Chemistry 206

Advanced Organic Chemistry

Handout09B
Simmons-Smith Reaction: Enantioselective
Variants
D. A. Evans
Friday ,
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)
09B-00-Cover page 2/26/02 1:22 PM
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 Reference
Charette, A.; Marcoux, J. Synlett 1995, 1197
Some Cyclopropane Containing Natural Products
O
H
N
O
HO
OH
H
N
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
09B-01 12/17/99 12:18 PM
Methods of Olefin Cyclopropanation
R
HCCl
3
Base
+
R
Cl
Cl Dihalocarbene
O
O
O
O
H
N
2
R
+
O
O
H
N
2
R
R
CO
2
R
H
Cu(I), Rh(II) ....
Metal Carbenoids
X-ZnCH
2
Y
Simmons - Smith Reaction
(Carbenoid)
O
S
H
2
C
O
O
Ylides
+
First Reports
R
4
R
2
R
1
R
3
CH
2
I
2
+ Zn(Cu)
R
4
R
2
R
1
R
3
Et
2
O
reflux, 48 h
Ph
Ph
Ph
Ph
48
29
49
32
27
35
31
Olefin Product Yield
OAc
Cyclopropanation is highly stereoselective :
cis-3-hexene gives only cis cyclopropane
Authors believe that I-Zn-CH
2
I is present in solution
and is the active reagent or a precursor to a low-
energy carbene
Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323.
OAc
+
09B-02 3/29/98 12:20 PM
R
1
R
4
R
2
R
3
R
1
R
4
R
2
R
3
In all cases investigated, cyclopropanation is
completely stereoselective.
Electron-rich olefins give higher yields
than electron-deficient ones.

O-methoxystyrene gave a higher yield of
cyclopropane than m- or p-methoxystyrene.
First Mechanistic Investigations
Et
2
O
R
R
ZnI
I
R
R
ZnI
I
R
R
Zn(Cu)
ZnI
I
CH
2
I
2
+ "I-Zn-CH
2
I" A
+ A
+
O
Zn I
CH
3
reflux, 48 h
+
Simmons, H.; Smith, R. J. Am. Chem. Soc., 1959, 81, 4256
A
filter
Cu
A (Cu free)
H
2
O
CH
3
I
I
2
CH
2
I
2
R
1
R
4
R
2
R
3
R
1
R
4
R
2
R
3
Zn(Cu) "I-Zn-CH
2
I" A
First Mechanistic Investigations
Zn
Cl I
Zn
Cl I
Zn
Cl I
Y
Zn
X
Zn
Y
X
Zn
X
CH
2
I
2
+
+ A
Et
2
O
reflux, 48h
Y
Simmons, H; Smith, R. J. Am. Chem. Soc., 1964, 86, 1337
No carbene insertion products.
Both ethylene production (olefin absent) and
cyclopropane formation show marked induction
period. Addition of ZnI
2
shortens the induction
period slightly.

Use of ICH
2
Cl instead of CH
2
I
2
gives an active
cyclopropanating reagent that releases CH
3
I upon addition
of H
2
O and only sparing amounts of CH
3
Cl. CH
2
Cl
2
and CH
2
Br
2
do not form active cyclopropanation reagents.
I-Zn-CH
2
I Zn(CH
2
I)
2
+ ZnI
2
09B-03 3/29/98 12:21 PM
Improvements on Reaction Logistics
Furukawa, J.; Kawabata, C.; Nishimura,
N. Tet. Lett., 1966, 28, 3353
Reproducibility of Zn reagent:
Zn - Ag couple
CH
2
I
2
More reactive towards CH
2
I
2
Higher yielding
Denis, J.; Girard, C.; Conia, J. Synthesis, 1972,
549
Reaction Accelerators:
Zn - Cu couple
CH
2
Br
2
, additive
TiCl
4
, acetyl chloride, and TMSCl accelerate
cyclopropanation dramatically (1 - 2 mol%)
Friedrich, E. et al.; J. Org. Chem., 1990, 2491
New Zinc Source:
CH
2
N
2
, ZnI
2
Wittig, et al.; Angew. Chem., 1959, 71, 652
R
2
Zn
CH
2
I
2
Furukawa's Breakthrough
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53
O
O
O
Cl
Et
2
Zn, CH
2
I
2
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 trans products.
Ph
Et
2
Zn, PhCHI
2
ether, rt 69%
syn : anti
94 : 6
Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243
09B-04 3/29/98 12:22 PM
ANTI
OH OH
OH
OH
OH
OH
OH
OH
O
H
Zn
I
X
Y
150:1 cis : trans 75% yield
Winstein, S.; Sonnenberg, J.
J. Am. Chem. Soc., 1961, 91,
3235
Authors note that the reaction with cyclopentenol is much faster than
with the corresponding acetate or cyclopentadiene
> 99 : 1
9 : 1
> 99 : 1
O
H
Simmons-Smith Directed Cyclopropanations
Substrate
Zn
I
Product Selectivity
X
Y
Favored
Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc., 1969, 91, 6892
Disfavored
SYN
Zn(Cu)
CH
2
I
2
1.54 0.1
OH
OCH
3
OH
OH
OH
OH OH
OH OH
O
Zn
Solvent
I
I
Zn I
I
1.00
0.46 0.05
0.50 0.05
H
Simmons-Smith Directed Cyclopropanations
0.091 0.012
All substrates give exclusively cis
cyclopropane adducts
Substrate k
rel
Rickborn, B.; Chan, J. J. Am. Chem. Soc., 1968, 90, 6406
Author's Proposal
Stereoelectronic effects: (C-O) thus reducing the
nucleophilicity of the olefin
(Hoveyda, A.; Evans, D. A.; Fu, G.; Chem. Rev. 1993, 93, 1307)
09B-05 3/29/98 12:23 PM
Ph
CH
3
Ph
O
O
OH
OBn
Ph
O
O
na
100 (70)
CO
2
i-Pr
99 (>99.5)
CO
2
i-Pr
78 (> 99.5)
94 (12)
92 (88)
100 (85)
89 (41)
64 (98)
Denmark: Studies of Zn(CH
2
Cl)
2
and Zn(CH
2
I)
2
+ Zn(CH
2
X)
2
(2 equiv)
82 (91)
na
na
Substrate
Yield X = Cl
(X = I)
d.e. X = Cl
(X = I)
(ClCH
2
)
2
Zn reactions in benzene were plagued by
numerous side products resulting from reaction with
solvent
Denmark, S.; Edwards, J. J. Org. Chem. 1991, 56, 6974
2 ICH
2
Cl + Et
2
Zn Zn(CH
2
Cl)
2
2 CH
2
I
2
+ Et
2
Zn Zn(CH
2
I)
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
Et
2
Zn
(equiv)
ICH
2
X
(equiv)
solvent
X = I (4) ClCH
2
CH
2
Cl
2 X = Cl (4)
"
2 X = I (4) toluene
Et
2
Zn
(equiv)
ICH
2
X
(equiv)
solvent
10 X = I (10) toluene 1 : >25
2 X = Cl (2) toluene 6 : 1
2 X = Cl (4) ClCH
2
CH
2
Cl 1 : >25
2 X = I (4)
2 X = I (4)
Zn(CH
2
I)
2
DME (2 equiv)
toluene (0.35M)
toluene (0.05M)
toluene
1 : >25
1 : 2
>25 : 1
09B-06 3/29/98 12:25 PM
Chiral Auxiliary Methods: Acetals
Arai, I; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254
R
1
O
O
CO
2
R
2
CO
2
R
2
R
1
O
O
CO
2
R
2
CO
2
R
2
O
O
CO
2
i-Pr
CO
2
i-Pr
O
O
Et
2
Zn, CH
2
I
2
hexane,
-20 C to 0 C
CO
2
Et
CO
2
Et
There was no mention of stereochemical rationale. However,
later publications state that the mechanism of induction is
unclear.
(Mori, A; Arai, I; Yamamoto, H. Tetrahedron, 1986, 42, 6458)
R
1
= Me
R
2
= i- Pr
R
1
= n- Pr
R
2
= i - Pr
R
1
= Ph
R
2
= i- Pr
90
91
92
94
91
91
81
61
89
88
Acetal
Yield (%) d.e. (%)
O
O
O
O
OBn
OBn
OBn
OBn
O
O
O
O
Substrate
n
O
O
n
d.e.
MeO
2
C
Yield
n=1
n=2
n=3
O
O
Zn-Cu, CH
2
I
2
Et
2
O, reflux
3
80
80
77
90
33
86
0
98
72
90
99
88
88
62
Ketals formed from corresponding
ketones in good yields (43-93%)
No mention of stereochemical
rationale
Mash, E.; Nelson, K. J. Am. Chem. Soc. 1985, 107, 8256
Mash: Ketals for Cyclic Olefins
09B-07 3/29/98 12:26 PM
R
X
RO
2
C
R
1
O
O
CO
2
R
2
CO
2
R
2
R
1
O
O
CO
2
R
2
CO
2
R
2
O
O
H
R
RO
2
C
Zn
I
I
Zn
I
RO
2
C
O
O
H
R
RO
2
C
O
O
CO
2
R
CO
2
R
H
Zn
I
I
Zn
I
MAJOR
O
O
Possible Explanation for Yamamoto's Results
CO
2
R
CO
2
R
Et
2
Zn, CH
2
I
2
hexane,
-20C to 0C
H
R
Sterically favored conformation and stereoelectronically
alligned: C-I and C-Zn -
Sterically disfavored and stereoelectronically
misaligned
MAJOR
R
X
RO
2
C
O
O
H
RO
2
C
Zn
I
I
Zn
I
RO
2
C
O
O
H
R
RO
2
C
MINOR
Sterically favored conformation but
stereoelectronically misaligned for
cyclopropanation
O
O
CO
2
R
CO
2
R
H
R
Zn
I
I
Zn
O
O
CO
2
R
CO
2
R
H
R
Disfavored due to steric interactions with the
ester group
MINOR
O
O
O
O
OBn
OBn
OBn
OBn
MINOR
O
O
O
CH
2
OBn
n
Bn
n
Zn
I
I
Zn-Cu, CH
2
I
2
Et
2
O, reflux
O
O
O
CH
2
OBn
Chelation reduces the electrophilicity of the Zn reagent
enough to slow cyclopropanation from this face of the olefin
Bn
Possible Explanation for Mash's Ketals
X
O
O
Zn
I
I
Zn
I
BnO
BnO
O
O
BnO
BnO
MAJOR
Coordinated away from BnO-CH
2
group and
stereoelectronically aligned: C-I and C-Zn -
09B-08 3/29/98 12:30 PM
O O
Ph Ph
O
O
n n
Ph
Ph
Zn-Cu, CH
2
I
2
Et
2
O, reflux
n = 1
n = 2
n = 3
O O
Ph Ph
66
90
77
62
Diastereomer
ratio
13:1
19:1
15:1
16:1
yield Substrate
Ketalization of starting enones proceed
in good yields (48 - 87%)
Most cyclopropane ketal products are
highly 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
Et
2
Zn, CH
2
I
2
Et
2
O, 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
OH
1. PCC
2. K
2
CO
3
, MeOH
60%
Sugimura, T.; Yoshikawa, M.; Futugawa, T.; Tai, A. Tetrahedron 1990, 46, 5955
Chiral Enol Ethers
Substrates are derived from the appropriate
ketals by treatment with i-Bu
3
Al.
Diastereoselectivity improved with higher
temperatures; ZnI
2
generally slowed the reaction
and had variable effects on d.e.
09B-09 3/29/98 12:31 PM
OHC CO
2
Me
CO
2
Me
O
O
i-PrO
2
C
i-PrO
2
C
CO
2
Me
O
Bu
3
Sn
OEt
Chiral Acetals in Synthesis
1. HC(OEt)
3
NH
4
NO
3
2. L-DIPT, TsOH
pyr. 78%
1. CH
2
I
2
,
Et
2
Zn
2. TsOH,
MeOH, H
2
O
CO
2
Me
1. BuLi,
OHC
2. TsOH, THF-H
2
O
Ph
3
P
94%
74%
41%
4
I
BuLi, HMPA
2. NaOH, MeOH-THF-H
2
O
CO
2
H
1.
24% yield
5,6-methanoleukotriene A
4
H
Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron, 1986, 42, 6447
X=
R
B
O
O
COX
COX
R
B
O
O
COX
COX
R
OH
Zn(Cu), CH
2
I
2
Et
2
O, reflux
O
O
B
H
2
O
2
, KHCO
3
THF
Chiral Auxiliary Methods: Boronic Esters
n- Butyl
"
"
Benzyl
"
Phenyl
"
O
X
O
X
O-Me
O-i Pr
N(Me)
2
O- i Pr
N(Me)
2
O- i Pr
N(Me)
2
41
44
48
57
61
60
46
73
86
93
81
89
73
91
R=
R
Yield(%)
Zn
%ee of ROH
R
I
Imai, T.; Mineta, H.; Nishida, S. J. Org. Chem.. 1990, 55, 4996
Proposed Model of Stereochemical Induction
09B-10 3/29/98 12:33 PM
I
OR
HN
O
Ph
OR
HN
O
Ph
X
c
HN
O
Ph
X
c
HN
O
Ph
O
NH
O
Ph
Zn
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
Et
2
Zn, CH
2
I
2
CH
2
Cl
2
, rt
Tanaka, K.; et al.; Tet. Asymm. 1994, 5, 1175
Addition of (0.5 equiv) of L(-), D(+) or meso-diethyl
tartrate to the reaction improved the yield in both
substrates without compromising selectivity.
H
N
R
O
Ph
H
N
R
R = H
R = TIPS
Davies' Iron Acyl Complexes as Chiral Auxiliaries
Ambler, P.; Davies, S. Tet. Lett. 1988, 29, 6979
CO
Fe
O R
Cp
Ph
3
P
CO
Fe
O R
Cp
Ph
3
P
ZnCl
2
(4 equiv), R
n
M (1.5 equiv)
CH
2
I
2
(4 equiv), toluene, r.t.
Me
n-Pr
n-Bu
i-Pr
9 : 1
14 : 1
16 : 1
24 : 1
91
91
95
93
R= selectivity Yield(%)
Using Et
2
Zn, CH
2
I
2
Using Et
3
Al, CH
2
I
2
Me
n-Pr
n-Bu
i-Pr
16 : 1
18 : 1
19 : 1
24 : 1
74
86
62
49
R= selectivity Yield(%)
09B-11 3/29/98 12:34 PM
Ambler, P.; Davies, S. Tet. Lett. 1988, 29, 6979
CO
Fe
O R
1
Cp
Ph
3
P
CO
Fe
Ph
2
P
O
Fe
Ph
2
P
O
Cp
CO
Fe
Ph
2
P
O
Cp
CO
Davies' Rationale for Selectivity
"CH
2
"
R
2
R
1
= H
R
2
= Me
63 1.3 : 1 11 1 : 1
R
1
= Me
R
2
= Me
89 11 : 1 80 30 : 1
Yield(%) selectivity Yield(%) selectivity
"X-Zn-CH
2
I"
Et
3
Al, CH
2
I
2
Lewis acid complexation to the carbonyl introduces
severe non-bonding interactions with the cis-methyl
group
The "methylene" approaches the olefin away from CO
and Ph
3
P appendages
L.A.
LA
Charette's Chiral Auxilary
O
OBn
BnO
BnO
OH
O
R
1
R
2
R
3
O
OBn
BnO
BnO
OH
O
R
1
R
2
R
3
Sugar-O Pr
Sugar-O Me
Sugar-O Ph
Sugar-O Me
Sugar-O Pr
Sugar-O
Sugar-O
Et
2
Zn (10 equiv)
CH
2
I
2
(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 of
tri -O- benzyl-D-glucal followed by reaction with
the desired allylic alcohol
Enantiomeric cyclopropanes can be formed
using L-rhamnose as the chiral auxiliary with
virtually the same selectivities
OTBS
09B-12 3/29/98 12:35 PM
O
O
O
OH
OR
RO
HO
RO
HO
O
OH
BnOH
2
C
BnO
BnO
O
R
1
R
3
R
2
O
OH
BnOH
2
C
BnO
BnO
O
R
1
R
3
R
2
Me
Pr
Me
Ph
D-series
D-series (readily available)
Me
L-glucopyranoside series
(expensive)
Et
2
Zn, CH
2
I
2
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
BnO
BnO
R
1
R
3
R
2
O
Zn
I
O
O
O
OBn
OBn
OBn R
1
R
2
R
3
Zn
I
R
R
O
O
BnO
BnO
R
1
R
3
R
2
O
Zn
Zn
I
Et
Free hydroxyl group reacts immediately
to form Zn-alkoxide. This intermediate
complexes RZn(CH
2
I), the active reagent.
O-ZnEt may serve to activate the (CH
2
I)ZnR
moeity, not only enhancing the electrophilicity
of the methylene, but rigidifying the chelate
structure as well
R
Unfavorable bonding interations with
-series might explain slower reaction and
lower selectivites.
EtZn
ZnEt
Stereochemical Rationale for Charette Auxiliary
Charette, A.; Marcoux, J. Synlett 1995, 1197
BnO
BnO
09B-13 3/29/98 12:37 PM
O
AcO
BnO
BnO
O
O
OH
BnO
BnO
O
R
1
R
3
R
2
O
OH
BnO
BnO
R
1
R
3
R
2
NH
CCl
3
O
O
OH
BnO
BnO
O
R
1
R
3
R
2
O
OH
BnO
BnO
R
1
R
3
R
2
O
R
1
R
3
R
2
HO
O
CHO
BnO
BnO
1. BF
3
OEt
2
(1 equiv), ROH
2. TiCl
4
(1 equiv)
3. MeONa, MeOH
O
1. BF
3
OEt
2
(cat), ROH
2. MeONa, MeOH
BnO
BnO
BnO
1. Tf
2
O, pyr
2. DMF, pyr,
H
2
O,
or and
70-80%
1. SmI
2
, THF,
EtOH
2. Ms
2
O,
67%
Installation and Removal of Charette's Auxiliary
Charette, A.; Marcoux, J. Synlett 1995, 1197
BnO
BnO
BnO
BnO
BnO
BnO
OX
O R
OX
O R
-O Pr
Pr -O
-O Ph
-O Me
Me
-O Ph
-O
ICH
2
Cl, Et
2
Zn
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
Substrate
Et
2
Zn,
ClCH
2
I
(equiv)
OX =
Yield(%) d.s.
Both enantiomers of the cyclohexane diol are
available through enzymatic resolution
Charette, A.; Marcoux, J. Tet. Lett. 1993, 34, 7157.
Charette: Simplifying the Auxiliary
OP
OH
1. RBr
2. deprotect
OH
OR
OP
OR
1. Tf
2
O, Bu
4
NI
2. BuLi
ROH
(92-97%)
(ca 80%)
Installation:
Removal:
OTIPS
09B-14 3/29/98 12:38 PM
CO
2
H
H
2
N
Et
Et
OH O
OMe
Et
CO
2
Me
O-p-NO
2
Bz
Et
CO
2
Me
OH
Et
CO
2
Me
OH
O
AcO
BnO
BnO
OCNHCCl
3
O
OH
BnO
BnO
O
TIPSO
Et
H
O
OH
BnO
BnO
O
TIPSO
H
Et
O
OH
BnO
BnO
O
TIPSO
Et
H
O
OH
BnO
BnO
O
TIPSO
H
Et
O
OH
BnO
BnO
K
2
CO
3
MeOH
87%
Charette, A.; Ct. B. J. Am. Chem. Soc. 1995,117, 12721
Charette: Synthesis of Coronamic Acids
Ph
3
P, DEAD, THF
p-NO
2
C
6
H
4
CO
2
H
85% yield
O
TIPSO
Et
H
A
1. A, BF
3
OEt
2. DIBAL-H
3. TIPSOTf
1. TIPSOTf
2. DIBAL-H
3. A, BF
3
OEt
4. K
2
CO
3
, MeOH
O
OH
BnO
BnO
73% y
O
TIPSO
H
Et
78% y
Et
2
Zn (7 equiv)
CH
2
I
2
(5 equiv)
CH
2
Cl
2
, -30 C
Et
2
Zn (4 equiv)
ClCH
2
I (4 equiv)
CH
2
Cl
2
, -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 auxiliary
removal
80% from auxiliary
removal
RuCl
3
, NaIO
4

(83%)
HO
2
C
TIPSO
Et
H
Charette, A.; Ct. B. J. Am. Chem. Soc. 1995,117, 12721
BOCNH
CO
2
H
Et
A
RuCl
3
, NaIO
4

(91%)
HO
2
C
TIPSO
H
Et
B
t-BuO
2
C
NHBOC
Et
BOCNH
CO
2
H
Et
t-BuO
2
C
NHBOC
Et
N-BOC-(-)-allo-
Coronamic acid
N-BOC-(+)-Coronamic Acid
N-BOC-(-)-Coronamic
acid 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
09B-15 3/29/98 12:39 PM
N
CH
3
OH
H
3
C
H
3
C Ph
Et
2
Zn
N
Zn
O
H
3
C
H
3
C Ph
H
3
C
n
Et
Ph
CH
2
OH
Zn(CH
2
I)
2
Ph
CH
2
OH
Et
2
Zn
(equiv)
CH
2
I
2
(equiv)
A
(equiv)
A
Yield (%) %ee Solvent
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 dramatically
decelerate the reaction.
Denmark: Ephedrine-Derived Chiral Controller
Denmark, S.; Edwards, J. Synlett 1992, 229
nd = not determined
R
2
R
1
OH
1. Et
2
Zn
2.
XOC COX
HO OH
3. Et
2
Zn, CH
2
I
2
R
2
R
1
OH
OEt
OEt
OMe
OMe
Oi-Pr
On-Bu
OEt
OEt
Ph OH
Ph CH
2
OH
Ph(H
2
C)
3
CH
2
OH
"
"
"
"
"
CH
2
Cl
2
Cl(CH
2
)
2
Cl*
CH
2
Cl
2
Cl(CH
2
)
2
Cl
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
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 difficult
purification
All enantiomeric excesses were determined
by rotation.
*Reaction performed at -12 C
0 C to rt
Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61
Fujisawa: Tartrate-Controlled Cyclopropanation
09B-16 3/29/98 12:40 PM
R
1
R
3
Si OH
1. Et
2
Zn
2. (+)-DET, 0 C
3. Et
2
Zn, CH
2
I
2
R
1
R
3
Si OH
PhMe
2
Si OH 42
Substrate Yield(%) %ee
Silyl substrates react much faster
than the all-alkyl substrates (4 - 20 h).
Ukaji, Y.; Sada, M.; Inomata, K. Chem. Lett. 1993, 1227
Ukaji: Tartrate-Controlled Cyclopropanation of Silated Olefins
PhMe
2
Si OH
Me
Me
3
Si OH
Me
Ph
3
Si OH
Me
PhMe
2
Si OH
Bu
Me OH
SiMe
3
Ph OH
SiMe
3
88
53
82
84
50
84
-22
-30
-30
0
-30
0
0
Temp (C)
77
92
87
90
87
46
80
OH Ph
O
O
B
Me
2
NOC
CONMe
2
Bu
(1.1 equiv) 1.
2. Zn(CH
2
I)
2
, rt, 2 h
OH Ph
OM Ph
Li
Na
K
MgBr
ZnEt
H
H
H
H
H
M =
Zn(CH
2
I)
2
(equiv)
Solvent
enantioselectivity
(%ee)
5
5
5
5
5
5
5
5
2.2
1 *
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
CH
2
Cl
2
toluene
DME
CH
2
Cl
2
CH
2
Cl
2
(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 ether
of cinnamyl alcohol afforded racemic material
O
O
B
O
R
O
NMe
2
O
NMe
2 Zn
I
X
Proposed Transition State
Charette: Chiral Dioxaborolane Chiral Controller
Charette, A.; Juteau, H. J. Am. Chem. Soc. 1994,116, 2651
<95% Yield
* 85% yield
09B-17 3/29/98 12:41 PM
OH
R
3
R
2
R
1
O
O
B
Me
2
NOC
CONMe
2
Bu
(1.1 equiv) 1.
2. Zn(CH
2
I)
2
, rt, 2 h
OH
R
3
R
2
R
1
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 or
explodes upon scale-up due to uncontrolled
exotherms.
Charette, A.; Prescott, S.; Brochu, C. J. Org. Chem. 1995,60, 1081
OH Ph
O
O
B
Me
2
NOC
CONMe
2
Bu
(1.1 equiv)
Zn(MeCHI)
2
, CH
2
Cl
2
OH Ph
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
OH Ph
OH Ph
OH BnO
OH
Et OH
OH Pr
>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
OH Ph
Zn(CHICH
2
CH
2
OTIPS)
2
(2.2 equiv)
A (1.1 equiv)
OH Ph
TIPSO
> 95% ee
> 95 : 5 d.s.
OH
Zn(CHICH
2
CH
2
OTIPS)
2
(2.2 equiv)
A (1.1 equiv)
OH
TIPSO
> 95% ee
> 95 : 5 d.s.
Relative stereochemistry of the cyclopropanation was
the alkyl group (derived from the Zn reagent) is anti
to the hydroxymethyl group
Lower diastereoselectivity observed in the absence of
the chiral promoter
09B-18 3/29/98 12:43 PM
Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki, T. Chem. Lett. 1995, 1113
BINOL-Derived Chiral Promoters
OH
OH
CONR
2
CONR
2
A
Et
2
Zn, CH
2
I
2
, (3 equiv) CH
2
Cl
2
, 0 C, 15 h
Ph OH Ph OH
A (1 equiv)
Chiral Auxilary
(R =)
Et
2
Zn
(equiv)
Yield (%) %ee
Me
Me
Me
Me
Et
Et
n-Pr
n-Pr
n-Bu
2
4
6
6 + ZnI
2
(1 equiv)
6
6 + ZnI
2
(1 equiv)
6
6 + ZnI
2
(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 BINOL
nucleus 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
CONEt
2
CONEt
2
A
Et
2
Zn (6 equiv), CH
2
I
2
, (3 equiv)
CH
2
Cl
2
, 0 C
R
1
OH R
1
OH
A (1 equiv)
Yield (%) %ee
R
2
R
2
Ph OH
p -MeO-Ph OH
p -Cl-Ph OH
OH Ph
OH
TBDPSO
OH
TrO
OH TrO
44
78
59
65
59
64
34
92
94
90
89
87
88
65
Substrate
O
O
Zn
O
NEt
2
O
NEt
2
Zn
Zn
I
O
Zn
Et
Et
Et
Author's Proposed Transition State
BINOL-Derived Chiral Promoters
09B-19 3/29/98 12:43 PM
OH
1. Zn(CH
2
I)
2
(-78 C to -20 C)
2. L.A.
Ph
OH Ph
OH Ph
OH Pr
OH Me
OH
"
"
"
"
"
"
"
none
BBr
3
TiCl
4
ZnI
2
Zn(OTf)
2
Et
2
AlCl
SnCl
4
TiCl
2
(O-i-Pr)
TiCl
4
"
"
Me
TBDPSO
<5
90
90
14
18
87
55
80
85
90
85
Substrate Lewis Acid Yield (%)
NMR studies indicate that allyl alcohol and
Zn(CH
2
I)
2
react at -78 C to form the
(allyloxy)-Zn(CH
2
I) complex and CH
3
I.
This complex does not react to form
cyclopropane for at least four hours at -20 C.
Upon addition of a Lewis acid, cyclopropanation
was complete within 2 hours at -20 C.
Charette: Lewis Acid-Catalyzed Cyclopropanation of Allylic Alcohols
Charette, A.; Brochu, C. J. Am. Chem. Soc. 1995, 117,
11367
OH
1. Zn(CH
2
I)
2
(-78 C to 0 C)
2. A (25 mol%), 1.5 h
Ph
OH Ph
Charette: Lewis Acid-Catalyzed Allylic Cyclopropanation
Charette, A.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367
O O
Ti
Ph
Ph
Ph
Ph
O O
i-Pr-O O-i-Pr
A
OH 1. Zn(CH
2
I)
2
(-78 C to 0 C)
2. A (25 mol%), 1.5 h
Me
Me
OH Me
Me
80% yield
90% ee
90% yield
60%ee
OH
Zn(CH
2
I)
2
(1 equiv)
OZnCH
2
I
CH
3
I +
O
ZnCH
2
I
LA
O
ZnI
LA
OZnI
LA
09B-20 3/29/98 12:45 PM
R
1
OH
R
2
H
NHSO
2
Ar
NHSO
2
Ar
R
1
OH
R
2
H
Ph OH
OH Ph
OH Ph
Reaction proceeds to approximately 20% in the
absence of the ligand under the reaction
conditions
Cinnamyl methyl ether reacted under similar
conditions as cinnamyl alcohol, yet afforded
racemic material
OH
CH
2
I
2
TrO
Et
2
Zn
(2.0 equiv)
(3.0 equiv)
(0.12 equiv)
bissulfonamide
(Ar = )
Substrate yield (%) %ee
OH BnO
C
6
H
5
o-NO
2
-C
6
H
4
m-NO
2
-C
6
H
4
p-NO
2
-C
6
H
4
"
"
"
"
"
"
OH
68
75
33
76
75
82
36
80
13
66
75
92
72
82
71
quant.
70
86
36
79
OH
BnO
TrO
CH
2
Cl
2
, -23 C, 5 h
Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett. 1992, 2575
Kobayashi: First Catalytic Asymmetric Simmons-Smith Reaction
"
"
SO
2
R
N
N
SO
2
R
"
Zn
R
1
OH
R
2
H
SO
2
Ar
N
N
SO
2
Ar
Al-R
R
1
OH
R
2
H
Ph OH
OH Ph
OH
Me
Me
Et
i-Bu
"
"
"
"
Ph
(2 equiv)
Et
2
Zn CH
2
I
2
bissulfonamide
(Ar = )
OH
(3 equiv)
yield (%)
TrO
(0.1 equiv)
"
"
"
"
Substrate
%ee
CF
3
p-NO
2
-C
6
H
4
p-NO
2
-C
6
H
4
p-NO
2
-C
6
H
4
p-CF
3
-C
6
H
4
C
6
H
5
"
"
quant
"
"
"
"
"
"
92
14
70
66
71
66
76
73
78
CH
2
Cl
2
, -20 C
Imai, N.; Takahashi, H.; Kobayashi, S. Chem. Lett. 1994, 177
Kobayashi: Aluminum-Catalyzed Asymmetric Simmons-Smith Reaction
R
09B-21 3/29/98 12:46 PM
R
1
OH
R
2
H
NHSO
2
-C
6
H
4
-p-NO
2
NHSO
2
C
6
H
4
-p-NO
2
SO
2
R
N
N
SO
2
R
Zn
R
1
OH
R
2
H
(2.0 equiv)
Et
2
Zn CH
2
I
2
(3.0 equiv)
(0.1 equiv)
CH
2
Cl
2
, -20 C
Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tet. Lett., 1992, 33, 2575
Chiral Silyl and Stannyl Cyclopropylmethanols
PhMe
2
Si OH
Bu
3
Sn OH
OH PhMe
2
Si
OH Bu
3
Sn
75
67
94
83 81
86
59
66
Substrate Yield(%) %ee
Ph OH
R
2
O
2
SHN NHSO
2
R
3
R
1
Et
2
Zn, CH
2
I
2
, CH
2
Cl
2
-23 C, 20 h
Ph OH
Ph
Me
Ph
Me
Me
Me
Me
Me
Me
Ph
Me
Ph
Me
CF
3
p-MeC
6
H
4
p-NO
2
C
6
H
4
Me
Me
Me
3
C
Me
3
C
PhCH
2
PhCH
2
PhCH
2
PhCH
2
quant
"
"
"
"
"
93
quant
58
61
42
46
74
34
82
85
R
1
R
2
R
3
Yield (%) %ee
Other substrates were examined, but gave
lower 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%)
09B-22 3/29/98 12:47 PM
Ph OH
NHSO
2
R
NHSO
2
R
Ph OH
CH
2
I
2
Et
2
Zn
(1.0 equiv) (2.0 equiv)
(0.1 equiv)
CH
2
Cl
2
, -23 C
Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett. 1995, 2219
Denmark: Optimization of Reaction Protocols
SO
2
R
N
N
SO
2
R
Zn
Et
2
Zn
(1.1 equiv)
Bissulfonamide
(R = )
t
1/2
(min) %ee
CH
3
CH
3
CH
2
i-Pr
C
6
H
5
1-naphthyl
4-NO
2
-C
6
H
4
4-CH
3
OC
6
H
4
C
6
F
5
50
130
140
70
50
70
60
100
80
67
49
77
48
76
74
29
There is a clear linear relationship between
the promoter %ee and the enantioselectivity
of the reaction.
There is a marked induction period early in reaction
that disappears upon addition of ZnI
2
(t
1/2
= 3 min).
Enantioselectivities improved from 80% to 86%
with ZnI
2
Denmark, S.; Christenson, B.; Coe, D.; O'Connor, S. Tet. Lett. 1995, 2215
Ph OH
Ph OH
CH
2
I
2
Et
2
Zn
(1.0 equiv) (2.0 equiv)
(0.1 equiv)
CH
2
Cl
2
, -23 C, 5 h
Denmark: Optimization of Chiral Promoter
Et
2
Zn
(1.1 equiv)
NHSO
2
CH
3
NHSO
2
CH
3
Ph
Ph NHSO
2
CH
3
NHSO
2
CH
3
H
3
C
Ph OCH
3
NHSO
2
CH
3 H
3
C
Ph OH
NHSO
2
CH
3
NHSO
2
CH
3
NHSO
2
CH
3
Promoter
NH
S
O
2
NHSO
2
CH
3
NHSO
2
CH
3
NHSO
2
CH
3
NHSO
2
CH
3
(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)
(T
1/2
, %ee)
Denmark, S.; Christenson, B.; O'Connor, S. Tet. Lett. 1995, 2219
09B-23 3/29/98 12:48 PM
Ph OH
NHSO
2
CH
3
NHSO
2
CH
3
Et
2
Zn
(1.1 equiv)
MX
n
(1.0 equiv)
Ph OH
(0.1 equiv)
CH
2
I
2
(2.0 equiv)
Et
2
Zn
(1.0 equiv)
none
ZnI
2
ZnBr
2
ZnCl
2
ZnF
2
Zn(OAc)
2
CdCl
2
CdI
2
MgI
2
PbI
2
MnI
2
HgI
2
GaI
3
8
>3
>3
4
10
10
11
11
50
8
12
15
decomp.
80
86
80
76
72
45
83
75
26
72
35
39
n.d.
additive t
1/2
(min) %ee
Using higher chiral ligand loadings resulted in slower
conversions and lower enantioselectivity

Use of in situ prepared ZnI
2
(Et
2
Zn + 2 I
2
) 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 ZnI
2
?
Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 3390
Zn(CH
2
I)
2
+ ZnI
2
2 IZn(CH
2
I)
Ph OH
NHSO
2
CH
3
NHSO
2
CH
3
Et
2
Zn
(1.1 equiv)
Ph OH
Et
2
Zn + 2CH
2
I
2
A
Denmark: Role of ZnI
2
?
Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 3390
NMR studies indicate for A and D clear
formation of bis-iodomethylzinc species.
Route B also showed formation of a single
species from I
2
and appears to form
ICH
2
-Zn-I upon CH
2
I
2
addition.
C forms multiple species postulated to be
Et-Zn-CH
2
I, Zn(CH
2
I)
2
and Et
2
Zn indicating
another Schlenk equilibrium.
Route D formed ICH
2
ZnI, but contaminated
with another Zn species as yet unidentified
"I-CH
2
-Zn-I"
(0.1 equiv)
ZnI
2
2 ICH
2
-Zn-I
Et
2
Zn + I
2
Et-Zn-I
CH
2
I
2
ICH
2
-Zn-I
Et
2
Zn + CH
2
I
2
Et-Zn-CH
2
I
I
2
ICH
2
-Zn-I
Et
2
Zn + 2CH
2
I
2
Zn(CH
2
I)
2
I
2
ICH
2
-Zn-I
Zn(CH
2
I)
2
B
C
D
A
B
C
D
>3
3
10
20
86
86
73
23
method t
1/2
(min) %ee
Zn(CH
2
I)
2
+ ZnI
2
I-CH
2
-ZnI
Author's conclude that the Schlenk equilibrium:


lies on the side of ICH
2
-ZnI. This was
independently confirmed by Charette:
(Charette, A.; et al. J. Am. Chem. Soc. 1996, 118,
4539).
09B-24 3/29/98 12:48 PM
OCH
3
OCH
3
O
O
Zn
I
I
+ Zn(CH
2
I)
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 identical
with respect to bond distances and angles. They
are related by a pseudo-rotational center about
the Zn atom.
Distance between Zn(1) and I(2) is within the sum
of their van der Waals radii.
The endo iodomethylene unit bisects the O-Zn-O
angle, possibly due to a stereoelectronic
stablization:
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
R
2
OH
NHSO
2
CH
3
NHSO
2
CH
3
R
2
OH
Et
2
Zn
(1.1 equiv)
R
1
R
3
R
1
R
3
ZnI
2
(1.0 equiv)
(0.1 equiv)
CH
2
I
2
(2.0 equiv)
Et
2
Zn
(1.0 equiv)
Ph
H
Ph(CH
2
)
2
H
Ph
CH
3
Ph
H
Ph(CH
2
)
2
H
Ph
CH
3
H
Ph
H
Ph(CH
2
)
2
CH
3
Ph
H
Ph
H
Ph(CH
2
)
2
CH
3
Ph
H
"
"
"
"
"
CH
3
"
"
"
"
"
7
<3
5
<3
<3
<3
40
18
9
5
25
45
91
81
89
89
91
88
90
97
98
90
85
85
80
81
81
72
73
81
5
10
26
50
43
16
R
1
R
2
R
3
t
1/2
(min) Yield(%) %ee
Cinnamyl alcohol has been cyclopropanated
by this group previously in 89% ee using
distilled Et
2
Zn and I
2
to generate ZnI
2
.
09B-25 3/29/98 12:50 PM
I
N
N
Zn
S
H
3
C
O
O O
I
Zn
Zn
Et
I
Ph H
H
X
N
N
Zn
S
O
R
O
S
O
R O
O
Zn
I
R
3
R
2
R
1
Denmark: Working Transition State Hypothesis
R
1
OH
NHSO
2
CH
3
NHSO
2
CH
3
Et
2
Zn
(1.1 equiv)
ZnI
2
(1.0 equiv)
R
1
OH
(0.1 equiv)
CH
2
I
2
(2.0 equiv)
Et
2
Zn
(1.0 equiv)
R
2
R
3
R
2
R
3
Substitution alpha to the CH
2
OH group
experiences unfavorable steric interactions
with the "spectator" sulfonamide group.
Activation of I-CH
2
-ZnI moiety occurs
by I coordination to the chiral promoter-Zn
complex.
Denmark, S.; O'Connor, S. J. Org. Chem. 1997, 62, 584.
Zn
Et
Summary
What we know:
Activated zinc metal reacts with CH
2
I
2
to form an active cyclopropanation reagent that shows remarkable
directing effects with Lewis basic sites on molecules. The Furukawa reagent (Et
2
Zn, CH
2
I
2
) also shows
the 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 in
chiral 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.
09B-26 3/29/98 12:50 PM