New Route to the Synthesis of the Isocryptolepine Alkaloid and Its Related Skeletons Using a Modified Pictet–Spengler Reaction

• Published in: European journal of organic chemistry 2009-01, Vol.2009 (2), p.292-303
• Main Authors: Agarwal, Piyush K., Sawant, Devesh, Sharma, Sunil, Kundu, Bijoy
• Format: Article
• Language: English
• Subjects: Chemistry; Cyclization; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Natural products; Nitrogen heterocycles; Organic chemistry; Polycycles; Preparations and properties
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200800929

A new route to the synthesis of the isocryptolepine alkaloid with antimalarial activity using a modified Pictet–Spengler reaction has been devised. The strategy was then used to generate libraries based on three structural variants of the alkaloid. Compounds based on these three variants in general were accessed in three steps through a modified Pictet–Spengler cyclization reaction as the key step. The C‐2‐, C‐3‐, or N‐1‐linked (aminoaryl)indoles (8, 12, 13) required for cyclization were obtained by treating the corresponding indoles with o‐halonitrobenzene using either nucleophilic replacement or Pd‐based chemistry (Heck/Suzuki reaction) followed by reduction of the nitroaryl functionality. The substrates 8, 12, and 13 were then subjected to the Pictet–Spengler reaction to furnish polycyclic structures, indolo‐quinolines 4 and 19 and indolo‐quinoxalines 20 with three‐point diversity in high yields and purities. One of the indolo‐quinolines 4a after treatment with CH3I furnished the isocryptolepine alkaloid in excellent yield. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) A modified Pictet–Spengler reaction has been applied to generate libraries based onthree structural variants of the isocryptolepine alkaloid.