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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
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
Enediyne Natural Products

Calicheamicin α1

Neocarzinostatin

Chromophore

Kedarcidin

Chromophore

Dynemicin A

C-1027

Chromophore

2

discovery of kedarcidin
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.

mode of action of kedarcidin
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

kedarcidin revised structure
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

kedarcidin revised structure1
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

kedarcidin revised structure2
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

kedarcidin revised structure3
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

kedarcidin revised structure4
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

kedarcidin revised structure5
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

atropisomerism in molecules
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.

atropisomerism in kedarcidin chromophore
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.

issues with kedarcidin chromophore
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

syntheses of kedarcidin chromophore aglycon
Syntheses of Kedarcidin Chromophore Aglycon

Aldehyde Addition

Cyclisation

Transannular

Cyclisation

M. Hirama 2007

(partial synthesis)

A. G. Myers 2002/2007

14

hirama s synthesis
Hirama’s Synthesis

16

Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

arndt eistert homologation wolff rearrangement
Arndt-Eistert Homologation - Wolff Rearrangement
  • Arndt-Eistert Homologation

Wolff Rearrangement

Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. Engl.1975, 14, 32.

17

hirama s synthesis1
Hirama’s Synthesis

18

Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

electrocyclisation
Electrocyclisation

19

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

hirama s synthesis2
Hirama’s Synthesis

20

Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

hirama s synthesis3
Hirama’s Synthesis

21

Kawata, S.; Ashizawa, S.; Hirama, M. J.Am. Chem. Soc. 1997, 119,12012.

hirama s synthesis4
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

hirama s synthesis5
Hirama’s Synthesis

23

Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

reductive opening
Reductive Opening

24

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

hirama s synthesis6
Hirama’s Synthesis

25

Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

hirama s synthesis7
Hirama’s Synthesis

26

Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

grignard via iodine magnesium exchange
Grignard via Iodine-Magnesium Exchange

27

Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

hirama s synthesis8
Hirama’s Synthesis

28

Koyama, Y.; Lear, M. J.; Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,267.

hirama s synthesis9
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

hirama s synthesis10
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

hirama s synthesis11
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

hirama s synthesis12
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

hirama s synthesis13
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

hirama s synthesis14
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

hirama s synthesis15
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

hirama s synthesis16
Hirama’s Synthesis

36

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

hirama s synthesis17
Hirama’s Synthesis

37

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

peptide coupling
Peptide Coupling

HOAt

EDC.HCl

Carpino, L. A. J. Am. Chem. Soc.1993, 115, 4397.

38

hirama s synthesis18
Hirama’s Synthesis

39

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

hirama s synthesis19
Hirama’s Synthesis

40

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

hirama s synthesis20
Hirama’s Synthesis

Unstable, use immediately

41

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

hirama s synthesis21
Hirama’s Synthesis

Unstable, use immediately

42

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

hirama s synthesis22
Hirama’s Synthesis

Unstable, use immediately

43

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

hirama s synthesis23
Hirama’s Synthesis

Unstable, use immediately

44

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

hirama s synthesis24
Hirama’s Synthesis

Unstable, use immediately

45

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

hirama s synthesis25
Hirama’s Synthesis

Unstable, use immediately

46

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

hirama s synthesis26
Hirama’s Synthesis

47

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

overview hirama s synthesis
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

myers synthesis
Myers’ Synthesis

50

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

myers synthesis1
Myers’ Synthesis

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

51

carreira singer aldol
Carreira-Singer Aldol

Carreira-Singer Catalyst

Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116,8837.

52

myers synthesis2
Myers’ Synthesis

Staudinger Reaction

53

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis3
Myers’ Synthesis

54

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis4
Myers’ Synthesis

55

Myers, A. G.; Goldberg, S. D. Angew. Chem. Int. Ed. 2000, 39,2732.

myers synthesis5
Myers’ Synthesis

Prepared in 4 steps

Iida, K.; Hirama, M. J. Am. Chem. Soc. 1994, 116,10310.

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

56

myers synthesis6
Myers’ Synthesis

57

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis7
Myers’ Synthesis

58

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis8
Myers’ Synthesis

59

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis9
Myers’ Synthesis

60

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis10
Myers’ Synthesis

61

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis11
Myers’ Synthesis

62

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis12
Myers’ Synthesis

63

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis13
Myers’ Synthesis

Unstable, use immediately

Mixture of atropisomers

64

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis14
Myers’ Synthesis

Unstable, use immediately

Mixture of atropisomers

65

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis15
Myers’ Synthesis

Unstable, use immediately

Mixture of atropisomers

66

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis16
Myers’ Synthesis

Unstable, use immediately

Mixture of atropisomers

67

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

glaser coupling
Glaser Coupling

Eglinton Modification:

Proposed Mechanism:

Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.

Eglinton, G.; Galbraith, A. R. J. Chem. Soc.1959, 889.

68

myers synthesis17
Myers’ Synthesis

Unstable, use immediately

Mixture of atropisomers

69

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis18
Myers’ Synthesis

70

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis19
Myers’ Synthesis

71

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

myers synthesis20
Myers’ Synthesis

Martin Sulfurane

72

Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,1062.

martin sulfurane dehydration
Martin Sulfurane Dehydration

Martin Sulfurane

Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc.1971, 93, 4327.

73

overview myers synthesis
Overview Myers’ Synthesis
  • Key step: Transannular Cyclisation
  • 82%average yield per step and 1% overall yield
  • Longest linear sequence is 25 steps

74

summary
Summary
  • Hirama’s Synthesis: 16 steps, 1% overall yield

Still 4 steps to go

  • Key Step: Aldehyde Addition Cyclisation
  • Myers’ Synthesis: 25 steps, 1% overall yield

Synthesis applied to Kedarcidin Chromophore glycon in 2007

  • Key Step: Transannular Cyclisation

75

acknowledgements
Acknowledgements

Prof. Keith Fagnou

76