Transcript Document

A Panoply of Pericyclic Processes
Lecture Notes
Key Reviews:
Ene Reaction
H. M. R. Hoffmann, Angew. Chem. Int. Ed. Engl. 1969, 8, 556.
W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1978, 17, 476.
J. M. Conia, Synthesis 1975, 1.
[2+2]-Cycloadditions
Org. React. 1993, 44, 297.
W. Dermuth, Synthesis 1989, 152.
Cyclopropanation
H. E. Simmons, Org. React. 1973, 20, 1.
S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.
Pauson-Khand Reaction
W. Pauson, Tetrahedron 1978, 41, 5855.
Ene Reactions:
Background and Key Principles
H
+
ene
H
Y
X
Y
X
eneophile
Q u ic k T im e ™ a n d a
Ph o t o - J PE G
d ec om pr es so r
a r e n e e d e d t o s e e t h is p ic t u r e .
O
+
H
Ph
O
O
O

Ene
reaction
O
Ph
O
This reaction is often referred to as the Alder ene
reaction, particularly in older (pre-1980s) literature
Kurt Alder (1902-1958)
K. Alder and co-workers, Chem. Ber. 1943, 76, 27.
Ene Reactions:
Background and Key Principles
H
+
ene
Y
X
H
Y
X
eneophile
This reaction is formally classified as a [4+2] cyclization.
(Ene = HOMO, Eneophile = LUMO)
However, ene reactions typically require much higher temperatures than the DielsAlder reaction to initiate, especially for intermolecular ene reactions as they have
a high negative entropy of activation
K. Alder and co-workers, Chem. Ber. 1943, 76, 27.
Ene Reactions:
Background and Key Principles
H
ene
H
Y
X
+
Y
X
eneophile
This reaction is formally classified as a [4+2] cyclization.
(Ene = HOMO, Eneophile = LUMO)
However, ene reactions typically require much higher temperatures than the DielsAlder reaction to initiate, especially for intermolecular ene reactions as they have
a high negative entropy of activation
O
N
R3
S
Typical enophiles
R1
Hetero ene
reactions
Z
R2
R1
Z
R2
+
H
X
Y
R1
R2
Z
H
R3
R4
R1
R2
X
Y
Z = O, N
not S
K. Alder and co-workers, Chem. Ber. 1943, 76, 27.
Ene Reactions in Total Synthesis:
Ene/Retro-Ene Sequence to Protect Indole
O
H CO2Me
NAc
+
N
H Me Me
O
N
N
CH2Cl2,
0 °C,
1 min
MeN
O
NH
N
NAc
N
H
NMe
O
MTAD
150 °C,
1 min
N
O
H CO2Me
Me Me
N
N
NMe
O
MTAD = N-methyltriazolinedione
P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628.
P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999.
Ene Reactions in Total Synthesis:
Ene/Retro-Ene Sequence to Protect Indole
O
H CO2Me
O
NAc
+
N
H Me Me
Me
Me
O
H
N
N
H Me Me
MTAD,
CH2Cl2,
0 °C, 1 h;
H
O
MeN
NH
N
O
1O
2
(O2,
methylene
blue)
Ene
reaction
150 °C,
1 min
NAc
N
N
Me
O Me H
O
MeN
NH
H
N
O
N
O
H CO2Me
N
H
NMe
O
MTAD
N
H
N
N
N
CH2Cl2,
0 °C,
1 min
Me Me
N
Me Me
H
O
NMe
O
MTAD = N-methyltriazolinedione
OH
N
N
N
110 °C,
30 min
(70%
overall
based on
r.s.m.)
Retro
Ene
reaction
N
Me
Me H
O
H
OH
N
N
N
H Me Me
okaramine N
P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628.
P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999.
H
O
Ene Reactions in Total Synthesis:
Double Ene Sequence
O
Ph
HN
O
CH3CN,
25 °C
H
+
N
H
O
Me Aza-ene
reaction
O
Ph
HN
Me
Imineenamine
tautomerization
O
O
Ph
Me
HN
N
NH
Intramolecular
(56-75%)
cyclization
O
Ph
HN
J.-H. Zhang and co-workers, Tetrahedron Lett. 1998, 39, 9237.
N
Me
OH
Ene Reactions in Total Synthesis:
Double Ene Sequence
O
Ph
HN
O
CH3CN,
25 °C
H
+
N
H
O
Me Aza-ene
reaction
O
Ph
Me
HN
Imineenamine
tautomerization
O
O
Ph
Me
HN
N
NH
Intramolecular
(56-75%)
cyclization
Ar
O
O
-[ArCOOH]
Me
HO
N
N
Me
OH
imidazo[1,2,3-ij][1,8]
naphthyridine
(70%)
O
Me
HO
N
N
Me
OH
Me
Ph
CH3CN, H2O,
25 °C
[repetition of
sequence above]
J.-H. Zhang and co-workers, Tetrahedron Lett. 1998, 39, 9237.
HN
N
Me
OH
Ene Reactions in Total Synthesis:
Tandem Oxy-Cope/Carbonyl Ene Sequence
H
Me
H H
OH
Me
Me
HO
OTBDPS
OH
Me
DBU,
toluene
220 °C
Oxy-Cope
OTBDPS
rearrangement
Me
Me
Enol-Keto
tautoOTBDPS merization
O
H
Me
H
OTBDPS
TBDPS = t-butyldiphenylsilyl
TBDPSO
H
H
H H
L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925.
O
Me
Ene Reactions in Total Synthesis:
Tandem Oxy-Cope/Carbonyl Ene Sequence
H
Me
H H
OH
Me
HO
OTBDPS
OH
Me
Me
Me
DBU,
toluene
220 °C
Oxy-Cope
OTBDPS
rearrangement
Me
Enol-Keto
tautoOTBDPS merization
O
H
Me
H
OTBDPS
TBDPS = t-butyldiphenylsilyl
H
Me
O
HO
HO
Me
Me
O
arteannuin M
H
Me
H
OTBDPS
Transannular
ene reaction
OH Me
HO
(63%)
OTBDPS
L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925.
TBDPSO
H
H
H H
O
Me
Ene Reactions in Total Synthesis:
A Carbonyl Ene Reaction (Oxidative Prins Cyclization)
PCC,
CH2Cl2
OH
Carbonyl
ene reaction
H
H
H
O
OH
PCC,
(67%)
CH2Cl2
Acid-catalyzed reactions of
aldehydes with alkenes are known
collectively as Prins reactions.
When they are conducted in the
absence of water, a carbonyl ene
reaction takes place.
O
isocycloseychellene
S. C. Welch and co-workers, J. Org. Chem. 1985, 50, 2668.
Oxy-Ene Reactions:
Also Known as Conia Reactions
Me
O
Me
350-370 °C
30 min
OH
Me
Conia
reaction
O
Me
Epimerized to the more
stable trans isomer
J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818.
J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.
Me
O
Me
Oxy-Ene Reactions:
Also Known as Conia Reactions
Me
Me
350-370 °C
30 min
O
Me
OH
Me
O
Conia
reaction
O
Me
Epimerized to the more
stable trans isomer
Me
Me
O
Me
350-370 °C
30 min
Me
Me
Me
O
OH
Conia
reaction
Me
J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818.
J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.
Me
Oxy-Ene Reactions:
Also Known as Conia Reactions
Me
Me
350-370 °C
30 min
O
Me
OH
Me
O
Conia
reaction
O
Me
Epimerized to the more
stable trans isomer
Me
Me
O
Me
350-370 °C
Me
Me
O
Me
Me
O
OH
Conia
reaction
30 min
Me
335 °C
60 h
Conia
reaction
O
Me
Me
Me
O
(50%)
Conia
reaction
H
J. M. Conia and co-workers, Bull. Chim. Soc. Fr. 1969, 818.
J. M. Conia and co-workers, Tetrahedron Lett. 1974, 2931.
Me
Oxy-Ene Reactions:
Metal-Catalyzed Conia-Type Reactions
O
PAr2
Pd(OTf)2
PAr2
(10 mol %)
O
O
O
R1
O
OR2
O
Yb(OTf)3 (20 mol %)
Conia reaction
O
R1
O
OR2
HO
O
Me
laurebiphenyl
Me
B. K. Corkey, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 17168.
Ene Reactions in Total Synthesis:
Asymmetric, Metal-Promoted Ene Reaction
Me Me
O
H
H
O
N
N
H
Ph MgClO4, Ph
Me
CH2Cl2,
25 °C, 3 h
(72%)
O
N
(65% e.e.)
R
Metal-promoted
R = COPh
ene reaction
EtO2C
EtO2C
Me
O
N
R
R = COPh
First of 53 total syntheses of this compound
that can produce gram quantities readily;
only 6 steps and 20% yield overall
Q. Xia, B. Ganem, Org. Lett. 2001, 3, 485.
HO2C
HO2C
N
H
kainic acid
Me
Ene Reactions in Total Synthesis:
Selenium Dioxide Oxidation Reactions
CO2Me
SeO2,
t-BuOOH
(38%)
HO
CO2Me
O
O
mokupalide
H
Se
O
O
Ene
reaction
O
Se
OH
[2,3]-sigmatropic
rearrangement
O
Se
OH
OH
Nu
F. W. Sum, L. Weiler, J. Am. Chem. Soc. 1979, 101, 4401.
K. B. Sharpless and co-workers, J. Am. Chem. Soc. 1973, 95, 7917.
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
OEt
OEt
Me
Me
1. LDA, MeI
2.
MgBr
O
Me
O
Me
OH
Me
HCl
work-up
(74%
overall)
Me
Me
Me
[2+2] h
cycloaddition (77%)
O
Me
Me
Ph3P CH2
Me
DMSO, 70 °C
(77%)
Me
M. C. Pirrung, J. Am. Chem. Soc. 1979, 101, 7130.
M. C. Pirrung, J. Am. Chem. Soc. 1981, 103, 82.
Me
Me
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
OEt
OEt
Me
Me
1. LDA, MeI
2.
MgBr
O
O
Me
Me
OH
Me
HCl
work-up
(74%
overall)
Me
Me
Me
[2+2] h
cycloaddition (77%)
Me Me
Me
Me
isocomene
O
p-TsOH,
benzene, 
(98%)
Can you rationalize
a mechanism?
Me
Me
Ph3P CH2
Me
DMSO, 70 °C
(77%)
Me
M. C. Pirrung, J. Am. Chem. Soc. 1979, 101, 7130.
M. C. Pirrung, J. Am. Chem. Soc. 1981, 103, 82.
Me
Me
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
O
Me
Me
sunlight
Me
H
O
O
1 year
carvonecamphor
carvone
HO
Me
h
H
H
H
H
O
O
Incredibly strained systems can be fashioned by [2+2] cycloadditions!
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
O
O
Br
O
H
H
h
[2+2]
cycloaddition
Br
O
Br
50% aq. KOH
(50% overall)
Br
P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 962.
P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157.
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
O
O
Br
O
H
H
h
Br
O
[2+2]
cycloaddition
(50% overall)
Br
O
50% aq. KOH
Br
O
Br
Br
Note: The Favorskii rearrangement is an excellent
way to achieve ring contraction on symmetrical substrates;
on non-symmetrical compounds, two products will often result
unless there is a distinct bond breaking preference.
CO2H
HO2C
Favorskii
rearrangement
(30%)
O
O
O
O
HO
cubane
P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 962.
P. E. Eaton, T. W. Cole, J. Am. Chem. Soc. 1964, 86, 3157.
OH
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
Me
O
MgBr
O
Me
Me
Me
Me
CuI, THF
O
H2CO
Me
Tandem
vicinal
functionalization
Me
OH Me
Me
1. TsCl
2. DBU
Me
Me
Me
panasinene
O
Me
Me
O
Olefination
h
(reaction to
be unveiled
later)
(67%)
[2+2]
cycloaddition
Me
Me
Me
Me
C. R. Johnson and co-workers, J. Am. Chem. Soc. 1981, 103, 7667.
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
EtO
O
EtO
O
O
LiAlH4
LDA
Me
Me
I
Me
Me
Me
[2+2]
cycloaddition
O
O
O
O
Me
H
Me
Me
hibiscone C
O
O
Me
Me
h
O
O3
H
Me
Me
A. B. Smith and co-workers, J. Am. Chem. Soc. 1982, 104, 5568.
H
Me
Photochemical [2+2] Reactions in Total Synthesis:
Intramolecular Examples
TBDPSO
O
O
OH
L-Proline
O
O
DMSO
Me
N
H
OTBDPS
(91%)
H
Me
TBDPSO
TBDPSO
H
O
Me H OH
kinetic product
H
thermodynamic
O product
Me H OH
OH
OBn
O
O
O
H
H
O OH
O
O
Me H
littoralisone
1. h
2. H2, Pd/C
[2+2]
OH cycloaddition
(84%)
OH
O
O
O
H
O OBn OBn
O
Me H
O
OBn
H
Me H OAc
I. K. Mangion, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 3696.
Photochemical [2+2] Reactions:
Intermolecular Examples and Regiochemistry
Intermolecular reactions typically lack regioselectivity . . .
+
h
Et
and
Me
E. J. Corey and co-workers, J. Am. Chem. Soc. 1964, 86, 5570.
Me
Et
Photochemical [2+2] Reactions:
Intermolecular Examples and Regiochemistry
Intermolecular reactions typically lack regioselectivity . . .
h
+
Et
and
Me
Me
Et
unless strongly electron-withdrawing and/or donating substituents are involved
O
O
+
CO2Me
H
h
CO2Me
O
Ground
state
reaction
H
O
O
MeO
+
OMe
h
O
H
H
OMe
OMe
E. J. Corey and co-workers, J. Am. Chem. Soc. 1964, 86, 5570.
Excited
state
reaction
Photochemical [2+2] Reactions in Total Synthesis:
An Inter-/Intramolecular Cascade
O
O
MeO2C
+
h
[2+2]
cycloaddition
H CO2Me
Ph3P=CH2
Me H
Wittig
reaction
H CO2Me
Me H
P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.
Photochemical [2+2] Reactions in Total Synthesis:
An Inter-/Intramolecular Cascade
O
O
MeO2C
+
h
[2+2]
cycloaddition
H CO2Me
Ph3P=CH2
Me H
Wittig
reaction
H CO2Me
Me H
Retro [2+2] 210 °C,
cycloaddition 2 h
CO2Me
P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.
Photochemical [2+2] Reactions in Total Synthesis:
An Inter-/Intramolecular Cascade
O
O
MeO2C
+
h
[2+2]
cycloaddition
H CO2Me
H CO2Me
Ph3P=CH2
Me H
Wittig
reaction
Me H
Retro [2+2] 210 °C,
cycloaddition 2 h
OHC
Me OH
CHO
Me
CO2Me
Ene
reaction
H
CO2Me
H
Me Me
warburganal
H
P. A. Wender and co-workers, Tetrahedron Lett. 1982, 23, 1871.
Photochemical [2+2] Reactions in Total Synthesis:
Intermolecular Examples
N
BzC N
CBz
Br
Zn,
AcOH
N
BzC N
(80%)
Br
CBz
+
O
h
N
BzC N
MeCN
(40%)
[2+2]
CBz
O
CO2H
Hf = +19.6 kcal/mol
pentacycloanemmoxic acid
V. Mascitti, E. J. Corey, J. Am. Chem. Soc. 2004, 126, 15664.
Photochemical [2+2] Reactions in Total Synthesis:
Tethered Intramolecular Example for Ladderane Synthesis
N
OH
MeO
N
HO
N
OH
OMe
HO
N
h in solid state
(100%)
Structure
organized by
a series of
hydrogen bonds
[2+2] cycloaddition
cascade sequence
Pyr
Pyr
Pyr
Pyr
X. Gao, T. Friscic, L. R. MacGillivray, Angew. Chem. Int. Ed. 2004, 43, 232.
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction
Paterno (1909)
Me
+
Me
Me
Me
O
sunlight
Me
Me
Ph
Me
O
Ph
+
O
Me
Me
Ph
Buchi (1954)
Me
O
+
Me
Me
n-Pr
h
Me
O
Me
Me
oxetane
ring system
n-Pr
E. Paterno, Gazz. Chim. Ital. 1909, 39, 237.
G. Buchi and co-workers, J. Am. Chem. Soc. 1954, 76, 4327.
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction
Paterno (1909)
Me
+
Me
Me
Me
O
sunlight
Me
Me
Ph
Me
O
Ph
+
O
Me
Me
Ph
Buchi (1954)
Me
O
+
Me
Me
Me
h
O
Me
Me
n-Pr
oxetane
ring system
n-Pr
General features:
-carbonyl can be either an aldehyde or ketone; alkene should be electron-rich
-carbonyl substrate is energy absorbing
-often highly regioselective due to radical-based mechanism for coupling
Me
Me
O
O
Me
Me
n-Pr
Me
Me
n-Pr
E. Paterno, Gazz. Chim. Ital. 1909, 39, 237.
G. Buchi and co-workers, J. Am. Chem. Soc. 1954, 76, 4327.
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction in Action
Me
h
Me
O
Me
(79%)
Me
Me
Me
O
Me
Me
O
Me
Me
Me
H
Me
What pericyclic reaction was
used to generate the starting
material for this sequence?
LDBB, THF,
-78 to -10 °C,
35 h
Li+
LDBB
O Me
Me
H
Me
oxosilphipefol-6-ene
Me
PCC,
DMF
(84%)
O Me
HO Me
Me
(57%)
Me
H
Me
T. J. Reddy, V. H. Rawal, Org. Lett. 2000, 2, 2711.
Me
Me
H
Me
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction in Action
H
O
Ph
+
C9H19
N
CO2Me
h
(53%)
[2+2]
H2,
Pd(OH)2/C
O
Ph
C9H19
N
CO2Me
note the stereochemistry
of this addition
H
HO
(81%)
Ph
C9H19
N
CO2Me
LiAlH4,
(91%)
THF, 
HO
HO
HO
C9H19
N
Ph
Me
preussin
N
Ph
C9H19
N
Ph
T. Bach, H. Brummerhop, Angew. Chem. Int. Ed. 1999, 37, 3400.
C9H19
OH
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction in Action
EtO2C
+
O
H
O
H
h
(65%)
[2+2]
CO2Et
O
O
EtSH,
BF3•OEt2
H
Why this ring closure
regiochemistry?
H
OH
CO2Et
O
(70%)
O
H
H
O
H
euplotin A
H
H
O
OH
CO2Et
OAc
O
R. A. Aungst, R. L. Funk, J. Am. Chem. Soc. 2001, 123, 9455.
SEt
Photochemical [2+2] Reactions:
The Paterno-Buchi Reaction in Action
C8H17
+
O
H
O
C8H17
H
h
(100%)
[2+2]
cycloaddition
O
O
C8H17
H
H2,
Rh/Al2O3
O
(97%)
O
H
H
0.1 N HCl (96%)
in THF
Note: These photocycloadditions
are all racemic events; rendering
them asymmetric remains an
unexplored frontier for synthetic
methods development
H
O
C8H17
H
C8H17
OH
O
O
H O
avenaciolide
OH
O
[putative aldol
product]
S. L. Schreiber, A. H. Hoveyda, J. Am. Chem. Soc. 1984, 106, 7200.
For more on furans, see: Classics in Total Synthesis I, Chapter 20.
The Simmons-Smith Cyclopropanation:
A [2+2] Pericyclic Reaction
Et2Zn
+ R5CHI2
-[EtI]
R5 = H, Me, Ph
Formally the addition of
a carbene to an olefin
EtZnCH2I
R2
R3
R1
R4
EtZn
R2
R1
CH2
R3
R4
-[EtZnI]
R2
I
CH2
R3
R1
R4
butterfly mechanism
For a review, see: H. E. Simmons, Org. React. 1973, 20, 1.
The Simmons-Smith Cyclopropanation:
A [2+2] Pericyclic Reaction
Et2Zn
+ R5CHI2
-[EtI]
R5 = H, Me, Ph
Formally the addition of
a carbene to an olefin
EtZnCH2I
R2
R3
R1
R4
EtZn
R2
R1
CH2
R3
R4
-[EtZnI]
R2
I
CH2
R3
R1
R4
butterfly mechanism
Stereochemistry of starting alkene is preserved in the product
If a fragment installs a group other than H on the new cyclopropane
ring system (i.e. R5 = Me, Ph), it prefers to be syn to the substituents on the alkene
For a review, see: H. E. Simmons, Org. React. 1973, 20, 1.
The Simmons-Smith Cyclopropanation:
Examples in Natural Product Total Synthesis
Me Me
O
Me
Me Me
Zn-Cu,
CH2I2, Et2O,
O
Me
35 °C, 6 h
(60%)
Double-directed
Simmons-Smith
Cyclopropanation
O
O
Me
H
Me
H H
H
3 steps
Me
O
S
H N
MeO
Me
H
H
HO
Me
H
curacin A
S. Iwasaki and co-workers, Tetrahedron Lett. 1996, 37, 4397.
H
The Simmons-Smith Cyclopropanation:
Examples in Natural Product Total Synthesis
Me Me
O
Me
Me Me
Zn-Cu,
CH2I2, Et2O,
O
Me
O
35 °C, 6 h
(60%)
Double-directed
Simmons-Smith
Cyclopropanation
O
Me
H
Me
H H
Can you guess
the transformations?
H
3 steps
Me
O
S
H N
MeO
Me
H
H
HO
Me
H
curacin A
S. Iwasaki and co-workers, Tetrahedron Lett. 1996, 37, 4397.
H
The Simmons-Smith Cyclopropanation:
Examples in Natural Product Total Synthesis
O H
Me
O
TBDPSO
H
H O
Me
made from a Claisen
rearrangement
O HH
CH2I2,
Et2Zn
benzene
(92%)
Simmons-Smith TBDPSO
cyclopropanation
O
H
H
O
H
H O
Me
H
Me
O
H OAc
Me
acetoxycrenulide
L. A. Paquette and co-workers, J. Am. Chem. Soc. 1995, 117, 1455.
Me
The Simmons-Smith Cyclopropanation:
Examples in Natural Product Total Synthesis
O
Me
Me
O
Me
MeCN, 
(66%)
Intramolecular
Diels-Alder reaction
SimmonsSmith
cyclopropanation
(92%)
O
O
H
Me Me
trans-dihydroconfertifolin
Me
H2, PtO2
AcOH
(99%)
O
H
Me
CH2I2 (16 equiv),
Et2Zn (8 equiv),
toluene,
25 °C, 6 h
Me
O
O
H
Me
D. F. Taber and co-workers, J. Org. Chem. 2002, 67, 4501.
O
The Simmons-Smith Cyclopropanation:
Examples in Natural Product Total Synthesis
O O
Me2N
Me
OH
O
Me
Me
Me
CH3CHI2, Et2Zn,
CH2Cl2/DME, -10 °C
Asymmetric
Simmons-Smith
cyclopropanation
NMe2
O
(86%)
O (1.2 equiv)
B
Bu
Me
OH
Best method for asymmetric cyclopropanation;
requires stoichiometric ligand and works
for allylic alcohols only
O
Me
Me
Me
Me
OH
OH
O
CO2H
Me
O
Me Me
Me
(+)-ambruticin
Me
P. Liu, E. N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 10772.
Cyclopropanation method: A. B. Charette, H. Juteau, J. Am. Chem. Soc. 1994, 116, 2651.
Other Cyclopropanation Methods:
The Reactions of Carbenes
+
CH2
CH2 > CHCl > CCl2 > CBr2 > CF2
For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.
Other Cyclopropanation Methods:
The Reactions of Carbenes
+
CH2
CH2 > CHCl > CCl2 > CBr2 > CF2
OMe
Cl
KOtBu,
CHCl3
Cl
OMe
[:CCl2]
MeLi,
CH2Cl2
N
H
[:CHCl]
H
Cl
N
H
For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.
Other Cyclopropanation Methods:
The Reactions of Carbenes
+
CH2
CH2 > CHCl > CCl2 > CBr2 > CF2
OMe
Cl
KOtBu,
CHCl3
Cl
OMe
Cl
[:CCl2]
O
MeLi,
CH2Cl2
N
H
[:CHCl]
H
Cl
N
H
For a review, see: W. Kirmse, Carbene Chemistry 1971, 313.
N
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
Cl
N2
CH2N2
Me
Me
O
Cu, 
Me
Me
Me
Me
Carbene-based
cyclopronation
O
Me
Me
For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
Cl
O
N2
CH2N2
Me
Cu, 
Me
Me
Me
Me
Me
Carbene-based
cyclopronation
O
OLi
Li/NH3
Regioselective
enolate
formation
Me
Me
Me
Me
For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
Cl
O
N2
CH2N2
Me
Cu, 
Me
Me
Me
Me
Me
Carbene-based
cyclopronation
O
O
OLi
Li/NH3
Regioselective
enolate formation
Me
Me
HCO2H
H2O
Me
For a review, see: S. Burke, P. A. Grieco, Org. React. 1979, 26, 361.
OH
Me
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
Me
O
Me
Cu, 
O
Me
O
Me
Carbene-based
cyclopronation
O
Me
Me
O
N2
O
O
1. NaH,
CO(OMe)2
2. NaBH4
O
O
H
Me
MeO2C
P. Deslongshamps and co-workers, Can. J. Chem. 1980, 58, 2460.
Me
OH
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
Me
O
Me
Cu, 
O
Me
O
Me
Carbene-based
cyclopronation
O
Me
Me
O
N2
O
O
O
Me
1. NaH,
CO(OMe)2
2. NaBH4
O
O
Me
Me
HO Me
agarospirol
H
HCl,
THF
Me
MeO2C
Me
O
Me
MeO2C
P. Deslongshamps and co-workers, Can. J. Chem. 1980, 58, 2460.
Me
OH
Other Cyclopropanation Methods:
The Reactions of Carbenes
O
O
CO2Et
O
CO2Et
TsN3
N2
Diazo
transfer
C5H11
C5H11
Cu, 
CO2Et
toluene
Carbene-based
cyclopronation
C5H11
H
Homoconjugate PhSH,
addition KOtBu
O
O
CO2Et
CO2H
C5H11
H
OH
prostaglandin A2
sulfoxide [2,3]-sigmatropic
rearrangement employed
in these steps
C5H11
H
SPh
D. F. Taber and co-workers, J. Am. Chem. Soc. 1977, 99, 3513.
The Pauson-Khand Reaction:
A [2+2+1] Cycloaddition
R1
R2
R5
R6
R3
R4
+
terminal or
internal alkyne
transition metal
complex (1 equiv),
solvent, heat
or transition metal
complex (<1 equiv),
promoter, solvent,
CO atmosphere
O
R1
R6
R5
R
R3 4
cyclopentenone
R2
For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.
The Pauson-Khand Reaction:
A [2+2+1] Cycloaddition
R1
R2
R5
R6
R3
R4
+
terminal or
internal alkyne
>
>
transition metal
complex (1 equiv),
solvent, heat
or transition metal
complex (<1 equiv),
promoter, solvent,
CO atmosphere
O
R1
R6
R5
R
R3 4
cyclopentenone
R2
>>
does not react
For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.
The Pauson-Khand Reaction:
A [2+2+1] Cycloaddition
R1
R2
R5
R6
R3
R4
+
terminal or
internal alkyne
>
>
transition metal
complex (1 equiv),
solvent, heat
or transition metal
complex (<1 equiv),
promoter, solvent,
CO atmosphere
O
R1
R6
R5
R
R3 4
cyclopentenone
R2
>>
does not react
metal complexes: Co2(CO)8, Fe(CO5), Ru2(CO)12, Ni(COD)2, W(CO)6, Mo(Co)6
promoter: NMO, TMANO, RSCH3, h, "hard" Lewis bases
Regioselectivity: Larger alkyne substituent ends up next to the ketone of the product;
alkene selectivity is low in intermolecular reactions, high in intramolecular events.
For a review, see: P. Schore, Chem. Rev. 1988, 88, 1081.
The Pauson-Khand Reaction:
Examples in Complex Molecule Synthesis
Me
O
H
Me
H
Me
H
Me
carene
H
Me
O
Co2(CO)8,
pet. ether
Me
25 °C
(100%)
O
(CO)6Co2
H
Me
H2C=CH2 (25 atm),
TMANO, toluene,
40 °C, 24 h
(81%)
Me
O
•2H2O
N
Me
Me
TMANO
H
H
Me
Me
taylorione
Me
H
Me
PausonKhand
Reaction
O
O
Me
O
H
Me
J. G. Donkervoort and co-workers, Tetrahedron 1996, 52, 7391.
O
H
Me
O
Me
The Pauson-Khand Reaction:
Examples in Complex Molecule Synthesis
Me
Co2(CO)8,
benzene
OTBDPS
OTBDPS
Co2(CO)6
Co2(CO)6
(87%)
OTBDPS
Me
Me
TMANO (6 equiv), PausonCH2Cl2, -78 °C to 25 °C Khand
(85%) Reaction
HO
HO Me
H
H
H
OH
Me HO
Me HO
kalmanol
H
Me
OH
O
MeO2C H
Me
O
O
TBSO
Me
MeH
H
L. A. Paquette and co-workers, J. Org. Chem. 1995, 60, 6912.
H
H
OTBDPS
The Pauson-Khand Reaction:
Examples in Complex Molecule Synthesis
Me H
Me
Me
O
H
OEt
1. Co2(CO)8
2. EtAlCl, CH2Cl2
(83%)
Nicholas reaction
Me H
Co(CO)3
Co(CO)3
Me Me
H
H
O
TMS
NMO, CH2Cl2,
25 °C, 12 h
(70%)
PausonKhand
Reaction
O
Me H Me
H
O
H
Me H
H
H
H
Me
Me
O
H
H
epoxydictymene
S. L. Schreiber and co-workers, J. Am. Chem. Soc. 1997, 119, 4353.
Me
Me
The Pauson-Khand Reaction:
Examples in Complex Molecule Synthesis
Me OTBS
Me OTBS
Co2(CO)8,
benzene
Me
OTHP
OTBS
(92%)
(CO)6Co2
THPO
THPO
Co2(CO)6
NMO•H2O,
CH2Cl2, THF
(89%, 94% d.s.)
Me OH
Highly diastereoselective
reaction; OTBS group occupies
a pseudoequatorial position
based on its bulk
PausonKhand
Reaction
Me OTBS
H
N
O
H
THPO
13-deoxyserratine
S. Z. Zard and co-workers, Angew. Chem. Int. Ed. 2002, 41, 1783.
O