Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

Cryptolepine, neocryptolepine, and isocryptolepine have remained popular synthetic targets ever since their isolation from the aqueous extracts of the West African climbing shrub Cryptolepis sanguinolenta. These natural alkaloids were found to contain significant antimalarial, antiproliferative and antimicrobial activities, making them ideal starting points for the development of novel drug candidates. As natural product synthesis is often plagued with step-heavy procedures and poor atom economy, the discovery of synthetic protocols addressing these concerns are sorely needed. In our laboratories, we have devoted our efforts into the development of regiodivergent synthesis whereby two of the indoloquinoline natural products, namely neocryptolepine and 11H-indolo[3,2-c]quinolines, could be assembled in only a few steps from a common and readily available starting material. Our synthetic endeavors to meet these goals include a cascade palladium-catalyzed Suzuki-Miyuara cross-coupling and intramolecular C-N bond formation and a photochemical nitrene insertion strategy. Furthermore, our methods also allowed for the construction of several diversely functionalized natural product derivatives which were subjected to biological evaluations.