24 10-ヒドロキシ-ジヒドロシンコニジン誘導体の立体選択的合成

概要

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Stereoselective synthesis of the metabolites (2 and 3) of 7'-trifluoromethyl dihydrocinchonidine (1), antiarrhythmic agent, has been achieved as described below. The key synthon (14) of guinuclidine moiety of 2 (C_<10>-R) was synthesized starting from loganin (4). Reductive amination of the aglycone of 4 followed by the successive treatments of 5 with 3N HCl, NaBH_3CN, and PhCOCl gave 8. The Baeyer-Villiger oxidation of 10, Jones' oxidation product of 8, afforded the lactone (12), which was transformed to 14 in 3 steps. Another synthon (30) was synthesized from 1S-(3-pyridyl)ethanol (15). Hydroboration of the key intermediate, E-olefine (27) prepared from 15 in 7 steps, gave the C_<10>-S lactone (28), which was converted to the synthon (30). Condensation of 30 with 7-trifluoromethyllepidine (32) afforded the ketone (34). Then 34 was converted to the olefine (40) via 37 and 38. Reduction of 40 with DIBAH followed by refluxing the resulting amine (42) in 10% H_2O-MeOH gave the cyclized product (44a,b). Finally, stereospecific hydroxylation at C-9 of 44a,b with oxygen and desilylation of (45a dnd 45b) gave 10S-metabolite 3 and the isomer 50. In a similar manner, 10R-metabolite (2) was also synthesized from 14 and 32.
1982-09-10