the cope rearrangement - university of chicagosnyder-group.uchicago.edu/downloads/lectures2020/the...
TRANSCRIPT
The Cope RearrangementLecture Notes
Key Reviews:
H. M. L. Davies, Tetrahedron 1993, 49, 5203.
D. Enders, M. Knopp, R. Schiffers, Tetrahedron: Asymmetry 1996, 7, 1847.
U. Nubbemeyer, Synthesis 2003, 961.
[3,3]
D D
[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
[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.
OH OH O
[Claisenrearrangement]
[Claisenrearrangement]
OOOH
[Enol-ketotauto-
merization]
Δ
[Cope]
[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.
OH OH O
[Claisenrearrangement]
[Claisenrearrangement]
OOOH
[Enol-ketotauto-
merization]
Δ
[Cope]
The Cope Reaction: Initial Discovery
150 oC4 h
A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441.
Reaction process involves chair-like intermediates in most cases, but is an equilibrium.Special tactical features are required to drive the process towards a single product.
Bonds Broken2 C C1 C C
Bonds FormedC CC C
21
EtO2CNC
EtO2C
NC
The Cope Reaction: Initial Discovery
150 oC4 h
A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441.
Reaction process involves chair-like intermediates in most cases, but is an equilibrium.Special tactical features are required to drive the process towards a single product.
Bonds Broken2 C C1 C C
Bonds FormedC CC C
21
EtO2CNC
EtO2C
NC
The Cope Reaction: Initial Discovery
150 oC4 h
A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441.
Reaction process involves chair-like intermediates in most cases, but is an equilibrium.Special tactical features are required to drive the process towards a single product.
Bonds Broken2 C C1 C C
Bonds FormedC CC C
21
EtO2CNC
EtO2C
NC
The Cope Reaction: Ways to Get Single Products
A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441.
1. Olefin conjugation and increased degree of alkene substitution
150 oC4 h
EtO2CNC
EtO2C
NC
2. Relief of ring strain
Δ
Δ
The Cope Reaction: Ways to Get Single Products
A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441.
1. Olefin conjugation and increased degree of alkene substitution
150 oC4 h
EtO2CNC
EtO2C
NC
2. Relief of ring strain
Δ
Δ
The Cope Reaction: Ways to Get Single Products
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.
3. Product isomerization
HO HO O
D D
This process is known as the oxy-Cope rearrangement
O O
Standard Cope rearrangement Claisen rearrangement
4. Ensuing rearrangements/reactions (can be inter- or intramolecular)
O O O[Cope] [Claisen]
The Cope Reaction: Ways to Get Single Products
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.
3. Product isomerization
HO HO O
D D
This process is known as the oxy-Cope rearrangement
O O
Standard Cope rearrangement Claisen rearrangement
4. Ensuing rearrangements/reactions (can be inter- or intramolecular)
O O O[Cope] [Claisen]
The Cope Reaction: Ways to Get Single Products
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.
3. Product isomerization
HO HO O
D D
This process is known as the oxy-Cope rearrangement
O O
Standard Cope rearrangement Claisen rearrangement
4. Ensuing rearrangements/reactions (can be inter- or intramolecular)
O O O[Cope] [Claisen]
The Cope Reaction: Use in Complex Molecule Synthesis
T. Hudlicky, C. H. Boros, E. E. Boros, Synthesis 1992, 174.
O
OH
How was this made?
O
O
PCC
(94%)
O
O
OH
OMeN
OHO
OH
O
HHO
NMe
250 oC,xylenes
sealed tube,22 h
(88%)[Cope]
morphinemorphine
The Cope Reaction: Use in Complex Molecule Synthesis
J. Limanto, M. L. Snapper, J. Am. Chem. Soc. 2000, 122, 8071.
OO
OH
HH
(+)-asteriscanolide
O
H
HHH
O
H
HH
H Grubb'scatalyst
H2C CH2benzene,
80 oC, 10 hO
H
HH
H
O
[Cope] (74%)
O
The Cope Reaction: Use in Complex Molecule Synthesis
H. M. L. Davies, B. D. Doan, J. Org. Chem. 1998, 63, 657.
tremulenolide A
N2
CO2Me
OAc
Rh(OOct)4CO2Me
OAc
MeO2CAcO
HH
OO
140 oC,Kugelrohr distillation
(49% overall)[Cope]
(12 equiv)
hexane, Δ+
how?
The Oxy-Cope Reaction: Perhaps the Most Valuable Version
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
HO HO O250 oC
[slow]
O
KH
O OH3O25 oC
1010 to 1017 fold rate increase at room temperatureAffords an enolate intermediate which can be used directly in further chemistry
The Oxy-Cope Reaction: Perhaps the Most Valuable Version
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
HO HO O250 oC
[slow]
O
KH
O OH3O25 oC
1010 to 1017 fold rate increase at room temperatureAffords an enolate intermediate which can be used directly in further chemistry
The Oxy-Cope Reaction: Perhaps the Most Valuable Version
J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019.D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
HO HO O250 oC
[slow]
O
KH
O OH3O25 oC
1010 to 1017 fold rate increase at room temperatureAffords an enolate intermediate which can be used directly in further chemistry
Anion Accelerated Oxy-Cope Reaction in Action
D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
OH250 oC
[slow]
KH
H3O25 oC
OHH
H
OH
H
OOH
H
OH
H
4π-Electrocyclic Reactions:Part of a Total Synthesis of Periplanone B
S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038.For a review, see: Classics in Total Synthesis I, Chapter 21
OH
Me
Me
O
Me
Me
O
Me
Me
H
Me
Me
175 °C, toluene
O
Me
Me
hν
O
Me
Me
O
O
O
periplanone B
Oxy-Coperearrangement
4π-conrotatoryelectrocyclicring opening
KH,18-Crown-6
OO
OO
O
O
18-crown-6
(75%)
(82%)
Olefin isomerization
+
Ene Reactions in Total Synthesis:Tandem Oxy-Cope/Carbonyl Ene Sequence
L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925.
OTBDPS
HO
H
Me
Me
MeOH
OTBDPS
MeDBU,
toluene220 °C
MeOH Me
OTBDPS
MeO
OTBDPS
TBDPS = t-butyldiphenylsilyl
MeO
H HH
H
TBDPSOH
HHHMeOH
OTBDPSH
OTBDPS
HO
H
Me
H Me
O
OMe
HOMe
HO
arteannuin M
Transannularene reaction
Oxy-Coperearrangement
Enol-Ketotauto-
merization
(63%)
Anion Accelerated Cope Reaction: Not Just Oxygen!
D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
NHBnKH H3O-60 oC
NBnNBnH
H
OH
H
KH H3O-40 oC
PhS
RHN
PhS
RN
PhS
RN O
PhS
Have intermediate enamine nucleophile which can be used in varied ways
toluene
THF
Anion Accelerated Cope Reaction: Not Just Oxygen!
D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
NHBnKH H3O-60 oC
NBnNBnH
H
OH
H
KH H3O-40 oC
PhS
RHN
PhS
RN
PhS
RN O
PhS
Have intermediate enamine nucleophile which can be used in varied ways
toluene
THF
Working Backwards: Recognizing Oxy-Cope Products
O HOHO
[oxy-Cope]1 23
456
1,5-diene is the critical structural unit of initial productAn alkene and carbonyl linked by three carbons is the key unit in final product
O
OH OH OH
[oxy-Cope]
Working Backwards: Recognizing Oxy-Cope Products
O HOHO
[oxy-Cope]1 23
456
1,5-diene is the critical structural unit of initial productAn alkene and carbonyl linked by three carbons is the key unit in final product
O OHOH X
OH OH OH
[oxy-Cope]
Working Backwards: Recognizing Oxy-Cope Products
O HOHO
[oxy-Cope]1 23
456
1,5-diene is the critical structural unit of initial productAn alkene and carbonyl linked by three carbons is the key unit in final product
O OH12
3 5
6
4
OH12
3 5
6
4
X
1,6-diene 1,5-diene
OH OH OH
[oxy-Cope]
Working Backwards: Recognizing Oxy-Cope Products
O HOHO
[oxy-Cope]1 23
456
1,5-diene is the critical structural unit of initial productAn alkene and carbonyl linked by three carbons is the key unit in final product
O OH12
3 5
6
4
OH12
3 5
6
4
X
1,6-diene 1,5-diene
OH OH OH
[oxy-Cope]
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
O
O
O
1. Add a carbonyl at any position which has 3 carbons before either end of the alkene2. Evaluate each ketone for oxy-Cope viability
A B C D
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
O
O
O
1. Add a carbonyl at any position which has 3 carbons before either end of the alkene2. Evaluate each ketone for oxy-Cope viability
A B C D
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
A
OH OH
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
A
OH
12
345
6 OH12 3
45
6
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
A
OH
12
345
6 OH12 3
45
6
OH OH
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
A
OH
12
345
6 OH12 3
45
6
OH OH
OH OH
[Cope] [Cope]
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
OB
HO HO
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
12
3
45
6
OB
HO
12 3 4
5
6HO
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
12
3
45
6
OB
HO
HO HO
12 3 4
5
6HO
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
12
3
45
6
[Cope] [Cope]OB
HO
HO HO
12 3 4
5
6HO
HO HO
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
C
OH OHOH
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
123
4 5
6
O
C
OH OH12 3
4 5
6OH
12 3
4 5
6
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
123
4 5
6
O
C
OH OH OH
OH OH12 3
4 5
6OH
12 3
4 5
6
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
123
4 5
6
[Cope] [Cope]
O
C[Cope]
OH OH
OH OH
OH
OH
OH OH12 3
4 5
6OH
12 3
4 5
6
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
C
OH OH OH
HO OHOH
OHO O
Cl
CN
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
C
OH OH OH
HO OHOH
OHO O
Cl
CN
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
C
OH OH OH
HO OHOH
OHO O
Cl
CN
Working Backwards: Recognizing Oxy-Cope Products
G. Berube, A. G. Fallis, Tetrahedron Lett. 1989, 30, 4045.
O
C
OH OH OH
HO OHOH
OHO O
Cl
CN
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
1. Add an olefin at any position which has 3 carbons between it and the carbonyl2. Evaluate each ketone for oxy-Cope viability as before
H H
HH
OMeOMe
O
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
1. Add an olefin at any position which has 3 carbons between it and the carbonyl2. Evaluate each ketone for oxy-Cope viability as before
H H
HH
OMeOMe
O
H H
HH
OMeOMe
OH H
H
OMeOMe
O
A B C
H H
HH
OMeOMe
O
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
H H
H
OMeOMe
O
H H
H
OMeOMe
HO
H H
HH
OMeOMe
O
A B
no 1,5-dienes!
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
H H
H
OMeOMe
O
H H
H
OMeOMe
HO
H H
HH
OMeOMe
O
123 4
56
A B
no 1,5-dienes!
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
H H
H
OMeOMe
O
H H
H
OMeOMe
HO
H H
HH
OMeOMe
O
H H
H
OMeOMe
HO
123 4
56
A B
no 1,5-dienes!
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
H H
H
OMeOMe
O
H H
H
OMeOMe
HO
H OMeOMe
HO
H H
HH
OMeOMe
O
H H
H
OMeOMe
HO
[Cope]
123 4
56
A B
no 1,5-dienes!
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
H H
HH
OMeOMe
O
C
H
HH
OMeOMe
HOH H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
12
3456
H H
HH
OMeOMe
O
C
H
HH
OMeOMe
HOH H
HH
OMeOMe
HOH H
HH
OMeOMe
HO6
12
345
12
34
56
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
12
3456
H H
HH
OMeOMe
O
C
H
HH
OMeOMe
HO
H
HH
OMeOMe
HO
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
6
12
345
12
34
56
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
[Cope]
12
3456
H H
HH
OMeOMe
O
C
H
HH
OMeOMe
HO
H
HH
OMeOMe
HO
H OMeOMe
HO
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
[Cope] [Cope]
6
12
345
12
34
56
H
H
OMeOMe
HOH
HH
OMeOMe
HO
Working Backwards: Recognizing Oxy-Cope Products
L. A. Paquette, J. L. Romine, H.-S. Lin, Tetrahedron Lett. 1987, 28, 31.
[Cope]
12
3456
H H
HH
OMeOMe
O
C
H
HH
OMeOMe
HO
H
HH
OMeOMe
HO
H OMeOMe
HO
MeO OMe
OH
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
H H
HH
OMeOMe
HOH H
HH
OMeOMe
HO
[Cope] [Cope]
6
12
345
12
34
56
H
H
OMeOMe
HOH
HH
OMeOMe
HO
Further Practice Problems to Recognize Oxy-Cope Products
O
H
H
HIreland, J. Org. Chem. 1981, 46, 4863 Gadwood, J. Org. Chem. 1982, 47, 2268
O
Clive, Chem. Comm. 1997, 2157Leighton, J. Am. Chem. Soc. 1999, 121, 890.