Example 1
(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (lC)
A. 4-(tert-Butyldimethylsiloxy)-2H-thiopyran (1A)
2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.14 mol, synthesized as described in Richards et al, J. Org. Chem. 46, 4836-4842 (1981)) was dissolved in CH2C12 (130 mL) and triethylamine (5.47 mL, 39.41 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.77 mmol) was then added. After 10 minutes, the volatiles were removed by rotary evaporator at 25°C. The resulting yellow oil was passed through a short column of SiO2 eluting with 3% TEA in hexanes to yield 1.82 g of compound 1A as an orange oil.
B. l-[4-bromo-3-methylphenyl]-lH-pyrrole-2,5-dione (IB)
4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115 °C for 12 h. The reaction was then cooled to 25°C and the acetic acid was removed in vacuo. The resulting residue was suspended in 5% K2CO3 (100 mL), stirred for 25 minutes and followed by filtering and rinsing with water. The material was then dried in vacuo to give compound IB as a light brown solid (1.65 g). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
C. (3 a ,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (IC)
Compound 1A (0.313 g, 1.41 mmol) and compound IB (0.250 g, 0.94 mmol) were dissolved in toluene and heated to reflux for 5 h. The toluene was then removed by passing a stream of argon through the reaction flask. The residue was then purified by flash chromatography on SiO2 eluting with 20% hexane in chloroform. This gave 0.168 g ofthe enol ether intermediate as a yellow solid. The enol ether intermediate was dissolved in dichloroethane (2.0 mL) and TFA (0.25 mL) was added. After 0.5 h, the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2C12 (2 x 30 mL). The organics were dried over anhydrous sodium sulfate and evaporated to give 0.079 g of compound IC as a white solid. HPLC: 99% at 3.010 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90%) aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS (ES): m z 396.9 [M+ NH4]+.
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