O
HO
H
Me
O
OH
Me
O
H
F
Transition-Metal Catalyzed
Asymmetric Conjugate Addition
of Organometallic Reagents
CO2Me
O
N
H
O
Me
Ashley M. Berman
O
O
Introduction to the Asymmetric Conjugate
Addition (ACA) of Organometallic Reagents
R2
R1
R3-M
EWG
R2 E
R2
R1 ∗
R3
E
R1 ∗
∗ EWG
EWG
3
R
EWG = COR, COOR, CONR2, NO2, PO(OR)2
R3 = alkyl, aryl, alkenyl, alkynyl
• Powerful tool for the construction of C-C bonds
• Wide availability of Michael acceptors and organometallic
reagents
• Possibility to set multiple stereocenters in a single synthetic
operation
Pertinent Reviews: 1) Rossiter, B. E.; Swingle, N. Chem. Rev. 1992, 92, 771.
2) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
3) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 2, 171.
4) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
Strategies for ACA
A. Covalently Bound Chiral Auxiliaries
R*
R1
R2-M
R1
EWG
OR*
R
R*
N
R
S
O
EWG
EWG
R2
R*
O
O
∗
Ar S
O
Chiral Esters
O
R1 ∗
R2
O
N
∗
R*
Chiral Amides
SiPhMe2
O
N-Enoyl-Sultams
1) EtCu . P(Bu)3
2) LiOH
Chiral Sulfoxides
HO
SiPhMe2
O
Et
62 % yield
92 % ee
Oppolzer, W.; Poli, G.; Kingma, A.; Starkemann, C.; Bernardinelli, G. Helv. Chim. Acta. 1987, 70, 2201.
B. Heterocuprates
R1 ∗
R1
R 2-Cu-ZR * M
EWG
ZR * = OR * , NR 2*
EWG
R2
Preparation of Heterocuprates
Li-ZR*
O
1) CuX
2) RM
R-Cu-ZR* M
M = Li, MgX
O
R-Cu-ZR*
Me
M
heterocuprate =
Et
EtCu O
Ph
N
Me
90 % yield
92 % ee
Corey, E. J.; Naef, R.; Hannon, F. J. J. Am. Chem. Soc. 1986, 108, 7114.
NMe2 Li
C. External Chiral Ligands
R2-M,
L*
R1
R1 ∗
EWG
EWG
R2
Organocuprates
O
O
EtCu(CN)Li (1.5 eq)
L* (4.5 eq)
L* =
Et
PPh2
N
t-Bu
O
89 % yield
91 % ee
RLi
n-BuLi (3 eq)
L* (4.2 eq)
t-Bu
Me
O
O t-Bu
OMe
t-Bu
Me
O
Bu
OMe
L* =
O t-Bu
77 % yield, 99 % ee
1) Kanai, M.; Tomioko, K. Tetrahedron Lett. 1994, 35, 895.
2) Asano, Y.; Iida, A.; Tomioko, K. Tetrahedron Lett. 1997, 38, 8973.
N
N
D. Transition-Metal Catalysis
R1
R2-M
TM (cat), L* (cat)
R1 ∗
EWG
R2-M
RMgX
R3Al
R2Zn
RB(OH) 2
EWG
R2
TM
Ni
Co
Cu
Rh
Cu/RMgX Catalytic System
O
Ph2P
O
CuI (10 mol %)
L* (12 mol %)
*
L =
BuMgCl
Ph
N
O
Bu
97 % yield
83 % ee
Strangeland, E. L.; Sammakia, T. Tetrahedron 1997, 53, 16503.
Fe
• The Cu/R2Zn and Rh/RB(OH)2 catalytic systems have
been the most thoroughly examined
• These systems offer complimentary methods to 1,4 adducts
Cu (cat), L* (cat)
R22 Zn
R1
R1 ∗
EWG
R2
R2 = alkyl
EWG
Rh (cat), L* (cat)
2
R B(OH)2
R1 ∗
EWG
R2
R2 = aryl, alkenyl
The Cu/R2Zn Catalytic System
A. Mechanistic Considerations
O
O
OZnR
CuX, 2L*
R2Zn
C7H8 or CH2Cl2
∗
E (usually H2O)
E ∗
∗
R
R
R2Zn
RZn
O
E ∗
E
∗
R
O
O
L2 CuX
∗
L2CuR
RZnX
R
L
L Cu
R
O
XZn
R
Theoretical analysis of R2CuLi·LiCl conjugate addition
Li
R
O
Cu
R
Electron
Transfer
Li
R
O
Cu
Li
R
Cu(I)
Cu(III)
R
Int
R
O
Cu
Li
Li
R
R
O
R
O
Cu
Cu
R
R
TS
Cu(III)
Cu(I)
TS
R
Energy
R
Li
Int
O
Cu
R
FMO Interaction
HOMO
Cu(I)
LUMO
P
P
Reaction Coordinate
Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39, 3750.
d-
π*
B. Ligand Development
R22Zn
CuX, L*
R1
R1 ∗
EWG
EWG
R2
Trivalent Phosphorus Ligands
Monophosphorus
O
P ZRn*
O
*
O
O
P X P
O
O
*
*
Diphosphorus
X = binaphthol, biphenol, diaminoalkyl
ZRn * = OR*, NR2*, R*
O
= binaphthol, biphenol, TADDOL, tartrate
*
O
Peptide-Based Ligands
*
*
N AA1 AA2
PPh2
Miscellaneous Ligands
Phosphane
t-Bu P
Me
AA = amino acid
P Me
t-Bu
Phosphane P, N
O
NH
N
PPh2 Me
Pertinent Review: Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
1. Trivalent Phosphorus Ligands
Feringa’s Phosphoramidites
O
Et2Zn
Ph
Ph
Et2Zn
O
L* =
O
Cu(OTf)2 (3 mol %)
L* (6.5 mol %)
78 % yield, 63 % ee
o
C7H8, -15 C
Cu(OTf)2 (3 mol %)
L* (6.5 mol %)
Et
Ph
C7H8, -15o C
Ph
Et
88 % yield, 87 % ee
O
O
P N
O
De Vries, A. H. M; Meetsma, A.; Feringa, B. L. Angew. Chem. Int. Ed. 1996, 35, 2374.
O
R2Zn
n
Cu(OTf)2 (2 mol %)
L* (4 mol %)
C7 H8, -30oC
O
Me
L*
n
O
P N
O
=
R
Ph
Ph
Me
Entry
R2Zn
n
% yield
% ee
1
Et
1
94
98
2
iPr
1
95
94
3
(CH2)5OAc
1
77
95
4
Et
2
95
98
5
Et
3
95
97
6
Et
0
75
10
1) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M.. Angew. Chem. Int. Ed. 1997, 36, 2620.
2) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
Ligands for ACA to cyclopentenone
O
O
Cu(OTf)2 , L
*
Et2 Zn
∗
Et
L*
Entry
% yield % ee
Ph
Me
1
O
P N
O
Ph
N P
O
O
trace
83
41
94
92
98
Me
R
2
O
P O
O
O
N
t-Bu
R
O
3
O P
O
R=
O
P
O
O
=
O
O
1) Mandoli, A.; Arnold, L. A.; Salvadori, P.; Feringa, B. L. Tetrahedron Asymmetry 2001, 12, 1929.
2) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
3) Liang, L.; Au-Yeung, T. L.; Chan, A. S. Org. Lett. 2002, 4, 3799.
TADDOL Derived Ligands
O
Et2Zn
C7H8,
Ph
Ph
Et2Zn
O
Cu(OTf)2 (1 mol %)
L* (2 mol %)
95 % yield, 96 % ee
-30oC
Et
Cu(OTf) 2 (1 mol %)
L* (2 mol %)
Ph
C7H8, -20oC
O
Ph Ph
L* =
Me
O
Me
O
Ph
Et
O
96 % yield, 50 % ee
Ph
O
P O
O
Ph Ph
Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; et. al. Eur. J. Org. Chem. 2000, 4011.
Miscellaneous Phosphorus Ligands
O
O
Cu(OTf)2 (1 mol %)
L* (2 mol %)
Et2Zn
THF, -30oC
O
P
O
Et
L* =
89-94 % conversion, 95 % ee
Ph
Ph
Et2Zn
O
Cu(OTf)2 (1 mol %)
L* (2 mol %)
THF,
Fe
P
Ph
-30o C
O
O
Ph
Et
O
29-37 % conversion, 69-71 % ee
O
Et2Zn
O
Cu(OTf)2 (1 mol %)
L* (1 mol %)
C7H8, -80oC
∗
Et
91 % yield, 97 % ee
L* =
Ph
Ph
O
Et2Zn
Cu(OTf)2 (1 mol %)
L* (1 mol %)
C7H8, -80oC
Ph
t-Bu P
Me
Ph
Et
O
96 % yield, 71 % ee
1) Reetz, M. T.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002, 43, 1189.
2) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988.
P Me
t-Bu
2. Peptide-Based Ligands
Ligand for ACA to aliphatic enones
R1
R2
Et2Zn
O
t-Bu
CuOTf (1 mol %)
L* (2.4 mol %)
o
R1
R2
o
C7H8, -20 C to 22 C
Et
N
L* =
O
PPh2
H
N
O
NHBu
O
Ot-Bu
Entry
R1
R2
% yield
% ee
1
Ph
Me
90
93
2
n-Pent
Me
85
95
3
n-Pent
tBu
42
58a
4
iPr
Me
69
91a
5
(CH2)3OAc
Me
88
89a
(a) Absolute configuration not determined
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779.
Ligand for ACA to Cyclic Trisubstituted Enones
O
R1
R2Zn
iPr
O
CuOTf (2.5 -5 mol %)
L* (6 - 12 mol %)
R1
C7H8, 0oC
L*
=
PPh2
R
NHBu
N
anti:syna % yield
O
Entry
R1
R2Zn
1
iPr
Et
16:1
77
96
2
n-Hex
iPr
25:1
66
97
3
Me
(CH2)5OAc
25:1
47
94
% ee
(a) Following base induced isomerization of 1,4 adduct
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362.
Other Peptide-Based Ligands Developed by Hoveyda
iPr
H
N
N
PPh2
Me
O
O
NHBu
N
H
PPh2
O
CuOTf,
L*
OtBu
H
N
O
O
NHBu
iPr
Ligand for ACA to unsaturated Nacyloxazolidinones
Ligand for ACA to cyclic disubstituted enones
O
H
O
O
O
Et2Zn
Me
Et
78 % yield, 98 % ee
N
Et
CuOTf, L*
O
Et2 Zn
Me
O
O
N
O
95 % yield, 95 % ee
1) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755.
2) Hird, A. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 1276.
C. ACA to other Michael Acceptors
1. Nitroalkenes (Acyclic Substrates)
OMe
MeO
NO2
R2Zn
Cu(OTf)2 (1 mol %)
L* (2 mol %)
C7 H8, -45oC
Me
OMe
MeO
NO2
O
P N
O
L* =
R
Me
Entry
R2Zn
% yield
% ee
1
Et
78
96
2
Me
86
98
3
Bu
75
95
4
(CH2)5OAc
74
88
Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700.
Ph
Ph
Conversion of 1,4 adducts into versatile chiral building blocks
OMe
MeO
NO2
Me
98 % ee
1) Raney Ni, H2
2) Boc2O, NEt3
OMe
MeO
NHBoc
Me
64 % yield, 98 % ee
H5IO6, H2O
CrO3 (1 mol %)
Amberlyst-15, H2O
O
O
HO
NHBoc
Me
82 % yield, 98 % ee
H
NHBoc
NaBH4
Me
89 % yield, 98 % ee
HO
NHBoc
Me
91 % yield, 98 % ee
Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700.
Cyclic Substrates
NO2
R2Zn
CuOTf (0.5 - 5 mol %)
L* (1 - 10 mol %)
t-Bu
NO2
R
L* =
C7H8 , 0o C
N
PPh2
H
N
O
NHBu
O
OBn
syn:antia % yield
entry
R2Zn
% ee
1
Et
85:15
92
96
2
Me
83:17
72
95
3
(CH2)4OAc
81:19
76
95
(a) Base induced isomerization to anti 1,4 adduct proceeds without lowering of enantiomeric excess
Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192.
Cyclic Substrates (continued)
NO2
Me
Zn
Me
2
NO2
CuOTf (2.5 mol %)
L* (5 mol %)
Me
Me
C7H8, 0oC
61 % yield, 93 % ee, 87:13 anti:syn
NO2
O
Me2Zn
Me
1) CuOTf (2.5 mol %)
L* (5 mol %)
2) H2SO4, H2O
86 % yield, 96 % ee
t-Bu
L* =
N
PPh2
H
N
O
NHBu
O
OBn
Luchaco-Cullis, C. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192.
2. N-Acyloxazolidinones
O
R1
O
N
O
R2 Zn
Cu(OTf)2 (0.5 - 2.5 mol %)
L* (2.4 - 6 mol %)
C7H8,
R
R1
O
O
N
O
0oC
Me
O
L* =
N
H
PPh2
H
Entry
R1
R2Zn
% yield
% ee
1
Me
Et
95
95
2
iPr
Me
88
92
3
Me
iPr
95
76
4
Me
(CH2)3 iPr
61
93
Hird, A. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 1276.
OtBu
H
N
O
O
NHBu
i
Pr
N-Acyloxazolidinones (continued)
Me
Me
AlMe3,
MeONHMe Me
O
Me
Me
Me
N
OMe
Me
O
Me
O
N
t-BuLi
Me
O
Me
Et
Me
O
O
N
95 % ee
Et
LiOH, H2O2
O
t-Bu
81 % yield, 93 % ee
93 % ee
74 % yield, 93 % ee
O
Me
O
OH
98 % yield, 95 % ee
Hird, A. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 1276.
D. Tandem Reactions
O
∗
H3O+
R
OZnR
O
CuX, L*
R2Zn
∗
R
O
E
OE
E ∗
chiral zinc enolate
∗
∗
R
R
E = R1X, R1CHO, R13SiX
X
, R
• Following ACA, a chiral zinc enolate is generated
• While commonly quenched with H2O, this enolate can
likewise be trapped with other electrophiles
O
R1
O
R2
1. Alkylation of Zinc Enolates
TsO
Et
CuOTf (1 mol %)
L*(2.5 mol%)
O
Me
OZn
Et
Me
Et2Zn, C7H8, 22oC
O
Me
OTs
81 % yield, 95 % ee
98:2 anti:syn
Et
Et
O
O
Me
Me
OTs
78 % yield, 85 % ee
98:2 anti:syn
91 % yield, 95 % ee
no cyclized product observed
t-Bu
L* =
N
PPh2
H
N
O
NHBu
O
Ot-Bu
Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779.
Alkylation of Zinc Enolates - Application in the Enantioselective
Synthesis of Clavularin B
O
I
Me
Me2Zn, C7H8, -30oC
iPr
L* =
N
PPh2
H
N
O
OZnMe
CuOTf (1 mol %)
L* (2 mol %)
Me
HMPA
80 % yield, 97 % ee
15:1 trans:cis
O
NHBu
O
1) TMSOTf, NEt3
2) Pd(OAc)2 (50 mol %), Cu(OAc)2
O
O
Me
Me
Clavularin B
PdCl2 (20 mol %)
CuCl2, DMF, H2O
O
Me
61 % yield
42 % overall yield, 97 % ee
15:1 trans:cis
Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755.
2. Allylation of Zinc Enolates
O
CuOTf2 (0.5 mol %)
L* (1 mol %)
OZn
O
Pd(PPh3)4 (4 mol %)
Et2 Zn, C7H8, -30oC
OAc
Et
Et
88 % yield, 96 % ee
9:1 trans:cis
MgBr
HO
HO
Grubbs (7.5 mol %)
92 % yield, 96 % ee
Et
Et
60 % yield, 96 % ee
all trans
Me
L*
=
O
P N
O
Ph
Ph
Me
Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2001, 735.
3. Silylation of Zinc Enolates
Cu(OTf)2 (2 mol %)
L* (4 mol %)
O
Et2Zn
C7 H8, -30oC
OZnEt
O
H2O
Et
Et
97 % yield, 99 % ee
TMSOTf
1)
HO2C
OTMS
O3, Me2 S
CHO
Me
N I
Me
O
2) mCPBA
Et
82 % yield
99 % ee
Et
72 % yield
99 % ee
Et
1) MeLi
2) PhNTf2
mCPBA
O
OTf
OTMS
Me
L* =
O
P N
O
Ph
Ph
Et
91 % yield
99 % ee
Et
74 % yield
99 % ee
Me
Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 3835.
4. Tandem 1,4 Addition/Aldol Reaction
O
O
Bu2 Zn
O
Ph
O
Cu(OTf)2 (2 mol %)
L* (4 mol %)
C7H8 , -45oC;
ArCHO
H
Ph
H
Ar
O
O Bu
Ph
O
OH
H
OH
Ar
H
O
O Bu
Ph
Ph
Ph
97:3 trans-threo:trans-erythro
64 % yield
97 % ee
Zimmerman-Traxler Transition-State Model
Ar
Bu
Bu
vs
O H
O
Ph
H
O
O ZnBu
O
O ZnBu
Ph Ph
Ph
Me
O Ar
O
L* =
O
P N
O
Me
major diastereomer
minor diastereomer
Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244.
Ph
Ph
Application in the Enantioselective Synthesis of (-)
Prostaglandin E1 Methyl Ester
HO
O
OH
H
HO
OH
O
CO2Me
H
H
CO2Me
OH
Ph
Ph
PGE1 methyl ester
O
O
SiPhMe2
O
H
OH
SiPhMe2
H
O
Zn
O
CO2Me
O
OH
2
CO2Me
Ph
Ph
Ph
Ph
Tandem 1,4 addition / Aldol
Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2002, 67, 7244.
O
O
Cu(OTf)2 (3 mol %)
L* (6 mol %)
Zn
O
CO2 Me
O
Ph
OH
SiPhMe2
O
2
O
SiPhMe2
CO2Me
OH
Ph
H
Ph
H
Ph
83:17 epimeric ratio
OH OH
H
O
OH
Zn(BH4 )2
SiPhMe2
60 % yield
CO2Me
Ph
Ph
isolated as a single isomer
63 % yield, 94 % ee
HO
H
Me
L* =
O
P N
O
Me
Ph
O
H
OH
CO2Me
Ph
(-) PGE1 methyl ester
7 % overall yield, 94 % ee
The Rh/RB(OH)2 Catalytic System
A. Mechanistic Considerations
O
O
RhX, L*
RB(OH)2
∗
dioxane/H2O (10:1)
R = aryl, alkenyl
R
O
∗
RB(OH)2
R
L
transmetallation
Rh OH
L
hydrolysis
hydroxorhodium
HO-B(OH)2
H2O
O
L
Rh
L
L
Rh R
L
∗
R
oxa-pi-allyl complex
O
migratory insertion
arylrhodium complex
Preparation of Key Intermediates in Catalytic Cycle
migratory insertion
∗
P
Rh
Ph3P
O
∗
t-Bu
P
Ph
Ph
t-Bu
oxa-pi-allyl complex
phenylrhodium complex
transmetallation
P
O
P Rh
H2O
PhB(OH)2
∗
P
H
O
P
Rh Rh
P O
P
H
hydrolysis
O
∗
Ph
t-Bu
hydroxorhodium complex
P
=
P
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
PPh2
PPh2
Model of Stereoinduction (BINAP System)
P
P
Rh
O
P
vs
Rh
O
R
R
α re face
P
P
α si face
O
P
P
Rh
P
Rh
R
O
R
O
R
migratory insertion
H2O/RB(OH)2
hydrolysis/transmetallation
P
P
Rh
R
O
H
Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579.
B. Ligand Development
O
P
O
P O
O
PPh2
PPh2
(Reetz)
diphosphonites
BINAP
Me
O
P N
(Feringa)
O
Me
phosphoramidites
N
t-Bu
Ph
PPh2
O
(Tomioko)
amidomonophosphines
(Hayashi)
Ph
dienes
1) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083.
2) Boiteau, J.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 681.
3) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.; Tomioko, K. J. Am. Chem. Soc. 2002, 124, 8932.
4) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K.; J. Am. Chem. Soc. 2003, 125, 11508.
C. ACA to Enones
O
RB(OH)2
O
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
dioxane/H2O (10:1), 100o C
R
Entry
R
% yield
% ee
1
Ph
64
97
2
4-MePh
99
97
3
4-CF3Ph
70
99
4
(E)-1-heptenyl
88
94
Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579.
Other cyclic enones
O
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
PhB(OH)2
O
93 % yield, 97 % ee
dioxane/H2O (10:1), 100oC
Ph
O
Rh(acac)(C2H4 )2 (3 mol %)
(S)-BINAP (3 mol %)
PhB(OH)2
O
dioxane/H2O (10:1), 100oC
51 % yield, 93 %ee
Ph
Acyclic enones
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
Me
Me
Me
O
PhB(OH)2
dioxane/H2O (10:1), 100oC
Me
Me
∗
Ph
Me
O
82 % yield, 97 % ee
Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120, 5579.
D. ACA to other Michael Acceptors
1. Nitroalkenes (Cyclic Substrates)
NO2
RB(OH)2
R
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
R
NO2
dioxane/H2 O (10:1), 100oC
NO2
NaHCO3
EtOH
% ee
cis:trans following
base isomerization
89
98.5
3:97
88:12
89
97.6
3:97
4-CF3Ph
85:15
88
99.0
3:97
(E)-1-heptenyl
75:25
90
82.9
10:90
Entry
R
cis:trans % yield
1
Ph
87:13
2
4-MePh
3
4
Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
Acyclic substrates
NO2
PhB(OH)2
Ph
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
∗
NO2
dioxane/H2O (10:1),100oC
39:61 cis:trans
33 % yield, 96.8 % ee
NO2
Me
Me
PhB(OH)2
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
dioxane/H2O (10:1), 100oC
Ph
∗
Me
NO2
Me
88 % yield, 63 % ee
Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
Conversion of 1,4 adducts into versatile chiral building blocks
CO2 Me
Ph
Ph
H2, Raney Ni
NO2
CO2Me
N
H
PhCH2NMe3OH
single isomer
91 % yield, 98 % ee
single isomer
91 % yield, 98 % ee
Ph
NO2
87:13 cis:trans
O
1) NaOMe, MeOH
2) H2SO4, MeOH
3) HCl, H2O
98 % ee
Ph
O
76 % yield, 90 % ee
Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
2. 1-Alkenylphosphonates
Me
O
P(OEt)2
(PhBO)3
Rh(acac)(C2H4 )2 (3 mol %)
(S)-BINAP (3 mol %)
H2O (1 eq to B), dioxane,
Me O
P(OEt)2
(PhBO)3
100oC
Ph
Me
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (3 mol %)
H2O (1 eq to B), dioxane, 100oC
Ph
Me
O
P(OEt)2
94 % yield, 96 % ee
O
P(OEt)2
96 % yield, 89 % ee
Conversion to Optically Active Alkenes
Ph
Me
O
P(OEt)2
96 % ee
1) PCl5
2) PhOH, NEt3
Ph
Me
1) t-BuLi
O
2) PhCHO
P(OPh)2
Ph
Me
Ph
82:18 E:Z
92 % ee
Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591.
3. α,β-Unsaturated Esters
Rh(acac)(C2H4) 2 (3 mol %)
(S)-BINAP (3 mol %)
O
O
[PhB(OMe)3]Li
R
Ph
dioxane/H2O,100oC
O
O
Entry
R
% yield
% ee
1
Me
99
89
2
Et
99
91
3
i-Pr
96
95
4
t-Bu
92
96
R
Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi, T. Tetrahedron Asymmetry 1999, 10, 4047.
4. α,β-Unsaturated Amides
Rh(acac)(C2H4)2 (3 mol %)
(S)-BINAP (4.5 mol %)
O
R1
PhB(OH)2
NHR2
K2CO3, dioxane/H2O (10:1)
100oC
Ph
R1
O
NHR2
Entry
R1
R2
% yield
% ee
1
Me
H
62
89
3
Me
Cy
80
93
4
Me
Bn
85
93
5
n-Pent
Bn
89
91
6
iPr
Bn
19
95
7
Ph
Bn
trace
-
Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944.
Enantioselective Synthesis of 4-Aryl-2-Piperidinones
Ar
Rh(acac)(C2H4)2 (3 mol %)
(R)-BINAP (3 mol %)
(ArBO)3
N
H
dioxane/H2 O,
O
Ar = 4-FPh
100oC
N
H
O
73 % yield, 97.8 % ee
F
F
O
O
O
N
H
N
H
(-) Paroxetine
O
4-aryl-2-piperidinone
Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
N
H
O
E. ACA in the Absence of Water; Chiral Boron Enolates
B
O
O
[Rh(OMe)(COD)]2 (1.5 mol %)
(S)-BINAP (3 mol %)
Ph B
C7H8, 80oC
Ph
characterized by 1H NMR, 11B NMR, and 13C NMR
O
O
B
O
MeOH
Ph
MeOD
Ph
Ph
81 % yield, 98 % ee
EtCHO
O
H
OH
D
1) n-BuLi
Br
2)
81 % yield, 98 % ee
single isomer
O
Et
Ph
46 % yield, 98 % ee
single isomer
Ph
71 % yield, 98 % ee
single isomer
Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2003, 68, 1901.
Mechanistic Considerations
∗
B
O
O
P
P
Rh
Ph
phenylrhodium
Ph
migratory insertion
transmetallation
Ph B
O
P
Rh P
∗
∗
P
PPh2
PPh2
=
P
Ph
oxa-pi-allyl complex
∗
O
∗
P
Ph3P
Rh
O
P
Rh P
P
Ph
phenylrhodium
Ph B
∗
B
O
P
Rh
Ph3P Ph
P
Ph
oxa-pi-allyl complex
Ph
phenylrhodium
Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2003, 68, 1901.
Chiral Titanium Enolates
O
O
Ti(Oi-Pr)3
[Rh(OH)((S)-BINAP)]2 (1.5 mol %)
PhTi(Oi-Pr)3
THF, 20oC
Ph
characterized by 1H NMR
OSiMe3
O
Ti(Oi-Pr) 3
LiOi-Pr, TMSCl
84 % yield, 99.5 % ee
Ph
Ph
LiOi-Pr, ClCOt-Bu
LiOi-Pr
allyl bromide
EtCHO
OCOt-Bu
O
Ph
O
Et
Ph
82 % yield, 99 % ee
79 % yield, 99 % ee
Ph
95:5 E:Z
45 % yield, 99 % ee
Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem. Soc. 2002,124, 12102.
Titanium Enolates (continued)
O
OSiMe3
1) Rh/BINAP cat., PhTi(Oi-Pr)3
2) LiOi-Pr, TMSCl
62 % yield, 99.8 % ee
Ph
O
OSiMe3
1) Rh/BINAP cat., PhTi(Oi-Pr)3
2) LiOi-Pr, TMSCl
89 % yield, 98 % ee
Ph
1) Rh/BINAP cat., PhTi(Oi-Pr)3
2) LiOi-Pr, TMSCl
O
Me
Me
Me
Ph
Me
OSiMe3
Me
77 % yield, 99.8 % ee
Me
Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem. Soc. 2002,124, 12102.
Conclusion
• Numerous strategies have been developed for the ACA of
organometallic reagents, including transition-metal catalysis
• The Cu/R2Zn and Rh/RB(OH)2 catalytic systems offer
complimentary methods to 1,4 adducts
Cu (cat), L* (cat)
R1 ∗
R
EWG
2
R2 = alkyl
R22Zn
R1
Rh (cat), L* (cat)
EWG
R2B(OH)2
R1 ∗
R
EWG
2
R2 = aryl, alkenyl
Acknowledgements
Prof. Jeffrey Johnson
The Johnson Research Group
Model of Stereoinduction
O
P(OEt)2
Me
E-isomer
P
P
= PO(OEt) 2
Ph
Me
Z-isomer
P
O
P(OEt)2
P
Rh
Rh
Me
Ph
Me
P
Ph
P
Rh
Me
P
P
Rh
Ph
Me
Ph
Me
O
P(OEt)2
=
Me
Ph
P(OEt)2
O
H
P(OEt)2
Ph Me O
Ph
=
Me
O
P(OEt)2
Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591.