1. Enantioselective Protonation: Fundamental Insights and New Concepts
A presentation by
Guillaume Pelletier
Literature meeting
October 12th 2011

2. 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

3. What is the Important Facts to Know Before Exploring «AP» of Enolates
Enantioselective protonation processes are necessarily kinetically controlled reactions
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

4. 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,
Eames, J.; Weerasooriya, N. Tetrahedron : Asymmetry 2001, 12, 1-24.
Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron : Asymmetry 2004, 15,
Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nature Chem. 2009, 1,

5. First « Synthetically Useful » Example of AP with Substituted Benzylidene Glycinates
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

6. Influence of the Chiral Acid
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

7. Influence of the Tartaric Acyl Substituents
Entry R3
Yield (%)
ee (%)
[α]D25 1 Me 85
2.6
‒2.2 (S) 2
i-Pr
12.1
‒10.5 (S) 3
t-Bu 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,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

8. Influence of the Amino Acid Side-Chain
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

9. Influence of the Benzylidene Electronic Properties
Entry R2
Yield (%)
ee (%) 1
p-CN 75
12.3 2
p-Cl
31.3 3 H 85 50 4
p-CH3 82 55 5
o-OMe 70
36.6 6
p-OMe 57 7
p-NMe2 61
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

10. Influence of the Base Additive
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

11. Results Interpretation
Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100,
Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II
Duhamel, L. et al. Tetrahedron 1988, 44,

12. 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,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

13. 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,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

14. 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,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

15. α-Damascone Synthesis – Ligand effect
Entry
Proton source
Enolate composition
Enolate
generation
Yield (%)
ee (%) 1
MgCl•MeOLi
Grignard 60 58 2
MgCl
Ketene 76 51

16. α-Damascone Synthesis – Ligand effect
Entry
Proton source
Enolate composition
Enolate
generation
Yield (%)
ee (%) 1
MgCl•MeOLi
Grignard 60 58 2
MgCl
Ketene 76 51 3
N.D. 16 4 75 70 5
MgCl•t-BuOLi 79

17. α-Damascone Synthesis – Ligand effect
Entry
Proton source
Enolate composition
Enolate
generation
Yield (%)
ee (%) 1
MgCl•MeOLi
Grignard 60 58 2
MgCl
Ketene 76 51 3
N.D. 16 4 75 70 5
MgCl•t-BuOLi 79 6 73 84 7
t-BuOH 62

18. α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

19. α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

20. α-Damascone Synthesis – Enolate Stereoselectivity Effect
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

21. γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

22. γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

23. γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

24. γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

25. γ-Damascone Synthesis – Effect of Alkoxide additives
Entry
Equiv 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
inverse 26 35 49 3
1.0 - 65 68 4
2.0 69 70 5
THF 75
The elucidation of the reaction mechanism is rendered more complex from the non- linear relationship between reaction product and H-A* enantiomeric purity.
Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53,
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

26. γ-Damascone Synthesis – Effect of Alkoxide additives
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,

27. α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,

28. α and γ-Damascone Synthesis – Application to Thioester enolate
Entry X
Deprotonnation
Protonnation
B/A
ee (%)
Yield (%) 1
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
LDA (3.0 equiv)
-78 °C, 3 h
(+)-H-A* (3.3 equiv) -100 to -10°C,2.25h
33/67
50 (S) 3
aq. HCl (excess), °C
72/28 4
SPh
n-BuLi (2.0 equiv)
(‒)-H-A* (2.7 equiv) -100 to -10°C,1.75h
43/57
96 (R) 81 5
(‒)-H-A* (4.0 equiv) -100 to -10°C,1.5h
56/44
97 (R) 84 6
LDA (1.5 equiv)
-78 °C, 3.5 h
(+)-H-A* (2.0 equiv) -100 to -10°C,1.5h
45/55
94 (S) 76
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem. Int. Ed. 1993, 32,

29. α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,

30. α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,

31. α and γ-Damascone Synthesis – Application to Thioester enolate
Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,

32. α-Damascone Synthesis – Catalytic Enantioselective Process
Slow and reversible generation of the transient enolate

33. α-Damascone Synthesis – Catalytic Enantioselective Process
Slow and reversible generation of the transient enolate
Rapid and irreversible protonation of the enolate by H-A*

34. 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]

35. α-Damascone Synthesis – Catalytic Enantioselective Process
Entry
ArSH
Li-A* (mol %)
Temperature (°C)
ArSH Addition time (h)
ee (%)
Yield (%) 1
PhSH
100
-55 3 95 84 2
4-ClPhSh 4 97 85 5
-27 89 86 77 87
4-ClPhSH 90 81 6 57 -
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,
Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32,

36. 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,

37. What About Preformed Enolates? (Autocalatylic)
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

38. 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 non- inducing proton donnor (Z-H).
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

39. Catalytic Enantioselective Protonation – General Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

40. Catalytic Enantioselective Protonation – General Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

41. Catalytic Enantioselective Protonation – General Scheme
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,
Fehr, C. Angew. Chem., Int. Ed. 1996, 35,

42. Catalytic Enantioselective Protonation – General Scheme
Entry
H-A* (equiv)
PhCH2Ac (equiv)
ee (%)
Yield (%) 1
1.1 - 96 90 2
0.2
0.85 94 3
0.1
0.95 85 99 4
0.8(TMSCl) 98 91

43. Catalytic Enantioselective Protonation – Protonnation of H-A
Catalytic Enantioselective Protonation – Protonnation of H-A*/enolate aggregate
Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33,

44. Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1994, 33,
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995,
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997,

45. Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46,
Rebek, J., Jr.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-T. J. Am. Chem. Soc. 1987, 109,

46. Catalytic Enantioselective Protonation of Cylic Lithium Enolates
*With a TMSCl quench at -78 °C!
Entry
Achiral proton
H-A* (equiv)
ee (%) 1
1.0 87 2
0.10 83 3
0.05 72 4 90 5
0.01 81 6 88 7 80
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995,
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997,

47. Catalytic Enantioselective Protonation of Cylic Lithium Enolates
Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995,
Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997,

48. Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

49. 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,
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

50. Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

51. Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

52. Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals
Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

53. Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

54. Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

55. Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

56. Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
Entry
Chiral LBA (mol %)
SnCl4 (mol %)
Time (h)
ee (%) 1
(R)-BINOL-OMe (2)
110 90 2
(R)-BINOL-OMe (5)
0.5 91 3
(R)-BINOL (5) 80 4 50 5
(R)-BINOL-OMe (20) 16 6
(R)-BINOL-OMe (100)
100
0.2 98
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

57. Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals
Entry
Chiral LBA (mol %)
SnCl4 (mol %)
Time (h)
ee (%) 1
(R)-BINOL-OMe (2)
110 90 2
(R)-BINOL-OMe (5)
0.5 91 3
(R)-BINOL (5) 80 4 50 5
(R)-BINOL-OMe (20) 16 6
(R)-BINOL-OMe (100)
100
0.2 98
Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,

58. 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,

59. Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,

60. Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,

61. Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)
Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,

62. 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,

63. 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,

64. 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,

65. 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,

66. Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43,
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,

67. Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43,
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,

68. 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
9.4 92 43
11.0 3
Boc
9.6 82
11.2 4
Phth - 10 5
COCF3
8.05
100 15
9.67 6
i-Pr 87 7 76 93 8
t-Bu 70 95
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43,
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,

69. Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43,
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,

70. Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation
Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43,
Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130,

71. Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,

72. 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,
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,

73. Protonation by Chiral Brønsted Base – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
M. Poirier Literature Meeting (Oct 2th 2007)

74. Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,

75. Protonation by Chiral Brønsted Acid – G. C. Fu
Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,

76. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,

77. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,

78. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,

79. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,

80. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,

81. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,

82. Protonation by Palladium Mediated Decarboxylative Protonation – B. M
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,
Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10,

83. 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,
Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.; Rouden, J. Eur. J. Org. Chem. 2008,