Peptidomimetics and Mimicry of b-Strand /
Sheets and b-Sheet Sandwiches
Jian Liu
Merck & Co., Inc.
Rahway, NJ 07065
Research Summary
CN
O
O
R
N
R
Enantioselective Epoxidation



O 
O R

R
s-trans
s-cis
Ground state of enol ethers
X
X


O 
O 

O 
R
s-cis


O


R
Me
O
H
N
N
N
(CH2)2 H
O H
O R
O
Orn H
N
N
N
N
H
H
O RVal
CN
Me
O
O
O
O
H
N
N
N
N
H
(CH2)2
O H
O R
O
Ala H
N
N
N
N
H
H
O RLys
s-trans
Transition States
Cycloaddition of Enol Ethers
1994-1998
UCLA
O
CbzHN
CH3
O
O
i-Pr
N
H
BnO
Ph
H
N
N
H
CH3
O
Pyrrolinone b-Strand
Peptidomimetic
i-Pr
H
N
O
CH3
O
OH
Ph
H
N
O
Ph
O
O
O Ph
b-Sheet Sandwich
HIV-1 Protease Inhibitor
1998-1999
UC Irvine
1999-present
UPenn
NH2
Part I
a. Computational Study on Epoxidation
Reactions
b. Conformational Switch for Enol Ethers in
Cycloaddition Reactions
Reaction Path Investigation by Computational Methods
TS1*
TS2*
Ea1
Ea2
Ea
k1/k2 = e -Ea/RT
R
P1
P2
Epoxidations of Unfunctionalized Olefins
O H
(1)
O
(2)
O
+
O
R'
R'
O
R
(3)
N
+
(4)
R'
R"
N R"
R
R" +
R"' N O
R
+
+
R
R"'
+
R'
N+ R"
O
R
+
R'
R'
O
O
R'
O
R
+
O
R'
R"
R"
O H
R
O
R
+
O
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
N
O
O
R
s-cis in ground state
O
R
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
Ph
H
O2N
O
Ph
O
+
O
H
Ph
O
-
N+
O
O
O
Ph
H
Ti(O-i-Pr)2Cl2
CH2Cl2
O
13 : 1
Denmark, S. E. et. al. J. Org. Chem. 1994, 59, 5672; 1995, 60, 3205; 1995, 60, 3574.
O
Ph
O
N
O
+
O
O
O O
O
O
N
R*
Diastereomerically pure
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
O
trans
O
cis
trans
cis
Designed Diels-Alder Reactions with the Conformation
Fixed Enol Ethers
N
(1)
O
Y
+
N
Ph
N
(2)
O
Y
Y= CH2 : yield = 14%
Y= O :
Ph
O
+
Y
N
Ph
O
Y= CH2 : yield = 90%
Y
Y= O :
Ph
(3) Competitive Reactions:
N
a:
Product Ratio
1
O
+
13.5
Ph
O
N
b:
Ph
1
O
+
O
yield = 84%
33.5
yield = 95%
Designed 1,3-dipolar Cycloaddition With the Conformation
Fixed Enol Ethers
Ph
(1)
N+
O-
O
Ph N
Y
+
COPh
Y
Y = CH2, endo : yield= 46%
exo : yield= 38%
COPh
Y = O,
endo : yield= 51%
exo : yield= 47%
Ph
(2)
N+
O-
O
N
Ph
+ Y
COPh
Y
Y = CH2:
Y = O,
COPh
(3) Competitive Reactions:
Ph
a:
N+
1
+
10.0
COPh
Ph
b:
+O
O
-
N
1
+
COPh
O
endo : yield= 72%
exo :
Product Ratio
O-
yield= 85%
12.2
yield= 23%
Comparison of the Calculated and Experimental Results
k1/k2 = e -Ea/RT
Calculated Ea (kcal/mol)
Experimental Ea (kcal/mol)
Diels-Alder of Enol Ethers
2.4
2.1 ( 33.5 : 1)
Diels-Alder of Alkenes
1.0
1.5 (13.5 : 1)
1,3-Dipolar of Enol Ethers
3.0
1.5 (12.2 : 1)
1,3-Dipolar of Alkenes
1.4
1.4 (10.4 : 1)
Rationalization of Conformation Switch



O 


R
O R

s-trans
s-cis
Ground state of enol ethers
X


O 
O 
R
s-cis
X



O 
O

s-trans
Transition States
R
Summary for Ph.D Research at UCLA
a. Computation study on epoxidation reaction:
O
R
R
b. Conformation switch of enol ether in cycloaddition reaction:


O
N
O
R
s-cis
O
O

O 
R
s-trans
s-cis
Ground state of enol ethers
X
X
O
s-trans
O R

O 
R


O 
R


O 
O

s-cis
s-trans
Transition States
R
Part II
Design, Synthesis and Structure Study of Artificial
b-Sheet Sandwiches
Previous Study on Artificial b-Sheet Structures
NC
CH3
O
H
N
O
N
N
H
Ph
O
N
Ph
N
H
O
H
N
O
N
H
N
H
CH3
O
O
b-Sheet Mimic
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.
CH3
O
H
N
H
N
O
CH3
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
Design of an Artificial b-Sheet Sandwich
CN
O
N
Xanthene
Template
Hydrophilic Back
Hydrophobic Face
Me
O
H
N
O
N
N
(CH2)2 H
O H
O R
O
Orn H
N
N
N
N
H
O RVal H
CN
Me
O
O
O
O
H
N
N
N
N
H
(CH2)2
O H
O R
O
Ala H
N
N
N
N
H
H
O RLys
i-Pr
CH3
i-Pr
CH3
Artificial b-Sheet Sandwich
NC
Synthesis of a Model with one Template
Holding two b-Turn Scaffold Structures
O
N
O
N
H
N
N
H
N
H
N
O
O
CO2H
NHCbz
DPPA, Et3N
O
BnOH, Tolune (80°C)
CO2H
( 78 % )
O
NH2
H2, Pd/C
NHCbz
NH2
( 95 % )
Xanthene Diacid
NO2
NHSO2Ar
SO2Cl
1. PPh3, DEAD, THF
HOCH2CH2NHBoc
( 80 % )
NHBoc
O
O
Collidine, CH2Cl2
NH
2. HSCH2CH2OH, LiOH
NHSO2Ar DMF
( 85 %, two steps )
NH
O
NC
O
MeOH
NHBoc
H
N
N
Ph
Ph
Ph
Ph
Synthesis of a Model with One Template
Holding Two b-Turn Scaffold Structures (Cont.)
NH
1) TFA/CH2Cl2
NHBoc
O
3) MeOH,
NH
( 70 % )
NHBoc
NC
O
N
N
H
Ph
O
PhCNO
80°C
NH
2) NaHCO3
N
N
H
N
H
N
Ph
O
( 95 % )
O
H
N
N
O
Ph
Ph
NC
Template with Two Scaffolds
CN
H
N
CN
O
NH
N
H
CN
Crystal Structure of the Model with a Template Holding Two
b-Turn Scaffolds
Synthesis of the Designed b-Sheet Sandwich
CH3
O
H
N
NC
NC
O
CH3
O
H
N
NH
OCN
NH
O
N
H
N
O
N
H
O
O
N
H
NH
O
O
THF, 30 min
NH
NH
CH3
O
H
N
O
( 94% )
NH
NC
N
NC
NC
H
N
OCN
N
H
N
O
O
N
N
H
N
O
NH
O
( 95 % )
N
NC
N
H
O
N
H
O
ROrn(Z)
H
N
O
N
O
RVal
O
THF, rt, 19 hr
O
CH3
O
H
N
O
ROrn(Z)
N
H
CH3
O
H
N
O
O
N
H
O
N
H
Synthesis of the Designed b-Sheet Sandwich (Cont.)
CH3
O
H
N
NC
O
N
O
H R
Orn(Z)
O
H
N
N
N
H
O
N
O
O
N
N
H
O
O
COCl2, CH2Cl2
N
RVal
O
O
NaHCO3 ( sat ), 0 °C, 15 min
H2N
CH3
O
H
N
NC
N
H
N
O
O
N
O
RLys(Z)
•HCl
N
N
H
O
N
RVal
Cl
N
H
N
O
H
N
N
O
NC
O
NC
O
N
RVal
O
RLys(Z)
N
N
H
O
O
N
H
O
RAla
H
N
N
O
ROrn(Z)
H
N
O
TEA, THF, rt, 19 hr
( 90 %, two steps )
N
H
O
O
H
N
N
O
N
H
O
N
NC
RAla
N
O
H R
Orn(Z)
O
H
N
N
N
H
O
N
H
O
CH3
O
H
N
NH
CH3
O
H
N
NC
O
H
N N
H
O
O
CH3
b-Sheet Sandwich
O
H
N N
H
O
O
CH3
Two Dimensional TLC Test on the Interconvergence
of Different Conformations for b-Sheet Sandwich 11
Solvent 10 % MeOH / CHCl3
1D TLC
2D TLC
Possible Conformations for b-Sheet Sandwich
Back - Face
Back - Back
Face - Face
Face - Back
New Design for b-Sheet Sandwich with an Additional
Linkage between b-Sheets
CN
Me
O
O
H
N
N
N
H
O
N
N
H
CN
O
ROrn
S
N
Me
O
H
N
S
O
O
H
N
N
N
H
O
H
N
N
N
H
N
H
O
O
O
O
O
O
N
H
O
N
RTyr
Synthesis of b-Sheet Sandwich with S-S Linkage
CH3
O
H
N
NC
O
N
H
N
O
N
H
N
O
H
N
N
O
O
NC
O
N
H
O
O
RCys(Acm)
RTyr(Bn)
O
N
N
H
N
H
O
CH3
N
H
N
1. NPSCl, AcOH
O
2. Dithiothritol
H
N
N
O
O
N
H
N
N
RCys(Acm)
H
N
N
O
O
ROrn(Z)
H
N
O
CH3
O
H
N
NC
O
H
N
O
O
NC
N
H
O
O
ROrn(Z)
H
N
O
N
RCys
RTyr(Bn)
O
RCys
H
N
N
O
N
N
H
O
O
N
H
O
CH3
H
N
O
Synthesis of b-Sheet Sandwich with S-S Linkage (Cont.)
CN
O
N
H
N
O
N
H
N
H
N
O
O
N
O
NC
O
N
H
N
H
i-Pr
N
O
N
N
N
H
CN
(1) O2, MeOH, Cu
RCys
RTyr(Bn)
O
RCys
H
N
N
O
ROrn(Z)
H
N
O
N
O
CH3
O
H
N
NC
Me
O
H
N
O
(2) HBr/AcOH
O
H
N
N
N
H
50%
S
O
O
N
H
O
CH3
H
N
i-Pr
O
N
H
i-Pr
O
O R
O
Orn H
N
N
N
H
O
S Me
O
O
O
H
N
N
N
H
O
O
O
i-Pr
N
H
O
N
RTyr
Synthesis of b-Sheet Sandwich with C-C Linkage
CN
CH3
O
H
N
NC
O
N
H
N
O
N
H
N
O
H
N
N
O
N
O
NC
N
H
N
H
N
O
N
RAllyl
RTyr(Bn)
O
RAllyl
H
N
N
O
ROrn(Z) O
H
N
O
Me
O
H
N
O
N
N
H
1. Grubbs Ru Catalyst
CHCl3, 48 hrs, 70%
2. Pd/C, H2, MeOH
CN
O
O R
Orn H
N
N
H
O
N
N
H
O
O
O
O
N
H
O
CH3
H
N
H
N
N
O
N
H
O
N
H
O
N
Me
O
H
N
O
O
O
O
N
H
O
N
RTyr
Metathesis Product:
( 3 : 1, trans to cis )
NMR Study of the b-Sheet Sandwiches with C=C Linkage
CN
OH14
Bu7
H4
H13
N
N
H9
H15
O H19 ROrn
N
H1
N
H10
CN
OH
N
Me6
O
N
17
H3
H18
H20
N
H12
Bu8
OH14
O
Me
Me
N
H24
O
Bu7
H4
N
H9
H33
Me
H15
N
H1
Me21
O
H23
N
O H19 ROrn
N
H29
H13
N
O
H25
N
O
H16
N
H11
H2
O
CN
N
H10
Me
O
O
N
H24
O
H25
N
N
H29
O
H
Me
Me
Me
Me
CN
H31
Me5
O
Me21
O
H23
N
Me22
O
H26
N
O
H32
H28
N
Me5
N
H27
OH
O
O
Me
Me
N
Me6
O
O
N
H30
RTyr
No Inter Sheet NOEs Observed
17
N
H11
H34
Me
H16
H2
N
H20
N
H12
Me
Bu8
H3
H18
Me22
O
H26
N
O
H28
N
O
H31
O
Me
N
Me
H27 H
H32
O
N
H30
Me
Me
RTyr
Inter Sheet NOEs: H15 - H18; H15 - H20; H18 - H19;
H23 - H27; H26 - H21; H27 - H21.
Summary of Postdoc Research at UC Irvine
a. Designed and synthesized the
artificial b-sheet sandwich:
b. Designed and synthesized the
b-sheet sandwich with
homogenous conformation:
CN
CN
O
N
(CH2)2
N
CN
N
H
N
O
N
H
Me
O
H
N
Me
O
H
N
O
N
N
H
i-Pr
O
O R
O
Orn H
N
CH3
N
N
H
O RVal H
O
O
Me
O
H
N
O
N
N
i-Pr
(CH2)2 H
O H
O R
O
Ala H
N
N
CH3
N
N
H
H
O RLys
Artificial b-Sheet Sandwich
N
CN
O
N
H
i-Pr
O R
O
Orn H
N
N
N
H
O
S Me
O
O
O
O
H
N
N
N
H
S
O
H
N
N
N
H
O
O
O
N
H
i-Pr
O
N
RTyr
Artificial b-Sheet Sandwich
with a Second Linkage
Part III
Design, Synthesis and Structure Study of b-Strand
Peptidomimetic Based on Pyrrolinone Backbone
Concept for the Design of b-Strand Peptidomimetic Based
on Pyrrolinone Backbone
O R H
O R H
H
N
N
N
H
H
Displace
R H
R
H
O
O
Peptide b-Strand Conformation Nitrogens
H
O R N
H
N
O
H
R N
R N
H
R N
H
O R N
H
O
O R H
R N
O
H
O
Cyclize
Pyrrolinone
Rings
O R H
H
R N
R N
H
Incorporate
Enaminone
Functionality
O
O R H
O
R N
H
O
Nitrogen-Displaced Pyrrolinones
O H R
O H R
H
H
N
N
N
N
H
H R H
O H R
O
Peptide b-Strand Conformation
H
N
N
H R H
O
R H
N
H
N
Displace
Carbonyls
O
R
N
R H
O
O
N
H R H
H
N
Cyclize
Pyrrolinone
Rings
O
R H
N
N
H R H
O
R
N
R H
O
O
R H
N
Incorporate
Enaminone
Functionality
O
O
R
N
R H
O
O
Carbonyl-Displaced Pyrrolinones
Peptides and Peptidomimetics Which Forms
b-Strand/Sheets
OH
O
H2N
O
H
N
N
H
H
N
N
H
O
O
NH2
N
H
O
Parallelb-Sheet in Solid State
Ph
O
O
NHBoc
CO2Me
N
H
Ph
CO2Me
O
Parallelb-Sheet in Solid State
O
O
OH
N
H
O
H
N
O
N
H
Anti-parallel b-Sheet in Solid State
CbzHN
BnO
N
H
Ph
H
N
N
H
CH3
O
What Kind of Conformation?
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.
Retrosynthesis of Tris Carbonyl Displaced Pyrrolinone
O
CbzHN
BnO
O
N
H
O
Ph
H
N
N
H
CH3
H
Te ocHN
Te ocHN
O
O
B
BocHN
CH3
N
H
Ph
CH3
O
+
+
O
CbzHN
O
CH3
BnO
BocHN
BnO
Te ocHN
A
CH3
O
Ph
N
H
N
H
BnO
O
H
N
A
Ph
H
N
CbzHN
O
O
O
O
B
CHO
O
CH3
BnO
Ph
CH3
H
NHCbz
C
D
Synthesis of Fragment A and B
1. NaOH, EtOH, H2O
O
2. t-BuCHO, pentane
reflux, 3d
3. Alloc-Cl, CH2Cl2
0 °C, 14d
( 60 %, three steps )
HO2C
NH2
L-Leu
O
KHMDS, BnOCH2Cl
O
N
THF, -78°C
( 65 % )
Alloc
1. 1N NaOH, MeOH
O
N
OBn 2. (COCl)2, PhH, reflux
Alloc
over 20 : 1
cis : trans
NaBH4, MeOH
0 °C
O
NH
O
CbzCl, TEA, CH2Cl2
HO
O
1. TPAP, NMO
MS 4Å, CH2Cl2
OBn
NH2
OBn
( 61 % )
( 88 %, three steps )
HO
CbzNH
Teoc-succimide,
TEA, CH2Cl2
HO
Te ocNH
OBn
TPAP, NMO
MS 4Å, CH2Cl2
2. MeMgBr, THF
OBn
- 78 °C
3. TPAP, NMO
MS 4Å, CH2Cl2
O
H3C
CbzNH
( 72 %, three steps )
O
H
Te ocNH
( 85 % )
B
( 94 % )
OBn
A
OBn
Synthesis of Fragment D
1. NaOH, EtOH, H2O
2. t-BuCHO, pentane
reflux, 3d
HO2C
Ph
NH2
D-Phe
O
O
O
Ph
N
3. Alloc-Cl, CH2Cl2
Alloc
KHMDS, CH3I
THF, -78 °C
O
1. 1N NaOH, MeOH
Ph
CH
3
N
Alloc 2. (COCl)2, PhH, reflux
0 °C, 15d
( 74 %, three steps )
O
O
NH
O
Ph
CH3
1. Cbz-Cl, DMAP
Et3N, THF, 0 °C
2. NaBH4, MeOH
( 44 %, five steps )
O
HO
Ph
CH
3
CbzHN
TPAP, NMO
MS 4Å, CH2Cl2
H
Ph
CbzHN CH3
( 81 % )
D
S. Knight
Synthesis of Fragment C
1. NaOH, EtOH, H2O
O
2. t-BuCHO, petane, reflux, 3d
HO2C
NH2
L-Val
O
O
N
Alloc
3. Alloc-Cl, CH2Cl2
0 °C, 14d
O
KHMDS, BnOCH2Cl
THF, -78 °C
OBn
N
Alloc
( 84 % )
( 84 %, three steps )
1. 1N NaOH, MeOH
1. Boc2O, DMAP
Et3N, THF
O
2. (COCl)2, PhH, reflux
O
NH
TPAP, NMO
CH2Cl2, MS 4Å
HO
OBn
OBn
NHBoc
2. NaBH4, MeOH
0°C,
O
( 96 % )
( 61 %, four steps )
MeMgBr
THF, -78 °C
O
H
OBn
NHBoc
OH
H3C
( 60 % )
OBn
NHBoc
TPAP, NMO
CH2Cl2, MS 4Å
H3C
( 99 % )
O
O
BocHN
OBn
NHBoc
BnO
C
S. Knight
Synthesis of Mono Pyrrolinone
O
O
BocHN
Ph
CH3
+ H
BnO
NHCbz
C
O
LiHMDS
THF, -78 °C
OH
BocHN
( 81% )
BnO
NHCbz
O
BocHN
BnO
Ph
CH3
NHCbz
O
H2, Pd/C
O
Ph
O
CH2Cl2
( 86% )
BocHN
MeOH, rt
1. HCO2H, Pd black
MeOH
Ph
BnO
N
H
CH3
2. TPAP, NMO
( 98% )
H
Dess-Martin
periodinane
D
O
BocHN
Ph
CH3
N
H
CH3
( 60 %, for two steps )
1. MeMgBr, THF
O
Ph
2. Dess-Martin
( 70 %, two steps )
BocHN
N
H
CH3
O
S. Knight
Synthesis of Bis Pyrrolinone
KHMDS (1.1 eq),
Boc2O ( 2.5 eq )
O
O
Ph
Ph
BocHN
N
H
BocHN
CH3
LiHMDS ( 5 eq ), THF, -78 °C
N CH3
Boc
THF, -78 °C - 0 °C
( 85 % )
BnO
O
O
Te ocHN
CHO
B ( 2 eq )
O
BnO
Te ocHN
BocHN
N
Boc
Ph 1. NaHSO ( sat ), THF, rt, 24 hr
4
CH3
2. Dess- Martin, Pyr, CH2Cl2, rt
OH O
O
Ph
BnO
Te ocHN
BocHN
O
( 76 % )
N
H
CH3
O
( 60 - 85 % )
TsOH ( 4 eq ), EtOH
85 °C, 25 min
O
BnO
O
Ph
H
N
N
H
Te ocHN
O
( 82 % )
CH3
+
BnO
Ph
H
N
N
H
H2N
O
(0-5%)
CH3
Synthesis of Tris Pyrrolinone
O
BnO
Ph
H
N
CH3
N
H
Te ocHN
( 91 % )
Ph
H
N
CH3
N
H
Te ocHN
N
H
Te ocHN
MeOH
O
Ph
H
N
HO
O
TMSO
O
HCOOH, Pd Black
KHMDS(1.1 eq),
Boc2O (3.0 eq)
THF, -78 °C - 0 °C
CH3
O
Ph 4 % AcOH / MeOH
H
N
TMSO
Te ocHN
O
N CH3
Boc
( 85 % )
HO
H
N
Ph
Te ocHN
O
N CH3
Boc
DMSO, DCC
Pyridine, TFA, PhH
( 89 % )
O
O
O
TMSCl ( 2 eq ),
TEA (4 eq)
O
O
H
H
N
Ph
Te ocHN
O
N CH3
Boc
( 95 % )
Synthesis of Tris Pyrrolinone (Cont.)
O
O
H
N
H
LiHMDS, THF, -78 °C
Ph
Te ocHN
O
N CH3
Boc
O
CbzHN
BnO
O
CbzHN
BnO
OH
O
Ph
H
N
Te ocHN
CH3
O
N CH3
Boc
A
( 23 %, two steps )
Retro Aldol Reaction:
O
CbzHN
BnO
OH
Te ocHN
O
O
Ph
H
N
O
N CH3
Boc
CbzHN
BnO
O
O
H
H
+ Te ocHN
Ph
H
N
O
N CH3
Boc
Synthesis of Tris Pyrrolinone (Cont.)
O
O
CbzHN
O
CbzHN
BnO
OH
Te ocHN
1. Dess-Martin,
Pyr, CH2Cl2
O
BnO
Ph
H
N
N
H
CH3
N
H
O
Ph
H
N
O
N CH3
Boc
2. TFA, rt, 15 min
( 18 %, two steps )
+
O
CbzHN
BnO
H2N
74 %
BnO
N
H
Ph
H
N
N
H
N
H
O
O
O
H2, Pd/C
N
Ph
H
N
CH3
O
X - Ray Crystallography and NMR Study
CH3
Part IV
Design and Synthesis of Pyrrolinone Based
HIV-1 Protease Inhibitor
Previous Peptidomimetic HIV-1 Protease Inhibitors
H
N
O
PhH
OH N
O
NH2
O
Ph
O
Ph
N
H
O
O
H
N
O
IC50 2 nM, CIC95 100 nM
Ph
N
H
O
OH
O
O
Ph
H
N
O
Ph
PhH
OH N
O
Ph
O
O
IC50 1.3 nM, CIC95 800 nM
OH
H
N
H
N
O
CH3
O
O
Ph
OH
Ph
H
N
O
O
NH2
O Ph
10 % inhibition at 3 M
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
H
N
O
O
Ph
H
N
OH
O
O
O
NH2
O Ph
Ph
O
Ph
O
BocN
H
O
Ph
O
O
BocHN
BocHN
OH
Ph
Ph
L-Phe
Available from Previous
Carbonyl-Displaced Pyrrolinone
HIV-1 Inhibitor Project
+
O
O
OBn
Ph
BocHN
O
Ph
NHCbz
O
N
Alloc
Ph
D-Phe
OH
Synthesis of Carbonyl Displaced Pyrrolinone HIV-1
Protease Inhibitor
a. LiHMDS, THF, -78 °C
OBn
O
b.
Ph
H
O
O
BocN
Ph
BocN
Ph
NHCbz
( 35 - 43 % )
O
BocN
Ph
H
N
Ph
O
Ph
OBn
BocN
O
b. K2CO3, MeOH / H2O
Ph
1. 1N HCl / MeOH
O ON
O
O
Et3N, CH2Cl2
( 62 %, two steps )
H
N
O
O
2. O
Ph
( 54 % )
O Ph
O
O
Ph
2. H2, Pd(OH)2, MeOH,
Overnight
( 72 %, two steps )
a. Cl3CCON=C=O, CH2Cl2
OH
NHCbz
OH O
Ph
1. Dess-Martin Periodinane
Pyr, CH2CL2
OH
Ph
H
N
O Ph
O
O
O Ph
O
O
Ph
H
N
NH2
NH2
X-Ray Crystal Structure of HIV-1 Protease Complexed with
Inhibitor
Asp225
Asp25
O
H
N
Ph
H
OH N
OH
Gly27
O
O
Ph
O
Asp29
H2O
IC50 2 nM, CIC95 100 nM
H2O
Ile250
Ile50
A. Pasternak
X-Ray Crystal Structure of HIV-1 Protease Complexed with
Inhibitor
Asp230
Asp225
Gly227
Asp25
O
O
Asp29
H
N
O
Ph
O
Ph
H
OH N
O
O
IC50 2.1 nM, CIC95 250 nM
H2O
Ile250
Ile50
L. Zawaki
NH2
Design of New Carbonyl Displaced Pyrrolinone HIV-1
Protease Inhibitor
Asp230
Ph
Asp225
O
Asp25
Gly227
Asp29
Ile250
Ile50
O
H
N
O
Ph
OH
H
N
NH2
OH
Ph
O
Summary of Postdoc Research at UPenn
a. The tris carbonyl-displaced
pyrrolinone was synthesized
and the structure is being
studied:
O
O
CbzHN
BnO
Ph
H
N
N
H
b. A carbonyl-displaced pyrrolinone HIV-1
protease inhibitor was designed and
synthesized. A new design was made
based on modeling:
N
H
O
CH3
O
BnO
N
H
Ph
Ph
N
H
O
O
CH3
O
O
O
NH2
O Ph
Ph
O
H
N
Ph
H
N
O
O
O
H2N
OH
H
N
H
N
O
Ph
OH
H
N
NH2
OH
Ph
O
Acknowledgements
Professor Ken N. Houk (UCLA)
Professor James S. Nowick (UC Irvine)
Professor Amos B. Smith, III (UPenn)
Professor Ralph Hirschmann (UPenn)
Thank You