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Synthesis of the Kedarcidin Chromophore Aglycon

Synthesis of the Kedarcidin Chromophore Aglycon. Mégan Bertrand-Laperle Prof. Keith Fagnou Department of Chemistry Center for Catalysis Research and Innovation University of Ottawa. Enediyne Natural Products. Calicheamicin α 1. Neocarzinostatin Chromophore. Kedarcidin Chromophore.

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Synthesis of the Kedarcidin Chromophore Aglycon

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  1. Synthesis of the Kedarcidin Chromophore Aglycon Mégan Bertrand-Laperle Prof. Keith Fagnou Department of Chemistry Center for Catalysis Research and Innovation University of Ottawa

  2. Enediyne Natural Products Calicheamicin α1 Neocarzinostatin Chromophore Kedarcidin Chromophore Dynemicin A C-1027 Chromophore 2

  3. Discovery of Kedarcidin « most complex and reactive of the natural enediyne antitumor agents isolated to date » A. G. Myers • 1991 – BMS • Kedarcidin isolated from soils collected in India • 1992 – BMS Structure of the chromophore elucidated • 1997 and 2007 – Hirama and Myers Revised the chromophore structure • Potent antiproliferative and antibiotic activities • Chromophore is highly unstable under acidic and basic conditions and upon concentration 3 Lam, K. S.; Hesler, G. A.; Gustavson, D. R.; Crosswell, A. R.; Veith, J. M.; Forenze, S. J. Antibiot. 1991, 44,472.

  4. Mode of Action of Kedarcidin Kedarcidin Chromoprotein Kedarcidin Chromophore DNA radical Single strand breaks Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39. 4

  5. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein Consists of 112 to 114 amino acids Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore 5

  6. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein • Consists of 112 to 114 amino acids • Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore • Chromophore • 1 dienediyne 6

  7. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein • Consists of 112 to 114 amino acids • Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore • Chromophore 1 dienediyne • One ansa-bridge • 17 membered ring macrolactone 7

  8. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein • Consists of 112 to 114 amino acids Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore • Chromophore 1 dienediyne • One ansa-bridge • 17 membered ring macrolactone • 14 chiral centers 8

  9. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein • Consists of 112 to 114 amino acids • Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore • Chromophore 1 dienediyne • One ansa-bridge • 17 membered ring macrolactone • 14 chiral centers • Two carbohydrate units 9

  10. Kedarcidin Revised Structure • Chromoprotein Molecular weight is 12,400 D • Protein Consists of 112 to 114 amino acids • Ratio vary from 1:1 to 18:1 • Stabilizes and delivers the chromophore • Chromophore 1 dienediyne • One ansa-bridge • 17 membered ring macrolactone • 14 chiral centers • Two carbohydrate units • One element of atropisomerism 10

  11. Atropisomerism in Molecules • Atropisomers: stereoisomers resulting from limited free rotation around single bond at room temperature • First detected in 1922 • Axial chirality: arrangement of groups around an axis • Planar chirality: arrangement of groups with respect to a plane Axial Chirality Planar Chirality 11 Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145.

  12. Atropisomerism in Kedarcidin Chromophore Major atropisomer Minor atropisomer • Kedarcidin: Planar chirality Interconversion possible at ambient temperature Single atropisomer 12 Myers, A. G.; Hurd, A. R.; Hogan, P. C. J.Am. Chem. Soc. 2002, 124, 4583.

  13. Issues with Kedarcidin Chromophore • Stability of enediyne moiety limited under concentration • All intermediates stored in dilute form at -20°C • Yields obtained using internal standard (1H NMR) Reng, F.; Hogan, P. C.; Anderson, A. J.;Myers, A. G. J.Am. Chem. Soc. 2007, 129,5381. 13

  14. Syntheses of Kedarcidin Chromophore Aglycon Aldehyde Addition Cyclisation Transannular Cyclisation M. Hirama 2007 (partial synthesis) A. G. Myers 2002/2007 14

  15. Hirama’s Retrosynthesis 15

  16. Hirama’s Synthesis 16 Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

  17. Arndt-Eistert Homologation - Wolff Rearrangement • Arndt-Eistert Homologation Wolff Rearrangement Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. Engl.1975, 14, 32. 17

  18. Hirama’s Synthesis 18 Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

  19. Electrocyclisation 19 Myers, A. G.; Horiguchi. Y. Tetrahedron Lett. 1997, 38,4363.

  20. Hirama’s Synthesis 20 Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

  21. Hirama’s Synthesis 21 Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

  22. Hirama’s Synthesis Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 22

  23. Hirama’s Synthesis 23 Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

  24. Reductive Opening 24 Ferrier, R. J.; Schmidt, P.; Tyler, P. C. J. Chem. Soc. Perkin, Trans. 11985, 301.

  25. Hirama’s Synthesis 25 Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

  26. Hirama’s Synthesis 26 Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

  27. Grignard via Iodine-Magnesium Exchange 27 Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

  28. Hirama’s Synthesis 28 Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

  29. Hirama’s Synthesis Iida, K.; Hirama, M. J. Am. Chem. Soc.1994, 116, 10310. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 29

  30. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 30

  31. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 31

  32. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 32

  33. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 33

  34. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 34

  35. Hirama’s Synthesis Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267. Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057. 35

  36. Hirama’s Synthesis 36 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  37. Hirama’s Synthesis 37 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  38. Peptide Coupling HOAt EDC.HCl Carpino, L. A. J. Am. Chem. Soc.1993, 115, 4397. 38

  39. Hirama’s Synthesis 39 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  40. Hirama’s Synthesis 40 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  41. Hirama’s Synthesis Unstable, use immediately 41 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  42. Hirama’s Synthesis Unstable, use immediately 42 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  43. Hirama’s Synthesis Unstable, use immediately 43 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  44. Hirama’s Synthesis Unstable, use immediately 44 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  45. Hirama’s Synthesis Unstable, use immediately 45 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29, 3057.

  46. Hirama’s Synthesis Unstable, use immediately 46 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29,3057.

  47. Hirama’s Synthesis 47 Yoshiramura, F.; Lear, M. J.; Ohashi, I., Koyama, Y.; Hirama, M. Chem. Commun. 2007, 29,3057.

  48. Overview Hirama’s Synthesis • Key step: Nucleophilic Addition-Cyclisation • 1% overall yield from the longest linear sequence (16 steps) • Still 4 steps to achieve the total synthesis of kedarcidin chromophore aglycon 48

  49. Myers’ Retrosynthesis 49

  50. Myers’ Synthesis 50 Myers, A. G.; Horiguchi. Y. Tetrahedron Lett. 1997, 38,4363.

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