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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.

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Total Synthesis of (+)- Haplophytine

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  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

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