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Electronics and Regioselectivity of
Claisen Rearrangements
Thu NguyenDepartment of ChemistryMichigan State University
20 September 2006
Outline
Introduction Claisen rearrangement
Use of catalysts in regioselectivity[3,3] selectivity[1,3] selectivity
Stereoelectronic effects on Claisen rearrangement in natural products
Selectivity in allyl aryl ethersLaterifloroneForbesioneTricycloillicinone
ConclusionsAcknowledgements
Introduction: Claisen Rearrangement
Claisen, L. Ber. 1912, 45, 3157.Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002.
[3,3] sigmatropicrearrangement of allylaryl (vinyl) ethersGives γ,δ-unsaturated carbonylCan be chemo-, regio-, diastereo-, enatioselectiveFormation of product is highly favored at equilibrium
O Δ or L.A. O
OR
OHR
+
OHR
ortho para
Δ
Introduction: Claisen Rearrangement
Present in nature – in vivo catalyzed
Used in natural product synthesis
O COO-
COO-
OH
chorismate mutase
OH
-OOCO
COO-
chorismate prephenate
Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002.Mattia, K.M., Ganem, B. Angew. Chem. Int. Ed. Engl. 1996, 35, 936-945.
O
OH O
HO
O
O
forbesione laterif lorone
O OO
tricycloillicinone
O
O
O
O
O
O
O
O OH
Introduction: Claisen Rearrangement
Generally described as a suprafacial, concerted, nonsynchronous rearrangement
O
RΔ, [3,3]-sigmatropic
rearrangement
O
R
O
R
Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002.Gajewski, J.J. Acc. Chem. Res. 1997, 30, 219-225.
O O
suprafacial antarafacial
Introduction: Claisen Rearrangement
Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002.Gajewski, J.J. Acc. Chem. Res. 1997, 30, 219-225.
O
ion pair
O
radical pair
O
CH3TBSO
RH
O
OTBSCH3
R
O
CH3TBSO
RH
O
CH3TBSO
RH
12
45 6
12
5
6
O
TBSO CH3
HR
Introduction: Claisen Rearrangement
O
O
O
O
O
O
O
O
HOMO
LUMO
σ
σ*
Challenges faced with Claisen
High temperature reactionsLong reaction timesNot always selective
stereoisomersenantiomersregioisomers
Can be low yielding
Substituent effects on rateO 1
2
4
56
O 12
45
6
Electron Donating Group Acceleration1
Position Group
1 -O, -NH2, -F, -CH3
-CH3, -OCH3
-CH3, -OCH3
-OSi(CH3)3, -CH3, -CH-SO2Ph, -F2
4
6
Electron Withdrawing Group Acceleration1
Position Group
2
4
-CN, -CO2-, -CO2CH3, -CF3
-CN, -CF3
1.Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002
O
O
O
O
HOMO
LUMO
O
O
O
O
HOMO
LUMOEDG
EDG
EDG
EDG
Outline
Introduction Claisen rearrangement
Use of catalysts in regioselectivity[3,3] selectivity[1,3] selectivity
Stereoelectronic effects on Claisen rearrangement in natural products
Selectivity in ally aryl ethersLaterifloroneForbesioneTricycloillicinone
ConclusionsAcknowledgements
Regioselectivity with Lewis acids
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron. 2006, 62, 9467-9474.Gansauer, A., Fielenbach, D., Stock, C., Geich-Gimbel, D. Adv. Synth. Catal. 2003, 345, 1017-1030.
[3,3]
[1,3]
O
R1
[3,3]
[1,3]
O
R2
R1
R1
R2
LA
R2
O LA
O
R2
R1
R2
R1 O
R3
R3R3
R3
R3
Substituent effects
Martin Castro, A.M. Chem. Rev. 2004, 104, 2939-3002
Electron Donating Group Acceleration
Position Group
-CH3, -OCH3, Ph, n-Bu
-CH3, -OCH3, Ph
-OSi(CH3)3, -CH3, -CH-SO2Ph, -F2
4
6
O
R2
R1 R3
[3,3]
[1,3]R1
R2
O LAR3
Regioselectivity with Lewis Acids: Mechanism
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.
Same major product in both cases.
O
Me
O
Ph Me+
O
MePh
MeAl(OAr)2
Ph
O
MePh78:22
O
MePh95:5
[1,3] major
[3,3] major
Regioselectivity with Lewis Acids: Mechanism
R
OLA
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.Gansäuer, A., Fielenbach, D., Stock, C. Adv. Synth. Catal. 2002, 344, 845-848.
O
Ph Me
O
MePh Ph Me
O
[1, 3] [3, 3]
D
27% D 7% D
O
Tol Me
O
MeTol Tol Me
O
[1, 3] [3, 3]
toluene, -78°C
MeAl(OC6Br3H2)2
25% D 21% D
59% D
Regioselectivity with Lewis acids: [3,3] selectivity
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron 2006, 62, 9467-9474.
NN N
NM PhPh
Ph
Ph
X
O
MePh
5 mol % M (TPP)X
Cl(CH2)2Cl, 83°C, 7hrO
MePh
O
MePh
[3,3] [1,3]
1
entry catalyst Time (hr) [3,3] (%) [1,3] (%)
None 58 40 02 7 94 0
3 Mn(TPP)Cl 24 62 0
4 Fe(TPP)Cl 24 83 0
5
6
Cr(TPP)OTf 24 19 26
Fe(TPP)OTf 2 16 27
Cr(TPP)Cl
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron 2006, 62, 9467-9474.
Regioselectivity with Lewis acids: [3,3] selectivity
entry time (hr) yield (%)productsubstrate
1
7 94O
MePh
O
MePh2
5 93O
MePh
Me
O
MePh
Me
3
0.5 82O
MePh
Ph
O
MePh
Ph
O
Ph
O
Ph
4
52 41
5
6 72O
Ph
Me
O
Ph
Me
Conditions: 5 mol % Cr(TPP)Cl, Cl2(CH2)2, 83°C
[3,3] selectivity with a parasubstituent
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron 2006, 62, 9467-9474.
entry time (hr) yield (%)productsubstrate
O
Me
O
Me1 7 62
2 8 57
MeO MeO
O
Me
O
Me
Me Me
NN N
NM PhPh
Ph
Ph
X
O
Me 5 mol % M (TPP)X
ClCH2CH2Cl, 83°C
O
Me
R R
[3,3] selectivivity with allyl vinyl ethers
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron 2006, 62, 9467-9474.
entry time (hr) yield (%)productsubstrate
1
9 86O
PhMe
O
PhMe2
2 93
3 12 62
4 3 89
5 1 93
O O
Ph Ph
O
Men-Bu
O
Men-Bu
O
Men-Bu
O
Men-Bu
Me Me
O
Men-Bu
O
Men-Bu
Ph Ph
Conditions: 5 mol % Cr(TPP)Cl, Cl2(CH2)2, 83°C
[3,3] selectivivity with trisubstitutedallyl vinyl ethers
Takanami, T., Hayashi, M., Iso, K., Nakamoto, H., Suda, K. Tetrahedron 2006, 62, 9467-9474.
entry time (hr) yield (%)productsubstrate
1 20 57
2 50 51
3 3 78
O
Men-Bu
O
Men-Bu
MeMe
O
MePh
O
MePh
MeMe
O
Me
O
Me
MeMe
Ph
Conditions: 5 mol % Cr(TPP)Cl, Cl2(CH2)2, 83°C
Ph
Regioselectivity with Lewis acids:Lewis acid screen for [1,3]
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.
O
Ph Me
Lewis Acid-78°C
O
MePh Ph Me
O
[1, 3] [3, 3]
entry Lewis Acid ratio [1,3] : [3,3]
1 Cu(OTf)2 50 : 50
2 SnCl4 50 : 50
3 TiCl4 67 : 33
4 5 : 95
5 78 : 22
OAl
O
MePh
PhPhPh
OAl
O
MeBr
BrBrBr
Br
Br
Regioselectivity with Lewis acids: [1,3] selective with para substituent
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.
O
R Metoluene, -78°C
O
MeR R Me
O
[1, 3] [3, 3]
entry cinnamylvinyl ether yield(%) ratio [1:3] : [3:3]
MeAl(OC6Br3H2)2
1
O
Me 75 78 : 22
2 61 81 : 19Me
O
Me
3 44 75 : 25Me
O
MeO
4 Me
O
F3C
NP No reaction
[1,3] Selectivity of trisubstitutedallyl vinyl ethers
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.
O
Ph Me
Lewis Acid-78°C MePh Ph Me
O
[ 1, 3] [3, 3]
entry Lewis Acid yield (%) ratio [1,3] : [3,3]
1 Cu(OTf)2 81 >95 : 5
2
3
TiCl4 44 >95 : 5
4
Me2AlCl 73 >95 : 5
44 >95 : 5O Al O
MeBr
BrBrBr
Br
Br
Me Me O Me
Regioselectivity with Lewis acids: [1,3] selectivity
Nasveschuk, C.G., Rovis, T. Org. Lett. 2005, 7, 2173-2176.
R2
R1
O
R3
R2
R1
O
R3 R1 R3
Cu(OTf)2CH2Cl2
-50°C, 5 hr
entry Product yield (%) ratio [1,3] : [3,3]
1 81 >95 : 5
2 63 85 : 15
3 64 >95 : 5
4b 50 80 : 20
5b 84 69 : 31
R2O
[1, 3] [3, 3]
Me
Ph
O
Me
Me
Ph
O
t-Bu
Me
n-Bu
O
Me
Me
n-Bu
O
Ph
Et
Ph
O
Me
b Reaction performed at -30°C for 48 hr
Gansauer, A., Fielenbach, D., Stock, C., Geich-Gimbel, D. Adv. Synth. Catal. 2003, 345, 1017-1030.
Regioselectivity of allyl vinyl ethersentry catalyst/condition yield (%)productsubstrate
O
O1 BF3•Et2O, 5 mol %, 0.01M 84
2
Ot-Bu
O
t-Bu
3
63BF3•Et2O, 5 mol %, 0.1M
Oc-C6H11
O
c-C6H11
4
Cu( OTf)2, 5 mol %, -15°C 59
Ot-Bu
O
t-Bu
5
BF3•Et2O, 5 mol %, 0.1M 59
OPh
O
PhCu( OTf)2, 5 mol %, -40°C 77
Outline
Introduction Claisen rearrangement
Use of catalysts in regioselectivity[3,3] selectivity[1,3] selectivity
Stereoelectronic effects on Claisen rearrangement in natural products
Selectivity in allyl aryl ethersLaterifloroneForbesioneTricycloillicinone
ConclusionsAcknowledgements
Gozzo, F.C., Fernandes, S.A., Rodrigues, D.C., Eberlin, M.N., Marsaioli, A.J. J. Org. Chem. 2003, 68, 5493-5499.
Regioselectivity of allyl aryl ethers
allyl aryl ether totalyield (%)
populationratio A : B product ratio
CH3
H HA
OHB
HCH3
OH
CH3
OH
H
entry
1 90 1 : 1
OHHA
OHB
OH
OH
OH
OH2 56 2.1 : 1
O
3 90 1 : 11
HB
O
HA
OH
OH
1 : 1
14 : 1
0 : 1
OO
R1R6 HA
OHB
R6
R1
OH
R1
OH
R6
+
220-235°C, 2 hrsealed ampuleR1
HB
HA
O
A
B
R6
R1
HB
HA
O
R6
25°C
Potential energy diagrams
O
8.6
CH3
O
CH3
O
CH3
O
CH3
O
CH3
O
CH3
33.7 33.7
9.6
0 0
1IB
1B 1A
1IA
1TSA1TSA
Gozzo, F.C., Fernandes, S.A., Rodrigues, D.C., Eberlin, M.N., Marsaioli, A.J. J. Org. Chem. 2003, 68, 5493-5499.
Potential energy diagrams
H3C O
OH
O
H3C O
OH
O
H3C O
OH
O
H3C O
OH
O
H3C O
OH
O
H3C O
OH
O
12.5
36.0
0.5 0
31.7
5.32IB
2B
2TSB
2TSA
2IA
2A
Gozzo, F.C., Fernandes, S.A., Rodrigues, D.C., Eberlin, M.N., Marsaioli, A.J. J. Org. Chem. 2003, 68, 5493-5499.
Potential energy diagrams
Gozzo, F.C., Fernandes, S.A., Rodrigues, D.C., Eberlin, M.N., Marsaioli, A.J. J. Org. Chem. 2003, 68, 5493-5499.
12.5
41.1
30.9
1.51.70.0
O
O
O
O
O
O
3B
3IB
3TSB
3TSA
3IA
3A
Gozzo, F.C., Fernandes, S.A., Rodrigues, D.C., Eberlin, M.N., Marsaioli, A.J. J. Org. Chem. 2003, 68, 5493-5499.
Regioselectivity of allyl aryl ethers
allyl aryl ether totalyield (%)
populationratio A : B product ratio
CH3
H HA
OHB
HCH3
OH
CH3
OH
H
entry
1 90 1 : 1
OHHA
OHB
OH
OH
OH
OH2 56 2.1 : 1
O
3 90 1 : 11
HB
O
HA
OH
OH
1 : 1
14 : 1
0 : 1
OO
R1R6 HA
OHB
R6
R1
OH
R1
OH
R6
+
220-235°C, 2 hrsealed ampule
R1
HB
HA
O
A
B
R6
R1
HB
HA
O
R6
25°C
Natural product: Lateriflorone
Isolated from Garciniaplants Potential biological activityIn class of caged xanthonoidsTricyclic structure attached to spiroxalactone core
Tisdale, W.J., Vong, B.F., Li, H., Kim, S.H., Chowdhury, C., Theodorakis, E.A., Tetrahedron 2003, 59, 6873-6887.Tisdale, E.J., Li, H., Vong, B.G., Kim, S.H., Theodorakis, E.A. Org. Lett. 2003, 5, 1491-1494.
O
O
O
O
O
O
O
O OH
Toward synthesis of Lateriflorone
O O
OSEM
O
O
O
1
37
89
13 12
11
5
610O O
OSEM
O
O
O
1
37
89
13 12
11
5
610
O O
OSEM
O
O
O
(85%)
O
OO
OO OSEM
HO
HOO
OO OH
110°C, 1 hrtoluene
1
3
789 11
12
13
5
610
13
8 91112
13
5
6 10
2
Tisdale, W.J., Vong, B.F., Li, H., Kim, S.H., Chowdhury, C., Theodorakis, E.A., Tetrahedron 2003, 59, 6873-6887.Tisdale, E.J., Li, H., Vong, B.G., Kim, S.H., Theodorakis, E.A. Org. Lett. 2003, 5,1491-1494.
XO O
SEMO
O
O
O O
OO
1
33
O
OSEM
O
17
88 99
11
11
12
12
13
13
5
5
6
61010
110°C, 1 hrtoluene
X
Another route to Lateriflorone
Nicolaou, K.C., Sasmal, P.K., Xu, H. J. Am. Chem. Soc. 2004, 126, 5493-5501.Nicolaou, K.C., Sasmal, P.K., Xu, H., Namoto, K., Ritzen, A. Angew. Chem. Int. Ed. 2003, 42, 4225-4229.
O
O
O O
OMe DMF 120°C
1 hr
O
O
O O
OMeO
OOMe
OH
O
47%
DMF 120°C1 hr
O
O
O O
OMeO
OOMe
HHH
O
O
42%
OHO O
OOMe
HO
1
3
13
13
1
3
Importance of para carbonyl
Tisdale, W.J., Vong, B.F., Li, H., Kim, S.H., Chowdhury, C., Theodorakis, E.A., Tetrahedron 2003, 59, 6873-6887.Nicolaou, K.C., Sasmal, P.K., Xu, H., Namoto, K., Ritzen, A. Angew. Chem. Int. Ed. 2003, 42, 4225-4229.
DMF, Δ
47% 42%
O
O
O O
OMe
O
OOMe
HHH
O
O
+
O
OOMe
OH
O
O
O OSEM
O
OO
110°C, 1 hrtoluene
O
OO
OO OSEM
85%
What is controlling regiochemistry?
Hayden, A.E., Xu, H., Nicolaou, K.C., Houk, K.N. Org. Lett. 2006, 8, 2989-2992.
0.0
26.7
7.6
43.3
8.5
28.4
11.8
29.3
-14.8
OO
OO
OO
O
O
O
O
O
O
O
O
Ea=28.4 Ea=26.7
(0.0)
(11.8) (7.6)
(-14.8) (8.5)
Ea = 29.3 Ea = 43.3X X X
12
6
12
61
2
6
What is controlling regiochemistry?
Hayden, A.E., Xu, H., Nicolaou, K.C., Houk, K.N. Org. Lett. 2006, 8, 2989-2992.
O
O
MeOO
O
O
O
MeOO
O
O
O
MeOO
O
O
O
O
OOMe
O
O
O
OOMe
Ea = 24.7 Ea = 25.1
(9.5) (3.9)
(-10.4) (-7.9)
Ea = 25.6 Ea = 26.0
13
1 3 1 3
What is controlling regiochemistry?
Hayden, A.E., Xu, H., Nicolaou, K.C., Houk, K.N. Org. Lett. 2006, 8, 2989-2992.
0.0
24.7
25.126.928.6
9.5
3.9
3.4
9.3
25.6
26.0
53.9
58.1
-10.8
-7.9
16.7
23.5
O
O
O
OOMe
O
O
O
OOMe
RO OO
S
(-10.8) (-7.9)
Toward synthesis of Lateriflorone
O
O
O
O
O
O
O
O OHO
O
OHO
A B+
HO
HOO
OO OSEM
C HATU, DIPEA
O
O
O
O
O
HO
O
O
AB
OSEM
X
HCl, MeOH1 hr, RT (93%)
O
O
O
O
O
HO
O
O
AB
OH
ACN, RT (51%) L.A
AcidsandL.A
O
O
O
O
O
O
O
O OH
X
Tisdale, W.J., Vong, B.F., Li, H., Kim, S.H., Chowdhury, C., Theodorakis, E.A., Tetrahedron 2003, 59, 6873-6887.Tisdale, E.J., Li, H., Vong, B.G., Kim, S.H., Theodorakis, E.A. Org. Lett. 2003, 5,1491-1494.
Seco-lateriflorone NNN
N
O
N
N
PF6
Synthesis of 1-O-Methylateriflorone
Nicolaou, K.C., Sasmal, P.K., Xu, H. J. Am. Chem. Soc. 2004, 126, 5493-5501.Nicolaou, K.C., Sasmal, P.K., Xu, H., Namoto, K., Ritzen, A. Angew. Chem. Int. Ed. 2003, 42, 4225-4229.
1-O-Methylateriflorone
O
OMe
OMOMOH
OHO O
OOMe
HO+EDCI, DMAP
O
OMe
MOMOO
O
O
OOMe
HO0→25°C16 hr (64%)
OO
O
OO OMe
O
O O
Synthetic applications
Nicolaou, K.C., Sasmal, P.K., Xu, H. J. Am. Chem. Soc. 2004, 126, 5493-5501.
OO
OMe
OO OMe
O
O O
O
O
OO
O
O
OOMe
HOO
OO
O
O
OOMe
HO
OMeMeO
O
O
OHO
O
O
OOMe
HO O
OH
OOO
O
O OMe
HO
OO
O
OO OMe
O
O O
IC50 = 5 μM
IC50 = 9 μM
IC50 = 25 μM
Natural Product: Forbesione
Isolated from Garcinia forbesiiDried resin used for pigments and folk medicinesBiologically activeIn family of cytotoxic
agents
O
O
HO
O
O
OH
Nicolaou, K.C., Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264-4266.Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.
A B
Claisen/Diels-Alder products
Nicolaou, K.C., Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264-4266.
O
OOMe
O OO
O
OMe
HO
O O
O
O
OMe
HO
O O
O
A B
DMF, 120°C20 min
Claisen/Diels-Alder products
Nicolaou, K.C., Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264-4266.
O
OMe
HO
O
OO
O
OMe
HO
O
OO
C D
O
OOMe
O OO
DMF, 120°C20 min
Claisen/Diels-Alder Timing
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
O
OAc
O
O
OO
O
OAc
O
O
OO
O
OAc
O
O
OO
DMF120°C
DMF120°C
O
OAc
O
O
OO
d7-DMF120°C
O
OAc
OO
O
OH
δ 7.31
O
OAc
HOO
O
OH
δ 7.34
Nicolaou, K.C., Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264-4266.
Claisen/Diels-Alder intermediates1-O-methylforbesione
O
OOMe
O OO
Δ
O
OMe O
OO
O
O
OMe
O
O O
O
O
OMe
O
O O
O
O
OMe
HO
O O
O
O
OMe
HO
O O
O
A
B
Decalin63%
2%
56
Nicolaou, K.C., Li, J. Angew. Chem. Int. Ed. 2001, 40, 4264-4266.
Claisen/Diels-Alder intermediates
O
OOMe
O OO
O
OMe O
O OO
O
OMe
O
O
OO
O
OMe
O
O
OO
O
OMe
HO
O
OO
O
OMe
HO
O
OO
C
D
ΔDecalin <1%
26%
56
Alternate path to Forbesione
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
O
OR
O
O
OO
R= HR= AcR= Me
O
OR
HOO
O
O O
OR
HOO
OO
O
OMe
HOO
O
O
A B C
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
Electronic factors in regioselectivity
O
O
O
O
OO
O
OH
O
O
OO
O
OH
HOO
O
O
O
OH
HOO
O
O
DMF
120°C
123
4 5
69
10
2
4 5
69
10
2
4 9
10 65
2
4 9
10 65
H 49%
35%
+
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
Electronic factors in regioselectivity
O
OAc
O
O
OO
O
OAc
O
O
OO O
OAc
HOO
O
O
DMF
120°C
123
4 5
69
10
2
4 5
69
10
2
4 9
10 65
79%
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
Electronic factors in regioselectivity
O
OMe
O
O
OO
O
OMe
O
O
OO O
OMe
HOO
O
O
DMF120°C
123
4 5
69
10
2
4 5
69
10
2
4 9
10 65
51%
O
OMe
O
O
O
O
O
OMe
HOO
O
O
24%
45 6
9
104 9
10
65
+
Tisdale, E.J., Slobodov, I., Theodorakis, Org. Biomol. Chem. 2003, 1, 4418-4422.Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
Resonance factors in regioselectivity
XClaisen
O
OR
O
O
OO
R= HR= AcR= Me
O
OR
O
O
OO
O
OR
O
O
OO
+
12
4 5
69
10
5
5
6
6
9
9
Site selectivity in A ring
O
OOR
O
R= HR= AcR= Me
DMF,120°C, 1 hr
O
OOR
HO
123
4
C4-prenylation
O
OOR
HO
C2-prenylation
2
44
2
R= H - 39%R= Ac - 0%R= Me - 0%
R= H - 41%R= Ac - 75%R= Me - 82%
O
OR
O
O
OO
O
OR
HOO
O
O O
OR
HOO
O
O
R= H - 49%R= Ac - 79%R= Me - 51%
R= H - 35%R= Ac - 0%R= Me - 0%
DMF,120°C, 1 hr
123
44
2
4
Tisdale, E.J., Slobodov, I., Theodorakis, E.A. PNAS. 2004, 101, 12030-12035.
A
Natural Product: Tricycloillicinone
Isolated from IlliciumtachiroiInducer of choline
acetyltransferaseCould be treatment of neurodegenerative diseases
Pettus, T.R.R., Chen, X.T., Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 12684-12685.Pettus, T.R.R., Inoue, M., Chen. X.T., Danishefsky, S.J. J. Am. Chem. Soc. 2000, 122, 6160-6168.Wilson, R.M. Danishefsky, S.J. Acc. Chem. Res. 2006, 39, 539-549.
OO
O
Natural Product: Tricycloillicinone
Pettus, T.R.R., Chen, X.T., Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 12684-12685.Pettus, T.R.R., Inoue, M., Chen. X.T., Danishefsky, S.J. J. Am. Chem. Soc. 2000, 122, 6160-6168.Wilson, R.M. Danishefsky, S.J. Acc. Chem. Res. 2006, 39, 539-549.
Minor(Desired)
R
O
O
O OO
O
RH O
OR
OH
R
OH
O
OOO
O
RH
Cope
R = CO2Me (12%)R = OTBS (15%)
R = CO2Me (55%)R = OTBS (70%)
220°Cxylenes
220°Cxylenes
Major
Can regioselectivity be obtained?
Pettus, T.R.R., Chen, X.T., Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 12684-12685.Pettus, T.R.R., Inoue, M., Chen. X.T., Danishefsky, S.J. J. Am. Chem. Soc. 2000, 122, 6160-6168.Wilson, R.M. Danishefsky, S.J. Acc. Chem. Res. 2006, 39, 539-549.
MeO2C
O
O
O
R
R = ?
?O
OMeO2C
OH
R
OH
O
O
Desired Major
Can regioselectivity be obtained?
Pettus, T.R.R., Chen, X.T., Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 12684-12685.Pettus, T.R.R., Inoue, M., Chen. X.T., Danishefsky, S.J. J. Am. Chem. Soc. 2000, 122, 6160-6168.Wilson, R.M. Danishefsky, S.J. Acc. Chem. Res. 2006, 39, 539-549.
MeO2C
OH
O
O
O
O
O
MeO2C
PhO2S
O
O
OH
MeO2C
PhO2SK2CO3, acetone
RT (85%)
165°C toluene
K2CO3, acetone
O
O
O
MeO2C
PhO2S
2e−
Br
BrPhO2S
12 hr (94%)
reflux (94%)
O
OMeO2C
OH
10% Na-HgMeOH-EtOAc-20°C (87%)
Synthesis of tricycloillicinone
Pettus, T.R.R., Chen, X.T., Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 12684-12685.Pettus, T.R.R., Inoue, M., Chen. X.T., Danishefsky, S.J. J. Am. Chem. Soc. 2000, 122, 6160-6168.Wilson, R.M. Danishefsky, S.J. Acc. Chem. Res. 2006, 39, 539-549.
Tricycloillicinone
O
OMeO2C
OH
OO
OOO
O
OR
R = C(S)OPh
Bu3SnH, AIBN
benzene, 80°Covernight (42%)
Conclusions
Claisen rearrangement selectivity can be predicted by population ratio of conformers Regioselectivity (ortho-para) can be controlled with an auxiliary Claisen/Diels-Alder rearrangements can be controlled with proper electronics[3,3] and [1,3] rearrangements can both be
achieved regioselectively with Lewis acidsAlthough Lewis acids have been applied toward synthetic intermediates, they have not yet been applied toward natural product synthesis
Acknowledgments
Dr. TepeDr. BorhanDr. WalkerDr. Jackson
Dr. Wulff
Tepe Group Teri, Tim, Adam, Chris, Jason, Sam
Amanda, Brian, Brandon
Dan
![Dearomatising Claisen Rearrangements · The Claisen rearrangement is the [3,3]-sigmatropic rearrangement of an allyl vinyl ether to give a γ,δ-unsaturated ketone (Scheme 3). The](https://img.pdfslide.us/doc/110x75/60393c1a162a8c30570a3f2b/dearomatising-claisen-rearrangements-the-claisen-rearrangement-is-the-33-sigmatropic.jpg)
![Catalytic Asymmetric Claisen Rearrangements. The ...d-scholarship.pitt.edu/16662/1/Maryll_Geherty_ETD_Thesis...iv The Claisen rearrangement, a [3,3] sigmatropic rearrangement, remains](https://img.pdfslide.us/doc/110x75/60a68d13b7998e79f4088654/catalytic-asymmetric-claisen-rearrangements-the-d-iv-the-claisen-rearrangement.jpg)
