Chemistry 206
Advanced Organic Chemistry
Handout–03A
Steric, Electronic, &
Conformational Effects in
Epoxide–Nucleophile Reactions
Matthew D. Shair MondaySeptember 23, 2002
Mick Dart
Evans Group Seminar, December, 1993
O
R'
H
Nu
HH
O
R' R' Nu
OH
Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206
Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799.
Rosowsky, A. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Ed.; Interscience: New York,1964: Vol 19, Part 1, p 1.
Buchanon, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley: New York,1972: Vol. 2, p 1.
Berti, G. In Topics in Stereochemistry; Allinger, N. L. ; Eliel, E. L., Eds.; Interscience Publishers: New York, 973: Vol. 7, p 93.
Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323.
Sharpless, B. K.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodward, S. S. Pure Appl. Chem. 1983, 55, 589-604.
Behrens, C. H.; Sharpless, B. K. Aldrichimica Acta 1983, 16, 67-80.
Gorzynski Smith, J.; Synthesis 1984, 629-656.
Lewars, E. G. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon Press: New York,1984: Vol. 7, p 100.
Weissberger, A.; Taylor, E.C. In The Chemistry of Heterocyclic Compounds; Hassner A., Ed.; Wiley: New York, 1985: Vol. 42, Part 3, p 1.
Rossiter, B. E. In Assymetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1985; Vol. 5, Chapter 7. Hanson, R. M. Chem Rev. 1991, 91, 437-475.
Also see: Larock, R. C. Comprehensive Organic Transformations, p 505-526.
STERIC, ELECTRONIC, AND CONFORMATIONAL EFFECTS IN EPOXIDE / NUCLEOPHILE REACTIONS
Reviews
Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799.
R = various alkyl, aryl, or vinyl substituents
SN2 Transition-State
Due to ring strain, bond breaking is more advanced than bond making in the transition-state relative to a normal S
N2 reaction. In addition, the carbon atomat which displacement takes place will bear a partial positive charge in the
transition-state.
"Normal" S
N2 behavior is observed under neutral or basic conditions to providenucleophilic attack at the least substituted carbon with inversion.
R' is alkyl or a group having no marked inductive or conjugative effects.
Exceptions: Hydrogenation in the presence of Raney-nickel proceeds with opposite regioselection.
δ?
δ?
δ+
H-
N3-
RO-
RS-
RNH2
R2NH
NH3
R-
Nu =
Nu
REGIOSELECTIVITY OF EPOXIDE RING OPENING
NEUTRAL OR BASIC CONDITIONS: SN2
?
H H
Nu
H
R
HO
R
O H+
R OH
+ OH
R
Nu
R
O
HO
H
H
R
H
Nu
R
O
OH
NuR
Nu
R OH
Me
O OH X
Me
X
Me OH
O
Me
Me
Me Cl
OH
Me Me
OH
Me
Cl
HI
HBr
HCl
HX
B
A
More "abnormal" is formed in H2O than in Et2O which is expected since the
reaction proceeds through a polar transirtion state.
The electron donating inductive effect of an extra methyl substituent slightly
overrides the additional steric effect thereby enhancing C_α attack.
HI, whose anion is most nucleophilic in the series of acids, provides the highest
proportion of normal product as expected.
74HCl, Et2O, ? 26
1882
71 29
4456
REGIOSELECTIVITY OF EPOXIDE RING OPENING
ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1
Abnormal ProdNormal Prod
HX, H2O
70-85 °C
HCl, H2O
45 55
α
β
α
β
Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol. 2, p 1.
Stewart, C. A.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 1259.
Swain, C. G.; Scott, C. B. J. Am. Chem. Soc. 1953, 75, 141.
REGIOSELECTIVITY OF EPOXIDE RING OPENING
Nucleophilic attack occurs on the conjugate acid of the epoxide.
The transiton state is more polar and C_O bond cleavage is more advanced
than in SN2 reactions.
Epoxides which exhibit normal SN2 behavior under basic or neutral conditions
give mixtures under acidic conditions.
Steric factors are important although less so than observed in SN2 reactions.
The positive charge build up is stabilized by electron releasing groups.
a73 In the borderline SN2 mechanisms:
"Normal Product"
"Abnormal Product"
"BORDERLINE" SN2
β
α
δ+
δ?
++
++
δ?
δ+
δ+
δ+
ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1
β
α
SN1
SN1
Favored electronically
Disfavored sterically
Disfavored electronically
Favored sterically
R = alkyl
Major product usually
Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206
Me OH
O O OHO
NHR
OHMe
OO
OEtMe
Me
F3C OEt
O O
OEt
O
O
O
O
NH2
O
NH2
HO
OEtF3C
Me OEt
NH2
OH
O
Me
H2N OH
O
OEt
NH2
O
H2N OH
O
R'
R'
H
Nu
EWG
OH
OMe
NH2
O
Me
OAr
Me OAr
O
O
OMe
OMe
O
OMe
OH
OMe
OMe
OH
OMe
O
Me
NHiPr
OArMe
OH
NHiPr
Me OAr
OH
F3C Me
O OH
OEt
MeF
3C
NaOMe
NaOMe
NH3
(NH2)
RNH2
NH3
Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799.Lemieux, R. U.; Kullnig, R. K.; Moir, R. Y. J. Am. Chem. Soc. 1958, 80, 2237.
Steric effects dominate regioselectivity, especially in acyclic systems in which conformational considerations (Fürst-Plattner rule) may not be as important. However,
in many systems sterics on each side of the epoxide may be similar and substituent electronic effects emerge as the important factors in determining regioselection.
EtOH, H2SO4
aq iPrNH2
aq iPrNH2
or NH3
δ+
δ?
δ? EWG = Electron Withdrawing Group
Attack at C- is discouraged due to destabilization
of the transition state by juxtaposition of positive charge.
α β
EFFECT OF ELECTRONEGATIVE, NONCONJUGATING SUBSTITUENTS
Conformational effects are guiding theregioselectivity of reaction 3.
1.
2.
3.
δ?
δ+
?
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
EPOXIDES ADJACENT TO CARBONYLS
Other nucleophiles such as amines,various hydrides, and malonate anions show the same regioselectivity.
REGIOSELECTIVITY OF EPOXIDE RING OPENINGS
Liwschitz, Y.; Rabinsohn, Y.; Perera, D. J. Chem. Soc. 1962, 1116.
R = H or Bn
The opposite selectivity observed in this case is due to stabilization of the developing positive charge at C-2 by the carboxylate anion. The reaction
proceeds with inversion of stereochemistry at this center.
Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799.
2
3
O OH Nu Nu OH
O
X
Nu
OH
X
OH
Nu
X
NaOMe -H
NaOPh
-OMe
-H
-NO2
NaOPh
HOPh
NaN3
MeONa
PhLi
LiBH4
LiAlH4
30:70
Nu
100:0
76:24
36:64
Ratiosubstituent (X)
Lewars, E. G.; In "Comprehensive Heterocyclic Chemistry"; Katritzky,A. R., Ed.;
Good pi donors (OMe) can stabilize the incipient carbocation to offset steric
effects.
Methoxide, which is more nucleophilic than phenoxide, has increased
sensitivity to sterics and exibits more SN2 behavior with attack at C-β being
somewhat favored relative to phenoxide.
REGIOSELECTIVITY OF EPOXIDE RING OPENINGS
EFFECT OF CONJUGATING SUBSTITUENTS
Nu-
α
β
24:76
12:88
06:94HOPh, TsOH
00:100
10:90MeOH, H2SO4
100: 00
70:30
74:26
RatioNucleophile
100: 00
Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799.
REGIOSELECTIVITY OF EPOXIDE RING OPENINGS
EFFECT OF CONJUGATING SUBSTITUENTS
Nu-
The reaction of styrene oxide with nucleophiles is a balance between resonance and steric effects:
Resonance stabilization favors attack at the -carbon.
Steric effects direct attack to the -carbon.
Olefinic and acetylenic substituents behave similarly.
Under acidic conditions attack at the α-carbon becomes more favorable.
α
β
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
O
X
Me
MeO Me
OPh
Ph O
MeMeO
Me
R2NH
OH
X
MeO OH
Nu
MePh Me
Ph NR2
O
Me Me
OH
X
O
Me
Me
H
H
H
Me
HO
X
HO
X
Me
H
HX
HX
O
Me
H
H
Me
O
H
H OH
Me
Me
OH
LiAlH4
LiAlH4
Me
Me
OH
OHH
H
HO
Me
H
H
MeHO
CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS
FüRST-PLATTNER RULE
Aq H2SO4, acetone
(90 %)
only product no cis diol observed
Fürst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275.Alt, G. H.; Barton, D. H. R. J. Chem. Soc. 1954, 4284.
Henbest, H. B; Smith, M.; Thomas, A. J. Chem. Soc. 1958, 3293.Rickborn, B.; Murphy, D. K. J. Org. Chem. 1969, 34, 3209.
The major product in the reactions of rigid cyclohexene epoxides is derived from diaxial ring opening.
Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol. 2, p 1.
Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1958, 80, 1919.Stevens, C. L.; Chang, C. H. J. Org. Chem. 1962, 27, 4392.
LiAlH4
NaOMeMeOH
MeOH, H2SO4
Nu -
(39 to 93 %)
Conjugative stabilization by oxygen is responsible for the regioselectivity observedin eq 1. The opposite regioselection observed in eq 2 is surprising.
1
2
REGIOSELECTIVITY OF EPOXIDE RING OPENINGS
EFFECT OF CONJUGATING SUBSTITUENTS
H -α
β
X = NO2 38 62Br 84 16
H 74 26
OMe 5 95
H 100 0OMe 80 20
H 2-10 90-98
H- = LiBH4
H- = LiAlH4
H- = LiAlH4
with xs AlCl3
Anomalous result with the p-NO2 derivative; a priori one would expect more
attack at C-β than C-α.
Fuchs, R.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 1631-1634.Kayser, M. M.; Morand, P. Can. J. Chem. 1980, 58, 302-306.
Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737-799.
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
O
Me
H
Nu
OH
H
H
H
Me
HO
Nu
H HO
O HH O
Nu
-
Nu
HO
H
H
O
OR
O
OR
OR
Nu
OH
OR
OH
Nu
OR
OH
Nu
OR
Nu
OH
H
ORO
Nu
HO OR
O H
OR
O
OR
H
OR
H
O
ORHO
Nu
OR
HO
Nu
HO
ORNu
B C
DA
DC
BA
INDUCTIVE, STERIC, AND CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS
Bannard, R. A. B.; Casselman, A. A.; Hawkins, L. R. Can. J. Chem. 1965, 43, 2398.Bannard, R. A. B.; Casselman, A. A.; Langstaff, E. J.; Moir, R. Y. Can. J. Chem. 1968, 46, 35.
Conformationally andinductively favored Conformationallyfavored
0 %
100 % 10 %
90 %
Inductively favored
Nu-
Nu-
Nu-
Nu-
Inductive withdrawal of electron density by the C-1ethereal oxygen favors attack at C-3.
1
2
3
1
3
2
NH3
OMe-
Basic catalysis
Cl-
Br-
OAc-
OMe-
Acidic catalysis
10 %90 %
only product
Nu-
Nu-
Nu-
1
2
In this simple model, the transition-state leading to 1 involves diaxial opening of the epoxide ring and is chairlike.
However, formation of diequatorial isomer 2 requires a boat- (or skew) like transition-state. Therefore, according to the Fürst-Plattner rule, diaxial opening
of the epoxide ring to afford the diaxial product 1 is preferred.
Consider a rigid cyclohexene oxide system:
CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS
FüRST-PLATTNER RULE
Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol 2, p 1.
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
O
CN
-
O
CN
OH
H CN
CN
O
H
OH
CN
Me
O
CN
O
CN-
OHMe
CN
O
Me
NC -
H
C
O
NC
-
CNMe
O
Me R
HO (CH2)n
O
CNMe
OHMe R
HO
(CH2)nHO
+
HO (CH2)n
HO+
R
O
N
Me
Me
MeM
R
Me
Me
MeO
N
M
O (CH2)n
OH
H
OR
HO
O
HO
R
H
H
OHO
R H
(CH2)nO
OH
H H
CNR
O
H
H
R
O
H CN
H
R
CN
HO
H
HO
CN
R H
CNR
HO
R
CN
HO H
BA
-CH2CH2CO2Me
-CH=CHCO2Me
-CH=CH2
-CH=CBr2
cis-epoxide gives cyclobutanes exclusively
R 5:4 Yield %
Me 72:28 90
Bu 62:38 88
C5H11 65:35 88
Ratio of 5:4 membered ring formation
NaNH2, THF
4 h, 40 °C
NaNH2, THF
4 h, 40 °C
CIS VS TRANS GEOMETRY IN EPOXYNITRILE CYCLIZATIONS
Lellemand, J. Y.; Onanga, M. Tetrahedron lett. 1975, 585.
Trans-epoxides afford mixtures of cyclobutanesand cyclopentanes. Stork's studies exclusively
involved cis-epoxides.
5-exo6-endo
Nicolaou, JACS 1989, 111, 5330-5334.
exo ring closureendo ring closure
Developing positive charge can be stabilized
through electron donation from an adjacent
orbital in A.
δ+ δ
+
0.1 equiv CSA
CH2Cl2, -40 to 25 °C
b a
ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS
Substrate Product Ratio Yield
0:100 94%
96%60:40
100:0 95%
90%100:0
Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206
Stork, G.; Cama, L. D.; Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268.Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270.
Geometrical constraints for ring closure with epoxides are relaxed relative to normal ring forming reactions. (Consider the Walsh
model or bent-bonding in the epoxide ring).
"6-endo-tet"
"5-endo-tet"
5-exo-tet
5.5 h
(77 %)
(75 %)
2 h
(70 %)
2. tBuOH
1. KNH2, NH3
glyme, 7 min
STORK'S EPOXYNITRILE CYCLIZATIONS
?
?
?
4-exo-tet
Analysis of transition-state requirements show that proper alignment for C-O bond cleavage is more easily attained in a
4-exo rather than a 5-endo ring closure.
KHMDS, PhH
1.25 h, (70 %)
Proposed Transition-State:
favored
The effective steric hindrance of the metal salt of the cyano anion is
larger than the alkyl substituent.
R = H, Me
O
Me
O-MeO
H
H
OMeO
O-
Me
H
H
O
HO
R
H
H
OHO
R H
O
HO
R
OTBSMeO2C
H
H
O
O
HOR
HO
R
H
H
H
H
O
O
R
O
OH
OH O
O
H
H
R
HOO
O
H
H
H
H
R
HO
O
OMe
Me
O HO
Me O
OMe
Br O
OTBSO
O
A B
-CH=CH2
-CH=CHCO2Me
-CCBr
-CH=CHCO2Me
-CH=CH2
favored
2 LDA
α
The olefinic substituent can
stabilize positve charge build-
up at C- therefore the cyclo-
hexane is formed.
ALLYLIC EPOXIDE CYCLIZATION
Stork claims that the axial orientation of the enolate has severe 1,3-diaxial interactions resembling those of a tert-butyl group. Therefore transition-state B, with the enolate in
an equatorial position, is preferred and accounts for the stereoselectivity observed in the reaction.
-78 °C to rt
(43 %)
Stork, G.; Kobayashi, Y.; Suzuki, T.; Zhao, K. JACS 1990, 112, 1661-1663.Stork, G.; Zhoa, K. JACS 1990, 112, 5875-5876.
24:76 86%
81%0:100
Yield Product RatioSubstrate (R)
0:100 87%
-CH=CHCl (Z)
-CH=CHCl (E)
Substrate (R) Product Ratio Yield
0:100 86%
95%44:56
76:24 94%
92%33:67
5-exo6-endo
(92-100 %)
0.1 equiv CSA
CH2Cl2, -40
to 25 °C
0.1 equiv CSA
CH2Cl2, -40
to 25 °C
The cis-epoxide stereochemistry disfavors highly selective 6-endo ring closure. This may be due to failure of these substrates to attain a planar arrangement necessary for
maximum orbital overlap and stabilization of the transition-state.
CIS-EPOXIDES
0.1 equiv CSA
CH2Cl2, -40
to 25 °C
ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
O
H
H H
HHO
Me
HO
H
H
O
O
HO
O
H
H
HO
Me
O
O
O
H
H H
H
O
D
H
HO
H
O
DCH2
OH
D
H
H
O
O H
HO
O
H
H OD
DCH2
O
H
H
O
D
H
H
O
-
O
O
H
H
O
H
H
D
O
H
H
-
D
H
H
O
O
H
H-
D
H
D
O
H OH
H-
-
O
DCH2
OH
D
H
H
O
O
O
H
H
D
HO
H
H
H
H
O
D
H
O
H
-
O
O
H
AlD3H
D
D
OH
DCH2
O
D-
D-
D-
AlD3
A
LiAlD4
H2O
LiAlD4
REDUCTION OF CYCLOBUTENE EPOXIDES
POSSIBLE MECHANISMS:
a73 1. Initial carbon-carbon bond cleavage
a73 2. Initial carbon-oxygen bond cleavage
D- then H2O
quench
Products are stable to the reaction conditions, therefore mechanism 2 may be disfavored. However the cyclobutane anions may not be identical under both sets of
reaction conditions. The relative position of the aluminum species may have an influential role. The proximity of the aluminum (immediately after hydride delivery) to t
he backside of the -C may be necessary for C-C bond cleavage.
β
No product from fragmentation pathway b is observed, which one would expect to be
competitive with (or favored over) reaction a. Paquette concludes that the anomalous reduction of cyclobutene epoxides proceeds by initial C-O bond
cleavage (mechanism 2).
a
b
Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206
LiAlH4, THF
reflux, 8 hD
2O quench
Ratio 55:45
Ratio 52:48
H2O quench
LiAlD4, THF
reflux, 8 h
Deuterium labelling studies:
ratio is 46:54 in ether
60:40
64:36
(100 %)
(90-95 %)
LiAlH4, THF
reflux, 8 h
LiAlH4, THF
reflux, 2 d
REDUCTION OF CYCLOBUTENE EPOXIDES
Only 2 of the 4 possible alcohols were formed,therefore only attack at C- is observed.
α
β
Paquette, L. A.; Youssef, A. A.; Wise, M. L. J. Am. Chem. Soc. 1967, 89, 5246.
Red-Al
4:94
1:99
1:99
50:50
20:80
0:100
LiBH4/Ti(OiPr)4
98:2
99:1
87:13
Ph OHO
O OHBnO
OHOC5H11
O OH
Me
Me
Me
O OHR
R OH
OH
OH
OHR
O OHR
OH
OHR
R OH
OH
H Al O
O
R
X X
O
O
M H
RH
R OHO
O OHR
OH
OHR
Nu
R OH
OH
Nu
H-
LiAlH4
Dai, L.; Lou, B; Zhang, Y.; Guo, G. Tetrahedron Lett. 1986, 4343.Sharpless, B. M.; Caron, M. J. Org. Chem. 1985, 50, 1557.
No reaction is observed in
the absence of Ti(OiPr)4.
The reaction is unselective ifthe alcohol is protected.
20-100 : 1 100 : 1
6-9 : 1 14 : 1
100 : 1 100 : 1
R2NH
ROH
PhSH,PhSNa
TMSN3
NH4OBz
PhCO2H
Nu
Ti(OiPr)4
This chelated structure is purported to be responsible for a number of Nu/Ti(OiPr)4 and other Nu/metal regioselective epoxide ring opening reactions.
C-3 opening
C-2 opening
a
Sharpless attributes selective C-3 attack to overlap of bond a with an empty d orbital on the metal. Cleavage of this bond also affords a 5-membered chelated ring which
is favorable.
DIBAL or
LiBH4/Ti(OiPr)4
3
2
13
2
1
5-exo
REGIOSELECTIVE OPENING OF EPOXYALCOHOLS
The reaction is thought to involve initial complexation of the aluminum species to the alcohol followed by internal hydride delivery.
Kishi, Y. K.; Finan, J. M. Tetahedron Lett. 1982, 2719.
R = CH2CH2OCH3
Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206
C-2 opening1,3-DiolC-3 opening1,2-Diol
3
2
1
Reduction selectivity C-3 vs C-2 opening
3
2
1
REGIOSELECTIVE OPENING OF EPOXYALCOHOLS
Hanson, R. M. Chem. Rev. 1991, 91, 437-475.
DIBAL
92:8
Na2AlH2(OR)2
O OHR
O
O
O
(RO)3Ti H
RH
O
O
R OH
OH
Nu OH
Nu
OHR
O
O
R OO -
O
nC7H15 OHO
Me
OH
OHR
OO
R OH
Me
OH
Nu
OH
OHR
O
-
O
R OH
Nu
OH
OH
Me
OHR
O
O OH
OH15C7 O
R OH
OH
Me
O OHBu Bu OHOH
R
O
O
R2Al H
R'H
-
R' OHO
OH
Me
OHR' R' OH
OH
Me
O
Cu
O
R
Me
Me
AlR3
R-
Chong, J. M.; Cyr, D. R.; Mar, E. K. Tetrahedron Lett. 1987, 28, 5009.Roush, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron Lett. 1983, 24, 1983.
Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K. Tetrahedron Lett. 1982, 23, 3597.
REGIOSELECTIVE OPENING OF EPOXYALCOHOLS
Reactions with organoaluminum compounds:
R' = Bu
AlMe3PhCCAlEt
2DIBAL
Yields 70-90 %
Selectivities for C-3 openings are generally >10:1
3
2
1
Best selectivies are obtained in nonpolarsolvents such as hexane or PhH.
Opposite regioselection is observed for cuprates:
THF-polar cosolvent
For R' = alkyl 84:16 regioselectivity
5-exo3
2
Best selectivities are observed with polar cosolvents.
1 : 17 (84%)
Nu Ratio
No explanation for the dramatic shift in regioselectivity of the epoxide isomers provided.
Cis-epoxyacids unselective.
Chong, J. M.; Sharpless, B. M. Tetrahedron Lett. 1985, 26, 4683.
3
2
Cis-epoxyacids exhibit opposite regioselection and are opened at C-3.
3 equiv Me2CuLi
Et2O, 0 °C, 3 h
Trans-epoxyacids are attacked at C-2.
3
2
Sharpless, K. B.; Chong, J. M. J. Org. Chem. 1985, 50, 1560.
2
3
REGIOSELECTIVE OPENING OF EPOXYACIDS
Nu
Et2NH-Ti(iOPr)4
PhSH-Ti(iOPr)4
Et2NH
>20 : 1 10 : 1
1 : 6
C-3 attack
C-2 attack
Cuprates and Epoxyacids:
3 equiv Me2CuLi
Et2O, 0 °C, 3 h
8 : 1 (91%)
2
3
Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles
Me2CuCNLi2