1. Asymmetric Organocatalysis By Chiral Brønsted Acids :
Focus on Chiral Phosphoric Acids
Maryon Ginisty
Pr. A.B. Charette
Literature Meeting - November 6th, 2007

2. quantity of an organic compound which does not contain a metal atom »
Organocatalysis: an Old Story…
« Acceleration of chemical reactions through the addition of a substoechiometric
quantity of an organic compound which does not contain a metal atom »
Role in the formation of prebiotic key building blocks, such as sugars
Introduction and spread of homochirality in living organisms.
Enantiomerically enriched amino acids L-Alanine and L-Isovaline:
Present up to 15 % ee in carbonaceous meteorites
Catalysis of dimerization of glycal and aldol-type reaction between glycal and formaldehyde.
Term introduced in 1900 by Ostwald 1 to distinguish small organic molecules-mediated reactions from
enzymatic or inorganic catalyzed reactions.
1) Ostwald W. Z. Phys. Chem. 1900, 32, 509.

3. Organocatalysis: Development and Fast Evolution
First publications= Desymmetrization of prochiral substrates by alkaloids1,2
1932 Early treatise on « organic catalysis » : reaction mechanism, kinetics
and catalyst optimization for amine-catalyzed decarboxylations3
Increase in publications containing the words « organocatalysis »,
« organocatalytic » or « organocatalyst »
LIST - Cross-aldol reactions between acetone and different aldehydes catalyzed by the simple proline4
MacMILLAN- Diels-Alder reactions activated by chiral imidazolidinium salts5
1) Marckwald W. Ber. Dtsch. Chem. Ges. 1904, 37, ) Bredig G.; Fajans K. Ber. Dtsch. Chem. Ges. 1908, 41, ) Langenbeck W. Angew. Chem. 1932, 45, 97. 4) List B.; Lerner A.; Barbas III C. F. J. Am. Chem. Soc. 2000, 122, ) Ahrendt K. A.; Borths C. J.; MacMillan D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.

4. Organocatalysis: Reaction Characteristics
Scope Typical transition metal-mediated coupling reactions: Suzuki, Sonogashira,
Ullmann, Heck-type and Tsuji-Trost reactions
Organocatalysis Features Evolved essentially from the ligand chemistry of organometallic reactions
The most effective organocatalysts are ligands developed for metal-
mediated enantioselective catalytic reactions.
More closely related to enzyme- or antibody-catalyzed reactions than to
organometallic processes.
The organocatalysts often show some characteristic features of
bioorganic reactions (e.g. Michaelis-Menten kinetics)

5. Organocatalysis: a New Orientation of Organometallic Processes
None Ti Mn Fe Ru Co Cu Zn Gd Nd Yb Eu
ee (%) 19 4 5 10 13 9 1 2 3
Conversion (%) 59 30 61 69 63 68 55 91 95 84 94 34
Sigman M. S.; Jacobsen E. N.; J. Am. Chem. Soc. 1998, 4901.

6. « Third order reaction »
Organocatalysis: Evidence of Lewis Acid Efficiency
Brønsted Acid Catalysis
« Third order reaction »
Wasserman A. J. Chem. Soc. 1942, 618.
Lewis Acid Catalysis
≈ 3200 x increase
Yates P.; Eaton P. J. Am. Chem. Soc. 1960, 4436.

7. Lewis Acids vs Brønsted Acids: Application to Asymmetric Catalysis
Metal Lewis Acid
Difficult to immobilize on
polymers or other stationary
phases for easier catalyst removal
and flow processes without washout
Stoichiometric amount
due to presence of a basic moiety
on the product that binds the LA
High price
Toxicity
Product contamination
Product Inhibition
Strong bonding between LA and basic sites
Limited use in aqueous media
Metal-free catalysis through hydrogen bonding interactions offers attractive alternatives to metal-
catalyzed reactions.

8. Lewis Acids vs Brønsted Acids: Application to Asymmetric Catalysis
Metal Lewis Acid
Brønsted Acid
Y = O, P, N, S or
Y4 = diene
Organizational role of the metal by translating
chiral information and activating the reagents
Multiple coordination opportunities available
Catalytic activity relative to the formation of a
donor-acceptor complex
Tunable electronic properties between
electron-deficient metal sites and excess
electron densities
Tunable steric parameters
TS formed by passive interactions (hydrophobic, VDW,
electrostatic…) or dynamic interactions (between cata-
-lysts and substrates at the reaction centers)
One valence orbital and spherical symmetry
Catalytic activity relative to the establishment of an
ionic hydrogen bond (1-6 kcal/ mol)
Supramolecular design required for steric control:
formation of rigid three-dimensional structures
Contribution to affinity and selectivity of molecular
recognition

9. to C=O, C=C and C=N Double Bonds
Brønsted Acids : Powerful Catalysts for Addition Reactions
to C=O, C=C and C=N Double Bonds
Single hydrogen bonding
Double hydrogen bonding
Brønsted acid catalysis
Monofunctional and bifunctional thiourea catalysts
TADDOL derivatives
BINOL derivatives
Phosphoric acids

10. Early Bidentate Catalysts
Applications in Diels-Alder Reactions
Diene
Dienophile
Temp. (°C)
Time
% Product Formation
Product(s)
Without B
With B
(mol. equiv. B)
r.t.
10 min 3
90 (0.4)
30 min 10
76 (0.4) 55
2 h 16
97 (0.5)
45 h 21
95 (0.5)
48 h 5
60 (0.5)
120 h 7
10 (0.5)
Kelly T. R.; Meghani P.; Ekkundi V. S. Tetrahedron Lett. 1990, 31, 3381.

11. Early Bidentate Catalysts
Applications in Allylation Reactions
of Phenylseleno Sulfoxide
Jorgensen’s
hydration model
Entry
Solvent
Additive
trans/ cis (yield, %) 1
benzene -
2.5/ 1 (60) 2
DCM
5.5/ 1 (62) 3
EtOH
4.9/ 1 (87) 4
AcOH
6.7/ 1 (51) 5
CF3CH2OH
8.1/ 1 (83) 6
A (0.2 equiv)
3.7/ 1 (57) 7
A (0.6 equiv)
5.8/ 1 (72) 8
A (1.0 equiv)
7.0/ 1 (81)
A :
1 Severance D. L.; Jorgensen W. J. Am. Chem. Soc. 1992, 114, Curran D. P.; Kuo L. H. J. Org. Chem. 1994, 59, 3259.

12. Bidentate Catalysts : a Short Lineage
T. R. Kelly
P. R. Scheiner
M. C. Etter
D. P. Curran
1990
E. N. Jacobsen
1 Etter M. C.; Reutzel S. M. J. Am. Chem. Soc. 1991, 113, 2586.
2 Schreiner P. R.; Wittkopp A. Org. Lett. 2002, 4, 217.
1998

13. Catalysis by Hydrogen Bond
Monofunctional Thiourea and Urea Catalysts
Asymmetric hydrocyanation of N-allyl- or N-benzylaldimines
(Strecker reaction)
High degree of generality
High enantioselectivity
Michaelis-Menten kinetics st order dependance on catalyst and HCN
Saturation kinetics with respect to the imine
Reversible formation of an imine-catalyst complex
Synthesis of a series of analogues of the catalyst Only urea protons essential for catalytic activity
NMR studies of a model solution of a ketoimine derivative Downfield shift of the Z-imine methyl group exclusively
Interaction between catalyst and Z-isomer
Vachal P.; Jacobsen E. N. J. Am. Chem. Soc. 2002, 124,

14. Catalysis by Hydrogen Bond
Monofunctional Thiourea and Urea Catalysts
Asymmetric Mannich-type reaction of N-Boc aldimines with
silylketene acetals
Goal Catalyst capable of activating imines toward nucleophilic attack,
yet resistant to inhibition by the strongly Lewis-basic amine products
TBS > TMS
Better reactivity
and catalyst loading
R’ = Me → Et → iPr
reaction rate
R’ = tBu
ee (51 %)
Entry
R imine
Catalyst
Temp. (°C)
Yield (%)
ee (%) 1 Ph
1a (10 mol%)
r.t. 92 47 2
1b (5 mol%) 93 68 3 40 90 91 4
1c (5 mol%) 95 97
Wenzel A. G.; Jacobsen E. N. J. Am. Chem. Soc. 2002, 124,

15. Catalysis by Hydrogen Bond
Monofunctional Thiourea Catalysts
Baylis-Hillman reaction
NMR studies
Interaction of the thiourea 1b
with both the enone and aldehyde
1b involved in 2 steps of the
BH reaction
Aldol reaction
Hetero-Michael reaction
Sohtome Y.; Tanatami A.; Hashimoto Y.; Nagasawa K. Tetrahedron Lett. 2004, 45, 5589.

16. Catalysis by Hydrogen Bond
Bifunctional Thiourea Catalysts A
Baylis-Hillman Reaction
Nagasawa’s Catalyst
Aldehyde
Yield (%)
ee (%) 88 33 38 30 19 99 63 60 72 90
Sohtome Y.; Tanatami A.; Hashimoto Y.; Nagasawa K. Tetrahedron Lett. 2004, 45, 5589.

17. Takemoto’s Transition State
Catalysis by Hydrogen Bond
Bifunctional Thiourea Catalysts
Michael Reactions of Malonates to Nitroolefines
Takemoto’s Transition State 8
(10 mol%)
Takemoto : R’ = Et
72-99 % yield, % ee 9
(2-5 mol%)
Connon : R’ = Me
75-99 % ee
(10 mol%)
Okino T.; Hoashi Y.; Furukawa T.; Xu X.; Takemoto Y. J. Am. Chem. Soc. 2005, 127, 119.
McCooey S. H.; Connon S. J. Angew. Chem. Int. Ed. 2005, 44, 6367.
Ye J.; Dixon D. J.; Hynes P. S. Chem. Commun. 2005, 4481.
Dixon : R’ = Me
82-97 % ee

18. Catalysis by Hydrogen Bond
Bifunctional Thiourea Catalysts A
Michael Reactions of Ketones to Nitroolefines R
Yield (%)
ee (%) Ph 92 47
4-MeOC6H4 93 68
4-MeC6H4 90 91
2-thienyl 95 97 Me 70 98
nBu 78
Favored
Z-enamine
Disfavored
E-enamine
Huang H.; Jacobsen E. N. J. Am. Chem. Soc. 2006, 128, 7170.

19. Catalysis by Hydrogen Bond
TADDOL Derived Catalysts A
Without A : no reaction
= poor catalysts
⇒ hydrogen bond
crucial for the catalysis
Huang Y.; Unni A. K.; Thadini A. N.; Rawal V. H. Nature 2003, 424, 146.

20. Catalysis by Hydrogen Bond
TADDOL Derived Catalysts
BAMOL
Axial Chirality
Tweak of the
chiral environment
1 : 1 association between BAMOL and PhCHO
Presence of an intramolecular H-bond
Presence of an intermolecular H-bond to the carbonyl O of PhCHO
TADDOL Catalysis: C=O activation through a single-point H-bond
Unni A. K.; Takenaka N.; Yamamoto H.; Rawal V. H. J. Am. Chem. Soc. 2005, 127, 1336.
Ar = Ph

21. Catalysis by Hydrogen Bond
BINOL Derived Catalysts
Morita-Baylis-Hillman Reaction
Bulky substituents on the 3,3’-positions essential for excellent ee
Mesityl group restricting rotation about the biaryl bond of the 3-
substituent, prerequisite for catalysis
Removal of one BA equiv : no enantioselectivity and catalytic activity
Best results with 5 and 6
Catalyst
Yield (%)
ee (%) - 5
(R) -BINOL 74 32 1 73 48 2 79 3 69 86 4 9 31 70 88 6 84 7 43 8 15
McDougal N. T.; Schaus S. E. J. Am. Chem. Soc. 2003, 125,

22. Chiral Phosphoric Acids: A New Class of Strong Brønsted Acids
Strong Brønsted Acid relied on one single proton
(pKa (EtO)2PO3H = 1, 39)
Hydrogen bonding with the substrate
without loose ion-pair formation
Tetradentate P(V)
Formation of a rigid ring structure
Prevent free rotation at a of the P center
Transfer of stereochemical information to the substrate
Lewis basic phosphoryl moiety
Bifunctional catalysis (electophilic and nucleophilic activations)
Connon S. J. Angew. Chem. Int. Ed. 2006, 45, 3909.

23. Phosphoric Acid Catalysis : Mannich-Type Reactions
Akiyama’s Work X
Catalyst
t (h)
Yield (%)
ee (%) 1a 22 57 1b 20
100 27 1c 60 1d 46 99 52 1e 4 96 87 R1 R2 R3
Yield (%)
Syn/ anti
ee (%) Ph Me Et
100
87:13 96
p-MeOC6H4
92:8 88
p-FC6H4
91:9 84
p-ClC6H4
86:14 83
p-MeC6H4
94:6 81
PhCH=CH 91
95:5 90 Bn
93:7 92 87
Ph3SiO 79
100:0 X
t (h)
Y(%)
ee (%)
2-OH 13 98 89
4-OH 33 28 20
2-OCH3 46 56 3 H 43 76 39
Akiyama T.; Itoh J.; Yokota K.; Fuchibe K. JACS 2007, 129, 6756.
Akiyama T.; Itoh J.; Yokota K.; Fuchibe K. Angew. Chem. Int. Ed. 2004, 43, 1566.

24. Phosphoric Acid Catalysis : Mannich-Type Reactions
Akiyama’s Work: Mechanism and Transition State
TSd
Nine membered-cyclic TS
Dicoordination
Pathway
(TS: 0.0 kcal/ mol)
TSm
Monocoordination
pathway
Dicoordination
pathway
More crowded concave
structure for the attacking
nucleophile
Longer forming bond C-C
Monocoordination
Pathway
(TS: kcal/ mol)
FAVORED

25. Phosphoric Acid Catalysis : Mannich-Type Reactions
Akiyama’s Work : Origin of Selectivity
repulsive
interaction
re facial attack
P - stacking interaction

26. Phosphoric Acid Catalysis : Mannich-Type Reactions
Terada’s Work
Catalyst
Yield (%)
ee (%) 1a 92 12 1b 95 56 1c 88 90 1d 99 98
re facial attack
Formation of 1:1 adducts (catalyst: imine)
sterically controlled by the bulky substituents
of the phosphoric acid
One side of C=N shielded by one of the
biphenyl substituents
Another side completely open for
the approach of the nucleophile R2
Yield (%)
ee (%)
tBu 88
90 (S) Bn 76 26 Me 96 6
Terada and coll. Tetrahedron Lett. 2007, 48, 497.
Terada and coll. J. Am. Chem. Soc. 2004, 126, 5356.

27. Phosphoric Acid Catalysis : Mannich-Type Reactions
Akiyama: A New TADDOL-Based Catalyst
Catalyst
Time (h)
Yield (%)
ee (%) 1a 24 - 1b 66 47 31 1c 26 63 34 1d 21 97 73
R1 = Ph
re facial attack
Adv. Synth. Catal. 2005, 347, 1523.

28. Phosphoric Acid Catalysis : Aza-Ene Reaction
Terada’s Work Ar
Yield (%)
ee (%)
p-Me-C6H4 90 95
o-Me-C6H4 61 93
p-MeO-C6H4 82 92
p-F-C6H4 89
p-CN-C6H4 97 98
2-naphtyl 91
Angew. Chem. Int. Ed. 2006, 45, 2254.
J. Am. Chem. Soc. 2007, 129,

29. Phosphoric Acid Catalysis : Aza-Ene Reaction
Terada’s Work Ar
Yield (%)
trans:cis
ee (%)
of trans
of cis
p-Br-C6H4
> 99
94:6 99 23
pMe-C6H4
95:5 98 4
2-furyl 76
88:12 14
c-C6H11 68 97 40
Angew. Chem; Int. Ed. 2006, 45, 2254.
J. Am. Chem. Soc. 2007, 129,

30. Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives
Hydrophosphonylation of Imines - Akiyama R
Time (h)
Yield (%)
ee (%)
C6H5 24 84 52
o-Me-C6H4 46 76 69
C6H5CH=CH
101 92
p-CH3C6H4CH=CH
170 88 86
p-Cl-C6H4CH=CH
145 97 83
o-CH3C6H4CH=CH
171 80 82
o-Cl-C6H4CH=CH 70 87
1-naphtyl-CH=CH
168 81
re facial attack
Org. Lett. 2005, 7, 2583.

31. Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives
Strecker Reaction - Rueping
re facial attack
si face efficiently shielded
by the large phenanthryl
group of the catalyst
Angew. Chem. Int. Ed. 2006,45, 2617.

32. Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives
Imine Amidation - Antilla Ar R
mol% acid
Time
Yield (%)
C6H5
SO2Me
0.5 mol% A
20 min 99
SO2–C6H4-Me
5 mol% B
20 h 91
4-BrC6H4
C(O)CH=CH2
10 mol% B
2.5 h 94
4-MeOC6H4
14 h
2-furyl
11 h
89-99 %
(73-99 % ee) Ar R
mol% acid
Time (h)
Yield (ee) (%) Ph Ts
5 mol% C 16
95 (<5)
4 mol% D 20
96 (60)
5 mol% E 24
99 (71)
5 mol% F 1
95 (94) Ms
86 (93)
89 (91)
4-BrC6H4
10 mol% F 13
96 (92)
4-CF3C6H4
99 (99)
J. Am. Chem. Soc. 2005, 127, 1596.

33. Phosphoric Acid Catalysis : Hetero-Diels-Alder Reactions
Akiyama’s Work
Catalyst
Time (h)
Yield (%)
ee (%) 1a 23 67 3 1b 21 90 5 1c 20 32 42
Additive
Yield (%)
ee (%)
None 29 34
MeOH 97 46
CF3CH2OH 88 41
PhCO2H 85 63
CH3CO2H 78 67
PhSO3H 87 15 Ar
Time (h)
Yield (%)
ee (%)
C6H5 18 99 80
p-I-C6H4 24 86 84
p-Br-C6H4 13
100
p-Cl-C6H4 35 72
p-F-C6H4 77 78
p-CF3-C6H4 21 82 81
o-Br-C6H4 10 96
o-Cl-C6H4 12 76
1-naphtyl 91
Ar = Ph
si facial
approach
Synlett 2006, 1, 141.

34. Phosphoric Acid Catalysis : Friedel-Crafts Reactions
Terada’s Work : FC Reactions on Furan R
Yield (%)
ee (%)
C6H5 95 97
p-MeO-C6H4 84 94
o-Br-C6H4 85 91
p-Br-C6H4 86 96
p-Cl-C6H4 88
p-F-C6H4 82
p-CF3-C6H4 81
2-furyl
1-naphtyl
100
Temp (°C)
Yield (%)
ee (%) 86 92
-20 89 95
-35 87 97
Synthetic Utility of Furan-2-ylamine
Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2004, 126,

35. Phosphoric Acid Catalysis : Friedel-Crafts Reactions
Antilla’s Work : FC Reactions on Indole and Pyrrole R1
Yield (%)
ee (%) H 99 94
p-MeO 93
m-MeO 96 92
p-Br
p-Cl 97
p-F 95
p-NO2
1-naphtyl R1
Temp. (°C)
Catalyst
Yield (%)
ee (%) H 60 B 89 86
A (10 mol%) 92 97
-30
A (5 mol%) 99 94
Application to Pyrroles
Rowland G. B.; Rowland E. B.; Liang Y.; Perman J. A.; Antilla J. C. Org. Lett. 2007, 14, 2609.
Li G.; Rowland G. B.; Rowland E. B.; Antilla J. C. Org. Lett. 2007, 20,

36. Friedel-Crafts adduct
Phosphoric Acid Catalysis : Alkylation of a-Diazoester
Friedel-Crafts adduct A
« slow »
Aziridine
(usual fate) B
« fast »
« Friedel-Crafts type » adduct C
Phosphoryl oxygen = intramolecular basic site
Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2005, 127, 9360.

37. Phosphoric Acid Catalysis : Alkylation of a-Diazoester
Yield (%)
ee (%)
C6H5 59 90
o-Br-C6H4 80
o-Me-C6H4 84
o-MeO-C6H4 77 92
m-MeO-C6H4 76 91
1-naphtyl 82
p-Br-C6H4 68 86
p-Me-C6H4 72
p-MeO-C6H4 73 93
p-Me2N-C6H4 81 97 Ar
Yield (%)
ee (%)
p-F-C6H4 74 97
p-Ph-C6H4 71
p-Me-C6H4
p-MeO-C6H4 62
o-F-C6H4 89 91
o-MeO-C6H4 85 84 93
Ar, R’
Catalyst
Yield (%)
ee (%) Ph A 70 - B 59 90
Synthetic Utility of b-Amino-a-Diazoesters
Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2005, 127, 9360.

38. Pictet-Spengler Reaction
Phosphoric Acid Catalysis : Pictet-Spengler Reaction
List’s Work
Aldol Condensation
Pictet-Spengler Reaction R1 R2
Yield (%)
ee (%)
OMe Et 96 90 H 76 88
n-Bu 87 91 Bn 85 72 58
p-NO2-C6H4 98 60
p-CN-C6H4 80 40 89
+ Toleration of aromatic aldehydes (especially electron-poor ones)
- Requirement of a geminal diester functionality (Thorpe-Ingold effect)
Seayad J.; Seayad A. M.; List B. J. Am. Chem. Soc. 2006, 128, 1086.

39. Phosphoric Acid Catalysis : Pictet-Spengler Reaction
Hiemstra’s Work R R’
Time (h)
Yield 3 (%)
ee 3 (%)
CPh3
n-hept 2 87 84
i-Pr 24 77 78 Me 1 88 30
c-hex 81 72
CH2Bn
0.5 76 Bn 4 90 Ph 82
p-NO2-C6H4
+ Easy preparation of Pictet-Spengler precursors
Stabilization of th iminium ion by the sulfenyl substituent
Easy removal of the sulfenyl group
Fast reactions
- Unstability of N-tritylsulfenyl tetrahydro-b-carboline
⇒ Use of BHT
Slightly lower yields and ees
Wanner M. J.; Van der Haas R. N. S.; de Cuba K. R.; Van Maarseven J. H.; Hiemstra H. Angew. Chem. Int. Ed. 2007, 46, 7485.

40. Phosphoric Acid Catalysis :
Asymmetric Transfer Hydrogenation with Hantzsch Esters
General Mechanism: Reduction of C=N Bonds
Hantzsch method vs H2 or metal hydride process
1/ Mild Reaction Conditions
(r.t. or slight heating in conventional solvents)
2/ Operational simplicity (no HP apparatus
or air-free conditions)
3/ Availability of Hantzsch Esters
4/ Safe handling
5/ Compatiblity with Organocatalysts
1/ Poor atom economy
2/ Problematic removal of pyridine
by-products + II I -
III
You S.-L. Chem. Asian J. 2007, 2, 820.

41. Phosphoric Acid Catalysis :
Asymmetric Transfer Hydrogenation with Hantzsch Esters
Reduction of C=N Bonds: Rueping’s Work
amine
Yield (%)
ee (%) 82
70 (94)*
R = CF3: 71
R = Ph: 71
R = OMe: 76 72
74 (98) 76 74 84 46 91 78
R = PMP R R’
Catalyst
Yield (%)
ee (%)
Napht
PMP 1a 20
rac 1b 42 38 1c 37 44 1d 54 40 1e 59 48 1f 57 62
si face
selectivity
Rueping M.; Sugiono E.; Azap C.; Theissmann T.; Bolte M. Org. Lett. 2005, 17, 3781.
* In parenthesis, ee obtained after one
recrystallization from MeOH

42. Phosphoric Acid Catalysis : Asymmetric Transfer Hydrogenation
with Hantzsch Esters (A) R
t (h)
Yield (%)
ee (%)
t (d) Ph 45 96 88 3 76 74 19 93 42 85 84 82 94 - 95 71 91 78 22 98 92 72 21
List B. and coll. Angew. Chem. Int. Ed. 2005, 44, Rueping M. and coll. Org. Lett. 2005, 17, Antilla J. C. and coll. JACS 2007, 129, 5830.

43. Phosphoric Acid Catalysis : Enantiomeric Reductive Amination
with Hantzsch Esters (A)
Me Et
87 % %
Catalyst R
Additive
Temp. (°C)
Conv (%)
ee (%) 3a
2-naphtyl - 80 6 37
5 Ǻ MS 41 45 3b H 43 7 3c
3,5-NO2-Ph 16 3d
3,5-CF3-Ph 39 65 4
TBDPS 35 61 5
SiPh3 70 87 40 85 94
Storer R. I.; Carrera D. E.; Ni Y.; MacMillan D. W. C. J. Am. Chem. Soc. 2006, 128, 84.

44. Phosphoric Acid Catalysis : Enantiomeric Reductive Amination
with Hantzsch Esters (A)
Chemoselectivity Study
Selectivity for the reduction of iminium ions derived from methyl ketones
18 : 1 Methyl vs Ethyl ketone selectivity % yield, 96 % ee
71 % yield, 83 % ee
Viable conditions for substrates containing substituents of
similar steric and electronic character
Storer R. I.; Carrera D. E.; Ni Y.; MacMillan D. W. C. J. Am. Chem. Soc. 2006, 128, 84.

45. Phosphoric Acid Catalysis : Enantiomeric Reduction of
a,b-Unsaturated Ketones with Hantzsch Esters (A)
Development of Ammonium Phosphates
Enone
Yield (%)
er (%)
R = Me 99
97:3
R = Et 98
98:2
R = CH2CH2Ph
R = Ph
92:8 78
99:1
R = Et 71 68
Enone
Yield (%)
er (%)
> 99
98:2
R = CO2Et 99
92:8
R = Ph 81
85:15
Catalyst anion R’
Conv (%)
er (%)
CF3CO2 - 23
75:25 66
77:23 72
76:24 1a 25
87:13 1b
81a
97:3
a in Bu2O
Martin N. J. A.; List B. J. Am. Chem. Soc. 2006, 128,

46. Conclusion
Difficulties previously thought to hinder Bronsted acid catalysis overcome in three ways: bidentate hydrogen
bonding, supramolecular architecture and bifunctional hydrogen bonding
Large variety of Brønsted acid catalysts presented, but many not discussed (proline, Fu’s PPY, ammonium salts…)
and more that I’ve missed (I’m sure…)
Strong Brønsted acid catalysts = easy to handle (stable toward water and oxygen), easy to prepare, non toxic,
potentially recoverable and recyclable
Significant expansion of the scope of asymmetric nucleophilic additions to carbonyl and carbonyl derivatives
New applications and advances in terms of both catalyst design and the expansion of substrate scope for Brønsted
acid catalysts and particularly for Phosphoric Acids