Ruben Martinez Cheletropic Reactions Baran Group Meeting

06/01/13

Background Stereochemical outcome

"We define as cheletropic reactions those processes in
which two σ bonds which terminate at a single atom H3C CH3 150 °C H3C H 150 °C
H3C CH3 H3C H
are made, or broken, in concert." H S H -SO2 H H H S CH3 -SO2 H CH3
O2 O2
Woodward, R.B.; Hoffman, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853.
disrotatory elimination disrotatory elimination
Cheletropic reactions are a separate class of pericyclic reactions J. Am. Chem. Soc. 1966, 88, 2857.
that are subject to orbital symmetry analysis. They must obey the J. Am. Chem. Soc. 1966, 88, 2858.
Woodward-Hoffman rules the same way that cycloadditions and
sigmatropic rearrangements do. Most frequently encountered examples Reactivity general guidline

Cycloreversion
Linear approach vs. Non-linear approach O Cycloreversion &
Cheletropic reaction analysis is typically done in the addition direction. S SO2 Only Cycloaddition
Consider fragment "x" to be a single atom that contributes two O
C O S
electrons to the pericyclic transition state. The approach of "x" O O
can be either linear or non-linear. The rotation of the π system
N N + N N
will be either disrotatory or conrotatory based on the approach N N
of fragment "x" C
Linear Non-linear O R1 R2
N N O singlet carbenes
The HOMO of x + C O
The HOMO of x approaches the
points directly at π system at
x x
the π system. a skew angle.
Singlet carbene addition to olefins
Disrotatory Conrotatory Singlet carbenes have an unoccupied p orbital and
two non-bonding electrons in the σ orbital. Only
singlet carbenes can participate in cheletropic reactions.
LUMO LUMO
HOMO HOMO "The most importatnt cheletropic reaction is the addition of singlet
carbenes to make cyclopropanes."
Anslyn and Dougherty

Selection rules for cheletropic reactions Linear approach Non-linear approach

Allowed Ground State Reactions
π electrons
Linear Nonlinear
4n disrotatory conrotatory
4n+2 conrotatory disrotatory 4-electron 2-electron 4-electron 2-electron
Allowed Excited State Reaction Hückel forbidden Möbius forbidden Möbius allowed Hückel allowed
4n conrotatory disrotatory
4n+2 disrotatory conrotatory Only select carbene examples will be discussed here.
See K. Chen's GM on carbenes
Angew. Chem. Int. Ed. Engl. 1969, 8, 781.
Sankararaman, S. Pericyclic Reactions; Wiley-VCH: Weinheim, 2005.
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Sequential cycloaddition-cycloreversion and a strange caged structure Intramolecular [4+1] Cycloaddition

Howard, J. A. K. Tetrahedron, 1993, 49, 4699. Spino, C. J. Am. Chem. Soc. 2004, 126, 9926.
O
Cl Evidence: Org. Lett. 2007, 9, 5361. MeO2C
Cl Ph Ph Ph
Cl Ph Cl N N OMe CO2Me
Ph Cl PhMe, reflux
Cl Ph Ph Cl O OMe
Ph O 80%
Cl Cl bromobenzene, 160 °C, 48h Cl O

Cl 40% Cl Cl O [4+1]
[π2s+π2a+ σ2a] N2
Cl CO Cl
Cl Cl Ph
Ph OMe CO2Me OMe CO2Me
Cl Cl via: O
Cl Ph
Cl O O 3 O 3 MeO CO2Me
Cl Cl Ph Cl Cl Ph
Ph Ph Ph Ph Cl
Ph Cl
O Ph Ph An unprecedented tandem 1,3-dipolar cycloaddition-cheletropic elimination:
Cl Cl a facile approach to novel push-pull olefins
Cheng, Y. Org. Biomol. Chem. 2007, 5, 1282.
Cheletropic elimination of CO and formation of annulenes
Helv. Chim. Acta. 1989, 72, 1311. Ph
O Et Et N Et S
O N CO2Me
R 1 R4 N SH N S
R4 R1 DMAD
R3 -CO R2 N NPh CH2Cl2, 30 °C N N CO2Me
R2 R3 CO2Me
Bn Bn CO Me Bn
2 78%
R1, R4 = CO2Me R2 R3
Ph N C
R2, R3 = Ph R1 R4
Germanium Analogues of Carbenes
90%
Chrostowska. A. J. Organomet. Chem. 2009, 694, 43.
2 2
Synthesis of new chiral σ λ -phosphenium cations
Buono, G. Tetrahedron Lett. 1999, 40, 4669. Et Et
R R N N X X
Ge Δ Ge Δ
N Ge + Ge +
CH2Cl2, rt N
P + N N Y X=O,S Y
P
N 40% N OTf Et Et Y=S, NH
R=o-anisyl The Chemistry of Organic Germanium, Tin and Lead Compounds,
R OTf R
John Wiley and Sons, Chichester, 2002 (Chapter 1)
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. Tellurium Extrusion: Synthesis of Benzocyclobutene
MacNicol, D.D. Tetrahedron Lett. 1975, 24, 1893.

1.) EtMgBr 500 °C

Br Na2Te
Br2 Te
Br
2.) t-BuOK, PhH, rt C6H5
SO2 95% O "moderate yield" 74%
THF, -78 °C C6H5
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Tandem Cope-cheletropic reaction: a new molecular rearrangment Nitric oxide cheletropic traps (NOCTs)
Mai, D. Chem. Comm. 1996, 1181. 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 hυ NO
O N O
89% -CO
H
O O O
12h, rt
O

hυ
O
-CO
O O
CO "magic dust"

Ph Ph Ph
retro-Cheletropic ene Reactions with 2-carbena-1,3-dioxolane as the chelefuge
Vidal, A.; Sanchez-Andrada, P. Tetrahedron 2011, 67, 5590. hυ NO
O N O
-CO
Ph
O Ph Ph
PhMe, reflux, 1 h Ph
Ph
H O Ph 44% N
N C C fluorescent reduction
EtO2C Ph CO2Et non-radical products
Phenanthryne and bis-benzyne
Murata, S. J. Org. Chem. 1995, 60, 2344.
Yabe, A. J. Am. Chem. Soc. 2002, 124, 4512.
Me
O N OMe O
NH hυ hυ
O C -CO2 -CO
PhMe, 160 °C, 24 h O O + CO
H N N
S Ar matrix hυ
55%
S O -197 °C +CO
CO2Et CO2Et
Ar matrix
6π electrocyclic
ring closure
J. Am. Chem. Soc. 1966, 88, 582. O CF3 O O CF3 O CF3 CF3
Chem. Commun. 1994, 2155.
Ar hυ hυ
O retro-cheletropic O O O O O
O H N ene reaction -CO2
O O CO2 + H2C CH2
N O CF3 O Ar matrix O CF3
Ar matrix
O CF3 CF3
S CO2Et characterized by IR
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Applications in Total Synthesis Synthesis of estra-1,3,5,(10)-trien-17-one

Nicolaou, K.C. J. Org. Chem. 1980, 45, 1463.
-The examples presented here will consist of the three main cheletropic reactions
seen in total synthesis. Cheletropic reactions involving Fischer carbenes will not be O
discussed here beyond examples of the Simmons-Smith cyclopropanation. For an O O
in depth presentation and discussion of Fischer carbenes see K. Chen's group TsO 1.) KH
meeting on Fischer carbenes. DME, 25 °C, 15 h
SO2 + SO2
2.) AcOH-THF-H2O
Early studies on the formation of cyclobutarene 45 °C, 24 h
Cava, M.P. J. Am. Chem. Soc. 1959, 81, 4266. 2 equiv. 1 equiv. 77%,1:1 mixture DBP, 210 °C, 8 h
separated by chromatography
Δ
SO2 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. H H 85%
Staudinger, H. German Patent 506,839; [Chem. Abstr. 1913, 25, 522]
Staudinger, H. Chem. Ber. 1935, 68B, 455.
Stereoselective Synthesis of the Taxane Ring System.
Cheletropic extrusion of SO2: The search for a diene equivalent Winkler. J.; Houk, K. J. Org. Chem. 1997, 62, 2957.

Inspiration from W. Oppolzer Winkler's retrosynthetic analysis:

H H
+

H H H
Oppolzer, W. Synthesis 1978, 11, 793. O O O

K.C.N.'s idea: intramolecular trapping of o-quinodimethanes I S

O O
LHMDS, THF O2S PhMe, reflux
2 steps from
-78 C, 57% brsm 50 min, 80%
SO2 known diene alcohol
O
H
BF3-Et2O (6 equiv)
ZnCl2 (2 equiv)
5 mM in PhMe
Potential problem DCM, rt
82% H
n O 63%
n The methylstyrene side product
1,5-hydride shift was observed in only a small H
H (unspecified) amount. "It is interesting to note that neither Lewis acid is
CH3
capable of catalyzing both Diels-Alder reactions."
n= 2,3 n= 2,3 H H
O
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Total Synthesis of Colombiasin A O Total Synthesis of (+)-Rishirilide B

Nicolaou, K.C. Angew. Chem. Int. Ed. 2001, 40, 2482. 2 OH Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625.
Full paper: Chem. Eur. J. 2001, 7, 5359. 12
1
O OMe OMe
H 1.) SO2, h υ ZnO
First generation: 7 O 11
2.) MeOH, p-TsOH 155 °C
8
9 SO2
OMe O H 10
colombiasin A O
OMe OMe OBn OBn
Me OBn
AgO, 6M HNO 3
+ "numerous unidentified steps
TBSO HO by-products"
H OMe 1,4-dioxane, rt, 3 h H O O Diel-Alder and
7 12 27% 7
12 O β -elimination
9 9
O

O O
Second generation: H steps
OMe O O DDQ
Me
OMe OMe HO OH O
HO O
AgO, 6M HNO 3 many by-products O O
+ HO O
TBSO HO lacking the
H 1,4-dioxane, rt, 3 h H (+)-rishirilide B
OMe O diene system O O
7
12 <1% desired product 7
12

9 9

An "almost" cheletropic elimination of SO3 from 11-gorgiacerol

The solution: Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834.
OMe
OMe OMe CO 2Me CO 2Me
OMe
AgO
SO2 TBSO 6M HNO 3 O
H OMe O
TBSO Burgess' reagent
H rt, 20 min 7 1,4-dioxane NHR
OMe H O PhH, reflux
7 9 rt, 3h
12 91% O
SO2 85 % 40%
9 O OH
12 R = CO 2Me
O
O
CO 2Me
O OMe
BBr 3 2 OH
cyclooctene 12 PhMe HO O H
colombiasin A 1 H O H O
DCM HO H 180 °C, 20 min 7 O O O
-78 °C, 30 min 7 O 11 89% 9 H MeO 2H 2CN S O
43% brsm 8
9
exclusive endo product SO2 O O SO2
H 10 O
12 NHCO 2Me
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Ramberg–Bäcklund Reaction Total Synthesis of (+)-Estradiol

The reaction was first discovered in 1940 but no further Rigby, J. H. J. Am. Chem. Soc. 1999, 121, 8237.
work was published until 1950. O2 O2
O2
LG 1.) PhMe, reflux S S
R1 R2 R1 R2 S (MeCN)3Cr(CO)3
Base SO2 30%
+ TMSC CH Co2(CO)6
LG H R1 S R2 S (Z) 2.) Br2, Et3N THF
O O O O (CO)3Cr
+ + 70% TMS 85% TMS
R1 S R2
O O R1 R2
LG
R2 OTBS
S R1
R1 S R2 O O (E) O2 OTBS
O O HH 1.) t-BuOk, -105 °C
S
1.) hυ 2.) NCS (1 equiv.)
+ H
Early studies toward the synthesis of the enediyne moeity of calicheamicin 2.) CO SO2 3.) t-BuOK, 105 °C
Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 7360. (CO)3Cr H 70% 65%
TMS TMS
H
TBDPSO TBDPSO
1.) Na2SAl2O3 Cl 1.) MeLi
Br OH
2.) mCPBA 2.)TBAF OTBS OTBS
O2S
3.) SO2Cl2
Br OH
4.) mCPBA TBDPSO
TBDPSO 1.) HF/MeCN KNH(CH2)3NH2
2.) Et3SiH/TFA H H H
THF, rt
A Novel application of the Ramberg-Bäcklund Rearrangement 38% TMS 71% TMS
inseparable mixture
to a Highly StereoselectiveSynthesis of (+)-Eremantholide A
Boeckman, R. K. J. Am. Chem. Soc. 1991, 113, 9682. OH OH
6N HCl-THF
O O 25 °C, 10 h
H Pb(OTFA)4 H
oxone
steps O O TMS2S O O MeOH-H2O TFA H
H H H
NaOMe 25 °C, 6h 80%
TMS HO
H THF, 0 °C H Amberlyst-15
I estradiol
O 50% S O DCM, 25 °C, 4h
99%
O O Total Synthesis of Ampelopsin D
Br
O Snyder, S. A. J. Am. Chem. Soc. 2009, 131, 1753. MeO
1.) (Et)3COK O OMe
O MeO OMe 1.) p-TsOH
OH HMPA
O O HS OMe
O DME, 70 °C O O 1.) LiHMDS
O steps OMe OMe
5 min THF, - 78 °C H
O OMe
H
O 2.) 6N HCl-THF O2S H O 2.) Cl3CCCl3 S O OH 2.) m-CPBA
25 °C, 4h 20 °C, 1 h O MeO
O
70 % O 57% O MeO S
O Cl
eremantholide A over two steps O
OMe OMe
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Total Synthesis of Ampelopsin D continued Directed Heterodimerization: Stereocontrolled Assembly

via Solvent-Caged Unsymmetrical Diazene Fragmentation
Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 13002.
MeO HO
OMe 1.) t-BuOH, OH ONa O
aq. KOH O S O Cl S O
OMe OH
CCl4 HN CO2Me HN CO2Me
80 °C oxalyl chloride
OMe OH N N
2.) BBr3 CO2Me DMF CO2Me
MeO HO N H N H
O
S 40% over two steps CO2Me CO2Me
O OH MeO2C
OMe
ampelopsin D H N
MeO2C
N DMAP, Et3N
CH2Cl2
BnO2C NH2
Total Synthesis of Hirsutellone B
Nicolaou, K. C. Angew. Chem. Int. Ed. 2009, 48, 6870. MeO2C
MeO2C
O
H N H N
I S O MeO2C MeO2C
AcS N
N
O O O
1.) NaOMe O N NCS, BEMP BnO2C HN O
steps H H H H BnO2C S O
N CO2Me HN CO2Me
2.)H2O2
Na2WO4 N N
H H H H CO2Me CO2Me
Me Me N H N H
CO2Me CO2Me
CF2Br2, hυ "...the first example of directed and stereoselective C–C
KOH/Al2O3 t-BuOH bond construction fusing two different cyclotryptamine
DCM, t-BuOH, fragments at vicinal quaternary stereocenters."
0 °C to rt

MeO2C MeO2C
OH H N H N
MeO2C MeO2C
O NH steps O O N N
O
H H H H
BnO2C BnO2C CO2Me
O
CO2Me
N
H H Me H H N CO2Me
Me CO2Me N H
hirsutellone B N H CO2Me
CO2Me
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Simmons-Smith cyclopropanation
First discovered in 1944. Many asymmetric modifications
have been throughout the years. The most notable being Hydroxyl directed Simmons-Smith
the Charette asymmetric modification. O O
Et O
R2 R3
Zn I H
CH2 13
Li, NH3
R1 R4
R2 R2 R3 H 1.) Zn-Ag, CH2I2 O O
ZnEt2 + CH2I2 EtZnCH2I R3 -78 °C, 15 min
R4 R1 R4 OH 2.) PDC H
R1 H
H
EtI
For an excellent review on stereoselective EtZnI
cyclopropanation reactions see: Chem. Rev. 2003, 103, 977.

Total synthesis of (±)longifolene

Oppolzer, W. J. Am. Chem. Soc. 1978, 100, 2583. Enantioselective total synthesis of oleanolic acid, erythrodiol, β-amyrin, and other
O pentacyclic triterpenes from a common intermediate
O
Corey, E.J. J. Am. Chem. Soc. 1993, 115, 8873.
BzO BzO 1.) H2 (3 atm)
3 steps O O
hυ, pyrex filter Pd/C (10%)
cyclohexane 2.) selective
15-30 °C Wittig 12 18
83% olefination O
11 13 Et2Zn, CH2I2
O O 17
PhMe, rt, 8h
56% H
H
BzO
BzO H
3 steps Zn-Ag, CH2I2 H
PtO2
HOAc, rt, 18h Et2O, 35 °C, 60 h
96% 78%
O O 1.) PhCO2O-t-Bu, CuBr
longifolene PhCl, 115 °C, 4h
CH2OH 51%
2.) aq. NaOH,
H H
Simple synthetic route to the limonoid system MeOH-THF
Corey, E.J. J. Am. Chem. Soc. 1987, 109, 918. BzO 95% TBSO
H H
"The most obvious approach" gave poor results

O
β-amyrin
O O
various H
13 organocopper Li, NH3-THF
reagents R CH2OH erythrodiol
O O + -78 °C, 2 h
OH
93% H
H H H H
BzO oleanolic acid
1,2-addition H
H unreacted S.M.
Ruben Martinez Cheletropic Reactions Baran Group Meeting
06/01/13

Total Synthesis of (±)-Taxusin Total Synthesis of (±)-Maoecrystal V

Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186. Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860.
OBn OBn OMOM OMOE
OBn OBn
steps steps
1.) Et2Zn, CH2I2 OH 1.) Lombardo reagent OH
TESO Et2O, rt, 6h TESO
O 2.) CH2I2, Zn/Ag O
O
2.) PDC 75%
H H
85% O O O O
HO O
O O
OAc OH O O
OAc OH H2, PtO2 PCC
1.) Li, NH3
4 steps AcOH
AcO t-BuOH O O
HO
2.) MeOH 40% 76%
O O O O
H H H H 91%
OAc O O Me
taxusin O

Me O
Total Synthesis of (+)-Ambruticin Me O
O
Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. maoecrystal V
Regioselective, asymmetric cyclopropanation

Highly Enantioselective Simmons-Smith Fluorocyclopropanation of Allylic Alcohols

Charette A. B. J. Am. Chem. Soc. 2013, 135, 7819.
Zn(CH3CHI)2•DME
HO O HO O
CONMe2 State of the art in cyclopropanation
Me ICHF2 F ZnI
O CONMe2 IZnEt
86% -EtI
B O F
Bu halogen
∗ scrambling
O F ZnF F
OH R3 trans
B O
OH i.) Et2Zn Bu O ZnEt I R2 R1
R2 OH
CONMe2 R3
R1 OH
O R1
CONMe2
CO2H O R3
Me B O R2
(+)-ambruticin Bu