Synthesis of Pleurotin Progress toward the Totalccc.chem.pitt.edu/wipf/Topics/Shinya.pdf · Progress toward the Total Synthesis of Pleurotin SHINYA IIMURA Wipf Research Group Meeting

Progress toward the Total Synthesis of Pleurotin

SHINYA IIMURA

Wipf Research Group Meeting

July 9th, 2005

Shinya Iimura @ Wipf Group 1 7/10/2005

Presentation Outline

! Isolation and Structure

! Biological Activity

! Current Total Synthesis Efforts in the Wipf Group

! Previous Studies in the Wipf Group

! Hart's Total Synthesis (Racemic)

! Kraus' Studies toward Total Synthesis

! Future Plans


Isolation and Properties of Pleurotin

!"First isolated from the fungus Pleurotus griseus in 1947 by Robbins et al., and later obtained from

Hohenbuehelia geogenius.

O

O

HO

O

O

CH3

Pleurotin

Robbins, W. J. et al. Proc. Natl. Acad. Sci. USA, 1947, 33, 171.

! Pleurotin began to melt with decomposition at temperatures between 200 ˚C and 215 ˚C depending

upon the rate of heating.

! Pleurotin was optically active with [#]23D

= -20˚ (c 0.59, CHCl3).

! The solubility of pleurotin at 25 ˚C: 0.125 mg/mL (water), 6.8 mg/mL (95% ethanol), 0.37 mg/mL

(5% ethanol), 3.5 mg/mL (ether), more than 200 mg/mL (chloroform).

! Pleurotin in solution was rendered inactive by exposure to light for a few hours.

! Pleurotin was not thermostable. Solutions of pleurotin in 0.1 M. phosphate buffer when boiled for 10 min

lost 50% of their biological activity at pH 3, 75% at pH 6.5, and all of their activity at pH 8.5.

! Pleurotin was 75% destroyed in 1 h at pH 8.5 and 25 ˚C.


Poster Presented at the 2004 International Congress on Natural Products Research, A joint meeting of the ASP, AFERP, GA and the PSE July 31–August 4, 2004 Phoenix, AZ; Podium Presentation at the July 2004 Society of Microbiology meeting, Anaheim, CA


Structure and the Synthetic Challenges

! Structure originally assigned on the basis of degrative studies in 1968 and later

confirmed by X-ray crystallography in 1981.

O

O

HO

O

O

CH3

Pleurotin

Oddoux, L. et al. Arzneim. Forsch. 1981, 31, 293.Cohen-Addad, P. C. et al. Acta Crystallogr. 1981, B37, 1309.

! The Challenge to Synthetic Chemists: The unique compact hexacyclic framework

The six contiguous stereogenetic centers

No enantioselective total synthesis


O

O

HO

O

O

CH3

Pleurotin

Oddoux, L. et al. Arzneim. Forsch. 1981, 31, 293.

Biological Activity

! Antibiotic activity against Gram-positive bacteria.

! Antitumor activity against two rapidly grafted tumors: Ehrlich ascites carcinoma and

L-1210 lymphoid leukemia, as well as a slow growing spontaneous mammary tumor.

! A potent inhibitor of the thioredoxin–thioredoxin reductase system (IC50 170 nM).

Robbins, W. J. et al. Proc. Natl. Acad. Sci. USA, 1947, 33, 171.

Powis, G. et al. Anti-Cancer Drug Des., 1997, 12, 659.Powis, G. et al. Mol. Cancer Ther., 2003, 2, 235.Wipf, P. et al. Org. Biomol. Chem., 2004, 2, 1651.


Bioreductive Alkylation

Lin. A. J. et al., J. Med. Chem. 1972, 15, 1247.Moore, H. W. Science (Washington, D.C.) 1977, 197, 527.

The concept of bioactivation as a mechanism of drug action is one

that is especially appealing to the medicinal and synthetic organic

chemist. The challenge of designing compounds in a biologically

inactive form which become activated only subsequent to an in vivo

transformation allows the synthesis chemist to take advantage of his

arsenal of methodology and mechanistic probes and to directly apply

them to potentially important problems of drug action.

The concept of bioreductive alkylation which is compounds which

become potent alkylating agents after they undergo a reduction in

vivo, is a particularly fascinating area within the field of bioactivation.

Moore, H. W. Science (Washington, D.C.) 1977, 197, 527.

!

!


Bioreductive Alkylation

Tomasz, M., Chem. Biol. 1995, 2, 575.

H2N

O

O

N

OMe

OCONH2

NH

Mitomycin C

H2N

OH

OH

N

OMe

OCONH2

NH

H2N

OH

O

N

OCONH2

NH

H

– MeOH

H2N

OH

O

N

OCONH2

NH2

DNA

First alkylation stepH2N

OH

OH

N

OCONH2

NH2

DNA

H2N

OH

OH

N

NH2

DNA

– OCONH2

H2N

O

O

N

NH2

DNA

Second alkylation step(cross-linking) O2


Suggested Bioactivation of Pleuotin

O

OO H

O

O

OH

HOO H

O

O

OH

OO H

HO

O

O

OO H

HO

O

O

OH

HO

O

O

OH

HO

ONu1

Nu2

OH

OH

Moore, H. W. Science (Washington, D.C.) 1977, 197, 527.Hart, D. J. et al. J. Am. Chem. Soc. 1989, 111, 7507.

pleurotin

dihydropleurotin acid

Nu


Hart: First Total Synthesis of Pleurotin (Racemic)

O

OO H

O

O

O

OO H

HO

O

Hart, D. J. et al. J. Am. Chem. Soc. 1988, 110, 1634.Hart, D. J. et al. J. Am. Chem. Soc. 1989, 111, 7507.

pleurotin dihydropleurotin acid

CH3CO2Et

OO H

OOCO2Et

CH3

Key feature

Biomimetic conversion of dihydropleurotin acid to pleurotin*

Stereoselective free-radical cyclization

*Arigoni group has demonstrated that dihydropleurotin acid is converted to pleurotin by cultures of Pleurotus griseus. Vogt, P.M. Ph. D. Thesis, Eidgenossischen Technischen Hochschule, Zurich, Switzerland, 1982.




CO2H

1. Li, NH3; Br(CH2)2CH(OCH2CH2O)

2. DPPA, Et3N, pyrrolidine, THFO N

O

O1. I2, THF/H2O2. HCO2H, H2O

3. Ph3P=C(CH3)CO2Et

CO2Et

I

O

O

nBu3SnH, AIBN

benzene, !O

O

CO2EtH

H1. LiOEt, MeOH, H2O; HCl, H2O2. (COCl)2; NaBH4

3. TBSCl, imidazole, DMF

O

O

CH2OTBSH

H 1. mCPBA2. LiNEt2, Et2O

O

O

CH2OTBSH

H

HO

1. Li, EtNH22. CH2N2

3. (COCl)2, DMSO, Et3N

CO2Me

CH2OTBSH

H

O

THFCO2Me

CH2OTBSH

H

OH

OMe

OMe

66% (2 steps) 78% (3 steps)

80%85% (3 steps)

66% (2 steps)

59% (3 steps) 91%

2,5-(MeO)C6H3CH2MgClCeCl3


Hart: Stereoselectivity in the Free-Radical Cyclization

R1

R2

I

O

O

nBu3SnH, AIBN

benzene, ! O

O

CO2EtH Me

H

O

O

CO2EtH Me

H

OOR2

R1

+

OO+

OO

R1R2

R1R2

1: R1 = Me, R2 = CO2Et 80% 4% 4% 4%

2: R1 = CO2Et, R2 = Me 37% 2% 15% 12%

O

O

MeH CO2Et

H

+ O

O

CO2EtH Me

H

+

OO Me CO2Et OO MeO. (OEt)

OEt (O.)

OO Me

H

CO2Et

HHSnnBu3




CO2Me

CH2OTBSH

H

OH

OMe

OMe

1. SOCl2, pyridine*2. LiAlH4

3. (COCl)2, DMSO, Et3N CHO

CH2OTBSH

H

OMe

OMe

Dowex-50 (H+), MeOH

H

H

OMe

OMe

O

BF3•Et2O

toluene

OMe

H

H

OMe

MeO

O1. BH3•THF; NaOH, H2O22. (COCl)2, DMSO, Et3N

3. TosMIC, KOtBu, DME

4. DIBAL-H, toluene

5. Ag2O, NaOH

OMe

MeOO H

HO

O

H

H

OMe

MeO

O

HO2CH

*Inseparable 1:1 mixture

37% (3 steps)99%

52%

36% (5 steps)




O

OO H

O

O

OMe

MeOO H

HO

O

CAN

CH3CN/H2O

O

OO H

HO

O

MnO2

CH2Cl2

26 steps from benzoic acid0.3% overall yieldan average of 80% yield per step

89% 32%


Kraus: Retrosynthetic Analysis of Pleurotin

O

O

HO

O

O

CH3

OMe

OMe

OH

O

G

O

CHO

OMe

OMe

O

O

G

Kraus, G. A. et al. Synlett 1991, 89.Kraus, G. A. et al. Synth. Commun. 1993, 23, 2041.

Tandem Photoenolization/Diels–Alder Reaction


Kraus: Synthetic Studies toward Pleurotin

Kraus, G. A. et al. Synlett 1991, 89.Kraus, G. A. et al. Synth. Commun. 1993, 23, 2041.

OMe

OMe

OH

nBuLi, THF

DMF

OMe

OMe

O

OH

66%

1. HS(CH2)2SH, BF3•OEt22. RCO2H, DCC, DMAP

3. MeI, aq. MeCN

CHO

OMe

OMe

O

O31% (3 steps)

CHO

OMe

OMe

O

O

O

O

HO

O

OHH

OMe

OMe

HO

O

OHH

1. h!, Benzene

2. 165 ˚C, 40 h

50%

AgO, HNO3

THF

28%

Comparable activity with pleurotin against SR leukemia cell line

{log10GI50 = -5.33 (pleurotin: -5.51)} and most colon cancer cell lines

{log10GI50 ranging from -4.65 to -4.77 (pleurotin: -5.17)}.O

O

HO

O

OHH


Acknowledgments

Wipf research group members

University of Pittsburgh

$ National Institutes of Health (GM66509) $

Prof. Dr. Peter Wipf

Dr. Sonia Rodríguez

Dr. Steven Geib (X-ray)


Documents

Synthesis of Pleurotin Progress toward the Totalccc.chem.pitt.edu/wipf/Topics/Shinya.pdf · Progress toward the Total Synthesis of Pleurotin SHINYA IIMURA Wipf Research Group Meeting