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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
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
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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
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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”
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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:
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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%
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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
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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
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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
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9
Strategies in Stereoselective Synthesis
R1R2
Advantages
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
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9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
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9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
Monday, October 26, 2009
9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
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9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable
Disadvantage
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
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9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable
Disadvantage• 3-step for 1 transformation
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
Monday, October 26, 2009
9
Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable
Disadvantage• 3-step for 1 transformation
Chiral Stoichiometric Reagent
R1 R2R1 R2
Chiral reagent(≥1.0 equiv)
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
Monday, October 26, 2009
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Strategies in Stereoselective Synthesis
R1R2
Advantages• The desired diastereomer can be enriched (crystallization, chromatography)• Cheap reagent (relative to other strategies)• Reliable
Disadvantage• 3-step for 1 transformation
Chiral Stoichiometric Reagent
R1 R2R1 R2
Chiral reagent(≥1.0 equiv)
Chiral Stoichiometric Reagent
R1 R2R1 R2
Achiral reagent(≥1.0 equiv)
Chiral ligand (<0.1 equiv)or
Chiral catalyst (<0.1 equiv)
Chiral Auxiliary Approach
R1 R2
R1 R2Chiral groupR1 R2Chiral group
R1 R2Chiral group+
Diastereoisomers(>90:10)
>50% <50%
Cleavage of Chiral auxiliary
R1 R2
Monday, October 26, 2009
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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
Monday, October 26, 2009
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.
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
+
Monday, October 26, 2009
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.
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
22
Catalytic Asymmetric MIRC Reaction: Intramolecular Version
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
Monday, October 26, 2009
23
Catalytic Asymmetric MIRC Reaction: Intramolecular Version
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
Monday, October 26, 2009
24
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
Gaunt, M. J. Angew. Chem. Int. Ed. 2004, 43, 4641-4644.
Chiral nucleophile generated in catalytic amounts
Monday, October 26, 2009
24
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
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
Monday, October 26, 2009
25
Catalytic Asymmetric MIRC Reaction
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
Monday, October 26, 2009
26
Catalytic Asymmetric MIRC Reaction
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
Monday, October 26, 2009
27
Catalytic Asymmetric MIRC Reaction
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
Monday, October 26, 2009
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
Monday, October 26, 2009
29
Catalytic Asymmetric MIRC Reaction
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
Monday, October 26, 2009
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
+
Monday, October 26, 2009
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)
Monday, October 26, 2009
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.
Monday, October 26, 2009
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)
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
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
Monday, October 26, 2009
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
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
Monday, October 26, 2009
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%
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
40
Alternative Synthesis of the anti-Isomer
O LiTMP, Et2O, 0 °C
then rt, > 12 h
OH
70%
OLi
OLi
H
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25
Zn(CH2I)2•DME (2 eq), PhMe >25 : 1
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25
Zn(CH2I)2•DME (2 eq), PhMe >25 : 1
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.
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25
Zn(CH2I)2•DME (2 eq), PhMe >25 : 1
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.
O
OBn
IH2CZn
unreactive
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25
Zn(CH2I)2•DME (2 eq), PhMe >25 : 1
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.
O
OBn
IH2CZn
unreactive
O
OBn
IH2CZn ZnCH2I
CH2I
Monday, October 26, 2009
41
Relative Directing Ability of Lewis Basic Groups
OH
OBn
OH
OBn
+
OH
OBn
Et2Zn (10 eq), CH2I2 (10 eq), PhMe 1 : >25
Zn(CH2I)2•DME (2 eq), PhMe >25 : 1
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.
O
OBn
IH2CZn
unreactive
O
OBn
IH2CZn ZnCH2I
CH2I O
BnO
IH2CZn ZnCH2I
CH2I
ZnEt
CH2I
weakercomplex
Strongercomplex
Monday, October 26, 2009
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
Monday, October 26, 2009
43
Cyclopropanation of Acyclic, Chiral Allylic Alcohols
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
Monday, October 26, 2009
44
Cyclopropanation of Acyclic, Chiral Allylic Alcohols
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
Monday, October 26, 2009
45
Cyclopropanation of Acyclic, Chiral Allylic Alcohols
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
Monday, October 26, 2009
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.
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
49
Carbohydrates as Chiral Auxiliairies
HO R2
R3
R1
HO R2
R3
R1
Monday, October 26, 2009
49
Carbohydrates as Chiral Auxiliairies
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
Monday, October 26, 2009
49
Carbohydrates as Chiral Auxiliairies
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
Monday, October 26, 2009
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)
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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)
Monday, October 26, 2009
57
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
Monday, October 26, 2009
57
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
Monday, October 26, 2009
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)
Monday, October 26, 2009
59
Kobayashi/Denmark Catalytic System
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
Monday, October 26, 2009
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)
Monday, October 26, 2009
61
Kobayashi/Denmark Catalytic System
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
Monday, October 26, 2009
62
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
Monday, October 26, 2009
62
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
Monday, October 26, 2009
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
Monday, October 26, 2009
64
Enantioselective Cyclopropanation of Allylic Alcohols
R2HO
R3
R1
R2HO
R3
R1
R2HO
R3
R1
+RZnCH2I
Chiral Additive
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
Broadest scope Best substrates:trans-disubstituted allylic alcohols
Best substrates:aryl-substituted allylic alcohols
Monday, October 26, 2009
65
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
Enantioselective Iodo-cyclopropanation vs Zinco-Cyclopropanation
71
Lucie Zimmer EtZnI•OEt2 (2.4 equiv)CHI3 (1.2 equiv)
-40 °C IZn I
ZnI
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
R
ZnI
O B(OR)2Bu
AmideO
BO
OMe2N
O
Bu
R
IZn
I
H
ZnI
Monday, October 26, 2009
Stereoselecive Synthesis of 1,2,3-Substituted Cyclopropanes
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
Monday, October 26, 2009
Stereoselecive Synthesis of 1,2,3-Substituted Cyclopropanes
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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
Monday, October 26, 2009
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%
Monday, October 26, 2009