Transcript Document

Electrocyclic Reactions
Lecture Notes
Key Reviews:
Electrocyclic Reactions:
Comprehensive Organic Synthesis, Vol. 5, p. 699
Nazarov Cyclization (4-electrocyclization):
S. E. Denmark, Org. React. 1994, 45, 1-158.
A Series of Observations:
The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
Me
Me
Me
Me
Me
H
HO
ergosterol
Me
Me
Me
h
Me
HO
Me
Me
Me
precalciferol
(previtamin D)
Me
Me
Me
H
HO
lumisterol
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.
E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
A Series of Observations:
The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
Me
Me
Me
Me
Me
H
HO
ergosterol
Me
Me
Me
h
Me
HO
Me
Me
Me
precalciferol
(previtamin D)
Me
Me
Me
H
HO
lumisterol
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.
E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
A Series of Observations:
The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
HO
HO
isopyrocalciferol
ergosterol
Me
Me
100200 °C
Me
HO
Me
Me
Me
Me
h
precalciferol
(previtamin D)
Me
Me
Me
Me
Me
H
H
lumisterol
Me
Me
Me
HO
Me
HO
pyrocalciferol
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.
E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
A Series of Observations:
The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
HO
HO
isopyrocalciferol
ergosterol
Me
Me
6-conrotatory
electrocyclization
Me
Me
Me
Me
h
100200 °C 6-disrotatory
electrocyclization
Me
HO
precalciferol
(previtamin D)
Me
Me
Me
Me
Me
H
H
lumisterol
Me
Me
Me
HO
Me
HO
pyrocalciferol
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.
E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
Electrocyclic Reactions:
Background and Basic Principles
Conrotatory versus disrotatory cyclization: how can I differentiate them?
A
A
B
B
A
A
B
B
conrotatory
ring opening
A
B
A
conrotatory
ring closing
B
disrotatory
ring opening
disrotatory
ring closing
A
B
B
A
B
A
A
or
B
Electrocyclic Reactions:
Background and Basic Principles
Conrotatory versus disrotatory cyclization: how can I differentiate them?
conrotatory
ring opening
A
A
B
B
A A
B
disrotatory
ring opening
A
B
B
disrotatory
ring closing
disrotatory
ring opening
B
B
A
conrotatory
ring closing
B
A
A
B
A
A
B
A
A
B
conrotatory
ring opening
B
B
disrotatory
ring closing
A
A
or
B
B
conrotatory
ring closing
A B
A
A Series of Observations:
The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
HO
HO
isopyrocalciferol
ergosterol
Me
Me
6-conrotatory
electrocyclization
Me
Me
Me
Me
h
100200 °C 6-disrotatory
electrocyclization
Me
HO
precalciferol
(previtamin D)
Me
Me
Me
Me
Me
H
H
lumisterol
Me
Me
Me
HO
Me
HO
pyrocalciferol
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.
E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
Electrocyclic Reactions:
Background and Basic Principles
Thermal reaction
butadiene HOMO (2)
(4-electron system)
allowed
Photochemical reaction
butadiene HOMO (3)
(4-electron system)
disallowed
disallowed
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
allowed
The Woodward-Hoffmann rules predict that photochemical reactions
will be precisely complementary to thermal reactions. Thus, what is allowed
photochemically is forbidden thermally, and vice versa. This prediction is true.
Electrocyclic Reactions:
Background and Basic Principles
Conrotatory versus disrotatory cyclization: how can I differentiate them?
conrotatory
ring opening
A
A
B
B
A A
B
disrotatory
ring opening
A
B
B
disrotatory
ring closing
disrotatory
ring opening
B
B
A
conrotatory
ring closing
B
A
A
B
A
A
B
A
A
B
conrotatory
ring opening
B
B
disrotatory
ring closing
A
A
or
B
B
conrotatory
ring closing
A B
A
Electrocyclic Reactions:
Background and Basic Principles
What happens when the rotating groups are different? Will one product predominate?
F
F
F
F
CF3
F
F
CF3
CF3
F
F
CF3

4-conrotatory
electrocyclic
ring opening
CF3
CF3
F
F
h
4-disrotatory
electrocyclic
ring opening
F
F
Guiding Principle:
Electron donors go outward;
electron withdrawers go inward.
CF3
F
F
CF3
F
F
Here, the products are
degenerate; i.e., the same
Electrocyclic Reactions:
Background and Basic Principles
H
H O
O
H
H O
h
4-disrotatory
electrocyclization
O
H
HH
O
H
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
O
Electrocyclic Reactions:
Background and Basic Principles
H
H O
O
H
H
H O
H O
O
H
h
4-disrotatory
electrocyclization
H O
O
H
HH
O
H
O
O
H
HH

X
4-conrotatory
electrocyclization
O
H
O
trans-fused
4-membered ring
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
impossible
structure!
Electrocyclic Reactions:
Background and Basic Principles
H
H
h
4-disrotatory
electrocyclization
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Electrocyclic Reactions:
Background and Basic Principles
H
H
h
4-disrotatory
electrocyclization

H
H
H
H
X
4-conrotatory
electrocyclization
H
H
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
impossible
structure!
Electrocyclic Reactions:
Background and Basic Principles
a
b
c
a
b
d
c

8-conrotatory
electrocyclization

6-disrotatory
electrocyclization
d
H
H
a
b
d
c
a
b
c
d
a
b
c
d
h
8-disrotatory
electrocyclization
h
H
X
6-conrotatory
electrocyclization
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
H
a
b impossible
c structure!
d
Electrocyclic Reactions:
Background and Basic Principles
Note: Electrocyclic reactions can involve both cationic and anionic intermediates
O
OH
H3PO4
4-conrotatory
electrocyclization

OH
O
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Electrocyclic Reactions:
Background and Basic Principles
Note: Electrocyclic reactions can involve both cationic and anionic intermediates
O
OH
H3PO4
4-conrotatory
electrocyclization

OH
O
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
This reaction
is known as the
Nazarov
cyclization and
was first
discovered
in 1948
Electrocyclic Reactions:
Background and Basic Principles
The Nazarov reaction is highly regioselective based on carbocation stability
OH
O
OH
H3PO4
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.
O
Electrocyclic Reactions:
Background and Basic Principles
The Nazarov reaction is highly regioselective based on carbocation stability
OH
O
OH
O
OH
O
H3PO4
OH
O
FeCl3
TMS
TMS
TMS
Cl
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.
Electrocyclic Reactions:
First Discovery of an Electrocyclic Reaction
Ph
O
N
H
3
Q u ic k T im e ™ a n d a
T I F F ( Un c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
Ph
Ph
120 °C
Ph
HN
A
l
e
x
(
P
i
e
c
t
h
e
y
e
P
l
n
1
8
o
P
o
a
i
v
e
3
u
r
o
d
3
h
n
t
-
e
c
e
r
1
I
i
a
o
8
a
e
s
B
r
g
n
r
8
o
7
d
d
a
r
D
Ph
Ph
amarine
n
Ph
Ph
)
w
o
i
N
Ph
6-disrotatory
electrocyclization
o
a
s
p
n
f
e
c
r
r
e
a
o
m
:
s
For discussion, see: E. J. Corey, F. N. M. Kuhnle, Tetrahedron Lett. 1997, 38, 8631.
Electrocyclic Reactions:
First Discovery of an Electrocyclic Reaction
Ph
O
N
H
3
Q u ic k T im e ™ a n d a
T I F F ( Un c o m p r e s s e d ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
Ph
Ph
120 °C
Ph
HN
A
l
e
x
(
a
n
1
8
d
e
3
r
3
-
B
1
o
8
r
8
o
7
d
i
N
Ph
Ph
Ph
amarine
n
Ph
6-disrotatory
electrocyclization
Ph
)
Process is still used today . . .
P
i
e
c
t
h
e
y
e
P
o
P
o
l
u
r
o
i
v
h
n
e
c
e
t
a
e
s
I
i
a
r
g
n
d
w
o
a
r
D
o
a
s
p
n
f
e
c
r
r
e
a
s
o
m
:
H2N
NH2
H2N
NH2
Ph
Ph
Ph
Ph
For discussion, see: E. J. Corey, F. N. M. Kuhnle, Tetrahedron Lett. 1997, 38, 8631.
Electrocyclic Reactions:
Background and Basic Principles
OTs
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Electrocyclic Reactions:
Background and Basic Principles
krel
OTs
1
4
Me
Me
OTs
Me
Me
Me
40,000
Me
Me
OTs
Me
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Electrocyclic Reactions:
Background and Basic Principles
krel
OTs
1
4
Me
Me
Me
Me
OTs
Me
Me
Me
40,000
Me
Me
Me
Me
OTs
Rule: groups opposite
leaving group migrate
outwards
Me
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
lobe system required
after opening for cation
Electrocyclic Reactions:
Background and Basic Principles
krel
1
H
TsO
OTs
Essentially an
impossible structure!
H
1,000,000
Rule: groups opposite
leaving group migrate
outwards
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Electrocyclic Reactions:
Background and Basic Principles
krel
1
H
TsO
OTs
Essentially an
impossible structure!
H
1,000,000
LVG1
LVG2
LVG2
Rule: groups opposite
leaving group migrate
outwards
e
thermal
photochemical
2
4
6
8
disrotatory
conrotatory
disrotatory
conrotatory
conrotatory
disrotatory
conrotatory
disrotatory
Can predict easily
which of the two
groups will depart
Electrocyclic Reactions:
Examples You Have Already Seen
O
O
O
BnO
O
N
O
O
O
4-conrotatory
electrocyclic
ring opening
O
BnO
o-xylene, 
N
O
O
o-quinodimethane
Remember: Electron donating
substituents turn outward
Intramolecular (73%)
Diels-Alder
O
O
Me
N
H
O
O
BnO
N
O
O
O
O
H
OH
chelidonine
O
W. Oppolzer, C. Robbiani, Helv. Chim. Acta 1983, 66, 1119.
Electrocyclic Reactions:
Examples You Have Already Seen
O
HO
MeO
O
MeN3
N
toluene,
25 °C
[3+2] addition
(99%)
MeO
A
Me
HO
MeO
N
N
N
N
Me
MeO
h,
Pyrex
dioxane
(90%)
Me
N
O2S
Me
N
H
O
CO2H
N
H
MeO
H
N
N Me
H
MeO
Me
HO O
N
MeO
quinocarcin
HO
MeO
4-disrotatory
h,
electrocyclic quartz
ring opening
O
N
O
CONX
O Me
A
[3+2]
addition
HO
MeO
exo product
P. Garner, W.B. Ho, H. Shin, J. Am. Chem. Soc. 1993, 115, 10742.
O
N
N
Me O
Me
4-Electrocyclic Reactions:
Part of a Total Synthesis of Periplanone B
O
OH
OH
Me
KH,
18-Crown-6
Me
Oxy-Cope
rearrangement
Me
(75%)
H
Me
Me
O
O
O
O
O
175 °C, toluene
4-conrotatory
electrocyclic
ring opening
Me
(82%)
O
18-crown-6
O
O
O
O
O
Me
Me
periplanone B
Me
+
Me
h
Olefin isomerization
S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038.
For a review, see: Classics in Total Synthesis I, Chapter 21
Me
Me
4-Electrocyclic Reactions:
Part of a Cascade Sequence to Coriolin
Me
i-PrO
O
O
Me
O
Li
Me
i-PrO
i-PrO
O
trans Addition
H
O
4-Electron
conrotatory
O
O
Li
Me
O
Oi-Pr
O
O
O
ring
opening
O
i-PrO
i-PrO
O
H
Me
Me
i-PrO
HO
Note: The electrocyclization
points the carbon substituents inward
Dianionic
oxy-Cope
O
i-PrO
(24%) aq. NH4Cl
Me
Me
Me
H
Ring
opening
H
O
O
O
O
Aldol
H
i-PrO
i-PrO
Me
Me
i-PrO
O
i-PrO
i-PrO
O
H
O
O
O
i-PrO
L. A. Paquette and co-workers, J. Am. Chem. Soc. 2002, 124, 9199.
For a review, see: L. A. Paquette, Eur. J. Org. Chem. 1998, 1709.
Me
O
O
O
6-Electrocyclic Reactions:
Erasure of the Ring-Opened Product
Me
Br
H
O
Me
Al(Oi-Pr)3,
i-PrOH, 
H
O
Me
H
Me O
Me
LiBr,
DMF,
120 °C
Me
H
Me O
H
HO
O
O
Me
H
Me O
O
Me
H
What is the name
reaction in the
second step?
Al2O3,
pyridine,
220 °C
Me
H
Me O
O
6-disrotatory
electrocyclization 25 °C
Me
H
Me
Me
O
O
dihydrocostunolide
H2,
Raney Ni
MeOH,
-18 °C
Me
H
Me
Me
O
O
h, MeOH,
-18 °C
6-conrotatory
electrocyclic
ring opening
E. J. Corey, A. G. Hortmann, J. Am. Chem. Soc. 1965, 87, 5736.
Me
H
Me
H
Me O
O
6-Electrocyclic Reactions:
Total Synthesis of Torreyanic Acid
O
HO
O
Dess-Martin
periodinane,
CH2Cl2, SiO2,
CO2t-Bu 25 °C, 1 h Me
O
Me
O
Me
O
O
Tandem oxidation/
6-conrotatory
electrocyclization
O
CO2t-Bu
Me
Dimerization
CO2R
Me
O
O
O
H
H
TFA
O
CO2t-Bu
Me
O
H
H
Me
O
O
O
O
Me
CO2R
O
Me
R = t-Bu
R = H, (+)-torreyanic acid
Diels-Alder
reaction
O
O
O
(39%)
Me
O
O
Me
O
J. A. Porco and co-workers, J. Am. Chem. Soc. 2000, 122, 10484.
CO2t-Bu
Me
6-Electrocyclic Reactions:
One of Three Pericyclic Reactions in a Colchicine Total Synthesis
O
Cl
O
MeO
O
MeO
O
MeO
MeO
MeO
Cl
O
MeO
Diels-Alder
reaction
MeO
O
O
H
O
-[CO2]
Cl
O
MeO
Retro
O Diels-Alder
reaction
MeO
O
6-disrotatory electrocyclic ring openings are
often referred to as norcaradiene rearrangements
colchicine
MeO
MeO
O
H
O
1. MeOH,
H2SO4
2. CH2N2
MeO
Cl
MeO
CO2Me
MeO
CO2Me
6disrotatory
opening
MeO
MeO
t-BuOK MeO
CO2Me
25 °C
MeO
CO2Me
norcaradiene derivative
A. Eschenmoser and co-workers, Helv. Chim. Acta 1961, 44, 540.
CO2Me
H CO2Me
Hetero Diels-Alder Reactions:
Oxime Ethers as Diene Components
O
TIB,
175 °C, O
36 h
O
N
Me Hetero
nPr
DielsOR
Alder
R = Me or Bn
nPr
-[ROH]
(70%)
N
Me
OR
O
O
nPr
N
MeO
MeO
Me
nPr
N
Me
Me
A, 25 °C, (97%)
45 min (100% exo)
O
Me
Rare dienes unless used
in an intramolecular sense
O
A
O
Me
HO
OH
O
O
Me
N
Me
rubrolone aglycon
Me
O
O H H
O
O
H
H
MeO
MeO
nPr
MeO
O
MeO
Me
O
Me
N
nPr
O
N
Me
exo transition state
D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.
Me
6-Electrocyclic Reactions:
A Pericyclic Reaction in a Rubrolone Total Synthesis
Me
Me
Me
O H H
O
Me
O
H
H
MeO
MeO
nPr
O
1. NBS,
MeOH
2. TFA
(80%)
N
O H H
O
Me
Me
O
H
H
Br
O H
Me
O
OMe
O
O
H
DBU
O
OMe
O
O
nPr
N
nPr
Me
N
Me
aq. TFA
OH
HO
OH
OH O
HO
O
O
6disrotatory
opening
O (72% overall)
O
nPr
O H
Me
O
O
H
OH
O
O
Me
N
Me
rubrolone aglycon
Me
N
Me
nPr
D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.
N
Me
6-Electrocyclic Reactions:
A Pericyclic Reaction in the Synthesis of Tropoisoquinolines
MeO
MeO
MeO
MeO
O
N
MeO
O
MeO
Me
O
N
MeO
CH3Cl, pyridine,
25 °C, 2.5 h
Diels-Alder
reaction
O
HCl, EtOAc
25 °C,
6 days
Me
O
OH
O
H O
MeO
N
MeO
Retro
Diels-Alder
reaction
Me
H
O
Me
H O
Me
Me
6-disrotatory
ring opening
MeO
MeO
MeO
MeO
MeO
N
+ MeO
MeO
MeO
MeO
N
CH2N2
MeO
MeO
N
(76%)
(1:1)
O
OMe
imerubrine
OMe
O
isoimerubrine
(40-60%)
KOH,
MeOH
MeO
O
OH
grandirubrine
D. L. Boger, K. Takahashi, J. Am. Chem. Soc. 1995, 117, 12452.
N
O
granditropone
8-Electrocyclic Reactions:
Possible Role in the Biosynthesis of Trichodimerol
O
Aldol
reaction
HO
O
Me
Me
Me
OH
Me
Me
Me
HO
O
OH O
trichodimerol
O
HO
Me
Me
O
Me
OH
Me
RO
OR
O
[4+4]
8-electron
electrocyclization
HO
Me
Me
O
Me
OH
Me
RO
OR
K. C. Nicolaou and co-workers, Chem. Eur. J. 1999, 5, 3651.
Electrocyclization Cascades:
Black's Hypothesis for the Biosynthesis of the Endiandric Acids
A = conrotatory 8
electrocyclization
B = disrotatory 6
electrocyclization
A
H
H
B
CO2H
HO2C
HO2C
Ph
H
endiandric acid D
Ph
A
H
H
B
CO2H
CO2H
Ph
Ph
Ph
Ph
H
Ph
H
H
H
CO2H
H
endiandric acid E
H
CO2H
endiandric acid A
D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.
Diels-Alder
reaction
Electrocyclization Cascades:
Black's Hypothesis for the Biosynthesis of the Endiandric Acids
A = conrotatory 8
electrocyclization
H endiandric acid C
H
H
Diels-Alder
Ph reaction
HO2C
H
H
A
H
B
H
H
HO2C
CO2H
Ph
HO2C
Ph
H
Ph
endiandric acid G
H
H
A
B
CO2H
Ph
CO2H
Ph
Ph
H
H
endiandric acid F
CO2H
Ph
B = disrotatory 6
electrocyclization
H
H
H
Diels-Alder
reaction
H
H
endiandric acid B
CO2H
D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.
Electrocyclization Cascades:
Total Synthesis of the Endiandric Acids
CO2Me
1. H2, Pd/BaSO4,
quinoline
2. toluene, 100 °C
Ph
CO2Me
Ph
same conditions
CO2Me
Ph
Ph
CO2Me
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.
For a review, see Classics in Total Synthesis I.
Electrocyclization Cascades:
Total Synthesis of the Endiandric Acids
CO2Me
CO2Me
1. H2, Pd/BaSO4,
quinoline
2. toluene, 100 °C
Ph
Ph
same conditions
CO2Me
Ph
Ph
CO2Me
Ph
H
Ph
H
H
H
CO2Me
H
H
endiandric acid A
H
H
H
H
H
endiandric acid B
H
MeO2C
H
CO2Me
H
H
H
H
endiandric acid C
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.
For a review, see Classics in Total Synthesis I.
Ph
Current Frontiers in Electrocyclic Reactions:
Access to Benzodiazepine Derivatives
R
O
Me
N
Cl
N N
4-conrotatory
electrocyclic
ring opening
OR
Li
N
R
N
N
N
8-conrotatory
electrocyclization
O
N
O
O
O
R
N
NH
(67-82%)
diazepam (valium)
H. Nemoto and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP.
R
N
N