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Seminar presented by Kassandra Lepack Department of Chemistry March 25 th 2010

The Long Journey to Azadirachtin. Seminar presented by Kassandra Lepack Department of Chemistry March 25 th 2010. How the Journey Began . . . Azadirachtin was first isolated from Neem seeds in 1968 by Morgan and coworkers

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Seminar presented by Kassandra Lepack Department of Chemistry March 25 th 2010

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  1. The Long Journey to Azadirachtin Seminar presented by Kassandra Lepack Department of Chemistry March 25th 2010

  2. How the Journey Began . . . • Azadirachtin was first isolated from Neem seeds in 1968 by Morgan and coworkers • The Neem tree (also known as Azadirachta indica) is part of the Meliaceae family and is native to India, but is also distributed in South and South east Asian countries - Bangladesh, Sri Lanka, Pakistan - and other tropical and sub-tropical regions. • It is a secondary metabolite and can be found in 0.1% - 0.5% by weight in Neem seeds • Azadirachtin was initially found to be active as a feeding inhibitor towards the desert locust (Schistocerca gregaria) Butterworth, J. H.;Morgan,E. D. J. Chem. Soc., Chem. Commun. 1968, 23 2

  3. Biological Activity • Insect antifeedant and affects well over • 200 species of insects • The mode of action of azadirachtin: • (i) effects on deterrent and other chemoreceptors resulting in antifeedancy • (ii) mimics insect hormones called ecdysones that regulate pupation of insects and interrupts their development • (iii) direct effects on most tissues resulting in an overall loss of fitness of the insect • Yet low mammalian toxicity (LD50(rat) > 5 g / kg) National Research Council. National Academy Press, 1992, Washington, DC Blaney, W. M.; Sommonds, M. S. J.; Ley, W. V.; Anderson, J. C.; Toogood, P. L., Entomol. Exp. Appl. 1990, 55, 149-160 3

  4. Structural Properties • Azadirachtin belongs to the C-seco limonoids which are classified as tetranortriterpenes • Limonoids are phytochemicals and consist of variations of the furanolactone core structure (ex: limonin) • Other C-seco limonoids include: Siddiqui, S.; Siddiqui, B. S.; Faizi, S.; Mahmood, T., J. Nat. Prod., 1988, 51, 30–43 Ley, S.V., Denhom, A. A., Wood, A. Nat. Prod. Rep. 1993, 109-157 4

  5. Biosynthesis No general theory has yet appeared, but these triterpenoids appear to be all derived from the steroidal intermediate, tirucallol Ley, S.V., Denhom, A. A., Wood, A. Nat. Prod. Rep. 1993, 109-157 5

  6. Structural Elucidation • The structural elucidation took place over some 17 years • Structure was first proposed by Nakanishi • in 1975 using extensive NMR • Revised by Kraus in 1985 whom proposed a C13‐C14 epoxide Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc.1975, 97,1975-1977 W. Kraus.; M. Bokel.; A. Klenk.; H. P. Khnl. Tet. Lett. 1985, 26, 6435-6438 6

  7. Structural Elucidation • Finally Ley and coworkers determined its structural arrangement due to one of its derivatives • In 1994, Govindachari and coworkers were able to crystallize azadirachtin for the first time Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986 Govindachari, T. R.; Suresh, G.; Gopalakrishnan, G., J. Liquid Chromatogr., 1995, 18, 3465-3472 7

  8. Total synthesis may take years . . . Ryanodol 12 years to synthesize Taxol 22 years to synthesize Erythromycin 29 years to synthesize Azadirachtin 22 years to synthesize Brevetoxin A 12 years to synthesize Vinigrol 22 years to synthesize P. Deslongchamps, et al.; Can. J. Chem. 1979, 57, 3348 Woodward, R. B. Et al.; J. Am. Chem. Soc., 1981,103. 3215-3217 Holton, R. B. et al.; J. Am. Chem. Soc. 1994,116 , 1597–1600 Baran, P. S., et al.; J. Am. Chem. Soc., 2009, 131, 17066–17067 Nicolaou, K. C. Et al.; Nature ,1998, 392, 264 8

  9. Interesting Synthetic Target • Reveals 16 CONTIGUOUS STEREOGENIC CENTRES, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to produce it by a synthetic approach. C35H44O16 IUPAC NAME: dimethyl (2aR,​3S,​4S,​4aR,​5S,​7aS,​8S,​10R,​10aS,​10bR)-​10-​(acetyloxy)-​3,​5-​dihydroxy-​4-​[(1S,​2S,​6S,​8S,​9R,​11S)-​2-​hydroxy-​11-​methyl-​5,​7,​10-​trioxatetracyclo[6.3.1.02,6.09,11]dodec-​3-​en-​9-​yl]-​4-​methyl-​8-​{[(2E)-​2-​methylbut-​2-​enoyl]​oxy}​octahydro-​1H-​furo[3',4':​4,4a]​naphtho[1,​8-bc]​furan-​5,​10a(8H)-​dicarboxylate Stereogenic centers Quaternary carbons Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 9

  10. Interesting Synthetic Target • “We call it the who’s who of oxygen atoms as it contains almost every type of oxygen functionality” Ley explained. • 16 oxygen atoms are contained within a variety of functional groups including an enol ether, a hemi-acetal moiety, four distinct ester groups, two hydroxyl groups and a tetrasubstitutedepoxide Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 10

  11. Ventures Towards Azadirachtin Many research groups attempted the synthesis of azadirachtin: • Murai – 2002 • Nicolaou and coworkers – 2005 • Ley and coworkers – 2005 (first attempt) • Watanabe and coworkers – 2007 • Ley and coworkers – 2007 (second attempt) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877-2880 Nicolaou, K. C.;Follmann,M.; Roecker, A. J. Angew. Chem. Int. Ed. 2005, 3443 Ley, S. V. Pure Appl. Chem.1994, 66, 2099-2102 Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512-1516 11

  12. Ventures Towards Azadirachtin Many research groups attempted the synthesis of azadirachtin • Murai and coworkers - 2002 Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877-2880 12

  13. Ventures Towards Azadirachtin • Nicolaou and coworkers - 2005 • Ley and coworkers – 2005 (first attempt) Nicolaou, K. C.;Follmann,M.; Roecker, A. J. Angew. Chem. Int. Ed. 2005, 3443 Ley, S. V. Pure Appl. Chem.1994, 66, 2099-2102 Ley, S. V.; Santafianosa, D.Tetrahedron Lett. 1987, 28(2), 221 13

  14. Ventures Towards Azadirachtin • Ley and coworkers – 2005 (first attempt) Ley, S. V. Pure Appl. Chem.2005, 77, 1115-1130 14

  15. Ventures Towards Azadirachtin • Watanabe and coworkers - 2007 Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512-1516 15

  16. Retrosynthetic Analysis of Azadirachtin • Ley and coworkers – 2007 (second attempt) Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629 16

  17. Sit Back . . . Relax . . . 22 years of chemistry in the making . . . 17

  18. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 Kolb, H. C.; Ley, S. V., Tet. Lett., 1991, 32, 6187-6190 18

  19. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 Kolb, H. C.; Ley, S. V., Tet. Lett., 1991, 32, 6187-6190 19

  20. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 20

  21. Decalin Fragment IMDA (Intramolecular Diels-Alder reaction) Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 21

  22. IMDA (Intramolecular Diels-Alder) Reaction • Establishes 4 stereogenic centers with the correct relative configuration Ley, S. V.; Somovilla, A. A.; Toogood, P. T.; Brasca, M. G.; Broughton, H. B., Craig, D., Tet. Lett , 1989, 29, 1853-1856 Ley, S. V.; Somovilla, A. A.; Broughton, H. B., Craig, D., Tetrahedron ,1989, 45, 2143-2164 22

  23. Decalin Fragment Decalin Fragment 12 b Azadirachtin 23

  24. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 24

  25. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 25

  26. Decalin Fragment – Optically pure Correct absolute configuration Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 26

  27. Decalin Fragment Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 27

  28. Decalin Fragment Decalin Fragment 21 Azadirachtin 28

  29. Decalin Fragment Ley, S. V., Pure Appl. Chem.2005, 77, 1115‐1130 Ley, S. V.; Lovell, P. J.; Smith, S. C.; Wood, A., Tet. Lett., 1991, 32, 6183-6186 Koot, W-J.; Ley, S. V., Tetrahedron, 1995, 51, 2077-2090 29

  30. Decalin Fragment 4 : 1 mixture of hemiketal epimers in favor of the desired isomer 4 : 1 Ley, S. V., Pure Appl. Chem.2005, 77, 1115‐1130 Ley, S. V.; Lovell, P. J.; Smith, S. C.; Wood, A., Tet. Lett., 1991, 32, 6183-6186 Koot, W-J.; Ley, S. V., Tetrahedron, 1995, 51, 2077-2090 30

  31. Relay Synthesis • Degradation of azadirachtin to the decalin fragment allowed for enantiopure product Ley, S. V.; Lovell, P.; Smith, S. C.; Wood, A., Tet. Lett.,1991, 43, 6183-6186 Koot, J-W.; Ley, S. V. Tetrahedron. 1995, 51, 2077-2090 Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 31

  32. Pyran Fragment Madsen, R.; et al. J. Chem. Soc. Perkin Trans. 1, 2001, 543‐551 Cleator, E.; McCusker, C. F.; Steltzer, F., Ley, S. V., Tet. Lett., 2004, 45, 3077-3080 Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629 32

  33. Pyran Fragment Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 33

  34. Pyran Fragment Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 34

  35. Coupling of Fragments – Claisen Rearrangement A highly diastereoselective, microwave-induced Claisen rearrangement allows the formation of the sterically congested C8-C14 bond Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 35

  36. Coupling of Fragments Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 36

  37. Coupling of Fragments - Radical Cyclization Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 37

  38. Coupling of Fragments - Epoxidation . MMPP H2O = Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 38

  39. END GAME Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 39

  40. END GAME AZADIRACHTIN Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 40

  41. Highlights of the synthesis Intramolecular Diels-Alder reaction Intramolecular Claisen Rearrangement 41 Intramolecular Radical Cyclization

  42. What a Journey . . . • “We’ve had a lot of champagne this year” Ley explained. • 0.00015% overall yield • 71 synthetic steps (longest linear sequence 48 steps) • 22 protection and deprotection steps • 17 carbon-carbon bond formation steps • 13 oxygen-carbon bond formation steps • 22 YEAR SYNTHESIS! • Ley and about 40 PhD scholars Ley, S. V.; et al. J. Chem. Soc. Perkin Trans. 1 1992, 2735‐2762 Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633 Jauch, J., Angew. Chem. Int. Ed. 2008, 47, 34-37 42

  43. Acknowledgements • THE BARRIAULT GROUP: • Prof. Louis Barriault • Current Members: • - Jason Poulin • - Francis Barabé • - Boubacar Sow • - Daniel Newbury • - Geneviève Bétournay • - Joel Marcotte • - Patrick Levesque • Past Members: • Christiane Grisé-Bard • Steve Arns • - Anik Chartrand • - Gabriel Bellavance • - Jean-François Vincent-Rocan 43

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