Lipase-catalyzed resolution of 2-fluorodecanoic acid

Article abstract of DOI:10.1016/S0957-4166(99)00572-8

Kinetic resolutions of alkyl (±)-2-fluorodecanoates by lipase-catalyzed hydrolysis and of (±)-2-fluorodecanoic acid by lipase-catalyzed esterification are described for the first time. Copyright (C) 2000.

Full text of DOI:10.1016/S0957-4166(99)00572-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 889–896
Lipase-catalyzed resolution of 2-fluorodecanoic acid
∗
Frank Tranel and Günter Haufe
Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Received 22 November 1999; accepted 8 December 1999
Abstract
Kinetic resolutions of alkyl (±)-2-fluorodecanoates by lipase-catalyzed hydrolysis and of (±)-2-fluorodecanoic
acid by lipase-catalyzed esterification are described for the first time. © 2000 Published by Elsevier Science Ltd.
All rights reserved.
1
. Introduction
Optically active 2-fluoro-substituted carboxylic acids are widely used as drugs, shift reagents and
1
2
3
building blocks for synthesis. Several examples of the asymmetric synthesis of such compounds
have been published, but mostly expensive and/or dangerous chemicals were used and frequently
4
only one enantiomer was made accessible. Especially for the application of such compounds in
ferroelectric liquid crystals, fluorinated long chain carboxylic acids are of great interest.4d,5 Lipase-
catalyzed resolutions have been widely employed in this context either by hydrolysis of fluoro-substituted
6
carboxylic esters or by acetylation of 2-fluoroalcohols in non-polar solvents and subsequent oxidation of
the fluorohydrins.6a,7 In most examples the fluorine is attached to a side-chain but not at the stereogenic
carbon. In some rare cases when the fluorine substituent is placed at the asymmetric center, this is a
quaternary carbon. On the other hand, when fluorine is attached to a secondary carbon, the similarity of
8
the van der Waals radii of hydrogen (1.2 Å) and fluorine (1.35 Å) suggests that enzymes in general can
hardly distinguish between these atoms on steric grounds. On the other hand, substitution of hydrogen
by fluorine induces electronic perturbation of the molecule. Based on an Anh–Eisenstein stabilization
and results of lipase-catalyzed hydrolysis of several fluoro-substituted benzhydrol acetates, O’Hagan et
al. raised the question of whether it is a sterically or electronically induced discrimination.8 The most
impressive example for a discrimination between hydrogen and fluorine is the lipase-catalyzed kinetic
resolution of ethyl 2-fluorohexanoate 1 (Scheme 1).6g
,9
∗
Corresponding author. Fax: +49 (0)251-833 97 72; e-mail: haufe@uni-muenster.de
0
957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00572-8
tetasy 3206

8
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F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
Scheme 1. Lipase-catalyzed deracemization of ethyl 2-fluorohexanoate 16g
2. Results and dicussion
We wish to report here our results on lipase-catalyzed kinetic resolution of 2-fluorocaprinic acid 7.
Compound 7 has been found to be less toxic than would have been expected for compounds which
10
principally can undergo β-oxidation, to form highly toxic fluoroacetic acid. In this case applications in
1
1
medicinal chemistry might be possible. Long chain α-fluorinated carboxylic acids are reported to be of
4
d,5
special interest for the application in ferroelectric liquid crystals which have a fast growing market.
Racemic 2-fluorocaprinic acid 7 was first synthesized from 1-decene 3 by Pattison et al.11 in 47%
overall yield in 1965. The key-step in their synthesis was the bromofluorination of the olefin 3 in liquid
HF. After bromine to acetate exchange to form 5 and saponification, the formed fluorohydrin 6 was
7
,10
oxidized to 7.
Olah’s reagent (70% HF in pyridine).
Nohira et al. by ring opening with Olah’s reagent of the expensive enantiopure 1-decene oxide in poor
Alternatively, 6 has been generated by oxirane ring opening of 1-decene oxide using
4
b–d
The optically active acid 7 has previously been synthesized by
4
b
yield.
12
According to our method demonstrated for other 2-fluorocarboxylic acids, racemic 2-fluorodecanoic
acid 7 has been synthesized from 1-decene 3 in four steps in analytically pure form in 42% overall
yield (Scheme 2) without the need of difficult to handle chemicals such as liquid HF and without any
4
b,d
chromatography or distillation which is necessary by Nohira’s method.
Scheme 2. Synthesis of (±)-2-fluorodecanoic acid 7: (a) NBS, Me
68%]; (c) KOH/methanol, [96%]; (d) Jones oxidation, [67%]
3
N·3HF, dichloromethane, [95%]; (b) KOAc, DMF, 153°C,
[
Two principal enzymatic methods are known in the literature to cleave substituted racemic carboxylic
25
acids, the lipase-catalyzed esterification of the acid or hydrolysis of the corresponding ester. We applied
both methods to cleave 7.
2.1. Lipase-catalyzed hydrolysis
Alkyl 2-fluorodecanoates 8, obtained in the usual way by refluxing acid 7 with the corresponding
alcohol in the presence of a catalytic amount of H SO , have been resolved with moderate enantiomeric
2
4
®
excess by the lipases from Candida antarctica (CAL, Novozym 435), Candida rugosa (CRL) and
Pseudomonas cepacia (PCL, Amano PS) (Scheme 3, Table 1). These lipases have also been used
successfully for the resolution of other α-branched alkanoic acids.6
,13
The enantioselective hydrolysis of the esters 8 with the lipases mentioned above has been accomplished
in phosphate buffer (c=0.1 mol/l) at pH 7.0 or in distilled water in which the pH 6.0 has been kept constant
by a continuous addition of 0.5 molar aqueous NaOH without any co-solvent. The best result (entry 8)
was found with the methyl ester 8b and with PCL as the biocatalyst at pH 6.0.

F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
891
Scheme 3. Synthesis and lipase-catalyzed resolution of alkyl 2-fluorodecanoates 8
Table 1
Lipase-catalyzed hydrolysis of alkyl 2-fluorodecanoates 8
2.2. Lipase-catalyzed esterification
As shown above, the ee values in the enzymatic hydrolysis of alkyl 2-fluorodecanoates 8 (Table 1)
were only moderate. Consequently, we decided to investigate the enzymatic esterification of 7 in order
to get higher enantioselectivities. Högberg et al. have shown that lipase-catalyzed esterifications of 2-
substituted fatty acids in hydrocarbon solvents occur with better enantiomeric excess than hydrolysis
1
5
of the corresponding esters. Proper selection of the chain length of the alcohol used led to high
16
E-values and yields. Long chain alcohols mostly give higher ees, but at higher concentration these
1
5c,16
alcohols inhibit the activity of the lipase,
enantioselectivities.
whereas short chain alcohols such as ethanol give poor
1
6b,d
On the other hand, there is no doubt that the most important point in lipase-catalyzed esterification of
fatty acid derivatives is the water-activity (a ) of the reaction mixture. Uncontrolled changes in water-
w
activity before and during the reaction are responsible for variation in the E-values and in the rate of the
1
6–18
esterification.
Acknowledging the results from the literature, we decided to use a non-polar solvent,
cyclohexane, a small amount of a long chain alcohol (1.3 equiv. 1-octanol), and a constant water-activity.
Addition of inorganic salt/salt hydrate mixtures to the reaction medium is known to keep a constant,
w
which is necessary to keep catalytic activity and enantioselectivity of the enzyme.18 The results obtained
by esterification of 2-fluorodecanoic acid 7 (Scheme 4) are summarized in Table 2.
Scheme 4. Lipase-catalyzed esterification of racemic 2-fluorodecanoic acid 7

8
92
F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
Table 2
Enzymatic esterification of 2-fluorodecanoic acid 7 in Table 1
In order to investigate whether the selectivity of the lipase-catalyzed esterification changes during
the reaction we measured the conversion and the ee of acid 7 and ester 9 over time. The results are
summarized in Scheme 5 and are in agreement with results which were obtained by esterification of
-methyldecanoic acid under similar conditions.1
5,16a,c,17,18k
2
Scheme 5. Dependence of conversion and ee values on time for esterification of 7 with 1-octanol. (a) Conversion [%]/time [h]
for PCL and CRL reaction (entries 1 and 2, Table 2); (b) ee [%]/conversion [%] for PCL reaction (entry 1, Table 2); (c) ee
[%]/conversion [%] for CRL reaction (entry 2, Table 2)
All the used lipases are (S)-selective in agreement with the empirical Kazlauskas rule for 2-substituted
1
9
chiral carboxylic acids and CRL. The absolute configuration of 7 was determined by comparison of the
4
d
specific rotation with known values.
3. Experimental
1H (300 MHz), 13C (75.5 MHz): Bruker WM 300, TMS for H and CDCl for 13C NMR as internal
1
3

F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
893
standards. 19F NMR: Bruker WM 300 (282.3 MHz), CFCl as internal standard. Mass spectra (electron-
3
impact ionization, 70 eV): GC/MS coupling: Varian GC 3400 MAT and data system of Finnigan/MAT.
GC: Hewlett–Packard 5890 II gas chromatograph, quartz capillary column 0.32 mm×30 m, 0.25 µm
HP-5 (Hewlett–Packard), nitrogen as carrier gas, and FID. Conversion of the substrates during the
enzymatic reactions was determined by GC after silylation with BSA. Optical rotations: Perkin–Elmer
2
41 polarimeter (Na–D-line: λ=589 nm). Lipase from Candida rugosa (CRL) was purchased from
Sigma, lipase from Candida antarctica (CAL) from Novo Nordisk and lipase Pseudomonas cepacia
PCL, Amano PS) was a gift from Amano Pharmaceuticals Co. Phosphate buffer (0.1 M, pH=7.0) was
prepared from K HPO and KH PO . Cyclohexane was purified by distillation prior to use.
(
2
4
2
4
3.1. Preparation of 1-bromo-2-fluoro-decane 4
Compound 3 (14.2 g, 100 mmol) was dissolved in 100 ml of dry dichloromethane and 26.4 g (220
mmol) of Me N·3HF was added. The solution was cooled to 0°C and 21.1 g (120 mmol) of NBS was
3
added in small portions. The reaction mixture was stirred at room temperature for 12 h, poured into
ice-water, and a concentrated aqueous NH solution was added up to pH 8–10. Then the phases were
3
separated and the aqueous phase was extracted four times with 150 ml of dichloromethane. The combined
organic layers were washed twice with 150 ml of 2N HCl, three times with 150 ml of aqueous NaHCO3
(
5%), and dried over MgSO . Removal of the solvent under reduced pressure led to 22.74 g of a product
4
mixture containing 90% of a 93:7 mixture (GC) of 4 and its regioisomer, 5% (GC) of 1,2-dibromodecane,
and 5% of starting material 3 (for the formation of dibromides under the conditions of bromofluorination
2
0
21
of alkenes with NBS/Et N·3HF, cf. ). Spectroscopic data of 4 agree with published values.
3
3.2. Preparation of 1-acetoxy-2-fluorodecane 5
The crude mixture of 4 (22.74 g) was dissolved in 240 ml of DMF. Then 38.0 g (387 mmol) of
potassium acetate was added and the mixture was refluxed for 18 h. The reaction mixture was poured
into 200 ml of cyclohexane:ethyl acetate (1:1) and extracted six times with water. The organic layer was
dried over MgSO and the solvent was removed under reduced pressure. The crude product was filtered
4
through a short column (3 cm) with silica gel using cyclohexane:ethyl acetate (9:1). Yield: 15.65 g of a
mixture containing 90% of 5 and its regioisomer (93:7) and 5% of a diacetate. Spectroscopic data of 5
4
d,22
agree with published values.
3.3. Preparation of 2-fluorodecan-1-ol 6
The crude mixture of 5 (15.65 g) was dissolved in 100 ml of methanol and 11.23 g (200 mmol) of
KOH was added. The mixture was stirred at room temperature for 18 h, poured into 160 ml of ice-water,
and extracted six times with 100 ml of dichloromethane. The combined organic layers were washed three
times with 160 ml of water, dried over MgSO , and the solvent was removed under reduced pressure.
4
Yield: 11.98 g of a mixture of isomers containing nearly 90% of 6 and its regioisomer (93:7). Fp of 6:
2°C. Spectroscopic data of 6 agree with published values.4
d,22,23
3
3.4. Preparation of 2-fluorodecanoic acid 7
The crude mixture of 6 was dissolved in 500 ml of acetone and cooled to 0°C. After dropwise addition
of 61 ml of Jones-reagent (prepared from 26 g of CrO , 23 ml of concentrated H SO , and 77 ml of
3
2
4

8
94
F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
water) the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled to
°C and 50 ml of isopropanol was added dropwise. Water was added until everything was dissolved and
0
the mixture was extracted five times with 100 ml of dichloromethane. To the combined organic layers 100
ml of saturated aqueous NaHCO solution was added and stirred for 10 min, while the sodium salt of 7
3
precipitated as a white solid. This solid was separated, dissolved in 40 ml of 2N HCl, and extracted
three times with 100 ml of dichloromethane. The combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. Yield: 7.98 g (42 mmol) analytically pure 7. Fp
1
1
6
1°C (cyclohexane) (lit.: Fp 62–65°C, petroleum ether). Spectroscopic data of 7 agree with published
4
d
values.
3.5. Preparation of methyl 2-fluorodecanoate 8b
Compound 7 (4.18 g, 22 mmol), dry methanol (3.52 g, 110 mmol), and 3 ml of concentrated H SO
2
4
were refluxed for 5 h under anhydrous conditions. The reaction mixture was dissolved in 100 ml of water
and extracted three times with 50 ml of diethyl ether. The combined organic layers were washed with
saturated NaHCO , water and brine, and dried over MgSO . Distillation under reduced pressure gave
3
4
1
3
3
1
1
3
.51 g (78%) of product 8b. Bp: 114°C/13 mmHg. H NMR: δ 0.88 (t, 3H, JH,H=6.7 Hz, 10-CH3),
.27 (m, 10H, 5-CH -9-CH ), 1.46 (m, 2H, 4-CH ), 1.88 (m, 2H, 3-CH ), 3.59 (s, 3H, OCH ), 4.90 (dt,
H, J =49.1 Hz, JH,H=6.3 Hz, 2-CHF). C NMR: δ 14.0 (q, C-10), 22.6, 24.4, 29.1, 29.3, 31.8,
2.6, 32.9 (t, C-3-C-9), 52.2 (q, OCH ), 89.1 (dd, J =183.1 Hz, C-2), 170.51 (d, J =25.4 Hz, C-1).
2
2
2
2
3
2
3
13
H,F
1
2
3
C,F
C,F
1
9
2
3
+
F NMR: δ 191.5 (dt, J =50.4 Hz, J =25.2 Hz). MS (GC/MS, ion trap): m/z (%) 204 (4) [M ],
H,F
H,F
+
+
+
+
1
(
[
61 (21) [M −C H ], 127 (6) [M −HF], 113 (4) [C H ], 105 (23) [M −C H ], 92 (100) [C H O F
3
7
8
17
7
15
3
5
2
+ + + +
McLafferty)], 87 (15), 71 (6) [C H ], 69 (6) [C H ], 59 (12) [C H O ], 57 (12) [C H ], 55 (13)
5 11 5 9 2 3 2 4 9
+
+
+
C H ], 43 (17) [C H ], 41 (16) [C H ].
4
7
3
7
3
5
3.6. Preparation of ethyl 2-fluorodecanoate 8a
Compound 7 (1.90 g, 10 mmol), ethanol (2.30 g, 50 mmol), and 200 mg of concentrated H SO4
2
were refluxed under anhydrous conditions for 5 h. The reaction mixture was dissolved in 25 ml of water
and extracted three times with diethyl ether. The combined organic layers were washed with saturated
NaHCO , water and brine, and dried over MgSO . Yield: 1.90 g (87%). Spectroscopic data of 8a agree
3
4
2
4
with published values.
3.7. General procedure for the lipase-catalyzed hydrolysis of 8 in phosphate buffer
Compound 8 (2 mmol) was suspended in 60 ml of 0.1 M phosphate buffer (pH=7.0) and 10 mg of the
enzyme was added. The reaction mixture was stirred at room temperature for the mentioned time (Table
) and after addition of 10 ml of 2N HCl the mixture was extracted three times with dichloromethane.
1
After GC-analysis to determine conversion, the combined organic layers were extracted three times with
saturated NaHCO . After drying with MgSO and evaporation of the solvent under reduced pressure the
3
4
optically enriched 8 was isolated. An amount of 2N HCl was added to the combined NaHCO layers
3
until pH 1–2 was reached and this mixture was extracted twice with dichloromethane. After drying and
removal of the solvent the enantiomerically enriched 7 was isolated.

F. Tranel, G. Haufe / Tetrahedron: Asymmetry 11 (2000) 889–896
895
3.8. General procedure for the enzymatic hydrolysis of 8 in distilled water
Compound 8 (2 mmol) was suspended in 50 ml of distilled water and 2 drops of 2 M HCl were
added. After that a pre-titration with 0.5 M NaOH was done in order to reach pH 6.0 or 7.0, respectively.
Then 10 mg of the enzyme was added and the reaction mixture was stirred at room temperature for the
time mentioned in Table 1, while the pH was kept constant by continuous addition of 0.5 M NaOH.
2
0
20
The reaction mixture was worked up as mentioned above. [α] =+3.84 (R)-8b, 65% ee, [α]D =−6.00
D
20
20
(
S)-7, 59% ee (lit.:4d [α]D =−9.7, 86% ee, [α]D =−2.69 (R)-8a, 32% ee).
3.9. General procedure for enzymatic esterification of 2-fluorodecanoic acid 7
Compound 7 (3.00 g, 15.8 mmol) was dissolved in 110 ml of cyclohexane. Then 11.1 mmol of the
salt mixture and 2.57 g (19.8 mmol) of 1-octanol were added and the reaction mixture was stirred for
5 min at room temperature in order to get a constant a value. Then 789 mg of lipase was added and
1
w
the conversion was controlled by GC analysis after filtration and silylation. At the end of the reaction
the mixture was filtered and extracted five times with saturated NaHCO . The organic layer was dried
3
over MgSO , and the solvent was evaporated under reduced pressure to isolate optically enriched 9. The
4
combined water layers were acidified with 2 M HCl, and extracted three times with dichloromethane. The
combined organic layers were washed with water, dried over MgSO , and the solvent was removed under
4
2
0
reduced pressure in order to isolate enantiomerically enriched 7. Spectroscopic data of 9: [α] =−4.8
D
1
3
(
1
S)-9, 24% ee. H NMR: δ 0.88 (t, 6H, J =6.7 Hz, CH ), 1.28 (m, 20H, CH ), 1.45 (m, 2H, 4-CH ),
H,H
3
2
2
3
2
3
.78–1.97 (m, 2H, 3-CH ), 4.18 (t, 2H, J =6.7 Hz, CH O), 4.87 (dt, 1H, J =49.4 Hz, JH,H=6.0
2 H,H 2 H,F
1
3
1
Hz, 2-CHF). C NMR: δ 14.0 (t, CH ), 22.6–32.6 (t, CH ), 65.5 (t, CH O), 89.1 (dt, JC,F=183.1 Hz,
C-2), 170.3 (d, J =22.9 Hz, C-1). F NMR: δ 197.9 (dt, J =49.6 Hz, J =24.8 Hz). MS (GC/MS,
3
2
2
2
2
19
3
H,F
H,F
H,F
+
+
+
+
ion trap), m/z (%): 302 (1) [M ], 259 (0.2) [M −C H ], 231 (0.2) [M −C H ], 191 (18) [C H O F
3
7
5
11
10 19
2
+
+
+
+
(
(
McLafferty)], 112 (36) [M −190], 97 (5) [C H ], 83 (22) [C H ], 71 (63) [C H ], 69 (24), 57
7
13
6
11
5
11
+
100) [C H ], 55 (37), 43 (85), 41 (50).
4
9
Acknowledgements
Financial support of this work by the Deutsche Forschungsgesellschaft and the Fonds der chemischen
Industrie is gratefully acknowledged. We thank the Hoechst AG for kind donation of chemicals and
Amano Pharmaceuticals Co. for a gift of lipase from Pseudomonas cepacia (Amano PS).
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