Convergent Total Synthesis of (+)-Ophiobolin Accc.chem.pitt.edu/wipf/Current...

Eric E. Buck Current Literature October 8, 2011

Convergent Total Synthesis of (+)-Ophiobolin A Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, 50, ASAP

OHC

O H

HOH

HO

(+)-ophiobolin A

Eric Buck @ Wipf Group of 16 12/28/2011

Background and Bioactivity of (+)-Ophiobolin A!

Shen, X.; Krasnoff, S. B.; Lu, S.; Dunbar, C. D.; O’Neal, J.; Turgeon, B. G.; Yoder, O. C.; Gibson, D. M.; Hamann, M. T. J. Nat. Prod. 1999, 62, 895-897 Leung, P. C.; Taylor, W. A.; Wang, J. H.; Tipton, C. L. J. Bio. Chem. 1984, 259, 2742-2747 Au, T. K.; Chick, W. S. H.; Leung, P. C. Life Sci. 2000, 67, 733-742 Fujiwara, H.; Matsunaga, K.; Kumagai, H.; Ishizuka, M.; Ohizumo, Y. Pharm. Pharmacol. Commun. 2000, 6, 427-431

•  Isolated from the culture broth of the pathogenic plant fungus Ophiobolus miyabeanus (among others) in 1958. The picture right is the effect of this fungus on rice plants.

•  The absolute structure was elucidated through X-ray analysis of a derivative.

•  Induces apoptotic cell death in the L1210 cell line.

•  Inhibits calmodulin-activated cyclic nucleotide phosphodiesterase through interaction with the ε-amino lysine group of calmodulin and the aldehyde function of ophiobolin A.

•  Shows potent (IC50 62.5 to 125 nM) cytotoxicity against several cancer cell lines.


Biosynthesis of (+)-Ophiobolin A and Related Family Members!

Canonica, L.; Fiecchi, A.; M. Galli Kienle; Ranzi, B. M.; Scala, A.; Salvatori, T.; Pella, E. Tetrahedron Lett. 1967, 35, 3371-3376

OHC

O H

HOH

HO

(+)-ophiobolin A

H

HCO2HH

albolic acid

H

HH

H

OH

(+)-ceroplastol I

HOAc

CH2OMe

fusicoccin A

HO O

OH

OHO

AcOOH

O

OPP

geranylfarnesyl pyrophosphate

H

HO HO


Recent Efforts Towards the 5,8,5 Ring System!

Ruprah, P. K.; Cros, J-P.; Pease, J. E.; Whittingham, W. G.; Williams*, M. J. Eur. J. Org. Chem. 2002, 3145-3152

OGrubbs I, 103 oC

toluene

O

97:3 (Pdt:SM), 49%

McGee, Jr., K. F; Al-Tel, T. H.; Sieburth*, S. M. Synthesis 2001, 8, 1185-1191

NO

N

O

OTBS

O

OTBS

NH

HNO

O

hv

OO

84%

toluene, 0 oCHN

O

HN

OOTBS

0 oC


Recent Efforts Towards the 5,8,5 Ring System!

Br

HOTMS

HO

EE

Bu3Sn

Pd(PPh3)4, PhH, 85 oC

HOHO TMS

EE

TMS

EE

O

H

OH

20%

Salem, B.; Suffert*, J. Angew. Chem. Int. Ed. 2004, 43, 2826-2830 Bour, C.; Blond, G.; Salem, B.; Suffert*, J. Tetrahedron. 2006, 62, 10567-10581

O

tBuS

TMSO

1) TMSOTf, CH2Cl2, -78 oC2) A, Pd(OAc)2, dppb, THF

+

OBoc

A

O

HO StBu

2) Grubb's II

1) MeOK

O

HCO2Me

86% yield over 2 steps

Michalak, K.; Michalak, M.; Wicha, J. Molecules. 2005, 10, 1084-1100


Total Synthesis of Albolic Acid!

Kato, N.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.; Takeshita, H. J. Chem. Soc., Chem. Commun. 1988, 354-356 Kato, N.; Takeshita, H. J. Chem. Soc. Perkin. Trans. I. 1989, 165-174

H

HCO2HH

Albolic acid

H

H OHHHO OH

H

H OHHO O

H

BnO OH

OTMSO

H

OTMS

McMurray coupling

OBnH

Hboat TS

Cope

H

OBnH

H

OH

CH2ClOBnH

OH

+

CrCl2-mediated condensation


Total Synthesis of (+)-Ceroplastol I!

Paquette, L. A.; Wang, T-Z.; Vo, N. J. Am. Chem. Soc. 1993, 115, 1676-1683

H

HH

H

OH

(+)-ceroplastol I

O

OO

O

OO

HO

OO

OH

[3,3]sigmatropic

rearrangement

OO

HO

Cl

OO

H

H

H

OH

H

H O

Wittig olefinationalkylation


Total Synthesis of (±)-Ceroplastol I!

Boeckman, Jr., R. K.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739

H

HH

H

OH

(±)-ceroplastol I

CO2Me

H

H

H

H

H

H O

CO2Me

H

HOMs

CO2Me

O

H

MsO H

MeO2C

O

Dieckmann condensation

HMOMO

O CO2Me

OEE OO

O O

OOH

H

GrobFragmentation


Total synthesis of (+)-Ophiobolin C!

H

HOHC H

H (+)-Ophiobolin C

O

HO

O

THPOH

OPivH+

TMS

Li

OTBS

TBDPSO

TMS H

TBDPSO

OTBSOH

OPiv

OTHP

I H

TBDPSO

O

OPiv

O

H

HOPivH

H

TBDPSO

HO

O

NHK coupling

Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111, 2735-2737


Title Paper: Retrosynthesis!

Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042 Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP

OHC

O H

HOH

HO

(+)-ophiobolin A

BnOH

HOH

HOTBSO

HO

RCM

Couplingstereo selective hydrogenation

OHC

HO

PivO

OTBDPS + TBDPSO

O

Br

TBSO


Title Paper: The Prelude!

MeO2C CO2Me

Ph 1) PLE, KPB8, 30 oC, 9 h

2) PLE, KPB8, 30 oC, 7 d MeO2C CO2H

Ph

100%, 89% ee to 88%, 96% ee

step-wise oxidation state changes and FG protection

6 steps, 80% yield OMOMOAc

OH 1) protection2) Hydrolysis3) Swern [O]

6 steps, 81% yield

4) HWE5) Reduction6) MsCl, LiCl

OMOM

OEE

Cl1) Me3SiSiMe3, MeLi

HMPA / Et2O

2) PPTs

3) PPh3, I2, imidazole

OMOM

I

TMS

3 steps, 81% yield

Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042


Title Paper: The Prelude!

Noguchi, N.; Nakada, M. Org. Lett. 2006, 8, 2039-2042

N O

O

i-Pr

O

1) NCS, NaI, NaHCO3

EtOAc / H2O OOOTBDPS

2) CF3CO2Na; Et2NH

3)TBDPSCl A, 3 steps, 56% yield

OMOM

I

TMSt-BuLi, Et2O, -78 oC, 15 min;

A, 1.5 h O OTBDPS

TMS

MOMO

HO

84 %

HO OTBDPS

MOMO

BF3•OEt2 (3.0 equiv)

CH2Cl2, -78 oC, 4 h

2006: 45%

2011: 68%


Title Paper: Coupling the Two Pieces!

HO OTBDPS

MOMO

1) Hydroboration2) PivCl

3) BF3•OEt24) DMP [O] OHC

HO OTBDPS

PivO

Ph3SnH, Et3B, benzene, rt

TBDPSO

O

Br

TBSO

TBSO

TBDPSOH

HOTBDPSO

OH OH

PivO

wrong epimer Non-required functionality

4 steps, 86% yield

90% (83% from other Br-isomer)Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP


Title Paper: Middle Game and Oxidation State Changes!

Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP

TBSO

TBDPSO H

HO

OH OH

PivO1) Burgess reagent

2) H2, Raney Ni, MeOH / THF

TBSO

TBDPSO H

HO

O

PivO

H

1) MeLi2) Swern [O]3) Wittig4) PPTs

5) IBX [O]6) MeLi7) DMP [O]8) TMSCl

TBDPSO H

HOTBDPSO

OTMSH

O

TBDPSOH

HOTBDPSO

OTMSH

1) Comin's reagent, KHMDS2) Pd(PPh3)4. Et3N, CO (1 atm)

3) DIBAL-H

OH

2 steps, 75% yield

8 steps, 75% yield

3 steps, 47% yield

OTBDPSOTBDPS


Title Paper: Formation of B Ring and End Game!

Tsuna, K.; Noguchi, N.; Nakada, M. Angew. Chem. Int. Ed. 2011, ASAP

TBDPSO H

HOTBDPSO

OTMSH

OH 1) PivCl2) TBAF

3) TBSCl4) BnBr5) DIBAL-H

BnO H

HOTBSO

OHH

OH

(Note: RCM did not work on this substrate)

1) Hoveyda-Grubbs II

BQ, toluene, 110 oCBnO H

HOH

HO

OBnOH

1) Swern [O]2) Wittig

3) Li, Naphthalene4) Swern [O]

OHC

O H

HOH

HO

(+)-ophiobolin A

5 steps, 76% yield

2) BnBr3) PPTS

3 steps, 68% yield

4 steps, 49% yield


Summary!

•  The Nakada group finished the synthesis of (+)-Ophiobolin A in 57 steps (0.77 % overall yield) utilizing a key Reformatsky type reaction to couple the two 5-membered rings together and a RCM reaction to form the central B-ring.

•  Other methods to construct the 5,8,5 core of this family of compounds included various RCM strategies, [4+4] photocycloaddition of pyridones, and a 4-exo-dig cyclocarbopalladation/ 8π electrocyclization strategy.

•  The Takeshita group assembled albolic acid utilizing a key Cr (II) mediated coupling, cope rearrangement, and a McMurray coupling was used to for the B-ring.

•  Boeckman Jr’s group assembled the core of (+)-ceroplastol I with a key [3,3]-sigmatropic rearrangement to establish the B-ring and a simple alkylation installed the A-ring.

•  Through the use of a grob fragmentation to set the 8-membered B-ring and late stage Dieckmann condensationo install the C-ring, the Paquette group completed the total synthesis of (±)-seroplastol I.

•  A vinyl lithium addition into a complex aldehyde brought rings A and C together in Kishi’s synthesis of (+)-ophiobolin C. An NHK coupling finished the assembly of the B-ring.


Convergent Total Synthesis of (+)-Ophiobolin Accc.chem.pitt.edu/wipf/Current...

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