Organic Chemistry

Collective Total Syntheses of Benzo[c]phenanthridine Alkaloids via A Sequential Transition Metal-Catalyzed Pot-Economy Approach

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Abstract

The collective total syntheses of a series of benzo[c]phenanthridine alkaloids were accomplished via a pot-economy approach. The synthetic strategy was achieved by constructing ring C and ring B on pre-installed ring A and ring D via sequential transition metal-catalyzed reactions and condition-controlled Mannich reactions in a three-pot protocol. A palladium-catalyzed Sonogashira coupling reaction and a following Wittig reaction were utilized to connect ring A and ring D from readily available starting materials to finish the preparation of the 1,5-enyne substrates (the first pot). A gold(I)-catalyzed cycloisomerization and in situ iododeauration cascade of 1,5-enyne substrates was developed to form ring C (the second pot). A copper-catalyzed Ullman coupling reaction, followed by a flexible condition-controlled Mannich reaction, was designed to install ring B in the final stage of the synthesis (the third pot). The synthetic naturally occurring alkaloids and related analogues were evaluated in cytotoxic activity against K562, MCF-7 and A549 cells.

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Supplementary material

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Collective Total Syntheses of Benzo[c]phenanthridine Alkaloids via A Sequential Transition Metal-Catalyzed Pot-Economy Approach
Collective total syntheses of ten benzo[c]phenanthridines were achieved based on construction of rings C and B through sequential transition metal-catalyzed reactions and flexible condition-controlled Mannich reaction via 3 pots in 25-34% yields, which provided an efficient route to benzo[c]phenanthridines in a pot-economy approach. The exploration of the cytotoxic activity and the verification of the mechanism indicated that benzo[c]phenanthridines may serve as the potential anticancer lead compounds.