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TRANSCRIPT
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Electrocyclic Reactions
OO
OMeMe
OPMB
XX
OTBSLecture Notes
Key Reviews:
Electrocyclic Reactions:Comprehensive Organic Synthesis, Vol. 5, p. 699
Nazarov Cyclization (4π-electrocyclization):S. E. Denmark, Org. React. 1994, 45, 1-158.
-
A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
OO
OMeMe
OPMB
XX
OTBS
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
HO
Me
MeMe Me
Me
precalciferol(previtamin D)
HO
MeMe Me
Me
ergosterol
HO
MeMe Me
Me
lumisterol
Me
H
Me
H
hν
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A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
OO
OMeMe
OPMB
XX
OTBS
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
HO
Me
MeMe Me
Me
precalciferol(previtamin D)
HO
MeMe Me
Me
ergosterol
HO
MeMe Me
Me
lumisterol
Me
H
Me
H
hν
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A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
OO
OMeMe
OPMB
XX
OTBS
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
HO
Me
MeMe Me
Me
precalciferol(previtamin D)
HO
MeMe Me
Me
ergosterol
HO
MeMe Me
Me
lumisterol
Me
H
Me
H
HO
MeMe Me
MeMe
H
HO
MeMe Me
MeMe
H
pyrocalciferol
isopyrocalciferol
100-200 °Chν
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A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
OO
OMeMe
OPMB
XX
OTBS
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
HO
Me
MeMe Me
Me
precalciferol(previtamin D)
HO
MeMe Me
Me
ergosterol
HO
MeMe Me
Me
lumisterol
Me
H
Me
H
HO
MeMe Me
MeMe
H
HO
MeMe Me
MeMe
H
pyrocalciferol
isopyrocalciferol
100-200 °Chν6π-conrotatory
electrocyclization 6π-disrotatoryelectrocyclization
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBSA
BB
AA
AB
B
A
BB
AA
BA
B
Conrotatory versus disrotatory cyclization: how can I differentiate them?
or
B
AB
A
disrotatoryring opening
conrotatoryring opening
conrotatoryring closing
disrotatoryring closing
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBSA
BB
AA
AB
B
A
BB
AA
BA
B
Conrotatory versus disrotatory cyclization: how can I differentiate them?
A
B
A
BAB
AB A
BB
A
or
B
AB
A
disrotatoryring opening
conrotatoryring opening
conrotatoryring closing
disrotatoryring closing
disrotatoryring opening
disrotatoryring closing
conrotatoryring opening
conrotatoryring closing
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A Series of Observations:The Birth of the Woodward-Hoffmann Rules and Electrocyclizations
OO
OMeMe
OPMB
XX
OTBS
E. Havinga and co-workers, Tetrahedron 1960, 11, 276.E. Havinga and co-workers, Tetrahedron 1961, 12, 146.
HO
Me
MeMe Me
Me
precalciferol(previtamin D)
HO
MeMe Me
Me
ergosterol
HO
MeMe Me
Me
lumisterol
Me
H
Me
H
HO
MeMe Me
MeMe
H
HO
MeMe Me
MeMe
H
pyrocalciferol
isopyrocalciferol
100-200 °Chν6π-conrotatory
electrocyclization 6π-disrotatoryelectrocyclization
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
The Woodward-Hoffmann rules predict that photochemical reactionswill be precisely complementary to thermal reactions. Thus, what is allowed
photochemically is forbidden thermally, and vice versa. This prediction is true.
butadiene HOMO (Ψ2)(4π-electron system)
Thermal reactionbutadiene HOMO (Ψ3)(4π-electron system)
disallowedallowed
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
Photochemical reaction
disallowed allowed
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBSA
BB
AA
AB
B
A
BB
AA
BA
B
Conrotatory versus disrotatory cyclization: how can I differentiate them?
A
B
A
BAB
AB A
BB
A
or
B
AB
A
disrotatoryring opening
conrotatoryring opening
conrotatoryring closing
disrotatoryring closing
disrotatoryring opening
disrotatoryring closing
conrotatoryring opening
conrotatoryring closing
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
Guiding Principle:Electron donors go outward;
electron withdrawers go inward.4π-conrotatoryelectrocyclicring opening
F
F
CF3
FCF3
FΔ
F
F
F
CF3F
CF3
F
F
CF3
FCF3
FF
F
CF3
CF3F
Fhν
4π-disrotatoryelectrocyclicring opening
What happens when the rotating groups are different? Will one product predominate?
Here, the products aredegenerate; i.e., the same
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O
O
OH
H
O
O
O
HH
HH
H
H
hν4π-disrotatory
electrocyclization
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O
O
OH
H
O
O
O
HH
HH
H
H
hν4π-disrotatory
electrocyclization
O
O
OH
H
H
H
H
O
O
O
HH
Himpossiblestructure!4π-conrotatory
electrocyclizationtrans-fused
4-membered ring
Δ
X
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
HH hν
4π-disrotatoryelectrocyclization
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
HH
HH
H
HH
H
hν4π-disrotatory
electrocyclization
4π-conrotatoryelectrocyclization
Δ
X impossiblestructure!
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
impossiblestructure!
cb
a
d
bd
a
c
H
H
a
c
bd
cb
a
d
bc
a
d
H
H
a
d
bc
hν
6π-disrotatoryelectrocyclization
6π-conrotatoryelectrocyclization
Δ
Xhν
8π-conrotatoryelectrocyclization
8π-disrotatoryelectrocyclization
Δ
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
impossiblestructure!
cb
a
d
bd
a
c
H
H
a
c
bd
cb
a
d
bc
a
d
H
H
a
d
bc
hν
6π-disrotatoryelectrocyclization
6π-conrotatoryelectrocyclization
Δ
Xhν
8π-conrotatoryelectrocyclization
8π-disrotatoryelectrocyclization
Δ
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O OH
OH
Δ4π-conrotatory
electrocyclizationO
Note: Electrocyclic reactions can involve both cationic and anionic intermediates
H3PO4
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O OH
OH
Δ4π-conrotatory
electrocyclizationO
Note: Electrocyclic reactions can involve both cationic and anionic intermediates
H3PO4
This reactionis known as the
Nazarovcyclization and
was firstdiscovered
in 1948
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O OHH3PO4
OH O
The Nazarov reaction is highly regioselective based on carbocation stability
S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
O OHH3PO4
OH O
The Nazarov reaction is highly regioselective based on carbocation stability
O OHFeCl3
OH O
TMS TMS TMS
Cl
S. E. Denmark and co-workers, J. Am. Chem. Soc. 1982, 104, 2642.
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Electrocyclic Reactions:First Discovery of an Electrocyclic Reaction
For discussion, see: E. J. Corey, F. N. M. Kuhnle, Tetrahedron Lett. 1997, 38, 8631.
Alexander Borodin (1833-1887)
Piece you heard was from the Prince Igor opera:Polovetsian Dances
ONH3
Ph
N N
Ph
Ph
Ph
N N
Ph
Ph
NHN
Ph
Ph Ph
6π-disrotatoryelectrocyclization
NH2H2N
Ph Ph
NH2H2N
Ph Ph
Process is still used today . . .
120 °C
amarine
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Electrocyclic Reactions:First Discovery of an Electrocyclic Reaction
For discussion, see: E. J. Corey, F. N. M. Kuhnle, Tetrahedron Lett. 1997, 38, 8631.
Alexander Borodin (1833-1887)
Piece you heard was from the Prince Igor opera:Polovetsian Dances
ONH3
Ph
N N
Ph
Ph
Ph
N N
Ph
Ph
NHN
Ph
Ph Ph
6π-disrotatoryelectrocyclization
NH2H2N
Ph Ph
NH2H2N
Ph Ph
Process is still used today . . .
120 °C
amarine
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
OTs
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
MeMeMe
Me OTs
krel1
MeMe
OTs Me
Me
40,000
OTs
4
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
MeMeMe
Me OTsMe
Me
krel1
MeMe
OTs
MeMe
Me
Me
40,000
OTs
4
lobe system requiredafter opening for cation
Rule: groups oppositeleaving group migrate
outwards
-
Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
krel1
1,000,000
Rule: groups oppositeleaving group migrate
outwards
H OTs Essentially animpossible structure!
TsO H
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Electrocyclic Reactions:Background and Basic Principles
OO
OMeMe
OPMB
XX
OTBS
e thermal photochemical
2 4 6 8
disrotatoryconrotatorydisrotatoryconrotatory
conrotatorydisrotatoryconrotatorydisrotatory
krel1
1,000,000
Rule: groups oppositeleaving group migrate
outwards
H OTs Essentially animpossible structure!
TsO H
LVG1
LVG2 LVG2Can predict easilywhich of the two
groups will depart
-
OO
OMeMe
OPMB
XX
OTBS
W. Oppolzer, C. Robbiani, Helv. Chim. Acta 1983, 66, 1119.
O
O
N OOBnO
O
O
O
N
O
BnOO
O
O
O
N
O
BnOO
O
O
O
NMeO
O
H
H
OH
o-quinodimethane
chelidonine
o-xylene, Δ
IntramolecularDiels-Alder (73%)
4π-conrotatoryelectrocyclicring opening
Electrocyclic Reactions:Examples You Have Already Seen
Remember: Electron donatingsubstituents turn outward
-
Electrocyclic Reactions:Examples You Have Already Seen
P. Garner, W.B. Ho, H. Shin, J. Am. Chem. Soc. 1993, 115, 10742.
N
N
HCO2H
Me
OH
quinocarcin
N
O
O
HOMeO
Me
MeN3toluene,
25 °C
(99%)
N
O
O
HOMeO
MeNN
N
Me
N
O
O
HOMeO
Me
N Mehν,
Pyrexdioxane(90%)
hν,quartz
MeON
HOMeO
Me
NO
O
Me
NO2S
OMe Me
Me
N
N
CONX
Me
MeO
O
O
HO
4π-disrotatoryelectrocyclicring opening
A
A[3+2]
addition
[3+2] addition
exo product
H
H
-
4π-Electrocyclic Reactions:Part of a Total Synthesis of Periplanone B
OO
OMeMe
OPMB
XX
OTBS
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
OH
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
+
-
4π-Electrocyclic Reactions:Part of a Cascade Sequence to Coriolin
OO
OMeMe
OPMB
XX
OTBS
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.
O
O
i-PrO
i-PrO
O OMeMe
Li
O
i-PrO
i-PrO
O
O
O
MeMe i-PrO Oi-Pr
OO
O
Oring
openingtrans AdditionLi
4π-Electronconrotatory
i-PrO
i-PrO
OO
MeMe
HO
O
Ringopening
i-PrO
i-PrO
OO
O
O
MeMe
H
Dianionicoxy-Cope
i-PrO
i-PrO
OO
MeMe
HO
O
H
i-PrOHO
H
MeMe
i-PrO
H
O
O
aq. NH4Cl(24%)
Aldol
Note: The electrocyclizationpoints the carbon substituents inward
-
6π-Electrocyclic Reactions:Erasure of the Ring-Opened Product
OO
OMeMe
OPMB
XX
OTBS
E. J. Corey, A. G. Hortmann, J. Am. Chem. Soc. 1965, 87, 5736.
OO
MeMe
Me
dihydrocostunolide
H
OO
MeMe
H
Me
HO
Br
OO
MeMe
H
Me
HOO
O
MeMe
H
Me
HHO
OO
MeMe
H
Me
HOO
MeMe
Me Hhν, MeOH,
-18 °C
Al(Oi-Pr)3,i-PrOH, Δ
Al2O3,pyridine,
220 °C
LiBr,DMF,
120 °C
What is the name reaction in the second step?
H2,Raney NiMeOH,-18 °C
6π-conrotatoryelectrocyclicring opening
25 °C
OO
MeMe
H
Me
H
6π-disrotatoryelectrocyclization
-
6π-Electrocyclic Reactions:Total Synthesis of Torreyanic Acid
OO
OMeMe
OPMB
XX
OTBS
J. A. Porco and co-workers, J. Am. Chem. Soc. 2000, 122, 10484.
HO
O
O
O
Me
CO2t-BuMe
O
O
O
O
Me
CO2t-BuMe
Dess-Martinperiodinane,CH2Cl2, SiO2,
25 °C, 1 h
Tandem oxidation/6π-conrotatory
electrocyclization
O
O
O
O
Me
CO2t-Bu
O
O
O
OCO2t-Bu
Me
MeMe
Dimerization
Diels-Alderreaction
(39%)OOO
OMe
CO2RH
O
OMe
CO2R
O O
H
H
H
Me
Me
TFA R = t-BuR = H, (+)-torreyanic acid
-
6π-Electrocyclic Reactions:One of Three Pericyclic Reactions in a Colchicine Total Synthesis
OO
OMeMe
OPMB
XX
OTBS
A. Eschenmoser and co-workers, Helv. Chim. Acta 1961, 44, 540.
O
O
MeO
MeOMeO
O
O
O
Cl
Diels-Alderreaction
MeO
MeOMeO
OH
O
O
Cl
O O
MeO
MeOMeO
OH
O
O
Cl
MeO
MeOMeO
CO2Me
CO2Me
H
ClMeO
MeOMeO
CO2Me
CO2Me
norcaradiene derivative
MeO
MeOMeO
CO2Me
CO2Me
colchicine
RetroDiels-Alder
reaction
-[CO2]
t-BuOK
1. MeOH, H2SO42. CH2N2
6π-disrotatory electrocyclic ring openings are often referred to as norcaradiene rearrangements
6π-dis-
rotatoryopening
25 °C
-
Hetero Diels-Alder Reactions:Oxime Ethers as Diene Components
D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.
N
O
MeN
O
MenPrOR
N
O
MeOR
R = Me or Bn
TIB,175 °C,
36 hHeteroDiels-Alder
nPr
-[ROH](70%)
nPr
N MenPr
MeOMeO
O
O
O
O
MeMe A, 25 °C,45 min
NMe
nPr
OO
O
O
MeMe
MeOMeO
exo transition state
(97%)(100% exo)
N MenPr
MeOMeO
O
OO
O
MeMe H
HH
H
N
O
O
MeMe
OHHO
rubrolone aglycon
Rare dienes unless usedin an intramolecular sense
A
-
6π-Electrocyclic Reactions:A Pericyclic Reaction in a Rubrolone Total Synthesis
D. L. Boger, S. Ichikawa, H. Jiang, J. Am. Chem. Soc. 2000, 122, 12169.
N MenPr
MeOMeO
O
OO
O
MeMe H
HH
H
N
O
O
MeMe
OHHO
rubrolone aglycon
N MenPr
O
OO
O
MeMe H
HH
H
BrOMe
O
N MenPr
O
OO
O
MeMe H
H
OOMe
N MenPr
OO
O
MeMe H
H
O
N
O
O
MenPr
OOOHHO
OH
OH
6π-dis-
rotatoryopening
1. NBS, MeOH
(80%)2. TFA
DBU
aq. TFA
(72% overall)
-
6π-Electrocyclic Reactions:A Pericyclic Reaction in the Synthesis of Tropoisoquinolines
D. L. Boger, K. Takahashi, J. Am. Chem. Soc. 1995, 117, 12452.
O
O
MeMeH
H
6π-disrotatoryring opening
(40-60%)
N
MeOMeO
MeO
O O
O
O
MeMeN
MeOMeO
MeO
O
ODiels-Alder
reaction
CH3Cl, pyridine,25 °C, 2.5 h
HCl, EtOAc25 °C,6 days
O
O
MeMeH
H
N
MeOMeO
MeO
N
MeOMeO
MeO
Ogranditropone
N
MeOMeO
MeO
O
grandirubrine
KOH,MeOH
OH
N
MeOMeO
MeO
O
imerubrineOMe
N
MeOMeO
MeO
OMe
isoimerubrineO
(76%)
RetroDiels-Alder
reaction
(1:1)
CH2N2+
-
8π-Electrocyclic Reactions:Possible Role in the Biosynthesis of Trichodimerol
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, Chem. Eur. J. 1999, 5, 3651.
Me
O O
OHHOO
O
MeHO
Me OHMe
trichodimerol
MeMe
Aldolreaction
Me
O O
ORRO
MeHO
Me OHMe
8π-electronelectrocyclization
[4+4] Me
O O
ORRO
MeHO
Me OHMe
-
Electrocyclization Cascades:Black's Hypothesis for the Biosynthesis of the Endiandric Acids
OO
OMeMe
OPMB
XX
OTBS
D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.
CO2H
HO2C
Ph
CO2H
PhCO2H
Ph
Ph
HO2CPh
HH
H
CO2H
HH
HPh
endiandric acid D
endiandric acid E
Diels-Alderreaction
A = conrotatory 8πelectrocyclization
B = disrotatory 6πelectrocyclization
A
A
B
B
HH
PhH
HH
endiandric acid A
CO2H
-
Electrocyclization Cascades:Black's Hypothesis for the Biosynthesis of the Endiandric Acids
OO
OMeMe
OPMB
XX
OTBS
D. St. C. Black and co-workers, Aust. J. Chem. 1982, 35, 2247.
Diels-Alderreaction
A = conrotatory 8πelectrocyclization
B = disrotatory 6πelectrocyclization
A
A
B
B
HH
HPh CO2H
endiandric acid F
Ph
HH
HHO2C
endiandric acid G
HO2CH
H
H HH
Ph
endiandric acid C
H
H
H H
PhH
HH CO2H
Diels-Alderreaction
endiandric acid B
Ph
Ph
Ph
Ph
CO2H
CO2H
HO2C
CO2H
-
Electrocyclization Cascades:Total Synthesis of the Endiandric Acids
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.For a review, see Classics in Total Synthesis I.
CO2Me
Ph Ph CO2Me
CO2Me
Ph PhCO2Me1. H2, Pd/BaSO4,
quinoline2. toluene, 100 °C
same conditions
-
Electrocyclization Cascades:Total Synthesis of the Endiandric Acids
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1982, 104, 5555.For a review, see Classics in Total Synthesis I.
CO2Me
Ph Ph CO2Me
CO2Me
Ph PhCO2Me1. H2, Pd/BaSO4,
quinoline2. toluene, 100 °C
H H
PhH
HHendiandric acid A
CO2Me
MeO2CH
H
H HH
Ph
endiandric acid CHH
H H
PhH
HH CO2Meendiandric acid B
same conditions
-
Current Frontiers in Electrocyclic Reactions:Access to Benzodiazepine Derivatives
H. Nemoto and co-workers, J. Am. Chem. Soc. 2006, 128, 13072.
OR
LiN N O
R
N N
OR
NN
NN
O R
NHN
O R
diazepam (valium)
4π-conrotatoryelectrocyclicring opening
8π-conrotatoryelectrocyclization
Cl N
NOMe
(67-82%)