the claisen rearrangement

57
The Claisen Rearrangement Lecture Notes O O O Key Reviews: F. E. Zeigler, Chem. Rev. 1988, 88, 1423. P. Wipf in Comprehensive Organic Synthesis, 1991, vol. 5, p. 827. A. M. Castro, Chem. Rev. 2004, 104, 2939. [3,3]

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Page 1: The Claisen Rearrangement

The Claisen RearrangementLecture Notes

O O O

Key Reviews:

F. E. Zeigler, Chem. Rev. 1988, 88, 1423.

P. Wipf in Comprehensive Organic Synthesis, 1991, vol. 5, p. 827.

A. M. Castro, Chem. Rev. 2004, 104, 2939.

[3,3]

Page 2: The Claisen Rearrangement

[3,3]-Rearrangements: The Claisen and Cope Reactions/Rearrangements

J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435.

O O

OO[Cope

rearrangement]

[Claisenrearrangement]

Δ

Page 3: The Claisen Rearrangement

O O

The Claisen Reaction: Initial Discovery

CO2Me distillationNH4Cl

CO2Me

L. Claisen, Chem. Ber. 1912, 45, 3157.

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

R1

O

X

R2

R3

Reaction can be regarded as the sigmatropic homologation of an allylic alcohol,meaning the migration of a sigma bond across a conjugated pi system to a new position.

Bonds Broken2 C C1 C O

Bonds FormedC CC OC C

111

[3,3]

Page 4: The Claisen Rearrangement

O O

The Claisen Reaction: Initial Discovery

CO2Me distillationNH4Cl

CO2Me

L. Claisen, Chem. Ber. 1912, 45, 3157.

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

R1

O

X

R2

R3

Reaction can be regarded as the sigmatropic homologation of an allylic alcohol,meaning the migration of a sigma bond across a conjugated pi system to a new position.

Bonds Broken2 C C1 C O

Bonds FormedC CC OC C

111

[3,3]

Page 5: The Claisen Rearrangement

The Claisen Reaction: Why is it So Useful?

L. Claisen, Chem. Ber. 1912, 45, 3157.

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

R1

O

X

R2

R3[3,3]

1. Experimental procedures are very reliable

2. Compatible with a wide range of functional groups

3. Substrates are readily made, and the δ,γ-unsaturated product can be chemoselectively adjusted at either end (alkene or carbonyl) to give further materials

4. High stereoselectivity in formation of double bonds and chiral centers.

OO O O

Key points:

Page 6: The Claisen Rearrangement

The Claisen Reaction: Why is it So Useful?

L. Claisen, Chem. Ber. 1912, 45, 3157.

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

R1

O

X

R2

R3[3,3]

1. Experimental procedures are very reliable

2. Compatible with a wide range of functional groups

3. Substrates are readily made, and the δ,γ-unsaturated product can be chemoselectively adjusted at either end (alkene or carbonyl) to give further materials

4. High stereoselectivity in formation of double bonds and chiral centers.

OO O O

Key points:

Page 7: The Claisen Rearrangement

The Claisen Reaction: Why is it So Useful?

L. Claisen, Chem. Ber. 1912, 45, 3157.

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

R1

O

X

R2

R3[3,3]

1. Experimental procedures are very reliable

2. Compatible with a wide range of functional groups

3. Substrates are readily made, and the δ,γ-unsaturated product can be chemoselectively adjusted at either end (alkene or carbonyl) to give further materials

4. High stereoselectivity in formation of double bonds and chiral centers.

OO O O

Key points:

Page 8: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435.

OH R

MeO OMe

R = H, Me, alkyl

p-TsOH,xylene, Δ

O

R OMe

O

R

O

R

Potential drawbacks

Competing acid-catalyzed reactions with resident functional groups

If R is an alkyl group other than methyl, regiochemicalproblems in vinyl ether synthesis can occur

[3,3]

Page 9: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

S. D. Burke and co-workers, Strategies and Tactics in Organic Synthesis 1987, 2, 57.

OH

Hg(OAc)2O

OEtHgOAcOEt

-[EtOHgOAc]

O O[3,3]

A much milder procedure for cases where substrates cannot tolerate acid and heat;in the case below it succeeded where others failed.

HH

OH

OO

Hg(OAc)2,

OEt

o-xylene,240 oC,

sealed tube

HH

OO

O

Δ

Page 10: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

S. D. Burke and co-workers, Strategies and Tactics in Organic Synthesis 1987, 2, 57.

OH

Hg(OAc)2O

OEtHgOAcOEt

-[EtOHgOAc]

O O[3,3]

A much milder procedure for cases where substrates cannot tolerate acid and heat;in the case below it succeeded where others failed.

HH

OH

OO

Hg(OAc)2,

OEt

o-xylene,240 oC,

sealed tube

HH

OO

O

Δ

Page 11: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

P. T. Lansbury, N. Y. Wang, J. E. Rhodes, Tetrahedron Lett. 1971,12, 1829 and 1833F. Johnson, K. G. Paul, D. Favaro, R. Ciabatti, U. Guzzi, J. Am. Chem. Soc. 1982, 104, 2198.

OMeO2C

H

H

ClOH

MeO OMe

p-TsOH, Δ

In both cases the Claisen reaction occurs on the more accessible, convex face of the molecule

OMeO2C

H

H

Cl

OMeO2C

H

H

Cl

CN

O

KH,Br

CN

O

NC

O

Li, NH3;MeI

[3,3]

[3,3]

Page 12: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

P. T. Lansbury, N. Y. Wang, J. E. Rhodes, Tetrahedron Lett. 1971,12, 1829 and 1833F. Johnson, K. G. Paul, D. Favaro, R. Ciabatti, U. Guzzi, J. Am. Chem. Soc. 1982, 104, 2198.

OMeO2C

H

H

ClOH

MeO OMe

p-TsOH, Δ

In both cases the Claisen reaction occurs on the more accessible, convex face of the molecule

OMeO2C

H

H

Cl

OMeO2C

H

H

Cl

CN

O

KH,Br

CN

O

NC

O

Li, NH3;MeI

[3,3]

[3,3]

Page 13: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

XXX, Tetrahedron Lett. 1971, 1829 and 1833XXX, J. Am. Chem. Soc. 1982, 104, 2198.

HO O HOO

OH OH O

Aromaticity can be broken through the Claisen rearrangement

Brbase,

[3,3] [Keto-enol

tauto-merization]

Page 14: The Claisen Rearrangement

The Claisen Reaction: Substrate Preparation

XXX, Tetrahedron Lett. 1971, 1829 and 1833XXX, J. Am. Chem. Soc. 1982, 104, 2198.

HO O HOO

OH OH O

Aromaticity can be broken through the Claisen rearrangement

Brbase,

[3,3] [Keto-enol

tauto-merization]

Page 15: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

P. A. Bartlett, Tetrahedron 1980, 36, 2.

O O

O

OO O O

O O

OO O

Reactions proceed through chair-like transition states

[3,3]

[3,3]

[3,3]

Page 16: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

P. A. Bartlett, Tetrahedron 1980, 36, 2.

O O

O

OO O O

O O

OO O

Reactions proceed through chair-like transition states

[3,3]

[3,3]

[3,3]

Page 17: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

P. A. Bartlett, Tetrahedron 1980, 36, 2.

O O

O

OO O O

O O

OO O

Reactions proceed through chair-like transition states

[3,3]

[3,3]

[3,3]

Page 18: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

L. Claisen, Chem. Ber. 1912, 45, 3157.

O

Me

OMeOMe

O Me

Pre-existing chirality determines the stereoselectivity of the rearrangement

MeH Me

H

MeH Me

OMe

HMe O

Me

Me

HMe OMe

As a general rule, unless there are strange geometrical constraints(i.e. the reaction proceeds in a chair, not a boat, transition state),

E-olefins result from the Claisen rearrangement

[3,3]

[3,3]

Page 19: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

L. Claisen, Chem. Ber. 1912, 45, 3157.

O

Me

OMeOMe

O Me

Pre-existing chirality determines the stereoselectivity of the rearrangement

MeH Me

H

MeH Me

OMe

HMe O

Me

Me

HMe OMe

typicallynot observed

As a general rule, unless there are strange geometrical constraints(i.e. the reaction proceeds in a chair, not a boat, transition state),

E-olefins result from the Claisen rearrangement

majorproduct

[3,3]

[3,3]

Page 20: The Claisen Rearrangement

XX

The Claisen Reaction: Stereochemical Considerations

C. L. Perrin, D. J. Faulkner, Tetrahedron Lett. 1969, 2783.

O

Me

OMeOMe

O Me

Pre-existing chirality determines the stereoselectivity of the rearrangement

MeH Me

H

MeH Me

OMe

HMe O

Me

Me

HMe OMe

X

X

X = H, E/Z = ~9:1X = OEt or NMe2, E/Z = >99:1

X

X

X

Preference for equatorial position of substituents correlates with A-values

[3,3]

[3,3]

Page 21: The Claisen Rearrangement

XX

The Claisen Reaction: Stereochemical Considerations

C. L. Perrin, D. J. Faulkner, Tetrahedron Lett. 1969, 2783.

O

Me

OMeOMe

O Me

Pre-existing chirality determines the stereoselectivity of the rearrangement

MeH Me

H

MeH Me

OMe

HMe O

Me

Me

HMe OMe

typicallynot observed

majorproduct

X

X

X = H, E/Z = ~9:1X = OEt or NMe2, E/Z = >99:1

X

X

X

Preference for equatorial position of substituents correlates with A-values

[3,3]

[3,3]

Page 22: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

A. S. Franklin, L. E. Overman, Chem. Rev. 1996, 96, 505

Pre-existing chirality determines the stereoselectivity of the rearrangement,even if multiple substituents are present

MeOBn

MeO

OMe

LDA, HMPA;TBSCl

MeOBn

MeO

OTBSMe

OMe

Me

TBSO

MeOBn

OMe

Me

TBSO

MeOBn

Me

MeMe

O

TBSOOBn

MeOH,HCl

(90%overall)(7:1 d.r.)

Me

MeMe

O

MeOOBn

-78 oCto 23 oC

[3,3]

Page 23: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

A. S. Franklin, L. E. Overman, Chem. Rev. 1996, 96, 505

Many different ways to access chiral allylic alcohols:

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

[3,3]

* *

Chiral pool building block

Resolution of achiral starting material

Asymmetric reduction of α,β-unsaturated system

Page 24: The Claisen Rearrangement

The Claisen Reaction: Stereochemical Considerations

A. S. Franklin, L. E. Overman, Chem. Rev. 1996, 96, 505

Many different ways to access chiral allylic alcohols:

R1 R2

OH

R1 R2

O R3X

R1 R2

O R3X

[3,3]

* *

Chiral pool building block

Resolution of achiral starting material

Asymmetric reduction of α,β-unsaturated system

Page 25: The Claisen Rearrangement

The Roche Synthesis of α-Tocopherol

J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435.

OH

OH

OH

Na, NH3

Lindlarreduction

OH

OH

[resolution]

Page 26: The Claisen Rearrangement

X

The Roche Synthesis of α-Tocopherol

J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435.

OH

OH

O

O

X

X

X = OMe, OTBS, or NMe2O

X

O

O

X

Δ

Δ

97-99% e.e.

[3,3]

[3,3]

Page 27: The Claisen Rearrangement

The Roche Synthesis of α-Tocopherol

J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435.

O

X97-99% e.e.

OH

[Repeat of process]

O

X94-99% e.e.

O

OH

α-tocopherol

Page 28: The Claisen Rearrangement

The Johnson Orthoester Claisen Rearrangement: A Useful Variant of the Claisen Reaction

W.S. Johnson, L. Werthemann, W.R. Bartless, T.J. Brocksom, T.-T. Li, D. J. Faulkner, M.R. Petersen,J. Am. Chem. Soc. 1970, 92, 741.

OEt

EtO OEt

OEt

EtO OEt

OEt

OEtacid

acid, ΔR

OH

R

O OEtOEt

R

O OEt

R

O OEt

R

O

OEt

R

O

OEt

[3,3]

Page 29: The Claisen Rearrangement

The Johnson Orthoester Claisen Rearrangement: Key Stereochemical Difference from Eschenmoser Variant

XXX, Chem. Ber. 1971, 104, 3679.

OEt

EtO OEt

Δ

EtOEtO

O

R

ORO

RO

RH

~50%

OEt

X

OH

RO

R

OEt

O

R

OEt

or

EtOEtO

O

R

ORO

RO

RH

~50%

OEt

X

H

H

Stereocontrol can become a concern with non-methyl alkyl chains

Page 30: The Claisen Rearrangement

The Johnson Orthoester Claisen Rearrangement: Key Stereochemical Difference from Eschenmoser Variant

XXX, Chem. Ber. 1971, 104, 3679.

OEt

EtO OEt

Δ

EtOEtO

O

R

ORO

RO

RH

OEt

X

OH

RO

R

OEt

O

R

OEt

or

EtOEtO

O

R

ORO

RO

RH

OEt

X

H

H

Stereocontrol can become a concern with non-methyl alkyl chains

Page 31: The Claisen Rearrangement

The Johnson Orthoester Claisen Rearrangement: Key Stereochemical Difference from Eschenmoser Variant

XXX, Chem. Ber. 1971, 104, 3679.

OEt

EtO OEt

Δ

EtOEtO

O

R

ORO

RO

RH

~50%

OEt

X

OH

RO

R

OEt

O

R

OEt

or

EtOEtO

O

R

ORO

RO

RH

~50%

OEt

X

H

H

Stereocontrol can become a concern with non-methyl alkyl chains

Page 32: The Claisen Rearrangement

Johnson Orthoester Claisen Rearrangements in Synthesis

B. Lythgoe, D. A. Roberts, I. Waterhouse, J. Chem. Soc., Perkin Trans. 1 1977, 2608.

HO

OHOMe

HA,xylene, Δ O

O O

O

O

O

OEt

EtO

CO2EtEtO2C

[3,3]

xylene, Δ[3,3]

squalene

Page 33: The Claisen Rearrangement

Johnson Orthoester Claisen Rearrangements in Synthesis

B. Lythgoe, D. A. Roberts, I. Waterhouse, J. Chem. Soc., Perkin Trans. 1 1977, 2608.

HO

OHOMe

HA,xylene, Δ O

O O

O

O

O

OEt

EtO

CO2EtEtO2C

[3,3]

xylene, Δ[3,3]

squalene

Page 34: The Claisen Rearrangement

Johnson Orthoester Claisen Rearrangements in Synthesis

B. Lythgoe, D. A. Roberts, I. Waterhouse, J. Chem. Soc., Perkin Trans. 1 1977, 2608.

O

HBzO

OH

HBzO

OH

HBzO

HBzO

CO2Et

HOWindaus-Grundman ketone

OEt

EtO OEtacid, Δ[3,3]

how? and/or

Page 35: The Claisen Rearrangement

OMe

Johnson Orthoester Claisen Rearrangements in Synthesis

G. Stork, S. Raucher, J. Am. Chem. Soc. 1975, 98, 1583.

OHO

O O

Me MeO O

Me Me

OOH

O

OMe

O O

Me Me

OO

O

OMe

MeO

OMe

MeO OMe

propanoic acid,140 oC

O

O

O

O

O

OMe

MeMeO O

OO

OMe

MeO2C

Me

OH

OCO2Me

(+)-prostaglandin A2

[3,3]

(86%)

how?

Page 36: The Claisen Rearrangement

Johnson Orthoester Claisen Rearrangements in Synthesis

C. B. Chapleo, P. Hallett, B. Lythgoe, I. Waterhouse, P. W. Wright, J. Chem. Soc., Perkin Trans. 1 1977, 1211.

O

EtO OEtMe

BzOOH

+

Me

BzOO

O

propanoic acid, xylene, Δ

BzO Me

OO

O

boat t.s. forced byconstraint of rings BzO

O

OHO

=

boat t.s.

Page 37: The Claisen Rearrangement

S. A. Snyder, Z. Tang, R. Gupta, J. Am. Chem. Soc. 2009, 131, 5744.

HO O

MeO OO

MeMe

ClCl

MeO O

MeO OO

MeMe

OHCl

MeO O

MeO OO

MeMe

OCl

OMe

CH3C(OMe)3, toluene (1:20),propionic acid, 130 °C, 15 h

3. PTSA

1. KOAc, 18-Crown-62. NaH, Me2SO4

(84%overall)

MeO O

MeO OO

MeMe

Cl

CO2Me

[Johnson-Claisenrearrangement]

(72%)

First example of a Claisenrearrangement creating

a quaternary carbon nextto a glycal oxygen

Johnson Orthoester Claisen Rearrangements in Synthesis

Page 38: The Claisen Rearrangement

The Eschenmosher Amide Acetal Rearrangement: A Useful Variant of the Claisen Reaction

A. Eschenmoser, Helv. Chim. Acta. 1964, 47, 2425.

N

OH

Bz

NMe2

MeO OMe

NMe2

MeO OMe

NMe2

OMeacid

acid, Δ

N

O

Bz

NMe2OMe

N

O

Bz

NMe2

N

O

Bz

NMe2

N

O

Bz

NMe2

NBz

NMe2

O [3,3]

Page 39: The Claisen Rearrangement

The Eschenmosher Amide Acetal Rearrangement: A Useful Variant of the Claisen Reaction

W. Sucrow, W. Richter, Chem. Ber. 1971, 104, 3679.

NMe2

MeO OMe

Δ

Me2NMe2N

O

R

ORO

RO

RH

NMe2

X

OH

RO

R

NMe2

O

R

NMe2

or

Me2NMe2N

O

R

ORO

RO

RH

NMe2

X

H

H

Stereocontrol can become a concern with non-methyl alkyl chains

Page 40: The Claisen Rearrangement

The Eschenmosher Amide Acetal Rearrangement: A Useful Variant of the Claisen Reaction

W. Sucrow, W. Richter, Chem. Ber. 1971, 104, 3679.

NMe2

MeO OMe

Δ

Me2NMe2N

O

R

ORO

RO

RH

~95%

NMe2

X

OH

RO

R

NMe2

O

R

NMe2

or

Me2NMe2N

O

R

ORO

RO

RH ~5%

NMe2

X

H

H

Stereocontrol can become a concern with non-methyl alkyl chains

Page 41: The Claisen Rearrangement

The Eschenmosher Amide Acetal Rearrangement: A Useful Variant of the Claisen Reaction

F. E. Zeigler, J. M. Fang, C. C. Tam, J. Am. Chem. Soc. 1982, 104, 7174.H. F. Strauss, A. Wiechers, Tetrahedron 1978, 34, 127.

HO

OHH

NMe2

MeO OMe

Δ

HO

HO

NMe2

MeO

S

S

HO S

S

NMe2

MeO OMe

Δ

MeO

Me2N O

MeO

Me2N O

O-methyljoubertiamine

(71%)

[3,3]

[3,3]

Page 42: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

OOHOTMS

O

OTMS

O

Key feature of chemistry is the ability to control enolate

geometry to then controlthe formation of either syn-

or anti- products

OH

O

OH

O

O

OH

O

OH

Z-enolate E-enolate

Work out the transition statesfor these on your own!

Base;TMSCl and/or

[3,3] [3,3]

Page 43: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

OOHOTMS

O

OTMS

O

Key feature of chemistry is the ability to control enolate

geometry to then controlthe formation of either syn-

or anti- products

OH

O

OH

O

O

OH

O

OH

Z-enolate E-enolate

Work out the transition statesfor these on your own!

Base;TMSCl and/or

[3,3] [3,3]

Page 44: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

O

OTMS

O

OTMS

O

Z-enolate

E-enolate

LDA, THF,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

A1,2-strain 1,3-diaxial interaction

givesanti-

product

O

O

LDA, THFHMPA orDMPU,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

1,3-diaxial interaction

givessyn-

product

A1,2-strain

or

or

Page 45: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

O

OTMS

O

OTMS

O

Z-enolate

E-enolate

LDA, THF,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

A1,2-strain 1,3-diaxial interaction[more favorable]

usually4:1 to 8:1

givesanti-

product

O

O

LDA, THFHMPA orDMPU,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

1,3-diaxial interaction

givessyn-

product

A1,2-strain

or

or

Page 46: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

O

OTMS

O

OTMS

O

Z-enolate

E-enolate

LDA, THF,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

A1,2-strain 1,3-diaxial interaction[more favorable]

usually4:1 to 8:1

givesanti-

product

O

O

LDA, THFHMPA orDMPU,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

1,3-diaxial interaction

givessyn-

product

A1,2-strain

or

or

Page 47: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, R. H. Mueller, J. Am. Chem. Soc. 1972, 94, 5897.R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc. 1976, 98, 2868.

O

O

OTMS

O

OTMS

O

Z-enolate

E-enolate

LDA, THF,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

A1,2-strain 1,3-diaxial interaction[more favorable]

usually4:1 to 8:1

givesanti-

product

O

O

LDA, THFHMPA orDMPU,-78 oC

O

LiN H

OR

H RO

LiN H

OR

R H

1,3-diaxial interaction usually> 8:1

[decreasesdegree of

lithium coordination]

[now looser and preferred][could even be acyclic t.s.]

givessyn-

product

A1,2-strain

or

or

Page 48: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Use of Enolates to Generate Well-Defined Precursors

R. E. Ireland, P. Wipf, J. D. Armstrong, J. Org. Chem. 1991, 56, 650.

O

OO

HO H

O

HO H

A: syn-product B: anti-product

Enolization conditions A B

LDA, 23% HMPA/THF

LDA, 45% DMPU/THF

LDA, THF

90

98

25

10

2

75

1. Enolization2. TBSCl; Δ3. NaOH, H2O

Remember: in cyclic systems boat-like transition states are possible. Here, the Z-enolate formed from the use of HMPA and DMPU likely goes through such a transition state. The

standard chair should be favored with the formation of the E-enolate.

and/or

Page 49: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Applications in Complex Molecule Synthesis

R. E. Ireland, J. P. Vevert, J. Org. Chem. 1980, 45, 4259.

O

OHHO OH

HO OH

D-mannose O

OOMOM

O

O

OOMOM

OTMS

E-enolate

O

OOMOM

TMSO

boat t.s.

O

OMOM

H H

O

HOOH H

O

HO OH

(–)-nonactic acid

LDA,THF;

TMSCl

25 oC

[3,3]

Page 50: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Applications in Complex Molecule Synthesis

R. E. Ireland, M. D. Varney, J. Org. Chem. 1986, 56, 635.

CO2H

OH

OO

Me

Me

H

OO

HO

(–)-chlorothricolide

OSEM

OMOM

OO

Me

Me

H

OO

MeOHO2C

O

OSEM

OMOM

OO

Me

Me

H

OO

MeOO

KHMDS,THF, HMPA;

TMSCl(50-72%)

[3,3]

Page 51: The Claisen Rearrangement

The Ireland-Claisen Rearrangement: Applications in Complex Molecule Synthesis

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

THPO

OO

TBS

OBnTBSO

THPO

OOTBS OBn

TBSOxylene, Δ

[Brookrearrangement]

Z-enolate

(6:1 d.r.)

THPO

TBSO

OBn

OTBSO

O

O

HO

H

ophiobolin C

[3,3]

Page 52: The Claisen Rearrangement

The Carroll Rearrangement: An Early Variant of the Claisen Reaction

M. F. Carroll, J. Am. Chem. Soc. 1940, 62, 704.

MeO

OO HO

base or acid,Δ

O

OOH

or O

OO

O

OOH

or O

OOO

[-CO2]

[3,3]

Page 53: The Claisen Rearrangement

The Buchi-Claisen Rearrangement: A Method for the Preparation of Certain Cyclohexenes

G. Buchi, J. E. Powell, J. Am. Chem. Soc. 1970, 92, 3126.

OO

PPh3O

OO

O

Reaction process must proceed via a boat transition state

O O

low yield at best

O

Cis-oriented exocyclic olefins afford poor yields of productReaction temperatures are high

425 oC

sealed tube

O OO

major minor

[3,3]

425 oC

sealed tube

[3,3]

[Diels-Alder]

and

Page 54: The Claisen Rearrangement

The Buchi-Claisen Rearrangement: A Method for the Preparation of Certain Cyclohexenes

G. Buchi, J. E. Powell, J. Am. Chem. Soc. 1970, 92, 3126.

OO

PPh3O

OO

O

Reaction process must proceed via a boat transition state

O O

low yield at best

O

Cis-oriented exocyclic olefins afford poor yields of productReaction temperatures are high

425 oC

sealed tube

O OO

major minor

[3,3]

425 oC

sealed tube

[3,3]

[Diels-Alder]

and

Page 55: The Claisen Rearrangement

The Buchi-Claisen Rearrangement: A Method for the Preparation of Certain Cyclohexenes

G. Buchi, J. E. Powell, J. Am. Chem. Soc. 1970, 92, 3126.

OO

PPh3O

OO

O

Reaction process must proceed via a boat transition state

O O

low yield at best

O

Cis-oriented exocyclic olefins afford poor yields of productReaction temperatures are high

425 oC

sealed tube

O OO

major minor

[3,3]

425 oC

sealed tube

[3,3]

[Diels-Alder]

and

Page 56: The Claisen Rearrangement

A Modified Buchi-Claisen Rearrangement: Large Ring Synthesis

W. A. Kinney, M. J. Coghlan, L. A. Paquette, J. Am. Chem. Soc. 1984, 106, 6868.

O

O

H

O

H

Tebbereagent 200 oC

H

O

H

H

O

*

(38%)[3,3]

precapnelladiene

O

H

TL 1990, 31, 6799

Page 57: The Claisen Rearrangement

The Danishefsky-Claisen Rearrangement: Combining the Virtues of the Buchi- and Ireland-Claisen Reactions

S. J. Danishefsky, R. L. Funk, J. F. Kerwin, J. Am. Chem. Soc. 1980, 102, 6889.

O O

OTBS OTBSR

O

R

OLDA,

TBSCl O

R

TBSOR R

O

TBSO105 oC

O

O

O

TBSO

O

HOLDA,

TBSCl 105 oC

toluene

toluene;HCl/H2O

[3,3]

[3,3]