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

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.

Organocatalysis: Development and Fast Evolution 1904-1908 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 2000-2006 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, 349. 2) Bredig G.; Fajans K. Ber. Dtsch. Chem. Ges. 1908, 41, 752. 3) Langenbeck W. Angew. Chem. 1932, 45, 97. 4) List B.; Lerner A.; Barbas III C. F. J. Am. Chem. Soc. 2000, 122, 2395. 5) Ahrendt K. A.; Borths C. J.; MacMillan D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.

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)

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.

« 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.

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.

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

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

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.

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, 10966. 2 Curran D. P.; Kuo L. H. J. Org. Chem. 1994, 59, 3259.

Bidentate Catalysts : a Short Lineage T. R. Kelly P. R. Scheiner M. C. Etter D. P. Curran 1990 E. N. Jacobsen 1994-2003 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

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 1st 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, 10012.

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, 12964.

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.

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.

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, 81-93 % 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

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.

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.

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

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, 12094.

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.

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.

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: + 3.4 kcal/ mol) FAVORED

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

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.

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.

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, 10336.

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, 10336.

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.

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.

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.

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.

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, 11804.

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, 4065.

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.

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.

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.

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.

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.

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

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, 7424. Rueping M. and coll. Org. Lett. 2005, 17, 3781. Antilla J. C. and coll. JACS 2007, 129, 5830.

Phosphoric Acid Catalysis : Enantiomeric Reductive Amination with Hantzsch Esters (A) Me Et 87 % 27 % 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.

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 85 % 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.

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, 13368.

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