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The Diels-Alder Reaction
OO
OMeMe
OPMB
XX
OTBSLecture Notes
Key Reviews:
Total SynthesisK.C. Nicolaou, S.A. Snyder, T. Montagnon, G. Vasillikogiannakis,
Angew. Chem. Int. Ed. 2002, 41, 1668.
AsymmetricE.J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650.
HeteroD. L. Boger, Comprehensive Organic Synthesis, Vol. 5., 1991, p. 451-512.
BiomimeticE. M. Stocking, R. M. Williams, Angew. Chem. Int. Ed. 2003, 42, 3078.
TransannularP. Deslongchamps, Tetrahedron 2001, 57, 4243.
The Diels-Alder Reaction:Regioselectivity
OO
OMeMe
OPMB
XX
OTBSEDG
EWGEDG
EWG
EWG EWG
EDG EDG
EWG EWG
EDG2 EDG2
EDG1 EDG1
OMe
OMe
MeO
OMe
MeO
MeO
O
O
O
synergisticdiene
+
+
+
+
+
+or
H
H
H
Regioselective Diels-Alder Reactions:Danishefsky's Diene
S. J. Danishefsky, T. Kitahara, J. Am. Chem. Soc. 1974, 96, 7808.S. J. Danishefsky, Acc. Chem. Res. 1981, 14, 400.
OMe
TMSODanishefsky's
diene
+R1 EWG
Diels-Alder
reaction
OMeEWGR1
TMSO O
EWGR1H
R2 R3
Synergistic diene: the methoxy and silyloxy substituents reinforce each other in termsof regioselectivity and provide sufficient electron density on the diene subunit that most
Diels-Alder reactions proceed with good dienophiles at low temperature (withoutthe need for Lewis acid catalysis) with incredible regioselectivity.
R3 R3R2 R2
Regioselective Diels-Alder Reactions:Danishefsky's Diene
OO
OMeMe
OPMB
XX
OTBS
S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1979, 101, 7013.
OMe
TMSO SO Ph TMSO
MeO
SOPh
1. 9-BBN2. NaOH
HO O
CO2NaCO2Na
+ 100 °C
Diels-Alderreaction
AcOH, EtOAc
neat, 26 h
O CO2Me
OMe
O
O
O CO2Me
OMe
O
OO
OMe
CO2Me
disodium prephenate
Regioselective Diels-Alder Reactions:Danishefsky's Diene
OO
OMeMe
OPMB
XX
OTBS
S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1992, 114, 8883.S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1994, 116, 11213.
MeTBSO
O
O
+THF, 25 °C,
5 days
Diels-Alderreaction
O
OH
H
TBSOMe
H
O
H
MeCHOH
HOO
Me HO
HOO
Me H
benzene,
O O
(94%)(100% endo)
CHOMe
(90%, 100% endo)Intramolecular
Diels-Alderreaction
80 °C, 13 h
Me
HOO
Me OH
OHO
myrocin C
The Rawal Diene - Another Synergistic Diene
OSePh
Br
OTBS
NMe2
+
OSePh
O
H
BrO
O
H
Br
O
OH
H
Br
H2O2,pyr
OH
H Ni(cod)2O
O
H
precursor to platencin
DIBAL-H
J. Hayashida, V. Rawal, Angew. Chem. Int. Ed. 2008, 47, 4373.
Rawal diene
40 oC;then HF(72%) (71%)
(69%over two
steps)
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBSEDG1
However . . .
EDG2
EDG1
EGD2
EDG2
EDG1
Predictions are hard since these groups are battling
each other for control
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBSEDG1
However . . .
EDG2
EDG1
EGD2
EDG2
EDG1
Predictions are hard since these groups are battling
each other for control
NHCO2R SR OR alkyl> > >
What Determines Who Wins? Both position and electronics matter
MeMe
O MeMe CHO The C-1 methyl group
dominates the reaction
MeO O
MeMe MeO COMeMe
PhS PhS
+
+
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBSEDG1
However . . .
EDG2
EDG1
EGD2
EDG2
EDG1
Predictions are hard since these groups are battling
each other for control
NHCO2R SR OR alkyl> > >
What Determines Who Wins? Both position and electronics matter
MeMe
O MeMe CHO The C-1 methyl group
dominates the reaction
MeO O
MeMe MeO COMeMe
PhS PhSMe
EtOO Me
EtO CHO When a group is at C-1, it tends to win even if the C-2
group is a better donor
+
+
+
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBS
+Me
OMe
CO2Me
O2N
Me
OMeNO2
CO2Me Me CO2Me
Me
CO2Me
+Me
OMe
"reverse polarity"dienophile
CO2Me
Me
OMeCO2Me
acid
acid
These contrasting outcomes are quite striking
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBS
+Me
OMe
CO2Me
O2N
Me
OMeNO2
CO2Me Me CO2Me
Me
CO2Me
+Me
OMe
"reverse polarity"dienophile
CO2Me
Me
OMeCO2Me
acid
acid
These contrasting outcomes are quite striking
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBS
+Me
OMe
CO2Me
O2N
Me
OMeNO2
CO2Me Me CO2Me
Me
CO2Me
+Me
OMe
"reverse polarity"dienophile
CO2Me
Me
OMeCO2Me
acid
acid
These contrasting outcomes are quite striking
The Diels-Alder Reaction: General Principles
OO
OMeMe
OPMB
XX
OTBS+ 200 °C
+
O
Me
+
O
OSiMe3 O
80 °C
0 °C
O
OMe3SiO
H
H
O
Synthetic Equivalence: Alternate Forms of "Impossible" Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS
EtO
SO2Ph
SO2Ph EtO
SO2Ph
EtOΔ
OO O
NO2
NO2n-Bu3SnH,
AIBN 2°, 3°, allylic,benzylic nitro only
+
1. LDA, alkyl halide2. Na/Hg acid
1. Na/Hg2. acid
+
NO2
Synthetic Equivalence: Alternate Forms of "Impossible" Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS•PPh3
Br
+CH3CN,150 °C LDA, HCHO
(80%)PPh3Br
PPh3Br
Diels-Alderreaction Wittig Reaction
Synthetic Equivalence: Alternate Forms of "Impossible" Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS
For a review, see: O. De Lucchi, G. Modena, Tetrahedron 1984, 40, 2585.
+SO2Ph SO2Ph Na/Hg
SO2Ph
Me3Si
Me3SiSO2Ph
SO2Ph
PhO2SSO2Ph
SO2Ph
SO2Ph SO2Ph
Me3Si
SO2Ph
PhO2S
+
+
toluene115 °C
toluene115 °C
toluene160 °C TBAF
Na/Hg
Synthetic Equivalence: Alternate Forms of "Impossible" Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS
For a review, see: O. De Lucchi, G. Modena, Tetrahedron 1984, 40, 2585.
+SO2Ph SO2Ph Na/Hg
SO2Ph
Me3Si
Me3SiSO2Ph
F
SO2Ph
PhO2SSO2Ph
SO2Ph
SO2Ph SO2Ph
Me3Si
SO2Ph
PhO2S
+
+
toluene115 °C
toluene115 °C
toluene160 °C TBAF
Na/Hg
Synthetic Equivalence: Alternate Forms of "Impossible" Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS
E. J. Corey and co-workers, J. Am. Chem. Soc. 1969, 91, 5675.
CNCl+ Cu(BF4)2, 0 °C
Lewis acid-catalyzedDiels-Alder
KOH, H2O
HO
HO
CO2HMe
HOPGF2α
(>90%)(80%)
H
MeO H
CNCl
MeO H
O
OMe
•O
CNCl AcO CN ClOC Cl O2N
Words of Wisdom from Our Synthetic Elders
OO
OMeMe
OPMB
XX
OTBS
Albert Eschenmoser
Whenever in the synthesis of organic molecules one is confronted with a situation where the success
of an intermolecular synthetic process is thwarted by any type of
kinetically controlled lack of reactivity, one should look out for
opportunities of altering the structural stage in such a way that
the critical synthetic step can proceed intramolecularly rather than
intermolecularly.
A. Eschenmoser, Quart. Rev. 1970, 24, 366.
Improving Diels-Alder Reactivity:Intramolecular Reactions Via Temporary Tethers
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, Nature 1994, 367, 630.
OH
Me OEt
OO
OOH
+PhB(OH)2 O
O
EtO2CMe
O
BO Ph
benzene,80 °C, 48 h
-[H2O]
O O
OHHO
HO OHMe Me
Boronate cleavage
MeEtO2C
OO
EtO2CMe
O
BO Ph
25 °C, 1 h
O OH
H
OHMe
O
EtO2C
O
OHO
OAcH
BzO
AcOMe
MeMe
HO
ONH
Ph
O
OH
PhO Me
Taxol
C
Improving Diels-Alder Reactivity:Intramolecular Reactions Via Temporary Tethers
OO
OMeMe
OPMB
XX
OTBS
A. D. Brosius, L. E. Overman, L. Schwink, J. Am. Chem. Soc. 1999, 121, 700.
IntramolecularDiels-Alder
NBoc
NTs
N
NTs
SiMeMe
CO2Me
TMSI, 2,6-lutidine, CH2Cl2, 25 °C;MeOH, NaOH;
TfOMe2SiCO2Me
Et3N, A
NTs
NSi
MeMe
H
H
H
HCO2Me
(5:1 ds)
0→25 °C, 3.5 h
1. HF•pyr, 25 °C
2. mesitylene, ΔLactamizationN N
Ts
H
H
SiMe2F
O(+)-aloperine
N NH
H
H
A
Improving Diels-Alder Reactivity:Intramolecular Reactions Via Temporary Tethers
OO
OMeMe
OPMB
XX
OTBS
A. D. Brosius, L. E. Overman, L. Schwink, J. Am. Chem. Soc. 1999, 121, 700.
IntramolecularDiels-Alder
NBoc
NTs
N
NTs
SiMeMe
CO2Me
TMSI, 2,6-lutidine, CH2Cl2, 25 °C;MeOH, NaOH;
TfOMe2SiCO2Me
Et3N, A
NTs
NSi
MeMe
H
H
H
HCO2Me
(5:1 ds)
0→25 °C, 3.5 h
F
1. HF•pyr, 25 °C
2. mesitylene, ΔLactamizationN N
Ts
H
H
SiMe2F
O(+)-aloperine
N NH
H
H
A
Lewis Acid Complexation:A Way to Improve Reaction Conditions and Endo Selectivity
OO
OMeMe
OPMB
XX
OTBS
EDGEWG
LUMO
HOMO
Normal demandDiels-Alder
reaction(HOMOdiene-
LUMOdienophile)
E
ΔE1
EDGEWG
LUMO
HOMO
Lewis acid-catalyzed
Diels-Alderreaction
ΔE2
LA Lewis acid complexationlowers the energy of the LUMO of the diene.
Consequently, reactionsoccur at lower temperatureand are more endo selectivesince they are better underkinetic control.
Regioselective Diels-Alder Reactions:Using Lewis Acid Catalysis
OO
OMeMe
OPMB
XX
OTBSO
Me
OMe
+
O
O
OMeH
O
Me
Me
MeO
O
OMeH
MeMe
heat (100 °C)
BF3•OEt2 (-16 °C)
SnCl4 (-16 °C)
1
4
1
1
1
20
most Lewisbasic carbonyl
+
Regioselective Diels-Alder Reactions:Using Lewis Acid Catalysis
OO
OMeMe
OPMB
XX
OTBSO
Me
OMe
+
O
O
OMeH
O
Me
Me
MeO
O
OMeH
MeMe
O
O
MeO Me
heat (100 °C)
BF3•OEt2 (-16 °C)
SnCl4 (-16 °C)
1
4
1
1
1
20
most Lewisbasic carbonyl
vs.
+
BF3 O
O
MeO Me
SnClCl
Regioselective Diels-Alder Reactions:Using Lewis Acid Catalysis
OO
OMeMe
OPMB
XX
OTBS
Y. Kishi and co-workers, J. Am. Chem. Soc. 1972, 94, 9217.Y. Kishi and co-workers, J. Am. Chem. Soc. 1972, 94, 9219.
OH
OH
O
(83%)
Me
Me
N
+
O
O
MeH
MeN
tetrodotoxin
O
Lewis acid-catalyzed intermolecular
Diels-Alder reaction
O
O
Me
HN NH
O
H2NHO
HO
OH
N
Me
OHSnCl4,MeCN
SnCl
Cl
HO
In the absence of this Lewis acid,1,3-butadiene engages the other olefin
of the quinone exclusively!
For first LA catalyzed D-A reaction, see: P. Yates, P. Eaton, J. Am. Chem. Soc. 1960, 82, 4436.
Regioselective Diels-Alder Reactions: Early Examples
OO
OMeMe
OPMB
XX
OTBS
R. B, Woodward and co-workers, J. Am. Chem. Soc. 1956, 78, 2023.R. B, Woodward and co-workers, Tetrahedron 1958, 2, 1.
O
O
O
O
+
CO2Me CO2Me
NH
NH H
HMeO2C
OMeO
OOMe
OMeOMe
AB C
D
MeO
H
H
reserpine
O
O
MeO2C
benzeneDiels-Alder
reaction D EΔ
E
(27%)
endo TS
Asymmetric Diels-Alder Reactions: Diastereoselective
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, J. Org. Chem. 1985, 50, 1440.
CO2Me
TBDPSOH
HMe
TBDPSO
Me
MeO2C toluene,130 °C, 48 h
O
Me
Me
CO2Me Me
H
H
H
HMe
O NH
IntramolecularDiels-Alder
antibiotic X-14547A
(70%)
Asymmetric Diels-Alder Reactions: Diastereoselective
OO
OMe
Me
OPMB
XX
OTBS
E. J. Corey and co-workers, J. Am. Chem. Soc. 1975, 97, 6908.
HO
HO
CO2HMe
HOPGF2α
H
Me OMe
MeO
MeO H
O OR(89%)(97:3 diastereoselectivity)Cl3Al
Chiral auxiliary-mediated Diels-Alder
OBn
R = MeMe
Me
PhAlCl3, CH2Cl2, -55 °C
Diastereoselective Diels-Alder Reactions:Using Implanted Auxiliaries
OO
OMeMe
OPMB
XX
OTBS
D. A. Evans, W. C. Black, J. Am. Chem. Soc. 1993, 115, 4497.
O
O
OX
HHH
H
OMe
O OMe
NMe2
H
Me
(+)-lepicidin A
O
O
OTBS
H
Me
OTIPS
H
Me
HH
O
N O
O
Bn
OTES
O
O
Me
OTIPS
H
MeOTES
NO
OO AlMe
MeRTBSO
OTBS
O N
OO
Bn
endo transition state
Stillecoupling
Me2AlCl,CH2Cl2
0→25 °C
(71%)(10:1 ds)
Lewis acid-catalyzedDiels-Alder reaction
H
R = macrocycle
O
OMeOMeOMe
MeX =
Note: Withoutauxiliary, the alternateendo product results
preferentially
Asymmetric Diels-Alder Reactions: Enantioselective
OO
OMeMe
OPMB
XX
OTBS
E. J. Corey and co-workers, J. Am. Chem. Soc. 1989, 111, 5493.
HO
HO
CO2HMe
HOPGF2α
H
+
O
N O
O NAlN
Ph Ph
Me
NNAl
R Me
O
NO
ORH
BnO
BnO H
O N O
O
R = SO2CF3
CH2Cl2,-78 °C, 18 hAsymmetricDiels-Alder
OBn
(93%)(95% ee)
endo adduct
RR
Asymmetric Diels-Alder Reactions: Enantioselective
OO
OMeMe
OPMB
XX
OTBS
E. J. Corey and co-workers, J. Am. Chem. Soc. 1992, 114, 8290.
HO
HO
CO2HMe
HOPGF2α
H
+
exo adduct
BnO H
BrCH2Cl2,
-78 °C, 8 hAsymmetricDiels-Alder
OBn
(82%)(19:1 exo/endo)
N BO
OHN
H
HOBn
O
Br
H
OB N
O
HN
H HTs
Ts
CHOBrCHO
H
(92% ee)
Enantioselective Diels-Alder ReactionsUsing Chiral Oxaborolidinium Cations
OO
OMeMe
OPMB
XX
OTBS
ON BH
Me
HO
NB
O
R
XX
H
HNTf2
E.J. Corey, T. Shibata, T.W. Lee, J. Am. Chem. Soc. 2002, 124, 3808.D.H. Ryu, T.W. Lee, E.J. Corey, J. Am. Chem. Soc. 2002, 124, 9992.
or OTfN
BO
R
XX
H
NH OH
XX
HO B OB O B
R
RR+ toluene
Δ, 12 h tolueneor CH2Cl2,
-30 °C, 15 min
HNTf2or TfOH
Me
Me CHO+
Me
MeCHO
NB
O
o-tol
PhPh
H
HNTf2
toluene,-78 °C, 13 h
(96%)(97% e.e.)
Me
For a review on enantioselective Diels-Alder reactions, see:E.J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650.
Enantioselective Diels-Alder ReactionsUsing Chiral Oxaborolidinium Cations
OO
OMeMe
OPMB
XX
OTBS
ON BH
Me
HO
NB
O
R
XX
H
HNTf2
E.J. Corey, T. Shibata, T.W. Lee, J. Am. Chem. Soc. 2002, 124, 3808.D.H. Ryu, T.W. Lee, E.J. Corey, J. Am. Chem. Soc. 2002, 124, 9992.
or OTfN
BO
R
XX
H
NH OH
XX
HO B OB O B
R
RR+ toluene
Δ, 12 h tolueneor CH2Cl2,
-30 °C, 15 min
HNTf2or TfOH
Me
Me CHO+
Me
MeCHO
NB
O
o-tol
PhPh
H
HNTf2
toluene,-78 °C, 13 h
(96%)(97% e.e.)
Me
For a review on enantioselective Diels-Alder reactions, see:E.J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650.
Regioselective Diels-Alder Reactions: Early Examples
OO
OMeMe
OPMB
XX
OTBS
R. B, Woodward and co-workers, J. Am. Chem. Soc. 1956, 78, 2023.R. B, Woodward and co-workers, Tetrahedron 1958, 2, 1.
O
O
O
O
+
CO2Me CO2Me
NH
NH H
HMeO2C
OMeO
OOMe
OMeOMe
AB C
D
MeO
H
H
reserpine
O
O
MeO2C
benzeneDiels-Alder
reaction D EΔ
E
(27%)
endo TS
Regioselective Diels-Alder Reactions: Early Examples
OO
OMeMe
OPMB
XX
OTBS
R. B. Woodward and co-workers, J. Am. Chem. Soc. 1952, 74, 4223.
butadiene,benzene,
100 °C, 96 h
Diels-Alderreaction
aq. NaOH, dioxane;then 1 N aq. HCl
O
OMeO
Me
H
O
OMeO
Me
H
C D
C D
(86%)
O
O
MeO MeO
OMeO
Me
endo TS
[epimerization]
Me
H
Me
O
H
H
O OH
O
OH
cortisone
Me
H
Me
HO
H
H
cholesterol
H
Me
Me
Me
D+
Note the regioselectivity in this reaction
Enantioselective Diels-Alder ReactionsUsing Chiral Oxaborolidinium Cations
OO
OMeMe
OPMB
XX
OTBS
ON BH
Me
O
OOMe
Me
Me
HMe
Tf2N
O
OOMe
Me
Me
Me
O
OOMe
Me
Me+
Me
HO
OMeO
Me
Me
Me
H
N
H
HH
O
OMe
Me
Me(–)-dendrobine
NBO
o-tol
PhPh
H
HNTf2
Me
O
OMeO
Me
Me
Me
H
OH
toluene, -50 °C, 48 h(99%, 99% e.e.)
Q.-Y. Hu, G. Zhou, E.J. Corey, J. Am. Chem. Soc. 2004, 126, 13708.Original dendrobine synthesis: A.S. Kende, T.J. Bentley, J. Am. Chem. Soc. 1974, 96, 4332.
Asymmetric Diels-Alder Reactions: Enantioselective
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, Chem. Eur. J. 2001, 7, 5359.
Me
TBSO
O
O
OMe
Me
Lewis acid-catalyzed
asymmetricDiels-Alder
Me
TBSOO
OOMe
Me
(S)-BINOL-TiCl2,toluene,
-60→-10 °C, 7 h O
OMe
O
Me
MeOTBS
H
H
(90%) (94% ee)
O
OTi
O
O
Me
Me
OH
MeMe
H
H(–)-colombiasin A
This system is known as Mikami's catalyst
Hetero Diels-Alder Reactions:Furans as Diene Components
For a review, see: D. L. Boger, Comprehensive Organic Synthesis, Vol. 5., 1991, p. 451-512.
N
Me
H
H
H
O
OMe
Me
Medendrobine
NH
Me
tBuO2C
Me
MeH
O
NMe
Me
Me
tBuO2CN H
Me
tBuO2C
Me
Me H
O
NH
Me
tBuO2C
Me
Me HO
IntramolecularDiels-Alder
(74%)
toluene,165 °C, 15 h
exo adduct
Ringopening
OH
Hydrideshift
Furans are normally poor dienes;retro Diels-Alder reactions occur withequal facility as Diels-Alder reactions
Note: Thiopheneand pyrrole are
not viable dienes
Reaction Energy Diagrams:Kinetic and Thermodynamic Products
Reactants
Product B
Energy(E)
Reaction Progress
ΔG1++
ΔG1o
Product A
ΔG2++
ΔG2o
Kineticproduct
Thermodynamicproduct
endotransition
state(secondary
orbitaloverlap)
O+
O
exotransition
state(no secondary
orbitaloverlap)
O
HH
H
H
H
H O
O
Hetero Diels-Alder Reactions:Oxazoles as Diene Components
OO
OMeMe
OPMB
XX
OTBS
P. A. Jacobi and co-workers, Tetrahedron Lett. 1989, 30, 7173.
N
HN
O
O
Me
TMS
N
H
O
OOMe
TMSRetro
Diels-Alder
-[MeCN]
N
HN
O
Me
OMe
HeteroDiels-Alder
mesitylene,163 °C
(50% overall)
OMe
OTBSH
NH
ON
Me OMe
O
TMS
H OTBSOTBSH
OTBSO
TMS
N
HO
O
H(–)-norsecurinine
Michael addition
Hetero Diels-Alder Reactions:Imines/Iminium Ions as Diene Components
OO
OMeMe
OPMB
XX
OTBS
C. H. Heathcock, Angew. Chem. Int. Ed. Engl. 1992, 31, 665.C. H. Heathcock, Proc. Natl. Acad. Sci. 1996, 93, 14323.
HNMe
Me
Me
Me Me
OBnH
N HNMe
Me
HNMe
Me
aza-Prins
BnO BnO
BnO
AcOH,NH4OAc,
25 °C, 5 min
70 °C
HN
Me -[H ]1. H2, Pd/C2. CrO3
3. H2SO4, MeOH
BnO
(85% overall)
(77%)HNMe
Me
methyl homoseco-daphniphyllate
MeO2C
Hetero Diels-Alder Reactions:Imines/Iminium Ions as Diene Components
OO
OMeMe
OPMB
XX
OTBS
P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746.
N
N
O Me
BF3•OEt2,toluene,
100 °C, 2 h
Bn
Hetero Diels-Alder Reactions:Imines/Iminium Ions as Diene Components
OO
OMeMe
OPMB
XX
OTBS
P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746.
N
N
O Me
BF3•OEt2,toluene,
100 °C, 2 h
-
RetroDiels-Alder
AzaDiels-Alder(61%)
(1.5:1 ds)Bn
NBn
O
N Me
NBn
O
N MeH
H
NBn
N MeH
H
CH(OEt)2OH
Li
CH(OEt)2Note the use of cyclopentadiene
as a protective group
Hetero Diels-Alder Reactions:Imines/Iminium Ions as Diene Components
OO
OMeMe
OPMB
XX
OTBS
P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746.
N
N
O Me
BF3•OEt2,toluene,
100 °C, 2 h
-
RetroDiels-Alder
AzaDiels-Alder(61%)
(1.5:1 ds)Bn
NBn
O
N Me
NBn
O
N MeH
H
NBn
N MeH
H
CH(OEt)2OH
Li
CH(OEt)2
H
NMe
CHONBn
NMe
CHONBn
H
H Intramolecular Diels-Alder
(50%)
pseudotabersonine Note the use of cyclopentadieneas a protective group
H
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
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
Hetero Diels-Alder Reactions:Often an Inverse Electron Demand Scenario
OO
OMeMe
OPMB
XX
OTBS
For a review, see: D. L. Boger, Comprehensive Organic Synthesis, Vol. 5., 1991, p. 451-512.
EDGEWG
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
EWGEDG
Normal demandDiels-Alder
reaction(HOMOdiene-
LUMOdienophile)
Inverse demandDiels-Alder
reaction(LUMOdiene-
HOMOdienophile)
NeutralDiels-Alder
reaction
E
ΔE1 ΔE2 ΔE3
Hetero Diels-Alder Reactions:Often an Inverse Electron Demand Scenario
OO
OMeMe
OPMB
XX
OTBS
For a review, see: D. L. Boger, Comprehensive Organic Synthesis, Vol. 5., 1991, p. 451-512.
EDGEWG
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
EWGEDG
Normal demandDiels-Alder
reaction(HOMOdiene-
LUMOdienophile)
Inverse demandDiels-Alder
reaction(LUMOdiene-
HOMOdienophile)
NeutralDiels-Alder
reaction
E
ΔE1 ΔE2 ΔE3
Hetero Diels-Alder Reactions:Azadienes as Diene Components
OO
OMeMe
OPMB
XX
OTBS
D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733.
NN
O
O
OMeMeO
SO2CH3
BnOBr
OMeMeO
Me
NN
O
O
OMeMeO
SO2CH3
BnOBr
OMeOMeMe
H
NN
O
O
OMeMeO
BnOBr
OMe
Me
NHN
H2NHO
OMeMeO
OH2N
O
Me
OMeO
streptonigrone
benzene,30 min,25 °C
t-BuOK,THF, -30 °C;
then DDQ(65%)
+Inverseelectrondemand
Diels-Alderreaction
N
MeO OMe
SO2Me
Me
R 2
endo
Hetero Diels-Alder Reactions:Azadienes as Diene Components
OO
OMeMe
OPMB
XX
OTBS
D. L. Boger, C. Baldino, J. Am. Chem. Soc. 1993, 115, 11418.For a review, see: Classics in Total Synthesis II, Chapter 2.
60 °C, CHCl3, 5 days
(65%)
N N
NN
CO2MeCO2Me
MeOMeO
MeO2C
MeO2C
OMe
OMe
MeO
MeO NN N
N
CO2Me
CO2MeN
NN
NNN
NN
dienophile diene
R
RMeOMeO
OMeOMe
N N
NN
CO2MeCO2Me
MeOMeO
MeO2C
MeO2C
MeO
MeO
R
R
R = CO2Me
Doubleazadiene
Diels-Alder
RetroDiels-Alder -[N2]
Aromatization-[MeOH]
+
Early-Stage Dimerization and Elaboration to Final Target
ReferenceD. L Boger, C. M. Baldino, J. Am. Chem. Soc. 1993, 115, 11418.
+
N
N
OO
MeO
HO O
Me
HO
MeO
MeON N
NN
CO2MeMeO2C
MeOMeO
MeO2C
CO2Me
N
N
O
O
MeO
MeO
MeO2CHO
OHMeO2CMe
Memeso-isochrysohermidin
Hetero Diels-Alder Reactions:Imines/Iminium Ions as Diene Components
OO
OMeMe
OPMB
XX
OTBS
P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746.
N
N
O Me
BF3•OEt2,toluene,
100 °C, 2 h
-
RetroDiels-Alder
AzaDiels-Alder(61%)
(1.5:1 ds)Bn
NBn
O
N Me
NBn
O
N MeH
H
NBn
N MeH
H
CH(OEt)2OH
Li
CH(OEt)2
H
NMe
CHONBn
NMe
CHONBn
H
H Intramolecular Diels-Alder
(50%)
pseudotabersonine Note the use of cyclopentadieneas a protective group
H
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
NMe OO
H
H
OH
o-quinodimethane
chelidonine
o-xylene, Δ
IntramolecularDiels-Alder (73%)
Conrotatoryring opening
Masked Dienes/Dienophiles
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou, W. E. Barnette, J. Chem. Soc., Chem. Commun. 1979, 1119.
SO2
MeO
DBP,210 °C,8 h
Cheletropic elimination of SO2
H
o-quinodimethane
IntramolecularDiels-Alder
H H
H
Me O
estra-1,3,5(10)-trien-17-one
H
Me O
(85%)
SO2
OO
TsO
Me
+1. KH, DME, 0→25 °C
(77%)
2. AcOH/THF/H2O 45 °C, 15 h
DBP = di-n-butyl phthalate
Masked Dienes/Dienophiles
Cascade Reactions:Diels-Alder Reactions Set-up by Prior Events
OO
OMeMe
OPMB
XX
OTBS
S. F. Martin and co-workers, J. Am. Chem. Soc. 1999, 121, 866.For a review, see: Classics in Total Synthesis II, Chapter 8.
NBoc
OTBDPS
N
Br
CO2Me
OTBDPS
O
N
NBoc
CO2Me
H H
OTBDPSOTBDPS
Sn(n-Bu)3
Pd(PPh3)4,toluene, Δ, 30 h
Stille coupling
Diels-Aldercycloaddition
O
(68%)
NBoc
OTBDPS
N
MeO2C
OTBDPS
O
H
N
N
NNH
OHH
H
H
manzamine A
Non-Obvious Diels-Alder Products
OO
OMeMe
OPMB
XX
OTBS
A. G. Myers and co-workers, J. Am. Chem. Soc. 1997, 119, 6072.For a review, see: Classics in Total Synthesis II, Chapter 4.
dynemicin A
HO
HO O
O HNO
CO2H
OMe
MeH
HO
H
TMSO
TMSO
O
OTMS
NO
CO2TIPS
OMe
MeH
O
H
TMSO
TMSO OR
O
R = TMS
Diels-Alderreaction
MnO2, 3HF•Et3N,THF, 25 °C, 9 min
(40% overall)
O
OTMSO
TMSOKHMDS, THF,-78 °C, 25 min;
TMSCl•Et3N,-20 °C, 1 min
NO
CO2TIPS
OMe
MeH
O
H
O
O OR
O
R = TMS
-20→55 °C,5 min
H
H
H
H
Non-Obvious Diels-Alder Products
OO
OMeMe
OPMB
XX
OTBS
D. L. Boger and co-workers, J. Org. Chem. 1988, 53, 1415.D. L. Boger and co-workers, J. Am. Chem. Soc. 1988, 110, 4796.
NN
O
N
N O
H2N
OH
OMe
H
N
O
H
O
NHMe
OHMeO(+)-CC-1065
NN CO2Me
MeO2CO
MeMeO
NN N
O
MeMeO
TBSOCOMe
NN
N
OMeMeO
N
OMe
MeOCOMe
OTBS
MeOC
OTBS
(87%)-[N2] Retro Diels-
Alder reaction
TIPB,230 °C,16-18 h
Azadiene Diels-Alder
reaction
Asymmetric Diels-Alder Reactions: Diastereoselective
OO
OMeMe
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, J. Org. Chem. 1985, 50, 1440.
CO2Me
TBDPSOH
HMe
TBDPSO
Me
MeO2C toluene,130 °C, 48 h
O
Me
Me
CO2Me Me
H
H
H
HMe
O NH
IntramolecularDiels-Alder
antibiotic X-14547A
(70%)
Diels-Alder Reactions Leading to Macrocyclic Rings:Possible Modes of Cyclization
OO
OMeMe
OPMB
XX
OTBSn
n
Type Icyclization
Type IIcyclization
fused system
bridged system
Most reactions of this kind furnish fused ring systems, though bridged systems may form if the connecting chain is of sufficient length.
Macrocyclization With the Diels-Alder Reaction:The First Proof of Principle
OO
OMeMe
OPMB
XX
OTBS
E.J. Corey, M. Petrzilka, Tetrahedron Lett. 1975, 16, 2537.
O
O
O
O
O
O
O
OH
H
O
O
O
OH
H
O
O
OO
H
HtolueneΔ, 70 h(77%)
6.2 6.8 1.0
+ +
Diels-Alder Reactions Leading to Macrocyclic Rings:The 14-Membered Ring of Cytochalasin D
OO
OMeMe
OPMB
XX
OTBS
G. Stork, E. Nakamura, J. Am. Chem. Soc. 1983, 105, 5510.
N
O
Me
OH O OTBS
MeMe
mesitylene,180-190 °C, 6 days
IntramolecularDiels-Alderreaction
(35%)
Ac
N
OHMe
O
Me
OH
O
OHcytochalasin D
H
H
N
MeMe
O
Me
OH
O
OTBS
H
Ac
Diels-Alder Reactions Leading to Macrocyclic Rings:The 9-Membered Ring of the CP-Molecules
HOOC
C8H15
OOO
OO
HOHOHC5H9
O
HOOCC8H15
OOO
OO
OH
C5H9
O
(+)-CP-263,114(–)-CP-225,917
C8H15
PMBOO
O O
MeMe
OO
OMeMe
OPMBO
O
OMeMe
OPMBC8H15
toluene, -80 °C
(88%, 5.7:1 ds)IntramolecularDiels-Alderreaction
and
XX
TBSOOTBS
OTBSOTBS
Me OAlCl2 OTBS
C8H15
OO
OMeMe
OPMBTBSO OTBS
K.C. Nicolaou, P.S. Baran, Angew. Chem. Int. Ed. 2002, 41, 2678.
The Diels-Alder Reaction To Make Macrocyclic Systems:A Provocative Example
OO
OMeMe
OPMB
XX
OTBS
Y. Kishi and co-workers, J. Am. Chem. Soc. 1998, 120, 7647.
HN
CO2
HOO
HOMe
O
O
H
H
MeHO
Me
Me
O
pinnatoxin A
CO2tBu
HOO
TBSOMe
O
O
H
H
MeTESO
O
O
OO
H
TBSOMe
O
O
H
H
MeTESO
O
O
H H
CO2tBuOMs
OO
TBSOMe
O
O
H
H
MeTESO
O
O
H
Me
HMe
MeMe
NHAlloc
IntramolecularDiels-Alder
(34%)(44% undesired stereoisomers)
CO2tBu70 °C
dodecane,
NHAlloc
NHAlloc
Me
Me
DABCO, Et3N;
2532 25 32
Diels-Alder Reactions Leading to Macrocyclic Rings:The 10-Membered Ring of Dynemicin A
OO
OMeMe
OPMB
XX
OTBS
J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10378.
N
O
MeO
OMe
NH
OMe
O
O
O
MeO
HO2CMe Me
COClCl
ClCl
Yamaguchimacrolactonization
CH2Cl2, 25 °C, 13 hPyBroP, Et3N
NH
OMe
H
O
O
H
H
O
MeO
MeMeO
MeO O
O HNO
CO2Me
OMe
MeH
OMe
H
Transannular Diels-Alder reaction (50%)
OH
H
tri-O-methyl dynemicin A
Macrocyclization With the Diels-Alder Reaction:The First Enantioselective Reaction
OO
OMeMe
OPMB
XX
OTBS
S.A. Snyder, E.J. Corey, J. Am. Chem. Soc. 2006, 128, 740.
Me
MeH
OTIPS
O
Me
Me OTIPSOHC 0.06 M, 1.5 h
Me
Me
Me Me
Me
HOH
palominol
ON BH
Me
HOMe
Me
OTIPS
(71-74%)(90% e.e.)
NBO
o-tol
PhPh
H
HNTf2
Enantioselective Diels-Alder Macrocyclization
Me
Me
Me Me
Me
H
dolabellatrienone
O +
No other Lewis Acid (chiral or achiral)enabled this reaction to proceed without
destroying the sensitive diene
Diels-Alder Reactions Leading to Macrocyclic Rings:The 10-Membered Ring of Dynemicin A
OO
OMeMe
OPMB
XX
OTBS
J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10378.
N
O
MeO
OMe
NH
OMe
O
O
O
MeO
HO2CMe Me
COClCl
ClCl
Yamaguchimacrolactonization
CH2Cl2, 25 °C, 13 hPyBroP, Et3N
NH
OMe
H
O
O
H
H
O
MeO
MeMeO
MeO O
O HNO
CO2Me
OMe
MeH
OMe
H
Transannular Diels-Alder reaction (50%)
OH
H
tri-O-methyl dynemicin A
The Diels-Alder Reaction Within Rings:Transannular Cycloadditions
OO
OMeMe
OPMB
XX
OTBS
A. Toro, P. Nowak, P. Deslongchamps, J. Am. Chem. Soc. 2000, 122, 4526.For a review, see: P. Deslongchamps and co-workers, Tetrahedron 2001, 57, 4243.
NC
OHMe
H
Me
HMeMe
HO
Me
CN
O
O
MeMe
H
Me
HMeMe
O
O CN
O Me
Me
H
MeMeO2C
MeO2C
H
Me
HMeMe
HO
O CN
CNH
Me
Me
Me
O
MeO2COO
MeO2C
DMSO,H2O,
155 °C,4 h
(87%)
TransannularDiels-Alder
reaction
Enolization
Decarboxyl-ation
(+)-maritimol
Esterhydrolysis
The Diels-Alder Reaction Within Rings:Transannular Cycloadditions
OO
OMeMe
OPMB
XX
OTBS
A. Toro, P. Nowak, P. Deslongchamps, J. Am. Chem. Soc. 2000, 122, 4526.For a review, see: P. Deslongchamps and co-workers, Tetrahedron 2001, 57, 4243.
H
Me
HMeMe
O
O CN
Me
OTIPS
MeO
NC HMe
CN
O
Me
TIPSO H
Me
HTIPSO
O CN
Me
TransannularDiels-Alder
reaction0 °C, 2 h
Me2AlCN,CH2Cl2,
(95%)
Product from previous slide
This example reveals how subtlestereochemical effects within
the intervening carbogenic chaincan influence the outcome of
Diels-Alder reactions.
These effects are often impossibleto predict prior to experimentation.
The Diels-Alder Reaction in Nature?Some Provocative Examples
OO
OMeMe
OPMB
XX
OTBS
E. J. Sorensen and co-workers, J. Am. Chem. Soc. 2002, 124, 4552.For a review, see: Classics in Total Synthesis II, Chapter 17
O
O
MeTMSO
MeTESO OTES
Me
Me
Ot-Bu
O
O
MeTMSO
MeTESO OTES
Me
Me
Ot-Bu
X = SePh
XmCPBA, CH2Cl2,
-78 °C, 1 min
(E:Z = 2.2:1)
O
O
MeTMSO
Me
Ot-Bu
Me
Me
OTESTESOH
HH
Me
Me
OTESO
H
OP
Me
H
Me
H
ROH
HH
H O Ot-Bu
P = TMS, R = TES
Transannularhetero
Diels-Alderreaction
(61-66%)
(−)-FR182877 TransannularDiels-Alder
reaction
The Diels-Alder Reaction in Nature?Some Provocative Examples
OO
OMeMe
OPMB
XX
OTBS
M. E. Layton, C. A. Morales, M. D. Shair, J. Am. Chem. Soc. 2002, 124, 773.
H
OHO
Me
O
Me
OO
Me
(–)-longithorine A
MeO OTBS
O H
Me
Me
TBSO OMe
MeMeO OTBS
Me
Me
TBSOOMe
MeH
O
O O
Me
Me
OO
MeH
O
Me2AlCl,CH2Cl2, -20 °C
(70%)(1:1.4 mixture)
IntermolecularDiels-Alder
1. TBAF2. PhI(O)
TransannularDiels-Alder
(90% overall)
25 °C, 40 h
The Diels-Alder Reaction in Nature?Some Provocative Examples
OO
OMe
Me
OPMB
XX
OTBS
K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 2000, 122, 3071.
O
Me
OH
MeHO O
HO Medienophile
diene
OR
O
R
MeR =
Me
O
O
Me
RO
OHMe O
O
R
HO
O
RO
MeHO
HO
(+)-bisorbicillinol
MeOAc
IntermolecularDiels-Alder
OHMe O
O
R
HO
O
RO
MeHO
O
Me
OHMe O
OHO
OMe
OHMe O
OHO
O
RMe
O
OOH
Me
O
OOH
Me
H
(+)-bisorbibutenolide
KHMDS
HCl (aq)
H
THF/conc.HCl (9:1),25 °C, 2 h
R RR
(43%)
(80%)
OH
Me
Ringcontraction