Synthesis of the Kedarcidin Chromophore Aglycon

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 a1
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 11 to 181
• 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 11 to 181
• 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 11 to 181
• 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 11 to 181
• 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 11 to 181
• 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 11 to 181
• 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

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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 -20C

• 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
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Syntheses of Kedarcidin Chromophore Aglycon
Aldehyde Addition Cyclisation
Transannular Cyclisation
M. Hirama 2007 (partial synthesis)
A. G. Myers 2002/2007
14
15
Hiramas Retrosynthesis
15
16
Hiramas 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
Hiramas 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
Hiramas Synthesis
20
Kawata, S. Ashizawa, S. Hirama, M. J. Am. Chem.
Soc. 1997, 119, 12012.
21
Hiramas Synthesis
21
Kawata, S. Ashizawa, S. Hirama, M. J. Am. Chem.
Soc. 1997, 119, 12012.
22
Hiramas 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
Hiramas 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. 1 1985, 301.
25
Hiramas Synthesis
25
Koyama, Y. Lear, M. J. Yoshimura, F. Ohashi,
I. Mashimo, T. Hirama, M. Org. Lett. 2005, 7,
267.
26
Hiramas 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
Hiramas Synthesis
28
Koyama, Y. Lear, M. J. Yoshimura, F. Ohashi,
I. Mashimo, T. Hirama, M. Org. Lett. 2005, 7,
267.
29
Hiramas 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
Hiramas 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
Hiramas 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
Hiramas 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
Hiramas 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
Hiramas 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
Hiramas 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
Hiramas Synthesis
36
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
37
Hiramas 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
Hiramas Synthesis
39
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
40
Hiramas Synthesis
40
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
41
Hiramas Synthesis
Unstable, use immediately
41
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
42
Hiramas Synthesis
Unstable, use immediately
42
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
43
Hiramas Synthesis
Unstable, use immediately
43
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
44
Hiramas Synthesis
Unstable, use immediately
44
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
45
Hiramas Synthesis
Unstable, use immediately
45
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
46
Hiramas Synthesis
Unstable, use immediately
46
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
47
Hiramas Synthesis
47
Yoshiramura, F. Lear, M. J. Ohashi, I., Koyama,
Y. Hirama, M. Chem. Commun. 2007, 29, 3057.
48
Overview Hiramas 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

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Myers Retrosynthesis
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50
Myers Synthesis
50
Myers, A. G. Horiguchi. Y. Tetrahedron Lett.
1997, 38, 4363.
51
Myers Synthesis
51
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
52
Carreira-Singer Aldol
Carreira-Singer Catalyst
52
Carreira, E. M. Singer, R. A. Lee, W. J. Am.
Chem. Soc. 1994, 116, 8837.
53
Myers Synthesis
Staudinger Reaction
53
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
54
Myers Synthesis
54
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
55
Myers Synthesis
55
Myers, A. G. Goldberg, S. D. Angew. Chem. Int.
Ed. 2000, 39, 2732.
56
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
57
Myers Synthesis
57
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
58
Myers Synthesis
58
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
59
Myers Synthesis
59
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
60
Myers Synthesis
60
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
61
Myers Synthesis
61
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
62
Myers Synthesis
62
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
63
Myers Synthesis
63
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
64
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.
65
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.
66
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.
67
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.
68
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
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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.
70
Myers Synthesis
70
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
71
Myers Synthesis
71
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
72
Myers Synthesis
Martin Sulfurane
72
Myers, A. G. Hogan, P. C. Hurd, A. R.
Goldberg, S. D. Angew. Chem. Int. Ed. 2002, 41,
1062.
73
Martin Sulfurane Dehydration
Martin Sulfurane
Martin, J. C. Arhart, R. J. J. Am. Chem. Soc.
1971, 93, 4327.
73
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Overview Myers Synthesis

• Key step Transannular Cyclisation

• 82 average yield per step and 1 overall yield

• Longest linear sequence is 25 steps

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Summary

• Hiramas 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

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Acknowledgements
Prof. Keith Fagnou
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