total synthesis of peloruside a through kinetic ...ccc.chem.pitt.edu/wipf/current...

Eric E. Buck Current Literature August 28, 2010

Total Synthesis of Peloruside A Through Kinetic Lactonization and Relay Ring-Closing Metathesis

Cyclization Reactions Thomas R. Hoye, Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and

Yini Wang. Angew. Chem. Int. Ed. 2010, 6151-6155

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

Peloruside A

Eric Buck @ Wipf Group of 16 9/26/2010

•  Peloruside A demonstrated LD50 vaulues in the 6-18 nM range towards several cancer cell lines.

•  Peloruside A is a microtubule stabilizer that binds to a different site than paclitaxel.

Isolation and Background"

West, L. M.; Northcote, P. T. J. Org. Chem. 2000, 65, 445-449 Hood, K. A.; West, L. M.; Rouwé, B.; Northcote, P. T.; Berridfe, M.V.; Wakefield, St. J.; Miller, J. H. Cancer Res. 2002, 64, 3356-3360 Teesdale-Spittle, p.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004, 64, 5063-5067

•  Peloruside A was Isolated from the marine sponge Mycale hentscheli (pictured left) by Northcote in 2000.

•  The marine sponge Mycale hentscheli, located in Pelorus Sound (pictured below), is also responsible for the production of mycalamide A and pateamine.


First Synthesis and the Confirmation of Absolute Configuration"

Liao, X.; Wu, Y. De Brabander, J. K. Angew. Chem. Int. Ed. 2003, 42, 1648-1652

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

(-)-peloruside A

Mukaiyama aldol

Mitsunobu macrolactonization

OMePGO

OPGO

CHOOPG

CO2Me

PGO OMeOPG

Et

O+

OBn

O

O

OTES

R

1) PTSA2) Luche Reduction

O

OBn

OH

R O

OBn

OH

R

HOMeO

mCPBA, NaHCO3

DCM/MeOH


Taylorʼs and Ghoshʼs Synthesis of Peloruside A"

Gosh, A. K.; Xu, X.; Kim, J.; Xu, C. Org. Lett. 2008, 10, 1001-1004

Jin, M.; Taylor, R. Org. Lett. 2005, 7, 1303-1305

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

aldol addition

Yamaguchi macrolactonization

Acid mediated annulationand selective methylation

TBSO

O

OH

MeO

O O

MOMO OMe

OBnEt

OO

O

MeO

OTES

OBnEt

TBSO

OO

+

MOMO

OPMB

OMe

O

H

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside Aaldol addition


OMe

O

OMOM

MeO

OTBS

OTIPSEt

Xc

O

OMe

MOMO

OMOM

MeO

OTBS

OTIPSEt

O

O

OTESOMe

Xc

O

OMOM

+1) LDA2) [O]

3) PTSA


OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

aldol addition


aldol addition

Xc

O O

OMOM

OMe+ H

O OTES

TBSO

OBn+

O OPMBEt OH

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

aldol addition


O

MeO

OPMB

OBnEt

TBSOMOMO

OTBS

OMe

O

TBSOOMe

+MOMO

OTBS

OMe

OBnO

AcOOMe

Evanʼs and Jacobsenʼs Synthesis of Peloruside A"

Evans, D. A.; Welch, D. S.; Speed, A. W. H.; Moniz, G. A.; Reichelt, A.; Ho, S. J. Am. Chem. Soc. 2009, 131, 3840-3841

McGrown, M. A.; Stevenson, P. C.; Schiffler, M. A.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, 6147-6150


Title Paper: Retro Synthesis"

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

aldol addition


Me(H)

O

OPMB

OTBSEt

OMeMOMO

OBPSOPMB

(Me)H O

CO2Me

MOMO OMe

+

NC

O

XY

Et

X = -CH2OPh2Si-Y = H

X = C(O), Y = Me

MeO2C

OMeMOMO

O

CO2MeOMe

MOMO

RRCM

Thomas R. Hoye, Junha Jeon, Lucas C. Kopel, Troy D. Ryba, Manomi A. Tennakoon, and Yini Wang. Angew. Chem. Int. Ed. 2010, 6151-6155


Tennakoon and Yini: Initial Work on Peloruside A"

Tennakoon, M. A., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2001

NC

O

XY

Et

(R) citronellene

SeO2

tBuOOH O

H

1) LiCH2CN

2) SP-435

OAc

OH

CN

95:5 er

NHO

O

Bn

Cl

O

Me NO

O

Bn

O

Me LiHMDS, HMPAEt2Zn

NO

O

Bn

O

Et

dr = 70 : 30

LiBH4 HOEt

Low diastereoselectivity and seperation of diastereomers

proved difficult

OH

CN

i) Ph2SiCl2, pyr

ii)HO

Et

OSi

O

Et

NCPh Ph

dr = 95 : 540 %

OSi

O

Et

Ph PhO

SiO

NCPh Ph

21%

CN

18%

+ +


Tennakoon and Yini: Initial Work on Peloruside A"

RuG2

OSiPh2

O

CN

OSi

O

Et

NCPh Ph

Ru

OSi

O

Et

NCPh Ph

RuO

SiO

Et

NCPh Ph

Et

92%

1) TBAF2) TBSCl

3) CSA

PMBO CCl3

NH

OTBS

OPMB

CN

Et

Tennakoon, M. A., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2001 Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210-10211

MeO2C

OMeMOMO

O

CO2MeOMe

MOMO

H OEt

O 1) Zn,2) NaH, PMBCl

Br OPMB 1) i) O3ii) NaBH42) TBSCl

3) SO3•pyrTBSO H

OPMBO

Bu2BOTf, Et3N

ON

OOBnO

Bn

TBSO

OHPMBO

N

O

O

O

Bn

Ac2O-or-

MOMClTBSO

ORPMBO

N

O

O

O

Bn

R = Ac or MOM

OBn OBn


Troy : The Issue of Scalability"

OTBS

OPMB

CN

Et OH

O

Et

CN

Et

O

O

CN

OH

+

N

O

EtO

O

Bn

O

H+ CH3CN

HN O

O

BnnBuLi

Cl

O

Me

Me N

O

O

O

BnnBuLi

BrN

O

EtO

O

Bn1) RhCl3•3H2O, EtOH/H2O, 98%

2) LiOH, H2O2, THF/H2O, 99%O

EtOH

E:Z 15:1

O

NC

OEt

(COCl)2, Et3N

OH

CN

RuG2

C2H2 O

NC

OEt

O

NC

OEt

RuG2+

CN

Et

O

O

Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005 Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225-228


Junha : Completion of a Scalable Route to the Northern Fragment "

OH

CN

DCC, DMAP, 82%O

NC

OEt

O

EtOH

OH

CNA poor substrate for

lipase resolution

RuG2, 70%

CN

Et

O

O 1) NaBH4, AcOH

2) TBSCl3) CSA

PMBO CCl3

NH

3 steps 77%

CN

Et

OPMB

OTBS

1) Zn0, Cp2TiCl2, allyl 2-bromoacetate

2) pH 3 buffer, iPrOH/H2O/THF (4:1:2)

Pd(Ph3)4, HCO2H, Et3N

Et

OPMB

OTBS

O

O

OAllyl

Et

OPMB

OTBS

O

Me

3 steps 61%

“… although Troy’s diastereoselective RRCM was a great reaction, I thought it was not scalable.”

“Nitrile to ketone or to complementary aldehyde was not easy. The nitrile was extremely base sensitive.”



Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005

“…from a total synthesis perspective it was a total nightmare. From a training exercise it was a blessing.”

OCO2MeMeO2C

1) NaBH4

2) TBSCl3) DIBAL-H

H

O OTBS

O H

(+)-(Icr-4)2B

OMOM OTBS

OMOM

OH OH

OMOM

OTBS

OMOM

OH OH

OMOM

OTBS

OMOM

OH OH

OMOM

dr = 1:2:1er = 5:1

OTBS

OMOM

OH OH

OMOM

1) NaH, MeI

2) O3, NaOH, MeOH

3) HF, MeCNMeO2C CO2Me

OMOM

OMe OMe

OMOMC6D6

20 mol% cat. O

OMOMO

MeOCO2Me

OMe

OMe

+

O

OOMOM

OMeMeO2C

OMe

OMe

Catalyst time Lactone Ratio

DBU

TMG

DBN

15

40

40

10:1

13:1

10:1

OH



OOMeO2C CO2Me

DIBAL-H;

(EtO)2PO O

OC6H13

Na

80%

OOnHexCO2 CO2nHex

SAD, 88% OOnHexCO2 CO2nHex

OH

OH

OH

OH

1) HI, 83%2) Me3OBF4, 84%

O O

OMe

CO2nHexnHexCO2

MeO

1) BF3•OEt2

HS SH

SSnHexCO2 CO2nHex

MeO

OMOM

OMe

OMOM2) MOMCl

2 steps 90%

1) I2, NaHCO3, 91%

2) Raney-Ni H2 C6D6

20 mol% cat.

Catalyst Time (h) Lactone Ratio

DBU

TMG

DBN

15

40

40

10:1

13:1

10:1

% Conv.

100

<10

70

nHexCO2 CO2nHexMeO

OMOM

OMe

OMOM

OHO

OMOMO

MeOCO2nHex

OMe

OMe

+

O

OOMOM

OMenHexCO2

OMe

OMe

Ryba, T. D., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2005

“ The formation of the spirocycle was the big breakthrough.”


Lucas: Optimization of the Kinetic Lactonization"

SSnHexCO2 CO2nHex

MeO

OMOM

OMe

OMOM

1) I2, NaHCO3, 91%

2) Otera's Catalyst, MeOH, 77%

MeO2C CO2MeMeO

OMOM

OMe

OMOM

OH

3) Raney-Ni, H2, 91%

TMG, C6H6;

TFA, 98% (d.r. 12:1) OH

HOOMe

MeO2C

OMeOMOM

OMe

O

MOMO MOMOMeO

O

MeC2O

OMe

OMOMOMe

O

OMOMO

MeOCO2Me

OMe

OMe

“… I observed that as the ratio of DBN increased, so too did the peaks that I initially assigned as being associated with by-products.

“… it was decided to use TMG as the catalyst in C6D6 because of its high selectivity for forming the desired product. TMG was also reported not to have the problems associated with decomposition of product.”

“… the additional peaks are in fact coming from an amine-product complex and unpon treatment with TFA, this adduct collapses to regenerate the desired lactone product.”

Kopel, L. C., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2009


Lucas: Finishing the Southern Fragment"

O

OMOMO

MeO CO2MeOMe

OMe

1) L-Selectride, 87%

2) indium powder

Br Me

Me

OMe

OMOM

OH O

OOMOM

OMe

1) AlCl3, NaI, 92%

2) (p-MeO)-PhCH(OMe)2, CSA, 87%3) MOMCl, 99%

OMe

O

O

OOMOM

OMe

80%

O

PMP

1) LAH, 96%2) TBDPSCl, 92%

OMe

OH

O

3) DIBAL-H, 95%

OBPSOME

OMOM

BPSOPMB

1) DMP2) Zn(BH4)2, 62%

3) TBSOTf, 89%

OMe

OTBS

O OBPSOMe

OMOM

BPSOPMB

1) HF•pyr, 91%

2) DMP3) NaClO2, NaH2PO4

4) CH2N2

3 steps 87%

OMe

OTBS

OCO2Me

OMe

OMOM

BPSOPMB

OMe

OTBS

OCO2Me

OMe

OMOM

BPSOOPMB

H

O3, 75%

“ The C8 stereocenter was previously inverted by a lengthy intramolecular inversion strategy: mesylation, ozonolysis, oxidation to the acid, cyclization to invert, DIBAL-H reduction, and wittig to reveal the inverted C8 hydroxyl.”

Kopel, L. C., Ph.D. Thesis, University of Minnesota, Minneapolis, MN, 2009


Junha and Lucas: End Game"

“ After a final removal of 5 protecting groups, on TLC I saw two spots, which correspond to peloruside A and isopeloruside. I don’t understand why others didn’t see the this because virtually all the synthesis used almost identical deprotection conditions.”

OMe

OTBS

OCO2Me

OMe

OMOM

BPSOOPMB

H

Et

OPMB

OTBS

O

Me

+ OMe

OTBS

OCO2Me

OMe

OMOM

BPSOOHPMB

OHPMBO

OTBSEt

1) cHex2BCl, 64%2) NMe4BH(OAc)3, 95%

1) Me3OBF4, 82%

2) MOMCl, 98%3) DDQ, 94%

OMe

OTBS

OCO2Me

OMe

OMOM

BPSOHOOMeOH

MOMEt

OTBS1) LiOH, H2O2, 100%

2) Yamaguchi macrolactonization, 54%

OMeTBSO

BPSOOH

OMOM

MeO

O O

MOMO OMe

OTBSEt

1) DMP, 83%2) HF•pyr

3) HCl

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

2 steps 49%

OMeHO

OH

MeO

OH

OHEt

O O

OOH

OMe

isopeloruside A

2 steps 5%

+


Summary"

OMeHO

OOHOH

MeO

O O

HO OMe

OHEt

peloruside A

aldol addition


RRCM

•  A detailed look into the synthesis of peloruside A from an author perspective.

•  Highlights from the synthesis include a RRCM strategy to set the z-olefin and desymmetrizing kinetic lactonization to assemble the southern fragment.

•  The final synthesis yielded 6.9 mg followed by another 5 mg. There remains enough addition material to produce ca 100 mg.

•  A Special thanks to Lucas, Junha, and Troy.


total synthesis of peloruside a through kinetic ...ccc.chem.pitt.edu/wipf/current...

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