1. Literature Meeting - Charette Group – Marc K. Janes – December 6 th 2004 ACTIVATIONS BY HYDROGEN BONDING – SUCCESS STORIES Born Rajkot, India, 1958. University of Connecticut, B.S., 1980. University of Pennsylvania, Ph.D., 1986. Columbia University, Postdoctoral Fellow, 1986-1988. The Ohio State University Professor 1995. The University of Chicago, Professor, 1995-. 1986-1988: Postdoctoral Fellow, MIT Professor K. Barry Sharpless 1982-1986: University of California, Ph.D. Professor Robert G. Bergman 1978-1982: New York University B.S. Professor Yorke E. Rhodes Eric N. Jacobsen Viresh H. Rawal

2. Literature Meeting - Charette Group – Marc K. Janes – December 6 th 2004 ACTIVATIONS BY HYDROGEN BONDING – OUTLINE 1)The Hydrogen Bond 2)Acid catalysis (concepts) 3)Recent examples in organic chemistry 1)Seminal work (from hine to jacobsen) 2)Diels-Alders (Rawal) 3)Other reactions

3. Steiner, ACIEE 2002, 48 (review) THE HYDROGEN BOND – DEFINITIONS Pimentel and McClellan: ‘’…a hydrogen bond exists 1)There is evidence of a bond 2)There is evidence that this bond sterically involves a hydrogen atom already bonded to another atom…’’. Drawback: May include van der Waals interactions and agostic interactions (3 center 2 electrons). Proposed definition: An X-H - - - A interaction is called a ‘’hydrogen bond’’: 1.It constitutes a local bond. 2.X-H acts as proton donor to A. E tot = E electrostatic + E polarization + E charge transfer + E despersion + E exchange repulsion

4. Steiner, ACIEE 2002, 48 (review) THE HYDROGEN BOND – A REVIEW

5. Steiner, ACIEE 2002, 48 (review) THE HYDROGEN BOND – ENERGY IN GAS PHASE TO BE TAKEN WITH CAUTION NO MEDIUM EFFECT IN GAS PHASE IDEAL GEOMETRY WAS USED IN THE CALCULATIONS H-BONDS OFTEN FORM NETWORKS AND ARE NOT ADDITIVE (CANNOT SPLIT ENERGY ON EACH BOND)

6. Steiner, ACIEE 2002, 48 (review) THE HYDROGEN BOND – A REVIEW

7. Steiner, ACIEE 2002, 48 (review) THE HYDROGEN BOND – A REVIEW

8. TYPES OF BRONSTED ACID CATALYSIS HYDROGEN BONDS ARE INVOLVED IN THE ACTIVATION OF THE SUBSTRATE AND THESE HYDROGENS ARE TRANSFERRED ONLY AT THE TRANSITION STATE

9. THE BRONSTED CATALYSIS LAW Rate depends on [H 3 O + ] : SAC Rate depends on [HA] : GAC

10. Pihko, ACIEE 2004, 2062 (highlight) MODES OF CARBONYL ACTIVATION BY COORDINATION

11. Etter, JACS 1988, 5896; Acc. Chem. Res. 1990, 120. Kelly, TL 1990, 3381. EXAMPLES OF INTERACTIONS

12. Curran, JOC 1994, 3259; TL 1995, 6647. Radical allylation EXAMPLES OF INTERACTIONS

13. Jacobsen, JACS 1998, 1401 JACOBSEN (SIGMAN) – STRECKER (must find a project that works…)

14. Jacobsen, JACS 1998, 1401; ACIEE 2000, 1279 JACOBSEN (SIGMAN) - STRECKER

15. Jacobsen, ACIEE 2000, 1279 JACOBSEN (SIGMAN) - STRECKER

16. Jacobsen, ACIEE 2000, 1279 JACOBSEN (SIGMAN) – STRECKER (MACHOISM)

17. Jacobsen, ACIEE 2000, 1279 JACOBSEN (SIGMAN) - STRECKER

18. Jacobsen, OL 2000, 867 JACOBSEN – STRECKER ON KETOIMINES 1c

19. Jacobsen, JACS 2002, 10012 JACOBSEN – REACTION KINETICS Model reaction Previously optimal catalyst

20. Jacobsen, JACS 2002, 10012 JACOBSEN – KINETIC STUDY OF UREA CATALYST INTERCEPT IS 1/v MAX Indicating that There is a V MAX

21. Jacobsen, JACS 2002, 10012 JACOBSEN – REACTION KINETICS CONCLUSIONS Model reaction Previously optimal catalyst - 1 st order in HCN and Catalyst -Saturation kinetics of imine (proven by Lineweaver Burk) - Obeys Michaelis-Meten kinetics (steady state kinetics) Implicates the reversible formation of an IMINE – CATALYST COMPLEX

22. Jacobsen, JACS 2002, 10012 JACOBSEN – PROBES INTO BINDING (where are the interactions?)

23. Jacobsen, JACS 2002, 10012; SEE MARCELO IN JANUARY JACOBSEN – BINDING STUDY OF UREA CATALYST

24. Jacobsen, JACS 2002, 10012; SEE MARCELO IN JANUARY JACOBSEN – BINDING STUDY OF UREA CATALYST

25. Jacobsen, JACS 2002, 10012 JACOBSEN – BINDING STUDY OF UREA CATALYST 3

26. Jacobsen, JACS 2002, 10012 JACOBSEN – IMINE GEOMETRY IN SOLUTION AND REACTIVE FORM Only the Z Interacts! Good reaction with fixed Z imine (ACIEE)Unreactive Fixed E imine ADDITION OF CATALYST

27. Jacobsen, JACS 2002, 10012; SEE CLAUDE ANY TIME JACOBSEN – OUR FRIEND THE COMPUTER Solvent has little effect on solution phase structure (justification for gas phase approximation)

28. Jacobsen, JACS 2002, 10012 JACOBSEN – BINDING STUDY OF UREA CATALYST Adopts a well defined secondary structure in solution (1) The large group on the imine carbon is directed away from the catalyst and into solvent (Figure 1B); this serves to explain why 1 catalyzes hydrocyanation of most aldimines with high ee, regardless of the steric and electronic properties of the substrate. (2) The small group (H for aldimines, Me for methylketoimines) is aimed directly into the catalyst; ketoimines bearing larger substituents are poor substrates for the reaction,2c presumably because they cannot be accommodated within the optimal geometry. (3) The N-substituent is also directed away from the catalyst. However, its size is restricted as a result of the requirement to access the Z-isomer of the imine. (4) On the basis of the observed sense of stereoinduction, addition of HCN takes place over the diaminocyclohexane portion of the catalyst (i.e., from the right-hand side in Figure 1C) and away from the amino acid/amide portion. The last hypothesis leads to the prediction that increasing the steric properties of the amino acid/amide portion of the catalyst should lead to higher enantioselectivity in the hydrocyanation reactions.

29. Jacobsen, JACS 2002, 10012 JACOBSEN – UREA RATIONAL DESIGN

30. Jacobsen, JACS 2002, 10012 JACOBSEN – UREA RATIONAL DESIGN (MACHOISM)

31. Jacobsen, JACS 2002, 12964 JACOBSEN – MANNICH (NO STUDY)

32. Jacobsen, JACS 2004, 4102 JACOBSEN – HYDROPHOSPHONYLATION (NO STUDY)

33. Jacobsen, JACS 2004, 4102 JACOBSEN – HYDROPHOSPHONYLATION (NO STUDY)

34. Jacobsen, JACS 2004, 10558. JACOBSEN - PICTET-SPENGLER

35. Jacobsen, JACS 2004, 10558. JACOBSEN - PICTET-SPENGLER (NO STUDY)

36. Jacobsen, JACS 2004, 10558. JACOBSEN - PICTET-SPENGLER (NO STUDY)

37. Jorgensen, ACIEE 2000, 3559 JORGENSEN – REVIEW ON HDA Warning, the following slide contains explicit content

38. Jorgensen, ACIEE 2000, 3559 JORGENSEN – REVIEW ON HDA

39. Rawal JACS 2000, 7843; OL 2002, 1163; JACS 2002, 4628 (SUBTLE CHIRALITY) RAWAL – LEWIS ACID CATALYZED DA (SALEN-Cr) 1-amino-3-siloxy-1,3-butadienes

40. Rawal, JACS 2002, 4628 RAWAL - HDA OF UNACTIVATED KETONES Rawal, OL 2002, 3321 Rawal, JACS 2002, 4628

41. Rawal, OL 2002, 3321 RAWAL - REACTION OF UNACTIVATED KETONES Not due to prensence of DCl

42. Rawal, OL 2002, 3321; Jurczak, SYNTHESIS 1979, 41 RAWAL – VERY REACTIVE DIENE

43. Rawal, JACS 2002, 9662 RAWAL – HDA SOLVENT SCAN

44. Rawal, JACS 2002, 9662 RAWAL - HDA OF UNACTIVATED KETONES Dihydropone Solvolysis Product :

45. Rawal, JACS 2002, 9662 RAWAL – FIRST GENERAL HDA FOR UNACTIVATED KETONES

46. Houk-List, JACS 2003, 16; JACS 2003, 2475 MACMILLAN/HOUK/LIST – ORGANOCATALYSIS OTHER THAN H BOND MacMillan, JACS 2000, 4243; TL 2003, 2475

47. Braddock, Synlett 2003, 1121 BRADDOCK – PHANOLS FOR DA (NOT ENANTIOSELECTIVE)

48. Göbel, OL 2000, 179 GÖBEL – H BOND ASSISTED ASYMMETRIC DA

49. Rawal, Nature 2003, 146 RAWAL - FIRST ASYMM. HDA THROUGH HYDROGEN BONDING Ar = 1-naphtyl

50. Rawal, PNAS 2004, 5846 RAWAL - ALL CARBON ASYMM. DA CAT. BY H-BONDING

51. Rawal, PNAS 2004, 5846 ALL CARBON DA CAT. BY HYDROGEN BONDING

52. Rawal, PNAS 2004, 5846 ALL CARBON DA CAT. BY HYDROGEN BONDING More persistent hydrogen bond at lower temperatures

53. Rawal, PNAS 2004, 5846 RAWAL - ALL CARBON DA CAT. BY HYDROGEN BONDING REACTION WORK BEST WITH ALPHA SUBSTITUTION; MACMILLAN: BEST WITH BETA SUBSTITUTION (COMPLEMENTARY)

54. Literature Meeting - Charette Group – Marc K. Janes – December 6 th 2004 THE END Eric N. Jacobsen Viresh H. Rawal Pioneers for a new mode of asymmetric catalysis involving one one the most important bond in nature?

55. Schaus, JACS 2003, 12094 T

56. Ref or note TITLE

57. Göbel, OL 2000, 179 GÖBEL – H BOND ASSISTED ASYMMETRIC DA

58. Göbel, OL 2000, 179 GÖBEL – H BOND ASSISTED ASYMMETRIC DA

59. Göbel, OL 2000, 179 GÖBEL – H BOND ASSISTED ASYMMETRIC DA

60. Note or ref TYPES OF ACID CATALYSIS

61. Hine, JOC 1985, 5096; JOC 1987, 2083; Kelly, TL 1990, 2083 DOUBLE HYDROGEN BONDING - SEMINAL WORK

62. Schreiner, Chem. Soc. Rev. 2003, 289; Chem. Euro. J. 2003, 407 TITLE