D. A.

Evans

Pericyclic Reactions: Part5

! Other Reading Material:

Chem 206

http://www.courses.fas.harvard.edu/colgsas/1063

Chemistry 206 Advanced Organic Chemistry

Lecture Number 15

Pericyclic Reactions5
! Claisen Rearrangements & Variants

Enders, D.; Knopp, M.; Schiffers, R. "Asymmetric [3.3]-sigmatropic rearrangements in organic synthesis." Tetrahedron: Asymmetry 1996, 7, 1847-1882 Ziegler, F. E. "The Thermal Aliphatic Claisen Rearrangement." Chem. Rev. 1988, 88, 1423. Gajewski, J. J. "The Claisen rearrangement. Response to solvents and substituents: The case for both hydrophobic and hydrogen bond acceleration in water and for a variable transition state." Acc. Chem. Res. 1997, 30, 219-225. Tietze, L. F. "Domino reactions in organic synthesis." Chem. Rev. 1996, 96, 115-136. Parsons, P. J.; Penkett, C. S.; Shell, A. J. "Tandem reactions in organic synthesis: Novel strategies for natural product elaboration and the development of new synthetic methodology." Chem. Rev. 1996, 96, 195-206.

! Problems of the Day:

Propose a mechanism for this transformation
N O Cl O Me Me EtN(iPr)2 TiCl4 O N Me O Me

! Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations
Wipf, P. Claisen Rearrangements.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 827. (handout)

MacMillan, JACS 1999, 121, 9726

Problem 816. As part of a program directed toward the synthesis of the pinnatoxins, Pelc and Zakarian reported the single-pot conversion of sulfone A into cyclohexene B (OL, 2005, 7, 1629). Using clear threedimensional representations please provide a concise mechanism for this transformation and predict the stereochemical outcome.
Me PivO Me Me PMBO PMBO O O Me O Me S O (EtO)3P 91% yield 150 oC Me O O O Me OH PivO Me Me

D. A. Evans

Monday October 23, 2006

D. A. Evans

Pericyclic Reactions: Part5

Chem 206

Propose a mechanism for this transformation

N O Cl O Me Me EtN(iPr)2 TiCl4 O N Me O Me

Problem 816. As part of a program directed toward the synthesis of the pinnatoxins, Pelc and Zakarian reported the single-pot conversion of sulfone A into cyclohexene B (OL, 2005, 7, 1629). Using clear three-dimensional representations please provide a concise mechanism for this transformation and predict the stereochemical outcome. R1 R2
O S O

Ar

(EtO)3P 150 oC

R1 R2
OH O 91% yield

MacMillan, JACS 1999, 121, 9726

R3

R3

EtN(iPr)2 O C H
N O Me O N Me (Z) Enolate Me
R1 R2

Identilfy Claisen retron

Me

R2
O

R1

H S(O)Ar

R3

S O

Ar

O R3 H

[3,3]
Ar R1 S O

H N Me R

O Me

H N Me R

O Me

R2
O

R2
R3

R1

equivalent to:

H S(O)Ar

O R3

[2,3]
R1 R2
O

Key to Problem solution:

O N O Me
O C C H

S O

Ar

R1
(EtO)3P

Me

R2
O

disfavored
Et

OH R3

R3

favored

D. A. Evans
R2 R1 X Y R3 R2

Allylic Rearrangements via [3,3] Processes

Me Me O OTBS 138 C Me TBSO HN O CF3 20 h TBSO Me O Me O

Chem 206

[3, 3]

R1 X Y

R3

X = C, N, O, S

OTBS Me HN O CF3

90% as a single isomer

X = O; Y = N:
The Trichloroacetimidate Rearrangement, Overman, JACS 1974, 96, 597
R O Cl3C CN O N CCl3 R heat O H CCl3 N H R

steps

Thomas, Chem. Commun 1989 717

O OH RO OH NH2 O N H HN CO2H O N CH2OH HO OH NH2 OH O OH

H3O+

This reaction is also catalyzed by Hg(II) ion

C3H7 OH CCl3 C3H7 HN O Hg(OTFA)2 THF, 0 C (or 138 C, 9 h) R Me
MeO

C3H7

OH OH

The polyoxins (antifungal antibiotics)

79%
HN O CCl3

The "Burgess Reagent" is normally used for alcohol dehydration

O N O S O O MeO N S

however, rearrangement is obsteved with allylic alcohols

+
NEt3 Me Et OM O MeO2C N Me O S O MeO2C Et Me N Et

Hg(OTFA)2 Me Me Me OH THF, 0 C (or 138 C, 6 h)

79%
HN O CCl3

For an excellent review see: Overman, Angew. Chem. Int. Ed. 1984, 23, 579
NHBoc Me HN O CCl3 Me O BnO Me Me O O heat HN O CCl3 BnO Me O PdCl2(MeCN)2 THF, 25 C, 3h Me HN O CCl3 NHBoc

+ NEt3
O

OM

E. Burgess, JACS 1970, 92, 5224

A new approach to the synthesis of !-amino acids

99% anti (45-62%)
R O N O R' O Me LDA R N OLi O R N H H Me H3 O+ OLi N O R' Me R N OLi OLi N O Me

Gonda, Synthesis 1993 729

R'HN

a 1:1 mixture was obtained

HN O CCl3

Endo, SynLett 1991 649 This may not be a concerted process

Saksena, JOC 1986 51, 5024

R'

moderate yields

Problem 108. The fumagillin natural products possess several interesting biological properties including antibiotic activity against Staphylococcus auereus. In Sorensen's recent synthesis of fumagillol (Angew. Chem, Int. Ed. 1999, 38, 971), intermediate 1 was transformed into its a-oxygenated counterpart 3 through the indicated reaction sequence. CHO Me Me Me 1 O O Me Me RNHOH H2O acetyl chloride Et3N O O Me Me X AcO H Me Me Me 2 X = NR 3 X=O H3O+

Me

Me Me H

MeO OR

fumagillol

In the space below, identify the structure of intermediate A and provide a mechanism for the transformation of 1 into 2.
R CHO Me Me Me R' O O Me Me O Me
Me OAc R R N O O Me Me R torsional control O N O R O O Me Me [3,3]

R OH R' - H2O O N H R'

Me O Cl Me O O R N H R'

RNHOH

HO

O Me

O O Me
O Me O

Me

=
R N O

O Me H R'

Me

O Me Me

D. A. Evans

Johnson & Eschenmoser Claisen Rearrangements

Johnson Orthoester Claisen

Chem 206

Eschenmoser-Claisen
Eschenmoser, A. Helv. Chem. Acta 1964, 47, 2425; Helv. Chim.Acta 1969, 52, 1030.
Xylene, 150oC

! Lead paper: Johnson, Faulkner, Peterson, JACS 1970, 92, 741

OEt OH Me C OEt OEt
EtCO2H (cat) !

Me EtO

O OEt O O OEt

OH

Me Et2N

OMe OMe

O NEt2

O Et2N
Me Me
Et Me

O NEt2
H H

! Compare the two variants:

Me Me
CH3C(OEt)3

OEt

OMe
NMe2 Et O Me
Faulkner and Peterson

NMe2 Me

CH3CH2CO2H (cat)

EtO2C 92% (E:Z = 98:2)

CH3C(NMe2)(OMe)2

Et O

OH
60% Hg(OAc)2, EVE

138oC

OH

Xylene, 110oC

High yield, E:Z = 99:1 Me O Me CO2Me 70%

CO2Me

Me

Me
98oC

Me OHC

Me

Me Me

CH2=C(OMe)(NEt2) Xylene, 140oC, 14h

Me2N

98% (E:Z = 86:14)

OH

! Synthesis of Amide Acetals

The Saucy Marbet Alternative

OMe Me Me OH Me Me
H3PO4 or TsOH 125oC

Et
O Me Me
BF4 + O Et
-

O Me NMe2 Et2O Me

OEt
NaOEt NMe2 EtOH +

EtO Me

OEt NMe2

Me O 94% Me

Et

! Reactions to ponder:
C3H5
Me Me CHO

Me

R Me OLi N Me O Me OLi N

Me

Me Me

OH

Me

OEt
H3PO4 125oC

Me Me

Me 60% Me Me

+N Me OMe + N Et

OMe

diastereoselection 6:1 Predict the major diastereomer

Stevenson, Tet. Let. 1991, 32, 4199 Me

Me

Me

Saucy, Marbet, Helv. Chim. Acta 1967, 50, 2091,2095

CMe2(OBn)

Predict the major diastereomer Me Welch, JACS 1987, 109, 6716 CMe2(OBn)

D. A. Evans

Applications of the Claisen Rearrangement

Chem 206

The Johnson Squalene Synthesis: JACS 1970, 92, 741

Me Me Me Me ! ! Me Me Me Me

The Faulkner Juvenile Hormone Synthesis: JACS 1973, 95, 553

Et Me O Et Me CO2Me

Cecropia Juvenile Hormone

Observations: Molecule contains an obvious symmetry plane The trisubstituted C=C's are the issue
! OHC ! Me ! Me OH Li Me ! EtO2C ! Me Me CO2Et ! Me OH MeC(OEt)3 EtCO2H 138 C

HO Me

Et

Et

Me CO2Me

OH
CHO

HO Me

Et
3

Et

Me CO2Me
6

Et
6

Me CO2Me

Me LiAlH4 CrO3-pyr Li MeC(OEt)3 EtCO2H 138 C Me ! CO2Et ! Me

LiAlH4 CrO3-pyr Me Me ! CHO ! Me Me Me

1O

Me CO2Me OH OMe H+ 110 C

Et

Me CO2Me O

OR

Me

87% (E)-(E) 97%

Me EtO2C

Et
6

Me CO2Me

Et Et

85-90% (E)

Me

NaBH4
Et
6

Me CO2Me
H+ 110 C Et
6

Me CO2Me OMe OMe

OHC

Et Et
3

OR

Me Me CO2Me

OH Me

Me Me Me Me Me ! !

PPh3

HO Me

Et

Et

OR

Me

6 1O

Me

HO NaBH4 Me

Et

Et

Me CO2Me

Me

Me

Me

Isomeric purity is Ca 95%

nonselective [H]

OH

TSCl/pyr MeONa

Cecropia Juvenile Hormone

D. A. Evans

Claisen Rearrangement & Chirality Transfer

R1 O
H H

Chem 206

Chirality transfer via the Claisen rxn is an integral aspect of the general utility of process
R. K. Hill, Asymmetric Synthesis vol 3, Ch 8, p503 (chirality transfer)
OEt OH R2
!

Sense of Asymmetric induction may be controlled by olefin geometry

R2
!

R1

MeC(OEt)3 H+

R2

R2 ! CO2Et

R1

OEt O R1 R2 ! R1
Na/NH3 H2 Pd CaCO3

OH

OEt

MeC(OEt)3 H+ R1 R2 O
!

R1

R2

OH

Such chirality permutation processes are only as stereoselective as the energy difference between diastereomeric chair transiltion states:
R1 O
H H

MeC(OEt)3
!

R1 O R2
H

R2 ! CO2Et

R1

R2

R2 O

R1

R1

H+

OEt

favored
R2
!

R2

OH

R1

X X R2

O X

disfavored
R2

R1
H

R1 O X

Since stereoselection in reduction of acetylenes is >98%, either product accessible tocopherol (Vitamin E) Cohen JOC 1976, 41, 3497 JACS 1979, 101, 6710 Me
HO Me O Me Me Me Me
O H Me OH Me Me Me Me MgBr OH Me Me Me Me Me Me Me

Note that chirality transfer is coupled to olefin geometry in product. Prior arguments (Faulkner) imply that the X substituent will play significant role in promoting selectivity.
Me
!

Me

Me

Me

MeC(OEt)3 H+

Me ! O X
CO2Me

Me

50%

50%

O X
CO2Me N Me OH Me Me
!

ee > 90% (E)-selection > 90% R. K. Hill JOC 1972, 37, 3737

MeC(OEt)3 H+

N Me

68% enantiomerically pure Uskokovic, JACS 1979, 101, 6742

Me OH Me

H2 Pd/CaCO3 Me Me Me

NaAlH2(OR)2 OH Me Me Me

CO2Me OTMS Me MeC(OEt)3 H+ ETO2C Me

!

(Z):(E) = 98:2
R O

Me

(E):(Z) = >99:1
O EtO Me Me Me Me

92%

77%

OH

Me

Heathcock JOC 1988, 53, 1922

diastereoselection ~ 99% from both routes

D. A. Evans
Ireland-Enolate Claisen
Recent Review: Tetrahedron 2002, 58, 2905-2928

Ireland Enolate Claisen Rearrangement

Chem 206

Substituted enolates afford an additional stereocenter

R2 Me O OTBS R2 Me O
! ! !

R1 R2

Me

R1 O

R2 Me

Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868 O O Me
LDA Me3SiCl

(E)

O OTBS

OTMS O
t1/2 (32oC) = 3.5 h

OH O
LDA, TBSCl

OTBS

66%

R1

conditions
Et O OEt
LDA, TBSCl LDA, TBSCl DMPU

(E):(Z)
94:6 7:93

control
kinetic thermo

LDA, TBSCl DMPU

! Enolization: Amide Bases Stereoelectronic Requirements: The !-C-H bond must be able to overlap with "# CO

R2 Me

R1 R2 Me H

R1 O
H

R2 Me O OTBS

R1

O OTBS (Z)

OTBS

Ha
"# CO

R Hc

O Hb

base Ha+

Hc R

Hb O

key study: Ireland, JOC 1991, 56, 650 and earlier cited papers

Double Claisen Rearrangements are also possible

Paterson, Tet Lett 1991, 32, 7601

Me
OLi R

Me

Me

Me

Me

Me

Me

Me

favored
O R Me LMNR2 R

H N R

O Li H

Me

OH
Me

OH

Me O

O O
LDA, TMSCl Et3N

Me

R O Me Li N R H H

(E) Geometry
OLi R Me

disfavored
R

1,2 syn aldol relation permuted into 1,5 syn relationship via Claisen rearrangement

Me Me RO O Me Me Me Me Me OR O O 63% yield (diastereoselection 86%)

20-60 C

Me

Me

Me Me O OTBS

(Z) Geometry

Me O OTBS

The Ireland Model (JACS 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650

D. A. Evans

Ireland Claisen Rearrangements: Prostaglandin Synthesis

Chem 206

Consider the prostaglandin nucleus

O H
O

PP-A2 Synthesis, G. Stork, JACS 1976, 98, 1583

O H
8

COOH Me

O COOH ! Me
15

H COOH ! H OH Me

Aldol

Me O H H OH

COOH Me
H

MeO2C

HO

OH

OH
11O O

Claisen retrons
O RO
OR H

Claisen retrons

C-8 center can be controlled by equilibration

Dieckmann Dieckmann
H H
33

Claisen (chirality transfer)

COOH Me
1 OR

MeO MeO

COOH COOH ! ! Me Me

COOH Me
O OR H OH

MeO22C MeOC
COOH Me

H 55 H

O RO
1O 3 5

OH OH

OH

! OR

Claisen
O O COOH Me OH O HO HO OH COOR Me
HO HO O O O OR OR OR

Claisen

Claisen (trans C=C)

COOH Me OH

OR O ! O OR Me COOH

HOOC

COOR OH ! OH OR C4H9

COOH Me
HO

OR
MeO2C O ! O O Me MgBr Cl-CO2Me O Me OH ! O Me OCO2Me MeC(OMe)3 H+ ! O Me (CH2)3CO2Me OH MeO2C(CH2)2 ! O O O H+ 160 C, 1h MeO
12

Unrealized plan to generate the required enolate

OMe CONH2 O O O Me OMe

OCO2Me H3O+ O Me Et3N

Me

83%

Li(0)
O O M OH

CONH2 Me

via erythrose
(MeO)3C

O (CH2)3CO2Me ! H O O O

An Application PGA1: Ireland JOC 1976, 41, 986; Aldrichimica Acta 1988, 21, 59

MeO2C

C12 center and D13 C=C set in this rxn

59%

D. A. Evans

Claisen Rearrangement & Chirality Transfer

The analysis:
O H H H O

Chem 206
H

Boat transition states more accessible in Claisen than in Cope rearrangements

A case where the chair-boat preference depends on enol geometry
Factors controlling diastereoselection Enolate geometry Chair vs Boat transition states Bartlett, JOC 1981, 46, 3896 Ireland, JACS 1991, 56, 3572
H H Me O OR H H
OR

OR

Ireland, JACS 1991, 56, 3572

H

H Me

O OR

Me H

Boat (Z)-enolate

Chair (Z)-enolate

Me H

O
O

LDA,TBSCl
O

A
O OR

O Me OR O

Me Me

Boat (Z)-enolate
Ireland study supports Bartlett's conclusions
O O

Chair (Z)-enolate
conditions LDA,THF LDA,THF DMPU
Me OR O

A:B 29:71 86:14

TS (E)-boat (Z)-boat

LDA,TBSCl

A
O OR

H O H
OR

H O H

Me

conditions LDA,THF LDA,THF DMPU

(E):(Z) 83:17 04:96

A:B 84:16 72:28

TS (E)-chair (Z)-boat

Me

H Me

Me H

O OR

H H
OR

H H

A further example:
OTBS Me

Chair (E)-enolate

Boat (E)-enolate

Boat geometies can be favored in these and related systems

H Me

Me H

O OR

O OMe boat-preferred RO O Me OMe Me O H TBSO O Me

O O

OMe

Chair (E)-enolate

Boat (E)-enolate

Me

Me

In this case the boat geometry is preferred from either enol geometry
O O O

OMe Me O H H Me O OTBS

LDA,TBSCl
O

A
O OR

Me

destabilizing
TS (E)-boat (Z)-boat
Me Me OR O

?
H

conditions LDA,THF LDA,THF DMPU

A:B 29:71 86:14

It appears that both of the indicated interactions contribute to the destabilization of chair geometry

D. A. Evans

Ireland Claisen Rearrangements: Ionophore Synthesis

The relevant rearrangements:
Me Me RO

Chem 206

Ireland lasalocid synthesis: JACS 1983, 105, 1988

Me OH HO CO2H Me Me Et O Me

A
Et H O O

H O

A
H O Et

Claisen

A
RO Et O H HO O O

OR

B
Et Me

B
Me

OH Et

B
Me

OR Et Me

Me O HO CO2H Me H

aldol
O

Me Me O

Claisen construction

O OH Et HEt Et B B OR OR O Me O Me Et Et Et Me Me

AH

H
BnO

Me Me

A
BnO

H
CO2H

A
Et H O Cl OH O

O BnO Et H

A
O O O

Et O

B
OMOM Me

LDA THF/HMPA TMSCl

Me RO Et

Note that neither retron for Claisen exists in this intermediate

B
OMOM Me

50% overall yield

B
OMOM Me

add Claisen retrons A

H O O O O

Claisen
RO

Me H

A
O H Et HO O O

OR

The Ireland monensin synthesis:

Claisen construction
HO Me MeO O Me HO Me HO Me Me

B
Et Me

B
Me

OR Et

Me OH

enolate face selectivity is anticipated problem. This results in CO2H epimers B

Me

A
O

B
O Me H

C
O Et H

D
O O

E
HO

Me CH2OH

A
RO Et H O COOR O

OR Et

Me!COOH

Here is another potential Claisen construction

Me O

Methyl-bearing stereocenter to be established by selective reduction

A
H Et Et O Me OR Et O

Me MeO R

A
O Me

B
O

O O Me

JACS 1993, 115, 7152-65 JACS 1993, 115, 7166-72 (and previously cited papers)
Me

X Et

B
Me

A
O

R Et

O RO

Me O

C
O Et H

D
O O

A
Et H O

R Et

Me

E
HO

Me CH2OH

Claisen construction

Ireland Claisen Rearrangements: Cyclic Enolates

The previous cases were derived from a connection between R2 &R3
OR O R2 R1 R3 R1 O OR R1 O OR
Me H CO2H
R O

Chem 206

The Indanomycin Synthesis, Burke, Tet. Lett. 1985, 26, 1163; ibid, 1986, 27, 6295
O Me O N H H N H H

X Me

O Et H Me Et H CO2H O

Consider consequence of connecting R1 &R2

R R O R1 R3 R O O R3 O

H O

Et

"Right wing"

Et

O R2

O R3

The Left Wing: Tet. Lett. 1985, 26, 1163

Me

"Left wing"
Me Me

equivalent representations
O

add Claisen retrons

O Me H CO2H O

Me H CO2H

Claisen
O OR Me

O Et

O OR R3 R3

"Left wing"
Me H O O LDA/TMSCl Me H BnO Me H O OTMS 110 C 4h

H CO2H

Examples:
Me MeO TBSO O Ph3C+ -78 C Me CHO OM TMSO MeO2C MeO2C Me H O Me H Me

Me Me H BnO O OTMS

Me
H

H BnO

80% yield

The Right Wing: Tet. Lett. 1986, 27, 6295

O XCO X Y H TMSO H

Danishefsky, Tet. Let 29, 1371 (1988)

TMSO2C Me H Me

[4+2]

Claisen
H

O H Et

Me TMSO O H

H LDA/TMSCl O O H OTMS Me

Me

Et
H 135 C 4h H Et TMSO2C

Et
O

CH2X
OTMS H

H H

TMSO
O

OTMS

Me

Et

65% yield

see also Danishefsky, JACS 1980, 102, 6889, 6891

Et

The "apparent" Claisen process is more complicated than anticipated.

D. A. Evans

Ireland Claisen Rearrangements: Cyclic Enolates

HO

Chem 206
R R1 R3 R

R
29

The FK 506 application

MeO

Now connect R1 &R3

H Me Me O

Schreiber Synthesis JACS 1990,112, 5583

O R2

O R2 R2

FK 506
The Schreiber Route:
O Me

O H O O O

OH

Examples: Funk, JACS 1982, 104, 4030

Me Me OMe

O O LDA/TMSCl TMSO H O O

H H

TMSO O

OH

Claisen disconnection
R3SiO MeO
29

70%
TMSO H

OMe OR O OR O MeO O O

LDA/TMSCl

MeO

29

81%
H

H TBSOTf Et3N MeO H O 110 C OTBS MeO

29

O O LDA/TMSCl CHMe2

TMSO O

OR O

89%
H

MeO

71%

Me2HC

The previous cases were derived from a connection between R2 &R3

OR O R2 R1 R3 R1 O OR R1 O

Recent improvments: Funk, JACS 1993, 115, 8847

O O O
OR

O O O P(OEt)2 R1 R2 R3

O R1 R2 LDA ClPO(OEt)2 R3 O

P(OEt)2 R1 R2

and R1 &R2
R O R1 O R2 R3 R3 R3 R O

R3

chrysanthemic acid application

O OR

O Me Me O LDA Me Me ClPO(OEt)2

XO

H H 65 C Me

TMSO O

H Me

O Me Me Me

83%
Me H Me Me

X = TMS; T1/2 = 58 min X = PO(OEt)2; T1/2 = 10 min

D. A. Evans
R1 R2 Me O O R2 Me

Claisen Rearrangements: Acyclic Cases with Stereoinduction

Exocyclic Stereochemical Issues
R1 OR O R2 R1 ! Me ! OR O

Chem 206
Kurth, JACS 1985, 107, 443
R

N-Allylketene-N-O-Acetals:
R N O alkylate base Br R' N O R 185 C

O N O

OH

R' R' R'

These rearrangements present many of the same issues which were encountered during our discussion of carbonyl addition with regrad to assymmetric induction.

b-Hydroxy ester enolates: Kurth, JOC 1985, 50, 5769

Chelate Control: !-Hydroxy ester enolates: Kurth, JOC 1985, 50, 1840
OH Me OH Me Me O O 2 LDA, TMSCl H H H Me O O R 2 LDA Me O O Li O Li R El(+) Me El OH Me Me H O OTMS OH O O R

Me2HC N Me O alkylate base Br

Me2HC N O 185 C

Me2HC O N O OH

chelate control
Me O Li O O

R' Me Me

diastereoselection 87:13
Me Me2HC N O Me2HC N H Me Me O

chair TS

diastereoselection 81:19

We again see the consequence of chelate-organized asymmetric induction

185 C

diastereoselection 94:6

Felkin Control ?: Cha, Tet. Lett. 1984, 25, 5263

Me O Me Me O OTMS O Me O Me O OMe OTMS O THPO Me O OEt 110 C Me O 25 C Me O 25 C Me Me O OMe OTMS O THPO OEt O O Me O OTMS O Me O Me O OTMS O Me O OMe OTMS O
O

57%
Me Me

The Claisen Rearrangement is subject to acid catalysis

LA LA + O LA + O LA O

57:43

BF3-HOAc: Bryusova, J. Gen. Chem. (USSR) 1941, 11, 722 BCl3: Gerrard, Proc. Chem. Soc. 1957, 19; Schmid, Helv. Chem. Acta 1973. 56, 14 Et2AlCl: Sonnenberg, J. Org. Chem. 1970, 35, 3166 TiCl4: Mukaiyama, Chem. Lett. 1975, 35, 1041 (RO)2AlMe: Yamamoto, JACS. 1988, 110, 7922 (RO)2AlMe: Yamamoto, Tet. Lett. 1989, 30, 1265 (RO)2AlMe: Yamamoto, JACS. 1990, 112, 316 LiClO4: Reetz, Tetrahedron. 1993, 49, 6025

81:19

75:25 (Felkin model, RO = large)

Takano, Tet. Lett. 1985, 26, 865

D. A. Evans

Lewis Acid Catalyzed Claisen Rearrangements

(RO)2AlMe: Yamamoto, Tet. Lett. 1990, 31, 377
CMe3 Me3C O Al CMe3 Me Me3C
O Me Me OH

Chem 206

Catalyzed Claisen Rearrangement of Allyl-phenyl Ethers

Catalyzed Claisen Rearrangement of Allyl-vinyl Ethers

(RO)2AlMe: Yamamoto, JACS. 1990, 112, 316

The thermal process

Br

The Lewis Acid (LA)

Br

favored

R H

O X R R O X

heat

Me

Me "high yield"

disfavored
H O

X O X

Me

Me

LA
LA Me

The catalyzed process

+
O Me Me OH Me

disfavored

R H Al

O H R R R H O O H O H

+ LA
Me -78 C Me
R O H

favored
H Al

B
Me Me O

nonbonding interactions favor this TS

R

+ LA
Me

Claisen Cope
Me Me Me

A:B = 3:4
R O H O H

Me OH O Me
iBu O H

43%

19:81

LA

Claisen Cope
Me

40%
O TMS O H H

07:93

85%

Me

94%

03:97

The hindered Lewis acid will alter the partitioning of the Claisen process to the two ortho positions

D. A. Evans

Lewis Acid Catalyzed Claisen Rearrangements

Yamamoto, JACS. 1990, 112, 7791 Yamamoto, Tet. Asymmetry 1991, 2, 647-662
Si(t-Bu)Ph2 O Al O Me

Chem 206

Chiral Lewis Acid Promoted Claisen Rearrangements

Allylic rearrangements may be included as a subset of other sigmatropic processes:

R1 1
3

R2

R1 1 Y R2 R3

R2

Note that these reactions are not catalytic

X R2

(R)-1 (R)-1 (1.1-2 equiv.) CH2Cl2, -20C 76-95%

SiMe3

Si(t-Bu)Ph2 R

R1 X Y

[3, 3]

R1 X Y

R3

X = C, N, O, S

O Ph

O R

SiMe3

R Ph C6H11

% ee 88% 71%

X = O; Y = S Faulkner, Synthesis 1971 175 (see pg 183)

Me Me Me Et O S OPh O S OPh

(R)-1 (1.1-2 equiv.) CH2Cl2, -40C 68-76%

O R O R

R SiMe2Ph GeMe3

% ee 90% 93%

Et OH Cl

pyr
S OPh

Et

Enantioselective Claisen Rearrangements: Metal-Centered Chirality

Corey, JACS. 1991, 113, 4026
Ph ArO2S N B Br O L2BBr i-Pr2NEt CH2Cl2 Me Me L2BBr Et3N toluene O Me Me O BL2 O OH Me Me 20 C O BL2 OH Me Me 20 C O Me Me Ph N SO2Ar CF3
Me R SOCl2 OH R O Cl Me

(E) selectivity: 96.5%

A stereochemically related case Johnson, JACS 1970 92, 735

Me R O Cl S O

Ar =
CF3

(LA)

ether

S O

(E) selectivity: >98%

R 200 C

X = O; Y = N
Threo: erythro 99:1 >97% ee (75%)
R

O O

Roberts, JACS 1960 82, 1950 Hill, JOC 1968 33, 1111
R R

O H

O Ph H R

Ph

Threo: erythro 10:90 96% ee (65%) 8 cases reported

O O

H N

200 C Ph O N ONa O Ph ONa N Ph

H3O+ H N

Ph