anionic oxy-cope rearrangement: recent development in ... · anionic oxy-cope rearrangement: recent...

Anionic Oxy-Cope Rearrangement:Recent Development in Mechanistic Study and

Synthetic Application

Lingling WangChemistry Department

Michigan State UniversityFebruary 11, 2004

Outline

I. IntroductionFrom Cope to Anionic Oxy-Cope (AOC) RearrangementRate-acceleration Effect of C3-Oxy-Anionic Substituent

II. Recent Mechanistic Study of AOC RearrangementFurther Mechanistic Study toward Rate-accelerationRole of Chelation Effect in AOCVariations of Classic AOC

III. Recent Synthetic Developments in AOCUsing Transition-metal Complexes to Form AOC PrecursorsAOC-involved Tandem Rearrangement Processes

Cope Rearrangement

-Highly ordered cyclic transition state-Generally reversible

Oxy-Cope Rearrangement

O1

2

3

4

5

6O

H [ 1,5 ]-H shift

-Generally irreversible -A competitive retro-ene fragmentation

1

2

3

45

6

HO340 - 390oC

HOtautomerization O

HO

Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441-444.Berson, J.A. J. Am. Chem. Soc. 1964, 86, 5017-5018.

Introduction

RL

1

2

3

45 6

E

300-350 C°RL

RL

E

E

RL

Z

E *

RL

*

major

minor

favored

disfavored

[ 3,3 ] Sigmatropic

Introduction

Anionic Oxy-Cope (AOC) Rearrangement

-Rate enhancement of 1010 - 1017

-No fragmentation byproduct

-Low reaction temperature

KH18-Crown-6

OK KO1

2

3

45

6

HO

O= 0 C° K

Evans, D. A.; Golob, A.M. J. Am. Chem. Soc.1975, 97,4765-4766.

Introduction

Anionic Oxy-Cope (AOC) Rearrangement

-Rate enhancement of 1010 - 1017

-No fragmentation byproduct

-Low reaction temperature

KH18-Crown-6

OK KO1

2

3

45

6

HO

O= 0 C° K

Evans, D. A.; Golob, A.M. J. Am. Chem. Soc.1975, 97,4765-4766.

Previous Reviews

•Paquette, L. A. Tetrahedron 1997, 53, 13971-14020.

•Wilson, S. R. Org. Reactions 1993, 43, 93-250.

•Paquette, L. A. Synlett 1990, 67-73.

IntroductionRate-acceleration Effect of C3 Oxy-anion

1.63×10-14

1.05 × 10-12

1.64 × 108

36.3

33.8

6.3

1.548

1.552

1.604

H

OH

O

1

2

3

k (s -1)

ΔG≠

(kcal/mol)

Bond Distance (Å)

C3 –C4RSubstance

Baumann, H.; Chen, P. Helvetica Chemica Acta, 2001, 84, 124-130. .

MO[3,3]

MO1

23

45

6 6

12

3

45

1

23

4

5 6

1

23

4

5 6

RR

1 R=H 2 R=OH 3 R=O

Cope Rearrangement

Mechanistic Study-Substituent Effect

Can C4 or C6 Heteroatom Substituents Also Help Rate-accelerating in AOC ?

Evans, D. A.; Ballallargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100, 2242-2243.

HO

MeO

MeKH, THF

° MeO

OMe

1

54

3

2

HOMe

NaH, Et2O

° PhS

OMe

PhS

1

2

3

45

6

KH, THF

°25 C, 1h+

6

PhS

OMeHO

Me

PhS

1

2

3

45

6

85 C, 9.5 h

85%

25 C, 6 h71%

42%

Cleavage Products

A

B

B



Paquette, L. A.; Wang, H.; Zeng, Q.; Shih, T. L. J. Org. Chem. 1998, 63, 6432-6433.

C

D

OMOM

O

TMS

OH

BnO

OPMB

OPMB

OTBS

KHMDS,18-Crown-6

THF, 0 C°

OMOM

HO

O

TMS

H

OTBS

BnOOPMB

OPMB

OMOM

SPh

OH

BnOOPMB

OTBS

OPMB

KHMDS,18-Crown-6

THF, -78 C°

OMOM

HO

PhS H

OTBS

BnOOPMB

OPMB

70%

(COMPLETE IN 5 MIN)

85%

(COMPLETE IN 5 MIN)

1

2

34

5

6

1

2

34

56


Computational Calculation of C4 & C6-Substituent Effect

24.419.4-19.6

25.321.7-21.9

-

Homo BDE

12.08.4-9.3

5.05.3-5.6

8.3

Activation Energy

28.523.4-23.7

6- OMe4- OMe

13.19.6-9.8

6- SMe4- SMe

-H

Hetero BDER

Computed Energies of Activation and BDEs ( kcal/mol) for Cleavage C3-C4

Paquette, L. A.; Haeffner, F.; Houk, K. N.; Reddy, R. Y. J. Am. Chem. Soc. 1999, 121, 11880-11884.

R

O

4

AOC Rearrangement O

R

O

R

O

R

6

AOC Rearrangement

3

4

3



Evans, D. A.; Ballallargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100, 2242-2243.

HO

MeO

MeKH, THF

° MeO

OMe

1

54

3

2

HOMe

NaH, Et2O

° PhS

OMe

PhS

1

2

3

45

6

KH, THF

°25 C, 1h+

6

PhS

OMeHO

Me

PhS

1

2

3

45

6

85 C, 9.5 h

85%

25 C, 6 h71%

42%

Cleavage Products

A

B

B



Paquette, L. A.; Wang, H.; Zeng, Q.; Shih, T. L. J. Org. Chem. 1998, 63, 6432-6433.

C

D

OMOM

O

TMS

OH

BnO

OPMB

OPMB

OTBS

KHMDS,18-Crown-6

THF, 0 C°

OMOM

HO

O

TMS

H

OTBS

BnOOPMB

OPMB

OMOM

SPh

OH

BnOOPMB

OTBS

OPMB

KHMDS,18-Crown-6

THF, -78 C°

OMOM

HO

PhS H

OTBS

BnOOPMB

OPMB

70%

(COMPLETE IN 5 MIN)

85%

(COMPLETE IN 5 MIN)

1

2

34

5

6

1

2

34

56

Mechanistic Study-Substituent EffectRate-acceleration by Additional Unsaturation on C1

Hanna, I.; Gentric, L.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631-3634.

OH

OH

OO

OO

12

345

6

B

C

KH,THF,reflux,

22 hH

O88%

KH, THF, reflux, 18-Crown-6

orKHMDS,

toluene,reflux,18-Crown-6

or decalin, reflux

HO

OO

OO

H

OHOH

OH

Vinigrol

opposite stereochemistry

12

345

6

7

A

D



NaH, THF, reflux,

18 h

HO

92%

H2, Rh/Al2O3AcOEt,

3h

OO

100%

HO

OO

AF

OH

OH

KH, THF, refluxor

KHMDS, 18-Crown-6THF, rt, 20h

OH

HO

G H

OH

OO

12

345

6

E



OR

OR

RO

RO

Mechanistic Study— Chelation Effect

Chelation–assisted Aromatic AOC Rearrangement

Uyehara, T.; Ueno, M.; seki, K.; Tooya, M.; Sato, T. Tetrahedron Lett. 1998, 39, 8673-8676.

HO Me

Me

H

O

1

HO

H

H

O

2

MeO

MeO

HO

MeMe

H

O OMe

3

Entry Oxy-Cope system Products

KH, 18-Crown-6,

70 C, 4h°

Conditions

KH, 18-Crown-6,

70oC, 4h

KH, 18-Crown-6,

70oC, 0.5h

MeO

Me

59

Yields

89

Mechanistic Study— Chelation Effect

Chelation–assisted Aromatic AOC Rearrangement

Uyehara, T.; Ueno, M.; seki, K.; Tooya, M.; Sato, T. Tetrahedron Lett. 1998, 39, 8673-8676.

59%

89%

HO

H

H

O

MeO

MeO

HO

Me

Me

H

O OMe

KH, 18-Crown-6,

70oC, 4h

KH, 18-Crown-6,

70oC, 0.5h

MeO

Me

O

O

OMe

MeO

K

K

Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement

Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.

OH

ORPh

3 eq. KH2 eq. 18-Crown-6

THF, rtPh

OR

Oor Ph

ORO

AOC rearrangementR = iPr

ORO

OR

O

Ph Ph

1 M HCl(aq)

O

HO

Ph

OHO

Ph

Intramolecular Aldol

34

72%



OH

ORPh


THF, rtPh

OR

Oor Ph

ORO


ORO

OR

O

Ph Ph

1 M HCl(aq)

O

HO

Ph

OHO

Ph


34



OH

ORPh


THF, rt


1 M HCl(aq)

O

HO

Ph

OHO

Ph


ORO

or Ph ORO

ORO

OR

O

Ph Ph

Ph3

4

69%



OH

ORPh


THF, rt


1 M HCl(aq)

O

HO

Ph

OHO

Ph


ORO

or Ph ORO

ORO

OR

O

Ph Ph

Ph3

4



OH

ORPh


THF, rt

34

Ph

ORO

K

PhORO

K

ORO

Ph

OH

ORPh

34


THF, rt

O

ORPh

Mechanistic Study— Variations of Classic AOC

A Radical Alternative of AOC

One limitation of AOC: two reacting terminals must be in proximity

A scheme of radical alternative to the oxy-Cope rearrangement

Renaud, P.; Giraud, A.; Churd, R. Angew. Chem. Int. Ed. 2002, 22, 4321 –4323.

R1

O

R2

M

(M = Li, MgX)

R1

OH

R2 AOC product

X

OH

X

O

radicalgeneration

β -fragmen-tation XO XO

6-endocyclization

XH

H

OreductionXH

H

O


A Radical Alternative of AOC

Renaud, P.; Giraud, A.; Churd, R. Angew. Chem. Int. Ed. 2002, 22, 4321 –4323.

The tricyclic oxetane approach to form alkoxy radical

Synthetic application — preparation of a tricyclic system

O

Li

87%OH

1) PhSeCl, NEt3, -40 C

2) Bu3SnH, AIBN, Na2CO3 toluene, reflux

70%

H

HH

OH +

H

HH

OH

°

1 : 1

X

OH

X

O

PhSeX

H

H

O

X = CH2 , O

X

O

PhSeCl, NEt3 Bu3SnH, AIBN

53-60% 64-69%


Base effect on AOC: Li Na K

faster rearrangement

no counterion

more 'naked' alkoxide

Phosphazene super-base P4-t-Bu

pKBH =42.6 (in MeCN)

- Soluble in organic solvents- No crown ether required

Hartley, R.C.; Mamdani, H.T. Tetrahedron Lett. 2000, 41, 747-749.Schwesinger, R.; Schlemper, H. Angew. Chem. Int. Ed. Engl. 1987, 11, 1167-1169.

Metal-free Base Induced AOC

PhOH

R

1.1 eq. P4-t-Bu THF-hexane (5:1) 0 C to rt, overnight°

(2) pH 7 bufferR

Ph O

44-58%R = H, Ph

(1)

H PNMe2

Me2NNMe2

N PN

NN

But H

PNMe2

Me2N NMe2

PNMe2

NMe2

NMe2PNMe2

Me2NNMe2

N PNBut

NN

PNMe2

Me2N NMe2

PNMe2

NMe2

NMe2 PNMe2

Me2NNMe2

N PN

NN

But H

PNMe2

Me2N NMe2

PNMe2

NMe2

NMe2

Summary –Mechanistic Study Part

•Why C3-oxy-anionic substituent can accelerate AOC rearrangement?- Weakening of the adjacent C-C bond by oxygen anion

•What kinds of substituents can further accelerate the reaction?- Thioalkoxy group on C4 or C6 position- Additional unsaturated substituents on terminal position

•What is the role of chelation effect in AOC rearrangment?- Change the stereoselectivity of the products- Promote aromatic AOC rearrangement

•What if the AOC precursor does not have the required geometry?- Turn to the radical alternative of AOC

•What’s the alternative base for AOC?- Metal-free phosphazene super-base

Outline

I. IntroductionFrom Cope to Anionic Oxy-Cope (AOC) RearrangementRate-acceleration Effect of C3-Oxy Anionic Substituent

II. Recent Mechanistic Study of AOC RearrangementFurther Mechanistic Study toward Rate-accelerationRole of Chelation Effect in AOCVariations of Classic AOC

III. Recent Synthetic Developments in AOCUsing Transition-metal Complexes to Form AOC PrecursorsAOC-involved Tandem Rearrangement Processes

Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors

ROM/RCM Used in AOC Precursor Synthesis

Snapper, M. L.; Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478-1479.Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.

R'

"R

R R'

"RR

∆

R

R'

"R

O

Me

Me

OO

Me

Asteriscanolide

O O

HOMe

Me

O

9-Deoxyxeniolide A

Me

O

Me O

OMe

Me

HO

Clavirolide A

HO

Cope rearrangement

Grubbs' catalyst

ROM



Snapper, M. L.; Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478-1479.Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.

R'

"R

R R'

"RR

∆

R

R'

"R

O

Me

Me

OO

Me

Asteriscanolide

O O

HOMe

Me

O

9-Deoxyxeniolide A

Me

O

Me O

OMe

Me

HO

Clavirolide A

HO

Cope rearrangement

Grubbs' catalyst

ROM

OHOH



O

R

+

O

n

n'

n

OH

R

O

n'On

n'

O

R

oxy-Copealkylation

E/Z mixture

Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.

n= 1-3n'=1-2

n= 1-3n'=1-2

OTBS

+

CO2Et1) ZrCl42) DIBAL-H

Brnn'

R3)

O

nn'

R

olefin metathesis

n

OH

R

O

n'

On

n'

O

R

oxy-Cope

OTBS

H H

H

H




entry cyclobutene metathesis product yield(%) Cope product yield(%)

OOTBS

H

TBSO O

H

OOTBS

H

TBSOO

H

OOTBS

H

TBSO

H

O

82

82

83

O

HO

O

OH

OH

O

82

82

64

2

3

4

H

H

H

OOTBS

H

TBSO O

H

O

O

89 802.1:1 cis/trans

1

H

H




O

Me

HO

H

O

OH

H

Me

OO

H

H

H

Me

H

O

Me

HHO

O

H

Me

H

O

chair TS

boat TS

not observed

O

O

Me

O

O

Me

H

H

not observed

B

A

H

78%, A:B= 1.8: 1

AOC

OOMe

H

H

OOMe

Palladium Catalysts used in AOC Precursor SynthesisSynthetic Developments-Using Transition-metal Complexes to Form AOC Precursors

O O

RRRR

Meijere, A.; Noltemeyer, M.; Voigt, K.; Zezschwitz, P. Synthesis 2000, 9, 1327-1340.

n

Br

Br

CO2tBu

Pd(OAc)2, PPh3

NEt3, DMF90-100 C, 20h°

n

CO2tBu

CO2tBu

m-CPBA (2equiv.)

24h, 0-20 C° n

CO2tBu

CO2tBu

O

n=1n=2

56%57%

82%74%

Pd2(dba)3 CHCl3

Bu3P/HCO2H/Et3N

n

CO2tBu

CO2tBu

OH KHMDS or KH 18-Crown-6,-78oC

1)

2) EtOH, NH4Cl (aq.), THFO

CO2tBu

CO2tBun

n=1 60% n=2 94%

80%81%

R=CO2tBu

Organozirconcene Reagent Used in AOC Precursor Synthesis


Huang, X. ; Pi, J. Synlett 2003, 15, 2413-2415.

93:7

88:12

82:18

85:15

56:44

50:50

74

81

81

82

82

84

H

CH3

CH3

CH3

C6H5

C6H5

C6H5

C6H5

p-CH3OC6H4

p-BrC6H4

C6H5

p-CH3OC6H4

1

2

3

4

5

6

Ratio (A/B)Yield (%)R2R1Entry

ZrCp2ClO

R2

Me3SiCH2

R1

Me3SiCH2

Cp2Zr(H)ClMe3SiCH2 Zr(Cl)Cp2CH2Cl2

-78-25 C°

1)0 C°

2) NaHCO3

R1 R2

OMe3SiH2C

R2HO R1

+

Me3SiH2C

R2HO R1

A Bmajor minor

Organozirconcene Reagent Used in AOC Precursor SynthesisSynthetic Developments-Using Transition-metal Complexes to Form AOC Precursors

Huang, X. ; Pi, J. Synlett 2003, 15, 2413-2415.

Me3SiH2C

O

R2 R1

TBAF

THF, rt.

OHR2

R1

74-81%

C D82-89%

Me3SiH2C

R2HO R1

A

KH, THF, rt.

R1O

R2CH2SiMe3 H2O

Tandem [2,3]-Wittig-AOC Rearrangement

Earliest Example

Greeves, N.; Vines, K. J. Tetrahedron Lett. 1994 35, 7077-7080.

A

Bu

Ph O

HH

Ph BuO

Bu

Ph O

HH

Ph BuO

O Ph

Bu 18-Crown-6KH

DMSO25 C°

Bu

Ph O

H2O Bu

Ph O

[2,3]-Wittig AOC

58%

O

Ph

Bu

A

Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes

Tandem [2,3]-Wittig-AOC Rearrangement

Greeves, N.; Lee, W.; Mclachlan, S. P.; Oakes, G. H.; Purdie, M; Bickley, J. F. Tetrahedron Lett. 2003, 44, 9035-9038.

Functionalization of the Rearrangement Products

OH 1 eq. KH,1 eq. 18-Crown-6

Ph Br

O 2 eq. KH,

2 eq. 18-Crown-6

Ph

50%

O

Ph

1 eq.

THF, rt.

Etherification

O

Ph

A

[2,3]-Wittig AOC

Ph3P=CHCO2Me

1.3 eq.

THF, reflux

70%

Ph

CO2Me

2 mol% K2OsO4 2H2O1.3 eq. NMO

Acetone/H2O 3:1

Ph

CO2MeOH

HO

73%

3 eq. NaHCO3

3 eq. I2

MeCN

57%

Ph

CO2MeO

HO I

1.5 eq. Bu3SnHAIBN

THF, reflux

88%

Ph

CO2Me

OHO

Me

Ph

CO2Me

OHO

MeH H

Major Minor

+

A


Tandem Brook Rearrangement /AOC: [3+4] Annulation

[3+2] Annulation via Tandem Brook Rearrangement/intramolecualr Carbonyl Addition

Expected [3+4] Annulation

O

X

TBSOLiR

O

R

X

O

TBS

Brook Rearrangement

O

R

X

TBSO

Michael Addition

TBSO

O

R

X

Takeda, K.; Fujisawa, M; Makino, T; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.

O

Me3Si

TBS RLiO

-80 C to -30 C° ° O

O TBS

RMe3Si

BrookRearrangement

O

OTBS

RMe3Si

Carbonyl Addition

Me3SiR

OH

OTBS


84

84

73

82

CHMe2

(CH2)4Me

-(CH2)3-

-(CH2)4-

1

2

3

4

Yield of B (%)REntry

29

11

24

32

CHMe2

(CH2)4Me

-(CH2)3-

-(CH2)4-

1

2

3

4

Yield of C (%)REntry


X=TMS

Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.

O

Me3Si

TBS

+

OLi

R

-80oC to -30oC

THF

TBSO

O

R

SiMe3

O

SiMe3

TBS

(Z)-A+

OLi

R

-80oC to -30oC

THFTBSO

O

R

SiMe3

56

56

B 5,6-syn C 5,6-anti

(E)- A


72

72

42

63

CHMe2

(CH2)4Me

-(CH2)3-

-(CH2)4-

1

2

3

4

Yield of E (%)REntry

14

18

15

11

CHMe2

(CH2)4Me

-(CH2)3-

-(CH2)4-

1

2

3

4

Yield of F (%)REntry


X=SnBu3


O

Bu3Sn

TBS

(E)- D

+

OLi

R

-80oC to -30oC

THF

TBSO

O

R

SnBu3

O

SnBu3

TBS

(Z)- D

+

OLi

R

THFTBSO

O

R

SnBu3

56

56

E 5,6-syn F 5,6-anti

-80oC to -30oC




O

X

TBS

OLi

R

+

O

RO

TBS

X

O

R

X

TBSO

TBSO

OLi

R

XzXEX

R

O

TBSO

O

R

X

TBSO

G

Brook

AOC

Revised Mechanism

RXE

Xz

OOR'3Si

Intermediate observed


Tandem Anionic [ 1,3 ] Sigmatropic/ Oxy-Cope Rearrangement

Seki, K.; Haga, K.; Tadao, U.; Hashimoto, H.; Jin, T.; Karikomi, M. Tetrahedron Lett. 2002, 43, 3633-3636.

OH

Ph

diglymeKHDMS

-78oC

[ 1,3 ] sigmatropic

H

H

Ph

HO

diglymeKHMDS

100 C° PhO

1 2 3 90%

HOO

O

OH

H

OAcO

OH

OAcOBzO H

Taxol

Ph NH

PhO

PhO

4

123

4

AOC




-

-

-

81

23

22

-78/15

145/15

120/60

1

1

2

1

2

3

32

Yield(%)Temp.(°C) / time(min)

SubstrateEntry

Ph

HO

2

OH

Ph

H

H

Ph

HOPh

O

1

[ 1 ,3 ]

2 3

Sigmatropic

3 eq. KHDMS

AOC





24

Trace

38

86

32

42

-

-

50/120

100/60

100/15

-40/30→100/15

4a ( R2=H )

4a ( R2=H )

4b ( R2=Me )

4b ( R2=Me )

1

2

3

4

65

Yield(%)Temp.(°C) / time(min)SubstrateEntry

Reactivity Toward AOC: Ph

HO

>

HO

>Ph

HO

Ph

5b 5a 2

OHR2

Ph

H

R2

Ph

HO

R2

PhO

4 5 6

[ 1, 3 ]Sigmatropic

3 eq. KHDMS

AOC

Summary–Synthetic Application Part

Transition Metal Complexes Can Help Forming AOC Precursors in a Stereocontrolled Fashion

-ROM/RCM

-Twofold Heck Reaction/ Hydrogenation

- Organozirconcene Reagent

AOC-involved Tandem Rearrangement Processes - Waiting for Further Application into Total Synthesis

-Tandem [2,3]-Wittig-AOC rearrangement

-Tandem Brook /AOC Rearrangement

-Tandem Anionic [ 1,3 ]/ Oxy-Cope Rearrangement

Acknowledgement

Dr. Tepe

Dr. Wagner

Professors

Friends

Yu

Zhenjie

Yana

Tao

Jun

Lei

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