A.
2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione. A
1-L, round-bottomed flask equipped with a
thermometer and a
reflux condenser capped with an
argon-inlet tube is charged with
126.1 g (1 mol) of 2-methyl-1,3-cyclohexanedione (Note
1) and 300 mL of distilled water. To the well-stirred suspension are added
3 mL of acetic acid,
1.1 g of hydroquinone, and
142 g (167 mL, 2 mol) of freshly distilled methyl vinyl ketone (Note
2). The reaction mixture is stirred under
argon at 72–75°C for 1 hr, cooled to room temperature, treated with
sodium chloride (103 g), and poured into a
separatory funnel containing
ethyl acetate (400 mL). The organic phase is collected and the aqueous phase is reextracted twice with
ethyl acetate (150 mL each time). The combined extracts are washed with two
200-mL portions of saturated brine, dried over anhydrous
magnesium sulfate, and filtered, and the filtrate is evaporated at 40°C under reduced pressure (
water aspirator) on a
rotary evaporator. The residue is kept under high vacuum (1.0 mm) at 40°C for 30 min to give
210.8 g of crude
2-methyl-2-(3-oxobutyl)-1,3-cyclohexanedione (
1, "trione") as a pale-yellow oil, homogeneous by thin-layer chromatography (Note
3). This crude material is used in Step B.
B.
(S)-8a-Methyl-3,4,8,8a-tetrahydro-1,6(2H, 7H)-naphthalenedione (3-S). A
3-L, one-necked, round-bottomed flask, equipped with an argon-inlet tube and containing a
magnetic stirrer, is charged with
5.75 g (0.05 mol) of finely ground L-proline (Note
4) and a solution of
210.8 g of crude trione 1 (from Step A) in
1 L of anhydrous dimethyl sulfoxide (Note
5). The mixture is stirred at room temperature (ca. 25°C) under
argon for 120 hr, the magnetic bar is removed, and the solvent is removed under high vacuum (1.0 mm) at 65°C (Note
6) on a rotary evaporator to give 206.9 g of a dark reddish-violet oil. The oil is dissolved in
toluene (100 mL) and is absorbed on a
column (9 cm X 60 cm) of silica gel (1.5 kg, 70–230 mesh) (Note
7), which was previously packed in
hexane. Elution is carried out under a slight positive pressure of
argon (ca. 1 atm) (Note
8) initially with
1 L of hexane: ethyl acetate (5 : 1) and then with a 3 : 2 mixture of hexane : ethyl acetate taking 300-mL fractions. The progress of the purification is monitored by thin-layer chromatography (Note
9): no product is observed until ca. 5 L of eluant is collected. Fractions containing the product are combined, and the solvents are removed under reduced pressure (water aspirator) at 45–50°C. The residue is then kept under high vacuum (0.1 mm) at 40°C for 30 min to give
154.2 g of an orange-colored oil, which became glassy and sometimes crystalline on standing at room temperature,
[α]D25 + 68° (
toluene,
c 1.5) (Note
10). This material is dissolved in
535 mL of ether and is filtered through a fluted filter paper to remove small particles. The flask is rinsed with
500 mL of ether, and this is passed through the filter paper. After cooling to 3°C, the combined filtrates are seeded with a few crystals of pure 3-S (Note
11), and the mixture is left undisturbed at −20°C for 18 hr. Most of the supernatant liquid is carefully decanted without agitation, and the crystals are collected by filtration. The flask is rinsed with cold (0°C)
50% ether in hexane and the rinse is used to wash the crystals. The crystals are dried for 16 hr under high vacuum at room temperature to yield
85.9 g of (
S)-enedione (first crop), mp
49–50°C,
[α]D25 + 96.9° (
toluene,
c 1.2). The combined filtrate and washings are evaporated to give
67.1 g of an orange-colored oil, which is dissolved in
604 mL of ether, cooled to 3°C, and seeded with (
R,S)-enedione (Note
12). The mixture is left at −20°C for 18 hr, and the supernatant liquid is carefully decanted (no agitation). The wet crystals are then collected by filtration, washed with cold (0°C)
50% ether in hexane, and dried under reduced pressure at room temperature to give
36.3 g of racemic material (3
R + 3
S). The filtrate and washing are evaporated to give
30.6 g of an oil, which is dissolved in
100 mL of ether, and filtered through a fluted filter paper. The flask is rinsed with
114 mL of ether, and filtered through the fluted filter paper, and the combined filtrates are cooled to 3°C and seeded with crystals of the pure 3-S. The mixture is left at −20°C overnight, the supernatant liquid is carefully decanted without much agitation and the wet crystals are collected by filtration and washed with cold (0°C)
50% hexane in ether. After drying
15.3 g of light amber-colored crystals (second crop), (mp
49–50°C, (or
[α]D25 + 97.3° (
toluene,
c 1.0). The total yield of (
S)-enedione is
101.2 g (56.8%) (Note
13).