Enantioselective Protonation:
Fundamental Insights and New
Concepts
• A presentation by
Guillaume Pelletier
• Literature meeting
October 12th 2011
Enantioselective Protonnation : An Extremely Simple
Transformation!(?)
• Enolates are important as synthetic intermediates : regio and
stereoselective generation with the desired counterion, increased
knowledge of their structure and reactivity
• Enantioselective protonnation via enol tautomerisation : require only
catalytic amounts of chiral reagent.
• Protonnation of a chiral enolate/ligand complex
What is the Important Facts to Know Before Exploring
«AP» of Enolates
• Enantioselective protonation
controlled reactions
processes
are
necessarily
kinetically
• Match the pKa of the proton donnor and the product
• Be concerned about the stereochemistry of the proton acceptor : the ability
to generate a stereodefined proton acceptor is critical (or not) in order to
have good enantioselectivity
• Detailed mechanistic explanations are rare : mixture of many mechanisms
Presentation Outline
• Lucette Duhamel and J.-C. Plaquevent’s Asymmetric
Protonation of Benzylidene Glycinates (1978)
• Charles Fehr’s Synthesis of α- and γ-Damascone (1988)
• Hisashi Yamamoto’s Catalytic Asymmetric Protonation
of Silyl Enol Ether with LBA (1994)
• Recent Contributions (Levacher, Genet, Fu, Stoltz…)
(2005+)
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Eames, J.; Weerasooriya, N. Tetrahedron : Asymmetry 2001, 12, 1-24.
Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron : Asymmetry 2004, 15, 3653-3691.
Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nature Chem. 2009, 1, 359-369.
First « Synthetically Useful » Example of AP with
Substituted Benzylidene Glycinates
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Influence of the Chiral Acid
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Influence of the Tartaric Acyl Substituents
Entry
R3
Yield (%)
ee (%)
[α]D25
1
Me
85
2.6
‒2.2 (S)
2
i-Pr
85
12.1
‒10.5 (S)
3
t-Bu
85
50
‒41.9 (S)
4
1-adamantyl
79
53.2
-44.7 (S)
5
Ph
80
12.3
-10.3 (S)
6
CH2Ph
81
8.5
-6.95 (S)
7
(CH2)2Ph
83
6.5
+0.4 (R)
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Influence of the Amino Acid Side-Chain
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Influence of the Benzylidene Electronic Properties
Entry
R2
Yield (%)
ee (%)
1
p-CN
75
12.3
2
p-Cl
75
31.3
3
H
85
50
4
p-CH3
82
55
5
o-OMe
70
36.6
6
p-OMe
70
57
7
p-NMe2
75
61
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Influence of the Base Additive
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Results Interpretation
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.
Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.
Enantioselective Protonation of Open-Chain Enolates
Without Internal Chelating Atom
•
•
•
•
Proton donnor should be only weakly acidic (pKa~15-20)
Proton donnor should contain an electron-rich group with chelating ability
The transferred proton should be located in the proximitiy of the stereogenic center
Proton donnor should be readily accessible in both enantiomeric form and easily
recoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Enantioselective Protonation of Open-Chain Enolates
Without Internal Chelating Atom
•
•
•
•
Proton donnor should be only weakly acidic (pKa~15-20)
Proton donnor should contain an electron-rich group with chelating ability
The transferred proton should be located in the proximitiy of the stereogenic center
Proton donnor should be readily accessible in both enantiomeric form and easily
recoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Enantioselective Protonation of Open-Chain Enolates
Without Internal Chelating Atom
•
•
•
•
Proton donnor should be only weakly acidic (pKa~15-20)
Proton donnor should contain an electron-rich group with chelating ability
The transferred proton should be located in the proximitiy of the stereogenic center
Proton donnor should be readily accessible in both enantiomeric form and easily
recoverable
Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
α-Damascone Synthesis – Ligand effect
Enolate
composition
Enolate
generation
Yield
(%)
ee
(%)
1
MgCl•MeOLi
Grignard
60
58
2
MgCl
Ketene
76
51
Entry
Proton
source
α-Damascone Synthesis – Ligand effect
Enolate
composition
Enolate
generation
Yield
(%)
ee
(%)
1
MgCl•MeOLi
Grignard
60
58
2
MgCl
Ketene
76
51
3
MgCl
Ketene
N.D.
16
4
MgCl•MeOLi
Ketene
75
70
5
MgCl•t-BuOLi
Ketene
70
79
Entry
Proton
source
α-Damascone Synthesis – Ligand effect
Enolate
composition
Enolate
generation
Yield
(%)
ee
(%)
1
MgCl•MeOLi
Grignard
60
58
2
MgCl
Ketene
76
51
3
MgCl
Ketene
N.D.
16
4
MgCl•MeOLi
Ketene
75
70
5
MgCl•t-BuOLi
Ketene
70
79
73
84
70
62
Entry
Proton
source
6
7
t-BuOH
Ketene
α-Damascone Synthesis – Enolate Stereoselectivity
Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
α-Damascone Synthesis – Enolate Stereoselectivity
Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
α-Damascone Synthesis – Enolate Stereoselectivity
Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
Equiv
Entry
H-A*
Addition
mode
Solvent
Li-A*
(equiv)
ee (%)
at 25%
Conv
ee (%)
at 50%
Conv
ee (%)
at 100%
Conv
1
1.2
normal
THF/Et2O
none
8
39
62
2
1.2
inverse
THF/Et2O
none
26
35
49
3
1.0
inverse
THF/Et2O
1.0
-
65
68
4
1.0
inverse
THF/Et2O
2.0
-
69
70
5
1.0
inverse
THF
2.0
-
75
75
• The elucidation of the reaction mechanism is rendered more complex from the nonlinear relationship between reaction product and H-A* enantiomeric purity.
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
α and γ-Damascone Synthesis – Application to
Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
α and γ-Damascone Synthesis – Application to
Thioester enolate
X
Deprotonnation
Protonnation
B/A
ee
(%)
Yield
(%)
OMe
n-BuLi (1.5 equiv)
-78 °C, 2.75 h
(‒)-H-A* (2.0 equiv)
-100 to 10°C,1.75h
22/78
36 (R)
-
2
OMe
LDA (3.0 equiv)
-78 °C, 3 h
(+)-H-A* (3.3 equiv)
-100 to 10°C,2.25h
33/67
50 (S)
-
3
OMe
LDA (3.0 equiv)
-78 °C, 3 h
aq. HCl (excess),
-78 °C
72/28
-
-
SPh
n-BuLi (2.0 equiv)
-78 °C, 3 h
(‒)-H-A* (2.7 equiv)
-100 to 10°C,1.75h
43/57
96 (R)
81
Fehr, C.; Galindo, J. Helv. Chim
. Acta
1995,
78, 539-552 (‒)-H-A* (4.0 equiv)
LDA
(3.0
equiv)
Fehr,5
C.; Stempf,
I.; Galindo, J. Angew. Chem. Int. Ed. 1993, 32, 1042-1044.
SPh
56/44
97 (R)
84
Entry
1
4
-78 °C, 2.75 h
-100 to -10°C,1.5h
α and γ-Damascone Synthesis – Application to
Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
α and γ-Damascone Synthesis – Application to
Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
α and γ-Damascone Synthesis – Application to
Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
α-Damascone Synthesis – Catalytic Enantioselective
Process
• Slow and reversible generation of the transient enolate
α-Damascone Synthesis – Catalytic Enantioselective
Process
• Slow and reversible generation of the transient enolate
• Rapid and irreversible protonation of the enolate by H-A*
α-Damascone Synthesis – Catalytic Enantioselective
Process
• Slow and reversible generation of the transient enolate
• Rapid and irreversible protonation of the enolate by H-A*
• The rate of regeneration of the catalyst and enolate can be ajusted with the
external proton source (PhSH)
• Proton exchange between A*- and PhSH must be rapid and complete and
PhSLi must be more nucleophilic than Li-A*
• Background reaction is suppressed by low [PhSH]
α-Damascone Synthesis – Catalytic Enantioselective
Process
Temperature
(°C)
ArSH
Addition
time (h)
ee (%)
Yield
(%)
Entry
ArSH
Li-A*
(mol %)
1
PhSH
100
-55
3
95
84
2
4-ClPhSh
100
-55
4
97
85
3
PhSH
5
-27
3
89
86
4
PhSH
2
-27
1
77
87
5
4-ClPhSH
5
-27
3
90
81
6
4-ClPhSH
2
-27
3
57
-
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1044-1046.
Catalytic Enantioselective Protonation – General
Scheme
• With preformed enolates, [enolate] > [H-A*]
• Formally, an external, achiral proton source Z-H selectively protonates A* and not the enolate
• Protonation of A*- should be rapid with Z-H (unless there is a catalytic
enantioselective tautomerisation mechanism)
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
What About Preformed Enolates? (Autocalatylic)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
What About Preformed Enolates? (Autocalatylic)
• This autocatalytic process is based on subtile kinetic differences in the
proton transfer reactions between H-A*, A*-, the enolate and the noninducing proton donnor (Z-H).
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General
Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General
Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General
Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.
Catalytic Enantioselective Protonation – General
Scheme
Entry
H-A*
(equiv)
PhCH2Ac
(equiv)
ee (%)
Yield
(%)
1
1.1
-
96
90
2
0.2
0.85
94
94
3
0.1
0.95
85
99
4
0.2
0.8(TMSCl)
98
91
Catalytic Enantioselective Protonation – Protonnation
of H-A*/enolate aggregate
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.
Catalytic Enantioselective Protonation of Cylic
Lithium Enolates
Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1994, 33, 107-109.
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
Catalytic Enantioselective Protonation of Cylic
Lithium Enolates
Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140-5149.
Rebek, J., Jr.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-T. J. Am. Chem. Soc. 1987, 109, 2426-2433.
Catalytic Enantioselective Protonation of Cylic
Lithium Enolates
*With a TMSCl quench at -78 °C!
H-A*
(equiv)
ee (%)
1
1.0
87
2
0.10
83
3
0.05
72
4
0.10
90
5
0.01
81
6
0.10
88
7
0.01
80
Entry
Achiral
proton
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
Catalytic Enantioselective Protonation of Cylic
Lithium Enolates
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.
Enantioselective Protonation of Prochiral Silyl Enol
Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Enantioselective Protonation of Prochiral Silyl Enol
Ethers and Ketene Silyl Acetals
• Silyl enol ether is a « stable metal enolate equivalent » which can be isolated
• In general, it is difficult the control the enantioselectivity with protonation of silyl
enol ether with chiral Brønsted acids
• Two main reason for poor induction is bonding flexibility between H and A* and
chiral pool of H-A* is limited to sulfonic and carboxylic acids
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Enantioselective Protonation of Prochiral Silyl Enol
Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Enantioselective Protonation of Prochiral Silyl Enol
Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Enantioselective Protonation of Prochiral Silyl Enol
Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Ketene Acetals
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Ketene Acetals
Entry
Chiral LBA (mol %)
SnCl4
(mol %)
Time
(h)
ee (%)
1
(R)-BINOL-OMe (2)
110
1
90
2
(R)-BINOL-OMe (5)
110
0.5
91
3
(R)-BINOL (5)
110
0.5
80
4
(R)-BINOL-OMe (2)
50
2
90
5
(R)-BINOL-OMe (20)
16
1
0
6
(R)-BINOL-OMe (100)
100
0.2
98
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Ketene Acetals
Entry
Chiral LBA (mol %)
SnCl4
(mol %)
Time
(h)
ee (%)
1
(R)-BINOL-OMe (2)
110
1
90
2
(R)-BINOL-OMe (5)
110
0.5
91
3
(R)-BINOL (5)
110
0.5
80
4
(R)-BINOL-OMe (2)
50
2
90
5
(R)-BINOL-OMe (20)
16
1
0
6
(R)-BINOL-OMe (100)
100
0.2
98
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Catalytic Enantioselective Protonation of Prochiral
Silyl Ketene Acetals
• 97% Conversion with (R)-BINOL-OMe LBA vs 17% Conversion with phenol-LBA
and 0% with SnCl4 (no acid present)!
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.
Recent Improvements with Chiral Brønsted Acids
(Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
Recent Improvements with Chiral Brønsted Acids
(Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
Recent Improvements with Chiral Brønsted Acids
(Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.
Recent Improvements with Chiral Chincona as Latent
HF Source
Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.
Recent Improvements with Chiral Chincona as Latent
HF Source
Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.
Chiral Guanidine Catalyzed Conjugate Addition/
Enantioselective Protonation
Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.
Chiral Guanidine Catalyzed Conjugate Addition/
Enantioselective Protonation
Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.
Rhodium Catalyzed Conjugate
Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Rhodium Catalyzed Conjugate
Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Rhodium Catalyzed Conjugate
Addition/Enantioselective Protonation
Entry
PG
R
pKa of
SM
Yield
(%)
ee (%)
pKa of
Prod
1
Ac
Me
13.1
91
90
14.7
2
CBz
Me
9.4
92
43
11.0
3
Boc
Me
9.6
82
90
11.2
4
Phth
Me
-
91
10
-
5
COCF3
Me
8.05
100
15
9.67
6
Ac
i-Pr
-
87
91
-
7
Boc
i-Pr
-
76
93
-
8
Boc
t-Bu
-
70
95
-
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Rhodium Catalyzed Conjugate
Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Rhodium Catalyzed Conjugate
Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.
Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Protonation by Chiral Brønsted Base – G. C. Fu
•
ee% of product varies linearly with with ee% of starting catalyst
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
M. Poirier Literature Meeting (Oct 2th 2007)
Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
• Excess of HCO2H led to decreased enantioselectivity, while smaller amounts of
HCO2H increased allylation.
• Small amount of 4Å MS decreased enantioselectivity, while large quantity
increased allylation.
• 5-8 equiv of HCO2H and 1.80g 4Å MS/mmol substrate was optimal…
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Protonation by Palladium Mediated Decarboxylative
Protonation – B. M. Stoltz
Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.
Concluding Remarks – Take Home Message
• A great deal of energy has been put to introduce a simple proton to form chiral
enantioenriched tertiary carbon center
• Although we have ennumerated numerous parameters that are critical to achieve
high enantioselectivities, few mechanistic understanding of their behaviour are
proposed yet.
• ‘‘AP’’ can be used for making α- and β-amino acids and few natural products
• Enantioselective protonnation should continue to rise as an important tool for
understanding general organic chemistry
Matoishi, K.; Ueda, M.; Miyamoto, M.; Ohta, H. J. Mol. Catal. B 2004, 27, 161-168.
Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.; Rouden, J. Eur. J. Org. Chem. 2008, 5493-5506.