Anionic Oxy-Cope Rearrangement:Recent Development in Mechanistic Study and
Synthetic Application
Lingling WangChemistry Department
Michigan State UniversityFebruary 11, 2004
Outline
I. IntroductionFrom Cope to Anionic Oxy-Cope (AOC) RearrangementRate-acceleration Effect of C3-Oxy-Anionic Substituent
II. Recent Mechanistic Study of AOC RearrangementFurther Mechanistic Study toward Rate-accelerationRole of Chelation Effect in AOCVariations of Classic AOC
III. Recent Synthetic Developments in AOCUsing Transition-metal Complexes to Form AOC PrecursorsAOC-involved Tandem Rearrangement Processes
Cope Rearrangement
-Highly ordered cyclic transition state-Generally reversible
Oxy-Cope Rearrangement
O1
2
3
4
5
6O
H [ 1,5 ]-H shift
-Generally irreversible -A competitive retro-ene fragmentation
1
2
3
45
6
HO340 - 390oC
HOtautomerization O
HO
Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441-444.Berson, J.A. J. Am. Chem. Soc. 1964, 86, 5017-5018.
Introduction
RL
1
2
3
45 6
E
300-350 C°RL
RL
E
E
RL
Z
E *
RL
*
major
minor
favored
disfavored
[ 3,3 ] Sigmatropic
Introduction
Anionic Oxy-Cope (AOC) Rearrangement
-Rate enhancement of 1010 - 1017
-No fragmentation byproduct
-Low reaction temperature
KH18-Crown-6
OK KO1
2
3
45
6
HO
O= 0 C° K
Evans, D. A.; Golob, A.M. J. Am. Chem. Soc.1975, 97,4765-4766.
Introduction
Anionic Oxy-Cope (AOC) Rearrangement
-Rate enhancement of 1010 - 1017
-No fragmentation byproduct
-Low reaction temperature
KH18-Crown-6
OK KO1
2
3
45
6
HO
O= 0 C° K
Evans, D. A.; Golob, A.M. J. Am. Chem. Soc.1975, 97,4765-4766.
Previous Reviews
•Paquette, L. A. Tetrahedron 1997, 53, 13971-14020.
•Wilson, S. R. Org. Reactions 1993, 43, 93-250.
•Paquette, L. A. Synlett 1990, 67-73.
IntroductionRate-acceleration Effect of C3 Oxy-anion
1.63×10-14
1.05 × 10-12
1.64 × 108
36.3
33.8
6.3
1.548
1.552
1.604
H
OH
O
1
2
3
k (s -1)
ΔG≠
(kcal/mol)
Bond Distance (Å)
C3 –C4RSubstance
Baumann, H.; Chen, P. Helvetica Chemica Acta, 2001, 84, 124-130. .
MO[3,3]
MO1
23
45
6 6
12
3
45
1
23
4
5 6
1
23
4
5 6
RR
1 R=H 2 R=OH 3 R=O
Cope Rearrangement
Mechanistic Study-Substituent Effect
Can C4 or C6 Heteroatom Substituents Also Help Rate-accelerating in AOC ?
Evans, D. A.; Ballallargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100, 2242-2243.
HO
MeO
MeKH, THF
° MeO
OMe
1
54
3
2
HOMe
NaH, Et2O
° PhS
OMe
PhS
1
2
3
45
6
KH, THF
°25 C, 1h+
6
PhS
OMeHO
Me
PhS
1
2
3
45
6
85 C, 9.5 h
85%
25 C, 6 h71%
42%
Cleavage Products
A
B
B
Mechanistic Study-Substituent Effect
Can C4 or C6 Heteroatom Substituents Also Help Rate-accelerating in AOC ?
Paquette, L. A.; Wang, H.; Zeng, Q.; Shih, T. L. J. Org. Chem. 1998, 63, 6432-6433.
C
D
OMOM
O
TMS
OH
BnO
OPMB
OPMB
OTBS
KHMDS,18-Crown-6
THF, 0 C°
OMOM
HO
O
TMS
H
OTBS
BnOOPMB
OPMB
OMOM
SPh
OH
BnOOPMB
OTBS
OPMB
KHMDS,18-Crown-6
THF, -78 C°
OMOM
HO
PhS H
OTBS
BnOOPMB
OPMB
70%
(COMPLETE IN 5 MIN)
85%
(COMPLETE IN 5 MIN)
1
2
34
5
6
1
2
34
56
Mechanistic Study-Substituent Effect
Computational Calculation of C4 & C6-Substituent Effect
24.419.4-19.6
25.321.7-21.9
-
Homo BDE
12.08.4-9.3
5.05.3-5.6
8.3
Activation Energy
28.523.4-23.7
6- OMe4- OMe
13.19.6-9.8
6- SMe4- SMe
-H
Hetero BDER
Computed Energies of Activation and BDEs ( kcal/mol) for Cleavage C3-C4
Paquette, L. A.; Haeffner, F.; Houk, K. N.; Reddy, R. Y. J. Am. Chem. Soc. 1999, 121, 11880-11884.
R
O
4
AOC Rearrangement O
R
O
R
O
R
6
AOC Rearrangement
3
4
3
Mechanistic Study-Substituent Effect
Can C4 or C6 Heteroatom Substituents Also Help Rate-accelerating in AOC ?
Evans, D. A.; Ballallargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978, 100, 2242-2243.
HO
MeO
MeKH, THF
° MeO
OMe
1
54
3
2
HOMe
NaH, Et2O
° PhS
OMe
PhS
1
2
3
45
6
KH, THF
°25 C, 1h+
6
PhS
OMeHO
Me
PhS
1
2
3
45
6
85 C, 9.5 h
85%
25 C, 6 h71%
42%
Cleavage Products
A
B
B
Mechanistic Study-Substituent Effect
Can C4 or C6 Heteroatom Substituents Also Help Rate-accelerating in AOC ?
Paquette, L. A.; Wang, H.; Zeng, Q.; Shih, T. L. J. Org. Chem. 1998, 63, 6432-6433.
C
D
OMOM
O
TMS
OH
BnO
OPMB
OPMB
OTBS
KHMDS,18-Crown-6
THF, 0 C°
OMOM
HO
O
TMS
H
OTBS
BnOOPMB
OPMB
OMOM
SPh
OH
BnOOPMB
OTBS
OPMB
KHMDS,18-Crown-6
THF, -78 C°
OMOM
HO
PhS H
OTBS
BnOOPMB
OPMB
70%
(COMPLETE IN 5 MIN)
85%
(COMPLETE IN 5 MIN)
1
2
34
5
6
1
2
34
56
Mechanistic Study-Substituent EffectRate-acceleration by Additional Unsaturation on C1
Hanna, I.; Gentric, L.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631-3634.
OH
OH
OO
OO
12
345
6
B
C
KH,THF,reflux,
22 hH
O88%
KH, THF, reflux, 18-Crown-6
orKHMDS,
toluene,reflux,18-Crown-6
or decalin, reflux
HO
OO
OO
H
OHOH
OH
Vinigrol
opposite stereochemistry
12
345
6
7
A
D
Mechanistic Study-Substituent EffectRate-acceleration by Additional Unsaturation on C1
Hanna, I.; Gentric, L.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631-3634.
NaH, THF, reflux,
18 h
HO
92%
H2, Rh/Al2O3AcOEt,
3h
OO
100%
HO
OO
AF
OH
OH
KH, THF, refluxor
KHMDS, 18-Crown-6THF, rt, 20h
OH
HO
G H
OH
OO
12
345
6
E
Mechanistic Study-Substituent EffectRate-acceleration by Additional Unsaturation on C1
Hanna, I.; Gentric, L.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631-3634.
OR
OR
RO
RO
Mechanistic Study— Chelation Effect
Chelation–assisted Aromatic AOC Rearrangement
Uyehara, T.; Ueno, M.; seki, K.; Tooya, M.; Sato, T. Tetrahedron Lett. 1998, 39, 8673-8676.
HO Me
Me
H
O
1
HO
H
H
O
2
MeO
MeO
HO
MeMe
H
O OMe
3
Entry Oxy-Cope system Products
KH, 18-Crown-6,
70 C, 4h°
Conditions
KH, 18-Crown-6,
70oC, 4h
KH, 18-Crown-6,
70oC, 0.5h
MeO
Me
59
Yields
89
Mechanistic Study— Chelation Effect
Chelation–assisted Aromatic AOC Rearrangement
Uyehara, T.; Ueno, M.; seki, K.; Tooya, M.; Sato, T. Tetrahedron Lett. 1998, 39, 8673-8676.
59%
89%
HO
H
H
O
MeO
MeO
HO
Me
Me
H
O OMe
KH, 18-Crown-6,
70oC, 4h
KH, 18-Crown-6,
70oC, 0.5h
MeO
Me
O
O
OMe
MeO
K
K
Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement
Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.
OH
ORPh
3 eq. KH2 eq. 18-Crown-6
THF, rtPh
OR
Oor Ph
ORO
AOC rearrangementR = iPr
ORO
OR
O
Ph Ph
1 M HCl(aq)
O
HO
Ph
OHO
Ph
Intramolecular Aldol
34
72%
Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement
Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.
OH
ORPh
3 eq. KH2 eq. 18-Crown-6
THF, rtPh
OR
Oor Ph
ORO
AOC rearrangementR = iPr
ORO
OR
O
Ph Ph
1 M HCl(aq)
O
HO
Ph
OHO
Ph
Intramolecular Aldol
34
Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement
Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.
OH
ORPh
3 eq. KH2 eq. 18-Crown-6
THF, rt
AOC rearrangementR = iPr
1 M HCl(aq)
O
HO
Ph
OHO
Ph
Intramolecular Aldol
ORO
or Ph ORO
ORO
OR
O
Ph Ph
Ph3
4
69%
Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement
Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.
OH
ORPh
3 eq. KH2 eq. 18-Crown-6
THF, rt
AOC rearrangementR = iPr
1 M HCl(aq)
O
HO
Ph
OHO
Ph
Intramolecular Aldol
ORO
or Ph ORO
ORO
OR
O
Ph Ph
Ph3
4
Mechanistic Study— Chelation EffectChelation–controlled AOC Rearrangement
Hartley, R. C.; Rutherford, A. P. Tetrahedron Lett. 2000, 41, 737-741.
OH
ORPh
3 eq. KH2 eq. 18-Crown-6
THF, rt
34
Ph
ORO
K
PhORO
K
ORO
Ph
OH
ORPh
34
3 eq. KH2 eq. 18-Crown-6
THF, rt
O
ORPh
Mechanistic Study— Variations of Classic AOC
A Radical Alternative of AOC
One limitation of AOC: two reacting terminals must be in proximity
A scheme of radical alternative to the oxy-Cope rearrangement
Renaud, P.; Giraud, A.; Churd, R. Angew. Chem. Int. Ed. 2002, 22, 4321 –4323.
R1
O
R2
M
(M = Li, MgX)
R1
OH
R2 AOC product
X
OH
X
O
radicalgeneration
β -fragmen-tation XO XO
6-endocyclization
XH
H
OreductionXH
H
O
Mechanistic Study— Variations of Classic AOC
A Radical Alternative of AOC
Renaud, P.; Giraud, A.; Churd, R. Angew. Chem. Int. Ed. 2002, 22, 4321 –4323.
The tricyclic oxetane approach to form alkoxy radical
Synthetic application — preparation of a tricyclic system
O
Li
87%OH
1) PhSeCl, NEt3, -40 C
2) Bu3SnH, AIBN, Na2CO3 toluene, reflux
70%
H
HH
OH +
H
HH
OH
°
1 : 1
X
OH
X
O
PhSeX
H
H
O
X = CH2 , O
X
O
PhSeCl, NEt3 Bu3SnH, AIBN
53-60% 64-69%
Mechanistic Study— Variations of Classic AOC
Base effect on AOC: Li Na K
faster rearrangement
no counterion
more 'naked' alkoxide
Phosphazene super-base P4-t-Bu
pKBH =42.6 (in MeCN)
- Soluble in organic solvents- No crown ether required
Hartley, R.C.; Mamdani, H.T. Tetrahedron Lett. 2000, 41, 747-749.Schwesinger, R.; Schlemper, H. Angew. Chem. Int. Ed. Engl. 1987, 11, 1167-1169.
Metal-free Base Induced AOC
PhOH
R
1.1 eq. P4-t-Bu THF-hexane (5:1) 0 C to rt, overnight°
(2) pH 7 bufferR
Ph O
44-58%R = H, Ph
(1)
H PNMe2
Me2NNMe2
N PN
NN
But H
PNMe2
Me2N NMe2
PNMe2
NMe2
NMe2PNMe2
Me2NNMe2
N PNBut
NN
PNMe2
Me2N NMe2
PNMe2
NMe2
NMe2 PNMe2
Me2NNMe2
N PN
NN
But H
PNMe2
Me2N NMe2
PNMe2
NMe2
NMe2
Summary –Mechanistic Study Part
•Why C3-oxy-anionic substituent can accelerate AOC rearrangement?- Weakening of the adjacent C-C bond by oxygen anion
•What kinds of substituents can further accelerate the reaction?- Thioalkoxy group on C4 or C6 position- Additional unsaturated substituents on terminal position
•What is the role of chelation effect in AOC rearrangment?- Change the stereoselectivity of the products- Promote aromatic AOC rearrangement
•What if the AOC precursor does not have the required geometry?- Turn to the radical alternative of AOC
•What’s the alternative base for AOC?- Metal-free phosphazene super-base
Outline
I. IntroductionFrom Cope to Anionic Oxy-Cope (AOC) RearrangementRate-acceleration Effect of C3-Oxy Anionic Substituent
II. Recent Mechanistic Study of AOC RearrangementFurther Mechanistic Study toward Rate-accelerationRole of Chelation Effect in AOCVariations of Classic AOC
III. Recent Synthetic Developments in AOCUsing Transition-metal Complexes to Form AOC PrecursorsAOC-involved Tandem Rearrangement Processes
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
ROM/RCM Used in AOC Precursor Synthesis
Snapper, M. L.; Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478-1479.Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.
R'
"R
R R'
"RR
∆
R
R'
"R
O
Me
Me
OO
Me
Asteriscanolide
O O
HOMe
Me
O
9-Deoxyxeniolide A
Me
O
Me O
OMe
Me
HO
Clavirolide A
HO
Cope rearrangement
Grubbs' catalyst
ROM
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
ROM/RCM Used in AOC Precursor Synthesis
Snapper, M. L.; Tallarico, J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478-1479.Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.
R'
"R
R R'
"RR
∆
R
R'
"R
O
Me
Me
OO
Me
Asteriscanolide
O O
HOMe
Me
O
9-Deoxyxeniolide A
Me
O
Me O
OMe
Me
HO
Clavirolide A
HO
Cope rearrangement
Grubbs' catalyst
ROM
OHOH
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
ROM/RCM Used in AOC Precursor Synthesis
O
R
+
O
n
n'
n
OH
R
O
n'On
n'
O
R
oxy-Copealkylation
E/Z mixture
Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.
n= 1-3n'=1-2
n= 1-3n'=1-2
OTBS
+
CO2Et1) ZrCl42) DIBAL-H
Brnn'
R3)
O
nn'
R
olefin metathesis
n
OH
R
O
n'
On
n'
O
R
oxy-Cope
OTBS
H H
H
H
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
ROM/RCM Used in AOC Precursor Synthesis
Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.
entry cyclobutene metathesis product yield(%) Cope product yield(%)
OOTBS
H
TBSO O
H
OOTBS
H
TBSOO
H
OOTBS
H
TBSO
H
O
82
82
83
O
HO
O
OH
OH
O
82
82
64
2
3
4
H
H
H
OOTBS
H
TBSO O
H
O
O
89 802.1:1 cis/trans
1
H
H
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
ROM/RCM Used in AOC Precursor Synthesis
Snapper, M. L.; White, B. H. J. Am. Chem. Soc. 2003, 125, 14901-14904.
O
Me
HO
H
O
OH
H
Me
OO
H
H
H
Me
H
O
Me
HHO
O
H
Me
H
O
chair TS
boat TS
not observed
O
O
Me
O
O
Me
H
H
not observed
B
A
H
78%, A:B= 1.8: 1
AOC
OOMe
H
H
OOMe
Palladium Catalysts used in AOC Precursor SynthesisSynthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
O O
RRRR
Meijere, A.; Noltemeyer, M.; Voigt, K.; Zezschwitz, P. Synthesis 2000, 9, 1327-1340.
n
Br
Br
CO2tBu
Pd(OAc)2, PPh3
NEt3, DMF90-100 C, 20h°
n
CO2tBu
CO2tBu
m-CPBA (2equiv.)
24h, 0-20 C° n
CO2tBu
CO2tBu
O
n=1n=2
56%57%
82%74%
Pd2(dba)3 CHCl3
Bu3P/HCO2H/Et3N
n
CO2tBu
CO2tBu
OH KHMDS or KH 18-Crown-6,-78oC
1)
2) EtOH, NH4Cl (aq.), THFO
CO2tBu
CO2tBun
n=1 60% n=2 94%
80%81%
R=CO2tBu
Organozirconcene Reagent Used in AOC Precursor Synthesis
Synthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
Huang, X. ; Pi, J. Synlett 2003, 15, 2413-2415.
93:7
88:12
82:18
85:15
56:44
50:50
74
81
81
82
82
84
H
CH3
CH3
CH3
C6H5
C6H5
C6H5
C6H5
p-CH3OC6H4
p-BrC6H4
C6H5
p-CH3OC6H4
1
2
3
4
5
6
Ratio (A/B)Yield (%)R2R1Entry
ZrCp2ClO
R2
Me3SiCH2
R1
Me3SiCH2
Cp2Zr(H)ClMe3SiCH2 Zr(Cl)Cp2CH2Cl2
-78-25 C°
1)0 C°
2) NaHCO3
R1 R2
OMe3SiH2C
R2HO R1
+
Me3SiH2C
R2HO R1
A Bmajor minor
Organozirconcene Reagent Used in AOC Precursor SynthesisSynthetic Developments-Using Transition-metal Complexes to Form AOC Precursors
Huang, X. ; Pi, J. Synlett 2003, 15, 2413-2415.
Me3SiH2C
O
R2 R1
TBAF
THF, rt.
OHR2
R1
74-81%
C D82-89%
Me3SiH2C
R2HO R1
A
KH, THF, rt.
R1O
R2CH2SiMe3 H2O
Tandem [2,3]-Wittig-AOC Rearrangement
Earliest Example
Greeves, N.; Vines, K. J. Tetrahedron Lett. 1994 35, 7077-7080.
A
Bu
Ph O
HH
Ph BuO
Bu
Ph O
HH
Ph BuO
O Ph
Bu 18-Crown-6KH
DMSO25 C°
Bu
Ph O
H2O Bu
Ph O
[2,3]-Wittig AOC
58%
O
Ph
Bu
A
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem [2,3]-Wittig-AOC Rearrangement
Greeves, N.; Lee, W.; Mclachlan, S. P.; Oakes, G. H.; Purdie, M; Bickley, J. F. Tetrahedron Lett. 2003, 44, 9035-9038.
Functionalization of the Rearrangement Products
OH 1 eq. KH,1 eq. 18-Crown-6
Ph Br
O 2 eq. KH,
2 eq. 18-Crown-6
Ph
50%
O
Ph
1 eq.
THF, rt.
Etherification
O
Ph
A
[2,3]-Wittig AOC
Ph3P=CHCO2Me
1.3 eq.
THF, reflux
70%
Ph
CO2Me
2 mol% K2OsO4 2H2O1.3 eq. NMO
Acetone/H2O 3:1
Ph
CO2MeOH
HO
73%
3 eq. NaHCO3
3 eq. I2
MeCN
57%
Ph
CO2MeO
HO I
1.5 eq. Bu3SnHAIBN
THF, reflux
88%
Ph
CO2Me
OHO
Me
Ph
CO2Me
OHO
MeH H
Major Minor
+
A
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem Brook Rearrangement /AOC: [3+4] Annulation
[3+2] Annulation via Tandem Brook Rearrangement/intramolecualr Carbonyl Addition
Expected [3+4] Annulation
O
X
TBSOLiR
O
R
X
O
TBS
Brook Rearrangement
O
R
X
TBSO
Michael Addition
TBSO
O
R
X
Takeda, K.; Fujisawa, M; Makino, T; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
O
Me3Si
TBS RLiO
-80 C to -30 C° ° O
O TBS
RMe3Si
BrookRearrangement
O
OTBS
RMe3Si
Carbonyl Addition
Me3SiR
OH
OTBS
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
84
84
73
82
CHMe2
(CH2)4Me
-(CH2)3-
-(CH2)4-
1
2
3
4
Yield of B (%)REntry
29
11
24
32
CHMe2
(CH2)4Me
-(CH2)3-
-(CH2)4-
1
2
3
4
Yield of C (%)REntry
Tandem Brook Rearrangement /AOC: [3+4] Annulation
X=TMS
Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
O
Me3Si
TBS
+
OLi
R
-80oC to -30oC
THF
TBSO
O
R
SiMe3
O
SiMe3
TBS
(Z)-A+
OLi
R
-80oC to -30oC
THFTBSO
O
R
SiMe3
56
56
B 5,6-syn C 5,6-anti
(E)- A
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
72
72
42
63
CHMe2
(CH2)4Me
-(CH2)3-
-(CH2)4-
1
2
3
4
Yield of E (%)REntry
14
18
15
11
CHMe2
(CH2)4Me
-(CH2)3-
-(CH2)4-
1
2
3
4
Yield of F (%)REntry
Tandem Brook Rearrangement /AOC: [3+4] Annulation
X=SnBu3
Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
O
Bu3Sn
TBS
(E)- D
+
OLi
R
-80oC to -30oC
THF
TBSO
O
R
SnBu3
O
SnBu3
TBS
(Z)- D
+
OLi
R
THFTBSO
O
R
SnBu3
56
56
E 5,6-syn F 5,6-anti
-80oC to -30oC
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem Brook Rearrangement /AOC: [3+4] Annulation
Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947-4959.
O
X
TBS
OLi
R
+
O
RO
TBS
X
O
R
X
TBSO
TBSO
OLi
R
XzXEX
R
O
TBSO
O
R
X
TBSO
G
Brook
AOC
Revised Mechanism
RXE
Xz
OOR'3Si
Intermediate observed
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem Anionic [ 1,3 ] Sigmatropic/ Oxy-Cope Rearrangement
Seki, K.; Haga, K.; Tadao, U.; Hashimoto, H.; Jin, T.; Karikomi, M. Tetrahedron Lett. 2002, 43, 3633-3636.
OH
Ph
diglymeKHDMS
-78oC
[ 1,3 ] sigmatropic
H
H
Ph
HO
diglymeKHMDS
100 C° PhO
1 2 3 90%
HOO
O
OH
H
OAcO
OH
OAcOBzO H
Taxol
Ph NH
PhO
PhO
4
123
4
AOC
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem Anionic [ 1,3 ] Sigmatropic/ Oxy-Cope Rearrangement
Seki, K.; Haga, K.; Tadao, U.; Hashimoto, H.; Jin, T.; Karikomi, M. Tetrahedron Lett. 2002, 43, 3633-3636.
-
-
-
81
23
22
-78/15
145/15
120/60
1
1
2
1
2
3
32
Yield(%)Temp.(°C) / time(min)
SubstrateEntry
Ph
HO
2
OH
Ph
H
H
Ph
HOPh
O
1
[ 1 ,3 ]
2 3
Sigmatropic
3 eq. KHDMS
AOC
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Recent Synthetic Developments- AOC-Involved Tandem Rearrangement Processes
Tandem Anionic [ 1,3 ] Sigmatropic/ Oxy-Cope Rearrangement
Seki, K.; Haga, K.; Tadao, U.; Hashimoto, H.; Jin, T.; Karikomi, M. Tetrahedron Lett. 2002, 43, 3633-3636.
24
Trace
38
86
32
42
-
-
50/120
100/60
100/15
-40/30→100/15
4a ( R2=H )
4a ( R2=H )
4b ( R2=Me )
4b ( R2=Me )
1
2
3
4
65
Yield(%)Temp.(°C) / time(min)SubstrateEntry
Reactivity Toward AOC: Ph
HO
>
HO
>Ph
HO
Ph
5b 5a 2
OHR2
Ph
H
R2
Ph
HO
R2
PhO
4 5 6
[ 1, 3 ]Sigmatropic
3 eq. KHDMS
AOC
Summary–Synthetic Application Part
Transition Metal Complexes Can Help Forming AOC Precursors in a Stereocontrolled Fashion
-ROM/RCM
-Twofold Heck Reaction/ Hydrogenation
- Organozirconcene Reagent
AOC-involved Tandem Rearrangement Processes - Waiting for Further Application into Total Synthesis
-Tandem [2,3]-Wittig-AOC rearrangement
-Tandem Brook /AOC Rearrangement
-Tandem Anionic [ 1,3 ]/ Oxy-Cope Rearrangement
Acknowledgement
Dr. Tepe
Dr. Wagner
Professors
Friends
Yu
Zhenjie
Yana
Tao
Jun
Lei
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