(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione

 




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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(3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione

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Example 8 (3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione (8)

3,5-Bis-(trifluoromethyl)-aniline (0.017 g, 0.0075 mmol) was dissolved in acetic acid (0.300 mL) and transfeπed to a 1.5 mL conical vial with a septa cap. Stock solutions of an additional 95 amines were prepared as described above. To each of the above vials was added 0.4 mL (0.12 mmol) of a stock solution of exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride in acetic acid. The vials were then sealed and heated at 110°C for 11 h. Upon cooling to 25°C, the caps were removed from the vials and the acetic acid was removed in vacuo. To each vial was added 1 mL of 2:1 acetone/methylene chloride and the vials were heated at 40°C for 1 h. Once all products were in solution, they were transfeπed via robot to filter tubes with coarse frits pre- wetted with 0.2 mL of water. Nitrogen was blown through each tube until the volatile organics were removed. 1.5 mL of 10% aq K₂CO₃ was then added to each tube followed by vigorous shaking at 25°C for 15 min. The tubes were then drained, resealed and 1.0 mL of water was added to each tube followed by shaking. The tubes were drained again and washed with water a second time. The resulting residues in each tube was then dried in vacuo for 48 h. After drying, 1.0 mL of 20% TFA in methylene chloride was added to each tube and the racks were shaken for 30 min. The tubes were then drained into a 96-well plate with pre-tared custom micro-tubes present. Each tube was assayed for product purity (analytical LC) and identity (LC-MS). The tubes were then concentrated in vacuo and weighed for yields. The tube containing the reaction of 3,5-bistrifluoromethylaniline and exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride, yielded 0.022 g of compound 8 as a white solid. HPLC: 94% at 4.03 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 434.2 [M+Na+MeOH]⁺\ Of the remaining 95 additional reactions run, a total of 80 final compounds were obtained in >70% purity and >5 mg yield. Several samples needed further purification which was performed by short SiO₂ column eluting with methylene chloride/acetone. See Table 2 below.










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