The Synthesis of Cyclopropane Derivatives

1

The Synthesis of Cyclopropane Derivatives

CHM-6351

André B. Charette

Fall 2009

Copie pdf disponible à http://charette.corg.umontreal.ca/cours/chm6351.html

Monday, October 26, 2009

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2

Enantioselective Synthesis of Cyclopropanes

I. Introduction to cyclopropanesII. Synthesis of Cyclopropanes by Ring Closure Processes a. Ring closure reactions b. Kulinkovich Reaction c. Michael-induced ring closure reactions d. Cyclopropane from Diols or EpoxidesIII. Synthesis of Cyclopropanes from Carbenoids a. Carbenes vs metal carbenes vs carbenoids b. Diastereoselective Cyclopropanations with Carbenoids c. Enantioselective Cyclopropanations with Carbenoids d. Synthesis of 1,2,3-Substituted Cyclopropanes with CarbenoidsIV. Catalytic asymmetric cyclopropanation via the transition metal catalyzed diazo decompositionV. Miscellaneous


3

Reviews on Cyclopropane Chemistry

Cyclopropane chemistry - generalLebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977-1050.

Donaldson, W. A. Tetrahedron 2001, 57, 8589-8627. Pellissier, H. Tetrahedron 2008, 64, 7041-7095.

Kunlinkovich Reaction Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597-2632.

Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789-2834.

Zinc CarbenoidsCharette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1-415.

Transition metal catalyzed decomposition of diazo compoundsDavies, H. W. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1-326.

Mass, G. Chem. Soc. Rev. 2004, 33, 183-190.

Cyclopropanation via ring closureTaylor, R. E.; Engelhardt, F. C.; Schmitt, M. J. Tetrahedron 2003, 59, 5623-5634.

Other referencesComprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds; Springer: Berlin 1999; vol I-III, 1483

Comprehensive Asymmetric Synthesis; Ojima, I. Ed.; Second Edition; Wiley-VCH inc.: New York, 2000, 864 p.Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From

Cyclopropanes to Ylides: John Wiley & Sons, Inc.: New York, 1998.Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091

Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911Calter, M. A. Curr. Org. Chem. 1997, 1, 37

Sing, V. K.; DattaGupta, A.; Sekar, G. Synthesis 1997, 137Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463

Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341


4

Physical Properties of Cyclopropanes

Ring strain: 28.1 kcalmol-1

LG

Entropically: the most favored

krel : 5 > 6 > 3 > 7 > 4 > 15 etc.

Br

Nuc

Nuc

MetCH2

CH2

cyclopropylcarbinyl cation

H2CCH2 CH2

k1 1.3 x 108 sec-1

k-1 1 x 104 sec-1

CH2

PPh3 SO2Ph

“Radical clock”


5

Preferred Bond Construction for Vinyclcyclopropanes

R2 R1

R2

O

H

X

R1R2

X O

R1H

NH

OO

HO OH

N

HNO O

FR-900848

Yoshida, J. Antibiot. 1990, 43, 748Isolation:

Total Syntheses:Barrett, A. G. M.; Kasdorf, K. J. C. S. Chem. Comm. 1996, 325-326.Barrett, A. G. M.; Kasdorf, K. J. Am. Chem. Soc. 1996, 118, 11030-11037.Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc. 1996, 118, 6096-6097.

NH

O

U-106305

Kuo and coworkers, J. Am. Chem. Soc. 1995, 117, 10629-10634(Upjohn)

Total Syntheses:Barrett, A. G. M. and coworkers J. Am. Chem. Soc. 1996, 118, 7863-7864. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327-10328.

Isolation:


6

1,2-Dicyclopropyl Alkene Synthesis: The FR-900848 Problem

NH

OO

HO OH

N

HNO O

FR-900848

SO2Ph

TMS

1. BuLi

OOTBDPS

H

2.

OTBDPS

3. Li, naphthalene. 70%

65% "Julia elimination under a variety of conditionsresulted in extensive structural collapse"

Falck JACS 1996, 6096.

Barrett Chem. Comm. 1996, 325

OTBSOTBSHO

1. Cyclopropanation2. N-(PhS)succinimideBu3P, PhH, 89%

3. RaNi, 49%


7

1,2-Dicyclopropyl Alkene Synthesis: The U-106305 Problem

NH

O

U-106305

OTIPS OTIPS

Me

H

O

S

NaHMDS, THFDMF, -60 ˚C

95%

4.4 : 1

(E:Z)

S

N

O O

MeSN

S

O ONa

Charette JACS 1997, 8608


8

1,2-Dicyclopropyl Alkene Synthesis: Olefin MetathesisZercher Tetrahedron Lett. 2000, 8723.

(Cy3P)2Cl2Ru=CHPh (5 mol%)

CH2Cl2, 62%, 6:1 (E:Z)

RuLx LxRu

Hepatitis C Virus NS3 Protease Inhibitors (Boehringer Ingelheim)

IC50 = 0.011µm

Lamarre, D. et al. Nature 2003, 426, 186.

O

O

OHN

N

O

O NHCO2H

N

S

N

NH

OMe


9

Strategies in Stereoselective Synthesis

R1R2

Chiral Auxiliary Approach

R1 R2

R1 R2Chiral groupR1 R2Chiral group

R1 R2Chiral group+

Diastereoisomers(>90:10)

>50% <50%

Cleavage of Chiral auxiliary

R1 R2


9


R1R2

Advantages


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2

Advantages• The desired diastereomer can be enriched (crystallization, chromatography)


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2

Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2

Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2


Disadvantage


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2


Disadvantage• 3-step for 1 transformation


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2



Chiral Stoichiometric Reagent

R1 R2R1 R2

Chiral reagent(≥1.0 equiv)


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


9


R1R2




R1 R2R1 R2

Chiral reagent(≥1.0 equiv)


R1 R2R1 R2

Achiral reagent(≥1.0 equiv)

Chiral ligand (<0.1 equiv)or

Chiral catalyst (<0.1 equiv)


R1 R2


R1 R2Chiral group+


>50% <50%


R1 R2


10

Most Common Approaches to Cyclopropane Derivatives

RR

MRR M

X

Metal carbeneCuRh

Ru(Os)CoPd

CarbenoidZnSmAlIn

(Hg, Cd)

EWG

LG

EWGLG

Electrophile:Oxonium

-OSO2CF3

Nucleophile:alkene

allylsilaneenecarbamate


11

Cationic Cyclization of Homoallylic Alcohols and Ethers

AcOOAc

BF3•OEt2, Ac2O

70%

BnOOH SiMe2Cl

BnOO

Me2Si

O

Me2Si

BnO

BnO

SiMe2F

OHBnO

SiMe2F

OTf

BnO

BnO

SiMe3

OH

Me

BnO

MeH

H

base (Cy3P)2Cl2Ru=CHPh

HF, pyr

Tf2O, 2,6-lutidine

71%

SOCl2 89%

O

Matumoto Tetrahedron Lett. 1980, 4853.

Taylor Org. Lett. 1999, 1257. Org. Lett. 2000, 601. JACS 2001, 2964.


12

Cationic Cyclization of Homoallylic Alcohols and Ethers

HR3

TfOO

R1

R2 H

Cb

HR3

CbOO

R1

R2 HR1 R3

CbO R2

OH

Tf2O, 2,6-lutidine

NaH, Δ

R2

R3

O

R1

dr 88-98:12-2ee as starting material

R1 R2

O

O

Ni-Pr

i-Pr

R1 R2

O

O

Ni-Pr

i-Pr

1. BuLi, (-)-sparteine, -78 °C2. ClTi(NEt2)33. R3CHO

1. BuLi, (-)-sparteine, -78 °C2. Ti(Oi-Pr)43. R3CHO

R1 R3

CbO R2

OH

30-96% ee

OCb

Kalkofen, R.; Brandau, S.; Wibbeling, B.; Hoppe, D. Angew. Chem. Int. Ed. 2004, 43, 6667-6669.Risatti, C. A.; Taylor, R. E. Angew. Chem. Int. Ed. 2004, 43, 6671-6672.

R1 = H, PhR2 = Me, PrR3 = Ph, alkyl, cycloalkyl


The Kulinkovich-De Meijere Reaction

13

R1 OR2

O

EtMgBr(2 eqv)

Ti(OiPr)4 (5-10 mol%)

Et2O, 18-20 °C

1.

2. H3O+

R1

HO

Met Met

1,2-dicarbanion equivalent


The Kulinkovich-De Meijere Reaction

14

(OR')2TiEt

EtTi(Oi-Pr)4

2 EtMgBr 2 iPrOMgBr

R' = iPr or R2

CH3-CH3

(OR')2TiR1 OR2

O

(R'O)2TiO R1

OR2

R1

O(R'O)2Ti

OR2

(OR')2Ti

O

OR2

R1

2 EtMgBr

R1 OMgBr

+R2OMgBr

H3O+R1 OH

R'OH

R' = iPr or R2

(R'O)2TiO R1

OR2

Et

MgBr

(R'O)2TiO

R1

Et


Kulinkovich Reaction on Amides

15

NBn

+H NBn2

O MeTi(Oi-Pr)3 (1.2 equiv)

MgCl

(2.5 equiv) NBn

NBn2

HH

H2, Pd/CMeOH/AcOH

NH

NH2

HH

N N

HO

O O

N

H

H

NH2

F

F

F

Trovafloxacin (Trovan - Pfizer)Antibiotic - inhibits the uncoiling of supercoiled DNA


16

Most Common Approaches to Cyclopropane Derivatives:MIRC

RR

MRR M

X

Metal carbeneCuRh

Ru(Os)CoPd

CarbenoidZnSmAlIn

(Hg, Cd)

EWG

LG

EWGLG

EWG EWGR

LG EWGR

RCH-LG

EWG LG EWG LG

RRCH2

EWG R


17

MIRC Reaction: Relative Stereocontrol - Chrysanthemic Acids

COOHMe Me

Me

Me

trans-chrysanthemic acid

COOH

Me Me

Me

Me

cis-chrysanthemic acid

COOH

Me Me

MeOOC

Me

cis-chrysanthemic acidMe Me

Br

Br

OO

NCO

Decamethrin

Me

OO

MeO2C CO2Me

Me

Me Me Me Me

OOMeO2C CO2Me

O

MeO2C

O

CO2MeMe Me Me Me

CO2Me

Me

OO

MeO2C

Me

O

Me

Me

O

MeO2C CO2Me

Me

Me Me Me

LiI, THF, 75%

dr: 88 : 12

+Me2C=PPh3 (2.5 equiv)

LiI, THF, 65%

Me2C=PPh3 (2.5 equiv)

A. Krief


18

MIRC: Chiral Auxiliary Approach

NO

Me

O

NO

Me

O Me Me

HH

94%dr: >99:1

Ph2S=CMe2

Romo, D.; Romine, J. L.; Midura, W.; Meyers, A. I. Tetrahedron 1990, 46, 4951-4994.

NP

N OCl

NP

N OOH3C

HH

OTESH3C

HH

O

BuLi / THF-78°C

90%dr: 96:4

1. NaBH42. TESCl3. O3

Hanessian, S.; Andreotti, D.; Gomtsyan, A. J. Am. Chem. Soc. 1995, 117, 10393-10394.

O

Me

+


19

Catalytic Asymmetric MIRC Reaction

R1 R2

O

O

NR3R1 Br

O

R1 NR3

O Br

R1 NR3

O

Cs2CO3

CsHCO3 + CsBr

R2

O

R1 R2

O

NR3

O

Papageorgiou, C. D.; de Dios, M. A. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641-4644.


20

Intermolecular Catalytic Asymmetric MIRC Reaction

a b cQuinine Quinidine

N

OMeN

OMe

H N

N

OMe

OMeN

Et

ON

OMe

N

N

Ph

Ph O

N

Et

N

MeODihydroquinine

N

Et

N

OMe

O

Ph

Ph

N

Et

O

N

MeO

dDihydroquinidine

R1 R2

O

O

R1 BrO

R2

O

R3

+

Cs2CO3 (1.3 equiv), MeCN80 °C 24 h, 10-20 mol% NR3

R3

esteramide

Weinreb amide

t-BuOPh

O

O

a, 96%, 86% eeb, 92%, 88% ee

t-BuOp-C6H4OMe

O

O

a, 73%, 84% eeb, 73%, 84% ee

t-BuOp-C6H4Br

O

O

a, 83%, 85% ee

Et2NPh

O

O

a, 94%, 97% eeb, 85%, 97% ee

Np-C6H4Br

O

O

c, 67%, 96% eed, 74%, 97% ee

Me

MeOt-BuO

PhO

O

a, 63%, 92% ee

Me

t-BuOOBn

O

Oa, 75%, 80% ee

t-BuOOMe

O

Oa, 90%, 97% eed, 83%, 90% ee

NBoc2

NC5H11

O

O

a, 65%, 96% eed, 77%, 92% ee

Me

MeO


21

Catalytic Asymmetric MIRC Reaction: Intramolecular Version

XCl

O

EWG

X = CH2, NBnEWG = ketone, aldehyde, SO2Ph, CH=CHC(O)Ph, esters

XH

H

EWG

O

Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 2681-2684.

NN

20 mol%

Na2CO3, DCE or MeCN80 °C

ClO

O

Ph

H

H

O

PhO

20 mol% a or bNa2CO3, MeCN, 80 °CNaI or NaBr (40 mol%) a, 64%, 95% ee

b, 48%, 94% ee

a bQuinine Quinidine

N

OMeN

OMe

H N

N

OMe

OMe


22


a

b

Quinine (Me-MQ)

Quinidine (Me-MQD)

N

OMeN

OMe

H

N

N

OMe

OMe

ClO

R

OH

H

O

R

OH

H

O

R

O

20 mol% aNa2CO3, MeCN, 80 °C

NaBr (40 mol%)

20 mol% bNa2CO3, MeCN, 80 °C

NaBr (40 mol%)

H

H

O

O

H

H

O

Me

O

H

H

O

c-C6H13

O

84%, 97% ee

68%, 98% ee

79%, 95% ee

H

H

O

Ph

O

H

H

O

4-BrC6H4

O

H

H

O

3-MeOC6H4

O

78%, 98% ee

83%, 96% ee

77%, 99% ee

H

H

O

O

BnNH

H

O

Et

O

H

H

O

N

O

95%, 98% ee

27%, 97% ee

77%, 99% ee

PhNMe

O


23


a

b

Quinine (Me-MQ)

Quinidine (Me-MQD)

N

OMeN

OMe

H

N

N

OMe

OMe

ClO

R

OH

H

O

R

OH

H

O

R

O

20 mol% aNa2CO3, MeCN, 80 °C

NaBr (40 mol%)

20 mol% bNa2CO3, MeCN, 80 °C

NaBr (40 mol%)

H

H

O

O

H

H

O

Me

O

H

H

O

c-C6H13

O

75%, 93% ee

65%, 99% ee

71%, 99% ee

H

H

O

Ph

O

H

H

O

4-BrC6H4

O

H

H

O

3-MeOC6H4

O

85%, 98% ee

88%, 99% ee

83%, 99% ee

H

H

O

O

BnNH

H

O

Et

O

H

H

O

N

O

85%, 99% ee

NA

87%, 99% ee

PhNMe

O


24


R1 R2

O

O

NR3R1 Br

O

R1 NR3

O Br

R1 NR3

O

Cs2CO3

CsHCO3 + CsBr

R2

O

R1 R2

O

NR3

O

Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641-4644.

Chiral nucleophile generated in catalytic amounts


24


R1 R2

O

O

NR3R1 Br

O

R1 NR3

O Br

R1 NR3

O

Cs2CO3

CsHCO3 + CsBr

R2

O

R1 R2

O

NR3

O

Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641-4644.

Chiral nucleophile generated in catalytic amounts

MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240-3241.

R1 SMe2

O

R2

O NH

R2

N

R2

NMe2S

O Ph

H2O

O

Ph

N

R2

NH

O

Ph

O

R2

H2O

+

Chiral activated electrophile generated in catalytic amounts


25


Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240-3241.

n-Pr O

H

MeS

Ph

OMe

NH

COOH

CHCl3, -10 °C, 85%

20 mol%

CHOn-Pr

PhO

85%, dr 30:1, 95% ee

N CO2

n-Pr

N CO2N CO2

HN CO2

H

Poor iminium geometry controlSelective (Z)-iminium formation


26


Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240-3241.

R1 O

H

MeS

R2

OMe

NH

COOH

CHCl3, -10 °C

20 mol%

CHOR1

R2O

CHOi-Pr

PhO

85%, dr 30:195% ee

CHO

PhO

77%, dr 21:191% ee

AllOCHOMe

PhO

67%, dr >19:190% ee

CHO

PhO

74%, dr 24:196% ee

CHOPh

PhO

73%, dr 33:189% ee

CHO

PhO

63%, dr 43:196% ee

CHOi-Pr

p-C6H4BrO

67%, dr 72:192% ee

CHOi-Pr

p-C6H4OMeO

64%, dr >11:193% ee

CHOi-Pr

O

82%, dr 6:195% ee


27


NH OTMS

PhPh or N

HOTMSR

CHO BrCO2Et

CO2Et+

Cordova, 2007

RCHO

EtO2C CO2EtCatalyst (20 mol%)

Et3N (1 equiv), CH2Cl2rt, 3 - 14 h

50 - 88%14:1 to >25:1 (dr)

93 - 99% eePh, n-Pr, PhCH2CH2-, Me, 4-NO2C6H4CO2Et, 2-naphthyl, CH3CH=CH-, 4-ClC6H4

R1 O

H

MeS

R2

OMe

CHOR1

R2O

+Catalyst (20 mol%)

Arvidsson, 2007

CHCl3

74 - 91%≥98:2 (dr)≥99:1 (ee)

NH

NH

NNN


28

Aggarwal’s Cyclopropanation Reaction

R1

H R3

R2Ph N

NTs

Na

+

Rh2(OAc)4 (1 mol%)BnEt3N+Cl- (20 mol%)

1,4-dioxane, 40 °CChiral Sulfide

Ph

R1R2

R3

S

O

S

O

2a

2b


29


Ph NN

Ts

Na

COOEt

N

O

O+Ph

COOEt

N OOcis:trans 7:1

90% ee

Rh2(OAc)4 (1 mol%)BnEt3N+Cl- (20 mol%)1,4-dioxane, 40 °CChiral Sulfide

S

O

S

O

Ph NN

H

Ph Rh(OOCMe)x

H

S

O

S

O

Ph

COOEt

N

O

O


30

MIRC: From a SAE or SAD Precursor

n-C8H17

OSO

OO

n-C8H17

O3SO CO2Me

CO2Me

n-C8H17CO2Me

CO2Me

NaH, CH2(CO2Me)2

DME, reflux

ClO

MeO2C CO2Me

O

MeO2C

O

Reflux

Na, MeOH

36%, 93% ee

+


A Practical Case

31

OHO

O

EtOP

OEt

OEtO

O

NaOt-Bu (2 equiv)

(2.3 equiv)

DME

Sharpless AsymmetricDihydroxylation

OOH

OH

HO COOEt

H

HO COOH

H

Singh, A. K.; Rao, M. N.; Simpson, J. H.; Li, W. S.; Thornton, J. E.; Kuehner, D. E.; Kacsur, D. J. Org. Proc. Res. Dev. 2002, 6, 618-620.Monday, October 26, 2009

32

Carbenes, Metal Carbenes and Carbenoids

R1 CR2

Carbenes

singlet

triplet

CHCl3 + base:CCl2

R1

R2

LnM CR1

R2

LnM CR1

R2

LnM CR1

R2

(CO)5Cr COMeMeCp2Ti C

HH

Metal Carbene Complex

Nucleophiliccarbene complex(Schrock-type)

Electrophiliccarbene complex

(Fischer-type)

d0, 16 e d6, 18 e

LnM CX

R2R1

Carbenoids

X = I, Br, ClM = Zn, Al, Sm, In

Cyclopropanation

Cyclopropanation (Cycloaddition)

olefin metathesis

X-H insertion

ylide formation (ethers, thioethers, tertiary amines)


33

Free Carbene Chemistry: Generation and Reactivity

OEE

OMOM

OEE

OMOM

ClCl

BrO

HO

F

F

BCF2 + NaBr + CO2

CCl2 + H2O + NaClCHCl3 + NaOH

CHCl3, NaOH (50% aq),

Et3(Bn)N+Cl-

N

FO

COOH

Cl

H2N

F

Sitafloxacin(antibacterial agent)

N

O

MeOCHFBr2, sat. KOHBnNBu3Cl, 92%

N

O

MeO

Br F

60:27:8:5

Matsuo, J.; Tani, Y.; Hayakawa, Y. Chem. Lett. 2004, 33, 464-465.


34

Carbenes, Metal Carbenes and Carbenoids

R1 CR2

Carbenes

singlet

triplet

CHCl3 + base:CCl2

R1

R2

LnM CR1

R2

LnM CR1

R2

LnM CR1

R2

(CO)5Cr COMeMeCp2Ti C

HH

Metal Carbene Complex

Nucleophiliccarbene complex(Schrock-type)

Electrophiliccarbene complex

(Fischer-type)

d0, 16 e d6, 18 e

LnM CX

R2R1

Carbenoids

X = I, Br, ClM = Zn, Al, Sm, In

Cyclopropanation

Cyclopropanation (Cycloaddition)

olefin metathesis

X-H insertion

ylide formation (ethers, thioethers, tertiary amines)


35

Methods for Metal Carbenoid Synthesis

CH2I2 + Zn-Cuether / reflux

IZnCH2I 0.5 [ ICH2ZnCH2I + ZnI2 ]

IZnCH2I ICH2ZnCH2I + ZnI2ZnI2 + CH2N2ether CH2N2

CH2I2 + Et2Zn EtZnCH2ICH2I2

ICH2ZnCH2I

EtI

- 60 oC

Oxidative addition

Diazoalkane with zinc salts

Alkyl exchange

EtI

- 40 oC

Reactivity: CH2Cl2 (ClCH2CH2Cl, hexane, benzene, toluene) > ether > THF > DME

PrZnI IZnCH2I

EmschwillerSimmons-Smith Charette

Wittig Wittig

Furukawa

Denmark

SmIn

ISmCH2i

i-Bu3Al

i-Bu2AlCH2I


36

Generation of New Achiral Zinc Carbenoid Reagents

R ZnX

X = ClClCH2I + Et2Zn

Denmark, S. E. J. Org. Chem. 1991, 56, 6974

X = OC(O)PhCharette

J. Am. Chem. Soc. 2001, 123, 8139

R = Et, CH2I, I X = I


36


R ZnX



X = OC(O)PhCharette

J. Am. Chem. Soc. 2001, 123, 8139


Very good reagent for the cyclopropanationof less reactive alkenes

(such as styrene or halosubstituted alkenes).Very high reactivity

Shi, Y.Tetrahedron Lett. 1998, 39, 8621

J. Org. Chem. 2004, 69, 327

CharetteJ. Am. Chem. Soc. 1998, 120, 5114

Tetrahedron Lett. 1999, 40, 33

F3C OZn I

O

CF3COOH + Et2Zn + CH2I2

Me2NZnCH2I

O


36


R ZnX



X = OC(O)PhCharette

J. Am. Chem. Soc. 2001, 123, 8139


Very good reagent for the cyclopropanationof less reactive alkenes

(such as styrene or halosubstituted alkenes).Very high reactivity

Shi, Y.Tetrahedron Lett. 1998, 39, 8621

J. Org. Chem. 2004, 69, 327

CharetteJ. Am. Chem. Soc. 1998, 120, 5114

Tetrahedron Lett. 1999, 40, 33

F3C OZn I

O

CF3COOH + Et2Zn + CH2I2

Me2NZnCH2I

OO

ZnCH2I

R

CharetteAngew. Chem. Int. Ed. . 2000, 4539.

OH

Cl

Cl

Cl Et2Zn + CH2I2

PhOP

OZnCH2I

OPhO

+

CharetteJ. Am. Chem. Soc. 2005, 12440

PhOP

OH

OPhO + Et2Zn + CH2I2


37

Reactivity of Achiral Zinc Carbenoid Reagents

Electrophilic Carbenoids:• Usually electron rich alkenes react faster• Alkenes bearing electron-withdrawing groups are usually not good substrates

OMe IZnCH2I (1 equiv), Et2O OMe80%

OTMS IZnCH2I (1 equiv), Et2OOTMS

80%


38

Lewis Acidity of Zinc Carbenoids: Lewis Base Directed Cyclopropanation

Hydroxyl- or Lewis base-directed reactions

OH

0,1,2

OH

0,1,2

IZnCH2IZn(CH2I)2

Zn(CH2Cl)2EtZnCH2I

(CH2Cl2, Et2O, ClCH2CH2Cl)ISmCH2I

diastereoselection >20 : 1

RZnO

0,1,2

R = CH2I, I, CH2Cl

Zn(CH2I)2

Zn(CH2I)2

RZnO

0,1,2

ZnR

I


39

Lewis Acidity of Zinc Carbenoids: Lewis Base Directed Cyclopropanation

99%

54%

>23%

R = Bn

R = Me

R = Ac

>99 : 1

>99 : 1

4 : 1

Denmark

Dauben

Sawada

OR OR

+

OR

HO HO

81%

MossZn Cu, CH2I2

Et2O, DME, 65 °C


40

Alternative Synthesis of the anti-Isomer

O LiTMP, Et2O, 0 °C

then rt, > 12 h

OH

70%

OLi

OLi

H


41

Relative Directing Ability of Lewis Basic Groups


41


OH

OBn

OH

OBn

+

OH

OBn


41


OH

OBn

OH

OBn

+

OH

OBn

Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25

Zn(CH2I)2•DME (2 eq), PhMe >25 : 1


41


OH

OBn

OH

OBn

+

OH

OBn



With excess reagent: the weaker complexing group is the one leading to the cyclopropanationWith 1 equiv of the reagent: the stronger complexing group (ROZnR') is the one leading to the cyclopropanation.


41


OH

OBn

OH

OBn

+

OH

OBn




O

OBn

IH2CZn

unreactive


41


OH

OBn

OH

OBn

+

OH

OBn




O

OBn

IH2CZn

unreactive

O

OBn

IH2CZn ZnCH2I

CH2I


41


OH

OBn

OH

OBn

+

OH

OBn




O

OBn

IH2CZn

unreactive

O

OBn

IH2CZn ZnCH2I

CH2I O

BnO

IH2CZn ZnCH2I

CH2I

ZnEt

CH2I

weakercomplex

Strongercomplex


42

Cyclopropanation of Acyclic, Chiral Allylic Alcohols

General rules: Z-alkenes (R ≠ H) are converted to the syn-cyclopropylmethanol with very high ds with a wide range of reagents (minimization of A-1,3 strain; Sm, Zn)

E-alkenes: Need to use EtZnCH2I (minimization of A-1,3 strain). Sm lead to anti-isomer insome cases.

R3 R1

OHR4

R2

R3 R1

OHR4

R2

R3 R1

OHR4

R2

R3 R1

OPGR4

R2

Me

OHMe Zn/Cu, CH2I2

EtherMe

OHMe

Only 1 isomer observedPereyre


43


Me

OH

Me Me

OH

Me Me Me

OH

+

syn:anti

57 : 4388 : 1282 : 1873 : 2725 : 75

Conditions

Zn/Cu, CH2I2, Et2OEt2Zn (5 eq), CH2I2 (5 eq), CH2Cl2Et2Zn (5 eq), CH2I2 (5 eq), Et2O

Zn(CH2I)2 (2 eq), CH2Cl2Sm/Hg, CH2I2, THF

Conditions

syn anti

(%)

(—)(>95%)(50%)(90%)(75%)

Me

OH

Ph7 : 1

Et

OH

Ph7 : 1

Et

OH

Pr110 : 1

Bu

OH

Ph150 : 1

i-Pr

OH

Ph>200 : 1

t-Bu

OH

Ph>200 : 1

Me

OH

Ph

33 : 1Me

Me

OH

>200 : 1

Ph


44


Ph R

OPG OPG

RPh

OPG

RPhCH2Cl2

CF3CO2ZnCH2I (2 equiv)+

TBDMS

TIPS

R

Me

Et

Et

Et

i-Pr

TES

PG Yield (%) anti : synT (°C) t (h)

TES

0

-20

0

0.5

3.0

1.0

87

85

87

98 : 2

> 99 : 1

97 : 3

97 : 3

-20 4.5 88

TES -20 7.0 78 70 : 30

Entry

1

3

2

4

5


45


R2 R4

OGP

R3

R1 OGP

R4R2

R1

R3

OGP

R4R2

R3

R1

CH2Cl2

CF3COOZnCH2I (2 équiv.)+

Ph(CH2)2

OTIPS

Ph Me

OTES OTIPSPh(CH2)2

OTESPh

Ph Et

OTBDMS

84% anti : syn

96 : 41.25 h, 0 °C

88%anti : syn> 99 : 1

4 h, -20 °C

88%anti : syn

99 : 14.5 h, -20 °C

52%anti : syn

97 : 32 h, 0 °C

89%anti : syn25 : 75

6 h, 0 °C

OBn

Cl

OTIPS

Cl

54%anti : syn

8 : 926 h, 25 °C

86%anti : syn

3 : 976 h, 25 °C


46

Transition Structures for the Cyclopropanation of Acyclic Allylic Alcohols

H

MO

RZn I

H

R4

R3

R2

R1

R3

R2

R1

I ZnR

R4

OPGR4

MO

IRZn

H

R3

R2

R1

R3

R2

R1H

ZnRI

OPG

B

R4

anti syn

anti syn

Non-directed Process (or oxonium formation)

Directed Process

Conformational preference of protected allylic alcohols:

(a) Gung, B. W.; Melnick, J. P.; Wolf, M. A.; King, A. J. Org. Chem. 1995, 60, 1947.(b) Khan, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 650.


47

Cyclopropanation of Acyclic, Chiral Allylic Alcohols: Callipeltoside A

O

NHO

O

H

H3C

O

OO

CH3

OH3C

H3CO H

CH3

H3CO

HHH3C

H

OHHCl

H

H

Callipeltoside AIsolation: Minale J. Am. Chem. Soc. 1996, 118, 11085-11088 (marine sponge)

Activity: inhibit in vitro proliferation of KB and P388 cells.Protect cells infected with the HIV virus.

Cl

OO

Et2Zn, CF3COOH, CH2I2CH2Cl2, rt

Cl

OO

1. Dowex H+, MeOH2. Pb(OAc)4, K2CO3

Cl

O

H

Evans Org. Lett. 2001, 3, 503


48

Chiral Auxiliaries for the Cyclopropanation of Alkenes

R2 O

R1

R3

Aux*R2 O

R1

R3

Aux*O

*Aux

R2 M

R1

R3

L*O

R2 YR1

R3

Aux*

Y = B, N, O


49

Carbohydrates as Chiral Auxiliairies

HO R2

R3

R1

HO R2

R3

R1


49


HO R2

R3

R1

HO R2

R3

R1

OOBnO

BnO

BnO

R2

OHR3

R1O

LGBnOBnO

BnO

OAc

LG = OAc, OC(NH)CCl3

Et2Zn, CH2I2

OOBnO

BnO

BnO

R2

OHR3

R1O

OBnOBnO

BnO

R2

OR3

R1

EtZnZn

R

I

Charette JACS 1991, 113, 8166.

>95:5


49


HO R2

R3

R1

HO R2

R3

R1

OOBnO

BnO

BnO

R2

OHR3

R1O

LGBnOBnO

BnO

OAc

LG = OAc, OC(NH)CCl3

Et2Zn, CH2I2

OOBnO

BnO

BnO

R2

OHR3

R1O

OBnOBnO

BnO

R2

OR3

R1

EtZnZn

R

I

Charette JACS 1991, 113, 8166.

>95:5Tf2O, pyr, Δ

HO R2

R3

R1


50

Preparation of Cyclopropylboronic Acids

R2 YR1

R3

Aux*

Y = B, N, O RB

O

OCONMe2

CONMe2

Zn/CuCH2I2

(3 equiv)

RB

O

OCONMe2

CONMe2

10-16:1 dr67%

Et2O

R = Bu, Bn, Ph

CH2N2, Pd(OAc)2Ether

94.5:5.5 er (R = Ph)

RB

O

O

PhOMePh

OMe

PhPh

CH2N2, Pd(OAc)2Ether, 0 ˚C

RB

O

O

PhOMePh

OMe

PhPh

86:14 to 95:5(when R = CH2OH: 70:30)


51

Cross Coupling Reactions of Cyclopropylboronic Acids

RB

OH

OH

RR'

IR' Pd(OAc)2

PPh3, DME, KOt-Bu60-71%

Charette, 1997

ArBr

Pd(PPh3)4K3PO4•3H2O

83-98%

RAr

Deng, 1996

Marsden, 1996ArI and ArBr

Pd(PPh3)4DME, KOt-Bu

60-71%

H2O2

KHCO3R

OH

57-67% Imai, 1990

BrR'

Pd(PPh3)4Tl2CO3, NaOH or Ag2O, KOH

76-82%

RR'

Deng, 2000


52

Synthesis of Amino Cyclopropanes

NR

O

O

R2

NR

O

O

R2

NR

O

O

R2H

H

Minimization of A-1,3 strain

ZnCH2Cl

I

R1 R1 R1

ZnEt2, ICH2Cl

ClCH2CH2Clrt, 48 h

NR

O

O

Ph

80%, 95:5 (dr) (R = n-C5H11)50%, 83:17 (dr) (R = Ph)

NO

O

Bn

60%, >95:5 (dr)

OTBS

Nn-Bu

O

O

Ph

61%, >95:5 (dr)

Ph

NAr

N

O

Ph

92%, 72:28 (dr) (Ar = PMB)70%, 80:20 (dr) (Ar = Ph)

Me

Me

NO

O

Ph

72%, >95:5 (dr)

Me

NO

O

Ph

40%, 88:12 (dr)

Et

MeNO

O

Ph

80%, >95:5 (dr)

NO

O

Ph

57%, >95:5 (dr) (R = n-C6H13)64%, >95:5 (dr) (R = Ph)

RNO

O

Ph

>95%, 86:14 (dr)

Ph OBn

Song, Z. L.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C. H.; Tang, Y. Angew. Chem. Int. Ed. 2007, 46, 4069.Monday, October 26, 2009

53

Synthesis of Amino Cyclopropanes

NR

O

O

R2

NR

O

O

R2

NR

O

O

R2H

H

Minimization of A-1,3 strain

ZnCH2Cl

I

R1 R1 R1

ZnEt2, ICH2Cl

ClCH2CH2Clrt, 48 h

NO

O

Ph

>95%, 86:14 (dr)

Ph OBn

10% Pd/C, H2 (60 psi)

AcOH, 48 h, rt, and thenHCl (1.25 M in MeOH) H2N OH


54

Enantioselective Cyclopropanation of Alkenes

R2HO

R3

R1

R2HO

R3

R1

R2HO

R3

R1

+

R4 R2

R3

R1

R4 R2

R3

R1

R4 R2

R3

R1

+

RZnCH2I

RZnCH2I

Chiral Additive

R1, R2, R3, R4 = H, alkyl, aryl

BocNN

O CO2Me

Shi JACS 2003, 125,13632 (1.2 equiv)Shi Tet. Lett. 2005, 2737 (0.25 equiv)

ICH2Zn

OO

PO

OZnCH2I

Ar

Ar

(1.2 equiv)(0.1 equiv)

Charette JACS 2005, 12440Ar =

OB

O

Me2NOC CONMe2

Bu

Stoichiometric Chiral AdditiveCharette, 1994

Chiral catalyst (0.1 equiv)Kobayashi, Denmark,1992

NHSO2Me

NHSO2Me

Chiral catalyst (0.2 equiv)Charette, 2000

OTi

O

OO

i-PrO Oi-Pr

PhPhPh

Ph


55

Cyclopropanation of Allylic Alcohols with Stoichiometric Chiral Ligands

R2

R1

R3

OH R2

R1

R3

OH

Ph OHOH

Bu3Sn OHBu3Sn OH

95% yield94% ee

BnO

93% yield91% ee

I OHI OH

88% yield90% ee73% yield

90% ee83% yield90% ee71% yield

83% ee

OH

85% yield94% ee

OH

OTIPS85% yield88% ee

Ph OH

96% yield85% ee

OB

O

Me2NOC CONMe2

Bu

2. 2 equiv Zn(CH2I)2 or Zn(CH2I)2•DME

1. 1.1 equiv


56

Transition Structure for the Cyclopropanation

OB

O

Me2NOC CONMe2

Bu

R2 OH+

Zn(CH2I)2(1 equiv)

OB

O

Me2NOC CONMe2

Bu

R2 O

+

ZnCH2I

OB

O

Me2NOC CONMe2

Bu OZn R2

OB

O

Me2NOC CONMe2

Bu OZn R2

I

HighlyDiastereoselective

STEP A

STEP B

STEP C

R1

R3

R1

R3

R1R1

R3

I

R3

0 o C to rt

(CH3I)


57


R2HO

R3

R1

R2HO

R3

R1

R2HO

R3

R1

+

R4 R2

R3

R1

R4 R2

R3

R1

R4 R2

R3

R1

+

RZnCH2I

RZnCH2I

Chiral Additive


BocNN

O CO2Me


ICH2Zn

OO

PO

OZnCH2I

Ar

Ar



OB

O

Me2NOC CONMe2

Bu



NHSO2Me

NHSO2Me


OTi

O

OO

i-PrO Oi-Pr

PhPhPh

Ph


58

Kobayashi/Denmark Catalytic System

Ph OHNHSO2Me

NHSO2Me

H

H

(0.1 equiv)

Et2Zn (1.1 equiv), ZnI2 (1 equiv),then add to:

Et2Zn (1 equiv), CH2I2 (2 equiv),CH2Cl2, 0˚

Ph OH

89% ee92% yield

Ph OZnEt +

Et2Zn(1.0 equiv)

NHSO2CH3

NHSO2CH3

H

H

(0.1 equiv)

Zn(CH2I)2 (1.0 equiv)

+ Et2Zn(0.1 equiv)

CH2Cl2, -20°C

ZnI2(1.0 equiv) +

ZnI2(1.0 equiv)

Zn(CH2I)2(1.0 equiv)

+ IZnCH2I(2 equiv)


59


Ph OH

Me

85%

43%

MeMe OH

Ph

85%

16%

Me

R1 OH

1. Et2Zn (1.1 equiv) / CH2Cl2, 0°C2. ZnI2 (0.1 equiv) / CH2Cl2, 0°C

NHSO2CH3

NHSO2CH3

H

H

0.1 equiv

R1 OH

3. Zn(CH2I)2 (1.0 equiv) / CH2Cl2, 0°C+

R2

R3

R2

R3

Ph OH

Me

91%Yield:ee: 73% (89%)

Me OH

98%

66% (82%)

PhPh OH

90%

5%

MePh OH

91%

80% (89%)

OH

89%

81% (89%)

Ph

OH

81%

81%

Ph

OH

93%

72%

Ph

Yield:ee:

Me OH

Ph

88%

81%

OH

94%

79%

PhOH

97%

10%

Me

PhMe

OH

98%

26%

Me

Ph

OH

90%

50%

Ph

Me

Yield:ee:

ee with 2 equiv of ZnI2


60

Basic Principle for Catalytic Effect of Chiral Ligand: Lewis Acid

HH

HH

Zn CH2

ClZn

Cl

Cl

Cl

NakamuraLewis acidActivation

Intermolecular LA

HH

HH

Zn

H2C

I

Classical Model

I

HH

HH

Zn CH2

OO

R

R

Intramolecular LA

HH

HH

H O

OO

R

Epoxidation Model

Charette, A. B.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367 (Lewis-Acid catalysis)Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844 (DFT Studies)


61


Three zinc metal centers are involved (catalyst, zinc alkoxide, reagent)

Lewis acid activation of the iodide group of IZnCH2I

Bipyridine complex is catalytically active in the presence of ZnI2


62


R2HO

R3

R1

R2HO

R3

R1

R2HO

R3

R1

+

R4 R2

R3

R1

R4 R2

R3

R1

R4 R2

R3

R1

+

RZnCH2I

RZnCH2I

Chiral Additive


BocNN

O CO2Me


ICH2Zn

OO

PO

OZnCH2I

Ar

Ar



OB

O

Me2NOC CONMe2

Bu



NHSO2Me

NHSO2Me


OTi

O

OO

i-PrO Oi-Pr

PhPhPh

Ph


63

Catalytic Asymmetric Cyclopropanation of Allylic Alcohols

OO

MeMe

OTi

O

i-PrO Oi-Pr

Ph

Ph

Ph

Ph

Ph OH2. Zn(CH2I)2, (1 equiv), -78 ˚C3. -78 °C to 0 °C (25 ˚C)

25 mol %

1.

Ph OH

1. Cinnamyl alcohol, -40 ˚C2. Zn(CH2I)2, -40 ˚C3. Taddol-Ti(Oi-Pr)2 + 4A Mol. sieves4. Warm to 0 ˚C (1.5h)

93% ee

OH OHMe

Me

OH

OH

OH

Me

OH

91% ee (86%)

83% ee (80%)

93% ee (85%)91% ee (80%) 87% ee (80%)

84% ee (75%)

R

R=H76% ee (75%)R=Cl91% ee (90%)

OH

50% ee (65%)

Me

R=OMe

OH

66% ee (62%)

Me OH

Me Pr OH

OH

66% ee (71% ee) (89%)

70% ee (60%)

60% ee (74% ee) (68%)

Ph OH

63% ee (68%)

OH

89% ee(80%)

83% ee(89%)

O

NTs

OH


64

Enantioselective Cyclopropanation of Allylic Alcohols

R2HO

R3

R1

R2HO

R3

R1

R2HO

R3

R1

+RZnCH2I

Chiral Additive

OB

O

Me2NOC CONMe2

Bu



NHSO2Me

NHSO2Me


OTi

O

OO

i-PrO Oi-Pr

PhPhPh

Ph

Broadest scope Best substrates:trans-disubstituted allylic alcohols

Best substrates:aryl-substituted allylic alcohols


65


R2HO

R3

R1

R2HO

R3

R1

R2HO

R3

R1

+

R4 R2

R3

R1

R4 R2

R3

R1

R4 R2

R3

R1

+

RZnCH2I

RZnCH2I

Chiral Additive


BocNN

O CO2Me


ICH2Zn

OO

PO

OZnCH2I

Ar

Ar



OB

O

Me2NOC CONMe2

Bu



NHSO2Me

NHSO2Me


OTi

O

OO

i-PrO Oi-Pr

PhPhPh

Ph


66

Enantioselective Cyclopropanation of Unfunctionalized Alkenes

R4

R3

R1BocHN

N

O CO2Me

(1.2 equiv)

Et2Zn (2.3 equiv), CH2I2 (3.3 equiv)CH2Cl2, 0 °C, 24h

R4

R1 83% yield90% ee

(99% after recrystallisation)

Shi JACS 2003, 125,13632.

R3

R2R2

71%72% ee

PhPh

83%75% ee

Me

Me

MeMe

43%, 69% ee

OMe

71%, 75% ee

n-Pr

78%, 90% ee

Ph

83%, 90% ee87%, 89% ee

Ph

84%, 78% ee85%, 77% ee

Me

71%, 91% ee60%, 89% ee

71%, 79% ee52%, 78% ee

OBz

PhMe

68%, 85% ee96%, 87% ee

OTMS


67

Chiral Iodomethylzinc Phosphate Reagents

OO

PO

OH

Ar

ArEt2Zn (10 mol%), CH2I2 (10 mol%)CH2Cl2, 0 ° C, 5h

Ph Ph

3. 1.0M H3PO4, NH4F, 40 °C, 1.5h

1.

(10 mol%)

> 95% conversion88% ee

2. Zn(CH2I)2 (0.9 equiv), DME (0.54 equiv)

OTES OH

8

0 °C,42 h

OO

PO

OH

Ar

Et2Zn (1.2 equiv), CH2I2 (1.2 equiv)CH2Cl2, 0 °C, 38 h

PhR

(1.2 equiv)

PhR

Ar

Ar =

R = CH2OMe, CH2OBn, CH2OTES 90-92% eeR = CH2CH2OBn 93% ee>90% yield


68

Zinc Carbenoids for the Preparation of 1,2,3-Substituted Cyclopropanes?

R1R2

R3

R1R2

R1R2

RZnCH2I

R1 R2

RZn I

R3H

Stability?Diastereoselectivity?Enantioselectivity?

I I

R3H


69

Synthesis of 1,2,3-Substituted Cyclopropane Derivatives

HO R1

R2CHI2, Et2Zn

OB

O

Me2NOC CONMe2

Bu

R1

R2

HO

er 19-99:1dr 10->99:1

Ph

Me

HO

er 99:1dr >99:1

With MeCHI2:

Ph

Me

HO

er 19:1dr 14:1

Me

Me

HO

er 32:1dr >50:1

OBn Pr

Me

HO

er 28:1dr 10:1

Et

Me

HO

er 32:1dr 15:1

Charette, A. B.; Lemay, J. Angew. Chem. Int. Ed. 1997, 36, 1090-1092.Monday, October 26, 2009

Tandem Cyclopropanation with gem-Dizinc Reagent/Suzuki Coupling

70

OB

O

Me2NOC CONMe2

Bu

1. Et2Zn (1 equiv)2. Dioxaborolane (1.2 equiv)3. EtZnI (4.2 equiv) CHI3 (2.1 equiv) Et2O (8.4 equiv)

CH2Cl2, -78 °C to -40 °C, 24 h4. Pd(PPh3)4 (5 mol%) PhI (2 equiv), KOH 3 N (6 equiv) THF, 65 °C, 16 h

R2 OH

R1

R3

R2OH

R1

R3Ph

OH

Ph

Ph

59%, 92% eedr: >20 : 1

OH

p-ClC6H4

Ph

58%, 94% eedr: >20 : 1

OH

o-ClC6H4

Ph

59%, 91% eedr: >20 : 1

OH

p-MeOC6H4

Ph

59%, 88% eedr: >20 : 1

OH

m-MeOC6H4

Ph

49%, 89% eedr: >20 : 1

OH

Pr

Ph

51%, 94% eedr: >20 : 1

OH

Ph

61%, 91% eedr: >20 : 1

OH

c-C6H11

Ph

71%, 93% eedr: >20 : 1

OH

Ph

70%, 94% eedr: >20 : 1

OH

Ph

56%, 96% eedr: >20 : 1

Ph

Me

Me

Me Pr

OH

Ph

51%, 94% eedr: >20 : 1

TIPSO


Enantioselective Iodo-cyclopropanation vs Zinco-Cyclopropanation

71

Lucie Zimmer EtZnI•OEt2 (2.4 equiv)CHI3 (1.2 equiv)

-40 °C IZn I

ZnI


Enantioselective Iodo-cyclopropanation vs Zinco-Cyclopropanation

71

Lucie Zimmer EtZnI•OEt2 (2.4 equiv)CHI3 (1.2 equiv)

-40 °C IZn I

ZnI

Ph OZnI

OB

O

Me2NOC CONMe2

Bu

1. EtZnI•2Et2O (2.4 equiv)2. CHI3 (1.2 equiv), -40 °C, 10 min3. alkoxide + Dioxaborolane (1.1 equiv)

-40 °C for 20 h, CH2Cl2

Ph

BBu

OAcOH

PhOH

89%, 95% ee

I2, NaOMeMeOH, reflux Ph

OH

I 50%, 95% ee

PhOH

Ph 50%, 95% ee

Pd(PPh3)4 (1 mol%)PhI (2 equiv)

KOH (6 equiv), THF65 °C, 16 h

Ph OH

EtZnI•2Et2O

(IZn)2CHIPh OZnI

IZnCH2I+

Ph

ZnI

OBBu(OR)2


Tandem Cyclopropanation with gem-Dizinc Reagent/Suzuki Coupling

72

OB

O

Me2NOC CONMe2

Bu

1. Et2Zn (1 equiv)2. Dioxaborolane (1.2 equiv)3. EtZnI (4.2 equiv) CHI3 (2.1 equiv) Et2O (8.4 equiv)

CH2Cl2, -78 °C to -40 °C, 24 h4. Pd(PPh3)4 (5 mol%) ArI (2 equiv), KOH 3 N (6 equiv) THF, 65 °C, 16 h

OH OH

Ar

OH

54%, 94% eedr: >20 : 1

Me

OH

75%, 94% eedr: >20 : 1

OMe

OH

61%, 94% eedr: >20 : 1

NO2

OH

69%, 94% eedr: >20 : 1

OH

61%, 94% eedr: >20 : 1

Cl

OH

43%, 94% eedr: >20 : 1

OMe


Stereoselecive Synthesis of 1,2,3-Substituted Cyclopropanes

73

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

H

R O B(OR)2Bu

HH



73

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

H

R O B(OR)2Bu

HH

R

ZnI

O B(OR)2Bu

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

ZnI



73

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

Me

R O B(OR)2Bu

Me

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

H

R O B(OR)2Bu

HH

R

ZnI

O B(OR)2Bu

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

ZnI



74

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

I

R O B(OR)2Bu

I

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

H

R O B(OR)2Bu

HH

R

ZnI

O B(OR)2Bu

AmideO

BO

OMe2N

O

Bu

R

IZn

I

H

ZnI


Enantioselective Cyclopropanation: Scope-1

75

OB

O

Me2NOC CONMe2

Bu

1. CHI3 (4.4 equiv)2. Et2Zn (2.2 equiv)3. Dioxaborolane (1.1 equiv) allylic alcohol, rt, 15 - 24 h

R2 OH

R1

R3

R2OH

R1

R3I

OH

Ph

66%, 98% eedr: 9 : 1

OH

p-ClC6H4

69%, 98% eedr: 9 : 1

OH

p-NO2C6H4

64%, 97% eedr: 7 : 1

OH

p-MeOC6H4

55%, 98% eedr: 7 : 1

OH

m-MeOC6H4

70%, 96% eedr: 7 : 1

OH

2,4,6-Me3C6H2

73%, 96% eedr: 9 : 1

OH

o-ClC6H4

81%, 98% eedr: 12 : 1

I I I I

II I

IZnI

HI


Enantioselective Cyclopropanation: Scope-2

76

OB

O

Me2NOC CONMe2

Bu

1. CHI3 (4.4 equiv)2. Et2Zn (2.2 equiv)3. Dioxaborolane (1.1 equiv) allylic alcohol, rt, 15 - 24 h

R2 OH

R1

R3

R2OH

R1

R3I

OH

53%, 98% eedr: 4 : 1

OH

Pr

66%, 96% eedr: 6 : 1

OH

63%, 96% eedr: 5 : 1

59%, 95% eedr: 6 : 1

OH

Ph

68%, 93% eedr: >20 : 1

OH

c-C6H11

67%, 98% eedr: 4 : 1

OH

Pr

42%, 99% eedr: 3.5 : 1

II I

II I

PhTBDMSO

OHI

Cl

OH

65%, 91% eedr: 20 : 1

I

Ph

MeMe


Functionalization of Iodocyclopropanes

77

OBn

Ph

I

t-BuLi, Et2O-78 °C then CO2

t-BuLi, Et2O-78 °C then MeI

1. t-BuLi, Et2O2. ZnBr23. Pd2(dba)3, 120 °C (o-tolyl)3P

MeI

I

F

I

MeO2C

OBn

Ph

HOOCOBn

Ph

Me

OBn

Ph

F

OBn

Ph

MeO2C

OBn

Ph

Me80%

65%

84%

75% 97%


The Synthesis of Cyclopropane Derivatives

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