studies toward the total synthesis of noelaquinone and...

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Studies toward the Total Synthesis of

Noelaquinone and Pleurotin

N

N

NH

O

O

O

O

O

Stephan ElznerResearch Topic Seminar

July 29th, 2006

OO

O

O

O

Stephan Elzner @ Wipf Group 1 8/16/2006

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Outline

Part 1: Noelaquinone

Part 2: Pleurotin

Isolation and Characterization Studies toward the DEF-Ring System of Noelaquinone

Isolation, Characterization and Biological Properties Synthetic Approaches towards Pleurotin and Analogues Previous Studies in the Wipf Group Current Approach


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Part 1: Noelaquinone

N

N

NH

O

O

O

O

O


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First isolated in 1998 from an unidentified Xestospongia sp.(Indonesia) by Paul Scheuer. 67 g sponge yielded 6 mgnatural product

Structure determination based upon NMR-analysis andbiological activity is still waiting to be further investigated

Structurally related to a class of marine metabolites isolatablefrom the same Xestospongia sp.

(+)-halenaquinone and (+)-xestoquinone

The thermodynamically stable naphthoquinone is replaced bya tetrahydro-1,2,4-triazine moiety

sole example in a natural product

(+)-Halenaquinone and (+)-xestoquinone showantiproliferative activity at nanomolar concentrations in vivothrough the blocking of PI-3 kinase. Common origin of thebiological potency of these compounds is presumably thetricyclic furan moiety, also present in noelaquinone

Isolation and Characterization of Noelaquinone

Xestospongia sp.(California Academy of Sciences

www.calacademy.org)

O

O

O

X

O

X = O : HalenaquinoneX = H2: Xestoquinone

N

N

NH

O

O

O

O

O

Noelaquinone

Y. Zhu, W.Y. Yoshida, M. Kelly-Borges, P. J. Scheuer, Heterocycles 1998, 49, 355-360P. Wipf et al., Org. Biomol. Chem. 2004, 2, 1911-1920N. Ihle et al. Mol. Cancer Therap. 2004, 3, 763-772


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Part 2: Pleurotin

OO

O

O

O


.

Isolation and Characterization

First isolated 1947 from the fungus pleurota griseus, the compound could also be found in extracts from Hohenbruehelia

geogenius and Hohenbruhelia atrocaerulea

W. J. Robbins, F. Kavanaugh, A. Hervey, Proc. Natl. Acad. Sci. U.S.A. 1947, 33, 171 J. Riondel, H. Beriel, A. Dardas, G. Carraz, L. Oddoux, Arzneim. Forsch. 1981, 31, 293 S. M. Shipley, A. L. Barr, S. J. Graf, R. P. Collins, T. G. McCloud, D. J. Newman,

J. Ind. Microbiol. Biotechnol. 2006, 33, 463

Strucure was assigned by degradative studies in 1968 andlater confirmed by X-ray crystallographic analysis

H. Schelling, Ph.D. thesis, ETH Zürich, Switzerland, 1968J. Grandjean, R. Huls, Tetrahedron Lett. 1974, 15, 1893P. C. Cohen-Addad, J. Rionel, Acta Crystallogr. 1981, B37, 1309

Structure: - Hexacyclic framework containing 8 stereocenters - Quinone moiety substituted with two benzylic leaving groups, which play an inmportant role in the biological activity

Hohenbruhelia atrocaerulea(www.mykoweb.com)

Pleurotin

OO

O

O

O

10

9

1117

16 14

7


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Biological Activity

• Antibiotic activity against gram-positive bacteria

W. J. Robbins, F. Kavanagh, A. Hervey, Proc. Natl. Acad. Sci. U.S.A. 1947, 33, 171

• Antitumor activity against Ehrlich ascites, L-1210 lymphoid carcinoma and mammary carcinoma

J. Riondel, H. Beriel, A. Dardas, G. Carraz, L. Oddoux, Arzneimittel Forschung 1981, 31, 293

• Potent inhibitor of the thioredoxin-thioredoxin reductase system (IC50 = 170 nM)

S. J. Welsh, R. R. Williams, A. Birmingham, D. J. Newman, D. Kirkpatrick, G. Powis, Mol. Cancer Ther. 2003, 235-243P. Wipf, S. M. Lynch, A. Birmingham, G. Tamayo, A. Jiménez, N. Campos, G. Powis, Org. Biomol. Chem. 2004, 2, 1651-1658


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Thioredoxin-Thioredoxin Reductase Redox System

Thioredoxin

• 12 kDa protein containing cystein residues, which can switch between reduced (-SH) and oxidized (-S-S-) state• Regenerated by thioredoxin-reductase, which is autoreduced in a mechanism involving NADPH and FAD• Regulates several transcription factors (e.g. NFκ-B)• Overexpressed in human solid tumors (lung, colon)• Growth factor playing a role in tumor promotion• Stimulates tumor growth and inhibits apoptosis in vivo

⇒ target for the developement of anti-cancer agents

B. W. Lennon, C. H. Williams, M. L. Ludwig, Science 2000, 289, 1190G. Powis, D. L. Kirkpatrick, M. Angulo, A. Baker, Chem.-Biol. Interact. 1998, 111, 23


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Proposed Bioactivation of Pleurotin

Bioreductive bisalkylating agent:

Conversion of the inactive form to a potent alkylating agent through in vivo transformation

H. W. Moore, Science 1977, 197, 527D. J. Hart, H.C. Huang, R. Krishnamurthy, T. Schwartz, J. Am. Chem. Soc 1989, 111, 7507

OO

O

O

O

Pleurotin

OO

OH

HO2C

HOO

O

O

OH

reduction(in vivo)

OOH

O

HO2C

OOH

O

HO2CNu1

Nu2

elimination

elimination

alkylation of biologically relevant nucleophiles, cell damage


.

Hart: First Racemic Total Synthesis of Pleurotin

D. J. Hart, H.C. Huang, J. Am. Chem. Soc 1988, 110, 1634D. J. Hart, H.C. Huang, R. Krishnamurthy, T. Schwartz, J. Am. Chem. Soc 1989, 111, 7507

O

O

H

H Me

OTBS

H

OMe

OMe

O

H CH3

HO

OO

O

HO2C

OO

O

O

O

O

O

I

CO2Et

Stereoselective Free Radical Cyclisation

Pleurotin


.

Hart: Synthesis of Pleurotin (cont.)


COOH

Br O

O

O

O

1)

Li, NH3, 89%

2) DPPA, NEt3 pyrrolidine, 74% O N

1) I2, THF, H2O, 94%2) HCOOH, 88%

3) Ph3P=C(CH3)CO2Et 94% O

O

I

CO2Et

Bu3SnH, AIBN

80%

O

O

H

H MeCOOEt 1) LiOH, MeOH, H2O;

aq. HCl, 89%

2) (COCl)2; NaBH43) TBSCl, imidazole 95% (2 steps) O

O

H

H Me

OTBS 1) MCPBA, 87%

2) LiNEt2, 76%

O

O

H

H Me

OTBS

OH

1) Li, EtNH2, 67%2) CH2N2, quant.

3) Swern, 88%

H

H Me

OTBS

COOMeO


.



H

H Me

OTBS

CO2MeOMe

OMe

OMe

MeOMgCl

CeCl3

91%

OH

H

H Me

OTBS

OMe

OMe

1) SOCl2, pyridine

2) LiAlH4

H

H Me

OTBS

OMe

OMe50% 43%

H

H Me

OTBS

COOMeO

OH OH

H

H Me

OTBS

OMe

OMe

OH

H

OMe

OMe

O

H CH3

HO

1) Swern

2) Dowex-50, MeOH

H

O

H CH3

BF3*OEt2

toluene, 52% OMe

MeO

MeOO

OMe


.


• 26 steps• Average 80% yield per step• 0.3 % overall yield


MeOO

OMe

MeOO

OMe

1) BH3; H2O2, NaOH, 90%

2) Swern, 92%

1) TosCH2NC, KOtBu, 75%2) DIBAL, 93%

3) Ag2O, NaOH, 62%

O

MeOO

OMe

HOOC

CAN

CH3CN, 89%

OO

O

HOOC

MnO2

32% + 33% s.m.

OO

O

O

O

Pleurotin (rac.)


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Kraus: Synthesis of Pleurotin Core

Tandem Photoenolisation/Diels-Alder

G. A. Kraus, L. Chen, Synlett 1991, 89G. A. Kraus, L. Chen, Synth. Commmun. 1993, 23, 2041

R

O

OMe

OMe

O

O

R'

OO

O

O

O O

OMe O

O

R

O

HMe

R'

PhotoenolisationH


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Kraus: Pleurotin Core (cont.)


OMe

OMe

OH

nBuLi, DMF

THF, 66%

OMe

OMe

O

OH 1) 1,2-ethanedithiol BF3, 91%

2) RCO2H DCC, DMAP3) MeI, aq. CH3CN 55%

O

OMe

OMe

OH

O

H

H

H

H

O

OMe

MeOO

O H

h!

benzene, 4h

O

O

O

OH

O

H

H

H

H

AgO, HNO3

THF, 28%170°C, 40h50%

O

OMe

MeOOH

O H


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Kraus: Pleurotin Core (cont.)

Comparable biologicalactivity with Pleurotinagainst SR leukemia cellline and colon cancer celllines


OMe

OMe

OH

nBuLi, DMF

THF, 66%

OMe

OMe

O

OH 1) 1,2-ethanedithiol BF3, 91%

2) RCO2H DCC, DMAP3) MeI, aq. CH3CN 55%

O

OMe

OMe

OH

O

H

H

H

H

O

OMe

MeOO

O H

h!

benzene, 4h

O

O

O

OH

O

H

H

H

H

AgO, HNO3

THF, 28%170°C, 40h50%

O

OMe

MeOOH

O H


.

Acknowledgements

Prof. Peter Wipf

Dr. David AmantiniDr. Sonia RodriguezDr. Shinya Iimura

Wipf Group members (past and present)Steve Geib (XRay)Funding: DFG, NIH


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