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Synthesis of Daphnilongeranine C

Synthesis of Daphnilongeranine C. A synthethic route presented by Lab B members : Guillaume Pelletier, Gérald Lemonnier, Philipp Gritsch , William S. Bechara , Léa Constantineau-Forget and Alexandra Aubé May 14th 2010. Background on the Natural Molecule.

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Synthesis of Daphnilongeranine C

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  1. Synthesis of Daphnilongeranine C A synthethic route presented by Lab B members : Guillaume Pelletier, Gérald Lemonnier, PhilippGritsch, William S. Bechara, Léa Constantineau-Forget and Alexandra Aubé May 14th 2010

  2. Background on the Natural Molecule • Isolated from Daphniphyllum longeracemosum, an evergreen tree in the Yunnan Province of China • 2 quarternary and 5 tertiary centers • 1 tertiary amine • 8 stereogenic centers • Hexacyclic sytem

  3. Retrosynthetic analysis

  4. Retrosynthetic analysis

  5. Synthesis of the cyclohexenone core a) Funk, R.L.; Bolton, G. L.J. Org. Chem. 1987, 52, 3174. b) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.

  6. Synthesis of the cyclohexenone core a) Funk, R.L.; Bolton, G. L.J. Org. Chem. 1987, 52, 3174. b) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.

  7. Synthesis of the cyclohexenone core a) Funk, R.L.; Bolton, G. L.J. Org. Chem. 1987, 52, 3174. b) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.

  8. Synthesis of the cyclohexenone core

  9. Synthesis of the cyclohexenone core a) Kanematsu, M. et al. Synthesis2009, 17, 2893. b) Fischer, C.; Fu, G.C. J. Am. Chem. Soc.2005, 127, 4594. c) Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed.2009, 48, 2. d) Genicot, C.; Gobeaux, B.; Ghosez, L. Tetrahedron Lett. 1991, 32, 3827.

  10. Synthesis of the cyclohexenone core (alternative) a) Kanematsu, M. et al. Synthesis2009, 17, 2893. b) Fischer, C.; Fu, G.C. J. Am. Chem. Soc.2005, 127, 4594. c) Rudolph, A.; Lautens, M. Angew. Chem. Int. Ed.2009, 48, 2. d) Genicot, C.; Gobeaux, B.; Ghosez, L. Tetrahedron Lett. 1991, 32, 3827.

  11. Intramolecular [2+2] on a keteniminium intermediate Genicot, C.; Gobeaux, B.; Ghosez, L. Tetrahedron Lett. 1991, 32, 3827.

  12. Ring expansion via an intramolecular Schmidt reaction a) Martinelli, M. J.; et al.Tetrahedron Lett. 2000, 41, 3773. b) Zhen, Z. B. et al J. Org. Chem. 2008, 73, 7310 c) Zeng, Y.; Aubé, J. J. Am. Chem. Soc. 2005, 127, 15712.

  13. Ring expansion via an intramolecular Schmidt reaction Zeng, Y.; Aubé, J. J. Am. Chem. Soc. 2005, 127, 15712.

  14. Synthesis of the cyclopentene core a) Babler, J. H. et al. Synth. Commun. 1996, 26, 1943. b) Kvita, V. etal. Helv. Chem. Acta 1990, 73, 883.

  15. Synthesis of the cyclopentene core a) Babler, J. H. et al. Synth. Commun. 1996, 26, 1943. b) Kvita, V. etal. Helv. Chem. Acta 1990, 73, 883. c) Marko, I. E. et al. Tetrahedron Lett. 1994, 35, 2771. d) Marko, I. E. et al Org. Lett. 2000, 2, 2123.

  16. Radical-mediated ring fragmentation c) Marko, I. E. et al. Tetrahedron Lett. 1994, 35, 2771. d) Marko, I. E. et al Org. Lett. 2000, 2, 2123.

  17. Radical-mediated ring fragmentation c) Marko, I. E. et al. Tetrahedron Lett. 1994, 35, 2771. d) Marko, I. E. et al Org. Lett. 2000, 2, 2123.

  18. Synthesis of the cyclopentene core a) Kende, A. S. et al. J. Am. Chem. Soc. 1990, 112, 4070. c) Kazahawa, K. et al. Synlett2004, 1640. d) Paquette, L. E. et al. J. Org. Chem. 1996, 61, 3268.

  19. Synthesis of the cyclopentene core a) Paquette, L. E. et al. J. Org. Chem. 1996, 61, 3268. b) Hoye, T. R.; Caruso, A. J. Dellaria, J. F.; Kurth, M. J. J. Am. Chem. Soc.1982, 104, 6704. c) Schuppan et al. Angew. Chem. Int. Ed. 2001, 40, 2063.

  20. Synthesis of the cyclopentene core a) Paquette, L. E. et al. J. Org. Chem. 1996, 61, 3268. b) Hoye, T. R.; Caruso, A. J. Dellaria, J. F.; Kurth, M. J. J. Am. Chem. Soc.1982, 104, 6704. c) Schuppan et al. Angew. Chem. Int. Ed. 2001, 40, 2063.

  21. Coupling of both partners a) Trost, B. M.; Dong, G.Nature2008, 456, 485.

  22. Coupling of both partners a) Trost, B. M.; Dong, G.Nature2008, 456, 485.

  23. Movassaghi’s deoxygenation reaction a) Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572.

  24. Intramolecular Stille reaction

  25. Chemoselective reduction of tertiary amide and endmath Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.

  26. Conclusion • Enantioselective and diastereoselective synthesis • of (+)-Daphnilongeranine C •  25 steps for the longest linear sequence •  38 steps total •  Key steps include : • An intramolecular [2+2] cycloaddition on a keteniminum intermediate • An intramolecular Schmidt reaction • A diastereoselective and enantioselective inverse-demand Diels-Alder • An intramolecular Stille reaction

  27. Caracterization

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