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Chemistry 206
Advanced Organic Chemistry
Handout09B
Simmons-Smith Reaction: Enantioselective
Variants
D. A. EvansFriday ,October 1, 2001
Jason S. Tedrow
Evans Group Seminar, February 13, 1998
For a recent general review of the Simmons-Smith reaction see:Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
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The Simmons-Smith Reaction: Enantioselective Variants
Jason S. Tedrow
Evans group Friday seminar, February 13, 1998
I. Discovery and Mechanistic Insights
II. Chiral Auxiliaries
III. Chiral Promoters
IV. Catalytic Enantioselective Variants
Leading ReferenceCharette, A.; Marcoux, J. Synlett 1995, 1197
Some Cyclopropane Containing Natural Products
O
HN
O
HO
OH
HN
O
O
FR - 900848
O O
O
NH
O
Me
MeO
Me
O
O
Me
MeO
H
Me
H OH
O
H
Cl
Callipeltoside
Minale, et al, J. Am. Chem. Soc.1996, 118, 6202
Yoshida, et al. J. Antibiotics, 1990,43, 748
Barrett, et al. J. Chem. Soc. Chem. Commun., 1995, 649
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Methods of Olefin Cyclopropanation
R
HCCl3Base
+ R
Cl
Cl Dihalocarbene
O
O
O
O
H
N2
R
+ O
O
H
N2
RR
CO2R
H
Cu(I), Rh(II) .... Metal Carbenoids
X-ZnCH2Y Simmons - Smith Reaction(Carbenoid)
O
SH2C O
O
Ylides+
First Reports
R4
R2R1
R3
CH2I2 + Zn(Cu)R4
R2R1
R3
Et2O
reflux, 48 hPh
Ph
Ph
Ph
48
29
49
32
27
35
31
Olefin Product Yield
OAc
Cyclopropanation is highly stereoselective : cis-3-hexene gives only ciscyclopropane
Authors believe that I-Zn-CH2I is present in solutionand is the active reagent or a precursor to a low-energy carbene
Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323.
OAc
+
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R1
R4
R2
R3
R1
R4
R2
R3
In all cases investigated, cyclopropanation iscompletely stereoselective.
Electron-rich olefins give higher yieldsthan electron-deficient ones.
O-methoxystyrene gave a higher yield ofcyclopropane than m-or p-methoxystyrene.
First Mechanistic Investigations
Et2O
R
R
ZnI
I
R
R
ZnI
I
R
R
Zn(Cu)
ZnI
I
CH2I2 + "I-Zn-CH2I" A
+ A
+
O
Zn I
CH3
reflux, 48 h
+
Simmons, H.; Smith, R. J. Am. Chem. Soc.,1959, 81, 4256
Afilter
Cu
A (Cu free)H2O
CH3I
I2CH2I2
R1
R4
R2
R3
R1
R4
R2
R3
Zn(Cu) "I-Zn-CH2I" A
First Mechanistic Investigations
Zn
Cl I
Zn
Cl I
Zn
Cl I
Y
Zn
X
Zn
Y
X
Zn
X
CH2I2 +
+ AEt2O
reflux, 48h
Y
Simmons, H; Smith, R. J. Am. Chem. Soc.,1964, 86, 1337
No carbene insertion products.
Both ethylene production (olefin absent) andcyclopropane formation show marked inductionperiod. Addition of ZnI2 shortens the inductionperiod slightly.
Use of ICH2Cl instead of CH2I2 gives an activecyclopropanating reagent that releases CH3I upon additionof H2O and only sparing amounts of CH3Cl. CH2Cl2and CH2Br2 do not form active cyclopropanation reagents.
I-Zn-CH2I Zn(CH2I)2 + ZnI2
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Improvements on Reaction Logistics
Furukawa, J.; Kawabata, C.; Nishimura,N. Tet. Lett.,1966, 28, 3353
Reproducibility of Zn reagent:
Zn - Ag couple
CH2I2
More reactive towards CH2I2 Higher yielding
Denis, J.; Girard, C.; Conia, J. Synthesis,1972,549
Reaction Accelerators:
Zn - Cu couple
CH2Br2, additive
TiCl4, acetyl chloride, and TMSCl acceleratecyclopropanation dramatically (1 - 2 mol%)
Friedrich, E. et al.; J. Org. Chem.,1990, 2491
New Zinc Source:
CH2N2, ZnI2Wittig, et al.; Angew. Chem.,1959, 71, 652
R2Zn
CH2I2
Furukawa's Breakthrough
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron,1968, 24, 53
O
O
O
Cl
Et2Zn, CH2I2
Solvent
benzene
benzene
benzene
benzene
benzene
ether
11
11
10
3
15
26
79
76
60
92
80
42
Substrate Solvent Time (h) Yield (%)
Electron-rich olefins react much faster than electron-poor ones.
Complete retention of olefin geometry: cis-olefins give cis-cyclopropanes and trans-olefins
produce transproducts.
PhEt2Zn, PhCHI2
ether, rt 69%
syn : anti94 : 6
Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron,1970, 26, 243
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ANTI
OH OH
OH
OH
OH
OH
OH
OH
O
H
Zn
I
X Y
150:1 cis : trans 75% yieldWinstein, S.; Sonnenberg, J.J. Am. Chem. Soc., 1961, 91,3235
Authors note that the reaction with cyclopentenol is much faster thanwith the corresponding acetate or cyclopentadiene
> 99 : 1
9 : 1
> 99 : 1
O
H
Simmons-Smith Directed Cyclopropanations
Substrate
ZnI
Product Selectivity
X
Y
Favored
Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc.,1969, 91, 6892
Disfavored
SYN
Zn(Cu)
CH2I2
1.54 0.1
OH
OCH3
OH
OH
OH
OH OH
OH OH
O
ZnSolvent
II
ZnI
I
1.00
0.46 0.05
0.50 0.05
H
Simmons-Smith Directed Cyclopropanations
0.091 0.012
All substrates give exclusively ciscyclopropane adducts
Substrate krel
Rickborn, B.; Chan, J. J. Am. Chem. Soc.,1968, 90, 6406
Author's Proposal
Stereoelectronic effects: (C-O) thus reducing thenucleophilicity of the olefin(Hoveyda, A.; Evans, D. A.; Fu, G.; Chem. Rev. 1993, 93, 1307)
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Ph
CH3
Ph
O
O
OH
OBn
Ph
O
O
na
100 (70)
CO2i-Pr
99 (>99.5)
CO2i-Pr
78 (> 99.5)
94 (12)
92 (88)
100 (85)
89 (41)
64 (98)
Denmark: Studies of Zn(CH2Cl)2 and Zn(CH2I)2
+ Zn(CH2X)2 (2 equiv)
82 (91)
na
na
SubstrateYield X = Cl
(X = I)d.e. X = Cl
(X = I)
(ClCH2)2Zn reactions in benzene were plagued bynumerous side products resulting from reaction withsolvent
Denmark, S.; Edwards, J. J. Org. Chem.1991, 56, 6974
2 ICH2Cl + Et2Zn Zn(CH2Cl)2
2 CH2I2 + Et2Zn Zn(CH2I)2
DCE
OBn OBn OBn
2
OH
OBn
>99 :1
OH
9 : 1
OH
1 : 1
OBn OBn
syn:anti
syn:anti
Charette, A.; Marcoux, J. Synlett, 1995, 1197
Charette: Selective Cyclopropanation Conditions
Syn Anti
Et2Zn(equiv) ICH2X(equiv) solvent
X = I (4) ClCH2CH2Cl
2 X = Cl (4) "
2 X = I (4) toluene
Et2Zn(equiv)
ICH2X(equiv)
solvent
10 X = I (10) toluene 1 : >25
2 X = Cl (2) toluene 6 : 1
2 X = Cl (4) ClCH2CH2Cl 1 : >25
2 X = I (4)
2 X = I (4)
Zn(CH2I)2DME (2 equiv)
toluene (0.35M)
toluene (0.05M)
toluene
1 : >25
1 : 2
>25 : 1
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Chiral Auxiliary Methods: Acetals
Arai, I; Mori, A.; Yamamoto, H. J. Am. Chem. Soc.1985, 107, 8254
R1
O
O
CO2R2
CO2R2
R1
O
O
CO2R2
CO2R2
O
O
CO2i-Pr
CO2i-Pr
O
O
Et2Zn, CH2I2
hexane,-20 C to 0 C
CO2Et
CO2Et
There was no mention of stereochemical rationale. However,later publications state that the mechanism of induction isunclear.
(Mori, A; Arai, I; Yamamoto, H. Tetrahedron, 1986,42, 6458)
R1 = MeR2 = i-Pr
R1 = n-PrR2 = i -Pr
R1 = PhR2 = i-Pr
90
91
92
94
91
91
81
61
89
88
Acetal Yield (%) d.e. (%)
O
O
O
OOBn
OBn
OBn
OBn
O
O
O
O
Substrate
n
O
O
n
d.e.
MeO2C
Yield
n=1
n=2
n=3
O
O
Zn-Cu, CH2I2
Et2O, reflux
3
80
80
77
90
33
86
0
98
72
90
99
88
88
62
Ketals formed from correspondingketones in good yields (43-93%)
No mention of stereochemicalrationale
Mash, E.; Nelson, K. J. Am. Chem. Soc. 1985, 107, 8256
Mash: Ketals for Cyclic Olefins
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R
X
RO2C
R1
O
O
CO2R2
CO2R2
R1
O
O
CO2R2
CO2R2
OO
H
R
RO2C
ZnII
Zn
I
RO2C
O
O
H
R
RO2C
O
O
CO2R
CO2RH
Zn
I
I
Zn
I
MAJOR
O
O
Possible Explanation for Yamamoto's Results
CO2R
CO2R
Et2Zn, CH2I2
hexane,-20C to 0C
H
R
Sterically favored conformation and stereoelectronicallyalligned: C-I and C-Zn -
Sterically disfavored and stereoelectronicallymisaligned
MAJOR
RX
RO2C
OO
H
RO2C
ZnII
Zn
I
RO2C
OO
H
R
RO2C
MINOR
Sterically favored conformation butstereoelectronically misaligned forcyclopropanation
O
O
CO2R
CO2RH
R Zn
I
I
Zn
O
O
CO2R
CO2RH
R
Disfavored due to steric interactions with theester group
MINOR
O
O
O
OOBn
OBn
OBn
OBn
MINOR
O
O
O
CH2OBn
n
Bn
n
Zn
I
I
Zn-Cu, CH2I2
Et2O, reflux
O
O
O
CH2OBn
Chelation reduces the electrophilicity of the Zn reagentenough to slow cyclopropanation from this face of the olefin
Bn
Possible Explanation for Mash's Ketals
X
O
O
ZnII
Zn
I
BnO
BnO
O
O
BnO
BnO
MAJOR
Coordinated away from BnO-CH2 group andstereoelectronically aligned: C-I and C-Zn -
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OO
PhPh
OO
nn
Ph Ph
Zn-Cu, CH2I2
Et2O, reflux
n = 1
n = 2
n = 3
OO
PhPh
66
90
77
62
Diastereomerratio
13:1
19:1
15:1
16:1
yieldSubstrate
Ketalization of starting enones proceedin good yields (48 - 87%)
Most cyclopropane ketal products arehighly crystalline
No mention of stereochemical rationale
Mash, E.; Torok, D. J. Org. Chem. 1989, 54, 250
Mash: New Ketals For Directed Cyclopropanation
O
OH
O
OH
OR
OR
n n
Et2Zn, CH2I2
Et2O, rt
n = 0
n = 1
n = 2
n = 3
81
86
77
58
80
57
>99
>99
>99
>99
O
>99
i-Pr OH
>99
i-Pr
Yield d.e.Susbstrate
OH1. PCC
2. K2CO3, MeOH
60%
Sugimura, T.; Yoshikawa, M.; Futugawa, T.; Tai, A. Tetrahedron1990, 46, 5955
Chiral Enol Ethers
Substrates are derived from the appropriateketals by treatment with i-Bu3Al.
Diastereoselectivity improved with highertemperatures; ZnI2 generally slowed the reactionand had variable effects on d.e.
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OHC CO2Me
CO2Me
O
O
i-PrO2C
i-PrO2C
CO2MeO
Bu3Sn
OEt
Chiral Acetals in Synthesis
1. HC(OEt)3NH4NO3
2. L-DIPT, TsOHpyr. 78%
1. CH2I2,Et2Zn
2. TsOH,MeOH, H2O
CO2Me
1. BuLi,
OHC
2. TsOH, THF-H2O
Ph3P
94% 74%
41%
4I
BuLi, HMPA
2. NaOH, MeOH-THF-H2O
CO2H
1.
24% yield
5,6-methanoleukotriene A4
H
Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron, 1986, 42, 6447
X=
RB
O
O
COX
COX
RB
O
O
COX
COX ROH
Zn(Cu), CH2I2
Et2O, reflux
O
OB
H2O2, KHCO3
THF
Chiral Auxiliary Methods: Boronic Esters
n-Butyl
"
"
Benzyl
"
Phenyl
"
O X
O
X
O-Me
O-iPr
N(Me)2
O- iPr
N(Me)2
O- iPr
N(Me)2
41
44
48
57
61
60
46
73
86
93
81
89
73
91
R=
R
Yield(%)
Zn
%ee of ROH
RI
Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem.. 1990, 55, 4996
Proposed Model of Stereochemical Induction
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I
OR
HN
O
Ph
OR
HN
O
Ph
XcHN
O
Ph
XcHN
O
Ph
O
NH
O
PhZn
Et
Zn
I
O
Ph
O
NH
O
TIPS
R = H
16-62% y
Zn
X
R = TIPS
24 to 56% y
99 : 1
99 : 1
Ph
Camphor Derived Auxiliaries
Et2Zn, CH2I2
CH2Cl2, rt
Tanaka, K.; et al.; Tet. Asymm.1994, 5, 1175
Addition of (0.5 equiv) of L(-), D(+) or meso-diethyltartrate to the reaction improved the yield in bothsubstrates without compromising selectivity.
HN
R
O
PhHNR
R = H
R = TIPS
Davies' Iron Acyl Complexes as Chiral Auxiliaries
Ambler, P.; Davies, S. Tet. Lett.1988, 29, 6979
CO
Fe
O RCp
Ph3P
CO
Fe
O RCp
Ph3PZnCl2 (4 equiv), RnM (1.5 equiv)
CH2I2 (4 equiv), toluene, r.t.
Me
n-Pr
n-Bu
i-Pr
9 : 1
14 : 116 : 1
24 : 1
91
9195
93
R= selectivity Yield(%)
Using Et2Zn, CH2I2 Using Et3Al, CH2I2
Me
n-Pr
n-Bu
i-Pr
16 : 1
18 : 119 : 1
24 : 1
74
8662
49
R= selectivity Yield(%)
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Ambler, P.; Davies, S. Tet. Lett.1988, 29, 6979
CO
Fe
O R1
CpPh3P
CO
Fe
Ph2P
O
Fe
Ph2P
O
CpCO
Fe
Ph2P
O
CpCO
Davies' Rationale for Selectivity
"CH2"
R2
R1 = HR2 = Me
63 1.3 : 1 11 1 : 1
R1 = MeR2 = Me
89 11 : 1 80 30 : 1
Yield(%) selectivity Yield(%) selectivity
"X-Zn-CH2I" Et3Al, CH2I2
Lewis acid complexation to the carbonyl introducessevere non-bonding interactions with the cis-methylgroup
The "methylene" approaches the olefin away from COand Ph3P appendages
L.A.
LA
Charette's Chiral Auxilary
O
OBn
BnO
BnOOH
OR1
R2
R3
O
OBn
BnO
BnOOH
OR1
R2
R3
Sugar-O Pr
Sugar-O Me
Sugar-O Ph
Sugar-O Me
Sugar-O Pr
Sugar-O
Sugar-O
Et2Zn (10 equiv)
CH2I2 (10 equiv)toluene, >97% y
Me
Charette, A.; Ct, B.; Marcoux, J. J. Am. Chem. Soc.1991, 113, 8166
-35 to 0
-35 to 0
-35 to 0
-35 to 0
-50 to -20
-20 to 0
-35 to 0
124 : 1
>50 : 1
130 : 1
111 : 1
114 : 1
>50 : 1
100 : 1
Substrate Temp (C) Diastereoselectivity
Auxiliary is derived from DMDO epoxidation oftri -O-benzyl-D-glucal followed by reaction withthe desired allylic alcohol
Enantiomeric cyclopropanes can be formedusing L-rhamnose as the chiral auxiliary withvirtually the same selectivities
OTBS
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O
O
O
OH
OR
RO
HO
RO
HO
O
OH
BnOH2CBnO
BnO
O
R1
R3
R2
O
OH
BnOH2CBnO
BnO
O
R1
R3
R2
Me
Pr
Me
Ph
D-series
D-series (readily available)
Me
L-glucopyranoside series(expensive)
Et2Zn, CH2I2
t-BuOMe, 0C
93
83
95
93
16.5 : 1
12.3 : 1
11.0 : 1
15.0 : 1
Substrate Yield (%) Selectivity
D-Glucopyranosides:A Cheaper Alternative to
L-Rhamnose
Charette, A.; Turcotte, N.; Marcoux, J. Tet. Lett.1994,35, 513
Sugar-O
Sugar-O
Sugar-O
Sugar-O
O
O
BnOBnO
R1
R3
R2O
Zn
I
OO
O
OBnOBn
OBnR1
R2
R3
Zn
I
R
R
O
O
BnOBnO
R1
R3
R2O
Zn
Zn IEt
Free hydroxyl group reacts immediatelyto form Zn-alkoxide. This intermediatecomplexes RZn(CH2I), the active reagent.
O-ZnEt may serve to activate the (CH2I)ZnRmoeity, not only enhancing the electrophilicityof the methylene, but rigidifying the chelatestructure as well
R
Unfavorable bonding interations with-series might explain slower reaction andlower selectivites.
EtZnZnEt
Stereochemical Rationale for Charette Auxiliary
Charette, A.; Marcoux, J. Synlett 1995, 1197
BnO
BnO
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O
AcO
BnOBnO
O
O
OH
BnOBnO
O
R1
R3
R2
O
OH
BnOBnO
R1
R3
R2
NH
CCl3
O
O
OH
BnOBnO
O
R1
R3
R2
O
OH
BnOBnO
R1
R3
R2O
R1
R3
R2HO
O
CHO
BnOBnO
1. BF3OEt2 (1 equiv), ROH
2. TiCl4 (1 equiv)
3. MeONa, MeOH
O
1. BF3OEt2 (cat), ROH
2. MeONa, MeOH
BnO
BnOBnO
1. Tf2O, pyr
2. DMF, pyr,H2O,
or and
70-80%
1. SmI2, THF,EtOH
2. Ms2O,
67%
Installation and Removal of Charette's Auxiliary
Charette, A.; Marcoux, J. Synlett 1995, 1197
BnO
BnO
BnO
BnOBnO
BnO
OX
O R
OX
O R
-O Pr
Pr-O
-O Ph
-O Me
Me
-O Ph
-O
ICH2Cl, Et2Zn
toluene -20 C
Me
"
"
"
"
3
5
5
5
5
3
3
3
3
3
-OH
-OH
-OMe
-OAc
-OTBS
-OH
-OH
-OH
-OH
-OH
>97
88
97
85
>95
97
97
98
90
95
>20 : 1
> 15 : 1
1.6 : 1
5.3 : 1
1.3 : 1
24 : 1
24 : 1
23 : 1
15 : 1
> 20 : 1
SubstrateEt
2Zn,
ClCH2I(equiv)
OX = Yield(%) d.s.
Both enantiomers of the cyclohexane diol areavailable through enzymatic resolution
Charette, A.; Marcoux, J. Tet. Lett. 1993, 34, 7157.
Charette: Simplifying the Auxiliary
OP
OH 1. RBr
2. deprotectOH
OR
OP
OR1. Tf2O, Bu4NI
2. BuLi
ROH
(92-97%)
(ca 80%)
Installation:
Removal:
OTIPS
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CO2H
H2NEt
Et
OH O
OMe
EtCO2Me
O-p-NO2Bz
EtCO2Me
OH
EtCO2Me
OHO
AcO
BnOBnO
OCNHCCl3
O
OH
BnOBnO O
TIPSO
Et
H
O
OH
BnOBnO O
TIPSO
H
Et
O
OH
BnOBnO O
TIPSO
Et
H
O
OH
BnOBnO O
TIPSO
H
Et
O
OH
BnOBnO
K2CO3
MeOH87%
Charette, A.; Ct. B. J. Am. Chem. Soc.1995,117, 12721
Charette: Synthesis of Coronamic Acids
Ph3P, DEAD, THF
p-NO2C6H4CO2H85% yield
O
TIPSO
Et
H
A
1. A, BF3OEt2. DIBAL-H3. TIPSOTf
1. TIPSOTf2. DIBAL-H
3. A, BF3OEt4. K2CO3, MeOH
O
OH
BnOBnO
73% y
O
TIPSO
H
Et
78% y
Et2Zn (7 equiv)CH2I2 (5 equiv)
CH2Cl2, -30 C
Et2Zn (4 equiv)ClCH2I (4 equiv)
CH2Cl2, -60 C
93% yield> 99 : 1
98 % yield> 66 : 1
BnO
BnO
BnO
BnO
BnO
BnO
BnO
Charette: Synthesis of Coronamic Acids
HO
TIPSO
Et
H
HO
TIPSO
H
Et
75% from auxiliaryremoval
80% from auxiliaryremoval
RuCl3, NaIO4(83%) HO2C
TIPSO
Et
H
Charette, A.; Ct. B. J. Am. Chem. Soc.1995,117, 12721
BOCNH
CO2H
Et
A
RuCl3, NaIO4(91%) HO2C
TIPSO
H
Et
B
t-BuO2C
NHBOC
Et
BOCNH
CO2H
Et
t-BuO2C
NHBOC
Et
N-BOC-(-)-allo-Coronamic acid
N-BOC-(+)-Coronamic Acid
N-BOC-(-)-Coronamicacid t-Bu ester
N-BOC-(+)-allo-Coronamic acid
t-Bu ester
82% Yield
42% Yield
64% Yield
41% Yield
5 steps
5 steps
5 steps
5 steps
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NCH3
OHH3C
H3C Ph
Et2ZnN
ZnO
H3C
H3C Ph
H3C
nEt
PhCH2OH
Zn(CH2I)2Ph
CH2OH
Et2Zn(equiv)
CH2I2(equiv)
A(equiv)
A
Yield (%) %eeSolvent
toluene
THF
toluene
THF
DME
toluene
DME
2
2
2
2
2
1
1
2
2
2
2
2
2
2
4
4
2
2
4
4
4
82
81
nd
nd
85
63
54
18
-11
nd
nd
23
15
19
The chiral controller A was shown to dramaticallydecelerate the reaction.
Denmark: Ephedrine-Derived Chiral Controller
Denmark, S.; Edwards, J. Synlett1992, 229
nd = not determined
R2
R1 OH
1. Et2Zn
2.XOC COX
HO OH
3. Et2Zn, CH2I2R2
R1 OH
OEt
OEt
OMe
OMe
Oi-Pr
On-Bu
OEt
OEt
Ph OH
Ph CH2OH
Ph(H2C)3 CH2OH
"
"
"
"
"
CH2Cl2
Cl(CH2)2Cl*
CH2Cl2
Cl(CH2)2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
22
54
12
52
24
17
60
46
50
79
64
23
27
58
70
81
Substrate X = Solvent Yield(%) %ee
Reactions are very slow, even at rt.
Reaction work-up is plagued by difficultpurification
All enantiomeric excesses were determinedby rotation.
*Reaction performed at -12 C
0 C to rt
Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett.1992, 61
Fujisawa: Tartrate-Controlled Cyclopropanation
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R1
R3Si OH
1. Et2Zn
2. (+)-DET, 0 C
3. Et2Zn, CH2I2
R1
R3Si OH
PhMe2Si OH 42
Substrate Yield(%) %ee
Silyl substrates react much fasterthan the all-alkyl substrates (4 - 20 h).
Ukaji, Y.; Sada, M.; Inomata, K. Chem. Lett.1993, 1227
Ukaji: Tartrate-Controlled Cyclopropanation of Silated Olefins
PhMe2Si OH
Me
Me3Si OH
Me
Ph3Si OH
Me
PhMe2Si OH
Bu
Me OH
SiMe3
Ph OH
SiMe3
88
53
82
84
50
84
-22
-30
-30
0
-30
0
0
Temp (C)
77
92
87
90
87
46
80
OHPh
OO
B
Me2NOC CONMe2
Bu
(1.1 equiv)1.
2. Zn(CH2I)2, rt, 2 hOHPh
OMPh
Li
Na
K
MgBr
ZnEt
H
H
H
H
H
M =Zn(CH2I)2
(equiv) Solventenantioselectivity
(%ee)
5
5
5
5
5
5
5
5
2.2
1 *
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DME
CH2Cl2
CH2Cl2
(89)
(58)
(91)
(33)
(85)
(93)
(93)
(81)
(93)
(93)
17.1 : 1
3.8 : 1
22 : 1
2 : 1
12 : 1
26 : 1
26 : 1
9.7 : 1
29 : 1
29 : 1
Cyclopropanation of the methyl or TIPS etherof cinnamyl alcohol afforded racemic material
O O
BO
R
O NMe2
O NMe2Zn
I X
Proposed Transition State
Charette: Chiral Dioxaborolane Chiral Controller
Charette, A.; Juteau, H. J. Am. Chem. Soc.1994,116, 2651
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OH
R3
R2
R1OO
B
Me2NOC CONMe2
Bu
(1.1 equiv)1.
2. Zn(CH2I)2, rt, 2 hOH
R3
R2
R1
Charette: Chiral Dioxaborolane Chiral Controler
Charette, A.; Juteau, H. J. Am. Chem. Soc.1994,116, 2651
Ph OH
Pr OH
OH
Me OH
OH
Et
Me
TBDPSO
>98
80
90
85
80
29 : 1 (93)
27 : 1 (93)
29 : 1 (93)
32 : 1 (94)
21 : 1 (91)
Substrate Yield (%)enantioselectivity
(%ee)
Reaction tends to become less selective orexplodes upon scale-up due to uncontrolledexotherms.
Charette, A.; Prescott, S.; Brochu, C. J. Org. Chem.1995,60, 1081
OHPhOO
B
Me2NOC CONMe2
Bu
(1.1 equiv)
Zn(MeCHI)2, CH2Cl2 OHPh
Charette: 1,2,3-Trisubstituted Cyclopropanes
Charette, A.; Lemay, J. Angew. Chem. Int. Ed. Eng.1997,36, 1090
Me>50 : 1 d.s.> 95% ee
OHPh
OHPh
OHBnO
OH
Et OH
OHPr
>50 : 1
14 : 1
>50 : 1
20 : 1
15 : 1
10 : 1
98
90
94
90
94
93
96
83
80
84
87
93
Substrate d.s. %ee %Yield
A
A
OHPh
Zn(CHICH2CH2OTIPS)2
(2.2 equiv)
A (1.1 equiv) OHPh
TIPSO
> 95% ee> 95 : 5 d.s.
OH
Zn(CHICH2CH2OTIPS)2(2.2 equiv)
A (1.1 equiv) OH
TIPSO
> 95% ee> 95 : 5 d.s.
Relative stereochemistry of the cyclopropanation wasthe alkyl group (derived from the Zn reagent) is antito the hydroxymethyl group
Lower diastereoselectivity observed in the absence ofthe chiral promoter
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Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett.1995, 1113
BINOL-Derived Chiral Promoters
OH
OH
CONR2
CONR2
A
Et2Zn, CH2I2, (3 equiv) CH2Cl2, 0 C, 15 hPh OHPh OH
A (1 equiv)
Chiral Auxilary(R =)
Et2Zn(equiv)
Yield (%) %ee
Me
Me
Me
Me
Et
Et
n-Pr
n-Pr
n-Bu
2
4
6
6 + ZnI2 (1 equiv)
6
6 + ZnI2 (1 equiv)
6
6 + ZnI2 (1 equiv)
6
-14
26
67
75
94
90
85
79
89
7
85
90
87
55
87
51
88
58
Chiral controller is derived from the BINOLnucleus in three steps (Me = 37%,Et = 33%, n-Pr = 16%, n-Bu = 30%)
Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn.1997, 207
OH
OH
CONEt2
CONEt2
A
Et2Zn (6 equiv), CH2I2, (3 equiv)CH2Cl2, 0 C
R1 OHR1 OH
A (1 equiv)
Yield (%) %ee
R2 R2
Ph OH
p-MeO-Ph OH
p-Cl-Ph OH
OHPh
OHTBDPSO
OHTrO
OHTrO
44
78
59
65
59
64
34
92
94
90
89
87
88
65
Substrate
O
OZn
O
NEt2
O
NEt2
Zn
Zn
I
O
Zn
Et
EtEt
Author's Proposed Transition State
BINOL-Derived Chiral Promoters
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OH1. Zn(CH2I)2 (-78 C to -20 C)
2. L.A.
Ph OHPh
OHPh
OHPr
OHMe
OH
"
"
"
"
"
"
"
none
BBr3
TiCl4
ZnI2
Zn(OTf)2
Et2AlCl
SnCl4
TiCl2(O-i-Pr)
TiCl4
"
"
Me
TBDPSO
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R1 OH
R2
H
NHSO2Ar
NHSO2Ar
R1 OH
R2
H
Ph OH
OHPh
OHPh
Reaction proceeds to approximately 20% in theabsence of the ligand under the reactionconditions
Cinnamyl methyl ether reacted under similarconditions as cinnamyl alcohol, yet affordedracemic material
OH
CH2I2
TrO
Et2Zn(2.0 equiv) (3.0 equiv)
(0.12 equiv)
bissulfonamide(Ar = )
Substrate yield (%) %ee
OHBnO
C6H5
o-NO2-C6H4
m-NO2-C6H4
p-NO2-C6H4
"
"
"
"
"
"
OH
68
75
33
76
75
82
36
80
13
66
75
92
72
82
71
quant.
70
86
36
79
OH
BnO
TrO
CH2Cl2, -23 C, 5 h
Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett.1992, 2575
Kobayashi: First Catalytic Asymmetric Simmons-Smith Reaction
"
"
SO2RN
NSO2R
"
Zn
R1 OH
R2
H
SO2ArN
NSO2Ar
Al-R
R1 OH
R2
H
Ph OH
OHPh
OH
Me
Me
Et
i-Bu
"
"
"
"
Ph
(2 equiv)Et2Zn CH2I2
bissulfonamide(Ar = )
OH
(3 equiv)
yield (%)
TrO
(0.1 equiv)
"
"
"
"
Substrate %ee
CF3
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
p-CF3-C6H4
C6H5
"
"
quant
"
"
"
"
"
"
92
14
70
66
7166
76
73
78
CH2Cl2, -20 C
Imai, N.; Takahashi, H.; Kobayashi, S. Chem. Lett.1994, 177
Kobayashi: Aluminum-Catalyzed Asymmetric Simmons-Smith Reaction
R
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R1 OH
R2
H
NHSO2-C6H4-p-NO2
NHSO2C6H4-p-NO2
SO2RN
NSO2R
Zn
R1 OH
R2
H(2.0 equiv)
Et2Zn CH2I2(3.0 equiv)
(0.1 equiv)
CH2Cl2, -20 C
Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett., 1992, 33, 2575
Chiral Silyl and Stannyl Cyclopropylmethanols
PhMe2Si OH
Bu3Sn OH
OHPhMe2Si
OHBu3Sn 75
67
94
83 81
86
59
66
Substrate Yield(%) %ee
Ph OHR2O2SHN NHSO2R3
R1
Et2Zn, CH2I2, CH2Cl2 -23 C, 20 hPh OH
Ph
Me
Ph
MeMe
Me
Me
Me
Me
Ph
Me
Ph
Me
CF3
p-MeC6H4
p-NO2C6H4
Me
Me
Me3C
Me3C
PhCH2
PhCH2
PhCH2
PhCH2
quant
"
"
"
"
"
93
quant
58
61
42
4674
34
82
85
R1 R2 R3 Yield (%) %ee
Other substrates were examined, but gavelower selectivites (ca. 60% ee).
(2 equiv)(3 equiv)
Imai, N.; Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J. Tet. Lett.1997, 38, 1423
Chiral Sulfonamide Promoters Derived from Amino Acids
(10 mol%)
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Ph OH
NHSO2R
NHSO2R
Ph OHCH2I2Et2Zn
(1.0 equiv) (2.0 equiv)
(0.1 equiv)
CH2Cl2, -23 C
Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett.1995, 2219
Denmark: Optimization of Reaction Protocols SO2RN
NSO2R
Zn
Et2Zn
(1.1 equiv)
Bissulfonamide(R = )
t1/2 (min) %ee
CH3
CH3CH2
i-Pr
C6H5
1-naphthyl
4-NO2 -C6H4
4-CH3OC6H4
C6F5
50
130
140
70
50
70
60
100
80
67
49
77
48
76
74
29
There is a clear linear relationship betweenthe promoter %ee and the enantioselectivityof the reaction.
There is a marked induction period early in reactionthat disappears upon addition of ZnI2 (t1/2 = 3 min).Enantioselectivities improved from 80% to 86%with ZnI2
Denmark, S.; Christenson, B.; Coe, D.; O'Connor, S. Tet. Lett.1995, 2215
Ph OH Ph OHCH2I2Et2Zn(1.0 equiv) (2.0 equiv)
(0.1 equiv) CH2Cl2, -23 C, 5 h
Denmark: Optimization of Chiral Promoter
Et2Zn
(1.1 equiv)
NHSO2CH3
NHSO2CH3
Ph
Ph NHSO2CH3
NHSO2CH3 H3C
Ph OCH3
NHSO2CH3 H3C
Ph OH
NHSO2CH3
NHSO2CH3
NHSO2CH3
Promoter
NH
SO2
NHSO2CH3
NHSO2CH3NHSO2CH3
NHSO2CH3
(80 min, 20% ee) (110 min, 14% ee) (150 min, rac) (180 min, 29% ee) (80 min, 5% ee)
(90 min, 79% ee) (>240 min, nd) (50 min, 80% ee)
(T1/2, %ee)
Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett.1995, 2219
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Ph OH
NHSO2CH3
NHSO2CH3
Et2Zn(1.1 equiv)
MXn(1.0 equiv)
Ph OH(0.1 equiv)CH2I2
(2.0 equiv)
Et2Zn(1.0 equiv)
none
ZnI2
ZnBr2
ZnCl2
ZnF2
Zn(OAc)2
CdCl2
CdI2
MgI2
PbI2
MnI2
HgI2
GaI3
8
>3
>3
4
10
10
11
11
50
8
12
15
decomp.
80
86
80
76
72
45
83
75
26
7235
39
n.d.
additive t1/2(min) %ee
Using higher chiral ligand loadings resulted in slowerconversions and lower enantioselectivity
Use of in situprepared ZnI2 (Et2Zn + 2 I2) reproducibly
give 92% yield and 89% ee with cinnamyl alcohol.
1
5
10
25
50
100
50%
80%
80%
64%
41%
16%
mol% %ee
Denmark: Role of ZnI2?
Denmark, S.; O'Connor, S. J. Org. Chem.1997, 62, 3390
Zn(CH2I)2 + ZnI2 2 IZn(CH2I)
Ph OH
NHSO2CH3
NHSO2CH3
Et2Zn(1.1 equiv)
Ph OH
Et2Zn + 2CH2I2A
Denmark: Role of ZnI2?
Denmark, S.; O'Connor, S. J. Org. Chem.1997, 62, 3390
NMR studies indicate for A and D clearformation of bis-iodomethylzinc species.
Route B also showed formation of a singlespecies from I2 and appears to formICH2-Zn-I upon CH2I2 addition.
C forms multiple species postulated to beEt-Zn-CH2I, Zn(CH2I)2 and Et2Zn indicatinganother Schlenk equilibrium.
Route D formed ICH2ZnI, but contaminatedwith another Zn species as yet unidentified
"I-CH2-Zn-I"(0.1 equiv)
ZnI2 2 ICH2-Zn-I
Et2Zn + I2 Et-Zn-ICH2I2 ICH2-Zn-I
Et2Zn + CH2I2 Et-Zn-CH2II2 ICH2-Zn-I
Et2Zn + 2CH2I2 Zn(CH2I)2I2 ICH2-Zn-I
Zn(CH2I)2
B
C
D
A
B
C
D
>3
3
10
20
86
86
73
23
method t1/2(min) %ee
Zn(CH2I)2 + ZnI2 I-CH2-ZnI
Author's conclude that the Schlenk equilibrium:
lies on the side of ICH2-ZnI. This wasindependently confirmed by Charette:(Charette, A.; et al. J. Am. Chem. Soc. 1996, 118,4539).
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OCH3
OCH3 O
O
Zn
I
I+ Zn(CH2I)2
Zn(1) - O(1) 2.103(10)Zn(1) - O(2) 2.20(1)Zn(1) - C(13) 1.92(2)Zn(1) - C(14) 1.98(2)I(1) - C(13) 2.21(2)I(2) - C(14) 2.16(2)
I(1) -C(13) - Zn(1) 116.4(9)I(2) -C(14) - Zn(1) 107.9(8)
Zn(1) - I(2) 3.513(2)Zn(1) - I(1) 3.350(3)Zn(1) - I(4) 3.929(2)
Bond Lengths ()
Bond Angles (deg)
Non-Bonded Distances ()
Two molecules in unit cell are virtually identicalwith respect to bond distances and angles. Theyare related by a pseudo-rotational center aboutthe Zn atom.
Distance between Zn(1) and I(2) is within the sumof their van der Waals radii.
The endo iodomethylene unit bisects the O-Zn-Oangle, possibly due to a stereoelectronicstablization:
C-Zn donation into * C-I.
Denmark: X-Ray Structure of a Bis-Iodomethyl Zinc Complex
Denmark. S.; Edwards, J.; Wilson, S. J. Am. Chem. Soc.1991. 113, 723
Denmark: Substrate Generality
Denmark, S.; O'Connor, S. J. Org. Chem.1997, 62, 584
R2 OH
NHSO2CH3
NHSO2CH
3 R2 OH
Et2Zn(1.1 equiv)R1
R3
R1
R3
ZnI2(1.0 equiv)
(0.1 equiv) CH2I2(2.0 equiv)
Et2Zn(1.0 equiv)
Ph
H
Ph(CH2)2
H
Ph
CH3
Ph
H
Ph(CH2)2
H
Ph
CH3
H
Ph
H
Ph(CH2)2
CH3
Ph
H
Ph
H
Ph(CH2)2
CH3
Ph
H
"
"
"
"
"
CH3
"
"
"
"
"
7
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I
N
N
ZnS
H3C O
O O
I
Zn
Zn
Et
I
PhH
H
X
NNZn
SO
R
O
S
O
ROO
ZnI
R3R2
R1
Denmark: Working Transition State Hypothesis
R1 OH
NHSO2CH3
NHSO2CH3
Et2Zn(1.1 equiv)
ZnI2(1.0 equiv)
R1 OH(0.1 equiv)CH2I2
(2.0 equiv)
Et2Zn(1.0 equiv)
R2
R3
R2
R3
Substitution alpha to the CH2OH groupexperiences unfavorable steric interactions
with the "spectator" sulfonamide group.
Activation of I-CH2-ZnI moiety occursby I coordination to the chiral promoter-Zncomplex.
Denmark, S.; O'Connor, S. J. Org. Chem.1997, 62, 584.
Zn
Et
Summary
What we know:
Activated zinc metal reacts with CH2I2 to form an active cyclopropanation reagent that shows remarkabledirecting effects with Lewis basic sites on molecules. The Furukawa reagent (Et2Zn, CH2I2) also showsthe same reactivity trends.
Zinc alkoxides are necessary appendages to most chiral auxiliary-based methods and all enantio-selective methods in order to achieve any selectivity.
Lewis acids accelerate cyclopropanation of allylic alcohols.
Various auxiliary methods exist for cyclopropanation of both cyclic and acyclic ketones and aldehydes.
Glucose-derived auxiliaries give excellent induction in the cyclopropanation of allylic alcohols.
Several methods for enantioselective cyclopropanation exist; however, most are stoichiometric inchiral reagent.
So far only the bissulfonamide promoted Simmons-Smith reaction gives high induction in several cases.
Mechanism of cyclopropanation and the exact nature of the reagents involved is unclear at present.
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