Organic Syntheses, CV 9, 136
(4S)-(−)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE
[(4S)-(−)-tert-Butyldimethylsiloxy-2-cyclopenten-1-one]
Submitted by Leo A. Paquette and Todd M. Heidelbaugh
1.
Checked by Thomas Kirrane and Albert I. Meyers.
1. Procedure
A.
(1R,4S)-(−)-4-tert-Butyldimethylsiloxy-2-cyclopentenyl acetate. A dry,
500-mL, three-necked, round-bottomed flask, equipped with a
Teflon-coated magnetic stirring bar,
rubber septum, and
nitrogen inlet, is purged with
nitrogen and charged with
7.67 g (54 mmol) of (1R,4S)-(+)-4-hydroxy-2-cyclopentenyl acetate (Note
1),
660 mg (5.4 mmol) of 4-dimethylaminopyridine (Note
2),
17 mL (122 mmol) of triethylamine (Note
3), and
175 mL of dichloromethane (Note
3). The reaction mixture is cooled to 0°C in an
ice-water bath, and
tert-butyldimethylsilyl chloride (10.24 g, 68 mmol) (Note
2) is introduced in one portion. The ice-water bath is removed and the mixture is allowed to warm to room temperature and stir for 3 hr. At this point, more silyl chloride is added if necessary (Note
4). After 5 hr, 200 mL of water is added, the mixture is transferred to a
separatory funnel and the organic phase separated. The aqueous phase is extracted with three
100-mL portions of dichloromethane. The combined organic layers are washed with
100 mL of saturated sodium bicarbonate solution and
100 mL of brine prior to drying over anhydrous
magnesium sulfate. After filtration and solvent removal with a
rotary evaporator, the residual solids are removed by filtration (Note
5), and the resulting yellow oil is purified by bulb-to-bulb distillation at 0.4–0.6 mm (pot temperature 80–100°C) to give
10.67–11.08 g (
77–80%) of
(1R,4S)-(−)-4-tert-butyldimethylsiloxy-2-cyclopentenyl acetate as a colorless liquid,
[α]D20 −1.32° (CH
3OH,
c 1.52) (Note
6).
B.
(4S)-(−)-tert-Butyldimethylsiloxy-2-cyclopenten-1-one. A dry,
500-mL, one-necked, round-bottomed flask, equipped with a Teflon-coated magnetic stirring bar, is purged with
nitrogen and charged with
11.7 g (45.6 mmol) of (1R,4S)-(−)-tert-butyldimethylsiloxy-2-cyclopentenyl acetate and
250 mL of anhydrous methanol (Note
7) to which
4.94 g (91.5 mmol) of powdered sodium methoxide (Note
8) is added. The reaction mixture is stirred for 15 min at ambient temperature, freed of most of the
methanol using a rotary evaporator, and taken up in
400 mL of dichloromethane. The solution is washed with three 200-mL portions of water, dried over anhydrous
magnesium sulfate, filtered, and concentrated using a rotary evaporator, giving 11.2 g of crude allylic alcohol which is carried into the next reaction without further purification.
A 500-mL, round-bottomed flask, equipped with a Teflon-coated magnetic stirring bar, is charged with the 11.2 g of crude allylic alcohol obtained above and
300 mL of dichloromethane, and the resulting vigorously stirred solution is treated with
33 g of active manganese dioxide (380 mmol) (Note
9). Additional 2–5 g lots of the oxidant are added every 2–3 hr until the reaction is complete (Note
10). The reaction mixture is vacuum-filtered through a pad of diatomaceous earth, and the pad is washed with
200 mL of dichloromethane. The resulting clear filtrate is concentrated carefully using a rotary evaporator, and the residual oil is purified by bulb-to-bulb distillation at 0.3 mm (pot temperature 100°C) affording
8.43–8.71 g (
87–90%) of enone as a pale yellow oil that solidifies when cooled below 15°C. Crystallization of the crude product from
pentane at −70°C gives
(4S)-(−)-tert-butyldimethylsiloxy-2-cyclopenten-1-one as colorless needles having mp
32–33°C,
[α]D23 −65.1° (CH
3OH,
c 0.94) (Note
11).
2. Notes
1. High purity (≥99% ee) (1R,4S)-4-hydroxy-2-cyclopentenyl acetate exhibiting
[α]D20 values of +71.1 to +71.3° in CHCl
3 can be obtained by enzymatic hydrolysis of the racemic diacetate
2,3,4 either with electric eel cholinesterase
2 or with A.K. lipase (Amano International Enzyme Company).
5 The checkers employed the EEAC procedure.
2
4. The progress of the reaction is easily monitored by TLC analysis. Silyl chloride is added until the starting hydroxy acetate is no longer detected.
5. Filtration is performed only to prevent bumping during the ensuing distillation.
6. The spectral data are as follows:
1H NMR (300 MHz, CDCl
3) δ: 0.09 (s, 6 H), 0.90 (s, 9 H), 1.57–1.65 (m, 1 H), 2.04 (s, 3 H), 2.75–2.85 (dt, 1 H, J = 7.3, 3.8), 4.69–4.73 (m, 1 H), 5.44–5.48 (m, 1 H), 5.87–5.98 (m, 2 H);
13C NMR (75 MHz, CDCl
3) δ: −4.7, −4.6, 18.2, 21.1, 25.9, 41.2, 74.9, 77.4, 131.2, 138.9, 170.9; IR (neat) cm
−1: 2940, 2870, 1740, 1610, 1375, 1250.
10. The time required to achieve complete reaction varies from 20–48 hr depending on the activity of the
manganese dioxide. The progress of the oxidation is easily monitored by TLC analysis on silica gel.
11. The spectral data are identical to those reported for the (4R) enantiomer.
7
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Although
(1R,4S)-(+)- and (1S,4R)-(−)-4-hydroxy-2-cyclopentenyl acetate are both available by enzyme-promoted enantioselective hydrolysis,
8,9 different enzymes are, of course, required to achieve this stereochemical divergence. Economy would be realized if one of these enantiomeric products could serve as the starting point for the preparation of both antipodal forms of structurally more advanced intermediates. The importance of (4R)-(+)-
10,11 and
(4S)-(−)-tert-butyldimethylsiloxy-2-cyclopenten-1-one12 to prostaglandin synthesis is well established. The latent potential of these highly functionalized building blocks for the enantiospecific synthesis of other natural products is beginning to emerge.
13,14,15 Use of the present procedure makes possible the direct, efficient acquisition of the 4S enantiomer from the same hydroxy acetate that serves as a convenient progenitor to the 4R isomer.
7 The synthetic route is closely similar to that outlined earlier by Danishefsky, Cabal, and Chow.
13
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