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1
The NazarovCyclization
Shanina SandersFeb 16, 2006
Johnson Group
Cyclopentenone Core in Natural Products Synthesis
O
OH
cucumin H
O
ON
OCH3
HOH
cephalotaxine
O
methylenomycin B
O
AcO
OHCOH
guancastepene A
N
OO
NO(CH2)2NMe2
X
H
X=H,Cl
ligands for 5HT1D serotonin receptors
OHO
HO CO2H
xanthocidin
2
Electrocyclizations
∆
hυ
§Concerted pericyclic reaction in which a single bond is formed between the ends of a linear conjugated system of π electrons and the reverse process
§Stereospecific- must proceed with conservation of orbital symmetry
Carery, F.A.’ Sundberg, R.J.; Advanced Organic Chemistry 2000, 4
§HOMO participates in bond forming process
Orbital Symmetry Requirements
∆
∆
Carery, F.A.’ Sundberg, R.J.; Advanced Organic Chemistry 2000, 4
OLA
OLA
conrotatory
OLA
disrotatoryOLA
X
§Systems with 4nπ electrons undergo conrotatory rotation under thermal conditions§Systems with 4n + 2π electrons react by the disrotatory mode
3
Mechanism
§Nazarov discovered ~1950§Shoppee elucidated mechanism in 1969§Promoted by Lewis or Bronsted acid
O
R2R1
O
R2R1
O
R1
O
R2R1
LA
OO
R1 R2 R1 R2
LAO
R2R1
LA LA
4π conrotatory
LA
deprotonation
LA
H+
R2
Shoppee, C.W.; Lack, R.E. J. Am. Chem. Soc. 1969, 1346-1349
Evidence for Mechanism
R AcOHH3PO450 °C
O
O
R R
R R
H
H
O
R
disrotatory
conrotatory
254 nm
O O O
s-trans/s-trans s-cis/s-trans s-cis/s-cis
•Reactivity
§Stereochemical
Woodward, R.B. Chem. Soc. Special Publication No. 21 1969, 217
OH
Denmark, S.E. ; Habermas, L.L.; Hite, G.A. Helv. Chim. Acta 1988, 71,168-194
4
Synthetic Challenges
§ Harsh conditions§ By-product formation common§ Control of regioselectivity
O
R2R1
O
R2R1
LALA O
R1
LA 4π conrotatory
R2
O
R2R1
OO
R1 R2 R1 R2
LA
deprotonation
LA
H+
O
R1 R2
+/or
Control of the Nazarov Cyclization
§ Substituent effects
§ Control of absolute stereochemistry
§ Novel reactivity patterns
Frontier, A.J.; Collison, C. Tetrahedron 2005, 61, 7577-7606Pellissier, H. Tetrahedron 2005, 61, 6479-517Tius, M. A. Eur. J. Org. Chem. 2005, 2193-2206
5
Substituent Effects
R R
X XO
α
β
§ Substituents could be used to exert control over the intermediate species in the reaction
Denmark, S.E.; Jones, T.K. J. Am. Chem. Soc. 1982, 104, 2642-2645Denmark, S.E.; Habermas, K.L.; Hite, G.A. Helv. Chim. Acta 1988, 71, 168-194Marion, J.P.; Lindermann J. Org. Chem. 1981, 46, 3696-3702Andrews, J.F.P.; Regan, A.C. Tetrahedrom Lett. 1991, 32, 7731-7734
§Oxyallyl stabilizing substituents at the α or β positions will promote cyclization
Regioselectivity Control
Me3Si
R'O
R'
Me3Si
OLA
Me3Si
R'
OLA
Me3Si
R'
OLA
R'O
HR'
O
H+LAX
Denmark, S. J. Am. Chem. Soc. 1982,104, 2642-2645
§ β-silicon effect can achieve charge localization
§Electrofugal leaving group prevents side reactions
§Regioselective for thermodynamically less stable enone product
6
Allylsilane Directed Reactions
O SiMe2Ph
Ph
O
Ph
TFA (3 eq) THF
0-20 °C 83%
SiMe2Ph
OH
Ph
SiPh2t-Bu
O
SiPh2t-Bu
OTFA (3 eq) THF
60 °C 75%
SiPh2t-Bu
HOH
Barbero, A.; Garcia, C.; Pulido, F.J. Tetrahedron 2000, 56, 2739-2751
Bu3Sn
nC7H15
OBn
nC5H11
O
BnOnC5H11
O
nC7H15
BF3·OEt2 (4 eq)
CH2Cl2, 20 °C
§Process terminated by loss of tri-n-butylstannyl cation
O
F F
O
F
n-Bun-Bu TMSOTfCH2Cl2/HFIP 20 °C 86%
OTMS
FF
n-Bu
Ichikawa, J.; Miyazaki, M. Fujiwara, T. Minami, J. Org. Chem. 1995, 60, 2320-2321
Peel, M.R.; Johnson, C.R.; Tetrahedron Lett. 1986, 27, 5947-5950
§β-cation destablilizing effect§Nucleofugal leaving group
Fluorine & Tin Directed Reactions
7
Fluorine Directed Reactions
n-Bu n-Bu
O
F
n-Bu n-Bu
O
FTMSB(OTf)4
CH2Cl2r.t., .25 h
OTMS
F
n-Bu n-Bu
Ichikawa, J. Pure Appl. Chem. 2000, 72, 1685-1689
§α-cation stabilizing effect
n-Pr
F3C EtO
n-Pr
F3C EtOTMSOTf
CH2Cl2/HFIP r.t. 8 min 79%
O
Et
n-Pr
F3C
TMS
Ichikawa, M. Fujiwara T. Okauchi, T. Minami, Synlett 1998, 927-929
Polarization
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
R R
X YO
electron-donating
electron-withdrawing
8
Polarization
R R
X Y
O
R R
X YO
electron-donating
electron-withdrawing
LA
LA
δ+ δ−
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
Polarization
R R
XO
LA
R R
X Y
O
R R
X YO
electron-donating
electron-withdrawing
LA
LA
δ+ δ−
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
9
Polarization Effects
OO
CO2Me
R
O CO2Me
R
OLA
OO
CO2Me
R
LA
O
R
O
CO2Meselective
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
Polarization Effects
OO
CO2Me
R
O CO2Me
R
OLA
OO
CO2Me
R
LA
O
R
O
CO2MeselectiveLA
R R'
R R'
O O
R'R
LA
R R'
R R'
R R'
OLA O
R R'
O
R R'
+/orunselective R R' R R'
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
10
Polarization Induced Catalysis
OO
CO2MeOMe
OMeMeO
2 mol % Cu(OTf)20.2 M (ClCH2)2
25 °C, 5 min >99%
O
O
CO2Me
OMe
OMe
MeO
OO
10 mol % AlCl3
CH2Cl2, r.t. 91%
OO
H
Liang,G.X.; Gradl, S.N.; Trauner, D. Org Lett. 2003, 5, 4931-4934
§Isolated as single regio- and stereoisomer§Nonpolar substitution at α-positions not as efficient
He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279
Palladium Catalysis
MeOO
10 mol % PdCl2(MeCN)2
wet acetone, rt, 14h 90%
HO
O
H
Ph
OEtO
Pd(OAc)2 20 mol %
DMSO, O2, 80 °C 78% crude
OEt
O
Ph
Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930
11
Mechanism of Palladium Catalysis
O
OEt
Ph
PdX
XL
O
OEt
Pd
Ph
L
LX O
OEt
Pd
Ph
L
LAcO
+ HOAc
Ph
O
OEtX= OAc
X= ClH2O
X-
OPh
OPdL
LCl
HCl EtOH O
OH
Ph
-H
β-elim
-EtOH
Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927-4930
Iridium Catalysis
O
O
O OMe
O
TMP
O
O
O
OMe
O
TMP
2 mol % cat
>99%
§Reactivity lies in the labile diodobenzene ligands
Janka, M.; He, W.; Frontier, A.J.; Eisenberg, R. J.Am. Chem. Soc. 2004, 126, 6864- 865
Ir
CH3
OCP
P
II
2+
TMP = 2,4,6, trimethoxyphenyl
12
cat = [IrMe(CO)(dppe)(DIB)](BArF)2O
O
O
OMe
O
TMP
O
O
O
TMP
OMe
O
2+
O
O
O
TMP
OMe
O
2+
O
O
O
TMP
OMe
O
2+
O
O
O OMe
O
TMP
O
O
O
OMe
O
TMP
IrLn
>99%
IrLn
IrLn
Janka, M.; He, W.; Frontier, A.J.; Eisenberg, R. Tetrahedron, 2005, 61, 6193-6206
Asymmetric Nazarov
n Control sense of conrotation at β-carbon-Substrate -Chiral auxiliaries-Chiral Lewis acids
n Control facial selectivity for enol protonation at α-carbon
13
Torquoselectivity
cw
OOH
OOH
ccw
OH
OH
§Control of conrotation in such a way that one direction is preferred
§Attributed to steric and electronic effects of the substrate
Houk, K.N. In Strain and its Implications in Organic Chemistry; de Meijere, Al, Blechert, S., Eds.; Lkuwer Academic; Dodrecht, 1989
Allylic Substituents
R2
O
R1
FeCl3
CH2Cl2, 0 °C
O OH
HR1
H
HR1
A B
•Stereocenters in the substrate can influence the sense of conrotation
R1 R2 Product ratio Yield(%) (A/B)
Ph SiMe3 94/6 76t-Bu SiMe3 94/6 63CH3 SiMe3 78/22 99CH3 SiPh2Me 86/14 83CH3 Si(i-Pr)3 90/10 70
Jones, T.L.; Denmark, S.E. Helv. Chim.Acta 1983, 66, 2377-2396
14
Cyclopentafused-Heterocycles
NOEtCBz
NOCBz
Amberlyst 15
CHCl3, r.t. 67%
N
MeH
Me
EtO
BzC
Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna,A.; Deagostino, A.; Venturello, P. J. Org. Chem, 2002,67, 7144-7146
§Single diastereomer obtained with the lactam derivative
OOEt
OO
Amberlyst 15
CHCl3, r.t. 76%
O
MeH
HMe
EtO
§Mixture of products for lactone derivative 16:1 trans to cis
Cationic Cyclopentannelation
Tius, M. A. Acc. Chem. Res. 2003, 36, 284-290
NOMeO
TMS
n-C6H13
OCH3O
•Li
OEt
OCH3
O
•
O
n-C6H13
TMS
OEt
O
n-C6H13
OEt
HO
TMS
-78°C
THF, Et2O
NaH2PO4
ccw
80%, Z/E = 6/1
§Mild Conditions
§Kinetic preference for Z isomer of the exocyclic double bond
§Used in synthesis of guanacastepene A and roseophilin
Not isolated
15
Chiralty Transfer
H
HOTMSFeCl3
CH2Cl2
O
H
H
H
86%ee 86%eecw
5d, 72%
Li OSit-BuMe2
O t-Bu
HO
H OTBS
64% , 95% ee
ON
O
•
H t-Bu
O
OMe
1.THF, -78 °C2. KH2PO4 (aq)
O
•
HOTBS
O OMeccw
Denmark, S.E.; Wallace, M.A.; Walker, Jr. C.B.; J. Org. Chem. 1990, 55, 5543-5545
98% ee
§Continuous overlap of oxyallyl cation with silyl group required§Silyl group is traceless auxiliary
Harrington, P.E.; Tius, M.A.; Org. Lett. 2000, 2, 2447-2450
Sugar Derived Auxiliaries
N
O
O
1. -78 °C 1h2. HCl, EtOH, -78 °C
HO
O
OMeO
H
MeO
H
OOMe
H H
OMeO
H
MeO
H
MeO
H
OHOMeH H
OMe
67%, 67% ee
• Li
§Key intermediate in roseophilin
§β-anomer leads to enantiomer in 82% ee
§Problematic systemHarrington, P.E.; Tius, M.A. Org. Lett. 2000, 2, 2447-2450
α−anomer of D- glucose
16
Camphor-Derived Auxiliary
OO
N
O
O
OHO
78%, 86% ee
1.-78 to -30 °C, 1h2. HCl, HFIP/TFE (1:1)3. -78 °C
•HH
Li
Harrington, P.E.; Murai, T.; Chu, C.; Tius, M.A. J. Am. Chem.Soc. 2002, 124, 10091-10100
§Scope expanded to include variety of substitution patterns and heteroatoms
§Tolerance of many differing substitutients suggests broad synthetic utility
Camphor-Derived Auxiliary
OO
O
HO
PhN
O
O80%, 96% ee
1. HFIP/ TFE (1:1)2. HCl (39eq), -78 °C
•H
Li
Harrington, P.E.; Murai, T.; Chu, C.; Tius, M.A. J. Am. Chem. Soc. 2002, 124, 10091-10100
§Auxiliary and allene work in concert to promote one direction of conrotation
§Unmatched case, 79% ee
17
β, β Disubstituted Camphor Auxiliary
OO N
O
O
O
HO
Ph
14%, 65% ee
HCl, HFIP/TFE (1:1), -78 °C
•HH
Li Ph
Harrington, P.E.; Murai, T.; Chu, C.; Tius, M.A. J. Am. Chem. Soc. 2002, 124, 10091-10100
§Low yield due to migration from β-methyl to lithio-allene
§Quarternary carbon can be constructed enantioselectively
Indane Synthesis
O O
PrOO
O O
OO
X
X
Oacid 1.1-2 eq
O O
OO
X
major minor
PrOPrO
NO
O
N O
O
OX1 =
X2 =
X3 =
X Acid % Yield Isomer ratio
X1 MeSO3H 85 88/12
X2 SnCl4 74 82/18
X3 SnCl4 90 96/4
Pridgen, L.N.; Huang, K. Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse, C.; Haltiwanger, R.C. Synlett, 1999, 10, 1612-1614
18
Asymmetric LA Catalysis
§Catalyst turnover difficult
§Bond formation is distant from chelation site
§Blocking one face may not result in enantioselective conrotatory cyclization
Challenges:
Scandium Py-Box Catalyst
Liang,G.X.; Gradl, S.N.; Trauner, D. Org Lett. 2003, 5, 4931-4934
OO
OO
H
H
ON Sc
N
NO
Ph Ph
20 mol %
THF, r.t. 53%, 61% ee
3+
3 OTf -
§Asymmetric catalytic induction possible
§Enantioselective control of conrotatory electrocyclization difficult
19
Cu-Py-Box Catalysts
O
NEt2
Ph Ph
PhO
Ph Ph
Ph
O
NEt2
ON
O
NO
PhPh
CuBr2, AgSbF6CH2Cl2, 20 °C56%, 86% ee
50 mol %
Aggarwal V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075-5078
N
O
NO
H tBuCu
tBuH
O
O
R1 R2
R3
X§Catalyst turnover limited
Indane-Pybox Catalyst
N
O NN
OH H
H
OO
O
O
O
O10 mol %
Sc(OTf)3, MeCN, 3 Å m.s., r.t.
62%40% ee
18%79% ee
3.4:1 dr
H
Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544-9545
§Low yielding
§Not reproducible
§Diastereomers formation problematic
20
Chiral Proton Transfer
OO
t-Bu 10 mol %
Sc(OTf)3, MeCN, 3 Å m.s., 0 °C or r.t. 94%, 97% ee
OO
t-Bu
Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544-9545
§Protonation very selective
§Highest levels of enantioselectivity with bulky α-substituents
N
O NN
OH
H
H
H
Other Reactivity Patterns
n Retro-Nazarov
n Interrupted Nazarov
21
Retro-Nazarov
R R
X RO
electron-donating
X Y
R RO
electron-donating
Retro-Nazarov
R R
X RO
electron-donating
t-BuO R
Br
O O
t-BuO R
Br
t-BuO R
O
t-BuO R
OTEA
TFE,reflux
42-69%
X Y
R RO
electron-donating
electron-donating
R = aryl or alkenyl
§Oxyallyl cation generated through solvolytic loss of bromine
Harmata, .; Lee, D.R. J. Am. Chem. Soc. 2002, 124, 14328-14329
22
Limits of the Retro-Nazarov
Harmata, M.; Schreiner, P.R.; Lee, D.R.; Kirchhoefer, P.L. J. Am. Chem. Soc. 2004, 126, 10954- 10957
Ph Me
O TEA
(CF3)2CHOH, reflux, 1h
Ph Me
O
59%
Br
O TEA
CF3CH2OH 65-70 °C
t-BuO
O
51%t-BuO
Br
§Related electrocyclic systems exhibit torqouselectivity
§Is the process torquoselective?
Limits of the Retro-Nazarov
Harmata, M.; Schreiner, P.R.; Lee, D.R.; Kirchhoefer, P.L. J. Am. Chem. Soc. 2004, 126, 10954- 10957
Ph Me
O TEA
(CF3)2CHOH, reflux, 1h
Ph Me
O
59%
Br
O TEA
CF3CH2OH 65-70 °C
t-BuO
O
51%t-BuO
Br
23
Selectivity Probe
RO
R1
R2
R3
O •Cl
Cl ClCl
O
R2
R3
ROR1
CH2N2
OCl
Cl
R1R3
R2RO
O-
Cl
R1R3
R2RO
OCl
RO R3R2R1
base
Barnes, C.L.; Lee, D.R.; Harmata, M.; Org. Lett. 2005, 7, 1881-1883
Selectivity of Retro-Nazarov
t-BuO
H
Et
H
MeO
H
H
Cy
OCl
t-BuO HEt
OCl
MeO CyH
1. Cl2C=C=O
2. CH2N23. TMP, HFIP reflux
1. Cl2C=C=O
2. CH2N23. TMP, HFIP reflux
§Only single diastereomers produced
§Reaction is torquoselective and stereospecific
Barnes, C.L.; Lee, D.R.; Harmata, M.; Org. Lett. 2005, 7, 1881-1883
24
Retro-Nazarov Variant
OH
MeO
O
OH
Ot-Bu PMPO Ot-Bu
OTHFPPh3
0 °CDIAD, rt
14%
Etheridge, Z.C.; Caddick, S. Tetrahedron; Asymmetry 2004, 15, 503-507
§Different substrates than used previously
§Ionization possibly driven by formation of triphenylphosphine oxide
O
ON
NO
ODIAD =
Interrupted Nazarov
n Nucleophilic species can capture oxyallyl cation
n Pathway can be used to construct polycyclic systems with multiple stereocenters and high stereoselectivities
O
R2R1
LA
Bender, J.A.; Blize, A.E. Browder, C.C; Giese, S.; West, F.G. J. Org. Chem. 1998, 63, 2430-2431
25
Intramolecular Alkene Trapping
OEt 4 eq BF3.OEt2
H
Et
OF3B
H
O
Et
F3B
O
H
HEt
O
H
HEt
HOH2O
73%
•Requires two-carbon tether between alkene and dienone•Substitution needed at both α-positions
Bender, J.A.; Blize, A.E. Browder, C.C; Giese, S.; West, F.G. J. Org. Chem. 1998, 63, 2430-2431
Intramolecular [4+3] Trapping
O
R
n
FeCl3
0.2 eq RH
H
On - 2
exoR
OLAn - 2
n = 4
R = Me, 67%R = Ph , 75%
§Catalytic
§High diasterofacial selectivity
§Both exo and endo products obtained depending on length of tether
Wang, Y.; Arif, A.M.; West, F.G. J. Am. Chem. Soc. 1999, 121, 876-877
26
Benzohydrindenones
OMe
OEt
Me
OTiCl4Et
Me
OMe
OMe
OTiCl4Et
Me H
OMe
OEt
Me H
TiCl4 (1 eq)
-78 °C 5 min, 99%
convex face
protonation
§Highly stereoselective and chemoselective
§Attack of the aromatic group on the cation syn to tether
Browder, C.C.; Marmsater, F.P.; West, F.G. Org. Lett. 2001, 3, 3033-3035
Cascade Polycyclization
O
TiCl4 (1.1 eq)
CH2Cl2 -78 °C 99%
O
HH
O-TiCl4
H
Cl4Ti-O
Bender, J. A.; Arif, A.M.; West, F.G. J. Am. Chem. Soc. 1999, 121, 876-877
§Complete diastereoselectivity
§Requires α-substitution on dienone
27
Intermolecular Trapping
Ph Ph
OO
BF3·Et2O
CH2Cl2 -78 °C, 30 min 70%
O
Ph Ph
SiR3
SiR3
Ph
Ph
Ph
Ph SiR3
SnCl4
R=Me: 49%
R=iPr:51%
BF3.Et2O
O
O
Y.Wang, A. M. Arif, F. G. West, Org Lett. 2003, 5, 2747-2750
O
Ph
Ph
O
Giese, S.; Lars, K.; Stiens, D.; West, F. G.; Angew. Chem. Int. Ed. 2000, 39, 1970-1973
Oxygen Trapping
R•
t-Bu
O
OO
O
t-Bu
RR •
t-Bu
OHO
t-BuR
acid
O OH
R•
t-Bu
O
O
acidR•
t-Bu
O
H
Z
E
§Must have Z-vinyl acetal
§Allene stereocenter does not encourage diastereoselective cyclization
1:1 E/Z
de Lera, A.R.; Rey, J.G.; Hrovat, D.; Iglesias, B.; Loez, S. Tetrahedron Lett. 1997, 38, 7425-7428
28
Reductive Cyclization
O
Ph Ph Ph Ph
O
Ph Ph
OSiEt31. LA, HSiEt3
2. work-up
1. AlEt2Cl 2. H2O 44% + 49%
1. BF3•Et2O 2. HCl 98% ketone
§Subject to catalysis with 10 mol % of Lewis acid
Giese, S.; West, F.G.; Tetrahedron 2000, 56, 10221-10228
Summaryn Substituent Effects
Directing or polarizing substituents provide a means of controlling theregioselectivity and/or rendering the cyclization catalytic
n Asymmetric ReactionsBased on control of conrotation by the substrate, an auxiliary, or a chiral catalyst
n Novel PathwaysInterrupted Nazarov conserves stereocenters created by ring
closure and can construct polycyclic systems with good diastereoselectivity
29
Acknowledgements
Prof. Johnson
Johnson Group