Checked by Ronan Guevel and Leo A. Paquette.
1. Procedure
For preparation of
ethyl 2-fluorohexanoate (Note
1), a
1-L flask equipped with a
mechanical stirrer,
thermometer,
condenser and a gas adapter is charged under an atmosphere of
argon with
38.5 g of acetamide and
80 g (0.36 mol) of ethyl 2-bromohexanoate (Note
2). The mixture is heated to 80°C until solution is effected and
38.6 g (0.65 mol) of potassium fluoride (Note
3) is added to it followed by
2.7 mL of tetra-n-butylammonium fluoride (Note
4). The resulting mixture is heated at 140°C with rapid stirring for 4–5 (Note
5). The reaction mixture is allowed to cool to 90°C and then is poured into 600 mL of ice. The reaction flask is rinsed with 100 mL of water and
100 mL of dichloromethane, which are added to the ice mixture. The aqueous phase is extracted with
dichloromethane (4 × 200 mL). The combined organic layers are dried over anhydrous
sodium sulfate and filtered. The
dichloromethane solution is then cooled to 5°C and treated under an atmosphere of
argon with
15 mL of bromine (Note
6). The reaction is judged complete after ca. 3 hr. It is quenched by adding
200 mL of saturated sodium thiosulfate solution. The two phases are separated and the organic phase is successively partitioned with saturated aqueous
sodium bicarbonate solution (2 × 150 mL) and then with
200 mL of brine. It is finally dried over anhydrous
sodium sulfate and concentrated to an oil at 40°C / 7 mm (Note
7). Vacuum distillation at
36–37°C / 0.8-0.9 mm affords
26.2–31.4 g (
45–54% yield) of pure
ethyl 2-fluorohexanoate as a colorless liquid (Note
8).
Method A.
Enantiomerically pure ethyl (R)-2-fluorohexanoate (60% hydrolysis). A
1-L Morton flask equipped with a mechanical stirrer, a
glass baffle, an electrode connected to a pH control unit, and an addition tube connected to a
syringe pump is charged with 300 mL of 0.05
M aqueous phosphate buffer (pH 7.0) (Fisher), 300 mL of deionized water, and
70 g (0.43 mol) of ethyl 2-fluorohexanoate. The resulting mixture is stirred for several minutes and the pH is adjusted to 7.0 with the addition of a few drops of
0.1 N sodium hydroxide solution. Then 0.43 g of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, VA) is added and the hydrolysis is allowed to proceed at 5°C with stirring (reaction time ca. 2 hr). The pH is kept constant at 7.0 by adding
0.1 N sodium hydroxide solution via the syringe pump, which is activated by the pH control unit. The hydrolysis is discontinued when
260 mL of 1.0 N sodium hydroxide solution has been added (60% conversion, (Note
9)). The mixture is extracted with
diethyl ether (5 × 300 mL). The combined organic layers are dried over anhydrous
potassium carbonate, filtered, and concentrated at 40°C / 70 mm. Vacuum distillation at
36–38°C / 0.7–0.8 mm gives
24.0 g (
34% yield,
85% of theory, (Note
10)) of pure
ethyl (R)-2-fluorohexanoate, which is 97.5–99% enantiomerically pure,
[α]D25 + 13.0 to + 13.2° (CHCl
3,
c 1.3) (Note
9). The aqueous layer is acidified to pH 2 with
3 N hydrochloric acid and extracted with
diethyl ether (3 × 500 mL). The combined organic layers are dried over anhydrous
sodium sulfate, filtered, and concentrated at 40°C / 70 mm. The residue is distilled at
71–72°C / 0.7 mm to give
30.9 g (
53% yield:
89% of theory) of
(S)-2-fluorohexanoic acid, which is 53–68% enantiomerically pure (Note
11)
[α]D25 −6.8 to −8.7° (CHCl
3,
c 1.3).
Method B.
Enantiomerically pure ethyl (S)-2-fluorohexanoate. A
1-L, three-necked flask equipped with a mechanical stirrer, a glass baffle, an electrode connected to a pH control unit, and an addition tube connected to a syringe pump is charged with 300 mL of deionized water, 300 mL of 0.05
M phosphate buffer (pH 7.0) (Fisher), and
80 g (0.49 mol) of racemic ethyl 2-fluorohexanoate. The pH is adjusted to 7.0 with a few drops of
1 N aqueous sodium hydroxide solution, and 23 mg of Pseudomonas lipase enzyme (P-30, Amano International) is added to the mixture. The hydrolysis is allowed to proceed at 5–10°C with stirring. The pH is maintained at 7.0 by adding adequate
1 N aqueous sodium hydroxide solution via the syringe pump. The hydrolysis is discontinued when
197 mL (40% conversion) of 1 N aqueous sodium hydroxide solution has been added (total reaction time: 2.5 hr). The reaction mixture is immediately transferred to an
extractor containing
750 mL of ethyl ether. The mixture is agitated for 5 min and the two phases are separated. The aqueous phase is extracted with
ethyl ether (3 × 400 mL). The combined organic layers are dried over anhydrous
potassium carbonate, filtered, and concentrated at 30°C/70 mm to afford
47.2 g (
98% of theory) of optically active
ethyl (R)-2-fluorohexanoate. The aqueous phase is transferred back into the extractor and carefully acidified to pH 2.0 with concentrated
hydrochloric acid. It is subsequently extracted with
diethyl ether (4 × 500 mL). The combined organic layers are dried over anhydrous
sodium sulfate and concentrated at 30°C/70 mm to provide
26.1 g (
39% yield; 98% of theory) of
(S)-2-fluorohexanoic acid (81–86% ee).
O
PTICAL P
URITY E
NHANCEMENT. A 1-L, three-necked flask equipped as described above is charged with
28.4 g (0.175 mol) of ethyl (S)-2-fluorohexanoate (81% ee) (Note
12), 300 mL of deionized water and 300 mL of 0.05
M phosphate buffer (pH 7.0). The pH is adjusted to 7.0 with a few drops of
1 N aqueous sodium hydroxide solution and 36 mg of Pseudomonas lipase enzyme (P-30, Amano International) is added to the mixture. The hydrolysis is allowed to proceed at 5°C. The pH is kept at 7.0 by adding adequate
1 N aqueous sodium hydroxide solution via the syringe pump. The hydrolysis is discontinued when
131.3 mL (75% conversion) of 1 N aqueous sodium hydroxide solution has been added (total reaction time: 4 hr). The mixture is quickly extracted with
ethyl ether (3 × 500 mL). The combined organic layers are dried over anhydrous
potassium carbonate and concentrated at 35°C/70 mm to provide
5.66 g of nearly racemic
ethyl 2-fluorohexanoate. The aqueous phase is acidified to pH 2.0 with concentrated
hydrochloric acid and extracted with
ethyl ether (4 × 500 mL). The combined organic layers are dried over anhydrous
sodium sulfate and concentrated at 35°C/70 mm to give
16.8 g (
71% yield; 95.5% of theory) of
(S)-2-fluorohexanoic acid. This acid is distilled at
67°C/0.4–0.5 mm to give
14.2 g of enantiomerically pure
(S)-2-fluorohexanoic acid as a colorless oil:
[α]D25 −13.8° (CHCl
3,
c 1.7) (Note
11) and (Note
13).
2. Notes
1. This procedure was originally used by P. Rosen, G. Holland, and R. J. Karasiewicz at Hoffmann-La Roche. A similar procedure has appeared in the literature.
2
3.
Potassium fluoride was purchased from Fluka and was ground to a fine powder prior to use.
5. The progress of the reaction was monitored by gas chromatography on an
OV-17 column at 100–250°C (20°/min).
6.
Bromine was added dropwise keeping the temperature below 10°C at all times. The progress of the reaction was monitored by gas chromatography as described in (Note
4).
Bromine was added to brominate the α,β-unsaturated ester that was present as a product in the crude material. This procedure simplified the isolation of the
ethyl 2-fluorohexanoate by distillation.
7. Some yellow solids appeared on removing the solvent; they were filtered prior to distillation.
8. The purity of
ethyl 2-fluorohexanoate was determined by gas chromatography as described above. The reaction yield varied from
42 to 70%.
9. Percent conversion is based on the amount of base added.
10. Percent theoretical yield is based on percent conversion.
11. The enantiomeric excess (% ee) of these compounds was determined by the submitters as follows. The ester and acids were first reduced to the corresponding alcohols with DIBAL and LAH, respectively. The alcohols were then allowed to react with
100% excess of (S)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride (Mosher's reagent) in
(1 : 1) pyridine–carbon tetrachloride for 18 hr. The diastereomeric ratio of these derivatives was finally determined by isothermal gas chromatography on a capillary OV-17 column at 160°C.
12. This ester was prepared from the optically active
(S)-2-fluorohexanoic acid isolated above, by the esterification method described in this procedure.
13. The checkers have noted that the
2-fluorohexanoic acid crystallizes when allowed to stand at room temperature. This material can be recrystallized from
pentane at low temperature. The crystals liquify on standing in the open air at room temperature.
3. Discussion
In recent years there has been an increasing interest in the use of enzymes and microorganisms to produce optically active compounds by means of either a kinetic resolution or stereospecific chemical transformations (e.g., reductions, oxidations, epoxidations, hydroxylations).
3 Hydrolases in general have been used to effect kinetic resolutions of racemic esters and alcohols via their corresponding esters.
4 Lipases, a subclass of hydrolases, are commercially available and relatively inexpensive. As a result, they constitute a very attractive class of catalysts for effecting kinetic resolutions, some of which might be difficult by other means.
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