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Peptidomimetics and Mimicry of
b
-
却牡湤S⼠
Sheets and
b
-
卨敥琠卡湤睩捨敳w

Jian Liu

Merck & Co., Inc.

Rahway, NJ 07065


Research Summary

Pyrrolinone
b
-
却S慮d

健瑩do浩浥瑩c

䡉H
-
ㄠ偲潴敡獥oI湨i扩瑯b


1999
-
present

UPenn

b
-
卨敥琠卡湤睩捨



ㄹ㤸
-
ㄹ㤹

啃 Ir癩湥

C祣yo慤di瑩on o映䕮ol 䕴b敲s



1994
-
1998

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,
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

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 state

s
-
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, 3574.

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



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

b
-
卨敥琠ea湤w楣i敳


Previous Study on Artificial
b
-
卨敥S 却牵St畲敳

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.

The Importance of the
b
-
S桥整hS慮aw楣栠楮⁎慴畲

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
-
獨敥琠t慮aw楣h


To build a chemical model to mimic the three
dimensional structures of globular proteins.

Lipid binding protein:
1lif

Design of an Artificial
b
-
卨敥S 卡湤wi捨

Hydrophilic Back

Hydrophobic Face

Synthesis of a Model with one Template

Holding two
b
-
呵牮T卣慦f潬搠却牵St畲敳

Synthesis of a Model with One Template

Holding Two
b
-
呵牮T卣慦S潬搠却牵捴畲敳u⡃潮琮o

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

Synthesis of the Designed
b
-
卨敥S 卡湤wi捨

Synthesis of the Designed
b
-
S桥整hS慮awi捨c⡃潮琮o

Two Dimensional TLC Test on the Interconvergence

of Different Conformations for
b
-
卨敥t 卡湤w楣栠ㄱ

Possible Conformations for
b
-
S桥整hS慮awi捨

Back
-

Face

Face
-

Face

Back
-

Back

Face
-

Back

New Design for
b
-
卨敥S 卡湤w楣栠w楴栠慮⁁a摩瑩潮慬d

Linkage between
b
-
卨敥ts

Synthesis of
b
-
卨敥S 卡湤w楣栠w楴栠S
-
匠䱩湫慧L

Synthesis of
b
-
S桥整hS慮aw楣栠w楴栠S
-
S⁌楮歡来k⡃潮琮o

Synthesis of
b
-
卨敥S 卡湤w楣栠w楴栠C
-
䌠䱩湫慧L

Metathesis Product:

(
3 : 1
,
trans to cis

)

NMR Study of the
b
-
卨敥S 卡湤w楣桥h w楴栠䌽䌠䱩湫慧L

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
b
-
獨敥琠獡湤w楣栺


戮b䑥獩杮敤e慮a 獹湴桥獩穥搠瑨攠
b
-
獨敥琠獡湤w楣栠w楴i
桯浯来g潵猠捯c景牭慴楯渺

Part III


Design, Synthesis and Structure Study of
b
-
却牡r搠
Peptidomimetic Based on Pyrrolinone Backbone

Concept for the Design of
b
-
却牡湤S健灴楤潭業整楣i䉡獥搠
on Pyrrolinone Backbone

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

b
-
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.)

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
, 2440
-
2444

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