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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)

09B-00-Cover page 2/26/02 1:22 PM


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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

+

09B-02 3/29/98 12:20 PM


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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

09B-03 3/29/98 12:21 PM


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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)

09B-05 3/29/98 12:23 PM


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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

09B-06 3/29/98 12:25 PM


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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

09B-07 3/29/98 12:26 PM


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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 -

09B-08 3/29/98 12:30 PM


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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.

09B-09 3/29/98 12:31 PM


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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

09B-10 3/29/98 12:33 PM


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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(%)

09B-11 3/29/98 12:34 PM


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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

09B-12 3/29/98 12:35 PM


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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

09B-13 3/29/98 12:37 PM


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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

09B-14 3/29/98 12:38 PM


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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

09B-15 3/29/98 12:39 PM


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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

09B-16 3/29/98 12:40 PM


18/27

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


19/27

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

09B-18 3/29/98 12:43 PM


20/27

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

09B-19 3/29/98 12:43 PM


21/27

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


22/27

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

09B-21 3/29/98 12:46 PM


23/27

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%)

09B-22 3/29/98 12:47 PM


24/27

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

09B-23 3/29/98 12:48 PM


25/27

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?


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).

09B-24 3/29/98 12:48 PM


26/27

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


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


27/27

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.

010 simmons-smith ho

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