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Asymmetric Organocatalysis By Chiral Br ø nsted Acids : Focus on Chiral Phosphoric Acids

Asymmetric Organocatalysis By Chiral Br ø nsted Acids : Focus on Chiral Phosphoric Acids Maryon Ginisty Pr. A.B. Charette Literature Meeting - November 6 th , 2007. Organocatalysis: an Old Story…. « Acceleration of chemical reactions through the addition of a substoechiometric

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Asymmetric Organocatalysis By Chiral Br ø nsted Acids : Focus on Chiral Phosphoric Acids

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

  2. 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 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.

  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 Sigman M. S.; Jacobsen E. N.; J. Am. Chem. Soc.1998, 4901.

  6. 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 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 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

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

  10. Early Bidentate Catalysts Applications in Diels-Alder Reactions 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 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.

  12. 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

  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 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.

  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 %) Wenzel A. G.; Jacobsen E. N. J. Am. Chem. Soc.2002, 124, 12964.

  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 Sohtome Y.; Tanatami A.; Hashimoto Y.; Nagasawa K. Tetrahedron Lett.2004, 45, 5589.

  17. 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%) Dixon : R’ = Me 82-97 % ee 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.

  18. Catalysis by Hydrogen Bond Bifunctional Thiourea Catalysts A Michael Reactions of Ketones to Nitroolefines 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. Nature2003, 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 McDougal N. T.; Schaus S. E. J. Am. Chem. Soc. 2003, 125, 12094.

  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 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 Dicoordination pathway Monocoordination pathway More crowded concave structure for the attacking nucleophile Longer forming bond C-C Monocoordination Pathway (TS: + 3.4 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 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 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 R1 = Ph re facial attack Adv. Synth. Catal. 2005, 347,1523.

  28. Phosphoric Acid Catalysis : Aza-Ene Reaction Terada’s Work Angew. Chem. Int. Ed. 2006, 45, 2254. J. Am. Chem. Soc. 2007, 129,10336.

  29. Phosphoric Acid Catalysis : Aza-Ene Reaction Terada’s Work Angew. Chem; Int. Ed. 2006, 45, 2254. J. Am. Chem. Soc. 2007, 129,10336.

  30. Phosphoric Acid Catalysis : Addition on Activated Imine Derivatives Hydrophosphonylation of Imines - Akiyama 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 89-99 % (73-99 % ee) J. Am. Chem. Soc. 2005, 127,1596.

  33. Phosphoric Acid Catalysis : Hetero-Diels-Alder Reactions Akiyama’s Work Ar = Ph si facial approach Synlett 2006, 1,141.

  34. Phosphoric Acid Catalysis : Friedel-Crafts Reactions Terada’s Work : FC Reactions on Furan Synthetic Utility of Furan-2-ylamine Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2004, 126,11804.

  35. Phosphoric Acid Catalysis : Friedel-Crafts Reactions Antilla’s Work : FC Reactions on Indole and Pyrrole 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.

  36. 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 Synthetic Utility of b-Amino-a-Diazoesters Uraguchi D.; Sorimachi K.; Terada M. J. Am. Chem. Soc. 2005, 127,9360.

  38. Phosphoric Acid Catalysis : Pictet-Spengler Reaction List’s Work Aldol Condensation Pictet-Spengler Reaction +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 + 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 R = PMP si face selectivity * In parenthesis, ee obtained after one recrystallization from MeOH Rueping M.; Sugiono E.; Azap C.; Theissmann T.; Bolte M. Org. Lett. 2005, 17,3781.

  42. Phosphoric Acid Catalysis : Asymmetric Transfer Hydrogenation with Hantzsch Esters (A) 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. JACS2007, 129, 5830.

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

  45. Phosphoric Acid Catalysis : Enantiomeric Reduction of a,b-Unsaturated Ketones with Hantzsch Esters (A) Development of Ammonium Phosphates a in Bu2O Martin N. J. A.; List B. J. Am. Chem. Soc. 2006, 128,13368.

  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

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