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Hydrogen-Bond Catalysis For reviews see: M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520-1543 A. G. Doyle, E. N. Jacobsen, Chem. Rev.,

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Presentation on theme: "Hydrogen-Bond Catalysis For reviews see: M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520-1543 A. G. Doyle, E. N. Jacobsen, Chem. Rev.,"— Presentation transcript:

1 Hydrogen-Bond Catalysis For reviews see: M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007, Nadia Fleary-Roberts 03/02/10

2 Lewis acids has dominated enantioselective catalysis acceleration of Diels Alder reaction with AlCl 3 A brief history… Wynberg reported asymmetric conjugate addition reactions with cinchona alkaloids bearing a free hydroxyl group. Hiemstra H.; Wynberg H., J. Am. Chem. Soc. 1981, 103, Yates P.; Eaton P., J.Am. Chem. Soc. 1960, 82, 4436

3 Jacobsen reported asymmetric hydrocyanation of aliphatic and aromatic aldehydes Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901

4 Lewis acid catalysis Highly tunable Can vary counter ion, chiral ligand Lewis base/acid interactions are stronger Interactions are more directional H-bond catalysis Moderately tunable Active catalyst Potentially recoverable

5 Strength can vary from 0.4 to 40 kcalmol -1. What is a hydrogen bond? “An XH···A interaction is called a,hydrogen bond', if 1. it constitutes a local bond, and 2. XH acts as a proton donor to A.” Steiner, Angew. Chem. Int. Ed. 2002, 41, 48 Most Hydrogen bonding in H-bond catalysis is of moderate strength G.A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, New York, 1997 Role of H-bonds: DNA base pairing Ligand/receptor binding

6 Specific acid catalysis General acid catalysis Brønsted acids can accelerate organic reactions by either of two fundamental mechanisms: protonation of the electrophile in a prior to nucleophilic attack proton transfer to the transition state in the rate-determining step

7 Modes of bonding Double H-bond donors Increased strength and directionality e.g. Ureas, thioureas, Guanidinium and Amidinium ions X = O, S

8 Less strength than double H-bond donors Less directionality Single H-bond donors e.g. Diols, biphenols, chiral phosphoric acids

9 Bifunctional catalysis a single or dual H-bond donor site flanked by sites for secondary interaction with substrates. e.g. Proline and proline analogs, cinchona alkaloids and derivatives

10 Ureas and Thioureas Originally developed as ligands for lewis acidic metals. Most applicable class of chiral H- bond donors Can promote addition of a range of nucleophiles Imine activation Double H-bond donors b R 1 = Bn, R 2 = H, R 3 = OCH 3, X= S c R 1 = Bn, R 2 = H, R 3 = OCOtBu, X = O d R 1 = R 2 = CH 3, R 3 = OCOtBu, X =S e R 1 = Bn, R 2 = CH 3, R 3 = tBu, X = S

11 Diels Alder reaction Aza Baylis-Hillman reaction Double H-bond donors e R 1 = Bn, R 2 = CH 3, R 3 = tBu, X = S Wittkopp A.; Schreiner P. R., Chem. Eur. J. 2003, 9, Raheem, I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701

12 Asymmetric Strecker reaction Double H-bond donors Scaleable catalytic synthesis Imines derived from alky, aryl, heteroaryl aldehydes Aqueous cyanide salts Robust catalyst Access to the (R)-enantiomer of tert-leucine Zuend S.J.; Coughlin M. P.; Lalonde M. P.; Jacobsen E. N., Nature, 2009, 461, 968

13 Asymmetric Pictet Spengler reaction Double H-bond donors Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558

14 Bifunctional Thiourea derivatives Takemoto catalyst Aza-henry reaction-( addition of nitroalkanes to imines ) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, – ,4- additions T. Okino, S. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett. 2004, 6, 625 B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 4, 603

15 1,2-additions D. E. Fuerst, E. N. Jacobsen, J. Am. Chem. Soc. 2005, 127, 8964 efficient catalyst for Baylis-Hillman reactions Other thiourea catalysts

16 Capable of double H-bond interactions Are positively charged so result in increased H-bond donor abiltity. Double H-bond donors Guanidinium and Amidinium ions Strecker reaction T. Steiner, Angew. Chem. 2002, 114, 50; Angew. Chem. Int. Ed. 2002, 41, 48.

17 Double H-bond donors Diels Alder reaction Nitro-Mannich reaction Schuster T.; Bauch M.; Durner G.; Gmbel M. W.; Org. Lett. 2000, 2, 179 – 181. k Ar = 3,5-(CF 3 ) 2 C 6 H 3 Amidinium catalysed reactions

18 Hetero Diels Alder reaction catalysed by chiral diols Single H-bond donors Baylis-Hillman reaction -Binol derivatives Diols and Biphenols Huang Y.; Unni, A. K.; Thadani, A. N.; Rawal V.H., Nature, 2003, 424, 146

19 Chiral phosphoric acids Mannich reaction T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004, 116, 1592 – 1594 Angew. Chem. Int. Ed. 2004, 43, 1566 –1568 D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 – 5357 Single H-bond donors

20 Reductive amination R. I. Storer, D. E. Carrera, Y. Ni, D. W. C. Macmillan, J. Am. Chem. Soc. 2006, 128, 84 HEH = ethyl Hantzsch ester

21 Bifunctional catalysis enatioselective aldol cyclizations Proline catalysed reactions Z. G. Hajos, D. R. Parrish, (Hoffman-La-Roche), German Patent DE , 1971 [Chem. Abstr. 1972, 76, 59072];

22 Proposed mechanism for proline catalysed transformations A. G. Doyle, E. N. Jacobsen, Chem. Rev., 2007,

23 u higher yields and selectivity compared to proline Proline analogues x increased solubility Tetrazole is a pharmacore for carboxylic acid

24 Cinchona alkaloids Bifunctional catalysis Enatioselective conjugate additions Baylis-Hillman reaction Nakano A. et. al. 2006, 62, 381 Iwabuchi Y. et. al. J. Am. Chem. Soc. 1999, 121, Connon S.J., Chem. Comm., 2008, 2499

25 Oligiopeptides Cyclo(l-phenylalanine-l-histidine) hydrocyanation of aldehydes S. Inoue, J.-I. Oku, J. Chem. Soc. Chem. Commun. 1981, 229 –230 Bifunctional catalysis Uncertainty concerning mechanism

26 Summary A dynamic and large area of research which is continuing to be explored Applicable to a wide number of transformations

27 CAKE-OFF 2010!! Don’t forget to vote!!


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