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Evans Group Friday Seminar
June 28, 2002
André Beauchemin
Catalytic, Enantioselective Addition of Carbon Nucleophiles to C=N Double Bonds
1. Background
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on imine (ex. Acylhydrazones)
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
Keywords: Amines, Allylation, Asymmetric, Bifunctional Catalysis, Catalytic, Chiral, Enantioselective, Imine, Imine Aldol, Mannich, Nucleophilic Addition, Staudinger
01-Title 6/25/02 8:29 PM
"Asymmetric Synthesis of Amines by Nucleophilic 1,2-Addition of Organometallic Reagents to the CN-Double Bond"
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946
Leading References
"Addition of Organometallic Reagents to C=N Bonds: Reactivity and Selectivity"
Bloch, R. Chem. Rev. 1998, 98, 1407-1438
"syn-anti Isomerizations and Rearrangements"
McCarty, C. G. in The Chemistry of the Carbon-Nitrogen Double Bond, Patai, S., Ed., John Wiley &
Sons (London), 1970, chapter 9.
"Catalytic Enantioselective Addition to Imines"
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094
"Stereoselective Imine Aldol Reactions"
Tedrow, J. S. Evans Group Evening Seminar 1997
"Modern Variants of the Mannich Reaction"
Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045-1070
"Rearrangements and tautomerizations of enamines"
Huang, Z.-T.; Wang, M.-X. in The Chemistry of Enamines, Rappoport, Z., Ed., John Wiley & Sons
(London), 1994, chapter 16.
02-Leading References 6/26/02 6:33 PM
Me Me
O
H
O
Me
MeH2N OMe
Me
O HNPMP
Me
Me
Other Catalytic Enantioselective Synthesis of Chiral Amines
Direct 3-Component Mannich Reaction
+ +
90% yield, 93%ee
L-Proline (20-35 mol%)
Strecker Reaction
Ph H
N Ph
Ph
+ HCN
HN
NH
O
O
Ph
HN NH2
NH
(2 mol%)
Ph CN
HN Ph
Ph
97% yield, ≥99% ee
Reduction P
P
Et
Et
Et
Et
Ph Me
N
HN Ph
OPh Me
HN
HN Ph
O0.2 mol% [Rh]+, H2
95% ee
Ph
NHAc
MePh
NHAc
0.2 mol% [Rh]+, H2
95% ee
P P
Me
Me
Me
Me
• imines
• enamines
03-Chiral amines from catalysis 6/26/02 7:15 PM
R H (R')
O
R H (R')
NR''
R H (R')
NR'''R''
Comparison between C=O and C=N
E-Z geometry problem associated with C=N double bonds
Reduced electrophilicity of the C=N double bond
1.21 Å 1.28 Å 1.26-1.30 Å
173-181 kcal.mol–1C=X bond E: 143
+ 0.51Polarization (δ): + 0.33 + 0.54
XXX
Side reactions observed with organometallics
04-C=O vs C=N 6/25/02 4:44 PM
H N
R
n-Bu NHPMPCHO
n-Bu n-BuLi/THF
OMe
Tomioka: Imine Substituent Influences the Reaction Pathway
Tomioka et al. Tetrahedron 1994, 50, 4429For calculations (MOPAC PM3): J. Org. Chem. 2001, 66, 7051
n-BuLi/THF
(91%)(80%)
R = R =
OMeR =
i-Pr
i-Pr
CHO
Ph
PhLi/THF
Relative magnitude of the LUMO coefficients account for the regioselectivity
Conjugation is not possible (steric)
05-Tomioka-1,2 vs 1,4-addition 6/27/02 8:41 PM
Buchwald: Different Behavior of E and Z Isomers under Reaction Conditions
Buchwald et al. J. Am. Chem. Soc. 1994, 116, 8952; 11703Related hydrosilylation (Optimized) system: Buchwald et al. J. Am. Chem. Soc. 1996, 118, 6784
N
Me
Ph NH
Me
Ph
TiH
H2 (80-2000 psig), THF, 65 ˚C
Similar stereodivergent results were observed in the reduction of ketoximes ethers:Stoichiometric reduction: Sakito et al. Tetrahedron Lett. 1988, 29, 223
Didler et al. Tetrahedron 1991, 47, 4941Catalytic reduction: Bolm et al. Synlett 1994, 655
E:Z = 11:1 81% ee (~10:1 er)
• Reaction is stereodivergent: E imine gives R amine; Z imine gives S amine
• Reaction shows ee dependence on H2 pressure
• Z imine reacts faster than E imine; interconversion of imines is slow
• Best ee obtained at high temperature and pressure
(5 mol%)
06-E-Z impact 6/26/02 2:24 PM
Mechanisms of Interconversion between E and Z Imines
Equilibration via formation of N,O-acetal
Homolytic or Heterolytic π-Bond Cleavage
"Lateral Shift" Mechanism
R1 NR3
R2
R1 NR3
R2
R1 NR3
R2
R1
N
R2R1
NR3
R2
R3
R1
N
R2
R3
sp
• Eact estimated to be 50 kcal/mol or higher; lower energy pathways available• Equilibrium can be induced using hυυυυ
• Rates studies are consistent with this mechanism
"syn-anti Isomerizations and Rearrangements" McCarty, C. G. in The Chemistry of the Carbon-Nitrogen Double Bond, Patai, S., Ed., John Wiley & Sons (London), 1970, chapter 9.
• Hammett ρ of 1.5 found for substituents on R3 = Ar (EWG at 4-position accelerate isomerization)• Rate enhancement increases with increasing size of ortho substituents (R3 = Ar)
• Pathway only available when H2O or ROH present
Tautomerization
• C-H bond must be present α to the imine group
07-Mechanism 6/26/02 5:59 PM
NB
NS S
Br
PhPh
O OO O
F3C
F3C
CF3
CF3
MeSt-Bu
O
St-Bu
OBR2*
MeSt-Bu
O
R1
NH
Me
R2
R1 H
NR2
Ph
Ph
1-naphthyl
(E)-PhCH=CH
Ph(CH2)2
Ph(CH2)2
Corey: First Example Usingan "External" Source of Chirality
Corey et al. Tetrahedron Lett. 1991, 32, 5287
1
PhMe/hexane
1, Et3N, –78 ˚C
R1 anti:syn ee (%)
>99:1
>99:1
>99:1
>99:1
97:3
92:8
90
92
>99
>99
90
90
R2
allyl
Bn
allyl
allyl
allyl
Bn
yield (%)
92
96
91
86
90
86
• Chair transition state with Z imine accounts for the results
08-Corey 6/26/02 6:09 PM
Me
N
R
Ph
R
NH
Ot-Bu
OOTMS
Ot-Bu
OTMS
Ot-Bu
N
TMS
Me
Ph NH
TMS
Ot-Bu
O
Me
Ph
O
OB OPh
Yamamoto: Synthesis of β-Amino Estersvia Double Stereodifferentiation
Yamamoto et al. J. Am. Chem. Soc. 1993, 115, 1151
1 (>1 equiv.)
CH2Cl2, –78 ˚C+
(50-60%)R = Ph, R-1R = Ph, S-1R = n-Pr, R-1R = n-Pr, S-1
92% de74% de94% de86% de
CH2Cl2, –78 ˚C+
(50-60%)
R-1: anti/syn = 40:1,dr (anti) = 99:1
S-1: anti/syn = 2:1,dr (anti) = 94:6
1
Me
Ph
1 (>1 equiv.)
09-Yamamoto1-Chiral Additive 6/28/02 8:04 AM
N
TMS
Me
PhMe
N
Ph
Ph
O BO
O
NH
H
MePh
Yamamoto: Effect of Lewis Acid on Imine Geometry
Yamamoto et al. J. Am. Chem. Soc. 1993, 115, 1151
equiv. of (R)-1 Imine 2 Imine 3
E:Z ratio (–60 ˚C, CD2Cl2)
0
0.3
0.7
1.0
2.0
≥95:5
≥95:5
≥95:5
≥95:5
≥≥≥≥95:5
67:33
60:40
41:59
29:71
≤≤≤≤5:95
32
Observed imine geometry explains the stereochemical outcome of the reaction
10-Yamamoto2-Lewis Acid Effect 6/26/02 6:11 PM
R1
R2
NS
O
R1
R2
NH
S
OR3
i-Pr
Ph
Ph
n-Bu
Me
Me
n-Bu
Me
S
ON RL
RS
AlLi R
Ellman: Synthesis of Chiral Tertiary Amines
Ellman et al. J. Am. Chem. Soc. 1999, 121, 268
R3Li, Me3Al
R1 yield (%) dr
65
93
61
26
86
>99
93
94:6
97:3
99:1
99:1
98:2
99:1
89:11*
R2 R3
Ph
Ph
n-Bu
n-Bu
n-Bu
Me
Ph
Me3Al (equiv.)
0
1.1
1.1
0
1.1
1.1
1.1
Me3Al required for both high yield and diastereoselectivity
E isomer only
* E:Z ratio of imine in CDCl3 = 83:17
For a review on synthesis of chiral 2˚ amines using this auxiliary: Davis et al. Chem. Soc. Rev. 1998, 27, 13
11-Ellman 6/27/02 9:04 PM
1. Background
– E-Z geometry problem
– C=N reduced electrophilicity
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on azomethine group
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
12-Bidentate on imine 6/27/02 6:33 PM
OMe
OTMS
α-Nap OMe
ONH
20
20
20
10
5
2
N
α-Nap H
HO
Me
Me
Me Me
O
O O
OZr
OH
R
R
R
R
NN Me
R'
Kobayashi: Optimization of the Reaction Procedure
Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153
+(X mol%)
CH2Cl2, –15 ˚C
X (mol %) yield (%) ee (%)
>99
80
73
>99
>99
75
34
70
90
92*
91
86*
Additive (X mol%)
–
NMI
NMI
NMI
DMI
NMI
R
H
H
Br
Br
Br
Br
* Reaction was carried out at –45 ˚C
R' = H :R' = Me :
NMIDMI
• Imine prepared from aniline or 2-methoxyaniline showed almost no chiral induction
13-Kobayashi1-Zr-Optimization 6/27/02 7:15 PM
R3
OTMS
Ph
4-(Cl)C6H4
Ph
1-naphthyl
2-furyl
c-C6H11
R2
R2
O
O O
OZr
Br
Br
Br
BrN
R1 H
HO
R1 R3
ONH
R2 R2
OH
Kobayashi: Scope of the Zr-Catalyzed Addition
Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153J. Am. Chem. Soc. 2000, 122, 8180
+ (5-10 mol%)
NMI (5-30 mol%)CH2Cl2, –45 ˚C
R1 yield (%) ee (%)
70
86
78
>99
89
56
87
83
88
>98
89
80*
R2
Me
Me
H
H
H
H
R3
OMe
OMe
SEt
SEt
SEt
SEt
* Imine prepared using 2-amino-3-methylphenol
Substitution of –Br for –CF3 at the 6,6' positions of BINOL increase catalyst efficiency (2 mol%)
14-Kobayashi2-Zr-Scope1997 6/27/02 8:46 PM
Oi-Pr
OTMS
OTBS
O
O O
OZr
Br
Br
Br
Br
N
Ph H
Ar
Ph Oi-Pr
ONHAr
DMI
DMI
Ar
HO
OTBS
Oc-C6H11
OTMSN
α-Nap H
Ar
α-Nap Oc-C6H11
ONHAr
OBn
BnO
Kobayashi: Scope of the Zr-Catalyzed Addition-2
Kobayashi et al. J. Am. Chem. Soc. 1998, 120, 431
+
1
>99% yield, syn/anti = 96/4, 99% ee (syn)65% yield, syn/anti = >99/1, 96% ee (syn)
+ 1 (10 mol%)
PhMe, –78 ˚C
91% yield, syn/anti = 6:9480% ee (anti)
1 (10 mol%)
PhMe, –78 ˚C
E – OTBS:Z – OTBS:
15-Kobayashi3-Zr-Scope1998 6/27/02 7:06 PM
R2
OTMS
R1 H
N
HO
ZrO
O
O
O
L
L
ZrO
O
O
OO
N
R1
H
ZrO
O
O
OO
N
R1
R2
OTMS
ZrO
O
O
OTMS
O
N
R1
R2
O
R2
O
N
R1
Ar
TMS
R2
O
NH
R1
OTMS
Kobayashi: Mechanism of the Zr-Catalyzed Addition
Kobayashi et al. J. Am. Chem. Soc. 1997, 119, 7153J. Am. Chem. Soc. 2000, 122, 8180
Tetrahedron 2001, 57, 861
• No mention of the role of DMI as possible TMS shuttle• Silyl crossover observed if imine is reacted with 2 different thiosilylketeneacetals
16-Kobayashi4-Zr-Mechanism 6/25/02 4:38 PM
Ph
2,3-(MeO)2C6H3
2-furyl
Ph
2,3-(MeO)2C6H3
2-furyl
H
R2
O
O Ot-Bu
Ot-BuZr
N
R1 H
HO
R1
NH
OH
SnBu3
R2
Br
Br
Me
Me
Me
H
H
H
Kobayashi: Scope of the Zr-Catalyzed Addition
Kobayashi et al. Angew. Chem., Int. Ed. 2001, 40, 1896
+
(10 mol%)
PhMe, 0 ˚C
R1 yield (%) ee (%)
84
72
76
77
80
68
93
91
92*
96**
87**
96**
R2
* 3,3'-Cl2BINOL-derived catalyst was used** Catalyst prepared with 2 equivalent of MeOH in THF; then 0.1 mmHg
syn:anti> 95:5
OH
OH
O
N
R1 H
Zr
OO
O
Me
SnBu3
*
• Replacement of CH2OH for Me or CH2OTBS results in enantioselection (~55% ee)
17-Kobayashi5-Zr-Allylation 6/26/02 6:43 PM
R1 O R1 NH
Et
Ph
2-furyl
3-pyridyl
n-Bu
i-Bu
c-C3H5
TBDPSOCH2
NH
HN
O
NH
O
n-Bu
PhOH
MeO
H2N
OMeOMe
H
Hoveyda & Snapper: Three-Component Catalytic Asymmetric Synthesis of Aromatic and Aliphatic Amines
Hoveyda, Snapper et al. J. Am. Chem. Soc. 2001, 123, 984 J. Am. Chem. Soc. 2001, 123, 10409
+
R1 ee (%)
91
83
85
97
95
98
>98
yield (%)
92
98
>98
69
58
83
48
Zr(Oi-Pr)4•i-PrOH (10 mol%)Et2Zn (6 equiv.)
PhMe/THF (7:1), –40 ˚C
(10 mol%)
No examples of functionalized dialkylzincs
18-Hoveyda-Snapper 6/26/02 1:36 PM
R3
OTMS
R1 R3
OHN
Ph(CH2)2
C6H13
Ph
ClCH2
N
R1 H
NH
O C6H4(CF3)-4
NH
C6H4(CF3)-4O
R2
R2R2 R2
O
O O
OZr
Br
Br Br
Br
Kobayashi: Zr-Catalyzed Addition to Acylhydrazones
Kobayashi et al. Chem. Lett. 1998, 1131
+ (20 mol%)
PhMe, 0 ˚C
R1 yield (%) ee (%)
66
42
60
39
59
59
86
88
96
87
81*
93
R2
Me
H
Me
H
Me
Me
R3
OMe
SEt
OMe
SEt
OMe
OMe
* 50 mol% catalyst was used
19-Kobayashi5-Zr-Acylhydra 6/25/02 1:21 PM
R1 NPPh2
O
R1 NH
PPh2
ONO2
MeNO2
Ph
4-(Cl)C6H4
4-(Me)C6H4
2-furyl
2-(HS)C6H4
Yb
O O
K
O O
OHOH
Shibasaki: Catalytic Asymmetric Nitro-Mannich-Type Reaction
Shibasaki et al. Angew. Chem., Int. Ed. 1999, 38, 3504
+
R1 ee (%)
91
87
89
83
69
yield (%)
79
93
85
57
41
PhMe/THF (7:1), –40 ˚C
from: (R)-binaphthol,KOt-Bu, Yb(OTf)3
(3:1:1)
(20 mol%)
* *
*
20-Shibasaki-Nitro 6/25/02 1:23 PM
1. Background
– E-Z geometry problem
– C=N reduced electrophilicity
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on azomethine group
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
21-Bidentate on substrate 6/27/02 6:33 PM
N
EtO
O
H
Ts
Ph
OTMS
Ph
NHTs
EtO
O
O
P
P
R
R
MLn
R
R
AgSbF6
Pd(ClO4)2
CuClO4
CuClO4
Ni(SbF6)2
+2-10 mol%
THF or CH2Cl2, T
MLn T (˚C) ee (%)
– 80
– 40
–
– 78
0
–
90
67
80
89
98
30
R
Ph
Ph
Ph
4-(Me)C6H4
Ph
Lectka: Catalytic Enantioselective Alkylation of Imino Esters
Lectka et al. J. Am. Chem. Soc. 1998, 120, 4548J. Am. Chem. Soc. 2002, 124, 67
22-Lectka1-Metal 6/27/02 10:06 AM
N
EtO
O
H
Ts
R'
NHTs
EtO
O
P
P
R
R
CuClO4
R
R
R1
OTMS
Ph
OTMS
OTMS
+2-10 mol%
THF or CH2Cl2
Nuc anti/syn ee (%)yield (%)
Lectka: Scope of the Alkylation Reaction
Lectka et al. J. Am. Chem. Soc. 1998, 120, 4548J. Org. Chem. 1998, 63, 6090
J. Am. Chem. Soc. 2002, 124, 67
Nuc
86 25:1 98
82 >9920:1
R1 = OPh
Ph
3-(NO2)C6H4
4-(MeO)C6H4
t-Bu
83
95
87
94
65
–
–
–
–
–
72
98
94
86
90
R= 4-(Me)C6H4
23-Lectka2-Scope 6/27/02 11:22 AM
N H
O OEt
Ts
P
R'R'
Cu
PR'
R'
N H
O OEt
Ts
P
R'R'
Cu
PR'
R'
N
O OEt
Ts
P
R'R'
Cu
PR'
R'
P
R'R'
CuClO4
PR'
R'
RO
TMS
N
EtO
O
R
O
R
OTMS
Ts TMS
N
H
O
EtO
Ts
Lectka: Proposed Mechanism
Lectka et al. J. Am. Chem. Soc. 2002, 124, 67
Re Attack
ComplexFormation
Silyl transfer
24-Lectka3-Mechanism 6/20/02 10:44 PM
N
EtO
O
H
Ts
R2
NHTs
EtO
O
P
P
R
R
CuClO4
R
R
+(2-10 mol%)
PhCF3, rt
Olefin ee (%)yield (%)
Lectka: Scope of the Ene Reaction
Lectka et al. J. Am. Chem. Soc. 1998, 120, 11006J. Am. Chem. Soc. 2002, 124, 67
See also: Jørgensen et al. J. Chem. Soc., Chem. Commun. 1998, 2547 (CuPF6 catalyst)
Olefin
94 99
85 89
R1 = Ph
SPh
92
85
99
98
Product
R1
O
N
Ts
R1EtO2C
NHTs
EtO2C
NHTs
EtO2C
NHTs
EtO2C
NHTsO
EtO2C
NHTsN
Ts
85 95
90 85
R= 4-(Me)C6H4
25-Lectka4-Ene 6/27/02 3:43 PM
N
EtO
O
H
Ts
R2
NHTs
EtO
O
P
P
R
R
CuClO4
R
R
+(2-10 mol%)
Allylsilane ee (%)yield (%)
Lectka: Scope of the Allylation Reaction
Lectka et al. J. Am. Chem. Soc. 2002, 124, 67See also: Jørgensen et al. J. Org. Chem. 1999, 64, 4844
Allylsilane
85 75
88 92
88 72*
Product
91 94
88 87
TES
CH2Cl2, – 78 ˚C
EtO2C
NHTs
TMS
EtO2C Ph
NHTs
Ph
TMS
EtO2C Ph
NHTs
PhMe
Me
EtO2C
NHTsTMS
anti:syn
–
20:1
–
–
10:1
TMS EtO2C
NHTs
Ph
Ph
R= 4-(Me)C6H4
* Can be improved to 80% ee by using CuPF6 catalyst and tri(n-butyl)allylstannane (Jørgensen)
26-Lectka4-Allylation 6/27/02 3:49 PM
N
EtO
O
H
Ts
TsHN OEt
O+
Johannsen, Jørgensen: Catalytic Enantioselective Friedel-CraftsReactions of α-Imino Esters
Jørgensen et al. Angew. Chem., Int. Ed. 2000, 39, 4114
THF, – 78 ˚CNH
NH
P
P
R
R
CuClO4
R
R
(2-10 mol%)
R= 4-(Me)C6H4
Johannsen, M. J. Chem. Soc., Chem. Commun. 1999, 2233
89% yield, 96% ee
NCO2Et
EtO
O
H
HN
OEt
O
+ THF, – 78 ˚C
P
P
R
R
CuPF6
R
R
(2-10 mol%)
R= 4-(Me)C6H4
75% yield, 96% ee
CO2Et
N
N
27-Friedel-Crafts 6/28/02 8:06 AM
O
EtON R1
OR2
OTMS
Ph
NH
Ph
NH
α-Napα-Nap CuTfO OTf
R2
O
EtO
O
NH
O
R1
C11H23
Me
Ph
Kobayashi: Reaction of N-Acylimino Esters using Cu(II)-Catalyst
Kobayashi et al. Org. Lett. 2002, 4, 143
+ (10 mol%)
CH2Cl2, T, 18h
R1 yield (%) ee (%)
92
97
88
85
79
81
76
94
92
93
94
97
96
90
R2
Ph
4-(MeO)C6H4
4-(Cl)C6H4
Ph
Ph
OMe
SEt
T (˚C)
0
0
0
0
–78
–78
–78
• Reaction is also efficent with methyl enol ethers, to afford the parent "internal" methyl enol ether in similar yields and ee• Proposed: [4+2]-cycloaddition
N
O
OTMS
R1EtO2C
R2
28-Kobayashi-Cu 6/26/02 6:30 PM
O
EtON
R1
OTMS
Ph
NH
Ph
HN
PhPh
R1
O
EtO
O
NH
Ph
Ph
4-(Cl)C6H4
4-(Me)C6H4
4-(MeO)C6H4
Ph
i-Pr
NHBz
BzHN
R2
R2
H
H
H
H
H
Me
Me
Kobayashi: Reaction using Zn(II)-Catalyst in Aqueous Media
Kobayashi et al. J. Am. Chem. Soc. 2002, 124, 5640
+
(10 mol%)
TfOH (1 mol%)H2O:THF (1:9), 0 ˚C
R1 syn:anti ee (%)
—
—
—
—
—
96:4
90:10
90*
92
89
91
91
91
30
R2
ZnF2 (50 mol%)
(3 equiv.)
yield (%)
19
89
88
82
63
91
30
* Reaction run without TfOH
29-Kobayashi-Zn 6/25/02 1:37 PM
1. Background
– E-Z geometry problem
– C=N reduced electrophilicity
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on imine
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
30-Single Point binding 6/27/02 6:36 PM
Ph
2-naphthyl
4-(Me)C6H4
3-pyridyl
3,4-(OCH2O)C6H3
O
OTi
N
R H
Bn
Murahashi: Titanium-Catalyzed Enantioselective Addition to Nitrones
Murahashi et al. J. Am. Chem. Soc. 2002, 124, 2888
+(10 mol%)
PhMe, –78 ˚C
R yield (%) ee (%)
99
94
66
90
74
92
88
88
80
80
O
O t-BuO
OMe
OTBS
OMe
O
R
NHO Bn
• Reaction exhibit a positive nonlinear relationship
• Biphenoxide catalyst affords the opposite enantiomer (55% ee, R = Ph)
31-Murahashi 6/28/02 1:09 PM
1. Background
– E-Z geometry problem
– C=N reduced electrophilicity
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on imine
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
32-Electrophile activatio copy 6/27/02 6:38 PM
Ph H
N
Ph Me
HN
OMe OMe
Tomioka, Denmark: Catalytic Asymmetric Addition of Organolithium Reagents
Tomioka et al. Tetrahedron Lett. 1991, 32, 3095Tetrahedron 1994, 50, 4429
+PhMe, –100 ˚C
(30 mol%)
MeLi
97% yield, 90% ee
Ph H
N
Ph Bn
HN
Et Et
N
O
N
O
t-But-Bu
OMe OMe
Denmark et al. J. Am. Chem. Soc. 1994, 116, 8797J. Org. Chem. 2000, 65, 5875
+DMF, 0 ˚C
(10-20 mol%)
BnLi
62% yield, 81% ee
Me Me
MeO
O
Bn
Me2N
N.B. The best results obtained by the authors are shown on this slide
33-Chiral ligands 6/28/02 8:09 AM
4-(CF3)C6H4
4-(MeO2C)C6H4
4-(F)C6H4
Ph
Ar1
Hayashi: Rhodium Catalyzed Arylation of Imines
Hayashi et al. J. Am. Chem. Soc. 2000, 122, 976
ee (%)
96
96
92
92
92
82
yield (%)
90
89
90
69
86
31
Ar1 H
NNs
+ Ar2-SnMe3
Me
OMe
Me
Ph2P (6 mol%)
Rh(acac)(C2H4)2 (3 mol%),LiF, dioxane, 110 ˚C
Ar1 Ar2
HNNs
Ph
4-(MeO)C6H4
Ph
Ph
4-(MeO)C6H4
4-(CF3)C6H4
Ar2
Reactions with bidentate phosphines were very slow
(5 equiv.)
34-Hayashi 6/25/02 1:48 PM
R1 NR2
R1 NH
R2
Me
Et2Zn
Ph
4-(MeO)C6H4
4-(Cl)C6H4
2-(Cl)C6H4
2-furyl
N
OPPh2Me
MeMe
BnBn
Ts
Ms
SES
Ms
Ms
Ms
SES
Tomioka: Copper-Amidophosphine Catalyst for Asymmetric Addition of Diethylzinc to Imines
Tomioka et al. J. Am. Chem. Soc. 2000, 122, 12055
+
R1 ee (%)
93
94
90
92
94
92
93
yield (%)
98
97
98
83
95
95
98
Cu(OTf)2 (1-8 mol%),PhMe, 0 ˚C
(1-10 mol%)
R2
35-Tomioka 6/26/02 1:58 PM
OBz
N
N
H
O
ClR
N
HOEt
O
Ts
N
R CO2Et
TsO
NMe2 NMe2
Lectka: Catalytic Asymmetric Staudinger Reaction
Lectka et al. J. Am. Chem. Soc. 2000, 122, 7831
+(10 mol%)
Catalyst plays two distinct roles: base (ketene generation) and nucleophilic catalyst
, PhMe, –78 ˚C to rt
cis:trans ee (%)
99:1
99:1
99:1
>99:1
99:1
96
99
99
98
95
yield(%)
65
57
45
61
56
R
Ph
Et
OPh
OAc
OBn
OMe
36-Lectka-Staudinger 6/26/02 5:45 PM
Fe
MeMe Me
MeMe
R3 H
NTs
NO
R3
Ts
R1
R2
N
N
O
C
R1 R2
Fu: Catalytic Asymmetric Staudinger Reaction
Fu et al. J. Am. Chem. Soc. 2002, 124, 1578
+
(10 mol%)
PhMe, rt
cis/trans ee (%)
–
–
–
8:1
10:1
9:1
10:1
81
91
94
98
95
95
98
R2
i-Bu
i-Bu
Et
Et
R1
Ph
Ph
Ph
Ph
R3
Ph
(E)-PhCH=CH2
c-C6H11
Ph
(E)-PhCH=CH2
2-furyl
c-C3H5
yield (%)
84
91
76
88
95
97
98
–(CH2)6–
–(CH2)6–
–(CH2)6–
37-Fu-Staudinger 6/27/02 3:20 PM
Fe
MeMe Me
MeMe
N
N
O
C
R R
catalyst*
O
R
R
catalyst*
O
R1
N
R R
Ts
NTs
R1H
N
R1
O Ts
R
R
Fu: Mechanism of the Staudinger Reaction
Fu et al. J. Am. Chem. Soc. 2002, 124, 1578
38-Fu-Staudinger-Mechanism 6/25/02 1:42 PM
N
N
O
N
O
PhPhO
Ar1 HHPh Ar1
Ph
NHAr2
Ar2-NH2
Me
Me Ph
NHO Bn
HMe
Me
NO Bn
Ph
H
Me Me
N
O
N
O
PhPh
Carreira, Li: Catalytic Asymmetric Addition of Metal Acetylides
For more on Catalytic Additions of M-acetylides: Janey, J. Evans Group Friday Seminar 2002
Li et al. J. Am. Chem. Soc. 2002, 124, 5638
+ +(10 mol%)
CuOTf (10 mol%),H2O or PhMe
48-93% yield,78-96% ee
Carreira et al. Acc. Chem. Res. 2000, 33, 373
+(cat.)
Zn(OTf)2 (cat.),i-Pr2NEt (cat.)
85% yield, 88% ee
39-Acetylides 6/26/02 1:16 PM
1. Background
– E-Z geometry problem
– C=N reduced electrophilicity
2. Activation of the electrophile
2.1. Activation via bidentate complexation
– Basic sites present on imine
– Basic sites present on substrate (ex. Imino esters)
2.2. Activation via single point binding
3. Activation of the nucleophile
4. Bifunctional catalysis
40-Bifunct catalysis 6/27/02 6:40 PM
Ph
4-(MeO)C6H4
(E)-PhCH=CH
R1 H
NR2
Sn(n-Bu)3
R1
HNR2
Me
Me
ClPdPd
Cl
Bn
PMB
Ph
n-Pr
Bn
Bn
Yamamoto: Catalytic Asymmetric Allylation of Imines
Yamamoto et al. J. Am. Chem. Soc. 1998, 120, 4242J. Org. Chem. 1999, 64, 2614
R1 yield (%) ee (%)
62
50
74
30
48
68
81
80
0
70
78
61
R2
+DMF, 0 ˚C
(5 mol%)
Running the reaction with allylsilane also possible under the following conditions:5 mol% cat., allyltrimethylsilane (2 equiv.), TBAF (0.5 equiv.), n-hexane/THF, 0 ˚C
(similar yields and ee)
41-Yamamoto 6/27/02 3:15 PM
R1 H
NR2
(n-Bu)3Sn
R1
NR2
Me
Sn(n-Bu)3
Pd
Me
Pd
Me
Pd N
n-Bu3SnCl
N
R2
R1
H
R2
R1
(n-Bu)3Sn
Yamamoto: Catalytic Asymmetric Allylation of Imines
Yamamoto et al. J. Am. Chem. Soc. 1998, 120, 4242
Dimer
42-Yamamoto - Mechanism 6/24/02 12:02 PM
NPMP
i-PrO
O
H R
OTMS
R
HN
i-PrO
O
O
P
P
R
R
Pd
R
RP
P
R
R
Pd
R
RHO
OH
Sodeoka: Catalytic Enantioselective Alkylation of Imino Esters
Sodeoka et al. J. Am. Chem. Soc. 1998, 120, 2474J. Am. Chem. Soc. 1999, 121, 5450
+5 mol%
Solvent, rt, 5-19 h
R ee (%)yield (%)
Ph
2-naphthyl3,4-(Cl)2C6H4
2-(MeO)C6H4
3-(NO2)C6H4
Me
9560458280876279
9067*53*8384716053
2+2 BF4
–
Solvent
DMFTHF
CH2Cl2DMFDMFDMFDMFDMF
* Reaction required 4.5 days
PMP
R = Tolyl
43-Sodeoka1-Scope 6/26/02 1:29 PM
Pd
HO
PdP
P
P
POH L
Pd
HO
PdP
P
P
PO
R1
PdP
P O
L
R1
PdP
P O
N
R1
CO2R2
R3H
P
P
N
CO2R2
R1O
Pd
R3
PdP
P OH
L
Pd
HO
PdP
P
P
P OH – TMSOH
R1
OTMS
R1
OTMS
–TMSOHH2O
HN
CO2R2R1
OR3
Sodeoka: Proposed Mechanism
Sodeoka et al. J. Am. Chem. Soc. 1999, 121, 5450
2+ 2+
2+
L
L
X– = BF4–
2+
2+
2+
2+
44-Sodeoka2-Mechanism 6/27/02 6:44 PM
N
CO2Et
PMP
H
O2NCO2Et
HN
R
PMP
Me Me
N
O
N
O
PhPhCu
H
Me
Et
n-C5H11
Bn
Ph
Jørgensen: Catalytic Asymmetric Aza-Henry Reaction
Jørgensen et al. Angew. Chem. Int. Ed. 2001, 40, 2992 See also: J. Am. Chem. Soc. 2001, 123, 5843 (silyl nitronates: in Appendix)
+ (10-20 mol%)
Et3N (10-20 mol%), CH2Cl2, rt
R syn/anti ee, syn (%)
–
70:30
95:5
93:7
95:5
55:45
87
97
97
97
95
74
yield (%)
38
61
81
52
80
59
TfO OTf
Me
MeN
O
NO
Cu
O NN
PMPEt
O OEt
H
O
Ph
R NO2
45-Jorgensen-Nitro 6/28/02 11:25 AM
N
EtO
O
H
TsNHTs
OEt
O
+(10 mol%)
Jørgensen: Catalytic Enantioselective DirectMannich Reaction of α-Imino Esters
Jørgensen et al. Angew. Chem., Int. Ed. 2001, 40, 2995
CH2Cl2, rt, 20-40h
N
O
N
O
Me Me
PhPhCu
TfO OTfO
EtO2C
R R
EtO2C
O
yield (%) ee (%)
70
89
98
94
79
89
>98
94*
97
78
R
H
Me
Me
Bn
Br
syn:anti
–
>10:1
>10:1
>10:1
>10:1
* 5 mol% catalyst was used
Me
MeN
O
NO
Cu
ON
PMPR
O OEt
HPh
H
OOEt
46-Jorgensen-Direct 6/27/02 5:23 PM
Et2Zn
Ph
3-(Cl)C6H4
4-(Cl)C6H4
4-(MeO)C6H4
2,6-(Cl)2C6H3
4-(t-Bu)C6H4
OHN
Me
Ph
Me
ArMe
HN
O
H
Ar SO2Tol
HN
O
H
Ar H
N
O
H
Ar
Bräse: Catalytic Asymmetric Addition of Dialkylzincs
Bräse et al. J. Am. Chem. Soc. 2002, 124, 5940
ee (%)
95
93
89
95
95
75
yield (%)
>99
99
>99
97
98
>99
Et2Zn (3 equiv.),hexane, 0-20 ˚C
(2-5 mol%)
47-Brase 6/26/02 2:04 PM
Conclusion
– Great progress has been made over the past 5 years in the development of catalytic, enantioselective additions to C=N double bonds
– Catalysis via nucleophile activation was achieved
– Catalysis via electrophile activation was achieved
– Bifunctional catalysis was achieved
– However, most systems have poor generality with regards to
aromatic vs. aliphatic (C=N)
nucleophile
nitrogen protective group
– No catalytic, enantioselective approaches to tertiary amines reported to date...
48-Conclusion 6/26/02 5:24 PM
HN
EtO
O
P
P
R
R
CuClO4
R
R
+ 2-10 mol%
THF or CH2Cl2
ee (%)yield (%)
Lectka: Reaction with N,O- and N,N-Acetals and Hemiacetals
Lectka et al. J. Org. Chem. 1999, 64, 2168Tetrahedron 1999, 55, 8869
93
85
81
90
89
78
95
90
76
95
87
96
R3
OTMS
R3
OR1
R2
NHR1
EtO
O
R3
Ph
TMSCH2
OPh
Ph
Ph
Ph
R2
OH
OH
OH
NTs
OEt
OH
R1
Ts
Ts
Ts
Ts
Ns
SES
• First equivalent of enol ether leads to formation of the iminoester (alternatively, 1
equiv. of TMSCl can be used, followed by 1 equiv. of enolsilane)
• Desilylated material is isolated after the reaction (no need for F–) in contrast with
parent reaction with iminoester
• If R1 = Bz, exclusive formation of the ethyl glyoxylate adduct!!!
(2 equiv.)
49-Lectka-NOacetals 6/27/02 11:49 AM
R1 NPPh2
O
R1 NH
PPh2
OEtEt2Zn
Ph
2-furyl
3-pyridyl
(4-MeO)C6H4
(4-Me)C6H4
(4-Cl)C6H4
NPh
PhOH
Ph
H
Andersson: Chiral Aminoalcohol-Promoted Addition of Diethylzinc
Andersson et al. Tetrahedron 2001, 57, 1615
+
R1 ee (%)
98
89
87
98
97
95
yield (%)
75
92
70
91
70
67
PhCl, rt, 18h
(1 equiv.)
(3 equiv)
Attempts to make this process catalytic failed
Many other reports of chiral promoters for the same transformation (aminoalcohols)
50-Andersson-Et2Zn 6/20/02 10:51 PM
N
R1
TMSO O N
CO2Et
PMP
H
O2NCO2Et
HN
R1
PMP
R3 R3
N
O
N
O
Ph
R2
Ph
R2
MLn
Et
Me
n-C5H11
Bn
Jørgensen: Catalytic Asymmetric Aza-Henry Reaction
Jørgensen et al. J. Am. Chem. Soc. 2001, 123, 5843
+ (20 mol%)
THF, –100 ˚C
R1 syn/anti ee (%)
3:1
18:1
10:1
25:1
5:1
39:1
32:1
90
89
97
95*
>98
83*
88
R2
H
H
Ph
Ph
H
Ph
Ph
MLn
Cu(I)ClO4
Cu(II)(OTf)2
Cu(I)PF6
Cu(II)(SbF6)2
Cu(I)ClO4
Cu(II)(SbF6)2
Cu(I)ClO4
yield (%)
90
67
68
94
67
87
93
* CH2Cl2 was used as solvent
R3
Me
Me
H
H
Me
H
H
51-Jorgensen-Nitro-Silyl 6/27/02 5:48 PM
N
PMP
HO2N
CO2Et
HN
Et
PMP
Me
MeN
O
NO
Cu
O OEt
(R)-PhBox-Cu
N
Et
TMSO
O
H
O NN
PMPEt
O OEt
H
O
Ph
– TMS
Jørgensen: Proposed Mechanism and Transition State Model
Rapid equilibrium between the E and Z form of the copper nitronate is assumed(TMS nitronate = ca. 10 kcal/mol: Dunitz, Seebach et al. Helv. Chim. Acta 1980, 63, 697)
No clear statement about the dissociation of the TMS group...
Jørgensen et al. J. Am. Chem. Soc. 2001, 123, 5843
52-Jorgensen-Nitro-rationale 6/28/02 11:26 AM
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