Synthesis of enantiopure oxoindolo-quinolizines

Methyl (1S,3S and 1R,3S)-1-(2,2-dimethoxyethyl)1,2,3,4-tetrahydrocarboline- 3-carboxylate (3) was hydrolyzed in the presence of sodium hydroxide to giv e (1S,3S and 1R, 3S)-1-(2,2-dimethoxyethyl)- 1,2,3,4-tetrahydrocarboline-3- carboxylic acid (4) which was reduced with LiAlH4 to provide (1S,3S)- and ( 1R,3S)-1-(2,2-dimethoxyethyl)-3-hydroxymethyl-1,2,3,4-tetrahydrocarboline ( 10) and then amidated in ammonia containing methanol to obtain (1S,3S)and ( 1R,3S)-1-(2,2-dimethoxyethyl)- 1,2,3,4-tetrahydrocarboline-3-carboxamide (1 4). Acylation of (1S,3S and 1R,3S)-3, (1S,3S and 1R,3S)-4, (1S,3S)-10, (1R, 3S)-10, (1S,3S)-14 and (1R,3S)-14 afforded the corresponding methyl (1S,3S and 1R, 3S)-1-(2,2-dimethoxyethyl)-2-(1,3-dioxobutyl)-1,2,3,4-tetrahydrocar bolines-3-carboxylate (6), (IS,3S and 1R,3S)-1(2,2-dimethoxyethyl) -2-(1,3- dioxobutyl)-1,2,3,4-tetrahydrocarboline-3-carboxylic acid (5), (1S,3S)- and (1R,3S)-1-(2,2-dimethoxyethyl)-2-(1,3-dioxobutyl)-3-(1,3-dioxobutyl)oxymet hyl-1,2,3,4-tetrahydrocarboline (11), (1S,3S)- and (1R,3S)-1-(2,2-dimethoxy ethyl)-2-(1,3-dioxobutyl)-1,2,3,4,-tetrahydrocarboline-3-carboxamide (15), respectively. After Aldol reaction, dehydration and dehydrogenation the des ired (6S)-6-substituted 4,6,7,12-tetrahydro-4-oxoindolo [2,3-a]quinolizines 8, 9, 12, 13, and 16 were obtained. Their anticancer activities in vitro w ere investigated.