Synthesis of New Analogues of the Tetraponerines

• Published in: European Journal of Organic Chemistry 2009-06, Vol.2009 (16), p.2666-2674
• Main Authors: Rouchaud, Anne, Braekman, Jean-Claude
• Format: Article
• Language: English
• Subjects: Alkaloids; Chemistry; 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; Nitrogen heterocycles; Organic chemistry; Preparations and properties; Structure-activity relationships; Tetraponera; Tetraponerine analogues
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200900064

To evaluate the influences of the tetraponerine alkyl chains and tricyclic ring systems on their cytotoxic activities, we have prepared a series of alkyl derivatives (3a, 3b and 4a–f) of the non‐natural tricyclic skeletons decahydro‐2H,6H‐dipyrido[1,2‐a:1′,2′‐c]pyrimidine (3, 6–6–6 skeleton) and dodecahydro‐2H‐1,8a‐diazaphenanthrene (4, iso‐6–6–6 skeleton). In this study, two ways to synthesise the 6–6–6 analogues have been developed and compared. One is based on the condensation of α‐tripiperideine with diethyl malonate (DEM) in water at pH 11. This yielded oxo ester 11, precursor of the amino nitrile 8, but only in moderate yield. In the second pathway, the key intermediate 8 was more efficiently synthesised by starting from 2‐(2‐piperidyl)ethanol. Treatment of 8 with alkyl Grignard reagents led to the 6–6–6 analogues 3a and 3b. When the one‐pot reaction between α‐tripiperideine and DEM was performed in water at pH 8, the lactam 12, precursor of the iso‐6–6–6 skeleton, was obtained in a yield of 76 %. The same lactam was also obtained in a yield of 86 % by treatment of tetrahydroanabasine 14 with DEM in water at pH 8. Lactam 12 was transformed into the iso‐6–6–6 analogues 4a–4f. The cytotoxic activities of the 6–6–6 and iso‐6–6–6 analogues against HT29 cancer cells were compared with those of the 5–6–5 and 6–6–5 tetraponerines and with those of solenopsin analogues. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) Effective syntheses of 6–6–6 (3) and iso‐6–6–6 (4) analogues of the tetraponerines, major constituents of the contact poison produced by the ant Tetraponera sp., have been developed, and their cytotoxic activities against HT29 cancer cells have been evaluated.