Checked by Thomas Kirrane and Albert I. Meyers.
1. Procedure
B.
(4R)-(+)-Hydroxy-2-cyclopenten-1-one. A
2-L, one-necked, round-bottomed flask, fitted with a Teflon-coated magnetic stirring bar, is charged with
1.5 L of 0.05 M phosphate buffer (Note
8) and
18.8 g (134 mmol) of (4R)-(+)-acetoxy-2-cyclopenten-1-one. A 4.0-g lot of wheat germ lipase (Note
9) is added slowly with rapid stirring. Once the enzyme is dispersed, the speed of the stirrer is reduced and the flask is sealed with a
glass stopper prior to being stirred at room temperature for 7 days (Note
10). The stopper is removed and the contents of the flask are transferred to the body of a lighter than water continuous extraction apparatus whose pot is charged with
1 L of ethyl acetate. After extraction for 3 days, the
ethyl acetate solution is concentrated on a rotary evaporator, and the residue is subjected to flash chromatography on silica gel using
30% ethyl acetate in
petroleum ether (bp
35–60°C) as eluent (Note
11). After recovery of
4.60 g (
25%) of the less polar, unreacted
acetoxy ketone (Note
12),
7.80 g (
60%) of the colorless, oily (R)-(+)-hydroxy ketone is obtained (Note
13).
C.
(4R)-(+)-tert-Butyldimethylsiloxy-2-cyclopenten-1-one. A
500-mL, three-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar,
pressure-equalizing addition funnel, and
nitrogen inlet, is flame-dried under a stream of dry
nitrogen. The apparatus is charged with
7.7 g (78 mmol) of (4R)-(+)-hydroxy-2-cyclopenten-1-one,
0.96 g (10 mol %) of 4-dimethylaminopyridine (Note
14),
20 g (200 mmol) of triethylamine (Note
2), and
150 mL of dry dichloromethane (Note
1). The dropping funnel is charged with a solution of
14.2 g (94 mmol) of tert-butyldimethylsilyl chloride (Note
14) in
50 mL of dry dichloromethane. Magnetic stirring is initiated, the reaction mixture is cooled in an
ice-water bath, and the silyl chloride solution is added dropwise during 10 min. The ice-water bath is removed, and the mixture is stirred at room temperature for 3 hr; then 100 mL of deionized water is added with stirring. After the organic layer is separated, the aqueous phase is extracted three times with
50 mL of dichloromethane and the combined organic solutions are dried over anhydrous
magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue is filtered through a
short column of silica gel with elution by
5% ethyl acetate in petroleum ether (bp
35–60°C). After concentration of the fractions containing the product, the resulting oil is distilled in a short path distillation apparatus (bp
60°C at 0.1 mm) to give
13.2 g of a colorless oil. Crystallization of this material from
pentane with cooling by an
acetone-dry ice bath gives
10.6 g (
64%) of colorless needles, mp
27–28°C,
[α]D20 +65.3° (CH
3OH,
c 0.4) (Note
15) and (Note
16).
2. Notes
3. The 4 Å molecular sieves were purchased from the Aldrich Chemical Company, Inc., and activated by drying in a
vacuum oven at 150°C for 24 hr prior to storing in an oven at 140°C. Both powdered and pelletized forms of the sieve were used without affecting the yield of product.
4. High purity (≥99% ee) (1R,4S)-4-hydroxy-2-cyclopentenyl acetate exhibiting
[α]D23 values of +71.1° to +71.3° in CHCl
3 can be obtained by enzymatic hydrolysis of the racemic diacetate (
Org. Synth., Coll. Vol. IX 1998, 487)
2,3,4 with electric eel acetyl cholinesterase
4 or with A.K. lipase (Amano International Enzyme Company).
5
5. The progress of this reaction is conveniently monitored by TLC. The silica gel plates are eluted with
50% ethyl acetate in petroleum ether (bp
35–60°C). Under these conditions, the alcohol exhibits an R
f of 0.45 and the acetate an R
f of 0.80.
6. The column consists of
300 g of silica gel; 100-mL sized fractions are collected. Since release of the product from the chromium salts occurs slowly, fractions 5–20 are found to contain the acetoxy ketone and are combined.
7. The spectral data for
(4R)-(+)-acetoxy-2-cyclopenten-1-one are as follows:
1H NMR (300 MHz, CDCl
3) δ: 2.06 (s, 3 H), 2.29 (dd, 1 H, J = 2.2, 18.7), 2.78 (dd, 1 H, J = 6.4, 18.7), 5.81 (m, 1 H), 6.29 (dd, 1 H, J = 1.3, 5.7), 7.53 (dd, 1 H, J = 2.4, 5.7);
13C NMR (75 MHz, CDCl
3) δ: 20.7, 40.9, 71.9, 136.9, 158.8, 170.3, 204.7; IR (CHCl
3) cm
−1: 2950, 1740, 1720, 1600, 1375, 1355, 1190, 795;
[α]D20 +96.1° (CH
3OH,
c 0.17) [lit.
6 [α]D22 +97° (CH
3OH,
c 0.1].
9. Wheat germ lipase was purchased from the Sigma Chemical Company.
10. The reaction rate decreased significantly toward the end of the hydrolysis. The level of conversion can be improved either by increasing the amount of enzyme or by lengthening the reaction time. The course of the reaction can be monitored by TLC on silica gel (elution with
50% ethyl acetate in petroleum ether). The product has an R
f of 0.20 and the starting material an R
f of 0.40.
11. The column consists of
200 g of silica gel; 100-mL sized fractions are collected. The starting material was recovered in fractions 2–5 while the product was recovered from fractions 7–20.
12. This material can be recycled in future reactions.
13. The spectral data for (4R)-(+)-hydroxy-2-cyclopenten-1-one are as follows:
1H NMR (300 MHz, CDCl
3) δ: 2.27 (dd, 1 H, J = 3.0, 18.0), 2.78 (dd, 1 H, J = 6.0, 18.0), 3.27 (br s, 1 H), 4.88–5.22 (m, 1 H), 6.25 (d, 1 H, J = 6.0), 7.60 (dd, 1 H, J = 2.0, 6.0);
13C NMR (75 MHz, CDCl
3) δ: 44.1, 70.1, 134.7, 164.0, 207.3;
[α]D20 +78.1° (CH
3OH,
c 2.03).
15. The spectral data for
(4R)-(+)-tert-butyldimethylsiloxy-2-cyclopenten-1-one are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.12 (s, 3 H), 0.13 (s, 3 H), 0.91 (s, 9 H), 2.23 (dd, 1 H, J = 2.3, 18.2), 2.69 (dd, 1 H, J = 6.0, 18.2), 4.98 (m, 1 H), 6.17 (dd, 1 H, J = 1.2, 5.7), 7.44 (dd, 1 H, J = 2.3, 5.7);
13C NMR (75 MHz, CDCl
3) δ: −4.76, −4.74, 18.0, 25.7, 44.9, 70.9, 134.4, 163.7, 206.3.
16. The reported optical rotations are
[α]D21 +66.6° (CH
3OH,
c 1.0),
7 [α]D21 +67.0° (CH
3OH,
c 0.12),
6 and
[α]D21 +67.3° (CH
3OH,
c 0.82).
8
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
As a direct consequence of the quest for optically active prostaglandins,
9 derivatives of
(R)-4-hydroxy-2-cyclopenten-1-one have come to be regarded as important chiral building blocks. Initial efforts to obtain these compounds in enantiomerically pure form involved the chemical modification of
D-tartaric acid,
10 degradation of the fungal metabolite terrein,
11 ring contraction of
2,4,6-trichlorophenol with resolution,
9,12 chromatography of diastereomeric
13 or racemic hydroxy-protected derivatives,
14 and a multi-step conversion from
glucose.
15 Subsequent discoveries that excellent kinetic resolution can be achieved either by asymmetric BINAL-H reduction of
4-cyclopentene-1,3-dione16 or by enzymatic hydrolysis of the acetate
17 proved to be major advances.
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved