D. A. Evans, G. Lalic
Chem 530A
Question of the day:
CO2Me
H
TBSO
Chemistry 530A
MeO2C
Me
toluene, 130 °C
70%
TBSO
H
Me
Advanced Organic Chemistry
Lecture 16
Cycloaddition Reactions
Diels _ Alder Reaction
Photochemical [2+2] Cycloadditions
Ketene [2+2] Cycloadditions
Cheletropic reactions
[3+2] Cycloadditions
Crimmins, M. T. "Synthetic Applications of Intramolecular Enone-Olefin
Photocycloadditions", Chem. Rev. 1988, 88, 1453. (pdf)
Bach, T. "Stereoselective Intermolecular [2+2]-Photocycloaddition Reactions
and Their Application in Synthesis", Synthesis 1998, 683. (pdf)
Nicolaou, K. C. "The Diels _ Alder Reaction in Total Synthesis",
Angew. Chem., Int. Ed. 2002, 41, 1668. (pdf)
Evans D.A., Lalic G.
diene
Chem 530A
dienophile
Looks simple? How about this one?
FR182877
Evans D.A., Lalic G.
Chem 530A
Steric Effects
HOMO-LUMO Gap and the Reaction Rate
Steric hindrance at the terminus of the diene slows the reaction. The effect of
the methyl substituent is a combination of electronic and steric effects.
Z substituents at the terminal position have an unfavorable effect on the
equilibrium between s-cis and s-trans conformers.
In most cases the size of substituents in positions 2 of a diene has little effect
on the rate of the reaction.
Provide an explanation for the observed difference in relative rates.
Substituents on both the diene and the dienophile that decrease the gap will
contribute to the rate acceleration. Electron donating substituents on the
diene and electron withdrawing substituents on the dienophile.
Evans D.A., Lalic G.
Chem 530A
Lewis acid coordination to dienophile lowers the LUMO and accelerates the
reaction. Bases for a vast majority of catalytic DA reactions.
Orbitals with similar coefficients overlap.
Z
X
X
C
Z
C
Calculated HOMOs and LUMOs for some alkenes and dienes.
Regiochemistry of DA Reaction
Ortho-para rule. Meta products are not favored.
NEt2
NEt2
CO2Me
+
NEt2
CO2Me
20 °C
+
CO2Me
"ortho" is only product
CO2Me
EtO
+
160
°C
EtO
EtO
+
CO2Me
CO2Me
Resonance structure approach.
"para" is only product
O
allyl cation superimposed on alkene
C
C
X
LUMO C
C
X
C
C
X
OMe
LUMO
HOMO
alkene
O
C
C
OMe
Positive charge is on
the terminal carbon
X
LUMO
allyl cation
Draw relevant resonance structures of the starting materials
that explain the observed regiochemistry.
Evans D.A., Lalic G.
Chem 530A
Lewis acids improve regioselectivity of DA reactions by increasing the
contribution of the more polarized resonance structures.
Stronger group wins
The endo Diels-Alder adduct is formed faster even though the exo product is
more stable. There is thus some special stabilization in the transition state
leading to the endo product which is lacking the exo transition state.
Nitro group is particularly useful removable electron withdrawing group.
Secondary orbital interactions between the diene and the dienophile favor
the formation of the endo product.
Evans D.A., Lalic G.
Chem 530A
Relative stereochemistry of the product:
Endo rule
DA is both stereospecific and stereoselective. Relative orientation of
substituents in the diene and dienophile is preserved. There is a preference
for a relative orientation of substituents from the two reacting molecules.
Inverse electron demand DA
Diels Alder reaction is also possible when the HOMO of the dienophile is
close in energy to the LUMO of the diene. Such Diels Alder reactions are
called inverse electron demand.
Still endo-selective. Regiocemistry is a result of the same considerations
Hetero DA reaction
E
E
Z
Z
n
Z
Z
Z
x
Z
E
x
x E
+
n
x
x
n
n
E
E
x
n
n
Lewis acids improve the endo-exo selectivity of DA reactions by increasing
the importance of secondary orbital interactions.
Evans D.A., Lalic G.
Chem 530A
Biomimetic Synthesis of FR182877
Transannular Diels-Alder Reaction
Biomimetic Synthesis of longithorone A
E
E
Z
Z
Z
E
x
x E
+
n
x
n
E
E
Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773.
Z
Z
Z
x
n
n
Evans D.A., Lalic G.
Chem 530A
Evans D.A., Lalic G.
Chem 530A
New Type of Hydrogen Bonding
Similar model for coordination of enals with
Yamamoto’s catalyst correctly predicts the
stereochemistry of the product.
Aldehydes are monodentate dienophiles?
See Sherburn, M. S. Angew. Chem. Int. Ed. 2008, 47, 7013 for another model
operational with certain substrates.
Evans D.A., Lalic G.
Chem 530A
State of The Art
Enantioselective Hetero-Diels-Alder Reactions
Lewis acid activated Lewis acid. Concept first introduced by
Yamamoto. Lewis activation in this case expands the scope
of both dienes and dienophiles . Much less reactive dienes
can be used and a variety of dienophiles including
aldehydes esters, quinones, cyclic ketones.
Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398.
Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498.
Enantioselective Transannular Diels-Alder
Jacobsen, E. N. Science 2007, 317, 1736.
Catalyst Controlled
Diastereoselective Hetero-Diels-Alder Reaction
Evans D.A., Lalic G.
[2+2] Cycloadditions
Chem 530A
Applications of Photochemical [2+2] Cycloadditions
Thermal activation [ 2a + 2s]
Paterno-Buchi reaction (carbonyl + alkene)
Reaction proceeds through a triplet carbonyl excited state and a diradical
intermediate. Often gives a mixture of head-head and head-tail isomers.
Asteltoxin synthesis
Schreiber, S. L. J. Am. Chem. Soc. 1983, 105, 6723.
anti
O
Photochemical activation [ 2s + 2s]
Me
O
Me
+
hv
H
Me
80%
O
H
H
Ph
O
Me
>20:1 exo
Enone alkene cycloadditions
Reaction proceeds through a triplet carbonyl excited state and a diradical
intermediate. Intramolecular reactions are predictable and often used.
Fused ring is a five membered when ever possible.
Me
O
Me
O
hv
H
76%
OAc
OAc
O
Me
H
OAc
Substituents that stabilize the radical
intermediate, promote the reaction.
Oppolzer, W. Helv. Chim. Acta 1980, 62, 1198.
rev: Crimmins, M. T. Chem. Rev. 1988, 88, 1453.
Evans D.A., Lalic G.
Chem 530A
Cycloadditions of Ketenes
Deprotonation/elimination from acyl derivatives.
Decomposition of -diazocarbony compounds, Wolff rearrangement.
[2+2] cycloadditions preferred over
[4+2[ cycloaddtions with dienes
Keten Formation Reactions
Reduction of chloroacyl derivatives (most often chlorides).
Electrocyclic ring opening.
Evans D.A., Lalic G.
Chem 530A
FMO Description
Examples:
Key step in Corey's synthesis of Ginkgolide B
MeO
MeO
O
Concerted vs. Stepwise Mechanism
E alkenes stepwise process:
1. Slower reaction
2. Mixture if syn and anti products
3. KIE
Z alkenes concerted reaction:
1. Stereospecific
2. Faster
O
tBu
Bu3N
toluene,
CO2Cl
tBu
80% yield
H
O
H
Corey, E. J. J. Am. Chem. Soc. 1988, 110, 649.
Catalytic Enantioselective [2+2] Cycloadditions
Stepwise reaction with excellent diastereo and enantioselectivities.
Evans D.A., Lalic G.
Chem 530A
Evans D.A., Lalic G.
Chem 530A
Evans D.A., Lalic G.
Stereospecificity: The Dipole
Chem 530A
Evans D.A., Lalic G.
Chem 530A
Azomethine Ylides
 R2 is usually electron-withdrawing group
Wada, E. Bull. Chem. Soc. Jpn. 1990, 63, 2866.
Livinghouse, T. J. Org. Chem. 1983, 48, 1554.
Evans D.A., Lalic G.
Chem 530A
Huisgen 3+2 cycloaddition
Huisgen, R. Angew. Chem. 1963, 75, 604.
Sharpless Angew. Chem. Int. Ed. 2002, 41, 2596.
Carbonyl Ylides
Evans D.A., Lalic G.
Chem 530A
Padwa, A. Tetrahedron Lett. 1992, 33, 4731.
Provide the product and a detailed mechanism.