New Route to the Synthesis of Isocryptolepine Alkaloid and its Related Skeletons Using the Modified Pictet-Spengler Reaction

Abstract

A new route to the synthesis of isocryptolepine alkaloid with antimalarial activity has been described using the modified Pictet-Spengler reaction. The strategy was then applied to generate libraries based on the three structural variants of the alkaloid. Compounds based on the three variants in general were accessed in three steps with the modified Pictet-Spengler cyclization as the key step. The precursorsor C-2-, C-3- or N-1-linked aryl amine indoles (8, 11, 13) required for cyclization were obtained by treating indoles with o-halonitrobenzene using either nucleophilic replacement or Pd-based chemistry (Heck/Suzuki reac- tion) followed by reduction of the aryl nitro functionality. The substrates 8, 11, 13 were then subjected to the Pictet-Spengler reaction to furnish polycyclic structures, indoloquinolines (4, 12) and indoloquinoxalines (14) with three-point diversity in high yields and purities. One of the indoloquinolines 4a after treatment with CH3I furnished isocryptolepine alkaloid in excellent yield.