Transcript Catalytic, Enantioselective Nucleophilic Addition to N

“From Planarity to Chirality”
The research work of Gregory C. Fu
Me2 N
N
Ph
Fe
Me
Me
Ph
Ph
Me
MeFe
Ph
Ph
Me
Me
Me
N
N
O Fe
Ph
Me
Ph
N
Me
Me Fe Me
Ph
Me
Me
Me
Me
Me
OTBS
N
Me Fe Me
Me
Me
Me
by
Maude Poirier
October 2nd, 2007
N
N
Me
Fe
Me
Me
Me
Me
1
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
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
2007
2007
2006
2005
2004
2001
2000
2000
1999
1998
1998
1998
1997
1997
1997
1996
1996
1995
1994
1993
Fellow, American Academy of Arts and Sciences
Catalysis Science Award, Mitsui Chemicals
Mukaiyama Award, Society of Synthetic Organic Chemistry of Japan
Fellow, Royal Society of Chemistry
Corey Award, American Chemical Society
Springer Award in Organometallic Chemistry
School of Science Undergraduate Teaching Prize, Massachusetts Institute of Technology
Chan Memorial Award in Organic Chemistry
Innovation Recognition Award, Union Carbide
Bristol-Myers Squibb Award
Cope Scholar Award, American Chemical Society
Synthetic Organic Chemistry Award, Pfizer
Camille Dreyfus Teacher-Scholar Award
Alfred P. Sloan Research Fellow
Chemistry Scholar Award, Glaxo Wellcome
Lilly Grantee Award, Eli Lilly
Cottrell Scholar Award, Research Corporation
American Cancer Society Junior Faculty Research Award
National Science Foundation Young Investigator Award
Camille and Henry Dreyfus Foundation New Faculty Award
4
What is planar chirality ?
Chirality in molecules devoid of chiral centers
(CH 2)n
Fe
H
H
(CH 2)n
ferrocenes
OH
O
HO
H
N
H
O
O
Cl
O
H
N
O
NH
Cl
O
H
N
H
O
HO
OH
O
H
N
O
NH 2
HO 2C
tr ans-cyclooctene
cyclophanes
N
H
OH
NHMe
O
O
HO
CH 2CH(CH3 )2
HO
HO
O
M eO
OH
OH
vancomicyn aglycon
(-)-cavicularin
(+)-galeon
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins,
5
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.
What is planar chirality ?
Chirality in molecules devoid of chiral centers
(CH 2)n
Fe
H
H
(CH 2)n
ferrocenes
OH
O
HO
H
N
H
O
O
Cl
O
H
N
O
NH
Cl
O
H
N
H
O
HO
OH
O
H
N
O
NH 2
HO 2C
tr ans-cyclooctene
cyclophanes
N
H
OH
NHMe
O
O
HO
CH 2CH(CH3 )2
HO
HO
O
M eO
OH
OH
vancomicyn aglycon
(-)-cavicularin
(+)-galeon
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins,
6
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.
What is planar chirality ?
Chirality in molecules devoid of chiral centers
(CH 2)n
Fe
H
H
(CH 2)n
ferrocenes
OH
O
HO
H
N
H
O
O
Cl
O
H
N
O
NH
Cl
O
H
N
H
O
HO
OH
O
H
N
O
NH 2
HO 2C
tr ans-cyclooctene
cyclophanes
N
H
OH
NHMe
O
O
HO
CH 2CH(CH3 )2
HO
HO
O
M eO
OH
OH
vancomicyn aglycon
(-)-cavicularin
(+)-galeon
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins,
7
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.
What is planar chirality ?
Chirality in molecules devoid of chiral centers
(CH 2)n
Fe
H
H
(CH 2)n
ferrocenes
OH
O
HO
H
N
H
O
O
Cl
O
H
N
O
NH
Cl
O
H
N
H
O
HO
OH
O
H
N
O
NH 2
HO 2C
tr ans-cyclooctene
cyclophanes
N
H
OH
NHMe
O
O
HO
CH 2CH(CH3 )2
HO
HO
O
M eO
OH
OH
vancomicyn aglycon
(-)-cavicularin
(+)-galeon
1) For the synthesis of cyclophanes see: S. K. Collins, Y. El-Azizi, Pure App. Chem. 2006, 78, 783-789. S. K. Collins,
8
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.
Nucleophilic catalyst development
O
O
Me
DMAP
O
O
OH
+
Me
Ph
O
uncataly zed
(sl ow)
Me
Ph
catalyzed
( f ast)
Me
Me
OH
(f ast)
O
N
Ph
O
Me
O
Me
Me
Me2 N
M e2N
N
R
N
H
Me2 N
MLn
Void
top
top
C
N
C
H
N
R
bottom
left
right
ML n
left
G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.
bottom
right
9
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
R
Me 2N
Me 2N
NH
R
Fe
R
N
R
R
R
R
18 electrons
G. C. Fu, Acc. Chem. Res, 2000, 33, 412-420.
Fe
R
N
R
R
R
R
19 electrons
R
Fe
R
R
R
18 electrons
10
Planar-Chiral nucleophilic catalyst synthesis
N
1) CpMe5Li
Fe
Me
2)
NK
Me
Me
Me
Me
1
FeCl2
Me
2)
OH
N
1) CpMe5Li
Fe
TESCl
Me
OLi
NLi
Me
Me
Me
Et3N
OTES
N
Me
Fe
Me
Me
Me
Me
2
R
1) CpMe5Li
N
R
Me
2)
Li
N
Fe
Me
Me
Me
Me
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.
11
Kinetic resolution, basic principles
Me 2N
O
OH
Ph
Me
O
Me
N
O
O
cat.(-)-4
Me
base r.t.
O
Ph
Me
Me
Me
Fe
Me
Me
Me
Me
rac
(-)-4
Enantiomers react at different rates with other chiral compounds
The more theses rates are fart appart the better is
Selectivity factor s :
k( slow-reacting enantiomer )
^
S=
k( fast-reacting enantiomer )
10
For a review on kinetic resolution, see: H. B. Kagan, J. C. Flaud, Top. Stereochemi. 1988, 18, 249-330.
12
Kinetic resolution, basic principles
H
Me
O
Ph
NMe 2
N
Me
O
Me
Ph
NMe 2
H
Me
Me
N
Me
Me
Fe
CpFe
Me
Me
Me
Me
O
Me
O
CpFe
Me2 N
N
Me
N
O
Me2 N
Me
Me
O
DG
Fe
Me
O
O
Rs
CpFe
N
H
RL
NMe2
Me
O
H
Rs
RL
Ph
Me
OH
Ph
Me
H
H
S
R
OH
O
O
Ph
O
Me
O
Me
Ph
S
Rxn coordinates
R
Me
Me
13
Kinetic Resolution of Secondary Alcohols
Me 2N
Me 2N
N
Me
N
Fe
Me
Me
Ph
Me
Fe
Ph
Ph
Ph
Me
Ph
(-)-4
(-)-7
O
OH
Ph
Me
O
Me
O
O
2% (-)-4
Me
NEt 3
Toluene r.t.
O
Ph
O
OH
Me
Me
Ph
Me
O
Me
O
O
s = 1,7
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.
2% (-)-7
Me
NEt 3
Toluene r.t.
O
Ph
Me
Me
s = 12 t o 52
( 10 substr ates)
14
Kinetic Resolution of Secondary Alcohols
Me2 N
O
N
OH
R Aryl
O
R Alkyl
Entry
1
2
3
4
Me
1% (-)-7
O
O
Me
NEt 3

t-amyl alcohol, 0 C
Unreacted alcohol
major enantiomer
R = Me
Et
i -Pr
i -Bu
OH
Ph
R
O
R Aryl
Me
R Alkyl
s
%ee (%conversion)
43
59
87
95
99(55)
99(54)
97(52)
96(51)
32
98(56)
71
98(53)
65
95(52)
200
99(51)
Ph
Fe
Ph
Ph
Ph
Ph
OH
t-amyl alcohol
(-)-7
OH
5
Cl
Ph
OH
Me
6
Me
OH
7
Me
Me
OH
^
8
Me
G. C. Fu, Acc. Chem. Res. 2000, 33, 412-420.
15
Synthesis of Kagan’s ether analogue
BnO

1) nBuLi, THF, -78 C
OMe
2)
Br
OMe
BnO
BnO
CH(OMe) 2
OBn
CHO
65%
2
OH
3
4
Me 2N
1) Swern Ox
94%
N
Ph
Fe
Ph
Ph
Et3 N, Ac2 O
Ph
(R)-5
(S)-5
CH(OMe) 2
OBn
OH
(R)-5
OH
er: 9:1
48,6%
BnO
CH(OMe) 2
OBn
OAc
B
Me
BH 2

0 C, 50h
CH(OMe) 2
OBn
O
N
BnO
BnO
CH(OMe) 2
Ph
2) CBS red
t-am yl alcohol
Ph
0,76 mol%
BnO
Ph
H
er: 27.6 : 1
51,7%
7:1
72%
OBn
OH
(S)-5
1) TsOH, CH2 Cl2

-78 C to rt, 99%
LAH 96%
2)
BnO
1) TsOH, CH 2Cl2

CH(OMe) 2
-78 C to rt, 99%
OBn
(R)-6
HO
O
2)
OH
Pd/C, H2
MeOH/EtOAc, rt, 99%
Pd/C, H 2
MeOH/EtOAc, rt, 99%
OH
(R,R)-7
1) M. Harmata, M. Kahraman, J. Org. Chem. 1999, 64, 4949-4952.
16
Kinetic Resolution of Allylic Alcohols
OH
R
R
OH
1-2,5% (+)-1
R
R
1
R
t-amyl alcohol
R

N
R
R1
NEt3
Me2 N
OAc
R
R
R1
Ph
Ph
Ph
Ph
R
Ph
0 C
racemi c
Fe
(-)-1
R = H, aryl, alkyl
1
R = alkyl
Entry
Alcohol
s
Entry
5.4
92% ee
75% conv
8
OH
1
i -Pr
s
Alcohol
OH
Ph
i -Pr
14
93% ee
59% conv
n-Pr
OH
2
Me
64
99% ee
54% conv
OH
Me
9
Me
Ph
Ph
4.7
90% ee
77% conv
3
R = n-pentyl
Me
OH
Me
4
5
R = i-Pr
R =Et
OH
Me
6
R
R
R = i-Pr
OH
7
n-Bu
i -Pr
10
92% ee
63% conv
11
93% ee
63% conv
17
93% ee
58% conv
80
98% ee
53% conv
OH
i-Pr
10
5.3
90% ee
73% conv
n-Bu
12
97% ee
66% conv
OH
11
R = n-pentyl
R
12
R = i-Pr
Me
18
97% ee
60% conv
Me
OH
25
94% ee
55% conv
Me
13
Me
Me
Me
Me
29
99% ee
59% conv
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.
17
Epothilone A synthesis
Me 2N
O
Me
N
Ph
OH
Ph
Ph
O
Me
Fe
Me
Me
Ph
OH
Ph
Me
(-)-1
OH
Me
O
Me
MeO
Me
1% (+)-1
MeO
OH
Ac 2 O
O
Me
Me
Me
O
NEt 3
t -amyl alcohol

0 C
MeO
N
98% ee, 47% yield
s = 107
catalyst recovery: 95%
r acemic
O
O
Me
MeO
OH
OH
S
O
R
1: Epothilone A; R = H
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, 18
1998, 95, 14603.
Epothilone A synthesis
Me 2N
O
Me
N
Ph
OH
Ph
Ph
O
Me
Fe
Me
Me
Ph
OH
Ph
Me
(-)-1
OH
Me
O
Me
MeO
Me
1% (+)-1
MeO
OH
Ac 2 O
O
Me
Me
Me
O
NEt 3
t -amyl alcohol

0 C
MeO
N
98% ee, 47% yield
s = 107
catalyst recovery: 95%
r acemic
O
O
Me
MeO
OH
OH
S
O
R
1: Epothilone A; R = H
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, 19
1998, 95, 14603.
Kinetic Resolution of Secondary Amines
N
O
10% (-)-PPY*
tBu
Ph
Ph
OMe
O
NH2
O
Me
N
r ac
Entry
N
O
Amine
HN
OMe
Ph

Me
(-)-PPY*
Entry
Amine
Me
12
Me
5
F3C
NH2
2
s
NH 2
NH2
1
Ph
Ph
CHCl3
s
Ph
Ph
-50 C
-Naphthyl
Fe
27
6
13
NH2
MeO
Me
22
Me
Me
3
NH2
NH2
16
7
Me
NH 2
Me
4
MeO
O
11
8
16
Et
NH 2
H2 N
Cy
Me
11
O
1) S. Arai, S. Bellemin-Laponnaz, G. C. Fu, Angew. Chem. Int. Ed. 2001, 40, 234-236.
20
Asymmetric nucleophilic catalysist:
Planar-chiral heterocycles
OTBS
N
Me
Fe
Me
Me
Me
Me
(+)-2c
O
O
C
MeOH
Ph
Me
C
Me
MeO
Toluene
MeOH
H Ph

O
O
10% (+)-2c
10% (+)-2c
Me
MeO
Toluene
Ph
-78 C
H Ph

-78 C
56% ee
OTf
Suggested Mechanism

catalyst
RO
O
77% ee
N
H
O
C
Me
RL
H RS
RL
Step 2
Step 1
RS
RO
O
A

RL
catalyst
O
Step 3
catalyst
RL
H RS
RS
B
ROH
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
21
Asymmetric nucleophilic catalysist:
Planar-chiral heterocycles
OTBS
N
Me
Fe
Me
Me
Me
Me
(+)-2c
O
O
C
MeOH
Ph
Me
C
Me
MeO
Toluene
MeOH
H Ph

O
O
10% (+)-2c
10% (+)-2c
Me
MeO
Toluene
Ph
-78 C
H Ph

-78 C
56% ee
OTf
Suggested Mechanism

catalyst
RO
O
77% ee
N
H
O
C
Me
RL
H RS
RL
Step 2
Step 1
RS
RO
O
A

RL
catalyst
O
Step 3
catalyst
RL
H RS
RS
B
ROH
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
22
Asymmetric nucleophilic catalysist:
Planar-chiral heterocycles
H
H
OTBS
OTBS
O
N
N
Ph
Me
Fe
Me
Me
Me
Me
Me
Ph
Fe
Me
O
Me
Me
Me
Suggested Mechanism
Me
Me
O

catalyst
O
O
N
Fe
Me
H
H
Me
Me
Me
Me
Ph
Fe
Ph
Me
Me
Step 2
Step 1
RS
O
N
Me
RO
O
Me
Me
RL
catalyst
Me
Me
A
Step 3
O

catalyst
RL
H RS
RS
B
MeO
MeO
RL
H RS
RL
C
OTBS
OTBS
RO
ROH
O
MeO
O
Ph
MeO
H Me
S- Unf avor ed
Me
H Ph
R- Favored
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
23
Asymmetric nucleophilic catalysist:
Planar-chiral heterocycles
OTf
O
10% (+)-2c
C
Me
MeOH
Toluene
Entry
Subtrate
O
1
C
Me
Me
%ee
77
%Yield
87
Me
(+)-2c
H Ph

-78 C
Me
Me
Me
MeO
Ph
Fe
Me
N
H
O
OTBS
N
77% ee
Entry
4
Substrate
O
C Me
%ee
%Yield
74
96
68
92
80
97
Ph
PhO
O
C
Me
2
77
88
5
O
C
Ph
t-Bu
O
C
Et
Me
O
3
75
80
6
C
OMe
B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999, 121, 2637-2638.
24
Asymmetric Staudinger synthesis of -lactams
N
N
Me
O
NTs
C
Ph
O
Me
10% (-)-6
R1
H
R
Ph
Ph
NTs
H
R
CH 2 Cl2 and/or
toluene, r.t.
Ph
R
R
R
catalyst
R
1
NTf
NTf
R
catalyst
R1
NTf
O
C
R
R
10% (-)-6
1.15 equiv
O
R
O
NTf
C
(-)-6
O
R
O
Me
R1
R
1.15 equiv
Me
Me
NTs
toluene, r.t.
Fe
H
R
R
O
O
NTs
catalyst
R
R
catalyst
R R
R
NTs
H
R
"ketene-first" pathway
NTf
R
O
NTf
R
H
H
R
R
catalyst
catalyst
R
C
O
R
"imine-first" pathway
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.
25
Asymmetric Staudinger synthesis of -lactams
N
N
Me
O
NTs
C
Ph
O
Me
10% (-)-6
R1
H
R
Ph
Ph
NTs
H
R
CH 2 Cl2 and/or
toluene, r.t.
Ph
R
R
R
catalyst
R
1
NTf
NTf
R
catalyst
R1
NTf
O
C
R
R
10% (-)-6
1.15 equiv
O
R
O
NTf
C
(-)-6
O
R
O
Me
R1
R
1.15 equiv
Me
Me
NT s
toluene, r.t.
Fe
H
R
R
O
O
NTs
NTf
R
catalyst
R
catalyst
R R
R
NTs
H
R
"ketene-first" pathway
NTf
R
O
R
H
H
R
R
catalyst
catalyst
O
R
C
R
"imine-first" pathway
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.
26
Asymmetric Staudinger synthesis of -lactams
N
N
Me
Fe
Me
Me
Me
Me
(-)-6
O
Ph
O
NTs
C
R
H
10% (-)-6
R1
NTs
Ph
toluene, r.t.
R
1.15 equiv
Entry
1
R
i -Bu
R1
dr
Ph
8:1
ee (%)
98
R
Yield (%)
3
i -Bu
4
i -Bu
Ph
11 : 1
Ph
98
R
H
97
10 : 1
98
95
15 : 1
89
88
O
5
Et
9:1
95
97
6
Et
10 : 1
98
98
R1
1.15 equiv
88
Entry
i -Bu
NTf
C
O
2
O
1
1
2
3
4
5
6
7
8
9
10
R
Et
Me
i -Bu
Me
Me
Me
Me
Me
Me
Ph
O
10% (-)-6
CH 2Cl2 and/or
toluene, r.t.
R1
Ph
Ph
Ph
4-FC6 H4
4-(CF3 )C 6H 4
4-(OMe)C6 H4
o-tolyl
2-BrC 6H 4
2-naphthyl
Ph
dr
86:14
98:2
97:3
96:4
97:3
81:19
81:19
80:20
98:2
-
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.
NTf
Ph
R
ee (%)
63
81
63
85
69
82
99
84
94
98
R1
Yield (%)
60
83
72
84
80
76
89
79
76
62
27
Building quaternary centers
Steglich rearrangement
NMe2
N
O
or
X
O
N
O
O
N

R1
X
O
X = alkyl, OR
N
R1 N
O
2
2
R
R
r ac
Me
OMe
H 2N
O
O
BnO
Me
O
O
N
Ar
95%
Ar = 4-MeO-C6 H4
O
Me
BnO 2C
N
H
Me NHCOAr O
OMe
dipeptide
NaBH4
82%
Ar = Ph
BnO 2C
OH
Me NHCOAr
protected -methyl serine
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, 38828
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.
Rearrangement of O-Acylation azlactone
Mechanism
N
O
N
Me
Fe
BnO
Me
Me
Me
R
BnO
O
R
O
0 C
Step 2
Sl ow
O
O
O
BnO
R N

N
R
cat
Entry
R
% ee
1
2
3
4
5
6
Me
Et
CH2 Ph
allyl
CH 2CHMe2
CH2 CH2 SMe
91
90
90
91
92
88
O
N
Ar
Ar
N
Ar
O
BnO
Ar = 4-MeO-C6H4
O
R
Step 1
Fast
Ar
2% (-)-6
O
BnO
O
N
(-)-6
O
O
catalyst
Me
O
O
Ar
% Yield
94
93
93
93
95
94
O
CpFe
O
CpFe
Bn
Bn
N
N
O
N
O
O
R
O
N
Ar
N
O
R
O
N
Ar
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.
29
Rearrangement of O-Acylation azlactone
Mechanism
N
O
N
Me
Fe
BnO
Me
Me
Me
R
BnO
O
R
O
0 C
Step 2
Sl ow
O
O
O
BnO
R N

N
R
cat
Entry
R
% ee
1
2
3
4
5
6
Me
Et
CH2 Ph
allyl
CH 2CHMe2
CH2 CH2 SMe
91
90
90
91
92
88
O
N
Ar
Ar
N
Ar
O
BnO
Ar = 4-MeO-C6H4
O
R
Step 1
Fast
Ar
2% (-)-6
O
BnO
O
N
(-)-6
O
O
catalyst
Me
O
O
Ar
% Yield
94
93
93
93
95
94
O
CpFe
O
CpFe
Bn
Bn
N
N
O
N
O
O
N
R
O
O
N
Ar
R
O
N
Ar
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.
30
Building quaternary centers:
synthesis of oxindoles and benzofuranones
O
BnO
R
O
OR
O
O
R
O
N
X
N
N
Me
X = NPG, O
Ar
Fe
Me
Me
Me
Me
O
Ph O
OR
Ph
(-)-6
OR
O
O
N
Bn
N
Bn
O
Ph O
OR
Ph
OR
O
O
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
O
O
31
Building quaternary centers:
synthesis of oxindoles and benzofuranones
N
O
R
N
OR
Me
O
Fe
O
Me
O
Me
(-)-6
O
R
1
O
R3
O
CCl3 5% catalyst (-)-6
O
O

2
NR
35 C
O
R1 O
1
CH 2Cl2
O
NR
R
R3
2
O
OR
Me
Me
O
R
N
N
5% catalyst (-)-6
OR2
CCl3
O
R
O
O
R1
CH 2Cl2
O

O
35 C
OR
OR 2
N
Entry
R1
R2
1
Ph
Me
2
2-thienyl
Me
R3
O
ee(%)
Yield(%)
H
99
91
H
95
81
a
benzyl
Me
H
94
82
a
4
Me
Me
H
93
72
5
Ph
Me
I
98
94
6
Ph
Bn
H
98
88
3
Entry
O
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
N
1
2
3
a
a
R1
R2
ee(%)
Yield(%)
Ph
H
97
81
benzyl
H
88
95
Mel
Me
90
93

Reaction was run at -12 C with 10% catalyst.
32
Building quaternary centers:
synthesis of oxindoles and benzofuranones
I. D. Hills, G. C. Fu, Angew.Chem. Int. Ed. 2003, 42, 3921-3924.
33
Building quaternary centers:
synthesis of -ketoesters
N
Ar
Oi -Pr
R
O
Me
Me
Oi -Pr
Ar

0 C
O
O
O
t -AmylOH
Et
O
N
5% catalyst
Ac2 O
OTMS
Fe
Me
Me
Me
Me
Et
(-)-6
O
catalyst*
O
OR 3
R
R
R1 R 2
O
O
O
O
cat*
O
R
R
O
cat*
cat*
R
O
R
1
1
R
OR 3
R2
R
- cat*
OR 3
R2
O
OSiR 3
1
R
OR 3
R 3 SiO
R
2
R
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
34
Building quaternary centers:
synthesis of -ketoesters
N
Ar
Oi -Pr
R
O
Me
Me
Oi -Pr
Ar

0 C
O
O
O
t -AmylOH
Et
O
N
5% catalyst
Ac2 O
OTMS
Fe
Me
Me
Me
Me
Et
(-)-6
O
catalyst*
O
OR 3
R
R
R1 R 2
O
O
O
O
cat*
O
R
R
O
cat*
cat*
R
O
R
1
1
R
OR 3
R2
R
- cat*
OR 3
R2
O
OSiR 3
1
R
OR 3
R 3 SiO
R
2
R
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
35
Building quaternary centers:
synthesis of -ketoesters
Mechanistic studies
N
5% catalyst
Ac 2O
OTMS
Ar
Oi -Pr
t-AmylOH

Et
0 C
O
N
O
Me
Me
Me
Oi-Pr
Ar
Fe
Me
Me
Me
Et
(-)-6
O
OTMS
Ar
O
Me
O
OR
O
Me
Ar
OR
Ar
R
O
O
R
?
OR
R
O
Ar
OR
R
5% (-)-6
+
Me
OTMS
R
OR
Ar
O
O
Me
OR
R Ar
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
36
Building quaternary centers:
synthesis of -ketoesters
Mechanistic studies
N
5% catalyst
Ac2 O
OTMS
Ar
Oi -Pr
t -AmylOH

Et
0 C
O
N
O
Me
Me
Me
Oi -Pr
Ar
Fe
Me
Me
Me
Et
(-)-6
O
OTMS
Ar
O
Me
O
OR
O
Me
Ar
OR
Ar
R
O
O
R
?
OR
R
O
R
OR
Ar
5% (-)-6
+
Me
OTMS
R
OR
Ar
O
O
Me
OR
R Ar
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
37
Building quaternary centers:
synthesis of -ketoesters
Mechanistic studies
N
OTMS
Ar
N
5% catalyst
Ac2 O
Oi -Pr
t -AmylOH

Et
0 C
O
O
Me
Me
Oi -Pr
Ar
Fe
Me
Me
Me
Me
Et
(-)-6
O
OTMS
OTMS
OR
Ar
Ph
O
Me
O
O
R
Ot -Bu
Et
+
O
5% [Me4 N]OAc
6 2 , r.t. 60h
5%CD
(-)2 Cl
OR
Ar
Ar
Me
OR
no change in
Ar R
ratio of isomers
Me
exp 1: 1.6/1 mixture of isomers
exp 2: 2.6/1
mixture of isomers
OTMS
R
O
O
O
OR
R
X
R
OR
Ar
O
Me
OR
R Ar
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
38
Building quaternary centers:
synthesis of -ketoesters
Mechanistic studies
N
OTMS
Ar
Oi -Pr
t -AmylOH
O
Ar
Me
R
O
O
N
Me
Me
N
RO
OTMS OR
O
R
OR
N
Ar
R
O
Ar
N
Ar
OR
Ar
Me
N
O
Ar
CpFe
O
OR
Me
5% (-)-6
Me
O
R
N
R
Me
Me
O
O
+
Me
Et
CpFe
OR
Ar
Fe
(-)-6
OR
CpFe
O
Oi -Pr
Ar
R
Ar
Me
Me
OTMS
N
O
O
Me
0 C
O
N
O

Et
CpFe
N
5% catalyst
Ac2 O
O
OR
R
X
R
OR
Ar
R
Me
O O O
Me
OR
R Ar
A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 5604-5607.
39
Planar-chiral Brønsted Acid catalyst
N
N
NC
O
O
NC
C
Me
2% (-)-1
R
NH
Ar
Me
R
N
toluene, r.t.
Fe
Me
Me
Me
(-)-1
Ar
NC
O
N
H
R1
C
catalyst*
R
NC
NH
O
NC
R1
N
catalyst*
H
catalyst*
R
O
NC

N
R1
H R
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
40
Planar-chiral Brønsted Acid catalyst
N
N
NC
O
O
NC
C
Me
2% (-)-1
R
NH
Ar
Me
R
N
toluene, r.t.
Fe
Me
Me
Me
(-)-1
Ar
NC
O
N
H
R1
C
catalyst*
R
NC
NH
O
NC
R1
N
catalyst*
H
catalyst*
R
O
NC

N
R1
H R
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
41
Planar-chiral Brønsted Acid catalyst
N
N
NC
O
R
NH
Ar
entry
2% (-)-1
N
toluene, r.t.
Ar
R
R
ee(%)
Fe
Me
Me
Me
Me
(-)-1
Ar
yield(%)
1
Ph
Me
81
91
2
Ph
Et
90
93
3
Ph
i-Pr
95
96
4
Ph
t-Bu
81
90
5
o-tol
Et
98
95
6
o-anisyl
Me
94
94
7
3-(N-Methylindolyl)
Bn
86
89
a
a
O
NC
C
Me
5% catalyst
B. L. Hodous, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 10006-10007.
42
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.
N
NC
N
N
H Fe
Me
Me
Me
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.
Me
Me
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.
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.
N
N
The ee of the product is inversely proportional to the
N
NC
Fe
concentration of the reaction.
Me
ND
Stereochemical outcome of the reaction can be
explained by this pathway.
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
Me
NC
Me
Me
Me
N
N
D Fe
Me
Me
Me
Me
Me
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.
NC
O
NC
NH
R1
N
Stereochemical outcome of the reaction can
beO
NC
explained by this pathway.
N
H R
racemic
R1
R
H
catalyst*
O
NC

N
R1
H R
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.
G. C. Fu, Acc. Chem. Res. 2004, 37, 542-547.
46
Planar-chiral Brønsted Acid catalyst
N
N
N
N
N
Me
Fe
Me
PhOH
Me
Me
Fe
Me
Me
Me
Me
Me
Me
PhO
N
H Fe
Me
Me
Me
Me
Me
(-)-1
O
OH
O
C
t -Bu
entry
1
2
3
4
5
6
7
8
9
R
Ar
Ar
Ph
Ph
Ph
Ph
Ph
o-tol
o-anisyl
p-Cl
3-thienyl
3% (-)-1
R
O
toluene, r.t.
t-Bu
R
Me
Et
i -Bu
cyclopentyl
i -Pr
Et
Me
i -Pr
i -Pr
ee(%)
79
91
84
87
91
92
94
89
79
Ar
yield(%)
87
89
79
88
66
84
78
97
94
S. L. Wiskur, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 6176-6177.
47
Planar-chiral Brønsted Acid catalyst
N
N
O
O
N3 H
C
R
Ar
Me
3% (-)-1
toluene, r.t.
R
N3
Fe
Me
Me
Me
Me
Ar
(-)-1
27% ee
34% yield
reaction within the ion pair f avoerd by
lower concentrations and less-polar solvents
H catalyst*
O
R1
X
O
N3 H
pKa = 5
R
enantioenriched
N
X
N 3H
R
O
X
Me
Fe
Me
1
H X
N
N
R H
1
R
N3
Me
Me
Me
N
H
Fe
Me
Me
Me
Me
Me
R H
more abundant and
more acidic then
racemic
H catalyst*
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
48
Planar-chiral Brønsted Acid catalyst
N
N
O
O
N3 H
C
R
Ar
Me
3% (-)-1
toluene, r.t.
R
N3
Fe
Me
Me
Me
Me
Ar
(-)-1
27% ee
34% yield
reaction within the ion pair f avoerd by
lower concentrations and less-polar solvents
H catalyst*
O
R1
X
O
N3 H
pKa = 5
R
enantioenriched
N
X
N 3H
R
O
X
Me
Fe
Me
1
H X
N
N
R H
1
R
N3
Me
Me
Me
N
H
Fe
Me
Me
Me
Me
Me
R H
more abundant and
more acidic then
racemic
H catalyst*
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
49
Planar-chiral Brønsted Acid catalyst
Me
N
1) 10% (+)-2
O
C
R
1
N3 H
R
toluene/hexane


-78 C or -90 C
H
N
MeO
2) MeOH, D
O
R
1
R H
1
2
3
4
5
6
7
8
9
10
11
12
R
Ph
p-ClC6 H4
p-(MeO)C6 H 4
3-thienyl
Ph
Ph
Ph
Ph
o-tol
o-tol
p-(MeO)C6 H 4
o-(MeO)C6 H4
1
R
i -Pr
i -Pr
i -Pr
i -Pr
cyclohexyl
cyclopentyl
t -Bu
Et
Et
Me
Et
Me
ee(%)
93
90
94
92
92
93
94
89
93
90
92
90
Fe
Me
Me
Me
Me
(+)-2
1.1 equiv
entry
Me
yield(%)
96
92
97
94
96
96
76
4
94
80
55
70
K. Dai, T. Nakai, J. A. C. Romero, G. C. Fu, Angew. Chem. Int. Ed. 2007, 46, 4367-4369.
50
Planar-chiral ligands
for transition metal-catalyzed reactions
• cyclopropanation
Me
Me
Me
Me
M e Fe
Me
Me
N
N
Me Fe Me
Me
Me
Me
N
H
O
MeO
1,00 equiv
MeO
H
CuOTf 0,02 equiv
OR
N2
N
Ar
4,00 equiv CH 3Cl, 20h, r.t.
Ar
CO 2R
Ar
CO 2R
trans:cis up to 90:10
ee(%) trans isomer: 77-92
yield(%) trans isomer: 50-78
H-L. Kwong, W-S. Lee, H-F. Ng, W-H. Chiu, W-T. Wong, J. Chem. Soc. Dalton Trans. 1998, 1043-1046.
51
Planar-chiral ligands
for transition metal-catalyzed reactions
Me
POCl3
HO
Ac 2 O
H2 O2, AcOH
74%
N
Me
Me
Me
Cl
88%
N
Cl
58%
N
Cl
N
OAc
O
Me
Me
Me
H2 SO4
79%
Me
Me
Me Fe
Me
Cl
Me
Me
N
30 mol% NiBr 2(PPh3) 2
N
N

i. BuLi, -78 C
Zn, Et 4NI
58%
Me Fe Me
Me
Me Fe Me
ii. CpFeCl
58%
Cl
N
Me
Me
Me
Me
Me
single diastereoisomer
Me
Me
N
Fe
Me
Me
Me
Me
N
N
Me
Fe Me
Me
Me
Me
N
Fe
R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.
N
Me
Me
Me
Me
Me
Fe
Me
N
Me
Me
Me
Me
Fe
Me
Me
Me
Me
Me
Me
Me
Fe Me
Me
Me
Me
Me
Me
Me
Me
52
Planar-chiral ligands
for transition metal-catalyzed reactions
Me
POCl3
HO
Cl
88%
N
Cl
58%
N
2
1
Me
Ac 2 O
H2 O2, AcOH
74%
N
Me
Me
Me
Cl
N
3
O
4
Me
Me
OAc
H2 SO4
79%
Me
Me
Me Fe
Me
Cl
Me
Me
N
30 mol% NiBr 2(PPh3) 2
N

i. BuLi, -78 C
Zn, Et 4NI
58%
Me Fe Me
Me
Me Fe Me
(S,S)-7
N
Me
Cl
N
5
Me
Me
(+)-6
(-)-6
Me
ii. CpFeCl
58%
Me
single diastereoisomer
Me
Me
N
Me
Not formed
N
N
Me
Me
N
Fe Me
Fe
Me
Me
MeFe
N
Me
Me
Me
Me
Me
Fe
Me
Me
Me
Me
Me
Me
Me
Fe Me
Me
Me
Fe
Me
Me
N
(S,R)-7
Me
Not formed
Me
Me
Me
Me
(R,R)-7
Me
Me
Me
(R,S)-7
R. Rios, J. Liang, M. M.-C. Lo, G. C. Fu, Chem. Commun. 2000, 377-378.
Me
Me
53
Planar-chiral ligands
for transition metal-catalyzed reactions
• cyclopropanation
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Fe
Fe
Me
Me
N
N
N
Me
Fe
N
Me
Me
Me
Me Fe Me
Me
Me
Entry
1
2
3
4
5
CO2 Ar
tBu
O
1,0 mol% CuOTf
1,2 mol% (+)-(S,S)-1
tBu
2,0 equiv
R
Ph
p-(MeO)C 6H 4
p-(F3 C)C6 H4
n-Hexyl
Et3 Si
O
R
97
95
94
94
96
:
:
:
:
:
3
5
6
6
4
ee(%) (trans)
87
75
94
78
80
CH 2 Cl2, r.t.
Ar = BHT
R
O
tBu
trans:cis
1% CuOTf
1,2% (R,R)-1
entry
Yield (%)
78
71
83
78
60
CO2 Ar
N2
tBu
CH 2Cl2 r.t.
N2
R
Me
Me
(+)-(S,S)-1
O
(R, R)-1
R
trans:cis
R
%ee, trans
yield (%)
1
Ph
96:4
94
79
2a
p-(F3 C)C6 H4
94:6
96
81
3a
p-(MeO)C6 H 4
94:6
87
90
4
PhCH 2
94:6
91
78
5
n-Hex
93:7
90
80
6
Et 3 Si
99:1
95
64
a
The yield refers to the isolated yield of a mixture of
cis ans trans isomers.
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.
54
Planar-chiral ligands
for transition metal-catalyzed reactions
Me
Me
• O-H insertion
M
e
Me
Me
Fe
N
2.0% Cu(OTf)2
3.8% (+)-1
4.0% H 2O
O
RO H
Ar
OMe
1.05 equiv
Me
Me
O
Me
Ar
ClCH2 CH 2Cl
r.t.
N2
Fe
N
OMe
Me
Me
RO H
(+)-1
R = CH 2CH2 TMS
entry
1
Ar
yield (%)
ee (%)
entry
94
90
9
Ph
Ar
yield (%)
ee (%)
(4-NHAc)C 6H 4
89
99 a
2
(2-OMe)C6 H 4
90
96
10
(4-Ph)C6 H4
91
86
3
(2-Me)C 6 H4
94
79
11
(4-Br)C6 H4
95
79
4
(2-Cl)C6 H4
96
96
12
(4-F)C6 H4
92
89
5
(2-F)C 6H 4
98
98
13
(4-CF3 )C 6H 4
90
21
6
(3-OMe)C6 H 4
96
89
14
2-naphthyl
93
84
7
(3-Cl)C6 H4
92
65
8
(4-OMe)C6 H 4
85
86
88
89
88
88
O
15
O
16
a
3-thienyl
After recrystallization.
O
Ph
O H
TMS
OMe
BF3.OEt 2
O
Ph
CH2 Cl2
r.t.
98%
T. C. Maier, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 4594-4595.
OMe
HO H
55
Planar-chiral ligands
for transition metal-catalyzed reactions
• N-H insertion
Me
Me
O
Boc
Ar
NH2
Ot-Bu
N2
ClCH 2 CH 2Cl
r.t.
N
O
Ar
BocHN H
Ot-Bu
Me
Fe
Me
1.05 equiv
Me
Fe Me
Me
Me
7.0% CuBr
6.0% AgSbF6
8.0% (-)-bpy*
Me
N
Me
Me
(-)-bpy*
Me
entry
1
Ar
Ph
yield (%)
ee (%)
75
94
2
(2-Me)C 6 H4
71
81
3
(3-Me)C 6 H4
75
88
4
(4-OMe)C6 H4
61
95
5
(4-NHBoc)C 6H 4
77
91
6
(4-Br)C 6 H4
86
95a
7
(4-CF3 )C 6H 4
89
85
8
2-naphthyl
73
91
74
90
48
80
O
9
O
10
a
3-thienyl
After recrystallization.
E. C. Lee, G. C. Fu, J. Am. Chem. Soc. ASAP
56
Planar-chiral ligands
for transition metal-catalyzed reactions
• Asymmetric [4+1] cycloaddition
Me
Me
Me
O
O
R
R
1.0% CuOTf
1.3% (-)-bpy*
OAr
1
N2
~1.2 equiv
entry
1
2
3
4
5
6
7
8
9
10
11
12
a
R
Ph
4-(F3C)C 6H 4
4-ClC6 H 4
4-(MeO)C6 H 4
Ph
Ph
N-Boc-2-pyrrolyl
Ph
Ph
Ph
n-Hex
n-Hex
R1
Ph
Ph
Ph
Ph
4-ClC6 H4
4-(MeO)C6 H 4
Ph
3-furyl
CH=CHPh
n-Bu
Ph
Me
O
R1
Me
yield(%)a
79
59
77
84
81
84
68
63
76
92
69
80
N
N
R
CH2 Cl2
r.t.
Fe Me
Me
Me
CO2Ar
dr
13:1
19:1
19:1
20:1
20:1
9:1
20:1
6:1
7:1
20:1
13:1
20:1
Isolated yield of the trans diastereomer.
S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046-1047.
ee(%)
85
76
88
92
88
93
93
87
93
78
75
71
Fe
Me
Me
Me
Me
(-)-bpy*
Me
OH
O
R
OH
O
.
BF3 OEt 2
OH
deoxy-C-nucleoside
94% ee, 20:1 dr
r.t.
86%
R
OTES
77%
over three steps
57
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
Me
Me
Me
Me
Me
Fe
N
R
R
R
O
CuLn
catalytic
2
H
N
R
O
CuLn
CuCl . 2
R1
base
-H+
Me
N
O
R
H+
R2
Me
R2
R
Fe
N
Me
Me
R
R = H: (+)-(R,R)-1
R = Me: (+)-(R,R)-2
Me
1
CuLn
H
N
1
R
R
1
R
N R2
[3+2]
LnCu
O
R1
R
N
L nCuO
R
2
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.
58
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
Me
Me
Me
Me
Me
Fe
N
R
R
R
O
CuLn
catalytic
2
H
N
CuCl
R1
2
base
-H+
R
O
Me
N
O
R
H+
R2
Me
Me
R
R = H: (+)-(R,R)-1
R = Me: (+)-(R,R)-2
Me
1
CuLn
H
N
R1
R
1
R
LnCu
O
R1
R
N R2
[3+2]
CuLn
.
Me
R2
R
Fe
N
N
L nCuO
R
2
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.
59
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
Me
Me
R1
R
O
N
R1
R
1% CuCl
1.1% (R,R)-2
H
Me
Fe
N

Cy 2NMe, -20 C
Ar
O
Ar
MeCN
Cy
O
O
H
Me
O
entry
OMe
nitrone
R
N
Ph
cis:trans
%ee cis
Me
(R,R)-2
yield cis(%)
Ph
95:5
92
65
2
3
4-(F3 C)C6 H4
95:5
93
57
3
3
4-(MeO)C 6H 4
92:8
91
60
4
3
PhCH2
71:29
73
43
a
4
Ph
90:10
90
56
a
4
90:10
91
45
1-cyclhexenyl
Me
4
3
6
Me
Me
1
5
a
Me
Fe
N
H
Ph
3
N
Me
N
Me
Me

Run at -40 C
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.
60
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
Me
Me
Me
Me
Me
Fe
N
Me
Me
Fe
N
O
P
Me
Me
Me
Fe
Me
Me
N
R
Me
i Pr
O
N
P
Me
Fe
Me
O
O
Me
Me
N
N
(R,R)-2
H
Me
Me
Me
Me
Me
i Pr
i Pr
1
5a: R = i Pr; 5b: R = tBu
4
6
5% CuBr
5.5% ligand
O
Entry
N
Cy 2 NMe 0.5 equiv
Ligand
1
a
N

0 C MeCN
Ar
1
O
ee(%)
6
Ar
Yield (%)
30
a
2
4
62
39
3
5a
88
74
4
5b
90
47
5
6
58
52
R,R enantiomer
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
61
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
O
5% CuBr
5.5% ligand
O
N
N
Cy 2NMe 0.5 equiv Ar

Ar
Entry
Product
1
88
4
N
O
86
60
90
N
5
Ar
ee(%)
Yield (%)
5b
90
64
6
85
53
5b
91
68
S
Me
N
N
Fe Me
Me
1
Me
O
N
46
Ar
6
N
O
P
O
O
N
N
Me
Ligand
O
5a
Me
Fe
Me
4
Me
Me
Me
74
OMe
Me
Me
Product
O
N
Ar
Entry
Ar
O
3
Yield (%)
N
Ar
O
Ar
ee(%)
O
O
1
2
Ligand
0 C MeCN
Me
iPr
iPr
Me
Fe
H
N
Me
O
i Pr
O
N
P
R
Me
Me
4
5a: R = i Pr; 5b: R = t Bu
Me
Fe
Me
Me
Me
Me
6
(R ,R)-2
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
R
1
H
N
R2
O
H
+
R1
R
usual
Kinugasa Ln CuO
pathway
N
R
E+
R
R
1
E
N
2
O
R2
O
Me
Fe
Me
OTMS
CuBr (5%)
5a (5.5%)
I
O
N
Ar
3.0 equiv
3.0 equiv
O
N Ar
i Pr
Me
5a
KOAc (1.0 equiv)
MeCN, r.t.
CuBr (5%)
5a (5.5%)
Me
Me
N
O
Ar
85% ee
76% yield
OTMS
I
N
Ph
2.0 equiv
Ar = p-carboethoxyphenyl
S
H
P
S
Ph
2.0 equiv
KOAc (1.0 equiv)
MeCN, r.t.
Ar = p-carboethoxyphenyl
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
N
O
Ar
90% ee
70% yield
63
Planar-chiral ligands
for transition metal-catalyzed reactions
• -lactams synthesis, the Kinugasa reaction
R
R
1
H
N
R2
O
H
+
R1
R
usual
Kinugasa Ln CuO
pathway
N
R
E+
R
R
1
E
N
2
O
R2
O
Me
Fe
Me
OTMS
CuBr (5%)
5a (5.5%)
I
O
N
Ar
3.0 equiv
3.0 equiv
O
N Ar
i Pr
Me
5a
KOAc (1.0 equiv)
MeCN, r.t.
CuBr (5%)
5a (5.5%)
Me
Me
N
O
Ar
85% ee
76% yield
OTMS
I
N
Ph
2.0 equiv
Ar = p-carboethoxyphenyl
S
H
P
S
Ph
2.0 equiv
KOAc (1.0 equiv)
MeCN, r.t.
Ar = p-carboethoxyphenyl
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082-4085.
N
O
Ar
90% ee
70% yield
64
Conclusion
R1
R
• Nucleophilic catalysts
•Brønsted acid
catalyst
N
O
NTf
R
Ar
t-Bu
Ar
NTf
R
OH
H
t -Bu
R
R
CO2 Ar
O
1
R
NH
R
N
Ph
O
O
Me
N3 H
H
R1
O
O
CO 2CMeCy 2
OTES
R
•Transition-metal ligands
O
Ar
R
MeOH
H
N
R1
O
R
1
MeO
OR
O
Et
MeO
O
Ph
R
O
Oi -Pr
Ar
N
Bn
C
Ar
OR
O
O
BocHN H
NTs
Ar
O
CO 2CMeCy 2
R
NTs
O
O
Ot-Bu
OMe
RO H
R
1
NC
NC
Ar
Ph
O
O
O
O
CO2 Ar
O
Ar
O
O
BnO
R H
Me
H Ph
O
R N
Ar
• Building quaternary centers
65