.2012.06.002
22.Villoutreix, B.; Reboud-Ravaux, M.; Basse, N.; Vidal, J.; Montes, M.
Nitrogen heterocycle derivatives as proteasome modulators. WIPO
Patent 2010/001365 A1, Jan 7, 2010.
45.Paul, C. E.; Gotor-Fernández, V.; Lavandera, I.; Montejo-Bernardo, J.;
García-Granda, S.; Gotor, V. RSC Adv. 2012, 2, 6455–6463.
doi:10.1039/c2ra20876h
23.Granberg, K.; Slassi, A.; Stefanac, T.; Wållberg, A. 1,2,4-Triazole
carboxylic acid derivatives as modulators of mGluR5. WIPO Patent
2009/054787 A1, April 30, 2009.
46.Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2007, 63, 469–473.
doi:10.1016/j.tet.2006.10.055
24.Bryans, J. S.; Johnson, P. S.; Ryckmans, T.; Stobie, A.
3-Heterocyclyl-4-phenyl-triazole derivatives as inhibitors of the
vasopressin V1a receptor. WIPO Patent 2005/105779 A1, Nov 10,
2005.
47.Kinoshita, M.; Ohno, A. Tetrahedron 1996, 52, 5397–5406.
doi:10.1016/0040-4020(96)00179-2
48.Herbst, D.; Peper, S.; Niemeyer, B. J. Biotechnol. 2012, 162, 398–403.
doi:10.1016/j.jbiotec.2012.03.011
25.Walker, J. M.; Bowen, W. D.; Walker, F. O.; Matsumoto, R. R.;
de Costa, B.; Rice, K. C. Pharmacol. Rev. 1990, 42, 355–402.
26.Jagerovic, N.; Cumella-Montanchez, J.; Goya-Laza, M.;
Dordal Zueras, A.; Cuberes-Altisent, M. R. 1,2,4-Triazole derivatives as
sigma receptor inhibitors. EP patent 1 921 073 A1, May 14, 2008.
Also U.S. Patent 8,349,878 B2, Jan. 5, 2013.
49.Burke, P. A.; Griffin, R. G.; Klibanov, A. M. Biotechnol. Bioeng. 1993,
42, 87–94. doi:10.1002/bit.260420112
50.Moniruzzaman, M.; Nakashima, K.; Kamiya, N.; Goto, M.
Biochem. Eng. J. 2010, 48, 295–314. doi:10.1016/j.bej.2009.10.002
51.Yang, C.; Wang, F.; Lan, D.; Whiteley, C.; Yang, B.; Wang, Y.
Process Biochem. 2012, 47, 533–537.
27.Bonanomi, G.; Di Fabio, R.; Fazzolari, E.; Hamprecht, D.; Micheli, F.;
Tarsi, L.; Terreni, S. Triazole derivatives as modulators of dopamine
D3 receptors. WIPO Patent 2007/022933 A1, March 3, 2007.
28.Siddiqui, N.; Ahsan, W. Eur. J. Med. Chem. 2010, 45, 1536–1543.
doi:10.1016/j.ejmech.2009.12.062
doi:10.1016/j.procbio.2011.11.017
52.Margolin, A. L.; Tai, D. F.; Klibanov, A. M. J. Am. Chem. Soc. 1987,
109, 7885–7887. doi:10.1021/ja00259a049
53.Priego, J.; Ortíz-Nava, C.; Carrillo-Morales, M.; López-Munguía, A.;
Escalante, J.; Castillo, E. Tetrahedron 2009, 65, 536–539.
doi:10.1016/j.tet.2008.10.103
524

Beilstein J. Org. Chem. 2013, 9, 516–525.
54.Wang, J.; Sun, G.-X.; Yu, L.; Wu, F.-A.; Guo, X.-J. Bioresour. Technol.
2013, 128, 156–163. doi:10.1016/j.biortech.2012.10.098
55.Sakurai, T.; Margolin, A. L.; Russell, A. J.; Klibanov, A. M.
J. Am. Chem. Soc. 1988, 110, 7236–7237. doi:10.1021/ja00229a061
56.Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294–7299. doi:10.1021/ja00389a064
57.Seco, J. M.; Quiñoá, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915–2925. doi:10.1016/S0957-4166(01)00508-0
58.Borowiecki, P.; Poterała, M.; Maurin, J.; Wielechowska, M.;
Plenkiewicz, J. ARKIVOC 2012, No. viii, 262–281.
59.Carson, L.; Chau, P. K. W.; Earle, M. J.; Gilea, M. A.; Gilmore, B. F.;
Gorman, S. P.; McCann, M. T.; Seddon, K. R. Green Chem. 2009, 11,
492–497. doi:10.1039/b821842k
60.Petkovic, M.; Seddon, K. R.; Rebelo, L. P. N.; Silva Pereira, C.
Chem. Soc. Rev. 2011, 40, 1383–1403. doi:10.1039/c004968a
61.Petkovic, M.; Ferguson, J.; Bohn, A.; Trindade, J.; Martins, I.;
Carvalho, M. B.; Leitão, M. C.; Rodrigues, C.; Garcia, H.; Ferreira, R.;
Seddon, K. R.; Rebelo, L. P. N.; Silva Pereira, C. Green Chem. 2009,
11, 889–894. doi:10.1039/b823225c
62.Faber, K. Biotransformations in Organic Chemistry; Springer Verlag:
Berlin, 1997; pp 90–91. doi:10.1007/978-3-662-00431-9
63.Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A.
J. Org. Chem. 1991, 56, 2656–2665. doi:10.1021/jo00008a016
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