1. Peptidomimetics and Mimicry of  -Strand / Sheets and  -Sheet Sandwiches Jian Liu Merck & Co., Inc. Rahway, NJ 07065

2. Research Summary Pyrrolinone  -Strand Peptidomimetic HIV-1 Protease Inhibitor 1999-present UPenn  -Sheet Sandwich 1998-1999 UC Irvine Cycloaddition of Enol Ethers 1994-1998 UCLA Enantioselective Epoxidation

3. Part I a.Computational Study on Epoxidation Reactions b. Conformational Switch for Enol Ethers in Cycloaddition Reactions

4. Reaction Path Investigation by Computational Methods

5. Epoxidations of Unfunctionalized Olefins Liu, J., Houk, K. N. et. al. J. Am. Chem. Soc. 1997, 119, 3385-3386; J. Am. Chem. Soc. 1997, 119, 10147-10152; J. Am. Chem. Soc. 1997, 119, 12982-12983; J. Org. Chem. 1998, 63, 8565-8569

6. Part I a.Computational Study on Epoxidation Reactions b. Conformational Switch for Enol Ethers in Cycloaddition Reactions

7. Conformational Switch in Cycloaddition of Enol Ethers s-cis in ground states-trans in transition state Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63, 1064.

8. Stereoselective Cycloaddition Reactions of Chiral Enol Ether Denmark, S. E. et. al. J. Org. Chem. 1994, 59, 5672; 1995, 60, 3205; 1995, 60, 3574. Reissig, H. U. et. al. SYNLETT 1990, 514; Angew. Chem. Int. Ed. Engl. 1992, 31, 1033.

9. Ground State Conformations of Chiral Enol Ethers

10. Conformations of Vinyl Methyl Ether in Ground and Transition States

11. Design of Conformation Fixed Enol Ethers trans cis

12. Designed Diels-Alder Reactions with the Conformation Fixed Enol Ethers

13. Designed 1,3-dipolar Cycloaddition With the Conformation Fixed Enol Ethers

14. Comparison of the Calculated and Experimental Results

15. Rationalization of Conformation Switch

16. Summary for Ph.D Research at UCLA a. Computation study on epoxidation reaction: b. Conformation switch of enol ether in cycloaddition reaction:

17. Part II Design, Synthesis and Structure Study of Artificial  -Sheet Sandwiches

18. Previous Study on Artificial  -Sheet Structures Nowick, J. S. et al J. Org. Chem. 1997, 62, 7906-7907. Nowick, J. S. et al Chem. Soc. Rev. 1996, 25, 401-415. Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296.

19. The Importance of the  -Sheet Sandwich in Nature Definition: The  -Sheet sandwich is a structure motif in proteins in which two  -sheets face each other to form a sandwich. The  -sheet sandwich can act as a binding pocket. Goal of building the artificial  -sheet sandwich: To build a chemical model to mimic the three dimensional structures of globular proteins. Lipid binding protein: 1lif

20. Design of an Artificial  -Sheet Sandwich Hydrophilic Back Hydrophobic Face

21. Synthesis of a Model with one Template Holding two  -Turn Scaffold Structures

22. Synthesis of a Model with One Template Holding Two  -Turn Scaffold Structures (Cont.)

23. Crystal Structure of the Model with a Template Holding Two  -Turn Scaffolds

24. Synthesis of the Designed  -Sheet Sandwich

25. Synthesis of the Designed  -Sheet Sandwich (Cont.)

26. Two Dimensional TLC Test on the Interconvergence of Different Conformations for  -Sheet Sandwich 11

27. Possible Conformations for  -Sheet Sandwich Back - FaceFace - Face Back - BackFace - Back

28. New Design for  -Sheet Sandwich with an Additional Linkage between  -Sheets

29. Synthesis of  -Sheet Sandwich with S-S Linkage

30. Synthesis of  -Sheet Sandwich with S-S Linkage (Cont.)

31. Synthesis of  -Sheet Sandwich with C-C Linkage Metathesis Product: ( 3 : 1, trans to cis )

32. NMR Study of the  -Sheet Sandwiches with C=C Linkage No Inter Sheet NOEs Observed Inter Sheet NOEs: H 15 - H 18 ; H 15 - H 20 ; H 18 - H 19 ; H 23 - H 27 ; H 26 - H 21 ; H 27 - H 21.

33. Summary of Postdoc Research at UC Irvine a. Designed and synthesized the artificial  -sheet sandwich: b. Designed and synthesized the  -sheet sandwich with homogenous conformation:

34. Part III Design, Synthesis and Structure Study of  -Strand Peptidomimetic Based on Pyrrolinone Backbone

35. Concept for the Design of  -Strand Peptidomimetic Based on Pyrrolinone Backbone

36. Precigoux, G et. al. J. Am. Chem. Soc. 1987, 109, 7463. Smith, A. B. III; Hirschmann, R. et. al. J. Am. Chem. Soc. 1994, 116, 9947. Peptides and Peptidomimetics Which Forms  -Strand/Sheets

37. Retrosynthesis of Tris Carbonyl Displaced Pyrrolinone

38. Synthesis of Fragment A and B

39. Synthesis of Fragment D S. Knight

40. Synthesis of Fragment C S. Knight

41. Synthesis of Mono Pyrrolinone S. Knight

42. Synthesis of Bis Pyrrolinone

43. Synthesis of Tris Pyrrolinone

44. Synthesis of Tris Pyrrolinone (Cont.)

46. Part IV Design and Synthesis of Pyrrolinone Based HIV-1 Protease Inhibitor

47. Previous Peptidomimetic HIV-1 Protease Inhibitors Smith, A. B., III, Pasternak, A., Hirschmann, R. et. al. J. Med. Chem. 1997, 40, 2440-2444

48. Retrosynthesis of Second Generation Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor

49. Synthesis of Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor

50. X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor A. Pasternak

51. X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor L. Zawaki

52. Design of New Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor

53. Summary of Postdoc Research at UPenn a. The tris carbonyl-displaced pyrrolinone was synthesized and the structure is being studied: b. A carbonyl-displaced pyrrolinone HIV-1 protease inhibitor was designed and synthesized. A new design was made based on modeling:

54. Acknowledgements Professor Ken N. Houk (UCLA) Professor James S. Nowick (UC Irvine) Professor Amos B. Smith, III (UPenn) Professor Ralph Hirschmann (UPenn)

55. Thank You