Towards new camptothecins. Part 2: Synthesis of the ABCD ring scaffold substituted by a carboxyl group in the 5-position

In the context of formation of camptothecins substituted by a carbonyl function on position 5 of cycle C, synthesis of a new keto tetrahydroindolizine was realized. This compound was obtained from the reaction of Bredereckʹs reagent with an indolizine derived from pyroglutamic acid. That yielded a dimethylaminovinyl group whose NaIO4 oxidation gave a ketone. The indolizinone obtained was reacted in Friedlander condition to give the ABCD ring scaffold of camptothecins substituted by a methoxycarbonyl group on the 5-position. It was also shown that, if it is desired, a 5-carboxamide group does not need to be introduced at the beginning of the synthesis sequence.