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Synthesis of the Kedarcidin Chromophore Aglycon

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Title: 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

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 -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
14
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

48
49
Myers Retrosynthesis
49
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
69
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
74
Overview Myers Synthesis