Cheletropic Reactions
Ruben Martinez
Stereochemical outcome
Background
"We define as cheletropic reactions those processes in
which two σ bonds which terminate at a single atom
are made, or broken, in concert."
Woodward, R.B.; Hoffman, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853.
Cheletropic reactions are a separate class of pericyclic reactions
that are subject to orbital symmetry analysis. They must obey the
Woodward-Hoffman rules the same way that cycloadditions and
sigmatropic rearrangements do.
The HOMO of x
points directly at
the π system.
x
Disrotatory
LUMO
HOMO
HOMO
Selection rules for cheletropic reactions
π electrons
4n
4n+2
4n
4n+2
S
O2
CH3 150 °C
H3C
H
-SO2
CH3
H H
disrotatory elimination
O
S
Allowed Ground State Reactions
Linear
Nonlinear
disrotatory
conrotatory
conrotatory
disrotatory
Allowed Excited State Reaction
conrotatory
disrotatory
disrotatory
conrotatory
Angew. Chem. Int. Ed. Engl. 1969, 8, 781.
Sankararaman, S. Pericyclic Reactions; Wiley-VCH: Weinheim, 2005.
H3C
H
S
O2
H 150 °C
H3C
CH3 -SO2
Reactivity general guidline
Cycloreversion
&
Cycloaddition
C O
+ N N
N N
O
S
O
N N
O
C
R1 R2
singlet carbenes
N N O
+
H
H CH3
disrotatory elimination
J. Am. Chem. Soc. 1966, 88, 2857.
J. Am. Chem. Soc. 1966, 88, 2858.
Cycloreversion
Only
SO2
O
The HOMO of x
approaches the
π system at
a skew angle.
Conrotatory
LUMO
H3C
H
Most frequently encountered examples
Linear approach vs. Non-linear approach
Cheletropic reaction analysis is typically done in the addition direction.
Consider fragment "x" to be a single atom that contributes two
electrons to the pericyclic transition state. The approach of "x"
can be either linear or non-linear. The rotation of the π system
will be either disrotatory or conrotatory based on the approach
of fragment "x"
Linear
Non-linear
x
Baran Group Meeting
06/01/13
C O
Singlet carbene addition to olefins
Singlet carbenes have an unoccupied p orbital and
two non-bonding electrons in the σ orbital. Only
singlet carbenes can participate in cheletropic reactions.
"The most importatnt cheletropic reaction is the addition of singlet
carbenes to make cyclopropanes."
Anslyn and Dougherty
Linear approach
4-electron
Hückel forbidden
2-electron
Möbius forbidden
Non-linear approach
4-electron
Möbius allowed
2-electron
Hückel allowed
Only select carbene examples will be discussed here.
See K. Chen's GM on carbenes
Cheletropic Reactions
Ruben Martinez
Sequential cycloaddition-cycloreversion and a strange caged structure
Howard, J. A. K. Tetrahedron, 1993, 49, 4699.
O
Cl
Ph
Ph
Cl
Ph
Ph
Cl
Cl
Cl
Ph
Cl
Ph
Ph
Cl
Ph
Cl
Cl Cl
bromobenzene, 160 °C, 48h
40%
Cl
Cl
Cl
[π2s+π2a+ σ2a]
Cl
CO
Cl
Ph
Cl
Cl
Ph
Cl
Cl
Ph
Cl
Cl
Cl Cl
Ph
Cl Cl
Ph
Ph
Ph
Ph
Cl
Ph
Cl
Ph
Ph
Ph
O
Cl Cl
Cheletropic elimination of CO and formation of annulenes
Helv. Chim. Acta. 1989, 72, 1311.
O
O
1
R4
R
R4
R3
-CO
R3
R2
R1, R4 = CO2Me
R2, R3 = Ph
R2
R1
R4
90%
Synthesis of new chiral σ λ -phosphenium cations
Buono, G. Tetrahedron Lett. 1999, 40, 4669.
R
P
+
N
80%
OMe
O
O
3
N
40%
N
P
N
Bn
SH
Et N
N
DMAD
NPh CH2Cl2, 30 °C
O
via:
CO2Me
MeO
3
Ph
Et S
N
S
N
Bn
N
CO2Me
Bn CO Me
2
CO2Me
CO2Me
78%
Ph N C
Δ
N
Et
OTf
Et
N
X
Ge
Ge +
Y
N
Et
Δ
X=O,S
Y=S, NH
X
Ge +
Y
The Chemistry of Organic Germanium, Tin and Lead Compounds,
John Wiley and Sons, Chichester, 2002 (Chapter 1)
Tellurium Extrusion: Synthesis of Benzocyclobutene
MacNicol, D.D. Tetrahedron Lett. 1975, 24, 1893.
1.) EtMgBr
Br2
PhH, rt
95%
CO2Me
An unprecedented tandem 1,3-dipolar cycloaddition-cheletropic elimination:
a facile approach to novel push-pull olefins
Cheng, Y. Org. Biomol. Chem. 2007, 5, 1282.
Et
N
Ge
R
CH2Cl2, rt
OMe
Germanium Analogues of Carbenes
Chrostowska. A. J. Organomet. Chem. 2009, 694, 43.
R OTf
R
The intramolecular Ramberg-Bäcklund reaction: a convenient
method for the synthesis of strained bridgehead olefins O
Becker, K. B. Helv. Chim. Acta, 1983, 66, 1090.
2.) t-BuOK,
THF, -78 °C
OMe
CO2Me
O
[4+1]
O
N2
O
MeO2C
PhMe, reflux
O
O
R=o-anisyl
SO2
CO2Me
N N OMe
R3
R2
2 2
N
Intramolecular [4+1] Cycloaddition
Spino, C. J. Am. Chem. Soc. 2004, 126, 9926.
Evidence: Org. Lett. 2007, 9, 5361.
Et
N
R1
Baran Group Meeting
06/01/13
O
C6H5
C6H5
Br Na2Te
Br
"moderate yield"
Te
500 °C
74%
Cheletropic Reactions
Ruben Martinez
Tandem Cope-cheletropic reaction: a new molecular rearrangment
Mai, D. Chem. Comm. 1996, 1181.
Nitric oxide cheletropic traps (NOCTs)
Ingold, K.U. J. Am. Chem. Soc. 1994, 116, 2767.
Korth, H.G. Angew. Chem. Int. Ed. Engl. 1997, 36, 1501.
O
O
heat
H
89%
O
O
O
Baran Group Meeting
06/01/13
O
H
hυ
NO
N O
-CO
12h, rt
O
hυ
O
O
O
CO
"magic dust"
Ph
retro-Cheletropic ene Reactions with 2-carbena-1,3-dioxolane as the chelefuge
Vidal, A.; Sanchez-Andrada, P. Tetrahedron 2011, 67, 5590.
PhMe, reflux, 1 h
H O
44%
Ph
Ph
EtO2C
H
N
OMe
C
O
N
S
O
NH
PhMe, 160 °C, 24 h
55%
CO2Et
O
N
S
O
Ar
J. Am. Chem. Soc. 1966, 88, 582.
Chem. Commun. 1994, 2155.
retro-cheletropic
ene reaction
N
S
CO2Et
O
CF3
O
O
O
CO2 + H2C CH2
O
O
O
CF3
hυ
-CO2
-CO2
O Ar matrix
+
CO
hυ
+CO
Ar matrix
O
hυ
hυ
-CO
O
Ar matrix
-197 °C
O
CO2Et
6π electrocyclic
ring closure
O
H N
reduction
Phenanthryne and bis-benzyne
Murata, S. J. Org. Chem. 1995, 60, 2344.
Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512.
Me
O
Ph
Ph
fluorescent
non-radical products
CO2Et
N O
-CO
N
N C C
NO
hυ
Ph
Ph
Ph
Ph
O
Ph
O
-CO
CF3
O
O
O
O
CF3
hυ
Ar matrix
CF3
CF3
O
O
CF3
CF3
characterized by IR
Cheletropic Reactions
Ruben Martinez
Applications in Total Synthesis
-The examples presented here will consist of the three main cheletropic reactions
seen in total synthesis. Cheletropic reactions involving Fischer carbenes will not be
discussed here beyond examples of the Simmons-Smith cyclopropanation. For an
in depth presentation and discussion of Fischer carbenes see K. Chen's group
meeting on Fischer carbenes.
Synthesis of estra-1,3,5,(10)-trien-17-one
Nicolaou, K.C. J. Org. Chem. 1980, 45, 1463.
O
SO2
O
TsO
SO2
Early studies on the formation of cyclobutarene
Cava, M.P. J. Am. Chem. Soc. 1959, 81, 4266.
Baran Group Meeting
06/01/13
+
2 equiv.
O
1.) KH
DME, 25 °C, 15 h
SO2
2.) AcOH-THF-H2O
45 °C, 24 h
1 equiv.
77%,1:1 mixture
separated by chromatography
DBP, 210 °C, 8 h
Δ
O
O
H
-The first report of this type of reactivity dates back to 1913. This topic remained
unexplored until it was returned to in 1935.
Staudinger, H. German Patent 506,839; [Chem. Abstr. 1913, 25, 522]
Staudinger, H. Chem. Ber. 1935, 68B, 455.
H
85%
H
Cheletropic extrusion of SO2: The search for a diene equivalent
Stereoselective Synthesis of the Taxane Ring System.
Winkler. J.; Houk, K. J. Org. Chem. 1997, 62, 2957.
Inspiration from W. Oppolzer
Winkler's retrosynthetic analysis:
H
H
+
Oppolzer, W. Synthesis 1978, 11, 793.
H
O
H
O
K.C.N.'s idea: intramolecular trapping of o-quinodimethanes
H
I
O
S
O
O2S
LHMDS, THF
-78 C, 57% brsm
2 steps from
known diene alcohol
SO2
O
O
H
BF3-Et2O (6 equiv)
5 mM in PhMe
82%
Potential problem
n
H
n= 2,3
n
1,5-hydride shift
CH3
n= 2,3
The methylstyrene side product
was observed in only a small
(unspecified) amount.
ZnCl2 (2 equiv)
O
H
DCM, rt
63%
H
"It is interesting to note that neither Lewis acid is
capable of catalyzing both Diels-Alder reactions."
H
O
H
PhMe, reflux
50 min, 80%
Cheletropic Reactions
Ruben Martinez
O
Total Synthesis of Colombiasin A
Nicolaou, K.C. Angew. Chem. Int. Ed. 2001, 40, 2482.
Full paper: Chem. Eur. J. 2001, 7, 5359.
OH
2
Total Synthesis of (+)-Rishirilide B
Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625.
12
1
O
H
First generation:
7
AgO, 6M HNO 3
H
7
HO
1,4-dioxane, rt, 3 h
27%
OMe
12
H
O
OBn
O
O
12
HO
OMe
1,4-dioxane, rt, 3 h
<1% desired product
HO
+
H
O
7
many by-products
lacking the
diene system
H
steps
DDQ
Me
OH
O
O
HO
O
HO
(+)-rishirilide B
O
O
O
O
12
9
9
The solution:
An "almost" cheletropic elimination of SO3 from 11-gorgiacerol
Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834.
OMe
OMe
SO2
OMe
12
CO 2Me
OMe
OMe
7
O
O
OMe
H
β -elimination
O
AgO, 6M HNO 3
7
Diel-Alder and
O
O
OMe
H
OBn
Me
steps
12
Second generation:
OMe
TBSO
OBn
SO2
OMe
ZnO
155 °C
9
9
TBSO
OMe
1.) SO2, h υ
2.) MeOH, p-TsOH
+ "numerous unidentified
by-products"
O
7
11
H 10
colombiasin A
OMe
OMe
TBSO
9
8
O
OMe
O
Baran Group Meeting
06/01/13
TBSO
H
rt, 20 min
OMe
7
9
91%
9
H
SO2
AgO
6M HNO 3
1,4-dioxane
rt, 3h
85 %
O
CO 2Me
O
NHR
Burgess' reagent
O
PhH, reflux
OH
O
O
40%
12
colombiasin A
BBr 3
cyclooctene
DCM
HO H
-78 °C, 30 min
7
43% brsm
OH
2
8
PhMe
12
1
9
H
O
10
CO 2Me
OMe
O
11
HO
O
H
180 °C, 20 min
89%
exclusive endo product
O
7
9
H
SO2
12
R = CO 2Me
O
O
H O
O
O
O SO2
NHCO 2Me
MeO 2H 2CN
H
O
O
S O
O
Cheletropic Reactions
Ruben Martinez
Total Synthesis of (+)-Estradiol
Rigby, J. H. J. Am. Chem. Soc. 1999, 121, 8237.
Ramberg–Bäcklund Reaction
The reaction was first discovered in 1940 but no further
work was published until 1950.
LG
Base
LG
R1
O
S
R1
H
O
O
R1
S
O
R2
O
R2
R1
O
S
R2
S
O
R2
O
R1
SO2
+ TMSC CH Co2(CO)6
+
+
R2
S
O2
S
R2
(Z)
O
R1
LG
O
Br
Br
TBDPSO
1.) Na2SAl2O3 Cl
2.) mCPBA
O2S
3.) SO2Cl2
4.) mCPBA
TBDPSO
O2
S
1.) MeLi
2.)TBAF
steps
O
H
O
I
Br
O
OH
O
O
H
O
O
O
eremantholide A
TMS2S
NaOMe
O
THF, 0 °C
50%
S
O
H
O
O
O
1.) (Et)3COK O
HMPA
DME, 70 °C O
5 min
2.) 6N HCl-THF O2S H O
25 °C, 4h
70 %
Cl
over two steps
HH
1.) hυ
2.) CO
70%
TMS
H
TMS
1.) HF/MeCN
TMS
SO2
1.) t-BuOk, -105 °C
2.) NCS (1 equiv.)
H
3.) t-BuOK, 105 °C
65%
H
2.) Cl3CCCl3
20 °C, 1 h
57%
S
O
inseparable mixture
THF, rt
71%
H
OH
H
H
Pb(OTFA)4
TFA
80%
H
TMS
H
H
steps
MeO
OMe
OMe
1.) p-TsOH
HS
OMe
OMe
OMe
OH
O
H
HO
estradiol
O
H
O
H
TMS
Total Synthesis of Ampelopsin D
Snyder, S. A. J. Am. Chem. Soc. 2009, 131, 1753.
O
O
H
OH
6N HCl-THF
25 °C, 10 h
oxone
MeOH-H2O
25 °C, 6h
Amberlyst-15
DCM, 25 °C, 4h
99%
1.) LiHMDS
THF, - 78 °C
OTBS
KNH(CH2)3NH2
2.) Et3SiH/TFA
TMS
38%
MeO
O
(CO)3Cr
85%
OTBS
O
O
TMS
OH
OH
O
OTBS
+
(CO)3Cr
TBDPSO
O
(MeCN)3Cr(CO)3
THF
2.) Br2, Et3N
70%
O2
S
OTBS
(E)
A Novel application of the Ramberg-Bäcklund Rearrangement
to a Highly StereoselectiveSynthesis of (+)-Eremantholide A
Boeckman, R. K. J. Am. Chem. Soc. 1991, 113, 9682.
O2
S
1.) PhMe, reflux
30%
R2
R1
Early studies toward the synthesis of the enediyne moeity of calicheamicin
Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 7360.
TBDPSO
Baran Group Meeting
06/01/13
2.) m-CPBA
MeO
OMe
OMe
MeO
O
S
O
OMe
Cheletropic Reactions
Ruben Martinez
Total Synthesis of Ampelopsin D continued
MeO
OMe
OMe
MeO
2.) BBr3
O
S
O
Directed Heterodimerization: Stereocontrolled Assembly
via Solvent-Caged Unsymmetrical Diazene Fragmentation
Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 13002.
HO
1.) t-BuOH,
aq. KOH
CCl4
80 °C
OMe
ONa
O S O
HN
OH
OH
40% over two steps
OH
ampelopsin D
O
S O
I
AcS
steps
O
H
O
H
1.) NaOMe
H
O
O
H
MeO2C
H N
MeO2C
N
H H
Me
O
NH
steps
H
O
Me
H H
hirsutellone B
Me
O
O
H
H
H H
BnO2C
CO2Me
hυ
t-BuOH
HN
HN
N
CO2Me
N H
CO2Me
OH
O
NCS, BEMP
N
H H
Me
CF2Br2,
KOH/Al2O3
DCM, t-BuOH,
0 °C to rt
H
MeO2C
H N
MeO2C
N
N
2.)H2O2
Na2WO4
DMAP, Et3N
CH2Cl2
NH2
MeO2C
H N
MeO2C
N
BnO2C
CO2Me
N
CO2Me
N H
CO2Me
DMF
BnO2C
Total Synthesis of Hirsutellone B
Nicolaou, K. C. Angew. Chem. Int. Ed. 2009, 48, 6870.
O
Cl S O
HN
CO2Me
oxalyl chloride
N
CO2Me
N H
CO2Me
OH
HO
OMe
Baran Group Meeting
06/01/13
O
S O
CO2Me
N
CO2Me
N H
CO2Me
"...the first example of directed and stereoselective C–C
bond construction fusing two different cyclotryptamine
fragments at vicinal quaternary stereocenters."
MeO2C
H N
MeO2C
N
MeO2C
H N
MeO2C
N
BnO2C
CO2Me
N
BnO2C
CO2Me
N
CO2Me
N H
CO2Me
CO2Me
N H
CO2Me
Cheletropic Reactions
Ruben Martinez
Simmons-Smith cyclopropanation
First discovered in 1944. Many asymmetric modifications
have been throughout the years. The most notable being
the Charette asymmetric modification.
Et
R2
R3
Zn
ZnEt2 + CH2I2
EtZnCH2I
EtI
R1
R4
R2
R1
Hydroxyl directed Simmons-Smith
I
CH2
R2
R1
R3
R4
R3
R4
BzO
cyclohexane
15-30 °C
83%
O
O
hυ, pyrex filter
1.) H2 (3 atm)
Pd/C (10%)
2.) selective
Wittig
olefination
O
11
O
12
13
18
17
H
BzO
3 steps
O
PtO2
HOAc, rt, 18h
96%
longifolene
O
H
Zn-Ag, CH2I2
PhMe, rt, 8h
56%
BzO
H
H
Simple synthetic route to the limonoid system
Corey, E.J. J. Am. Chem. Soc. 1987, 109, 918.
BzO
"The most obvious approach" gave poor results
13
O
H
H
H
O
various
organocopper
reagents
O
H
H
R
OH
H
H
unreacted S.M.
1,2-addition
H
H
H
β-amyrin
O
+
H
1.) PhCO2O-t-Bu, CuBr
PhCl, 115 °C, 4h
51%
2.) aq. NaOH,
MeOH-THF
TBSO
95%
CH2OH
O
O
-78 °C, 15 min
Et2Zn, CH2I2
Et2O, 35 °C, 60 h
78%
O
H
Li, NH3
Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other
pentacyclic triterpenes from a common intermediate
Corey, E.J. J. Am. Chem. Soc. 1993, 115, 8873.
O
O
H 1.) Zn-Ag, CH2I2
2.) PDC
OH
H
For an excellent review on stereoselective EtZnI
cyclopropanation reactions see: Chem. Rev. 2003, 103, 977.
O
3 steps
13
O
O
O
Total synthesis of (±)longifolene
Oppolzer, W. J. Am. Chem. Soc. 1978, 100, 2583.
BzO
Baran Group Meeting
06/01/13
H
Li, NH3-THF
CH2OH
-78 °C, 2 h
93%
erythrodiol
H
BzO
H
oleanolic acid
Cheletropic Reactions
Ruben Martinez
Total Synthesis of (±)-Taxusin
Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186.
OBn
OBn
1.) Et2Zn, CH2I2
Et2O, rt, 6h
TESO
HO
4 steps
AcO
H
H
O
O
1.) Li, NH3
t-BuOH
H
O
H
O
40%
O
O
O
Me
O
Me
O
Highly Enantioselective Simmons-Smith Fluorocyclopropanation of Allylic Alcohols
Charette A. B. J. Am. Chem. Soc. 2013, 135, 7819.
Zn(CH3CHI)2•DME
HO
CONMe2
O
B O
Bu
O
76%
O
Me O
O
maoecrystal V
Total Synthesis of (+)-Ambruticin
Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772.
Regioselective, asymmetric cyclopropanation
HO
O
Me
CONMe2
State of the art in cyclopropanation
IZnEt
86%
ICHF2
F
-EtI
ZnI
F
halogen
scrambling
∗
OH
O
B O
Bu O ZnEt
R3
OH
CO2H
R2
O
Me
(+)-ambruticin
O
O
PCC
O
taxusin
O
O
H2, PtO2
AcOH
O
O
O
O
2.) MeOH
91%
OH
2.) CH2I2, Zn/Ag
75%
O
O
OH
OMOE
1.) Lombardo reagent
OH
O
HO
OAc
OMOM
steps
H
OH
OAc
OBn
TESO
2.) PDC
85%
H
OAc
Total Synthesis of (±)-Maoecrystal V
Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860.
OBn
steps
Baran Group Meeting
06/01/13
OH
R1
i.) Et2Zn
CONMe2
O
B O
Bu
CONMe2
R1
R3
R2
F
ZnF
I
F
R2
R3
trans
R1
OH