Checked by Terry Rosen and Clayton H. Heathcock.
1. Procedure
A
4-L, three-necked, round-bottomed flask equipped with
mechanical stirrer,
bubble counter, and a
stopper is charged with 1.6 L of tap water,
300 g of sucrose (Note
1), and 200 g of baker's yeast (Note
2), which are added with stirring in this order. The mixture is stirred for 1 hr at about 30°C,
20.0 g (0.154 mol) of ethyl acetoacetate (Note
3) is added, and the fermenting suspension (Note
4) is stirred for another 24 hr at room temperature. A warm (ca. 40°C) solution of
200 g of sucrose (Note
1) in 1 L of tap water is then added, followed 1 hr later by an additional
20.0 g (0.154 mol) of ethyl acetoacetate (Note
3). Stirring is continued for 50–60 hr at room temperature. When the reaction is complete by gas chromatographic analysis (Note
5), the mixture is worked up by first adding 80 g of Celite and filtering through a
sintered-glass funnel (porosity 4, 17-cm diam). After the filtrate is washed with 200 mL of water, it is saturated with
sodium chloride and extracted with five
500-mL portions of ethyl ether (Note
6). The combined
ether extracts are dried over
magnesium sulfate, filtered, and concentrated with a
rotary evaporator at 35°C bath temperature to a volume of 50–80 mL. This residue is fractionally distilled at a pressure of 12 mm through a
10-cm Vigreux column, and the fraction boiling at
71–73°C (12 mm) is collected to give
24–31 g (
59–76%) of
(S)-( + )-ethyl 3-hydroxybutanoate (Note
7) and (Note
8); the specific rotation
[α]25D + 37.2° (
chloroform,
c 1.3) corresponds to an enantiomeric excess of
85% (Note
9).
The enantiomeric excess may be enhanced by several crystallizations of the 3,5-dinitrobenzoate derivative (Note
10) or else by using "starved" yeast (Note
11).
2. Notes
1. Commercially available sugar (
sucrose) from a grocery store is used.
2. Commercially available baker's yeast can be used. The submitters used baker's yeast from E. Klipfel & Co. AG, CH-4310 Rheinfelden (Switzerland). The checkers used Fleischmann's yeast (cubes), obtained from a supermarket, or Red Star Baker's yeast (Universal Food Corporation), obtained from a bakery. The optical rotation of the final product was essentially the same for runs in which the two brands were employed.
4. One to two bubbles per second of
CO2 are developed.
6. In the case of emulsions, addition of
methanol may be helpful. The very fine and stable emulsion that still remains is included with the aqueous phase.
7. The spectral properties of
(S)-( + )-ethyl 3-hydroxybutanoate are as follows: IR
2a (film) cm
−1: 3440, 2980, 1730, 1375, 1300, 1180, 1030;
1H NMR
2b (CCl
4) δ: 1.15 (d, 3 H,
J = 6.5, CH
3), 1.28 (t, 3 H,
J = 7 Hz, CH
3), 2.35 (d, 2 H,
J = 6.5, CH
2CO), 3.15 (s, 1 H, OH), 4.05 (q, 2 H,
J = 7, CH
2O), 4.15 (m, 1 H, CHOH).
8. This ester should be stored in a
refrigerator as there has been some indication that it may undergo a transesterification–oligomerization upon standing at room temperature.
9. The specific rotation
[α]25D varies from +35.5° to +38° (82–87% enantiomeric excess). The enantiomeric purity can also be checked by formation of the ester with
(R)-( + )-1-methoxy-1-trifluoromethylphenylacetyl (MTPA) chloride.
2 The
19F NMR chemical shifts of the diastereomeric esters are 6.13 (
R,R) and 6.01 (
R,S) ppm downfield of external
trifluoroacetic acid.
10. The procedure of enriching the (
S)-( + )-enantiomer to 100% enantiomeric excess by the previously described crystallization method is tedious.
3 It provides optically pure
ethyl (S)-( + )-3-(3',5'-dinitrobenzoyloxy)butanoate of
[α]25D +26.3° (
chloroform,
c 2), which after cleavage gives enantiomerically pure
(S)-( + )-ethyl 3-hydroxybutanoate of
[α]25D + 43.5° (
chloroform,
c 1.0). This optically pure compound has recently become commercially available from Fluka AG, CH-9470 Buchs (Switzerland), but it is very expensive. After submission and checking of this procedure, it was shown
4 that the ee of the product can be increased to >95% by working under aerobic conditions and by adding the keto ester more slowly; see also (Note
11).
11. The analysis of the published procedures for reductions of β-keto esters by baker's yeast indicated
5 that aerobic conditions,
4 the presence of
5–15% ethanol in the medium,
4,6 and "aging" of the yeast
4 might be important for high selectivity. The optimum conditions—"starving" the yeast for at least 4 days in
5% aqueous ethanol aerobically—lead to an activation of the enzyme(s)
7 producing the
S-enantiomer of
ethyl-3-hydroxybutanoate.
The procedure
5 was as follows. A suspension of 125 g of baker's yeast in 1000 mL of H
2O/
EtOH (95 : 5) was shaken (120 rpm) at 30°C in a
2-L Erlenmeyer flask with indentations for 4 days. After the addition of
5 g (38 mmol) of ethyl acetoacetate the reaction was followed by GLC. When the reaction had reached completion (2–3 days), the mixture was centrifuged and the supernatant was extracted continuously with
ether (4 days). The organic layer was dried over
magnesium sulfate, filtered, and concentrated with a rotary evaporator at 35°C bath temperature. The crude product was purified by bulb to bulb distillation to give
ethyl 3-hydroxybutanoate,
3.54 g (
70%), as a colorless liquid with an optical purity of 94% e.e. (enantiomeric excess).
3. Discussion
3-Hydroxybutanoic acid in both enantiomeric forms has been obtained by resolution of the racemic mixture.
8 Hydrogenation of
methyl acetoacetate using a
Raney nickel catalyst that had been treated with
tartaric acid resulted in
methyl 3-hydroxybutanoate with an enantiomeric excess of
83–88%.
9 Most recently it was found that enantiomerically pure
(R-) or (S-)-ethyl 3-hydroxybutanoate is available by enantioselective hydrogenation with a chiral homogeneous
ruthenium catalyst.
10 Furthermore, optically active
3-hydroxybutanoic acid has been obtained in good chemical and optical yield by condensation of chiral α-sulfinyl ester enolates with aldehydes followed by desulfurization.
11 (R-)-( − )-Ethyl 3-hydroxybutanoate in
100% enantiomeric excess resulted from depolymerization of poly-(
R)-3-hydroxybutanoate, an intracellular storage product of
Alcaligenes eutrophus H 16.
12 The method presented in the Seebach–Züger paper
12 is easy to perform. The
(S)-( + )-ethyl 3-hydroxybutanoate obtained may be enriched to
100% enantiomeric excess by crystallization of its 3,5-dinitrobenzoate derivative, followed by alcoholysis.
3
The yeast reduction is not limited to
ethyl acetoacetate. It has been applied to other β-keto esters, α-keto esters, α-keto alcohols, α-keto phosphates, and some ketones (Table II). The reductions show a high degree of stereoselectivity. The absolute configuration of the product obtained by reduction of a carbonyl group containing a large group L and a small group S to the alcohol may be determined by application of Prelog's rule.
15,16
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