Rearrangement of isoindolo[1,2-b][3]benzazepinium to dibenze[a,g]quinolizinium ions: application to the total synthesis of (±)-tetrahyropalmatine

Abstract

(±)-Tetrahydropalmatine (17) has been synthesized in 16% yield from 6,7-dimethoxy-3-(3,4-dimethoxybenzylidene)phthalide (4) as follows. Reaction of compound (4) with glycine afforded 6,7-dimethoxy-3-(3,4-dimethoxybenzylidene)phthalimidin-2-ylacetic acid (6) which, on hydrogenation to compound (8) followed by cyclization, gave 13,13a-dihydro-3,4,10,11-tetramethoxyisoindolo[1,2-b]-[3]benzazepine-5,8(7H)-dione (10). Reduction of the ethylene acetal of (10)[(11)], and quaternization with methyl iodide gave 7,8,13,13a-tetrahydro-3,4,10,11-tetramethoxy-6-methyl-8-oxo-5H-isoindolo[1,2-b][3]benzazepinium iodide ethylene acetal (12) which, on treatment with base, rearranged to 5,6,13,13a-tetrahydro-2,3,9,10-tetramethoxy-7-methyl-5-oxo-8H-dibenzo[a,g]-quinolizinium iodide ethylene acetal (13). Conversion of this latter compound to the corresponding acetate followed by pyrolysis and treatment with borane led to compound (17). Attempts to cyclize a methylenedioxy derivative of 3-benzylidenephthalimidin-2-ylacetic acid under various conditions have so far given unsatisfactory results.