asymmetric total synthesis of cylindrocyclophanes …ccc.chem.pitt.edu/wipf/current...

Asymmetric Total Synthesis of Cylindrocyclophanes Aand F through Cyclodimerization and a Ramberg-

Bäcklund Reaction

R

R

Me

MeOHHO

MeH

MeH

HO OH

cylindrocyclophane A: R = OHcylindrocyclophane F: R = H

K. C. Nicolaou, Ya-Ping Sun, Henry Korman and David SarlahAngew. Chem. Int. Ed. 2010, 49, 5875-5878.

Current Literature Presentation: 8/28/10David Arnold

David Arnold @ Wipf Group of 11 9/26/2010

Cylindrocyclophanes A – F: Isolation, Biological Activities andPreliminary SAR Data

R1

R2

Me

MeOHHO

MeH

MeH

HO OH

cylindrocyclophanesA: R1 = R2 = OHB: R1 = OH, R2 = OAcC: R1 = OH, R2 = HD: R1 = R2 = OAcE: R1 = OAc, R2 = HF: R1 = R2 = H

• Cylindrocyclophane A was first isolated in 1990 by Moore et al. from the blue-green algae Cylindrospermum licheniforme Kutzing.• Cylindrocyclophane B-F were later isolated in 1992 again by Moore et al.• This class of compounds has been found to be biologically active showing moderate cytotoxicity against

several tumor cell lines.• Plemininary SAR data has been obtained for (-) cylindrocyclophane A, (+) cylindrocyclophane A, 1 and2 as cell growth inhibitors against human colon cancer cell line HCT116.

202

>501

2(+) cylindrocyclophane A

2(-) cylindrocyclophane A

GI50 (µM)CompoundMe

MeOMeMeO

Me

Me

MeO OMe

HO

OH

1

OHHO

MeHO

2

JACS 1990, 112, 4061.Tetrahedron 1992, 48, 3001.Org. Biomol. Chem. 2009, 7, 3772.


Previous Total Syntheses of Cylindrocyclophanes A and/or F:Key Cyclodimerization Approaches

• Amos B. Smith, III: Utilization of a cross olefin metathesis / ring closing metathesis cyclodimerizationapproach to the synthesis of both (-)-cylindrocyclophanes A and F.

• Thomas R. Hoye: Utilization of a double Horner-Emmons cyclodimerization approach to the synthesisof (-)-cylindrocyclophane A.

Me

MeOMeMeO

Me

Me

MeO OMe

CM/RCM

CM/RCM

MeOMeMeO

Me

Smith et. al.

R

R

R

R = H or OH

Me

MeOMeMeO

CO2Me

CO2Me

MeO OMe

Horner-Emmons

OMeMeO

O

(MeO)2P

CO2Me

OMeHoye et. al.


Smith’s First Generation Synthesis of (-)-Cylindrocyclophane F

• 20 Steps, 8.3% overall yield

JACS 2001, 123, 5925.

Me

Me

OHHO

Me

Me

HO OH

RCM

Me

Me

OMeMeO

Me

Me

MeO OMe

Reduc tive Coupling

Me

OMeMeO

Me

IMe

Me

MeO OMe

MOMO

NN(TBS)Ts

+

Me

OMeMeO

Me

OMOM

MeOMeMeO

Me

OMOM

CO2MeBnO

10 S teps

1) HCl, MeOH, 60 oC2) I2, PPh3, imid(91%, 2 s teps)

1) O sO4, NMO2) NaIO4, THF3) T sNHNH2;TBSOTf, Et3N(72%, 3 steps )

Me

OMeMeO

Me

IMe

Me

MeO OMe

MOMO

NN(TBS) Ts

+

1) t -BuLi, e ther, -78 oC2) HCl , MeO H, THF, 60 oC

73%, 2 steps

Me

Me

OMeMeO

Me

Me

MeO OMe

HO

1) Dess -Martin Ox idation

2) P h3P=CH2, THF, - 78oC

(88%, 2 steps)

Me

MeOMeMeO

Me

Me

MeO OMeR uPCy3

PCy3

PhCl

Cl (6 mol%)

20 oC, 0.004 MDCM, 22 h: 88%

Me

Me

OMeMeO

Me

Me

MeO OMe

1) H2, Pd/C, E tOAc

2) BB r3, DCM(84%, 2 s teps)

Me

MeO HHO

Me

Me

HO OH

(-) -cylindrocyclophane F

(-)-cylin drocycloph ane F


Smith’s Second Generation Synthesis of (-)-Cylindrocyclophane F

Me

Me

OHHO

Me

Me

HO OH

RCM

(- )-cylindrocyclophane F

Me

Me

OMeMeO

Me

Me

MeO OMe

CM /RCM

CM /RCM

Me

OMeMeO

Me

OTIPS

O

+

DanheiserAnnulation

O

N O

O

Ph

NaHMDSallyl brom ide

T HF, -78 oC77%, > 98% de

O

N O

O

Ph

LiOH, H2O2

THF , H2O97%

O

OHEtI, K2CO3

ac etone, H2O98%

O

O EtCH2Br2

L iT MP , -78 oC72-80%

O

B r

Br

a) L iN(TMS)2; b) n-B uLi ;

c ) TIPSO Tf -78 oC - > r t92 - 100%

OTIPS

HOI2, PPh3, im id.

82%

It -BuLi, ether;

O OE t

67% O

OTIPS

Toluene, 80 oC

1)

2) TBAF, T HF, 69%, 2 steps3) MeI, K2CO3, 80

oC, 91%

MeOMeMeO

Me

Me

MeOMeMeO

Me

Me

MeO OMeConditions 1) H2, P d/C

2) BBr3, DCM84%, 2 steps

See Table

(-)- cylindro cyclo phane F

Kowalsk i homologation

• 11 steps, 22% overall yieldJACS 2000, 122, 4984., JACS 2001, 123, 5925.


Smith’s Synthesis of (-)-Cylindrocyclophane A

JACS 2000, 122, 4984., JACS 2001, 123, 5925.

• 16 steps, 8.1% overall yield

O

SnBu3

1) OTIPS

Toluene, 80 oC

2) I2, DCM3) TBAF, AcOH, THF

68%, 3 steps

HO OH

I

MeI, K 2CO 3

89%

MeO OMe

I

N

O

OH

Ph

t-B uLi , THF;

68%

MeO OMe

O

(+)-DIPCl , THF

0 oC -> r t, 84 h81%, 19:1 dr

MeO OMe

HO

TESO Tf

2,6- Lutid ine92%

MeO OMe

TESOSchrock s cat.( 34 mol %)

Benzene, 1 h77%

Me

Me

OMeMeO

Me

Me

MeO OMe

TESO

OTES

1) TBAF, THF

2) H2, P tO2, E tOH

Me

MeOMeMeO

Me

Me

MeO OMe

HO

OH

PhSH, K2CO3

215 oC, s ealed tube60%, 3 steps

Me

MeOHHO

Me

Me

HO OH

HO

OH

(-) -Cylindrocyclophane A


Hoye’s Synthesis of (-)-Cylindrocyclophane A

• 22 steps, 3.3% overall yieldJACS 2001, 122, 4982.

Br

MeO OMe

OH

1) TBDPSCl, Et3N, DCM : 98%2) t-B uLi, E ther, -78 oC; DMF: 92%

3) LiCl, DBU, ACN: 70%

PO

MeO

MeOO

MeO OMe

O TBDPS

O1) NaBH4, CeCl3.7H2OE tO H, 0 oC: 97%

2) Amano P -30 l ipase, hexanesvinyl acetate, 4 Å MS , r t:50% conversion, 94% yie ld

99.4% ee

MeO OMe

O TBDPS

O O

KHMDS, THF, - 78 oC;

TBSCl , -78 oC -> rt: 80%

MeO OMe

O TBDPS

OTBSO

1) DIBAL, DCM, -78 oC: 95%2) H2, Pd/C, E tOH: 99%

3) (CO Cl)2, DMSO, DCM -60 oC;E t3N, -60

oC to rt, 90%

MeO OMe

OTBDPS

HO

LiCl, DBU, ACN: 80%

P

O

MeO

MeOO

O

MeO OMe

OTBDPS

O

O

1) DIBAL, DCM , - 78 oC: 95%2) NCS , Me2S, DCM , - 30

oC: 89%

3) t-B uOK , DMSO : 80%

PO

MeO

MeOO

O

MeO OMe

OTBDPS

P (OMe) 2

CO2Me

O

1) TBAF, T HF, 0 oC: 94%2) H2, Pt/C, EtOAc: 99%

3) PDC, DCM : 96%

MeO OMe

O

P (OMe) 2

CO2Me

ONaH, cat. 15-cr own-5

benz ene: 55%

MeO OMe

CO2Me

CO2Me

MeO OMe

1) DIBAL, DCM, 100%2) CBr 4, PPh3, DCM

3) LiBHEt3, THF, rt91% over 2 steps

MeO OMe

MeO OMe

1) IpcBH2, THF, -20oC to r t;

H2O2, NaO H: 58%

2) MeMgI, neat, 160 oC, 1 h: 60%

HO OH

Me

Me

HO OH

OH

HO

(-) -Cylindrocyclophane A

Key monomer

Double Horner-EmmonsMacrocy cl ic Dimerization


Title Paper:Nicolaou’s Retrosynthetic Analysis of (-)-Cylindrocyclophanes A and F

Angew. Chem. Int. Ed. 2010, 49, 5875.

R

R

Me

MeOHHO

MeH

MeH

HO OH

cyl indrocyc lophane A : R = OHcyl indrocyc lophane F: R = H

S

S

Me

MeOMeMeO

H

H

MeO OMe

O

O

O

O

SN2 dimerization

[Ramberg-Bäcklun d]

SAc

MeOMeMeO

H

OMs

[dimerization]

B r

O TBS

OMeMeO

[as ymmetricfunc tional ization]


Nicolaou’s Synthesis of (-)-Cylindrocyclophanes A and F:The Synthesis of a Common Intermediate

Angew. Chem. Int. Ed. 2010, 49, 5875.

B r

O TBS

OMeMeO

1) n -BuLi, THF,-78 to - 30 oC;

O

2) TMEPO/BAIBDCM

76%, 2 steps

OTBS

OMeMeO

O

1) t-B uLi, E ther, -78 oC to rt

B r OTBS ;

k etone, -78 to 0 oC

2) PDC, DCM48%, 2 s teps

O TBS

OMeMeO

OO TBS

1) ( S)- CBS, catec holboranetoluene, - 78 -> 0 oC:85% yie ld , 95% ee

2) Cr abtree 's cata lys t ( 9 mol%)H2, DCM :

76% y ie ld , 93% ee

OTBS

OMeMeO

HOOTBS

H

MsCl , E t3N, THF, 0oC;

L iBE t3H, 80oC; T BAF, 0 oC

73 %

O H

OMeMeO

OTBSH

1) PPh3, DIAD, AcSH, THF, 0oC

2) TsOH, A cOH/H2O , 23oC

3) MsCl, Et3N, DCM , 0oC

76%, 3 s teps

SAc

Me

OMeMeO

HOMs

1) NaOMe, MeOH: 64%

2) (NH4) 6Mo7O 24.4H2O,H2O2, EtOH: 80 %

S

S

Me

Me

OMeMeO

H

H

MeO OMe

O

O

O

O

Key monomer

CF2Br2, KOH/A l2O3,DCM/tBuO H, 0 oC to r t;

[P d(CH3CN)2Cl2], 40oC

70%

Me

H

Me

H

MeO OMe

MeO OMe

Ramberg-Bäck lund 1) AD-mix-! , MeSO 2NH2tBuO H/H2O

2) S=C(im id)2, to luene, 125oC

62%, 2 steps

3) A IBN, nBu3SnH, toluene, 100oC

81%

Me

MeOMeMeO

O HH

OHH

MeO OMe


Nicolaou’s Synthesis of (-)-Cylindrocyclophanes A and F

Me

MeOMeMeO

OHH

OHH

MeO OMe MsCl, Et3N, DCM , 0 oC;AlMe3, 0 oC; BBr3

One pot, 71% yield

Me

MeOHHO

MeH

MeH

HO OH

(-)-cylindrocyclophane F

1) DMP, NaHCO3, DCM: 92%2) KHMDS, Comins reagent, THF, -78 oC3) Fe(acac)3, MeMgBr, THF/NMP, 0 oC 80%, 2 steps

Me

MeOMeMeO

MeH

MeH

MeO OMe

Me

MeOHHO

MeH

MeH

HO OH

(-)-cylindrocyclophane AFormal total synthesis

2 Steps

Hoye's Synthesis

Angew. Chem. Int. Ed. 2010, 49, 5875.

17 steps, 1.7% Overall yield

19 steps, 1.7% Overall yield


Conclusion

• The Nicolaou group has demonstrated an elegant synthesis of (-) cylindrocyclophane F and formalsynthesis of (-) cylindrocyclophane A utilizing a key SN2 dimerization and Ramberg-Bäcklund reactionstrategy to generate the [7.7]paracyclophane framework.

• The Nicalou synthesis has the advantage of generating both cylindrocyclophanes from a commonintermediate 1; a strategy that may provide useful for the derivatization of this family of compoundsfor further SAR studies against tumor cell lines.

Me

MeOMeMeO

OHH

OHH

MeO OMe

1


asymmetric total synthesis of cylindrocyclophanes …ccc.chem.pitt.edu/wipf/current...

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