A Formidable Challenge: ���Asymmetric Halogenation in
Organic Synthesis
Frontiers in Chemistry Seminar
Filip R. Petronijević The Wipf Group
December 10th, 2011
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Highlights in Asymmetric Halogenation
ClCl
OSO3H
Cl
Cl
ClCl
Chlorosulpholipid cytotoxin
C8H17OSO3
-
ClCl
Cl
OSO3-
Cl
Cl
Cl
Malhamensilipin A
C6H13OSO3
-ClCl
Cl
OSO3-
Cl Cl
Cl
Danicalipin A
Nilewski, C.; Geisser, R.W.; Carreira, E.M.! Nature 2009, 457, 573.!
Shibuya, G.M.; Kanady, J.S.; Vanderwal, C.D.! J. Am. Chem. Soc. 2008, 130, 12514.!
Yoshimitsu, T.; Nakatani, R.; Kobayashi, A.; Tanaka, T.! Org. Lett. 2011, 13, 908.!
Snyder, S.A.; Tang, Z.-Y.; Gupta, R.!J. Am. Chem. Soc. 2009, 131, 5744.! Nicolaou, K.C.; Simmons, N.L.; Ying, Y.; Heretsch, P.M.; Chen, J.S.!
J. Am. Chem. Soc. 2011, 133, 8134.!
O
O
O
OH
MOMO
BH3•THF, 1
Cl2, THF, -78 °C
OHOH
1
O
O
O
OH
MOMO
ClCl
93%, 87% e.e. (95% e.e. after crystalization)
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The Need for Halogenated Compounds
N
NN
NO
NH2
HO OH
FH2NO2S
Nucleocidin
O
Cl
ClH
HO
Br H
Rogioloxepane C
O
OH
BrH
(E )- Prelauretin
O
BrH
O•
Br
H
Laurallene
CH3Br
HO H H
Prepinnaterpene
OOHCCH3
ClCH3
Laurencial
O
Cl
Laurenyne
O HH Br
AcO
Kumausyne
O Cl
O
BrManeonene B
OCH3
CH3OH
BrCl
Aplysiapyranoid D
O O
O O OH
Br
H3C
CH3 OH H3CH
H
H3C
OH
Venusatriol
HN CH3
CH3
CH3
HO2C
OCH3
ClVirantmycin
NH
H
Cl CH3
H3CH3C H NC
Hapalindole G
N
HNCl
HO
NH
HNNHHO
NH
HN
ONH
Br
Br
NHO
HN
BrBr
H
Axinellamines
NH
NClHO
NH2
HN
NNH2
H2N
H
NN
O
Palau'amine
“Many organisms use organohalogens in chemical defense, in food gathering, or as regulatory hormones. … The chlorine atoms in the clinical antibiotic vancomycin are crucial in enforcing the requisite conformation for receptor binding. … Not counting terrestrial organisms, the 500.000 species of marine animals, plants, and bacteria guarantees that thousands of new organohalogen compounds are awaiting discovery. Of the 4.000 species of bryozoans, fewer than 20 have been examined for their chemical content. … Chlorine – once called the “devil’s element” – and the other halogens play an important role in natural processes, both biogenic and abiogenic … … As organohalogen natural products research unfolds, new antibiotics, anticancer and antifungal agents, pesticides, herbicides, and other important medicinal drugs will be discovered”
1. For general reviews, see: a) Gribble, G.W. Acc. Chem. Res. 1998, 31, 141-152. b) Gribble, G.W. Progress in the Chemistry of Organic Natural Products 1996, 68, 1-498. 2. For review on fluorinated natural products, see: Harper, D.B.; OʼHagan, D.O. Nat. Prod. Rep. 1994, 11, 123-133.!
Gribble, G. W. Acc. Chem. Res. 1998, 31, 141-152.!
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Halogenated Compounds in Nature
N
NN
NO
NH2
HO OH
FH2NO2S
Nucleocidin
O
Cl
ClH
HO
Br H
Rogioloxepane C
O
OH
BrH
(E )- Prelauretin
O
BrH
O•
Br
H
Laurallene
CH3Br
HO H H
Prepinnaterpene
OOHCCH3
ClCH3
Laurencial
O
Cl
Laurenyne
O HH Br
AcO
Kumausyne
O Cl
O
BrManeonene B
OCH3
CH3OH
BrCl
Aplysiapyranoid D
O O
O O OH
Br
H3C
CH3 OH H3CH
H
H3C
OH
Venusatriol
HN CH3
CH3
CH3
HO2C
OCH3
ClVirantmycin
NH
H
Cl CH3
H3CH3C H NC
Hapalindole G
N
HNCl
HO
NH
HNNHHO
NH
HN
ONH
Br
Br
NHO
HN
BrBr
H
Axinellamines
NH
NClHO
NH2
HN
NNH2
H2N
H
NN
O
Palau'amine
OH
Cl
O O Cl
HO OH
NH
O HN
OO
ONH
NH
NH2O
OHHO
NH
O
HO2C
O HN
OO OHOH
OHOONH2
OH
Vancomycin
NNH
HN OO
Cl ClO OH
HOMeO
HO
Rebeccamycin
HNOO
HN
O
NH HN
O
OHNHN
O
O
NHO
HN
O
HO
NH2
NH2
NH
NH
NH2HO2C OH
ClOH
O
HN
OOH
C9H19
Syringomycin
OCH3BrBr
BrN
OHConvolutamine A
O
OHII
II
CO2H
NH2Thyroxine
• To date, more than 4500 halogenated natural products have been discovered
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.;!Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
• 2300 organochlorines, 2100 organobromines, 120 organoiodines, and 30 organofluorines
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Nature’s Inventory of Halogenation Catalysts Fluorinating Enzymes: Nonoxidative Construction of the C-F Bond
N
NN
NO
NH2
HO OH
S+
CO2HH2N
N
NN
NO
NH2
HO OH
F
S
CO2HH2N
+
F-
fluorinase
1. Dong, C.; Huang, F.; Deng, H.; Schaffrath, C.; Spencer, J. B.; OʼHagan, D.; Naismith, J. H. Nature 2004, 427, 561-565. 2. Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
F-+ -
+ -+-
+-
+-
+- +-
+-
"F-" n H2O + F- (naked) !H >> 0
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Nature’s Inventory of Halogenation Catalysts Oxidative Logic in Chlorinating, Brominating and Iodinating Enzymes
Halogena(ng enzymes use four different cofactors
H2O2 as cosubstrate
haloperoxidases!O2 as reducible cosubstrate
O2-dependent halogenases!
NH
RN
NH
HN O
OFADH2
FeIIOO
O
-O2C
NCl
HNO2
N
NH
Nonheme iron
N
N N
NFeIII
Heme iron
HN N VO-
OHO--O
Vanadium
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.;!Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
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Nature’s Inventory of Halogenation Catalysts Oxidative Logic in Chlorinating, Brominating and Iodinating Enzymes
Halogena(ng enzymes use four different cofactors
H2O2 as cosubstrate
haloperoxidases!
N
N N
NFeIII
Heme iron
HN N VO-
OHO--O
Vanadium
N
N N
NFeIII H2O2 N
N N
NFeIV
OX- N
N N
NFeIII
O X
HN N VO-
OHO--O
H2O2HN N V
OOO--O X- HN N V
O-OO--O
X
O2 as reducible cosubstrate
O2-dependent halogenases!
NH
RN
NH
HN O
OFADH2
FeIIOO
O
-O2C
NCl
HNO2
N
NH
Nonheme iron
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.;!Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
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Nature’s Inventory of Halogenation Catalysts Oxidative Logic in Chlorinating, Brominating and Iodinating Enzymes
O2 as reducible cosubstrate
O2-dependent halogenases!
NH
RN
NH
HN O
OFADH2
FeIIOO
O
-O2C
NCl
HNO2
N
NH
Nonheme iron
NH
RN
NH
HN O
O
O2
NH
RN
NH
N O
OOHO
Cl- HOCl
FeIIOO
O
-O2C
NCl
HNH2O
N
NH
O2 FeIIOO
O
-O2C
NCl
HNO2
N
NH
FeIIOO
-O2C
NCl
HNO
N
NHCO2
H2C
H
R
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.;!Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
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Heme-Dependent Haloperoxidases
NN N
NFeIII
S-Cys
O O
E183
H
N
N
H105
H O O H
NN N
NFeIII
S-Cys
O OH
E183
O OH
N
N
H105
H
NN N
NFeIV
S-Cys
O
Cl-
NN N
NFeIII
S-Cys
O ClHOH
H
+
HOCl
O
OHII
II
CO2H
NH2Thyroxine
NN N
NFeIII
Nu
O I
mammaliancells
OHO OOCl Cl
Cladariomycinfungal cells
• the halogenating species are electropilic • formation of these species is rate-determining steps
• HOCl is the electrophilic agent
• Cl2 and HOCl could be detected in the absence of substrate
1. Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378. 2. Morrison, M.; Schonbaum, G. R. Annu. Rev. Biochem. 1976, 45, 861-888. 3. Corbet, M. D.; Chipko, B. R.; Baden, D. G. Biochem. J. 1978, 175, 353-360. !
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Non-heme Iron Halogenases for Unactivated Carbon Sites
HNOO
HN
O
NH HN
O
OHNHN
O
O
NHO
HN
O
HO
NH2
NH2
NH
NH
NH2HO2C OH
ClOH
O
HN
OOH
C9H19
Syringomycin
HN
HOH
O
Thr
SyrB2halogenase
FeII OHisCl O O
CO2-His
H2O H3CR H2O
FeII OHisCl O O
CO2-His
H3CR
O2
FeII OHisCl O O
CO2-His
OO
H3CR
FeIV OHisCl
CO2-His
O
H2CR
H
OCO2
FeIII OHisCl
CO2-His
OH
H2CR
OCO2
H2CR
Cl
+ succinate + CO2
Cl- + !"KG
1. Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378. 2. Krebs, C.; Fujimori, D. G.; Walsh, !C. T.; Bollinger, Jr., J. M. Acc. Chem. Res. 2007, 40, 484.!
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Manganese Porphyrins Catalyze Selective C-H Bond Halogenations
H Cl 38%
NN N
NMn
Cl
Mn(TPP)Cl
NN N
NMn
Cl
Mn(TMP)Cl
H Cl 12%
Cl
28%
R HMn(TPP)Cl (2 mol%)
PTC (4 mol%), DCM, rtNaOCl
PTC = Bu4N+Cl-
R Cl
H
H
H
Cl
Cl
Cl
69%
57%
74%
H Cl 31%Mn(TMP)Cl
Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847-12849. !
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Manganese Porphyrins Catalyze Selective C-H Bond Halogenations
H Cl 38%
NN N
NMn
Cl
Mn(TPP)Cl
NN N
NMn
Cl
Mn(TMP)Cl
H Cl 12%
Cl
28%
R HMn(TPP)Cl (2 mol%)
PTC (4 mol%), DCM, rtNaOCl
PTC = Bu4N+Cl-
R Cl
H
H
H
Cl
Cl
Cl
69%
57%
74%
H Cl 31%Mn(TMP)Cl
38% (19%)
58% (76%)
4% (5%)
Mn(TPP)Cl/NaOCl (55%)(Mn(TMP)Cl/NaOCl (51%))
22% (equatorial:axial = 15:1)
33% (equatorial:axial = 1:2)Mn(TMP)Cl (15 mol%)
NaOCl (3 equiv.)
cholestane
O
O42%
6%
sclareolide
Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847-12849. !
Steric effects lead to selective chlorination
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Manganese, Iron or Nickel: Site-Selective Halogenations
MnIII
L
MnV
L
O
MnIV
L
OH
MnIV
L
O Cl
ClO-HO-
R H
R•
L = O, OH, OCl
R•
R Cl
Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847-12849. !
NN N
NMn
Cl
Mn(TPP)Cl
NN N
NMn
Cl
Mn(TMP)Cl
Cong, Z.; Kurahashi, T.; Fuijii, H. Angew. Chem. Int. Ed. 2011, 50, 1-6. !
NN N
NFe
OF
F
F
FFF
F
FF
LFF
FF
F
FF
F
F
F
L = C6F5CO2L = NO3
• +
((TPFPP+•)FeIVO(L))
O
N N
ONi
Ni(salen)
Querci, C.; Strologo, S.; Ricci, M. Tetrahedron Lett. 1990, 31, 6577-6580.!
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Conventional Halogenation Methods
Nucleophilic Displacement
R R'
OR
R R'
BrBr-
or CBr4/PR3
R R'O
LA/Br-
R R'
OH
Br
R'
R
Br
R
R' Br
O
R Cl
O
OMeClROR
BromoetherificationOxymercuration-Bromination
Cycloaddition/SigmatropicRearrangement
OH "Br+"OBr
OH Hg(OTf)2OTfHg
LiBrOBr
Polyene Cyclization
R
MeMe
"Br+"
Me MeBr
R
Karasch Reaction
R
O
CCl3 R
O
Cl
Cl
Cu, Fe, Ru, MoR'
R''R
O R'
Cl
R''
Cl Cl
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Conventional Halogenation Methods
Nucleophilic Displacement
R R'
OR
R R'
BrBr-
or CBr4/PR3
R R'O
LA/Br-
R R'
OH
Br
CH3
BnO
BnOMsO
CH3
BnO
BnOBrBu4NBr
100 °C63%
Fukuzawa, A.; Sato, H.; Masamune, T. Tetrahedron Lett. 1987, 28, 4303-4306. !
OCH3
H3C CH3OH
CH3O
CH3
H3C CH3Cl
CH3SOCl2
ZnCl281%
Miyashita, K; Tanaka, A.; Shintaku, K.; Iwata, C. Tetrahedron 1998, 54, 1395-1406. !
OHRO
OHROH
XTi(Oi-Pr)4
Et2NH•HX
RO OH
Et2AlCl
Et2NH•HX ROH
XOH
Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248-2256. !
Murai’s Regioselective Epoxy Alcohol Opening.
O
OH
CH3
TMS
O
Br
CH3
TMS
CBr4/Oct3P
87%
Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 30, 4345-4348. !
TMS
OH
O
Et3N•HClTi(Oi-Pr)468%
TMS
OHOH
Cl
Gao, L. –X.; Murai, A. Tetrahedron Lett. 1992, 33, 4349-4352. !
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Chiral Epoxides as Substrates for Dichlorination
OTBDPSO OTBDPSCl
Cl
OTBDPS
Cl
+NCS, Ph3P
toluene, 90 °C45 min
76% 17%
OTBDPSO
NCS, Ph3P
toluene, 90 °C45 min
OTBDPSCl
Cl90%
OTBDPS
Cl
+
6%
N
O
O
Cl:PPh3
N-
O
O
Cl PPh3+
N
O
O
PPh3Cl-
+N
O
O
PPh3Cl-
+
N
O
O
PPh3Cl-+
R2 R1O:
:
R2 R1OPPh3+
+
N-
O
O
Cl-
R2 R1OPPh3+
ClSN2
N-
O
O
Cl-
OTBDPSOOO
NCS, Ph3P
toluene, 90 °C2.7 h
OTBDPSO
O
Cl
Cl
42% (syn:anti = 3:1)
+
OTBDPSOO
HCl
33% (4:3 regioisomers)
R2R1
Cl
HN
O
O
R2 R1
Cl
Cl
Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696-702. !
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Halonium-Induced Cyclizations
H3CCH3
H3C OHCH3
O NH4Br/DMSO
Ti(Oi-Pr)494% CH3
H3C OHH3C OH
Br CH3
OHCH3
OH
Br
1. Swern2. CrCl2, CHCl3 22%
H3C
CH3
CH3OH
Br
Cl
TBCD
40%H3C
CH3
CH3O
Br
Cl
Br
Aplysiapyranoid A
OH "Br+"OBr
Bromoetherification
O
Br Br
BrBr
TBCD
Jung, M. E.; Dʼamico, D. C.; Lew, W. Tetrahedron Lett. 1993, 34, 923-926. !
Snyder, S. A.; Treitler, D. S. Angew. Chem. Int. Ed. 2009, 48, 7899-7903. !
R
MeMe
"Br+"
Me MeBr
R
Polyene Cyclization
H3C
CH3
H3C CH3MeMe
BrMe Me
H
H
S+Et Et
Br
-SbCl5BrBDSB
BDSBCH3NO2
-25 °C, 5 min58%
R'R
Br2
R'R
Br
Br
Halogen Addition
C8H17OTBS
Cl ClCl
OH
Cl
Cl
7
C8H17OTBS
Cl Cl
Cl
OH
Cl
Cl
7
Cl
Cl
Et4NCl3CH2Cl2
-78 to 0 °C97%, 8:1 dr
Bedke, D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwall, C. D.! J. Am. Chem. Soc. 2010, 132, 2542-2543. !
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To Do or Not to Do Enantioselectively
RO
R'
?R
O
R'X
RO
R'X
orenantioselectiveketone/aldehyde!-halogenation
R'R
?R'
RX
XR'
RX
X
or enantioselectivedihalogenation
R'R
R'R
X?regio- and enantioselective
halogenationR'R
Xor
Sterics
Electronics Stereoelectronics
predictibleselectivity
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Logic behind Halogenation of Carbonyl Compound
R1O
R2
R1O
R2: R1O-
R2
R1OH
R2
R1OSi
R2
"X+"R1
O
R2X
*
R1O
YR2
R [X+]*R1
O
YR2
X*
R1O
Y*R2
[X+] R1O
Y*R2
X*
R1O
YR2
Catalyst[X+]
R1O
YR2
X*
Reagent-controlled halogenation Substrate-controlled halogenation Catalytic asymmetric halogenation
1. For general reviews on carbonyl compounds halogenations, see: a) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147-1155. b) Oestreich, M. Angew,! Chem. Int. Ed. 2005, 44, 2324-2327. 2. For the review about fluorination of the organic compounds, see: Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron!1999, 55, 12431-12477. !
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Enantioselective Fluorination of Ketones
O O
OEt1. NaH, 0 °C to rt
2. A (1.5 equiv.)
O O
OEtFSO2
N F
A63%, 70% ee
SO2
N F
B
Cl
Cl
N F
Ts
C
N F
Ts
D
OAc
N
O2S
F
E
NO2SO2N F
F
NO2S F
G
NSH3C FO
O
OLi
L
S
OR
ORF
1. Base
2. N-F* reagent
N-F* Base Product Yield (%) ee (%) Config.
B NaHMDS a 53 76 S
E LDA a 67 74 S
G LiHMDS a 65 70 S
F LiHMDS a 79 62 R
E LDA b 79 88 S
C KHMDS b 53 48 -
a: R = Meb: R = Bn
1. Davis, F. A.; Zhou, P.; Murphy, C. K. Tetrahedron Lett. 1993, 34, 3971-3974. 2. Davis, F. A.; Zhau, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.; Han, W.;!Przeslawski, R. M.; Chen, B. –C.; Carroll, P. J. A J. Org. Chem. 1998, 63, 2273-2280. 3. Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.; Shibata, N. J. Org.!Chem. 1999, 64, 5708-5711. 4. Liu, Z.; Shibata, N.; Takeuchi, Y. J. Org. Chem. 2000, 65, 7583.!
Differding, E.; Lang, R. W. Tetrahedron Lett. 1998, 29, 6087-6090. !
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Cinchona Alkaloids Fluorinating Reagents
N
OMe
N
H HOH
N
OMe
N+FH H
OHBF4
-
NF-Q • BF4
F-TEDA
or NFSI
N+N+
Cl
F
2BF4-
NPhO2S
PhO2SF
F-TEDA
NFSI
Bn
OTMSNF-DHQB • BF4
CH3CN, -20 °Covernight
86%, 91% ee
Bn
OF
TolCO2Et
CN
NF-DHQDA • BF4Tol
CO2Et
CNFCH3CN/CH2Cl2
-80 °C, 3-6 h80%, 87% ee
O
CO2EtF
*O
O
CO2EtF
* NH
* O
F Bn
NF-DHQDA • BF4 NF-DHQDA • BF4 NF-(DHQ)2AQN • BF4
89%, 87% ee 92%, 80% ee 100%, 78% ee
N
OMe
N+FH H
O
BF4-
O
Cl
NF-DHQB • BF4
N
MeO
N+
HF
HAcOBF4-
NF-DHQDA • BF4
N
MeO
N+FH
OBF4-
N
OMe
N
HO
O O
NF-(DHQ)2AQN • BF4
1. Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001-7009. 2. Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, !122, 10728-10729. 3. Shibata, N.; Ishimaru. T.; Suzuki, E.; Kirk, K. L.; J. Org. Chem. 2003, 68, 2494-2497. !
NH
O
FOMeCl
F3C
NF-(DHQ)2AQN • BF4
94%, 84% ee
Filip Petronijevic @ Wipf Group Page 21 of 48 12/10/2011
More in Depth: Origin of Stereoselectivity
Bn
OTMSNF-DHQB • BF4
CH3CN, -20 °Covernight
86%, 91% ee
Bn
OF
A!
(S) - A
(R) - A
Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001-7009.!
Filip Petronijevic @ Wipf Group Page 22 of 48 12/10/2011
Cinchona Alkaloids in PTC Asymmetric Fluorination: A Catalytic Version
O
CO2Rn
NFSI, base
1, PhMe, rt
O
CO2Rn
F*
N
N+
HHO
OMet-Bu
t-Bu
Br-
1
R Base n Yield (%) ee (%)
Me K2CO3 1 92 69
Me Cs2CO3 1 94 60
Et K2CO3 1 92 50
Et Cs2CO3 1 91 63
Me RbOH 2 87 40
Me Cs2CO3 2 88 48
Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545-547.!
Filip Petronijevic @ Wipf Group Page 23 of 48 12/10/2011
L-Proline Derivatives in Enantioselective Fluorination: A Challenging Task
O
HR
NH
R*
"F+"N+
HR
R*
N
HR
R*O
HR
F*
O
HR
F*
NH
R*
N+
HR
R*
N
HR
R*
F F
racemization
difluorination
O
HR
F
O
HR
FF
NH
O
X
L-Pro-OH, X = OHL-Pro-NH2, X = NH2
NH
PhPh
1
NH
OTMSArAr
2
Ar =
CF3
CF3
O
HR
O
HR
F NaBH4
MeOH, rt
OH
R
FNFSI, 2
MTBE, rt
R = Pr (95%, 96% ee); Bu (90%, 91% ee); Hex (55%, 96% ee); BnO(CH2)3 (64%, 91% ee);! Bn (74%, 93% ee); Cy (69%, 96% ee); t-Bu (> 90%, 97% ee); 1-Ad (75%, 96% ee).!
Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard, A.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 3703-3706.!
N+
H
R
F
OTMS CF3
CF3CF3F3C
H
hydrophobic pocket
H2OX
Filip Petronijevic @ Wipf Group Page 24 of 48 12/10/2011
MacMillan’s Catalyst in Action: Enantioselective Organocatalytic α-Fluorination of Aldehydes
O
HR N SS
O OPh
OOPh
F
O
HR
F
N
R
H
+XO
NFSI NRH
+
XO
FN S
O
OPhPhO2S
Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826-8828.!
N
NH Ph
MeMe
OMe•DCA O
HR
OHR
F
1. 1, NFSI, THF, i-PrOH -10 °C, 10-12 h
12. NaBH4, DCM
R = Oct (70%, 94% ee); 1-Octenyl (79%, 94% ee), Cy (96%, 99% ee) Ph (54% 99% ee); Bn (71%, 96% ee); 1-Ad (82%, 98% ee)
Filip Petronijevic @ Wipf Group Page 25 of 48 12/10/2011
TiCl2[R,R-(TADDOLLato)] Catalyzed Asymmetric Fluorination
R1
O O
R3R2
N+N+
Cl
F
2BF4-
F-TEDA
R1
O O
R3R2 F5 mol% 1 or 2
MeCN, rt
TiO OMeCN NCMe
OOCl
Cl
TiO OO O
OO
Cl
ClMeMe
1 2
O OO
i-Pr
i-Pr i-PrMeF
O O
OPhMeF
O O
SPhMeF
O O
OBnMeF
Ph
O O
OEtMeF
Me
O O
OBni-PrF
Bn
O
OF
O
Me
O O
N(Ph)2MeF
O
MeFO
N
89%, 90% ee 50%, 88% ee 78%, 91% ee
82%, 71% ee 71%, 62% ee 40%, 24% ee
63%, 51% ee 75%, 55% ee 85%, 62% ee
Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359-4362.!
Filip Petronijevic @ Wipf Group Page 26 of 48 12/10/2011
TiCl2[R,R-(TADDOLLato)] Catalyzed Asymmetric Fluorination: Mechanism
Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359-4362.!
TiMeCN OO O
Cl
O
OO1-Nph1-Nph
1-Nph1-Nph
OR3
R2R1
TiMeCN OO O
Cl
O
OO1-Nph1-Nph
1-Nph1-Nph
OR3
R2R1
TiMeCN OO O
Cl
O
OO1-Nph1-Nph
1-Nph1-Nph
OR3
R2R1F
N+N+
Cl
F
2BF4-
F-TEDA
N+N+
Cl
H
2BF4-
HCl
+ Cl-
R1
O O
OR3R2
R1
O O
OR3R2F
+ Cl-
HCl
R1
O O
OR3R2
N+N+
Cl
F
2BF4-
F-TEDA
R1
O O
OR3R2 F
5 mol% 1MeCN, rt
TiO OMeCN NCMe
OOCl
Cl
1
Filip Petronijevic @ Wipf Group Page 27 of 48 12/10/2011
TiO O
MeCN O
Nph
O
ONph Nph
O
Cl
O
H3C
1. Hintermann, L.; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359-4362. 2. Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147-1155. 3. Pianna, S.; !Devillers, I.; Togni, A.; Rothlisberger, U. Angew. Chem. Int. Ed. 2002, 41, 979.!
TiCl2[R,R-(TADDOLLato)]: Almost Perfectly Parallel Arrangement
TiO O
MeCN O
Nph
O
ONph Nph
O
Cl
O
H3C
O O
O
i-Pr
i-Pr
i-Pr
CH3
Filip Petronijevic @ Wipf Group Page 28 of 48 12/10/2011
Similar or Not Similar: Titanium Complex Chemistry in Organic Synthesis
ETiMeCN O
O OCl
O
OO1-Nph1-Nph
1-Nph1-Nph
OR3
R2R1
TiO O Ti
OOO
EE
OEtO
i-PrO
i-PrO
O
t-Bu
O
Togni's catalyst Sharpless' catalyst
Et OBn
O O Togni'scatalyst5 mol%
Et OBn
O O
Et OBn
O O
F-TEDA
F
ClNCS
Togni'scatalyst5 mol%
NCS
F-TEDA
Et OBn
O O
FCl
Et OBn
O O
ClF
65%, 65% ee
60%, 57% ee
Frantz, R.; Hintermann, L.; Perseghini, M.; Broggni, D.; Togni, A. Org. Lett. 2003, 5, 1709-1712.!
Filip Petronijevic @ Wipf Group Page 29 of 48 12/10/2011
Other Lewis Acids as Catalyst: Asymmetric Fluorination
R1 Ot-Bu
O O
R2
NPhO2S
PhO2SF
5 mol% 1 or2.5 mol% 2
EtOH
R1 Ot-Bu
O O
R2F
Ar2P
PAr2
PdOH2
OH2
2+
2TfO- Ar2P
PAr2
PdHO
OH
Pd
Ar2P
PAr2
1 2a 2BF4-
2b 2TfO-Ar = 3,5-dimethylphenyl
+ +
up to 94% ee
Hamashima, Y.; Yagi, K.; Takano, H.; Tomas, L.; Sodeoka, M.! J. Am. Chem. Soc. 2002, 124, 14530-14531.!
Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147-1155;! Ma, J. -A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007-1011.!
O O
Ot-Bu NPhO2S
PhO2SF
10 mol% 3DCM, rt
1 mol% 4HFIP, Et2O, rt
O O
Ot-BuF
3: 69%, 92% ee
4: 96%, 85% ee
N N
PPh2
PPh2
Ru
HHCl
OEt2
PF6-
ONN
O
Ph PhCu
2 OTf-
(S,S)-3 (R,R)-4
2+
O
CO2t-Bu
O
CO2t-BuF
O
CO2t-BuF
ONN
O
Ph Ph(S,S)-5
NFSI, Cu(OTf)2
NFSI, Ni(ClO4)2 • 6H2O
94%, 60% ee
87%, 93% ee
Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 10, 1703-1706!.!
Filip Petronijevic @ Wipf Group Page 30 of 48 12/10/2011
Asymmetric Chlorination of Aldehydes: MacMillan
N
NH Ph
MeMe
OMe•TFA
1
H
O
Ph
Me
99% ee
H
O
Ph
Me
OCl
Cl
ClCl Cl
Cl
N
NH Ph
MeMe
OMe•TFA
N
NH Ph
MeMe
OMe•TFA
acetone, -30 °C
acetone, -30 °C
H
O
Ph
Me
H
O
Ph
Me
Cl
Cl
71%, 98% ee, 7:1 dr
79%, 98% ee, 24:1 dr
Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc 2004, 126, 4108-4109.!
H
OR
OCl
Cl
ClCl Cl
Cl secondary amine
enamine catalysisH
OR
Cl
N+
R
H
NR
H
+
XO
Cl OCl
Cl
Cl Cl
ClXOH
R = n-Hex (71%, 92% ee); Cy (87%, 94% ee); 1-Ad (85%, 95% ee);
Ph (92%, 80% ee); CH2CH2OMOM (94%, 93% ee); CH2CH2CO2Me (78%, 87% ee)
Filip Petronijevic @ Wipf Group Page 31 of 48 12/10/2011
H
OR
NCS1 or 2 (10 mol%)
CH2Cl2, rt, 1-10 hH
OR
Cl
*
NH
CONH2
R = Me (99%, 75% ee R); Et (99%, 80% ee R); i-Pr (95%, 87% ee R); t-Bu (93%, 95% ee R); Allyl (90%, 74% ee); Bn (99%, 78% ee).
1
NH
Ph
2
PhR = Et (90%, 97% ee S); i-Pr (90%, 94% ee S); t-Bu (30%, 94% ee S); Allyl (90%, 95% ee); Bn (82%, 95% ee).
N OOCl
NCS
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc 2004, 126, 4790-4791.!
Asymmetric Halogenation of Aldehydes and Ketones: Jørgensen
Filip Petronijevic @ Wipf Group Page 32 of 48 12/10/2011
Asymmetric Halogenation of Aldehydes and Ketones: Jørgensen
H
OR
NCS1 or 2 (10 mol%)
CH2Cl2, rt, 1-10 hH
OR
Cl
*
NH
CONH2
R = Me (99%, 75% ee R); Et (99%, 80% ee R); i-Pr (95%, 87% ee R); t-Bu (93%, 95% ee R); Allyl (90%, 74% ee); Bn (99%, 78% ee).
1
NH
Ph
2
PhR = Et (90%, 97% ee S); i-Pr (90%, 94% ee S); t-Bu (30%, 94% ee S); Allyl (90%, 95% ee); Bn (82%, 95% ee).
N OOCl
NCS
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc 2004, 126, 4790-4791.!
Addition of acid: • promotion of enamine formation • supression of catalyst chlorination
RO
RNCS (2 equiv.), 3 (20 mol%)
2-NO2-C6H4CO2H (50 mol%)CH3CN, 20 h
RO
R
Cl
*
O
O
O O
N
O O O
BocO O
82%97% ee
72%98% ee
83%93% ee
76%93% ee
62%86% ee
40%89% ee
NH
HN
Ph
Ph
• AcOH3 O
Cl3 (10 mol%)
NCS
CH2Cl2, rt
OClCl
OCl
+
27%87% ee 47% ee
rac-A B (S)-A
Marigo, M.; Bachman, S.; Halland, N.; Braunton, A.;!Jørgensen, K. A. Angew. Chem. Int. Ed. 2004, 43, 5507-5510.!
H
O
H
O
Br
*
NBS2 (10 mol%)
CH2Cl2, rt80% ee
H
O
H
O
I
*
NIS2 (10 mol%)
CH2Cl2, rt24% ee
N OOBrNBS
N OOI
NIS
Filip Petronijevic @ Wipf Group Page 33 of 48 12/10/2011
Asymmetric Bromination and Iodination of Aldehydes
H
OR
1, 2 (20 mol%)
CH2Cl2/pentanePhCO2H (20 mol%)
H2O (200 mol%)
H
OR
Br
NH
Ph
2
Ph
Ot-But-Bu
Br Br1
R = i-Pr (87%, 96% ee); t-Bu (94%, 89% ee); Et (72%, 77% ee); n-Pr (82%, 85% ee); Cy (92%, 73% ee); Allyl (74%, 76% ee)
Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005, 4821-4823.!
H
O NIS, 2 (20 mol%)
CH2Cl2/pentanePhCO2H (20 mol%)
H2O (200 mol%)78%, 89% ee
H
O
I*
H
O
R
NIS
5 mol% 35 mol% PhCO2HEt2O, 0 °C, 4 h
H
O
R
I
R = i-Pr (93%, 99% ee); Cy (86%, 98% ee); Et (76%, 98% ee); Allyl (76%, 95% ee); Bn (81%, 92% ee); CH2Cy (74%, 90% ee)
NH
PhPhOH
OHPhPh
3
N OOINIS
Kano, T.; Ueda, M.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 3728-3729.!
Filip Petronijevic @ Wipf Group Page 34 of 48 12/10/2011
Asymmetric Bromination of Ketones
X
O
NH
HN
Ph
Ph
2
Ot-But-Bu
Br Br1
X
OBr1, 2 (20 mol%)
THF, -30 °C
X = CH2 (76%, 91% ee) O (80%, 89% ee) C(OCH2CH2O) (67%, 73% ee)
Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005, 4821-4823.!
El-Qisairi, A.; Qaseer, H. Jordan J. Chem. 2007, 2, 69-78.!
Ar2P
PAr2
PdNCCH3
NCCH3
2+
2BF4-
3, Ar = p-Tolyl
ON N
O
t-But-BuPd
H3CCN NCCH32BF4
-
4
LiBr, CuBr2
THF/H2O
OBr
3 or 4
3: 78% (76% ee)4: 86% (85% ee)
OBr
3: 75% (78% ee)4: 84% (82% ee)
OBr
3: 70% (80% ee)4: 80% (89% ee)
O
Br
*
3: 80% (68% ee)4: 88% (72% ee)
O
Filip Petronijevic @ Wipf Group Page 35 of 48 12/10/2011
Chiral Lewis Acid Catalyzed Asymmetric Chlorinations and Brominations
R1
O O
OR2CH3
N
O
O
X
R1
O O
OR2CH3X5 mol% 1 or 2
CH3CN, rtX = Cl, up to 88% eeX = Br, up to 23% ee
TiO OMeCN NCMe
OO
Cl
Cl
TiO OO O
Ph
Ph
Ph
Ph
OO
Cl
ClMeMe
1
2
1-Nph1-Nph
1-Nph1-Nph
Hintermann, L.; Togni, A. Helv. Chim. Acta 2000, 83, 2425-2435.!
H3C
O O
OBnCH3
ICl
Cl
5 mol% 11.2 equiv. pyrtoluene, 50 °C
H3C
O O
OBnCH3Cl
67%, 71% ee
Hintermann, L.; Togni, A. Helv. Chim. Acta 2004, 87, 605-610.!
R1
O O
OR3R2
N
O
O
X
R1
O O
OR2CH3X10 mol% 3
CH3CN, rtX = Cl, up to 77% eeX = Br, up to 82% ee
ONN
O
t-Bu t-BuCu
2 OTf-
2+
3
Mariago, M. ; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Eur. J. 2004, 10, 2133-2137.!
Filip Petronijevic @ Wipf Group Page 36 of 48 12/10/2011
Chlorination and Bromination of Acyl Halides
Cl
OR
Base, THF
-78 °CO
RH H
1 (10 mol%)
2 or 3 (1.0 equiv.)THF, -78 °C
ArO
OR
X
N
N
HO
O
Ph
MeO
1
OBrBr
Br Br3
OCl
Cl
ClCl Cl
Cl
2
= Nu
Nu
OR
H
+Nu
O-
R
Lg-XLg-
+Nu
OR
X
Lg-
Lg
OR
XCl
OR
H
Base
1. Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J. III; Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531-1532. 2. France, S.; Wack, H.; Taggi, A. E.!Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245-4255. !
Filip Petronijevic @ Wipf Group Page 37 of 48 12/10/2011
Chlorination and Bromination of Acyl Halides
Cl
OR
Base, THF
-78 °CO
RH H
1 (10 mol%)
2 or 3 (1.0 equiv.)THF, -78 °C
ArO
OR
X
N
N
HO
O
Ph
MeO
1
OBrBr
Br Br3
OCl
Cl
ClCl Cl
Cl
2
= Nu
1. Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J. III; Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531-1532. 2. France, S.; Wack, H.; Taggi, A. E.!Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245-4255. !
Me2N NMe2
4
N NMeP
N NEt2t-Bu
5 (BEMP)
Choice of base: reactive, cheap, easy to handle
Ph
O
Cl Ph
O
OC6Cl5
Cl
chlorination source base yield (%) ee (%)
2 4 40 95
2 5 80 99
2 5 81 99
1, THF, -78 °C
(ent-1) (R)
O
OC6Cl5
Cl
PhO
57%, 97% ee
O
OC6Cl5
Cl
1-Np
57%, 95% ee
O
OC6Cl5
Cl
2-Np
63%, 94% ee
Br
O
OC6Cl5
Cl
51%, 97% ee(no racemization after weeks)
O
OC6Cl5
Br
PhO
50%, 99% ee
Filip Petronijevic @ Wipf Group Page 38 of 48 12/10/2011
Asymmetric Halogenations
Sterics
Electronics Stereoelectronics
predictibleselectivity
R1
R
R1
R
Nu
X
Nu X
chiral catalyst
R'RR'R
X?regio- and enantioselective
halogenation
R'R?
R'RX
XR'R
X
X
or enantioselectivedihalogenation
RO
R'
?R
O
R'X
RO
R'X
orenantioselectiveketone/aldehyde!-halogenation
R'RX
or
RR1H
H
X+
RR1H
H
X+
Filip Petronijevic @ Wipf Group Page 39 of 48 12/10/2011
Early Times in Asymmetric Olefin Halogentaions
HO2C 1 (1 equiv.), I2
CH2Cl2, -78 °C to rt92%, 15% ee
OOI
N
MeO
NH
AcO
2
I+ BF4-
1
OH OBr
2 (1.1 equiv.)
CH2Cl2, -78 °C2.4% ee
N
2
Br+ OTf-
2
Grossman, R. B.; Trupp, R. J. Can. J. Chem. 1998, 76, 1233-1237.!
Cui, X. L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653-5658.!
R CO2H3 (> 100 mol%), IClCH2Cl2, -78 °C, 24 h
OI
RO
R = Ar ( ca. 50% ee); R = Me (0% ee)
NH2
3
Haas, J.; Bissmire, S.; Wirth, T. Chem. Eur. J. 2005, 11, 5777-5785.!
Filip Petronijevic @ Wipf Group Page 40 of 48 12/10/2011
Desymmetrization by Chiral Titanium Complexes
CO2Bn
CO2Bn
BnO2C CO2BnH
I
2, I2, CuO
CH2Cl2-78 to 0 °C
O
O OO
Ph Ph
Ph PhMeMe
2
Ti
2
Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T. J. Chem. Soc Chem. Commun. 1992, 1005-1007.!
Inoue, T.; Kitagawa, O.; Ochiai, O.; Shiro, M.; Taguchi, T. Tetrahedron Lett. 1995, 36, 9333-9336.!
OHCO2H
O
OH
OI1, Ti(Oi-Pr)4, Pyr, I2CH2Cl2, -78 to 0 °Cp-TsOH, benzene
67%, 65% ee
O
O OHOH
Ph Ph
Ph PhPhMe
1
OH
OH
L-(+)-DIPT
Ti(Oi-Pr)4, Pyr, I2CH2Cl2, -78 °C to rt
64%, 36% ee
O
OH
I
(trans:cis = 5.4:1)
Filip Petronijevic @ Wipf Group Page 41 of 48 12/10/2011
Enantioselective Halocyclization of Popyprenoids
R
I H
RNIS (1.1 equiv.)1 (1 equiv.)
toluene, -40 °C24 h
ClSO3H
i-PrNO2-78 °C, 4 h
R = p-OMe, 58%, 91% eeR = Me, 57%, 95% ee
OO P
SiPh3
SiPh3
NH
Ph
1
N
O
O
X
LA* !"
!+N
O
O
X
LA*
N-
O
O
X Nu*+
Nu*
*Nu X
N-O O
HX
O
OPNH
Ph
I+
O O
N
SiPh
Ph
SiPhPh
Me H
ISi
Ph
PhMe H
I
SiPhPh
the mosthindered
the leasthindered
MeMe
HR Me
Me
HR
si-faceapproach
re-faceapproach
Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900-903.!
Filip Petronijevic @ Wipf Group Page 42 of 48 12/10/2011
Asymmetric Chlorination of an Isolated Olefin: Synthesis of Napyradiomycin A1
OHOH
1
OOOO
MOMO
MeMe
OBO
O
OB
!"Stackinginteraction
Top-facesteric blocking
OOOO
MOMO
Me
MeCl+
BL*
L*
BL*
L*Cl-
O
O
O
OH
MOMO
BH3•THF (4 equiv.)(S)-1 (4 equiv.), AcOH (4 equiv.)
Cl2, CH2Cl2, -78 °C, 20 min93%, 87% ee O
O
O
OH
MOMO
ClCl
OH
O
O
OH
HO
1. Oethylenediaminediacetate
2. NaH, MOMCl
1. NaOH, KOH Ba(OH)2, 275 °C
2. O2, DMF 64% (2 steps)
OHOH
SO3NaNaO3SO
O
O
OH
HO
ClCl
(-)-Napyradiomycin A1
Snyder, S.A.; Tang, Z.-Y.; Gupta, R. J. Am. Chem. Soc. 2009, 131, 5744-5745.!
Filip Petronijevic @ Wipf Group Page 43 of 48 12/10/2011
Asymmetric Halogenations of Olefins: Catalytic Methods
R
PdIIL2*
+[Cl-] > 0.2 M
[CuCl2-] > 2.5 M
Cl
R
HO[Br-] > 0.2 M
[CuBr2-] > 2 M
Br
R
Br
1. El-Qisairi, A.; Hamed, O.; Henry, P. M. J. Org. Chem. 1998, 63, 2790-2791. 2. El-Qisari, A.; Quaseer, H. A.; Katsigras, G.; Lorenzi, P.; Trivedi, U.; Tracz, S.; Hartman, A.; Miller, J. A.; Henry, P. M. Org. Lett. 2003, 5, 439-441. 3. El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M. J. Organomet. Chem.!
2002, 656, 168-176. !
R
10-30% 1 (Tol-BINAP)CuCl2, LiCl, O2
THF:H2O, 25 °C Cl R
OH*HO R
Cl*
R = Me, 94% ee (ratio = 3.5:1)R = CH2OPh, 93% ee (ratio > 95:5)
OR5-12% 1
CuBr2, LiBr, O2
THF:H2O, 25 °C
OR
BrBr*
R = p-CNC6H4, (S)-Tol-BINAP, 95%, 97% eeR = Ph, (S)-METBOX, 95%, 95% ee
Me Ph
O O OPd PdL* L*X X
bimetalic complex 1
PTol2PTol2
L
L
Tol-BINAP
O
NN
O
t-Bu t-Bu
METBOX
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Organocatalytic Enantioselective Halolactonization
RO
OH
(DHQD)2PHAL (0.1 equiv.)DCDPH (1.1 equiv.)
PhCO2H (1 equiv.)CHCl3/Hex (1:1), -40 °C
30-180 min
O
O
RCl
R = Ph, 86%, 89% eeR = p-CF3C6H4, 61%, 90% eeR = Cy, 55%, 43% eeN
Et
R
H H
+
N N
O
O PhPh
ClCl
Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298-3300.!
Ph OH
O
OPh
I
O1 (15 mol%), 2 (1-2 equiv.)
I2 (15 mol%), toluene-80 °C, 5 d, 87%, 94% ee
PhO
OH1 (15 mol%), 2 (2 equiv.)
I2 (0.1 mol%), toluene-80 °C, 5 d, 82%, 90% ee
O
I
PhO
CF3
F3C N
O
NNPent2H H
1
N
O
OF
I
2
CF3
F3C N
O
NNPent2H H
NOO
F
OO I+R
-
Veitch, G. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, 7332-7335.!
RO
OH
3 (10 mol%), NsNH2NBS (1.2 equiv.)
CHCl3:Toluene (1:2), -78 °C40 h
O
O
RBr
R = Ph, 99%, 90% eeR = p-CF3C6H4, 71%, 85% eeR = Cy, 99%, 92% ee
N
NO
S
NHOMe
MeO
3
Zhou. L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y. -Y. J. Am. Chem. Soc. 2010, 132, 15474-15476.!
Filip Petronijevic @ Wipf Group Page 45 of 48 12/10/2011
Enantioselective Dichlorination of Allylic Alcohols (DHQ)2PHAL
(20 mol%)
p-Ph(C6H4)ICl2 (1.6 equiv.)CH2Cl2 (0.05 M), -78 °C
R
OH
R
OHCl
Cl
OHCl
Cl
63%, 81% ee
OHCl
Cl
81%, 71% ee
Cl
OHCl
Cl
63%, 68% ee
CH3
OHCl
Cl
84%, 74% ee
OHCl
Cl
59%, 54% ee
OHCl
Cl
73%, 72% ee
F
BnO
N
MeO
N
HO
N
OMe
N
HO
NN
H H
(DHQ)2PHAL
Nicolaou, K.C.; Simmons, N.L.; Ying, Y.; Heretsch, P.M.; Chen, J.S. J. Am. Chem. Soc. 2011, 133, 8134-8137.!Monaco, M. R.; Bella, M. Angew. Chem. Int. Ed. 2011, 50, 2-5.!
Filip Petronijevic @ Wipf Group Page 46 of 48 12/10/2011
Conclusions
C X
NATURE
C-F, C-Cl, C-Br, C-Ienzymatically
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-!Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
unactivated C-H chlorination
Groves, J. T. (Mn); Fuijii, H. (Fe); Ricci, M. (Ni)!
NN N
NMn
Cl
SO2
N F
N
OMe
N+FH H
OHBF4
-
NF-Q • BF4
Differding, LangTakeuchi, Davis
Takeuchi, Cahard
NH
O
X
N
NH Ph
MeMe
OMe•DCA
MacMillan, Jorgensen
TiO OMeCN NCMe
Np
Np
Np
Np
OOCl
Cl
Togni
!-halogenationsof carbonyl compounds
Sodeoka (Pd); Togni (Ru); Cahard (Cu); Shibata, Toru (Cu, Ni) !!
Lectka: chlorination and bromination of acyl chlorides!
asymmetric halogenationsof olefines
OO P
SiPh3
SiPh3
NH
Ph
Ishihara
OHOH
Snyder
N
MeO
NH
O
N
OMe
NH
ONN
H H
Nicolaou
Filip Petronijevic @ Wipf Group Page 47 of 48 12/10/2011
Conclusions
C X
NATURE
C-F, C-Cl, C-Br, C-Ienzymatically
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-!Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364-3378.!
unactivated C-H chlorination
Groves, J. T. (Mn); Fuijii, H. (Fe); Ricci, M. (Ni)!
NN N
NMn
Cl
SO2
N F
N
OMe
N+FH H
OHBF4
-
NF-Q • BF4
Differding, LangTakeuchi, Davis
Takeuchi, Cahard
NH
O
X
N
NH Ph
MeMe
OMe•DCA
MacMillan, Jorgensen
TiO OMeCN NCMe
Np
Np
Np
Np
OOCl
Cl
Togni
!-halogenationsof carbonyl compounds
Sodeoka (Pd); Togni (Ru); Cahard (Cu); Shibata, Toru (Cu, Ni) !!
Lectka: chlorination and bromination of acyl chlorides!
asymmetric halogenationsof olefines
OO P
SiPh3
SiPh3
NH
Ph
Ishihara
OHOH
Snyder
N
MeO
NH
O
N
OMe
NH
ONN
H H
Nicolaou
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