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Peptidomimetics and Mimicry of b -Strand / Sheets and b -Sheet Sandwiches

Peptidomimetics and Mimicry of b -Strand / Sheets and b -Sheet Sandwiches. Jian Liu Merck & Co., Inc. Rahway, NJ 07065. Research Summary. Enantioselective Epoxidation. Pyrrolinone b -Strand Peptidomimetic. HIV-1 Protease Inhibitor 1999-present UPenn. b -Sheet Sandwich 1998-1999

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Peptidomimetics and Mimicry of b -Strand / Sheets and b -Sheet Sandwiches

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

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

  3. Part I • 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 • 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 state s-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.SYNLETT1990, 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 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 b-Sheet Sandwiches

  18. Previous Study on Artificial b-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 b-Sheet Sandwich in Nature Definition: The b-Sheet sandwich is a structure motif in proteins in which two b-sheets face each other to form a sandwich. The b-sheet sandwich can act as a binding pocket. Goal of building the artificial b-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 b-Sheet Sandwich Hydrophilic Back Hydrophobic Face

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

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

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

  24. Synthesis of the Designed b-Sheet Sandwich

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

  26. Two Dimensional TLC Test on the Interconvergenceof Different Conformations for b-Sheet Sandwich 11

  27. Possible Conformations for b-Sheet Sandwich Back - Face Face - Face Back - Back Face - Back

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

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

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

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

  32. NMR Study of the b-Sheet Sandwiches with C=C Linkage No Inter Sheet NOEs Observed Inter Sheet NOEs: H15 - H18; H15 - H20; H18 - H19; H23 - H27; H26 - H21; H27 - H21.

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

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

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

  36. Peptides and Peptidomimetics Which Forms b-Strand/Sheets 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.

  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.)

  45. 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

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