Transcript Asymmetric Baylis-Hillman Reaction

Asymmetric Baylis-Hillman
Reaction
Matt Bowman
Blackwell Group
April 24, 2003
Outline
General remarks
History
Utility
Mechanism
Improvements
Asymmetric variants
General Reaction
O
+
R
EWG
H
OH
Nuc:
R
EWG
Strengths:
Complete Atom Economy
Adducts are “Loaded with Functionality”
Weaknesses:
Long Reaction Times
Side Reactions
Early Years
1968- Morita used Cy3P as a catalyst
“Carbinol Addition”
O
O
+
Me
85% Yield
Cy3P
OMe
H
x
OH
Me
Dioxane
23% Conversion
=
O
OMe
20% Overall Yield
Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.
Early Years
1968- Morita used Cy3P as a catalyst
“Carbinol Addition”
O
O
+
Me
85% Yield
Cy3P
OMe
H
x
OH
Me
Dioxane
23% Conversion
=
O
OMe
20% Overall Yield
Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.
Early Years
1968- Morita used Cy3P as a catalyst
“Carbinol Addition”
O
O
+
Me
85% Yield
Cy3P
OMe
H
x
OH
Me
Dioxane
23% Conversion
=
O
OMe
20% Overall Yield
2 hours at reflux
Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.
Middle Ages
1972- A.B. Baylis and M.E.D. Hillman
Celanese Corporation
O
O
+
Me
OEt
H
OH
DABCO
Me
O
OEt
N
75% Overall Yield
DABCO=
N
1 week room temperature
Baylis, A.B.; Hillman, M.E.D. German Patent 2155113, 1972; Chem. Abstr. 1972, 77, 34174q.
Renaissance
1983-1988
Reaction scope was explored.
Main Players: Drewes and Basavaiah
1988- Termed “Baylis-Hillman reaction”
Drewes, S.E.; Roos, G.H.P. Tetrahedron 1988,44, 4653-4670.
Today
1988-Present day attention
New catalysts
Broadened scope
Asymmetric variants
Basavaiah, D.; Rao, A.J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811-891.
Utility
Inexpensive starting materials
Lots of functionality
Complete atom economy
Amenable to industrial scale reactions
Utility: Sampatrilat
Pfizer
Inhibitor
zinc metalloprotease
neutral endopeptidadase
angiotensin converting enzyme
NHSO2Me
H2N
O
N
H
HO2C
H
N
O
CO2H
OH
Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article
Utility: Sampatrilat
O
OH
O
+
H
OtBu
+
H
N
HO
O
OtBu
NHSO2Me
H2 N
O
N
H
HO2C
H
N
O
CO2 H
OH
Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article
Utility: Sampatrilat
O
OH
O
+
H
OtBu
+
H
N
HO
O
OtBu
NHSO2Me
H2N
O
N
H
HO2C
H
N
O
CO2H
OH
Dunn, P.J.; Hughes, M.L.; Searle, P.M.; Wood, A.S. Org. Proc. Res. Dev. ASAP Article
Utility:
Natural Products
O
O
O
OH
O
OH
OH
MeO
O
Tulipalin B
Furaquinocin E
OH
CO2H
HO
O
(-)-mycestericin E
NH2
Proposed Mechanism
O
O
O
EtO
H
EtO
O
Me
O
Me
EtO
+
H
O
+
+
N
N
N
N
N
N
OH
Me
EtO
O
+
H
+
OH
O
Me
EtO
+
N
N
N
N
EtO
OH
Me
N
+
N
Mechanistic Studies
N
O
N
H
K1
N
Me
+
O
Me
k2
k3
N
+
N
N
N
N
N
N
OH
Me
rate=k[Acrylonitrile][MeCHO][DABCO]
kH/kD=1.03  0.1
Strong solvent dependence
Polar Protic Solvents
Hill, J.S.; Isaacs, N.S. J. Phys. Org. Chem. 1990,40, 5611-5614.
Baylis-Hillman Advances
Focus on increasing reaction rate
Baylis-Hillman Advances
Focus on increasing reaction rate
Increased pKa of Lewis base
N
N
8.5
<
OH
N
H
N
<
9.9
La(OTf)3
Triethanolamine
DABCO
N
N
11.3
TiCl4
Me2S
Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700.
Baylis-Hillman Advances
Focus on increasing reaction rate
Increased pKa of Lewis base
N
N
<
8.5
OH
N
<
N
N
9.9
N
11.3
Lewis acid
La(OTf)3
Triethanolamine
DABCO
TiCl4
Me2S
Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700.
Aggarwal, V.K.; Mereu, A.; Tarver, G.J.; McCague, R. J. Org. Chem. 1998, 63, 7183-7189.
Baylis-Hillman Advances
Focus on increasing reaction rate
Increased pKa of Lewis base
N
N
<
8.5
OH
N
H
N
<
N
N
9.9
11.3
Lewis acid
La(OTf)3
Triethanolamine
DABCO
TiCl4
Me2S
Aggarwal, V.K.; Emme, I.; Fulford, S.Y. J. Org. Chem. 2003, 68, 692-700.
Aggarwal, V.K.; Mereu, A.; Tarver, G.J.; McCague, R. J. Org. Chem. 1998, 63, 7183-7189.
Kataoka, T.; Iwama, T.; Tsujiyama, S-I.; Iwamura, T.; Watanabe, S-I. Tetrahedron 1998, 54, 11813-11824.
Asymmetric Variants
Traditional Baylis-Hillman: 3 component
Electrophile
Activated alkene
Lewis-Base catalyst
4th component
Lewis-Acid catalyst
Kinetic resolution
Electrophile:
Electrophile:
Chiral Glyoxylates
R
Me2S
TiCl4
O
O
H +
O
O
R
OH
O
O
n
CH2Cl2
O
n
Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12, 1741-1745.
Electrophile:
Chiral Glyoxylates
R
Me2S
TiCl4
O
O
H +
O
O
R
OH
O
O
n
CH2Cl2
O
n
21 hours 0°C
R
n
% Yield
% de
H
1
45
8.7
Ph
1
78
>95
Ph
0
76
>95
Bauer, T.; Tarasiuk, J. Tetrahedron: Asymmetry 2001, 12, 1741-1745.
Electrophile:
Chiral N-Sulfinimines
O
O
O
H
+ Ph
PR3
O
HN S
S
N
p-Tol
Ph
(S,S)
major
O
O HN
p-Tol
+
S
p-Tol
Ph
(S,R)
minor
Shi, M.; Xu, Y-M. Tetrahedron: Asymmetry 2002, 13, 1195-1200.
Electrophile:
Chiral N-Sulfinimines
O
O
O
H
+ Ph
PR3
O
HN S
S
N
p-Tol
Ph
5 days 20°C
(S,S)
major
O
O HN
p-Tol
+
S
p-Tol
Ph
(S,R)
minor
Solvent
PR3
% Yield % de
Toluene PBu3
69
68
Toluene PhPMe2
72
82
THF
PhPMe2
67
70
THF
PBu3
85
50
Shi, M.; Xu, Y-M. Tetrahedron: Asymmetry 2002, 13, 1195-1200.
Activated Alkene:
Activated Alkene:
Oppolzer’s Sultam
O
N
O
S
O
O
+
R
O
DABCO
H
O
CH2Cl2
R
O
R
Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.
Activated Alkene:
Oppolzer’s Sultam
O
N
O
S
O
O
+
R
O
DABCO
H
12 hours 0°C
O
CH2Cl2
% Yield
R
85
Me
98
Et
33
i-Pr
68
AcOCHCH2
0
Ph
R
O
R
% ee
>99
>99
>99
>99
-
Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.
Activated Alkene:
Oppolzer’s Sultam
RCHO
O
O
DABCO
N
O
S
O
N
O
S
O
O
H
XcN
O
NR3+
O
NR3+
H
O
addition to re face
RCHO
NR3+
O
XcN
XcN
R
NR3+
N
O
S
O
RCHO
O
NR3+
RCHO
O
NR3+
O
O
R
R
O
R
O
R
O
R
R
O
O
Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.
R
Activated Alkene:
Oppolzer’s Sultam
O
O
+
N
O
S
O
H
CH2Cl2
AcO
OAc
O
MeOH
OAc
75%
O
O
NEt3
O
O
O
AcO
68%
O
AcO
DABCO
O
O
CSA
HO
+
O
MeO
OAc PhH
O
OH
25%
Tulipalin B
OAc
65%
Brzezinski, L.J.; Rafel, S.; Leahy, J.W. J. Am. Chem. Soc. 1997, 119, 4317-4318.
Activated Alkene:
Acryloylhydrazide
O
N
N
O
O
Ph
+
R
DABCO
N
H
DMSO
4 days 25°C
R
Me
Et
Ph
N
O
% Yield
88
85
80
O
Ph
R
OH
% de
94
98
98
Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.
Activated Alkene:
Acryloylhydrazide
O
N
N
O
O
Ph
+
R
DABCO
N
H
THF/H2O
4 days 25°C
R
Me
Et
Ph
N
O
% Yield
73
85
0
O
Ph
R
OH
% de
94
98
-
Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.
N
R
H
Activated Alkene:
Acryloylhydrazide
N
O
R +
O
Ph
THF/H2O
OH
N
N
O
R
O
Ph
OH
NR3+
N
N
N
N
4
O
days
R
Me
N
Et
N
O
O
PhPh
O
NR3+
25°C
Ph
O
% Yield
73
H
R
85
O
NR +
0
3
O
Ph
% de
94
98
-
Yang, K-S.; Chen, K. Org. Lett. 2002, 2(6), 729-731.
Activated Alkene:
4-Menthyloxy-butenolide
O
O
PhSeLi
O
THF
-60oC
O
LiO
RCHO
O
O
O
THF
-60oC
LiO
SePh
O
SePh
R
Bu4 NI
BnBr
O
O
O
Se
LiO
R
O
O
O
+
Ph
Ph
R
Ph
i-Pr
t-Bu
HO
R
% Yield
82
89
67
4 hours -60°C
% de
>99
>99
>99
Jauch, J. J. Org. Chem. 2001, 66, 609-611.
Activated Alkene:
4-Menthyloxy-butenolide
O
O
PhSeLi
O
THF
-60oC
LiO
RCHO
O
O
O
O
THF
-60oC
SePh
LiO
O
SePh
R
O
H
O
H
Li
O
O
H
Ph
Se
Ph
Jauch, J. J. Org. Chem. 2001, 66, 609-611.
Activated Alkene:
4-Menthyloxy-butenolide
O
O
HO
SePh
R
NH4Cl
H2O
O
O
Bu4 NI
BnBr
O
O
R
LiO
THF
-60oC
O
SePh
R
-20oC
O
O
O
Se
LiO
O
+
Ph
O
HO
R
Ph
Jauch, J. J. Org. Chem. 2001, 66, 609-611.
Lewis-Base Catalyst:
chiral DABCO?
OMe
OMe
OH
OMe
OH
OH
OH
N
HO
N
N
N
N
N
N
quinidine
QD-2
QD-1
OH
OMe
O
O
N
N
N
N
QD-3
QD-4
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloids
OMe
OMe
OH
OMe
OH
HO
OH
OH
N
N
N
N
N
N
quinidine
QD-2
QD-1
OH
OMe
O
O
N
N
N
N
QD-3
QD-4
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
OMe
OMe
OH
OMe
OH
HO
OH
OH
N
N
N
N
N
N
quinidine
QD-2
QD-1
OH
OMe
O
O
N
N
N
N
QD-3
QD-4
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
OMe
OMe
OH
OH
N
N
quinidine
12%
+
O2N
N
N
N
CHO
HO
OH
OH
N
Yield
OMe
O
CF3
O
CF3
QD-1
QD-2
2%
10%
OH
catalyst
THF
O
CF3
O
CF3
O2N
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
OH
OMe
O
O
N
N
N
N
QD-3
Yield
ee
configuration
58%
91%
R
74%
10%
R
CHO
+
O2N
QD-4
O
CF3
O
CF3
OH
catalyst
DMF
O
CF3
O
CF3
O2N
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
OH
OMe
O
O
N
N
N
N
QD-3
Yield
ee
configuration
58%
91%
R
74%
10%
R
CHO
+
O2N
QD-4
O
CF3
O
CF3
OH
catalyst
DMF
O
CF3
O
CF3
O2N
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
CHO
+
O
O2N
OH
CF3
O
QD-4
CF3
CF3
O
CF3
DMF
O2N
O
O
+
N
N
H
OH
+
O
H O
R
O
N
CF3
CF3
N
R
OH
O
H O
CF3
CF3
H
O
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
CHO
+
O
O2N
OH
CF3
O
QD-4
CF3
CF3
O
CF3
DMF
O2N
O
O
+
N
N
H
OH
+
O
H O
R
O
N
CF3
CF3
N
R
OH
O
H O
CF3
CF3
H
O
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
O
+
R
H
OH
O
N
N
QD-4
CF3
O
OH
QD-4
CF3
R
Ph
Et
i-Pr
c-Hex
t-Bu
DMF
R
% Yield
57
40
36
31
0
O
CF3
O
CF3
% ee
95
97
99
99
-
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
O
O
+
H
CF3
O
CF3
O
OH
O
N
N
47% Yield
>97% ee
DMF/CH2Cl2
OH
O
CF3
O
O
OH
H2N
CF3
O
OH
O
O
(-)-mycestericin E
OH
Iwabuchi, Y.; Furukawa, M. Esumi, T.; Hatakeyama, S. Chem. Comm. 2001, 2030-2031.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
NTs
+
Ar
H
NTs O
QD-4
Solvent
Ar
Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
NTs
+
Ar
Ar
p-EtC6H4
p-EtC6H4
p-EtC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
Solvent
H
Solvent
DMF
MeCN
THF
DMF
MeCN
THF
NTs O
QD-4
Ar
% Yield
55
64
33
51
80
65
24 hours -30°C
% ee
93
86
76
95
81
63
Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
NTs
+
Ar
Solvent
H
Ar
Solvent
p-EtC6H4
DMF
p-EtC6H4
MeCN
p-EtC6H4 DMF/MeCN
p-ClC6H4
DMF
p-ClC6H4
MeCN
p-ClC6H4 DMF/MeCN
NTs O
QD-4
Ar
% Yield
55
64
74
51
80
68
% ee
93
86
96
95
81
93
Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.
Lewis-Base Catalyst:
cinchona alkaloid derivatives
O
NTs
+
R
H
NTs O
QD-4
DMF/MeCN
Ar
Aliphatic imines “Many unidentified products”
Shi, M.; Xu, Y-M. Angew. Chem. Int. Ed. 2002, 41(23), 4507-4510.
Chiral Lewis-Acid Approach
Chiral Lewis-Acid Approach
+
R1
La(OTf)3
Ligand
O
O
H
OR2
DABCO
CH3CN
OH
R1
HO
O
OR2
O
10 hours RT
N
Ligand=
N
OH
O
R1
Et
i-Pr
p-MeOC6H4
R2
Me
Me
Me
% Yield
89
75
55
% ee
7
6
66
Chen, K-Y.; Lee, W-D.; Pan, J-F.; Chen, K. J. Org. Chem. 2003, 68, 915-919.
Chiral Lewis-Acid Approach
+
R1
La(OTf)3
Ligand
O
O
OR2
H
DABCO
CH3CN
OH
R1
HO
O
OR2
O
10 hours RT
N
Ligand=
N
OH
O
R1
Et
Et
Et
R2
Me
Bn
-napthyl
% Yield
89
85
75
% ee
7
65
70
Chen, K-Y.; Lee, W-D.; Pan, J-F.; Chen, K. J. Org. Chem. 2003, 68, 915-919.
Chiral Lewis-Acid Approach
+
R1
La(OTf)3
Ligand
O
O
H
OR2
DABCO
CH3CN
OH
R1
HO
O
OR2
O
10 hours RT
N
Ligand=
N
OH
O
R1
R2
p-MeOC6H6
Bn
p-NO2C6H6
Bn
p-NO2C6H6 -napthyl
% Yield
50
93
82
% ee
95
85
93
Chen, K-Y.; Lee, W-D.; Pan, J-F.; Chen, K. J. Org. Chem. 2003, 68, 915-919.
Kinetic Resolution
O
+
R
OH
EWG
catalyst
R
H
OH
R
EWG
OH
OH
EWG
catalyst
R
EWG
or
R
EWG
Kinetic Resolution
O
+
R
OH
EWG
catalyst
R
H
OH
R
EWG
OH
OH
EWG
catalyst
R
EWG
or
R
EWG
Deracemization
(dba)3Pd2.CHCl3
Ligand
OH
R
CN
ClCO2Me
R
OCO2Me MeO
CN
MeO
OH
O
R
CH2Cl2
R
Ph
O
O
Ligand=
CN CH CN/H O
3
2
87% Yield
69% Yield
93% ee
Ph
OH
CAN
N
H
N
H
PPh2Ph2P
Trost, B.M.; Tsui, H-C.; Toste, F.D. J. Am. Chem. Soc. 2000, 122, 3534-3535.
CN
Deracemization
(dba)3Pd2.CHCl3
Ligand
OH
R
CN
ClCO2Me
R
OCO2Me MeO
CN
OH
CH2Cl2
R
N
N
H
H
PhCH
2CH2
PPh Ph P
TBDMSO(CH2)3
t-BuO2CCH2CH2
Ph
Ph
O
Ligand=
O
2
2
MeO
O
R
OH
CAN
CN CH CN/H O
3
2
R
% Yield % ee
75-77
93
67-68
89
75
>99
Trost, B.M.; Tsui, H-C.; Toste, F.D. J. Am. Chem. Soc. 2000, 122, 3534-3535.
C
Deracemization
anti manifold
R M+
M
H Nu
syn manifold
M
R
HX
2
H Nu
MM
R
R
EWG
M+
MM
EWG
EWG
EWG
MM
R
EWG
2
M
1
R
R
Nu
Nu
EWG
EWG
M
R Nu
MM
R M+
MM
H
EWG
ent-2
MM
M+
HX
M
R
EWG
M
R
EWG
ent-1
H Nu
R
EWG
EWG
ent-2
Trost, B.M.; Tsui, H-C.; Toste, F.D. J. Am. Chem. Soc. 2000, 122, 3534-3535.
Deracemization
HO
I
OH
+
OCO2Me
CN
(dba)3Pd2.CHCl3
Ligand
CN
O
1.) PdCl2(CH3CN)2
HCOOH, PMP, DMF
O
CN
I
CH2Cl2
O
Ph
CN
Ph
O
O
N
Ligand=
OAc
81%
87% ee
N
PPh 2Ph 2P
O
2.) Ac2O, TEA,
DMAP, CH2Cl2
97%
O
OH
MeO
OH
O
Furaquinocin E
Trost, B.M.; Thiel, O.R.; Tsui, H-C. J. Am. Chem. Soc. 2002, 124, 11616-11617.
Conclusions
The Baylis-Hillman Reaction has advanced
considerably in the past decade.
Asymmetric versions still are very substrate
dependent.
Methods using chiral auxillaries provide the
highest amount of asymmetric induction.
A general catalytic asymmetric reaction still has
not been developed.