A Key Intermediate for the Synthesis of Antitumor Lignan Prototypes

References

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• Commercially available 3-(3,4,5-trimethoxyphenyl) propionic acid was converted into its acid chloride (IR(CCl4) vmax = 1800 cm−1) via treatment with (COCl)2 in benzene at R. T. The acid chloride was reacted with two equivalents of KH and 1 equivalent of benzenesulfonamide to give after acidification the highly crystalline acylsulfonamide 27 (mp 116–117°C) (from EtOAc); 73.6% yield; IR (CHCl3) vmax = 1730 cm−1; 1H-NMR (300 MHz, CDCl3) δ 2.45 (t, 2H), 2.8 (t, 2H), 3.75 (s, 6H), 3.85 (s, 3H), 6.3 (s, 2H), 7.5–7.7 (m, 3H), 8.05 (d, 2H), 9.25 (br s, 1H); M+ Calc'd 379.1090, Found 379.1091). Reaction of dianion 26 (derived from 27 by treatment at -78°C with 2 equiv. of n-BuLi followed by warming to 0°C over several hours) with 2-iodocarboxylate 13 (prepared from 12 by treatment with 1 equiv. NaH at 0°C) at -78°C (cannula transfer) followed by warming to R. T., evaporation of volatiles, acidification, extraction with EtOAc, and flash chromatography (SiO2) gave acid-acylsulfonamide 28 (56%) (IR v = 1730, 1705 cm−1; 1H-NMR (300 MHz, CDCl3/CD3SOCD3) 2.7–3.05 (m, 6H), 3.75 (s, 6H), 3.85 (s, 3H), 5.95 (s, 2H), 6.3 (s, 2H), 6.5–6.7 (m, 3H), 7.4–7.65 (m, 3H), 7.8–7.9 (m, 2H)). Target 9 was obtained by first treating 28 at 0°C in THF with BH3·SMe2 (1.9 equiv.) with gradual warming to R. T. over 14 hours. Removal of volatiles, addition of EtOAc/4N aq. HCl, stirring at R. T. over 4 hours, partitioning in a separatory funnel, washing with sat'd brine, drying, filtration, removal of solvent, and flash chromatography gave 9 as a pale yellow syrup (ca. 75% from 28
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• Alternatively, isolation of the bromoacid after only a short (ca. 20 min) low temperature exposure to CBr4 followed by a careful base/acid extraction cycle performed prior to a final flash filtration leads to yellowish crystalline material of high quality.
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