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FeN
Me2N
Ph
PhPh
Ph
Ph
Fe
N
Ph
Ph
Ph Me
MeMe
Me
O
FeN
Me
Me
Me
MeMe
OTBSFe
N
N
Me
MeMe
Me
Me
N
Me
N
MeFe
FeMe
Me
Me
MeMe
Me
Me
Me
MeMe
“From Planarity to Chirality”
The research work of Gregory C. Fu
byMaude Poirier
October 2nd, 2007
2
Gregory C. Fu
1963 Born in Galion, Ohio
1984-1985 Researcher with Professor K. Barry Sharpless MIT
1985-1991Graduate student with Professor David A. Evans Harvard University
1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs CALTECH
1993-1996 Assistant Professor of Chemistry MIT
1996-1998 Firmenich Assistant Professor of Chemistry MIT
1998-1999 Firmenich Associate Professor of Chemistry MIT
1999-present Professor of Chemistry MIT
3
Gregory C. Fu
1963 Born in Galion, Ohio
1984-1985 Researcher with Professor K. Barry Sharpless MIT
1985-1991Graduate student with Professor David A. Evans Harvard University
1991-1993 Postdoctoral fellow with Professor Robert H. Grubbs CALTECH
1993-1996 Assistant Professor of Chemistry MIT
1996-1998 Firmenich Assistant Professor of Chemistry MIT
1998-1999 Firmenich Associate Professor of Chemistry MIT
1999-present Professor of Chemistry MIT
4
Gregory C. Fu
2007 Fellow, American Academy of Arts and Sciences 2007 Catalysis Science Award, Mitsui Chemicals 2006 Mukaiyama Award, Society of Synthetic Organic Chemistry of Japan 2005 Fellow, Royal Society of Chemistry 2004 Corey Award, American Chemical Society 2001 Springer Award in Organometallic Chemistry 2000 School of Science Undergraduate Teaching Prize, Massachusetts Institute of Technology 2000 Chan Memorial Award in Organic Chemistry 1999 Innovation Recognition Award, Union Carbide 1998 Bristol-Myers Squibb Award 1998 Cope Scholar Award, American Chemical Society 1998 Synthetic Organic Chemistry Award, Pfizer 1997 Camille Dreyfus Teacher-Scholar Award 1997 Alfred P. Sloan Research Fellow 1997 Chemistry Scholar Award, Glaxo Wellcome 1996 Lilly Grantee Award, Eli Lilly 1996 Cottrell Scholar Award, Research Corporation 1995 American Cancer Society Junior Faculty Research Award 1994 National Science Foundation Young Investigator Award 1993 Camille and Henry Dreyfus Foundation New Faculty Award
5
What is planar chirality ?
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.
2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.
OH
O O
NH
OHN
O
OH
NH
NH2
O
O
CH2CH(CH3)2
NHMeHN
O
H
OHN
HO
NH
HO
OHOH
HO
HO2C
Cl
Cl
OHO
HO
OH
(-)-cavicularin
(CH2)n
(CH2)n
cyclophanes
Fe
ferrocenes
vancomicyn aglycon
O
MeO
O
HO
(+)-galeon
HH
trans-cyclooctene
Chirality in molecules devoid of chiral centers
6
What is planar chirality ?
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.
2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.
OH
O O
NH
OHN
O
OH
NH
NH2
O
O
CH2CH(CH3)2
NHMeHN
O
H
OHN
HO
NH
HO
OHOH
HO
HO2C
Cl
Cl
OHO
HO
OH
(-)-cavicularin
(CH2)n
(CH2)n
cyclophanes
Fe
ferrocenes
vancomicyn aglycon
O
MeO
O
HO
(+)-galeon
HH
trans-cyclooctene
Chirality in molecules devoid of chiral centers
7
What is planar chirality ?
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.
2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.
OH
O O
NH
OHN
O
OH
NH
NH2
O
O
CH2CH(CH3)2
NHMeHN
O
H
OHN
HO
NH
HO
OHOH
HO
HO2C
Cl
Cl
OHO
HO
OH
(-)-cavicularin
(CH2)n
(CH2)n
cyclophanes
Fe
ferrocenes
vancomicyn aglycon
O
MeO
O
HO
(+)-galeon
HH
trans-cyclooctene
Chirality in molecules devoid of chiral centers
8
What is planar chirality ?
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins, Y. El Azizi, A. Schmitzer, Angew. Chem. Int. Ed. 2006, 45, 968-973.
2) E. M. Brzostowska, M. Paulynice, R. Bentley, A. Greer, Chem. Res. Toxicol. 2007, 20, 1046-1052.
OH
O O
NH
OHN
O
OH
NH
NH2
O
O
CH2CH(CH3)2
NHMeHN
O
H
OHN
HO
NH
HO
OHOH
HO
HO2C
Cl
Cl
OHO
HO
OH
(-)-cavicularin
(CH2)n
(CH2)n
cyclophanes
Fe
ferrocenes
vancomicyn aglycon
O
MeO
O
HO
(+)-galeon
HH
trans-cyclooctene
Chirality in molecules devoid of chiral centers
9
Nucleophilic catalyst development
O
OMe Me
O OH
MePh
uncatalyzed
(slow)
O
MePh
O
Me
DMAPcatalyzed
(fast)
N Me
O
Me2N
O Me
O
(fast)OH
MePh
+
NMe2N NMe2NR
H
MLn
NC C
left right
top
bottomNH
MLn
Void
Rtop
bottom
left right
G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.
10
Nucleophilic catalyst development
Should be electron rich, enhancing the nucleophilicity of the catalyst It’s steric environment should be tunable Should lead to robust planar-chiral complexes for maximum versatility and for ease of handling
Fe
NH
R
FeR
R
R
R
R
N
Me2N
FeN
Me2N
R R
R
R
R R
R R
R
R19 electrons 18 electrons18 electrons
G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.
11
Planar-Chiral nucleophilic catalyst synthesis
FeCl2
1) CpMe5Li
2)
NK
Fe
N
Me
Me
Me
Me
Me
FeN
R
Me
Me Me
Me
Me
1) CpMe5Li
2)NLi
OLi
Fe
N
Me
Me
Me
Me
Me
OH
TESCl
Et3NFe
N
Me
Me
Me
Me
Me
OTES
1) CpMe5Li
2)
N
R
Li
1
2
3(R=H)4(R=NMe2)
G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420. J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61, 7230-7231.
12
Kinetic resolution, basic principles
Enantiomers react at different rates with other chiral compoundsThe more theses rates are fart appart the better isSelectivity factor s :
S =k( fast-reacting enantiomer )
k( slow-reacting enantiomer )
^
10
FeN
Me2N
Me
MeMe
Me
MeOH
MePh r.t.
cat.(-)-4
(-)-4
Me O
O
Me
O
Ph Me
O
O
Me
base
rac
For a review on kinetic resolution, see: H. B. Kagan, J. C. Flaud, Top. Stereochemi. 1988, 18, 249-330.
13
Kinetic resolution, basic principles
PhMe
OH
H
PhMe
H
OH
S
R
FeMe
MeMe
Me
Me
N
NMe2
MeO
OPhMe
NMe2NO
MeO
RLRs
H
CpFe
H
FeMe
MeMe
Me
Me
NNMe2
Me
O
O
H
PhMe
NMe2NO
MeO
RLRs
CpFe
H
Ph Me
O
O
Me
SPh Me
O
O
Me
R
G
Rxn coordinates
N
NMe2
O Me
CpFe
14
Kinetic Resolution of Secondary Alcohols
FeN
Me2N
Me
MeMe
Me
Me
OH
MePh NEt3Toluene r.t.
2% (-)-4
(-)-4
Me O
O
Me
O
Ph Me
O
O
Me
s=1,7
FeN
Me2N
PhPh
PhPh
Ph
(-)-7
OH
MePh NEt3Toluene r.t.
2% (-)-7
Me O
O
Me
O
Ph Me
O
O
Me
s= 12 to52(10substrates)
J. C. Ruble, H. A. Latham, G. C. Fu, J. Am. Chem. Soc. 1997, 119, 1492-1493. J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794-2795.B. Tao, J. C. Ruble, D. A. Holc, G. C. Fu, J. Am. Chem. Soc, 1999, 121, 5091-5092.
15
Kinetic Resolution of Secondary Alcohols
OH
RAryl RAlkyl
O
Me O
O
Me
1% (-)-7
NEt3t-amyl alcohol, 0C
O
RAryl RAlkyl
Me
O
Entry Unreacted alcohol s %ee (%conversion)major enantiomer
1234
5
6
7
8
OH
Ph R
R=MeEti-Pri-Bu
43598795
32
71
65
200
^
99(55)99(54)97(52)96(51)
98(56)
98(53)
95(52)
99(51)
OH
PhCl
Me
Me
OH
OH
Me
Me
Me
OH
FeN
Me2N
PhPh
PhPh
Ph
(-)-7
OH
t-amyl alcohol
G. C. Fu, Acc. Chem. Res. 2000, 33, 412-420.
16
Synthesis of Kagan’s ether analogue
BnO
BrOMe
OMe 1) nBuLi, THF, -78C
BnOCHO
2)
BnOCH(OMe)2
OH
OBn
TsOH, CH2Cl2-78Cto rt, 99%
Pd/C, H2MeOH/EtOAc, rt, 99%
O
HO
OH
1)
2)
65%
N B
O
BH2
HPh Ph
Me
BnOCH(OMe)2
OH
OBn
FeN
Me2N
Ph
PhPh
Ph
Ph Et3N, Ac2Ot-amyl alcohol
0C, 50h
BnOCH(OMe)2
OH
OBn
BnOCH(OMe)2
OAc
OBn
LAH 96%
er: 27.6 : 151,7%
er: 9:148,6%
BnOCH(OMe)2
OH
OBn
0,76 mol%
1) Swern Ox
2) CBSred
BnOCH(OMe)2
OH
OBn
7 : 172%
1) TsOH, CH2Cl2-78Cto rt, 99%
Pd/C, H2MeOH/EtOAc, rt, 99%
2)
(R,R)-7
23
4
(R)-5 (S)-5 (R)-5 (S)-5
(R)-6
94%
1) M. Harmata, M. Kahraman, J. Org. Chem. 1999, 64, 4949-4952.
17
Kinetic Resolution of Allylic Alcohols
1) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794-2795.2) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010.
FeN
Me2N
Ph
PhPh
PhPh
(-)-1
R
RR
R1
OH 1-2,5% (+)-1
NEt3t-amyl alcohol
0C
R
RR
R1
OH
R
RR
R1
OAc
racemic
R=H, aryl, alkylR1 = alkyl
n-Pr
i-Pr
OH
Ph
Me
OH
R
OH
Me
Me
R
OH
Me
1
2
3 R= n-pentyl
4 R= i-Pr
5 R=Et
6 R= i-Pr
7 i-Pr
OH
n-Bu
8
9
10
11 R= n-pentyl
12 R= i-Pr
13
i-Pr
OH
Ph
Me
OH
Me
Ph
i-Pr
OH
n-Bu
R
OH
Me Me
OH
Me Me
Me Me
Me
5.492%ee
75%conv
6499%ee
54%conv
4.790%ee
77%conv
1092%ee
63%conv
1193%ee
63%conv
1793%ee
58%conv
2594%ee
55%conv
1493%ee
59%conv
8098%ee
53%conv
5.390%ee
73%conv
1297%ee
66%conv
1897%ee
60%conv
2999%ee
59%conv
Entry Alcohol s Entry Alcohol s
18
Epothilone A synthesis
FeN
Me2N
PhPh
PhPh
Ph
(-)-1
MeO
Me
O
Me
OH
Me
1%(+)-1
NEt3t-amyl alcohol
0C
MeO
Me
O
Me
OH
Me
MeO
Me
O
Me
OH
MeAc2O
98% ee, 47%yields= 107
catalyst recovery: 95%racemic
O
O O
OH
OH
N
S
RO
1: Epothilone A; R =H
MeO
MeOH
O
Me Me
1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA, 1998, 95, 14603.
19
Epothilone A synthesis
FeN
Me2N
PhPh
PhPh
Ph
(-)-1
MeO
Me
O
Me
OH
Me
1%(+)-1
NEt3t-amyl alcohol
0C
MeO
Me
O
Me
OH
Me
MeO
Me
O
Me
OH
MeAc2O
98%ee, 47%yields= 107
catalyst recovery: 95%racemic
O
O O
OH
OH
N
S
RO
1: Epothilone A; R =H
MeO
MeOH
O
Me Me
1) S. Bellemen-Laponnaz, J. Tweddell, J. C. Ruble, F. M. Breitling, G. C. Fu, Chem. Commun. 2000, 1009-1010. 2) For the synthesis of Epothilone A, see: S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci. USA, 1998, 95, 14603.
20
Kinetic Resolution of Secondary Amines
NH2
Ph Me CHCl3-50C
HN
Ph Me
OMe
O
Entry Amine s Entry Amine s
rac
10%(-)-PPY*
12
27
16
11
NOtBu
O
-Naphthyl
O
OMeFe
N
N
PhPh
PhPh
Ph
(-)-PPY*
1
2
3
4
Me
NH2
Me
NH2
Me
Me
NH2
MeO
Me
NH2
F3C
Me
NH2
MeOMe
NH2
Me
NH2
H2N
O
OCy
Et
NH2
5
6
7
8
13
22
16
11
1) S. Arai, S. Bellemin-Laponnaz, G. C. Fu, Angew. Chem. Int. Ed. 2001, 40, 234-236.
21
Asymmetric nucleophilic catalysist: Planar-chiral heterocycles
Fe
N
Me
Me
Me
Me
Me
OTBS
OC
Ph
MeMeOH10% (+)-2c
Toluene-78C
O
MeOMe
PhH
(+)-2c
56%ee
OC
Ph
MeMeOH10% (+)-2c
Toluene-78C
O
MeOMe
PhH
77%ee
NH
OTf
OC
RS
RL
catalyst
O
catalystRL
RS
O
catalystRL
H RS
ROH
O
RORL
H RS
RO
Step1 Step2
Step3
AB
SuggestedMechanism
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
22
Asymmetric nucleophilic catalysist: Planar-chiral heterocycles
Fe
N
Me
Me
Me
Me
Me
OTBS
OC
Ph
MeMeOH10% (+)-2c
Toluene-78C
O
MeOMe
PhH
(+)-2c
56%ee
OC
Ph
MeMeOH10% (+)-2c
Toluene-78C
O
MeOMe
PhH
77%ee
NH
OTf
OC
RS
RL
catalyst
O
catalystRL
RS
O
catalystRL
H RS
ROH
O
RORL
H RS
RO
Step1 Step2
Step3
AB
SuggestedMechanism
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
23
Asymmetric nucleophilic catalysist: Planar-chiral heterocycles
OC
RS
RL
catalyst
O
catalystRL
RS
O
catalyst
RL
H RS
ROH
O
RO
RL
H RS
RO
Step1 Step2
Step3
AB
SuggestedMechanism
Fe
N
Me
Me
Me
Me
Me
OTBSO
PhMe
H
Fe
N
Me
Me
Me
Me
Me
OTBSO
Ph Me
H
MeO MeO
O
MeOMe
H Ph
O
MeOPh
H Me
S- Unfavored
Fe
N
Me
Me
Me
Me
Me
OTBSO
MePh
H
Fe
N
Me
Me
Me
Me
Me
OTBSO
Me Ph
H
R- Favored
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
24
Asymmetric nucleophilic catalysist: Planar-chiral heterocycles
Entry Subtrate %ee %Yield Entry Substrate %ee %Yield
1
2
3
4
5
6
O
Ph
MeC
O MeC
t-Bu
77 87
77 88
O MeC
OMe
75 80
O MeC
PhO
O
Ph
EtC
OC
74 96
68 92
80 97
OC
Ph
MeMeOH10% (+)-2c
Toluene-78C
O
MeOMe
PhH
77%ee
NH
OTf
Fe
N
Me
Me
Me
Me
Me
OTBS
(+)-2c
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
25
Asymmetric Staudinger synthesis of -lactams
1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.
O
C
Ph R
NTs
R1H
NTsO
PhR1
R
10%(-)-6
toluene, r.t.
1.15 equiv
O
C
Ph R
NTf
R1H
NTfO
Ph
R
10%(-)-6
CH2Cl2 and/ortoluene, r.t.1.15 equiv
R1
FeN
N
Me
MeMe
Me
Me
(-)-6
NTsO
catalyst
O
C
R R
O
catalystR
R
NTs
H R
O
catalyst
NTs
RR R
catalyst
NTf
H RR
R R
NTf
H Rcatalyst
OCR
R
NTf
H Rcatalyst
O
R
R
NTfO
R
R R
"imine-first" pathway"ketene-first" pathway
26
Asymmetric Staudinger synthesis of -lactams
1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.
O
C
Ph R
NTs
R1H
NTsO
PhR1
R
10%(-)-6
toluene, r.t.
1.15 equiv
O
C
Ph R
NTf
R1H
NTfO
Ph
R
10%(-)-6
CH2Cl2 and/ortoluene, r.t.1.15 equiv
R1
FeN
N
Me
MeMe
Me
Me
(-)-6
NTsO
catalyst
O
C
R R
O
catalystR
R
NTs
H R
O
catalyst
NTs
RR R
catalyst
NTf
H RR
R R
NTf
H Rcatalyst
OCR
R
NTf
H Rcatalyst
O
R
R
NTfO
R
R R
"imine-first" pathway"ketene-first" pathway
27
Asymmetric Staudinger synthesis of -lactams
O
C
Ph R
NTs
R1H
NTsO
PhR1
R
Entry R R1 dr ee (%) Yield (%)
1
2
3
4
5
6
i-Bu
i-Bu
i-Bu
i-Bu
Et
Et
Ph
O
Ph
O
8 : 1
11 : 1
10 : 1
15 : 1
9 : 1
10 : 1
98
98
98
89
95
98
88
97
95
88
97
98
10%(-)-6
toluene, r.t.
1.15 equivO
C
Ph R
NTf
R1H
NTfO
Ph
R
Entry R R1 dr ee (%) Yield (%)
10%(-)-6
CH2Cl2 and/ortoluene, r.t.1.15 equiv
12345678910
Et Ph 86:14Me Ph 98:2i-Bu Ph 97:3Me 4-FC6H4 96:4Me 4-(CF3)C6H4 97:3Me 4-(OMe)C6H4 81:19Me o-tolyl 81:19Me 2-BrC6H4 80:20Me 2-naphthyl 98:2Ph Ph -
63816385698299849498
60837284807689797662
R1
FeN
N
Me
MeMe
Me
Me
(-)-6
1) B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 1578-1579.2) E. C. Lee, B. L. Hodous, E. Bergin, C. Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586-11587.
28
Building quaternary centers
NO
O
R1
R2
O
X N N
NMe2 N
X =alkyl, OR
or
NO
R2
O
X
O
R1
rac
NO
Ar
O
MeBnO
O
H2NOMe
O
Me
95%Ar = 4-MeO-C6H4
BnO2C NH
O
OMe
ONHCOArMe
Me
NaBH4
82%Ar = Ph
BnO2C OHNHCOArMe
dipeptide
protected-methyl serine
Steglich rearrangement
1) W. Steglich, G. Hofle, Tetrahedron Lett. 1970, 4727-4730.2) For a review of asymmetric synthesis of quaternary stereocenter, see: E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 388-
401.3) For an overview on the synthesis and significance of a-alkylated a-amino acids, see: T. Wirth, Angew. Chem. Int. Ed. 1997, 36, 225-227.
29
Rearrangement of O-Acylation azlactone
NO
O
Ar
R
O
BnO2% (-)-6
Ar =4-MeO-C6H40C
FeN
N
Me
MeMe
Me
Me
NO
O
Ar
RBnO
O
(-)-6
Entry R %ee %Yield
123456
MeEt
CH2Phallyl
CH2CHMe2CH2CH2SMe
919090919288
949393939594
N
O
O
Ar
R
O
BnO
BnO cat
O
NO
O
R
Ar
N
O
O
Ar
O
BnOR
catalyst
Step1Fast
Step2Slow
Mechanism
1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533.2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.
N
N
O
O
CpFe
O
NOR
Ar
O
NO R
Ar
N
N
O
O
CpFe
Bn Bn
30
Rearrangement of O-Acylation azlactone
NO
O
Ar
R
O
BnO2% (-)-6
Ar =4-MeO-C6H40C
FeN
N
Me
MeMe
Me
Me
NO
O
Ar
RBnO
O
(-)-6
Entry R %ee %Yield
123456
MeEt
CH2Phallyl
CH2CHMe2CH2CH2SMe
919090919288
949393939594
N
O
O
Ar
R
O
BnO
BnO cat
O
NO
O
R
Ar
N
O
O
Ar
O
BnOR
catalyst
Step1Fast
Step2Slow
Mechanism
1) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532-11533.2) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem, 1998, 63, 3154-3155.
N
N
O
O
CpFe
O
NOR
Ar
O
NO R
Ar
N
N
O
O
CpFe
Bn Bn
31
Building quaternary centers: synthesis of oxindoles and benzofuranones
NBn
OOR
OPh
NBn
O
PhOR
O
OO
OROPh
OO
PhOR
O
FeN
N
Me
MeMe
Me
Me
(-)-6
XO
OROR
X =NPG, ON
O
O
Ar
R
BnO
O
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
32
Building quaternary centers: synthesis of oxindoles and benzofuranones
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
OO
OROR
N
N
OO
R
N
N
O
OR
OO
OR
OR
NR2O
OOR1
NR2O
R1O
O
5%catalyst (-)-6
OO
OR2OR1
OO
R1OR2
O
5%catalyst (-)-6
CH2Cl235C
CH2Cl235C
FeN
N
Me
MeMe
Me
Me
(-)-6
Entry R1 R2 R3 ee(%) Yield(%)
1 Ph Me H 99 912 2-thienyl Me H 95 813a benzyl Me H 94 824a Me Me H 93 725 Ph Me I 98 946 Ph Bn H 98 88
Entry R1 R2 ee(%) Yield(%)
1 Ph H 97 812 benzyl H 88 953a Mel Me 90 93
a Reaction was run at -12Cwith 10%catalyst.
CCl3 CCl3R3 R3
33
Building quaternary centers: synthesis of oxindoles and benzofuranones
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
34
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
OTMS
Oi-PrAr
Et
5%catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
catalyst*O
R O
O
R
R
O
cat* O
O
R
OSiR3
OR3R1
R2
R
O
cat*
O
OR3R1
R2
R3SiO
O
R
O
OR3R1
R2
R
O
O
R
O
OR3
R2R1
cat*
- cat*
FeN
N
Me
MeMe
Me
Me
(-)-6
35
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
OTMS
Oi-PrAr
Et
5%catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
catalyst*O
R O
O
R
R
O
cat* O
O
R
OSiR3
OR3R1
R2
R
O
cat*
O
OR3R1
R2
R3SiO
O
R
O
OR3R1
R2
R
O
O
R
O
OR3
R2R1
cat*
- cat*
FeN
N
Me
MeMe
Me
Me
(-)-6
36
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
Mechanistic studies
OTMS
Oi-PrAr
Et
5% catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
FeN
N
MeMe
MeMe
Me
(-)-6
OTMS
ORAr
R
OTMS
ORR
Ar
+5% (-)-6
O
Me OR
O
RAr
O
Me OR
O
ArR
O
Ar
R
OR
O
Ar
R
OR
?
O
O
O
Me Me
37
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
Mechanistic studies
OTMS
Oi-PrAr
Et
5%catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
FeN
N
MeMe
MeMe
Me
(-)-6
OTMS
ORAr
R
OTMS
ORR
Ar
+5%(-)-6
O
Me OR
O
RAr
O
Me OR
O
ArR
O
Ar
R
OR
O
R
Ar
OR
?
O
O
O
Me Me
38
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
Mechanistic studies
OTMS
Oi-PrAr
Et
5%catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
FeN
N
Me
MeMe
Me
Me
(-)-6
OTMS
ORAr
R
OTMS
ORR
Ar
+5%(-)-6
O
Me OR
O
RAr
O
Me OR
O
ArR
O
Ar
R
OR
O
R
Ar
OR
O
O
O
Me Me
XOTMS
Ot-BuPh
Et
5%[Me4N]OAc
CD2Cl2, r.t. 60h
exp 1: 1.6/1 mixture of isomersexp 2: 2.6/1 mixture of isomers
no change inratio of isomers
39
Building quaternary centers: synthesis of -ketoesters
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
Mechanistic studies
OTMS
Oi-PrAr
Et
5%catalystAc2O
t-AmylOH0C
O
Me Oi-Pr
O
EtAr
FeN
N
Me
MeMe
Me
Me
(-)-6
OTMS
ORAr
R
OTMS
ORR
Ar
+5%(-)-6
O
Me OR
O
RAr
O
Me OR
O
ArR
O
Ar
R
OR
O
R
Ar
OR
O
O
O
Me Me
X
N
N
O
Me
CpFe
O
R
OR
Ar
N
N
O
Me
CpFe RAr
ORO
O
ORAr
R
O
ORR
Ar
N
N
O
Me
CpFe
N
N
O
Me
CpFe
40
Planar-chiral Brønsted Acid catalyst
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
FeN
N
Me
MeMe
Me
Me
(-)-1NH
NC OC R
Ar
2% (-)-1
toluene, r.t.
R
Ar
O
N
NC
NH
NC
N
NC
catalyst*
R1
O
N
NC
RH
R1
O
N
NC
R
H catalyst*
H catalyst*
OC
R
R1
41
Planar-chiral Brønsted Acid catalyst
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
FeN
N
Me
MeMe
Me
Me
(-)-1NH
NC OC R
Ar
2% (-)-1
toluene, r.t.
R
Ar
O
N
NC
NH
NC
N
NC
catalyst*
R1
O
N
NC
RH
R1
O
N
NC
R
H catalyst*
H catalyst*
OC
R
R1
42
Planar-chiral Brønsted Acid catalyst
FeN
N
Me
MeMe
Me
Me
(-)-1NH
NC OC R
Ar
2% (-)-1
toluene, r.t.
R
Ar
O
N
NC
entry Ar R ee(%) yield(%)
1 Ph Me 81 912 Ph Et 90 933 Ph i-Pr 95 964a Ph t-Bu 81 905 o-tol Et 98 956 o-anisyl Me 94 947 3-(N-Methylindolyl) Bn 86 89
a 5%catalyst
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
43
Planar-chiral Brønsted Acid catalyst
Support for a Brønsted-acid mechanism:
Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.
The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.
The ee of the product is inversely proportional to the concentration of the reaction.
Stereochemical outcome of the reaction can be explained by this pathway.
FeNH
N
Me
MeMe
Me
MeN
NC
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
44
Planar-chiral Brønsted Acid catalyst
Support for a Brønsted-acid mechanism:
Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.
The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.
The ee of the product is inversely proportional to the concentration of the reaction.
Stereochemical outcome of the reaction can be explained by this pathway.
N
NCFe
N
N
Me
MeMe
Me
Me FeND
N
Me
MeMe
Me
MeND
NC
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
45
Planar-chiral Brønsted Acid catalyst
Support for a Brønsted-acid mechanism:
Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.
The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.
The ee of the product is inversely proportional to the concentration of the reaction.
Stereochemical outcome of the reaction can be explained by this pathway.
NH
NC
R1
O
N
NC
RH
R1
O
N
NC
RH catalyst*
R1
O
N
NC
RH
racemic
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
46
Planar-chiral Brønsted Acid catalyst
Support for a Brønsted-acid mechanism:
Treatment of the nucleophiles result in protonation of the catalyst and formation of an ion pair.
The reaction rate has 1st order dependence on ketene and catalyst and zero-order dependence on the nucleophile KIE of 5 has been measured for the addition of 1-D-2-cyanopyrrole to ketenes.
The ee of the product is inversely proportional to the concentration of the reaction.
Stereochemical outcome of the reaction can be explained by this pathway.
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
47
Planar-chiral Brønsted Acid catalyst
S. L. Wiskur, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 6176-6177.
FeN
N
Me
MeMe
Me
Me
(-)-1
OC R
Ar
3% (-)-1
toluene, r.t.
R
Ar
O
Ot-Bu
OH
t-Bu
entry Ar R ee(%) yield(%)
1 Ph Me 79 872 Ph Et 91 893 Ph i-Bu 84 794 Ph cyclopentyl 87 885 Ph i-Pr 91 666 o-tol Et 92 847 o-anisyl Me 94 788 p-Cl i-Pr 89 979 3-thienyl i-Pr 79 94
FeN
N
Me
MeMe
Me
MePhOH FeNH
N
Me
MeMe
Me
MePhO
48
Planar-chiral Brønsted Acid catalyst
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
FeN
N
MeMe
MeMe
Me
(-)-1
OC R
Ar
3% (-)-1
toluene, r.t.
R
Ar
O
N3
FeN
N
Me
MeMe
Me
Me
N3H
N3H
pKa =5
O
XR1
R
H catalyst*
H X
O
XR1
R H
O
XR1
R H
enantioenriched
racemic
H catalyst*
reaction within the ion pair favoerd bylower concentrations and less-polar solvents
more abundant andmore acidic then
N3H Fe
NH
N
Me
MeMe
Me
MeN3
27%ee34%yield
49
Planar-chiral Brønsted Acid catalyst
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
FeN
N
MeMe
MeMe
Me
(-)-1
OC R
Ar
3% (-)-1
toluene, r.t.
R
Ar
O
N3
FeN
N
Me
MeMe
Me
Me
N3H
N3H
pKa =5
O
XR1
R
H catalyst*
H X
O
XR1
R H
O
XR1
R H
enantioenriched
racemic
H catalyst*
reaction within the ion pair favoerd bylower concentrations and less-polar solvents
more abundant andmore acidic then
N3H Fe
NH
N
Me
MeMe
Me
MeN3
27%ee34%yield
50
Planar-chiral Brønsted Acid catalyst
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
FeN
Me
Me
MeMe
Me
Me
(+)-2
OC R1
R
10%(+)-2
toluene/hexane-78C or -90C
HN R1
entry R R1 ee(%) yield(%)
1 Ph i-Pr 93 962 p-ClC6H4 i-Pr 90 923 p-(MeO)C6H4 i-Pr 94 974 3-thienyl i-Pr 92 945 Ph cyclohexyl 92 966 Ph cyclopentyl 93 967 Ph t-Bu 94 768 Ph Et 89 49 o-tol Et 93 9410 o-tol Me 90 8011 p-(MeO)C6H4 Et 92 5512 o-(MeO)C6H4 Me 90 70
N3H
1)
2) MeOH, 1.1 equiv
MeO
O R H
51
Planar-chiral ligands for transition metal-catalyzed reactions
H-L. Kwong, W-S. Lee, H-F. Ng, W-H. Chiu, W-T. Wong, J. Chem. Soc. Dalton Trans. 1998, 1043-1046.
N
Me
N
MeFe
FeMe
Me
Me
MeMe
Me
Me
Me
MeMe
• cyclopropanation
ArN2
O
OR
CH3Cl, 20h, r.t.
CuOTf 0,02 equiv
1,00 equiv4,00 equiv
Ar CO2R CO2RAr
N N
MeOHHMeO
trans:cis up to 90:10ee(%) trans isomer: 77-92
yield(%) trans isomer: 50-78
52
Planar-chiral ligands for transition metal-catalyzed reactions
N
Me
N
MeFe
FeMe
Me
Me
MeMe
Me
Me
Me
MeMe
N
Me
HO
POCl3 H2O2, AcOH
N
Me
Cl74% 88% N
Me
Cl
O
Ac2O
58% N
Me
ClOAc
N
Me
Cl
H2SO479%
i. BuLi, -78C
ii. CpFeCl58%
N
Me
FeMe
Me
Me
MeMe
Cl30 mol% NiBr2(PPh3)2
Zn, Et4NI58%
single diastereoisomer
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
MeMe
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
Me
Fe
Fe Fe Fe
N
Me
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Fe Fe
R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.
53
Planar-chiral ligands for transition metal-catalyzed reactions
N
Me
N
MeFe
FeMe
Me
Me
MeMe
Me
Me
Me
MeMe
N
Me
HO
POCl3 H2O2, AcOH
N
Me
Cl74% 88% N
Me
Cl
O
Ac2O
58% N
Me
ClOAc
N
Me
Cl
H2SO479%
i. BuLi, -78C
ii. CpFeCl58%
N
Me
FeMe
Me
Me
MeMe
Cl30 mol% NiBr2(PPh3)2
Zn, Et4NI58%
single diastereoisomer
1 2 3 4
5
(+)-6(-)-6
(S,S)-7
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
MeMe
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
Me
Me
Fe
Fe Fe Fe
N
Me
N
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Fe Fe
Not formed
Not formed
(R,R)-7 (R,S)-7
(S,R)-7
R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.
54
Planar-chiral ligands for transition metal-catalyzed reactions
N
Me
N
MeFe
FeMe
Me
Me
MeMe
Me
Me
Me
MeMe
R N2
O
OtBu
tBu
(+)-(S,S)-1
1,0 mol%CuOTf1,2 mol% (+)-(S,S)-1
2,0 equiv
R
O
O
tBu
tBu
CH2Cl2 r.t.
Entry R trans:cis ee(%) (trans) Yield (%)
12345
Php-(MeO)C6H4p-(F3C)C6H4n-HexylEt3Si
97 : 395 : 594 : 694 : 696 : 4
8775947880
7871837860
• cyclopropanation
R
N2
CO2Ar 1% CuOTf1,2%(R,R)-1
CH2Cl2, r.t.Ar =BHT R
CO2Ar
entry R trans:cis %ee, trans yield (%)
1 Ph 96:4 94 792a p-(F3C)C6H4 94:6 96 813a p-(MeO)C6H4 94:6 87 904 PhCH2 94:6 91 785 n-Hex 93:7 90 806 Et3Si 99:1 95 64
a The yield refers to the isolated yield of a mixture ofcis ans trans isomers.
Fe
N
Me
Me
Me
Me
Me(R,R)-1
N
Me
Me
Me
Me
MeFe
1) R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.2) M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 10270-10271.
55
Planar-chiral ligands for transition metal-catalyzed reactions
RO H Ar
N2
OMe
O2.0%Cu(OTf)2
3.8%(+)-14.0%H2O
ClCH2CH2Clr.t.
ArOMe
O
RO H
entry Ar yield (%) ee (%) entry Ar yield (%) ee (%)
1 Ph 94 90 9 (4-NHAc)C6H4 89 99a
2 (2-OMe)C6H4 90 96 10 (4-Ph)C6H4 91 863 (2-Me)C6H4 94 79 11 (4-Br)C6H4 95 794 (2-Cl)C6H4 96 96 12 (4-F)C6H4 92 895 (2-F)C6H4 98 98 13 (4-CF3)C6H4 90 216 (3-OMe)C6H4 96 89 14 2-naphthyl 93 847 (3-Cl)C6H4 92 658 (4-OMe)C6H4 85 86 15 88 89
16 3-thienyl 88 88
1.05 equiv
R=CH2CH2TMS
O
O
a After recrystallization.
Fe
N
Me
Me
Me
Me
Me(+)-1
N
Me
Me
Me
Me
MeFe
O
OMePh
O HTMS
BF3.OEt2
CH2Cl2r.t.98%
O
OMePh
HO H
T. C. Maier, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 4594-4595.
• O-H insertion
56
Planar-chiral ligands for transition metal-catalyzed reactions
Boc NH2Ar
N2
Ot-Bu
O7.0%CuBr
6.0%AgSbF68.0%(-)-bpy*
ClCH2CH2Clr.t.
ArOt-Bu
O
BocHN H
entry Ar yield (%) ee (%)
1 Ph 75 942 (2-Me)C6H4 71 813 (3-Me)C6H4 75 884 (4-OMe)C6H4 61 955 (4-NHBoc)C6H4 77 916 (4-Br)C6H4 86 95a
7 (4-CF3)C6H4 89 858 2-naphthyl 73 91
9 74 90
10 3-thienyl 48 80
1.05 equiv
O
O
a After recrystallization.
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
MeMe
Fe
Fe
(-)-bpy*
E. C. Lee, G. C. Fu, J. Am. Chem. Soc. ASAP
• N-H insertion
57
Planar-chiral ligands for transition metal-catalyzed reactions
N
Me
N
Me
Me
Me
Me
MeMe
Me
Me
Me
MeMe
Fe
Fe
(-)-bpy*
O
R R1N2
O
OAr1.0%CuOTf1.3% (-)-bpy*
CH2Cl2r.t.
OCO2Ar
R1R
~1.2 equiv
entry R R1 yield(%)a dr ee(%)
1 Ph Ph2 4-(F3C)C6H4 Ph3 4-ClC6H4 Ph4 4-(MeO)C6H4 Ph5 Ph 4-ClC6H46 Ph 4-(MeO)C6H47 N-Boc-2-pyrrolyl Ph8 Ph 3-furyl9 Ph CH=CHPh10 Ph n-Bu11 n-Hex Ph12 n-Hex Me
79 13:1 8559 19:1 7677 19:1 8884 20:1 9281 20:1 8884 9:1 9368 20:1 9363 6:1 8776 7:1 9392 20:1 7869 13:1 7580 20:1 71
a Isolated yield of the trans diastereomer.77%
over three steps
O
OTESR
OHO
OHR
OH
94%ee, 20:1 dr
BF3.OEt2
r.t.deoxy-C-nucleoside 86%
S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046-1047.
• Asymmetric [4+1] cycloaddition
58
Planar-chiral ligands for transition metal-catalyzed reactions
R HR2
NR1O
catalyticCuCl . 2
N
R R2
O R1
Fe
N
Me
Me
Me
Me
Me
N
Me
Me
Me
Me
MeFe
R =H: (+)-(R,R)-1R =Me: (+)-(R,R)-2
R R
R
CuLn
HR2
NR1O
[3+2] ON
LnCu
R
R2
R1
NR2
R1
LnCuO
R
CuLn H+-H+CuLn
base
M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For -lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.
• -lactams synthesis, the Kinugasa reaction
59
Planar-chiral ligands for transition metal-catalyzed reactions
R HR2
NR1O
catalyticCuCl . 2
N
R R2
O R1
Fe
N
Me
Me
Me
Me
Me
N
Me
Me
Me
Me
MeFe
R =H: (+)-(R,R)-1R =Me: (+)-(R,R)-2
R R
R
CuLn
HR2
NR1O
[3+2] ON
LnCu
R
R2
R1
NR2
R1
LnCuO
R
CuLn H+-H+CuLn
base
M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For -lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.
• -lactams synthesis, the Kinugasa reaction
60
Planar-chiral ligands for transition metal-catalyzed reactions
R HR1
NArO
1%CuCl1.1%(R,R)-2
N
R R1
O Ar
Fe
N
Me
Me
Me
Me
Me
N
Me
Me
Me
Me
MeFe
Me Me
Cy2NMe, -20CMeCN
(R,R)-2
entry nitrone R cis:trans %ee cis yield cis(%)
1 3 Ph 95:5 92 652 3 4-(F3C)C6H4 95:5 93 573 3 4-(MeO)C6H4 92:8 91 604 3 PhCH2 71:29 73 435a 4 Ph 90:10 90 566a 4 1-cyclhexenyl 90:10 91 45
HCy
NO
H
NPhO
OMe
Ph
O
3 4
a Run at -40C
M. M-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124,4572-4573.For mecanism, see: M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60, 4999-5004.For b-lactams trans-isomerization, see: M. Shimizu, K. Kume, T. Fujisawa, Chem. Lett. 1996, 545-546.
• -lactams synthesis, the Kinugasa reaction
61
Planar-chiral ligands for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
NArO
5%CuBr5.5%ligand
NO Ar
Fe
P
Me
Me
Me
Me
Me
N
O
R
Cy2NMe 0.5 equiv0C MeCN
H
N
O
N
O
iPriPr4 5a: R = iPr; 5b: R= tBu
Fe
P
Me
Me
Me
Me
Me
N
OiPr
6
Entry Ligand ee(%) Yield (%)
1 1 6 302 4 62a 393 5a 88 744 5b 90 475 6 58 52
aR,Renantiomer
Fe
N
Me
Me
Me
Me
Me
N
Me
Me
Me
Me
MeFe
Me Me
(R,R)-2
1
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
62
Planar-chiral ligands for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
NAr
O
5%CuBr5.5%ligand
N
O
Ar
FeP
Me
Me
Me
MeMe
N
O
R
Cy2NMe 0.5 equiv0CMeCN
H
N
O
N
O
iPriPr4
5a: R= iPr; 5b: R= tBu
FeP
Me
Me
Me
Me
Me
N
OiPr
6
Entry Product Ligand ee(%) Yield (%) Entry Product Ligand ee(%) Yield (%)
1 1 88 74 4 5b 90 64
2 4 86 60 5 6 85 53
3 5a 90 46 6 5b 91 68
FeN
Me
Me
Me
MeMe
N
Me
Me
Me
MeMeFe
Me Me
(R,R)-2
1
N
O
Ar
N
O
ArOMe
N
O
Ar O
N
O
Ar S
N
O
ArO
N
O
ArO
63
Planar-chiral ligands for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
NO
H
R R1
R2
H+
NLnCuO
R1
R2
R
NO
E
R R1
R2
E+
usualKinugasapathway
NArO
I
3.0 equiv
CuBr (5%)5a (5.5%)
OTMS
Ph2.0 equiv
KOAc (1.0 equiv)MeCN, r.t. N
O Ar
85%ee76%yield
S
NO
Ar
I
3.0 equiv
CuBr (5%)5a (5.5%)
OTMS
Ph2.0 equiv
KOAc (1.0 equiv)MeCN, r.t.
NO Ar
S
90%ee70%yield
Ar = p-carboethoxyphenyl
Ar = p-carboethoxyphenyl
Fe
P
Me
Me
Me
Me
Me
N
O
iPr
H
5a
64
Planar-chiral ligands for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
NO
H
R R1
R2
H+
NLnCuO
R1
R2
R
NO
E
R R1
R2
E+
usualKinugasapathway
NArO
I
3.0 equiv
CuBr (5%)5a (5.5%)
OTMS
Ph2.0 equiv
KOAc (1.0 equiv)MeCN, r.t. N
O Ar
85%ee76%yield
S
NO
Ar
I
3.0 equiv
CuBr (5%)5a (5.5%)
OTMS
Ph2.0 equiv
KOAc (1.0 equiv)MeCN, r.t.
NO Ar
S
90%ee70%yield
Ar = p-carboethoxyphenyl
Ar = p-carboethoxyphenyl
Fe
P
Me
Me
Me
Me
Me
N
O
iPr
H
5a
65
Conclusion
MeOH
O
MeOMe
PhH
NTf
R1H
NTfO
Ar
R R1
NTsO
ArR1
R
NO
O
Ar
RBnO
O
NBn
O
PhOR
O
OO
PhOR
O
O
Me Oi-Pr
O
EtAr
NH
NC
R
Ar
O
N
NCO
C R
Ar
R
Ar
O
O
t-Bu
OHt-Bu
HN R1
N3H
MeO
O R H
R
CO2ArPh
OMe
O
RO H
ArOt-Bu
O
BocHN H
OCO2Ar
OTESR
N
R R1
O Ar
O
R
CO2CMeCy2O
R
CO2CMeCy2
NTs
R1H
• Nucleophilic catalysts
•Transition-metal ligands
• Building quaternary centers
•Brønsted acid catalyst