1 / 56

Total Synthesis of (+)- Haplophytine

Total Synthesis of (+)- Haplophytine. Olivier René Prof. Keith Fagnou Prof. Louis Barriault. Discovery of (+)- Haplophytine. The Mexican flower Haplophyton cimicidum : An efficient insecticide valued by Aztecs. Haplophyton cimicidum. Source: www.fireflyforest.com.

arlo
Télécharger la présentation

Total Synthesis of (+)- Haplophytine

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Total Synthesis of (+)-Haplophytine Olivier René Prof. Keith Fagnou Prof. Louis Barriault

  2. Discovery of (+)-Haplophytine The Mexican flower Haplophytoncimicidum: An efficient insecticide valued by Aztecs Haplophytoncimicidum Source: www.fireflyforest.com 1952: - (+)-Haplophytine first isolated from the mexican flower - Exhibited biological activity 1973: - Structure elucidation completed Source: etc.usf.edu/clipart Isolation and bioactive properties: Rogers, E. F.; Snyder, H. R.; Fischer, R. F. J. Am. Chem Soc. 1952, 74, 1987. Structure elucidation: Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 2

  3. (+)-Haplophytine as An Acetylcholinesterase Inhibitor • Acetylcholine is a neurotransmitter • AChE hydrolyzes acetylcholine Inhibition of AChE • Excessive acetylcholine accumulation Source: www.dementiaguide.com/aboutdementia/ treatments/cholinesterase_inhibitors • Neuromuscular paralysis Dale, P.; Augustine, G. J.; Fitzpatrick, D.; Hall, W. C.; LaMantia, A.-S.; McNamara, O.; White, L. E. Neuroscience. 4th ed. 2008, 121. 3

  4. Biological Activity of HaplophytonCimicidum Alkaloids • 15 AChE inhibiting alkaloids isolated from Haplophytoncimicidum • Activity of haplophytine against AChE: 0.225 μM Acetylcholinesterase Source: en.wikipedia.org/wiki/acetylcholinesterase 4 Mroue, M. A.; Euler, K. L.; Ghuman, M. A.; Alam, M. J. Nat. Prod., 1996, 59, 890.

  5. Structure of (+)-Haplophytine Haplophytine is an architecturally intriguing and synthetically daunting heterodimeric alkaloid [..] [which] remains to this day as a thorny synthetic problem. - K. C. Nicolaou 1st Total Synthesis: Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H.Angew. Chem. Int. Ed. 2009, 48, 7600. 2nd Total Synthesis: Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616. 5 Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2007, 46, 4715.

  6. Structure of (+)-Haplophytine - Decacyclic alkaloid Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 6

  7. Structure of (+)-Haplophytine • Decacyclic alkaloid • 6 stereocenters 5 quaternary 3 all-carbon quaternary Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 7

  8. Structure of (+)-Haplophytine • Decacyclic alkaloid • Six stereocenters • Unique bicyclo[3.3.1] motif • (bridged ketone and aminal) Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 8

  9. Structure of (+)-Haplophytine • Decacyclic alkaloid • Six stereocenters • Unique bicyclo[3.3.1] motif • (bridged ketone and aminal) • Congested C-C bond linker Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 9

  10. Structure of (+)-Haplophytine Central Indole Linker Tetracyclic Left Domain Tetracyclic Right Domain Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 10

  11. Structure of (+)-Haplophytine • The Left Domain • 2007: First Total Synthesis • (Nicolaou and Chen) The Right Domain Aspidosperma Natural Product Named Aspidophytine • Five Total Syntheses • 1999: Corey • 2003: Tokuyama and Fukuyama • 2006: Padwa • 2006: Marino • 2008: Nicolaou Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715. He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771. Sumi, S.; Matsumoto, H.; Tokuyama, H.; Fukuyama, T. Org. Lett, 2003, 5, 1891. MejÍa-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275. Marino, J. P.; Cao, G.; Tetrahedron Lett.2006, 47, 7711. Nicolaou, K. C.; Dalby, S. M.; Majumder, U. J. Am. Chem. Soc. 2008, 130, 14942 11

  12. Structure of (+)-Haplophytine Reactivity of haplophytine under acidic conditions Reverse process under basic conditions Rearrangement used as an inspiration in both total syntheses of (+)-Haplophytine Yates, P.; MacLachlan, F. N.; Rae, I. D.; Roserberger, M.; Szabo, A. G.; Willis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842. 12

  13. Total Syntheses of (+)-Haplophytine • July 2009*: First Total Synthesis by T. Fukuyama and H. Tokuyama • (This seminar) • September 2009*: Second Total Synthesis by K. C. Nicolaou and D. Chen • (Briefly highlighted) * Published dates Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 13

  14. Fukuyama and Tokuyama’s Retrosynthetic Analysis 14 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  15. The Right Domain part 1 D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. Yeh, M. C. P.; Chen, H. G.; Knochel, P. Org. Synth. 1992, 70, 195. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.1998, 39, 3189. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.1980, 21, 1357. 15 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  16. Asymmetric Michael Addition 16 D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459.

  17. The Right Domain part 1 D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. Yeh, M. C. P.; Chen, H. G.; Knochel, P. Org. Synth. 1992, 70, 195. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.1998, 39, 3189. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.1980, 21, 1357. 17 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  18. The Fukuyama Coupling Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.1998, 39, 3189. Tokuyama, H.; Fukuyama, T. Aldrichim. Acta2004, 37, 87. 18

  19. The Right Domain part 1 D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459. Yeh, M. C. P.; Chen, H. G.; Knochel, P. Org. Synth. 1992, 70, 195. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.1998, 39, 3189. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.1980, 21, 1357. 19 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  20. The Right Domain part 2 20 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  21. The Right Domain part 3 Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron, 2002, 58, 6267 Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831. Presser, A.; Hüfner, A. Chemical Monthly, 2004, 135, 1015. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 21

  22. Thiophenol-Mediated NosylDeprotection No Mannich reaction possible under basic conditions 22 Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831.

  23. The MannichCyclization Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed.1998, 3, 459. 23 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  24. The Right Domain part 3 Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron, 2002, 58, 6267 Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831. Presser, A.; Hüfner, A. Chemical Monthly, 2004, 135, 1015. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 24

  25. The Left Domain part 1 Aldrich: $90/g 25 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  26. The Leimgruber-BatchoIndole Synthesis Batcho, D.; Leimgruber, W. Org. Synth. 1985, 63, 214. 26 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  27. The Left Domain part 1 27 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  28. The Left Domain part 2 Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem.2004, 69, 1283. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 28

  29. The Bischler-NapieralskiCyclization 29 Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem.2004, 69, 1283.

  30. The Left Domain part 2 Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem.2004, 69, 1283. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 30

  31. The Noyori Asymmetric Transfer Hydrogenation Prediction Model Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. 31

  32. The Left Domain part 2 Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem.2004, 69, 1283. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 32

  33. Cyclization Via A Ketene Intermediate 33 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  34. The Left Domain part 3 Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109. Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett2007, 3137. Yakhontov, C. N.; Marshalkin, M. F. Chem. Heterocycl. Compd. (Engl. Transl.)1972, 8, 1486. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 34

  35. Palladium-Catalyzed Deallylation 35 Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109.

  36. The Left Domain part 3 Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109. Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett2007, 3137. Yakhontov, C. N.; Marshalkin, M. F. Chem. Heterocycl. Compd. (Engl. Transl.)1972, 8, 1486. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 36

  37. Epoxide-Initiated Oxidative Skeletal Rearrangement Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett2007, 3137. 37

  38. The Left Domain part 3 Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109. Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett2007, 3137. Yakhontov, C. N.; Marshalkin, M. F. Chem. Heterocycl. Compd. (Engl. Transl.)1972, 8, 1486. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 38

  39. Hydrazine Formation With Nitrite Yakhontov, C. N.; Marshalkin, M. F. Chem. Heterocycl. Compd. (Engl. Transl.)1972, 8, 1486. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 39

  40. The Fisher Indole Assembly of Both Domains Left Domain Right Domain Desired Regioisomer Miller, F. M.; Schinske, W. N. J. Org. Chem. 1978, 43, 3384. Barton, D. H. R.; Lester, D. J.; Ley, S. V. J. Chem Soc. Chem. Commun. 1978, 130. 40 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  41. The Fisher Indole Synthesis 41 Miller, F. M.; Schinske, W. N. J. Org. Chem. 1978, 43, 3384.

  42. The Fisher Indole Assembly of Both Domains Left Domain Right Domain Desired Regioisomer Miller, F. M.; Schinske, W. N. J. Org. Chem. 1978, 43, 3384. Barton, D. H. R.; Lester, D. J.; Ley, S. V. J. Chem Soc. Chem. Commun. 1978, 130. 42 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  43. End Game Sequence And Final Lactone Ring Formation Okano, K.; Okuyama, K.; Fukuyama, T.; Tokuyama, H. Synlett, 2008, 1977. He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem Soc. 1999, 121, 6771. Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600. 43

  44. Oxidative Lactone Formation Audeh, C. A.; Smith, J. R. L. J. Chem. Soc. (B) 1970, 1280. He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. J. Am. Chem Soc. 1999, 121, 6771. 44

  45. Overview of Fukuyama and Tokuyama’s Total Synthesis • Key Step: Fisher Indole Assembly • of Both Domains • 46 Total Steps • Longest Linear Sequence: 26 Steps • Overall Yield: 0.28% 45 Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2009, 48, 7600.

  46. Nicolaou and Chen’s Retrosynthetic Analysis • This Seminar: • Radical cyclization • Oxidative Phenolic Coupling 46 Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616.

  47. Oxidative Phenolic Coupling Nicolaou, K. C.; Majunder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715. Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616. 47

  48. Oxidative Phenolic Coupling Quideau, S.; Pouységu, L.; Deffieux, D. Synlett2008, 467. Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616. 48

  49. Oxidative Phenolic Coupling Nicolaou, K. C.; Majunder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715. Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew. Chem. Int. Ed.2009, 48, 7616. 49

  50. Towards The Complete Skeleton of (+)-Haplophytine 50

More Related