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

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Presentation transcript:

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

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

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

Reaction Path Investigation by Computational Methods

Epoxidations of Unfunctionalized Olefins Liu, J., Houk, K. N. et. al. J. Am. Chem. Soc. 1997, 119, ; J. Am. Chem. Soc. 1997, 119, ; J. Am. Chem. Soc. 1997, 119, ; J. Org. Chem. 1998, 63,

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

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.

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

Ground State Conformations of Chiral Enol Ethers

Conformations of Vinyl Methyl Ether in Ground and Transition States

Design of Conformation Fixed Enol Ethers trans cis

Designed Diels-Alder Reactions with the Conformation Fixed Enol Ethers

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

Comparison of the Calculated and Experimental Results

Rationalization of Conformation Switch

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

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

Previous Study on Artificial  -Sheet Structures Nowick, J. S. et al J. Org. Chem. 1997, 62, Nowick, J. S. et al Chem. Soc. Rev. 1996, 25, Nowick, J. S. Acc. Chem. Res. 1999, 32,

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

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

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

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

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

Synthesis of the Designed  -Sheet Sandwich

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

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

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

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

Synthesis of  -Sheet Sandwich with S-S Linkage

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

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

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.

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:

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

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

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

Retrosynthesis of Tris Carbonyl Displaced Pyrrolinone

Synthesis of Fragment A and B

Synthesis of Fragment D S. Knight

Synthesis of Fragment C S. Knight

Synthesis of Mono Pyrrolinone S. Knight

Synthesis of Bis Pyrrolinone

Synthesis of Tris Pyrrolinone

Synthesis of Tris Pyrrolinone (Cont.)

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

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

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

Synthesis of Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor

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

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

Design of New Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor

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:

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

Thank You